CN109415327A - Azilsartan intermediate, Azilsartan and their manufacturing method - Google Patents
Azilsartan intermediate, Azilsartan and their manufacturing method Download PDFInfo
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Abstract
根据本发明，提供在包含碳原子数2～7的醇的反应溶剂中使腈化合物与羟基胺和/或羟基胺酸盐反应的偕胺肟化合物的制造方法；在包含碳原子数1～8的醇的反应溶剂中对含有酯保护基的化合物进行环化反应的阿齐沙坦烷基酯的制造方法；使阿齐沙坦烷基酯在丙酮或者丙酮与醇的混合溶剂中结晶化的阿齐沙坦烷基酯的制造方法；对阿齐沙坦烷基酯进行水解的阿齐沙坦的制造方法。According to the present invention, there is provided a method for producing an amidoxime compound in which a nitrile compound is reacted with hydroxylamine and/or a hydroxylamine salt in a reaction solvent containing an alcohol having 2 to 7 carbon atoms; The production method of azilsartan alkyl ester which carries out cyclization reaction to the compound containing ester protecting group in the reaction solvent of the alcohol; The production method of azilsartan alkyl ester; The production method of azilsartan by hydrolyzing azilsartan alkyl ester.
Description
Technical field
The present invention relates to Azilsartan intermediate, Azilsartan and their manufacturing methods.
More particularly, to as Azilsartan intermediate, 2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4-
Base] methyl] [[(2,5- dihydro -5- oxo -1,2,4- is disliked 2'- by -1H- benzimidazole -7- alkyl carboxylates and 2- ethyoxyl -1-
Diazole -3- base) biphenyl -4- base] methyl] benzimidazole -7- alkyl carboxylates；As Azilsartan, 2- ethyoxyl -1-
[[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic acid and they
Manufacturing method.
Background technique
By following formula (5)
[changing 1]
Azilsartan (the alias: 1- [[2'- (4,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) [1,1'- of expression
Biphenyl -4- base] methyl] -2- ethyoxyl -1H- benzimidazole -7- carboxylic acid) it is the compound highly useful as medicine, it is described
Medicine shows excellent effect (patent document 1) as angiotensin-ii receptor antagonistic.
The Azilsartan is using following such manufacturing method synthesis.
[changing 2]
That is, firstly, making hydroxylamine and/or hydroxyl amino acid salt and the 1- [(2'- cyanobiphenyl -4- by above-mentioned formula (1) expression
Base) methyl] -2- ethoxybenzoimidazole -7- alkyl carboxylates (being also sometimes referred to simply as " nitrile compound " below) reaction, manufacture by
2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4- base] methyl] -1H- benzimidazole -7- carboxylic acid alkane that above-mentioned formula (2) indicates
Base ester (below also sometimes referred to as " amidoxime compound ").
Next, amidoxime compound is directly used in cyclization, or it is made the hydroxyl of the amidoxime compound
2- ethyoxyl -1- [[2'- (alkoxy-carbonyloxy group amidino groups) biphenyl -4- indicated by above-mentioned formula (3) protected with ester protecting group
Base] methyl] after -1H- benzimidazole -7- alkyl carboxylates (being also sometimes referred to simply as " compound containing ester protecting group " below),
Cyclization is carried out, [[(2,5- dihydro -5- oxos -1,2,4- dislike two to 2'- to the 2- ethyoxyl -1- that manufacture is indicated by above-mentioned formula (4)
Azoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- alkyl carboxylates (are also sometimes referred to simply as " Azilsartan alkyl below
Ester ").
Then, finally by by the Azilsartan alkyl ester hydrolysis, thus the Azilsartan that manufacture is indicated by above-mentioned formula (5)
(referring for example to Patent Documents 1 to 3, non-patent literature 1).
For raw medicine as Azilsartan, it is desirable to reduce impurity.But due to passing through multiple process systems as described above
It makes, therefore generates the impurity different from object sometimes in each process.The impurity is since structure is similar to object, such as
Its amount of fruit increases, then purification etc. becomes extremely difficult.Therefore, in the case where manufacturing raw medicine, even the manufacture of intermediate,
Wish to reduce impurity.
Existing technical literature
Patent document
Patent document 1: No. 26459962 bulletins of Japan Patent
Patent document 2: Japanese Unexamined Patent Application Publication 2014-506898 bulletin
Patent document 3: Japanese Unexamined Patent Application Publication 2014-505097 bulletin
Patent document 4: Japanese Unexamined Patent Application Publication 2014-530805 bulletin
Non-patent literature
Non-patent literature 1:Journal of Medicinal Chemis try, (U.S.), 1996, volume 39, the
5228-5235 pages
Summary of the invention
Subject to be solved by the invention
(1) the first project of the invention
The research of people etc. according to the present invention, when being informed in the amidoxime compound that manufacture is indicated by above-mentioned formula (2), existing
There is room for improvement in technology in the following areas.
For example, in patent document 1, using hydroxy amine hydrochloric acid salt, in the presence of the sodium methoxide as alkali, in dimethyl
Implement reaction in the reaction dissolvent of sulfoxide.According to this method, main product is by following formula (7)
[changing 3]
The de- ethyl body (being also sometimes referred to simply as " nitrile takes off ethyl body " below) of the nitrile compound of expression, above-mentioned amidoxim chemical combination
The generation ratio of object is small.
In addition, in the method recorded in non-patent literature 1, using hydroxy amine hydrochloric acid salt, the triethylamine as alkali this
In the presence of the organic base of sample, implement reaction in the reaction dissolvent of dimethyl sulfoxide.The research of people etc. according to the present invention, at this
In method, the generation ratio of above-mentioned amidoxime compound increases.But know at the same by-product and amidoxim body isodose under
State formula (8)
[changing 4]
The amide body (being also sometimes referred to simply as " amide body " below) of expression.In turn, know if extending the reaction time, by
Following formula (9)
[changing 5]
The de- ethyl body (being also sometimes referred to simply as " amidoxim takes off ethyl body " below) of the amidoxime compound of expression and under
State formula (10)
[changing 6]
The de- ethyl body (being also sometimes referred to simply as " amide takes off ethyl body " below) of the amide body of expression tends to increase.
It is non-proton as the dimethyl sulfoxide using the aqueous solution of hydroxylamine in the method recorded in patent document 2
Property the reaction dissolvents such as polar solvent in implement reaction.The research of people etc. according to the present invention subtracts above-mentioned amide body in the method
It is few, the amidoxime compound of target can be increased.But in the method, the purity of above-mentioned amidoxime compound is 70% left
10% or so above-mentioned amide body is contained on the right side.The research of people etc. according to the present invention is known even if making above-mentioned amidoxime compound
In the case where taking out from reaction system as crystallization, the purity of above-mentioned amidoxime compound is also about 85% or so, is contained
About 5% or so above-mentioned amide body.Moreover, knowing if extending the reaction time, above-mentioned amidoxim takes off ethyl body and above-mentioned acyl
Amine takes off ethyl body and tends to increase.
It should be noted that in the present invention, the purity of above-mentioned amidoxime compound, the purity of other compounds and impurity contain
Proportional is the area % at each peak measured using the determination condition for the high performance liquid chromatography (HPLC) recorded in embodiment.
In addition, in addition to this, in the method recorded in patent document 3, using hydroxy amine hydrochloric acid salt, in the carbon as alkali
In the presence of sour hydrogen sodium, implement reaction in the reaction dissolvent of dimethyl sulfoxide.
The method for being not only to record in the patent document 3, as described above, remembering in non-patent literature 1, patent document 1 and 2
In the method for load, as reaction dissolvent, dimethyl sulfoxide is also mainly used.The research of people is known according to the present invention: as reaction
Solvent, if dimethyl sulfoxide becomes principal component, the crystallization of above-mentioned amidoxime compound is difficult to be precipitated.Therefore, for using
It is general to make amidoxim using water is added in solution after the reaction for dimethyl sulfoxide is as the existing method of reaction dissolvent
The method of compound crystallization.In the method, it can only obtain the crystallization of the amidoxime compound of low-purity.Moreover, in order to take
Obtain the crystallization of the amidoxime compound of high-purity, it is necessary to be additionally carried out the purification operations such as recrystallization, there is operations to become miscellaneous
The problem of.
Therefore, the first object of the present invention, which is to provide, can use easy operation to obtain the upper of high-purity in high yield
State amidoxime compound, above-mentioned amidoxime compound manufacturing method.And then it is to provide using using this method manufacture
Above-mentioned amidoxime compound is come the method that manufactures the Azilsartan of high-purity.
(2) the second project of the invention
The research of people etc. according to the present invention is known in the prior art when manufacturing Azilsartan Arrcostab in side below
There is room for improvement in face.
For example, in non-patent literature 1, use dimethylbenzene as reaction dissolvent, in the dimethylbenzene, reflux temperature it is (anti-
Answer the reflux temperature of solution；About 130 DEG C) under to R2Be cyclized instead for the compound containing ester protecting group of 2- ethylhexyl
It answers, manufactures Azilsartan methyl esters.Using this method, can be obtained with the shorter reaction time Azilsartan methyl esters (yield:
52%).But the research of people etc. according to the present invention, know in the method recorded in non-patent literature 1 structure it is unclear but
10 molecule is added on the molecular weight of Azilsartan methyl esters in the analysis result of liquid chromatographic mass analysis meter (LC-MASS)
The impurity of amount increases.
On the other hand, in patent document 1, use dimethylbenzene as reaction dissolvent, in the dimethylbenzene, reflux temperature
(the reflux temperature of reaction solution；About 130 DEG C) under to R2Cyclization, system are carried out for the compound containing ester protecting group of ethyl
Make Azilsartan methyl esters.But know that above-mentioned impurity also increases in the method.In turn, for being recorded in above patent document 1
Method for, yield has room for improvement down to 23% or so.
In addition, in patent document 1, being also shown in ethyl acetate, alkali (potassium carbonate, diazabicyclo endecatylene)
In the presence of carry out cyclization method.But in the reaction, Azilsartan methyl esters is precipitated on the way in the reaction.Therefore, with
The solid of state comprising the alkali obtains Azilsartan methyl esters.Its result has more than improvement in terms of refining step becomes miscellaneous
Ground.
Therefore, the second object of the present invention is to provide to manufacture the side of the Azilsartan Arrcostab of high-purity in high yield
Method.In addition, being to provide the manufacturing method for the Azilsartan Arrcostab that the refining step as rear process can be made to become easy.
Moreover, being finally to provide using the Azilsartan Arrcostab using this method manufacture the side for manufacturing the Azilsartan of high-purity
Method.
(3) third project of the invention
In addition, the research of people etc. according to the present invention, know in the prior art when manufacturing Azilsartan Arrcostab with
Under aspect have room for improvement.
For example, describing the following method in patent document 1.It is following method: firstly, to R in dimethylbenzene1For
Methyl, R2Implement cyclization for the compound containing ester protecting group of ethyl, synthesizes Azilsartan methyl esters.Next, anti-
It answers and ethyl acetate is added in liquid, after washing and drying, dimethylbenzene distillation refines residue with silica gel chromatograph, the thick knot that will be obtained
Crystalline substance is recrystallized from ethyl acetate and isopropyl ether.
In addition, describing the following method in non-patent literature 1.It is following method: firstly, to R in dimethylbenzene1
For methyl, R2Implement cyclization for the compound containing ester protecting group of 2- ethylhexyl, synthesizes Azilsartan methyl esters.It connects down
Come, dimethylbenzene distillation is recrystallized using ethyl acetate.
But the research of people etc. according to the present invention, it is informed in above patent document 1 and above-mentioned non-patent literature 1 and records
Method in by following formula (11)
[changing 7]
(in formula, R1For alkyl)
The hydrolysate (be also sometimes referred to simply as below " de- ethyl body ") of the Azilsartan Arrcostab of expression or by following formula
(12)
[changing 8]
(in formula, R1For alkyl)
The dimer (being also sometimes referred to simply as " dimer " below) of the Azilsartan Arrcostab of expression, structure is unclear in turn
But point in the analysis result of liquid chromatographic mass analysis meter (LC-MASS) on the molecular weight of Azilsartan methyl esters plus 10
The aspect that the impurity of son amount not can be reduced has room for improvement.
That is, having room for improvement in terms of impurity reduction in the case where being recrystallized with the solvent comprising ethyl acetate.
In addition, the temperature that the fusing point for the Azilsartan methyl esters known is up to 190~200 DEG C in the past.As long as it is therefore contemplated that
The lower Azilsartan methyl esters of fusing point can be further manufactured, is just easily soluble in solvent, in the case where Azilsartan is made, no
Unwanted impurity can be made to increase.Therefore, it is necessary to develop the Azilsartan methyl esters with novel crystal form.
Therefore, the third object of the present invention is to provide the method for the Azilsartan Arrcostab of manufacture high-purity.In addition,
There is the Azilsartan methyl esters of the novel crystal form of low melting point part in offer.Moreover, being finally to provide using using the party
The Azilsartan Arrcostab of the purity is high of method manufacture, and/or above-mentioned Azilsartan methyl esters with high purity and for novel crystal form come
The method for manufacturing the Azilsartan of high-purity.
Means for solving the problems
The present inventor conscientiously studies repeatedly in order to solve the projects of above-mentioned (1)~(3).
Dimethyl sulfoxide is used in the prior art when manufacturing above-mentioned amidoxime compound moreover, having estimated as described below
The reasons why such aprotic polar solvent.I.e., it is believed that if indicated using protonic solvent etc. by above-mentioned formula (1)
Ester exchange reaction occurs for the part in nitrile compound ,-OR (R: the alkyl of carbon atom number 1~4) ,-OEt (Et: ethyl), and reaction has
It may become increasingly complex.
It is thus taken into account even if ester exchange reaction does not also occur in-OR ,-OEt using protic polar solvent, is
The no above-mentioned amidoxime compound to obtain high-purity in high yield, is studied.
Finally, it is found that by using the reaction dissolvent comprising specific alcohol, thus to obtain the upper of high-purity in high yield
Amidoxime compound is stated, first present invention is completed.
Next, for when carrying out cyclization for the compound containing ester protecting group and Azilsartan Arrcostab
In cyclization compound containing ester protecting group and Azilsartan Arrcostab can not promote anti-dissolubility height in which decompose
The condition answered is studied.Finally, it is found that by specific reaction dissolvent, i.e. comprising carbon atom number 1~8 alcohol it is anti-
It answers and carries out cyclization in solvent, so as to solve the above subject, complete second present invention.
In turn, the research of the recrystallization of Azilsartan Arrcostab has been carried out using various solvents.Its result is known: using third
The mixed solvent of ketone or acetone and alcohol has carried out the crystallization of Azilsartan Arrcostab, as a result can efficiently reduce Ah
The de- ethyl body of Qi Shatan Arrcostab or the impurity of dimer.Furthermore, it was found that by Azilsartan methyl esters in acetone or acetone
It is crystallized with the in the mixed solvent of alcohol, as a result obtains novel crystallization be not present in existing crystallization, with low melting point part,
Complete the third present invention.
That is, first present invention is by making in the reaction dissolvent of the alcohol comprising carbon atom number 2~7 by following formula (1)
[changing 9]
(in formula, R1For 1~4 alkyl of carbon atom number)
The nitrile compound of expression is reacted with hydroxylamine and/or hydroxyl amino acid salt, so that manufacture is by following formula (2)
[changing 10]
(in formula, R1With the R in above-mentioned formula (1)1It is synonymous) indicate amidoxime compound method.
In first present invention, above-mentioned reaction is preferably carried out in the presence of base.By being reacted in the presence of base, from
And the by-product of above-mentioned amide body and the de- ethyl body of above-mentioned amide can be further suppressed.Wherein, in order to more highly inhibit above-mentioned
Amide body and above-mentioned amide take off the by-product of ethyl body, and improve operability, and preferably above-mentioned alkali includes organic base, particularly preferably
Ground, relative to 1 mole of the nitrile compound indicated by above-mentioned formula (1), the use level of the organic base is set as 0.01~0.5 mole.
In addition, in order to manufacture the above-mentioned amidoxime compound of high-purity, and further increasing operation in the present invention
Property, preferably above-mentioned alcohol is the straight-chain or branch-like alcohol of carbon atom number 3~7.It is highly preferred that using hydroxylamine, and it is above-mentioned anti-
Answering solvent includes water.
Adopting the amidoxime compound being obtained by the present invention is high-purity, and impurity is few.Therefore, using side of the invention
The amidoxime compound that method obtains can be suitble in the Azilsartan Arrcostab indicated by above-mentioned formula (4) and by above-mentioned formula (5) table
It is used in the manufacture of the Azilsartan shown.
Second present invention is by making in the reaction dissolvent of the alcohol comprising carbon atom number 1~8 by following formula (3)
[changing 11]
(in formula, R1For alkyl, R2For the protecting group for protecting hydroxyl)
The compound containing ester protecting group indicated carries out cyclization, so that manufacture is by following formula (4)
[changing 12]
(in formula, R1With the R in above-mentioned formula (3)1It is synonymous)
The method of the Azilsartan Arrcostab of expression.
In the present invention, in order to further increase yield, preferably below 50 DEG C or more and the reflux temperature of reaction solution into
The above-mentioned cyclization of row.It should be noted that above-mentioned reflux temperature is roughly the same with the temperature that reaction dissolvent flows back.But, why
Referred to as " reflux temperature of reaction solution " is because of the R due to by-product2- OH (has R2The alcohol of base), dissolution Azilsartan alkane
The difference of base ester concentration etc. generates some differences with the reflux temperature of reaction dissolvent.In the present invention, so-called reaction solution refers to
Compound and/or the dissolution of Azilsartan Arrcostab, the R comprising by-product in reaction dissolvent containing ester group2The reaction of-OH is molten
Liquid.It should be noted that also including alkali certainly in reaction solution in the case where using alkali as needed.
In the present invention, preferably above-mentioned alcohol is the straight-chain or branch-like alcohol of carbon atom number 3~8.By using the alcohol, not only
To obtain the Azilsartan Arrcostab of high-purity in high yield, and become easy after completion of the reaction make in reaction dissolvent Ah
Qi Shatan Arrcostab crystallization.Its result can be such that postprocessing working procedures become easy.
In turn, in the present invention, in order to improve yield with the short time, preferably implement above-mentioned cyclization in the presence of a base.
Wherein, relative to 1 mole of compound containing ester protecting group indicated by above-mentioned formula (3), the usage amount of preferably above-mentioned alkali is
0.01~5 mole.In turn, preferably above-mentioned alkali is organic base.
Become the Azilsartan Arrcostab of novel crystalline texture according to the Azilsartan Arrcostab that second present invention obtains.
Specifically, it can obtain that at least there is spy in 2 θ=9.9 ± 0.2 °, 10.9 ± 0.2 ° in the X-ray diffraction using Cu-K α line
Levy the Azilsartan methyl esters at peak.
In addition, second present invention includes the A Qisha after using this method manufacture Azilsartan Arrcostab by will obtain
Smooth alkyl ester hydrolysis is to which manufacture is by following formula (5)
[changing 13]
The method of the Azilsartan of expression.In accordance with the invention it is possible to manufacture the Azilsartan Arrcostab of higher purity, therefore
The Azilsartan of high-purity can be made.
The third present invention is the manufacturing method of Azilsartan Arrcostab, which is characterized in that in acetone or acetone and alcohol
In the mixed solvent makes by following formula (4)
[changing 14]
(in formula, R1For alkyl)
The Azilsartan Arrcostab of expression crystallizes.
Third present invention R in above-mentioned formula (4) Chinese style1In the case where for methyl, that is, for 2- ethyoxyl -1- [[2'- (2,
5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylate methyl ester is (below also sometimes
Referred to as " Azilsartan methyl esters ") in the case where, especially play effect.Moreover, the Azilsartan methyl esters can be made, which to become, to be had
Low-melting part, quasi-crystalline state Azilsartan methyl esters.
The Azilsartan methyl esters according to the X-ray diffraction for using Cu-K α line, at least 2 θ=9.2 ± 0.2 °, 15.8 ±
0.2 °, 22.1 ± 0.2 ° has characteristic peak.In addition, Azilsartan methyl esters preferably becomes the temperature range at least at 150~165 DEG C
Temperature range with 185~195 DEG C at least has the compound of fusing point.
In turn, the third present invention includes the Azilsartan Arrcostab, and/or Azilsartan methyl esters that will be manufactured using this method
The method for hydrolyzing and manufacturing Azilsartan.By using them as raw material, so as to manufacture the higher Azilsartan of purity.
The manufacturing method of first~third Azilsartan of the invention includes to add to use active carbon that will contain as impurity
Azilsartan dimer remove process manufacturing method.
In addition, the manufacturing method of first~third Azilsartan of the invention includes to be attached to that Azilsartan is made to be dissolved in two
The solvent of ketone or esters, the manufacturer for the process that the Azilsartan is precipitated are added in solution obtained from methylformamide
Method.
In turn, the present invention includes following manufacturing method: being obtained using the first the manufacturing method of the present invention by above-mentioned nitrile compound
To above-mentioned amidoxime compound；
Next, obtaining the above-mentioned compound containing ester protecting group by above-mentioned amidoxime compound；
Above-mentioned Azilsartan alkane is obtained by the above-mentioned compound containing ester protecting group using the second the manufacturing method of the present invention
Base ester；
Above-mentioned Azilsartan is obtained by above-mentioned Azilsartan Arrcostab using third the manufacturing method of the present invention.
The effect of invention
According to first method of the invention, it is possible to easier operation can be used to obtain the amidoxim of high-purity in high yield
Close object.As a result, Azilsartan Arrcostab and Azilsartan are manufactured by using amidoxime compound obtained in the present invention,
Also them can be made to become the product of high-purity.
According to second method of the invention, it is possible to using easier operation to obtain the A Qisha of higher purity in high yield
Smooth Arrcostab.As a result, by the way that Azilsartan alkyl ester hydrolysis obtained in the present invention is manufactured Azilsartan, so as to
Obtain the Azilsartan of high-purity.Further, since being easier to take out Azilsartan Arrcostab as crystallization, therefore operability
It can be improved.
According to third method of the invention, it is possible to obtain high-purity Azilsartan Arrcostab, particularly high-purity Ah
Qi Shatan methyl esters.As a result, by by Azilsartan Arrcostab obtained in the present invention, and/or Azilsartan methyl esters hydrolysis come
Azilsartan is manufactured, so as to obtain the Azilsartan of high-purity.Furthermore it is possible to make to adopt be obtained by the present invention Ah
The quasi- crystallization with low-melting part can be made in Qi Shatan methyl esters.
These methods are especially the purity that can be improved Azilsartan that is finally obtained, using as raw medicine, therefore its
Industrial utility value is high.
Detailed description of the invention
Fig. 1 is the X-ray diffractogram of the Azilsartan methyl esters novel crystallization of the invention manufactured in embodiment 10.
Fig. 2 is the X-ray diffractogram of the existing Azilsartan methyl esters crystallization manufactured in comparative example 4.
Fig. 3 is that the X-ray of the novel crystallization (quasi- crystallization) of the Azilsartan methyl esters of the invention manufactured in embodiment 18 is spread out
Penetrate figure.
Fig. 4 is the X-ray diffractogram of the existing Azilsartan methyl esters crystallization manufactured in comparative example 5.
Fig. 5 is the DSC figure of the novel crystallization (quasi- crystallization) of the Azilsartan methyl esters of the invention manufactured in embodiment 18.
Fig. 6 is the DSC figure of the existing Azilsartan methyl esters crystallization manufactured in comparative example 5.
Fig. 7 is the X-ray diffractogram of the Azilsartan M type crystallization of the invention manufactured in embodiment 33.
Specific embodiment
1. first present invention
First it is a feature of the present invention that making by following formula (1)
[changing 15]
(in formula, R1For 1~4 alkyl of carbon atom number)
The nitrile compound of expression is reacted with hydroxylamine and/or hydroxyl amino acid salt and is manufactured by following formula (2)
[changing 16]
(in formula, R1With the R in above-mentioned formula (1)1It is synonymous)
When the amidoxime compound of expression, the reaction is carried out in the reaction dissolvent of the alcohol comprising carbon atom number 2~7.With
Under be illustrated in order.
(raw material compound；Nitrile compound)
To the nitrile compound indicated by above-mentioned formula (1), there is no particular restriction, can be manufactured using well known method.Specifically
Ground, can be using the method recorded in patent document 1, i.e., by 3- amino -2- [[(2'- cyanobiphenyl -4- base) methyl] ammonia
Base] benzoic acid alkyl base ester ethyl orthocarbonate solution in acetic acid is added, 80 DEG C below stirring 1 hour side make its react and make
Make (embodiment 1b referring to patent document 1).
(raw material compound: hydroxylamine and/or hydroxyl amino acid salt)
In the present invention, react the nitrile part of above-mentioned nitrile compound with hydroxylamine and/or hydroxyl amino acid salt, manufacture it is above-mentioned together with
Amidoxime compound.
To the hydroxylamine and/or hydroxyl amino acid salt used, there is no particular restriction, is able to use commercially available product.It should say
It is bright, "and/or" course refer to hydroxylamine individually, hydroxyl amino acid salt individually, the mixture of hydroxylamine and hydroxyl amino acid salt.Below will
When they summarize expression, it is also denoted as hydroxyl amine sometimes.
Hydroxyl amino acid salt can enumerate hydroxy amine hydrochloric acid salt, hydroxylamine sulfate, hydroxylamine phosphate, hydroxylamine oxalic acid
Salt etc..
These hydroxyl amino acid salts are also able to use alkali and are neutralized and use as hydroxylamine.
To the usage amount of hydroxylamine and/or hydroxyl amino acid salt, there is no particular restriction, relative to 1 mole of above-mentioned nitrile compound,
It is preferably set to 1~10 mole, is more preferably set as 2~7 moles.
In hydroxylamine and/or hydroxyl amino acid salt, in order to reduce, above-mentioned nitrile takes off ethyl body and above-mentioned amide body, raising obtain
Amidoxime compound purity, it is preferable to use hydroxylamine.Using hydroxylamine, in terms of the easiness obtained
It sets out, it is preferable to use aqueous hydroxylamine, such as the concentration of hydroxylamine are the aqueous solution of 30~50 mass %.In the present invention, make
It is not obvious with the advantages of hydroxylamine.But, inventors believe that due to can under the conditions of pH appropriate in the present reaction into
Row reaction, therefore can be improved the purity of above-mentioned amidoxime compound.Further more, the feelings that hydroxylamine is used to react as aqueous solution
Under condition, alcohol and water of the reaction dissolvent at least containing carbon atom number 2~7.Reaction dissolvent of the invention can be the aqueous reaction
Solvent.
(reaction dissolvent)
Maximum of the invention is characterized in that using this point of the reaction dissolvent of the alcohol comprising carbon atom number 2~7.By using this
Reaction dissolvent can manufacture the above-mentioned together with amine of high-purity so as to reduce the by-product amount of above-mentioned amide body, above-mentioned de- ethyl body
Oxime compound.
If illustrating the alcohol of carbon atom number 2~7, ethyl alcohol, 1- propyl alcohol, isopropanol, n-butyl alcohol, 2- methyl-1-can be enumerated
Propyl alcohol, 2- butanol, 2- methyl-2-propanol, 1- amylalcohol, 3- methyl-1-butanol, 1- hexanol, 2- methyl-1-pentene alcohol, 3- methyl-1-
Amylalcohol, 2- methyl -2- amylalcohol, 2,4- dimethyl -3- amylalcohol, 3- ethyl -3- amylalcohol etc..Wherein, from obtained amidoxim chemical combination
The yield of object, the ratio of purity and contained impurity and finally the aspect that reaction dissolvent removes is set out, preferred carbon atom number 3
~7 straight-chain or branch-like alcohol.And specifically, it is preferable to 1- propyl alcohol, isopropanol, n-butyl alcohol, 2- butanol, particularly preferred 1- propyl alcohol,
N-butyl alcohol.
The alcohol illustrated above is able to use a kind, is also able to use mixture of more than two kinds.What is used as mixture
In the case of, the benchmark of the amount used is using the total amount of mixture as object.
It may include other solvents as long as alcohol of the reaction dissolvent comprising carbon atom number 2~7 in the present invention.Specifically, energy
Enough the cooperation water as described above used when aqueous hydroxylamine, the water newly cooperated, it is furthermore compatible with the alcohol of carbon atom number 2~7
Solvent.If it is considered that the post-processing etc. of reaction, the content of other solvents preferably becomes in the 100 mass % of total amount of reaction dissolvent
Less than 50 mass %, more preferably as 30 mass % or less, (rest part of certain reaction dissolvent is carbon atom number 2~7
Alcohol.).The total amount of reaction dissolvent can be the alcohol of carbon atom number 2~7, the case where using aqueous hydroxylamine in the reaction
Under, when the total amount of reaction dissolvent is set as 100 mass %, the alcohol of carbon atom number 2~7 is preferably set as 70~99 mass %, it will
Water is set as 1~30 mass %.
In the present invention, to the usage amount of reaction dissolvent, there is no particular restriction, as long as using following amount: in the reaction
For the state that can be sufficiently mixed raw material compound, and can be by the above-mentioned amidoxim chemical combination of raw material compound and generation
Object fully dissolves.Wherein, it is taken out in order to enable being easy the amidoxime compound that will be obtained as crystallization, relative to above-mentioned nitrilation
Close object 1g, it is preferable to use 5~50ml reaction dissolvent, more preferably use 6~30ml.It should be noted that the use of the reaction dissolvent
Amount is the volume at 23 DEG C.
(reaction method)
In the present invention, in the reaction dissolvent of the alcohol comprising carbon atom number 2~7, by making above-mentioned nitrile compound and hydroxyl
Amine contact, so as to make its reaction.Therefore, in the reaction dissolvent, above-mentioned nitrile compound and hydroxyl amine can be carried out
It is stirred contact the two as raw material compound.
(alkali)
It in the method for the invention, also can be in the presence of alkali when the two as raw material compound being made to contact (reaction)
Lower implementation.By using alkali, the purity of above-mentioned amidoxime compound can be further increased, is especially able to suppress above-mentioned amide
Body and above-mentioned amide take off the by-product amount of ethyl body.
As the alkali used, it is able to use well known alkali.Specifically, sodium bicarbonate, saleratus, bicarbonate are able to use
Calcium, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide etc. this
Inorganic base and methylamine, ethamine, trimethylamine, triethylamine, diisopropylamine, tripropyl amine (TPA), diisopropyl ethyl amine, pyridine, the piperazine of sample
Piperazine, pyrrolidines, aniline, N, it is organic as N- dimethyl aminopyridine, diazabicyclo endecatylene, N-methylmorpholine etc.
Alkali.These alkali can be used alone, and can also use a variety of alkali simultaneously.At the same time using in the case where a variety of alkali, become benchmark
Use level be on the basis of the total amount of a variety of alkali.
In above such alkali, especially wanting that above-mentioned amide body and above-mentioned amide is inhibited to take off the by-product amount of ethyl body
In the case where, it is preferable to use organic base.By using organic base, the removing of the organic base is also become easy.In the organic base,
If it is considered that industrial production is, it is preferable to use triethylamine, pyridine, diisopropyl ethyl amine.
To the usage amount of alkali, there is no particular restriction, can be set as common catalytic amount.Wherein, the case where using organic base
Under, relative to 1 mole of the nitrile compound indicated by above-mentioned formula (1), the preferably usage amount of organic base is 0.01~0.5 mole.It is logical
The usage amount above range for making organic base is crossed, takes off ethyl body so as to further suppress above-mentioned amide body and above-mentioned amide
By-product amount.In turn, in order to inhibit above-mentioned amide body and above-mentioned amide to take off the by-product amount of ethyl body, relative to by above-mentioned formula (1) table
1 mole of the nitrile compound shown, the preferably usage amount of organic base are 0.1~0.5 mole, particularly preferably 0.2~0.5 mole.
(reaction condition)
In the present invention, to other reaction conditions, there is no particular restriction, it is preferred to use condition below is implemented.
By raw material compound, reaction dissolvent and when the alkali that cooperates mixes in the reaction vessel as needed, each ingredient is led
There is no particular restriction for the sequence for entering in reaction vessel.Specifically, can using by raw material compound, reaction dissolvent and as needed
The alkali of cooperation imports the method in reaction vessel simultaneously.In addition, also can be preparatory by the raw material compound of a side and reaction dissolvent
Reaction vessel is imported, next, by the raw material compound (available reaction dissolvent dilution as needed) of another party and as needed
The alkali (can be diluted with reaction dissolvent) of cooperation imports in reaction vessel.At this point, the raw material compound added below can be divided into for several times
It imports.Wherein, in order to keep operation more easy, it is initially introduced into above-mentioned nitrile compound and reaction dissolvent in the reaction vessel.It connects down
Come, imports the alkali cooperated as needed, and then import hydroxyl amine.At this point, hydroxyl amine can of course be diluted with reaction dissolvent.
In addition, being also able to use the aqueous solution of the concentration of 30~50 mass % using hydroxylamine.
In the present invention, to reaction temperature (by the temperature of the mixed reaction solution of whole components), there is no particular restriction, excellent
50 DEG C or more and the reflux temperature of the reaction solution or less are selected in implement.The reflux temperature of reaction solution is molten because of the reaction used
Type, concentration of raw material compound of agent etc. and it is different, therefore cannot entirely limit.But, in order to inhibit above-mentioned amidoxim
The decomposition of object is closed, the temperature of reaction solution is preferably set to 50~100 DEG C hereinafter, being more preferably set as 60~95 DEG C.
In the present invention, to the reaction time (by the whole components mixed time), there is no particular restriction, can side confirmation it is above-mentioned
The equilateral decision of generation ratio of this consumption ratio of nitrile compound, obtained amidoxime compound.But, if reaction time mistake
It is long, it is possible to the decomposition etc. of above-mentioned amidoxime compound to occur, therefore the usually reaction time is preferably set to 1~20 hour.In addition,
Atmosphere when to reaction is also not particularly limited, and can be implemented in the presence of the air or in the presence of inert gas.In addition, can subtract
Implement reaction under pressure, pressurization or under atmospheric pressure.Wherein, in order to improve operability, preferably in the presence of the air, under atmospheric pressure into
Row reaction.
(postprocessing working procedures)
According to the method described above, above-mentioned amidoxime compound can be manufactured.With regard to the amidoxime compound generated in reaction solution
For, preferably by reaction solution cooling or by reaction dissolvent distillation, it is made to crystallize and take out.Wherein it is preferred to making instead
Answering the temperature of solution becomes in 50 DEG C or more and the reflux temperature situation below of reaction solution, be preferably cooled to 30 DEG C hereinafter,
It is more preferably cooled to 10~30 DEG C of temperature, is precipitated the crystallization of above-mentioned amidoxime compound in the reaction dissolvent used.Its
In, for the purity of the amidoxime compound improved, preferably make cooling velocity when becoming 30 DEG C or less from reaction temperature
It is 5~50 DEG C/h.In addition, in order to improve yield, preferably placed 1 hour with 30 DEG C of temperature below or more, preferably 2 hours
Above and 10 hours or less.
The crystallization of the amidoxime compound of precipitation can be handled using well known method.Generally, it is preferred to pass through
Crystallization is taken out in filtering, is cleaned, is dried.In addition, in the case where purity to be obtained higher hydroxyl amidino compounds, it can
It is recrystallized with reaction dissolvent.
In accordance with the invention it is possible to the amidoxime compound made become purity 90.0~98.0%, amide body 0.1~
3.0%, above-mentioned nitrile takes off 0.0 (not detecting)~0.5% of ethyl body, above-mentioned amidoxim takes off ethyl body 0.1~1.0%, above-mentioned acyl
Amine takes off ethyl body 0.05~1.0%.Pass through further regularization condition, it is preferable that can also become purity 94.0~
98.0%, above-mentioned amide body 0.1~2.0%, above-mentioned nitrile take off 0.0 (not detecting)~0.1% of ethyl body, above-mentioned amidoxim takes off second
Matrix 0.1~1.0%, above-mentioned amide take off the product of the high-purity of ethyl body 0.05~0.5%.It is highly preferred that can also make it
As purity 94.0~98.0%, above-mentioned amide body 0.1~1.0%, above-mentioned nitrile take off 0.0 (not detecting)~0.1% of ethyl body,
Above-mentioned amidoxim takes off the product of the high-purity of the de- ethyl body 0.05~0.5% of ethyl body 0.1~1.0%, above-mentioned amide.
Further more, the purity of above-mentioned amidoxime compound, above-mentioned amide body, above-mentioned nitrile take off ethyl body, above-mentioned amidoxim takes off
Ethyl body, above-mentioned amide take off ethyl body ratio since there is also the situation for also including other compositions, adding up to may not become
100%.
Therefore, the amidoxime compound obtained, which can be suitable as Azilsartan Arrcostab and the raw material of Azilsartan, to be made
With.
(manufacturing method of Azilsartan methyl esters)
It, can be by being manufactured using amidoxime compound obtained by the above method by following formula (4) in the present invention
[changing 17]
(in formula, R is synonymous with the R in above-mentioned formula (1))
The Azilsartan Arrcostab of expression.
The method of manufacture Azilsartan Arrcostab can unlimitedly use well known method.
For example, as record in Org.Process.Res.Dev 2013,17 like that, by comprising 1,1'- carbonylic imidazole,
Diazabicyclo endecatylene, dimethyl sulfoxide reaction dissolvent in make its reaction, so as to by above-mentioned amidoxime compound
Directly implement cyclization, above-mentioned Azilsartan Arrcostab can be manufactured.
In addition, the following method can be used.For the method recorded in non-patent literature 1, patent document 1.Specifically, first
First, by making above-mentioned amidoxime compound and alkyl chloroformate, (protecting group of alkyl hydroxyl is specifically 2- ethyl hexyl
Base or ethyl) in the presence of organic base (pyridine or triethylamine), in dimethylformamide, tetrahydrofuran/dichloromethane solvent
Reaction, to obtain by following formula (3)
[changing 18]
(in formula, R2For the alkyl of the protecting group as hydroxyl, specifically, for 2- ethylhexyl or ethyl) containing of indicating
The compound of ester protecting group.Next, by the way that the obtained compound containing ester protecting group is placed in back in xylene solvent
At a temperature of stream (about 130 DEG C), to carry out cyclization, Azilsartan Arrcostab can be manufactured.
To obtained Azilsartan Arrcostab, there is no particular restriction, can be used Org.Process.Res.Dev 2013,17,
The method recorded in non-patent literature 1 and patent document 1 implement purification etc..
Specifically, it can enumerate and be recrystallized from acetone, ethyl acetate, ethyl acetate/isopropyl ether, chloroform/ethyl acetate
Method.In order to enable the purity of the Azilsartan Arrcostab arrived becomes higher purity, preferably selects and recrystallized from acetone
Method.
(Azilsartan manufacturing method)
In the present invention, by the way that Azilsartan alkyl ester hydrolysis obtained by the above method will be used, so as to manufacture under
State formula (5)
[changing 19]
The Azilsartan of expression.The Azilsartan Arrcostab used can be novel crystallization, be also possible to comprising ketone
The product that the solvent of solvent is recrystallized.
To the condition of hydrolysis, there is no particular restriction, can be using the method recorded in well known method such as patent document 1.
It specifically, can be by being hydrolyzed in the presence of alkali or acid, to make-COOR1(alkyl ester group) becomes-COOH (carboxylic acid).
Second it is a feature of the present invention that carrying out by following formula (3)
[changing 20]
(in formula, R1For alkyl, R2For the protecting group for protecting hydroxyl)
The cyclization of the compound containing ester protecting group indicated is manufactured by following formula (4)
[changing 21]
(in formula, R1With the R in above-mentioned formula (3)1It is synonymous)
When the Azilsartan Arrcostab of expression, it is anti-that the cyclisation is carried out in the reaction dissolvent of the alcohol comprising carbon atom number 1~8
It answers.
It should be noted that in above-mentioned formula, R1For alkyl.If it is considered that become raw material the compound containing ester protecting group, Ah
The easiness of the manufacture of the stability and Azilsartan of Qi Shatan Arrcostab, R1The preferably alkyl of carbon atom number 1~4.Specifically
Ground can enumerate methyl, ethyl, 1- propyl, isopropyl, 1- butyl, isobutyl group etc., particularly preferably methyl.
It is illustrated in order below.
(raw material compound；Compound containing ester protecting group)
To the compound containing ester protecting group indicated by above-mentioned formula (3), there is no particular restriction, can use well known side
Method manufacture.It specifically, can be using the method manufacture recorded in non-patent literature 1, patent document 1.Specifically, can according to
Under reaction equation manufacture.
[changing 22]
It is well known compound by the amidoxime compound that above-mentioned formula (2) indicate, manufacturing method is recorded in non-patent text
It offers in 1, patent document 1.In addition, it is also preferred that using according to the first product produced by the present invention.Make in the presence of base by above-mentioned
Formula (2) indicate amidoxime compound with by XCOOR2The compound of expression reacts, and can manufacture and be contained by what above-mentioned formula (3) indicated
There is the compound of ester protecting group.
In above-mentioned reaction equation, the XCOOR that is reacted with the compound indicated by above-mentioned formula (2)2X be halogen atom, R2With by
The R in the compound containing ester protecting group that above-mentioned formula (3) indicates2It is identical, it is the protecting group for protecting hydroxyl.
In XCOOR2In, X can enumerate chlorine atom, bromine atom, iodine atom.Wherein, if it is considered that the appearance industrially obtained
Yi Xing, reactivity etc., preferably chlorine atom.
R2Protecting group that protect hydroxyl, general can be enumerated.Specifically, can enumerate the alkyl that can have substituent group,
Benzyl, the phenyl that can have substituent group etc..Wherein, if it is considered that the easiness of industrial acquisition, the change containing ester protecting group
Close functional, the final removing etc. in object, the preferably unsubstituted alkyl of carbon atom number 1~8.The unsubstituted alkyl can be straight chain
The alkyl of shape, or the alkyl of branch-like.
If specifically illustrating XCOOR2, then methylchloroformate, ethyl chloroformate, propyl chlorocarbonate, chloromethane can be enumerated
Isopropyl propionate, butyl chlorocarbonate, isobutyl chlorocarbonate, amyl chlorocarbonate, chloro-carbonic acid -2- ethylhexyl, the own ester of chloro-carbonic acid, chloromethane
Heptyl heptylate, chloro-methyl-chloroformate, chloro-carbonic acid -2- chloroethene ester, benzyl chloroformate, phenyl chloroformate, chloro-carbonic acid -4- chlorobenzene ester etc..
Wherein, if it is considered that function etc. in the easiness of industrial acquisition, reactivity and compound containing ester protecting group, preferably
Use methylchloroformate, ethyl chloroformate, propyl chlorocarbonate etc..
To XCOOR2Usage amount there is no particular restriction.Specifically, it rubs relative to the compound 1 indicated by above-mentioned formula (2)
You, XCOOR2Usage amount can be set as 1~5 mole.
Above-mentioned reaction carries out in the presence of base.If illustrating the alkali used, sodium bicarbonate, bicarbonate can be enumerated
Potassium, calcium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, hydrogen
The inorganic bases such as lithia；
Methylamine, ethamine, trimethylamine, triethylamine, diisopropylamine, tripropyl amine (TPA), diisopropyl ethyl amine, pyridine, piperazine, pyrroles
Alkane, aniline, N, the organic bases such as N- dimethyl aminopyridine, diazabicyclo endecatylene, N-methylmorpholine.
Wherein, if it is considered that the progressive of reaction, removing easiness, the processing in rear process etc., preferably triethylamine, pyrrole
Pyridine, diisopropyl ethyl amine organic base.
For above-mentioned alkali, it is able to use a kind, is also able to use a variety of alkali.Using a variety of alkali, become
The amount of the alkali of benchmark is the total amount of a variety of alkali.
To the usage amount of above-mentioned alkali, there is no particular restriction.Specifically, it rubs relative to the compound 1 indicated by above-mentioned formula (2)
You, the usage amount of above-mentioned alkali may be designated as 1~5 mole.Further more, as described later, it is excellent when that will be cyclized containing the compound of ester group
Choosing is implemented in the presence of base.Therefore, in the case where the compound obtained in the reaction containing ester group to be cyclized, also can
Implement cyclization in the state that above-mentioned alkali is remaining.
In addition, the solvent used can never with XCOOR2It is selected in the non-protonic solvent of reaction.Specifically, it can enumerate
Benzene, toluene, methylene chloride, chloroform, 1,4- dioxanes etc. out.These reaction dissolvents can be used a kind, it is possible to use of more than two kinds
Mixed solvent.
For reaction, preferably in the presence of base, in solvent, with the amidoxime compound that is indicated by above-mentioned formula (2) with
XCOOR2The mode fully contacted is stirred mixing.Special limit is had no to the sequence for importing these ingredients in reaction vessel
System.As preferred method, the amidoxime compound and above-mentioned alkali indicated by above-mentioned formula (2) is preferably added in a solvent in advance,
The diluted XCOOR of solvent is used as needed next, being added2.At this point, fever sharply in order to prevent, preferably instillation XCOOR2。
In addition, to condition when carrying out above-mentioned reaction, there is no particular restriction.Reaction temperature is preferably -10~10 DEG C.In addition,
For the reaction time, as long as 0.5~15 hour is then enough.
By making its reaction under the conditions of above such, so as to manufacture the above-mentioned compound containing ester protecting group.
There is no particular restriction for the method that the above-mentioned compound containing ester protecting group is taken out from reaction system.Specifically, on by making
It is molten in the solvent of indissoluble in water as ethyl acetate, toluene, chloroform, the methylene chloride to state the compound containing ester protecting group
Solution, is washed, is concentrated, is dried, so as to take out the above-mentioned compound containing ester protecting group.Further more, in a solvent
In the case where solvent using above-mentioned indissoluble in water, also directly solution can be washed.
To the compound containing ester group obtained under the conditions of above such, there is no particular restriction, and purity, which can be made, is
90.0~99.5% compound.In addition, also can be by adjusting washing, so that the compound containing ester group that is somebody's turn to do in taking-up contains
Have and implements next cyclization in the state of alkali.
(cyclization)
It is a feature of the present invention that carrying out the cyclization of the above-mentioned compound containing ester protecting group to manufacture by following formula
(4)
[changing 23]
(in formula, R1With R in above-mentioned formula (3)1It is synonymous)
When the Azilsartan Arrcostab of expression, implement in the reaction dissolvent of the alcohol comprising carbon atom number 1~8.The cyclisation
By-product R when reaction2-OH。
For the cyclization, by being heated, so as to carry out the reaction.It specifically, will by heating
The above-mentioned compound containing ester protecting group is dissolved in reaction solution made of the alcohol of carbon atom number 1~8, to promote cyclisation anti-
It answers, the above-mentioned compound containing ester protecting group can be made to become Azilsartan Arrcostab.When the cyclization, preferably contain above-mentioned
There is the compound of ester protecting group to be dissolved in reaction dissolvent, is heated when being stirred.It should be noted that certainly can also side stirring on
It states compound and reaction dissolvent the side heating containing ester protecting group and reaction solution is made, like this heat the reaction solution.
(reaction dissolvent)
Reaction dissolvent used in the cyclization is the solvent of the alcohol comprising carbon atom number 1~8.If specifically illustrated
The alcohol of carbon atom number 1~8, can enumerate methanol, ethyl alcohol, 1- propyl alcohol, isopropanol, n-butyl alcohol, 2- methyl-1-propyl alcohol, 2- butanol,
2- methyl-2-propanol, 1- amylalcohol, 3- methyl-1-butanol, 1- hexanol, 2- methyl-1-pentene alcohol, 3- methyl-1-pentene alcohol, 2- methyl-
2- amylalcohol, 2,4- dimethyl -3- amylalcohol, 3- ethyl -3- amylalcohol, octanol etc..
Wherein, as when can be improved cyclization temperature, improve reaction speed and the solvent of impurity can be reduced,
It is preferable to use the alcohol of the straight-chain of carbon atom number 3~8 or branch-like.And specifically, it is preferable to using 1- propyl alcohol, isopropanol, n-butyl alcohol,
2- butanol, particularly preferred 1- propyl alcohol, n-butyl alcohol.
The alcohol of these carbon atom numbers 1~8 is able to use a kind, is also able to use a variety of mixed solvents.Molten using mixing
In the case where agent, the amount for becoming the alcohol of benchmark is the total amount of mixed solvent.
Further more, reaction dissolvent also can with the ratio less than 50 mass % include carbon atom number 1~8 alcohol other than other
Solvent, if it is considered that the easiness etc. of purification, other solvents are preferably 10 mass % hereinafter, more preferably 0 mass %.
In the present invention, to the usage amount of the alcohol of the carbon atom number 1~8 in reaction dissolvent, there is no particular restriction.If it is considered that
The reduction of the efficient activity, impurity of reaction and the operability of rear process, relative to the above-mentioned compound 1g containing ester protecting group, preferably
The amount of the alcohol of carbon atom number 1~8 in reaction dissolvent is 3~30ml.By meeting the range, after cyclization, into
Row cooling is easy to take out Azilsartan methyl esters as crystallization.In order to further play said effect, contain ester relative to above-mentioned
The compound 1g of protecting group, the amount of the alcohol of the carbon atom number 1~8 in more preferable reaction dissolvent are 5~20ml.It should be noted that anti-
Answering the above-mentioned volume of solvent is the volume at 23 DEG C.
For the reaction temperature of cyclization, in order to improve reaction speed and reduce impurity, it is preferably defined as 50 DEG C
Above and the reflux temperature of reaction solution hereinafter, be more preferably defined as the reflux temperature of 60 DEG C or more and reaction solution hereinafter, into
One step is preferably defined as 70 DEG C or more and the reflux temperature of reaction solution or less.The reflux temperature of reaction solution is because of the reaction that uses
Solvent, the concentration of the above-mentioned compound containing ester protecting group, by-product R2The type of-OH and it is different, therefore cannot entirely limit.
But, in order to further suppress the generation of impurity, reaction temperature is preferably defined as 100 DEG C or less.
(alkali)
In the present invention, cyclization can be promoted according to above-mentioned condition.Wherein, in order to further shorten the reaction time,
It is preferred that implementing in the presence of base.Specifically, as long as containing the state of alkali in above-mentioned reaction solution.
To the alkali being able to use in cyclization, there is no particular restriction, is able to use above-mentioned inorganic base or organic base.Its
In, the easiness of the purification of Azilsartan Arrcostab in order to obtain improves operability, it is preferable to use triethylamine, pyridine, two different
The organic bases such as ethylamine.
These alkali are able to use a kind, are also able to use a variety of alkali.Using a variety of alkali, become the alkali of benchmark
Amount be a variety of alkali total amount.
Further more, the alkali also can as described above, in the case where using alkali when manufacturing the above-mentioned compound containing ester protecting group
It is enough to use the alkali that be somebody's turn to do remaining when the compound containing ester protecting group takes out.
In the present invention, even if not using alkali, also cyclization can be made to carry out.But, using alkali, relatively
In 1 mole of the above-mentioned compound containing ester protecting group, the amount of the alkali used is preferably defined as 0.01~5 mole.By in the model
It encloses using alkali, so as to improve reaction speed, and can be improved the yield and purity of Azilsartan Arrcostab.In order into one
Step improves the effect, and relative to 1 mole of the above-mentioned compound containing ester protecting group, the amount of the alkali used is more preferably defined as 0.1
~1 mole.
In the present invention, using alkali, alkali can be also previously added in reaction dissolvent and above-mentioned containing ester guarantor
The compound of base is protected, heat while stirring mixing.In addition, also can be in the reaction solution heated when being stirred from midway
The additional alkali is to promote to react.In the case where alkali additional from midway, the total amount of the alkali used becomes the amount of benchmark.
(removing method of Azilsartan Arrcostab)
By carrying out cyclization under the conditions of above such, so as to manufacture Azilsartan Arrcostab.To will obtain
There is no particular restriction from the method that reaction system is taken out for the Azilsartan Arrcostab arrived, can be using non-patent literature 1, patent text
Offer the method recorded in 1.
Wherein, in the present invention, due in reaction dissolvent using comprising 1~8 alcohol solvent, preferably use with
Under method.And specifically, it is preferable to reaction solution is cooling, or wrapping a part of reaction dissolvent distillation from reaction solution
It is precipitated the crystallization of Azilsartan Arrcostab in the reaction dissolvent of the alcohol of carbon atom quantity 1~8, which is taken out.It is especially excellent
Choosing is cooling by reaction solution, and crystallization is precipitated.
In the case where being precipitated the crystallization of Azilsartan Arrcostab in reaction dissolvent, there is no particular restriction.Specifically, phase
For Azilsartan Arrcostab 1g, preferably make 3~30ml of amount of the alcohol of carbon atom number 1~8.Pass through the alcohol of carbon atom number 1~8
It meets the above range, so that operability improves, and can be improved purity.In order to further increase the effect, relative to A Qi
Husky smooth Arrcostab 1g, preferably makes 5~20ml of amount of the alcohol of carbon atom number 1~8.It should be noted that the alcohol of carbon atom number 1~8
Above-mentioned amount is the volume at 23 DEG C.
Cyclization preferably heats progress.Moreover, making the temperature (reaction of reaction solution in preferred embodiment
Temperature) become 50 DEG C or more.It is therefore preferable that reaction solution after reaction is cooled to 30 DEG C of ranges below, more preferably
It is cooled to -10~30 DEG C of range, is particularly preferably cooled to -10~10 DEG C of range.In the present invention, due to using carbon atom number
1~8 alcohol, therefore in the range of above-mentioned cooling temperature, the crystallization of Azilsartan Arrcostab is easy to be precipitated.In addition, making to tie
Also kind of a crystalline substance is able to use when partial crystallization goes out.Moreover, in the present invention, as long as being cooled down the crystallization precipitation with Azilsartan Arrcostab
Mode be adjusted, then the crystallization is difficult to take in by-product and alkali joined together as needed.
For the purity of the Azilsartan Arrcostab further increased, preferably with 10~30 DEG C/h of cooling speed
The cooling reaction solution after reaction of degree, become 30 DEG C or less, preferably 0~30 DEG C, more preferably -10~30 DEG C, it is special
It is preferred that -10~20 DEG C of temperature.In turn, for the yield of the Azilsartan Arrcostab improved, preferably 30 DEG C or less, it is excellent
Select 0~30 DEG C, more preferably -10~30 DEG C, particularly preferably place at a temperature of -10~20 DEG C 1 hour or more, preferably 2 hours with
It is upper and 20 hours or less.
Crystallization for the Azilsartan Arrcostab of precipitation can be handled using well known method.It is generally preferably logical
Crystallization is taken out in filtering, is cleaned, is dried.In addition, in the case where the Azilsartan Arrcostab of higher purity to be obtained,
It is preferable to use the alcohol of carbon atom number 1~8 to be recrystallized.
(the crystallization of novel Azilsartan Arrcostab；The manufacturing method of novel crystallization)
Even if the Azilsartan Arrcostab obtained as described above is recrystallized with the alcohol of carbon atom number 1~8 again, also become packet
The crystallization of the solvate of the alcohol of carbon atom quantity 1~8.I.e., it is believed that a part of the alcohol of carbon atom number 1~8 is taken in into crystallization
It is internal.
R in the case where using 1- propyl alcohol in the alcohol of carbon atom number 1~81It can be made for the Azilsartan methyl esters of methyl
At least in 2 θ=9.9 ± 0.2 °, 10.9 ± 0.2 ° of crystallizations with characteristic peak in the X-ray diffraction using Cu-K α line.Separately
Outside, which is in addition to this in 2 θ=13.6 ± 0.2 °, 17.2 ± 0.2 °, the knots with peak such as 23.2 ± 0.2 °
It is brilliant.Crystallization with above such peak is not present in the prior art, is novel crystal form.The crystallization also can include 0.5
The crystallization (is also referred to as " novel crystallization " sometimes below by the 1- propyl alcohol of~5 mass %.).
Have intensity as maximum peak, simultaneously in 2 θ=9.9 ± 0.2 ° here, the features described above peak in the present invention refers to
Occurs the intensity for having 5% or more relative to maximum peak intensity (peak intensities of 2 θ=9.9 ± 0.2 °) in 2 θ=10.9 ± 0.2 °
Peak.Relative to maximum peak intensity there is the peak of the intensity less than 5% to be considered as noise etc., the feature not being equivalent in the present invention
Peak.
(recrystallization of Azilsartan Arrcostab)
In the present invention, also above-mentioned Azilsartan Arrcostab direct hydrolysis can be synthesized Azilsartan.But, in order to make
At the higher Azilsartan Arrcostab of purity, preferably with the solvent comprising ketone solvent to using novel crystalline substance obtained by the above method
The Azilsartan Arrcostab of type is recrystallized.Certainly, the Azilsartan Arrcostab of novel crystal form can for comprising 0.5~
The solvate of the 1- propyl alcohol of 5 mass %.
If illustrating the ketone solvent used, acetone, methyl ethyl ketone, metacetone, methyl isopropyl Ketone, methyl can be enumerated
Butyl ketone, methyl iso-butyl ketone (MIBK) etc..Wherein, in order to improve purity, improve operability, it is preferable to use acetone.These ketone solvent energy
1 kind is enough used, a variety of mixed solvents is also able to use.Using mixed solvent, become the ketone solvent of benchmark
Amount is the total amount of mixed solvent.
Further more, the solvent comprising ketone solvent also can include with the ratio less than 50 mass % other than ketone solvent other are molten
Agent, if it is considered that the easiness etc. of purification, other solvents are preferably 10 mass % hereinafter, more preferably 0 mass %.
To the amount of the ketone solvent used, there is no particular restriction.Specifically, the crystallization relative to above-mentioned Azilsartan Arrcostab
1g, the amount of ketone solvent are preferably set to 3~30ml, are more preferably set as 5~20ml.
As the method for recrystallization, it is dissolved in the crystallization of above-mentioned Azilsartan Arrcostab in the solvent comprising ketone solvent.
Preferably, it is heated to the reflux temperature (about 60 DEG C) of solution, dissolves the crystallization of above-mentioned Azilsartan Arrcostab.Next, excellent
Choosing is cooled down with 10~30 DEG C/h of cooling velocity, in 0~30 DEG C, more preferably -10~30 DEG C, particularly preferably -10~20
Certain time is placed within the temperature range of DEG C.
(manufacturing method of Azilsartan)
In the present invention, by the way that Azilsartan Arrcostab water obtained by the above method will be used in the same manner as above-mentioned first invention
Solution, so as to manufacture by following formula (5)
[changing 24]
The Azilsartan of expression.
The third present invention is the manufacturing method of Azilsartan Arrcostab, which is characterized in that in acetone or acetone and alcohol
In the mixed solvent makes by following formula (4)
[changing 25]
(in formula, R1For alkyl)
The Azilsartan methyl esters of expression crystallizes.It is illustrated in order below.
(object Azilsartan Arrcostab)
(it is also sometimes referred to as object Azilsartan below firstly, for the Azilsartan Arrcostab for the object for becoming crystallization
Arrcostab) it is illustrated.It should be noted that in above-mentioned formula, R1For alkyl.If it is considered that becoming the change containing ester protecting group of raw material
Close the easiness of the manufacture of object, the stability of Azilsartan Arrcostab and Azilsartan, R1The preferably alkane of carbon atom number 1~4
Base.Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group etc., particularly preferably methyl can be enumerated.
(manufacture of object Azilsartan Arrcostab)
To object Azilsartan Arrcostab used in the present invention, there is no particular restriction, is able to use using well known method
The product of synthesis.For example, it is preferable to using the product manufactured by the manufacturing method illustrated in above-mentioned second present invention.
That is, in the present invention, object Azilsartan Arrcostab it is preferable to use as illustrating in second present invention comprising carbon
Product obtained from cyclization is carried out in the reaction dissolvent of the alcohol of atomicity 1~8.The object A Qisha obtained using this method
Smooth Arrcostab and cyclization is carried out in xylene solvent, be precipitated in the solvent comprising ethyl acetate, with existing A Qi
Husky smooth Arrcostab is compared, and the unknown impurity of structure can be reduced.The existing Azilsartan Arrcostab tends to comprising molecular weight
The impurity bigger than Azilsartan Arrcostab is (in the case where Azilsartan methyl esters, it is intended to comprising molecular weight than Azilsartan first
The impurity of ester big 10.).Therefore, in the present invention, it is preferred to using by the reaction dissolvent of the alcohol comprising carbon atom number 1~8
It carries out cyclization and makes the object Azilsartan Arrcostab of impurity reduction.But, in the present invention, due to as will be described in detail
The Azilsartan Arrcostab of high-purity can be made like that, therefore also can of course be by big miscellaneous of, molecular weight unknown comprising structure
Matter, existing Azilsartan Arrcostab is as object Azilsartan Arrcostab.
(the crystallization method of Azilsartan Arrcostab；The manufacturing method of quasi- crystallization)
(solvent: the mixed solvent of acetone or acetone and alcohol)
In the present invention, in order to improve the purity of above-mentioned object Azilsartan Arrcostab, and crystal form is made to deform and be made molten
The low Azilsartan Arrcostab of point, it is necessary to make object Azilsartan Arrcostab in the in the mixed solvent of acetone or acetone and alcohol
Crystallization.By using acetone or the mixed solvent of acetone and alcohol, thus with the existing method phase that uses ethyl acetate
Than can expeditiously reduce the de- ethyl body of Azilsartan Arrcostab or the impurity of dimer.
Solvent used in the present invention is the mixed solvent of acetone or acetone and alcohol, by total appearance of acetone and alcohol
When product is set as 100, preferably the volume ratio of acetone becomes 100~50, and the volume ratio of alcohol becomes 0~50.People according to the present invention
Deng research, know even if with the range below of volume ratio 50% include alcohol in the case where, also can with not alcohol-containing (only
It is acetone) situation gets similarly novel crystal form.Therefore, as long as the volume ratio of alcohol does not become the acetone than using
The big range of volume ratio, it is not necessary to strictly manage the alcohol residual in object Azilsartan Arrcostab.That is, being wrapped in use
In the case where carrying out object Azilsartan Arrcostab obtained from cyclization in the reaction dissolvent of the alcohol of carbon atom quantity 1~8,
Strictly the alcohol need not be removed, therefore can be improved operability.It therefore, is to include the thick of alcohol in object Azilsartan Arrcostab
In the case where body, as long as measuring its alcohol amount to adjust the amount of the acetone used.
In the present invention, using alcohol, which is preferably the alcohol of carbon atom number 1~8.If specifically illustrated,
Methanol, ethyl alcohol, 1- propyl alcohol, isopropanol, n-butyl alcohol, 2- methyl-1-propyl alcohol, 2- butanol, 2- methyl-2-propanol, 1- can be enumerated
Amylalcohol, 3- methyl-1-butanol, 1- hexanol, 2- methyl-1-pentene alcohol, 3- methyl-1-pentene alcohol, 2- methyl -2- amylalcohol, 2,4- diformazan
Base -3- amylalcohol, 3- ethyl -3- amylalcohol, octanol etc..Wherein, if it is considered that the de- ethyl body of yield and Azilsartan Arrcostab or
The reduction effect of the impurity of dimer is, it is preferable to use the straight-chain of carbon atom number 3~8 or the alcohol of branch-like.And specifically, it is preferable to
Using 1- propyl alcohol, isopropanol, n-butyl alcohol, 2- butanol, particularly preferred 1- propyl alcohol, n-butyl alcohol.These alcohol are able to use a kind, also can
It is enough to be used in mixed way a variety of.In the present invention, using alcohol, preferably the volume ratio of acetone becomes 99~51, alcohol
Volume ratio becomes 1~49, and the volume ratio of more preferable acetone becomes 90~60, and the volume ratio of alcohol becomes 10~40.
(method of crystallization)
In addition, to the amount of the mixed solvent of the acetone or acetone and alcohol that use, there is no particular restriction, relative to above-mentioned right
As the crystallization 1g of Azilsartan Arrcostab, it is preferably set to 3~30ml, is more preferably set as 5~20ml.It should be noted that is used is molten
The above-mentioned volume of agent is the volume at 23 DEG C.In addition, the amount for becoming the solvent of benchmark is third using mixed solvent
The total amount of ketone and alcohol.
As the method for recrystallization, preferably make above-mentioned object A Qisha in the in the mixed solvent of acetone or acetone and alcohol
Smooth Arrcostab dissolution, the reflux temperature (about 60 DEG C) for the solution being preferably heated to, next, with 10~30 DEG C/h
Cooling velocity is cooling, preferably at 0~30 DEG C, more preferably at -10~30 DEG C, particularly preferably in -10~20 DEG C of temperature range guarantor
Hold certain time.
(Azilsartan Arrcostab, novel Azilsartan methyl esters)
It is suitable in the Azilsartan Arrcostab obtained from the in the mixed solvent of acetone or acetone and alcohol crystallization
Compound, that is, R1Azilsartan methyl esters as methyl become according to use the X-ray diffraction of Cu-K α line at least 2 θ=9.2 ±
0.2 °, 15.8 ± 0.2 °, 22.1 ± 0.2 ° of novel crystallizations with characteristic peak.As other peaks 2 θ=18.2 ±
0.2 °, 25.1 ± 0.2 °, 27.4 ± 0.2 ° of crystallizations with peak.
It is deposited in addition, the Azilsartan methyl esters obtained from the in the mixed solvent of acetone or acetone and alcohol crystallization becomes
In at least two fusing point, novel crystal form (the low-melting crystallization is also referred to as " standard crystallizes " sometimes below).Wherein, exist
Azilsartan methyl esters obtained from the in the mixed solvent of acetone or acetone and alcohol crystallizes it becomes following crystallization: extremely
Few condition measurement that the differential scanning calorimetry (DSC) shown in embodiment is observed in 150~165 DEG C, 185~195 DEG C is melted
Point.It should be noted that being the summit temperature of endothermic peak with the determining fusing point of the differential scanning calorimetry (DSC) measurement.The novel standard
Crystallization is since fusing point is lower than previously known Azilsartan Arrcostab, therefore, it is considered that being not fully crystallized body.Therefore, because purity
Height can easily dissolve, therefore can be suitble to use in next hydrolysis.
The melting caloric chart as shown in Figure 5 of the Azilsartan methyl esters of quasi- crystallization is such, cannot be by endothermic peak
It draws complete tangent line and finds out.Speculate this is because the Azilsartan methyl esters is the crystallization of unstable state.Therefore, should
Melting caloric is not correctly to be worth, in the case where having found out melting caloric as shown in Figure 5, the preferred temperature with 150~165 DEG C
The related melting caloric of fusing point (being also sometimes referred to simply as " low melting point " below) of range is 2~15J/g, the temperature with 185~195 DEG C
The related melting caloric of fusing point (being also sometimes referred to simply as " high-melting-point " below) for spending range is 40~70J/g.More preferably and eutectic
The related melting caloric of point is 4~10J/g, and melting caloric related with high-melting-point is 50~60J/g.
By to the novel crystallization obtained in the solvent of the alcohol comprising carbon atom number 1~8 so further use acetone,
Or the mixed solvent of acetone and alcohol is recrystallized, and can not only improve purity, and can be made to easily dissolve
Low-melting quasi- crystallization.
(Azilsartan manufacturing method)
In the present invention, by the way that Azilsartan Arrcostab water obtained by the above method will be used in the same manner as above-mentioned first invention
Solution, so as to manufacture by following formula (5)
[changing 26]
The Azilsartan of expression.
To obtained Azilsartan, there is no particular restriction, and well known method can be used and refined and raw medicine is made.Such as
The method using the methods of recrystallization or reslurried, column chromatography can be enumerated.
(removing of Azilsartan dimer)
It sometimes include by following formula (6) according to first present invention~third Azilsartan produced by the present invention
[changing 27]
The Azilsartan dimer of expression is as impurity.In this case, make to include the thick of Azilsartan dimer
After the solution of Azilsartan is contacted with active carbon, the process for separating the crystallization of Azilsartan from the solution can be added.
(thick Azilsartan)
So-called thick Azilsartan, it is intended that the Azilsartan comprising Azilsartan dimer as impurity.Thick Azilsartan can
To be the Azilsartan of 96.0~99.0% purity in high performance liquid chromatography (HPLC) analysis.In addition, in pair for becoming purification
It may include 0.01~0.50% above-mentioned Azilsartan dimer in the thick Azilsartan of elephant.
As will the Azilsartan dimer of object of reduction think to be discussed further below by-product.That is, being used as raw material
Amidoxime compound (compound of formula (2)) and think the generated Azilsartan when the amidoxime compound to be cyclized
(compound of formula (5)) reacts first, generates by following formula (12)
[changing 28]
(in formula, R1For alkyl)
The Azilsartan Arrcostab dimer of expression.Next, think to be obtained by the Azilsartan Arrcostab dimer Ah
Qi Shatan dimer.
(contact method of solution and active carbon dissolved with thick Azilsartan)
It is carried out below for the method for contacting the solution of the thick Azilsartan comprising Azilsartan dimer with active carbon
Explanation.
To the active carbon used, there is no particular restriction, it is preferred to use the specific surface area that BET method is found out is 1000~3500m2/
G, and accumulative pore volume is 0.6~1.5mL/g.By using the active carbon of the physical property with the range, so as to more
Efficiently reduce above-mentioned Azilsartan dimer.
To the tax of the active carbon used (activation) method living, there is no particular restriction, assigns the zinc chloride that method living obtains using drug
Charcoal can be used compatibly using the water vapour charcoal that water vapour tax method living obtains.In addition, to the type of active carbon also without especially
Limitation, dust active carbon, broken charcoal, granulated carbon, particle charcoal, forming charcoal etc., is able to use as long as meeting above-mentioned physical property.Wherein, such as
Fruit considers removal efficiency of ease of handling or active carbon itself etc., it is preferable to use dust active carbon, granulated carbon.For active carbon, such as
Fruit specifically illustrates, then can enumerate purification egression, characteristic egression, granular egression, egression A, egression P, egression C, egression M
(the above are the manufactures of Osaka gas chemistry), (the above are FUTAMURA CHEMICAL by too pavilion A, too pavilion CA, too pavilion K, too pavilion M
CO., LTD. is manufactured) etc..
As long as the solution of the thick Azilsartan contacted with active carbon is thick comprising the Azilsartan dimer as impurity
The solution of Azilsartan dissolution, then there is no particular restriction.Therefore, as long as the solvent used in the solution of thick Azilsartan should
The solvent that thick Azilsartan can dissolve, then can be organic solvent, be also possible to water.Wherein, as described above, it is preferred to make A Qi
(what is obtained after hydrolysis is molten comprising thick Azilsartan for solution obtained from husky smooth alkyl ester hydrolysis comprising thick Azilsartan
Liquid) it is contacted with active carbon.In this case, the solution comprising thick Azilsartan can include alkali.In addition, to reduce Azilsartan
For the purpose of dimer, can also make from the solution take out Azilsartan be dissolved in again solution made of alkaline aqueous solution etc. with
Active carbon contact.But, if it is considered that workability, then preferably make the solution comprising thick Azilsartan obtained after hydrolysis
For object.
The method for contacting the solution of thick Azilsartan with above-mentioned active carbon is not particularly limited.For example, can use
By thick Azilsartan, active carbon and the method that the solvent of thick Azilsartan simultaneously mixes can be dissolved；Prepare thick Azilsartan
The solution of dissolution adds active carbon and mixed method in the solution；Or the solution is made to pass through the column of filling active carbon
Method etc..Wherein, from the easiness of operation, it is preferred to use add active carbon and mixed method in the solution.
The usage amount of active carbon can suitably be determined according to type, impurity level of active carbon etc..Using using above-mentioned
In the case where the solution for the thick Azilsartan dissolution that method obtains, relative to thick Azilsartan 1g, it is preferable to use 0.03~0.2g
Active carbon.At this point, the mixing of the solution and active carbon is preferably carried out by stirring.In addition, temperature when being just stirred
For, it preferably carries out at 15~35 DEG C, is particularly preferably carried out at 20~30 DEG C.In addition, to the time of contact with active carbon
There is no particular restriction, in general, being enough if being carried out at such a temperature with 1~5 hour range.
(the removing method of active carbon)
As described above, after contacting the solution of thick Azilsartan with active carbon, next, by active carbon from the mixed liquor
Separation, separating liquid is recycled.To by the method for Activated carbon separation, there is no particular restriction, can be implemented using well known method.Example
Such as, the separation methods such as decantation, filtering, centrifugal filtration can be used.At this point, in order to improve the efficiency of filtering, be also able to use zeolite,
The filtration adjuvants such as sodalite.
(separation of Azilsartan)
In the present invention, it is necessary to by the Crystallization Separation of Azilsartan from the separating liquid obtained after the processing of above-mentioned active carbon.It is right
It, by the method for the Crystallization Separation of Azilsartan, is also not particularly limited, can be implemented using well known method in from separating liquid.Example
Such as, can use with no particular limitation: by from separating liquid by the direct distillation of solvent to by the Crystallization Separation of Azilsartan
Method or by separating liquid neutralize and make Azilsartan crystallization be precipitated method.
The crystallization for the Azilsartan being precipitated using the above method can be separated using well known method and (divide and take).Specifically
The separation methods such as decantation, decompression/pressure filtration, centrifugal filtration can be used in ground.In addition, just isolated Azilsartan crystallization and
Speech is, it is preferable to use the solvent of the same race with above-mentioned solvent is cleaned.The crystallization of the Azilsartan obtained in this way be wet body, by
It is 3~20 hours dry at 30~50 DEG C, to obtain the hirudo leech of the crystallization of Azilsartan.
As described above, making after being contacted as the thick Azilsartan of impurity with active carbon comprising Azilsartan dimer, pass through
The crystallization of Azilsartan is separated from the solution, so as to obtain especially Azilsartan dimer content reduce,
The crystallization of the Azilsartan of high-purity.In turn, as above-mentioned active carbon, by using the specific surface area for using BET method to find out for
1000~3500m2The active carbon that/g, accumulative pore volume are 0.6~1.5mL/g, so as to further make above-mentioned A Qisha
The content of smooth dimer reduces, and obtains the crystallization of the Azilsartan of higher purity.
(crystallization of Azilsartan M type)
Had according to each crystallization of above-mentioned first present invention~third Azilsartan produced by the present invention for organic solvent
Very slightly solubility.Therefore, in the case where carrying out purification operations using organic solvent, a large amount of organic solvent is needed.In order to right
It is improved, it is also preferred that making to be become according to above-mentioned first present invention~third Azilsartan produced by the present invention for comprising first
The very high crystal habit of solubility of the various solvents of the esters such as the alcohols such as alcohol or ethyl alcohol or ethyl acetate.
And specifically, it is preferable to which the Azilsartan with following crystalline texture is made: according to the X-ray diffraction for using Cu-K α line,
At least characteristic peak is given in 2 θ=9.4 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 14.8 ± 0.2 °, 26.0 ± 0.2 °.It answers
Explanation is given, in the present specification, the Azilsartan of the invention with the crystalline texture is known as " Azilsartan M type knot sometimes
It is brilliant ".It should be noted that ± 0.2 ° of the evaluated error as x-ray diffraction angle includes to become ± 0.2 ° and rounding up
Range.The X-ray diffraction measure result that Azilsartan M type is crystallized is shown in Figure 7.
Wherein, the characteristic peak in the present invention, which refers to, in 2 θ=9.4 ± 0.2 ° there is intensity to become maximum peak, simultaneously in 2 θ
=11.5 ± 0.2 °, 13.3 ± 0.2 °, 14.8 ± 0.2 °, 26.0 ± 0.2 ° occur relative to maximum peak intensity (2 θ=9.4 ±
0.2 ° of peak intensity) with 7% or more intensity peak.Relative to maximum peak intensity there is the peak of the intensity less than 7% to be considered as
Noise etc., the characteristic peak not being equivalent in the present invention.
The known Azilsartan crystalline phase recorded in the crystallization of Azilsartan M type and Patent Documents 1 to 4, non-patent literature 1
Than for alcohols such as methanol or ethyl alcohol；The esters such as ethyl acetate；The ketones such as acetone；The organic solvent of the ethers such as tetrahydrofuran
Dissolubility is improved.Specifically, at room temperature, the crystallization of Azilsartan M type and known Azilsartan crystalline phase ratio, are being waited
About 7~10 times can be dissolved in the methanol of amount.
In addition, the crystallization of Azilsartan M type shows and crystallizes low fusing point than known Azilsartan.Specifically, by differential
Scanning calorimetric (DSC) and measuring identified fusing point is 115 DEG C or more and 135 DEG C or less.In the present invention, by differential scanning calorimetry
(DSC) fusing point determined by measuring refers to the summit temperature by measuring obtained endothermic peak.
(manufacturing method of Azilsartan M type crystallization)
The crystallization of Azilsartan M type can be manufactured by the following: and Azilsartan is dissolved in dimethylformamide
The solvent of ketone and/or esters is added in obtained solution, the crystallization of Azilsartan M type is precipitated.
In the case where Azilsartan is hydrate or solvate, to the molecular number of water or solvent, there is no particular restriction.
In addition, due to crystallized in Azilsartan M type manufacture when using dimethylformamide and ketone and/or the solvent of esters,
It can be the wet body comprising the organic solvent, for other solvents, remained in the range of can not being had an impact in crystallization.Tool
Body, it can be with 50 mass % of Azilsartan amount residual below.Most preferably without the solvent other than the organic solvent.Separately
Outside, to the purity of the Azilsartan used, there is no particular restriction, can directly use according to first present invention~third present invention
Obtained Azilsartan.
(preparation method of Azilsartan solution)
Azilsartan M type crystallization manufacturing method obtained and Azilsartan is dissolved in dimethylformamide first Ah
Qi Shatan solution.At this point, to the dimethylformamide used, there is no particular restriction, can directly use commercially available product.Diformazan
The usage amount of base formamide can suitably determine according to the crystal form of the Azilsartan used, generally, relative to Azilsartan 1g,
It may be designated as 0.5mL or more and 10mL or less.If the usage amount of dimethylformamide increases, yield is reduced, therefore preferably
It is defined as 0.5mL or more and 5mL or less.It should be noted that the volume of solvent is defined as the volume at 25 DEG C.In addition, making A Qisha
Temperature when smooth dissolution can suitably be determined according to the crystal form of the Azilsartan used or the amount of dimethylformamide, preferably 10
DEG C or more and 50 DEG C or less of range in make it dissolve.Further more, there is the case where without fully dissolving Azilsartan certainly
Under, the Azilsartan not dissolved can be also separated by filtration to handle.In turn, the method for obtaining Azilsartan solution is had no
Especially limitation can mix Azilsartan and dimethylformamide to adjust solution, to mixed method or sequence also without especially
Limitation.
(crystallization of Azilsartan M type crystallization)
The manufacturing method of Azilsartan M type crystallization, which is characterized in that ketone is added in obtained Azilsartan solution
And/or the solvent of esters, the crystallization of Azilsartan M type is precipitated.By using this method, so as to obtain having in high yield
The improved Azilsartan M type crystallization of solubility in solvent.The solvent being added in Azilsartan solution can be from
The ketones such as acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), diisobutyl ketone, cyclohexanone；And/or methyl acetate, ethyl acetate, acetic acid
It is selected in the esters such as propyl ester, isopropyl acetate, butyl acetate, isobutyl acetate.The Azilsartan of higher purity in order to obtain, it is excellent
The solvent of esters is added in choosing, wherein most preferably with ethyl acetate.In addition, in the present invention, it also can be by the molten of these ketones
Agent is mixed with the solvent of esters and is added.In the present invention, the solvent by the way that ketone and/or esters is added analyses Azilsartan
Out, the Azilsartan M type crystallization so as to improve the dissolubility for organic solvent is precipitated.
The usage amount that the solvent of the ketone in Azilsartan solution and/or esters is added can be according to the type of the solvent of selection
Suitably determine.In general, dimethylformamide 1mL used in modulation relative to above-mentioned Azilsartan solution, may be designated as
1mL or more and 50mL are hereinafter, if it is considered that yield, operability, are preferably defined as 5mL or more and 20mL or less.At this point, to addition
There is no particular restriction for the temperature of ketone and/or the solvent of esters, also can be dissolved in dimethylformamide in confirmation Azilsartan
It is added, is more preferably added at 30 DEG C or less immediately at such a temperature afterwards.By being added at 30 DEG C or less, so as to inhibit heat point
The purity of the increase of impurity caused by solving, obtained Azilsartan M type crystallization also becomes higher purity.In addition, to ketone is added
And/or the method for the solvent of esters is also not particularly limited, primary method, any for the method being added in several times that whole amount is added
Kind can use.In the present invention, after ketone and/or the solvent of esters is added, by being stirred at a certain temperature, thus
The crystallization of Azilsartan M type is precipitated.The temperature kept at this time may be designated as -5 DEG C or more and 30 DEG C hereinafter, in order to higher yield
Azilsartan is obtained, preferably remains in 0 DEG C or more and 10 DEG C or less.In addition, the time kept can be appropriate according to the temperature of holding
Ground determines, is preferably generally specified as 5 hours or more.In addition, at this point, in the case where the crystallization of Azilsartan is difficult to be precipitated,
Kind of a crystalline substance can be added.
The Azilsartan M type crystallization being precipitated like this for, by after filtering or be centrifugated etc. and being separated by solid-liquid separation, by adopting
It is dried with the methods of natural drying, air-supply drying, vacuum drying, so as to isolate.
It is that there is the Azilsartan M type of novel crystalline texture to crystallize using the Azilsartan that this method obtains.With regard to this hair
For bright Azilsartan M type crystallization, the solubility of organic solvent is improved, compared with known crystal form, for alcohol
Class, esters, ketone, ethers solvent solubility it is high.Therefore, the crystallization of Azilsartan M type is subjected to purification behaviour as object
In the case where work, be able to use alcohols, esters, ketone, ethers each solvent be easy to carry out recrystallization etc. purification operations.
Embodiment
It is exemplified below embodiment to explain the present invention in detail, these embodiments are concrete example, and the present invention is not by these
Embodiment is limited.
It should be noted that the Purity assessment in embodiment and comparative example is used using high performance liquid chromatography below (HPLC)
Method carries out.
The determination condition > of < HPLC
Device: high performance liquid chromatography (HPLC).
Machine: 2695-2489-2998 (manufacture of Waters company)
Detector: ultraviolet light absorption photometer (measurement wavelength: 210nm)
Column: Kromasil C18, internal diameter 4.6mm, long 15cm (5 μm of partial size) (Akzo Nobel N.V.'s manufacture)
Column temperature: 30 DEG C constant
Sample temperature: 25 DEG C constant
Mobile phase A: acetonitrile
Mobile phase B: 15mM potassium dihydrogen phosphate aqueous solution (pH=2.5 is adjusted with phosphoric acid)
The liquor charging of mobile phase: changing mobile phase A, the mixing ratio of B as was the case with table 1, carries out concentration gradient control.
[table 1]
Flow velocity: 1.0mL/ minutes
Minute: 0~90 minute
Under the above conditions, confirm that above-mentioned amidoxim takes off ethyl body in about 1.8 minutes, above-mentioned amidoxime compound about
2.8 minutes, above-mentioned amide take off ethyl body about 4.0 minutes, above-mentioned amide body about 8.5 minutes, above-mentioned nitrile take off ethyl body about
11.2 minutes, above-mentioned nitrile compound is in about 25.0 minutes, the above-mentioned compound A (R containing ester protecting group1: methyl, R2: ethyl)
About 16.2 minutes, the above-mentioned compound B (R containing ester protecting group1: methyl, R2: 2- ethylhexyl) about 52.3 minutes, above-mentioned Ah
Qi Shatan methyl esters is in about 14.5 minutes, above-mentioned de- ethyl body in about 7.0 minutes, above-mentioned Azilsartan about 7.3 minutes, above-mentioned two
Impurity of the aggressiveness about 49.1 minutes, molecular weight bigger than Azilsartan methyl esters 10 had peak at about 5.5 minutes.Embodiment below,
In comparative example, above-mentioned amidoxime compound, the above-mentioned compound containing ester protecting group, above-mentioned Azilsartan methyl esters, above-mentioned A Qi
The all area values (not including the peak from solvent) relative to the whole peaks measured under above-mentioned condition of each purity of Sha Tan
Total each compound peak area value ratio.
< Azilsartan Arrcostab, Azilsartan crystal form measurement >
Device: X-ray diffraction device (XRD)
Machine: SmartLab (manufacture of Co., Ltd.'s リ ガ Network)
Measuring method: ASC6BB Dtex
X-ray output: 40kV-30mA
Wavelength:
The measurement > of the fusing point of < Azilsartan Arrcostab
Device: differential scanning calorimetry (DSC) (DSC)
Machine: DSC6200 (SII Nanotechnology Inc. manufacture)
Elevated Temperature Conditions: 10 DEG C/min
Gas: argon gas.
The measurement > of the fusing point of < Azilsartan
Device: differential scanning calorimetry (DSC) (DSC)
Machine: DSC6200 (SII Nanotechnology Inc. manufacture)
Elevated Temperature Conditions: 5 DEG C/min
Gas: argon gas
A. about the first examples and comparative examples of the present invention comparative example
[embodiment 1]
Above-mentioned nitrile compound 5g is measured in the 100mL three-necked flask for having 2 stirring blades of diameter 2.5cm
(12.2mmol) is added 1- propyl alcohol 50mL, commercially available 50 mass % aqueous hydroxylamine 4.0g (60.8mmol), is heated to flow back
After temperature (about 92 DEG C), carry out reacting for 12 hours at such a temperature.For above-mentioned amidoxime compound purity: 82.2%, above-mentioned acyl
Amine body: 9.1%, above-mentioned nitrile compound: 2.2%, above-mentioned amidoxim takes off ethyl body: 6.0%, above-mentioned amide takes off ethyl body:
0.3%, the de- ethyl body of above-mentioned nitrile: 0.05%.
Solution after reaction is cooled to 20 DEG C with 30 DEG C/h of speed, the stirred overnight at 20 DEG C.Next, right
Obtained slurries are filtered under diminished pressure, and the crystallization for taking precipitation is divided, dry at 50 DEG C, obtain the above-mentioned amidoxime compound of 4.0g
The crystallization (purity of above-mentioned amidoxime compound: 94.7%, above-mentioned amide body: 3.0%, above-mentioned nitrile compound: 0.2%, above-mentioned
Amidoxim takes off ethyl body: 0.7%, above-mentioned amide takes off ethyl body: 0.3%, above-mentioned nitrile takes off ethyl body: not detecting) (yield:
77.1%).Result is summarized in table 2,3.
[embodiment 2]
Above-mentioned nitrile compound 70g is measured in the 1L three-necked flask for having 2 stirring blades of diameter 10cm
1- propyl alcohol 700mL, triethylamine 5.16g (51.0mmol), commercially available 50 mass % aqueous hydroxylamine is added in (170.1mmol)
56.2g (850.5mmol) after being heated to reflux temperature (about 92 DEG C), carries out reacting for 13 hours at such a temperature.To be above-mentioned together with amine
The purity of oxime compound: 83.9%, above-mentioned amide body: 2.4%, above-mentioned nitrile compound: 2.4%, above-mentioned amidoxim takes off ethyl body:
7.6%, above-mentioned amide takes off ethyl body: 0.2%, the de- ethyl body of above-mentioned nitrile: 0.01%.
Solution after reaction is cooled to 20 DEG C with 20 DEG C/h of speed, is stirred 13 hours at 20 DEG C.Next,
Obtained slurries are filtered under diminished pressure, the crystallization for taking precipitation is divided, it is dry at 50 DEG C, obtain the above-mentioned amidoxime compound of 61.0g
The crystallization (purity of above-mentioned amidoxime compound: 96.9%, above-mentioned amide body: 0.5%, above-mentioned nitrile compound: 0.1%, above-mentioned
Amidoxim takes off ethyl body: 0.5%, above-mentioned amide takes off ethyl body: 0.1%, above-mentioned nitrile takes off ethyl body: not detecting) (yield:
81.0%).Result is summarized in table 2,3.
[embodiment 3]
Nitrile compound 5g is measured in the 100mL three-necked flask for having 2 stirring blades of diameter 2.5cm
1- propyl alcohol 50mL, triethylamine 0.62g (6.1mmol), commercially available 50 mass % aqueous hydroxylamine 4.0g is added in (12.2mmol)
(60.8mmol) after being heated to reflux temperature (about 92 DEG C), carries out reacting for 13 hours at such a temperature.For above-mentioned amidoxim chemical combination
The purity of object: 84.2%, above-mentioned amide body: 1.8%, above-mentioned nitrile compound: 2.6%, above-mentioned amidoxim takes off ethyl body: 7.4%,
Above-mentioned amide takes off ethyl body: 0.2%, the de- ethyl body of above-mentioned nitrile: 0.01%.
Solution after reaction is cooled to 20 DEG C with 20 DEG C/h of speed, is stirred 13 hours at 20 DEG C.Next,
Obtained slurries are filtered under diminished pressure, the crystallization for taking precipitation is divided, it is dry at 50 DEG C, obtain the above-mentioned amidoxime compound of 4.1g
Crystallization (purity of above-mentioned amidoxime compound: 97.1%, above-mentioned amide body: 0.3%, above-mentioned nitrile compound: 0.1%, it is above-mentioned together with
Amidoxime takes off ethyl body: 0.5%, above-mentioned amide takes off ethyl body: 0.1%, above-mentioned nitrile takes off ethyl body: not detecting) (yield:
77.4%).Result is summarized in table 2,3.
[embodiment 4]
In embodiment 3, in addition to reaction dissolvent is become n-butyl alcohol from 1- propyl alcohol, by the usage amount of triethylamine from 0.62g
(6.1mmol) becomes similarly being operated other than 0.37g (3.66mmol).
Obtain the crystallization (purity of above-mentioned amidoxime compound: 97.0%, above-mentioned acyl of the above-mentioned amidoxime compound of 4.4g
Amine body: 0.4%, above-mentioned nitrile compound: 0.1%, above-mentioned amidoxim takes off ethyl body: 0.6%, above-mentioned amide takes off ethyl body:
0.1%, above-mentioned nitrile takes off ethyl body: not detecting) (yield: 81.1%).Result is summarized in table 2,3.
[embodiment 5]
In embodiment 3, in addition to the alkali used is become pyridine from triethylamine, by the usage amount of alkali from 0.62g
(6.1mmol) becomes similarly being operated other than 0.37g (3.66mmol).
Obtain the crystallization (purity of above-mentioned amidoxime compound: 96.5%, above-mentioned acyl of the above-mentioned amidoxime compound of 4.3g
Amine body: 0.4%, above-mentioned nitrile compound: 0.2%, above-mentioned amidoxim takes off ethyl body: 0.6%, above-mentioned amide takes off ethyl body:
0.1%, above-mentioned nitrile takes off ethyl body: not detecting) (yield: 79.4%).Result is summarized in table 2,3.
[embodiment 6]
In embodiment 3, in addition to by the usage amount of triethylamine from 0.62g (6.1mmol) become 0.12g (1.22mmol) with
Outside, it is similarly operated.
Obtain the crystallization (purity of above-mentioned amidoxime compound: 95.3%, above-mentioned acyl of the above-mentioned amidoxime compound of 4.3g
Amine body: 1.5%, above-mentioned nitrile compound: 0.2%, above-mentioned amidoxim takes off ethyl body: 0.6%, above-mentioned amide takes off ethyl body:
0.3%, above-mentioned nitrile takes off ethyl body: not detecting) (yield: 80.2%).Result is summarized in table 2,3.
[embodiment 7]
In embodiment 1, it other than the usage amount of 1- propyl alcohol is become 75mL from 50mL, is similarly operated.
Obtain the crystallization (purity of above-mentioned amidoxime compound: 94.9%, above-mentioned acyl of the above-mentioned amidoxime compound of 3.9g
Amine body: 2.8%, above-mentioned nitrile compound: 0.2%, above-mentioned amidoxim takes off ethyl body: 0.7%, above-mentioned amide takes off ethyl body:
0.3%, above-mentioned nitrile takes off ethyl body: not detecting) (yield: 73.1%).Result is summarized in table 2,3.
[embodiment 8] (synthesis of Azilsartan methyl esters)
It is measured in the 1L three-necked flask for having 2 stirring blades of diameter 10cm above-mentioned together with amine obtained in embodiment 2
Dimethyl sulfoxide 350mL, 1,1'- carbonylic imidazole 17.5g, diazabicyclo endecatylene 15.5g is added in oxime compound 40g,
Room temperature stirs 4 hours sides below and is reacted.Water 1500mL is measured in the 3L three-necked flask in addition prepared, instilling at leisure should
Reaction solution.5% aqueous hydrochloric acid solution is added in obtained solution, pH is adjusted to after about 4, point takes precipitation by being filtered under diminished pressure
The crystallization of Azilsartan methyl esters is recrystallized by acetone 400mL, is depressurized to obtained slurries after dry at 50 DEG C
Filtering point takes the crystallization of precipitation, dry at 50 DEG C, obtain the Azilsartan methyl esters of 32.0g crystallization (Azilsartan methyl esters
Purity: 99.4%).
[embodiment 9] (synthesis of Azilsartan)
Azilsartan obtained in embodiment 8 is measured in the 1L three-necked flask for having 2 stirring blades of diameter 10cm
1.25M sodium hydrate aqueous solution 200mL is added in methyl esters 20g, after being heated to 50 DEG C, carries out reacting for 3 hours at such a temperature.It will
After reaction solution is cooled to 45 DEG C, acetone 100mL, acetic acid 75mL, water 70mL are added at such a temperature, analyses the crystallization of Azilsartan
Out.After reaction solution is cooled to 20 DEG C with 20 DEG C/h of speed, stir 5 hours at such a temperature.Next, to obtaining
Slurries are filtered under diminished pressure, and the crystallization for taking precipitation is divided, dry at 40 DEG C, obtain the crystallization (A Qisha of the Azilsartan of 16.6g
Smooth purity: 99.4%).
[comparative example 1] (using the manufacture of the above-mentioned amidoxime compound for the method recorded in non-patent literature 1)
Above-mentioned nitrile compound 5g is measured in the 500mL three-necked flask for having 2 stirring blades of diameter 7.5cm
Dimethyl sulfoxide 50mL, hydroxy amine hydrochloric acid salt 4.2g (60.8mmol), triethylamine 6.15g is added in (12.2mmol)
(60.8mmol) after being heated to 90 DEG C, carries out reacting for 16 hours at such a temperature.For above-mentioned amidoxime compound purity:
42.6%, above-mentioned amide body: 37.0%, above-mentioned nitrile compound: 4.5%, above-mentioned amidoxim takes off ethyl body: 9.3%, above-mentioned amide
De- ethyl body: 4.8%, the de- ethyl body of above-mentioned nitrile: 1.0%.
Solution after reaction is cooled to 20 DEG C, is stirred 12 hours, but the crystallization of above-mentioned amidoxime compound is not precipitated.
Therefore, water 125mL is added in reaction solution, the crystallization of above-mentioned amidoxime compound is precipitated.Next, to obtained slurries into
Row is filtered under diminished pressure, and divides the crystallization for taking precipitation, dry at 50 DEG C, and the crystallization for obtaining the above-mentioned amidoxime compound of 3.1g is (above-mentioned
The purity of amidoxime compound: 49.9%, above-mentioned amide body: 46.4%, above-mentioned nitrile compound: 0.5%, above-mentioned amidoxim takes off second
Matrix: 1.7%, above-mentioned amide takes off ethyl body: 0.9%, above-mentioned nitrile takes off ethyl body: 0.1%) (yield: 57.1%).Result is converged
Always in table 2,3.
[comparative example 2] (using the manufacture of the amidoxime compound for the method recorded in patent document 2)
Above-mentioned nitrile compound 5g is measured in the 500mL three-necked flask for having 2 stirring blades of diameter 7.5cm
(12.2mmol) is added dimethyl sulfoxide 50mL, commercially available 50 mass % aqueous hydroxylamine 2.0g (30.4mmol), is heated to
After 90 DEG C, carry out reacting for 15 hours at such a temperature.For the purity of above-mentioned amidoxime compound: 72.0%, above-mentioned amide body:
9.8%, above-mentioned nitrile compound: 0.5%, above-mentioned amidoxim takes off ethyl body: 9.3%, above-mentioned amide takes off ethyl body: 1.0%, above-mentioned
Nitrile takes off ethyl body: 0.2%.
Solution after reaction is cooled to 20 DEG C, is stirred 12 hours, but the crystallization of above-mentioned amidoxime compound is not precipitated.
Therefore, water 125mL is added in reaction solution, the crystallization of above-mentioned amidoxime compound is precipitated.Next, to obtained slurries into
Row is filtered under diminished pressure, and divides the crystallization for taking precipitation, dry at 50 DEG C, and the crystallization for obtaining the above-mentioned amidoxime compound of 4.2g is (above-mentioned
Amidoxime compound purity: 85.7%, above-mentioned amide body: 5.1%, above-mentioned nitrile compound: 0.5%, above-mentioned amidoxim takes off ethyl
Body: 5.9%, above-mentioned amide takes off ethyl body: 0.4%, above-mentioned nitrile takes off ethyl body: 0.1%) (yield: 78.8%).Result is summarized
In table 2,3.
[table 2]
Table 2
* the usage amount (mL) of every 1g nitrile compound
The usage amount (mol) of the every 1mol nitrile compound of *
[table 3]
Table 3
B. the second embodiment of the present invention and comparative example
[Production Example 1] (compound A containing ester protecting group；R1: methyl, R2: the synthesis of ethyl)
Above-mentioned amidoxime compound 120g is measured in the 2L four-hole boiling flask for having 2 stirring blades of diameter 15cm
(270.0mmol) is added methylene chloride 840mL, triethylamine 33.0g (324.0mmol), is cooled to 0 DEG C while stirring.It is obtaining
Solution in be slowly added dropwise by ethyl chloroformate 35.4g (324.0mmol) with methylene chloride 360mL dilute made of solution.
After whole amount is instilled, reacted on 0 DEG C of following stirring, 2 hours sides.Solution after reaction is warming up to 20 DEG C, water 480mL is added,
Organic layer is extracted out.After obtained organic layer is concentrated under reduced pressure, 1- propyl alcohol 600mL is added in residue, it is small that 3 are stirred at 20 DEG C
When.By obtained pulp solution by being filtered under diminished pressure separation of solid and liquid after, be dried under reduced pressure, obtained containing ester protecting group at 40 DEG C
Compound A 122.86g (the compound A purity containing ester protecting group: 96.1%) (yield 88.1%).
[Production Example 2] (compound B containing ester protecting group；R1: methyl, R2: the synthesis of 2- ethylhexyl)
Above-mentioned amidoxime compound 30g is measured in the 500mL four-hole boiling flask for having 2 stirring blades of diameter 7.5cm
(67.5mmol) is added methylene chloride 210mL, triethylamine 8.2g (81.0mmol), is cooled to 0 DEG C while stirring.What is obtained
It is slowly added dropwise in solution by chloro-carbonic acid -2- ethylhexyl 15.6g (81.0mmol) the diluted solution of methylene chloride 90mL.Entirely
After portion's amount instills, reacted on 0 DEG C of following stirring, 2 hours sides.Solution after reaction is warming up to 20 DEG C, water 120mL is added, will have
The extraction of machine layer.After obtained organic layer is concentrated under reduced pressure, 1- propyl alcohol 150mL is added in residue, is stirred 3 hours at 20 DEG C.
By obtained pulp solution by being filtered under diminished pressure separation of solid and liquid after, be dried under reduced pressure at 40 DEG C, obtain the change containing ester protecting group
Close object B 31.9g (the compound B purity containing ester protecting group: 94.5%) (yield 78.7%).
[embodiment 10]
It measures in the 100mL three-necked flask with 2 stirring blades of diameter 3.5cm and contains obtained in Production Example 1
1- propyl alcohol 45mL is added, after being heated to reflux temperature (about 95 DEG C), in the temperature in the compound A 5g (9.7mmol) of ester protecting group
Degree is lower react within 16 hours.For the purity of above-mentioned Azilsartan methyl esters: 91.5%, above-mentioned compound A containing ester protecting group:
1.8%.Reaction solution after reaction is cooled to 0 DEG C with 20 DEG C/h of speed, is stirred 14 hours at 0 DEG C.Next,
Obtained slurries are filtered under diminished pressure, divides the crystallization for taking precipitation, is dried under reduced pressure at 40 DEG C, obtains the above-mentioned Azilsartan first of 3.7g
Crystallization (the purity of above-mentioned Azilsartan Arrcostab: 97.3%) (yield: 81.1%) of ester.Result is summarized in table 4.Fail
Confirm the impurity of molecular weight bigger than Azilsartan methyl esters 10.In addition, measuring XRD using the Azilsartan methyl esters as sample, obtaining
X-ray diffractogram shown in Fig. 1.Known to the crystallization be with being given in 2 θ=9.9 °, 10.9 °, 13.6 °, 17.2 °, 23.2 °
The compound of the novel crystallization structure of characteristic peak.
[embodiment 11]
It is measured in the 200mL three-necked flask with 2 stirring blades of diameter 5cm obtained in Production Example 1 and contains ester
1- propyl alcohol 90mL, triethylamine 0.4g (3.9mmol) is added in the compound A 10g (19.4mmol) of protecting group, is heated to reflux temperature
After spending (about 94 DEG C), carry out reacting for 9 hours at such a temperature.For the purity of above-mentioned Azilsartan methyl esters: 93.0%, it is above-mentioned containing
The compound A:0.7% of ester protecting group.Reaction solution after reaction is cooled to 0 DEG C with 20 DEG C/h of speed, at 0 DEG C
Stirring 12 hours.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, be dried under reduced pressure, obtain at 40 DEG C
Crystallization (the purity of above-mentioned Azilsartan methyl esters: 97.8%) (yield: 83.4%) of the above-mentioned Azilsartan methyl esters of 7.6g.It will knot
Fruit is summarized in table 4.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, the Azilsartan methyl esters is made
For sample, XRD is measured, it is known that it is with giving the novel of characteristic peak in 2 θ=9.8 °, 10.9 °, 13.6 °, 17.2 °, 23.2 °
The compound of crystalline texture.
[embodiment 12]
It measures in the 100mL three-necked flask for having 2 stirring blades of diameter 3.5cm and contains obtained in Production Example 2
1- propyl alcohol 45mL, triethylamine 0.2g (1.7mmol) is added in the compound B 5g (8.3mmol) of ester protecting group, is heated to reflux temperature
After spending (about 94 DEG C), carry out reacting for 10 hours at such a temperature.For the purity of above-mentioned Azilsartan methyl esters: 91.7%, above-mentioned to contain
There is the compound B:0.6% of ester protecting group.Reaction solution after reaction is cooled to 0 DEG C with 20 DEG C/h of speed, at 0 DEG C
Lower stirring 12 hours.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, be dried under reduced pressure, obtain at 40 DEG C
Crystallization (the purity of above-mentioned Azilsartan methyl esters: 97.5%) (yield: 81.8%) of the above-mentioned Azilsartan methyl esters of 3.2g.It will knot
Fruit is summarized in table 4.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, the result of XRD also with embodiment
10,11 Azilsartan methyl esters does not change.
[embodiment 13]
In embodiment 11, in addition to by the usage amount of triethylamine from 0.4g (3.9mmol) become 1.96g (19.4mmol) with
Outside, it is similarly operated.Reaction was set to finish with 6 hours.
Obtain the above-mentioned Azilsartan methyl esters of 5.9g crystallization (purity of above-mentioned Azilsartan methyl esters: 98.6%) (yield:
64.4%).Result is summarized in table 4.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, the knot of XRD
Azilsartan methyl esters of the fruit also with embodiment 10,11 does not change.
[embodiment 14]
In embodiment 10, other than reaction dissolvent is become n-butyl alcohol from 1- propyl alcohol, similarly operated.
Obtain the above-mentioned Azilsartan methyl esters of 3.7g crystallization (purity of above-mentioned Azilsartan methyl esters: 97.1%) (yield:
80.9%).Result is summarized in table 4.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, the result of XRD
Also the Azilsartan methyl esters with embodiment 10,11 does not change.
[embodiment 15]
In embodiment 10, other than the usage amount of 1- propyl alcohol is become 125mL from 45mL, similarly operated.
Obtain the above-mentioned Azilsartan methyl esters of 2.3g crystallization (purity of above-mentioned Azilsartan methyl esters: 98.2%) (yield:
50.9%).Result is summarized in table 4.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, the result of XRD
Also the Azilsartan methyl esters with embodiment 10,11 does not change.
[embodiment 16]
In embodiment 11, other than the alkali used is become pyridine from triethylamine, similarly operated.
Obtain the above-mentioned Azilsartan methyl esters of 7.6g crystallization (purity of above-mentioned Azilsartan methyl esters: 97.7%) (yield:
83.8%).Result is summarized in table 4.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, the result of XRD
Also the Azilsartan methyl esters with embodiment 10,11 does not change.
[embodiment 17] (synthesis of Azilsartan)
Azilsartan obtained in embodiment 11 is measured in the 1L three-necked flask for having 2 stirring blades of diameter 10cm
1.25M sodium hydrate aqueous solution 50mL is added in methyl esters 5g, after being heated to 50 DEG C, carries out reacting for 3 hours at such a temperature.It will be anti-
After answering liquid to be cooled to 45 DEG C, acetone 25mL, acetic acid 17mL, water 17mL are added at such a temperature, the crystallization of Azilsartan is precipitated.
After reaction solution is cooled to 20 DEG C with 20 DEG C/h of speed, stir 6 hours at such a temperature.Next, the slurries that will be obtained
Be filtered under diminished pressure, point take the crystallization of precipitation, it is dry at 40 DEG C, obtain the Azilsartan of 4.2g crystallization (purity of Azilsartan:
99.0%).
[comparative example 3] (using the manufacture of the above-mentioned Azilsartan methyl esters of method described in Patent Document 1)
It is measured in the 200mL three-necked flask for having 2 stirring blades of diameter 5cm obtained in Production Example 1 and contains ester
The compound A 5g of protecting group is added dimethylbenzene 50mL and carries out 1.5 at such a temperature after being heated to reflux temperature (about 130 DEG C)
Hour reaction.For the purity of above-mentioned Azilsartan methyl esters: 70.1%, the above-mentioned compound A containing ester protecting group: not detecting.
Solution after reaction is concentrated under reduced pressure, ethyl acetate 100mL is added in residue, but the crystallization in residue is undissolved.Therefore, add
Enter isopropyl ether 50mL, is stirred 12 hours at 20 DEG C.Obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, at 40 DEG C
It is dried under reduced pressure, the crystallization for obtaining the above-mentioned Azilsartan methyl esters of 1.4g (purity of above-mentioned Azilsartan Arrcostab: 79.8%) (is received
Rate: 30.4%).The impurity of molecular weight bigger than Azilsartan methyl esters 10 is 12.1%.Result is summarized in table 4.
[comparative example 4] (using the manufacture of the above-mentioned Azilsartan methyl esters of the method for the record of non-patent literature 1)
It is measured in the 200mL three-necked flask for having 2 stirring blades of diameter 5cm obtained in Production Example 2 and contains ester
Dimethylbenzene 50mL is added in the compound B 5g of protecting group, and after being heated to reflux temperature (about 130 DEG C), it is small to carry out 2 at such a temperature
Shi Fanying.For the purity of above-mentioned Azilsartan methyl esters: 72.8%, the above-mentioned compound B containing ester protecting group: not detecting.It will
Solution after reaction is concentrated under reduced pressure, and ethyl acetate 50mL is added in residue, is warming up to reflux temperature (about 80 DEG C), makes to be concentrated residual
The crystallization of slag is fully dissolved.Obtained solution is cooled to 20 DEG C, is stirred 12 hours at 20 DEG C.Next, will obtain
Slurries are filtered under diminished pressure, and are divided the crystallization for taking precipitation, are dried under reduced pressure at 40 DEG C, obtain the crystallization of the above-mentioned Azilsartan methyl esters of 2.0g
(the purity of above-mentioned Azilsartan methyl esters: 88.4%) (yield: 50.2%).The impurity of molecular weight bigger than Azilsartan methyl esters 10 is
10.8%.Result is summarized in table 4.In addition, measuring XRD using the Azilsartan methyl esters as sample, obtaining shown in Fig. 2
X-ray diffractogram, it is known that the crystallization is to give the chemical combination of characteristic peak in 2 θ=8.0 °, 10.4 °, 12.0 °, 15.9 °, 21.4 °
Object.
[table 4]
Table 4
* every 1g contains the usage amount (mL) of the compound of ester protecting group
The every lmol of * contains the usage amount (mol) of the compound of ester protecting group
C. third embodiment of the present invention and comparative example
[Production Example 3] (synthesis of object Azilsartan methyl esters)
The compound containing ester protecting group is measured in the 1000mL four-hole boiling flask for having 2 stirring blades of diameter 10cm
(R in above-mentioned formula (3)1For methyl, R2For the compound of ethyl) 50g (96.80mmol), 1- propyl alcohol 400mL, triethylamine is added
1.96g (19.36mmol) after being heated to reflux temperature (about 95 DEG C), carries out reacting for 14 hours at such a temperature.After reaction
Solution is cooled to 0 DEG C with 20 DEG C/h of speed, stirs 14 hours at 0 DEG C.Next, obtained slurries are filtered under diminished pressure,
Divide the crystallization for taking precipitation, is dried under reduced pressure at 40 DEG C, obtains crystallization (the Azilsartan first of the object Azilsartan methyl esters of 38.3g
The purity of ester: 97.3%, above-mentioned de- ethyl body: 0.10%, above-mentioned dimer: 0.16%) (yield: 84.2%).In addition, failing
Confirm the impurity of molecular weight bigger than Azilsartan methyl esters 10.In addition, XRD is measured using the object Azilsartan methyl esters as sample,
It obtains giving the X-ray diffractogram of characteristic peak in 2 θ=9.9 °, 10.9 °, 13.6 °, 17.2 °, 23.2 °.In turn, DSC survey is carried out
Fixed, being able to confirm that has fusing point at 90.9 DEG C (melting caloric 15.790J/g) and 186.6 DEG C (melting caloric 58.886J/g).
[embodiment 18] (crystallization of Azilsartan methyl esters)
Measured in the 200mL three-necked flask for having 2 stirring blades of diameter 5cm obtained in Production Example 3 object Ah
Qi Shatan methyl esters 10g is added acetone 100mL, is heated to reflux temperature (about 57 DEG C), and object Azilsartan methyl esters is dissolved.It is molten
Xie Hou is cooled to 0 DEG C with 20 DEG C/h of speed, stirs 12 hours at 0 DEG C.Next, obtained slurries were depressurized
Filter divides the crystallization for taking precipitation, is dried under reduced pressure at 40 DEG C, obtains crystallization (the Azilsartan methyl esters of the Azilsartan methyl esters of 8.7g
Purity: 99.1%, above-mentioned de- ethyl body: do not detect, above-mentioned dimer: 0.04%) (yield: 87.2%).Result is converged
Always in table 5.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, using the Azilsartan methyl esters as sample,
XRD is measured, knows and gives feature in 2 θ=9.2 °, 15.8 °, 18.2 °, 22.1 °, 25.1 °, 27.4 ° as illustrated
The quasi- crystallization of the Azilsartan methyl esters at peak.Result is summarized in table 6.In turn, DSC measurement is carried out, is able to confirm that as shown in Figure 5
There is fusing point at 160.6 DEG C (melting caloric 9.635J/g) and 189.9 DEG C (melting caloric 51.766J/g) like that.
[embodiment 19] (recrystallization of Azilsartan methyl esters)
Object obtained in Production Example 3 is measured in the 100mL three-necked flask for having 2 stirring blades of diameter 3.5cm
Azilsartan methyl esters 5g is added acetone 30mL, 1- propyl alcohol 20mL, is heated to reflux temperature, and object Azilsartan methyl esters is dissolved.
After dissolution, it is cooled to 0 DEG C with 20 DEG C/h of speed, is stirred 12 hours at 0 DEG C.Next, obtained slurries were depressurized
Filter divides the crystallization for taking precipitation, is dried under reduced pressure at 40 DEG C, obtains crystallization (the Azilsartan methyl esters of the Azilsartan methyl esters of 4.3g
Purity: 99.0%, above-mentioned de- ethyl body: do not detect, above-mentioned dimer: 0.04%) (yield: 86.0%).Result is converged
Always in table 5.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.In addition, using the Azilsartan methyl esters as sample,
XRD is measured, knows and gives the Azilsartan first of characteristic peak in 2 θ=9.2 °, 15.7 °, 18.2 °, 22.1 °, 25.2 °, 27.4 °
The quasi- crystallization of ester.Result is summarized in table 6.In turn, DSC measurement is carried out, is able to confirm that in 157.2 DEG C of (melting caloric 5.249J/
G) and 189.7 DEG C (melting caloric 57.266J/g) have fusing point.
[embodiment 20] (crystallization of Azilsartan methyl esters)
In embodiment 19, other than 1- propyl alcohol is become n-butyl alcohol, similarly operated.
Obtain the Azilsartan methyl esters of 4.2g crystallization (purity of Azilsartan methyl esters: 99.1%, above-mentioned de- ethyl body:
It does not detect, above-mentioned dimer: 0.04%) (yield: 85.4%).Result is summarized in table 5.Molecular weight ratio A Qi is not can confirm that
The impurity of husky smooth methyl esters big 10.In addition, the result of XRD is also identical as the Azilsartan methyl esters of embodiment 19.Result is summarized in
Table 6.In turn, DSC measurement is carried out, is able to confirm that in 158.1 DEG C (melting caloric 4.191J/g) and 189.5 DEG C of (melting calorics
58.734J/g) there is fusing point.
[embodiment 21] (crystallization of Azilsartan methyl esters)
It measures in the 100mL three-necked flask for having 2 stirring blades of diameter 3.5cm using following comparative examples 5
The object Azilsartan methyl esters 4g of method manufacture, is added acetone 40mL, is heated to reflux temperature, and object Azilsartan methyl esters is molten
Solution.After dissolution, it is cooled to 0 DEG C with 20 DEG C/h of speed, is stirred 14 hours at 0 DEG C.Next, obtained slurries are subtracted
Press filtration divides the crystallization for taking precipitation, is dried under reduced pressure at 40 DEG C, obtains the crystallization (Azilsartan of the Azilsartan methyl esters of 2.8g
The purity of methyl esters: 96.6%, it above-mentioned de- ethyl body: does not detect, above-mentioned dimer: 0.07%) (yield: 70.2%).It will knot
Fruit is summarized in table 5.The impurity of molecular weight bigger than Azilsartan methyl esters 10 is 1.64%.In addition, using the Azilsartan methyl esters as
Sample measures XRD, knows and give the A Qisha of characteristic peak in 2 θ=9.2 °, 15.7 °, 18.1 °, 22.1 °, 25.3 °, 27.4 °
The quasi- crystallization of smooth methyl esters.Result is summarized in table 6.In turn, DSC measurement is carried out, is able to confirm that in 159.4 DEG C of (melting calorics
7.921J/g) and 190.2 DEG C (melting caloric 55.015J/g) have fusing point.
[embodiment 22] (recrystallization of Azilsartan methyl esters)
Using the Azilsartan methyl esters manufactured in embodiment 21 as object Azilsartan methyl esters.
Using the Azilsartan methyl esters 2g manufactured in embodiment 21, operation similarly to Example 21 is repeated.
Obtain the Azilsartan methyl esters of 1.7g crystallization (purity of Azilsartan methyl esters: 99.3%, above-mentioned de- ethyl body:
It does not detect, above-mentioned dimer: 0.02%) (yield: 85.9%).Result is summarized in table 5.Molecular weight ratio A Qi is not can confirm that
The impurity of husky smooth methyl esters big 10.In addition, the result of XRD is also identical as the Azilsartan methyl esters of embodiment 18.Result is summarized in
Table 5.In turn, DSC measurement is carried out, is able to confirm that in 160.2 DEG C (melting caloric 6.424J/g) and 190.1 DEG C of (melting calorics
56.971J/g) there is fusing point.
[embodiment 23] (synthesis of Azilsartan)
A Qi obtained in embodiment 19 is measured in the 100mL three-necked flask for having 2 stirring blades of diameter 3.5cm
Husky smooth methyl esters 5g, is added 1.25M sodium hydrate aqueous solution 50mL, after being heated to 50 DEG C, carries out reacting for 3 hours at such a temperature.
After reaction solution is cooled to 45 DEG C, acetone 25mL, acetic acid 17mL, water 17mL are added at such a temperature, makes the crystallization of Azilsartan
It is precipitated.After reaction solution is cooled to 20 DEG C with 20 DEG C/h of speed, stir 6 hours at such a temperature.Next, will obtain
Slurries be filtered under diminished pressure, point take the crystallization of precipitation, it is dry at 40 DEG C, obtain the crystallization (Azilsartan of the Azilsartan of 4.3g
Purity: 99.7%).
[comparative example 5] (using the manufacture of the above-mentioned Azilsartan methyl esters of the method for the record of non-patent literature 1)
The compound containing ester protecting group is measured in the 200mL three-necked flask for having 2 stirring blades of diameter 5cm
(R in above-mentioned formula (3)1For methyl, R2For the compound of 2- ethylhexyl) 10g, dimethylbenzene 100mL is added, is heated to reflux temperature
After (about 130 DEG C), carry out reacting for 2 hours at such a temperature.Solution after reaction is concentrated under reduced pressure, acetic acid second is added in residue
Ester 100mL is warming up to reflux temperature (about 80 DEG C), dissolves the crystallization of concentrated residue fully.Obtained solution is cooled to
It 20 DEG C, is stirred 12 hours at 20 DEG C.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, subtract at 40 DEG C
Press dry it is dry, obtain the Azilsartan methyl esters of 4.1g crystallization (purity of Azilsartan methyl esters: 88.3%, above-mentioned de- ethyl body:
0.34%, above-mentioned dimer: 0.27%)) (yield: 50.2%).The impurity of molecular weight bigger than Azilsartan methyl esters 10 is
10.8%.In addition, measuring XRD using the Azilsartan methyl esters as sample, obtaining X-ray diffractogram shown in Fig. 4, know
The crystallization is to give the compound of characteristic peak in 2 θ=8.0 °, 10.4 °, 12.0 °, 15.9 °, 21.4 °.Result is summarized in table 6.
In turn, DSC measurement is carried out, as shown in Figure 6, is able to confirm that have at 193.6 DEG C (melting caloric 76.619J/g) and melt
Point.
【Table 5】
Table 5
* the numerical value in parantheses indicates the volume ratio of solvent.
The usage amount (ml) of the every 1g object Azilsartan Arrcostab of *
The impurity of * * molecular weight bigger than Azilsartan methyl esters 10
[table 6]
Table 6
D. other embodiments
[Production Example 4] (manufacture of Azilsartan methyl esters)
(ester protection reaction)
Above-mentioned amidoxime compound (R is measured in the 2L four-hole boiling flask for having 2 stirring blades of diameter 15cm1For first
The compound of base) 120g (270.0mmol), methylene chloride 840mL, triethylamine 33.0g (324.0mmol) is added, while stirring
It is cooled to 0 DEG C.It is added dropwise at leisure in obtained solution and ethyl chloroformate 35.4g (324.0mmol) is used into methylene chloride 360mL
Solution made of dilution.After whole amount is instilled, reacted on 0 DEG C of following stirring, 2 hours sides.Solution after reaction is warming up to 20
DEG C, water 480mL is added, organic layer is extracted out.Obtained organic layer is concentrated under reduced pressure, is obtained as residue above-mentioned containing ester protection
Compound (the R of base1For methyl, R2For the compound of ethyl).For the purity of the above-mentioned compound containing ester group: 96.1%, above-mentioned
Amidoxime compound: 0.14%.
(cyclization)
1- propyl alcohol 960mL is added in the residue after above-mentioned reduced pressure, after being heated to reflux temperature (about 95 DEG C), at this
At a temperature of carry out 12 hours react.For the purity of above-mentioned Azilsartan methyl esters: 91.5%, the above-mentioned chemical combination containing ester protecting group
Object: 1.8%.Reaction solution after reaction is cooled to 0 DEG C with 20 DEG C/h of speed, is stirred 14 hours at 0 DEG C.It connects down
Come, obtained slurries are filtered under diminished pressure, divides the crystallization for taking precipitation, be dried under reduced pressure at 40 DEG C, obtain the above-mentioned A Qi of 107.6g
(purity of Azilsartan methyl esters: 97.3%, above-mentioned Azilsartan methyl esters takes off ethyl body: 0.14%, above-mentioned for the crystallization of husky smooth methyl esters
Azilsartan methyl esters dimer: 0.20%) (yield: 84.7%).In addition, not can confirm that molecular weight is bigger than Azilsartan methyl esters by 10
Impurity.
[Production Example 5] (recrystallization of Azilsartan methyl esters)
A Qi obtained in Production Example 4 is measured in the 1000mL three-necked flask for having 2 stirring blades of diameter 10cm
Husky smooth methyl esters 90g, is added acetone 900mL, is heated to reflux temperature (about 57 DEG C), Azilsartan methyl esters is dissolved.After dissolution, with
20 DEG C/h of speed is cooled to 0 DEG C, stirs 12 hours at 0 DEG C.Next, obtained slurries are filtered under diminished pressure, divide and take analysis
Crystallization out is dried under reduced pressure at 40 DEG C, obtain the Azilsartan methyl esters of 78.9g crystallization (purity of Azilsartan methyl esters:
99.1%, above-mentioned de- ethyl body: 0.02%, above-mentioned Azilsartan methyl esters dimer: 0.07%) (yield: 87.7%).In addition,
The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.
[Production Example 6] (using the manufacture of the Azilsartan methyl esters of the method for the record of non-patent literature 1)
(ester protection reaction)
Above-mentioned amidoxime compound (R is measured in the 500mL four-hole boiling flask for having 2 stirring blades of diameter 7.5cm1
For the compound of methyl) 30g (67.5mmol), dimethylformamide 120mL, pyridine 5.9g (74.3mmol), side stirring is added
While being cooled to 0 DEG C.Chloro-carbonic acid -2- ethylhexyl 13.0g (67.5mmol) is added dropwise at leisure in obtained solution.By whole amount
After instillation, reacted on 0 DEG C of following stirring, 1 hour side.Solution after reaction is warming up to 20 DEG C, ethyl acetate 270mL, water is added
60mL extracts organic layer out.After obtained organic layer is further cleaned with water 60mL, organic layer is concentrated under reduced pressure, as residual
Slag obtains the above-mentioned compound (R containing ester protecting group1For methyl, R2For the compound of 2- ethylhexyl).Contain ester group to be above-mentioned
Compound purity: 94.5%, above-mentioned amidoxime compound: 1.26%.
(cyclization)
Dimethylbenzene 420mL is added in the residue after above-mentioned reduced pressure, after being heated to reflux temperature (about 130 DEG C),
It carries out reacting for 2 hours at this temperature.Solution after reaction is concentrated under reduced pressure, ethyl acetate 420mL is added in residue, is warming up to
Reflux temperature (about 80 DEG C), the crystallization of concentrated residue is fully dissolved.Obtained solution is cooled to 20 DEG C, is stirred at 20 DEG C
It mixes 12 hours.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, be dried under reduced pressure, obtain at 40 DEG C
Crystallization (the purity of Azilsartan methyl esters: 88.3%, above-mentioned de- ethyl body: 0.36%, above-mentioned of the Azilsartan methyl esters of 15.9g
Azilsartan methyl esters dimer: 0.27%)) (yield: 50.1%).The impurity of molecular weight bigger than Azilsartan methyl esters 10 is
10.8%.
[embodiment 24] (manufacture of Azilsartan；Active charcoal processing)
(hydrolysis)
A Qi obtained in Production Example 5 is measured in the 100mL three-necked flask for having 2 stirring blades of diameter 3.5cm
Husky smooth methyl esters 5g, is added 1.25M sodium hydrate aqueous solution 40mL, after being heated to 70 DEG C, carries out reacting for 2 hours at such a temperature.
For the Azilsartan purity of the thick Azilsartan solution after reaction: 99.61%, Azilsartan takes off ethyl body: 0.06%, A Qisha
Smooth dimer: 0.08%.By after reaction the Azilsartan purity of thick Azilsartan solution and the result of impurity level be shown in table 7
In.
(active carbon processing)
After solution after the completion of hydrolysis is cooled to 30 DEG C, purification egression is added, and (table is compared in gas chemistry manufacture in Osaka
Area: 1430m2/ g, accumulative pore volume: 1.17mL/g) 0.24g, it carries out stirring for 1 hour at 20~30 DEG C.For active carbon
The Azilsartan purity of treated solution: 99.85%, Azilsartan takes off ethyl body: 0.05%, Azilsartan dimer:
0.01%.
(removing and purification of active carbon)
Next, be filtered under diminished pressure, purification egression is removed, after obtained filtrate is heated to 40 DEG C, at such a temperature plus
Enter acetone 25mL, acetic acid 17mL, water 17mL, the crystallization of Azilsartan is precipitated.Reaction solution is cooling with 20 DEG C/h of speed
To after 20 DEG C, stir 6 hours at such a temperature.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, 40
It is dry at DEG C, obtain the crystallization (yield: 95.6%) of the Azilsartan of 4.6g.For the purity of above-mentioned Azilsartan: 99.89%,
Azilsartan takes off ethyl body: 0.03%, Azilsartan dimer: not detecting, unknown impurity: not detecting.It shows the result in
In table 8.
[embodiment 25~26]
(hydrolysis)
In addition to use the Azilsartan Arrcostab of Production Example shown in table 7 as raw material other than, similarly to Example 24
Reaction is hydrolyzed in ground.By after hydrolysis the purity of thick Azilsartan solution and the measurement result of impurity level be shown in Table 7.
((active carbon processing), (removing and purification of active carbon))
In addition, carrying out (active carbon processing), (active carbon using method similarly to Example 24 to the solution after hydrolysis
Removing and purification), obtain the crystallization of Azilsartan.Crystallization for obtained Azilsartan is carried out similarly purity and miscellaneous
The measurement of quality.It the results are shown in table 8.
[embodiment 27~28]
(hydrolysis)
Reaction is hydrolyzed similarly to Example 24.By the purity of the thick Azilsartan solution after reaction and impurity level
Measurement result is shown in Table 7.
(active carbon processing)
In addition, other than the usage amount of active carbon when changing active carbon processing as shown in table 8, with embodiment
24 are carried out similarly processing.
(removing and purification of active carbon)
About the removing and purification of active carbon, operation similarly to Example 24 is carried out.For obtained Azilsartan
Crystallization carries out the measurement of purity and impurity level.It the results are shown in table 8.
[embodiment 29~32]
(hydrolysis)
Reaction is hydrolyzed similarly to Example 24.By the purity of the thick Azilsartan solution after reaction and impurity level
Measurement result is shown in Table 7.
(active carbon processing)
In addition, other than the type of active carbon when changing active carbon processing as shown in table 8, usage amount, with
Embodiment 24 is carried out similarly processing.The characteristic that active carbon used in embodiment is summarized in table 9 is (specific surface area, accumulative
Pore volume).
(removing and purification of active carbon)
About the removing and purification of active carbon, operation similarly to Example 24 is carried out.For obtained Azilsartan
Crystallization carries out the measurement of purity and impurity level.It the results are shown in table 8.
[reference example 1] (manufacture of Azilsartan；Inactive charcoal processing)
A Qi obtained in Production Example 4 is measured in the 100mL three-necked flask for having 2 stirring blades of diameter 3.5cm
Husky smooth methyl esters 5g, is added 1.25M sodium hydrate aqueous solution 40mL, after being heated to 70 DEG C, carries out reacting for 2 hours at such a temperature.
For the Azilsartan purity of the thick Azilsartan solution after reaction: 98.98%, Azilsartan takes off ethyl body: 0.20%, A Qisha
Smooth dimer: 0.22%.By after reaction the Azilsartan purity of thick Azilsartan solution and the result of impurity level be shown in table 7
In.
Next, acetone 25mL, acetic acid 17mL, water are added at such a temperature after obtained reaction solution is cooled to 45 DEG C
The crystallization of Azilsartan is precipitated in 17mL.After reaction solution is cooled to 20 DEG C with 20 DEG C/h of speed, stir at such a temperature
It mixes 6 hours.Next, obtained slurries are filtered under diminished pressure, point take the crystallization of precipitation, it is dry at 40 DEG C, obtain 4.7g Ah
Crystallization (the yield: 96.5%) of Qi Shatan.For the purity of above-mentioned Azilsartan: 99.17%, Azilsartan takes off ethyl body:
0.15%, it Azilsartan dimer: 0.20%, unknown impurity: does not detect.It shows the result in table 8.
[reference example 2~3] (manufacture of Azilsartan；Inactive charcoal processing)
In addition to use the Azilsartan Arrcostab of Production Example shown in table 7 as raw material other than, in the same manner as reference example 1
Reaction is hydrolyzed.By after reaction the purity of thick Azilsartan solution and the measurement result of impurity level be shown in Table 8.
In addition, the crystallization of Azilsartan is taken out from the reaction solution obtained using method same as reference example 1.For
The crystallization of obtained Azilsartan is carried out similarly the measurement of purity and impurity level.It the results are shown in table 8.
[table 7]
Table 7
* the impurity of molecular weight bigger than Azilsartan methyl esters 10
[table 8]
Table 8
* the impurity of molecular weight bigger than Azilsartan methyl esters 10
The usage amount (g) of the every 1g Azilsartan of *
[table 9]
Table 9
E. other embodiments
[embodiment 33]
(first step: hydroxyl amidination)
Above-mentioned nitrile compound 70g is measured in the 1L four-hole boiling flask for having 2 stirring blades of diameter 10cm
1- propyl alcohol 700mL, triethylamine 5.16g (51.0mmol), commercially available 50 mass % aqueous hydroxylamine is added in (170.1mmol)
56.2g (850.5mmol) after being heated to reflux temperature (about 92 DEG C), carries out reacting for 13 hours at such a temperature.To be above-mentioned together with amine
The purity of oxime compound: 83.5%, above-mentioned amide body: 2.5%, above-mentioned nitrile compound: 2.4%, above-mentioned amidoxim takes off ethyl body:
7.6%, above-mentioned amide takes off ethyl body: 0.6%, the de- ethyl body of above-mentioned nitrile: 0.01%.
Solution after reaction is cooled to 20 DEG C with 20 DEG C/h of speed, is stirred 13 hours at 20 DEG C.Next,
Obtained slurries are filtered under diminished pressure, the crystallization for taking precipitation is divided, it is dry at 50 DEG C, obtain the above-mentioned amidoxime compound of 60.9g
The crystallization (purity of above-mentioned amidoxime compound: 96.6%, above-mentioned amide body: 0.6%, above-mentioned nitrile compound: 0.1%, above-mentioned
Amidoxim takes off ethyl body: 0.6%, above-mentioned amide takes off ethyl body: 0.1%, above-mentioned nitrile takes off ethyl body: not detecting) (yield:
80.6%).
(the second step: cyclisation)
Above-mentioned amidoxime compound 60g is measured in the 1L four-hole boiling flask for having 2 stirring blades of diameter 10cm
(135.0mmol) is added methylene chloride 420mL, triethylamine 16.4g (162.0mmol), is cooled to 0 DEG C while stirring.It is obtaining
Solution in be slowly added dropwise by ethyl chloroformate 17.6g (162.0mmol) with methylene chloride 180mL dilute made of solution.
After whole amount is instilled, reacted on 0 DEG C of following stirring, 2 hours sides.Solution after reaction is warming up to 20 DEG C, water 240mL is added,
Organic layer is extracted out.It is after obtained organic layer is cleaned with 10% saline solution 240mL, the solvent in organic layer is dense under reduced pressure
Contracting, the compound (compound purity containing ester protecting group: 96.4%) containing ester protecting group is obtained as residue.
1- propyl alcohol 480mL is added in obtained residue to carry out at such a temperature after being heated to reflux temperature (about 92 DEG C)
It reacts within 12 hours.For the purity of above-mentioned Azilsartan methyl esters: 91.7%, the above-mentioned compound containing ester protecting group: 1.7%.It will
Reaction solution after reaction is cooled to 4 DEG C with 20 DEG C/h of speed, stirs 12 hours at 4 DEG C.Next, will obtain
Slurries are filtered under diminished pressure, and are divided the crystallization for taking precipitation, are dried under reduced pressure at 40 DEG C, obtain the knot of the object Azilsartan methyl esters of 54.0g
It is brilliant that (purity of object Azilsartan Arrcostab: 97.5%, above-mentioned Azilsartan methyl esters takes off ethyl body: 0.09%, above-mentioned A Qisha
Smooth methyl esters dimer: 0.15%) (yield: 85.0%).The impurity of molecular weight bigger than Azilsartan methyl esters 10 is not can confirm that.
(the third step: AL-02 purification)
Object Azilsartan methyl esters 50g is measured in the 1L four-hole boiling flask for having 2 stirring blades of diameter 10cm, is added
Acetone 500mL is heated to reflux temperature (about 57 DEG C), and object Azilsartan methyl esters is dissolved.After dissolution, with 20 DEG C/h
Speed is cooled to 0 DEG C, stirs 16 hours at 0 DEG C.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation,
Be dried under reduced pressure at 40 DEG C, obtain the Azilsartan methyl esters of 44.0g crystallization (purity of Azilsartan methyl esters: 98.9%, above-mentioned Ah
Qi Shatan methyl esters takes off ethyl body: not detecting, above-mentioned Azilsartan methyl esters dimer: 0.04%) (yield: 88.1%).
(the fourth step: hydrolysis)
Above-mentioned Azilsartan methyl esters 40g is measured in the 1L four-hole boiling flask for having 2 stirring blades of diameter 10cm, is added
1.25M sodium hydrate aqueous solution 260mL after being heated to 70 DEG C, carries out reacting for 2 hours at such a temperature.For after reaction thick Ah
The Azilsartan purity of Qi Shatan solution: 99.69%, Azilsartan takes off ethyl body: 0.05%, Azilsartan dimer:
0.04%.
After solution after the completion of hydrolysis is cooled to 30 DEG C, purification egression is added, and (table is compared in gas chemistry manufacture in Osaka
Area: 1430m2/ g, accumulative pore volume: 1.17mL/g) 2.0g, it carries out stirring for 1 hour at 20~30 DEG C.At active carbon
The Azilsartan purity of solution after reason: 99.85%, Azilsartan takes off ethyl body: 0.04%, Azilsartan dimer: not examining
It measures.
Next, be filtered under diminished pressure, purification egression is removed, after obtained filtrate is heated to 40 DEG C, at such a temperature plus
Enter methanol 260mL, acetic acid 29.2mL, the crystallization of Azilsartan is precipitated.Reaction solution is cooled to 20 with 20 DEG C/h of speed
After DEG C, stir 6 hours at such a temperature.Next, obtained slurries are filtered under diminished pressure, divide the crystallization for taking precipitation, at 40 DEG C
It is dry, obtain the Azilsartan (purity of above-mentioned Azilsartan: 99.88%, the de- ethyl body of Azilsartan: 0.02%, of 38.2g
Azilsartan dimer: do not detect) crystallization (yield: 95.5%).
(the 5th process: AZL purification)
Above-mentioned Azilsartan 35g is measured in the 1L four-hole boiling flask for having 2 stirring blades of diameter 10cm, is packed into diformazan
Base formamide 70mL, dissolves by heating at 30 DEG C.It is cooling after ethyl acetate 350mL is added in obtained Azilsartan solution
To 5 DEG C, stir 15 hours.Next, being filtered under diminished pressure, divide the crystallization for taking precipitation, it is dry at 50 DEG C, obtain the A Qi of 34.7g
Crystallization (the yield: 99.2%) of Sha Tan.Using the Azilsartan as sample, XRD is measured, X-ray diffraction shown in fig. 7 is obtained
Figure knows that the crystallization is with the novel knot for giving characteristic peak in 2 θ=9.41 °, 11.52 °, 13.33 °, 14.81 °, 26.01 °
The compound of crystal structure.In addition, the fusing point for using DSC to measure is 127 DEG C.
Claims (26)
1. 2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4- base] the methyl] -1H- benzimidazole-indicated by following formula (2)
The manufacturing method of 7- alkyl carboxylates, which is characterized in that make in the reaction dissolvent of the alcohol comprising carbon atom number 2~7 by following
1- [(2'- cyanobiphenyl -4- base) the methyl] -2- ethoxybenzoimidazole -7- alkyl carboxylates and hydroxylamine that formula (1) indicates
And/or the reaction of hydroxyl amino acid salt,
[changing 1]
In formula, R1For 1~4 alkyl of carbon atom number,
[changing 2]
In formula, R1With the R in above-mentioned formula (1)1It is synonymous.
2. the manufacturing method according to claim 1, wherein reacted in the presence of base.
3. manufacturing method according to claim 2, wherein the alkali includes organic base.
4. manufacturing method according to claim 3, wherein relative to 1- [(2'- cyanobiphenyl-shown in the formula (1)
4- yl) methyl] 1 mole of alkyl carboxylates of -2- ethoxybenzoimidazole -7-, the use level of the organic base is rubbed for 0.01~0.5
You.
5. the manufacturing method according to claim 1, wherein the alcohol is the straight-chain or branch-like of carbon atom number 3~7
Alcohol.
6. the manufacturing method according to claim 1, wherein use the hydroxylamine, and the reaction dissolvent includes water.
7. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by following formula (4)
Benzene -4- base] methyl] benzimidazole -7- alkyl carboxylates manufacturing method, which is characterized in that using according to claim 1~6
Any one of described in manufacturing method manufacture 2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4- base] shown in the formula (2)
Methyl] after -1H- benzimidazole -7- alkyl carboxylates, use obtained 2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4-
Base] methyl] -1H- benzimidazole -7- alkyl carboxylates,
[changing 3]
In formula, R1With the R in the formula (1)1It is synonymous.
8. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by following formula (5)
Benzene -4- base] methyl] benzimidazole -7- carboxylic acid manufacturing method, which is characterized in that use system according to claim 7
It makes method and manufactures the 2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- indicated by above-mentioned formula (4)
Base) biphenyl -4- base] methyl] after benzimidazole -7- alkyl carboxylates, to obtained 2- ethyoxyl -1- [[2'- (2,5- dihydros -
5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- alkyl carboxylates are hydrolyzed,
[changing 4]
9. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by following formula (4)
Benzene -4- base] methyl] benzimidazole -7- alkyl carboxylates manufacturing method, which is characterized in that including carbon atom number 1~8
To 2- ethyoxyl -1- [[2'- (alkoxy-carbonyloxy group amidino groups) biphenyl -4- indicated by following formula (3) in the reaction dissolvent of alcohol
Base] methyl] -1H- benzimidazole -7- alkyl carboxylates progress cyclization,
[changing 5]
In formula, R1For alkyl, R2For protect hydroxyl protecting group,
[changing 6]
In formula, R1With the R in above-mentioned formula (3)1It is synonymous.
10. manufacturing method according to claim 9, wherein below 50 DEG C or more and the reflux temperature of reaction solution into
The row cyclization.
11. manufacturing method according to claim 9, wherein the alcohol is the straight-chain or branch-like of carbon atom number 3~8
Alcohol.
12. manufacturing method according to claim 9, wherein carry out the cyclization in the presence of base.
13. manufacturing method according to claim 12, wherein relative to the 2- ethyoxyl -1- indicated by the formula (3)
1 mole of alkyl carboxylates of -1H- benzimidazole -7- of [[2'- (alkoxy-carbonyloxy group amidino groups) biphenyl -4- base] methyl], the alkali
Usage amount be 0.01~5 mole.
14. manufacturing method according to claim 12 or 13, wherein the alkali is organic base.
15. manufacturing method according to claim 9, wherein make the 2- indicated by the formula (4) in the reaction dissolvent
Ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic
The crystallization of acid alkyl ester is precipitated.
16. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by following formula (5)
Benzene -4- base] methyl] benzimidazole -7- carboxylic acid manufacturing method, which is characterized in that using according in claim 9~15 appoint
2- ethyoxyl -1- that the manufacture of manufacturing method described in one is indicated by the formula (4) [[2'- (oxo -1,2 2,5- dihydro -5-,
4- oxadiazoles -3- base) biphenyl -4- base] methyl] after benzimidazole -7- alkyl carboxylates, to obtained 2- ethyoxyl -1- [[2'-
(2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- alkyl carboxylates progress water
Solution,
[changing 7]
17. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by the formula (4)
Benzene -4- base] methyl] benzimidazole -7- alkyl carboxylates, which is characterized in that in the X-ray diffraction using Cu-K α line, at least
There is characteristic peak in 2 θ=9.9 ± 0.2 °, 10.9 ± 0.2 °.
18.2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzo
The manufacturing method of imidazoles -7- alkyl carboxylates, which is characterized in that make under in the in the mixed solvent of acetone or acetone and alcohol
State 2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] first of formula (4) expression
Base] benzimidazole -7- alkyl carboxylates crystallization,
[changing 8]
In formula, R1For alkyl.
19. manufacturing method according to claim 18, wherein the R in the formula (4)1For methyl.
20.2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzo
Imidazoles -7- carboxylate methyl ester, which is characterized in that according to the X-ray diffraction for using Cu-K α line, at least 2 θ=9.2 ± 0.2 °,
15.8 ± 0.2 °, 22.1 ± 0.2 ° have characteristic peak.
21.2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzo
Imidazoles -7- carboxylate methyl ester, which is characterized in that at least in 150~165 DEG C of temperature range and 185~195 DEG C of temperature range tool
There is fusing point.
22. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by following formula (5)
Benzene -4- base] methyl] benzimidazole -7- carboxylic acid manufacturing method, which is characterized in that use system according to claim 18
It makes method and manufactures the 2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- indicated by the formula (4)
Base) biphenyl -4- base] methyl] after benzimidazole -7- alkyl carboxylates, to obtained 2- ethyoxyl -1- [[2'- (2,5- dihydros -
5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- alkyl carboxylates are hydrolyzed,
[changing 9]
23. [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) joins the 2- ethyoxyl -1- indicated by following formula (5)
Benzene -4- base] methyl] benzimidazole -7- carboxylic acid manufacturing method, which is characterized in that according to claim 20 or 21
2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7-
Carboxylate methyl ester is hydrolyzed,
[changing 10]
24.2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzo
The manufacturing method of imidazoles -7- carboxylic acid is the 2- indicated according to any one of claim 8,16,22 by following formula (5)
Ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic
The manufacturing method of acid, which is characterized in that include the A Qisha indicated by following formula (6) for using active carbon that will contain as impurity
The process that smooth dimer removes,
[changing 11]
[changing 12]
25.2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzo
The manufacturing method of imidazoles -7- carboxylic acid is the 2- indicated according to any one of claim 8,16,22 by following formula (5)
Ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic
The manufacturing method of acid, which is characterized in that include following processes: making the 2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxos -
1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic acid is molten obtained from dimethylformamide
The solvent of ketone or esters is added in liquid, makes the 2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxos -1,2,4- oxadiazoles -3-
Base) biphenyl -4- base] methyl] precipitation of benzimidazole -7- carboxylic acid,
[changing 13]
26.2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzo
The manufacturing method of imidazoles -7- carboxylic acid, which is characterized in that obtained using the manufacturing method according to claim 1 by following formula
(2) 2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4- base] methyl] -1H- benzimidazole -7- alkyl carboxylates indicated,
By the 2- ethyoxyl -1- [[2'- (oximido amido) biphenyl -4- base] methyl] -1H- benzimidazole -7- alkyl carboxylates, obtain
2- ethyoxyl -1- [[2'- (alkoxy-carbonyloxy group amidino groups) biphenyl -4- base] the methyl] -1H- benzo miaow indicated by following formula (3)
Azoles -7- carboxylate, using manufacturing method according to claim 9, by the 2- ethyoxyl -1- [[2'- (alkoxy-carbonyl
Oxygroup amidino groups) biphenyl -4- base] methyl] and -1H- benzimidazole -7- alkyl carboxylates obtain by following formula (4) indicate 2- ethoxy
Base -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic acid alkane
Base ester, using manufacturing method according to claim 21, by the 2- ethyoxyl -1- [[2'- (2,5- dihydro -5- oxos -
1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] and benzimidazole -7- alkyl carboxylates obtain by following formula (5) indicate 2-
Ethyoxyl -1- [[2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic
Acid,
[changing 14]
In formula, R1With the R in the formula (1)1It is synonymous,
[changing 15]
In formula, R1For alkyl, R2For protect hydroxyl protecting group,
[changing 16]
In formula, R1With the R in the formula (3)1It is synonymous,
[changing 17]
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
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| JP2016-133605 | 2016-07-05 | ||
| JP2016133605A JP6676487B2 (en) | 2016-07-05 | 2016-07-05 | Method for producing amidoxime compound as intermediate of azilsartan, and method for producing azilsartan |
| JP2016138165A JP6676491B2 (en) | 2016-07-13 | 2016-07-13 | Method for producing azilsartan alkyl ester and method for producing azilsartan |
| JP2016-138165 | 2016-07-13 | ||
| JP2016-219237 | 2016-11-09 | ||
| JP2016219237A JP2018076258A (en) | 2016-11-09 | 2016-11-09 | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| JP2016232241A JP6856365B2 (en) | 2016-11-30 | 2016-11-30 | Manufacturing method of azilsartan |
| JP2016-232241 | 2016-11-30 | ||
| PCT/JP2017/014529 WO2018008219A1 (en) | 2016-07-05 | 2017-04-07 | Azilsartan intermediate, azilsartan, method for producing azilsartan intermediate, and method for producing azilsartan |
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| JP6856365B2 (en) * | 2016-11-30 | 2021-04-07 | 株式会社トクヤマ | Manufacturing method of azilsartan |
| JP7486763B2 (en) * | 2019-06-21 | 2024-05-20 | 金剛化学株式会社 | Method for producing stable fine crystals of azilsartan |
| CN110519838B (en) | 2019-08-06 | 2021-07-13 | 三维通信股份有限公司 | Time division duplex synchronization method, apparatus, device and medium for distributed antenna system |
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| IL102183A (en) * | 1991-06-27 | 1999-11-30 | Takeda Chemical Industries Ltd | Biphenyl substituted heterocyclic compounds their production and pharmaceutical compositions comprising them |
| BR0107456A (en) * | 2000-01-07 | 2002-10-08 | Transform Pharmaceuticals Inc | Sample formation, methods of preparing a formation of multiple solid forms of a compound of interest, of screening a plurality of solid forms of a compound of interest and conditions and / or components for compatibility with one or more selected solid forms of a compound of interest, to identify optimal solid forms of a compound of interest and to determine sets of conditions and / or components to produce solid forms of a compound of interest, a set of processing parameters and / or components and the conditions and / or components that produce a compound of interest or a diastereomeric derivative and system for identifying optimal solid forms of a compound of interest |
| CN102344415B (en) * | 2010-07-29 | 2016-04-13 | 上海医药工业研究院 | The preparation method of Azilsartan intermediate |
| CN103664920B (en) * | 2012-09-24 | 2016-03-09 | 上海医药工业研究院 | Azilsartan intermediate and the preparation method with Azilsartan thereof |
| CN103664792B (en) * | 2012-09-24 | 2016-03-30 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
| CN103664793B (en) * | 2012-09-24 | 2017-04-19 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
| CN104418807A (en) * | 2013-09-09 | 2015-03-18 | 天津药物研究院 | Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof |
| CN103554031B (en) * | 2013-11-01 | 2015-04-15 | 深圳科兴生物工程有限公司 | Preparation method of azilsartan intermediate |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
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