CN102149669A - Process for producing carbonyloxy compound - Google Patents
Process for producing carbonyloxy compound Download PDFInfo
- Publication number
- CN102149669A CN102149669A CN2009801350565A CN200980135056A CN102149669A CN 102149669 A CN102149669 A CN 102149669A CN 2009801350565 A CN2009801350565 A CN 2009801350565A CN 200980135056 A CN200980135056 A CN 200980135056A CN 102149669 A CN102149669 A CN 102149669A
- Authority
- CN
- China
- Prior art keywords
- oxycompound
- carbonyl
- formula
- reaction
- expression
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CCC1(*)CCCCC1 Chemical compound CCC1(*)CCCCC1 0.000 description 5
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for carbonyloxy compound production is provided which comprises reacting an aniline compound with a nitrous acid salt in the presence of an acid to synthesize a diazonium salt and subsequently reacting the diazonium salt with an Alpha, Beta-unsaturated carbonyloxy compound in the presence of a copper catalyst to produce the desired carbonyloxy compound. This process is characterized in that the reaction between the diazonium salt and the Alpha, Beta-unsaturated carbonyloxy compound is conducted in the presence of a base having an acid dissociation index (pKa) at 25 DEG C of 7 or lower. According to the process, methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}propionate as an intermediate for a therapeutic agent that produces an excellent effect on type 2 diabetes, which is caused by a deficiency in the action of insulin, and other compounds can be highly efficiently obtained so as to have a high purity.
Description
Technical field
The present invention relates to use aniline compound and α, β-unsaturated carbon compound is as the new preparation method of the carbonyl oxycompound of feedstock production.Especially, relate to new preparation method as the useful carbonyl oxycompound of the preparation raw material of the former medicine that is used for the treatment of the diabetes B that causes because of the insulin action deficiency etc. or intermediate.
Background technology
Pioglitazone, ciglitazone and rosiglitazone etc. demonstrate the therapeutical agent (basic framework of therapeutical agent has been shown in the formula (10)) of excellent results at the diabetes B that is caused by the insulin action deficiency, adopt the method via the carbonyl oxycompound of following formula (8) expression to prepare in the past.
[changing 1]
The carbonyl oxycompound of formula (8) expression uses the aniline compound of formula (7) expression, adopts meerwein arylation (Meerwein arylation) to prepare (referring to for example non-patent literature 1 and patent documentation 1).This reaction is in the presence of hydrogen bromide, the reaction that diazonium salt that the aniline compound prepared in reaction by the expression of nitrite and formula (7) forms and carbonyl compound are reacted in the presence of copper catalyst.
The sharp document 1:Journal of non-patent of Medicinal Chemistry, 35 volumes, No. 14,2617-2626 (1992)
Patent documentation 1: special fair 5-66956 communique
Summary of the invention
The problem that invention will solve
As mentioned above, according to the method for record in non-patent literature 1 or the patent documentation 1, can preparation formula (8) the carbonyl oxycompound of expression.
But, in meerwein arylation, carry out various side reactions simultaneously.Therefore, when adopting above-mentioned prepared in reaction carbonyl oxycompound, aspect yield and purity, existence is room for improvement further.Especially, when the carbonyl oxycompound as formula (8) expression of the intermediate of former medicine contains impurity, be difficult to obtain highly purified former medicine with high yield.Therefore, in the reaction of this carbonyl oxycompound of preparation, the special generation of wishing to suppress impurity.
The objective of the invention is to, the method that can prepare highly purified carbonyl oxycompound with high yield is provided.
Solve the means of problem
The inventor has carried out deep research in order to solve above-mentioned problem.Found that, in the presence of acid, make the synthetic diazonium salt of aniline compound and nitrite reaction, then, in the presence of copper catalyst, use this diazonium salt and α, β-when unsaturated carbonyl oxycompound carries out meerwein arylation, there is alkali in the reaction system if make, then can suppresses side reaction, thereby can prepare highly purified carbonyl oxycompound with high yield with specific acid dissociation exponent.The present invention just is being based on above-mentioned discovery and is finishing.
That is, the present invention is the preparation method of carbonyl oxycompound, and it comprises following operation:
In the presence of hydrogenchloride or hydrogen bromide, make the aniline compound and the nitrite reaction of following formula (1) expression, the diazonium salt synthesis procedure of synthetic diazonium salt; And
In the presence of copper catalyst, make the α of the diazonium salt that obtains in this diazonium salt synthesis procedure and following formula (2) expression, β-unsaturated carbonyl oxycompound reaction, the carbonyl oxycompound synthesis procedure of the carbonyl oxycompound of synthetic following formula (3) expression;
[changing 2]
(in the formula,
R
1Be hydrogen atom, halogen atom, hydroxyl, cyano group or organic group; N is 1～5 integer; When n is 2 when above, R
1It can be identical or different group.)
[changing 3]
(in the formula,
R
2Be hydrogen atom, alkyl, thiazolinyl or aryl;
R
3Be hydrogen atom, alkyl or aryl.)
[changing 4]
(in the formula,
R
1Identical with n with the definition in the above-mentioned formula (1);
R
2And R
3Identical with the definition in the above-mentioned formula (2);
X is chlorine atom or bromine atoms.)
It is characterized in that,
In above-mentioned carbonyl oxycompound synthesis procedure, when making diazonium salt and α, during β-unsaturated carbonyl oxycompound reaction, making acid dissociation exponent (pKa) under having 25 ℃ in the reaction system is alkali below 7.
In carbonyl oxycompound synthesis procedure,, preferably there is 0.05～10 mole above-mentioned alkali with respect to 1 mole of above-mentioned diazonium salt.
It is 4～7 nitrogen-containing heterocycle compound that above-mentioned alkali is preferably acid dissociation exponent (pKa) under 25 ℃.
Preparation method of the present invention comprises 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group as the intermediate of pioglitazone hydrochloride] phenyl } preparation method of methyl propionate.This preparation method can reduce side reaction effectively.
In addition, preparation method of the present invention is 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl }-preparation method of 2-imino--4-thiazolidone, it is characterized in that, make 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group according to above-mentioned preparation method preparation] phenyl } methyl propionate reacts with thiocarbamide in the presence of alkali.
And then, the present invention is 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the preparation method of 4-dione hydrochloride, it is characterized in that, make 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of preparation according to the method described above] benzyl }-2-imino--4-thiazolidone and hcl reaction.
The invention effect
According to the present invention, in meerwein arylation, exist by the alkali that makes regulation, can prepare highly purified carbonyl oxycompound with high yield.Because it is highly purified adopting the carbonyl oxycompound of preparation method's preparation of high yield of the present invention, therefore, the raw material and the intermediate that are particularly suitable as medical former medicine use.Therefore, this preparation method's industrial utilization is worth very high.
Especially, according to the present invention, can prepare as 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group with high yield and high purity ground] benzyl } thiazolidine-2,2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that the raw material of 4-dione hydrochloride uses] phenyl } methyl propionate.
Because 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of preparation in accordance with the present invention preparation] phenyl } methyl propionate is highly purified, therefore, by it is reacted with thiocarbamide, can prepare highly purified 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group with high yield in the presence of alkali] benzyl }-2-imino--4-thiazolidone.
And then, by making highly purified 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that adopts aforesaid method to obtain] benzyl }-2-imino--4-thiazolidone and hcl reaction, can prepare highly purified 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group with high yield] benzyl } thiazolidine-2, the 4-dione hydrochloride.
Embodiment
The preparation method of the carbonyl oxycompound of formula of the present invention (3) expression comprises following operation:
In the presence of hydrogenchloride or hydrogen bromide, make the aniline compound and the nitrite reaction of above-mentioned formula (1) expression, the diazonium salt synthesis procedure of synthetic diazonium salt; And, in the presence of copper catalyst, make the α of the diazonium salt for preparing in this diazonium salt synthesis procedure and above-mentioned formula (2) expression, β-unsaturated carbonyl oxycompound reaction, the carbonyl oxycompound synthesis procedure of the carbonyl oxycompound of synthetic above-mentioned formula (3) expression.
And then, the preparation method of the carbonyl oxycompound of above-mentioned formula (3) expression is characterised in that, in this carbonyl oxycompound synthesis procedure, when making diazonium salt and α, during the reaction of β-unsaturated carbonyl oxycompound, making acid dissociation exponent (pKa) under having 25 ℃ in the reaction system is alkali below 7.
Below, the present invention is described in order.
The diazonium salt synthesis procedure
The diazonium salt synthesis procedure is in the presence of hydrogenchloride or hydrogen bromide, makes the aniline compound and the nitrite reaction of above-mentioned formula (1) expression, synthesizes the operation from the diazonium salt of this aniline compound.
(aniline compound)
In above-mentioned diazonium salt synthesis procedure, be the compound of following formula (1) expression as the aniline compound of raw material:
[changing 5]
(in the formula,
R
1Be hydrogen atom, halogen atom, hydroxyl, cyano group or organic group; N is 1～5 integer; When n is 2 when above, R
1It can be identical or different group.)
Above-mentioned aniline compound can not be subjected to any reagent or industrial raw material of restrictedly using.
In preparation method of the present invention, for the aniline compound of above-mentioned formula (1) expression, R
1Can be the atom of hydrogen atom, halogen atom and so on, also can be the functional group of hydroxyl, cyano group and so on.And then, R
1It also can be organic group.
Work as R
1During for organic group, this organic group does not have particular restriction.Yet, consider from the high viewpoint of purity, yield of the availability of the carbonyl oxycompound that finally obtains and the carbonyl oxycompound that obtains, as R
1Organic group, preferred alkyl or have the group of the ehter bond of following formula (4) expression.
[changing 6]
-O-R
4 (4)
In the formula,
R
4Be preferably the group of alkyl, aryl, following formula (5) or following formula (6) expression.
[changing 7]
(in the formula (5),
R
5And R
6Respectively do for oneself hydrogen atom or alkyl; M is 1～3 integer.)
[changing 8]
(in the formula (6),
R
7And R
8Respectively do for oneself hydrogen atom or alkyl.)
Radicals R in the aniline compound of formula (1) expression
1During for alkyl, consider radicals R from the aspects such as availability of reactive and the carbonyl oxycompound that obtains
1Be preferably the alkyl of carbon number 1～6.Work as radicals R
1During for alkyl,, specifically can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl or cyclohexyl etc. as alkyl.
Radicals R in the aniline compound of formula (1) expression
1Group and R for above-mentioned formula (4) expression
4During for alkyl, as this alkyl, the alkyl of preferred carbon number 1～6.As the concrete example of alkyl, can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl or cyclohexyl etc.
Radicals R in the aniline compound of formula (1) expression
1Group and R for above-mentioned formula (4) expression
4During for aryl,, for example can enumerate phenyl or benzyl etc. as aryl.
Radicals R in the aniline compound of formula (1) expression
1Group and R for above-mentioned formula (4) expression
4During for the group of above-mentioned formula (5) expression, radicals R
5And radicals R
6Respectively do for oneself hydrogen atom or alkyl.M is 1～3 integer.Work as radicals R
5And radicals R
6During for alkyl, as alkyl, the alkyl of preferred carbon number 1～6, can enumerate particularly with in radicals R
1The identical group of alkyl of middle explanation.
Radicals R in the aniline compound of formula (1) expression
1Group and R for above-mentioned formula (4) expression
4During for the group of above-mentioned formula (6) expression, radicals R
7And radicals R
8Respectively do for oneself hydrogen atom or alkyl.As alkyl, the alkyl of preferred carbon number 1～6, can enumerate particularly with in radicals R
1The identical group of alkyl of middle explanation.
In the above-mentioned formula (1), n is 1～5 integer, the expression radicals R
1Number.When n is integer more than 2, radicals R
1Can be different separately groups, also can be identical separately group.Consider that from the high viewpoint of purity, yield of the availability of the carbonyl oxycompound that obtains and the carbonyl oxycompound that obtains n is preferably 1～2.
Below example goes out the aniline compound of above-mentioned formula (1) expression particularly.But it is the situation of raw material that the present invention is not limited to these aniline compounds.
[changing 9]
According to the present invention, by adopting above-mentioned aniline compound, in carbonyl oxycompound synthesis procedure, specific amine is present in the reaction system, can suppress the generation of by product, can obtain highly purified carbonyl oxycompound with high yield.As a result, preparation method of the present invention is applicable to the carbonyl oxycompound of preparation as former medicine intermediate.When above-mentioned aniline compound is 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] during aniline, can more effectively prepare former medicine.
(hydrogenchloride, hydrogen bromide)
In the diazonium salt synthesis procedure, in the presence of hydrogenchloride or hydrogen bromide, make the reaction of above-mentioned aniline compound and nitrite, synthetic diazonium salt from above-mentioned aniline compound.
Hydrogen bromide or hydrogenchloride can not be subjected to any reagent or industrial raw material of restrictedly using.For hydrogenchloride or hydrogen bromide, consider the hydrochloric acid of preferred aqueous solutions state or Hydrogen bromide (below be referred to as hydrochloric acid and Hydrogen bromide, also be expressed as " acid " sometimes) from the viewpoint of the simplicity of operation.The concentration of acid is high more, and speed of response is big more, can suppress the generation of impurity more.Therefore, under the situation that adopts hydrochloric acid, the concentration of preferably using hydrogenchloride is the concentrated hydrochloric acid commonly used about 35 quality %.In addition, adopting under the hydrobromic situation, the concentration of preferably using hydrogen bromide is the Hydrogen bromide commonly used about 47 quality %.
By stoichiometry, the usage quantity of acid is 2 times of molar weights of aniline compound.Therefore, for the usage quantity of acid, with respect to 1 mole of above-mentioned aniline compound, hydrogenchloride or hydrogen bromide are preferably more than 2 moles.Radicals R when the aniline compound of above-mentioned formula (1)
1For can be the time, consider the preferred usage quantity that increases acid from the aspect of the amount that forms this salt with the salifiable functional group of sour shape.For example, work as radicals R
1Be the basic group of pyridyl and so on, under the salifiable situation of sour shape, according to radicals R
1Number increase acid usage quantity.For example, basic group R
1During 1 of bonding (during n=1), with respect to 1 mole of this aniline compound, the preferred usage quantity of hydrogenchloride or hydrogen bromide is 3～5 moles on aniline compound.
As mentioned above, preparation method of the present invention is applicable to the preparation method as the carbonyl oxycompound of former medicine intermediate.When using 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline is during as above-mentioned aniline compound, considers that from the good viewpoints such as yield of the carbonyl oxycompound that obtains employed acid is preferably Hydrogen bromide.
(nitrite)
The nitrite that uses among the present invention can not be subjected to any reagent or industrial raw material of restrictedly using.As nitrite, can enumerate Sodium Nitrite, potassium nitrite etc.
Consider that from the viewpoint of the yield that improves diazonium salt the usage quantity of nitrite with respect to 1 mole of above-mentioned aniline compound, is preferably more than 1 mole.In addition, consider economy, the usage quantity of nitrite with respect to 1 mole of above-mentioned aniline compound, more preferably 1～5 mole, more preferably 1～3 mole, is preferably 1～2 mole especially.
Nitrite can directly add in the reaction solution with solid state to former state.Yet in general, preferably the aqueous solution with nitrite splashes in the reaction solution.Under this situation, consider, be used to dissolve the amount of the water of nitrite, with respect to nitrite 1g, be preferably 1～3ml, more preferably 1.2～2.5ml from the solvability of nitrite and economy.
(other reaction conditionss)
In the diazonium salt synthesis procedure, the synthesis condition of diazonium salt considers that the raising of speed of response, the adjustment of temperature of reaction, the minimizing of side reaction thing wait to determine.Building-up reactions is preferably implemented in organic solvent.The solvent that organic solvent is preferably molten with water.Specifically can enumerate ketones such as acetone, butanone; Alcohols such as methyl alcohol, ethanol; Ethers such as tetrahydrofuran (THF); Nitriles such as acetonitrile.As these organic solvents, can not be subjected to any reagent or industrial raw material solvent of restrictedly using.Solvent can be used singly or two or more kinds mixed.Consider from the solubleness of speed of response, raw material, the solubleness of gained diazonium salt, the high aspect of selection rate of gained diazonium salt, as solvent, preferred ketone, alcohols.In addition, the also preferred mixed solvent that uses them.
The usage quantity of organic solvent or mixed solvent is considered from the minimizing aspect of economy and side reaction thing, with respect to employed above-mentioned aniline compound 1g, is preferably 5～25ml, more preferably 7～20ml.
In the building-up reactions of diazonium salt synthesis procedure, hydrogenchloride or hydrogen bromide, the aniline compound of above-mentioned formula (1) expression, the blending means and the interpolation of above-mentioned nitrite do not have particular restriction in proper order.For example, acid, aniline compound and nitrite can be introduced in the reaction vessel simultaneously and mixed.Perhaps, have in advance 2 kinds of compositions are mixed, in this mixing solutions, add other compositions again and carry out the blended method.
In order to suppress side reaction, preferred following blending means.That is, as required, the method for adding nitrite in the mixed solution that above-mentioned aniline compound in being dissolved or dispersed in organic solvent and acid mix.Nitrite preferably adds with the state of the aqueous solution.
In the reaction of above-mentioned synthetic diazonium salt, temperature of reaction is preferably 0～15 ℃, more preferably 0～10 ℃.When temperature of reaction surpasses 15 ℃, cause side reaction easily.In the reaction process, preferred stirring reaction solution.Reaction times does not have particular restriction.For the reaction times, under agitation, be preferably 0.01～10 hour, more preferably 0.1～5 hour.
In the diazonium salt synthesis procedure, by reacting according to above-mentioned reaction conditions, generate with as the corresponding diazonium salt of the aniline compound of raw material.In the carbonyl oxycompound synthesis procedure of subsequent handling, make the diazonium salt and the α of generation, β-unsaturated carbonyl oxycompound reaction.
The diazonium salt that obtains can be in subsequent handling, with α, makes with extra care before β-unsaturated carbonyl oxycompound reaction.Yet this diazonium salt is a unstable compounds.Therefore, preferably diazonium compound is not made with extra care, but the direct reaction that the diazonium salt that obtains is used for follow-up carbonyl oxycompound synthesis procedure.For the foregoing reasons, in follow-up carbonyl oxycompound synthesis procedure, not preferred the solution that contains diazonium salt (reaction solution) of preparation according to the method described above not being made with extra care and directly use.Illustrated that in the reaction of above-mentioned diazonium salt synthesis procedure, when with an organic solvent, this solution (reaction solution) contains organic solvent.
Carbonyl oxycompound synthesis procedure
Carbonyl oxycompound synthesis procedure is in the presence of copper catalyst, make the α of the diazonium salt that in this diazonium salt synthesis procedure, obtains and above-mentioned formula (2) expression, β-unsaturated carbonyl oxycompound reaction, the operation of the carbonyl oxycompound of synthetic above-mentioned formula (3) expression.To at length narrate below, maximum feature of the present invention is, in this operation, making acid dissociation exponent (pKa) under having 25 ℃ in the reaction system is alkali below 7.
(α, β-unsaturated carbonyl oxycompound)
In the present invention, be used for the α with the reaction of above-mentioned diazonium salt, β-unsaturated carbonyl oxycompound is represented by following formula (2):
[changing 10]
(in the formula,
R
2Be hydrogen atom, alkyl, thiazolinyl or aryl;
R
3Be hydrogen atom, alkyl or aryl).
Work as radicals R
2During for alkyl, as alkyl, the alkyl of preferred carbon number 1～6.When the carbon number of alkyl is 1～6, reactive high, the availability height of gained carbonyl oxycompound.As preferred alkyl, specifically can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl or cyclohexyl etc.
Work as radicals R
2During for thiazolinyl,, can enumerate carbon number and be 2～6 allyl group, vinyl etc. as thiazolinyl.
Work as radicals R
2During for aryl,, can enumerate carbon number and be 6～12 phenyl or benzyl etc. as aryl.
Work as radicals R
3During for alkyl or aryl, as alkyl or aryl, can enumerate with in above-mentioned radicals R
2The identical group of middle example.
The α of above-mentioned formula (2) expression, β-unsaturated carbonyl oxycompound can not be subjected to any reagent or industrial raw material of restrictedly using.Above-mentioned α, β-unsaturated carbonyl oxycompound can be determined according to want synthetic carbonyl oxycompound.
Under the situation of the carbonyl oxycompound of paying attention to high formula (3) expression of preparation availability and reactivity, as α, β-unsaturated carbonyl oxycompound, preferred vinylformic acid, methyl acrylate, ethyl propenoate, butyl acrylate, isobutyl acrylate, tert-butyl acrylate, methacrylic acid, methyl methacrylate, Jia Jibingxisuanyizhi, butyl methacrylate, Propenoic acid, 2-methyl, isobutyl ester, the methacrylic tert-butyl acrylate, allyl methacrylate(AMA), the methacrylic acid vinyl ester, benzyl methacrylate, styracin, methyl cinnamate, ethyl cinnamate, cinnamein, or the styracin vinyl ester etc.
Under the situation of the availability of considering gained carbonyl oxycompound especially, as α, β-unsaturated carbonyl oxycompound, preferred methyl acrylate or ethyl propenoate.And then, under the situation of the purified easiness of paying attention to gained carbonyl oxycompound, as α, β-unsaturated carbonyl oxycompound, preferred methyl acrylate.
The α of formula (2) expression, the usage quantity of β-unsaturated carbonyl oxycompound with respect to 1 mole of the employed diazonium salt of reaction, is preferably more than 1 mole, more preferably more than 2 moles.When less than 1 mole, yield descends.Illustrated, α, the higher limit of the usage quantity of β-unsaturated carbonyl oxycompound does not have particular restriction, but from considerations such as the operability of reacted aftertreatment, economy, with respect to from 1 mole of the diazonium salt of aniline compound, be preferably 50 moles, more preferably 40 moles.
(copper catalyst)
The copper catalyst that uses in the carbonyl oxycompound synthesis procedure can not be subjected to any reagent or industrial raw material of restrictedly using.If the spendable copper catalyst of example can be enumerated cupric oxide (I), cupric oxide (II), cupric bromide (I), cupric bromide (II) etc.The usage quantity of copper catalyst is identical with common catalytic amount.Particularly, with respect to from 1 mole of the diazonium salt of aniline compound, be preferably 0.01～0.2 mole, more preferably 0.02～0.1 mole.When less than 0.01 mole, there is the tendency of prolongation in the reaction times.When surpassing 0.2 mole, be difficult to make the reaction times to shorten pro rata with the amount of employed copper catalyst.
(acid dissociation exponent under 25 ℃ (pKa) is the alkali below 7)
Maximum feature of the present invention is, in this carbonyl oxycompound synthesis procedure, making acid dissociation exponent (pKa) under having 25 ℃ in the reaction system is alkali below 7.Even if there not being acid dissociation exponent (pKa) under 25 ℃ is that alkali below 7 is present under the situation in the reaction system, the reaction of synthetic carbonyl oxycompound also can be carried out.Yet, be that alkali below 7 exists by making acid dissociation exponent (pKa) under 25 ℃, can obtain the highly purified carbonyl oxycompound of formula (3) expression with high yield.
If make the acid dissociation exponent (pKa) under 25 ℃ surpass 7 alkali existence, the purity and the yield of the carbonyl oxycompound that then obtains all reduce.Considering from the easiness aspect that obtains alkali, is 4 with the lower limit set of the acid dissociation exponent (pKa) of spendable alkali under 25 ℃.
As the acid dissociation exponent (pKa) under 25 ℃ that use among the present invention is alkali below 7, can not be subjected to any alkali that restrictedly uses reagent or industrial raw material to use.As spendable alkali, can enumerate pyridine (5.42), 2-picoline (5.95), 3-picoline (5.76), 4-picoline (6.04), 2,4-lutidine (6.63), 2,6-lutidine (6.90), 2,2 '-dipyridyl (pKa2=4.42), 4,4 '-dipyridyl (pKa2=4.77), 1,10-phenanthroline (pKa2=4.98), O-Phenylene Diamine (pKa2=4.63), quinoline (4.97), 1-Methylimidazole (6.95) etc.Acid dissociation exponent under 25 ℃ of the value representations of record in the bracket is described.
In the middle of these alkali, preferred especially nitrogen-containing heterocycle compound.By these alkali are present in the reaction system, can obtain highly purified carbonyl oxycompound with high yield.That is, in carbonyl oxycompound synthesis procedure, as the alkali that exists in the reaction system, preferred especially 25 ℃ acid dissociation exponent (pKa) is to the nitrogen-containing heterocycle compound below 7 more than 4.Herein, nitrogen-containing heterocycle compound is meant that heterocycle contains the heterogeneous ring compound of at least 1 nitrogen-atoms.
If the preferred nitrogen-containing heterocycle compound of example can be enumerated pyridine, 2-picoline, 3-picoline, 4-picoline, 2,4-lutidine, 2,6-lutidine, 2,2 '-dipyridyl, 4,4 '-dipyridyl or 1,10-phenanthroline, 1-Methylimidazole etc.In these nitrogen-containing heterocycle compounds,, especially preferably has the compound of pyridine ring from the selection rate of reaction and the considerations such as easiness of operation.Particularly, can enumerate pyridine compounds and theirs such as pyridine and 2-picoline; 2,2 '-dipyridyl, 4, bipyridyliums compounds such as 4 '-dipyridyl.
The usage quantity of this alkali with respect to from 1 mole of the diazonium salt of aniline compound, is preferably 0.05～10 mole, more preferably 0.1～5 mole.In the scope of the usage quantity of above-mentioned alkali, can give play to the selection rate, yield and the purity that improve reaction, improve good effects such as operability, economy.
In the present invention, be that alkali below 7 exists by making acid dissociation exponent (pKa) under 25 ℃, can give play to above-mentioned effect.Its reason is still indeterminate.
Whether the inventor etc. think, be interaction takes place to have suppressed the cause that the Sang De mayer (Sandmeyer) as the side reaction of meerwein arylation reacts because 25 ℃ acid dissociation exponent (pKa) is alkali and a copper catalyst 7 below.
(other reaction conditionss)
In carbonyl oxycompound synthesis procedure, above-mentioned reaction conditions does not in addition have particular restriction.The addition means and the blending means of each composition in the carbonyl oxycompound synthesis procedure do not have particular restriction yet.
As the addition means and the blending means of each composition, can enumerate following method.That is, in the above-mentioned solution that contains diazonium salt, be mixed into above-mentioned α, β-unsaturated carbonyl oxycompound and above-mentioned alkali adds copper catalyst again and mixes, and reacts thus.Perhaps, in the presence of copper catalyst, the solution that will contain diazonium salt splashes into above-mentioned α, in the mixture of β-unsaturated carbonyl oxycompound and above-mentioned alkali, they is mixed, and reacts thus.
Under above-mentioned situation, above-mentioned copper catalyst can add above-mentioned α to simultaneously with the solution that contains diazonium salt, in the mixture of β-unsaturated carbonyl oxycompound and above-mentioned alkali.And then, also can in advance copper catalyst be added in the said mixture.From the easiness of reaction control, the considerations such as easy of device, preferably in advance copper catalyst is mixed into above-mentioned α, in the mixture of β-unsaturated carbonyl oxycompound and above-mentioned alkali.
As α under temperature of reaction, β-when unsaturated carbonyl oxycompound is solid state, preferably with an organic solvent, make α, β-unsaturated carbonyl oxycompound and above-mentioned alkali react under the state of mixture (mixed solution).On the other hand, as α under temperature of reaction, β-when unsaturated carbonyl oxycompound is liquid also can make α under with an organic solvent situation not, and β-unsaturated carbonyl oxycompound and alkali react under the state of mixture (mixed solution).
When temperature of reaction is too high, cause side reaction easily.On the other hand, spend when low when reaction temperature, speed of response descends.Therefore, temperature of reaction is preferably 10～60 ℃, more preferably 15～50 ℃.
Reaction times does not have particular restriction.As long as suit to determine while the situation of carrying out of confirming reaction.In general, when temperature of reaction being controlled in the said temperature scope, the reaction times is preferably 0.1～10 hour, more preferably 0.5～5 hour.Preferably stir in the reaction process.
React by reaction conditions, can obtain reaction solution according to above-mentioned carbonyl oxycompound synthesis procedure.With the reaction solution that obtains according to ordinary method, with in the alkaline aqueous solutions such as ammoniacal liquor and after, carry out extraction treatment with the ethyl acetate equal solvent.Then, with extraction solvent and reaction solution separatory.Then, extraction solvent is removed in distillation, can obtain the carbonyl oxycompound of following formula (3) expression thus.
The carbonyl oxycompound of the above-mentioned formula (3) that obtains like this expression can be according to the purpose purposes etc., further adopts known method such as partial crystallization, distillation, post be refining to make with extra care.
(carbonyl oxycompound)
In the present invention, by carrying out each reaction of above-mentioned diazonium salt synthesis procedure, carbonyl oxycompound synthesis procedure, can synthesize the carbonyl oxycompound of following formula (3) expression:
[changing 11]
(in the formula,
R
1Identical with n with the definition in the above-mentioned formula (1);
R
2And R
3Identical with the definition in the above-mentioned formula (2);
X is chlorine atom or bromine atoms.)
Illustrated, in the above-mentioned formula (3), radicals R
1, R
2And R
3For according to employed aniline compound and α, the functional group that β-unsaturated carbonyl oxycompound is determined.
In addition, radicals X is the functional group that determines according to employed acid (hydrogenchloride (hydrochloric acid) or hydrogen bromide (Hydrogen bromide)).
Therefore, when using hydrogen bromide as acid, use 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline is as aniline compound and use methyl acrylate as α, during β-unsaturated carbonyl oxycompound, can prepare oxyethyl group as the useful 2-bromo-3-{4-[2-of former medicine intermediate (5-ethyl-2-pyridyl)] phenyl } methyl propionate.
5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl }-2-imino--4-thiazole
The preparation of alkane ketone
Preparation in accordance with the present invention can prepare highly purified carbonyl oxycompound with high yield.Adopt preparation method of the present invention, 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group in the following formula of preparation (11) expression] phenyl } under the situation of methyl propionate as the carbonyl oxycompound of formula (3) expression, can be with high purity, obtain the compound of formula (11) expression with high yield.
[changing 12]
Therefore, by using this compound, can be to prepare 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group expeditiously as the expression of the formula (12) of useful former medicine intermediate] benzyl-2-imino--4-thiazolidone and as 5-{4-[2-(5-ethyl-2-pyrrole is than the pyridine base) oxyethyl group of formula (13) expression of useful former medicine] benzyl thiazolidine-2, the 4-dione hydrochloride.
[changing 13]
Below, for 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that uses according to formula (11) expression of this preparation method preparation] phenyl } methyl propionate comes 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of preparation formula (12) expression] benzyl }-method of 2-imino--4-thiazolidone describes.
5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of formula (12) expression] benzyl }-preparation method of 2-imino--4-thiazolidone itself is a known method.For example, can utilize the method for record in the patent documentation 1.
Particularly, the organic solvent that uses ethanol and so on is as reaction solvent, in the presence of alkali, make the compound and the thiocarbamide reaction of formula (11) expression, thus 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of preparation formula (12) expression efficiently] benzyl }-2-imino--4-thiazolidone.
As alkali, preferred lithium acetate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, Quilonum Retard, yellow soda ash, salt of wormwood, cesium carbonate, potassium tert.-butoxide, sodium hydride, sodium methylate, sodium ethylate, lithium hydroxide, sodium hydroxide, potassium hydroxide etc.
The usage quantity of alkali with respect to 1 mole of the compound of formula (11) expression, is preferably 1～3 mole.The usage quantity of thiocarbamide with respect to 1 mole of the compound of formula (11) expression, is preferably 1～3 mole.Temperature of reaction is preferably 25～120 ℃, and the reaction times is preferably 1～50 hour.The addition means of alkali and thiocarbamide does not have particular restriction yet, as long as all the components is mixed, carries out the reaction of above-mentioned time and get final product under above-mentioned temperature of reaction.
After reacting under the condition as described above,, make 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of formula (12) expression by with reaction soln cooling] benzyl }-crystallization of 2-imino--4-thiazolidone separates out.And then, in order to improve yield, above-mentioned reaction soln is under reduced pressure concentrated, with the residue that obtains with in the saturated aqueous sodium carbonate and after, add entry and ether, cooling obtains the crystallization of the compound of formula (12) expression thus.This crystallization can adopt conventional method to make with extra care.For example, can make with extra care by washing and exsiccant method.The compound of gained formula (12) expression can be used for follow-up reaction.
Adopt the purity height of the compound of the formula (11) that preparation method of the present invention obtains, and yield is also high.Therefore, compare, under the situation of the compound that uses the formula (11) that obtains according to method of the present invention, can obtain the compound of formula (12) expression with high yield with method in the past.
Next, its hydrochloride of method make to(for) the compound of the formula (12) that will adopt above-mentioned preparation method preparation describes.
5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the 4-diketone
The preparation of hydrochloride
As mentioned above, the preparation method's of the compound of formula of the present invention (12) expression yield height, and foreign matter content is few.Its result, the compound by using this formula (12) can obtain 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of formula (13) expression with high yield as raw material] benzyl } thiazolidine-2, the 4-dione hydrochloride.
Following example goes out the preparation method of the compound of formula (13) expression.
At first, 1 mole of the compound of formula (12) expression of adopting aforesaid method to obtain is dissolved in the aqueous solution of the hydrogenchloride that contains 3～20 moles, under reflux temperature, heated 0.5～10 hour then, be hydrolyzed.Then, with the aqueous solution cooling that obtains, the compound of formula (13) expression is separated out.This crystallization can adopt known method to make with extra care.
Embodiment
Below enumerate embodiment and explain the present invention, but the present invention is not subjected to any restriction of these embodiment.
Embodiment 1
(diazonium salt synthesis procedure)
Aniline 0.47g (5mmol) is dissolved among methyl alcohol 4.6ml, the acetone 5.7ml, is cooled to 10 ℃, add the Hydrogen bromide 1.76g (hydrogen bromide 10.2mmol) of 47 quality %.This is contained aniline and hydrobromic solution is cooled to 2 ℃.Keep on one side containing aniline and hydrobromic solution is no more than 5 ℃, on one side this solution in stirring splash into nitrous acid aqueous solution.Above-mentioned nitrous acid aqueous solution is to be dissolved in the water of 0.7ml formulated by the Sodium Nitrite with 0.35g (5.7mmol).After splashing into nitrous acid aqueous solution, stirred 20 minutes synthetic diazonium salt down at 3 ℃.
This diazonium salt is supplied with follow-up reaction without refining with the state that is contained in the solution.Illustrated, adopt HPLC (high performance liquid chromatography) to confirm that the purity of diazonium salt is 99.0 quality %, show and synthesized diazonium salt quantitatively.That is, aniline all is transformed into diazonium salt basically.
(carbonyl oxycompound synthesis procedure)
In other container, add methyl acrylate 5.14g (10mmol), pyridine 1.19g (15mmol, 25 ℃ acid dissociation exponent (pKa)=5.42), cupric bromide (I) 0.091g (0.63mmol), be warming up to 47 ℃.Be heated to 47 ℃ then, stir the mixed solution that contain methyl acrylate, pyridine and cupric bromide (I) on one side, on one side with dripping the solution that contains diazonium salt that in above-mentioned diazonium salt synthesis procedure, prepares in 30 fens these mixed solutions of clockwise.After the dropping, again 47 ℃ of following stirring reaction liquid 2 hours, distillation removes and desolvates then.The ammoniacal liquor 10ml that in the residue that obtains, adds ethyl acetate 20ml, 28 quality %.With organic layer washing, the drying that obtains behind the separatory.Then, the solvent of organic layer is removed in distillation.Its result obtains the 2-bromo-3-phenylpropionic acid methyl esters 1.08g as the carbonyl oxycompound.Confirm that by HPLC its purity is 81.2 quality %.Draw thus, the yield of 2-bromo-3-phenylpropionic acid methyl esters is 72.3%.
Embodiment 2～6
In the diazonium salt synthesis procedure of embodiment 1, except using the aniline compound replacement aniline shown in the table 1, all the other carry out operation similarly to Example 1.It the results are shown in the table 1.Illustrated, the diazonium salt that obtains in the diazonium salt synthesis procedure of each embodiment, its purity is all more than 99.0 quality %.Therefore, diazonium salt is a synthetic quantitatively.
Embodiment 7～11
In the carbonyl oxycompound synthesis procedure of embodiment 1, except using 2,2 '-dipyridyl (25 ℃ acid dissociation exponent (pKa)=4.42) replaces pyridine and 2, the usage quantity of 2 '-dipyridyl with respect to the aniline compound shown in the table 2 be 1.5 times of molar equivalents (promptly, with respect to 1 mole of diazonium salt, 2, the use equivalent of 2 '-dipyridyl is 1.5 moles) in addition, all the other carry out operation similarly to Example 1.It the results are shown in table 2.
Embodiment 12～14
In the carbonyl oxycompound synthesis procedure of embodiment 1, beyond compound (α, β-unsaturated carbonyl oxycompound) the replacement methyl acrylate shown in the use table 3, all the other carry out experiment similarly to Example 1.It the results are shown in table 3.
Table 3
Comparative example 1
In embodiment 1, except not adding pyridine, all the other carry out operation similarly to Example 1.Its result, the purity that obtains to record by HPLC is the 2-bromo-3-phenylpropionic acid methyl esters 1.07g (yield 52.8%) of 60.0 quality %.
Comparative example 2～6
In embodiment 2～6, except not adding pyridine, all the other carry out the operation same with embodiment 2～6.It the results are shown in table 4.
Table 4
*Comparative example 5 uses the Hydrogen bromide 2.66g (hydrogen bromide 15.5mmol) of 47 quality %.
Comparative example 7
In embodiment 5, except using triethylamine (acid dissociation exponent under 25 ℃ (pKa)=10.72) replacement pyridine, all the other carry out operation similarly to Example 5.Its result, the purity that obtains to record by HPLC is 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group of 12.7 quality %] phenyl } methyl propionate 1.68g (yield 10.9%).
Embodiment 15～19
In the carbonyl oxycompound synthesis procedure of embodiment 1, except using 1-Methylimidazole (25 ℃ acid dissociation exponent (pKa)=6.95) to replace pyridine and with respect to the aniline compound shown in the table 5, all the other carry out operation similarly to Example 1.It the results are shown in table 5.
Embodiment 20 (5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl }-preparation of 2-imino--4-thiazolidone)
With 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that obtains among the embodiment 5] phenyl } methyl propionate 1.73g (purity 82.1%) packs into and has in the three-necked bottle of D imroth return line and thermometer.Then, add ethanol 9ml, thiocarbamide 0.55g, make 2-bromo-3{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] phenyl } after the methyl propionate dissolving, under agitation, add sodium acetate 0.59g, refluxed 4 hours.After the backflow, cooling is separated out crystallization.With crystallization filtration, washing, the drying of separating out, obtain 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group thus] benzyl }-little yellow crystal 1.16g of 2-imino--4-thiazolidone (yield 90.1% is 65.2% by the total recovery of aniline compound).Confirm that by HPLC its purity is 99.01 quality %.
Embodiment 21 (5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the preparation of 4-dione hydrochloride)
With 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that obtains among the embodiment 20] benzyl }-2-imino--4-thiazolidone 1.16g packs into and has in the three-necked bottle of Dimroth return line and thermometer, add 1.0mol/L aqueous hydrochloric acid 9.8mL, at room temperature dissolving.On one side make solvent refluxing,, carry out 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group Yi Bian stirred 4 hours] benzyl }-hydrolysis of 2-imino--4-thiazolidone.After the reaction, the gained reaction solution is cooled to 5 ℃, crystallization is separated out with 1.5 hours.The crystallization that obtains is filtered, drying is 12 hours under vacuum, obtain (5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the white crystals 1.16g of 4-dione hydrochloride (yield 90.2% is 58.8% by the total recovery of aniline compound).Confirm that by HPLC its purity is 99.1 quality %.
Comparative example 8 (5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl }-preparation of 2-imino--4-thiazolidone)
With 2-bromo-3-{4-[2-(5-ethyl-2-is than the pyridine base) oxyethyl group that obtains in the comparative example 5] phenyl } methyl propionate 1.67g (purity 59.6%) packs into and has in the three-necked bottle of Dimroth return line and thermometer.Then, add ethanol 9ml, thiocarbamide 0.34g, make 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] phenyl } after the methyl propionate dissolving, under agitation, add sodium acetate 0.37g, refluxed 4 hours.After the backflow, cooling is separated out crystallization.With the crystallization of separating out filter, washing, carry out drying, obtain 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl-little yellow crystal 0.80g of 2-imino--4-thiazolidone (yield 88.7% is 45.0% by the total recovery of aniline compound).Confirm that by HPLC its purity is 98.98 quality %.
In comparative example 8, in carbonyl oxycompound synthesis procedure,, therefore cause the purity of carbonyl oxycompound lower owing to there is not alkali to exist, be 59.6%.Owing to use the carbonyl oxycompound of this low-purity to synthesize 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl }-2-imino--4-thiazolidone, therefore also very low by the total recovery of the aniline compound of this compound, be 45.0%.
Comparative example 9 (5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the preparation of 4-dione hydrochloride)
With 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that obtains in the comparative example 8] benzyl }-2-imino--4-thiazolidone 0.80g packs into and has in the three-necked bottle of Dimroth return line and thermometer, add 1.0mol/L aqueous hydrochloric acid 6.7mL, at room temperature dissolving.On one side make solvent refluxing,, carry out 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group Yi Bian stirred 4 hours] benzyl }-hydrolysis of 2-imino--4-thiazolidone.After the reaction, the gained reaction solution is cooled to 5 ℃, crystallization is separated out with 1.5 hours.The crystallization that obtains is filtered, drying is 12 hours under vacuum, obtain (5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the white crystals 0.80g of 4-dione hydrochloride (yield 90.5% is 40.7% by the total recovery of aniline compound).Confirm that by HPLC its purity is 99.12 quality %.
Claims (7)
1. the preparation method of carbonyl oxycompound, it comprises following operation:
In the presence of hydrogenchloride or hydrogen bromide, make the aniline compound and the nitrite reaction of following formula (1) expression, the diazonium salt synthesis procedure of synthetic diazonium salt; And
In the presence of copper catalyst, make the α of the diazonium salt that obtains in this diazonium salt synthesis procedure and following formula (2) expression, β-unsaturated carbonyl oxycompound reaction, the carbonyl oxycompound synthesis procedure of the carbonyl oxycompound of synthetic following formula (3) expression;
[changing 1]
In the formula,
R
1Be hydrogen atom, halogen atom, hydroxyl, cyano group or organic group; N is 1～5 integer; When n is 2 when above, R
1It can be identical or different group;
[changing 2]
In the formula,
R
2Be hydrogen atom, alkyl, thiazolinyl or aryl;
R
3Be hydrogen atom, alkyl or aryl;
[changing 3]
In the formula,
R
1Identical with n with the definition in the above-mentioned formula (1);
R
2And R
3Identical with the definition in the above-mentioned formula (2);
X is chlorine atom or bromine atoms;
It is characterized in that,
In above-mentioned carbonyl oxycompound synthesis procedure, when making diazonium salt and α, during β-unsaturated carbonyl oxycompound reaction, making acid dissociation exponent pKa under having 25 ℃ in the reaction system is alkali below 7.
2. the preparation method of the described carbonyl oxycompound of claim 1 wherein, uses the radicals R of above-mentioned formula (1)
1Aniline compound for the group of alkyl or following formula (4) expression:
[changing 4]
-O-R
4 (4)
In the formula,
R
4Be the group of alkyl, aryl, following formula (5) expression or the group of following formula (6) expression:
[changing 5]
In the formula,
R
5And R
6Respectively do for oneself hydrogen atom or alkyl; M is 1～3 integer;
[changing 6]
In the formula,
R
7And R
8Respectively do for oneself hydrogen atom or alkyl.
3. the preparation method of the described carbonyl oxycompound of claim 1, wherein, in above-mentioned carbonyl oxycompound synthesis procedure, with respect to 1 mole of diazonium salt, the acid dissociation exponent pKa that uses 25 ℃ is 0.05～10 mole in an alkali below 7.
4. the preparation method of the described carbonyl oxycompound of claim 1 wherein, in above-mentioned carbonyl oxycompound synthesis procedure, is a alkali below 7 as 25 ℃ acid dissociation exponent pKa, and the acid dissociation exponent pKa that uses 25 ℃ is 4～7 nitrogen-containing heterocycle compound.
5. the preparation method of the described carbonyl oxycompound of claim 1, it is characterized in that, in above-mentioned diazonium salt synthesis procedure, use hydrogen bromide, and using 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline is as the aniline compound of above-mentioned formula (1) expression, and, in above-mentioned carbonyl oxycompound synthesis procedure, use the α of methyl acrylate as above-mentioned formula (2) expression, β-unsaturated carbonyl oxycompound prepares 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group thus] phenyl } methyl propionate.
(6.5-{4-[2-5-ethyl-2-pyridyl) oxyethyl group] benzyl }-preparation method of 2-imino--4-thiazolidone, it is characterized in that, adopt the preparation method of the described carbonyl oxycompound of claim 5 to prepare 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] phenyl } methyl propionate, in the presence of alkali, make 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that obtains then] phenyl } methyl propionate and thiocarbamide reaction.
(7.5-{4-[2-5-ethyl-2-pyridyl) oxyethyl group] benzyl } thiazolidine-2, the preparation method of 4-dione hydrochloride, it is characterized in that, adopt the described method of claim 6 to prepare 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group] benzyl }-2-imino--4-thiazolidone, make 5-{4-[2-(5-ethyl-2-pyridyl) oxyethyl group that obtains then] benzyl }-2-imino--4-thiazolidone and hcl reaction.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008263450 | 2008-10-10 | ||
| JP2008-263450 | 2008-10-10 | ||
| JP2008293181 | 2008-11-17 | ||
| JP2008-293181 | 2008-11-17 | ||
| PCT/JP2009/066022 WO2010041538A1 (en) | 2008-10-10 | 2009-09-14 | Process for producing carbonyloxy compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102149669A true CN102149669A (en) | 2011-08-10 |
Family
ID=42100492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801350565A Pending CN102149669A (en) | 2008-10-10 | 2009-09-14 | Process for producing carbonyloxy compound |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5441913B2 (en) |
| KR (1) | KR20110068979A (en) |
| CN (1) | CN102149669A (en) |
| WO (1) | WO2010041538A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2682383A4 (en) | 2011-02-28 | 2015-12-09 | Riken | Auxin biosynthesis inhibitor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0140229A1 (en) * | 1983-10-13 | 1985-05-08 | Tosoh Corporation | Process for producing a halogen-containing ethylbenzene derivative |
| CN86100411A (en) * | 1985-01-19 | 1986-07-16 | 武田药品工业株式会社 | Produce the method for thiazolidinedione |
| CN1159445A (en) * | 1995-12-19 | 1997-09-17 | 罗纳-普朗克农业化学公司 | Novel Insecticides |
| CN1361759A (en) * | 1999-05-26 | 2002-07-31 | 三菱化学株式会社 | 6-Hydroxy-2-naphthylmethanol and its production method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4335748A1 (en) * | 1993-10-20 | 1995-04-27 | Hoechst Ag | Process for the preparation of 3- (p-fluorophenyl) -2-methyl propionic acid and 3- (p-fluorophenyl) -2-methyl propionic acid derivatives |
-
2009
- 2009-09-14 CN CN2009801350565A patent/CN102149669A/en active Pending
- 2009-09-14 WO PCT/JP2009/066022 patent/WO2010041538A1/en active Application Filing
- 2009-09-14 JP JP2010532869A patent/JP5441913B2/en not_active Expired - Fee Related
- 2009-09-14 KR KR1020117004006A patent/KR20110068979A/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0140229A1 (en) * | 1983-10-13 | 1985-05-08 | Tosoh Corporation | Process for producing a halogen-containing ethylbenzene derivative |
| CN86100411A (en) * | 1985-01-19 | 1986-07-16 | 武田药品工业株式会社 | Produce the method for thiazolidinedione |
| CN1159445A (en) * | 1995-12-19 | 1997-09-17 | 罗纳-普朗克农业化学公司 | Novel Insecticides |
| CN1361759A (en) * | 1999-05-26 | 2002-07-31 | 三菱化学株式会社 | 6-Hydroxy-2-naphthylmethanol and its production method |
Non-Patent Citations (1)
| Title |
|---|
| 马慧勇等: "5-对羟基苄基-2,4-噻唑烷二酮的合成", 《合成化学》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2010041538A1 (en) | 2012-03-08 |
| JP5441913B2 (en) | 2014-03-12 |
| WO2010041538A1 (en) | 2010-04-15 |
| KR20110068979A (en) | 2011-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101432263B (en) | Substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 | |
| CN101432275B (en) | Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 | |
| Teller et al. | Concise synthesis of the antidepressive drug candidate GSK1360707 by a highly enantioselective gold-catalyzed enyne cycloisomerization reaction | |
| CN101426783B (en) | Cyclohexylpyrazole-lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 | |
| CN101448816B (en) | Pieridinyl substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 | |
| CN102123999B (en) | Process for the preparation of an orexin receptor antagonist | |
| CN102241670B (en) | Preparation method of high-purity chiral sulphoxide compound | |
| CN101768154A (en) | New preparation method of iloperidone | |
| EP1556370B1 (en) | Method for the synthesis of a benzimidazole compound | |
| CN103113351B (en) | Method for preparing optically pure chiral sulfoxide compound | |
| CN1671669A (en) | Synthesis of diaryl pyrazoles | |
| CN102149669A (en) | Process for producing carbonyloxy compound | |
| CN1305989A (en) | Novel benzenesulfonamide compound, its preparation method and pharmaceutical composition containing it | |
| CN102516236B (en) | Preparation method of antipsychotic drug iloperidone | |
| JP6776226B2 (en) | Method for producing 1- (4-hydroxyphenyl) -4- (4-trifluoromethoxyphenoxy) piperidine or a salt thereof | |
| CN104001553B (en) | 1,2,3-triazoles derivative/Cu (I) composite catalyst that N replaces and Synthesis and application thereof | |
| JP5197063B2 (en) | Process for producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate | |
| CN104672180A (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN1230950A (en) | Method of production and method of separation of 2,4'-dipyridyl derivatives and methods of production of benzoxazepine derivatives and salts thereof | |
| CN1812988A (en) | Processes for making thiazolidinedione derivatives and compounds thereof | |
| CN102643273B (en) | A kind of preparation method of Zomaril | |
| CN117897379A (en) | Method for synthesizing naphthyridine derivatives and intermediates thereof | |
| AU2016378154A1 (en) | Phenylimidazole compound | |
| CN107304205B (en) | Maravirenz intermediate and preparation method thereof | |
| CN1942468A (en) | Process for producing pyrazole condensed ring derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20110810 |
|
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |