CN106632312B - A kind of related substance of Eliquis, intermediate, preparation method and applications - Google Patents
A kind of related substance of Eliquis, intermediate, preparation method and applications Download PDFInfo
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- CN106632312B CN106632312B CN201510734364.7A CN201510734364A CN106632312B CN 106632312 B CN106632312 B CN 106632312B CN 201510734364 A CN201510734364 A CN 201510734364A CN 106632312 B CN106632312 B CN 106632312B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of related substances of Eliquis, intermediate, preparation method and applications.The present invention provides related substance I of a kind of Eliquis and preparation method thereof, comprising the following steps: in organic solvent, under the conditions of sodium methoxide is existing, compound II and formamide is carried out amidation process, obtain the related substance I of Eliquis.Synthetic method yield of the invention is higher, and the subsequent quality in Eliquis preparation process is facilitated to control research.
Description
Technical field
The present invention relates to a kind of related substances of Eliquis, intermediate, preparation method and applications.
Background technique
Eliquis (Apixaban) (VII), chemical name are 1- (4- methoxyphenyl) -7- carbonyl -6- [4- (2- piperidines
Ketone) phenyl] -4,5,6,7- tetrahydro -1H- pyrazoles [3,4-c] pyridine-3-carboxamides.Molecular formula C25H25N5O4, trade name
Eliquis.Eliquis is used to prevent the select a time adult patients of hip joint or knee replacements of receiving and phlebothrombosis bolt occurs
Disease (VTE) event of plug.
The documents such as patent WO03049681, WO2010030983, CN201010277358.0, WO2010030983 describe
The synthesis of Eliquis, wherein a route of synthesis such as following formula:
WO2014/75648 A1, generation and synthetic method of the document reports such as 2014 in relation to substance 2.
Journal of Organic Chemistry, 2012, vol.77,1,775-779 describes the production in relation to substance 3
Raw and synthetic method:
Summary of the invention
The technical problem to be solved by the present invention is in order to overcome impurity in the preparation process of Eliquis in the prior art
The defect of bad control and provide a kind of related substance of Eliquis, intermediate, preparation method and applications, conjunction of the invention
It is higher at method yield, facilitate the subsequent quality in Eliquis preparation process to control research.
Inventor using document route (patent WO03049681, WO2010030983, CN201010277358.0,
The documents such as WO2010030983) synthesis Eliquis when, pass through the HPLC of crude product analysis, it was found that peak area is greater than 0.1%
Impurity, thus it is speculated that there may be an impurity compound I, designed, designed route, the related substance I of controlled syntheses for the first time.It is confirmed through HPLC, chemical combination
Object I is the impurity that retention time is 11.16min.
The present invention provides a kind of related substance I of Eliquis, structure is as follows:
Preparation method the present invention also provides Eliquis in relation to substance I comprising following steps: in organic solvent,
Under the conditions of sodium methoxide is existing, compound II and formamide are subjected to amidation process, obtain the related substance I of Eliquis i.e.
It can；
Preparation method of the Eliquis in relation to substance I can be the routine side of such amidation process in this field
Method, particularly preferably following reaction method and condition in the present invention:
In preparation method of the Eliquis in relation to substance I, the preferred chlorinated hydrocarbon solvent of the organic solvent；
The preferred methylene chloride of the chlorinated hydrocarbon solvent.
In preparation method of the Eliquis in relation to substance I, the organic solvent and the compound II
Volume mass than preferred 1mL/g~100mL/g.
In preparation method of the Eliquis in relation to substance I, the formamide is with the compound II's
Molar ratio preferably 1~20, further preferred 8~10, such as 9.2.
In preparation method of the Eliquis in relation to substance I, the sodium methoxide is with the compound II's
Molar ratio preferably 1~20, further preferred 3~5, such as 4.
In preparation method of the Eliquis in relation to substance I, the sodium methoxide can be with solid or its solution
Form use, preferably in the form of its solution use.When the sodium methoxide in the form of its solution in use, sodium methoxide is molten
The mass percent of liquid preferably 10%~50%, further preferred 20%~30%, such as 25%, the mass percent is
The quality of nail sodium alkoxide accounts for the percentage of the gross mass of the solution of sodium methoxide.The first of the preferred sodium methoxide of the solution of the sodium methoxide
Alcoholic solution.
In preparation method of the Eliquis in relation to substance I, the temperature of the amidation process preferably 0~60
DEG C, further preferred 40 DEG C~50 DEG C, such as 45 DEG C.
In preparation method of the Eliquis in relation to substance I, the process of the amidation process can be used
Routine monitoring method (such as TLC, HPLC or NMR) in this field is monitored, generally to react when compound II disappearance
Terminal, the time of the reaction preferably 1 hour~60 hours, further preferred 50 hours~60 hours, such as 54 hours.
The Eliquis preferably uses following steps in relation to the preparation method of substance I: 0 DEG C~5 DEG C, by sodium methoxide
Methanol solution is added drop-wise in the mixture that compound II, formamide and organic solvent are formed, then is warming up to 40 DEG C~50 DEG C, is carried out
Amidation process obtains the related substance I of Eliquis.
Preparation method of the Eliquis in relation to substance I preferably uses following post-processing step: after reaction, removing
Solvent is removed, pillar layer separation obtains the related substance I of Eliquis.The removing solvent and pillar layer separation can use ability
The conventional method of the generic operation in domain.
Preparation method of the Eliquis in relation to substance I is further preferably the following steps are included: in organic solvent, acid
Under the conditions of existing, compound II ' progress elimination reaction is obtained into the compound II；
The preparation method of the compound II can be the conventional method of such elimination reaction in this field, in the present invention
Particularly preferred following reaction method and condition:
In the preparation method of the compound II, the preferred chlorinated hydrocarbon solvent of the organic solvent；The chlorine
For the preferred chloroform of hydrocarbon solvent.
In the preparation method of the compound II, the volume matter of the organic solvent and the compound II '
Amount is than preferred 1mL/g~100mL/g, further preferred 50mL/g~70mL/g, such as 67.5mL/g.
In the preparation method of the compound II, the preferred inorganic acid of acid；The preferred hydrochloric acid of the inorganic acid.
The hydrochloric acid can be hydrochloric acid reagent conventional in the art, the preferred 3mol/L~4mol/ of the molar concentration of the hydrochloric acid
L, the molar concentration refer to the mole of hydrogen chloride and the ratio of hydrochloric acid volume.
In the preparation method of the compound II, the molar ratio preferably 1 of the acid and the compound II '
~10, further preferred 5~7, such as 6.1.
In the preparation method of the compound II, preferably 10 DEG C~100 DEG C of the temperature of the elimination reaction, into one
Preferably 20 DEG C~40 DEG C of step, such as 25 DEG C.
In the preparation method of the compound II, the process of the elimination reaction can be using normal in this field
Rule monitoring method (such as TLC, HPLC or NMR) are monitored, described as the terminal of reaction when generally being disappeared using compound II '
Time preferably 1 hour~10 hours of elimination reaction, further preferred 3 hours~6 hours, such as 4 hours.
The preparation method of the compound II preferably uses following steps: -5 DEG C~0 DEG C, acid being added drop-wise to compound
In the mixture that II ' and organic solvent are formed, carries out elimination reaction and obtain the compound II.The speed of the dropwise addition
Rate is subject to temperature of reaction system no more than 0 DEG C.
The preparation method of the compound II preferably includes following post-processing step: after reaction, wash, is dry,
It filters, removes solvent, obtains the crude product of compound II.
The washing, drying, filtering, remove solvent can be using the conventional method of the generic operation in this field.It is described
Washing preferably successively washed with saturated sodium bicarbonate aqueous solution, saturated common salt water washing.The number of the washing preferably 1~
2 times.The drying preferably uses anhydrous sodium sulfate dry.
The preparation method of the compound II preferably includes following purification step: by compound II crude product through recrystallizing
To compound II after purification.The recrystallization can be using the conventional method of the generic operation in this field.The knot again
The preferred alcohols solvent of solvent that crystalline substance uses, the alcohols solvent preferred alcohol.
Preparation method of the Eliquis in relation to substance I is still further preferably the following steps are included: protective gas is protected
Under shield, in organic solvent, under the conditions of alkali is existing, compound III and VI is subjected to 3+2 cycloaddition reaction, obtains the change
Close object II '；
The preparation method of the compound II ' can be the conventional method of such 3+2 cycloaddition reaction in this field, this
Particularly preferred following reaction method and condition in invention:
In the preparation method of the compound II ', the preferred nitrogen of the protective gas.
In the preparation method of the compound II ', the preferred chlorinated hydrocarbon solvent of the organic solvent；The chlorine
For the preferred chloroform of hydrocarbon solvent.
In the preparation method of the compound II ', the volume matter of the organic solvent and the compound III
Amount is than preferred 1mL/g~200mL/g, further preferred 100mL/g~120mL/g, such as 107.7mL/g.
In the preparation method of the compound II ', the preferred organic base of the alkali；The organic base preferably three second
Amine.
In the preparation method of the compound II ', the molar ratio of the alkali and the compound III is preferred
1~10, further preferred 2~4, such as 2.65.
In the preparation method of the compound II ', the molar ratio of the compound VI and the compound III
Value preferably 1~5, further preferred 1.1~2.0, such as 1.33 or 1.60, still further preferably 1.10~1.33.
In the preparation method of the compound II ', the temperature of the 3+2 cycloaddition reaction preferably 40 DEG C~62
DEG C, such as 62 DEG C.
In the preparation method of the compound II ', the process of the 3+2 cycloaddition reaction can use this field
In routine monitoring method (such as TLC, HPLC or NMR) be monitored, generally using compound III disappear when as the end of reaction
Point, the time of the 3+2 cycloaddition reaction preferably 50 hours~80 hours, further preferred 60 hours~70 hours, such as
64 hours.
The preparation method of the compound II ' preferably uses following steps: -5 DEG C~0 DEG C, by compound III with have
The mixture that solvent is formed is added drop-wise in the mixture that compound VI and organic solvent are formed, and forms compound III, VI and has
The mixture of solvent；Again at -5 DEG C~0 DEG C, alkali is added drop-wise to the mixture of described compound III, VI and organic solvent
In, it carries out 3+2 cycloaddition reaction and obtains the compound II '.The rate of the dropwise addition with maintenance system temperature not
Subject to 0 DEG C.
The preparation method of the compound II ' is preferably after being made the compound II ' without further rear place
Reason purifying, directly carries out the reaction of prepare compound II.
Preparation method of the Eliquis in relation to substance I is still further preferably the following steps are included: protective gas is protected
Under shield, in organic solvent, under the conditions of alkali and catalyst are existing, compound V and compound IV is subjected to Ullman coupling reaction
Obtain the compound III；
The preparation method of the compound III can be the conventional method of such Ullman coupling reaction in this field,
Particularly preferred following reaction method and condition in the present invention:
In the preparation method of the compound III, the preferred nitrogen of the protective gas.
In the preparation method of the compound III, the preferred chlorinated hydrocarbon solvent of the organic solvent；The chlorine
For the preferred chloroform of hydrocarbon solvent.
In the preparation method of the compound III, the volume mass of the organic solvent and the compound V
Than preferred 1mL/g~100mL/g, further preferred 30mL/g~50mL/g, such as 38.6mL/g.
In the preparation method of the compound III, the preferred inorganic base of the alkali, the preferred carbonic acid of the inorganic base
Caesium.
In the preparation method of the compound III, the catalyst triphenylphosphine cuprous bromide (Cu
(Ph3P)3Br)。
In the preparation method of the compound III, the molar ratio preferably 1 of the alkali and the compound V
~10, further preferred 2~3.
In the preparation method of the compound III, the molar ratio of the catalyst and the compound V is excellent
Select 0.3~2, further preferred 0.4~1, still further preferably 0.41~0.59.
In the preparation method of the compound III, the molar ratio of the compound IV and the compound V
It is preferred that 1~3, further preferred 1.1~1.5.
In the preparation method of the compound III, the temperature of the Ullman coupling reaction preferably 40 DEG C~62
℃。
In the preparation method of the compound III, the process of the Ullman coupling reaction can use ability
Routine monitoring method (such as TLC, HPLC or NMR) in domain is monitored, as the end of reaction when generally being disappeared using compound V
Point, the time of the Ullman coupling reaction preferably 70 hours~90 hours, further preferred 75 hours~80 hours.
The preparation method of the compound III preferably uses following post-processing step: after reaction, be quenched, filter,
The dissolution of filter cake methylene chloride, drying, removes solvent, is beaten, being dried to obtain the compound III washing.
It is described be quenched, be filtered, washed, drying, remove solvent or mashing can using in this field the generic operation it is normal
Rule method.Described is quenched preferably using ammonium hydroxide, and the ammonium hydroxide can be conventional commercial ammonium hydroxide reagent, the matter of the ammonium hydroxide
Concentration preferably 10%~25%, such as 14% are measured, the mass concentration refers to that the quality of ammonia accounts for ammonium hydroxide reagent gross mass
Percentage.The washing preferably uses saturated salt solution.The number of the washing preferably 1~2 time.The drying is preferred
Using anhydrous sodium sulfate.The mashing preferably uses alcohols solvent, the preferred dehydrated alcohol of the alcohols solvent or isopropyl
Alcohol.
Preparation method of the Eliquis in relation to substance I preferably uses following synthetic route:
The present invention also provides compound II or compound III, structure are as follows:
The present invention also provides the preparation methods of compound II a kind of comprising following steps: in organic solvent, acid exists
Under conditions of, compound II ' progress elimination reaction is obtained into the compound II；
Wherein, each reaction condition is as described above.
The present invention also provides the preparation methods of compound III a kind of comprising following steps: under protective gas protection,
In organic solvent, under the conditions of alkali and catalyst are existing, compound V and compound IV is subjected to Ullman coupling reaction and obtains institute
The compound III stated；
Wherein, each reaction condition is as described above.
Application the present invention also provides the Eliquis in relation to substance I, in the control of Eliquis quality
It is identified as reference substance or impurity.
The present invention also provides a kind of pharmaceutical composition, it includes the related substance I of the Eliquis, Eliquis with
And other pharmaceutic adjuvants.The Eliquis is generally 0.01%~10% in relation to the mass content of substance I, described
Mass content refer to that Eliquis accounts for the percentage of pharmaceutical composition gross mass in relation to the quality of substance I.The choosing of pharmaceutic adjuvant
Select it is different because of administration method and action character, generally can be filler, diluent, adhesive, wetting agent, disintegrating agent, lubricant,
Emulsifier or suspending agent etc..
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the present invention provides a kind of related substance of Eliquis and its preparation sides
Method overcomes the defect of the bad control of impurity in the preparation process of Eliquis in the prior art.And synthesis side of the invention
Method yield is higher, facilitates subsequent quality control research.
Detailed description of the invention
Fig. 1 is the HPLC map containing the Eliquis in relation to substance I prepared by embodiment 6, wherein when compound I retains
Between be 11.167 minutes, the appearance time of Eliquis is 9.147 minutes.
Fig. 2 is the HPLC map of related substance I prepared by embodiment 6.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Liquid-phase condition in the following example are as follows: octadecyl silane (Waters Xbridge ShieldRP18,
150nm × 4.6mm, 3.5 μm of equal columns are applicable in) it is packed column, with 30mmol/L ammonium acetate-acetonitrile solution (90: 10) for mobile phase
A, with 30mmol/L ammonium acetate-acetonitrile solution (5: 95) for Mobile phase B, according to the form below carries out gradient elution:
| Time (minute) | Mobile phase A % | Mobile phase B % |
| 0 | 86 | 14 |
| 2 | 86 | 14 |
| 19 | 60 | 40 |
| 27 | 10 | 90 |
| 32 | 10 | 90 |
| 32.01 | 86 | 14 |
| 36 | 86 | 14 |
Detection wavelength is 280nm Detection wavelength, and flow velocity 1.5ml/min, column temperature is 40 DEG C.
The preparation of embodiment 1:III
Nitrogen protection adds compound V (2.2g, 5.73mmol, 1equiv), 6- methyl piperidine -2- ketone (0.97g,
8.59mmol, 1.5equiv), cesium carbonate (5.6g, 17.2mmol, 3equiv) is added after being dissolved with chloroform 15ml, then plus Cu
(Ph3P)3Br (3.16g, 3.4mmol, 0.59equiv).Chlorination imitates 70ml.It is heated to reflux at 62 DEG C, there is anti-contact plate after 6 hours
It answers, end of reaction after 75 hours.Post-processing: being that 14% ammonium hydroxide is quenched that (mass concentration refers to ammonia with mass percent
Quality account for the percentage of ammonium hydroxide reagent gross mass), filtering, filter cake retains.Liquid separation.Water layer methylene chloride washes 15ml × 3, dissolution
Filter cake merges organic layer.Saturated common salt washes 120ml × 1.Anhydrous magnesium sulfate is dry.Revolving, ethyl alcohol mashing, is dried to obtain production
Object 1.29g, yield 61%.M+H+=370, M+Na+=392, TLC condition are as follows: Rf=0.36 ethyl acetate: methanol=4: 1.
The preparation of embodiment 2:III
Nitrogen protection adds compound V (2.2g, 5.73mmol, 1equiv), 6- methyl piperidine -2- ketone (0.97g,
8.59mmol, 1.5equiv), cesium carbonate (3.73g, 11.46mmol, 2equiv) is added after being dissolved with chloroform 15ml.Add Cu
(Ph3P)3Br (3.16g, 3.4mmol, 0.59equiv).Chlorination imitates 70ml.It is heated to reflux at 62 DEG C, there is anti-contact plate after 6 hours
It answers, reaction was completed after 75 hours.Post-processing: being that 14% ammonium hydroxide is quenched that (mass concentration refers to ammonia with mass percent
Quality account for the percentage of ammonium hydroxide reagent gross mass), filtering, filter cake retains.Liquid separation.Water layer methylene chloride washes 15ml × 3, dissolution
Filter cake merges organic layer.Saturated common salt washes 120ml × 1.Anhydrous magnesium sulfate is dry.Revolving, ethyl alcohol mashing, is dried to obtain production
Object 0.25g, yield 11.8%, TLC condition are as follows: Rf=0.36, ethyl acetate: methanol volume ratio is 4: 1.
The preparation of embodiment 3:III
Nitrogen protection adds compound V (2.2g, 5.73mmol, 1equiv), 6- methyl piperidine -2- ketone (0.97g,
8.59mmol, 1.5equiv), cesium carbonate (3.73g, 11.46mmol, 2equiv) is added after being dissolved with chloroform 15ml.Add Cu
(Ph3P)3Br (2.2g, 2.37mmol, 0.41equiv).Chlorination imitates 70ml.It is heated to reflux at 62 DEG C, there is anti-contact plate after 6 hours
It answers, reaction was completed after 75 hours.Post-processing: being that 14% ammonium hydroxide is quenched that (mass concentration refers to ammonia with mass percent
Quality account for the percentage of ammonium hydroxide reagent gross mass), filtering, filter cake retains.Liquid separation.Water layer methylene chloride washes 15ml × 3, dissolution
Filter cake merges organic layer.Saturated common salt washes 120ml × 1.Anhydrous magnesium sulfate is dry.Revolving, dehydrated alcohol mashing, dry
To product 0.54g, yield 25.5%.TLC condition are as follows: Rf=0.36, ethyl acetate: methanol volume ratio is 4: 1.
The preparation of embodiment 4:II
Nitrogen protection, magnetic agitation.Add compound VI (0.6g, 2.34mmol, 1.33equiv), makes it with 10ml chloroform
It dissolves, at 0 DEG C.It is added dropwise compound III (dissolution of 0.65g, 1.76mmol, 1equiv, 60ml chloroform).At 0 DEG C, triethylamine is added dropwise
(0.472g, 4.68mmol, 2.65equiv).It finishes, is heated to reflux at 62 DEG C, HCl is added dropwise at 0 DEG C in fully reacting after 64 hours
(4mol/L, 2.7ml) is dripped off in 30 minutes, stops reaction after rising to 25 DEG C, 4 hours.Post-processing: it is washed with saturated sodium bicarbonate
25ml × 2, saturated salt solution 30ml × 1, anhydrous magnesium sulfate are dry.Filtering, revolving, the dissolution of 10ml dehydrated alcohol, stirring and crystallizing
Overnight, filtering, dry weighing 0.74g.Calculated yield 83.7%.Mass spectrum: M+H+=503, M+NH4 +=520, M+Na+=525,
TLC testing conditions: Rf=0.53 (EA: methanol=9: 1).
Embodiment 5: the preparation of compound II
Nitrogen protection, magnetic agitation.Add compound VI (0.72g, 2.82mmol, 1.6equiv), makes it with 10ml chloroform
It dissolves, at 0 DEG C, is added dropwise compound III (dissolution of 0.65g, 1.76mmol, 1equiv, 60ml chloroform).At 0 DEG C, triethylamine is added dropwise
(0.472g, 4.68mmol, 2.65equiv).It finishes, is heated to reflux at 62 DEG C, fully reacting after 64 hours, at 0 DEG C plus HCl
(4mol/L, 2.7ml) is dripped off in 30 minutes, stops reaction after rising to 25 DEG C, 4 hours.Post-processing: it is washed with saturated sodium bicarbonate
25ml × 2, saturated salt solution 30ml × 1, anhydrous magnesium sulfate are dry.Filtering revolving, the dissolution of 10ml dehydrated alcohol, stirring and crystallizing mistake
Night, filtering, dry weighing 0.52g.Calculated yield 59%.Mass spectrum: M+H+=503, M+NH4 +=520, M+Na+=525, TLC
Testing conditions: Rf=0.53 (EA: methanol=9: 1).
Embodiment 6: the preparation of compound I
By weighed compound II (0.4g, 0.8mmol), is dissolved with methylene chloride (40ml), be added to four mouthfuls of 100ml
In bottle, mechanical stirring is faint yellow after dissolved clarification.Add formamide (0.3g, 7.34mmol), ice bath is to 0 DEG C.Mass percent, which is added dropwise, is
25%CH3(mass percent refers to that the quality of sodium methoxide accounts for sodium methoxide to the methanol solution (0.68g, 3.2mmol) of ONa
Methanol solution gross mass percentage).Oil bath is warming up to 45 DEG C, and end of reaction after 54 hours, reaction was completed.Revolving, oil
Shape object.Column is crossed, product (0.24g, 0.5mmol), yield 62.5% are obtained.HPLC test display, compound I retention time are about
11.16min, the retention time of Eliquis are about 9.14min, there is good separating degree.
Mass spectrum MS (ESI, m/z): 474 [M+H]+。
Hydrogen spectrum1H-NMR (400MHz, CDCl3): δ 7.48 (d, 2H), δ 7.34-7.36 (d, 2H), δ 7.15-7.17 (d,
2H), δ 6.93 (d, 2H), δ 6.84 (s, 1H), δ 3.86-3.92 (m, 1H), δ 3.82 (s, 1H), δ 3.36-3.39 (t, 2H), δ
2.51-2.54 (t, 2H), δ 1.79-2.06 (m, 4H).
The HPLC map of Eliquis containing Eliquis in relation to substance I is as shown in Figure 1, wherein Eliquis is related
Substance I retention time is 11.167 minutes, and the appearance time of Eliquis is 9.147 minutes.The related substance I's of Eliquis
HPLC map is as shown in Figure 2.
Comparative example 1 (preparation of compound III):
Nitrogen protection adds compound V (2.2g, 5.73mmol, 1equiv), 6- methyl piperidine -2- ketone (0.97g,
8.59mmol, 1.5equiv), cesium carbonate (3.73g, 11.46mmol, 2equiv) toluene 15ml adds Cu after dissolving addition
(Ph3P)3Br (1.065g, 1.146mmol, 0.2equiv).Add toluene 70ml.It is heated to reflux at 111 DEG C, contact plate does not have after 18 hours
Reaction.
Comparative example 2 (preparation of compound III):
Nitrogen protection adds compound V (2.2g, 5.73mmol, 1equiv), 6- methyl piperidine -2- ketone (0.97g,
8.59mmol, 1.5equiv), cesium carbonate (3.73g, 11.46mmol, 2equiv) chloroform 15ml adds Cu after dissolving addition
(Ph3P)3Br (1.065g, 1.146mmol, 0.2equiv).Chlorination imitates 70ml.It is heated to reflux at 62 DEG C, contact plate does not have after 18 hours
Reaction.
Comparative example 3 (preparation of compound II):
Nitrogen protection, magnetic agitation.Add compound VI (0.6g, 2.34mmol, 1.33equiv), with 10ml ethyl acetate
It makes it dissolve, at 0 DEG C.It is added dropwise compound III (dissolution of 0.65g, 1.76mmol, 1equiv, 60ml ethyl acetate).At 0 DEG C, drop
Add triethylamine (0.472g, 4.68mmol, 2equiv).Finish, be heated to reflux, after 64 hours plus HCl (4mol/L, 2.9ml,
5equiv) TLC after 4 hours, MS proof are not desired products.
Claims (14)
1. a kind of preparation method of compound II comprising following steps: in organic solvent, under the conditions of acid is existing, will change
It closes object II ' progress elimination reaction and obtains compound II；Organic solvent is chloroform；
2. the preparation method of compound II as described in claim 1, it is characterised in that: in the preparation side of the compound II
In method, the volume mass ratio of the organic solvent and the compound II' are 1mL/g~100mL/g；
In the preparation method of the compound II, the acid is inorganic acid；
In the preparation method of the compound II, the molar ratio of the acid and the compound II ' are 1~10；
In the preparation method of the compound II, the temperature of the elimination reaction is 10 DEG C~100 DEG C；
In the preparation method of the compound II, the time of the elimination reaction is 1 hour~10 hours；
The preparation method of the compound II use following steps: -5 DEG C~0 DEG C, by acid be added drop-wise to compound II ' with it is organic
In the mixture that solvent is formed, carries out elimination reaction and obtain the compound II；
The preparation method of the compound II includes following post-processing step: after reaction, washing, removes dry, filtering
Solvent, the crude product for obtaining compound II.
3. the preparation method of compound II as claimed in claim 2, it is characterised in that: in the preparation side of the compound II
In method, the volume mass ratio of the organic solvent and the compound II' are 50mL/g~70mL/g；
In the preparation method of the compound II, the inorganic acid is hydrochloric acid；
In the preparation method of the compound II, the molar ratio of the acid and the compound II ' are 5~7；
In the preparation method of the compound II, the temperature of the elimination reaction is 20 DEG C~40 DEG C；
In the preparation method of the compound II, the time of the elimination reaction is 3 hours~6 hours；
The preparation method of the compound II includes following purification step: by compound II crude product through being recrystallized to give after purification
Compound II.
4. the preparation method of compound II as described in claim 1, it is characterised in that: it further includes steps of guarantor
It protects under gas shield, in organic solvent, under the conditions of alkali is existing, compound III and VI is subjected to 3+2 cycloaddition reaction, is obtained
The compound II '；Organic solvent is chloroform；
5. the preparation method of compound II as claimed in claim 4, it is characterised in that:
In the preparation method of the compound II ', the protective gas is nitrogen；
In the preparation method of the compound II ', the volume mass ratio of the organic solvent and the compound III
For 1mL/g~200mL/g；
In the preparation method of the compound II ', the alkali is organic base；
In the preparation method of the compound II ', the molar ratio of the alkali and the compound III are 1~10；
In the preparation method of the compound II ', the molar ratio of the compound VI and the compound III are
1~5；
In the preparation method of the compound II ', the temperature of the 3+2 cycloaddition reaction is 40 DEG C~62 DEG C；
In the preparation method of the compound II ', the time of the 3+2 cycloaddition reaction is 50 hours~80 hours；
The preparation method of the compound II ' uses following steps: -5 DEG C~0 DEG C, compound III being formed with organic solvent
Mixture be added drop-wise in the mixture that compound VI and organic solvent are formed, form the mixed of compound III, VI and organic solvent
Close object；Again at -5 DEG C~0 DEG C, alkali is added drop-wise in the mixture of described compound III, VI and organic solvent, carries out 3+2 ring
Addition reaction obtains the compound II '；
The preparation method of the compound II ' is to purify after the compound II ' is made without further work-up,
Directly carry out the reaction of prepare compound II.
6. the preparation method of compound II as claimed in claim 5, it is characterised in that:
In the preparation method of the compound II ', the volume mass ratio of the organic solvent and the compound III
For 100mL/g~120mL/g；
In the preparation method of the compound II ', the organic base is triethylamine；
In the preparation method of the compound II ', the molar ratio of the alkali and the compound III are 2~4；
In the preparation method of the compound II ', the molar ratio of the compound VI and the compound III are
1.1~2.0；
In the preparation method of the compound II ', the time of the 3+2 cycloaddition reaction is 60 hours~70 hours；
In the step of preparation method of the compound II ' uses, the rate maintenance system temperature of the dropwise addition is no more than 0
℃。
7. the preparation method of compound II as claimed in claim 4, it is characterised in that: it further includes steps of guarantor
It protects under gas shield, in organic solvent, under the conditions of alkali and catalyst are existing, compound V and compound IV is subjected to Ullman
Coupling reaction obtains the compound III；The molar ratio of catalyst and compound V are 0.3~2；
8. the preparation method of compound II as claimed in claim 7, it is characterised in that: in the preparation of the compound III
In method, the protective gas is nitrogen；
In the preparation method of the compound III, the organic solvent is chlorinated hydrocarbon solvent；
In the preparation method of the compound III, the volume mass ratio of the organic solvent and the compound V is
1mL/g~100mL/g；
In the preparation method of the compound III, the alkali is inorganic base；
In the preparation method of the compound III, the catalyst is triphenylphosphine cuprous bromide；
In the preparation method of the compound III, the molar ratio of the alkali and the compound V are 1~10；
In the preparation method of the compound III, the molar ratio of the compound IV and the compound V are 1
~3；
In the preparation method of the compound III, the temperature of the Ullman coupling reaction is 40 DEG C~62 DEG C；
In the preparation method of the compound III, the time of the Ullman coupling reaction is 70 hours~90 hours；
The preparation method of the compound III uses following post-processing step: after reaction, be quenched, filter, filter cake is with two
Chloromethanes dissolution, washing, dry, removing solvent, mashing, obtain the compound III.
9. the preparation method of compound II as claimed in claim 8, it is characterised in that: in the preparation of the compound III
In method, the chlorinated hydrocarbon solvent is chloroform；
In the preparation method of the compound III, the volume mass ratio of the organic solvent and the compound V is
30mL/g~50mL/g；
In the preparation method of the compound III, the inorganic base is cesium carbonate；
In the preparation method of the compound III, the molar ratio of the alkali and the compound V are 2~3；
In the preparation method of the compound III, the molar ratio of the catalyst and the compound V are 0.4
~1；
In the preparation method of the compound III, the molar ratio of the compound IV and the compound V are
1.1~1.5；
In the preparation method of the compound III, the time of the Ullman coupling reaction is 75 hours~80 hours；
In the post-processing step that the preparation method of the compound III uses, described is quenched using ammonium hydroxide.
10. the preparation method of compound II as claimed in claim 9, it is characterised in that: in the preparation of the compound III
In method, the molar ratio of the catalyst and the compound V are 0.41~0.59.
11. a kind of preparation method of Eliquis in relation to substance I, it is characterised in that itself the following steps are included:
(1) compound II is prepared according to the preparation method of compound II such as of any of claims 1-10；
(2) in organic solvent, under the conditions of sodium methoxide is existing, compound II and formamide are subjected to amidation process, obtain Ah
Piperazine sand class is in relation to substance I；
12. preparation method of the Eliquis as claimed in claim 11 in relation to substance I, it is characterised in that:
In preparation method step (2) of the Eliquis in relation to substance I, the organic solvent is that chlorinated hydrocarbon is molten
Agent；
In preparation method step (2) of the Eliquis in relation to substance I, the organic solvent and the compound
The volume mass ratio of II is 1mL/g~100mL/g；
In preparation method step (2) of the Eliquis in relation to substance I, the formamide and the compound II
Molar ratio be 1~20；
In preparation method step (2) of the Eliquis in relation to substance I, the sodium methoxide and the compound II
Molar ratio be 1~20；
In preparation method step (2) of the Eliquis in relation to substance I, the sodium methoxide is with solid or its solution
Form uses；
In preparation method step (2) of the Eliquis in relation to substance I, the temperature of the amidation process is 0~
60℃；
In preparation method step (2) of the Eliquis in relation to substance I, the time of the amidation process is 1 small
When~60 hours；
Preparation method step (2) of the Eliquis in relation to substance I is using following steps: 0 DEG C~5 DEG C, by sodium methoxide
Methanol solution is added drop-wise in the mixture that compound II, formamide and organic solvent are formed, then is warming up to 40 DEG C~50 DEG C, is carried out
Amidation process obtains the related substance I of Eliquis；
The Eliquis uses following post-processing step in relation to the preparation method step (2) of substance I: after reaction, removing
Solvent is removed, pillar layer separation obtains the related substance I of Eliquis.
13. preparation method of the Eliquis as claimed in claim 12 in relation to substance I, it is characterised in that:
In preparation method step (2) of the Eliquis in relation to substance I, the chlorinated hydrocarbon solvent is dichloromethane
Alkane；
In preparation method step (2) of the Eliquis in relation to substance I, the formamide and the compound II
Molar ratio be 8~10；
In preparation method step (2) of the Eliquis in relation to substance I, the sodium methoxide and the compound II
Molar ratio be 3~5；
In preparation method step (2) of the Eliquis in relation to substance I, when the sodium methoxide is in the form of its solution
In use, the mass percent of sodium methoxide solution is 10%~50%, the mass percent refers to that the quality of sodium methoxide accounts for
The percentage of the gross mass of the solution of sodium methoxide；
In preparation method step (2) of the Eliquis in relation to substance I, when the sodium methoxide is in the form of its solution
In use, the solution of the sodium methoxide is the methanol solution of sodium methoxide；
In preparation method step (2) of the Eliquis in relation to substance I, the temperature of the amidation process is 40 DEG C
~50 DEG C；
In preparation method step (2) of the Eliquis in relation to substance I, the time of the amidation process is 50 small
When~60 hours.
14. a kind of preparation method of compound III comprising following steps: protective gas protection under, in organic solvent, alkali and
Under the conditions of catalyst is existing, compound V and compound IV progress Ullman coupling reaction is obtained into the compound III i.e.
It can；The molar ratio of catalyst and compound V are 0.3~2；
Wherein, each reaction condition is as described in any one of claim 7~10.
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| CN112142736B (en) * | 2020-10-29 | 2021-08-10 | 怀化学院 | Preparation method of apixaban impurity 1 |
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