CN114057725B - Synthesis method of zolpidem tartrate - Google Patents

Synthesis method of zolpidem tartrate Download PDF

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CN114057725B
CN114057725B CN202010757578.7A CN202010757578A CN114057725B CN 114057725 B CN114057725 B CN 114057725B CN 202010757578 A CN202010757578 A CN 202010757578A CN 114057725 B CN114057725 B CN 114057725B
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CN114057725A (en
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宿亮
赵静芝
金秉德
钟超泽
侯岳华
郑席冬
朱维君
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Hunan Qianjin Xiangjiang Pharmaceutical Co ltd
Qianjin Pharmaceutical Co ltd
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Qianjin Pharmaceutical Co ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a synthesis method of zolpidem tartrate, in the process of synthesizing an intermediate 1, methylene dichloride is firstly added into a reactor to serve as a reaction solvent, dimethylamine gas is then introduced into the reactor, and finally dichloroacetyl chloride is added into the reactor in a dropwise manner to react; in the process of synthesizing the intermediate 5, pd-C/H is used 2 As a reducing system. The invention optimizes the integral synthesis route of zolpidem tartrate, and can effectively improve the yield and purity of zolpidem tartrate. The method has better effect in industrialized mass production.

Description

Synthesis method of zolpidem tartrate
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of an zolpidem intermediate.
Background
Zolpidem tartrate is a white crystal, solid, stable to light and heat, and soluble in water. The commercial names of the medicine are levant, nobin, si-Si and L-pirated, the English name is Zolpidem Tartrate Tablets, and the chemical name is N, N, 6-trimethyl-2- (4-methylphenyl) -imidazo [1,2-a ] pyridine-3-acetamide tartrate. The medicine is a sedative hypnotic of non-benzodiazepine short-acting imidazopyridine, which is developed by French Sainophenanthrene company and is used for treating insomnia and brain diseases. Studies have shown that zolpidem tartrate, a new generation of hypnotics, has a high affinity for the receptor GABA unlike the traditional benzodiazepine drugs, but has a high selectivity for benzodiazepine receptor BZR1, which is stronger than BZR2, and has a specific binding site, which causes the opening of chloride ion channels, which causes chloride ions to flow into nerve cells, causing cell membrane superization, thus inhibiting neuronal activation.
Key to the preparation of zolpidem tartrate is the synthesis of zolpidem, which is disclosed in the prior art in a number of ways. Patent document US4794185 intermediate 5 is prepared by condensing 6-methyl-2- (4-methylphenyl) -imidazo [ l,2-a ] pyridine with N, N-dimethylglyoxylamide dimethyl acetal to give N, 6-trimethyl-2- (4-methylphenyl) -3- (2-hydroxy) dimethylaminocarbonylmethylimidazo [ l,2-a ] pyridine, followed by substitution reaction with thionyl chloride to give N, 6-trimethyl-2- (4-methylphenyl) -3- (2-chloro) dimethylaminocarbonylmethylimidazo [ l,2-a ] pyridine hydrochloride, and dechlorination with sodium borohydride, the reaction process being described as the following synthetic route:
the yield and purity of the zolpidem in the synthetic route are low, and various problems exist in the process of being applied to industrial production, and the lower yield of zolpidem tartrate is further caused.
Disclosure of Invention
Aiming at the problems existing in the process of preparing zolpidem tartrate in the prior art, the invention provides a high-purity and high-yield synthesis method of zolpidem tartrate, which is applicable to industrial production, and the synthesis route is as follows:
in the process of synthesizing the intermediate 1, firstly adding methylene dichloride into a reactor as a reaction solvent, then introducing dimethylamine gas into the reactor, and finally dropwise adding dichloroacetyl chloride into the reactor for reaction;
in the process of synthesizing the intermediate 5, pd-C/H is used 2 As a reducing system.
Preferably, during the synthesis of intermediate 2, the molar ratio of intermediate 1 to sodium methoxide is controlled to be 1:2 to 3.
Preferably, in the process of synthesizing the intermediate 1, the dichloroacetyl chloride is diluted by methylene dichloride and then is added dropwise;
preferably, the mass volume ratio of the dichloroacetyl chloride to the dichloromethane after dilution is 1:1-4.
Preferably, the temperature of the reaction system is controlled to be 1-5 ℃ in the process of synthesizing the intermediate 1.
Preferably, in the process of synthesizing the intermediate 1, the molar ratio of the dimethylamine gas to the dichloroacetyl chloride is 1-3:1.
Preferably, after the reaction for synthesizing intermediate 1 is completed, the pH of the system is adjusted to 7 to 8, and the organic phase is collected after standing.
Preferably, in the process of synthesizing the intermediate 2, the acetonitrile solution of the intermediate 1 is dropwise added into the methanol solution of sodium methoxide for reaction;
preferably, the concentration of the intermediate 1 in acetonitrile is controlled to be 1.5-2.5 g/ml.
Preferably, in the process of synthesizing the intermediate 5, the mass ratio of the intermediate 4 to Pd-C is 1:0.08-0.12.
Preferably, the intermediate 4 is combined with H in an organic solvent 2 Carrying out reduction reaction;
preferably, the organic solvent is one or more of methanol, acetonitrile, isopropanol or tetrahydrofuran;
further preferably, the mass-volume ratio of the intermediate 4 to the organic solvent is 1:5-10.
Preferably, the reaction for synthesizing the intermediate 5 is carried out at a temperature of 30 to 40 ℃.
The invention has the following beneficial effects:
1) The invention optimizes the integral synthesis route of zolpidem tartrate, and can effectively improve the yield and purity of zolpidem tartrate.
2) The method has better effect in industrialized mass production.
Drawings
FIG. 1 is a high performance liquid chromatogram of zolpidem tartrate control;
FIG. 2 is a high performance liquid chromatography peak results plot of zolpidem tartrate control;
fig. 3 is a high performance liquid chromatogram of zolpidem tartrate prepared in example 19 of the present invention.
Fig. 4 is a graph showing the results of high performance liquid chromatography peaks for preparing zolpidem tartrate in example 19 of the present invention.
Detailed Description
The invention is described in detail below with additional technical features.
The synthesis route of zolpidem tartrate of the invention is as follows:
in the process of synthesizing the intermediate 1, firstly adding methylene dichloride into a reactor as a reaction solvent, then introducing dimethylamine gas into the reactor, and finally dropwise adding dichloroacetyl chloride into the reactor for reaction;
in the process of synthesizing the intermediate 5, pd-C/H is used 2 As a reducing system.
Dichloroacetyl chloride is easy to decompose when meeting water, but in the prior art, dichloroacetyl chloride is generally added into an aqueous solution of dimethylamine in a dropwise manner to react, and the dichloroacetyl chloride is easier to react with dimethylamine compared with water, so that the dichloroacetyl chloride cannot be hydrolyzed. However, when the reaction is expanded, in the large-scale reaction, when the dichloroacetyl chloride encounters a large amount of water, the dichloroacetyl chloride is greatly hydrolyzed, and the yield and purity of the product are seriously affected. The prior art process for preparing zolpidem provides a 20% yield of product in intermediate 5About, the purity is about 60%, and the present invention has unexpectedly found that the catalyst is replaced with Pd-C and H is used 2 The reduction can effectively improve the yield and purity of the product, the yield is about 70 percent, and the purity is about 99 percent.
According to some preferred embodiments, the dichloroacetyl chloride is added dropwise after dilution with dichloromethane. The reaction can be more effectively promoted by diluting dichloroacetyl chloride with methylene chloride.
According to some preferred embodiments, the mass to volume ratio of the diluted dichloroacetyl chloride to the dichloromethane is 1:1-4. The dilution to the above degree can not cause incomplete reaction due to too high concentration of dichloromethane, and can not influence the reaction speed due to too small addition amount, and finally can improve the yield of the product.
According to some preferred embodiments, the temperature of the reaction system is controlled to be 1-5 ℃ during the synthesis of intermediate 1. Since the reaction between dimethylamine and dichloroacetyl chloride is relatively intense, the reaction speed is generally controlled by dripping and low temperature in the prior art to promote the reaction to be completely carried out, and the intermediate 1 with high yield is obtained, but in the invention, when dimethylamine gas is directly used for the reaction, the reaction temperature is properly increased, and the reaction is promoted to be completely carried out, so that the product with high yield is obtained.
According to some preferred embodiments, the molar ratio of dimethylamine to dichloroacetyl chloride is 1-3:1.
According to some preferred embodiments, after the reaction of synthesizing intermediate 1 is completed, the pH of the system is adjusted to 7-8, and the organic phase is collected after standing. Adjusting the pH of the system, on the one hand, removes the reaction byproduct hydrochloric acid and, on the other hand, allows intermediate 1 to form a free base, rather than the hydrochloride salt, which facilitates extraction and separation.
According to some preferred embodiments, during the synthesis of intermediate 2, the molar ratio of intermediate 1 to sodium methoxide is 1:2 to 3. The amount of sodium methoxide is controlled within the above range, and by-products are not easily produced.
According to some preferred embodiments, during the synthesis of intermediate 2, a solution of intermediate 1 in acetonitrile is added dropwise to a solution of sodium methoxide in methanol. The reaction rate can be controlled by the above operation, and the generation of by-products can be prevented.
According to some preferred embodiments, the mass concentration of intermediate 1 in the acetonitrile solution of intermediate 1 during the synthesis of intermediate 2 is 1.5-2.5 g/L.
According to some preferred embodiments, the mass fraction of sodium methoxide in the methanol solution of sodium methoxide is 20-40%.
According to some preferred embodiments, after the intermediate 2 is prepared, it is purified by the following method: cooling the reaction system to 30-35 ℃, adjusting the pH to 7-8 with hydrochloric acid, stirring, filtering, and spin-drying the filtrate; dichloromethane was added, stirred, filtered, the filtrate collected and concentrated to dryness.
The synthesis of the intermediate 3 is carried out by a conventional method.
According to some preferred embodiments, the intermediate 3 synthesis method is: adding the intermediate 2, water, glacial acetic acid and concentrated hydrochloric acid into a reactor, performing heat preservation and activation for 1-2h at 50 ℃, adding sodium acetate to adjust pH to be 4-5, and adding a cyclocompoundAnd 1, 2-dichloroethane to obtain intermediate 3.
The synthesis of intermediate 4 is also carried out by conventional methods.
According to some preferred embodiments, the mass ratio of the intermediate 4 to the Pd-C during the complete formation of the intermediate 5 is 1:0.08-0.12. Within the above amount range, pd-C may sufficiently catalyze intermediate 4.
According to some preferred embodiments, the intermediate 4 is reacted with H in an organic solvent 2 And carrying out a reduction reaction. Both substances have good dispersing agents in organic solvents, which is favorable for the full progress of the reaction.
According to some preferred embodiments, the specific manner of the above reaction is: pd-C is dissolved in an organic solvent to prepare a suspension, and the suspension is dripped into the intermediate 4 for reaction. By carrying out the reaction in the above manner, the catalyst Pd-C can be brought into sufficient contact with the intermediate 4, and the reaction can be advantageously carried out sufficiently particularly in an industrial scale-up reaction.
According to some preferred embodiments, the organic solvent is one or more of methanol, acetonitrile, isopropanol or tetrahydrofuran. Pd-C and intermediate 4 have better dispersibility in the above solvents.
According to some preferred embodiments, the mass to volume ratio of the intermediate 4 to the organic solvent is 1:5 to 10.
According to some preferred embodiments, the reaction is carried out at a temperature of 30 to 40 ℃. At the above temperatures, the reaction proceeds more thoroughly.
According to some preferred embodiments, the prepared intermediate 5 is purified by the following method:
1) Cooling the mixed solution obtained by the reaction, filtering, taking filtrate, and evaporating part of organic solvent in the filtrate;
2) Crystallizing the mixed system from which part of the organic solvent is evaporated at a low temperature, and drying the obtained crystals;
3) One or more of acetone, acetonitrile, isopropanol and tetrahydrofuran are added into the dried crystal, the mixture is heated and refluxed, and the mixture is crystallized at low temperature again to obtain an intermediate 5 solid.
The product prepared by the method is purified by adopting the method, so that the yield and purity of the final product can be effectively improved.
According to some preferred embodiments, the low temperature is-5 to 0 ℃.
According to some preferred embodiments, the synthesis of intermediate 5 comprises the steps of:
1) Placing the intermediate 4 in a reaction vessel, adding an organic solvent containing Pd-C into the reaction vessel, and introducing hydrogen to perform a reaction;
2) Cooling the mixed solution obtained by the reaction, filtering, and evaporating part of organic solvent in the filtrate; crystallizing the mixed system from which part of the organic solvent is evaporated at a low temperature, and drying the obtained crystals; one or more of acetone, acetonitrile, isopropanol and tetrahydrofuran are added into the dried crystal, the mixture is heated and refluxed, and the mixture is crystallized at low temperature again to obtain an intermediate 5 and a solid.
The preparation of intermediate 6 and zolpidem tartrate is also carried out using methods commonly used in the art.
The mass and volume in the mass-volume ratio are standard units, such as g and ml.
The present invention will be specifically described by way of examples.
Example 1
This example relates to the preparation of intermediate 1 comprising the steps of:
preparation of intermediate 1
200ml of methylene dichloride is put into a reaction bottle, dimethylamine gas is introduced so that the molar quantity of the dimethylamine reagent is 2 times that of dichloroacetyl chloride, (the dimethylamine gas is prepared by adding sodium hydroxide into a 40% dimethylamine solution), the reaction temperature is controlled to be 0-5 ℃, and a methylene dichloride solution (1 g/ml) containing 50.0g dichloroacetyl chloride is dropwise added.
After the reaction is completed, an acid is added to adjust the pH to 7-8. Stirring and standing for 20-30min, layering, and collecting organic layer. Drying under reduced pressure gives 47.85g of intermediate 1 (N, N-dimethyl-2, 2-dichloroacetamide). The detection shows that the yield is 92.1% and the purity is 99.66%.
Example 2
This example relates to the preparation of intermediate 1, which differs from example 1 in that:
a methylene chloride solution (2 ml/g) containing 50.0g of dichloroacetyl chloride was used to give intermediate 1 in a yield of 90.4% and a purity of 98.36%.
Example 3
This example relates to the preparation of intermediate 1, which differs from example 1 in that:
a methylene chloride solution (4 ml/g) containing 50.0g of dichloroacetyl chloride was added dropwise to give intermediate 1 in a yield of 90.4% and a purity of 98.36%.
Example 4
This example relates to the preparation of intermediate 1, which differs from example 1 in that:
an amplification experiment was performed to amplify the addition amount of dichloroacetyl chloride to 1kg, to obtain intermediate 1, with a yield of 99.1% and a purity of 99.51%.
Example 5
Compared to example 1, the difference was that 50.0 dichloroacetyl chloride was directly added dropwise without dilution to give 45.57g of intermediate 1 in 86.1% yield and 96.26% purity.
Example 6
Compared with example 1, the difference is that the reaction temperature is-10 to-5 ℃, 45.37g of intermediate 1 is obtained, the yield is 85.7%, and the purity is 99.64%.
Example 7
Compared to example 1, the difference was that the reaction temperature was-5-0deg.C, yielding 45.73g of intermediate 1 in 86.4% yield and 99.68% purity.
Example 8
The difference compared with example 1 was that 50.0g of dichloroacetyl chloride in methylene chloride (0.5 ml/g) was added dropwise, the yield was 87.25% and the purity was 99.51%.
Comparative example 1
Referring to patent US4794185, a 40% aqueous solution of dimethylamine is put into a reaction bottle, 50.0g of 2, 2-dichloroacetyl chloride is directly added dropwise, the dropping speed is controlled at-10-0 ℃, after the reaction is completed, filtering is carried out, filter residues are collected, the aqueous phase is extracted by methylene dichloride, the reduced pressure concentration is carried out, the products are combined, water washing and drying are carried out, 37.90g of intermediate 1 is obtained, the yield is 71.6%, and the purity is 89.58%.
Example 9
This example relates to the preparation of intermediate 2, comprising the steps of:
a methanol solution (mass fraction: 30%) containing 42.33g of sodium methoxide was introduced into a reaction flask, and the temperature was raised to reflux. 40g of a solution (2 ml/g) formed by the intermediate 1 (dichloroacetamide) and 80ml of acetonitrile is slowly added dropwise, the dropping speed is 2ml/min, and the reflux reaction is carried out for 2-3 hours after the dropping is completed. After the reaction is finished, cooling to 30-35 ℃, adjusting the pH to 7-8 by hydrochloric acid, and stirring for 10-20min. Filtration, spin-drying of the filtrate, addition of 50ml of dichloromethane, stirring for 10-20min, filtration, collection of the filtrate and concentration and drying gave 35.17g of intermediate 2: n, N-dimethyl-2, 2-dimethoxy acetamide with a yield of 93.2% and a purity of 99.89%.
Example 10
This example relates to the preparation of intermediate 2, which differs from example 9 in that:
when intermediate 1 was amplified to 2.2Kg by a scale-up experiment, the yield was 98% and the purity was 96.67%.
Comparative example 2
Referring to patent US4794185, 40.0g of intermediate 1 and 80ml of acetonitrile were added to a reaction flask, and a methanol solution containing 28.22g of sodium methoxide (mass fraction: 30%) was rapidly added, and heated to reflux for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated, 50ml of t-butyl methyl ether (TBME) was added and stirred for 10 to 20 minutes, filtered, and the filtrate was collected and concentrated to dryness to give intermediate 2 in a yield of 76.9% and a purity of 85.37%.
Comparative example 3
In comparison with example 9, the difference is that when sodium methoxide is 6.0-7.0eq of intermediate 1, the yield is 60.6% and the purity is 86.80%
Comparative example 4
The difference compared with example 9 is that when sodium methoxide is 1.0-2.0eq of intermediate 1, the yield is 75.8% and the purity is 84.12%.
Comparative example 5
The difference compared to example 5 is that the concentration of intermediate 1 added dropwise in acetonitrile is 4g ml, the yield is 85.21% and the purity is 98.47%.
Example 11
This example relates to the preparation of intermediate 3 comprising the steps of:
53.00g of intermediate 2, 9ml of water, 36ml of glacial acetic acid and 9ml of concentrated hydrochloric acid (volume ratio is 1:4:1) are put into a reaction bottle, stirred, heated to 50 ℃, and activated for 2 hours under the condition of heat preservation at 50 ℃. Sodium acetate is added to adjust the pH to be 4-5, 40.0g of the cyclic compound and 100ml of 1, 2-dichloroethane are added, the mixture is stirred and heated to reflux, the reflux is carried out for 2-3 hours, and the water knockout drum is used for removing water. Cooling to below 50deg.C after reflux, and dripping saturated Na 2 CO 3 The pH value of the solution is regulated to be 7.5, the solution is separated, the organic phase is decompressed, concentrated and dried, 100ml of isopropanol is added, the temperature is raised, the reflux is carried out for 20 minutes, the solution is slowly cooled until the product is just precipitated, the seed crystal is added, the temperature is reduced in a gradient way, the temperature is cooled to 0 ℃, and the crystallization is carried out for 24 hours. Filtering, washing with 50% isopropanol and a large amount of drinking water, continuously filtering to dry to obtain white solid, and drying for 20 hours. After drying, 42.02g of condensate was obtained, the yield was 72.21%, and the purity was 99.42%.
Example 12
The invention relates to a synthesis method of an intermediate 3, which specifically comprises the following steps:
1) Preparation of intermediate 1
200ml of methylene chloride was charged into a reaction flask, dimethylamine gas was introduced for 10-20 minutes, the reaction temperature was controlled at 0 to 5℃and a methylene chloride solution (1 ml/g) containing 50.0g of dichloroacetyl chloride was added dropwise.
After the reaction is completed, an acid is added to adjust the pH to 7-8. Stirring and standing for 20-30min, layering, and collecting organic layer. Drying under reduced pressure gives 47.85g of intermediate 1 (N, N-dimethyl-2, 2-dichloroacetamide). The detection shows that the yield is 92.1% and the purity is 99.66%.
2) Preparation of intermediate 2
A methanol solution (mass fraction: 30%) containing 42.33g of sodium methoxide was introduced into a reaction flask, and the temperature was raised to reflux. Slowly dripping 40g of dichloroacetamide (intermediate 1) and 60-80ml of acetonitrile (1.5-2 ml/g), wherein the dripping speed is 2ml/min, and carrying out heat preservation reflux reaction for 2-3 hours after dripping. After the reaction is finished, cooling to 30-35 ℃, adjusting the pH to 7-8 by hydrochloric acid, and stirring for 10-20min. Filtration, spin-drying of the filtrate, addition of 50ml of dichloromethane, stirring for 10-20min, filtration, collection of the filtrate and concentration and drying gave 35.17g of intermediate 2: n, N-dimethyl-2, 2-dimethoxy acetamide with a yield of 93.2% and a purity of 99.89%.
3) The preparation of intermediate 3 comprises the following steps:
53.00g of intermediate 2, 9ml of water, 36ml of glacial acetic acid and 9ml of concentrated hydrochloric acid (volume ratio is 1:4:1) are put into a reaction bottle, stirred, heated to 50 ℃, and activated for 2 hours under the condition of heat preservation at 50 ℃. Sodium acetate is added to adjust the pH to be 4-5, 40.0g of the cyclic compound and 100ml of 1, 2-dichloroethane are added, the mixture is stirred and heated to reflux, the reflux is carried out for 2-3 hours, and the water knockout drum is used for removing water. Cooling to below 50deg.C after reflux, and dripping saturated Na 2 CO 3 The pH value of the solution is regulated to be 7.5, the solution is separated, the organic phase is decompressed, concentrated and dried, 100ml of isopropanol is added, the temperature is raised, the reflux is carried out for 20 minutes, the solution is slowly cooled until the product is just precipitated, the seed crystal is added, the temperature is reduced in a gradient way, the temperature is cooled to 0 ℃, and the crystallization is carried out for 24 hours. Filtering, washing with 50% isopropanol and a large amount of drinking water, continuously filtering to dry to obtain white solid, and drying for 20 hours. After drying, 42.02g of condensate was obtained, the yield was 72.21%, and the purity was 99.42%.
Thus, the overall yield from intermediate 1 to intermediate 3 was 61.98% and the purity was 99.42%.
Comparative example 6
Referring to patent US4794185, the same preparation as comparative example 1, comparative example 2 and example 11, respectively, from intermediate 1 to intermediate 3 gave intermediate 3 in a total yield of 39.76% and a purity of 95.41%.
Example 13
This example relates to a process for the preparation of intermediate 5 comprising the steps of:
1) Adding 40g of intermediate 4 into a reactor, adding 200ml of methanol suspension containing 4.0g of Pd-C under the protection of nitrogen, introducing hydrogen, and reacting for 2-3h at 30-40 ℃;
2) Cooling to 30 ℃, filtering, evaporating part of methanol from the filtrate, controlling the temperature to be 0-5 ℃, freezing and crystallizing for 8-20 hours, filtering, drying for 2-4 hours, adding 100ml of acetone, refluxing for 20-30 minutes, cooling to be 0-5 ℃, and cooling and crystallizing for 8-20 hours. Filtration and washing with a small amount of acetone gave a white solid crystalline material which was dried at 40-60℃for 4h to give 26.57g of intermediate 5 in a yield of 73.07% and a purity of 99.95%.
Example 14
This example relates to a process for the preparation of intermediate 5, which differs from example 13 in that:
intermediate 4 (2-chloro-N, N-dimethyl-2- (6-methyl-2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) acetamide hydrochloride) was amplified to 1.0Kg in 78.93% yield, 98.39% purity
Example 15
This example relates to a process for the preparation of intermediate 5, which differs from example 13 in that methanol is replaced by isopropanol in a yield of 72.35% and a purity of 95.04%
Example 16
This example relates to a process for the preparation of intermediate 5, which differs from example 13 in that methanol is replaced by THF in a yield of 70.59% and a purity of 93.78%
Example 17
This example relates to a process for the preparation of intermediate 5, which differs from example 13 in that methanol is exchanged for acetonitrile in a yield of 72.50% and a purity of 94.95%.
Example 18
In comparison with example 13, the reflux solvent in the purification in step 2) was changed to one of acetonitrile, isopropanol and THF, and the yields were 70.03%, 72.35% and 71.28% respectively, and the purities were 94.38%,92.57% and 95.01% respectively.
Comparative example 7
Referring to patent US4794185, 5g of intermediate 4 was dissolved in 30ml of isopropanol and a solution containing 1.5g of sodium borohydride (NaBH 4 ) 30ml of water, and reacted at 20℃for 1 hour. 30ml of water were added and stirred again for 1 hour, the solid was filtered off, washed 3 times with 15ml of water and diisopropyl ether, respectively, and dried. The yield was 20.01% and the purity was 60.57%.
Comparative example 8
5g of intermediate 4 were dissolved in 25ml of methanol. A suspension of 2g of sodium borohydride in 15ml of water is added dropwise at 10 ℃. Stirring was continued for 1 hour 30 minutes. Then 50ml of water was added to precipitate out. Filtering, collecting filter cake, adding 25ml acetonitrile, heating, stirring to dissolve, filtering, cooling filtrate, crystallizing to obtain 1.33g product with yield of 29.3% and purity of 63.62%.
Comparative example 9
The difference compared to comparative example 8 is that the diluted aqueous suspension of sodium borohydride is exchanged for a methanolic suspension of sodium borohydride, yielding 1.32g of product with 29% yield and 64.07% purity.
Comparative example 10
In comparison with comparative example 8, the difference was that the diluted aqueous suspension of sodium borohydride was changed to THF suspension of sodium borohydride to give 0.46g of solid in a yield of 10.12% and a purity of 23.11%.
As can be seen from the above comparative examples, in the course of improving the preparation method of intermediate 5 based on the prior art, there are many alternative directions, and the inventors have tried to change the solvent used in the catalyst dilution, the solvent dissolving intermediate 4) 2-chloro-N, N-dimethyl-2- (6-methyl-2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) acetamide hydrochloride, and the like, did not achieve a good effect.
Comparative example 11
5g of intermediate 4 (2-chloro-N, N-dimethyl-2- (6-methyl-2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) acetamide hydrochloride) was dissolved in 100ml of 1, 2-dichloroethane, phosphorus tribromide (12 ml,8.2 eq.) was slowly added dropwise under nitrogen protection, after which the solution was heated at reflux for 2 hours to orange, cooled to 20-30℃and N-hexane (100 ml) was added and the precipitate collected by filtration and washed with N-hexane (50 ml). The hydrobromide salt of zolpidem was dissolved in water/ethyl acetate, and the organic layer was separated and dried over anhydrous sodium sulfate. Filtering, evaporating the filtrate to remove most of the solvent, adding acetone, pulping, filtering, washing the obtained product with a small amount of acetone, and drying the filter cake. 1.35g of solid was obtained in a yield of 29.7% and a purity of 99.92%.
Comparative example 12
The difference compared to comparative example 11 is that the replacement of 2-dichloroethane with tetrahydrofuran gives 1.73g of solid in a yield of 38.07% and a purity of 98.06%.
Comparative example 13
The difference compared to comparative example 11 is that methyl isobutyl ketone was used instead of 2-dichloroethane as solvent, the yield was 26.3% and the purity was 99.65%.
As is clear from comparative examples 11 to 13, no good effect was obtained by changing the reduction system and the reduction system.
Comparative example 14
The difference compared with example 13 is that the product was purified by the method of comparative example 7, which comprises the following steps: after the reaction was completed, pd-C was removed by filtration, and after concentrating the filtrate under reduced pressure to obtain a partial methanol solution, 240ml of water was added, stirred for 1 hour, and the solid was filtered off, washed 3 times with 120ml of water and diisopropyl ether, respectively, and dried. The yield was 71.58% and the purity was 86.71%.
Example 19
Preparation of intermediate 6
Adding 500g of intermediate 5 and 2500ml of water into a reaction vessel, stirring, dissolving, cooling to 0-10 ℃, adding saturated Na 2 CO 3 Stirring the solution until the pH value is more than or equal to 9 for 0.5-1 hour, filtering, washing with water until the pH value of the filtrate is=7, filtering, and drying to obtain 433.14g of the free base (i.e. N, N, 6-trimethyl-2- (4-methylphenyl) -imidazo [1, 2-alpha ]]Pyridine-3-acetamide). The yield was 96.9% and the purity was 99.52%.
Preparation of zolpidem tartrate
330g of intermediate 6 and 1650ml of methanol are added into a three-mouth bottle, stirred and heated to 60-70 ℃ for reflux, 80.56g of tartaric acid-containing methanol solution (10 g/ml) prepared (about 20min after the dropwise addition) is added dropwise, and the reflux reaction is continued for 2-3h under heat preservation. The material is filtered while hot, the filtrate is cooled to room temperature, and is stirred until crystals appear, the stirring is stopped, then the mixture is cooled to-5-5 ℃, the mixture is stood for crystallization for 10-12 hours, the mixture is filtered, a filter cake is washed by methanol, and after pumping, 36.46g zolpidem tartrate is obtained by vacuum drying, the yield is 73.6%, the purity is 100%, and ESI: m/z [ M+H ]] + 765.80 (the high performance liquid chromatogram of the obtained product is shown in figure 3, the chromatographic peak result is shown in figure 4, and the high performance liquid chromatogram of the zolpidem tartrate control is shown in figure 1, and the high performance liquid chromatogram peak result of the zolpidem tartrate control is shown in figure 2).
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims (12)

1. The synthesis method of zolpidem tartrate is characterized by comprising the following synthesis routes:
；
in the process of synthesizing the intermediate 1, firstly adding methylene dichloride into a reactor as a reaction solvent, then introducing dimethylamine gas into the reactor, and finally dropwise adding dichloroacetyl chloride into the reactor for reaction;
in the process of synthesizing the intermediate 2, controlling the molar ratio of the intermediate 1 to sodium methoxide to be 1: 2-3;
in the process of synthesizing the intermediate 2, dropwise adding an acetonitrile solution of the intermediate 1 into a methanol solution of sodium methoxide for reaction; after the intermediate 2 was prepared, it was purified by the following method: cooling the reaction system to 30-35 ℃, adjusting the pH to 7-8 with hydrochloric acid, stirring, filtering, and spin-drying the filtrate; adding dichloromethane, stirring, filtering, collecting filtrate, concentrating and drying;
in the process of synthesizing the intermediate 5, pd-C/H is used 2 As a reducing system.
2. The method according to claim 1, wherein the dichloroacetyl chloride is diluted with dichloromethane and then added dropwise during the synthesis of the intermediate 1.
3. The synthesis method according to claim 2, wherein the mass-volume ratio of the dichloroacetyl chloride to the dichloromethane after dilution is 1:1-4.
4. A synthesis method according to any one of claims 1 to 3, wherein the temperature of the reaction system is controlled to be 1 to 5 ℃ during the synthesis of the intermediate 1.
5. The synthesis method according to claim 1, wherein in the synthesis of the intermediate 1, a molar ratio of the dimethylamine gas to the dichloroacetyl chloride is 1-3:1.
6. The synthesis method according to claim 1, wherein after the reaction of synthesizing the intermediate 1 is completed, the pH of the system is adjusted to 7 to 8, and the organic phase is collected after standing.
7. The synthesis method according to claim 1, wherein the concentration of the intermediate 1 in acetonitrile is controlled to be 1.5-2.5 g/ml.
8. The synthesis method according to claim 1, wherein in the process of synthesizing the intermediate 5, the mass ratio of the intermediate 4 to Pd-C is 1:0.08-0.12.
9. The synthetic method according to claim 1 or 8, characterized in that the intermediate 4 is reacted with H in an organic solvent 2 And carrying out a reduction reaction.
10. The synthetic method according to claim 9, wherein the organic solvent is one or more of methanol, acetonitrile, isopropanol or tetrahydrofuran.
11. The synthesis method according to claim 10, wherein the mass-to-volume ratio of the intermediate 4 to the organic solvent is 1:5-10.
12. The synthesis method according to claim 1, wherein the reaction for synthesizing the intermediate 5 is performed at a temperature of 30 to 40 ℃.
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US4794185A (en) * 1986-06-27 1988-12-27 Synthelabo Process for the preparation of imidazopyridines
CN1972939A (en) * 2004-06-22 2007-05-30 马林克罗特公司 Synthesis of heteroaryl acetamides from reaction mixtures having reduced water content
CN102875379A (en) * 2012-11-01 2013-01-16 上海品沃化工有限公司 Industrialized synthetic method of ethyl difuoroacetate

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Publication number Priority date Publication date Assignee Title
US4794185A (en) * 1986-06-27 1988-12-27 Synthelabo Process for the preparation of imidazopyridines
CN1972939A (en) * 2004-06-22 2007-05-30 马林克罗特公司 Synthesis of heteroaryl acetamides from reaction mixtures having reduced water content
CN102875379A (en) * 2012-11-01 2013-01-16 上海品沃化工有限公司 Industrialized synthetic method of ethyl difuoroacetate

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Title
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