CN112724129A - Chiral purification method of compound B - Google Patents
Chiral purification method of compound B Download PDFInfo
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- CN112724129A CN112724129A CN202011427427.1A CN202011427427A CN112724129A CN 112724129 A CN112724129 A CN 112724129A CN 202011427427 A CN202011427427 A CN 202011427427A CN 112724129 A CN112724129 A CN 112724129A
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a chiral purification method of a compound B, wherein the compound B is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with chiral purity ee value of 90% -98%, the chiral purification method comprises the steps of further crystallizing and purifying the compound B after forming hydrohalic acid salt to obtain high-purity refined hydrohalic acid salt, and obtaining the high-chiral-purity (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane through alkali treatment and toluene extraction of the refined high-purity hydrohalic acid salt. The process avoids secondary resolution by using a relatively expensive optical resolving agent, the refining yield is more than 90 percent and is far higher than the yield of secondary resolution by using the resolving agent, the ee value of the obtained product is more than 99.5 percent, the process is easy to amplify and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of medical intermediates, in particular to the technical field of preparation of a chiral intermediate side chain (S, S) -2, 8-diazabicyclo [4.3.0] nonane of a quinolone antibacterial drug moxifloxacin hydrochloride.
Background
Moxifloxacin hydrochloride is a fluoroquinolone antibiotic drug developed by German Bayer medicines, belongs to fourth-generation quinolone drug broad-spectrum antibacterial drugs, has little drug-resistant gram-positive bacteria or has slow drug resistance generation compared with other fluoroquinolone drugs, and cross drug-resistant bacteria between gram-negative bacteria and enterococcus and other fluoroquinolone drugs are found.
(S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane (refined product of the following formula) is subjected to amide reduction to obtain (S, S) -8-benzyl-2, 8-diazabicyclo [4.3.0] nonane, and then subjected to palladium-carbon hydrodebenzylation to quantitatively obtain a moxifloxacin side chain, namely (S, S) -2, 8-diazabicyclo [4.3.0] nonane (high-purity nonane of the following formula), wherein the moxifloxacin side chain is a key chiral intermediate of moxifloxacin hydrochloride (moxifloxacin hydrochloride of the following formula).
Among them, various literature patents report (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, and the most typical reaction is shown in the following formula, for example, WO2009/125425, US6235908, CN101657448, etc., and these process routes all use 2,3 pyridinedicarboxylic acid or its derivative as a starting material to prepare an imidized product by reacting with benzylamine, then prepare a hydrogenated product by hydrogenation on palladium-carbon, and then obtain the product by resolution on tartaric acid, but the phenomenon of low resolution yield (yield < 30%) and low ee value (ee value < 98%) exists.
To achieve high chiral purity (> 99.5% ee), the resolved salt needs to be recrystallized with a loss of about 20%. CN102408427A describes acetonitrile recrystallization of (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, the ee value of the product varying from 95% to 99.5%; in addition, in the production, the operation of splitting the primary split product with low ee value by adding the splitting agent again is complicated, the overall splitting yield is low, and the production cost is high.
Therefore, the development of a low-cost intermediate chiral purification method for improving the ee value of the key chiral intermediate of moxifloxacin has high industrial production value.
The invention content is as follows:
in order to improve the chiral purity of a key intermediate (S, S) -2, 8-diazabicyclo [4.3.0] of moxifloxacin hydrochloride, the invention provides a chiral purification method of a compound B, wherein the compound B is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with chiral purity ee 90% -98%, the chiral purification method comprises the steps of further crystallizing and purifying the compound B after forming hydrohalic acid salt to obtain high-purity refined hydrohalic acid salt, and obtaining the high-chiral-purity (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane after the refined high-purity hydrohalic acid salt is subjected to alkali treatment and toluene extraction. The process avoids secondary resolution by using a relatively expensive optical resolving agent, the refining yield is more than 90 percent and is far higher than the yield of secondary resolution by using the resolving agent, the ee value of the obtained product is more than 99.5 percent, the process is easy to amplify and is suitable for industrial production. .
The technical scheme of the invention is realized as follows:
a chiral purification method of a compound B, comprising the steps of:
(1) preparation of acid salt: mixing the crude product 1, a solvent A and acid to prepare crude acid salt, evaporating the solvent A, heating in a solvent B, refluxing for refining, and cooling to room temperature to obtain refined acid salt;
(2) stripping alkaloid: and (2) carrying out alkaline hydrolysis and solvent C extraction on the refined product acid salt obtained in the step (1), and evaporating the solvent C to obtain a refined product, namely: (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having an ee value of greater than 99.5%;
the reaction equation is as follows:
the refining process conditions in the step (1) are as follows: the temperature is 55-80 ℃, the temperature is too low, the reaction is insufficient, and the purity of the product is reduced when the temperature is too high; the time is 1-2 hours, the time is too short, the crystallization is insufficient, the time is too long, and the working hours are increased; the temperature for cooling and crystallizing is 20-30 ℃, the product yield is reduced when the temperature is too high, and the product purity is reduced when the temperature is too low.
The acid of step (1) is a hydrohalic acid; specifically, hydrochloric acid or hydrobromic acid is preferable, and a hydrochloric acid solution having a mass fraction of 31% or a hydrobromic acid solution having a mass fraction of 47% is more preferable. This is because hydrochloric acid and hydrobromic acid are relatively stable in hydrohalic acid and are inexpensive.
The compound B, i.e., the crude product 1 in step (1), is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having a chiral purity ee of 90% -98%.
The crude product 1 in the step (1) is obtained by resolution or chiral synthesis, and the crude product 1 is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with an ee value of 90-98%; specific crude sources can be found in the literature: the synthesis research of a novel antibacterial moxifloxacin key intermediate; high golden flower; major academic paper of Zhejiang industrial university, 2012.
The solvent A in the step (1) is water or ethanol, and the purpose is to react the solid or oily crude product 1, the solvent A and acid to obtain a crude acid salt.
The solvent B in the step (1) is selected from an alcohol solvent or a ketone solvent or a mixed solvent of alcohol and ketone. The alcohol solvent is C1-4 alcohol, preferably methanol and ethanol; the ketone solvent is selected from acetone and butanone, preferably acetone. Aiming at the polarity and the solubility of the solvent, the screened solvent B can ensure the chiral purity and the yield of the product.
The volume fraction of the alcohol in the mixed solvent of the alcohol and the ketone is 5% -15%, under a specific solvent multiple, the ethanol can increase the solubility of the racemic salt, the chiral purity of the product is favorably improved, the yield is reduced when the chiral purity is too high, the chiral purity is reduced when the chiral purity is too low, and the volume fraction of the alcohol in the mixed solvent of the alcohol and the ketone is preferably 10%.
The mass of the solvent B in the step (1) is 3-8 times that of the crude acid salt, the yield is reduced due to overhigh solvent proportion, and the chiral purity of the product is reduced due to overlow solvent proportion.
Controlling the pH to be acidic at the salifying end point in the step (1), controlling the pH to be 1-2, causing acid waste due to too low pH, and generating excessive waste salt by adjusting alkali at the later stage; too high pH results in insufficient salt formation and a decrease in yield.
The solvent C in the step (2) is selected from one of toluene, dichloromethane and cyclohexane separated from water, and toluene is preferred, so that the advantages of inert solvent C and high recovery rate are achieved.
The alkali required by the alkaline hydrolysis in the step (2) is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate, and sodium bicarbonate is preferred, so that the reaction of the selected alkali is mild, the pH control is accurate, and the pH after the alkaline hydrolysis is 8-9.
Compared with the prior art, the invention has the following advantages:
(1) compared with the resolution and refining by using resolving agents such as D (-) tartaric acid and L (+) tartaric acid, the technical scheme of the invention has the advantages of simple operation, high yield, less three wastes and easy industrial production.
(2) The (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane obtained by the technical scheme of the invention is used for preparing the moxifloxacin hydrochloride key intermediate (S, S) -2, 8-diazabicyclo [4.3.0] nonane, so that the loss caused by refining an amide reduction product and nonane is avoided, and the residual chiral isomer can be converted into a chiral racemic mixture through configuration conversion during the preparation of the (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with high chiral purity, so that the secondary resolution is carried out, the yield is greatly improved, and the industrial production is facilitated.
Detailed Description
The invention is further illustrated by the following examples: the invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the specific material ratios, process conditions and results thereof described in the examples are illustrative only and should not be taken as limiting the invention as detailed in the claims.
The final product obtained in the invention, namely (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, is examined for chiral purity in reference: pre-column derivatization method the enantiomers Food and Drug 2013 of moxifloxacin small ring were determined at volume 15, phase 3.
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee 90% -98%, comprising the steps of:
(1) preparation of acid salt: adding acid into the crude product 1 and the solvent A to prepare crude acid salt, evaporating to remove the solvent A, heating in the solvent B, refluxing for refining, and cooling to room temperature to obtain refined acid salt;
(2) stripping alkaloid: and (2) carrying out alkaline hydrolysis and solvent C extraction on the refined product acid salt obtained in the step (1), and evaporating the solvent C to obtain a refined product, namely: (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having an ee value of more than 99.5%.
Example 1
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee of 90%, comprising the steps of:
(1) preparation of acid salt: crude 1, i.e., (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane 20.0 having an ee value of 90% was dissolved in 100mL of ethanol, a 31% hydrochloric acid solution was added thereto at a controlled pH of 1-2, and then ethanol was distilled off under reduced pressure to give 23.0g of (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane hydrochloride. Then adding 233mL butanone, heating to 50 ℃, keeping the temperature for 2 hours, cooling to room temperature and 20 ℃, keeping the temperature for 2 hours, crystallizing, filtering, washing with absolute ethyl alcohol, and drying the solid to obtain 20.0g of refined product acid salt with the yield of 87.0 percent; ee value 99.6%;
(2) stripping alkaloid: adding 50mL of purified water and 3.0g of caustic soda flakes into the refined product acid salt obtained in the step (1), adding 50mL of toluene and 2 into the refined product acid salt, extracting, drying the product by anhydrous sodium sulfate, and evaporating the toluene to obtain light yellow oily liquid, namely 17.1g of (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, wherein the yield is 85.5%; the ee value was 99.6%.
Example 2
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee of 94.5%, comprising the steps of:
(1) preparation of acid salt: crude 1, i.e., (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, having an ee value of 94.5%, 20.0g was dissolved in 100mL of ethanol, a 31% hydrochloric acid solution was added, the pH was controlled at 1-2, and then ethanol was distilled off under reduced pressure to give 23.0g of (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane hydrochloride. Then adding 87.5mL of absolute ethyl alcohol, heating to 80 ℃, preserving heat for 1 hour, cooling to room temperature and 30 ℃, preserving heat for 1 hour, crystallizing, filtering, washing with absolute ethyl alcohol, and drying the solid to obtain 20.9g of refined product acid salt with the yield of 91%; ee value 99.9%;
(2) stripping alkaloid: adding 50mL of purified water and 3.2g of potassium hydroxide into the refined product acid salt obtained in the step (1), adding 50mL of dichloromethane to extract, drying the mixture by using anhydrous sodium sulfate, and evaporating the solvent to obtain light yellow oily liquid, namely (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane 17.9g, wherein the yield is 89.5%; ee value 99.9%
Example 3
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee of 95.2%, comprising the steps of:
(1) preparation of acid salt: crude 1, i.e., (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having an ee value of 95.2%, 20.0g, 100mL of ethanol was added with a 31% hydrochloric acid solution, the pH was controlled at 1-2, and then ethanol was distilled off under reduced pressure to give (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane hydrochloride 23.0 g. Adding 145.8mL of mixed solvent of ethanol and acetone, wherein the volume fraction of the ethanol accounts for 10%, heating to 60 ℃, keeping the temperature for 1 hour, cooling to room temperature and keeping the temperature for 1 hour for crystallization, filtering, washing with absolute ethanol, and drying the solid to obtain 21.6g of refined product acid salt, wherein the yield is 93.9%; ee value 99.9%
(2) Stripping alkaloid: adding 50mL of purified water and 3.3g of sodium carbonate into the refined product acid salt obtained in the step (1), adding 50mL of cyclohexane into the refined product acid salt, extracting the mixture, drying the mixture by using anhydrous sodium sulfate, and evaporating the solvent to obtain light yellow oily liquid, namely 18.5g of (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, wherein the yield is 92.5 percent; ee value 99.9%
Example 4
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee of 98%, comprising the steps of:
(1) preparation of acid salt: crude product 1 having an ee value of 98%, i.e., (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, 40.0g and 100mL of ethanol were added to a 31% hydrochloric acid solution, the pH was controlled at 1-2, and ethanol was distilled off under reduced pressure to give (S, S) -8-benzyl-2, 8-diazabicyclo [4.3.0] nonane hydrochloride 46.0 g. Then adding 233mL of mixed solvent of ethanol and butanone, wherein the volume fraction of the ethanol accounts for 15%, heating to 70 ℃, preserving the temperature for 1 hour, cooling to room temperature and 25 ℃, preserving the temperature for 1 hour, crystallizing, filtering, washing with acetone, and drying the solid to obtain refined product acid salt 44.6g, wherein the yield is 97.0%; ee value 99.8%
(2) Stripping alkaloid: adding 100mL of purified water and 6.6g of sodium bicarbonate into the refined product acid salt obtained in the step (1), adding 100mL of toluene and 2 into the refined product acid salt, extracting the mixture, drying the mixture by using anhydrous sodium sulfate, and evaporating the solvent to obtain light yellow oily liquid, namely (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane 38.4g, wherein the yield is 96.0%; the ee value was 99.8%.
Example 5
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee of 96%, comprising the steps of:
(1) preparation of acid salt: crude 1, i.e., (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having an ee value of 96%, 30.0g and 100mL of ethanol were added to a 47% hydrobromic acid solution, the pH was controlled at 1-2, and ethanol was distilled off under reduced pressure to give 40.0g of a hydrobromide salt of (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane. Then adding 304mL of a mixed solvent of methanol and butanone, wherein the volume fraction of the methanol accounts for 5%, heating to 55 ℃, preserving the heat for 2 hours, cooling to room temperature and 24 ℃, preserving the heat for 2 hours, crystallizing, filtering, washing with the mixed solvent, and drying the solid to obtain a refined product acid salt 37.0g, wherein the yield is 92.5%; ee value 99.9%;
(2) stripping alkaloid: adding 75mL of purified water and 4.8g of caustic soda flakes into the refined product acid salt obtained in the step (1), adding 75mL of toluene and 2 into the refined product acid salt, extracting the mixture, drying the mixture by using anhydrous sodium sulfate, and evaporating the toluene to obtain light yellow oily liquid, namely (S, S) -8-benzyl-2, 8-diazabicyclo [4.3.0] nonane 27.4g, wherein the yield is 91.3%; the ee value was 99.9%.
Example 6
A chiral purification process of compound B which is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a chiral purity ee of 96%, comprising the steps of:
(1) preparation of acid salt: adding a 47% hydrobromic acid solution into a crude product 1 with an ee value of 96%, namely ((S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane 30.0 and 100mL of ethanol, controlling the pH value to 1-2, evaporating the ethanol under reduced pressure to obtain a hydrochloride of ((S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane 34.5g, then adding 305.7mL of methanol, heating to 55 ℃, keeping the temperature for 2 hours, cooling to room temperature for 24 ℃, keeping the temperature for 2 hours, crystallizing, filtering, washing with a mixed solvent, and drying a solid to obtain a refined hydrochloride 31.7g, the yield of 91.9% and an ee value of 99.9%;
(2) stripping alkaloid: and (2) adding 75mL of purified water and 4.8g of caustic soda flakes into the refined product acid salt obtained in the step (1), adding 75mL of cyclohexane into the refined product acid salt, extracting the mixture, drying the mixture by using anhydrous sodium sulfate, and evaporating the cyclohexane to obtain light yellow oily liquid, namely (S, S) -8-benzyl-2, 8-diazabicyclo [4.3.0] nonane 27.1g, wherein the yield is 90.3 percent, and the ee value is 99.9 percent.
Claims (10)
1. A chiral purification method of a compound B, which is characterized in that: the method comprises the following steps:
(1) preparation of acid salt: mixing the crude product 1, a solvent A and acid to prepare crude acid salt, evaporating the solvent A, heating in a solvent B, refluxing for refining, and cooling to room temperature to obtain refined acid salt;
(2) stripping alkaloid: and (2) carrying out alkaline hydrolysis and solvent C extraction on the refined product acid salt obtained in the step (1), and evaporating the solvent C to obtain a refined product, namely: (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having an ee value of greater than 99.5%;
the reaction equation is as follows:
the compound B, i.e., the crude product 1 in step (1), is (S, R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane having a chiral purity ee of 90% -98%;
the acid of step (1) is a hydrohalic acid;
the refining process conditions in the step (1) are as follows: the temperature is 55-80 ℃, the time is 1-2 hours, and the temperature for cooling and crystallizing is 20-30 ℃.
2. Chiral purification process of compound B according to claim 1, characterized in that: the acid in step (1) is hydrochloric acid or hydrobromic acid.
3. Chiral purification process of compound B according to claim 1, characterized in that: the crude product 1 in the step (1) is obtained by resolution or chiral synthesis.
4. Chiral purification process of compound B according to claim 1, characterized in that: the solvent A in the step (1) is water or ethanol.
5. Chiral purification process of compound B according to claim 1, characterized in that: the solvent B in the step (1) is selected from an alcohol solvent or a ketone solvent or a mixed solvent of alcohol and ketone.
6. Chiral purification process of compound B according to claim 1, characterized in that: and (3) the solvent C in the step (2) is one selected from toluene, dichloromethane and cyclohexane separated from water.
7. Chiral purification process of compound B according to claim 1, characterized in that: the alkali required by the alkaline hydrolysis in the step (2) is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate.
8. Chiral purification process of compound B according to claim 1, characterized in that: the mass of the solvent B in the step (1) is 3-8 times of that of the crude acid salt.
9. Chiral purification process of compound B according to claim 5, characterized in that: the alcohol solvent is C1-4 alcohol, and the ketone solvent is selected from acetone and butanone.
10. Chiral purification process of compound B according to claim 5, characterized in that: the volume fraction of the alcohol in the mixed solvent of the alcohol and the ketone is 5-15%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6566523B1 (en) * | 1999-06-16 | 2003-05-20 | Bayer Aktiengesellschaft | Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane |
| CN112574197A (en) * | 2020-12-07 | 2021-03-30 | 泰安汉威集团有限公司 | Chiral purification method of compound C |
| CN112707901A (en) * | 2020-12-07 | 2021-04-27 | 泰安汉威集团有限公司 | Preparation method of compound A |
-
2020
- 2020-12-07 CN CN202011427427.1A patent/CN112724129A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6566523B1 (en) * | 1999-06-16 | 2003-05-20 | Bayer Aktiengesellschaft | Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane |
| CN112574197A (en) * | 2020-12-07 | 2021-03-30 | 泰安汉威集团有限公司 | Chiral purification method of compound C |
| CN112707901A (en) * | 2020-12-07 | 2021-04-27 | 泰安汉威集团有限公司 | Preparation method of compound A |
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