CN108659004B - Preparation method of oxiracetam isomer - Google Patents
Preparation method of oxiracetam isomer Download PDFInfo
- Publication number
- CN108659004B CN108659004B CN201810764944.4A CN201810764944A CN108659004B CN 108659004 B CN108659004 B CN 108659004B CN 201810764944 A CN201810764944 A CN 201810764944A CN 108659004 B CN108659004 B CN 108659004B
- Authority
- CN
- China
- Prior art keywords
- oxiracetam
- lactone
- type
- salt
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of an oxiracetam isomer. The (S) -oxiracetam and (R) -oxiracetam are prepared by the following steps: 1) the oxiracetam acid is dehydrated in molecules to generate oxiracetam lactone; 2) reacting the lactone with D (+) -10-camphorsulfonic acid to generate oxiracetam lactone salt of (1R,5R), (1S,5R), (1R,5S) and (1S, 5S); 3) the (1R,5R) and (1S,5R) oxiracetam lactone salts react with ammonia to generate (R) -oxiracetam, and the (1R,5S) and (1S,5S) oxiracetam lactone salts react with ammonia water to generate (S) -oxiracetam. The method provided by the invention can be used for preparing (S) -oxiracetam and (R) -oxiracetam, does not waste materials, has the advantages of simple operation, high product yield (up to 60%) and high product purity (more than 99.8%), and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of oxiracetam isomers (S) -oxiracetam and (R) -oxiracetam.
Background
The invention relates to synthesis of 4-hydroxy-2-oxo-1-pyrrolidine acetamide (oxiracetam). The molecular formula of oxiracetam is C6H10N2O3The derivative is a synthesized hydroxyl aminobutyric acid cyclic derivative, and the structural formula is as follows:
oxiracetam is an intelligence-developing medicine acting on cholinergic brain stem network structures, is used for treating brain injury and induced neurological deficit, memory and intelligence disorder, and has wide market prospect.
Research has shown that the isomer of oxiracetam (S) -oxiracetam is able to exert a greater effect than (R) -oxiracetam.
The invention patent CN 106146379B discloses a synthesis method of (S) -oxiracetam, which comprises the following steps: (1) carrying out esterification reaction on S-4-amino-3-hydroxybutyric acid serving as an initial raw material and alcohol to obtain an intermediate I; (2) carrying out condensation reaction on the intermediate I and haloacetate to obtain an intermediate II; (3) carrying out ring closure reaction on the intermediate II to obtain an intermediate III; (4) and carrying out ammonolysis reaction on the intermediate III to obtain a target product (S) -oxiracetam. The yield of the (S) -oxiracetam is only 20%, and the method has the advantages of long synthesis steps, complex operation and higher product cost, and is not suitable for industrial mass production.
The oxiracetam acid used as a raw material for preparing oxiracetam has the advantage of short reaction steps. The invention patent CN106496989A discloses a process for preparing oxiracetam from oxiracetam acid, wherein oxiracetam acid and a compound R-CH2-OH reaction to produce a compound having a structure represented by formula (a):
the preparation process of the oxiracetam is simple, but the obtained oxiracetam cannot distinguish (S) -oxiracetam and (R) -oxiracetam. And the subsequent utilization is limited.
At present, no process report for preparing (S) -oxiracetam or (R) -oxiracetam by using oxiracetam acid as a raw material exists.
Therefore, a method for preparing high-quality oxiracetam isomers (S) -oxiracetam and (R) -oxiracetam with high yield by using oxiracetam acid as a raw material is developed, and the method has important significance for industrially preparing two isomers of oxiracetam in a large scale.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for separating oxiracetam lactone salt isomers, which can separate (1R,5R), (1S,5R) type oxiracetam lactone salts and (1R,5S), (1S,5S) type oxiracetam lactone salts, and has the advantages of mild reaction conditions, simple operation, high reaction efficiency, and high product yield.
The second purpose of the invention is to provide a preparation method of oxiracetam isomer, which can prepare (S) -oxiracetam and (R) -oxiracetam, and has mild reaction conditions and high product yield.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for separating oxiracetam lactone isomer is characterized in that oxiracetam lactone and D (+) -10-camphorsulfonic acid react in an aprotic solvent to generate oxiracetam lactone salt, and the reaction equation is as follows:
crystallizing and separating out (1R,5R) and (1S,5R) type oxiracetam lactone salts in a reaction system, wherein (1R,5S) and (1S,5S) type oxiracetam lactone salts exist in a solution;
the structural formulas of the (1R,5R), (1S,5R), (1R,5S) and (1S,5S) type oxiracetam lactone salt are respectively shown as formula I, formula II, formula III and formula IV:
preferably, the reaction is carried out for 30min to 3h under the condition of keeping the temperature of 40 to 60 ℃ and stirring.
As a preferable scheme, a process of low-temperature crystal growth is carried out after oxiracetam acid lactone salt is generated by reaction.
Further, the low-temperature crystal growing specifically comprises: cooling to-10-0 deg.c for 1-3 hr.
Preferably, the low-temperature crystal growth is carried out at 0 ℃ for 2 hours.
Preferably, the aprotic solvent is selected from one or more of acetone, dimethylsulfoxide, acetonitrile, cyclohexane, dichloromethane and chloroform.
Further, acetone is preferable.
Preferably, the oxiracetam lactone is produced by intramolecular dehydration of oxiracetam acid. The reaction equation is:
further, it is preferable that: adding oxiracetam acid and a small amount of concentrated sulfuric acid into an aprotic solvent, heating for reaction, and then concentrating under reduced pressure to dryness to obtain oxiracetam acid lactone.
Preferably, the aprotic solvent is selected from one or more of acetone, dimethyl sulfoxide, acetonitrile, cyclohexane, dichloromethane and chloroform.
Preferably, the concentrated sulfuric acid is 98% concentrated sulfuric acid, and the adding amount is 0.5% -2% of the mass of the aprotic solvent.
Preferably, 98% concentrated sulfuric acid is added in an amount of 2% by mass of the aprotic solvent.
Preferably, the reaction temperature is 40-60 deg.C, and the reaction time is 2-5 hr.
Further, the temperature was 50 ℃ and the time was 3 hours.
A method for separating oxiracetam lactone salt isomers specifically comprises the following steps: filtering, collecting (1R,5R) and (1S,5R) type oxiracetam lactone salts from filter cakes, and collecting (1R,5S) and (1S,5S) type oxiracetam lactone salts from filtrate.
As a preferable scheme, the step of collecting the (1R,5S) and (1S,5S) type oxiracetam lactone salts is specifically as follows: drying the filtrate under reduced pressure at 40-60 deg.C to dryness.
As a preferable scheme, the collecting of the (1R,5R) and (1S,5R) type oxiracetam lactone salt in the filter cake is specifically: washing the filter cake with the aprotic solvent, collecting the filter cake, and drying under reduced pressure at 40-60 deg.C.
A process for preparing an isomer of oxiracetam, comprising the steps of:
1) obtaining oxiracetam lactone salt of (1R,5R), (1S,5R) type and oxiracetam lactone salt of (1R,5S) type according to the method of the object one;
2) dissolving the (1R,5R), (1S,5R) type oxiracetam lactone salt or (1R,5S) and (1S,5S) type oxiracetam lactone salt obtained in the step 1) in a polar organic solvent, introducing ammonia gas, and reacting to generate (R) -oxiracetam and (S) -oxiracetam.
The reaction equation for preparing oxiracetam isomer is as follows:
wherein, the formula V is (R) -oxiracetam, and the formula VI is (S) -oxiracetam.
Preferably, the polar organic solvent in step 2) is one or more of methanol, ethanol, n-propanol, isopropanol and tert-butanol.
Further, methanol is preferable.
Preferably, the reaction system in step 2) further comprises water, and the volume of the water is not more than 2% of the volume of the reaction system.
Preferably, the reaction for forming oxiracetam further comprises the processes of low-temperature crystal growing, filtering, washing, recrystallizing, filtering and drying.
Further, the low-temperature crystal growing is specifically carried out for 1-3 hours when the temperature is reduced to-10-0 ℃.
Preferably, the low-temperature crystal growth is carried out at 0 ℃ for 2 hours.
Further, the recrystallization process specifically comprises: adding water and a small amount of glacial acetic acid, heating to 40-70 ℃ for dissolving, filtering while the solution is hot after the solution is clear, slowly cooling the filtrate to 40-45 ℃, preserving heat, crystallizing, and then cooling to 0-10 ℃ for crystal growing.
Preferably, step 2) can be optimized as follows:
a. dissolving an oxiracetam acid lactone salt in a polar organic solvent, cooling to-10 ℃, introducing ammonia gas, and adding a small amount of water, wherein the volume of the water is not more than 2% of the volume of a reaction system; stirring and reacting for 10-24 hours at the temperature of 15-30 ℃ to generate (S) -oxiracetam and (R) -oxiracetam;
b. and c, cooling to-10-0 ℃, growing the crystals for 1-3 hours, filtering to obtain a filter cake, and washing with the polar organic solvent in the step a to obtain a (S) -oxiracetam and/or (R) -oxiracetam crude product.
Further, the oxiracetam acid lactone salt and ammonia in the step a are stirred and react for 15 hours at 25 ℃.
In summary, preferably, the preparation method of oxiracetam isomers of the present invention can comprise the following steps:
1) the oxiracetam acid is dehydrated in molecules to generate oxiracetam lactone, and the oxiracetam lactone is obtained by decompression and concentration;
2) reacting the lactone obtained in the step 1) with D (+) -10-camphorsulfonic acid in an aprotic solvent to generate oxiracetam lactone salt, growing crystals at low temperature, filtering, collecting (1R,5R) and (1S,5R) type oxiracetam lactone salt in a filter cake, and collecting (1R,5S) and (1S,5S) type oxiracetam lactone salt in a filtrate;
3) dissolving the (1R,5R), (1S,5R) type oxiracetam lactone salt or (1R,5S) and (1S,5S) type oxiracetam lactone salt obtained in the step 2) in a polar organic solvent, introducing ammonia gas, and reacting to generate (R) -oxiracetam and (S) -oxiracetam. The reaction equation is as follows:
the invention has the beneficial effects that:
1) the invention provides a method for separating isomers of an oxiracetam acid lactone salt, and provides methods for preparing (S) -oxiracetam and (R) -oxiracetam from the isomers respectively.
2) The separation method of the oxiracetam isomer only obtains the isomer of the oxiracetam lactone salt by filtering, has simple operation, can be used for preparing (S) -oxiracetam and (R) -oxiracetam, and greatly simplifies the preparation process of the oxiracetam isomer.
3) The reaction condition is mild, the product yield is up to 60 percent, which is higher than the yield of the prior art, and the method is suitable for industrialized mass production.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1 preparation of a reaction System comprising Oxiracetam lactone salt isomers
1. Preparation of oxiracetam lactone
Adding 100g of oxiracetam acid and 2g of concentrated sulfuric acid into 200g of acetone, heating to 50 ℃, stirring for reacting for 3 hours, and then concentrating under reduced pressure to dryness to obtain oxiracetam acid lactone, wherein the yield of the step is 100%.
2. Reaction system for preparing oxiracetam lactone salt in (1R,5R), (1S,5R) and (1R,5S), (1S,5S) types
Adding 400g of acetone and 144g of D (+) -10-camphorsulfonic acid into the oxiracetam lactone obtained in the step 1, heating to 50 ℃, keeping the temperature, stirring, reacting for 1h, then cooling to 0 ℃, keeping the temperature, and growing crystals for 2 h.
At this time, (1R,5R) type oxiracetam lactone salt and (1S,5R) type oxiracetam lactone salt are crystallized and precipitated in the reaction system, and (1R,5S) type oxiracetam lactone salt and (1S,5S) type oxiracetam lactone salt are present in the solution. The reaction system containing the oxiracetam lactone salt isomer is obtained.
Example 2 separation of isomers in reaction System comprising Oxiracetam lactone salt isomers
1) Taking the reaction system in the example 1, filtering, washing a filter cake with 40g of acetone, collecting the filter cake, controlling the temperature to be 50 ℃, and drying under reduced pressure for 6 hours to obtain (1R,5R) and (1S,5R) type oxiracetam lactone salt;
3) collecting the filtrate, controlling the temperature at 50 ℃, and drying under reduced pressure until the filtrate is dry to obtain the (1R,5S) and (1S,5S) type oxiracetam lactone salt.
Example 3 preparation of Oxiracetam type (R)
1) Adding 160g of methanol into the (1R,5R) and (1S,5R) oxiracetam lactone salt obtained in example 2, cooling to below 10 ℃, adding 2ml of water, introducing 24g of ammonia gas, introducing the ammonia gas, heating to 25 ℃, keeping the temperature, stirring, reacting for 15 hours, sampling, controlling the purity of a main peak to be about 97%, and remaining 2% of raw materials;
2) after the reaction is finished, cooling to 0 ℃, preserving heat, growing the crystals for 2 hours, filtering, and washing a filter cake with 20g of methanol to obtain a (R) type oxiracetam crude product;
3) adding 40g of water and 0.1g of glacial acetic acid, heating to 60 ℃ for dissolution, filtering while the solution is hot after the dissolution is clear, slowly cooling the filtrate to 40-45 ℃, preserving heat, crystallizing for 30min, then cooling to 5 ℃, crystallizing for 2h, filtering, washing a filter cake with 20g of precooled methanol to obtain 31.5g of (R) type oxiracetam wet product, and drying under reduced pressure for 6 h at the temperature of 55 ℃; 30.5g of (R) type oxiracetam is obtained, the mass yield is 61 percent, and the purity is more than or equal to 99.8 percent.
Example 4 preparation of Oxiracetam form (S)
1) Adding 160g of methanol into the (1R,5S) and (1S,5S) oxiracetam lactone salt obtained in example 2, cooling to below 10 ℃, adding 2ml of water, introducing 24g of ammonia gas, introducing the ammonia gas, heating to 25 ℃, keeping the temperature, stirring, reacting for 15 hours, sampling, controlling the purity of a main peak to be about 97%, and remaining 2% of raw materials;
2) after the reaction is finished, cooling to 0 ℃, preserving heat, growing the crystals for 2 hours, filtering, and washing a filter cake with 20g of methanol to obtain an (S) type oxiracetam crude product;
3) adding 40g of water and 0.1g of glacial acetic acid, heating to 60 ℃ for dissolution, filtering while the solution is hot after the dissolution is clear, slowly cooling the filtrate to 40-45 ℃, preserving heat, crystallizing for 30min, then cooling to 5 ℃, crystallizing for 2h, filtering, adding pre-cooled 20g of methanol, washing a filter cake to obtain 31g of (S) -type oxiracetam wet product, and controlling the temperature to 55 ℃ and drying under reduced pressure for 6 h; 30g of (S) type oxiracetam is obtained, the mass yield is 60 percent, and the purity is more than or equal to 99.8 percent.
The preparation method of the oxiracetam isomer provided by the invention can separate the isomer of oxiracetam lactone salt, and is used for preparing (S) -oxiracetam and (R) -oxiracetam, so that materials are not wasted. And the reaction condition is mild, the product yield is high, the quality is high, and the method is suitable for industrial mass production.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (10)
1. The method for separating oxiracetam lactone isomer is characterized in that oxiracetam lactone and D (+) -10-camphorsulfonic acid react in an aprotic solvent to generate oxiracetam lactone salt, the oxiracetam lactone salt is filtered, the (1R,5R) type oxiracetam lactone salt and the (1S,5R) type oxiracetam lactone salt are collected from a filter cake, the (1R,5S) type oxiracetam lactone salt and the (1S,5S) type oxiracetam lactone salt are collected from a filtrate, and the reaction equation is as follows:
wherein formula I, formula II, formula III and formula IV are (1R,5R), (1S,5R), (1R,5S) and (1S,5S) oxiracetam lactone salt respectively.
2. The method according to claim 1, wherein the reaction is carried out at 40-60 ℃ for 30min-3h under stirring.
3. The method according to claim 1, wherein the reaction produces oxiracetam lactone salt and then has a low-temperature crystal growth process, specifically comprising: cooling to-10-0 deg.c for 1-3 hr.
4. The process according to claim 1, wherein the aprotic solvent is selected from one or more of acetone, dimethylsulfoxide, acetonitrile, cyclohexane, dichloromethane, trichloromethane.
5. The method of claim 1, wherein the oxiracetam lactone is formed from an intramolecular dehydration reaction of oxiracetam acid.
6. The preparation method of the oxiracetam isomer is characterized by comprising the following steps of:
1) isolating oxiracetam lactone salt of type (1R,5R), (1S,5R) and oxiracetam lactone salt of type (1R,5S), (1S,5S) according to the method of claim 1;
2) dissolving the (1R,5R), (1S,5R) type oxiracetam lactone salt or (1R,5S) and (1S,5S) type oxiracetam lactone salt obtained in the step 1) in a polar organic solvent, introducing ammonia gas, and reacting to generate (R) -oxiracetam and (S) -oxiracetam.
7. The method according to claim 6, wherein the polar organic solvent in step 2) is one or more of methanol, ethanol, n-propanol, isopropanol and tert-butanol.
8. The preparation method according to claim 6, wherein the reaction system in step 2) further contains water, and the volume of the water is not more than 2% of the volume of the reaction system;
the reaction condition of the step 2) is that the reaction is carried out for 10 to 24 hours under the condition of heat preservation and stirring at the temperature of 15 to 30 ℃.
9. The method as claimed in claim 6, wherein step 2) is followed by low temperature crystallization, filtration, washing, recrystallization and drying.
10. The method according to claim 9, characterized in that the recrystallization is in particular: adding water and glacial acetic acid accounting for 0.2-0.5% of the mass of the water into the product, heating to 40-70 ℃ for dissolving, filtering while the solution is hot after the solution is clear, carrying out heat preservation and crystallization on the filtrate at the temperature of 40-45 ℃, and then cooling to 0-10 ℃ for crystal growth.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810764944.4A CN108659004B (en) | 2018-07-12 | 2018-07-12 | Preparation method of oxiracetam isomer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810764944.4A CN108659004B (en) | 2018-07-12 | 2018-07-12 | Preparation method of oxiracetam isomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108659004A CN108659004A (en) | 2018-10-16 |
| CN108659004B true CN108659004B (en) | 2020-11-10 |
Family
ID=63774024
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810764944.4A Active CN108659004B (en) | 2018-07-12 | 2018-07-12 | Preparation method of oxiracetam isomer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108659004B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0205247A2 (en) * | 1985-05-10 | 1986-12-17 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
| KR20060010000A (en) * | 2004-07-27 | 2006-02-02 | 한국화학연구원 | Process for preparation of (s) or (r)-oxiracetam |
| CN102633686A (en) * | 2011-02-09 | 2012-08-15 | 重庆福安药业(集团)股份有限公司 | Preparation method of peramivir |
| CN104693108A (en) * | 2013-12-06 | 2015-06-10 | 重庆博腾制药科技股份有限公司 | Preparation method of Bruton's tyrosine kinase (Btk) intermediate |
| CN105899487A (en) * | 2013-12-27 | 2016-08-24 | 株式会社Api | Method for producing 5-hydroxypiperidine-2-carboxylic acid |
| CN106146379A (en) * | 2013-06-19 | 2016-11-23 | 成都百途医药科技有限公司 | A kind of synthetic method of oxiracetam |
| CN106349144A (en) * | 2016-08-30 | 2017-01-25 | 山东默得森生物制药有限公司 | Preparation method of (S)-oxiracetam intermediate |
| WO2018011823A1 (en) * | 2016-07-13 | 2018-01-18 | Mylan Laboratories Limited | Salt of amine-protected (1s,2r,4s)-1,2-amino-n,n-dimethylcyclohexane-4-carboxamide |
| CN107750245A (en) * | 2015-05-13 | 2018-03-02 | 詹森药业有限公司 | (S) the CSA salt of S ketamines, (R) the CSA salt of S ketamines and the method for preparing S ketamines |
-
2018
- 2018-07-12 CN CN201810764944.4A patent/CN108659004B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0205247A2 (en) * | 1985-05-10 | 1986-12-17 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
| KR20060010000A (en) * | 2004-07-27 | 2006-02-02 | 한국화학연구원 | Process for preparation of (s) or (r)-oxiracetam |
| CN102633686A (en) * | 2011-02-09 | 2012-08-15 | 重庆福安药业(集团)股份有限公司 | Preparation method of peramivir |
| CN106146379A (en) * | 2013-06-19 | 2016-11-23 | 成都百途医药科技有限公司 | A kind of synthetic method of oxiracetam |
| CN104693108A (en) * | 2013-12-06 | 2015-06-10 | 重庆博腾制药科技股份有限公司 | Preparation method of Bruton's tyrosine kinase (Btk) intermediate |
| CN105899487A (en) * | 2013-12-27 | 2016-08-24 | 株式会社Api | Method for producing 5-hydroxypiperidine-2-carboxylic acid |
| CN107750245A (en) * | 2015-05-13 | 2018-03-02 | 詹森药业有限公司 | (S) the CSA salt of S ketamines, (R) the CSA salt of S ketamines and the method for preparing S ketamines |
| WO2018011823A1 (en) * | 2016-07-13 | 2018-01-18 | Mylan Laboratories Limited | Salt of amine-protected (1s,2r,4s)-1,2-amino-n,n-dimethylcyclohexane-4-carboxamide |
| CN106349144A (en) * | 2016-08-30 | 2017-01-25 | 山东默得森生物制药有限公司 | Preparation method of (S)-oxiracetam intermediate |
Non-Patent Citations (2)
| Title |
|---|
| D-对羟基苯甘氨酸的不对称转化拆分;杨帆等;《中国医药工业杂志》;20051231;第36卷(第4期);第199-200页 * |
| 促智药物(S)-奥拉西坦的合成;李坤等;《中国新药杂志》;20111231;第20卷(第19期);第1920-1921、1925页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108659004A (en) | 2018-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2839344B2 (en) | Method for producing cyclic amino acid and intermediate thereof | |
| CN108726569B (en) | Preparation method of silver hexafluoroantimonate | |
| CN108659004B (en) | Preparation method of oxiracetam isomer | |
| CN108314696B (en) | Utilization method of 2-hydroxy-1, 3, 5-tri-O-benzoyl-alpha-D-ribofuranose crystallization mother liquor | |
| CN112047999A (en) | Preparation method of gamma-crystal form arginine perindopril salt | |
| CN108516568B (en) | Production method of potassium nitrate | |
| CN111039852A (en) | N-ethylpyridine methylamine hydrochloride crystal, preparation process and application thereof in preparation of tropicamide | |
| CN110156689A (en) | A kind of extracting method of cucoline | |
| CN104447758A (en) | Synthesis process of pyrazolo[3,4-d]pyrimidine compounds | |
| CN111978258B (en) | Method for preparing phenytoin sodium | |
| CN106588888B (en) | Method for preparing high-purity L-sunitinib malate | |
| CN109651234B (en) | Synthesis method of donepezil hydrochloride | |
| CN112225736B (en) | Preparation method of 6-bromoimidazo [1.2-a ] pyridine-3-formaldehyde | |
| CN113683495B (en) | Method for preparing 4,4' -dihydroxybenzophenone | |
| CN114716411B (en) | Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor | |
| CN113004245B (en) | Preparation method of desloratadine | |
| CN114195761B (en) | Preparation method of high-purity sitafloxacin hydrate 3/2 | |
| CN111233672B (en) | Method for synthesizing nifedipine intermediate by using combined catalyst | |
| CN112661719B (en) | Clean preparation process of aminothiazoly loximate | |
| CN116874499A (en) | Synthesis method of meropenem side chain | |
| CN115850109A (en) | CAM preparation process and application thereof | |
| CN111574462A (en) | Preparation method of sodium 5-ethyl-5-phenyl barbiturate | |
| US2999111A (en) | Recovery of 6-deoxy-6-demethyltetracycline | |
| CN107674046B (en) | Purification method of atazanavir epoxide intermediate | |
| CN116120245A (en) | Preparation process of 3-methyl-2-cinnamoyl quinoxaline-1, 4-dioxide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |