CN108947883A - The preparation of Bu Waxitan - Google Patents
The preparation of Bu Waxitan Download PDFInfo
- Publication number
- CN108947883A CN108947883A CN201710379948.6A CN201710379948A CN108947883A CN 108947883 A CN108947883 A CN 108947883A CN 201710379948 A CN201710379948 A CN 201710379948A CN 108947883 A CN108947883 A CN 108947883A
- Authority
- CN
- China
- Prior art keywords
- preparation
- organic solvent
- waxitan
- iodide
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the preparation methods of Bu Waxitan (formula IV), it includes the following steps: to obtain intermediate II by ammonolysis using (R) -4- propyl-dihydrofuran -2- ketone and (S) -2-amino-butyric acid as raw material, intermediate III is obtained through esterification, chloro, cyclization step again, last aminolysis step obtains Bu Waxitan (IV), wherein, esterification, chloro, cyclization step union operation.Mild condition of the present invention, easy to operate, raw material is easy to get, and is suitble to large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology fields.
Background technique
Bu Waxitan (Brivaracetam) is that have height by excellent when ratio (UCB) recent development of Belgian pharmacy giant
Affinity optionally combines synaptic vesicle proteins 2A(SV2A), it is wide spectrum antiepileptic (AED) Levetiracetam
(Keppra) action site.The affinity of Bu Waxitan is 15-30 times of Levetiracetam, its dosage is made to reduce about 10
Times.
On 2 18th, 2016, food and drug administration (FDA) approval Bu Waxitan (Briviact) conduct >=
The adjuvant treatment of patient part's property epileptic attack in 16 years old.Bu Waxitan is from approval eslicarbazepine (Aptiom) in 2013
Since FDA ratify first treatment part epileptic attack antiepileptic (AED).
European drug administration (European Medicines Agency, EMA) is in approved cloth on January 14th, 2016
Wa Xitan (brivaracetam) listing, for adult and 16 years old and the above teenager epileptic partial seizures, companion or
Not with the adjuvant treatment of secondary generalized seizures.
2 (5H)-furanones are reported in document J.Med.Chem.2004,47,530-549 to react with propyl magnesium bromide
To 4- propyl-dihydrofuran -2- ketone, Iodotrimethylsilane and furanone ring-opening reaction and chloride obtain 3-(iodomethyl) hexanoyl
Chlorine, then the mixture of Bu Waxitan and its diastereoisomer is obtained with (S) -2- amino-butanamide cyclization.The method is finally passed through
Silica gel column separating purification and chiral resolution obtain final products Bu Waxitan.This method higher cost, commercial viability is poor, instead
It should look like this:
。
It is reported in patent WO2005028435 by 5- hydroxyl -4- propyl furans -2- ketone and (2S) -2- amino-butanamide
Reductive amination and cyclization, obtain the mixture of Bu Waxitan and its diastereoisomer using hydrogenating reduction
Method finally still needs chiral resolution step.
It is disclosed in patent WO2007031263 using 2- hexenyl acetoacetic ester as starting material, is obtained by Macheal addition
To 3- nitre methylhexanoic acid methyl esters, hydro-reduction cyclization obtains 4- propyl pyrrole alkanone, and chirality preparation chromatography obtains (R) -4- propyl
Pyrrolidones, then react to obtain 2-((R with 2- bromo butyric acid methyl ester) -3 propyl pyrrole alkane -1- bases) methyl butyrate, then ammonolysis obtains
To 2-((R) -3- propyl pyrrole alkane -1- base) butyramide, finally by preparation chromatographic isolation obtain Bu Waxitan, the method last
Step obtains the mixture that product is Bu Waxitan He its diastereoisomer, needs to split by chiral column, limits industrialization
Using.
Patent WO2007065634 discloses one and obtains (R) -2- by asymmetric oxidation using n-pentene as starting material
Then hydroxyl amylalcohol reacts to obtain (4R) -4- propyl-glycol sulfite with thionyl chloride, obtains (4R) -4- third through peroxidating
Base-ethyl sulfate occurs affine substitution ring closure reaction with dimethyl malenate and obtains (S) -6,6- by pillar layer separation
Dimethyl -1- propyl -5,7- bis- dislikes 2,5 octane -4,8- diketone of spiral, then reacts to obtain with (S) -2- amino-butanamide
(4R) -1-((S) -1- amino -1- oxygen butyl- 2- yl) -2- oxygen -4- pyrrolidines -3- formic acid, last decarboxylation is simultaneously by pillar layer separation
Obtain Bu Waxitan.The method by upper protection, replaces, hydrolysis, again upper protection, ring expansion and de- since asymmetric oxidation reaction
Carboxylic reaction just obtains final products Bu Waxitan, and route steps are too long, and reaction type is more, increase industrialization difficulty.
A kind of preparation method for not needing chiral resolution is disclosed in patent CN201511028929.6, the method is with malonic acid
Diester and (R)-epoxychloropropane carry out ring-opening reaction under alkaline condition, and gained intermediate and ethyl metal reagent carry out addition
Reaction, then through decarboxylic reaction, halogenating agent open loop occurs that ring closure reaction is replaced to obtain Bu Waxi with (S) -2- amino-butanamide
Smooth, although which avoids chiral resolution, but still used active metal reagent, increases industrialization difficulty.Specific route
It is as follows:
。
From the point of view of existing literature report, existing synthetic route requires chiral resolution or column chromatography separating purification step substantially
Suddenly, and universal preparation step is longer, at high cost, is not suitable for industrialized production and therefore in the art, opens up a technique letter
Single, isolating and purifying easy Bu Waxitan preparation process is significantly.
Summary of the invention
For shortcoming and defect present in above-mentioned preparation method, the present invention provides a kind of simple processes, isolate and purify
Easy to operate, cost is relatively low, is easy to the Bu Waxitan preparation method of industrialization large-scale production.
The present invention includes the following steps: to pass through using (R) -4- propyl-dihydrofuran -2- ketone and (S) -2-amino-butyric acid as raw material
Cross ammonolysis and obtain intermediate II, then obtain intermediate III through esterification, chloro, cyclization step, last aminolysis step obtains Bu Waxi
Smooth (IV), wherein esterification, chloro, cyclization step union operation.
Reaction equation is as follows:
。
Technical characteristic of the invention is: a kind of preparation method of Bu Waxitan, characterized in that the following steps are included:
(1) (R) -4- propyl-dihydrofuran -2- ketone and (S) -2-amino-butyric acid are dissolved in polar organic solvent, in alkaline item
Reaction obtains intermediate II under part；The organic solvent includes dimethyl sulfoxide, n,N-Dimethylformamide, ethyl alcohol, methanol, tetrahydro
Furans, dioxane, the structural formula of the intermediate II are as follows:
；
(2) intermediate II obtained by step (1) is esterified in the methanol solution of thionyl chloride, and polar organic solvent is dissolved in after concentration,
It is reacted under alkaline condition with thionyl chloride, then obtains intermediate III through iodide catalysis reaction；The polar organic solvent packet
Include n,N-Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, the structural formula of the intermediate III are as follows:
；
(3) step (2) products obtained therefrom reacts to obtain Bu Waxitan (IV) with ammonium hydroxide in organic solvent；The organic solvent includes
N,N-Dimethylformamide, methanol, ethyl alcohol, dioxane, tetrahydrofuran.
Used alkali includes triethylamine, sodium carbonate, sodium hydroxide in the step (1) of the present invention.
Alkali employed in step (2) of the present invention includes triethylamine, pyridine, potassium hydroxide, sodium methoxide, sodium hydride；Institute
It include sodium iodide, potassium iodide using iodide.
(R) -4- propyl-dihydrofuran -2- ketone and (S) -2-amino-butyric acid mole ratio in the step (1) of the present invention
For 1:1 ~ 1:1.2；Used alkali and (S) -2-amino-butyric acid mole ratio are 1:1 ~ 1.1:1；Used reaction temperature is 50 ~ 80
℃。
The mole ratio of thionyl chloride employed in the step (2) of the present invention and intermediate II be 1.6:1 ~
2.5:1；The mole ratio of used alkali and intermediate II is 1:1 ~ 3:1；The mole ratio of used iodide and intermediate II
For 0.3:1 ~ 1:1；Used reaction temperature is 20 ~ 80 DEG C.
Ammonium hydroxide employed in step (3) of the present invention and the volume mass of intermediate III ratio are 5:1 ~ 20:1；Reaction
Used temperature is 20 ~ 50 DEG C.
Innovative point of the invention are as follows:
(1) using (R) -4- propyl-dihydrofuran -2- ketone and (S) -2-amino-butyric acid as raw material, chiral resolution or column color are avoided
Spectrum separation, simplifies technological operation；
(2) preparation route is short, and reaction condition is mild, reduces production cost to a certain extent.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, but protection scope of the present invention is not limited to
This.
Embodiment 1
A: (R) -4- propyl-dihydrofuran -2- ketone 10.0g(78.1mmol) is dissolved in 100mL DMF, sequentially adds sodium carbonate
9.1g(85.9mmol), (S) -2-amino-butyric acid 8.9g (86.4mmol), is warming up to 80 DEG C, is stirred to react 10h, reaction solution temperature
Degree is down to 0-5 DEG C, is diluted with water, and with the hydrochloric acid solution tune pH of 2N to 3, then is extracted with dichloromethane three times, merges organic phase, do
It is dry, it is concentrated to get 15.5g intermediate II, yield 86.1%.
B: 200mL methanol is added in thionyl chloride 8.4g(71.2mmol), 15.0g is added in temperature rising reflux 1h
(64.9mmol) intermediate II continues the 2h that flows back, after fully reacting, is down to room temperature, and directly gained residue is added after concentration
200mL DMF, adds triethylamine 7.2g(71.6mmol), lower addition thionyl chloride 8.4g(71.2mmol is stirred at room temperature), after
It is continuous to be stirred to react 3h, sodium iodide 4.9g(32.7mmol is added into reaction solution), it is warming up to 80 DEG C again, then add into reaction solution
Enter potassium hydroxide 3.6g(64.9mmol), continue 80 DEG C of stirring 2h, after fully reacting, near room temperature is diluted with water, uses dichloromethane
Alkane extracts three times, merges organic phase, dry, is concentrated to get 13.2g yellow oil, i.e. intermediate III, yield 89.8%.
C: the grease 13.0g of intermediate III is added in 100mL DMF, and ammonium hydroxide 100mL is added, 15h is stirred at room temperature,
It after fully reacting, is diluted with water, is extracted with dichloromethane three times, merges organic phase, be washed with water and wash twice, it is dry, it is concentrated to give
To 10g Bu Waxitan white solid, yield 82.6%.
Embodiment 2
A: (R) -4- propyl-dihydrofuran -2- ketone 10.0g(78.1mmol) is dissolved in 100mL DMSO, sequentially adds sodium carbonate
9.1g(85.9mmol), (S) -2-amino-butyric acid 9.7g (93.7mmol), is warming up to 80 DEG C, is stirred to react 10h, reaction solution temperature
Degree is down to 0-5 DEG C, is diluted with water, and with the hydrochloric acid solution tune pH of 2N to 3, then is extracted with dichloromethane three times, merges organic phase, do
It is dry, it is concentrated to get 15.1g intermediate II, yield 83.9%.
B: 200mL methanol is added in thionyl chloride 8.4g(71.2mmol), 15.0g is added in temperature rising reflux 1h
(64.9mmol) intermediate II continues the 2h that flows back, after fully reacting, is down to room temperature, and directly gained residue is added after concentration
200mL DMSO, adds pyridine 5.7g(71.6mmol), lower addition thionyl chloride 8.4g(71.2mmol is stirred at room temperature), continue
It is stirred to react 3h, sodium iodide 4.9g(32.7mmol is added into reaction solution), 30mins is stirred, then hydrogenation is added into reaction solution
Sodium 2.6g(64.9mmol), continue that 1h is stirred at room temperature, after fully reacting, temperature is down to 0-5 DEG C, and water quenching is added to go out, and dilutes, uses dichloro
Methane extracts three times, merges organic phase, dry, is concentrated to get 12.8g yellow oil, i.e. intermediate III, yield 87.1%.
C: the grease 12.0g of intermediate III is added in 100mL DMF, and ammonium hydroxide 180mL is added, 15h is stirred at room temperature,
It after fully reacting, is diluted with water, is extracted with dichloromethane three times, merges organic phase, be washed with water and wash twice, it is dry, it is concentrated to give
To 8.3g Bu Waxitan white solid, yield 74.1%.
Embodiment 3
A: (R) -4- propyl-dihydrofuran -2- ketone 10.0g(78.1mmol) is dissolved in 100mL DMF, sequentially adds potassium carbonate
11.9g(85.9mmol), (S) -2-amino-butyric acid 8.9g (86.4mmol), is warming up to 50 DEG C, is stirred to react 15h, reaction solution temperature
Degree is down to 0-5 DEG C, is diluted with water, and with the hydrochloric acid solution tune pH of 2N to 3, then is extracted with dichloromethane three times, merges organic phase, do
It is dry, it is concentrated to get 16.2g intermediate II, yield 90.0%.
B: 200mL methanol is added in thionyl chloride 8.4g(71.2mmol), 15.0g is added in temperature rising reflux 1h
(64.9mmol) intermediate II continues the 2h that flows back, after fully reacting, is down to room temperature, and directly gained residue is added after concentration
200mL dioxane, adds triethylamine 7.2g(71.6mmol), lower addition thionyl chloride 8.4g is stirred at room temperature
(71.2mmol) continues to be stirred to react 2h, and sodium iodide 4.9g(32.7mmol is added into reaction solution), it is warming up to 80 DEG C again,
Sodium methoxide 5.2g(96mmol is added into reaction solution again), continue 80 DEG C of stirring 5h, after fully reacting, near room temperature adds water dilute
It releases, is extracted with dichloromethane three times, merge organic phase, it is dry, it is concentrated to get 11.5g yellow oil, i.e. intermediate III, is received
Rate 78.2%.
C: the grease 11.0g of intermediate III is added in 100mL DMF, and ammonium hydroxide 80mL is added, 15h is stirred at room temperature, instead
It after answering completely, is diluted with water, is extracted with dichloromethane three times, merges organic phase, be washed with water and wash twice, it is dry, it is concentrated to get
8.9g Bu Waxitan white solid, yield 86.4%.
Claims (6)
1. the preparation method of Bu Waxitan, characterized in that the following steps are included:
(1) (R) -4- propyl-dihydrofuran -2- ketone and (S) -2-amino-butyric acid are dissolved in polar organic solvent, in alkaline item
Reaction obtains intermediate II under part；The organic solvent includes dimethyl sulfoxide, n,N-Dimethylformamide, ethyl alcohol, methanol, tetrahydro
Furans, dioxane, the structural formula of the intermediate II are as follows:
；
(2) intermediate II obtained by step (1) is esterified in the methanol solution of thionyl chloride, and polar organic solvent is dissolved in after concentration,
It is reacted under alkaline condition with thionyl chloride, then obtains intermediate III through iodide catalysis reaction；The polar organic solvent packet
Include n,N-Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, the structural formula of the intermediate III are as follows:
；
(3) step (2) products obtained therefrom reacts to obtain Bu Waxitan (IV) with ammonium hydroxide in organic solvent；The organic solvent includes
N,N-Dimethylformamide, methanol, ethyl alcohol, dioxane, tetrahydrofuran.
2. preparation method as described in claim 1, characterized in that alkali employed in the step (1) includes triethylamine, carbonic acid
Sodium, sodium hydroxide.
3. preparation method as described in claim 1, characterized in that alkali employed in the step (2) include triethylamine, pyridine,
Potassium hydroxide, sodium methoxide, sodium hydride；Used iodide include sodium iodide, potassium iodide.
4. the preparation method as described in claim 1 and 2, (R) -4- propyl-dihydrofuran -2- ketone and (S) -2- ammonia in step (1)
Base butyric acid mole ratio is 1:1 ~ 1:1.2；Used alkali and (S) -2-amino-butyric acid mole ratio are 1:1 ~ 1.1:1；It is used
Reaction temperature is 50 ~ 80 DEG C.
5. preparation method as claimed in claim 1 or 3, the mole of thionyl chloride and intermediate II employed in step (2)
Than for 1.6:1 ~ 2.5:1；The mole ratio of used alkali and intermediate II is 1:1 ~ 3:1；Used iodide and intermediate II
Mole ratio be 0.3:1 ~ 1:1；Used reaction temperature is 20 ~ 80 DEG C.
6. preparation method as described in claim 1, ammonium hydroxide employed in step (3) and the volume mass of intermediate III ratio are
5:1~20:1；Reacting used temperature is 20 ~ 50 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710379948.6A CN108947883A (en) | 2017-05-25 | 2017-05-25 | The preparation of Bu Waxitan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710379948.6A CN108947883A (en) | 2017-05-25 | 2017-05-25 | The preparation of Bu Waxitan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108947883A true CN108947883A (en) | 2018-12-07 |
Family
ID=64494452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710379948.6A Pending CN108947883A (en) | 2017-05-25 | 2017-05-25 | The preparation of Bu Waxitan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108947883A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942516A (en) * | 2019-03-27 | 2019-06-28 | 成都克莱蒙医药科技有限公司 | Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone |
| CN110357790A (en) * | 2018-07-26 | 2019-10-22 | 福建海西新药创制有限公司 | Compound and its purposes in synthesis Bu Waxitan bulk pharmaceutical chemicals |
| CN111187175A (en) * | 2020-01-08 | 2020-05-22 | 上海朴颐化学科技有限公司 | Method for preparing intermediate of brivaracetam by hydrogenation of microchannel reactor |
| WO2020143674A1 (en) * | 2019-01-09 | 2020-07-16 | Fujian Haixi Pharmaceuticals Co., Ltd | Compounds and their use in the synthesis of brivaracetam apis |
| CN113024434A (en) * | 2019-12-24 | 2021-06-25 | 上海科胜药物研发有限公司 | Preparation method of brivaracetam intermediate |
| CN114634437A (en) * | 2022-03-29 | 2022-06-17 | 武汉氟本氘合新材料科技有限公司 | Simple preparation method of brivaracetam |
| CN115340510A (en) * | 2022-10-18 | 2022-11-15 | 天津辰欣药物研究有限公司 | Preparation method of brivaracetam intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1190954A (en) * | 1995-05-26 | 1998-08-19 | 曾尼卡有限公司 | Process for the preparation of (thio-) carbonic/carbamic acid 2-pyrrolidonyl-3-esters, thio esters and amides |
| CN102947289A (en) * | 2010-04-13 | 2013-02-27 | 霍夫曼-拉罗奇有限公司 | Arylethynyl derivatives |
| CN106279074A (en) * | 2015-05-25 | 2017-01-04 | 苏州鹏旭医药科技有限公司 | A kind of compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
| CN106365986A (en) * | 2015-07-21 | 2017-02-01 | 苏州鹏旭医药科技有限公司 | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam |
| CN106432030A (en) * | 2015-10-10 | 2017-02-22 | 苏州鹏旭医药科技有限公司 | Preparation method of brivaracetam |
-
2017
- 2017-05-25 CN CN201710379948.6A patent/CN108947883A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1190954A (en) * | 1995-05-26 | 1998-08-19 | 曾尼卡有限公司 | Process for the preparation of (thio-) carbonic/carbamic acid 2-pyrrolidonyl-3-esters, thio esters and amides |
| CN102947289A (en) * | 2010-04-13 | 2013-02-27 | 霍夫曼-拉罗奇有限公司 | Arylethynyl derivatives |
| CN106279074A (en) * | 2015-05-25 | 2017-01-04 | 苏州鹏旭医药科技有限公司 | A kind of compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
| CN106365986A (en) * | 2015-07-21 | 2017-02-01 | 苏州鹏旭医药科技有限公司 | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam |
| CN106432030A (en) * | 2015-10-10 | 2017-02-22 | 苏州鹏旭医药科技有限公司 | Preparation method of brivaracetam |
Non-Patent Citations (1)
| Title |
|---|
| BENOIT M. KENDA，等: "Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity", 《J. MED. CHEM.》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357790A (en) * | 2018-07-26 | 2019-10-22 | 福建海西新药创制有限公司 | Compound and its purposes in synthesis Bu Waxitan bulk pharmaceutical chemicals |
| WO2020143674A1 (en) * | 2019-01-09 | 2020-07-16 | Fujian Haixi Pharmaceuticals Co., Ltd | Compounds and their use in the synthesis of brivaracetam apis |
| CN112154140A (en) * | 2019-01-09 | 2020-12-29 | 福建海西新药创制有限公司 | Compound and application thereof in synthesizing bulk drug of Brivaracetam (Brivaracetam) |
| CN112154140B (en) * | 2019-01-09 | 2023-11-24 | 福建海西新药创制股份有限公司 | Compound and application thereof in synthesizing Brivaracetam (Brivaracetam) bulk drug |
| CN109942516A (en) * | 2019-03-27 | 2019-06-28 | 成都克莱蒙医药科技有限公司 | Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone |
| CN113024434A (en) * | 2019-12-24 | 2021-06-25 | 上海科胜药物研发有限公司 | Preparation method of brivaracetam intermediate |
| CN111187175A (en) * | 2020-01-08 | 2020-05-22 | 上海朴颐化学科技有限公司 | Method for preparing intermediate of brivaracetam by hydrogenation of microchannel reactor |
| CN114634437A (en) * | 2022-03-29 | 2022-06-17 | 武汉氟本氘合新材料科技有限公司 | Simple preparation method of brivaracetam |
| CN114634437B (en) * | 2022-03-29 | 2023-05-30 | 武汉氟本氘合新材料科技有限公司 | Simple preparation method of brivaracetam |
| CN115340510A (en) * | 2022-10-18 | 2022-11-15 | 天津辰欣药物研究有限公司 | Preparation method of brivaracetam intermediate |
| CN115340510B (en) * | 2022-10-18 | 2023-01-24 | 天津辰欣药物研究有限公司 | Preparation method of brivaracetam intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108947883A (en) | The preparation of Bu Waxitan | |
| CN108503573B (en) | A kind of new preparation method of Bu Waxitan | |
| CN105859721B (en) | A kind of Yi Bulu replaces the preparation method of Buddhist nun | |
| CN105968024A (en) | Synthesis method of oxiracetam | |
| CN107141207B (en) | Synthetic method of 3 '-acyl-2, 4' -dihydroxy benzophenone compound | |
| CN105732622A (en) | Preparation method of apixaban | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN108947884A (en) | A kind of Preparation Method And Their Intermediate of imrecoxib | |
| CN113234004A (en) | Novel preparation process of brivaracetam | |
| JP2006232802A (en) | Method for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane | |
| CN107629064B (en) | A kind of synthetic method of Azacyclooctane and Furanones compound | |
| CN107501278B (en) | A kind of synthetic method of 5H- furans -2- ketone and piperidines | |
| CN108503610A (en) | A kind of preparation method of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one | |
| JPH01246259A (en) | Synthesis of deoxymannodilimycin | |
| CN109053528A (en) | A kind of synthesis technology of Levetiracetam | |
| CN114989061A (en) | Preparation method of brivaracetam | |
| CN106554333B (en) | A kind of synthetic method of pharmaceutical intermediate | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| CN106588921A (en) | Synthetic method for 7-azaindole-3-methyl formate | |
| CN106432059A (en) | Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN103204810B (en) | A kind of tolvaptan intermediate and preparation method thereof | |
| EP1464638A1 (en) | Process for producing erythro-3-amino-2-hydroxybutyric acid derivatives | |
| CN108947919A (en) | A kind of novel processing step and its key intermediate of gout suppressant Lesinurad | |
| CN1326926A (en) | Preparing D-(-)-Su's 1-R-substituted phenyl-2-difluoro acetoamino-3-fluoro-1-propanol from L type substituted phenyl serine ester |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181207 |