CN109678739A - A kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride - Google Patents
A kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride Download PDFInfo
- Publication number
- CN109678739A CN109678739A CN201811613850.3A CN201811613850A CN109678739A CN 109678739 A CN109678739 A CN 109678739A CN 201811613850 A CN201811613850 A CN 201811613850A CN 109678739 A CN109678739 A CN 109678739A
- Authority
- CN
- China
- Prior art keywords
- chlorine
- methyl ester
- ester hydrochloride
- ser
- serine methyl
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention belongs to pharmaceutical synthesis fields, disclose a kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride: by D-Ser, paraformaldehyde, room temperature reaction are added, small size crystallizes to obtain D-Ser NCA；In methyl alcohol, thionyl chloride is added in D-Ser NCA, after room temperature reaction, petroleum ether is added and obtains R-3- chlorine serine methyl ester hydrochloride.This method technological operation is simple, environmental-friendly, and reaction condition is mild, and final products purity is up to 99%, and yield is up to 94.72%, is conducive to industrialized production.
Description
Technical field
Invention is related to pharmaceutical synthesis field, is related to a kind of preparation method of R-3- chlorine serine methyl ester hydrochloride.
Background technique
Antibiotic is produced in life process by microorganism (including bacterium, fungi, actinomyces) or high animals and plants
Raw has antipathogen or other active-class secondary metabolites, can interfere the chemistry of other living cells development functions
Substance.Existing clinically used antibiosis is known as transgenic engineered bacteria, extract and chemically synthesis or half in culture solution liquid
The compound of synthesis.Seromycin also known as D-4- amino -3- oxazolidone, are a kind of antibiotics, are had to tubercle bacillus
There is good inhibiting effect.Because bacterium is not likely to produce drug resistance to it, drug resistance tubercle bacillus clinically mainly used for treating
Infection.In addition the study found that D-Cycloserine is excitatory amino acid NMDA (N-methyl-D- in central nervous system
Aspartate) a kind of special regulatory factor of receptor, to psychological diseases such as the psychological neurosis for the treatment of, depression, schizophrenia
Disease also has good auxiliary curative effect, while it is also the important centre for synthesizing atypia beta-Lactam antibiotic Lactivicin
Body.Therefore, D-Cycloserine is with a wide range of applications and great market demand.
The synthetic route of existing seromycin is mainly synthesized by following route:
Synthetic route following (US2772280, US2772281, US2640565, US2794022, US2918472 and circumfili
The research West China Journal of Pharmaceutical Sciences of propylhomoserin chemical synthesis process, 1995,10 (1): 39~39): route steps are long, also need to split,
Synthesis cost is higher.
GB 1031267 is reported using β-(α '-ethoxyethylidene) alpha-brominated methyl propionate of-imido oxygen-as raw material D-
The preparation method of seromycin.The alpha-brominated methyl propionate of β-(α '-ethoxyethylidene)-imido oxygen-amine under the action of liquefied ammonia
Metaplasia is at β-(α '-ethoxyethylidene)-imido oxygen-alanyl amine, then by obtaining β-azyloxy after HCl gas treatment
Alanimamides dihydrochloride, then cyclization generates DL- seromycin under the action of KOH, finally splits to obtain D- circumfili with tartaric acid
Propylhomoserin.This preparation method expensive raw material price is not easy to obtain, and production cost is higher, is not suitable for industrialized production.
GB854922 is reported using D-1- trityl group ethylene imine -2- methyl formate as the preparation of raw material D-Cycloserine
Method.D-1- trityl group ethylene imine -2- methyl formate is first reacted with hydroxylamine hydrochloride at room temperature generates D-1- triphenyl
Methylaziridine -2- hydroxamic acid, then open loop generates D- pantonine-chloro propyl hydroxamic acid under the effect of HCl gas
Hydrochloride, then D- seromycin is made in cyclization under strong-base anion-exchange resin effect.This preparation method reaction time compared with
It is long, and the preparation of raw material D-1- trityl group ethylene imine -2- methyl formate is difficult, is unfavorable for being mass produced.
Etc. PlttenerP.A. propose using D-Ser methyl ester hydrochloride as raw material and synthesize the simple of D-Cycloserine
Method.I.e. propylhomoserin first in chlorination generation D-2- amino -3- chlorine occurs for the intoxicated hydrochloride of D-Ser first (1) and phosphorus pentachloride
Ester hydrochloride (II), II generate D circumfili nitronic acid (I) with azanol cyclization in sodium hydroxide solution, and cyclization yield is 40%.Synthesis
Route is shown below:
The method raw material has used more expensive D-Ser methyl ester hydrochloride, and cost is excessively high, and big in production process
Amount uses not tractable PCl5, causes the serious pollution of environment.
R-3- chlorine serine methyl ester hydrochloride is an important intermediate of seromycin, both at home and abroad to R-3- chlorine silk
The synthesis of propylhomoserin methyl ester hydrochloride does not have been reported that temporarily.In order to overcome expensive starting materials, the purity of existing D seromycin synthetic technology
It is not high, yield is relatively low, deficiency not environmentally, present applicant proposes a new R-3- chlorine serine methyl ester hydrochloride routes, instead
It should be routine operation, it is easy to operate；And raw material be all it is commercially available, price is suitable and in liberal supply, there is preferable industrial prospect.
Summary of the invention
Technical problems based on background technology, the invention proposes a kind of R-3- chlorine serine methyl ester hydrochlorides, should
Method is at low cost, and environmental pressure is small, and yield is high, is conducive to large-scale production.
A kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride, which is characterized in that method and step is as follows:
1) synthesis of D-Ser-N- carboxy acid anhydride: being added paraformaldehyde for D-Ser in a solvent, room temperature reaction
0.5-3 hours, recycling design crystallized to obtain D-Ser-N- carboxy acid anhydride (D-Ser NCA) to small size；
2) synthesis of R-3- chlorine serine methyl ester hydrochloride: D-Ser NCA is added in a solvent, and thionyl chloride is added,
15-25 DEG C reaction 1-3 hours, after recycling design, be added petroleum ether crystallize to obtain R-3- chlorine serine methyl ester hydrochloride.
Preferably, the molar ratio of D-Ser and paraformaldehyde is 1:1.2-1.5 in the reaction.
Preferably, the molar ratio of D-Ser NCA and thionyl chloride and petroleum ether is 1:1.5-2.0 in the reaction:
1。
Preferably, the step 1) solvent is anhydrous tetrahydro furan or methylene chloride.
Preferably, the step 2) solvent is methanol or ethyl alcohol.
Synthetic route of the invention is as follows:
(1)
(2)
Compared with prior art, the device have the advantages that being:
R-3- chlorine serine methyl ester hydrochloride is an important intermediate of seromycin, both at home and abroad to R-3- chlorine silk
The synthesis of propylhomoserin methyl ester hydrochloride does not have been reported that temporarily, since hydroxyl is not easy to be substituted during cyclization, so the prior art is not
Use the intermediate.Compared to the synthetic intermediate of existing seromycin, the invention proposes a kind of R-3- chlorine serine methylester salt
The synthetic method of hydrochlorate forms NCA in step 1), and hydroxyl is easier to be substituted, and R-3- chlorine serine methyl ester hydrochloride is easily made
It is standby, to obtain higher yield, it is suitble to industrialized production, purity is high has direct influence to the yield of seromycin；Together
When avoid a large amount of uses of PCl5 or acyl chlorides reagent in the synthetic technology of existing seromycin, it is more environmentally-friendly；End process, mistake
Salt is filtered off, is concentrated to get product, process is simple, is easier to industrialize, and final products purity is up to 99%, and yield is up to 94.72%.
Specific embodiment
Combined with specific embodiments below the present invention is made further to explain.
Embodiment 1
1) 105gD- serine is added to paraformaldehyde 108g in 500ml tetrahydrofuran, is reacted at room temperature 2 hours, recycling
Tetrahydrofuran crystallizes to obtain D-Ser NCA to small size；
2) in methyl alcohol, 110ml thionyl chloride is added in D-Ser NCA, and 15 DEG C are reacted 1 hour, and recycling methanol is added
300mL petroleum ether obtains R-3- chlorine serine methyl ester hydrochloride；(obtaining product R-3- chlorine serine methyl ester hydrochloride quality is
160.92g, purity 99.421%, yield 91.93%).
Embodiment 2
1) 105gD- serine is added to paraformaldehyde 126g in 500ml tetrahydrofuran, is reacted at room temperature 0.5 hour, is returned
Tetrahydrofuran is received, crystallizes to obtain D-Ser NCA to small size；
2) in methyl alcohol, 130ml thionyl chloride is added in D-Ser NCA, and 20 DEG C are reacted 3 hours, and recycling methanol is added
300mL petroleum ether obtains R-3- chlorine serine methyl ester hydrochloride；(obtaining product R-3- chlorine serine methyl ester hydrochloride quality is
166.87g, purity 99.488%, yield 93.11%).
Embodiment 3
1) 105gD- serine is added to paraformaldehyde 135g in 500ml tetrahydrofuran, is reacted at room temperature 3 hours, recycling
Tetrahydrofuran crystallizes to obtain D-Ser NCA to small size；
2) in methyl alcohol, 145ml thionyl chloride is added in D-Ser NCA, and 25 DEG C are reacted 2 hours, and recycling methanol is added
300mL petroleum ether obtains R-3- chlorine serine methyl ester hydrochloride；(obtaining product R-3- chlorine serine methyl ester hydrochloride quality is
165.63g, purity 99.526%, yield 94.72%).
Claims (5)
1. a kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride, which is characterized in that method and step is as follows:
1) synthesis of D-Ser-N- carboxy acid anhydride: paraformaldehyde is added in D-Ser in a solvent, reacts at room temperature 0.5-3
Hour, recycling design crystallizes to obtain D-Ser-N- carboxy acid anhydride to small size；
2) synthesis of R-3- chlorine serine methyl ester hydrochloride: D-Ser NCA is added in a solvent, and thionyl chloride, 15-25 is added
DEG C reaction 1-3 hour, after recycling design, addition petroleum ether crystallize to obtain R-3- chlorine serine methyl ester hydrochloride.
2. a kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride according to claim 1, which is characterized in that described
The molar ratio of D-Ser and paraformaldehyde is 1:1.2-1.5 in reaction.
3. a kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride according to claim 1, which is characterized in that described
The molar ratio of D-Ser NCA and thionyl chloride and petroleum ether is 1:1.5-2.0:1 in reaction.
4. a kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride according to claim 1, which is characterized in that step
1) solvent is anhydrous tetrahydro furan or methylene chloride.
5. a kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride according to claim 1, which is characterized in that step
2) solvent is methanol or ethyl alcohol.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811613850.3A CN109678739B (en) | 2018-12-27 | 2018-12-27 | Synthetic method of R-3-chloroserine methyl ester hydrochloride |
| PCT/CN2019/103059 WO2020134137A1 (en) | 2018-12-27 | 2019-08-28 | Method for synthesizing r-3-chloroalanine methyl ester hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811613850.3A CN109678739B (en) | 2018-12-27 | 2018-12-27 | Synthetic method of R-3-chloroserine methyl ester hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109678739A true CN109678739A (en) | 2019-04-26 |
| CN109678739B CN109678739B (en) | 2020-05-05 |
Family
ID=66190633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811613850.3A Active CN109678739B (en) | 2018-12-27 | 2018-12-27 | Synthetic method of R-3-chloroserine methyl ester hydrochloride |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN109678739B (en) |
| WO (1) | WO2020134137A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590587A (en) * | 2019-09-23 | 2019-12-20 | 湖北宇阳药业有限公司 | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride |
| CN110606811A (en) * | 2019-09-23 | 2019-12-24 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3936469A (en) * | 1972-11-13 | 1976-02-03 | Kyowa Hakko Kogyo Kabushiki Kaisha | Process for preparing N-carboxylic anhydrides of amino acids |
| CN104003894A (en) * | 2013-02-21 | 2014-08-27 | 浙江嘉华化工有限公司 | Method for preparing N-acetyl-beta-chlorine-L-alanine methyl ester |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106518694A (en) * | 2016-10-24 | 2017-03-22 | 浙江金伯士药业有限公司 | Novel preparation method of L-alanine isopropyl ester hydrochloride |
| CN106518695A (en) * | 2016-11-03 | 2017-03-22 | 安徽省诚联医药科技有限公司 | A synthetic method of (R)-methyl 2-amino-3-chloropropanoate hydrochloride |
-
2018
- 2018-12-27 CN CN201811613850.3A patent/CN109678739B/en active Active
-
2019
- 2019-08-28 WO PCT/CN2019/103059 patent/WO2020134137A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3936469A (en) * | 1972-11-13 | 1976-02-03 | Kyowa Hakko Kogyo Kabushiki Kaisha | Process for preparing N-carboxylic anhydrides of amino acids |
| CN104003894A (en) * | 2013-02-21 | 2014-08-27 | 浙江嘉华化工有限公司 | Method for preparing N-acetyl-beta-chlorine-L-alanine methyl ester |
Non-Patent Citations (1)
| Title |
|---|
| LAPIDOT, Y.等: "Reaction of phosgene with serine and ethanolamine", 《ISRAEL JOURNAL OF CHEMISTRY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590587A (en) * | 2019-09-23 | 2019-12-20 | 湖北宇阳药业有限公司 | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride |
| CN110606811A (en) * | 2019-09-23 | 2019-12-24 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN110606811B (en) * | 2019-09-23 | 2022-12-02 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109678739B (en) | 2020-05-05 |
| WO2020134137A1 (en) | 2020-07-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109678739A (en) | A kind of synthetic method of R-3- chlorine serine methyl ester hydrochloride | |
| CN110878032B (en) | Synthesis method of N-benzylacetamidine hydrochloride | |
| CN114057594A (en) | Process for preparing 2-amino-N- (2,2, 2-trifluoroethyl) acetamide or its salt | |
| CN101979376B (en) | Method for preparing glycinamide hydrochloride | |
| CN101260381B (en) | Engineering bacterium, construction thereof and method for preparing D-valine by using the same | |
| CN101891645A (en) | Method for preparing salicylamide | |
| CN101333175A (en) | Method for preparing D-asparagine and D-homoserine | |
| CN107011190A (en) | A kind of 1,2 7-oxa-bicyclo[4.1.0 open loop prepares the new technology of β aminocyclohexanols | |
| CN105566257A (en) | Industrial preparation method of acetyl tetrahydrofuran with high optical purity | |
| CN102304102B (en) | Preparation method of 1-methyl piperazine | |
| CN112266364B (en) | Preparation method of tetrahydroquinoxaline compound | |
| CN112552184B (en) | Synthetic method of cyclopropyl-containing chiral amine hydrochloride | |
| CN110684028B (en) | Preparation method of 2, 6-diazabicyclo [3,3,0] octane compound | |
| CN103351386A (en) | Synthetic method of azasetron hydrochloride | |
| CN109734680A (en) | A kind of D-Cycloserine synthetic method | |
| CN105198825B (en) | A kind of preparation method of D seromycins | |
| CN111848535A (en) | Process for synthesizing 1H-tetrazole acetic acid | |
| CN102351733B (en) | Method for preparing 2-amino-dimethyl acetamide hydrochloride | |
| CN109111371B (en) | Preparation method of hydrazino ethyl acetate hydrochloride | |
| CN101525641A (en) | Method for producing L-tryptophan by microbial enzyme method | |
| CN113636980B (en) | Preparation method of dexrazoxane | |
| CN110845356B (en) | Synthesis method of hydrazino ethyl acetate hydrochloride | |
| CN101250116B (en) | Method for suppressing impurity substance during preparation of benzo ammonia alcohol | |
| CN114957288B (en) | Synthesis method of tetramisole hydrochloride | |
| CN116621838A (en) | Butterfly acid active ester and synthesis method thereof |
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 | ||
| CB02 | Change of applicant information |
Address after: Room 2708, 27th floor, No. 4 Huixin East Street, Chaoyang District, Beijing Applicant after: Beijing Fusheng Jiahua Pharmaceutical Technology Co., Ltd. Address before: Room 2708, 27th floor, No. 4 Huixin East Street, Chaoyang District, Beijing Applicant before: Beijing Fusheng Jiahua International Trade Co., Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CB03 | Change of inventor or designer information |
Inventor after: Liu Lili Inventor after: Yuan Zhifa Inventor after: Wang Dan Inventor after: Yang Wen Inventor after: Li Jun Inventor after: Zhang Xinwei Inventor before: Wang Dan Inventor before: Yang Wen Inventor before: Li Jun Inventor before: Zhang Xinwei Inventor before: Liu Lili Inventor before: Yuan Zhifa |
|
| CB03 | Change of inventor or designer information |