CN106146327A - A kind of synthetic method of D-Cycloserine intermediate - Google Patents
A kind of synthetic method of D-Cycloserine intermediate Download PDFInfo
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- CN106146327A CN106146327A CN201510159035.4A CN201510159035A CN106146327A CN 106146327 A CN106146327 A CN 106146327A CN 201510159035 A CN201510159035 A CN 201510159035A CN 106146327 A CN106146327 A CN 106146327A
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- methyl ester
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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Abstract
The present invention relates to the synthetic method of a kind of D-Cycloserine intermediate, the method is reacted with halogenating agent in organic solvent by D-Ser methyl ester or its acid salt, preparing 3-halo-D-alanine methyl ester or its acid salt, this compound is the important intermediate preparing D-Cycloserine.The method applied in the present invention technological operation is easy, safety is high, and reaction condition is gentle, and yield is high, low cost, and greatly reduces the generation of spent acid, is especially suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to the synthetic method of a kind of D-Cycloserine intermediate.
Background technology
D-Cycloserine (Cycloserine) is as antituberculotic Second line Drug, and owing to its drug resistance occurs slowly than other antitubercular agent, and without cross resistance between other antitubercular agent, therefore market prospect ratio is broader.Chemical name: dextrorotation-4-amino-3-tetrahydrochysene isoxazolone；Its structural formula is as follows:
The at present D-Cycloserine synthetic method of document report, typically with D-Ser or D-Ser methyl ester acid salt as initiation material, the most all must pass through halo, cyclization two-step reaction prepares D-Cycloserine.3-halo-D-alanine methyl ester or its acid salt are to prepare D-Cycloserine important intermediate, and wherein halo step is to prepare the difficult point in D-Cycloserine whole piece technique.
Current domestic general technique is to use PCl5Doing chlorinating agent, this technique needs (-20 to-10 DEG C) to be at low temperatures dividedly in some parts PCl5Powder, course of reaction can produce substantial amounts of spent acid, amplifies production and acquires a certain degree of difficulty.
Plattener P A et al. proposes a kind of straightforward procedure synthesizing D-2-amino-3-methyl chloropropionate hydrochlorate.The method, with D-Ser methyl ester hydrochloride as raw material, generates D-2-amino-3-methyl chloropropionate hydrochlorate with phosphorus pentachloride generation chlorination in chloroform, and this technique exists some deficiency following: one is the PCl used5For pressed powder, danger is higher, and is difficult to feed intake, and two is PCl5As producing the substantial amounts of spent acid (H of HCl and 1eq of 4eq during chlorinating agent3PO4), three is need to react at low temperatures (-20～-15 DEG C), and energy consumption is relatively big, and product is difficult to filter.
United States Patent (USP) US 6372941 discloses a kind of method preparing β-halogenno-alpha ,-amino carboxylic acid, its process is: with D-Ser and thionyl (two) chlorine as raw material, chlorination is carried out in preferably ether solvent, reactant liquor is concentrated under vacuum to the half of original volume, filter this concentrate (slurry), filtrate is lower dry in decompression, obtains dry crystal, and technological process is as follows:
This patent documentation further points out, in order to reach higher yield, this reaction is preferably carried out in the presence of HCl gas, the shortcoming of this method is: (1) raw material HCl is gas, it is stored in compression steel cylinder, there is potential safety hazard during use, (2) HCl gas can have certain corrosiveness in amplifying production process to equipment；(3), when this technique wants to obtain higher yields in course of reaction, the usage amount of HCl gas need to may eventually form substantial amounts of spent acid more than the molar equivalent of the 3 of substrate.
Hee-Kwon Kim etc. reports a kind of synthetic method preparing 3-bromine methyl lactamine hydrogen bromide salt in document Simple and efficient synthetic routes to D-cycloserine (Tetrahedron Letters 53 (2012) 1,668 1670), this technique is with D-Ser methyl ester hydrochloride as initiation material, cyclohexane give is reaction dissolvent, dibromo sulfoxide is as halogenating agent, 3-bromine methyl lactamine hydrogen bromide salt is generated under the catalytic action of DMF, the defect of this technique is: the halogenating agent dibromo sulfoxide used in (1) this technique is on the high side, Atom economy is relatively low compared with thionyl chloride；(2) total recovery of this technique low (85%), by-product is many.
3-halo disclosed above-D-alanine methyl ester acid salt or synthesis all existing defects of its analog, it is impossible to meet the demand of industrialized production, therefore, be badly in need of a kind of easy and simple to handle, safety, mild condition, with low cost and eco-friendly production technology.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of new method preparing 3-halo-D-alanine methyl ester hydrochloride, the method is simple to operate, safety, reaction condition is gentle, production cost is low, yield and purity are high, greatly reduce the generation of spent acid simultaneously, are especially suitable for industrialized production.
The present invention is achieved by the following technical solutions:
The invention provides and a kind of prepare 3-halo-D-alanine methyl ester or the method for its acid salt, described method includes: in organic solvent, makes halogenating agent react with D-Ser methyl ester or its acid salt, obtains 3-halo-D-alanine methyl ester or its acid salt.
Preferably, the method includes: first D-Ser methyl ester or its acid salt is joined in organic solvent, then is slowly dropped in reaction system by halogenating agent, and system temperature controls at-10-10 DEG C, preferably-5-5 DEG C, after halogenating agent is added dropwise to complete, system temperature is risen to 20-50 DEG C, preferably 30-45 DEG C, start reaction, response time is 8-16 hour, preferably 12 hours, is filtrated to get 3-halo-D-alanine methyl ester or its acid salt.
In the present invention, halogenating agent is 2:1-1:1, preferably 1.5:1-1.2:1 with the mol ratio of D-Ser methyl ester or its acid salt；Further preferably halogenating agent is thionyl chloride, and 3-halo-D-alanine methyl ester acid salt is 3-chloro-D-alanine methyl ester or its acid salt, the wherein preferred hydrochlorate of acid salt；Organic solvent is selected from acetonitrile, dichloromethane, chloroform, hexamethylene, ether solvent or the mixed solution of its mixture, preferably acetonitrile and dichloromethane.
In the present invention, the volume ratio of dichloromethane and acetonitrile is 1:3-3:1, preferably 1:2-2:1, more preferably 0.75-1.75:1.
The concrete reaction process of the present invention is as follows:
The present invention is by using acetonitrile and dichloromethane as reaction dissolvent first, successfully solve technical problem present in prior art, substantially increase the processing safety during D-Cycloserine intermediate industry metaplasia is produced, and technique is more environmentally-friendly, reaction condition is gentle, low cost, the halogenating agent SOCl simultaneously used2For liquid, compare PCl5It is more convenient for putting in reaction system, and product is prone to filter, and is especially suitable for industrialized production, it is simple to industrialization is amplified, and the product yield and the purity that finally obtain are the highest.
The present invention is further illustrated below by embodiment.It should be understood that following example are only used for illustrating the present invention rather than limitation of the present invention, all according to the simple modifications done under the concept thereof of the present invention, all should contain within protection scope of the present invention.
Detailed description of the invention:
Embodiment 1
In 1L four-hole boiling flask, add acetonitrile 150ml and dichloromethane 450ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl234.4ml (0.463mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 30 DEG C.After reaction 12h, filter to obtain white solid 61.4g (purity 96.8%), product yield 88.5%.
Embodiment 2
In 1L four-hole boiling flask, add acetonitrile 200ml and dichloromethane 400ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl234.4ml (0.463mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 30 DEG C.After reaction 12h, filter to obtain white solid 63.4g (purity 97%), yield 91.6%.
Embodiment 3
In 1L four-hole boiling flask, add acetonitrile 300ml and dichloromethane 300ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl234.4ml (0.463mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 20 DEG C.After reaction 12h, filter to obtain white solid 64.92g (purity 97%), yield 93.8%.
Embodiment 4
In 1L four-hole boiling flask, add acetonitrile 400ml and dichloromethane 200ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl243ml (0.579mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 30 DEG C.After reaction 12h, filter to obtain white solid 63.6g (purity 96.3%), yield 91.2%.
Embodiment 5
In 1L four-hole boiling flask, add acetonitrile 450ml and dichloromethane 150ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl234.4ml (0.463mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 30 DEG C.After reaction 12h, filter to obtain white solid 61.6g (purity 96.3%), yield 88.4%.
Embodiment 6
In 1L four-hole boiling flask, add acetonitrile 300ml and dichloromethane 300ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl257.4ml (0.772mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 30 DEG C.After reaction 12h, filter to obtain white solid 62.2g (purity 95.9%), product yield 88.8%.
Embodiment 7
In 1L four-hole boiling flask, add acetonitrile 300ml and dichloromethane 300ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl234.4ml (0.463mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 50 DEG C.After reaction 12h, filter to obtain white solid 63.9g (purity 95%), yield 90.4%.
Embodiment 8
In 1L four-hole boiling flask, add acetonitrile 342ml and dichloromethane 257ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl234.4ml (0.463mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 45 DEG C.After reaction 12h, filter to obtain white solid 64.7g (purity 97.1%), product yield 93.6%.
Embodiment 9
In 1L four-hole boiling flask, add acetonitrile 218ml and dichloromethane 382ml, weigh 60gD-serine methyl ester hydrochloride (0.386mol) and join in mixed solvent, stir, be cooled to 0 DEG C, be then slowly added into SOCl228.7ml (0.386mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 30 DEG C.After reaction 12h, filter to obtain white solid 63.4g (purity 96.1%), yield 90%.
Embodiment 10
In 500ml four-hole boiling flask, add acetonitrile 300ml, 30gD-serine methyl ester hydrochloride is joined in acetonitrile, stirs, be cooled to 0 DEG C, be then slowly added into SOCl217.2ml (0.23mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 35 DEG C.After reaction 12h, filter to obtain brown solid 21.1g (purity 82.1%), yield 51.6%.
Embodiment 11
In 500ml four-hole boiling flask, add dichloromethane 300ml, weigh 30gD-serine methyl ester hydrochloride and join in dichloromethane, stir, be cooled to 0 DEG C, be then slowly added into SOCl217.2ml (0.23mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 35 DEG C.After reaction 12h, filter to obtain faint yellow solid 29.6g (purity 5.5%), yield 5%, wherein remain substantial amounts of D-Ser methyl ester hydrochloride.
Embodiment 12
In 500ml four-hole boiling flask, add chloroform 300ml, weigh 30gD-serine methyl ester hydrochloride and join in chloroform, stir, be cooled to 0 DEG C, be then slowly added into SOCl217.2ml (0.23mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 40 DEG C.After 12h, reaction terminates, and filters to obtain faint yellow solid 24.3g (purity 66.7%), yield 48.3%, wherein remains more D-Ser methyl ester hydrochloride.
Embodiment 13
In 500ml four-hole boiling flask, add oxolane 300ml, weigh 30gD-serine methyl ester hydrochloride and join in oxolane, stir, be cooled to 0 DEG C, be then slowly added into SOCl217.2ml (0.23mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 40 DEG C.After 6h, reaction terminates, and filters to obtain brown solid 16.2g (purity 85.3%), yield 41.16%.
Embodiment 14
In 500ml four-hole boiling flask, add glycol dimethyl ether 300ml, weigh 30gD-serine methyl ester hydrochloride and join in glycol dimethyl ether, stir, be cooled to 0 DEG C, be then slowly added into SOCl217.2ml (0.23mol), maintains the temperature at 0 DEG C, adds SOCl2After be warming up to 40 DEG C.After 6h, reaction terminates, and filters to obtain brown solid 18.4g (purity 83.2%), yield 45.6%.
Embodiment 15
In 500ml four-hole boiling flask, add hexamethylene 300ml, weigh 30gD-serine methyl ester hydrochloride and join in hexamethylene, stir, be cooled to 0 DEG C, be then slowly added into SOCl217.2ml (0.23mol), maintains the temperature at 0 DEG C, then heats to 40 DEG C.After 6h, reaction terminates, and filters to obtain brown solid 11g (purity 73.6%), yield 24.1%.
Claims (10)
1. prepare 3-halo-D-alanine methyl ester or the method for its acid salt for one kind, it is characterised in that described method
Including: in organic solvent, make halogenating agent react with D-Ser methyl ester or its acid salt,
Obtain 3-halo-D-alanine methyl ester or its acid salt.
Method the most according to claim 1, it is characterised in that described organic solvent is selected from: acetonitrile,
Dichloromethane, chloroform, hexamethylene, ether solvent or its mixture.
Method the most according to claim 1 and 2, it is characterised in that described organic solvent is acetonitrile and two
The mixed solution of chloromethanes.
4. according to the method described in claim 1-3, it is characterised in that described dichloromethane and the volume of acetonitrile
Ratio is 1:3-3:1, preferably 1:2-2:1.
5. according to the method described in any one of claim 1-4, it is characterised in that described dichloromethane and acetonitrile
Volume ratio be 0.75-1.75:1.
6. according to the method described in any one of claim 1-5, it is characterised in that described reaction temperature is
20-50 DEG C, preferably 30-45 DEG C.
7. according to the method described in any one of claim 1-6, it is characterised in that described halogenating agent and D-silk
The mol ratio of propylhomoserin methyl ester or its acid salt is 2:1-1:1, preferably 1.5:1-1.2:1.
8. according to the method described in any one of claim 1-7, it is characterised in that described halogenating agent is dichloro
Sulfoxide.
9. according to the method described in any one of claim 1-8, it is characterised in that described 3-halo-D-the third ammonia
Acid methyl ester or its acid salt are 3-chloro-D-alanine methyl ester or its acid salt.
10. according to the method described in any one of claim 1-9, it is characterised in that described acid salt is hydrochloric acid
Salt.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510159035.4A CN106146327B (en) | 2015-04-03 | 2015-04-03 | A kind of synthetic method of D-Cycloserine intermediate |
| PCT/CN2016/077537 WO2016155596A1 (en) | 2015-04-03 | 2016-03-28 | Method of synthesizing 3-halo-d-alanine methyl ester or acid salt thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510159035.4A CN106146327B (en) | 2015-04-03 | 2015-04-03 | A kind of synthetic method of D-Cycloserine intermediate |
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| CN106146327A true CN106146327A (en) | 2016-11-23 |
| CN106146327B CN106146327B (en) | 2019-03-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115872882A (en) * | 2021-09-27 | 2023-03-31 | 中国科学院大连化学物理研究所 | Synthetic method of 3-chloro-alanine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283178A (en) * | 1997-12-27 | 2001-02-07 | 钟渊化学工业株式会社 | Processes for producing beta-halogenno-alpha, -amino-carboxylic acids and phenylcy steine derivatives and intermediates thereof |
| CN101550100A (en) * | 2009-04-21 | 2009-10-07 | 无锡盛福药业有限公司 | Method for preparing Levetiracetam |
| CN103288710A (en) * | 2013-05-20 | 2013-09-11 | 大连海荣科技开发有限公司 | Preparation method of trandolapril midbody (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2997032B1 (en) * | 2013-05-17 | 2018-07-25 | F.Hoffmann-La Roche Ag | 6-bridged heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
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- 2016-03-28 WO PCT/CN2016/077537 patent/WO2016155596A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283178A (en) * | 1997-12-27 | 2001-02-07 | 钟渊化学工业株式会社 | Processes for producing beta-halogenno-alpha, -amino-carboxylic acids and phenylcy steine derivatives and intermediates thereof |
| CN101550100A (en) * | 2009-04-21 | 2009-10-07 | 无锡盛福药业有限公司 | Method for preparing Levetiracetam |
| 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 |
| CN103288710A (en) * | 2013-05-20 | 2013-09-11 | 大连海荣科技开发有限公司 | Preparation method of trandolapril midbody (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid |
Non-Patent Citations (2)
| Title |
|---|
| HEE-KWON KIM 等: "Simple and efficient synthetic routes to D-cycloserine", 《TETRAHEDRON LETTERS》 * |
| NAGLE, ADVAIT S 等: "Efficient synthesis of β-amino bromides", 《TETRAHEDRON LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115872882A (en) * | 2021-09-27 | 2023-03-31 | 中国科学院大连化学物理研究所 | Synthetic method of 3-chloro-alanine |
| CN115872882B (en) * | 2021-09-27 | 2024-05-10 | 中国科学院大连化学物理研究所 | Synthesis method of 3-chloro-alanine |
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| WO2016155596A1 (en) | 2016-10-06 |
| CN106146327B (en) | 2019-03-19 |
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