WO2020134137A1 - 一种r-3-氯丝氨酸甲酯盐酸盐的制备方法 - Google Patents

一种r-3-氯丝氨酸甲酯盐酸盐的制备方法 Download PDF

Info

Publication number
WO2020134137A1
WO2020134137A1 PCT/CN2019/103059 CN2019103059W WO2020134137A1 WO 2020134137 A1 WO2020134137 A1 WO 2020134137A1 CN 2019103059 W CN2019103059 W CN 2019103059W WO 2020134137 A1 WO2020134137 A1 WO 2020134137A1
Authority
WO
WIPO (PCT)
Prior art keywords
serine
methyl ester
ester hydrochloride
synthesis method
chloroserine
Prior art date
Application number
PCT/CN2019/103059
Other languages
English (en)
French (fr)
Inventor
王丹
杨文�
李军
张新伟
刘丽莉
袁志法
Original Assignee
北京富盛嘉华医药科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 北京富盛嘉华医药科技有限公司 filed Critical 北京富盛嘉华医药科技有限公司
Publication of WO2020134137A1 publication Critical patent/WO2020134137A1/zh

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

Definitions

  • the present application relates to the field of drug synthesis, in particular to a method for preparing R-3-chloroserine methyl ester hydrochloride.
  • Antibiotics are chemical substances that are produced by microorganisms (including bacteria, fungi, actinomycetes) or higher animals and plants in the course of life and have anti-pathogens or other activities-secondary metabolites that can interfere with the development of other living cells .
  • Antibiotics commonly used in clinical practice include genetically engineered bacteria, extracts from culture broths, and chemically synthesized or semi-synthetic compounds.
  • D-cycloserine also known as D-4-amino-3-oxazolidinone, is an antibiotic drug that has a good inhibitory effect on tuberculosis bacteria. Because the bacteria are not easy to develop drug resistance, it is mainly used in the clinical treatment of infection with drug-resistant tuberculosis.
  • D-cycloserine is a special regulatory factor of the excitatory amino acid NMDA (N-methyl-D-aspartate) receptor in the central nervous system, which is used to treat psychophobia, depression, schizophrenia and other psychology The disease also has a good auxiliary effect, and it is also an important intermediate for the synthesis of the atypical ⁇ -lactam antibiotic Lactivicin. Therefore, D-cycloserine has broad application prospects and huge market demand.
  • NMDA N-methyl-D-aspartate
  • D-cycloserine is mainly synthesized by the following route:
  • GB 1031267 reports a method for preparing D-cycloserine by using ⁇ -( ⁇ '-ethoxyethylene)-imidoxy- ⁇ -bromopropionic acid methyl ester as a raw material.
  • ⁇ -( ⁇ '-ethoxyethylene)-imidoxy- ⁇ -bromopropionic acid methyl ester is aminated under liquid ammonia to generate ⁇ -( ⁇ '-ethoxyethylene)-ethylene Aminooxy- ⁇ -aminopropionamide, and then treated with HCl gas to obtain ⁇ -aminooxyalaninamide dihydrochloride, then cyclized under the action of KOH to form DL-cycloserine, and finally resolved with tartaric acid to obtain D -Cyclic serine.
  • the raw materials of this preparation method are expensive and difficult to obtain, and the production cost is relatively high, which is not suitable for industrial production.
  • GB 854922 reported the preparation of D-cycloserine using D-1-triphenylmethylaziridine-2-carboxylic acid methyl ester as raw material.
  • D-1-Triphenylmethylaziridine-2-carboxylic acid methyl ester first reacts with hydroxylamine hydrochloride at room temperature to form D-1-triphenylmethylaziridine-2-hydroxamic acid, then Under the action of HCl gas, the ring is opened to form D- ⁇ -amino- ⁇ -chloropropyl hydroxamate hydrochloride, which is then cyclized under the action of strong basic anion exchange resin to produce D-cycloserine.
  • This preparation method has a long reaction time, and the preparation of the raw material methyl D-1-triphenylmethylaziridine-2-carboxylate is difficult, which is not conducive to large-scale production.
  • Plttener P.A. et al. proposed a simple method for synthesizing D-cycloserine from D-serine methyl ester hydrochloride. That is, D-serine methyl ester hydrochloride (I) and phosphorus pentachloride undergo chlorination reaction to form D-2-amino-3-chloroserine methyl ester hydrochloride (II), (II) in sodium hydroxide solution It is combined with hydroxylamine to form D-ring seric acid (III) with a ring yield of 40%.
  • the synthetic route is shown below:
  • This method uses the relatively expensive D-serine methyl ester hydrochloride as a raw material, the cost is too high, and a large amount of PCl 5 that is not easy to handle is used in the production process, causing serious environmental pollution.
  • the present application provides a new method for synthesizing D-cycloserine.
  • the method has low cost, low environmental pressure, high purity, and high yield.
  • the high rate is conducive to large-scale production.
  • the present application provides a method for synthesizing R-3-chloroserine methyl ester hydrochloride, which includes the following steps:
  • D-serine reacts with paraformaldehyde to form D-serine-N-carboxy anhydride shown in formula III;
  • step 1) specific reaction conditions are: dissolve D-serine in a solvent and add paraformaldehyde, react at room temperature for 0.5-3 hours, concentrate the reaction solution, and crystallize in a small volume to obtain D-serine represented by formula III -N-carboxy anhydride.
  • small volume crystallization refers to the process of crystallization as the solvent decreases and the solute concentration increases.
  • the molar ratio of D-serine to paraformaldehyde is 1:1.2-1.5.
  • the solvent in step 1) is anhydrous tetrahydrofuran or dichloromethane.
  • the solvent in step 1) is n-butanol or ethyl acetate.
  • step 2) specific reaction conditions are: adding D-serine-N-carboxy anhydride represented by formula III to a solvent, adding the chlorinating reagent, reacting at 15-25°C for 1-3 hours, and concentrating the reaction The liquid was crystallized from petroleum ether to obtain R-3-chloroserine methyl ester hydrochloride.
  • the chlorinating agent in step 2) is dichlorosulfoxide.
  • the molar ratio of D-serine-N-carboxy anhydride, sulfoxide chloride and petroleum ether in step 2) is 1:1.5-2.0:1.
  • the solvent in step 2) is methanol or ethanol.
  • the present application provides a method for preparing D-cycloserine, which includes the synthesis method described in any one of the foregoing.
  • the present application also provides the use of R-3-chloroserine methyl ester hydrochloride in the preparation of D-cycloserine, wherein the R-3-chloroserine methyl ester hydrochloride It is prepared by the synthesis method described above.
  • This application provides a method for synthesizing D-cycloserine via R-3-chloroserine methyl ester hydrochloride, which has a low cost; at the same time, it avoids a large amount of PCl 5 or acid chloride reagents in the existing D-cycloserine synthesis technology It is more environmentally friendly to use; the product can be obtained by filtering and removing the salt during the post-treatment, and the process is simple, which is easier to industrialize; in addition, the purity of the final product is as high as 99% and the yield is as high as 94.72%.
  • D-serine NCA ie D-serine-N-carboxy anhydride

Abstract

本申请涉及药物合成领域，具体公开了一种R-3-氯丝氨酸甲酯盐酸盐的合成方法：其包括以下步骤：1)D-丝氨酸与多聚甲醛反应生成式III所示D-丝氨酸-N-羧基酸酐；2)式III所示D-丝氨酸-N-羧基酸酐与氯化试剂反应生成式V所示R-3-氯丝氨酸甲酯盐酸盐。该方法工艺操作简单、环境友好，反应条件温和，最终产品纯度高达99％，产率高达94.72％，有利于工业化生产。

Description

一种R-3-氯丝氨酸甲酯盐酸盐的制备方法 技术领域
本申请涉及药物合成领域，具体涉及一种R-3-氯丝氨酸甲酯盐酸盐的制备方法。
背景技术
抗生素是由微生物(包括细菌、真菌、放线菌属)或高等动植物在生活过程中所产生的具有抗病原体或其它活性的-类次级代谢产物，能干扰其他生活细胞发育功能的化学物质。现临床常用的抗生素有转基因工程菌、培养液液中提取物以及用化学方法合成或半合成的化合物。D-环丝氨酸又名D-4-氨基-3-噁唑烷酮，是一种抗生素类药物，对结核杆菌具有很好的抑制作用。因细菌对之不易产生耐药性，在临床上主要用于治疗耐药结核杆菌的感染。另外研究发现，D-环丝氨酸是中枢神经系统内兴奋性氨基酸NMDA(N-methyl-D-aspartate)受体的一种特别的调控因子，对治疗心理恐惧症、抑郁症、精神分裂症等心理疾病也有很好的辅助疗效，同时它也是合成非典型β-内酰胺抗生素Lactivicin的重要中间体。因此，D-环丝氨酸具有广泛的应用前景和巨大市场需求。
目前，D-环丝氨酸主要通过以下路线合成：
例如，US2772280、US2772281、US2640565、US2794022、US2918472及“环丝氨酸化学合成工艺的研究”(《华西药学杂志》，1995,10(1)：39～39)中公开了下述合成路线。但是其存在反应路线长，需拆分，合成成本较高的缺点。
Figure PCTCN2019103059-appb-000001
GB 1031267报道了以β-(α'-乙氧基亚乙基)-亚氨氧-α-溴代丙酸甲酯为原料制备D-环丝氨酸的方法。β-(α'-乙氧基亚乙基)-亚氨氧-α-溴代丙酸甲酯在液氨的作用下胺化生成β-(α'-乙氧基亚乙基)-亚氨氧-α-氨基丙酰胺，然后通过HCl气体处理后得β-胺氧基丙氨酰胺二盐酸盐，再在KOH的作用下环合生成DL-环丝氨酸，最后用酒石酸拆分得D-环丝氨酸。此制备方法原料价格昂贵不易得，生产成本较高，不适合工业化生产。
GB 854922报道了以D-1-三苯基甲基吖丙啶-2-甲酸甲酯为原料合成D-环丝氨酸的制备方法。D-1-三苯基甲基吖丙啶-2-甲酸甲酯先与羟胺盐酸盐在室温下反应生成D-1-三苯基甲基吖丙啶-2-异羟肟酸，然后在HCl气体作用下开环生成D-α-氨基-β-氯代丙基异羟肟酸盐酸盐，再在强碱性阴离子交换树脂作用下环合制得D-环丝氨酸。此制备方法反应时间较长，且原料D-1-三苯基甲基吖丙啶-2-甲酸甲酯制备困难，不利于大规模生产。
Plttener P.A.等提出了以D-丝氨酸甲酯盐酸盐为原料来合成D-环丝氨酸的简单方法。即D-丝氨酸甲酯盐酸盐(I)和五氯化磷发生氯代反应生成D-2-氨基-3-氯丝氨酸甲酯盐酸盐(II)，(II)在氢氧化钠溶液中与羟胺环合生成D环丝氮酸(III)，环合收率为40％。合成路线如下图所示：
Figure PCTCN2019103059-appb-000002
此方法以比较昂贵的D-丝氨酸甲酯盐酸盐作为原料，成本过高，且生产过程中大量使用不易处理的PCl 5，造成环境的严重污染。
发明内容
针对背景技术中所提及的现有合成D-环丝氨酸路线中存在的问题，本申请提供了一种新的合成D-环丝氨酸的方法，该方法成本低，环境压力小，纯度高，产率高，利于大规模生产。
因此，在一个方面，本申请提供一种R-3-氯丝氨酸甲酯盐酸盐的合成方法，其包括以下步骤：
1)D-丝氨酸与多聚甲醛反应生成式III所示D-丝氨酸-N-羧基酸酐；
2)式III所示D-丝氨酸-N-羧基酸酐与氯化试剂反应生成式V所示R-3-氯丝氨酸甲酯盐酸盐；
具体反应路线如下所示：
Figure PCTCN2019103059-appb-000003
在一些实施方案中，步骤1)具体反应条件为：将D-丝氨酸溶于溶剂中并加入多聚甲醛，室温反应0.5-3小时，浓缩反应液，小体积结晶得到式III所示D-丝氨酸-N-羧基酸酐。
如本文中所使用的，术语“小体积结晶”是指，随着溶剂减少，溶质浓度增大而结晶的过程。
在一些实施方案中，D-丝氨酸和多聚甲醛的摩尔比值为1:1.2-1.5。
在一些实施方案中，步骤1)中所述溶剂为无水四氢呋喃或二氯甲烷。
在一些实施方案中，步骤1)中所述溶剂为正丁醇或乙酸乙酯。
在一些实施方案中，步骤2)具体反应条件为：将式III所示D-丝氨酸-N-羧基酸酐加入溶剂中，加入所述氯化试剂，15-25℃反应1-3小时，浓缩反应液，经石油醚结晶得到R-3-氯丝氨酸甲酯盐酸盐。
在一些实施方案中，步骤2)中所述氯化试剂为二氯亚砜。
在一些实施方案中，步骤2)中所述D-丝氨酸-N-羧基酸酐和氯化亚砜和石油醚的摩尔比值为1：1.5-2.0：1。
在一些实施方案中，步骤2)所述溶剂为甲醇或乙醇。
在另一个方面，本申请提供D-环丝氨酸的制备方法，其包括前述任一项所述的合成方法。
在另一个方面，本申请还提供R-3-氯丝氨酸甲酯盐酸盐在制备D-环丝氨酸中的用途，其中所述R-3-氯丝氨酸甲酯盐酸盐经前述任一项所述的合成方法制备得到。
发明的有益效果
本申请提供一种经R-3-氯丝氨酸甲酯盐酸盐合成D-环丝氨酸的方法，该方法成本低；同时避免了现有D-环丝氨酸的合成技术中PCl 5或酰氯试剂的大量使用，更加环保；后处 理时经过滤去盐，浓缩即可得到产品，过程简单，更易工业化；另外，最终产品纯度高达99％，产率高达94.72％。
具体实施方式
下面结合具体实施例对本发明作进一步解说。
Figure PCTCN2019103059-appb-000004
实施例1
1)将105gD-丝氨酸在500ml四氢呋喃中加入多聚甲醛108g，室温反应2小时，回收四氢呋喃，小体积结晶得到D-丝氨酸NCA(即D-丝氨酸-N-羧基酸酐)；
2)D-丝氨酸NCA在甲醇中，加入110ml氯化亚砜，15℃反应1小时，回收甲醇加入300mL石油醚得到R-3-氯丝氨酸甲酯盐酸盐；(得到产品R-3-氯丝氨酸甲酯盐酸盐质量为160.92g，纯度为99.421％，收率为91.93％)。
实施例2
1)将105gD-丝氨酸在500ml四氢呋喃中加入多聚甲醛126g，室温反应0.5小时，回收四氢呋喃，小体积结晶得到D-丝氨酸NCA；
2)D-丝氨酸NCA在甲醇中，加入130ml氯化亚砜，20℃反应3小时，回收甲醇加入300mL石油醚得到R-3-氯丝氨酸甲酯盐酸盐；(得到产品R-3-氯丝氨酸甲酯盐酸盐质量为166.87g，纯度为99.488％，收率为93.11％)。
实施例3
1)将105gD-丝氨酸在500ml四氢呋喃中加入多聚甲醛135g，室温反应3小时，回收四氢呋喃，小体积结晶得到D-丝氨酸NCA；
2)D-丝氨酸NCA在甲醇中，加入145ml氯化亚砜，25℃反应2小时，回收甲醇加入300mL石油醚得到R-3-氯丝氨酸甲酯盐酸盐；(得到产品R-3-氯丝氨酸甲酯盐酸盐质量为165.63g，纯度为99.526％，收率为94.72％)。

Claims (9)

  1. 一种R-3-氯丝氨酸甲酯盐酸盐的合成方法，其包括以下步骤：
    1)D-丝氨酸与多聚甲醛反应生成式III所示D-丝氨酸-N-羧基酸酐；
    2)式III所示D-丝氨酸-N-羧基酸酐与氯化试剂反应生成式V所示R-3-氯丝氨酸甲酯盐酸盐；
    具体反应路线如下所示：
    Figure PCTCN2019103059-appb-100001
  2. 权利要求1的合成方法，其中步骤1)具体反应条件为：将D-丝氨酸溶于溶剂中并加入多聚甲醛，室温反应0.5-3小时，浓缩反应液，结晶得到式III所示D-丝氨酸-N-羧基酸酐。
  3. 权利要求1或2的合成方法，其中D-丝氨酸和多聚甲醛的摩尔比值为1:1.2-1.5。
  4. 权利要求2或3的合成方法，其中步骤1)中所述溶剂为无水四氢呋喃或二氯甲烷。
  5. 权利要求1-4任一项的合成方法，其中步骤2)具体反应条件为：将式III所示D-丝氨酸-N-羧基酸酐加入溶剂中，加入所述氯化试剂，15-25℃反应1-3小时，浓缩反应液，经石油醚结晶得到R-3-氯丝氨酸甲酯盐酸盐。
  6. 权利要求1-5任一项的合成方法，其中步骤2)中所述氯化试剂为二氯亚砜；
    优选地，步骤2)中所述D-丝氨酸-N-羧基酸酐和氯化亚砜和石油醚的摩尔比值为1：1.5-2.0：1。
  7. 根据权利要求5或6的合成方法，其中步骤2)所述溶剂为甲醇或乙醇。
  8. D-环丝氨酸的制备方法，其包括权利要求1-7任一项所述合成方法。
  9. R-3-氯丝氨酸甲酯盐酸盐在制备D-环丝氨酸中的用途，其中所述R-3-氯丝氨酸甲酯盐酸盐经权利要求1-7任一项所述合成方法制备得到。
PCT/CN2019/103059 2018-12-27 2019-08-28 一种r-3-氯丝氨酸甲酯盐酸盐的制备方法 WO2020134137A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811613850.3A CN109678739B (zh) 2018-12-27 2018-12-27 一种r-3-氯丝氨酸甲酯盐酸盐的合成方法
CN201811613850.3 2018-12-27

Publications (1)

Publication Number Publication Date
WO2020134137A1 true WO2020134137A1 (zh) 2020-07-02

Family

ID=66190633

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/103059 WO2020134137A1 (zh) 2018-12-27 2019-08-28 一种r-3-氯丝氨酸甲酯盐酸盐的制备方法

Country Status (2)

Country Link
CN (1) CN109678739B (zh)
WO (1) WO2020134137A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110590587A (zh) * 2019-09-23 2019-12-20 湖北宇阳药业有限公司 一种3-氯-l-丙氨酸甲酯盐酸盐的合成方法
CN110606811B (zh) * 2019-09-23 2022-12-02 湖北宇阳药业有限公司 一种l-丝氨酸甲酯盐酸盐的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106518694A (zh) * 2016-10-24 2017-03-22 浙江金伯士药业有限公司 一种l‑丙氨酸异丙酯盐酸盐的制备新方法
CN106518695A (zh) * 2016-11-03 2017-03-22 安徽省诚联医药科技有限公司 一种r‑氯丝氨酸甲酯盐酸盐的合成方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2206321B1 (zh) * 1972-11-13 1976-06-25 Kyowa Hakko Kogyo Kk
CN104003894B (zh) * 2013-02-21 2016-02-17 浙江嘉华化工有限公司 N-乙酰-β-氯-L-丙氨酸甲酯的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106518694A (zh) * 2016-10-24 2017-03-22 浙江金伯士药业有限公司 一种l‑丙氨酸异丙酯盐酸盐的制备新方法
CN106518695A (zh) * 2016-11-03 2017-03-22 安徽省诚联医药科技有限公司 一种r‑氯丝氨酸甲酯盐酸盐的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
I.A , RIVERO ET AL: "Esterification of Amino Acids and Mono Acids Using Triphosgene", SYNTHETIC COMMUNICTIONS, vol. 31, no. 14, 1 January 2001 (2001-01-01), pages 2169 - 2175, XP055715513, ISSN: 0039-7911, DOI: 10.1081/SCC-100104468 *
LI, XIAOMENG: "Study on the Synthesis and Property of the Derivates from Amino Acid", MASTER THESIS, no. 04, 30 April 2011 (2011-04-30), pages 1 - 77, XP009521802 *

Also Published As

Publication number Publication date
CN109678739B (zh) 2020-05-05
CN109678739A (zh) 2019-04-26

Similar Documents

Publication Publication Date Title
WO2020134137A1 (zh) 一种r-3-氯丝氨酸甲酯盐酸盐的制备方法
US20230045135A1 (en) Tedizolid intermediate and efficient preparation method thereof
CN101979376B (zh) 甘氨酰胺盐酸盐的制备方法
US8809581B2 (en) Method of making 6-aminocaproic acid as active pharmaceutical ingredient
CN108440409B (zh) 一种瑞巴匹特的绿色高效制备方法
CN106631885B (zh) 一种制备4-甲醛肟基苯甲酸酯类衍生物的方法
King et al. β-Aletheine1 and Pantetheine2
CN101333175A (zh) 制备d-天冬酰胺及d-高丝氨酸的方法
CN101125878B (zh) 甾体类肌松药物罗库溴铵的制备方法
WO2011091677A1 (zh) 阿利吉仑中间体3-氨基-2，2-二甲基丙酰胺的制备方法
CN107417606B (zh) N-氰甲基双（三氟甲基）烟酰胺转化为氟啶虫酰胺的方法及应用
JP6028606B2 (ja) アミン化合物の製造方法
CN105152975B (zh) 一种乙酰氧肟酸的合成方法
CN101759553A (zh) α-酮酸钙的制备方法
CN115536541A (zh) 氟雷拉纳和阿福拉纳共同中间体的合成方法
CN108033972A (zh) 一种头孢丙烯的合成方法
CN109734680B (zh) 一种d-环丝氨酸合成的方法
CN104003887A (zh) 一种盐酸溴己新的制备方法
CN110015969A (zh) 一种利奈唑胺杂质的合成方法
CN105198825B (zh) 一种d‑环丝氨酸的制备方法
CN113087655B (zh) 一种左布比卡因中间体化合物
CN103787903B (zh) 一种制备左乙拉西坦中间体2-氨基丁酸的方法
CN113105385B (zh) 一种左布比卡因的制备方法
CN113636980B (zh) 一种右丙亚胺的制备方法
CN110343074B (zh) 2-氨基-4-氯-5-氟嘧啶的合成方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19904431

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19904431

Country of ref document: EP

Kind code of ref document: A1