CN103193657A - 一种合成依佐加滨中间体的方法 - Google Patents

一种合成依佐加滨中间体的方法 Download PDF

Info

Publication number
CN103193657A
CN103193657A CN2013101311785A CN201310131178A CN103193657A CN 103193657 A CN103193657 A CN 103193657A CN 2013101311785 A CN2013101311785 A CN 2013101311785A CN 201310131178 A CN201310131178 A CN 201310131178A CN 103193657 A CN103193657 A CN 103193657A
Authority
CN
China
Prior art keywords
ezogabine
intermediate preparation
formula
phenylenediamine
sodium borohydride
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
Application number
CN2013101311785A
Other languages
English (en)
Other versions
CN103193657B (zh
Inventor
杜玉民
方瑜
张蓉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHIJIAZHUANG DUZHI PHARMACEUTICAL TECHNOLOGY Co.,Ltd.
Original Assignee
Shijiazhuang Duen Medicine Science And Technology Co Ltd
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 Shijiazhuang Duen Medicine Science And Technology Co Ltd filed Critical Shijiazhuang Duen Medicine Science And Technology Co Ltd
Priority to CN201310131178.5A priority Critical patent/CN103193657B/zh
Publication of CN103193657A publication Critical patent/CN103193657A/zh
Application granted granted Critical
Publication of CN103193657B publication Critical patent/CN103193657B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Saccharide Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

本发明公开了依佐加滨（式A）的中间体4-（4-氟苄基氨基）-1,2-苯二胺（式C）的合成方法。

Description

一种合成依佐加滨中间体的方法
发明领域
本发明涉及的是化合物依佐加滨中间体的制备方法。该化合物用以合成抗癫痫及神经保护药物依佐加滨。
背景技术
依佐加滨（Ezogabine），化学名称：N-[2-氨基-4-（4-氟苄氨基）苯基]氨基甲酸乙酯二盐酸盐，商品名：Potiga，是由Valeant制药公司和葛兰素史克( GSK )公司合作开发的一种新型抗癫痫药物。该药是一种神经元钾离子通道开放剂，2011年3月在欧洲上市，称为瑞替加滨 (retigabine)，商品名：Trobalt。2011年6月由美国FDA批准用于辅助治疗成年人部分性癫痫发作。依佐加滨的结构如下：
Figure 292858DEST_PATH_IMAGE001
已公开报道的依佐加滨合成方法有以下几种：
美国专利US5384330、EP0554543、WO2013011518、WO2012098075报道了五条合成路线。
路线一
Figure 209999DEST_PATH_IMAGE002
路线二
Figure 52053DEST_PATH_IMAGE004
路线三
Figure 447262DEST_PATH_IMAGE005
路线四
Figure 77613DEST_PATH_IMAGE006
路线五
Figure 900076DEST_PATH_IMAGE007
WO2013011518报道了化合物B的两种合成方法：
Figure 167109DEST_PATH_IMAGE008
鉴于依佐加滨（Ezogabine）作为首个神经元钾离子通道开放剂抗癫痫药，临床上辅助治疗癫痫部分发作，有快速明确并且比较显著的临床疗效及较好的耐受性，为成人癫痫患者带来了希望，拥有较好的应用前景。因此，有必要寻操作简便、成本低廉、反应周期短、收率高、质量好的合成路线。本发明提供了一种简单、高效，能在保证产品收率的前提下明显缩短反应时间，提高产品质量的中间体（C）的合成方法。
Figure 428326DEST_PATH_IMAGE009
实施例4-（4-氟苄氨基）-2-硝基苯胺的合成
室温搅拌下，将4-氟苯甲醛（12.4g，0.1mol）溶于200ml甲醇中，加入2-硝基-1,4-苯二胺（15.3g，0.1mol）、碘（0.51 g，0.02mol）。然后，室温搅拌下，分批加入硼氢化钠（7.18 g, 0.19mol），加毕后搅拌2 h，减压浓缩至干，加入45 ml水，得悬浮液。二氯甲烷萃取（30 ml×4），合并有机相，30 ml水洗，无水硫酸钠干燥，抽滤，减压浓缩，得暗红色油状物，加入40 ml甲苯，室温下放置，析出暗红色结晶，过滤，干燥，得4-（4-氟苄氨基）-2-硝基苯胺23.3 g，产率89.2%。 
实施例4-（4-氟苄氨基）-1,2-苯二胺的合成
硼氢化钠7.6 g （0.20 mol）分批加入到硫酸铵66 g（0.50 mol）和硝基化合物26.1 g（0.10 mol）的300ml乙醇溶液中。室温搅拌1.5h，然后加入200ml水和100ml甲基叔丁基醚，水层用甲基叔丁基醚萃取（50 ml×4），合并有机相，无水硫酸钠干燥，减压蒸出溶剂。剩余物用乙醇重结晶，得目标化合物4-（4-氟苄氨基）-1，2-苯二胺19.7g，收率85.28%。 

Claims (10)

1.一种依佐加滨中间体的制备方法，其特征在于，包括以下步骤：将2-硝基-1,4-苯二胺和对氟苯甲醛为原料, 经亲核加成/脱水、还原两步反应一锅法合成4-（4-氟苄基氨基）-2-硝基苯胺（式B），在低级醇中用硼氢化钠-硫酸铵还原B合成依佐加滨中间体4-（4-氟苄基氨基）-1,2-苯二胺（式C）。
2.根据权利要求1所述的一种依佐加滨中间体制备方法，其特征在于，所述的亲核加成/脱水、还原两步反应，是采用在还原剂硼氢化钠-碘存在下，以低级醇为溶剂的一锅合成法。
3.根据权利要求2所述的一种依佐加滨中间体制备方法，其特征在于，所述低级醇为甲醇、乙醇、乙二醇、异丙醇中的一种。
4.根据权利要求3所述的一种依佐加滨中间体制备方法，其特征在于，所述的溶剂为甲醇。
5.根据权利要求1所述的一种依佐加滨中间体制备方法，其特征在于，所述的还原剂为硼氢化钠-碘。
6.根据权利要求1所述的一种依佐加滨中间体制备方法，其特征在于，所述的还原剂为硼氢化钠-硫酸铵。
7.根据权利要求1所述的一种依佐加滨中间体制备方法，其特征在于，所述的硼氢化钠-硫酸铵还原反应中低级醇为甲醇、乙醇、乙二醇、异丙醇中的一种。
8.根据权利要求7所述的一种依佐加滨中间体制备方法，其特征在于，所述低级醇为乙醇。
9.根据权利要求1所述的一种依佐加滨中间体制备方法，其特征在于，生成B的反应温度为室温。
10.根据权利要求1所述的一种依佐加滨中间体制备方法，其特征在于，生成C的反应温度为室温。
CN201310131178.5A 2013-04-16 2013-04-16 一种合成依佐加滨中间体的方法 Active CN103193657B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310131178.5A CN103193657B (zh) 2013-04-16 2013-04-16 一种合成依佐加滨中间体的方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310131178.5A CN103193657B (zh) 2013-04-16 2013-04-16 一种合成依佐加滨中间体的方法

Publications (2)

Publication Number Publication Date
CN103193657A true CN103193657A (zh) 2013-07-10
CN103193657B CN103193657B (zh) 2015-08-05

Family

ID=48716494

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310131178.5A Active CN103193657B (zh) 2013-04-16 2013-04-16 一种合成依佐加滨中间体的方法

Country Status (1)

Country Link
CN (1) CN103193657B (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5384330A (en) * 1992-01-08 1995-01-24 Asta Medica Aktiengesellschaft Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them
WO2011012659A2 (en) * 2009-07-28 2011-02-03 Medichem S.A. Diethyl 4-(4-fluorobenzylamino)-1,2-phenylenedicarbamate, and salts thereof
WO2013011518A1 (en) * 2011-07-21 2013-01-24 Arch Pharmalabs Limited Process for the preparation of retigabine of the formula i and pharmaceutically acceptable salts thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5384330A (en) * 1992-01-08 1995-01-24 Asta Medica Aktiengesellschaft Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them
WO2011012659A2 (en) * 2009-07-28 2011-02-03 Medichem S.A. Diethyl 4-(4-fluorobenzylamino)-1,2-phenylenedicarbamate, and salts thereof
WO2013011518A1 (en) * 2011-07-21 2013-01-24 Arch Pharmalabs Limited Process for the preparation of retigabine of the formula i and pharmaceutically acceptable salts thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MARIAPPAN PERIASAMY等: "Methods of enhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》, vol. 69, 31 December 2000 (2000-12-31), pages 137 - 151 *
SUJATA GOHAIN等: "A new and Efficient Method for the Selective Reduction of Nitroarenes: Use of Ammonium Sulphate-Sodium Borohydride", 《CHEMISTRY LETTERS》, 31 December 1995 (1995-12-31), pages 725 - 726 *

Also Published As

Publication number Publication date
CN103193657B (zh) 2015-08-05

Similar Documents

Publication Publication Date Title
Maetani et al. Synthesis of a bicyclic azetidine with in vivo antimalarial activity enabled by stereospecific, directed C (sp3)–H arylation
CN101066945B (zh) 一种合成3-位取代内酰胺类化合物的方法
Huang et al. Mild metal-free hydrosilylation of secondary amides to amines
CN105153016B (zh) 一种匹莫范色林的制备方法
JP2021517901A (ja) アルコラート塩基の存在下でのニコチン酸エチルとｎ−ビニルピロリドンとの反応によるラセミ体ニコチンの調製及びその後の工程
KR101791119B1 (ko) N-[4-(1-아미노에틸)-페닐]-술폰아미드 유도체의 카이랄 분할 방법
Silverio et al. N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo-and enantioselective vinylogous Mannich reactions
EP3246324A3 (en) Phenyl c-glucoside derivative containing deoxyglucose structure, preparation method and uses thereof
CN104402793A (zh) 一种3-取代氧化吲哚衍生物及其合成方法和应用
JP2019501923A (ja) 極性非プロトン性溶媒を用いたｎ−［４−（１−アミノエチル）−フェニル］−スルホンアミド誘導体のキラル分割方法
CN104447451A (zh) 一种奥司他韦中间体的新制备方法
Saha et al. Practical application of PhI (OAc) 2/I2 combination to synthesize benzimidazoles from 2-aminobenzylamine through ring distortion strategy
CN103193657A (zh) 一种合成依佐加滨中间体的方法
CA2663080A1 (fr) Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique.
Puglisi et al. Stereoselective nucleophilic addition to imines catalyzed by chiral bifunctional thiourea organocatalysts
CN103159747A (zh) 一种二对甲苯磺酸拉帕替尼的合成方法
CN101519374B (zh) 一种手性吡啶类芳环氨基醇的衍生物的合成方法及其部分中间产物与最终产物
Mizota et al. Synthesis of 1, 2-Diamino Acid Derivatives Utilizing Diastereoselective Tandem N-Alkylation/Homo-and Cross-Addition Reaction of α-Aldimino Thioesters
Rivera et al. New cyclic aminals derived from rac-trans-1, 2-diaminocyclohexane: synthesis and crystal structure of racemic 1, 8, 10, 12-tetraazatetracyclo [8.3. 1.1. 8, 1202, 7] pentadecane and a route to its enantiomerically pure (R, R) and (S, S) isomers
CN104829553A (zh) 一种合成2,4-二取代苯并噻唑的新方法
Peddie et al. A Study on the Diastereoselective Synthesis of α‐Fluorinated β3‐Amino Acids by α‐Fluorination
CN103588699A (zh) (r)-3-氨基哌啶(i)的不对称合成方法及相关中间体
CN103787921B (zh) 一种制备高光学纯度的反式1,2-环二胺的方法
Yamada et al. Ruthenium-Catalyzed Direct Asymmetric Reductive Amination for the Synthesis of a Chiral Primary Amine Intermediate En Route to a PDE2A Inhibitor, TAK-915
WO2012040853A1 (en) Group 5 metal complexes useful for amine functionalization and synthetic process for manufacture thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20200727

Address after: 050000 Shijiazhuang, Yuhua Province, Green Park Street, No. 1-1-102, No. 284

Patentee after: SHIJIAZHUANG DUZHI PHARMACEUTICAL TECHNOLOGY Co.,Ltd.

Address before: 050017 dormitory 4-2-103, Hebei Medical University, 361 East Zhongshan Road, Hebei, Shijiazhuang

Patentee before: SHIJIAZHUANG DUEN PHARMACEUTICAL TECHNOLOGY Co.,Ltd.