CN101643433A - 合成阿戈美拉汀的新方法 - Google Patents

合成阿戈美拉汀的新方法 Download PDF

Info

Publication number
CN101643433A
CN101643433A CN200910160308A CN200910160308A CN101643433A CN 101643433 A CN101643433 A CN 101643433A CN 200910160308 A CN200910160308 A CN 200910160308A CN 200910160308 A CN200910160308 A CN 200910160308A CN 101643433 A CN101643433 A CN 101643433A
Authority
CN
China
Prior art keywords
compound
formula
reaction
methoxyl group
agomelatine
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
CN200910160308A
Other languages
English (en)
Other versions
CN101643433B (zh
Inventor
P·邦滕佩利
X·雅朗克
J-B·斯塔克
J-P·塞里
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.)
Laboratoires Servier SAS
Original Assignee
Laboratoires Servier SAS
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40404415&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN101643433(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of CN101643433A publication Critical patent/CN101643433A/zh
Application granted granted Critical
Publication of CN101643433B publication Critical patent/CN101643433B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明涉及合成阿戈美拉汀的新方法。更具体地讲，本发明涉及工业合成式(I)化合物的方法。

Description

合成阿戈美拉汀的新方法
技术领域：
本发明涉及工业合成式(I)的阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的新方法：
Figure G2009101603081D00011
背景技术：
阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺具有有价值的药理学性质。
实际上，其具有双重特性，其一方面是褪黑激素能系统受体的激动剂，另一方面，其又是5-HT2C受体的拮抗剂。这些性质使其具有中枢神经系统活性，并且更尤其是使其具有治疗重症抑郁、季节性情感障碍、睡眠障碍、心血管病状、消化系统病状、由于时差导致的失眠和疲劳、食欲障碍和肥胖的活性。
已经在欧洲专利EP 0 447 285和EP 1 564 202中对阿戈美拉汀、其制备以及其在治疗中的应用进行了描述。
鉴于这种化合物的药用价值，能用可容易地转移至工业规模并且能以良好的收率和极佳的纯度提供阿戈美拉汀的有效工业合成方法来制备这种化合物是很重要的。
专利说明书EP 0 447 285描述了由7-甲氧基-1-四氢萘酮开始经八步来制备阿戈美拉汀，其平均收率低于30％。
在专利说明书EP 1 564 202中，申请人建立了一种仅四步的更有效且更易工业化的合成途径，该途径使得可以以高再现性的方式获得定义明确的结晶形式的阿戈美拉汀。
申请人通过继续研究而建立了一种比现有技术中所述的方法更有效的合成阿戈美拉汀的新方法：直接由(7-甲氧基-1-萘基)乙腈开始来获得阿戈美拉汀，这使得可以由7-甲氧基-1-四氢萘酮开始仅经三步来实现全合成。这种新方法使得可以以可再现的方式获得阿戈美拉汀并且不需要进行费力的纯化，获得的阿戈美拉汀具有与其作为药学活性成分相符的纯度。
因为可以节省时间、增加收率并最终降低成本，因此，在工业上，总是希望在合成方法中节省一步或多步。但是，减少合成操作的步骤数不是一种通常进行的操作，当涉及工业数量时尤其如此：将两步合并成一步涉及增加存在的试剂数目和数量，并且由于混合物的复杂性增加，反应产物的纯化变得更困难。最后，因为同时存在的试剂数目增加，出现副产物的可能性很高。
发明内容
申请人现在建立了一种使得可以直接由(7-甲氧基-1-萘基)乙腈开始来获得阿戈美拉汀的工业方法。
更具体地讲，本发明涉及一种工业合成式(I)化合物的方法：
Figure G2009101603081D00021
该方法的特征在于将式(II)的(7-甲氧基-1-萘基)乙腈：
Figure G2009101603081D00022
在存在阮内镍的情况下在介质中用氢气还原从而得到式(I)的化合物，将该化合物以固体形式分离出来，其中所述介质在极性质子介质中包含乙酸酐。
式(II)的化合物用常规有机化学反应来获得。例如，式(II)的化合物可以如专利说明书EP1564204和EP1564205中所述的那样，通过使氰基乙酸与7-甲氧基-四氢萘酮缩合，然后对缩合产物进行氧化来获得。
根据本发明，式(II)化合物向式(I)化合物的转化优选地是在5巴的最小压力下进行的，并且更优选地是用10巴至50巴的氢气压进行的。
根据本发明，式(II)化合物向式(I)化合物的转化有利地是在25℃至90C下进行的，并且更优选是在50℃至70℃下进行的。
在将式(II)化合物转化成式(I)化合物的反应中，所用阮内镍的数量为至少5％重量，并且更优选地为10％至20％重量。
将式(II)化合物转化成式(I)化合物的反应中所用的反应介质优选包含一种或多种极性质子溶剂如乙醇、乙酸和/或水，并且更优选为乙醇和/或水。该反应介质还任选地含有乙酸钠。
由于下面的原因，这种方法尤其有价值：
-其使得在工业规模可从(7-甲氧基-1-萘基)乙腈开始，以高于85％的极佳收率以单步获得式(I)的化合物；因此，这种新方法使得可以由7-甲氧基-四氢萘酮开始仅经3步制备式(I)的化合物；
-以可再现方式获得的式(I)化合物具有专利说明书EP 1564202中所述的晶形特征；
-建立的操作条件使得可以将该反应的主要副产物：N，N-二[2-(7-甲氧基-1-萘基)乙基]乙酰胺的形成最小化，该副产物来源于两种反应中间体之间的二聚作用；由于这种副反应的存在(当该反应以“一罐式”反应进行时其在幅度上显著增加)，因此以前实际上难以想象直接由(7-甲氧基-1-萘基)乙腈开始，在可以与其随后的药学应用相容的纯度条件下直接获得式(I)的化合物；必需对操作条件下进行漫长和十分详细的研究以获得随后式(I)化合物作为药物进行应用时可接受的二聚化合物的杂质水平。
具体实施方式
用下文的实施例对本发明进行非限制性说明。
实施例1：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
步骤A：(7-甲氧基-3，4-二氢-1-萘基)乙腈
在存在12.7kg苄胺(或11.0kg苯胺)的情况下向一个670升的反应器中加入位于甲苯中的85.0kg 7-甲氧基-1-四氢萘酮、60.3kg氰基乙酸和15.6kg庚酸。将该混合物在回流下加热。当所有的起始底物都消失时，将该溶液冷却并过滤。将所得沉淀用甲苯洗涤，然后将所得滤液用2N氢氧化钠溶液洗涤，然后用水洗涤至中性。在蒸发掉溶剂后，将所得固体用乙醇/水(80/20)混合物重结晶，从而以90％的收率得到化学纯度高于99％的标题产物。
熔点：48-50℃
步骤B：(7-甲氧基-1-萘基)乙腈
向一个670升的反应器中加入12.6kg位于甲苯中的5％钯碳，将其在回流下加热；然后向其中加入96.1kg溶解于甲苯中的(7-甲氧基-3，4-二氢-1-萘基)乙腈并向其中加入63.7kg甲基丙烯酸烯丙酯。使该反应在回流下继续进行并用气相色谱对其进行监测。当所有的起始底物都消失时，将反应混合物冷却至环境温度，然后对其进行过滤。在蒸发掉甲苯后，将所得固体残余物用乙醇/水(80/20)混合物重结晶，从而以91％的收率得到化学纯度高于99％的标题产物。
熔点：83℃
步骤C：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
向一个8升的反应器中加入136 g阮内镍、2.06升乙醇和0.23升水。在将其在70℃和30巴氢气下搅拌的同时，缓慢向其中加入溶解于乙酸酐(2.4升)中的步骤B所得的化合物(0.8kg)。在加入结束时，将该反应混合物在30巴氢气下搅拌1小时；然后，将该反应器减压并对液体进行过滤。在将该混合物浓缩后，将残余物用乙醇/水35/65混合物结晶，从而以89％的收率得到化学纯度高于99％的标题产物。
熔点：108℃
实施例2：实施例1所得化合物N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺晶形的测定
用得自Bruker AXS的D8高分辨衍射仪进行数据记录，使用下面的参数：3°-90°的2θ角范围，0.01°的跨距且每个跨距30秒。将实施例1获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺粉末放置在一个传输固定件支撑物上。X-射线源是铜管(λCuKα1＝1.54056
Figure G2009101603081D00051
)。该固定件包括一个前单色器(Ge(111)结晶)和能量解析固态检测器(MXP-D1，Moxtec-SEPH)。该化合物结晶良好：半高线宽为0.07°(以2θ计)。
相应地测定下面的参数：
-晶胞的晶体结构：单斜晶，
-晶胞参数：a＝20.0903
Figure G2009101603081D00052
b＝9.3194
Figure G2009101603081D00053
c＝15.4796
Figure G2009101603081D00054
β＝108.667°
-空间群：P21/n
-晶胞中分子的数目：8
-晶胞的体积：V晶胞＝2746.742
-密度：d＝1.13g/cm3。
实施例3：用X-射线粉末衍射图进行的实施例1获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺化合物的晶形测定
用下面的X-射线粉末衍射图对实施例1所得化合物的晶形进行表征，该衍射图是用Siemens D5005衍射仪(铜对阴极)测得的，并且以晶面间距d、Bragg′s角2θ和相对强度(表示为相对于最强线的百分比)进行表达：
Figure G2009101603081D00061

Claims (5)

1.工业合成式(I)化合物的方法
Figure A2009101603080002C1
该方法的特征在于将式(II)的(7-甲氧基-1-萘基)乙腈：
在存在阮内镍的情况下在介质中用氢气还原从而得到式(I)的化合物，将该化合物以固体形式分离出来，其中所述介质在极性质子介质中包含乙酸酐。
2.如权利要求1所述的式(I)化合物的合成方法，其特征在于该反应是在10巴至50巴的氢气压下进行的。
3.如权利要求1所述的式(I)化合物的合成方法，其特征在于该反应是在25℃至90℃下进行的。
4.如权利要求1所述的式(I)化合物的合成方法，其特征在于在该反应中所用阮内镍的数量为10％至20％重量。
5.如权利要求1所述的式(I)化合物的合成方法，其特征在于用于该反应的反应介质包含乙醇和/或水。
CN200910160308.1A 2008-08-05 2009-08-05 合成阿戈美拉汀的新方法 Active CN101643433B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR08/04463 2008-08-05
FR0804463A FR2934857B1 (fr) 2008-08-05 2008-08-05 Nouveau procede de synthese de l'agomelatine

Publications (2)

Publication Number Publication Date
CN101643433A true CN101643433A (zh) 2010-02-10
CN101643433B CN101643433B (zh) 2014-11-26

Family

ID=40404415

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910160308.1A Active CN101643433B (zh) 2008-08-05 2009-08-05 合成阿戈美拉汀的新方法

Country Status (45)

Country Link
US (1) US8329947B2 (zh)
EP (1) EP2151427B1 (zh)
JP (1) JP5112399B2 (zh)
KR (1) KR101135336B1 (zh)
CN (1) CN101643433B (zh)
AP (1) AP2009004935A0 (zh)
AR (1) AR075644A1 (zh)
AU (1) AU2009203052B2 (zh)
BR (1) BRPI0902948A2 (zh)
CA (1) CA2674901C (zh)
CL (1) CL2009001684A1 (zh)
CO (1) CO6120162A1 (zh)
CR (1) CR10955A (zh)
CU (1) CU23861B1 (zh)
CY (1) CY1113716T1 (zh)
DK (1) DK2151427T3 (zh)
EA (1) EA015545B1 (zh)
EC (1) ECSP099550A (zh)
ES (1) ES2401534T3 (zh)
FR (1) FR2934857B1 (zh)
GE (1) GEP20115345B (zh)
GT (1) GT200900216A (zh)
HK (1) HK1141006A1 (zh)
HR (1) HRP20130201T1 (zh)
IL (1) IL200127A (zh)
JO (1) JO2816B1 (zh)
MA (1) MA31224B1 (zh)
ME (1) ME02073B (zh)
MX (1) MX2009008047A (zh)
MY (1) MY162033A (zh)
NI (1) NI200900151A (zh)
NZ (1) NZ578827A (zh)
PE (1) PE20100261A1 (zh)
PL (1) PL2151427T3 (zh)
PT (1) PT2151427E (zh)
RS (1) RS52644B (zh)
SA (1) SA109300497B1 (zh)
SG (1) SG158829A1 (zh)
SI (1) SI2151427T1 (zh)
SV (1) SV2009003342A (zh)
TW (1) TWI386385B (zh)
UA (1) UA102817C2 (zh)
UY (1) UY32013A (zh)
WO (1) WO2010015744A1 (zh)
ZA (1) ZA200905333B (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102206170A (zh) * 2011-03-18 2011-10-05 青岛黄海制药有限责任公司 一种制备阿戈美拉汀的方法
CN107085044A (zh) * 2017-03-27 2017-08-22 万全万特制药（厦门）有限公司 气相色谱法分离检测阿戈美拉汀中间体有关物质的方法
CN107151221A (zh) * 2017-06-19 2017-09-12 太仓卡斯特姆新材料有限公司 一种制备阿戈美拉汀重要中间体7‑甲氧基萘乙腈的方法
CN107353229A (zh) * 2017-08-08 2017-11-17 许昌恒生制药有限公司 一种阿戈美拉汀中间体的制备方法

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2580183B1 (en) 2010-06-10 2014-07-23 Gador S.A. New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide
CN102229541A (zh) * 2010-09-17 2011-11-02 福建广生堂药业有限公司 阿戈美拉汀n-[2-(7-甲氧基萘-1-基)乙基]乙酰胺的制备方法
WO2013054273A2 (en) 2011-10-11 2013-04-18 Ranbaxy Laboratories Limited Process for the preparation of agomelatine
EP2785681A1 (en) 2011-12-01 2014-10-08 Ranbaxy Laboratories Limited Process for the preparation of agomelatine
ITMI20121444A1 (it) 2012-08-27 2014-02-28 Procos Spa Processo per la produzione di agomelatine
CN102942501B (zh) * 2012-12-10 2015-08-19 天津泰普药品科技发展有限公司 一种氢化制备阿戈美拉汀的生产方法
CN104130154A (zh) * 2013-05-03 2014-11-05 郭炳华 一种制备高纯度阿戈美拉汀的方法
US9781669B2 (en) 2013-09-20 2017-10-03 Telefonaktiebolaget Lm Ericsson (Publ) Statistics-assisted sCell selection
US9756532B2 (en) 2013-09-20 2017-09-05 Telefonaktiebolaget L M Ericsson (Publ) Carrier aggregation sCell selection for LTE-A
FR3014437B1 (fr) * 2013-12-05 2016-12-23 Servier Lab Nouveau procede de synthese de l'agomelatine
US10149214B2 (en) 2014-02-03 2018-12-04 Telefonaktiebolaget Lm Ericsson (Publ) Secondary cell selection based on geographic signatures
CN104557591B (zh) * 2014-12-26 2016-09-07 扬子江药业集团四川海蓉药业有限公司 一种制备阿戈美拉汀乙酰二胺的方法
JP6158255B2 (ja) * 2015-07-13 2017-07-05 株式会社三共 遊技機

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1141276A (fr) * 1955-02-14 1957-08-29 Geigy Ag J R Procédé de préparation de l'hexahydro-benzylamine
US3062869A (en) * 1958-11-07 1962-11-06 Fmc Corp Reduction of nitriles
US6037495A (en) * 1994-09-06 2000-03-14 Shinonogi & Co., Ltd. Process for producing alkoxyiminoacetamide derivatives
FR2773798B1 (fr) * 1998-01-16 2001-02-02 Adir Nouveaux composes tricycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102206170A (zh) * 2011-03-18 2011-10-05 青岛黄海制药有限责任公司 一种制备阿戈美拉汀的方法
CN107085044A (zh) * 2017-03-27 2017-08-22 万全万特制药（厦门）有限公司 气相色谱法分离检测阿戈美拉汀中间体有关物质的方法
CN107151221A (zh) * 2017-06-19 2017-09-12 太仓卡斯特姆新材料有限公司 一种制备阿戈美拉汀重要中间体7‑甲氧基萘乙腈的方法
CN107353229A (zh) * 2017-08-08 2017-11-17 许昌恒生制药有限公司 一种阿戈美拉汀中间体的制备方法

Also Published As

Publication number Publication date
JP5112399B2 (ja) 2013-01-09
HK1141006A1 (zh) 2010-10-29
TWI386385B (zh) 2013-02-21
UY32013A (es) 2010-01-29
AP2009004935A0 (en) 2009-08-31
MA31224B1 (fr) 2010-03-01
IL200127A (en) 2013-10-31
KR101135336B1 (ko) 2012-04-17
RS52644B (en) 2013-06-28
CR10955A (es) 2009-10-15
CY1113716T1 (el) 2016-06-22
MY162033A (en) 2017-05-31
KR20100017068A (ko) 2010-02-16
AR075644A1 (es) 2011-04-20
US20100036161A1 (en) 2010-02-11
FR2934857B1 (fr) 2010-08-27
CL2009001684A1 (es) 2010-07-19
PL2151427T3 (pl) 2013-04-30
HRP20130201T1 (hr) 2013-04-30
CN101643433B (zh) 2014-11-26
AU2009203052B2 (en) 2013-09-05
NI200900151A (es) 2010-03-25
EP2151427A1 (fr) 2010-02-10
FR2934857A1 (fr) 2010-02-12
SV2009003342A (es) 2010-02-01
BRPI0902948A2 (pt) 2010-06-01
JO2816B1 (en) 2014-09-15
ECSP099550A (es) 2010-03-31
WO2010015744A1 (fr) 2010-02-11
CA2674901C (fr) 2012-11-13
SI2151427T1 (sl) 2013-03-29
JP2010111654A (ja) 2010-05-20
EP2151427B1 (fr) 2012-12-19
SA109300497B1 (ar) 2013-07-28
US8329947B2 (en) 2012-12-11
AU2009203052A1 (en) 2010-02-25
PT2151427E (pt) 2013-01-22
CU23861B1 (es) 2013-03-27
NZ578827A (en) 2010-12-24
GEP20115345B (en) 2011-12-12
UA102817C2 (ru) 2013-08-27
TW201008900A (en) 2010-03-01
EA200900945A1 (ru) 2010-04-30
ZA200905333B (en) 2010-05-26
CO6120162A1 (es) 2010-01-29
MX2009008047A (es) 2010-03-23
IL200127A0 (en) 2010-05-31
ES2401534T3 (es) 2013-04-22
CU20090139A7 (es) 2012-06-21
ME02073B (me) 2013-06-28
CA2674901A1 (fr) 2010-02-05
EA015545B1 (ru) 2011-08-30
DK2151427T3 (da) 2013-04-02
SG158829A1 (en) 2010-02-26
PE20100261A1 (es) 2010-04-10
GT200900216A (es) 2010-03-15

Similar Documents

Publication Publication Date Title
CN101643433B (zh) 合成阿戈美拉汀的新方法
KR101127278B1 (ko) 아고멜라틴의 합성 방법
CN1315794C (zh) (7－甲氧基－1－萘基)乙腈的新合成方法，及其在阿戈美拉汀的合成中的应用
EA008473B1 (ru) Новый способ синтеза и новая кристаллическая форма агомелатина и фармацевтические композиции, которые её содержат
EP3450426B1 (en) Method for synthesizing silodosin and intermediate thereof
CN101643431B (zh) 合成阿戈美拉汀的新方法
CN101921205A (zh) 阿戈美拉汀ⅰ晶型的制备方法
EA007787B1 (ru) Новый способ синтеза (7-метокси-1-нафтил)ацетонитрила и его применение при синтезе агомелатина
CN105793226A (zh) 7-甲氧基-萘-1-甲醛的新的合成方法及其在阿戈美拉汀的合成中的用途

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1141006

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1141006

Country of ref document: HK