CN101107229A - α-芳基-α-哌啶-2-基-乙酰胺的制备及其酸解的方法 - Google Patents

α-芳基-α-哌啶-2-基-乙酰胺的制备及其酸解的方法 Download PDF

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CN101107229A
CN101107229A CNA2005800431213A CN200580043121A CN101107229A CN 101107229 A CN101107229 A CN 101107229A CN A2005800431213 A CNA2005800431213 A CN A2005800431213A CN 200580043121 A CN200580043121 A CN 200580043121A CN 101107229 A CN101107229 A CN 101107229A
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alpha
ethanamide
aromatic
base
acid
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M·福里杰里奥
S·马库兰
D·韦尔加尼
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Archimica SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives

Abstract

本发明涉及制备式(I)的α－芳基－α－哌啶－2－基－乙酰胺的方法，其中Ar如公开内容中所定义的，该方法通过用铑催化剂催化还原α－芳基－α－吡啶－2－基－乙酰胺进行。然后，式(II)的乙酰胺可以水解为相应的芳基乙酸，例如苯哌啶醋酸，其为苯哌啶醋酸甲酯的直接前体。

Description

α-芳基-α-哌啶-2-基-乙酰胺的制备及其酸解的方法
发明领域
本发明涉及α-芳基-α-哌啶-2-基-乙酰胺，该化合物用于制备芳基乙酸。
背景技术
α-芳基-α-哌啶-2-基-乙酸(III)及其酯是在药学上有用的化合物，其主要是由于其对中枢神经系统的作用
Figure A20058004312100041
其中Ar式芳基。苯哌啶醋酸甲酯(methylphenidate)(IV)是例如用于治疗儿童的多动综合征的药物。
Figure A20058004312100042
酸(III)可以通过将式(II)的α-芳基-α-吡啶-2-基-乙酰胺催化还原并且然后将产生的哌啶基乙酰胺(I)水解而获得，
Figure A20058004312100043
或者通过将α-芳基-α-吡啶-2-基-乙酸盐或酯(V)催化还原而获得。
Figure A20058004312100052
US  2,838,519和Journal of Labelled Compounds andRadiopharmaceuticals，vol.IX，No.4，pp.485-490公开了例如通过在冰醋酸中用PtO2还原而将2-苯基-2-(2’-吡啶基)-乙酰胺还原，而描述于J.Heterocyclic Chemistry中的方法涉及Pt/C的用途。
Journal of Organic Chemistry 1962，vol.27，pp.284-286描述了用Rh/C作为催化剂将吡啶羧酸氢化。根据作者的意思，该催化剂避免了应用防止由碱性反应底物引起的催化剂中毒所通常必需的酸。但是催化剂的量很高(占待还原的吡啶乙酸的40％)。
基于Rh的催化剂在还原吡啶乙酰胺中的用途还没有公开。
发明公开内容
现在已经发现式(I)的α-芳基-α-哌啶-2-基-乙酰胺可以通过将α-芳基-α-吡啶-2-基-乙酰胺(II)催化还原而方便地制备，
Figure A20058004312100053
其中Ar为苯基或萘基，任选被一个或多个下列基团取代：C1-C3烷基、C1-C3烷氧基、氯、氟、三氟甲基；
Figure A20058004312100061
该反应用铑催化剂，优选Rh/C，在完全溶解α-芳基-α-吡啶-2-基-乙酰胺和α-芳基-α-哌啶-2-基-乙酰胺的溶剂中进行，该溶剂选自例如乙酸或无机酸水溶液，例如盐酸或硫酸。优选的溶剂是乙酸。
在Rh/C的情况中，每10g式(II)化合物应用1g催化剂(相当于当Ar为苯时，1mmol金属/193mmol式II化合物)，其在温度范围为40℃至60℃、优选50℃至55℃下进行。
该方法特别有利于制备酰胺(Ia)
Figure A20058004312100062
其中Ar为苯基，
其中酰胺是苯哌啶醋酸甲酯的前体。在这种情况中，氢化产物是d，l苏式/赤式10/90混合物；用氢氧化钾处理后，获得高于70/30的d，l苏式/赤式混合物，该方法通过酸解产生d，l苏式苯哌啶醋酸(ritalinic acid)(IIIa)，其纯度高于99％。
通过以下实施例更详细地说明本发明。
实施例-苯哌啶醋酸的制备
步骤1-氢化
在加压反应器中装入20g 2-吡啶基-苯基乙酰胺和70mL乙酸，在其中鼓入氮气并且加入2g 5％Rh/C，并且在15巴和50-55℃下进行氢化。约5/6小时后，将催化剂滤出并且将溶液在减压下浓缩。
将残留物用20mL水稀释并且滴加至氢氧化钾溶液中(pH＞11)。将沉淀的固体过滤并且在随后的步骤中应用其潮湿形式。
步骤2-异构化
将得自步骤1的湿产物混悬于36mL水中并且加入19.24g 90％氢氧化钾。将得到的白色混悬液在95-105℃下加热6小时。然后将混合物冷却至0-5℃，过滤并且用水洗涤。将产生的固体真空干燥或在随后的步骤中应用其潮湿形式。
步骤3-水解
在安装有磁力搅拌器、温度计、冷凝器和滴液漏斗，用冰浴冷却的250mL圆底烧瓶中装入混悬于73mL水中的20g得自步骤2的化合物。向该混悬液中滴加27mL 98％硫酸。在搅拌下将混合物加热至80-85℃以完成酰胺的水解(通常为8小时)，然后，将溶液冷却至室温并且倾倒至350mL水中。向溶液中加入1.2g炭并且保持搅拌30分钟，然后过滤并且用30mL水洗涤。然后用30％NaOH将溶液的pH调节至6.0-6.2。将产生的混悬液在室温下搅拌30分钟，然后过滤。
将产生的固体用水洗涤并且在50℃下真空干燥过夜。
产量：10-15g苯哌啶醋酸，纯度高于99.0％。

Claims (9)

1.制备式(I)的α-芳基-α-哌啶-2-基-乙酰胺的方法
其中Ar为苯基或萘基，任选被一个或多个下列基团取代：C1-C3烷基、C1-C3烷氧基、氯、氟、三氟甲基；
该方法包括在使α-芳基-α-吡啶-2-基-乙酰胺和α-芳基-α-哌啶-2-基-乙酰胺完全溶解的溶剂中用铑催化剂将α-芳基-α-吡啶-2-基-乙酰胺(II)催化还原
Figure A2005800431210002C2
2.权利要求1的方法，其中溶剂选自乙酸或盐酸或硫酸水溶液。
3.权利要求2的方法，其中溶剂为乙酸。
4.权利要求1-3中任意一项的方法，其中催化剂为Rh/C。
5.权利要求4的方法，其中每10g式(II)化合物应用1g催化剂。
6.权利要求1-5中任意一项的方法，其中温度范围为40℃至60℃。
7.权利要求1-6中任意一项的方法，其中温度范围为50℃至55℃。
8.权利要求1-7中任意一项的方法，其中Ar为苯基。
9.制备苯哌啶醋酸(IIIa)的方法，
Figure A2005800431210003C1
该方法包括以下步骤：
a)用权利要求8的方法制备酰胺(Ia)
b)将酰胺(Ia)异构化以得到d，l混合物，在该混合物中苏式/赤式的比例高于70/30；
c)将酰胺酸解以得到苯哌啶醋酸。
CNA2005800431213A 2004-12-17 2005-12-16 α-芳基-α-哌啶-2-基-乙酰胺的制备及其酸解的方法 Pending CN101107229A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115463549A (zh) * 2022-08-25 2022-12-13 万华化学集团股份有限公司 一种抗生物污染的膜元件进水流道网的制备方法及应用

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US4191828A (en) * 1976-04-14 1980-03-04 Richardson-Merrell Inc. Process for preparing 2-(2,2-dicyclohexylethyl)piperidine
US5965734A (en) * 1997-01-31 1999-10-12 Celgene Corporation Processes and intermediates for preparing 2-substituted piperidine stereoisomers
US6713627B2 (en) * 1998-03-13 2004-03-30 Aventis Pharmaceuticals Inc. Processes for the preparation of (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
TW486468B (en) * 1998-08-28 2002-05-11 Reilly Ind Inc Processes for preparing 2-piperidineethanol compounds

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Publication number Priority date Publication date Assignee Title
CN115463549A (zh) * 2022-08-25 2022-12-13 万华化学集团股份有限公司 一种抗生物污染的膜元件进水流道网的制备方法及应用

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ITMI20042415A1 (it) 2005-03-17
US20080269494A1 (en) 2008-10-30
AU2005315556A1 (en) 2006-06-22
MX2007007315A (es) 2007-10-19
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KR20070114115A (ko) 2007-11-29
BRPI0515793A (pt) 2008-08-05
WO2006064052A1 (en) 2006-06-22

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