CN1172912C - 用于生产左旋丁哌卡因以及相关的哌啶甲酰苯胺麻醉剂的外消旋化方法 - Google Patents

用于生产左旋丁哌卡因以及相关的哌啶甲酰苯胺麻醉剂的外消旋化方法 Download PDF

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CN1172912C
CN1172912C CNB961915242A CN96191524A CN1172912C CN 1172912 C CN1172912 C CN 1172912C CN B961915242 A CNB961915242 A CN B961915242A CN 96191524 A CN96191524 A CN 96191524A CN 1172912 C CN1172912 C CN 1172912C
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racemization
bupivacaine
levobupivacaine
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U��C������
U·C·戴尔
M·朗司顿
M·伍得
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    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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Abstract

通过将富有光学活性的哌啶-2-甲酰苯胺化合物在水溶液介质中加热将其外消旋化，其中的哌啶为选择性N-烷基化的，条件是如果化合物是N-烷基化的，则该介质中含有有机助溶剂。将该方法与拆分方法联合特别适用于左旋丁哌卡因的制备。

Description

用于生产左旋丁哌卡因以及相关的哌啶甲酰苯胺 麻醉剂的外消旋化方法
发明领域
本发明涉及富有光学活性的哌啶-2-甲酰苯胺的外消旋化。具体地讲，该方法适用于左旋丁哌卡因以及相关的哌啶甲酰苯胺麻醉剂的生产。
发明背景
结构式1的化合物
Figure C9619152400031
其中R2是2，6-二甲基苯基并且R1是甲基(甲哌卡因)、正丙基(丙哌卡因，为S-对映体)或正丁基(丁哌卡因)，被广泛地用作局部麻醉剂。R1是H的相应化合物是有用的中间体。
生物学研究表明，这些N-烷基-哌啶-2-甲酰苯胺的(S)-对映体在保持了同等麻醉效力的同时，其心脏毒性要比相应的外消旋体低，从而更有利于临床应用。因此需要一种生产单一对映体形式的结构式1化合物的有效方法。为达到该目的，常规的拆分方法必然产生多达50％的无用的对映体。为了提高该方法的原子利用率，最好是通过将无用的对映体外消旋化使其再循环，以得到适于随后拆分过程的物质。
Friberger等，Acta.Pharm.Suec.(1971)8：361-364，报道了关于甲哌卡因和丁哌卡因的外消旋体和对映体的溶解度和分配系数的研究。据报道，在pH大于6时，外消旋的丁哌卡因比其异构体更易溶解。在pH值接近中性时，所有试验化合物(尤其是丁哌卡因)的溶解度均下降至低水平。
Fyhr等，Acta.Pharm.Suec.(1988)25：121-132，报道了富有光学活性的丙哌卡因盐酸盐的稀水溶液在pH 1-6和80-130℃下的外消旋化。为达到所述pH值，在溶液中加入了HCl或枸橼酸。该稳定性研究的结论是外消旋化涉及N-质子化产物上羟基的离子催化的外消旋化。该研究对于如何进行所述外消旋化没有给出有用的指示，并且没有给出任何减少体积的商业方法。
发明概述
本发明是基于如下令人惊奇的发现，即在水溶液中加热时，哌啶-2-甲酰苯胺(包括结构式1的化合物，其中R1是H、甲基、正丙基、正丁基并且R2是2，6-二甲基)经历迅速的外消旋化，条件是当R1不是H时含有有机助溶剂。很明显，该发现的实践特性是可以使用比现有技术浓度大得多的系统。
在浓度为30mg/ml、pH大于5时，使用Fyhr等所述的条件将导致丙哌卡因和丁哌卡因外消旋化的完全抑制，与此相反，在本发明所用的条件下，通过增加溶液的pH值，可以使外消旋化的速率增加。外消旋化在pH大于6时可以最有效的进行而不会降低溶解度，这意味着无需加入酸。
发明详述
本发明提供了外消旋化富有光学活性的下式化合物的方法，
Figure C9619152400041
其中R1为C1-6烷基，该化合物为游离碱形式，所述方法包括将化合物在含有有机助溶剂的水溶液介质中加热。
当R1是H时，反应可以单独在水中进行。在这种情况下，本发明的优选实施方案是富有光学活性的2′’，6′’-二甲基哌啶-2-甲酰苯胺(1∶R1＝H，R2＝2’，6’-二甲基)的外消旋化。
或者，对于结构式1的N-烷基哌啶化合物，反应可以在含有溶剂助溶剂(例如醇或多羟基化合物，例如乙二醇)的条件下进行，从而可以使用比现有技术的浓度更高的溶液。关于这点，本发明的优选的实施方案是富有光学活性的丁哌卡因在含有10％v/v水的乙二醇中的外消旋化。结构式1化合物的盐的存在并不影响该外消旋化方法的效率。
如需要，该反应条件可以包括加热。适当的反应条件取决于反应物的性质，但本领域技术人员可以对其方便地进行选择。
总而言之，本发明建立了简单、经济的外消旋化哌啶-2-甲酰苯胺的方法，该方法在单纯的水溶液介质中或含有惰性有机助溶剂的水溶液介质中均可进行。本发明特别适用于最大限度地利用无用的对映体来制备对映体纯的治疗剂，因此在实践中的起始原料通常富含(R)-对映体。当R1是H时，结构式1的化合物是制备麻醉剂的中间体。当R1是正丁基时，将本发明与拆分方法(例如PCT/GB95/02513和南非申请95/8993中所述的方法)联合，特别适用于制备(S)-丁哌卡因。
用以下实施例说明本发明。
实施例1
将(S)-2′，6′-二甲基哌啶-2-甲酰苯胺(＞99％ ee，155mg，0.67mmol)溶于水(14.5ml)。测得pH为9.97。将该溶液加热回流19小时。向冷却的溶液中加入氨水(28％ w/v；1ml)并将该混合物用乙酸乙酯(2×20ml)提取。将合并的有机层用硫酸镁干燥，减压蒸除溶剂得到白色结晶状固体(128mg)。手性HPLC分析表明该固体为外消旋的2′，6′-二甲基哌啶-2-甲酰苯胺。
实施例2
将(S)-丁哌卡因(＞99％ ee，1.5g，mmol)、乙二醇(13.5ml)和水(1.5ml)的混合物在138℃加热9小时。冷却至室温时有固体结晶析出。滤出固体得到定量产率的丁哌卡因，手性HPLC分析表明为52∶48的(S)-丁哌卡因和(R)-丁哌卡因的混合物。
实施例3
将(S)-丁哌卡因(＞99％ee，0.27g，0.94mmol)和(S)-丁哌卡因(-)-酒石酸(2∶1盐，0.23g，0.32mmol)在丙-2-醇(2.5ml)和水(2.5ml)中用封管在150℃下加热22小时。移去部分溶液，用28％的氨水碱化并用庚烷提取。将有机溶液用硫酸镁干燥并减压蒸除溶剂。手性HPLC表明该残余物为63∶37的(S)-丁哌卡因和(R)-丁哌卡因的混合物。

Claims (4)

1.外消旋化富有光学活性的下式化合物的方法，
其中R1为C1-6烷基，该化合物为游离碱形式，所述方法包括将化合物在含有有机助溶剂的水溶液介质中加热。
2.根据权利要求1的方法，其中的助溶剂是醇或多羟基化合物。
3.根据权利要求2的方法，其中的助溶剂是乙二醇。
4.根据权利要求1-3中的任一权利要求的方法，其中R1是正丁基，用于制备降低光学纯度的丁哌卡因。
CNB961915242A 1995-01-18 1996-01-12 用于生产左旋丁哌卡因以及相关的哌啶甲酰苯胺麻醉剂的外消旋化方法 Expired - Lifetime CN1172912C (zh)

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US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
PT2218448E (pt) 2002-12-13 2016-01-26 Durect Corp Sistema oral de entrega de fármaco que compreende materiais transportadores líquidos de alta viscosidade
SI2415484T1 (sl) 2004-09-17 2014-10-30 Durect Corporation Pripravek, ki vsebuje lokalni anestetik SAIB, s podaljšanim sproščanjem
US20070027105A1 (en) 2005-07-26 2007-02-01 Alza Corporation Peroxide removal from drug delivery vehicle
PT2117521E (pt) 2006-11-03 2012-09-10 Durect Corp Sistemas de administração transdérmica que compreendem bupivacaína
EP3326621A1 (en) 2007-12-06 2018-05-30 Durect Corporation Oral pharmaceutical dosage forms
US20100260844A1 (en) 2008-11-03 2010-10-14 Scicinski Jan J Oral pharmaceutical dosage forms
CN102093284B (zh) * 2010-12-29 2013-05-08 宜昌人福药业有限责任公司 富集哌啶-2-甲酰苯胺类旋光化合物的方法
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CN106187864B (zh) * 2016-07-11 2018-11-23 江苏天和制药有限公司 一种由盐酸布比卡因制备高纯度布比卡因碱的方法
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KR19980701432A (ko) 1998-05-15
PT804417E (pt) 2003-09-30
AU701221B2 (en) 1999-01-21
FI973040A0 (fi) 1997-07-17
NO973312L (no) 1997-07-17
CA2208522C (en) 2007-03-13
KR100404390B1 (ko) 2004-01-31
EP0804417A1 (en) 1997-11-05
ZA96403B (en) 1997-01-20
GB9501071D0 (en) 1995-03-08
HU227426B1 (en) 2011-05-30
CA2208522A1 (en) 1996-07-25
BR9606821A (pt) 1997-12-23
ATE242214T1 (de) 2003-06-15
PL321378A1 (en) 1997-12-08
DE69628540D1 (de) 2003-07-10
ES2201166T3 (es) 2004-03-16
DK0804417T3 (da) 2003-10-06
JPH11501905A (ja) 1999-02-16
HUP9901418A3 (en) 2001-01-29
AU4394896A (en) 1996-08-07
PL184091B1 (pl) 2002-08-30
JP4015696B2 (ja) 2007-11-28
WO1996022281A1 (en) 1996-07-25
EP0804417B1 (en) 2003-06-04
FI117437B (fi) 2006-10-13
HUP9901418A2 (hu) 1999-08-30
FI973040A (fi) 1997-07-17
MX9705428A (es) 1997-11-29
DE69628540T2 (de) 2004-01-08
NO973312D0 (no) 1997-07-17
NO308843B1 (no) 2000-11-06

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