CN1068871C - 2－芳基－2－烷基－ω－烷氨基链烷腈的外消旋体的拆分方法 - Google Patents
2－芳基－2－烷基－ω－烷氨基链烷腈的外消旋体的拆分方法 Download PDFInfo
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- 150000002825 nitriles Chemical class 0.000 title description 2
- 238000000926 separation method Methods 0.000 title 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 11
- 150000003839 salts Chemical class 0.000 abstract description 9
- 150000007962 benzene acetonitriles Chemical class 0.000 abstract description 7
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- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 abstract description 3
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- MWUHTZXHCYOWQG-UHFFFAOYSA-N 5-(methylamino)-2-propan-2-yl-2-(3,4,5-trimethoxyphenyl)pentanenitrile Chemical compound CNCCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 MWUHTZXHCYOWQG-UHFFFAOYSA-N 0.000 description 1
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- GAQWDBUWBUOFLS-QPQWKYTISA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C GAQWDBUWBUOFLS-QPQWKYTISA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
式Ⅰ的苯基乙腈的外消旋体拆分的方法，
式中R1、R2、R3和n具有说明书中给出的含义，该方法是将外消旋体Ⅰ溶于极性溶剂中，每mol化合物Ⅰ加入0.5～1.0mol旋光樟脑磺酸，加热到40～100℃，冷却和从这样得到的盐中释放出旋光苯基乙腈Ⅰ。
Description
已经发现在苯基上具有各种不同的取代基和具有碱性侧链的苯基乙腈可作为有效的药物活性物质。所以在DE 11 54 810中描述的通式Ⅱ的具有碱性取代基的苯基乙腈的维拉帕米(Ⅱ,R=H)和加洛帕米(Ⅱ,R=OCH3)被证明在治疗冠心病和高血压方面是有效的。
EP 0 271 013描述了氮上的二甲氧基苯乙基基团被脂族的侧链取代的苯基乙腈作为治疗心血管和哮喘疾病的活性物质。
取代的苯基乙腈具有手性的碳原子，所以在没有其它手性中心时它构成两个旋光异构体(旋光对映体)。在常规的由非手性起始原料的化学合成范围内产生两种等量的旋光异构体，所以存在外消旋体。
由维拉帕米和加洛帕米已知，鉴于它们的药效学和药物动力学旋光异构体在数量上是显著不同的(M.Raschack,Naunyn-Schmiedeberg的药物学论文集(Arch.Pharmacol)1976,294,285；M.Eichelbaum等英国临床药物学杂志(Br.J.Clin.Pharmacol.)17(1984)453)。因此，左旋的旋光异构体是非常有效的冠状扩张药，同时发现右旋对映体在疾病和肿瘤治疗中作为阻断剂。
因此，旋光体的苯基乙腈的制备具有重大意义。
然而这种制备是非常困难的：在维拉帕米合成时，当使用手性催化剂时旋光异构体的过剩量最大达10％，也就是说旋光异构体的比例为55∶45(H.Brunner和H.Zintl，《化学月刊》(Monatsh.Chemie)122,841-848[1991])。同样由其它手性催化剂提供的旋光异构体的过剩量是完全不够的。
L.J.Theodore和W.L.Nelson(《有机化学杂志》(J.Org.Chem.)52,1309-1315(1987))描述的维拉帕米和加洛帕米旋光异构体的立体有择合成从立体异构的乳酸开始和由于众多的反应步骤和复杂的官能度的化学改变而不能达到工业化规模。
外消旋体的拆分方法已经常公开。特别的情况在WO 92/07821中，这里通过与将要成为活性物质的组成部分的旋光β-甲基氨基四氢化萘的连接和非对映异构体的分级结晶作用进行苯基乙腈部分的外消旋体的拆分：
更为广泛使用的是中间生成的借助于结晶作用或色谱法拆分的非对映异构体盐和由该盐稀释的所希望的旋光产物。
外消旋体的拆分困难表现在，长时间以来不能成功地拆分最终产物本身，也就是说它的活性物质或在合成方法中通常进行的它的碱性前体之一；可是具有手性碱的羧基衍生物Ⅲ或Ⅳ可被拆分，羧基衍生物Ⅲ或Ⅳ转化为所希望的产物维拉帕米需要附加的合成步骤：
为了拆分Ⅲ而使用马钱子碱(DE 2059 985)，但由于马钱子碱的剧烈的毒性和高的价格使用它是不利的。尽管可以用辛可尼丁拆分Ⅳ，但是为了成功地得到所希望的产物必须对其二官能度改性，这在技术操作上是困难的(H.Ramuz,Helv.Chim.Acta 58,2050-2060[1975])。
在EP 0271 013中在实施例6和7中应用的手性前体Ⅴ和Ⅵ按照DE 2059 985中描述的方法制备。
最近描述了维拉帕米的游离碱的外消旋体拆分方法。在DE-OS 3723 684中使用(R)-或(S)-2,2′-(1,1′-联萘)磷酸作为拆分酸，然而其制备是非常昂贵的和不能大量地提供。DE-OS 4 203547利用1～2当量的O,O′-二苯甲酰-或O,O′-二-对甲苯-酒石酸，它们是非常昂贵的和在维拉帕米释放时易于被水解并因此而损失掉。
特别是考虑到H.Ramuz(Helv.Chim.Acta 58,2050[1975])的论断即樟脑磺酸不适用于维拉帕米的外消旋体拆分，令人惊奇地是，用樟脑磺酸可以容易地将碱性取代的苯基乙腈拆分为高旋光异构体纯度的旋光对映体。
本发明的主题是式Ⅰ的2-芳基-2-烷基-ω-烷氨基-链烷腈的外消旋体按照已知的方式的拆分方法，
式中，
R1是氢或甲氧基，
R2和R3是相同的或不同的，表示C1-4烷基和
m为2或3，
其特征是使用旋光樟脑磺酸作为拆分剂。
作为C1-4烷基列举出的是：甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基。
本发明的方法优选地如下进行：在一种醇如甲醇、乙醇、正丙醇、异丙醇、乙二醇、二乙二醇或醇的混合物或一种醇与丙酮或醋酸乙酯的混合物(优选异丙醇)中加入1当量的外消旋体Ⅰ，和添加0.5～1(优选0.75)当量樟脑磺酸一水化物。然后将混合物加热到40℃至100℃或至所用溶剂的沸点(优选60℃)。在冷却时化合物Ⅰ的非对映异构体樟脑磺酸盐结晶出：
(Z)-(+)-樟脑磺酸作为(S)-Ⅰ盐沉淀出，
(R)-(-)-樟脑磺酸作为(R)-Ⅰ盐沉淀出。
这种盐优选地从先前使用的溶剂或溶剂混合物中重结晶一次。
为了释放出旋光Ⅰ将该盐溶解在稀释的碱性溶液(例如氢氧化钠、氢氧化钾、碳酸钾溶液)中，用与水不混溶的溶剂萃取(例如醋酸乙酯、MTBE(二甲基叔丁基醚)、二氯甲烷)。旋光化合物Ⅰ可以从此溶液中沉淀出或者在其中直接进一步反应。
本发明的方法是特别令人满意的，因为樟脑磺酸非常便宜并且可以大量得到以及因为所得到的通式Ⅰ的中间产物允许活性物质如维拉帕米、加洛帕米和在EP 0271 013中描述的化合物的大量制备。
按照下列流程制备本发明方法中使用的式Ⅵ的外消旋起始化合物：
下面的实施例用于进一步说明本发明的方法，而不是对它的限制。
实施例1
(S)-(-)-5-(N-甲氨基)-2-(1-甲乙基)-2-(3,4,5-三甲氧基苯基)戊腈[Ⅰ,R1=OCH3,R2=CH(CH3)2,R3=CH3]
95.4kg(297.8mol)外消旋的5-(N-甲氨基)-2-(1-甲基乙基)-2-(3,4,5-三甲氧基苯基)-戊腈与55.9kg(223.4mol)(S)-(+)-樟脑-10-磺酸一水化物一起放入200L异丙醇中。
加热使内部温度为60℃，这样得到一种透明的溶液。然后缓慢地冷却。在30～50℃加入盐晶种之后开始结晶。在搅拌下冷却到20℃。过滤出沉淀物，用50L异丙醇冲洗和从300L异丙醇中再结晶。
将干燥的非对映异构体盐溶解在300L含有30kg 50％的氢氧化钠溶液的水中，每次用100L甲基叔丁基醚萃取，共萃取两次。
产量：30.9kg(96.5mol)
理论值的66％
[α]D 20-17.8°(c=1，甲苯)。
产物以油的形式存在。在192-194℃下其盐酸盐熔化，
[α]D 20-9.0°(c=1，无水乙醇)。
实施例2
(R)-(+)-5-N-甲氨基-2-(1-甲基乙基)-2-(3,4,5-三甲氧基苯基)戊腈
类似于实施例1，在使用(R)-(-)-樟脑-10-磺酸一水化物作为拆分酸下得到右旋的旋光异构体。纯碱具有特定的旋转角：
[α]D 20=+17.8°(c=10mg/ml，甲苯)。
在192-194℃下其盐酸盐熔化，[α]D 20=9.1°(c=1，无水乙醇)。
实施例3
(S)-(-)-5-N-甲氨基-2-(1-甲基乙基)-2-(3,4-二甲氧基苯基)戊腈
类似于实施例1制备该物质。游离碱的特定旋转角为[(α]D 20=-5.0°(c=1，无水乙醇)。在172～173℃下其盐酸盐熔化。
实施例4
(R)-(+)-5-N-甲氨基-2-(1-甲基乙基)-2-(3,4-二甲氧基苯基)戊腈
类似于实施例2制备该物质。碱以油的形式存在，具有[α]D 20=+5°(c=1，无水乙醇)的特定旋转角。在172～175℃下其盐酸盐熔化。
Claims (1)
1．式Ⅰ的2-芳基-2-烷基-ω-烷基氨基-链烷腈的外消旋体以已知方式的拆分方法，
式中R1是氢或甲氧基，R2和R3是相同的或不同的，表示C1-4烷基和m为2或3，其特征是使用旋光樟脑磺酸作为拆分剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19502967.4 | 1995-01-31 | ||
| DE19502967A DE19502967A1 (de) | 1995-01-31 | 1995-01-31 | Verfahren zur Racemattrennung von 2-Aryl-2-omega-alkylaminoalkannitrilen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1172470A CN1172470A (zh) | 1998-02-04 |
| CN1068871C true CN1068871C (zh) | 2001-07-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN96191705A Expired - Fee Related CN1068871C (zh) | 1995-01-31 | 1996-01-20 | 2－芳基－2－烷基－ω－烷氨基链烷腈的外消旋体的拆分方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5786498A (zh) |
| EP (1) | EP0808302B1 (zh) |
| JP (1) | JPH10512890A (zh) |
| CN (1) | CN1068871C (zh) |
| AT (1) | ATE191464T1 (zh) |
| CA (1) | CA2210337C (zh) |
| DE (2) | DE19502967A1 (zh) |
| DK (1) | DK0808302T3 (zh) |
| ES (1) | ES2145427T3 (zh) |
| GR (1) | GR3033164T3 (zh) |
| MX (1) | MX9705200A (zh) |
| PT (1) | PT808302E (zh) |
| WO (1) | WO1996023764A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6130302A (en) | 1996-08-19 | 2000-10-10 | Northwestern University | Synthesis and use of (polyfluoroaryl)fluoroanions of aluminum, gallium and indium |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4962223A (en) * | 1988-07-12 | 1990-10-09 | Ministero dell'Universita e delle Ricerca Scientifica e Tecnologica | Process for the synthesis of the levodopa |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2059985C3 (de) * | 1970-12-05 | 1979-10-04 | Knoll Ag, 6700 Ludwigshafen | Rechtsdrehende, basisch substituierte Phenylacetonitrile, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
| DE3642331A1 (de) * | 1986-12-11 | 1988-06-23 | Basf Ag | Basisch substituierte phenylacetonitrile, ihre herstellung und diese enthaltende arzneimittel |
| DE3723684A1 (de) * | 1987-07-17 | 1989-01-26 | Basf Ag | Verfahren zur herstellung der enantiomeren von verapamil |
| SE8803012L (sv) * | 1988-08-29 | 1990-03-01 | Skf Nova Ab | Anordning foer aastadkommande av bromsning av ett vridmomentoeverfoerande organ |
| AU8904091A (en) * | 1990-11-01 | 1992-05-26 | G.D. Searle & Co. | Diastereoisomers of bicyclo-substituted phenylacetonitrile derivatives |
| DE4203547A1 (de) * | 1992-02-07 | 1993-08-12 | Knoll Ag | Verfahren zur racemattrennung von verapamil |
| GB9319918D0 (en) * | 1993-09-27 | 1993-11-10 | Chiros Ltd | Chiral compounds and their preparation |
-
1995
- 1995-01-31 DE DE19502967A patent/DE19502967A1/de not_active Withdrawn
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1996
- 1996-01-20 MX MX9705200A patent/MX9705200A/es not_active IP Right Cessation
- 1996-01-20 ES ES96901746T patent/ES2145427T3/es not_active Expired - Lifetime
- 1996-01-20 EP EP96901746A patent/EP0808302B1/de not_active Expired - Lifetime
- 1996-01-20 CN CN96191705A patent/CN1068871C/zh not_active Expired - Fee Related
- 1996-01-20 AT AT96901746T patent/ATE191464T1/de not_active IP Right Cessation
- 1996-01-20 JP JP8523206A patent/JPH10512890A/ja active Pending
- 1996-01-20 CA CA002210337A patent/CA2210337C/en not_active Expired - Fee Related
- 1996-01-20 DK DK96901746T patent/DK0808302T3/da active
- 1996-01-20 DE DE59604890T patent/DE59604890D1/de not_active Expired - Fee Related
- 1996-01-20 US US08/860,664 patent/US5786498A/en not_active Expired - Lifetime
- 1996-01-20 PT PT96901746T patent/PT808302E/pt unknown
- 1996-01-20 WO PCT/EP1996/000236 patent/WO1996023764A1/de active IP Right Grant
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4962223A (en) * | 1988-07-12 | 1990-10-09 | Ministero dell'Universita e delle Ricerca Scientifica e Tecnologica | Process for the synthesis of the levodopa |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2210337C (en) | 2004-04-27 |
| DK0808302T3 (da) | 2000-07-17 |
| ATE191464T1 (de) | 2000-04-15 |
| GR3033164T3 (en) | 2000-08-31 |
| EP0808302A1 (de) | 1997-11-26 |
| EP0808302B1 (de) | 2000-04-05 |
| DE19502967A1 (de) | 1996-08-01 |
| JPH10512890A (ja) | 1998-12-08 |
| MX9705200A (es) | 1997-10-31 |
| US5786498A (en) | 1998-07-28 |
| PT808302E (pt) | 2000-09-29 |
| ES2145427T3 (es) | 2000-07-01 |
| WO1996023764A1 (de) | 1996-08-08 |
| CA2210337A1 (en) | 1996-08-08 |
| DE59604890D1 (de) | 2000-05-11 |
| CN1172470A (zh) | 1998-02-04 |
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