CN1091424A - 安尼帕米外消旋体的拆分 - Google Patents
安尼帕米外消旋体的拆分 Download PDFInfo
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- CN1091424A CN1091424A CN 93118516 CN93118516A CN1091424A CN 1091424 A CN1091424 A CN 1091424A CN 93118516 CN93118516 CN 93118516 CN 93118516 A CN93118516 A CN 93118516A CN 1091424 A CN1091424 A CN 1091424A
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- anipamil
- racemate
- diastereomer
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- PHFDAOXXIZOUIX-UHFFFAOYSA-N anipamil Chemical class C=1C=CC(OC)=CC=1C(CCCCCCCCCCCC)(C#N)CCCN(C)CCC1=CC=CC(OC)=C1 PHFDAOXXIZOUIX-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000005194 fractionation Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 claims abstract description 14
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940095064 tartrate Drugs 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract 3
- 229950011530 anipamil Drugs 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000000711 polarimetry Methods 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- LQERIDTXQFOHKA-UHFFFAOYSA-N nonadecane Chemical compound CCCCCCCCCCCCCCCCCCC LQERIDTXQFOHKA-UHFFFAOYSA-N 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- UQTCSFPVHNDUOG-UHFFFAOYSA-N azanium 4-carboxy-2,6-dihydroxyphenolate Chemical compound [NH4+].OC(=O)C1=CC(O)=C([O-])C(O)=C1 UQTCSFPVHNDUOG-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- -1 inorganic acid salt Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical class N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Detergent Compositions (AREA)
Abstract
本发明涉及用二苯甲酰基酒石酸或二甲苯酰基
酒石酸拆分安尼帕米外消旋体的方法。
Description
EP-C 64158（参见实施例78和79）描述了安尼帕米（anipamil）的对映体。它们由下述方法获得：将适宜的前体用生物碱拆分成其对映体，并将后者在多级合成系列中转化成旋光的最终产物。这些方法极
其复杂且花费大，而且不能工业生产安尼帕米的对映体。用碱性成分拆分苯乙腈类外消旋体的难点已在以下几篇文献中以戊脉安和胺棓戊腈为例做了描述：Helv.Chim.Acta 58，（1975）第2050页;J.Org.Chem.52，（1987）第1309页;DE-OS 3723684;EP-C 29175。
现在我们发现了即使是工业规模也可以用于将安尼帕米拆分成对映体的非常便利的方法。
本发明涉及下式安尼帕米外消旋体的拆分方法：
所述拆分方法包括：将游离的安尼帕米碱与旋光的二苯甲酰基酒石酸或二甲苯酰基酒石酸反应，用结晶法分离生成的非对映体的混合物，并将生成的非对映体转化成游离碱，如果需要，随后将其转化成盐。
安尼帕米与旋光的二苯甲酰基酒石酸或二甲苯酰基酒石酸的反应在二异丙醚和异丙醇混合溶剂中进行，二者的混合比例为5∶1-20∶1。
外消旋化合物和手性酸按1∶1的摩尔比一起反应。当将二异丙醚/异丙醇溶液冷却时，一种对映体的盐就结晶析出，而另一种对映体留在母液中。若所用的酸是（-）-0，0′-二苯甲酰基-L-酒石酸，则结晶析出（+）-安尼帕米的二苯甲酰基-L-酒石酸氢盐;而若用（+）-0，0′-二苯甲酰基-D-酒石酸，则结晶析出（-）-安尼帕米的二苯甲酰基-D-酒石酸氢盐。通过将该非对映的盐反复结晶可获得所需的旋光纯度。
若加入无机酸、最好是0.5当量时，对安尼帕米外消旋体拆分十分有利而且花费少，这可使旋光的二苯甲酰基酒石酸或二甲苯酰基酒石酸的需要量减少一半。结晶析出的一种对映体的非对映的盐具有很高的旋光纯度，不需进一步重结晶。另一个对映体以无机酸盐的形式大量地存于溶液中，可用常规方法如将溶液浓缩而将其从中分出。特别适宜的无机酸是磷酸和硫酸，优先选用盐酸。
旋光的安尼帕米按常规方法在水性介质中用碱从非对映的盐中释出，并用提取法将其分离。得到的碱可按常规方法用生理上可耐受的酸转化成它们的盐。
实施例1
a）
将54g（0.1mol）外消旋安尼帕米和39.0g（0.1mol）（-）0，0′-二苯甲酰基-L-酒石酸水合物加热溶解于540ml二异丙醚/异丙醇（15∶1）中。将经过夜析出的晶体吸滤出并干燥。该晶体的熔点为58-60℃，旋光度[α]20 D＝-39.4°（乙醇，c＝15mg/ml）。用二异丙醚/异丙醇（15∶1）重结晶三次，得晶体，其熔点为60-61℃，旋光度[α]20 D＝-38.5℃（乙醇，c＝15mg/ml）。再次重结晶后该值没发生改变。从该盐中释出的右旋安尼帕米（18.4g，68.2%）的旋光度[α]20 D＝+7.5°且[α]20 489nm＝+12.4°（苯，c＝30mg/ml）。该盐酸盐的熔点为82-83℃，其旋光度为[α]20 D＝+2.0°和[α]20 489nm＝+3.5°（乙醇，c＝10mg/ml）以及[α]20 D＝+22.4°和[α]20 489nm＝+36.0°（苯，c＝30mg/ml）。
b）
将a）中沉淀后的母液减压浓缩。将残留物溶于水中并通过加入稀氨水使碱释出。用甲苯提取，硫酸钠干燥，蒸馏法除去溶剂，得油，其旋光度为[α]20 D＝-4.3以及[α]20 489nm＝-6.9°（苯，c＝30mg/ml）。
将该油和19.5g（0.05mol）（+）-0，0′-二苯甲酰基-D-酒石酸水合物加热溶于270ml二异丙醚/异丙醇（15∶1）中。吸滤出过夜析出的晶体并干燥之。
该晶体的旋光度为[α]20 D＝+39.1°（乙醇，c＝15mg/ml）。将该盐用二异丙醚/异丙醇（15∶1）结晶三次，得到的晶体的熔点为56-59℃，且旋光度为[α]20 D＝+40.2°（乙醇，c＝15mg/ml），该值在再次重结晶后没发生改变。从该盐中释出的左旋安尼帕米（16.4g，60.8%）的旋光度为[α]20 D＝-7.4°和[α]20 489nm＝-12.3°（苯，c＝30mg/ml）。
实施例2
重复实施例1，但在a）中使用（+）-0，0′-二苯甲酰基-D-酒石酸，而在b）中使用（-）-0，0′-二苯甲酰基-L-酒石酸。尽管在相反的程序中获得了该对映体，但结果与实施例1中的相同。
实施例3
在步骤同实施例1a、1b和2，但旋光体0，0′-二苯甲酰基酒石酸由旋光体0，0′-二-4-甲苯酰基酒石酸所代替，同样获得了1，7-二（3-甲氧基苯基）-3-甲基-氮杂-7-氰基十九烷的右旋体和左旋体。
实施例4
将20.1g（0.035mol）盐酸安尼帕米-水合物、18.0g（0.035mol）安尼帕米和13.2g（0.035mol）（+）-二-0，0′-苯甲酰基-D-酒石酸水合物溶于热的（约50℃）二异丙醚（200ml）和异丙醇（15ml）的混合溶剂中。将混合物于室温搅拌20小时并于10℃搅拌10小时。将晶体吸滤出并于30℃减压干燥，得20.5g（67%）纯的非对映的盐，其旋光纯度经HPLC测定为99.9%。
该非对映的盐和从中释出的碱的物理化学性质与实施例1b的相符。
由36.0g（0.07mol）安尼帕米碱和0.035mol盐酸水溶液开始可取得相同的结果。
Claims (3)
1、下式Ⅰ安尼帕米外消旋体的拆分方法：
所述拆分方法包括：将游离的安尼帕米碱与旋光的二苯甲酰基酒石酸或二甲苯酰基酒石酸反应，用结晶法分离生成的非对映体的混合物，并将生成的非对映体转化成游离碱，如果需要，随后将其转化成盐。
2、权利要求1所述的方法，其中，外消旋体的拆分用0.5当量旋光的二苯甲酰基酒石酸或二甲苯酰基酒石酸并加入0.5当量无机酸来进行。
3、权利要求1或2所述的方法，其中，非对映体的混合物在5∶1-20∶1的二异丙醚/异丙醇中制备。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19924234000 DE4234000A1 (de) | 1992-10-09 | 1992-10-09 | Verfahren zur Racemattrennung von Anipamil |
| DEP42340004 | 1992-10-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1091424A true CN1091424A (zh) | 1994-08-31 |
Family
ID=6470024
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93118516 Pending CN1091424A (zh) | 1992-10-09 | 1993-10-09 | 安尼帕米外消旋体的拆分 |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1091424A (zh) |
| DE (1) | DE4234000A1 (zh) |
| MX (1) | MX9306085A (zh) |
| WO (1) | WO1994008950A1 (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1314658C (zh) * | 2002-09-05 | 2007-05-09 | 武汉大学 | 光学纯n－甲基－3－苯基－3－羟基丙胺的制备方法 |
| CN1332934C (zh) * | 2005-01-14 | 2007-08-22 | 清华大学 | 一种用于氨基酸对映体分离的新型试剂 |
| CN103497145A (zh) * | 2013-10-10 | 2014-01-08 | 南昌大学 | 一种光学纯多奈哌齐的制备工艺 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2946545A1 (de) * | 1979-11-17 | 1981-05-27 | Basf Ag, 6700 Ludwigshafen | Verfahren zur gewinnung der enantiomeren formen von 4-cyan-1-(n-methyl-n-(2'-((3'',4'',-dimethoxyphenyl))-aethyl)-amino)-5-methyl-4-(3',4',5'-trimethoxyphenyl)-hexan und dessen salzen |
| DE3144150A1 (de) * | 1981-04-10 | 1982-12-09 | Basf Ag, 6700 Ludwigshafen | (omega)-cyan-1,(omega)-diphenyl-azaalkan-derivate, ihre herstellung und diese enthaltende arzneimittel |
| DE3723684A1 (de) * | 1987-07-17 | 1989-01-26 | Basf Ag | Verfahren zur herstellung der enantiomeren von verapamil |
-
1992
- 1992-10-09 DE DE19924234000 patent/DE4234000A1/de not_active Withdrawn
-
1993
- 1993-09-30 MX MX9306085A patent/MX9306085A/es unknown
- 1993-09-30 WO PCT/EP1993/002657 patent/WO1994008950A1/de active Application Filing
- 1993-10-09 CN CN 93118516 patent/CN1091424A/zh active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1314658C (zh) * | 2002-09-05 | 2007-05-09 | 武汉大学 | 光学纯n－甲基－3－苯基－3－羟基丙胺的制备方法 |
| CN1332934C (zh) * | 2005-01-14 | 2007-08-22 | 清华大学 | 一种用于氨基酸对映体分离的新型试剂 |
| CN103497145A (zh) * | 2013-10-10 | 2014-01-08 | 南昌大学 | 一种光学纯多奈哌齐的制备工艺 |
| CN103497145B (zh) * | 2013-10-10 | 2016-01-27 | 南昌大学 | 一种光学纯多奈哌齐的制备工艺 |
Also Published As
| Publication number | Publication date |
|---|---|
| MX9306085A (es) | 1994-06-30 |
| WO1994008950A1 (de) | 1994-04-28 |
| DE4234000A1 (de) | 1994-04-14 |
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