CN1177805C - 降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯溶液中3-二甲氨基-2-苯基丙酸乙酯含量的方法 - Google Patents
降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯溶液中3-二甲氨基-2-苯基丙酸乙酯含量的方法 Download PDFInfo
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- 239000002253 acid Substances 0.000 title description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 3
- WYVAVFURKHCMTG-UHFFFAOYSA-N ethyl 3-(dimethylamino)-2-phenylpropanoate Chemical compound CCOC(=O)C(CN(C)C)C1=CC=CC=C1 WYVAVFURKHCMTG-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002904 solvent Substances 0.000 abstract description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 description 7
- BOIWYTYYWPXGAT-UHFFFAOYSA-N ethyl 2-phenylprop-2-enoate Chemical compound CCOC(=O)C(=C)C1=CC=CC=C1 BOIWYTYYWPXGAT-UHFFFAOYSA-N 0.000 description 6
- 229960001402 tilidine Drugs 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 4
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- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 2
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- WHYVWQHDUOALSV-UMJMSJQKSA-N ethyl (1s,2r)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate;hydrate;dihydrochloride Chemical group O.Cl.Cl.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WHYVWQHDUOALSV-UMJMSJQKSA-N 0.000 description 1
- MUWDJVKYGSDUSH-KALLACGZSA-N ethyl (1s,2r)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate;hydron;chloride Chemical compound Cl.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C MUWDJVKYGSDUSH-KALLACGZSA-N 0.000 description 1
- LJVHNFLIHXPAAY-UHFFFAOYSA-N ethyl 3-(dimethylamino)-3-phenylpropanoate Chemical compound CCOC(=O)CC(N(C)C)C1=CC=CC=C1 LJVHNFLIHXPAAY-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
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- 238000006068 polycondensation reaction Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229960001502 tilidine hydrochloride Drugs 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Abstract
描述了一种降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯在水不溶混性溶剂中的受污染溶液中3-二甲氨基-2-苯基丙酸乙酯含量的方法，包括向该溶液中相对每摩尔2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯加入0.5-2.0当量的羧酸并在50-100℃的温度下搅拌该混合物。
Description
本发明涉及降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯(1)中3-二甲氨基-2-苯基丙酸乙酯(2)含量的方法，第一种化合物是制备止痛药痛立定的起始原料。痛立定是2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯的反式异构体并可以盐酸痛立定半水合物形式市购得到。
当阿托酸乙酯与1-二甲氨基丁二烯反应时，得到的2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯是其顺式和反式异构体的混合物。DE 1 923 620描述了一种制备2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯的方法，其中与阿托酸乙酯反应时不需要使用分离形式的1-二甲氨基丁二烯；相反，该方法需要在碳酸钾作为水结合剂和催化量的醌存在下在惰性溶剂和3-5℃条件下使丁烯醛和二甲胺反应，和使以上反应中得到的产物与阿托酸乙酯反应，得到2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯(顺式和反式异构体的混合物)。
合成时伴随有副组分3-二甲氨基-2-苯基丙酸乙酯的形成。
3-二甲氨基-2-苯基丙酸乙酯一般通过将二甲胺加成到阿托酸乙酯上的形式而在反应混合物中生成，其中二甲胺是例如由于1-二甲氨基丁二烯的缩聚反应或由于1-二甲氨基丁二烯和过量丁烯醛缩合反应过程中释放出来的。
形成3-二甲氨基-2-苯基丙酸乙酯的程度取决于阿托酸乙酯和二甲胺反应量的摩尔比，此外还受所用溶剂性质的影响[Ann.Chem.728，64(1969)]。反应过程中碳酸钾的存在似乎会抑制3-二甲氨基-2-苯基丙酸乙酯的生成。
按照分离和纯化2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯(顺式和反式异构体的混合物)的已知方式(DE 1 923 620)不能除去3-二甲氨基-2-苯基丙酸乙酯。在按已知方式(DE 1 923 620，GB 1 226 318)，例如通过与锌离子选择性形成配合物或与草酸选择性形成盐分离异构体时，它是分离痛立定(反式异构体)所必需的，事实上，相对于活性物质(DE 1 923 620)有杂质的富集，结果是为了满足盐酸痛立定半水合物中3-二甲氨基-2-苯基丙酸乙酯最大0.10％的规格，必须进行分离，例如经由痛立定盐的重结晶。
在DE 1 923 620中明白地提到，在经由上述方法制备2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯时原则上可取得大约0.1％的3-二甲氨基-2-苯基丙酸乙酯含量。然而，实际出现的是该含量为0.3-2％。
本发明的目的是，提供一种降低在痛立定制备早期阶段中3-二甲氨基-2-苯基丙酸乙酯含量的简单、低成本方法。
现已发现，该目的可经由一种降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯在水不溶混性溶剂中的受污染溶液中3-二甲氨基-2-苯基丙酸乙酯含量的方法解决，该方法包括：向该溶液中每摩尔2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯加入0.5-2.0当量羧酸，并在50-100℃的温度下搅拌该混合物。
合适的水不溶混性溶剂为芳族烃例如甲苯，环状或非环状脂族烃例如环己烷，或脂族醚例如二异丙醚。适宜的羧酸是芳族和脂族羧酸例如甲酸和优选为乙酸。相对每摩尔2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯，酸的用量为0.5-2.0当量，优选0.75-1.25当量。
由此方式得到的混合物在50-100℃，优选70-90℃的温度下搅拌，直到3-二甲氨基-2-苯基丙酸乙酯含量达到后续制备工艺容许的程度，通常时间为大约0.5-2小时。
反应结束时，以常规方式从反应混合物中分离出2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯。这样，通过向反应混合物中加水并使其呈碱性而可以分离和纯化该酯。接着，可分离掉水相，适当时可用亚硫酸氢钠溶液洗涤有机相并浓缩。
得到的2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯中3-二甲氨基-2-苯基丙酸乙酯含量低于0.10％。
优选将在2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯合成中初始生成的顺式和反式异构体混合物用于纯化。实质上，在由本发明方法去除3-二甲氨基-3-苯基丙酸乙酯时没有发现2-二甲氨基-1-苯基-3-环己烯-1-羧酯乙酯的顺/反异构化反应。这与在冰醋酸或醋酸水溶液中加热2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯时观察到的异构体平衡的建立(DE 1 951 587)形成了对比。由于在本发明的纯化方法中实质上未发生顺/反异构化反应，它也可特别适用于痛立定本身，即2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯的反式异构体。然而，2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯当然也可以以顺式构型用于纯化反应。
本发明方法形式上是基于从3-二甲氨基-2-苯基丙酸乙酯中消去二甲胺。由消去反应形成的阿托酸乙酯不会对后续工艺产生干扰，但可以通过用酸萃取2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯溶液并用水不溶混性有机溶剂洗涤酸萃取液而很容易去除。
因此，本发明方法的优势在于在加工处理的早期阶段以简单、快速和低成本的方式大大地降低了制备痛立定时3-二甲氨基-2-苯基丙酸乙酯的含量，从而不再对最终产物产生干扰作用。
实施例
溶解于40ml环己烷中的13.7g(0.05mol)2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯(顺式和反式异构体的混合物)[3-二甲氨基-2-苯基丙酸乙酯含量(HPLC)：1％]，与3.0g(0.05mol)乙酸一起回流2小时。冷却后，加入30ml水。用氢氧化钠溶液使两相混合物成碱性。接着分离掉水相。用30ml水洗涤有机相并浓缩。得到13.4g(98％)在顺/反比方面组成未变的2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯异构体混合物，其中3-二甲氨基-2-苯基丙酸乙酯含量为0.05％(HPLC)。
Claims (1)
1.一种降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯在水不溶混性溶剂中的受污染溶液中3-二甲氨基-2-苯基丙酸乙酯含量的方法，包括向该溶液中相对每摩尔2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯加入0.75-2.0当量的羧酸并在50-100℃的温度下搅拌该混合物，其中在2-二甲氨基-1-苯基-3-环己烯-1-羧酯乙酯中的3-二甲氨基-2-苯基丙酸乙酯含量低于0.10％。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19902590A DE19902590A1 (de) | 1999-01-22 | 1999-01-22 | Verfahren zur Reduktion des an 3-Dimethylamino-2-phenylpropionsäureethylester-Gehalts in Lösungen von 2-Dimethylamino-1-phenyl-3-cyclohexen-1-carbonsäureehtylester |
| DE19902590.8 | 1999-01-22 |
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| Publication Number | Publication Date |
|---|---|
| CN1373746A CN1373746A (zh) | 2002-10-09 |
| CN1177805C true CN1177805C (zh) | 2004-12-01 |
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| CNB008029539A Expired - Fee Related CN1177805C (zh) | 1999-01-22 | 2000-01-15 | 降低2-二甲氨基-1-苯基-3-环己烯-1-羧酸乙酯溶液中3-二甲氨基-2-苯基丙酸乙酯含量的方法 |
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| CN (1) | CN1177805C (zh) |
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| CA (1) | CA2359080C (zh) |
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| DE (2) | DE19902590A1 (zh) |
| ES (1) | ES2226777T3 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1768704B1 (de) * | 1968-06-21 | 1971-11-11 | Goedecke Ag | Verfahren zur Abtrennung von 3-trans-Dimethylamino-4-phenyl-4-trans-carbaethoxy-delta?-cyclohexen |
| US3679732A (en) * | 1969-04-17 | 1972-07-25 | Warner Lambert Co | Process for obtaining 3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-{66 {11 -cyclohexene |
| DE2261462B1 (de) * | 1972-12-15 | 1974-04-25 | Goedecke Ag | Verfahren zur Abtrennung von (+)-3r-N-Dimethylamino-4c-phenyl-4t-aethoxycarbonyl-cyclohexen-(1) |
-
1999
- 1999-01-22 DE DE19902590A patent/DE19902590A1/de not_active Withdrawn
- 1999-12-16 TW TW088122113A patent/TW462958B/zh not_active IP Right Cessation
-
2000
- 2000-01-15 MX MXPA01007249A patent/MXPA01007249A/es not_active IP Right Cessation
- 2000-01-15 BR BR0007646-5A patent/BR0007646A/pt not_active IP Right Cessation
- 2000-01-15 WO PCT/EP2000/000306 patent/WO2000043353A1/de active IP Right Grant
- 2000-01-15 ES ES00902598T patent/ES2226777T3/es not_active Expired - Lifetime
- 2000-01-15 AU AU24376/00A patent/AU766196B2/en not_active Ceased
- 2000-01-15 DE DE50007472T patent/DE50007472D1/de not_active Expired - Lifetime
- 2000-01-15 AT AT00902598T patent/ATE273947T1/de not_active IP Right Cessation
- 2000-01-15 CN CNB008029539A patent/CN1177805C/zh not_active Expired - Fee Related
- 2000-01-15 RU RU2001123589/04A patent/RU2201918C1/ru not_active IP Right Cessation
- 2000-01-15 KR KR1020017009188A patent/KR20010102987A/ko active IP Right Grant
- 2000-01-15 JP JP2000594771A patent/JP3635032B2/ja not_active Expired - Fee Related
- 2000-01-15 HU HU0200531A patent/HUP0200531A3/hu unknown
- 2000-01-15 CA CA002359080A patent/CA2359080C/en not_active Expired - Fee Related
- 2000-01-15 US US09/889,383 patent/US7273947B1/en not_active Expired - Fee Related
- 2000-01-15 IL IL14420300A patent/IL144203A0/xx active IP Right Grant
- 2000-01-15 EP EP00902598A patent/EP1144361B1/de not_active Expired - Lifetime
- 2000-01-15 CZ CZ20012602A patent/CZ20012602A3/cs unknown
-
2001
- 2001-07-05 ZA ZA200105537A patent/ZA200105537B/en unknown
- 2001-07-09 IL IL144203A patent/IL144203A/en not_active IP Right Cessation
- 2001-07-17 NO NO20013528A patent/NO20013528D0/no not_active Application Discontinuation
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2003
- 2003-03-18 HK HK03101980.7A patent/HK1050181B/zh not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JP3635032B2 (ja) | 2005-03-30 |
| DE19902590A1 (de) | 2000-07-27 |
| KR20010102987A (ko) | 2001-11-17 |
| EP1144361B1 (de) | 2004-08-18 |
| HUP0200531A2 (en) | 2002-08-28 |
| MXPA01007249A (es) | 2002-06-04 |
| IL144203A0 (en) | 2002-05-23 |
| NO20013528L (no) | 2001-07-17 |
| RU2201918C1 (ru) | 2003-04-10 |
| ATE273947T1 (de) | 2004-09-15 |
| CZ20012602A3 (cs) | 2003-01-15 |
| WO2000043353A1 (de) | 2000-07-27 |
| US7273947B1 (en) | 2007-09-25 |
| CA2359080C (en) | 2005-06-14 |
| AU2437600A (en) | 2000-08-07 |
| HK1050181A1 (en) | 2003-06-13 |
| TW462958B (en) | 2001-11-11 |
| ZA200105537B (en) | 2002-07-05 |
| EP1144361A1 (de) | 2001-10-17 |
| AU766196B2 (en) | 2003-10-09 |
| NO20013528D0 (no) | 2001-07-17 |
| CA2359080A1 (en) | 2000-07-27 |
| BR0007646A (pt) | 2001-10-16 |
| ES2226777T3 (es) | 2005-04-01 |
| CN1373746A (zh) | 2002-10-09 |
| JP2002535303A (ja) | 2002-10-22 |
| HUP0200531A3 (en) | 2004-03-29 |
| DE50007472D1 (de) | 2004-09-23 |
| HK1050181B (zh) | 2005-09-09 |
| IL144203A (en) | 2008-08-07 |
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