CN1312791A - 阿托酸乙酯的制备方法 - Google Patents
阿托酸乙酯的制备方法 Download PDFInfo
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- CN1312791A CN1312791A CN99809480A CN99809480A CN1312791A CN 1312791 A CN1312791 A CN 1312791A CN 99809480 A CN99809480 A CN 99809480A CN 99809480 A CN99809480 A CN 99809480A CN 1312791 A CN1312791 A CN 1312791A
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- Prior art keywords
- ethyl ester
- acid ethyl
- ethyl
- producing
- methyl esters
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- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 17
- DULCUDSUACXJJC-UHFFFAOYSA-N benzeneacetic acid ethyl ester Natural products CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 11
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 7
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 7
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 claims abstract description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- BOIWYTYYWPXGAT-UHFFFAOYSA-N ethyl 2-phenylprop-2-enoate Chemical compound CCOC(=O)C(=C)C1=CC=CC=C1 BOIWYTYYWPXGAT-UHFFFAOYSA-N 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract 3
- JLIDRDJNLAWIKT-UHFFFAOYSA-N 1,2-dimethyl-3h-benzo[e]indole Chemical compound C1=CC=CC2=C(C(=C(C)N3)C)C3=CC=C21 JLIDRDJNLAWIKT-UHFFFAOYSA-N 0.000 abstract 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- -1 atropic acid methyl esters Chemical class 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229960001402 tilidine Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BDNMABJZSXTKAQ-VCPDFFEISA-N 3-(diethylamino)propyl (1r,4s)-3-phenylbicyclo[2.2.1]heptane-3-carboxylate Chemical compound CCN(CC)CCCOC(=O)C1([C@H]2CC[C@H](C2)C1)C1=CC=CC=C1 BDNMABJZSXTKAQ-VCPDFFEISA-N 0.000 description 1
- 238000005705 Cannizzaro reaction Methods 0.000 description 1
- SQZCNGDPQFCFMO-MARPTJLWSA-N O=C(OCCN1CCCC1)C1(C[C@@H]2CC[C@H]1C2)c1ccccc1 Chemical compound O=C(OCCN1CCCC1)C1(C[C@@H]2CC[C@H]1C2)c1ccccc1 SQZCNGDPQFCFMO-MARPTJLWSA-N 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229960001793 bornaprine Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种制备甲酯含量最大0.05%的阿托酸乙酯的方法,该方法包括苯基乙酸乙酯与多聚甲醛在碱存在下进行反应。所述方法的特征在于,用作苯基乙酸乙酯的物料包含不超过0.03%相应的苯基乙酸甲酯,而且反应是在N－甲基吡咯烷酮或N,N－二甲基甲酰胺中进行的。
Description
本发明涉及阿托酸乙酯的制备方法。
阿托酸乙酯是制备诸如双环非那明、波那普令和替利定之类药物活性成分的重要中间体。例如，鸦片类止痛药替利定，可通过阿托酸乙酯与二甲基氨基丁二烯起反应制备。对这一合成来说重要的是，作为原料的阿托酸乙酯必须具有极小阿托酸甲酯含量，因为此种杂质将导致替利定被相应的甲基酯污染，该杂质必须花费不成比例地大的代价才能除掉。因此，任何可实用的替利定合成必须采用甲酯含量不超过0.05％的阿托酸乙酯作为原料。
阿托酸甲酯含量不超过0.05％的阿托酸乙酯可采用比较复杂的两步法制取(Helv.Chim.Acta(瑞士化学学报)30,1349(1947))，只要原料的甲基化合物含量不超过0.05％。该方法涉及苯基乙酸乙酯与草酸二乙酯在乙醇钠存在下缩合生成2-氧代-3-苯基琥珀酸二乙酯的钠盐。随后与甲醛，在碳酸钾存在下起反应生成阿托酸乙酯，其甲酯含量不超过0.05％。
DE3317356描述了一种一步法，按此法，苯基乙酸乙酯与多聚甲醛在碳酸钾存在下经固/液相转移催化反应生成阿托酸乙酯。然而，在这种情况下，即便使用甲酯含量等于0.1％的苯基乙酸乙酯，仍然生成含量大得不可接受的阿托酸甲酯，可能是由于甲醛通过坎尼扎罗反应生成甲醇所致。于是，在使用甲苯作为溶剂的情况下，将获得约2％甲酯。
EP-A3670描述了一种制备2-芳基丙烯酸酯的一步法，按此法，芳基乙酸酯与甲醛在极性溶剂中、碱存在下起反应生成2-芳基丙烯酸酯。但是，苯基乙酸乙酯与多聚甲醛按此种一般方法起反应却生成一种仅含有约25％阿托酸乙酯的反应混合物。
我们现已发现一种制备甲酯含量不超过0.05％的阿托酸乙酯的实用而简单的方法。
本发明涉及一种制备甲酯含量不超过0.05％的阿托酸乙酯的方法，该方法包括使苯基乙酸乙酯与多聚甲醛在碱存在下进行反应，其中用作苯基乙酸乙酯的物料包含不超过0.03％相应的苯基乙酸甲酯，而且反应是在N-甲基吡咯烷酮或N,N-二甲基甲酰胺中进行的。
在该方法中，1mol苯基乙酸乙酯与1～2，优选1.4～1.6当量多聚甲醛进行反应。
通常使用的碱是碳酸钾，其用量介于1～2，优选1.4～1.8mol每摩尔苯基乙酸乙酯。
反应在70～90℃进行。一般，在1.5～3h后完成。
本发明方法可在超过50％的收率条件下产出高产物纯度(大于90％(GC))阿托酸乙酯产物。按该新方法制备的阿托酸乙酯中，甲酯含量介于0.02～0.05％。
不同于Helv.Chim.Acta(瑞士化学学报)30,1349(1947)中的两步法，在该新方法中不存在中间体的分离和贮存。而且，该新方法还可在短得多的时间内完成。最后，该新方法不需要只能在有限时间内贮存并具有腐蚀性的甲醇钠(sodium methoxide)。
实例
94 g苯基乙酸乙酯(甲酯含量0.01％)在300 mLN-甲基吡咯烷酮中与120g碳酸钾和25g多聚甲醛在75～80℃一起搅拌1.5h。冷却后，加入150mL水，分离出水相。N-甲基吡咯烷酮相以75mL二异丙醚每次，萃取2次。合并的二异丙醚相用50mL水洗涤并真空浓缩。获得58g产物，对应于54g阿托酸乙酯(理论值的53％)，阿托酸甲酯含量等于0.03％。
Claims (1)
1．一种制备甲酯含量不超过0.05％的阿托酸乙酯的方法，该方法包括苯基乙酸乙酯与多聚甲醛在碱存在下进行反应，其中用作苯基乙酸乙酯的物料包含不超过0.03％相应的苯基乙酸甲酯，而且反应是在N-甲基吡咯烷酮或N,N-二甲基甲酰胺中进行的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19836222A DE19836222A1 (de) | 1998-08-11 | 1998-08-11 | Verfahren zur Herstellung von Atropasäureethylester |
| DE19836222.6 | 1998-08-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1312791A true CN1312791A (zh) | 2001-09-12 |
Family
ID=7877098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99809480A Pending CN1312791A (zh) | 1998-08-11 | 1999-07-28 | 阿托酸乙酯的制备方法 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6509493B1 (zh) |
| EP (1) | EP1104397B1 (zh) |
| JP (1) | JP2002522520A (zh) |
| KR (1) | KR20010071084A (zh) |
| CN (1) | CN1312791A (zh) |
| AT (1) | ATE260883T1 (zh) |
| AU (1) | AU752614B2 (zh) |
| BR (1) | BR9912887A (zh) |
| CA (1) | CA2339997C (zh) |
| DE (2) | DE19836222A1 (zh) |
| ES (1) | ES2217795T3 (zh) |
| HU (1) | HUP0103103A3 (zh) |
| IL (2) | IL141010A0 (zh) |
| NO (1) | NO20010625D0 (zh) |
| PT (1) | PT1104397E (zh) |
| WO (1) | WO2000009469A1 (zh) |
| ZA (1) | ZA200101974B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993013A (zh) * | 2012-12-28 | 2013-03-27 | 成都爱博协诺化学技术有限公司 | 四氟醚唑中间体的合成方法 |
| CN107466289A (zh) * | 2015-04-14 | 2017-12-12 | 璐彩特国际英国有限公司 | 用于产生烯属不饱和羧酸或羧酸酯的工艺 |
| CN110551027A (zh) * | 2018-05-31 | 2019-12-10 | 南京理工大学 | 3-羟基-2-苯基丙酸的合成方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4394979A (en) * | 1978-02-06 | 1979-08-16 | Commonwealth Scientific And Industrial Research Organisation | Preparation of alkyl 1-aryl arylates |
| DE3317356A1 (de) * | 1982-05-14 | 1983-11-17 | Basf Ag, 6700 Ludwigshafen | Verfahren zur herstellung substituierter alpha-phenylacrylsaeureester |
-
1998
- 1998-08-11 DE DE19836222A patent/DE19836222A1/de not_active Withdrawn
-
1999
- 1999-07-28 IL IL14101099A patent/IL141010A0/xx active IP Right Grant
- 1999-07-28 PT PT99940069T patent/PT1104397E/pt unknown
- 1999-07-28 WO PCT/EP1999/005403 patent/WO2000009469A1/de not_active Application Discontinuation
- 1999-07-28 AU AU54146/99A patent/AU752614B2/en not_active Expired
- 1999-07-28 CA CA002339997A patent/CA2339997C/en not_active Expired - Fee Related
- 1999-07-28 EP EP99940069A patent/EP1104397B1/de not_active Expired - Lifetime
- 1999-07-28 AT AT99940069T patent/ATE260883T1/de not_active IP Right Cessation
- 1999-07-28 JP JP2000564924A patent/JP2002522520A/ja active Pending
- 1999-07-28 CN CN99809480A patent/CN1312791A/zh active Pending
- 1999-07-28 US US09/743,894 patent/US6509493B1/en not_active Expired - Lifetime
- 1999-07-28 KR KR1020017001770A patent/KR20010071084A/ko not_active Application Discontinuation
- 1999-07-28 BR BR9912887-0A patent/BR9912887A/pt not_active IP Right Cessation
- 1999-07-28 HU HU0103103A patent/HUP0103103A3/hu unknown
- 1999-07-28 DE DE59908757T patent/DE59908757D1/de not_active Expired - Lifetime
- 1999-07-28 ES ES99940069T patent/ES2217795T3/es not_active Expired - Lifetime
-
2001
- 2001-01-22 IL IL141010A patent/IL141010A/en not_active IP Right Cessation
- 2001-02-06 NO NO20010625A patent/NO20010625D0/no not_active Application Discontinuation
- 2001-03-09 ZA ZA200101974A patent/ZA200101974B/en unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993013A (zh) * | 2012-12-28 | 2013-03-27 | 成都爱博协诺化学技术有限公司 | 四氟醚唑中间体的合成方法 |
| CN102993013B (zh) * | 2012-12-28 | 2015-03-18 | 成都爱博协诺化学技术有限公司 | 四氟醚唑中间体的合成方法 |
| CN107466289A (zh) * | 2015-04-14 | 2017-12-12 | 璐彩特国际英国有限公司 | 用于产生烯属不饱和羧酸或羧酸酯的工艺 |
| CN107466289B (zh) * | 2015-04-14 | 2021-09-17 | 三菱化学英国有限公司 | 用于产生烯属不饱和羧酸或羧酸酯的工艺 |
| TWI780025B (zh) * | 2015-04-14 | 2022-10-11 | 英商三菱化學英國有限公司 | 生產乙烯性不飽和羧酸或酯的方法 |
| CN110551027A (zh) * | 2018-05-31 | 2019-12-10 | 南京理工大学 | 3-羟基-2-苯基丙酸的合成方法 |
| CN110551027B (zh) * | 2018-05-31 | 2022-03-22 | 南京理工大学 | 3-羟基-2-苯基丙酸的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US6509493B1 (en) | 2003-01-21 |
| CA2339997C (en) | 2007-05-29 |
| WO2000009469A1 (de) | 2000-02-24 |
| JP2002522520A (ja) | 2002-07-23 |
| IL141010A (en) | 2007-02-11 |
| BR9912887A (pt) | 2001-05-08 |
| DE19836222A1 (de) | 2000-02-17 |
| CA2339997A1 (en) | 2000-02-24 |
| HUP0103103A2 (hu) | 2001-12-28 |
| HUP0103103A3 (en) | 2002-12-28 |
| KR20010071084A (ko) | 2001-07-28 |
| ZA200101974B (en) | 2002-03-11 |
| EP1104397B1 (de) | 2004-03-03 |
| PT1104397E (pt) | 2004-05-31 |
| IL141010A0 (en) | 2002-02-10 |
| ES2217795T3 (es) | 2004-11-01 |
| NO20010625L (no) | 2001-02-06 |
| DE59908757D1 (de) | 2004-04-08 |
| NO20010625D0 (no) | 2001-02-06 |
| AU5414699A (en) | 2000-03-06 |
| AU752614B2 (en) | 2002-09-26 |
| EP1104397A1 (de) | 2001-06-06 |
| ATE260883T1 (de) | 2004-03-15 |
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