CN102952064A - Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide - Google Patents

Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide Download PDF

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CN102952064A
CN102952064A CN201110238653XA CN201110238653A CN102952064A CN 102952064 A CN102952064 A CN 102952064A CN 201110238653X A CN201110238653X A CN 201110238653XA CN 201110238653 A CN201110238653 A CN 201110238653A CN 102952064 A CN102952064 A CN 102952064A
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heptane
cis
preparation
ring
reaction
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陈蔚
潘毅
陶勇
康江鹏
程玉红
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention belongs to the technical field of medicine, and specifically relates to a preparation method of a medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide. According to the invention, cis-ex-bicyclo[2.2.1]heptane-2.3-dimethyl anhydride, an organic solvent, and urea are added into a reaction vessel; the temperature is maintained at 110-180 DEG C, and a reaction is carried out for 0.5-10h while stirring; the reaction is finished, the reaction liquid is cooled, and is poured into ice water; the mixture is sufficiently stirred, and is subjected to standing and pump-filtration; the obtained material is dried, such that the target compound is obtained. The method provided by the invention has the advantages of mild reaction condition, easy operation, low requirement on equipment, and suitability for large-scale productions.

Description

The preparation method of a kind of medicine intermediate cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides
Technical field
The invention belongs to medical technical field, be specifically related to the preparation method of a kind of medicine intermediate cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides.
Background technology
Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides are important intermediate of anxiolytic Tandospirone and antischizophrinic thing Lurasidone.Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides generally are as starting raw material take norbornene dicarboxylic anhydride (I), by the high temperature external form-norbornene dicarboxylic anhydride (II) that makes the transition to get, then adopt palladium charcoal catalytic hydrogenating reduction to get cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic anhydrides (III), last and ammoniacal liquor reacts to get target product (IV) in autoclave.Wherein the reaction with ammoniacal liquor needs to carry out in autoclave, and temperature is up to 190 ℃, and is high to equipment requirements, not easy to operate, is unfavorable for scale operation.
Figure BDA0000084626980000011
Summary of the invention
The invention provides the preparation method of a kind of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides, with cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydrides, organic solvent and urea join in the reactor, are incubated 110~180 ℃, stirring reaction 0.5~10 hour; React complete, with the reaction solution cooling, pour in the frozen water, fully stir again, leave standstill, suction filtration, the dry target compound that gets.
Figure BDA0000084626980000021
Used organic solvent is DMF or N,N-dimethylacetamide.The mol ratio of used cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydrides and urea is 1: 0.5~5.
Beneficial effect: it is gentle to the invention provides a kind of reaction conditions, easy to operate, the preparation method of cis low for equipment requirements-outer-two ring [2.2.1] heptane-2.3-dicarboximides.
Description of drawings
Fig. 1 is cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide proton nmr spectras
Embodiment
Embodiment 1: the preparation of external form-norbornene dicarboxylic anhydride (II)
Norbornene dicarboxylic anhydride 100g is added in the reaction flask, and heated and stirred is warming up to 190 ℃, and insulation reaction 1.5 hours is cooled to 50 ℃, adds 300ml benzene recrystallization and gets external form-norbornene dicarboxylic anhydride 70g, mp142~144 ℃.
Embodiment 2: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydrides (III)
External form-norbornene dicarboxylic anhydride 16.4g (0.1mol) and 150ml tetrahydrofuran (THF) are added in the reaction flask, add 5% palladium charcoal 1g, the hydrogenation catalyst reduction, stopped reaction when no longer inhaling hydrogen, suction filtration, the filtrate evaporate to dryness adds benzene and normal hexane (1: 1 volume ratio) mixed solution recrystallization and gets 13g, mp83~84 ℃.
Embodiment 3: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides (IV)
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydride 16.6g (0.1mol), urea 6g (0.1mol) and DMF 16ml add in the reaction flask, slowly be heated to 140 ℃ of reactions 2 hours, be cooled to 70 ℃, pour in the frozen water, solid is separated out, suction filtration, drying, washing, normal hexane is washed, dry white solid 13.2g, mp153~154 ℃, nuclear magnetic spectrum is seen Fig. 1.
Embodiment 4: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides (IV)
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydride 16.6g (0.1mol), urea 3g (0.05mol) and DMF 16ml add in the reaction flask, slowly be heated to 160 ℃ of reactions 4 hours, be cooled to 70 ℃, pour in the frozen water, solid is separated out, suction filtration, drying, washing, normal hexane is washed, dry white solid 13g, mp153~154 ℃, nuclear magnetic spectrum is seen Fig. 1.
Embodiment 5: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides (IV)
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydride 16.6g (0.1mol), urea 6g (0.1mol) and DMF 16ml add in the reaction flask, slowly be heated to 180 ℃ of reactions 0.5 hour, be cooled to 70 ℃, pour in the frozen water, solid is separated out, suction filtration, drying, washing, normal hexane is washed, dry white solid 13.3g, mp153~154 ℃, nuclear magnetic spectrum is seen Fig. 1.
Embodiment 6: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides (IV)
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydride 16.6g (0.1mol), urea 6g (0.1mol) and N,N-dimethylacetamide 16ml add in the reaction flask, slowly be heated to 160 ℃ of reactions 1 hour, be cooled to 70 ℃, pour in the frozen water, solid is separated out, suction filtration, drying, washing, normal hexane is washed, dry white solid 13g, mp153~154 ℃, nuclear magnetic spectrum is seen Fig. 1.
Embodiment 7: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides (IV)
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydride 16.6g (0.1mol), urea 12g (0.2mol) and N,N-dimethylacetamide 16ml add in the reaction flask, slowly be heated to 110 ℃ of reactions 10 hours, be cooled to 70 ℃, pour in the frozen water, solid is separated out, suction filtration, drying, washing, normal hexane is washed, dry white solid 13g, mp153~154 ℃, nuclear magnetic spectrum is seen Fig. 1.
Embodiment 8: the preparation of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides (IV)
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydride 16.6g (0.1mol), urea 30g (0.5mol) and N,N-dimethylacetamide 16ml add in the reaction flask, slowly be heated to 160 ℃ of reactions 1 hour, be cooled to 70 ℃, pour in the frozen water, solid is separated out, suction filtration, drying, washing, normal hexane is washed, dry white solid 13.1g, mp153~154 ℃, nuclear magnetic spectrum is seen Fig. 1.

Claims (4)

1. a medicine intermediate cis-outer-two is encircled the preparation method of [22.1] heptane-2.3-dicarboximides (IV), it is characterized in that: cis-outer-two ring [2.2.1] heptane-2.3-dicarboxylic acid anhydrides (III), organic solvent and urea are joined in the reactor, insulation reaction for some time, obtain cis-outer-two ring [22.1] heptane-2.3-dicarboximides
2. preparation method as claimed in claim 1 is characterized in that, used organic solvent is DMF, N,N-dimethylacetamide.
3. preparation method as claimed in claim 1 is characterized in that, described holding temperature is 110~180 ℃, and described reaction for some time is 0.5~10 hour.
4. preparation method as claimed in claim 1 is characterized in that, the mol ratio of used cis-outer-two ring [22.1] heptane-2.3-dicarboxylic acid anhydrides and urea is 1: 0.5~5.
CN201110238653XA 2011-08-19 2011-08-19 Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide Pending CN102952064A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4937249A (en) * 1987-10-26 1990-06-26 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and their pharmaceutical use
CN1832946A (en) * 2003-07-29 2006-09-13 大日本住友制药株式会社 Process for producing imide compound
CN101362751A (en) * 2007-08-10 2009-02-11 成都市律凯医药科技有限公司 Tandospirone citrate, preparation method thereof, formulations and quality control method
CN102101837A (en) * 2010-12-06 2011-06-22 张家港田由新材料科技有限公司 Preparation method of cis-hexahydroisoindoline
WO2011093522A1 (en) * 2010-01-28 2011-08-04 Dainippon Sumitomo Pharma Co., Ltd. A cycloalkane derivative

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4937249A (en) * 1987-10-26 1990-06-26 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and their pharmaceutical use
CN1832946A (en) * 2003-07-29 2006-09-13 大日本住友制药株式会社 Process for producing imide compound
CN101362751A (en) * 2007-08-10 2009-02-11 成都市律凯医药科技有限公司 Tandospirone citrate, preparation method thereof, formulations and quality control method
WO2011093522A1 (en) * 2010-01-28 2011-08-04 Dainippon Sumitomo Pharma Co., Ltd. A cycloalkane derivative
CN102101837A (en) * 2010-12-06 2011-06-22 张家港田由新材料科技有限公司 Preparation method of cis-hexahydroisoindoline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIKUO ISHIZUMI,等: "Synthesis and anxiolutic activity of N-Substituted cyclic imides (1R*,2S*,3S*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl] butyl-2,3-bicyclo[2.2.1]heptanedicarboximide(Tandospirone) and related compounds", 《CHEM PHARM BULL.》, vol. 39, no. 9, 30 September 1991 (1991-09-30), pages 2297 - 68 *

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Application publication date: 20130306