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 PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- heptane
- cis
- preparation
- ring
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
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
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.
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.
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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110238653XA CN102952064A (en) | 2011-08-19 | 2011-08-19 | Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110238653XA CN102952064A (en) | 2011-08-19 | 2011-08-19 | Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102952064A true CN102952064A (en) | 2013-03-06 |
Family
ID=47761508
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110238653XA Pending CN102952064A (en) | 2011-08-19 | 2011-08-19 | Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102952064A (en) |
Citations (5)
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 |
-
2011
- 2011-08-19 CN CN201110238653XA patent/CN102952064A/en active Pending
Patent Citations (5)
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)
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 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103739539A (en) | Method for preparing anti-vulcanization reversion agent 1,3-bis(citraconimidomethyl)benzene | |
CN101607894B (en) | Preparation method of 3,3',4,4'-tetra carboxylic acid biphenyl | |
CN103694306A (en) | Method for preparing R-isomer by using S-isomer of budesonide | |
CN108503613A (en) | A method of preparing 2,5- furandicarboxylic acids | |
CN102531994B (en) | Method for synthesizing bismaleimide | |
CN103214385B (en) | Microwave synthesis method for diarylamine compound | |
CN102827015B (en) | Preparation method of 5-aminolevulinic acid (ALA) hydrochloride | |
CN102952064A (en) | Preparation method of medicine intermediate cis-ex-bicyclo[2.2.1]heptane-2.3-dicarboximide | |
CN102101837A (en) | Preparation method of cis-hexahydroisoindoline | |
CN108191858A (en) | A kind of intermediate and preparation method for preparing pyrroloquinoline quinone | |
CN102363607B (en) | Method for synthesizing maleimide by using strongly acidic room-temperature ionic liquid as medium | |
CN101704788B (en) | Improved preparation process of 2-Butyl-1,3-diazapira[4,4]nonane-1-en-4-one | |
CN107118088A (en) | A kind of preparation method of m-hydroxy acetophenone | |
CN109096205B (en) | Synthesis method of benzimidazole compound | |
CN106928119A (en) | A kind of 5 cyano group 3(4 chlorobutyls)The preparation method of indoles | |
CN105399718A (en) | Solid phase synthesis method of 2H-benzopyran compounds | |
CN108299224A (en) | A kind of preparation method of N- acetyl group -1- cyclohexylethylamines | |
CN108911972A (en) | A kind of racemization recovery method for splitting by-product in mother liquor of sitafloxacin intermediate | |
CN110305058A (en) | A kind of 4- bromine carbazole preparation method | |
CN103980257B (en) | The synthetic method of 8-nitro-2-tetrazole base-4-carbonyl chromene | |
CN103570612B (en) | A kind of preparation method of 6-chlorine apellagrin | |
CN114591176B (en) | Preparation method of 3-nitrophthalic acid | |
CN102942564A (en) | Asymmetric bismaleimide containing 1, 3, 4-oxadiazole structure and preparation method thereof | |
CN106831536A (en) | A kind of preparation method of gliclazide green synthesis process | |
CN101560144B (en) | Synthetic method of 6, 11-dichloro-5, 12-naphthacenequinone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130306 |