CN102816101A - Synthesis method of (S)-N-methyl-2 chloro-ethyl-pyrrolidine - Google Patents
Synthesis method of (S)-N-methyl-2 chloro-ethyl-pyrrolidine Download PDFInfo
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- CN102816101A CN102816101A CN2012102978109A CN201210297810A CN102816101A CN 102816101 A CN102816101 A CN 102816101A CN 2012102978109 A CN2012102978109 A CN 2012102978109A CN 201210297810 A CN201210297810 A CN 201210297810A CN 102816101 A CN102816101 A CN 102816101A
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- Prior art keywords
- methyl
- tetramethyleneimine
- aminoethyl
- pyrrolidine
- compound method
- 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.)
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- CLVNTYZKUHNUEF-ZETCQYMHSA-N (2s)-2-(2-chloroethyl)-1-methylpyrrolidine Chemical compound CN1CCC[C@H]1CCCl CLVNTYZKUHNUEF-ZETCQYMHSA-N 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title abstract 2
- DHVHKLWWQUTSLS-FJXQXJEOSA-N C(=O)(O)C(O)C(O)C(=O)O.CN1[C@@H](CCC1)CCCl Chemical compound C(=O)(O)C(O)C(O)C(=O)O.CN1[C@@H](CCC1)CCCl DHVHKLWWQUTSLS-FJXQXJEOSA-N 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- -1 N-methyl-2 aminoethyl tetramethyleneimine Chemical compound 0.000 claims description 15
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- CLVNTYZKUHNUEF-UHFFFAOYSA-N 2-(2-chloroethyl)-1-methylpyrrolidine Chemical compound CN1CCCC1CCCl CLVNTYZKUHNUEF-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 230000003113 alkalizing effect Effects 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- 238000011084 recovery Methods 0.000 description 4
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229960002689 clemastine fumarate Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- PNHGJPJOMCXSKN-UHFFFAOYSA-N CN1C(CCN)CCC1 Chemical compound CN1C(CCN)CCC1 PNHGJPJOMCXSKN-UHFFFAOYSA-N 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a synthesis method of (S)-N-methyl-2 chloro-ethyl-pyrrolidine, which comprises the steps of: firstly resolving raw material N-methyl-2 chloro-ethyl-pyrrolidine by resolving agent laevotartaric acid to obtain (S)-N-methyl-2 chloro-ethyl-pyrrolidine tartrate, wherein the loss of the raw material is reduced to a certain extent during post-resolving; and dissolving by water, alkalizing, extracting and vacuum rectifying to obtain the (S)-N-methyl-2 chloro-ethyl-pyrrolidine. The yield is more than 75%, the purity is higher than 99% and the optical rotation is less than -94 degrees.
Description
Technical field
The present invention relates to a kind of compound method of (S)-N-methyl-2 chloroethyl pyrrolidine.
Background technology
Clemastine fumarate is a kind of white or off-white color crystalline powder, odorless, mildly bitter flavor.It is one of best antihistaminic of generally acknowledging in the world at present, is used to treat the various anaphylactic diseases of having been drawn by histamine clinically.(S)-N-methyl-2 aminoethyl tetramethyleneimine is the important intermediate of preparation antihistamine drug clemastine fumarate.
The building-up process of this compound is not also appeared in the newspapers at present.
Summary of the invention
The object of the present invention is to provide a kind of 1, the compound method of 4-cyclohexyl diisocyanate.
In order to solve the problems of the technologies described above, the technical scheme that the present invention adopts is following: a kind of compound method of (S)-N-methyl-2 chloroethyl pyrrolidine may further comprise the steps:
(1) levotartaric acid is joined in the methyl alcohol, after stirring and dissolving is complete, be cooled to 0-10 ℃; Again N-methyl-2 aminoethyl tetramethyleneimine is splashed into mixed solution through funnel; The dropping time is 10min-5h, finishes, and controlled temperature is 5 ℃-30 ℃; Behind the stirred solution reaction 3-12h, centrifugal obtaining (S)-N-methyl-2 chloroethyl pyrrolidine tartrate;
(2) salt that step (1) is obtained is dissolved in the water; With 30% aqueous sodium hydroxide solution alkalize to the pH value to 10-11, control alkalization temperature below 30 ℃, use chloroform extraction again three times; Merge organic phase; After reclaiming chloroform, rectification under vacuum obtains (S)-N-methyl-2 chloroethyl pyrrolidine, and reaction equation is following:
Preferably, the mol ratio of levotartaric acid described in the step (1) and N-methyl-2 aminoethyl tetramethyleneimine is 1-3:1, the mass ratio 3-15:1 of methyl alcohol and N-methyl-2 aminoethyl tetramethyleneimine.
Preferably, the mol ratio of levotartaric acid described in the step (1) and N-methyl-2 aminoethyl tetramethyleneimine is 1.3:1, the mass ratio 5:1 of methyl alcohol and N-methyl-2 aminoethyl tetramethyleneimine.
Preferably, the dropping time described in the step (1) is 1h, and controlled temperature is 0 ℃-10 ℃, and the reaction times is 6h.
Preferably, the consumption of (the S)-N-methyl-2 chloroethyl pyrrolidine tartrate described in the step (2) is 1.025 times of levotartaric acid quality.
The invention has the advantages that: raw material N-methyl-2 aminoethyl tetramethyleneimine is carried out first fractionation through the resolving agent levotartaric acid; Obtain (S)-N-methyl-2 chloroethyl pyrrolidine tartrate; The loss of raw material obtains (S)-N-methyl-2 chloroethyl pyrrolidine through water-soluble, alkalization, extraction and rectification under vacuum again in the time to a certain degree can reducing the back fractionation, and yield is greater than 75%; Purity is greater than 99%, and optically-active is less than-94 °.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, these embodiment only are exemplary, scope of the present invention are not constituted any restriction.Down can make amendment with form or replacing without departing from the spirit and scope of the present invention the details of technical scheme of the present invention, but these modifications and replace and all fall into protection scope of the present invention.
Embodiment 1:
48.75g (0.325mol) levotartaric acid is joined in the 160g methyl alcohol, after stirring and dissolving is complete, be cooled to 0-10 ℃; Again 32g (0.25mol) N-methyl-2 aminoethyl tetramethyleneimine is splashed into mixed solution through funnel; The dropping time is 1h, finishes, and controlled temperature is 0-10 ℃; Behind the stirred solution reaction 6h, centrifugal obtaining (S)-N-methyl-2 chloroethyl pyrrolidine tartrate 34.1g; The salt of gained is joined among the water 50g, with 30% aqueous sodium hydroxide solution alkalize to the pH value to 10-11, control alkalization temperature below 30 ℃; Use (15g * 3) chloroform extraction three times again, merge organic phase, behind the recovery chloroform; Rectification under vacuum obtains 12.1g's (S)-N-methyl-2 chloroethyl pyrrolidine; Yield 75.1%, content 99.12% (GC), optically-active-94.7 ° (in the chloroform).
Embodiment 2:
97.6g (0.65mol) levotartaric acid is joined in the 320g methyl alcohol, after stirring and dissolving is complete, be cooled to 0-10 ℃; Again 64g (0.5mol) N-methyl-2 aminoethyl tetramethyleneimine is splashed into mixed solution through funnel; The dropping time is 1h, finishes, and controlled temperature is 0-10 ℃; Behind the stirred solution reaction 6h, centrifugal obtaining (S)-N-methyl-2 chloroethyl pyrrolidine tartrate 70.2g; The salt of gained is joined among the water 100g, with 30% aqueous sodium hydroxide solution alkalize to the pH value to 10-11, control alkalization temperature below 30 ℃; Use (30g * 3) chloroform extraction three times again, merge organic phase, behind the recovery chloroform; Rectification under vacuum obtains 25.2g's (S)-N-methyl-2 chloroethyl pyrrolidine; Yield 78.8%, content 99.22% (GC), optically-active-94.8 ° (in the chloroform).
Embodiment 3:
195.2g (1.3mol) levotartaric acid is joined in the 640g methyl alcohol, after stirring and dissolving is complete, be cooled to 0-10 ℃; Again 128g (1.0mol) N-methyl-2 aminoethyl tetramethyleneimine is splashed into mixed solution through funnel; The dropping time is 1h, finishes, and controlled temperature is 0-10 ℃; Behind the stirred solution reaction 6h, centrifugal obtaining (S)-N-methyl-2 chloroethyl pyrrolidine tartrate 150g; The salt of gained is joined among the water 200g, with 30% aqueous sodium hydroxide solution alkalize to the pH value to 10-11, control alkalization temperature below 30 ℃; Use (60g * 3) chloroform extraction three times again, merge organic phase, behind the recovery chloroform; Rectification under vacuum obtains 52.1g's (S)-N-methyl-2 chloroethyl pyrrolidine; Yield 81.4%, content 99.42% (GC), optically-active-95.2 ° (in the chloroform).
Embodiment 4:
292.8g (1.95mol) levotartaric acid is joined in the 960g methyl alcohol, after stirring and dissolving is complete, be cooled to 0-10 ℃; Again 192g (1.5mol) N-methyl-2 aminoethyl tetramethyleneimine is splashed into mixed solution through funnel; The dropping time is 1h, finishes, and controlled temperature is 0-10 ℃; Behind the stirred solution reaction 6h, centrifugal obtaining (S)-N-methyl-2 chloroethyl pyrrolidine tartrate 228g; The salt of gained is joined among the water 300g, with 30% aqueous sodium hydroxide solution alkalize to the pH value to 10-11, control alkalization temperature below 30 ℃; Use (75g * 3) chloroform extraction three times again, merge organic phase, behind the recovery chloroform; Rectification under vacuum obtains 78.5g's (S)-N-methyl-2 chloroethyl pyrrolidine; Yield 81.8%, content 99.40% (GC), optically-active-95.1 ° (in the chloroform).
Claims (5)
1. the compound method of (S)-N-methyl-2 chloroethyl pyrrolidine may further comprise the steps:
(1) levotartaric acid is joined in the methyl alcohol, after stirring and dissolving is complete, be cooled to 0-10 ℃; Again N-methyl-2 aminoethyl tetramethyleneimine is splashed into mixed solution through funnel; The dropping time is 10min-5h, finishes, and controlled temperature is 5 ℃-30 ℃; Behind the stirred solution reaction 3-12h, centrifugal obtaining (S)-N-methyl-2 chloroethyl pyrrolidine tartrate;
(2) salt that step (1) is obtained is dissolved in the water; With 30% aqueous sodium hydroxide solution alkalize to the pH value to 10-11, control alkalization temperature below 30 ℃, use chloroform extraction again three times; Merge organic phase; After reclaiming chloroform, rectification under vacuum obtains (S)-N-methyl-2 chloroethyl pyrrolidine, and reaction equation is following:
2. compound method according to claim 1 is characterized in that: the mol ratio of levotartaric acid described in the step (1) and N-methyl-2 aminoethyl tetramethyleneimine is 1-3:1, the mass ratio 3-15:1 of methyl alcohol and N-methyl-2 aminoethyl tetramethyleneimine.
3. compound method according to claim 2 is characterized in that: the mol ratio of levotartaric acid described in the step (1) and N-methyl-2 aminoethyl tetramethyleneimine is 1.3:1, the mass ratio 5:1 of methyl alcohol and N-methyl-2 aminoethyl tetramethyleneimine.
4. compound method according to claim 1 is characterized in that: the dropping time described in the step (1) is 1h, and controlled temperature is 0 ℃-10 ℃, and the reaction times is 6h.
5. compound method according to claim 1 is characterized in that: the consumption of (the S)-N-methyl-2 chloroethyl pyrrolidine tartrate described in the step (2) is 1.025 times of levotartaric acid quality.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2012102978109A CN102816101A (en) | 2012-08-21 | 2012-08-21 | Synthesis method of (S)-N-methyl-2 chloro-ethyl-pyrrolidine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102978109A CN102816101A (en) | 2012-08-21 | 2012-08-21 | Synthesis method of (S)-N-methyl-2 chloro-ethyl-pyrrolidine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115521238A (en) * | 2022-07-02 | 2022-12-27 | 甘肃瀚聚药业有限公司 | Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5382773A (en) * | 1976-12-28 | 1978-07-21 | Sanwa Kagaku Kenkyusho Co | Process for preparing fumaric cremastine useful as medicine |
| CN1602860A (en) * | 2004-08-23 | 2005-04-06 | 南昌弘益科技有限公司 | Dripping pills of clemastine fumarate and its preparation method |
| CN1621403A (en) * | 2003-11-28 | 2005-06-01 | 如皋市恒祥化工有限责任公司 | 2-(2-aminoethyl)methyl-pyrrolidine and preparation process thereof |
| WO2011109675A2 (en) * | 2010-03-05 | 2011-09-09 | Sanofi | Process for the preparation of 2-(cyclohexylmethyl)-n-{2- [(2s)-1-methylpyrrolidin-2-yl]ethyl}-1, 2, 3, 4- tetrahydroisoquinoline-7-sulfonamide |
-
2012
- 2012-08-21 CN CN2012102978109A patent/CN102816101A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5382773A (en) * | 1976-12-28 | 1978-07-21 | Sanwa Kagaku Kenkyusho Co | Process for preparing fumaric cremastine useful as medicine |
| CN1621403A (en) * | 2003-11-28 | 2005-06-01 | 如皋市恒祥化工有限责任公司 | 2-(2-aminoethyl)methyl-pyrrolidine and preparation process thereof |
| CN1602860A (en) * | 2004-08-23 | 2005-04-06 | 南昌弘益科技有限公司 | Dripping pills of clemastine fumarate and its preparation method |
| WO2011109675A2 (en) * | 2010-03-05 | 2011-09-09 | Sanofi | Process for the preparation of 2-(cyclohexylmethyl)-n-{2- [(2s)-1-methylpyrrolidin-2-yl]ethyl}-1, 2, 3, 4- tetrahydroisoquinoline-7-sulfonamide |
Non-Patent Citations (2)
| Title |
|---|
| ANNE M. FOURNIER，等: "Synthesis of (-)-(S,S)-clemastine by Invertive N f C Aryl Migration in a Lithiated Carbamate", 《ORGANIC LETTERS》 * |
| THEO NIKIFOROV，等: "A route to optically active benzyl ester of (1-methyl-2- pyrrolidinyl)-acetic acid, an intermediate in the synthesis", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115521238A (en) * | 2022-07-02 | 2022-12-27 | 甘肃瀚聚药业有限公司 | Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine |
| CN115521238B (en) * | 2022-07-02 | 2024-05-31 | 甘肃瀚聚药业有限公司 | Preparation method of N-methyl-2- (2-chloroethyl) pyrrolidine |
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Application publication date: 20121212 |