CN105646456A - High-yield production method of ramosetron - Google Patents
High-yield production method of ramosetron Download PDFInfo
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- CN105646456A CN105646456A CN201610112860.3A CN201610112860A CN105646456A CN 105646456 A CN105646456 A CN 105646456A CN 201610112860 A CN201610112860 A CN 201610112860A CN 105646456 A CN105646456 A CN 105646456A
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Abstract
The invention provides a high-yield production method of ramosetron. The production method is characterized by comprising steps as follows: (1) 1-chlorohexane, N-methylindole and trifluoroacetic acid are mixed, heated and stirred, a mixed solution is prepared, R-4,5,6,7-tetrahydro-1H-benzimidazole-5-formic anhydride is added, the mixture is heated, has a reflux reaction for 6-8 h and then is cooled to the room temperature, and a mixed product is obtained; (2) water is added to the mixed product prepared in the step (1), the mixture is stirred for layering, a water phase is taken and washed with 1-chloroethane, the PH value of the solution is adjusted, the mixture is stirred and left to stand for layering, methanol is added, organic phases are combined, and white powder, namely, ramosetron, is obtained through filtration and drying. A one-step preparation process is adopted in the production method, difficulty caused by purification of an intermediate is reduced, side reactions are reduced, the yield is increased, the production method is simple and convenient to operate, industrial production is facilitated, the cost is reduced, and market popularization is facilitated.
Description
Technical field:
The invention belongs to medicinal chemistry art, be specifically related to the production method of the ramosetron of a kind of high yield.
Background technology:
The chemical name of ramosetron is R-5-[(1-Methyl-1H-indole-3-base) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzimidazoles, is a new generation 5-HT3Receptor antagonist, is mainly used in preventing and treating cancer chemotherapy, radiotherapy and anesthesia, the postoperative maximally effective medicine of prevention Nausea and vomiting clinically, especially that polarity Nausea and vomiting effective percentage is high, better tolerance.
Ramosetron, ondansetron, granisetron, holder department fine jade, azasetron, dolasetron etc. broadly fall into 5-HT3Receptor antagonist, wherein ramosetron is to 5-HT3The affinity of receptor is better than ondansetron, granisetron and tropisetron. Clinical research finds, the nausea and vomiting that ramosetron injection for curing cisplatin causes is effective, and acting duration is long, and the vomiting caused for chemotherapy or Post operation is equally effective. For occurring the vomiting at 6-48h to be more suitable for using ramosetron.
A kind of new preparation process of ramosetron disclosed in Chinese patent CN100486977C (publication date 2006.5.3), adopt the synthetic technology first splitting after-condensation, by R-5-formic acid-4,5,6,7-tetrahydrochysene-1H-benzo miaow is frustrated or derivatives thereof or its salt and is formed R-5-formic acid pyrrolidine-4 with pyrrolidine condensation, 5,6,7-tetrahydrochysene-1H-benzo miaows are frustrated or its salt, then form R-5-[(1-Methyl-1H-indole-3-base) carbonyl]-4 with 1-methylindole condensation, 5,6,7-tetrahydrochysene-1H-benzimidazole and hydrochlorate thereof, i.e. ramosetron and hydrochlorates thereof. The method makes side chain N-methylindole consumption reduce, and total recovery improves, and simplifies operation, reduces cost, so as to be easier to industrialized production. The synthetic method of ramosetron disclosed in Chinese patent CN101585831B (publication date 2009.11.25), by N-methylindole and R-4,5,6,7-tetrahydrochysene-1H-benzo miaow is frustrated-5-formic acid and is carried out condensation under trifluoroacetic anhydride and polyphosphoric acids exist in atent solvent thus preparing R-5-[(1-Methyl-1H-indole-3-base) carbonyl]-4,5,6 further, 7-tetrahydrochysene-1H-benzimidazole, i.e. ramosetron.The method avoids frustrating 4,5,6,7-tetrahydrochysene-1H-benzo miaows the derivants such as acyl chlorides or the amide of-5-formic acid, and in the technical process of condensation, selectivity is good, yield is high, safety, operating process are easy, can meet the requirement of large-scale production.
From prior art, the method preparing ramosetron at present even develops in one-step method direction from original multi-step to few step, reduce the formation of intermediate, production process is made more easily to control, but the production yield of ramosetron is always present in relatively low water-mark, cause that cost is always higher, be unfavorable for marketing.
Summary of the invention:
The present invention to solve the production method that technology this subject originally is to provide the ramosetron of a kind of high yield, synthetic method by modified ramosetron, the ramosetron that total recovery is high is obtained by a synthetic method, this production method is easy and simple to handle, it is easy to industrialized production, and cost reduces, be conducive to marketing.
For solving this above-mentioned technology this subject, the technical scheme is that
A kind of production method of the ramosetron of high yield, it is characterised in that: comprise the following steps:
(1) 1-chlorohexane, N-methylindole and trifluoroacetic acid three being mixed, heated and stirred makes mixed solution, is subsequently adding R-4, and 5,6,7-tetrahydrochysene-1H-benzo miaows frustrate-5-formic anhydride, temperature rising reflux reaction 6-8h, is down to room temperature, obtains mix products;
(2) mix products prepared by step (1) is initially charged water, stirring layering, phase of fetching water, wash aqueous phase with 1-ethyl chloride, regulate solution pH value, stir stratification, add methanol and merge organic facies, obtain white powder through filtration drying, i.e. ramosetron.
Preferred as technique scheme, in described step (1), it is 3-6:1-2:6-10:1 that 1-chlorohexane, N-methylindole, trifluoroacetic acid and R-4,5,6,7-tetrahydrochysene-1H-benzo miaows frustrate the mol ratio of-5-formic anhydride.
Preferred as technique scheme, described step (1) or in step (2), 1-chlorohexane can be changed to chloroform and dichloroethanes.
Preferred as technique scheme, in described step (1), the temperature of temperature rising reflux reaction is 100-120 DEG C.
Preferred as technique scheme, in described step (1), the temperature of room temperature is 20-25 DEG C.
Preferred as technique scheme, in described step (2), the volume ratio of mix products and water is 1:0.8-1.2.
Preferred as technique scheme, in described step (2), the volume ratio of 1-ethyl chloride and aqueous phase is 1.5-2:1.
Preferred as technique scheme, in described step (2), regulates solution pH value to 8-9.
Preferred as technique scheme, in described step (2), the consumption of methanol is the 0.3-0.5 of aqueous phase consumption.
Preferred as technique scheme, in described step (2), the purity of white powder is more than 99%.
Compared with prior art, the method have the advantages that
The present invention select 1-chlorohexane and trifluoroacetic acid as reaction promoter, by N-methylindole and R-4,5,6,7-tetrahydrochysene-1H-benzo miaow is frustrated-5-formic anhydride and is carried out direct reaction formation R-5-[(1-Methyl-1H-indole-3-base) carbonyl]-4,5,6,7-tetrahydrochysene-1H-benzimidazoles, pass through one-step preparation process, reduce the difficulty that purification of intermediate is brought, decrease the generation of side reaction, improve earning rate, and production method is easy and simple to handle, it is easy to industrialized production, and cost reduces, and is conducive to marketing.
Detailed description of the invention:
Describing the present invention in detail below in conjunction with specific embodiment, illustrative examples and explanation in this present invention are used for explaining the present invention, but not as a limitation of the invention.
Embodiment 1:
(1) count by molar, the 1-chlorohexane of 3 parts, the N-methylindole of 1 part and the trifluoroacetic acid three of 6 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 100 DEG C, temperature rising reflux reaction 6h, is down to room temperature 20 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 0.8 part, stirring layering, water intaking phase, washs the aqueous phase of 1 part with the 1-chlorohexane of 1.5 parts, regulates solution pH value to 8, stirring stratification, the methanol adding 0.3 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
Embodiment 2:
(1) count by molar, the 1-chlorohexane of 6 parts, the N-methylindole of 2 parts and the trifluoroacetic acid three of 10 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 120 DEG C, temperature rising reflux reaction 8h, is down to room temperature 25 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 1.2 parts, stirring layering, water intaking phase, washs the aqueous phase of 1 part with the chloroforms of 2 parts, dichloroethanes or 1-chlorohexane, regulates solution pH value to 9, stirring stratification, the methanol adding 0.5 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
Embodiment 3:
(1) count by molar, the chloroforms of 4 parts, the N-methylindole of 1.2 parts and the trifluoroacetic acid three of 8 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 110 DEG C, temperature rising reflux reaction 7h, is down to room temperature 23 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 1 part, stirring layering, water intaking phase, with the aqueous phase of the chloroform 1 part of 1.7 parts, regulates solution pH value to 8.3, stirring stratification, the methanol adding 0.4 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
Embodiment 4:
(1) count by molar, the dichloroethanes of 4 parts, the N-methylindole of 1.5 parts and the trifluoroacetic acid three of 7 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 105 DEG C, temperature rising reflux reaction 6.5h, is down to room temperature 23 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 0.9 part, stirring layering, water intaking phase, washs the aqueous phase of 1 part with the dichloroethanes of 1.8 parts, regulates solution pH value to 8.5, stirring stratification, the methanol adding 0.3 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
Embodiment 5:
(1) count by molar, the 1-chlorohexane of 5 parts, the N-methylindole of 1.4 parts and the trifluoroacetic acid three of 9 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 120 DEG C, temperature rising reflux reaction 6h, is down to room temperature 25 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 0.8 part, stirring layering, water intaking phase, with the aqueous phase of the chloroform 1 part of 1.7 parts, regulates solution pH value to 8.4, stirring stratification, the methanol adding 0.3 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
Embodiment 6:
(1) count by molar, the dichloroethanes of 3 parts, the N-methylindole of 2 parts and the trifluoroacetic acid three of 7 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 120 DEG C, temperature rising reflux reaction 8h, is down to room temperature 25 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 1.2 parts, stirring layering, water intaking phase, washs the aqueous phase of 1 part with the 1-chlorohexane of 1.5 parts, regulates solution pH value to 8.6, stirring stratification, the methanol adding 0.5 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
Embodiment 7:
(1) count by molar, the 1-chlorohexane of 6 parts, the N-methylindole of 1.4 parts and the trifluoroacetic acid three of 8 parts are mixed, heated and stirred makes mixed solution, it is subsequently adding R-4, the 5,6 of 1 part, 7-tetrahydrochysene-1H-benzo miaow frustrates-5-formic anhydride, at 115 DEG C, temperature rising reflux reaction 8h, is down to room temperature 20 DEG C, obtains mix products.
(2) count by volume, the mix products of 1 part step (1) prepared is initially charged the water of 1 part, stirring layering, water intaking phase, with the aqueous phase of the chloroform 1 part of 2 parts, regulates solution pH value to 8.6, stirring stratification, the methanol adding 0.4 part that consumption is aqueous phase consumption merges organic facies, obtains white powder through filtration drying, i.e. ramosetron.
After testing, the ramosetron that prepared by embodiment 1-7 is as follows with the result of the yield of ramosetron of prior art, fusing point:
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Comparative example | |
| Purity (%) | 99.2 | 99.7 | 99.6 | 99.4 | 99.5 | 99.3 | 99.6 | 99.0-99.6 |
| Yield (%) | 91.2 | 92.4 | 91.6 | 92.5 | 91.7 | 91.9 | 92.2 | 84.2-91.5 |
| Fusing point (DEG C) | 226-237 | 225-240 | 226-238 | 225-240 | 230-247 | 223-235 | 226-240 | 242-245 |
As seen from the above table, ramosetron prepared by present invention purity compared with the Lei Mosiqiong of prior art is close, but yield is obviously improved, and melting range is stable.
Above-described embodiment only in fact the property shown principles of the invention and effect thereof are described, not for the restriction present invention. Above-described embodiment all under the spirit and category of the present invention, can be modified or change by any those skilled in the art. Therefore, art has usually intellectual such as modifying without departing from all equivalences completed under disclosed spirit and technological thought or change, must be contained by the claim of the present invention.
Claims (10)
1. the production method of the ramosetron of a high yield, it is characterised in that comprise the following steps:
(1) 1-chlorohexane, N-methylindole and trifluoroacetic acid three being mixed, heated and stirred makes mixed solution, is subsequently adding R-4, and 5,6,7-tetrahydrochysene-1H-benzo miaows frustrate-5-formic anhydride, temperature rising reflux reaction 6-8h, is down to room temperature, obtains mix products;
(2) mix products prepared by step (1) is initially charged water, stirring layering, phase of fetching water, wash aqueous phase with 1-ethyl chloride, regulate solution pH value, stir stratification, add methanol and merge organic facies, obtain white powder through filtration drying, i.e. ramosetron.
2. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterized in that: in described step (1), 1-chlorohexane, N-methylindole, trifluoroacetic acid and R-4,5, it is 3-6:1-2:6-10:1 that 6,7-tetrahydrochysene-1H-benzo miaows frustrate the mol ratio of-5-formic anhydride.
3. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: described step (1) or in step (2), 1-chlorohexane can be changed to chloroform and dichloroethanes.
4. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (1), the temperature of temperature rising reflux reaction is 100-120 DEG C.
5. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (1), the temperature of room temperature is 20-25 DEG C.
6. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (2), the volume ratio of mix products and water is 1:0.8-1.2.
7. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (2), the volume ratio of 1-ethyl chloride and aqueous phase is 1.5-2:1.
8. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (2), regulate solution pH value to 8-9.
9. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (2), the consumption of methanol is the 0.3-0.5 of aqueous phase consumption.
10. the production method of the ramosetron of a kind of high yield according to claim 1, it is characterised in that: in described step (2), the purity of white powder is more than 99%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696128A (en) * | 2004-11-02 | 2005-11-16 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
| CN1847242A (en) * | 2005-04-11 | 2006-10-18 | 安斯泰来制药株式会社 | Novel process for producing ramosetron or its salt |
| CN101585831A (en) * | 2008-05-23 | 2009-11-25 | 北京成宇化工有限公司 | The synthetic method of ranimustine |
-
2016
- 2016-03-01 CN CN201610112860.3A patent/CN105646456A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696128A (en) * | 2004-11-02 | 2005-11-16 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
| CN1847242A (en) * | 2005-04-11 | 2006-10-18 | 安斯泰来制药株式会社 | Novel process for producing ramosetron or its salt |
| CN101585831A (en) * | 2008-05-23 | 2009-11-25 | 北京成宇化工有限公司 | The synthetic method of ranimustine |
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