CN1915982A - Method for synthesizing Ranolazine - Google Patents
Method for synthesizing Ranolazine Download PDFInfo
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- CN1915982A CN1915982A CN 200610152726 CN200610152726A CN1915982A CN 1915982 A CN1915982 A CN 1915982A CN 200610152726 CN200610152726 CN 200610152726 CN 200610152726 A CN200610152726 A CN 200610152726A CN 1915982 A CN1915982 A CN 1915982A
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Abstract
This invention relates to a method for synthesizing ranolazine drug for treating stenocardia. The method comprises: performing amidation and N-monoalkylation on 2, 6-dimethylaniline to obtain N-(2, 6-xylyl)-2-(1-piperazine) acetamide, and then reacting with 2-(2-methoxyphenoxy) epoxyethane generated from o-methoxyphenol and epoxy chloropropane to obtain anolazine. The reactions include the refinery of 2-chloro-N-(2,6-xylyl)acetamide by cyclohexane and the recrystallization of ranolazine by ethanol/ethyl acetate (2:1), thus can raise the yield.
Description
Technical field:
The present invention relates to a kind of new synthetic method of antianginal drug ranolazine.
Background technology:
Ranolazine (ranolazine) is by a kind of novel metabolism regulators of U.S. Syntex company exploitation and the antianginal drug of heart selectivity.Its chemistry (±) N-(2, the 6-3,5-dimethylphenyl) by name-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group)-propyl group]-1-piperazine ethanamide.Can be used for treating diseases such as myocardial infarction, congestive heart disease, stenocardia, arrhythmia, its mechanism of action is for suppressing partial fatty acid oxidation, make the metabolism of heart fat acid oxidase change into the glucose oxidase metabolism, thereby reduce the oxygen-consumption of heart, do not cause the variation of heart rate and blood pressure.Patent documentation US4567264, EP0483932 and Chinese periodical West China Journal of Pharmaceutical Sciences 2004,19 (3): 191-192 has reported the synthetic method of several ranolazines:
1) with 2, the 6-xylidene(s) through the single hydrocarbonylation of amidation, N-, (reaction of 2-methoxy phenoxy methyl oxirane makes ranolazine with the 2-that is obtained by hydroxyanisole and epichlorohydrin reaction again to make N-(2, the 6-xylyl)-2 (1-piperazinyl) ethanamide." synthetic technology of Ranolazine " West China pharmaceutical journal 2004,19 (3): 191-192
2) with the hydroxyanisole be raw material and epichlorohydrin reaction again with the piperazine addition, contract with N-(2, the 6-3,5-dimethylphenyl)-2-chlor(o)acetamide again and make ranolazine.
3) be that raw material and epichlorohydrin reaction make [N, N-two (2-chloroethyl) amino]-2,6 dimethylated phenyl methyl ketone amine through amidation, condensation, hydrolysis with the hydroxyanisole, make ranolazine with 3-(2-methoxyl group phenoxy group)-1-amino-2-propyl alcohol cyclization again.
Article one, synthetic route reactions steps weak point, raw material are easy to get, though the piperazine large usage quantity is cheap and easy to get; The difference of second route and article one route makes ranolazine with N-(2, the 6-3,5-dimethylphenyl)-2-chlor(o)acetamide reaction again with piperazine condensation after being to adopt hydroxyanisole and epichlorohydrin reaction; Article three, the synthetic route reactions steps is long.
Above synthetic method yield is not high, though article one synthetic route using value is bigger, but still improved step of many needs and condition is arranged, to improve yield, the present invention passes through screening study based on this promptly, find better processing condition, solved the problem of the synthetic difficulty of ranolazine.
Summary of the invention:
The present invention is based on article one synthetic route, promptly with 2, the 6-xylidene(s) through the single hydrocarbonylation of amidation, N-, make N-(2, the 6-xylyl)-2 (route that the reaction of 2-methoxy phenoxy methyl oxirane makes ranolazine is the basis to (1-piperazinyl) ethanamide with the 2-that is obtained by hydroxyanisole and epichlorohydrin reaction again, in the concrete operations step to the reaction times, solvent, operation steps and starting material consumption screen and limit, and have found the method for improving the quality of products with productive rate.
Concrete operations step of the present invention can be divided into for 5 steps, and step is as follows:
Step 1
O-methoxy phenol, dioxane, water and NaOH are joined in the reaction flask, add epoxy chloropropane under the stirring at room, back flow reaction 2 hours; Be chilled to room temperature, the adding ethyl acetate is filtered, and tells organic layer, and water layer ethyl acetate extraction 2 times merge organic layer, use anhydrous sodium sulfate drying, and 121-124 ℃/2KPa cut is collected in underpressure distillation, gets 3-(2-methoxyl group phenoxy group)-1,2 epoxy prapane;
Step 2
With 2,6-xylidine, triethylamine, toluene join in three mouthfuls of reaction flasks of 3L successively, and ice bath is chilled to below 0 ℃, stir, add chloroacetyl chloride lentamente, drip and finish room temperature reaction 4 hours, with 2N salt pickling 2 times, tell organic layer, anhydrous magnesium sulfate drying is concentrated into dried, resistates with hexanaphthene refining 2-chloro-N-(2,6 xylyl) ethanamide;
Step 3
2-chloro-N-(2,6 xylyl) ethanamide, piperazine, dehydrated alcohol are joined in the reaction flask, be heated to back flow reaction 4 hours; Be chilled to room temperature, add ammoniacal liquor and transfer to reaction solution PH=8-9, filter, filtrate is used dichloromethane extraction, extracting solution merges, and washes once anhydrous sodium sulfate drying with water, be concentrated into dried, resistates with ether refining N-(2,6 xylyl)-2-(1-piperazinyl) ethanamide;
Step 4
3-(2-methoxyl group phenoxy group)-1,2 epoxy prapane, N-(2,6 xylyl)-2-(1-piperazinyl) ethanamide, methyl alcohol are joined in the reaction flask, back flow reaction 3 hours, steam desolventize the ranolazine crude product;
Step 5
With the ranolazine crude product with ethanol/acetic acid ethyl dissolution, activated carbon decolorizing, filtered while hot, filtrate is freezing, filter the ranolazine crystallization.
The most preferred method of the present invention is listed in the embodiment of the invention.
The present invention is characterized in, in step 1 reaction reflux time is shortened to 2 hours, reduced the reaction times, during underpressure distillation simultaneously, be collected in the cut under the 121-124 ℃/2KPa condition, product yield is reached more than 80%.
Step 2 increases by one and goes on foot with hexanaphthene purified step, improves the purity of intermediate product, helps next step reaction.
In the step 4, only use methyl alcohol and reflux, saved cost and operation steps, improved efficient simultaneously as solvent.
Step 5 purification step is carried out recrystallization with ethanol/ethyl acetate (2: 1), has improved yield.
In a word,, make the yield of the present invention at product by the improvement of above reactions steps and reaction conditions, purity, operation steps control, many-sides such as the control of product cost have obtained progress, have excellent application value.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
1, the preparation (yield: 80%) of 3-(2-methoxyl group phenoxy group)-1,2 epoxy prapane (intermediate compound I)
Feed ratio: O-methoxy phenol: epoxy chloropropane dioxane: water: NaOH=1: 1.68: 2.7: 1.2: 0.36 (w/v/v/w)
150g O-methoxy phenol, 378ml dioxane, 168ml water and 50g NaOH are joined in three mouthfuls of reaction flasks of 2L, add 252ml epoxy chloropropane, back flow reaction 2 hours under the stirring at room.Be chilled to room temperature, add ethyl acetate, filter, tell organic layer, water layer ethyl acetate extraction 2 times merge organic layer, use anhydrous sodium sulfate drying, and underpressure distillation is collected 121-124 ℃/2KPa cut and got the 163g product.
2, the preparation (yield: 84.3%) of 2-chloro-N-(2,6 xylyl) ethanamide
Feed ratio: 2,6-xylidine: chloroacetyl chloride: triethylamine: toluene=1: 0.94: 1.0: 10 (w/w/w/v)
With 165g 2,6-xylidine, 165g triethylamine, 1650ml toluene join in three mouthfuls of reaction flasks of 3L successively, and ice bath is chilled to below 0 ℃, stir 15 minutes, add the 155g chloroacetyl chloride lentamente, drip and finish, room temperature reaction 4 hours is with 2N salt pickling 2 times, tell organic layer, anhydrous magnesium sulfate drying, be concentrated into dried, resistates with hexanaphthene refining 225.9g off-white color solid.mp146-148℃。
Quality controlling means: fusing point 146-148 ℃
3, the preparation of N-(2,6 xylyl)-2-(1-piperazinyl) ethanamide (intermediate II): (yield: feed ratio 71%): 2-chloro-N-(2,6 xylyl) ethanamide: piperazine: dehydrated alcohol=1: 1.7: 10 (w/w/v)
2-chloro-N-(2,6 xylyl) ethanamide 226g, piperazine 382g, 2250ml dehydrated alcohol are joined in three mouthfuls of reaction flasks of 3L, be heated to back flow reaction 4 hours.Be chilled to room temperature, add ammoniacal liquor and transfer to reaction solution PH=8-9, filter, filtrate is extracted with methylene dichloride 500ml * 4, and extracting solution merges, with the 200ml washing once, anhydrous sodium sulfate drying, be concentrated into dried, resistates with ether refining 200.8g off-white color solid.mp103-104℃
Quality controlling means: fusing point 102-104 ℃.
4, the preparation of ranolazine: (yield 85%)
Feed ratio: intermediate compound I: intermediate II: dehydrated alcohol=1: 1.42: 3.57 (w/w/v)
With 140g 3-(2-methoxyl group phenoxy group)-1,2-propylene oxide (intermediate compound I), 200g N-(2,6 xylyls)-2-(1-piperazinyl) ethanamide (intermediate II), 500ml methyl alcohol join in the reaction flask, back flow reaction 3h, steam desolventize the 125g crude product.
5, refining: (yield: 80%)
With the 125g crude product with ethanol/ethyl acetate (2: 1) 2000ml dissolving, the proper amount of active carbon decolouring, filtered while hot, filtrate is put into the refrigerator freeze overnight, filter next day mp110-112 ℃ of 100g white solid.
Claims (2)
1, a kind of ranolazine synthetic method is characterized in that, the process following steps:
Step 1
O-methoxy phenol, dioxane, water and NaOH are joined in the reaction flask, add epoxy chloropropane under the stirring at room, back flow reaction 2 hours; Be chilled to room temperature, the adding ethyl acetate is filtered, and tells organic layer, and water layer ethyl acetate extraction 2 times merge organic layer, use anhydrous sodium sulfate drying, and 121-124 ℃/2KPa cut is collected in underpressure distillation, gets 3-(2-methoxyl group phenoxy group)-1,2 epoxy prapane;
Step 2
With 2,6-xylidine, triethylamine, toluene join in three mouthfuls of reaction flasks of 3L successively, and ice bath is chilled to below 0 ℃, stir, add chloroacetyl chloride lentamente, drip and finish room temperature reaction 4 hours, with 2N salt pickling 2 times, tell organic layer, anhydrous magnesium sulfate drying is concentrated into dried, resistates with hexanaphthene refining 2-chloro-N-(2,6 xylyl) ethanamide;
Step 3
2-chloro-N-(2,6 xylyl) ethanamide, piperazine, dehydrated alcohol are joined in the reaction flask, be heated to back flow reaction 4 hours; Be chilled to room temperature, add ammoniacal liquor and transfer to reaction solution PH=8-9, filter, filtrate is used dichloromethane extraction, extracting solution merges, and washes once anhydrous sodium sulfate drying with water, be concentrated into dried, resistates with ether refining N-(2,6 xylyl)-2-(1-piperazinyl) ethanamide;
Step 4
3-(2-methoxyl group phenoxy group)-1,2 epoxy prapane, N-(2,6 xylyl)-2-(1-piperazinyl) ethanamide, methyl alcohol are joined in the reaction flask, back flow reaction 3 hours, steam desolventize the ranolazine crude product;
Step 5
With the ranolazine crude product with ethanol/acetic acid ethyl dissolution, activated carbon decolorizing, filtered while hot, filtrate is freezing, filter the ranolazine crystallization.
2, the synthetic method of claim 1 is characterized in that, step is as follows
Step 1,
150g O-methoxy phenol, 378ml dioxane, 168ml water and 50g NaOH are joined in three mouthfuls of reaction flasks of 2L, add 252ml epoxy chloropropane, back flow reaction 2 hours under the stirring at room; Be chilled to room temperature, add ethyl acetate, filter, tell organic layer, water layer ethyl acetate extraction 2 times merge organic layer, use anhydrous sodium sulfate drying, and 121-124 ℃/2KPa cut is collected in underpressure distillation;
Step 2,
With 165g 2,6-xylidine, 165g triethylamine, 1650ml toluene join in three mouthfuls of reaction flasks of 3L successively, and ice bath is chilled to below 0 ℃, stir 15 minutes, add the 155g chloroacetyl chloride lentamente, drip and finish, room temperature reaction 4 hours is with 2N salt pickling 2 times, tell organic layer, anhydrous magnesium sulfate drying is concentrated into driedly, and resistates is refining with hexanaphthene;
Step 3,
2-chloro-N-(2,6 xylyl) ethanamide 226g, piperazine 382g, 2250ml dehydrated alcohol are joined in three mouthfuls of reaction flasks of 3L, be heated to back flow reaction 4 hours; Be chilled to room temperature, add ammoniacal liquor and transfer to reaction solution PH=8-9, filter, filtrate is extracted with methylene dichloride 500ml * 4, and extracting solution merges, with the 200ml washing once, anhydrous sodium sulfate drying, concentrate as for, resistates is refining with ether;
Step 4,
140g 3-(2-methoxyl group phenoxy group)-1,2 epoxy prapane, 200g N-(2,6 xylyl)-2-(1-piperazinyl) ethanamide, 500ml methyl alcohol are joined in the reaction flask, back flow reaction 3h, steam desolventize crude product;
Step 5,
With 125g crude product ethanol: the mixed solvent 2000ml dissolving of ethyl acetate=2: 1, the proper amount of active carbon decolouring, filtered while hot, filtrate is put into the refrigerator freeze overnight, filter next day, the ranolazine crystallization.
Priority Applications (1)
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| CNB2006101527262A CN100494187C (en) | 2006-09-26 | 2006-09-26 | Method for synthesizing Ranolazine |
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| CNB2006101527262A CN100494187C (en) | 2006-09-26 | 2006-09-26 | Method for synthesizing Ranolazine |
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| CN1915982A true CN1915982A (en) | 2007-02-21 |
| CN100494187C CN100494187C (en) | 2009-06-03 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008047388A2 (en) * | 2006-10-20 | 2008-04-24 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
| CN101838249A (en) * | 2010-03-19 | 2010-09-22 | 浙江华海药业股份有限公司 | Method for preparing high-purity guaiacol glycidyl ether |
| CN102295622A (en) * | 2010-06-25 | 2011-12-28 | 上海冠杰生物医药科技有限公司 | Preparation method of ranolazine |
| CN102367241A (en) * | 2011-12-12 | 2012-03-07 | 齐鲁天和惠世制药有限公司 | Preparation method of ranolazine |
-
2006
- 2006-09-26 CN CNB2006101527262A patent/CN100494187C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008047388A2 (en) * | 2006-10-20 | 2008-04-24 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
| WO2008047388A3 (en) * | 2006-10-20 | 2009-10-15 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
| CN101838249A (en) * | 2010-03-19 | 2010-09-22 | 浙江华海药业股份有限公司 | Method for preparing high-purity guaiacol glycidyl ether |
| WO2011113228A1 (en) * | 2010-03-19 | 2011-09-22 | 浙江华海药业股份有限公司 | A process for preparing guaiacol glycidyl |
| CN101838249B (en) * | 2010-03-19 | 2015-08-19 | 浙江华海药业股份有限公司 | A kind of method preparing high-purity guaiacol glycidyl ether |
| CN102295622A (en) * | 2010-06-25 | 2011-12-28 | 上海冠杰生物医药科技有限公司 | Preparation method of ranolazine |
| WO2011160396A1 (en) | 2010-06-25 | 2011-12-29 | 上海冠杰生物医药科技有限公司 | Method for preparation of ranolazine |
| CN102367241A (en) * | 2011-12-12 | 2012-03-07 | 齐鲁天和惠世制药有限公司 | Preparation method of ranolazine |
| CN102367241B (en) * | 2011-12-12 | 2013-04-17 | 齐鲁天和惠世制药有限公司 | Preparation method of ranolazine |
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| CN100494187C (en) | 2009-06-03 |
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Owner name: TIANJIN HANKANG PHARMACEUTICAL BIOTECHNOLOGY CO., Free format text: FORMER OWNER: YAN JIE Effective date: 20120213 |
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Effective date of registration: 20120213 Address after: 300203, Tianjin Dagu South Road, respect 4, 3, Hexi District Patentee after: Tianjin Hankang Pharmaceutical Biotechnology Co., Ltd. Address before: 300203, Tianjin Dagu South Road, respect 4, 3, Hexi District Patentee before: Yan Jie |
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