CN102731436A - Preparation and refining method of repaglinide - Google Patents
Preparation and refining method of repaglinide Download PDFInfo
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- CN102731436A CN102731436A CN2012101097518A CN201210109751A CN102731436A CN 102731436 A CN102731436 A CN 102731436A CN 2012101097518 A CN2012101097518 A CN 2012101097518A CN 201210109751 A CN201210109751 A CN 201210109751A CN 102731436 A CN102731436 A CN 102731436A
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- ZHBKQYMGZIZPQF-UHFFFAOYSA-N CC(C)CC(c(cccc1)c1N1CCCCC1)=N Chemical compound CC(C)CC(c(cccc1)c1N1CCCCC1)=N ZHBKQYMGZIZPQF-UHFFFAOYSA-N 0.000 description 1
- RHPPSMDKAMAVAI-OAHLLOKOSA-N CCC[C@H](CC(C)C)NC(Cc(cc1)cc(OCC)c1C(O)=O)=O Chemical compound CCC[C@H](CC(C)C)NC(Cc(cc1)cc(OCC)c1C(O)=O)=O RHPPSMDKAMAVAI-OAHLLOKOSA-N 0.000 description 1
- OTGSESBEJUHCES-UHFFFAOYSA-N CCOC(c(ccc(CC(O)=O)c1)c1OCC)=O Chemical compound CCOC(c(ccc(CC(O)=O)c1)c1OCC)=O OTGSESBEJUHCES-UHFFFAOYSA-N 0.000 description 1
- FTCMVLQJMIXDSI-VWLOTQADSA-N CCOC(c1ccc(CC(N[C@@H](CC(C)C)c(cccc2)c2N2CCCCC2)=O)cc1OCC)=O Chemical compound CCOC(c1ccc(CC(N[C@@H](CC(C)C)c(cccc2)c2N2CCCCC2)=O)cc1OCC)=O FTCMVLQJMIXDSI-VWLOTQADSA-N 0.000 description 1
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Abstract
The invention relates to a preparation and refining method of repaglinide. The preparation method comprises the steps that: (S)-3-Methyl-1-(2-piperidinophenyl)butylamine glutamate (II) is adopted as a raw material, and is subjected to hydrolysis and an acylation reaction; an obtained material is subjected to an amidation reaction with 4-ethoxycabonyl-3-ethoxyphenylacetic acid (IV) under the existence of a condensing agent, such that 4-ethoxycabonyl-3-ethoxyphenylacetic ester (V) is obtained; the material V is hydrolyzed under an alkaline condition, such that a repaglinide crude product is obtained; the repaglinide crude product is subjected to ethanol-water solvent crystallization, such that repaglinide (I) is obtained. According to the invention, (S)-3-Methyl-1-(2-piperidinophenyl)butylamine glutamate is adopted as an initial raw material; the reaction conditions are optimized; the yield is improved; and good safety is ensured. An ethanol-water refining method is adopted, such that the product quality is improved, and environment pollution is reduced. Therefore, the method is suitable for industrialized productions.
Description
Technical field
The present invention relates to medicine organic synthesis field, particularly relate to a kind of preparation and process for purification of treating the diabetes medicament repaglinide.
Background technology
Repaglinide chemistry S (+) by name-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amino carbonyl methyl] phenylformic acid, be a kind of novel orally-taken blood sugar reducing medicine, can promote insulin secretion; Have the characteristics fast, that action time is short that absorb; Can in the type ii diabetes patient, simulate the physiological insulin secretion, effectively control postprandial hyperglycemia, higher protein binding rate is arranged; Can in tissue, not accumulate, security is good.Repaglinide both can be used as a line antidiabetic medicine and had used separately, also can increase curative effect with other ofhypoglycemic medicine combined utilization.
The synthetic route of the repaglinide of bibliographical information mainly is to obtain compound V with compound IV and compound III through condensation in the prior art, obtains product I through hydrolysis again, and its reaction equation is following:
The N that uses in the above synthetic route, N '-carbon back diimidazole (III) price is more expensive relatively, and reaction process is easy to generate by product, causes production cost to increase, and product yield is low in addition, is not suitable for suitability for industrialized production.
In bibliographical information, in (like US5312924, CN1571769 or US2005/0107614), mainly be to study to the condensation process of compound IV and compound III.Report compound IV and compound III are at carbonyl dimidazoles in US5312924, CN1571769, and there are condensation down in DCC or triphenylphosphine, triethylamine, tetracol phenixin, and under-80 ℃, carry out; Product needed is through the chromatographic column purifying; Cost is high, and yield is low, is inappropriate for suitability for industrialized production.And report is condensation under the condition of tertiary butyl Acetyl Chloride 98Min. and alkali among the US2005/0107614, and this technological operation is simple, and product is easy to purifying, but the reaction times is longer, and yield is not high yet.In document WO 2001035900 reports; Need to use dangerous and expensive reagent such as lithium diisopropylamine, DMPU in the reaction, above-mentioned various methodologies has all increased the difficulty of suitability for industrialized production, has increased cost; Thereby increased the repaglinide production cost, be unfavorable for industrialization promotion.
Therefore develop meaning and value that an operational path that can solve an above-mentioned difficult problem has.The invention provides the preparation and the process for purification of a new repaglinide, is that starting raw material prepares midbody N with auspicious lattice amine glutaminate, and N '-carbon back diimidazole reduces cost; Improved the purity of midbody, FF adopts the method for alcohol-water recrystallization, has simple to operately, and cost is low; Yield is high, and low toxicity is low dangerous; Product purity is high, reduces characteristics such as environmental pollution, is an operational path with fine industrial prospect.
Summary of the invention
The object of the present invention is to provide a cost low, yield is high, high and suitable industrial preparation and the process for purification of going up the repaglinide of using of product purity.
Method provided by the invention is a raw material with auspicious lattice amine glutaminate (II); Through hydrolysis; After the acylation reaction; In the presence of condensing agent, generate auspicious lattice ester (V) through amidate action with auspicious lattice acid (IV), hydrolysis generates the repaglinide bullion under alkaline condition, obtains repaglinide (I) through the alcohol-water solvent crystal again.This method prepares repaglinide through optimizing processing condition, and simple to operate, FF adopts the method for alcohol-water recrystallization in addition, greatly reduces production cost and pollution, has improved product gas purity and yield.
Scheme involved in the present invention may further comprise the steps successively:
(1) is the starting raw material preparation with auspicious lattice amine glutaminate (II), is dissolved in the reaction solvent methylene dichloride that the dropping sodium aqueous solution under the whipped state adds back stirring at room 1～2h.Standing demix, water layer merge organic layer with organic solvent extraction 2 times, add anhydrous sodium sulfate drying, filter, and filtrating is evaporated to original volume 1/2 at 30 ℃～35 ℃, De Ruige amine dichloromethane solution.
(2) auspicious lattice acid (IV) are dissolved in the methylene dichloride, stir, be cooled to 2～6 ℃, slow dripping thionyl chloride behind the adding DMF, about 0.5～1h drips off; Be warming up to backflow 1h, after reacting completely, concentrating under reduced pressure takes off dried solvent, adds the dissolving of exsiccant methylene dichloride, obtains the dichloromethane solution of auspicious lattice isoxazolecarboxylic acid, seals subsequent use.
(3) auspicious lattice amine aqueous solution ice bath is cooled to 2～6 ℃, adds sodium hydrogencarbonate and stir 0.5h.Slowly drip the dichloromethane solution of auspicious lattice isoxazolecarboxylic acid, 1～2h drips off; Be incubated 2～6 ℃ of reaction 12h, reaction finishes and slowly adds water, has gas to produce.Water layer merges organic layer with dichloromethane extraction 2 times, and 35～38 ℃ of concentrating under reduced pressure take off dried solvent and get white-yellowish solid.Add methyl alcohol and stir dissolving fully, drip water, have solid to separate out, 10～15 ℃ are stirred 3～4h; Filter,, drain, again with n-hexane/ethyl acetate mixing solutions making beating 0.5h with the drip washing of methanol mixing solutions; Filtration is drained, 50～55 ℃ of drying under reduced pressure, and getting the off-white color solid is auspicious lattice ester (V).
(4) (V) is added in the ethanol stirring and dissolving.Drip the 1N sodium hydroxide solution, dropwise and be warming up to 55～60 ℃, reaction 2～4h.Be cooled to 35～40 ℃ after reaction finishes, with about 1N hydrochloric acid adjust pH to 4.3, stirring at room 3～4h is cooled to 0～5 ℃ and stirs 1h, filters, and filter cake use pH is 4.0～4.5 aqueous hydrochloric acid washing.65～70 ℃ of vacuum-dryings get repaglinide (I) bullion.
(5) repaglinide (I) bullion is added ethanol, stirring and dissolving filters out insoluble impurity; Be heated to 60～65 ℃, adding pH4.0～4.5, temperature are 65 ℃ water, add the back and reduce to room temperature naturally; Stirring and crystallizing 3h; Filter, filter cake is with the water washing of pH4.0～4.5, and 65～70 ℃ of vacuum-dryings get repaglinide highly finished product (I).This preparation process is represented as follows with chemical equation:
In step (1), starting raw material is an auspicious lattice amine glutaminate (II); Reaction solvent is a methylene dichloride;
In step (1), the concentration of aqueous sodium hydroxide solution is 0.8mol/L;
In step (1), the concentrating under reduced pressure temperature is 30～35 ℃, and pressure is 0.095MPa;
In step (2), the amount that drips DMF is 1% of auspicious lattice acid.
In step (2), the temperature that drips DMF is 2～6 ℃.
In step (3), the ratio of methanol/water solution is a methyl alcohol: water=4: 1;
In step (3), normal hexane in the n-hexane/ethyl acetate mixed solvent: ETHYLE ACETATE=8: 1
In step (4), auspicious lattice ester (quality): ethanol (volume)=1: 10;
In step (4), drying temperature is 65～70 ℃;
In step (5), consumption of ethanol is advisable with 8～10 times for 5～12 times of wet bullion;
In step (5), the pH of water is 4.0～4.5, and temperature is 60～70 ℃, and its consumption is 5～20 times of alcoholic acid, is advisable with 8～15 times;
In step (5), add in the water process, temperature is not less than 60 ℃ in the reaction vessel;
In step (5),, can re-refine 1 time if single assorted greater than 0.1%;
Embodiment
Now face is described further repaglinide preparation method according to the invention with by way of example again:
Embodiment 1:
According to the preparation method of the repaglinide of present embodiment, it wraps successively
Draw together following steps:
The preparation of the dichloromethane solution of auspicious lattice amine (III)
19.6g auspicious lattice amine glutaminate and 80ml methylene dichloride, stirring and dissolving drips the alkali lye that 6.37g sodium hydroxide and 200ml water prepare; Finish stirring at room 1～2h.Methylene dichloride 40ml * 2 extractions are used in layering, water layer again, merge organic layer, anhydrous sodium sulfate drying; Filter, half solvent is approximately sloughed in 30～35 ℃ of decompressions of filtrating, and directly gets into next step.(TLC condition-chloroform: methyl alcohol=10: 1);
The preparation of auspicious lattice ester (V)
Auspicious lattice acid (IV) 10g, anhydrous methylene chloride 75ml, stirring and dissolving is cooled to 2～6 ℃; Add DMF 0.1g, slow dripping thionyl chloride 9g, about 0.5～1h drips, and drips to finish; Be warming up to backflow, reaction 1h, the TLC monitoring (chloroform: methyl alcohol=10: 1), after reacting completely; Dried solvent is taken off in decompression, adds dry methylene chloride 40ml, and dissolving seals subsequent use fully.
Auspicious lattice amine aqueous solution ice-water bath of last step is cooled to 2～6 ℃, adds sodium hydrogencarbonate 25.2g, adds to stir 0.5h; Slowly drip the dichloromethane solution that contains auspicious lattice isoxazolecarboxylic acid, 1～2h drips off, and drips 2～6 ℃ of reactions of Bi Baowen; The TLC monitoring, (chloroform: methyl alcohol=10: 1), reaction is finished to keep thermotonus to spend the night; Continue to stir, slowly add water 200ml, have gas to produce; Stir, layering, water layer is used methylene dichloride 50ml * 2 extracted twice again.Merge organic layer, dried solvent is taken off in 35～38 ℃ of decompressions, gets white-yellowish solid, adds methyl alcohol 100ml, and stirring and dissolving is complete, slowly drips water 50ml, has solid to separate out.10～15 ℃ are stirred 3～4h, filter, and 10ml left and right sides methanol (4/1) drip washing is drained.Add n-hexane/ethyl acetate (8/1) 60ml making beating 0.5h again, drain, the drip washing of about 15ml mixed solvent progressively is warming up to 50～55 ℃ of drying under reduced pressure, De Ruige ester off-white color solid 12～13g.
The preparation of repaglinide bullion
With auspicious lattice ester 12g, ethanol 120ml, stirring and dissolving; Drip 38ml 1N sodium hydroxide solution, drip and finish, be warming up to 55～60 ℃, reaction 2～4h, TLC monitors (TLC condition-chloroform: methyl alcohol=10: 1).Reaction is finished, and is cooled to 35～40 ℃, adds 1N hydrochloric acid, transfers about pH4.3.Stirring at room 3～4h lowers the temperature 0～5 ℃ and stirs 1h.Filter, filter cake is with the aqueous hydrochloric acid 30ml washing of pH4.0～4.5; Progressively be warming up to 65～70 ℃ of vacuum-dryings, get repaglinide bullion 9.0～9.5g;
Making with extra care of repaglinide
With repaglinide bullion 9.0g, add ethanol 108ml, stirring and dissolving is complete; Through the smart filter of strainer, filtrating is heated to 60～65 ℃, adds 77.4ml pH 4.0～4.5 temperature and be 65 ℃ water (the smart filter of strainer), adds the water process and keeps temperature in the kettle to be not less than 60 ℃ not having solid and separate out.Drip the back and reduce to room temperature, stirring and crystallizing 3h naturally.Filter, filter cake is with purified water (smart filterable) washing of pH 4.0～4.5.Progressively be warming up to 65～70 ℃ of vacuum-dryings, get repaglinide highly finished product 7.6～8.1g.
Embodiment 2:
According to the preparation method of the repaglinide of present embodiment, it in turn includes the following steps:
The preparation of the dichloromethane solution of auspicious lattice amine (III)
3.92kg auspicious lattice amine glutaminate and 16L methylene dichloride, stirring and dissolving drips the alkali lye that 1.28kg sodium hydroxide and 40L water prepare; Finish stirring at room 1～2h.Layering, water layer use methylene dichloride 8L * 30～35 ℃ of decompressions of 2 filtratings to slough half solvent approximately, directly get into next step again.(TLC condition-chloroform: methyl alcohol=10: 1).
The preparation of auspicious lattice ester (V)
Auspicious lattice acid (IV) 2kg, anhydrous methylene chloride 15L, stirring and dissolving is cooled to 2～6 ℃; Add DMF 20g, slow dripping thionyl chloride 1.8kg, about 0.5～1h drips, and drips to finish; Be warming up to backflow, reaction 1h, the TLC monitoring (chloroform: methyl alcohol=10: 1), after reacting completely; Dried solvent is taken off in decompression, adds dry methylene chloride 8L, and dissolving seals subsequent use fully.
Auspicious lattice amine aqueous solution ice-water bath of last step is cooled to 2～6 ℃, adds sodium hydrogencarbonate 5.04kg, adds to stir 0.5h; Slowly drip the dichloromethane solution that contains auspicious lattice isoxazolecarboxylic acid, 1～2h drips off, and drips 2～6 ℃ of reactions of Bi Baowen; The TLC monitoring, (chloroform: methyl alcohol=10: 1), reaction is finished to keep thermotonus to spend the night; Continue to stir, slowly add water 200ml, have gas to produce; Stir, layering, water layer is used methylene dichloride 10L l * 2 extracted twice again.Merge organic layer, dried solvent is taken off in 35～38 ℃ of decompressions, gets white-yellowish solid, adds methyl alcohol 20L, and stirring and dissolving is complete, slowly drips water 10L, has solid to separate out.10～15 ℃ are stirred 3～4h, filter, and 2L left and right sides methanol (4/1) drip washing is drained.Add n-hexane/ethyl acetate (8/1) 12L making beating 0.5h again, drain, the drip washing of about 3L mixed solvent progressively is warming up to 50～55 ℃ of drying under reduced pressure, De Ruige ester off-white color solid 2.4～2.5kg.
The preparation of repaglinide bullion
With auspicious lattice ester 2.4kg, ethanol 24L, stirring and dissolving; Drip 7.6L 1N sodium hydroxide solution, drip and finish, be warming up to 55～60 ℃, reaction 2～4h, TLC monitors (TLC condition-chloroform: methyl alcohol=10: 1).Reaction is finished, and is cooled to 35～40 ℃, adds 1N hydrochloric acid, transfers pH about 4.3.Stirring at room 3～4h lowers the temperature 0～5 ℃ and stirs 1h.Filter, filter cake is with the aqueous hydrochloric acid 6L washing of pH 4.0～4.5.Progressively be warming up to 65～70 ℃ of vacuum-dryings, get repaglinide bullion 1.8～1.9kg.
Making with extra care of repaglinide
With repaglinide bullion 1.8kg, add ethanol 21.6L, stirring and dissolving is complete; Through the smart filter of strainer, filtrating is heated to 60～65 ℃, adds 15.48L pH 4.0～4.5 temperature and be 65 ℃ water (the smart filter of strainer), adds the water process and keeps temperature in the kettle to be not less than 60 ℃ not having solid and separate out.Drip the back and reduce to room temperature, stirring and crystallizing 3h naturally.Filter, filter cake is with purified water (smart filterable) washing of pH 4.0～4.5.Progressively be warming up to 65～70 ℃ of vacuum-dryings, get repaglinide highly finished product 1.5～1.6kg.
After having read above-mentioned teachings of the present invention, those skilled in the art can make various changes or modification to the present invention, and these equivalent form of values fall within the application's appended claims institute limited range equally.
Claims (10)
1. the preparation of a repaglinide and process for purification, it is characterized in that: the preparation method may further comprise the steps:
(1) with the preparation of auspicious lattice amine glutaminate (II) starting substance, is dissolved in the reaction solvent methylene dichloride dropping sodium aqueous solution under the whipped state.Standing demix, extraction, organic layer adds anhydrous sodium sulfate drying, filters, and filtrating is concentrated into original volume 1/2 De Ruige amine dichloromethane solution;
(2) auspicious lattice acid (IV) are dissolved in the methylene dichloride, stir, slow dripping thionyl chloride behind the adding DMF; After reacting completely, concentrating under reduced pressure takes off dried solvent, adds the dissolving of exsiccant methylene dichloride, and the dichloromethane solution of De Ruige isoxazolecarboxylic acid seals subsequent use;
(3) auspicious lattice amine dichloromethane solution ice bath is cooled to 2～6 ℃, adds sodium hydrogencarbonate and stir 0.5h, slowly drip the dichloromethane solution of auspicious lattice isoxazolecarboxylic acid, reaction finishes and slowly adds water, has gas to produce.Water layer is used dichloromethane extraction, merges organic layer, concentrates to take off dried white-yellowish solid.Add methyl alcohol stirring dissolving fully, drip water, have solid to separate out, filter, with the drip washing of methanol mixing solutions, drain, with n-hexane/ethyl acetate mixing solutions making beating 0.5h, filtration is drained again, drying under reduced pressure, and getting the off-white color solid is auspicious lattice ester (V);
(4) (V) is added in the ethanol, drips the 1N sodium hydroxide solution.Reaction finishes the back with about 1N hydrochloric acid adjust pH to 4.3, filters, and filter cake washs with aqueous hydrochloric acid.65～70 ℃ of vacuum-dryings get repaglinide bullion (I);
This preparation process is represented as follows with chemical equation:
2. the preparation of a repaglinide and process for purification, it is characterized in that: process for purification comprises the steps:
(I) added in the organic solvent, and stirring and dissolving filters out insoluble impurity; Be heated to 60～65 ℃, adding pH4.0～4.5, temperature are 65 ℃ water, add the back and reduce to room temperature naturally; Stirring and crystallizing 2～4h; Filter, filter cake is with the water washing of pH4.0～4.5, and 65～70 ℃ of vacuum-dryings get the repaglinide highly finished product.
3. the preparation method of a kind of repaglinide as claimed in claim 1, it is characterized in that: in step (1), starting raw material is an auspicious lattice amine glutaminate (II), and reaction solvent is a methylene dichloride, and the concentration of aqueous sodium hydroxide solution is 0.8mol/L.
4. the preparation method of a kind of repaglinide as claimed in claim 1, it is characterized in that: in step (2), solubility promoter is an anhydrous methylene chloride, the amount of DMF is 1% of auspicious lattice acid.
5. the preparation method of a kind of repaglinide as claimed in claim 1, it is characterized in that: in step (3), the ratio of methanol/water solution is a methyl alcohol: water=4: 1, normal hexane in the n-hexane/ethyl acetate mixed solvent: ETHYLE ACETATE=8: 1.
6. the preparation method of a kind of repaglinide as claimed in claim 1 is characterized in that: in step (4), and auspicious lattice ester (quality): ethanol (volume)=1: 10.
7. the process for purification of a kind of repaglinide according to claim 2, it is characterized in that: organic solvent is an ethanol, the pH value of water is 4.0～4.5.
8. the process for purification of a kind of repaglinide according to claim 2 is characterized in that: the consumption of organic solvent volume is advisable with 8～10 times for 5～12 times of wet bullion; The pH value is that the consumption of 4.0～4.5 water is 5～20 times of consumption of organic solvent, is advisable with 8～15 times.
9. the process for purification of a kind of repaglinide according to claim 2, it is characterized in that: the time of room temperature crystallization is 2～6 hours, is advisable with 3～4 hours.
10. the process for purification of a kind of repaglinide according to claim 2, it is characterized in that: drying temperature is controlled at 65～70 ℃.
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| CN103772322A (en) * | 2012-10-25 | 2014-05-07 | 天津汉瑞药业有限公司 | Repaglinide compound |
| CN104557778A (en) * | 2015-01-09 | 2015-04-29 | 蔡伦 | Preparation method and application of repaglinide |
| CN105198838A (en) * | 2015-10-21 | 2015-12-30 | 河南普瑞制药有限公司 | Preparation method of repaglinide |
| CN108129419A (en) * | 2017-12-22 | 2018-06-08 | 陈益德 | A kind of Synthetic method of repaglinide |
| CN111635379A (en) * | 2020-07-21 | 2020-09-08 | 江西博雅欣和制药有限公司 | Synthesis process of blood sugar reducing medicine repaglinide |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103772322A (en) * | 2012-10-25 | 2014-05-07 | 天津汉瑞药业有限公司 | Repaglinide compound |
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| CN104557778A (en) * | 2015-01-09 | 2015-04-29 | 蔡伦 | Preparation method and application of repaglinide |
| CN105198838A (en) * | 2015-10-21 | 2015-12-30 | 河南普瑞制药有限公司 | Preparation method of repaglinide |
| CN108129419A (en) * | 2017-12-22 | 2018-06-08 | 陈益德 | A kind of Synthetic method of repaglinide |
| CN111635379A (en) * | 2020-07-21 | 2020-09-08 | 江西博雅欣和制药有限公司 | Synthesis process of blood sugar reducing medicine repaglinide |
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Application publication date: 20121017 |