CN102633750A - One-pot method for synthesizing repaglinide for treating diabetes - Google Patents
One-pot method for synthesizing repaglinide for treating diabetes Download PDFInfo
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- CN102633750A CN102633750A CN2012100811229A CN201210081122A CN102633750A CN 102633750 A CN102633750 A CN 102633750A CN 2012100811229 A CN2012100811229 A CN 2012100811229A CN 201210081122 A CN201210081122 A CN 201210081122A CN 102633750 A CN102633750 A CN 102633750A
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- CARYLRSDNWJCJV-HNNXBMFYSA-N CC(C)C[C@@H](c(cccc1)c1N1CCCCC1)N Chemical compound CC(C)C[C@@H](c(cccc1)c1N1CCCCC1)N CARYLRSDNWJCJV-HNNXBMFYSA-N 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N CC(N[C@@H](CCC(O)=O)C(O)=O)=O Chemical compound CC(N[C@@H](CCC(O)=O)C(O)=O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- VNNYEXSABSADDW-UHFFFAOYSA-N NCc(cccc1)c1N1CCCCC1 Chemical compound NCc(cccc1)c1N1CCCCC1 VNNYEXSABSADDW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a one-pot method for synthesizing repaglinide. In the method, commercial (S)-3-methyl-1[2-(1-piperidyl) phenyl] butyl amine L-N-acetylglutamate and 4-ethoxycarbonyl-3-ethoxy phenylacetic acid are used as raw materials to prepare repaglinide, thereby greatly shortening the reaction route and facilitating the production stability and continuity; and in esterification reaction, an acylating agent/acid-binding agent replaces triphenyl phosphorus/carbon tetrachloride to perform reaction, the intermediate does not needed to be crystallized, direct hydrolysis is performed according to the one-pot method, the intermediate meeting the requirements is obtained by a crude product recrystallization method, the column chromatographic separation is not needed, waste liquid is easy to treat, the yield is greatly improved, and the industrial production is facilitated.
Description
Technical field
The present invention relates to the synthetic method of controlling repaglinide of one kettle way, belong to the repaglinide synthesis technical field of chemical pharmacy industry.
The structure of repaglinide is following:
Background technology
Repaglinide (Repaglinide) is a kind of novel non-sulfonylurea Drugs Promoting Insulin Secretion; The clinical treatment that is mainly used in non-insulin-depending type (II type) diabetic subject that treatment dietary control and motion exercise can not effectively control, effective in cure definite, the characteristics such as dosage is little, spinoff is low of this medical instrument.Present preparation for repaglinide; Usually earlier with 1-[2-(piperidino) phenyl]-3-espeleton or adjacent piperidyl benzene nitrile prepared in reaction 3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine; Split with N-acetyl-L-L-glutamic acid and to obtain (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine; Subsequently with 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid dock reaction, thereby hydrolysis obtains the repaglinide finished product, concrete reaction scheme is following: with 1-[2-(piperidino) phenyl]-3-espeleton is feedstock production 3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine
(2) be feedstock production 3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine with adjacent piperidyl benzene nitrile
(3) preparation of repaglinide
The route that document adopts is longer, causes instability and production cycle in the production long easily, is unfavorable for suitability for industrialized production; Use triphen phosphorus/tetracol phenixin to react during esterification; The product that obtains need separate the midbody that can obtain satisfactory purity through chromatographic column; Do not meet industrial production requirement; The aftertreatment that contains phosphorus waste liquid that this step reaction simultaneously produces is also relatively more difficult, and the acetonitrile price comparison is expensive, and these all are unfavorable for the production of product and the reduction of cost.Therefore, need carry out suitable optimization, enable to adapt to preferably industrial production requirement the synthetic route of repaglinide.
Summary of the invention
To the existing defective of above-mentioned existing repaglinide preparation method, the present invention seeks to seek one and can improve yield and quality product, reduce production costs, easy and simple to handle, the compound method of suitable industrial repaglinide.To achieve these goals, we have carried out further exploration and optimization to the synthesis technique of repaglinide.At first; Directly using commercially available (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine L-N-acetylglutamate and 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid instead is that raw material prepares; Thereby shortened reaction scheme greatly, stability that helps producing and continuity; For esterification; Replace triphenyl phosphorus/tetracol phenixin to react with acylating agent/acid binding agent; And need not carry out crystallization to midbody (S)-4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester, can directly be hydrolyzed through one kettle way, the method for recrystallization that can be through bullion obtains satisfactory midbody; Avoided the post layer to separate; Waste liquid also more is prone to handle simultaneously, and yield also improves greatly simultaneously, more helps carrying out smoothly of suitability for industrialized production.
The synthetic method of controlling repaglinide of one kettle way may further comprise the steps:
The preparation of A, (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine: regulate pH under with alkali normal temperature at (S)-3-methyl isophthalic acid in the presence of solvent and the water-(2-piperidyl phenyl) butylamine L-N-acetylglutamate; After steps such as SX, washing, dry, the concentrated organic solvent of siccative; After adding the required dissolution with solvents of step reaction down, directly be used for step reaction down.
The preparation of B, (S)-4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester: adding 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid, reaction solvent, acylating agent, acid binding agent, stirring are dissolved clear in reaction kettle; After low temperature carried out acidylate, dropping was gone up to go on foot and is made (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine solution again.TLC monitoring reaction terminal point.Add the water extraction,, steam the oily matter that obtains behind the solvent, directly descend the step reaction through aftertreatment.
The preparation of C, repaglinide bullion: in oily matter, add solvent, alkaline hydrolysis, TLC monitoring reaction terminal point.Obtain the slightly wet article of repaglinide through aftertreatment.
The preparation of D, repaglinide elaboration: add solvent in the slightly wet article of repaglinide, dissolve clear back adding activated carbon decolorizing, filtration, crystallization, suction filtration, drying obtain the repaglinide elaboration.
The reaction formula that the present invention relates to is following:
Beneficial effect of the present invention:
1, directly to adopt commercially available (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine L-N-acetylglutamate and 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid be that raw material prepares in the present invention; Thereby shortened reaction scheme greatly, stability that helps producing and continuity
2, the present invention adopts acylating agent/acid binding agent to replace triphenyl phosphorus/tetracol phenixin to react, do not produce processing relatively difficulty contain phosphorus waste liquid, further reduced pollution.
3, the present invention adopts one kettle way directly to be hydrolyzed, and the method for recrystallization that can be through bullion obtains satisfactory midbody.Simplified operation.
All indexs of repaglinide that the inventive method obtains can both reach 2010 editions two ministerial standards of the Pharmacopoeia of the People's Republic of China.
With the specific embodiment mode embodiment preferred is described below, with explanation the inventive method.Yet these embodiment do not constitute the restriction of the scope of the invention.To those skilled in the art, various combinations and the replacement under design of the present invention, these embodiment carried out should be included in protection scope of the present invention.
Embodiment
Embodiment one:
A: (S)-preparation of 3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine
(S)-and 3-methyl isophthalic acid-(2-piperidyl phenyl) butylamine L-N-acetylglutamate 16g, methylene dichloride 75ml, tap water 20ml stirs 0～5 ℃ of cooling; Drip the 1N sodium hydroxide solution, regulate pH=9～10, solid dissolves entirely.0～5 ℃ was stirred 30 minutes, and left standstill and tell organic phase.Water adds the 20ml methylene dichloride and extracts once.Water discards, and merges organic phase water 100ml and washes once, and water discards, organic addition SODIUM SULPHATE ANHYDROUS 99PCT 5～10g, stirring at normal temperature dehydration 1 hour, suction filtration.Oil reservoir removes methylene dichloride under reduced pressure to doing; After adding toluene 30ml dissolving, directly be used for step reaction down.
Embodiment two:
A: (S)-preparation of 3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine
Extraction solvent is replaced by ETHYLE ACETATE, toluene, hexanaphthene etc., and all the other are identical.
Embodiment three:
B: (S)-preparation of 4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester
4-ethoxycarbonyl-3-ethoxy-phenylacetic acid 9.25g, toluene 50ml, triethylamine 4.4g stirs and dissolves clearly.Be cooled to-10～-20 ℃ of solution that add 5g trimethyl-acetyl chloride and 10ml toluene, insulation reaction 1 hour; (S)-3-methyl isophthalic acid-(2-piperidyl phenyl) butylamine and toluene solution that step obtains on adding.Stirring reaction 10 hours.TLC monitoring reaction terminal point.Reaction finishes and adds 60ml water, stirs, leaves standstill, and water discards.Organic phase adds the washing of 50ml salt once, and water layer discarded, organic phase concentrate toluene to doing, and obtain midbody oily matter.
Embodiment four:
B: (S)-preparation of 4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester
4-ethoxycarbonyl-3-ethoxy-phenylacetic acid 10g, ETHYLE ACETATE 50ml, triethylamine 4.4g stirs and dissolves clearly.Be cooled to-10～-20 ℃ of solution that add 5g trimethyl-acetyl chloride and ETHYLE ACETATE 10ml, insulation reaction 1 hour; (S)-3-methyl isophthalic acid-(2-piperidyl phenyl) butylamine and ethyl acetate solution that step obtains on adding.Stirring reaction 10 hours.TLC monitoring reaction terminal point.Reaction finishes and adds 60ml water, stirs, leaves standstill, and water discards.Organic phase adds the washing of 50ml salt once, and water layer discarded, organic phase concentrate ETHYLE ACETATE to doing, and obtain midbody oily matter.
Embodiment five:
B: (S)-preparation of 4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester
4-ethoxycarbonyl-3-ethoxy-phenylacetic acid 10g, toluene 50ml, triethylamine 4.4g stirs and dissolves clearly.Be cooled to-10～-20 ℃ of solution that add 5.8g Benzoyl chloride 99min. and 10ml toluene, insulation reaction 1 hour; (S)-3-methyl isophthalic acid-(2-piperidyl phenyl) butylamine and toluene solution that step obtains on adding.Stirring reaction 10 hours.TLC monitoring reaction terminal point.Reaction finishes and adds 60ml water, stirs, leaves standstill, and water discards.Organic phase adds the washing of 50ml salt once, and water layer discarded, organic phase concentrate toluene to doing, and obtain midbody oily matter.
Embodiment six:
B: (S)-preparation of 4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester
4-ethoxycarbonyl-3-ethoxy-phenylacetic acid 10g, toluene 50ml, tri-n-butylamine 8g stirs and dissolves clearly.Be cooled to-10～-20 ℃ of solution that add 5g trimethyl-acetyl chloride and 10ml toluene, insulation reaction 1 hour; (S)-3-methyl isophthalic acid-(2-piperidyl phenyl) butylamine and toluene solution that step obtains on adding.Stirring reaction 10 hours.TLC monitoring reaction terminal point.Reaction finishes and adds 60ml water, stirs, leaves standstill, and water discards.Organic phase adds the washing of 50ml salt once, and water layer discarded, organic phase concentrate toluene to doing, and obtain midbody oily matter.
Embodiment seven:
C: the preparation of repaglinide bullion
Add 95% ethanol 150ml in the oily matter.Be warming up to 70 ℃, add 1N aqueous sodium hydroxide solution 50g, stir hydrolysis 1-2 hour.TLC monitoring reaction terminal point.Confirming reacts completely cools to 25 ℃, after stablizing with dripping hydrochloric acid adjusting pH=5.0, and restir 1-2 hour, the 0-5 ℃ of freezing stirring 2 hours of lowering the temperature.Suction filtration, 60% cold ethanolic soln rinsing.Get the repaglinide bullion.
Embodiment eight:
C: the preparation of repaglinide bullion
Add 95% methyl alcohol 150ml in the oily matter.Be warming up to 70 ℃, add 1N aqueous sodium hydroxide solution 50g, stir hydrolysis 1-2 hour.TLC monitoring reaction terminal point.Confirming reacts completely cools to 25 ℃, after stablizing with dripping hydrochloric acid adjusting pH=5.0, and restir 1-2 hour, the 0-5 ℃ of freezing stirring 2 hours of lowering the temperature.Suction filtration, 60% cold methanol solution rinsing.Get the repaglinide bullion.
Embodiment nine:
C: the preparation of repaglinide bullion
Add 95% ethanol 150ml in the oily matter.Be warming up to 70 ℃, add 1N aqueous sodium hydroxide solution 50g, stir hydrolysis 1-2 hour.TLC monitoring reaction terminal point.Confirming reacts completely cools to 25 ℃, after stablizing with dropping dilute sulphuric acid adjusting pH=5.0, and restir 1-2 hour, the 0-5 ℃ of freezing stirring 2 hours of lowering the temperature.Suction filtration, 60% cold ethanolic soln rinsing.Get the repaglinide bullion.
Embodiment ten:
D: the preparation of repaglinide elaboration
Add 60% ethanol 160ml in the bullion, it is clear to add thermosol.Add gac 2g, 50 ℃ decoloured 1-2 hour.Suction filtration, filtrating is stirred at a slow speed, is cooled to 20～25 ℃ of crystallizatioies naturally 1 hour, and is freezing again to 0-5 ℃, stirred 2 hours.Suction filtration, an amount of 60% ethanol rinsing.50 ℃ of vacuum-dryings get finished product 13-14g to constant weight.Total molar yield is: 78.17%-84.19%
Embodiment 11:
D: the preparation of repaglinide elaboration
Add 60% methyl alcohol alcohol 160ml in the bullion, it is clear to add thermosol.Add gac 2g, 50 ℃ decoloured 1-2 hour.Suction filtration, filtrating is stirred at a slow speed, is cooled to 20～25 ℃ of crystallizatioies naturally 1 hour, and is freezing again to 0-5 ℃, stirred 2 hours.Suction filtration, an amount of 60% ethanol rinsing.50 ℃ of vacuum-dryings get finished product 13-14g to constant weight.Total molar yield is: 78.17%-84.19%
Being merely embodiments of the invention in sum, is not to be used for limiting practical range of the present invention.Be that all equivalences of doing according to the content of claim of the present invention change and modification, all should be technological category of the present invention.
Claims (15)
1. one kettle way synthesizes the method for repaglinide, may further comprise the steps:
The preparation of A, (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine: regulate pH under with alkali normal temperature at (S)-3-methyl isophthalic acid in the presence of solvent and the water-(2-piperidyl phenyl) butylamine L-N-acetylglutamate; After steps such as SX, washing, dry, the concentrated organic solvent of siccative; After adding the required dissolution with solvents of step reaction down, directly be used for step reaction down.
The preparation of B, (S)-4-(2-((4-methoxy-benzyl) (3-methyl isophthalic acid-(2-(piperidino) phenyl) butyl) amino)-2-oxoethyl)-2-ethoxy benzonitrile acetoacetic ester: adding 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid, reaction solvent, acylating agent, acid binding agent, stirring are dissolved clear in reaction kettle; After low temperature carried out acidylate, dropping was gone up to go on foot and is made (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine solution again.TLC monitoring reaction terminal point.Add the water extraction,, steam the oily matter that obtains behind the solvent, directly descend the step reaction through aftertreatment.
The preparation of C, repaglinide bullion: in oily matter, add solvent, alkaline hydrolysis, TLC monitoring reaction terminal point.After acid adjustment, handle the slightly wet article of repaglinide that obtain.
The preparation of D, repaglinide elaboration: add solvent in the slightly wet article of repaglinide, dissolve clear back adding activated carbon decolorizing, filtration, crystallization, suction filtration, drying obtain the repaglinide elaboration.
2. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1, it is characterized in that: described (S)-3-methyl isophthalic acid-(2-piperidyl phenyl) butylamine L-N-acetylglutamate: acylating agent: the mol ratio of 4-ethoxycarbonyl-3-ethoxy-phenylacetic acid is 1: 1～1.5: 1～1.2.
3. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1, it is characterized in that: the said solvent of described steps A is selected from any one or a few of methylene dichloride, chloroform, normal hexane, hexanaphthene, ETHYLE ACETATE, butylacetate, ether, sherwood oil, isopropyl ether etc.
4. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: the described alkali of described steps A is selected from any one of sodium hydroxide, Pottasium Hydroxide, calcium hydroxide, triethylamine, tri-n-butylamine.
5. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1, it is characterized in that: the said normal temperature of described steps A is 0～40 ℃.
6. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: it is neutral dry that the said siccative of described steps A is selected from Calcium Chloride Powder Anhydrous, anhydrous magnesium sulfate, SODIUM SULPHATE ANHYDROUS 99PCT, molecular sieve etc.
7. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: any one of the described methylene chloride of described step B, chloroform, ETHYLE ACETATE, butylacetate, benzene,toluene,xylene.
8. as claimed in claim 1 " the synthetic method of controlling repaglinide of one kettle way is characterized in that: the described acid binding agent of described step B be quadrol, triethylamine, pyridine, Pottasium Hydroxide, sodium hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium hydrogencarbonate etc. any one.
9. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1, it is characterized in that: the described low temperature of step B is-20 ℃～40 ℃.
10. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: the chloride reagent described in the described step B be succinic chloride, trimethyl-acetyl chloride, sulfur oxychloride, oxalyl chloride, phosphorus pentachloride, Benzoyl chloride 99min. etc. any one.
11. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: among the described step C solvent be methyl alcohol, ethanol, Virahol, acetone acetonitrile etc. any one.
12. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: described step C hydrolysising alkali be Pottasium Hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, sodium methylate, sodium ethylate, potassium tert.-butoxide etc. any one or with the mixed solvent of water.
13. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1, it is characterized in that: described step C hydrolysis temperature is 50 ℃～70 ℃.
14. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: the used acid of described step C acid adjustment be hydrochloric acid, sulfuric acid, glacial acetic acid, trifluoroacetic acid etc. any one.
15. the synthetic method of controlling repaglinide of one kettle way as claimed in claim 1 is characterized in that: among the described step D solvent be methyl alcohol, ethanol, Virahol, acetone acetonitrile etc. any one or with the mixed solvent of water.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664828A (en) * | 2012-09-12 | 2014-03-26 | 高瑞耀业(北京)科技有限公司 | Method for preparing high-purity repaglinide |
| CN104557778A (en) * | 2015-01-09 | 2015-04-29 | 蔡伦 | Preparation method and application of repaglinide |
| CN108047163A (en) * | 2018-01-29 | 2018-05-18 | 广州小桔生物科技有限公司 | A kind of preparation method of Repaglinide |
| CN114014825A (en) * | 2021-11-10 | 2022-02-08 | 河南师范大学 | Efficient synthesis method of histamine H3 receptor antagonist teloprolofen |
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| CN1571769A (en) * | 2001-09-25 | 2005-01-26 | 兰贝克赛实验室有限公司 | Process for the preparation of repaglinide |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664828A (en) * | 2012-09-12 | 2014-03-26 | 高瑞耀业(北京)科技有限公司 | Method for preparing high-purity repaglinide |
| CN104557778A (en) * | 2015-01-09 | 2015-04-29 | 蔡伦 | Preparation method and application of repaglinide |
| CN108047163A (en) * | 2018-01-29 | 2018-05-18 | 广州小桔生物科技有限公司 | A kind of preparation method of Repaglinide |
| CN114014825A (en) * | 2021-11-10 | 2022-02-08 | 河南师范大学 | Efficient synthesis method of histamine H3 receptor antagonist teloprolofen |
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Application publication date: 20120815 |