CN105198838A - Preparation method of repaglinide - Google Patents
Preparation method of repaglinide Download PDFInfo
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- CN105198838A CN105198838A CN201510692793.2A CN201510692793A CN105198838A CN 105198838 A CN105198838 A CN 105198838A CN 201510692793 A CN201510692793 A CN 201510692793A CN 105198838 A CN105198838 A CN 105198838A
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- repaglinide
- organic solvent
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- butyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
A preparation method of repaglinide comprises the following steps: a. adding 3-ethoxy-4-ethoxycarbonyl benzeneacetic acid, N-hydroxyphthalimide and a dehydrating agent into an organic solvent, and reacting for 1.5 to 2 hours under a reflux temperature of 55 to 80 DEG C; performing filtration after the reaction is finished, and adding (S)-3-methyl-1-(2-piperidin-1-ylphenyl)butylamine into filtrate, and reacting for 2 to 3 hours under room temperature, then removing the organic solvent by reducing pressure, and performing recrystallization on remainder by using a mixed solvent of methylbenzene and normal hexane to obtain ethoxy4-(2-(((1S)-3-methyl-1-(2-(1-piperidyl)phenyl)butyl)amino group)-2-bioxyethyl)ethyl benzoate; b. carrying out a hydrolysis reaction for 3 to 4 hours by heating the ethoxy4-(2-(((1S)-3-methyl-1-(2-(1-piperidyl)phenyl)butyl)amino group)-2-bioxyethyl)ethyl benzoate in step a and an alkaline solution of a monovalent metallic hydroxide in the organic solvent, boiling off the organic solvent, cooling to the room temperature, and adding hydrochloric acid of 2.0 moL/L into reaction liquid, and regulating the pH of the reaction liquid to 4-6, and stirring to crystalize, and filtering and drying to obtain the repaglinide.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of preparation method of repaglinide.
Background technology
Repaglinide chemistry is called (
s)-2-oxyethyl group-4-[2-[[methyl-l-[2-(l-piperidyl) phenyl] butyl] is amino] 2-oxoethyl] phenylformic acid, the development of German Boehringeringelheim company the earliest, listing is developed, trade(brand)name NovoNorm by Novonordisk company.Within 1998, first in U.S.'s listing, 2000 in Discussion on Chinese Listed.
Repaglinide is as non-sulfourea Drugs Promoting Insulin Secretion; the glucose level of reduction patients with NIDDM that can be safe rapidly; good provide protection is had to beta Cell of islet, can not inducing beta cell apoptosis, there is positive meaning to the development delaying diabetes and the complication that reduces diabetes.Because repaglinide medicining mode is flexible, untoward reaction is slight, and tolerance is better, as a line medication of patients with NIDDM, has good therapeutic action and wide market outlook.
Domestic and foreign literature is a lot of about the synthesis report of repaglinide, but main route obtains compounds Ⅳ with chemical compounds I and compound III through condensation reaction, and compounds Ⅳ is hydrolyzed in the basic conditions again, acidifying obtains repaglinide.Operational path is as follows:
uS5312924 reports this compound and synthetic method thereof at first, chemical compounds I and compound III at carbonyl dimidazoles, N, N-dicyclohexylcarbodiimide (DCC) or triphenylphosphine, triethylamine, there is lower condensation and generate compounds Ⅳ in tetracol phenixin, compounds Ⅳ is hydrolyzed repaglinide again; Use DCC in this synthetic route, can produce by product 1,3-dicyclohexylurea (DCU) (DCU), aftertreatment needs repeatedly crystallization, productive rate reduces, and carbonyl dimidazoles is more expensive comparatively speaking simultaneously; And when utilizing triphenylphosphine, triethylamine and tetracol phenixin, solvent toxicity is comparatively large, product purity only has just can reach requirement by column chromatography.
European patent EP 1432682B1, US Patent No. 20050107614, Chinese patent CN1865253A report the synthetic method of new repaglinide subsequently, chemical compounds I and acyl chloride compound as trimethyl-acetyl chloride, t-butylacetyl chloride, sulfur oxychloride etc. react after again with compound III condensation, hydrolysis obtains product repaglinide; Use trimethyl-acetyl chloride in these class methods, t-butylacetyl chloride price is higher, the reaction times is longer, and yield does not also significantly improve; What use in Chinese patent is that sulfur oxychloride class chloride reagent not easily transports preservation, has certain corrodibility and react the rear spent acid produced not easily to process in reaction to equipment, virtually adds production cost.
Drug effect based on repaglinide is worth and good market outlook, finds one efficiently, high, the environment amenable repaglinide new synthetic process of low toxicity, yield is imperative.
Summary of the invention
Object of the present invention is exactly for above-mentioned the deficiencies in the prior art, and provides a kind of novel preparation method of repaglinide, and the method reaction conditions is gentle, and easy and simple to handle, total recovery is high, is suitable for suitability for industrialized production.
The preparation were established of repaglinide of the present invention is as follows:
said method comprising the steps of:
A) be the 3-Ethoxy-4-ethoxycarbonylphenylacetic acid of 1:1:1 by mol ratio, HP and dewatering agent join in organic solvent, under the reflux temperature of 55-80 DEG C, react 1.5-2 hour; After reaction terminates, filter, add in filtrate and (S)-3-methyl isophthalic acid of 3-Ethoxy-4-ethoxycarbonylphenylacetic acid equimolar amount-[2-(piperidino) phenyl] butylamine, at room temperature react 2-3 hour, decompression removing organic solvent, the mixed solvent recrystallization of residuum toluene and normal hexane obtains oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate;
B) oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] the is amino]-2-oxoethyl] ethyl benzoate in a step is reacted 3-4 hour with the oxyhydroxide alkaline solution heating hydrolysis of the monovalent metal of 2.0moL/L in organic solvent, boil off organic solvent, be chilled to room temperature, the hydrochloric acid of 2.0moL/L is added in reaction solution, regulate reaction solution pH to 4-6, stirring and crystallizing, filtration drying obtains repaglinide.
Organic solvent in step a) of the present invention takes from any one of acetone, tetrahydrofuran (THF) or acetonitrile.
Dewatering agent in step a) of the present invention is DCC.
In toluene in step a) of the present invention and the mixed solvent of normal hexane, the volume ratio of toluene and normal hexane is 1:2-3.
Organic solvent in step b) of the present invention takes from any one of methyl alcohol, ethanol or Virahol.
Monovalent metal oxyhydroxide in step b) of the present invention is sodium hydroxide or potassium hydroxide.
Hydrolysising reacting temperature in step b) of the present invention is 50-80 DEG C.
The invention has the beneficial effects as follows: the efficient high and low poison of preparation method of repaglinide of the present invention, yield is high, environmental pollution is less, application prospect is better.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
embodiment 1:
The preparation method of a kind of repaglinide of the present invention comprises the following steps:
A) by 3-Ethoxy-4-ethoxycarbonylphenylacetic acid (15g, 59.4mmol), DCC(12.3g, 59.4mmol) and HP (9.6g, 59.4mmol) join in 100mL acetone, heating reflux reaction 2 hours; Then reaction solution is cooled to room temperature, filters; (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine (14.6g is added in filtrate, 59.4mmol), room temperature reaction 2.5 hours, underpressure distillation is except desolventizing, the mixed solvent 75mL(toluene 25mL of residuum toluene and normal hexane, normal hexane 50mL) recrystallization obtains oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] amino]-2-oxoethyl] ethyl benzoate 24.8g, yield 86.8%.
B) by oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate (10.0g, 20.8mmol) be dissolved in 50mL ethanol, add the sodium hydroxide solution 40mL of 2.0moL/L, be heated to 80 DEG C of reactions 3 hours, boil off ethanol, be chilled to room temperature, the hydrochloric acid of 2.0moL/L is added in reaction solution, regulate reaction solution pH to 4-6, stirring and crystallizing, filtration drying obtains repaglinide 8.7g, yield 92.4%.
embodiment 2:
The preparation method of a kind of repaglinide of the present invention comprises the following steps:
A) by 3-Ethoxy-4-ethoxycarbonylphenylacetic acid (15g, 59.4mmol), DCC(12.3g, 59.4mmol) and HP (9.6g, 59.4mmol) join in 100mL tetrahydrofuran (THF), heating reflux reaction 2 hours; Then reaction solution is cooled to room temperature, filters; (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine is added in filtrate, room temperature reaction 3 hours, underpressure distillation is except desolventizing, the mixed solvent 75mL recrystallization of residuum toluene and normal hexane obtains oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate 24.2g, yield 84.7%.
B) by oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate (10.0g, 20.8mmol) be dissolved in 50mL methyl alcohol, add the sodium hydroxide solution 40mL of 2.0moL/L, be heated to 80 DEG C of reactions 3 hours, boil off methyl alcohol, be chilled to room temperature, the hydrochloric acid of 2.0moL/L is added in reaction solution, regulate reaction solution pH to 4-6, stirring and crystallizing, filtration drying obtains repaglinide 8.5g, yield 90.3%.
embodiment 3:
The preparation method of a kind of repaglinide of the present invention comprises the following steps:
A) by 3-Ethoxy-4-ethoxycarbonylphenylacetic acid (15g, 59.4mmol), DCC(12.3g, 59.4mmol) and HP (9.6g, 59.4mmol) join in 100mL acetonitrile, heating reflux reaction 1.5 hours; Then reaction solution is cooled to room temperature, filters; (S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine is added in filtrate, room temperature reaction 2.5 hours, underpressure distillation is except desolventizing, the mixed solvent 75mL recrystallization of residuum toluene and normal hexane obtains oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate 25.5g, yield 89.2%.
B) by oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate (10.0g, 20.8mmol) be dissolved in 50mL Virahol, add the sodium hydroxide solution 40mL of 2.0moL/L, be heated to 80 DEG C of reactions 3 hours, boil off Virahol, be chilled to room temperature, the hydrochloric acid of 2.0moL/L is added in reaction solution, regulate reaction solution pH to 4-6, stirring and crystallizing, filtration drying obtains repaglinide 8.3g, yield 88.1%.
Claims (7)
1. a preparation method for repaglinide, is characterized in that: the method comprises the following steps:
A) be the 3-Ethoxy-4-ethoxycarbonylphenylacetic acid of 1:1:1 by mol ratio, HP and dewatering agent join in organic solvent, under the reflux temperature of 55-80 DEG C, react 1.5-2 hour; After reaction terminates, filter, add in filtrate and (S)-3-methyl isophthalic acid of 3-Ethoxy-4-ethoxycarbonylphenylacetic acid equimolar amount-[2-(piperidino) phenyl] butylamine, at room temperature react 2-3 hour, decompression removing organic solvent, the mixed solvent recrystallization of residuum toluene and normal hexane obtains oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] is amino]-2-oxoethyl] ethyl benzoate;
B) oxyethyl group 4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl] the is amino]-2-oxoethyl] ethyl benzoate in a step is reacted 3-4 hour with the oxyhydroxide alkaline solution heating hydrolysis of the monovalent metal of 2.0moL/L in organic solvent, boil off organic solvent, be chilled to room temperature, the hydrochloric acid of 2.0moL/L is added in reaction solution, regulate reaction solution pH to 4-6, stirring and crystallizing, filtration drying obtains repaglinide.
2. the preparation method of repaglinide according to claim 1, is characterized in that: the organic solvent in step a) takes from any one of acetone, tetrahydrofuran (THF) or acetonitrile.
3. the preparation method of repaglinide according to claim 1, is characterized in that: the dewatering agent in step a) is DCC.
4. the preparation method of repaglinide according to claim 1, is characterized in that: in the toluene in step a) and the mixed solvent of normal hexane, the volume ratio of toluene and normal hexane is 1:2-3.
5. the preparation method of repaglinide according to claim 1, is characterized in that: the organic solvent in step b) takes from any one of methyl alcohol, ethanol or Virahol.
6. the preparation method of repaglinide according to claim 1, is characterized in that: the monovalent metal oxyhydroxide in step b) is sodium hydroxide or potassium hydroxide.
7. the preparation method of repaglinide according to claim 1, is characterized in that: the hydrolysising reacting temperature in step b) is 50-80 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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: 20151230 |