CN100445275C

CN100445275C - Repaglinide synthesis process

Info

Publication number: CN100445275C
Application number: CNB2006100520675A
Authority: CN
Inventors: 杨健; 许惠钢
Original assignee: Zhejiang University ZJU
Current assignee: Zhejiang University ZJU
Priority date: 2006-06-21
Filing date: 2006-06-21
Publication date: 2008-12-24
Anticipated expiration: 2026-06-21
Also published as: CN1865253A

Abstract

The present invention discloses a repaglinide synthesis technology. Acyl chloride is prepared from 4-carboxymethyl-3-ethoxybenzoate; then, the 4-carboxymethyl-3-ethoxybenzoate and s-(+)-1-(2-piperidinyl phenyl)-3-methyl n-butylamine (3) are condensed under an alkaline condition to prepare S(+)-2-ethoxy-4-[N-{1-(2-piperidinyl phenyl)-3-methyl-1-butyl}amine carboxymethyl]benzoate; subsequently, the repaglinide is prepared by hydrolyzation. Compared with other technologies, the present invention has the advantages of high efficiency, low toxicity, easy acquirement and low price of raw materials, simple operation and higher yield that the total yield of two-step reaction reaches 80.9%. The synthesis process is a repaglinide synthesis technical route with industrial prospects.

Description

A kind of technology of synthetic repaglinide

Technical field

The present invention relates to medicine organic synthesis field, particularly relate to a kind of technology of synthetic repaglinide

Background technology

Repaglinide (repaglinide) chemistry S (+) by name-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] phenylformic acid, a kind of new oral ofhypoglycemic medicine that belongs to methyl benzene methanamine phenylformic acid (CBMA) family, can promote insulin secretion, it is different with the binding site and the sulfonylurea drugs of β cell, have and absorb soon, rapid-action, the characteristics that action time is short, 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, tool is security preferably, and with biguanides synergy is arranged.Both can be used as a line antidiabetic medicine and used separately, also can increase curative effect, a kind of new means will be provided for the treatment of type ii diabetes with other antidiabetic drug combined utilization.

The route of the synthetic main literature report of repaglinide mainly is to obtain compound 4 with compound 2 and compound 3 through condensation, and hydrolysis obtains product 1 again, and its technical process is as follows:

US5,312,924 have reported the synthetic of this compound at first, compound 2 and compound 3 be at carbonyl dimidazoles, N, the condensation under N '-dicyclohexylcarbodiimide or triphenyl phosphorus, triethylamine, tetracol phenixin exist obtains compound 4.In the technology that this patent is mentioned, utilize N, N '-dicyclohexylcarbodiimide rice is synthetic, and product needed just can be removed byproduct N by recrystallization repeatedly, and N '-dicyclohexyl urine has improved production cost; Utilize the synthetic product yield that obtains of carbonyl dimidazoles catalysis low, have only 50～55%, and carbonyl dimidazoles price is more expensive comparatively speaking; And utilize triphenyl phosphorus, triethylamine, tetracol phenixin to synthesize, though this method yield increases, the purity of product has only by column chromatography just can reach requirement.

Subsequently, a kind of novel process of the synthetic repaglinide of US2005/0107614 report, it is that compound 2 and compound 3 condensations obtain in the presence of tertiary butyl Acetyl Chloride 98Min. and alkali, though this technological operation is simple, product is easy to purify, but this technological reaction time is longer, and yield is not high yet, have only about 73%, price is higher comparatively speaking for used tertiary butyl Acetyl Chloride 98Min. simultaneously.

In these two pieces of patents, US5,312, though the 924 technology yields of mentioning are comparatively speaking higher, product is difficult to purify, and realize relatively difficulty of suitability for industrialized production repaglinide.And the technology that patent US2005/0107614 provides a kind of product to be easy to purify, but the reaction times is long, and yield is not very high yet, and its application prospect is restricted.

Therefore, one of exploitation can solve above-mentioned insufficient operational path and has great importance and be worth.The invention provides a kind of novel process of synthetic repaglinide, it has efficiently, low toxicity, and simple to operate, yield is higher, and the total recovery of two-step reaction has reached 80.9%, is a synthetic repaglinide operational path that industrial prospect is arranged very much.

Summary of the invention

The method that the purpose of this invention is to provide a kind of synthetic repaglinide.

The technical solution adopted for the present invention to solve the technical problems is:

1, the step of this technology is as follows:

A. compound 2 is joined in the solvent, stir, add chloride reagent again and make acyl chlorides;

B. in the A step, add alkali, continue to stir, add compound 3 reactions then and obtain compound 4;

C. compound 4 is added in the water-soluble solvent, add the basic solution hydrolysis again, the back that reacts completely is adjusted pH value and is obtained repaglinide 1;

Wherein:

Compound 2 is 4-carboxyl methyl-3-ethoxy benzonitrile acid esters, and R represents that any one is easy to the protecting group of the carboxylic acid of deprotection in the ester;

Compound 3 is s-(+)-1-(2-piperidines phenyl)-3-methyl n-Butyl Amine 99;

Compound 4 is S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] benzoic ether, R represents that any one is easy to the protecting group of the carboxylic acid of deprotection in the ester;

R is methyl, ethyl, the tertiary butyl, benzyl, to nitrobenzyl or to methoxy-benzyl.

2, join in the solvent by compound 2, stir, add the chloride reagent of 0.5～4 times of compound 2 molar weight then, obtained the acyl chlorides intermediate in 0.2～5 hour-10 ℃～110 ℃ reactions.

3, after obtaining the acyl chlorides intermediate, add the alkali of 1～5 times of compound 2 molar weight, continue to stir, add the compound (3) of compound 2 molar weights 0.9～1.1 then, at-10～40 ℃ of following stirring reaction 0.5～24h, obtain compound 4.

4, compound 4 is joined in the water-soluble solvent, stir, temperature rises to 30～70 ℃, adds the basic solution of 1～4 times of compound 4 molar weight then, reacts 1～9 hour, adds acid again, and PH is obtained repaglinide 1 to modulating 4.5～5.5.

Solvent described in the A step is methylene dichloride, chloroform, toluene, dimethylbenzene or tetrahydrofuran (THF).

Described chloride reagent can be sulfur oxychloride, oxalyl chloride or phosphorus pentachloride; Wherein the add-on of chlorination industry sulfone is 1～4 times of compound 2 molar weights, oxalyl chloride, and the add-on of phosphorus pentachloride is 0.5～3 times of compound 2 molar weights.

Alkali described in the step B is organic bases or mineral alkali, and organic bases comprises triethylamine, Tributylamine, N, accelerine, 4-(N, N-dimethyl amido) pyridine, diisopropylethylamine, Diisopropylamine, dicyclohexylamine or 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene; Mineral alkali comprises salt of wormwood or yellow soda ash

Described water-soluble solvent is methyl alcohol, ethanol or acetone.

Described basic solution is potassium hydroxide aqueous solution or aqueous sodium hydroxide solution.

The acid of adjusting pH value comprises hydrochloric acid, sulfuric acid, nitric acid or acetic acid.

The beneficial effect that the present invention has is: the technology that a kind of synthetic repaglinide is provided, compare with other technology, it has efficiently, low toxicity, raw material is easy to get and low price, and is simple to operate, and yield is higher, the total recovery of two-step reaction has reached 80.9%, is a synthetic repaglinide operational path that industrial prospect is arranged very much.

Embodiment

For embodiment the present invention is further specified again below:

Embodiment 1:

S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] preparation of ethyl benzoate

With ethyl benzoate compound (2) (2.31g, 9.13mmol) join among the methylene dichloride 20ml, 25 ℃ are stirred down, (1.36g 11.4mmol), dropwised back 40 ℃ of heating reflux reactions 1 hour slowly to add sulfur oxychloride, be cooled to 0～5 ℃, (1.15g 11.4mmol), slowly drips compound 3 (2.25g then to add triethylamine, 9.13mmol) methylene dichloride (10ml) solution, be warming up to 25 ℃ after dropwising, continued stirring reaction 3 hours, add 10 * 2ml water washing then, anhydrous sodium sulfate drying, decompression is steamed down and is desolventized, and recrystallization obtains product 3.82g in the toluene normal hexane, yield 87%.

Embodiment 2

The preparation of repaglinide

(2.15g 4.47mmol) joins among the methyl alcohol 25ml, 65 ℃ of following stirring and refluxing with ethyl benzoate compound 4, slowly add 0.9mol/L sodium hydroxide solution (9.94ml then, 8.94mmol), reacted 3 hours, be cooled to 40～45 ℃, add the 0.6mol/L hydrochloric acid soln then to PH ≈ 5, cooling and stirring 0.5h in the ice bath filters, washing, the product 1.88g of oven dry, yield 93%.

Embodiment 3

S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] preparation of methyl benzoate

With methyl benzoate compound (2) (1.42g, 5.95mmol) join in the chloroform (12ml), stir, be cooled to-10 ℃, slowly add oxalyl chloride (0.38g, 2.98mmol), dropwising the back continues this thermotonus 3 hours, (0.81g 5.95mmol), is warming up to 60 ℃ to add salt of wormwood then, slowly drip compound 3 (1.47g, 5.95mmol) chloroformic solution 8ml, dropwise the back and continued stirring reaction 2 hours, add 10 * 2ml water washing then, anhydrous sodium sulfate drying, decompression is steamed down and is desolventized, and recrystallization obtains product 1.49g in the toluene normal hexane, yield 53.6%.

Embodiment 4

S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] preparation of peruscabin

With Benzyl Benzoate ester cpds (2) (1.87g, 5.95mmol) join in the toluene (12ml), stir under the room temperature, slowly add phosphorus pentachloride (4.96g, 23.8mmol), dropwised back 110 ℃ of heating reflux reactions 5 hours, be cooled to-10 ℃, add triethylamine (0.84g, 8.32mmol), slowly drip compound 3 (1.32g, toluene 8ml solution 5.36mmol) then, dropwise the back and continued under this temperature stirring reaction 24 hours, add 10 * 2ml water washing then, anhydrous sodium sulfate drying, decompression is steamed down and is desolventized, recrystallization obtains product 1.46g in the toluene normal hexane, yield 45.2%.

Embodiment 5

S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] phenylformic acid is to the preparation of methoxy benzyl ester

With phenylformic acid to methoxybenzyl ester cpds (2) (2.05g, 5.95mmol) join in the methylene dichloride (12ml), stir under the room temperature, (1.42g 11.9mmol), dropwised the post-heating back flow reaction 1 hour slowly to add sulfur oxychloride, be cooled to 0～5 ℃, (3.15g 29.8mmol), slowly drips compound 3 (1.62g then to add yellow soda ash, 6.55mmol) methylene dichloride 8ml solution, slowly be warming up to room temperature after dropwising, continued stirring reaction 2 hours, add 10 * 2ml water washing then, anhydrous sodium sulfate drying, decompression is steamed down and is desolventized, and recrystallization obtains product 2.61g in the toluene normal hexane, yield 76.4%.

Embodiment 6

With ethyl benzoate compound 2 (1.5g, 5.95mmol) join in the methylene dichloride (12ml), stir under the room temperature, slowly add sulfur oxychloride (0.85g, 7.13mmol), dropwised the post-heating back flow reaction 1 hour, be cooled to-10～-5 ℃, add 4-(N, N-dimethyl amido) pyridine (2.17g, 17.85mmol), slowly drip then compound 3 (1.47g, methylene dichloride 8ml solution 5.95mmol) slowly is warming up to room temperature after dropwising, continued stirring reaction 2 hours, the after washing organic layer twice that reacts completely, anhydrous sodium sulfate drying, decompression is steamed down and is desolventized, recrystallization obtains product 2.38g in the toluene normal hexane, yield 83.5%.

Embodiment 7

The preparation of repaglinide

(2.42g 4.47mmol) joins among the ethanol 25ml, 70 ℃ of stirrings with Benzyl Benzoate ester cpds 4, slowly add 0.5mol/L potassium hydroxide solution (8.94ml then, 4.47mmol), reacted 5 hours, be cooled to 40～45 ℃, add the 0.6mol/L hydrochloric acid soln then to PH ≈ 5.5, cooling and stirring 0.5h in the ice bath filters, washing, the product 1.73g of oven dry, yield 85.4%.

Embodiment 8

The preparation of repaglinide

(2.08g 4.47mmol) joins among the ethanol 25ml, and 30 ℃ are stirred down with methyl benzoate compound 4, slowly add 0.5mol/L sodium hydroxide solution (35.8ml then, 17.9mmol), reacted 9 hours, be cooled to 40～45 ℃, add the 0.6mol/L hydrochloric acid soln then to PH ≈ 4.5, cooling and stirring 0.5h in the ice bath filters, washing, the product 1.61g of oven dry, yield 79.3%.

Claims

1, a kind of technology of synthetic repaglinide is characterized in that the step of this technology is as follows:

A. compound 2 is joined in the solvent, stir, add sulfur oxychloride again and make acyl chlorides;

C. compound 4 is added in the water-soluble solvent, add the basic solution hydrolysis again, the back that reacts completely is adjusted the pH value and is obtained repaglinide;

Wherein:

Compound 2 is 4-carboxyl methyl-2-ethoxy benzonitrile acid esters, in the ester R be methyl, ethyl, the tertiary butyl, benzyl, to nitrobenzyl or to methoxy-benzyl;

Compound 3 is S-(+)-1-(2-piperidines phenyl)-3-methyl n-Butyl Amine 99;

Compound 4 is S-(+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amido carbonyl methyl] benzoic ether, in the ester R be methyl, ethyl, the tertiary butyl, benzyl, to nitrobenzyl or to methoxy-benzyl;

2, the technology of a kind of synthetic repaglinide according to claim 1, it is characterized in that: join in the solvent by compound 2, stir, add the sulfur oxychloride of 1～4 times of compound 2 molar weight then, obtained the acyl chlorides intermediate in 0.2～5 hour-10 ℃～110 ℃ reactions.

3, according to the technology of synthesizing repaglinide in the claim 1, it is characterized in that: after obtaining the acyl chlorides intermediate, the alkali that adds 1～5 times of compound 2 molar weight, continue to stir, the compound 3 that adds compound 2 molar weights 0.9～1.1 then, at-10～40 ℃ of following stirring reaction 0.5～24h, obtain compound 4.

4, the technology of a kind of synthetic repaglinide according to claim 1, it is characterized in that: compound 4 is joined in the water-soluble solvent, stir, temperature rises to 30～70 ℃, the basic solution that adds 1～4 times of compound 4 molar weight then, reacted 1～9 hour, and added acid again, the pH value is transferred to 4.5～5.5 obtain repaglinide.

5, the technology of a kind of synthetic repaglinide according to claim 1 and 2 is characterized in that: the solvent described in the A step is methylene dichloride, chloroform, toluene, dimethylbenzene or tetrahydrofuran (THF).

6, according to the technology of claim 1 or 3 described a kind of synthetic repaglinides, it is characterized in that: the alkali described in the step B is organic bases or mineral alkali, organic bases is selected from triethylamine, Tributylamine, N, accelerine, 4-(N, N-dimethyl amido) pyridine, diisopropylethylamine, Diisopropylamine, dicyclohexylamine or 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene; Mineral alkali is selected from salt of wormwood or yellow soda ash.

7, according to the technology of claim 1 or 4 described a kind of synthetic repaglinides, it is characterized in that: described water-soluble solvent is methyl alcohol, ethanol or acetone.

8, according to the technology of claim 1 or 4 described a kind of synthetic repaglinides, it is characterized in that: described basic solution is potassium hydroxide aqueous solution or aqueous sodium hydroxide solution.

9, the technology of a kind of synthetic repaglinide according to claim 4 is characterized in that: the acid of adjusting the pH value is selected from hydrochloric acid, sulfuric acid, nitric acid or acetic acid.