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Synthesis method of repaglinide

A synthetic method and compound technology, applied in the field of drug synthesis, can solve problems such as poor stereoselectivity and low yield, and achieve the effects of good quality, high reaction conversion rate, and cost reduction

Pending Publication Date: 2019-07-05
ANHUI HAIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The yield of compound 3 obtained by this method is low, only 33.7%, the stereoselectivity is poor, and the ee value is 90%

Method used

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  • Synthesis method of repaglinide
  • Synthesis method of repaglinide
  • Synthesis method of repaglinide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of step a 2-piperidine-1-benzaldehyde (1)

[0045] 62.0g (0.5mol, 1.0eq) of o-fluorobenzaldehyde, 200g of N,N-dimethylformamide, 138.2g (1.0mol, 2.0eq) of potassium carbonate, and 63.9g (0.75mol, 1.5eq) of piperidine were reacted In the bottle, heated to reflux for 15 hours, the reaction of the raw materials controlled by TLC was complete, and the temperature was lowered. The reaction solution was poured into ice water, extracted with methyl tert-butyl ether, and the organic layers were combined and concentrated under reduced pressure to obtain 87.1 g of a yellow oil with a purity of 95.3% by HPLC. Yield 92.1%. 1 H (400MHz, CDCl 3):δ10.26(s,1H),7.75(dd,J=7.4Hz,J=1.8Hz,1H),7.46(ddd,J=8.3Hz,J=7.4Hz,J=1.8Hz,1H), 7.09-7.02(m,2H),3.01(t,J=5.4Hz,4H),1.77-1.73(m,4H),1.60-1.54(m,2H).MS(m / z)=190.1[M+ 1] +

[0046] Synthesis of step b sulfinyl imide (2)

[0047] Compound 187.1g (0.46mol, 1.0eq), pyridine 4-methylbenzenesulfonate 3.5g (13.8mmol, 0.03eq), (R)-(+)-te...

Embodiment 2

[0056] Synthesis of step a 2-piperidine-1-benzaldehyde (1)

[0057] 70.3g (0.5mol, 1.0eq) of o-chlorobenzaldehyde, 210g of N,N-dimethylformamide, 488.7g of cesium carbonate (1.5mol, 3.0eq), 106.4g of piperidine (85.15, 1.25mol, 2.5eq) Put it in a reaction bottle, heat and reflux for 11 hours, the reaction of the raw material in TLC is complete, lower the temperature, pour the reaction solution into ice water, extract with methyl tert-butyl ether, combine the organic layers and concentrate under reduced pressure to obtain 89.8 g of yellow oil, HPLC purity 96.0 %, yield 94.9%, MS(m / z)=190.1[M+1] +

[0058] Synthesis of step b sulfinyl imide (2)

[0059] Compound 189.8g (0.47mol, 1.0eq), pyridine 4-methylbenzenesulfonate 1.2g (4.8mmol, 0.01eq), (R)-(+)-tert-butylsulfinyl 86.2g (0.71mol, 1.5 eq) and 450g of dichloromethane were placed in a reaction flask, heated to reflux for 10 hours, the remaining 8% of the raw material was controlled in HPLC, the temperature was lowered, 2g ...

Embodiment 3

[0068] Synthesis of step a 2-piperidine-1-benzaldehyde (1)

[0069] 92.5g (0.5mol, 1.0eq) of o-bromobenzaldehyde, 300g of N,N-dimethylsulfoxide, 276.4g (2.0mol, 4.0eq) of potassium carbonate, and 127.7g (1.5mol, 3.0eq) of piperidine In the bottle, heated to reflux for 15 hours, the reaction of the raw materials controlled by TLC was complete, and the temperature was lowered. The reaction solution was poured into ice water, extracted with methyl tert-butyl ether, and the organic layers were combined and concentrated under reduced pressure to obtain 90.5 g of a yellow oil with a purity of 96.1% by HPLC. Yield 95.6%. MS(m / z)=190.1[M+1] +

[0070] Synthesis of step b sulfinyl imide (2)

[0071] Compound 190.5g (0.478mol, 1.0eq), pyridine 4-methylbenzenesulfonate 6.0g (23.9mmol, 0.05eq), (R)-(+)-tert-butylsulfinyl 144.8g (121.20, 1.19mol , 2.5eq) and 450g of 1,4-dioxane were placed in a reaction flask, heated to reflux for 5 hours, and the reaction of raw materials in HPLC was ...

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Abstract

The invention discloses a synthesis method of repaglinide, and belongs to the technical field of medicine synthesis. The method comprises the following steps that ortho-halogenated benzaldehyde is taken as a raw material, a 2-piperidine-1-benzaldehyde compound 1 is obtained through piperidine substitution and reacts with (R)-methylpropane-2-sulfinamide to obtain an imine compound 2, then the iminecompound 2 reacts with a 2-methyl-1-propylene Grignard reagent lithium chloride, and through reduction, an S-(+)-1-(2-piperidine phenyl)-3-methyl n-butylamine compound 3 is obtained; then the S-(+)-1-(2-piperidine phenyl)-3-methyl n-butylamine compound 3 and 4-carboxyl methyl-2-ethoxy benzoate are condensed to obtain an S-(+)-2-oxethyl-4-[N-{1-(2-piperidine phenyl)-3-methyl-1-butyl}amine carbonylmethyl]benzoate compound 4; finally, the repaglinide 5 is obtained through hydrolysis. Compared with other technologies, the synthesis method has the advantages that operation is simple, the raw materials are easy to obtain, the yield is high, the cost is low, and the method is environmentally friendly; the product repaglinide has very high optical purity and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of repaglinide. Background technique [0002] Repaglinide, chemical name: (S)-2-ethoxy-4-[2-[methyl-1-[2-(1-piperidinyl)phenyl]-butyl]-amino]- 2-oxoethyl] benzoic acid (structure shown in formula (I)). [0003] [0004] Repaglinide is a new type of short-acting oral insulin-stimulating hypoglycemic drug. It binds to specific receptors on the islet β-cell membrane, promotes the closing of the ATP-sensitive potassium channel coupled with the receptor, and inhibits the release of potassium ions from β-cells. Outflow, depolarization of the cell membrane, opening of calcium channels, inflow of calcium ions, and promotion of insulin secretion. Its action is faster than that of sulfonylureas, so the postprandial hypoglycemic effect is faster. Glucose regulators taken with the first meal. The biggest advantage is that it can imitate the physiologica...

Claims

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Application Information

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IPC IPC(8): C07D295/135C07B53/00
CPCC07D295/135C07B53/00C07B2200/07
Inventor 张小顺
Owner ANHUI HAIKANG PHARMA
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