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Preparation method of (R)-N1,N1-diethyl-1,4-pentanediamine

A diethyl, -N1 technology, applied in the field of chiral amine preparation, can solve the problems of not finding ω-transaminase, high difficulty in preparation of transaminase, high price, etc., and achieves good industrial application prospects, good stereoselectivity, and simple operation. handy effect

Active Publication Date: 2019-12-27
暨明医药科技(苏州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, ω-transaminase is used in the synthesis of chiral amines, mostly by combining amino acids and transaminases to prepare S-configuration amines, but the preparation of transaminases used in this combination of chiral amines is difficult and expensive, making The production cost of chiral amine is high, which is not conducive to controlling the cost of industrial production
[0009] After searching, the use of ω-transaminase in the preparation of (R)-N1,N1-diethyl-1,4-pentanediamine has not been found in the prior art

Method used

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  • Preparation method of (R)-N1,N1-diethyl-1,4-pentanediamine
  • Preparation method of (R)-N1,N1-diethyl-1,4-pentanediamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A kind of (R)-N1, the synthetic method of N1-diethyl-1,4-pentanediamine, it comprises the steps:

[0033] S1 Add 157g 5-diethylamino-2-pentanone (1mol, 52.3g / L), 1.50L DMSO and 1.50L water into the reaction vessel; use 100mM phosphate buffer solution to adjust the pH value of the reaction system to 8.5, then add 177g Isopropylamine (3mol), 15g (5g / L) ω-transaminase ATA-117 and 15g (5g / L) coenzyme 5-phosphate-pyridoxal 40 ℃ stirring reaction for 15 hours; Among them, ω-transaminase ATA-117 is the market Purchased, its activity is 300U / L.

[0034] S2 Add 6M hydrochloric acid to the reaction system to adjust the pH value to 2, extract twice with 1500mL dichloromethane; adjust the pH to 12-13 with 6M sodium hydroxide in the aqueous phase, extract three times with 1000mL dichloromethane, combine the organic phases, and wash with water ( 1000mL) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness to obtain about 150g of crude product;

...

Embodiment 2

[0038] A kind of (R)-N1, the synthetic method of N1-diethyl-1,4-pentanediamine, it comprises the steps:

[0039] S1 Add 157g of 5-diethylamino-2-pentanone (1mol), 1.50L of DMSO and 1.00L of water into the reaction vessel; use 100mM phosphate buffer solution to adjust the pH value of the reaction system to 8.5, then add 177g of isopropylamine (3mol) , 15g ω-transaminase ATA-117 and 15g coenzyme 5-phosphate-pyridoxal were stirred and reacted at 40°C for 15 hours;

[0040] S2 Add 6M hydrochloric acid to the reaction system to adjust the pH value to 2, extract twice with 1500mL dichloromethane; adjust the pH to 12-13 with 6M sodium hydroxide in the aqueous phase, extract three times with 1000mL dichloromethane, combine the organic phases, and wash with water ( 1000mL) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness to obtain about 135g of crude product;

[0041] The crude product described in S3 was distilled under reduced pressure to obt...

Embodiment 3

[0045] A kind of (R)-N1, the synthetic method of N1-diethyl-1,4-pentanediamine, it comprises the steps:

[0046] S1 Add 157g of 5-diethylamino-2-pentanone (1mol), 1.50L of DMSO and 1.50L of water into the reaction vessel; use 100mM phosphate buffer solution to adjust the pH value of the reaction system to 8.5, then add 118g of isopropylamine (2mol) , 15g ω-transaminase ATA-117 and 15g coenzyme 5-phosphate-pyridoxal were stirred and reacted at 40°C for 15 hours;

[0047]S2 Add 6M hydrochloric acid to the reaction system to adjust the pH value to 2, extract twice with 1500mL dichloromethane; adjust the pH to 12-13 with 6M sodium hydroxide in the aqueous phase, extract three times with 1000mL dichloromethane, combine the organic phases, and wash with water ( 1000mL) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness to obtain about 150g of crude product;

[0048] The crude product described in S3 was distilled under reduced pressure to obta...

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Abstract

The present invention belongs to the technical field of chiral amine preparations and particularly relates to a preparation method of chiral amine (R)-N1,N1-diethyl-1,4-pentanediamine. A synthesis ofthe (R)-N1,N1-diethyl-1,4-pentanediamine comprises the following steps: using 5-diethylamino-2-pentanone as a raw material and catalyzing the 5-diethylamino-2-pentanone with an amino group donor isopropylamine to conduct a transamination reaction under catalysis of omega-transaminase ATA-117 and coenzyme pyridoxal phosphate to produce the(R)-N1,N1-diethyl-1,4-pentanediamine. The product prepared by the provided method is good in stereoselectivity and produced enantiomer by-products are less than 0.5%; after purification by distillation, purity reaches 99.3% or more and single impurity reachesstarting raw material indexes of raw material medicines; and a total yield can reach as high as 70-85%, the yield is obviously higher than that of traditional process, and the preparation method has avery good industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of chiral amine preparation, and in particular relates to a preparation method of chiral amine (R)-N1,N1-diethyl-1,4-pentanediamine. Background technique [0002] Chloroquine is a common antimalarial drug, which can quickly and effectively control the clinical outbreak of malaria. It has the characteristics of fast onset and high curative effect. It has a high concentration in the liver, can kill amoeba trophozoites, and has immunosuppressive effects. Large doses are used in rheumatoid arthritis, systemic lupus erythematosus and other immune dysfunction diseases. (R)-Chloroquine is one of the enantiomers of chloroquine, which is being used to treat non-alcoholic steatohepatitis or reduce the risk and severity of liver cancer, reduce liver inflammation and improve liver function. [0003] (R)-N1,N1-diethyl-1,4-pentanediamine is a key intermediate for the preparation of (R)-chloroquine and has huge potential ...

Claims

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Application Information

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IPC IPC(8): C12P13/00
CPCC12P13/001
Inventor 陈剑戈李斌峰顾志锋
Owner 暨明医药科技(苏州)有限公司
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