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Synthesis method of (R)-5-methylpyrrolidone-2-one

A technology of methylpyrrolidone and synthetic method, which is applied in the direction of organic chemistry, organic chemistry, etc., can solve the problems of expensive raw materials, poor universality, and high development difficulty, and achieve high yield, low raw material price, and atom utilization high rate effect

Active Publication Date: 2020-02-28
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at present, bio-enzyme technology has not been popularized in China, and bio-enzymes need to be modified for different substrates. The universality is not strong, and the development is difficult. It takes a lot of time and money to complete the enzyme modification work.
And the activity of biological enzymes needs specific external conditions to maintain, otherwise it will be inactivated and cause losses
The current synthesis method of (R)-5-methylpyrrolidone-2-one has problems such as low atom utilization, high production cost, and expensive raw materials.

Method used

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  • Synthesis method of (R)-5-methylpyrrolidone-2-one
  • Synthesis method of (R)-5-methylpyrrolidone-2-one
  • Synthesis method of (R)-5-methylpyrrolidone-2-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: In a 1L three-necked flask, add 500 mL of dichloromethane, cool down by about 5 degrees in an ice bath, add 80 g of methyl levulinate, 17 g of (S)-Me-CBS, pass nitrogen flow, and dropwise add borane dimethyl Thioether 56.04g, after dropping and stirring for 0.5h, the temperature was raised to 30°C and reacted for 3h, and the reaction was completed as detected by HPLC. Methanol was added dropwise, hydrochloric acid was used to quench the reaction, and 69.8 g of (R)-4-hydroxyvalerate methyl ester was obtained after treatment, >99% ee, yield 85.8%.

[0034] (R) 50g of methyl 4-hydroxyvalerate was put into a 2L autoclave, 400g of ammonia water, 400g of methanol, and 5g of Raney nickel were added. The temperature was increased to 90°C, and the reaction was completed in 6h. The catalyst was filtered, water and EA were added for extraction, and 48 g of (R)-4-aminovaleric acid methyl ester was obtained after the treatment, with a yield of 96.8%.

[0035] (R) 50 g o...

Embodiment 2

[0036] Example 2: In a 1L three-necked flask, add 500 mL of acetonitrile, lower the temperature in an ice bath by about 5 degrees, add 80 g of methyl levulinate, 17 g of (S)-Me-CBS, pass nitrogen flow, and add borane dimethyl sulfide dropwise 56.04g, stirred for 0.5h after dropping, heated to 30°C and reacted for 3h, and HPLC detected the end of the reaction. Methanol was added dropwise, hydrochloric acid was used to quench the reaction, and 70.5 g of (R)-4-hydroxyvalerate methyl ester was obtained after treatment, >99% ee, yield 86.6%.

[0037] (R) 50g of methyl 4-hydroxyvalerate was put into a 2L autoclave, 400g of ammonia water, 400g of methanol, and 5g of Raney nickel were added. The temperature was increased to 90°C, and the reaction was completed in 6h. The catalyst was filtered, water and EA were added for extraction, and 47 g of (R)-4-aminovaleric acid methyl ester was obtained after the treatment, with a yield of 94.8%.

[0038] (R) 50g of methyl 4-aminovalerate was...

Embodiment 3

[0039]Example 3: In a 1L three-necked flask, add 500 mL of dimethylformamide, lower the temperature in an ice bath by about 5 degrees, add 80 g of methyl levulinate and 17 g of (S)-Me-CBS, pass nitrogen flow, and add borane dropwise 56.04 g of dimethyl sulfide, stirred for 0.5 h after dropping, heated to 30° C. and reacted for 3 h, and the reaction was completed as detected by HPLC. Methanol was added dropwise, hydrochloric acid was used to quench the reaction, and 70 g of (R)-4-hydroxyvalerate methyl ester was obtained after treatment, >99% ee, yield 86%.

[0040] (R) 50g of methyl 4-hydroxyvalerate was put into a 2L autoclave, 400g of ammonia water, 400g of methanol, and 5g of Raney nickel were added. The temperature was increased to 90°C, and the reaction was completed in 6h. The catalyst was filtered, water and EA were added for extraction, and 49 g of (R)-4-aminovaleric acid methyl ester was obtained after the treatment, with a yield of 98.8%.

[0041] (R) 50 g of methy...

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Abstract

The invention discloses a synthesis method of (R)-5-methylpyrrolidone-2-one. The synthesis method comprises following steps: step one, adding methyl levulinate, borane dimethyl sulfide, and a catalystinto a solvent, and carrying out reactions for 1 to 5 hours to obtain (R)-4-hydroxylmethyl pentanoate; step two, adding (R)-4-hydroxylmethyl pentanoate obtained in the step (1) into a reactor, introducing a nitrogen source and Raney nickel into the reactor, and carrying out catalytic reactions under a pressurized condition to obtain (R)-4-aminomethyl pentanoate; step three, adding (R)-4-aminomethyl pentanoate into a solvent, adding an alkaline catalyst, raising the temperature to 30-80 DEG C, and carrying out reactions for 0.5 to 5 hours to obtain the target product (R)-5-methylpyrrolidone-2-one; wherein the solvent in the step (1) is one or more of dichloromethane, toluene, dimethyl formamide, dimethyl sulfoxide, dichloromethane, and tetrahydrofuran. The synthesis method has the advantages of easily available and cheap raw materials, high atom utilization rate, high purity, easy purification, and high yield, and the chiral center does not need to be splitted.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a method for synthesizing (R)-5-methylpyrrolidone-2-one. Background technique [0002] (R)-5-Methylpyrrolidone-2-one, the chemical formula is: [0003] [0004] (R)-5-Methylpyrrolidone-2-one is an intermediate of the heart failure drug sacubitril. [0005] Sacubitril, the original research company is Novartis, listing time: FDA 2015 / 7 / 7, EMA2015 / 11 / 19, indications: sacubitril combined with valsartan for the treatment of heart failure. Heart failure (heart failure) refers to the failure of the systolic function and / or diastolic function of the heart to fully discharge the venous blood back to the heart, resulting in blood stasis in the venous system and insufficient blood perfusion in the arterial system, thereby causing the heart Circulatory disorder syndrome, which is manifested as pulmonary congestion and vena cava congestion in this disorder syndrome clus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/267
CPCC07D207/267C07B2200/07
Inventor 高元崔槐杰宗杨磊
Owner SUZHOU UUGENE BIOPHARMA
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