Synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone

A technology for pyrrolidine and intermediates, which is applied in the field of preparation of raw materials and intermediates, can solve the problems of increased cost, increased risk factor, large amount of consumption, etc., and achieves the effects of reducing production cost, shortening reaction period and improving production efficiency.

Active Publication Date: 2015-12-09
大连微凯化学有限公司
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  • Abstract
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Problems solved by technology

[0009] This method relates to the synthetic method of intermediate (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one, the required 2.2 equivalents of 4-biphenyl magnesium bromide, the consumption is relatively large, and 4- The synthetic yield of biphenylmagnesium bromide is low. Due to the increase in usage, the risk factor also increases, making industrial production difficult and costly.

Method used

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  • Synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone
  • Synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone
  • Synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Add 19.8g (0.1mol) of (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one into a 250mL three-necked flask, add solvent toluene (100mL), stir, and add triethylamine 10.6 g (0.105mol), turn on the heating, add 12.6g (0.1mol) of benzyl chloride dropwise at 50-60°C, raise the temperature to 80°C for 4 hours, and detect (S)-5-(morpholine-4-carbonyl) by HPLC ) pyrrolidin-2-one is less than 2%.

[0038] (2) Cool the reaction solution obtained in (1) to -15~-20°C, at this temperature, add 30.71 g (0.12 mol) of a tetrahydrofuran solution of biphenylmagnesium bromide dropwise, and keep the reaction for 5 hours after the addition is completed. Then add aluminum trichloride 20.0g (0.15mol) in batches under this condition, react for 1 hour, then slowly drop the reaction solution into the aqueous solution of 2N HCl to quench the reaction solution, static layering, ethyl acetate extracts the aqueous phase, The organic phases were combined, washed with saturated brine, dried, and concen...

Embodiment 2

[0040] (1) Add 19.8g (0.1mol) of (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one into a 250mL three-necked flask, add solvent toluene (100mL), stir, and add triethylamine 10.6 g (0.105mol), turn on the heating, add 16.9g (0.1mol) of benzyl bromide dropwise at 50-60°C, raise the temperature to 80°C for 4 hours, and detect (S)-5-(morpholine-4 -carbonyl)pyrrolidin-2-one is less than 2%.

[0041] (2) Cool the reaction solution obtained in (1) to -15~-20°C, at this temperature, add 30.71 g (0.12 mol) of a tetrahydrofuran solution of biphenylmagnesium bromide dropwise, and keep the reaction for 5 hours after the addition is completed. Then add aluminum trichloride 20.0g (0.15mol) in batches under this condition, react for 1 hour, then slowly drop the reaction solution into the aqueous solution of 2N HCl to quench the reaction solution, static layering, ethyl acetate extracts the aqueous phase, The organic phases were combined, washed with saturated brine, dried, and concentrated to d...

Embodiment 3

[0043](1) (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one 19.8g (0.1mol) was added to a 250mL three-necked flask, toluene (100mL) was added, stirred, and triethylamine 10.6 g (0.105mol), turn on the heating, add 12.6g (0.1mol) of benzyl chloride dropwise at 50-60°C, raise the temperature to 80°C for 4 hours, and detect (S)-5-(morpholine-4 -carbonyl)pyrrolidin-2-one is less than 2%,

[0044] (2) Cool the reaction solution obtained in (1) to -15~-20°C, at this temperature, add 30.71 g (0.12 mol) of a tetrahydrofuran solution of biphenylmagnesium bromide dropwise, and keep the reaction for 5 hours after the addition is completed. Then add palladium carbon 0.2g under this condition, feed hydrogen, and react at room temperature for 2 hours. After the reaction is completed, the palladium carbon will be filtered off and concentrated to dryness in vacuo to obtain 19.55 g of the product, yield: 73.6%, enantiomeric excess (ee) 98.15%, determined by HPLC.

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Abstract

The invention discloses a synthetic method of Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone. The synthetic method comprises the following steps: taking (S)-5-(morpholine-4-carbonyl) pyrrolidine-2-ketone and (chloromethyl) benzene as raw materials, dissolving in organic solvent, and obtaining (S)-1-benzyl-5-(morpholine-4-carbonyl) pyrrolidine-2-ketone under the action of alkali, then reacting with an organic solution of 4-diphenyl magnesium bromide, and carrying out the debenzylation reaction to generate the Entresto midbody (S)-5-(diphenyl-4-carbonyl) pyrrolidine-2-ketone. By adopting the synthetic method, the dosage of diphenyl magnesium bromide is remarkably reduced, so that the production cost is obviously reduced, and the production period is greatly shortened; during the process for manufacturing a diphenyl magnesium bromide Grignard reagent, the yield is relatively low. According to the synthetic method, due to the reduction of the dosage of the diphenyl magnesium bromide, the danger coefficient is also reduced (the production is safer). The synthetic method is more suitable for the industrialized production.

Description

technical field [0001] The invention belongs to the design of organic synthesis routes, and in particular relates to the technical field of preparation of raw materials and intermediates, in particular to an (industrial) production method of dual inhibitors of angiotensin II receptor and enkephalinase. Background technique [0002] Entresto is a new type of drug developed by Novartis for the treatment of heart failure, which can reduce the mortality rate of heart failure caused by decreased ejection fraction. The drug is composed of two components: valsartan and experimental drug Sacubitril (AHU377). The composition is an angiotensin Ⅱ receptor and neprilysin dual inhibitor drug. Clinically, the drug has a unique mode of action and excellent antihypertensive effect, which was approved by the US FDA and the EU EMEA and was launched in July 2015. [0003] The composition of Entresto, Sacubitril (AHU377), has the following structure: [0004] [0005] The intermediate (S)-...

Claims

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Application Information

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IPC IPC(8): C07D207/26
CPCC07D207/26
Inventor 曾伟方典军杜大鹏于淼赵月
Owner 大连微凯化学有限公司
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