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A kind of preparation method of 2,2-dimethylcyanoacetamide

A technology of dimethyl cyanoacetamide and cyanoacetamide, which is applied in the preparation of the side chain intermediate of antihypertensive drug Aliskiren and the field of preparation 2, which can solve the problem of high cost

Inactive Publication Date: 2015-08-19
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But using this method, there is a risk of hydrolysis of the amino group on the cyanoacetamide, and the cost of avoiding this risk is very high

Method used

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  • A kind of preparation method of 2,2-dimethylcyanoacetamide
  • A kind of preparation method of 2,2-dimethylcyanoacetamide
  • A kind of preparation method of 2,2-dimethylcyanoacetamide

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preparation example Construction

[0027] The preparation method of 2,2-dimethylcyanoacetamide provided by the invention comprises steps:

[0028] In the first step, cyanoacetamide and methylating reagent are simultaneously added to the tetrahydrofuran solution of sodium hydrogen, and cooled to minus 25 degrees Celsius to room temperature (preferably minus 25 degrees Celsius to 5 degrees Celsius) with an ice bath;

[0029] In the second step, after adding the materials, the temperature is raised to room temperature to 45 degrees Celsius, and the reaction is performed for 15 minutes to 2 hours;

[0030] The third step is quenching with saturated ammonium chloride, then the solvent is evaporated, and then water is added to form a saturated solution;

[0031] The fourth step is to extract 5-15 times with dichloromethane, dry, filter, and evaporate to dryness;

[0032] In the fifth step, crystallize with ethyl acetate:n-hexane=1:1 to obtain 2,2-dimethylcyanoacetamide.

[0033] Another preparation method of 2,2-di...

Embodiment 1

[0051] In a solution of sodium hydrogen (5.75g, 2.3eq) in tetrahydrofuran, cyanoacetamide (5.23g, 1eq) and dimethyl sulfate (17.35g, 2.2eq) were added simultaneously, and cooled to about 5 degrees Celsius with an ice bath, After adding the material, raise the temperature to about 45 degrees Celsius, react for 15 minutes to 30 minutes, quench with 40ml of saturated ammonium chloride, then evaporate the solvent, add water to make a saturated solution, and extract 10 times with 50ml of dichloromethane. Dry, filter, evaporate to dryness, and repeat crystallization with ethyl acetate:n-hexane=1:1 to obtain product I (5.95g), yield 85%, melting point 105-106°C. ESI-MS (M+NH 4 + ) = 130.1.

Embodiment 2

[0053] In tetrahydrofuran solution of sodium hydrogen (5.75g, 2.3eq), add cyanoacetamide (5.23g, 1eq) and dimethyl sulfate (17.35g, 2.2eq) at the same time, and cool to about -25 degrees Celsius with an ice bath , after adding the material, warm up to room temperature, react for 2 hours, quench with 40ml of saturated ammonium chloride, then evaporate the solvent, then add water to form a saturated solution, extract 10 times with 50ml of dichloromethane, dry, filter, After evaporation to dryness, repeated crystallization with ethyl acetate: n-hexane = 1:1, the product I (5.60 g) was obtained with a yield of 80% and a melting point of 105-106°C. ESI-MS (M+NH 4 + ) = 130.1.

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Abstract

The invention discloses a preparation method for 2, 2-dimethyl cyano acetamide. The method comprises the steps of mixing sodium hydrogen, cyano acetamide and a methylation reagent and reacting the above mixed materials to obtain 2,2 - dimethyl-cyano acetamide.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical manufacturing, in particular to a new method for preparing an antihypertensive drug Aliskiren (Aliskiren) side chain intermediate, that is, a new method for preparing 2,2-dimethylcyanoacetamide . Background technique [0002] 2,2-Dimethylcyanoacetamide, American Chemical Abstracts Registration Number CAS: 7505-93-3, has the structure of formula I: [0003] [0004] Aliskiren is a renin inhibitor with antihypertensive effect developed by Novartis. The drug has been marketed in Europe, America, China and other regions. Its structure has a key terminal fragment of 3-amino-2,2-dimethyl Propionamide II, I is an intermediate in the preparation of II. [0005] [0006] At present, there is only one preparation method of I disclosed in the international literature, which is limited to the following literature reports Dong Hua et al.Tetrahedron Lett., 2005, 46(37): 6337-6340; Errera.Gazzetta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C255/19C07C253/30
Inventor 王冠郭晔堃钟静芬时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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