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Industrial preparation method for 3-amino-2, 2-dimethyl propionamide

The technology of bismethylpropionamide and cyanoacetamide is applied in the field of industrialized preparation of 3-amino-2,2-bismethylpropionamide, which can solve the problems of rare raw materials and incapability of large-scale production, and achieves easy reaction Control, low preparation cost and reasonable selection of reaction process

Inactive Publication Date: 2010-02-10
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The technical problem to be solved in the present invention is: the raw materials required in the existing 3-amino-2,2-bismethylpropionamide preparation process are difficult to obtain, column chromatography purification is required, and highly toxic reagent potassium cyanide is used, which cannot be scaled up. The problem of chemical production; Provide a kind of brand-new, the large-scale industrial preparation method of 3-amino-2,2-bismethyl propionamide with simple and convenient steps, higher overall yield and lower preparation cost

Method used

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  • Industrial preparation method for 3-amino-2, 2-dimethyl propionamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis of 3-amino-2,2-dimethylpropanamide:

[0030] Step 1: Synthesis of Dimethylcyanoacetamide

[0031] Sodium ethoxide (204g, 3mol) was slowly added to 2000ml of absolute ethanol, stirred for half an hour after the addition, then added cyanoacetamide (84g, 1mol), at an internal temperature of 80°C, refluxed for 2 hours, and then cooled to At 30°C, methyl iodide (426 g, 3 mol) was added, the system was closed, and the reaction was carried out at room temperature for 12 hours. Evaporate the solvent to dryness, add 500ml of water, then extract six times with 250ml of dichloromethane, combine the dichloromethane layers, wash with saturated brine, dry over anhydrous sodium sulfate, spin dry, wash with 100ml of dichloromethane and filter to obtain the filter cake as Dimethylcyanoacetamide (90 g, 0.80 mol), 80% yield. 1 H NMR (400MHz, DMSO-d 6 ): δ7.63 (brs, 1H), 7.46 (brs, 1H), 1.58 (s, 6H); MS (m / z): 113 (M+H) + .

[0032] The second step: the synthesis of 3-...

Embodiment 2

[0035] Synthesis of 3-amino-2,2-dimethylpropanamide:

[0036] Step 1: Synthesis of Dimethylcyanoacetamide

[0037] According to the process conditions and operation steps described in the first step of the above-mentioned Example 1, dimethylcyanoacetamide was prepared with a yield of 80%, and the test data were as shown in the first step of the above-mentioned Example 1.

[0038] The second step: the synthesis of 3-amino-2,2-bismethylpropionamide

[0039] Dissolve dimethylcyanoacetamide (5.6g, 0.05mol) in anhydrous methanol solution (40ml), add ammonia water (10ml) and Raney Ni catalyst (1.1g), and hydrogenate 3 Hour. The catalyst was removed by filtration and concentrated to obtain 3-amino-2,2-bismethylpropionamide (5.2 g, 0.045 mol) with a yield of 90%. Its test data is as shown in the second step of the above-mentioned embodiment 1.

Embodiment 3

[0041] Synthesis of 3-amino-2,2-dimethylpropanamide:

[0042] Step 1: Synthesis of Dimethylcyanoacetamide

[0043] According to the process conditions and operation steps described in the first step of the above-mentioned Example 1, dimethylcyanoacetamide was prepared with a yield of 80%, and the test data were as shown in the first step of the above-mentioned Example 1.

[0044] The second step: the synthesis of 3-amino-2,2-bismethylpropionamide

[0045] Dissolve dimethylcyanoacetamide (5.6g, 0.05mol) in anhydrous methanol solution (40ml), add 5% Pd / C catalyst (0.28g), and hydrogenate at 3 atmospheric pressure at 60°C for 3 hours . The catalyst was removed by filtration and concentrated to obtain 3-amino-2,2-bismethylpropionamide (5.0 g, 0.043 mol) with a yield of 86%. Its test data is as shown in the second step of the above-mentioned embodiment 1.

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Abstract

The invention relates to an industrial method for preparing 3- amino- 2, 2- bimethyl propionamide, which is a segment in high pressure protein proenzyme inhibitor. The invention takes normal and cheapcyanoacetamide as raw material, alkalyating two nethyls, catalytic hydrogenating or adding reducant agent and getting 3- amnio- 2, 2- bimethyl propionamide. The chenmical reaction is shown in the graph. The invention solves problems of difficulty of getting raw material, low productivity and long process line, needs no column chromatography and purification, avoids toxic potassium cyanide and realizes large scale production.

Description

Technical field: [0001] The invention relates to an industrialized preparation method for the synthesis of a fragment 3-amino-2,2-bismethylpropanamide of the hypertensinogenase inhibitor Aliskiren. Background technique: [0002] The antihypertensive drug Aliskiren is a protease inhibitor of high blood pressure. At present, the Swiss company Speedel has completed the phase I and phase II clinical research work for the treatment of hypertension. At the same time, the study of this drug in the treatment of congestive heart failure and chronic renal failure has completed phase II clinical evaluation. Speedel pointed out that Aliskiren is the first oral hypertensive protease inhibitor to enter phase III clinical research. Novartis will fund its phase III clinical research and be responsible for the future registration of this drug. Aliskiren acts on the renin-angiotensin system at the beginning, which is different from the existing drugs acting on angiotensin-converting enzyme ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C237/06
Inventor 董华吴颢董径超马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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