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A kind of synthetic method of boceprevir intermediate 2-hydroxyl-3-amino-4-cyclobutylbutanamide hydrochloride

A technology of cyclobutylbutanamide and synthesis method, which is applied in the field of synthesis of boceprevir intermediates, can solve the problems of high equipment requirements, cumbersome handling, lengthy reaction steps, etc., and achieve simple post-treatment operation, simple reaction conditions, The effect of shortening the production cycle

Active Publication Date: 2016-04-27
江苏欣德瑞医药科技有限公司
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Problems solved by technology

[0009] Although the raw materials of this synthetic method are simple and easy to obtain, the conditions for preparing cyclobutylformaldehyde are harsh and require high equipment; the remaining steps are long, and the reaction time is long, which increases the production cost; in addition, the post-reaction treatment of the preparation method is loaded down with trivial details, requiring High-purity products can only be obtained by multiple treatments with a large amount of reagents, which is not conducive to industrial production
[0010] Another example is PCT International Patent Application (publication number: WO2005 / 085242), a method for synthesizing 2-hydroxyl-3-amino-4-cyclobutylbutanamide hydrochloride, and the synthetic method needs to go through 11 steps of reaction. The final product can be obtained, the reaction steps are extremely lengthy, and the flammable lithium tetrahydrogen aluminum and highly toxic cyanide are required in the reaction process, which is not conducive to large-scale industrial production and has great potential safety hazards
[0011] For another example, PCT International Patent Application (publication number: WO2013 / 066734), the synthetic method of 2-hydroxyl-3-amino-4-cyclobutylbutanamide hydrochloride disclosed by this patent needs to go through eight steps of reaction to obtain the final product , the reaction steps are long, the reaction intermediate compound is not easy to purify, and the highly toxic cyanide needs to be used in the reaction process, which has potential safety hazards and is not conducive to large-scale industrial production

Method used

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  • A kind of synthetic method of boceprevir intermediate 2-hydroxyl-3-amino-4-cyclobutylbutanamide hydrochloride
  • A kind of synthetic method of boceprevir intermediate 2-hydroxyl-3-amino-4-cyclobutylbutanamide hydrochloride
  • A kind of synthetic method of boceprevir intermediate 2-hydroxyl-3-amino-4-cyclobutylbutanamide hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] At room temperature, 50 g (0.43 mol) of cyclobutylacetic acid, 73.4 g (0.47 mol) of monomethyl malonate potassium salt, and 300 mL of tetrahydrofuran were successively added to the three-necked reaction flask, and 103.7 g (0.64 mol) of carbonyldiimidazole was added under stirring. ), magnesium chloride 15g to form a reaction solution, after the addition, the reaction solution was reacted at room temperature for 12h, then 100mL of water was added to the reaction solution, stirring was continued for 0.5h, liquid separation, the organic phase continued to be washed once with saturated brine 50mL, and dried. Concentration gave 66.5 g of the compound of formula A 4-cyclobutyl-3-oxo-butyric acid methyl ester, with a yield of 89.2%.

[0039] Add 200mL of formic acid to the three-necked reaction flask, add sodium percarbonate 33.2g (0.2mol), 4-cyclobutyl-3-oxo-butyric acid methyl ester 66.5g (0.39mol), iodine 4 g (0.02 mol) of benzene forms a reaction solution. After the additi...

Embodiment 2

[0043] At room temperature, 30 g (0.26 mol) of cyclobutylacetic acid, 44 g (0.28 mol) of monomethyl malonate potassium salt, and 300 mL of 2-methyltetrahydrofuran were successively added to the three-necked reaction flask, and after stirring, 47.8 cyanuric chloride was added. g (0.26mol), magnesium chloride 10g to form a reaction solution, after the addition, react the reaction solution at room temperature for 10h, then add 100mL of water to the reaction solution, continue to stir for 0.4h, separate the liquids, and continue to wash the organic phase with 50mL of saturated saline Once, dried and concentrated to obtain 39.5 g of the compound of formula A, 4-cyclobutyl-3-oxo-butyric acid methyl ester, with a yield of 88.5%.

[0044] Add 150mL of formic acid to the three-necked reaction flask, add sodium perborate 35.8g (0.23mol), 4-cyclobutyl-3-oxo-butyric acid methyl ester 39.5g (0.23mol), iodine 3 g (0.02 mol) of benzene forms a reaction solution, and after the addition, keep ...

Embodiment 3

[0048] At room temperature, add 18 g (0.16 mol) of cyclobutylacetic acid, 24.6 g (0.16 mol) of monomethyl malonate potassium salt, and 200 mL of ethylene glycol dimethyl ether into the three-necked reaction flask in sequence, and continue to add dicarbonate dicarbonate after stirring. 35.04g (0.16mol) of tert-butyl ester and 10g of magnesium chloride form a reaction solution. After the addition, the reaction solution is reacted at room temperature for 11h, then 100mL of water is added to the reaction solution, and the stirring is continued for 0.6h. Wash once with 50 mL of saline, dry, and concentrate to obtain 22.3 g of the compound of formula A, 4-cyclobutyl-3-oxo-butyric acid methyl ester, with a yield of 83.1%.

[0049] Add 150mL of formic acid to the three-necked reaction flask, then add 4.4g (0.13mol) of hydrogen peroxide, 13.78g (0.13mol) of sodium carbonate, and 22g of methyl 4-cyclobutyl-3-oxo-butyrate at 15-20°C (0.13mol), iodobenzene 2g (0.01mol) to form a reaction ...

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Abstract

The invention relates to a synthetic method of a boceprevir intermediate namely 2-hydroxy-3-amino-4-cyclobutane amide hydrochloride, belonging to the technical field of medicament synthesis. By adopting the synthetic method, the problems that a method for synthesizing the boceprevir intermediate is high in cost, complex in reaction, low in efficiency and the like in the prior art can be solved. The synthetic method comprises the following steps: by adopting cyclobutyl acetate and monomethyl mono potassium malonate as raw materials, reacting for 10-12 hours at room temperature under the action of an activating agent and magnesium chloride; sequentially adding an oxidizing agent, 4-cyclobutyl-3-oxo-ethyl butyrate and a catalyst into methanoic acid at 15-20 DEG C, and reacting for 1.5-2.5 hours at 15-20 DEG C; adding a condensation agent and organic alkali at 10-15 DEG C, performing condensation reaction with ammonium chloride at room temperature, and reacting for 10-12 hours; and finally performing ammoniation and acidification to obtain a final product. The synthetic method disclosed by the invention is relatively low in cost, simple in reaction condition, less in reaction step and short in time, and the final product, namely the boceprevir intermediate, is relatively high in purity and yield.

Description

technical field [0001] The present invention relates to a method for synthesizing a boceprevir intermediate, in particular to a method for synthesizing a boceprevir intermediate 2-hydroxy-3-amino-4-cyclobutylbutanamide hydrochloride, belonging to a pharmaceutical intermediate Body synthesis technology field. Background technique [0002] Hepatitis C protease inhibitor Boceprevir (Boceprevir), its Chinese name: (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutane-2 -yl)-3-[(2S)-2-(tert-butylcarbamoylamino)-3,3-dimethylbutyryl]-6,6-dimethyl-3-azabicyclo[3.1. 0]Hexane-2-carboxamide; English chemical name: (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S) -2-(tert-butylcarbamoylamino)-3,3-dimethylbutanonyl]-6,6-dimethyl-3-azabicylo[3.1.0]hexane-2-carboxamide; Molecular formula: C 27 h 45 N 5 o 5 ; Molecular Weight: 519.68; CAS Registry Number: 394730-60-0. Its structural formula is as follows: [0003] [0004] Boceprevir (SCH-503034) was developed by Sche...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/14C07C231/02
Inventor 李志强王伸勇王晓俊胡长春
Owner 江苏欣德瑞医药科技有限公司
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