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A kind of synthetic method of β-amino-alpha-hydroxycyclobutanamide hydrochloride

A technology of hydroxycyclobutylbutanamide and synthetic method, which is applied in the field of synthesis of boceprevir intermediates, can solve the problems of low product purity and yield, unfavorable industrial production, unfavorable continuous production, etc., and achieve improved yield and The effects of purity, reduced need for auxiliary raw materials, and fewer reaction steps

Inactive Publication Date: 2015-09-09
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although the preparation method is simple and easy to obtain starting materials, the conditions are harsh when preparing cyclobutylformaldehyde, and the equipment requirements are relatively high; the remaining steps have a long reaction time; the whole reaction needs several days to complete, which is not conducive to continuous production
In addition, the post-treatment of each step in the preparation method is very cumbersome, requiring a large number of reagents to undergo multiple treatments to obtain the reaction product, which is not only unfavorable for industrial production, but also has low purity and yield of the final product

Method used

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  • A kind of synthetic method of β-amino-alpha-hydroxycyclobutanamide hydrochloride
  • A kind of synthetic method of β-amino-alpha-hydroxycyclobutanamide hydrochloride
  • A kind of synthetic method of β-amino-alpha-hydroxycyclobutanamide hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Dissolve 150g Boc-tert-butyl glycine in 1.5L THF, stir for 0.5h, cool down to -30°C; slowly add 648ml LDA dropwise to the system, keep warm and continue stirring for 0.5h; add dropwise 96.7g cyclobutane to the system methyl bromide, drop the system and continue to keep warm at -30°C for 2 hours; add 1.5L of 10% ammonium chloride aqueous solution and 1.5L MBTE to the system, extract and separate the liquid, extract the aqueous phase with 1.5L MBTE, combine the organic phases, and use Wash with 1.5L saturated brine, then wash with 300g anhydrous NaSO 4 After drying and suction filtration, the filtrate was concentrated under reduced pressure to no solvent to obtain tert-butyl 2-tert-butoxycarbonylamino acid-3-cyclobutylpropionate with a yield of 90.0%.

[0040] Dissolve 150g of 2-tert-butoxycarbonyl amino acid-3-cyclobutylpropionate tert-butyl in 1.5LTHF, lower the temperature to -20°C under the protection of nitrogen, and slowly add 551mL of 1.1eq diisobutylaluminum hydri...

Embodiment 2

[0047] Dissolve 150g Boc-glycine tert-butyl ester in 2.0L methyl tert-butyl ether, stir for 20 minutes, cool down to -40°C; slowly add 1000ml HMDSLi dropwise to the system, keep warm and continue stirring for 20 minutes; drop into the system Add 136g of cyclobutylchloromethane, drop the system and continue to keep warm at -40°C for 2 hours; add 2.0L of 10% ammonium chloride aqueous solution and 2.0L of MBTE to the system, extract and separate the liquid, and then extract the water phase with 2.0L of MBTE. The organic phases were combined, washed with 2.0L saturated brine, and then washed with 450g of anhydrous NaSO 4 After drying and suction filtration, the filtrate was concentrated under reduced pressure to no solvent to obtain tert-butyl 2-tert-butoxycarbonylamino acid-3-cyclobutylpropionate with a yield of 91.6%.

[0048] Dissolve 150g of 2-tert-butoxycarbonyl amino acid-3-cyclobutylpropionate tert-butyl in 2.0L of methyl tert-butyl ether, lower the temperature to -20°C und...

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Abstract

The invention relates to a synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride as a boceprevir intermediate. The synthesis method comprises the following steps of: with Boc-tert-butyl glycinate as a compound as shown in the formula (I) as a starting raw material, subjecting the Boc-tert-butyl glycinate and cyclobutyl halogenated methane as a compound as shown in the formula (II) to reaction to generate a compound as shown in the formula (III), reducing the compound to generate a compound as shown in the formula (IV), adding a cyanide and inorganic acid to generate a compound as shown in the formula (V), subjecting the compound and acid to reaction to generate a compound as shown in the formula (VI), adding a hydroxyl protective agent and a catalyst to react to generate a compound as shown in the formula (VII), oxidizing the compound to generate a compound as shown in the formula (VIII), and finally, adding acid to react to generate the beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride (IX). The synthesis method is few in synthesis step, short in time, less in required auxiliary reagent, low in cost, simple and feasible in after-treatment, simple in equipment and higher in purity and yield.

Description

technical field [0001] The invention relates to a method for synthesizing a boceprevir intermediate, in particular to a method for synthesizing a boceprevir intermediate β-amino-alpha-hydroxycyclobutylbutanamide hydrochloride, which belongs to the technical field of drug synthesis. Background technique [0002] In 2011, Merck successfully developed a hepatitis C virus (HCV) NS3 / 4A protease inhibitor Boceprevir (Boceprevir), its chemical name is: (1R, 2S, 5S)-N-(4-amino- 1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S)-2-(tert-butylcarbamoylamido)-3,3-dimethylbutyryl] -6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, CAS registration number: 394730-60-0, the structural formula is: [0003] [0004] It is a small molecule inhibitor with high NS3 inhibitory activity discovered during the systematic truncation and modification of amino acid residues on the ketoamide undecapeptide. It can capture the serine in the active site of NS3 and the carbonyl group on its ketoamide Carb...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/14C07C231/12
Inventor 肖坤福江锋王伸勇王晓俊胡长春
Owner SUZHOU UUGENE BIOPHARMA
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