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Synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride

A technology of hydroxycyclobutylbutanamide and a synthetic method, which is applied in the field of synthesis of boceprevir intermediates, can solve problems such as low product purity and yield, unfavorable industrial production, and harsh conditions, so as to improve yield and The effects of purity, reduced need for auxiliary raw materials, and fewer reaction steps

Inactive Publication Date: 2013-11-13
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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  • Synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride
  • Synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride
  • Synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0039] Dissolve 150g of Boc-glycine tert-butyl ester in 1.5L of THF, stir for 0.5h, and cool down to -30°C; slowly add 648ml of LDA dropwise to the system, keep stirring for 0.5h; add 96.7g of cyclobutane to the system dropwise After dropping the system, the system was kept at -30°C for 2 hours; 1.5L of 10% ammonium chloride aqueous solution and 1.5L of MBTE were added to the system, extracted and separated, the aqueous phase was extracted with 1.5L of MBTE, the organic phases were combined, and Wash with 1.5L saturated brine, then wash with 300g anhydrous NaSO 4 Dry, filter with suction, and concentrate the filtrate under reduced pressure until solvent-free to obtain tert-butyl 2-tert-butoxycarbonyl amino acid-3-cyclobutylpropanoate with a yield of 90.0%.

[0040] Dissolve 150g of 2-tert-butoxycarbonyl amino acid-tert-butyl 3-cyclobutylpropanoate in 1.5LTHF, under nitrogen protection, warm to -20°C, slowly add 551mL of 1.1eq of diisobutylaluminum hydride dropwise, After the ...

Embodiment 2

[0047] Dissolve 150g Boc-glycine tert-butyl ester in 2.0L methyl tert-butyl ether, stir for 20 minutes, and cool down to -40°C; slowly add 1000ml HMDSLi dropwise to the system, keep stirring for 20 minutes; add dropwise to the system Add 136 g of cyclobutylchloromethane, and after dropping the system, continue to keep the temperature 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 liquids, and then extract the aqueous phase with 2.0L of MBTE, The organic phases were combined, washed with 2.0L saturated brine, and then washed with 450g anhydrous NaSO 4 Dry, filter with suction, and concentrate the filtrate under reduced pressure until solvent-free to obtain tert-butyl 2-tert-butoxycarbonyl amino acid-3-cyclobutylpropanoate with a yield of 91.6%.

[0048] Dissolve 150g of 2-tert-butoxycarbonyl amino acid-tert-butyl 3-cyclobutylpropanoate in 2.0L of methyl tert-butyl ether, under nitrogen protection, wa...

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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, and 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, whose chemical name is: (1R, 2S, 5S)-N-(4-amino- 1-Cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S)-2-(tert-butylcarbamomido)-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 ketoamide undecapeptides, which can capture serine at the active site of NS3, and its carbonyl group on ketoamide Carbon binds to this catal...

Claims

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Application Information

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IPC IPC(8): C07C237/14C07C231/12
Inventor 肖坤福江锋王伸勇王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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