Synthesis method of Telaprevir intermediate

A technology of telaprevir and synthetic method, which is applied in the field of drug synthesis, can solve problems such as high energy consumption and equipment occupancy rate, health hazards of operators, and easy pollution of the environment, so as to improve conversion rate and yield and shorten reaction time , reduce the effect of side effects

Inactive Publication Date: 2015-04-08
SUZHOU UUGENE BIOPHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] 1. In this synthesis method, expensive cyanoyl cyclopropane is used. Because of its extremely smelly smell and unstable chemical properties, special protective measures need to be taken in operation, and flammable aluminum hydride with special requirements for equipment is used. Lithium and dioxane solution, etc., resulting in high cost of raw materials, high energy consumption and high occupancy rate of equipment
[0009] 2. In this synthesis method, the benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) reagent, which is prone to carcinogenic hexamethylphosphoramide (HMPA), is used , not only cause great harm to the health of operators, but also easily pollute the environment, which is not conducive to large-scale industrial production

Method used

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  • Synthesis method of Telaprevir intermediate
  • Synthesis method of Telaprevir intermediate
  • Synthesis method of Telaprevir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] At room temperature, 1.58g of ethyl 2-oxohexanoate and 1.82g of 1,8-diazabicyclo[5.4.0]undec-7-ene were dissolved in 20mL of acetonitrile to form a reaction solution. The diimide was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours until the reaction was completed as detected by TLC. The reaction solution after the completion of the reaction was poured into 100 mL of water, followed by extraction with dichloromethane three times, and the organic phases were combined. The organic phase was washed three times with 100 mL of water, dried with anhydrous magnesium sulfate, suction filtered to obtain a filtrate, the filtrate was concentrated under reduced pressure, and recrystallized with n-heptane and ethyl acetate to obtain 2.22 g of (S)-3-(2,5-dioxane) pyrrol-1-yl)-2-oxohexanoic acid ethyl ester, the yield is 87%, and the purity is 99.50%.

[0057]2.22g of (S)-3-(2,5-dioxopyrrol-1-yl)-2-oxohexanoic acid ethyl ester prepared abov...

Embodiment 2

[0063] At room temperature, 3.16g of ethyl 2-oxohexanoate and 3.64g of 1,8-diazabicyclo[5.4.0]undec-7-ene were dissolved in 40mL of tetrahydrofuran to form a reaction solution, and 4.28g of N-bromobutan The diimide was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours until the reaction was completed as detected by TLC. The reaction solution after the completion of the reaction was poured into 200 mL of water, extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed three times with 200 mL of water, dried with anhydrous magnesium sulfate, suction filtered to obtain a filtrate, the filtrate was concentrated under reduced pressure, and recrystallized with n-heptane and ethyl acetate to obtain 4.44 g of (S)-3-(2,5-dioxane) pyrrol-1-yl)-2-oxohexanoic acid ethyl ester.

[0064] 4.44g (S)-3-(2,5-dioxopyrrol-1-yl)-2-oxohexanoic acid ethyl ester prepared above was added to a 250mL three-n...

Embodiment 3

[0070] At room temperature, 4.74g of ethyl 2-oxohexanoate and 5.46g of 1,8-diazabicyclo[5.4.0]undec-7-ene were dissolved in 60mL of dichloromethane to form a reaction solution, and 6.42g of N-bromo The succinimide was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours until the reaction was completed as detected by TLC. The reaction solution after the completion of the reaction was poured into 300 mL of water, followed by extraction with dichloromethane three times, and the organic phases were combined. The organic phase was washed three times with 300 mL of water, dried with anhydrous magnesium sulfate, suction filtered to obtain a filtrate, the filtrate was concentrated under reduced pressure, and recrystallized with n-heptane and ethyl acetate to obtain 6.66 g of (S)-3-(2,5-dioxane) pyrrol-1-yl)-2-oxohexanoic acid ethyl ester.

[0071] The 6.66g (S)-3-(2,5-dioxopyrrol-1-yl)-2-oxohexanoic acid ethyl ester obtained above was added to...

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Abstract

The invention relates to a synthesis method of a Telaprevir intermediate. The synthesis method comprises the following steps: preparing a compound of a formula I from 2-oxo ethyl hexanoate, 1,8-diazabicyclo[5.4.0]undecylenic-7-alkene and N-bromosuccinimide; reducing the compound of the formula I into a compound of a formula II; protecting the amino group on the compound of the formula II to obtain a compound of a formula III; performing condensation reaction on the compound of the formula III and cyclopropylamine to obtain a Telaprevir intermediate IV; removing the amino protecting group from the Telaprevir intermediate IV under the action of a catalyst to obtain a compound of a formula V; or adding acid into the Telaprevir intermediate IV and removing the amino protecting group to obtain a Telaprevir intermediate VI; and reducing the Telaprevir intermediate V or VI, adding acid and salifying to obtain a Telaprevir intermediate VII. The synthesis method is low in production cost, simple in condition and high in yield. The compounds of the formulae I, II and III, and the Telaprevir intermediates IV, V, VI and VII have the structural formulae as shown in specifications, wherein R is the amino protective group and HX is acid.

Description

technical field [0001] The invention relates to a method for synthesizing a telaprevir intermediate, and belongs to the technical field of drug synthesis. Background technique [0002] Telaprevir is a new antiviral drug developed and marketed by Vertex Pharmaceuticals, which is specific for hepatitis C. It is reversible, selective, covalent, tightly and slowly combined with HCV NS3-4A protease. inhibitors, this protease is critical in viral replication. Telaprevir is approved in combination with peginterferon alfa and ribavirin for the treatment of patients who have not been treated with interferon-based anti-infective drugs or who have not responded well to such treatment. The chemical name for Telaprevir is (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrainylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-(( cyclopropylamino)oxoacetyl)butyl)octahydrocyclopenta[c]pyrrole-1-carboxamide, CAS registration number: 402957-28-2, its chemical structure is: [0003] [0004] And (S)-3-NHR-N...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/04C07C231/12C07C53/18C07C51/41C07C271/20C07C269/06
CPCY02P20/55
Inventor 胡凡王伸勇邵长坤王晓俊胡长春
Owner SUZHOU UUGENE BIOPHARMA
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