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Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative

A technology of octahydrocyclopentyl and pyrrole carboxylic acid, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of low yield, long route, and difficulty in large-scale production, and achieve short synthesis route and high yield Effect

Inactive Publication Date: 2011-08-31
ACME BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis of its key intermediate, octahydrocyclopenta[c]pyrrole-2-carboxylic acid, has problems such as long route and low yield, which brings difficulties to large-scale production

Method used

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  • Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative
  • Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative
  • Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative

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Experimental program
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Effect test

Embodiment 1

[0023] N-Boc octahydrocyclopenty[c]pyrrole III (0.42 g, 2 mmol) and (+)-cytisine (0.56 g) were dissolved in methyl tert-butyl ether (20 mL) and washed with dry ice -Cool in an acetone cooling bath to -78°C, and add sec-butyllithium (1.4 M sec-butyllithium in cyclohexane, 2.1 mL) dropwise. After stirring at -78°C for 3 hours, dry carbon dioxide was bubbled in (0.5 hours). The reaction was gradually warmed to room temperature and stirred overnight. Cool to 0-5°C, add HCl (1N), adjust pH to 2-3, extract twice with ethyl acetate, combine organic layers, wash twice with water and brine, dry over anhydrous sodium sulfate, filter, reduce After the solvent was evaporated to dryness under pressure, the residue was separated by silica gel column chromatography to obtain N-tert-butoxycarbonyl octahydrocyclopenta[c]pyrrole-2-carboxylic acid IV (0.33 g).

Embodiment 2

[0025] N-Boc octahydrocyclopenta[c]pyrrole III (4.2 g, 20 mmol) and (+)-3-methyl-dodecahydro-1,5-methylene-pyridine-[1,2-a ][1,5]Diazocine (4.07 g, 21 mmol) was dissolved in methyl tert-butyl ether (150 mL), cooled to -78 o C. Add sec-butyllithium (1.4 M in cyclohexane, 15 mL, 21 mmol) dropwise. at -78 o C. After 3 hours in a stirred cold bath, dry carbon dioxide was bubbled in (0.5 hours). The reaction was gradually warmed to room temperature and stirred overnight. Cool down to 0-5 o C. Add HCl (1N), adjust the pH to 2-3, extract with ethyl acetate (2 x 200 mL), and combine the organic layers. After the organic layer was washed twice with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure, the residue was separated by silica gel column chromatography to obtain chiral N-tert-butoxycarbonyl octahydrocyclopentyl[ c] Pyrrole-2-carboxylic acid IV (2.9 g).

Embodiment 3

[0027] N-Boc octahydrocyclopenta[c]pyrrole III (1.39 g, 6.6 mmol) and (+)-3-methyl-dodecahydro-1,5-methylene-pyridine-[1,2-a ][1,5]Diazocine (1.54 g, 7.92 mmol) was dissolved in diethyl ether (20 mL), cooled to -50 o C, Add sec-butyllithium (1.4 M in cyclohexane, 5.66 mL, 7.92 mmol) dropwise. at -50 o After stirring in a cold bath for 2 hours, a solution of ethyl chloroformate (1.25 mL, 13.2 mmol) in ether (10 mL) was added. The reaction was gradually warmed to room temperature and stirred overnight. Cool down to 0-5 o C. Add HCl (1 N) to adjust the pH to 5-6, extract with ethyl acetate (2 x 50 mL), and combine the organic layers. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography (10% ethyl acetate and n-hexane), the chiral N-tert-butoxycarbonyl octane was obtained. Ethyl hydrocyclopenta[c]pyrrole-2-carboxylate (0.62 g)

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Abstract

The invention discloses a preparation method of an octahydrocyclopenta[c]pyrrole carboxylic acid derivative. The method comprises the following steps: octahydrocyclopenta[c]pyrrole protected by N is used as raw material, one of tetrahydrofuran, methyl tert-butyl ether and dioxane is used as solvent, chiral organic ligand is added to react with lithium alkylide for 2-3 hours at -50 DEG C to -78 DEG C, then the reaction product reacts with carbon dioxide or ethyl chloroformate to obtain the octahydrocyclopenta[c]pyrrole carboxylic acid derivative. The preparation method of the octahydrocyclopenta[c]pyrrole carboxylic acid derivative has short synthetic route and high yield and can be used to realize mass production successfully.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of an octahydrocyclopentyl[c]pyrrole carboxylic acid derivative. Background technique [0002] Since the hepatitis C (HCV) virus was discovered in 1989, there have been approximately 170 million viral hepatitis C patients worldwide, and 3 to 4 million new cases each year, with HCV type 1 infection as the main infection, accounting for 70%. Hepatitis C is mainly transmitted by blood. The global average infection rate is 3%, and the infection rate in China is about 3.2%. There are about 40 million hepatitis C antibody positive people in China (1b, 2a). Hepatitis C is easy to become chronic, and if it is not treated, the conversion rate is as high as 75% to 85%. After 20 to 30 years of hepatitis C infection, 10% to 20% will develop liver cirrhosis; after 30 years of hepatitis C infection, 1 to 3% will develop liver cancer. According to s...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 张志家倪志杰杨东
Owner ACME BIOPHARMA
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