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Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative

A technology of octahydrocyclopentene and pyrrole carboxylic acid, which is applied in the synthesis of octahydrocyclopenteno[c]pyrrole carboxylic acid derivatives and the synthesis of pharmaceutical intermediates, can solve the problem of being difficult to be suitable for large-scale industrial production and synthesis The problems of short route and harsh reaction conditions can achieve the effect of convenient large-scale industrial production, short synthesis route and good product quality.

Active Publication Date: 2013-05-22
SUZHOU UUGENE BIOPHARMA
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Problems solved by technology

[0010] Although this method can be completed in one step and the synthesis route is short, the reaction conditions are harsh, and it needs to be reacted under ultra-low temperature and anhydrous and oxygen-free conditions, and it is difficult to be suitable for large-scale industrial production.

Method used

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  • Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative
  • Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative
  • Synthesis method of octahydro-cyclopenta[c]pyrrole carboxylic acid derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Preparation of (1S,3aR,6aS)-2-tert-butoxycarbonyl-4-hydroxy-octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester: add 10g (1S,3aR, 6aS) Ethyl 2-tert-butoxycarbonyl-4-oxoctahydrocyclopenta[c]pyrrole-1-carboxylate was dissolved in 100ml of ethanol to form a reaction solution. The reaction liquid was cooled to 0° C., and then 1.89 g of sodium borohydride was added to the reaction liquid in batches. After the addition was complete, the reaction solution was raised to room temperature and stirred for 2 hours. After ethyl (1S,3aR,6aS)-2-tert-butoxycarbonyl-4-oxoctahydrocyclopenta[c]pyrrole-1-carboxylate was completely reduced, the mixture was concentrated to remove ethanol. Pour the residue into 50ml of water, extract three times with ethyl acetate to obtain the extract, combine and concentrate the extract to obtain 10g of (1S,3aR,6aS)-2-tert-butoxycarbonyl-4-hydroxy-octahydrocyclopentenene [c] Ethyl pyrrole-1-carboxylate.

[0047] Preparation of (1S,3aR,6aS)-2-tert...

Embodiment 2

[0050] Preparation of (1S,3aR,6aS)-2-trityl-4-hydroxy-octahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester: add 17g (1S,3aR, 6aS)-2-trityl-4-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester was dissolved in 120ml of methanol to form a reaction solution. The reaction liquid was first cooled to 2° C., and then 3.28 g of potassium borohydride was added to the reaction liquid in batches. After the addition was complete, the reaction solution was raised to room temperature and stirred for 3 hours. After methyl (1S,3aR,6aS)-2-trityl-4-oxoctahydrocyclopenta[c]pyrrole-1-carboxylate was completely reduced, the mixture was concentrated to remove methanol. Pour the residue into 60ml of water, extract three times with ethyl acetate to obtain the extract, combine and concentrate the extract to obtain 17g of (1S,3aR,6aS)-2-trityl-4-hydroxy-octahydrocyclopentacene [c] Methyl pyrrole-1-carboxylate.

[0051] Preparation of (1S, 3aR, 6aS)-2-trityl-1,2,3,3a,6,6a-hexahyd...

Embodiment 3

[0054] Preparation of (1S,3aR,6aS)-2-acetyl-4-hydroxy-octahydrocyclopenta[c]pyrrole-1-carboxylic acid: Add 9 g of (1S,3aR,6aS)-2 -Acetyl-4-oxooctahydrocyclopenta[c]pyrrole-1-carboxylic acid was dissolved in 100 ml of isopropanol to form a reaction solution. The reaction liquid was first cooled to -1°C, and then 2.0 g of sodium borohydride was added to the reaction liquid in batches. After the addition was complete, the reaction solution was raised to room temperature and stirred for 1 hour. After (1S,3aR,6aS)-2-acetyl-4-oxoctahydrocyclopenta[c]pyrrole-1-carboxylic acid was completely reduced, it was concentrated to remove isopropanol. Pour the residue into 50ml of water, extract three times with ethyl acetate to obtain the extract, combine and concentrate the extract to obtain 9g of (1S, 3aR, 6aS)-2-acetyl-4-hydroxy-octahydrocyclopenta[c ] pyrrole-1-carboxylic acid.

[0055] Preparation of (1S,3aR,6aS)-2-acetyl-1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrole-1-carboxylic acid: ...

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Abstract

The invention relates to a synthesis method of a telaprevir intermediate octahydro-cyclopenta[c]pyrrole carboxylic acid derivative, which belongs to the technical field of pharmaceutical synthesis. The synthesis method comprises the following steps: dissolving a compound shown in formula (I) in a solvent, and adding a reducing agent for reducing ketonic groups to hydroxyl, thereby obtaining a compound shown in formula (II); dissolving the compound shown in formula (II) in a solvent, and under the action of organic alkali and a dehydrating agent, forming a carbon-carbon double bond, thereby obtaining a compound shown in formula (III); dissolving the compound shown in formula (III) in an organic solvent, carrying out hydrogenation reduction on the obtained object under the action of a catalyst so as to obtain a compound shown in formula (IV), and the synthetic route is described in the specification, wherein PG refers to protecting groups over N, and the protecting groups include benzyl, p-methoxybenzyl, benzyloxycarbonyl, triphenylmethyl, t-butyloxycarboryl, acetyl and fluorenl methoxy carbonyl; and R refers to hydrogen, alkyl or cycloalkyl with the carbon atom numbers of less than or equal to 6, halogenated alkyl, aryl or heteroaryl. The method is short in synthetic route, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing a drug intermediate, in particular to a method for synthesizing an octahydrocyclopenta[c]pyrrole carboxylic acid derivative, and belongs to the technical field of drug synthesis. Background technique [0002] Telaprevir (telaprevir) is a new drug for the treatment of hepatitis C developed and marketed by Vertex Pharmaceuticals. It is approved to be used in combination with pegylated interferon α and ribavirin to treat non-interferon-based anti-infective drugs patients, or patients who do not respond well to such treatments. The chemical name of 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 accession number: 402957-28-2, its chemical structural formula is: [0003] [0004] Octahydrocyclopenteno[c]pyrrole carboxylic acid derivative is an important intermedia...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 王伸勇李志强王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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