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Method for preparing cidofovir key intermediate

A compound, -N4- technology, applied in organic chemistry and other directions, can solve the problems of many side reactions, high cost, application limitations, etc., and achieve the effect of reducing reaction cost, improving yield and reducing side reactions.

Active Publication Date: 2008-06-25
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Because (R)-2,3-glycidide derivatives and (R)-2,3-dipropylene glycol derivatives cost higher, and raw materials are not easy to obtain, side reaction in reaction process simultaneously More, the generated products are not easy to purify, the application of the reaction is limited, and it is not suitable for industrial production

Method used

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  • Method for preparing cidofovir key intermediate
  • Method for preparing cidofovir key intermediate
  • Method for preparing cidofovir key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1. Preparation of (S)-N-(2,3-epoxypropyl)-4-methoxy-2-pyrimidinone (IV)

[0033] N 2 Under protection, 4-methoxy-2-pyrimidinone (12.6g, 0.1mol) was dissolved in dried DMF (1L), heated to 100°C, 80% NaH (9g, 0.3mol) was added, stirred 0.5h, add (R)-epichlorohydrin (9.25g, 0.1mol), react at 110°C for 2h, cool to room temperature, pour the reaction solution into a large amount of ice water, extract with ethyl acetate (300ml×3), combine acetic acid Ethyl ester was concentrated, and the oil was poured into petroleum ether (500ml), stirred, and filtered to obtain 11g of a yellow solid, with a yield of 61%.

[0034] 2. Preparation of (S)-N-(2,3-epoxypropyl)-cytosine (V)

[0035] Compound (IV) (11 g, 0.06 mol) was added to 30% methylamino alcohol solution (200 ml), and reacted at 120° C. for 8 h. After the reaction was completed, it was concentrated under reduced pressure and recrystallized from ethanol to obtain 8.03 g of a dark yellow solid. Yield 80%.

[0036] 3. Prepara...

Embodiment 2

[0041] 1. Preparation of (S)-N-(2,3-epoxypropyl)-4-methoxy-2-pyrimidinone (IV)

[0042] N 2 Under protection, 4-methoxy-2-pyrimidinone (12.6g, 0.1mol) was dissolved in dried THF (1L), heated to 100°C, 80% NaH (9g, 0.3mol) was added, stirred 0.5h, add (R)-epibromohydrin (9.25g, 0.1mol), react at 110°C for 4h, cool to room temperature, pour the reaction solution into a large amount of ice water, extract with ethyl acetate (300ml×3), combine acetic acid Ethyl ester was concentrated, and the oil was poured into petroleum ether (500ml), stirred, and filtered to obtain 11g of a yellow solid, with a yield of 61%.

[0043] 2. Preparation of (S)-N-(2,3-epoxypropyl)-cytosine (V)

[0044] Compound (IV) (11 g, 0.06 mol) was added to 30% methylamino alcohol solution (200 ml), and reacted at 120° C. for 8 h. After the reaction was completed, it was concentrated under reduced pressure and recrystallized from methanol to obtain 8.03 g of a dark yellow solid. Yield 80%.

[0045] 3. Prepara...

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PUM

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Abstract

The invention relates to a method for preparing a 1-(S)-(2, 3-dihydroxypropxyl)-N<4>-benzoyl cytosine (formula I compound). The compound is a key intermediate for preparing an anti-viral drug called cidofovir (formula II compound).

Description

technical field [0001] The present invention relates to 1-(S)-(2,3-dihydroxypropyl)-N 4 - A new preparation method of benzoylcytosine (compound of formula I), which can be used to prepare antiviral drug cidofovir. Background technique [0002] Cidofovir (Cidofovir, HPMPC) is a ring-opening nucleotide analog developed by Gilead Corporation of the United States. Cidofovir for injection was approved by the US FDA in May 1996 and is suitable for the treatment of CMV retinitis in AIDS patients. Cidofovir can inhibit viral DNA polymerase and has a strong inhibitory effect on human CMV. Papillomaviruses are also highly active. Its chemical name is (S)-1-[3-hydroxy-2-(phosphomethoxy)propyl]cytosine. The structural formula is as follows: [0003] [0004] The compound represented by the above formula (I) is an important intermediate for the synthesis of cidofovir. Patents CN1690065A, CN1690066A and CN1690067A report a conventional synthetic route of the compound of formula I:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
Inventor 张海平
Owner AVENTIS PHARMA HAINAN
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