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Method for preparing 4beta;-amino-4'-demethyl-4-desoxypodophyllotoxin

A deoxypodophyllotoxin and demethylation technology, applied in organic chemistry and other fields, can solve problems such as by-products and unfavorable reaction time

Inactive Publication Date: 2008-07-16
PIERRE FABRE MEDICAMENT SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Longer reaction times are detrimental to purity and by-products occur

Method used

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  • Method for preparing 4beta;-amino-4'-demethyl-4-desoxypodophyllotoxin
  • Method for preparing 4beta;-amino-4'-demethyl-4-desoxypodophyllotoxin
  • Method for preparing 4beta;-amino-4'-demethyl-4-desoxypodophyllotoxin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1 : Preparation of 4β-chloroacetamido-4'-desmethyl-4-deoxypodophyllotoxin (Formula 3).

[0065] 0.5 mL of concentrated sulfuric acid was added dropwise to a suspension of 30 g (0.075 mol) of 4'-desmethylepipodophyllotoxin in 47.5 mL (0.75 mol) of chloroacetonitrile at ambient temperature. It was stirred at this temperature for 1 h, dissolved, and reprecipitation was observed. Add 300 mL of 2-propanol. The precipitate was filtered and rinsed with 200 mL of 2-propanol and water to return to pH 7. The resulting white solid was dried under vacuum at 40°C to afford 32.9 g of the chloroacetamido compound of formula 3, or a molar yield of 93%.

[0066] Melting point F=240°C.

[0067] NMR analysis of protons: 1 H RMN(DMSO)δ8,65(d,1H,J=7Hz,NH),8,26(s,1H,4'-OH),6,78(s,1H,H 5 ), 6,54(s, 1H, H 8 ), 6, 24(s, 2H, H 2′ , H 6′ ), 5,99 (d, 2H, J=11.3Hz, OCH 2 O), 5, 17 (dd, 1H, J=4, 56 and 7Hz, H 4 ), 4,51 (d, 1H, J=5,2Hz, H 1 ), 4, 29 (t, 1H, J=8Hz, H 11a ), 4...

Embodiment 2

[0072] Example 2 : Preparation of 4β-amino-4'-desmethyl-4-deoxypodophyllotoxin (formula 1) - method using pure glacial acetic acid - first method according to the invention

[0073] Table 1: No. 2.

[0074] A suspension of 17 g (0.0358 mol) of 4β-chloroacetamido-4'-demethyl-4-deoxypodophyllotoxin obtained in Example 1 in 75 mL of glacial acetic acid was heated to 80° C. under stirring. Add 4.2 g (0.0537 mol) thiourea in one portion. It was stirred at this temperature for 1 hour and 30 minutes, dissolved, and reprecipitation was observed. The reaction medium was filtered hot and rinsed with 75 mL of glacial acetic acid and diisopropyl ether. The resulting white solid was dried under vacuum at 40° C. to afford 14.6 g of the compound of formula 1 as the hydrochloride salt, corresponding to a molar yield of 93%.

[0075] Melting point F>260°C.

[0076] NMR analysis of protons: 1 H RMN(DMSO)δ8,63(m,2H),8,32(m,1H),7,23(s,1H,H 5 ), 6,60(s, 1H, H 8 ), 6, 18(s, 2H, H 2′ , H ...

Embodiment 3

[0077] Example 3 : Preparation of 4β-amino-4'-desmethyl-4-deoxypodophyllotoxin (formula 1) - method using ethanol and 1N hydrochloric acid - first possibility of the first variant of the second method according to the invention alternative plan.

[0078] Table 1: No. 3.

[0079] A suspension of 0.5 g (1.05 mmol) of 4β-chloroacetamido-4'-demethyl-4-deoxypodophyllotoxin obtained in Example 1 in a mixture of 2.5 mL of ethanol and 1 mL of 1N hydrochloric acid was The temperature was raised to 80°C with stirring. 0.12 g (1.57 mmol) thiourea was added in one portion. It was stirred at this temperature for 9 hours, dissolved, and reprecipitation was observed. The cooled reaction medium is filtered, rinsed with ethanol and diisopropyl ether. The resulting white solid was dried under vacuum at 40° C. to afford 0.4 g of the compound of formula 1 as the hydrochloride salt, corresponding to a molar yield of 90%.

[0080] Melting point F>260°C.

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Abstract

The invention relates to a method for synthesizing 4&bgr;-amino-4′-demethyl-4-desoxypodophyllotoxin of formula (1), characterized by comprising the following successive steps: a) reacting, in a pure weak acid or in a mixture consisting of acid, water and of organic solvent, without another solvent, at a temperature higher than the ambient temperature, thiourea with 4&bgr;-halogenoacetamido-4′-demethyl-4-desoxypodophyllotoxin, and; b) recovering the 4&bgr;-amino-4′-demethyl-4-desoxypodophyllotoxin.

Description

technical field [0001] The present invention relates to a 4β-haloacetamido-4'-demethyl-4-deoxypodophyllotoxin (X=Cl, Br or I) of formula 3 by cleavage in the presence of thiourea and acid Process for the preparation of 4β-amino-4'-desmethyl-4-deoxypodophyllotoxin of formula 1. Specifically, the present invention relates to a 4'-desmethyl epipodophyllotoxin of formula 2 via 4β-haloacetamido-4'-demethyl-4-deoxypodophyllotoxin of formula 3 (X= Cl, Br or I) Process for preparing 4β-amino-4'-desmethyl-4-deoxypodophyllotoxin of formula 1. [0002] [0003] Formula 1 Formula 2 [0004] [0005] Formula 3 Formula 4 Background technique [0006] 4β-Amino-4'-desmethyl-4-deoxypodophyllotoxin is a synthetic intermediate useful for the preparation of anticancer compounds (French Patent Application No. 0404053). [0007] The strategy for the preparation of this intermediate is based on the conversion of 4'-desmethylepipodophyllotoxin (Formula 2) to 4β-azido-4'-desmethyl-4-deoxyp...

Claims

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Application Information

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IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 伊夫·古明斯基马夏尔·格鲁索蒂埃里·安贝特
Owner PIERRE FABRE MEDICAMENT SAS
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