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
View PDF2 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Longer reaction times are detrimen

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Melting pointaaaaaaaaaa
Login to view more

Abstract

The present invention relates to a method for synthesizing 4β-amino-4'-demethyl-4-deoxypodophyllotoxin of formula (1), which is characterized in that it comprises the following continuous steps: a) in pure weak acid or by acid reacting thiourea with 4β-haloacetamido-4'-desmethyl-4-deoxypodophyllotoxin in a mixture consisting of , water and an organic solvent but no other solvent at a temperature above ambient temperature; and b ) to recover 4β-amino-4'-demethyl-4-deoxypodophyllotoxin.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap