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Process for preparing intermediates for synthesis of antifungal agents

A compound and chiral compound technology, applied in bulk chemical production, organic chemistry, fermentation, etc., can solve the problems of high cost and low efficiency of prior art methods for tosylate intermediates

Inactive Publication Date: 2000-10-04
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Prior art methods for the preparation of tosylate intermediates are inefficient and require the use of costly chiral epoxidations to introduce the proper stereochemistry into the molecule. Therefore, there is a need to develop a method that overcomes the aforementioned prior art methods. Disadvantages of the chiral synthesis of this key intermediate

Method used

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  • Process for preparing intermediates for synthesis of antifungal agents

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0117] (4S)-(-)-4-Isopropyl-2-oxazolidinone (400 mg, 3.1 mmol) was dissolved in 4 ml THF and cooled to -78°C. 2ml (3.2mmol) of 1.6M n-butyllithium in hexane was added and the mixture was stirred at -78°C for 10 minutes to give a solution of the title oxazolidinone salt.

preparation example 2

[0119] step (a)

[0120] Allyl alcohol (6.25g, 31.53mmol), triethyl orthoacetate (20.46g, 126.12mmol) and 5 drops of propionic acid were mixed, the mixture was heated at 120°C, and 4ml of EtOH was collected by distillation. Heating was continued and excess triethyl orthoacetate (14ml) was distilled off to give a residue. The residue was mixed with KOH (3.5 g, 63 mmol), 16 ml MeOH and 4 ml water and stirred at room temperature overnight (@18 hours). Dilute the mixture with water and wash with cold CH 2 Cl 2 After washing, the aqueous layer was acidified to pH=3 by adding 0.1M HCl. Extract with 3 portions of EtOAc, combine the EtOAc extracts, wash with Na 2 SO 4 Drying and concentration afforded 6.75 g of the acid product. MS=213(M+H) + . step (b)

[0121] The acid product from step (a) (0.5 g, 2.36 mmol), KOH (0.13 g, 2.36 mmol) and 5 ml EtOH were combined and stirred at room temperature for 2 hours. Evaporation of the solvent gave a residue which was dissolved in...

preparation example 3

[0124] Allyl alcohol (5.37g, 31.58mmol) was dissolved in 50ml CH 2 Cl 2 and cool the resulting solution to 0-5 °C. Join PBr 3 (1.0 mL, 10.53 mmol), warmed to room temperature and stirred for 1 h while monitoring the reaction by TLC (silica gel, 25% EtOAc / hexanes). Add 50 ml of ice water, stir for 5 min, separate the layers and wash with MgSO 4 Dry the organic layer. Concentration in vacuo afforded 6.45 g of bromide product. MS=233M + .

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Abstract

Disclosed is a process for preparing chiral compounds of formula (I) wherein: X<1> and X<2> are independently F or Cl; and E is -SO2R<2>, wherein R<2> is C1-C6 alkyl, -C6H4CH3 or -CF3; its enantiomer and racemates thereof, useful in the synthesis of tetrahydrofuran azole antifungals. Novel compounds of formula (II) or (III) wherein: X<1> and X<2> are independently F or Cl; B represents -C(O)Q* or -CH2OR'; Q* represents a chiral auxiliary group; R'' represents a hydroxy protecting group; and A represents Cl, Br, I, triazolyl or imidazolyl; are also disclosed.

Description

background of the invention [0001] The invention relates to a preparation method of a chiral intermediate used for preparing trisubstituted tetrahydrofurantriazole or imidazole antifungal agent. [0002] WIPO publications WO 89 / 04829 and USP 5,039,676 disclose (±)-cis and (±)-trans antifungal compounds represented by the formula: Wherein: a is N or CH; X is F or Cl; Z is lower alkyl, (C 2 -C 8 ) alkanoyl or 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl substituted phenyl. Examples of such compounds are (±)-cis and (±)-trans-1-[4-[[2-(2,4-difluorophenyl)-2-[(1H-1,2,4-tri Azol-1-yl)methyl]tetrahydro-4-furyl]methoxy]phenyl]-4-(1-methylethyl)piperazine. [0003] In addition, PCT International Application PCT / US 92 / 08981 relates to antifungal compounds represented by the following formula and pharmaceutically acceptable salts thereof: Wherein: X is both F or Cl, or one X is F, and the other is Cl; Y is a group shown in the following formula: where: R 1 for (C 1 -C 10 ) Alkyl, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/63C07C69/65C07D263/26C07D307/12C07D405/06C07D413/06C07D417/06C07D521/00C12P7/04C12P7/62C12P41/00
CPCC07D405/06C07D417/06C07C69/63C07D231/12C12P7/62C12P41/004C07C69/65C07D307/12C07D263/26C07D233/56C07D249/08C07D413/06Y02P20/55
Inventor A·K·沙森纳V·M·吉里瓦华拉汉R·E·派克H·王R·罗维Y·-T·刘A·K·甘古利W·B·莫根A·沙克斯
Owner SCHERING AG
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