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Preparation of posaconazole intermediates

A technology of cis isomer and trans isomer, applied in the field of preparation of chiral compounds

Inactive Publication Date: 2013-01-23
SANDOZ LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, by methods known in the literature, compounds of formula (IX) and salts thereof, especially wherein Y 1 and Y 2 Compounds of formula (IX), both F, were not obtained as at least partially crystalline compounds

Method used

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  • Preparation of posaconazole intermediates
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  • Preparation of posaconazole intermediates

Examples

Experimental program
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Effect test

Embodiment approach

[0123] According to another preferred embodiment of the present invention, the compound of formula (III) obtained from step (2) is suitably reduced to obtain the compound of formula (IV):

[0124]

[0125] The reduction in step (3) can be carried out according to any suitable method involving any suitable reducing agent. According to the invention, preference is given to using hydride reducing agents. Such hydride reducing agents are for example sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ), lithium aluminum hydride (LiAlH4 ), diisobutylaluminum hydride (DIBAL) or lithium triethylborohydride (LiEt 3 BH). According to a preferred embodiment of the present invention, use LiBH in step (3) 4 as a reducing agent.

[0126] According to the prior art, at least 3 molar equivalents of LiBH must be used relative to the compound of formula (III) 4 . Reference may be made to WO 94 / 25452, page 31, section "Preparation 5". However, contrary to the teaching of the pr...

Embodiment 1

[0259] Embodiment 1: the preparation of formula (IX) compound

[0260] (a) preparation of formula (IIa) compound

[0261] 3.8g Mg was suspended in 20ml MTBE. The temperature of the suspension was 55°C. Then, 0.5 g of Grignard reagent (CH 3 ) 3 Si-CH 2 MgCl was added to dry the system (if this Grignard reagent was not available in the first batch, commercially available 1.0 M solution from Sigma-Aldrich in diethyl ether (CH 3 ) 3 Si-CH 2 MgCl (CAS registry number: 13170-43-9)), followed by the addition of 1.0 ml of chloromethyltrimethylsilane (CM-TMS; CAS registry number: 2344-80-1; commercially available from Sigma-Aldrich). A solution of 14 ml CM-TMS in 43 ml MTBE was added slowly over 2 hours at a temperature of 55°C. The mixture was stirred at 55°C for 2 hours and then cooled to a temperature of -10°C. Then 10.0 g of commercially available compound of formula (Ia) (CAS registry number: 51336-94-8; commercially available from Sigma-Aldrich) in 30 ml of MTBE was adde...

Embodiment 2

[0275] Embodiment 2: the preparation of the salt of formula (IX) compound

[0276] (a) Preparation of hydrochloride

[0277] 10.0 g of the compound of formula (IXa) obtained in Example 1(f) before crystallization as a crude oil was dissolved in 200 ml of acetone at 30-40° C. with stirring. The resulting solution was cooled to 25-30°C. Then HCl (10 wt%) in MTBE was added within 15 min at 25-30°C. A solid crystallized when the mixture was stirred for 15 min. Then 200ml MTBE was added slowly over 30min. The suspension was cooled to 0°C to -5°C and stirred for 2 hours. The product was filtered and the wet cake was washed with 20ml MTBE. After drying under vacuum at 70° C., the HCl salt of compound (IXa) was obtained as a colorless solid. The yield was 9.5 g, corresponding to 85.0% of theory.

[0278] The HCl salt of the compound of formula (IXa) was obtained as a mixture of the cis isomer and the corresponding trans isomer in a cis:trans ratio of 9:1.

[0279] (b) Preparat...

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Abstract

The present invention relates to process for the preparation of a chiral compound of formula (IX) or a salt thereof, wherein Y1 and Y2 are independently F or C1, preferably F, the crystalline compound of formula (IX) as such, and its use for the preparation of an antifungal agent.

Description

[0001] The present invention relates to the preparation of chiral compounds, especially the preparation of chiral compounds that can be used as intermediates to prepare antifungal agents, preferably posaconazole. Background technique [0002] Posaconazole (CAS Registry No. 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4- [[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-tri Azol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol ) is a triazole antifungal represented by the structure: [0003] [0004] Posaconazole is indicated in immunocompromised patients and / or in patients with disease refractory to other antifungal agents such as amphotericin B (amphotericin B), fluconazole, or itraconazole and / or in response to these antifungal agents For example, prophylaxis and / or treatment caused by Candida, Mucor, Aspergillus, Fusarium or Coccidioides in patients who do not tolerate the drug inv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06
CPCC07D405/06C07D405/14A61P31/10C07D249/08
Inventor D·德苏扎S·V·乔西S·布塔A·C·派斯D·N·查万S·D·麦特卡尔
Owner SANDOZ LTD
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