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Process for ixabepilone, and intermediates thereof

一种选自、化合物的技术，应用在有机化学等方向，能够解决昂贵负担、重大等问题

Inactive Publication Date: 2016-02-03
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, if arsenic-containing reagents are used in API manufacture, the manufacturer will bear the significant (and expensive) burden of controlling arsenic levels to acceptable levels

Method used

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  • Process for ixabepilone, and intermediates thereof
  • Process for ixabepilone, and intermediates thereof
  • Process for ixabepilone, and intermediates thereof

Examples

Experimental program
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preparation example Construction

[0156] Unlike other routes for the preparation of ixabepilone, the method described herein does not require triphenylarsenic (AsPh 3 )The presence. Triphenylarsenic is an organic compound of arsenic, and arsenic is known to be toxic. Unexpectedly, in the described embodiments, a rapid and efficient Suzuki reaction occurs in the absence of arsenic-containing catalysts. This result is particularly beneficial for the safety of production personnel and the management of waste associated with avoiding arsenic-containing toxic chemicals.

[0157] Furthermore, the Suzuki reaction described herein coupling compound II and compound III to provide product IV gave higher yields than the method described in J. Org. Chem. 2001, 66, 4369-4378. For example, when N-BOC-protected amine IIIa' is coupled with IIax', >90% yields can usually be obtained. In contrast, the yield of the coupling of N-BOC-protected amine IIIa' to compound D2a reported in J.Org.Chem. 2001, 66, 4369-4378 was only 10%...

Embodiment 1

[0310] Example 1 - Preparation of XIXa and XIXa'

[0311] Preparation of compound XVIII'

[0312]

[0313] in N 2 To a solution of compound XVI' (100 g, 389 mmol) in anhydrous DCM (800 mL) was added dropwise Et at room temperature under atmosphere. 3 N (73 mL, 506 mmol) and TBSOTf (113 g, 428 mmol). The resulting mixture was stirred overnight at room temperature (Solution A). In another flask, under N 2 To a solution of XVII (80 g, 622 mmol) in anhydrous DCM (500 mL) was added TiCl at -78 °C under atmosphere 4 (IN in DCM, 650 mL, 650 mmol). After stirring at -78°C for 10 minutes, solvent A was added dropwise to XVII over about 1 hour, and the resulting mixture was allowed to warm to room temperature and then stirred overnight. After the completion of the reaction was demonstrated by TLC, the reaction mixture was washed with saturated NH 4 Aqueous Cl solution was quenched, and the aqueous layer was extracted with DCM (400 mL×2). The combined organic layers were washe...

Embodiment 2

[0329] Example 2 - Preparation of XIVax

[0330] Preparation of XIa

[0331]

[0332] in N 2 To a solution of C-C29a (35 g, 200 mmol, Rf=0.5, EtOAc:petroleum ether 1:3, UV) in anhydrous THF (414 mL) was added (R)-tert-butylsulfinate under atmosphere and at room temperature Amide (29g, 400mmol) and Ti(i-PrO) 4 (118 mL, 400 mmol), then the reaction mixture was stirred overnight. The mixture was cooled to 5°C with an ice bath and brine (150 mL) was added carefully. The resulting suspension was diluted with EtOAc (100 mL), filtered through a pad of diatomaceous earth, and the filter cake was washed twice with EtOAc (150 mL). The filtrate was washed with brine (3x260mL), washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc:petroleum ether=1:5) to yield XIa (42 g, yield: 77%, Rf=0.4, EtOAc:petroleum ether=1:3, UV) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )δ8.25(s,1H),7.31(s,1H),7.0...

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Abstract

The present invention relates to a novel process of making ixabepilone, ixabepilone derivatives and analogues, and intermediates thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 61 / 775,461 (filed March 8, 2013) and Chinese Patent Application No. 201410077611.6 (filed March 4, 2014), each of which is incorporated by reference All incorporated herein. [0003] Claims of title to inventions made under federally funded research and development [0004] Not applicable [0005] References to Sequence Listings, Tables, or Computer Program Attachments Submitted on CD-ROM [0006] Not applicable Background of the invention [0007] Ishape (International Nonproprietary Name (INN): ixabepilone) is an injectable antineoplastic agent belonging to the epothilone class. It is a synthetic derivative of the natural product ebolamycin B (also known as EpoB), in which the oxygen atom of the alicyclic ring in the macrocycle is replaced by a nitrogen atom, thereby obtaining the corresponding macrocyclic lactam. The chemical name of Ix...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C07D491/044C07D285/14
CPCC07D491/044
Inventor J·P·亨施克陈悦萧宗育
Owner SCINOPHARM TAIWAN LTD
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