Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

An improved process for the preparation of boronic acid esters

A compound, selected technology, applied in the field of preparing crystalline forms of bortezomib, which can solve the problems of being unsuitable for commercial scale, etc.

Inactive Publication Date: 2019-10-08
FRESENIUS KABI ONCOLOGY LTD
View PDF13 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, lengthy work-up procedures at several stages and / or preparation of typical intermediates make this method unsuitable for commercial scale

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
  • An improved process for the preparation of boronic acid esters
  • An improved process for the preparation of boronic acid esters
  • An improved process for the preparation of boronic acid esters

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0075] Salts of compounds may be prepared according to general standard methods of salt preparation known in the art.

[0076] As used herein, the term "single-phase solvent system" refers to a solvent system that uses only a single solvent during a reaction.

[0077] The term "boronic acid acceptor" as used herein refers to an agent that promotes the cleavage of the ester bond of the boronic acid moiety and releases pinanediol. Those skilled in the art are familiar with the selection of boronic acid acceptors and will appreciate that many different boronic acid acceptors are known in the art such as isobutylboronic acid, isopropylboronic acid, 2-methyl-1-propylboronic acid, boronic acid acceptor The suitability of the individual or otherwise depends on the specific synthetic scheme of the scheme.

[0078] The term "compound of formula I free of deboronation and dimer impurities" refers to a compound of formula I in which these impurities are not detected by HPLC measurement....

Embodiment

[0141] In order to demonstrate the benefit of this specification, an example of the prior art was performed and shown as a reference example.

[0142] X-Ray Powder Diffraction (XRPD): XRPD analysis was performed on a Panalytical, Model-Empyrean X-Ray powder diffractometer. The instrument parameters are as follows:

[0143]

[0144] Use (Chiralpak AD-H post, measure chiral purity by HPLC, parameter is as follows:

[0145]

[0146]

Embodiment -1

[0148] Preparation of (1S, 2S, 3R, 5S)-pinanediol N-BOC-L-phenylalanine-L-leucine boronate (formula I)

[0149] Boc-L-phenylalanine (100 g) was added to a mixture of acetonitrile (1000 mL), diisopropylethylamine (146.1 g) and TBTU (145.2 g) at a temperature range of -10 to 5 degrees Celsius. The trifluoroacetate salt of pinanediol-leu-boronate (143 g) was added and the reaction mixture was stirred at a temperature ranging from -5 to 5°C for 2 hours.

[0150] Distilled water (1500 mL) was added to the reaction mixture at 10 to 30 degrees Celsius and stirred at 20 to 30 degrees Celsius for 1-2 hours. The resulting solid was filtered, washed with distilled water (2 x 400 mL) and dried in vacuo. The solid was recrystallized from a mixture of acetonitrile and water.

[0151] Yield: 93.3% (180g)

[0152] HPLC purity: ~99.8%

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
chiral purityaaaaaaaaaa
chiral purityaaaaaaaaaa
Login to View More

Abstract

The present invention relates to an improved process for the preparation of a compound of formula (I), wherein PG1 may be independently selected from tert-butyloxycarbonyl (Boc), phthaloyl, 9-fluorenylmethyloxycarbonyl (Fmoc), triphenylmethyl (Trityl), carboxybenzyl (Cbz), trifluoroacetyl, benzyl (Bn), benzylidene, methanesulfonyl (Mesyl), toluene sulfonyl (Tosyl) or acyl; its isolation as solid and use for the preparation of the compound of formula (IV), in particular the compound of formula (IV) i.e. [(1R)-3-methyl-1[[(2S)-1-oxo-3-phenyl-2- [(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid with more than 99.95% chiral purity, as measured by HPLC.

Description

[0001] field of invention [0002] The present invention relates to an improved process for the synthesis of compounds of formula I of bortezomib. [0003] [0004] of which PG 1 can be independently selected from tert-butoxycarbonyl (Boc), phthaloyl, 9-fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trityl), carboxybenzyl (Cbz), trifluoro Acetyl, benzyl (Bn), benzylidene, mesyl (Mesyl), tosyl (Tosyl) or acyl. [0005] The present invention also relates to improved processes for converting compounds of formula I to compounds of formula III. [0006] [0007] The present invention also relates to an improved process for the synthesis of bortezomib from compounds of formula I or III. [0008] The present invention further relates to a process for the preparation of a crystalline form of bortezomib characterized by an X-ray powder diffraction pattern having peaks at 6.11, 12.18, 17.25, 18.98, 19.22, 24.55, 24.39 ± 0.2 degrees 2Θ. The crystalline form of bortezomib of th...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/025C07B2200/07
Inventor M·K·潘迪R·N·逖瓦利S·舒克拉S·S·索希G·辛格S·拉西里W·卡布里
Owner FRESENIUS KABI ONCOLOGY LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com