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Preparation method of ruxolitinib phosphate

A technology of aloth phosphate and tini, which is applied in the field of medicine, can solve the problems of low chiral purity, high cost of noble metal catalysts, unsuitable for scale-up production, etc., and achieve high yield

Active Publication Date: 2022-02-15
南京佰麦生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Method 3: In the literature Angew.Chem.Int.Ed.2015,54,7149–7153, compound 2 is used as the starting material, and compound 3 is added under the catalytic conditions of metal rhodium and chiral ligand to obtain a chiral compound intermediate 4. The starting material compound 2 of this route is not easy to obtain, the purification of intermediates is difficult, the chiral purity is not high, and the cost of noble metal catalysts used is high, which is not suitable for scale-up production

Method used

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  • Preparation method of ruxolitinib phosphate

Examples

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Effect test

Embodiment 1

[0055] Preparation of 4-chloro-7 - ((2- (trimethylsiliconyl) ethoxy) methyl) -7H-pyrrole [2,3-D] pyrimidine (Compound 2)

[0056] First, several 4-chloro-7H-pyrrols are first soluble in 3x volume N, N-diethylthycelamide, nitrogen protection, cooling - 10 ° C or less, sodium hydride is added. (1.05 eq), after the addition, the temperature is warmed to 20 to 25 ° C, stirred for 1 to 2 h, then control the temperature of -5 ° C or lower, dried 2- (trimethylsilyl) ethoxymethyl chloride (1.05 eq), after the bet is finished, the temperature is 10 to 25 ° C, the reaction is 1 to 2 h, TLC monitors to the end reaction, and 6-fold volume saturated ammonium chloride solution is added to quench the reaction. Map the precipitated solid, the filter cake was washed with water and a tertiary ether. 40 ~ 45 ° C drying, 4-chloro-7 - ((2- (trimethylsilicilicidal) ethoxy) methyl) -7H-pyrrole [2,3-D] pyrimidine, yield 95 %, Purity ≥ 94.0%. Directly used in the next reaction.

[0057] Mass spectrum figu...

Embodiment 2

[0059] Preparation of 4-chloro-7 - ((2- (trimethylsiliconyl) ethoxy) methyl) -7H-pyrrole [2,3-D] pyrimidine (Compound 2)

[0060] First, several 4-chloro-7H-pyrrols [2,3-D] pyrimidine are dissolved in 4x volume N, N-diethylcene amide, nitrogen protection, cooling - 10 ° C or lower, sodium hydride is added batch (1.05 eq), after the addition, the temperature is warmed to 20 to 25 ° C, stirred for 1 to 2 h, then control the temperature of -5 ° C or lower, dried 2- (trimethylsilyl) ethoxymethyl chloride (1.0 Eq), after the bet is finished, the temperature is 20 to 25 ° C, the reaction is 1 to 2 h, and TLC is monitored to the end reaction, and the addition of 6-fold volume saturated ammonium chloride solution is added to quench the reaction. Map the precipitated solid, the filter cake was washed with water and a tertiary ether. 40 ~ 45 ° C blast drying, 4-chloro-7 - ((2- (trimethylsilica) ethoxy) methyl) -7H-pyrrole [2,3-D] pyrimidine, yield 91 %, Purity ≥ 91.0%. Directly used in the ...

Embodiment 3

[0062] 4- (4,4,5,5-tetramethyl-1,3,2-dioxolacytic ring-2-yl) -7 - ((2- (trimethylsiliconyl) ethoxy) Base) -7H-pyrrole and [2,3-D] pyrimidine (Compound 3)

[0063] First, several 4-chloro-7 - ((2- (trimethylsilicilicidal) ethoxy) methyl) -7H-pyrrol is first soluble in 4x volume dimethyl sulfoxide , Nitrogen protection, cooling to -10 ° C or lower, dripping isopropyl magnesium chloride (1.05 eq), after completion, temperature rise to 0 ~ 5 ° C, stir the reaction 1 to 2 h, then control temperature 0 ~ 5 ° C or less, add The dry boronic acid-cell-ravate (1.05 eq), after the addition, 0 to 5 ° C for 1 to 2 h, TLC monitored to the end reaction, 6-fold volume saturated ammonium chloride solution to quench the reaction. 6x glycetate extraction, water washing, saturated brine washing, water washed, mixed with water, filtered, concentrated under reduced pressure to concentrate 4- (4, 4, 5, 5-tetramethyl-1, 3, 2) - Dioxolam-2-yl) -7 - ((2- (trimethylsilicilicide) ethoxy) methyl) -7H-pyrrol [...

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Abstract

The invention relates to a preparation method of ruxolitinib phosphate. The invention provides a new route for preparing rucotinib phosphate, and the reaction route is high in resolution yield which can be up to 45%. The optical purity of the obtained multiple batches of ruxolitinib phosphate finished products can reach 99.8%, and the chemical purity can reach 99.7%. Post-treatment of the reaction is simple, and column chromatography is not needed. By adopting the route, the required raw materials or used reagents and other substances are easy to obtain. Compared with the prior art, the method disclosed by the invention is more economical and more suitable for industrial production.

Description

Technical field [0001] The present invention belongs to the field of medical technology, and more particularly to a novel phosphate replacement intermediate body, and a method of preparation of rug replacement of phosphate. Background technique [0002] RuxolitiniB Phosphate, RUXOLITINIB Phosphate, has been developed from IncyTE and Novartis, approved by US FDA in November 2011, became the first drug for the treatment of bone marrow fibrosis. [0003] Lutinibi is anti-tumor drug. Primary bone marrow fibrosis (PMF) (also known as chronic idiomy bone marrow fibrosis), bone marrow fibrosis (PPV-MF) or primary platelets increased by severe red blood cells The bone marrow fibrosis (PET-MF) of the symptoms, the treatment of relevant disease-related splenometers or disease-related symptoms. [0004] Its structural formula is as follows: [0005] [0006] The alternative synthesis method that has been reported is as follows: [0007] Method 1: Document OL.2009, 11 (9), 1999-2002, based...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/07
Inventor 蒋玉伟华德智李浩冬李桃园米多龙
Owner 南京佰麦生物技术有限公司
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