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A kind of preparation method of ruxolitinib phosphate

A technology of arus phosphate and tinib, applied in the field of medicine, can solve the problems of low chiral purity, high cost of precious metal catalysts, unsuitable for scale-up production, etc., and achieve the effect of high yield

Active Publication Date: 2022-04-19
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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  • A kind of preparation method of ruxolitinib phosphate
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Compound 2)

[0056] Dissolve some 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in 3 volumes of N,N-diethylphenylacetamide, protect with nitrogen, lower the temperature below -10°C, and add sodium hydride in batches (1.05eq), after adding, raise the temperature to 20~25°C, stir for 1~2h, then control the temperature below -5°C, add dry 2-(trimethylsilyl)ethoxymethyl chloride dropwise (1.05eq), after dropping, raise the temperature to 20-25°C, react for 1-2h, monitor by TLC until the reaction is completed, add 6 times the volume of saturated ammonium chloride solution to quench the reaction. The precipitated solid was filtered, and the filter cake was washed with water and tertiary methyl ether. Blast drying at 40~45°C to obtain 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 95 %, purity ≥ 94.0%. used directly in the next reaction.

[0057] Mass ...

Embodiment 2

[0059] Preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 2)

[0060] Dissolve some 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in 4 volumes of N,N-diethylphenylacetamide, protect with nitrogen, lower the temperature below -10°C, and add sodium hydride in batches (1.05eq), after adding, raise the temperature to 20~25°C, stir for 1~2h, then control the temperature below -5°C, add dry 2-(trimethylsilyl)ethoxymethyl chloride dropwise (1.0eq), after dropping, raise the temperature to 20-25°C, react for 1-2h, monitor by TLC until the reaction is completed, add 6 times the volume of saturated ammonium chloride solution to quench the reaction. The precipitated solid was filtered, and the filter cake was washed with water and tertiary methyl ether. Blast drying at 40~45°C to obtain 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 91 %, purity ≥ 91.0%. used directly in the next reaction.

Embodiment 3

[0062] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl base)-7H-pyrrolo[2,3-d]pyrimidine (compound 3)

[0063] Dissolve some 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine in 4 volumes of dimethyl sulfoxide , under nitrogen protection, lower the temperature to below -10°C, add isopropylmagnesium chloride (1.05eq) dropwise, after the addition, raise the temperature to 0-5°C, stir for 1-2 hours, then control the temperature below 0-5°C, add After the addition of dry pinacol ester borate (1.05eq), react at 0-5°C for 1-2h, monitor by TLC until the reaction is complete, add 6 times the volume of saturated ammonium chloride solution to quench the reaction. Add 6 times the volume of ethyl acetate to the feed solution for extraction, wash with water, wash with saturated brine, dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain 4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-7-((2-(trimet...

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Abstract

The invention relates to a preparation method of ruxolitinib phosphate. The invention provides a new route for the preparation of ruxolitinib phosphate. The reaction route has a high split yield, up to 45%; the obtained multi-batch ruxolitinib The optical purity of the finished product of Cotinib can reach 99.8%, and the chemical purity can reach 99.7%; the post-treatment of the reaction is simple and does not require column chromatography; and with this route, the required raw materials or reagents and other substances are relatively easy to obtain, Compared with the prior art, the method of the invention is more economical and more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a novel ruxolitinib phosphate intermediate and a preparation method thereof, as well as a preparation method of ruxolitinib phosphate. Background technique [0002] Ruxolitinib Phosphate, jointly developed by Incyte and Novartis, was approved by the US FDA in November 2011, becoming the first approved drug for the treatment of myelofibrosis. [0003] Ruxolitinib phosphate is an antineoplastic drug. For intermediate- or high-risk primary myelofibrosis (PMF) (also known as chronic idiopathic myelofibrosis), myelofibrosis secondary to polycythemia vera (PPV-MF), or essential thrombocythemia Treatment of disease-related splenomegaly or disease-related symptoms in adult patients with myelofibrosis secondary to myelofibrosis (PET-MF). [0004] Its structural formula is as follows: [0005] [0006] The synthetic method of ruxolitinib phosphate reported at present is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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