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Synthesis method of siponimod intermediate

A synthetic method and intermediate technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of easy agglomeration of finished products, high production costs, and long synthetic routes, and achieve the effects of easy scale-up production, low production costs, and short synthetic routes

Pending Publication Date: 2022-01-07
成都科圣原医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Its disadvantages are: the synthetic route is too long, and the production cost is high; and the trifluorinated reagent is very expensive, and the reaction risk is high
[0010] Its disadvantages are: direct reduction of carboxylic acid to alcohol with lithium tetrahydrogen aluminum, high risk of reaction, bromination of carbon tetrabromide and triphenylphosphine, there are a large number of by-products of triphenylphosphine oxide, which is difficult to remove
[0011] Moreover, the conventional ones on the market are 1 / 2 oxalate or hydrochloride. The finished product is easy to form agglomerates and is not easy to disperse, which affects the yield and product quality.

Method used

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  • Synthesis method of siponimod intermediate
  • Synthesis method of siponimod intermediate
  • Synthesis method of siponimod intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] A kind of synthetic method of Siponimod intermediate, comprises the steps:

[0041] a) Esterification reaction: compound 1 reacts with methanol under concentrated sulfuric acid conditions to obtain compound 2;

[0042] b) Reduction reaction: compound 2 reacts with absolute alcohol and tetrahydrofuran under reducing agent conditions to obtain compound 3; the absolute alcohol is any one of absolute ethanol, isopropanol, methanol or tert-butanol, the resulting The reducing agent is one of sodium borohydride, potassium borohydride, lithium borohydride or boron trifluoride ether;

[0043] c) bromination reaction: compound 3 reacts with hydrobromic acid to obtain compound 4;

[0044] d) Coupling reaction: compound 4 reacts with N-hydroxyphthalimide to obtain compound 5;

[0045] e) Deprotection reaction: compound 5 reacts with methanesulfonic acid to obtain compound 6;

[0046] Among them, the structure of compound 1 is 4-cyclohexyl-3-(trifluoromethyl)benzoic acid;

[0...

Embodiment 2

[0056] This implementation carried out relevant parallel tests of the synthesis of Siponimod intermediates:

[0057] The specific operation for the synthesis of compound 2 in this example is as follows: add compound 1 and methanol into the reaction flask, add concentrated sulfuric acid under stirring, and stir until the reaction is complete; add 5 times the volume of water to the reaction solution, add methyl tert-butyl extracted with base ether, dried, and concentrated under reduced pressure to obtain compound 2.

[0058] The synthetic operation of compound 3 is as follows:

[0059] b1. Install a 0-100°C thermometer, mechanical stirring and liquid seal on a clean and dry reaction kettle, and inject nitrogen gas;

[0060] b2. Add 90 mL of anhydrous alcohol and 90 mL of tetrahydrofuran, start stirring, add 31.26 mmol of compound 2, and then add the reducing agent according to the molar ratio of reducing agent to compound 2 (2-3):1;

[0061] b3. After the addition, slowly heat...

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Abstract

The invention relates to the field of synthesis of drug intermediates, and discloses a synthesis method of a siponimod intermediate, which comprises the following steps of: synthesizing a compound 1 by using a bromide material with trifluoromethyl, esterifying carboxylic acid by using the compound 1, then reducing by using sodium borohydride, finally brominating by using hydrogen bromide, and carrying out coupling reaction to obtain a compound 5. The compound 5 is acidized into salt by using methanesulfonic acid, the salt is easier to form by using the methanesulfonic acid, the solids are easier to separate out and not easy to cake, the uniformity of the texture of the intermediate is met, and the obtained finished product is better in state, easier to disperse and not easy to wrap with a solvent. The problem that solids are not easy to take out after hydrochloric acid is adopted for salifying, and the problem that solids are easy to cake when 1 / 2 oxalate is adopted are solved.

Description

technical field [0001] The invention relates to the field of synthesizing pharmaceutical intermediates, in particular to a method for synthesizing siponimod intermediates. Background technique [0002] Siponimod (Siponimod) was developed by Novartis and launched in the United States on March 26, 2019. It is mainly used for the treatment of adult patients with relapsing multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsed Remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS). Siponimod (Siponimod) is a sphingosine-1-phosphate (S1P) receptor modulator. Has high affinity to SlP receptors 1 and 5, prevents lymphocyte outflow from lymph nodes, thereby reducing the number of lymphocytes in the peripheral blood. [0003] In the prior art, the synthetic methods adopted by the siponimod intermediate are: [0004] 1. In the presence of a copper catalyst, compound A04 is reacted with a trifluoromethylation reagent, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C239/20C07C309/04C07C303/32C07D209/48C07C17/16C07C22/08C07C29/147C07C33/50C07C67/08C07C69/78
CPCC07C239/20C07C309/04C07C303/32C07D209/48C07C17/16C07C29/147C07C67/08C07C2601/14C07C69/78C07C33/50C07C22/08
Inventor 李久军龚万鑫寿越晗付薇
Owner 成都科圣原医药科技有限公司
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