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Intermediate of siponimod and synthesis method thereof

A compound and generative technology, applied in the field of organic compound synthesis, can solve the problems of poor bromination selectivity, difficult to purify oily substances, and unsuitable for industrial production.

Pending Publication Date: 2021-05-04
SUZHOU KELUN PHARMA RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] However, the synthetic route I requires 7 steps of reaction, the operation is cumbersome, and the yield is low-cost, and the first step and the fourth step both use Grignard reagents, which require harsh reaction conditions of anhydrous and oxygen-free operation, so that industrial scale-up production Extremely difficult, so not suitable for industrial production
The product obtained in each step in the synthetic route II is an oily substance that is difficult to purify, and the hydrogenation in the third step requires high pressure and many by-products
Synthetic route III has the least number of steps, but the selectivity of bromination is poor and the product is difficult to purify as an oil, and it is difficult to industrialized production
The method provided by route IV is the same as that of synthetic route II, there are intermediates that are difficult to purify, and the reduction requires high pressure, which requires high equipment and safety
In other words, in the above synthetic routes, there are problems such as harsh reaction conditions, difficult purification of intermediate products, unsuitability for industrial production, and low yields.

Method used

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  • Intermediate of siponimod and synthesis method thereof
  • Intermediate of siponimod and synthesis method thereof
  • Intermediate of siponimod and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: Synthesis of N-((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)acetamide

[0072] In Example 1, X 1 and x 2 are both bromine and R is Ac.

[0073] Step a, synthesis of 4-bromo-3-trifluoromethyl benzyl alcohol

[0074]

[0075] 4-Bromo-3-trifluoromethylbenzoic acid (1.75g, 6.5mmol) was dissolved in THF (5ml), and a THF solution of borane dimethyl sulfide complex (2M, 6.5 ml, 13.0 mmol). After reacting at room temperature for 3 hours, the reaction solution was concentrated to dryness to obtain 1.65 g of a colorless oil with a yield of 99%, which was directly used in the next reaction without further purification.

[0076] Step b, synthesis of 4-bromo-3-trifluoromethylbenzyl bromide

[0077]

[0078] Dissolve 4-bromo-3-trifluoromethylbenzyl alcohol (1.65g, 6.5mmol) obtained in step a in acetic acid (3.3ml), add 33% HBr in acetic acid solution (9ml) at room temperature, add ethyl Anhydride (0.9 g). Then react overnight at room temperature. Subsequent...

Embodiment 2

[0091] Example 2: Synthesis of tert-butyl 4-cyclohexyl-3-trifluoromethylbenzylhydroxycarbamate

[0092] In Example 2, X 1 and x 2 are bromo, and R is Boc.

[0093] Step a and step b are carried out in the same manner as in Example 1.

[0094] Step c, synthesis of ((4-bromo-3-trifluoromethyl)benzyl)oxycarbamate tert-butyl ester

[0095]

[0096] Dissolve tert-butyl N-hydroxycarbamate (0.79g, 5.9mmol) in THF (5ml), add potassium carbonate (0.81g, 5.9mmol) and stir at room temperature for 1h. Subsequently, a solution of 4-bromo-3-trifluoromethylbenzyl bromide (1.88 g, 5.9 mmol) obtained in step b in THF (5 ml) was added and reacted overnight at room temperature. Then the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain a yellow oil (2.0 g), with a yield of 92%, which was directly used in the next reaction without further purification.

[0097] Step d, synthesis of tert-butyl 4-cyclohex-1-enyl-3-trifluoromethylbenzylhydroxycarbamate ...

Embodiment 3

[0105] Embodiment 3: the synthesis of formula 2A-Ac and 2A-Boc compound

[0106] The present invention also proposes the following specific synthetic routes:

[0107]

[0108] Step a1: Synthesis of 4-bromo-3-trifluoromethylbenzyl bromide (2A-3')

[0109] 4-Bromo-3-trifluoromethyltoluene (3A-1') (0.51g, 2.1mmol) was dissolved in carbon tetrachloride (30ml), and AIBN (0.07g, 0.4mmol) and NBS ( 0.38g, 2.1mmol), heated to 80°C and reacted overnight. After the reaction was completed, DCM (30ml) was added, filtered, and the filtrate was concentrated to dryness. The crude product was mixed with silica gel and passed through the column to obtain 0.2 g of a colorless oil.

[0110] The 4-bromo-3-trifluoromethylbenzyl bromide (2A-3') obtained in the above steps is subsequently carried out from step c to step e in the above Example 1, thereby obtaining the compound of formula 2A-Ac;

[0111] Alternatively, the 4-bromo-3-trifluoromethylbenzyl bromide (2A-3') obtained in the above s...

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Abstract

The invention relates to a novel intermediate compound (a compound as shown in a formula 2A) of siponimod, a synthesis method of the novel intermediate compound, and a method for synthesizing siponimod by adopting the compound as shown in the formula 2A. Specifically, 3-trifluoromethyl-4-halogenated benzoic acid or 3-trifluoromethyl-4-halogenated toluene is taken as an initial raw material and is subjected to reduction, bromination, coupling, substitution and reduction to obtain a compound as shown in a formula 2A, and R is Boc or Ac.

Description

technical field [0001] The invention relates to the field of organic compound synthesis, in particular to a method for synthesizing siponimod intermediates and corresponding intermediate compounds. Background technique [0002] Siponimod (Compound name: 1-{4-1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}- Azetidine-3-carboxylic acid) is a sphingosine-1-phosphate (S1P) receptor modulator for the treatment of immune diseases such as multiple sclerosis. On March 26, 2019, it was officially approved by the US FDA for the treatment of human Relapsing multiple sclerosis, including clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), active secondary progressive multiple sclerosis (SPMS), etc. Its structural formula is as follows: [0003] [0004] At present, among the existing methods for synthesizing siponimod, it is mainly the synthesis method disclosed in the patent application CN104105687B by its original research c...

Claims

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Application Information

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IPC IPC(8): C07C259/06C07C291/02C07D205/04
CPCC07C259/06C07C291/02C07D205/04C07C2601/14
Inventor 周海亮田辉巫循伟马帅吴灵静王晶翼
Owner SUZHOU KELUN PHARMA RES CO LTD
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