The synthetic method of slx-2119

A technology of slx-2119 and a synthesis method, which is applied in the synthesis field of SLx-2119, can solve the problems of high cost, unfriendly environment, high price and the like, and achieves the effects of low cost, environmental friendliness and short reaction route.

Active Publication Date: 2019-06-04
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although this route only needs five steps of reaction to obtain the target product, it uses expensive dihydroxyphenyl borate, Pd(dppf)Cl 2 and reagents such as 2,4 dihydroquinazoline, the cost is high, and heavy metal palladium is also used in the reaction, which is not friendly to the environment

Method used

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  • The synthetic method of slx-2119
  • The synthetic method of slx-2119
  • The synthetic method of slx-2119

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) Preparation of 2-bromo-N-isopropylacetamide I:

[0037]

[0038] In a 25mL round bottom flask, add dichloromethane (5mL) and isopropylamine (1.2mmol) successively, plug a rubber stopper, and protect with nitrogen; under stirring in an ice-water bath, bromoacetyl bromide (1mmol) After dropping, turn to room temperature and stir after 5 minutes, and detect the reaction by TLC after 1 hour. After the bromoacetyl bromide disappears, stop stirring, filter off the white solid, and wash with dichloromethane, add dilute hydrochloric acid solution to the filtrate for washing, two The organic layer was extracted with methyl chloride, washed with saturated brine, anhydrous Na 2 SO 4 Drying, spin-drying, and column chromatography gave 2-bromo-N-isopropylacetamide I as a white solid (yield 71%), 1 H NMR (500MHz, CDCl 3 ) δ (ppm): 6.39 (br, NH, 1H), 4.11-4.04 (m, 1H), 3.84 (s, 2H), 1.19 (d, J=6.0Hz, 6H).

[0039] (2) Preparation of 3-(isopropylcarbamoyl-methoxy)-methyl ben...

Embodiment 2

[0058] (1) Preparation of 2-bromo-N-isopropylacetamide Ⅰ: Add dichloromethane (1mL) and isopropylamine (1mmol) successively in a 25mL round bottom flask, put on a rubber stopper, and protect under nitrogen; Under stirring in an ice-water bath, drop bromoacetyl bromide (1 mmol) within 2 minutes. After 5 minutes, stir at room temperature. After 1 hour, the reaction was detected by TLC. After the bromoacetyl bromide disappeared, stop stirring, filter off the white solid, and use Washing with dichloromethane, adding dilute hydrochloric acid solution to the filtrate for washing, extracting the organic layer with dichloromethane, washing with saturated brine, anhydrous Na 2 SO 4 Drying, spin-drying, and column chromatography gave 2-bromo-N-isopropylacetamide I as a white solid (68% yield).

[0059] (2) Preparation of 3-(isopropylcarbamoyl-methoxy)-methyl benzoate II: In a 25mL round bottom flask, add DMF (1.0mL), 2-bromo-N-isopropyl Acetamide I (1mmol), methyl 3-hydroxybenzoate (1...

Embodiment 3

[0066] (1) Preparation of 2-bromo-N-isopropylacetamide I: Add dichloromethane (10mL) and isopropylamine (1.5mmol) sequentially into a 25mL round bottom flask, plug the rubber stopper, and insert nitrogen gas Under stirring in an ice-water bath, drop bromoacetyl bromide (1mmol) within 2 minutes, and then stir at room temperature after 5 minutes. After 1 hour, the reaction was detected by TLC. After the bromoacetyl bromide disappeared, stop stirring and filter off the white solid. , and washed with dichloromethane, adding dilute hydrochloric acid solution to the filtrate for washing, dichloromethane extracted the organic layer, washed with saturated brine, anhydrous Na 2 SO 4 Drying, spin-drying, and column chromatography gave 2-bromo-N-isopropylacetamide I as a white solid (yield 71%).

[0067] (2) Preparation of 3-(isopropylcarbamoyl-methoxy)-methyl benzoate II: In a 25mL round bottom flask, add DMF (10.0mL), 2-bromo-N-isopropyl Acetamide Ⅰ (1mmol), methyl 3-hydroxybenzoate ...

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Abstract

The invention belongs to the field of drug synthesis, and particularly, discloses a synthesis method of SLx-2119, wherein the synthesis method comprises the steps: firstly, with isopropylamine and bromoacetyl bromide as raw materials, preparing 2-bromo-N-isopropyl acetamide I, and then successively carrying out nucleophilic substitution reaction and ester hydrolysis reaction with 3-methyl hydroxybenzoate, carrying out amination reaction, cyclization reaction and chlorination reaction with 2-aminobenzamide, and finally carrying out nucleophilic substitution reaction with 5-aminoindazole, to prepare the SLx-2119. The use of expensive dihydroxy phenyl borate, Pd(dppf)Cl2, 2,4-dihydrogen quinazoline and other reagents is avoided, so the costs are reduced; the use of heavy metal palladium is also avoided, so the synthesis method has the advantages of no heavy metal pollution, environmental friendliness, raw materials without heavy metal residues, short reaction route, high yield and low cost, and is beneficial for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of SLx-2119. Background technique [0002] SLx-2119 is an orally active and selective ROCK2 inhibitor with IC50 and Ki of 60nM and 41nM, respectively, also known as KD-025. Currently, the compound is in the second clinical phase for the treatment of psoriasis, and the compound is also in the first clinical phase for the treatment of non-alcoholic steatohepatitis. [0003] There are two routes for the synthesis of SLx-2119 in the existing literature. Route 1: This route has been reported in WO 2006105081, WO2008054599, WO 2010104851 and WO 2012040499, specifically: [0004] [0005] The reaction steps of this route are as many as ten steps, and the reagents used are more, and because the number of reaction steps is more, the corresponding productive rate is just lower. Route 2: This route has also been reported in WO 2014055996 and WO...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12
CPCC07D403/12
Inventor 殷燕孙玉星张华孙国峰陶瑞衡段永斌孙越江沁楠
Owner SHANGHAI SCIENPHARM CO LTD
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