Preparation methods of suplatast tosilate and intermediates

A technology of sulfamilast and intermediates, which is applied in the field of preparation of sulfamilast and its intermediates, can solve the problems of difficulty in reaction monitoring and purification, poor production operability, and high safety risks, and avoid palladium-carbon catalytic hydrogenation reduction The steps of nitro group are beneficial to the production operation and the effect of shortening the reaction steps

Active Publication Date: 2018-08-24
重庆柳江医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route also uses palladium carbon hydrogenation to reduce nitro groups, but also has the problems of expensive reagents, high equipment requirements, high safety risks, and poor production operability. It also uses boron trifluoride ether to prepare 1-ethoxy-2,3- Propylene oxide, the reagent is highly toxic, and the epoxy ring opening has the problem of difficult reaction monitoring and purification

Method used

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  • Preparation methods of suplatast tosilate and intermediates
  • Preparation methods of suplatast tosilate and intermediates
  • Preparation methods of suplatast tosilate and intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of Intermediate 1

[0038] At 20~30°C, add 20.0 g (0.18 mol) of 4-aminophenol and 2-methyltetrahydrofuran (200 mL) into the reaction flask, add 30.8 g (0.55 mol) of crushed calcium oxide under stirring, Stir for 0.5~1.0 h, cool down to -10~5°C, control the temperature at -10~5°C, add 28.0 g (0.20 mol) of 3-methylthiopropionyl chloride dropwise, after 0.5~1 h dropwise, raise the temperature to 20~30 Stir at ℃ for 4~6 h, the raw material point disappeared in TLC, filter with suction, wash the filter cake with 100 mL of 2-methyltetrahydrofuran, collect the filtrate and wash with 200 mL of saturated sodium bicarbonate, separate the layers, and the organic layer (2-methyltetrahydrofuran Tetrahydrofuran) was dried with an appropriate amount of anhydrous magnesium sulfate, filtered, and the filtrate was distilled off under reduced pressure to remove the solvent to obtain 32.0 g of intermediate 1 with a yield of 83.0%, which was directly used in the next r...

Embodiment 2

[0040] Example 2 Preparation of Intermediate 2

[0041] At 20~30°C, add 10.0 g (47.33 mmol) of intermediate 1, 13.1 g of epichlorohydrin (141.99 mmol), and 0.1 g (1 mmol) of triethylamine into the reaction flask, stir and heat up to 60~70°C for reaction After 6~8 h, the point of raw material in TLC disappears, distill under reduced pressure, cool the residue to room temperature, add 200ml of acetone, 150ml of 5 mol / L KOH aqueous solution, stir at 20~30°C for 3 hours, keep the temperature below 30°C , evaporate the solvent under reduced pressure, cool to room temperature, extract with 3×150ml dichloromethane, wash with 3×150ml saturated brine, distill to dryness, add 250ml ethanol, 2.5g activated carbon, stir and reflux at 20~30°C for 3 hours for decolorization , filtered while hot, the filter cake was washed with a small amount of ethanol, the filtrates were combined, and about 150 ml of ethanol was evaporated by heating to obtain 9.6 g of intermediate 2, with a yield of 75.9%...

Embodiment 3

[0042] Example 3 Preparation of Intermediate 3

[0043] At 20~30°C, add 8.0 g (29.92 mmol) of intermediate 2, ethanol (160 mL), 0.4 g (1.14 mmol) of tin tetrachloride pentahydrate into the reaction flask, stir, heat to reflux for 2 h, and depressurize Ethanol was distilled off. The residue was cooled to room temperature, added 100 mL of dichloromethane, washed with 80 mL of 2mol / L HCl aqueous solution, and then washed with 2×40 mL of saturated brine, the organic phase was collected, spin-dried, and recrystallized by adding 80 mL of acetone to obtain 7.3 g of intermediate Body 3, yield 77.8%. 1 H-NMR (DMSO-d 6 )δ: 1.06~1.11(t, 3H, CH 3 ),2.06(s, 3H, S-CH 3 ),2.48~2.74(m, 4H, SCH 2 CH 2 ),3.40~3.47 (m, 4H,CH 2 OCH 2 ),3.81~3.89(m, 3H, CH, Ar-OCH 2), 4.00~5.00(d, 1H, OH), 6.81~6.84(d, 2H, Ar-H), 7.44~7.47 (d, 2H, Ar-H), 9.75 (s, 1H, CONH).

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PUM

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Abstract

The invention relates to preparation methods of suplatast tosilate and intermediates thereof. According to the method, 4-aminophenol is taken as an initial material, and a target compound is obtainedthrough steps of amidation, addition of epichlorohydrin, ring opening and the like. The method avoids a palladium-carbon catalytic hydrogenation step, comprises a short synthesis route and is high inyield, simple to operate and suitable for industrial application. The invention also provides novel intermediates for preparation of suplatast tosilate and preparation methods of the novel intermediates.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of tosulfonast and its intermediate. Background technique [0002] Suplatast tosilate, as shown in formula (I): [0003] [0004] The chemical name of sulfonastilast is [±-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium-p-toluenesulfonate]. Racemic drug, an anti-asthma drug developed and marketed by Japan Dapeng Pharmaceutical Co., Ltd., was launched in Japan in 1995. It has excellent IgE antibody formation inhibitory effect and can be effectively used for various allergic diseases such as bronchial asthma, allergy Treatment of atopic dermatitis and allergic rhinitis. [0005] The preparation method of sulfonilast is described in J.Med.Chem,1998; 18(41):3330-3336, it is reported in this document that with 4-nitrophenol as starting material, by reacting with epichlorohydrin, concentrated Sulfuric acid-ethanol ring-o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C381/12C07D303/20C07D301/28C07C319/20C07C323/60C07C303/26C07C309/73
CPCC07C303/26C07C319/20C07C323/60C07C381/12C07D301/28C07D303/20C07C309/73
Inventor 牟祥钟齐昌肖光林邓祥林
Owner 重庆柳江医药科技有限公司
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