A kind of synthetic method of silodosin

A synthesis method and technology of silodosin are applied in the field of preparation of silodosin, a drug for treating benign prostatic hyperplasia, can solve the problems of difficult reaction operation, complicated preparation process, unfavorable industrial production and the like, and achieve easy industrial production and product purity. The effect of high and low labor intensity

Active Publication Date: 2022-04-05
杭州乐敦科技有限公司
View PDF7 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] The technical problem to be solved by the present invention is that when preparing silodosin in the prior art, due to the complicated preparation process and the need for procedures such as column chromatography, chiral resolution is required during the synthesis of intermediates, resulting in difficult reaction operations. Yield is low, be unfavorable for industrial production etc. deficiency, provide a kind of new synthetic method of silodosin, it utilizes Grignard reagent, protecting group, Mannich reaction, a series of substitution reaction and catalytic hydrogenation reduction, simplifies disassembly Separate process, improve the yield, high product purity, reduce labor intensity, and facilitate industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of synthetic method of silodosin
  • A kind of synthetic method of silodosin
  • A kind of synthetic method of silodosin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Embodiment 1 general formula 2 is synthesized

[0081] Add 20g (0.168mol) of general formula 1 indoline into the flask, add dropwise 14.5g (0.185mol) acetyl chloride at 20°C, add 100g water to quench after the reaction is complete, then extract with 100g DCM (dichloromethane), and the DCM phase The solvent was removed under reduced pressure to obtain intermediate 1, 20ml of acetic acid was added and used directly for the next step; 26.8g (0.168mol) of Br was added dropwise at 20-25°C 2 Mix the solution with 20ml of acetic acid, react at 25-30°C for 3 hours, add 100g of water, add 100ml of DCM, separate the liquid, remove the solvent from the DCM phase under reduced pressure to obtain 38.68g of intermediate 2, Y=96%, directly used in the next step; Add 100g ETOH / water (2:1), add 20g concentrated hydrochloric acid, heat up to 78°C, react for 4 hours, cool down to room temperature after the reaction, remove ethanol under reduced pressure, extract three times with 50g DCM e...

Embodiment 2

[0083] Embodiment 2 general formula 3 is synthesized

[0084] Add compound 2 (5-bromoindoline) 30g (0.151mol), 23g (0.166mol) potassium carbonate, 12.6g (0.08mol) potassium iodide, 90gDMF to the flask, heat up to 90-100°C, add dropwise 29.8g ( 0.167mol) 2-(3-chloropropoxy)tetrahydro-2H-pyran Raise the temperature to 130°C and react for 6 hours. After the reaction is complete, add 200g of water, extract three times with 80g of ethyl acetate each time, remove the solvent from the organic phase under reduced pressure, and recrystallize with 110g of toluene to obtain 46.4g of 5-bromo-1-[2-tetra Hydropyran]ethyl}-2Hindole, Y=90%, HPLC purity 98%.

[0085] 1 H NMR (500MHz, CDCl 3 ): δ7.22-7.18(m,2H), 7.06(m,1H), 4.60(m,1H), 3.78-3.61(m,6H), 3.35(m,2H), 2.96(m,2H), 1.81-1.56 (m, 8H). MS: 339-340 (MH). HPLC: XDB-C184.6*250, acetonitrile / water 1:1, 230nm, 45min.

Embodiment 3

[0086] Embodiment 3 general formula 6 is synthesized

[0087] Add 35g (0.393mol) D-alanine (compound 4), 33g (0.825mol) sodium hydroxide, 150g water to the flask, add 1.05 equivalents of 70.4g (0.41mol) CbzCl (benzyl chloroformate) dropwise at 10-15°C Esters), raised to 20-30°C after adding, reacted for 5 hours, after the reaction, adjusted the pH to 2 with 3M hydrochloric acid, extracted three times with 100g toluene each time, removed the solvent under reduced pressure to obtain the general formula 5, which was directly used in the next step Reaction; then add 180g toluene, 1.1 equivalents of 74.4g (0.432mol) p-toluenesulfonic acid and 11.8g (0.393mol) formaldehyde to the general formula 5, start stirring, and react at 20-25°C for 12h. After the reaction, the toluene phase is washed with water Twice, the toluene phase was collected, and the solvent was removed under reduced pressure to obtain 86.9 g of the compound of general formula 6, Y=94%, HPLC purity 97%.

[0088] 1 H...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a synthesis method of silodosin. The synthesis method takes indoline as a raw material, and sequentially carries out amino protection, bromination, and deprotection; 2 Reaction obtains compound 3; Use D-alanine and benzyl chloroformate to obtain chiral compound 6 through substitution reaction and Mannich reaction; Then compound 3 and chiral compound 6 are joined together with Grignard reagent; Then use triethyl silane and TFA to reduce the carbon group to obtain compound 8; then substitute and deprotect Cbz to obtain compound 9; compound 9 and compound 12 generate SN 2 Substitution reaction to obtain compound 10; finally hydrogenation / Pd / C deprotection, hydrogen peroxide oxidation of cyano to amide to obtain the product silodosin. Compound 3 and chiral compound 6 were synthesized to obtain the key chiral compound 7, which avoids resolution, has controllable optical purity, improves the reaction yield, has mild reaction conditions, and is easy for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of silodosin, a drug for treating benign prostatic hyperplasia. Background technique [0002] Silodosin is a selective α1A-adrenergic blocker. Preclinical studies have shown that its selective effect on the urethra is 12 and 7.5 times higher than that of prazosin and tamsulosin, respectively. times. Silodosin can significantly inhibit norepinephrine-induced human prostate contraction; it has a dose-dependent inhibitory effect on bladder hyperactivity in rat benign prostatic hypertrophy model, and can increase the pressure threshold of bladder contraction. These data suggest that, in addition to improving bladder function, silodosin is also effective in relieving symptoms associated with benign prostatic hypertrophy. [0003] Benign prostatic hyperplasia (BPHI) is one of the common diseases in elderly men, characterized by non-malignant enlargement of the ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08
CPCC07D209/08Y02P20/55
Inventor 任峰波徐国轩戴学仁王岩马鑫
Owner 杭州乐敦科技有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap