Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Chiral synthesis method of dorzolamide hydrochloride

A technology of dorzolamide hydrochloride and chiral synthesis, which is applied in the field of chiral synthesis of dorzolamide hydrochloride, can solve the problems of lack of chiral selectivity of reaction products, and achieves simple and feasible synthesis method, low cost and chiral selection. strong effect

Active Publication Date: 2021-09-03
CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOGY
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the reaction products obtained by this method lack chiral selectivity

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
  • Chiral synthesis method of dorzolamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The chiral synthesis method of dorzolamide hydrochloride in this embodiment comprises the following steps:

[0038] (1) At 0°C, add 12L of ethanol to a 20L reaction kettle, then add 2.95 kg (10.0 mol) of compound I and 495 g (11 mol) of ethylamine, then raise the temperature to 20°C, imidize for 10 hours, TLC Monitor the reaction, cool to room temperature, concentrate the organic phase under reduced pressure (0.2 mmHg), and recrystallize with toluene to obtain 2.83 kg of compound II (8.8 mol, molar yield: 88%), with a purity of 97.4% by HPLC;

[0039] (2) Add 12L of ethanol to the 20L autoclave, then add 2.83kg (8.8mol) of compound II and 100g of water obtained in step (1), and then add 45g (0.09mol) of catalyst bis(1,5-cyclo Octadiene) iridium(I) tetrafluoroborate and 90 g (0.18 mol) of the chiral ligand (R)-(+)-1,1'-binaphthyl-2'-isopropoxy-2-diphenylphosphine , heated to 40°C, carried out asymmetric hydrogenation reaction under 1Mpa hydrogen pressure for 4 h, monito...

Embodiment 2

[0046] The chiral synthesis method of dorzolamide hydrochloride in this embodiment comprises the following steps:

[0047] (1) At 0°C, add 12L of isopropanol to a 20L reaction kettle, then add 2.95 kg (10.0 mol) of compound I and 495 g (11 mol) of ethylamine, and imidize for 14 hours, monitor the reaction by TLC, and cool After reaching room temperature, the organic phase was concentrated under reduced pressure (0.2 mmHg), and then recrystallized with toluene to obtain 2.86 kg of compound II (8.90 mol, molar yield: 89.0%), with a purity of 98.2% by HPLC;

[0048](2) Add 12L of isopropanol to a 20L autoclave, then add 2.86kg (8.9mol) of compound II and 100g of water obtained in step (1) in sequence, and then add 19.9g (0.05mol) of catalyst 1,5-cyclooctyl Diene (acetylacetonate) iridium(I) and 49.6 g (0.1 mol) of the chiral ligand (R)-(+)-1,1'-binaphthyl-2'-isopropoxy-2-diphenylphosphine , heated up to 50°C, carried out asymmetric hydrogenation reaction under 1Mpa hydrogen pres...

Embodiment 3

[0051] The chiral synthesis method of dorzolamide hydrochloride in this embodiment comprises the following steps:

[0052] (1) At 0°C, add 12L tetrahydrofuran to a 20L reaction kettle, then add 2.95 kg (10.0 mol) of compound I and 540 g (12 mol) of ethylamine, then control the temperature to -10°C, and imidize for 14 hours , the reaction was monitored by TLC, cooled to room temperature, the organic phase was concentrated under reduced pressure (0.2 mmHg), and then recrystallized with toluene to obtain 2.93 kg of compound II (9.1 mol, molar yield 91%), with a purity of 97.8% by HPLC ;

[0053] (2) Add 12L of sec-butanol to a 20L autoclave, then add 2.93kg (9.1mol) of compound II and 100g of water obtained in step (1) in sequence, and then add 45.7g (0.09mol) of catalyst 1,5-cyclooct Diene (hexafluoroacetylacetonate) iridium (I) and 89.3 g (0.18 mol) of the chiral ligand (R)-(+)-1,1'-binaphthyl-2'-isopropoxy-2-di For phenylphosphine, heat up to 60°C, carry out asymmetric hydro...

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 relates to a chiral synthesis method of dorzolamide hydrochloride, which comprises the following steps: (1) by taking a compound I that is (6S)-4-carbonyl-5,6-dihydro-4H-6-methyl-thieno[2,3b] thiopyran-2-sulfonamide-7,7-dioxide as an initial raw material, carrying out imidization reaction on the initial raw material and ethylamine to obtain a compound II that is (6S)-4-ethyl imino-5,6-dihydro-4H-6-methyl-thieno[2, 3b]thiopyran-2-sulfonamide-7,7-dioxide; (2) carrying out asymmetric hydrogenation reaction on the compound II obtained in the step (1), a catalyst and a chiral ligand (R)-(+)-1,1'-binaphthyl-2'-isopropoxy-2-diphenylphosphine to obtain a compound III that is dorzolamide; and (3) mixing the compound III obtained in the step (2) with hydrochloric acid, acidifying, washing and drying to obtain a compound IV, namely dorzolamide hydrochloride. The synthesis method is simple and easy to implement, high in chiral selectivity and low in cost, and the obtained dorzolamide hydrochloride is high in purity and suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of dorzolamide hydrochloride, in particular to a chiral synthesis method of dorzolamide hydrochloride. Background technique [0002] Glaucoma is a kind of eye disease characterized by specific optic nerve damage and visual field defect, and it is one of the main and irreversible blinding eye diseases at present. Dorzolamide hydrochloride (trade name Trusopt) is a topical ophthalmic carbonic anhydrase inhibitor, which can be widely used in the treatment of ocular hypertension, glaucoma and other eye diseases. [0003] The Chinese chemical name of dorzolamide hydrochloride is: (4S,6S)-4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3b]thiopyran-2- Sulfonamide-7,7-dioxide hydrochloride, the structural formula is shown in Formula 1: [0004] Formula 1 [0005] In the chemical synthesis of dorzolamide hydrochloride, the synthesis of chiral intermediates is often involved. The existing synthetic methods of chira...

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 Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04C07B2200/07Y02P20/55
Inventor 袁遥
Owner CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOGY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com