Novel synthesizing method for dorzolamide HCL midbody

A compound, reaction time technology, applied in the direction of organic chemistry, etc., can solve the problems of increasing process complexity, loss of yield and purity, and many reaction steps.

Inactive Publication Date: 2008-10-29
北京精华耀邦医药科技有限公司
View PDF4 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The biggest disadvantage of this type of route is: the intermediates are all racemates, and the resolution is carried out at the end. In the synthetic route, several times more reagents and reactants will be used to generate the racemates in order to obtain the target enantiomer, and finally Separation and removal of its enantiomers, which leads to a great increase in the cost of the final product
[0031] The disadvantages of the chiral synthesis of the above method are: (1) the chiral raw materials used in the reaction need to be synthesized additionally, which increases the complexity of the process and increases the cost; (2) a large amount of expensive and environmentally unfriendly heavy metal oxidation is used in the process. (3) There are many reaction steps, complex operation, large loss and time-consuming
[0034] In this method, the optical puri

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
  • Novel synthesizing method for dorzolamide HCL midbody
  • Novel synthesizing method for dorzolamide HCL midbody
  • Novel synthesizing method for dorzolamide HCL midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Preparation of 3-(2-mercaptothiophene) butanoic acid

[0052] Install the glass instrument, protect it with nitrogen, add 750 ml of THF, heat, add 48 g of magnesium chips, 5 g of iodine under stirring, heat to about 75 ° C and start to reflux, and slowly add 81.5 g of 2-bromothiophene dropwise under reflux and 500 milliliters of tetrahydrofuran, after the dropwise addition was completed, the solution was kept under reflux and stirred for 4 hours.

[0053] Cool the reaction solution to room temperature and stop stirring. After standing still, pour the supernatant into another three-necked flask that is also dry, under nitrogen protection, under ice bath conditions, add 38 grams of settled sulfur in three batches, and keep the temperature at - 5°C to 5°C. After the addition, the reaction system was naturally raised to room temperature (15°C to 25°C), and then kept at this temperature and stirred for 20 hours.

[0054] A mixed solution of 172 grams of crotonic a...

Embodiment 2

[0055] The preparation of embodiment 2 (S)-3-(2-mercaptothiophene) butanoic acid

[0056] Mix 202 grams of 3-(2-mercaptothiophene) butanoic acid and 122 grams of (-)-α-phenylethylamine in 500 milliliters of ethyl acetate, heat and stir until completely dissolved, heat and reflux for 15 hours, and cool to 10°C , crystals are precipitated, gradually cooled to -15°C under stirring, until the crystals are completely precipitated, filtered, the filter cake is repeated 3 times after the above operation, and dried to obtain a solid dissolved in water, add 300 ml of 10% NaOH solution, and heat Stir, and finally add HCl solution dropwise to adjust the pH value to 2, separate the liquid, wash with water several times, dry over anhydrous sodium sulfate, filter, and spin dry the solvent to obtain 82 g of light yellow oil with an optical purity of 98%.

Embodiment 3

[0057] Example 3 (S)-6-methyl-2-sulfonyl chloride-5,6-dihydro-4H-thiophene[2,3b]thiopyran-4-carbonyl

[0058] Add 228 ml of fuming sulfuric acid into a three-necked flask in an ice bath to -7°C, add dropwise 82 g of (S)-3-(2-mercaptothiophene) butanoic acid under stirring, and react at room temperature for 7 hours. 200 ml of sulfoxide, heated to 37-40°C, reacted for 8 hours, cooled to -10°C, added dropwise 26 ml of tin tetrachloride in dichloromethane solution, kept the temperature not higher than 0°C during the dropwise addition, completed Then stir at 0°C for 1 hour. The reaction solution was poured into a mixture of ice and water, and 93 g of solid was obtained by filtration, with a yield of 81.2%.

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 new synthetic method of a dorzolamide intermediate (S)-6-methyl-2-chlorosulfuryl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-carboxide, comprising the steps of synthesizing raceme 3-(thien-2-ylthio)butyric acid, performing chiral resolution to obtain stereoisomer thereof (S)-3-(thien-2-ylthio)butyric acid, and performing addition and ring-closing reactions to obtain (S)-6-methyl-2-chlorosulfuryl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-carboxide. The inventive method shortens conventional synthesis route, and performs chiral resolution of the intermediate raceme at the beginning of the synthesis route with a chiral resolution agent, so as to save a large amount of subsequent raw materials consumption. In addition, the synthetic method adopts 'one-pot' method, so as to reduce loss and the steps and cost of the subsequent operations, resulting in a more convenient, economical and effective synthesis route, compared with the known synthesis routes.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, in particular to (S)-6-methyl-2-sulfonyl chloride-5,6-dihydro-4H-thiophene[2,3b]thiopyran-4- A new preparation process of the carbonyl group, the compound can be used to prepare dorzolamide hydrochloride for treating glaucoma. technical background [0002] Glaucoma is an eye disorder caused by high pressure inside the eye, which can lead to vision loss and even blindness if left untreated. At present, many ophthalmologists believe that high eye pressure is an early symptom of glaucoma. It is generally believed that controlling the onset and development of glaucoma is accomplished by controlling the increase in intraocular pressure. [0003] Dorzolamide hydrochloride, the Chinese name is (4S,6S)-4-ethylamino-5,6-dihydro-6-methyl-4H-thiophene[2,3b]thiopyran-2-sulfonamide- 7,7-dioxyhydrochloride, the structure is as follows: [0004] [0005] Dorzolamide Hydrochlorid...

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
IPC IPC(8): C07D495/04C07D333/00C07D335/00
Inventor 卫永刚田兆桐张秋越
Owner 北京精华耀邦医药科技有限公司
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