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The synthetic method of dorzolamide hydrochloride intermediate

A synthesis method and enantiomer technology, applied in the field of drug synthesis, can solve problems such as inconvenient reaction operation, large environmental pollution, and difficult wastewater treatment, and achieve the effects of reducing damage, reducing risk, and high yield

Active Publication Date: 2015-12-02
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The reaction of sodium borohydride and Lewis acid is a common method for synthesizing borane, and its disadvantages are also obvious.
Traditional Lewis acid: the reaction of metal chlorides such as aluminum trichloride, zinc chloride, and cobalt dichloride will generate a large amount of solid waste, which is used in a large amount for the inconvenience of reaction operation, and aluminum ions, zinc ions, and cobalt ions in industrial wastewater produced Difficult to remove, more polluting to the environment
Boron trifluoride compounds are not only highly toxic, but also difficult to treat wastewater
[0020] As can be seen from the above disclosed process route: in the process for preparing dorzolamide, the reduction reaction has great defects, therefore, it is necessary to improve the reduction reaction process in the process for preparing dorzolamide

Method used

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  • The synthetic method of dorzolamide hydrochloride intermediate
  • The synthetic method of dorzolamide hydrochloride intermediate
  • The synthetic method of dorzolamide hydrochloride intermediate

Examples

Experimental program
Comparison scheme
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Embodiment 1I

[0032] One of the preparation methods of embodiment 11a:

[0033] Add 50g 2-acetylamino-4-methyl-5,5-dioxo-5,7-dithiobicyclo[4.3.0]nona-8,10-diene-8-sulfonamide (IIa ), 33.5g (0.89mol) of sodium borohydride and 300ml of anhydrous ether, stirred and cooled to 0°C. Dissolve 76g (0.30mol) of iodine in 200ml of anhydrous ether, drop it into the reaction kettle, and control the rate of addition so that the temperature is lower than 10°C. After the dropwise addition, gradually raise the temperature and stir at 25°C for 8-16 hours. After the reaction is complete, add 250ml of methanol and stir for 30 minutes. Slowly add 300ml of 2M sulfuric acid, stir for 2 hours, then raise the temperature and distill at normal pressure to 90°C and no fraction flows out, cool to room temperature, adjust the pH to 6-8 with 20% sodium hydroxide solution, and control the temperature below 40°C during the process . Extract 300mlx3 with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate...

Embodiment 2I

[0034] Two of the preparation method of embodiment 21a:

[0035] Add 50g 2-acetylamino-4-methyl-5,5-dioxo-5,7-dithiobicyclo[4.3.0]nona-8,10-diene-8-sulfonamide (IIa ), 22.4g (0.60mol) sodium borohydride and 300ml THF, stirred and cooled to 5°C. Dissolve 76g (0.30mol) of iodine in 200ml of tetrahydrofuran and add it dropwise to the reaction kettle, and control the rate of addition so that the temperature is lower than 10°C. After the dropwise addition, gradually rise to room temperature and stir for 8-16 hours. After the reaction is complete, add 250ml of acetone and stir for 30 minutes. Slowly add 150g of hydrochloric acid, stir for 2 hours, then heat up and distill at normal pressure to 90°C without distillate flow out, cool to room temperature, adjust pH to 6 with 20% sodium hydroxide solution, then adjust pH to 8 with saturated sodium bicarbonate solution, During this process, the temperature was controlled below 40°C. Extract 300mlx3 with ethyl acetate, dry over anhydro...

Embodiment 3I

[0036] Three of the preparation method of embodiment 31a:

[0037] Add 50g 2-acetylamino-4-methyl-5,5-dioxo-5,7-dithiobicyclo[4.3.0]nona-8,10-diene-8-sulfonamide (IIa ), 33.5g (0.89mol) sodium borohydride and 300ml methyl tert-butyl ether, stirred and cooled to 5°C. 152g (0.6mol) of iodine was dissolved in 200ml of methyl tert-butyl ether, and added dropwise to the reaction kettle, and the rate of addition was controlled so that the temperature was lower than 10°C. After the dropwise addition, gradually rise to room temperature and stir for 8-16 hours. After the reaction is complete, add 250ml of ethanol and stir for 30 minutes. Slowly add 150g of hydrochloric acid, stir for 2 hours, then raise the temperature and distill to 90°C without distillate flow out, cool to room temperature, adjust the pH to 6-8 with 20% sodium hydroxide solution, and control the temperature below 40°C during the process . Extract 300mlx3 with ethyl acetate, dry over anhydrous sodium sulfate, and c...

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Abstract

The invention relates to a synthetic method of a dorzolamide hydrochloride intermediate Ia (4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b] thiapyran-2-sulfamide-7,7-dioxide) and Ib (4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b] thiapyran-2-sulfamide-7,7-dioxide) used for treating glaucoma. The preparation method of the Ia comprises the steps that IIa (4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b] thiapyran-2-sulfamide-7,7-dioxide) reacts in a solvent under the condition of the existence of sodium borohydride and iodine, and acetamido is reduced into ethylamino in a synthesis mode. The preparation method of the Ib comprises the steps that IIb ((4s,6s)-4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b] thiapyran-2-sulfamide-7,7-dioxide) reacts in a solvent under the condition of the existence of sodium borohydride and iodine, and acetamido is reduced into ethylamino in a synthesis mode. Compared with existing methods, the synthetic method of the dorzolamide hydrochloride intermediate is high in yield, eliminates highly toxic raw materials, is mild in reaction condition, is free of intense heat release or intensely released gas in postprocessing, and reduces operating dangers.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of an intermediate of dorzolamide hydrochloride used for treating glaucoma. Background technique [0002] Dorzolamide hydrochloride, the chemical name is (4S,6S)-4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide- 7,7-dioxide hydrochloride, having the formula: [0003] [0004] Dorzolamide hydrochloride (1), an aromatic sulfonamide compound useful in the treatment of elevated intraocular pressure, is a carbonic anhydrase inhibitor (Carbonic Anhydrase Inhibitor, CAI), used to treat or improve intraocular pressure, Eye drops Trusopt, which uses it as the main ingredient, was approved by the FDA in 1994. [0005] Ia and Ib are important intermediates of dorzolamide hydrochloride. [0006] The chemical name of Ia is: 4-ethylamino-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide [0007] Structural f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 翁飞郭亚兵杨波耿海明陈国华乔春莲
Owner WUHAN WUYAO SCI & TECH