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A kind of chiral synthesis method of dorzolamide hydrochloride

A technology for chiral synthesis of dorzolamide hydrochloride, which is applied in the field of chiral synthesis of dorzolamide hydrochloride, can solve problems such as the lack of chiral selectivity of reaction products, and achieve simple synthesis methods, strong chiral selectivity, low cost effect

Active Publication Date: 2022-05-20
CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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

Method used

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  • A kind of chiral synthesis method of dorzolamide hydrochloride
  • A kind of chiral synthesis method of dorzolamide hydrochloride

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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 of 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 pr...

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...

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Abstract

A chiral synthesis method of dorzolamide hydrochloride, comprising the following steps: (1) compound I (6S)-4-carbonyl-5,6-dihydro-4H-6-methyl-thieno[2,3b ] Thiopyran-2-sulfonamide-7,7-dioxide as the starting material, carries out imidization reaction with ethylamine to obtain compound II(6S)-4-ethylimino-5,6- Dihydro-4H-6-methyl-thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide; (2) compound II obtained in step (1) with catalyst, hand Sexual ligand (R)-(+)-1,1'-binaphthyl-2'-isopropoxy-2-diphenylphosphine is subjected to asymmetric hydrogenation reaction to obtain compound III dorzolamide; (3) the step (2) The obtained compound III was mixed with hydrochloric acid, acidified, washed and dried to obtain compound IV, namely dorzolamide hydrochloride. The synthesis method of the invention is simple and easy, has strong chiral selectivity and low cost, and the obtained dorzolamide hydrochloride has high purity and is 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

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
CPCC07D495/04C07B2200/07Y02P20/55
Inventor 袁遥
Owner CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOGY
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