A kind of preparation method of chiral amino compound and its intermediate

A compound and system technology, which is applied in the field of preparation of chiral amine compounds and intermediates thereof, can solve the problems of low reaction yield, bad smell of reaction material benzene mercaptan, elimination of side reactions and the like

Active Publication Date: 2021-03-05
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the sulfonic acid ester on the allyl position in the preparation step of brinzolamide in the prior art, which is easy to eliminate side reactions under alkaline conditions, and the reaction material benzenethiol has a foul smell, The reaction yield is low, not suitable for defects such as industrialized production, and a kind of preparation method of brinzolamide and its intermediate is provided

Method used

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  • A kind of preparation method of chiral amino compound and its intermediate
  • A kind of preparation method of chiral amino compound and its intermediate
  • A kind of preparation method of chiral amino compound and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] The preparation of embodiment 1 formula B-1 compound

[0083]

[0084] References Organic Process Research & Development1999, 3, 114-120 preparation, specific operations include: prepare a 1L three-neck flask, equipped with a mechanical stirrer, constant pressure low liquid funnel and ice water bath. Add formula A compound (100g, 0.28mol) and acetonitrile (400mL), N 2 Under protection, stirring and cooling to 5-10°C, then trimethyl orthoacetate (77.3 g, 0.64 mol) was added dropwise thereto at a speed to keep the system stable and not exceeding 15°C. After the addition, the cooling was removed, and the reaction was continued for 1 hour. TLC detected that the starting material disappeared, and a new spot with slightly higher polarity was generated. Concentrate under normal pressure, recover the solvent, add DCM to the residue, replace the precipitation with rotary evaporation, and finally dry under high vacuum for 1 hour. The residue is the compound of formula B-1, wh...

Embodiment 2

[0085] The preparation of embodiment 2 formula B-2 compound

[0086]

[0087] The reference document Organic Process Research & Development 1999, 3, 114-120 was prepared, and the specific operations included: preparing a 1L three-neck flask, equipped with a mechanical stirrer, a constant pressure dropping funnel, and an ice-water bath. Added formula A compound (50g, 0.14mol) and acetonitrile (250mL), N 2 Under protection, stirred and cooled to 5-10°C, and then added DMF-DMA (17.5 g, 0.147 mol) dropwise thereto at a speed to keep the system stable and not exceeding 15°C. After the addition, the cooling was removed, and the reaction was continued for 1 hour, and TLC detected that the starting material disappeared. Concentrate under normal pressure, recover the solvent, add DCM to the residue, replace the precipitation with rotary evaporation, and finally dry under high vacuum for 1 hour, the residue is the compound of formula B-2, which can be directly used in subsequent rea...

Embodiment 3

[0088] Example 3 Preparation of Formula C-2 Compound 4-Nitrobenzenesulfonylethylamine

[0089] References Organic Process Research & Development 1999, 3, 114-120 preparation, specific operations include: prepare a 1L there-necked flask, equipped with a mechanical stirrer, add ethylamine aqueous solution (63.5mL, 70%wt%, 0.65mol) and methanol ( 200 mL), under stirring at room temperature, p-nitrobenzenesulfonyl chloride solid (50 g, 0.226 mol) was added in batches. After the addition was complete, the stirring reaction was continued at this temperature for 2 hours, and the reaction was terminated after the TLC detection of the complete disappearance of the raw material. Concentrate under reduced pressure to remove most of the methanol, add 200mL of DCM to dissolve it completely, separate layers, dry the organic phase, concentrate to the remaining 50mL of solvent, add 200mL of n-hexane, stir at room temperature for 30 minutes, filter and dry to obtain white The solid was change...

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Abstract

The invention discloses a preparation method of brinzolamide and its intermediate. The preparation method of the present invention comprises the following steps: in a solvent, carry out the following deprotection reaction on the compound of formula D and thiolate; wherein, in the compound of formula D, X is selected from O or NMe; X is When O, Y is Me, when X is NMe, Y is H; n is selected from 0, 1, 2, 3, 4 or 5; each R is independently NO 2 or CN; the thiol salt is the salt formed by thiol and metal, expressed as RS ‑ m + ; among them, M + Is an alkali metal ion, specifically can be selected from Li + 、Na + 、K + 、Ru + and Cs + One or more of; R is C 14‑24 alkyl. The preparation method of the invention has the advantages of simple and convenient operation, mild reaction conditions, high yield and good product quality, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a chiral amino compound and an intermediate thereof, in particular to a preparation method of brinzolamide and an intermediate thereof. Background technique [0002] Brinzolamide is a novel topical heterocyclic sulfonamide carbonic anhydrase inhibitor with strong affinity and inhibitory effect on carbonic anhydrase isozyme II (CAII) in human ciliary body, selectivity, high affinity And significantly inhibit the activity of carbonic anhydrase isoenzyme II, effectively reduce intraocular pressure, has the advantages of high efficiency, low toxicity, and small side effects, and its physiological pH value and suspension design make the drug eye comfortable. Favored by patients. It can be used as a single treatment drug for patients who are ineffective or contraindicated by β-receptor blockers, or as a synergistic treatment drug for β-receptor blockers. Body, choroid, retina, lens and blood have a long half...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04
CPCC07B2200/07C07D513/04Y02P20/55
Inventor 王东王方道王猛蔡茂军
Owner CHEMVON BIOTECH CO LTD
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