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A kind of synthetic method of adamantane glycine derivative and salt thereof

A technology for the synthesis of adamantane glycine, which is applied in chemical instruments and methods, the preparation of organic compounds, and the preparation of cyanide reactions, etc., which can solve the problems of large production safety hazards, difficult quality control, and high cost, and achieve reaction stereoselectivity High, good chiral induction effect, and the effect of reducing environmental pressure

Active Publication Date: 2018-06-26
SHANGHAI SHYNDEC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to provide a kind of adamantane glycine derivatives in order to overcome the disadvantages of complicated operation, long route, high cost, difficult quality control, and very large production safety hazards in the preparation method of adamantane glycine derivatives in the prior art. Synthetic method of alkylglycine derivatives and salts thereof

Method used

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  • A kind of synthetic method of adamantane glycine derivative and salt thereof
  • A kind of synthetic method of adamantane glycine derivative and salt thereof
  • A kind of synthetic method of adamantane glycine derivative and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 1S-(3-hydroxyl-1-adamantyl)-(1R-phenyl-ethylamino)-acetic acid ethyl ester hydrochloride (R 1 for ethyl)

[0035]

[0036]Add the compound shown in the above formula 2 (30g, 84.5mmol) into the reaction flask, dissolve and clarify the added toluene 300ml, put it in an ice bath to 5°C, add trichlorosilane (11.4g, 84.4mmol) in batches to maintain -5-0°C , slowly added acetic acid (2.5g, 42mmol) dropwise, after the dropwise addition, the temperature was raised to 25°C, and the reaction was stirred for 18 hours. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure, 200ml of ethyl acetate was added, and 200ml of water was used for extraction. Sodium oxide aqueous solution, adjust the pH=8-9, let stand to separate layers, extract the aqueous phase with 50ml of ethyl acetate, combine the organic layer and raise the temperature to 45°C, add concentrated hydrochloric acid dropwise, adjust the pH=3-4, and precipitate part...

Embodiment 2

[0039] Preparation of 1S-(3-hydroxyl-1-adamantyl)-(1R-phenyl-ethylamino)-acetic acid ethyl ester hydrochloride (R 1 for ethyl)

[0040]

[0041] Add the compound shown in the above formula 2 (20g, 56mmol) into the reaction flask, add 200ml of toluene to dissolve and clarify, ice-bath to 0°C, add trichlorosilane (15.2g, 113mmol) in batches to maintain -10°C, slowly drop Add acetic acid (3.38g, 56mmol), after the dropwise addition, heat up to 20°C and stir for 14 hours. After the reaction is complete, evaporate the solvent to dryness under reduced pressure, add 200ml of ethyl acetate, extract with 200ml of water, and use 6N aqueous sodium hydroxide solution. Adjust the pH=8-9, let stand to separate the layers, extract the water phase with 50ml of ethyl acetate, combine the organic layer and raise the temperature to 45°C, add concentrated hydrochloric acid dropwise, adjust the pH=3-4, after the addition is complete, granular crystals are precipitated, keep warm After 20 minut...

Embodiment 3

[0043] Preparation of 1S-(3-hydroxyl-1-adamantyl)-(1R-phenyl-ethylamino)-acetic acid ethyl ester hydrochloride (R 1 for ethyl)

[0044]

[0045] Add the compound shown in the above formula 2 (30g, 84mmol) into the reaction flask, add 300ml of tetrahydrofuran to dissolve and clarify, ice-bath to 5°C, add trichlorosilane (34.2g, 253mmol) in batches, maintain -5-5°C, Slowly add acetic acid (7.6g, 176mmol) dropwise to release gas, heat up to 30°C and stir for 16 hours to react. After the reaction is complete, evaporate the solvent to dryness under reduced pressure, add 250ml of ethyl acetate, extract with 200ml of water, and use 6N sodium hydroxide Aqueous solution, adjust pH = 8-9, let stand to separate layers, extract the aqueous phase with 50ml of ethyl acetate, combine the organic layer and raise the temperature to 45°C, add concentrated hydrochloric acid dropwise, adjust pH = 3-4, and precipitate granular crystals after the addition , kept warm for 20 minutes, dropped to ...

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Abstract

The invention discloses a synthesis method of an adamantylglycine derivative and a salt thereof. The synthesis method is characterized in that a compound represented by formula 2 undergoes a reduction reaction in a solvent under the action of a halogenated silane reagent and an acid in order to obtain the adamantylglycine derivative represented by formula 1 or the salt thereof. The synthesis method has the advantages of simplicity in operation, mild conditions, low cost, environmental protection, and meeting of industrial production demands.

Description

technical field [0001] The invention relates to a synthesis method of adamantane glycine derivatives and salts thereof. Background technique [0002] Saxagliptin is a highly effective dipeptidyl peptidase-4 (Dipeptidyl Peptidase 4, DPP-4) inhibitor. By selectively inhibiting DPP-4, it can increase endogenous glucagon-like peptide-1 (Glucagon-like Peptide-1, GLP-1) and glucose-dependent insulinotropic peptide (Glucose-dependent Insulinotropic Peptide, GIP) levels, thereby regulating blood sugar. [0003] N-tert-butoxycarbonyl-(3-hydroxy-1-adamantyl)-D-glycine compound is the key intermediate for the synthesis of saxagliptin, refer to the literature Preparation of Saxagliptin, a Novel DPP-IV Inhibitor (Organic Process Research&Development 2009 ,13,1169–1176) can be prepared to saxagliptin, the route is as follows: [0004] [0005] When preparing N-tert-butoxycarbonyl-(3-hydroxyl-1-adamantyl)-D-glycine, the key lies in the construction of chiral amino groups. At present,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/18C07C229/28
CPCC07C227/18C07C229/28
Inventor 李春刚黄文武孙一平占轶鹏
Owner SHANGHAI SHYNDEC PHARMA CO LTD