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Saxagliptin intermediate, its salt, preparation method and application

An intermediate and inert gas technology, applied in the field of saxagliptin intermediates, can solve problems such as cumbersome operation, harsh reaction conditions, and difficult control

Active Publication Date: 2014-08-06
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is that, in order to overcome the long route of the preparation method of the saxagliptin intermediate in the prior art - N-tert-butoxycarbonyl-(3-hydroxyl-1-adamantyl)-D-glycine compound , the reaction conditions are harsh, difficult to control, cumbersome to operate, costly, unfavorable for environmental protection and defects in industrialized production, and provide a saxagliptin intermediate, its salt, its preparation method and its use

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  • Saxagliptin intermediate, its salt, preparation method and application
  • Saxagliptin intermediate, its salt, preparation method and application
  • Saxagliptin intermediate, its salt, preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0086] Preparation of ethyl 3-hydroxy-1-adamantanyl ketoate (compound B, R 1 group is ethyl)

[0087] Under the protection of nitrogen, add 50g (220mmol) of 3-hydroxy-1-adamantanyl ketoacid into the reaction flask, add it into 500ml of absolute ethanol, dissolve and clarify, lower the temperature to 0°C, and slowly add Equivalent of 26.56g of thionyl chloride, keep the temperature at 0-5°C, after the dropwise addition is completed, raise the temperature to reflux, react for 1 hour, evaporate the reaction solution to dryness under reduced pressure, add 200ml of toluene, and extract with 200ml of water , liquid separation, the toluene layer was washed with 100ml of aqueous sodium bicarbonate solution, 100ml of salt water, and separated, and the organic layer was washed twice with 50ml of salt water. After the liquid separation, the organic layer was dried and evaporated to dryness to obtain the product 3- Ethyl hydroxy-1-adamantanyl ketoate, white solid 50g, yield 90%.

Embodiment 2

[0089] Preparation of the compound of general structural formula 2 (R 1 group is ethyl)

[0090] Under the protection of nitrogen, add 50g (220mmol) of ethyl 3-hydroxy-1-adamantanyl ketone into the reaction flask, add it into 500ml of toluene, dissolve and clarify, then add 26.4g of R-phenylethylamine

[0091] (242mmol), add 0.5g of p-toluenesulfonic acid, install a water separator, heat to reflux to separate water, react for 24 hours, after the reaction is completed, evaporate to dryness under reduced pressure to obtain 70g of brown oil, with a yield of 99%.

Embodiment 3

[0093] Preparation of 1S-(3-hydroxyl-1-adamantyl)-(1R-phenyl-ethylamino)-acetic acid ethyl ester hydrochloride (structural formula 1, R 1 for ethyl)

[0094] Put 70g of the product prepared in Example 2 into the reaction flask, add 700ml of acetonitrile to dissolve and clarify, ice-bath to 5°C, add 11g of sodium borohydride in batches, maintain -5~0°C, slowly add 140g of acetic acid dropwise, and stir the reaction After 2 hours, the reaction is complete, evaporate the solvent to dryness under reduced pressure, add 200ml of ethyl acetate, extract with 200ml of water, use 6N aqueous sodium hydroxide solution to adjust pH=8-9, let stand to separate layers, and extract with 100ml of ethyl acetate For the aqueous phase, the combined organic layer was heated to 45°C, concentrated hydrochloric acid was added dropwise, and the pH was adjusted to 3-4. Granular crystals were precipitated after the dropwise addition, kept for 20 minutes, cooled to room temperature, stirred overnight, and...

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Abstract

The invention discloses a saxagliptin intermediate, its salt, preparation method and application. The preparation method for the compound 1 or its salt comprises the step of: subjecting an intermediate compound 2 to reduction reaction at a reaction temperature ranging from -15DEG C to 45DEG C in a solvent under the effects of a reducing agent and an organic acid to obtain an intermediate compound 1 or its salt, with the reducing agent being a borohydride of an alkali metal. The preparation method for the compound 2 comprises the step of: under the protection of an inert gas and the action of the organic acid, reacting a compound B with a compound F in a solvent. The invention also discloses application of the intermediate compound or its salt in preparation of saxagliptin. The saxagliptin intermediate involved in the invention has the advantages of easy preparation, simple operation, mild condition, low cost and environmental friendliness, and can meet the requirements of industrial production. (formula 1 and formula 2).

Description

technical field [0001] The invention relates to a saxagliptin intermediate, its salt, its preparation method and its use. Background technique [0002] Saxagliptin is a highly effective inhibitor of dipeptidyl peptidase-4 (DPP-4). By selectively inhibiting DPP-4, it can increase endogenous glucagon-like peptide-1 ( Glucagon-like Peptide-1, GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels, thereby regulating blood sugar. The process research of the medicine is of great significance. N-tert-butoxycarbonyl-(3-hydroxy-1-adamantyl)-D-glycine compound is the key intermediate for the synthesis of saxagliptin, refer to the literature Preparationof Saxagliptin, a Novel DPP-IV Inhibitor (Organic Process Research&Development2009, 13,1169–1176) can be prepared to saxagliptin, the route is as follows: [0003] [0004] For N-tert-butoxycarbonyl-(3-hydroxy-1-adamantyl)-D-glycine, the key is the construction of chiral amino groups. At present, there are literature Adv...

Claims

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Application Information

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IPC IPC(8): C07C229/28C07C227/06C07C251/18C07C249/02C07D209/52
Inventor 李春刚魏宝康郭璠王国平侯建李传刚孙一平
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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