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Method of synthesizing saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine

A technology of tert-butoxycarbonyl and adamantyl, applied in the field of organic preparation, can solve the problems of unsafe operation, environmental pollution, long process steps and the like

Active Publication Date: 2014-07-30
HUAIHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the long process steps, difficult raw materials and low yield in the technology reported in the existing preparation formula (I) compound N-tert-butoxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine. Low efficiency, polluting the environment, unsafe operation, unfavorable for the defects of large-scale industrial production, provide an effective method for preparing N-tert-butoxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine, the method The raw materials are cheap and easy to obtain, the steps are short, the reaction conditions are mild, the operation is simple, the synthesis efficiency is high, the environment is friendly, and it is suitable for industrial production

Method used

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  • Method of synthesizing saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine
  • Method of synthesizing saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine
  • Method of synthesizing saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine

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Effect test

Embodiment 1

[0024] The preparation of embodiment 1 formula (III) compound 3-hydroxyl-1-adamantyl-D-glycine

[0025] 10mmol 2-(3-hydroxyl-1-adamantyl)-2-oxoacetic acid tert-butyl ester, 1.5g Molecular sieves, 10mmol o-nitroaniline and 20mL toluene were added into the reaction flask, stirred and mixed evenly. Raise the temperature of the system to 65-75°C, and stir the reaction at this temperature for 5h, stop heating, and wait until the temperature of the system drops to 40-50°C, add 0.8mmol of homemade chiral squaryl amido alcohol (R=NO 2 ) catalyst and 20mL of toluene were added, the temperature of the system was maintained at 45-55°C, and the reaction was stirred overnight at this temperature, the reaction was stopped, and filtered off after cooling Molecular sieves, add 20mL5N HCl to the filtrate at room temperature, let stand after stirring for 1h, separate the organic layer, wash with 5mL5N HCl, combine the water layer, adjust the pH value of the water layer to 8.0 with sodium car...

Embodiment 2

[0026] The preparation of embodiment 2 formula (III) compound 3-hydroxyl-1-adamantyl-D-glycine

[0027] 10mmol 2-(3-hydroxyl-1-adamantyl)-2-oxoacetic acid tert-butyl ester, 1.5g Molecular sieves, 10mmol m-chloroaniline and 20mL toluene were added into the reaction flask, stirred and mixed evenly. Raise the temperature of the system to 65-75°C, and stir the reaction at this temperature for 5h, stop heating, wait until the temperature of the system drops to 45°C, add 0.7mmol of homemade chiral squaramido alcohol (R=H) and 20mL of toluene , maintain the temperature of the system at 45-55°C, and stir the reaction overnight at this temperature, stop the reaction, filter off after cooling Molecular sieves, add 20mL5N HCl to the filtrate at room temperature, let stand after stirring for 1h, separate the organic layer, wash with 5mL5N HCl, combine the water layer, adjust the pH value of the water layer to 8.0 with sodium carbonate solid, add 90mL dichloromethane, Separate the orga...

Embodiment 3

[0028] Embodiment 3 The preparation of formula (I) compound N-tert-butoxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine

[0029] Add 10mmol of 3-hydroxy-1-adamantyl-D-glycine, 0.6mmol of potassium carbonate, 12mmol of di-tert-butyl dicarbonate and 30mL of tetrahydrofuran into the reaction flask, stir and mix evenly, and react at room temperature for 12 hours. The solvent was evaporated under reduced pressure, 50 mL of petroleum ether was added to the residue, and the pH value was adjusted to 1 with 5M HCl, a white solid was precipitated, filtered by suction, and dried under reduced pressure to obtain the compound of formula (I), with a yield of 98%.

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Abstract

The invention discloses a novel method of preparing an important saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine. The method comprises the following steps: S1, carrying out an asymmetric reduction amination reaction on 2-(3-hydroxyl-1-adamantyl)-2-oxo-tert-butyl acetate and benzylamine under the effect of a self-made chiral acylamino alcohol catalyst, and hydrolyzing ester to obtain 3-hydroxyl-1-adamantyl-D-glycine; and S2, carrying out a reaction on 3-hydroxyl-1-adamantyl-D-glycine and di-tert-butyl dicarbonate ester to obtain N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine. The synthetic method of the important saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine provided by the invention is low in cost and available in raw materials, short in step, mild in reaction condition, simple and convenient to operate, high in synthetic efficiency, environment-friendly and suitable for industrialized production, and provides a novel path for preparing saxagliptin and intermediates thereof.

Description

technical field [0001] The invention belongs to the technical field of organic preparation, and in particular relates to a new method for preparing a saxagliptin intermediate N-tert-butoxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine. Background technique [0002] Saxagliptin, the chemical name is (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl ]-2-Azabicyclo[3.1.0]-hexane-3-carbonitrile, jointly developed by Bristol-Myers Squibb Company and AstraZeneca Company, was approved by the US Food and Drug Administration for the first time in July 2009, and the trade name is Onglyza . Saxagliptin is a highly selective and reversible competitive dipeptidyl peptidase IV (DPP-IV) inhibitor, which is well tolerated and does not cause obesity. It is clinically used for the treatment of type 2 diabetes. The drug has a unique mechanism of action. By inhibiting the DPP-IV enzyme, it increases and prolongs the effect of incretin, prompts the pancreas to accelerate ...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/22C07C227/32C07C229/28
Inventor 程青芳张金彪王静文沈梦瑶王启发
Owner HUAIHAI INST OF TECH
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