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Synthetic method of saxagliptin intermediate

A synthesis method and intermediate technology, applied in the field of synthesis of saxagliptin intermediates, can solve the problems of dangerous operation, expensive raw materials, environmental pollution, etc., and achieve the effects of short route, reduced production cost and stable process

Inactive Publication Date: 2020-11-06
陈华荣
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process of this method is complicated, the raw materials are relatively expensive, and strong oxidants such as potassium permanganate and active metal sodium are required. The operation is dangerous and is not conducive to post-reaction treatment, and it is easy to cause environmental pollution.

Method used

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  • Synthetic method of saxagliptin intermediate
  • Synthetic method of saxagliptin intermediate
  • Synthetic method of saxagliptin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 1,3-dibromoadamantane (compound 2):

[0035] Get adamantane (13.6g, 100mmol), aluminum tribromide (58.6g, 220mmol) and boron tribromide (7.5g, 30mmol) and join in the reactor, add the liquid bromine of 109mL under the condition of 0 ℃, and Stir at 0°C for 30 minutes, then raise the temperature to 70°C and react for 48 hours. After the reaction, cool to room temperature, add saturated sodium bisulfite to quench the reaction, filter and wash with deionized water to obtain 23.0 g of yellow solid 1,3-di Bromoadamantane, the yield is 78%.

[0036] 1 H-NMR (400MHz, DMSO-d 6 ):δ2.83(s,1H),2.73(s,1H),2.48(s,4H),2.35-2.21(m,8H).

Embodiment 2

[0038] Preparation of 3-bromo-1-adamantyl-D-glycine (compound 3):

[0039] Add sodium (1.7g, 74.8mmol) to 500mL of petroleum ether, add diethyl acetamidomalonate (16.2g, 74.8mmol) while stirring, and stir at room temperature. After the metal sodium is completely dissolved, add Compound 2 (20.0 g, 68 mmol), and reacted at room temperature for 12 hours. After the reaction, 200ml of distilled water was added, the organic layer was separated, the solvent was concentrated, and L-arginine (17.8g, 102mmol) was dissolved in a mixed solvent of 7.5mL of concentrated sulfuric acid, 22.5mL of distilled water and 75mL of glacial acetic acid to form L- The acidic solution of arginine, then the acidic solution of L-arginine was added to the reaction after the concentrated solvent, stirred and refluxed for 6 hours, cooled to room temperature after the reaction and poured into ice water, extracted with dichloromethane, combined organic layer, the solvent was evaporated, and the residue was re...

Embodiment 3

[0042] Preparation of 3-bromo-1-adamantyl-D-glycine (compound 4):

[0043] Dissolve KOH (32.0g, 57.2mmol) in 200mL of water, add compound 3 (15g, 52.0mmol), and reflux for 8h under stirring. After the reaction, extract and concentrate and recrystallize to obtain 9.6g of white solid with a yield of 82%. The ee value is 99%.

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Abstract

The invention provides a synthesis method of a saxagliptin intermediate. The process comprises the following steps: (1) carrying out a substitution reaction on adamantane (compound 1) and liquid bromine under the catalysis of aluminum tribromide and boron tribromide to obtain a compound 2; (2) dissolving the compound 2 and diethyl acetamido malonate into petroleum ether, reacting under the actionof sodium ethoxide, then adding into an acid solution of L-arginine, carrying out a reflux reaction for 8 hours, and carrying out hydrolysis decarboxylation to form a compound 3; (3) stirring and refluxing the compound 3 for 8 hours in the presence of alkali, and hydrolyzing to form a compound 4; and (4) reacting the compound 4 with Boc anhydride under an alkaline condition at room temperature for12 hours to obtain the saxagliptin intermediate. The method has the advantages of cheap and easily available raw materials and reagents, simple reaction operation, mild reaction conditions, high yield and excellent quality, allows the resolution end product to reach 99% ee value, and meets the requirements of drug intermediates.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, in particular to a method for synthesizing a saxagliptin intermediate. Background technique [0002] Diabetes has become one of the major diseases affecting human health. According to the latest data released by the International Diabetes Federation, by the end of 2040, the number of adults with diabetes worldwide is expected to exceed 600 million. Diabetes is mainly divided into type Ⅰ diabetes, type Ⅱ diabetes, gestational diabetes and special type of diabetes. Most of them suffer from type 2 diabetes. The relative imbalance of insulin and glucagon is the main cause of type Ⅱ diabetes. [0003] Saxagliptin, chemical name {(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3,3,1,13,7]decane-1 -yl)acetyl]-2-azabicyclo[3,1,0]-hexane-3-carbonitrile}, is a DPP-4 inhibitor. Saxagliptin can potently and selectively act on DPP-4, inhibit its activity, increase the concentration of glucagon-like pepti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C17/10C07C23/38C07C227/20C07C227/16C07C229/28C07C269/04C07C271/22
CPCC07C17/10C07C227/20C07C227/16C07C269/04C07C2603/74C07B2200/07C07C23/38C07C229/28C07C271/22C07D209/52C07C269/06
Inventor 陈华荣
Owner 陈华荣
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