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Preparation method for omarigliptin midbody

A technology for intermediates and pyridines, applied in the field of medicine, can solve the problems of potential safety hazards, low yields, easy ignition of low-boiling by-products, etc., and achieves the effects of simple operation, high yields and less three wastes

Active Publication Date: 2017-06-30
济南同路医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This route uses a high-temperature, high-boiling-point solvent, and when the pyrazole ring is synthesized, the low-boiling-point by-products are easy to catch fire, posing a safety hazard
The total yield of the route is less than 30%, and the yield is low

Method used

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  • Preparation method for omarigliptin midbody
  • Preparation method for omarigliptin midbody
  • Preparation method for omarigliptin midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of Intermediate 1:

[0032] Add 120g of Boc-pyrrolidone and 600ml of DMF to a 1000ml four-neck flask, stir to cool down to 0-5°C, add 26g of sodium hydride, slowly add 70.5g of ethyl chloroformate dropwise under stirring, and complete the dropwise addition in 40 minutes. After reacting at 0-5°C for 2 hours, after the completion of the reaction detected by TLC, slowly add 3L of ice water, adjust the pH to 7 with dilute hydrochloric acid, extract with ethyl acetate, dry, and concentrate to obtain intermediate 1. Yield 85%.

[0033] Preparation of intermediate 3:

[0034] Add the intermediate 1 obtained above, 500 ml of ethanol to a 1000 ml four-necked flask, and add 45 ml of hydrazine hydrate under stirring at 20-25°C. Stir at 20-25°C for 3 hours. After the reaction is detected by TLC, raise the temperature to reflux temperature of 78°C and continue the reaction for 4 hours. After the reaction is completed, the reaction solution is concentrated, and 500ml of...

Embodiment 2

[0045] Preparation of Intermediate 1:

[0046] Add 120g of Boc-pyrrolidone and 600ml of acetonitrile into a 1000ml four-necked bottle, stir to cool down to 0-5°C, add 30g of sodium hydroxide, slowly add 70.5g of ethyl chloroformate dropwise under stirring, and the dropwise addition is completed in 40 minutes. After reacting at 15°C for 2 hours, TLC detected the completion of the reaction, slowly added 3L of ice water, adjusted the pH to 7.4 with dilute hydrochloric acid, extracted with ethyl acetate, dried, and concentrated to obtain Intermediate 1. Yield 78%.

[0047] Preparation of intermediate 3:

[0048] Add the intermediate 1 obtained above, 500 ml of methanol into a 1000 ml four-necked flask, and add 45 ml of hydrazine hydrate under stirring at 22°C. Stir at 22°C for 3h. After the reaction was detected by TLC, the temperature was raised to 60°C to continue the reaction for 6h. After the reaction was complete, the reaction solution was concentrated, and 500ml of petrole...

Embodiment 3

[0054] Preparation of Intermediate 1:

[0055] Add 120g of Boc-pyrrolidone and 600ml of tetrahydrofuran into a 1000ml four-neck flask, stir to cool down to 20°C, add 52g of potassium carbonate, slowly add 70.5g of ethyl chloroformate dropwise under stirring, and the dropwise addition is completed in 40 minutes. After reacting at ℃ for 2 hours, after the completion of the reaction as detected by TLC, slowly add 3L of ice water, adjust the pH to 6.7 with dilute hydrochloric acid, extract with ethyl acetate, dry, and concentrate to obtain Intermediate 1. Yield 82%.

[0056] Preparation of intermediate 3:

[0057] Add the intermediate 1 obtained above, 500 ml of acetonitrile into a 1000 ml four-necked flask, and add 45 ml of hydrazine hydrate under stirring at 24°C. Stir at 24°C for 3h. After the reaction was detected by TLC, the temperature was raised to reflux temperature of 78°C to continue the reaction for 4h. After the reaction was completed, the reaction solution was conce...

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Abstract

The invention provides an efficient and simple preparation method for omarigliptin midbody pyrrole and [3,4-c] pyrazol-5(2H,4H,6H)-carboxylic acid tert-butyl ester, wherein the total recovery ratio is close to 50%. The preparation method is easy to operate, the recovery ratio is higher, three produced wastes are less, and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a method for preparing an alogliptin intermediate. Background technique [0002] Ologliptin was developed by Merck and was approved for marketing by the Japan Medical Devices Agency (PMDA) on September 28, 2015. Ologliptin is an ultra-long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor. Its mechanism of action is to inhibit the degradation of glucagon-like peptide-1 (GLP-1) by DPP-4 enzyme in the body, prolong the action time of GLP-1, thereby increasing the concentration of endogenous GLP-1 and GIP in the blood. concentration, and ultimately improve blood sugar control. Ologliptin is an oral hypoglycemic drug administered once a week as a DPP-4 inhibitor, which improves medication compliance. [0003] Its structure is as follows: [0004] [0005] The pyrrolopyrazole ring structure is an important structural unit of alogliptin, and how to synthesize it easily, safely and efficient...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 俞仑王海波李家园刘鸽刘静秦京艳王瑞峰
Owner 济南同路医药科技发展有限公司
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