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Method for preparing saxagliptin intermediate

An intermediate, acetonitrile technology, applied in the field of preparation of saxagliptin intermediates, can solve problems such as low yield, unfavorable large-scale production, environmental protection, and complicated treatment, so as to improve product yield and purity, and yield is stable , the effect of high-purity post-processing

Active Publication Date: 2019-07-05
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] From the above route, it can be concluded that the saxagliptin intermediate 2 shown in the following formula is an important intermediate for the synthesis of saxagliptin, but as documented in WO 2013175395, Preparation of Saxagliptin, a Novel DPP-IV Inhibitor (Organic Process Research & Development , Volume 13, Issue 6, 1169-1176), the existing technical route has problems such as low yield and complex post-reaction treatment, which is not conducive to industrialized large-scale production and environmental protection

Method used

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  • Method for preparing saxagliptin intermediate
  • Method for preparing saxagliptin intermediate
  • Method for preparing saxagliptin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] Add 2.5kg of acetonitrile, 1.77kg of ethyl acetate, and 2.03kg of N,N-diisopropylethylamine to the reaction kettle in sequence, and stir for later use. Then add raw material A 2.33kg, saxagliptin intermediate 1 1.67kg, hydroxybenzotriazole 1.11kg, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1.51kg kg, acetonitrile 2.83kg, stirred for 2-3 hours.

[0029] After most of the acetonitrile was distilled off under reduced pressure, 20.90 kg of ethyl acetate was added to the reaction liquid and stirred. After adjusting the pH to neutral, 11.80kg of sodium chloride solution was added, stirred at room temperature, left to stand, and then the water layer was removed. Add 12.76 kg of 20% potassium bicarbonate solution to the organic phase, stir, let stand and remove the water layer. Add 12.76 kg of 20% potassium bicarbonate solution to the organic phase, stir, and remove the water layer after standing.

[0030] Precipitate the organic phase to 4.0-5.9...

Embodiment 2

[0032]

[0033] 10kg of acetonitrile, 7.1kg of ethyl acetate, and 8.1kg of N,N-diisopropylethylamine were successively added into the reaction kettle, and stirred for later use. Then add raw material A 9.32kg, saxagliptin intermediate 1 6.68kg, hydroxybenzotriazole 4.4kg, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 6.0kg kg, acetonitrile 11.3kg, stirred for 3 hours.

[0034] After most of the acetonitrile was distilled off under reduced pressure, 83.6 kg of ethyl acetate was added to the reaction solution and stirred. After adjusting the pH to neutral, add 47.2kg of sodium chloride solution, stir at room temperature, and remove the water layer after standing still. Add 51.0 kg of 20% potassium bicarbonate solution to the organic phase, stir, let stand, and remove the water layer.

[0035] Precipitate the organic phase to 16-25L under reduced pressure, add 23.2kg of ethyl acetate, and then precipitate under reduced pressure to 16-25L; stop the precipitation...

Embodiment 3

[0037]

[0038] 25.0 g of acetonitrile, 17.7 g of ethyl acetate, and 20.3 g of N,N-diisopropylethylamine were successively added into the reactor, and stirred for use. Then add raw material A 23.3g, saxagliptin intermediate 1 16.8g, hydroxybenzotriazole 11.12g, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 15.1g g, 28.3 g of acetonitrile, stirred for 2 hours.

[0039] To the reaction liquid, 209.0 g of ethyl acetate was added and stirred. After adjusting the pH to neutral, 118.0 g of sodium chloride solution was added, stirred at room temperature, left to stand, and then the water layer was removed. Add 127.6 g of 20% potassium bicarbonate solution to the organic phase, stir, and remove the water layer after standing. Add 127.6 g of 20% potassium bicarbonate solution to the organic phase, stir, leave to stand and remove the water layer.

[0040] Precipitate the organic phase to 40-60mL under reduced pressure, add 60.0g of ethyl acetate, and then precipitate...

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Abstract

The invention provides a method for preparing a saxagliptin intermediate 2 as shown in the specification. An existing process is improved by using the method, so that the yield and purity of a productare greatly increased, in addition, it is convenient realize aftertreatment, and the method is particularly suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing a saxagliptin intermediate. Background technique [0002] Saxagliptin (Saxagliptin) is a kind of dipeptidyl peptidase-4 (DPP4) inhibitor, is the medicine that U.S. Bristol-Myers Squibb pharmaceutical company develops and is used for the treatment of adult type II diabetes, and its structural formula is as follows: [0003] [0004] At present, the synthesis and purification methods of saxagliptin have been reported in the literature, and the main synthesis route is as follows: [0005] The synthesis scheme reported in WO2004052850 is to react 3-hydroxyadamantane-S-glycine with Boc2O under the action of sodium hydroxide to obtain 3-hydroxyadamantane-Boc-S-glycine, and then 3-hydroxyadamantane-Boc-S- Glycine is condensed with (1S, 3S, 5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide, and the formyl group in the condensation product structure is r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52Y02P20/55
Inventor 任英梅江宁张敏张帅阳龚彦春刘雪芳刘永强
Owner JIANGSU VCARE PHARMATECH
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