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Method for preparing saxagliptin intermediate

An intermediate, reaction time technology, applied in chemical instruments and methods, organic compound/hydride/coordination complex catalysts, organic chemistry, etc., can solve the problem of long route, achieve short route, high yield, no The effect of polluting the ee value

Active Publication Date: 2017-05-31
JIAXING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] A Chinese patent reports a preparation method of a saxagliptin intermediate (201310124347.2) (such as reaction formula 3), but the route is too long, and the cis-trans isomerization ratio is 1:1

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

[0042] Add (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxamide (5.0g, 23.6mmol) and a chiral catalyst (0.15 g) and 30.0g of dichloromethane, reacted at room temperature 25°C for 12h, filtered to remove the catalyst, and then concentrated the organic phase. After removing the solvent, the concentrate was recrystallized with ethyl acetate / n-hexane=1:2 (volume ratio) , freeze-dried after suction filtration to obtain 4.50 g (theoretical 5.33 g) of the product, the ee value was 97%, and the yield was 84.4%.

Embodiment 2

[0044]Add (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxamide (5.0g, 23.6mmol) and the chiral Catalyst (0.1g) and 35.0g dichloromethane, after room temperature 25 ℃ reaction 12h, remove catalyst by filtration first, organic phase is concentrated again, after removing solvent, concentrate is ethyl acetate / n-hexane=1:2 (volume ratio ) recrystallization, suction filtration and freeze-drying to obtain 5.15 g (theoretical 5.33 g) of the product, the ee value was 99.5%, and the yield was 96.6%.

Embodiment 3

[0046] Add (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxamide (5.0g, 23.6mmol) and the chiral Catalyst (0.1g) and 20.0g dichloromethane, after reacting at 0°C for 30h, first filter to remove the catalyst, and then concentrate the organic phase. After removing the solvent, the concentrate is mixed with ethyl acetate / n-hexane=1:2 (volume ratio) After recrystallization, suction filtration and freeze-drying, 4.9 g of the product (theoretical 5.33 g) was obtained, the ee value was 98%, and the yield was 92.0%.

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Abstract

The invention discloses a method for preparing a saxagliptin intermediate, namely a method for preparing (1S, 3S, 5S)-3-(amino carbonyl)-2-azabicyalo [3.1.0] hexane-2-formic acid-tert-butyl ester, and belongs to the field of chemical synthesis. The method comprises the following steps: in a dichloromethane solvent, under the action of a chiral catalyst, performing Simmons-Smith cyclopropanation preparation on (S)-1-N-tert-butyloxycarboryl-2,3-dihydro-2-pyrrole formamide, thereby obtaining the (1S, 3S, 5S)-3-(amino carbonyl)-2-azabicyalo [3.1.0] hexane-2-formic acid-tert-butyl ester, wherein the reaction temperature is minus 30-40 DEG C, and the reaction time is 1-48 hours. The method has the characteristics of being short in route, simple and convenient to operate, free of pollution and easy in industrial production, and is a very economic, simple and convenient method.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a preparation method of a saxagliptin intermediate, namely (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2 -The preparation method of tert-butyl formate. Background technique [0002] (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (CAS No.: 361440-67-7) is a chiral compound for the treatment of diabetes The important intermediate of drug saxagliptin (trade name Onglyza), its chemical formula is as follows: [0003] [0004] Saxagliptin products are marketed by Bristol-Myers Squibb. The important advantages of the drug are that it is convenient to use, has few adverse reactions, has a low risk of hypoglycemia and does not cause weight gain, and has a good market prospect (chemical review, 2011, 111, 6557-6602.). [0005] The synthesis of (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl este...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52B01J31/22
CPCB01J31/22B01J2531/0238B01J2531/847C07D209/52
Inventor 牟安卿宗乾收刘倩曹乾秀蒋亚文包琳张新克
Owner JIAXING UNIV
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