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A kind of preparation method of saxagliptin intermediate

A technology of intermediate and reaction time, which is applied in the field of preparation of saxagliptin intermediate, can solve the problem of long route and achieve the effects of short route, pollution-free yield and pollution-free industrial production

Active Publication Date: 2019-03-29
JIAXING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of preparation method of saxagliptin intermediate
  • A kind of preparation method of saxagliptin intermediate
  • A kind of preparation method of saxagliptin intermediate

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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 Patents(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