Benzylthioacetamidoacetylpyrazinetriazole derivatives and their preparation and application

A technology of acetylpyrazine triazole and benzylthioacetamide, applied in the field of benzylthioacetamido acetylpyrazinetriazole derivatives and preparation thereof, can solve the problems of harsh production conditions, reduced cost, high cost and the like , to achieve the effect of easy operation, reasonable design and good production feasibility

Active Publication Date: 2011-11-30
HANGZHOU ADAMERCK PHARMLABS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the synthetic route of sitagliptin and its intermediates has the disadvantage of high cost
[0006] For example, in documents WO2004085378A1, WO2005020920A2 and WO2005097733A1, the last step requires the use of chiral catalytic reagents: 1,5-cyclopentadiene rhodium chloride dimer and iridium and ferrocene diphosphine (now called Josiphos) ligand Complexes, these two reagents are extremely expensive metal catalysts; in the document WO2004085661A2, after introducing the amino group using a chiral auxiliary ((S)-phenylglycinamide), under the catalysis of the oxidation pot Hydrogenation, and finally remove phenylglycine to obtain the final product, which is slightly lower than the cost of the above synthetic route; while in the document WO2004087650A2, although the chiral catalyst is abandoned, the low temperature (-20°C) reaction has to be used at the same time, The last step requires high-pressure hydrogenation, and the production conditions are relatively harsh

Method used

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  • Benzylthioacetamidoacetylpyrazinetriazole derivatives and their preparation and application
  • Benzylthioacetamidoacetylpyrazinetriazole derivatives and their preparation and application
  • Benzylthioacetamidoacetylpyrazinetriazole derivatives and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Weigh N-(2-mercaptopropionyl)-glycine (tiopronin) (3.92g, 0.024mol) and dissolve it in 20ml of N,N-dimethylformamide (DMF), then weigh potassium carbonate (8.28g , 0.06mol), stirred at room temperature for 15min; dropwise added p-methoxychlorbenzyl (3.76g, 0.024mol) into the single-necked bottle, stirred at room temperature for 3h, TLC detected that the reaction was complete; after the reaction was complete, adjust the pH with saturated aqueous sodium hydroxide solution value to 13, extracted 3 times with ethyl acetate (20ml / time), mainly to remove impurities; then adjusted the pH value to about 2 at low temperature, extracted 3 times with ethyl acetate (40ml / time), and combined the organic layers and dried, filtered, and evaporated to dryness under reduced pressure to obtain compound (b-1) with a yield of 82%.

[0034] The 1H NMR spectrum of the compound in deuterated chloroform: δ1.48(CH3,d,3H),3.65(CH,m,H),3.70(CH2,m,2H),3.72(CH3,m,3H) , 4.14 (CH2, s, 2H), 6.65 (2CH...

Embodiment 2

[0037]

[0038] Weigh compound (b-1) (0.85g, 0.003mol) and dissolve it in 10ml of DMF, then add 1ml of triethylamine, stir at room temperature for 10min; then add EDC (0.86g, 0.0045mol), HOBT (0.2g, 0.0015mol ) and 2-piperazinone (0.3g, 0.003mol), stirred at room temperature for 5h, TLC detected to complete reaction; evaporated DMF under reduced pressure, added saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, combined organic layer, dried and filtered , and evaporated to dryness under reduced pressure to obtain compound (c-1) with a yield of 85%.

[0039] The 1H NMR spectrum of the compound in deuterated chloroform: δ1.48(CH3,d,3H),3.46(2CH2,s,4H),3.65(CH,m,H),3.70(CH2,m,2H) , 3.72 (CH3, m, 3H), 4.09 (2CH2, s, 4H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.

[0040] MS: m / z: 366.14 (M+1).

Embodiment 3

[0042]

[0043] Add trimethyloxonium tetrafluoroboric acid (207mg, 1.4mmol) to a solution of compound (c-1) (438.54mg, 1.2mmol) in dichloromethane (6ml), stir at room temperature overnight, and mix the reaction solution with bicarbonate Sodium aqueous solution was mixed, extracted twice with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound (d-1) with a yield of 86%.

[0044] The 1H NMR spectrum of the compound in deuterated chloroform: δ1.48(CH3,d,3H),1.6(CH2,t,2H),3.2(2CH2,t,4H),3.39(CH3,s,3H) ,3.65(CH,m,H),3.70(CH2,m,2H),3.72(CH3,m,3H),4.09(CH2,s,2H),6.65(2CH,d,2H),6.95(2CH, d,2H) ppm.

[0045] MS: m / z: 380.16 (M+1).

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Abstract

The invention provides a benzylthio acetamido acetylpyrazine triazole derivative. A target compound (I) is obtained by condensing a sulfydryl acetamido acetic acid derivative and a benzyl chloride derivative, condensing the condensed derivatives and 2-piperazinone, reacting the obtained condensed product and trimethyloxonium tetrafluoroborate so as to obtain a methoxy imide compound, and carryingout cyclization on the methoxy imide compound and hydrazine, trifluoroaceticanhydride, acetic anhydride, propionic anhydride, trifluoroacetyl chloride, acetyl chloride or acrylyl chloride. The preparation method provided by the invention has the advantages of reasonable design, stable process, easily obtained raw materials for production, no use of high pressure hydrogenation and good production feasibility. By using the benzylthio acetamido acetylpyrazine triazole derivative provided by the invention, dipeptidyl peptidase-IV (DPP-4) can be selectively inhibited; an effect of reducing blood sugar is obtained; and the derivative can be applied to the preparation of drugs for reducing the blood sugar and has the following structural formula (I).

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to benzylthioacetamidoacetylpyrazine triazole derivatives and a preparation method and application thereof. The benzylthioacetamidoacetylpyrazine triazole derivative of the present invention has the effect of lowering blood sugar. technical background [0002] Sitagliptin (Sitagliptin) is the first dipeptidyl peptidase IV (DPP-4) inhibitor approved by the FDA. It can increase insulin secretion in a blood sugar-dependent manner, and has the effect of significantly lowering blood sugar. It is suitable for patients with intolerance Type 2 diabetic patients receiving other hypoglycemic drugs. [0003] The chemical name of sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4 ,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, the structural formula is as follows: [0004] [0005] At present, the synthetic route of sitagliptin and its intermed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P3/10
Inventor 漆又毛
Owner HANGZHOU ADAMERCK PHARMLABS INC
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