Preparation method of sitagliptin

A technology of sitagliptin and trifluoromethyl, applied in the field of pharmaceutical preparation, can solve the problems of unstable intermediate products, complicated operation, long time and the like, and achieve the effects of convenient industrial production, simple post-processing, and easy operation.

Active Publication Date: 2012-08-08
NANTONG SHIMEIKANG PHARMA CHEM
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

In addition, this route also has the following disadvantages: platinum oxide needs to be pretreated before use, the high pressure reaction time is long, and some intermediate products are relatively unstable.
[0008]2) Scientific literature First generation process for the prepara-tion of the DPP·IV inhibitor Sitagliptin. (Hansen KB, Balsells J, Dreher S, et a1. Org Pro Res Dev, 2005, 9(5): 634-639.) disclose a preparation method of sitagliptin, the specific route is shown in the figure below, the The asymmetric hydrogenation catalyst (S)-binaphthalene diphenylphosphine-ruthenium chloride used in the route is more expensive and the total yield is lower, which is not conducive to industrial scale-up production
[0010] 3) Scientific literature (2R-4-Oxo-4-[3-(trifluoromethyl)-5,6-d

Method used

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  • Preparation method of sitagliptin
  • Preparation method of sitagliptin
  • Preparation method of sitagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Compound methyl 3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine- Preparation of 7(8H)-yl)propyl Ester

[0043] Add 3-trifluoromethyl-[1,2,4]triazolo[4,3-a]piperazine hydrochloride (100.00g, 0.44mol) and methanol (300ml) into a 500mL three-necked reaction flask, The temperature of the system was lowered to -10°C, and a methanol solution of malonyl chloride (65.67 g, 0.48 moL) was slowly added dropwise at this temperature, stirred at room temperature, and the reaction of the raw materials was monitored by TLC. The solvent was recovered under reduced pressure, water (200ml) was added to the residue, the aqueous phase was extracted with ethyl acetate (200ml×2), the organic phases were combined, washed with water, and dried overnight with anhydrous magnesium sulfate. Filtration, the filtrate was concentrated to dryness under reduced pressure to obtain methyl 3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a ]pyrazin-7(8H)-yl)...

Embodiment 2

[0045] Example 2 Compound Methyl 3-oxo-2-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a] Preparation of pyrazine-7-carbonyl)-4-(2,4,5-trifluorophenyl)propyl ester

[0046] Add 2,4,5-trifluorophenylacetic acid (50.0g, 0.26mol) and acetonitrile (300ml), tert-butyryl chloride (10g), diisopropylethylamine (33.5g, 0.26mol) into a 500mL three-necked reaction flask and 4-dimethylaminopyridine (10g), after stirring for 1 hour, slowly drop into methyl 3-oxo-3-(3-(trifluoromethyl)-5,6-dihydro-[1, 2,4]Triazolo[4,3-a]pyrazin-7(8H)-yl)propyl ester (92g, 0.32moL) in acetonitrile solution, after dripping, slowly rise to 75°C to react, TLC monitoring until the raw material The response is over. Acetonitrile was recovered under reduced pressure, water (200ml) was added to the residue, the aqueous phase was extracted with ethyl acetate (200ml×3), the organic phases were combined, washed with water, and dried overnight over anhydrous magnesium sulfate. Filtration, and the filt...

Embodiment 3

[0048] Example 3 Compound (S,E)-methyl 3-(2-amino-2-oxo-1-phenethylamino)-2-(3-(trifluoromethyl)-5,6,7,8 -Tetrahydro-1,2,4-triazolo[4,3-a]pyrazine-7-carbonyl l)-4-(2,4,5-trifluorophenyl)but-2-enol ester preparation of

[0049] Add methyl 3-oxo-2-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3 -a] pyrazine-7-carbonyl)-4-(2,4,5-trifluorophenyl) propyl ester (51.0g, 0.11mol), isopropanol (150ml) and acetic acid (200ml), stirred at room temperature for 20 minute. (S)-Phenylglycineamide (21.0 g, 0.14 moL) was slowly added, and after the addition was completed, the reaction was slowly raised to reflux, and the reaction of the raw materials was monitored by TLC. Water (200ml) was added to the system, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with water, and dried overnight. Filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain (S, E)-methyl 3-(2-amino-2-oxo-1-phenethylamino)-...

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Abstract

The invention provides a preparation method of sitagliptin. The preparation method comprises the following steps of: performing condensation reaction on hydrochloride of 3-trifluoromethyl-[1,2,4] triazol [4,3-a] piperazine serving as a starting raw material and methyl malonyl chloride under a normal temperature condition; reacting an obtained product with 2,4,5-trifluorophenylacetic acid under an alkaline condition and then performing condensation reaction with (S)-phenylglycinamide under normal temperature condition to obtain a product; reducing the obtained product through a reducing agent; removing an ester group through heating reflux; and reacting with a hydrogenation reducing reagent to obtain the sitagliptin. The preparation method has the advantages of low cost, high yield, easiness in operation, all used reagents of conventional reagents, simple post-treatment and convenience for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a preparation method of sitagliptin. Background technique [0002] Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor drug, which is characterized by stimulating insulin secretion and reducing hunger without causing weight gain or Hypoglycemia and edema, suitable for diabetic patients with poor blood sugar control and frequent hypoglycemia. On October 17, 2006, Merck announced that the US Food and Drug Administration had approved sitagliptin phosphate. The drug has become the only dipeptidyl peptidase-4 (DPP-4) inhibitor drug for the treatment of type 2 diabetes in the US market so far. [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 (CAS NO: 486460-32-6), its chemical structure is as follows: [0004] [0005] At present, the ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 刘一超王巧玲王秀云王俊华
Owner NANTONG SHIMEIKANG PHARMA CHEM
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