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Low-cost preparation method of sitagliptin phosphate

A technology of sitagliptin and phosphate, which is applied in the field of preparation of sitagliptin phosphate, can solve the problem of incapable of using sitagliptin phosphate and the like, and achieves easy operation, simple synthesis process and short process. Effect

Active Publication Date: 2015-11-18
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But at present, the estimated number of diabetic patients in China has reached 60 million, of which about 95% are type 2 diabetic patients, and the vast majority of diabetic patients have no financial ability to use sitagliptin phosphate

Method used

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  • Low-cost preparation method of sitagliptin phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1: the preparation of N-benzyl-2S-cyanomethylacridine (II)

[0075] Add 200 grams of N,N-dimethylformamide, 92.5 grams (1.0 moles) of S-epichlorohydrin, and 107 grams (1.0 moles) of benzylamine to a 500-milliliter four-necked flask, and stir at 10-15°C for reaction 1 Hour. Add 50 grams (1.0 moles) of sodium cyanide powder, stir and react at 20-25°C for 2 hours, filter, add the filtrate dropwise to 262 grams of triphenylphosphine, 202 grams of DIAD (diisopropyl azodicarboxylate) , 300 grams of N,N-dimethylformamide mixture, the temperature of the dropping process is controlled between 10-20°C, and the dropwise addition is completed in 75 minutes. After that, the reaction is stirred at 20-25°C for 8 hours, and the pressure is reduced Distill (50°C, 15mmHg) to recover N,N-dimethylformamide, add 1000 g of water and 300 g of ethyl acetate to the residue, stir for 30 minutes, separate the layers, and extract the aqueous layer three times with ethyl acetate, each ...

Embodiment 2

[0076] Embodiment 2: the preparation of N-benzyl-2S-cyanomethylacridine (Ⅱ)

[0077]Add 200 grams of N,N-dimethylformamide, 92.5 grams (1.0 moles) of R-epichlorohydrin, 50 grams (1.0 moles) of sodium cyanide powder to a 500 milliliter four-neck flask in sequence, The reaction was stirred for 2 hours. 107 g (1.0 mole) of benzylamine was then added, and the reaction was stirred at 15-20° C. for 1 hour. Filter and add the filtrate dropwise to a mixture of 262 grams of triphenylphosphine, 202 grams of DIAD (diisopropyl azodicarboxylate), and 300 grams of N,N-dimethylformamide, and the temperature of the dropping process is controlled at 10 Between -15°C, the dropwise addition was completed in 75 minutes. After that, the reaction was stirred at 20-25°C for 10 hours, and N,N-dimethylformamide was recovered by vacuum distillation (50°C, 15mmHg), and added to the residue 1000 g of water and 300 g of ethyl acetate were stirred for 30 minutes, separated into layers, and the water laye...

Embodiment 3

[0078] Embodiment 3: the preparation of N-benzyl-2S-cyanomethylacridine (Ⅱ)

[0079] 300 g of acetonitrile, 92.5 g (1.0 mole) of S-epichlorohydrin, and 107 g (1.0 mole) of benzylamine were successively added to a 500 ml four-necked flask, and the reaction was stirred at 15-20° C. for 2 hours. Add 50 grams (1.0 moles) of sodium cyanide powder, stir and react at 20-25°C for 2 hours, filter, add the filtrate dropwise to 262 grams of triphenylphosphine, 202 grams of DIAD (diisopropyl azodicarboxylate) , 300 grams of acetonitrile, the temperature of the dropping process is controlled between 15-20°C, and the dropwise addition is completed in 75 minutes. After that, the stirring reaction is between 20-25°C for 8 hours, and the vacuum distillation (50°C, 15mmHg) is recovered Acetonitrile, add 1000 grams of water and 300 grams of ethyl acetate to the residue, stir for 30 minutes, separate layers, extract the water layer with ethyl acetate three times, each time with 100 grams of ethyl...

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Abstract

The invention relates to a low-cost preparation method of sitagliptin phosphate. The preparation method comprises the following steps: preparing N-arylmethyl-2S-cyanmethylacridine (II) from S-epoxy chloropropane or R-epoxy chloropropane; then preparing (3R)-3-arylmethylamino-4-(2,4,5-trifluorophenyl)butyric acid (III) from newly-made 2,4,5-trifluorophenyl zinc bromide and N-arylmethyl-2S-cyanmethylacridine (II) through ring-opening addition reactions, cyan basic hydrolysis, and acidification; then reacting (3R)-3-arylmethylamino-4-(2,4,5-trifluorophenyl)butyric acid (III) with an aryl-chlorination reagent to generate corresponding aryl chlorine, carrying out condensation reactions between the corresponding aryl chlorine and 3-trifluoromethyl-5,6,7,8-tetrahydro-triazole[4,3-a]pyrazine hydrochloride (IV) to prepare corresponding amide, carrying out catalytic hydrogenation to remove the aryl methyl protective groups, and acidifying the products by phosphoric acid to obtain phosphate so as to obtain sitagliptin phosphate (I). According to the preparation method, easily-available S-epoxy chloropropane or R-epoxy chloropropane is used to prepare N-arylmethyl-2S-cyanmethylacridine (II) so as to construct a chiral center of the sitagliptin phosphate; the reaction conditions are mild, the operation is easy, the sitagliptin phosphate yield is high, the impurities are little, and the cost is low.

Description

technical field [0001] The invention relates to a preparation method of sitagliptin phosphate, which belongs to the field of medicine and chemical industry. Background technique [0002] Sitagliptin phosphate is a dipeptidyl enzyme-4 (DPP-4) inhibitor type 2 diabetes treatment drug. In October 2006, the US FDA approved sitagliptin phosphate to go on the market. Since then, sitagliptin phosphate has It has been approved for the treatment of type 2 diabetes in 95 countries including China. Different from previous oral hypoglycemic drugs, sitagliptin phosphate reduces the degradation of glucagon-like peptide-I by inhibiting DPP-4, and improves the ability of diabetic patients' own islet β cells to produce insulin to control blood sugar in diabetic patients Level. Sitagliptin phosphate is highly selective, and its selectivity to DPP-4 is 2500 times higher than that of DPP-8 and DPP-9, so there is no side effect caused by the inhibition of DPP-8 and DPP-9. It can be used alone...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D203/02C07D203/08A61P3/10
CPCY02P20/55C07D487/04C07D203/02C07D203/08
Inventor 戚聿新鞠立柱牛伟张明峰陈军李新发
Owner XINFA PHARMA
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