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Preparation methods for sitagliptin intermediates

A technology for sitagliptin and an intermediate, which is applied in the field of pharmaceutical synthesis chemistry, can solve problems such as unfavorable large-scale production, complicated reaction process operations, etc., and achieves the effects of good industrialization prospects, simple operation and easy availability of raw materials

Active Publication Date: 2012-06-20
SHANDONG BOYUAN PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Though above-mentioned route can make intermediate I and II with better yield, reaction process operation is numerous and diverse, is unfavorable for large-scale production

Method used

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  • Preparation methods for sitagliptin intermediates
  • Preparation methods for sitagliptin intermediates
  • Preparation methods for sitagliptin intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Preparation of 3-carbonyl-4-(2,4,5-trifluorophenyl)-butyric acid methyl ester (I, R=Me)

[0036] Put magnesium chips (2.64g, 0.11mol) and diethyl ether (25mL) in a 250mL reaction flask, and slightly reflux for 10 minutes (to activate the magnesium powder). Cool down to room temperature, add a grain of iodine (initiator), and dropwise add a solution of methyl 2-bromoacetate (15.3 g, 0.10 mol) in ether 75 mL. After dropping, react at a temperature of 35°C for 1 hour to prepare the Grignard reagent for use.

[0037] Put 2,4,5-trifluorophenylacetonitrile (17.1 g, 0.10 mol) and diethyl ether (120 mL) in a 250 mL reaction flask, cool down to 0° C., and slowly add the above Grignard reagent dropwise. The temperature was controlled not to exceed 15°C, and the reaction was carried out at room temperature for 2 hours after the drop was completed. After the reaction is complete, lower the temperature to 0°C, add hydrochloric acid (2N, 75mL) dropwise under temperature c...

Embodiment 2

[0038] Example 2 Preparation of 3-carbonyl-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester (I, R=Et)

[0039] Put magnesium chips (3.46g, 0.14mol) and tetrahydrofuran (35mL) in a 250mL reaction flask, and stir at 40°C for 10 minutes under temperature control. After cooling down to room temperature, a grain of iodine was added, and a solution of ethyl 2-bromoacetate (21.7 g, 0.13 mol) in tetrahydrofuran (85 mL) was added dropwise. After dropping, react at a temperature of 40°C for 1 hour to prepare the Grignard reagent for use.

[0040] Put 2,4,5-trifluorophenylacetonitrile (22.2g, 0.13mol) and tetrahydrofuran (120mL) into a 500mL reaction flask, cool down to 0°C, and slowly add the above Grignard reagent dropwise. The temperature was controlled not to exceed 15°C, and the reaction was carried out at room temperature for 3 hours after the drop was completed. After the reaction is complete, lower the temperature to 0°C, add hydrochloric acid (2N, 100mL) dropwise at a temper...

Embodiment 3

[0041] Example 3 1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazole-[4,3-a]pyrazine-7-)-4-(2 , 4,5-trifluorophenyl)-1,3-butanedione (II) preparation

[0042] Bromoacetic acid (13.9g, 0.10mol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Hydrochloride (III, 22.8g, 0.10mol) and acetonitrile (100mL) were placed in a 250mL reaction flask, and thionyl chloride (17.7g, 0.15mol) was added dropwise at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane (150 mL), washed with water (50 mL), 5% sodium bicarbonate solution (50 mL) and saturated brine (50 mL) successively. Dry over anhydrous magnesium sulfate, filter with suction, and concentrate under reduced pressure to obtain intermediate IV (29.1 g, yield 93%).

[0043] Magnesium chips (2.43g, 0.10mol) and ether (50mL) were placed in a 250mL reaction flask, and a solution of intermediate IV (28.8g, 0.092mol) in ether (100mL) was added dropwi...

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Abstract

The invention discloses preparation methods for sitagliptin intermediates including 3-carbonyl-4-(2,4,5-trifluorophenyl)-butyrate (I) and 1-(3-trifluoromethyl-5,6-dihydro-8H-(1,2,4) triazole-(4,3-a) pyrazine-7-)-4-(2,4,5-trifluorophenyl)-1,3-butanedione (II). The preparation method for the intermediate (I) includes the steps of preparing corresponding Grignard reagent by bromoacetate and magnesium powder by means of Grignard reaction, and preparing the intermediate I by means of addition reaction between the Grignard reagent and 2,4,5-trifluoro-benzeneacetonitrile. The preparation method for the intermediate (II) includes the steps of carrying out acylation reaction between bromoacetic acid and III under the action of condensing agent so that IV is prepared, carrying out Grignard reaction between the IV and magnesium powder so that corresponding Grignard reagent V is prepared, and finally preparing the intermediate (II) via addition reaction between the Grignard reagent V and 2,4,5-trifluoro-benzeneacetonitrile in organic solvent. The preparation methods for the sitagliptin intermediates are mild in reaction conditions, simple and convenient in operation and available in raw materials and have excellent industrialized prospect.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis chemistry and relates to a sitagliptin intermediate 3-carbonyl-4-(2,4,5-trifluorophenyl)-butyrate and 1-(3-trifluoromethyl- 5,6-dihydro-8H-[1,2,4]triazole-[4,3-a]pyrazine-7-)-4-(2,4,5-trifluorophenyl)-1, The preparation method of 3-butanedione. Background technique [0002] Sitagliptin, English name is Sitagliptin, chemical name 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: [0003] [0004] Sitagliptin is the first dipeptidyl peptidase-IV (DPP-IV) inhibitor drug approved by the US Food and Drug Administration (FDA) for the treatment of type II diabetes. It was developed by Merck and launched in 2006 . Sitagliptin improves the ability of diabetic patients to produce insulin by their own pancreatic β cells, and increases the secretion of insulin in the body when ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/738C07C67/343C07D487/04
Inventor 张立鹏张高峰赵孝杰陈贵军
Owner SHANDONG BOYUAN PHARM CO LTD
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