Preparation method of sitagliptin intermediate

A volume ratio, compound technology, applied in the field of preparation of sitagliptin intermediates, can solve the problems of low yield, unsuitable for industrial production, environmental pollution, etc., and achieve the effect of high yield

Inactive Publication Date: 2021-06-18
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The technical problem to be solved by the present invention is to overcome the defects in the intermediate preparation method of sitagliptin in the prior art that the yield is low, the reagent used is explosive, easily causes environmental pollution or is expensive, and is not suitable for industrial production, and provides A kind of preparation method of sitagliptin intermediate

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069]

[0070] In a 100ml single-neck bottle, add Intermediate 1 (2g, 10mmol) and dissolve it in dichloromethane (40ml), add methyl trifluoromethanesulfonate (3.28g, 2eq, 20mmol) dropwise under an ice-water bath, and slowly add The temperature was slowly raised to 40°C, and the reaction was carried out at this temperature for two hours, and the completion of the reaction was monitored by TLC. The reaction was cooled to room temperature, potassium carbonate (3.06g, 2.2eq, 22mmol) aqueous solution (20ml) was added, stirred for half an hour, and the organic phase was collected by separation. The aqueous phase was extracted three times with dichloromethane (30ml*3), the organic phases were combined and concentrated to obtain a colorless oily liquid 2 (1.8g, yield 84.1%), 1 H-NMR (400MHz, DMSO-d6): δ3.81 (s, 2H), 3.58 (s, 3H), 3.41-3.39 (m, J=8.0Hz, 2H), 3.31-3.26 (m, J=10.0 Hz, 2H), 1.41(s, 9H).

Embodiment 2

[0072]

[0073] In a 100ml single-necked bottle, add Intermediate 2 (1g, 4.67mmol) dissolved in acetonitrile (20ml), add trifluoroacetonitrile (658mg, 1.1eq, 5.14mmol) in acetonitrile (20ml) dropwise at room temperature, after the addition is complete The reaction was carried out at room temperature for 5 h, and the reaction was completed by TLC monitoring. The reaction solution was concentrated, separated and purified by normal phase silica gel column (methanol: dichloromethane=0-5% as mobile phase) to obtain colorless oily liquid 4 (1.2g, yield 82.8%), LCMS[M+Na] - :333.7. 1 H-NMR (400MHz, DMSO-d6): δ4.77(s, 2H), 4.18-4.15(t, J=12.0Hz, 2H), 3.84-3.81(t, J=12.0Hz, 2H), 1.44( s, 3H).

Embodiment 3

[0075]

[0076] In a 100ml single-neck bottle, intermediate 4 (120mg, 0.39mmol) was dissolved in methanol (10ml), the reaction solution was heated to 55°C, and concentrated hydrochloric acid (0.05ml, 1eq, 0.39mmol) was slowly added dropwise at this temperature. , After the dropwise addition, the reaction was carried out at this temperature for 2h, and a solid was gradually precipitated, and the TLC monitoring reaction was completed. The reaction solution was cooled to room temperature, stirred at room temperature for 0.5 h, added MTBE (30 ml), a solid was precipitated, filtered, and the filter cake was washed with ethanol: MTBE=1:3 (30 ml) to obtain a white solid, which was vacuum-dried at 45 °C to obtain the key intermediate The hydrochloride salt of 5 (78 mg, 88.1% yield), LCMS [M+H] - : 192.8. 1 H-NMR (400 MHz, DMSO-d6): δ10.50(s, 2H), 4.61(s, 2H), 4.46-4.43(t, J=12.0Hz, 2H), 3.65-3.62(t, J= 12.0Hz, 2H).

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Abstract

The invention discloses a preparation method of a sitagliptin intermediate. The preparation method of the sitagliptin intermediate comprises the following step: in a solvent, carrying out a reaction as shown in the specification on a compound as shown in a formula 2 and a compound as shown in a formula 3 to obtain a compound as shown in a formula 4. The preparation method is high in yield, avoids the use of explosive reagents and phosphorus oxychloride, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a sitagliptin intermediate. Background technique [0002] Diabetes is a chronic non-communicable disease sweeping the world. According to the 2017 Global Diabetes Overview recently updated on the IDF official website, about 425 million people worldwide suffer from diabetes, and the prevalence of diabetes among adults aged 20-79 is 8.8%. Type 2 diabetes, formerly known as adult-onset diabetes, mostly occurs after the age of 35 to 40, accounting for more than 90% of diabetic patients. The ability of type 2 diabetes patients to produce insulin is not completely lost. Some patients even produce too much insulin in their body, but the effect of insulin is poor. Therefore, the insulin in the patient's body is a relative deficiency, which can be stimulated by some oral drugs in the body. secretion of insulin. However, some patients still need to use insulin therapy in the later stage. [0003] Sitagliptin Ph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/08C07D241/06C07D487/04
CPCC07D241/06C07D241/08C07D487/04
Inventor 田松川王雪梅施玉芳
Owner SHANGHAI SUNTECH PHARMA
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