A kind of preparation method of alogliptin and its intermediate

An intermediate and volumetric technology, applied in organic chemistry, bulk chemical production, etc., can solve the problems of unfavorable industrial production, long reaction time, and low yield

Active Publication Date: 2019-03-19
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome the long reaction time of the preparation method of the alogliptin intermediate in the prior art, the yield is relatively low, many by-products are difficult to purify, and the product needs column chromatography, which is not conducive to industrial production and other defects. And provide a kind of preparation method of alogliptin and its intermediate

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  • A kind of preparation method of alogliptin and its intermediate
  • A kind of preparation method of alogliptin and its intermediate
  • A kind of preparation method of alogliptin and its intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Embodiment 1: the preparation method of alogliptin intermediate II

[0049]

[0050] Add 6.65g of benzenesulfonic acid to 30ml of ethyl acetate to dissolve, and cool down to 5-15°C in an ice-water bath; Add 5.75g of pyrrolo[3,4-c]pyrazole to 30ml of ethyl acetate to dissolve it, add it dropwise into the solution of ethyl benzenesulfonate acetate at 5~15℃, stir for 30 minutes, remove from the ice-water bath, and store at 25±5℃ Stir at ℃ for 16 hours, filter with suction, add 35ml ethyl acetate to the filter cake to make slurry, filter with suction, wash the filter cake with 10ml ethyl acetate, dry the filter cake in vacuum at -0.08MPa~-0.1MPa, 40℃ for 10 hours, and get light yellow 6.3 g of off-white solid compound II was obtained, the HPLC purity was 96.52%, and the yield was 91.3%.

Embodiment 2

[0051] Embodiment 2: the preparation method of alogliptin intermediate II

[0052]

[0053] Add 3.3Kg of benzenesulfonic acid to 14L of ethyl acetate to dissolve, and circulate the refrigerated brine bath to drop to 5-15°C; 2.85Kg of )-pyrrolo[3,4-c]pyrazole was dissolved in 14L of ethyl acetate, and added dropwise into ethyl benzenesulfonic acid acetate solution at 5-15°C, stirred for 30 minutes, removed from the ice-water bath, and cooled at 25 Stir at ±5°C for 16 hours, centrifuge, add 17L ethyl acetate to the solid and stir for 1.5 hours; centrifuge, wash the solid with 4L ethyl acetate, dry the wet product at -0.08MPa~-0.1MPa, and vacuum dry at 40°C for 8 hours to obtain a light yellow solid Compound II 3.16Kg, yield 92.3%. HPLC: 96.75%.

Embodiment 3

[0054] Embodiment 3: the preparation method of alogliptin intermediate I

[0055]

[0056] Add 3.27g of compound III and 4.14g of compound II into 20mL N,N-dimethylacetamide, under nitrogen protection, add 2.93g of triethyl orthoformate at 5±5°C, and add 4.23g of sodium acetate borohydride in batches, After the addition, stir in an ice-water bath for 2 hours, heat to 50±5°C and react for about 10 hours; in an ice-water bath, add 60ml of water dropwise below 15°C, stir at this temperature for 1 hour after adding, heat to 50±5°C and stir for 2 hours hour, filter with suction, rinse the filter cake with water three times, add 20ml of water for beating for 1 hour, and filter with suction. Add 16ml of isopropyl ether to the filter cake, heat to 60±5°C, then add 16ml of n-heptane, cool to 15±5°C, keep stirring for 1 hour, filter with suction, -0.08~-0.1MPa, dry in vacuum at 40°C, 3.99 g of a white solid was obtained, with a yield of 80%. LCMS: m / z=499 (M+H) + ; HPLC: 98.62%; C...

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Abstract

The invention discloses Omarigliptin and a preparation method of an intermediate of the Omarigliptin, and provides a preparation method of an Omarigliptin intermediate I. The preparation method comprises the following step: enabling a compound II and a compound III to undergo a condensation reaction in a polar aprotic organic solvent in the presence of lewis acid and sodium borohydride acetate to obtain the Omarigliptin intermediate I. The preparation method disclosed by the invention has the advantages of simple and safe operation, no need of special purification equipment, short reaction time, fewer by products, high yield and simple post treatment operation; column chromatography separating operation in a post treatment process is avoided; a prepared product is high in purity, the optical purity is greater than or equal to 99,9 percent, the purity of a related substance is greater than or equal to 98.5 percent, and the purities of all impurities are smaller than or equal to 0.5 percent separately; the preparation method is low in production cost and is suitable for industrial production. In addition, according to the Omarigliptin prepared from the Omarigliptin intermediate I obtained by adopting the preparation method disclosed by the invention, the purity is greater than or equal to 99.5 percent, the purities of all the impurities are smaller than or equal to 0.1 percent separately, and the standards of crude drugs are reached. (The formula is shown in the description).

Description

technical field [0001] The invention relates to a preparation method of alogliptin and its intermediate. Background technique [0002] Alogliptin (MK-3102) is an ultra-long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor oral hypoglycemic drug developed by Merck in the United States. It is taken orally once a week and can produce sustained DPP -4 inhibitory effect, has a brand-new hypoglycemic mechanism, and has the advantages of not increasing body weight, not causing hypoglycemic reactions, and not causing edema. Its mechanism of action is to inhibit the degradation of glucagon-like peptide-1 (GLP-1) by DPP-4 enzyme in the body, prolong the action time of GLP-1, thereby increasing the concentration of endogenous GLP-1 and GIP in the blood. concentration, and ultimately improve blood sugar control, the structure of alogliptin is shown in Formula IV. [0003] [0004] Alogliptin intermediate I is the key intermediate of alogliptin IV. The synthesis method under the exis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 应述欢皮红军陈健
Owner SHANGHAI BOCIMED PHARMA CO LTD
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