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Preparation method of omarigliptin intermediate

A technology of intermediates and chiral intermediates, which is applied in the field of preparation of alogliptin intermediates, can solve the problems of unavailable raw materials, high costs, and low yields, and achieve novel routes, stable properties, and high yields Effect

Active Publication Date: 2017-12-15
ANHUI HAIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is to provide a kind of oligliptin in order to overcome the defects of the existing chiral intermediate preparation method of ologliptin, the raw material is not easy to get, the cost is high, and the yield is low. The preparation method of the chiral intermediate of ting

Method used

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  • Preparation method of omarigliptin intermediate
  • Preparation method of omarigliptin intermediate
  • Preparation method of omarigliptin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The synthesis of embodiment 1 intermediate (I)

[0035]

[0036] Mix 12g (0.123mol) propargyl urea and 42.8ml (0.308mol) triethylamine, add 200ml of anhydrous THF, under the protection of nitrogen, lower the temperature to -25°C, slowly add 16.6ml (0.135mol) ) pivaloyl chloride, the dropwise addition was completed, and stirred for 2 hours. Then add 5.74g (0.135mol) anhydrous lithium chloride and 20g (0.123mol) (S)-4-benzyl-2-oxazolidinone successively, then slowly warming up to room temperature, stirring overnight, TLC shows that the raw material has disappeared, THF was removed under reduced pressure, ethyl acetate was added, washed twice with water, dried, concentrated, and silica gel column chromatography gave intermediate (I), 28.4g, yield: 90%, [M+H + ]: 258.1.

Embodiment 2

[0037] The synthesis of embodiment 2 intermediate (II)

[0038]

[0039] Method 1: replace the nitrogen reaction bottle, add 25.7g (0.1mol) of intermediate (I) and 163ml of anhydrous dichloromethane, lower the temperature to -5°C, and slowly add 32.9g (0.12mol) of trifluoroform Dibutylboron sulfonate, stirred for 10 minutes after dropping. Then 21 ml (0.15 mol) of triethylamine were added dropwise. After the dropwise addition was completed, the temperature was lowered to -70° C., and a solution of 15 g (0.105 mol) of 2,5-difluorobenzaldehyde in 50 ml of dichloromethane was slowly added dropwise. The temperature rose to -10°C over 1 hour and stirred for 1 hour. TLC shows that the reaction is complete, adding 102ml of potassium phosphate buffer successively, 53ml of methyl alcohol and 53ml of 35% hydrogen peroxide, separating the organic layer, washing with saturated sodium bicarbonate, washing with sodium thiosulfate, drying, and separating the intermediate (II) by silica ...

Embodiment 3

[0041] The synthesis of embodiment 3 intermediate (III)

[0042]

[0043] Into the reaction flask, 20 g (0.05 mol) of intermediate (II) 13.7 g (0.053 mmol), 226 ml of tetrahydrofuran and 57 ml of water were added. The temperature was cooled to 0 °C. 21.3ml (0.185mol) of 30% hydrogen peroxide and 80ml (0.08mol) of 1M lithium hydroxide were added dropwise in sequence. After the dropwise addition was completed, the reaction was stirred for 2 hours. TLC showed that the reaction was complete, and 142 ml of aqueous sodium sulfite (25 g of sodium sulfite) was added, extracted once with dichloromethane, and the pH value of the aqueous layer was adjusted to 2-3 with concentrated sulfuric acid. Ethyl acetate was extracted three times, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 11.4 g of intermediate (III), with a yield of 95%, [M+H + ]: 241.1.

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Abstract

The invention discloses a novel synthesis method for preparing a chiral intermediate of omarigliptin. The method disclosed by the invention comprises the following steps: taking crotonyl chloride and (S)-4-benzyl-2-oxazolidone as starting raw materials and carrying out amidation, alder condensation, hydrolysis, Curtius rearrangement, Boc addition and ring opening to obtain the chiral intermediate (VI). The preparation method disclosed by the invention has the advantages of relatively short route, relatively low cost, easiness for obtaining the raw materials and relatively high yield so that the preparation method is suitable for industrial production. A formula is shown in the description.

Description

technical field [0001] The present invention specifically relates to the preparation method of the intermediate of alogliptin. Background technique [0002] Omarigliptin (Omarigliptin, research and development code MK-3102) is an ultra-long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor oral hypoglycemic drug developed by Merck & Co. of the United States, its chemical name: (2R , 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-C]pyrazole-5(2H,4H,6H) -base) tetrahydro-2H-pyran-3-amine, chemical structure as shown in formula (1): [0003] [0004] Oral administration of Ologliptin once a week can produce a 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 increas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/16
CPCC07C51/06C07C269/06C07D263/20C07D263/26C07C271/16C07C59/48
Inventor 钟桂发兰小兵吴毅武
Owner ANHUI HAIKANG PHARMA
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