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Preparation method of chiral intermediate of omarigliptin

A technology of chiral intermediates and intermediates, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of high cost, unavailable raw materials, and low yield, and achieve the effects of stable properties, novel routes, and high yield

Active Publication Date: 2017-12-12
钟桂发
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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 chiral intermediate of omarigliptin
  • Preparation method of chiral intermediate of omarigliptin
  • Preparation method of chiral intermediate of omarigliptin

Examples

Experimental program
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Effect test

Embodiment 1

[0040] The synthesis of embodiment 1 intermediate (I)

[0041]

[0042] Dissolve 20g (0.123mol) (S)-4-benzyl-2-oxazolidinone in 200ml of dichloromethane, add 25.6ml (0.184mol) of triethylamine and 0.45g (0.0037mol) of 4-dimethylamino pyridine. With stirring in an ice bath at 0°C, (15.4 g, 0.15 mol) crotonyl chloride was added dropwise. Maintained at 0°C and stirred for 3h, TLC showed that the raw material had disappeared, added dichloromethane and water, separated the organic layer, dried, concentrated, and obtained intermediate (I) by silica gel column chromatography, 26.8g, yield: 89%, [M +H + ]: 246.1.

Embodiment 2

[0043] The synthesis of embodiment 2 intermediate (II)

[0044]

[0045] Method 1: Replace the nitrogen reaction bottle, add 24.5g (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

[0047] The synthesis of embodiment 3 intermediate (III)

[0048]

[0049] 19.3g (0.05mol) of intermediate (II) was dissolved in 150ml of tetrahydrofuran, and 3.6ml (0.0735mol) of hydrazine hydrate was slowly added dropwise under stirring in an ice bath at 0°C. Maintain stirring at 0 ° C for 2h. After TLC detection showed that the reaction was complete, ethyl acetate and water were added. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. 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 94%. , [M+H + ]: 243.1.

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Abstract

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

Description

technical field [0001] The present invention specifically relates to a preparation method of a chiral 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 incr...

Claims

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Application Information

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IPC IPC(8): C07D309/30
CPCC07B2200/07C07D309/30
Inventor 钟桂发吴毅武兰小兵
Owner 钟桂发
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