Preparation method of selective PPAR delta agonist GW501516
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An agonist and selective technology, which is applied in the synthesis of pharmaceutical intermediates and the preparation of selective PPARδ agonist GW501516, which can solve the problems of synthetic safety hazards and achieve the effects of short steps, high reaction yield and mild reaction conditions
Active Publication Date: 2019-06-18
无锡科华生物科技有限公司
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[0004]
In this reaction, there are hidden dangers of synthetic safety, so it is necessary to develop a suitable synthetic method to solve the problem of simple and stable synthetic operation, high yield, environmental friendliness, low production cost, safe operation and suitable for industrial scale-up production.
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Embodiment 1
[0034]
[0035] 108.1 g (1 mol) of o-cresol, 130.9 g (1.1 eq) of potassium bromide, and 2.5 Kg of acetonitrile were put into the reaction flask. Under stirring at room temperature, add 677g (1.1eq) of potassium monopersulfate compound salt in batches under temperature control at 25-30°C, react at room temperature for 6 hours, HPLC detects that the raw material is 1 HNMR (400MHz, CDCl3): 7.36-7.34(d, 1H), 6.71-6.75(d, 1H), 6.58-6.53(dd, 1H), 4.73(s, 1H), 2.34(s, 3H).
Embodiment 2
[0037]
[0038] 108.1 g (1 mol) of o-cresol, 183 g (1.1 eq) of potassium iodide, and 2 Kg of methanol were put into the reaction flask. Under stirring at room temperature, add 677g (1.1eq) of potassium monopersulfate compound salt in batches under temperature control at 25-30°C, react at room temperature for 8 hours, HPLC detects that the raw material is 1 HNMR (400MHz, CDCl3): 7.45-7.41(d,1H), 7.36-7.34(d,1H), 6.56-6.52(dd,1H), 4.78(s,1H), 2.20(s,3H).
Embodiment 3
[0040]
[0041] 108.1 g (1 mol) of o-cresol, 183 g (1.1 eq) of potassium iodide, and 0.6 Kg of acetonitrile were put into the reaction flask. Under stirring at room temperature, 340g (1.25eq) of 23% peracetic acid was added dropwise under temperature control at 25-35°C, reacted at room temperature for 5 hours, and the raw material was detected by HPLC 1 HNMR(400MHz, CDCl3):7.45-7.41(d,1H),
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Abstract
The invention discloses a preparation method of selective PPAR delta agonist GW501516 and belongs to the technical field of medical intermediate synthesis. The preparation method includes: allowing o-methylphenol serving as the raw material to have reaction with iodine / potassium bromide by the aid of an oxidizing agent to obtain 4-iodine / bromo-2-methylphenol, allowing the 4-iodine / bromo-2-methylphenol to have reaction with chlorine / tert-butyl bromoacetate to obtain (4-bromo / iodine-2-methyl phenoxy)-tert-butyl acetate, performing Grignard reagent exchanging, allowing the product obtained afterthe Grignard reagent exchanging to sequentially have reaction with sulfur powder and 5-(bromomethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole to obtain 2-[2-methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]methyl]sulfo]phenoxy] tert-butyl acetate, and performing hydrolysis to obtain the selective PPAR delta agonist GW501516. The preparation process is simple in process operation, mild in conditions, cheap in raw materials, easy in raw material obtaining and capable of providing reference for the large-scale synthesis of the agonist.
Description
technical field [0001] The invention relates to the synthesis of pharmaceutical intermediates, in particular to a preparation method of selective PPARδ agonist GW501516, which belongs to the technical field of organic synthesis. Background technique [0002] 2-(4-((2-(4-(trifluoromethyl)phenyl)-5-methylthiazol-4-yl)methylthio)-2-methylphenoxy)acetic acid, also known as 2-[2-Methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]methyl]thio]phenoxy]acetic acid, Abbreviation: GW501516, CAS: 317318-70-0, molecular formula: C 21 h 18 f 3 NO 3 S 2 . GW501516 is a peroxisome proliferator-activated receptor PPARδ agonist, which can significantly improve body functions. It can be used in the synthesis of related drugs and has attracted widespread attention in the scientific community as an important intermediate. The market demand for this product is increasing, and the market prospect is good. [0003] At present, this product shows more and more application value, ...
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