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A kind of method for preparing evacetrapib (evacetrapib) intermediate
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A technology of esetrapib and intermediates, applied in the field of preparation of esetrapib (Evacetrapib) intermediates
Active Publication Date: 2016-01-06
WUHAN WUYAO PHARMA
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Embodiment 1
[0027] The synthesis of embodiment 1 compound 4-azepanenone
[0028] N-vinylpyrrolidone (30g, 0.27mol) was irradiated with a 50-watt low-pressure mercury UV light in 1600mL of methanol at 40°C, stirred for 45 hours, concentrated under reduced pressure, and the resulting oil was recrystallized in acetonitrile to obtain 4-azacyclic Heptenone 24g, yield 80%. Melting point: 74-76°C. 1 HNMR (400MHz, CDCl 3 ):δ6.90(d,J=10.9Hz,1H),5.14(d,J=10.9Hz,1H),2.99-2.90(m,4H),2.00(s,1H),1.96-1.86(m, 2H).
Embodiment 2
[0029] The preparation of embodiment 2N-p-toluenesulfonyl-4-azepanenone
[0030] Add 24g (0.216mol) of 4-azepanenone, 125ml of dichloromethane, 125ml of pyridine, and 0.3g of 4-dimethylaminopyridine into a 500mL single-necked round bottom flask, and then add 41.18g of p-toluenesulfonyl chloride ( 0.216mol), the mixture was stirred at room temperature for 8 hours. Then add 100mL1N hydrochloric acid, extract with dichloromethane (50mL×3), combine the organic phases, wash with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure to obtain 55.0 g (0.207 mol) of a white solid, with a yield of 96%. 1 HNMR (400MHz, CDCl 3 ):δ7.74(dd,J=7.5,1.5Hz,2H),7.40(dd,J=7.5,1.5Hz,2H),6.92(d,J=10.9Hz,1H),5.14(d,J= 10.9Hz, 1H), 3.16(m, 2H), 2.94(m, 2H), 2.34(s, 3H), 1.96-1.86(m, 2H).
Embodiment 3
[0031] Example 3 Preparation of N-p-toluenesulfonyl-7,9-dimethyl-2,3,4,5,9,10-hexahydro-1H-1-benzazepin-5-one
[0032] Add N-p-toluenesulfonyl-4-azepanenone (2.65g, 10mmol), 2-butenal (800mg, 1.0mmol), (S)-diphenyltrimethyl Siloxymethylpyrrolidine (5mg), chloroform (15ml), and p-nitrobenzoic acid (5mg) were reacted at room temperature for 48 hours and separated by column chromatography to obtain 213mg (0.68mmol) of the product, with a yield of 68%. 1 HNMR (400MHz, CDCl 3 )δ7.74(d,J=7.5Hz,2H),7.40(d,J=7.4Hz,2H),6.81(d,J=0.8Hz,1H),5.58(dd,J=6.2,0.7Hz, 1H),3.29(dt,J=12.4,4.8Hz,1H),3.27(s,1H),3.21(pd,J=6.4,0.8Hz,1H),3.11(dt,J=12.4,4.9Hz,1H ),2.89–2.98(m,2H),2.34(s,3H),1.47–1.57(m,2H),2.21(d,J=0.5Hz,3H),1.11(d,J=6.5Hz,3H) .
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Abstract
The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing an important intermediate 7, 9-dimethyl-2, 3, 4, 5-tetrahydro-1H-1-benzo-azepine-5-one of cholesteryl ester transfer protein (CETP) inhibitor evacetrapib. The method takes N-vinyl pyrrolidone as the raw material, and comprises steps of carrying out rearrangement in illumination, protecting through tosyl, reacting with 2-methyl-2-pentenal so as to generate nitrogen-protected 7, 9-dimethyl-2, 3, 4, 5, 9, 10-hexahydro-1H-1-benzo-azepine-5-one, in the presence of manganese dioxide, dehydrogenizing and aromatizing, and finally removing protecting group, so as to obtain 7, 9-dimethyl-2, 3, 4, 5-tetrahydro-1H-1-benzo-azepine-5-one. The method saves the Kleiman condensation reaction or Friedle-Crafts reaction in the conventional synthesis method, thus avoiding use of potassium tert-butoxide and aluminum trichloride, having mild reaction conditions, using the raw materials easy to obtain, lowering the cost, and being more applicable to industrial production.
Description
technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of an Evacetrapib intermediate. Background technique [0002] CETP is a glycoprotein in plasma, which can change cholesterol ester from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and even very low-density lipoprotein (VLDL), and exchange triglyceride, so that in It plays an important role in regulating plasma HDL levels and remodeling HDL particle composition. Therefore, CETP inhibitors are considered to be one of the drugs with the most therapeutic potential for coronary atherosclerosis. [0003] There are two main types of CETP inhibitors currently under development: one is Merck’s anacetrapib, which Thomson Reuters predicts has a “blockbuster” sales prospect, and the other is Eli Lilly’s drug that has entered phase III clinical trials. Evacetrapib. Evacetrapib inhibits the cholesteryl ester transfer protein (CETP) that transport...
Claims
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