* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With toluene-4-sulfonic acid In ethanol at 20℃; for 48 h; Stage #2: With sodium hydrogencarbonate In ethyl acetate
The alkyne of formula II (R=Me) (200 mg, 0.40 mmol) is dissolved in absolute ethanol (0.8 ml) and then treated with monohydrate p-toluenesulfonic acid (383 mg, 2.02 mmol). After 10 minutes, Ph3AuCl (4 mg, 0.0081 mmol, 2percent molar) and AgCF3SO3 (2 mg, 0.0081 mmol, 2percent molar) are added. After 48 h, at room temperature, the ethanol is evaporated under reduced pressure and the residue is taken up with ethyl acetate and basified till pH 10-11 with a NaHCO3 solution. The phases are separated, and the aqueous one is extracted with ethyl acetate. The organic phases are collected, dried with Na2SO4, filtered off and evaporated under reduced pressure. The crude reaction is purified by flash chromatography (acetate/methanol 9:1 as eluent) and 198 mg of title keto compound are obtained as a white solid, with a yield of 95percent.1H NMR (400 MHz, CDCl3) δ ppm: 7.94 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 4H), 7.43 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 4H), 7.22-7.17 (m, 2H), 3.65 (s, 3H), 3.04-2.95 (m, 4H), 2.49-2.42 (m, 3H), 2.05-1.92 (m, 4H, 1H exchanges with D2O), 1.62 (s, 6H), 1.52-1.41 (m, 4H).
28.3%
at 55℃; for 3.5 h;
Methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate To a vial was added the methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)but-1-yn-1-yl)phenyl)-2-methylpropanoate (KSC-335-054) (0.074 g, 0.149 mmol). The mercuric oxide (1.493 ml, 0.045 mmol) was made into a 0.03 M solution in 4percent w/v sulfuric acid and added to the starting material then heated to 55° C. and stirred for 3.5 h. The reaction turned a milky white color upon addition of the mercuric oxide solution. The reaction was removed from heat and diluted with saturated NaHCO3 (10 mL) and extracted with DCM (3*10 mL). The DCM layers were combined and dried with MgSO4, filtered and concentrated then purified by reverse-phase MPLC (10-100percent MeCN:water) to produce methyl 2-(4-(4-(4-(hydroxydiphenylmethyl) piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate (0.0217 g, 0.042 mmol, 28.3percent yield). 1H NMR (400 MHz, CDCl3): δ 7.93-7.91 (m, 2H), 7.48-7.45 (m, 4H), 7.42-7.39 (m, 2H), 7.30-7.26 (m, 4H), 7.19-7.14 (m, 2H), 3.63 (s, 3H), 2.96-2.88 (m, 4H), 2.44-2.34 (m, 3H), 2.08 (br s, 1H), 1.60 (s, 6H), 1.62-1.56 (m, 4H), 1.46-1.30 (m, 4H).
Reference：
[1] Patent: US2010/228034, 2010, A1, . Location in patent: Page/Page column 3
[2] Patent: EP1260505, 2002, A1, . Location in patent: Example 6
[3] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562
[5] Patent: US2015/238473, 2015, A1, . Location in patent: Paragraph 0237
2
[ 115-46-8 ]
[ 154477-54-0 ]
[ 154477-55-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium hydrogencarbonate; potassium iodide In toluene at 80℃; for 30 h; Reflux
1000 mL reaction flask, 55.4 g of diphenylpiperidine methanol was added successively, 42.1 g of potassium bicarbonate, 3.1g potassium iodide, 310 mL of toluene, Heated to 80 ° C, A solution of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI) (53.3 g) in toluene (150 ml) was slowly added dropwise, Plus, Reflux reaction about 30h, HPLC monitoring reaction is complete, The reaction solution was cooled to 10 to 15 ° C, filter, The filtrate was concentrated to give 107 g of crude product; With 250mL anhydrous ethanol heated reflux solution, Dropping 80 mL of water, After refluxing for 30 min, Natural cooling to 10 ~ 15 deg C, Insulation stirring 4h, Filtration gave an off-white solid, Drying 90g; And then recrystallized with EA, To obtain 77.4 g of methyl 2- [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -butanoyl] phenyl] -2-methylpropionate (VII) as a white solid, Purity 99.5percent Yield 80percent. among them, The molar ratio of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI), potassium iodide and base is 1: 0.1: 2.23.
With zinc(II) fluoride; tri-tert-butyl phosphine In N,N-dimethyl-formamide at 80℃; for 2 h;
EXAMPLE 8 Two grams of 3, 90 mg of P(tBu)3, 300 mg of Pd(dba)2, 250 mg of ZnF2 and 1.1 g of 5 were dissolved in 330 mL of DMF under argon. The mixture was heated to 80° for two hours, cooled to room temperature, diluted with ether and worked up as described in example 1. The resulting product was filtered through silica to provide 1.3 g (62percent) of 6.
Scheme A, optional step f: Preparation of 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid methyl ester 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid methyl ester (2.05 g, 0.00398 mol) was dissolved in 100 mL of acetone and chilled in an ice-bath. To the solution was added Jones reagent (Prepared via the method of Feiser and Feiser) dropwise until a red color persisted. The reaction was allowed to warm to room temperature and then stirred for 18 hours at ambient temperature. The mixture was concentrated under vacuum to give a green solid. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was separated, washed with water (3*100 mL), brine (1*100 mL) and treated with MgSO4, filtered and concentrated in vacuo to give a light green solid. Purification via column chromatography yielded 1.25 g (61percent yield) of the title compound as a white solid. MH+514.6.
Reference：
[1] Patent: US2003/105329, 2003, A1,
5
[ 1451149-72-6 ]
[ 154477-55-1 ]
Yield
Reaction Conditions
Operation in experiment
5.8 g
With sulfuric acid; water In methanol at 40℃; for 12 h;
EXAMPLE 12 Synthesis of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate (Compound VIII) In a reaction flask 7.0 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methylpropanoate (0.01 mol), 35 ml methanol, 5 ml water, 1.5 g sulfuric acid 96percent (0.015 mol) were charged, the temperature was brought to 40° C. and the reaction mixture was kept under these conditions for twelve hours. At the end of the reaction, the temperature was brought to 15° C., 20 ml water and ammonia 30percent solution up to pH 8 were added, the resultant solid was filtered and dried in oven at 40° C. under vacuum to give 5.8 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate.
With sodium hydrogencarbonate; potassium iodide In water; toluene for 20 h; Reflux
EXAMPLE 8 Preparation of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate In a reaction flask 5 g methyl 4-(4-bromo-1-oxybutyl)-α,α-dimethylphenylacetate (0.15 mol), 25 ml toluene, 4.08 g azacyclonol (0.015 mol), 10 ml water, 1.53 g sodium bicarbonate (0018 mol) and 0.25 g potassium iodide (0.0015 mol) were charged, the reaction mixture was brought to the reflux temperature and kept under these conditions for 20 hours. At the end of the reaction, the temperature was brought to 25° C., the separated organic phase was concentrated to residue by distillation under vacuum to give 7 g methyl 2-(4-(4-(4-(hydroxy-diphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate.
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