................DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution
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Thursday, 9 February 2017
Example 6 - Preparation Of Compound (l-(2-methylpentyl)-4-(3-(methylsulfonyl)phenyl)piperidine)
Into a 1L autoclave was added KI (28.4g, 171mmol leq) and potassium carbonate (47.4g, 343mmol, 2eq). 4-(3-(methylsulfonyl)phenyl)piperidine (41g, 171mmol, leq) was dissolved in acetonitrile (420mL) and the mixture was added into the autoclave followed by l-chloro-2-methylpentane (25.8mL, 188mmol, l .leq). The autoclave was closed and the reaction mixture was heated under nitrogen atmosphere to 120°C for 30hr. The reaction mixture was cooled down and filtered. The cake was washed with acetonitrile and the filtrate was concentrated in vacuum to give 70g crude product with the following HPLC areas: 60% of Compound 6, 1% of 4-(3-(methylsulfonyl)phenyl)piperidine and 10% of a by-product. The crude product was dissolved in toluene (350ml) and about 20g solid material was filtered. The toluene phase was washed with water (200mL) and concentrated in a rotavapor to give 35.5g (73% area of product by HPLC). The residue was then dissolved in ethyl acetate (180mL) and cooled on ice bath. Into the reaction mixture was then added 33mL of 18% HC1 solution in ethyl acetate in lhr and the mixture was stirred for an additional lh. The precipitate that was formed was then filtered, washed with ethyl acetate and dried to give 36.3g white solid (HPLC: 94% area. The product was recrystallized by dissolving in methanol (290mL), heating to 70°C, adding ethyl acetate (400mL) and cooling to room temperature. The precipitate was filtered, washed with ethyl acetate (60mL) and dried in vacuum at 50°C to give 28.3g Compound 6 (HPLC: 99.5% area, 1H-NMR assay: 99.6%).
NMR Identity Analysis of Compound 6
The following data in Tables 12 and 13 was determined using a sample of 33.93 mg Compound 6, a solvent of 8 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΓΠ 400 MHz. Two conformers (ca 10: 1) at room temperature are observed. Due to the overlap of proton signals of the major and minor conformers and relatively weak signal of the minor isomer in 2D speactra only some of the peaks of minor isomer on 1 H spectra and corresponding 1 H-l H COSY cross peaks are given. Due to the low solubility of the material in D6-DMSO some of the expected HMBC signals are masked by background noise.
Table 12: Assignment of ¾ NMRa'c
a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts.
b Weak signal.
c Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 13: Assignment of 13C NMRa'b
a The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and HMBC experiments.
b Spectra is calibrated by a solvent peak (39.54 ppm)