................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 4 - Preparation Of Compound 4 ((3R,4S)-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-3-ol)
Preparation of dS,6S)-6-(3-(methylsulfonvnphenyl)-3-propyl-7-oxa-3-azabicyclo [4.1.Olheptane
Into a 4L reactor was added at room temperature Compound 8 (229g, 820mmol, leq) and 2N sulfuric acid (1147mL, 112g sulfuric acid, 1.147mol, 1.4eq). The reaction light yellow mixture was stirred and sodium bromate (126g, 836mmol, 1.02eq) was added. The mixture became yellow and the temperature dropped (endothermic dissolution). After 30min the reaction temperature reached 35°C and heated further to 40°C for 6h to give dark yellow solution with precipitate in the bottom of reactor. Toluene (2L) and NaOH (24%, 546g, 131g NaOH, 3.28mol, 4.0eq) were added and the reaction mixture was vigorously stirred for 1 hour at 42°C. The reaction mixture was then poured into a 4 L separation funnel. The dark water phase was discarded and the dark red organic phase was washed with 1.1L 5% sodium sulphite solution and 1L 20% brine. The organic phase was then concentrated on a rotavapor (50°C, 90-65 mbar, finally at 45mbar) to give l l lg dark red oil with crystals in the flask. A GC analysis (5mg red oil dissolved in 0.6 ml toluene) showed 53% area product, 29% and 5.2% area unknown peaks and 0.4% Compound 8. The product goes to the reduction in the next stage.
Preparation of (3S,4R -4-(3-(methylsulfonyl phenyl)-l-propylpiperidin-3-ol (Compound 4)
The epoxide from the previous stage (11 lg of 53% GC purity, 62.0g, 210mmol, leq) was dissolved in ethanol (1.2L) for lh. The red colored mixture was potired into 2L Parr reactor and a solution of 10% Pd/C (I4.6g, dry) in ethanol (50mL) was added. The mixture was reacted with hydrogen (4bar) at 30°C for lOhr. Pd/C was filtered through a Celite and the filtrate was concentrated in the rotavapor to give 108g red oil (65% area product by GC). The product was added to 200g silica gel, 0.5% triethylamine in dichloromethane were added and the mixture was concentrated and loaded on a column with 620g silica gel. The purification was done with 0.5% triethylamine in dichloromethane to give 28g hard residue (97.0% area by GC). The residue was heated to reflux in 34mL dichloromethane until complete dissolution to give clear red solution which was cooled slowly with parallel removal of some solvent by nitrogen flow over the solvent. The precipitation was filtered and washed with dichloromethane (5mL) to give 20g white solid, HPLC: 99.0% area, 1H-NMR assay: 99.4%.
NMR Identity Analysis of Compound 4
The following data in Tables 8 and 9 was determined using a sample of 54.06 mg Compound 4, a solvent of 0.55 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance III 400 MHz.
Table 8: 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.
0 Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 9: 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)