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(2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]octanamide[ No CAS ]
[ 173334-57-1 ]
Yield
Reaction Conditions
Operation in experiment
29%Chromat.; 71%Chromat.
With 2-hydroxypyridin; triethylamine; at 65℃;
EXAMPLE 58Preparation of compound according to formula 13 with X = NHR^,obtained by reacting a compound according to formula 2 (R? = H) with 3-amino-2,2-dimethylpropanamide.A round bottom flask was charged with compound according to formula 2 (R8 = H) (8.8 g), 3-amino-2,2-dimethylpropanamide (7.08 g) and triethylamine (3.50 g) and the viscous mixture was stirred at reflux in the presence of MTBE in order to obtain a homogeneous mixture. Under slow heating to 650C, the MTBE was removed by distillation and the remaining residue allowed to stir for 20 hours at 650C in the presence of 2-hydroxypyridine (1.94 g). At complete conversion of compound according to formula 2, the reaction mixture was dissolved in MTBE (71 ml.) and the MTBE layer extracted by 5 % NaCI in water (2 x 71 ml_). The combined water layers were washed by MTBE ( 3 X 71 ml.) and the combined MTBE layers (total of 4 fractions) dried over Na2SO4 anhydrous, filtrated and the MTBE evaporated in vacuo giving the crude product in 10.29 g. The crude product was dissolved in MTBE (71 ml.) followed by extraction with 1 N HCI (15 ml.) and water (2 x 15 ml_). The combined water layers washed with MTBE (71 ml.) and the combined MTBE layers washed with water (2 x 14 ml_). Under cooling and vigorous stirring, the pH of the combined water layers was adjusted to pH 11 by 32 % NaOH in the presence of MTBE (71 ml_), MTBE separated and the remaining basic water layer washed with MTBE (5 x 71 ml_). The combined MTBE layers were dried over Na2SO4 anhydrous, filtrated and removal of MTBE in vacuo affording compound according to formula 13 in with stereomeric ratios of (4S,5S)-13 (71 area %) and other stereoisomers of 13 (29 area %) according to HPLC.
(3S,5S)-5-{(1R,3S)-1-bromo-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-4-methylpentyl}-dihydro-3-(1-methylethyl)furan-2(3H)-one[ No CAS ]
[ 324763-51-1 ]
[ 173334-57-1 ]
Yield
Reaction Conditions
Operation in experiment
A mixture of (3S,5S)-5-((lR,3S)-l-bromo-3-(4-methoxy-3-(3-methoxy propoxy)benzyl)-4-methyl pentyl)-3 -isopropyl dihydrofuran-2(3H)-one compound of formula- 10a (10 gm), sodium azide (3.9 gm) and DMPU (80 ml) was heated to 75-80C and then stirred for 4 hours at 75-80C. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with methyl tert.butyl ether. The methyl tert.butyl ether layer was washed with sodium bicarbonate solution followed by brine solution. Distilled off the solvent completely to get (3S,5S)-5-((lS,3S)- l-azido-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-iso- propyldihydrofuran-2(3H)-one compound of formula- 11 as a residue. 3-amino-2,2- dimethyl propanamide compound fo formula- 12 (8.8 gm), 2-hydroxy pyridine (2gm) and triethyl amine (10 ml) were added to the above residue and heated to 85-90C and then stirred for 15 hours at 85-90C. After completion of the reaction, the reaction mixture was cooled to 25-30C and quenched with 5% aqueous sodium bicarbonate solution. Extracted the product with ethyl acetate and the ethyl acetate layer was washed with 5% aqueous sodium bicarbonate followed by brine solution. Distilled off the solvent completely under reduced pressure to get the (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3- oxopropyl)-5 -azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3 -(3 -methoxypropoxy)benzy 1)- 8-methyl nonanamide compound of formula- 13 as a residue. The above residue was dissolved in isopropyl alcohol (100 ml), added Pd/C (5 gm) and applied hydrogen pressure for 3 hours. After completion of the reaction, the reaction mixture was filtered through hyflow bed and washed the bed with isopropyl alcohol. Distilled off isopropyl alcohol from the filtrate, water and methyl tert.butyl ether were added to the reaction mixture and stirred for 10 minutes. Adjusted the pH of the reaction mixture to 3.0 with aqueous HC1 and separated the methyl tert.butyl ether layer. The aqueous layer was washed repeatedly with methyl tert.butyl ether and added dichloromethane into the aqueous layer. Adjusted the pH to 9.5 with aqueous sodium carbonate solution, then separated both the organic layer and aqueous layers. The organic layer was washed with water. Distilled off the solvent completely to get the title compound. Yield: 4.0 grams; Purity by HPLC: 90%.
With 2-hydroxypyridin; hydrogenchloride; triethylamine; In methanol; at 80℃;
(2S, 4S) -4-isopropyl-5-oxofuran-2-ylmethyl) -2-Yl) -3- (4-methoxy-3- (3-methoxypropoxy) benzyl) -4-methylpentyl) -2-tert-butylsulfinamide(XIV) (2.7 g, 5 mmol), triethylamine (3 mL), 2-hydroxypyridine (1.42 g, 15 mmol) and 3-Amino-2,2-dimethylpropanamide (1.74 g, 15 mmol) was added and the reaction was heated to 80 C overnight. After completion of the reaction,20 mL of methanol and 3 mL of concentrated hydrochloric acid (36 mmol) were added and the reaction was stirred overnight at room temperature.The solvent was removed by concentration under reduced pressure, and the residue was subjected to column chromatography to give aliskiren (1.87 g, yield: 68%).The purity of the prepared alikren was 98.5% by HPLC.
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