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With phosphorus(V) oxybromide In N,N-dimethyl-formamide at 20℃; for 8 h;
Embodiment 1 Synthesis of (R)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl bromide Dissolve (R)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl butanol (14.82 g, 50 mmol) in N,N-dimethyl formamide (234 ml), add phosphorus oxybromide (14.33 g, 50 mmol) in droplets slowly and control the temperature at 20° C. in that process, and then let them to react at 20□ for 8 hours. Cool down to room temperature, and pour the reactant liquid into water (702 ml) slowly, extract with normal hexane for three cycles, combine the normal hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 17 g of oily matter. Add 51 ml of methanol, control the product to crystallize at -10° C., filter, and then treat the filter cake by vacuum drying at room temperature, so as to obtain 14.3 g of white solid matter; the yield is 79.6percent, mp: 51-53° C., chiral purity: ≧99.9percent. 1HNMR (ppm, CDCl3): 6.72-6.81 (m, 3H), 4.11 (t, J=6.4 Hz, 2H), 3.84 (s, 3H), 3.58 (t, J=6.4 Hz, 2H), 3.42 (dd, J=4.5, 10.2, 1H), 3.36 (s, 3H), 3.30 (dd, J=4.5, 10.2, 1H), 2.77 (dd, J=4.8, 13.8, 1H), 2.48 (dd, J=4.8, 13.8, 1H), 2.11 (m, 2H), 1.86 (m, 1H), 1.60 (m, 1H), 0.99 (m, 6H).
Reference：
[1] Helvetica Chimica Acta, 2003, vol. 86, # 8, p. 2848 - 2870
[2] Tetrahedron Letters, 2005, vol. 46, # 37, p. 6337 - 6340
[3] Patent: US2013/231509, 2013, A1, . Location in patent: Paragraph 0021-0022
[4] Patent: WO2011/148392, 2011, A1, . Location in patent: Page/Page column 62
[5] Patent: WO2012/78147, 2012, A1, . Location in patent: Page/Page column 19-20
[6] Organic Process Research and Development, 2013, vol. 17, # 11, p. 1458 - 1462
With phosphorus(V) oxybromide; In N,N-dimethyl-formamide; at 20℃; for 8h;
Embodiment 1 Synthesis of (R)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl bromide Dissolve (R)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl butanol (14.82 g, 50 mmol) in N,N-dimethyl formamide (234 ml), add phosphorus oxybromide (14.33 g, 50 mmol) in droplets slowly and control the temperature at 20 C. in that process, and then let them to react at 20? for 8 hours. Cool down to room temperature, and pour the reactant liquid into water (702 ml) slowly, extract with normal hexane for three cycles, combine the normal hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 17 g of oily matter. Add 51 ml of methanol, control the product to crystallize at -10 C., filter, and then treat the filter cake by vacuum drying at room temperature, so as to obtain 14.3 g of white solid matter; the yield is 79.6%, mp: 51-53 C., chiral purity: ?99.9%. 1HNMR (ppm, CDCl3): 6.72-6.81 (m, 3H), 4.11 (t, J=6.4 Hz, 2H), 3.84 (s, 3H), 3.58 (t, J=6.4 Hz, 2H), 3.42 (dd, J=4.5, 10.2, 1H), 3.36 (s, 3H), 3.30 (dd, J=4.5, 10.2, 1H), 2.77 (dd, J=4.8, 13.8, 1H), 2.48 (dd, J=4.8, 13.8, 1H), 2.11 (m, 2H), 1.86 (m, 1H), 1.60 (m, 1H), 0.99 (m, 6H).
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at -40 - 30℃; for 5.5h;Product distribution / selectivity;
49 grams of triphenyl phosphine was added to the mixture of (R)-2-(4-methoxy- 3-(3-methoxypropoxy)benzyl)-3-methylbutan-l-ol compound of formula-23 (30 gm) and dichloro methane (450 ml) at -30 to -40C. 35 grams of N-bromo succinimide was added to the reaction mixture at -30 to -40C and stirred for 30 minutes at same temperature. The temperature of the reaction mixture was raised to 25-30C and stirred for 5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution. Separated the both the organic and aqueous layers and the aqueous layer was extracted with dichloro methane. The organic layer was distilled off completely and the obtained residue was co-distilled with ethyl acetate. Cyclohexane was added to the obtained residue and stirred for 1 hour. The reaction mixture was filtered. Distilled off the solvent completely from filtrate under reduced pressure. N-hexane was added to the obtained residue and stirred for 1 hour at 0-5C. The reaction mixture was filtered, and the solvent from the filtrate was distilled off completely. N-hexane and diethyl ether were added to the obtained residue and cooled to -20C. The reaction mixture was stirred for 1 hour, filtered, washed with chilled N- hexane and dried to get the title compound as a solid. Yield: 20 grams.
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 5 - 10℃; for 4h;
100 gm of 4-[(2R)-2-(hydroxymethyl)-3-methylbutyl]-1 -methoxy-2-(3- methoxypropoxy)-benzene as prepared in Example 6 was dissolved in 2200 ml of MDC and cooled to about 5C. 152 gm of thphenyl phosphine and 103 gm of N-bromo succinimide were added to the reaction mass while maintaining the temperature below 10C. The reaction mixture was stirred for about 4 hours while maintaining the temperature below 10C. The reaction mass was then concentrated under vacuum to obtain a black residue. 500 ml of hexane was added to the residue, and the reaction mass was stirred at reflux for 1 hour. The insoluble solids were filtered off. The clear filtrate was concentrated under vacuum to obtain the product 4-[(2R)-2-(bromomethyl)- 3-methylbutyl]-1 -methoxy-2-(3-methoxypropoxy)-benzene.
In 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; at 50℃; for 2h;
To a solution of 4-((/?)-2-bromomethyl-3-methyl-butyl)-1-methoxy-2-(3-methoxy-propoxy)- benzene, prepared as described in HeIv. Chimica Acta 2003, 86, 2848-2870, (30.5 g, 84.9 mmol) in DMPU (450 mL) is added in portions NaCN (17.5 g, 357 mmol) with stirring. The reaction mixture is warmed to 50 C for 2 h, followed by addition of water after cooling to ambient temperature. The aqueous layer is extracted with EtOAc1 and the combined organics are repeatedly washed with water, dried (Na2SO4) and concentrated. The crude product is purified by flash chromatography on silica gel (eluent gradient: hexane/EtOAc 85:15 to 70:30) to give the title compound as colorless oil. TLC, Rf (hexane/EtOAc 3:1) = 0.32. MS: 306.2 [M+H]+and 323.2 [M+18]+.
In 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; at 50℃; for 2h;
A. (S)-3-[4-Methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentanenitrile; To a solution of 4-((/?)-2-bromomethyl-3-methyl-butyl)-1-methoxy-2-(3-methoxy-propoxy)- benzene, prepared as described in HeIv. Chimica Acta 2003, 86, 2848-2870, (30.5 g, 84.9 mmol) in DMPU (450 ml_) is added in portions NaCN (17.5 g, 357 mmol) with stirring. The reaction mixture is warmed to 50 0C for 2 h, followed by addition of water after cooling to ambient temperature. The aqueous layer is extracted with EtOAc, and the combined organics are repeatedly washed with water, dried (Na2SO4) and concentrated. The crude product is purified by flash chromatography on silica gel (eluent gradient: hexane/EtOAc 85:15 to 70:30) to give the title compound as colorless oil. TLC, Rf (hexane/EtOAc 3:1) = 0.32. MS: 306.2 [M+H]+and 323.2 [M+18]+.
(S)-3-Isopropyl-5-((1S,3S)-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-1-[1-phenyl-meth-(E)-ylidene]-amino}-pentyl)-dihydro-furan-2-one[ No CAS ]
(3R,5S)-dihydro-5-[(1S,3S)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(phenylmethyl)amino]pentyl]-3-(1-methylethyl)-2(3H)-furanone[ No CAS ]
{(1S,3S)-1-[(S)-4-(1-Hydroxy-1-methyl-ethyl)-5-oxo-tetrahydro-furan-2-yl]-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-carbamic acid benzyl ester[ No CAS ]
((1S,2S,4R)-4-Butylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester[ No CAS ]
(1S,4S,2'S)-(4-benzyloxymethyl-2-hydroxy-1-{2'-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl}-5-methylhexyl)carbamic acid tert-butyl ester[ No CAS ]
((1S,2R,4S)-4-(2-Carbamoyl-2-methyl-propylcarbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester[ No CAS ]
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