Triethylamine → GSI-136

Temperature

0 °C

To a reaction vessel was added a mixture of 3-pentanone (6.4 g), triethyl phosphonoacetate (34 g), NaH (3.6 g), and enough dry THF (250 mL), at 0° C. and maintained for 8 h to obtain α,β-unsaturated ester (ethyl 3-ethylpent-2-enoate) (2) (93%). This was followed by passing hydrogen gas (1 atm) over 10% Pd/C (250 mg), in MeOH (100 mL), for about 12 h at 25° C. To the reaction mixture was further added LiAlH4 (1.8 g), and dry THF (100 mL), at 0° C. for 12 h to obtain alcohol (3-ethylpentan-1-ol) (3) (83% for two steps). Alcohol (3) (6 g), was reacted with (o-iodoxy benzoic acid) (21.6 g), in dry DMSO (65 mL), at 25° C. for 2 h to yield aldehyde (3-ethylpentanal) (4). This is followed by addition of PhNO (nitrosobenzene)(5 g), L-proline (20 mol %)(1.3 g), in acetonitrile (250 mL), at −20° C. for 24 h and then added NaBH4 (7 g), in MeOH (100 mL). To the mixture is passed H2 gas (1 atm) over 10% Pd/C (250 mg), in MeOH (100 mL), for 12 h at 25° C., (77% over two steps) to obtain diol (3-ethylpentane-1,2-diol) (5). Then tert-butyl silylchloride (TBSCl) (7.5 g), in imidazole (4.5 g), and methylene chloride (200 mL), is added to the diol (5) at 0-25° C. (addition at 0° C. stirring at 25° C.) for 2 h to obtain (3-ethyl-2-hydroxy-pent-1-yloxy(tert-butyl)dimethylsilane) (6) (81%) followed by treatment with mesyl chloride (7.7 g), in triethyl amine (20 mL), for 45 min to yield (7). To the protected diol (3-ethyl-2-methansolphonyl-pent-1-yloxy(tert-butyl)dimethylsilane) (7) was added NaN3 (4 g), in dry DMF (100 mL), at 60° C. for 30 h, (78% for two steps) to obtain compound (2-azido-3-ethylpentyloxy tet-butyl dimethylsilane) (8). To the compound (8) was added LiAlH4 (2 g), in dry THF (100 mL), at 50° C. for 12 h to afford (S)-2-amino 3ethyl pentan-1-ol (9)(75%). A mixture of (S)-2-amino 3ethyl pentan-1-ol (9) (200 mg) and methylene chloride (20 mL) was placed under argon, and cooled to 0° C. Triethyl amine (484 mg) was added followed by the drop wise addition of 5-chlorothiophene-2-sulfonyl chloride (347.2) in methylene chloride (5 mL) for 30 min to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol (1A) (45.2% overall yield and 98% ee).

ORD record

ord-00785b674fc244afba14d49aa9a14fdd

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08440844B2