(<I>S</I>)-(+)-2-氨基-3-甲基-1-丁醇

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The synthesis is schematically shown in Scheme-2. L-Valinol (40 mg) was reacted with commercially available Fmoc-Lys(MMT)-OH (253 mg) and EEDQ (107 mg) in 10 mL of anhydrous dichloromethane at ambient temperature, under argon, for 3 h. Extractive work up followed by flash chromatography furnished the product Fmoc-Lys(MMT)-valinol as a pale yellow liquid (200 mg; ˜70% yield). HPLC: tR14.38 min; electrospray mass spectrum. M+H: m/z 727. This intermediate (200 mg) was deprotected with diethylamine (10 mL), and the product (135 mg) was obtained in ˜90% purity after flash chromatography. HPLC: tR 10.91 min; electrospray mass spectrum: M+Na at m/z 527. This product (135 mg) was coupled with the commercially available O-(2-azidoethyl)-O′—(N-diglycolyl-2-aminoethyl)heptaethyleneglycol (‘PEG-N3’; 150 mg, 1.1 equiv.) in presence of EEDQ (72 mg, 1.1 equiv.) in 10 mL of dichloromethane, and stirred overnight at ambient temperature. The crude material was purified by flash chromatography to obtain 240 mg of the purified product as a light yellow oil (˜87% yield). HPLC: tR 11.55 min; electrospray mass spectrum: M+H and M+Na at m/z 1041 and 1063, respectively.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The synthesis is schematically shown in Scheme-2. L-Valinol (40 mg) was reacted with commercially available Fmoc-Lys(MMT)-OH (253 mg) and EEDQ (107 mg) in 10 mL of anhydrous dichloromethane at ambient temperature, under argon, for 3 h. Extractive work up followed by flash chromatography furnished the product Fmoc-Lys(MMT)-valinol as a pale yellow liquid (200 mg; ˜70% yield). HPLC: tR14.38 min; electrospray mass spectrum: M+H: m/z 727. This intermediate (200 mg) was deprotected with diethylamine (10 mL), and the product (135 mg) was obtained in ˜90% purity after flash chromatography. HPLC: tR 10.91 min; electrospray mass spectrum: M+Na at m/z 527. This product (135 mg) was coupled with the commercially available O-(2-azidoethyl)-O′—(N-diglycolyl-2-aminoethyl)heptaethyleneglycol (‘PEG-N3’; 150 mg, 1.1 equiv.) in presence of EEDQ (72 mg, 1.1 equiv.) in 10 mL of dichloromethane, and stirred overnight at ambient temperature. The crude material was purified by flash chromatography to obtain 240 mg of the purified product as a light yellow oil (˜87% yield). HPLC: tR 11.55 min; electrospray mass spectrum: M+H and M+Na at m/z 1041 and 1063, respectively.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylic acid ethyl ester prepared in Step XII in toluene was added (S)-2-amino-3-methylbutan-1-ol (3.96 g) with stirring at room temperature. After stirring for 30 min, 1N hydrochloric acid (60 ml) was added, and the mixture was further stirred for 1 hr. The organic layer was separated, and washed successively with water (60 ml), 5% sodium hydrogencarbonate (60 ml) and water (60 ml). The organic layer was concentrated under reduced pressure. N,N-dimethylformamide (40 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in N,N-dimethylformamide (60 ml) to give a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylic acid ethyl ester in N,N-dimethylformamide. This was identified as the title compound by HPLC. After stirring for 30 min the mixture was further stirred for 1 hr The organic layer was separated washed successively with water (60 ml), 5% sodium hydrogencarbonate (60 ml) and water (60 ml) The organic layer was concentrated under reduced pressure N,N-dimethylformamide (40 ml) was added to the residue the mixture was concentrated again under reduced pressure The residue was dissolved in N,N-dimethylformamide (60 ml)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylic acid ethyl ester prepared in Step VIII in toluene was added (S)-2-amino-3-methylbutan-1-ol (3.96 g) with stirring at room temperature. After stirring for 30 min, 1N hydrochloric acid (60 ml) was added, and the mixture was further stirred for 1 hr. The organic layer was separated and washed successively with water (60 ml), 5% sodium hydrogencarbonate (60 ml) and water (60 ml). The organic layer was concentrated under reduced pressure, N,N-dimethylformamide (40 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 ml) to give a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylic acid ethyl ester in N,N-dimethylformamide. This was identified as the title compound by HPLC. After stirring for 30 min the mixture was further stirred for 1 hr The organic layer was separated washed successively with water (60 ml), 5% sodium hydrogencarbonate (60 ml) and water (60 ml) The organic layer was concentrated under reduced pressure, N,N-dimethylformamide (40 ml) was added to the residue the mixture was concentrated again under reduced pressure The residue was dissolved in N,N-dimethylformamide (50 ml)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of valinol (13.96 g, 0.14 mol) and triethylamine (18.87 mL, 0.14 mol) in 250 mL of dry methylene chloride cooled to 0° C. under a nitrogen atmosphere was added 19.3 mL (0.14 mol) of benzyl chloroformate dropwise over 20 min. After warming to RT overnight, the mixture was diluted with methylene chloride (100 mL) and washed with 1N HCl (2X), brine and dried with anhydrous magnesium sulfate. The resulting mixture was filtered and evaporated to give 30.70 g (95.6%) of N-benzyloxycarbonyl-valinol as a white solid: Rf =0.27 (silica gel; 1:1 hexane:ethyl acetate). Used without further purification. washed with 1N HCl (2X), brine dried with anhydrous magnesium sulfate The resulting mixture was filtered evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Treatment of valinol in basic ethanol with chloroacetyl chloride using the procedure of Surry, et. al., J. Am. Chem. Soc. (1955) 77, 633, gives 5-(2-propyl)-3-morpholinone. Deprotonation of the latter with NaH in DMF solution and reaction with methyl iodide gives the title compound.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2CO3.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using L-valinol instead of 2-aminoethyl isopropylether, to the title compound (220 mg, 86%) which was obtained as a white solid. MS: m/e=394.2 [M−H]−.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using L-valinol instead of 2-aminoethyl isopropylether, to the title compound (220 mg, 86%) which was obtained as a white solid. MS: m/e=394.2 [M−H]−.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2CO3.

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Benzyl chloroformate (91.0 g, 95% purity) was added dropwise over a period of 1 h to a precooled (0° C.) solution of L-valinol (50.0 g) and triethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 h at 0° C. and then allowed to warm to,room temperature over 2 h. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue and the organic solution was washed (1N NaOH, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, using a stepwise gradient elution of ether:hexane (1:5) followed by ether, to give the alcohol (91.4 g) as a white waxy solid; TLC, Rf =0.23, hexane:ethanol (50:50). to warm to,room temperature over 2 h After the reaction mixture was evaporated ethyl acetate (1500 ml) was added to the residue the organic solution was washed (1N NaOH, brine) dried (MgSO4) evaporated The residue was purified by flash chromatography a stepwise gradient elution of ether:hexane (1:5)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (L)-Valine methyl ester was reduced to (1S)-1-(hydroxymethyl)-2-methylpropylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2,4diisopropyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-oxazolidine.