methyl (3R)-4-chloro-3-hydroxybutanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-4-chloroacetoacetate (VII) (100 mg) was incubated with 29 units of porcine heart (EC 1.1.1.35), B-hydroxyacyl CoA dehydrogenase (Sigma, H4626), and 1.36 g of NADH (Sigma, 90%) in 30 ml of 0.1 M sodium phosphate buffer, pH 6.5.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The procedure of example 369 was repeated using methyl-4-chloroacetoacetate as the substrate to afford methyl-4-chloro-3(R)-hydroxybutyrate, [α]D23 +21.15° (c, 4.2 CHCl3).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An amount of 100 g of (3R)-4-chloro-3-hydroxybutyrylamide of L-tyrosine methylester is submitted to methanolysis under the same operating conditions as reported in Example 2. An amount is obtained of 20 g (70%) of (3R)-4-chloro-3-hydroxybutyric acid methylester with [α]D20 =-23° (c=1.5 in CHCL3). (3R)-4-Chloro-3-hydroxybutyric acid methylester is treated with trimethylamine and L-carnitine is obtained (yield 32%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An amount of 100 g of (3R)-4-chloro-3-hydroxybutyrylamide of L-tyrosine methylester is submitted to methanolysis under the same operating conditions as reported in Example 2. An amount is obtained of 20 g (70%) of (3R)-4-chloro-3-hydroxybutyric acid methylester with [α]D20 =-23° (c=1.5 in CHCL3). (3R)-4-Chloro-3-hydroxybutyric acid methylester is treated with trimethylamine and L-carnitine is obtained (yield 32%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (R)-methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 mL) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol.) at room temperature under N2. The reaction mixture was poured into water (150 mL) and acidified to pH 6-7 by dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3×60 mL). The combined organic phases were washed with sat. Na2CO3 solution, brine, dried over anhydrous Na2SO4 and concentrated to give (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (30 g, crude). at room temperature The aqueous phase was extracted with CH2Cl2 (3×60 mL) The combined organic phases were washed with sat. Na2CO3 solution, brine dried over anhydrous Na2SO4 concentrated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-methyl 3,4-dihydroxybutanoate (125.1 g, 0.93 mol) in CH2Cl2 (1.8 L) was added PPh3 (244.5 g, 0.93 mol) and slowly added NCS (124.2 g, 0.93 mol) under ice water cooling. The mixture was stirred at 5° C. for 20 min and then stirred for 18 h at room temperature. After evaporating the solvent, the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient) to give (R)methyl 4-chloro-3-hydroxybutanoate (33 g, 26% over 3 steps). 1H NMR (300 MHz, CDCl3)δ 4.18-4.25 (m, 1H), 3.68 (s, 3H), 3.55-3.60 (m, 2H), 3.32-3.33 (d, J=42 Hz, 1H), 2.52-2.68 (m, 2H). stirred for 18 h at room temperature After evaporating the solvent the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-4-chloroacetoacetate (VII) (100 mg) was incubated with 29 units of porcine heart (EC 1.1.1.35), B-hydroxyacyl CoA dehydrogenase (Sigma, H4626), and 1.36 g of NADH (Sigma, 90%) in 30 ml of 0.1 M sodium phosphate buffer, pH 6.5.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (R)-methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 mL) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol) at room temperature under N2. The reaction mixture was poured into water (150 mL) and acidified to pH 6-7 by dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3×60 mL). The combined organic phases were washed with sat. Na2CO3 solution, brine, dried over anhydrous Na2SO4 and concentrated to give (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (30 g, crude). at room temperature The aqueous phase was extracted with CH2Cl2 (3×60 mL) The combined organic phases were washed with sat. Na2CO3 solution, brine dried over anhydrous Na2SO4 concentrated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-methyl 3,4-dihydroxybutanoate (125.1 g, 0.93 mol) in CH2Cl2 (1.8 L) was added PPh3 (244.5 g, 0.93 mol) and slowly added NCS (124.2 g, 0.93 mol) under ice water cooling. The mixture was stirred at 5° C. for 20 min and then stirred for 18 h at room temperature. After evaporating the solvent, the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient) to give (R)-methyl 4-chloro-3-hydroxybutanoate (33 g, 26% over 3 steps). 1H NMR (300 MHz, CDCl3) δ 4.18-4.25 (m, 1H), 3.68 (s, 3H), 3.55-3.60 (m, 2H), 3.32-3.33 (d, J=4.2 Hz, 1H), 2.52-2.68 (m, 2H). stirred for 18 h at room temperature After evaporating the solvent the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5 g (40 mmole) of (3R)-4-chloro-1,3-butanediol in 30 ml of methylene chloride, said (3R)-4-chloro-1,3-butanediol being obtainable in a similar manner as in Example 1 starting from methyl (3R)-4-chloro-3-hydroxybutyrate, was cooled to -20° C. on a dry ice-acetone bath, and 8.13 g (80 mmole) of triethylamine was added dropwise thereto over 30 minutes. A solution of 7.66 g (40.2 mmole) of p-toluenesulfonyl chloride in 100 ml of methylene chloride was added dropwise thereto over 50 minutes. After returning to room temperature, the mixture was stirred for 20 hours. The reaction mixture was poured into 200 ml of ice-water for liquid separation. The organic layer was washed successively with 100 ml of 1N hydrochloric acid, 100 ml ×2 of a saturated sodium hydrogencarbonate aqueous solution and 100 ml of a saturated sodium chloride aqueous solution and then freed of the solvent by distillation to obtain 7.8 g of a concentrate. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=2:1 by volume) to obtain 6.1 g (yield: 54%) of the titled compound. 1H-NMR (CDCl3) δ ppm: 1.78-2.00 (m, 2H), 2.46 (s, 3H), 3.45-3.65 (dd, 2H), 3.95 (m, 1H), 4.20 (m, 2H), 7.40 (d, 2H), 7.80 (d, 2H) over 50 minutes After returning to room temperature The organic layer was washed successively with 100 ml of 1N hydrochloric acid, 100 ml ×2 of a saturated sodium hydrogencarbonate aqueous solution and 100 ml of a saturated sodium chloride aqueous solution freed of the solvent by distillation to obtain 7.8 g of a concentrate The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=2:1 by volume)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (R)-methyl 4-chloro-3-hydroxybutanoate (15 g, 98.7 mmol) in CH2Cl2 (240 mL) was stirred overnight with tert-butyl-chloro-dimethyl-silane (17.82 g, 118.2 mmol), imidazole (33.6 g, 493.5 mmol) and a catalytic amount of DMAP (0.6 g, 4.92 mmol) at room temperature under N2. The reaction mixture was poured into water (150 mL) and acidified to pH 6-7 by dropwise addition of cold aqueous HCl (0.5 M). The aqueous phase was extracted with CH2Cl2 (3×60 mL). The combined organic phases were washed with sat. Na2CO3 solution, brine, dried over anhydrous Na2SO4 and concentrated to give (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (30 g, crude). at room temperature The aqueous phase was extracted with CH2Cl2 (3×60 mL) The combined organic phases were washed with sat. Na2CO3 solution, brine dried over anhydrous Na2SO4 concentrated

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-methyl 3,4-dihydroxybutanoate (125.1 g, 0.93 mol) in CH2Cl2 (1.8 L) was added PPh3 (244.5 g, 0.93 mol) and slowly added NCS (124.2 g, 0.93 mol) under ice water cooling. The mixture was stirred at 5° C. for 20 min and then stirred for 18 h at room temperature. After evaporating the solvent, the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient) to give (R)-methyl 4-chloro-3-hydroxybutanoate (33 g, 26% over 3 steps). 1H NMR (300 MHz, CDCl3) δ 4.18-4.25 (m, 1H), 3.68 (s, 3H), 3.55-3.60 (m, 2H), 3.32-3.33 (d, J=4.2 Hz, 1H), 2.52-2.68 (m, 2H). stirred for 18 h at room temperature After evaporating the solvent the residue was purified by column chromatography (P.E\E.A 20:1-5:1, gradient)