1-chlorobutan-2-one

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

Procedure: 67.99 g (492 mmol) of potassium carbonate and 1.87 g (8.2 mmol) of benzyltriethylammonium chloride are suspended in 500 ml of acetonitrile. 59.86 g (410 mmol) of methyl 4-methoxyacetoacetate are added thereto while stirring. 65.50 g (615 mmol) of 1-chloro-2-butanone are added dropwise thereto within 30 minutes and the mixture is stirred at 20°-25° C. for 23 hours. The reaction mixture is poured into 1 l of 1N HCl (pH value=1) and extracted 3 times with 700 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 115° C./0.05 mbar. There results 49.01 g (55.3%) of methyl 4-methoxy-2-(2-oxobutyl)-acetoacetate. the mixture is stirred at 20°-25° C. for 23 hours extracted 3 times with 700 ml of ethyl acetate each time The combined organic phases are dried over magnesium sulphate concentrated on a rotary evaporator The crude product distils at 115° C./0.05 mbar

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

Procedure: The procedure of Example 4 is followed but starting with triethylammonium (6-ethylpyrid-2-yl)dithiocarbamate (72.0 g) and 1-chlorobutan-2-one (25.5 g) in anhydrous acetonitrile (400 cc) at a maximum temperature of 25° C. The reaction is continued for 4 hours at 20°-25° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) contained in a column 3.8 cm in diameter, eluting with chloroform (5 liters). The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc) to give 4-ethyl-3-(6-ethylpyrid-2-yl)-4-hydroxythiazolidine-2-thione (37.2 g) melting at 84° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) eluting with chloroform (5 liters) The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc)

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

Procedure: The procedure of Example 4 is followed but starting with triethylammonium (6-ethylpyrid-2-yl)dithiocarbamate (72.0 g) and 1-chlorobutan-2-one (25.5 g) in anhydrous acetonitrile (400 cc) at a maximum temperature of 25° C. The reaction is continued for 4 hours at 20°-25° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) contained in a column 3.8 cm in diameter, eluting with chloroform (5 liters). The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc) to give 4-ethyl-3-(6-ethylpyrid-2-yl)-4-hydroxythiazolidine-2-thione (37.2 g) melting at 84° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) eluting with chloroform (5 liters) The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc)

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

Procedure: The procedure of Example 1 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (71.0 g) and 1-chlorobutan-2-one (26.6 g) in distilled water (300 cc) at 20° C. The reaction is carried out for 3 hours at 20° C. After recrystallisation of the product from ethanol (250 cc), there is obtained 4-ethyl-4-hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (45.0 g) melting at 118° C. After recrystallisation of the product from ethanol (250 cc)

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

Procedure: The procedure of Example 1 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (71.0 g) and 1-chlorobutan-2-one (26.6 g) in distilled water (300 cc) at 20° C. The reaction is carried out for 3 hours at 20° C. After recrystallisation of the product from ethanol (250 cc), there is obtained 4-ethyl-4-hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (45.0 g) melting at 118° C. After recrystallisation of the product from ethanol (250 cc)

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

Procedure: 67.99 g (492 mmol) of potassium carbonate and 1.87 g (8.2 mmol) of benzyltriethylammonium chloride are suspended in 500 ml of acetonitrile. 59.86 g (410 mmol) of methyl 4-methoxyacetoacetate are added thereto while stirring. 65.50 g (615 mmol) of 1-chloro-2-butanone are added dropwise thereto within 30 minutes and the mixture is stirred at 20°-25° C. for 23 hours. The reaction mixture is poured into 1 l of 1N HCl (pH value=1) and extracted 3 times with 700 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 115° C./0.05 mbar. There results 49.01 g (55.3%) of methyl 4-methoxy-2-(2-oxobutyl)-acetoacetate. the mixture is stirred at 20°-25° C. for 23 hours extracted 3 times with 700 ml of ethyl acetate each time The combined organic phases are dried over magnesium sulphate concentrated on a rotary evaporator The crude product distils at 115° C./0.05 mbar

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

Procedure: 67.99 g (492 mmol) of potassium carbonate and 1.87 g (8.2 mmol) of benzyltriethylammonium chloride are suspended in 500 ml of acetonitrile. 59.86 g (410 mmol) of methyl 4-methoxyacetoacetate are added thereto while stirring. 65.50 g (615 mmol) of 1-chloro-2-butanone are added dropwise thereto within 30 minutes and the mixture is stirred at 20°-25° C. for 23 hours. The reaction mixture is poured into 1 l of 1N HCl (pH value=1) and extracted 3 times with 700 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 115° C./0.05 mbar. There results 49.01 g (55.3%) of methyl 4-methoxy-2-(2-oxobutyl)-acetoacetate. the mixture is stirred at 20°-25° C. for 23 hours extracted 3 times with 700 ml of ethyl acetate each time The combined organic phases are dried over magnesium sulphate concentrated on a rotary evaporator The crude product distils at 115° C./0.05 mbar

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

Procedure: The procedure of Example 4 is followed but starting with triethylammonium (6-ethylpyrid-2-yl)dithiocarbamate (72.0 g) and 1-chlorobutan-2-one (25.5 g) in anhydrous acetonitrile (400 cc) at a maximum temperature of 25° C. The reaction is continued for 4 hours at 20°-25° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) contained in a column 3.8 cm in diameter, eluting with chloroform (5 liters). The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc) to give 4-ethyl-3-(6-ethylpyrid-2-yl)-4-hydroxythiazolidine-2-thione (37.2 g) melting at 84° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) eluting with chloroform (5 liters) The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc)

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

Procedure: The procedure of Example 1 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (71.0 g) and 1-chlorobutan-2-one (26.6 g) in distilled water (300 cc) at 20° C. The reaction is carried out for 3 hours at 20° C. After recrystallisation of the product from ethanol (250 cc), there is obtained 4-ethyl-4-hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (45.0 g) melting at 118° C. After recrystallisation of the product from ethanol (250 cc)

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

Procedure: The procedure of Example 1 (a) is followed using 2,3-butanedithiol and 1-chloro-2-butanone to give 2-ethyl-5,6-dihydro-5,6-dimethyl-1,4-dithiin as a colorless oil, b.p. 55°-58°10.03- 0.05 mm, yield 53%. NMR 1.08 (3t), 1.36 (6d), 2.18 (2q), 2.7-3.1 (2m), 5.78 (1s, broadened) (CDCl 3). IR 3000 (shoulder), 2955, 1570, 1440, 1365, 1110, 825, 705.

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate (0.5 g, 0.0012 mol, see Example 12f, Step 2) in dry benzene (20 ml) under nitrogen was added 1-chloro-butan-2-one (0.42 g, 0.0039 mol) of and the reaction mixture was heated at 75° C. for over night. Benzene was removed under vaccum and the crude product was extracted with ethyl acetate. The organic layer was washed with brine, concentrated, and purified by recrystallization from ether to give 0.2 g (35%) of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(4-ethylthiazol-2-yl)cyclohexylcarbamate as a white solid obtained. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.44 (s, 9H), 1.62 (m, 2H), 1.81 (m, 3 H), 2.22 (m, 2H), 2.78 (q, 2H), 3.50 (bs, 1H), 3.72 (bs, 1H), 4.12 (bs, 1H), 5.04 (s, 2H), 5.40 (bs, 1H), 5.74 (s, 1H), 7.33 (m, 5H); 13H NMR (400 MHz, CDCl3) 13.45, 24.7, 28.0, 28.24, 28.4, 33.3, 42.3, 47.0, 50.4, 61.0, 66.5, 79.0, 111.6, 127.9, 128.0, 128.4, 136.5, 155.2, 155.8, 158.8, 169.8. MS found: (M+H)+=460. Benzene was removed under vaccum the crude product was extracted with ethyl acetate The organic layer was washed with brine concentrated purified by recrystallization from ether

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate (0.5 g, 0.0012 mol, see Example 12f, Step 2) in dry benzene (20 ml) under nitrogen was added 1-chloro-butan-2-one (0.42 g, 0.0039 mol) of and the reaction mixture was heated at 75° C. for over night. Benzene was removed under vaccum and the crude product was extracted with ethyl acetate. The organic layer was washed with brine, concentrated, and purified by recrystallization from ether to give 0.2 g (35%) of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(4-ethylthiazol-2-yl)cyclohexylcarbamate as a white solid obtained. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.44 (s, 9H), 1.62 (m, 2H), 1.81 (m, 3 H), 2.22 (m, 2H), 2.78 (q, 2H), 3.50 (bs, 1H), 3.72 (bs, 1H), 4.12 (bs, 1H), 5.04 (s, 2H), 5.40 (bs, 1H), 5.74 (s, 1H), 7.33 (m, 5H); 13H NMR (400 MHz, CDCl3) 13.45, 24.7, 28.0, 28.24, 28.4, 33.3, 42.3, 47.0, 50.4, 61.0, 66.5, 79.0, 111.6, 127.9, 128.0, 128.4, 136.5, 155.2, 155.8, 158.8, 169.8. MS found: (M+H)+=460. Benzene was removed under vaccum the crude product was extracted with ethyl acetate The organic layer was washed with brine concentrated purified by recrystallization from ether