4-chloro-3-oxobutanoyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 144.3 g of 4-(trifluoromethyl)-2,6-dichloroaniline (96 percent) was dissolved in 120 ml of acetic acid and mixed within one hour at 20° C. with 209.7 g of nitrosylsulfuric acid (40 percent in sulfuric acid monohydrate). Then the reaction mixture was cooled to 0° C. and diluted with 480 ml of water. This solution was instilled in a solution of 111.6 g of γ-chloroacetoacetyl chloride in 400 ml of dichloromethane (produced according to Swiss Patent No. 642,611) at -5° to 0° C. within one hour. The mixture was stirred for one more hour at 10° C., and then the phases were separated. The aqueous phase was extracted with 100 ml of dichloromethane, the combined organic phase concentrated by evaporation and the residue suspended with 300 ml of cyclohexane. The undissolved solid was filtered off, washed two times each with 100 ml of cyclohexane and dried at 40 torr. The yield of the product was 183.6 g of ochre crystals. Data concerning the product was: the phases were separated The aqueous phase was extracted with 100 ml of dichloromethane the combined organic phase concentrated by evaporation The undissolved solid was filtered off washed two times each with 100 ml of cyclohexane dried at 40 torr

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 144.3 g of 4-(trifluoromethyl)-2,6-dichloroaniline (96 percent) was dissolved in 120 ml of acetic acid and mixed within one hour at 20° C. with 209.7 g of nitrosylsulfuric acid (40 percent in sulfuric acid monohydrate). Then the reaction mixture was cooled to 0° C. and diluted with 480 ml of water. This solution was instilled in a solution of 111.6 g of γ-chloroacetoacetyl chloride in 400 ml of dichloromethane (produced according to Swiss Patent No. 642,611) at -5° to 0° C. within one hour. The mixture was stirred for one more hour at 10° C., and then the phases were separated. The aqueous phase was extracted with 100 ml of dichloromethane, the combined organic phase concentrated by evaporation and the residue suspended with 300 ml of cyclohexane. The undissolved solid was filtered off, washed two times each with 100 ml of cyclohexane and dried at 40 torr. The yield of the product was 183.6 g of ochre crystals. Data concerning the product was: the phases were separated The aqueous phase was extracted with 100 ml of dichloromethane the combined organic phase concentrated by evaporation The undissolved solid was filtered off washed two times each with 100 ml of cyclohexane dried at 40 torr

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 147.2 g (3.2 mol) of ethanol was added in 30 minutes, and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of diethyl sulfite). The temperature was raised to 55° to 60° C. in an hour, and then it was stirred for 1 hour more at 55° to 60° C. Then the excess ethanol and methylene chloride was distilled off at reduced pressure. The residue (raw 4-chloro-3,3-diethoxybutanoic acid ester) was mixed with 0.27 g of methanesulfonic acid and warmed at a pressure of 75 mbars to 125° to 130° C. Thus, the formed ethanol and excess diethyl sulfite were distilled off. The residue (raw 4-chloro-3- ethoxy -but-2E-enoic acid ethyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 2 mbars and a temperature of 78° to 80° C. 4-chloro-3-ethoxy-but-2E-enoic acid ethyl ester was obtained in a yield of 80.6 g (88.5 percent) in a purity of 99.8 percent (GC). The temperature was raised to 55° to 60° C. in an hour Then the excess ethanol and methylene chloride was distilled off at reduced pressure The residue (raw 4-chloro-3,3-diethoxybutanoic acid ester) was mixed with 0.27 g of methanesulfonic acid Thus, the formed ethanol and excess diethyl sulfite were distilled off the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of aqueous 10 percent sodium chloride solution for 10 minutes The toluene was then evaporated off the residue was distilled at a pressure of 2 mbars a temperature of 78° to 80° C

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

Procedure: 206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 102.4 g (3.2 mol) of methanol was added in 30 minutes and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of dimethyl sulfite). The temperature was raised to room temperature and the solution was stirred for 3 hours at 20° to 25° C. The excess methanol and methylene chloride were then distilled off at reduced pressure. The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid and warmed to 125° to 130° C. at a pressure of 100 mbars. Thus, the formed methanol and the excess dimethyl sulfite was distilled off. The residue (raw 4-chloro-3-methoxy-but-2E-enoic acid methyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 20 mbars and a temperature of 95° to 97° C. 4-chloro-3-methoxybut-2E-enoic acid methyl ester was obtained in a yield of 61.7 g (80 percent) in a purity of 99.5 percent (GC). The excess methanol and methylene chloride were then distilled off at reduced pressure The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid warmed to 125° to 130° C. at a pressure of 100 mbars Thus, the formed methanol and the excess dimethyl sulfite was distilled off the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes The toluene was then evaporated off the residue was distilled at a pressure of 20 mbars a temperature of 95° to 97° C

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

Procedure: 206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 102.4 g (3.2 mol) of methanol was added in 30 minutes and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of dimethyl sulfite). The temperature was raised to room temperature and the solution was stirred for 3 hours at 20° to 25° C. The excess methanol and methylene chloride were then distilled off at reduced pressure. The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid and warmed to 125° to 130° C. at a pressure of 100 mbars. Thus, the formed methanol and the excess dimethyl sulfite was distilled off. The residue (raw 4-chloro-3-methoxy-but-2E-enoic acid methyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 20 mbars and a temperature of 95° to 97° C. 4-chloro-3-methoxybut-2E-enoic acid methyl ester was obtained in a yield of 61.7 g (80 percent) in a purity of 99.5 percent (GC). The excess methanol and methylene chloride were then distilled off at reduced pressure The residue (raw 4-chloro-3,3-dimethoxybutanoic acid methyl ester) was mixed with 0.21 g of methanesulfonic acid warmed to 125° to 130° C. at a pressure of 100 mbars Thus, the formed methanol and the excess dimethyl sulfite was distilled off the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes The toluene was then evaporated off the residue was distilled at a pressure of 20 mbars a temperature of 95° to 97° C

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

Procedure: 7-Amino-3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-3-cephem-4-carboxylic acid (3.8 g; 0.01 mole) was suspended in anhydrous N,N-dimethylformamide (50 ml) and N,O-bis(trimethylsilyl)acetamide (8.13 g; 0.04 mole) was added. After 2 hours of stirring at room temperature almost all the starting material was dissolved. A solution of 4-chloroacetoacetyl chloride (2.35 g; approximately 0.015 mole) in anhydrous methylene chloride (20 cc) was dropped into the cooled mixture (at -30° C.). The mixture was stirred at -30° C. for 2 hours and allowed to come to room temperature within an additional hour, after which time isopropanol (40 ml) was added, in order to decompose the silylated compounds. The solvents were evaporated under reduced pressure and the oily residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with aqueous sodium chloride solution, concentrated to a small volume under reduced pressure, and diethyl ether was added to complete the precipitation. The solid was collected by filtration, washed with fresh ether and dried under vacuum, thus giving 4.6 g of the title compound, which was used in the following step without further purification. was dissolved The mixture was stirred at -30° C. for 2 hours to come to room temperature within an additional hour The solvents were evaporated under reduced pressure the oily residue was partitioned between water and ethyl acetate The organic layer was separated washed with aqueous sodium chloride solution concentrated to a small volume under reduced pressure, and diethyl ether was added the precipitation The solid was collected by filtration washed with fresh ether dried under vacuum

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

Procedure: German OS No. 2,025,247 teaches that orotic acid can be prepared by converting, in a first stage, diketene and chlorine to γ-chloroacetoacetic acid chloride, in a second stage, reacting the γ-chloroacetoacetic acid chloride with urea to form 6-chloromethyluracil, separating the 6-chloromethyluracil and oxidizing the 6-chloromethyluracil with hydrogen peroxide to orotic acid. can be prepared

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 144.3 g of 4-(trifluoromethyl)-2,6-dichloroaniline (96 percent) was dissolved in 120 ml of acetic acid and mixed within one hour at 20° C. with 209.7 g of nitrosylsulfuric acid (40 percent in sulfuric acid monohydrate). Then the reaction mixture was cooled to 0° C. and diluted with 480 ml of water. This solution was instilled in a solution of 111.6 g of γ-chloroacetoacetyl chloride in 400 ml of dichloromethane (produced according to Swiss Patent No. 642,611) at -5° to 0° C. within one hour. The mixture was stirred for one more hour at 10° C., and then the phases were separated. The aqueous phase was extracted with 100 ml of dichloromethane, the combined organic phase concentrated by evaporation and the residue suspended with 300 ml of cyclohexane. The undissolved solid was filtered off, washed two times each with 100 ml of cyclohexane and dried at 40 torr. The yield of the product was 183.6 g of ochre crystals. Data concerning the product was: the phases were separated The aqueous phase was extracted with 100 ml of dichloromethane the combined organic phase concentrated by evaporation The undissolved solid was filtered off washed two times each with 100 ml of cyclohexane dried at 40 torr

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

Procedure: A reactor having interior enameling, a total capacity of 630 liters, an effective capacity of 500 liters and a cooling surface of 2.73 m3, was charged with 500 liters of a 15 weight-percent solution of diketene in methylene chloride, and cooled to -20° C. During a period of about 6 hours, a total of 82 kg of chlorine gas was fed into the reactor. The addition of the chlorine gas was in such a way that the temperature at no time rised above -10° C. The reaction mixture was stirred by means of an impeller during the entire time. To the γ-chloroacetoacetic acid chloride a equimolar quantity of ethyl alcohol was added to form the corresponding γ-chloroacetoacetic ethyl ester. The total reaction time was about two hours. The unreacted excess of chlorine and the methylene chloride were removed by distilling them off. A gas chromatographic analysis showed a yield of: A reactor having rised above -10° C