N-methylcarbamoyl chloride

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

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

Procedure: To a solution of ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (62.8 g, 74.1 mmol; Preparation 3) and N,N-diisopropylethylamine (20.1 mL, 115.2 mmol) in DCM (750 mL) was slowly added 1 M methylaminoformyl chloride in DMA (68.4 mL) over 10 min at 10-15° C. After 50 min, 1 M methylaminoformyl chloride in DMA (3.6 mL) was added and the reaction mixture was stirred overnight. To the reaction mixture was added water (750 mL) and 1 N HCl (40 mL). The organic layer was washed with water, dried over Na2SO4, and evaporated. Methanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product and the reaction mixture was stirred for 30 min. Water (110 mL) was added slowly to the reaction mixture. Seeds of crystalline title product were added after 50 mL of water. The reaction mixture was stirred for 2 days and then methanol (60 mL) and water (24 mL) were added. After 30 min, the mixture was filtered. The solid was washed with 2:1 methanol:water (120 mL), and dried under vacuum at 35° C. overnight to provide the title compound (54 g). over 10 min at 10-15° C The organic layer was washed with water dried over Na2SO4 evaporated Methanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product the reaction mixture was stirred for 30 min Water (110 mL) was added slowly to the reaction mixture Seeds of crystalline title product were added after 50 mL of water The reaction mixture was stirred for 2 days methanol (60 mL) and water (24 mL) were added After 30 min the mixture was filtered The solid was washed with 2:1 methanol water (120 mL), and dried under vacuum at 35° C. overnight

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the present invention two novel methods relate to syntheses of VNP40101M with higher yields. Method B directly uses the intermediate BMH, the starting material for preparation of VNP4090CE. As showed in FIG. 3, a one-pot reaction of BMH with methylcarbamic chloride (MCC) affords VNP40101M in a 60+% yield. In this method, the carbonyl coupling reaction of the substituted hydrazine and the chloro-replacement reaction of the alkyl mesylate take place concurrently. Triethylamine (TEA) is preferably used as a base for the reaction, and acetonitrile is usually used as solvent. The molar ratio of the reactant, BMH to MCC to TEA, is preferable in 1:2:2. The two concurrent reactions are usually heated at approximately 90° C. Other important aspects of the present invention include improvement over the prior art synthesis. In the prior art (FIG. 1), product from the mesylation reaction was not isolated and directly used for the chloro-replacement reaction to generate VNP4090CE in an approximately 20% yield. In the instant invention the mesylated product BMH is isolated as a pale solid in a 55+% yield by easy operations of precipitation and filtration. Thus the total yield of the process to VNP40101M can be increased to 30+%. By the performing this mesylation and two concurrent reactions, the instant invention, in addition to reducing the number of steps required for the synthesis and improving overall yield, also makes handling easier and therefore makes commercial large-scale production easier. Alternatively, the two concurrent reactions in method B were changed to two separation reactions by using an alkyl or aryl chloroformate ClC(O)OR to form a stable carbamade intermediate, followed by a conversion of the carbamade into the corresponding urea (VNP40101M). For example, the reaction of ethyl chloroformate ClC(O)OEt with BMH resulted in a stable intermediate 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(ethyloxycarbonyl)-hydrazine (CEE), which were reacted with methylamine in the presence of a Lewis acid (preferable AlCl3) to form VNP40101M (FIG. 4). R in ClC(O)OR could be alkyl (e.g. methyl, ethyl, t-butyl, and etc) and aryl (e.g. phenyl, 4-nitrophenyl, and etc). The Lewis acid could be AlCl3, SnCl4, TiCl4, FeCl3, and etc. art synthesis In the prior art (FIG. 1), product from the mesylation reaction was not isolated In the instant invention the mesylated product BMH is isolated as a pale solid in a 55+% yield by easy operations of precipitation and filtration Thus the total yield of the process to VNP40101M can be increased to 30+% By the performing this mesylation and two concurrent reactions, the instant invention, in addition required for the synthesis Alternatively, the two concurrent reactions in method B were changed to two separation reactions to form a stable carbamade intermediate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the present invention two novel methods relate to syntheses of VNP40101M with higher yields. Method B directly uses the intermediate BMH, the starting material for preparation of VNP4090CE. As showed in FIG. 3, a one-pot reaction of BMH with methylcarbamic chloride (MCC) affords VNP40101M in a 60+% yield. In this method, the carbonyl coupling reaction of the substituted hydrazine and the chloro-replacement reaction of the alkyl mesylate take place concurrently. Triethylamine (TEA) is preferably used as a base for the reaction, and acetonitrile is usually used as solvent. The molar ratio of the reactant, BMH to MCC to TEA, is preferable in 1:2:2. The two concurrent reactions are usually heated at approximately 90° C. Other important aspects of the present invention include improvement over the prior art synthesis. In the prior art (FIG. 1), product from the mesylation reaction was not isolated and directly used for the chloro-replacement reaction to generate VNP4090CE in an approximately 20% yield. In the instant invention the mesylated product BMH is isolated as a pale solid in a 55+% yield by easy operations of precipitation and filtration. Thus the total yield of the process to VNP40101M can be increased to 30+%. By the performing this mesylation and two concurrent reactions, the instant invention, in addition to reducing the number of steps required for the synthesis and improving overall yield, also makes handling easier and therefore makes commercial large-scale production easier. Alternatively, the two concurrent reactions in method B were changed to two separation reactions by using an alkyl or aryl chloroformate ClC(O)OR to form a stable carbamade intermediate, followed by a conversion of the carbamade into the corresponding urea (VNP40101M). For example, the reaction of ethyl chloroformate ClC(O)OEt with BMH resulted in a stable intermediate 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(ethyloxycarbonyl)-hydrazine (CEE), which were reacted with methylamine in the presence of a Lewis acid (preferable AlCl3) to form VNP40101M (FIG. 4). R in ClC(O)OR could be alkyl (e.g. methyl, ethyl, t-butyl, and etc) and aryl (e.g. phenyl, 4-nitrophenyl, and etc). The Lewis acid could be AlCl3, SnCl4, TiCl4, FeCl3, and etc. art synthesis In the prior art (FIG. 1), product from the mesylation reaction was not isolated In the instant invention the mesylated product BMH is isolated as a pale solid in a 55+% yield by easy operations of precipitation and filtration Thus the total yield of the process to VNP40101M can be increased to 30+% By the performing this mesylation and two concurrent reactions, the instant invention, in addition required for the synthesis Alternatively, the two concurrent reactions in method B were changed to two separation reactions to form a stable carbamade intermediate

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

Procedure: To a cold solution (ice bath) of piperazine-1-carboxylic acid tert-butyl ester (9.0 g, 48.32 mmol) and triethylamine (9.8 g, 96.64 mmol) in dichloromethane (100 mL) was slowly added a solution of methylaminoformyl chloride (5.0 g, 53.5 mmol) in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then partitioned in dichloromethane (200 mL) and water (100 mL). Organic layer was separated, dried (MgSO4), and concentrated to yield tert-butyl 4-(methylcarbamoyl)piperazine-1-carboxylate as a solid which was dissolved in dichloromethane (100 mL) and TFA (20 mL). The solution was stirred for 12 h and the volatiles were evaporated under pressure, the oily residue was dissolved in methanol and 1N hydrogen chloride solution was added. The solid formed was filtered and washed with ether, dried to give N-methylpiperazine-1-carboxamide hydrochloride, 8.12 g (93%) partitioned in dichloromethane (200 mL) Organic layer was separated dried (MgSO4) concentrated

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

Procedure: To a cold solution (ice bath) of piperazine-1-carboxylic acid tert-butyl ester (9.0 g, 48.32 mmol) and triethylamine (9.8 g, 96.64 mmol) in dichloromethane (100 mL) was slowly added a solution of methylaminoformyl chloride (5.0 g, 53.5 mmol) in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then partitioned in dichloromethane (200 mL) and water (100 mL). Organic layer was separated, dried (MgSO4), and concentrated to yield tert-butyl 4-(methylcarbamoyl)piperazine-1-carboxylate as a solid which was dissolved in dichloromethane (100 mL) and TFA (20 mL). The solution was stirred for 12 h and the volatiles were evaporated under pressure, the oily residue was dissolved in methanol and 1N hydrogen chloride solution was added. The solid formed was filtered and washed with ether, dried to give N-methylpiperazine-1-carboxamide hydrochloride, 8.12 g (93%) partitioned in dichloromethane (200 mL) Organic layer was separated dried (MgSO4) concentrated

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

Procedure: A process for the manufacture of α-naphthyl-N-methylcarbamate by the reaction of methylcarbamyl chloride and α-naphthol containing β-naphthol as an impurity, which comprises reacting methylcarbamyl chloride, which is essentially free from phosgene and hydrogen chloride, in the absence of an acid-binding agent, with α-naphthol containing β-naphthol as an impurity at a temperature in the range of 60° to 130° C in, as solvent, cumene, the starting concentration of said naphthol in the cumene being in the range of 20 to 40% by weight, based on the cumene, and cooling the reaction mixture to precipitate the α-naphthyl-N-methylcarbamate as a pure crystalline solid, the β-naphthyl-N-methylcarbamate formed in the reaction remaining in solution in the cumene when the reaction mixture is cooled. cooling the reaction mixture to precipitate the α-naphthyl-N-methylcarbamate as a pure crystalline solid

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

Procedure: A process for the manufacture of α-naphthyl-N-methylcarbamate by the reaction of methylcarbamyl chloride and α-naphthol containing β-naphthol as an impurity, which comprises reacting methylcarbamyl chloride, which is essentially free from phosgene and hydrogen chloride, in the absence of an acid-binding agent, with α-naphthol containing β-naphthol as an impurity at a temperature in the range of 60° to 130° C in, as solvent, cumene, the starting concentration of said naphthol in the cumene being in the range of 20 to 40% by weight, based on the cumene, and cooling the reaction mixture to precipitate the α-naphthyl-N-methylcarbamate as a pure crystalline solid, the β-naphthyl-N-methylcarbamate formed in the reaction remaining in solution in the cumene when the reaction mixture is cooled. cooling the reaction mixture to precipitate the α-naphthyl-N-methylcarbamate as a pure crystalline solid

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

Procedure: 72 parts by weight of β-naphthol are dissolved in 250 parts by weight of cumene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are stirred into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is cooled to 0° C and the precipitated β-naphthyl-N-methylcarbamate is isolated. The yield is 85% of theory. is simultaneously bubbled through the solution

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

Procedure: 72 parts by weight of β-naphthol are dissolved in 250 parts by weight of t-butylbenzene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are passed into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is then cooled to 0° C. 83.5 parts by weight of β-naphthyl-N-methylcarbamate are precipitated, this being equivalent to a yield of 83% of theory. The melting point is 119° C. is simultaneously bubbled through the solution 83.5 parts by weight of β-naphthyl-N-methylcarbamate are precipitated

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

Procedure: 72 parts by weight of β-naphthol are dissolved in 250 parts by weight of t-butylbenzene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are passed into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is then cooled to 0° C. 83.5 parts by weight of β-naphthyl-N-methylcarbamate are precipitated, this being equivalent to a yield of 83% of theory. The melting point is 119° C. is simultaneously bubbled through the solution 83.5 parts by weight of β-naphthyl-N-methylcarbamate are precipitated

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

Procedure: Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.4 g, 1.7 mmol) in anhydrous pyridine. Add a solution of methylcarbamyl chloride (0.17 g, 1.8 mmol) in anhydrous tetrahydrofuran carefully to the reaction and stir overnight at room temperature. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:dichloromethane, and then further purify on C-18 silica, eluting with 10:90 to 50:50 using an aqueous 0.1% solution of trifluoroacetic acid and a 0.1% solution of trifluoroacetic acid in acetonitrile). Concentrate, partition the residue between ethyl acetate and an aqueous saturated solution of sodium bicarbonate and separate the layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter and concentrate to give the title compound as a white solid (25 mg, 5%). carefully to the reaction Concentrate dissolve the crude reaction in ethyl acetate Wash the organic layer with water an aqueous saturated solution of sodium chloride, dry (potassium carbonate) filter concentrate purify (silica gel chromatography eluting with 0:100 to 10:90 ethyl acetate dichloromethane, and then further purify on C-18 silica eluting with 10:90 to 50:50 using an aqueous 0.1% solution of trifluoroacetic acid Concentrate partition the residue between ethyl acetate an aqueous saturated solution of sodium bicarbonate and separate the layers Wash the organic layer with an aqueous saturated solution of sodium chloride dry (potassium carbonate) filter concentrate