NOVEL PROCESS FOR THE MANUFACTURE OF 4-AMINOBENZOAMIDINE DIHYDROCHLORIDE

Abstract

The present invention relates to a process for the preparation of 4-aminobenzoamidine (4-AMBA) salts of general formula (I)

##STR00001##

preferably the salts thereof with hydrochloric or hydrobromic acid, particularly preferred the dichloride salt.

Claims

1. A compound of formula (II), ##STR00015## wherein R is methyl and X is Cl.

Description

EXAMPLES

Example 1

Step A Pinner Reaction

[0077] 515 mL (8.5 v/w of 4-ABN) ethanol and 60.8 g (0.514 mol, 1.0 eq) 4-ABN are charged into a 1000 mL flask under N.sub.2, obtained a solution. Then cooled to 10 C., 240.0 g (6.58 mol, 12.8 eq) HCl gas is bubbled into the reaction solution (dried through conc. H.sub.2SO.sub.4) while keeping the temperature below 20 C. Heated up to 3540 C. the reaction is monitored by HPLC and checked every 4 h. The reaction is finished in about 16 h. The reaction mixture is cooled down to room temperature (rt=20 to 22 C.) and stirred 1 h. The suspension is filtered to obtain 194.8 g of wet product (Ethyl 4-aminobenzimidine salt) as solid 92.85% HPLC purity.

[0078] Mass spectrum (ESI.sup.+): m+1-2HCl/z=165;

[0079] .sup.1H NMR: .sub.H 1.36-1.43 (3H, triple, 7-C); 4.51-4.57 (2H, tetra, 6-C); 6.76-6.80 (2H, d, 3-C); 7.90-7.99 (2H, d, 2-C).

[0080] .sup.13C NMR: .sub.C 13.6 (7-C); 68.4 (6-C); 111.2 (1-C); 114.0 (3-C); 123.1 (2-C); 133.5 (4-C); 169.5 (5-C).

Step B and C Amination and Precipitation

[0081] 45 mL (3 v/w of 4-ABN) ethanol and 48.7 g wet intermediate (Ethyl 4-aminobenzimidine salt) (C.sub.9H.sub.12N.sub.2O.2HCl, from 0.129 mol 4-ABN) are charged into a 250 mL flask under N.sub.2 at rt. 103.0 g (10.6% in ethanol, 0.64 mol, 5.0 eq) ammonia ethanol solution is added drop wise into the flask while keeping the temperature below 35 C. After addition the reaction mixture is heated up to 3540 C. and stirred for 2 h. 5.3 g (0.072 mol, 0.55 eq) Ca(OH).sub.2 are charged into the flask, then heated up to 4550 C. and stirred at this temperature 0.5 h. Hot filtration is used to remove some inorganic insoluble impurities to obtained 160.0 g of filtrate. Excess of NH.sub.3 in the filtrate is removed by distillation under vacuum. After distillation, the resulting residue is diluted by adding fresh ethanol and then heated up to 6070 C. 30.6 g (0.31 mol, 2.4 eq) conc. HCl aq. is added dropwise into the flask and stirring continued at 6070 C. for 0.5 h, then cooled down to 05 C. slowly, stirring continued for 1 h. The suspension is then filtered and washed with ethanol to obtain 40.8 g wet product as solid, which is dried at 55 C. under a vacuum for 6 h to obtain 22.6 g product as solid. Isolated yield 84% with 98.5%

[0082] HPLC purity.

[0083] Mass spectrum (ESI.sup.+): m+1-2HCl/z=136

Example 2

Step A Pinner Reaction

[0084] 82 mL (6.8 v/w of 4-ABN) methanol and 12.0 g (0.102 mol, 1.0 eq) 4-ABN are charged into a 250 mL flask under N.sub.2 to give a solution. The mixture is then cooled to 10 C., 37.0 g (1.02 mol, 10.0 eq) HCl gas is bubbled into the reaction solution (dried through conc. H.sub.2SO.sub.4) while keeping the temperature below 20 C. After bubbling the HCl gas, the reaction mixture is set to 2530 C. and allowed to stir for 34 h. Then the mixture is filtered to give 25.3 g of wet product as solid. This product is used in next step without further treatment.

[0085] Mass spectrum (ESI.sup.+): m+1-2HCl/z=151;

[0086] .sup.1H NMR: .sub.H 4.17-4.19 (3H, s, 6-C); 6.70-6.74 (2H, d, 3-C); 7.88-7.92 (2H, d, 2-C).

[0087] .sup.13C NMR: .sub.C 58.9 (6-C); 113.3 (1-C); 122.6 (3-C); 128.9 (2-C); 131.4 (4-C); 166.9 (5-C).

Step B and C Amination

[0088] 35 mL (3 v/w of 4-ABN) ethanol and 25.3 g wet intermediate (C.sub.9H.sub.12N.sub.2O.2HCl, from 0.102 mol 4-ABN) are charged into a 250 mL flask under N.sub.2 at rt. 77.2 g (11.2% in ethanol, 0.508 mol, 5.0 eq) ammonia ethanol solution is added drop wise into the flask while keeping the temperature below 35 C. After complete addition, the mixture is heated up to 3540 C. and allowed to stir for 2 h. 4.14 g (0.056 mol, 0.55 eq) Ca(OH).sub.2 is charged into the flask, then heated up to 4550 C. and stirred at this temperature for 0.5 h. A hot filtration used to remove some inorganic insoluable impurities gives 124.0 g of filtrate. Excess of NH.sub.3 in the filtrate is removed by distillation under vacuum and the resulting residue is diluted by adding fresh ethanol. Then the solution is heated to 6070 C. and 24.1 g (0.244 mol, 2.4 eq) conc. HCl aq. is added drop wise into the flask to give a suspension. The suspension is stirred at 6070 C. for 0.5 h, then cooled down to 05 C. slowly and allowed to stir for an additional hour. The suspension is filtered and washed with ethanol two times to obtain 29.0 g wet product as solid, which is dried at 55 C. using vacuum for 8 h to obtain 18.3 g product as solid (86.2% in yield with 99.77% HPLC-purity).

[0089] Mass spectrum (ESI.sup.+): m+1-2HCl/z=136

Example 3

Step A Pinner Reaction

[0090] 98 mL (6.8 v/w of 4-ABN) methanol and 14.4 g (0.122 mol, 1.0 eq) 4-ABN are charged into a 250 mL flask under N.sub.2 to obtain a solution. The mixture is cooled to 10 C., 44.5 g (1.22 mol, 10.0 eq) HCl gas is bubbled into the reaction solution (dried through conc. H.sub.2SO.sub.4) while keeping the temperature below 20 C. After bubbling the HCl gas, the reaction mixture is heated up to reflux for 10 h, cooled to room temperature and allowed to stir for an additional hour.

[0091] The suspension is then filtered to obtain 28.0 g of wet product as solid.

[0092] Mass spectrum (ESI.sup.+): m+1-2HCl/z=151;

[0093] .sup.1H NMR: .sub.H 4.17-4.19 (3H, s, 6-C); 6.70-6.74 (2H, d, 3-C); 7.88-7.92 (2H, d, 2-C).

[0094] .sup.13C NMR: .sub.C 58.9 (6-C); 113.3 (1-C); 122.6 (3-C); 128.9 (2-C); 131.4 (4-C); 166.9 (5-C).

[0095] Step B and C: are the same as in example 2.

Example 4

Step A Pinner Reaction

[0096] 32.5 mL (2.5 v/w of 4-ABN) MeOH and 13.0 g (0.110 mol, 1.0 eq) 4-ABN are charged into a 250 mL flask, stirred to obtain a solution. Then 60.8 g (27.4% v/w, 0.456 mol, 4.15 eq) HCl in MeOH solution are added drop wise into the flask while maintaining the temperature below 20 C. The mixture is cooled to 10 C., 23.5 g (0.644 mol, 5.85 eq) HCl gas is bubbled into the reaction solution (dried through conc. H.sub.2SO.sub.4) while keeping the temperature below 20 C. The reaction mixture is heated up to 3540 C. and allowed to stir for 17 h and cooled down to room temperature. After stirring for an additional 1 h, the suspension is filtered and washed with methanol to give 23.9 g of wet product as solid with 94.7% HPLC purity. The wet product is used for the next step without further treatment.

[0097] Mass spectrum (ESI.sup.+): m+1-2HCl/z=151;

[0098] .sup.1H NMR: .sub.H 4.17-4.19 (3H, s, 6-C); 6.70-6.74 (2H, d, 3-C); 7.88-7.92 (2H, d, 2-C).

[0099] .sup.13C NMR: .sub.C 58.9 (6-C); 113.3 (1-C); 122.6 (3-C); 128.9 (2-C); 131.4 (4-C); 166.9 (5-C).

Step B and C Amination

[0100] 39 mL (3 v/w of 4-ABN) ethanol and 23.9 g wet intermediate (C.sub.9H.sub.12N.sub.2O.2HCl, from 0.110 mol 4-ABN) are charged into a 250 mL flask under N.sub.2 at rt. 83.6 g (11.2% in ethanol, 0.551 mol, 5.0 eq) ammonia ethanol solution is added drop wise into the flask while keeping the temperature below 35 C. After addition, the reaction mixture is heated up to 3540 C. for 2 h. 4.5 g (0.061 mol, 0.55 eq) Ca(OH).sub.2 is charged into the flask, then heated up to 4550 C. and stirred at this temperature for 0.5 h. The suspension is hot filtered to remove some inorganic insoluble impurities to obtained 139.0 g of filtrate. Excess NH.sub.3 in the filtrate is removed by distillation using vacuum, the resulting residue is diluted by adding fresh ethanol. Then this solution is heated to 6070 C. and 19.6 g (0.199 mol, 2.4 eq) conc. HCl aq. is added drop wise into the flask to give a suspension, which is allowed to stir for 30 minutes and then cooled to 05 C. slowly. After additional stirring at 05 C. for 1 h, the suspension is filtered and washed with ethanol twice to give 22.1 g wet product as solid. After drying at 55 C. under vacuum for 8 h, 19.3 g product as solid (Overall yield 84.3% with 99.66% HPLC) is isolated.

[0101] Mass spectrum (ESI.sup.+): m+1-2HCl/z=136

Example 5

[0102] Step A Pinner reaction 47.0 mL (2 v/w of 4-ABN) MeOH and 23.6 g (0.200 mol, 1.0 eq) 4-ABN are charged into a 250 mL flask, stirred to obtain a solution. Then 26.0 g (30%, 0.22 mol, 1.1 eq) HCl in MeOH solution is added drop wise into the flask while keeping the temperature below to 30 C.

[0103] The resulting mixture is cooled to 5 C., 43.3 g (1.18 mol, 5.9 eq) HCl gas is bubbled into the reaction solution (dried through conc. H.sub.2SO.sub.4) while maintaining the temperature below 30 C. The reaction mixture is transferred into a pressure tube equipped with pressure gauge. (The total amount of methanol is 80 mL, 3.4 v/w of 4-ABN). The pressure tube is then sealed and heated to 3540 C. for 5 h, where a maximum pressure of 3 atm is reached.

[0104] After cooling to room temperature and stirring for an additional 1 h, the pressure is released. The suspension is filtered and rinsed by methanol twice to obtain 48.0 g of wet product as solid, which is dried under vacuum at 50 C. for 8 h. 42.0 g product as solid is isolated (yield 94% with 94.7% HPLC purity).

[0105] Mass spectrum (ESI.sup.+): m+1-2HCl/z=151;

[0106] .sup.1H NMR: .sub.H 4.17-4.19 (3H, s, 6-C); 6.70-6.74 (2H, d, 3-C); 7.88-7.92 (2H, d, 2-C).

[0107] .sup.13C NMR: .sub.C 58.9 (6-C); 113.3 (1-C); 122.6 (3-C); 128.9 (2-C); 131.4 (4-C); 166.9 (5-C).

Step B and C: Amination

[0108] 18 mL (3 v/w of 4-ABN) methanol and 10.5 g wet intermediate (C.sub.9H.sub.12N.sub.2O.2HCl, from 0.050 mol 4-ABN) are charged into a 250 mL flask under N.sub.2 at rt. 31.0 g (11.0% in methanol, 0.200 mol, 4.0 eq) ammonia in methanolic solution is added drop wise into the flask while maintaining the temperature below 35 C. After complete addition the mixture is heated up to 3540 C. for 2 h. 2.05 g (0.028 mol, 0.55 eq) Ca(OH).sub.2 is then charged into the flask, heated to 4550 C. and stirred at this temperature for 0.5 h followed by hot filtration to remove some inorganic insoluble impurities to give 65.0 g filtrate. Excess NH.sub.3 in the filtrate is removed by distillation using vacuum and the resulting residue is diluted by adding fresh methanol. The solution is heated to reflux and 7.4 g (0.075 mol, 1.5 eq) conc. HCl is added drop wise into the flask to give a suspension. Stirring is continued for 0.5 h at 6070 C., then slowly cooled down to 05 C. and stirring continued for 1 h. The suspension is then filtered and washed with methanol twice to give 11.2 g wet product as solid, which is dried at 55 C. using vacuum for 10 h to obtain 8.84 g product as solid (yield 84.9% with 99.7% HPLC-purity).

[0109] Mass spectrum (ESI.sup.+): m+1-2HCl/z=136

Example 6

Step B and C Amination

[0110] 18 mL (3 v/w of 4-ABN) methanol and 10.5 g wet intermediate (C.sub.9H.sub.12N.sub.2O.2HCl, from 0.050 mol 4-ABN) are charged into a 250 mL flask under N.sub.2 at rt. 31.0 g (11.0% in methanol, 0.200 mol, 4.0 eq) ammonia in methanol solution is added drop wise into the flask while maintaining the temperature below 35 C. After charging of ammonia, the reaction mixture is heated to 3540 C. for 2 h, then the mixture is cooled to rt slowly and stirred for an additional 1 h. The reaction mixture is filtered to remove inorganic salts and rinsed with 10 mL methanol to obtain 65.0 g of filtrate. Excess NH.sub.3 in the filtrate is removed by distillation using vacuum, the resulting residue is diluted by adding fresh methanol. The mixture is heated to reflux and 7.4 g (0.075 mol, 1.5 eq) conc. HCl is added drop wise into the flask to give a suspension. Stirred at 6070 C. is continued for 0.5 h and the mixture subsequently cooled down to 05 C. and stirred for an additional 1 h at 05 C. The suspension is filtered and washed with methanol twice to give 13.0 g wet product as solid, which is dried at 55 C. using vacuum for 10 h to give 9.2 g product as solid (88.4% in yield with 99.8% HPLC purity).

[0111] Mass spectrum (ESI.sup.+): m+1-2HCl/z=136

Example 7

Step B and C, Amination

[0112] 253 mL (3 v/w of 4-ABN) methanol and 184.0 g wet intermediate (C.sub.9H.sub.12N.sub.2O.2HCl, from 0.715 mol 4-ABN) are charged into a 2 L flask at rt. 486.0 g (10.0% in methanol, 2.86 mol, 4.0 eq) ammonia in methanol solution is added drop wise into the flask while keeping the temperature below 35 C. After addition of ammonia the reaction mixture is heated to 3540 C. for 2 h, then the mixture is cooled down to rt and stirred for an additional 1 h. The reaction mixture is filtered and rinsed with 85 mL methanol to obtain 1.0 L of filtrate. Excess NH.sub.3 in the filtrate is removed by distillation using vacuum, the resulting residue is diluted by adding fresh methanol. The reaction mixture is heated to reflux to obtain a solution and 106.0 g (1.07 mol, 1.5 eq) conc. HCl aq. is added drop wise into the flask under reflux. The mixture is stirred at 6070 C. for 0.5 h, cooled down to 05 C. slowly and allowed to stir at 05 C. for 1 h. The suspension is then filtered and washed with methanol twice to obtain 170.0 g wet product as solid, which is dried at 55 C. under vacuum for 11 h to obtain 132.0 g product as solid (88.7% yield with 99.3% HPLC purity).

[0113] Mass spectrum (ESI.sup.+): m+1-2HCl/z=136

Example 8

Step A Pinner Reaction

[0114] 61.0 mL (5.2 v/w of 4-ABN) EtOH and 11.8 g (0.100 mol, 1.0 eq) 4-ABN are charged into a 250 mL flask to obtain a solution. The mixture is cooled down to 5 C., 44.0 g (1.2 mol, 12.0 eq) HCl gas is bubbled into the reaction solution (dried through conc. H.sub.2SO.sub.4) while maintaining the temperature below 20 C. The reaction mixture is transferred into a pressure tube equipped with pressure gauge, rinsed with 10 mL EtOH (The total amount of ethanol is 71 mL, 6.0 v/w of 4-ABN), sealed and heated to 3540 C. for 5 h (maximum inner pressure is 3.4 atm. The mixture is then allowed to cool to rt, stirred 1 h, and the pressure released. The resulting suspension is filtered, and the filter cake rinsed with 12 mL ethanol two times to obtained 23.0 g of wet product as solid, which is used for the following step without further treatment.

[0115] Mass spectrum (ESI.sup.+): m/z=m+1-2HCl/z=165;

[0116] .sup.1H NMR: .sub.H 1.36-1.43 (3H, triple, 7-C); 4.51-4.57 (2H, tetra, 6-C); 6.76-6.80 (2H, d, 3-C); 7.90-7.99 (2H, d, 2-C).

[0117] .sup.13C NMR: .sub.C 13.6 (7-C); 68.4 (6-C); 111.2 (1-C); 114.0 (3-C); 123.1 (2-C); 133.5 (4-C); 169.5 (5-C).

[0118] Compounds of general formula (I) are prepared analogously to the procedure described above.