| 59% |
With nitric acid In water; butan-1-ol at 0 - 95℃; for 12h; |
1.1; 2.1; 3.1; 4.1 Example-1: Process for the preparation of Imatinib of the formula (la);Step-1; The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)
Charged a suspension of 34 Kg of 2-amino-4-nitro toluene in 200 L n-butanol into reactor. 14.3 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 14.1 Kg of cyanamide dissolved in 14 L DM water is charged. Reaction mass is heated to 90-95C for 12 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then cooled to 0-10C. Charge 235 L isopropyl ether and 235 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (100 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70C Id : 22 Kg - 61% (based on recovery of III).: 214-220CitybyHPLC:99.8%Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate (IV)Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 25 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95C for 12 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then cooled to 0-10C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70C Yield : 2.2 Kg - 61% (based on recovery of III) MR:215-218CPurity by HPLC: 99.80% Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 20 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 1.4 Kg of syanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95C for 14 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then sooled to 0-10C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (HI)Centrifuged product is dried at 60-70CYield : 2.1 Kg - 59% (based on recovery of HI)MR: 216-219CPurity by HPLC: 99.9% Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 25 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95C for 14 hours, cooled to 65-70C. n-butanol is distilled off not crossing mass temperature 40-50C to the residual volume of 80 L. Reaction mass is Cooled to 25-35C and then cooled to 0-10C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10C. Maintained 1 hour at 10-15C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70C Yield : 2.1 Kg - 59% (based on recovery of III) MR: 214-220C Purity by HPLC : 99.85% |
| 58% |
With nitric acid In ethanol for 24h; Reflux; |
|
| 58% |
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol at 20℃; for 0.166667h;
Stage #2: CYANAMID In ethanol; water at 80 - 85℃; for 12h; |
5.1.1. 1-(2-Methyl-5-nitrophenyl)guanidine nitrate (5)
To a solution of 2-methyl-5-nitroaniline (1.5 g, 10 mmol) in ethanol (25 mL) was added drop wise nitric acid (2 mL) at room temperature. After the completion of addition, the reaction mixture was stirred for 10 min at room temperature. 50% aqueous solution of cyanamide (3 mL, 25 mmol) was added droop wise to the reaction mixture and stirred for 12 h at 80-85 °C. The crude product was collected by filtration and washed with ethyl acetate and recrystallized from ethanol to afford the compound 5 as light yellow solid (1.12 g, 58%). Mp 216-218; 1H NMR (DMSO-d6, 300 MHz): δ 2.32 (s, 3H, -CH3), 7.44 (m, 4H, ArH), 7.64 (d, 1H, J = 8.2 Hz, ArH), 8.09 (d, 1H, J = 2.5 Hz, ArH), 8.15 (dd, 1H, J = 8.2, 2.5 Hz, ArH), 9.51 (m, 1H, ArH); MS (EI): m/z 194 [M+]. |
| 54% |
With nitric acid In propan-1-ol; water for 24h; Reflux; |
2.1.2. Preparation of N-(2-methyl-5-nitrophenyl)guanidiniumnitrate (2).
To a solution of 1 (500 mg, 3.12 mmol) inpropanol (4 ml), 65% nitric acid (0.4 ml, 3.75 mmol) wasadded until a yellow solid formed, whereupon a 50% solutionof cyanamide in water (265 mg, 6.24 mmol) was added. Thereaction was refluxed for 24 h and then cooled to 0 C. Theyellow precipitate was filtered off and washed with propanoland methanol (yield 54%; m.p 210 C). 1H NMR (400 MHz,DMSO-d6): 8.13 (d, J = 8.5 Hz, 1H, Ar-H), 8.06 (s, 1H,Ar-H), 7.62 (d, J = 8.4 Hz, 1H, Ar-H), 7.43 (s, 1H, -NH-CNHNH2), 2.31 (s, 1H, -CH3). 13C{H} NMR (100 MHz,DMSO-d6): 156.42, 146.61, 144.01, 134.62, 132.52, 122.99,122.86, 17.82 (-CH3). |
| 53% |
Stage #1: 2-methyl-5-nitroaniline With nitric acid In butan-1-ol
Stage #2: CYANAMID In water; butan-1-ol at 100℃; for 12h; |
|
| 34% |
With nitric acid In ethanol; water at 80℃; for 16 - 18h; |
1.2
Step 2: N-(2-Methyl-5-nitro-phenyl)-guanidinium nitrate: 2-Methyl-5-nitro aniline (10 g, 65 mmol) was dissolved in ethanol (25 mL), and concentrated HNO3 (4.6 mL) was added to the solution dropwise followed by 50% aqueous solution of cyanamide (99 mmol). The reaction mixture was refluxed overnight and then cooled to 0° C. The mixture was filtered and the residue was washed with ethyl acetate and diethyl ether and dried to provide N-(2-Methyl-5-nitro-phenyl)-guanidinium nitrate (4.25 g, yield: 34%). |
|
With nitric acid In ethanol Heating; |
|
|
With nitric acid In diethyl ether; ethanol; water |
20.1 Step 20.1
Step 20.1 9.1 ml (0.13 mol) of 65% nitric acid are added dropwise in the course of 5 minutes to a yellow suspension of 20.0 g (0.13 mol) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol. When the exothermic reaction has subsided, 8.32 g (0.198 mol) of cyanamide dissolved in 8.3 ml of water are added. The brown reaction mixture is boiled at reflux for 25 hours, cooled to 0° and filtered. Washing with 4*100 mi of ethanol/diethyl ether (1:1) and drying yield 2-methyl-5-nitrophenyl-guanidine nitrate; m.p. 219°-226°. |
|
With nitric acid In ethanol; water |
I Preparation I
Preparation I N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (A) To a suspension of 10.0 g (0.065 mol) of 2-amino-4-nitrotoluene in ethanol (20 ml) was added 65% nitric acid (4.6 ml, 0.065 mol) dropwise at 0° C. and stirred for 10 minutes. Cyanamide (8.32 g, 0.198 mol) in water (5 ml) was added to the reaction mixture then was refluxed for 25 hours, cooled to 0° C. and filtered and washed with water to yield 2-methyl-5-nitrophenyl-guanidine nitrate. |
|
With water; nitric acid; butan-1-ol for 25h; Heating / reflux; |
To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 niL) is added2.1 g of 65% aq. nitric acid to form the nitrate salt followed by condensation with cyanamide (0.047 mmol) in water (2 mL). The resulting mixture is heated at reflux for 25 h. After cooling to 0 0C, the precipitate is collected by filtration and washed with ethanol/diethyl ether (1 : 1 v/v, 30 mL) to afford 2-methyl-5-nitrophenyl guanidine nitrate 2 |
|
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water
Stage #2: CYANAMID In ethanol; water for 24h; Heating / reflux; |
B.1.4; E
Step 1.4 2.Methyl-5-nitroaniline (100 g, 0.657 mol) was dissolved in ethanol (250 ml), and 65% aqueous nitric acid solution (48 ml, 0.65 mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4 g) dissolved in water (41.4 g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0° C, filtered, and washed with ethanol: diethyl ether(l :l, v/v) to give 2-methyl-5-nitrophenyl-guanidine nitrate (98 g) (U.S. 4,623,486). Rf=O.1 (Methylene chloride:Methanol:25% Aqueous ammonia=150:10:l). MS: 195.2 (M+H); 1H-NMR(DMSO- d6)=1.43(s, 3H), 6.59(s, 3H), 6.72-6.76(d, IH), 7.21-7.27(m, IH), 8.63-8.64(br, IH). |
|
With nitric acid In ethanol; water for 4h; Reflux; |
6
Reference Example 6 N-(2-Methyl-5-nitro-phenyI)-guanidne nitric acid salt; To a solution of 2-methyl-5-nitroaniline (1.90 g) in ethanol (3 mL) at 0 °C was added dropwise nitric acid (0.90 mL of a 70% solution in water). After complete addition, a solution of cyanamide (1.57 g) in water (1 mL) was added and the mixture was stirred at reflux for 4 h. After cooling to room temperature, the mixture was poured into diethyl ether (20 mL) and the resulting solid was filtered to give N- (2-methyl-5-nitro-phenyl)-guanidine nitric acid salt as a yellow solid (1.84 g). |
|
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water
Stage #2: CYANAMID In ethanol; water for 24h; Heating / reflux; |
1; 1.2 Reaction Scheme 1; Step 1.2
2-METHYL-5-NITROANILINE (100G, 0. 657MOL) was dissolved in ethanol (250MA), and 65% aqueous nitric acid solution (48MA, 0. 65MOL) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4g) dissolved in water (41.4g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0°C, filtered, and washed with ethanol : diethyl ether (l : L, V/V) to give 2-metliyl-5-nitrophenyl-guanidine nitrate (98G). Rf= 0.1 (Methylene chloride: Methanol: 25% Aqueous ammonia = 150 : 10: 1) LH-NMR (DMSO-D6) = 1.43 (s, 3H), 6.59 (s, 3H), 6.72-6. 76 (d, LH), 7.21-7. 27 (m, LH), 8.63-8. 64 (br, lH) |
|
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water
Stage #2: CYANAMID In ethanol; water for 24h; Heating / reflux; |
1; 1.2 Reaction Scheme 1; Step 1.2
2-Methyl-5-nitroaniline (100g, 0. 657MOL) was dissolved in ethanol (250 M), and 65% aqueous nitric acid solution (48 M, 0.65mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4g) dissolved in water (41.4g) was added thereto. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was COOLED) to 0 C, filtered, and washed with ethanol: diethyl ether (L : 1, V/V) to give 2-methyl-5-nitrophenyl-guanidine nitrate (98g). [143] [144] Rf = 0.1 (Methylene chloride : Methanol : 25% Aqueous ammonia = 150 : 10 : 1) [145] 1H-NMR(DMSO-d)= 1.43(s,3H), 6.59(s,3H), 6.72-6.76 (d,1H), 7.21-7.27(m,1H), 6 8.63-8. 64 (br, 1H) |
| 98 g |
Stage #1: 2-methyl-5-nitroaniline With nitric acid In ethanol; water
Stage #2: CYANAMID In ethanol; water for 24h; Reflux; |
8.2.1 2-Methyl-5-nitrophenyl-guanidine nitrate (2)
2-Methyl-5-nitroaniline 1 (100g, 0.657mol) was dissolved in ethanol (250mL), and a 65% aqueous nitric acid solution (48mL, 0.65mol) was added thereto. When the exothermic reaction was stopped, cyanamide (41.4g) dissolved in water (41.4g) was added. The brown mixture was reacted under reflux for 24h. The reaction mixture was cooled to 0°C, filtered, and washed with ethanol-diethyl ether (1:1, v/v) to give 2-methyl-5-nitrophenyl-guanidine nitrate 2 (98g). |
|
With nitric acid In ethanol for 21h; Reflux; |
|
|
With nitric acid |
12.A (The A) 4- methyl-3-[4- (3-pyridinyl) -2-pyrimidinyl amino] aniline
2-methyl-5-nitroanilinewith cyanamide, guanidine nitrate was the addition, and then (E) -3-dimethylamino-1- (pyridin-3-yl) -1-oxo-2-propenyl cyclization was pyrimidinaminecompound, and finally reducing the nitro group to give. |
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With nitric acid In water; butan-1-ol for 25h; Heating / reflux; |
Experimental Preparation of intermediates; Synthesis of 6-methyl-Nl-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-l,3-diamine 5; To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 mL) is added nitric acid (2.1 g, 65% in water) followed by cyanamide solution in water (2 mL, 0.047 mmol). The resulting mixture is heated at reflux for 25 h. After cooling to 0 0C, filtration and washing with 1 : 1 = ethanol : diethyl ether (30 mL), 2-methyl-5-nitrophenyl guanidine nitrate 2 is obtained. To 2-methyl-5-nitrophenyl guanidine 2 (0.0074 mol) in isopropanol (15 mL) is added 3 (0.0074 mol) and sodium hydroxide flakes (0.008 mol). The resulting mixture is heated at reflux for 12 h. After cooling to 0 0C, the product is collected by filtration and washed with isopropanol (6 mL) and methanol (3 mL) to afford 4. 1H NMR (400MHz, Cl6-DMSO) δ 9.31 (s, IH), 9.24 (s, IH), 8.78 (m, IH), 8.70 (m, IH), 8.61 (m, IH), 8.47 (m, IH), 7.88 (m, IH), 7.55 (m, 3H), 2.39 (s, 3H). MS (m/z) (M+l)+: 278.2. |
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With nitric acid |
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