| 91% |
With hydrogen In ethyl acetate at 50℃; for 4 - 5h; |
3.B
Variant B: Pd/C 10%; 25 g (0.07 mol) 4-methylamino-3-nitrobenzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide, 2.5 g 10% palladium on charcoal catalyst and 83 ml of ethyl acetate are placed in a hydrogenating autoclave. The mixture is hydrogenated under a hydrogen atmosphere of 3-4 bar at 500C until the hydrogen uptake is constant (4-5h). After cooling to 200C the hydrogenating solution is filtered off from the catalyst and evaporated down in vacuo using the rotary evaporator. The residue is dissolved warm in a little ethyl acetate and combined with 68 ml of toluene. After cooling to 5°C the mixture is left for 1 h with stirring, then the precipitate is filtered off and washed with toluene. The product obtained is dried at 400C in the vacuum dryer. Yield: 20.9 g (corr. 91% of theory) |
| 89.1% |
With sodium dithionite In ethanol; water at 50℃; for 1h; |
I Example 1 Preparation of ethyl 3 - [(4-methylamino-3-aminobenzoyl) (pyridin-2-yl) amino] propionate (2)
Weigh 3 - [(4-amino-3-nitrobenzoyl) (pyridin-2-yl) amino] propanoate (1) 10g, was added a mixed solvent of ethanol and water, 200ml, was heated to 50 , was added at once 21.3 g of sodium dithionite, reaction was continued for 1h, after completion of the reaction ethanol was distilled off, and the aqueous layer was extracted three times with methylene chloride, then washed with saturated brine, and evaporated to dryness to give the desired product as a red oil 8.2g yield 89.1%. |
| 83% |
With hydrogen In ethyl acetate at 35 - 55℃; for 1 - 2h; |
3.A
Example 3; Preparation of 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide (AMBPA) (3); Variant A:; Pd/C 5%15O g (0.4 mol) 4-methylamino-3-nitrobenzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide, 12 g 5% palladium on charcoal catalyst and 627 ml of ethyl acetate are placed in a hydrogenating autoclave. The mixture is hydrogenated under a hydrogen atmosphere of 3-4 bar at 35-55°C until the hydrogen uptake is constant (l-2h). After cooling to 200C the hydrogenating solution is filtered off from the catalyst and evaporated down in vacuo using the rotary evaporator. The residue is taken up in 650 ml isopropanol, distilled down to half the original volume and cooled to 5-100C. After 4h the resulting suspension is filtered, and the precipitate thus isolated is washed batchwise with a total of 100 ml isopropanol. The solid obtained is dried in the vacuum dryer at 500C. Yield: 114.2 g (corr. 83% of theory) |
| 83% |
With hydrogen In ethyl acetate at 35 - 55℃; for 1 - 2h; |
3.A
Variant A: Pd/C 5%; 15O g (0.4 mol) 4-methylamino-3-nitrobenzoic acid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)-amide, 12 g 5% palladium on charcoal catalyst and 627 ml of ethyl acetate are placed in a hydrogenating autoclave. The mixture is hydrogenated under a hydrogen atmosphere of 3-4 bar at 35-55°C until the hydrogen uptake is constant (l-2h). After cooling to 200C the hydrogenating solution is filtered off from the catalyst and evaporated down in vacuo using the rotary evaporator. The residue is taken up in 650 ml isopropanol, distilled down to half the original volume and cooled to 5-100C. After 4h the resulting suspension is filtered, and the precipitate thus isolated is washed batchwise with a total of 100 ml isopropanol. The solid obtained is dried in the vacuum dryer at 500C. Yield: 114.2 g (corr. 83% of theory) |
| 75% |
With palladium on activated charcoal In ethyl acetate at 25 - 55℃; |
2 Example-2 Preparation of Crystalline ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate of Formula (2A)
113.6 g of 4-(methylamino)-3-nitrobenzoic acid of Formula (A), 1.2 mL dimethylformamide and thionyl chloride (170.5 mL) were stirred for 15 minutes at 25° C. to 35° C. The reaction mixture was heated to 75° C. to 80° C. for one hour. Excess of thionyl chloride was distilled out. 75 g of ethyl 3-(pyridin-2-ylamino)propanoate of Formula (B) and ethyl acetate (100 mL) were added to the reaction mixture. 121 mL of triethylamine to was added and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with mixture of water and ethyl acetate and charcoalized. The reaction mixture was filtered to obtain of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate of Formula (C). The compound (C) in-situ in ethyl acetate layer was added 3.75 g Pd/C at 25° C. to 35° C. and stirred for 20 min. The reaction mixture was maintained under 5 Kg pressure at 50° C. to 55° C. The reaction mixture was filtered and washed with ethyl acetate and distilled to obtain residue. 150 mL isopropanol was added and heated for 5-10 minutes at 70° C. to 75° C. The reaction mixture was cooled to 0° C. to 5° C. and filtered. The wet-cake was washed with isopropanol and dried to afforded 75% ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (2A) with 98% purity. The compound of Formula (2A) is characterized by x-ray powder diffraction as depicted in . FIG.1. |
| 65% |
With hydrogen In methanol at 20℃; |
|
|
With hydrogen; triethylamine In ethyl acetate at 30 - 50℃; Inert atmosphere; Autoclave; |
Under inert atmosphere (N2) an autoclave is charged with 150g of compound 2, 6g of a 10% Palladium on Charcoal catalyst, 7 ml of triethylamine and 630ml of ethyl acetate. The autoclave is heated to 30°C and hydrogen added until a pressure of 4 bars is observed. Then the temperature is adjusted to 50°C. The usual time for complete conversion of the starting material is 1 to 2h. The autoclave is then allowed to cool and the suspension filtered to remove the catalyst. The organic filtrate is concentrated on a rotary evaporator and diluted with 350ml of either isopropanol or toluene. Again the solution is concentrated using mild vacuum and 400ml of either isopropanol or toluene are added. The solution is cooled to 10C to allow crystallisation of the product. The crude product is isolated by filtration and dried under vacuum to yield 123g (90%) of theoretical yield) of compound 1. |
|
With palladium on activated charcoal In ethyl acetate at 25 - 55℃; for 0.333333h; High pressure; |
2 Example 2: Preparation of crystalline ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- yl)benzamido) propanoate of Formula (2A)
The compound (C) in-situ in ethyl acetate layer was added 3.75 g Pd/C at 25°C to 35°C and stirred for 20 min. The reaction mixture was maintained under 5 Kg pressure at 50°C to 55°C. The reaction mixture was filtered and washed with ethyl acetate and distilled to obtain residue. 150 mL isopropanol was added and heated for 5-10 minutes at 70°C to 75°C. The reaction mixture was cooled to 0°C to 5°C and filtered. The wet-cake was washed with isopropanol and dried to afforded 75% ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (2A) with 98% purity. The compound of Formula (2 A) is characterized by x-ray powder diffraction as depicted in Fig.1. |
| 116.1 g |
With palladium 10% on activated carbon; ammonium formate at 20℃; for 12h; |
3-[(3-Amino-4-methylaminobenzoyl)-pyridin-2-ylamino]propionic Acid Ethyl Ester (6)
To a solution of 4-chloro-3-nitrobenzoic acid (1, 80 g, 0.40 mol) in a mixture of toluene(650 ml) and N,N-dimethylformamide (2 ml) at 70C, thionyl chloride (34 ml, 0.47 mol)was added dropwise and the mixture was stirred for 2 h. After the volatiles were removedin vacuo at 55C, the remaining liquid was dissolved in anhydrous dichloro- methane(400 ml). A solution of 3-(pyridin-2-ylamino)propionic acid ethyl ester 4 (77 g, 0.40 mol)in anhydrous dichloromethane (400 ml), and N,N-diisopropylethylamine (131 ml) wereadded, and the reaction temperature was maintained between 0 and -5C. The mixture wasstirred for 1 h at 0C, and then the solvents were removed in vacuo at 30C to give anoff-white powder. HPLC analysis of an aliquot of the powder indicated a purity of 93%(determined by peak areas).N,N-dimethylformamide (DMF, 740 ml) was added and the mixture was stirred at70C for 15 min. Then a solution of 27∼30% methylamine in ethanol (140 ml) was added dropwise. The mixture was cooled to 25C. After 30 min, ananlysis by HPLC indicatedthat it was the complete consumption of 8.To the above solution, 10% Pd/C (11.1 g) and ammonium formate (65.1 g, 1.03 mol)were then added. The mixture was stirred for 12 h at room temperature. The resultingmixture was filtered through Celite by gravity and the filtrate was evaporated to yield anoil which was dissolved in ethyl acetate (500 ml), and the solution was washed with water(300 ml × 3) and brine (300 ml), respectively. The organic layer was dried over anhydrousNa2SO4, evaporated in vacuo at 35C. The residual solid was recrystallized from toluene(350 ml) to give 6 (116.1 g, 85% overall yield from 1) as a white powder, mp. 103-104C. |
| 61 g |
With hydrogenchloride; iron In tetrahydrofuran; water for 2h; Reflux; |
8 Preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate (Formula-7)
Iron powder (35.9 g) was added to a mixture of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate compound of formula-6 (60 g), tetrahydrofuran (63 ml) and water (63 ml) and heated the reaction mixture to reflux temperature. Hydrochloric acid (17.6 g) was slowly added to the reaction mixture at the same temperature over a period of 2 hours. After completion of the reaction, the reaction mixture was cooled to 25-35° C. and dichloromethane and water were added. Filtered the reaction mixture through hyflow bed, both organic and aqueous layers were separated from the filtrate and the organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and then co-distilled with ethyl acetate to obtain the title compound. The obtained compound was recrystallized from ethyl acetate. Yield: 61.0 g; MR: 103-108° C. |
| 85.4 g |
With hydrogen In ethyl acetate at 60 - 65℃; |
g g)Ethyl3- { [ {2-amino-1-(methylamino)phen-4-yl)carbonyl] (pyridyn-2- yl)amino)Propanoate (III):
100gm ‘ (0.268 mol) pure ethyl3 - { [{ 1 -(methylamino)-2-nitrophen-4- yl}carbonyl](pyridyn-2-yl)aminol propanoate as obtained in example c) was dissolved in 1.0 lit ethyl acetate to obtain clear solution. To this clear solution (20 gm) Raney nickel was added and reaction mixture was hydrogenated at 60-65°C under 10 bar’ pressure. Completion of reaction was monitored by TLC. Upon completion of reaction, reaction mixture was filtered over celite bed and bed was subsequently washed with 200 ml ethyl acetate. Combined filtrate was concentrated under vacuum to obtain crude Ethyl3 - { [{2-amino- 1 .-(methylamino)phen.-4- yl } carbonyl] (pyridyn.-2-yl)amino } Propanoate.Yield: 85.4g (9286%); Purity by HPLC: 99.40 %. |
|
With palladium 10% on activated carbon for 20h; |
1.6 Synthesis of 3- (1-methylamino-2-amino-phenyl-4-yl) -carboxylic acid- (N-2-pyridyl) amido-propionic acid ethyl ester
The 3 - (2-nitro-1-methylamino-benzenesulfonyl-4-yl)-carboxylic acid-(N-2-pyridyl) amide yl- ethyl propionate (10.0g, 0 . 027mol) dissolved in 120 ml anhydrous ethanol, adding 1.0g 10% Pd/C, for 30atm. The continuous reaction 20h, filtered, concentrated to obtain 3 - (1-methylamino-2-amino-benzene-4-yl)-carboxylic acid-(N-2-pyridyl) amide yl- ethyl propionate (7.8g, yield 85%). Mass spectrometric (ESI-MS): 343.4(M+H) +, 365.3(M+Na) +; C 18 H 22 N 4 O 3 (342). |
|
With sodium dithionite; potassium carbonate In 1,4-dioxane; water at 50℃; for 6h; |
Synthesis and characterization of compounds 3, 4
10 g of compound 2 was dissolved in 1 L ofdichloromethane under the nitrogen atmosphere and cooled to 0-5 °C. Thionyl chloride was added to the reaction mixture for1 h and the reaction mixture was heated to reflux for 5-6 h. Acid chloride compound 3 was obtained by removing excessthionyl chloride under vacuum and it was used at the next step.Compound 3 (7.91 g, 0.0369 mol) was then dissolved in dichloromethane (100 mL) under an inert atmosphere andtriethyl amine (7.47 g, 0.0738 mol) was added. To the reaction mixture a solution of ethyl-3-(pyridine-2-ylamino)propanoate(8.60 g, 0.0443 mol) in dichloromethane (20 mL) was added slowly at 0-5 °C. After the completion of the reaction, thereaction mass was diluted with water (150 mL) and the product was extracted with dichloromethane (200 mL). Compound 4was obtained by distilling off the solvent under vacuum and purified by hexane. 1H NMR (DMSO-d6, 400 MHz): δ 1.11 (t,3H, -CH2CH3), 2.65 (t, 2H, -COCH2), 2.89 (d, 3H, -NHCH3), 3.95 (q, 2H, -NCH2), 4.17 (t, 2H, -CO2CH2), 6.82 (s, 1H,NH), 7.08 (d, 1H, Ar-H), 7.21 (m, 1H, Py-H), 7.30 (d, 1H, Py-H), 7.69 (s, 1H, Ar-H), 7.93 (s, 1H, Ar-H), 8.43 (m, 2H,Py-H). IR: νmax (cm-1): 3306 (s), 1632 (s), 1532 (s), 1406 (s), 1322 (m), 1187 (m), 1027 (s), 950 (w), 860 (w), 786 (w).10 g of compound 4 was dissolved in 100 mL of a mixture of dioxane and water and heated to 50 °C. Sodiumdithionate (24.90 g, 0.1208 mol) and potassium carbonate (1.11 g, 0.0081 mol) was added to the reaction mixture andmaintained at 50 °C for 6 h. Title compound 1 was obtained by removing the solvent under vacuum and purified byrecrystallization from ethylacetate. 1H NMR (DMSO-d6, 400 MHz): δ 1.11 (t, 3H, -CH2CH3), 2.65 (t, 2H, -COCH2), 2.89 (d,3H, -NHCH3), 3.95 (q, 2H, -NCH2), 4.17 (t, 2H, -CO2CH2), 4.53 (s, 2H, -NH2), 5.06 (s, 1H, -NH), 6.67 (s, 1H, Ar-H), 6.75(d, 1H, Ar-H), 7.10 (s, 1H, Ar-H), 7.56 (d, 1H, Py-H), 7.76 (t, 1H, Py-H), 8.38 (d, 1H, Py-H). IR: νmax (cm-1): 1607 (s),1555 (s), 1397 (s), 1321 (m), 1193 (m), 1028 (w), 948 (w), 861 (w), 797 (w), 704 (w). HRMS (ESI+), m/z: calc. forC18H22N4O3: 365.1590 [M+Na+], found 365.1546. |
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