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CAS No. : | 42288-26-6 | MDL No. : | MFCD01464022 |
Formula : | C9H8N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KJRQMXRCZULRHF-UHFFFAOYSA-N |
M.W : | 176.17 | Pubchem ID : | 817965 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 47.04 |
TPSA : | 73.12 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.13 cm/s |
Log Po/w (iLOGP) : | 1.09 |
Log Po/w (XLOGP3) : | 0.34 |
Log Po/w (WLOGP) : | 0.86 |
Log Po/w (MLOGP) : | -1.78 |
Log Po/w (SILICOS-IT) : | 0.76 |
Consensus Log Po/w : | 0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.29 |
Solubility : | 9.04 mg/ml ; 0.0513 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.44 |
Solubility : | 6.4 mg/ml ; 0.0363 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.31 |
Solubility : | 0.861 mg/ml ; 0.00489 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.44 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 100 - 110℃; for 3 h; | 3.2.3 Preparation of [(4-cyanophenyl)amino]acetic acid (V) C7H6N2 C2H3DPψ2 C9H8N2O2 MoI. Wt.: 1 18,14 MoI. Wt.: 138,95 MoI. Wt.: 176,17VIngredientsF: 90 g - 0.75 molG: 211.7 g - 1.5 molSodium bicarbonate: 35 g, 0.42 molThe starting substances F and G were mixed in 1250 ml of water and this suspension was inserted into a bath heated up to 100-110 0C. After three hours of heating the reaction container was removed from the bath, cooled in the fridge and the separated substance was sucked off. The substance was dried in a vacuum drier at the temperature of 100 °C. Yield: Crude product: 122 g (92.8percent), HPLC: 97percentThe crude product was purified by conversion to the sodium salt and re-acidification using an aqueous solution of sodium bicarbonate. The acid was released by means of diluted hydrochloric acid (1 :1). After sucking off and washing with water the product was dried in a vacuum drier (105 °C). Yield: Purified product: 115 g (88percent), HPLC: 99.1percent, water content: 0.13percent; sulphate ash: 1.8percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Reflux | In the 4-cyanato aniline (6.0g, 0 . 05mol) and 1-chloro acetic acid (10g, 0.11mol) adding water in 150 ml, heating to reflux until a large amount of yellow solid is separated out so far, the filter at room temperature, with water, anhydrous ethanol, anhydrous ethyl ether eluviation, that is, to get the yellow solid 4-cyanato anilino-acetic acid (6.4g, yield 73percent). Mass spectrometric (ESI-MS): 177.3(M+H) +, 199.2(M+Na) +; C 9 H 8 N 2 O 2 (176). |
58% | Heating / reflux | a) (4-Cyano-phenylamino)-acetic acid A solution of 4-aminobenzonitrile (12 g, 101.6 mmol) and chloroacetic acid (20 g, 211.6 mmol) in water (250 mL) was refluxed until the product began to separate out. After cooled down to the room temperature, the solids were collected by filtration, washed with ether, and dried in vacuo to afford 10.35 g (58percent) of the title compound which was pure enough for the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.46 (dd, 2H), 6.93 (t, 1H), 6.65 (dd, 2H), 3.91 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.2% | for 6.5 h; Reflux | e) 2-(4-Cyanophenylamino)acetic acid (compound III) 77.4 g (0.66 mol) of 4-aminobenzonitrile and 150 g (1.31 mol) of sodium chloroacetate were suspended in 1.1 L of water, and the resulting mixture was stirred at reflux temperature for 6.5 hours. After cooling to 0°C, the resulting suspension was stirred at this temperature overnight. The solid was filtered and washed with 200 mL of water. The resulting solid was suspended in 200 mL of ethyl acetate and stirred at room temperature for 1 hour. The solid was filtered, washed with 400 mL of ethyl acetate and dried at 60°C under vacuum for 5 hours to yield 84.5 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 73.2 percent. Purity (HPLC, method 3): 98.4 percent. |
73.2% | at 0℃; Reflux | e) 2-(4-Cyanophenylamino)acetic acid (compound III) 77.4 g (0.66 mol) of 4-aminobenzonitrile and 150 g (1.31 mol) of sodium chloroacetate were suspended in 1.1 L of water, and the resulting mixture was stirred at reflux temperature for 6.5 hours. After cooling to 0°C, the resulting suspension was stirred at this temperature overnight. The solid was filtered and washed with 200 mL of water. The resulting solid was suspended in 200 mL of ethyl acetate and stirred at room temperature for 1 hour. The solid was filtered, washed with 400 mL of ethyl acetate and dri e d at 60 ° C under v acuum for 5 hours to yield 84.5 g of 2-(4- cyanophenylamino)acetic acid as an off-white solid. Yield: 73.2 percent. Purity (HPLC, method 3): 98.4 percent. |
131 g | With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide In water at 90 - 95℃; for 24 h; | Sodium bicarbonate (21.35 g) was added to a mixture of 4-aminobenzonitrile compound of formula-12 (100 g) and water (1000 ml) followed by sodium 2-chloroacetate (197.42 g). Potassium iodide (5 g) followed by tertiary butyl ammonium bromide (2.5 g) were added to the reaction mixture. The reaction mixture was heated to the 90-95° C. and stirred for 24 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 20-25° C. and pH was adjusted to 7.5 with ammonia. The reaction mixture was stirred for 20 minutes at 20-30° C. Filtered the reaction mixture and ethylacetate was added to the filtrate. The reaction mixture was stirred for 15 minutes. Both the ethylacetate and aqueous layers were separated and the pH of aqueous layer was adjusted to 2.5 using hydrochloric acid. The reaction mixture was stirred for 3 hours at 20-30° C. to precipitate the solid. Filtered the precipitated solid, water followed by hydrochloric acid were added to the obtained solid and stirred for 4 hours at 25-30° C. Filtered the solid, the obtained solid was slurried twice in water for 30-45 minutes and then dried to get the title compound. The same process can be repeated one more time to eliminates the impurities if present. Yield: 131 g |
120 g | With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide In water at 85 - 90℃; for 24 h; | Sodium mono chloroacetate (197.42 g), followed by potassium iodide (5 g) and tetrabutyl ammonium bromide (2.5 g) were added to a mixture of 4-aminobenzonitrile (100 g), water (1000 ml) and sodium bicarbonate (42.71 g). The reaction mixture was heated to 85-90° C. and stirred for 24 hours. The reaction mixture was cooled to 25-30° C. and treated with ammonia followed by hydrochloric acid. Filtered the solid, washed with water and then dried to get title compound. Yield: 120 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium hydroxide; In dimethyl sulfoxide; at 20℃; | a) (4-Cyano-phenyl-methylamino)-acetic acid methyl ester Potassium hydroxide powder (1.12 g, 20 mmol) in DMSO (7 mL) was stirred for 30 min at room temperature, then the compound of Example 4-step a (0.88 g, 5 mmol) was added and stirred for another 15 minutes. To the above reaction mixture was added dropwise iodomethane (1.25 mL, 20 mmol) and the mixture was stirred at room temperature overnight, quenched by addition of water (70 mL). The reaction mixture was extracted with diethyl ether (5*50 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (100 mL), brine (50 mL), and dried over Na2SO4, filtered, concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to afford the title compound (0.48 g, 47%). 1H NMR (400 MHz, CDCl3) delta: 7.49 (m, 2H), 6.65 (m, 1H), 4.07 (s, 2H), 3.71 (s, 3H), 3.06 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 1,1'-carbonyldiimidazole; In acetic acid; | e. 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(tert.butyloxycarbonylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Prepared analogously to Example 1g/h from 2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(tert.butyloxycarbonylamino)-1-pyrrolidino-propan-1-one, 4-cyano-phenylglycine/carbonyldiimidazole and subsequent treatment with glacial acetic acid. Yield: 58% of theory, Rf value: 0.5 (aluminium oxide; methylene chloride/ethanol=19:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Step 1 : Crude product 10.0 g of N-(4-cyanophenyl)glycine and 10.35 g of N,N'-carbonyldiimidazole (CDI) are mixed at room temperature in 150 mL of isopropyl acetate. Then, 19.43 g of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate are added and the mixture reacts for 4 hours at room temperature. After this time, 20 mL of acetic acid are added and the mixture is refluxed for 2 hours. It is allowed to cool at room temperature and 33 mL of water are added. The organic phase is separated and further 33 mL of water are added. The pH of the mixture is adjusted to 10-11 with a dissolution of 25% of sodium hydroxide, forming a suspension. The suspension is filtered and the solid obtained is dried at 45 C in a vacuum oven. Yield: 24.6 g of crude base of the compound (III); (90% yield). Product purity: 94% measured by HPLC. Melting point: 1 16 C measured by differential scanning calorimetry technique (DSC); X-rays (angle 2-theta values ()): 7.6, 10.2, 10.9, 14.6, 15.2, 20.5, and 25.5 measured on a x-ray diffractometer with Cu K alpha radiation (1.5418 A). - Step 2: Purification of the compound (III) in free base form The crude product is recrystallized from 100 mL of ethanol, and a white solid with a high purity of 99% (HPLC) is obtained. Yield: 23,4 g of the purified base of the compound (III); (95% recrystallization yield). Product purity: 99% measured by HPLC; Melting point: 148C measured by differential scanning calorimetry technique (DSC); X-rays (angle 2-theta values ()): 5.9; 12.0; 13.7; 16.8; 18.9; 19.5; 21 .3; 24.4, and 27.6 measured on a x-ray diffractometer with Cu K alpha radiation (1.5418 A). | |
93.97% | Take SM02 (20.00g, 58.41mmol) in a 100ml single-mouth bottle, toluene (60ml) was added, magnetically stirred at ambient temperature, and set aside.At room temperature, SM01 (12.35g, 70.09mmol), CDI (11 · 84g, 73 · 01mmol) and toluene (120.0ml) were added to the reaction flask. Stirred and heated to 50 C. After 2-4 h, the reaction was monitored by TLC and the reaction was completed. The heating was stopped, the temperature of the reaction solution was lowered to 25 C, the toluene solution of SM02 was quickly added, and the mixture was stirred at 20-25 C for 5-16 h. The reaction was monitored by TLC. After completion of the reaction, acetic acid (8.0 ml) was added, and the reaction mixture was heated to 100 C, and kept for 1-2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and then concentrated, the residue was dissolved in a solvent, and the solvent used were dichloromethane, chloroform, 1, 2-dichloroethane or the like. The resulting solution was adjusted to pH 7, using a saturated aqueous solution of sodium bicarbonate, after layering, the aqueous phase was extracted once with dichloromethane, and the organic phase was combined; Washed once with water, after stratification, the aqueous phase was extracted once more with dichloromethane, organic phases were combined, the solvent was concentrated under reduced pressure to give DB02 crude material. | |
91.1% | In a 500 ml reaction flask,23.2 g (0.132 mol) of N- (4-cyanophenyl) -aminoacetic acid were added,100 ml of dimethylformamide,19.6 g (0.145 mol) of 1-hydroxybenzotriazole was added at 3 C,A solution of 29.9 g (0.145 mmol) of dicyclohexylcarbodiimide in 50 ml of dimethylformamide was added dropwise.Stirring reaction 1h,Slowly rose to room temperature,A solution of 50.0 g (0.145 mol) of compound 3 in dimethylformamide (100 ml) was added dropwise,The reaction was stirred for 6 h.The reaction solution was filtered,The filtrate was added dropwise to 750 ml of water at 1 C,Insulation 1 hour,filter.300 ml of toluene and 20.0 g of glacial acetic acid were heated to 90 C,Incubation reaction 6 hours,After cooling to room temperature, 120 g of water was added,40 ml of ammonia was added dropwise to adjust pH to 9,Stirring to precipitate a solid,Cooling 2 ,Holding 2 hours,filter,Drying was a gray solid .0g,The yield was 91.1%Directly used in the next step reaction. |
86% | This embodiment's darbey adds the group ester method for the preparation of intermediates with the following steps:(1) under the protection of nitrogen, the 28.3g the N-(4-cyano-phenyl)-glycine (0.16mol) and 25.9g condensing agent CDI (0.16mol) dissolved in the 100 ml of methylene chloride and 100 ml of a mixed solvent of the ether in a, stirring and heating to 40 ±2 C reflux, thermal insulation reaction 1-2h.(2) added to the above-mentioned reaction system 50.0g of 3-amino-4-methyl amino-benzoic acid-N-(2-pyridyl)-N - (2-ethoxy carbonyl-ethyl)-amide (0.14mol), in 40 ±2 C continue to return to the temperature of the condensation reaction, to 3-amino-4-methyl amino-benzoic acid-N-(2-pyridyl)-N - (2-ethoxy carbonyl-ethyl)-amide reaction is complete, to stop the reaction.Generating compound IV does not need separation directly used for the next step.(3) in the above-mentioned reaction system is added to 160 ml of acetic acid, first decompression concentrating evaporating methylene chloride and ethyl ether, then heating to 50-60 C to cyclization reaction, until the compound IV the reaction is complete, to stop the reaction.(4) after the reaction, water is poured in the reaction system, cooling to 20-30C, crystallization, filtration, the filter cake after re-crystallization with ethanol, again filtered, the filter cake is drying to obtain 60.6g compound I, to yield 86.0%, | |
85% | (1) at room temperature,75 g of compound of formula 6,1000 mL THF,100mL triethylamine mixed,Cooled to 0 ,70mL pivaloyl chloride was added below 10 and the reaction was incubated for 0.5h; After the reaction was completed, 155g of compound of formula 4 was added,45 reaction 2h;The organic layer was evaporated to dryness and added to 1500mL n-butyl acetate, at 90 for 4h,700 mL of butyl acetate was distilled off under reduced pressure,The crystals were stirred at 5 C,Filtered and dried to give a dry product of formula 3 175g,The yield is 85%; | |
83% | 4-Nitriloanilino-acetic acid (2.32 g, 13.2 mmol) was dissolved in 80 ml of DMF,1-Hydroxybenzotriazole (H0BT) (1.96 g, 14.5 mmol) was added,Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (2.77 g, 14.5 mmol) was added at 0 C under stirring for 45 min,Slowly rise to room temperature,Ethyl 3- (1-methylamino-2-amino-phenyl-4-yl) -carboxylic acid- (N-2-pyridyl) amidopropionic acid ethyl ester (5.50111111.01) was added at room temperature the reaction overnight, concentrated, diluted with ethyl acetate and large, washed three times with brine, dried over Na2S04 after dried, concentrated and the crude product in 60ml of acetic acid was refluxed for 1.5h, was concentrated, basified added 1.5N aqueous ammonia, extracted three times with ethyl acetate. (60 mL X 3). The organic phase was washed once with brine, dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography.The amorphous solid, 3- (1-methyl-2- (4-nitrile-phenylaminomethyl) -5-yl-carboxylic acid- (N-2-pyridyl) amido) propionic acid ethyl ester (6.4 g, yield 83%). Mass spectrum (ESI-MS): 482 ? 1 (M + H) +, 505.4 (M + Na) +; C27H26N6O3 (482) | |
61% | a) 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 61% of theory, Rf value: 0.62 (silica gel; dichloromethane/methanol=19:1) | |
Example 1 - Large-scale industrial synthesis of the compound of formula 4-Br88 kg carbonyl-di-(l,2,4-triazole) are taken and combined with 920 1 tetrahydrofuran. The contents of the apparatus are heated to 35C with stirring. Then 90 kg of compound 3 are added batchwise at 35C within 1 to 2 hours.160 kg of compound 2 are placed in a second reaction vessel, then 350 1 tetrahydrofuran are added and the mixture is heated to 500C with stirring.The solution of 3 is metered into the solution of 2 within 2 to 3 hours at 47C - 53C and the solution obtained is diluted with 115 1 tetrahydrofuran. Then the mixture is stirred for another 4 hours at 47C - 53C ( preferably 500C ). Then 670 1- 695 1 tetrahydrofuran are distilled off in vacuo at 50C-60C. 235 1 of n-butyl acetate are then allowed to flow into the residue. After this, 600 1 -630 1 of a butyl acetate/THF mixture are distilled off in vacuo at 50C-85C. During the distillation 700 1 butyl acetate are metered in. 65 kg acetic acid are allowed to flow into the residue, the contents are heated to 85C-90C and stirred for at least another 2.5 h at this temperature. Then the mixture is cooled to 65C-75C. A solution of 165 1 water and 20 kg common salt is added to the contents and the mixture is rinsed with 300 1 water. Then the temperature is adjusted to 60C-70C and the mixture is stirred for a minimum of 15 min. at this temperature. For phase separation the stirrer is stopped and the mixture is left to settle for at least 15 min. The aqueous phase is drained off into another reaction vessel which contains 120 1 of n-butyl acetate. The mixture is heated to 60C-70C with stirring and stirred for at least 10 min. After phase separation the aqueous phase is drained off into the chemical waste drain. The butyl acetate phases and 20 1 of butyl acetate for rinsing are combined. 590 1 - 620 1 of n-butyl acetate are distilled off from this content in vacuo at a max. internal temperature of 800C. <n="12"/>880 1 isopropanol are allowed to flow into the distillation residue and the content is adjusted to 32C-38C. Then approx. 90 kg of 48% hydrobromic acid are metered in at 32C-38C until the pH value is 0.6 to 1.3. The mixture is stirred for a minimum of 20 min. at 32C-38C and then cooled to 7C-13C and stirred at this temperature for at least one hour. The resulting suspension is centrifuged, washed with a total of 840 1 isopropanol and dried in vacuo at max. 55C. Yield: 211 kg-250 kg. Mp.: 200-2150C (with decomposition).The compound 4-HBr may be isolated using any standard commercially available centrifuge. | ||
Example 1 : Ethyl N-[(2-[(p-cyanophenyl)amino1methyl)-1 -methyl-1 H- benzimidazole-5-carbonyl1-N-(2-pyridyl)-3-aminopropionate hydrochloride (IV-HCI)Under Ar atmosphere, A/-(p-cyanophenyl)-glycine (V) (7.22 g, 41 .0 mmol) and 1 ,1 '-carbonyldiimidazole (6.64 g, 41 .0 mmol) were suspended in anhydrous THF (315 mL). It was refluxed for 45 minutes and a solution of compound (VI) (12.74 g, 37.2 mmol) in anhydrous THF (56 mL) was added slowly. After 6 h under reflux, the reaction mixture was cooled down, and the solvent was distilled under low pressure. The oil obtained was dissolved in glacial acetic acid (155 mL) and refluxed for 1 h. The solvent was removed under low pressure, the residue was dissolved in CH2CI2 (130 mL) and washed with H2O (2 x 130 mL). The organic phase was dried over anhydrous MgSO4 and the solvent was distilled under low pressure. The residue obtained was dried under vacuum, obtaining 20.19 g of crude (IV) (75% a/a purity according to HPLC/MS).The brown oil was dissolved in isopropanol (101 mL) at 35 C and HCI(c) (37%, 3.40 mL, 41 .1 mmol) was added slowly. After a short time an abundant white solid appeared. It was stirred at 35 C for 30 min and next at 0 C for 30 min. The solid was filtered out, washed with IPA (15 mL) and dried under vacuum, obtaining the product (IV-HCI) (14.25 g, 74% yield, 97% a/a purity according to HPLC/MS). This solid was recrystallized from EtOH (160 mL), washed with EtOH (2 x 10 mL) and dried under vacuum, obtaining 12.13 g (23.4 mmol, 63% global yield, 99% a/a purity according to HPLC/MS) of the product (IV-HCI).1H RMN (400 MHz, CD3OD) : delta (ppm) = 8.33 (ddd, J = 4.8, 2.0, 0.8, 1 H), 7.77 (d, J = 8.8, 1 H), 7.66 (dd, J = 1 .6, 0.8, 1 H), 7.60 (ddd, J = 8.0, 8.0, 2.0, 1 H), 7.55-7.50 (m, 3H), 7.17 (ddd, J = 7.6, 4.8, 0.8, 1 H), 7.09 (d, J = 8.0, 1 H), 6.83 (d, J = 8.8, 2H), 5.02 (s, 2H), 4.34 (t, J = 7.2, 2H), 4.05 (q, J = 7.2, 2H), 4.02 (s, 3H), 2.76 (t, J = 7.2, 2H), 1 .19 (t, J = 7.2, 3H).Melting point (Tme,t): 213-215 CPXRD: FIG. 2, 2theta angle values () = 3.7, 10.0, 10.9, 17.7, 18.3, 20.9, 22.0, 22.5, 23.7, 25.9, 26.4. | ||
Example-20: Preparation of l-methyI-2-[N-(4-cyanophenyl) aminomethyl] benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-14 A mixture of 2-(4-cyanophenylamino)acetic acid (139 g) and tetrahydrofuran (750 ml) was heated to 50-55C. A solution of N,N'-carbonyldiimidazole (177.6 g) in tetrahydrofuran (1000 ml) was added to the above reaction mixture at the same temperature over a period of 1 hour and stirred for 2 hours at 50-55C. A solution of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula- 12 (250 g) in tetrahydrofuran (1500 ml) was added over a period of 2 hours at 50-55C and heated to 60-65C. The reaction mixture was stirred for 50 hours at 60- 65C. After completion of the reaction, distilled off the solvent from the reaction mixture. Acetic acid was added to the reaction mixture and heated to 95-100C. The reaction mixture was stirred for 5 hours at 95-100C. Distilled off the solvent completely under the reduced pressure and the reaction mixture was cooled to 25-30C. Water was added to the reaction mixture and the product was extracted with dichloromethane. Dichloromethane layer was washed with water followed by sodium chloride. Distilled off the solvent completely from the dichloromethane layer to obtain title compound.Yield: 300 g | ||
Example-4: Process for preparation of the crystalline ethyl 3-(2-((4-cvanophenylamino)methylVl- methvl-N-(pvridin-2-vO-lH-benzotdUmidazole-5-carboxamido) propanoate of Formula (2B) 77 g 2-(4-cyanophenylamino) acetic acid of Formula (E), 71.04 g CDI in 1000 mL Toluene were stirred at 25C to 35C. The reaction mixture was heated to 55C to 60C and maintained for 2 hours. 100 g ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- yl)benzamido)propanoate of Formula (2A) was added to the reaction mixture and stirred for 3 hours at 60C to 65C. The reaction mixture was further heated at 100C for 3 hours. Toluene was distilled under vacuum. The residue was treated with 500 mL methylene dichloride and organic layer was washed with water. The organic layer was filtered and washed with methylene dichloride. The methylene dichloride was distilled under vacuum and 100 mL ethyl acetate was added at 40C to 45C and stirred for 15 minutes. The reaction mixture was heated to 75C and cooled to 10C to 15C. The reaction mixture was stirred for 2 hours and the precipitated product was filtered and washed with 150 mL ethyl acetate to obtain crystalline ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (2B). The compound of Formula (2B) is characterized by x-ray powder diffraction as depicted in Fig.2. | ||
300 g | A mixture of 2-(4-cyanophenylamino)acetic acid (139 g) and tetrahydrofuran (750 ml) was heated to 50-55 C. A solution of N,N?-carbonyldiimidazole (177.6 g) in tetrahydrofuran (1000 ml) was added to the above reaction mixture at the same temperature over a period of 1 hour and stirred for 2 hours at 50-55 C. A solution of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula-12 (250 g) in tetrahydrofuran (1500 ml) was added over a period of 2 hours at 50-55 C. and heated to 60-65 C. The reaction mixture was stirred for 50 hours at 60-65 C. After completion of the reaction, distilled off the solvent from the reaction mixture. Acetic acid was added to the reaction mixture and heated to 95-100 C. The reaction mixture was stirred for 5 hours at 95-100 C. Distilled off the solvent completely under the reduced pressure and the reaction mixture was cooled to 25-30 C. Water was added to the reaction mixture and the product was extracted with dichloromethane. Dichloromethane layer was washed with water followed by sodium chloride. Distilled off the solvent completely from the dichloromethane layer to obtain title compound. | |
127 g | A mixture of N-(4-cyanophenyl) glycine (56.6 g), CDI (61.6 g) and imidazole*HC1 (7.6g) in anhydrous EtOAc (1000 mL), was stirred for lh at 45-50C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (lOOg) was, lot-wise, charged to the reaction mass. After stirring for another lh at the same temp, Glacial acetic acid (100mL) was added and the temperature of the reaction mass maintained at reflux for another6h. The reaction mixture cooled to 45-50C, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum, till approx. 3 volumes were left behind. The reaction mass was cooled to room temp and 5% Brine solution (500 mL) was charged and the precipitate obtained was slurred for 3h. Theprecipitate was filtered, washed with EtOAc and dried under vacuum at 50C, to afford compound of formula 3 as off-white solid material (127.Og, 98.8% HPL pure). | |
77 g 2-(4-cyanophenylamino) acetic acid of Formula (E), 71.04 g CDI in 1000 mL Toluene were stirred at 25 C. to 35 C. The reaction mixture was heated to 55 C. to 60 C. and maintained for 2 hours. 100 g ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (2A) was added to the reaction mixture and stirred for 3 hours at 60 C. to 65 C. The reaction mixture was further heated at 100 C. for 3 hours. Toluene was distilled under vacuum. The residue was treated with 500 mL methylene dichloride and organic layer was washed with water. The organic layer was filtered and washed with methylene dichloride. The methylene dichloride was distilled under vacuum and 100 mL ethyl acetate was added at 40 C. to 45 C. and stirred for 15 minutes. The reaction mixture was heated to 75 C. and cooled to 10 C. to 15 C. The reaction mixture was stirred for 2 hours and the precipitated product was filtered and washed with 150 mL ethyl acetate to obtain crystalline ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoate of Formula (2B). The compound of Formula (2B) is characterized by x-ray powder diffraction as depicted in FIG.2. | ||
1 kg of organic solvent a, 1.5 kg of SM2, and 1.2 kg of CDI were sequentially added to the reaction vessel, and the reaction was stirred at 10 to 50 C for 3 hours.Then, 1 kg of SM1 and 1 kg of organic solvent b were sequentially added, and the reaction was further stirred for 12 hours, and the solvent was distilled off under reduced pressure at 40 C to the reaction kettle.The acetic acid was put into the mixture, heated to 110 C for 5 hours, and the solvent was distilled off under reduced pressure at 100 C or less.Washing with water, recovering the solvent under reduced pressure in the organic phase, adding ethyl acetate to the residue, stirring to dissolve, and adding oxalic acidThe hydrate solution was stirred and crystallized at 22 C for 2 hours, centrifuged, and the filter cake was washed with ethyl acetate. The filter cake was dried under reduced pressure at 45 C for 6 hours.When, a pale yellow solid PR-I;Wherein, the solution of oxalic acid dihydrate is an ethanol solution containing oxalic acid dihydrate, and the oxalic acid dihydrate is in solution.The part by mass is 10%.Wherein, the organic solvent a and the organic solvent b are both N,N-dimethylformamide;Among them, the mass ratio of other materials is SM1: acetic acid = 1:8, SM1: dichloromethane = 1:3, dichloromethane: water =1:3, SM1: solution containing oxalic acid dihydrate = 1:5; |
Yield | Reaction Conditions | Operation in experiment |
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81% | 4-Nitroanilino-acetic acid (2.32 g, 13.2 mmol) was dissolved in 80 ml of DMF and 1-hydroxybenzotriazole (HOBT) (1.96 g, 14.5 mmol) was added and at 1- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (2.77 g, 14.5 mmol) was stirred for 45 min and slowly warmed to room temperature. 3- (1-Methylamino- Amino-phen-4-yl) -carboxylic acid- (N-phenyl) -amidopropionic acid ethyl ester (5.0 g, 14.5 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, diluted with a large amount of ethyl acetate, washed with saturated brine three times, dried over Na 2 SO 4 and concentrated. The crude product was refluxed in 60 ml of acetic acid for 1.5 h, concentrated, and basified with 1.5 N aqueous ammonia. The organic layer was washed once with saturated brine, dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography to give 3- (1-methyl-2- (4-nitrile Phenylaminomethyl) -benzoimidazol-5-yl-carboxylic acid- (N-phenyl) -amido) propionic acid ethyl ester (5.1 g, yield 81%). Mass spectrum (ESI-MS): 482 ? 2 (M + H) +, 504 ? 2 (M + Na) +; C28H27N5O3 (481) | |
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; dichloromethane; acetic acid; | c 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide 6.17 g (0.035 mol) of N-<strong>[42288-26-6](4-cyanophenyl)glycine</strong> and 5.68 g (0.035 mol) of N,N'-carbonyldiimidazole were refluxed in 300 ml of tetrahydrofuran for 30 minutes, then 10.6 g (0.032 mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were added and the mixture was refluxed for a further five hours. Then the solvent was distilled off in vacuo, the residue was dissolved in 150 ml of glacial acetic acid and refluxed for one hour. Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in about 300 ml of dichloromethane, the solution was washed twice with about 150 ml water and then dried over sodium sulphate. After evaporation of the solvent the crude product thus obtained was purified by column chromatography (800 g silica gel; eluant: dichloromethane with 1-2% ethanol). Yield: 8.5 g (57% of theory), Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | a 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxy-carbonylpropyl)-amide Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide. Yield: 65% of theory, Rf value: 0.17 (silica gel; dichloromethane/methanol=19:1) |
Yield | Reaction Conditions | Operation in experiment |
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24% | a 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide. Yield: 24% of theory, Rf value: 0.56 (silica gel; dichloromethane/methanol=4:1) |
Yield | Reaction Conditions | Operation in experiment |
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11% | In trichlorophosphate; | a. 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-benzyloxy-benzimidazole Prepared analogously to Example 1a from 2-methylamino-5-benzyloxy-aniline and <strong>[42288-26-6]4-cyanophenylaminoacetic acid</strong> in phosphorus oxychloride. Yield: 11% of theory, Melting point: >350 C.; Rf -value: 0.60 (silica gel; ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
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100% | In tetrahydrofuran; acetic acid; | h. (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole Prepared analogously to Example 1c/1f from (R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone, 4-cyanophenylglycine, carbonyl diimidazole in tetrahydrofurane and subsequent cyclisation in glacial acetic acid. Yield: 100% of theory. |
Yield | Reaction Conditions | Operation in experiment |
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96% | With triethylamine; In N-methyl-acetamide; | f. 4-[1-(N-(3-ethoxycarbonylpropionyl)-N-cyclopentyl-amino)-cyclopropyl]-2-(4-cyanophenyl)-aminomethylcarbonylamino-N-methyl-aniline Prepared analogously to Example 1c 4-[1-(N-(3-ethoxycarbonyl-propionyl)-N-cyclopentyl-amino)cyclopropyl]-2-amino-N-methyl-aniline, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-cyano-phenylglycine and triethylamine in dimethylformamide. Yield: 96% of theory, Rf value: 0.54 (silica gel; methylene chloride/methanol=9.5:0.5) |
Yield | Reaction Conditions | Operation in experiment |
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88% | In water; at 100 - 110℃; for 3h; | 3.2.3 Preparation of [(4-cyanophenyl)amino]acetic acid (V) C7H6N2 C2H3DPtheta2 C9H8N2O2 MoI. Wt.: 1 18,14 MoI. Wt.: 138,95 MoI. Wt.: 176,17VIngredientsF: 90 g - 0.75 molG: 211.7 g - 1.5 molSodium bicarbonate: 35 g, 0.42 molThe starting substances F and G were mixed in 1250 ml of water and this suspension was inserted into a bath heated up to 100-110 0C. After three hours of heating the reaction container was removed from the bath, cooled in the fridge and the separated substance was sucked off. The substance was dried in a vacuum drier at the temperature of 100 C. Yield: Crude product: 122 g (92.8%), HPLC: 97%The crude product was purified by conversion to the sodium salt and re-acidification using an aqueous solution of sodium bicarbonate. The acid was released by means of diluted hydrochloric acid (1 :1). After sucking off and washing with water the product was dried in a vacuum drier (105 C). Yield: Purified product: 115 g (88%), HPLC: 99.1%, water content: 0.13%; sulphate ash: 1.8% |
In water; at 100℃; for 16h; | Example-3: Preparation of 2-(4-cyanophenylamino) acetic acid of Formula (D) 100 g 4-Aminobenzonitrile and 234.7 g bromoacetic acid in 1400 mL water were stirred for 15 min in round bottom flask. The reaction mixture was heated to 100C and maintained for 16 hours. The reaction mixture was cooled to 10C and stirred for 2 hours. The reaction mixture was filtered and washed with water to obtain 2-(4- cyanophenylamino) acetic acid of Formula (D). | |
In water; at 20 - 100℃; for 16.4h; | 100 g 4-Aminobenzonitrile and 234.7 g bromoacetic acid in 1400 mL water were stirred for 15 min in round bottom flask. The reaction mixture was heated to 100 C. and maintained for 16 hours. The reaction mixture was cooled to 10 C. and stirred for 2 hours. The reaction mixture was filtered and washed with water to obtain 2-(4-cyanophenylamino) acetic acid of Formula (D). |
In water; at 100℃; for 5h; | A mixture of aminobenzyl cyanide (0.1 mol) and bromoaceticacid (0.15 mol) was stirred at 100 C inwater for 5 h cooled to roomtemperature, solid separated.We obtained white solid (4-cyano-2-substituted-phenylamino)-acetic acid (6), yield 80-87%. |
Yield | Reaction Conditions | Operation in experiment |
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92% | Preparation of 3-([2-[(4-cyanophenyl amino)-methyl]-1-methyl-1H- benzimidazole-5-carbonyl]-pyridin-2-yl-amino)ethyl propionate oxalate (Vl) IngredientsIntermediate IV: 82.5 g - 0.24 mol Intermediate V: 46.4 g - 0.26 mol l,l'-carbonyldiimidazole (CDI): 42.2 g - 0.26 molProcedureSubstance V and l,l'-carbonyldiimidazole are put into a flask blown with an inert gas. 2000 ml of dry THF are added and the mixture is boiled under a reflux condenser with a calcium- chloride tube for 40 minutes. After 40 minutes a solution of substance IV in 330 ml of dry THF is added to the mixture and the mixture is boiled for another 5 hours. After expiration of this time period the reaction mixture is slightly cooled and THF is removed by distillation in vacuum. 1000 ml of glacial acetic acid are added to the honey-like brown residue and the resulting solution is boiled for 1 hour. The acid is distilled off and the produced residue is dissolved in dichloromethane (850 ml) and shaken with water. The separated organic layer is dried with sodium sulphate and the solvent is evaporated. A dark brown honey-like residue is obtained.Yield: 119 g (92% as the acetate); HPLC: 82% |
Yield | Reaction Conditions | Operation in experiment |
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73.2% | In water; for 6.5h;Reflux;Product distribution / selectivity; | e) 2-(4-Cyanophenylamino)acetic acid (compound III) 77.4 g (0.66 mol) of 4-aminobenzonitrile and 150 g (1.31 mol) of sodium chloroacetate were suspended in 1.1 L of water, and the resulting mixture was stirred at reflux temperature for 6.5 hours. After cooling to 0C, the resulting suspension was stirred at this temperature overnight. The solid was filtered and washed with 200 mL of water. The resulting solid was suspended in 200 mL of ethyl acetate and stirred at room temperature for 1 hour. The solid was filtered, washed with 400 mL of ethyl acetate and dried at 60C under vacuum for 5 hours to yield 84.5 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 73.2 %. Purity (HPLC, method 3): 98.4 %. |
73.2% | With water; at 0℃;Reflux;Product distribution / selectivity; | e) 2-(4-Cyanophenylamino)acetic acid (compound III) 77.4 g (0.66 mol) of 4-aminobenzonitrile and 150 g (1.31 mol) of sodium chloroacetate were suspended in 1.1 L of water, and the resulting mixture was stirred at reflux temperature for 6.5 hours. After cooling to 0C, the resulting suspension was stirred at this temperature overnight. The solid was filtered and washed with 200 mL of water. The resulting solid was suspended in 200 mL of ethyl acetate and stirred at room temperature for 1 hour. The solid was filtered, washed with 400 mL of ethyl acetate and dri e d at 60 C under v acuum for 5 hours to yield 84.5 g of 2-(4- cyanophenylamino)acetic acid as an off-white solid. Yield: 73.2 %. Purity (HPLC, method 3): 98.4 %. |
Example-19: Preparation of 2-(4-cyanophenyIamino)acetic acid compound of formula-13Sodium bicarbonate (21.35 g) was added to a mixture of 4-aminobenzonitrile compound of formula- 12 (100 g) and water (1000 ml) followed by sodium 2- chloroacetate (197.42 g). Potassium iodide (5 g) followed by tertiary butyl ammonium bromide (2.5 g) were added to the reaction mixture. The reaction mixture was heated to the 90-95C and stirred for 24 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 20-25C and pH was adjusted to 7.5 with ammonia. The reaction mixture was stirred for 20 minutes at 20-30C. Filtered the reaction mixture and ethylacetate was added to the filtrate. The reaction mixture was stirred for 15 minutes. Both the ethylacetate and aqueous layers were separated and the pH of aqueous layer was adjusted to 2.5 using hydrochloric acid. The reaction mixture was stirred for 3 hours at 20-30C to precipitate the solid. Filtered the precipitated solid, water followed by hydrochloric acid were added to the obtained solid and stirred for 4 hours at 25-30C. Filtered the solid, the obtained solid was slurried twice in water for 30-45 minutes and then dried to get the title compound. The same process can be repeated one more time to eliminates the impurities if present. Yield: 131 g |
131 g | With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide; In water; at 90 - 95℃; for 24h; | Sodium bicarbonate (21.35 g) was added to a mixture of 4-aminobenzonitrile compound of formula-12 (100 g) and water (1000 ml) followed by sodium 2-chloroacetate (197.42 g). Potassium iodide (5 g) followed by tertiary butyl ammonium bromide (2.5 g) were added to the reaction mixture. The reaction mixture was heated to the 90-95 C. and stirred for 24 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 20-25 C. and pH was adjusted to 7.5 with ammonia. The reaction mixture was stirred for 20 minutes at 20-30 C. Filtered the reaction mixture and ethylacetate was added to the filtrate. The reaction mixture was stirred for 15 minutes. Both the ethylacetate and aqueous layers were separated and the pH of aqueous layer was adjusted to 2.5 using hydrochloric acid. The reaction mixture was stirred for 3 hours at 20-30 C. to precipitate the solid. Filtered the precipitated solid, water followed by hydrochloric acid were added to the obtained solid and stirred for 4 hours at 25-30 C. Filtered the solid, the obtained solid was slurried twice in water for 30-45 minutes and then dried to get the title compound. The same process can be repeated one more time to eliminates the impurities if present. Yield: 131 g |
120 g | With tetrabutylammomium bromide; sodium hydrogencarbonate; potassium iodide; In water; at 85 - 90℃; for 24h; | Sodium mono chloroacetate (197.42 g), followed by potassium iodide (5 g) and tetrabutyl ammonium bromide (2.5 g) were added to a mixture of 4-aminobenzonitrile (100 g), water (1000 ml) and sodium bicarbonate (42.71 g). The reaction mixture was heated to 85-90 C. and stirred for 24 hours. The reaction mixture was cooled to 25-30 C. and treated with ammonia followed by hydrochloric acid. Filtered the solid, washed with water and then dried to get title compound. Yield: 120 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.3% | f) Ethyl 3-[(2-[(4-cyanophenyl)amino]methyl}-l-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate (salt of compound IV) 14.1 g (80 mmol) of <strong>[42288-26-6]2-(4-cyanophenylamino)acetic acid</strong> as obtained in step (e) and 14.2 g (88 mmol) of 1,1'-carbonyldiimidazole were suspended in 600 mL of tetrahydrofuran. The mixture was stirred at reflux temperature for 1 hour. Then, a solution of 25.0 g (73 mmol) of ethyl 3-[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate as obtained in step (d) in 100 mL of tetrahydrofuran was added dropwise over the reaction mixture. The resulting mixture was stirred at reflux temperature for 10 hours, and the solvent was removed by distillation under vacuum. The resulting residue was dissolved in 300 mL of acetic acid and heated to reflux temperature for 1 hour. After cooling to room temperature, solvent was removed by distillation under vacuum. The resulting residue was dissolved in 400 mL of dichloromethane, and the solution was washed with 2 x 400 mL of water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was dissolved in 350 mL of ethyl acetate at 40C. At this temperature, 12.6 g (0.14 mol) of oxalic acid were added, and the resulting mixture was stirred for 30 minutes at 40C. After cooling to room temperature, the precipitated solid was isolated by filtration. The solid was stirred with 800 mL of ethanol at reflux temperature for 1 hour. After cooling to room temperature, the solid was isolated by filtration, washed with 50 mL of ethanol and dried at 60C under vacuum, to yield 29.8 g of ethyl 3-[(2-[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate as an off-white solid. Yield: 71.3 %. Purity (HPLC, method 1): 97.5 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.3% | f ) E t h y l 3-([(2-[(4-cyanophenyl)aminolmethyl|-l-methyl-lH-benzimidazol-5- yl)carbonyll(pyridin-2-yl)amino|propanoate oxalate (salt of compound IV) 14.1 g (80 mmol) of <strong>[42288-26-6]2-(4-cyanophenylamino)acetic acid</strong> as obtained in step (e) and 14.2 g (88 mmol) of 1,1 '-carbonyldiimidazole were suspended in 600 mL of tetrahydrofuran. The mixture was stirred at reflux temperature for 1 hour. Then, a solution of 25.0 g (73 m m o l ) o f e t h y l 3-[{2-amino-l-(methylamino)phen-4-yl}carbonyl](pyridyn-2- yl)amino}propanoate as obtained in step (d) in 100 mL of tetrahydrofuran was added dropwise over the reaction mixture. The resulting mixture was stirred at reflux temperature for 10 hours, and the solvent was removed by distillation under vacuum. The resulting residue was dissolved in 300 mL of acetic acid and heated to reflux temperature for 1 hour. After cooling to room temperature, solvent was removed by distillation under vacuum. The resulting residue was dissolved in 400 mL of dichloromethane, and the solution was washed with 2 x 400 mL of water. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was dissolved in 350 mL of ethyl acetate at 40C. At this temperature, 12.6 g (0.14 mol) of oxalic acid were added, and the resulting mixture was stirred for 30 minutes at 40C. After cooling to room temperature, the precipitated solid was isolated by filtration. The solid was stirred with 800 mL of ethanol at reflux temperature for 1 hour. After cooling to room temperature, the solid was isolated by filtration, washed with 50 mL of ethanol and dried at 60C under vacuum, to yield 29.8 g o f e t h y l 3-[(2-[(4-cyanophenyl)amino]methyl}-l-methyl-lH-benzimidazol-5- yl)carbonyl](pyridin-2-yl)amino}propanoate oxalate as an off-white solid. Yield: 71.3 %. Purity (HPLC, method 1): 97.5 %. |
Yield | Reaction Conditions | Operation in experiment |
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0 035 mol of N-<strong>[42288-26-6](4-cyanophenyl)glycine</strong> 5 and 5.68 g (0.035 mol) of N,N'carbonyldiimidazole were refluxed in 300 mL of tetrahydrofuran for 30 rninutes, then0.032 mol of compound 4 'Nere added, and the mixture was retluxed for a further five hours Then the solvent waS distilled in vacuo, the residue was dissolved in 150 rnL of glacial acetic acid and retluxed for one hour. Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in about 300 mL of dichlorornethane,, the solution·Vas washed tvice with about 150 mL water and then dried over sodium sulfate. Atlerevaporation of the solvent,. the crude product thus obtained was purified by columnchromatography (800 g silica gel; eluent: dichloromethane wid1 1-2% ethanol) to obtaincompound 6. |
Yield | Reaction Conditions | Operation in experiment |
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8.35 g | Nu,Nu-Carbonyl diimidazole (5.82 g) and 2-[(4-Cyanophenyl)amino]acetic acid (compound of Formula VII) (6.28 g) were added to tetrahydrofuran (120 mL) at 20C to 25C. Ethyl N- { [3-amino-4-(methylamino)cyclohexa- 1 ,5-dien- 1 -yljcarbonyl} -N-pyridin- 2-yl- -alaninate (compound of Formula VI) (10 g) was added to the reaction mixture and the temperature of the reaction mixture was increased to 50C to 55C. Butylated hydroxyl toluene (1 g) was added to the reaction mixture and tetrahydrofuran was recovered under vacuum at 55C. Acetic acid (40 mL) was added to the reaction mixture and stirred at 90C to 95C until the reaction was complete. Acetic acid was completely recovered under vacuum at 65C to 70C. The reaction mixture was cooled to 20C to 25C. De-ionized water (50 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with 5% aqueous sodium bicarbonate solution (70 mL). Ethyl acetate was recovered under vacuum at 55C to 60C. 2-Propanol (60 mL) was added to the reaction mixture and stirred at 55C to 60C. The reaction mixture was cooled to 20C to 25C and stirred for 16 hours at 20C to 25C. The reaction mixture was filtered and washed with 2-propanol (10 mL). The wet material was dried under vacuum to obtain the title compound. Yield: 8.35 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1,1'-carbonyldiimidazole; In tetrahydrofuran; | 1c 3-({3-[2-(4-Cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-phenyl-amino)-propionic acid methyl ester The product of 1b (23.2 mmol) and N-(4-cyano-phenyl)-glycine (23.2 mmol) were coupled with CDI (23.2 mmol) in dry THF at room temperature. After completion of the reaction the mixture was evaporated to dryness and the crude product was used without further purification. Yield: 97% C27H27N5O4 (485.54) Mass spectrum (ESI): [M+H]+=486 |
Yield | Reaction Conditions | Operation in experiment |
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89.59% | 66 gm (0.379mo1) of <strong>[42288-26-6]2-(4-cyanophenylamino) acetic acid</strong> was suspended in 500m1 tetrahydrofuran and suspension was cooled to 0-5C. To the cooled suspension to 45.7 gm (0.379 mol) pivaloyl chloride was added and stirred at 0-5C for 10-15 mm. To the obtained clear solution was added 49 gm (0.379 mol) diisopropyl ethyl amine and stirred for 10 mm.To the reaction mixture was added 100 gm (0.292 mol) ethyl3-[{2-amino-1.- (methylamino)phen-4-yl } carbonyl] (pyridyn-2-yl)amino}propanoate and stirred for 5 mm at 0-5C. To the reaction mixture was charged 200 ml acetic acid and stirred for 10-15 mm at 0-15C. Reaction mixture was then heated to 80-85C and maintained the temperature for 2-4 hr. Completion of reaction was monitored by TLC. Upon completion of react.ion, reaction mass was concentrated under vacuum at below 70C to obtain residue. Obtained residue was cooled to 25-30C. To the obtained residue was charged purified 500 ml water and 500 ml dichloromethane, pH of the reaction mass was adjusted to 8-9 using aq.ammonia. Reaction mixture was stirred for 30 mm. and layers were separated. Aqueous layer was again extracted with 500 ml dichloromethane. Combined organic layer was washed with water 500 ml Dichloromethane layer was then distilled out under vacuum at below 45C to obtain. residue. Obtained residue was cooled to 25-30C and was charged with 500 ml acetone and stirred to dissolve. The obtained solution was heated to 50-55C and was charged with para toluene sulphonic acid solution prepared by using 55 gm paratoluenesuiphonic acid and 100 ml ethanol, reaction mixture was stirred for 20-30 mm. at 50-55C and then cooled to 0-5C. Precipitated solid was stirred at 0-5C for around 60 mm. and filtered. Obtained wet cake was dried under vacuum at 50-55C to obtain p-toluene sulfonate salt of ethyl3-[(2-[(4-cyanophenyl)amino]methyl}-i- methyl-i h-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino } propanoate.Yield: 172 g (89.59 %); Purity by HPLC: 97.1%. | |
15.8 g | A mixture of N-(4-cyanophenyl) glycine (5.6 g), CDI (6.1 g) and imidazole*HC1 (4.6g) in anhydrous dichioromethane (40 mL), was stirred for 1h at 3 5-40C, under inert atmosphere. phenylene-1, 2-diamine of formula 2 (lOg), dissolved in anhydrous dichloromethane (20 mL), was charged to the reaction mass. After stirring for another lh at reflux the resulted reaction mass was concentrated under reduced pressure. n-BuOAc(50 mL) and para-toluene sulphonic acid monohydrate (19.5 g) were added and the temperature of the reaction mass wasraised to 85-90C.After maintaining for lh at the same temperature. The reaction mixture concentrated under reduced pressure to half of the original volume. The precipitated material was slurred at 40-45C for 30 mm, filteredand washed with water. The wet material was slurred in water (100 mE) for 30mm at room temp. The precipitate was filtered, washed, successively with water and EtOAc.The material dried under vacuum at 50C, to afford p-TSA salt of compound of formula 3 as off-white solid material (1 5.8g, 98.1% HPLC pure). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To the solution 4-cyano phenyl glycine (15.4 g; mol) in absolute THF (25 mL). The CDI (16.1 g was in four lots over a period of 40-45 min and stirred at room temperature. Slowly charge (20 g) maintain the reaction mixture for 20-24 h at 30-35 C, charge acetic acid (120 mL) to reaction mixture and heated to 60-65 C and maintained 6-7 h. Cool the reaction mixture 20-30 C and add water (120 mL) separate the organic layer distill off total solvent under vacuum and dried with sodium sulphate. Add acetone (20 mL) and methane sulphonic acid (4.2 g) heated to 50-55 C for 45- 60 min. Cooled at 2-8 C filter the solid and wash the solid with acetone (120 mL) and cyclohexane (40 mL) dry at 55-60 C the solid is 22-23 g molar yield is 85 %. 1 H NMR (500 MHz, in DMSO) delta: 8.39 (dd, 1H), 7.55 (dt, 1H), 7.47 (dd, 3H), 7.41 (d, 1H), 7.25 (t, 1H for NH), 7.17 (dd, 1H), 7.12 (dd, 1H), 6.82 (d, 2H), 6.90 (d, 1H), 4.60 (d, 2H), 4.23 (t, 2H), 3.98 (q, 2H), 3.76 (s, 3H), 2.69 (t, 2H), 1.13 (t, 3H). 13C NMR (500 MHz, in DMSO) delta: 170.9 (ethyl ester), 170.2 (amide), 109.4 (cyano), 155.9, 153.2, 151.7, 148.6, 140.8, 137.8, 137.2, 133.2, 129.3, 122.7, 122.04, 121.2, 120.3, 119.4, 112.3, 96.7, 59.9, 44.3, 39.5, 33.04, 29.8, 13.9. IR (neat, lambdamax, cm-1): 3271.27, 2940.47, 2215.24, 1731.11, 1639.49, 1604.77, 1581.62, 1529.55, 1435.03, 1389.31, 1328.95, 1273.01, 1243.32, 1179.35, 827.46, 777.31, 746.45. MS: m/z = 483.2 [M + H] +, m.w.: 482. | |
220 g | A mixture of <strong>[42288-26-6]2-(4-cyanophenylamino)acetic acid</strong> compound of formula-9 (154.32 g) and toluene (800 ml) was heated to reflux temperature and water was collected by azeotropic distillation. Toluene was distilled off completely from the reaction mixture. The reaction mixture was cooled to 25-35 C.; tetrahydrofuran (600 ml) was added to the reaction mixture and stirred for 20 minutes. A solution of N, N-carbonyldiimidazole (161.04 g) and tetrahydrofuran (1000 ml) was added slowly to the above reaction mixture under nitrogen atmosphere and stirred for 3 hours at 25-35 C. to form an amide compound. Yield: 220 g; MR: 188-190 C.; purity by HPLC: 98%; 1H NMR (DMSO-d6, TMS as internal standard) delta: 1.09-1.13 (3H, t), 2.32 (3H, s), 2.67-2.72 (2H, t), 3.92 (3H, brs), 3.95-4.00 (2H, q), 4.19-4.24 (2H, t), 4.49 (1H, brs), 4.91 (2H, brs), 6.83-6.86 (2H, d), 7.05-7.08 (1H, d), 7.14-7.18 (1H, q), 7.38-7.41 (1H, d), 7.53-7.64 (4H, m), 7.78-7.80 (1H, d), 8.36-8.37 (1H, brd). [0263] PXRD, IR spectrum and DSC thermogram of the obtained compound of formula-10 is illustrated in figure-1, figure-2 and figure-3 respectively |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.035 mol of N-<strong>[42288-26-6](4-cyanophenyl)glycine</strong> 5 and 5.68 g (0.035 mol) of N,N'-carbonyldiimidazole were refluxed in 300 mL of tetrahydrofuran for 30 minutes, then 0.032 mol of compound 4 were added, and the mixture was refluxed for a further five hours. Then the solvent was distilled in vacuo, the residue was dissolved in 150 mL of glacial acetic acid and refluxed for one hour. Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in about 300 mL of dichloromethane, the solution was washed twice with about 150 mL water and then dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g silica gel; eluent: dichloromethane with 1-2% ethanol) to obtain compound 6. |
A1267759[ 1919877-35-2 ]
N-(4-Cyanophenyl)-glycine-13C6
Reason: Stable Isotope
[ 21911-75-1 ]
2-(Methyl(phenyl)amino)acetic acid hydrochloride
Similarity: 0.69
[ 139393-02-5 ]
(S)-2-Amino-3-(5-cyano-1H-indol-3-yl)propanoic acid
Similarity: 0.68
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