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CAS No. : | 18342-66-0 | MDL No. : | MFCD00800292 |
Formula : | C6H8N2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XMNGSPOWUCNRMO-UHFFFAOYSA-N |
M.W : | 172.14 | Pubchem ID : | 4381935 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 40.53 |
TPSA : | 75.71 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.02 cm/s |
Log Po/w (iLOGP) : | 1.08 |
Log Po/w (XLOGP3) : | -0.94 |
Log Po/w (WLOGP) : | -0.97 |
Log Po/w (MLOGP) : | -0.67 |
Log Po/w (SILICOS-IT) : | -0.84 |
Consensus Log Po/w : | -0.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.12 |
Solubility : | 131.0 mg/ml ; 0.764 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.17 |
Solubility : | 118.0 mg/ml ; 0.683 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.23 |
Solubility : | 102.0 mg/ml ; 0.593 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.21 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-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 |
---|---|---|
86% | With triethylamine In ethyl acetate at 0 - 20℃; for 24 h; | A dried round-bottom flask was charged with N-hydroxysuccinimide (5.83 g, 50.7 mmol), ethyl acetate (20 mL) as a solvent and cooled at 0 °C. To the mixture were slowly added triethylamine (4.76 g) and methylisocyanate (6.39 g, 0.112 mmol) at the same temperature. The reaction temperature was slowly raised to rt, and the mixture was stirred for 24 h at rt. After the volatile materials were removed under reduced pressure the crude residue was re-crystallized from ethyl acetate/diethyl ether to give 51a (86 percent). Colorless needles, mp 148.0–149.0 °C (lit [19]. 148.0–152.0°C); 1H NMR (300 MHz, CDCl3): δ 8.15 (1H, br, NH), 2.76 (4H, s, CH2CH2), 2.67 (3H, s-like, CH3); 13C NMR (22.5 MHz, CDCl3): δ 170.66, 151.98, 27.98, 25.47; MS (FAB+) m/z 173 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In ethyl acetate; at 0 - 20℃; for 24h; | A dried round-bottom flask was charged with N-hydroxysuccinimide (5.83 g, 50.7 mmol), ethyl acetate (20 mL) as a solvent and cooled at 0 C. To the mixture were slowly added triethylamine (4.76 g) and methylisocyanate (6.39 g, 0.112 mmol) at the same temperature. The reaction temperature was slowly raised to rt, and the mixture was stirred for 24 h at rt. After the volatile materials were removed under reduced pressure the crude residue was re-crystallized from ethyl acetate/diethyl ether to give 51a (86 %). Colorless needles, mp 148.0-149.0 C (lit [19]. 148.0-152.0C); 1H NMR (300 MHz, CDCl3): delta 8.15 (1H, br, NH), 2.76 (4H, s, CH2CH2), 2.67 (3H, s-like, CH3); 13C NMR (22.5 MHz, CDCl3): delta 170.66, 151.98, 27.98, 25.47; MS (FAB+) m/z 173 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium acetate; dinitrogen tetraoxide; In dichloromethane; at -40 - 20℃; for 2h; | A dried round-bottom flask was charged with sodium acetate (409 mg, 4.99 mmol), 51a (2.0 g, 8.0 mmol), and dichloromethane (25 mL) as a solvent, and a suspension of the mixture was stirred at-40 C. To the mixture, N2O4 (5.08 g, 55.2 mmol) in dichloromethane (10 mL) was added drop-by-drop with stirring. The mixture was stirred at-40 C for 1 h, and then the temperature was slowly raised to the room temperature followed by an additional 1 h stirring. The reaction mixture was poured into iced water, and an aqueous layer was extracted with dichloromethane. The combined organic layer was successively washed with 10 % NaHCO3 and a brine, and dried over Na2SO4 over-night in a refrigerator. To the concentrated filtrate (5 mL) was added petroleum ether to precipitate a crude product, which was recrystallized from chloroform/ether to give 51b (73 %). light yellow needles, mp not determined (lit [31]. 148-152C); 1H NMR (300 MHz, CDCl3): delta 3.22 (4H, s, CH2CH2), 2.95 (3H, s, CH3); 13C NMR (22.5 MHz, CDCl3): delta 168.53, 151.09, 28.44, 25.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h; | a) Benzyl 3-{7-bromo-3-methyl-1-[2-(3-methylureido)ethyl]-1H-indol-6-ylmethoxy}-4-{4-[3-(2- methoxvbenzvioxy propoxy] phenvl} piperidine-1-carboxvlate The solution of 0.270 g of benzyl 3- [1- (2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4- 4- [3- (2-methoxybenzyloxy) propoxy] phenyl} piperidine-1-carboxylate (Example 76b) in 1.5 mi of N, N- dimethylformamide is cooled to 0C and admixed successively with 0.066 g of N-succinimidyl N- methyl carbamate and 0.043 ml of triethylamine. The reaction mixture is stirred at room temperature over 2 hours, subsequently poured onto water (40 mi) and extracted with dichloromethane (2 x 40 ml). The organic phases are washed successively with water (40 ml), 1 M sodium hydrogencarbonate solution (40 mi) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.10 (2: 1 EtOAc-heptane); Rt = 5.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 72h; | To a solution of commercially available (4-amino-benzyl)-carbamic acid tert- butyl ester (229 mg) in dry dichloromethane (1 mL) were successively added ethyl diisopropyl amine (349 muL) and N-succinimidyl N-methylcarbamate (355 mg). The resulting reaction mixture was stirred at room temperature for 72 h, then diluted with ethyl acetate (20 mL) and washed with 0.1 M aqueous sodium hydroxide (3×10 mL). The combined organic layer were dried (MgSO4), filtered and concentrated to afford the title compound (269 mg; 96%). [MH]+=280, [MNa]+=302. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 72h; | To a solution of commercially available (3-amino-benzyl)-carbamic acid tert- butyl ester (222 mg) in dry dichloromethane (1 mL) were successively added ethyl diisopropyl amine (349 muL) and N-succinimidyl N-methylcarbamate (355 mg). The resulting reaction mixture was stirred at room temperature for 72 h, then diluted with ethyl acetate (20 mL) and washed with 0.1 M aqueous sodium hydroxide (3×10 mL). The combined organic layer were dried (MgSO4), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (223 mg; 80%). [MH]+=280, [MNa]+=302. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | In water; acetonitrile; at 150℃; for 0.0833333h;Irradiation; | Examples Final compounds .3aSR,10RS)-10-(3-Hydroxy-phenyl)-2,3a-dimethyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenty[b]fluorene-1,3-dioneTo a suspension of 250 mg (740 |jmol) RS,3SR)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1 H-p-carboline-3-carboxylic acid methyl ester (compound A1) in 4 ml acteonitrile and 1 ml water are added 511 mg (3 mmol) N-succinimidyl-N-methylcarbamate. The mixture is heated to 150 C for 5 min using a microwave reactor. The solvents are removed under reduced pressure. The residue is dissolved in ethyl acetate and the organic layer is washed with water. The solution is dried with magnesium sulfate and the solvent is removed under reduced pressure. After column chromatography (toluene, ethyl acetate 4:1), 68 mg (25 %) of the title compound are obtained as a white solid (m.p.: 299-305 C; m/z (MH+) = 362.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 150℃; for 0.0833333h;Irradiation; | A3. (3aR,10R)-10-(3-Hydroxy-phenyl)-2-methyl-4,10-dihydro-3aH-9-thia-2,10-diaza-cyclopenta[b]fluorene-1,3-dione405 mg (2.35 mmol) of N-succinimidyl-N-methyl carbamate are added to a solution of 200 mg (590 |jmol) of (1 R,3R)-1-(3-hydroxy-phenyl)-1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridine-3-carboxylic acid methyl ester (compound A4) in 4 ml of acetone. The mixture is heated to 150C for 5 min. using a microwave reactor. The solvent is removed under reduced pressure. The crude product obtained can be used as starting material to obtain compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; at 150℃; for 0.5h;Microwave irradiation; | 1. (SaSR.IORSJ-e-Ethoxy-IO-CS-hydroxy-phenyO^.Sa-dimethyl-Salambdatheta.IO-tetrahydro^.theta.iOa- triaza-cyclopenta[b]fluorene-1,3-dione; A solution of 125 mg (1 RS,3SR)-6-ethoxy-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1 H-beta- carboline-3-carboxylic acid methyl ester and 226 mg N-succinimidyl-N-methylcarbamate in a mixture of 5 ml acetonitrile and 1 ml water is heated to 150 0C for 30 min using a microwave reactor. Water and ethylacetate are added to the solution. The aqueous phase is extracted with ethylacetate and the combined organic layers are dried with magnesium sulfate. The solvents are removed under reduced pressure. After purification by column chromatography (toluene/ethylactate 4:1 ) 15 mg of the title compound are obtained as a colorless foam (MS: m/z (MH+) = 406.1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; at 150℃; for 0.5 - 0.666667h;microwave irradiation; | 2. (3aSR,10RS)-6-Methoxy-2,3a-dimethyl-10-phenyl-3a, 4,9,10-tetrahydro-2, 9,10a-triaza- cyclopenta[b]fluorene-1,3-dione; A solution of (I RS.SSRJ-e-methoxy-S-methyl-i-phenyl^.S^.theta-tetrahydro-I H-beta-carboline-S-carboxylic acid methyl ester and N-succinimidyl-N-methylcarbamate in a mixture of acetonitrile and water (5:1 ) is heated to 150 0C for 30 min using a microwave reactor.Water and ethylacetate are added to the solution. The aqueous phase is extracted with ethylacetate and the combined organic layers are dried with magnesium sulfate. The solvents are removed under reduced pressure. After purification by column chromatography the title compound will be obtained. In more detail, the title compound can be obtained as follows: To a suspension of 200 mg (1 RS, 3SR)- 6-Methoxy-3-methyl-1-phenyl-2,3,4,9-tetrahydro-1 H-beta-carboline-3-carboxylic acid methyl ester in a mixture of 4 ml acetonitrile and 1 ml water are added 395 mg N-succinimidyl N-methyl carbamate. The mixture is heated in a sealed tube for 40 min to 150 0C using a microwave reactor. After cooling to room temperature water and brine is added and the mixture is extracted with ethyl acetate. The combined organic layers are dried with magnesium sulfate and the solvent is removed under reduced <n="90"/>pressure. After purification of the residue by column chromatography (silica gel, toluene/ethyl acetate) and triturating with diisopropyl ether, 65 mg of the title compound are obtained. MS: m/z (MH+) = 376.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 96h;Heating / reflux; | A mixture of (S)-3-(3-benzyloxy-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino- propionic acid methyl ester (1.15g, 2.87mmol) and N-succinimidyl N- methylcarbamate (1.975g, 11.47mmol) in acetonitrile (15mL) was refluxed 4 days. After the removal of solvent, the residue was purified with chromatography using EtOAc/hexane(1 :1.5) as an eluent to obtain (S)-3-(3-benzyloxy-4- methylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester as a white solid, 0.83g. 1H NMR (400MHz, CDCI3) 1.43 (s, 9H), 2.86 (d, 3H), 3.03 (m, 2H), 3.66 (s, 3H), 4.56 (m, 1 H), 4.98 (m, 2H), 5.05 (s, 2H), 6.70-6.90 (m, 2H), 7.03 (m, 1H), 7.29-7.43 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 96h;Heating / reflux; | N-Succinimidyl N-methylcarbamate (1.89g, 11 mmol) was added to a solution of (S)- 3-(4-Benzyloxy-3-hydiOxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.1g, 2.74 mmol) in acetonitrile (15ml). The mixture was refluxed 4 days. After removal of the solvent, the residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (2:3). (S)-3-(4-Benzyloxy-3-methylcarbamoyloxy-phenyl)-2- tert-butoxycarbonylamino-propionic acid methyl ester was obtained as a white solid, 0.83g. 1 H NMR (400MHz, CDCI3) 1.42 (s, 9H), 2.86 (d, J = 4.9Hz, 3H), 3.01 (m, 2H), 3.70 (s, 3H), 4.53 (m, 1 H), 5.00 (m, 2H), 5.07 (s, 2H), 6.89 (m, 3H), 7.29-7.42 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of the crude mixture of (1 RS,3RS)-6-fluoro-1-(3-hydroxy-phenyl)-2,3,4,9-tetrahydro- 1 H-beta-carboline-3-carboxylic acid methyl ester and (1 RS,3SR)-6-fluoro-1-(3-hydroxy-phenyl)- 2,3,4,9-tetrahydro-1 H-beta-carboline-3-carboxylic acid methyl ester in 10 ml acetone are added 1.34 g (7.80 mmol) N-succinimidyl-N-methylcarbamate. The mixture is heated to 150 0C for 20 min using a microwave reactor. The solvent is removed at reduced pressure and the residue is dissolved in 20 ml acetonitrile. 2.7 g potassium carbonate are added and the suspension is heated to reflux for 210 min. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. The solution is washed with water and brine. The organic layer is dried with magnesium sulfate and the solvent is removed at reduced pressure. The crude product is suspended in a mixture of methanol and dichloromethane and heated to reflux. After cooling to room temperature the desired product is filtered from the suspension and dried. 460 mg of the title compound are obtained as a colourless solid. m.p.: 328-331 0CMF: C20 H16 F N3 03 (365.37) MS: m/z (M-H+) = 364,1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | To a solution of the mixture of (1 RS,3RS)-6-methoxy-1-(3-hydroxy-phenyl)-2,3,4,9-tetrahydro-1 H- beta-carboline-3-carboxylic acid methyl ester and (1 RS,3SR)-6-methoxy-1-(3-hydroxy-phenyl)- 2,3,4,9-tetrahydro-1 H-beta-carboline-3-carboxylic acid methyl ester in 10 ml acetone are added 156 mg (900 mumol, 4.00 eq) N-succinimidyl-N-methylcarbamate. The mixture is heated to 150 0C for 10 min using a microwave reactor. The solvent is removed at reduced pressure and the residue is dissolved in 5 ml acetonitrile. 313 mg potassium carbonate are added and the suspension is heated to reflux for 150 min. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. The solution is washed with water and brine. The organic layer is dried with magnesium sulfate and the solvent is removed at reduced pressure. After column chromatography (silica gel, toluene/ethyl acetate 4:1 ) 42 mg (48 %) of the desired product are obtained as a pale solid, m.p.: 172-175 0C; MF: C21 H19 N3 04 (377.40) MS: m/z (MH+) = 378.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 25℃; for 17h; | EXAMPLE 1 Synthesis of Carbamoyl AICA 200 g of base AICA as is (K. F. 11 %) corresponding to 178 g of 100% base AICA and 1000 ml of acetonitrile are charged in a 2-liter reactor. The mixture is stirred at room temperature (about 20 C.) and 267 g of N-Succinimidyl-N'-methyl carbamate and 191.7 g of diisopropylethylamine (DIPEA) are added to the suspension. The temperature of the mixture is kept at 25+2 C. for 16 hours, then the mixture is cooled at 0÷5 C., held for an hour and the suspension is filtered on a Buchner, by washing with 2*200 ml of deionised water. 313.0 g of wet product are discharged, which is then dried on a rotavapor for 5 hours at 50 C. with vacuum line. 212 g of Carbamoyl AICA (96.9% HPLC purity) are obtained, with 0.13% K. F. 88% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 3h; | A mixture of N2-(2-amino-ethyl)-6-methoxy-N4-(4-methoxy-phenyl)-N4-methyl-quinazoline-2,4-diamine (0.13 g, 0.36 mmol) and N-succinimidyl-N-methylcarbamate (82 mg, 0.47 mmol) in DCM (5 mL) was stirred at ambient temperature for 3 hours. The precipitate was filtered off. The filtrate was concentrated and the crude extract was purified by preparative RPLC. 1H NMR (DMSO-d6) delta 7.45-6.02 (m, 8H), 3.81 (s, 3H), 3.63 (s, 3H), 3.55 (m, 2H), 3.27 (m, 2H), 3.26 (s, 3H); LC-MS (ESI+; 411 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 70℃; for 9h; | (Example 1 Synthesis of Compound I-1) [Show Image] A solution of the compound (1, 7.11 g, 42.2 mmol) obtained in Reference Example 1 and a compound (2, 21.78 g, 126 mmol) in pyridine (200 mL) was stirred at 70 degrees Celsius for 9 hours. The reaction solution was then concentrated in vacuo. The resulting crystals were filtrated, washed with water, and then dried. The filtrate was then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried with anhydrous magnesium sulfate. The solvent was then concentrated in vacuo. The residue was mixed with the previous crystals, washed with methanol, and then dried to yield a compound (I-1, 7.51 g, 33.3 mmol). LC-MS: 1.07 min, [M+H] = 226 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 2.5h;Inert atmosphere; | Step 1 Compound 21 was synthesized using a method described in Heterocycles, 63(7), 1555 (2004). To a solution of Compound 21 (97.0 mg, 0.380 mmol) in dimethylformamide (1.0 mL), diisopropylethylamine (199 muL, 1.140 mmol) and 2,5-dioxopyrrolidin-1-ylmethylcarbamate C (131.0mg, 0.706 mmol) were added. The reaction solution was then stirred under nitrogen atmosphere at 80C for 2 hours and a half. Aqueous saturated sodium bicarbonate solution was added to the reaction solution, and then extracted with ethyl acetate. The extract was washed sequentially with water (two times) and saturated brine, and then dried with anhydrous magnesium sulfate. After concentrating in vacuo, purification by aminosilica gel column chromatography (chloroform:methanol = 100:0 ? 95:5) yielded Compound I-66 (110.2 mg, 93%). LC/MS (Method D): 1.36 min, [M+H]+ = 313 1H-NMR (DMSO-d6) delta: 10.34 (1H, s), 6.41 (1H, br s), 4.42 (2H, s), 3.61 (2H, t, J = 5.3 Hz), 2.67 (3H, d, J = 4.5 Hz), 2.56 (2H, t, J = 5.3 Hz), 1.42 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 15h;Inert atmosphere; | Step 9 To a solution of Compound I-55 (278.2 mg, 1.168 mmol) in acetonitrile (4.0 mL), diisopropylethylamine (306 muL, 1.751 mmol) and <strong>[18342-66-0]2,5-dioxopyrrolidin-1-yl methylcarbamate</strong> C (241.0 g, 1.401 mmol) was added. The solution was then stirred under nitrogen atmosphere at 60 C for 5 hours. To the reaction solution, diisopropylethylamine (204 muL, 1.168 mmol) and 2,5-dioxopyrrolidin-1-ylmethylcarbamate C (161.0 g, 0.934 mmol) were added. The solution was then stirred under nitrogen atmosphere at 60C for 5 hours. To the reaction solution, diisopropylethylamine (102 muL, 0.584 mmol) and 2,5-dioxopyrrolidin-1-ylmethylcarbamate C (100.0 g, 0.584 mmol) were added. The solution was then stirred under nitrogen atmosphere at 60C for 5 hours. Aqueous saturated sodium bicarbonate solution was added to the reaction solution, and then extracted with ethyl acetate. The extract was washed sequentially with water and saturated brine, and then dried with anhydrous magnesium sulfate. After concentrating in vacuo, purification by aminosilica gel column chromatography (chloroform) yielded Compound I-60 (331.8 mg, 96%) . LC/MS (Method D): 1.20 min, [M+H]+ = 296 1H-NMR (CDCl3) delta: 7.56 (1H, br s), 7.23 (1H, br s), 5.60 (1H, s), 4.57 (2H, s), 4.02 (2H, t, J = 5.2 Hz), 3.87 (2H, t, J = 5.2 Hz), 2.91 (3H, d, J = 4.3 Hz), 1.49 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 14: Preparation of (2S)-2-[(methylcarbamoyl)amino]hexyl bis(2- thienylmethyl)carbamate (2-23).[0150] To a suspension of 2-4 (39 mg, 0.11 mol) in 1 ,2-dichloroethane (0.25 mL), a solution of N-succinimidyl-N-methylcarbamate (NSMC, 29 mg, 0.17 mmol) in 1 ,2-dichloroethane (0.5 mL) was added. The reaction was stirred at room temperature for 1 day and N,N-dimethylformamide (0.50 mL) was added to improve the solubility. The mixture was stirred 2 days and additional NSMC (38 mg, 0.22 mmol) was added. The mixture was stirred for 2 additional days and NSMC (98 mg, 0.57 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol) were added. The reaction was stirred for 3 hours, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate :hexanes (1 : 1). The organic layer was washed sequentially with saturated aqueous sodium bicarbonate, hydrochloric acid (0.1 N), water (3 times), and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with methanol (1 to 1.5%) in ethyl acetate:hexanes (3:2) to give the title compound 2-23 as a colorless solid (22 mg). [0151] This procedure was also used to prepare (2S)-2-[(methylcarbamoyl)amino] thienylmethyl)hexanamide (3-40) from 3-13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Step 1 : 2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine-8- carboxylic acid methylamideA solution of 2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (0.50 g, 1.55 mmol) and N,N,N',N- tetramethylethylenediamine (0.35 mL, 2.33 mmol) in dry THF (14 mL) was cooled to -78C. Butyllithium (2.5M in hexanes, 1.22 mL, 3.05 mmol) was added dropwise and the dark yellow solution was stirred at -78 C for 45 min. N-Succinimidyl N- methylcarbamate (0.4 g, 2.33 mmol) was added as a suspension in a small volume of THF and the mixture was allowed to warm to room temperature while stirring for 18 h. The reaction mixture was diluted with water, neutralized with 1M hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (Si02, gradient 0-100% ethyl acetate in cyclohexane) to give 2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H- purine-8-carboxylic acid methylamide (104 mg, 18%). LCMS RT= 3.26, [M+H] = 381/383 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium hydride; In methanol; dimethyl sulfoxide; mineral oil; | Example 46 1-(5-Methoxy-2-pyridin-2-yl-pyrimidin-4-yl)-3-methyl-urea Sodium hydride (60% in mineral oil, 12 mg, 0.29 mmol) was added at 0 C. to a solution of 5-methoxy-2-pyridin-2-yl-pyrimidin-4-ylamine (50 mg, 0.24 mmol) in DMSO (1 ml) and the mixture was stirred for 0.25 h. N-succinimidyl-N-methyl carbamate (51 mg, 0.29 mmol) was added dropwise and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ice-water (10 ml) and the aqueous phase was extracted with EtOAc (*2). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/0.1% NH3 in MeOH (97:3) as the eluent to give the title compound (21 mg, 32%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.4% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | To a solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.15 g, 0.323 mmol, Preparation No.K.1) and DIEA (0.0835 g, 0.647 mmol, Sd Fine Chem) in DCM (15 mL) was added N-succinimidyl N-methylcarbamate (0.11 g, 0.647 mmol, Aldrich). The reaction mixture was stirred for about 24 h at RT. The reaction mixture was diluted with water (15 mL) and the product extracted with DCM (3×20 mL). The combined organic layers were washed successively with 0.1M aqueous NaOH (3×15 mL) and brine (1×50 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The crude material obtained was triturated with diethyl ether to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(S-(1-(methylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 0.06 mg (38.4%) as a pale yellow solid. LC/MS (Table 1, Method e) Rt=3.13 min; MS m/z: 485.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 20℃; | General procedure: To a solution of amine hydrochloride salt (1 equiv) and DIEA (2-4 equiv, preferably 2 equiv) in an organic solvent (such as DCM, THF, or 1,4-dioxane, preferably DCM) is added N-succinimidyl N-methylcarbamate (2 to 4 equiv, preferably 2 equiv). The reaction mixture is stirred for about 24-48 h (preferably about 24 h) at RT. The reaction mixture is diluted with water and the product extracted with DCM. The combined organic layers are washed successively with 0.1M aqueous NaOH and brine. The organic layer is dried over sodium sulphate and evaporated to dryness under reduced pressure. The crude material obtained is triturated with diethyl ether to afford the target urea. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Nu,Nu-diisopropylethylamine and N-succinimidyl-N-methylcarbamate were added successively to a solution of compound 49-a (29.6 mg, 0.046 mmol) in DCM (5ml_). The resulting mixture was stirred at room temperature over night, then diluted with EtOAc and washed with brine (x3). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude was purified using Biotage Isolera, SNAP 10 g eluted with DCM/ MeOH which gave the title compound (14 mg, 43 %). MS (ESI): 707.6 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure for the preparation of compounds 28, 29 and 30: [0153] To a solution of one of the amine-modified intermediate 25, 26 or 27 (0.46 mmol) in 5 ml of DMF was added diisopropylethylamine (0.92 mmol) followed by <strong>[18342-66-0]N-succinimidyl N-methylcarboxamide</strong> (0.92 mmol). The reaction was stirred at room temperature overnight and then concentrated. The resulting material was taken up into ethyl acetate, washed with saturated NaHCO3, saturated NaCl and dried over MgSO4. The residue obtained after solvent evaporation was chromatographed on silica eluting with a gradient (5-10%) of MeOH in dichloromethane. Concentration of the pure product fractions afforded compounds 28, 29 or 30 in 70-80% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Procedure A.3: Urea formation with isocyantes or equivalents of isocyanates A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2CI2 (0.5 mL) was treated at rt for 2 - 15 h with an isocyanate (1 .1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followed by aq. workup (CHCb, sat. aq. Na2C03 soln; Na2S04). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 20℃; for 3h; | General procedure: A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2C12 (0.5 mE) was treated at it for 2-15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followedby aq. workup (CHC13, sat. aq. Na2CO3 soln; Na2504). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPEC) to afford the targeted macrocyclic urea. N-[(lOS,125,l 65)-20-methyl-l 6-[(methylamino)carbonyl]amino}-15,21-dioxo-8-oxa- 14,20-diazatetracyclo [20.3.1.027.0 ??4]hexacosa- 1 (26),2,4,6,22,24-hexaen-1 2-yl]-2-(2-naphthyl)acetamide |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Procedure A.3: Urea formation with isocyantes or equivalents of isocyanates A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2CI2 (0.5 mL) was treated at rt for 2 - 15 h with an isocyanate (1 .1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followed by aq. workup (CHCb, sat. aq. Na2C03 soln; Na2S04). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | Procedure A.3: Urea formation with isocyantes or equivalents of isocyanates A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2CI2 (0.5 mL) was treated at rt for 2 - 15 h with an isocyanate (1 .1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followed by aq. workup (CHCb, sat. aq. Na2C03 soln; Na2S04). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Procedure A.3: Urea formation with isocyantes or equivalents of isocyanates A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2CI2 (0.5 mL) was treated at rt for 2 - 15 h with an isocyanate (1 .1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followed by aq. workup (CHCb, sat. aq. Na2C03 soln; Na2S04). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 20h; | Procedure A.3: Urea formation with isocyantes or equivalents of isocyanates A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2CI2 (0.5 mL) was treated at rt for 2 - 15 h with an isocyanate (1 .1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followed by aq. workup (CHCb, sat. aq. Na2C03 soln; Na2S04). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea |
49% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 20℃; for 20h; | General procedure: A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2C12 (0.5 mE) was treated at it for 2-15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followedby aq. workup (CHC13, sat. aq. Na2CO3 soln; Na2504). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPEC) to afford the targeted macrocyclic urea. N-methyl-N?-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8X6-thia-15-azatricyclo[17.3.1 .02?]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 6h; | Example compound 42 (30 mg, 0.070 mmol) was dissolved in DCM (350 mu), then O- succinimidyl methyl carbamate (24 mg, 0.140 mmol) and DIPEA (18 iL, 0.105 mmol) were added. The solution was allowed to stir 6 hours at room temperature. The reaction was halted by the addition of water, followed by extraction into DCM. The organic extract was washed with water and brine, then dried over MgSO/t, filtered, and concentrated in vacuo. Purification via flash chromatography (20-70% EtOAc:hex) isolated the desired compound as a white powder (22 mg, 65% yield). 1H NMR (500 MHz, Chloroform-J) delta 8.02 (d, J= 8.6 Hz, 1H), 6.86 (dd, J = 8.6, 2.5 Hz, 1H), 6.74 (d, J= 2.5 Hz, 1H), 5.91 (ddt, J= 15.9, 10.7, 5.6 Hz, 1H), 5.31 - 5.23 (m, 2H), 4.67 (d, J= 5.6 Hz, 2H), 4.42 (d, J= 4.6 Hz, 1H), 3.86 (s, 3H), 3.82 - 3.72 (m, 4H), 3.52 (t, J= 6.3 Hz, 2H), 3.42 (s, 3H), 3.17 (td, J= 12.7, 3.0 Hz, 2H), 3.01 (s, 2H), 2.81 (d, J= 4.6 Hz, 3H), 2.74 (td, J= 13.2, 4.9 Hz, 2H), 1.43 (d, J= 13.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 2h; | A reaction flask was charged with 40 (20.5 mg, 0.055 mmol), diisopropylethylamine (9.30 mg, 0.072 mmol), and DMF (10 mL), and cooled to 0 C. To the mixture, succinimidyl N-methylcarbamate (51a, 10.6 mg, 0.062 mmol) in DMF (3 mL) was slowly added, and the reaction mixture was stirred at 0 C for 2 h. After the volatile materials were removed under reduced pressure, the crude residue, precipitated from methanol solution with ethyl acetate, was purified by ODS column chromatography (H2O/MeOH=6:4) to yield 42 (78 %). Decomp. ?250 C; 1H NMR (500 MHz, D2O): delta 8.53 (1H, s, 1-H), 8.19 (1H, d, J=7.7Hz, 3-H), 7.72 (1H, d, J=7.7Hz, 4-H), 6.88 (1H, d, J=8.1Hz, 7-H), 6.79 (1H, d, J=7.9Hz, 10-H), 6.55 (1H, dd, J=7.5, 8.1Hz, 8-H), 6.38 (1H, dd, J=7.5, 7.9Hz, 9-H), 4.02 (2H, t, J=5.3Hz, N+CH2CH2), 3.57 (3H, s, OCH3), 3.48 (2H, t, J=5.3 Hz, N+CH2CH2), 2.47 (3H, s, CH3), 1.83 (3H, s, CH3). MS (FAB) m/z 391 (M+-Cl-); HRMS (FAB): Calcd for C22H23N4O3+: 391.1770, found: 391.1762. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 2h; | A reaction flask was charged with 41 (22.5 mg, 0.066 mmol), diisopropylethylamine (10.23 mg, 0.079 mmol), and DMF (10 mL), and cooled to 0C. To the mixture, succinimidyl N-methylcarbamate (51a, 11.7 mg, 0.066 mmol) in DMF (3 mL) was slowly added, and the reaction mixture was stirred at 0 C for 2 h. After the volatile materials were removed under reduced pressure, the crude residue, precipitated from methanol solution with ethyl acetate, was purified by ODS column chromatography (H2O/MeOH=6:4) to yield 44 (79 %). Decomp. ?250C; 1H NMR (500 MHz, D2O): delta 8.53 (1H, s, 1-H), 8.19 (1H, d, J=7.7Hz, 3-H), 7.72 (1H, d, J=7.7Hz, 4-H), 6.88 (1H, d, J=8.1Hz, 7-H), 6.79 (1H, d, J=7.9Hz, 10-H), 6.55 (1H, dd, J=7.5, 8.1Hz, 8-H), 6.38 (1H, dd, J=7.5, 7.9Hz, 9-H), 4.15 (2H, t, N+CH2CH2CH2), 3.66 (3H, s, OCH3), 3.22 (2H, t, N+CH2CH2CH2), 1.96 (3H, s, CH3), 2.47 (3H, s, CH3), 1.88 (2H, m, N+CH2CH2CH2). MS (FAB) m/z 405 (M+- Cl-); HRMS (FAB): Calcd for C23H25N4O3+: 405.1937, found: 405.1941. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | A solution of Example 229F (0.049 g, 0.137 mmol) and triethylamine (0.057 mL, 0.41 1 mmol) in N,N-dimethylformamide (1.4 mL) was treated with 2,5-dioxopyrrolidin- l-yl methylcarbamate (0.035 g, 0.205 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and the solid was filtered and dried under vacuum to afford the title compound. lH NMR (500 MHz, DMSO-d6) delta 2.32 - 2.43 (m, 2H), 2.58 (d, J = 4.3 Hz, 3H), 3.46 (t, J = 5.7 Hz, 2H), 3.70 (s, 3H), 3.96 - 4.03 (m, 2H), 6.01 - 6.08 (m, 1H), 6.40 - 6.47 (m, 1H), 6.47 - 6.55 (m, 1H), 7.14 (dd, J = 8.6, 3.1 Hz, 1H), 7.20 (dd, J = 9.2, 4.5 Hz, 1H), 7.26 - 7.39 (m, 1H), 8.24 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 415.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 689A (100 mg, 0.166 mmol), 2,5-dioxopyrrolidin-l-yl methylcarbamate (42.9 mg, 0.249 mmol) and N-ethyl-N-isopropylpropan-2-amine (87 mu, 0.498 mmol) in 2 mL N,N- dimethylformamide was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic solution was washed with brine, dried with magnesium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was dissolved in 2 mL methanol and 1M aqueous sodium hydroxide solution (830 mu, 0.830 mmol) was added. The mixture was stirred at room temperature overnight, neutralized to pH 5, extracted with dichloromethane and purified by column chromatography eluting with 0-8% methanol in dichloromethane using an Analogix purification system to obtained the title compound. lH NMR (500 MHz, DMSO-d6) delta 2.40-2.50 ( br, 2H), 2.59 (d, J= 4.2 Hz, 3H), 3.43 - 3.55 (m, 2H), 3.76 (s, 3H), 3.99 - 4.04 (m, 2H), 6.31 (s, 1H), 6.44 - 6.50 (m, 1H), 6.60 (bs, 1H), 7.22 - 7.35 (m, 2H), 7.39 (td, J= 8.7, 3.2 Hz, 1H), 8.61 (s, 1H), 12.48 (bs, 1H). MS (ESI+) m/z 406 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of Example 864 (78 mg, 0.212 mmol) in 1.5 mL Nu,Nu-dimethylformamide was added triethylamine (100 0.717 mmol) followed by N-succinimidyl-N-methylcarbamate (50 mg, 0.290 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were rinsed with brine , dried over MgSO/t, filtered and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound. lH NMR (500 MHz, DMSO-d6) delta 12.14 (s, 1H), 8.28 (d, J= 4.9 Hz, 1H), 7.32 - 7.20 (m, 3H), 7.10 (d, J= 4.9 Hz, 1H), 6.48 (d, J= 2.1 Hz, 1H), 6.41 - 6.37 (m, 1H), 6.21 (d, J= 2.0 Hz, 1H), 5.16 (m, 1H), 4.53 - 4.43 (m, 2H), 3.74 (s, 3H), 3.66 (s, 3H), 2.60 (d, J= 4.3 Hz, 3H). MS (ESI+) m/e 425 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h; | Example 977E (60 mg, 0.14 mmol), N-succinimidyl-N-methylcarbamate (48 mg, 0.28 mmol) and triethylamine (0.12 mL, 5.9 mmol) were dissolved in Nu,Nu-dimethylformamide (1 mL) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered; and the resultant solid was washed with methanol and dried with magnesium sulfate to provide the title compound. 1HNMR (400 MHz, DMSO-d6) delta 1.56 (m, 1H), 1.87 (m, 1H), 2.05 (m, 1H), 2.44 (m, 3H), 2.55 (d, 3H), 3.71 (m, 1H), 3.74 (s, 3H), 5.66 (m, 1H), 5.89 (d, 1H), 6.19 (br s, 1H), 6.46 (m, 1H), 7.02 (d, 1H), 7.24 (m, 3H), 8.17 (d, 1H), 1 1.72 br s, 1H). MS (ESI) m/e 395.1 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of Example 284A (2.14 g, 4.76 mmol) in ethyl acetate (13 mL) was added methanol (13 mL) and 2M hydrogen chloride in diethyl ether (2 mL, 4.00 mmol). The mixture was stirred at 35C for 2 hours and cooled. Diethyl ether (50 mL) was added and the suspension was stirred vigorously at room temperature for 10 minutes and filtered. The solid was washed with 50 mL of diethyl ether and 50 mL of heptane and the solid wascollected and dried under high vacuum to provide the deprotected intermediate as the hydrochloride salt. To a solution of this intermediate (100 mg, 0.237 mmol) in N,N-dimethylformamide (1.5 mL) was added 2,5-dioxopyrrolidin- l-yl methylcarbamate (44.8 mg, 0.260 mmol) and triethylamine (0.165 mL, 1.184 mmol) and the mixture was stirred at room temperature for 3 hours. Water was slowly added, and the precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to provide the title compound. lH NMR (500 MHz, DMSO-d6) delta 2.51 - 2.60 (m, 4 H) 2.84 - 3.07 (m, 3 H) 3.35 - 3.40 (m, 2 H) 3.46 - 3.55 (m, 2 H) 3.73 (s, 3 H) 5.96 - 6.07 (m, 1 H) 6.15 - 6.20 (m, 1 H) 6.31 (s, 1 H) 7.03 (d, J=4.88 Hz, 1 H) 7.16 - 7.32 (m, 3 H) 8.21 (d, J=4.88 Hz, 1 H) 1 1.89 (d, J=1.53 Hz, 1 H). MS (ESI+) m/z 407 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; | To a mixture of Example 1215B (46.1 mg, 0.1 mmol) in dimethylformamide (0.75mL) was added 2,5-dioxopyrrolidin-l-yl methylcarbamate (20.66 mg, 0.120 mmol) and triethylamine (0.070 mL, 0.500 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by reverse-phase HPLC performed on Waters PrepLC 4000 System with a Phenomenex Luna C8 AXIA column (30 x 75 mm, 100 A) using a gradient of 10% to 95% acetonitrile: 10 mM ammonium acetate in water to afford the title compound. lH NMR (400 MHz, DMSO-ds) delta ppm 1.49 - 1.60 (m, 2 H) 2.26 - 2.38 (m, 2 H) 2.54 (s, 3 H) 2.64 - 2.75 (m, 2 H) 3.17 - 3.35 (m, 5 H) 3.72 (s, 3 H) 5.91 - 6.10 (m, 2 H) 7.04 (d, J=5.19 Hz, 1 H) 7.13 - 7.33 (m, 3 H) 8.15 (d, J=5.19 Hz, 1 H) 1 1.73 (s, 1 H). MS (ESI+) m/z 409 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; for 3h; | To a suspension of Example 282A (80.0 mg, 0.182 mmol) and N-succinimidyl-N- methylcarbamate (46.9 mg, 0.273 mmol) in N,N-dimethylformamide (2.5 mL) was added triethylamine (0.152 mL, 1.090 mmol) and the mixture was stirred for 3 hours. The mixture was treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated until most of the solvent was removed. The suspension was filtered, washed with ethyl acetate and vacuum oven-dried to provide the title compound. lH NMR (400 MHz, Pyridine-d5) delta 2.56 - 2.86 (m, 1H), 2.86 - 2.95 (m, 5H), 3.31 - 3.42 (m, 1H), 3.47 (bs, 1H), 3.61 - 3.75 (m, 4H), 3.73 - 3.91 (m, 2H), 6.40 (bs, 2H), 6.48 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 9.1, 4.5 Hz, 1H), 7.31 (td, J = 8.5, 3.2 Hz, 1H), 7.48-7.54, (m, 1H), 8.53 (d, J = 2.6 Hz, 1H), 13.12 (bs, 1H). MS (ESI+) m/z 425.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To Example 337 (120 mg; 0.21 mmol) in 4 mL of dichloromethane was added 1 mL trifluoroacetic acid. The mixture was stirred at room temperature for 4 hours and concentrated. The residue was dissolved in 1.5 mL N,N-dimethylformamide. Triethylamine (0.1 mL; 0.72 mmol) and N-succinimidyl-N-methylcarbamate (50 mg, 0.290 mmol) were added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was removed and the aqueous phase was extracted with two 10 mL portions of ethyl acetate. The combined extracts were rinsed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The product was isolated by HPLC (Phenomenex Luna C8(2) 5 mum 100 AXIA column) using a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water to afford the title compound as the trifluoroacetate salt. 1H NMR (DMSO-d6) delta: 1.34 (qd, J=12.0, 4.5 Hz, 2H), 1.42-1.61 (m, 4H), 2.10-2.21 (m, 3H), 2.56-2.66 (m, 2H), 3.03-3.32 (m, 9H), 3.84 (dd, J=11.8, 4.5 Hz, 2H), 4.37 (d, J=8.4 Hz, 3H), 6.02 (bs, 1H), 7.58 (dd, J=8.5, 1.6 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 8.28 (s, 1H), 8.52 (s, 1H), 9.29 (s, 1H), 10.79 (s, 1H). MS (ESI) m/e 537 (M-H)1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 24 4-{4-[1-(3-fluorobenzyl)-1H-benzimidazol-6-yl}-1H-pyrrolo[2,3-b]pyridin-2-yl]-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide To a suspension of Example 14E (65.0 mg, 0.131 mmol) and N-succinimidyl-N-methylcarbamate (33.8 mg, 0.196 mmol) in N,N-dimethylformamide (2.5 mL) was added triethylamine (0.110 mL, 0.786 mmol). The reaction was stirred for 16 hours. The reaction mixture was treated with brine and aqueous NaHCO3 and extracted with ethyl acetate (twice). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by HPLC (see protocols in Example 15) to give the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, methanol-d4) delta ppm 2.47-2.56 (m, 2H), 2.77 (s, 3H), 3.67 (t, J=5.6 Hz, 2H), 4.11-4.16 (m, 2H), 5.82 (s, 2H), 6.46-6.52 (m, 1H), 6.53 (s, 1H), 7.14-7.28 (m, 3H), 7.41-7.50 (m, 2H), 7.99 (dd, J=8.5, 1.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.10 (d, J=1.4 Hz, 1H), 8.31 (d, J=5.7 Hz, 1H), 9.34 (s, 1H). MS (ESI+) m/z 481 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; | To a suspension of Example 87D (70.0 mg, 0.177 mmol) in N,N-dimethylformamide (2 mL) was added n-succinimidyl-n-methylcarbamate (45.6 mg, 0.265 mmol) and triethylamine (0.148 mL, 1.06 mmol) and the mixture was stirred overnight. Water was slowly added and the solids were filtered, rinsed with water, and oven-dried to provide the title compound. H NMR (400 MHz, DMSO-d6) delta 2.44 (bs, 2H), 2.59 (d, J = 3.3 Hz, 3H), 3.50 (t, J = 5.6 Hz, 2H), 3.74 (s, 3H), 3.97 - 4.03 (m, 2H), 6.22 - 6.27 (m, 1H), 6.41 - 6.54 (m, 2H), 7.04 (d, J = 4.9 Hz, 1H), 7.15 - 7.31 (m, 3H), 8.20 (d, J = 4.9 Hz, 1H), 1 1.81 (bs, 1H) MS (ESI+) m/z 381.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; for 3h; | To a suspension of Example 222C (72.0 mg, 0.187 mmol) and N-succinimidyl-N- methylcarbamate (48.4 mg, 0.281 mmol) in N,N-dimethylformamide (2.5 mL) was added triethylamine (0.157 mL, 1.124 mmol) and the mixture was stirred for 3 hours and treated slowly with water. The precipitate was filtered, washed with water, dried over magnesium sulfate, filtered, and purified by HPLC (same protocol as Example 221) to provide the title compound as a trifluoroacetate salt. lH NMR (400 MHz, Methanol-d4) delta 2.56 - 2.62 (m, 2H), 2.76 (s, 3H), 3.63 (t, J = 5.6 Hz, 2H), 4.13 (q, J = 2.8 Hz, 2H), 6.48 - 6.54 (m, 1H), 6.57 (d, J = 2.1 Hz, 1H), 7.29 - 7.53 (m, 4H), 8.31 (d, J = 5.6 Hz, 1H). MS (ESI+) m/z 369.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | General procedure: A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2C12 (0.5 mE) was treated at it for 2-15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followedby aq. workup (CHC13, sat. aq. Na2CO3 soln; Na2504). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPEC) to afford the targeted macrocyclic urea. 2-(dimethylamino)-N- [(10S,1 2S,1 6S)-20-methyl- 12-{ [(methylamino)carbonyl] amino}-1 5,21 -dioxo-8-oxa- 14,20-diazatetracyclo[20.3. 1 .02?7.0??4]hexacosa- 1 (26),2,4,6,22,24-hexaen- 1 6-yl]acetamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 20℃; for 16h; | General procedure: A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2C12 (0.5 mE) was treated at it for 2-15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followedby aq. workup (CHC13, sat. aq. Na2CO3 soln; Na2504). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPEC) to afford the targeted macrocyclic urea. N-methyl-N?-[(135,16Rj-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.02?]tricosa- 1(23),2,4,6,19,21-hexaen-13-yl)urea |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | To a suspension of Example 1 (80 mg, 0.239 mmol) in dichloromethane (7 mL) was added triethylamine (0.1 mL, 0.718 mmol) and N-succinimidyl-N-methylcarbamate (62 mg, 0.359 mmol) and the mixture was stirred at room temperature overnight. Methanol was added to dissolve the solid, and the mixture was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 5-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): delta 2.55-2.58 (m, 2H), 2.61 (d, J=4.58 Hz, 3H), 2.89 (s, 3H), 3.54 (t, J=5.49 Hz, 2H), 4.02-4.04 (m, 2H), 4.15 (s, 2H), 5.90 (s, 1H), 6.47-6.50 (m, 1H), 7.21-7.26 (m, 1H), 7.27-7.30 (m, 1H), 7.31-7.33 (m, 1H), 7.69 (dd, J=10.68, 3.05 Hz, 1H), 8.23 (d, J=5.19 Hz, 1H), 11.52 (s, 1H). MS (ESI+) m/z 420 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a suspension of Example 99D (0.100 mmol) in N,N-dimethylformamide (0.8 mL) were added <strong>[18342-66-0]2,5-dioxopyrrolidin-1-yl methylcarbamate</strong> (20.57 mg, 0.120 mmol) and triethylamine (0.069 mL, 0.498 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase HPLC performed on a Phenomenex Luna C8 AXIA column (30*75 mm, 100 A) using a gradient of 10% to 95% acetonitrile:10 mM ammonium acetate in water to provide the title compound. 1H NMR (400 MHz, DMSO-d6) delta 1.46-1.59 (m, 2H), 1.57-1.90 (m, 4H), 2.45 (d, J=17.8 Hz, 1H), 2.61 (d, J=4.1 Hz, 3H), 2.92-2.87 (m, 1H), 2.87 (s, 3H), 4.12 (d, J=3.5 Hz, 2H), 4.30-4.55 (m, 1H), 4.75 (d, J=5.2 Hz, 1H), 5.85 (d, J=5.4 Hz, 1H), 6.48 (q, J=4.3 Hz, 1H), 7.13-7.43 (m, 3H), 7.71 (dd, J=10.5, 3.0 Hz, 1H), 8.24 (d, J=5.2 Hz, 1H), 11.52 (s, 1H). MS (ESI) m/e 432.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 19 Compound I-28 (4-(4-(4-(3-acrylamidophenylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methoxyphenyl)-N-methylpiperazine-1-carboxamide)A mixture of the intermediate 1 (16 mg) and tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (20 mg) in dioxane (1.0 mL) with catalytic trifluoroacetic acid was stirred overnight at 50 C. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier). The intermediate was dissolved in dichloromethane (1.0 mL) and treated with TFA (0.3 mL). After 10 minutes, the mixture was concentrated under reduced pressure. To the residue were added N,N-diethylisopropylamine (20 uL), dichloromethane (1.0 mL), and <strong>[18342-66-0]N-methyl-N-hydroxysuccinyl carbamate</strong> (50 mg) at 0 C. The reaction mixture was stirred room temperature overnight. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier) to give the desired as a TFA salt. Calculated mass for C27H29F3N8O3: 570.2. found: 571.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | H Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride (104a) (2.43 g, 9.00 mrnol) was suspended in acetonitrile (25.0 mL), and diisopropylethylamine (2.5 inL) was added with stirring. To the resulting solution N-succinimidyl-iV-methyl-carbamate (1.88 g, 10.80 mol) was added and the mixture stirred at room temperature for 16 h. The solvent was evaporated completely and the residue reacted without further purification. In the second step dioxane and cesium carbonate (2 eq.) were added and the mixture heated to 90 C for 1 h. Yield 1.65g (6.46 mmol, 71 % over 2 steps) colorless crystals after column chromatography with dichloromethane and ethyl acetate (10: 1); mp: 243 - 245 C, IR (KBr): 1713, 1761 , 3313 cm-1 1H NMR (400 MHz, DMSO): 6 1 1.02 (s, 1H), 7.47 (t, J = 8.3 Hz, 1H), 7.35 (d, J - 8.0 Hz, 1H), 7.17 - 6.90 (m, 2H), 4.97 - 4.81 (m, 1H), 4.48 - 4.35 (m, 2H), 3.23 (dd, J = 14.9, 4.7 Hz, 1H), 2.93 (s, J = 9.6 Hz, 3H), 2.83 - 2.61 (m, 1H). ESI-MS m/z (%): 256 [MH+] (100). Anal, calcd for Ci4H13N3O2: C 65.87; H 5.13; N 16.46; found: C 65.63; H 5.16; N 16.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | General procedure: Methyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-caxboxylate hydrochloride (13a) (0.67 g; 2.50 mmol) was suspended in acetonitrile (13.4 mL). With stirring diisopropylethylamine (2.5 mL) was added. After addition of N-succinimidyl-N-methyl-carbamate (0.52 g; 3.00 mmol) stirring was continued for 16 h at room temperature. The mixture was poured into water and the crude product was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried (Na2SO4) and evaporated. Methyl 2-(methylcarbamoyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylate (16a) Recrystallization from ethyl acetate: 0.66 g (2.30 mmol; 92 %) colorless crystals; mp 202.5- 203.1 C. IR (KBr): 3380, 3275, 2945, 1716 cm-1. 1H NMR (300 MHz, DMSO-d6): delta 1 1 .06 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.10 - 7.01 (m, 1H), 7.00 - 6.89 (m, 1H), 6.65 (q, J = 4.0 Hz, 1H), 4.61 (d, J- 16.4 Hz, 1H), 4.51 (d, J= 16.2 Hz, 1H), 4.03 - 3.87 (m, 2H), 3.73 (dd, J = 12.7, 3.9 Hz, 1H), 3.64 (s, 3H), 2.61 (d, J = 4.3 Hz, 3H). ESI-MS m/z (%): 675 [2 MH+] (100), 288 [MH+] (35). Anal, calcd for C15H17N3O3: C 62.71 ; H 5.96; N 14.63; found: C 62.39; H 6.26; N 14.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -10 - -5℃; for 7h;Inert atmosphere; | 2,5-Dioxopyrrolidin-1-yl N-methylcarbamate (22.4 mg, 0.087 mmol) was placed in a reaction flask and dissolved in 3 mL of DMF. After being cooled at -10 C, a solution of 5aa (50 mg, 0.072 mmol) and diisopropylethylamine (DIPEA, 53.4 mg, 0.276 mmol) in DMF (2 mL) was added drop-by-drop through a Teflon cannula under an argon atmosphere. The reaction mixture was stirred at -10 to -5 C for 7 h. After the volatile materials were removed under reduced pressure, the residue was dissolved in a small amount of MeOH. To this solution, ethyl acetate was gradually added to re-precipitate the product, which was collected by filtration using a membrane filter (PTFE 0.5 mum) to give 7aa (71%) as a yellow solid; indefinite melting; 1H NMR (300 MHz, CD3OD): delta 10.1 (1H, s), 8.56 (2H, m), 8.43 (1H, d, J=1.5Hz), 7.92 (1H, m), 7.78 (1H, m), 7.55 (1H, m), 4.59 (3H, s), 3.74 (2H, t, J=3.0Hz), 3.66 (2H, t, J=3.0Hz), 3.51 (3H, s), 2.82(3H, s); MS (FAB): m/z 390 [M+-Cl-]; HRMS (FAB): calcd for C22H24N5O2+: 390.4665, Found: 390.4672. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 24h; | Sulfamethoxazole 1 (1 mmol) was dissolved in dry acetonitrile (5 mL), then N,Ndiisopropylethylamine(2 mmol) followed by <strong>[18342-66-0]2,5-dioxopyrrolidin-1-yl methylcarbamate</strong> (1.5 mmol)was added. The solution was stirred for 24 h. The resulting crystals were filtered, washed with a smallvolume of MeCN and dried. The product was recrystallized from EtOAc if necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | Ethyl 5-(4-(tert-butoxycarbonyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-1-carboxylate (27) (3.00 g; 6.90 mmol) was dissolved in acetonitrile (15.0 mL). Diisopropylethylamine (3.0 mL) was added to the stirred mixture. After addition of N-succinimidyl-N-methyl-carbamate (1.31 g; 7.60 mmol) stirring was continued for 16 h at rt. The mixture was poured into water and the crude product was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4) and evaporated. Yield 1.44g (3.23 mmol,47 %) colorless foam after cc (CH2Cl2, ethyl acetate 10:1). 1H NMR (300 MHz, CDCl3): delta 8.12 - 8.01 (m, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.19 - 7.08 (m, 3H), 6.96 (d, J = 8.3 Hz, 2H), 5.34 (t, J = 1.8 Hz, 1H), 5.24 (s, 2H), 4.48 (dd, J = 13.7, 6.0 Hz, 1H), 3.20 - 3.05 (m, 1H), 2.97 (s, 3H), 2.88 - 2.71 (m, 1H), 2.56 (dd, J = 16.0, 4.7 Hz, 1H), 1.51 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 24h; | Isoniazid 1 (137.0mg, 1.0mmol) was mixed with N,N-diisopropylethylamine (DIPEA, 348muL, 2.0mmol) and N-succinimidyl N-methylcarbamate (258.2mg, 1.5mmol) in acetonitrile (4mL). The reaction mixture was stirred at the room temperature for 24h, formed precipitate was filtered off and recrystallised from ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 2-methyltetrahydrofuran; 1-methyl-pyrrolidin-2-one; dichloromethane; dimethyl sulfoxide; at 20℃; | Example 1e (0.05 g, 0.149 mmol) and 2, 5-dioxopyrrolidin-1-yl methylcarbamate (0.031 g, 0.179 mmol) were combined with dichloromethane (1 mL) and stirred at ambient temperature for 10 minutes. 2-Methyl tetrahydrofuran (0.4 mL) was added and stirring was continued for 6 hours. Triethylamine (0.05 mL, 0.359 mmol) , N-methyl-2-pyrrolidinone (0.4 mL) , dimethyl sulfoxide (1.3 mL) and additional 2, 5-dioxopyrrolidin-1-yl methylcarbamate (0.031 g, 0.179 mmol) were added sequentially and stirring was continued overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide 0.0386 g (54.6yield, 75purity) of the title compound as a mixture with a succinimide by-product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In dichloromethane; at 20℃; for 72h; | Example 113c (0.515 g, 1.61 mmol) , 2, 5-dioxopyrrolidin-1-yl methylcarbamate (0.324 g, 1.88 mmol) and triethylamine (1.00 mL, 7.17 mmol) were combined in dichloromethane (10 mL) . The reaction mixture was stirred at ambient temperature for 72 hours, and then partitioned with dichloromethane and water. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-10ammonia saturated methanol in dichloromethane) to provide the title compound (407 mg, 67%yield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | A mixture of tert-butyl 4-(4-(hydrazinecarbonyl) phenyl)piperazine-1-carboxylate (2.0 g, 6.3 mmol) and 2,5- dioxopyrrolidin-1 -yl methylcarbamate (1.1 g, 6.3 mmol) in acetonitrile (30 mE) was stirred at room temperature overnight. The mixture was poured into water (30 mE) and filtered to give tert-butyl 4-(4-(2-(methylcarbamoyl)hydra- zinecarbonyl)phenyl)piperazine-1 -carboxylate (1.7 g, 70%) as a white solid. Chemical Formula: C1 8H27N504, Molecular Weight: 377.44 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Over a solution of (4-(4-isopentylpiperazin-1-yl)-2,2-dimethylpiperidin-4-yl)(pyridin-2- yl)methanone (Ex 15, 72 mg, 0.15 mmol) in anh DCM (5 ml) at 0 C, DIPEA (100 muIota, 0.61 mmol) and 2,5-dioxopyrrolidin-l-yl methylcarbamate (53 mg, 0.31 mmol ) were added. The solution was allowed to reach rt overnight, after which the reaction was quenched with cold water/ ice and extracted with DCM (3x10 mL). The combined organic layers were washed several times with water, dried over Na2S04and concentrated. The crude residue was purified by flash chromatography, eluents DCM/ MeOH from 100:0 to 95:5, to give the title compound as yellow oil (25 mg, yield 38%). HPLC-MS (Method B): Ret, 2.26 min; ESI+-MS m/z, 430.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In acetonitrile; at 0℃;Inert atmosphere; | Procedure. To an oven-dried 25 mL round bottom flask, 16 (186 mg, 0.89 mmol, 1 eq.) and /V-succinimidyl /V-methylcarbamate (321 mg, 1.86 mmol, 2.1 eq.) were added and suspended in anhydrous acetonitrile (1.5 mL, 0.6 M). Next, under nitrogen, dry triethylamine (0.34 mL, 2.4 mmol, 2.7 eq.) was added slowly and the solution was stirred overnight at room temperature. Upon completion, the mixture was concentrated and purified by silica gel flash chromatography (100% dichloromethane to 4: 1 dichloromethane: methanol) to afford 106 mg (66%) of intermediate 16a as a gold solid.*H NMR (500 MHz, d-DMSO) d 8.17 (br s, 1H), 7.97 (s, 1H), 7.56 (s, 2H), 3.36 (d, J = 4.5 Hz, 3H), 2.73 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide In water monomer at 50℃; for 2h; Inert atmosphere; | General procedure C: N-methylcarbamoylation by SNMC General procedure: Amino acid (1.0 mmol) was dissolved in 0.05M borax (50 ml) resulting in pH 9.5-10.SNMC (1.5 mmol) was then added and the reaction mixture was stirred at 50 C for2-3 h until at least 97% conversion of the amino acid was achieved as determined byLC/MS. The reaction mixture was worked up as described above for the general procedureB. |
Tags: 18342-66-0 synthesis path| 18342-66-0 SDS| 18342-66-0 COA| 18342-66-0 purity| 18342-66-0 application| 18342-66-0 NMR| 18342-66-0 COA| 18342-66-0 structure
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H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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