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CAS No. : | 26893-73-2 | MDL No. : | MFCD06800962 |
Formula : | C7H7NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KSWBODXXZITTPO-UHFFFAOYSA-N |
M.W : | 153.14 | Pubchem ID : | 570891 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 37.69 |
TPSA : | 59.42 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.64 cm/s |
Log Po/w (iLOGP) : | 1.3 |
Log Po/w (XLOGP3) : | 0.84 |
Log Po/w (WLOGP) : | 0.79 |
Log Po/w (MLOGP) : | -0.96 |
Log Po/w (SILICOS-IT) : | 0.71 |
Consensus Log Po/w : | 0.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.59 |
Solubility : | 3.93 mg/ml ; 0.0257 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.67 |
Solubility : | 3.27 mg/ml ; 0.0213 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.51 |
Solubility : | 4.73 mg/ml ; 0.0309 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.64 |
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 |
---|---|---|
87% | With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water; toluene | PREPARATION 234 6-Methoxy-pyridine-2-carboxylic acid To 6-hydroxypicolinic acid (1.39 g, 10.0 mmol) in toluene (35 mL) was added silver oxide (2.43 g, 10.5 mmol) and the mixture was stirred for 30 minutes. To the reaction was added iodomethane (1.31 mL, 21.0 mmol), and the reaction was heated to reflux overnight. The reaction was filtered over celite and concentrated to give 1.45 g of the methyl ester as a yellow solid. The resulting solid was dissolved in tetrahydrofuran (50 mL), and added to a solution of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After one hour, the reaction was acidified to pH 3 with 5N HCl and concentrated. To the resulting white solids was added 20percent MeOH/CHCl3 and the mixture was sonicated for 20 minutes. The mixture was filtered, and the mother liquor was dried over MgSO4 and concentrated to give 1.33 g of the title compound as a white solid, 87percent yield. 1H NMR: consistent with structure. MS (ion spray) 152 (M-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: With water; rochelle salt In tetrahydrofuran at 20℃; for 1 h; |
Step A: Preparation of (6-methoxypyridin-2-yl)methanol: A cold solution of6-methoxypicolinic acid (1.8 g, 11.8 mmol) in tetrahydrofuran (0.3M, 40 mL) was treated with lithium aluminum hydride (11.8 mL, 11.8 mmol) at 0 °C. This mixture was stirred at 0 °C for 30 minutes, poured into a beaker containing aqueous saturated Rochelle's salt and stirring at ambient temperature continued for 1 hour. The product was extracted from EtO Ac, dried (phase separator silicone treated filter paper) paper, concentrated (1.13 g, 69percent yield) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In ethanol; water; | EXAMPLE 26 0.48 g of <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong>, 0.51 g of N,N'-carbonyldiimidazole and 0.29 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.32 g of N-(5-tetrazolyl)-6-methoxy-2-pyridinecarboxamide is obtained. M.p. 252-253 C. (decomp.) Sodium salt: M.p. 288-290 C. (decomp.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water; toluene; | PREPARATION 234 6-Methoxy-pyridine-2-carboxylic acid To 6-hydroxypicolinic acid (1.39 g, 10.0 mmol) in toluene (35 mL) was added silver oxide (2.43 g, 10.5 mmol) and the mixture was stirred for 30 minutes. To the reaction was added iodomethane (1.31 mL, 21.0 mmol), and the reaction was heated to reflux overnight. The reaction was filtered over celite and concentrated to give 1.45 g of the methyl ester as a yellow solid. The resulting solid was dissolved in tetrahydrofuran (50 mL), and added to a solution of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After one hour, the reaction was acidified to pH 3 with 5N HCl and concentrated. To the resulting white solids was added 20% MeOH/CHCl3 and the mixture was sonicated for 20 minutes. The mixture was filtered, and the mother liquor was dried over MgSO4 and concentrated to give 1.33 g of the title compound as a white solid, 87% yield. 1H NMR: consistent with structure. MS (ion spray) 152 (M-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
starting from 1.7 g of <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong> there was obtained t-butyl [2-(6-methoxypyridine-2-carboxamido)ethyl]carbamate, m.p. 104-105, which, in turn, was converted into N-(2-aminoethyl)-6-methoxypyridine-2-carboxamide hydrochloride, white crystals (alcohol/ether), m.p. 124-125. The <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong> used as the starting material was prepared according to E. V. Brown and M. B. Shamhu, J. Org. Chem., 36 (14) (1971) 2002, m.p. 129-130. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To a solution of 0.040g (0.26 mmol) of <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong> dissolved in 8 mL of anhydrous dichloromethane was added 0.11 mL (0.79 mmol) of triethylamine, 0.050g (0.26 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.035g (0.26 mmol) of 1-hydroxybenzotriazole. The resulting mixture was stirred at room temperature for 10 min and added slowly at -10C to a solution of 0.110g (0.26 mmol) of (+/-)-9-amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-5H-1,4a,7-triaza-benzocyclohepten-4-one dihydrobromide (2 :1) dissolved in a mixture of 17 mL of anhydrous dichloromethane and 0.15 mL (1.05 mmol) of triethylamine. The resulting mixture was stirred at -10C for 1 hour and at room temperature for 16 hours. After addition of water, extraction with dichloromethane; the reaction mixture was washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 90/10/1 to afford 0.100g (90%) of the pure product as a powder. Mp : 236-238C RMN 1H (DMSO; 400 MHz) delta (ppm) : 9.42 (m, 2H), 9.21 (d, 1 H), 8.41 (m, 3H), 7.38 (s, 1 H), 7.30 (m, 1 H), 5.61 (m, 1 H), 4.98 (m, 1 H), 4.15 (s, 3H), 4.01 (m, 1 H), 3.18 (m, 2H), 2.94 (m, 1 H), 2.71 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | [00403] Step A: A solution of 5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2CL (10 mL) was treated with <strong>[26893-73-2]6-methoxypicolinic acid</strong> (160 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour, and then 2M aqueous LiOH (3 mL) was added. The reaction was stirred for 1 hour, and then water was added (10 mL). The solid, which separated, was filtered and washed with CH2CL (10 mL). The filtered cake was dried to yield N-(5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)- 6-methoxypicolinamide (229 mg, 72% yield). 1H NMR (400 MHz, (CD3^SO) delta 12.17 (s, IH),12.25 (s, IH), 8.40 (d, IH), 7 96 (dd, IH), 7.92 (dd. IH), 7.74 (dd. IH), 7.11 (dd, IH), 4.05 (s, 3H); LCMS (APCI+) m/z 365, 366.9 (M+H)+, Retention time = 3.75 minutes (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[26893-73-2]6-(methyloxy)-2-pyridinecarboxylic acid</strong> (1.00 g, 6.53 mmol) in dichloromethane (DCM) (13.52 ml) was stirred and cooled to 0 0C. Oxalyl chloride (0.686 ml, 7.84 mmol) was added dropwise followed by DMF (5.06 mul, 0.065 mmol). The solution immediately turned yellow and the reaction was followed by LCMS. LCMS after circa 1 hour showed the methyl ester of the acid chloride to be present. The solvent was removed under reduced pressure and the residue was azeotroped with toluene. The residue was dissolved in dichloromethane (DCM) (27.0 ml) and cooled to O 0C. DIPEA (1.71 1 ml, 9.80 mmol) was added dropwise followed by 1 ,1- dimethylethyl hydrazinecarboxylate (0.949 g, 7.18 mmol) and the solution was left to stir at 20 0C, under an argon atmosphere for 18 hours. A dark brown solution formed and LCMS showed the desired compound to be present. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate, saturated ammonium chloride, water and brine. The organic extracts were dried over magnesium sulfate and the solvent was removed under vacuum to yield the desired product in 1.685 g. LCMS m/z 268.16 [M+H] (at)0.83 min ( 2 min run) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Step A: Preparation of (6-methoxypyridin-2-yl)methanol: A cold solution of<strong>[26893-73-2]6-methoxypicolinic acid</strong> (1.8 g, 11.8 mmol) in tetrahydrofuran (0.3M, 40 mL) was treated with lithium aluminum hydride (11.8 mL, 11.8 mmol) at 0 C. This mixture was stirred at 0 C for 30 minutes, poured into a beaker containing aqueous saturated Rochelle's salt and stirring at ambient temperature continued for 1 hour. The product was extracted from EtO Ac, dried (phase separator silicone treated filter paper) paper, concentrated (1.13 g, 69% yield) as a clear oil. | |
To a 100-mL round-bottomed flask was added 6-methoxypyridine-2- carboxylic acid (1.5 g, 9.80 mmol, Aldrich, St. Louis, MO) and borane methyl sulfide complex (3.72 mL, 39.2 mmol, Aldrich, St. Louis, MO) in THF (20 mL). The reaction mixture was stirred at 70 C for 18 h, cooled to 0 C, and then carefully quenched by the addition of MeOH (10 mL). After the addition was completed, the reaction mixture was stirred for an additional 20 min at rt. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give 6-methoxy-2- pyridinyl)methanol (1.09 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 1 1.1 : 4-(6-Methoxy-pyridine-2-carbonyl)-2,2-dimethyl-piperazine- 1 -carboxylic acid ester 510 mg (3.31 mmol) <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong> was stirred with 1.17 g (3.31 mmol) TBTU and 1.50 mL (8.72 mmol) DIPEA in 10 mL DCM at RT. After 10 min, 1.20 g (3.31 mmol) 2,2-dimethyl-piperazine-l -carboxylic acid benzyl ester trifluoro acetate was added and the reaction mixture was stirred at RT for 2 h. Then the reaction mixture was washed with saturated aqueous NaHCOs solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc = 9/1 -> 1/2). Yield: 1.10 g (87 %) ESI-MS: m/z = 384 (M+H)+ Rt(HPLC): 1.07 min (method 3) | |
87% | 11.1: 4-(6-Methoxy-pyridine-2-carbonyl)-2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester 510 mg (3.31 mmol) <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong> was stirred with 1.17 g (3.31 mmol) TBTU and 1.50 mL (8.72 mmol) DIPEA in 10 mL DCM at RT. After 10 min, 1.20 g (3.31 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate was added and the reaction mixture was stirred at RT for 2 h. Then the reaction mixture was washed with saturated aqueous NaHCO3 solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1?1/2). Yield: 1.10 g (87%) ESI-MS: m/z=384 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | 81.4: (4-Benzyl-3-methoxymethyl-3-methyl-piperazin-l-yl)-(6-methoxy-pyridin-2-yl)- methanone A mixture of 77.6 mg (507 muiotaetaomicron) <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong>, 125 mg (507 muiotaetaomicron) 1- benzyl-2-methoxymethyl-2-methyl-piperazine, 177 mg (551 muiotaetaomicron) TBTU and 100 (581 mumol) DIPEA in 1.5 mL DMF was stirred at RT for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Yield: 170 mg (82 %), purity: 90% ESI-MS: m/z = 370 (M+H)+ Rt(HPLC) : 1.48 min (method 1 ) | |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | 81.4: (4-Benzyl-3-methoxymethyl-3-methyl-piperazin-1-yl)-(6-methoxy-pyridin-2-yl)-methanone A mixture of 77.6 mg (507 mumol) <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong>, 125 mg (507 mumol) 1-benzyl-2-methoxymethyl-2-methyl-piperazine, 177 mg (551 mumol) TBTU and 100 muL (581 mumol) DIPEA in 1.5 mL DMF was stirred at RT for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.Yield: 170 mg (82%), purity: 90%ESI-MS: m/z=370 (M+H)+ Rt(HPLC): 1.48 min (method 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 248 : (R)- {4-[ l-(3-Chloro-phenyl)- 1Eta-[ 1 ,2,4]triazole-3-carbonyl]-2-methyl- piperazin- 1 -yl} -(6-methoxy-pyridin-2-yl)-methanone A mixture of 92 mg (0.30 mmol) [l-(3-chloro-phenyl)-lH-[l ,2,4]triazol-3-yl]-((R)-3-methyl- piperazin-l-yl)-methanone, 46 mg (0.30 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 106 mg (0.330 mmol) TBTU and 77 muEpsilon (0.46 mmol) DIPEA in 3.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC. yield: 70 mg (53 %) ESI-MS : m/z = 441 (M+H)+ Rt(HPLC) : 1.24 min (method 8) |
53% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 248 (R)-{4-[1-(3-Chloro-phenyl)-1H-[1,2,4]triazole-3-carbonyl]-2-methyl-piperazin-1-yl}-(6-methoxy-pyridin-2-yl)-methanone A mixture of 92 mg (0.30 mmol) [1-(3-chloro-phenyl)-1H-[1,2,4]-triazol-3-yl]-((R)-3-methyl-piperazin-1-yl)-methanone, 46 mg (0.30 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 106 mg (0.330 mmol) TBTU and 77 muL (0.46 mmol) DIPEA in 3.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.yield: 70 mg (53%)ESI-MS: m/z=441 (M+H)+ Rt(HPLC): 1.24 min (method 8) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 251 : (R)-(6-Methoxy-pyridin-2-yl)-[2-methyl-4-(l -m-tolyl- 1 H-[ 1 ,2,4]triazole-3- carbonyl)-piperazin- 1 -yl] -methanone A mixture of 86 mg (0.30 mmol) ((R)-3-methyl-piperazin-l-yl)-(l-m-tolyl-lH-[l ,2,4]triazol-3- yl)-methanone, 46 mg (0.30 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 0.1 1 g (0.33 mmol) TBTU and 80 muEpsilon (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. yield: 108 mg (86 %) ESI-MS : m/z = 421 (M+H)+ Rt(HPLC) : 1.29 min (method 8) |
86% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 251 (R)-(6-Methoxy-pyridin-2-yl)-[2-methyl-4-(1-m-tolyl-1H-[1,2,4]-triazole-3-carbonyl)-piperazin-1-yl]-methanone A mixture of 86 mg (0.30 mmol) ((R)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]-triazol-3-yl)-methanone, 46 mg (0.30 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 0.11 g (0.33 mmol) TBTU and 80 muL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. yield: 108 mg (86%) ESI-MS: m/z=421 (M+H)+ Rt(HPLC): 1.29 min (method 8) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 252: (S)- {4-[l-(3-Chloro-phenyl)-lH-[l ,2,4]triazole-3-carbonyl]-2-methyl-piperazin- 1 -yl} -(6-methoxy-pyridin-2-yl)-methanone A mixture of 92 mg (0.30 mmol) [l-(3-chloro-phenyl)-lH-[l ,2,4]triazol-3-yl]-((S)-3-methyl- piperazin-l-yl)-methanone, 46 mg (0.30 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 0.1 1 g (0.33 mmol) TBTU and 80 (0.45 mmol) DIPEA in 3.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC. yield: 101 mg (76 %) ESI-MS : m/z = 441 (M+H)+ Rt(HPLC): 1.30 min (method 8) |
76% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 252 (S)-{4-[1-(3-Chloro-phenyl)-1H-[1,2,4]triazole-3-carbonyl]-2-methyl-piperazin-1-yl}-(6-methoxy-pyridin-2-yl)-methanone A mixture of 92 mg (0.30 mmol) [1-(3-chloro-phenyl)-1H-[1,2,4]-triazol-3-yl]-((S)-3-methyl-piperazin-1-yl)-methanone, 46 mg (0.30 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 0.11 g (0.33 mmol) TBTU and 80 muL (0.45 mmol) DIPEA in 3.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.yield: 101 mg (76%)ESI-MS: m/z=441 (M+H)+ Rt(HPLC): 1.30 min (method 8) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 96h; | Example 261 : (S)-{4-[l-(3-Fluoro-phenyl)-lH-[l,2,4]triazole-3-carbonyl]-2-propyl-piperazin- 1 -yl} -(6-methoxy-pyridin-2-yl)-methanone A mixture of 30 mg (90 muiotaetaomicron) [l-(3-fluoro-phenyl)-lH-[l ,2,4]triazol-3-yl]-((S)-3-propyl- piperazin-l-yl)-methanone, 14 mg (91 muiotaetaomicron) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 30 mg (93 mupiiotaomicron) TBTU and 0.10 mL (0.59 mmol) DIPEA in 1.0 mL DMF was stirred at RT for 4 days. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, concentrated in vacuo and purified by HPLC. yield: 26 mg (61 %) ESI-MS: m/z = 453 (M+H)+ Rt(HPLC): 1.37 min (method 8) |
61% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 96h; | Example 261 (S)-{4-[1-(3-Fluoro-phenyl)-1H-[1,2,4]triazole-3-carbonyl]-2-propyl-piperazin-1-yl}-(6-methoxy-pyridin-2-yl)-methanone A mixture of 30 mg (90 mumol) [1-(3-fluoro-phenyl)-1H-[1,2,4]triazol-3-yl]-((S)-3-propyl-piperazin-1-yl)-methanone, 14 mg (91 mumol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 30 mg (93 mumol) TBTU and 0.10 mL (0.59 mmol) DIPEA in 1.0 mL DMF was stirred at RT for 4 days. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, concentrated in vacuo and purified by HPLC.yield: 26 mg (61%)ESI-MS: m/z=453 (M+H)+ Rt(HPLC): 1.37 min (method 8) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 263 : (2R*,6Si:)-l-[(6-Methoxypyridin-2-yl)carbonyl]-2,6-dimethyl-4- [l-(3- methylphenyl)- 1 H- 1 ,2,4-triazo -3 -yl] carbonyl} piperazine A mixture of 99 mg (0.33 mmol) (3R*,5Si:)-3,5-dimethyl-piperazin-l-yl)-(l-m-tolyl-lH-[l ,2,4]- triazol-3-yl)-methanone, 51 mg (0.33 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 0.12 g (0.36 mmol) TBTU and 86 muEpsilon (0.50 mmol) DIPEA in 2.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC. yield: 85.0 mg (59 %); ESI-MS: m/z = 435 (M+H)+; Rt(HPLC): 1.34 min (method 8) |
59% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 263 (2R*,6S*)-1-[(6-Methoxypyridin-2-yl)carbonyl]-2,6-dimethyl-4-[1-(3-methylphenyl)-1H-[1,2,4]-triazol-3-yl]carbonyl}piperazine A mixture of 99 mg (0.33 mmol) (3R*,5S*)-3,5-dimethyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]-triazol-3-yl)-methanone, 51 mg (0.33 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 0.12 g (0.36 mmol) TBTU and 86 muL (0.50 mmol) DIPEA in 2.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC. yield: 85.0 mg (59%); ESI-MS: m/z=435 (M+H)+; Rt(HPLC): 1.34 min (method 8) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 265 : {4-[ 1 -(3-Chloro-phenyl)- 1Eta-[ 1 ,2,4]triazole-3-carbonyl]-3-methyl-piperazin- 1 - yl}-(6-methoxy-pyridin-2-yl)-methanone A mixture of 200 mg (0.654 mmol) [l-(3-chloro-phenyl)-lH-[l,2,4]triazol-3-yl]-(2-methyl- piperazin-l-yl)-methanone, 100 mg (0.650 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 225 mg (0.700 mmol) TBTU and 170 muEpsilon (1.00 mmol) DIPEA in 3.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, concentrated in vacuo and purified by HPLC. yield: 190 mg (66 %) ESI-MS: m/z = 441 (M+H)+ Rt(HPLC) : 1.19 min (method 5) |
66% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 265 {4-[1-(3-Chloro-phenyl)-1H-[1,2,4]-triazole-3-carbonyl]-3-methyl-piperazin-1-yl}-(6-methoxy-pyridin-2-yl)-methanone A mixture of 200 mg (0.654 mmol) [1-(3-chloro-phenyl)-1H-[1,2,4]-triazol-3-yl]-(2-methyl-piperazin-1-yl)-methanone, 100 mg (0.650 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 225 mg (0.700 mmol) TBTU and 170 muL (1.00 mmol) DIPEA in 3.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, concentrated in vacuo and purified by HPLC.yield: 190 mg (66%)ESI-MS: m/z=441 (M+H)+ Rt(HPLC): 1.19 min (method 5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Intermediate 80 : (2,2-Dimethyl-piperazin- 1 -yl)-(6-methoxy-pyridin-2-yl)-methanone trifluoro acetate 80.1 : 4-(6-Methoxy-pyridine-2-carbonyl)-3,3-dimetyl-piperazine-l-carboxylic acid tert- ester A mixture of 410 mg (2.28 mmol) <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong> and 400 (3.02 mmol) l-chloro-N,N,2-trimethylpropenylamine in 10 mL THF was stirred at RT. After 1.5 h, 600 mg (2.66 mmol) 3,3-dimethyl-piperazine-l-carboxylic acid tert-butyl ester and 1.00 mL (5.81 mmol) DIPEA was added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with saturated NaHCC"3 solution and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc = 1/1). Yield: 780 mg (84 %) ESI-MS: m/z = 350 (M+H)+ Rt(HPLC) : 1.23 min (method 3) | |
84% | 80.1: 4-(6-Methoxy-pyridine-2-carbonyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester A mixture of 410 mg (2.28 mmol) <strong>[26893-73-2]6-methoxy-2-pyridinecarboxylic acid</strong> and 400 muL (3.02 mmol) 1-chloro-N,N,2-trimethylpropenylamine in 10 mL THF was stirred at RT. After 1.5 h, 600 mg (2.66 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 1.00 mL (5.81 mmol) DIPEA was added and the reaction mixture was stirred at RT for 30 min The reaction mixture was diluted with saturated NaHCO3 solution and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=1/1).Yield: 780 mg (84%)ESI-MS: m/z=350 (M+H)+ Rt(HPLC): 1.23 min (method 3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride; In dichloromethane; at 40℃; for 2h; | Intermediate 49: 6-Methoxy-pyridine-2-carbonyl chloride To a mixture of 5.00g (32.7 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong> in 100 mL DCM was added 40.8 mL (81.6 mmol) 2 M oxalyl chloride solution in DCM and stirred at 40 C for 2 h. The solvent was removed by distillation. Yield: 5.60 g (100 %) ESI-MS : m/z = 168 (M+H)+ (methyl ester) Rt(HPLC) : 1.04 min (method 8) (methyl ester) |
100% | With oxalyl dichloride; In dichloromethane; at 40℃; for 2h; | Intermediate 49: 6-Methoxy-pyridine-2-carbonyl chloride To a mixture of 5.00 g (32.7 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong> in 100 mL DCM was added 40.8 mL (81.6 mmol) 2 M oxalyl chloride solution in DCM and stirred at 40 C. for 2 h. The solvent was removed by distillation. Yield: 5.60 g (100%) ESI-MS: m/z=168 (M+H)+ (methyl ester) Rt(HPLC): 1.04 min (method 8) (methyl ester) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 7 : [4-(6-Methoxy-pyridine-2-carbonyl)-2,2-dimethyl-piperazin- 1 -yl]-[ 1 -m-tolyl- 1 H- [ 1 ,2,4]triazol-3yl]-methanone A mixture of 83 mg (0.20 mmol) (2,2-dimethyl-piperazin-l-yl)-(l-m-tolyl-lH-[l ,2,4]triazol-3- yl)-methanone trifluoroacetate, 32 mg (0.20 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 71 mg (0.22 mmol) TBTU and 85 muEpsilon (0.50 mmol) DIPEA in 1.0 mL DMF was stirred at RT for 2 h. The reaction mixture was purified by HPLC. yield: 44.0 mg (51 %) ESI-MS: m/z = 435 (M+H)+ Rt(HPLC): 1.02 min (method 4) |
51% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 7 [4-(6-Methoxy-pyridine-2-carbonyl)-2,2-dimethyl-piperazin-1-yl]-[1-m-tolyl-1H-[1,2,4]triazol-3yl]-methanone A mixture of 83 mg (0.20 mmol) (2,2-dimethyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]triazol-3-yl)-methanone trifluoroacetate, 32 mg (0.20 mmol) <strong>[26893-73-2]6-methoxy-pyridine-2-carboxylic acid</strong>, 71 mg (0.22 mmol) TBTU and 85 muL (0.50 mmol) DIPEA in 1.0 mL DMF was stirred at RT for 2 h. The reaction mixture was purified by HPLC.yield: 44.0 mg (51%)ESI-MS: m/z=435 (M+H)+ Rt(HPLC): 1.02 min (method 4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 50℃; for 4h; | <strong>[26893-73-2]6-methoxypicolinic acid</strong> (40.0 mg, 0.26 mmol) was dissolved in dimethylformamide (1.0 mL). HATU (147.0 mg, 0.39 mmol) was added, followed by diisopropylethylamine (0.18 mL, 1.03 mmol). 2,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-3-amine (79.0 mg, 0.26 mmol) was dissolved in 2.1 mL dimethylformamide and added to the reaction mixture, which was then warmed to 50 C for 4 h. The mixture was cooled to room temp and saturated aqueous NaHCO3 (4 mL) and water (4 mL) were added. An orange precipitate formed, and the mixture was filtered through a glass frit. The solid was washed with water and dried under vacuum, followed by purification by silica gel column chromatography (0-10% gradient MeOH in CH2Cl2) to give N-(2,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-6-methoxypicolinamide (24.0 mg, 21%). MS (ESI) calcd for C22H18F3N4O2: 441.14; found: 442.1 [M+H] |
21% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 50℃; for 4h; | <strong>[26893-73-2]6-methoxypicolinic acid</strong> (40.0 mg, 0.26 mmol) was dissolved in dimethylformamide (1.0 mL). HATU (147.0 mg, 0.39 mmol) was added, followed by diisopropylethylamine (0.18 mL, 1.03 mmol). 2,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-3-amine (79.0 mg, 0.26 mmol) was dissolved in 2.1 mL dimethylformamide and added to the reaction mixture, which was then warmed to 50 C for 4 h. The mixture was cooled to room temp and saturated aqueous NaHCO3 (4 mL) and water (4 mL) were added. An orange precipitate formed, and the mixture was filtered through a glass frit. The solid was washed with water and dried under vacuum, followed by purification by silica gel column chromatography (0-10% gradient MeOH in CH2Cl2) to give N-(2,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-6-methoxypicolinamide (24.0 mg, 21%). MS (ESI) calcd for C22H18F3N4O2: 441.14; found: 442.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 mg | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 2h;pH 9.0; | General procedure: Removal of the Boc protecting group of compound 5 was preformed at room temperature for 1 h with a solution of HCl 4N in dioxane. The mixture was then concentrated in vacuo, diluted with MeOH, and concentrated several times in vacuo. The residue was coupled with various carboxylic acids (1.1 equiv), in the presence of BOP (1.1 equiv) and DIEA (pH=9) for 2 h, in DCM. The mixture was then concentrated in vacuo, and the residue was dissolved in AcOEt. The organic layer was successively washed with aqueous solutions of 1M KHSO4, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield the desired compound. All the final compounds were purified by preparative HPLC on a C18 column using a water/acetonitrile/TFA 0.1% gradient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 13h; | To a solution of 3-aminopyridine (60 mg, 0.6mmol) in DMF (2.0 mL) was added HBTU (315 mg, 0.8 mmol), TEA (0.3 mL, 1.9 mmol) and <strong>[26893-73-2]6-methoxypicolinic acid</strong> (125 mg, 0.8 mmol). After stirring at room temperature for 13 h, the reaction mixture was diluted with EtOAc, washed withH2O. The organic layer was dried over MgSO4, and concentrated. The residue was purified by column (ethylacetate/hexane = 1:1, Rf = 0.28) to give the product 5h (40 mg, 27%) as a white solid; 1HNMR (400 MHz, CDCl3) : delta 4.05 (s, 1H), 6.98-6.96 (d, 1H, J = 8.4 Hz ), 7.34-7.31 (q, 1H, J = 4.1 Hz), 7.81-7.76 (td, 1H, J = 1.6, 7.8 Hz), 7.90-7.88 (d, 1H, J = 7.6 Hz), 8.37-8.36 (d, 1H, J = 2.4 Hz), 8.39-8.38 (d, 1H, J = 3.6 Hz), 8.75 (s, 1H), 9.77 (s, 1H).13C NMR (300 MHz, CDCl3) : delta 53.6, 115.1, 116.0, 123.7,126.8, 134.5, 140.1, 141.3, 145.4, 146.6, 162.5, 162.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A solution of <strong>[26893-73-2]6-methoxypicolinic acid</strong> (2.018g,13.2 mmol) in DCM (70 mL) was treated with DMF (0.1 mL, 1.3 mmol) and oxalylchloride (1.34 mL, 15.8 mmol), after 1 h the solution was cooled to 0 C and N,O-dimethylhydroxylamineHCl (1.42 g, 14.6 mmol) and pyridine (2.34 mL, 28.9 mmol) were added. Themixture was stirred at room temperature for 18 h, sat. aq. NaHCO3 (200mL) was added and the mixture was partitioned between DCM and water. Theorganic fractions were dried and evaporated, column chromatography (97.5:2.5DCM:MeOH) gave N,6-dimethoxy-N-methylpicolinamide (2.372 g, 92%) asan oil. 1H NMR (CD3SOCD3) delta 7.86 (dd, J = 8.3, 7.3 Hz, 1H), 7.66 (dd, J = 7.3, 0.7 Hz, 1H), 7.05 (dd, J = 8.3, 0.7 Hz, 1H), 3.90 (s, 3H), 3.28(bs, 3H). Found: [M+H] = 197.2. | |
92% | General procedure: Oxalyl chloride (1.85 mL, 21.88 mmol) was added to a suspensionof 6-methylpicolinic acid (2.50 g, 18.23 mmol) in DCM (75 mL,anhydrous) and DMF (1.3 mmol) at 20 C. The mixture was stirred at20 C for 1 h to give a colorless solution which was cooled to 0 C. N,ODimethylhydroxylaminehydrochloride (1.95 g, 20.1 mmol) andpyridine (3.25 mL, 40.11 mmol) were added sequentially and themixture was stirred at 20 C for 18 h, then partitioned between EtOAcand sat. aq. NaHCO3. Column chromatography with hexanes:EtOAc 1:1gave N-methoxy-N,6-dimethylpicolinamide as an oil (2.68 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.11 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | A) N-((3S,4R)-1-(8-Chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-6-methoxypicolinamide To a solution of <strong>[26893-73-2]6-methoxypicolinic acid</strong> (0.052 g), ((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone (0.083 g) and N-ethyldiisopropylamine (0.12 mL) in DMF (2.0 mL), HATU (0.13 g) was added at room temperature, and the mixture was stirred for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate/THF. The extract was washed with a saturated aqueous solution of potassium carbonate, water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.11 g). MS: [M+H]+ 502.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N,N-dimethyl-formamide; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of 2-amino-i -[4-[3-(i ,3-dimethylindazol-6-yl)-i ,2,4-oxadiazol-5-yl]-i -piperidyl]ethanone (130 mg, 366.81 imol) in N,N-dimethylformamide (2 mL) was added <strong>[26893-73-2]6-methoxypyridine-2-carboxylic acid</strong> (56 mg, 366.81 imol), (2-(i H-benzotriazol-i -yl)-i ,i 3,3- tetramethyluronium hexafluorophosphate) (166 mg, 440 imol) and N-ethyl-N-(propan-2-yl)propan-2- amine (142 mg, 1.10 mmol, 192 iL). The mixture was stirred at2O 00 for 1 h and concentrated under reduced pressure. The resulting residue was purified by chromatography (column: Luna 018 1 00x30SlIm; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,i0min) to give N[2-[4-[3-(i ,3-dimethylindazol-6-yl)-i ,2,4-oxadiazol-5-yl]-i -piperidyl]-2-oxo-ethyl]-6-methoxy-pyridine-2- carboxamide (92 mg, 187.6 imol, 51 %) as a white solid. 1H NMR (400 MHz, ODd3) O 8.82 (br s, 1 H), 8.10 (s, 1 H), 7.86 - 7.69 (m, 4H), 6.92 (d, J8.2 Hz, 1 H), 4.55 (br d, Ji 3.9 Hz, 1 H), 4.34 (d, J4.2 Hz, 2H), 4.08 (s, 3H), 4.05 (s, 3H), 4.01 - 3.92 (m, 1 H), 3.43 - 3.32 (m, 2H), 3.17 (br t, Ji 1.1 Hz, 1 H), 2.60 (s,3H), 2.34 -2.23 (m, 2H), 2.12 - 1.97 (m, 2H); LOMS (ESI) m/z: [M÷H] 490.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The opportune carboxylic acid (1.46mmol) and 1,1'-carbonyldiimidazole (CDI, 1.46mmol)were dissolved in DMF (10 mL) and stirred for 30 min at r.t.. After this period, the correspondentamidoxime derivatives (1.46 mmol) was added and the reaction mixture was stirred at r.t. overnight.CDI (1.46 mmol) was further added and the reaction mixture was heated at 150 C for 6 h. After coolingdown, the resulting solution was poured into water to induce the precipitation of a solid, which wasfiltered and characterised as pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: [0506] For Examples 175 through 238, a solution of HATU (0.057 g, 0.150 mmol) and DIPEA (0.052 mL, 0,300 mmol) in NMP (0.5 mL) was added to the requisite carboxylic acid R-COOH (0.150 mmol) in a 4 mL vial equipped with a stir bar. After stirring for 5-10 minutes, a solution of 3-amino-4-(4-(2,4-difluorophenoxy)piperidin- l-yl)benzonitrile (0.033 g, 0.1 mmol) in NMP (0.5 mL) was added and the resulting solution was stirred for an additional 30-60 minutes at 100- 140C. The product was purified by preparative HPLC (Phenomenex Gemini-NX C 18, 5 um, 150 mm x 30 mm column) elating with a gradient of 45-100% acetonitrile in water (acid mode) to give each of the title compounds as a TEA salt. The compound in Example 210 was re- dissolved in GCN, treated with Si-carbonate, filtered and evaporated to give the title compound as the free form. EXAMPLE 175: Af-(5-cvno-2-(4-(2,4-difluoro0henoxY 0iperidin-l-Yj)ohenyS -6- (1598) (1599) [0507] ESI-MS m/z [M+H] " 465. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
106 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | Synthesis Method 1 65 mg (0.42 mmol) of <strong>[26893-73-2]6-methoxypyridine-2-carboxylic acid</strong> were dissolved in 2 ml of DMF, 174 mg (0.46 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) were added and the mixture was stirred at room temperature for 30 min. 150 mg (0.35 mmol) of 2-(4-chlorophenyl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylmethyl)imidazo[1,2-a]pyridine dihydrochloride and 0.18 ml (1.06 mmol) of N,N-diisopropylethylamine were then added, and the mixture was stirred further at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 7). 106 mg (0.22 mmol, 62% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=0.70 min; m/z=488/490 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=2.41-2.52 (m, 2H, partially obscured by DMSO signal), 2.55-2.64 (m, 2H), 2.79 (br. s, 2H), 3.44-3.60 (m, 2H), 3.66-3.84 (m, 2H), 3.76 (s, 3H), 4.00-4.13 (m, 2H), 6.84-6.92 (m, 2H), 7.24 (d, 1H), 7.28 (t, 1H), 7.49 (d, 2H), 7.58 (d, 1H), 7.78 (t, 1H), 7.89 (d, 2H), 8.57 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | 46 mg (0.30 mmol) of <strong>[26893-73-2]6-methoxypyridine-2-carboxylic acid</strong> were dissolved in 1.5 ml of DMF, 124 mg (0.33 mmol) of 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) were added and the mixture was stirred at room temperature for 30 min. 100 mg (0.25 mmol) of 2-(4-chlorophenyl)-3-(piperazin-1-ylmethyl)imidazo[1,2-a]pyridine dihydrochloride and 0.13 ml (0.75 mmol) of N,N-diisopropylethylamine were then added, and the mixture was stirred further at room temperature overnight. The reaction mixture was then separated directly into its components by preparative HPLC (Method 6). This gave 81 mg (0.15 mmol, 60% of theory) of the title compound. LC-MS (Method 1): Rt=0.74 min; m/z=462/464 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=2.42-2.48 (m, 2H), 2.48-2.59 (m, 2H, partially hidden by DMSO signal), 3.37-3.47 (m, 2H), 3.55-3.67 (m, 2H), 3.80 (s, 3H), 4.04 (s, 2H), 6.89 (d, 1H), 6.98 (t, 1H), 7.15 (d, 1H), 7.32 (t, 1H), 7.53 (d, 2H), 7.61 (d, 1H), 7.80 (t, 1H), 7.92 (d, 2H), 8.58 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a solution of <strong>[26893-73-2]6-methoxypicolinic acid</strong> (15.0 g, 98.0 mmol, 1 equiv) and 2,6- dimethoxyaniline (16.5 g, 107.8 mmol, 1.1 equiv) in DCM (40 mL) was added DMAP (598 mg, 4.9 mmol, 0.05 equiv) and EDCI (22.5 g, 117.6 mmol, 1.2 equiv) successively at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with DCM (300 mL) and washed with water (3*100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography eluted with PE/ EtOAc (20/1-1/1) to afford the title N-(2,6-dimethoxyphenyl)-6- methoxypicolinamide as a solid (20 g, 71% yield). LC-MS: m/z 289.1 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of <strong>[26893-73-2]6-methoxypicolinic acid</strong> (2.0 g, 13.0 mmol, 1 equiv) in DCM (50 mL) was added oxalyl dichloride (2.5 g, 19.6 mmol, 1.5 equiv) and DMF (0.5 mL) dropwise at 0C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in DCM (100 mL). DIPEA (26 mmol, 3.25 g) and 2,6-dichloroaniline (14.3 mmol, 2.32 g) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc = 2/1) to afford the title compound N-(2,6-dichlorophenyl)-6-methoxypicolinamide as a white solid (1.9 g, 50% yield). LC-MS: m/z 297.0 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride; at 20℃; for 1h; | Compound 1 (<strong>[26893-73-2]6-methoxypyridine-2-carboxylic acid</strong>, 5.0 g, 32.7 mmol) was dissolved in HCl / MeOH (4M, 100 mL) and stirred at room temperature for 1 h; after the reaction was completed, the solvent was distilled off to obtain a yellow oily compound (5.4 g, 32.3 mmol).Yield: 99%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 6-Methoxypyridine-2-carboxylic acid (35.1 mg, 230 mumol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 mumol) was added and the mixture was stirred at room temperature for 30 min. 7-[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3-oxa-7,9-diazabicyclo[3.3.1]nonane dihydrochloride (100 mg) and N,N-diisopropylethylamine (180 mul, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 74 mg (0.15 mmol, 70% of theory) of the title compound were obtained. (0576) LC-MS (Method 2): Rt=1.48 min; m/z=505/507 (M+H)+. (0577) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=2.46-2.66 (m, 2H, partially obscured by DMSO signal), 2.91 (br. d, 1H), 3.05 (br. d, 1H), 3.66-3.83 (m, 3H), 3.80 (s, 3H), 3.89 (d, 1H), 3.93-4.03 (m, 2H), 4.20 (br. s, 1H), 4.44 (br. s, 1H), 6.93 (d, 1H), 7.09 (dd, 1H), 7.29 (d, 1H), 7.54 (d, 2H), 7.83 (t, 1H), 7.97 (d, 2H), 8.58 (dd, 1H), 9.28 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 6-Methoxypyridine-2-carboxylic acid (36.4 mg, 237 mumol) was dissolved in 1.5 ml of DMF, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (119 mg, 313 mumol) was added and the mixture was stirred at room temperature for 30 min. 2-(4-Chlorophenyl)-3-(3,8-diazabicyclo[3.2.1]oct-3-ylmethyl)imidazo[1,2-a]pyrimidine dihydrochloride (100 mg) and N,N-diisopropylethylamine (190 mul, 1.1 mmol) were then added and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was separated directly into its components via preparative HPLC (Method 8). 79 mg (0.16 mmol, 74% of theory) of the title compound were obtained. (0603) LC-MS (Method 1): Rt=1.76 min; m/z=489/491 (M+H)+. (0604) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.63-1.84 (m, 4H), 2.45 (br. d, 1H), 2.56-2.65 (m, 2H), 2.73 (dd, 1H), 3.77 (s, 3H), 4.00-4.12 (m, 2H), 4.67 (br. d, 2H), 6.93 (d, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.57 (d, 2H), 7.82 (t, 1H), 7.96 (d, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). |
Tags: 26893-73-2 synthesis path| 26893-73-2 SDS| 26893-73-2 COA| 26893-73-2 purity| 26893-73-2 application| 26893-73-2 NMR| 26893-73-2 COA| 26893-73-2 structure
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