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CAS No. : | 37718-11-9 | MDL No. : | MFCD00011558 |
Formula : | C4H4N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IMBBXSASDSZJSX-UHFFFAOYSA-N |
M.W : | 112.09 | Pubchem ID : | 3015937 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 25.55 |
TPSA : | 65.98 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) : | -7.17 cm/s |
Log Po/w (iLOGP) : | 0.06 |
Log Po/w (XLOGP3) : | -0.26 |
Log Po/w (WLOGP) : | 0.11 |
Log Po/w (MLOGP) : | -0.81 |
Log Po/w (SILICOS-IT) : | 0.44 |
Consensus Log Po/w : | -0.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.77 |
Solubility : | 19.1 mg/ml ; 0.171 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.67 |
Solubility : | 24.1 mg/ml ; 0.215 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.55 |
Solubility : | 31.7 mg/ml ; 0.282 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
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 |
---|---|---|
78% | at 70℃; for 20 h; | 1 H-pyrazole-4-carboxylic acid (20 g, 178.4 mmol) and sulfuric acid (39.65 ml)in MeOH (200 ml) were heated at 70°C for 20 h. The reactbn mixture was cooled to room temperature and concentrated in vacuo. Aqueous NaOH solution was added to adjust the pH to ~6. The aqueous layer was extracted with EtOAc (3 x 200 ml) and the combined organic extracts were dried (MgSQ;), filtered and evaporated in vacuo to afford the title compound (18.5 g , 78percent) as a white solid. 1 H-NMR (CDCI3, 500 MHz): d[ppm]= 8.10 (s, 2H), 3.87 (s, 3H) HPLCMS (Method A): [m/z]: 126.85 [M+H]+ |
5 g | at 10 - 35℃; | A) methyl 1H-pyrazol-4-carboxylate A mixture of 1H-pyrazol-4-carboxylic acid (4.00 g) and 4 M hydrogen chloride/methanol solution (150 mL) was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure to give the title compound (5.0 g). 1H NMR (400 MHz, DMSO-d6) δ 3.72 (3H, s), 8.09 (2H, s), 11.62 (1H, s). |
4.5 g | at 0℃; Reflux | To a mixture of lH-pyrazole-4-carboxylic acid (5.00 g, 44.6 mmol) in dry CH3OH (100 mL) was added drop-wise H2S04 (874 mg, 8.92 mmol) at 0°C. The mixture was stirred at reflux overnight. A solution of NaOH (3.83 g, 95.7 mmol, 10 N) was added drop- wise to the reaction mixture. The mixture was poured into ice-water and diluted with ethyl acetate. The organic layer was washed with saturated aqueous lithium chloride solution and brine successively, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 10 : 1) to give methyl 1H- pyrazole-4-carboxylate (4.50 g) as a white solid. LC-MS (ESI) found: 127 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | With hydrogenchloride In methanol; water | 3. Preparation of 4-carbomethoxypyrazole (5): To an ice cold saturated solution of HCl in methanol (500 ml), pyrazole-4-carboxylic acid (4) (19.2 g, 0.17 m) was added and the solution stirred at 0° C. for 3 hours and at ambient temperature overnight. The solvent was distilled off and the brown residue was dissolved in water. The aqueous solution was neutralized with NaHCO3 and the product was repeatedly extracted with ether (25*100 ml). The ether extract was dried over Mg SO4 and concentrated to give the methyl ester (5) as a pale yellow solid (13.59 g, 79.6percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 23℃; for 17h; | To a solid mixture of N-[((5S)-3-{O4-[exo-(1R,5S)-3-azabicyclo [3.1. 0] hex-6- YL]-3-FLUOROPHENYL}-2-OXO-1, 3-oxazolidin-5-yl) methyl] acetamide (0.12 g, 0.36 mmol, 1 equivalent), HOBT (74 mg, 0.54 mmol, 1.5 equiv. ), EDCI (120 mg, 0.626 mmol, 1.74 equiv. ) and <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> (47 mg, 0.42 mmol, 1.2 equiv. ) at 23°C was added DMF (5 mL), followed by DIEA (0.3 mL, 1.7 mmol, 4.7 equiv. ). The reaction mixture was stirred at the same temperature for 17 hours, diluted with saturated NaHC03 aqueous and extracted with CH2C12 (3X100 mL). The combined organic layers were washed (H20, brine), dried (NaSO4), filtered and evaporated to dryness. The crude product was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 5percent methanol in methylene chloride. Relevant fractions were combined to give the title compound. Yield 0.059 g (38percent). MS (m/z): [M+H] + = 428. HPLC (SYMMETRY C18 3.5 JIM, 4.6 x 30 mm column; gradient elution 2percent- 98percent MECN with 0. 1percent TFA over 5 min; 2 mL/min rate): retention time = 1.71 min. H NMR (300 MHz, DMSO-d6): 1.69 (m, 1H), 1.81 (s, 3H), 1.99 (bs, 1H), 2.07 (bs, 1H), 3.39 (t, J=5. 4 Hz, 2H), 3.52 (m, 1H), 3.69 (m, 1H), 3.98 (m, 3H), 4.08 (t, J=8. 7 Hz, 1H), 4.71 (m, 1H), 7.09 (t, J=8. 7 Hz, 1H), 7.19 (m, 1H), 7.44 (dd, J=12. 9 Hz, 2.1 Hz, 1H), 7.82 (s, 1H), 8.16 (s, 1H), 8.24 (t, J=6. 0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid; In DMF (N,N-dimethyl-formamide); ethyl acetate; at 20℃; for 3h; | Step 1 : Preparation of L-(TETRAHYDRO-PYRAN-2-YL)-LH-PYRAZOLE-4-CARBOXYLIC acid :; To a solution of 4-pyrazole carboxylic acid (6. 3 mmol, 947 mg) in ETOAC/DMF (50/5ML) at room temperature was added 3, 4-dihydro-2H-pyran (12. 45mmoles, 1. 135ML) followed bypara-toluenesulfonic acid (0. leq, 79mg). The mixture was stirred for 3 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue partitioned between saturated aqueous sodium carbonate (150ml) and EtOAc (50ML), the aqueous layer was decanted and acidified to pH 5 then extracted with EtOAc (4X100ML). The EtOAc layers were combined, dried over NA2S04 and concentrated to afford the title compound as a white solid (1. 46g, 90%). LH NMR (400 MHz, DMSO-d6) 5 12. 44 (s, 1H, Broad) ; 8. 36 (s, 1H, Broad) ; 7. 84 (s, 1H) ; 5. 44 (dd, 1H, J=9. 9, 2. 1) ; 3. 96-3. 91 (m, 1H) ; 3. 65- 3. 59 (m, 1H) ; 2. 15-2. 05 (m, 1H) ; 1. 94-1. 87 (m, 2H) ; 1. 71-1. 60 (m, 1H) ; 1. 56-1. 48 (m, 1H). LCMS : method A, Rt =1. 95 min, [MH+=197]. |
70% | With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 20℃; for 20h; | Step 6.1, 1-(tetrahydro-2H-pyran-2-yl)-<strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50 C. to give 61.2 g of a white powder (yield: 70%). |
70% | With toluene-4-sulfonic acid; at 20℃; for 20h; | Step 6.1. 1 -(tetrahydro-2H-pyran-2-yl)-1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> To a suspension of 1 /-/-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHC03 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50C to give 61.2 g of a white powder (yield: 70%). LCMS (Method D): MH+ = 197.1 , RT = 0.60 min |
70% | With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 20℃; for 20h; | Step 6.1. 1-(tetrahydro-2H-pyran-2-yl)-<strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50C to give 61.2 g of a white powder (yield: 70%). LCMS (Method D): MH+= 197.1, RT = 0.60 min |
70% | With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 5 - 25℃; for 20h; | To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50 C. to give 61.2 g of a white powder (yield: 70%). [0867] LCMS (Method D): MH+=197.1, RT=0.60 min |
70% | With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 20℃; for 20h;Darkness; | To a suspension of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (50 g, 446 mmol) in 500 ml DMF was added p-toluenesulfonic acid(8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol).The reaction medium turned yellow and then changed at room temperature for 20 hoursblack. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The aqueous phase was added by the addition of 6M hydrochloric acid solutionTo pH = 3. The resulting precipitate was filtered off and washed with water and then dried in vacuo at 50 C to give 61.2 g of a white powder(Yield: 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of tert-butyl { [(5S)-5-(hydroxymethyl)tetrahydro-2H-pyran-2- yl] methyl} carbamate (300 mg, 1.22 mmol) and 3,4-difluorophenol (397.7 mg, 3.06 mmol) in THF (4.9 mL), were added PPh3 (737.7 mg, 2.81 mmol) and DIAD (0.56 mL, 2.32 mmol) at 0 °C. The mixture was irradiated by microwave at 180 °C for 5 min. Then the mixture was cooled to room temprature and was diluted AcOEt. The oganic layer was washed with 2N NaOH aq. and brine. The organic layer was dried over Na2SO4, was filtered and evaporated. The crude product was purified by silica gel column chromatography (hexane: AcOEt = 50: 1-20: 1) to give tert-butyl ({(2R, SR)-5-[(3, 4- difluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl} methyl) carbamate (55.5 mg, 0.155 mmol) This was dissolved in HCl-MeOH (1 mL) and the mixture was stirred at 40 °C for 2hr. The mixture was evaporated to give the crude amine. The amine was dissolved in DMF (2 mL) and were added lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (17.4 mg, 0.155 mmol), Et3N (0.064 mL, 0.466 mmol), HOBt (28.5 mg, 0.186 mmol) and WSC (35.6 mg, 0.186 mmol) at 0 °C. The mixture was stirred at room temperature overnight. 2N NaOH aq was added to the mixture and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with AcOEt and the organic layer was washed with brine. The organic layer was dried over Na2S04, was filtered and evaporated. The crude product was purified by silica gel column chromatography (CH2CI2 : MeOH = 20 : 1) to give the titled compound. 'H NMR (DMSO-d) 6 : 13.08 (br, 1H), 8.17-7. 92 (m, 3H), 7.35-7. 25 (m, 1H), 7.13-7. 05 (m, 1H), 6. 84-6. 75 (m, 1H), 4.14 (t, J = 9.1 Hz, 1H), 4.03-3. 87 (m, 2H), 3.58-3. 11 (m, 4H), 1.94 (br, 1H), 1. 88-1. 64 (m, 2H), 1.53-1. 29 (m, 2H) ppm. MS (ESI): 352.20 (M+H) +, 350.15 (M-H)- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of LiAlH4 (119.7 mg, 3., 15 mmol) in THF (10 mL) the solution of 2- (azidomethyl)-5- [ (4-chlorophenoxy) methyl] tetrahydro-2H-pyran (444.3 mg, 1. 58 mmol) in THF (6 mL) was added at 0 °C. Then the mixture was stirred at 0 °C for 1.25 hr. The reaction was quenched by Na2S04-10H20 (1. 6 g, 4.97 mmol) and KF (200 mg, 3.44 mmol). The mixture was stirred at room temperature for lhr. The mixture was filtered through a pad of celite and the filtrate was evaporated to give the crude compound. To a solution of the crude compound in DMF (5 mL), were added lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (177.1 mg, 1.58 mmol), HOBt (290.4 mg, 1.90 mmol) and WSC (363.5 mg, 1.90 mmol) at 0 °C. The mixture was stirred at room temperature overnight. 2N NaOH aq was added to the mixture and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with AcOEt and the organic layer was washed with brine. The organic layer was dried over Na2S04, was filtered and evaporated. The crude product was purified by silica gel column chromatography (CHzCI2 : MeOH = 20 : 1) to give the mixture of 4 stereoisomers. 4 stereoisomers were separated by Chiral column (Chiralcel OJ-H, 20 mm I. D. x 250 mm (No. OJHOCJ-DH004), DAICEL) using n-Hexane: EtOH: Et2NH = 88: 12: 0.1 as an eluent (18. 9 mLJmin). Example 120 N-({(2R,5R)-5-[(4-Chlorophenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole- 4-carboxamide Retention time 12 min-20 min (13 min) lH NMR (DMSO-d) 8 : 13. 10 (br, 1H), 8.23-7. 83 (m, 3H), 7.33 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 9.0 Hz, 1H), 4.05-3. 86 (m, 2H), 3. 58-3. 12 (m, 4H), 1.95 (br, 1H), 1.89-1. 66 (m, 2H), 1.53-1. 20 (m, 2H) ppm. MS (ESI) : 350.05 (M+H) +, 348. 06 (M-H)- Example 121 N-({(2S,5S)-5-[(4-Chlorophenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole- 4-carboxamide Retetntion time 20 min-24 min (22 min) 'H NMR (DMSO-d) b : 13.09 (br, 1H), 8. 20-7. 85 (m, 3H), 7.32-7. 28 (m, 2H), 7.04-6. 94 (m, 2H), 4.14 (t, J= 8.7 Hz, 1H), 4.05-3. 86 (m, 2H), 3.60-3. 10 (m, 4H), 1.95 (br, 1H), 1. 86-1. 64 (m, 2H), 1.53-1. 20 (m, 2H) ppm. MS (ESI): 350.04 (M+H)+, 348.06 (M-H)- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With thionyl chloride; for 18h;Heating / reflux; | Step B: 1H-pyrazole-4-carbonyl chloride; A mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (1.03 g, 9.2 mmol) in thionyl chloride (20 mL) was heated for 18 h at reflux. Upon evaporation, 1.16 g (97percent) of a white solid was obtained. |
97% | With thionyl chloride; for 18h;Reflux; | Step B: 1H-pyrazole-4-carbonyl chlorideA mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (1.03 g, 9.2 mmol) in thionyl chloride (20 mL) was heated for 18 h at reflux. Upon evaporation, 1.16 g (97percent) of a white solid was obtained. |
With thionyl chloride; at 90℃; for 18h; | Step 1: 4-pyrazolecarbonyl chloride A mixture of <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> (600 mg) in thionyl chloride (5 mL) was heated to 90° C. under nitrogen. After 18 hr., the mixture was allowed to cool to room temperature and the solvent removed in vacuo to provide 579 mg of 4-pyrazolecarbonyl chloride 12, which was used without further purification for the next step (Step 2). El-HRMS m/e calcd for C16H11N3OS (M+) 293.0623, found 293.0621. |
With thionyl chloride; In dichloromethane; at 40℃; | A 250-mL round-bottom flask was charged with lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (5.00 g, 44.6 mmol, 1.00 equiv), DCM (50 mL), and thionyl chloride (21.3 g, 179 mmol, 4.00 equiv). The resulting solution was stirred overnight at 40 °C and concentrated under reduced pressure to provide 6.00 g (crude) of lH-pyrazole-4-carbonyl chloride as a white solid. | |
With oxalyl dichloride; N,N-dimethyl-formamide; at 0 - 30℃; for 2h; | In a 3L three-necked bottle, <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (SM1, 112.0 g, 1.0 mol) and DMF (500 ml) were added and controlled.The system temperature is 0-5°C, and a solution of 254 g (2.0 mol) oxalyl chloride in DMF (500 ml) is slowly added dropwise to the solution of oxalyl chloride in DMF.During the liquid process, the temperature of the control system is maintained at 0-5°C. After the DMF solution of the acyl chloride reagent is added dropwise,Warm to room temperature (25-30°C) and stir for 2h. Then spin to obtain <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> chloride; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | <strong>[37718-11-9]1H-Pyrazole-4-carboxylic acid</strong> (300 mg, 2.1 mmol), 4-(2-chloroethyl)morpholine (822 mg, 4.3 mmol) and potassium carbonate (1.2 g, 8.6 mmol) are dissolved in dimethylformamide (12 ml) and stirred for 6.5 h at 75° C. Aftr stnding for another 18 h at ambient temperature, the reaction mixture was treated with water (25 ml) and extracted four times with ethyl acetate (25 ml each). The combined organic layers are extracted four times with water, dryed with magnesium sulphate and evaporated in vacuo. Flash chromatography (silice, eluent dichloromethane containing 4percent methanol) afforded the title compound as colorles liquid (70percent yield). MS: m/e=254(M+H+). Following the general method of example 30 the compounds of examples 31 to 32 were prepared. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.6 g(90%) | In methanol; | Methyl 3-pyrazolcarboxylate hydrochloride 10 mL of methanol at 0° C. was treated dropwise with lmL acetyl chloride, followed by addition of 2.0 g(17.84 mmol) of 4-pyrazolcarboxylic acid, followed by warming the mixture at reflux for 18 h. The solution was cooled and concentrated in vacuo to afford 2.6 g(90percent) of the title compound as a white solid. 1 H NMR (CD3 OD) delta8.25, 3.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium chloride; sodium hydrogencarbonate; triethylamine; In N-methyl-acetamide; | EXAMPLE 13 N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]pyrazole-4-carboxamide A solution of 2.39 g of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1.08 g of <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> in 40 ml of dry dimethylformamide was stirred for 5 minutes, whilst ice-cooling. 1.89 g of diethyl cyanophosphonate and 1.65 ml of triethylamine were added to the mixture, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.65 g (yield 51percent) of the title compound as a white powder, melting at 121°-123° C. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.38-1.52 (2H, multiplet); 1.52-1.66 (4H, multiplet); 2.32-2.48 (4H, multiplet); 3.42 (2H, singlet); 4.16 (2H, triplet, J=5.6 Hz); 4.95 (2H, doublet, J=5.9 Hz); 5.72-5.96 (2H, multiplet); 6.74 (1H, singlet); 6.81 (1H, broad triplet, J=5.6 Hz); 6.87 (1H, doublet, J=5.3 Hz); 7.99 (2H, singlet); 8.03 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (KBr), numax cm-1: 2933, 1629, 1611, 1566, 1530, 1408, 1342, 1299. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium chloride; sodium hydrogencarbonate; triethylamine; In N-methyl-acetamide; | EXAMPLE 64 N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-pyrazole-4-carboxamide A solution of 1.0 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.45 g of <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> dissolved in 15 ml of dimethylformamide was stirred for 5 minutes, whilst ice-cooling, after which 734 mg of diethyl cyanophosphonate and 0.68 ml of triethylamine were added to the resulting mixture. The mixture was then stirred at room temperature for 3 hours, after which it was diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.2 g (yield 85%) of the title compound as a white powder, melting at 117-119 C. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.39-1.47 (2H, multiplet); 1.50-1.62 (4H, multiplet); 1.99-2.11 (2H, multiplet); 2.34-2.44 (4H, multiplet); 3.41 (2H, singlet); 3.55 (2H, quartet, J=5.9 Hz); 4.42 (2H, triplet, J=5.9 Hz); 6.72 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.16 (2H, broad triplet, J=5.9 Hz); 7.99-8.05 (2H, multiplet); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (KBr), numax cm-1: 3250, 2935, 1631, 1607, 1566, 1421, 1386, 1302, 1212. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | EXAMPLE 28 N-{4-[4-(1-Pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}pyrazole-4-carboxamide Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 57°-61° C., in a 34percent yield. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.75-1.90 (4H, multiplet); 2.50-2.67 (4H, multiplet); 3.61 (2H, singlet); 4.17 (2H, triplet, J=5.9 Hz); 4.95 (2H, doublet, J=6.4 Hz); 5.69-5.92 (2H, multiplet); 6.72 (1H, broad triplet, J=5.4 Hz); 6.77 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 7.96 (2H, singlet); 8.04 (1H, doublet, J=5.4 Hz). Infrared Absorption Spectrum (KBr), numax cm-1: 2962, 1626, 1610, 1568, 1539, 1421, 1410, 1400. |
Yield | Reaction Conditions | Operation in experiment |
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71% | EXAMPLE 65 N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-pyrazole-4-carboxamide Following a procedure similar to that described in Example 64, but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 145°-147° C., in a 71percent yield. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm. 1.39-1.50 (2H, multiplet); 1.53-1.62 (4H, multiplet); 1.71-1.92 (4H, multiplet); 2.31-2.42 (4H, multiplet); 3.41 (2H, singlet); 3.49 (2H, doublet of doublets, J=12.5 and 6.6 Hz); 4.29 (2H, doublet of doublets, J=11.2 and 6.1 Hz); 6.36-6.42 (1H, broad); 6.71 (1H, singlet); 6.85 (1H, doublet, J=5.3 Hz); 7.96 (2H, singlet); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (KBr), numax cm-1: 3335, 2940, 1628, 1619, 1560, 1426, 1366, 1299, 992. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 66 N-[5-(4-Piperidinomethyl-2-pyridyloxy)pentyl]pyrazole-4-carboxamide Following a procedure similar to that described in Example 64, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 105°-106° C., in a yield. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.42-1.60 (4H, multiplet); 1.60-1.74 (6H, multiplet); 1.76-1.88 (2H, multiplet); 2.40-2.63 (4H, multiplet); 3.43 (2H, quartet, J=6.7 Hz); 3.51 (2H, singlet); 4.27 (2H, triplet, J=6.3 Hz); 6.15-6.25 (1H, broad); 6.75 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.96 (2H, singlet); 8.07 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl3), numax cm-1: 3460, 2930, 1640, 1610, 1570, 1418, 1320. |
Yield | Reaction Conditions | Operation in experiment |
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INTERMEDIATE 61H N-N1 H-Pyrazole-4-carboxamide The mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (2.0 g, 17.8 mmol) and thionyl chloride (20 mL, 168 mmol) was heated to reflux. After 4 h, the reaction mixture was concentrated, and then dried at reduced pressure for 0.5 h. The resulting residue was dissolved in CH2Cl2 (35 mL), cooled to 0 C and added to a solution of ammonium hydroxide (46.8 mL, 357 mmol) in CH2Cl2 (20 mL). The reaction mixture was warmed to rt and stirred for 12 h. After which point, the mixture was concentrated and CH3OH /CHiCl2 (1 : 10, 40 ml) were added and stirred for 10 min. The solution was filtered and washed with CH3OH /CH2Cl2 (1:10). The filtrate was concentrated to give the title compound (1.5 g), which was used in the next step without purification. LC/MS: m/e 112.0 (M+H)+. | ||
Description 16;. llZ-Pyrazole-4~carboxamideA solution of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (56 mg, 0,50 mmol) in thionyl chloride (4 mL) was heated at 75°C for 4 hours. After cooling, the solution was evaporated to dryness. The residue was dissolved in dioxane (5 mL) and this solution was added to a rapidly stirred solution of ammonium hydroxide in water. After 1 hour the mixture was evaporated to dryness to give the title compound. | ||
The mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (2.0 g, 17.8 mmol) and thionyl chloride (20 mL, 168 mmol) was heated to reflux. After 4 h, the reaction mixture was concentrated, and then dried at reduced pressure for 0.5 h. The resulting residue was dissolved in CH2Cl2 (35 mL), cooled to 0° C. and added to a solution of ammonium hydroxide (46.8 mL, 357 mmol) in CH2Cl2 (20 mL). The reaction mixture was warmed to rt and stirred for 12 h. After which point, the mixture was concentrated and CH3OH/CH2Cl2 (1:10, 40 ml) were added and stirred for 10 min. The solution was filtered and washed with CH3OH/CH2Cl2 (1:10). The filtrate was concentrated to give the title compound (1.5 g), which was used in the next step without purification. LC/MS: m/e 112.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; n-butyllithium; In hexane; water; | 2. Preparation of Pyrazole -4-carboxylic acid (4): To a solution 4-bromopyrazole (3) (3.82 g, 0.026 m) in ether (30 ml) at -78° C., was added a solution of 2-4 M n-butyllithium in hexane (21.7 ml, 0.052 m) in drops over a period of 40 minutes. After stirring at -78° C. for 31/2 hours, the solution was warmed to ambient temperature and stirred for a further period of 5 hours. The solution was cooled again to -78° C. and excess dry ice was added. After stirring for 2 hours at -78° C., the reaction mixture was allowed to warm to ambient temperature overnight. Water was added to quench the reaction and the heterogeneous mixture was neutralized to ph 7 by the careful addition of concentrated HCl. The mixture was further diluted with water to dissolve all the solids and was washed with ether. Water was removed from the aqueous layer by distillation under vacuum to yield an off-white solid (4.38 g, crude 4). The product was not purified and was carried on for the subsequent reaction. |
Yield | Reaction Conditions | Operation in experiment |
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2.6 g (90%) | In methanol; | Methyl 3-pyrazolecarboxylate hydrochloride 10 mL of methanol at 0° C. was treated dropwise with 1 mL acetyl chloride, followed by addition of 2.0 g (17.84 mmol) of <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong>, followed by warming the mixture at reflux for 18 h. The solution was cooled and concentrated in vacuo to afford 2.6 g (90percent) of the title compound as a white solid. 1 H NMR (CD3 OD) delta 8.25, 3.86. |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 20h; | Example 36; (R)-1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (4-(3,4-dimethoxy-phenyl)-4-{1 ,3-dioxo-4-[4-(1 R)-(I -phenyl-ethyl)-piperazin-1 -yl]-1 ,3-dihydro- isoindol-2-yl}-butyl)-amide Cpd 190; A 50-mL round bottom flask was charged with Compound 23I (30 mg, 0.05 mmol) and dimethylformamide (1.0 mL). The mixture was cooled using an ice/water bath. N-Methylmorpholine (NMM) (16.0 muL, 0.147 mmol), <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> (9.0 mg, 0.08 mmol), hydroxybenzotriazole hydrate (HOBT) (6.0 mg, 0.044 mmol), and O-benzotiazoM-yl-N.N.N'.N'- <n="261"/>tetramethyluronium hexafluorophosphate (HBTU) (37 mg, 0.10 mmol) were added. The mixture was stirred at room temperature for 20 h. The mixture was diluted with ethylacetate (100 mL), washed with 1 N sodium hydroxide (2 X 30 mL), and saturated aqueous sodium chloride (30 mL). The organic layer was dried using Na2SO4, filtered through Celite.(R)., and concentrated in vacuo. The crude material was purified on a Gilson HPLC with a reversed phase Kromasil column (10t/, 1OpsiA C18, column length 250x50 mm, gradient 85:15-0:100 H2O:MeCN) to give 10.0 mg of the title Compound 190 as a yellow solid. 1H NMR (300 MHz, CDCI3) delta 8.07 (s, 1 H), 7.58 (ovdd, J = 8.0 Hz, 1 H), 7.41-7.49 (m, 6 H), 6.98-7.09 (m, 3 H), 6.77- 6.88 (m, 3 H), 6.40-6.51 (m, 1 H), 5.20-5.24 (m, 1 H), 4.34-4.36 (m, 1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.71-3.80 (m, 3 H), 3.36-3.51 (m, 5 H), 2.92-3.18 (m, 3 H), 2.62- 2.74 (m, 1 H), 2.19-2.28 (m, 1 H), 1.85 (d, J = 5.9 Hz, 3 H), and 1.51-1.75 (m, 2 H); MS (ES+) 637.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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In toluene; at 70 - 78℃; for 21.25h; | Description 13: 1 H-Pvrazole-4-carboxylic acid ter-butyl ester A stirred suspension of 1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (1. 12g) in dry toluene (20ml) was heated at 70°C for 15min under an atmosphere of nitrogen. To the hot suspension was added a solution of N, N-dimethylformamide-di-tert-butyl acetal (8ml) in dry toluene (8ml). The resultant solution was heated at 78°C for 21 hrs. After cooling, the mixture was diluted with ethyl acetate (100ml) and washed with saturated aqueous brine solution (5x25mi). The organic phase was dried over magnesium sulphate, filtered, and evaporated to dryness to give a gum. The gum was purified by flash column chromatography on silica gel (60g of Merck 9385) and eluted with dichloromethane/methanol 50: 1. The required fractions were combined and evaporated to dryness to give the title compound as a gum which solidified upon standing (0.481g). Mpt. 96-97 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a solution of ethyl 1 H-pyrazole-4-carboxylate (0.475 g, 3.39 mmol) and potassium carbonate (0.56 g, 4.05 mmol) in DMF (20 ml.) was added dropwise 1 ,2-dichloro-4-(bromomethyl)benzene (0.98 g, 4.08 mmol) and the reaction mixture was stirred at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue was diluted with water and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/EtOAc: 92/8 to give the title compound as a white solid (0.92 g, 91percent). LC/MS: m/z 299 (M+H)+, Rt:3.44 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 24h; | A N, N-dimethylformamide solution (3 mL) of 4- <n="216"/>pyrazolecarboxylic acid (150 mg, 1.34 mmol) , N,0- dimethylhydroxylamine hydrochloride (261.4 mg, 2.68 mmol), 1 -ethyl -3- (3-dimethylaminopropyl) carbodiimide, hydrochloride (513.8 mg, 2.68 mmol), 1- hydroxybenzotriazoleimidazole anhydride (54.2 mg, 0.40 mmol), and triethylamine (0.38 mL, 2.68 mmol) was stirred for 1 day. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (142.7 mg) .Morphology: colorless oil 1H-NMR(CDCl3) delta: 2.89 (s, 3H), 2.96 (s, 3H), 8.03 (s, 1H), 8.13 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 18 - 25℃; for 2h; | STEP D(4-((l-(2-(dimethylamino)ethyl)-2-neopentyl-lH-benzo[dlimidazol-5-ylsulfonyl)met hvDpiperidin- 1 - yl) ( 1 H-p yrazol-4- vDmethanone . [Chem.94][0450] To a solution ofN,N-dimethyl-2-(2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-lH-benzo[d]imidazol- 1-yl) ethanamine (STEP C, 687 mg, 1.63 mmol) in dichloromethane (8 mL) were added triethylamine (230 microL, 1.63 mmol), lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (201 mg, 1.80 mmol) and O-benzo- triazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (638 mg, 1,68 mmol) at room temperature. After 2 h, the mixture was diluted with dichloromethane (80 mL) and washed with sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by amine gel column chromatography (ethyl acetate - methanol, gradient) to give the title compound (757 mg, 90percent) as a pale yellow grease.[0451 ] MS (ESI) m/z 515 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; | (1) Preparation of 4-(1H-pyrazol-4-ylcarbonyl)morpholine A suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (1.05 g), 1-{3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (2.5 g), 1-hydroxybenzotriazole hydrate (1.6 g) and morpholine (1.2 g) in chloroform (18 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluding solvent: chloroform:methanol = 100:0 to 95:5) and silica gel column chromatography (eluding solvent: chloroform:methanol = 100:0 to 90:10). The resulting colorless solid was washed with ethyl acetate to give the titled compound (1.00 g) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
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10% | To a solution of Preparation 28 (0.15 g, 0.33 mmol) and 1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (55 mg, 0.39 mmol) in DMF (3 mL) NaH (40 mg, 1 mmol) was added and mixture stirred overnight at r.t and for 6h at 60°C. Reaction was stopped by adding 2N HCl and product extracted with dichloromethane. The crude thus obtained was purified according to the General Purification Method to give the title compound (10percent yield). LRMS: m/z 475 (M+1)+ Retention time: 19.55 min (Method C) 1H NMR (300 MHz, DMSO-d6) delta ppm 1.03 (s, 6 H) 1.55 (t, J=6.32 Hz, 2 H) 2.34 (s, 6 H) 2.48 (s, 2 H) 2.81 (t, J=5.63 Hz, 2 H) 3.19 (m, 2 H) 3.82 (s, 3 H) 4.31 (t, J=7.42 Hz, 2 H) 7.73 (s, 2 H) 7.84 (s, 1 H) 8.18 (s, 1 H). | |
10% | To a solution of Preparation 28 (0.15 g, 0.33 mmol) and 1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (55 mg, 0.39 mmol) in DMF (3 mL) NaH (40 mg, 1 mmol) was added and mixture stirred overnight at r.t and for 6h at 60°C. Reaction was stopped by adding 2N HCI and product extracted with dichloromethane. The crude thus obtained was purified according to the General Purification Method to give the title compound (10percent yield). LRMS: m/z 475 (M+1)+ Retention time: 19.55 min (Method C)1H NMR (300 MHz, DMSO-d6) delta ppm 1.03 (s, 6 H) 1.55 (t, J=6.32 Hz, 2 H) 2.34 (s, 6 H) 2.48 (s, 2 H) 2.81 (t, J=5.63 Hz, 2 H) 3.19 (m, 2 H) 3.82 (s, 3 H) 4.31 (t, J=7.42 Hz, 2 H) 7.73 (s, 2 H) 7.84 (s, 1 H) 8.18 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.5h; | c)tert-butyl (5-((1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamateThe starting material ethyl pyrazole-4-carboxylate was saponified in analogy to Example 157, Step a), To a solution of the free acid (1 g, 5.86 mmol) in DMF (40 ml) were added DIPEA (4.10 ml, 23.46 mmol) and tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (1.531 g, 6.45 mmol).At 0° C., propylphosphonic anhydride (50percent in DMF, 3.42 ml, 5.86 mmol) was added dropwise.Reaction mixture was stirred for 30 min at 0° C., then diluted with ethyl acetate and water.Phases were separated and organic layer was washed with NaHCO3 sat. solution and brine.Organic layer was dried over sodium sulfate, filtered and evaporated to afford the crude material, which was purified by silicagel chromatography (DCM/MeOH from 100/0 to 9/1 in 30 min) to afford the title compound. HPLC (Method G) Rt=1.209 min, MS (Method V) [M+H]+=332.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Iota,Gamma-Carbonyldiimidazole (4.9 g, 30.7 mmol) is added to a mixture of lH-pyrazole-4- carboxylic acid (3.4 g, 30.7 mmol) in 1,4-dioxane (150 ml). The mixture is stirred at 50°C for 30 minutes, 1- 16 is added and the reaction mixture is heated at 85°C for 48 hours. The reaction mixture is cooled to room temperature, poored into a solution of saturated NaHC03 and extracted with EtOAc. The organic layers are dried over MgS04, filtered and concentrated to afford the crude product that is purified via flash chromatography (Si02, 0-6percent MeOH/CH2Cl2) to afford the title intermediate (6.9 g); m/z 359,361 [M, M+2H] . | ||
6.9 g | Synthesis of 3-[1-(4-bromo-phenyl)-1-cyclopropyl-ethyl]-5-(1H-pyrazol-4-yl)-[1,2,4]oxadiazole 1,1'-Carbonyldiimidazole (4.9 g, 30.7 mmol) is added to a mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (3.4 g, 30.7 mmol) in 1,4-dioxane (150 ml). The mixture is stirred at 50° C. for 30 minutes, I-16 is added and the reaction mixture is heated at 85° C. for 48 hours. The reaction mixture is cooled to room temperature, poored into a solution of saturated NaHCO3 and extracted with EtOAc. The organic layers are dried over MgSO4, filtered and concentrated to afford the crude product that is purified via flash chromatography (SiO2, 0-6percent MeOH/CH2Cl2) to afford the title intermediate (6.9 g); m/z 359,361 [M, M+2H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a sealed tube is added lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (484 mg, 4.2 mmol) in 1,4- dioxane (8 ml), followed by the addition of Iota,Gamma-carbonyldiimidazole (679 mg, 4.2 mmol). The reaction mixture is stirred at 55 °C for 30 minutes. Then 1-17 (1.1 g, 4.0 mmol) in 1,4-dioxane (5 ml) is added to the above mixture. The reaction mixture is stirred at 120 °C for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, brine, dried under anhy. Na2S04, filtered and concentrated. The residue is purified by flash chromatography (Si02, 0-5percent MeOH/CH2Cl2) to afford the title intermediate (1.3 g); m/z 359.0, 361.0 [M, M+2H]. | ||
1.3 g | Synthesis of 3-[(R)-1-(4-bromo-phenyl)-1-cyclopropyl-ethyl]-5-(1H-pyrazol-4-yl)-[1,2,4]oxadiazole To a sealed tube is added <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (484 mg, 4.2 mmol) in 1,4-dioxane (8 ml), followed by the addition of 1,1'-carbonyldiimidazole (679 mg, 4.2 mmol). The reaction mixture is stirred at 55° C. for 30 minutes. Then I-17 (1.1 g, 4.0 mmol) in 1,4-dioxane (5 ml) is added to the above mixture. The reaction mixture is stirred at 120° C. for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0-5percent MeOH/CH2Cl2) to afford the title intermediate (1.3 g); m/z 359.0, 361.0 [M, M+2H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (7.1 g, 0.063 mol) in THF (200 mL) is added Iota,Gamma-carbonyldiimidazole (10.2 g, 0.063 mol) at room temperature. The mixture is stirred at 50 °C for 30 minutes. A suspension of 1-29 (12.5 g, 0.042 mol) in THF (100 mL) is added to the above mixture and the resulting mixture is heated under reflux for 24 hours. The mixture is cooled down and the solid is collected by means of filtration. The solid is then suspended in AcOH (150 mL) at room temperature. The mixture is heated to 90 °C for 2 hours. The solution is cooled down and is concentrated under vaccuum. The residue is dissolved in EtOAc (100 mL) and the solution is washed with H20 (200 mL) and saturated NaHC03 solution (200 mL). The organic layer is concentrated to afford the title compound (14.7 g, 0.040 mol). | ||
14.7 g | To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (7.1 g, 0.063 mol) in THF (200 mL) is added 1,1?-carbonyldiimidazole (10.2 g, 0.063 mol) at room temperature. The mixture is stirred at 50° C. for 30 minutes. A suspension of I-29 (12.5 g, 0.042 mol) in THF (100 mL) is added to the above mixture and the resulting mixture is heated under reflux for 24 hours. The mixture is cooled down and the solid is collected by means of filtration. The solid is then suspended in AcOH (150 mL) at room temperature. The mixture is heated to 90° C. for 2 hours. The solution is cooled down and is concentrated under vacuum. The residue is dissolved in EtOAc (100 mL) and the solution is washed with H2O (200 mL) and saturated NaHCO3 solution (200 mL). The organic layer is concentrated to afford the title compound (14.7 g, 0.040 mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Method 14Synthesis of 2-r4-(3-{l-r4-(2-amino-pyrimidin-5-yl)-phenyl1-cvclobutyl}-l,2,4- oxadiazol-5-yl)-pyrazol-l-yl1-N V-dimethyl-acetamide (Example 188 in Table 8)Step 1: Synthesis of 5-(4-{ l-r5-(lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl1-cyclobutyl)- phenyl)-pyrimidin-2-ylamine (R66)R65 (8.703 g, 77.648 mmol) and CDI (12.591 g, 77.648 mmol) are stirred at 50°C in NMP (80 mL) for 30 minutes. 1-2.5 (20 g, 70.589 mmol) is added and the mixture heated at 130°C for 2 h. The reaction is cooled to room temperature and 1L of distilled water is added and allowed to stir for 48h. The water is decanted to afford title compound as an oil (24.566 g); m/z 360.4 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In 1,4-dioxane; at 55℃; for 0.5h; | Method 3: Synthesis of 5-(5-{(2R)-3-methyl-2-r5-(lH-pyrazol-4-yl)-l,2,4-oxadiazol- 3- l1butan-2-yl}pyridin-2-yl)pyrimidin-2-amine (Example 43).In a sealed tube R9 (4.4 g, 37.9 mmol) is added in 1,4-dioxane (100.0 mL), followed by the addition of Iota,Gamma-carbonyldiimidazole (6.1 g, 37.9 mmol). The reaction mixture is stirred at 55 °C for 30 minutes. The reaction mixture first becomes a clear solution, then cloudy. A solution of 1-8.1 (10.8 g, 32.1 mmol) in 1,4-dioxane (10.0 mL) is added. The reaction mixture is stirred at 120 °C for 8 hours. The solvent is removed under reduced pressure, the crude is purified by silica gel column chromatography (DCM/MeOH) to afford Example 43 (11.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Method J: Synthesis of Intermediate 1-14.1.A suspension of R9 (0.3 g, 4.58 mmol) and Iota,Gamma-carbonyldiimidazole. (0.74 g, 4.58 mmol) in NMP (4.0 niL) is heated at 50°C for 20 min. 1-8.4 is added (1.25 g, 4.16 mmol) and the solution is heated at 130°C for 2 hours. The reaction mixture is cooled to room temperature, water is added and it is stirred overnight. A gooey residue is formed, the liquid is decanted and the crude is purified via silica gel column chromatography (DCM/MeOH) affords 1-14.1 (1.41 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of 2-Chloro-5-{l-r5-(lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yll-cvclobutyl}- pyridine (Intermediate 1-4.2)1-2.1 R1 1 R12 |_4 2 Rl l (156 mg, 1.40 mmol) is treated with pyridine (10.0 mL) and R12 (116 mu,, 1.60 mmol) and the resulting mixture is stirred for 30 minutes. 1-2.1 (300 mg, 1.33 mmol) is then added and the reaction is stirred at 110 °C for 18 hours. The resulting mixture is cooled to room temperature and the solvent is removed in vacuo. The residue is partitioned between CH2C12 and saturated aqueous NaHC03 and the phases are separated. The organic phase is dried over Na2S04, filtered, and the solvent is removed in vacuo to give 1-4.2 (187 mg); m/z 301.9 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3: Synthesis of 5-(5-{ l-[5-(lH-pyrazol-4-yl)-[l,2,4]oxadiazol-3-yl]-cyclobutyl}- pyridin-2-yl)-pyrazin-2-ylamine (R67)To a suspension of Rl l (68 mg, 0.61 mmol) in THF (5 ml) is added CDI (98 mg, 0.61 mmol) at room temperature. The mixture is stirred at 50°C for 30 minutes after which time R66 (115 mg, 0.40 mmol) is added. The resulting mixture is heated at 80°C for 3 hours, cooled to room temperature and treated with acetic acid (AcOH) (8 ml). The reaction is warmed to 80°C and stirred overnight. Upon cooling to room temperature, the reaction is concentrated and diluted with water. The product is extracted into DCM (2x). The combined organics are washed with brine, dried (MgS04), filtered and concentrated. The remaining residue is purified via flash chromatography (Silica gel, 0-10percentMeOH/DCM) to afford R67 (50 mg); m/z 361.2 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 100℃; for 0.166667h;Microwave irradiation; Sealed tube; | General procedure: A mixture of o-aminobenzenethiol (1 mmol), carboxylic acid (1 mmol), N,N-diisopropylethylamine (1.5 mmol) and propylphosphonic anhydride (1 mmol, 50percent w/w in AcOEt) was irradiated for 10 min under microwave at 100 °C in a sealed tube. It was diluted with H2O, followed by alkalinization with saturated aqueous NaHCO3 solution. The precipitate was collected by filtration and washed thoroughly with H2O to afford the respective benzothiazole. If necessary, simple recrystallization was carried out in EtOH/H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 0 - 50℃; for 4h; | <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (CAS 37718-11-9) (97.5 mg, 844 mumol, Eq: 1.00) was dissolved in methanol (6 ml). (S)-tert-butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate(prepared as described in example 83) (0.250 g, 844 mumol, Eq: 1.00) was added. At 0° C., a solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (303 mg, 1.1 mmol, Eq: 1.3) in Methanol (5 ml) was added over 1 hour. The RM was stirred at 50° C. over 3 hours. After cooling down to RT, the solvent was evaporated and the residue was purified by flash chromatography (silica gel, 50 g, 10percent to 100percent EtOAc in heptane). White solid (0.25 g, 74percent). MS (EIC): 413.2 ([M+Na]+) |
74% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 0 - 50℃; for 4h; | lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (CAS 37718-11-9) (97.5 mg, 844 muiotaetaomicron, Eq: 1.00) was dissolved in methanol (6 ml). (S)-tert-butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate(prepared as described in example 83) (0.250 g, 844 muiotaetaomicron, Eq: 1.00) was added. At 0°C, a solution of 4-(4,6-dimethoxy-l, 3, 5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (303 mg, 1.1 mmol, Eq: 1.3) in Methanol (5 ml) was added over 1 hour. The RM was stirred at 50°C over 3 hours. After cooling dpwn to RT, the solvent was evaporated and the residue was purified by flash chromatography (silica gel, 50g, 10percent to 100percent EtOAc in heptane). White solid (0.25 g,74percent). MS (EIC): 413.2 ([M+Na ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In a 1 dram vial, 3-[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5- chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 1 H- <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (9.01 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1 percent TFA) to afford the title compound (0.013 g, 31 percent) as a white solid. 1H NMR (400 MHz, Acetone-cfe): delta ppm 8.09 (br. s., 2 H), 8.00 (br. s., 1 H), 7.63 (t, 1 H), 7.40 - 7.48 (m, 2 H), 7.36 - 7.40 (m, 2 H), 5.63 (br. s., 1 H), 4.60 (d, 2 H). LCMS m/z 404.9 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-<strong>[37718-11-9]1H-Pyrazole-4-carboxylic acid</strong> [1 -(4-bromo-phenyl)-ethyl]-amide D To 5.0 g (44.6 mmol) <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> in 100 mL DMF 15.2 mL (89.2 mmol) DIPEA and 15.7 g (49.1 mmol) TBTU are added and the mixture is stirred for 10 min at rt. Subsequently 8.9 g (44.6 mmol) (S)-1 -(4-bromophenyl)ethylamine are added and stirring is continued over night. The mixture is poured on water and is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate and the solvent is removed in vacuo. The residue is triturated with DCM to yield the desired product. Ci2Hi2BrN3O (M = 294.1 g/mol), ESI-MS: 294 [M+H]+ Rt (HPLC): 1 .23 min (method E1 ) | ||
To 5.0 g (44.6 mmol) <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> in 100 mL DMF 15.2 mL (89.2 mmol) DIPEA and 15.7 g (49.1 mmol) TBTU are added and the mixture is stirred for 10 min at rt. Subsequently 8.9 g (44.6 mmol) (S)-1-(4-bromophenyl)ethylamine are added and stirring is continued over night. The mixture is poured on water and is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate and the solvent is removed in vacuo. The residue is triturated with DCM to yield the desired product. C12H12BrN3O (M=294.1 g/mol), ESI-MS: 294 [M+H]+ Rt (HPLC): 1.23 min (method E1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution containing the appropriate carboxylic acid (2.25 mmol, 1.0 equiv.) in THF (4.50 mL,0.50 M) was treated with CDI (2.48 mmol, 1.1 equiv.) at 23 °C for 2.0 h. The suspension wasthen treated with hydrazine monohydrate (6.75 mmol, 3.0 equiv.) at 23 °C for 16 h. The reactionmixture was concentrated under diminished pressure, and the obtained residue was applied to asilica gel column (50 g); eluting with 95:5 ? 75:25 DCM-MeOH afforded the hydrazide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.8 g | With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 72h; | In a 100 mL round-bottomed flask, (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (12.5 g, 44.9 mmol, Eq: 1.00), lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (5.03 g, 44.9 mmol, Eq: 1.00), HBTU (25.5 g, 67.4 mmol, Eq: 1.5) and N-methylmorpholine (13.6 g, 14.8 ml, 135 mmol, Eq: 3) were combined with DMF (1250 ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 200 mL H20, extracted with EtOAc (2 x) and washed with brine. The combined organic layers were dried over MgS04 and concentrated in vacuo. The crude material was purified by silica gel column chromatography leading to 8.8 g off-white solid. MS (ISP): 373.2 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | A) tert-butyl (cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate A solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75 mg) in DMF (3 mL) was ice-cooled, and <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (33.4 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg), 1-hydroxybenzotriazole (49.4 mg) and diisopropylethylamine (80 mg) were added. The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (72 mg). MS (API+): [M-tBu+2H]+ 341.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With polyphosphoric acid; at 150℃; for 18h;Inert atmosphere; Sealed tube; | A mixture of 6-chloro-N -methylpyridine-3,4-diamine (prepared using a procedure analogous to that described for Example 7, steps 1-2) (92 mg, 0.58 mmol) and lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (67 mg, 0.58 mmol) in polyphosphoric acid (-0.5 mL) was purged with argon and heated in a sealed vial at 150 °C for 18 h with stirring. The cooled mixture was diluted with water (1 mL) and taken to pH 7 by addition of NaOH (50percent aq.). A solid precipitated which was isolated by filtration. The solid was suspended in MeOH and sonicated for 15 min. The MeOH was removed in vacuo. This process was repeated (x2) and the resulting solid was dried in vacuo to give a grey solid (130 mg, quant.). LCMS (ESI): [M+H]+ 234/236 (35C1/37C1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With polyphosphoric acid; at 200℃; for 5h;Sealed tube; | A mixture of 6-bromo-N -methylpyridine-3,4-diamine (54 mg, 0.27 mmol), lH-pyrazole-4- carboxylic acid (30 mg, 0.27 mmol) and polyphosphoric acid (0.5 mL) was heated at 200 °C in a sealed tube for 5 h. After cooling, the reaction mixture was diluted with water and taken to pH 7 by addition of 50percent> aq. NaOH. A white suspension formed and the solid was collected by filtration affording the title compound (69 mg, 93percent). LCMS (ESI): [M+H]+ 278.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.44 mg | H) N-((2S)-1-((2-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)-1H-pyrazole-4-carboxamide A mixture of tert-butyl ((2S)-1-((2-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)phenyl) [1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (18.0 mg), 4M hydrogen chloride/ethyl acetate (1 mL) and ethyl acetate (1 mL) was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was mixed with <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (5.09 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.71 mg), 1-hydroxybenzotriazole (6.14 mg), triethylamine (0.026 mL) and DMF (1 mL). The obtained mixture was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.44 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-ol; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 18h;Inert atmosphere; | <strong>[37718-11-9]4-Pyrazolecarboxylic acid</strong> (400mg, 3.57mmol) was dissolved in CH2CI2 (SOmis) and5 DMF(2.5mls). This solution was cooled to 0°C. tert-Butyl 4-(aminomethyl)benzylcarbamate(1.01g, 4.28mmol) was added followed by HOBt (530mg, 3.93mmol) and triethylamine (1.08g,10.71mmol). Water soluble carbodiimide (821mg, 4.28mmol) was then added. After 18 hours atOOC to room temperature reaction mixture was diluted with chloroform (400mls) washedwith 0.3M KHS04 (1x30mls), NaHC03 (1x30mls), water (1x30mls), brine (1x30mls), dried10 (Na2S04) and evaporated in vacuo giving a yellow oil. The residue was purified by flashchromatography (silica), eluant 7percentMeOH, 93percent CHCI3 , fractions combined and evaporated invacuo to give a white solid identified as (4-[(1 H-pyrazole-4-carbonyl)-amino]-methyl}-benzyl)carbamicacid tert-butyl ester (1.10g, 3.33mmol, 93percent).15[M+Hr = 352.95 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 18h; | Preparation 7Synthesis of [2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-(lH- pyrazol-4-yl)methanone.Place <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> (700.7 mg, 5 mmoles ), N-indan-2-yl-5, 6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2-amine (2.00 g, 7.51 mmoles), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.16 g, 11.26 mmoles), and 4-pyridinamine, N,N-dimethyl (45.9 mg, 0.3 mmoles) in a 250 mL round bottom flask and dissolve in dichloromethane (60 mL). Stir the reaction mixture for 18 hours at 25 °C. Quench the reaction with saturated sodium bicarbonate (50 mL) and extract two times with dichloromethane. Dry over sodium sulfate, filter and concentrate under reduced pressure. The residue is recrystallized from methanol/ethyl acetate to give the title compound (0.98 g, 28percent). LCMS (m/z): 361.2 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 mul (0.51 mmol) DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for 10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (ACN/H2O/TFA).The following compounds are prepared analogously to example 2.1, using the appropriate carboxylic acid: For the examples 2.7, 2.15 and 2.17 the intermediate is added in methanol and the final product is treated with aq. HCl solution (c=1 mol/L) to cleave the THP protecting group. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.1% | In methanol; at 50℃;Sealed tube; | 327A. tert-Butyl 4-(5-(4-methoxypiperidin- 1 -yl)-2-(lH-pyrazole-4-carbonyl)- l,2,3,4-tetrahydroisoquinoline-l-carboxamido)benzoate: To a septa capped pressure vial was charged lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (148 mg, 1.320 mmol), Intermediate 4 (322.5 mg, 1.320 mmol) and tert-butyl 4-isocyanobenzoate (268 mg, 1.320 mmol) followed by MeOH (2.6 mL). The vial was sealed and the contents heated to 50 °C overnight. Reaction mixture was evaporated and purified by normal phase column chromatography to give the title compound (392.0 mg, 53.1percent yield) as a straw colored solid. MS (ESI) m/z: 560.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20 - 25℃; for 48h; | Triethylamine (0.836 mL, 6.00 mmol) was added to a suspension of 3-[4-chloro-2- (trifluoromethyl)phenyl]piperidine hydrochloride (0.6 g, 1.999 mmol) (Intermediate la6), lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (0.246 g, 2.199 mmol), EDC (0.575 g, 3.00 mmol) and 1- hydroxybenzotriazole hydrate (0.408 g, 3.00 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 48 hours. The mixture was diluted with DCM, washed with saturated aqueous NaHC03 (1 x 50 mL), 5percent aqueous citric acid (1 x 50 mL), water (1 x 50 mL) and the organic phase was isolated using a phase separator cartridge and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with 0-100percent ethyl acetate/petrol to afford 3-[4-chloro-2-(trifluoromethyl)phenyl]-l-[(lH- pyrazol-4-yl)carbonyl]piperidine (0.473 g, 1.322 mmol, 66 percent yield) as a colourless glass. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | N,N-Diisopropylethylamine (0.59 mL, 3.4 mmol) was added to a mixture of 2,2,2-trifluoro-N-[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide (Example 35, Step 6: 0.50 g, 1.3 mmol), <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (Ark Pharm, catNo.AK-25877: 0.18 g, 1.6 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.71 g, 1.6 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (gradient elution with 0 to 5percent MeOH in DCM) to afford the desired product. LC-MS calculated for C23H28F3N4O3 [M+H]+: m/z=465.2. found 464.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | To a solution of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (14.5 mg, 0.135 mmol) in DCM (2 mL) EDC-HCI (27 mg, 0.057 mmol), HOBt (35 mg, 0.258 mmol) and TEA (36 mu, 0.258 mmol) were added. After 20 min at RT, 4-(aminomethyl)-l-[4-(3-fluorophenoxy)-6-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-ol (Ell, 50 mg, 0.129 mmol) was added. The resulting solution was stirred at RT for 3 hrs. Solvent was evaporated and the residue was purified by FC on Silica gel (eluent: Cy to AcOEt) affording N-({l-[4-(3-fluorophenoxy)-6- (trifluoromethyl)pyrimidin-2-yl]-4-hydroxypiperidin-4-yl}methyl)-lH-pyrazole-4-carboxamide (E27, 30 mg, y= 48percent) MS (ES) (m/z): 481 [M+H]+ Eta NMR (DMSO-rfe): delta ppm 13.11 (br. s., 1H), 8.21 (br. s., 1H), 7.94 (t, J=6.0 Hz, 2H), 7.57-7.45 (m, 1H), 7.26 (d, 1H), 7.20-7. 05 (m, 2H), 6.61 (s, 1H), 4.75 (s, 1H), 4.27 (br. s., 1H), 3.88 (br. s., 1H), 3.23 (d, 4H), 1.42 (br. s., 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 30℃; | General procedure: Step 4. Synthesis of A21 and A22. To a solution of A20 (1.4 g, 3.28 mmol) and 2H-1,2,3- triazole (1.13 g, 16.41 mmol) in DMF (25 mL) was added K2CO3 (2.27 g, 16.41 mmol). The reaction was stirred at 30 oC overnight. TLC (petroleum ether/ethyl acetate=1/2) showed that the reaction was completed. The reaction was added brine (20 mL). The resulting solution was extracted with EtOAc (25 mL*3). The combined organic layers was dried and concentrated to give crude, which was purified by column chromatagraphy on silica gel (ethyl acetate/petroleum ether=2/1 to 1/2) to afford A21 (460 mg) and A22 (480 mg) as white solid. Example 40. Synthesis of 89. The synthesis of A47 was carried out according to Example 5, step 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; at 20℃; for 3.5h; | (1) weighing 1 mmol (0.136 g) zinc chloride dissolved in 10 ml of anhydrous ethanol, zinc chloride ethanol solution is prepared.(2) weighing 1 mmol (0.114 g) <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> is dissolved in 10 ml of anhydrous ethanol, to make <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> ethanol solution.(3) weighing 1 mmol (0.4 g) sodium hydroxide dissolved in 10 ml of distilled water, aqueous sodium hydroxide solution prepared.(4) the step (3) prepared by adding an aqueous solution of sodium hydroxide of step (2) the prepared <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> in ethanol solution, magnetic stirring at room temperature, then adding step (1) the prepared zinc chloride ethanol solution is continuously stirred for 3.5 hours, forming a white solution, the filter can be clarified white filtrate, the filtrate naturally volatilized under the room temperature condition for crystallization, after a week to obtain white crystal, in other words single nucleus pyrazole -4-carboxylic acid zinc complex. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; water; at 20℃; | Weighing 0.5 to 1 millimole of cobalt chloride hexahydrate dissolved in 5 to 10 ml of anhydrous ethanol, obtained in ethanol solution of cobalt chloride. 1 mmol (0.14 g) of <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> was weighed and dissolved in 10 ml of absolute ethanol, (1) A solution of pyrazole-3-carboxylic acid in ethanol was prepared. (3) weighing 0.5 to 1 mmol of sodium hydroxide dissolved in 5 to 10 ml of distilled water, in aqueous sodium hydroxide solution. The aqueous sodium hydroxide solution obtained in the step (3) was added to the ethanolic solution of the <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> obtained in the step (2), and the mixture was magnetically stirred at room temperature, Cobalt chloride ethanol solution to continue stirring for 2 to 5 hours to form a wine red solution, filtered to get a clear wine red filtrate, the filtrate at room temperature under natural evaporation crystallization, a week after the light red crystals, namely pyrazole 4- Cobalt formate complex. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.6% | Preparation ofN-( ( lR,4R)-4-( ( 5-chloro-4-( 5-(cyclopropylmethyl)-l-methyl- lH-pyrazol-4-yl)pyHmMin-2-yl)amino)cyclohexyl)-lH-pyrazole-4-carboxamide (A87) To a solution of compound 87_1 (46.59 mg, 415.65 muetaiotaomicron, 1.00 eq) in DCM (4 mL) were added DIEA (181.5 mu,, 1.04 mmol, 2.50 eq), EDCI (95.62 mg, 498.78 mupiiotaomicron, 1.20 eq) and HOBt (11.23 mg, 83.13 mupiiotaomicron, 0.20 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour. The solution of A-51 (150.00 mg, 415.65 mupiiotaomicron, 1.00 eq) in DCM (4.5 mL) was added. The resulting mixture was stirred at 20 °C for 16 hours. The mixture was diluted with H2O (50 mL) and extracted with DCM (40 mL*3). The organic layer was concentrated and purified by prep-HPLC (HCl condition) to give A-87 (80.00 mg, 160.61 mupiiotaomicron, 38.6percent yield, 98.6percent purity, HCl) as a yellow solid. LCMS: RT = 2.391 m/z 455.2[M+H]+ 02429524H5-01 NMR (MeOD, 400 MHz) delta 8.48 (s, 1H), 8.39 (s, 1H), 8.16 (s, 2H), 4.04 (s, 1H), 3.96 (s, 3H), 3.93-3.90 (m, 1H), 3.24 (d, /=6.4Hz, 2H), 2.18-2.04 (m, 4H), 1.67- 1.53(m, 4H), 1.18 (s, 1H), 0.57-0.55 (m, 2H), 0.30-0.29 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | [00344] To a stirred solution of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (1.0 g, 8.92 mmol) and DIPEA (5.4 mL, 31.2 mmol) in THF (15 mL) was added T3P (50percent in EtOAc, 10.5 mL, 17.8 mmol) and stirred at r.t. for 5 mins. 4-(trifluoromethyl)piperidine hydrochloride (2.03 g, 10.7 mmol) was then added and the solution was stirred at r.t. overnight. The reaction mixture was cooled, partitioned between DCM (30 mL) and saturated NaHC03 solution (40 mL) and the aqueous fraction extracted with DCM (2 x 30 mL). The combined organic fractions were dried over MgS04 and the solvent removed in vacuo. The resulting oil was purified via chromatography on Si02 MeOH/DCM (gradient 100:0 - 90: 10) to afford the title compound (673 mg, 61percent) as a yellow powder. [00345] Method A: LC-MS m/z = 248.0 [M + H]+; RT = 0.98 min. |
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P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
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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