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CAS No. : | 5334-39-4 | MDL No. : | MFCD00037864 |
Formula : | C4H5N3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WTZYTQJELOHMMJ-UHFFFAOYSA-N |
M.W : | 127.10 | Pubchem ID : | 79255 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.38 |
TPSA : | 74.5 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) : | -6.35 cm/s |
Log Po/w (iLOGP) : | 0.43 |
Log Po/w (XLOGP3) : | 1.02 |
Log Po/w (WLOGP) : | 0.63 |
Log Po/w (MLOGP) : | -0.35 |
Log Po/w (SILICOS-IT) : | -0.63 |
Consensus Log Po/w : | 0.22 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.62 |
Solubility : | 3.08 mg/ml ; 0.0242 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.17 |
Solubility : | 0.851 mg/ml ; 0.0067 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.96 |
Solubility : | 13.8 mg/ml ; 0.109 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.75 |
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 |
---|---|---|
73% | With nitric acid In tetrahydrofuran; water at 20℃; for 3 h; | General procedure: To iodopyrazole (1 mmol) dissolved in THF (10 mL), Fuajasite (250 mg) was added. Nitric acid (d 1.52 g/cm3, 10 mL) was added slowly and the mixture was stirred at room temperature for required time. The catalyst was recovered by filtration and the filtrate was extracted repeatedly with dichloromethane. The solvent was removed under vacuum to obtain nitropyrazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 27℃; for 4.0h; | To a stirred suspension of sodium hydride (4.9 g, 60% in mineral oil, 20.74 mmol) in THF (100 mL), 3-rnethyl-4-nitro-IH-pyrazole 48 (10.0 g, 7.8 mmol) and iodomethane (21.0 g, 14.7 mmol) were charged at 0C. Hydrogen gas evolved. The mixture was then stirred at room temperature for 4h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuum to give an inseparable mixture of 1,3-dimethyl-4-nitro-1H-pyrazole 49-a and 1,5-dimethyl- 4-nitro-1H-pyrazole 49-b (5.70 g, 78% yield) that was carried to the next step without further purification. ?HNMR (400 MHz, CDCl3): delta 8.04 (s, 1H), 3.84 (s, 3H), 2.52 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With toluene-4-sulfonic acid; In ethyl acetate; at 20℃; | To a solution of <strong>[5334-39-4]3-methyl-4-nitro-1H-pyrazole</strong> (50 g, 393 mmol) in EtOAc (500 mL) was added DHP (49.6 g, 590 mmol) and pTsOH.H20 (3.66 g, 20 mmol) at room temperature. The reaction was stirred overnight at room temperature. EpsilonbetaNu (6 mL) was added and the organic was washed with brine (2x300 mL). The organic layer was dried over Na2S04and concentrated in vacuo to give the title compound as colorless oilsolid, which was used in next step without further purification (65 g, 78%). LC-MS: 233.9 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | palladium-charcoal; | Ethyl 3-(3-methylpyrazol-4-ylamino) crotonate (D3) STR18 3-Methyl-4-nitropyrazole (6.0 g), 10% palladium-charcoal (0.6 g) and ethanol were shaken with hydrogen until theoretical uptake of hydrogen was complete. The catalyst was filtered off and ethyl acetoacetate (7.8 g, 0.06 mole) added to the ethanol filterate. The ethanol was removed in vacuo and the oily residue heated under nitrogen on a steam bath for 30 minutes. The yellow oil was purified by column chromatography (silica gel eluted with ether/ethyl acetate) to yield the crotonate (7.0 g, 71%) as a pale yellow oil. delta (CDCl3) 1.22 (3H, t, J=7 Hz) 1.80 (3H, s) 2.20 (3H, s) 4.10 (1H, brs, exchanges with D2 O) 4.11 (2H, q, J=7 Hz) 4.72 (1H, s) 7.30 (1H, s) 9.55 (1H, s, exchanges with D2 O) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Procedure B:General Procedure for the Synthesis of 4-Amino-3 -methyl- 1-N-alkylated pyrazolesA solution of 3-methylpyrazole (1.96mL, 24.0mmol) in sulfuric acid (15mL) was cooled to - 5C and potassium nitrate (l . leq) was added portion-wise. The reaction was warmed to rt and stirred for 16h. The mixture was cooled to 0C and neutralized with ammonium hydroxide solution. The resulting solid was filtered and air-dried to give 3-methyl-4-nitro- 1H-pyrazole. To a solution of 3-methyl-4-nitropyrazole (300mg, 2.6mmol), potassium carbonate (2eq) and the alkylating reagent (l. leq) in acetonitrile (lOmL) was heated at 60C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSC^) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give the desired product.Example 23: 2-((6-(l-(2-methoxyethyl)-3 -methyl- 1 H-pyrazo 1-4-ylamino)- 1 H-pyrazo lo [3,4- d]pyrimidin- 1 -yl)methyl)benzonitrileThe following compound was made according to the procedure in Example 1, using l-(2- methoxyethyl)-3 -methyl- lH-pyrazo 1-4-amine. 1 -(2 -methoxyethyl)-3 -methyl- lH-pyrazo 1-4- amine was prepared by Procedure B using l-bromo-2-methoxyethane as alkylating agent:1H NMR (d6-DMSO) delta 9.29-9.36 (m, 1Eta), 8.94 (s, 1Eta), 8.09 (s, 1Eta), 7.89 (d, 1Eta), 7.65 (td, 1Eta), 7.51 (t, 1Eta), 7.28-7.30 (m, 1Eta), 5.68 (s, 2Eta), 4.15 (t, 2Eta), 3.63 (t, 2Eta), 3.18 (s, 3Eta), 2.14 (s, 3H); LC-MS method B, (ES+) 389.1, RT = 7.86min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; for 16h; | To <strong>[5334-39-4]3-methyl-4-nitropyrazole</strong> (0.5 g) in THF (20 ml) was added triethylamine (0.55 ml) followed by a solution of di-tert-butyl dicarbonate (0.86 g) in THF (5 ml). The reaction was stirred for 16 hours, water (10 ml) was added and the mixture was extracted with EtOAc (2 x 30ml). The combined organics were washed with brine (15 ml), dried, filtered and the solvent removed in vacuo to yield crude material (1.1 g) as a pink solid. Column chromatography on silica (25 g), eluting with 1 :2 EtO Ac-Heptane (300 ml) gave tert-butyl <strong>[5334-39-4]3-methyl-4-nitropyrazole</strong>-l-carboxylate, 815 mg, 91% yield. tert-Butyl <strong>[5334-39-4]3-methyl-4-nitropyrazole</strong>-l-carboxylate (815 mg) was dissolved in MeOH (20 ml) and hydrogenated at room temperature for 40 hours with 10% Pd/C (0.2 g, 50% wet). The catalyst was filtered off and the solvent removed in vacuo. Column chromatography on silica (4 g), eluting with 1 :1 EtO Ac-heptane (500 ml) gave tert-butyl 4-amino-3- methylpyrazole-1-carboxylate (400 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 3-methyl-4-nitro-lH-pyrazole (15.7 g) in toluene (525 mL) was added potassium carbonate (20.5 g). The suspension was stirred for 20 minute at room temperature followed by the addition of ethyl bromoacetate (16.5 mL). The mixture was heated to 8O0C and stirred overnight. Further ethyl bromo acetate (6.5 mL) was added and the reaction mixture stirred for a further 12 h at 8O0C. Upon cooling, the mixture was filtered from suspended solids, washing with DCM (100 mL) and dried (Na2SO4). Volatiles were removed in vacuo to give a yellow oil (35 g). Dry column (SiO2, 420 g; 14- 40 muM, Merck, 100 % DCM) chromatography was performed on the bulk material (25 g) giving material enriched in the desired isomer. Dry flash column chromatography was repeated on the material enriched in the desired isomer until 2.4 g of ethyl 2-(3-methyl-4-nitropyrazol-l-yl)acetate (> 90 % isomerically purity material) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Methyl-4-nitro-lH-pyrazole (0.35 g, 2.8 mmol) was dissolved in DMF (10 mL), Potassium carbonate (0.86 g, 6.2 mmol) was added and the mixture stirred at room temperature for 5 minutes. The resulting solution was purged with chlorodifluoromethane for 5 hours after which time no starting material remained. The mixture was cautiously poured into H2O (100 mL) and extracted into ether (5 x 30 mL). The combined ethereal extracts were dried (MgSO4) and the solvent removed to give a yellow oil (0.65 g). Column chromatography (SiO2; 100 g, 50 / 50: DCM : heptane) was perfomed to give 3- methyl-4-nitro-l-(difluoromethyl)pyrazole as a colourless oil (200 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 17 - 25℃; for 3h; | To a stirred of solution of 3-methyl-4-nitro-lH-pyrazole (0.3 g, 2.4 mmol) in DMF (10 mL) was added potassium carbonate (0.4 g, 2.9 mmol) and 2-iodopropane (0.72 mL, 7.2 mmol). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL) and extracted into ether (4 x 30 mL). The combined ethereal extracts were dried (MgSO4) and the solvent removed under vacuum to give a pale yellow oil. Several purifications were performed via column chromatography (SiO2; 200 equiv. 100 % DCM) to give 1 -isopropyl-3 -methyl-4-nitropyrazole (11 mg, 93 % isomeric purity). This was combined with another batch (110 mg, purified identically). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyf-4-nitropyrazole (Apollo, Cheshire, UK, 500 mg, 3 93 mmoi) in DMF (10 mt) was added 55% NaH in oil (198 mg, 4 54 mmol) and the reaction mixture was stirred for 30 mm at rt Then to the reaction mixture was added a solution of 2-bromo-N.N- dimethylacetamide (stage L.3, 720 mg, 4.34 mmol) in DMF (3 ml) The reaction mixture was stirred for 1 h at rt then quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2x) The combined organic layers were washed with water (2x), brine, dried over Na2SO4, filtered and evaporated The crude product was purified by Prep HPLC (H2O (0 1% TFA)/CH3CN 97 2 to 75.25, ?verse phase silica gel) The fractions containing product were collected together, basified with NaHCOe and concentrated before being extracted with EtOAc (3x) The combined organic layers were washed with brine, dned over Na?SO«, filtered and evaporated to give the title compound as a white solid (HPLC tR 2 06 mm (Method A), M+H = 213 MS-ES). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 60℃; for 18h; | Procedure B:General Procedure for the Synthesis of 4-Amino-3 -methyl- 1-N-alkylated pyrazolesA solution of 3-methylpyrazole (1.96mL, 24.0mmol) in sulfuric acid (15mL) was cooled to - 5C and potassium nitrate (l . leq) was added portion-wise. The reaction was warmed to rt and stirred for 16h. The mixture was cooled to 0C and neutralized with ammonium hydroxide solution. The resulting solid was filtered and air-dried to give 3-methyl-4-nitro- 1H-pyrazole. To a solution of <strong>[5334-39-4]3-methyl-4-nitropyrazole</strong> (300mg, 2.6mmol), potassium carbonate (2eq) and the alkylating reagent (l. leq) in acetonitrile (lOmL) was heated at 60C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSC^) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give the desired product.Example 23: 2-((6-(l-(2-methoxyethyl)-3 -methyl- 1 H-pyrazo 1-4-ylamino)- 1 H-pyrazo lo [3,4- d]pyrimidin- 1 -yl)methyl)benzonitrileThe following compound was made according to the procedure in Example 1, using l-(2- methoxyethyl)-3 -methyl- lH-pyrazo 1-4-amine. 1 -(2 -methoxyethyl)-3 -methyl- lH-pyrazo 1-4- amine was prepared by Procedure B using l-bromo-2-methoxyethane as alkylating agent:1H NMR (d6-DMSO) delta 9.29-9.36 (m, 1Eta), 8.94 (s, 1Eta), 8.09 (s, 1Eta), 7.89 (d, 1Eta), 7.65 (td, 1Eta), 7.51 (t, 1Eta), 7.28-7.30 (m, 1Eta), 5.68 (s, 2Eta), 4.15 (t, 2Eta), 3.63 (t, 2Eta), 3.18 (s, 3Eta), 2.14 (s, 3H); LC-MS method B, (ES+) 389.1, RT = 7.86min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; oxygen; copper(II) acetate monohydrate; In N,N-dimethyl-formamide; at 95℃; for 7h; | A mixture of 3-methyl-4-nitro-lH-pyrazole (2.1 g, 17 mmol) and 4- methylsulfonylphenylboronic acid (5.0 g, 25 mmol), copper (II) acetate monohydrate (0.91 g, 5.0 mmol) and pyridine (0.5 g, 6.6 mmol) in DMF was stirred at 95 C under an oxygen atmosphere for 7 hours. The reaction was diluted with water, extracted with EtOAc (3x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give a mixture of 3 -methyl- 1 -(4- (methylsulfonyl)phenyl)-4-nitro-lH-pyrazole compound and 5 -methyl- 1 -(4-(methylsulfonyl)phenyl)-4-nitro-lH-pyrazole (1.3 g, 28%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of 3-methyl-l-(4-(methylsulfonyl)phenyl)-4-nitro-lH-pyrazole compound and 5-methyl-l-(4-(methylsulfonyl)phenyl)-4-nitro-lH-pyrazole (0.57 g, 2.0 mmol) and palladium on carbon (10 wt%, 0.2 g) in ethanol was stirred under a hydrogen atmosphere at 55 C for 18 hours. The reaction mixture was filtered through celite and concentrated to give the title compounds as a mixture of regioisomers (446 mg, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | To a mixture of 3-methyl-4-nitro-pyrazole (0.80 g, 6.3 mmol), cesium carbonate (4.1 g, 12 mmol) in DMF (10 mL) was added <strong>[26272-85-5]3-iodo-oxetane</strong> (3.47 g, 19 mmol). The mixture was stirred at 100 C for 3 h. The reaction was diluted with water and extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatrography (20-100% EtO Ac- heptane) to give a mixture of 5 -methyl-4-nitro-l -(oxetan-3 -yl)-l H-pyrazole and 3-methyl-4- nitro-1 -(oxetan-3 -yl)- 1 H-pyrazole (0.85 g, 74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5 -methyl-4-nitro-l -(oxetan-3 -yl)-l H-pyrazole and 3-methyl-4-nitro-l- (oxetan-3-yl)-l H-pyrazole (0.137 g, 0.75 mmol) in ethanol (2 mL) was added Pd-C (10 wt%, 0.10 g). The mixture was stirred under a hydrogen atmosphere for 24 hours. The reaction was filtered through Celite and concentrated to give a mixture of 5 -methyl- 1 -(oxetan-3 -yl)-lH- pyrazol-4-amine and 3 -methyl- 1 -(oxetan-3 -yl)-lH-pyrazol-4-amine (83 mg, 73%), which were used together in the following Examples. Additional intermediates made using the above procedure are shown in Table 2 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With nitric acid; In tetrahydrofuran; water; at 20℃; for 3h; | General procedure: To iodopyrazole (1 mmol) dissolved in THF (10 mL), Fuajasite (250 mg) was added. Nitric acid (d 1.52 g/cm3, 10 mL) was added slowly and the mixture was stirred at room temperature for required time. The catalyst was recovered by filtration and the filtrate was extracted repeatedly with dichloromethane. The solvent was removed under vacuum to obtain nitropyrazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | Step 1: Preparation of (3-methyl-4-nitro-1H-pyrazol-1-yl)acetonitrile A mixture of <strong>[5334-39-4]3-methyl-4-nitro-1H-pyrazole</strong> (7 g, 0.055 mol), bromoacetonitrile (13.2 g, 0.11 mol) and K2CO3 (23 g, 0.165 mol) in DMF (120 mL) was stirred at 80 C. for 2 hrs. TLC (petroleum ether:EtOAc=2:1) showed the reaction was complete. The mixture was filtered, concentrated and the residue purified by flash chromatography (petroleum ether:EtOAc=4:1) to give the title compound (3.5 g, 38% yield) as light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; oxygen; copper diacetate; In N,N-dimethyl-formamide; at 95℃; for 12h; | To a suspension of 3-methyl-4-nitro-lH-pyrazole (350 mg, 2.76 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (859 mg, 4.13 mmol), and copper(II) acetate (150 mg, 0.825 mmol) in DMF (8 mL) was added pyridine (87 mg 1.1 mmol). The mixture was stirred at 95 C under oxygen for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (30 mL x 3). The combined extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1/5) to give a mixture of two regioisomers (71 mg, 13%) as an off white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of the mixture of r,5-dimethyl-4-nitro-l'H-l,4'-bipyrazole and ,3- dimethyl-4-nitro-l'H-l ,4'-bipyrazole (71 mg, 0.34 mmol) and 10% Pd/C (50 mg ) in methanol (10 mL) was stirred at 55 C under H2 for 3 h. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to afford the two title compounds as a mixture (50 mg, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; | A solution of 3-methyl-4-nitro-lH-pyrazole (1.00 g, 7.87 mmol), methyl 3-methylbut-2- enoate (2.20 g, 18.9 mmol), and DBU (3.10 g, 20.5 mmol) in DMF (5.0 mL) was stirred overnight. The mixture was purified by reverse phase Combifiash to afford the title compound (130 mg, 7%) as yellow oil. LC-MS (ESI): m/z = 242 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | A mixture of 3-fluoro-tetrahydro-2H-pyran-4-yl methanesulfonate (60 mg, 0.50 mmol), 3-methyl-4-nitro-lH-pyrazole (98 mg, 0.50 mmol), and Cs2C03 (243 mg, 0.750 mmol) in DMF (2.0 mL) was stirred at 100 C for 2 h. After cooling down, the resulting mixture was extracted with ethyl acetate (20 mL 3), washed with H20 (20 mL). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compounds (60 mg, 56 %) as oil. LC-MS (ESI): m/z = 230 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | A mixture of 2-(l-methyl-lH-pyrazol-3-yl)ethyl methanesulfonate (600 mg, 2.94 mmol), 3-methyl-4-nitro-lH-pyrazole (373 mg, 2.94 mmol), and Cs2C03 (1.92 g, 5.882 mmol) in DMF (20 ml) was stirred at 100 C for 2 h. H20 (20 ml) was added and the resulting mixture was extracted with EtOAc (20 ml x 3). The organic layers were combined, washed with brine (20 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether/ethyl acetate (1/1) to afford the title compound (600 mg, 87%) as a white solid. LC-MS (ESI): m/z = 236 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3-methyl-l-(2-(l-methyl-lH-pyrazol-3-yl)ethyl)-4-nitro-lH-pyrazole and 5-methyl-l-(2-(l-methyl-lH-pyrazol-3-yl)ethyl)-4-nitro-lH-pyrazole (300 mg, 1.28 mmol) in methanol (25 ml) was added 10% Pd/C (30 mg). The reaction mixture was stirred under H2 at room temperature for 1 h. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to afford the title compound (260 mg, 99%>) as a white solid. LC-MS (ESI): m/z = 206 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h; | To a solution of 3-methyl-4-nitro-lH-pyrazole (3.81 g, 30.0 mmol) in DMF (20 mL) was added K2CO3 (8.28 g, 60.0 mmol) and <strong>[29263-94-3]diethyl 2-bromo-2-methylmalonate</strong> (9.10 g, 36.0 mmol). The mixture was stirred at 100 C for 20 h. The reaction mixture was then treated with H20 (500 mL), extracted with ethyl acetate (20 mL x 3). The organic layer was evaporated and the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10/1) to afford the title compound (3.6 g, 41%) as oil. LC-MS (ESI): m z = 300 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With dmap; In dichloromethane; at 20℃; for 16h; | (a) tert-Butyl 3-methyl-4-nitro- 1H-pyrazole- 1-carboxylate or tert-butyl 5-methyl-4- nitro- 1H-pyrazole- 1-carboxylate (A25)Di-tert-butyl dicarbonate (5.15 g, 23.6 mmol) and 4-dimethylaminopyridine (0.481 g, 3.93 mmol) were added to a solution of <strong>[5334-39-4]3-methyl-4-nitropyrazole</strong> (2.50 g, 19.7 mmol)in DCM (100 mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (100 mL), brine (100 mL), dried (phase separator) and concentrated under reduced pressure. The residue was adsorbed onto Si02 and purified by column chromatography (Biotage Isolera, 2 x 40 g Si02 cartridges, 0-50% EtOAc in petroleum benzine 40-60 00) to give the title compoundA25 as a white solid (2.54 g, 57%). LCMS-D: rt 3.39 mm; no product ion detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution 49-a and 49-b (5.7 g, 4.04 mmol) in ethanol (50 mL), 0.8 g of Pd(OH)2 was added and then stirred reaction under H2 gas atm for 14h. After the completion of reaction (TLC monitoring), the solution was filtered through celite bed, washed with methanol.and concentrated the solvent to get a crude mixture precursor-25 (3.0 g, 67% yield) that was carried as such for the next step without further purification. ?HNMR (400 MHz, DMSO-d6): oe 6.81 (s, 11-1), 3.57 (s, 3H), 3.52 (s, 2H), 2.05 (s, 3H). MS: 112.08 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 20h; | To a solution of <strong>[5334-39-4]3-methyl-4-nitro-1H-pyrazole</strong> (3.0 g, 23.6 mmol, 1.00 eq), tert-butyl-3-hydroxypyrrolidine-1-carboxylate (4.42 g, 23.6 mmol, 1.00 eq), and triphenylphosphine (6.19 g, 23.6 mmol, 1.00 eq) in THF (60 mL) was added a solution of diethyl azodicarboxylate (4.34 mL, 23.6 mmol, 1.00 eq) in THF (10 mL) in a drop-wise manner over 30 min. The reaction mixture was allowed to stir at ambient temperature for 20 hr and then concentrated. The crude reaction mixture was purified via repeated flash chromatography on silica gel eluting with a gradient of 0-35% EtOAc in heptane to give the title compound (2.48 g, 35% yield) as a colorless oil that was the early eluting of two structural isomers. 1H NMR (400 MHz, CDCl3) delta ppm 8.15 (s, 1H) 4.80 (quin, J=5.7 Hz, 1H) 3.83 (dd, J=6.0, 12.0 Hz, 1H) 3.79-3.45 (m, 3H) 2.52 (s, 3H) 2.38 (q, J=7.0 Hz, 2H) 1.46 (s, 9H). m/z (APCI+) for C13H21N4O4 197.2 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.85% | With sodium hydroxide; In acetonitrile; at 80℃; for 15h; | To a solution of 3-methyl-4-nitro-1 H-pyrazole (2.Og, 15.74 mmol) and 1, 3-dioxolan-2-one (6.939, 79 mmol) in acetonitrile (5 mL) was added sodium hydroxide (1.888 g, 47.2 mmcl). The reaction mixture was stirred at 80 C for 15 hours. The mixture was then diluted with water (100 ml) and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude was purified by pre-HPLC to give the title compound D14 (400mg, 2.337 mmcl, 14.85 % yield) as a white solid.LCMS: 172 [M-i-H]. tR =1.130 mins. (LCMS condition 2) 1H NMR (400MHz, CHLOROFORM-d): 58.11 (s, IH), 4.17-4.26 (m, 2H), 3.99-4.13 (m,2H), 2.77 (t, 1 H), 2.68 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 120h; | DIAD (930 muIota_, 4.7 mmol) was added to a solution of 3-methyl-4-nitro-1 H-pyrazole (500 mg, 3.93 mmol), /V-methyl-4-piperidinol (453 mg, 3.93 mmol) and triphenylphosphine (1238 mg, 4.7 mmol) in THF (25ml_). The reaction mixture was stirred at rt for 5 days. The mixture was cone, in vacuo before purification by flash chromatography on silica, washing with 50% EtOAc/DCM, followed by 5/45/50 MeOH/EtOAc/DCM mixture. The product was eluted with 2/5/43/50 NEt3/MeOH/EtOAc/DCM mixture to give the title compound as an off-white low melting solid (202 mg, 23%). LCMS (Method 1 ) Rt 2.7 min, ESIMS m/z [M+H]+ 225.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 144h; | Added <strong>[39267-79-3]3-bromooxetane</strong> (451 ul, 5.901 mmol) to a mixture of 3-methyl-4-nitro-1 H-pyrazole (500 mg, 3.934 mmol) and cesium carbonate (2.564 g, 7.868 mmol) in DMF (5 mL) and stirred at 70 C for 6 d. Added ether (50ml_) and filtered off the residues. Removed the solvent from the filtrate in vacuo and purified the residue by flash chromatography using dichloromethane/ethyl acetate (3/7) to give the titled compound (589 mg, 82%). LCMS (Method 1 ) Rt 1.865 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 144h; | Added 3-bromotetrahydropuran (651 ul, 5.901 mmol) to a mixture of 3-methyl-4-nitro-1 H- pyrazole (500 mg, 3.934 mmol) and cesium carbonate (2.564 g, 7.868 mmol) in DMF (5 mL) and stirred at 70 C for 6 d. Added ether (50mL) and filtered off the residues. Removed the solvent from the filtrate in vacuo and purified the residue by flash chromatography on neutral alumina using methanol/dichloromethane (1/99) to give the titled compound (334 mg, 40%). LCMS (Method 1 ) Rt 2.042 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 6B 1-(4-methoxybenzyl)-3-methyl-4-nitro-1 H-pyrazole and 1-(4-methoxybenzyl)-5- methyl-4-nitro- 1 H-pyrazole In analogy to intermediate 4B), 2.5 g (19.7 mmol) 3-methyl-4-nitro-1 H-pyrazole and 3.70 g (23.6 mmol) 1 -(bromomethyl)-4-methoxybenzene were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Si L column, hexane / 10 - 100% ethyl acetate, then ethyl acetate / 0 - 25% methanol) 4.9 g (100%) of the desired title compounds as a mixture. 1H-NMR (300 MHz, DMSO d6) delta (ppm) = 2.38 / 2.60 (s, 3H), 3.72 / 3.72 (s, 3H), 5.21 / 5.34 (s, 2H), 6.85 - 6.94 (m, 2H), 7.18 / 7.29 (d, 2H), 8.24 / 8.89 (s, 1 H). Intermediate 6C 1-(4-methoxybenzyl)-3-methyl-1 H-pyrazol-4-amine and 1-(4-methoxybenzyl)-5- methyl- 1 H-pyrazol-4-amine 4.94 g (20.0 mmol) 1 -(4-methoxybenzyl)-3-methyl-4-nitro-1 H-pyrazole and 1 -(4- methoxybenzyl)-5-methyl-4-nitro-1 H-pyrazole (intermediate 6B) was dissolved in 78 mL methanol, and 522 mg palladium on carbon (10 wt. %) and 10.1 g (160 mmol) ammonium formiate were added. The reaction mixture was heated for 1 h at 80 C. Afterwards the suspension was filtered through Celite and the filtrate was evaporated. The residue was diluted with 50 mL water and this phase was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude material which was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 20 - 70% ethyl acetate) to give 3.64 g (84%) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 1.96 / 1.98 (s, 3H), 3.55 (s, 2H), 3.70 / 3.71 (s, 3H), 4.94 / 5.05 (s, 2H), 6.83 - 6.88 (m, 2H), 6.90 / 6.94 (s, 1 H), 6.98 - 7.02 / 7.09 - 7.14 (m, 2H). | ||
A mixture of 4.94 g (20.0 mmol) 1 -(4-methoxybenzyl)-5-methyl-4-nitro-1 H-pyrazole and 1 -(4-methoxybenzyl)-3-methyl-4-nitro-1 H-pyrazole (intermediate 6B) was dissolved in 78 mL methanol, and 522 mg palladium on carbon (10 wt. %) and 10.1 g (160 mmol) ammonium formiate were added. The reaction mixture was heated for 1 h at 80 C. Afterwards the suspension was filtered through Celite and the filtrate was evaporated. The residue was diluted with 50 mL water and this phase was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude material which was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 20 - 70% ethyl acetate) to give 3.64 g (84%) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 1.96 / 1.98 (s, 3H), 3.55 (s, 2H), 3.70 / 3.71 (s, 3H), 4.94 / 5.05 (s, 2H), 6.83 - 6.88 (m, 2H), 6.90 / 6.94 (s, 1 H), 6.98 - 7.02 / 7.09 - 7.14 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51%; 23% | Example 1 N-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4- carboxamide To a solution of 245 mg (1.19 mmol) of a mixture of 1 -(4-fluorobenzyl)-3-methyl-1 H- pyrazol-4-amine and 1 -(4-fluorobenzyl)-5-methyl-1 H-pyrazol-4-amine (intermediate 1C) in 4.0 mL DMSO was added 453 mg (1.19 mmol) HATU, 0.26 mL N,N- diisopropylethylamine and 200 mg (0.99 mmol) commercially available 2,6- dimethylquinoline-4-carboxylic acid. The reaction mixture was stirred for 20 hours at 25C. This mixture was directly purified via preparative HPLC (method A1) to obtain 208 mg (51%) of the desired title compound together with 92 mg (23%) of the regioisomer N-[1 -(4-fluorobenzyl)-5-methyl-1 H-pyrazol-4-yl]-2,6-dimethylquinoline-4- carboxamide. 1H NMR (500 MHz, DMSO d6): delta (ppm) = 2.18 (s, 3H), 2.48 (s, 3H), 2.68 (s, 3H), 5.25 (s, 2H), 7.19 (t, 2H), 7.36 (dd, 2H), 7.50 (s, 1H), 7.60 (dd, 1H), 7.80 (s, 1H), 7.89 (d, 1H), 8.23 (s, 1H), 10.21 (s, 1H). | |
51%; 23% | To a solution of 245 mg (1.19 mmol) of a mixture of 1 -(4-fluorobenzyl)-5-methyl-1 H- pyrazol-4-amine and 1 -(4-fluorobenzyl)-3-methyl-1 H-pyrazol-4-amine (intermediate 1C) in 4.0 mL DMSO was added 453 mg (1.19 mmol) HATU, 0.26 mL N,N- diisopropylethylamine and 200 mg (0.99 mmol) commercially available 2,6- dimethylquinoline-4-carboxylic acid. The reaction mixture was stirred for 20 hours at 25 C. This mixture was directly purified via preparative HPLC (method A1 ) to obtain 92 mg (23%) of the desired title compound together with 208 mg (51%) of the regioisomer N-[1 -(4-fluorobenzyl)-3-methyl-1 H-pyrazol-4-yl]-2,6-dimethylquinoline-4- carboxamide. 1 H NMR (500 MHz, DMSO d6): delta (ppm) = 2.22 (s, 3H), 2.48 (s, 3H), 2.68 (s, 3H), 5.31 (s, 2H), 7.16 - 7.26 (m, 4H), 7.53 (s, 1 H), 7.60 (dd, 1 H), 7.79 (s, 1 H), 7.85 (s, 1 H), 7.89 (d, 1 H), 10.12 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 20℃; for 2h; | Intermediate 1 B 1-(4-fluorobenzyl)-3-methyl-4-nitro-1 H-pyrazole and 1-(4-fluorobenzyl)-5-methyl- 4-nitro- 1 H-pyrazole 1.0 g (7.87 mmol) 3-methyl-4-nitro-1 H-pyrazole (CAS-No. 5334-39-4) was dissolved in 20 mL DMSO and 1.78 g (9.44 mmol) 1 -(bromomethyl)-4-fluorobenzene and 1.76 mL (11.8 mmol) DBU were added. The suspension was stirred at rt for 2 h. Afterwards the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified via a Biotage chromatography system (50 g snap KP- Sil column, hexane / 30 - 100% ethyl acetate). Using this methodology we obtained 1.72 g (93%) of the desired title compounds as a mixture. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 2.40 / 2.62 (s, 3H), 5.31 / 5.43 (s, 2H), 7.16 - 7.25 (m, 2H), 7.26 - 7.34 / 7.36 - 7.46 (m, 2H), 8.28 / 8.96 (s, 1 H). | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 20℃; for 2h; | 1.0 g (7.87 mmol) 3-methyl-4-nitro-1 H-pyrazole (CAS-No. 5334-39-4) was dissolved in 20 mL DMSO and 1.78 g (9.44 mmol) 1 -(bromomethyl)-4-fluorobenzene and 1.76 mL (11.8 mmol) DBU were added. The suspension was stirred at rt for 2 h. Afterwards the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified via a Biotage chromatography system (50 g snap KP- Sil column, hexane / 30 - 100% ethyl acetate). Using this methodology we obtained 1.72 g (93%) of the desired title compounds as a mixture. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 2.40 / 2.62 (s, 3H), 5.31 / 5.43 (s, 2H), 7.16 - 7.25 (m, 2H), 7.26 - 7.34 / 7.36 - 7.46 (m, 2H), 8.28 / 8.96 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 1 B 1-(4-fluorobenzyl)-3-methyl-4-nitro-1 H-pyrazole and 1-(4-fluorobenzyl)-5-methyl- 4-nitro- 1 H-pyrazole 1.0 g (7.87 mmol) 3-methyl-4-nitro-1 H-pyrazole (CAS-No. 5334-39-4) was dissolved in 20 mL DMSO and 1.78 g (9.44 mmol) 1 -(bromomethyl)-4-fluorobenzene and 1.76 mL (11.8 mmol) DBU were added. The suspension was stirred at rt for 2 h. Afterwards the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified via a Biotage chromatography system (50 g snap KP- Sil column, hexane / 30 - 100% ethyl acetate). Using this methodology we obtained 1.72 g (93%) of the desired title compounds as a mixture. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 2.40 / 2.62 (s, 3H), 5.31 / 5.43 (s, 2H), 7.16 - 7.25 (m, 2H), 7.26 - 7.34 / 7.36 - 7.46 (m, 2H), 8.28 / 8.96 (s, 1 H).Intermediate 1 C 1-(4-fluorobenzyl)-3-methyl-1 H-pyrazol-4-amine and 1-(4-fluorobenzyl)-5-methyl- 1 H-pyrazol-4-amine To a solution of 9.48 g (40.3 mmol) of 1 -(4-fluorobenzyl)-3-methyl-4-nitro-1 H- pyrazole and 1 -(4-fluorobenzyl)-5-methyl-4-nitro-1 H-pyrazole (intermediate 1 B) in 211 mL ethanol was added 45.5 g (202 mmol) stannous chloride dihydrate. This reaction mixture was stirred at reflux for 2 hours and then at 70 C for 18 hours. After cooling to 25 C the mixture was evaporated. To the residue diluted with 250 ml ethyl acetate, 5M aq. sodium hydroxide solution was added to get a basic pH. The formed precipitate was separated by filtration and the separated aqueous phase was extracted three times with 150 mL ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 50 - 100% ethyl acetate, then ethyl acetate / 0 - 40% methanol) to obtain 6.06 g (73%) of the desired title compounds as a mixture. 1 H NMR (300 MHz, DMSO d6): delta (ppm) = 1.97 / 1.99 (s, 3H), 3.69 (br. s., 2H), 5.01 / 5.12 (s, 2H), 6.93 / 7.00 (s, 1 H), 7.04 - 7.23 (m, 4H). | ||
To a solution of 9.48 g (40.3 mmol) of 1 -(4-fluorobenzyl)-5-methyl-4-nitro-1 H- pyrazole and 1 -(4-fluorobenzyl)-3-methyl-4-nitro-1 H-pyrazole (intermediate 1 B) in 211 mL ethanol was added 45.5 g (202 mmol) stannous chloride dihydrate. This reaction mixture was stirred at reflux for 2 hours and then at 70 C for 18 hours. After cooling to 25 C the mixture was evaporated. To the residue diluted with 250 ml ethyl acetate, 5M aq. sodium hydroxide solution was added to get a basic pH. The formed precipitate was separated by filtration and the separated aqueous phase was extracted three times with 150 ml. ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and evaporated to obtain a crude product, which was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 50 - 100% ethyl acetate, then ethyl acetate / 0 - 40% methanol) to obtain 6.06 g (73%) of the desired title compounds as a mixture. 1 H NMR (300 MHz, DMSO d6): delta (ppm) = 1.97 / 1.99 (s, 3H), 3.69 (br. s., 2H), 5.01 / 5.12 (s, 2H), 6.93 / 7.00 (s, 1 H), 7.04 - 7.23 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 60℃; for 3h; | Intermediate 4B 4-[(3-methyl-4-nitro-1 H-pyrazol-1-yl)methyl]benzonitrile and 4-[(5-methyl-4- nitro- 1 H-pyrazol- 1 -yl)methyl]benzonitrile 5.00 g (39.4 mmol) 3-methyl-4-nitro-1 H-pyrazole was dissolved in 1 15 mL acetonitrile and 9.26 g (47.2 mmol) 4-(bromomethyl)-benzonitrile and 15.4 g (47.2 mmol) cesium carbonate were added. The suspension was stirred at 60 C for 3 h. Afterwards the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 40 - 100% ethyl acetate) to give 7.27 g (76%) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 2.39 / 2.59 (s, 3H), 5.42 / 5.55 (s, 2H), 7.35 / 7.47 (d, 2H), 7.80 - 7.85 (m, 2H), 8.29 / 8.99 (s, 1 H). | |
With caesium carbonate; In acetonitrile; at 60℃; for 3h; | 5.00 g (39.4 mmol) 3-methyl-4-nitro-1 H-pyrazole was dissolved in 115 mL acetonitrile and 9.26 g (47.2 mmol) 4-(bromomethyl)-benzonitrile and 15.4 g (47.2 mmol) cesium carbonate were added. The suspension was stirred at 60 C for 3 h. Afterwards the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 40 - 100% ethyl acetate) to give 7.27 g (76%) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 2.39 / 2.59 (s, 3H), 5.42 / 5.55 (s, 2H), 7.35 / 7.47 (d, 2H), 7.80 - 7.85 (m, 2H), 8.29 / 8.99 (s, 1 H). | |
With caesium carbonate; In acetonitrile; at 60℃; for 2h; | 5.00 g (39.4 mmol) <strong>[5334-39-4]3-methyl-4-nitro-1H-pyrazole</strong> was dissolved in 115 mL acetonitrile and 9.26 g (47.2 mmol) 4-(bromomethyl)-benzonitrile and 15.4 g (47.2 mmol) cesium carbonate were added. The suspension was stirred at 60C for 3 h. Afterwards the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 40- 100% ethyl acetate) to give 7.27 g (76% yield) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 2.39 / 2.59 (s, 3H), 5.42 / 5.55 (s, 2H), 7.35 / 7.47 (d, 2H), 7.80 - 7.85 (m, 2H), 8.29 / 8.99 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 23B tert-butyl 4-[(3-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxylate and tert-butyl 4-[(5-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxy- late In analogy to intermediate 1 B, 381 mg (3.00 mmol) 3-methyl-4-nitro-1 H-pyrazole and 1.00 g (3.60 mmol) tert-butyl 4-(bromomethyl)piperidine-1 -carboxylate (CAS-No. 158407-04-6) were reacted to give after purification of the crude product by flash chromatography 940 mg (97 %) of the desired title compounds as a 60 : 40 mixture of regioisomers. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.05 / 1.11 (m, 2H), 1.38 (s, 9H), 1.46 (m, 2H), 2.01 (m, 1 H), 2.42 / 2.61 (s, 3H), 2.67 (m, 2H), 3.92 (m, 2H), 4.00 / 4.05 (d, 2H), 8.78 / 8.23 (s, 1 H). Intermediate 24B 4-[(3-methyl-4-nitro-1 H-pyrazol- 1-yl)methyl]piperidine and 4-[(5-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine A solution of 940 mg (2.90 mmol) tert-butyl 4- [(3-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate and tert-butyl 4- [(5-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate (intermediate 23B) in 5 mL dichloromethane was stirred with 2.2 mL (29.0 mmol) trifluoroacetic acid for three hours. The reaction mixture was filtered over NH2 derivatized silica gel, and the filtrate was evaporated yielding 557 mg of the desired title compounds as crude product which was used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.04 / 1.11 (m, 2H), 1.39 (m, 2H), 1.89 (m, 1 H), 2.38 (m, 2H), 2.42 / 2.60 (s, 3H), 2.90 (m, 2H), 3.95 / 4.01 (d, 2H), 8.80 / 8.23 (s, 1 H). | ||
A solution of 940 mg (2.90 mmol) tert-butyl 4-[(5-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate and tert-butyl 4-[(3-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate (intermediate 17B) in 5 mL dichloromethane was stirred with 2.2 mL (29.0 mmol) trifluoroacetic acid for three hours. The reaction mixture was filtered over NH2 derivatized silica gel, and the filtrate was evaporated yielding 557 mg of the desired title compounds as crude product which was used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.04 / 1.11 (m, 2H), 1.39 (m, 2H), 1.89 (m, 1 H), 2.38 (m, 2H), 2.42 / 2.60 (s, 3H), 2.90 (m, 2H), 3.95 / 4.01 (d, 2H), 8.80 / 8.23 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 23B tert-butyl 4-[(3-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxylate and tert-butyl 4-[(5-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxy- late In analogy to intermediate 1 B, 381 mg (3.00 mmol) 3-methyl-4-nitro-1 H-pyrazole and 1.00 g (3.60 mmol) tert-butyl 4-(bromomethyl)piperidine-1 -carboxylate (CAS-No. 158407-04-6) were reacted to give after purification of the crude product by flash chromatography 940 mg (97 %) of the desired title compounds as a 60 : 40 mixture of regioisomers. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.05 / 1.11 (m, 2H), 1.38 (s, 9H), 1.46 (m, 2H), 2.01 (m, 1 H), 2.42 / 2.61 (s, 3H), 2.67 (m, 2H), 3.92 (m, 2H), 4.00 / 4.05 (d, 2H), 8.78 / 8.23 (s, 1 H). Intermediate 24B 4-[(3-methyl-4-nitro-1 H-pyrazol- 1-yl)methyl]piperidine and 4-[(5-methyl-4-nitro- 1 H-pyrazol- 1 -yl)methyl]piperidine A solution of 940 mg (2.90 mmol) tert-butyl 4- [(3-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate and tert-butyl 4- [(5-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine-1 -carboxylate (intermediate 23B) in 5 mL dichloromethane was stirred with 2.2 mL (29.0 mmol) trifluoroacetic acid for three hours. The reaction mixture was filtered over NH2 derivatized silica gel, and the filtrate was evaporated yielding 557 mg of the desired title compounds as crude product which was used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.04 / 1.11 (m, 2H), 1.39 (m, 2H), 1.89 (m, 1 H), 2.38 (m, 2H), 2.42 / 2.60 (s, 3H), 2.90 (m, 2H), 3.95 / 4.01 (d, 2H), 8.80 / 8.23 (s, 1 H). Intermediate 25B 1-(ethylsulfonyl)-4-[(3-methyl-4-nitro-1 H-pyrazol-1-yl)methyl]piperidine and 1- iperidine A solution of 550 mg (2.45 mmol) 4-[(3-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine and 4-[(5-methyl-4-nitro-1 H-pyrazol-1 -yl)methyl]piperidine (intermediate 24B) in 5 mL DMF was stirred with 195 mu (2.06 mmol) ethanesulfonyl chloride and 1 .23 mL (8.83 mmol) triethylamine overnight. Saturated aqueous sodium bicarbonate was added to the reaction. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried, filtered, and evaporated. 628 mg of the desired title compounds as crude product were obtained which were used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.19 (t, 3H), 1.20 / 1.27 (m, 2H), 1.57 (m, 2H), 2.00 (m, 1 H), 2.42 / 2.62 (s, 3H), 2.76 (m, 2H), 3.01 (q, 2H), 3.58 (m, 2H), 4.03 / 4.09 (d, 2H), 8.80 / 8.24 (s, 1 H). | ||
A solution of 550 mg (2.45 mmol) 4-[(5-methyl-4-nitro-1 H-pyrazol-1 - yl)methyl]piperidine and 4-[(3-methyl-4-nitro-1 H-pyrazol-1 -yl)methyl]piperidine (intermediate 18B) in 5 mL DMF was stirred with 195 muL (2.06 mmol) ethanesulfonyl chloride and 1.23 mL (8.83 mmol) triethylamine overnight. Saturated aqueous sodium bicarbonate was added to the reaction. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried, filtered, and evaporated. 628 mg of the desired title compounds as crude product were obtained which were used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.19 (t, 3H), 1.20 / 1.27 (m, 2H), 1.57 (m, 2H), 2.00 (m, 1 H), 2.42 / 2.62 (s, 3H), 2.76 (m, 2H), 3.01 (q, 2H), 3.58 (m, 2H), 4.03 / 4.09 (d, 2H), 8.80 / 8.24 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of methyl 3-((l-(l-(tert-butoxycarbonyl)piperidin-4-yl) -3- methyl-lH-pyrazol-4-yl)amino)isonicotinate (1.0 g, 2.40 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.07 g, 2.0 mL). The reaction mixture was stirred at 15 °C for lh. Then concentrated to give the methyl 3-(3-methyl-l-(piperidin-4- yl)-lH-pyrazol-4-yl (0729) amino)isonicotinate (1.2 g , Yield: 92percent) as 2 TFA salt which was used directly in next reaction without further purification. ESI-LCMS (m/z): 316.1 [M+1]. Same protocol used for methyl 3-((5-methyl-l-(piperidin-4-yl)- lH-pyrazol-4-yl)amino) isonicotinate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyl-4-nitro-lH-pyrazole (5.08 g, 40 mmol) in anhydrous THF (60 mL) was added tert-butyl 4-hydroxypiperidine- 1 -carboxylate (8.84 g, 44 mmol) and RhoRho1 (15.7 g, 60 mmol). The resulting solution was stirred at 0 C for 5 min, then DEAD (10.4 g, 60 mmol) was added dropwise at 0C. After addition the resulting mixture was stirred at room temperature for 3 hours, and the LCMS indicated the starting material was consumed. After concentration, the residue was purified by silica gel chromatography (eluted with EtO Ac/petroleum ether = 4/1 to 2/1) to give a mixture of two regioisomers (totally 8.9 g, Yield: 72 %, isomeric ratio: around 7/3 based on HNMR): tert- butyl 4-(3-methyl-4-nitro-lH-pyrazol-l-yl)piperidine-l -carboxylate (major) and tert-butyl 4- (5 -methyl-4-nitro-lH-pyrazol-l-yl)piperidine-l -carboxylate (minor) as light yellow oil. ESI- LCMS (m/z): 255.1 [M-55] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of tert-butyl 4-(3-methyl-4-nitro-lH- pyrazol-1- yl)piperidine-l- carboxylate and tert-butyl 4-(5-methyl-4-nitro-lH- pyrazol- 1 -yl)piperidine- 1- carboxylate (4.8 g, 15.5 mmol, form step 1) in MeOH (20 mL) was added 10% Pd/C (480 mg), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The LCMS indicated the starting materials were consumed. After filtration, the filtrate was concentrated to give a mixture of tert-butyl 4-(4-amino-3 -methyl- lH-pyrazol-1- yl) piperidine- 1 -carboxylate and tert-butyl 4-(4-amino-5 -methyl- IH-pyrazol-l-yl) piperidine- 1-carboxylate (4.1 g, Yield: 94%, isomeric ratio: around 5/3 based on HNMR) as light yellow oil. ESI-LCMS (m/z): 281.2 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | To a solution of 3-methyl-4-nitro-lH-pyrazole (2.54 g, 20 mmol) in anhydrous THF (40 mL) under nitrogen atmosphere was added 2-(dimethylamino)ethanol (1.8 g, 20 mmol), RhoRho1 (7.86 g, 30 mmol). The solution was cooled to 0 C and DIAD (6.06 g, 30 mmol) was added dropwise. After the addition the reaction mixture was stirred for 15 min at 0 C, warmed to room temperature and stirred overnight. The resulting solution was diluted with EtOAc (100 mL) and washed with water (20 mL x 3), the organic phase was dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with petroleum ether/EtOAc = 6/1) to give an inseparable mixture of regioisomers: N,N-dimethyl- 2-(3-methyl-4-nitro-lH- pyrazol-l-yl)ethanamine and N,N-dimethyl-2-(5-methyl-4-nitro-lH- pyrazol-l-yl) ethanamine (937 mg, Yield: 23%) as yellow oil. ESI-LCMS (m/z): 199.1 (0828) [M+l] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of N,N-dimethyl-2-(3-methyl-4-nitro-lH-pyrazol-l-yl)ethanamine and N,N-dimethyl-2-(5- methyl-4-nitro-lH-pyrazol-l-yl) ethanamine (868 mg, 4.37 mmol) in MeOH (14 mL) was added Pd/C (10%, 90 mg) with nitrogen protected. The system was degassed, recharged with and stirred at room temperature overnight. The reaction mixture was filtered through Celite and filtrate was concentrated to give a mixture of l-(2-(dimethylamino)ethyl)-3- methyl-lH- pyrazol-4-amine and l-(2-(di- methylamino)ethyl)-5-methyl-lH-pyrazol-4-amine (740 mg, 100%) as white solid. ESI-LCMS (m/z): 169.2 [M+l] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | To a solution of 3-methyl-4-nitro- lH-pyrazole (500 mg, 3.93 mmol) in dry THF (10 mL) was added (3R,4S)-benzyl- 3-hydroxyl-4- methylpyrrolidine-1 -carboxylate (924 mg, 3.93 mmol), and PPh3 (2.06 g, 7.86 mmol). The solution was stirred at room temperature for 5 min, and then DIAD (1.58 g, 7.86 mmol) was added dropwise. After addition the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (eluted with EtO Ac/petroleum ether = 1/5 to 1/1) to give (3,S,45)-benzyl 3- methyl- 4-(5-methyl-4-nitro-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate (1.2 g, Yield: 88% yield). ESI-LCMS (m/z): 345.2 [M+l] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In analogy to intermediate 3C-2, 7.27 g (30.0 mmol) 4-[(3-methyl-4-nitro-1H-pyrazol- 1-yl)methyl]benzonitrile and 4-[(5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate 17B-2 and 18B-2) were reacted to give after purification of the crude product via a Biotage chromatography system (100g snap KP-Sil column, hexane / 50 - 100% ethyl acetate, then ethyl acetate / 0- 40% methanol) 4.42 g (69% yield) of the desired title compounds as a mixture. 1H-NMR (300 MHz, DMSO d6) delta (ppm) = 1.98 (s, 3H), 3.66 (br. s., 2H), 5.15 / 5.25 (s, 2H), 6.97 / 7.06 (s, 1H), 7.15 / 7.26 (d, 2H), 7.77 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67%; 9% | In analogy to example 6-2, 98.2 mg (0.46 mmol) of a mixture of 4-[(4-amino-3- methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-methyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 17C-2 and 18C-2) and 102 mg (0.39 mmol) 6- methyl-2-phenylquinoline-4-carboxylic acid ([CAS-No. 60538-98-9], commercially available at e.g. Enamine, Chemical Diversity Labs, Matrix, Zerenex), were reacted to give after purification using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 50- 100% ethyl acetate, then ethyl acetate / 0- 100% methanol) followed by a separation and purification via preparative HPLC (method 6a) 121 mg (67% yield) of the desired example 41 and 16 mg (9.0% yield) of the desired example 42-2. N-[1-(4-cyanobenzyl)-3-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide, example 41-2: 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 2.21 (s, 3H), 2.52 (s, 3H), 5.41 (s, 2H), 7.44 (d, 2H), 7.49 - 7.61 (m, 3H), 7.68 (dd, 1H), 7.85 (d, 2H), 7.90 (s, 1H), 8.06 (d, 1H), 8.23 (s, 1H), 8.30 - 8.34 (m, 3H), 8.36 (s, 1H), 10.34 (s, 1H). N-[1-(4-cyanobenzyl)-5-methyl-1H-pyrazol-4-yl]-6-methyl-2-phenylquinoline-4- carboxamide, example 42-2: 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 2.24 (s, 3H), 2.53 (s, 3H), 5.47 (s, 2H), 7.32 (d, 2H), 7.50 - 7.62 (m, 3H), 7.69 (dd, 1H), 7.84 - 7.88 (m, 2H), 7.89 (s, 1H), 7.96 (s, 1H), 8.06 (d, 1H), 8.26 (s, 1H), 8.31 - 8.36 (m, 2H), 10.27 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 100℃; for 3h; | To a mixture of 3 -methyl -4-niiro-lH-pyrazole (1.50 g, 11.80 mmol) and 2,2-dimethyloxirane (2.43 g, 33.75 mmol, 3 mL) in DMF (19 mL) was added Cs2COr, (7.69 g, 23.60 mmol) at 25 C then heated to 100 C and stirred for 3 h. The mixture was cooled to 25 C and poured into water (100 mL) then extracted with EtOAc (5 40 mL), washed with brine (3 20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a mixture of compound 2-methyl-l-(3-methyl-4-nitro-pyrazol-l-yl)propan-2-ol and 2-methyl-l-(5-methyl-4-nitro-lH- pyrazol-l-yl)propan-2-ol as a red brown oil . LCMS: RT 0.485 min, m/z = 200.2 [M + H , |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3 -methyl -4-niiro-lH-pyrazole (1.50 g, 11.80 mmol) and 2,2-dimethyloxirane (2.43 g, 33.75 mmol, 3 mL) in DMF (19 mL) was added Cs2COr, (7.69 g, 23.60 mmol) at 25 C then heated to 100 C and stirred for 3 h. The mixture was cooled to 25 C and poured into water (100 mL) then extracted with EtOAc (5 40 mL), washed with brine (3 20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a mixture of compound 2-methyl-l-(3-methyl-4-nitro-pyrazol-l-yl)propan-2-ol and 2-methyl-l-(5-methyl-4-nitro-lH- pyrazol-l-yl)propan-2-ol as a red brown oil . LCMS: RT 0.485 min, m/z = 200.2 [M + H ] A solution of the mixture 2-methyl-l -(3-methyl-4-nitro-pyrazol-l - yl)propan-2-ol and 2-methyl-l-(5-methyl-4-nitro-lH-pyrazol-l-yl)propan-2-ol(1.00 g, 5.02 mmol) in EtOH (20 mL) was treated with Pd/C (10%, 0.3 g). The suspension was degassed and purged with H? for 3 times. The mixture was stirred under H2 (15 PSI) at 25 C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give the mixture compound 1 -(4-amino-3- methyl-pyrazol-l-yl)-2-methyl-propan-2-ol and l -(4-amino-5-methyl-lH-pyrazol-l-yl)-2-methylpropan- 2-ol as a brown oil. LCMS: RT 0.111 mm, m/z ----- 170.2 [M +H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3 -methyl -4-niiro-lH-pyrazole (1.50 g, 11.80 mmol) and 2,2-dimethyloxirane (2.43 g, 33.75 mmol, 3 mL) in DMF (19 mL) was added Cs2COr, (7.69 g, 23.60 mmol) at 25 C then heated to 100 C and stirred for 3 h. The mixture was cooled to 25 C and poured into water (100 mL) then extracted with EtOAc (5 40 mL), washed with brine (3 20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a mixture of compound 2-methyl-l-(3-methyl-4-nitro-pyrazol-l-yl)propan-2-ol and 2-methyl-l-(5-methyl-4-nitro-lH- pyrazol-l-yl)propan-2-ol as a red brown oil . LCMS: RT 0.485 min, m/z = 200.2 [M + H ] A solution of the mixture 2-methyl-l -(3-methyl-4-nitro-pyrazol-l - yl)propan-2-ol and 2-methyl-l-(5-methyl-4-nitro-lH-pyrazol-l-yl)propan-2-ol(1.00 g, 5.02 mmol) in EtOH (20 mL) was treated with Pd/C (10%, 0.3 g). The suspension was degassed and purged with H? for 3 times. The mixture was stirred under H2 (15 PSI) at 25 C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give the mixture compound 1 -(4-amino-3- methyl-pyrazol-l-yl)-2-methyl-propan-2-ol and l -(4-amino-5-methyl-lH-pyrazol-l-yl)-2-methylpropan- 2-ol as a brown oil. LCMS: RT 0.111 mm, m/z ----- 170.2 [M +H]+ A mixture of 1 -(4-amino-3 -methyl -pyrazol-1 -yl)-2-methyl-propan- 2-ol and l-(4-amino-5-methyl-pyrazol-l-yl)-2-methyl-propan-2-ol ) (300 mg, 1.77 mmol), 2-chloro-4- cyclopropyl-5-(trifiuoromethyl)pynmidine (591 mg, 1.59 mmol) and Et3N (537 mg, 5.31 mmol, 736.05 mu,) were taken up into a microwave tube in n-BuOH (3 mL). The sealed tube was heated at 120 C for 60 min under microwave. The reaction mixture was cooled to 25 C and filtered. The residue was purified by prep-HPLC (neutral) and further separated by SFC to provide l-[4-[[4-cyclopropyl-5- (tri.fiuoromethyl)pyri.midin~2-yl]amino]-3~methyl-pyrazol~l -yl]~2-methy as a white solid and 1- [4~[[4-cyclopropyl~5-(trifiuorome2- ol as a white solid. 1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-l-yl]-2- methyl-propan-2-ol (A-19): H MR (400 MHz, CDC13): delta rhoiotaeta 8.39 (s, 1 H), 7.65 (s, 1 H), 6.50 (br. s? 1 H), 4.40 (s, 1 H), 3.98 (s, 2 H), 2.26 (s, 1 H), 2.19 (s, 3 H), 1 .24 - 1.28 (m, 1 H), 1.19 (s, 8 H), 1.04 - 1.12 (m, 2 H). HPLC: RT 2.91 mm. MS: | M - H j ' m/z 356.2. 1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yljamino]-5-methyl-pyrazol-l-yl]-2- methyl-propan-2-ol (A-18): lH NMR (400 MHz, CDC13): delta rhoetaiota 8.42 (br. s,, 1 1 1). 7.78 (br. s., 1 H), 6.73 (br. s., 1 H), 3.88 - 4.06 (m, 3 H), 2.25 (s, 4 H), 1.23 - 1 ,28 (m, 2 H), 1.19 (s, 6 H), 1 .09 - 1 .15 (m, 2 H). HPLC: RT 2.91 min. MS: | M 1 11 m/z: 356.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 16h;Inert atmosphere; | To a mixture of 1 -(4 -hydroxy- l-piperidyl)ethanone (500 mg, 3.49 mmo), 3-methyl-4-nitro-lH-pyrazole (487 mg, 3.84 mmol) and PPh3 (1.37 g, 5.24 mmo3) in THF (30 mL) was added DIAD (1 .06 g, 5.24 mmol) at 0 C under N2. The mixture was then stirred at 25 C for 16 h. The mixture was poured into ice-water (100 mL) and extracted with EiOAc (3 chi 50 mL). The combined organic phase was washed with brine, dried with anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 1: 1) to afford a mixture of 1- [4-(5-methyl-4-nitro-pyrazol-l -yl)-l -piperidy]]ethanone and l-[4-(3-methyl-4-nitro-pyrazol-l -yl)-l - piperidyljjeihanone as a white solid. LCMS: RT 0.603 rnin, m/z ~- 253.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 1 -(4 -hydroxy- l-piperidyl)ethanone (500 mg, 3.49 mmo), 3-methyl-4-nitro-lH-pyrazole (487 mg, 3.84 mmol) and PPh3 (1.37 g, 5.24 mmo3) in THF (30 mL) was added DIAD (1 .06 g, 5.24 mmol) at 0 C under N2. The mixture was then stirred at 25 C for 16 h. The mixture was poured into ice-water (100 mL) and extracted with EiOAc (3 chi 50 mL). The combined organic phase was washed with brine, dried with anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 1: 1) to afford a mixture of 1- [4-(5-methyl-4-nitro-pyrazol-l -yl)-l -piperidy]]ethanone and l-[4-(3-methyl-4-nitro-pyrazol-l -yl)-l - piperidyljjeihanone as a white solid. LCMS: RT 0.603 rnin, m/z ~- 253.2 [M + H|+. To a mixture of l -[4-(5~methyl-4-nitro-pyrazol-l-yi)-l- piperidyl]ethanone and l-[4-(3-methyl-4-nitro-pyrazol-l-yl)-l-piperidyl]ethanone (400 mg, 1.59 mmol) was in Me OH (20 mL) added Pd-C (0.2 g) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25C for 1 h. The reaction mixture was filtered and the filtrate was concentrated to give a mixture l-[4-(4-amino-5-methyl-pyrazol- l-yl)-l-piperidyl]ethanone and l-[4-(4-arnino-3-methy]-pyrazo]-l-yl)-l-piperidyl]etlianone as a dark- brown solid. LCMS: RT 0.731 mm, m/z == 223.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 1 -(4 -hydroxy- l-piperidyl)ethanone (500 mg, 3.49 mmo), 3-methyl-4-nitro-lH-pyrazole (487 mg, 3.84 mmol) and PPh3 (1.37 g, 5.24 mmo3) in THF (30 mL) was added DIAD (1 .06 g, 5.24 mmol) at 0 C under N2. The mixture was then stirred at 25 C for 16 h. The mixture was poured into ice-water (100 mL) and extracted with EiOAc (3 chi 50 mL). The combined organic phase was washed with brine, dried with anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 1: 1) to afford a mixture of 1- [4-(5-methyl-4-nitro-pyrazol-l -yl)-l -piperidy]]ethanone and l-[4-(3-methyl-4-nitro-pyrazol-l -yl)-l - piperidyljjeihanone as a white solid. LCMS: RT 0.603 rnin, m/z ~- 253.2 [M + H|+. To a mixture of l -[4-(5~methyl-4-nitro-pyrazol-l-yi)-l- piperidyl]ethanone and l-[4-(3-methyl-4-nitro-pyrazol-l-yl)-l-piperidyl]ethanone (400 mg, 1.59 mmol) was in Me OH (20 mL) added Pd-C (0.2 g) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25C for 1 h. The reaction mixture was filtered and the filtrate was concentrated to give a mixture l-[4-(4-amino-5-methyl-pyrazol- l-yl)-l-piperidyl]ethanone and l-[4-(4-arnino-3-methy]-pyrazo]-l-yl)-l-piperidyl]etlianone as a dark- brown solid. LCMS: RT 0.731 mm, m/z == 223.1 [M + H]+.To a msxture of l-[4-(4-amino-5-methyl-pyrazol- l -yl)-l -piperidyl]ethanone and l -[4-(4-amino-3-methyl-pyrazol-l -yl)-l -piperidy]]ethanone (250 mg, 1.13 mmol) in 1,4-dioxane (2 mL) was added 4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyi)pyrimidine (150 mg, 563 umol) and p-TsOH (29 mg, 169 umol) at 25 C under N2. The mixture was then heated to 100 C and stirred for 2 h. The mixture was cooled to 25 C and poured into ice-water (30 mL). The aqueous phase was extracted with EtOAc (20 mL chi 3). The combined organic phase was washed with brine, dried with anhydrous NajSO,], filtered and concentrated. The residue was purified by prep- HPLC (neutral), which was further separated by SFC to give l-[4-[4-[[4-cyclopropyl-5- (trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyrazol-l -ylj-l -piperidyl]ethanone (A-20) and l-[4-[4- [[4-cyxlopropyl-5~(trifluoromethyl)pyrimidin-2-yl]amino]-3-methy-pyrazol-l-yl]-l- piperidyI]ethanooe (A-21) 1_[4- [4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl] amino]-5-methyl-pyrazol-l-yl]-l- piperidyJethanone (A-20): 'H NMR (400 MHz, CDC13): delta 8.37 (s, I I I). 7.63 (br. s., 1H), 6.60 (br. s., 1H), 4.76 (d, J = 13 ,43 Hz, 1H), 4.20 (tt, J= 4.20, l l . i l Hz, 1 H), 4.01 (d, J = 13 ,93 Hz, 1H), 3.18-3.28 (m, 1H), 2.69-2.79 (m, 1H), 2.17-2.31 (m, 5H), 2.12-2.16 (m, 3H), 1.90-2.1 1 (m, 3H), 1.16-1.25 (rn, 2H), 1.03- 1.10 (m, 2H). HPLC: RT 2.413 min. MS: j . m/z: 409.2. l-[4- [4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl] amino|-3-methyl-pyrazol-l-yl]-l- piperidyI]ethanooe (A-21): NMR (400 MHz, CDCU): delta 8.43 (br, s,, 1H), 7.81 (br. s, 1H), 6.67 (br. s., 1H), 4.76 (d, J = 14,05 Hz, 1H), 4.25 (tt, J = 4,00, 1 1.37 Hz, 1H), 3.96 (d, J = 13 ,80 Hz, 1H), 3.24 (t, J = 12.05 Hz, 1H), 2.69-2.84 (m, i l l ). 2.16-2.28 (m, 6H), 2.15 (s, 3H), 1 .84-2.02 (m, 2H), 1.24-1.28 (m, 2H), 1.14 (br. s., 21 1 ). HPLC: RT 2.406 min. MS: | .M H I m/z: 409.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl ~4-nitro- lH-pyrazole ( 10 g, 78,68 mmol) in DMF (50 mL) was added portionwise NaH (4.72 g, 1 18 ,02 mmol, 60% purity) at 0 C over 30 min. After addition, the mixture was stirred at 20 C for 30 min, and then 3- bromo-3-methylbutan-2-one ( 15.58 g, 94.42 mmol) was added dropwise at 0 C. The resulting mixture was stirred at 20 C for 1 1 h. The reaction mixture was quenched by addition of H20 (250 mL) at 0C, and extracted with EtOAc (3 chi 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO/j, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE/EtOAc = 20/1 to 3/1). 3-methyl-3-(3-methyi-4- nitro-lH-pyrazol-l-yl)butan-2-one was obtained as a yellow solid. LCMS: RT 0.674 min, m/z = 212 [M + H]+. 'H NMR (400 MHz, CDC13): 6 ppm 8.30 (s, 1 H) 2.56 (s, 3 H) 1.98 (s, 3 H) 1.75 (s, 6 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 17h;Inert atmosphere; | To a mixture of 3-methyl-4-nitro-lH-pyrazole (5 g, 39.34 mmol) and tetrahydropyran-4-ol (4.82 g, 47.21 mmol, 4.73 mL) in THF (70 mL) was added PI3 (15.48 g, 59.01 mmol) and DIAD (11.93 g, 59.01 mmol . 1.47 mL) in one portion at 0C under N2. The mixture was stirred at 0 C for 60 min, then warmed to 25 C and stirred for 16 h. The mixture was poured into the mixture of PE and EtOAc (PE:Ei()Ac = 1 : 1) (100 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1) to afford 5- methyl-4-iiitro-l-tetrahydropyran-4-yl-pyrazole and 3-methyl-4-nitro~l -tetrahydro-2H~pyran~4-yl~ pyrazole as yellow solids. LCMS: RT 0.610 min, m/z = 212.2 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3-methyl-4-nitro-lH-pyrazole (5 g, 39.34 mmol) and tetrahydropyran-4-ol (4.82 g, 47.21 mmol, 4.73 mL) in THF (70 mL) was added PI3 (15.48 g, 59.01 mmol) and DIAD (11.93 g, 59.01 mmol . 1.47 mL) in one portion at 0C under N2. The mixture was stirred at 0 C for 60 min, then warmed to 25 C and stirred for 16 h. The mixture was poured into the mixture of PE and EtOAc (PE:Ei()Ac = 1 : 1) (100 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1) to afford 5- methyl-4-iiitro-l-tetrahydropyran-4-yl-pyrazole and 3-methyl-4-nitro~l -tetrahydro-2H~pyran~4-yl~ pyrazole as yellow solids. LCMS: RT 0.610 min, m/z = 212.2 [M+H] To a mixture of 5-methyl-4-nitro-l-(tetrahydropyran-4-yl)-lH-pyrazole and 3- methyl-4-nitro~l-tetrahydro-2H-pyran~4-y3-pyrazo3e (3 g, 14.20 mmol) in MeOH (60 mL) was added Pd/C (1 g, 10%) under N2. The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product 5 -methyl- 1- tetrahydropyran-4-yl-pyrazol-4-amine and 3 -methyl- l-tetrahydro-2H-pyran-4-yl-pyrazol-4-amine was used into the next step without further purification. LCMS: RT 0.482 min, m/z = 182.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3-methyl-4-nitro-lH-pyrazole (5 g, 39.34 mmol) and tetrahydropyran-4-ol (4.82 g, 47.21 mmol, 4.73 mL) in THF (70 mL) was added PI3 (15.48 g, 59.01 mmol) and DIAD (11.93 g, 59.01 mmol . 1.47 mL) in one portion at 0C under N2. The mixture was stirred at 0 C for 60 min, then warmed to 25 C and stirred for 16 h. The mixture was poured into the mixture of PE and EtOAc (PE:Ei()Ac = 1 : 1) (100 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1) to afford 5- methyl-4-iiitro-l-tetrahydropyran-4-yl-pyrazole and 3-methyl-4-nitro~l -tetrahydro-2H~pyran~4-yl~ pyrazole as yellow solids. LCMS: RT 0.610 min, m/z = 212.2 [M+H] To a mixture of 5-methyl-4-nitro-l-(tetrahydropyran-4-yl)-lH-pyrazole and 3- methyl-4-nitro~l-tetrahydro-2H-pyran~4-y3-pyrazo3e (3 g, 14.20 mmol) in MeOH (60 mL) was added Pd/C (1 g, 10%) under N2. The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product 5 -methyl- 1- tetrahydropyran-4-yl-pyrazol-4-amine and 3 -methyl- l-tetrahydro-2H-pyran-4-yl-pyrazol-4-amine was used into the next step without further purification. LCMS: RT 0.482 min, m/z = 182.1 [M+H]+. 5 -methyl- l-tetrahydropyran-4- yl-pyrazol-4-amine, 3 -methyl -l-tetrahydro-pyran-4-yl-pyrazol-4-amine (200 mg, 1.31 mmol), 2-chloro-4- cyclopropyl-5-(trifluoromethyl)pyrimidine (251 mg, 1.13 mmol) and TEA (398 mg, 3.93 mmol, 544.77 mu,) were taken up into a microwave tube in n-BuOH (2 mL). The sealed tube was heated at 120 C for 90 mm under microwave. The mixture was cooled to 25 C and concentrated under reduced pressure. The residue was poured into ice-water (5 mL). The aqueous phase was extracted with EtOAc (3 chi 2 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous a2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Si02, PE: EtOAc = 1 : 1 ) to provide 4-cyciopropyl-N-(5 -methyl- 1 -tetrahy dropyran-4-yl-pyrazoi-4-yi)-5 -(trifluoromethy l)pyrimidin- 2-amine and 4-cyclopropyl- -(3-niethyl-l~tetrahydropyran-4-yl-pyrazol-4-yl)-5- (trifluoromemyl)pyrimidin-2-aniine was obtained. 4-cyclopropyl-N-(5-methyl-l-tetrahydropyran-4-yl-pyrazoI-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (A-24): H NMR (400 MHz, CDClj) : 5 8.39 (s, 1 H), 7.66 (br. s., 1 H), 6.28 - 6.92 (m, 1 H i. 4.12 - 4.26 (m, 3 H), 3.49 - 3.62 ( m. 2 l i s. 2.33 (qd, ./ 12.40. 4.58 Hz, 2 H), 2.23 (s, 3 I }. 1.87 (dd, .7=12.80, 2.13 Hz, 2 H), 1.23 (br. s,, 2 H), 1.04 - 1.12 (m, 2 H). HPLC: RT 3.06 niin, MS: [M+H]+ m/z = 368.2. 4- cyclopropyl-N-(3-methyl-l-tetrahydropyran-4-yl-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (A-25): lH NMR (400 MHz, CDC13) : delta 8.42 (br. s., 1 H), 7.83 (br. s., 1 H), 4,23 - 4.33 (m, 1 H), 4.12 (d, J=l 1.04 Hz, 2 H), 3.56 (t, .7=1 1 ,73 Hz, 2 H), 2.26 (s, 3 H), 1.98 - 2.1 7 (m, 4 I I ). 1 ,25 - 1.31 (m, 2 1 1} 1. 16 (br, s, 2 H). HPLC: RT 3 , 15 min. MS: | M 1 11 m/z = 368 ,2. |
Yield | Reaction Conditions | Operation in experiment |
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With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 12h; | To a solution of 5-hydroxy-l-methyl-piperidin-2-one (175 nig, 1.35 mniol) , 3 -methyl -4-nitro-lH-pyrazole (5) (205.9 rag, 1.62 mmol) and PPh3 (531.14 mg, 2.03 mmol) in THF (15 mL) was added DIAD (409.48 mg, 2.03 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue, which was purified by prep-TLC (Si02, DCM: MeOH :=: 20: 1) to give a mixture of l-methyl-5-(5-methyl-4-nitro-lH- pyrazol-l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-iiitro-lH-pyrazol-l-yl)piperidin-2-one as yellow solid, LCMS: RT 0,577 min, m/z = 239.1 [M+H . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-hydroxy-l-methyl-piperidin-2-one (175 nig, 1.35 mniol) , 3 -methyl -4-nitro-lH-pyrazole (5) (205.9 rag, 1.62 mmol) and PPh3 (531.14 mg, 2.03 mmol) in THF (15 mL) was added DIAD (409.48 mg, 2.03 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue, which was purified by prep-TLC (Si02, DCM: MeOH :=: 20: 1) to give a mixture of l-methyl-5-(5-methyl-4-nitro-lH- pyrazol-l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-iiitro-lH-pyrazol-l-yl)piperidin-2-one as yellow solid, LCMS: RT 0,577 min, m/z = 239.1 [M+H . To a mixture of l-methyl-5-(5-methyl-4-nitro-lH-pyrazol- l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-nitro-lH-pyrazol-l-yl)piperidin-2-one (180 mg, 755.54 muetaiotaomicron) in MeOH (10 mL) was added Pd/C (10%, 60 mg) under 2. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 C for 4 h. It was filtered over celite, the filter cake was washed wtih MeOH (20 mL chi 2), the filtrate was combined and concentrated under reduced pressure to give a mixture of 5-(4-amino-5-meth}7l-lH-pyrazol-l-yl)-l-methylpiperidin-2- one and 5-(4-amino-3-methyl-lH-pyrazol-l -yl)-l -methylpiperidin-2-one (as yellow oil. LCMS: RT 0.194 mm, m/z = 209.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-hydroxy-l-methyl-piperidin-2-one (175 nig, 1.35 mniol) , 3 -methyl -4-nitro-lH-pyrazole (5) (205.9 rag, 1.62 mmol) and PPh3 (531.14 mg, 2.03 mmol) in THF (15 mL) was added DIAD (409.48 mg, 2.03 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue, which was purified by prep-TLC (Si02, DCM: MeOH :=: 20: 1) to give a mixture of l-methyl-5-(5-methyl-4-nitro-lH- pyrazol-l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-iiitro-lH-pyrazol-l-yl)piperidin-2-one as yellow solid, LCMS: RT 0,577 min, m/z = 239.1 [M+H . To a mixture of l-methyl-5-(5-methyl-4-nitro-lH-pyrazol- l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-nitro-lH-pyrazol-l-yl)piperidin-2-one (180 mg, 755.54 muetaiotaomicron) in MeOH (10 mL) was added Pd/C (10%, 60 mg) under 2. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 C for 4 h. It was filtered over celite, the filter cake was washed wtih MeOH (20 mL chi 2), the filtrate was combined and concentrated under reduced pressure to give a mixture of 5-(4-amino-5-meth}7l-lH-pyrazol-l-yl)-l-methylpiperidin-2- one and 5-(4-amino-3-methyl-lH-pyrazol-l -yl)-l -methylpiperidin-2-one (as yellow oil. LCMS: RT 0.194 mm, m/z = 209.1 [M+H]+. A mixture of 5-(4~amino-5~ methyl- lH-pyrazol-l-yl)-l-methylpiperidm-2-one and 5-(4-amino-3-methyl-lH-pyrazol-l-y])-l- methylpiperidin-2-one (107 mg, 513.78 mupiiotaomicron), 4-cyclopropyl-2-methylsulfonyl-5- (trifluoromethyl)pyrimidine (137 mg, 513.78 muetaiotaomicron) and TsQH.HjQ (49 mg, 256.89 mupiiotaomicron) in 1,4-dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the m ixture was stirred at 100 C for 2 h under N2. It was poured into H20 (15 mL), adjusted to pH = 8 with aq, NaHC03, extracted wtih EtOAc (2 x 30 mL). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to get a residue, which was purified by prep-HPLC (neutral) first and then it was re- purified by SFC to give 5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-lH- pyrazol-1 -yl)-l -methylpiperidin-2-one (14 mg) and 5-(4-((4-cyc]opropyl-5-(tri£luoromethyl)pyrimidin-2- yl)amino)-3 -methyl- 1 H-pyrazol- 1 -yl)- 1 -methylpiperidin-2-one . 5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-lH-pyrazol-l-yl)-l- methylpiperidin-2-one (A-26): H MR (400 MHz, CDC13): 3 8.39 (s, IH), 7.67 (br, s . 1H), 6.51 (br. s, H), 4.42 - 4.60 (m, IH), 3.91 (dd, J = 1 1.69, 9,92 Hz, 1H), 3.46 (ddd, J = 12.13, 5 ,51 , 1 ,76 Hz, IH), 3.00 (s, 3H), 2.65 (d, J ------- 3.97 Hz, 1H), 2.42 - 2.59 (m, 11 1 ). 2.25 (s, 3H), 2.17 (d. ./ 1.76 Hz, 2H), 1.22 (br. s.,2H), 1.09 (dd, J = 7.72, 3.31Hz, 2H). HPLC: Retention Time: 2.87 min. MS: (M+lT) m/z. 395.2. 5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-lH-pyrazol-l-yl)-l- methylpiperidin-2-one (A-27): MR (400 MHz, CDC13): delta 8.43 (s, IH), 7.86 (br, s,, IH), 6,49 - 6.87 (m, IH), 4.56 id. ./ 6.62 Hz, IH), 3.71 (d, ./ 7.06 Hz, 21 1 ). 3.00 (s, 3H), 2.48 - 2.64 (m, 2H), 2.34 - 2.45 (m, IH), 2.17 ·· 2.34 (m, 4H), 1.22 - 1.30 (m, 21 1 ). 1.15 (br. s., 2H). HPLC: Retention Time: 2.86 m in. MS: ( M l ) m/z: 395.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 100℃; for 12h;Inert atmosphere; | To a mixture of 3- methyl-4-nitro-lH-pyrazole (2.33 g, 18.35 mmol) in DMF (10 mL) was added NaH (927 rng, 23.18 mmol, 60%) in one portion at 0 C under N2. After that <strong>[35120-18-4]ethyl 1-bromocyclobutanecarboxylate</strong> (4 g, 19.32 mmol) was added and the mixture was stirred at 100 C for 12 h. The mixture was poured into ice-water (70 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 chi 30 mL). The combined organic phase was washed with brine (2 chi 20 mL), dried with anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 2: 1) to give ethyl 1 -(3-methyl-4-nitro- lH-pyrazol- 1 -yl)cycobutanecarboxylate as a white solid. lH NMR (400 MHz, CDC13): 5ppm 8.08 - 8,20 (m, 1 H) 4.00 - 4.22 (m, 2 H) 2.54 - 2.93 (m, 3 H) 2,48 (s, 3 H) 2.09 - 2,36 (m, 1 H) 1 .92 - 2.05 (m, 1 H) 1.14 - 1 .25 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; | : To a solution of l-ethyi-5-hydroxy-piperidin-2-one (530 mg, 3.70 mmol), 3-methyl-4-nitro-lH-pyrazole (706 mg, 5.55 mmol) and PPrn (i ,46 g, 5.55 mmol) in THF (20 mL) was added dropwise DIAD (1.12 g, 5.55 mmol ) at 0 C over 20 min. After addition, the mixture was stirred at this temperature for 40 min, and then the resulting mixture was stirred at 20 C for 1 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1 to 0: 1) to give a mixture of l-ethyl-5-(5-methyl-4-nitro-lH-pyrazol-l- yi)piperidin-2~one and l~ethyl-5-(3~methyl-4-nitro-lH~pyrazol-l~yl)piperidin~2-one as a yellow solid. LCMS: RT 0.881 min, m/z = 253.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
: To a solution of l-ethyi-5-hydroxy-piperidin-2-one (530 mg, 3.70 mmol), 3-methyl-4-nitro-lH-pyrazole (706 mg, 5.55 mmol) and PPrn (i ,46 g, 5.55 mmol) in THF (20 mL) was added dropwise DIAD (1.12 g, 5.55 mmol ) at 0 C over 20 min. After addition, the mixture was stirred at this temperature for 40 min, and then the resulting mixture was stirred at 20 C for 1 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1 to 0: 1) to give a mixture of l-ethyl-5-(5-methyl-4-nitro-lH-pyrazol-l- yi)piperidin-2~one and l~ethyl-5-(3~methyl-4-nitro-lH~pyrazol-l~yl)piperidin~2-one as a yellow solid. LCMS: RT 0.881 min, m/z = 253.1 [M+H]+ To a solution of l-ethyl-5-(5-methyl-4-nitro-pyrazol-l- yl)piperidin-2-one and l -ethyl-5-(3-metliyl-4-nitro-pyrazol-l-yl)piperidin-2-one (420 mg, 1.66 mmol) in MeOH (40 ml.) was added Pd/C (10%, 176 mg) under 2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give a mixture of 5-(4-amino-5-methyl-lH- pyrazol-l-yl)-l-ethylpiperidin-2-one and 5-(4-atnino-3-methyl-lH-pyrazol-l-yl)-l-ethylpiperidin-2-one as a brown oil , LCMS: RT 0.566 min, m/z = 223 ,3 [M+Hf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
: To a solution of l-ethyi-5-hydroxy-piperidin-2-one (530 mg, 3.70 mmol), 3-methyl-4-nitro-lH-pyrazole (706 mg, 5.55 mmol) and PPrn (i ,46 g, 5.55 mmol) in THF (20 mL) was added dropwise DIAD (1.12 g, 5.55 mmol ) at 0 C over 20 min. After addition, the mixture was stirred at this temperature for 40 min, and then the resulting mixture was stirred at 20 C for 1 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1 to 0: 1) to give a mixture of l-ethyl-5-(5-methyl-4-nitro-lH-pyrazol-l- yi)piperidin-2~one and l~ethyl-5-(3~methyl-4-nitro-lH~pyrazol-l~yl)piperidin~2-one as a yellow solid. LCMS: RT 0.881 min, m/z = 253.1 [M+H]+ To a solution of l-ethyl-5-(5-methyl-4-nitro-pyrazol-l- yl)piperidin-2-one and l -ethyl-5-(3-metliyl-4-nitro-pyrazol-l-yl)piperidin-2-one (420 mg, 1.66 mmol) in MeOH (40 ml.) was added Pd/C (10%, 176 mg) under 2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give a mixture of 5-(4-amino-5-methyl-lH- pyrazol-l-yl)-l-ethylpiperidin-2-one and 5-(4-atnino-3-methyl-lH-pyrazol-l-yl)-l-ethylpiperidin-2-one as a brown oil , LCMS: RT 0.566 min, m/z = 223 ,3 [M+Hf. To a solution of 5-(4-amino--5-methyi-pyrazoi-1--yl)-i -ethyl-piperidin-2.-one and 5-(4-arnino-3-rnetlwi-pyrazoi- I -yl)- I .-ethyl-piperidin.-2-one (310 rng, 1.39 mmoi), and 4-cyciopropvi-2-(methyisuifonyi)-5-(trifiuoromethyi)pyrimidine (370 mg, 1.39 mmoi)in 1,4-dioxane (10 mL) was added TFA (317mg, 2.78 mmol). The mixture was stirred at 100 c for 2 h. The reaction mixture was diluted with H,O (30 mL), adjusted with aq. NaHCO3 (30 mU) to pH 8 and extracted with EtOAc (3 x 30 mE). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was triiurated with DMF (5 mE). The undissoived solid was filtered to givecrude product as a solid. This ciude product was separated by SFC to give 5-(4-((4-cyclopropyl--5- (trfiuoroniethyl)pyriniidin-2-yl)arnino)-3-methyl- 1H-pyrazoi- 1 -yl)- I -ethylpiperidin-2-one as a single enantiomer (Peak I in SFC) and 5-(4-((-cyciopropvi-5-(trifiuoromethyi)pvrimidin-2-yi)amino)-3- methyl-I H-pyrazol-1 -yi)-I -ethyipiperidin-2-one as a single enantiomer (Peak 2 in SFC). The DMF filtrate was concentrated to give crude product. This crude product was puiified by prep-HPLC TFA) and thentwice of SFC to give 5-(4-((-cyclopropyI-5-(tf1uoroinethyl)pyriinidin-2-yi)arnino)-5-metliyI- 1H- pyrazoi-i-yi)-i-cthyipiperidin-2-one as a single enantiomer (Peak 1 in SFC) and 5-(4--((4-cyciopropyi-5- (trifiuoroniethyl)pyrimidin-2-yi)amino)-5--mcthyi- I H-pyrazoi- 1 -yl)- I -ethyipiperidin-2-one as a single enantiomer (Peak 2 in SFC).First eluting isomer (Peak 1): (S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yI)ainino)-5-inethyl-IH-pyrazol4-yl)-1-ethylpiperidin-2-one (4-59): 1H NMR (400 MHz, MD3OD): dppm 8.25 - 8-45 (m. 1 H), 748 - 767 (m, I H), 4.64 4.79 (in, I H), 3.72 - 3.8-4 (in. 1 H), 356 - 363 (m,1 H), 344 - 354 (m, 1 H), 3.35 - 3.43 (in, I H), 2.50-2.61 (m, 2 H), 232 -244 (rn, I H), 2.25 (s, 3 H),2.09 -2.21 (in, 2 H), 0.98 1.34 (in, 7 H). HPLC: RT 2.480 miii. MS: m: 409.2 FM-f-Hi?. SFC: RT 5.72mm, == 100%.Second ehiting isomer (Peak 2): 5-(4-((4-cyclopropyl-5-(trifluoromethyi)pyrimidin-2-y)amino)-5-methy1-1H-pyrazoi-1-yl)-1-ethypiperidin-2-one (A-60): 1H NMR (400 MHz, CD3OD): dppm 8.21 - 8.48 (in, 1 H), 743 - 7.71 (in, I H), 4.67 - 4.80 (in, I H), 3.72 - 3.83 (in, I H), 356 - 362 (in,I H), 344 - 3.54 (in, 1 H), 3.34 - 3.43 (in, I H), 2.49 - 2.60 (in, 2 H), 233 - 244 (in, I H), 2.25 (s, 3 H),2.08 -2.21 (in, 2 H), 0.97- 1.34 (rn, 7 H). HPEC: RT 2.487 mm. MS; m/z; 409.1 [M+Hf. SFC: RT 6.33mm, cc = 100%.First eiuting isomer (Peak 1): 5-(4-((4-cyclopropvI-5-(trif1uoromethy)pvrimidin-2- yI)arnino)-3-rnethyl-1H-pyrazol-1-yl)-1.-ethylpiperidin-2-one (4-61): ?H NMR (400 MHz, CD3OD): oe ppm 8.34-8.43 (in, I H), 7.84 - 7.94 (in. I H), 4.54 -469 in, 1 H), 369 -3.79 (in, 2 H), 3.38-3.52 (in,2 H), 2.46- 2.57 (m. 2 H). 2.32-243 (m, 1 H). 2.22-2.30 (m, I H), 2.19 (s. 4 H). 1.18 - 131 (m, 2 H).1.07 - 1.17 (m, 5 Fl). FIPLC: RT 2.468 miii. MS: ith: 409.1 [M+Tlj. SFC: RT 4.87 miii, cc 100%. Second eluting isomer (Peak 2) :5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyriinidin-2-yI)arnino)-3-rnethyi-1H-pyrazol-1-yI)-l -ethylpiperidin-2-one (A-62): ?H NMR (400 MHz, CD3OD): oeppm 8.34 - 8.42 (m, I H), 7.83 - 7.).S (m. I H). 4.56 - 471 (m, I H). 3.68 - 3.80 (m, 2 H), 3.37 - 3.53 (m.2 Fl). 2.45 - 2.58 (in, 2 H), 2.32- 2.43 (m, I H), 2.23 -2.30 (in, 1 Fl). 2.19 (s, 4 H), 1.19- 1.30 (m, 2 H),1.06 - 1.18 (in, 5 H). HPLC: RT 2.464 mm. MS: rn/i?: 40g. I [M+Hf. SFC: Rf 5.67 mm, cc 98.02%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyl-4-nitro-lH-pyrazole (20 g, 157.36 mmol), cyclopent-3- en-l-ol (15.88 g, 188.83 mmol) and PPh3 (61.91 g, 236.04 mmol) in THF (300 mL) was added D1AD (47.73 g, 236.04 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, w hich was purified by silica gel chromatography (PE:EtOAc = 50: 1 to 20: 1) to give a mixture of l-(cyclopent-3-en-l-yi)-5-methyl-4-nitro-lH-pyrazoie and 1 -(cyclopent-3-en- 1 -yl)-3-methyl-4-nitro- lH-pyrazole as a yellow oil. LCMS: RT 1.301 min, m/z = 194.1 [M+H].To a mixture of 1-cyclopent- 3-en-l-yl-5-methyl-4-nitro-pyrazole and l-cyciopent-3-en-l-yl-<strong>[5334-39-4]3-methyl-4-nitro-pyrazole</strong> (10 g, 51.76 mmol), bis [(Z)-l-methyl-3-oxo-but-l-enoxy]copper (948 mg, 3.62 mmol) in DCE (300 mL) was added a solution of ethyl 2-diazoacetate (23.6 g, 207.04 mmol) in DCE (600 mL) over a period of 12 h at 90 C. The mixture was stirred at 90 C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc :=: 20: 1 to 5: 1) to give a mixture of ethyl 3-(5-methyl-4-nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate and ethyl 3-(3-methy3-4~nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6~carboxy as a yellow solid. LCMS: RT 0.831 mm, m/z = 280.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyl-4-nitro-lH-pyrazole (20 g, 157.36 mmol), cyclopent-3- en-l-ol (15.88 g, 188.83 mmol) and PPh3 (61.91 g, 236.04 mmol) in THF (300 mL) was added D1AD (47.73 g, 236.04 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, w hich was purified by silica gel chromatography (PE:EtOAc = 50: 1 to 20: 1) to give a mixture of l-(cyclopent-3-en-l-yi)-5-methyl-4-nitro-lH-pyrazoie and 1 -(cyclopent-3-en- 1 -yl)-3-methyl-4-nitro- lH-pyrazole as a yellow oil. LCMS: RT 1.301 min, m/z = 194.1 [M+H].To a mixture of 1-cyclopent- 3-en-l-yl-5-methyl-4-nitro-pyrazole and l-cyciopent-3-en-l-yl-<strong>[5334-39-4]3-methyl-4-nitro-pyrazole</strong> (10 g, 51.76 mmol), bis [(Z)-l-methyl-3-oxo-but-l-enoxy]copper (948 mg, 3.62 mmol) in DCE (300 mL) was added a solution of ethyl 2-diazoacetate (23.6 g, 207.04 mmol) in DCE (600 mL) over a period of 12 h at 90 C. The mixture was stirred at 90 C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc :=: 20: 1 to 5: 1) to give a mixture of ethyl 3-(5-methyl-4-nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate and ethyl 3-(3-methy3-4~nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6~carboxy as a yellow solid. LCMS: RT 0.831 mm, m/z = 280.1 [M+H]+.To a mixture of ethyl 3-(5- methyl -4 -nitro-pyrazol- 1 -yl)bicyclo [3.1.0]hexane-6-carboxylate (4) and ethyl 3 ~(3 -methyl -4-nitro- 1 H- pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate (4A) (2.6 g, 9.31 mmol) in THF (40 mL) and H20 (10 mL) was added LiOH.H20 (781 mg, 18.62 ramol). The mixture was stirred at 25 C for 12 h. The reaction mixture was poured into H2() (30 mL) and extracted with MTBE (20 rnL chi 2), the aqueous layer was separated and adjusted to pH = 3 by 1 N HO, then it was extracted with EtOAc (2 chi 30 mL), dried over Na2S04, concentrated under reduced pressure to give a mixture of 3-(5-methyl-4-nitro- lH-pyrazol- 1- yl)bicyclo[3.1.0]hexane-6-carboxylic acid and 3-(3-methyl-4-nitro-lH-pyrazol-l- yl)bicyclo[3.1.0]hexane-6-carboxylic acid as a white solid. LCMS: RT 1.072 min, m/z ------ 252.1 I [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyl-4-nitro-lH-pyrazole (20 g, 157.36 mmol), cyclopent-3- en-l-ol (15.88 g, 188.83 mmol) and PPh3 (61.91 g, 236.04 mmol) in THF (300 mL) was added D1AD (47.73 g, 236.04 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, w hich was purified by silica gel chromatography (PE:EtOAc = 50: 1 to 20: 1) to give a mixture of l-(cyclopent-3-en-l-yi)-5-methyl-4-nitro-lH-pyrazoie and 1 -(cyclopent-3-en- 1 -yl)-3-methyl-4-nitro- lH-pyrazole as a yellow oil. LCMS: RT 1.301 min, m/z = 194.1 [M+H].To a mixture of 1-cyclopent- 3-en-l-yl-5-methyl-4-nitro-pyrazole and l-cyciopent-3-en-l-yl-<strong>[5334-39-4]3-methyl-4-nitro-pyrazole</strong> (10 g, 51.76 mmol), bis [(Z)-l-methyl-3-oxo-but-l-enoxy]copper (948 mg, 3.62 mmol) in DCE (300 mL) was added a solution of ethyl 2-diazoacetate (23.6 g, 207.04 mmol) in DCE (600 mL) over a period of 12 h at 90 C. The mixture was stirred at 90 C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc :=: 20: 1 to 5: 1) to give a mixture of ethyl 3-(5-methyl-4-nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate and ethyl 3-(3-methy3-4~nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6~carboxy as a yellow solid. LCMS: RT 0.831 mm, m/z = 280.1 [M+H]+.To a mixture of ethyl 3-(5- methyl -4 -nitro-pyrazol- 1 -yl)bicyclo [3.1.0]hexane-6-carboxylate (4) and ethyl 3 ~(3 -methyl -4-nitro- 1 H- pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate (4A) (2.6 g, 9.31 mmol) in THF (40 mL) and H20 (10 mL) was added LiOH.H20 (781 mg, 18.62 ramol). The mixture was stirred at 25 C for 12 h. The reaction mixture was poured into H2() (30 mL) and extracted with MTBE (20 rnL chi 2), the aqueous layer was separated and adjusted to pH = 3 by 1 N HO, then it was extracted with EtOAc (2 chi 30 mL), dried over Na2S04, concentrated under reduced pressure to give a mixture of 3-(5-methyl-4-nitro- lH-pyrazol- 1- yl)bicyclo[3.1.0]hexane-6-carboxylic acid and 3-(3-methyl-4-nitro-lH-pyrazol-l- yl)bicyclo[3.1.0]hexane-6-carboxylic acid as a white solid. LCMS: RT 1.072 min, m/z ------ 252.1 I [M+H]+A mixture of 3-(5-methyl-4-nitro-pyrazol-l- yl)bicyclo[3.1.0]hexane-6-carboxamide and 3-(3-methyl-4-nitro-pyrazol-l-yl)bicyclo[3.1.0]hexane-6- carboxamide (800 mg, 3.2 mmol) in DMF-DMA (3.81 g, 32 mmol) was heated to 95 C and stirred for 2 h. The mixture was cooled to 25 C, concentrated under reduced pressure to give a residue, which was slurried with MTBE (10 mL), filtered to give pure (E)-N-((dimethylamino)methylene)-3-(3-methyl-4- nitro-lH-pyrazo]-l-yl)bicyc]o[3.1.0]hexane-6-carboxamide (0,6 g) as a white solid. Tire filtrate was concentrated under reduced pressure to give a mixture of (E)-N-((dimethylamino)methylene)-3-(5- meth}7l-4-nitro-lH-pyrazol-l-yl)bic}7clo[3.1.0]hexane-6-carboxamide and (E)-N- ((dini6thy3amino)methy1ene)~3~(3- LCMS: RT 1.16 min, m/z = 306.1 j .M | |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyl-4-nitro-lH-pyrazole (20 g, 157.36 mmol), cyclopent-3- en-l-ol (15.88 g, 188.83 mmol) and PPh3 (61.91 g, 236.04 mmol) in THF (300 mL) was added D1AD (47.73 g, 236.04 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, w hich was purified by silica gel chromatography (PE:EtOAc = 50: 1 to 20: 1) to give a mixture of l-(cyclopent-3-en-l-yi)-5-methyl-4-nitro-lH-pyrazoie and 1 -(cyclopent-3-en- 1 -yl)-3-methyl-4-nitro- lH-pyrazole as a yellow oil. LCMS: RT 1.301 min, m/z = 194.1 [M+H].To a mixture of 1-cyclopent- 3-en-l-yl-5-methyl-4-nitro-pyrazole and l-cyciopent-3-en-l-yl-<strong>[5334-39-4]3-methyl-4-nitro-pyrazole</strong> (10 g, 51.76 mmol), bis [(Z)-l-methyl-3-oxo-but-l-enoxy]copper (948 mg, 3.62 mmol) in DCE (300 mL) was added a solution of ethyl 2-diazoacetate (23.6 g, 207.04 mmol) in DCE (600 mL) over a period of 12 h at 90 C. The mixture was stirred at 90 C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc :=: 20: 1 to 5: 1) to give a mixture of ethyl 3-(5-methyl-4-nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate and ethyl 3-(3-methy3-4~nitro-lH-pyrazol-l-yl)bicyclo[3.1.0]hexane-6~carboxy as a yellow solid. LCMS: RT 0.831 mm, m/z = 280.1 [M+H]+.To a mixture of ethyl 3-(5- methyl -4 -nitro-pyrazol- 1 -yl)bicyclo [3.1.0]hexane-6-carboxylate (4) and ethyl 3 ~(3 -methyl -4-nitro- 1 H- pyrazol-l-yl)bicyclo[3.1.0]hexane-6-carboxylate (4A) (2.6 g, 9.31 mmol) in THF (40 mL) and H20 (10 mL) was added LiOH.H20 (781 mg, 18.62 ramol). The mixture was stirred at 25 C for 12 h. The reaction mixture was poured into H2() (30 mL) and extracted with MTBE (20 rnL chi 2), the aqueous layer was separated and adjusted to pH = 3 by 1 N HO, then it was extracted with EtOAc (2 chi 30 mL), dried over Na2S04, concentrated under reduced pressure to give a mixture of 3-(5-methyl-4-nitro- lH-pyrazol- 1- yl)bicyclo[3.1.0]hexane-6-carboxylic acid and 3-(3-methyl-4-nitro-lH-pyrazol-l- yl)bicyclo[3.1.0]hexane-6-carboxylic acid as a white solid. LCMS: RT 1.072 min, m/z ------ 252.1 I [M+H]+A mixture of 3-(5-methyl-4-nitro-pyrazol-l- yl)bicyclo[3.1.0]hexane-6-carboxamide and 3-(3-methyl-4-nitro-pyrazol-l-yl)bicyclo[3.1.0]hexane-6- carboxamide (800 mg, 3.2 mmol) in DMF-DMA (3.81 g, 32 mmol) was heated to 95 C and stirred for 2 h. The mixture was cooled to 25 C, concentrated under reduced pressure to give a residue, which was slurried with MTBE (10 mL), filtered to give pure (E)-N-((dimethylamino)methylene)-3-(3-methyl-4- nitro-lH-pyrazo]-l-yl)bicyc]o[3.1.0]hexane-6-carboxamide (0,6 g) as a white solid. Tire filtrate was concentrated under reduced pressure to give a mixture of (E)-N-((dimethylamino)methylene)-3-(5- meth}7l-4-nitro-lH-pyrazol-l-yl)bic}7clo[3.1.0]hexane-6-carboxamide and (E)-N- ((dini6thy3amino)methy1ene)~3~(3- LCMS: RT 1.16 min, m/z = 306.1 j .M | toa mixture of (E)-N-((dirnethyiarnino)inethyiene)-3-(5-rnethyi-4-nitro- 1H-pyrazoi- 1- yl)bicyclo[3. 1 .Oihexane-6-carhoxamide and (E)-N-((dirnethyiarnino)methyiene)-3-(3-methyl-4-nitro- I Hpyrazoi-1-yI)bicycio[3. i.Oihexane-6-carboxaxnide (200 rng, crude) in AcOK (8 rnL) wasadded methyihydrazine (1.32 g, 11.50 inniol). The mixture was stirred at 95 C for 2 Ii. The reaction mixture was concentrated under reduced pressure and poured into ice-water (20 mL), adjusted to pH9 with aq. NaHCO3. and extracted with FtOAc (50 mL c 2). The combined organic layers were washed with brine (50 inL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a mixture of I .-rnethyl-5-(3 -(5-methyl-4-nitro- IH-pyrazoi- I .-yi)bicycioi3.1 .0]hexan-6-yi)- 1K-I ,2,4-triazoleand i-methyi-5-(3--rnethyi-4-nitro-1H-pvrazoi-i-vi)bicycio[3. I .Ojhexan-6-yi)-1H-i,2,4-triazoie as yellow oil. LCMS: RI 0.950 mm, mz = 289,1 [M+Kit.. A mixture of I -methyi-5-(3-(5-methyi-4-nitro- IK-pyrazol- I -yi)bicycio[3 .1 .Ojhexan-6-yi)- 1K-i ,2,4-triazoieand I -methyl -5-(3-(3-methvl -4-nitro- I H-pyrazol- I -yl)bicyclo[3. 1 .Oihexan-6-yI)- I H-i ,2,4-iriazoie (0.2 g, crude), NH4C1 (195 mg, 3.64 mnmol) and Fe (203 ing, 3.64 mmnol) in EtOH (25 mL) and K20 (5 mnL) was stirrred at 90 C for 2 h. It was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was siurmy with DCM:MeOH (V:V, 10:1, 15 mL), filtered and the filtrate was concentrated under reduced pressure to give a mixture of 5-methyi-i-(6-(i-methyi-1H-i,2,4-triazoi-5-yl)bicyclo[3. 1 .Oihexan-3-yI)- 1 H-pyrazoi-4-arnine and 3-methyl-i -(6-( 1-methyl-lW 1 ,2.4-triazol-5- yl)bicyclo[3. 1.0hexari-3-y-1)-iH-pyra.zo1-4-amiiie as a yellow oil. LCMS: RT 0.320 miii, mlz= 259.2 IM-F-Hj. Amixture of 5-methyl-I -(6-( i-methyl-li-I-i ,2,4-tiiazol-5-yi)bicyclo[3.1 .0Iiexan-3-yl)- I l-{-pyrazol-4-amine and 3-methyl-i-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.i .0]hexan-3-yl)- 1H-pyrazol-4-amine (188 mg, crude), 4-cyciopropyi-2-methyis... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 12h; | To a solution of 3-methyl-4-nitro-lH-pyrazole (20 g, 157.36 mmol), cyclopent-3- en-l-ol (15.88 g, 188.83 mmol) and PPh3 (61.91 g, 236.04 mmol) in THF (300 mL) was added D1AD (47.73 g, 236.04 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, w hich was purified by silica gel chromatography (PE:EtOAc = 50: 1 to 20: 1) to give a mixture of l-(cyclopent-3-en-l-yi)-5-methyl-4-nitro-lH-pyrazoie and 1 -(cyclopent-3-en- 1 -yl)-3-methyl-4-nitro- lH-pyrazole as a yellow oil. LCMS: RT 1.301 min, m/z = 194.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 6h;Inert atmosphere; | To a solution of 3-methyl-4-nitro- lH- pyrazole (4.15 g, 32.64 mmol), <strong>[15166-68-4]3-hydroxypyrrolidin-2-one</strong> (3 g, 29.67 mmol) and PPh3 ( 11.67 g, 44.51 mmol) in THF (100 mL) was added DIAD (9 g, 44.51 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 6 h. The mixture was filtered and filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (PE:EtOAc = 1 : 1) to give a crude product, which was triturated with MTBE (20 mL), to give 3-(3-methyl-4-nitro-pyrazol-l -yl)pyrrolidin-2-one as a white solid. LCMS: RT 0.226 min, m/z = 21 1.2 [M + H]+.1H NMR (400 MHz, DMSO-d6): o 8.89 i s. 1H), 8.25 (br. s, 1H), 5 ,09 (t, J=9.10 Hz, 1H), 3.27-3.42 (m, 3H), 2.53-2.60 (m, 2H), 2.43 (s,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 12h; | To a solution of [1-(hydroxymethyl)cyclopropyl]methanol (9-1, 3 g, 29.37 mmol), 3 -methyl -4-nitro- IH-pyrazole ( 3.39 g, 26,70 mmol) and PPh3 (7 g, 26.70 mmol) in THF (30 mL) was added dropwise DIAD (5.4 g, 26.70 mmol) at 0 C over 30 min. After addition, the mixture was stirred at this temperature for 30 min. The resulting mixture was stirred at 25 C for 11 h. The reaction mixture was diluted with FLO (90 mL) and extracted with EtOAc (3 chi 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, PE:EtOAc = 10: 1 to 0: 1 ) to give a mixture of (l-((3-methyl-4-nitro-lH-pyrazol-l- yl)methyl)cydopropyi)methanol and (l -((5-methyl-4-nitro-lH-pyrazol-l- yl)methyl)cyclopropyi)methanol as an off-white solid, winch was used into the next step without further purification, LCMS: RT 0.568 min, m/z = 212,2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 6,7-dihydro-5H- pyrrolofl,2-a]imidazol-7-ol (1 g, 8.06 mmol) and 3-methyl-4-nitro-lH-pyrazole (1.13 g, 8.87 mmol) in THF (20 mL) was added PPh3 (3.17 g, 12.09 mmol) and then D1AD (2.44 g, 12.09 mmol, 2.4mL) dropwise at 0 C over a period of 30 min under N2. The mixture was warmed to 20 C and stirred for 12 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient PE:EtOAc from 10: 1 to 0: 1) to give the mixture of 7-(3-methyl-4-nitro-pyrazol-l-yl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole and 7-(5-methyl- 4-nitro-lH-pyrazol-l -yl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole as a white solid. LCMS: RT 0.112 min, m/z ------ 234.1 [M + H .] To a solution of 7-(3- methyl-4-nitro-pyrazol-l-yl)-6,7-dihydro-5H-pyrrolo| l,2-a|imidazole and 7-(5-methyl-4-nitro-lH- pyrazol-l-yl)-6,7-dih}'dro-5H-pyrrolo[ l,2-a]imidazole (650 mg, 2.79 mmol) in MeOH (20 mL) was added Pd-C (10%, 0.3 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 C for 4 h, then filteredand concentrated under reduced pressure, to give the mixture of l-(6,7-dihydro-5H-pyrrolo|T,2- a]imidazol-7-yl)-3-methyl-pyrazol-4-amine and l-(6,7-dihydro-5H-pyrrolo[ l,2-a]imidazol-7-yl)-5- methyl-lH-pyrazol-4-amine as a light yellow solid. LCMS: RT 0.62-0.878 min, m/z = 204.2 [M+H]~. To a solution of the mixture l -(6,7-dihydro-5H- pyrrolo[ l,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-ainine and l-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7- yl)-5-methyl-lH-pyrazol-4-amine (220 mg, 1.08 mol) and 2-chloro-N-methyl-5- (trifluoromethyl)pyrimidin-4-amiiie (251.35 mg, 1.19 mol, 1.10 eq) in 1,4-dioxane (2 mL) was added TFA (246 mg, 2.16 mol, 0.16 mL) at 20 C. The mixture was heated to 90 C and stirred for 1 h. The mixture was cooled to 20 C and concentrated under reduced pressure. To the residue was added aq. sat. NaHC03, extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral) to give To a solution of the mixture l -(6,7-dihydro-5H- pyrrolo[ l,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-ainine and l-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7- yl)-5-methyl-lH-pyrazol-4-amine (220 mg, 1.08 mol) and 2-chloro-N-methyl-5- (trifluoromethyl)pyrimidin-4-amiiie (251.35 mg, 1.19 mol, 1.10 eq) in 1,4-dioxane (2 mL) was added TFA (246 mg, 2.16 mol, 0.16 mL) at 20 C. The mixture was heated to 90 C and stirred for 1 h. The mixture was cooled to 20 C and concentrated under reduced pressure. To the residue was added aq. sat. NaHC03, extracted with EtOAc (3 x 5 mL). The combined organics weTo a solution of the mixture l -(6,7-dihydro-5H- pyrrolo[ l,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-ainine and l-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7- yl)-5-methyl-lH-pyrazol-4-amine (220 mg, 1.08 mol) and 2-chloro-N-methyl-5- (trifluoromethyl)pyrimidin-4-amiiie (251.35 mg, 1.19 mol, 1.10 eq) in 1,4-dioxane (2 mL) was added TFA (246 mg, 2.16 mol, 0.16 mL) at 20 C. The mixture was heated N2-[l-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-N4-methyl-5- (trifluoromethyl)pyrimidine-2,4-diamine (D-2): Iota NMR (400 MHz, CDC13): delta ppm 8.09 (s, 1 H), 7.76 (br. s? 1 H), 7.12 (s, 1 H), 6.96 (s, 1 H), 6.44 (br. s? 1 H), 5 ,55 - 5.66 (m, 1 H), 5.13 (br, s,, 1 W), 4.39 - 4.51 (m, 1 H), 4.10 (t, ./ 11.04 Hz, 1 I I). 3.08 - 3.26 (rn, 2 H), 3.00 (d, ./ 4.52 Hz, 3 H), 2.40 (s, 3 H); HPLC: RT: 1.703 min; MS: m/z: 379.1 [M+H]+. N2-[l-[6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-7-yl]-3-methyl-lH-pyrazol-4-yl]-N4-methyl- 5-(trifluoromethyl)pyrimidine-2,4-diamine (First eluting stereoisomer, D-3): 'H NMR (400 MHz, CDCL): delta ppm 8.09 (br. s, 1 H), 7.89 (s, 1 H), 7.18 (s, 1 H), 6.99 (s, 1 H), 6.72 (br. s, 1 H), 5.57 - 5.68 (m, 1 H), 5.19 (br. s., 1 H), 4.22 (br. s., 1 H), 3.99 - 4.12 (m, 1 H), 3.02 - 3.24 (rn, 2 H), 2.97 (d, J=3.09 Hz, 3 H), 2.25 (s, 3 H): HPLC: RT 1.769 min; MS: m/z: 379.1 I M H ] : SFC: RT 2.71min. N2-[l-[6,7-dihydro-5H-pyrrolo|l,2-a]imidazol-7-yl]-3-methyl-lH-pyrazol-4-ylj-N4-methyl- 5-(trifluoromethyl)pyrimidine-2,4-diamine (Second eluting stereoisomer, D-4): 'H MR (400 MHz, CDCL): delta ppm 8.09 (br. s., 1 H), 7.88 (br. s., 1 H), 7.18 (s, 1 H), 6.99 (s, 1 H), 6.66 (br. s., 1 H), 5.58 - 5.67 (m, 1 H), 5.18 (br. s? 1 H), 4.22 (br. s? 1 H), 4,03 - 4, 12 (m, 1 H), 3.04 - 3.24 (m, 2 H), 2.97 (br. s., 3 H) 2.24 (s, 3 H); HPLC: RT 1.768 rain; MS: m/z: 379.1 ] · Pi | : SFC: RT 3.21 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; | General procedure: Compound 45-1 is combined with compound 1-1, PPh3, and DIAD in THF to give compound 45- 2. Compound 45-2 is combined with N-chlorosuccinimide to give compound 45-3. To compound 45-3 in MeOH is added Pd/C, and the mixture is stirred under H2 to produce compound 45-4. Compound 45-4, compound 5-5, and TsOH are combined in 1,4-dioxane to give compound D-41 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12.5h; | To a mixture of 6,7-dihydro-5H- pyrrolofl,2-a]imidazol-7-ol (1 g, 8.06 mmol) and 3-methyl-4-nitro-lH-pyrazole (1.13 g, 8.87 mmol) in THF (20 mL) was added PPh3 (3.17 g, 12.09 mmol) and then D1AD (2.44 g, 12.09 mmol, 2.4mL) dropwise at 0 C over a period of 30 min under N2. The mixture was warmed to 20 C and stirred for 12 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient PE:EtOAc from 10: 1 to 0: 1) to give the mixture of 7-(3-methyl-4-nitro-pyrazol-l-yl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole and 7-(5-methyl- 4-nitro-lH-pyrazol-l -yl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole as a white solid. LCMS: RT 0.112 min, m/z ------ 234.1 [M + H .] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 6,7-dihydro-5H- pyrrolofl,2-a]imidazol-7-ol (1 g, 8.06 mmol) and 3-methyl-4-nitro-lH-pyrazole (1.13 g, 8.87 mmol) in THF (20 mL) was added PPh3 (3.17 g, 12.09 mmol) and then D1AD (2.44 g, 12.09 mmol, 2.4mL) dropwise at 0 C over a period of 30 min under N2. The mixture was warmed to 20 C and stirred for 12 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient PE:EtOAc from 10: 1 to 0: 1) to give the mixture of 7-(3-methyl-4-nitro-pyrazol-l-yl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole and 7-(5-methyl- 4-nitro-lH-pyrazol-l -yl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole as a white solid. LCMS: RT 0.112 min, m/z ------ 234.1 [M + H .] To a solution of 7-(3- methyl-4-nitro-pyrazol-l-yl)-6,7-dihydro-5H-pyrrolo| l,2-a|imidazole and 7-(5-methyl-4-nitro-lH- pyrazol-l-yl)-6,7-dih}'dro-5H-pyrrolo[ l,2-a]imidazole (650 mg, 2.79 mmol) in MeOH (20 mL) was added Pd-C (10%, 0.3 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 C for 4 h, then filteredand concentrated under reduced pressure, to give the mixture of l-(6,7-dihydro-5H-pyrrolo|T,2- a]imidazol-7-yl)-3-methyl-pyrazol-4-amine and l-(6,7-dihydro-5H-pyrrolo[ l,2-a]imidazol-7-yl)-5- methyl-lH-pyrazol-4-amine as a light yellow solid. LCMS: RT 0.62-0.878 min, m/z = 204.2 [M+H]~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49%; 36% | A mixture of 3-methyl-4-nitro-lH-pyrazole (1.36 g, 10.71 mmol), tert-butyl-4- iodopiperidine-l-carboxylate (10.00 g, 32.14 mmol) and K2CO3 (2.96 g, 21.42 mmol) in DMF (16.6 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over MgS04, filtered and was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH 40 muiotaeta, 80 g, mobile phase: heptane/DCM, gradient from 50:50 to 0: 100). The pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 349 and intermediate 349' (540.00 mg, 16% yield). intermediate 350 intermediate 350' At 0C, HC1 (4M in dioxane) (15.00 mL, 60.00 mmol) was added to a solution of a mixture of intermediates 349 and 349' (0.54 g, 1.74 mmol) in 1,4-dioxane (4 mL). The reaction was stirred at rt overnight. The solvent was evaporated until dryness. The residue was taken up into DCM and basified with a 10% aqueous solution of K2C03. The organic layer was dried over MgS04, filtered and the solvent was evaporated until dryness. The residue (817 mg) was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 muiotaeta, 40 g, mobile phase: 98% DCM, 2% MeOH (+ 10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 0.480 g of a mixture of intermediates 350 and 350' used as it for the next step. A mixture of intermediates 350 and 350' (0.48 g, 2.28 mmol), formaldehyde (0.21 mL, 2.80 mmol) in MeOH (2.70 mL) and AcOH (0.32 mL, 5.59 mmol) was stirred for 10 min. Then, sodium cyanoborohydride (0.17 g, 2.75 mmol) was added. The reaction was stirred at rt over the weekend. DCM and a 10% solution of K2CO3 were added. The organic layer was washed with water, dried over MgS04, filtered and evaporated. The residue (538 mg) was purified by achiral SFC (Stationary phase: CHIRALPAK IC 5 muetaiota 250 x 20 mm, mobile phase: 75% CO2, 25% MeOH). The pure fractions were collected and the solvent was evaporated until dryness to give: 248 mg of intermediate 351 (49% yield) and 184 mg of intermediate 351 ' (36% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 3-methyl-4-nitro-lH-pyrazole (1.24 g, 0.009 mol, 1 equiv) in DMF (20 mL) was added K2CO3 (1.86 g, 0.013 mol, 1 equiv) portion wise at 0C and stirred for 10 minutes. l-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (3 gm, 0.009 mol, 1 equiv) was added drop wise 0C. The reaction mixture was allowed to stir for 1 hour at RT. Product formation was confirmed by LCMS. After completion of reaction, reaction mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). Combined organic extracts were washed with water (100 mL x 4), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain mixture of l-(2,4-bis(trifluoromethyl)benzyl)- 3-methyl-4-nitro-lH-pyrazole(peak 1) and l-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-4- nitro-lH-pyrazole(peak 2). obtained crude was sent for separation in prep. LCMS: 353 [M+H] +. | ||
0.6 g; 1.4 g | To a stirred solution of 3-methyl-4-nitro-lH-pyrazole (1.48 g, 0.01 mol, 1 equiv) in DMF (20 mL) was added K2CO3 (2.71 g, 0.019 mol, 1.5 equiv) portion wise at 0C and stirred for 10 minutes. l-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (4 gm, 0.01 mol, 1 equiv) was added drop wise 0 C. The reaction mixture was allowed to stir for 1 hour at room temperature. Product formation was confirmed by LCMS. After completion of reaction, reaction mixture was diluted with water and extracted with ethyl acetate (3x100 mL). Combined organic extracts were washed with water (4x100 mL), dried over anhydrous NaSCL and concentrated under reduced pressure to obtain residue which was purified by flash column chromatography (EtO Ac/Hexane) to obtain the title compound as 1- (2,4-bis(trifluoromethyl)benzyl)-3-methyl-4-nitro-lH-pyrazole (0.6 g) and l-(2,4- bis(trifluoromethyl)benzyl)-5-methyl-4-nitro-lH-pyrazole (1.4 g). LCMS: 354 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.0 g | With copper(l) iodide; potassium carbonate; L-proline; In N,N-dimethyl-formamide; at 100℃; for 24h; | To a stirred solution of 3-methyl-4-nitro-lH-pyrazole (869 mg, 0.068 mmol, 1 equiv) l-bromo-2,4-bis(trifluoromethyl)benzene (2 g, 0.068 mmoles, leq) in DMF (20 mL) was added K CO (1.89 g, 0.0136 mmol, 2 equiv) and the reaction mixture was stirred for 15 minutes. Cul (0.026 g, 0.2eq, O.OOlmoles) and L-proline (0.317 g, 0.02 mmol, 0.4 equiv.) were added to the reaction mixture. The reaction mixture was allowed to stir for 24 hour at 100 C. Product formation was confirmed by LCMS. After completion of reaction, reaction mixture was diluted with water and extracted with ethyl acetate (3x100 mL). Combined organic extracts were washed with water (4x100 mL), dried over anhydrous NaSCL and concentrated under reduced pressure to obtain which was purified by flash chromatography (EtOAc/ Hexane) to obtain titile compound l-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-4- nitro-lH-pyrazole (1.0 g). LCMS 339 [M+H] +. |
Tags: 5334-39-4 synthesis path| 5334-39-4 SDS| 5334-39-4 COA| 5334-39-4 purity| 5334-39-4 application| 5334-39-4 NMR| 5334-39-4 COA| 5334-39-4 structure
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