Structure of 1125-29-7
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CAS No. : | 1125-29-7 |
Formula : | C7H10N2O2 |
M.W : | 154.17 |
SMILES Code : | CN1N=C(C)C(C(O)=O)=C1C |
MDL No. : | MFCD00159648 |
InChI Key : | NOIOGQJFLIPRBI-UHFFFAOYSA-N |
Pubchem ID : | 736514 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.43 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.38 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.13 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.56 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.33 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.59 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.67 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.42 |
Solubility | 5.87 mg/ml ; 0.0381 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.29 |
Solubility | 7.91 mg/ml ; 0.0513 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.93 |
Solubility | 18.1 mg/ml ; 0.117 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.84 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.46 |
* 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 |
---|---|---|
The following were prepared as described above using the appropriate pyrazole ester:3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid1,3-Dimethyl-1H-pyrazole-4-carboxylic acid1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid3-(Difluoromethyl)-1-(2-propenyl)-1H-pyrazole-4-carboxylic acid3-(Methylthio)-1-methyl-1H-pyrazole-4-carboxylic acid3-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid3-Cyano-1-methyl-1H-pyrazole-4-carboxylic acid3-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid3-Iodo-1-methyl-1H-pyrazole-4-carboxylic acid... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 79℃; for 3h; | 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide was prepared from 3-nitrobenzoyl chloride using the following multiple step procedure: Step 1: 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide.; A dry flask was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (0.122 g, 0.791 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (5 mL) and collected to afford the 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.169 g, 0.440 mmol, 56percent). | |
With thionyl chloride; for 2h;Heating / reflux; | Example 1-2 Production of N-{2-(1,3-dimethylbutyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxamide (compound No. 1-103) 5-Chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (230 mg, 1 mmol) was dissolved in thionyl chloride (2 ml), and the solution was stirred at reflux temperature for 2 hours.. After concentration under reduced pressure, the resulting acid chloride was added to a solution of 2-(1,3-dimethylbutyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (330 mg, 1 mmol) and triethylamine (150 mg, 1.5 mmol) in tetrahydrofuran (10 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours.. The reaction mixture was diluted with ethyl acetate and then washed with water.. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 233 mg of the desired compound. Physical property: melting point 102-104°C. Yield: 43percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | EXAMPLE 16 1,3,5-Trimethyl-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrazole-4-carboxamide Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and <strong>[1125-29-7]1,3,5-trimethyl-4-pyrazolecarboxylic acid</strong> as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 75°-77° C., in a 69percent yield. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.37-1.52 (2H, multiplet); 1.52-1.69 (4H, multiplet); 2.36 (3H, singlet); 2.30-2.49 (4H, multiplet); 2.46 (3H, singlet); 3.44 (2H, singlet); 3.71 (3H, singlet); 4.19 (2H, triplet, J=6.1 Hz); 4.96 (2H, doublet, J=6.4 Hz); 5.75-5.91 (3H, multiplet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=4.9 Hz); 8.00 (1H, doublet, J=4.9 Hz). Infrared Absorption Spectrum (KBr), numax cm-1: 3344, 2930, 1617, 1561, 1410. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-chloro-succinimide; triphenylphosphine; trifluoroacetic acid; In methanol; dichloromethane; | Example 102 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluorobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide A mixture of <strong>[1125-29-7]1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid</strong> (71 mg, 0.46 mmol) in dichloromethane (2.5 mL) at 0° C. was treated with triphenylphosphine (145 mg, 0.55 mmol) and N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 10 min. At this time, the reaction was treated with a solution of 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (400 mg, 0.92 mmol) in dichloromethane (2.5 mL). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1*50 mL). The aqueous layer was re-extracted with dichloromethane (2*50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3:97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15-60percent acetonitrile/water (0.075percent trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The water layer was re-extracted with dichloromethane (2*50 mL). The organic layers were combined and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in vacuo for 24 h to afford <strong>[1125-29-7]1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid</strong> {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (169 mg, 65percent) as a white solid: (ES)+-HRMS m/e calcd for C31H32N7O3F (M+H)+ 570.2623, found 570.2619. |
65% | A mixture of [1,] 3, 5-trimethyl-lH-pyrazole-4-carboxylic acid (71 mg, 0.46 mmol) in dichloromethane (2.5 mL) at [0 oC] was treated with triphenylphosphine (145 mg, 0.55 mmol) and N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at [0 oC] for 30 min and then was warmed to [25 oC] for 10 min. At this time, the reaction was treated with a solution [OF 3-CYCLOPROPYLMETHYL-1- (2-FLUORO-BENZYL)-8- (4-METHYLAMINO-] benzyl) -3,7-dihydro-purine-2, 6-dione (400 mg, 0.92 mmol) in dichloromethane (2.5 mL). The reaction was stirred at [25 oC] for 24 h. At this time, the reaction was diluted. with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution [(1] x 50 mL). The aqueous layer was re-extracted with dichloromethane (2 x 50 mL). The combined organics were dried over magnesium sulfate, filtered, [AND CONCENTRATED IN VACUO.] Flash chromatography (Merck Silica gel 60,230-400 mesh, 3: 97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15-60percent acetonitrile/water (0.075percent trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The water layer was re-extracted with dichloromethane (2 x 50 mL). The organic layers were combined and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in vacuo for 24 h to afford [1,] 3, 5-trimethyl-lH-pyrazole-4-carboxylic acid [{4- [3-] cyclopropylmethyl-l- (2-fluoro-benzyl)-2, 6-dioxo-2,3, 6, 7-tetrahydro-lH-purin-8- [YLMETHYL]-PHENYL}-METHYL-AMIDE] (169 mg, 65percent) as a white solid: (ES) +-HRMS m/e calcd for [C3LH32N703F] (M+H) + 570. 2623, found 570.2619. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | A suspension of triphenylphosphine (59.3 mg, 0.226 mmol) and 1,3, [5-TRIMETHYL-LH-] pyrazole-4-carboxylic acid (SALOR) (26.8 mg, 0.174 mmol) in dichloromethane was cooled to [0 oC AND N-CHLOROSUCCINIMIDE] added. The mixture was stirred at [0 oC] for 0.5 h then ambient temperature for an additional 0.5 h. [3-CYCLOPROPYLMETHYL-8- [4-] (ETHYL-AMINO)-BENZYL]-1-(2-FLUOROBENZYL)-3,] 7-dihydro-purine-2,6-dione (93.4 mg, 0.209 mmol) was added followed by triethylamine (30.2 mg, 0.226 mmol) and 4- dimethylaminopyridine (a few crystals). The reaction was left to stir at ambient temperature overnight before washing with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, drying the organic extract (sodium sulfate) and concentrating in vacuo. Purification by chromatography using silica eluted with 5: 9 methanol/dichloromethane gave the product as a colorless solid (83.5 mg, 69percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 19; 2'-O-(3-[(1,3,5-Trimethyl-1 H-pyrazol-4-yl)carbonyl]amino}propyl)-9-deoxo-9a- methyl-9a-aza-9a-homoerythromycin APS-Carbodiimide resin (PS-CDI, loading: 1.24 mmol/g; 390 mg, 0.806 mmol, 1.3eq) was added to a dry reaction vessel. The 1,3,5-trimethyl-1 H-pyrazole-4-carboxylic acid (60.2 mg, 0.391 mmol) and HOBt (35.2 mg, 0.261 mmol) diluted in a mixture of dry DCM (5 mL) and dry DMF (0.2 mL) were added to the dry resin. The mixture was stirred at room temperature for 5 minutes upon which 2'-O-(3-aminopropyl)-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, Intermediate 1 (300 mg, 0.372 mmol), dissolved in DCM (dried over molecular sieves) (7 mL) was added. The reaction mixture was heated by microwave at 75 0C for 7 minutes. HOBt was scavenged using PS-trisamine (loading:4.1 1 mmol/g) (318 mg, 5eq according to HOBt) for 4 hours at room temperature. The resin was removed from the reaction mixture by filtration and washed with DCM (2x10 mL). Solvent was evaporated in vacuum yielding 540 mg of transparent oil that was diluted in EtOAc (20 ml) and extracted with water (20 ml) at pH 4. Organic layer was discarded and aqueous extracted with DCM (20ml) at pH 5.5. Organic layer was discarded and aqueous extracted with DCM (3x20 ml) at pH 6. To the combined organic layers water (20 ml) was added, pH adjusted to 9 and layers separated. DCM was evaporated in vacuum yielding transparent oil which was precipitated from EtOAc/n-hexane, filtered off and dried at 50 0C for 5 hours yielding title compound (141 mg) as a white powder. MS (ES+): 942.58 [MH]+ 13C NMR (DMSO, 125 MHz) delta 177.5, 164.4, 144.9, 139.7, 1 14.9, 102.5, 94.7, 82.4, 80.6, 77.7, 77.4, 76.7, 75.3, 73.9, 73.2, 72.9, 71.3, 68.9, 67.2, 65.0, 64.0, 61.8, 49.2, 45.3, 42.2, 41.9, 40.9, 37.2, 36.1 , 35.8, 35.0, 32.1 , 30.5, 27.8, 26.3, 22.3, 21.8, 21.4, 21.3, 18.9, 18.0, 15.2, 13.3, 1 1.3, 10.5, 8.6, 7.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With propylphosphonic anhydride; N-ethyl-N,N-diisopropylamine; In ethyl acetate; acetonitrile; at 70℃; for 72h;Sealed tube; | To a suspension of 6-(2-amino-5-chlorothiazol-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.05 g, 0.20 mmol) and <strong>[1125-29-7]1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid</strong> (0.035 g, 0.22 mmol), and DIPEA (0.08 mL, 0.51 mmol in acetonitrile (5 mL) in a sealed tube was added propylphosphonic anhydride solution (50 wt percent in ethyl acetate, 0.30 mL, 0.51 mmol). The sealed tube was heated to 70° C. for 72 h. The resulting mixture was cooled to room temperature, and partitioned between EtOAc (50 mL) and 50 mL of water. The organic layer was separated and the aqueous layer was extracted with EtOAc (3*25 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography by 0-5percent methanol-dichloromethane to give 1,3,5-trimethyl-N-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)-1H-pyrazole-4-carboxamide (0.018 g, 23percent). 1H NMR (400 MHz, DMSO-d): delta 11.77 (bs, 1H), 10.17 (s, 1H), 7.74 (m, 1H), 7.69 (dd, 1H, J=8.4, 2.0 Hz), 7.46 (s, 1H), 6.90 (d, 1H, J=8.0 Hz), delta, 3.69 (s, 3H), 2.93 (t, 2H, J=7.2 Hz), 2.50 (partial masked under d-DMSO, m, 2H), 2.40 (s, 3H), 2.30 (s, 3H); MS (ESI): Calcd. For C19H19N5O2S: 381, found 382 (M+1)+. |
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