Structure of 3405-77-4
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CAS No. : | 3405-77-4 |
Formula : | C5H5NO3 |
M.W : | 127.10 |
SMILES Code : | O=C(C1=NOC(C)=C1)O |
MDL No. : | MFCD01318162 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 28.43 |
TPSA ? Topological Polar Surface Area: Calculated from |
63.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.95 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.68 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.4 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.65 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.51 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.4 |
Solubility | 5.04 mg/ml ; 0.0397 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.59 |
Solubility | 3.29 mg/ml ; 0.0259 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.96 |
Solubility | 14.0 mg/ml ; 0.11 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 |
No |
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 |
-6.59 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) |
2.34 |
* 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 |
---|---|---|
70% | With sulfuric acid; potassium nitrate; at 50.0℃; for 4.0h; | 5-methylisoxazole-3-carboxylic acid (1.5 g, 12.04 mmol) was added to a mixture of potassium nitrate (1.83 g, 18.06 mmol) and sulfuric acid (5 ml) at room temperature. After complete dissolution, the mixture was warmed to 50C and stirred for 4 hours. The mixture was then cooled to 0C, ice was added, and the solution was neutralized with sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, filtered and concentrated to give 1.45 g of 4 as a white solid (8.43 mmol, 70%). The product could be further recrystallized from dichloromethane. |
51.6 g | With sodium nitrate; sulfuric acid; at 50.0℃; for 16.0h; | A) 5-Methyl-4-nitro-1,2-oxazole-3-carboxylic acid To a solution of 5-methyl-1,2-oxazole-3-carboxylic acid (50.84 g) in concentrated sulfuric acid (500 mL), sodium nitrate (50.99 g) was gradually added at room temperature. The reaction mixture was stirred at 50C for 16 hours. After cooling to room temperature, the reaction solution was gradually added to ice, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate to obtain the title compound (51.6 g). 1H NMR (400 MHz, DMSO-d6) delta 2.28 (3H, s), 10.66 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compounds 41-70 were part of a parallel set prepared in library plate format according to General Procedure L, outlined below. ; L. General Procedure for Plate Preparation-Amide Formation XXI: Resin bound deprotected biarylphenol XVII (prepared from intermediate XII, boronates XIVd and XIVe, following general procedures D-F) was distributed into a 96 well plate, 10 mg of resin (0.013 mmol) per well. To the resin 400 mul of dichloromethane was added, followed by 100 mul of DIEA, followed by 0.13 mmol (10 equiv) of heterocyclic carboxylic acid XXa-XXn was added followed by 61 mg (0.13 mmol, 10 equiv) of PyBrop. The plate was shaken at room temperature for 24 hours, then drained and washed with dichloromethane, methanol/dichloromethane, dimethylformamide, methanol/dichloromethane and dichloromethane. The compounds were cleaved with TFA/dichloromethane (600 mul, 1:1) into a 96 deep well plate and submitted for testing without further purification. (Mass spec results obtained are shown in Table 4). Carboxylic Acids Het-COOH XX: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00261] Isobutyl chloroformate (0.281 g, 2.06 mmcl) was added dropwise to a solution of 5-methylisooxazole-3-carboxylic acid (0.25 g, 1 .7 mmol) in THE (2.5 mL), followed by addition of N-methylmorpholine (0.208 g, 2.06 mmol). The reaction mixture was stirred at rt for 30 mm and then filtered to remove solids. In a separate flask, a solution of LHMDS (1 .3 M in THE, 2.6 mL, 3.4 mmol) was added dropwise to a solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1- carboxylate (0.37 g, 1 .7 mmol) in THE (2.5 mL) at 0 00 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 1 0 mm and then cooled to -78 00. To this reaction mixture, the filtrate containing the mixed anhydride from the first flask was added dropwise at -78 00. After the addition was complete, the reaction mixture was stirred at rt for 2 h. The reaction mixture was then acidified with aqueous 1 N HCI. The mixture was extracted with EtOAc (twice). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a mixture of crude tert-butyl (2S)-2-methyl-5-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate and tert-butyl (2S) -2-methyl-3-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate (0.43 g) which was used without further purification. MS m/z 323.5 (M+H).[00262] Hydroxylamine hydrochloride (0.56 g, 8.0 mmol) and N,N-diisopropylethylamine (2.1 g,16 mmol) were added to a solution of crude tert-butyl (25)-2-methyl-5-(5- methylisoxazole-3-carbonyl)-4-oxopiperidine- 1 -carboxylate and tert-butyl (25)-2-methyl-3-(5- methylisoxazole-3-carbonyl)-4-oxopiperidine-1-carboxylate (0.43 g) in ethanol (5 mL). The mixture was stirred at rt for 12 h and then concentrated. The residue was diluted with DOM and washed with water. The organic layer was dried over Na2504, filtered, and concentrated to give a mixture of crude tert-butyl (25)-4-(hydroxyimino)-2-methyl-5-(5-methylisoxazole-3- carbonyl)piperidine- 1 -carboxylate and tert-butyl (25)-4-(hydroxyimino)-2-methyl-3-(5- methylisoxazole-3-carbonyl)piperidine-1 -carboxylate (0.39 g) which was used without further purification.Step 3: (S)-6-methyl-3-(5-methyllsoxazol-3-yI)-4, 5,6, 7-tetrahydroisoxazolo[4,3-c]pyridine and (S)-4-methyl-3-(5-methylisoxazol-3-yI)-4, 5,6, 7-t etra hydrois oxazolo[4 , 3-c]pyridine [00263] A solution of HCI (4.0 M in dioxane, 1 .5 mL, 6.2 mmol) was added to a solution of crude tert-butyl (25)-4-(hydroxyim ino)-2-methyl-5-(5-methylisoxazole-3-carbonyl)piperidine- 1 -carboxylate and tert-butyl (25)-4-(hydroxyim ino)-2-methyl-3-(5-methylisoxazole-3- carbonyl)piperidine-1 -carboxylate (0.39 g) in DOM (4 mL). The mixture was stirred at 70 00 for1 h, then cooled to rt. The reaction was quenched with a solution of saturated aqueousNaHCO3 and then extracted with DCM (twice). The combined organic layers were dried overNa2SO4, filtered, and concentrated to give a mixture of crude (S)-6-methyl-3-(5-methylisoxazol-3-yl)-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine and (S)-4-methyl-3-(5-methyl isoxazol-3-yl)-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (0.26 g) which was used without further purification.MS m/z 220.2 (M+H).[00264] Phenyl N-(3,4,5-trifluorophenyl)carbamate (see WO 2018011163 Al) (0.31 g, 1 .2 mmol) and N,N diisopropylethylamine (310 mg, 2.4 mmol) were added to a solution of crude (S)-6-methyl-3-(5-methylisoxazol-3-yl)-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine and (5)- 4-methyl-3-(5-methylisoxazol-3-yl)-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (0.26 g) in acetonitrile (3 mL). The mixture was stirred at rt for 1 h and then quenched with water. The mixture was extracted with EtOAc (twice) and the combined extracts were dried over Na2504, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane) provided a mixture of (S)-6-methyl-3-(5-methylisoxazol-3-yl)-N-(3,4,5-trifluorophenyl)-6,7- dihydroisoxazolo[4,3-c]pyridine-5(4H)-carboxamide and (S)-4-methyl-3-(5-methylisoxazol-3-yl)- N-(3,4,5-trifluorophenyl)-6,7-dihydroisoxazolo[4,3-c]pyridine-5(4H)-carboxamide (0.10 g). The mixture was re-purified by chiral SEC (Chiralpak AD-H column, 0.1% DEA in MeOH) to give:Example 25. (S)-6-methyl-3-(5-methylisoxazol-3-yl)-N-(3,4, 5-trifluorophenyl) -6,7- dthydroisoxazolo[4,3-c]pyridine-5(4H)-carboxamide[00265] (0.042 g, Fr-l). MS m/z 393.3 (M+H). 1H NMR (400 MHz, ODd3) 5 ppm 7.20 (dd, J = 9.5, 6.1 Hz, 2H), 6.66 (s, 1 H), 6.56 (s, 1 H), 5.23 (q, J = 6.6 Hz, 1 H), 4.95 (d, J = 15.9 Hz, 1 H), 4.56 (d, J = 15.9 Hz, 1 H), 3.12 (dd, J = 16.4, 5.7 Hz, 1 H), 2.96 (dd, J = 16.4, 1.6 Hz,H), 2.60 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).Example 26. (S)-4-methyl-3-(5-methylisoxazol-3-yl)-N-(3, 4, 5-trifluorophenyl) -6,7- dihydroisoxazolo[4, 3-c]pyridine-5(4H)-carboxamide[00266] (0.025 g, Fr-2). MS m/z 393.3 (M+H). 1H NMR (400 MHz, ODd3) 5 ppm 7.18 (dd, J = 9.5, 6.0 Hz, 2H), 6.65 (s, 1H), 6.54 (s, 1H), 5.46 (q, J = 6.7 Hz, 1H), 4.60 (dd, J = 14.1, 5.7 Hz, 1 H), 3.26 (td, J = 14.0, 13.4, 3.9 Hz, 1 H), 3.11 -3.01 (m, 1 H), 2.95 (ddd, J = 17.1, 12.6,... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00261] Isobutyl chloroformate (0.281 g, 2.06 mmcl) was added dropwise to a solution of 5-methylisooxazole-3-carboxylic acid (0.25 g, 1 .7 mmol) in THE (2.5 mL), followed by addition of N-methylmorpholine (0.208 g, 2.06 mmol). The reaction mixture was stirred at rt for 30 mm and then filtered to remove solids. In a separate flask, a solution of LHMDS (1 .3 M in THE, 2.6 mL, 3.4 mmol) was added dropwise to a solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1- carboxylate (0.37 g, 1 .7 mmol) in THE (2.5 mL) at 0 00 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 1 0 mm and then cooled to -78 00. To this reaction mixture, the filtrate containing the mixed anhydride from the first flask was added dropwise at -78 00. After the addition was complete, the reaction mixture was stirred at rt for 2 h. The reaction mixture was then acidified with aqueous 1 N HCI. The mixture was extracted with EtOAc (twice). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a mixture of crude tert-butyl (2S)-2-methyl-5-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate and tert-butyl (2S) -2-methyl-3-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate (0.43 g) which was used without further purification. MS m/z 323.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00261] Isobutyl chloroformate (0.281 g, 2.06 mmcl) was added dropwise to a solution of 5-methylisooxazole-3-carboxylic acid (0.25 g, 1 .7 mmol) in THE (2.5 mL), followed by addition of N-methylmorpholine (0.208 g, 2.06 mmol). The reaction mixture was stirred at rt for 30 mm and then filtered to remove solids. In a separate flask, a solution of LHMDS (1 .3 M in THE, 2.6 mL, 3.4 mmol) was added dropwise to a solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1- carboxylate (0.37 g, 1 .7 mmol) in THE (2.5 mL) at 0 00 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 1 0 mm and then cooled to -78 00. To this reaction mixture, the filtrate containing the mixed anhydride from the first flask was added dropwise at -78 00. After the addition was complete, the reaction mixture was stirred at rt for 2 h. The reaction mixture was then acidified with aqueous 1 N HCI. The mixture was extracted with EtOAc (twice). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a mixture of crude tert-butyl (2S)-2-methyl-5-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate and tert-butyl (2S) -2-methyl-3-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate (0.43 g) which was used without further purification. MS m/z 323.5 (M+H).[00262] Hydroxylamine hydrochloride (0.56 g, 8.0 mmol) and N,N-diisopropylethylamine (2.1 g,16 mmol) were added to a solution of crude tert-butyl (25)-2-methyl-5-(5- methylisoxazole-3-carbonyl)-4-oxopiperidine- 1 -carboxylate and tert-butyl (25)-2-methyl-3-(5- methylisoxazole-3-carbonyl)-4-oxopiperidine-1-carboxylate (0.43 g) in ethanol (5 mL). The mixture was stirred at rt for 12 h and then concentrated. The residue was diluted with DOM and washed with water. The organic layer was dried over Na2504, filtered, and concentrated to give a mixture of crude tert-butyl (25)-4-(hydroxyimino)-2-methyl-5-(5-methylisoxazole-3- carbonyl)piperidine- 1 -carboxylate and tert-butyl (25)-4-(hydroxyimino)-2-methyl-3-(5- methylisoxazole-3-carbonyl)piperidine-1 -carboxylate (0.39 g) which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00261] Isobutyl chloroformate (0.281 g, 2.06 mmcl) was added dropwise to a solution of 5-methylisooxazole-3-carboxylic acid (0.25 g, 1 .7 mmol) in THE (2.5 mL), followed by addition of N-methylmorpholine (0.208 g, 2.06 mmol). The reaction mixture was stirred at rt for 30 mm and then filtered to remove solids. In a separate flask, a solution of LHMDS (1 .3 M in THE, 2.6 mL, 3.4 mmol) was added dropwise to a solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1- carboxylate (0.37 g, 1 .7 mmol) in THE (2.5 mL) at 0 00 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 1 0 mm and then cooled to -78 00. To this reaction mixture, the filtrate containing the mixed anhydride from the first flask was added dropwise at -78 00. After the addition was complete, the reaction mixture was stirred at rt for 2 h. The reaction mixture was then acidified with aqueous 1 N HCI. The mixture was extracted with EtOAc (twice). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a mixture of crude tert-butyl (2S)-2-methyl-5-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate and tert-butyl (2S) -2-methyl-3-(5-methylisoxazole-3-carbonyl)-4-oxopiperidine- 1- carboxylate (0.43 g) which was used without further purification. MS m/z 323.5 (M+H).[00262] Hydroxylamine hydrochloride (0.56 g, 8.0 mmol) and N,N-diisopropylethylamine (2.1 g,16 mmol) were added to a solution of crude tert-butyl (25)-2-methyl-5-(5- methylisoxazole-3-carbonyl)-4-oxopiperidine- 1 -carboxylate and tert-butyl (25)-2-methyl-3-(5- methylisoxazole-3-carbonyl)-4-oxopiperidine-1-carboxylate (0.43 g) in ethanol (5 mL). The mixture was stirred at rt for 12 h and then concentrated. The residue was diluted with DOM and washed with water. The organic layer was dried over Na2504, filtered, and concentrated to give a mixture of crude tert-butyl (25)-4-(hydroxyimino)-2-methyl-5-(5-methylisoxazole-3- carbonyl)piperidine- 1 -carboxylate and tert-butyl (25)-4-(hydroxyimino)-2-methyl-3-(5- methylisoxazole-3-carbonyl)piperidine-1 -carboxylate (0.39 g) which was used without further purification.[00263] A solution of HCI (4.0 M in dioxane, 1 .5 mL, 6.2 mmol) was added to a solution of crude tert-butyl (25)-4-(hydroxyim ino)-2-methyl-5-(5-methylisoxazole-3-carbonyl)piperidine- 1 -carboxylate and tert-butyl (25)-4-(hydroxyim ino)-2-methyl-3-(5-methylisoxazole-3- carbonyl)piperidine-1 -carboxylate (0.39 g) in DOM (4 mL). The mixture was stirred at 70 00 for1 h, then cooled to rt. The reaction was quenched with a solution of saturated aqueousNaHCO3 and then extracted with DCM (twice). The combined organic layers were dried overNa2SO4, filtered, and concentrated to give a mixture of crude (S)-6-methyl-3-(5-methylisoxazol-3-yl)-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine and (S)-4-methyl-3-(5-methyl isoxazol-3-yl)-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (0.26 g) which was used without further purification.MS m/z 220.2 (M+H). |
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