Structure of 4100-13-4
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CAS No. : | 4100-13-4 |
Formula : | C3H2N2O2S |
M.W : | 130.13 |
SMILES Code : | OC(=O)C1=CSN=N1 |
MDL No. : | MFCD00052099 |
InChI Key : | HJZYBDPHAHGHAZ-UHFFFAOYSA-N |
Pubchem ID : | 351418 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 26.87 |
TPSA ? Topological Polar Surface Area: Calculated from |
91.32 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.58 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.3 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.26 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.31 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.23 |
Solubility | 7.62 mg/ml ; 0.0586 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.78 |
Solubility | 2.16 mg/ml ; 0.0166 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.26 |
Solubility | 71.8 mg/ml ; 0.552 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 |
-6.88 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 |
2.0 |
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) |
2.5 |
* 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 |
---|---|---|
99.9% | With hydrogenchloride; at 65℃; for 16h; | <strong>[4100-13-4]1,2,3-Thiadiazole-4-carboxylic acid</strong> (1.0, 1g, 7.7 mmol) was added to HCl (1.25 M in MeOH, 10 mL) and the reaction mixture was stirred at 65 C for 16 h. The solvent was removed under reduced pressure and the resulting crude mixture was purified (FCC, SiO2, 0-100 % EtOAc in DCM) to provide the title compound (1.1g, 99.9%). MS (ESI): mass calcd. for C4H4N2O2S, 144.0; m/z found, 145 [M+H]+.1H NMR (300 MHz, CDCl3) delta 9.27 (s, 1H), 4.07 (s, 3H). |
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 |
---|---|---|
52% | EXAMPLE 27 N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-1,2,3-thiadiazole-4-carboxamide Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and <strong>[4100-13-4]1,2,3-thiadiazole-4-carboxylic acid</strong> as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 70-72 C., in a 52% yield. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.28-1.53 (2H, multiplet); 1.53-1.82 (4H, multiplet); 2.24-2.55 (4H, multiplet); 3.46 (2H, singlet); 4.35 (2H, triplet, J=6.3 Hz); 5.01 (2H, doublet, J=6.3 Hz); 5.75-5.87 (1H, multiplet); 5.87-6.00 (1H, multiplet); 6.77 (1H, singlet); 6.85-7.00 (1H, multiplet); 7.72-7.90 (1H, broad); 8.13 (1H, doublet, J=5.4 Hz); 9.23 (1H, singlet). Infrared Absorption Spectrum (CHCl3), numax cm-1: 3425, 2940, 1675, 1612, 1540, 1420, 1402, 1300, 1290, 1260, 1035. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.7% | With N-chloro-succinimide; triethylamine; In methanol; dichloromethane; | Example 111 [1,2,3]Thiadiazole-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>[4100-13-4][1,2,3]thiadiazole-4-carboxylic acid</strong> (29 mg, 0.30 mmol) in dichloromethane (6 mL) at 25 C. was treated with triphenylphosphine-polystyrene 100-200 mesh (372 mg, 0.46 mmol). This mixture was cooled to 0 C. and then treated with N-chlorosuccinimide (49 mg, 0.37 mmol). This mixture was stirred at 0 C. for 15 min and at 25 C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (55 mg, 0.12mmol) and triethylamine (96 [IL, 0.69 mmol). The reaction was then stirred at 25 C. for 3 days. At this time, the reaction was filtered to remove solids and rinsed with dichloromethane. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1:99 methanol/dichloromethane) afforded <strong>[4100-13-4][1,2,3]thiadiazole-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 (17 mg, 24.7%): LR-MS for C27H24FN7O3S (M+H)+ at m/z=546. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.7% | A mixture of [1, 2,3] thiadiazole-4-carboxylic acid (29 mg, 0.30 mmol) in dichloromethane (6 mL) at [25 oC] was treated with triphenylphosphine-polystyrene [100-200] mesh (372 mg, 0.46 mmol). This mixture was cooled to [0 oC] and then treated with N-chlorosuccinimide (49 mg, 0.37 mmol). This mixture was stirred at 0 oC for 15 min and at [25 oC] for 15 min. At this time, the reaction was treated with 3- [CYCLOPROPYLMETHYL-1- (2-FLUORO-BENZYL)-8- (4-METHYLAMINO-BENZYL)-3,] 7-dihydro-purine- 2,6-dione (55 mg, 0.12mmol) and triethylamine [(96] [. L,] 0.69 mmol). The reaction was then stirred at [25 oC] for 3 days. At this time, the reaction was filtered to remove solids and rinsed with dichloromethane. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and [CONCENTRATED IN VACUO.] Flash chromatography (Merck Silica gel [60,] 230-400 mesh, 1: 99 methanol/ dichloromethane) afforded [[1,] 2,3] thiadiazole-4-carboxylic acid [14- [3-] [CYCLOPROPYLMETHYL-1-(2-FLUORO-BENZYL)-2,] 6-dioxo-2,3, 6, 7-tetrahydro-1H-purin-8- [YLMETHYL]-PHENYL}-METHYL-AMIDE] (17 mg, 24.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To an individual well in a Bohdan XT reactor was added 150 uL of a 0.25 M solution of either a carboxylic acid in dimethylformamide (DMF)(0.038 mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol in DMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution of N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hychloride (0.038 mmol; 1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine in similar molar ratio to the carboxylic acid reagent. The reactor was agitated for 10 minutes via orbital shaker. Then 150 uL of a solution of 0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine (0.150; 5 eq) was added to each reactor well and the reactor was agitated for 16 hours at 650C. The library was dried via centrifugal evaporation and BOC groups were removed by adding 600 uL of a 30% by volume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM) to each reactor (that had a BOC group) and the reactor was agitated for 2 hours. The library was dried via centrifugal evaporation and was EPO <DP n="168"/>dissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entire contents for each reactor were transferred to an STR plate was was purified by standard preparative HPLC-MS (H2O/MeOH/0.1% TFA, gradient 35-90% MeOH over 15 min, 2Ox 100mm 5mum YMC ODS-A column) utilizing mass-directed fractionation. The purified sample was reconstituted in l:l/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, dried via centrifugal evaporation and weighed. The final product was analyzed by HPLC-MS (H2O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetate salts. Examples prepared by this method are described in Table A8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | 5-[(15*,45)-2,5-diazabicyclo[2.2.1]hept-2-yl]-l-(2,2-dimethylpropyl)-3-methyl- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one (29-2, 25 mg, 0.079 mmol) was added to anhydrous dimethylformamide (793 l,2,3-thiadiazole-4-carboxylic acid (11.4 mg, 0.087 mmol), EDC (15.19 mg, 0.079 mmol), EtaOmicronBetaTau (12.14 mg, 0.079 mmol) and triethylamine (22 pL, 0.159 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (5-95%, 0.1% TFA in H20:acetonitrile) to give 1- (2,2-dimethylpropyl)-3-methyl-5-[(15*,45)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (29-3) as a white solid. MS m/z (Mu+Eta): calculated = 428.1863; observed = 428.1860. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1,4-dioxane; at 150℃; for 0.166667h; | 5-[3-(Aminomethyl)piperidin- 1 -yl]- 1 -(2,2-dimethylpropyl)-3-methyl-l ,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (2-1, 131 mg, 0.397 mmol) was added to anhydrous 1,4-dioxane (2 mL). l,2,3-Thiadiazole-4-carboxylic acid (86 mg, 0.66 mmol), EDC (127 mg, 0.66 mmol) and EtaOmicronBetaTau (101 mg, 0.66 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at 150 C for 10 min. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H20:acetonitrile) to give l-(2,2-dimethylpropyl)-3-methyl-2-oxo-5-(3-[(l,2,3-thiadiazol-4- ylcarbonyl)amino]methyl}piperidin- 1 -yl)-2,3-dihydro- lH-imidazo[4,5-b]pyridin-4-ium chloride (3-1) as a white solid. MS m/z (M+H): calculated = 444.2176; observed = 444.2166. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | In a 1 dram vial, 3-[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5- chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 1 ,2,3- thiadiazole-4-carboxylic acid (10.46 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1 % TFA) to afford the title compound (0.016 g, 46%) as a white solid. 1H NMR (400 MHz, Acetone-d6): delta ppm 9.55 (s, 1 <n="110"/>H), 8.94 (br. s., 1 H), 7.63 (t, 1 H), 7.53 (t, 1 H), 7.41 - 7.46 (m, 1 H), 7.37 - 7.41 (m, 2 H), 4.79 (d, 2 H). LCMS m/z 422.8 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Theta445] To a 4 mL scintillation vial equipped with a stir bar was charged l,2,3-thiadiazole-4- carboxylic acid (21,7 mg, 0.167 mmol), DMF (0.5 mL), 2,4,6-tripropyl- 1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (0.186 mL, 0.304 mmol) and pyridine (0.05 mL, 0.607 mmol). The mixture was stirred for 5 minutes at ambient temperature and then a solution of 3- amino-4-(4-(2,4-difluorophenoxy)piperidin-l -yl)benzonitrile (50 mg, 0.152 mmol) in DMF (0.5 mL) was added in a single portion. The reaction mixture was stirred at 70C overnight, then cooled to ambient temperature, and diluted with water (2 mL), The mixture was sonicated and stirred until a residue was observed around the inside of the vessel. The liquids were decanted, leaving an oily residue to which was added MeOH (~1 mL). The mixture was heated until it became a translucent solution and was then sonicated and stirred at ambient temperature until a precipitate was observed. The material was filtered and the solids were washed with minimal MeOH, collected, and dried under vacuum to give the title compound as a white solid (2.1 mg, 3%). NMR (400 MHz, DMSO-ifc) delta pprn 1.98 - 2.07 (rn, 2 H), 2.20 - 2.26 (m, 2 H), 2.93 (ddd,.7=11.87, 8.34, 3.28 Hz, 2 H), 3.21 (ddd, J= 1.68, 7.01, 4.04 Hz, 2 H), 4.53 (dt,.7=7,77, 3.82 Hz, 1H), 6.86 - 6.95 (m, 1H), 7.02 (ddd, J=11.49, 8.72, 3.03 Hz, 1H), 7.18 (td,.7=9,22, 5.56 Hz,l H), 7.39 (d, J=8.34 Hz, 1 I I). 7.52 (dd,./ 8.2 1. 1.89 Hz, 1H), 8.78 (d, J=2.02 Hz, 1H), 9,51 (s, 1H), 10.39 (br s, 1 1 1): ESI-MS m/z | i H I 442.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
754 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 10 - 35℃; | A mixture of 5-bromopyridine-2,3-diamine (723 mg), <strong>[4100-13-4]1,2,3-thiadiazole-4-carboxylic acid</strong> (500 mg), HATU (2050 mg), Et3N (1.6 mL) and DMF (8 mL) was stirred overnight at room temperature. The mixture was diluted with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (754 mg). The title compound was used for the subsequent reaction without being further purified. MS: [M+H]+ 299.9. |