Structure of 848841-68-9
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CAS No. : | 848841-68-9 |
Formula : | C7H9ClN2OS |
M.W : | 204.68 |
SMILES Code : | ClC1=CSC(=N1)N2CCOCC2 |
MDL No. : | MFCD09909639 |
InChI Key : | MTZAHLFTBUJSIJ-UHFFFAOYSA-N |
Pubchem ID : | 53440095 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.57 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 52.85 |
TPSA ? Topological Polar Surface Area: Calculated from |
53.6 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.32 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.0 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.25 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.66 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.82 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.61 |
Solubility | 0.501 mg/ml ; 0.00245 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.75 |
Solubility | 0.362 mg/ml ; 0.00177 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.1 |
Solubility | 1.62 mg/ml ; 0.00791 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) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
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 |
-6.13 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 |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
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) |
2.74 |
* 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 |
---|---|---|
62% | With caesium carbonate; triphenylphosphine;palladium diacetate; copper(l) iodide; In N,N-dimethyl-formamide; at 125.0℃; for 16.0h; | Alternate Preparation from Preparation 6: Combine 7-(l-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[l,5-alpha]pyrimidine, (9 g,26.2 mmol) and <strong>[848841-68-9]4-chloro-2-morpholino-thiazole</strong> (7.5 g, 36.7 mmol) in dimethylformamide (90 mL) previously degassed with nitrogen. Add cesium carbonate (17.8 g, 55 mmol), copper iodide (250 mg, 1.31 mmol), triphenylphosphine (550 mg, 2.09 mmol) and palladium acetate (117 mg, 0.52 mmol). Heat the mixture to 125 0C for 16 h and then cool to 22 0C. Add water (900 mL) and extract with methyl-?-butyl ether (3 x 200 mL). Combine the organic portions and evaporate the solvent. Purify by silica gel chromatography eluting with hexanes/ethyl acetate (4/1) to afford the title compound (6.4 g, 62%). ES/MS m/z (35Cl) 420 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In acetonitrile; at 40.0℃; for 0.5h;Heating / reflux; | Preparation 194-chloro-2-morpholino-thiazoleTo a mixture of 2,4-dichlorothiazole (34 g, 0.22 mol) in acetonitrile (425 mL) add potassium carbonate (60.9 g, 0.44 mol) and then morpholine (21.2 mL, 0.225 mol) dropwise over 30 min. Reflux the mixture at 40 0C and then cool to 22 C. Filter the mixture and evaporate the filtrate. Triturate the residue with /-propyl alcohol (60 mL) at 22 0C for one hour. Filter the solids and dry under vacuum to a constant weight to afford the title compound (34.5 g, 76%). ES/MS m/z (35Cl) 205 (M+l)+. |
With caesium carbonate; In tetrahydrofuran; at 110.0℃; for 3.0h; | Part B: 4-(4-Chloro-l,3-thiazol-2-yl)morpholine; In a sealed tube dissolve 2,4-dichloro-l,3-thiazole (1,00 g, 6.49 mmol), morpholine (1.13 g, 32.99 mmol) in dry THF (4 mL) and then add Cs2CO3 (3.17 g, 9.74 mmol). Heat the resultant mixture at 1 10 C for 3 hrs. Concentrate the reaction mixture in vacuo and treat the residue with dichloromethane (30 mL). Filter the insoluble material and evaporate the filtrate in vacuo to afford off-white solid. .H NMR (400 MHz, CDC13) 6.33 (1 H, s), 3.80 (4 H, t, J = 9 Hz), 3.45 (4 H1 1, J = 9 Hz). | |
at 20.0℃; | 26a) 4- (4-CHLORO-THIAZOL-2-VL)-MORPHOLINE A solution of thiazolidine-2, 4-dione (0.5 g, 4.27 MMOL) and POC13 (2 mL, 21 MMOL} in CH3CN (20 mL) and 4N HCI/DIOXANE (1 mL) was heated to 70C overnight. The mixture was poured to the ice water and neutralized with saturated NAHCO3 then extracted by EtOAc. The organic layer was dried, concentrated and treated with morpholine (1.8 g, 21 MMOL). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed by water (3 x 50 mL) and brine (50 mL). The EtOAc phase was concentrated by reduced pressure and purified by silica gel chromatography to afford the product (126 mg, 15%). M+H+=205. 6. H NMR (300MHZ, DMSO-D6) 8 6.81 (s, 1H), 3.69 (m, 4H), 3.35 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate;triphenylphosphine; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 130.0℃; | D. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-2,6-dimethyl-8-(1-propyl-butyl)- imidazo[1,2-b]pyridazine.; EPO <DP n="143"/>A 15 mL round bottom flask is charged with 3-iodo-2,6-dimethyl-8-(1-propyl- butyl)-imidazo[1,2-b]pyridazine (0.200 g, 0.000539 moles), 4-(4-chloro-thiazol-2-yl)- morpholine (0.165 g, 0.000808 moles), Cs2CO3 (0.361 g, 0.00108 moles, 2.0 equiv), Pd(dba)2 (0.0092 g, 0.0000161 moles, 0.03 equiv), PPh3 (0.00847 gram, 0.000323 moles, 0.060 equiv) and DMF (2.0 mL). Nitrogen is bubbled through the reaction mixture for 15 minutes; then, the reaction mixture is heated at 130 C overnight. The next day, the reaction mixture is partitioned between Et2O and a saturated solution of NH4Cl. The aqueous layer is extracted twice more with Et2O. The organic extracts are combined, washed 2-3 times with H2O, washed once with brine, and dried over Na2SO4. The solvents are evaporated in vacuo and the crude reaction mixture is purified via silica gel chromatography. Yield = 0.1737 g (72%). 1H-NMR (CDCl3), delta 0.87 (t, J = 7 Hz, 6H), 1.14- 1.37 (m, 4H), 1.74 (q, J = 8 Hz, 4H), 2.54 (s, 3H), 2.50 (s, 3H), 3.48 (m, 1H), 3.53 (t, J = 5 Hz, 4H), 3.83 (t, J = 5 Hz, 4H), 6.71(br s, 1H) ppm. LC/MS (m/z): calcd. for C22H30ClN5OS (M+H)+: 448; found: 448. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | With caesium carbonate;palladium diacetate; copper(l) iodide; triphenylphosphine; In N,N-dimethyl-formamide; at 120.0℃; for 17.0h;Product distribution / selectivity; | Method B; N- { 4-Chloro-5-[8-( 1 -ethyl-propyl)-2,6-dimethyl-imidazo [1,2- b]pyridazin-3-yl]-thiazol-2-yl } -morpholine.; A 20L reactor flask under nitrogen is charged with 2900 ml of dry and degassed DMF then with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (287 g, 0.836 mol), 2-morpholino-4-chlorothiazole (205.4 g, 1.01 mol, 1.2 equv.), Pd(OAc)2 (3.74 g, 7.91 mmol, 0.01 equiv.), triphenylphosphine (8.77g, 33.1 mmol, 0.04 equiv.), Copper iodide (8 g, 41.59 mmol, 0.05 equiv.) and cesium carbonate (544.9 g, 1.65 mol). The reaction mixture is heated at 120C. After 16 h at 120C, 1.87 g of Pd(OAc)2 and 4.38 g of triphenylphosphine more is added. After 1 h, the mixture is cooled, quenched with NH4CI solution (4300 mL) and extracted with MTBE (2900 mL), the aqueous phase is extracted twice more with 2000 ml of MTBE. The organic phases are washed with sat NaCl aq (2000 mL), then treated with charcoal 72 g in flask bottle and filtered on Celite. The filtrate is concentrated under vacuum to afford 373.8 g (79.3%) of the title compound which is 81.4%-area HPLC analysis the rest being solvent and with no detectable Example 200 by-product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; copper(l) iodide; triphenylphosphine; In N,N-dimethyl-formamide; at 120.0℃; | Example 30: Preparation of: 2-(4-Chloro-2-morrhoholin-4-yl-1.2-thiazol-5-yl)-5-(l-cyclorhoropylethv?-3,7-dimethyl-5H-pyitauolo[2.3- j>1pyrazine; Part A: 2-(4-ChioiO-2-morpholiniota-4-yl-1 ,2-thiazol-5-ylV3.7-dimethyl-SH-pvitauolof2.3--?lpyrazine; A Teflon screw-cap vial is charged with crude 2-bromo-3.7-trimethyl-5-H-pyrrolo[3.2-&]pyrazine (800 mg, 2.43 mmol, 1.0 equiv) and DMF (8 mL). To the solution is added <strong>[848841-68-9]4-(4-chlorothiazol-2-yl)morpholine</strong> (498 mg, 2.43 mmol, 1.0 equiv), triphenylphosphine (127 mg, 0.49 mmol, 0.20 equiv), copper(I) iodide (1 16 mg, 0.61 mmol, 0.25 equiv), cesium carbonate (1.59 g, 4.87 mmol, 2.0 equiv), and palladium acetate (27 mg, 0.61 mmol, 0.05 equiv). The reaction vial is evacuated and purged with nitrogen three times before being tightly capped and heated overnight at 120 C. The reaction mixture is cooled to rt, diluted with water and extracted with EtOAc (3 X 10 mL). The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using 30% EtOAc in hexanes to give the desired compound as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; copper(l) iodide; triphenylphosphine; In N,N-dimethyl-formamide; at 120.0℃; | Part F: Title compound; <n="88"/>A Teflon screw-cap vial is charged with crude 3-chloro-2,5-dimethyl-7-(pentan-3-yl)-5H-pyrrolo[2J3- b]pyrazine (100 mg, 0.31 mmoL 1.0 equiv) and 2 mL of DMF. To the solution is added 4-(4- chlorothiazoI-2-yl)morphoIine (77 mg, 0.37 mmol, 1.2 equiv) , triphenylphosphine (17 mg, 0.062 mmoi, 0.20 equiv), copper(l) iodide (15 mg, 0.078 mmoi, 0.25 equiv), cesium carbonate (203 mg, 0.62 mmol, 2.0 equiv), and palladium acetate (3.5 mg, 0.016 mmol, 0.05 equiv). The reaction vial is evacuated and purged with nitrogen three times before being tightly capped and heated overnight at 120 C. The reaction mixture is cooled to rt, diluted with water and extracted with EtOAc (3 X 10 mL). The combined organic extracts are washed with brine, dried over NaiSC^ and concentrated under reduced pressure. The resulting residue is purified by preparative thin layer chromatography using 30% EtOAc in hexanes to give the desired compound as yellow foam. MS = 444.04 (M +] ). 1H NMR (400 MHz, OMSO-dg) delta 7.93 (IH, s), 3.72-3.74 (4H, m), 3.37-3.44 (5H, m), 2.52 (3H, s) 2.27 (3 H, s), 1.51-1.58 (2H, m), 0.61-0.68 (2H, m), 0.53-0.59 (2H, m), 0.30-0.36 (2H, m), 0.13-0.19 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; copper(l) iodide; triphenylphosphine; In N,N-dimethyl-formamide; at 110.0℃; | Part F: Title compound; A Teflon screw-cap via) is charged with 100 mg (0.40 mmol, 1.0 equiv) of crude 3-chloro-2,5-dimethyI-7-(pentan-3-yI)-5H-pyrrolo[2,3-b]rhoyrazine and 2 mL of DMF. To the solution is added 98 mg (0.48 mmol, 1.2 equiv) of 4-(4-chlorothiazol-2-yI)morphoIine, 21 mg (0.08 mmol, 0.20 equiv) of tripbenylphosphine, 19 mg (0.1 mmol, 0.25 equiv) of copper(I) iodide, 261 mg (0.8 mmoi, 2.0 equiv) of cesium carbonate, and lastly 5 rag (0.02 mmol, 0.05 equiv) of palladium acetate. The reaction vial is evacuated and purged with nitrogen three times before being tightly capped and heated overnight at 1 10 C, The reaction mixture is cooled to it, diluted with water and extracted with EtOAc (3 X 10 mL). The combined organic extracts are washed with brine, dried over NaiSO^ and concentrated under reduced pressure. The resulting residue is purified by preparative thin layer chromatography using 30% EtOAc in hexanes to give the desired compound as a yellow solid (26 mg, 15% yield). MS = 420.08 (M +1). 1H NMR (300 MHz, CDC13) delta 7.22 (IH, s), 3.82-3.85 (4H, m), 3.84 (3H, s), 3.44-3.56 (4H, m), 2.96 (IH, m) 2.70 (3 H, s), 1.73-1 .85 (4H, m), 0.86 (6H, q, J = 7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; copper(l) iodide; triphenylphosphine; In N,N-dimethyl-formamide; at 120.0℃; for 15.0h; | Example 3: Preparation of:(R)-2-[2-(4-choro-2-mophiho]in-4»yl-I,3-thiazo.-5-yl)-3,7-dimethyl-5H-pyrro]o[2,3-b]pyrazi?-5-yl]butan- l-ol; Heat a mixture of (R)-2-(2-bromo-3,7-dimethyI-5H-pyrrolo[2,3-b]pyrazin-5-yl)butan-l-ol (75 mg, 0.25 mmol), 4-(4-chloro-l,3-thiazoi-2-y])morpholine (61 mg, 0.30 mmol), palladium acetate (1.1 mg, 0.005 mmol), triphenylphosphine (2.6 mg. 0.01 mmol), copper (]) iodide (2.4 mg. 0.0125 inmol), and cesium carbonate (163 mg, 0.50 mrnol) in 2.0 nil of dry and degassed DMF at 120 C for 15 h. Remove DMF in vacuo, and purify the residue by silica gel column chromatography (gradient from 50% EtOAc/hexane to 70% EtOAc/hexane) to afford the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.25 (IH, s), 4.39 (IH, m). 4. . 2 (IH5 m), 4,04 (2H5 m), 3.82 (4H5 1, 74.8), 3.50 (4H, t, J 5.6). 2.64 (3H. s). 2.36 (3 H, s), 2.00 (2H, m), 0.89 (3 H, t, J 7.2); Mass spec. 422.02 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; copper(l) iodide; triphenylphosphine; In N,N-dimethyl-formamide; at 120.0℃; for 20.0h; | Part C: Title compound; Heat a mixture of 2-biOmo-3.7-dimethyl-5-(pentan-3-yl)-5H-pyrrolol"3,2-blpyrazine (296 mg, 1.0 mmol), 4-(4-chIoiO-l,3-thiazo]-2-yl)morrhoholine (244 mg, 1.2 mmol), palladium acetate (1 1.3 mg, 0.05 mmol), triphenylphosphine (26.3 mg, 0.1 mmol), copper (1) iodide (19. mg, 0.1 mmol), and cesium carbonate (750 mg, 2.0 mmol) in 5.0 ml of diy and degassed DMF at 120 C for 20 h. Cool the reaction mixture to room temp, dilute with EtOAc (15 mL) and saturated NH1Cl (15 mL) and filter the mixture through celite. Wash the celite with EtOAc (2 x 5 mL), separate the organic layer and dry with MgSO4. Filter the dried extract, concentrate in vacuo, and purify the residue by silica gel column chromatography using 30% EtOAc/hexane to afford dark yellow viscous oil. Crystallize the oil from hexane (1.0 mL) and filter the white solid to afford title compound. 1H NMR (400 MHz1 CDCi5) 7.23 (IH, s), 4.59 (IH, m), 3.81 (4H, t), 3.49 (4H, t), 2.64 (3H, s). 1.81-1.92 (4H, m), 0.76 (3H, t); Mass spec. 420.09 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.7% | With copper(l) iodide; palladium diacetate; caesium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 110.0℃; | In a 20 mL reaction vial were added 4-(4-chlorothiazol- 2-yl)morpholine (237 mg, 1.160 mmol), palladium(II) acetate (3.72 mg, 0.017 mmol), cesium carbonate (567 mg, 1.740 mmol), triphenylphosphine (17.38 mg, 0.066 mmol), copper(I) iodide (7.89 mg, 0.041 mmol) and 6-iodo-N-methyl-2-(pyridin-3- yl)quinazolin-4-amine (300 mg, 0.828 mmol) in DMF (10 ml), and the mixture was heated at 110 C overnight. After cooling to room temperature the reaction was poured into water (40 mL) and the resultant precipitate was collected by filtration, washed with water and methanol and dried to give the crude product. The product was recrystallized from methanol to afford 206 mg of 6-(4-chloro-2- morpholinothiazol-5-yl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as a brown solid (56.7%). LC-MS m/z = 439 (M+l) (retention time = 2.13) JH NMR (300 MHz, DMSO) delta 9.72 (s, 1H), 8.77 (d, / = 7.6 Hz, 1H), 8.62 (d, / = 4.2 Hz, 1H), 8.31 (d, / = 1.6 Hz, 1H), 8.05 (dd, / = 8.8, 1.8 Hz, 1H), 7.83 (d, / = 8.7 Hz, 1H), 7.57 (s, 1H), 3.85 - 3.65 (m, 4H), 3.44 (dd, / = 14.9, 10.5 Hz, 4H), 3.16 (d, / = 4.2 Hz, 3H). NH was not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium phosphate; (1,2-bis(diphenylphosphanyl)ethane)dichloridopalladium(II); at 80.0℃; for 2.0h;Inert atmosphere; | Step 1 : Synthesis of tert-butyl (l-(2-(3-amino-6-(2-morpholinothiazol-4-yl) pyrazine-2- carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate To a 25 mL round bottom flask was added (5-amino-6-((3-(4-((tert- butoxycarbonyl)amino)piperidin-l-yl)pyridin-2-yl)carbamoyl)pyrazin-2-yl)boronic acid (0.36 g, 0.787 mmol), <strong>[848841-68-9]4-(4-chlorothiazol-2-yl)morpholine</strong> (0.161 g, 0.787 mmol), Pd (dppe) dichloride (0.085 g, 0.116 mmol), potassium phosphate 1 M (1 mL) and a magnetic stirrer. The resultant mixture was degassed with nitrogen and then placed in an 80C preheated oil bath and heated for 2 hours. The reaction was removed from heat, cooled and then poured into 100 ml of dichloromethane. Magnesium sulfate was added to dry the reaction, followed by filtration and concentration to a thick residue. The residue was chromatographed on silica gel using ethyl acetate and heptane which gave tert-butyl (l-(2-(3-amino-6-(2-morpholinothiazol-4-yl)pyrazine- 2-carboxamido)pyridin-3-yl)piperidin-4-yl)carbamate (0.187 g, 0.289 mmol) in 37% yield. LC-MS (basic method): ret.time= 1.30 min, M+H = 582.5. |
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