Structure of 1003-61-8
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CAS No. : | 1003-61-8 |
Formula : | C4H4N2OS |
M.W : | 128.15 |
SMILES Code : | C1=C(SC(=N1)N)C=O |
MDL No. : | MFCD02179570 |
InChI Key : | HZKMBJCDAXLMDN-UHFFFAOYSA-N |
Pubchem ID : | 2737798 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H317-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 31.91 |
TPSA ? Topological Polar Surface Area: Calculated from |
84.22 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.82 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.4 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.55 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.17 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.44 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.28 |
Solubility | 6.68 mg/ml ; 0.0521 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.73 |
Solubility | 2.36 mg/ml ; 0.0184 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.84 |
Solubility | 18.4 mg/ml ; 0.143 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 |
-6.8 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 |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 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) |
2.06 |
* 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 |
---|---|---|
43% | With sodium tetrahydroborate In methanol for 1 h; Cooling with ice | 2-Amino-5-formylthiazole (11.5 g, 90 mmol) was dissolved in methanol (120 mL), and sodium borohydride (5.11 g, 135 mmol) was added thereto while cooling with ice, followed by stirring at the same temperature for 1 hour. Acetone (6 mL) and water (10 mL) were added to the reaction mixture, followed by stirring. The residue obtained by evaporating the reaction mixture under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:15), thereby giving the title compound (5.09 g, 43percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2.5h; | Example 1-15 Synthesis of the present aldehyde derivative [Compound No. (w)] To a solution of 2.50 g of <strong>[1003-61-8]2-amino-5-formylthiazole</strong> and 2.44 g of triethylamine in 30 ml of tetrahydrofuran was added dropwise a solution of 2.22 g of methoxyacetyl chloride in 8 ml of tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 2 hours and 30 minutes. Insolubles were filtered, and the filtrate was added to ice water and then extracted with ethyl acetate. An organic layer was washed with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.83 g of N-(5-formylthiazol-2-yl)-2-methoxyacetamide [Compound No. (w)] as pale yellow powder. 1H-NMR (270MHz, DMSO-d6) delta (ppm): 3.36 (s, 3H), 4.22 (s, 2H), 8.42 (s, 1H), 9.97 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃; for 16h;Product distribution / selectivity; | Oxalyl chloride (203 muL of a 2 M solution in DCM; 0.406 mmol) was added to a 0 C. mixture of Example 1 Part D compound (80 mg; 0.270 mmol) in DCM (0.70 mL). DMF (10 uL) was added. Gas evolution occurred. The reaction mixture was stirred at RT for 1.5 h, then was concentrated in vacuo. The residue was stripped from CHCl3 (2×2 mL). The crude acid chloride was dissolved in DCM (0.90 mL). <strong>[1003-61-8]2-amino-5-formylthiazole</strong> (45.0 mg; 0.351 mmol) was added followed by pyridine (66.0 uL; 0.810 mmol). After 16 h at RT the reaction was concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient from 0 to 100% solvent B over 6 min, hold at 100% solvent B for 8 min, where solvent A=hexanes and solvent B=EtOAc) to give Part A compound (27 mg; 25%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Product distribution / selectivity; | DIPEA (66 muL; 0.378 mmol) was added to a stirred solution of Example 1 Part D compound (80 mg; 0.270 mmol), <strong>[1003-61-8]2-amino-5-formylthiazole</strong> (43.3 mg; 0.338 mmol) and HOAt (44.0 mg; 0.324 mmol) in DMF (1.0 mL). EDAC (62.0 mg; 0.324 mmol) was added. After 3 h at RT, the reaction mixture was partitioned between EtOAc (8 mL) and H2O (8 mL). The organic phase was washed with 1N aqueous HCl (5 mL), sat. aqueous NaHCO3 (5 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient from 0 to 100% EtOAc in hexanes over 11 min, hold at 100% EtOAc for 4 min) to give Part A compound (81 mg; 74%) as a foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In tetrahydrofuran; at 20℃; for 12h; | [0337] To a solution of 1.0 g of <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> in 20 ml of THF was added 2.5 g of DIBOC and 1.4 g of DMAP at room temperature, and the mixture was stirred for 12 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give 600 mg of t-butyl (5-formylthiazole-2-yl)carbamate (FAB-MS m/z: 229 (M++1)). | |
In dichloromethane; at 20℃; | Compound 75 was prepared from commercially available <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> by a standard procedure ((BOC)2O, DCM, room temperature). | |
With dmap; In tetrahydrofuran; at 0 - 20℃; for 1h; | Step a. To a solution of <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (3.9 mmol) in THF (10 ml) was added DMAP (5.85 mmol) and (BOC)20 (5.85 mmol) at 0C. The reaction mixture was stirred at rt for 1 h. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was collected, dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (40% EtOAc in hexane) yielding tert-butyl (5-formylthiazol-2-yl) carbamate (2.63 mmol). This material was used directly for the next step without further purification. MS: ES+ 229.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | Example 3 [ 2- (2-HYDROXY-3, 3-DIMETHYL-BUTYRYLAMINO)-PENTANOIC ACID (5-FORMYL-THIAZOL-2-YL)-AMIDE] A mixture of (S, [S)-2- (2-HYDROXY-3, 3-DIMETHYL-BUTYRYLAMINO)-PENTANOIC] acid (1.09 g, 4.71 [MMOL),] [2-AMINO-THIAZOLE-5-CARBALDEHYDE] (0.606 g, 4.71 [MMOL),] HOBt (0.763 g, 5.65 [MMOL),] EDC. [HCI] (1.348 g, 7.07 mmol), and triethylamine (2.7 [ML,] 18.84 [MMOL)] in methylene chloride (50 [ML)] was stirred at room temperature overnight. The mixture was quenched with water, extracted with methylene chloride. The organic layer was washed with diluted HCI, separated, dried and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in methylene chloride as eluent to give the title compound (505 mg) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.13% | With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 25℃; for 5h;Inert atmosphere; | Under N2 protection,250mLIn a two-necked flask, tert-butyl nitrite (4.8 g, 47 mmol) and copper bromide (8.2 g, 40 mmol) and anhydrous acetonitrile (180 mL) were added, and the mixture was stirred at 25 C for 0.5 h.The compound <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (4.0 g, 31 mmol) was dissolved in anhydrous acetonitrile (30 mL) and slowly added dropwise to the above solution.The reaction was stirred at 25 C for 12.0 h. concentrate,Add ethyl acetate (200 mL),The organic layer was washed once with saturated brine (60 mL).Dry anhydrous sodium sulfate (20g), concentrated,4.12 g of a red solid were obtained in a yield: 69.13%. |
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 4h; | 2-Amino-1, 3-THIAZOLE-5-CARBOXALDEHYDE (13.78 g, 0.108 mol, 1 eq) in acetonitrile (200 mL) (SLURRY) was added portionwise to a stirred suspension of CuBr2 (36.03 g, 0.129 mol) and t-butyl nitrite (19 mL, 0.161 mL) in acetonitrile (550 mL). The reaction was stirred at room temperature for 4 hours then evaporated to give a solid. This was treated with ethyl acetate (400 mL) and 2M HCI (400 mL). Water (200 mL), brine (100 mL) and ethyl acetate (200 mL) were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layers were dried (MGS04) and evaporated to give the title compound. 'H NMR (CDCI3) : 8 9.97 (1H, s), 8.19 (1H, s) | |
Compounds 85 and 86 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 252; 1, 1-Dicyclohexyl-3- 5-formyl-thiazol-2-yl)-urea; 2-Amino-5-formylthiazole (215 mg, 1.67 mmol), carbonyldiimidazole (275 mg, 1.70 mmol) and a catalytic amount of DMAP were heated together in 5 mL THF at 40 C for 2h. To this solution was added dicyclohexylamine (0.34 mL, 1.70 mmol) and the reaction mixture was stirred for an additional 6 h at room temperature. The reaction mixture was concentrated and the crude product was purified by flash chromatography (silica, CH2CI2-EtOAc, 4: 1) to obtain 1, 1-dicyclohexyl-3- (5-formyl-thiazol-2-yl)-urea. HPLC-MS: m/z 336 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In toluene; | B. Preparation of 2-acetamido-thiazol-5-ylcarboxaldehyde To a suspension of 2-amino-thiazol-5-ylcarboxaldehyde (5.0 g, 39 mmol) in toluene (500 mL) was added acetic anhydride (11.0 mL, 117 mmol). The mixture was heated to 110 C. for 5 hours. Upon cooling to room temperature, a solid precipitated out of the solution. The reaction mixture was concentrated under vacuum to give 2-acetamido-thiazol-5-ylcarboxaldehyde as a light brown colored solid (6.5 g, 98%, C6H6N2O2S, MS m/e 171 (M+H)+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 7h;Heating / reflux; | In a dry 100 mL round bottom flask were combined intermediate 19 (2.8 g, 8.9 mmol), 2-amino-thiazole-5-carbaldehyde (1.4 g, 10.7 mmol), cesium carbonate (8.7 g, 26.7 mmol), Xantphos (1.03 g, 1.8 mmol) and tris(dibenzylideneacetone) dipalladium (0.82 g, 0.89 mmol). Reactants were diluted with dioxane (40 mL), flushed with argon and refluxed for 7 h. Reaction was then diluted with EtOAc and filtered. Solvents were then removed and resulting residue purified via column chromatography (silica gel) to provide title intermediate as yellow powder (1.5 g, 42%).[0130] 1H NMR (500 MHz, DMSO-d6): d 1.42 (s, 9H), 2.42 (s, 3H), 3.42 (m, 4H), 3.54 (m, 4H), 6.10 (s, IH), 8.30 (s, IH), 9.85 (s, IH), 11.90 (s, IH). MS (ES+): m/z 405 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.25h;Irradiation; | In a dry 15mL microwave vial were combined intermediate 31 (1.1 g, 3.7 mmol), 2-amino-thiazole-5-carbaldehyde (0.56 g, 4.4 mmol), cesium carbonate (3.6 g, 11 mmol), Xantphos (0.42 g, 0.73 mmol) and tris(dibenzylideneacetone) dipalladium (0.34 g, 0.37 mmol). Reactants were diluted with dioxane (12 mL), flushed with argon and irradiated for 15 min at 160 0C. Reaction was then diluted with EtOAc and filtered. Solvents were then removed and resulting residue purified via column chromatography (silica gel) to provide title intermediate as brown powder (I g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.25h;Irradiation; | In a dry 15mL microwave vial were combined 2-amino-thiazole-5-carbaldehyde (0.354 g, 2.77 mmol), intermediate 25 (1.23 g, 3.04 mmol), cesium carbonate (2.7 g, 8.29 mmol), Xantphos (0.32 g, 0.55 mmol) and tris(dibenzylideneacetone) dipalladium (0.25 g, 0.28 mmol). Reactants were diluted with dioxane (12 mL), flushed with argon and irradiated for 15 min at 160 0C. Reaction was then diluted with EtOAc, decanted and washed with water followed by brine. Organic phase cut from aqueous layer, dried over sodium sulfate, filtered and evaporated to dark oil. Crude product was purified via silica gel chromatography. The title intermediate was isolated as pale yellow solids (0.34 g, 27%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Heating / reflux; | To a solution of 4-bromo-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (1.33 g, 4.0 mmol) in 1,4-dioxane (200 mL) was added <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (0.51 g, 4.0 mmol), Cs2CO3 (5.2 g, 16.0 mmol), Pd2(dba)3 (0.37 g, 0.4 mmol), and 4,5- bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 0.69 g, 1.6 mmol). The mixture was heated under reflux overnight under Ar. The solid was filtered off and the filtrate washed with brine (I x 200 mL). The organic solution was separated and dried (Na2SO4). The solution was concentrated until 5 mL remaining and hexanes (50 mL) added, the solid was collected by filtration to afford the title intermediate (0.62 g, 41%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.25h;Irradiation; | In a dry 15mL microwave vial were combined intermediate 35 (0.35 g, 1 mmol), 2- amino-thiazole-5-carbaldehyde (0.12 g, 0.9 mmol), cesium carbonate (0.58 g, 1.8 mmol), Xantphos (0.052 g, 0.09 mmol) and tris(dibenzylideneacetone) dipalladium (0.041 g, 0.045 mmol). Reactants were diluted with dioxane (12 mL), flushed with argon and irradiated for 15 min at 160 0C. Reaction was then diluted with EtOAc and filtered. Solvents were then removed and resulting residue purified via column chromatography (silica gel) to provide title intermediate as brown powder (0.11 g, 29%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Heating / reflux; | To a solution of intermediate 10 (1.33 g, 4.0 mmol) in 1,4-dioxane (200 mL) was added 2-ammothiazole-5-carbaldehyde (1.0 g, 3.5 mmol), Cs2C?3 (4.4 g, 13.5 mmol), Pd2(dba)3 (0.24 g, 0.3 mmol), and 4,5-bis(diphenylphos?hino)-9,9-dimethyxanthene (Xant Phos, 0.52 g, 0.9 mmol). The mixture was heated under reflux overnight under Ar. The solid was filtered off and the filtrate washed with brine (1 x 200 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The residue was dissolved in MeOH (20 mL) followed by added 30% KOH (20 mL). The mixture was heated at 100 0C for 4 h. After reaction cool down, EtOAc (100 mL) was added and organic layer separated. The aqueous was extracted with EtOAc (2 x 50 mL). Combined organic layer was dried (Na2SO4). The solvent was removed to afford the title intermediate (0.41 g, 53%) as a black solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Heating / reflux; | To a solution of intermediate 15 (470 mg, 1.5 mmol) in 1,4-dioxane (200 mL) was added <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (193 mg, 1.5 mmol), Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 260 mg, 0.45 mmol). The mixture was heated under reflux overnight under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The residue was purified by flash column (SiO2/60% EtOAc in hexanes) to afford the title intermediate (600 mg, 98%) as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0393] 2-Arninothiazole-5-carbaldehyde (1 eq) was added to a stirring solution of diethylamine (4 eq) in anhydrous MeOH at 00C. Sodium cyanoborohydride (1.5 eq) was then added in portions at 00C. The reaction mixture was stirred at 700C for 10 hours. After this time, the solution was quenched with H2O and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to afford a viscous brown oil. LC/MS (m/z): 186.2 (MH+), R10.33 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 70℃; for 1h; | EXAMPLE 4; 6-{2-[3-(2-Fluoro-5-trifluoromethyl phenyl)ureido]thiazol-5-yl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide trifluoroacetate The product of example 4 can be prepared by the process described above in scheme 4:Synthesis of Intermediate 1:2-Fluoro-(5-trifluoromethyl)phenylisocyanate (4 g, 19.5 mmol) is added to a solution of <strong>[1003-61-8]2-aminothiazole-5-carboxaldehyde</strong> (2.5 g, 19.5 mmol) in DMF (120 ml). The solution is heated at 70 C. for 1 h, evaporated, and purified by chromatography on silica gel, eluting with 1:1 hexane/EtOAc. The fractions containing intermediate 1 are combined and evaporated so as to provide intermediate 1 in the form of a yellow solid (4.28 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 4; 6-(4-Chlorophenyl)-5-(hydroxymethyl)imidazo [2, 1-b] [ 1 ,3] thiazoIe-2-carbaldehyde; A solution of <strong>[1003-61-8]2-aminothiazole-5-carboxaldehyde</strong> (1.0 g, 7.8 mmol) and 2-bromo-4'- chloroacetophenone (1.8 g, 7.8 mmol) in acetone (5 mL) was heated at reflux for 5 h. The solvent was evaporated and the crude material purified by preparative HPLC (Xterra Cl 8, 50 mM NH4HCO3 (pH 10) - CH3CN) to give the intermediate compound 6-(4- chlorophenyl)imidazo[2,l-b][l,3]thiazole-2-carbaldehyde as a yellow solid (176 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; for 6h; | In a 25 ml flask are added 0.5 g of <strong>[1003-61-8]2-aminothiazole-5-carboxaldehyde</strong>, 1.35 g of K2CO3 in 5 ml of DMF. After dissolution, 0.901 g of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride are added. The mixture is left at room temperature for lh then heated to 90C for 5h. Next, the mixture is evaporated, dissolved in 100 ml of water, and the aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated solution, dried over sodium sulfate, filtered, and evaporated to yield 420 mg (50%) of 2-(4- methylpiperazin-l-yl)thiazole-5-carboxaldehyde.1H-NMR: deltaEta pm 400 MHz, DMSO: 9.70 (1H, s), 8.13 (1H, s), 3.60 (4H, m), 2.43 (4H, m), 2.24 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In tetrahydrofuran; at 20℃; | Compound 129 was synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With diisopropylamine; In dichloromethane; at 0 - 20℃; for 17h; | Acetyl choride (6 mL, 84.38 mmol) was added to a solution of 2-amino-5- formylthiazole (10 g, 78 mmol) and diisopropylamine (45 mL, 261.1 mmol) in DCM (100 mL) at 0 C. The resulting mixture was allowed to warm to rt and further stirred atrt for 17 h. NH4C1 (aq. sat. soltn.) was added and the mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue thus obtained was purified by flash column chromatography (silica; dry load, EtOAc in DCM 0/100 to 50/50) and the desired fractions were concentrated in vacuo to yield intermediate 12 as yellow solid (8.6 g, 65% yield). |
65% | With diisopropylamine; In dichloromethane; at 0 - 20℃; for 17h; | Acetyl choride (6 mL, 84.38 mmol) was added to a solution of 2-amino-5- formylthiazole (10 g, 78 mmol) and diisopropylamine (45 mL, 261.1 mmol) in DCM (100 mL) at 0 C. The resulting mixture was allowed to warm to rt and further stirred at rt for 17 h. NH4C1 (aq. sat. soltn.) was added and the mixture was extracted with EtOAc. The organic layer was separated, dried over MgS04, filtered and concentrated in vacuo. The residue thus obtained was purified by flash column chromatography (silica; dry load, EtOAc in DCM 0/100 to 50/50) and the desired fractions were concentrated in vacuo to yield intermediate 40 as yellow solid (8.6 g, 65% yield). |
65% | With diisopropylamine; In dichloromethane; at 0 - 20℃; for 17h; | Acetyl chloride (6 mL, 84.38 mmol) was added to a solution of 2-amino-5- formylthiazole (10 g, 78 mmol) and diisopropylamine (45 mL, 261.1 mmol) in DCM (100 mL) at 0 C. The resulting mixture was allowed to warm to rt and further stirred at rt for 17 h. NH4C1 (aq. sat. soltn.) was added and the mixture was extracted with EtOAc. The organic layer was separated, dried over MgS04, filtered and concentrated in vacuo. The residue thus obtained was purified by flash column chromatography (silica; dry load, EtOAc in DCM 0/100 to 50/50) and the desired fractions were concentrated in vacuo to yield Intermediate 1 as yellow solid (8.6 g, 65% yield). |
65% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 17h; | Acetyl choride (6 mL, 84.38 mmol) was added to a solution of 2-amino-5- formylthiazole (10 g, 78 mmol) and diisopropylamine (45 mL, 261.1 mmol) in DCM (100 mL) at 0 C. The resulting mixture was allowed to warm to rt and further stirred at rt for 17 h. NH4C1 (aq. sat. soltn.) was added and the mixture was extracted with EtOAc. The organic layer was separated, dried over MgS04, filtered and concentrated in vacuo. The residue thus obtained was purified by flash column chromatography (silica; dry load, EtOAc in DCM 0/100 to 50/50) and the desired fractions were concentrated in vacuo to yield intermediate 38 as yellow solid (8.6 g, 65 % yield). |
With pyridine; In tetrahydrofuran; at 20℃; | Compounds 88, 89, 90, 91, 93, 94, 95, 96, 97, 98, 106 and 107 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. | |
With pyridine; at 0 - 20℃; for 12h; | To a stirred solution of 2-formyl-5-amino thiazole (1 eq.) in dry pyridine at 0C was added CH3COCI (1 .2 eq.) dropwise for 10 min. After the addition, the reaction was allowed to stir at RT for 12h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and H20 was added to get a precipitate which was filtered and air dried to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 80% | With pyridine; In tetrahydrofuran; at 20℃; | Compounds 74 and 81 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reflux; | Compound 134 was synthesized according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Compounds 108, 109, 143, 144 and 145 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In ethanol;Reflux; | Compounds 71 and 72 were synthesized according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Compounds 104 and 105 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20 - 65℃; | (E)-ethyl 3-(2-aminothiazol-5-yl)acrylate2-Aminothiazole-5-carbaldehyde (0.25 g, 2 mmol) was dissolved in anhydrous THF (20mL). (Ethoxycarbonylmethylene)triphenylphosphorane (0.790 g, 2.2 mmol) was added at room temperature and the reaction mixture was heated overnight at 65C. The reaction mixture was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(2-aminothiazol-5-yl)acrylate (0.24g) as a white solid. ES+ (M+H)+ 199. | |
0.24 g | In tetrahydrofuran; at 20 - 65℃; | 2-Aminothiazole-5-carbaldehyde (0.25 g, 2 mmol) was dissolved in anhydrous THF (20 mL). (Ethoxycarbonylmethylene)triphenylphosphorane (0.790 g, 2.2 mmol) was added at room temperature and the reaction mixture was heated overnight at 65 C. The reaction mixture was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(2-aminothiazol-5-yl)acrylate (0.24 g) as a white solid. ES+(M+H)+199. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 4h;Cooling with ice; | 2-Amino-5-formylthiazole (457 mg, 2.0 mmol) was dissolved in dichloromethane (15 mL), and morpholine (0.26 mL, 3.0 mmol) and sodium triacetoxyborohydride (636 mg, 3.0 mmol) were added thereto while cooling with ice, followed by stirring at room temperature for 4 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:30), thereby giving the title compound (412 mg, 69%) as a white solid. |
Tags: 1003-61-8 synthesis path| 1003-61-8 SDS| 1003-61-8 COA| 1003-61-8 purity| 1003-61-8 application| 1003-61-8 NMR| 1003-61-8 COA| 1003-61-8 structure
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