Structure of 104146-17-0
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CAS No. : | 104146-17-0 |
Formula : | C4H2ClNOS |
M.W : | 147.58 |
SMILES Code : | O=CC1=C(Cl)N=CS1 |
MDL No. : | MFCD09837291 |
InChI Key : | GJTWEAFBOIYNLZ-UHFFFAOYSA-N |
Pubchem ID : | 14501317 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-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 | 0.0 |
Molar Refractivity | 32.51 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.2 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.25 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.71 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.61 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.29 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.96 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
Solubility | 0.871 mg/ml ; 0.0059 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.55 |
Solubility | 0.418 mg/ml ; 0.00283 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.84 |
Solubility | 2.14 mg/ml ; 0.0145 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 |
-5.99 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) |
2.27 |
* 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 |
---|---|---|
76% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; water; at 20℃; for 1h; | Step 5. <strong>[104146-17-0]4-chloro-1,3-thiazole-5-carbaldehyde</strong> oximeTo a stirred solution of sodium bicarbonate (0.17 g, 2.0 mmol) in water (6.4 mL) was added hydroxylamine hydrochloride (0.14 g, 2.0 mmol) in portions. To the mixture was added a solution of <strong>[104146-17-0]4-chloro-1,3-thiazole-5-carbaldehyde</strong> (0.30 g, 2.0 mmol) in ethanol (2.0 mL). The mixture was stirred for 1 h at ambient temperature. The reaction solution was diluted with water. The resultant precipitate was collected and dried under vacuum to give the desired product as white solid (0.25 g, 76percent). 1H NMR (300 MHz, CD3OD): delta 9.02 (s, 1H), 7.83 (s, 1H); LCMS (M+H)+: 162.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 18h; | Add sodium triacetoxyborohydride (30. 50 g, 144 mmol) to a stirred solution of 4- amino-1-N Boc-piperidine (18.00 g, 89.9 mmol), <strong>[104146-17-0]4-chloro-thiazole-5-carbaldehyde</strong> (13.09 g, 88.7 mmol), acetic acid (5.5 mL, 96.1 mmol), and 1, 2-dichloroethane (350 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (400 mL) and extract with ethyl acetate (3 X 150 mL). Wash the ethyl acetate with brine (2 X 150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 75percent ethyl acetate/hexanes then with 100 percent ethyl acetate to yield 21.78 g (74percent) of 4-f [ (4-chloro-thiazol-5-yl) methyl]-amino}- piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z = 332.1 (M+1) ; IH NMR (CDC13) : 8 = 8.67 (s, 1H), 4.10-4. 02 (m, 4H), 2.88-2. 82 (m, 2H), 2.74- 2.67 (m, 1H), 1.92-1. 89 (m, 2H), 1.49 (s, 9H), 1.37-1. 28 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride; In tetrahydrofuran; 1,4-dioxane; water; at 20℃; for 3h; | [000273] Synthesis of 4-chlorothiazole-5-carbaldehyde (333): To a stirred solution of compound 332 (1.1 g, 5.75 mmol) in THF (10 mL) was added 5 N aqueous HC1 in 1, 4-dioxane (6 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into brine (20 mL) extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 333 (800 mg, 95percent) as yellow oil. TLC: 10percent EtOAc/ hexanes (R 0.3); 1H NMR (CDC13, 500 MHz): oe 10.11 (s, 1H), 9.00 (s, 1H). |
92% | Step 4. 4-chloro-1,3-thiazole-5-carbaldehydeTo a solution of 4-chloro-5-(1,3-dioxolan-2-yl)-1,3-thiazole (0.75 g, 3.9 mmol) in THF (10 mL) was added 5.0 M of HCl solution in water (2 mL, 10 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The reaction solution was poured into brine and extracted with ethyl acetate three times. The combined extracts were washed with saturated sodium bicarbonate, brine, dried over MgSO4, filtered, and concentrated to give the desired product as an off-white solid (0.53 g, 92percent). 1H NMR (300 MHz, CDCl3): delta 10.16 (s, 1H), 9.03 (s, 1H). | |
88% | With hydrogenchloride; In tetrahydrofuran; at 20℃; for 1.5h; | Add 5 N HC1 (50 mL, 250 mmol) to a stirred solution of 4-chloro-5- [1, 3] dioxolan-2- yl-thiazole (19.2482 g, 100 mmol) and tetrahydrofuran (250 mL). Stir the reaction for 1.5 h at room temperature. Pour the reaction into brine (300 mL) and extract with ethyl acetate (3 X 100 mL). Wash the ethyl acetate with saturated sodium bicarbonate (150 mL) and then with brine (100 mL). Dry the ethyl acetate over sodium sulfate and filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 20 percent ethyl acetate/hexanes to yield 13. 09 g (88percent) of4-chloro-thiazole-5-carbaldehyde : IHNMR (CDCl3) : 5 = 10. 13 (s, 1H), 9.04 (s, 1H). |
245 mg (38%) | With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; | c) 4-Chloro-thiazole-5-carbaldehyde A 1.6 M solution of n-butyl-lithium in hexane (2.7 mL, 4.32 mmol) was added dropwise to a stirred solution of 4-chloro-5-[1,3]dioxolan-2-yl-thiazole (787.2 mg, 4.32 mmol) and tetrahydrofuran (20.0 mL) in an ice bath. The solution was stirred for 1 h, equilibrated to room temperature, and poured into a 10percent aqueous hydrochloric acid solution (50 mL). The solution was extracted with ether (100 mL). To the extracts were added 10percent aqueous hydrochloric acid solution and the resultant solution was stirred for 6 h. The ether layer was washed with brine, dried over sodium sulfate, decanted, and concentrated. The product was purified by column chromatography (dichloromethane) to yield 245 mg (38percent) of the title compound as an off-white solid. 1H NMR (CDCl3): 10.11 (s, 1H), 9.01 (s, 1H). |
With hydrogenchloride; In tetrahydrofuran; water; at 20℃; for 2h; | To a solution of 4-chloro-5-(l,3-dioxolan-2-yl)-l,3-thiazole (2.1 g, 11.1 mmol) in THF (25 mL) was added 6N HCl (5 mL). The solution was stirred at room temperature for 2 hours. The solution was poured into brine (50 mL). The mixture was extracted with EtOAc (2 x 50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 4-chloro-l,3-thiazole- 5-carbaldehyde (1.4 g, 86percent yield). The product was used without further purification. | |
With hydrogenchloride; water; In tetrahydrofuran; at 20℃; for 3h; | General procedure for the synthesis of M3 To a stirred solution of M2 (0.53 g, 2.74 mmol) in tetrahydrofuran (6.0 mL) was added 6 N HC1 (1.2 m) and the mixture was stirred at room temperaturefor 3 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo to give M3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
170 mg (75%) | With sulfuric acid; In water; ethyl acetate; | d) 4-Chloro-thiazole-5-carboxylic acid A solution of chomium(IV)oxide (149 mg, 1.49 mmol) in 300 mL deionized water was added dropwise to a stirred solution of <strong>[104146-17-0]4-chloro-thiazole-5-carbaldehyde</strong> (205 mg, 1.37 mmol) and in an ice bath (1.0 mL), followed by addition of sulfuric acid (8 drops). The ice bath was removed and the solution was stirred at ambient temperature for 30 min. Ethyl acetate (30 mL) was added to the solution and the solution was washed with deionized water (4*10 mL) and brine (2*10 mL). The ethyl acetate layer was extracted by a 10percent saturated sodium bicarbonate solution (2*20 mL). The aqueous extracts were acidified to pH 3 with a 10percent aqueous hydrochloric acid solution and were extracted with 1:1 dichloromethane:ethyl acetate solution (5*15 mL) and ethyl acetate (20 mL). The organic extracts were dried over sodium sulfate, decanted, and concentrated to yield 170 mg (75percent) of the title compound as a white solid. 1H NMR (Acetone-d6): 9.20 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To the resultant solution in methylene chloride were added 4-chloro-thiazol-5-yl-carboaldehyde (1.100 g) which was obtained in Reference Example 3 described hereinbefore, and then saturated aqueous sodium hydrogen carbonate (10 ml). The mixture obtained was stirred for 6 hours at ambient temperature and then was left until it separated into the aqueous phase and organic phase. The aqueous phase as separated was extracted with methylene chloride (10 ml). The extract in methylene chloride and the organic solvent phase were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by flash-column chromatography on a column of silica-gel (Wako-gel C-300) as developed with benzene-ethyl acetate (5:1) as eluent solvent. The titled compound was obtained (yield 2.891 g, 74percent). NMR, delta (CDCl3): 3.15 (1H, d, J=18 Hz), 3.42 (1H, d=18 Hz), 3.61 (2H, s), 3.74 (3H, s), 5.00 (1H, d, J=5 Hz), 5.06 (2H, s), 5.84 (1H, dd, J=5 Hz, 9 Hz), 6.14 (1H, d, J=9 Hz), 6.27 (1H, d, J=12 Hz), 6.56 (1H, d, J=12 Hz), 6.7-6.75 (2H, m), 7.05-7.4 (7H, m), 8.50 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; trichlorophosphate; In N-methyl-acetamide; dichloromethane; 1,2-dichloro-ethane; | REFERENCE EXAMPLE 4 Production of 2,4-dichloro-thiazol-4-yl-carboaldehyde of the formula STR22 To a solution of dimethylformamide (73.1 g) in dichloroethylene (200 ml) was added dropwise phosphorus oxychloride (122.7 g) under ice-cooling, followed by stirring for 30 minutes (for preparation of Vilsmeier reagent). The resultant solution was admixed with thiazolin-2,4-dione (23.4 g) and heated for 1 hour under refluxing. The reaction solution obtained was cooled to ambient temperature, poured onto ice (200 g), neutralized by addition of sodium acetate and then extracted 3 times with 200 ml-portions of methylene chloride. The resultant extract in methylene chloride was washed with a small volume of saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified chromatographically on a column of silica-gel as developed with benzene-ethyl acetate (10:1) as eluent. 4-Chloro-thiazol-5-yl-carboaldehyde (0.34 g) was afforded, and the titled compound (2.05 g) was also obtained as light yellow colored crystals. NMR, delta (CDCl3): 9.90 (1H, s) MS (m/e): 182 (M+ +1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; trichlorophosphate; In N-methyl-acetamide; dichloromethane; | REFERENCE EXAMPLE 3 Production of 4-chloro-thiazol-5-yl-carboaldehyde of the formula STR20 Phosphorus oxychloride (122.7 g) was added dropwise to dimethylformamide (73.1 g) under ice-cooling, and the mixture obtained was stirred for 30 minutes (for preparation of Vilsmeier reagent). The mixture was then admixed with thiazoline-2,4-dione STR21 (23.4 g), followed by heating at 100° C. for 3 hours. The reaction solution was cooled to ambient temperature, poured onto ice (200 g), neutralized by addition of sodium acetate and then extracted 4 times with 200 ml-portions of methylene chloride. The resultant extract in methylene chloride was washed with a small volume of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified chromatographically on a column of silica gel as developed with benzene-ethyl acetate (10:1) as eluent. The titled compound (1.10 g) was obtained as light yellow colored crystals. NMR, delta (CDCl3): 8.93 (1H, d, J=1 Hz), 10.03 (1H, d, J=1 Hz). MS (m/e): 148 (M+ +1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 100℃; for 0.5h; | A mixture of <strong>[104146-17-0]4-chlorothiazole-5-carbaldehyde</strong> (0.15 g), benzenesulfinic acid sodium salt (0.25 g) and dimethyl sulfoxide (7.0 mL) was stirred at 1000C for 30 minutes. The mixture was cooled to room temperature, poured onto ice/water (50 mL) and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a tan oil (0.23 g).1H NMR (CDCI3): delta 7.57-7.63 (m, 2H), 7.67-7.73 (m, 1H), 8.11-8.14 (m, 2H), 8.95 (d, J = 0.9 Hz, 1 H), 10.83 (d, J = 0.9 Hz, 1 H). | |
In dimethyl sulfoxide; at 100℃; for 0.333333h; | 4-benzenesulfonylthiazole-5-carbaldehydeA mixture of <strong>[104146-17-0]4-chlorothiazole-5-carbaldehyde</strong> (2.9 g) and benzenesulfinic acid sodium salt (4.9 g) in anhydrous dimethyl sulfoxide (50 ml_) was heated at 1000C for 20 minutes. The resulting solution was cooled then poured onto a mixture of ice and saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (5.03 g) as a pale yellow solid.1H NMR (300 MHz, CDCI3): delta 7.56-7.65 (m, 2H); 7.66-7.74 (m, 1 H); 8.09- 8.15 (m, 2H); 8.94 (d, J = 0.9 Hz, 1 H); 10.83 (d, J = 0.9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere; | [000274] Synthesis of (4-chlorothiazol-5-yl) methanol (334): To a stirred solution of compound 333 (750 mg, 5.10 mmol) in dry THF (20 mL) under inert atmosphere was added lithium aluminium hydride (193 mg, 5.10 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 30percent aqueous sodium hydroxide solution (3 mL) extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 334 (520 mg, 68percent) as yellow oil. TLC: 10percent EtOAc/ hexanes (R 0.3); 1H NMR (CDC13, 500 MHz): oe 8.69 (m, 1H), 4.88 (s, 2H). |
With methanol; sodium tetrahydroborate; at 20℃; for 3h; | To a 0°C solution of 4-chloro-l,3-thiazole-5-carbaldehyde (1.4 g, 9.5 mmol) in anhydrous methanol (100 mL) was added sodium borohydride (570 mg, 15.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added. MeOH was evaporated. The resultant residue was extracted with EtOAc (1 x 20 mL) and 2-butanol (1 x 20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (4-chloro-l,3-thiazol-5- yl)methanol (1.3 g, 91percent yield). The product was used without further purification. |
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