Structure of 167366-05-4
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CAS No. : | 167366-05-4 |
Formula : | C4H2BrNOS |
M.W : | 192.03 |
SMILES Code : | O=CC1=NC(Br)=CS1 |
MDL No. : | MFCD06660122 |
InChI Key : | JDUXMFGFGCJNGO-UHFFFAOYSA-N |
Pubchem ID : | 2763187 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | 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 | 35.2 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.2 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.26 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.77 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.72 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.53 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.54 |
Solubility | 0.551 mg/ml ; 0.00287 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.61 |
Solubility | 0.471 mg/ml ; 0.00245 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.1 |
Solubility | 1.53 mg/ml ; 0.00798 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) |
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 |
-6.21 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) |
2.41 |
* 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 |
---|---|---|
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 ml.) was treated with n-BuLi (5.9 ml. of a 2.5M solution in hexanes, 14.72 mmol) at -78 0C. The reaction mixture was stirred at this temperature for 30 min. lambda/,lambda/-Dimethylformamide (1.35 ml_, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4CI (50 ml_). The layers were separated and the aq. layer extracted with Et2O (3 x 50 ml_). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 -> 3:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.21. LC-MS-conditions 02: tR = 0.81 min. | ||
With n-butyllithium; In diethyl ether; at -78 - 20℃; for 1.25h; | To a solution of 2,4-dibromothiazole (2.50 g, 10.28 mmol) in diethyl ether (50 ml) cooled to -78 C. was added n-butyl lithium (1.40 M, 8.80 ml, 12.38 mmol) and the resulting reaction mixture was stirred for 15 min at the same temperature followed by addition of DMF (5.0 ml, 64.30 mmol). The reaction mass was then allowed to come to room temperature and stirred for 1 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0 C. and quenched with saturated NH4Cl solution (aqueous). Water was then added to the reaction mass and extracted with diethyl ether (3×100 ml). The combined organics was then dried over anhydrous Na2SO4, filtered and concentrated to get the desired product (2.10 g, quantitative crude yield) that was carried forward to the next step without further purification. | |
4-Bromo-thiazole-2-carbaldehyde:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 mL) was treated with n-BuLi (5.9 mL of a 2.5M solution in hexanes, 14.72 mmol) at -78 0C. The reaction mixture was stirred at this temperature for 30 min. Lambda/,Lambda/-Dimethylformamide (1.35 mL, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4CI (50 mL). The layers were separated and the aq. layer extracted with Et2O (3 x 50 mL). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 ->; 3:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.21. LC-MS-conditions 02: tR = 0.81 min. |
(Example 30a) (4-bromo-1,3-thiazol-2-yl)methanol [Show Image] Under a nitrogen atmosphere at -78C, to a solution (20 mL) of 2,4-dibromothiazole (5 g, 20.6 mmol) in diethyl ether was added n-butyllithium (1.6 M hexane solution, 15.4 mL, 24.7 mmol), and the mixture was stirred at the same temperature for 30 min. N,N-Dimethylformamide (2.3 g, 30.9 mmol) was added to the reaction mixture at -78C, and the mixture was gradually warmed to room temperature. After confirmation of the termination of the reaction by TLC, hexane was added. The resulting salt was filtered and the solvent was evaporated under reduced pressure to give 4-bromo-1,3-thiazole-2-carbaldehyde as a crude product. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.68 (1 H, d, J=1.0 Hz), 9.95 (1 H, d, J=1.2 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With methanol; sodium tetrahydroborate; at 20℃; for 0.5h; | Sodium borohydride (99 mg, 2.60 mmol) was added to a stirring solution of 5- chlorothiazole-2-carboxaldehyde (500 mg, 2.60 mmol) in MeOH (5.2 mL) at RT. The mixture was stirred for 30 min at RT and then concentrated in vacuo. The residue was taken up in EtOAc (40 mL) and washed sequentially with water (30 mL) and brine (20 mL). The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo to give (4-bromothiazol-2-yl)methanol as a brown oil that was used without further purification (406A, 499 mg, 99%). LC/MS (ESI+) m/z = 194.0 (M+H)+. 1H NMR (400 MHz, chloroform-d) delta 7.23 (s, 1 H), 4.97 (d, J=6.06 Hz, 2H), 2.51 (t, J=5.38 Hz, 1 H). |
95.2% | With sodium tetrahydroborate; | (4-Bromothiazol-2-yl)methanol (2) To a solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (10.4 g, 0.0542 mol) in MeOH (150 mL) was added NaBH4 (4.10 g, 0.108 mol) at 0 C. The mixture was stirred at 25 C. for 2 hrs. TLC showed the reaction was completed and one new spot was observed. The mixture was quenched with water (70 mL), stirred for 0.5 hr and concentrated to remove most of MeOH. The aqueous layer was extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, Petroleum ether/Ethyl acetate=10: to 3:1) to give (4-bromothiazol-2-yl)methanol (10.0 g, 0.0515 mol, yield: 95.2%) as white solid. 1H NMR (400 MHz, CDCl3) delta 7.23 (s, 1H), 4.96 (d, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 1H). |
With sodium tetrahydroborate; In methanol; at 20℃; | 2,4-Dibromothiazole (4.31 g, 17.7 mmol) are dissolved in anhydrous diethyl ether (170 ml) and the solution is cooled to -78 C. (dry ice-acetone bath). n-Butyllithium (1.6 M in hexanes, 13 ml, 20.8 mmol) is added dropwise to the reaction mixture and the resulting solution is stirred at the same temperature for 30 minutes. Anhydrous DMF (ml, mmol) is then added at -78 C. and, after being stirred at the -78 C. for 30 minutes, the reaction mixture is warmed to room temperature over a period of 2 hours. Hexanes (300 ml), were added and the resulting mixture is passed through a short silica cake eluting with 30% EtOAc-hexanes. The solvents are evaporated to yield the crude aldehyde which is used directly in the next step. To a solution of the above aldehyde in MeOH (80 ml) is added sodium borohydride (g, mmol), and the resulting mixture is stirred room temperature for hours. Hexanes (300 ml) are added and the mixture is passed through a short silica cake eluting with EtOAc. The crude alcohol is further purified by flash chromatography on silica with 20-50% EtOAc-hexanes as an eluant to yield g (mmol, %) of the pure desired product. |
With sodium tetrahydroborate; In methanol; at 0 - 25℃;Inert atmosphere; | In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), <strong>[167366-05-4]4-bromo-thiazole-2-carbaldehyde</strong> (1.68 g, 8.75 mmol) was dissolved in MeOH (10 mL). NaBH4 (428 mg, 10.86 mmol) was added portionwise at 0 0C and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted with EA (3 x 20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:1 -> 2:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.31. LC-MS-conditions 02: tR = 0.62 min [M+H]+ = 194.31. | |
With sodium tetrahydroborate; In methanol; at 20℃; | To an ice-cold solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1.78 g, 9.27 mmol, crude obtained above), in methanol (30 ml) was added NaBH4 (1.76 g, 46.35 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (TLC monitoring), the reaction mass was cooled to 0 C., quenched it with 25 ml of water and concentrated under vacuum. Added 50 ml water and extracted with EtOAc (3×100 ml). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (1.40 g, 78%). MS: 194.01 (M+H)+. | |
With sodium tetrahydroborate; In methanol; at 0 - 20℃;Inert atmosphere; | (4-Bromo-thiazol-2-yl)-methanol:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), <strong>[167366-05-4]4-bromo-thiazole-2-carbaldehyde</strong> (1.68 g, 8.75 mmol) was dissolved in MeOH (10 ml_). NaBH4 (428 mg, 10.86 mmol) was added portionwise at 0 0C and the reaction mixture stirred at rt for 1 h. Water (10 ml.) was added and the mixture extracted with EA (3 x 20 ml_). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:1 ->; 2:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 : 1 hept-EA) = 0.31. LC-MS-conditions 02: tR = 0.62 min [M+H]+ = 194.31. | |
To a solution (20 mL) of crude <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> in ethanol was added sodium tetrahydroborate (935 mg, 24.7 mmol), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane - hexane/ethyl acetate=75/25) to give the title compound (1.8 g, 44%) as a pale-yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.60 (1 H, t, J=6.2 Hz), 4.96 (2 H, d, J=6.2 Hz), 7.22 (1 H, s) | ||
865 mg | With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0 - 35℃; for 1h; | A) (4-bromothiazol-2-yl)methanol To a solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1.20 g) in THF (10 mL) were successively added sodium borohydride (236 mg) and methanol (1.0 mL) at 0C, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (865 mg) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) delta 4.72 (2H, d, J = 6.0 Hz), 6.19 (1H, t, J = 5.9 Hz), 7.75 (1H, s). |
3.28 g | With sodium tetrahydroborate; In methanol; at 20℃; for 0.333333h; | Step 1: (4-Bromo-thiazol-2-yI)-methanol [00308] To a solution of <strong>[167366-05-4]4-bromo-2-formylthiazole</strong> (4.00 g, 20.8 mmol) in methanol (60.0 mL, 1480 mmol) was slowly added sodium tetrahydroborate (0.946 g, 25.0 mmol), and the reaction was stirred at rt for 20 min. The reaction was concentrated in vacuo, diluted with EtOAc, and washed with water 2x and then brine l x. Organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified via column chromatograpy (40g column, 20% - 50% EtOAc in hexanes over 30min) to give a light yellow oil. Yield = 3.28 g. NMR (400 MHz, Chloroform-d) delta 7.22 (s, 1H), 4.95 (d, J = 6.2 Hz, 2H), 2.76 (t, J = 6.2 Hz, 1H). LCMS (FA): 196.0 m/z (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With toluene-4-sulfonic acid; In toluene; for 12h;Dean-Stark; Reflux; | A toluene (120 mL) solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (7 g, 36.50 mmol) and ethyleneglycol (2.72 g, 43.7 mmol) in a RB flask was added catalytic amount of pTsOH (0.347 g, 1.823mmol). The RB flask was attached with Dean-Stark apparatus and reaction mixture was heated to reflux for 12h. The mixture was cooled to RT, and was partitioned with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with saturated aqueous NaHCO3 (2 X 120 mL) solution and then once with brine (100 mL). The organic layer was dried over anhydroussodium sulphate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by combiflash chromatography (40 g Redisep 5i02 column, eluting with 20% EtOAc in pet ether) to afford the title compound 137A (8 g, 97%) as a colourless liquid. LC-MS retention time = 1.557 mm; m/z = 236.0 [M+2Hj + K1NETIX XB-C18, (3 X 75) mm, 2.6 micron column; Flow rate: 1 mL/min; Mobile Phase A: 10mM HCO2NH4in 98% Water/ 2% ACN; Mobile PhaseB: 10 mM HCO2NH4 in 2% Water/ 98% ACN; 20% B to 100% B over 4.6 mm, then hold 0.5 mm. at 20% B with flow rate 1-1.5 mL/min; Detection: UV at 254 nm. ?H NMR (400 MHz, DMSO-d6) oe 7.94 (s, 1H), 6.08 (s, 1H), 3.99 -4.08 (m, 4H). |
With toluene-4-sulfonic acid; In benzene; for 3h;Heating / reflux; | To a rb flask with an attached Dean-Stark trap containing molecular sieves, 4A (0.25g) was added <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (4.4 g, 22.91 mmol). The starting material was dissolved in Benzene (45 ml) and Ethylene glycol (1.406 ml, 25.2 mmol) was added followed by pTsOH (0.218 g, 1.146 mmol). The mixture was heated to reflux for 3 h. The mixture was cooled to rt, and was partitioned with sat. aq. NaHCO3. The mixture was washed 2* with sat. NaHCO3 (40 mL), then once with sat. NaCl (40 mL). The organic layer was dried with Na2SO4. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by biotage flash chromatography using a 40+M column and a 0 to 20% EtOAc in hexanes gradient. The product, 4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.1 g, 21.60 mmol, 94% yield), was collected as a light-yellow oil. To a solution of 4-bromo-2-(1,3-dioxolan-2-yl)thiazole (5.09 g, 21.56 mmol) in Toluene (100 ml) was added Hexamethylditin (10 g, 30.5 mmol) followed by Tetrakis (2.491 g, 2.156 mmol). The mixture was attached to a reflux condenser, and was flushed with N2. The mixture was heated to 100 C. for 4 h. The mixture was cooled to rt, and was loaded onto a 40+M biotage cartridge that was pre-saturated with hexanes with 0.1% Et3N. The desired product was purified using a 0-20% EtOAc in hexanes with 0.1% Et3N gradient. After concentrating in vacuo, the product, 2-(1,3-dioxolan-2-yl)-4-(trimethylstannyl)thiazole (4.64 g, 14.50 mmol, 67.3% yield), was isolated as a light-yellow oil. LCMS: m/e 322.0 (M+H)+, ret time 2.23 min (method 7); 1H NMR (500 MHz, CDCl3) delta ppm 7.39 (s, 1H) 6.20 (s, 1H) 4.03-4.20 (m, 4H) 0.27-0.42 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,4-Dibromothiazole (4.31 g, 17.7 mmol) are dissolved in anhydrous diethyl ether (170 ml) and the solution is cooled to -78 C. (dry ice-acetone bath). n-Butyllithium (1.6 M in hexanes, 13 ml, 20.8 mmol) is added dropwise to the reaction mixture and the resulting solution is stirred at the same temperature for 30 minutes. Anhydrous DMF (ml, mmol) is then added at -78 C. and, after being stirred at the -78 C. for 30 minutes, the reaction mixture is warmed to room temperature over a period of 2 hours. Hexanes (300 ml), were added and the resulting mixture is passed through a short silica cake eluting with 30% EtOAc-hexanes. The solvents are evaporated to yield the crude aldehyde which is used directly in the next step. To a solution of the above aldehyde in MeOH (80 ml) is added sodium borohydride (g, mmol), and the resulting mixture is stirred room temperature for hours. Hexanes (300 ml) are added and the mixture is passed through a short silica cake eluting with EtOAc. The crude alcohol is further purified by flash chromatography on silica with 20-50% EtOAc-hexanes as an eluant to yield g (mmol, %) of the pure desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-bromo-1 ,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 ml_) was added acetic acid (3 drops) and 2,2,2-trifluoroethanamine (120 mul_, 1.5 mmol). The reaction was stirred overnight. Sodium triacetoxyborohydride (335 mg, 1.5 mmol) was then added and reaction was stirred for 6 h. It was then quenched with sodium bicarbonate to yield 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1/-/-indole-7-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | N-((4-bromothiazol-2-yl)methyl)cyclopropanamine <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (2.5 g, 13 mmol) was dissolved in tetrahydrofuran (65 mL) and cyclopropylamine (3.72 mL, 53.7 mmol) and sodium triacetoxyborohydride (11.4 g, 53.7 mmol) added. The reaction mixture was stirred 20 h at RT and then hydrolyzed at 0 C. with sat. sodium hydrogencarbonate sol. (150 mL). The product was extracted with ethyl acetate (2*300 mL) and the organic phase dried. (Yield: 3.0 g, 97%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; acetic acid; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Example 354 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-piperidinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide To a solution of <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (192 mg, 1.0 mmol) in DCM (4.0 mL) was added piperidine (150 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 166 mg of the title compound (64%). The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting piperidine (78 mg, 0.3 mmol) for 2-methyl-1-propanamine to afford 15.5 mg of the title compound (51.6%). LC/MS=m/z 517.4 [M+H] Ret. Time: 1.29 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydrogencarbonate; acetic acid; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Example 351 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide trifluoroacetate To a solution of <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (192 mg, 1.0 mmol) in DCM (4.0 mL) was added morpholine (130 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; potassium carbonate; acetic acid; dimethyl amine; In 1,4-dioxane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Example 355 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate To a solution of <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (192 mg, 1.0 mmol) in DCM (4.0 mL) was added dimethyl amine (2.0M, 3.0 mL) and 3 drops of AcOH. The mixture was stirred for 48 hr and then Na(OAc)3BH (1.33 g, 6.0 mmol) was added. After 12 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL) and separator was used to get the DCM organic layer. The organic layer was concentrated to give 90 mg of desired product (40%). To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol), dimethylamine (69 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL) and water (0.7 mL) was added triacetoxyborohydride (12 mg, 0.01 mmol). This mixture was degassed for 5 min. The mixture was then reacted in a microwave for 20 min at 160 C. The organic layers were separated and concentrated. It was then purified using Gilson Preparatory HPLC to afford 23 mg of the title compound (59%) LC/MS=m/z 474.4 [M+H] Ret. Time: 1.20 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 1h;Inert atmosphere; Microwave irradiation; | Intermediate 391 -methylethyl [(cis)-1 -acetyl-6-(2-formyl-1 ,3-thiazol-4-yl)-2-methyl-1 ,2,3,4-tetrahydro- 4-quinolinyl]carbamate1 -methylethyl [(cis)-1 -acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 12)(50 mg, 0.120 mmol) was mixed with 4-bromo-1 ,3-thiazole-2-carbaldehyde (34.6 mg, 0.180 mmol, available from Frontier), potassium carbonate (33.2 mg, 0.240 mmol), tetrakis(triphenylphosphine)palladium(0) (6.94 mg, 6.01 muetaetaomicronIota) and dissolved in ethanol (0.5 mL) and toluene (0.5 mL). The mixture was heated in a nitrogen-flushed microwave vial at 90C for 1 hour in a Biotage initiator and the mixture was left to cool to room temperature overnight. The residue was partitoned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid. This was purified on a 12+M Biotage silica column eluting with a 0-60% gradient of ethyl acetate in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (23 mg). LCMS (Method C): Rt = 0.96, MH+ = 402 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | General procedure: The reaction was carried out in a sealed tube under N2 using THF (4 mL) as the solvent. To the solution of tert-butyl 2-bromothiazole-4-carboxylate 1a (0.397 mmol), iPrMgCl·LiCl (1.3 M, 0.52 mmol) was added dropwise at -78 C. After 15 min the corresponding aldehyde (0.79-0.99 mmol) or N-formyl-morpholine (in the case of 2-formylthiazoles 3a-b) was added dropwise under stirring and the reaction mixture was stirred at -78 C for 10 min, then 1.5 h at 0 C. Saturated aqueous NH4Cl was added and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with 5% aqueous HCl (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mixture of EtOAc:P (petroleum ether) as eluent (see below) to give tert-butyl 2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | General procedure: In a dried round bottom flask, a solution of aldehyde 3a or 3b (100 mg, 0.469 mmol) in THF (4 mL) was cooled to -78 C under N2, and the Grignard reagent (0.47-1.62 mmol in THF) was added slowly. After complete consumption of the starting material (monitored by TLC), the reaction was quenched with saturated aqueous NH4Cl (2 mL). The aqueous layer was extracted with Et2O (3 × 5 mL) and the combined organic layers were washed with 5% aqueous HCl (5 mL) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using a mixture of EtOAc:P as eluent to give tert-butyl-2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2i-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: In a dried round bottom flask, a solution of aldehyde 3a or 3b (100 mg, 0.469 mmol) in THF (4 mL) was cooled to -78 C under N2, and the Grignard reagent (0.47-1.62 mmol in THF) was added slowly. After complete consumption of the starting material (monitored by TLC), the reaction was quenched with saturated aqueous NH4Cl (2 mL). The aqueous layer was extracted with Et2O (3 × 5 mL) and the combined organic layers were washed with 5% aqueous HCl (5 mL) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using a mixture of EtOAc:P as eluent to give tert-butyl-2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2i-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 1h;Biotage initiator; | 1-methylethyl [(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 12) (50 mg, 0.120 mmol) was mixed with <strong>[167366-05-4]4-bromo-1,3-thiazole-2-carbaldehyde</strong> (34.6 mg, 0.180 mmol, available from Frontier), potassium carbonate (33.2 mg, 0.240 mmol), tetrakis(triphenylphosphine)palladium(0) (6.94 mg, 6.01 mumol) and dissolved in ethanol (0.5 mL) and toluene (0.5 mL). The mixture was heated in a nitrogen-flushed microwave vial at 90 C. for 1 hour in a Biotage initiator and the mixture was left to cool to room temperature overnight. The residue was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid. This was purified on a 12+M Biotage silica column eluting with a 0-60% gradient of ethyl acetate in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (23 mg). LCMS (Method C): Rt=0.96, MH+=402 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 80℃; for 24h; | To a stirred solution of <strong>[167366-05-4]4-bromo-thiazole-2-carbaldehyde</strong> (5.0 g, 26 mmol) in EtOH (50 mL) was added successively diethoxymethoxy-ethane (14 mL) at room temperature. After the mixture was heated at 80 C for 24 hours, the solvent was removed under reduced pressure. The DCM (50 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL x 2). The combined organic layers were washed with sat. NaHC03 (30 mL), brine (30 mL) and then dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford the crude product W (7.0 g) as an oil, which was used in the next step. | |
In ethanol; at 80℃; for 24h;Inert atmosphere; | To a stirred solution of <strong>[167366-05-4]4-bromo-thiazole-2-carbaldehyde</strong> (5.0 g, 26 mmol) in EtOH (50 mL) was added successively diethoxymethoxy-ethane (14 mL) at room temperature. After the mixture was heated at 80 C. for 24 hours, the solvent was removed under reduced pressure. The DCM (50 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL×2). The combined organic layers were washed with sat. NaHCO3 (30 mL), brine (30 mL) and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford the crude product W (7.0 g) as an oil, which was used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20 - 80℃; for 4h; | Example 79: Ethyl 3-((4-bromothiazol-2-yl)methylamino)propanoate [00229] A mixture of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1.91 g, 10.0 mmol, 1.0 eq), ethyl 3-aminopropanoate HC1 (1.75 g, 15.0 mmol, 1.5 eq) in DCE (30 mL) was stirred at 80C for 2 h. The mixture was cooled down to rt, and NaBH(AcO)3 (5.3 g, 25.0 mmol, 2.5 eq) was added, the resultant mixture was stirred at rt for 2 h. The reaction mixture was diluted with EA (60 mL), followed by filtration, the filtrate was concerntrated in vacuo, and the residue was purified by column chromatography on silica gel (PE/EA = 5/1) to give the title compound as a yellow oil (1.1 g, 37% yield). LCMS mlz 293.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
178 mg | With toluene-4-sulfonic acid; In methanol;Inert atmosphere; Reflux; | To a solution of <strong>[167366-05-4]4-bromothiazole-2-carboxaldehyde</strong> (200 mg) in MeOH (3.5 mL) were added trimethylorthoformate (0.57 mL) and PTSA (165 mg). The reaction mixture was stirred under reflux overnight. The mixture was diluted with sat. aq. NaHC03 and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with 1 N aq. NaOH and sat. aq. NaCI, dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 5g cartridge, solvent A: Heptane, solvent B: EA, gradient in %B: 0 to 1 , flow rate: 7 imL/min) to afford 178 mg of yellow oil. LC- MS (A) tR = 0.71 min; [M+H]+: 238.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.2% | General procedure: Bromoarylaldehyde (1 mmol), aryl or alkenyl-boronicacid (1.2 mmol), and Cs2CO3(2.5 mmol) were dissolved orsuspended in a mixture of 1,4-dioxane (10 mL) and water (5 mL). The resulting mixture was stirred at RT for 5min. Tetrakis (triphenylphosphine) palladium(0) (0.05mmol) was added and the mixture was refluxed for 4-6 h under N2 protection. After cooling to RT, the mixture was dilutedwith CH2Cl2 (10 mL) and the separated aqueous layer wasextracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4,filtered, and the solution was concentrated in vacuo to obtain a residue, whichwas purified by silica gel CC using ethyl acetate-petroleum ether gradientelution (1:200-1:4, v/v) to afford the aldehydes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.3% | General procedure: Bromoarylaldehyde (1 mmol), aryl or alkenyl-boronicacid (1.2 mmol), and Cs2CO3(2.5 mmol) were dissolved orsuspended in a mixture of 1,4-dioxane (10 mL) and water (5 mL). The resulting mixture was stirred at RT for 5min. Tetrakis (triphenylphosphine) palladium(0) (0.05mmol) was added and the mixture was refluxed for 4-6 h under N2 protection. After cooling to RT, the mixture was dilutedwith CH2Cl2 (10 mL) and the separated aqueous layer wasextracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4,filtered, and the solution was concentrated in vacuo to obtain a residue, whichwas purified by silica gel CC using ethyl acetate-petroleum ether gradientelution (1:200-1:4, v/v) to afford the aldehydes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.9% | General procedure: Bromoarylaldehyde (1 mmol), aryl or alkenyl-boronicacid (1.2 mmol), and Cs2CO3(2.5 mmol) were dissolved orsuspended in a mixture of 1,4-dioxane (10 mL) and water (5 mL). The resulting mixture was stirred at RT for 5min. Tetrakis (triphenylphosphine) palladium(0) (0.05mmol) was added and the mixture was refluxed for 4-6 h under N2 protection. After cooling to RT, the mixture was dilutedwith CH2Cl2 (10 mL) and the separated aqueous layer wasextracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4,filtered, and the solution was concentrated in vacuo to obtain a residue, whichwas purified by silica gel CC using ethyl acetate-petroleum ether gradientelution (1:200-1:4, v/v) to afford the aldehydes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 91% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 4h;Inert atmosphere; Reflux; | Under the strict protection of argon, 0.950 g (0.005 mol) of <strong>[167366-05-4]4-bromo-2-thiazolecarboxaldehyde</strong>, 0.765 g (0.005 mol) of 6-methoxy-2-pyridineboronic acid dissolved in 20 mL of toluene, 20 mL of ethanol, and 5 mL of an aqueous 2 mol / L potassium carbonate solution was heated to reflux for 4h. After completion of the reaction, it was left to stand. The aqueous layer was removed. The aqueous layer was washed three times with ethyl acetate. The washing solution and the reaction solution were combined. The solvent was distilled off under reduced pressure. Column chromatography separation gave pure product 1.006 g, yield of about 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With cesium fluoride; In 1,2-dimethoxyethane; at 20℃;Inert atmosphere; | Stepl :To a stirred solution of commercial <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (1 eq), CF3TMS (1.1 eq) in dimethoxyethane was added CsF (10 mol%) under argon atmosphere. The reaction mixture was allowed to stir for overnight. The solvent was removed under vacuum, water was added, and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, concentrated under vacuum, and purified by flash chromatography using 10-20% of ethyl acetate in hexanes, and isolated in 67% yield. This material was then converted to the boronic ester to be used in the Suzuki reaction, following the procedure of Example 1 ,step 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; for 0.75h;Reflux; | To a stirred solution of the <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> 14 (2 g, 10.4 mmol) in 30mL of EtOH, a solution of NH2OH*HCl (0.73 g, 10.5 mmol) in water (100 mL) and an aqueous solution of 20% NaOH (5 mL) are added and the mixture refluxed for 45 min. After completion, the reaction mixture is cooled down and upon standing a precipitate separates off. Filtration allowed for the isolation of the oxime 15 as a mixture of synand anti stereoisomers in quantitative yield and fully characterized (NMR signals in brackets refer to the second stereoisomer, see below). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | A reaction vial was charged with 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (0.58 g, 2.20 mmol), <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (0.38 g, 2.00 mmol), XPhos Pd G2 (0.047 g, 0.060 mmol). The vial was degassed and refilled with nitrogen. To the vial was added dioxane (6.5 mL) and aq. K3PO4 (6.5 mL, 0.62 M, 4.00 mmol). The reaction vial was re-degassed, refilled with nitrogen, sealed, and then heated to 60 C. for 24 h. The mixture was diluted with water, added 3 mL of 2N NaOH, and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography using gradient elution (EtOAc:Hex 0:100 to 10:90) to afford 0.36 g (72% yield) of 4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl) thiazole-2-carbaldehyde as a colorless solid. | |
59% | A reaction vial was charged with 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (0.33 g, 1.25 mmol), <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (0.19 g, 1.00 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(H) (0.016 g, 0.020 mmol). The vial was degassed and refilled with nitrogen. To the vial was added dioxane (3 mL) and aq. K3PO4 (3 mL, 0.68 M, 2.0 mmol). The reaction vial was re-degassed, refilled with nitrogen, sealed, and then heated to 80 C. overnight. The mixture was diluted with water, and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography using gradient elution (EtOAc:Hex 0:100 to 10:90) to afford 0.15 g (59% yield) of 4-(7-fluorobenzo[c][1,2,5]oxadiazol-5-yl)thiazole-2-carbaldehyde as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In toluene; at 100℃; for 16h;Inert atmosphere; | To a stirred solution of <strong>[167366-05-4]4-bromothiazole-2-carbaldehyde</strong> (2 g, 10.41 mmol) in toluene (30 mL) under nitrogen atmosphere was added (carbethoxymethylene)triphenylphosphorane (4.35 g, 12.5 mmol) and the resulting reaction mixture was stirred at 100 C for 16 h. The reaction mixture was concentrated and the crude product was purified by combiflash chromatography (24 g Redisep S1O2 column, eluting with 23% EtOAc in ra-hexanes) to afford 13 A (2 g, 73%) as a white solid. NMR (400 MHz, CDC13) delta 7.67 (d, J = 16.00 Hz, 1H), 7.29 (s, 1H), 6.75 (d, J = 15.6 Hz, 1H), 4.28 (q, J = 7.20 Hz, 2H), 1.33 (t, J = 7.20 Hz, 3H). LCMS (ES): m/z 264.2 [M+H]+. |
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