Structure of 885069-14-7
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CAS No. : | 885069-14-7 |
Formula : | C15H19BN2O3S |
M.W : | 318.20 |
SMILES Code : | CC(NC1=NC2=CC=C(B3OC(C)(C)C(C)(C)O3)C=C2S1)=O |
MDL No. : | MFCD22571502 |
InChI Key : | CBVRCXVIFJCOJK-UHFFFAOYSA-N |
Pubchem ID : | 51354026 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
56% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Step 3. N-(6-(2-Chloropyrimidin-4-yl)benzo[dlthiazol-2-yl)acetamide; 2,4-Dichloropyrimidine (1.060 g, 7115 mumol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[d]thiazol-2-yl)acetamide (2.86 g, 8988 mumol) were suspended in 1 ,4-dioxane (40 mL) to which palladium tetrakis (triphenylphosphine) (782 mg, 677 mumol) was added, followed by 2 mL of 1 ,4-dioxane and sodium carbonate (7.1 mL, 2.0 M in water, 14200 mumol). Argon was bubbled through the solution for about 1 minute, and the flask was fit with a reflux condensor and placed in a preheated oil bath (95 C) and heated while stirring under argon. When LCMS indicated a complete reaction, the reaction flask was cooled to RT and filtered through Celite (diatomaceous earth). The Celite (diatomaceous earth) pad was washed with 1 ,4-dioxane, and 1 : 1 DCM / MeOH. The filtrate was concentrated, treated with DCM, and filtered. The solid was washed with DCM, collected, and dried under vacuum to afford the desired <n="55"/>product (1.28 g, 4.20 mmol, 95% purity, 56% yield). MS (ESI pos. ion) m/z: 305. Calculated exact mass for C13H9ClN4OS: 304. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; | Example 101; N-(6-(2-Amino-6-methylpyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide; To a suspension of tetrakis(triphenylphosphine)palladium (0) (0.1 15 g, 0.0999 mmol), 4-chloro-6- methylpyrimidin-2-amine (0.142 g, 0.999 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[d]thiazol-2-yl)acetamide (0.318 g, 0.999 mmol) under nitrogen was added sodium carbonate (1 mL, 2M in water, 2 mmol) and then 1 ,4-dioxane (6 mL). The flask was heated in a pre-heated (90 C) bath and stirred under an inert atmosphere overnight. The mixture was allowed to cool to ambient <n="74"/>temperature and concentrated. The crude material was diluted with DCM and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0- 10 % MeOH in DCM) to give N-(6-(Z-amino-6-methylpyrimidin^-yl)benzofdjthiazol^-yl)acetamide (200 mg , 67%) as a brown solid. MS (ESI pos. ion) m/r. 300 (MH+). Calculated exact mass for C14H13N5OS: 299. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃; for 8h;Inert atmosphere; | A mixture of N-(6-bromobenzo[d]thiazol-2-yl)acetamide (2.10 g, 7.75 mmol), bis(pinacolato)diboron (3.00 g, 11.8 mmol), Pd(dppf)Cl2 (560 mg, 0.77 mmol), KOAc (3.00 g, 30.6 mmol) and DMSO (50 mL) was stirred at 90 C under N2 atmosphere for 8 h. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with ethyl acetate (200 mL), washed with brine (20 mL * 3), dried overNa2SO4, and concentrated. The resulting residue was washed with petroleum ether (50 mL) to give a pale brown solid (2.40 g, 97%). |
97% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃; for 8h;Inert atmosphere; | A 100 mL flask was charged with A42-1 (2.10 g, 7.75 mmol), bis(pinacolato)diboron (3.00 g, 11.8 mmol), KOAc (3.00 g, 30.6 mmol) and Pd(dppf)Cl2 (560 mg, 0.765 mmol) followed by addition of 50 mL DMSO. The equipment was evacuated and refilled with N2 three times. The reaction was carried out at 90 C for 8 h. After cooled to r.t., the mixture was filtered. The filtrate was diluted with ethyl acetate. The organic phase was washed with brine. The organic phase was dried with Na2S04 and the solvent was removed by vacuum. The residue was recrystallized in petroleum ether to give A42-2 as a brown solid (2.40 g, 97%). FontWeight="Bold" FontSize="10" H NMR(300 MHz, CDC13) delta 8.30 (s, 1H), 7.87 (d, / = 8.0 Hz, 1H), 7.72 (d, / = 8.0 Hz, 1H), 2.30 (s, 3H), 1.37 (s, 12H). |
97% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃; for 8h;Inert atmosphere; | In a 100 mL round bottom flask,I-1 (2.10 g, 7.75 mmol) was added in sequence.Riboponic boron ester (3.00 g, 11.8 mmol),KOAc (3.00 g, 30.6 mmol)And Pd(dppf)Cl2(560mg, 0.765mmol)Soluble in 50mL DMSO,After reacting at 90C for 8h under nitrogen protection,Filtration, the filtrate was diluted with ethyl acetate, the organic phase was washed with saturated brine, and the organic phase was dried and evaporated. The solvent was derotated and the solute was recrystallized from petroleum ether to give a pale yellow solid (2.40 g, 97%). |
93% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 2h; | To a stirred mixture of N-(6-bromobenzo[d]thiazol-2-yl) acetamide (I-3) (32.5 g, 120 mmol) and 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (I-4) (36.5 g, 144 mmol) in 1,4-dioxane (1000 mL), dppf(PdCl2) (10 g, 12 mmol) and KOAc (70 g, 720 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at 110 C. for 2 h. The mixture was allowed to cool to RT, filtered through silica gel (10 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/petroether) to afford the desired product, N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (I-5) (35 g, 93% yield) as a white solid. ESI-MS (M+H)+ m/z: 317.05. |
75% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 5h; | Intermediate 2: Formation of Lambda/-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,3-benzothiazol-2-yl]acetamide A mixture of Lambda/-(6-bromo-1 ,3-benzothiazol-2-yl)acetamide (2.0 g, 7.38 mmol), bis(pinacolato)diboron (3.75 g, 14.75 mmol), 1 ,1'- bis(diphenylphosphino)ferrocenedichloro palladium(ll) (325 mg, 0.44 mmol) and potassium acetate (3.62 g, 36.88 mmol) in DMSO (24 ml) was prepared and the resulting mixture was heated at 800C for 5 hours. The reaction mixture was cooled at RT and poured into water (80 ml_), then extracted with EtOAc (2x50 ml_). The organic layers were combined, dried (MgSO4) and the solvents were concentrated under reduced pressure to give a brown oil. Purification by precipitation from methanol gave the title compound as an off-white powder (1.75 g, 75%). UPLC/MS, M+(ESI): 319.2,M-(ESI): 317.3. 1 H-NMR (DMSO-d6): delta 12.44 (s, 1 H), 8.26 (brs, 1 H), 7.71 (brs, 2H), 2.21 (s, 3H), 1.31 (s, 12H). |
75% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere; | Step 2: n-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazol-2-yl]-acetamide A mixture of n-(6-bromo-benzothiazol-2-yl)-acetamide (1.35 g, 5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.51 g, 10 mmol), Pd(dppf)Cl2 (0.25 g, 0.3 mmol) and potassium acetate CH3COOK (2.45 g, 25 mmol)in DMSO (20 mL) was stirred at 80 for 2 hrs under N2. Then the mixture was cooled to room temperature, added H2O (100 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EtOAc=3:1) to give n-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazol-2-yl]-acetamide (1.2 g, yield 75%) as a yellow solid. |
75% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 5h; | A mixture of lambda/-(6-bromo-1 ,3-benzothiazol-2-yl)acetamide (2.0 g, 7.38 mmol), bis(pinacolato)diboron (3.75 g, 14.75 mmol), 1 ,1 '- bis(diphenylphosphino)ferrocenedichloro palladium(ll) (325 mg, 0.44 mmol) and potassium acetate (3.62 g, 36.88 mmol) in DMSO (24 ml) was prepared and the resulting mixture was heated at 800C for 5 hours. The reaction mixture was cooled at RT and poured into water (80 ml_), then extracted with EtOAc (2x50 ml_). The organic layers were combined, dried (MgSO4) and the solvents were concentrated under reduced pressure to give a brown oil. Purification by precipitation from methanol gave the title compound as an off- white powder (1.75 g, 75%). UPLC/MS, M+(ESI): 319.2, M-(ESI): 317.3. 1 H- NMR (DMSO-d6): delta 12.44 (s, 1 H), 8.26 (brs, 1 H), 7.71 (brs, 2H), 2.21 (s, 3H), 1.31 (s, 12H). |
72% | With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In dimethyl sulfoxide; at 90℃; for 7h;Inert atmosphere; Sealed vessel; | As shown in step 2-ii of Scheme 2, lambda/-(6-bromobenzo[<i]thiazol-2-yl)acetamide (10.0 g, 36.88 mmol), bis(pinacol)diboron (14.05 g, 55.32 mmol), and KOAc (14.48 g, 147.5 mmol) were dissolved in DMSO (70 mL) and the reaction mixture flushed with nitrogen for 10 minutes. Pd(PPh3)4 (2.557 g, 2.213 mmol) was added, the reaction vessel sealed, and the mixture stirred at 9O0C for 7 hours, giving an orange solution. The reaction mixture was diluted with EtOAc and filtered through a plug of Florisil, which was flushed with additional ethyl acetate. The combined organics were washed with NaCl (3x), dried over Na2SO4, filtered, and evaporated under reduced pressure to give iV-(6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzo[<i]thiazol-2-yl)acetamide (Compound 1002, 8.406 g, 72% yield): ESMS (M+H) 319.44; 1H NMR (300.0 MHz, DMSO-d6) delta 12.44 (s, IH), 8.26 (s, IH), 7.71 (s, 2H), 2.54 (s, H), 2.21 (s, 3H), 1.31 (s, 12H). |
70% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 100℃; | Step 7; To a solution of 50 (5 g, 0.019 mol) in DMSO (100 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.7 g), potassium acetate (7.5 g), and Pd(dppf)Cl2 (1.5 g) were added. The solution was stirred at 100C overnight. The reaction mixture was cooled, and then partitioned between ethyl acetate and water. The organic layer was washed sequentially with water and brine, and then dried over sodium sulfate. The solvent was evaporated off to yield target compound 51 as a white solid (4.2 g, y. 70%). 1H-NMR (DMSO-D6): 8.32 (s, 1H), 7.88 (d, 1H, J = 8.1), 7.76 (d, 1H, J = 8.1), 2.27 (s, 3H), 1.37 (s, 12H). |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 100℃; | Step 2. N-(6-(4,4,5,5-tetramethyl-l .3.2-dioxaborolan-2-yl)benzordlthiazol-2-yl)acetamide; N-(6-Bromobenzo[d]thiazol-2-yl)acetamide (10.29 g, 38.0 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-l ,3,2-dioxaborolane (13.34 g, 52.53 mmol), and potassium acetate (14.9 g, 152 mmol) were suspended in DMSO (140 mL) to which 1,1'- bis(diphenylphosphino)ferrocene]dichloride palladium(ii) (2.81 g, 3.84 mmol) (a 1 : 1 complex with DCM, 3.44 mmol) was added. Argon was bubbled through the suspension for about 1 minute, and the reaction flask was placed in a preheated oil bath (100 C) and heated while stirring under argon overnight. The reaction was then cooled to RT and filtered through Celite (diatomaceous earth), which was washed with MeOH. The filtrate was partially concentrated, and poured into water (500 mL), and extracted repeatedly with DCM. The organic extracts were combined, concentrated, and purified on a silica gel filter (~ 3 inches; DCM to 50: 1 to 30: 1 DCM / MeOH). The fractions containing product were collected, concentrated, and dried under vacuum to afford the desired boronic ester (14.22 g). MS (ESI pos. ion) m/z: 319. Calculated exact mass for C15Hi9BN2O3S: 318. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; | A compound of Formula P-1 is treated with, for example, potassium thiocyanate and bromine in acetic acid to produce a compound of Formula P-2. The compound of Formula P-2 is treated with an acetylating reagent such as acetyl chloride to produce a compound of Formula P-3. The compound of P-3 is reacted with, for example, bis(pinacolato)diboron (compound P-4) in the presence of a catalyst such as palladium chloride to produce a compound of Formula P-5. | |
6 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 100℃; for 5h;Inert atmosphere; | To a solution of compound 14 (20 mg, 0.078 mmol) and bis(pinacolato)diboron (39.8 mg, 0.156 mmol) in DMSO (0.5mL) was added Pd(dppf)C12 (300 mg) and AcOK (38 g, 0.392 mmol) under N2 protection. The resulting mixture was stirred at 100 C for 5 hours. The mixture was dissolved in DCM and filtrated over celite. The orgatmc phase was washed w1th H20 and brine. After dried over Na2SO4, filtered and concentrated, the crude product was purified by Pre-TLC (PE / EA = 1 : 1) to give compound 15 (6 mg, yield: 25.3%) as solid. ?H-NIVIR (CDC13, 400 MHz) oe 7.89 (s, 1H), 7.77 (d, 1H, J 7.6 Hz), 7.57 (d, 1H, J 7.2 Hz), 2.52 (s, 3H), 1.36 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Example 99; <n="73"/>N-(6-(1H-Indazol-4-yl)benzo[d]thiazol-2-yl)acetamide; 4-Bromo-1H-indazole (96.8 mg, 0.491 mmol), N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)benzo[d]thiazol-2-yl)acetamide (193.2 mg, 6.072 mmol), and tetrakis(triphenylphosphine)palladium(0) (51.5 mg, 44.6 mumol) were suspended in 1 ,4-dioxane (2.0 mL) and sodium carbonate (0.50 mL, 2M in water, 1.0 mmol) was added. The flask was fit with a reflux condensor and placed in a preheated oil bath (95 C) and stirred under nitrogen overnight. The mixture was then cooled to RT and filtered through a pad of Celite(diatomaceous earth). The filtrate was concentrated and purified on HPLC ( 10- 95% MeCN / water with 0.1% TFA over 40 minutes) to give N-(6-(1H-indazol-4-yl)benzo[d]thiazol-2- yl)acetamide. MS (ESI pos. ion) m/z: 309 (MH+). Calculated exact mass for C16H12N4OS: 308. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 2h; | Example 268; <n="116"/>N-(6-(5-amino-6-cyanopyridin-3-yl)benzo[d]thiazol-2-yl)acetamide; To a 50 mL round-bottomed flask was added 3-amino-5-bromopicolinonitrile (100mg, 505 mumol) and N- (6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (193 mg, 606 mumol) in 5mL DME, Ar was bubbled in for 2 minutes. Na2CO3 (2M, 3mL) was mixed followed by addition of PdCl2(dppf) (80 mg). The mixture heated at 100 C for 2h and cooled to RT. the mixture was diluted by EtOAc(200mL), washed by water and brine, dried over MgSO4, concentrated in vacuo to provide 100mg brown oil, 10% methanol in DCM was added, solid was formed, after filtration, N-(6-(5-amino-6- cyanopyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (20mg, 13% yield) was obtained as an off-white solid. MS (ESI neg. ion) Found m/z: 308, (M-H)- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Example 73; (Method E) N-(6-(6-(2-Fluorophenylsulfonamido)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide; Step 1. N-(6-(6-aminopyridin-2-yl)benzo[d]thiazol-2-yl)acetamide; 6-Bromopyridin-2-amine (0.5 g, 3 mmol) was dissolved in 1,4-dioxane (6 mL). Then N-(6-(4,4,5,5- tetramethyl-1,3-dioxolan-2-yl)benzo[d]thiazol-2-yl)acetamide (1.0 g, 3.1 mmol), 2M Na2CO3 (3 mL, 6 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.4 g, 0.4 mmol) were added to the mixture. The flask was fitted with a reflux condenser, placed into a pre-heated (95 C) bath, and allowed to stir under an inert atmosphere overnight. The flask was removed from the heat bath and allowed to cool to ambient temperature. The mixture was diluted with 5: 1 DCM / MeOH and saturated NaHCO3. The aqueous layer was extracted with 5:1 DCM/MeOH three times, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (1-5% MeOH/DCM ) to give N-(6-(6-aminopyridin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.23 g, 28% yield) as a light yellow solid. MS (ESI pos. ion) m/z: 285 (MH+). Calculated exact mass for C14Hi2N4OS: 284. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 1.33333h; | Step 4. N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d1thiazol-2-yl)acetamide; 5-bromo-2-methylpyridin-3-amine (224.9 mg, 1.202 mmol), N-(6-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (413.7 mg, 1.300 mmol), potassium carbonate (549.4 mg, 3.975 mmol), and Pd(dppf)Cl2*DCM complex (108.7 mg, 0.133 mmol) were suspended in DME (5.0 ml) and water (1.25 ml), and the flask was fit with a reflux condensor and argon was bubbled through for about 15 seconds. Then, the flask was placed in a preheated oil bath (100 C) and stirred under argon for 80 minutes. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated, treated with MeOH, and filtered. Solid washed with MeOH, water, MeOH, and Et2O. Solid then collected and dried under high vacuum to afford N-(6-(5-amino-6- methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (179.7 mg, 50% yield). MS (ESI pos. ion) m/z: 299. Calculated exact mass for C15Hi4N4OS: 298. |
50% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 8h;Inert atmosphere; | A 25 mL flask was charged with A42-2 (318 mg, 1.00 mmol), 5-bromo-2-methylpyridin- 3-amine A42-3 (187 mg, 1.00 mmol), K2C03(345 mg, 2.50 mmol) and Pd(PPh3)4 (90 mg, 0.078 mmol) followed by addition of dioxane/H20 (10 mL/0.5 mL). The equipment was evacuated and refilled with N2 three times. The reaction was carried out at 80 C for 8 h. After cooled to r.t., the resulting precipitate was filtered. The cake was washed with ethyl acetate to give A42-4 as a white solid (150 mg, 50%).1H NMR (400 MHz, DMSO-d<5) delta 8.13 (s, 1H), 8.00 (s, 1H), 7.73 (d, 7 = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 5.14 (s, 2H), 2.30 (s, 3H), 2.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Step 3. N-(6-(6-(2-fluorophenylsulfonyl)pyridin-2-yl')benzo[d1thiazol-2-yl)acetamide; A RBF was charged with N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2- yl)acetamide (0.6 g, 2 mmol), 2-chloro-6-(2-fluorophenylsulfonyl) pyridine (0.400 g, 1 mmol), 2M sodium carbonate (1 mL, 2 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (8 mL). The flask was heated in a pre-heated (95 C) heat bath while stirring under inert atmosphere overnight. The mixture was cooled, diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to provide N-(6-(6-(2-fluorophenylsulfonyl) pyridin-2-yl)benzo[d]thiazol-2- yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428. Calculated exact mass for C20H14FN3O3S3: 427. 1H NMR (400 MHz, DMSO-d6): 8.49 (s, 1H), 8.20-8.36 (m, 2H), 8.08-8.19 (m, 2H), 7.95 (d, J = 7.5 Hz, 1H), 7.79-7.88 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.56 (m, 1H), 7.44 (m, 1H), 2.21 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80 - 90℃; for 3h; | N-(6-(2-(4-methoxyphenylsulfonyl)thiazol-5-yl)benzo[d]thiazol-2-yl)acetamide; 5-Bromo-2-(4-methoxyphenylsulfonyl)thiazole (134.8 mg, 4.034 mmol), N-(6-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (163.6 mg, 0.5141 mmol), sodium carbonate (0.40 mL, 2.0 M in water, 0.80 mmol), and palladiumtetrakis(triphenyl phosphine) (59.5 mg, 51.5 mumol) were suspended in 1 ,4-dioxane (3.2 mL) and the reaction mixture was stirred and heated at 80 C for 1.5 hours. Additional Pd(PPh3)4 (78 mg) was added to the mixture and stirring and heating were continued at 90 C <n="59"/>for another 90 minutes, at which time the reaction was cooled to RT. The organic phase was decanted, and the residual solid was washed with DCM and MeOH and filtered through a Celite (diatomaceous earth) pad. This pad was washed with DCM and MeOH, and the filtrate was combined with the decanted suspension and concentrated. The solid was treated with Et2O and filtered. Solid washed with Et2O and purified on HPLC ( 10% to 95% MeCN / water with 0.1% TFA over 40 minutes) to afford N-(6-(2-(4- methoxyphenylsulfonyl)thiazol-5-yl) benzo[d] thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 446. Calculated exact mass for C9H15N3O4S3: 445. 1H NMR (400 MHz, DMSO-4): 12.51 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.99 (d, J = 9.0 Hz, 2H), 7.81 (m, 2H), 7.22 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H), 2.22 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 2.5h; | Step 2. N-(6-(6-(4-Fluorophenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide; A RBF was charged with N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2- yl)acetamide (0.3 g, 1 mmol), 2-chloro-6-(4-fluorophenylsulfonyl)pyridine (0.230 g, 0.8 mmol), 2M Na2CO3 (0.8 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.1 mmol), and dioxane (6 mL). The flask was heated in a pre-heated (95 C) bath and allowed to stir under an inert atmosphere for 2.5 hours. The mixture was allowed to cool to ambient temperature and diluted with DMSO and filtered. The crude material was purified by reverse-phase HPLC to give N-(6-(6-(4-fluorophenylsulfonyl) pyridin- 2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428 (MH+). Calculated exact mass for C20H14FN3O3S2: 427. 1H NMR (400 MHz, DMSO-d6): 8.06-8.27 (m, 5H), 7.97-7.99 (m, 1H), 7.82-7.84 (m, 1H), 7.52-7.54 (m, 2H), 7.37-7.40 (m, 1H), 1.96 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Step 3. N-(6-(6-(4-Methoxyphenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide; 2-Chloro-6-(4-methoxyphenylsulfonyl)pyridine (0.300 g, 1.06 mmol) was dissolved in 1 ,4-dioxane (6 mL) and then <strong>[885069-14-7]N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide</strong> (0.4 g, 1 mmol), tetrakis(triphenylphosphine)palladium (0) (0.2 g, 0.1 mmol) and 2M sodium carbonate (1 mL, 2 mmol) were added to it. The flask was fit with a reflux condensor and placed into a pre-heated (95 C) bath. The mixture was allowed to stir under inert atmosphere overnight. The mixture was allowed to cool to ambient temperature and diluted with DMSO. The crude was filtered and purified by reverse-phase HPLC. This gave N-(6-(6-(4-methoxyphenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 440 (MH+). Calculated exact mass for C2IHnN3O4S2: 439. 1H NMR (400 MHz, DMSO-^6): 8.53 (s, 1H), 8.15-8.24 (m, 2H), 8.02 (br s, 4H), 7.70 (d, J= 7.53 Hz, 1H), 7.7.19 (d, J= 7.53 Hz, 2H), 3.83 (s, 3H), 2.15 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Step 2. N-(6-(2-Aminobenzo[d1thiazol-6-yl)pyridin-2-yl)benzenesulfonamide; N-(6-Chloropyridin-2-yl) benzenesulfonamide (0.480 g, 1.90 mmol) was dissolved in 1 ,4-dioxane (6 mL). Then N-(6-(4,4,5,5-tetramethyl-l ,3-dioxolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.7 g, 2 mmol), 2M Na2CO3 (2 mL, 4 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.3 g, 0.2 mmol) was added to the mixture. The flask was fit with a reflux condensor, then placed into a pre-heated (95 C) bath and allowed to stir under inert atmosphere overnight. The flask was removed from the heat bath and allowed <n="63"/>to cool to ambient temperature. The mixture was filtered through a fritted funnel and the crude filtrate was purified by reverse-phase HPLC. This gave N-(6-(2-aminobenzo[d]thiazol-6-yl)pyridin-2- yl)benzenesulfonamide. MS (ESI pos. ion) m/z: 383 (MH+). Calculated exact mass for C18Hi4N4O2S2: 382. 1H NMR (400 MHz, acetone-^): 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.86 (d, J= 8.0 Hz, 1H), 7.74 (t, J= 8.0 Hz, 1H), 7.53-7.64 (m, 4H), 7.44 (d, J= 8.5 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 6.98 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Step 2. N-(6-(6-(N,4-dimethylphenylsulfonamido)pyridin-2-yl)benzo[d1thiazol-2-yl)acetamide; N-(6-Chloropyridin-2-yl)-N,4-dimethylbenzenesulfonamide (0.080 g, 0.27 mmol) was dissolved in 1,4- dioxane (6 mL), and <strong>[885069-14-7]N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide</strong> (0.1 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.04 mmol) and 2M Na2CO3 (0.3 mL, 0.6 mmol) were added to the mixture. The flask was fit with a reflux condensor and placed into a pre-heated (95 C) bath and stirred under an inert atmosphere overnight. The mixture was then allowed to cool to ambient temperature and diluted with DCM and saturated NaHCO3. The organic layers were collected by extracting with DCM three times, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (1-10% IPA/DCM ) to give N-(6-(6-(N,4-dimethylphenylsulfonamido)pyridin-2-yl)benzo[d]thiazol-2- yl)acetamide as a tan solid. MS (ESI pos. ion) m/z: 453 (MH+). Calculated exact mass for C22H20N4O3S2: 452. 1H NMR (400 MHz, DMSO-4): 8.35 (s, 1H), 7.93 (t, J = 8.0 Hz, 2H), 7.83 (d, J = 7.5 Hz, 1H),7.74 (d, J= 8.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.48 (d, J= 8.0 Hz, 1H), 7.37 (d, J = 7.5 Hz, 2H), 3.38 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; | Step 3. N-(6-(2-(4-Fluorophenylsulfonyl')thiazol-4-yl)benzordlthiazol-2-yl)acetamide; A RBF was charged with N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2- yl)acetamide (0.5 g, 1 mmol), 4-bromo-2-(4-fluorophenylsulfonyl)thiazole (0.4 g, 1 mmol), 2 M Na2CO3 (1 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (6 mL). The flask was placed into a pre-heated (95 C) bath and allowed to stir under an inert atmosphere overnight.The mixture was diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to give N-(6-(2-(4-fluorophenylsulfonyl)thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 434 (MH+). Calculated exact mass for C18H12FN3O3S3: 433. 1H NMR (400 MHz, DMSO-^6): 8.53 (s, 1H), 8.30 (s, 1H), 8.21 (s, 2H), 7.81 (s, 1H), 7.56 (s, 3H), 2.07 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 1.66667h; | Step 2. N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d1thiazol-2-yl)acetamide; 5-bromo-2-chloro-N-isopropylpyridin-3-amine (127.6 mg, 0.51 1 mmol), N-(6-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (191.5 mg, 0.602 mmol), potassium carbonate (317.8 mg, 2.299 mmol), and Pd(dppf)Cl2-DCM complex (42.9 mg, 0.0526 mmol) were suspended in 1,2- dimethoxyethane (2.0 ml) and water (0.5 ml). Argon was bubbled through the suspension for about 15 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (100 C) and stirred under argon for 100 minutes. The reaction was cooled to room temperature, concentrated, and treated with DCM and MeOH. These organic washings were decanted, concentrated, treated with water, and filtered. The solid was washed with water and the filtrate was discarded. Solid also washed with <n="79"/>MeOH and Et2O, but the filtrate and solid contain product. The solid and filtrate were combined, concentrated, and purified on a silica gel column (25: 1 to 20: 1 DCM / MeOH to 15: 1 DCM / 2 N ammonia in MeOH) to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2- yl)acetamide (64.5 mg, 35% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C17H17ClN4OS 360. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;Pd FibreCat; In 1,4-dioxane; water; at 20 - 100℃; | Step 2. N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d1thiazol-2-yl)acetamide; To a solution of N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.22 g, 0.71 mmol) and 3-[N,N-bis(4-fluorophenylsulfonyl)amino]-5-bromo-2-chloropyridine (0.37 g, 0.71 mmol) in dioxane (3 mL) was added aqueous Na2CO3 (10%, 1.0 mL) followed by Pd FibreCat(Anchored homogeneous catalyst, Johnson Matthey, West Deptford, NJ)(20 mg) in a microwave vial. <n="85"/>The reaction was heated to 100 C for 12 minutes. The mixture was then filtered. The filtrate was diluted with NaHCO3 (40 mL) and of EtOAc (60 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a prep-HPLC to give the desired product as light yellow solid (0.010 g). The filtered solid, mainly the bis(sulfonamide), was stirred in a mixture of dioxane (20 mL) and aqueous Na2CO3 (10%) at rt. After the completion of the reaction, the solid was collected and recrystallized in MeOH/CHCl3 solution to give additional N-(6-(6-chloro-5-(4-fluorophenylsulfonamido)pyridin-3- yl)benzo[d]thiazol-2-yl)acetamide (0.10 g). MS (ESI pos. ion) m/z: calc'd for C20Hi4ClFN4O3S2 : 476.0; found: 476.9 (MH+). 1H NMR (300 MHz, DMSO-d6) delta ppm 2.23 (s, 3 H) 7.44 (t, J=8.77 Hz, 2 H) 7.67 - 7.77 (m, 1 H) 7.77 - 7.89 (m, 3 H) 8.04 (d, J=2.05 Hz, 1 H) 8.35 (d, J=I .46 Hz, 1 H) 8.64 (d, J=2.19 Hz, 1 H) 10.50 (s, l H) 12.46 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium carbonate;Pd FibreCat; In 1,4-dioxane; water; at 100℃; for 0.2h; | Step 2. N-(6-(6-Chloro-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[dlthiazol-2-yl)acetamide; A mixture of <strong>[885069-14-7]N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide</strong> (0.18 g, 0.6 mmol), N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (0.15 g, 0.4 mmol) and Pd FibreCat in 1 mL of 10% Na2CO3 and 3 mL of dioxane was heated at 100 C for 12 minutes. The mixture was then filtered and the filtrate was concnetrated in vacuo, washed with small amount of EtOAc, and recrystallized in MeOH to give white solid N-(6-(6-chloro-5-(4-methoxyphenylsulfonamido)pyridin- 3-yl)benzo[d]thiazol-2-yl)acetamide (0.08 g, 41% yield). MS (ESI pos. ion) m/z: calc'd for C2IH17ClN4O4S2: 488.0; found: 489.0 (MH+). 1H NMR (300 MHz, MeOH) delta ppm 2.29 (s, 3 H) 3.85 (s, 3 H) 6.97 - 7.07 (m, 2 H) 7.66 (dd, J=8.48, 1.90 Hz, 1 H) 7.70 - 7.78 (m, 2 H) 7.81 - 7.90 (m, 2 H) 8.11 (d, J=1.61 Hz, 1 H) 8.17 (d, J=2.34 Hz, 1 H) 8.44 (d, J=2.34 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Pd FibreCat; In 1,4-dioxane; water; at 100℃; for 0.166667h;Microwave irradiation; | Step 2. N-(6-(5-(4-methylphenylsulfonamido')pyridin-3-yl)benzo[dlthiazol-2-yl)acetamide; To a microwave vial equipped with a stir bar was charged with N-(5-bromopyridin-3-yl)-4- methylbenzenesulfonamide (0.180 g, 0.6 mmol) in 1,4-dioxane (3 ml), was added N-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.223 g, 0.7 mmol), Pd FibreCat (Anchored homogeneous catalyst, Johnson Matthey, West Deptford, NJ) (0.024 g, 20%) and 2M sodium carbonate (0.7 ml, 1 mmol). The vial was capped and then placed into a CEM Microwave for 10 minutes at 100 C, while 100 watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product, N- deacylated material and boronic ester in the mixture. The reaction was stopped at this point, to prevent further de-acylation of product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3 x 20 ml). Combined organic extracts, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by reverse- phase HPLC. This gave N-(6-(5-(4-methylphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2- yl)acetamide (0.016 g, 7% yield) as a white crystalline solid. MS (ESI pos. ion) m/z: 439 (MH+). Calc'd exact mass for C21H18N4O3S2: 438. 1H NMR (400 MHz, DMSO-d6): 2.19 (s, 3H), 2.27 (s, 3H), 7.16 (d, 2H), 7.37 (s, 1H), 7.49 (s, 1H), 7.62 (d, 2H), 7.73 (d, 1H), 7.90 (s, 1H), 7.94 (s, 1H), 8.02 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium carbonate;Pd FibreCat; In 1,4-dioxane; water; at 100℃; for 0.25h;Microwave irradiation; | Step 3. N-(6-(5-(N-methyl-4-(trifluoromethyl)phenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2- yl)acetamide; To a microwave vial equipped with a stir bar was charged with N-(5 -bromopyridin-3 -yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.250 g, 0.6 mmol) in 1 ,4-dioxane (3 ml), was added N-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.300 g, 0.9 mmol), Pd FibreCat (0.024 g, 20%) and 2M sodium carbonate (0.8 ml, 2 mmol). The vial was capped and then placed into a CEM Microwave for 15 minutes at 100 C, while 100 watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product, N-deacylated material and boronic ester in the mixture. The reaction was stopped at this point, to prevent further de-acylation of product. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3 x 20 ml). Combined organic extracts, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was diluted with ethyl acetate and stirred 10 minutes. The precipitate was collected by filtration and washed with 1 : 1 ethyl acetate/hexanes. This gave N-(6-(5-(N-methyl-4- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 3h; | Step 3. N-(6-(6-rN.3-dimethylphenylsulfonamido)pyridin-2-yl)benzo[d1thiazol-2-yl)acetamide; N-(6-chloropyridin-2-yl)-N,3-dimethylbenzenesulfonamide (0.200 g, 0.7 mmol) was dissolved in 1,4- dioxane (6 ml), then <strong>[885069-14-7]N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide</strong> (0.300 g, 1 mmol), tetrakis (triphenylphosphine)palladium(0) (0.100 g, 0.1 mmol) and 2M sodium carbonate (1 ml, 2 mmol) was added to the mixture. The flask was fitted with a reflux condenser and placed into a pre-heated (95 C) bath. The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product. The mixture was allowed to cool to ambient temperature and diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3 x 20 ml). Combined organic extracts, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was filtered and purified by silica-gel chromatography, in a gradient of 1-10% IPA/DCM over 30 minutes. The fractions with desired product were combined and concentrated. The crude was recrystallized from DCM/Hexanes to give N-(6-(6-(N,3- dimethylphenylsulfonamido)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.175 g, 57% yield) as a yellow crystalline solid. MS (ESI pos. ion) m/z: 453 (MH+). Calc'd exact mass for C22H20N4O3S2: 452. 1H NMR (400 MHz, DMSO-d6): 2.22 (s, 3H), 2.31 (s, 3H), 3.40 (s, 3H), 7.34-7.56 (m, 5H), 7.75 (d, J=8.53 Hz, 1H), 7.84 (d, J=7.53 Hz, 1H), 7.93 (t, J=6.53 Hz, 2H), 8.40 (s, 1H), 12.42 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation; | Example 259; N-(6-(5-(4-(1-hydroxyethyl)phenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide; A mixture of N-(5-bromopyridin-3-yl)-4-(1-hydroxyethyl)benzenesulfonamide (0.120 g, 0.34 mmol), N- (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.11 g, 0.34 mmol), tetrkis(triphenylphosphine)palladium (0.019 g, 0.017 mmol) in 1 ml of dioxane and ImI of aq. 2M sodium carbonate was heated under microwave (CEM) at 120 W, 100 C for 20 min. Then, the resultant was diluted with DCM and water. The organic layer was separated, dried and concentrated. The residue was purified by HPLC (5-60 % CH3CN in water gradient) to give a light yellow solid (25 mg, 16 %). MS (ESI pos. ion) Found m/z: 469, (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 2h; | Example 267; N-(6-(6-cyano-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide; To a 100 mL round-bottomed flask was added 3N-(5-bromo-2-cyanopyridin-3-yl)-4- methoxybenzenesulfonamide (100mg, 272 mumol) and N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)benzo[d]thiazol-2-yl)acetamide (108 mg, 339 mumol) in 10 mL DME, Ar was bubbled in for 2 minutes. Na2CO3 (2M, 5 mL) was mixed, followed by addition of PdCl2(dppf)(80 mg). The mixture heated at 100 C for 2h and cooled to RT. The mixture was diluted by EtOAc (200mL), solid was formed. Filtration provided 50 mg N-(6-(6-cyano-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2- yl)acetamide as a brown solid with 92% purity. Prep-HPLC couldn't provide the desire product. The filtrate was concentrate in vacuo, ISCO purification (5-20% methanol in DCM) provided N-(6-(6-cyano- 5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (5mg, 4% yield) as a brown solid. MS (ESI neg. ion) Found m/z: 478, (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; at 40 - 85℃; for 5.5h; | Example 277; Bis(tert-butyl) 5-(2-acetamidobenzo[d]thiazol-6-yl)-2-chloropyridin-3-ylcarbamate; A mixture of bis(tert-butyl) 5-bromo-2-chloropyridin-3-ylcarbamate (1.70 g, 4.2 mmol), Pd2(dba)3 (0.16 g, 0.17 mmol), <strong>[885069-14-7]N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide</strong> (1.3 g, 4.2 mmol), Pd(dppf)Cl2(160 mg) and Na2CO3 (1.10 g, 10 mmol) in DME (25 mL)-H2O (5 mL) was heated under nitrogen at 85 C. After 5 h, the mixture was concentrated to a sludge. H2O (20 mL) was added and the mixture was heated at 40 C for 30 min before it was filtered. The solid was triturated with hot THF-hexane (1 :3) and filtered. The solid was dissolved in hot EtOAc-DCM and filtered. The filtrate was concentrated. This pink solid was triturated with hot hexane (30 mL) and DCM (15 mL) to give the product as a tan solid (1.05 g, 49%). MS (ESI, pos. ion) m/z: calc'd for C24H27ClN4O5S: 518.1; found:519.1 (M+l). 1H NMR (400 MHz, chloroform-d) delta ppm 1.46 (s, 18 H) 2.32 (s, 3 H) 7.55 (dd, J=8.51 , 1.27 Hz, 1 H) 7.78 (d, J=8.41 Hz, 1 H) 7.84 (d, J=2.15 Hz, 1 H) 7.95 (s, 1 H) 8.61 (d, J=I .96 Hz, 1 H) 10.06 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.3% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; | Example 288; N-(6-(5-(Cyanomethoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide; A dry 15 mL, one neck round bottom flask was charged with 2-(5-bromopyridin-3-yloxy)acetonitrile (0.162 g, 0.762 mmol), N-(6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (.2021 g, 0.635 mmol), 5 mL THF and a stirbar. The flask was flushed with Ar for 2 minutes, and fitted with an inert atmosphere inlet. To the stirring solution was added tetrakis(triphenylphosphine)palladium (0.147 g, 0.127 mmol) followed by 2 M sodium carbonate (0.953 ml, 1.91 mmol). The slurry was refluxed overnight, and cooled to room temperature. The mixture was poured onto 15 mL water and extracted with DCM (3 x 20 mL). The DCM extracts were Loaded onto an unbuffered Varian Chem elute CE1010 (100 mL, PN 12198010). The tube was extracted with DCM (4 x 20 mL). The combined <n="126"/>extracts were concentrated in vacuo, and the residue was taken up in 1 mL DCM. A precipitate formed, which was collected using a course glass filter fitted with a 0.22 mum syringe filter. The solid was dried at 60 C at < 1 mmHg for 1 h to afford N-(6-(5-(Cyanomethoxy)pyridin-3-yl)benzo[d]thiazol-2- yl)acetamide (15 mg, 7.3%). 1H NMR (300 MHz, Pyr) delta ppm 2.36 (s, 3 H) 4.98 (br. s., 1 H) 5.56 (s, 2 H) 7.75 (dd, J=8.40, 1.90 Hz, 1 H) 7.93 (dd, 7=2.81 , 1.86 Hz, 1 H) 8.02 (dd, J=8.44, 0.48 Hz, 1 H) 8.27 (dd, J=I .90, 0.44 Hz, 1 H) 8.77 (d, 7=2.85 Hz, 1 H) 8.93 (d, 7=1.83 Hz, 1 H). 13C NMR (75 MHz, Pyr) delta ppm 23.71 (s, 1 C) 55.20 (s, 1 C) 116.92 (s, 1 C) 120.84 (s, 1 C) 121.15 (s, 1 C) 122.27 (s, 1 C) 126.25 (s, 1 C) 133.18 (s, 1 C) 134.41 (s, 1 C) 137.61 (s, 1 C) 138.12 (s, 1 C) 143.50 (s, 1 C) 150.53 (s, 1 C) 154.29 (s, 1 C) 160.70 (s, 1 C) 170.19 (s, 1 C). HPLC-MS: retention time =1.34 min (93.6%(at)215 nm; 96.7% (at)254 nm; m/z = 325.6, calculated for C6H12N2O4S + H+ = 325.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With sodium carbonate;Pd FibreCat; In tetrahydrofuran; water; at 130℃; for 0.416667h; | Example 298; N-(2-(5-(2-(N-actyl)aminobenzo[d]thiazol-6-yl)pyridin-3-yloxy)ethyl)-2-methoxyacetamide; A Biotage high recovery microwave vessel was charged with sodium carbonate hydrate (0.048 g, 0.38 mmol), 0.15 mL water and a stirbar. The slurry was sonicated and stirred for 10 minutes. An inert atmosphere inlet was placed over the vessel and the remaining reagents were added under a flow of nitrogen. To the vessel was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2- yl)acetamide (0.043 g, 0.14 mmol), 100 mg Pd FibreCat palladium catalyst, and N-(2-(5-bromopyridin- 3-yloxy)ethyl)-2-methoxyacetamide (0.0247 g, 0.085 mmol) dissolved in 1 mL THF. The vessel was sealed, and irratiated using a Biotage personal chemistry microwave reactor to 130 C for 25 minutes. The cooled reaction was diluted with 5 mL THF, and filtered through a 0.22 mum PTFE membrane. The catalyst was washed with THF (2 x 5 mL), and the combined filtrates were concentrated in vacuo. The residue was sonicated in 2 mL water, and filtered. The precipitate was then dissolved in 3 mL MeOH, filtered, and concentrated in vacuo. The crude was purified using a 19 x 150 mm Waters Xterra Prep Cl 8 OBD column (100 A pore diameter, 5 mum particle size, spherical shape, PN 186002381 ; Gradient: 0 -? 5 min(at)20 mL/min, 10% B; 5.0 ? 35 min(at)20 mL/min, linear gradient to 40% B; 35 ? 45(at)20 mL/min, isocratic at 40%B, 45 ? 55 min(at)20 mL/min, step to 100%B; 55 ? 60 min(at)20 mL/min, step to 10%B; 60min end; A = 10.7 mM NH4HCO3 in water, pH adjusted to 8.6 with concentrated NH4OH; B acetonitrile). A band that eluted from 24.2 to 26.0 minutes was isolated. The solvent was removed in vacuo to afford N-(2-(5-(2-(N-actyl)aminobenzo[d]thiazol-6-yl)pyridin-3-yloxy)ethyl)-2- methoxyacetamide. (0.0090 g, 26% yield). 1H NMR (400 MHz, DMF) delta ppm 2.34 (s, 3 H) 3.37 (s, 3 H) <n="131"/>3.70 (q, J=5.84 Hz, 2 H) 3.89 (s, 2 H) 4.35 (t, 7=5.97 Hz, 2 H) 7.81 (dd, J=2.54, 1.96 Hz, 1 H) 7.83 (s, 1 H) 7.85 (s, 1 H) 7.86 - 7.90 (m, J=8.41 , 1.86 Hz, 1 H) 8.32 (d, 7=2.25 Hz, 1 H) 8.47 (d, 7=1.47 Hz, 1 H) 8.62 (br. s., 1 H) 12.35 (br. s., 1 H). 13C NMR (101 MHz, DMF) delta ppm 22.46 (s, 1 C) 38.02 (s, 1 C) 58.54 (s, 1 C) 66.92 (s, 1 C) 71.91 (s, 1 C) 1 18.91 (s, 1 C) 120.35 (s, 1 C) 121.07 (s, 1 C) 125.49 (s, 1 C) 132.82 (s, 1 C) 133.22 (s, 1 C) 136.79 (s, 1 C) 137.04 (s, 1 C) 140.37 (s, 1 C) 149.26 (s, 1 C) 155.35 (s, 1 C)159.21 (s, 1 C) 169.69 (s, 1 C) 169.72 (s, 1 C). HPLC-MS: retention time = 1.12 min (99.3%(at)215 nm; 98.1% (at)254 nm; m/z = 401.1, calculated for C19H20N4O4S + H+ = 401.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 100℃; for 0.166667h; | Step 2. N-(6-(6-chloro-5-(piperidine-l -sulfonamido)pyridin-3-yl)benzofd-|thiazol-2-yl)acetarriide; To a microwave vial equipped with a stirbar and charged with N-(6-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.16 g, 0.51 mmol), cesium carbonate (0.41 g, 1.3 mmol), Pd Cl2 (dppf)-DCM (0.062 g, 0.076 mmol), N-(5-bromo-2-chloropyridin-3-yl)piperidine-1- sulfonamide (0.150 g, 0.42 mmol) in THF (3 ml) was added water (0.5 ml). The vial was capped and placed into CEM Microwave for 10 minutes at 100 C, while 100 watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired material in the mixture. The organic layer was extracted from the microwave vial by pipet and then diluted the organic with acetonitrile (15 ml) and TFA (0.1 ml). The crude was purified by reverse-phase HPLC. The fractions with desired product were combined and concentrated. The crude was recrystallized from 5:1 EtOAc/Methanol and Hexanes to give N-(6-(6- chloro-5-(piperidine-1-sulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.025 g, 13% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 466 (MH+). Calc'd exact mass for C19H20ClN5O3S2: 465. 1H NMR (400 MHz, DMSO-d6): 1.39 (s, 2H), 1.47 (s, 3H), 1.65 (s, 4H), 2.14 (s, 3H), 2.93 (s, 3H), 7.51 (s, 1H), 7.69 (s, 1H), 7.74 (s, 1H), 7.90 (s, 1H), 8.02 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 85℃; for 11h; | Example 98 (Method H); N-(6-(2-oxo-2,3-Dihydrobenzo [d] thiazol-4-yl)benzo [d] thiazol-2-yl)acetamide; Step 1 : 4-Bromobenzo[d]thiazol-2(3H)-one (69.9 mg, 0.304 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (124.9 mg, 3.925 mmol), dichlorobis(triphenyl- phosphine)palladium (II) (39.7 mg, 56.6 mumol), and sodium carbonate (0.30 mL, 2.0 M in water, 0.60 mmol) were suspended in 1 ,2-dimethoxyethane (1.4 mL) and ethanol (0.39 mL). The reaction flask was fit with a reflux condensor and the solution was heated in a preheated oil bath (85 C) and stirred under nitrogen for 7 hours, at which time the reaction was slowly allowed to cool to RT. After sitting at RT for 4 days, more PdCl2(PPh3)2 (37.3 mg) was added, and stirring was resumed at 85 C for 4 hours. Then, the reaction was cooled to RT and filtered through a silica gel plug with 10: 1 DCM / MeOH. The filtrate was concentrated and purified on HPLC (10-95% MeCN / water with 0.1% TFA over 40 minutes) to provide N-(6-(2-oxo-2,3-dihydrobenzo[d]thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 342 (MH+). Calculated exact mass for C16HnN3O2S2: 341. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.4% | With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; dimethyl sulfoxide; at 110℃; for 3h;Inert atmosphere; | As shown in step 3-i of Scheme 3, 3-bromo-5-(trifluoromethyl)pyridine (2.0 g, 8.85 mmol) and N-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-benzothiazol-2- yljacetamide (4.23 g, 13.3 mmol) were combined in DMSO (60.0 mL) and stirred. Once the reagents had dissolved, CS2CO3 (8.65 g, 26.55 mmol) was added, followed by addition of water (12.0 mL). The reaction mixture was flushed with nitrogen gas for 30 min. and Pd(dppf)Cl2 (648 g, 0.885 mmol) was added. The reaction was heated at HO0C for 3 hours. After the reaction mixture was cooled to room temperature a precipitate formed, which was filtered off in a Buchner funnel to provide lambda/-(6-(5-(trifluoromethyl)pyridin-3- yl)benzo[<i]thiazol-2-yl)acetamide (Compound 1002a, 1.72 g, 5.0 mmol, 56.4% yield) as a grey solid: ESMS (M+H) 338.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 90℃; | A mixture of lambda/-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3- benzothiazol-2-yl]acetamide (1 eq), the halogenated derivative (1.5 to 2 eq), cesium fluoride (3 to 5 eq) and bis(thphenylphosphine)palladium(ll) chloride(0.05 to 0.15 eq) was prepared in dioxane/water (ratio 2:1 to 3:1 , typical concentration from 0.05 to 0.5M). The resulting mixture was heated at 900C for 30 min to 15 hours typically. Depending of the solubility of the final product, the same work-ups as described in Method A were applied. The title compound was prepared following procedure described in Method B (work-up C) starting from 4-bromo-1 -methyl-2-(methylsulfonyl)benzene. The title compound (14) was obtained as a pale orange powder (13 mg, 23%).HPLC, Rt: 3.7 min (purity: 95.3%). UPLC/MS, M+(ESI): 361.2, M-(ESI): 359.2. 1H-NMR (DMSO-de): delta 12.43 (s, 1 H), 8.36 (d, J=1.7 Hz, 1 H), 8.18 (d, J=1.9 Hz, 1 H), 7.97 (dd, J=1.9, 8.0 Hz, 1 H), 7.84 (d, J=8.5 Hz, 1 H), 7.76 (dd, J=1.7, 8.5 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 3.29 (s, 3H), 2.68 (s, 3H), 2.22 (s, 3H). |
With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 90℃; | Method B: Suzuki cross-coupling reaction (Conditions B) A mixture of Lambda/-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-benzothiazol-2- yl]acetamide (1 eq), the halogenated derivative (1.5 to 2 eq), cesium fluoride (3 to 5 eq) and bis(triphenylphosphine)palladium(ll) chloride (0.05 to 0.15 eq) was prepared in dioxane/water (ratio 2:1 to 3:1 , typical concentration from 0.05 to 0.5M). The resulting mixture was heated at 900C for 30 min to 15 hours typically. Depending of the solubility of the final product, the same work-ups as described in Method A were applied.; Example 14: Formation of Lambda/-{6-[4-methyl-3-(methylsulfonyl)phenyl]-1 ,3- benzothiazol-2-yl}acetamide (14)The title compound was prepared following procedure described in Method B (workup C) starting from 4-bromo-1-methyl-2-(methylsulfonyl)benzene. The title compound (14) was obtained as a pale orange powder. HPLC, Rt: 3.7 min (purity: 95.3%).UPLC/MS, M+(ESI): 361.2, M-(ESI): 359.2. 1H-NMR (DMSOd6): delta 12.43 (s, 1 H), 8.36 (d, J=1.7 Hz, 1 H), 8.18 (d, J=1.9 Hz, 1 H), 7.97 (dd, J=1.9, 8.0 Hz, 1 H), 7.84 (d, J=8.5 Hz, 1 H), 7.76 (dd, J=1.7, 8.5 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 3.29 (s, 3H), 2.68 (s, 3H), 2.22 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere; Microwave irradiation; | Example 104: N-(6-{5-[(3-hydroxypyrrolidin-1 -yl)sulfonyl]pyridin-3-yl}-1 ,3- benzothiazol-2-yl)acetamideA mixture of Lambda/-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-benzothiazol-2- yl]acetamide (39.4 mg, 0.124 mmol), 1-[(5-bromopyridin-3-yl)sulfonyl]pyrrolidin-3-ol (57 mg, 0.186 mmol) and cesium fluoride (75 mg, 0.49mmol) in dioxane/water (ratio 2:1 , 1.5 ml.) was purged with nitrogen in a MW vial. Bis(triphenylphosphine)palladium(ll) chloride (13 mg, 0.019 mmol 0.05 to 0.15 eq) was then added and the reaction mixture was heated at 900C for 1 h under MW irradiations. The solvent was removed under reduced pressure and the residue was slurred in DCM. The solid obtained was filtered, washed with water and dried to give the title compound as a white solid. HPLC (Atlantis-1 ), Rt: 3.08 min (purity 99.9%). LC/MS (Atlantis), M+(ESI): 418.8, 1H-NMR (DMSO-d6) delta 12.45 (brs, 1 H), 9.23 (s, 1 H), 8.91 (s, 1 H), 8.49 (s, 1 H), 8.40 (s, 1 H), 7.86 (m, 2H), 4.89 (s, 1 H), 4.17 (s, 1 H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 8h;Inert atmosphere; | In a 25 mL round bottom flask,I-2 (255 mg, 0.802 mmol) was added sequentially,5-bromo-2-chloro-3-aminopyridine (200 mg, 0.964 mmol),Potassium carbonate (322 mg, 2.41 mmol),Tetratriphenylphosphine palladium (90 mg, 0.078 mmol) and 1,4-dioxane/water (4 mL/0.4 mL)After reacting under a nitrogen atmosphere at 80C for 8 hours, the reaction solution was diluted with ethyl acetate and suction filtered.The solid was rinsed with ethyl acetate and dried to give a white solid (246 mg, 95%). |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 8h;Inert atmosphere; | A solution of 5-bromo-2-chloropyridin-3-amine (200 mg, 0.96 mmol),<strong>[885069-14-7]N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide</strong> (255 mg, 0.80mmol), K2CO3 (332 mg, 2.41 mmol) and Pd(PPh3)4 (90 mg, 0.078 mmol) in 1,4-dioxane/H2O (10 : 1, 4mL) was stirred at 80 C under N2 atmosphere for 8 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was recrystallized in ethyl acetate to give the title compound (246 mg, 96%) as a pale brown solid. |