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CAS No. : | 149104-88-1 | MDL No. : | MFCD01630820 |
Formula : | C7H9BO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VDUKDQTYMWUSAC-UHFFFAOYSA-N |
M.W : | 200.02 | Pubchem ID : | 2734364 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 49.36 |
TPSA : | 82.98 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.48 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.06 |
Log Po/w (WLOGP) : | -0.15 |
Log Po/w (MLOGP) : | -0.22 |
Log Po/w (SILICOS-IT) : | -1.42 |
Consensus Log Po/w : | -0.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.33 |
Solubility : | 9.41 mg/ml ; 0.047 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.36 |
Solubility : | 8.81 mg/ml ; 0.0441 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.61 |
Solubility : | 4.96 mg/ml ; 0.0248 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.14 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
78% | With potassium carbonate In ethanol; toluene for 5h; Heating; | |
73% | Stage #1: 4-Bromothiophen-2-aldehyde; 4-methanesulphonylphenylboronic acid With caesium carbonate In 1,4-dioxane; water at 20℃; for 0.0833333h; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water Inert atmosphere; Reflux; | 1. Suzuki cross-coupling for the preparation of 4a-h, 7a-j and 10a-i 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. |
With sodium carbonate In ethanol; toluene for 5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With palladium diacetate; cesium fluoride; tricyclohexylphosphine In acetonitrile at 90℃; for 0.5h; | |
96% | Stage #1: trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-ylethoxy)phenoxy]naphthalen-2-yl ester; 4-methanesulphonylphenylboronic acid With cesium fluoride In acetonitrile Heating / reflux; Stage #2: In acetonitrile at 90℃; for 0.666667h; | 1 Combine 4- (methanesulfonyl) phenylboronic acid (6.8 g, 34 mmol), the compound of Preparation 1 (6.6 g, 12.6 mmol), cesium fluoride (17.2 g, 113 mmol) and acetonitrile (130 mL) in a 500 mL flame-dried flask fitted with a reflux condenser. In a separate flask combine palladium (II) acetate (283 mg, 1.26 mmol) and tricyclohexylphosphine (530 mg, 1.9 mmol). Add acetonitrile (65 mL) and sonicate for 10 minutes under nitrogen. Add the catalyst slurry to the mixture of substrates and heat in a 90°C oil bath for 30 minutes. Cool the suspension to room temperature and filter through packed celite. Rinse the celite with ethyl acetate and wash the filtrate with a 50: 50 mixture of water and saturated aqueous Na2CO3, saturated aqueous NH4Cl, and brine. Dry the organic layer (Na2S04), filter, and evaporate to obtain 10 grams of crude material. Treat this crude material with a solution of 1% methanol (MeOH) in CH2C12 and remove the resulting white solid impurity (400 mg) by filtration. Concentrate the filtrate and pre-adsorb the crude product on to silica gel. Chromatograph the residue on a Si02 column eluting the material with methanol in dichloromethane (0 to 10%) to give 5.2 grams of the title compound (78%). Concentrate the crude fractions, evaporate, and recrystallize from ethyl acetate to obtain another 1.2 grams of the title compound (18%): mass spectrum (ion spray): m/z = 532.3 (M+H). |
With cesium fluoride; tricyclohexylphosphine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane for 4h; Heating; | |
100% | With sodium carbonate In 1,2-dimethoxyethane; water for 4h; Heating / reflux; | 74 Dissolve trifluoro-methanesulfonic acid 6-methoxy-1-{4-(2-piperidin-1-yl- ethoxy)-benzoyl]-naphthalen-2-yl ester (555 mg, 1.0 mmol), 4- methansulfonylphenylboronic acid (310 mg, 1. 55 mmol), Pd (OAc) 2 (23. 9 mg, 0.11 mmol), Ph3P (54.2 mg, 0.21 mmol) and Na2CO3 (2.5 mL, 2M in water) in ethyleneglycol dimethyl ether (DME, 30 mL). Reflux the mixture for 2 hours and add additional Pd (OAc) 2 (25.2 mg) and Ph3P (58.9 mg). Reflux for 2 hours then dilute the reaction mixture with water and extract with chloroform. Dry the organic phase over Na2SO4, filter and concentrate. Purify the crude material by loading on an SCX column and eluting with 2M NH3/MeOH to afford 569 mg of the title compound (101%). LCMS: m/z = 544 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In 1,4-dioxane; water at 95℃; | A1.1 3-Methyl-6-[4-(methylsulfonyl)phenyl]pyridazine Intermediate A1 3-Methyl-6-[4-(methylsulfonyl)phenyl]pyridazineA suspension of 3-chloro-6-methylpyridazine (1.0 g, 7.78 mmol), (4-methylsulfonyl-phenyl)boronic acid (1.71 g, 8.56 mmol), Pd(PPh3)4 (450 mg, 0.39 mmol), potassium carbonate (2.69 g, 19.45 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was heated at 95 C. overnight. Upon evaporation of the solvents, the residue was partitioned between water (150 mL) and chloroform (150 mL). The layers were separated and the water phase was extracted with chloroform (2 100 mL). The combined organic layers were evaporated and purified by flash chromatography (1:1 DCM/EtOAc, then 100% EtOAc). Yield 1.36 g (70%); Analytical HPLC: purity 99% (System A, RT=1.04 min); LRESIMS for C12H12N2O2S m/z 249 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium phosphate In 1,4-dioxane at 80℃; for 38h; | 17 Example 17: Synthesis [OF 7-CYCLOHEXYL-6- (3'-METHOXY-BIPHENYL-4-YL)-PYRAZOLO [1,] 5- [A] PYRIMIDINE-3-CARBOXYLIC] acid, 7-cyclohexyl-6- (4'-methanesulfonyl-biphenyl-4-yl)-3- (lH- tetrazol-5-yl) -pyrazolo [1, [5-A] PYRIMIDINE, AND 6- (4-BENZYL-PHENYL)-7-CYCLOHEXYL-] pyrazolo [[1,] [5-A] PYRIMIDINE-3-CARBOXYLIC] acid A mixture of 60 mg (0.126 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5- [AJPYRIMIDINE-3-CARBOXYLIC ACID ETHYL ESTER,] 29 mg (0.19 mmol, 1.5 equiv) [OF 3-] [METHOXYPHEFZYLBORONIC ACID,] 5 mg (0.0063 mmol, 5 mol%) of Pd catalyst, and 80 mg (0.378 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at [80 C] under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 29 mg (0.19 mmol, 1.5 equiv) of 3-methoxyphenylboronic acid, 10 mg (0.012 mmol, 10 mol%) [OF PD CATALYST, AND] 80 mg (0. [378] mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 5% ethyl acetate in dichloromethane) to afford 47 mg (82% yield) of desired 7-cyclohexyl-6-(3'-methoxy-biphenyl-4-yl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR; [LC-MS-CALCD] for [C2SH2GN303 [M +H] +] : 456.22, found: 456.2. To a solution of 47 mg (0.103 mmol) of [7-CYCLOHEXYL-6-(3'-METHOXY-BIPHE7LYL-4-YL)-] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester in 3 mL of tetrahydrofuran was added 0.62 mL (0.62 mmol) of 1 M LiOH solution, and the resulting mixture was heated at reflux overnight. The reaction mixture was then acidified with 1 M HC1 solution to pH=2, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated to give a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 15 mg (34% yield) of [7-CYCLOHEXYL-6-(3T-METHOXY-BIPHENYL-4-YL)-] [PYRAZOLO [1, 5-AJPYRIFNIDINE-3-CARBOXYLIC ACID] (446) as a solid (90% purity) as indicated by [IH] NMR; LC-MS-calcd for [C26H25N303] [[M +H] +] : 428. 19, found: 428.2. A mixture of 65 mg (0.15 mmol) of [7-CYCLOHEXYL-6- (4-IODO-PHENYL)-PYRAZOLO [1, 5-] [AJPYRIMIDINE-3-CARBONITRILE,] 45 mg (0.225 mmol, 1.5 equiv) [OF 4-] (methanesulfonyl)phenylboronic acid, 6 mg (0.0075 mmol, 5 mol%) of Pd catalyst, and 95 mg (0.45 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (3 mL) was added, and the resulting mixture was heated at [80 C] under argon for 14 h. Since analysis by LC-MS revealed unreacted starting material still present, 45 mg (0.225 mmol, 1.5 equiv) [OF 4- (METHANESULFONYL) PHENYLBORONIC ACID,] 12 mg (0. [015] mmol, 10 mol%) of Pd catalyst, and 95 mg (0.45 mmol, 3 equiv) of potassium phosphate was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; gradient elution 2% to 10% ethyl acetate in dichloromethane) to afford 42 mg (62% yield) of desired 7-cyclohexyl-6-(4'-methanesulfonyl-biphenyl-4-yl)-pyrazolo[1,5- [AJPYRIMIDINE-3-CARBONITRILE] as indicated [BY LH NMR] ; LC-MS-calcd for [C26H24N402S] [[M +H] +] : 457.16, found: 457.1. To a solution of 42 mg (0.092 mmol) of 7-cyclohexyl-6-(4'-methanesulfonyl-biphenyl- [4-YL)-PYRAZOLO [1, 5-AJPYRIMIDIYAE-3-CARBONITRILE] in 1 mL of toluene and 1.2 mL of dimethylformamide (DMF) was added 76 mg (0.55 [MMOL) OF TFIETHYLAMINE HYDROCHLORIDE] [(ET3N-HCL),] and 36 mg (0.55 mmol) of sodium azide and the resulting heterogeneous mixture was heated at [120 C] for 72 h, during which time 76 mg (0.55 mmol) of triethylamine [HYDROCHLORIDE (ET3N-HCL),] and 36 mg (0.55 mmol) of sodium azide was added to the reaction mixture after every 24 h. The mixture was then cooled to rt, filtered and concentrated to a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 7 mg (15% yield) of 7-cyclohexyl-6-(4'-methanesulfonyl-biphenyl-4-yl)-3-(1H-tetrazol-5-yl)- [PYRAZOLO [1, 5-AGPYRIMIDINE] as a white solid (90% purity, entry 443) as indicated by [1H-NMR] ; LC-MS calcd for [C26H25N702S] [[M++H] + 500. 18] ; found 500.2. According to a modification of a literature procedure (Suzuki, A. et al Tetrahedron Lett. 1986,27, 6369-6372) a mixture of 57 mg (0.12 mmol) of [7-CYCLOHEXYL-6- (4-IODO-PHENYL)-] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester and 5 mg (0.006 mmol, 5 mol%) of Pd catalyst was placed into a carousel tube. After a vacuum and argon cycle, tetrahydrofuran (THF) (2 mL) was added, followed by 0.29 mL (0.144 mmol, 1.2 equiv) of B-Benzyl-9-BBN [0.] [5] Msolution in THF, and 0.12 mL (0.36 mmol, 3 equiv) of 3 [NNAOHSOLUTIOR,] and the resulting mixture was heated reflux under argon overnight. Since analysis by LC-MS revealed unreacted starting material still present, 0.12 mL (0.06 mmol) [OF B-BENZYL-9-BBN,] 5 mg (0.006 mmol, 5 mol%) of Pd catalyst, and 0.12 mL (0.36 mmol) of 3NNaOHsolution was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over sodium sulfate, passed through a small pad of Celite, and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; 2% ethyl acetate in dichloromethane) to afford 36 mg (68% yield) of desired 6-(4-benzyl-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated [BY LH] NMR (containing traces of impurities); LC-MS-calcd for [C28H29N302] [[M++H] +] : 440.23, found : 440.2. To a solution of 36 mg (0.082 mmol) [OF 6-(4-BENZYL-PHENYL)-7-CYCLOHEXYL-] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester in 3 mL of tetrahydrofuran was added 0.5 mL (0.5 mmol) of 1 M LiOH solution, and the resulting mixture was heated at reflux overnight. The reaction mixture was then acidified with 1 M [HC1] solution to pH=2, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated to give a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 7 mg (21% yield) of [6-(4-BENZYL-PHENYL)-7-CYCLOHEXYL-] [PYRAZOLO [1, 5-AJPYRIMIDINE-3-CARBOXYLIC ACID] as a solid (90% purity, entry 444) as indicated by ['H] NMR; LC-MS-calcd for [C26H25N302] [[M++H] +] : 412.19, found: 412.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium phosphate In DMF (N,N-dimethyl-formamide) at 120℃; for 14h; | 4 Intermediate 4 [2-R4- (METHYLSULFONVL) PHENYLL-4-METHYLPYRIDINE] Intermediate 4 [2-R4- (METHYLSULFONVL) PHENYLL-4-METHYLPYRIDINE] To a mixture of [2-CHLORO-4-METHYLPYRIDINE] (3g, 23. [5MMOL),] 4- [(METHYLSULFONYL) PHENYLBORONIC] acid (5.64g, 28. [2MMOL),] potassium phosphate (12. 0g, 56. [4MMOL)] and DMF (50mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (1.36g, 1. [18MMOL).] After heating at [120°C] for 14 hours, the reaction was cooled and the DMF removed in vacuo. The residue was partitioned between ethyl acetate [(100ML)] and water [(100ML),] separated and the organic layer dried over sodium sulfate and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of ethyl acetate in cyclohexane gave the title compound (4.29g, 74%) TLC RF 0.19 (1: 1 ethyl acetate: cyclohexane) LC retention time 2.36mins, MS [M/Z] 248 [(MH+)] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With sodium carbonate In 1,4-dioxane; DMF (N,N-dimethyl-formamide); water at 80℃; for 16h; | General procedure for the synthesis of compounds of formula (IIa). The Suzuki reactions were carried out in stem tubes using a 96 position STEM shaker. To a solution of the required intermediates (D) in DMF (0. 3MMOL, 0. 5ml) was added a solution of boronic acid (Box 4) in DMF (0. 36MMOL, 0. 6ml) and 1.5M NA2CO3 (AQ.) SOLUTION (0. 75MMOL, 0. 5MI). The reaction vessels were then placed in a nitrogen filled glovebox for 30min. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ML) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0. 3MI) was added to each reaction vessel inside the glovebox. The vessels were screw capped and then heated at 80°C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC. Typical example of compound of formula (IIa), as described in the general reaction SCHEME ; [5- (4-METHANESULPHOYLPHENYL) PYRIDIN-3-YL]-PHENYLAMINE (11). YIELD 17MG, 17% ; SH (250MHz, CDC13) 3.86 (3H, s), 6.23-6. 43 (6H, m) 7.63-7. 71 (3H, m), 7.95-7. 96 (2H, m), 8. 33-8.34 (2H, m); HPLC 100%; M/Z (ES) 325 [M+H] +. |
In 1,4-dioxane; DMF (N,N-dimethyl-formamide); water at 80℃; for 16h; | General procedure for the synthesis of compounds OF FORMULA (IIA). To a solution of the required intermediates (D) in DMF (0. 3MMOL, 0. 5ml) was added under nitrogen a solution of boronic acid in DMF (0. 36MMOL, 0. 6MOI) and 1.5M NA2CO3 (AQ.) SOLUTION (0. 75MMOL, 0. 5MOI). Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4- dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0. 3ml) was then added to reaction mixture under nitrogen. The reaction mixture was heated at 80°C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC or purified on silicagel by flash chromatography. | |
With sodium carbonate; triphenylphosphine In 1,4-dioxane; water; N,N-dimethyl-formamide at 80℃; for 16h; | To a solution of the required intermediates (D) in DMF (0.3mmol, 0.5ml) was added under nitrogen a solution of boronic acid in DMF (0.36mmol, 0.6ml) and 1.5M Na2CO3(aq.) solution (0.75mmol, 0.5ml). Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4- dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was then added to reaction mixture under nitrogen. The reaction mixture was heated at 8O0C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC or purified on silicagel by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium phosphate; tris-(o-tolyl)phosphine In ethanol; toluene at 20 - 90℃; for 2.33333h; | 54.d (d) 3- (4-CHLOROBENZOYLAMINO)-L- (3-CHLOROBENZYL)-6-4- (MEMYLSULFONYI)- PHENYL] INDOLE-2-CARBOXYLIC acid ethyl ester A mixture of 6-BROMO-3- (4-CHLOROBENZOYLAMINO)-1- (3-CHLOROBENZYL) indole- 2-carboxylic acid ethyl ester (160 mg, 0.29 mmol), 4- (methanesulfonyl)- phenylboronic acid (87.9 mg, 0.44 mmol), Pd (OAC) 2 (3.4 mg, 0. 015 mmol), tri-o-tolylphosphine (8.8 mg, 0.029 mmol), K3PO4 (215 mg, 1.02 mmol), toluene (3 ML) and ETOH (0.5 mL) was stirred at room temperature for 20 min and heated at 90 °C for 3h. The mixture was allowed to cool, poured into NAHC03 (aq. , sat. ) and extracted with EtOAc. The combined extracts were washed brine and dried over NA2CO;. CONCENTRATION and purification by chromatography gave the title compound (120 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper diacetate; triethylamine In dichloromethane at 18 - 25℃; for 48h; Molecular sieve; | Methyl 3-{(1-methylethyl)oxy}-5-[4-(methylsulfonyl)phenyl]oxy}benzoate; A suspension of methyl 3-hydroxy-5- [ (l-methylethyl) oxy] benzoate (24 mmol), boronic acid (1.1 equivalents), copper (II) acetate (1.1 equivalents), triethylamine (5 equivalents) and freshly activated 4A molecular sieves (31 g) in DCM (250 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, the DCM removed in vacuo and the residual oil partitioned between ethyl acetate and 1-2M hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried (MgS04), and evaporated to a residue which was chromatographed on silica (with 10-40% ethyl acetate in isohexane as eluant) to give the desired ester (64% yield). 'H NMR 8 (d6-DMSO): 1.25 (d, 3H), 3.2 (s, 3H), 4.64 (m, 1H), 6.95 (s, 1H), 7.06 (s, 1H), 7.2 (d, 2H), 7.25 (s, 1H), 7.95 (d, 2H); m/z 365 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With copper diacetate; triethylamine In dichloromethane at 20℃; for 48h; Molecular sieve; | Methyl 3-r (lS)-2-methoxy- (1-methyl) oxy]-5-f 4- (methylsulfon) phenyl] oxy} benzoate; A suspension of methyl 3-hydroxy-5- [ (lS)-2-methoxy- (l-methylethyl) oxy] benzoate (154 mmol), boronic acid (1.1 equivalents), copper (II) acetate (1. 1 equivalents), triethylamine (5 equivalents) and freshly activated 4A molecular sieves (200 g) in DCM (500 ml) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction-mixture was filtered, the DCM removed in vacuo and the residual oil partitioned between ethyl acetate and 1-2M hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried (MgS04), and evaporated to a residue which was chromatographed on silica (with 20-60% ethyl acetate in isohexane as eluant) to give the desired ester (58% yield). 'H NMR 8 (d6-DMSO): 1.2 (d, 3H), 3.2 (s, 3H), 3.26 (s, 3H), 3.44 (m, 2H), 3.8 (s, 3H), 4.65 (m, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.2 (d, 2H), 7.3 (s, 1H), 7.9 (d, 2H) |
58% | With copper diacetate; triethylamine In dichloromethane at 20℃; for 48h; Molecular sieve; | A suspension of methyl 3-hydroxy-5-[(1 S)-2-methoxy-(1-methylethyl)oxy ]benzoate (154 mmol), boronic acid ( 1.1 equivalents), copper (II) acetate (1.1 equivalents), triethylamine (5 equivalents) and freshly activated 4A molecular sieves (200 g) in DCM (500 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, the DCM removed in vacuo and the residual oil partitioned between ethyl acetate and 1-2M hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried (MgS04), and evaporated to a residue which was chromatographed on silica (with 20-60% ethyl acetate in isohexane as eluant) to give the desired ester (58% yield). ¹H NMR 8 (d6-DMSO) : 1.2 (d, 3H), 3.2 (s, 3H), 3.26 (s, 3H), 3.44 (m, 2H), 3.8'(s, 3H), 4.65 (m, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.2 (d, 2H), 7.3 (s, 1 H), 7.9 (d, 2H) |
58% | With copper diacetate; triethylamine In dichloromethane at 20℃; for 48h; Molecular sieve; | 4 A suspension of methyl 3-hydroxy-5-[(15)-2-methoxy-(l-methylethyl)oxy]benzoate (154 mmol), boronic acid ( 1.1 equivalents), copper (II) acetate (1.1 equivalents), triethylamine (5 equivalents) and freshly activated 4A molecular sieves (200 g) in DCM (500 ml) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, the DCM removed in vacuo and the residual oil partitioned between ethyl acetate and 1-2M hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica (with 20-60% ethyl acetate in isohexane as eluant) to give the desired ester (58% yield), 1H NMR δ (d6-DMSO): 1.2 (d, 3H), 3.2 (s, 3H), 3.26 (s, 3H), 3.44 (m, 2H), 3.8 (s, 3H), 4.65 (m, IH), 7.05 (s, IH), 7.11 (s, IH), 7.2 (d, 2H), 7.3 (s, IH), 7.9 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 1h; | 71 Add 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (0.200 g, 0.709 mmol), Pd(Ph3P)4 (0.031 g, 0.036 mmol), 4-methanesulfonyl boronic acid (0.213 g, 1.06 mmol), 2N Na2CC>3 (0.251 mL), and 1,4-dioxane (1 mL) to a microwave vessel. Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and water. Wash the organic layer with saturated sodium chloride solution. Dry the organic layer over Na2SC>4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give 2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethanol (0.167 g, 66%). |
With sodium carbonate In 1,4-dioxane; water for 2h; Heating / reflux; | 2-(4-Bromophenyl)-5-methyl-oxazoleethanol (4.0 g, 14.18 mmol) [which is obtained by the method of D. Brooks, J. Med. Chem., 2001, 44, 2061-2064 or see WO 0116120], 4-methylsulfonylphenylboronic acid (3.97 g, 19.85 mmol), [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2CI2 (1:1) (0.347 g, 0.425 mmol), and aqueous sodium carbonate (2M, 22.15 mL) is placed in a 500 mL flask with 150 mL dioxane and heated to reflux for 2 hours. The reaction is concentrated to about 100 mL and cooled in an ice bath. The solids are filtered and the filtrate is set aside. The solids are then stirred with 200 mL of 15 % methanol / dichloromethane. This slurry is filtered and the filtrate is concentrated to give 4.0 g of pure titled compound. MS (m/e) 358.1 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 0.5 - 0.75h; Microwave; | 92.a Add 3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propan-l-ol (See Intermediate 41) (0.189 g, 0.638 mmol), Pd(Ph3)4 (0.038 g, 0.032 mmol), 4-methylsulfonylphenylboronic acid (0.192 g, 0.957 mmol), 2N Na2C03 (1.6 mL), and 1,4-dioxane (2.0 mL) to a microwave vessel. Subject the reaction mixture to microwave irradiation at 30 W, 90 °C for 30-45 minutes. Concentrate and purify on silica gel eluting with 8% 2N NH3 in methanol/dichloromethane to give 3-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propan-l-ol (0.170 g, 72%): MS (m/e): 372(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 0.5 - 0.75h; Microwave; | 50.b Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (See Example 34) (0.290 g, 0.830 mmol), Pd(Ph3)4 (0.043 g, 0.037 mmol), 4-methanesulfonylphenylboronic acid (0.249 g, 1.25 mmol), 2N Na2CC>3 (2.1 mL), and 1,4-dioxane (1 mL) to a microwave vessel. Microwave at 30 W, 90 °C for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol / dichloromethane to give l-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.323 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 0.5 - 0.75h; Icrowave; | 52.b Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-5'-2-methylpiperidine (0.315 g, 0.867 mmol), Pd(Ph3)4 (0.044 g, 0.038 mmol), 4-methanesulfonylphenylboronic acid (0.260 g, 1.30 mmol), 2N Na2C03 (2.20 mL), and 1,4-dioxane (1.5 mL) to a microwave vessel. Microwave at 30 W, 90 °C for 30-45 minutes. Add dichloromethane (10 mL) and water (5 mL). Extract aqueous with dichloromethane (15 mL). Wash organics with saturated sodium chloride. Dry over Na2SC>4, filter and concentrate. Precipitate from ethyl acetate/hexanes to give l-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-5'-2-methylpiperidine (0.264 g, 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 1h; Microwave; | 67 Add 2-(4-bromo-phenyl)-4- [2-(2JR-ethyl-pyrrolidin-1 -yl)-efhyl] -5-methyl-oxazole (0.249 g, 0.685 mmol), Pd(Ph3P)4 (0.030 g, 0.035 mmol), 4-methanesulfonyl boronic acid (0.206 g, 1.03 mmol), 2N Na2C03 (1.7 mL), and 1,4-dioxane (2 mL) to a microwave vessel. Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and water. Wash the organic layer with saturated sodium chloride solution. Dry the organic layer over Na2S04, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give 4-[2-(2/?-ethyl-pyrrolidin-l-yl)-ethyl]-2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazole (0.170 g, 55%): MS (m/e): 439 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium carbonate In 1,4-dioxane; water at 90℃; for 0.5 - 0.75h; Microwave; | 93.b Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2R-methylpiperidine (0.094 g, 0.26 mmol), Pd(Ph3)4 (0.013 g, 0.011 mmol), 4-methylsulfonylphenylboronic acid (0.072 g, 0.36 mmol), 2N Na2C03 (0.64 mL), and 1,4-dioxane (1 mL) to a microwave vessel. Subject the reaction mixture to microwave irradiation at 30 W, 90 °C for 30-45 minutes. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2SC>4, filter, and concentrate. Purify on silica gel eluting with 8% ammoniated methanol in dichloromethane to give l-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2R-methyl-piperidine (0.094 g, 84%): MS (m/e): 439(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 14h; | 145 Reference Example 145 tert-butyl -[4-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate; A mixture of tert--bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4-(methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to give the title compound as an oil (yield 275 mg, 64%). 1H-NMR (CDCl3) δ: 1.26 (9H, s), 2.79 (3H, s), 3.13 (3H, s), 4.22 (2H, s), 6.26 (1H, s), 7.26-7.37 (2H, m), 7.44-7.71 (3H, m), 7.93 (2H, d, J=8.3 Hz), 8.58 (1H, d, J=2.1 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium fluoride; tris[tert-butyl]phosphonium tetrafluoroborate In tetrahydrofuran at 45℃; for 16h; | 20.D StIp D'; f^--3'-f4"-Fluoro-phenylV3-(4-methanesulfonyl-phenylVacrylonitrileA 100 mL flame dried round bottom flask dried under a nitrogen atmosphere is charged with 4-(methanesulphonyl)benzeneboronic acid (1.81 g; 9.1 mmol), 3-chloro-3-(4- fluororphenyl)acrylonitrile (1.52 g; 8.4 mmol), [(C4Hg)3PH]+BF4' (0.120 g, 0.42 mmol), Pd2(dba)3 (0.191 g, 0.21 mmol). The flask is then placed under vacuum for 5 minutes and backfilled with nitrogen (repeated 3 times). Potassium fluoride (1.490 g, 25.4 mmol) is added to the flask and the flask sealed with a septa, purged with nitrogen and tetrahydrofuran (17.5 mL) is introduced via a syringe. The reaction is placed into an oil bath at 45 0C for 16 hours. The reaction mixture is then filtered though a pad of silica gel, and the silica gel washed with copious amounts of tetrahydrofuran and diethyl ether. The combined organic phase is evaporated in vacuo to give a yellow solid that was recrystallized from hexanes/ethyl acetate to give the desired product (2.08 g, 82% yield). LCMS: 302.06 (IVB-H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 4h;Combinatorial reaction / High throughput screening (HTS);Product distribution / selectivity; | EXAMPLE 36The Preparation of a series of compounds using multiple parallel synthetic techquires from 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in Example 7 Combichem Procedure 1; In a 8 ml screw cap vial was added a solution of 9-Hydroxy-4-iodo-6H-pyrrolo[3,4-c]carbazole-1,3-dione, (0.1 mmol) prepared as in example 7 in dioxane (1 ml), a solution of Reagent 1 (see table) (0.1 mmol) in 1:1 dioxane/2.5 M K2CO3 (1 ml) and [1,1'Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.003 g, 0.0037 mmol). The vial was capped and the reaction mixture was shaken for 4 hours at 90 C. After cooling to room temperature, the solution was was removed under vacuum. Purification was carried out via reverse-phase HPLC (3% n-propanol in acetonitrile and 3% n-propanol in water as the eluent; C-18 column). The products were characterised by mass spectral analysis (See Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate In tetrahydrofuran at 80℃; for 18h; | |
38.9% | With potassium fluoride; tri tert-butylphosphoniumtetrafluoroborate In tetrahydrofuran at 45℃; for 16h; | 51.A 4-methylsulfonylbornic acid (6.Og, 30.0 mmol), 4bromobenzonirtile (4.91g, 27.0 mmol), Pd2(dba)3 (0.180 g, 0.198 mmol) and [(^u)3PH]BF4 (0.120 g,.0.198 mmol) arc weighed into a. flask and the flask is sealed with a. septum and purged with nitrogen for 5 minutes. Potassium flouride (5.22 g, 90.0 mmol) is added forllowed by THF (17 mL) and the reaction sealed, purged with nitrogen, and heated at 45 0C. for 16 hours. The reaciton is poured though a plug of silica gel and the silica gel washed with copius amound of THF. The solvents are evaporated in vacuo and the remaining solid is triturated with ehtyl acetate/ether to provied the desired product. (3.0Og, 38.9 %). LCMS: .258.31 (M+H4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 105℃; for 5.0h; | A mixture of 50 mg (0.203 mmol) of 3-Bromo-6-chloro-2-methyl-imidazo[1 ,2-b]pyridazine (BKS422; preparation see Stage 61.1 ), 92 mg (0.446 mmol) of (4-methylsulfonyl)- EPO <DP n="82"/>phenylboronic acid (Combi-Blocks), 0.51 ml of a aqueous 1 M K2CO3-solution, 8 mg of Pd(PPh3)2CI2 in 1.5 ml of DMF are heated in an oil bath at 1050C for 5 h. The reaction mixture is ppured into CH2CI2, washed with water and dried (Na2SO4). After the solvent is evaporated, the residue is purified by chromatography on silicagel. Solvent system: CH2CI2- EtOAc = 100-0 (start) to 0/100 (end). The title compound is isolated as a yellow solid. MS: 442 (M+1 ); HPLC: tR = 3.71 Omin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In ISOPROPYLAMIDE; water at 110℃; for 2.16667h; | 13 Preparation 13: 3'-(4-Methanesulfonyl-phenyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazine Dissolve 3'-chloro-2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-carboxylic acid t-butyl ester (6.92 g, 30.75 mmol), potassium carbonate (7.34 g, 53.09 mmol) and A- methanesulfonylbenzeneboronic acid (5.31 g, 26.55 mmol) in N,N-dimethylacetamide (90 mL) and purge for 15 min.. Add water (35 mL) and the mixture further purged for 15 min.. Add tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.11 mmol) and heat for 2 hr. 10 min. at 110 0C. Allow to cool to 65 0C, add water (30 mL) and t-butyl methyl ether (70 mL) and stir for 0.5 hr.. Filter off the solid and dry in a vacuum oven to give 3'- (4-methanesulfonylphenyl)-2,3 ,5,6-tetrahydro-[ 1 ,2']bipyrazinyl-4-carboxylic acid t-butyl ester (8.3 g, 86%). MS (ES): m/z = 419 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: C17H16BrF2NO; 4-methanesulphonylphenylboronic acid With caesium carbonate In water; N,N-dimethyl-formamide for 0.166667h; Stage #2: In water; N,N-dimethyl-formamide at 80℃; for 4h; | 47.A A mixture of the bromide (0.2 g, partially pure) from Step A in Example 36, 4-(methylsulfonyl)phenylboronic acid (0.15 g, 0.76 mmol), and cesium carbonate (0.49 g, 1.52 mmol) in a solution of DMF (3 mL) and water (0.75 mL) was purged with argon for about 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium (25 mg, 0.03 mmol) was added to the mixture, which was then heated at 80 0C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by preparative thin layer chromatography (90:10 chloroform/isopropanol) to give the desired aryloxybenzazepine (129 mg, 59%) as an off- white solid, which was resolved by preparative chiral ηPLC (CηIRALCEL OD column, using 80:20:0.1 heptanes/ethanol/diethylamine as the eluent) to give enantiomer A and enantiomer B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diisopropylamine;palladium diacetate; tris(4,6-dimethyl-3-sulfonatophenyl)phosphine trisodium salt hydrate; In water; N,N-dimethyl-formamide; at 50℃; for 2.5h; | Intermediate 2 A.1 -B: 4-fluoro-4'-Cmethylsulfonviy 1.1 '-biphenyl-2-amine <n="32"/>To a solution of <strong>[1003-98-1]2-bromo-4-fluoroaniline</strong> (5.0 g, 26.3 mmol) in DMF/water (80/20 v/v, 65.8 ml) under an atmosphere of nitrogen were added 4-(methanesulfonyl)phenylboronic acid (7.9 g, 39.5 mmol), tris(4,6- dimethyl-3-sulfanatophenyl)phosphine trisodium salt hydrate (2.6 g, 4.0 mmol), palladium(II) acetate (0.3 g, 1.3 mmol), and diisopropyl amine (11.3 ml, 79.0 mmol). The reaction was allowed to stir at 5O0C for 2.5 h. The reaction was diluted with EtOAc and washed with 3M LiCl (3x), water, and brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-fluoro-4'- (methylsulfonyl)-l,l'-biphenyl-2-amine as a yellow solid (95%). LCMS (M+H) 266.1. 1H NMR (400 MHz, CD3OD) delta 8.02 (m, 2H), 7.65 (m, 2H), 7.05 (dd, J = 8.6, 6.2 Hz, IH), 6.57-6.47 (m, 2H), 3.86 (s, 2H), 3.1 1 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); In 1,4-dioxane; water; at 80℃; for 3.0h; | To a mixture of ter/-butyl 3-bromo-l ,2,4-thiadiazol-5-ylcarbamate (1.90 g, 6.78 mmol), 4-(methylsulfonyl)phenylboronic acid (2.07 g, 10.3 mmol), cesium fluoride (2.09 g,13.8 mmol), and the palladium catalyst (0.271 g, 0.383 mmol) was added dioxane (20 mL) and water (2 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for5 min and the reaction mixture was heated to 80C for 3 h. The reaction mixture was diluted with EtOAc, and the organic phase was washed with saturated NH4Cl (1 x), brine (1 x), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in hexanes) gave ter/-butyl 3-(4-(methylsulfonyl)phenyl)-1 ,2,4-thiadiazol-5-ylcarbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.6% | With potassium carbonate In isopropyl alcohol; toluene at 20 - 120℃; Inert atmosphere; | 42 EXAMPLE 42^rt-Butyl 4-[methyl({5-[4-(methylsulfonyl)phenyl]pyrazin-2-yl}methyl)amino]- piperidine-1-carboxylate To a stirred solution of dry toluene (60 mL) and isopropyl alcohol (60 mL) at r t under nitrogen atmosphere were added tert-butyl 4-[[(5-chloropyrazin-2-yl)methyi](methyl)- ammo]pipeϖdine-l-carboxylate (6 g, 0 0176 mol; Intermediate 7) and (4-methylsulfonyl- phenyl)boromc acid (4 5 g, 0 0229 mol) After 2 minutes, a solution of K2CO3 (12 89 g, 0.0932 mol) was added. After additional 5 minutes, Pd(PPh3)4 (1 g, 0.0008 mol) was added and the reaction mixture was allowed to stir at 120 0C for 12 hours The reaction was monitored by TLC using DCM MeOH (9 5 0 5) as mobile phase The reaction mixture was concentrated under reduced pressure and to the residual solid was added water (100 mL) The aqueous mixture was extracted with DCM (3 x 60 mL) The combined organic layers were concentrated under reduced pressure to give 7 g of a semi-solid product The crude product was purified by column chromatography on silica using EtOAc hexane (7 3) as eluent to give the title compound. Yield 4 5 g (55.6%). Analytical HPLC: purity 99% (System B), HRESIMS (ESI+) calcd for C23H32N4O4S 460 2144, found 460 2144 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.91% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 20℃; for 16h;Inert atmosphere; Reflux; | To a solution of 5-bromo-pyrazine-2-amine according to formula (ii) (2.3 g, 13.21 mmol) in 1,4-dioxane (15 ml) was added a boronic acid of formula (vi) such as 4- methylsulfonylphenylboronic acid (CombiBlocks) (2.77 g, 13.87 mmol) at RT and the resulting mixture was purged with N2 gas for 30 minutes. Bis(triphenylphosphine)palladium(II)chloride (463 mg, 0.66 mmol) and 1 M aqueous solution of potassium carbonate (15.84 ml, pre-purged with N2 gas) were added to the reaction mixture. The reaction mixture was heated to reflux for 16 h, cooled to RT and concentrated under vacuum. 10 ml of water was added to the reaction mixture and extracted with ethyl acetate (15 ml X 4). Combined organic layers were washed with brine solution (10 ml), dried over anhydrous Na2S04 and concentrated under vacuum. The crude material was purified by column chromatography over silica gel 230-400 mesh by using 2-3% of MeOH in DCM as an eluent to yield to a 5-substituted pyrazine- 2-amine of formula (vii) (2.5g, 75.91%) as white solid. |
74% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; methanol; at 100℃; for 3h; | A mixture of 2-amino-5-bromopyrazine (0.5 g, 2.79 mmol) and [4-(methylsulfonyl)phenyl]boronic acid (0.57 g, 2.79 mmol) in 1,4-dioxane (10 mL) and MeOH (4 mL) was treated with 2M Na2CO3 (4 mL) and Pd(PPh3)4 (65 mg, 0.06 mmol). The reaction mixture was degassed with N2 and heated at 100 C. for 3 h. Most of 1,4-dioxane and MeOH was removed under reduced pressure. Water was added, and the mixture was extracted with EtOAc (50 mL×4). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid, which was triturated with CH2Cl2 to give 0.465 g (67%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellow solid. The filtrate was washed with 1 N HCl (25 mL), and the aqueous layer was separated and basified with 4N NaOH. The mixture was extracted with EtOAc (50 mL×2) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give additional 0.045 g (7%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 8.63 (s, 1H), 8.15 (d, 2H, J=8.5 Hz), 7.97 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 6.81 (s, 2H), 3.20 (s, 3H); LRMS (ESI), m/z 250 (M+H). |
With potassium phosphate;bis(tri-t-butylphosphine)palladium(0); In water; acetonitrile; at 60℃; for 1h; | 5-Bromopyrazin-2-amine (2.0 g, 11.49 mmol), (4-methylsulfonylphenyl)boronic acid (2.758 g, 13.79 mmol) and K3P04 (4.878 g, 22.98 mmol) were combined in MeCN (40 niL) / Water (10 mL) and Pd[P(tBu)3]2 (216 mg, 0.4227 mmol) was added. The reaction was heated at 60 C for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with water, then Et20 then dried in vacuo to give the sub-title compound as a beige solid which was used without further purification (2.53 g, 88% Yield). 3H NMR (400.0 MHz, DMSO) delta 3.20 (s, 3H), 6.80 (br s, 2H), 7.94 (d, 2H), 8.00 (d, 1H), 8.17 (d, 2H) and 8.64 (d, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium carbonate In 1,2-dimethoxyethane at 80℃; | 172.2 1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}amino)methyl]-1-piperidinecarboxylate trifluoroacetate A mixture of 1,1-dimethylethyl 4-[(6-bromo-3-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate (1.75 g, 4.55 mmol), [4-(methylsulfonyl)phenyl]boronic acid (911 mg, 4.55 mmol), 2M Na2CO3 (5 mL) and Pd(PPh3)2Cl2 (400 mg, 0.57 mmol) in DME (10 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, and the organic phase was separated and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 1.41 g (68%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}amino)carbonyl]-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.74 (bs, 1H), 8.57-8.46 (m, 1H), 8.16 (d, 2H, J=8.5 Hz), 8.03 (d, 2H, J=8.4 Hz), 7.81 (d, 1H, J=8.7 Hz), 4.28-4.11 (m, 2H), 3.07 (s, 3H), 2.85-2.74 (m, 2H), 2.55-2.44 (m, 1H), 2.00-1.80 (m, 2H), 1.82-1.69 (m, 2H), 1.45 (s, 9H); LRMS (ESI), m/z 460 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 59.59a Into a 30 mL vial, Palladium Acetate (0.11 g, 0.00049 mol) and Triphenylphosphine (0.32 g, 0.0012 mol) were added and purged under an atmosphere of Nitrogen for 5 minutes 1,4-Dioxane (10.8 mL, 0.138 mol) was added and stirred for 10 minutes. 7- Bromo-2-methylsulfanyl-pyrrolo[2,l-f][l,2,4]triazine (0.600 g, 0.00246 mol), (4- Methylsulfonylphenyl)boronic acid (0.983 g, 0.00492 mol), N,N-Dimethylformamide(23.7 mL, 0.306 mol) and 1.50 M of Sodium carbonate in Water(4.92 mL, 0.00737 mol) were added, respectively. The reaction mixture was heated at 80 0C overnight. The solvent was removed under vacuum. The solid was washed with DCM. The organic was removed under vacuum. The reaction was purified via ISCO column chromatography with hexane and EtOAc as eluant (0 to 100% EtOAc). The collected fraction afforded 7-(4- Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,l-f][l,2,4]triazine a yellow solid(0.63g, 83%). NMR 1H (DSMO-d6)- 9.09 (s, IH), 8.51 (d, 2H, J= 8.48 Hz), 8.05 (d,2H, J= 8.49 Hz), 7.58 (d, IH, J= 4.84 Hz), 7.15 (d, IH, J= 4.84 Hz), 3.27 (s, 3H), 2.62 (s,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium carbonate In 1,2-dimethoxyethane at 110℃; for 16h; Industry scale; Sealed tube; | 7.I.G.4 A mixture of 5-bromo-3-(5-phenyl-l ,2,4-oxadiazol-3-yl)pyrazin-2-amine (100 mg, 0.3143 mmol), (4-methylsulfonylphenyl)boronic acid (94.29 mg, 0.4714 mmol) andPdCl2(PPh3)2 (1 1.03 mg, 0.01572 mmol) in DMF (2 mL) was treated with Na2CO3 (471.4 μL of 2 M, 0.9429 mmol) and the reaction placed under an atmosphere of nitrogen and heated at1 10 °C in a sealed tube for 16 hours. The resultant precipitate was filtered, washed with water and dried under vacuum (83 mg, 67% Yield).[00332] 1H NMR (400.0 MHz, DMSO) d 3.27 (s, 3H), 7.58 (br s, 2H), 7.69 - 7.73 (m,2H), 7.77 - 7.81 (m, 1H), 8.05 (d, J = 8.5 Hz, 2H), 8.32 (dd, J = 8.5, 18.0 Hz, 4H) and 9.04 (s,1H) ppm; MS (ES+) 394 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With caesium carbonate In 1,2-dimethoxyethane at 20 - 96℃; Inert atmosphere; | 7.1 Step 1: Step 1: 4-{2-(2-Ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4'-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester To a mixture of 4-[3-[6-(3-bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethyoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.0 g, 3.34 mmol), 4-methanesulfonylphenylboronic acid (1.35 g, 6.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (369.8 mg, 0.51 mmol), and cesium carbonate (2.22 g, 6.74 mmol) was added dimethoxyethane (100 mL) at room temperature under nitrogen atmosphere. The resulting brown reaction mixture was heated to 96° C. and stirred for 15 h at which time the TLC analysis of the reaction mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The two layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under vacuum gave the colored residue which was purified by using an ISCO 120 g column to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4'-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (1.23 g, 55%) as a light brown oil: ES(+)-HRMS m/e calcd for C37H48O9S (M+Na)+ 691.2911, found 691.2913. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium carbonate In 1,4-dioxane; water at 115℃; for 3h; Inert atmosphere; | 49 Example 49; 5-[5-{4-Methanesulfonyl-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-3- trifluoromethyl-pyridin-2-ylamine3-(trifluoromethyl)-5-(5-iodoimidazo[2,1-b][1 ,3,4]thiadiazol-2-yl)pyridin-2-amine (0.100 g, 0.243 mmol, 1 eq) was dissolved in dioxane (1.5 mL), then 4- (methylsulfonyl)phenylboronic acid (0.078 g, 0.389 mmol, 1.6 eq) was added followed by 2M aq. Na2CO3 (0.5 mL, 4 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2CI2 (0.043 g, 0.061 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115 ºC). After stirring at reflux temperature for 3h the mixture was cooled to RT and concentrated. The residue was taken up in water, and the solid obtained was filtered off, washed with Et2O and dried. The crude product was suspended in CH3CN at 50 ºC, filtered off and dried in vacuo to afford the desired product (0.061 g, 57 %). HPLC-MS (10-95% B in 4 min at 0.5 mL + 2 min 100% B, flow 0.8 mL/min, 5OºC): tR= 4.04 min, [M+H]+ m/z 440.0; 1H-NMR (DMSO-d6+TFA): δ = 8.88 (1 H, s), 8.36 (2H, d, J= 8.4 Hz), 8.28 (1 H, s), 8.17 (1H, s), 8.06 (2H, d, J= 8.4 Hz), 3.24 (3H, s) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 75℃;Inert atmosphere; | Example 3A - Synthesis of Synthesis of 3-amino-6-[4-(dimethylamino)phenyl]-5-{4- (methylsulfony.)phenyl]pyrazine-2-carboxylic acid; [00171] Step 1 : A mixture of methyl 3-amino-5, 6-dichloro-2-pyrazi?ecarboxylate (1.0 mmol, 222.0 mg), 4-(methyisulfo?yl) phenyl boronic acid (1.2 mmol, 240.0 mg), and tetrakis (triphenylphosphine) Pd (0) (0.12 mmol, 138.7 mg) in 50 ml of anhydrous dimethylformamide was mixed via inert conditions. A solution of potassium carbonate (5 mmoles, 691.1 mg) in deionized water (3 ml) was added to the reaction mixture and heated at 75 0C overnight under an argon atmosphere. The product was purified by reversed phase HPLC (5-75 acetonitrile with 0.1% trifluoroacetic acid at 50 mi/min on XBridge Prep C18 OBD 5um 30 x 150 mm. Retention time 5.9 min) and characterized by 1H and 13C NMR. 1 H NMR (500 MHz, DMSO-d6) delta 8.08 (dt apparent, J = 9.0 Hz1 2.0 Hz, 2H)1 delta 7.99 (dt apparent, J = 8.5 Hz1 1.5 Hz, 2H), delta 7.66 (bs, 2H), delta 3.30 (s, 3H). 13C NMR (125 MHz, DMSO-d6) delta 43.8 (s), delta 122.5 (s), delta 127.2 (s), delta 130.7 (s), delta 130.9 (s), delta 141.1 (s), delta 142.1 (s), delta 153.3 (s), delta 154.9 (S), delta 167.2 (s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.7% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.583333h;microwave irradiation; | Methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 4-(methylsulfonyl)phenylboronic acid (7.58 g, 37.88 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (0.633 g, 0.87 mmol) were dissolved in methanol (30 mL) and divided up in two microwave vials. Each vial was heated to 100° C. in a single node microwave reactor for 35 min. DCM (250 mL) and water (250 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (250 mL). The combined organic phases were washed with brine (500 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on two Biotage.(R). KP-SIL 340 g columns. A gradient of 20-70percent EtOAc in heptane over 10 CV and then 70percent EtOAc in heptane over 5 CV was used as mobile phase. The product was collected using the wavelength 253 nm. The product fractions were collected and evaporated in vacuo yielding methyl 2-(4-(methylsulfonyl)phenyl)-isonicotinate (5.66 g, 66.7percent) as a white solid. 1H NMR (600 MHz, CDCl3) delta 3.09 (s, 3H), 3.98 (s, 3H), 7.85 (dd, 1H), 8.05 (d, 2H), 8.25 (d, 2H), 8.34 (s, 1H), 8.86 (t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere; Sealed tube; | A dry tube was charged with tetrakis(triphenylphopshine)palladium(0) (1.29 g, 1.1 mmol), 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (2.98 g, 14.0 mmol), (4- methylsulfonylphenyl) boronic acid (3.08 g, 15.4 mmol), sodium carbonate (3.26 g, 31.04 mmol), dioxane (30 mL), N,N-dimethylformamide (60 mL) and water (30 mL). The tube was evacuated with a high vacuum and backflushed under a stream of nitrogen three times. The mixture was stirred for 2 minutes at room temperature under nitrogen then the tube was sealed and heated at 800C for 18 hours. The mixture was transferred to a round bottom flask and evaporated under reduced pressure. Water (100 mL) was added and solution extracted with dichloromethane (3 portions of 50 mL). The combined organic was dried over magnesium sulfate, filtered and evaporated. The solid was triturated with ether/dichloromethane (4:1; 10 mL), filtered and rinsed with ether. The recovered material was consistent for 5-(4-methanesulfonyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1.3 g, 33%). 1H NMR (400 MHz, CDCl3, delta, ppm): 8.21 (d, J = 8.0 Hz, 2H) 8.08 (d, J = 8.0 Hz, 2H), 7.55 (m, IH), 7.44 (d, J = 9.1 Hz, IH), 7.13 (d, J = 7.5 Hz, IH), 6.10 (br s, 2H) 3.31 (s, 3H). MS = 289 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h; Microwave irradiation; | 12 To a mixture of toluene-4-sulfonic acid-1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (1.1 g, 2 mmol), 4-(methanesulfonyl)phenylboronic acid (800 mg, 4.0 mmol), and dichlorobis(triphenylphosphine)palladium (II) (141 mg, 0.2 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL, 5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (860 mg, 86%) as a light yellow solid: LC/MS m/e calcd for C28H28N2O5S2 [M+H]+ 537.67, observed 537.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h; Microwave irradiation; | 67 To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (0.45 g, 0.84 mmol), 4-(methanesulfonyl)phenylboronic acid (0.50 g, 2.5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (59 mg, 0.08 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 57%) as a white solid: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h; Microwave irradiation; | 1 To a mixture of 1-benzenesulfonyl-2-[3-methyl-1-(toluene-4-sulfonyloxy)-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.2 g, 2.1 mmol), 4-(methanesulfonyl)phenylboronic acid (1.0 g, 5.2 mmol), dichlorobis(triphenylphosphine)palladium (II) (150 mg, 0.21 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 5.2 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (820 mg, 73%) as a light yellow solid: LC/MS m/e calcd for C27H26N2O6S2 [M+H]+ 539.65, observed 539.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.6 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 2.68 (m, 1H), 3.08 (s, 3H), 3.99 (s, 3H), 6.27 (d, J=10.2 Hz, 1H), 6.67 (s, 1H), 7.28 (m, 2H), 7.36 (m, 2H), 7.49 (m, 1H), 7.67 (m, 2H), 7.78 (m, 2H), 8.55 (d, J=2.0 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h; Microwave irradiation; | 3 To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(toluene-4-sulfonyloxy)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (0.9 g, 1.55 mmol), 4-(methanesulfonyl)phenylboronic acid (930 mg, 4.6 mmol) and dichlorobis(triphenylphosphine)palladium (II) (110 mg, 0.15 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.3 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (815 mg, 73%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 4h; Microwave irradiation; | 78 To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-vinyl ester (1 g, 1.72 mmol), 4-(methanesulfonyl)phenylboronic acid (862 mg, 4.31 mmol) and dichlorobis(triphenylphosphine)palladium (II) (121 mg, 0.17 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 2.15 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded (Z)-1-benzenesulfonyl-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (800 mg, 82%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h; Microwave irradiation; | 99 To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (1 g, 2 mmol), 4-(methanesulfonyl)phenylboronic acid (1 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (140 mg, 0.2 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridine (0.9 g, 92%) as a white solid: LC/MS m/e calcd for C25H23FN2O4S2 [M+H]+ 499.60, observed 498.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h; Microwave irradiation; | 41 To a mixture of toluene-4-sulfonic acid 1-benzenesulfonyl-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (1.03 g, 1.82 mmol), 4-(methanesulfonyl)phenylboronic acid (910 mg, 4.55 mmol), dichlorobis(triphenylphosphine)palladium (II) (130 mg, 0.18 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.3 mL, 4.6 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 60%) as a light yellow solid: LC/MS m/e calcd for C29H30N2O5S2 [M+H]+ 551.70, observed 551.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium carbonate In 1,4-dioxane; water at 100℃; for 4h; Microwave irradiation; | 60 To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-yl)-vinyl ester (0.52 g, 0.97 mmol), 4-(methanesulfonyl)phenylboronic acid (0.48 g, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (68 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.2 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.36 g, 57%) as a white solid: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.9% | With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 16h;Inert atmosphere; Reflux; | Compound 28 was synthesized as described under Scheme 2 following the protocol below: 3-Bromo-5- [4-(methylsulfonyl)phenyl] pyridin-2-amine4-Methylsulphonyphenylboronic acid (34.82 g, 0.17 mol) was added to a stirred solution of <strong>[697300-73-5]5-iodo-3-bromo-2-aminopyridine</strong> (47.31 g, 0.16 mol) (commercially available or could be synthesized as described in Zhang et ah, 2004, J. Med. Chem., 47(10), 2453-2465) in 1 ,4- dioxane (470 ml) at RT and purged with N2 gas for 1 h. Pd[(PPh)3]2Cl2 (7.77 g, 0.01 mol) and an aqueous solution of potassium carbonate (1 M , 160.9 ml, pre-purged with N2 gas) were added to the reaction mixture, and subsequently heated under reflux for 16 h. The reaction mixture was then cooled to RT, followed by the addition of H20 (600 ml). The precipitate was filtered, washed with DCM/MeOH (1 : 1, 300 ml) and dried in vacuo to afford the final compound (30 g, 57.9 %) as a white solid. 1H NMR (400 MHz, DMSO-dg): delta 8.43 (s, 1H), 8.20 (s, 1H), 7.93 (s, 4H), 6.59 (bs, 2H) and 3.24 (s, 3H). LC-MS APCI: Calculated for Ci2HiiBrN202S 327; Observed m/z [M+H]+ 328. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate In 1,4-dioxane; water at 120℃; for 14h; Inert atmosphere; | 1 Ex am pl e 1 : Synth e si s o f 3-f6-Methoxypyridin-3-yl)-5-f4-methylsulfonylphenyl) Pyridin-2-amine (1)(1)K2CO3 aqueous solution (1 M, 5.4 mL) was added to a suspension of 5-bromo-3-(6- methoxypyridin-3-yl)pyridin-2-amine ( 1 .44 g, 5 . 14 mmol), 4-(methylsulfonyl)phenyl boronic acid (1.08 g, 5.40 mmol, 1.05 equiv.), and Pd(PPh)3 (300 mg, 5 mol %) in dioxane (15 mL) under N2. The reaction mixture was stirred at 120°C for 14h, poured onto H20 (50 mL) and extracted with EtOAc (3 X 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 2/8) providing 3-(6- methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine (1) (1.92 g, 65 %) as a pale yellow solid. IR (thin film cm"1): vmax 3378, 1594, 1301, 1148. H1 NMR (400MHz, CDCI3): δ 8.34 (d, 1H, J = 2.0Hz), 8.26 (d, 1H, J = 2.0Hz), 7.97 (d, 2H, J = 8.4Hz), 7.70 (d, 2H, J = 8.4Hz), 7.69 (d, 1H, J = 8.4Hz), 7.58 (d, 1H, J = 2.0), 6.86 (d, 1H, J = 8.4Hz), 4.80 (bs, 2H), 3.98 (s, 3H) and 3.06 (s, 3H). C13 NMR (100MHz, CDC13): δ 164.16, 156.30, 146.94, 146.82, 145.57, 143.34, 139.02, 138.86, 136.92, 128.17, 126.84, 125.84, 118.88, 111.49, 53.67 and 44.62. |
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In 1,4-dioxane at 110℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In 1,4-dioxane; water at 100℃; for 2.5h; | 51 To a degassed mixture of tert-butyl 4-(6-bromobenzo[d]thiazol-2- yloxy)piperidine-l-carboxylate (3 g, 7.26 mmol), 4-(methylsulfonyl)phenylboronic acid (2.9 g, 14.52 mmol) and K2C03 (4.01 g, 29.0 mmol) in dioxane (90 mL) and water (30 mL) was added Pd(PPh3)4 (0.839 g, 0.726 mmol) and the resulting mixture was heated at 100 °C for 2.5 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc (3 x 25 mL). The combined extracts were washed with brine, dried (Na2S04), and concentrated. The residue was purified by columnchromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 40% EtOAc) to afford a yellow solid, which was further triturated with Et20 to yield tert-butyl 4-(6-(4- (methylsulfonyl)phenyl)benzo[d]thiazol-2-yloxy)piperidine-l-carboxylate (2.62 g, 5.36 mmol, 74% yield) as a light yellow solid. ¾ NMR (500 MHz, CDC13) δ 8.02 (d, J=8.5 Hz, 2H), 7.89 (d, J=1.7 Hz, IH), 7.82 - 7.77 (m, 2H), 7.75 (d, J=8.3 Hz, IH), 7.61 (dd, J=8.5, 1.9 Hz, IH), 5.40 (tt, J=7.7, 3.7 Hz, IH), 3.82 - 3.71 (m, 2H), 3.43 - 3.33 (m, 2H), 3.10 (s, 3H), 2.16 - 2.05 (m, 2H), 1.91 (ddd, J=12.4, 8.3, 4.1 Hz, 2H), 1.48 (s, 9H). LCMS (m/z) =489 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.3% | With caesium carbonate In 1,2-dimethoxyethane; ethanol; water at 150℃; for 0.166667h; Microwave irradiation; | 18 Preparation of 4-(4-(benzyloxy)cyclohexyloxy)-3,5-difluoro-4'-(methylsulfonyl)biphenyl Example 18 Preparation of 4-(4-(benzyloxy)cyclohexyloxy)-3,5-difluoro-4'-(methylsulfonyl)biphenyl A mixture of 2-(4-(benzyloxy)cyclohexyloxy)-5-bromo-1,3-difluorobenzene (80 mg, 0.201 mmol), 4-(methylsulfonyl)phenylboronic acid (48.3 mg, 0.242 mmol), Cs2CO3 (197 mg, 0.604 mmol) and Pd(Ph3P)4 (6.98 mg, 6.04 μmol in H2O (0.24 ml), EtOH (0.36 ml) and DME (0.72 ml) was heated via microwave irradiation (150° C., 10 min). After being cooled to room temperature, the reaction mixture was extracted with EtOAc and water. The organic phase was separated, dried (MgSO4), filtered, concentrated in vacuo and purified by flash chromatography to afford the desired product (61.2 mg, 0.130 mmol, 64.3% yield). 1H-NMR (400 MHz, CDCl3) δ 1.63 (4H, m), 2.01 (4H, m), 3.09 (3H, s), 3.51 (1H, m), 4.35 (1H, m), 4.52 (2H, d, J=20.0 Hz), 7.15 (2H, m), 7.34 (5H, m), 7.95 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 180℃; for 0.166667h; Microwave irradiation; | 40 Preparation of 2-(4-(3,5-difluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)cyclo hexyloxy)-5-ethylpyrimidine Example 40 Preparation of 2-(4-(3,5-difluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)cyclo hexyloxy)-5-ethylpyrimidine A mixture of 2-(4-(4-bromo-2,6-difluorophenoxy)cyclohexyloxy)-5-ethylpyrimidine (58.9 mg, 0.143 mmol), 4-(methylsulfonyl)phenylboronic acid (34.2 mg, 0.171 mmol), Na2CO3 (45.3 mg, 0.428 mmol) and Pd(Ph3P)4 (16.5 mg, 0.014 mmol) in H2O (0.24 mL), EtOH (0.36 mL) and DME (0.72 mL) was subjected to microwave irradiation (180° C., 10 min). After being cooled to room temperature, the reaction mixture was extracted with EtOAc and Water. The organic layer was separated, dried (MgSO4), and purified by flash chromatography to give the desired product (41.2 mg, 59%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 1.24 (3H, t, J=8.8 Hz), 1.84 (4H, m), 2.16 (4H, m), 2.57 (2H, q), 3.09 (3H, s), 4.21 (1H, m), 5.07-5.17 (1H, m), 7.16 (2H, m), 7.70 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=6.8 Hz), 8.34 (2H, m). LC-MS Calcd. 488.16, Found 489.02 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; oxygen; copper(II) acetate monohydrate; In N,N-dimethyl-formamide; at 95℃; for 7h; | A mixture of 3-methyl-4-nitro-lH-pyrazole (2.1 g, 17 mmol) and 4- methylsulfonylphenylboronic acid (5.0 g, 25 mmol), copper (II) acetate monohydrate (0.91 g, 5.0 mmol) and pyridine (0.5 g, 6.6 mmol) in DMF was stirred at 95 C under an oxygen atmosphere for 7 hours. The reaction was diluted with water, extracted with EtOAc (3x). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give a mixture of 3 -methyl- 1 -(4- (methylsulfonyl)phenyl)-4-nitro-lH-pyrazole compound and 5 -methyl- 1 -(4-(methylsulfonyl)phenyl)-4-nitro-lH-pyrazole (1.3 g, 28%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of 3-methyl-l-(4-(methylsulfonyl)phenyl)-4-nitro-lH-pyrazole compound and 5-methyl-l-(4-(methylsulfonyl)phenyl)-4-nitro-lH-pyrazole (0.57 g, 2.0 mmol) and palladium on carbon (10 wt%, 0.2 g) in ethanol was stirred under a hydrogen atmosphere at 55 C for 18 hours. The reaction mixture was filtered through celite and concentrated to give the title compounds as a mixture of regioisomers (446 mg, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: N-[1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine; 4-methanesulphonylphenylboronic acid With potassium carbonate In 1,4-dioxane; water at 80℃; Microwave; Inert atmosphere; Stage #2: With hydrogenchloride; water In 1,4-dioxane for 0.5h; | 118.7 Step 7. N-{1-[5-Fluoro-2-methoxy-6-methyl-4'-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine N-[1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (21 mg, 0.044 mmol), [4-(methylsulfonyl)phenyl]boronic acid (13 mg, 0.066 mmol), potassium carbonate (15 mg, 0.11 mmol), water (0.2 mL), and 1,4-dioxane (0.40 mL) were added to a microwave vial. The mixture was degassed under nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 4.4 μmol) was added to the mixture and the vial was then sealed and bubbled under nitrogen for 5 minutes. The mixture was heated at 80° C. overnight. The cooled reaction mixture was then treated with 4.0 M hydrogen chloride in water (0.5 mL, 2 mmol) and was stirred at room temperature for 30 minutes. Purification by preparative LCMS (pH 10) RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) afforded N-{1-[5-Fluoro-2-methoxy-6-methyl-4'-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine (13 mg, 66%). LCMS calculated for C22H23FN5O3S (M+H)+: m/z=456.1. Found: 456.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium carbonate In N,N-dimethyl-formamide at 100℃; for 1.5h; Inert atmosphere; | Intermediate 7 4-[2-(4-Methanesulfonyl-phenyl)-furo[2,3-blpyrazin-6-yl1-piperidine-1 -carboxylic acid tert-butyl esterA mixture of 4-(2-chloro-furo[2,3-b]pyrazin-6-yl)-piperidine-1 -carboxylic acid tert-butyl ester (200 mg), 4-(methanesulfonyl)phenyl boronic acid (140 mg), Na2C03 (126 mg), water (2.5 ml_), and N,N-dimethylformamide (2.5 mL) is sparged with argon for 10 min and Pd(PPh3)4 (15 mg) is added. The resulting mixture is stirred at 100 °C for 1 .5 h. After cooling to room temperature, water and ethyl acetate are added. The organic phase is washed with brine, dried (MgS04), and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 60:40) to give an oily residue that is triturated with diehtyl ether and dried to afford the title compound as a colorless solid. Yield: 175 mg (65% of theory); LC (method 2): tR = 1 .35 min; Mass spectrum (EST): m/z = 458 [M+H]+. |
With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1.5h; Inert atmosphere; | A mixture of 4-(2-chloro-furo[2,3-b]pyrazin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg), 4-(methanesulfonyl)phenyl boronic acid (140 mg), Na2CO3 (126 mg), water (2.5 mL), and N,N-dimethylformamide (2.5 mL) is sparged with argon for 10 min and Pd(PPh3)4 (15 mg) is added. The resulting mixture is stirred at 100° C. for 1.5 h. After cooling to room temperature, water and ethyl acetate are added. The organic phase is washed with brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 60:40) to give an oily residue that is triturated with diethyl ether and dried to afford the title compound as a colorless solid. Yield: 175 mg (65% of theory); LC (method 2): tR=1.35 min; Mass spectrum (ESI+): m/z=458 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With sodium carbonate In water; N,N-dimethyl-formamide at 90℃; Inert atmosphere; | Intermediate 114-[5-(4-Methanesulfonyl-phenyl)-2,3-dihvdro-benzofuran-2-yl1-piperidineTo a mixture of 1 -[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1 -yl]-2,2,2- trifluoro-ethanone (2.50 g) and 4-(methanesulfonyl)phenyl boronic acid (1 .45 g), in N,N-dimethylformamide (25 mL) a 2 M aqueous Na2C03 solution (8.26 mL) is added. The mixture is sparged with argon for 10 min and PdCyi , 1 '-bis(diphenylphosphino)- ferrocene]*CH2Cl2 complex (540 mg) is added. The resulting mixture is stirred over night at 90°C. After cooling to room temperature, water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (MgS04), and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(methanol/NH4OH 9: 1 ) 90: 10→ 80:20] to give the title compound (the trifluoroacetate protecting group is already removed under the reaction condidtions). Yield: 930 mg (39% of theory); LC (method 1 ): tR = 0.88 min; Mass spectrum (EST): m/z = 358[M+H]+. |
With sodium carbonate In water; N,N-dimethyl-formamide at 90℃; Inert atmosphere; | 4 Intermediate 44-[5-(4-Methanesulfonyl-phenyl)-2,3-dihvdro-benzofuran-2-yl1-piperidineTo a mixture of 1 -[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1 -yl]-2,2,2- trifluoro-ethanone (2.50 g) and 4-(methanesulfonyl)phenyl boronic acid (1 .45 g) in N,N-dimethylformamide (25 mL) a 2 M aqueous Na2C03 solution (8.26 mL) is added. The mixture is sparged with argon for 10 min and PdCyi , 1 '-bis(diphenylphosphino)- ferrocene]*CH2Cl2 complex (540 mg) is added. The resulting mixture is stirred over night at 90 °C. After cooling to room temperature, water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (MgS04), and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(methanol/NH OH 9: 1 ) 90: 10 - 80:20] to give the title compound, since thetrifluoroacetyl group is removed under the reaction conditions. LC (method 1 ): tR = 0.88 min; Mass spectrum (EST): m/z = 358 [M+H]+. | |
With sodium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; | To a mixture of 1-[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone (2.50 g) and 4-(methanesulfonyl)phenyl boronic acid (1.45 g), in N,N-dimethylformamide (25 mL) a 2 M aqueous Na2CO3 solution (8.26 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1'-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (540 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(methanol/NH4OH 9:1) 90:10→80:20] to give the title compound (the trifluoroacetate protecting group is already removed under the reaction conditions). Yield: 930 mg (39% of theory); LC (method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=358 [M+H]+. |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In water; N,N-dimethyl-formamide at 90℃; Inert atmosphere; | 4-[5-(4-Methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine To a mixture of 1-[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone (2.50 g) and 4-(methanesulfonyl)phenyl boronic acid (1.45 g) in N,N-dimethylformamide (25 mL) a 2 M aqueous Na2CO3 solution (8.26 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1'-bis(diphenylphosphino)-ferrocene].CH2Cl2 complex (540 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(methanol/NH4OH 9:1) 90:10-80:20] to give the title compound, since the trifluoroacetyl group is removed under the reaction conditions. LC (method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=358 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium carbonate In 1,4-dioxane; water at 140℃; for 0.583333h; Inert atmosphere; Microwave irradiation; | Intermediate 144-[5-(4-Methanesulfonyl-phenyl)-furo[3,2-blpyridin-2-yl1-piperidine-1 -carboxylic acid tert-butyl esterTo a mixture of 4-(5-chloro-furo[3,2-b]pyridin-2-yl)-piperidine-1 -carboxylic acid tert- butyl ester (50 mg) and 4-(methanesulfonyl)phenyl boronic acid (45 mg) in[1 ,4]dioxane (1 .5 mL) in a microwave oven suited vessel charged with a stir bar a 2 M aqueous Na2C03 solution (190 μΙ_) is added. The mixture is sparged with argon for 10 min and Pd(PPh3)4 (21 mg) is added. The vessel is capped and the mixture is stirred under microwave irradiation at 140 °C for 35 min. After cooling the mixture to room temperature, dichloromethane and water are added. The organic phase is washed with brine, dried (MgS04) and the solvent is evaporated. The crude product is purified by HPLC on reversed phase (MeOH/H20/TFA). Yield: 25 mg (37% of theory); LC (method 2): tR = 1 .36 min; Mass spectrum (EST): m/z = 457 [M+H]+. |
With sodium carbonate In 1,4-dioxane at 140℃; for 0.583333h; Microwave irradiation; Inert atmosphere; | To a mixture of 4-(5-chloro-furo[3,2-b]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 4-(methanesulfonyl)phenyl boronic acid (45 mg) in [1,4]dioxane (1.5 mL) in a microwave oven suited vessel charged with a stir bar a 2 M aqueous Na2CO3 solution (1904) is added. The mixture is sparged with argon for 10 min and Pd(PPh3)4 (21 mg) is added. The vessel is capped and the mixture is stirred under microwave irradiation at 140° C. for 35 min. After cooling the mixture to room temperature, dichloromethane and water are added. The organic phase is washed with brine, dried (MgSO4) and the solvent is evaporated. The crude product is purified by HPLC on reversed phase (MeOH/H2O/TFA). Yield: 25 mg (37% of theory); LC (method 2): tR=1.36 min; Mass spectrum (ESI+): m/z=457 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium carbonate In water; N,N-dimethyl-formamide at 90℃; Inert atmosphere; | 4-[5-(4-Methanesulfonyl-phenyl)-2,3-dihvdro-benzofuran-2-yl1-piperidine-1 -carboxylic acid isopropyl esterTo a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1 -carboxylic acid isopropyl ester (200 mg) and 4-(methanesulfonyl)phenylboronic acid (1 19 mg) in N,N-dimethylformamide (2 ml_) a 2 M aqueous Na2C03 solution (0.68 ml_) is added. The mixture is sparged with argon for 10 min and PdCyi , 1 '-bis(diphenylphosphino)- ferrocene]*CH2Cl2 complex (44 mg) is added. The resulting mixture is stirred over night at 90°C. After cooling to room temperature, water (20 ml_) is added and the mixture is extracted three times with ethyl acetate. The organic phase is dried (Na2S04) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 1 :2→2: 1 ) to give the title compound. Yield: 149 mg (62% of theory); LC (method 1 ): tR = 1.29 min; Mass spectrum (EST): m/z = 444 [M+H]+. |
With sodium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; | 1 To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (200 mg) and 4-(methanesulfonyl)phenylboronic acid (119 mg) in N,N-dimethylformamide (2 mL) a 2 M aqueous Na2CO3 solution (0.68 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1'-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (44 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (20 mL) is added and the mixture is extracted three times with ethyl acetate. The organic phase is dried (Na2SO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 1:22:1) to give the title compound. Yield: 149 mg (62% of theory); LC (method 1): tR=1.29 min; Mass spectrum (ESI+): m/z=444 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.6 g | With palladium diacetate; sodium carbonate; triphenylphosphine; In 1,4-dioxane; water; N,N-dimethyl-formamide; at 20 - 80℃; for 18h;Inert atmosphere; Sealed tube; | An oven dried tube is charged with palladium acetate (about 0.2 g) and triphenylphosphine (about 0.6 g).The tube is evacuated under high vacuum and backflushed under a stream of nitrogen for about 5 minutes. A suitablesolvent such as 1,4-dioxane (about 10 mL) is added and the mixture is stirred under nitrogen for a suitable time(e.g., for about 10 minutes). 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 0.75 g), (4-methylsulfonylphenyl)boronic acid (about 1 g), a suitable solvent, such as N,N-dimethylformamide (about 10 mL) and a suitable base,such as about 1.5 M of sodium carbonate in water (about 10 mL) are added. The mixture is stirred for about 2minutes at room temperature under nitrogen then the tube is sealed and heated at about 80C for about 18 hours.The mixture is transferred to a round bottom flask and the volatiles are evaporated under reduced pressure. Theproduct is isolated in a suitable manner. For example, water (about 100 mL) may be added and the mixture stirred.The solid may then be collected by filtration, and optionally rinsed with water, air dried, triturated with ether/dichloromethane(about 4:1; about 10 mL), filtered and rinsed with ether. 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as a tan solid (about 0.6 g). MP = 236-239 C. 1H NMR (400 MHz, (D3C)2SO, delta,ppm): 8.63 (d, J=6.3 Hz, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.03 (d, J=7.9 Hz, 2H), 7.84 (d, J= 7.3 Hz, 1H), 7.03 (t, J=7.0Hz, 1H), 6.21 (br s, 2H), 3.28 (s, 3H). MS = 289 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium diacetate; sodium carbonate; tris-(o-tolyl)phosphine In 1,2-dimethoxyethane; water at 85℃; Inert atmosphere; Sealed tube; | 1; 2 2-(5-(4-methanesulphonyl-phenyl)-6-fluoro-pyridin-3-yl)-7-aza-bicyclo[2.2.1]heptane-7- carboxylic acid tert-butyl ester Compound 6 (259 mg, 0.7 mmol), 4-methanesulphonylphenylboronic acid (280 mg, 1.4 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), tris(o-tolyl)phosphine (43 mg, 0.14 mmol) and Na2CO3 (185 mg, 1.7 mmol) were mixed in DME (2 mL) and H20 (0.5 mL). The reaction mixture was purged with argon, sealed then heated in an 85 °C oil bath overnight. The reaction mixture was cooled, then filtered through Celite and washed with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated. After flash chromatography on a silica gel column with EtOAc- hexanes, the title compound 17was isolated as a white solid (312 mg, 99%). 1H NMR (CDC13): δ (ppm) 1.58 (s, 9H), 1.5 -1.9 (m, 5H), 2.02 (m, 1H), 3.00 (dd, 1H, J = 4.8, 9.0 Hz), 3.12 (s, 3H), 4.25 (br s, 1H), 4.41 (br s, 1H), 7.7-7.8 (m, 2H), 7.93 (dd, 1H, J = 2.4, 9.6 Hz), 8.0-8.1 (m, 2H), 8.13 (m, 1H). 13C NMR (CDC13): δ (ppm) 28.6, 29.2, 30.0, 41.0, 44.9, 45.0, 56.4, 62.4, 80.3, 116.4, 121.8 (d, J = 58.2 Hz), 128.1, 130.1 (d, J = 13.2 Hz), 139.7, 140.0, 140.4, 146.5 (d, J = 58.8 Hz), 155.4, 157.7, 160.9. |
With palladium diacetate; sodium carbonate; tris-(o-tolyl)phosphine In 1,2-dimethoxyethane; water at 85℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate In 1,4-dioxane at 130℃; for 0.5h; Microwave irradiation; | 2.6 A 5 mL reaction vial was charged with 7-iodo-4-(isopropylamino)cinnoline-3-carboxamide (16, 50mg, 0.14mmol), 4-(methylsulfonyl)phenylboronic acid 4 (56mg, 0.28mmol), Pd(Ph3P)4 (33mg, 0.028mmol), 2N K2C03 (0.15mL, 0.28mmol), and 1.5 mL of dioxane. The heterogeneous mixture was heated to 130 °C for 0.5 h using microwave irradiation. Upon cooling to 23 °C, the reaction mixture was quenched by addition of a saturated, aqueous NaHC(¾ solution. The heterogeneous mixture was extracted with EtOAc and the organic layer was dried over Na2SQ4, filtered and the filtrate concentrated under reduced pressure to give crude material, which was further purified by HPLC to give the desired compound (17, 38 mg, 71%). - R (400MHz, CDC13) δ: 8.56 (s, 1H), 8.29 (d, /=12.0Hz, 1H), 8.01 (d, =1 1 .1 2H), 7.89 (m, 3H), 4.54 (m, 1 H), 3.24 (m. 1 H), 3.04 (d, J=6.8Hz, 3H), 1.49 (d, J=8.3Hz, 6H). MS: 385.1 m/z (M+H)+. |
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water at 70℃; for 17h; | |
92% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; isopropyl alcohol at 110℃; for 0.0833333h; Microwave irradiation; | 2.12. Synthesis of acetophenones 7, 8 and 10 Synthesis of acetophenones 7, 8 and 10 [16] Reactions were performed in a Monowave 300 (Anton Paar GmbH) in 10 mL Pyrex microwave process vials using standard procedures in temperature control mode. Suzuki reactions under microwave conditions were carried out adding 1-(4-bromophenyl)-2,2,2-trifluoroethanol (5) (95.1 mg, 0.375 mmol, 1 equiv.), corresponding phenylboronic acid (0.375 mmol, 1 equiv.), potassium carbonate (103.6 mg, 0.75 mmol, 2 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.84 mg, 0.00075 mmol, 0.2 mol%) and a solution of distilled water and isopropanol (3 mL, 1:1). All the reactions were performed in closed vessels for 5 min at 110 °C. After that, the solvent was evaporated and the mixture was extracted with ethyl acetate (4 * 5 mL). The organic layer was dried (Na2SO4). Conversions were determined by GC-FID. The product 4'-(4-methylsulfonylphenyl)-2,2,2-trifluoroacetophenone (7) was obtained as a white powder in 92% yield, mp 165.7-166.8 °C. The melting point is in agreement with previous report (mp 157.9-158.8 °C) [18] . 1H NMR (300 MHz, DMSO-d6, TMS) δ (ppm): 3.27 (s, 3H, SO2CH3), 7.73-7.83 (m, 4H, hydrogen atoms of the aromatic ring), 7.96-8.04 (m, 4H, hydrogen atoms of the aromatic ring). 13C NMR (75 MHz, DMSO-d6, TMS) δ (ppm): 43.6 (SO2CH3), 92.5 (q, JC-F = 30.7 Hz, C1), 123.5 (d, JC-F = 287.2 Hz, CF3), 126.6 (C2 e C6), 127.7 (C3' e C5'), 128.2 (C3 e C5);139.0 (C2' e C6'), 139.1 (C1'), 139.9 (C4'), 144.5 (C4). |
92.6% | With palladium 10% on activated carbon; sodium carbonate In methanol; water at 30℃; for 8h; Inert atmosphere; | 1 Example 1 4-(Methanesulfonyl)benzeneboronic acid (10.0 g, 50 mmol) was added to a 1000 mL three-necked flask. 4'-Bromo-2,2,2-trifluoroacetophenone (12.5 g, 50 mmol), 10% palladium on carbon (0.5 g), Sodium carbonate (15.0 g, 150 mmol), 100 mL of methanol and water, and the reaction flask was vacuumed and filled with nitrogen. After reacting at 30 ° C for 8 h, TLC showed the reaction of all the starting materials, and the reaction was stopped. 200 mL of ethyl acetate was added to the reaction flask, and the mixture was stirred for 1 hour, and filtered, and the ethyl acetate phase was separated, and the solvent was evaporated to give a white solid. The yield was 92.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | A mixture of <strong>[158435-41-7]4-bromo-2-chlorobenzaldehyde</strong> (5.00 g, 22.8 mmol) and 4- (methanesulfonylphenyl)boronic acid (4.56 g, 22.8 mmol) in 1,4-dioxane (100 mL) and 2M aqueous sodium carbonate solution (34.6 mL, 69.2 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl2.DCM (930 mg, 1.14 mmol). The reaction mixture was heated at 80C for 2 h. The reaction mixture was cooled to r.t., diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgS04) and concentrated in vacuo. The resulting material was purified by flash column chromatography (Si02, 30-100%) EtO Ac/heptane), yielding the title compound (4.0 g, 58%) as an orange solid. deltaEta (500 MHz, CDC13) 10.53 (d, J 1.0 Hz, 1H), 8.09-8.02 (m, 3H), 7.82-7.78 (m, 2H), 7.70 (d, J 1.5 Hz, 1H), 7.64-7.61 (m, 1H), 3.11 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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81.6% | Stage #1: 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester; 4-methanesulphonylphenylboronic acid With caesium carbonate In N,N-dimethyl-formamide for 0.166667h; Inert atmosphere; Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere; | 3 Step 3 Step 3: To a pale yellow solution of 4-(methylsulfonyl)phenylboronic acid (0.8 g,1.0 eq) and teri-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-l(2H)-carboxylate (1.58 g, 1.2 eq) in DMF (15 mL) was added caesium carbonate (2.606 g, 1.5 eq). The resultant pale yellow suspension was degassed and stirred under nitrogen atmosphere for 10 minutes. To this mixture was added [l,l'-bis[(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane] (0.163 g,0.05 eq). The resultant red colour suspension was left for stirring for 6 h under nitrogen gas atmosphere at room temperature, during which time the contents became dark coloured. TLC had shown that complete consumption of starting materials and formation of new spot. The reaction mixture was diluted with ethyl acetate filtered on celite and the celite bed was washed twice with ethyl acetate. The filtrate was concentrated to dryness to get 1.7 g of black oil. This crude material was purified on a silica column hexane and ethyl acetate as eluents. The pure desired fractions were collected and concentrated under reduced pressure to get 1.1 g (yield: 81.6%) of tert-butyl 4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine- l(2H)-carboxylate as pale yellow solid. |
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In toluene at 0 - 20℃; for 3h; Inert atmosphere; | 9.1 Step 1: Preparation of tert-butyl 4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate 3.31 g of tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate and 50 ml of toluene were loaded in a 1000 mL flask in nitrogen atmosphere, followed by stifling for dissolving them. then, 2.0 g of 4-(methylsulfonyl)phenylboronic acid and 6.6 g of cesiumcarbonate were added thereto. The mixture was cooled down to 0° C., to which 1.16 g of tetrakis(triphenylphosphine)palladium (11.09 g) was slowly added. The mixture was stirred for at least 3 hours with raising the temperature to room temperature. Upon completion of the reaction, distilled water was slowly added thereto, followed by extraction using ethylacetate. The extracted organic layer was dried under reduced pressure. Then, silica gel column chromatography was performed to give the target compound. (0273) 1H NMR (400 MHz, CDCl3): δ 7.92 (2H, d), 7.56 (2H, d), 6.21 (1H, s), 4.14 (2H, d), 3.68 (2H, m), 3.07 (3H, s), 2.56 (2H, s), 1.49 (9H, s). | |
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In toluene at 0 - 20℃; for 3h; Inert atmosphere; | 9.1 tert-butyl 4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate Under a nitrogen atmosphere, 3.31 g of tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H) -carboxylate and 50 mL of toluene were loaded in a 1000-mL flask and stirred to dissolve, and then 2.0 g of 4-(methylsulfonyl)phenylboronic acid and 6.6 g of cesium carbonate were added. Thereafter, the mixture was cooled to 0□, followed by slowly adding 1.16 g of tetrakis(triphenylphosphine)palladium, and then stirred for 3 hours or longer while the temperature was again raised to room temperature. Upon completion of the reaction, distilled water was slowly added dropwise, and then extracted with ethyl acetate. The extracted organic layer was dried under reduced pressure, and then separated by silica column chromatography to give the title compound. (0167) 1H NMR (400MHz, CDCl3): δ 7.92(2H. d), 7.56(2H, d), 6.21(1H, s), 4.14(2H, d), 3.68(2H, m), 3.07(3H, s), 2.56(2H, s), 1.49(9H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 85℃; for 18h;Inert atmosphere; | Step A: 5-Bromo-2-chloro-4-f4-(methvlsulfonyl)phenvnpvridine A deoxygenated mixture of <strong>[401892-47-5]5-bromo-2-chloro-4-iodopyridine</strong> (6.01 g, 18.9 mmol), (4- (methylsulfonyl)phenyl)boronic acid (3.78 g, 18.9 mmol), 2 M aqueous sodium carbonate solution (14.2 mL, 28.3 mmol) and dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(ll) dichloromethane adduct (1.08 g, 1.32 mmol) in 1,4-dioxane (150 mL) was heated at 85 C for 18 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2CI2 (60 mL) and filtered. The filtrate was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 0:100, to give the title compound. MS: m/z = 346.0 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(tri-t-butylphosphine)palladium(0); caesium carbonate; In 1,4-dioxane; water; at 80℃; for 2h; | To a deoxygenated mixture of tert-butyl ( (5-bromopyridin-2-yl) methyl) carbamate (1.20 g, 4.18 mmol) , (4- (methylsulfonyl) phenyl) boronic acid (1.25 g, 6.27 mmol) and cesium carbonate (3.40 g, 10.5 mmol) in dioxane (25 mL) and water (5 mL) was added Pd (P (tBu)3)2(0.430 g, 0.863 mmol) , and the resulting mixture was heated at 80 for 2 h. The mixture was cooled, poured into saturated aqueous NaHCO3solution (200 mL) and extracted with EtOAc (200 mL x 2) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (0-100EtOAc/Hexanes) to afford the title compound. MS: m/z 363.1 (M + 1) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | To a deoxygenated mixture of <strong>[35857-89-7]6-chloropyridazine-3-carbonitrile</strong> (100 mg, 0.717 mmol) , (4- (methylsulfonyl) phenyl) boronic acid (215 mg, 1.08 mmol) , and sodium carbonate (190 mg, 1.79 mmol) in dioxane (3 mL) and water (0.600 mL) was added PdCl2(dppf) (58 mg, 0.072 mmol) , and the resulting mixture was heated at 80 for 3 h under a nitrogen atmosphere. The mixture was cooled and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (0-10MeOH/DCM) to afford the title compound. MS: m/z 260.0 (M + 1) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With oxygen; In 1-methyl-pyrrolidin-2-one; at 20.0℃; for 1.0h; | General procedure: Arylboronic acid 2 (0.12 mmol) and (bpy)Cu(SCF3) 1 (0.1 mmol) were added to a Schlenk flask fitted with magnetic stir bar and O2 balloon. The flask was evacuated and back filled with O2. The solvent NMP (2.0 mL) was added by syringe at room temperature and the solution was stirred for 1 h. For the products reported with isolated yields (3a, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u and 3w), the reaction mixture was diluted with EtOAc, then washed with water and brine. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (n-hexane/ethyl acetate gradient) to afford the desired compounds. Gram-scale synthesis of compound 5 was prepared following the similar procedure. The relatively volatile products (3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j and 3v) were not isolated and their yields were determined by 19F NMR measurement in CDCl3 of the reaction mixture. For the products reported with 19F NMR yields, PhOCF3 (1.0 equiv) was added to the reaction mixture as internal standard added after the reaction completed. The reaction mixture was purified by flash chromatography on silica gel (pentane/diethyl ether gradient) to afford the desired compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.94% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 90℃; for 16h;Inert atmosphere; | Step-1: Synthesis of 3-chloro-4-(4-(methylsulfonyl)phenyl)-1,2,5-thiadiazole To a stirred solution of <strong>[5728-20-1]<strong>[5728-20-1]3,4-dichloro-1,2,5-thiadiazol</strong>e</strong> (0.2 g, 1.307 mmol) and 4-(methylsulfonyl)phenylboronic acid (0.259 g, 1.307 mmol) in toluene (5 mL) was added KF (0.226 g, 3.898 mmol) in water (5 mL), reaction mass was purged with nitrogen for 30 min. After 30 min Pd(PPh3)4 (0.0075 g, 0.0653 mmol) was added to reaction mixture, heated at 90 C. for 16 h. Reaction was monitored by TLC. On completion, reaction was quenched with water, extracted with ethyl acetate. Organic layer was washed with water, brine, dried over sodium sulphate, concentrated under reduced pressure obtained crude which was purified by Combiflash chromatography; eluent 15% EtOAc/Hexane to afford 3-chloro-4-(4-(methylsulfonyl)phenyl)-1,2,5-thiadiazole (0.075 g, 20.94%) as off white solid. MS: 275.20 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.79% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 16h;Inert atmosphere; | <strong>[58530-53-3]2,4-Dibromopyridine</strong> 1a (6 g, 25.33 mmol) was dissolved in 126 mL of a mixed solvent of toluene, ethanol and water (V:V:V=4:2:1), (4-(methanesulfonyl)phenyl)boronic acid 1b (5066.1 mg, 25.33 mmol), sodium carbonate (5369.1 mg, 50.66 mmol) and tetrakis(triphenylphosphine)palladium (2926.7 mg, 2.53 mmol) were added, and the reaction solution was stirred for 16 hours at 100 C. under an argon atmosphere. The reaction was monitored by LC-MS until the starting material disappeared, then the reaction stopped and cooled. The reaction solution was added with ethyl acetate and water, and extracted with ethyl acetate (80 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 1c (7.09 g, white solid, yield: 89.79%). |
23% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 2h;Microwave irradiation; Inert atmosphere; | <strong>[58530-53-3]2,4-Dibromopyridine</strong> 3a (1 g, 4.22 mmol), (4-(methanesulfonyl)phenyl)boronic acid 3b (844 mg, 4.22 mmol, prepared according to the known method disclosed in "Journal of Organic Chemistry, 2008, 3(2), 4662-4670"), tetrakis(triphenylphosphine)palladium (487.6 mg, 0.422 mmol) and sodium carbonate (894.6 mg, 8.44 mmol) were dissolved in 21 mL of a mixed solvent of toluene, ethanol and water (V/V/V=4:2:1), then the reaction solution was warmed up to 100C and reacted under microwave for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 3c (300 mg, yield: 23%). |
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