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CAS No. : | 628692-15-9 |
Formula : | C5H7BN2O3 |
M.W : | 153.93 |
SMILES Code : | OB(C1=CN=C(OC)N=C1)O |
MDL No. : | MFCD03094664 |
InChI Key : | YPWAJLGHACDYQS-UHFFFAOYSA-N |
Pubchem ID : | 2736778 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | P264-P270-P280-P301+P312+P330-P305+P351+P338-P337+P313-P501 |
* 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 |
---|---|---|
EXAMPLE 1 2-Methoxy-5-(3-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)phenyl)pyrimidine. tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (60. 0 mg, 0.11 mmol), 2-methoxy-5-pyridine boronic acid (72.0 mg, 0.47 mmol), and tetrakis(triphenylphosphine) palladium(0) (17.1 mg, 0.011 mmol) were combined in dry tetrahydrofuran (2 mL) in a microwave tube and sealed. The mixture was flushed with nitrogen then 0.35 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. Concentration and preparative HPLC afforded 21.0 mg (42percent) of the desired compound as its TFA salt. 1H-NMR (CDCl3, 500 MHz) delta 8.57 (s, 2H), 7.54 (s, 1H), 7.25-7.31 (m, 8H), 4.40 (s, 2H), 4.03 (s, 3H), 3.40 (s, 2H), 2.83-2.88 (m, 2H), 2.64-2.69 (m, 2H), 2.10-2.18 (m, 2H), 1.77-1.86 (m, 2H). Mass spec.: 458.18 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 8h; | A mixture of 6-(methyloxy)-3-pyridinyl]boronic acid (225 mg, 1.5 mmol), 4- iodo-6-quinolinecarbaldehyde (283 mg, 1 mmol), tetrakistriphenylphosphine palladium (0) (57 mg, 0.05 mmol), 2 M aqueous K2CO3 (2.5 ml. of a 2 M solution), and dioxane (5 ml.) ) was heated at 100 0C for 8 h and cooled to room temperature. The dioxane was removed under reduced pressure and the residue dissolved in 2:1 mixture of methylene chloride/water and the solution filtered. The organic layer was separated and dried with sodium sulfate and the crude product obtained by decanting the solution and evaporation of the methylene chloride. The crude product was purified by silica gel chromatography eluting with methylene chloride/methanol (0-1percent methanol gradient) to give the title compound (250 mg, 95 percent). MS(ES)+ m/e 265 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 133A 3-(4-aminophenyl)-7-(2-methoxy-5-pyrimidinyl)thieno[3,2-c]pyridin-4-amine The desired product was prepared by substituting 2-methoxy-5-pyrimidinylboronic acid for 4-pyridylboronic acid in Examples 121A-B. MS (ESI(+)) m/e 350 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 48h;Heating / reflux; | To a stirred solution of (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl- pyrrolidin-l-yl)-methanone (100mg, 0.297mmol), sodium carbonate (94.4mg, 0.890mmol) and 2-Methoxy-5-pyrimidine boronic acid (230mg, 1.48mmol) in toluene (5ml), water (Iml) and ethanol (1.5ml) under nitrogen was added Tetrakis (triphenylphosphine) palladium (0) (34.3mg, 0.030mmol). The reaction was then heated to reflux for 48h. The reaction was allowed to cool and bound to a SCX-2 cartridge (5g). The cartridge was washed with two cartridge volumes of dimethylformamide and one volume of methanol. The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution was evaporated on a Genevac HT4. The sample was further purified by prep-LCMS. The resulting acetonitrile/water fractions were combined and evaporated using a Genevac to give 51mg of a colourless oil (47percent). MS (ES+) 367.3 |
47% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 48h;Reflux; Inert atmosphere; | Example 55[4-(2-Methoxy-pyrimidin-5-yl)-phenyl]-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone Procedure SS: To a stirred solution of (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (100 mg, 0.297 mmol), sodium carbonate (94.4 mg, 0.890 mmol) and 2-Methoxy-5-pyrimidine boronic acid (230 mg, 1.48 mmol) in toluene (5 ml), water (1 ml) and ethanol (1.5 ml) under nitrogen was added Tetrakis (triphenylphosphine) palladium (0) (34.3 mg, 0.030 mmol). The reaction was then heated to reflux for 48 h. The reaction was allowed to cool and bound to a SCX-2 cartridge (5 g). The cartridge was washed with two cartridge volumes of dimethylformamide and one volume of methanol. The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution was evaporated on a Genevac HT4. The sample was further purified by prep-LCMS. The resulting acetonitrile/water fractions were combined and evaporated using a Genevac to give 51 mg of a colourless oil (47percent). MS (ES+) 367.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 120℃; for 0.166667h;Microwave irradiation; | Step-2 Preparation of 8-[3-(2-methoxy-pyrimidin-5-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoline 43 In a microwave reaction tube, 8-(3-bromo-pyrrolo[2,3-b]pyridine-1-sulfonyl)-quinoline (44, 68 mg, 0.18 mmol), 2-methoxy-pyrimidine-4-boronic acid (67.4 mg, 0.438 mmol), and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0088 mmol) were mixed in 1.0 M of potassium carbonate (0.52 mL) and tetrahydrofuran (0.84 mL). The resulting mixture was heated at 120° C. in a CEM Discover microwave unit for 10 minutes. Ethyl acetate and water were added and two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. The product was concentrated under reduced pressure and the resultant crude material was purified by column chromatography (80-90percent ethyl acetate in hexane) to yield the desired product as a white solid (43, 0.005 g, 0.01 mmol). MS(ESI) [M+H+]+=417.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 60℃; for 36h; | A mixture of 2-(3-acetamidophenyl)-4-bromo-6-morpholinopyrimidine (0.037 g),<strong>[628692-15-9]2-methoxypyrimidin-5-ylboronic acid</strong> (0.019 g), tetrakis(triphenylphosphine)palladium(0)(3 mg), a saturated aqueous sodium bicarbonate solution (0.2 ml) and 1,2-dimethoxyethane(2 ml) was stirred and heated to 60°C for 18 hours under an atmosphere of nitrogen. A secondportion of each of <strong>[628692-15-9]2-methoxypyrimidin-5-ylboronic acid</strong> (0.019 g),tetrakis(triphenylphosphine)palladium(0) (2 mg), a saturated aqueous sodium bicarbonatesolution (0.2 ml) and 1,2-dimethoxyethane (1 ml) was added and the resultant mixture washeated to 60°C for a further 18 hours. The resultant reaction mixture was evaporated and theresidue was triturated under a 5:1 mixture (1 ml) of methylene chloride and methanol. Thesoluble material was purified by column chromatography on reversed-phase silica using an'Isolute SCX' column (1 g; International Sorbent Technology Limited, Mid Glamorgan, UK)by initially washing the column with methanol (5 ml) followed by elution with a 5:3:2 mixture of methanol, methylene chloride and a 7M methanolic ammonia solution. The material soobtained was dried under vacuum. There was thus obtained the title compound as a solid(0.034 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 3.66-3.8 (m, 8H), 3.97 (s, 3H), 7.3-7.37(m, 2H), 7.82 (d, 1H), 8.03-8.09 (m, 1H), 8.52 (s, 1H), 9.38 (s, 2H), 9.98 (s, 1H); MassSpectrum: M+HM07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 100℃; for 2h;Microwave irradiation; | Example 75;. iV-[(2,6-Dimethylphenyl)methyI]-2,3-dimethyl-6-[2-(methyIoxy)-5- pyrimidinyl] imidazo [1 ,2-a] pyridin-8-amine EPO <DP n="86"/>A mixture of 6-bromo-iV-[(2,6-dimethylphenyl)methyl]-2,3-dimethylimidazo[l ,2- alpha]rhoyridin-8-amine (500 mg, 1.39 mmol; WO 98/37080) and 2-methoxvpyrimidine-5- boronic acid (430 mg, 2.79 mmol) in 2M aqueous sodium carbonate (3 niL) and dimethylformamide (6 mL) was degassed with argon and then treated with [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.01 mmol). The mixture was heated in an Initiator.(TM). Microwave Synthesizer at 100°C for 2 hours. The resulting reaction mixture was applied to an Isolute.(R). SCX cartridge. Elution with methanol, then 2M and 7M NH3 in methanol gave, after evaporation, the crude product which was further purified by silica gel chromatography eluting with ethyl acetate/hexane mixtures to yield the title compound. MS (ES+ve): [M+H]+ at m/z 388 (C23H25N5O requires [M+H]+ at m/z 388). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In isopropyl alcohol; at 90℃; for 5h; | Example 16C; 2-Methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine; To a solution of the product from Example 16B (50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 2-methoxypyrimidine-5-boronic acid (Frontier Scientific, Inc., Logan, Utah, USA) (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 mumol), and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated at 90° C. for 5 hrs, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic extraction was washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed on silica gel eluting with 3percent (9:1 MeOH:concentrated NH4OH) in dichloromethane to provide 41 mg of the title compound. 1H NMR (300 MHz, CD3OD) delta 1.13 (d, J=6 Hz, 3H), 1.47 (m, 1H), 1.77 (m, 2H), 1.99 (m, 1H), 2.27 (m, 1H), 2.41 (m, 2H), 2.62 (m, 3H), 3.05 (m, 1H), 3.38 (m, 1H), 3.55 (m, 1H), 4.05 (s, 3H), 7.46 (d, J=9 Hz, 2H), 7.59 (d, J=9 Hz, 2H), 8.81 (s, 2H); (DCl/NH3) m/z 324 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(I) thiophene-2-carboxylate; zinc diacetate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 130℃; for 0.75h;Microwave irradiation; | The compounds shown in table 1 were prepared in an analogous manner to 4- (methylsulfonylmethyl)-6-morpholin-4-yl-2-thiophen-3-yl-pyrimidine (example 1), except where noted. Table 1Example 10: H NMR (300.132 MHz, DMSO) 53.19 (s, 3H), 3.72 (s, 8H), 4.01 (s, 3H),4.50 (s, 2H), 6.94 (s, IH), 9.38 (s, 2H) iPurification/Analysis details for examples 1 to 12:Dissolution Solvent 4 ml DMFInstrument Waters XBridge Prep, Cl 8 5 mum 100 x 19 mmColumn Phenomenex Gemini 5mu, Cl 8 100 x 21.2 mmFraction Trigger uv (at) 254 nmGradient 0 - 1 min 30percent MeCN, 9.5 min 60percent MeCNSolvent A WaterSolvent B AcetonitrileSolvent C - Modifier 5percent 4:3:3 880 Ammonia: Acetonitrile: WaterFlow Rate 20 ml/minAt Column Dilution Solvent AcetonitrileAt Column Dilution Flow Rate 1.0 ml/minTransfer solvent 1 ml DMF per tube + MeOH washLCMS 50 mul made upto 1 ml with MeCNAnalytical LCMS Method Phenomenex Gemini 5mu, C18 50 x 2 mm, 1.2 ml/min0 min 95:0:5 A:B:C, 4 min 0:95:5 A:B:CA MeCN, B H2O, C 1:1 MeCN:H2O 1percent Ammonia acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 12h; | A mixture of Intermediate 3 (602 mg), 2-methoxypyrimidme-5-boronic acid(Frontier, 1.5 eq, 706 mg), and tetrakis(triphenylphosphine)palladium (0) (352 mg) was heated in DME / 2N sodium carbonate (aq, 2:1, 20 ml) at 100 ° for 12 h. Aqueous workup between water and EtOAc gave a brown solid that purified by SPE (Si, 20 g) by elution with DCM (4x10 ml) then EtOAc (4x10 ml), to give a solid that was triturated with DCM / petrol, and filtered to give a light brown solid (660 mg).1H NMR delta 8.85 (2H, s), 7.8 (IH, s), 7.6 (>3H, m), 6.88 (IH, d, J 8.85Hz), 6.3 (2H, s), 3.93 (3H, s); LC-MS rt 2.39 m/z 226 ES-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 100℃; for 0.277778h;microwave irradiation; | To a solution of N-[3-(3-bromo-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-3-trifluoromethyl-benzamide, (100 mg, 0.216 mmol) in ethylene glycol dimethyl ether (3 mL) was added 2-methoxypyrimidine-5-boronic acid (66 mg, 0.433 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (35 mg, 0.043 mmol), sodium carbonate (2M aqueous solution, 0.43 mL, 0.864 mmol). After microwaving at 100° C. for 1000 seconds, the solution was diluted with ethyl acetate, filtered with celite, concentrated, and purified by HPLC (10 mg, 10percent yield). MS 489.2 [M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; ethanol; water; at 100℃; for 0.166667h;Microwave irradiation; | Intermediate 11: Cvclopentyl 5-r(5-(6-amino-5-ri-(2,6-dichloro-3-fluoro phenyl) ethoxv1pvridin-3-vl>pvrimidin-2-vl)oxv1-/V-(ferf-butoxvcarbonvpi-L-norvalinateThe title intermediate was prepared by the method outlined in Scheme 12.Stage 1Scheme 12Stage 1- 3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-(2-methoxypyrimidin-5-yl) pyridin-2-amineA solution of Intermediate 7 (224 mg, 0.591 mmol), <strong>[628692-15-9](2-methoxypyrimidin-5-yl)boronic acid</strong> (100 mg, 0.650 mmol) and PdCI2(dppf) (48.2 mg, 0.059 mmol) was made up in DME/EtOH (1 ml_). To this was added sodium carbonate (68.9 mg, 0.650 mmol) (0.69 mL of a 1 M solution) and the solution was subjected to microwave irradiation for 10 min at 100 0C. The dark mixture was poured onto water and extracted with EtOAc (5 mL). The combined organic phases were washed with water and brine (2 x 3 mL each), dried EPO <DP n="40"/>(MgSO4) and evaporated. The residue was subjected to column chromatography (40 g) eluting with 40percent EtOAc in hexanes to give the desired material (100 mg) as a colourless solid. ESMS: m/z 409 and 411 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In tetrahydrofuran; at 60℃; for 4h; | Example 64; [0203] (a) terf-Butyl 2-(4-hydroxy-6-(2-methoxypyrimidin-5-yl)-l- methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate. A mixture of 2-methoxypyrimidine-5-boronic acid (0.34 g, 2.2 mmol), tert-butyl 2- (4-hydroxy-6-iodo- 1 -methyl-2-oxo- 1 ,2-dihydro- 1 , 8-naphthyridine-3 - carboxamido)acetate (0.500 g, 1.1 mmol, Example 26 (g)), t-tert- butylphosphonium tetrafluoroborate (0.063 g, 0.22 mmol), Pd2(dba)3 (0.100 g, 0.11 mmol) and potassium fluoride (0.076 mg, 3.3 mmol) in THF (8 mL) was stirred at 60°C for 4 hours under an argon atmosphere. The reaction mixture was left to reach room temperature and was filtered. The filter cake was washed with EtOAc (3x100 mL). The combined filtrate was evaporated under reduced pressure, and the residue was diluted with DCM (100 mL), and was filtered. The filtrate was washed with deionized water (3x75 mL) and brine (75 mL), dried over MgSOphi and filtered. The filtrate was evaporated under reduced pressure, and the <n="73"/>residue was purified by silica gel column chromatography (gradient: 0-33percent EtOAc/hexanes) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.91%; 14.11% | Examples 57 and 58: (Trans)-3-(2-fluorophenyl)-8-{5-[2-(methyloxy)-5-pyrimidinyl1-1 H- benzimidazol-2-yl)-1-oxa-3-azaspiro[4.51decan-2-one (Example 57) and (trans)-8-(1 H- benzimidazol-2-yl)-3-(2-fluorophenyl)-1-oxa-3-azaspiro[4.51decan-2-one (Example 58); Example 57 Example 58To 8-(5-bromo-1 H-benzimidazol-2-yl)-3-(2-fluorophenyl)-1 -oxa-3-azaspiro[4.5]decan-2- one (Example 55, 50 mg, 0.113 mmol) dissolved in 1 ,4-dioxane (5 ml), Pd2dba3 (3.09 mg, 3.38 mumol), P(t-Bu)3 (22.77 mg, 0.1 13 mmol), [2-(methyloxy)-5-pyrimidinyl]boronic acid (26.0 mg, 0.169 mmol) and cesium carbonate (44.0 mg, 0.135 mmol) were added and the solution was stirred at 90 0C for 2 hours. Then the mixture was irradiated for 15 min at 160 0C. Pd2dba3 (3.09 mg, 3.38 mumol), P(t-Bu)3 (22.77 mg, 0.113 mmol), [2-(methyloxy)-5- pyrimidinyl]boronic acid (26.0 mg, 0.169 mmol) and cesium carbonate (44.0 mg, 0.135 mmol) were added and the mixture was irradiated for further 15 min at 160 0C. The reaction was cooled to room temperature and the mixture partitioned between water (3 ml) and DCM (3X3 ml). The organic layer was eluted through a SCX SPE cartridge (DCM 100, 2 CV, MeOH, 3 CV, MeOH/1 M Ammonia in methanol 8/2, 3 CV). Purification by chromatography on Si SPE cartridge (DCM/MeOH 100percent to 9/1 ) afforded 3-(2- fluorophenyl)-8-{5-[2-(methyloxy)-5-pyrimidinyl]-1 H-benzimidazol-2-yl}-1-oxa-3- azaspiro[4.5]decan-2-one and (trans)-8-(1 H-benzimidazol-2-yl)-3-(2-fluorophenyl)-1-oxa- 3-azaspiro[4.5]decan-2-one which were treated with 1.0M HCI in Et2O (0.135 ml) to afford the title compounds 3-(2-fluorophenyl)-8-{5-[2-(methyloxy)-5-pyrimidinyl]-1 H- benzimidazol-2-yl}-1-oxa-3-azaspiro[4.5]decan-2-one hydrochloride (Example 57, 9 mg, 14.1 1 percent) and (trans)-8-(1 H-benzimidazol-2-yl)-3-(2-fluorophenyl)-1-oxa-3- azaspiro[4.5]decan-2-one hydrochloride (Example 58, 9 mg, 18.91percent).Example 57: 1 H-NMR (400 MHz, CDCI3): delta 8.76 (2H, s), 7.77-7.93 (1 H, m), 7.46-7.61 (2H, m), 7.32-7.46 (1 H, m), 7.12-7.28 (3H, m), 4.09 (3H, s), 3.88-3.91 (2H, m), 3.12 (1 H, br s), 2.28-2.42 (2H, m), 2.12-2.26 (2H, m), 1.90-2.10 (4H, m); UPLC-MS: 0.56 min, m\\z 474 [M+H]+.Example 58: 1 H-NMR (400 MHz, CDCI3): delta 7.54 (2H, td), 7.34 (2H, dd), 7.12-7.23 (4H, m), 3.86 (3H, s), 3.03 (1 H, br s), 2.25-2.38 (2H, m), 2.11-2.22 (3H, m), 1.90-2.06 (4H, m); UPLC-MS: 0.54 min, m\\z 366 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | EXAMPLE 7 4-amino-8-(2-methoxypyrimidin-5-yl)-N-propyl-cinnoline-3-carboxamide Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.324 mmol) and <strong>[628692-15-9](2-methoxypyrimidin-5-yl)boronic acid</strong> (104 mg, 0.68 mmol) were reacted to afford the title compound (84 mg, 77percent yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 9.1-9.3 (m, 1.5H), 8.96 (s, 2H), 8.47 (dd, J=8.4, 1.0 Hz, 1H), 8.1-8.4 (bm, 0.5 H), 7.99 (dd, J=7.2, 1.0 Hz, 1H), 7.83 (dd, J=8.4, 7.2 Hz, 1H), 4.01 (s, 3H), 3.32 (apparent q, J=7.4 Hz, 2H), 1.60 (apparent sextet, J=7.2 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). MS APCI, m/z=339 (M+H) HPLC 1.75 min. |
Yield | Reaction Conditions | Operation in experiment |
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7V-(2-chloro-6-methylphenyl)-2-(2'-methoxy-2-methyl-4,5'-bipyrimidin-6- ylamino)thiazole-5-carboxamide32 A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-7V-(2-chloro-6- methylphenyl)-N-(4-methoxybenzyl)thiazole-5-carboxamide (37 mg, 0.072 mmol), 2- methoxypyrimidin-5-boronic acid (15 mg, 0.097 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol), sodium carbonate (24 mg, 0.23 mmol) in THF (3.0 mL) and water (0.30 mL) was microwave heated at 160 0C for 1 h. The solvent was removed and the residue was purified by silica gel chromatography. The product was dissolved in 50percent TFA in DCM (3 mL) and triflic acid (0.2 mL). The reaction mixture was stirred for 3 h at rt, diluted with EtOAc, washed with sat. sodium bicarbonate, brine, dried over sodium sulfate and the solvent was removed. The residue was purified by preparative HPLC (ACN/ 0.1 percent TFA in water) and lyophilized to yield the title compound as a fluffy solid.1H-NMR (400 MHz, d6-DMSO) delta 12.21 (br s, IH), 10.00 (s, IH), 9.18 (s, 2H), 8.32 (s, IH), 7.41 (dd, J = 1.6, 7.6 Hz, IH), 7.33-7.27 (m, 3H), 4.02 (s, 3H), 2.68 (s, 3H), 2.25 (s, 3H); MS (m/z): 468.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; | Example 5; Synthesis of propane-1-sulfonic acid {2,4-difluoro-3-[2-(2-methoxy-pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-phenyl}-amide P-0004; Propane-1-sulfonic acid {2,4-difluoro-3-[2-(2-methoxy-pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-phenyl}-amide P-0004 was prepared in one step from propane-1-sulfonic acid [3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-amide P-0002 as shown in Scheme 3.; Step 1-Preparation of propane-1-sulfonic acid {2,4-difluoro-3-[2-(2-methoxy-pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-phenyl}-amide (P-0004); In a microwave tube, propane-1-sulfonic acid [3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-amide (P-0002, 95.0 mg, 0.207 mmol) and 2-methoxypyrimidine-5-boronic acid (10, 38.0 mg, 0.247 mmol) were added, followed by 1.4 mL of acetonitrile and 0.70 mL of 1.00 M potassium carbonate in water. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.6 mg, 0.010 mmol) was added to reaction mixture and the resulting mixture was heated at 160° C. in the microwave for a total of 10 minutes. The reaction solution was extracted with ethyl acetate and water, followed by saturated sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography eluting with a gradient of 10 to 70percent ethyl acetate in hexanes. The resulting material was further purified by silica gel chromatography eluting with a gradient of 1 to 3percent methanol in dichloromethane, and fractions containing the desired compound were extracted with 10 mL each of ethyl acetate and 1 M sodium hydroxide. The aqueous layer was treated with 0.8 ml, of 6 N hydrochloric acid, then extracted with 2.x.10 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a white solid (P-0004, 32 mg). MS (ESI) [M+H+]+=489.3. |
Yield | Reaction Conditions | Operation in experiment |
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29.8% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | Example 285 l-Ethyl-3-(5-(2-methoxypyrimidin-5-yl)-4-(4-phenylthiazol-2-yl)pyridin-2-yl)urea To a nitrogen-purged mixture of l-(5-bromo-4-(4-phenylthiazol-2-yl)pyridin-2-yl)-3- ethylurea (Intermediate 16, 125 mg, 0.31 mmol) in DME (3 mL) were added 2- methoxypyrimidin-5-ylboronic acid (57.3 mg, 0.37 mmol), sodium bicarbonate (52.1 mg, 0.62 mmol) and water (1 mL), followed by tetrakis(triphenylphosphine)palladium(0) (71.6 mg, 0.06 mmol). The resulting mixture was microwaved for 60 min at 110°C. The solvent was evaporated from the reaction mixture, and the crude mass was washed with ethyl acetate and purified on reverse phase preparative HPLC to yield pure l-ethyl-3-(5-(2- methoxypyrimidin-5-yl)-4-(4-phenylthiazol-2-yl)pyridin-2-yl)urea (40.0 mg, 29.8 percent) as white solid powder.MS (ES+): 432.8 for C22H20N6O2S1H NMR a(DMSO Do): l.l(t, 3H), 3.2(qn, 2H), 4.0 (s, 3H), 7.32-7.45 (m, 3H), 7.61 (t, IH), 7.78 (d, 2H), 8.24 (s, IH), 8.27 (s, IH), 8.30 (s, IH), 8.61 (s, 2H), 9.40 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
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45% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 91℃; for 4h;Inert atmosphere; | Step 3 : 6-(2-Dimethylamino-ethoxy)-5-(2-methoxy-pyrimidin-5-yl)-pyridin-3-ylamine (Intermediatel3). To a stirred solution of 5-bromo-6- (2-(dimethylamino)ethoxy)pyridin-3-amine(800 mg, 3.08 mmol, Intermediated) in dimethoxy ethane (20 mL), 2-methoxypyrimidin- 5-ylboronic acid (710 mg, 4.61 mmol) was added to the reaction mixture, nitrogen was purged for 5-10 minutes to remove dissolved oxygen. To this PalladiumTetrakis (533 mg, 0.46 mmol) was added followed by addition of aq solution of sodium carbonate (652 mg, 6.15 mmol). The resulting reaction mixture was heated at 91 0C for 4 hrs. Solvent from the reaction mixture was evaporated in vacuo and and the crude product was purified by fish chromatography using 8percentMeOH/DCM as solvent system to give 6-(2- (dimethylamino)ethoxy)-5-(2-methoxypyrimidin-5-yl)pyridin-3-amine (400 mg, 45.0 percent). MS (ES+): 290 for C14Hi9N5O2 |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine;copper diacetate; In dichloromethane; at 20℃; for 156h; | 100 mg (0.2 mmol) 5-[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one, 62.5 mg (0.41 mmol) 2-methoxypyrimidine-5-yl boronic acid and 37 mg (0.2 mmol) water free copper acetate were stirred in 8.6 ml dichloromethane and 330 mul pyridine for 60 hours at room temperature. Then additional 35 mg 2-methoxypyrimidine-5-yl boronic acid and 20 mg water free copper acetate were added. After 4 days the solvent was removed column chromatography on silica gel (ethyl acetate/methanol 0 to 10percent) and additional preparative thin layer chromatography on silica gel (hexane/acetone 1:1) yielded 9.4 mg of the title compound. 1H-NMR (CDCl3); delta=3.25 (d, 1H), 3.29 (s, 3H), 3.64 (d, 1H), 3.89 (s, 3H), 4.09 (s, 3H), 5.24 (d, 1H), 5.66 (dd, 1H), 5.90 (dd, 1H), 6.16 (d, 1H), 6.65 (d, 1H), 6.90 (dd, 1H), 7.27 (d, 1H), 7.86 (d, 1H), 8.37 (d, 1H), 8.44 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; copper diacetate; In dichloromethane; at 20℃; for 60h; | Example 5 5-[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(methoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1-(2-methoxypyrimidine-5-yl)-1H-quinolin-2-one 100 mg (0.2 mmol) 5-[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one, 62.5 mg (0.41 mmol) 2-methoxypyrimidine-5-yl boronic acid and 37 mg (0.2 mmol) water free copper acetate were stirred in 8.6 ml dichloromethane and 330 mul pyridine for 60 hours at room temperature. Then additional 35 mg 2-methoxypyrimidine-5-yl boronic acid and 20 mg water free copper acetate were added. After 4 days the solvent was removed column chromatography on silica gel (ethyl acetate / methanol 0 to 10percent) and additional preparative thin layer chromatography on silica gel (hexane / acetone 1:1) yielded 9.4 mg of the title compound. 1H-NMR (CDCl3); delta = 3.25 (d, 1H), 3.29 (s, 3H), 3.64 (d, 1H), 3.89 (s, 3H), 4.09 (s, 3H), 5.24 (d, 1H), 5.66 (dd, 1H), 5.90 (dd, 1H), 6.16 (d, 1H), 6.65 (d, 1H), 6.90 (dd, 1H), 7.27 (d, 1H), 7.86 (d, 1H), 8.37 (d, 1H), 8.44 (d, 1H). |