Structure of 219735-99-6
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CAS No. : | 219735-99-6 |
Formula : | C7H8BClO3 |
M.W : | 186.40 |
SMILES Code : | C1=C(C(=CC=C1OC)B(O)O)Cl |
MDL No. : | MFCD03411935 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 47.77 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.69 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.43 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.03 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.6 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.39 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.13 |
Solubility | 1.37 mg/ml ; 0.00734 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.08 |
Solubility | 1.56 mg/ml ; 0.00834 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.03 |
Solubility | 1.73 mg/ml ; 0.00927 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.42 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.98 |
* 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 47; The mixture of <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (372 mg), 2-bromo-5- formylthiazole(576 mg), sodium bicarbonate (6 mL, 1 M), dioxane (6 mL) and palladium tetrakistriphenylphosphine (30 mg) was heated at 1000C for 4 hours. The mixture was filtered through celite and diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (50 mL). The organic fraction was dried with sodium sulfate and concentrated in vacuo to give the coupled product as a brown solid. To a solution of trimethyl phosphonoacetate (146 mg) in 5 mL of THF was added n-butyllithium (0.59 mL, 1.6 M in hexane) at O0C. The resulting solution was stirred at this temperature for 30 min. To this solution was added a THF solution (5 mL) of the above intermediate aldehyde (170 mg). The mixture was slowly warmed to rt and stirred for 2 hours. After quenching the mixture was water, the mixture was extracted with ethyl acetate, dried with sodium sulfate and concentrated in vacuo to give the enoate as a brown oily solid. To this enoate (83 mg) was added 5 mL of EPO <DP n="53"/>THF:MeOH:water (3:1:1) followed by LiOH (2 mL, 1 M). The mixture was stirred at rt for 5 hours. After acidified with concentrated HCl until pH = 4, the slurry was extracted with 30% isopropanol in chloroform, dried with sodium sulfate and concentrated in vacuo to give the enoic acid as a yellow solid. To this enoic acid (100 mg) was added toluene (5 mL) and thionyl chloride (2 mL). The mixture was heated to reflux for 1 hour and the solvent was distilled off under reduced pressure. The residue was taken up with toluene (5 mL) and to it was added anthranilic acid methyl ester (74 mg). The resulting mixture was heated to reflux for additional 1 hour. The solvent was removed and the residue was taken up with DMSO (6 mL). Only part of solid dissolved, the remaining solid was filtered and LC-MS showed it was mainly the desired compound, which was taken up with methanol (18 mL). To this mixture was added tosyl hydrazide (500 mg). The mixture was heated at reflux. After one day, an additional 300 mg of tosyl hydrazide was added. After two and a half days, the resulting mixture was concentrated and dissolved in acetone. The solution was directly purified by biotage (5%-25% ethyl acetate in petroleum ether) to give the anthranilide methyl ester as an oily solid. This methyl ester was dissolved in 5 mL of THF:MeOH: water (3:1:1) followed by LiOH (3 mL, 1 M). The mixture was stirred at rt for 4 hours. After Gilson purification, the acid was obtained as a white solid. To this methyl ether derivative was added 5 mL of dichloromethane and 0.23 mL of borontribromide (0.23 mL, IN in dichloromefhane) at O0C. After stirring at RT for 2h, the reaction was quenched by water at O0C. The mixture was concentrated in vacuo and then dissolved by DMSO. The DMSO solution was purified by Gilson to give Example 47 as a white solid. IH NMR (acetone-d6, 500 MHz) delta 11.42 (s, IH), 8.56 (d, IH), 8.07 (d, IH), 7.77 (d, IH), 7.70 (s, IH), 7.56 (t, IH), 7.15 (t, IH), 6.95 (d, IH), 6.84 (dd, IH), 3.34 (t, 2H), 2.88 (t, 2H); LCMS m/z 401 (M-I), 403 (M++l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In ethanol; toluene; for 5h;Heating / reflux; | To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (3.0 g, 11.3 mmol) in ethanol (10 mL) and toluene (40 mL), was added [NA2C03] (14.17 [ML,] 2 M), 2-chloro-4- methoxyphenylboronic acid (3.17 g, 17.0 mmol), and Pd (PPh3) 2Cl2 (0.48 g, 0.68 mmol) and the mixture was heated at reflux for 5h. The reaction was cooled and poured into EtOAc and H20 (500 mL). The EtOAc layer was washed with H20, brine, dried [(NA2SO4),] filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 1.51 g (36 %) of 2-benzyloxy-4- (2-chloro-4-methoxy-phenyl)-3-nitro-pyridine as a viscous oil: MS (AP) m/z 370.8 [[(M+H) +, 100].] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | [[00313]] 4, 6-Dichloro-5-aminopyrimidine (5.8 g, 0.036 mol) was diluted in [ETOH] (25 ml) and toluene (100 ml). A 2M [NA2CO3] (45.0 ml) was added followed by Pd (PPh3) 2Cl2 (1.5 g, 0.0021 mol), and <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (0.035 mol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over [ETOAC/H2O.] The organic layer was separated and washed with sat'd sodium chloride, dried [(MGS04),] filtered and concentrated. The material was flushed through a plug of silica using [50%] EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo and diluted in 5 ml butanol. [4-HEPTYAMINE] was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 80% EtOAc/hexane as the eluting solvent the desired intermediate [6- (2-CHLORO-4-METHOXY-PHENYL)-N4- (1-PROPYL-BUTYL)-] pyrimidine-4, 5-diamine was isolated (0.29 g, 73%). MS (AP) 349.3 [[(M+H) +,] 100]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium dihydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; nitrogen; water; at 80℃; for 3h; | Production Example 7 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 ML) and water (1 ML), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium (0) complex(0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80C for 3 hours under a nitrogen stream.. water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine, in that order.. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated. under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.1H NMR (400MHz, CDCl3) delta 1.30 (t, J = 7.6 Hz, 3H), 3.15 (q, J = 7.6 Hz, 2H), 3.90 (s, 3H), 6.96 (dd, J = 2.4, 8.4 Hz, 1H), 7.07 (dd, J = 1.6, 7.2 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.2, 8.8 Hz, 1H), 8.40 (dd, J = 1.6, 8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 16h; | Reference example 4 4-(2-chloro-4-methoxyphenyl)-5-methylisoxazole To a suspension of the compound prepared in reference example 3 (644 mg), 4-iodo-5-methylisoxazole (658 mg) and sodium bicarbonate (791 mg) in dimethoxyethane (2.5 ml) / water (2.5 ml), tetrakis (triphenylphosphine) palladium (36 mg) was added. The mixture was stirred for 16 hours at 80§C. To the reaction mixture that was cooled to room temperature, water and ethyl acetate were added. An insoluble matter was removed by filtration. An organic layer was separated from filtrate, it was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate = 19: 1 ? 15: 1) to give the title compound (637 m g) having the following physical data. TLC: Rf 0.44 (n-hexane: ethyl acetate = 3: 1); NMR (300MHz, CDCl3): delta 8.29 (brs, 1H), 7.16 (d, J = 8.4Hz, 1H), 7.04 (d, J = 2.4Hz, 1H), 6.87 (dd, J = 8.4, 2.4Hz, 1H), 3.84 (s, 3H), 2.41 (brs, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Example 94 tert-butyl (+-)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate The title compound was prepared by the method of Example 90 from tert-butyl (+-)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and corresponding <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (100 mg, 0.54 mmol), to afford after chromatographic purification the title compound (141 mg, 68%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) delta7.21 (d, 1H, J=8.4 Hz), 6.94-6.99 (m, 3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 441 (base, M+H). | |
68% | Example 94 tert-butyl (+-)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate The title compound was prepared by the method of Example 90 from tert-butyl (+-)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and corresponding <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (100 mg, 0.54 mmol), to afford after chromatographic purification the title compound (141 mg, 68%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) delta 7.21 (d, 1H, J=8.4 Hz), 6.94-6.99 (m, 3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (C1, NH3): 441 (base, M+H). | |
60% | tert-butyl (6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (187 mg, 1.0 mmol) to afford after chromatographic purification the title compound (133 mg, 60%). 1H NMR (CDCl3, 300 MHz) delta7.23 (d, 1H, J=8.8 Hz), 7.01 (s, 2H), 6.97 (s, 1H), 6.84 (dd, 1H, J=8.5, 2.6 Hz), 3.84-4.24 (m, 2H), 3.84 (s, 3H), 3.68-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.26 (m, 3H), 1.84-1.8 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 441 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate;Pd(PPh3)2Cl2; | Step A Tert-butyl (8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.15 g, 64%) was prepared by the general method of Example 89, step C from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (0.19 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. |
64% | With sodium carbonate;Pd(PPh3)2Cl2; | Step A Tert-butyl (8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.15 g, 64%) was prepared by the general method of Example 89, step C from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (0.19 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With sodium carbonate;Pd(PPh3)2Cl2; | Step A Tert-butyl (7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.053 g, 23%) was prepared by the general method of Example 89, step C from tert-butyl (7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (0.19 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; water; | Part I. A solution of the iodide compound from Part H (7.00 g, 26.1 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to 90 C., and treated with a hexane solution of n-butyllithium (16.5 mL, 1.6 M, 26.4 mmol). After 15 minutes, the solution was treated with triisopropylborate (6.10 mL, 26.4 mmol) and was allowed to warm to ambient temperature over 6 hours. The resulting mixture was treated with 6 N aqueous HCl (5 mL) and water (5 mL), which was stirred for 1 hour, then poured into water (100 mL) and extracted with ethyl acetate (2*100 mL). The extracts were washed in sequence with 1 N aqueous sodium bisulfite and brine (80 mL each), combined, dried over sodium sulfate, filtered and evaporated. The residual solid was triturated with 1:1 ether-hexane, collected by filtration and dried under vacuum to afford pure product, 2-chloro-4-methoxybenzeneboronic acid (3.05 g, 16.4 mmol, 63%). m.p. 191-195 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃; for 16h; | EXAMPLE 24; SYNTHESIS OF [3-(2-CHLORO-4-METHOXY-PHENYL)-2,5-DIMETHYL-PYRAZOLO[l,5- A]PYRIMIDIN-7-YL] - [ 1 -(3 -METHYL- [ 1 ,2,4] OXADIAZOL-5 - YL)-PROPYL] -AMINE; Step 24A; To Cmpd 5d (100 mgl) was added <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (70 mg) followed by potassium carbonate (80 mg) and a solution of dioxane/water (0.9 mL/0.2 mL). The reaction mixture was sparged with nitrogen for 5 min, then tetrakis(triphenyphosphine)palladium(0) (80 mg) was added, and the reaction vessel was sealed and heated at 850C for 16 hr. The solvent was evaporated, and the residue was purified directly by preparative thin-layer silica gel chromatography using 30% ethyl acetate in hexanes as eluant, providing Cmpd 24a as a solid (31 mg, 26%). LC/MS: 403.0 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The mixture of this bromoacid intermediate (0.71 g), the aryl boronic acid (0.67 g), Pd(PPh3)4 (323 mg), NaHCO3 solution (11.2 mL, 1 N) and dioxane (40 mL) was heated at 100 C. under nitrogen overnight in a sealed tube. The mixture was then partitioned between ethyl acetate and 1 N NaOH solution. The organic layer was washed with 1 N NaOH solution. The combined aqueous layers were acidified with concentrated HCl until pH=4-5. The resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine and dried with sodium sulfate. The removal of solvent afforded the biaryl product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 12h; | EXAMPLE 4; Commercially available 2-bromo-5-formylthiazole (5 g, 26 mmol) in tetrahydrofuran (50 mL) was cooled to 0 0C. To this solution was added portionwise, sodium <n="39"/>borohydride (1.23 g, 32 mmol), and the reaction mixture was stirred for 1 h at 0 0C, and then allowed to warm to room temperature and stirred for another hour. Upon reaction completion, water (100 ml) was added and the mixture was allowed to stir for 30 minutes. The reaction mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40M). To the corresponding thiazole-alcohol (3.87 g, 20 mmol) in CH2Cl2 (10OmL) at 0 0C was added carbon tetrabromide (13.2 g, 40 mmol) and triphenylphosphine (10 g, 40 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40 M). To a pre-cooled (0 0C) solution containing commercially available ethyl N-(diphenylmethylene) glycinate (2.87 g, 10.7 mmol) in tetrahydrofuran (18 mL), was added potassium tert-butoxide (1.2 g, 10.7 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at this temperature for 30 minutes and cooled to -78 0C. To this pre-cooled (-780C ) solution was added the thiazolyl bromide (1.83g, 7.1 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred at this temperature for 30 minutes, and then allowed to stir at room temperature for 1 h. A saturated solution of ammonium chloride (40 mL) was then added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Biotage 40M). To the corresponding Schiff base (3.17 g, 7.1 mmol) was added concentrated hydrochloric acid (9 mL), and the reaction mixture was allowed to stir for 1 h at room temperature. Following the completion of the reaction, the aqueous layer was washed 3 times with ethyl acetate (2OmL), and the aqueous layer was concentrated in vacuo. Without further purification, the amine (1.99g, 7.16 mmol) in CH2Cl2 (100 mL) was treated with triethylamine ( 2.89g, 29 mmol) and di- tert-butyl dicarbonate (3.1g, 14.3 mmol). The reaction mixture was stirred for 12 h at room temperature. Upon reaction completion, a saturated solution of sodium bicarbonate (100 mL) was added, and the mixture was allowed to stir for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Biotage 40 M). To the amino acid (0.82g, 2.1 mmol) in toluene (20 mL) was added (2- chloro-4-methoxyphenyl)boronic acid ( 0.81 g, 4.3 mmol), tetrakis-triphenylphosphine palladium (0.12 g, 0.1 mmol), and potassium carbonate (0.89 g, 6.4 mmol). The reaction mixture was heated to 100 0C for 12 h. Following the reaction completion, the mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40M). To the desired amino acid (0.57g, 1.3 mmol) in tetrahydrofuran (6 mL) was added water (6 mL), methanol (1 mL), and lithium hydroxide (0.12 g, 5.2 mmol). The biphasic reaction mixture was allowed to stir at room temperature for 12 h. The mixture was concentrated in vacuo, diluted with 10 mL of water, cooled to 0 0C and acidified with concentrated HCl to a pH of 3. The acidic solution was extracted three times with ethyl acetate (10 mL), and the organic extracts were dried with sodium sulfate and concentrated in vacuo. Without further purification, the carboxylic acid (0.14 g, 0.33 mmol) in tetrahydrofuran (5 mL) at -20 0C was treated with 4-methylmorpholine (0.067 g, 0.67 mmol), followed by the dropwise addition of isobutyl chloroformate (0.045 g, 0.33 mol). The reaction mixture was stirred for 10 minutes, followed by the <n="40"/>addition of ethyl-2-aminobenzoate (0.11 g, 0.67 mmol). The mixture was stirred at -20 0C for 2 h and then room temperature for 12 h. Following the reaction completion, the precipitate was filtered off and the filtrate was concentrated in vacuo and purified via flash chromatography (Biotage 40S). To the purified anthranilic acid derivative (18 mg, 33 mmol) in CH2Cl2 (3 xnL) at 0 0C, was added borontribromide (IM, 0.33 mmol). The mixture was allowed to stir at 0 0C for 10 minutes and then room temperature for 1 h. Following the reaction completion, water (10 mL) was added, and the Triphasic mixture was stirred for 10 minutes. The reaction mixture was then concentrated in vacuo, diluted with 10 mL of water, cooled to 0 0C and basified with sodium hydroxide to a pH of 14. The basic reaction mixture was allowed to stir for 12 h at room temperature. The mixture was concentrated in vacuo and then diluted with water (2 mL). The aqueous solution was acidified with concentrated hydrochloric acid (pH= 3) and then purified by reverse phase HPLC (Gilson) to provide the de... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃; for 6h; | To a mixture of delta-bromo^-trifluoromethyl-isonicotinonitrile 1-1 (2.51 g, 10 mmol) in dioxane (3.3 mL) and water (3.3 ml_), were added 2-chloro-4- methoxyphenylboronic acid (2.3 g, 12.5 mmol) and Na2CO3 (6.3 g). The mixture was purged with nitrogen gas for 10 min, then Pd(PPh3)4 (1.2 g, 1.0 mmol) was added. The mixture was stirred in a sealed vessel at 85 0C for 6 hrs, then extracted by ethyl acetate. The organic layer was washed with water, dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (10/1 ) yielded 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (1.31 g). tR = 2.96 min (method 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference example 3 2-chloro-4-methoxyboronic acid A solution of 3-chloro-4-bromoanisole (2.14 g) in anhydrous tetrahydrofuran (10 ml) was cooled at -78§C. 1.56 M n-butyl lithium / hexane (6.5 ml) was dropped into the solution, and the mixture was stirred for 30 minutes. Triisopropyl borate (2.3 ml) was dropped into the reaction mixture, and the mixture was stirred for 2 hours at -78§C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. A obtained solid was washed with t-butyl methyl ether (4 ml), filtered and dried over to give the title compound (681 mg) having the following physical data. TLC: Rf 0.55 (methylene chloride: methanol = 19: 1); NMR (300MHz, CDCl3): delta 7.22 (d, J = 8.4Hz, 1H), 6.93 (d, J = 2.4Hz, 1H), 6.86 (dd, J = 8.4, 2.4Hz, 1H), 3.79 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In ethanol; water; toluene; at 90℃; | Method 1G; Method 1A was used with the following exceptions: K2CO3 as the base, EtOH (0.15 M):water:toluene (2:1:1) as the solvent. The reaction was heated in the microwave at 50 C. for 2 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 37 5-[6-(2-Chloro-4-methoxy-phenyl)-pyridazin-3-ylmethyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine (Compound 228) From 5-(6-chloro-pyridazin-3-ylmethyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 2-chloro-4-methoxy-phenyl boronic acid following general procedure A. MS 465.0 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.63 (s, 1H), 9.81 (s, 1H), 7.98-8.20 (m, 3H), 7.74-7.80 (m, 1H), 7.56-7.58 (m, 1H), 7.47-7.54 (m, 1H), 7.22-7.23 (m, 1H), 7.07-7.12 (m, 1H), 6.48 (s, 2H), 3.84 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 20 - 80℃; | Step 3 4-[2-(2-Chloro-4-methoxy-phenyl)-1-trifluoromethanesulfonyl-1H-indol-5-yl]-3-methyl-benzonitrile Trifluoro-methanesulfonic acid 5-(4-cyano-2-methyl-phenyl)-1-trifluoromethanesulfonyl-1-indol-2-yl ester (31 mg, 0.06 mmol) and 2-Chloro-4-Methoxyphenylboronic acid (13.5 mg, 0.073 mmol) were mixed with toluene (0.5 ml), EtOH (0.3 ml) and NaHCO3 (19.2 mg, 0.018 mmol) aqueous solution (0.2 ml), while the mixture was degassed with N2, a catalytic amount of Pd(Ph3P)4 was added, the reaction mixture was heated to 80 C. for 3 hours, stirred overnight at room temperature; partitioned between EtOAc and water, the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by the filtering through a pad of silica gel (5% EtOAc/hexanes) to give 4-[2-(2-chloro-4-methoxy-phenyl)-1-trifluoromethanesulfonyl-1H-indol-5-yl]-3-methyl-benzonitrile as a white solid (30 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 2h; | Example 60Synthesis of N-[(E)-3-(2'-chloro-4'-hydroxy-biphenyl-2-yl)-2-methyl-acryloyl]-guanidine<Step 1>Intermediate 1 (50 mg, 0.126 mmol) and <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (25.9 mg, 0.139 mmol) were dissolved in a mixed solution of dioxane and water (v/v=3/1, 2.0 mL). Pd(PPh3)4 (8.04 mg, 6.95 mumol) and Na2CO3 (41.6 mg, 0.378 mmol) were added to the solution and then stirred at 90 C. for 2 hours. After cooling it to room temperature, the solvent was eliminated in vacuo and then purified by reversed phase HPLC (0.1% TFA in water/CH3CN) to obtain the objective coupling product (38.9 mg, 67.6%).MS: 345 |
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