Structure of 957198-30-0
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CAS No. : | 957198-30-0 |
Formula : | C14H22BN3O3 |
M.W : | 291.15 |
SMILES Code : | CC1(OB(C2=CN=C(N3CCOCC3)N=C2)OC1(C)C)C |
MDL No. : | MFCD07368246 |
InChI Key : | HNVAYPJNFUXYII-UHFFFAOYSA-N |
Pubchem ID : | 16414213 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 21 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.71 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 84.23 |
TPSA ? Topological Polar Surface Area: Calculated from | 56.71 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 | 1.27 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 0.23 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | -0.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 0.72 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 0.44 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.52 |
Solubility | 0.87 mg/ml ; 0.00299 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.06 |
Solubility | 2.54 mg/ml ; 0.00871 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.43 |
Solubility | 0.108 mg/ml ; 0.000371 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) | Yes |
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 | -7.17 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 | 0.0 |
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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 3.16 |
* 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 |
---|---|---|
39% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 100.0℃; for 0.5h;microwave irradiation; | 2-(4-Morpholino)pyrimidine-5-boronic acid pinacol ester (300 mg, 1.03 mmol), 1,2- dibromobenzene (243 mg, 1.03 mmol), Bis(triphenylphosphine)palladium (II) chloride (72 mg, 0.10 mmol), aqueous Na2CO3 (2N, 2.58 mL, 5.15 mmol) and DMF (5 mL) are added to a 10 mL microwave tube. Reaction is carried out in a microwave oven at 100 0C for 30 min. The reaction mixture turns black. The mixture is poured into water and extracted with EtOAc. The organic layers are washed with water, brine, dried (Na2SO4) and concentrated. The crude product is purified using biotage eluting with 0-30% EtOAc/Hexane. The desired mono-coupled product elutes at 30% EtOAc. The di- coupled by-product elutes earlier. Removal of the solvent gives 4-[5-(2-bromo-phenyl)- pyrimidin-2-yl]-morpholine as a white solid (130 mg, 39%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.4% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110.0℃; for 0.166667h;Inert atmosphere; Microwave irradiation; | Example 107 Ethyl 2-(3-(4-((3-(2-morpholinopyrimidin-5-yl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 107) To a solution of ethyl 2-(3-(4-((3-bromobenzyl)oxy)phenyl)oxetan-3-yl)acetate (compound of Step 1 a of Example 39, 120 mg, 0.296 mM) and 4-(5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (103 mg, 0.355 mM) in 4 ml dioxane:water (4:1 ), potassium carbonate (82 mg, 0.592 mM) was added and the mixture was degassed with argon for 3 min. To the resulting solution palladium tetrakistriphenylphosphine (17.10 mg, 0.015 mM) was added and the mixture was heated at 1 10 QC for 10 min in microwave. After completion of the reaction, reaction mixture was extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain the compound ethyl 2-(3-(4-((3-(2-morpholinopyrimidin-5- yl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (104 mg), as white solid. Yield: 71 .4 %; 1 HNMR (300 MHz, CDCI3) delta: 8.74 (s, 2H), 7.72 (s, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.50-7.40 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 5.14 (s, 2H), 4.75 (s, 4H), 3.90 (q, J = 7.2 Hz, 2H), 3.75 (d, J = 4.5 Hz, 4H), 3.67 (d, J = 4.5 Hz, 4H), 3.08 (s, 2H), 1.02 (t, J = 7.2 Hz, 3H); MS: (e/z) 490.4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 105.0℃; for 18h;Inert atmosphere; | Example 445 Method O 1-[2-(Difluoromethoxy)benzyl]-2-(methoxymethyl)-6-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-benzimidazole To Example 444 (50 mg, 0.12 mmol) were added <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (44 mg, 0.144 mmol), Pd(PPh3)4 (7.5 mg, 0.006 mmol), 2M aqueous Na2CO3 solution (0.5 mL) and 1,4-dioxane (2.5 mL). The reaction mixture was flushed with nitrogen and heated to 105 C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to ambient temperature, MP-TMT resin (Biotage, 0.76 mmol/g, 300 mg, 0.25 mmol) was added and the solution was agitated at room temperature overnight. Ethyl acetate (20 mL) was added and the mixture was passed through a silica pad cartridge, eluting with further ethyl acetate (2*5 mL) and finally a solution of 20% methanol in ethyl acetate (2*10 mL). The combined organic phases were concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC to give the title compound (17 mg, 30%) as a white solid. LCMS (pH 3) M+H 483, RT 1.92 minutes, UV purity 100%; LCMS (pH 10) M+H 483, RT 2.23 minutes, UV purity 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90.0℃;Inert atmosphere; | To a mixture of N- (3- ( (7-bromo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) oxy) phenyl) acrylamide (0.41 g, 0.84 mmol) , 4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl) morpholine (0.5 g, 2 mmol) , Pd (dppf) Cl2(0.1 g, 0.1 mmol) and potassium carbonate (0.20 g, 1.4 mmol) were added 1, 4-dioxane (20 mL) and water (5 mL) . The system was exchanged with N2and sitrred at 90 overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM/MeOH (v/v) 9/1 to give a yellow solid product (0.24 g, 51) .[1820]MS (ESI, pos. ion) m/z: 574.8 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90.0℃;Inert atmosphere; | A mixture of 4- (5-bromopyrimidin-2-yl) morpholine (2.01 g, 8.23 mmol) , bis (pinacolato) diboron (3.8 g, 15 mmol) , potassium acetate (2.5 g, 25 mmol) and Pd (dppf) Cl2(0.61 g, 0.83 mmol) in 1, 4-dioxane (30 mL) was stirred at 90 under N2overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 7/3 to give a white solid product (0.4 g, 88) .[1817]MS (ESI, pos. ion) m/z: 292.0 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 110.0℃; for 1h;Inert atmosphere; Microwave irradiation; | 100 mg (0.25mmol) 7-chloro-N- [(4-ethoxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl] -1- isopropylimidazo[1,5-a]pyridine-5-carboxamide (intermediate 201A), 79,5 mg (0.27 mmol) <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> and 29 mg (25 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.5 mmol) aqueous sodium carbonate solution (2N), 0.8 ml ethanol und 1.5 ml 1 ,2-dimethoxyethane was added and the resulting mixture heated for 1 h to 110 C in a Biotage Initiator microwave oven. The reaction mixture was concentrated in vacuo and the residue re10 dissolved in DM50, filtered and purified by HPLC (preparative HPLC conditions 1) to yield 37.5mg (28%) of the target compound.?H NMR (400 MHz, DMSO-d6) oe [ppm] = 1.23 (t, 3 H), 1.29 (d, 6 H), 2.17 (s, 3 H), 3.43 (sept, 1 H), 3.67-3.75 (m, 8 H), 4.09 (q, 2 H), 4.34 (d, 2 H), 6.08 (s, 1 H), 7.46 (s, 1 H), 8.04 (s, 1 H), 8.61(t, 1 H), 8.86 (s, 1 H), 8.88 (s, 2 H), 11.44 (s, 1 H).LCMS (conditions 2.1): R 0,9 mm; MS (ESI): [M + H] = 532. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 1.5h;Microwave irradiation; | Example 144A N-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanine 3-Bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine (368 mg, 0.76 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> were dissolved in dimethyl sulphoxide (6 ml), and tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.076 mmol), sodium carbonate (242 mg, 2.3 mmol) and water (1.15 ml, 63.6 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min and then purified chromatographically by HPLC (Method 8). This gave 61 mg (14% of theory) of the title compound. 1H NMR (300 MHz, DMSO-d6): delta=ppm 0.66-0.86 (m, 2H), 1.03-1.27 (m, 3H), 1.35 (s, 9H), 1.44-1.69 (m, 5H), 1.87-2.02 (m, 1H), 2.65-2.76 (m, 2H), 2.94 (dd, 1H), 3.09 (dd, 1H), 3.60-3.76 (m, 8H), 3.87-3.98 (m, 1H), 6.65-6.81 (m, 1H), 6.94 (d, 1H), 7.03 (d, 1H), 7.23 (t, 1H), 7.27-7.41 (m, 2H), 8.62 (s, 2H). LC-MS (Method 4): Rt=1.12 min; MS (ESIpos): m/z=568.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 2.5h;Microwave irradiation; | Example 110A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (111 mg, 0.38 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 150 min and reacted further as crude product. LC-MS (Method 4): Rt=1.15 min; MS (ESIpos): m/z=711.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 2h;Microwave irradiation; | Example 128A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.23 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (99 mg, 0.34 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 mumol), sodium carbonate (72 mg, 0.68 mmol) and water (0.34 ml, 19 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 120 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 43 mg (25% of theory) of the title compound. LC-MS (Method 4): Rt=1.26 min; MS (ESIpos): m/z=744.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 1.5h;Microwave irradiation; | Example 124A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]-L-phenylalaninamide (150 mg, 0.23 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (107 mg, 0.35 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 gmol), sodium carbonate (74 mg, 0.70 mmol) and water (0.35 ml, 19.5 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified by chromatography via HPLC (Method 9). This gave 15 mg (9% of theory) of the title compound. LC-MS (Method 4): Rt=1.19 min; MS (ESIpos): m/z=726.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In N,N-dimethyl-formamide; at 120.0℃; for 0.5h; | Example 86A 3-{5-[4-({N-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanyl}amino)phenyl]-1H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoic acid 125 mg (0.16 mmol) of methyl 3-{5-[4-({4-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanyl}amino)phenyl]triazol-3-yl}-2,2,3,3-tetrafluoropropanoate and 93 mg (0.32 mmol) of <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> were dissolved in 1.3 ml of dimethylformamide, 0.16 ml (0.32 mmol) of 2 M sodium carbonate solution was added and the mixture was degassed. After addition of 12 mg (0.02 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, the reaction mixture was stirred at 120 C. for 30 min. The reaction solution was filtered through a Millipore syringe filter and purified via preparative HPLC (mobile phase: acetonitrile/water with 0.1% trifluoroacetic acid (gradient)). This gave 72 mg (51% of theory) of the title compound. LC-MS (Method 1): Rt=0.95 min; MS (ESIpos): m/z=854.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Example 26A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide formate 4-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (107 mg, 0.36 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 120 min, cooled, filtered and purified by chromatography via HPLC (Method 9). This gave 28 mg (18% of theory) of the title compound. LC-MS (Method 4): Rt=1.19 min; MS (ESIpos): m/z=711 [M+H-HCOOH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90.0℃; for 16h;Inert atmosphere; Sealed tube; | A mixture of tert-butyl 8-bromo-7-methyl-3,4-dihydroimidazo [1,2-a: 5,4-b?j dipyridine- 1 (2H)-carboxylate (200 mg, 0.546 mmol), (6-methoxypyridin-3 -yl)boronic(84 mg, 0.546 mmol), 2 M solution of aqueous potassium carbonate (426 pi, 0.852mmol), and dioxane (4 mL) was purged with bubbled nitrogen for 10 mm. PdC12(dppf)- CH2C12 adduct (44.6 mg, 0.055 mmol) was added, the vial was purged with nitrogen, sealed with a Teflon cap and heated at 90 C for 16 h. The reaction mixture was cooledroom temperature and added to a saturated solution of aqueous sodium bicarbonate.mixture was extracted with ethyl acetate. The combined organic layers were washedbrine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (100% ethyl acetate) to afford tert-butyl 8-(6-methoxypyridin-3-yl)-7-methyl-3 ,4-dihydroimidazo[ 1,2-a: 5 ,4-b?j dipyridine-1(2H)-carboxylate (189 mg, 0.455 mmol, 83% yield). Following the metal-mediated coupling procedure and purification method used in the preparation of Intermediate 1 B, tert-butyl 8-bromo-3,4-dihydroimidazo[ 1,2-a: 5,4-b?j dipyridine-1(2H)-carboxylate (Intermediate 5A, 120 mg, 0.341 mmol) was reacted with 4-(5 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (109 mg,0.375 mmol) to afford tert-butyl 8-(2-morpholinopyrimidin-5 -yl)-3 ,4-dihydroimidazo[1,2-a:5,4-b?jdipyridine-1(2H)-carboxylate (120 mg, 0.275 mmol, 81% yield). LC/MS (M+H) 437.3; ?H NMR (500MHz, chloroform-d) oe 8.56 (s, 2H), 8.01 (s, 1H), 7.57 (d, J9.3 Hz, 1H), 7.25 (dd, J9.3, 1.7 Hz, 1H), 3.84 (dt, J33.3, 4.5 Hz, 1OH), 2.97 (t, J=6.6 Hz, 2H), 2.12 (dq,J=6.5, 5.8 Hz, 2H), 1.50 (br. s., 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85.0℃; for 0.75h;Inert atmosphere; | General procedure: Step 7: r c-(l ?,9b ?)-l-(2-(Difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2^-dihydro- lH-pyrrolo[2,l-a]isoiiidoI-5(9bH)-oise A flask under nitrogen was charged with 8-bromo-l-(2-(difluorometlioxy)phenyl)-2,3-diliydro-lH- pyrrolo[2,l -a]isoindol-5(9bH)-one (0.090 g, 0.228 mmol) as an approximately 1 :1 mixture of diastereomers, 1 ,4-dioxane (4 mL) and water (1 mL), 4-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)mo:^oline (0.073 g, 0.251 mmol), cesium carbonate (0.149 g, 0.457 mmol) and PdCl2(PPh3)2 (0.01 1 g, 0.016 mmol). The mixture was heated to about 85 C for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. The material was purified by preparative reverse phase chromatography (Table C, Method 1). The shorter Rt compound fraction was lyophilized to give the title compound (0.0206 g, 19%); LC/MS (Table A, Method a) R. = 2.20 min; MS m/z: 479 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19%; 22% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85.0℃; for 0.75h;Inert atmosphere; | Step 7: r c-(l ?,9b ?)-l-(2-(Difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2^-dihydro- lH-pyrrolo[2,l-a]isoiiidoI-5(9bH)-oise A flask under nitrogen was charged with 8-bromo-l-(2-(difluorometlioxy)phenyl)-2,3-diliydro-lH- pyrrolo[2,l -a]isoindol-5(9bH)-one (0.090 g, 0.228 mmol) as an approximately 1 :1 mixture of diastereomers, 1 ,4-dioxane (4 mL) and water (1 mL), 4-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)mo:^oline (0.073 g, 0.251 mmol), cesium carbonate (0.149 g, 0.457 mmol) and PdCl2(PPh3)2 (0.01 1 g, 0.016 mmol). The mixture was heated to about 85 C for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. The material was purified by preparative reverse phase chromatography (Table C, Method 1). The shorter Rt compound fraction was lyophilized to give the title compound (0.0206 g, 19%); LC/MS (Table A, Method a) R. = 2.20 min; MS m/z: 479 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 80.0℃; for 2.5h; | Step 4: rac-(l/^10bli)-l-(2-(Difluoromethoxy)phenyl)-9^^ 1 H~ [ 1 ,4] ox azi n o [3,4-a] isomdol-6( 10bH)~oae A flask under nitrogen was charged with with rac-(li?J 0bi?)-9-bromo-l-(2-(difluoromethoxy)phenyi)- 3,4-dihydro-lH-[l,4]oxazino[3,4-]isoindol-6(10bH)-one (0.200 g, 0.488 mmol), 4-(5-(4,4,5,5- tetramethyi-l,3,2-dioxaboroian-2-yl)pyrimidin-2-yl)moi"pholine (0.170 g, 0.585 mmol), 1,4-dioxane (8 mL), water (2 mL), cesium carbonate (0.238 g, 0.731 mmol) and dCi?i i'Pi i - (0.0342 g, 0.049 mmol). The mixture was warmed to about 80 C for about 2.5 h then cooled to rt, diluted with EtOAc (70 mL) and washed with water (2 x 10 mL). The organic layer was dried over MgS04 then filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (5- 80% EtOAc/heptane). The appropriate fractions were collected and concentrated under reduced pressure to give the title compound (0.150 g, 59%); LC/MS (Table A, Method a) R, = 2.13 min; MS m/z: 495 (M?H) FontWeight="Bold" FontSize="10" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90.0℃; for 0.5h;Inert atmosphere; | Example 1 : 3-(2-(Difluoromethoxy)phenyl)-6-(2-morphoIinop rimidin-5-yl)-2,3- dihydropyrizoIo[i,2-a]indaz I-9(Ui)-osie 6-Bromo~3-(2-(difluoromethoxy)phenyj)-2,3~dihydiOpyrazolo[l ,2-a]indazol-9(l H)-one (0.400 g, 1.012 mmol) (Preparation 1), 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimLdin-2-yl)mophiholine (0.442 g, 1.52 mmol) and cesium carbonate (0.989 g, 3.04 mmol) were added to a flask with 1,4-dioxane (3 mL) and water (0.75 mL). The flask was purged and flushed with N2. Pd(Ph3P)4 (0.082 g, 0.071 mmol) was then added and mixture was purged again and then heated to 90 C under N2 for about 30 min. The mixture was cooled to rt and aqueous sodium bicarbonate solution (5 ml.) and EtOAc (10 ml,) were added. The acqueous layer was extracted with EtOAc (3 x 5 mL), then the organics were dried over MgS04 and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (0 - 100% EtOAc/DCM then 0 - 10% MeOH/DCM). The fractions were concentrated then purified further via flash chromatography on silica gel (100% EtOAc) to give the title compound (0.335 g, 69%). LC/MS (Table A, Method a) R, - 2.07 min; MS m/z 480 (M+H) TNF IC50 = A |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; for 0.2h;Reflux; | Example 12: 3-(2-Methoxyphenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[l,2- oliiK A mixture of 2-(4-iotaetaomicron 1iotaomicron1etaomicron)rho)tau iotaeta{eta6-5-BetathetaGammaomicroneta? acid pinacol ester (0.063 g, 0.217 mmol), 6-bromo- 3-(2-mefhoxyphenyl)-2,3-dihydropyrazolo[l ,2-a]inda5:ol-9(lH)-one (0.052 g, 0.145 mmol) (Preparation 17), Pd(Ph3P)4 (0.017 g, 0.014 mmol), and cesium carbonate (0.141 g, 0.434 mmol) in 1,4-dioxa.ne ( 1.2 mLVwater (0.3 mL) was heated at reflux for about 12 min. After cooling, the reaction mixture was partitioned between EtOAc (5 mL) and water (5 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 2 mL). The combined organics were washed with saturated aqueous NaCl (5 mL), dried over Na2S0 , filtered, and concentrated under reduced pressure. The material was purified via flash chromatography on silica gel (0-50% of 1 :9 MeOH:EtOAc/DCM) to give the title compound (0.056 g, 87 %).; LC/MS (Table A, Method a) R, - 2.03 min; MS m/z: 444 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90.0℃; for 2h;Inert atmosphere; | Preparation 2 : 2-MethyI-6-(2-morpholinopyrimidin-5- l)-lH-indazol-3(2H)- i'dl PPh ; ') FontWeight="Bold" FontSize="10" (0.6 g, 0.5 mmol) was added to a suspension of 6-bromo-2-methyl-lH-indazol-3(2H)-one (1.67 g, 7.35 mmol) (Preparation 1), 4-(5-(4,4,5,5 elTamethyl-l ,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)morpholine (2.57 g, 8.83 mmol) and CsiC03(5.99 g, 18.4 mmol) in 1 ,4-dioxane (20 mL) and water (5.0 mL) under N2. The mixture purged with N2 and then heated to about 90 C for about 2 h. The reaction mixture was allowed to cool to rt. DCM (30 mL) with a few drops of MeOH and water (20 mL) were added. The solid was collected by filtration then dried to give the title product (1.88 g, 82%); LC/MS (Table A, Method e) R, = 1.41 min; MS m/z; 312 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100.0℃; for 2h;Inert atmosphere; | Example 5: l-(2-(Difluoromethoxy)bcnzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-lH-i 3(2H)-one 1,4-Dioxane (2 mL) and water (0.5 mL) were added to 6-bromo- l ~(2-(difluoromethoxy)benzyl)~2-methyl~ lH-indazol-3(2H)-one (0.060 g, 0.16 rnmol) (Preparation 4, step 1), 4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (0.059 g, 0.20 rnmol) and Cs2C03 (0.128 g, 0.391 rnmol). The mixture was placed under N2. Pd(PPh3)4 (0.013 g, 1 1 muiotaetaomicron) was added. The mixture was purged with N2 and then heated to about 100 C. After about 2 h, the reaction mixture was allowed to coo to rt. Water (5 mL) was added and then the mixture was extracted with 5% MeOH/DCM (2 x 1 0 mL). The combined organics were dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10-100% EtOAc/DCM) to give the title product (60 mg, 82%); LC/MS (Table A, Method a) R, = 2.07 min; MS m/z: 468 ( M i l s ' t/i X iC50 = A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85.0℃; for 0.75h;Inert atmosphere; | Step 4: l-(2-(Dflsoromettooxy)foeizy)-2-mettoy-6^ b]pyridiii-3(2H)-one A mixture of 6-bromo-l-(2-(difluoromethoxy)benzyr)-2-methyl-lH-pyrazolo[4,3-b]pyridin-3 (0.025 g, 0.065 rnmol, 4-(5~(4,4,5,5 etramethyl~l,3,2~dioxaborolan^ (0.023 g, 0.078 mmol), cesium carbonate (0.045 g, 0.14 mol) and PdCl2(PPh3)2 (0.004 g, 0.006 mmol) in 1,4-dioxane (1 mL) and water (0,25 mL) was degassed with N2 then heated to about 85 C for about 45 min. The reaction mixture was cooled, filtered through a 0.45 muMu filter then purified by preparative reverse phase ITPLC (Table A, Method c). Lyophilization of the appropriate fractions yielded the title compound (0.012 g, 40%); LC/MS (Table A, Method a) R, = 1.88 min; MS m/z: 469 (M+H)+(TNF 1C50 = C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 100.0℃; for 0.5h;Inert atmosphere; | Step 4: l-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-lH-pyrazolo[3,4- b]pyridin-3(2H)-one A mixture of 6-chloro- 1 -(2-(difluoromethoxy)benzyl)-2-methyl- lH-pyrazolo[3,4-b]pyridin-3(2H)-one (0.075 g, 0.22 mmol), 4-(5-(4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)moipholine (0.081 g, 0.28 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in 1 ,4-dioxane (2 ml.) and water (0.5 mL) under N2 was treated with PdCT2(PPh3)2 (0.011 g, 0.015 mmol). The mixture was purged with 2 and then heated to about 100 C for about 30 min. The reaction mixture was cooled, filtered through a 0.45 muMu filter then purified by preparative reverse phase HPLC (Table A, Method d). Lvophilization of the appropriate fractions yielded the title compound (0.086 g, 83%); LC/MS (Table A, Method a) R, = 2.15 min; MS m/z: 469 (M?H)+ (TNF IC50 = B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 100.0℃; for 1h;Inert atmosphere; | Step 4: l-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-lH-pyrazolo[4,3- c]pyridin-3(2H)-one A mixture of 6-chloro-l -(2-(difluoromethoxy)benzyl)-2-memyl-lH^yrazolo[4,3-c]pyridin-3(2/i)-one (0.270 g, 0.795 mmol), 4-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (0.301 g, 1.03 mmol), cesium carbonate (0.647 g, 1.99 mmol), 1 ,4-dioxane (6.0 mL) and water (1.5 ml,) was degassed with N2. PdCl2(PPh3)2 (0.056 g, 0.079 mmol) was added to the mixture. The reaction was degassed under N2 and heated at about 100 C for about 1 h then allowed to cool to rt. The reaction mixture was partitioned between EtOAc (30 mL) and sat. aq. NaCl (30 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The material was purified via flash chromatography on silica gel (0-3% MeOH/DCM) to yield the title compound (0.280 g, 71%); LC/MS (Table A, Method e) R, = 1.88 min; MS m/z: 469 (M+H)+. (TNF IC50 = C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; at 100.0℃; for 4h;Sealed tube; | In a 4 mL vial equipped with a magnetic stirrer was added 7-bromo-4-phenyl-3,4-dihydro-lH- benzo[4,5]imidazo[2, l-c][l,4]oxazine (0.100 g, 0.304 mmol, Preparation 26), 4-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)mophiholine (0.133 g, 0.456 mmol), and Pd(dppf)Cl2 FontWeight="Bold" FontSize="10" DCM (0.024 g, 0.030 mmol). 4 mL of dry, degassed 1,4-dioxane was added to the vial followed by the addition of 1M Cs2C03 (0.600 mL, 0.6 mmol). The vial was sealed and heated at about 100 C for about 4 h. The mixture was filtered through Celite, and evaporated to dryness, and purified by flash-column chromatography on silica gel (1-10% MeOH/DCM) to obtain the title compound (0.071 g, 64%); LC/MS (Table 1, Method e) P = 1.36 min; MS m/z: 414 (M+H)+ . (TNF IC50=A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90.0℃; for 24h;Inert atmosphere; | General procedure: To a mixture of tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (2; 226 mg, 0.63 mmol) in DME (2.3 mL)/water (1.1 mL) were added 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (3a; 193 mg, 0.66 mmol), Na2CO3 (201 mg, 1.90 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol)under a nitrogen atmosphere. The mixture was stirred at 90 C for 24 h. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with waterand extracted with CHCl3. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH = 98:2), and washed with iPr2O to give the product (230 mg, 83%) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With [(1,2-bis(diphenylphosphino)ethane)CuCl]; sodium t-butanolate; In toluene; at 50.0℃; for 2h;Glovebox; Sealed tube; | In the glove box, the DPPECuCl (25 mg, 10 muM %) and NaOt Bu (15 mg, 30 muM %) is added to the in tube sealing, and then adding <strong>[957198-30-0]4-(5-(boronic acid pinacol ester)pyrimidine-2-yl)morpholine</strong> (0.5 mmol, 1.0 equiv, 146 mg) and compound I-1 (0.6 mmol, 1.2 equiv, 178 mg), 2 ml toluene, 50 C stirring 2 h. After the reaction, steaming and under reduced pressure, the residue passes through the rapid silica gel column chromatography, to obtain white solid 143 mg, yield 88%. After hydrogen spectrum identifying the purity of greater than 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80.0℃; for 2.5h;Inert atmosphere; | General procedure: To a solution of 4-(5-bromopyrimidin-2-yl)morpholine (17;4.10 g, 16.8 mmol) and ethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (6.34 g, 21.8 mmol) in DME(82 mL)/H2O (41 mL) were added Na2CO3 (5.34 g, 50.4 mmol),and Pd(PPh3)4 (1.94 g, 1.68 mmol) under an argon atmosphere.The mixture was stirred at 80 C for 2.5 h. After being cooled toroom temperature, the mixture was diluted with H2O and EtOAc.The mixture was filtered, and the filtrate was separated. Theorganic layer was washed with H2O and brine, dried over Na2SO4,and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (hexane/EtOAc = 17:3 to 3:2) and columnchromatography on amino functionalized silica gel (hexane/EtOAc = 9:1 to 7:3) to give the product (5.29 g, 96%) as a colorlesssolid. 1H NMR (DMSO-d6): d 1.19 (3H, t, J = 7.1 Hz), 3.64-3.79 (8H,m), 3.72 (2H, s), 4.10 (2H, q, J = 7.1 Hz), 7.25 (1H, d, J = 7.6 Hz),7.35-7.45 (1H, m), 7.50-7.58 (2H, m), 8.70 (2H, s); MS (ESI) m/z[M+H]+ 328. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 120.0℃; for 1h;Microwave irradiation; Inert atmosphere; | In a 5 niL microwave vial N-(5-bromo-4-fluoro-2-(4-methylpiperazin- l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (29.67 mg, 0.062 mmol), <strong>[957198-30-0]2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester</strong> (54.3 mg, 0.187 mmol), sodium carbonate, anhydrous (65.9 mg, 0.622 mmol), XPhos (5.93 mg, 0.012 mmol) and XPhos Pd G2 (9.78 mg, 0.012 mmol) were dissolved in water (1166 mu) and 1,4-dioxane (1943 mu) to give a white suspension. The suspension was stirred for 5 min, degassed, purged with N2, and micro waved for 60 min at 120 C. The solvent was evaporated and 15 ml of CH2CI2 were added. The suspension was sonicated and extracted from water. The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0- 100%, 89% CH2CI2, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound in 61% yield. 11H NMR (500 MHz, MeOD) delta 8.55 (s, 2H), 7.97 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 3.86 - 3.82 (m, 4H), 3.78 - 3.74 (m, 4H), 3.01 (s, 4H), 2.66 (s, 4H), 2.37 (s, 3H); LCMS [M+H]+ 562.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 110.0℃; for 2h;Microwave irradiation; | To a 20 mL microwave vial charged with (2S,6R)-4-(4-bromo-5-fluoro-2- nitrophenyl)-l,2,6-trimethylpiperazine (1.04 g, 3 mmol), 2-(4^omicron etaomicron1etaomicron^etaetaeta^eta6-5- boronic acid pinacol ester (1.22 g, 4.2 mmol), and Pd(dppf)Cl2 (220 mg, 0.3 mmol, 10 mol%) was added dioxane (10 mL), followed by 1 M aq K3PO4 (5.0 mL, 5 mmol). The resulting mixture was irradiated in microwave at 110 oC for 2 h, diluted with H20 (10 mL) and extracted with EtOAc (30 mL x 2). The combined extracts were concentrated and purified by Biotage SNAP KP-Sil and 100 g column (EtO Ac/hex 0-100% then MeOH/DCM 0-15%) to give the crude nitro. LCMS [M+H]+ = 431.3. |
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