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[ CAS No. 102791-87-7 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 102791-87-7
Chemical Structure| 102791-87-7
Chemical Structure| 102791-87-7
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Product Details of [ 102791-87-7 ]

CAS No. :102791-87-7 MDL No. :MFCD09834629
Formula : C10H11N3 Boiling Point : -
Linear Structure Formula :- InChI Key :PJUPTRYCQKQLCI-UHFFFAOYSA-N
M.W : 173.21 Pubchem ID :16005170
Synonyms :

Calculated chemistry of [ 102791-87-7 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 11
Fraction Csp3 : 0.1
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 52.93
TPSA : 43.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : 1.39
Log Po/w (WLOGP) : 1.77
Log Po/w (MLOGP) : 1.02
Log Po/w (SILICOS-IT) : 1.25
Consensus Log Po/w : 1.42

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.35
Solubility : 0.774 mg/ml ; 0.00447 mol/l
Class : Soluble
Log S (Ali) : -1.91
Solubility : 2.11 mg/ml ; 0.0122 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.95
Solubility : 0.194 mg/ml ; 0.00112 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 1.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.74

Safety of [ 102791-87-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 102791-87-7 ]

* 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.

  • Downstream synthetic route of [ 102791-87-7 ]

[ 102791-87-7 ] Synthesis Path-Downstream   1~39

YieldReaction ConditionsOperation in experiment
55%
  • 2
  • [ 102791-87-7 ]
  • [ 936092-53-4 ]
  • N-tert-butyl-3-{5-methyl-2-[4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
15% With caesium carbonate In 1,4-dioxane at 160℃; for 0.333333h; Microwave irradiation; 167 [0340] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-methyl-imidazol- 1 -yl)- phenylamine (60 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 °C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (20 mg, 15%).[0341] 1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 2.15 (s, 3H), 2.16 (s, 3H), 7.30 (s, IH), 7.38 (d, J= 9.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.57 (s, IH), 7.76 (d, J= 9.0 Hz, 2H), 7.96 (s, IH), 7.97 (s, IH), 8.09-8.13 (m, 2H), 8.63 (s, IH), 9.16 (s, IH). MS (ES+): m/z 492 (M+H)+ .
  • 3
  • [ 102791-87-7 ]
  • [ 936092-60-3 ]
  • N4-(3-tert-butylphenyl)-5-methyl-N2-(4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% Stage #1: 4-methyl-1-(4-aminophenyl)-1H-imidazole; 2-chloro-N4-[3-(1,1-dimethylethyl)phenyl]-5-methylpyrimidin-4-amine With caesium carbonate In 1,4-dioxane for 20h; Heating / reflux; Stage #2: With hydrogenchloride 193 [0389] A mixture of intermediate 41 (318 mg, 1.15 mmol) and intermediate 62 (200 mg, 1.15 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (66 mg of HCl salt, 20%) as a white solid.[0390] 1H NMR (500 MHz, DMSO-d6): δ 1.26 (s, 9H), 2.19 (s, 3H), 2.36 (s, 3H), 7.30 (d, J= 7.9 Hz, IH), 7.41 (d, J= 7.9 Hz, IH), 7.44 (t, J= 1.8 Hz, IH), 7.54 (d, J= 7.9 Hz5 IH), 7.59 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 9.0 Hz, 2H), 7.94 (s, IH), 7.99 (s, IH), 9.53 (d, J= 1.3 Hz, IH), 9.72 (br s, IH), 10.81(br s, IH). MS (ES+): m/z 413 (M+H)+.
  • 4
  • [ 90946-21-7 ]
  • [ 102791-87-7 ]
YieldReaction ConditionsOperation in experiment
90% With ammonium formate In ethanol for 2h; Reflux; Inert atmosphere; 104 Ammonium formate (2.202 g, 34.9 mmol) and palladium (10% w/w on carbon, 50% wet, 0.473 g, 4.44 mmol) were added to a solution 4-methyl-1-(4-nitrophenyl)-1H-imidazole (4.73 g, 23.28 mmol) in ethanol (150 mL) and the resulting mixture was refluxed under nitrogen for 1 h then cooled to room temperature. An extra portion of ammonium formate (2.202 g, 34.9 mmol) was then added and the resulting mixture was refluxed for a further hour then cooled to room temperature and filtered through celite. Most of the solvent was removed in vacuo and the residue was loaded on a 50 g SCX column which was eluted with MeOH (5 CV) then with 2N NH3 in MeOH (5 CV). The ammonia fractions were combined and concentrated in vacuo to give 4-(4-methyl-1H-imidazol-1-yl)aniline (3.92 g, 21.06 mmol, 90%) as a yellow solid.LCMS (method G): Retention time 0.61 min, [M+H]+=164.03
90% With ammonium formate In ethanol for 2h; Reflux; Inert atmosphere; 64 Intermediate 644-(4-Methyl-1 /-/-imidazol-1 -yQanilineAmmonium formate (2.202 g, 34.9 mmol) and palladium (10% w/w on carbon, 50% wet, 0.473 g, 4.44 mmol) were added to a solution of 4-methyl-1 -(4-nitrophenyl)-1 H-imidazole (for a preparation see intermediate 93) (4.73 g, 23.28 mmol) in ethanol (150 mL) and the resulting mixture was refluxed under nitrogen for 1 h then cooled to room temperature. An extra portion of ammonium formate (2.202 g, 34.9 mmol) was then added and the resulting mixture was refluxed for a further hour then cooled to room temperature and filtered through celite. Most of the solvent was removed in vacuo and the residue was loaded on a 50 g SCX column which was eluted with MeOH (5 CV) then with 2N NH3 in MeOH (5 CV). The ammonia fractions were combined and concentrated in vacuo to give 4-(4-methyl-1 H-imidazol-1 -yl)aniline (3.92 g, 21.06 mmol, 90%) as a yellow solid.LCMS (Method A): Retention time 0.61 min, [M+H]+ = 174.08
90% With ammonium formate In ethanol; water at 2℃; for 2h; Reflux; 104 Intermediate 1044-(4-Methyl-1 H-imidazol-1 -yl);Ammonium formate (2.202 g, 34.9 mmol) and palladium (10% w/w on carbon, 50% wet, 0.473 g, 4.44 mmol) were added to a solution 4-methyl-1 -(4-nitrophenyl)-1 H-imidazole (4.73 g, 23.28 mmol) in ethanol (150 mL) and the resulting mixture was refluxed under nitrogen for 1 h then cooled to room temperature. An extra portion of ammonium formate (2.202 g, 34.9 mmol) was then added and the resulting mixture was refluxed for a further hour then cooled to room temperature and filtered through celite. Most of the solvent was removed in vacuo and the residue was loaded on a 50 g SCX column which was eluted with MeOH (5 CV) then with 2N NH3 in MeOH (5 CV). The ammonia fractions were combined and concentrated in vacuo to give 4-(4-methyl-1 /-/-imidazol-1 -yl)aniline (3.92 g, 21.06 mmol, 90%) as a yellow solid.LCMS (method G): Retention time 0.61 min, [M+H]+ = 164.03
83% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16h; 6 Synthesis of 4-(4-methyl-lH-imidazol-l-yl) aniline Synthesis of 4-(4-methyl-lH-imidazol-l-yl) aniline [0303] To a stirred solution of 4-methyl-l-(4-nitrophenyl)-lH-imidazole (1.7 g, 8.37 mmol) in MeOH (50 mL) under argon atmosphere was added 10%> Pd-C (0.3 g) and stirred at RT for 16 h under H2 atmosphere (balloon pressure). The reaction was filtered through celite, washed with MeOH (15 mL), and concentrated in vacuo to afford 4-(4-methyl-lH-imidazol- 1-yl) aniline (1.2 g, 83%) as a brown solid and used without further purification. 1H-NMR (DMSO-< 5, 500 MHz): δ 7.81 (s, 1H), 7.21-7.18 (m, 3H), 6.62 (d, 2H), 5.23 (br, s, 2H), 2.14 (s, 3H); Mass (ESI): 174 [M+l]; TLC: 10% MeOH:CH2Cl2 (R 0.4).
83% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16h; Inert atmosphere; 4 Synthesis of 4-(4-methyl-1H-imidazol-1-yl) aniline To a stirred solution of 4-methyl-1-(4-nitrophenyl)-1H-imidazole (1.7 g, 8.37 mmol) in MeOH (50 mL) under an argon atmosphere was added 10% Pd/C (0.3 g) and stirred at RT for 16 h under H2 atmosphere (balloon pressure). The reaction was filtered through celite, washed with MeOH (15 mL), and concentrated in vacuo to afford 4-(4-methyl-1H- imidazol-1-yl) aniline (1.2 g, 83%) as a brown solid used without further purification. 1H- NMR (DMSO-d6, 500 MHz): δ 7.81 (s, 1H), 7.21-7.18 (m, 3H), 6.62 (d, 2H), 5.23 (br, s, 2H), 2.14 (s, 3H); Mass (ESI): 174 [M+1]; TLC: 10% MeOH:CH2Cl2 (Rf 0.4).
83% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16h; 4 Synthesis of 4-(4-methyl-1H-imidazol-1-yl) aniline Synthesis of 4-(4-methyl-1H-imidazol-1-yl) aniline To a stirred solution of 4-methyl-1-(4-nitrophenyl)-1H-imidazole (1.7 g, 8.37 mmol) in MeOH (50 mL) under an argon atmosphere was added 10% Pd/C (0.3 g) and stirred at RT for 16 h under H2 atmosphere (balloon pressure). The reaction was filtered through celite, washed with MeOH (15 mL), and concentrated in vacuo to afford 4-(4-methyl-1H-imidazol-1-yl) aniline (1.2 g, 83%) as a brown solid used without further purification. 1H-NMR (DMSO-d6, 500 MHz): δ 7.81 (s, 1H), 7.21-7.18 (m, 3H), 6.62 (d, 2H), 5.23 (br, s, 2H), 2.14 (s, 3H); Mass (ESI): 174 [M+1]; TLC: 10% MeOH:CH2Cl2 (Rf 0.4).
80% With tin(II) chloride dihdyrate at 0 - 20℃; Reflux; 4-(4-methyl-lH-imidazol-l-yl)nitrobenzene (22.5 g; 0.87 mmol) is dissolved in abs. etha- nol (250 DiL), then SnCl2.2H2O (125 g; 0.55 mol) is added portion-wise, on cooling at O0C. The resulting mixture is stirred at r.t. for 2 hours and heated at reflux overnight. The reaction mixture is then cooled at r.t. and the pH is adjusted to 12, by adding 30% KOH (500 mL), then KOH pellets under stirring. The resulting suspension is filtered and the cake is washed with ethanol, the combined filtrate and washings are concentrated and the residue is extracted with DCM. Concentration of the combined organic extracts afforded the title product as a slight brown solid (15.3 g; 80%), m.p.: 122-125°C. C10HnN3, MW 173,22.
With hydrogen In methanol for 4h; 192 [0388] To a solution of 1 -fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF (100 niL) was added 4-methyl-lH-imidazole (0.82 g, 10 mmol) and K2CO3 (1 Ig, 80 mmol). The mixture was heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine (100 mL x 2). The organic layer was dried and concentrated. The solid was dissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd-C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (1.5 g, 87%) as brown solid.
With hydrogen In methanol at 20℃; 6 To a solution of compound 6.0 4-methyl imidazole (1 mL, 10 mmol, 1 equiv.) in DMF at room temperature was added 1 -fluoro-4-nitrobenzene 6.1 (820 mg, 10 mmol, 1 equiv.) and K2CO3 (1.38 g, 10 mmol, 1 equiv.). The resulting mixture was heated to 110°c for 4h before being cooled to room temperature, filtered through celite, and washed with EtOAc (20 mL X 4). The collected filtrate was further washed with brine (50 mL X 3) and dried over Na2SO4. After removal of solvent, the residue was diluted with MeOH (20 mL). Pd/C (50 mg, 5% mass equiv.) was added and the reaction flask was charged with a H2 balloon and stirred overnight at room temperature. The mixture was filtered through celite and washed with EtOAc (20 mL X 3). The collected filtrate was concentrated and the residue was purified via flash chromatography (hexanes: EtOAc=I :1) to afford the desired product 6.3 4- (4-methyl-1H-imidazol-1-yl)benzenamine (1.0 g; 60%). LC-MS (M+Η):174.15
20.9 g (64%) With hydrogenchloride; iron In methanol; water at 0 - 50℃; 72.b b) b) 4-(4-Methyl-imidazol-1-yl)-phenylamine A solution of 38.5 g (189 mmol) 4-methyl-1-(4-nitro-phenyl)-1H-imidazole in a mixture of 125 ml methanol and 120 ml hydrochloric acid 37% was cooled in an ice bath and 47.5 g (852 mmol) of iron powder was slowly added, keeping the temperature between 40 to 50° C. 500 ml ethyl acetate was added and the mixture was filtered. The organic phase was washed with diluted sodium carbonate solution, dried and evaporated. Crystallization from dichloromethane/heptane gave 20.9 g (64%) of the product as a slightly brownish solid. MS ISP (m/e): 174.3 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.80 (s, 1H), 7.20-7.14 (m, 3H), 6.62 (d, 2H), 5.23 (s broad, 2H), 2.13 (s, 3H).

  • 5
  • [ 102791-87-7 ]
  • [ 32315-10-9 ]
  • [ 1079178-75-8 ]
  • [ 1079169-51-9 ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: bis(trichloromethyl) carbonate; 5-ethyl-2,4-dimethylbenzylamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.5h; Stage #2: 4-methyl-1-(4-aminophenyl)-1H-imidazole In dichloromethane at 50℃; 2 EXAMPLE 2; PREPARATION OF INVENTION COMPOUNDS VIA SCHEME 2; [0195] To a solution of 5-ethyl-2,4-dimethyl benzyl amine 4 (0.1 mmol, 16.3 mg) in DCM (2.5 ml) at 0°C, i-Pr2NET (1 mmol, 0.18 ml) and triphosgene (0.13 mmol, 38 mg) were added slowly. After stirring the reaction mixture at O°C for 30 minutes, aniline 5 (0.15 mmol, 30.5 mg) was added. The reaction mixture was warmed up and stirred at 5O°C overnight. Aqueous NH3 (0.1 ml) was added to the reaction mixture. Following evaporative removal of the solvent, the residue was re-dissolved in the mixture of DMF and MeOH (1 ml, 1 :1), and purified by direct injection onto a reverse-phase HPLC column to yield compound 6 (30 mg, 63%; LCMS, [M+H]+ = 363.5).
  • 6
  • [ 102791-87-7 ]
  • [ 6191-99-7 ]
  • [ 1201902-62-6 ]
YieldReaction ConditionsOperation in experiment
75% With pyridine at 0 - 20℃; 4-(4-methyl-l H-imidazol- l-yl)aniline (15 g, 138 mmol) was dissolved in dry pyridine (80 mL), freshly distilled 3-ethoxyacryloyl chloride (19 g, 140 mmol) was then added drop- wise at 57O0C. The resulting mixture was stirred at 00C for 1 hours and at r.t. overnight. The reaction mixture was quenched with water (500 mL), the pH was adjusted to ρH=10, by adding K2CO3 and the resulting solid was filtered, washed with water and dried, to provide the title product as slight orange powder (18.6 g; 75%), m.p.: 214-216°C. C15H17N3O2 , MW: 271.32.
  • 7
  • [ 102791-87-7 ]
  • [ 1239719-55-1 ]
  • [ 1240608-23-4 ]
YieldReaction ConditionsOperation in experiment
20% With caesium carbonate; XPhos In <i>tert</i>-butyl alcohol at 110℃; for 20h; Inert atmosphere; B7 Preparation of compound 7l-(4-aminophenyl)-4-methyl- IH- imidazole (130 mg, 0.75 mmol), Pd2(dba)3 (60 mg, 0.065 mmol), X-Phos (69 mg, 0.144 mmol) and Cs2CO3 (641 mg, 1.97 mmol) were added to a sol. of intermediate 12 (200 mg, 0.65 mmol) in 2-methyl-2-propanol (5 ml) under a N2 atmosphere. The r.m. was heated at 110 0C for 20 h. Then, the r.m. was cooled to r.t., water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOΗ(NΗ3) from 100/0 to 98/2). The product fractions were collected and concentrated in vacuo. The residue was purified further by RP preparative SFC [RP Shandon Hyperprep Cl 8 BDS (8 μm, 250 g, LD. 5 cm); mobile phase: 35 % MeOH (with 0.2% isopropylamine), 65 % CO2. The product fractions were collected and worked up. Yield: 0.052 g of compound 7 (20 %).
  • 8
  • [ 350-46-9 ]
  • [ 102791-87-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 110 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 16 h / 20 °C
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 - 110 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 16 h / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 110 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C
Multi-step reaction with 2 steps 1: potassium carbonate / 20 - 120 °C 2: tin(II) chloride dihdyrate / 0 - 20 °C / Reflux
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 70 h / 60 °C / Inert atmosphere 2: ammonium formate / palladium 10% on activated carbon / ethanol / 2 h / Reflux; Inert atmosphere

  • 9
  • [ 102791-87-7 ]
  • [ 682812-14-2 ]
  • [ 1300695-70-8 ]
YieldReaction ConditionsOperation in experiment
33% With yttrium(lll) nitrate hexahydrate In acetonitrile at 50℃; for 22h; 103 Intermediate 1031 ,1 -Dimethylethyl (3-[4-(4-methyl-1 H-imidazol-1 - yl)phenyl]amino}butanoyl)carbamate(+/-)A mixture of 4-(4-methyl-1 H-imidazol-1 -yl)aniline (for a preparation see Intermediate 104) (500 mg, 2.89 mmol), 1 ,1 -dimethylethyl (2E)-2-butenoylcarbamate (for a preparation see Intermediate 105) (615 mg, 3.32 mmol) and yttrium(lll) nitrate hexahydrate (1 1 1 mg, 0.289 mmol) in acetonitrile (2 mL) was heated at 50°C for 15 h. An extra portion of yttrium(lll) nitrate hexahydrate (1 1 1 mg, 0.289 mmol) was added to the mixture which was stirred for 7 more hours before being cooled to room temperature. Half of the solvent was removed in vacuo and the residue was partitioned between AcOEt (40 mL) and a saturated NaHC03 aqueous solution (20 mL). The layers were separated and the organic phase was washed with brine (15 mL). The combined aqueous phases were extracted with AcOEt (35 mL) and the combined organic were dried over MgS04 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 4 to 8% MeOH in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient: 60-95% AcOEt in Hexanes) to give 1 ,1 -dimethylethyl (3-[4-(4-methyl- 1 H-imidazol-1 -yl)phenyl]amino}butanoyl)carbamate (343 mg, 0.956 mmol, 33%) as a colourless sticky solid. LCMS (method A): Retention time 0.94 min, [M+H]+ = 359.12
33% With yttrium(lll) nitrate hexahydrate In acetonitrile at 50℃; for 22h; Cooling with ice; 63 Intermediate 631 ,1 -Dimethylethyl (3-[4- -methyl-1 /-/-imidazol-1 -yl)phenyllamino)butanoyl)carbamate(+/-)A mixture of 4-(4-methyl-1 H-imidazol-1 -yl)aniline (for a preparation see intermediate 64) (500 mg, 2.89 mmol), 1 ,1 -dimethylethyl (2£)-2-butenoylcarbamate (for a preparation see intermediate 65) (615 mg, 3.32 mmol) and Yttrium(lll) Nitrate hexahydrate (1 1 1 mg, 0.289 mmol) in acetonitrile (2 mL) was heated at 50°C for 15 h. An extra portion of Yttrium(lll) Nitrate hexahydrate (1 1 1 mg, 0.289 mmol) was added to the mixture which was stirred for 7 more hours before being cooled to room temperature. Half of the solvent was removed in vacuo and the residue was partitioned between AcOEt (40 mL) and a saturated NaHC03 aqueous solution (20 mL). The layers were separated and the organic phase was washed with brine (15 mL). The combined aqueous phases were extracted with AcOEt (35 mL) and the combined organic were dried over MgS04 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 4 to 8% MeOH in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient: 60-95% AcOEt in Hexanes) to give 1 ,1 -dimethylethyl (3-[4-(4-methyl- 1 /-/-imidazol-1 -yl)phenyl]amino}butanoyl)carbamate (343 mg, 0.956 mmol, 33%) as a colourless sticky solid.LCMS (Method B): Retention time 0.94 min, [M+H]+ = 359.12
33% With yttrium(lll) nitrate hexahydrate In acetonitrile at 50℃; for 23h; 103 A mixture of 4-(4-methyl-1H-imidazol-1-yl)aniline (for a preparation see Intermediate 104) (500 mg, 2.89 mmol), 1,1-dimethylethyl (2E)-2-butenoylcarbamate (for a preparation see Intermediate 105) (615 mg, 3.32 mmol) and yttrium(III) nitrate hexahydrate (111 mg, 0.289 mmol) in acetonitrile (2 mL) was heated at 50° C. for 15 h. An extra portion of yttrium(III) nitrate hexahydrate (111 mg, 0.289 mmol) was added to the mixture which was stirred for 7 more hours before being cooled to room temperature. Half of the solvent was removed in vacuo and the residue was partitioned between AcOEt (40 mL) and a saturated NaHCO3 aqueous solution (20 mL). The layers were separated and the organic phase was washed with brine (15 mL). The combined aqueous phases were extracted with AcOEt (35 mL) and the combined organic were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 4 to 8% MeOH in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient: 60-95% AcOEt in Hexanes) to give 1,1-dimethylethyl (3-[4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}butanoyl)carbamate (343 mg, 0.956 mmol, 33%) as a colourless sticky solid. LCMS (method A): Retention time 0.94 min, [M+H]+=359.12
  • 10
  • [ 102791-87-7 ]
  • methyl 4-[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice 4.1: sodium t-butanolate / tris-(dibenzylideneacetone)dipalladium(0); DavePhos / toluene / 5 h / 70 °C / Inert atmosphere
  • 11
  • [ 102791-87-7 ]
  • (cis)-1-acetyl-N-(5-fluoro-2-pyridinyl)-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice 4.1: sodium t-butanolate / tris-(dibenzylideneacetone)dipalladium(0); DavePhos / toluene / 14 h / 70 °C / Inert atmosphere
  • 12
  • [ 102791-87-7 ]
  • 4-[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice 4.1: sodium t-butanolate / tris-(dibenzylideneacetone)dipalladium(0); DavePhos / toluene / 30 h / 85 °C / Inert atmosphere
  • 13
  • [ 102791-87-7 ]
  • 6-[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice 4.1: sodium t-butanolate / tris-(dibenzylideneacetone)dipalladium(0); DavePhos / toluene / 10 h / 85 °C / Inert atmosphere 4.2: 0.17 h
  • 14
  • [ 102791-87-7 ]
  • methyl 6-[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice 4.1: sodium t-butanolate / tris-(dibenzylideneacetone)dipalladium(0); DavePhos / toluene / 10 h / 85 °C / Inert atmosphere 4.2: 0.17 h 5.1: hydrogenchloride / 1,4-dioxane; methanol / 2 h / 20 °C / Reflux
  • 15
  • [ 102791-87-7 ]
  • 6-[1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice 4.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 0.5 h / 200 °C / Microwave irradiation
  • 16
  • [ 102791-87-7 ]
  • (cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / 1,3-dioxane; dichloromethane / 2 h / 20 °C / Cooling with ice
  • 17
  • [ 102791-87-7 ]
  • 1,1-dimethylethyl [(cis)-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: yttrium(lll) nitrate hexahydrate / acetonitrile / 23 h / 50 °C 2: sodium hydride; magnesium(II) chloride hexahydrate / ethanol; water / 1.5 h / -15 - 20 °C
Multi-step reaction with 2 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1 h / -15 - 20 °C 2.2: 1 h / 20 °C
  • 18
  • [ 102791-87-7 ]
  • 1,1-dimethylethyl [(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1 h / -15 - 20 °C 2.2: 1 h / 20 °C 3.1: 24 h / 20 °C / Inert atmosphere
  • 19
  • [ 102791-87-7 ]
  • 1,1-dimethylethyl [(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: yttrium(lll) nitrate hexahydrate / acetonitrile / 23 h / 50 °C 2: sodium hydride; magnesium(II) chloride hexahydrate / ethanol; water / 1.5 h / -15 - 20 °C 3: 24 h / 20 °C / Inert atmosphere
  • 21
  • [ 102791-87-7 ]
  • [ 17823-69-7 ]
  • [ 1456732-83-4 ]
YieldReaction ConditionsOperation in experiment
Dissolved 0.500 g <strong>[17823-69-7]2-cyano-3,3-bis(methylthio)acrylamide</strong> in 15 mL EtOH and added 4-methyl-l-(4-aminophenyl)-lH-imidazole (1.0 eq.) . Stirred reaction at 75 C until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75 C until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5 -amino-3-((4-(4-methyl-l H-imidazol- 1 -yl)phenyl)amino)- lH-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr. H3C 5-amino-3-((4-(4-methyl-lH-imidazol-l-yl)phenyl)amino)-lH-pyrazole-4-carboxamide
  • 22
  • [ 102791-87-7 ]
  • [ 1456730-75-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: ethanol / 18 h / 75 °C 1.2: 18 h / 75 °C 2.1: piperidine / ethanol / 18 h / Reflux 2.2: 1 h
  • 23
  • [ 102791-87-7 ]
  • 2-chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine [ No CAS ]
  • N<SUP>4</SUP>-methyl-N<SUP>2</SUP>-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-2,4-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With palladium diacetate; caesium carbonate; CyJohnPhos In 1,4-dioxane at 120℃; for 1.5h; Inert atmosphere; Microwave irradiation; 2 Example 2 N -Methyl-N2-(4-(4-methyl-lH-imidazol-l-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)- pyrimidine-2,4-diamine Example 2 N -Methyl-N2-(4-(4-methyl-lH-imidazol-l-yl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)- pyrimidine-2,4-diamine A mixture of 2-chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (85 mg, 0,33 mmol), 4-(4-methyl-lH-imidazol-l-yl)aniline (100 mg, 0.58 mmol), cesium carbonate (217 mg, 0.67 mmol), palladium(ll) acetate (11 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)- biphenyl (17 mg, 0.05 mmol) in dioxane (3 mL) was heated in a microwave reactor under notrogen atmosphere at 120°C for 90 min. The reaction mixture was filtered through a pad of diatomeous earth which was eluted with MeOH. The mixture was partitioned between EtOAc and sodium hydroxide (aq, 1 M). The organic phase was separated, dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a solid 52 mg, (40 %). MS (ES+) m/z 393 (M+H)+. XH NMR (500 MHz, DMSO-cf6) 0 ppm 2.15 (s, 3 H) 2.86 (br. s., 3 H) 4.20 (q, 2 H) 4.45 (s, 2 H) 6.01 (br. s., 1 H) 7.29 (br. s., 1 H) 7.32 (s, 1 H) 7.42 (d, 2 H) 7.91 (d, 2 H) 7.98 (s, 1 H) 9.21 (s, 1 H).
  • 24
  • [ 102791-87-7 ]
  • 2-chloro-8-(3,5-difluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • 8-(3,5-difluorophenyl)-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% With hydrogenchloride In water; isopropyl alcohol at 130℃; for 16h; Inert atmosphere; Sealed tube; 58 Synthesis of 8- (3, 5-difluorophenyl)-N-(4-(4-methyl-lH-imidazol-l-yl) phenyl)-, 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine Synthesis of 8- (3, 5-difluorophenyl)-N-(4-(4-methyl-lH-imidazol-l-yl) phenyl)-, 8-dihydro- 6H-pyrimido [5, 4-b] [I, 4] oxazin-2 -amine [0388] To a stirred solution of 2-chloro-8-(3, 5-difluorophenyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazine (150 mg, 0.53 mmol) in IPA (1.5 mL) under argon atmosphere were added 4-(4-methyl-lH-imidazol-l-yl) aniline (183 mg, 1.06 mmol) and concentrated hydrochloric acid (catalytic amount) at RT. The reaction mixture was stirred at 130 °C for 16 h in a sealed tube. After consumption of the starting materials (monitored by TLC), the volatile components were removed in vacuo. The residue was neutralized with a saturated sodium carbonate solution (20 mL) and extracted with 10% MeOH:CH2Cl2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [Kromasil CI 8, (250 x 21.2mm 10 μιη) (60 mg loading; CH3CN;0.05% TFA Aq; (0.1/90, 15/65, 30/10,35/10) as mobile phase with a Flow rate=15 mL/min] to afford 8-(3, 5-difluorophenyl)-N-(4-(4- methyl-lH-imidazol-l-yl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (40 mg, 18%) as an off-white solid. 1H-NMR (CD3OD, 400 MHz): δ 7.82 (s, 1H), 7.77 (s, 1H), 7.60-7.57 (m, 2H), 7.26-7.19 (m, 4H), 7.11 (s, 1H), 6.90-6.86 (m, 1H), 4.32-4.30 (m, 2H), 3.94-3.90 (m, 2H), 2.21 (s, 3H); Mass (ESI): 421.4 [M+l]; LC-MS: 421.3 (M+l); (column; X select CSH C-18 (50 3.0 mm, 3.5 μπι); RT 2.92 min. 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity UPLC BEH C-18 2.1 X 50 mm, 1.7 μπι); RT 1.49 min. ACN: 0.025% TFA (Aq); 0.50 mL/min.; TLC: 10% MeOH:CH2Cl2 (Rf. 0.1).
  • 25
  • [ 102791-87-7 ]
  • 2-chloro-8-(2-chlorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • 8-(2-chlorophenyl)-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 16h; Inert atmosphere; Sealed tube; 46 Synthesis of8-(2-chlorophenyl)-N-(4-(4-methyl-lH-imidazol-l-yl) phenyl)-, 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2 -amine Synthesis of8-(2-chlorophenyl)-N-(4-(4-methyl-lH-imidazol-l-yl) phenyl)-, 8-dihydro-6H- pyrimido [5, 4-b] [I, 4] oxazin-2 -amine [0376] A dry vial charged with Pd2(dba)3 (16 mg, 0.017 mmol) and Xantphos (31 mg, 0.53 mmol) in 1, 4-dioxane (0.5 mL) at RT was degassed with argon and stirred at 120 °C for 3 min. A mixture of 2-chloro-8-(2-chlorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (100 mg, 0.35 mmol), 4-(4-methyl-lH-imidazol-l-yl) aniline (122 mg, 0.70 mmol) and cesium carbonate (161 mg, 0.49 mmol) in 1, 4-dioxane (0.5 mL) was degassed with argon and the catalyst premixture was added. The resultant mixture was stirred at 120 °C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC and LCMS), the volatile components were removed in vacuo, the residue was diluted with water (20 mL) and extracted with CH2C12 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 5% MeOH:CH2Cl2 to afford 8-(2-chlorophenyl)-N-(4-(4- methyl-lH-imidazol-l-yl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (65 mg, 44%) as an off-white solid. 1H-NMR (OMSO-d6, 400 MHz): δ 9.00 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1 H), 7.67 (d, 1H), 7.59 (d, 1H), 7.52-7.45 (m, 4H), 7.23 (s, 1H), 7.12 (d, 2H), 4.37-4.26 (m, 2H), 3.91-3.76 (m, 2H), 2.14 (s, 3H); Mass (ESI): 419.4 [M+1]; LC-MS: 419.3 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 μιη); RT 2.72 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 μιη); RT 1.50 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 50% EtOAc:hexanes (R/. 0.3).
  • 26
  • [ 102791-87-7 ]
  • 2-chloro-7-(phenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With hydrogenchloride In isopropyl alcohol at 130℃; for 16h; Inert atmosphere; Sealed tube; 26 Example 26 Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-phenyl-7, 8-dihydro- 6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-phenyl-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine To a stirred solution of 2-chloro-8-methyl-7-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 0.19 mmol) in isopropanol (0.5 mL) under an argon atmosphere were added 4-(4-methyl-1H-imidazol-1-yl) aniline (66 mg, 0.38 mmol) and concentrated hydrochloric acid (catalytic amount) at room temperature. The reaction mixture was stirred at 130 oC for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with a saturated sodium bicarbonate solution (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH:CH2Cl2 to afford 8-methyl-N-(4-(4-methyl-1H- imidazol-1-yl) phenyl)-7-phenyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (20 mg, 26%) as an off-white solid.1H-NMR (CD3OD, 400 MHz): δ 7.89 (s, 1H), 7.78 (d, 2H), 7.50 (s, 1H), 7.40-7.32 (m, 5H), 7.23-7.20 (m, 3H), 4.70-4.68 (m, 1H), 4.23-4.18 (m, 2H), 3.10 (s, 3H), 2.20 (s, 3H); Mass (ESI): 399.3 [M+1]; LC-MS: 399.3 (M+1); (column; X- select C-18 (50 × 3.0 mm, 3.5 µm); RT 2.98 min0.05% Aq TFA: ACN; 0.80 mL/min); HPLC: (column; Eclipse XDB C-18 150 X 4.6 mm, 5.0 µm); RT 7.67 min. ACN: 5 mM Aq NH4OAc; 1.0 mL/min. TLC: 5% MeOH:CH2Cl2 (Rf: 0.3).
26% With hydrogenchloride In water; isopropyl alcohol at 130℃; for 16h; Inert atmosphere; Sealed tube; 26 Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine To a stirred solution of 2-chloro-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (50 mg, 0.19 mmol) in isopropanol (0.5 mL) under an argon atmosphere were added 4-(4-methyl-1H-imidazol-1-yl) aniline (66 mg, 0.38 mmol) and concentrated hydrochloric acid (catalytic amount) at room temperature. The reaction mixture was stirred at 130° C. for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC), the reaction was diluted with a saturated sodium bicarbonate solution (25 mL) and extracted with EtOAc (3*25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 2% MeOH:CH2Cl2 to afford 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine (20 mg, 26%) as an off-white solid. 1H-NMR (CD3OD, 400 MHz): δ 7.89 (s, 1H), 7.78 (d, 2H), 7.50 (s, 1H), 7.40-7.32 (m, 5H), 7.23-7.20 (m, 3H), 4.70-4.68 (m, 1H), 4.23-4.18 (m, 2H), 3.10 (s, 3H), 2.20 (s, 3H); Mass (ESI): 399.3 [M+1]; LC-MS: 399.3 (M+1); (column; X-select C-18 (50*3.0 mm, 3.5 μm); RT 2.98 min 0.05% Aq TFA: ACN; 0.80 mL/min); HPLC: (column; Eclipse XDB C-18 150*4.6 mm, 5.0 am); RT 7.67 min. ACN: 5 mM Aq NH4OAc; 1.0 mL/min. TLC: 5% MeOH:CH2Cl2 (Rf: 0.3).
  • 27
  • [ 102791-87-7 ]
  • 2-chloro-7-(phenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • (+)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
  • (-)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol / 16 h / 130 °C / Inert atmosphere; Sealed tube 2: Chiralpak IA / dichloromethane; methanol; hexane / Resolution of racemate
Multi-step reaction with 2 steps 1: hydrogenchloride / water; isopropyl alcohol / 16 h / 130 °C / Inert atmosphere; Sealed tube 2: diethylamine / dichloromethane; methanol; hexane / Resolution of racemate
  • 28
  • [ 102791-87-7 ]
  • 2-chloro-7-(3,5-difluorophenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • 7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 16h; 23 Example 23 Synthesis of 7-(3, 5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)- 7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine Synthesis of 7-(3, 5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine To a dry vial was added a suspension of Pd2(dba)3 (7 mg, 0.008 mmol) and Xantphos (14 mg, 0.02 mmol) in 1, 4-dioxane (0.25 mL). The suspension was degassed, heated to 120 oC and stirred for 3 min. A mixture of 2-chloro-7-(3, 5-difluorophenyl)-8- methyl-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 0.16 mmol), 4-(4-methyl- 1H-imidazol-1-yl) aniline (58 mg, 0.33 mmol) and cesium carbonate (76 mg, 0.02 mmol) in 1, 4-dioxane (0.25 mL) was degassed and the catalyst premix was added. The reaction mixture was heated to 120 oC and stirred for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [acentis-C18 (250 X 21.2 mm X 10 um ) (30 mg loading; CH3CN; 0.05% Aq TFA (0.01/95, 2/95,3/80, 15/65, 15.1/0, 25/ 0, 35/95) as the mobile phase with a Flow rate=15 mL/min] to afford 7-(3, 5-difluorophenyl)-8-methyl-N-(4- (4-methyl-1H-imidazol-1-yl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (20 mg, 27%) as an off-white solid. 1H-NMR (CD3OD, 400 MHz): δ 7.89 (s, 1H), 7.79 (d, 2H), 7.60 (s, 1H), 7.40 (d, 2H), 7.19 (s, 1H), 6.91-6.80 (m, 3H), 4.73 (s, 1H), 4.20 (s, 2H), 3.13 (s, 3H), 2.21 (s, 3H); Mass (ESI): 435.6 [M+1]; LC-MS: 435.6 (M+1); (column; X- Select CSH C-18 (50 × 3.0 mm, 3.5 µm); RT 2.76 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC: (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 µm); RT 1.55 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 10% MeOH:CH2Cl2 (Rf: 0.3).
27% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 16h; Inert atmosphere; 23 Synthesis of 7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine Synthesis of 7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine To a dry vial was added a suspension of Pd2(dba)3 (7 mg, 0.008 mmol) and Xantphos (14 mg, 0.02 mmol) in 1,4-dioxane (0.25 mL). The suspension was degassed, heated to 120° C. and stirred for 3 min. A mixture of 2-chloro-7-(3,5-difluorophenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (50 mg, 0.16 mmol), 4-(4-methyl-1H-imidazol-1-yl) aniline (58 mg, 0.33 mmol) and cesium carbonate (76 mg, 0.02 mmol) in 1,4-dioxane (0.25 mL) was degassed and the catalyst premix was added. The reaction mixture was heated to 120° C. and stirred for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2*10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC [acentis-C18 (250*21.2 mm*10 um) (30 mg loading; CH3CN; 0.05% Aq TFA (0.01/95, 2/95, 3/80, 15/65, 15.1/0, 25/0, 35/95) as the mobile phase with a Flow rate=15 mL/min] to afford 7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine (20 mg, 27%) as an off-white solid. 1H-NMR (CD3OD, 400 MHz): δ 7.89 (s, 1H), 7.79 (d, 2H), 7.60 (s, 1H), 7.40 (d, 2H), 7.19 (s, 1H), 6.91-6.80 (m, 3H), 4.73 (s, 1H), 4.20 (s, 2H), 3.13 (s, 3H), 2.21 (s, 3H); Mass (ESI): 435.6 [M+1]; LC-MS: 435.6 (M+1); (column; X-Select CSH C-18 (50*3.0 mm, 3.5 m); RT 2.76 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC: (column; Acquity BEH C-18 50*2.1 mm, 1.7 m); RT 1.55 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 10% MeOH:CH2Cl2 (Rf: 0.3).
  • 29
  • [ 102791-87-7 ]
  • 2-chloro-7-(3,5-difluorophenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • (-)-7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
  • (+)-7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate / 1,4-dioxane / 16 h / 120 °C 2: Chiralpak IA / dichloromethane; methanol; hexane / Resolution of racemate
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 2: diethylamine / dichloromethane; methanol; hexane / Resolution of racemate
  • 30
  • [ 102791-87-7 ]
  • 2-chloro-8-methyl-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 16h; Sealed tube; 44 Example 115 Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-(3, 4, 5- trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-(3, 4, 5-trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine A dry vial charged with Pd2(dba)3 (36 mg, 0.04 mmol) and Xantphos (69 mg, 0.11 mmol) in 1, 4-dioxane (1.25 mL) at room temperature was degassed and the resultant reaction mixture was stirred at 120 oC for 3 min. A mixture of 2-chloro-8-methyl-7-(3, 4, 5- trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (250 mg, 0.79 mmol), 4-(4- methyl-1H-imidazol-1-yl) aniline (274 mg, 1.58 mmol) and cesium carbonate (361 mg, 1.10 mmol) in 1, 4-dioxane (1.25 mL) was degassed and the catalyst premix was added. The resultant mixture was stirred at 120 oC for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by column chromatography using 4% MeOH: CH2Cl2 to afford 8-methyl-N-(4-(4-methyl-1H-imidazol- 1-yl) phenyl)-7-(3, 4, 5-trifluorophenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2- amine (90 mg, 25%) as an off-white solid. LCMS: 453.5 (M+1); (column; X-Select CSH C- 18 (50 × 3.0 mm, 3.5 µm); RT 3.84 min 5 mM NH4OAc: ACN; 0.80 mL/min); HPLC (column; Eclipse XDB C18, 150 × 4.6 mm, 5 µm); RT 10.81 min. ACN: 5 mM Aq NH4OAc; 1 mL/min; TLC: 5% MeOH/DCM (Rf: 0.3).
25% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 16h; Inert atmosphere; Sealed tube; 115 Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine A dry vial charged with Pd2(dba)3 (36 mg, 0.04 mmol) and Xantphos (69 mg, 0.11 mmol) in 1,4-dioxane (1.25 mL) at room temperature was degassed and the resultant reaction mixture was stirred at 120° C. for 3 min. A mixture of 2-chloro-8-methyl-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (250 mg, 0.79 mmol), 4-(4-methyl-1H-imidazol-1-yl) aniline (274 mg, 1.58 mmol) and cesium carbonate (361 mg, 1.10 mmol) in 1,4-dioxane (1.25 mL) was degassed and the catalyst premix was added. The resultant mixture was stirred at 120° C. for 16 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the reaction was diluted with water (5 mL) and extracted with EtOAc (2*5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by column chromatography using 4% MeOH: CH2Cl2 to afford 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine (90 mg, 25%) as an off-white solid. LCMS: 453.5 (M+1); (column; X-Select CSH C-18 (50*3.0 mm, 3.5 μm); RT 3.84 min 5 mM NH4OAc: ACN; 0.80 mL/min); HPLC (column; Eclipse XDB C18, 150*4.6 mm, 5 μm); RT 10.81 min. ACN: 5 mM Aq NH4OAc; 1 mL/min; TLC: 5% MeOH/DCM (Rf: 0.3).
  • 31
  • [ 102791-87-7 ]
  • 2-chloro-8-methyl-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • (-)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
  • (+)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(3,4,5-trifluorophenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate / 1,4-dioxane / 16 h / 120 °C / Sealed tube 2: Chiralpak ADH / methanol; ethanol; hexane / Resolution of racemate
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 16 h / 120 °C / Inert atmosphere; Sealed tube 2: diethylamine / methanol; ethanol; hexane / Resolution of racemate
  • 32
  • [ 102791-87-7 ]
  • 2-chloro-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 40h; Sealed tube; 43 Example 43 Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-(o-tolyl)-7, 8-dihydro- 6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-(o-tolyl)-7, 8-dihydro-6H- pyrimido [5, 4-b] [1, 4] oxazin-2-amine To a dry vial was added a suspension of Pd2(dba)3 (8 mg, 0.009 mmol) and Xantphos (16 mg, 0.02 mmol) in 1, 4-dioxane (0.5 mL). The suspension was degassed, heated to 120 oC and stirred for 3 min. A mixture of 2-chloro-8-methyl-7-(o-tolyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazine (50 mg, 0.18 mmol), 4-(4-methyl-1H-imidazol- 1-yl) aniline (63 mg, 0.36 mmol) and cesium carbonate (84 mg, 0.85 mmol) in 1, 4-dioxane (0.5 mL) was degassed and the catalyst premix was added. The reaction mixture was heated to 120 oC and stirred for 40 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 3-4% MeOH: CH2Cl2 which was further washed with ACN: pentane (1:1, 10 mL) to afford 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7-(o-tolyl)-7, 8- dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine (20 mg, 26%) as an off-white solid. 1H- NMR (CD3OD, 400 MHz): δ 7.89 (s, 1H), 7.79 (d, 2H), 7.54 (s, 1H), 7.39 (d, 2H), 7.26-7.15 (m, 4H), 6.99 (d, 1H), 5.00-4.98 (m, 1H), 4.25-4.21 (m, 1H), 4.13-4.10 (m, 1 H), 3.08 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H); Mass (ESI): 413.5 [M+1]; LC-MS: 413.1 (M+1); (column; X- Select CSH C-18 (50 × 3.0 mm, 3.5 µm); RT 2.33 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC: (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 µm); RT 1.55 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 50% EtOAc:hexanes (Rf: 0.7).
26% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 40h; Inert atmosphere; Sealed tube; 43 Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine Synthesis of 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine To a dry vial was added a suspension of Pd2(dba)3 (8 mg, 0.009 mmol) and Xantphos (16 mg, 0.02 mmol) in 1,4-dioxane (0.5 mL). The suspension was degassed, heated to 120° C. and stirred for 3 min. A mixture of 2-chloro-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (50 mg, 0.18 mmol), 4-(4-methyl-1H-imidazol-1-yl) aniline (63 mg, 0.36 mmol) and cesium carbonate (84 mg, 0.85 mmol) in 1,4-dioxane (0.5 mL) was degassed and the catalyst premix was added. The reaction mixture was heated to 120° C. and stirred for 40 h in a sealed tube. After consumption of the starting material (monitored by TLC and LCMS), the mixture was diluted with water (25 mL) and extracted with EtOAc (2*25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 3-4% MeOH: CH2Cl2 which was further washed with ACN: pentane (1:1, 10 mL) to afford 8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine (20 mg, 26%) as an off-white solid. 1H-NMR (CD3OD, 400 MHz): δ 7.89 (s, 1H), 7.79 (d, 2H), 7.54 (s, 1H), 7.39 (d, 2H), 7.26-7.15 (m, 4H), 6.99 (d, 1H), 5.00-4.98 (m, 1H), 4.25-4.21 (m, 1H), 4.13-4.10 (m, 1H), 3.08 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H); Mass (ESI): 413.5 [M+1]; LC-MS: 413.1 (M+1); (column; X-Select CSH C-18 (50*3.0 mm, 3.5 μm); RT 2.33 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC: (column; Acquity BEH C-18 50*2.1 mm, 1.7 μm); RT 1.55 min. ACN: 0.025% Aq TFA; 0.5 mL/min. TLC: 50% EtOAc:hexanes (Rf: 0.7).
  • 33
  • [ 102791-87-7 ]
  • 2-chloro-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine [ No CAS ]
  • (+)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
  • (-)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate / 1,4-dioxane / 40 h / 120 °C / Sealed tube 2: Chiralpak IB / dichloromethane; methanol; hexane / Resolution of racemate
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 40 h / 120 °C / Inert atmosphere; Sealed tube 2: diethylamine / dichloromethane; methanol; hexane / Resolution of racemate
  • 34
  • [ 102791-87-7 ]
  • [ 102791-40-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: pyridine / 0 - 20 °C 2: sulfuric acid / -10 - 20 °C
  • 35
  • [ 102791-87-7 ]
  • [ 1201902-19-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: pyridine / 0 - 20 °C 2: sulfuric acid / -10 - 20 °C 3: sodium hydride / N,N-dimethyl-formamide; mineral oil / -15 - 20 °C / Inert atmosphere 4: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene / 2 h / Inert atmosphere; Reflux
  • 36
  • [ 102791-87-7 ]
  • [ 1201902-60-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: pyridine / 0 - 20 °C 2: sulfuric acid / -10 - 20 °C 3: sodium hydride / N,N-dimethyl-formamide; mineral oil / -15 - 20 °C / Inert atmosphere
  • 37
  • [ 102791-87-7 ]
  • [ 1201902-61-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: pyridine / 0 - 20 °C 2: sulfuric acid / -10 - 20 °C 3: hydrogenchloride / water; isopropyl alcohol / 5 °C
  • 38
  • [ 102791-87-7 ]
  • [6-(4-methyl-1H-imidazol-1-yl)-2-(phenyl)]quinoline dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: pyridine / 0 - 20 °C 2: sulfuric acid / -10 - 20 °C 3: sodium hydride / N,N-dimethyl-formamide; mineral oil / -15 - 20 °C / Inert atmosphere 4: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene / 2 h / Inert atmosphere; Reflux 5: hydrogenchloride / toluene
  • 39
  • [ 102791-87-7 ]
  • [ 682812-14-2 ]
  • 1,1-dimethylethyl [(cis)-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: yttrium(lll) nitrate hexahydrate / acetonitrile / 22 h / 50 °C / Cooling with ice 2.1: sodium tetrahydroborate; magnesium(II) chloride hexahydrate; water / ethanol / 1.5 h / -15 - 20 °C 2.2: 0.5 h / 20 °C
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