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Product Details of [ 660838-05-1 ]

CAS No. :660838-05-1 MDL No. :MFCD04114554
Formula : C12H18N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :HOVDUPXBRBXFBP-UHFFFAOYSA-N
M.W : 222.28 Pubchem ID :24699786
Synonyms :

Calculated chemistry of [ 660838-05-1 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.42
Num. rotatable bonds : 4
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 66.06
TPSA : 64.35 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) : -6.12 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.47
Log Po/w (XLOGP3) : 2.17
Log Po/w (WLOGP) : 2.74
Log Po/w (MLOGP) : 2.07
Log Po/w (SILICOS-IT) : 1.47
Consensus Log Po/w : 2.18

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.6
Solubility : 0.56 mg/ml ; 0.00252 mol/l
Class : Soluble
Log S (Ali) : -3.15
Solubility : 0.156 mg/ml ; 0.000701 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.38
Solubility : 0.0918 mg/ml ; 0.000413 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.26

Safety of [ 660838-05-1 ]

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 [ 660838-05-1 ]

* 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 [ 660838-05-1 ]

[ 660838-05-1 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 24424-99-5 ]
  • [ 95-80-7 ]
  • [ 660838-05-1 ]
YieldReaction ConditionsOperation in experiment
67% With triethylamine In methanol at -10℃; for 6h; [2-METHYL-5-TERT-BUTOXYCARBONYLAMINO-ANILINE] A solution of di-tert-butyldicarbonate (70 g, 320 mmol) in methanol [(200] mL) was added over 2 h to a cold [(-10C)] solution of 2, 4-diaminotoluene (30 g, 245 mmol) and triethylamine (30 mL) in methanol (15 mL). The reaction was followed by thin layer chromatography (hexane/ethyl acetate, 3: 1) and stopped after 4h by adding 50 mL of water. The mixture was concentrated in vacuo and the residue was dissolved in 500 mL of ethyl acetate. This organic phase was washed with water [(LU150] mL) and brine [(2X150] mL), dried over [MGS04,] and concentrated under reduced pressure. The resulting light brown solid was washed with small amounts of diethyl ether to give off-white crystals of 2-methyl-5-tert-butoxycarbonylamino-aniline in 67% yield. IR (neat): 3359; 3246; 2970; 1719; 1609; 1557; 1173; 1050 cm-1- 1H NMR [(CDCL3)] : [8] = 1.50 (s, 9H, tBu); 2.10 (s, 3H, ArCH3) ; 3.61 (br s, 2H, [NH2)] ; 6.36 (br s, 1H, [NH)] ; 6.51 (dd, [1H,] J= 7.9 Hz, 2.3 Hz, ArH); 6.92 (d, [1H,] J= 7.9 Hz, ArH) ; 6.95 (s, 1H, [ARH)-13C] NMR [(CDCI3)] [8] [= 16.] 6 (ArCH3) ; 28.3 (C (CH3) 3); 80.0 (C [(CH3)] 3); 105.2 (ArC); 108.6 (ArC); 116.9 (ArC); 130.4 (ArC-CH3) ; 137.2 (ArC-NH); 145.0 (ArC- [NH2)] ; 152.8 (COOtBu) MS ESI (m/z) (%): 223 (M+1), 167 (55,100%).
67% With triethylamine In methanol at -10℃; for 6h; A solution of di-tert-butyldicarbonate (70 g, 320 mmol) in methanol (200 mL) was added over 2 h to a cold (-10°C) solution of 2,4-diaminotoluene (30 g, 245 mmol) and triethylamine (30 mL) in methanol (15 mL). The reaction was followed by thin layer chromatography (HEXANE/ETHYL acetate, 3: 1) and stopped after 4h by adding 50 mL of water. The mixture was concentrated in vacuo and the residue was dissolved in 500 mL of ethyl acetate. This organic phase was washed with water (1x150 mL) and brine (2X150 ML), dried over MGSO4, and concentrated under reduced pressure. The resulting light brown solid was washed with small amounts of diethyl ether to give off-white crystals of 2-methyl-5-tert-butoxycarbonylamino-aniline in 67% yield. IR (neat): 3359; 3246; 2970; 1719; 1609; 1557; 1173; 1050 CM~L-IH NMR (CDC13) : 8 = 1.50 (s, 9H, tBu) ; 2.10 (s, 3H, ArCH3) ; 3.61 (br s, 2H, NH2) ; 6.36 (br s, 1H, NH) ; 6.51 (dd, 1H, J= 7.9 Hz, 2.3 Hz, ArH) ; 6.92 (d, 1H, J= 7.9 Hz, ArH); 6.95 (s, 1H, ARH)-13C NMR (CDC13) 8 = 16.6 (ArCH3) ; 28.3 (C (CH3) 3) ; 80.0 (C (CH3) 3); 105.2 (ArC); 108.6 (ArC) ; 116.9 (ArC); 130.4 (ArC-CH3); 137.2 (ARC-NH) ; 145.0 (ArC- NH2) ; 152.8 (COOtBu) MS ESI (m/z) (%): 223 (M+1), 167 (55,100%).
27% In methanol at -10℃; 7.1' To a stirred solution of A (5 g, 0.04 mmol) in MeOH (75 niL) was added (BOC)2O (11.59 g, 0.050 mmol), slowly at -10 0C. The reaction was stirred at this temperature for 4 h and then reaction mixture was concentrated under reduced pressure. The residue obtained was taken in EtOAc (300 mL). It was washed with water (25 mL), brine (25 mL) and dried over Na2SO4. Filtration followed by concentration under reduced pressure offered 4 (2.5 g, 27%) as an off- white solid.
  • 2
  • [ 24424-99-5 ]
  • [ 2458-12-0 ]
  • [ 660838-05-1 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In methanol at 20℃; 56.1 Step 1. Preparation of (3-amino-4-methyl-phenyl)-carbamic acid tert-butyl ester; The title compound was prepared according to the procedure decribed in J. Med. Chem. 1994,37, 636-646. To 4-methyl- benzene-1,3-diamine (4.93 g, 40.4 mmol), MeOH (220 mL) and triethylamine (5.1 mL, 36.7 mmol) was added di-tert-butyl dicarbonate (8.00 g, 36.7 mmol). The mixture was stirred overnight at RT and concentrated. The residue was dissolved in EtOAc and extracted with 10% aqueous NaHC03. The organic layer was dried over Na2S04, filtered and concentrated about 90% of the way. At this point the product which precipitated out of solution, was filtered and washed with EtOAc to yield (3-amino-4-methyl-phenyl) -carbamic acid tert-butyl ester.
  • 3
  • [ 630410-29-6 ]
  • [ 660838-05-1 ]
YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In ethanol for 16h;
98% With hydrogen In ethanol for 12h; 230 A solution of tert-hutyl (4-methyl-3-nitrophenyl)carbamate (Method 229; 10.0 g, 39.6 mmol) was dissolved in EtOH (220 ml). The solution was treated with 10% Pd/C (650 mg) and placed on a Parr Hydrogenator at 50 psi of hydrogen for 12 h. The resulting solution was filtered through celite and the solvent was removed under reduced pressure to give 8.68 g (98%). NMR (300 MHz): 6.86 - 6.98 (m, 2H), 6.48 (d, IH), 6.36 (s, IH), 3.59 (s, 2H), 2.09 (s, 3H), 1.42 - 1.50 (m, 9H).
98% With hydrogen In ethanol for 12h; 2 Method 2; fe;^-Butyl (3-amino-4-methylphenyl)carbamate; A solution of ter^-butyl (4-methyl-3-nitrophenyl)carbamate (Method 1; 10.0 g, 39.6 mmol) was dissolved in EtOH (220 ml). The solution was treated with 10% Pd/C (650 mg) and placed on a Parr hydrogenator at 50 psi of hydrogen for 12 h. The resulting solution was filtered through diatomaceous earth and the solvent was removed under reduced pressure to give 8.68 g (98%). NMR (300 MHz): 6.86 - 6.98 (m, 2H), 6.48 (d, IH), 6.36 (s, IH), 3.59 (s, 2H), 2.09 (s, 3H), 1.42 - 1.50 (m, 9H).
98% With hydrogen In ethanol for 12h; 36 Method 36; tert-Butyl (3-amino-4-methylphenyl)carbamate; A solution of tert-butyl (4-methyl-3-nitrophenyl) carbamate (Method 35; 10.0 g, 39.6 mmol) was dissolved in EtOH (220 ml). The solution was treated with 10% Pd/C (650 mg) and placed on a Parr Hydrogenator at 50 psi of hydrogen for 12 h. The resulting solution was filtered through celite and the solvent was removed under reduced pressure to give 8.68 g (98%).
96% With hydrogen In methanol at 20℃; for 1.5h; 2 Method 2; tert-Butyl (3 -amino-4-methylphenyl)carbamate; tert-Butyl (4-methyl-3-nitrophenyl)carbamate (Method 1; 31.54 g, 0.125 mol) and 10% Pd/C (1.71 g, 1.6 mmol) in methanol (200 ml) were shaken under 45 psi hydrogen for 90 min. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure giving 26.62 g of the title product (96%); NMR (300 MHz): 8.93 (s, IH)5 6.83 (s, IH)5 6.73 (d, IH)5 6.47 (dd, IH), 4.74 (s, IH), 1.95 (s, 3H), 1.45 (s, 9H).
96% With hydrogen In ethanol at 20℃; for 18h; 25.2 Step 2: synthesis of (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (27)10% palladium on charcoal (6 g) was added to a solution of (4-methyl-3-nitro-phenyl)- carbamic acid tert-butyl ester 26 (60 g, 238 mmol) in ethanol (1200 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 18 h. The palladium catalyst was removed by filtration over celite and the solvent was removed by evaporation to give (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester 27 (51 g, 96%).
96% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 18h; 25.2 Step 2: synthesis of (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (27) Step 2: synthesis of (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (27) 10% palladium on charcoal (6 g) was added to a solution of (4-methyl-3-nitro-phenyl)-carbamic acid tert-butyl ester 26 (60 g, 238 mmol) in ethanol (1200 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 18 h. The palladium catalyst was removed by filtration over celite and the solvent was removed by evaporation to give (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester 27 (51 g, 96%).
96% With 5%-palladium/activated carbon; hydrogen In methanol at 25℃; for 3h; Inert atmosphere; Compound 139 Preparation of Compound 139, tert-butyl N-(3-amino-4-methylphenyl)carbamate Preparation of Compound 139, tert-butyl N-(3-amino-4-methylphenyl)carbamate[00182] Compound 138 (30.5 g, 120.90 mmol) and palladium on carbon (5% JM Type87L, 6.1 g) in MeOH (300 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25 °C for 3 hours. The catalyst was filtered off through a pad of celite, washed with methanol and filtrate concentrated in vacuo to give an orange oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in DCM, to afford the desired material as a white solid (22.60 g, 96%).1H NMR (400 MHz, DMSO, 30 °C) d 1 .45 (9H, s), 1 .96 (3H, s), 6.49 (1 H, dd), 6.74 (1 H, d), 6.82 (1 H, d), 8.85 (1 H, s). m/z (ES+) (M+H)+ = 223.5.
92% With 5% Pd(II)/C(eggshell); hydrogen In ethanol for 15h;
92% With 5%-palladium/activated carbon; hydrogen In ethanol for 15h; Tert-butyl 3-amino-4-methylphenylcarbamate - 26 Tert-butyl 4-methyl-3-nitrophenylcarbamate (20.7 g, 82.0 mmol) was dissolved in 200 mL EtOH and 1.0g of 5% Pd/C was added. The mixture was hydrogenated on a parr system at 50 PSI hydrogen for 15 hours. Completion of reaction was shown by TLC in 30% EtOAc/Hex, then filtered, concentrated, and dried in a vacuum oven to yield the product 26 (16.78 g, 75.0 mmol, 92% yield). 1H NMR (300 MHz, D6 DMSO): δ 8.93 (hr s, 1H), 6.85 (s, 1H), 6.75 (d, 1H, J=8.0 Hz), 6.5 (d, 1H, J=8.0 Hz), 4.75 (s, 2H), 1.97 (s, 3H), 1.46 (s, 9H). 13C NMR (75 MHz, D6 DMSO): δ 153.58, 147.37, 138.777, 130.51, 115.87, 107.53, 105.07, 79.20, 29.05, 17.71. ESMS: m/z 223.2 [MH]+.
91% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Inert atmosphere; 7.2 Step 2: Compound 7b (2.9 g, 11.5 mmol) and 10% Pd/C (290 mg) were added to 30 mL of methanol and reacted overnight at room temperature under 2 atm of hydrogen atmosphere. After the formation of reactant product was determined by LC-MS, the solid was filtered out and the filtrate was concentrated to obtain Compound 7c (2.3 g, Yield 91%). 1H NMR (400 MHz, CDCl3): δ ppm 6.97 (s, 1H), 6.94 (d, J=8.0, 1H), 6.51 (dd, J1=2.0, J2=2.0, 1H), 6.34 (brs, 1H), 3.62 (brs, 2H), 2.12 (s, 3H), 1.53 (s, 9H); MS [M - 55]+ 167.1.
91% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Inert atmosphere; 7.2 Compound 7b (2.9 g, 11.5 mmol) and 10% Pd/C(290 mg) were added to 30 mE of methanol and reactedovernight at room temperature under 2 atm ofhydrogen atmosphere. Afier the formation of reactant product was deterBocmined by EC-MS, the solid was filtered out and the filtratewas concentrated to obtain Compound 7c (2.3 g, Yield 91%).J=8.0, 1H), 6.51 (dd, J,=2.0, J220 ,H), 6.34 (brs, 1H), 3.62‘H NMR (400 MHz, CDC13): ö ppm 6.97 (s, 1H), 6.94 (d,(brs, 2H), 2.12 (s, 3H), 1.53 (s, 9H); MS [M-55] 167.1.
65% With 3% Pd/C; hydrogen In ethanol at 20℃;
With hydrogen In ethanol for 2h; 16; 9.2 t-Butyl 4-methyl-3-nitrophenyl carbamate (7.6g, 30.13mmol) was dissolved in ethanol (167mL) and subjected to a reaction under 50 psi H2 gas. The reaction mixture was stirred for 2 hours and then concentrated by filtering with Celite to obtain the title compound without further purification. NMR (400 MHz, DMSO-d6) 68.92 (s, 1H), 6.82 (s, 1H), 6.64 (d, 1H), 6.48 (d, 1H), 4.73 (s, 2H), 1.88 (s, 3H), 1.44 (s, 9H).
With 10% Pd/C; hydrogen In tetrahydrofuran; ethanol at 20℃; for 22h; 14 General procedure: General procedure: To a solution of 8 (10.1 g, 39.8 mmol) in EtOH (60 mL) and THF (20 mL) was added 10% Pd/C (2.12 g). The mixture was stirred at room temperature for 22 h under H2 atmosphere (3 atm). The mixture was diluted with EtOAc (80 mL) and passed through a pad of Celite. _The filtrate was concentrated in vacuo to give tert-butyl (3-amino-4-methylphenyl) carbamate 9 as colorless solid (8.82 g). This material was used for the next reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.44 (9H, s), 1.95 (3H, s), 4.72 (2H, br s), 6.48 (1H, d, J = 7.9 Hz), 6.73 (1H, d, J = 7.9 Hz), 6.82 (1H, s), 8.90 (1H, br s).
With hydrogen In ethanol for 2h; P.9.2 Step 2: t-Butyl 3-amino-4-methylphenylcarbamate t-Butyl 4-methyl-3-nitrophenylcarbamate (7.6 g, 30.13 mmol) was dissolved in ethanol (167 mL) and subjected to a reaction under 50 psi H2 gas. The reaction mixture was stirred for 2 hours and then concentrated by filtering with Celite to obtain the title compound without further purification. 1H NMR (400 MHz, DMSO-d6) δ8.92 (s, 1H), 6.82 (s, 1H), 6.64 (d, 1H), 6.48 (d, 1H), 4.73 (s, 2H), 1.88 (s, 3H), 1.44 (s, 9H).
5 g With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 2h;
With hydrogen In methanol for 24h; 3 Into a solution of (4-methyl-3-nitro-phenyl)-carbamic acid tert-butyl ester (1.0 g, 3.96 mmol, 1.0 eq.) in MeOH (25 ml) is added Pd-C (0.1 g, 10 wt %). The suspension is stirred under hydrogen atmosphere in a Parr shaker (60 psi) for 24 hours. The reaction mixture is then filtered over celite and the filtrate is concentrated under reduced pressure to give the desired product. IH P A T E N TGNF Docket No.: P1267PC10NMR δ 7.19 (s, IH), 6.93 (s, IH), 6.87 (d, IH, J = 8.0 Hz), 6.52 (d, IH, J =8.0 Hz), 6.32 (s, IH). MS m/z 223.1(M + 1).

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  • 4
  • [ 870221-17-3 ]
  • [ 660838-05-1 ]
  • [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 130℃; Step 2. Preparation of [4-methyl-3-(3-pyrimidin-4-yl- pyridin-2-ylamino) -phenyl]-carbamic acid tert-butyl ester; The title compound was prepared according to the procedure decribed in Tetrahedron 2001,51, 7027-7034. Pd(OAc)2 (47 mg, 0.21 mmol), and rac-BINAP (131 mg, 0.21 mmol) were stirred in toluene (12 mL) at RT for 12 minutes. This mixture was added to <strong>[870221-17-3]4-(2-chloro-pyridin-3-yl)-pyrimidine</strong> (1.01 g, 5.24 mmol), (3-amino-4-methyl-phenyl) -carbamic acid tert-butyl ester (1.63 g, 7.34 mmol), and K2C03 (14.5 g, 105 mmol) in toluene (40 mL). The mixture was heated overnight at 130 C in a sealed tube. The cooled reaction was filtered through a pad of Celite, partially concentrated and the resulting solid was filtered to yield [4-methyl-3-(3- pyrimidin-4-yl-pyridin-2-ylamino) -phenyl]-carbamic acid tert-butyl ester.
  • 5
  • [ 660838-05-1 ]
  • [ 872091-36-6 ]
  • [ 872092-02-9 ]
YieldReaction ConditionsOperation in experiment
21% In toluene for 12h; Heating / reflux; 38 Method 38; tert-Butyl [3-(8-methoxy-4-oxoquinazolin-3(4Hj-yl)-4-methylphenyllcarbamate; A solution of 8-methoxy-4H-3, I -benzoxazin-4-one (Method 37; 200 mg, 1.13 mmol) and tert-butyl (3-amino-4-methylphenyl) carbamate (Method 36; 138 mg, 1.13mmole) were refluxed in toluene (10 ml) for 12 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel) using EtOAc-DCM (3:1) to yield 90 mg of a white solid (21%).
  • 6
  • [ 6925-00-4 ]
  • [ 660838-05-1 ]
  • [ 884000-87-7 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 24h; Method 3; tert-Butyl {4-methyl-3-r(quinoxalin-6-ylcarbonyl')amino1phenyl>carbamate; A solution of tert-butyl (3-amino-4-methylphenyl)carbamate (Method 2; 50.10 g, 0.23 mol), <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (50.10 g, 0.23 mol) and diisoproplyethylamine (70 ml, 0.68 mol) in DMF (575 ml) was treated with HATU (94.3 g, 0.25 mol). The reaction was stirred at 25 0C for 24 h. The reaction was quenched with H2O and extracted with EtOAc. The organics were dried with NaCl (sat) and then Na2SO4 (s) and removed under reduced pressure. The resulting solid was recrystallized from DCM/hexanes affording the product as brown crystals; m/z 379.
  • 7
  • [ 660838-05-1 ]
  • [ 57573-59-8 ]
  • [ 878745-39-2 ]
YieldReaction ConditionsOperation in experiment
58% With caesium carbonate In 1,4-dioxane at 80℃; for 12h; 4 Method 4; ferf-Butyl (4-methyl-3 - [(3 -methyl-4-oxo-3 ,4-dihvdroquinazolm-6-10 vDaminolphenyll carbamate; A stirred mixture of fers-butyl (3-amino-4-methylphenyl)carbamate (Method 2; 3.08 g, 0.0135 mmol), 6-bromo-3-methylquinazolin-4(3H)-one (Method 3; 3.24 g, 0.0135 mmol), Cs2CO3 (13.20 g, 0.0405 mol, 3.0 equiv), BIνAP (841 mg, 1.35 mmol, 5 mol%) in dioxane (50 ml) was treated with Pd2(dba)3 (618 mg, 0.675 mmol). The reaction mixture was heated to15 80 0C for 12 h. The reaction was then quenched with 10% νaOη(aq) and extracted with EtOAc. The organics were dried with NaCl(sat) and then Na2SO4(S). The organics were removed under reduced pressure and the resulting solid was treated with DCM (100 ml). The resulting precipitate was collected by vacuum filtration (3.00 g, 58%); m/z 387.
  • 8
  • [ 660838-05-1 ]
  • N-chlorocarbonyl-N-methyl-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine [ No CAS ]
  • (4-methyl-3-{3-methyl-3-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ureido}-phenyl)-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 23℃; for 8.25h; 1 To a solution of 5 (0.182 g, 0.82 mmol, 1.0 eq.),) and diisopropylethylamine (0.14 ml, 0.82 mmol, 1.0 eq.) in dichloromethane (2.0 ml) at 230C is added carbamoyl chloride 4 (0.3 g, 0.82 mmol, 1.0 eq.) drop wise over a period of 15 EPO minutes. The reaction mixture is further stirred at room temperature for a period of 8 hours after which, it is partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated to afford the title product which is used in the next step without further purification
  • 9
  • [ 660838-05-1 ]
  • [ 946422-05-5 ]
  • [ 946422-07-7 ]
YieldReaction ConditionsOperation in experiment
With potassium <i>tert</i>-butylate In 1,4-dioxane at 100℃; for 16h; 5 Example 5; f3-l3-r6-(2λ-Diiτiethoxy-benzylamino')-pyrimidin-4-yl]-pyridin-2-ylamino>-4-rnethyl- phenylVcarbamic acid tert-butvl ester; [0096] [δ-CZ-Chloro-pyridin-S-y^-pyrimidin^-ylJ-Cl^-dimethoxy-benzy^-amine(360mg, lmmol) is mixed with (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (340mg, 1.5mmol), palladium acetate (112mg, 0.5mmol), Xantophos (435mg, 0.75mmol) and potassium t-butoxide (225mg, 2mmol). 1OmL anhydrous 1,4-dioxane is added under nitrogen environment and the mixture is heated to 1000C for 16 hours. After cooling down to room temperature and evaporating the solvent, the crude product is purified by silica gel column by elution with 10% MeOH in DCM. The final product is yellow solid, 390mg. MS m/z 543.2 (M + 1).
  • 10
  • [ 660838-05-1 ]
  • [ 946422-12-4 ]
  • [ 946422-15-7 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In iso-butanol at 110℃; for 24h; 7 A mixture of compound 4'-chloro-6-methylsulfanyl-[4,5']bipyrimidinyl(353 mg, 1.479 mmol), (3-amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (361 mg, 1.624 mmol), DIPEA (0.615 mL, 1.24 mmol) in 2-butanol (7 mL) is heated at 1100C for 24 hours. Then the reaction mixture is cooled to room temperature. The solid is filtered and washed with water, isopropanol, dried to afford [4-methyl-3-(6-methylsulfanyl- [4,51]bipyrimidinyl-4'-ylamino)-phenyl]-carbamic acid tert-butyl ester (587 mg). MS m/z 425.17 (M + 1).
  • 11
  • [ 660838-05-1 ]
  • [ 352529-36-3 ]
  • [ 1024583-35-4 ]
YieldReaction ConditionsOperation in experiment
86% With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; 3 (3-{ r2-(3-Ethyl-ureido)-benzothiazole-6-carbonyll-aminol-4-methyl-phenyl)-carbamic acid tert- butyl ester; [0095] To a flask is added 2-(3-ethyl-ureido)-benzothiazole-6-carboxylic acid (0.10 g), 3- amino-4-methylphenyl carbamic acid tert-butyl ester (0.083 g), HATU (0.14 g), Et3N (65 μL) and DMF (3 mL). After being stirred at rt overnight, the mixture is poured into water and extracted with EtOAc. The organic layer is separated, then concentrated and the residue is washed with DCM to afford (3-{ [2-(3-ethyl-ureido)-benzothiazole-6-carbonyl]-amino}-4-methyl-phenyl)- carbamic acid tert-butyl ester. 1H NMR (400 MHz, DMSO) δ 10.90 (s, IH), 9.85 (s, IH), 9.30 (s, IH), 8.50 (s, IH), 8.00 (d, J = 6.8 Hz, IH), 7.70 (d, J = 6.8 Hz, IH), 7.50 (s, IH), 7.20 (d, J = 6.8 Hz, IH), 7.10 (d, J = 7.0 Hz, IH), 6.80 (s, IH), 3.20 (p, J = 6.7 Hz, 2H), 2.15 (s, 3H), 1.45 (s, 9H), 1.10 (t, J = 6.7 Hz, 2H). MS (ESI) m/z: 470 (M+H)+.
82% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide
  • 12
  • [ 660838-05-1 ]
  • C17H24Cl2N2OSi [ No CAS ]
  • C29H41ClN4O3Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; 3 To a suspension of acyl chloride in CH2Cl2 (20 mL) at 0 0C is added (3-amino-4- methyl-phenyl)-carbamic acid tert-butyl ester (232 mg, 1.04 mmol), followed by slow addition of DIEA (1.05 mL). The yellow solution is warmed up slowly and stirred at rt overnight. EtOAc (100 mL) and water (20 mL) are added. The aqueous layer is separated. EtOAc is washed with brine (10 mL), dried over MgSO4, and evaporated to give a light amber colored residue.
  • 13
  • [ 660838-05-1 ]
  • [ 503-66-2 ]
  • C15H22N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-hydroxypropionic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.0833333h; Stage #2: t-butyl 3-amino-4-methylphenylcarbamate In N,N-dimethyl-formamide at 20℃; for 2h; 39.A N-(5-amino-2-methylphenyl)-3-hydroxypropanamide. To a solution of 3-hydroxypropanoic acid (2.03 g, 6.75 mmol) in DMF (7.5 mL) was added HOBt (1.03 g, 6.75 mmol) and EDC (1.29 g, 6.75 mmol). After 5 minutes, tert-butyl 3-amino-4- methylphenylcarbamate (750 mg, 3.37 mmol) was added and the reaction was stirred at room temperature. After 2 hours the reaction was partitioned between ethyl acetate and water, washing the aqueous layer with ethyl acetate (2x). The organics were combined, dried over magnesium sulfate, filtered, and concentrated to an oil. The crude residue was purified by silica gel chromatography (2-12% methanol in dichloromethane) and the fractions containing product were combined and condensed to a colorless oil. The product was dissolved in dichloromethane (10 mL), acidified with 6 mL of 4 M HCl and stirred at room temperature for 4 hours The residue was neutralized on a Strata-XC ion exchange column (Phenomenex). The product was loaded and the column washed successively with water, and methanol. The product was released with 5% ammonium hydroxide in methanol and product containing eluent was concentrated under reduced pressure and dried to give the title compound as a colorless oil (131 mg, 0.67 mmol, 20% yield); MS (ESI) MS (ESI) m/z 195.1 [M+l]+
  • 14
  • [ 660838-05-1 ]
  • [ 120-92-3 ]
  • C17H26N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium cyanoborohydride; zinc(II) chloride In methanol for 2h; 26.A To a solution of tert- butyl 3-amino-4-methylphenylcarbamate (0.43 g, 1.934 mmol) and cyclopentanone (0.65 g, 7.74 mmol) in methanol (5 mL) was added a solution of zinc(II) chloride (0.791 g, 5.80 mmol) and sodium cyanoborohydride (0.729 g, 11.61 mmol) in methanol (5 mL). The mixture was stirred 2h and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes) the fractions containing product were concentrated. The Boc-intermediate was dissolved in methanol (5 mL) and 4N HCl in dioxane (5 mL) was added. The mixture was stirred 3h and concentrated. The residue was dissolved in ethyl acetate (40 mL) followed by the addition of 4M potassium hydroxide (5 mL) and water (40 mL). The mixture was shaken and separated. The organic layer was dried (Na2SO4), filtered, and concentrated to afford the title compound (0.25 g, 68% yield over 2 steps); 1H NMR (400 MHz, CHLOROFORM-d) δ 6.92 (d, J- 7.81 Hz, IH), 6.69 (s, IH), 6.58 (d, J= 7.03 Hz, IH), 6.35 (br. s., IH), 3.72 - 3.89 (m, IH), 3.47 (br. s., 2H), 1.98 - 2.12 (m, 2H), 1.69 - 1.78 (m, 2H), 1.59 - 1.68 (m, 4H).
  • 15
  • [ 660838-05-1 ]
  • [ 75-36-5 ]
  • [ 1172621-17-8 ]
YieldReaction ConditionsOperation in experiment
65.1% With triethylamine In tetrahydrofuran; dichloromethane at 25℃; for 15h; 24.A Methylphenylcarbamate. To a solution of tert-butyl 3-amino-4-methylphenylcarbamate (0.445 g, 2 mmol), triethylamine (1.214 g, 12.00 mmol), in DCM (10 mL) and THF (2 mL) was added 2-(dimethylamino) acetyl chloride (0.729 g, 6.00 mmol). The reaction mixture was stirred at 25°C for 15 h and saturated aqueous sodium chloride (25 mL) was added and extracted with ethyl acetate (3 x 25 mL). The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by silica gel chromatography (90% ethyl acetate in hexanes) to give the title compound as light yellow solid (0.4 g, 1.301 mmol, 65.1% yield); 1H NMR (400 MHz, DMSO-d6) δ 9.26 (br s, 2H), 7.78 (d, J= 2.34 Hz, IH), 7.12 (dd, J= 1.95, 8.20 Hz, IH), 7.06 (d, J= 8.20 Hz, IH), 3.06 (s, 2H), 2.31 (s, 6H), 1.46 (s, 9H); MS (ESI) m/z 308.4 [M+l]+.
  • 16
  • [ 660838-05-1 ]
  • [ 103-71-9 ]
  • [ 1301267-30-0 ]
YieldReaction ConditionsOperation in experiment
In chloroform at 55℃; for 18h; 40.A A solution of tert-butyl 3-amino-4- methylphenylcarbamate (0.6 g, 2.70 mmol) and phenyl isocyanate (0.324 mL, 2.97 mmol) in chloroform (25 mL) was heated at 55°C for 18 hours. The white solid was filtered to give tert-butyl 4-methyl-3-(3-phenylureido)phenylcarbamate (900 mg). This intermediate was dissolved in methylene chloride (20 mL) and TFA was added (4 mL). of very clean boc protected l-(5-amino-2-methylphenyl)-3-phenylurea. After stirring for 1 hour, the reaction was concentrated and neutralized on a Strata-XC ion exchange column (Phenomenex). The product was loaded and the column washed successively with water, acetonitrile, and methanol. The product was released with 5% ammonium hydroxide in methanol and product containing eluent was concentrated under reduced pressure and dried to give the title compound; MS (ESI) m/z 242.2 [M+l]+.
  • 17
  • [ 660838-05-1 ]
  • [ 6780-38-7 ]
  • [ 1172621-18-9 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; for 15h; 25.A To a solution of tert-butyl 3-amino-4-methylphenylcarbamate (0.667 g, 3 mmol), 2-(l,3-dioxoisoindolin-2-yl)acetyl chloride (0.671 g, 3.00 mmol) in DCM (10 mL) was added diisopropylethylamine (1.048 mL, 6.00 mmol). After stirring 25 °C for 15 h, saturated aqueous sodium chloride (25 mL) was added and extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated. The crude product was purified by silica gel chromatography (100% ethyl acetate) to give the title compound as a white solid (1.15 g, 2.81 mmol, 94% yield); 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, IH), 9.29 (s, IH), 7.91 - 7.99 (m, 2H), 7.83 - 7.91 (m, 2H), 7.56 (s, IH), 7.13 (d, J= 8.20 Hz, IH), 7.07 (d, J- 8.20 Hz, IH), 4.45 (s, 2H), 2.11 (s, 3H), 1.45 (s, 9H).
  • 18
  • [ 5781-53-3 ]
  • [ 660838-05-1 ]
  • [ 1172621-34-9 ]
YieldReaction ConditionsOperation in experiment
82% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; 38.A To a solution of tert-butyl 3 -amino-4-methylphenyl carbamate (500 mg, 2.25 mmol) in dichloromethane (25 mL) was added methyl 2-chloro-2-oxoacetate (0.25 mL, 2.70 mmol) and N,N-diisopropylethylamine (0.6 mL, 3.4 mmol). The reaction was stirred at room temperature overnight and concentrated. The crude residue was purified by silica gel chromatography (10-70% ethyl acetate in hexanes) to give the title compound as a white solid (572 mg, 1.86 mmol, 82% yield); MS (ESI) MS (ESI) m/z 309.5 [M+l]+
  • 19
  • [ 660838-05-1 ]
  • [ 16064-09-8 ]
  • [ 878745-39-2 ]
YieldReaction ConditionsOperation in experiment
82% With tris-(dibenzylideneacetone)dipalladium(0); dibutyl butylphosphonate; sodium t-butanolate for 8h;
With tris-(dibenzylideneacetone)dipalladium(0); sodium methylate; johnphos In toluene for 8h; Reflux; Tert-butyl 4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl-amino)phenylcarbamate 29 To refluxing toluene (50 mL) in a 150 mL round bottom flask was added 2-methyl-5-t-butylcarbamate aniline 23 (3 g, 13.50 mmol, 1.2 eq), -chloro-3-methyl- 4-oxoquinazoline 28(2.19 g, 11.25 mmol, 1 eq), NaOMe (1.51 g, 15.75 mmol, 1.4 eq), and 2- diphenylbistbutylphosphine (168 mg, 5 mol %, 0.561 mmol), and Pd2(dba)3 (309 mg , 3 mol%, 0.336 mmol). This mixture was refluxed for 8 hours when it was observed there was complete amination of quinazolinone starting material. The reaction mixture was cooled to room temperature and poured into 250 mL EtOAc and then washed with sodium bicarbonate (2x100 mL), water (2x100 mL), and then brine (2x100 mL). The light brown solid was then purified by flash chromatography on silica (70% EtOAc/Hex) to yield desired product 29 as a light yellow solid (3.6 g, 9.33 mmol, 83% yield). 1H NMR (300 MHz, D6 DMSO): δ 7.91 (s, 1H), 7.64 (d, 1H, J=2.7 Hz), 7.61 (s, 1H, J=8.8 Hz), 7,34 (dd, 1H, J=2.7 Hz, J=8.8 Hz), 7.29 (s, 1H), 7.16 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=8.2 Hz), 6.47 (s, 1H), 5.70 (s, 1H), 3.59 (s, 3H), 1.64 (s, 3H), 1.51 (s, 9H). 13C NMR (75 MHz, D6 DMSO): δ 161.34, 153.57, 145.59, 145.58, 141.04, 139.09, 131.84, 129.01, 125.35,123.96, 123.24, 114.31, 112.49, 108.33, 79.70, 34.26, 28.97, 18.14. ESMS: m/z 381.2 [MH]+.
  • 20
  • [ 660838-05-1 ]
  • [ 1202759-59-8 ]
  • [ 1202759-64-5 ]
YieldReaction ConditionsOperation in experiment
22% With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene for 12h; Reflux; Inert atmosphere; 7.2 A solution of 3 (0.1 g, 0.43 mmol), 4 (0.14 g, 0.64 mmol), Pd(OAc)2 (10 mg, 0.043 mmol), BINAP (0.013 g, 0.021 mmol) and Cs2CO3 (0.2 g, 1.06 mmol) in degassed toluene (toluene was purged with N2 for 15 min) was refluxed for 12 h under N2 atmosphere. The reaction mixture was cooled and passed through a short bed of celite. The filtrate was diluted with EtOAc (25 mL) and washed with water (5 mL), brine (5 mL) and dried over Na2SO4. Filtration followed by concentration under reduced pressure offered a residue which was further purified by column chromatography (SiO2, 60-120, CHCl3/MeOH : 9/1) gave 5 (40 mg, 22%) as an off-white solid.
  • 21
  • [ 24424-99-5 ]
  • [ 660838-05-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran / 18 h / 65 °C 2: hydrogen / ethanol / 2 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 65 °C / Reflux 2: hydrogen / palladium 10% on activated carbon / ethanol / 18 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1.1: dmap / acetonitrile / 0.08 h 1.2: 72 h 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 16 h
Multi-step reaction with 2 steps 1: tetrahydrofuran / 15.5 h / 70 °C 2: 10% Pd/C; hydrogen / tetrahydrofuran; ethanol / 22 h / 20 °C / 2280.15 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / Reflux 2: 3% Pd/C; hydrogen / ethanol / 20 °C
Multi-step reaction with 2 steps 1: tetrahydrofuran / 65 °C / Reflux 2: 5%-palladium/activated carbon; hydrogen / ethanol / 15 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 18 h / 65 °C 2: hydrogen / ethanol / 2 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 60 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 20 °C / 1520.1 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 60 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 20 °C / 1520.1 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: tetrahydrofuran / 16.33 h / 65 °C 2: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 25 °C / 3750.38 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran / 20 h / Inert atmosphere; Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12.5 h / 65 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 12 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12 h / Heating / reflux 2: hydrogen / palladium 10% on activated carbon / methanol / 24 h / 3102.97 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12.5 h / 65 °C / Heating / reflux 2: hydrogen / palladium 10% on activated carbon / ethanol / 12 h / 2585.81 Torr

Reference: [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2
[2]Current Patent Assignee: MERCK & CO INC - WO2011/147764, 2011, A1
[3]Wylie, Laura; Innocenti, Paolo; Whelligan, Daniel K.; Hoelder, Swen [Organic and Biomolecular Chemistry, 2012, vol. 10, # 22, p. 4441 - 4447]
[4]Hirose, Masaaki; Okaniwa, Masanori; Miyazaki, Tohru; Imada, Takashi; Ohashi, Tomohiro; Tanaka, Yuta; Arita, Takeo; Yabuki, Masato; Kawamoto, Tomohiro; Tsutsumi, Shunichirou; Sumita, Akihiko; Takagi, Terufumi; Sang, Bi-Ching; Yano, Jason; Aertgeerts, Kathleen; Yoshida, Sei; Ishikawa, Tomoyasu [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5600 - 5615]
[5]Ranjitkar, Pratistha; Perera, B. Gayani K.; Swaney, Daniel L.; Hari, Sanjay B.; Larson, Eric T.; Krishnamurty, Ratika; Merritt, Ethan A.; Villén, Judit; Maly, Dustin J. [Journal of the American Chemical Society, 2012, vol. 134, # 46, p. 19017 - 19025]
[6]Current Patent Assignee: VIBLIOME THERAPEUTICS - WO2013/22766, 2013, A1
[7]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - US2013/53370, 2013, A1
[8]Current Patent Assignee: HISUN GROUP CO., LTD. - EP2754659, 2014, A1
[9]Current Patent Assignee: HISUN GROUP CO., LTD. - US2014/378488, 2014, A1
[10]Current Patent Assignee: CANCER RESEARCH UK - WO2015/49535, 2015, A1
[11]Liang, Xiaofei; Liu, Xiaochuan; Wang, Beilei; Zou, Fengming; Wang, Aoli; Qi, Shuang; Chen, Cheng; Zhao, Zheng; Wang, Wenchao; Qi, Ziping; Lv, Fengchao; Hu, Zhenquan; Wang, Li; Zhang, Shanchun; Liu, Qingsong; Liu, Jing [Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 1984 - 2004]
[12]Current Patent Assignee: ASTRAZENECA PLC - WO2007/113557, 2007, A1
[13]Current Patent Assignee: MERCK & CO INC - US2013/79341, 2013, A1
[14]Current Patent Assignee: IRM LLC - WO2008/144253, 2008, A1
[15]Current Patent Assignee: ASTRAZENECA PLC; DAKIN - WO2005/123696, 2005, A1
  • 22
  • [ 660838-05-1 ]
  • [ 1318242-88-4 ]
  • [ 1318243-02-5 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; 17; 82.1 4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxylic acid (5.3g, 22.49mmol) obtained in Step 3 of Preparation Example 4 was dissolved in DMF (60mL). t-Butyl 3-amino-4-methylphenylcarbamate (6g, 26.99mmol) obtained in Step 2 of Preparation Example 9, EDCI (6.5g, 33.74mmol), HOBT (6.1g, 44.98mmol) and TEA (4.7mL, 33.74mmol) were sequentially added to the reaction mixture, which was stirred at room temperature for 24 hours. After the reaction was completed water (120mL) was added thereto, and the resulting yellow solid was filtered and dried to obtain the title compound without further purification.MS m/z [M+l] 439.84.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; 82.1 Step 1: t-Butyl 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylphenylcarbamate Step 1: t-Butyl 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylphenylcarbamate 4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxylic acid (5.3 g, 22.49 mmol) obtained in Step 3 of Preparation Example 4 was dissolved in DMF (60 mL). t-Butyl 3-amino-4-methylphenylcarbamate (6 g, 26.99 mmol) obtained in Step 2 of Preparation Example 9, EDCI (6.5 g, 33.74 mmol), HOBT (6.1 g, 44.98 mmol) and TEA (4.7 mL, 33.74 mmol) were sequentially added to the reaction mixture, which was stirred at room temperature for 24 hours. After the reaction was completed water (120 mL) was added thereto, and the resulting yellow solid was filtered and dried to obtain the title compound without further purification. MS m/z [M+1] 439.84.
  • 23
  • [ 119-32-4 ]
  • [ 660838-05-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran / 18 h / 65 °C 2: hydrogen / ethanol / 2 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 65 °C / Reflux 2: hydrogen / palladium 10% on activated carbon / ethanol / 18 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1.1: dmap / acetonitrile / 0.08 h 1.2: 72 h 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 16 h
Multi-step reaction with 2 steps 1: tetrahydrofuran / 15.5 h / 70 °C 2: 10% Pd/C; hydrogen / tetrahydrofuran; ethanol / 22 h / 20 °C / 2280.15 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / Reflux 2: 3% Pd/C; hydrogen / ethanol / 20 °C
Multi-step reaction with 2 steps 1: tetrahydrofuran / 65 °C / Reflux 2: 5%-palladium/activated carbon; hydrogen / ethanol / 15 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 18 h / 65 °C 2: hydrogen / ethanol / 2 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 60 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 20 °C / 1520.1 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 60 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 20 °C / 1520.1 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: tetrahydrofuran / 16.33 h / 65 °C 2: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 25 °C / 3750.38 Torr / Inert atmosphere
Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran / 20 h / Inert atmosphere; Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12.5 h / 65 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 12 h / 2585.81 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 18 h / 20 °C / 760.05 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12 h / Heating / reflux 2: hydrogen / palladium 10% on activated carbon / methanol / 24 h / 3102.97 Torr
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12.5 h / 65 °C / Heating / reflux 2: hydrogen / palladium 10% on activated carbon / ethanol / 12 h / 2585.81 Torr

Reference: [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2
[2]Current Patent Assignee: MERCK & CO INC - WO2011/147764, 2011, A1
[3]Wylie, Laura; Innocenti, Paolo; Whelligan, Daniel K.; Hoelder, Swen [Organic and Biomolecular Chemistry, 2012, vol. 10, # 22, p. 4441 - 4447]
[4]Hirose, Masaaki; Okaniwa, Masanori; Miyazaki, Tohru; Imada, Takashi; Ohashi, Tomohiro; Tanaka, Yuta; Arita, Takeo; Yabuki, Masato; Kawamoto, Tomohiro; Tsutsumi, Shunichirou; Sumita, Akihiko; Takagi, Terufumi; Sang, Bi-Ching; Yano, Jason; Aertgeerts, Kathleen; Yoshida, Sei; Ishikawa, Tomoyasu [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5600 - 5615]
[5]Ranjitkar, Pratistha; Perera, B. Gayani K.; Swaney, Daniel L.; Hari, Sanjay B.; Larson, Eric T.; Krishnamurty, Ratika; Merritt, Ethan A.; Villén, Judit; Maly, Dustin J. [Journal of the American Chemical Society, 2012, vol. 134, # 46, p. 19017 - 19025]
[6]Current Patent Assignee: VIBLIOME THERAPEUTICS - WO2013/22766, 2013, A1
[7]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - US2013/53370, 2013, A1
[8]Current Patent Assignee: HISUN GROUP CO., LTD. - EP2754659, 2014, A1
[9]Current Patent Assignee: HISUN GROUP CO., LTD. - US2014/378488, 2014, A1
[10]Current Patent Assignee: CANCER RESEARCH UK - WO2015/49535, 2015, A1
[11]Liang, Xiaofei; Liu, Xiaochuan; Wang, Beilei; Zou, Fengming; Wang, Aoli; Qi, Shuang; Chen, Cheng; Zhao, Zheng; Wang, Wenchao; Qi, Ziping; Lv, Fengchao; Hu, Zhenquan; Wang, Li; Zhang, Shanchun; Liu, Qingsong; Liu, Jing [Journal of Medicinal Chemistry, 2016, vol. 59, # 5, p. 1984 - 2004]
[12]Current Patent Assignee: ASTRAZENECA PLC - WO2007/113557, 2007, A1
[13]Current Patent Assignee: MERCK & CO INC - US2013/79341, 2013, A1
[14]Current Patent Assignee: IRM LLC - WO2008/144253, 2008, A1
[15]Current Patent Assignee: ASTRAZENECA PLC; DAKIN - WO2005/123696, 2005, A1
  • 24
  • [ 660838-05-1 ]
  • [ 1351237-52-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: toluene; tetrahydrofuran / 1 h / 90 °C
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: diphenyl phosphoryl azide; triethylamine / toluene / 1 h / 100 °C 3.2: 1 h / 90 °C
  • 25
  • [ 660838-05-1 ]
  • [ 1351237-73-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: trimethylaluminum / toluene / 0.25 h 3.2: 60 °C
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: trimethylaluminum / toluene / 0.25 h 3.2: 60 °C
  • 26
  • [ 660838-05-1 ]
  • N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C
  • 27
  • [ 660838-05-1 ]
  • [ 1351238-26-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 3 h / 20 °C
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 3 h / 20 °C
  • 28
  • [ 660838-05-1 ]
  • [ 1351237-26-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 3 h / 20 °C 4.1: triethylamine / ethanol / 80 - 150 °C / Microwave irradiation
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h 1.2: 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 3 h / 20 °C 4.1: hydrogenchloride; triethylamine / ethanol / 80 - 150 °C / Microwave irradiation
  • 29
  • [ 660838-05-1 ]
  • [ 59944-79-5 ]
  • [ 1351238-24-8 ]
YieldReaction ConditionsOperation in experiment
66.4% Stage #1: thieno[2,3-b]pyrazine-6-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.25h; Stage #2: t-butyl 3-amino-4-methylphenylcarbamate In N,N-dimethyl-formamide at 20℃; 25.3 Step 3: synthesis of tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6- carboxamido)phenylcarbamate (28)A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (1.01 g, 5.61 mmol), HATU (1.8 g, 5.61 mmol) and DIPEA (1.953 mL, 11.21 mmol) in DMF (8 mL) was stirred for 15min. (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl 27 (1.246 g, 5.61 mmol), DIPEA (1 eq) in DMF (8 mL) were added and stirred overnight at rt. Citric acid solution (3%) was added and extracted with EtOAc. Organic layer was washed with NaHCC"3 solution, brine, dried and evaporated. Purification by chromatography (0-20% EtOAc in CH2CI2) gave tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6- carboxamido)phenylcarbamate 28 (1.43 g, 66.4 %). (m/z) = 385 (M+H)+.
66.4% Stage #1: thieno[2,3-b]pyrazine-6-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.25h; Stage #2: t-butyl 3-amino-4-methylphenylcarbamate In N,N-dimethyl-formamide at 20℃; 25.3 Step 3: synthesis of tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate (28) Step 3: synthesis of tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate (28) A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (1.01 g, 5.61 mmol), HATU (1.8 g, 5.61 mmol) and DIPEA (1.953 mL, 11.21 mmol) in DMF (8 mL) was stirred for 15 min. (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl 27 (1.246 g, 5.61 mmol), DIPEA (1 eq) in DMF (8 mL) were added and stirred overnight at rt. Citric acid solution (3%) was added and extracted with EtOAc. Organic layer was washed with NaHCO3 solution, brine, dried and evaporated. Purification by chromatography (0-20% EtOAc in CH2Cl2) gave tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate 28 (1.43 g, 66.4%). (m/z)=385 (M+H)+.
  • 30
  • [ 660838-05-1 ]
  • [ 1380445-54-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: Oxone / dichloromethane; water / 2 h 2: tetrahydrofuran; diethyl ether / 4 h / -40 °C
  • 31
  • [ 660838-05-1 ]
  • [ 1380445-53-3 ]
YieldReaction ConditionsOperation in experiment
62% With Oxone In dichloromethane; water for 2h;
  • 32
  • [ 660838-05-1 ]
  • [ 98027-74-8 ]
  • [ 1125633-20-6 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 10 - 20℃; for 0.5h; To a solution of 9 in THF (200 mL) were added i-Pr2NEt (10.4 mL, 59.8 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate 10 (9.49 g, 43.8 mmol) at 10 °C. The mixture was stirred at room temperature for 30 min. The mixture was partitioned between EtOAc (150 mL) and aqueous NaHCO3 solution (200 mL). The aqueous layer was extracted with EtOAc (2 * 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give tert-butyl {4-methyl-3-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate 11 as gray solid.
  • 33
  • [ 660838-05-1 ]
  • C14H10ClN5O*C6H15N [ No CAS ]
  • [ 1408285-83-5 ]
YieldReaction ConditionsOperation in experiment
41% With triethylamine triflouroacetate In dimethyl sulfoxide at 95℃;
  • 34
  • [ 660838-05-1 ]
  • [ 1426136-10-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 2: trifluoroacetic acid; dimethylsulfide / dichloromethane / 2 h
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 5 h / 20 °C 1.2: 20 °C 2.1: dimethylsulfide; trifluoroacetic acid / dichloromethane / 2 h
  • 35
  • [ 660838-05-1 ]
  • [ 1426136-51-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 2: trifluoroacetic acid; dimethylsulfide / dichloromethane / 2 h 3: potassium acetate / methanol / 0 - 20 °C
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 5 h / 20 °C 1.2: 20 °C 2.1: dimethylsulfide; trifluoroacetic acid / dichloromethane / 2 h 3.1: potassium acetate / methanol / 0.08 h / 0 - 20 °C 3.2: 0 - 20 °C
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 5 h / 20 °C 1.2: 20 °C 2.1: dimethylsulfide; trifluoroacetic acid / dichloromethane / 2 h 3.1: alkali metal acetate / methanol / 0 - 20 °C
  • 36
  • [ 660838-05-1 ]
  • [ 878745-42-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium methylate; johnphos; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 8 h / Reflux 2: trifluoroacetic acid / dichloromethane / 1 h
Multi-step reaction with 2 steps 1: caesium carbonate / tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane
  • 37
  • [ 660838-05-1 ]
  • imidazo[1,2-a]pyridine-3-carbonyl chloride [ No CAS ]
  • [ 1426136-50-6 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Synthesis of N-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (67) Oxalyl chloride (10 mL) was added dropwise to a stirred solution of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3 g, 18.5 mmol) in dry dichloromethane (100 mL) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the resulting acid chloride to make a suspension. In a separate flask, tert-butyl 3-amino-4-methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 mL) was dissolved in dichloromethane (100 mL) and the above acid chloride solution was added slowly. The resulting solution was stirred overnight at room temperature. Saturated NH4Cl was added to the reaction solution and the phases were separated. The organic layer was dried over Na2SO4 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) as a slightly yellow solid.
With N-ethyl-N,N-diisopropylamine In dichloromethane Synthesis of N-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (67) Oxalyl chloride (10 mL) was added dropwise to a stirred solution of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3 g, 18.5 mmol) in dry dichloromethane (100 mL) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the resulting acid chloride to make a suspension. In a separate flask, tert-butyl 3-amino-4-methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 mL) was dissolved in dichloromethane (100 mL) and the above acid chloride solution was added slowly. The resulting solution was stirred overnight at room temperature. Saturated NH4Cl was added to the reaction solution and the phases were separated. The organic layer was dried over Na2SO4 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) as a slightly yellow solid.; TFA (50 mL) was added to a stirred suspension of tert-butyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) in Me2S (5 mL) and dichloromethane (10 mL). After 2 hours the solution was evaporated and partitioned with dichloromethane and saturated NaHCO3. The aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried over Na2SO4. N-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (67) was isolated and used without further purification. 1H NMR (400 MHz, CDCl3) δ 9.44 (d, J=6.8 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.38-7.33 (m, 2H), 6.98-6.94 (m, 2H), 2.19 (s, 3H). MS m/z 267.1 (M+1)+.
  • 38
  • [ 660838-05-1 ]
  • [ 6200-60-8 ]
  • [ 1426136-50-6 ]
YieldReaction ConditionsOperation in experiment
Oxalyl chloride (10 ml_) was added dropwise to a stirred solution of imidazo[1 ,2- a]pyridine-3-carboxylic acid (1 ) (3 g, 18.5 mmol) in dry dichloromethane (100 ml_) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the resulting acid chloride to make a suspension. In a separate flask, tert-butyl 3-amino-4- methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 ml_) was dissolved in dichloromethane (100 ml_) and the above acid chloride solution was added slowly. The resulting solution was stirred overnight at room temperature. Saturated NH4CI was added to the reaction solution and the phases were separated. The organic layer was dried over Na2S04 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1 ,2-a]pyridine-3- carboxamido)-4-methylphenylcarbamate (66) as a slightly yellow solid.
Oxalyl chloride (10 ml_) was added dropwise to a stirred solution of imidazo[1 ,2- a]pyridine-3-carboxylic acid (1 ) (3 g, 18.5 mmol) in dry dichloromethane (100 ml_) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the resulting acid chloride to make a suspension. In a separate flask, tert-butyl 3-amino-4- methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 ml_) was dissolved in dichloromethane (100 ml_) and the above acid chloride solution was added slowly. The resulting solution was stirred overnight at room temperature. Saturated NH4CI was added to the reaction solution and the phases were separated. The organic layer was dried over Na2S04 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1 ,2-a]pyridine-3- carboxamido)-4-methylphenylcarbamate (66) as a slightly yellow solid. TFA (50 ml_) was added to a stirred suspension of tert-butyl 3-(imidazo[1 ,2- a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) in Me2S (5 ml_) and dichloromethane (10 ml_). After 2 hours the solution was evaporated and partitioned with dichloromethane and saturated NaHC03. The aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried over Na2S04. N-(5-amino-2-methylphenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (67) was isolated and used without further purification. 1 H NMR (400MHz, CDCI3) delta 9.44 (d, J = 6.8 Hz, 1 H), 8.05 (s, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.38 - 7.33 (m, 2 H), 6.98 - 6.94 (m, 2 H), 2.19 (s, 3 H). MS m/z 267.1 (M+1 )+.
  • 39
  • [ 660838-05-1 ]
  • [ 1079275-67-4 ]
  • [ 1427295-96-2 ]
YieldReaction ConditionsOperation in experiment
41% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 3h; Inert atmosphere; Reflux; 7.4 Step 4: Compound 7e (500 mg, 1.96 mmol), Compound 7c (480 mg, 2.16 mmol), Pd2(dba)3 (179 mg, 0.196 mmol), xantphos (226 mg, 0.39 mmol), Cs2CO3 (1.28 g , 3.92 mmol) and dioxane (15 mL) were added to a degassed flask and heated to reflux for 3 hours under the protection of argon. The solvent was concentrated, and the remainder was purified by silica gel column chromatography to obtain Compound 7f (350 mg, Yield 41%). 1H NMR (400 MHz, CD3OD): δ ppm 9.01 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.19 (d, J=7.6, 1H), 5.92 (s,1H), 2.19 (s, 3H), 2.11 (s, 3H), 1.49 (s, 9H); MS [M + 1]+ 441.2.
41% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 3h; Inert atmosphere; Reflux; 7.4 Compound 7e (500 mg, 1.96 mmol), Compound 7c (480 mg, 2.16 mmol), Pd2(dba)3 (179 mg, 0.196 mmol), xantphos (226 mg, 0.39 mmol), Cs2CO3 (1.28 g, 3.92 mmol) and dioxane (15 mE) were added to a degas sed flask and heated to reflux for 3 hours under the protection of argon.10364] The solvent was concentrated, and the remainder was purified by silica gel column chromatography to obtain Compound 7f (350 mg, Yield 41%). ‘H NMR (400 MHz, CD3OD): öppm 9.01 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.19 (d, J=7.6, 1H), 5.92 (s, 1H), 2.19 (s, 3H), 2.11 (s, 3H), 1.49 (s, 9H); MS [M+1] 441.2.
  • 40
  • [ 635-80-3 ]
  • [ 660838-05-1 ]
  • tert-butyl N-[4-methyl-3-[(2-methylquinoline-6-carbonyl)amino]phenyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dimethyl amine; at 20℃;Inert atmosphere; Preparation of Compound 140, tert-butyl N-[4-methyl-3-[(2-methylquinoline-6- carbonyl)amino]phenyl]carbamate[00183] HATU (20.12 g, 52.91 mmol) was added portionwise to Compound 139 (9.80 g, 44.09 mmol), <strong>[635-80-3]2-methylquinoline-6-carboxylic acid</strong> (8.67 g, 46.29 mmol) andDIPEA (23.04 mL, 132.26 mmol) in DMA (197 mL) at ambient temperature under an inert atmosphere and the resulting solution stirred overnight. The reaction mixture was concentrated, diluted with DCM (50 mL), and washed sequentially with a saturated solution of sodium bicarbonate (50 mL), saturated brine (50 mL), and water (50 mL). The organic layer was dried over MgS04, filtered and evaporated to afford a dark solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM, to afford the desired material as an off white solid (8.25 g, 48%).1H NMR (400 MHz, DMSO, 30 C) d 1 .37 (9H, d), 2.18 (3H, s), 2.61 - 2.85 (3H, m), 7.14 (1 H, d), 7.23 (1 H, dd), 7.52 (1 H, d), 7.56 (1 H, d), 8.02 (1 H, d), 8.22 (1 H, dd), 8.39 (1 H, d), 8.58 (1 H, d), 9.28 (1 H, s), 10.04 (1 H, s). m/z (ES+) (M+H)+ = 392.56.
  • 43
  • [ 660838-05-1 ]
  • N-{4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}-N-[3-(trifluoromethyl)phenyl]urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate / tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane 3: tetrahydrofuran / 0.08 h / 25 °C
  • 44
  • [ 660838-05-1 ]
  • N-[3-(1-cyano-1-methylethyl)phenyl]-N-{4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate / tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane 3: chloroform / 0.33 h / Heating / reflux
  • 45
  • [ 660838-05-1 ]
  • [ 1086423-50-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 2: sodium hydroxide; water / methanol / 4 h / 20 °C 3: hydrogen / palladium 10% on activated carbon / tetrahydrofuran; ethanol / 760.05 Torr 4: hydrogenchloride / tetrahydrofuran; methanol; water / 50 - 60 °C
  • 46
  • [ 660838-05-1 ]
  • C20H22N4O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 2: sodium hydroxide; water / methanol / 4 h / 20 °C 3: hydrogen / palladium 10% on activated carbon / tetrahydrofuran; ethanol / 760.05 Torr
  • 47
  • [ 660838-05-1 ]
  • [ 1086422-84-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 2.1: sodium hydroxide; water / methanol / 4 h / 20 °C 3.1: hydrogen / palladium 10% on activated carbon / tetrahydrofuran; ethanol / 760.05 Torr 4.1: hydrogenchloride / tetrahydrofuran; methanol; water / 50 - 60 °C 5.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.03 h / 20 °C 5.2: 20 °C
  • 48
  • [ 660838-05-1 ]
  • [ 1202759-65-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / palladium diacetate / toluene / 12 h / Reflux; Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 0 - 20 °C 2.2: Cooling with ice
  • 49
  • [ 660838-05-1 ]
  • [ 1202755-93-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / palladium diacetate / toluene / 12 h / Reflux; Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 0 - 20 °C 2.2: Cooling with ice 3.1: 1-methyl-pyrrolidin-2-one / 1 h / 0 - 20 °C
  • 50
  • [ 660838-05-1 ]
  • [ 796729-10-7 ]
  • tert-butyl 3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamido)-4-methylphenylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.166667h; Stage #2: t-butyl 3-amino-4-methylphenylcarbamate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 1h; Tert-butyl 3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamido)-4- methylphenylcarbamate To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (164.28 mg, 1.08 mmol, 1.2 eq) in DMF (3 mL) was added HATU (513.17 mg, 1.35 mmol, 1.5 eq) stirred at 25°C for 10 min. And then was added DIEA (348.86 mg, 2.70 mmol, 470.16 µL, 3 eq) and tert-butyl 3-amino-4-methylphenylcarbamate (200 mg, 899.75 µmol, 1 eq). The mixture was stirred at 25°C for 1h. LCMS showed the starting material was consumed and the desired MS (M+1,357.2) was detected. Reaction mixture was added to the H2O (30 mL) with stirred. And then was filtered and concentrated to give a white solid. The residue was used into the next step without purification. The crude product tert-butyl 3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamido)-4- methylphenylcarbamate (300 mg, 841.71 µmol, 93.55% yield) as a white solid was obtained. 1H-NMR (400 MHz, METHANOL-d4) ppm = 7.79 - 7.70 (m, 1H), 7.27 - 7.09 (m, 2H), 6.59 - 6.51 (m, 1H), 4.24 - 4.16 (m, 2H), 3.00 - 2.95 (m, 2H), 2.72 - 2.60 (m, 2H), 2.26 - 2.23 (m, 3H), 1.53 - 1.50 (m, 9H). LCMS: Retention time: 0.993 min, [M+H]+ calcd. for C19H24N4O3357.2; found 357.4
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