* 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.
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol at 20℃; for 10 h;
To a solution of 13 (2.06 g, 10.5 mmol) and AcOH (1.25 g, 20.9 mmol) in MeOH (100mL) was added 10percent Pd/C (100 mg) and the mixture was stirred at rt under H2atmosphere (H2 balloon) for 10 h. The solution was filtered through alayer of Celite and the filtrate was concentrated in vacuo to provide compound 14 as a brown oil (1.72 g, 98percent). 1HNMR (600 MHz, CDCl3) δ 6.77 (d, J= 8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz,2H), 4.06-4.03 (m, 2H), 3.72-3.70 (m, 2H), 3.44 (s, 3H), 3.42 (br s, 2H). HRMS(ESI+) calcd for C9H14NO2 (M+H)+168.1019, found 168.1019.
95.7%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16 h;
1- (2-methoxyethoxy) -4-nitrobenzene (1.97 g, 10 mmol)Was added to 50 mL of a methanol solution,10percent Pd / C197 mg was added,The reaction was carried out at room temperature for 16 h.The solid was removed by suction filtration,The filtrate was concentrated to give 1.6 g of a pale red oil,Yield 95.7percent.
94.34%
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 2 h; Inert atmosphere
Synthesis of compound 130.3. To a suspension of Pd/C (0.200g,) in MeOH (20ml) was added compound 130.2 (1.5g, 7.61mmol, l .Oeq) under nitrogen atmosphere. Reaction mixture was purged with H2 (gas) at room temperature for 2 hours. After completion of the reaction, mixture was filtered through celite. Solvent was removed under reduced pressureto afford compound 130.3 (1.2g, 94.34percent). MS (ES): m/z 167.2 [M+H]+.
93%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
[00547] 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 20 mmol), MeOH (80 mL), and 10percentPd on activated carbon ( 400 mg) were charged in a hydrogenation vessel and the reactionmixture was stirred at rt overnight under H2 atmosphere. The mixture was filtered through thecelite. The filtrate was concentrated in vacuo to afford 4-(2-methoxyethoxy)aniline (39) (3.1 g,93percent) as a black oil. LC-MS (ESI): m/z (M+1) 168.1.
56.7%
With iron; ammonium chloride In tetrahydrofuran; water for 4 h; Reflux
To a solution of compound 3 (25 g, 127 mmol) inTHF (180 mL), water (60 mL) was added. After stirred for ~ 5 min, NH4Cl (28 g, 523 mmol) and Fe (36 g, 635 mmol) were sequentially added. The reaction mixture was heated to refluxing and stirred for 4h. After cooled to room temperature, the mixture was filtered through Celite® and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude was re- dissolved in ethyl acetate (500 mL), washed with saturated NaHCO3 (200 mL) and water (200 mL). The organic layer was concentrated under reduced pressure. The crude was further purified by flash column chromatography to yield the desired product 4 (12 g, 56.7percent yield, M+H+= 168.5).
700 mg
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 3 h;
Compound 115 (lg, 5.08 mmol) was hydrogenated with 100 mg of Pd/C in 20mL of methanol under a hydrogen atmosphere for 3h. The reaction mixture was filtrated on Celite, washed with 20mL of methanol and concentrated under vacuum to yield 700 mg of the pure aniline 116. Light brown oil. Yield = 68percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5177 - 5181
[2] Patent: CN103864792, 2017, B, . Location in patent: Paragraph 0313; 0314; 0315; 0316
[3] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00768; 00770
[4] Patent: WO2014/130693, 2014, A1, . Location in patent: Paragraph 00544; 00547
[5] European Journal of Medicinal Chemistry, 1980, vol. 15, # 5, p. 399 - 404
[6] Patent: WO2015/6754, 2015, A2, . Location in patent: Paragraph 00243; 00245
[7] Collection of Czechoslovak Chemical Communications, 1971, vol. 36, p. 2527 - 2539
[8] Patent: US2005/277668, 2005, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2017/4543, 2017, A1, . Location in patent: Page/Page column 67
[10] Patent: WO2017/102014, 2017, A1, . Location in patent: Page/Page column 24
3
[ 109-86-4 ]
[ 540-37-4 ]
[ 33311-29-4 ]
Yield
Reaction Conditions
Operation in experiment
5.3%
With caesium carbonate In toluene at 110℃;
EXAMPLE 40; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide; a. 4-(2-Methoxy-ethoxy)-phenylamine; A mixture of 4-iodoaniline (219 mg, 1.0 mmol), 2-methoxyethanol (152 mg, 2.0 mmol), copper iodide (19.0 mg, 0.1 mmol), cesium carbonate (554 mg, 1.7 mmol) and 1,10-phenanthroline (36.0 mg, 0.2 mmol) was stirred in toluene (0.5 mL) at 110° C. overnight. The reaction was then cooled to RT and filtered through silica gel and washed with diethyl ether. The ether was removed in vacuo to obtain a crude solid. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a solid (8.9 mg, 5.3percent). 1H NMR (300 MHz, CDCl3) δ 6.82-6.72 (m, 4H), 4.06 (t, 2H), 3.72 (t, 2H), 3.45 (s, 3H).
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
4-Aminophenol (2.2 g, 19.8 mmol) and potassium carbonate (5.5 g, 39.6 mmol) were dissolved in DMF. To the reaction mixture was added 1 -chloro-2-methoxyethane (2 ml, 21.8 mmol) and the mixture was stirred overnight at 80 0C. The resulting solids were filtered and the filtrate was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by an ISCO system (50 -100 percent EtOAc in hexanes) to afford 538 mg of the desired product (16 percent yield); m/z 168.
Reference：
[1] Patent: WO2008/20203, 2008, A1, . Location in patent: Page/Page column 81
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 5, p. 1996 - 2015
Reference：
[1] Yakugaku Zasshi, 1952, vol. 72, p. 521[2] Chem.Abstr., 1952, p. 8810
8
[ 1202759-89-4 ]
[ 33311-29-4 ]
[ 1202759-91-8 ]
[ 1202759-90-7 ]
Yield
Reaction Conditions
Operation in experiment
0.55 g
With acetic acid In tert-Amyl alcohol for 4 h; Reflux
tert-Butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)carbamate (800 mg, 2.37 mmoL) and 4-(2-methoxyethoxy)aniline (576 mg, 2.84 mmoL) were suspended in tert-amyl alcohol (14 mL) and acetic acid (5 drops). Heated to reflux for 4 h. After cooling, solvent was removed via rotary evaporation. The dark oil was partitioned between water/brine and THF (10 mL each), agitated, and separated layers and dried organic phase over sodium sulfate. The solvent was removed via rotary evaporation to afford a purple solid, 0.55 g. LC/MS (RT=2.997/(M+1)) 470.2. Additional 150 mg of product minus the (BOC) protecting group crystallized from the aqueous layer
With palladium 10% on activated carbon; hydrogen; acetic acid; In methanol; at 20℃; for 10h;
To a solution of 13 (2.06 g, 10.5 mmol) and AcOH (1.25 g, 20.9 mmol) in MeOH (100mL) was added 10% Pd/C (100 mg) and the mixture was stirred at rt under H2atmosphere (H2 balloon) for 10 h. The solution was filtered through alayer of Celite and the filtrate was concentrated in vacuo to provide compound 14 as a brown oil (1.72 g, 98%). 1HNMR (600 MHz, CDCl3) delta 6.77 (d, J= 8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz,2H), 4.06-4.03 (m, 2H), 3.72-3.70 (m, 2H), 3.44 (s, 3H), 3.42 (br s, 2H). HRMS(ESI+) calcd for C9H14NO2 (M+H)+168.1019, found 168.1019.
95.7%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;
1- (2-methoxyethoxy) -4-nitrobenzene (1.97 g, 10 mmol)Was added to 50 mL of a methanol solution,10% Pd / C197 mg was added,The reaction was carried out at room temperature for 16 h.The solid was removed by suction filtration,The filtrate was concentrated to give 1.6 g of a pale red oil,Yield 95.7%.
94.34%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 2h;Inert atmosphere;
Synthesis of compound 130.3. To a suspension of Pd/C (0.200g,) in MeOH (20ml) was added compound 130.2 (1.5g, 7.61mmol, l .Oeq) under nitrogen atmosphere. Reaction mixture was purged with H2 (gas) at room temperature for 2 hours. After completion of the reaction, mixture was filtered through celite. Solvent was removed under reduced pressureto afford compound 130.3 (1.2g, 94.34%). MS (ES): m/z 167.2 [M+H]+.
93%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
[00547] 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 20 mmol), MeOH (80 mL), and 10%Pd on activated carbon ( 400 mg) were charged in a hydrogenation vessel and the reactionmixture was stirred at rt overnight under H2 atmosphere. The mixture was filtered through thecelite. The filtrate was concentrated in vacuo to afford 4-(2-methoxyethoxy)aniline (39) (3.1 g,93%) as a black oil. LC-MS (ESI): m/z (M+1) 168.1.
56.7%
With iron; ammonium chloride; In tetrahydrofuran; water; for 4h;Reflux;
To a solution of compound 3 (25 g, 127 mmol) inTHF (180 mL), water (60 mL) was added. After stirred for ~ 5 min, NH4Cl (28 g, 523 mmol) and Fe (36 g, 635 mmol) were sequentially added. The reaction mixture was heated to refluxing and stirred for 4h. After cooled to room temperature, the mixture was filtered through Celite and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude was re- dissolved in ethyl acetate (500 mL), washed with saturated NaHCO3 (200 mL) and water (200 mL). The organic layer was concentrated under reduced pressure. The crude was further purified by flash column chromatography to yield the desired product 4 (12 g, 56.7% yield, M+H+= 168.5).
With hydrogen;palladium 10% on activated carbon; In methanol; under 2068.65 Torr; for 1h;
The 4-nitrophenol (3.05 g), MeOH (30 mL), 10% Pd on activated carbon, (304 mg) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 1 h at 40 psi of hydrogen. The mixture was filtered through celite, the cake washed with MeOH and the solvent from the eluent removed in vacuo to afford the desired aniline (1.75 g, 68% 2 step) as a brown oil: 1H NMR (CDCl3) delta 3.44 (s, 3H), 3.70-3.73 (m, 2H), 4.03-4.06 (m, 2H), 6.64 (d, 2H, J=9 Hz), 6.78 (d, 2H, J=9 Hz).
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
PREPARATION 5 PREPARATION OF 4- 2-METHOXYETHOXY)ANILINE 1 -(2-Methoxyethoxy)-4-nitrobenzene (1 .02 g, 5.17 mmol) and 10% palladium on carbon (150 mg) were mixed in methanol (30 mL). After degassing, hydrogen gas balloon was applied to the mixture. The reaction mixture was stirred for 2 hours at ambient temperature, and then filtered through Celite. The filtrate was concentrated, and the residue was dried in vacuo to afford the title compound as a brown liquid in 70% yield (604 mg) and used for next step reaction without further purification.
700 mg
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 760.051 Torr; for 3h;
Compound 115 (lg, 5.08 mmol) was hydrogenated with 100 mg of Pd/C in 20mL of methanol under a hydrogen atmosphere for 3h. The reaction mixture was filtrated on Celite, washed with 20mL of methanol and concentrated under vacuum to yield 700 mg of the pure aniline 116. Light brown oil. Yield = 68%.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;
To a solution of (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (492 mg, 2.95 mmol) and 4-(2-methoxy-ethoxy)-phenylamine (492 mg, 2.95 mmol) in CH2Cl2 (12 mL) and glacial AcOH (14 drops) was added NaBH(OAc)3 (758 mg, 3.58 mmol) and the reaction stirred at room temperature overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 96:4) gave the desired aniline (R)-3-{4-[4-(2-methoxy-ethoxy)-phenylamino-piperidin-1-yl}-butyronitrile (0.72 g, 94%) as an orange oil.
With potassium tert-butylate; In 2-methoxy-ethanol; N,N-dimethyl-formamide;
The <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> used as starting material was obtained as follows: Potassium tert-butoxide (2 g) was added portionwise to a stirred mixture of 4-fluoronitrobenzene (2.8 g), 2-methoxyethanol (10 ml) and DMF (20 ml). The mixture was stirred and heated to 60 C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4)- and evaporated. The residue was recrystallized from a mixture of hexane and ethyl acetate. There was thus obtained 4-(2-methoxyethoxy)nitrobenzene (1.06 g), m.p. 86 C. The product so obtained was dissolved in ethyl acetate and hydrogenated in the presence of a 10% Pd/C catalyst to give <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (0.7 g). NMR Spectrum: (CD3 SOCD3) 3.3 (s, 3H), 3.6 (t, 2H), 3.9 (t, 2H), 4.6 (s, 2H), 6.5 (d, 2H), 6.7 (d, 2H).
With caesium carbonate;copper(l) iodide; 1,10-Phenanthroline; In toluene; at 110℃;
EXAMPLE 40; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide; a. 4-(2-Methoxy-ethoxy)-phenylamine; A mixture of 4-iodoaniline (219 mg, 1.0 mmol), 2-methoxyethanol (152 mg, 2.0 mmol), copper iodide (19.0 mg, 0.1 mmol), cesium carbonate (554 mg, 1.7 mmol) and 1,10-phenanthroline (36.0 mg, 0.2 mmol) was stirred in toluene (0.5 mL) at 110 C. overnight. The reaction was then cooled to RT and filtered through silica gel and washed with diethyl ether. The ether was removed in vacuo to obtain a crude solid. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a solid (8.9 mg, 5.3%). 1H NMR (300 MHz, CDCl3) delta 6.82-6.72 (m, 4H), 4.06 (t, 2H), 3.72 (t, 2H), 3.45 (s, 3H).
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With triethylamine; In dimethyl sulfoxide; at 50℃;
b. 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide; A mixture of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (18 mg, 0.0536 mmol), as prepared in Example 3a, 4-(2-methoxy-ethoxy)-phenylamine (8.9 mg, 0.0533 mmol), as prepared in the previous step, and triethylamine (14 muL, 0.1 mmol) was stirred in DMSO (0.5 mL) at 50 C. overnight. The reaction was then cooled to RT, partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (5.7 mg, 23%). 1H NMR (300 MHz, CDCl3) delta 9.16 (s, 1H), 7.28-7.25 (m, 4H), 6.89 (m, 2H), 6.33 (br s, NH), 4.29-4.24 (m, 2H), 4.12-4.07 (m, 8H), 3.74 (m, 2H), 3.59 (m, 1H), 3.45 (s, 3H), 3.17 (m, 2H), 2.22-2.08 (m, 2H), 2.05-1.97 (m, 2H); LC/MS (ESI): calcd mass 466.2, found 467.4 [M+1]+.
{6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In isopropyl alcohol; at 85℃;
Reference Example 5 Synthesis of {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}<strong>[33311-29-4][4-(2-methoxyethoxy)phenyl]amine</strong> To an isopropanol (3.0 mL) solution containing 6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyrimidine (512 mg, 1.49 mmol), triethylamine (836 muL, 5.96 mmol) and <strong>[33311-29-4]4-(2-methoxyethoxy)phenylamine</strong> (299 mg, 1.79 mmol) were added, and this mixture was heated at 85 C. with stirring. After the reaction, the solvent was concentrated, sodium hydrogen carbonate was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
To a solution of compound 3 (400 mg, 1.0 mmol) and <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (0.2 g, 1.2 mmol) in 8 ml dioxane was added 4-methylbenzenesulfonic acid monohydrate (0.15g, 0.8 mmol). The mixture was stirred at 100 0C for two hours. The solvent was evaporated. The residue was dissolved in 30 ml ethyl acetate and washed with NaHCO3 aqueous solution, water and brine. The organic layer was separated and dried over Na2SO4. After removal of solvent, the crude product was subject to chromatography on silica gel (hexane:EtOAc = 1 :1). 0.40 g of the title compound 5 was obtained: MS m/z: 530.1, 532.1(M+H+).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h;
To a solution of 2.4-dichloro-l,3,5-triazine A.91 (2 g, 13.34 mmol) in DMF (10 mL) at 0 0C were added DIEA (2.4 mL, 13.77 mmol) and 4-(2-methoxyethoxy)benzenamine (2.027 g, 12.12 mmol) and the mixture was stirred at 0 0C for 30 minutes and then room temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. The brown solid was purified by silica gel column chromatography using 30% of ethyl acetate in hexane as eluent to give 4-chloro-N-(4-(2-methoxyethoxy)phenyl)-l,3,5-triazin-2-amine A.92 (2.887 g, 84.8% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 10.58 (1 H, s), 8.56 (1 H, d, J=5.9 Hz), 7.51 (2 H, t, J=9.5 Hz), 6.96 (2 H, t, J=7.9 Hz), 4.04 - 4.1 1 (2 H, m), 3.65 (2 H, dd, J=5.3, 3.8 Hz), 3.31 (3 H, s); Mass Spectrum (ESI) m/e = 281.0 [M+l].
26.3%
With diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h;Inert atmosphere;
To a solution of compound 27-1 in DMF (50 mL) was added dropwise DIPEA (4.55 g, 35.23 mmol) and compound 27-1-1 (5 g, 30.2 mmol) under nitrogen atmosphere at 0 C., and the reaction solution was reacted at 0 C. for 0.5 h, followed by warmed to r.t. and reacted for another 1 h. The resulting reaction solution was diluted with EtOAc (50 mL) and washed with brine (30 mL×3). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give a residue was purified by column chromatography (3% to 8% of PE/EtOAc) to afford the title compound (360 mg, 26.3%) as white solid.
With hydrogenchloride; In 1,4-dioxane; methanol; at 140℃; for 0.0833333h;Microwave irradiation;
Example No. 104Preparation of [4- (2-Methoxy-ethoxy) -phenyl] - (8-methoxy-3H- pyrazolo [3 , 4-c] quinolin-4 -yl) -amine4-chloro-8-methoxy-2- (4 -methoxybenzyl) -2H-pyrazolo [3,4- c] quinoline (0.16 mmol) and 4- (2-methoxyethoxy) aniline (2 eq.,0.3 mmol) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL) , HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3mL) . The reaction mixture was irradiated in a microwave reactor for 5 min at 140 C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 364.1833 g/molHPLC-MS: analytical method Brt: 1.90 min - found mass: 365.2 (m/z+H)
<strong>[33311-29-4]4-(2-methoxyethoxy)phenylamine</strong>(2.7g) was added to a solution of Compound 2-5(3.7g) in n-butanol(80ml). The mixture was reacted at 90C for 4.0 hours, cooled to room temperature, filtered, washed and dried to obtain a yellow floc-like solid(4.53g) in a yield of 80.9%. MS m/z(ESI): 374[M+H]+; 1H NMR(400 MHz, DMSO-d6): delta10.34(s, 1H), 8.95(s, 1H), 8.50(s, 1H), 7.70(d, J=6.0Hz, 2H), 6.93(d, J=8.8Hz, 2H), 4.43(m, 1H), 4.07(m, 2H), 3.64(m, 2H), 3.30(s, 3H), 2.03(m, 2H), 1.72(m, 2H), 1.61(m, 4H)ppm.
4-(2-Methoxyethoxy)aniline (500mg) was added to acetic anhydride (2.38g) and the mixture was cooled down to 10C. HN03 (65% in water, 0.62ml) was added slowly in order to keep the temperature of the reaction mixture below 15C. After the end of the addition, the reaction mixture was allowed to warm to RT over 1 h, was quenched with ice-cold water and stirred for 10min. The resulting suspension was filtered off and dried in high vacuo. The resulting yellow powder was dissolved in dioxane (1.4ml) , treated with 6N HCl (1 .4ml_) and the reaction mixture was stirred at 70C for 3h. After cooling down to RT, water was added and the pH was adjusted to 10 with 1 M NaOH. The layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 303mg of yellow solid. LC-MS (B): tR = 0.99min; [M+H]+: 213.05.
303 mg
4-(2-Methoxyethoxy)aniline (500 mg) was added to acetic anhydride (2.38 g) and the mixture was cooled down to 10 C. HNO3 (65% in water, 0.62 mL) was added slowly in order to keep the temperature of the reaction mixture below 15 C. After the end of the addition, the reaction mixture was allowed to warm to RT over 1 h, was quenched with ice-cold water and stirred for 10 min. The resulting suspension was filtered off and dried in high vacuo. The resulting yellow powder was dissolved in dioxane (1.4 mL), treated with 6N HCl (1.4 mL) and the reaction mixture was stirred at 70 C. for 3 h. After cooling down to RT, water was added and the pH was adjusted to 10 with 1M NaOH. The layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 303 mg of yellow solid. LC-MS (B): tR=0.99 min; [M+H]+: 213.05.
2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]acetic acid[ No CAS ]
[ 33311-29-4 ]
2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]-N-[4-(2-methoxyethoxy)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
c) 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylidene imidazolidin-4-yl]-N-[4-(2-methoxyethoxy)phenyl]acetamide (example 53) [0196] HOBt (84 mg; 0.55 mmol; 1.5 eq), DIPEA (323 muL; 1.85 mmol; 5 eq) and <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (81 mg; 0.48 mmol; 1.3 eq) were added to a solution of 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]acetic acid (1-21) (150 mg; 0.37 mmol; 1 eq) in dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 2 days. Ethyl acetate (10 mL) and water (5 mL) were added and the layers were separated. The organic layer was washed with saturated ammonium chloride (10 mL), water (10 mL) and sodium chloride (2 x 15 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was triturated in ethyl acetate, washed with petroleum ether, and concentrated to dryness. The residue was taken up in ethyl acetate/cyclohexane (200 muL) until precipitation, filtration. The title compound, 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl]-N-[4-(2-methoxyethoxy)phenyl]acetamide, was obtained in 25 % yield (50 mg) as a yellow solid. 1H-NMR (Acetone-d6): delta (ppm) 2.85 (m, 1H), 3.17 (m, 2H), 3.36 (s, 3H), 3.40 (m, 1H), 3.65 (m, 2H), 3.68 (s, 3H), 3.70 (m, 1H), 4.09 (m, 2H), 4.31 (m, 1H), 4.63 (m, 1H), 6.87 (m, 4H), 7.25 (m, 4H), 7.49 (m, 4H), 9.34 (s, 1H); MS (ESI+): m/z = 551.9 [M+H]+.
25%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
c) 2-ri-(4-fluorophenyl)-3-r2-(4-methoxyphenyl)ethyll-5-oxo-2- sulfanylideneimidazolidin-4-yll-N-r4-(2-methoxyethoxy)phenyllacetamide (example 53) EDCI (107.4 mg; 0.55 mmol; 1.5 eq), followed by HOBt (84 mg; 0.55 mmol; 1.5 eq), DIPEA (323 mu; 1.85 mmol; 5 eq) and <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (81 mg; 0.48 mmol; 1.3 eq) were added to a solution of 2-[l-(4-fluorophenyl)-3-[2-(4- methoxyphenyl)ethyl] -5-oxo-2-sulfanylideneimidazolidin-4-yl] acetic acid (1-21 ) (150 mg; 0.37 mmol; 1 eq) in dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 2 days. Ethyl acetate (10 mL) and water (5 mL) were added and the layers were separated. The organic layer was washed with saturated ammonium chloride (10 mL), water (10 mL) and sodium chloride (2 x 15 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was triturated in ethyl acetate, washed with petroleum ether, and concentrated to dryness. The residue was taken up in ethyl acetate/cyclohexane (200 mu) until precipitation, filtration. The title compound, 2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-5-oxo-2- sulfanylideneimidazolidin-4-yl] -N- [4- (2-methoxyethoxy)phenyl] acetamide, was obtained in 25% yield (50 mg) as a yellow solid.1H-NMR (Acetone-d6): delta (ppm) 2.85 (m, 1H), 3.17 (m, 2H), 3.36 (s, 3H), 3.40 (m, 1H), 3.65 (m, 2H), 3.68 (s, 3H), 3.70 (m, 1H), 4.09 (m, 2H), 4.31 (m, 1H), 4.63 (m, 1H), 6.87 (m, 4H), 7.25 (m, 4H), 7.49 (m, 4H), 9.34 (s, 1H); MS (ESI+): m/z = 551.9 [M+H]+ .
In a 100 mL 3-neck RBF, N-(2-(benzyloxy)-5-nitrophenyl)-2-chloro-5-fluoropyrimidin-4-amine (0.205 g), <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (0.137 g), Cs2CO3 (0.266 g) and Xantphos (0.032 g) were taken in degassed 1,4-dioxane (8.0 mL) and reaction mixture was degassed under argon for 30 minutes. Palladium acetate (0.013 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80 C. and stirred for 3.5 h. The reaction was monitored on TLC using hexane:ethyl acetate: (5:5) as mobile phase. After completion, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 mL). The ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by triturating with diethyl ether to give 0.1 g of N4-(2-(benzyloxy)-5-nitrophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine. 1H NMR: CDCl3 (400 MHz): 3.47 (d, 3H, J=11.6), 3.77 (dd, 2H, J=4.8, 8.8), 4.15 (t, 2H, J=4.8), 5.28 (s, 2H), 6.96 (d, 1H, J=8.8), 7.03 (d, 1H, J=8.8), 7.08 (d, 1H, J=9.2), 7.45 (m, 7H), 7.83 (s, 1H), 7.9 (d, 2H, J=2.8), 8.02 (dd, 1H, J=2.1, 6.8), 9.18 (s, 1H).
0.1 g
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 3.5h;Inert atmosphere;
In a 100 mL 3-neck RBF, N-(2-(benzyloxy)-5-nitrophenyl)-2-chloro-5-fluoropyrimidin-4-amine (0.205 g), <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (0.137 g), Cs2CO3 (0.266 g) and Xantphos (0.032 g) were taken in degassed 1,4-dioxane (8.0 mL) and reaction mixture was degassed under argon for 30 minutes. Palladium acetate (0.013 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80 C. and stirred for 3.5 h. The reaction was monitored on TLC using hexane:ethyl acetate: (5:5) as mobile phase. After completion, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3*25 mL). The ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by triturating with diethyl ether to give 0.1 g of N4-(2-(benzyloxy)-5-nitrophenyl)-5-fluoro-N2-(4-(2-methoxyethoxyl)phenyl)pyrimidine-2,4-diamine. 1H NMR: CDCl3 (400 MHz): 3.47 (d, 3H, J=11.6), 3.77 (dd, 2H, J=4.8, 8.8), 4.15 (t, 2H, J=4.8), 5.28 (s, 2H), 6.96 (d, 1H, J=8.8), 7.03 (d, 1H, J=8.8), 7.08 (d, 1H, J=9.2), 7.45 (m, 7H), 7.83 (s, 1H), 7.9 (d, 2H, J=2.8), 8.02 (dd, 1H, J=2.1, 6.8), 9.18 (s, 1H).
In a 25 mL three neck RBF with thermometer pocket, a solution of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate (0.250 g) in 1,4-dioxane (8.0 mL) was added. 4-(2-Methoxyethoxy)aniline (0.122 g) was added and the reaction was degassed for 10 minutes under argon. After 10 minutes, Xantphose (0.0176 g) and Cs2CO3 (0.396 g) were added and again degassed the reaction for 10 minutes followed by addition of Pd (OAc)2 (0.003 g) under argon. The reaction was heated to 80 C. and stirred for 3.5 hr under argon. The reaction was monitored on TLC using hexane:ethyl acetate (2:8) as mobile phase. After completion of the reaction, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 ml). Ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 0.250 g of tert-butyl (5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate. This crude material was used in the next step without any further purification. M+1=539.9.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 3.5h;Inert atmosphere;
In a 25 mL three neck RBF with thermometer pocket, a solution of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate (0.250 g) in 1,4-dioxane (8.0 mL) was added. 4-(2-Methoxyethoxy)aniline (0.122 g) was added and the reaction was degassed for 10 minutes under argon. After 10 minutes, Xantphose (0.0176 g) and Cs2CO3 (0.396 g) were added and again degassed the reaction for 10 minutes followed by addition of Pd (OAc)2 (0.003 g) under argon. The reaction was heated to 80 C. and stirred for 3.5 hr under argon. The reaction was monitored on TLC using hexane:ethyl acetate (2:8) as mobile phase. After completion of the reaction, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3*25 ml). Ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 0.250 g of tert-butyl (5-fluoro-2-((4-(2-methoxyethoxyl)phenyl)amino)pyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate. This crude material was used in the next step without any further purification. M+1=539.9.
With toluene-4-sulfonic acid; In ethanol; for 24h;Reflux;
To a solution of <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (1.5 g) and tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl) (1.48 g) in ethanol (15 mL) was added para-toluenesulfonic acid (84.4 mg). The reaction mixture was heated to reflux for 24 hr. Completion of reaction was monitored by TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion, the reaction mixture was allowed to cool to room temperature and ethanol was distilled out under reduced pressure. Water was added and stirred for 30 minutes at room temperature. Solid precipitate was filtered, washed with water and dried to give 1.2 g of tert-butyl (3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)carbamate.
1.2 g
With toluene-4-sulfonic acid; In ethanol; for 24h;Reflux;
To a solution of <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (1.5 g) and tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl) (1.48 g) in ethanol (15 mL) was added para-toluenesulfonic acid (84.4 mg). The reaction mixture was heated to reflux for 24 hr. Completion of reaction was monitored by TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion, the reaction mixture was allowed to cool to room temperature and ethanol was distilled out under reduced pressure. Water was added and stirred for 30 minutes at room temperature. Solid precipitate was filtered, washed with water and dried to give 1.2 g of tert-butyl (3-((5-fluoro-2-((4-(2-methoxyethoxyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)carbamate.
N-(3-(2-chloro-5-nitropyrimidin-4-ylamino)phenyl)-N-methylacrylamide[ No CAS ]
[ 33311-29-4 ]
N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-nitropyrimidin-4-ylamino)phenyl)-N-methylacrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With hydrogenchloride; In water; butan-1-ol; at 120℃; for 2h;Microwave irradiation;
[00520] To a solution ofN-(3-(2-chloro-5-nitropyrimidin-4-ylamino )phenyl)-N-methylacrylamide (396 mg, 1.19 mmol) and <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (39) (218 mg, 1.42 mmol) innBuOH(5 mL) was added 2 drops of cone. HCI. The resulting mixture was heated to 120 C for2 hrs in a microwave reactor. The solvents were removed and the residue was purified by flashchromatography (silica gel, 0 to 70% ethyl acetate in petroleum, with 0.5% TEA) to provide N(3 -(2-( 4-(2-methoxyethoxy )phenylamino )-5-nitropyrimidin-4-ylamino )phenyl)-Nmethylacrylamide(11) (221 mg, 41%) as a yellow solid. LC-MS (ESI) m/z (M+1) 465.1.
N-(3-(2-chloro-5-nitropyrimidin-4-ylamino)phenyl)acrylamide[ No CAS ]
[ 33311-29-4 ]
N-(3-(2-(4-(2-methoxyethoxy)phenylamino)-5-nitropyrimidin-4-ylamino)phenyl)acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With hydrogenchloride; In water; butan-1-ol; at 120℃; for 0.75h;Sealed tube; Microwave irradiation;
[00549] A sealed tube was charged with N-(3-(2-chloro-5-nitropyrimidin-4-ylamino)phenyl)acrylamide (40) (878 mg, 2.99 mmol), <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (39) (551 mg, 3.59 mmol), adrop of cone. HCl and n-BuOH (3 mL). The mixture was stirred at 120 C under microwave for45 mins. The reaction mixture was cooled down to -5 C and a precipitate was generated. Theprecipitate was collected by filtration and dried to afford N -(3 -(2-( 4-(2-methoxyethoxy)phenylamino )-5-nitropyrimidin-4-ylamino )phenyl)acrylamide ( 41) (945 mg,70%) as a gray solid. LC-MS (ESI): m/z (M + 1) 451.1.
tert-butyl (3-((2-chloro-5-nitropyrimidin-4-yl)amino)-phenyl)carbamate[ No CAS ]
[ 33311-29-4 ]
tert-butyl 3-(2-(4-(2-methoxyethoxy)phenylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;
[00511] To a solution of tert-butyl 3-(2-chloro-5-nitropyrimidin-4-ylamino )phenylcarbamate(1) (430 mg, 1.37 mmol) in THF (10 mL) was added DIEA (530 mg, 4.1 mmol) and <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (39) (274 mg, 1.64 mmol) at r.t. under N2 atmosphere. The resultingmixture was stirred at r.t. overnight. The solvent was removed and the residue was purified byflash column chromatography (silica gel, 0 to 5% ethyl acetate in PE/DCM (1/1), with 0.5%TEA) to provide tert-butyl 3-(2-( 4-(2-methoxyethoxy)phenylamino )-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (559 mg, 96%) as a yellow solid. LC-MS (ESI) m/z (M+1) 497.1.
(2-chloro-5-nitropyrimidin-4-yl)-[4-(2-methoxy-ethoxy)-phenyl]amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 3 - 20℃; for 0.5h;
a reaction flask, 2,4-dichloro-5-nitro-pyrimidine (41.7 g, 215 mmol) is dissolved in THF (250 ml) and the solution is cooled in an ice bath. Under stirring and external cooling (3-5C), a solution of 4-(2-methoxy-ethoxy)- phenylamine (35.9 g, 215 mmol) in THF (250 ml) is added dropwise. Anorange precipitate develops. Then, still under cooling (2-5C), triethylamine (29.8 ml, 215 mmol) is added slowly. The reaction mixture is allowed to reach room temperature and stirred for 30 minutes. The reaction mixture is filtered with suction and the residue is washed well with THF. The filtrate is evaporatedand the residue is triturated with tert-butyl methyl ether to afford (2-chloro-5-n itro-pyrimidin-4-yl)-[4-(2-methoxy-ethoxy)-phenyll-amine as orange redcrystals; HPLC/MS 1.93 mm (B), [M+H] 325;1H NMR (400 MHz, DMSO-d6) 610.36 (s, 1H), 9.12 (s, IH), 7.41 (d, J= 9.0Hz, 2H), 7.01 (d, J = 9.0 Hz, 1 H), 4.38 - 3.96 (m, 2H), 3.87 - 3.56 (m, 2H),332 (s, 3H).
(2-(4-(2-methoxyethoxy)phenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.9 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol;Reflux; Inert atmosphere;
To a solution of (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (4 g,10 mmol), compound 4 (1.67 g, 10 mmol) in t-BuOH (40 mL), potassium carbonate (2.8 g, 20 mmol), tris(dibenzylideneacetone)dipalladium (500 mg) and dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine (500 mg) were sequentially added. The reaction mixture was stirred under N2 flow and heated to refluxing. After stirred for 3-4 , TLC (DCM/ MeOH = 10/1 as elution) indicated the completion of the reaction. The mixture was cooled to 40~50C, filtered through Celite. The filter cake was washed with t-BuOH. The filtrate was concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate (200 mL) washed with water, and concentrated under reduced pressure. The crude was further purified by flash column chromatography to yield the desired product 6 (5.9 g, M+H+=536.5).
(4-(3-(tert-butoxycarbonylamino)phenylamino)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate[ No CAS ]
[ 33311-29-4 ]
(4-(3-(tert-butoxycarbonylamino)phenylamino)-2-(4-(2-methoxyethoxy)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.74 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-butyl alcohol;Inert atmosphere; Reflux;
t-BuOH (80 mL) was added to a RBF (250mL) equipped with magic stirring. Compound 3 (3.92 g, 8.3 mmol) and <strong>[33311-29-4]4-(2-methoxyethoxy)aniline</strong> (1.5 g, 9 mmol) were sequentially added and stirred for 5-10 min. Potassium carbonate (2.28 g, 16.5 mmol), tris(dibenzylideneacetone)dipalladium (750 mg, 0.9 mmol) and dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl) phosphine (750 mg, 18 mmol) were sequentially added and one more portion of t-BuOH (20 mL) was added. The flask was placed on an oil-bath and stirred under a N2 flow. The reaction mixture was heated to refluxing. After stirred for 3-4 h, the reaction was complete indicated by TLC (DCM/MeOH = 10/1 as elution). The mixture was cooled to 40-50 C and filtered through Celite. The filter cake was washed with ethyl acetae (50 mL). The filtrate was concentrated under reduced pressure. The crude was then purified with Flash column chromatography (ethyl acetate: Hexane=1:10~1:3) to yield the desired product 4 (1.74 g, M+H+= 605.5) as brown solid.
ethyl 4-chloro-2-(2,6-difluorophenyl)-6-methylpyrimidine-5-carboxylate[ No CAS ]
C23H23F2N3O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.62%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 6h;
Synthesis of compound 130.4. To a solution of 2.5 (0.300 g, 0.96mmol, l .Oeq) in CH3CN (5 mL) was added 4-(2-methoxyethoxy) aniline (0.144g, 0.86mmol, 0.9eq) and DIPEA (0.5mL, 2.88 mmol, 3.0 eq). The reaction mixture was stirred at 90 C for 6 hours. After completion of the reaction, mixture was poured into water and product was extracted with EtOAC. Organic layers were combined, dried over Na2S04 and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get compound 130.4 (0.360 g, 84.62%). MS (ES): m/z 443.4 [M+H]+.
N,N-dibenzyl-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine[ No CAS ]
N6,N6-dibenzyl-N2-(4-(2-methoxyethoxy)phenyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.5 g
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 110℃; for 2.5h;Inert atmosphere;
Intermediate-3: N6,N6-Dibenzyl-N2-(4-(2-methoxyethoxy) phenyl)-9-(tetrahydro-2H- pyran-2-yl)-9H-purine-2, 6-diamineTo a solution of Intermediate-2 (0.5 g, 1.15 mmol), BINAP (2,2'-Bis(diphenylphosphino)- 1,1'-binaphthyl) (0.14 g, 0.23 mmol), Cs2CO3 (0.75 g, 2.30 mmol) and Pd(OAc)2 (0.03 g, 0.11 mmol) in 1,4-dioxane (5.0ml) was degassed for 30 min. Then add 4-(2-methoxyethoxy) aniline (0.23 g, 1.38 mmol) at room temperature under N2 atmosphere. The resulting mixture was heated to 110C for 2h. Filter the reaction mixture through celite pad. Distilled the reaction mixture under reduced pressure and the resulting residue was suspended in ethyl acetate (100.0 ml) and washed with water (50 ml x 2). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography using ethyl acetate-hexane (20%) to afford the title compounds 0.5g as brown solid. MS (M+H+) m/z 565.0. 1H NMR (CHCl3-d) 7.74 (s, 1H), 7.47- 7.21 (m, 13H), 6.77 (d, J = 8.6 Hz, 2H), 5.80- 5.35 (m, 3H), 4.87 (s, 2H), 4.20 (d, J = 11.2 Hz, 1H), 4.10- 4.04 (m, 2H), 3.88 (s, 1H), 3.78- 3.69 (m, 2H), 3.45 (s, 3H), 2.15- 2.07 (m, 2H), 1.87- 1.74 (m, 2H), 1.69-1.63 (m, 2H).
1-(1-(2-hydrazinyl-2-oxoethyl)-3-(4-(2-methoxyethoxy)phenyl)-5,5-dimethyl-2-oxoimidazolidin-4-yl)-1-hydroxy-3-(4-(2-methoxyethoxy)phenyl)urea[ No CAS ]
3-(4-chlorophenyl)-1-hydroxy-1-(3-(4-(2-methoxyethoxy)phenyl)-5,5-dimethyl-1-(2-((E)-2-((E)-3-(5-nitrofuran-2-yl)allylidene)hydrazinyl)-2-oxoethyl)-2-oxoimidazolidin-4-yl)urea[ No CAS ]
1-(3-(4-chlorophenyl)-5,5-dimethyl-1-(2-((E)-2-((E)-3-(5-nitrofuran-2-yl)allylidene)hydrazinyl)-2-oxoethyl)-2-oxoimidazolidin-4-yl)-1-hydroxy-3-(4-(2-methoxyethoxy)phenyl)urea[ No CAS ]
2.17. 1-hydroxy-3-(4-(2-methoxyethoxy)phenyl)-1-(3-(4-(2-methoxyethoxy)phenyl)-5,5-dimethyl-1-(2-((E)-2-((E)-3-(5-nitrofuran-2-yl)allylidene)hydrazinyl)-2-oxoethyl)-2-oxoimidazolidin-4-yl)urea[ No CAS ]
With triethylamine; In ethyl acetate; at 20℃; for 1h;Reflux;
To a solution of 14 (78 mg, 0.47 mmol) in EtOAc (4 mL) was added triphosgene (69 mg,0.23 mmol) and TEA (130 muL, 0.93 mmol). The resulting solution was refluxed for1 h and cooled to rt. The suspension was filtered through a layer of Celite andthe filtrate was concentrated in vacuo to give crude compound 15 as a brown solid, which was used inthe next step immediately without any purification.
[3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl]carbamic acid tert-butyl ester[ No CAS ]
(3-{5-fluoro-2-[4-(2-methoxyethoxy)phenylamino]pyrimidin-4-ylamino}cyclohexyl)carbamic acid-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; at 85℃; for 16h;
In a microwave vial containing [3 -(2-Chloro-5-fluoro-pyrimidin-4-ylamino)- cyclohexylj-carbamic acid tert-butyl ester (344.81 mg; 1.00 mmol; 1.00 eq.) and 4-(2- methoxyethoxy)aniline (183.93 mg; 1.10 mmol; 1.10 eq.) in 2-Methyl-butan-2-ol (4.00 ml; 35.67 mmol; 35.67 eq.) was added Acetic acid (6.01 mg; 0.10 mmol; 0.10 eq.). The reaction was stirred at 85C for 16h before it was concentrated and carried to the next step without further purification. MS: mlz = 476 [M+Hj+, RT= 3.17 min.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; for 5h;
To a solution of compound 13-3 (370 mg, 1.41 mmol), compound 13-3-1 (247 mg, 1.48 mmol) and Cs2CO3 (690 mg, 2.12 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2 (102 mg, 0.14 mmol), and the reaction solution was heated to 80 C. and reacted for 5 h, followed by washed with water (5 mL) and extracted with DCM/MeOH (5 mL×3, v/v=10/1). The organic phases were combined, dried over anhydrous Na2SO4, filtered and evaporated to give a residue which was purified by column chromatography to afford compound 13-4 (yellow oil, 120 mg, Yield 22%). 1H NMR (400 MHz, CDCl3): delta ppm 8.39-8.38 (d, 1H, J=4.8 Hz), 8.26 (s, 1H), 7.74-7.72 (d, 1H, J=8.4 Hz), 7.48-7.46 (d, 2H, J=8.8 Hz), 7.25-7.21 (t, 1H, J=8 Hz), 6.97-6.95 (d, 3H, J=8.8 Hz), 6.54-6.52 (d, 1H, J=7.6 Hz), 4.21 (s, 2H), 4.16-4.14 (t, 2H, J=4.6 Hz), 3.79-3.77 (t, 2H, J=4.6 Hz), 3.48 (s, 3H).
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