* 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 In methanol at 20℃; for 4 h;
Step-(ii): Synthesis of (4-aminophenyl)(morpholino)methanone:To a solution Intermediate-8a (8.5 g 35.9m mol) in methanol 200 mL, added 10percent Pd/C (850 mg) and stirred under H2 atmosphere for 4h at RT. After the reaction was completed, the reaction solvent was filtered through celite pad and washed with excess of MeOH. The filtrate was evaporated by vacuum to get the desired product as a pale yellow solid (7.0 g, 94.53percent); 1H- NMR (400 MHz, DMSO-d6)-ö 7.14 (d, 2H, J=8.4 Hz), 6.55 (d, 2H, J=8 Hz), 5.5 (bs, 2H), 3.66-3.28 (m, 8H); MS (ES) m/z 207 (M+1).
85%
With palladium on activated charcoal; hydrogen In methanol at 20℃;
A mixture of 2a (1060 mg, 4.49 mmol)and Pd/C (66 mg, 0.620 mmol) in MeOH (20 mL) was stirred overnight under H2 at room temperature. The mixture was then filtered and the filtrate was concentrated to give thetitle compound 2b (830 mg, 85percent yield). LCMS: 206.9 [M+H]+.
82%
With iron; ammonium chloride In ethanol; water at 80℃; for 3 h;
General procedure: A solution ofmorpholino(4-nitrophenyl)methanone (5a) (6.3 mmol) with NH4Cl(6.3 mmol) and Fe (31.5 mmol) in 4:1 ethanol:H2O (100 mL) washeated at 80 C for 3 h. After the mixture was cooled, the solventwas evaporated and the residue was purified by column chromatographyon silica gel to yield compound 6a (82percent) as a whitesolid. 1H NMR (600 MHz, CDCl3) d 7.26 (d, J = 8.4 Hz, 2H), 6.65 (d,J = 8.4 Hz, 2H), 3.89 (s, 2H, NH2), 3.70–3.64 (m, 8H).
Reference：
[1] Green Chemistry, 2018, vol. 20, # 1, p. 130 - 135
[2] Organic Letters, 2017, vol. 19, # 1, p. 194 - 197
[3] ACS Catalysis, 2015, vol. 5, # 3, p. 1526 - 1529
[4] Patent: WO2014/125410, 2014, A1, . Location in patent: Page/Page column 26; 27
[5] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 9, p. 1615 - 1620
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3217 - 3226
[7] Organic Letters, 2016, vol. 18, # 11, p. 2774 - 2776
[8] Organic and Biomolecular Chemistry, 2014, vol. 12, # 28, p. 5082 - 5088
[9] Patent: US2004/87575, 2004, A1,
[10] Patent: US2003/13708, 2003, A1,
[11] Patent: US2004/110745, 2004, A1,
[12] Patent: WO2008/33834, 2008, A1, . Location in patent: Page/Page column 67-68
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2740 - 2744
[14] Patent: WO2010/71885, 2010, A1, . Location in patent: Page/Page column 459
[15] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 3, p. 517 - 522
[16] Green Chemistry, 2015, vol. 17, # 2, p. 898 - 902
[17] ChemCatChem, 2017, vol. 9, # 6, p. 1128 - 1134
2
[ 110-91-8 ]
[ 150-13-0 ]
[ 51207-86-4 ]
Yield
Reaction Conditions
Operation in experiment
46.54%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 12 h;
Synthesis of compound 177.2. To a solution of 177.1 (0.5g, 3.72 mmol, 1.0 eq) in DMF (10 ml) were added morpholine (0.409g, 4.74mmol, 1.3eq), and HATU (2.8g, 7.29mmol, 2.0eq). Reaction mixture was cooled to 0°C. DIPEA(1.8ml, 32.8mmol, 3.0eq) was added at 0° C. Reaction mixture was stirred at room temperature for 12 h.Upon completion mixture was poured into water and product was extracted with EtOAC. Organic layers were combined and dried over Na2S04 and concentrated under reduced pressure to obtain crude which was purified using column chromatography to get pure 177.2 (0.350g, 46.54percent). MS (ES): m/z 206.2 [M+H]+.
Reference：
[1] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00953; 00954
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5536 - 5545
[3] European Journal of Medicinal Chemistry, 2017, vol. 131, p. 107 - 125
With copper(l) iodide; lithium chloride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
General procedure: Inan oven-dried 250 mL round-bottomed flask equipped with a stir bar was added 6.54 g of active zinc (Zn, 100.0 mmol) in 100 mL of THF. The flask was then cooled down to 0 C using an ice-bath. Next, 4-iodoaniline (10.9 g,50.0 mmol) solution dissolved in 40.0 mL of THF was can nulated into the flask at 0 C. The resulting mixture was allowed to warm up to room temperature and stirred at ambient temperature for 24 h. The whole mixture was settleddown and then the supernatant was used for the subsequent coupling reactions. (b) Cross-coupling reaction of A; Into a 25 mL round-bottomed flask was placed 4-aminophenylzinc iodide (4.0 mL, 0.25 M in THF, 1.0 mmol)under argon atmosphere, then the flask was cooled down to 0 C using an icebath. Next, 4-methoxybenzoyl chloride (0.13 g, 0.8 mmol) was added, then stirred at 0 C for 30 min., quenched with saturated NH4Cl solution, thenextracted with ethyl acetate (3 10 mL). It was washed with saturated NaHCO3, 8percent NH4OH solutions and brine, then dried over anhydrous MgSO4.Purification by recrystallization (hexanes/ethyl ether) afforded 0.13 g of (4-aminophenyl)(4-methoxyphenyl)methanone (1c)
{4-[(5-Methoxy-3-[4-(morpholine-4-carbonyl)-phenylamino]-methyl}-2-thioxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-amino]-phenyl}-morpholin-4-yl-methanone[ No CAS ]
With iron; ammonium chloride; In methanol; water; at 70℃; for 5h;
N,N-Dimethyl-4-nitrobenzamide (0.5 g, 1 eq), reduced iron powder (0.36 g, 2.5 eq.), ammonium chloride(0.35 ml, 2.5 eq.) in 20 ml of methanol The mixture was stirred with water at 70 C for 5 hours, and then subjected to water-purpuration, suction filtration, and column chromatography to give white solid10a (0.35 g, 82.7%).
With palladium 10% on activated carbon; ammonium formate; In methanol; at 20℃; for 2h;
General procedure: (2) 4-(N,N-diethylcarboxamido)aniline: A mixture of N,N-diethyl 4- nitrobenzamide (4.44 g) and 10% palladium on carbon (0.2 g) in 100 mL of methanol was treated with ammonium formate (4.0 g) for 2 h at ambient temperature. The mixture was filtered through Celite and concentrated. The residue was redissolved in DCM, washed successively with 0.5 M Na2C03, water, and brine, then dried over MgS04, filtered, and evaporated to provide a crystalline material. Recrystallization from ethyl acetate/hexane provided the product aniline. [0086] Also prepared according to the same procedure was 4-(morpholinocarbonyl)aniline by replacing diethylamine with morpholine.
With palladium 10% on activated carbon; ammonium formate; In methanol; at 20℃; for 2h;
General procedure: (2) 4-(N,N-diethylcarboxamido)aniline: A mixture of N,N-diethyl 4-nitrobenzamide (4.44 g) and 10% palladium on carbon (0.2 g) in 100 mL of methanol was treated with ammonium formate (4.0 g) for 2 h at ambient temperature. The mixture was filtered through Celite and concentrated. The residue was redissolved in DCM, washed successively with 0.5 M Na2C03, water, and brine, then dried over MgS04, filtered, and evaporated to provide a crystalline material. Recrystallization from ethyl acetate/hexane provided the product aniline.
24
[ 953039-49-1 ]
[ 51207-86-4 ]
C29H35N5O5[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In isopropyl alcohol; at 130℃; for 14h;
Step 2. DisplacementTo a 0.50M solution of 2-chloro-8-(l-isopropylpiperidin-4-yloxy)quinazoline in 2-propanol was added <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (1.0 eq). The reaction was stirred at 130 0C for 14 h. The crude mixture was concentrated and used without further purification. ES/MS m/z 534 (MH+).
(4-(7-bromo-5-chloro-8-methoxy-quinazolin-2-ylamino)phenyl)(morpholin-4-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In isopropyl alcohol; at 90℃; for 16h;
Step 3. Preparation of (4-(7-bromo-5-chloro-8-methoxyquinazolin-2:-ylamino)phenyl)(morpholino)methanoneTo 7-bromo-2,5-dichloro-8-methoxyquinazoline (leq) was added <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (leq) in isopropanol and the mixture was heated to 9O0C for 16h. The solid formed was filtered to give (4-(7-bromo-5-chloro-8-methoxyquinazolin-2-ylamino)phenyl)(morpholino)methanone and was confirmed by LC/MS. ES/MS m/z 478(MH+).
(4-(8-methoxy-5-trifluoromethyl-quinazolin-2-ylamino)phenyl)(morpholin-4-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
In isopropyl alcohol; at 110℃; for 16h;
Step 11. Preparation of 4-(8-methoxy-5- (trifluoromethyl) quinazolin-2-ylamino) phenyl)(mophiholino)methanoneA mixture of 2-chloro-8-methoxy-5- (trifluoromethyl) quinazoline (leq) and 4-ataunino phenyl)(morpholino)methanone (leq) in isopropanol was heated in sealed tube at 1100C for 16h. The solvent was evaporated and residue was purified by semi-prep HPLC to provide pure product as yellow solid in 50% yield. ES/MS m/z 433.2 (MH+).
6-(1H-indol-2-yl)-N-[4-(morpholin-4-ylcarbonyl)phenyl]pyrazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 135℃; for 16h;
2-(6-Chloropyrazin-2-yl)-l //-indole (16.7 mg, 0.07 mmol), 4-(morpholin-4- ylcarbonyl)aniline (37.1 mg, 0.18 mmol), sodium ter-butoxide (16.7 mg, 0.17 mmol), xantphos (1.0 mg, 0.002 mol) and bis(dibenzylideneacetone)palladium (0.5 mg, 0.001 mol) in dioxane (8 mL) were heated at 135C for 16h, let to ambient temperature, filtered and the solvent was removed. The crude was dissolved in methanol (1 mL) and DMSO (0.5 mL) and purified using preparative HPLC system E. Yield 2.0 mg (7%). HPLC 90%, Rtau: 2.38 (5-100% MeCN over 3min). MS 399.2 (M+H)+.
With caesium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 105℃; for 96h;
{4-[4-(2-Methyl-3-nitrophenyl)pyrimidin-2-ylamino]phenyl}morpholin-4-yl- methanone (4).; <n="70"/>[00182] A 50-mL reaction tube equipped with a magnetic stirrer was charged with 2-chloro-4-(2-methyl-3-nitro-phenyl)-pyrimidine (3) (191 mg, 0.765 mmol) and 1,4-dioxane (15 rnL). After sparging the resulting solution with nitrogen for 15 minutes, (4-aminophenyl)morpholin-4-yl-methanone (2) (173 mg, 0.839 mmol), 1,1'- bis(diphenylphosphino)ferrocene (35 mg, 0.063 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol) and cesium carbonate (500 mg, 1.53 mmol) were added. The reaction tube was then sealed and heated at 105 0C for 4 d. Upon cooling to room temperature, the reaction was partitioned between a 10% solution of sodium chloride in water (275 mL) and methylene chloride (75 mL). The aqueous phase was separated and re-extracted with methylene chloride (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, and after removal of the drying agent by filtration, evaporated in vacuo. Purification of the resulting residue by flash chromatography afforded {4-[4-(2-methyl-3- nitrophenyl)pyrimidin-2-ylamino]phenyl}morpholin-4-yl-methanone (258 mg) as an off-white solid: mp 187-188 0C; MS (ESI+) m/z 420 (M+H).
EXAMPLE 18 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 12, yielding a yellow solid. (21 mg 15%), LCMS-m/z=477.6
Example 18 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 12, yielding a yellow solid. (21 mg=15%), LCMS-m/z=477.6
EXAMPLE 40 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 12, yielding a yellow solid. (170 mg=80%), LCMS-m/z=507.5
Example 40 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 12, yielding a yellow solid. (170 mg=80%), LCMS-m/z=507.5
EXAMPLE 61 6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene -2-carboxylic acid hydrochloride (Reference Example 3) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 58, yielding a yellow solid (220 mg=quantitative yield). LC/MS-m/z=495.5
Example 61 6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 3) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 58, yielding a yellow solid (220 mg=quantitative yield). LC/MS-m/z=495.5
EXAMPLE 63 6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene -2-carboxylic acid hydrochloride (Reference Example 4) and 1-(4-amino-phenyl)-1-morpholin -4-yl-methanone (Reference Example 14) as prepared in Example 1, yielding a yellow solid. LCMS-m/z=491.6
Example 63 6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide. This compound was prepared from 6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 4) and <strong>[51207-86-4]1-(4-amino-phenyl)-1-morpholin-4-yl-methanone</strong> (Reference Example 14) as prepared in Example 1, yielding a yellow solid. LCMS-m/z=491.6
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;
Step-(ii): Synthesis of (4-aminophenyl)(morpholino)methanone:To a solution Intermediate-8a (8.5 g 35.9m mol) in methanol 200 mL, added 10% Pd/C (850 mg) and stirred under H2 atmosphere for 4h at RT. After the reaction was completed, the reaction solvent was filtered through celite pad and washed with excess of MeOH. The filtrate was evaporated by vacuum to get the desired product as a pale yellow solid (7.0 g, 94.53%); 1H- NMR (400 MHz, DMSO-d6)-oe 7.14 (d, 2H, J=8.4 Hz), 6.55 (d, 2H, J=8 Hz), 5.5 (bs, 2H), 3.66-3.28 (m, 8H); MS (ES) m/z 207 (M+1).
85%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃;
A mixture of 2a (1060 mg, 4.49 mmol)and Pd/C (66 mg, 0.620 mmol) in MeOH (20 mL) was stirred overnight under H2 at room temperature. The mixture was then filtered and the filtrate was concentrated to give thetitle compound 2b (830 mg, 85% yield). LCMS: 206.9 [M+H]+.
82%
With iron; ammonium chloride; In ethanol; water; at 80℃; for 3h;
General procedure: A solution ofmorpholino(4-nitrophenyl)methanone (5a) (6.3 mmol) with NH4Cl(6.3 mmol) and Fe (31.5 mmol) in 4:1 ethanol:H2O (100 mL) washeated at 80 C for 3 h. After the mixture was cooled, the solventwas evaporated and the residue was purified by column chromatographyon silica gel to yield compound 6a (82%) as a whitesolid. 1H NMR (600 MHz, CDCl3) d 7.26 (d, J = 8.4 Hz, 2H), 6.65 (d,J = 8.4 Hz, 2H), 3.89 (s, 2H, NH2), 3.70-3.64 (m, 8H).
REFERENCE EXAMPLE 14b 1-(4-Amino-phenyl)-1-morpholin-4-yl-methanone. This compound was prepared from 1-morpholin-4-yl-1-(4-nitro-phenyl)-methanone as prepared in Reference Example 13b.
Reference Example 14b 1-(4-Amino-phenyl)-1-morpholin-4-yl-methanone This compound was prepared from 1-morpholin-4-yl-1-(4-nitro-phenyl)-methanone as prepared in Reference Example 13b.
With hydrogen;palladium 10% on activated carbon; In methanol; under 2585.81 Torr; for 1.5h;
(4-Aminophenyl)morpholin-4-yl-methanone (2).; [00180] A 500-mL Parr hydrogenation bottle was purged with nitrogen and charged with morpholin-4-yl-(4-nitrophenyl)methanone (1) (6.79 g, 23.9 mmol), 10% palladium on carbon (50% wet, 1.07 g dry weight) and methanol (150 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 1.5 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged into the bottle. The catalyst was removed by filtration through a pad of Celite 521, the filter cake washed with methanol (100 mL) and the filtrate was concentrated in vacuo. Recrystallization of the resulting clear gum from a hot mixture of ethyl acetate (20-30 mL) and hexanes (5-10 mL) afforded (4- aminophenyl)morpholin-4-yl-methanone (4.94 g) as a white solid: mp 130-132 0C; <n="69"/>MS (ESI+) m/z 207 (M+H).
With hydrogen;palladium 10% on activated carbon; In methanol; under 2844.39 Torr;
Morpholin-4-yl-(4-nitro-phenyl)- methanone (2.01 g, 8.51 mmol) was dissolved in Methanol (35 mL, 860 mmol) and the solution was carefully added to a Parr vessel containing 10 % Palladium on Carbon (0.650 g, 48.7 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.75 g of (4-Amino-phenyl)-morpholin-4-yl-methanone without further purification. (M+H) = 207.6. 1U NMR (400 MHz, DMSO, d6) delta 7.12 (d, 2H, J = 8.40 Hz), 6.52 (d, 2H, J = 8.42 Hz), 5.51 (s, 2H), 3.58 (m, 4H), 3.46 (m, 4H).
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 6h;
To the solution of 50 (3g, 16.17 mmol) in DCM (30 mL), triethyl amine (7 mL, 49.81 mmol) and morpholine (2 mL, 23.12 mmol) were added at room temperature. The reaction mixture was stirred for 2h and then quenched with water and extracted with ethyl acetate (30 mL x 3). The organic layer was collected and dried over anhydrous MgSO4, concentrated in vacuo to get the oily residue. The residue was dissolved in MeOH (15ml) and 10% palladium on activated carbon (0.7g, 0.66mmol) was added to it. After continuous stirring for 6 h, the mixture was filtered through celite, dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (EtOAc:n-hexane = 1 : 1) and was used for the amide coupling with 2,4-Bis-benzyloxy-5-isopropyl-benzoic acid employing EDC/HOBt mediated coupling methodology as followed in the preceding compounds synthesis (employed for intermediate 48 and 49). The methodology afforded 51 in 50% yield as a white solid. 1H-NMR (500MHz, CDCl3) delta 1.26 (d, J= 7 Hz, 6H), 3.35 (m, 1H), 3.66 (bs, 8H), 5.13 (s, 2H), 5.17 (s, 2H), 6.64 (s, 1H), 7.41 (m, 14H), 8.18 (s, 1H), 10.20 (s, 1H).
With FeO(OH)/C; hydrazine hydrate; In ethanol;Reflux;
Add 8.5 g (36.2 mmol) of crude I-m to a 500 mL single-necked flask. FeO(OH)/C catalyst 2.0g and 95% ethanol 100mL, heated to reflux, Slowly add a mixture of 25 mL of hydrazine hydrate and 20 mL of 95% ethanol. The disappearance of the starting material by TLC (methanol: chloroform = 1:15). The filter cake was washed twice with hot ethanol (30 mL × 2). The solvent was evaporated under reduced pressure to give a white solid. 6.5g, The yield was 93.5%. The product was directly fed to the next reaction without further purification.
N-tert-butyl-3-[5-methyl-2-(4-(morpholine-4-carbonyl)-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.25h;Microwave irradiation;
[0406] A mixture of intermediate 33 (0.13 g, 0.37 mmol), (4-arnino-phenyl)-morpholin-4- yl-methanone (0.092 g, 0.45 mmol), Pd2(dba)3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 0C for 15 min. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.065 g, 33%).[0407] 1H NMR (500 MHz, DMSOd6): delta 1.11 (s, 9H), 2.14 (s, 3H), 3.49 (br s, 4H), 3.59 (br s, 4H), 5.75 (s, IH), 7.25 (d, J= 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, IH), 7.71 (d, J= 9.0 Hz, 2H), 7.98 (s, IH), 8.06-8.08 (m, 2H), 8.65 (br s, IH), 9.26 (s, IH). MS (ES+): m/z 525 (M+H)+.
(S)-2-[4-(morpholine-4-carbonyl)phenylcarbamoyl]pyrrolidine-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 69; 2-[4-(Morpholine-4-carbonyl)-phenylcarbamoyl]-pyrroIidine-l-carboxylic acid benzyl ester (Compound 6069)Using General Procedure A from 10 mg of (4-Amino-phenyl)-morpholin-4-yl- methanone. MS: 438.1 (M+H*). General Procedure A; A mixture of (S)-Pyrrolidine-l,2-dicarboxylic acid 1 -benzyl ester (F.W. = 249.27, 0.54 g, 2.15 mmol). HATU (F.W. = 380.25, 0.82 g, 2.16 mmol), and DIEA (0.4 mL, 0.05 mmol) in DMF (30 mL) was stirred at room temperature for 1 h to provide a 0.072 mM solution. To each of the amines described in the following Examples was added 1 mL of this solution (0.072 mM) and the reaction mixtures were stirred at room temperature <n="68"/>overnight. The resulting mixtures were diluted with DMF (5 mL) and water (0.5 mL) then purified by reverse phase HPLC to furnish the corresponding products.
[00122] To a solution of <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (1.05 g, 5.09 mmol) in THF (50 mL) was added potassium -butoxide (1.0 M in THF, 10.5 mL, 10.5 mmol) at rt over 3 min. Then, 2,4-bis(methylthio)imidazo[l,2-f][l,2,4]triazine (1.20 g, 5.65 mmol), prepared as described in Journal of The Chemical Society,Perkins Transactions I 1999, 20, 2929, was added at rt in one portion. The mixture was stirred at rt for 1 hr, and the reaction was quenched with ice-cold water (100 mL). The resulting solution was adjusted with 1 N HCl to pH 10. The product started to precipitate, and the first crop of product was collected by suction filtration. The filtrate was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, and concentrated under vacuum to a volume of about 10 mL. The precipitating second crop of product was collected by suction filtration. The two crops of product (total 1.51 g, 80% yield) were combined and dried over drierite under vacuum.
[00147] To a solution of <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (0.231 g, 1.122 mmol) in THF (15 mL) at rt was added potassium t-butoxide (1.0 M in THF, 3.37 mL, 3.37 mmol) over 5 min, followed by the addition of tert-butyl 2,4- bis(methylthio)imidazo[l,2-f][l,2,4]triazin-7-ylcarbamate (0.350 g, 1.069 mmol) in THF (5 mL). The resulting dark red mixture was stirred at rt for 1 hr before the reaction was quenched with ice-cold water (50 mL). The mixture was adjusted with 1 N HCl to pH 9-10 and diluted with ethyl acetate (300 mL). The aqueous layer was separated, and the organic layer was washed with brine (50 mL) and dried over anhydrous MgSO4. The solution was concentrated under vacuum to a volume of approximate 10 mL, and the precipitating product, tert-butyl 2-(methylthio)-4-(4- (morpholine-4-carbonyl)phenylamino)imidazo[l,2-fJ[l,2,4]triazin-7-ylcarbamate (0.387 g, 0.797 mmol, 74.6 % yield), was collected as a pale yellow solid by suction filtration and dried under vacuum.
00160] To a solution of <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (0.545 g, 2.64 mmol) in THF (45 mL) at rt was added potassium tert-butoxide solution (5.28 mL, 5.28 mmol) over 5 min, followed by the addition of 2,4-bis(methylthio)imidazo[l,2- f][l,2,4]triazine-7-carbonitrile (0.597 g, 2.52 mmol) in THF (35 mL). The resulting <n="76"/>mixture was stirred at rt for 1 hr before it was poured into ice-cold water (150 mL). The mixture was adjusted with 1 N HCl to pH 9-10 and extracted with ethyl acetate (3 x 80 mL). The combined extract was washed with brine (80 mL) and dried over anhydrous MgSO4. The desired product, 2-(methylthio)-4-(4-(morpholine-4- carbonyl)phenylamino)imidazo[l,2-f][l,2,4]triazine-7-carbonitrile (0.831 g, 2.101 mmol, 84 % yield), was isolated as a yellow solid with ISCO chromatography (80 g silica gel, 70-100 ethyl acetate/heptane).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 48h;Reflux;
E. (4-(6-Amino-3-(2-methyl-3-nitrophenyl)-l,2,4-triazin-5- ylamino)phenyl)(morpholino)methanone[00171] A mixture of 5-chloro-3-(2-methyl-3-nitrophenyl)-l,2,4-triazin-6-amine (1.05 g, 3.95 mmol), <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (1.630 g, 7.90 mmol), and N,N-diisopropylethylamine (1.243 mL, 7.11 mmol) in 1,4-dioxane (60 mL) was heated at reflux for 2 days. The volatiles were removed under vacuum. To the residue was added water (60 mL). The precipitating material was collected by suction filtration. The filter cake was purified by ISCO (120 g silica gel, solid loading, 3-8% MeOH/ CH2CI2) to provide the desired product, (4-(6-amino-3-(2-methyl-3- nitrophenyl)-l,2,4-triazin-5-ylamino)phenyl)(morpholino)methanone (0.595 g, 1.339 mmol, 33.9 % yield), as a yellow solid.
KOtBu (2.78 g, 24.75 mmol) was dissolved into 20ml DMSO in a round bottom flask. <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (5.10 g, 24.75 mmol) in 10ml DMSO was added and the resulting mixture was stirred for 35mins at r.t. The mixture was cooled in an iced bath for 5mins. 5-bromo-2-fluorobenzonitrile (4.5g, 22.50 mmol) in 10ml DMSO was added dropwise. Iced bath was removed and the mixture was stirred for lhr at r.t. The mixture was diluted with ethyl acetate, 100ml saturated NH4Cl water solution was added. The organic layer was separated. The water layer was extracted with ethyl acetate. The organic layers were combined and washed with H2O (4X), brine, dried over MgSO4 and concentrated. 8g crude product (84% purity) was obtained. MS (ESI) m/z 386 (M+H)+. 1H NMR (CDCl3) delta ppm 7.61 (d, 1H, J= 2.3), 7.47 (dd, 1H, J= 9, 2.5), 7.41 (m, 2H), 7.15 (m, 3H), 6.35 (bs, 1H), 3.65 (bm, 8H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere;
Intermediate 1 (236 mg, 0.81 mmol), Intermediate 8 (200 mg, 0.97 mmol), Pd2(dba)3 (26 mg, 0.028 mmol), xantphos (22 mg, 0.038 mmol) and sodium ferf-butoxide (135 mg, 2.42 mmol) were combined with dioxane (6 mL), sealed and then purged with nitrogen gas, and the reaction mixture was heated at 90 0C for 18 hours. The mixture was evaporated and purified through a silica plug, eluting with 0 to 10% methanol in DCM. Further purification by preparative LCMS (high pH buffer) gave the desired product as a white solid (113 mg, 36%). 1H NMR (400 MHz, DMSO-cfe) deltaH ppm 1.66 - 1.75 (m, 1 H), 1.77 - 2.00 (m, 5 H), 2.02 - 2.13 (m, 2 H), 2.90 - 2.99 (m, 1 H), 3.01 - 3.08 (m, 2 H), 3.48 - 3.56 (m, 4 H), 3.57 - 3.66 (m, 4 H), 4.12 - 4.20 (m, 2 H), 6.46 (d, J=3.7 Hz, 1 H), 7.31 - 7.41 (m, 3 H), 7.72 (br. s, 1 H), 7.94 (d, J=8.7 Hz, 2 H), 8.72 (s, 1 H), 9.71 (br. s, 1 H). m/z (ES+APCI)+: 463.3 [M+H]+.
[4-(Morpholine-4-carbonyl)-phenyl]-carbamic acid ferf-butyl ester as described in Step 1 (180 mg, 0.59 mmol) and 4M hydrogen chloride solution in dioxan (3 x mL) were combined and stirred at room temperature for 3 h. The volatiles were evaporated and water was added to the residue (20 mL), and pH adjusted to 8 with saturated NaHCO3. The resulting mixture was then extracted with DCM (3 x 20 mL), the combined organic phases were washed with brine, dried (MgSO4), and evaporated under reduced pressure to give the desired product as a yellow oil (159 mg, 91%). 1H NMR (400 MHz, DMSO-CZ6) deltaH ppm 3.46 - 3.49 (m, 4 H), 3.55 - 3.59 (m, 4 H), 5.54 (br. s, 2 H), 6.54 (d, J=8.2 Hz, 2 H), 7.12 (d, J=8.2 Hz, 2 H); m/z (ESMPCI)+: 207 [M+H]+.
EXAMPLE 1; (R)-tert-Butyl l-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2- yl)piperidin-3 -ylcarbamateA. 6-Chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid[00157] To a suspension of <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (9.02 g, 43.8 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (66.7 mL, 66.7 mmol, IM solution in THF) dropwise over 15 min. at -78C under nitrogen. The reaction mixture was stirred for one hour at -78C. To the resulting brown solution was added a solution of 2,6-dichloronicotinic acid (4 g, 20.83 mmol) in THF (12 ml) dropwise at -78C. The reaction mixture was removed from the dry ice bath and stirred overnight at rt. The resulting dark solids were washed with a small amount of THF to remove <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> on the surface, followed by the addition of water and 18 ml of 6N HCl (pH of 2). The solids were filtered and the resulting pink filter cake was washed with water (~1L) until the filter cake was white powder and the filtrate was colorless. The filter cake was transferred to a flask with MeOH and CH2Cl2, and dried on a rotary evaporator with MeOH to give 6.60 g of 6- chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid as a white solid. LCMS: (M+H)+ = 362.02, 364.03 (Cl pattern).
To a solution of <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (1.6 g, 9.77 mmol) in DMA (20 ml) was added intermediate-l (2.0 g, 7.51 mmol) and stirred at 110°C for 16 h. The reaction mixture was poured over crushed ice, the precipitate solid was filtered, dried under vacuum to get the desired product (1.7 g, 64.63 percent) as a pale brown solid. LC-MS: 394.2 (M+l)+.
63%
In ISOPROPYLAMIDE; at 105℃; for 14h;Inert atmosphere;
Example lOld 5 -Bromo- 1 -methyl- 3 - [4- (morpholine-4-carbonyl)phenylamino] - 1H- pyrazin-2-one lOld CGIPHARM60WOlOldA 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 3,5-dibromo-l-methylpyrazin-2(lH)-one (J. Heterocycl. Chem. 1983, 20, 919) (21.8 g, 81.4 mmol), 4-aminobenzmorpholide (23.6 g, 114 mmol) and dimethyl- acetamide (130 mL). The reaction mixture was then heated under nitrogen at 105 °C for 14 h (Note: A spatula was used to break up the solids formed after 4 h of heating). After this time the suspension was cooled to room temperature, poured into stirring water (1.5 L) and filtered. The resulting precipitate was washed with water (2 x 250 mL) and allowed to partially dry on the filter paper for 10-15 minutes. After this time the filter cake was washed with hot ethyl acetate (2 x 250 mL), followed by hot ethanol (250 mL) and dried under reduced pressure to afford a 63percent yield (24.3 g) of lOld as a light orange solid: mp 276-277 °C; ]H NMR (500 MHz, CDC13) delta 8.39 (bs, 1H), 7.81 (dd, 2H, / = 9.0, 2.0 Hz), 7.45 (dd, 2H, J = 9.0, 2.0 Hz), 6.81 (s, 1H), 3.71 (m, 8H), 3.55 (s, 3H); MS (ESI+) m/z 393 (M+H).
57%
In dimethyl amine; at 110℃; for 16h;
Step-(iii): Synthesis of 5-bromo- 1 -methyl-3-((4-(morpholine-4-carbonyl) phenyl) amino) pyrazin-2( 1H)-one:Intermediate-8b (0.5g, 1.87mmol), Intermediate-i (0.5 g, 2.49 mmol) in DMA (5 mL) were heated at 110°C for i6hrs. Then the reaction mixture was poured over crushed ice, theprecipitate was filtered, dried under vacuum to get desired product as a yellow solid (400 mg,57percent); 1H NMR (400 MHz, DMSO-d6) oe 9.6 (s, 1H), 8.01 (d, 2H, J=8.8 Hz), 7.40 - 7.38 (m, 3H),3.6-3.45 (m, 1 1H); MS (ES) m/z 395 (M+1).
General procedure: 2,3-Dichloro-1,4-naphthoquinone (2 mmol) and the corresponding amine (2 mmol) were suspended in 20 ml of anhydrous ethanol. The mixture was refluxed for 3 days. Then the reaction mixture was filtered immediately and purified to afford the target compounds. Spectroscopic data for target compounds are shown as follows.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20 - 30℃; for 2h;Inert atmosphere;
A mixture of 432 4-aminobenzoic acid 47b (137 g, 1 mmol), 434 morpholine (96 mg, 1.1 mmol), 272 DIPEA (387 mg, 3 mmol), and 69 HATU (380 mg, 1 mmol) in 67 N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 h. The reaction was quenched with 86 water and extracted with ethyl acetate (50 mL×2). The organic phase was combined and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1) to give the target 435 product (4-aminophenyl)(morpholino)methanone 47c (103 mg, brown oil). Yield: 50%. MS m/z (ESI): 207[M+1]
46.54%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
Synthesis of compound 177.2. To a solution of 177.1 (0.5g, 3.72 mmol, 1.0 eq) in DMF (10 ml) were added morpholine (0.409g, 4.74mmol, 1.3eq), and HATU (2.8g, 7.29mmol, 2.0eq). Reaction mixture was cooled to 0C. DIPEA(1.8ml, 32.8mmol, 3.0eq) was added at 0 C. Reaction mixture was stirred at room temperature for 12 h.Upon completion mixture was poured into water and product was extracted with EtOAC. Organic layers were combined and dried over Na2S04 and concentrated under reduced pressure to obtain crude which was purified using column chromatography to get pure 177.2 (0.350g, 46.54%). MS (ES): m/z 206.2 [M+H]+.
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 N,N-dimethyl-formamide; at 20℃; for 8h;
General procedure: To a mixture of 4-amino-2-nitrobenzoic acid (1.0 g, 5.49 mmol)in DMF (100 mL) was added morpholine (2.39 mL, 27.5 mmol),HATU (3.13 g, 8.23 mmol) and DIPEA (1.36 mL, 8.23 mmol). Thereaction mixture was stirred at room temperature overnight, thenconcentrated to remove the DMF. The residue was diluted withwater (100 mL) and extracted with DCM (3 x 80 mL). The organicphase was concentrated and purified by flash column chromatography(0-5% MeOH in DCM) to afford S3b (1.25 g, 91%) as a solid.
Example No. 294Preparation of morpholino (4- ( (5- (thiophen-2-yl) -1H- pyrazolo [4 , 3-d] pyrimidin-7-yl) amino) phenyl) methanone7-chloro-2- (4-methoxybenzyl) -5- ( thiophen-2-yl) -2H- pyrazolo [4 , 3-d] pyrimidine (0.16 mmol) and (4- aminophenyl) (morpholino) methanone (0.3 mmol 2 eq.,) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL) , HC1 in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140 C. 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 140C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 406.1454 g/molHPLC-MS: analytical method Lrt: 4.29 min - found mass: 407 (m/z+H)
Example No. 295Preparation of N- (4- (morpholinomethyl) phenyl) -5- (thiophen-2- yl) -IH-pyrazolo [4 , 3-d] pyrimidin-7 -amine7-chloro-2- (4 -methoxybenzyl) -5- (thiophen-2-yl) -2H- pyrazolo [4 , 3-d] pyrimidine (0.16 mmol) and (4 -Amino-phenyl) - morpholin-4-yl-methanone (0.3 mmol 2 eq. , ) 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 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 dissolved in THF (dry) LiAlH4 powder was added (excess, 2 by 2 eq) until completion of reaction is observed (by LCMS) . The reaction was quenched with water (lmL per gram LiAlH4) , then NaOH (ca. 15% aq. , lmL per g LiAlH4), water (3mL per gram LiAlH4) . The mixture was filtered, washed with THF, MeOH, MeCN(ca. 10ML each) . The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 392.1710 g/molHPLC-MS: analytical method Lrt: 3.20 min - found mass: 393 (m/z+H)
Example No. 157Preparation of morpholino (4- ( (5- (thiophen-3-yl) -1H- pyrazolo [4 , 3-d] pyrimidin-7-yl) amino) phenyl) methanone7-chloro-2- ( -methoxybenzyl) -5- (thiophen-3 -yl ) -2H- pyrazolo [4 , 3 -d] pyrimidine (0.16 mmol) and (4- aminophenyl) (morpholino) methanone (0.3 mmol 2 eq. , ) 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: 406.1454 g/molHPLC-MS: analytical method Art : 2.44 min - found mass: 407 (m/z+H)
With (1S)-10-camphorsulfonic acid; In isopropyl alcohol; at 90℃;
Step 1. Preparation of [4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (500 mg, 1.8 mmol), (4-aminophenyl)(morpholino)-methanone (408 mg, 1.98 mmol) and CSA (356 mg, 1.53 mmol) in iPrOH (30 mL) was stirred at 90 C. overnight. The solvent was evaporated. The residue was dissolved in DCM (30 mL). A NaHCO3 solution (10 mL) was added to adjust to pH=8. The organic layer was separated and dried over Na2SO4. The drying agent was removed by filtration and the resultant solution was concentrated in vacuo. The residue was purified through a silica-gel column (ethyl acetate:petroleum ether=1:1) to give the desired product as a yellow solid (500 mg, 69% yield). LC-MS: 404 [M+1]+, tR=1.409 min.
61%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 20h;
Step-(iii): Synthesis of (4-((6-bromoimidazo [1, 2-a] pyrazin-8-yl) amino) phenyl)(morpholino) methanone:To a stirred solution of Intermediate-lOb (7.0 g, 19.6 mmol), Intermediate-8b (4.0 g, 19.6 mmol) in 70 mL of DMF was added, DIPEA (10.68 mL, 58.82 mmol) and stirred at 110C for 20h. The reaction mixture was distilled under a reduced pressure to remove the solvent. Theresidue was taken in water and extracted with DCM (2 x 250 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by colunm chromatography using 100-200 mesh silica gel and 5% MeOH in DCM as eluent to give the titled product as a pale brown viscous solid (4.8 g, 61%); 1H NMR (400 MHz, DMSO-d6): oe 10.21 (s, 1H), 8.33 (s, 1H), 8.07 (d, 2H, J=8 Hz), 7.98 (s, 1H), 7.97 (s,1H), 7.43 (d, 2H, J=8.8 Hz), 3.61-3.5 1 (m, 8H); MS (ES) m/z 402 (M+1).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Reflux;
Step 2. Preparation of [4-(6-Bromo-imidazo[1,2-a]pyridin-8-ylamino)-phenyl]-morpholin-4-yl-methanone 6-Bromo-8-iodo-imidazo[1,2-a]pyridine (500 mg, 1.53 mmol), (4-aminophenyl)(morpholino)-methanone (348 mg, 1.69 mmol) and CsCO3 (998 mg, 3.06 mmol) were dissolved in dioxane (10 ml). Under N2 atmosphere, Pd2(dba)3 (70 mg, 0.077 mmol) and Xantphos (89 mg, 0.153 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature, poured into water (100 mL) and extracted with DCM (100 ml). The organic extracts were washed with saturated aqueous solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate 1:2) to afford the desired product as a yellow solid (270 mg, yield 44%). LC-MS: 401[M+1]+, tR=1.257 min.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Reflux;
Step 1. _reparation of [6-(5-chloro-pyridazin-3-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone ;P3,5-Dichloropyridazine (1.0 g, 4.83 mmol), <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (864 mg, 5.80 mmol), Cs2CO3 (3.15 g, 9.66 mmol) were dissolved in dioxane (20 ml). Under N2 atmosphere, Pd2(dba)3 (221 mg, 0.24 mmol) and Xantphos (280 mg, 0.48 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature, poured into water (100 ml), and extracted by DCM (100 ml). The combined organic phases were washed with saturated aqueous solution of sodium chloride (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:5). The desired product was obtained as a yellow solid (715 mg, yield 46%). LC-MS: 320[M+1]+, tR=1.208 min.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Inert atmosphere; Reflux;
Step 1. Preparation of [6-(4-Bromo-pyridin-2-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone 2,4-dibromopyridine (0.7 g, 3.34 mmol), <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (733 mg, 3.54 mmol) and Cs2CO3 (1.92 g, 5.90 mmol) were dissolved in dioxane (10 ml). Under N2 atmosphere, Pd2(dba)3 (135 mg, 0.15 mmol) and Xantphos (171 mg, 0.30 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature, poured into water (100 ml), extracted with DCM (100 ml) and then washed with saturated aqueous solution of sodium chloride (100 ml). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate=2:1). The desired product was obtained as a yellow solid (426 mg, yield 40%). 1H NMR (300 MHz, MeOD): delta 10.19 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.18-8.09 (m, 2H), 7.75 (dd, J=8.6, 2.3 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.19-7.09 (m, 1H), 3.55 (d, J=23.3 Hz, 8H). LC-MS: 363[M+1]+, tR=1.210 min.
2-{3-[2-(4-methoxyphenyl)ethyl]-1-[4-(morpholine-4-carbonyl)phenyl]-5-oxo-2-sulfanylideneimidazolidin-4-yl}-N-(5-methoxypyridin-2-yl)acetamide[ No CAS ]
(4-isothiocyanatophenyl)(morpholino)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In dichloromethane; at 20℃; for 1h;
a) 4-(4-Isothiocvanatobenzoyl)morpholine (1-112) l-(lH-imidazole-l-carbothioyl)-lH-imidazole (172.8 mg; 0.97 mmol; 1 eq) was added to a solution of 4-(morpholine-4-carbonyl)aniline (200 mg; 0.97 mmol; 1 eq) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated to dryness. The crude was purified on silica gel using dichloromethane as an eluent. The title compound 4-(4-isothiocyanatobenzoyl) morpholine was obtained in 89% yield (215 mg) as a yellow gum. 1H NMR (CDC13): delta (ppm) 3.62 (brs, 8Eta), 7.26 (s, 1Eta), 7.28 (s, 1Eta), 7.42 (m, 2H); MS (ESI+): m/z = 249.0 [M+H]+.
(4-isothiocyanatophenyl)(morpholino)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With calcium carbonate; In dichloromethane; water; at 0 - 20℃; under 760.051 Torr;Inert atmosphere;
To a suspension of calcium carbonate (1.21 g, 12.1 mmol, Eq: 2.5) and thiophosgene (615 mg, 410 mu., 5.35 mmol, Eq: 1.1) in dichloromethane (13.2 g, 10 mL, 155 mmol, Eq: 32.1)/water (10.0 g, 10 mL, 555 mmol, Eq: 114) at 0, was added (4- aminophenyl)(morpholino)methanone (1 g, 4.85 mmol, Eq: 1.00). The reaction was gradually warmed to room temperature and stirred overnight. Separated organic layer and dried over sodium sulfate. Chromatography (40 g Analogix, 50% ethyl acetate/hexane) gave 1.014 g (84%) of desired product as a white solid.
With hydrogenchloride; In 1,4-dioxane; methanol; at 140℃; for 0.0833333h;Microwave irradiation;
4-chloro-9-methoxy-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinoline (0.16 mmol) and (4- amino-phenyl)-morpholin-4-yl-methanone (2 eq., 0.3 mmol ) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL), HC1 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 140C. The reaction mixture was concentrated and dissolved in THF (dry) LiAlH4 powder was added (excess, 2 by 2 eq) until completion of reaction is observed (by LCMS). The reaction was queched with water (ImL per gram LiAlH4), then NaOH (ca. 15% aq., ImL per g LiAlH4), water (3mL per gram LiALH4). The mixture was filtered, washed with THF, MeOH, MeCN (ca. lOmL each). The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 389.2203 g/mol HPLC-MS: analytical method B rt: 2.20 min - found mass: 390.2 (m/z+H)
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