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With diborane In tetrahydrofuran at 0 - 20℃; for 2 h;
To a solution of (S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (2.50 g, 10.8 mmol) in THF (25 mL) was added dropwise borane (1 M, 20 mL) at 0 °C over 15 mm. After addition,the reaction mixture was warmed to room temperature and stirred for 2 hrs. The reaction was quenched with MeOH/AcOH (9:1, 10 mL) at 0°C. The mixture was then concentrated and the residue was poured into 35 mL of water and 35 mL of EtOAc. The organic layer was washed with saturated Na2CO3 (30 mL) aqueous solution, dried over Na2SO4 and concentrated to give the title compound D186 (2.6 g, 100percent) as colorless oil.LCMS: 118 [M-1 00-’-Hj. tR =1.96 mins. (LCMS condition 3)1H NMR (300 MHz, CHLOROFORM-d): 53.84-3.91 (m, 3H), 3.49-3.68 (m, 4H), 2.70-2.97 (m, 2H), 2.03 (t, 1H), 1.45 (s, 9H);
With phosphorus pentoxide; triethylamine; In dichloromethane; at 0 - 5℃; for 3h;
The acid 15, (32 g) was dissolved in 400 mL dichloromethane along with, the amine hydrochloride (15.1 g), triethylamine (35 g), and this solution was cooled to 0-5C. To this reaction mixture was added phosphoric acid cyclic anhydride (97 g) over 90 minutes at 0-5C. The reaction mixture was stirred for 1.5 hrs total and quenched with 250 ml of 20% K2CO3 solution at <15C. The organic phase was separated and washed with 2×400 ml 10% K2CO3 to afford, after removal of solvent, 35.7 g of the desired amide 16 as a colorless oil (94%)
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 5h;
1.60 g (6.92 mmol) of (S)-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester was placed in a 100 ml flask. To this flask was added 30 ml dry dichloromethane, 1.18 ml (6.78 mmol) diisopropylethylamine, 662 mg (6.78 mmol) N,O-dimethylhydroxylamine hydrochloride, and 1.37 g (7.12 mmol) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC-HCl). The mixture was stirred for 5 hours. The reaction mixture was diluted with dichloromethane, washed three times with water, once with saturated aqueous NH4Cl, and then once with brine. The dichloromethane layers were dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The crude material was purified by column chromatography using 1:1 hexanes/ethyl acetate as the eluent. This procedure provided 1.08 g (3.94 mmol) (S)-2-(methoxy-methyl-carbamoyl)-morpholine-4-carboxylic acid tert-butyl ester 3 as a clear oil. _
3.5 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;
A mixture of <strong>[868689-63-8](S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (3.46 g, 15 mmol), DIPEA (7.75 g, 60 mmol), and N,O-dimethylhydroxylamine HCl (4.39 g, 45 mmol) in DCM (100 mL) was treated with EDCl (9.63 g, 45 mmol) at room temperature. The reaction mixture was stirred for 16 hours and then poured into saturated aqueous sodium bicarbonate solution and extracted with CH2Cl2. The combined extracts were dried over MgSO4, filtered, and concentrated to provide light yellow oil 3.5 g. MS (m/z): 175 (M+H-Boc)+
At room temperature, compound (39-2) (2 g, 8.65 mmol) was dissolved in N,O-dimethylhydroxylamine hydrochloride (1.01 g, 10.38 mmol) were added, and the reaction was performed overnight. The reaction was added with 107 water (20 mL), and extracted with dichloromethane (20 mL×3). The organic phase was combined, which was successively washed with 0.05N hydrochloric acid (20 mL), a saturated solution of 245 sodium bicarbonate, water and a saturated solution of 316 sodium chloride, and dried over anhydrous sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated to afford the 317 title compound (2 g), which was used directly for the next reaction without purification. ESI-MS (m/z): 219.1 [M+1-56]+.
The appropriate S chiral morpholine alcohol 1 (15 g) was dissolved in a suitable amount dichloromethane and, TEMPO (160 mg), KBr (650 mg), and TBACl (1 g) were dissolved in a mixture of DCM (950 mL) and 40 mL 1 M NaHCO3. The reaction mixture was cooled to 0 C and a solution of NaOCl (13%, 300 mL), 300 mL satd NaCl, and 180 mL NaHCO3 was added dropwise over a period of 45 minutes. After stirring the resulting mixture for another 1.5 hours, it was washed with CH2Cl2 (4×500 mL). The aq. layer was cautiously acidified to pH 2 with 1M HCl and extracted with CH2Cl2. The combined organics were dried and concentrated to give a white solid. The acid thus obtained gives a good result in the subsequent coupling reaction.
EXAMPLE 37 (2S)-2-[(1S)-(2-chloro-4-fluorophenoxy)-(3-fluorophenyl)methyl]morpholine hydrochloride A 500 ml flask was charged with 5.0 g (23 mmol) of (S)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (1) (Beard Research), 0.219 g KBr (1.84 mmol), 0.3518 g (1.27 mmol) Bu4NCl, 54 mg (0.35 mmol) TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), 150 ml dichloromethane, and 50 ml 1M sodium bicarbonate solution. The biphasic solution was stirred and cooled in a 0 C. bath. To this biphasic solution was added dropwise a mixture of 50 ml 10% sodium hypochlorite, 50 ml saturated NaCl solution, and 25 ml 1M sodium bicarbonate over about 45 minutes. The solution was stirred overnight. The layers were separated, and the aqueous layer was washed with dichloromethane. The aqueous layer was then acidified (with concentrated HCl) slowly to a pH of 2. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried with sodium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure yielding 1.60 g (6.92 mmol) of (S)-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2 as a white/yellow solid. The acid was carried on with no further purification.
With trichloroisocyanuric acid; tetramethylpiperidinyloxy; sodium hydrogencarbonate; sodium bromide; In acetone; at 0 - 20℃;
At room temperature, 221 (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (39-1) (5 g, 23.01 mmol) was dissolved in 308 acetone (250 mL), and a saturated solution of 245 sodium bicarbonate (75 mL) was added. The reaction was cooled to 0C in an ice bath, 309 sodium bromide (474 mg, 4.6 mmol) and tetramethylpiperidinyloxy (65 mg, 0.46 mmol) were added, followed by slow addition oftrichloroisocyanuric acid (10.7 g, 46.03 mmol), and the reaction was performed at room temperature overnight. The reaction was added with 310 isopropanol (15 mL), stirred for 30 min, filtered with suction, and the filter cake was discarded. The filtrate was concentrated, added with a saturated solution of 311 sodium carbonate (75 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was discarded. The aqueous phase was neutralized with 6N hydrochloric acid, and extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated to afford the 312 title compound 3 g, which was used directly for the next reaction without purification. ESI-MS (m/z): 176.1 [M+1-56]+.
With diborane; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a solution of <strong>[868689-63-8](S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (2.50 g, 10.8 mmol) in THF (25 mL) was added dropwise borane (1 M, 20 mL) at 0 C over 15 mm. After addition,the reaction mixture was warmed to room temperature and stirred for 2 hrs. The reaction was quenched with MeOH/AcOH (9:1, 10 mL) at 0C. The mixture was then concentrated and the residue was poured into 35 mL of water and 35 mL of EtOAc. The organic layer was washed with saturated Na2CO3 (30 mL) aqueous solution, dried over Na2SO4 and concentrated to give the title compound D186 (2.6 g, 100%) as colorless oil.LCMS: 118 [M-1 00-?-Hj. tR =1.96 mins. (LCMS condition 3)1H NMR (300 MHz, CHLOROFORM-d): 53.84-3.91 (m, 3H), 3.49-3.68 (m, 4H), 2.70-2.97 (m, 2H), 2.03 (t, 1H), 1.45 (s, 9H);
With diborane; In tetrahydrofuran; for 2.5h;Reflux;
(S)-N-Boc-2-morpholine carboxylic acid (2.00 g, 8.65 mmol) was dissolved in THF (30 mL) and borane (25.9 mL, 1.0 M in THF, 25.9 mmol) was added dropwise. The reaction mixture was heated at reflux for 2.5 h and quenched with water (10 mL). The reaction mixture was concentrated in vacuo and the residue dissolved in DCM (30 mL), washed with sat aq Na2CO3 (2*20 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (1.74 g, 92%) as a pale yellow oil. LCMS (ES+): 240.3 [MNa]+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;
HATU (133 mg, 0,350 mmol) is added to (2S)-4-tert-butoxycarbonylmorpholine-2- carboxylic acid (63 mg, 0,270 mmol), example 12a (82 mg, 90% content, 0,243 mmol) and DIPEA (140 muIota, 0,804 mmol) in dry DMF (2 mL) and stirring is continued for overnight.The reaction mixture is diluted with DCM and water. The organic layers is separated, dried on a Phase separator cartridge and evaporated under reduced pressure to give a residue that is purified by flash chromatography (eluent 20-50% EtOAc/cyclohexane) to furnish the title compound (99 mg, 95% content, 98%). UPLC-MS (Method 2): Rt = 1 .27 min MS (ESI+): m/z = 404 (M+H)+
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In dichloromethane; at 20℃;
Example 35a (156 mg, 0.69 mmol), (2S)-4-fe/t-butoxycarbonylmorpholine-2- carboxylic acid (160 mg, 0.69 mmol), TBTU (221 mg, 0.69 mmol) and triethylamine (480 uL, 3.45 mmol) are suspended in dichloromethane (10 mL) and stirred overnight at room temperature. The mixture is diluted with dichloromethane, washed with water and dilute aqueous sodium hydroxide solution, dried and the solvent evaporated. The residue was purified by flash chromatography (30% EtOAc in cyclohexane) to give the title compound (151 mg) UPLC-MS (Method 2): Rt = 1 .10 min MS (ESI+): m/z = 403 (M+H)+
With triethylamine; HATU; In dichloromethane; at 20℃;
Example 35a (156 mg, 0.69 mmol), (2S)-4-fe/t-butoxycarbonylmorpholine-2- carboxylic acid (160 mg, 0.69 mmol), TBTU (221 mg, 0.69 mmol) and triethylamine (480 uL, 3.45 mmol) are suspended in dichloromethane (10 mL) and stirred overnight at room temperature. The mixture is diluted with dichloromethane, washed with water and dilute aqueous sodium hydroxide solution, dried and the solvent evaporated. The residue was purified by flash chromatography (30% EtOAc in cyclohexane) to give the title compound (151 mg) UPLC-MS (Method 2): Rt = 1 .10 min MS (ESI+): m/z = 403 (M+H)+_The following examples are synthesized in analogy to the preparation of example49a:
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;
HATU (157 mg, 0,412 mmol) is added to (2S)-4-tert-butoxycarbonylmorpholine-2- carboxylic acid (73 mg, 0,317 mmol), example 6a (100 mg, 60% content, 0,317 mmol) and DIPEA (166 muIota, 0,951 mmol) in dry DMF (2 ml_) and stirring is continued overnight.Volatiles are evaporated under reduced pressure to furnish a residue that is diluted with ethyl acetate and washed with saturated NaHCO3 and brine. The organic layers is separated, dried on a Phase separator cartridge and evaporated under reduced pressure to give a residue purified by flash chromatography (eluent 10-40% EtOAc/cyclohexane) to furnish the title compound (79 mg, 98% content, 61 %). UPLC-MS (Method 2): Rt = 1 .17 MS (ESI+): m/z = 403 (M+H)+
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide;
TBTU (153 mg, 0.477 mmol) is added to (2S)-4-tert-butoxycarbonylmorpholine-2- carboxylic acid (100 mg, 0,432 mmol), example 2a (76 mg, 0,432 mmol) and TEA (180 muIota, 1 ,297 mmol) in DMF (1 mL) and stirring is continued overnight. Water and ethyl ether are added and the organic layer is washed with NaHCO3 saturated solution and brine. The organic layer is dried and evaporated to furnish a residue that is purified by flash chromatography (eluent 10-50% EtOAc/cyclohexane) to furnish the title compound (80 mg, 47%). UPLC-MS (Method 2): Rt = 1 .43 min MS (ESI+): m/z = 393 (M+H)+
(S)-methyl morpholine-2-carboxylate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With thionyl chloride; at 0℃; for 1h;Reflux;
To a solution of (S)-4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid (1.00 g, 4.33 mmol) in MeOH (15 mL) was added SOd2 (2 mL) dropwise at 0 C. Then the mixture was refluxedfor 1 h. The mixture was cooled to rt and concentrated under reduced pressure to afford awhite solid (780 mg, yield 99%) which was used for next step without purification.1H NMR (400 MHz, DMSO-d6): oe 9.85 (br s, 1H), 9.56 (br s, 1H), 4.56-4.51 (m, 1H), 4.02-3.96 (m, 1H), 3.84-3.79 (m, 1H), 3.68 (s, 3H), 3.40-3.35 (m, 1H), 3.19-2.94 (m, 3H).
2-(aminomethyl)-7-bromo-5-cyclopropyl-6-methyl-[1,3]oxazolo[4,5-c]quinolin-4-one[ No CAS ]
tert-butyl (2S)-2-[(7-bromo-5-cyclopropyl-6-methyl-4-oxooxazolo[4,5-c]quinolin-2-yl)methylcarbamoyl]morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 1h;
To a stirred solution of 2-(ami nomethyl)-7-bromo-5-cyclopropyl-6-methyl-oxazolo[4, 5- c]quinolin-4-one (prepared as described in Example 3 step (b)) (70 mg, 0.20 mmol), HATU (152 mg, 0.40 mmol), (2S)-4-teit-butoxycarbonylmorpholine-2-carboxylic acid (97 mg, 0.42 mmol) in DCM (5 mL) was added Et3N (0.11 mL, 0.80 mmol) and the reaction was allowed to stir for 1 h at room temperature. The reaction was diluted with DCM (20 mL) and washed with H20 (20 mL). The organic layer was then washed with H20 (3 x 20 mL), dried through a hydrophobic frit and concentrated to dryness. This was then used in the following step without further purification.LC-MS (Method F) 561.5/563.5 [M+H]+; RT 3.20 mm
5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine[ No CAS ]
tert-butyl (S)-2-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.08 g
To a solution of <strong>[868689-63-8](S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid</strong> (CAS Number 868689-63-8; 0.100 g, 0.432 mmol) in THF (6 ml) was added HATU (0.197 g, 0.518 mmol) and DIPEA (0.15 ml, 0.86 mmol) at rt. The reaction mixture was stirred at rt for 20 min before addition of 5-phenyl-2,3-dihydro-1 H-pyrrolo[2,3- b]pyridine (0.067 g, 0.345 mmol). The reaction mixture was stirred at rt for 1 h then poured into saturated NaHCO3 solution (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure yield tert-butyl (S)-2-(5-phenyl-2,3-dihydro-1 H-pyrrolo[2,3- b]pyridine-1 -carbonyl)-morpholine-4-carboxylate (0.080 g, 0.195 mmol). LCMS: Method C, 2.374 min, MS: ES+ 410.38.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 20h;
S-Morpholine-2,4-dicarboxylic acid 4-tertbutylester (10 g, 43.2 mmoles) was dissolved in DMF (120 ml) and the temperature was lowered to 0 C.; TBTU was then added and the mixture stirred 15 min before the addition of TEA (12.05 ml) and 2,3 Diammino pyridine (4.7 g; 43.2 mmoles). The reaction mixture was stirred 20 hours at room temperature before the work-up: DMF was removed under reduced pressure; the crude was diluted with EtOAc (300 ml) and water (100 ml) and then filtered with a glass filter. The organic phase was separated and washed with a 5% aqueous solution of sodium hydrogen carbonate (50 ml). The sodium hydrogen carbonate solution was back extracted with 100 ml of EtOAc, the organic phases combined together and dried over Na2SO4. The residue obtained after evaporation of the solvents was purified by flash chromatography using EtOAc/MeOH/NH4OH (97/3/0.3).; Obtained 11.5 g; [table-us-00017-en] HPLC-MS; Method: Z011_S03; Rt [min]: 0.82 MS: 323 (M + H)+ Chiral SFC Rt Method: Rt [min]: R-enantiomer I_C2_20_MeOH_NH3_001.M 2.90; 4.7% (Area) Chiral SFC Rt Method: Rt [min]: S-enantiomer I_C2_20_MeOH_NH3_001.M 3.38; 95.3% (Area)