* 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.
Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 6 h; Stage #2: With methanol In tetrahydrofuran at 80℃; for 2 h;
Intermediate 65(R)-(4-Benzylmorpholin-3-yl)methanol[0351][Chemical Formula 96]To a solution of intermediate 66 (12.6 g, 53.6 mmol) in tetrahydrofuran (200 mL) was added borane-tetrahydrofuran-complex (1.0 M, 348 mL). After stirring for 6 hours at room temperature, to the mixture was added methanol, and after heated to 80°C, stirred for 2 hours. To the mixture were added saturated sodium bicarbonate water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate = 90/10 to 10/90) to give the title compound (9.60 g, 46.0 mmol, 86percent).MS (ESI+) 208 (IVT+l, 100percent)
Reference：
[1] Patent: WO2011/111875, 2011, A1, . Location in patent: Page/Page column 90-91
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2577 - 2580
[3] Helvetica Chimica Acta, 2004, vol. 87, # 1, p. 90 - 105
2
[ 211053-49-5 ]
[ 100-39-0 ]
[ 101376-26-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2 h;
Benzyl bromide (1.2 g, 7.06 mmol) was added in one portion to a stirred solution of (R)- morpholin-3-ylmethanol (986 mg, 6.42 mmol) and DIPEA (1.66 g, 12.8 mmol) in MeCN (50 ml) and the resulting solution was stirred at rt for 2h, whereafter the mixture was then concentrated under reduced pressure. The afforded residue was dissolved in DCM (50ml) was and washed sequentially with sat. aq. NaHC03 (50 ml) and 1 M KOH (10 ml). The aqueous phase was extracted with DCM (25 ml) and the combined organic layers were dried over Na2S04, filtered and concentrated which gave the title compound (1.19 g, 89percent). MS (ESI): 208 [M+H]+.
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6527 - 6530
5
[ 106910-76-3 ]
[ 101376-26-5 ]
Reference：
[1] Helvetica Chimica Acta, 2004, vol. 87, # 1, p. 90 - 105
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2577 - 2580
[3] Patent: WO2011/111875, 2011, A1,
6
[ 100-52-7 ]
[ 101376-26-5 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2577 - 2580
7
[ 101376-26-5 ]
[ 211053-49-5 ]
Yield
Reaction Conditions
Operation in experiment
57%
Stage #1: With hydrogen; acetic acid In ethanol at 20℃; Stage #2: With ammonia In methanol
(a) (3R)-Morpholin-3-ylmethanol; A solution of [(3i?)-4-benzylmorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 1288- 1290; 1.1 g, 5.4 mmol) in ethanol (25 mL) was mixed with palladium hydroxide (20percent on carbon, 0.7 g) and acetic acid (0.5 mL). The mixture was stirred under hydrogen overnight20 at 1.2 bar and RT. The catalyst was filtered off and the solvent was removed by evaporation. The residue (except 200 mg) was dissolved in ether (1 mL) and THF (10 mL). The solution was filtered through a strong cation exchange column (Isolute SCX-2, 10 g). The column was washed with THF and then the product was eluted with ammonia- saturated methanol. The solvent was removed by evaporation and there was obtained 0.3625 g (57percent) of (3i?)-morpholin-3-ylmethanol as an oil. 1H NMR (500 MHz, CD3OD): 2.9 (m, 3H), 3.3 (t, IH)5 3.5 (m, 3H), 3.7-3.9 (m, 2H).
Reference：
[1] Patent: WO2006/137790, 2006, A1, . Location in patent: Page/Page column 35
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244
8
[ 101376-26-5 ]
[ 696582-88-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244
9
[ 101376-26-5 ]
[ 917572-28-2 ]
Yield
Reaction Conditions
Operation in experiment
94%
With thionyl chloride In dichloromethane for 2.5 h; Heating / reflux
(a) (3S)-4-Benzyl-3-(chloromethyl)morpholine; To a solution of [(3i?)-4-benzykcιorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 0 1288-1290; 1.83 g, 8.8 mmol) in dry methylene chloride (15 mL) was added thionyl chloride (3.15 g, 26.5 mmol) and DMF (2 drops). The mixture was heated to reflux for 2 h 30 min and then the solvent was removed by evaporation. The residue was treated with aqueous NaHCO3 and the solution was extracted with ethyl acetate. The organic solution was separated and the solvent was removed by evaporation. There was obtained 1.88 g s (94percent) of (31S)-4-benzyl-3-(chloromethyl)morpholine as an oil. 1H NMR (500 MHz, CDCl3): 2.3-2.4 (m, IH), 2.7 (m, IH), 2.8 (m, IH), 3.5 (d, IH), 3.6-3.9 (m, 5H), 4.0 (d, IH), 7.3 (m, IH), 7.4 (m, 4H); LCMS: m/z 226 (M+l)+.
94%
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 2.5 h; Heating / reflux
(a) (3S)-4-Benzyl-3-(chloromethyl)morpholineTo a solution of [(3i?)-4-benzylmorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 1288-1290; 1.83 g, 8.8 mmol) in dry methylene chloride (15 mL) was added thionyl chloride (3.15 g, 26.5 mmol) and DMF (2 drops). The mixture was heated to refluxed for 2 h 30 min and then the solvent was removed by evaporation. The residue was treated with aqueous NaHCO3 and the solution was extracted with ethyl acetate. The organic solution was separated and the solvent was removed by evaporation. There was obtained 1.88 g (94percent) of (3S)-4-berLzyl-3-(chloromethyl)morpholine as an oil. 1H NMR (500 MHz, CDCl3): 2.3-2.4 (m, IH), 2.7 (m, IH), 2.8 (m, IH), 3.5 (d, IH), 3.6-3.9 (m, 5H), 4.0 (d, IH), 7.3 (m, IH), 7.4 (m, 4H); LCMS: m/z 226 (M+l)+.
Intermediate 65(R)-(4-Benzylmorpholin-3-yl)methanol[0351][Chemical Formula 96]To a solution of intermediate 66 (12.6 g, 53.6 mmol) in tetrahydrofuran (200 mL) was added borane-tetrahydrofuran-complex (1.0 M, 348 mL). After stirring for 6 hours at room temperature, to the mixture was added methanol, and after heated to 80C, stirred for 2 hours. To the mixture were added saturated sodium bicarbonate water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate = 90/10 to 10/90) to give the title compound (9.60 g, 46.0 mmol, 86%).MS (ESI+) 208 (IVT+l, 100%)
With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 20℃; for 1.5h;
A solution of 1.00 g (4. 82 mmol) (R)- (4-BENZYL-MORPHOLIN-3-YL)-METHANOL, 0.80 g (5.3 mmol) tert-butyl-chloro-dimethyl-silane and 0.72 g (0.11 mmol) imidazole in 10 ml N, N-dimethylformamide was stirred at room temperature for 90 min. Consecutive addition of water and 1 M aqueous sodium hydroxide solution was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with 1 M aqueous sodium hydroxide solution, dried over sodium sulphate and concentrated in vacuo to give 1.54 g (99.3%) of the crude title compound as a colorless oil.
STR31 <strong>[101376-26-5](3R)-4-Benzylmorpholine-3-methanol</strong> (1.04 g, 5.0 mmol), t-butyldimethylchlorosilane (0.83 g, 5.5 mol), and imidazole (0.41 g, 6.0 mmol) were allowed to react in 5 mL of dichloromethane at room temperature overnight. The reaction product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain (3S)-3-(t-butyldimethylsilyloxy)methyl-4-benzylmorpholine (1.53 g, 95%) as a colorless oil.
(R)-allyl 3-(hydroxymethyl)morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
palladium; In ethanol; hexane; ethyl acetate;
Preparation 43 The mixture of <strong>[101376-26-5](3R)-4-benzyl-3-hydroxymethylmorpholine</strong> (2.23 g) and 10% palladium on carbon (wet, 1.11 g) and ethanol was stirred under hydrogen atmosphere for 2 hours. The catalyst was filtrated and the filtrate was evaporated. The oily residue was taken up in ethyl acetate (50 ml) and water (50 ml). The mixture was treated with allyl chloroformate (1.23 ml) at pH 9-10 and stirred for 30 minutes. The separated organic layer was washed with brine (50 ml*2) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (40 ml) eluding with ethyl acetate in hexane (5-50%) to give (3R)-4-allyloxycarbonyl-3-hydroxymethylmorpholine (1.22 g). NMR (CDCl3, delta): 2.75 (1H, br. s), 2.9-4.4 (9H, m), 4.4-4.7 (2H, m), 4.9-5.4 (2H, m), 5.6-6.2 (1H, m)
(a) (3R)-Morpholin-3-ylmethanol; A solution of [(3i?)-4-benzylmorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 1288- 1290; 1.1 g, 5.4 mmol) in ethanol (25 mL) was mixed with palladium hydroxide (20% on carbon, 0.7 g) and acetic acid (0.5 mL). The mixture was stirred under hydrogen overnight20 at 1.2 bar and RT. The catalyst was filtered off and the solvent was removed by evaporation. The residue (except 200 mg) was dissolved in ether (1 mL) and THF (10 mL). The solution was filtered through a strong cation exchange column (Isolute SCX-2, 10 g). The column was washed with THF and then the product was eluted with ammonia- saturated methanol. The solvent was removed by evaporation and there was obtained 0.3625 g (57%) of (3i?)-morpholin-3-ylmethanol as an oil. 1H NMR (500 MHz, CD3OD): 2.9 (m, 3H), 3.3 (t, IH)5 3.5 (m, 3H), 3.7-3.9 (m, 2H).
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 2.5h;Heating / reflux;
(a) (3S)-4-Benzyl-3-(chloromethyl)morpholine; To a solution of [(3i?)-4-benzykciotaorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 0 1288-1290; 1.83 g, 8.8 mmol) in dry methylene chloride (15 mL) was added thionyl chloride (3.15 g, 26.5 mmol) and DMF (2 drops). The mixture was heated to reflux for 2 h 30 min and then the solvent was removed by evaporation. The residue was treated with aqueous NaHCO3 and the solution was extracted with ethyl acetate. The organic solution was separated and the solvent was removed by evaporation. There was obtained 1.88 g s (94%) of (31S)-4-benzyl-3-(chloromethyl)morpholine as an oil. 1H NMR (500 MHz, CDCl3): 2.3-2.4 (m, IH), 2.7 (m, IH), 2.8 (m, IH), 3.5 (d, IH), 3.6-3.9 (m, 5H), 4.0 (d, IH), 7.3 (m, IH), 7.4 (m, 4H); LCMS: m/z 226 (M+l)+.
94%
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 2.5h;Heating / reflux;
(a) (3S)-4-Benzyl-3-(chloromethyl)morpholineTo a solution of [(3i?)-4-benzylmorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 1288-1290; 1.83 g, 8.8 mmol) in dry methylene chloride (15 mL) was added thionyl chloride (3.15 g, 26.5 mmol) and DMF (2 drops). The mixture was heated to refluxed for 2 h 30 min and then the solvent was removed by evaporation. The residue was treated with aqueous NaHCO3 and the solution was extracted with ethyl acetate. The organic solution was separated and the solvent was removed by evaporation. There was obtained 1.88 g (94%) of (3S)-4-berLzyl-3-(chloromethyl)morpholine as an oil. 1H NMR (500 MHz, CDCl3): 2.3-2.4 (m, IH), 2.7 (m, IH), 2.8 (m, IH), 3.5 (d, IH), 3.6-3.9 (m, 5H), 4.0 (d, IH), 7.3 (m, IH), 7.4 (m, 4H); LCMS: m/z 226 (M+l)+.
With thionyl chloride; In dichloromethane; for 15h;
Intermediate 64(S)-4-Benzyl-3-(chloromethyl)morpholine[0349][Chemical Formula 95]To a solution of intermediate 65 (9.60 g, 46.3 mmol) in dichloromethane (230 mL) was added thionyl chloride (60.0 mL, 69.5 mmol). After stirring for 15 hours, to the mixture was added aqueous sodium hydroxide solution. The aqueous layer was neutralized with 2N hydrochloric acid, and then extracted with dichloromethane. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (10.4 g, 46.3 mmol, quant.).MS (ESI+) 226 (M++l, 100%)
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;
Benzyl bromide (1.2 g, 7.06 mmol) was added in one portion to a stirred solution of (R)- morpholin-3-ylmethanol (986 mg, 6.42 mmol) and DIPEA (1.66 g, 12.8 mmol) in MeCN (50 ml) and the resulting solution was stirred at rt for 2h, whereafter the mixture was then concentrated under reduced pressure. The afforded residue was dissolved in DCM (50ml) was and washed sequentially with sat. aq. NaHC03 (50 ml) and 1 M KOH (10 ml). The aqueous phase was extracted with DCM (25 ml) and the combined organic layers were dried over Na2S04, filtered and concentrated which gave the title compound (1.19 g, 89%). MS (ESI): 208 [M+H]+.
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 3h;
Step 1 (S)-4-benzyl-3-(fluoromethyl)morpholine To a solution of Int. N (6.81 g, 3.28 mmol) in CH2Cl2 (50 mL) at 0 C. was added diethylaminosulfur trifluoride (6.26 mL, 4.9 mmol) dropwise and the resulting mixture was stirred at RT for 3 h. The reaction mixture was added dropwise to ice-water, aq. sat. NaHCO3 was added to adjust to pH=8, and the aqueous layer was extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc in hexanes) to afford the title compound (5.18 g, 70% yield) as a yellow liquid. MS (ES+) Cl2H16FNO requires: 209, found: 210 [M+H]+.
Hexafluoropropene diethylamine complex (1.25 ml, 6.89 mmol) was added dropwise at -30 under N2 to a solution of BB14-a (1.19 g, 5.74 mmol) in dry DCM (100 ml) and the resulting reaction mixture was stirred at rt for 3h. The solution was then washed with water and sat. aq. NaHC03, dried over Na2S04 and evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solution was added to a 30% CH3ONa solution in methanol (209 ml). After 30 min of stirring, acetic acid (0.9 ml) was added and the mixture was concentrated in vacuo. DCM and water were added to the residue and the organic phase was separated, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica which gave a crude mixture (1.014 g) containing mainly the title compound and 4-benzyl-6- fluoroperhydro-1 ,4-ixazepine. The crude mixture was used in the next step without further purification. MS (ESI): 210 [M+H]+.
With oxalyl dichloride; dimethyl sulfoxide; In dichloromethane; at -78 - 20℃;
Step 1 (S)-4-benzylmorpholine-3-carbaldehyde To a solution of DMSO (20.6 mL, 290 mmol) in CH2Cl2 (100 mL) at -78 C. was added a solution of oxalyl chloride (12.2 mL, 145 mmol) in CH2Cl2 (50 mL) dropwise and the resulting mixture was stirred was at -78 C. for 15 minutes. A solution of Int. N (10 g, 48 mmol) in CH2Cl2 (50 mL) was added over 30 min. and the resulting mixture was warmed to RT and stirred for 30 min. To the reaction mixture was added sat. aq. NaHCO3 (200 mL) and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (9.9 g, 99% yield), which was used immediately without further purification. MS (ES+) Cl2H15NO2 requires: 205 found: 206 [M+H]+.
With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 16h;Inert atmosphere;
Step 6 (R)-(4-benzylmorpholin-3-yl)methanol To a solution of the product from the previous step (24 g, 108.55 mmol) in THF (50 mL) under an atmosphere of N2 was added borane-methyl sulfide complex (1.0 M in THF, 40 mL) and the resulting was heated at 80 C. for 16 h. The mixture was cooled to RT, MeOH (60 mL) was added dropwise and concentrated under reduced pressure. The residue was partitioned between MeOH (40 mL) and 1 N aq. NaOH (40 mL) and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% EtOAc in hexanes) to afford the title compound (21.8 g, 97% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 7.37-7.18 (m, 5H), 4.59 (t, J=5.3 Hz, 1H), 4.04 (d, J=13.6 Hz, 1H), 3.79-3.64 (m, 2H), 3.58 (dt, J=11.0, 3.4 Hz, 1H), 3.45-3.35 (m, 3H), 3.27 (d, J=13.6 Hz, 1H), 2.56-2.44 (m, 2H), 2.11 (ddd, J=12.1, 9.1, 3.2 Hz, 1H); MS (ES+)Cl2H17NO2 requires: 207, found: 208 [M+H]+.
4-(dimethoxymethyl)-5-((R)-4-((R)-3-methylmorpholino)-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin-2-yl)pyridin-2-amine[ No CAS ]
tert-butyl N-[(tert-butoxy)carbonyl]-N-[4-(dimethoxymethyl)-5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2(7),3,5-trien-4-yl]pyrimidin-2-yl]carbamate[ No CAS ]
4-(dimethoxymethyl)-5-((R)-4-((R)-3-methylmorpholino)-5a,6,8,9-tetrahydro-5H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-amine[ No CAS ]
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