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1
Synthesize Find similar Stage #1: With sodium tetrahydroborate; water in ethanol
T=0 - 20°C; Inert atmosphere; Stage #2: With hydrogenchloride in ethanol; water
T=0°C; Hide Experimental Procedure
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Rx-ID: 32108221 Find similar reactions
RESEARCH TRIANGLE INSTITUTE; UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, C/O NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER; BLOUGH, Bruce E.; ROTHMAN, Richard; LANDAVAZO, Antonio; PAGE, Kevin M.; DECKER, Ann Marie
Patent: WO2011/146850 A1, 2011 ; Location in patent: Page/Page column 55 ; Title/Abstract Full Text Show Details
1:
Pre aration of PAL-593; A solution of 2-(3-fluorophenyl)-3-methylmorpholin-2-ol fumarate salt (0.4326g, leq) in 1 : 1 ethanol:water (3.3mL) was chilled to 0°C under N2 (g). With constant stirring, a solution of sodium borohydride (0.2000g, 4eq) in water (2.2mL) was added drop wise. The reaction was allowed to warm to room temperature and stir overnight. The next morning the reaction was chilled to 0°C and 1.9mL of concentrated hydrochloric acid was added drop wise. The ethanol was then removed under reduced pressure and the crude mixture was diluted with water, chilled to 0°C, made basic by adding 40percent aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.176g of clear oil. The intermediate oil dissolved in methylene chloride was then added drop wise to 1.9mL of concentrated sulfuric acid at 0°C and stirred overnight. The next morning the reaction was poured into ice water, the layers were separated, and the aqueous layer was chilled to 0°C. The aqueous layer was then made basic with 40percent aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.168g of oil. The oil was then dissolved in methylene chloride and 0.0626g of fumaric acid in methanol was added to form
the fumarate salt of the product. Anal. Calcd for 2[CnHi4CFNO] [C4H4O4] : C 61.65, H 6.37, N 5.53; Found: C 61.67, H 6.36, N 5.53. 1H NMR (300 MHz, METHANOL-^) δ ppm 0.96 (d, J-6.78 Hz, 3 H) 3.04 - 3.17 (m, 1 H) 3.17 - 3.24 (m, 1 H) 3.26 (m, 1 H) 3.83 (t, J=l l . l l Hz, 1 H) 4.09 (d, J=1 1.68 Hz, 1 H) 4.23 (d, J=9.42 Hz, 1 H) 6.68 (s, 1 H) 7.03 - 7.24 (m, 3 H) 7.39 (dd, J=7.91, 7.16 Hz, 1 H).
2
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Rx-ID: 32108209 Find similar reactions
in methanol; dichloromethane
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RESEARCH TRIANGLE INSTITUTE; UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, C/O NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER; BLOUGH, Bruce E.; ROTHMAN, Richard; LANDAVAZO, Antonio; PAGE, Kevin M.; DECKER, Ann Marie
Patent: WO2011/146850 A1, 2011 ; Location in patent: Page/Page column 55 ; Title/Abstract Full Text Show Details
1:
Pre aration of PAL-593; A solution of 2-(3-fluorophenyl)-3-methylmorpholin-2-ol fumarate salt (0.4326g, leq) in 1 : 1 ethanol:water (3.3mL) was chilled to 0°C under N2 (g). With constant stirring, a solution of sodium borohydride (0.2000g, 4eq) in water (2.2mL) was added drop wise. The reaction was allowed to warm to room temperature and stir overnight. The next morning the reaction was chilled to 0°C and 1.9mL of concentrated hydrochloric acid was added drop wise. The ethanol was then removed under reduced pressure and the crude mixture was diluted with water, chilled to 0°C, made basic by adding 40percent aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.176g of clear oil. The intermediate oil dissolved in methylene chloride was then added drop wise to 1.9mL of concentrated sulfuric acid at 0°C and stirred overnight. The next morning the reaction was poured into ice water, the layers were separated, and the aqueous layer was chilled to 0°C. The aqueous layer was then made basic with 40percent aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.168g of oil. The oil was then dissolved in methylene chloride and 0.0626g of fumaric acid in methanol was added to form the fumarate salt of the product. Anal. Calcd for 2[CnHi4CFNO] [C4H4O4] : C 61.65, H 6.37, N 5.53; Found: C 61.67, H 6.36, N 5.53. 1H NMR (300 MHz, METHANOL-^) δ ppm 0.96 (d, J-6.78 Hz, 3 H) 3.04 - 3.17 (m, 1 H) 3.17 - 3.24 (m, 1 H) 3.26 (m, 1 H) 3.83 (t, J=l l . l l Hz, 1 H) 4.09 (d, J=1 1.68 Hz, 1 H) 4.23 (d, J=9.42 Hz, 1 H) 6.68 (s, 1 H) 7.03 - 7.24 (m, 3 H) 7.39 (dd, J=7.91, 7.16 Hz, 1 H).
3
Synthesize Find similar Multi-step reaction with 2 steps 1.1: water; sodium tetrahydroborate / ethanol / 0 - 20 °C / Inert atmosphere 1.2: 0 °C 2.1: dichloromethane; methanol View Scheme
Synthesize Find similar
Rx-ID: 32108222 Find similar reactions
RESEARCH TRIANGLE INSTITUTE; UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, C/O NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER; BLOUGH, Bruce E.; ROTHMAN, Richard; LANDAVAZO, Antonio; PAGE, Kevin M.; DECKER, Ann Marie
Patent: WO2011/146850 A1, 2011 ; Title/Abstract Full Text Show Details