`
`(2) 2-(4-Dodecylphenyl)ethanol
`
`5
`
`To a solution (50 ml) of the compound obtained above (34.5 g) in trifluoroacetic acid was added
`triethylsilane (22.7 ml) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The
`solvent was distilled away and ice water was poured to the residue. A cold, saturated aqueous sodium
`hydrogencarbonate
`solution was slowly added to the mixture. The mixture was extracted with ethyl acetate,
`and the ethyl acetate layer was washed and dried over magnesium
`sulfate. The solvent was distilled away
`and methanol (250 ml) was added to the residue to give a methanol solution. To the solution was added
`sodium methoxide (10.2 g) and the mixture was refluxed under heating for 4 hours. The reaction mixture
`io was concentrated and ice water was poured to the residue. The mixture was extracted with ethyl acetate.
`The ethyl acetate layer was washed with a 5% aqueous hydrochloric acid solution and saturated brine and
`dried over anhydrous magnesium sulfate. The solvent was distilled away to give the subject compound
`(27.1 g) as an oily substance.
`Rf :
`0.21 (ethyl acetate:hexane = 1:3)
`
`75
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`so
`
`55
`
`(3) 2-(4-Dodecylphenyl)ethyl
`
`iodide
`
`To a solution (500 ml) of the compound obtained above (27.1 g) in dichloromethane was added
`triethylamine (14.4 ml) and the mixture was stirred at room temperature
`for 3 hours. The reaction mixture
`was poured into ice water and the mixture was extracted with dichloromethane. The dichloromethane layer
`was washed with a saturated aqueous potassium hydrogencarbonate
`solution, a 1% aqueous hydrochloric
`acid solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled
`away and 2-butanone (500 ml) was added to the residue. Thereto was added sodium iodide (12.2 g) and
`the mixture was refluxed under heating for 3 hours. The reaction mixture was poured into ice water and
`extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over
`anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel
`column chromatography (eluent; ethyl acetate:hexane = 1:20) to give the subject compound (18.6 g) as an
`oily substance.
`H-NMR
`(CDCU)
`1
`
`5:
`
`IR(neat) max •
`
`0.37 (3H, t, J = 6Hz), 0.66-0.86 (18H, m), 1.05-1.10 (2H, m), 2.06(2H, t, J = 6Hz),
`
`2.63 (2H, t, J = 4Hz), 2.83 (2H, t, J = 4Hz), 6.60 (4H, dd, J 4Hz, 8Hz) =
`
`2919, 1513, 1467,
`1168
`cm
`
`(4) Diethyl 2-acetamido-2-[2-(4-dodecylphenyl)ethyl]malonate
`
`A solution (100 ml) of sodium ethoxide (6.3 g) in absolute ethanol was dropwise added to diethyl
`acetamidomalonate (20.2 g) in a stream of nitrogen and the mixture was stirred at 65 °C
`for 30 minutes.
`Then, a solution (50 ml) of the compound obtained above (18.6 g) in anhydrous tetrahydrofuran was
`dropwise added thereto and the mixture wad stirred at 65 °C for 3 hours. The reaction mixture was
`concentrated,
`poured into ice water and extracted with ethyl acetate. The extract was washed with saturated
`brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was
`purified by silica gel column chromatography (eluent; ethyl acetate:hexane = 1:3) to give the subject
`compound
`(8.9 g).
`melting point = 60-62 °C
`1 H-NMR
`(CDCI3) 6:
`
`0.86 (3H, t, J = 6Hz), 1.24 (6H, t, J=6Hz),
`1.23-1.59 (18H, m), 1.54-1.59 (2H, m),
`
`
`(3H, t, J = 6Hz), 2.67
`
`(3H, J = 6Hz), 4.15t,
`
`1.97 (3H, s), 2.45 (3H, t, J=6Hz),
`2.54
`4.24 (4H, m), 6.75 (1H, br.s), 7.06
`(4H, dd, J = 6Hz, 6Hz)
`3253, 2920, 2850, 1747, 1644,
`1517
`cm
`
`IR(KBr)max :
`
`(5) 2-Acetamido-1,3-diacetoxy-2-[2-(4-dodecylphenyl)ethyl]propane
`
`tetrahydrofuran was dropwise
`A solution (50 ml) of the compound obtained above (8.9 g) in anhydrous
`added to a solution (200 ml) of lithium aluminum hydride
`(1.38 g) in anhydrous
`tetrahydrofuran in a stream
`of nitrogen under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated
`aqueous sodium sulfate solution was added to the reaction mixture under ice-cooling and the resultant
`aluminum hydroxide was filtered off. The resultant mixture was dried over anhydrous sodium sulfate and the
`solvent was distilled away. Pyridine (28.7 ml) was added to the residue. Thereto was added acetic
`
`213
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`
`
`
`EP 0 627 406 A1
`
`(18.5 ml) under ice-cooling and the mixture was allowed to stand at room temperature overnight.
`anhydride
`The reaction mixture was poured
`into ice-cooled 5% hydrochloric
`acid and extracted with ethyl acetate. The
`ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The
`solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; ethyl
`acetate:hexane = 1:2) to give the subject compound (2.5 g) as white crystals,
`melting point = 111-113°C
`H-NMR (CDCh)
`5:
`1
`0.86 (3H, t, J =6Hz), 1.24-1.31 (18H, m), 1.53-1.58 (4H, m), 1.95 (3H, s), 2.09 (6H,
`s), 2.56 (2H, t, J = 6Hz), 2.58 (2H, t, J = 6Hz), 4.35 (4H, s), 5.62 (1H, br.s), 7.09
`(4H, s)
`3309, 2918, 2850, 1738, 1651 cm
`
`IR(KBr):
`
`(6) 2-Amino-2-[2-(4-dodecylphenyl)ethyl]-1,3-propanediol
`
`hydrochloride
`
`An aqueous solution (25 ml) of lithium hydroxide (1.7 g) was added to a solution (25 ml) of the
`compound obtained above (2.5 g) in methanol and the mixture was refluxed under heating for 3 hours. The
`reaction mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was washed
`with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and a
`26% hydrochloric acid - ethanol solution was added
`thereto, followed by stirring. The solvent was distilled
`away and the residue was recrystallized from ethanol to give the subject compound (770 mg) as white
`crystals.
`H-NMR (DMSO)
`1
`
`5:
`0.88 (3H, t, J = 6Hz), 1.25-1.30 (18H, m), 1.52-1.58 (2H, m), 1.94-2.02 (2H, m),
`2.56-2.60 (2H, m), 2.64-2.68
`(2H, m), 3.81 (4H, dd, J = 11, 26Hz), 4.79 (2H, br.s),
`7.09 (4H, dd, J = 6, 26Hz), 8.07 (3H, br.s)
`2921, 2852, 1738,
`1686,
`1240 cm-1
`
`
`IR(KBr):
`
`5
`
`10
`
`75
`
`20
`
`25
`
`
`
`Exmaple 291 : 2-Amino-2-[2-(2-octylphenyl)ethyl]-1,3-propanediol
`
`30
`
`(1) 1-(2-Bromophenyl)octanol
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Magnesium pieces (6.56 g) were added to anhydrous tetrahydrofuran (10 ml) in a stream of nitrogen
`and the mixture was stirred at room temperature. A solution (200 ml) of 1-bromoheptane (48.4 g) in
`anhydrous tetrahydrofuran was dropwise added
`thereto while heating gradually and the mixture was stirred
`at 40 °C
`for 1 hour. Thereto was dropwise added a solution (100 ml) of 2-bromobenzaldehyde (25 g) in
`anhydrous
`tetrahydrofuran at room temperature and the mixture was stirred
`for 1 hour. The reaction mixture
`was poured into a saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The
`ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The
`solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; ethyl
`acetate:hexane = 1:8) to give the subject compound (18.9 g) as an oily substance.
`H-NMR (CDCh)
`5:
`1
`0.85 (3H, t, J = 6Hz), 1.24-1.58 (10H, m), 1.61-1.79 (2H, m), 5.05(1 H, m, J=4Hz),
`7.08-7.12
`(1H, m, J = 6Hz), 7.29-7.31
`(1H, m, J = 6Hz), 7.50-7.54
`(2H, m, J = 4Hz)
`3350, 2927, 1466,
`
`1023 cm"1
`
`IRc (neat):
`
`(2) trans-2-(1 -Octenyl)bromobenzene
`
`Diphosphorus pentaoxide (7.1 g) was added to a solution (200 ml) of the compound obtained above
`(2.85 g) in benzene and the mixture was refluxed under heating
`for 2 hours. The diphosphorus pentaoxide
`was filtered off and the solvent was distilled away. Ice water was added to the residue. The mixture was
`extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and dried over
`anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel
`column chromatography (eluent; ethyl acetate:hexane = 1:15) to give the subject compound (2.4 g) as an
`oily substance.
`i
`H-NMR (CDCh)
`
`S:
`
`0.86 (3H, t, J = 7Hz), 1.18-1.45 (6H, m), 1.46-1.55 (2H, m), 2.24 (2H, m, J = 1Hz,
`
`7Hz), 6.16 (1H, m, J = 7Hz), 6.72 (1H, d, J = 16Hz), 7.02-7.08 (1H, m), 7.19-7.33
`(1H, m), 7.46-7.55 (2H, m)
`
`214
`
`SUN - IPR2017-01929, Ex. 1014, p. 327 of 970
`
`
`
`EP 0 627 406 A1
`
`IRf (neat):
`
`2957, 2855, 1466,
`
`1023cnrr1
`
`(3) trans-2-(1 -Octenyl)-benzaldehyde
`
`Magnesium pieces (3.74 g) were added to anhydrous tetrahydrofuran (10 ml) in a stream of nitrogen
`and the mixture was stirred at
`
`room temperature. A solution
`(100 ml) of the compound obtained above (37.4
`g) in anhydrous tetrahydrofuran was dropwise added thereto while heating gradually and the reaction
`mixture was stirred at 60 °C
`for 1.5 hours. Thereto was dropwise added a solution (100 ml) of dimethylfor-
`mamide
`(11.5 ml) in anhydrous tetrahydrofuran at room temperature and the mixture was stirred overnight.
`io The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with
`ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous
`magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column
`chromatography (eluent; ethyl acetate:hexane = 1:15) to give the subject compound (26.7 g) as an oily
`substance.
`1
`H-NMR (CDCb)
`
`5
`
`15
`
`5:
`0.88 (3H,
`(6H, m),
`t, J = 6Hz), 1.22-1.38
`6.18 (1 H, m), 7.15 (1H, d, J = 18Hz), 7.33-7.37
`(1 H, d, J =4Hz), 10.31
`(1H,
`s)
`2927, 2855, 1699,
`1597 cm
`
`
`IRf (neat):
`
`(2H, m), 6.11
`1.45-1.52 (2H, m), 2.24-2.36
`
`(1H, m), 7.48-7.53 (2H, m), 7.58
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`(4) 2-Octylbenzaldehyde
`
`(200 ml) of the compound obtained above (26.7 g) in methanol was added a solution (20
`To a solution
`ml) of 10% palladium carbon (1 g) in methanol and the mixture was stirred at ordinary temperature and at
`atmospheric pressure in a stream of hydrogen for 14 hours for catalytic reduction. The 10% palladium
`carbon was filtered off and the solvent was distilled away. The residue was purified by silica gel column
`chromatography (eluent; ethyl acetate:hexane = 1:20) to give the subject compound
`(22
`g) as an oil.
`
`1 H-NMR
`(CDCI3) 5:
`
`0.86 (3H, t, J = 7Hz), 1.25-1.38 (10H, m), 1.54-1.63 (2H, m), 3.00 (2H, t, J = 7Hz),
`7.24-7.26 (1H, m), 7.31-7.35 (1H, m), 7.46-7.50 (1H, m), 7.80-7.83
`(1H, m), 10.28
`(1 H, s)
`3335, 2926, 1701,
`
`1601cm-1
`
`IRf (neat):
`
`(5) Ethyl (2-octylphenyl)acetate
`
`Methyl methylsulfinylmethyl sulfide (12.4 g) and Triton B (9.16 ml) were added to a solution (100 ml) of
`the compound obtained above (22 g) in dioxane at room temperature and the mixture was refluxed under
`heating for 2 hours. The solvent was distilled away and ethyl acetate was added to the residue. The ethyl
`acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent
`was distilled away and ethanol (200 ml) was added to the residue. Thereto was added a 26% hydrochloric
`acid-ethanol solution and the mixture was stirred at room temperature for 30 minutes. The solvent was
`distilled away and ice water was poured to the residue. The mixture was extracted with ethyl acetate. The
`extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was
`distilled away and the residue was purified by silica gel column chromatography (eluent; ethyl ace-
`tate:hexane = 1:30) to give the subject compound
`(20.2 g) as an oily substance.
`1
`H-NMR
`(CDCI3) 5:
`
`0.86 (3H, t, J = 5Hz), 1.19-1.38 (10H, m), 1.24 (3H, t, J = 5Hz), 1.49-1.62 (2H, m),
`2.59 (2H, t, J = 6Hz), 3.85 (2H, s), 4.13 (2H, q, J=5Hz),
`7.10-7.35
`(4H,
`m)
`
`50
`
`(6) 2-(2-Octylphenyl)ethyl
`
`alcohol
`
`55
`
`A solution (50 ml) of the compound obtained above (20.2 g) in anhydrous tetrahydrofuran was dropwise
`added to a solution (200 ml) of lithium aluminum hydride
`(3.04 g) in anhydrous
`tetrahydrofuran in stream of
`nitrogen under ice-cooling and the mixture was stirred at room temperature for 2 hours. A saturated
`aqueous sodium sulfate solution was added to the reaction mixture under ice-cooling and the resultant
`aluminum hydroxide was filtered off. The filtrate was dried over anhydrous sodium sulfate and the solvent
`was distilled away. The residue was purified by silica gel column chromatography (eluent; ethyl ace-
`tate:hexane = 1:30) to give the subject compound
`(10.2 g) as an oily substance.
`
`215
`
`SUN - IPR2017-01929, Ex. 1014, p. 328 of 970
`
`
`
`EP 0 627 406 A1
`
`H-NMR (CDCh)
`
`IRc (neat):
`
`5
`
`5:
`1.21-1.46 (10H, m), 1.47-1.62 (2H, m), 2.61 (2H, t, J=6Hz),
`
`0.87 <3H, t, J =6Hz),
`(2H, dd, J = 6Hz,
`12Hz),
`7.14-7.24
`(4H,
`2.96 (3H, t, J = 6Hz), 3.82
`3335, 2926, 2854, 1467cm-1
`
`m)
`
`(7) 2-(2-Octylphenyl)ethyl methanesulfonate
`
`Triethylamine (7.37 ml) was added to a solution (250 ml) of the compound obtained above (10.2 g) in
`dichloromethane and the mixture was cooled with ice. Thereto was dropwise added methanesulfonyl
`70 chloride (6.04 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was
`poured into ice water and extracted with dichloromethane. The dichloromethane layer was washed with a
`saturated aqueous potassium hydrogencarbonate solution, a 1% aqueous hydrochloric acid solution and
`saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the
`residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane = 1:8) to give the
`75 subject compound (13.4 g) as an oily substance.
`i
`H-NMR (CDCh)
`5:
`0.86 (3H, t, J = 6Hz), 1.22-1.41 (10H, m), 1.51-1:59 (2H, m), 2.60 (2H, t, J=6Hz),
`2.84 (3H, s), 3.09 (2H, t, J = 6Hz), 4.38
`(2H,
`t,
`J
`= (4H, m)
`
`6Hz)>
`2929, 1467, 1357,
`1174
`cm-1
`
`IR(neat):
`
`7.10-7.20
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`(8) 2-(2-Octylphenyl)ethyl iodide
`
`To a solution of the compound obtained above (13.4 g) in 2-butanone (300 ml) was added sodium
`iodide (7.7 g) and the mixture was refluxed under heating
`for 2 hours. The reaction mixture was poured
`into
`ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and
`dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by
`silica gel column chromatography (eluent; ethyl acetate:hexane = 1:30) to give the subject compound
`(11.9
`g)-
`
`i H-NMR (CDCh)
`
`IR(neat):
`
`S:
`0.87 (3H, t, J = 6Hz), 1.18-1.74 (10H, m), 1.50-1.59 (2H, m), 2.57 (2H, t, J=6Hz),
`3.18 (2H,
`t,
`J 6Hz), 3.28 =
`
`
`
`(2H, t, J = 6Hz), 7.10-7.25 (4H, m)
`2923, 2854, 1490,
`1468
`cm"1
`
`(9) Diethyl 2-acetamido-2-[2-(2-octylphenyl)ethyl]malonate
`
`A solution (50 ml) of sodium ethoxide (6.39 g) in anhydrous ethanol was dropwise added to diethyl
`acetamidomalonate (20.4 g) in a stream of nitrogen and the mixture was stirred at 65 °C for 1.5 hours. A
`solution of the compound obtained above (10.8 g) in tetrahydrofuran was dropwise added thereto and the
`mixture was refluxed under heating for 7 hours. The reaction mixture was concentrated, poured into ice
`water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over
`anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel
`column chromatography (eluent; ethyl acetate:hexane = 1:3) to give the subject compound (5.8 g) as white
`crystals, melting
`point = 37-38 °C
`1 H-NMR (CDCh)
`5:
`0.86 (3H, t, J = 6Hz), 1.21-1.36 (10H, m), 1.25 (6H, t, J = 6Hz), 1.46-1.57 (2H, m),
`2.03 (3H, s), 2.38-2.47 (2H, m), 2.51 (2H, t, J = 6Hz), 2.55-2.63 (2H, m, J=6Hz),
`4.16-4.41
`(4H, m), 6.82 (2H, br.s), 7.05-7.15
`(4H, m)
`3415, 2977, 2855, 1741, 1683, 1492 cm
`
`IR(KBr):
`
`so
`
`(10) 2-Acetamido-1,3-diacetoxy-2-[2-(2-octylphenyl)ethyl]propane
`
`55
`
`A solution (50 ml) of the compound obtained above (4.3 g) in anhydrous tetrahydrofuran was dropwise
`added to a solution (200 ml) of lithium aluminum hydride (0.76 g) in anhydrous tetrahydrofuran
`
`in stream a
`
`of nitrogen under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated
`aqueous sodium sulfate solution was added to the reaction mixture under ice-cooling and the resultant
`aluminum hydroxide was filtered off. The filtrate was dried over anhydrous sodium sulfate and the solvent
`was distilled away. Pyridine (10 ml) was added to the residue and then, acetic anhydride
`(13 ml) was added
`thereto, and the mixture was allowed to stand at room temperature overnight. The reaction mixture was
`
`216
`
`SUN - IPR2017-01929, Ex. 1014, p. 329 of 970
`
`
`
`EP 0 627 406 A1
`
`layer was
`into ice-cooled 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate
`poured
`washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away
`and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane = 1:3) to
`give the subject
`
`compound g) as an oily substance. (2.2
`
`1H-NMR
`(CDCIs)
`5:
`0.86 (3H,
`s),
`(3H,
`1.47-1.58 (2H, m), 1.97
`
`m),
`(12H,
`t, = 6Hz), 1.21-1.38 J
`
`
`s), 2.56 (2H, t, J = 6Hz), 2.58 (2H, t, J = 6Hz), 4.35 (4H, s), 5.66 (1H, br.s), 7.09-
`7.13 (4H, m)
`3295, 2927, 1747,
`
`1660,
`
`1256
`
`cm"1
`
`IR(neat):
`
`(11) 2-Amino-2-[2-(2-octylphenyl)ethyl]-1,3-propanediol
`
`hydrochloride
`
`2.08
`
`(6H,
`
`An aqueous solution (20 ml) of lithium hydroxide (1.7 g) was added to a solution of the compound
`obtained above (2.2 g) in methanol (20 ml) and the mixture was refluxed under heating for 4 hours. The
`reaction mixture was concentrated
`and extracted with ethyl acetate. The extract was washed with saturated
`brine and dried over anhydrous magnesium
`sulfate. The solvent was distilled away and a 26% hydrochloric
`acid-ethanol solution was added to the residue. The solvent was distilled away and the residue was
`recrystallized from ethanol to give hydrochloride of the subject compound
`(800 mg). melting point = 168-
`170 "C
`1H-NMR
`
`(DMSO)
`
`5:
`0.85 (3H, t, J = 7Hz), 1.22-1.37 (10H, m), 1.43-1.54 (2H, m), 1.68-1.78 (2H, m),
`2.52-2.63 (4H, m), 3.49-3.59 (4H, m), 5.40 (2H, t, J = 4Hz), 7.05-7.17 (4H, m),
`7.89 (3H, br.s)
`3385, 3272, 2925,
`
`1519,
`
`1069
`
`cm
`
`IRf (KBr):
`
`Example 292
`
`:
`
`2-Amino-2-(4-octylthiobenzyl-)1,3-propanediolhydrochloride
`
`1/2
`
`(1) 4-(Methylthio)benzyl alcohol
`
`Sodium borohydride (3.78 g) was added to isopropyl alcohol (50 ml) and the mixture was stirred under
`ice-cooling. Thereto was dropwise added 4-(methylthio)benzaldehyde (15 g) and the mixture was stirred at
`room temperature
`for 30 minutes. The solvent was distilled away and water was added
`to the residue. The
`mixture was extracted with ethyl acetate. The organic
`layer was washed with saturated brine and dried over
`anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was recrystallized from
`hexane-ethyl acetate
`to give the subject compound
`
`(15 g) as white crystals,
`melting point = 41-43°C
`1H-NMR
`(CDCIs)
`5:
`
`2.40 (3H, s), 4.43 (2H, s), 7.10
`
`
`
`(4H, s), 3.36 (1H, br.s)
`
`elemental analysis(C8HioOS) calculated
`found
`
`C 62.30,
`C 61.90,
`
`H 6.54
`H 6.55
`
`MS:
`
`154 (M+)
`
`(2) 4-(Methylsulfinyl)benzyl alcohol
`
`m-Chloroperbenzoic acid (content 50%, 35 g) was added to a solution (100 ml) of the compound
`obtained above (15 g) in chloroform under ice-cooling and the mixture was stirred
`for 1 hour. Thereto was
`added calcium hydroxide (37 g) and the mixture was stirred at room temperature for 1 hour. The insoluble
`matters were filtered off, and the filtrate was washed with saturated brine and dried over anhydrous sodium
`sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column
`chromatography (eluent; chloroform:methanol = 20:1) to give the subject compound (15.56 g) as an oily
`substance.
`1H-NMR
`
`(CDCIs)
`
`IR(neat):
`
`&:
`2.73 (3H, s), 3.28
`3364, 1409, 1303,
`
`(1H, 4.45 (2H, s), 7.52 (4H, s) br.s),
`
`
`1148,
`1031
`cm
`
`217
`
`5
`
`10
`
`75
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`SUN - IPR2017-01929, Ex. 1014, p. 330 of 970
`
`
`
`EP 0 627 406 A1
`
`elemental analysis(C8Hio02S)
`
`calculated
`found
`
`C 56.45,
`C 56.51,
`
`H 5.92
`H 5.87
`
`5
`
`MS:
`
`170 (M+)
`
`(3) 4-(Methylsulfinyl)benzyl
`
`methanesulfonate
`
`to a solution (100 ml) of the compound obtained above (13.88 g) in
`Triethylamine (14 ml) was added
`io dichloromethane
`
`under ice-cooling. Thereto was dropwise added methanesulfonyl chloride
`(6.2 ml) and the
`mixture was stirred for 30 minutes. The reaction mixture was poured into ice water and extracted with
`dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate
`solution, 0.1 N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent
`was distilled away and the residue obtained was purified by silica gel column chromatography (eluent;
`75 chloroform:methanol = 10:1) to give the subject compound (15.38 g) as white
`crystals,
`melting point = 63-650 C
`1H-NMR(CDCl3)
`5:
`2.74 (3H, s),
`3015, 1349,
`
`IR(KBr):
`
`3.0
`1172,
`
`s), (2H, s), 7.52 5.22 (2H,
`(3H,
`
`
`1040,
`951
`
`d, 8Hz), 7.63
`
`
`cm-1
`
`J
`
`(2H,
`
`
`
`
`
`= d, = 8Hz)
`
`J
`
`20
`
`elemental analysis(C9Hi2 04-S2)
`
`calculated
`found
`
`C 43.53,
`C 43.51,
`
`H 4.87
`H 4.82
`
`25
`
`MS:
`
`248 (M+)
`
`(4) 4-(Methylsulfinyl)benzyl iodide
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`To a solution (100 ml) of the compound obtained above (8.25 g) in 2-butanone was added sodium
`iodide (7.5 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was
`concentrated, poured into ice water and extracted with ethyl acetate. The organic layer was washed with
`saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue
`was purified by silica gel column chromatography (eluent; chloroform:methanol = 10:1) to give the subject
`compound
`(8.65 g) as yellow crystals,
`melting point = 80-81 0 C
`1H-NMR
`(CDCh)
`5:
`2.70 (3H, s), 4.42 (3H, s), 7.50 (4H, s)
`1399, 1153, 1038,
`837,
`cm
`565
`
`IR(KBr):
`
`elemental analysis^gHgOSI) calculated
`found
`
`C 34.30,
`C 34.17,
`
`H 3.24
`H 3.21
`
`MS:
`
`280 (M+)
`
`(5) Diethyl 2-acetamido-2-(4-methylsulfinylbenzyl)malonate
`
`(13 g) in absolute
`
`(200 ml) of diethyl acetamidomalonate
`Sodium ethoxide (4 g) was added to a solution
`ethanol in a stream of nitrogen and the mixture was stirred at 65 °C
`for 1 hour. A solution of the compound
`obtained above (8.4 g) in absolute ethanol was dropwise added thereto and the mixture was stirred at 65 0C
`for 1 hour. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate.
`The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was
`distilled away and the residue was purified by silica gel column chromatography (eluent; chloro
`form :methanol = 20:1) to give the subject compound
`
`(8.2 g) as crystals,
`melting point = 135-136 °C
`i
`H-NMR (CDCb)
`S:
`1.28 (6H, t, J=7Hz), 2.02 (3H, s), 2.70 (3H, s), 3.70 (2H, s), 4.25 (4H, m), 6.52
`
`(1H, s), 7.15 (2H, d, J = 8Hz), 7.53
`(2H, d, J = 8Hz)
`
`218
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`SUN - IPR2017-01929, Ex. 1014, p. 331 of 970
`
`
`
`EP 0 627 406 A1
`
`IR(KBr):
`
`3253, 2986, 1748,
`
`
`
`1642, 1198, 1039 cm
`
`elemental analysisfCiyHkaNOsS)
`
`:
`
`calculated
`found
`
`C 55.27,
`C 55.09,
`
`H 6.27,
`H 6.25,
`
`N 3.79
`N 3.78
`
`(6) Diethyl 2-acetamido-2-(4-mercaptobenzyl)malonate
`
`(50 ml) under ice-cooling
`trifluoroacetic anhydride
`(6.22 g) was added to
`The compound obtained above
`and the mixture was stirred
`for 1 hour. The
`trifluoroacetic anhydride was removed, and
`
`ethanol (100 ml) and
`triethylamine (100 ml) were added thereto. The mixture was stirred at room temperature for 1 hour. The
`reaction mixture was concentrated and chloroform (200 ml) was added thereto. Then, the mixture was
`washed with a saturated aqueous ammonium chloride solution and dried over anhydrous sodium sulfate.
`The solvent was distilled away and the residue was purified by silica gel column chromatography (eluent;
`chloroform:methanol = 10:1) to give the subject compound (4.26 g) as crystals,
`melting point = 125-128 °C
`i
`H-NMR
`(CDCIs)
`5:
`
`IR(KBr):
`
`1.27 (6H, t, J = 7Hz), 2.00 (3H, s), 3.38 (1H, s), 3.57 (2H, s), 4.24 (4H, m), 6.50
`(1 H, s), 6.85 (2H, d, J = 8Hz), 7.14
`(2H, d, J=8Hz)
`3398, 2986, 2547, 1736, 1665, 1212,
`1018
`
`cm"1
`
`elemental analysis(CisH2i
`
`NO5S)
`
`calculated
`found
`
`C 56.62,
`C 56.61,
`
`H 6.24,
`H 6.20,
`
`N 4.13
`N 4.09
`
`5
`
`20
`
`25
`
`30
`
`MS:
`
`339 (M+)
`
`(7) Diethyl 2-acetamido-2-(4-octylthiobenzyl)malonate
`
`35
`
`40
`
`45
`
`50
`
`55
`
`1-Bromooctane (0.58 g) and potassium carbonate (0.5 g) were added to a solution (10 ml) of the
`compound obtained above (1 g) in dimethylformamide and the mixture was stirred at room temperature
`for
`5 hours. The reaction mixture was poured
`into ice water and extracted with ethyl acetate. The organic layer
`was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous sodium
`sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography
`(eluent; chloroform:methanol = 25:1) to give the subjected compound
`
`(1.16 g) as crystals,
`melting point = 82-84 °C
`H - N M R (CDCI3) S :
`1
`
`0.85 (3H, t, J = 7Hz), 1.27 (14H, m), 1.40 (2H, quint, J=7Hz), 1.61 (2H, quint,
`J = 7Hz), 2.01 (3H, s), 2.86 (2H, t, J=7Hz),
`3.58 (2H, s),4.25 (4H, m), 6.51 (1H, s),
`6.89 (2H, d, J = 8Hz), 7.17
`(2H,
`d,
`J=8Hz)
`3255, 2952, 1747,
`1644, 1298, 1274, 1220
`
`cm-1
`
`IR(KBr)
`
`:
`
`elemental analysis(C2^H37N05S)
`
`calculated
`found
`
`C 63.83,
`C 63.33,
`
`H 8.26,
`H 8.14,
`
`N 3.10
`N 3.06
`
`MS:
`
`451 (M+)
`
`(8) 2-Acetamido-2-(4-octylthiobenzyl)-1,3-propanediol
`
`A solution (10 ml) of the compound obtained above (1 g) in anhydrous tetrahydrofuran was dropwise
`added to a solution of lithium aluminum hydride (0.26 g) in anhydrous tetrahydrofuran (10 ml) under ice-
`cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. Then,
`
`219
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`SUN - IPR2017-01929, Ex. 1014, p. 332 of 970
`
`
`
`EP 0 627 406 A1
`
`thereto was dropwise added a saturated aqueous sodium sulfate solution to decompose the lithium
`aluminum hydride. The insoluble matters were filtered off and the filtrate was extracted with ethyl acetate.
`The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent
`was distilled away and the residue obtained was purified by silica gel column chromatography (eluent;
`chloroform:methanol = 10:1) to give the subjected compound
`(0.6 g) as crystals,
`
`melting point = 76-78 0C
`H-NMR (CDCh)
`5:
`1
`0.86 (3H, t, J = 7Hz), 1.25 (8H, m), 1.40 (2H, quint, J=7Hz), 1.61 (2H, quint,
`J = 7Hz), 1.99 (3H, s), 2.87 (2H, t, J = 7Hz), 2.89 (2H, s), 3.50 (2H, m), 3.70 (2H,
`m), 3.73 (2H, m, -OH x 2), 5.79 (1H, s, -NH), 7.14 (2H, d, J = 8Hz), 7.25 (2H, d,
`J = 8Hz)
`3422, 3347, 3192,
`
`
`
`2942, 1654, 1550, 1055
`
`cm"1
`
`IR(KBr):
`
`elemental analysis^oHsaNOsS)
`
`calculated
`found
`
`C 65.36,
`C 65.29,
`
`H 9.05
`H 9.11
`
`N 3.81
`N 3.75
`
`MS:
`
`367 (M+)
`
`(9) 2-Amino-2-(4-octylthiobenzyl)-1,3-propanediol
`
`hydrochloride
`
`An aqueous solution (5 ml) of lithium hydroxide (380 mg) was added to a solution (5ml) of the
`compound obtained above (400 mg) in methanol and the mixture was refluxed under heating for 4 hours.
`The reaction mixture was concentrated and extracted with ethyl acetate. The extract was washed with
`saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away to give white
`powder. The thus-obtained powder was dissolved in ethanol (2 ml) and thereto was added a 26%
`hydrochloric acid-ethanol solution(1 ml). The solvent was distilled away and the precipitated crystals were
`recrystallized
`from hexane-ethyl acetate
`to give the subjected compound
`
`(80 mg).
`melting point = 100-102 °C
`
`(CD3OD) 6:
`1 H-NMR
`
`35
`
`IR(KBr):
`
`0.76 (3H, t, J = 7Hz), 1.16 (8H, m), 1.30 (2H, m), 1.53 (2H, quint, J = 7Hz), 2.79
`(2H, t, J = 7Hz), 2.86 (2H, s), 3.43 (2H, m), 3.62 (3H, m), 7.06 (2H, d, J=8Hz),
`7.15 (2H, d, J = 8Hz)
`3363, 3286, 2924, 1516, 1494,
`
`1072
`
`cm
`
`5
`
`10
`
`75
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`elemental analysis(Ci8H3i
`
`calculated
`found
`
`C 58.28,
`C 58.44,
`
`NO2S I/2H2O)
`
`HCI
`N 3.78
`H 8.97,
`H 9.02,
`N 3.68
`
`Example 293 : 2-Amino-2-[2-(5-octyl-2-thienyl)ethyl]-1,3-propanediol hydrochloride
`
`(1) 2-(2-Thienylethyl)-2-tetrahydropyranyl
`
`ether
`
`(12.85 g) in dichloromethane, 3,4-dihydro-2H-pyran (9.25
`To a solution (100 ml) of 2-(2-thienyl)ethanol
`g) and p-toluenesulfonic acid (2 g) were added. The mixture was stirred at room temperature for 4 hours.
`The solvent was distilled away and ethyl acetate was added
`thereto. The mixture was washed with saturated
`brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the oily substance
`
`distillation to give 13.52 g of the subject compound as
`an oily substance,
`
`obtained was purified by
`boiling point = 107-108°C/1 mmHg
`1 H-NMR (CDCh)
`S:
`1.50 (4H, m), 1.70 (1H, m), 1.82 (1H, m), 3.11 (2H, t, J = 7Hz), 3.47 (1H, m), 3.60
`(1H, dt, J = 10, 7Hz), 3.79 (1H, m), 3.95 (1H, dt, J = 10,7Hz), 4.61 (1H, t,
`
`J = 3.5Hz), 6.83 (1H, dd, J = 1, 3.4Hz), 6.90 (1H, dd, J = 3.4, 5.4Hz), 7.11 (1H, dd,
`J = 1, 5.4Hz)
`
`220
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`SUN - IPR2017-01929, Ex. 1014, p. 333 of 970
`
`
`
`EP 0 627 406 A1
`
`IR(neat):
`
`2930, 1250, 1120,
`
`
`
`1030, 870 cm
`
`elemental analysis
`
`
`
`Ci i H1GO2S
`
`calculated
`found
`
`C 62.23,
`C 62.83,
`
`H 7.60
`H 7.01
`
`MS:
`
`212 (M+)
`
`(2) 2-(5-Octyl-2-thienyl)ethyi
`
`
`
`2-tetrahydropyranyl ether
`
`5
`
`10
`
`A solution (100 ml) of the above-mentioned compound
`tetrahydrofuran was cooled
`(8.5 g) in anhydrous
`to -780C and a solution (1.63 mol/l, 30 ml) of n-butyl lithium in hexane was dropwise added thereto. The
`mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 30 minutes. A
`solution
`(15 ml) of 1-bromooctane
`(10 g) in anhydrous
`tetrahydrofuran was dropwise added
`thereto and the
`15 mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into ice water and
`extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride
`solution and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained
`was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 20:1) to give 6.6 g of the
`subject compound as an oily substance.
`1
`H-NMR
`(CDCI3) 5:
`
`20
`
`0.85 (3H, t, 7Hz), 1.25 (10H, m), 1.53 (4H, m), 1.62 (2H, m), 1.72 (1H, m), 1.83
`(1H, m), 2.71 (2H, t, J=7Hz), 3.02 (2H, t, J = 7Hz), 3.46 (1H, m), 3.60 (1H, dt,
`J = 10, 7Hz), 3.80 (1H, m), 3.92 (1H, dt, J = 10, 7Hz), 4.61 (1H, t, J = 3.5Hz), 6.54
`
`(1 H, d, J =3.4Hz), 6.61 (1H, d, J = 3.4Hz)
`2927, 2854, 1135,
`1120, 1033 cm-1
`
`
`25
`
`IR(neat):
`
`elemental analysis
`
`calculated
`C19H32O2S
`found
`
`C 70.32,
`C 70.12,
`
`H 9.94
`H 10.03
`
`30
`
`35
`
`40
`
`MS:
`
`324 (M+)
`
`(3) 2-(5-Octyl-2-thienyl)ethanol
`
`Tetrahydrofuran (20 ml) and p-toluenesulfonic acid (0.3 g) were added to a solution (80 ml) of the
`above-mentioned
`compound (6.5 g) in methanol and the mixture was stirred at room temperature
`for 1 hour.
`The solvent was distilled away and ethyl acetate was added to the resulting mixture. The mixture was
`washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and
`the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 5:1)
`to give 4 g of the subject compound as an oil.
`H-NMR
`(CDCI3) 5:
`1
`
`45
`
`IR(neat):
`
`2.73 (2H, t, J 7Hz), =
`
`
`
`0.86 (3H, t, J = 7Hz), 1.27 (10H, m), 1.62 (2H, quint, J=7Hz),
`3.00 (2H, t, J = 6Hz), 3.80 (2H, t, J = 6Hz), 6.58 (1H, d, J = 3.4Hz), 6.64 (1H, d,
`J = 3.4Hz)
`3348, 2927, 2854, 1466, 1047,
`
`
`
`797 cm
`
`elemental analysis
`
`
`
`C14H24OS • 0.1 H2O
`
`calculated
`found
`
`C 69.43,
`C 69.34,
`
`H 10.07
`H 10.17
`
`so
`
`55
`
`MS:
`
`240 (M+)
`
`(4) 2-(5-Octyl-2-thienyl)ethyl
`
`methanesulfonate
`
`Triethylamine (3 ml) was added to a solution (50 ml) of the above-mentioned compound (4 g) in
`dichloromethane. Methanesulfonyl chloride
`(1.5 ml) was dropwise added
`
`thereto and the mixture was stirred
`for 30 minutes. The reaction mixture was poured into ice water and extracted with dichloromethane. The
`organic layer was washed with a saturated aqueous sodium hydrogencarbonate
`solution, 0.1 N hydrochloric
`
`221
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`SUN - IPR2017-01929, Ex. 1014, p. 334 of 970
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`
`EP 0