5,712,396
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`151-‘
`EXAMPLE 1??
`
`[3aR-[2(R*).3au.?af5JJ-[1-l[(Dimemy1amino}
`thioxomethy1]thio]-4-(3 -phenoxypheny1)butyl]
`octahydro- l3-d.irnethyl-2—1H- 1.3.2-
`benzodinzaphosphole. 2-oxide
`
`and
`
`[3aR-[2(S*).3act.7afl]]-[1-[[[Dimethy1amino)
`thioxomethyllthio]-4-(3-pheno:xyphenyl)butylI-
`octtahydro-1.3-dimetliyl-2-1H-1.3.2
`benzodiazaphosphole. 2-oxide
`[3 aR-(3 aot.'?aB}]—2—[ [ [(Dimeth ylamino)thioxomethyl]
`A.
`thio]]cctahydro—1.3~dimethy1-1H-1.3.2-
`benzodiamphosphole. 2-oxide
`To a stirred solution of 502 mg (2.48 mmol) of Example
`175 Pan B compound in 10 ml. ofTI-[F under argon at -78”
`C. was added 1.09 mL (2.73 mmol) of a 2.5N solution of
`n-butyllithium in hexanes dropwise over 10 minutes. After
`stirring at -78“ C. for one hour. 87 mg (2.73 mmol) of sulfur
`was added via a solid addition tube. and temperature of the
`reaction was raised to —20° C. over 1 horn: The reaction
`mixture was treated with 0.93 mL (6.69 mmol} of triethy-
`lamine and 276 mg (2.23 mmol) of dimethylthio-::a.rba.moy1
`chloride at -20“ C.. stirred for 5 minutes. then allowed to
`warm to room temperature. The mixture was diluted with
`ether and washed with water. The aqueous layer was back
`extracted with ether and the organics were combined. dried
`and concentrated to afford 558 mg of an oil. The crude
`product was purified by flash chromatography on silica gel
`(50 g) eluted with 96:4 ethyl acetateimetltanol. Pure frac-
`tions were combined and concentrated to yield 337 mg
`(47%) of title compound as a clear oil.
`TLC (Silica gel. 9:1 ethyl acetatdmethanol) lg;D.35.
`MS (CI. -t-ions} 332 (M+H).
`“P NMR (CDCI3. 121 MHz) 37.7 ppm.
`B. 3aR-[2(R*).3aDL,7aB]]-[ 1-[l(Dimethy1amino)
`thioxomethylltltio]-4-(3-phenoxyph.eny1)buty1]oaahydro-1.
`3—d.i.methyl—2-—1H—1.3.2-bcnzodiazaohosohole. 2-oxide
`To a stirred solution of 89 mg (0.28 mmol) of Part A
`compound in 1 mL of Tl-ll? under argon at —-78° C. was
`added 122 pL (0.31 mmol) of a 2.5N solution of
`n-butyllithium in hexanes dropwise over 10 mintues. After
`9D minutes at -73“ C. 0.096 mL (0.55 mmol) of hexan-
`ethylphosphoramide was added. followed by 98 mg (0.30
`mmol) of 3-(3-phenoxypheny1)propyliodide in 1 ml. of
`THF. After 28 hours at -—'?8° C.. the reaction was quenched
`with methanol and allowed to reach room temperature. The
`mixture was concentrated,
`then dissolved in ether and
`washed with water and brine. dried over sodium stilfatc. and
`conmntrated to alford 129 mg of a yellow oil. The cnrde
`product was purified by flash cltromatography on silica gel
`(15 g) eluted with 98:2 ethyl acetatefmethanol. Fractions
`(#11—19) containing pure material were combined and con-
`centrated to yield 50 mg (34%) of title or-(R) isomer as a
`clear oil.
`
`35
`
`40
`
`45
`
`'l"LC (Silica gel. 9:1 ethyl acetstdmethanol) R,=0.4-5.
`C.
`[3aR-[2(S*).3act,7afi3]]~[1~[[(I)imethy1arnino)
`dtioxomediyllthio]-4-(3-phenoxyphenyl)butyl]octahy1:h'o-1,
`3-dimcthyl-2-1H-1.3.2-ben2»od.ia.zaphosDhole. 2-oxide
`Fractions #2l—30 were combined and concentrated to
`trovide 10 mg (7%) of title isomer as a clear oil.
`TLC (Silica gel. 9:1 ethyl acetatt-Jmethanol) R,.=0.39.
`MS (CL -t-ions) 532 (M+H).
`"p NMR (CD03. 121 MHZ) 39.3 ppm
`The Parts B and C compounds may then be 10 separated
`and subjected to acid hydrolysis and linen oxidation and salt
`
`65
`
`158
`formation as described in Example 175 to form the title
`compound of Examples l':'5 and 176.
`EXAMPLE 173
`
`[3aR-[2(R' ).3at1.7a |3] ] -[ 1-[[(Dimethyla.m.i.no)
`ti1ioxo1ned1yl]thio]-4-(3-phenoxypheny1)butyl]
`octahydro- l.3-dimethy1-2—1H-1.3.2-
`benzodiazaphomhole. 2-oxide
`
`[3aR-(3a0t.7a[3]]-Octahydro-1.3-dimethyl-ll-l-1.3.2-
`A.
`benzodiazaphosoholeo 2-oxide
`To a stirred solution of 497 mg (3.49 mmol) of Example
`175 Part A {R.R)-diamine and 1.07 mL (‘$.89 mmol) of
`triethylarnine in 25 mL of tetrahydnofuran (THI) under
`argon at —':'3° C. was added dropwise over 5 minutes 335 pl.
`(3.84 mmol} of phosphorus n-ichloride. The cloudy solution
`was allowed to warm to room temperature and was filtered
`under argon through a pad of celite and magnesium sulfate.
`The filtrate was chilled to —78° C. under argon and treated
`with 536 ].tL of triethylnmine and 63 51L (3.49 mmol) of
`water. The tninttnre was allowed to warm to room tempera-
`ture and was filtered under mgon through a pad of celite and
`magnesium sulfate and concentrated to provide 544 mg
`(32%) of title compound as a yellow oil.
`"P NMR (CDCl,. 121 MHz) 3273 ppm.
`B. [3aR—I2(R*).3aot.7nf3)]-Octahyd:o-1.3-dimethyl-2-[4-(3-
`phe noxyp he nyl)- 1-[(trimetI1y1sily1)oxy]butylI-111-1.3 .2-
`benzodiazaphosohole. 2-oxide
`C.
`[3a.R-I2(S‘).3aoc.7a{3}]-C)cra.hydro-1.3-di.methyl—2—[4J(}
`phenoxyphenyl}1-[(n'imethylsilyl)oxy]bnty1]-1}l-1.3.2-
`benzodiazaphosphole. 2-oxide
`A solution of 544 mg (2.89 mmol) of Part A compound
`and 534 mg (2.22 mmol} of 3-phenoxybenzenebutanal
`(Example 180 Part B) in 5 mL of methylene chloride under
`argon was treated with 814 pL (3.33 mmol) of his
`llrimethylsilyl) acetatnide at room ternpaature and stirred.
`for 1? hours. The reaction was quenched with water and
`extracted with methylene chloride (3><3S mL). The com-
`bined organics were washed with brine. dried (sodium
`sulfate). and concentrated to provide 875 mg of a yellow oil.
`The crude product rni:Itt:ure was ptrified by flash chroma-
`tography on silica gel (80 g) eluted with 2 L of 9:1
`hexanefacetone followed by 2 L of 85:15 hexaneiacetone
`and 1.5 L of 82 hexandacetone. Fractions containing the
`more polar 0t—(R)
`isomer (title B) were combined and
`concentrated to yield 135 mg (14%) of title 13 compound as
`a clear ciL
`
`TLC Silica gel (1:l hexanefacetone) R3.=0.29.
`“P NMR (CDCI-3. 121 MHz) 541.1 ppm.
`Fractions #85436 were combined and concentrated to
`yield 112 mg (12%) of the pure Part C 0.-(S)isomer.
`TLC Silica gel (1:l hexaneiacetone) R,-=0.31.
`"PNMR(CDC13. 121 MHZ) 627.3 ppm.
`[3aR-i2(R*).3ant.7a[1l)]—Octahydro-2-[l-hydroJty-4-{3-
`D.
`phenoxypheny1)butyl]—1.3~dirnethy1—1H—1.3.2-
`benzod.iazaphospho1e.2-oxide
`To a stirred solution of 125 mg (0.20 mrnol) of Part B
`isomer in 1 mL ofTI-IF was added 0.29 mL (0.29 mmol) of
`a 1.010! solution of tetrabutylammonium fluoride in TI-ll‘.
`After stirring for three hours at room temperature.
`the
`mixture was diluted with ether. washed with saturated
`sodium bicarbonate. brine. dried (sodium sulfate). and con-
`centrated to lztovide 104- mg ofa white solid. The crude
`product was purified by flash chromatography on silica gel
`(15 g) eluted with 97.5125 ethyl acetatelmethanol. Clean
`fractions (#4141) were combined and concentrated to yield
`100 mg (93%) of title compound as a white solid. mp.
`l22°—l25" C.
`
`80 of 93
`
`PENN EX. 2205
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`159
`
`5.712.396
`
`160
`
`5
`
`10
`
`TLC Silica gel (1:1 hexanelacetone) R,=0.-44.
`“PNMR (CDCl,. 121 MHz) 541.1 ppm.
`[3aR-[2(R‘).3aot.7afi]]-[1-[[(DimethyIarn.ino)
`B.
`tlu'oxomethyl]thio]—4-(3-phenoxyphenyl)buty1]octahydro-1.
`3-di.methyl-2—1H-1.3.2-benzodiazaphosbhole. 2-oxide
`To a stirred suspension of 56 mg (0.13 mmol) of Part D
`compound. 30 mg (0.09 mmol) of dimethyldithiocatrbamic
`acid. zinc salt. and 47 mg (0.18 mmol) of triphenyIphos-
`phinein 1 mLcfTHFat0° Cundaargonwasaddeda
`solution of 52 |.lL (0.27 mmol) of cliisoptopyl azodicarboxy-
`late in 0.5 ml, ofTHIF overfifteen ruinutes.'I'he reaction was
`stirred at room temperature for 45 hours. then diluted with
`ether and quenched with water. The organics were washed
`with brine. dried (sodium sulfate). and concentrated to
`provide 150 mg of an oil. 'I'he crude rroduct was purified by
`flash chromatography on silica gel (15 g) eluted with ethyl
`acetate. Pure fractions were combined and concentrated to
`yield 15 mg (21%) of title compound as a film. the o'.-(R)-
`isomer.
`
`'I'l..C Silica gel (1:1 hexanelacetone) R,=0.20. Note: This
`is identical to Example 175 Part D compound and is the
`precursor to t.he Example 176 compound.
`MS (C1. +ions) 532 (M+H).
`“P NMR (coco. 121 MHz) a 41.2 ppm.
`EXAMPLE 179
`
`(S)-(—)-3-Phenoxy-ctr
`phosphonohennenebutanesulfonic acid. trip-otassium
`salt
`
`oil. The oil was purified by flash chromatography (200 g
`silica gel) eluting with methylene chloride (600 mL) fol-
`lowed by 93:? dichlororoethanefisopropanol (1000 ml.) to
`provide 6.60 g (85%) of title compound as a low melting
`solid.
`TLC Silica gel (1:9 2-propanolfdichloromethane)
`R,=0.58.
`IR (KBr) 2947. 2878. 1478. 1451. 1348. 1258. 1236.
`1215. 1165. 1123. 1026. 1005. 918 cm".
`Mass Spec (CI-N'H,. +ions) mic 638 (2M+NH,). 621
`(2Nl+1-1). 328 (M+NH..). 311 (M+H).
`Anal. Ca1c’d for C,1H23N2C|..PS: C. 42.57; H. 7.47: N.
`9.03:1’. 9.89: S. 10.33 Found; C. 42.95; H, 7.55; N. 9.10: P.
`9.81; 8. 10.59.
`[o.],,”°=-79" CHC13. (ml)
`‘H NMR (CDCl,. 300 MHz): 54.35 (q. 2H. J=6.9 Hz)
`3.82 (t. 11']. J=l4.1Hz)3.73(t, 1H. J=15.0 Hz) 2.93 (td. 1H.
`l=9.0. 2.0 Hz) 2.80 (Id. 1H. J=9.0. 2.0 Hz) 2.67 (d. 3H. l=8.0
`Hz) 2.63 (d 3H. J=8.0 Hz) 2.05 (tn. 21-1) 1.85 (m 2H) 1.40
`(t 3H. J=7.0 Hz) 1.30 (m 41-I) ppm.
`“C NMR (CDCl,. 75.6 MHz): 367.0 64.3 (d. J=6.8 Hz)
`62.8 (cl. J=9.0 Hz) 46.3 (d. J=102.0 112) 28.7 (d. J=2.0 Hz)
`27.8 (d. J==10.5 Hr.) 27.7 (d. J=8.3 Hz) 27.4 (cl. l=-4.5 Hz)
`24.0 23.9 ppm.
`3'PN'MR (CDC1,. 121.7 MHz): 826.7 ppm
`[3aR-(3atr.7a[5)l~Octahydro-1.3-dirnethyl-1H-13.2-
`c.
`benzodiazaphosphole-2-methanesulfonic acid.
`tetrabuty—
`latntnoniurn salt. 2-oxide
`Asuspension of5.00 g (16.12 rnmo1)of Part 13 compound
`and 6.02 g (16.29 mmol) of tetrabutylarnmouium iodide in
`30 ml. of anhydrous TI-117 atRT was stirred for 10 min. at 0°
`C. and wanned to RI‘. After 30 h the clear solution was
`concentrated to a thick oil. The oil was dried under vacuum
`(0.009 nun Hg) overnight. The honey—1t'.l:e oil was used
`without ftn-ther purification.
`‘I-I 1Nl'MIR(CD30D. 300 MHZ): 53.55 t. 11-I. I=14.l Hz)
`3.50 (t. ll-I,J=14.1 Hz) 3.30 (In. 3H) 3.00 (In. 1H) 2.67 (In.
`1H) 2.62 (d. 3H. J=10.0 Hz) 2.58 (d. 3H. J=10.0 Hz) 2.05
`(t,,,. 2H. J=10.0 Hz) 1.85 (nu. 2H) 1.70 (in. 8H) 1.40 (m.
`12H) 1.05 (t. 12H. J=8.0 Hz) ppm.
`"C NMR {CDCl,. 75.6 M112); 564.1 (d. J=6 Hz) 63.0 (d.
`.l=6.8 Hz) 48.4 (d, .l=10’7 Hz) 29.0 (d. J=2.0 1-12) 28.9 (d.
`J=4.5 Hz) 27.9 (cl. .l=10 Hz] 24.2 (d. J=18 Hz) 13.6 ppm.
`“P NMR (CD30D. 121.7 MHz): 635.4 ppm
`Mass Spec (FAB. +ions) rule 242 (Bu,,N).
`Mass Spec (high res.. FAB. -ions)
`Calcd for C9H,304N,PS: 281.0725 Found: 281.0717
`|ot1,,°°=—33.3° C.H,0H (c=1)
`D. (S)-(—)-3-phenoxy-ta-phosphonobenzenebutanesulfonic
`acid. tripotassium salt
`To a slurry of 3.29 g (6.29 mrnol) of Part C compound in
`20 ml. of dry THF at -90° C. (internal ternperanlre) under
`argon was added 3.0 ml. (7.50 mmol) of 2.5M o—BuLi in
`heranes to give a yellow solution. After 0.5 h at —90° C. the
`solution was treated with 2.10 g (6.29 mmol) of 3—(3-
`phenoxypheny1)propy1 iodide in 6 ml. of THF at such at rate
`to keep the internal temperature below -85" C. The reaction
`mixture was stirred at -90° C. for 3 h when it was gradually
`warmed to -74” C. overnight The rnixnne was quenched
`with360uLofacetic acidin3mLosfTHFandallowedto
`warm to RT. The ruixture was concentrated and acidified
`with 12 rul. of 2M I-1C1 solution (24 mmol). The reaction
`mass was extracted with hexane. the aqueous layer was
`heated to 80° C. for 3 hours and then diluted with 2-propanol
`until a clear solution resulted A.fl:er hearing an additional
`hour the solvent was evaporated and the residue pumped
`(=0.5 mm pressure] for 0.5 h. The remainder was dissolved
`
`A. [3aR-(3aot.7afl)]-2-Chlorooctahydro- 1.3-dimethyl-1H-1.
`3.2-IJ-enzodiazaphosphole. 2-oxide
`A solution of 4.72 g (33.20 mmol) of Example Part A
`diarnine and 12.63 g (125.0 mmol) of triethylaruine in 50 mL
`of toluene at 0° C. was treated with 5.00 g (33.20 rI:I.n1ol) of
`phosphorus oxychlcride dropvwise over 15 min. The reaction
`mixture was stirred for 10 min. at 0° C. and wa.t‘n1edtoKl".
`After 3 h the solids were filtered off and the filtrate concen-
`trated to a slurry. The slurry was purified by flash chroma-
`tography (100 g of silica gel‘) eluting with 15:85 acetone!
`toluene to provide 6.50 g (88%) of title chloride as a low
`melting solid.
`TLC Silica gel (1:-1. acetoneftoluene) R,=0.30.
`‘H NMR (CDC1,. 300 M112): 8285 (rd. 1}]. J=l0.8. 3.0
`Hz) 2.67 ((1. 3H. J=10.0 Hz.) 2.55 (d+m. 4-H. l=l8.0 Hz.) 2.05
`(In. 2H) 1.85 (tn. 2H) 1.35 (m. 4H) ppm.
`"C NMR (CDCL3. 75.6 MHz): 363.5 (:1. t=7.0 Hz) 62.5
`(d. J=10.0 Hz) 28.0 27.5 (d. J=7.0 Hz) 27.0 (d l=7.0 Hz)
`24.0 23.9 ppm.
`“P NMR (CDCI3. 121.7 MHZ): 836.6 ppm
`[3aR—(3aot.7afl)]-Octahydro—1.3-dirnethyl-1H-1.3.2-
`B.
`benzodiaraphosphole-2—methanesulfonic acid. ethyl ester.
`2-oxide
`To a rapidly stirred solution of 6.20 g (50.0 mmol) of ethyl
`Inethanesulfonate in 150 ml. of THF at ~73“ C- (internal
`temperature) was added 20 mL (50 mmol} of 2.5M
`n—butyll;ithi1.tm dropwise over 20 min (The intu1:ta1ternpera-
`ture was not allowed to rise above —-69° C. throughout the
`addition of n-Bu.l..i). After an additional 30
`5.56 g (25.0
`m.tn~o1)offresh1y prepared Pa'tAchloridei.I:1 25 m.LofTI-IF
`was added at a rate to keep the solution ternperature below
`-69” C. The reaction mixture was stirred for 0.3 h at -73“
`C. and for 3 h at -30° C. The reaction mixture was poured
`into 250 mL of a rapidly stirring mixttne of 1:1 saturated
`aqueous Na]-IC03 solutioulethyl acetate. The mixture was
`partitioned between ethyl acetate and water (3)05 mL). The
`organic extracts were dried (Na2SO.) and concentrated to an
`
`45
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`161
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`5,712,396
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`162
`
`in 30 ml.. (30 mmol) of 1M KOH solution and freeze dried
`to provide a cream colored solid. The solid was diluted with
`water and eluted through 24 g of AGSOXS (63 meq. KT
`form) ion exchange resin. Final purification was accom-
`plished by MPLC on a column of CI-lP20P gel (125 ml.)
`eluting with water (200 1'nL) followed by a gradient created
`by the gradual addition of 500 ml. of acetonitrile to a
`reservoir of 500 ml. of water. Approximately 10 mL frac-
`tions were collected. Pure fractions were pooled the aceto
`nitrile was removed under reduced pressure and the aqueous
`solution lyophilized to provide 1.48 g (47%) of title com-
`pound as a white lyophilate.
`TLC Silica gel (6:3:1 propanoliammonium hydroxidd
`water) R,=0.2
`Chiral HPLC analysis of enanti.orne.1-ic excess was per-
`formed on a ChromTecl1 D1-acid glycoprotein ((11-AGP)
`column: isocratic 85% 01M Kl-I,POJ15% Cl-l3CN. (pH
`4.6) in isccratic mode.
`For this sample title compound (S)-isomer: retention
`time=l0.3 min. 94% Example 176 compound (R)-isomer:
`retention time=19.0 min. 6% Therefore. the enaniornfiic
`excess is 88%.
`Anal. Calc‘d for Cm]-l.60.,PSK,_.+2.2 H20: C. 35.54: H.
`3.81; P. 533; S. 5.93 Found: C. 35.54: H. 3.98: P. 5.42: S.
`6.30.
`
`EXAMPLE 130
`
`(R)-(+}-3—Pltenoxy-Ob
`phosphonohenaenebutanesulfonic acid. lripotassium
`salt
`
`25
`
`3.5
`
`A. 4-(3-Phenoxyphenyl)butyl alcohol
`A(1) 3-Phenoxybenzyl alcohol
`Sodium borohydride (961 mg. 25.3 mmol) was added in
`one portion to a solution of 3-phenoaybenzaldehyde { 10.0 g.
`50.5 mmol) in methanol (150 mL) at RT under argon. Once
`the bubbling ceased the reaction was stirred atR'l‘for 5 min.
`then adjusted to pH 6 with glacial acetic acid (about 1 mL).
`The reaction was concentrated in vacuo to give a residue.
`which was partitioned between EtOAc (200 mL) and sam-
`rat;edNaI-ICO3 (50 m]..). The organic layer was washed wit:h
`water and brine (50 mL each). then dried over MgS0,..
`Evaporation gave title compound { 10.1 g_ i00%) as a tan oil.
`A(2) 3-Phenoxybenzylbromide
`Phosphorus tribromide solution (11.0 mL. 1M in CH,Cl,.
`11.0 mmol) was added over 5 min to a solution ofPa.rt l(A)
`alcohol (2.00 g. 10.0 mmol) in Cl-l,C1, (30 ml.) under argon
`at R1". The yellow reaction was stirred at RT for 10 min.
`diluted with CH,Cl, (100 mL). and washed with saturated
`NaHCO3 (2)60 m.L). The organic layer was dried over
`MgS04. Evaporation gave a pale yellow oil. which was
`purified by flash chromatography on silica gel (75 g) eluting
`with 10:90 CH2Clz}'hexane to provide title trornide (1.57 g.
`60%) as a yellow oil.
`A(3) 4—(3-Phenoxyphenylbutyl alcohol
`A Grignard solution of C11-‘ig(CH2)3OMgCl (19.2 mL.
`0.6M in THF. 11.5 mmol) was added to a mixture of Part
`A(2) bromide (1.51 g. 5.74 mmol) and copper(I) iodide (11
`mg. 0.057 mmol) in THF (10 ml.) at 0° C. under argon over
`a period of 5 min. The dark green reaction was stirred at 0°
`C. for 30 min. ‘then quenched by dropwise addition of
`2-propanol (2 mL). The reaction was diluted with diethyl
`ether (100 mL) and washed with IN K.HS04(2><50rn1.)."I'he
`aqueous layers were back-extracted with dicthyl ether (20
`mL). The combined organic layers were dried over MgS04. 65
`Evaporation gave a pale yellow oil. which was purified by
`flash d1.t'oIt10130£1'fiPhy on silica gel (100 g) eluting with
`
`30:70 Et0Ac!hexane to provide title alcohol (1.10 g. 79%)
`as a colorless oil.
`B. 3«-Phenoxybennenebutanal
`To a stirred solution of 3.4 mL (48.6 mmol) of methyl
`sulfoxide in 50 mL of C}l2Cl, under argon at -78” C. was
`added 3.9 mL (44.5 mmol) of oxalyl chloride dropwise over
`5 min. The reaction was stirred at -78° C. for 0.5 h at which
`time 9.8 g (40.4 mmol) of Part A alcohol in 15 ml. of CH,Cl,
`was added dropwise. The reaction was stirred at —78° C. for
`20 min. warmed to -30° C. for 5 min. cooled back down to
`—78° C. and treated with 22.6 mL (162 mrool) of triethy~
`lamine. The reaction gradually warmed to -20” C. and was
`quenched with 150 mL of water. The mixture was diluted
`with a 1:1 mixture cf hexanesfefliyl acetate and the layers
`were sepaated. The organics were dried over Na,SO,. and
`evaporated to dryness to provide 8.8 g (91%) of title
`compound as a pale yellow oil.
`TLC Silica gel (70:30 hexaneslethyl acetate) R_,=0.-4-0.
`C. 4.6-Dimethyl-2-[3-(3-phenoxyphenyhprcpyll-1.3-
`diottaue
`To a solution of 5.6 g (23.33 mmo1)ofPart B aldehyde in
`25 rnI.. of benzene was added 2.4 g (23.33 mmol) of
`(28.48)-(+)-pentanediol and a 50 mg (0.36 mol) of
`p-toluenesulfonic acid The reaction was refluxed for 2 h
`using a Dean—Starlr trap for the azeotropie removal of water.
`The reaction was diluted with ethyl acetate. washed with sat.
`NaHCO, solution. water. dried over MgS04 and evaporated
`to provide a crude yellow oil. Flash chromatography was
`performed on 300 g of silica gel eluting with 90:10 hexanesl
`ethyl acetate. Ptne product fractions were combined and
`evaporated to provide 5.5 g (72%) of title compound as a
`colorless oil.
`TLC Silica gel (90:10 hexaneslethyl acetate) R,-=0.21.
`[ot],,‘°—13.1° (c=1 CH2Cl;)
`MS (CI-N1-1,. +ions) mile 344 (M+NH,). 326 (M).
`[R-IR“‘IR*{R")]]]-I1-(3-Hydroxy-l-metl1ylbutoxy}3-
`D.
`phenoxybenzenebutanephosphonic acid. diethyl ester
`(Yolrcmatsu. T.. Shibuya. S.. Tetrahedron Asymmetry
`1992. 3. 327-8).
`Tb a solution of 2.9 mL(16.8'7 mmol) of triethyl phosphite
`in 7 mL of CH,Cl2 at —78° C. under argon was added
`drrpwise 1.5 mL (13.50 mmol) of titanium (IV) chloride.
`The resulting orange solution was stirred at —78° C. for 0.5
`h at which time 2.2 g (6.75 mmol) of Part C compound in
`5 ml. of CH2Cl, was added dropwise over 0.5 h (internal
`temperature of the reaction maintained at —68° C.). The
`reaction was stirred for 48 h at —78° C. at which time the
`reaction was poured into 200 mL of a 1:1 mixture of
`Nal-ICO,!ethyl acetate and extracted. The -organics were
`washed with water. brine, dried (MgSO4) and evaporated to
`provide 2.0 g of a crude oil.
`I-'-‘lash chromatography was
`performed on 200 g of silica gel eluting with 4:1
`dichloromethanetacetone. Pure product fractions were
`pooled and evaporated to provide 1.5 g (48%) of title
`compound as a colorless oil.
`TLC Silica gel (4:l ditzldorornettianemcetone) R_,=O.24.
`[u],,“°+1s.s (c.-:1 cH,c1,)
`IR (Film, CHZCI2) 3410. 30-1-0. 2969. 2870. 1584. 1487.
`1447. 1385. 1250. 1215. 1163. 1047 cm“.
`243$-NirR(coc1,. 121 MHz.ref. to 10% 11,90... 0 ppm):
`.
`ppm.
`HRMS (E1. -I-ions) mlz Calculated fcr C2,H3-.051’: M‘
`464.2328 Found: 464.2316
`13.
`(R)—ct-l-lydroxy—3-phenoxybenzenebutanephosphonic
`acid. diethyl ester
`To a solution of 3 ml. (6.00 mmol) of 2.0M oxalyl
`chloride in Cl-12C}; in 3.5 mL of Cl-l._.C1,. under argon at
`
`82 of 93
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`lPR20l5-01836
`
`

`
`5,712,396
`
`163
`-70“ C.. was added dropwise 535 11L (7.54 mmol] of DMSO
`(exothermic). This mixture was stirred at —70° C. for 15 min
`at which time 1.4 g (3.02 mmol) of Part D compound in 5
`ml. of CH,Cl, was added dropwise. The reaction was stirred
`at -'10“ C. for 1 h. treated with 1.7 ml. of triethylamine and
`allowed to warm to RT. The reaction was quenched with
`water and diluted with a 1:1 mixture of hesxanes/efliyl
`acetate. The organics were dried (MgS04) and evaporated to
`provide 1.4 g of acrude oil. The crude oilwas treated with
`14 mL of dioxane. 70 mg (0.37 mine]. 5%) of
`p~toluenesu1foaic acid. 1.4 ml. of water and refluxed for 0.5
`h then cooled to RI‘. The mixture was diluted with a 1:1
`mixtllre of wateIfNaHC03 and extracted 3 times with
`CH,CJ.2. The organics were dried (MgS0.) and evaporated
`to provide 1.2 g of a pale yellow oil. Flash chromatography
`was performed on 100 g of silica gel eluting with 4:1
`dicthloromethanelacetone. Pure product fractions were com-
`bined and evaporated to provide 690 mg (60%) of title
`co
`nd as a colorless oil.
`[o.],,”°~5.9° (c=l. CHCl,)
`TLC Silica gel (4:1 d.icl1lcrometha.ne’a.ce'tone)
`IR (Film. CH;C1;) 3306. 2982. 1584. 1485. 1445. 1335.
`1250. 1215. 1163. 1142. 1096. 1051. 1026. 966 cm“.
`‘H (300 MHz. CDCl3): 'o‘7.30—6.70 (in. 91-1) 4.15 (m. 4H)
`3.95 (111. 1H] 3.87 (in. 1H) 2.61 (In. 2H) 1.95 (111. 111) 1.70
`(in. 31-1) 1.30 (t. 6H. .l=7.l 112) ppm.
`"C NMR (75 MHz, CDCl,) 8157.2. 157.0. 144.1. 129.6.
`129.4. 123.3.l22.9.]l8.9. 118.6. 116.2, 611.5 (cl. J=161 Hz).
`62.6 (d. .l=6.8 Hz). 62.4 (C1. .l=6.8 112), 35.2. 30.8, 27.2 (d.
`J=12.3 Hz). 16.4 (cl. J=4.5 Hz) ppm.
`"PNMR(12l Ml-lz. CDC1,.ref.to10% l*l,P0.,. Oppm):
`25.28 ppm.
`HRMS (FAB. +ions) ml‘: Calculated for CmH,,O,P:
`(M+H)*=379. 1675 FOUND: 379.1692
`Anal. Calcd. for C~_.oH—_.-,.P0,-t-0.50 mo] H20. Effective
`MW=387.40. C. 62.00: H. 7.28; P. 7.99 Found: C. 62.00; H.
`7.05: P. 8.13.
`F.
`(R)-tt-[[(Dimethylaminofihioxomethyl]thio]-3-
`phenoxyhenzenebutanephosphonic acid
`To a stirred slurry of 415 mg (1.10 mmol) of Part E
`compound. 585 mg (2.23 mmol) of triphenylphosphine and
`252 mg (0.82 mmol) of dimethyldithiocarbamic acid. zinc
`salt.in3 mLof'I'HF at 0° C. underargon was added446m.g
`(2.21 mmol) of tliisopropyl diazodicarhoxylate in 2 ml. of
`THF over the course of 20 minutes. The resulting light
`yellow solution was allowed to warm to room temperature
`and stirred for 16 hours.
`'I‘he reaction mixture was then
`evaporated and immediately ptnitied by flash chromatogra-
`phy (5x15 cm column. eluting with 1:3 ether)‘
`dichloromethane). Fractions containing both me product and
`an impurity were collected. concentrated and
`re-chromatographed (5><15 cm. coltunn. 85:15 ethyl acetate’
`hexane). The resul.t.t'.ug yellow oil still contained ca. 13-10%
`of diiso1:a'opyld.ica.rbazide as an impurity. The yield of title
`compound was 490 mg (82% of 91% pure ma.tu‘i.a.l).
`[o.]r,’°=24.5° (c=0.99. CHCl,)
`(R)-{+)-3-Phenoxy-(1-phosphonobenzenebutanesulfonic
`(3.
`acid. tripotassium salt
`To a stirred solution of 410 mg (0.851 mmol} of Part F
`compound in 3 ml. of Cll;C1; at room temperalllre Lmder
`argon was added 0.7 mL (5.3 mmol] of lJromolIimethylsi-
`lane. The nearly colorless solution was stirred for 16 hours
`and then evaporated at less than 25° C. The residue was
`dissolved in 10 mL of dry methanol and stirred for 1 hour.
`Re-evaporation gave 358 mg (99%) of the diacid as a
`colorless glass.
`To a solution of 0.326 g (03? mmol. 1 eq) of the diacid
`in 50 mL of 98% formic acid was added 4.2 mL (38 lttmol.
`
`164
`
`I0
`
`50 eq) of 30% hydrogen peroxide in water. The reaction
`became cloudy after 0.5 min and a precipitate formed after
`—-2 min. After 1 h. the reaction was cooled to 0° C. and the
`excess peroxide was decomposed by the slow addition of 40
`ml. of IN potassium sulfite. The solution was concentrated
`and the residue was coevaporated twice with wata: The
`residue was dissolved in 10 ml. of water and the pH of the
`solution (pH-3) was brought to pH 12 with 1N potassium
`hydroxide. The solution was then chrornatographed on
`C1-[P-201’ gel (2.5 cmx25 cm) elutiug with water. Fractions
`containing product were analyzed by HPLC. then pooled
`and concentrated to alford a clear waxy residue which was
`dissolved in water. filtered and lyophiiized to afford 201 mg
`(48%) of title compound.
`TLC Silica gel (6:3:l n-propanol:ammoniutn
`hydroxide:wa.t.er): R’. 0.21.
`Chiral HPLC analysis of enanticrneric excess was per-
`formed on a Chr<ariTech ct-acid glycoprotein (ct,-AGP)
`column. eluted with 85% 0.1M [CH2P0., 15% CH3CN. pH
`4.6 in isocratic mode.
`tirne 18.5 min. 98.95% (R)-
`For title compound: ret.
`enantiomer ret. time 11.2 min. 1.05% (S)-enantiomer there-
`fore 9’i'.9'iIa enantiomeric excess of the (R)-isomer.
`Anal. Calc’d for C,5H15O-,PS1(3+2.5 1-1,0: C. 35.19; H.
`3.83:1’. 5.67‘. S. 5.87 Found: C. 35.19; H. 3.54; P. 5.32‘. S.
`6.27.
`
`EXAMPLE 181
`
`(S)-{—)-3-Phenoxy-ob
`phosphondoenzenebutanesulfonic acid. 1-
`adamantauamine (1:2) salt
`
`35
`
`45
`
`55
`
`65
`
`A sample of the (R)-(-)-trisalt (9-1:6. (S)'.(R)) prepared in
`Example 179 (70 mg. 0.14 mmol) was stirred with 3 g of
`Ag50-XS ion exchange resin (7.5 mcq. 11* form) for 1 h in
`5 ml. of water and 3 ml. of methanol. The mixture was
`slowly eluted through an additional column of Ag50-X8 ion
`exchange resin (1 g. 2.5 meq. H" fonn} with 1:1 methanol!
`water. Approximately 3 tn.L fractions were collected. Frac-
`tions #2 to 7 were pooled. l:he methanol was removed under
`reduced pressure and the aqueous solution lyophilized to
`provide 54 mg (100%) of the free acid form of the title salt
`as a thin film.
`
`ThefreeacidS4rug.0.14rnu:nol)in3mLofa 1:1
`rnethanolfwater solution was treated with 39 mg (0.28
`rnrnol.2eq)ofadamantanamineandtl1emixtI.trestirredfor
`0.5 h. The mixture was concentrated to a white solid. The
`solid was recrystallized from hot water and 2-pmpa.I1o1.'I‘he
`white granules were collected to yield 79 mg (85%) of title
`salt as a 97:3 mixture of (S):(R) enantiomers. The recrys-
`tallization procedure was repeated to provide 66 mg (35%)
`of title salt. as a white solid. mp 248°—252° C. The two
`recrystalizations from hot 2-propanolfwater improved the
`ratio (If(S):(R) enantiomers from 94:6 to 93:2 determined by
`HPLC as described on the or-acid glyooprotein column.
`TLC Silica gel (6'_3:1 n-propanollconc. arnmoniaiwater)
`R,=0.30.
`IR (KBr) 3426. 3086. 3065. 3036. 2915. 2855, 1609.
`1582. 1435. 1233. 1215. 1175. 1022. 882 cm".
`11-] NMR (CD-30D. 400 MHz): 87.30 (t. 2H, J=8.1 Hz)
`7.20 (t, 1H. Jfl.0 1-12.) 7.07 (t. 1H. l=6.2 Hz.) 6.95 (In. 311)
`6.36 (s. 1H) 6.73 (dd. 1H. J=8.5. 2.5 Hz) 3.05 (dr. 11-1.
`l=18.0, 6.2 Hz] 2.65 (In. 211) 2.15 (sun. 81-!) 2.00 (I11. 211)
`1.90 (s. 12H) 1.75 (d. 6H. J=l2.0 Hz) 1.68 (41. 61-1. J=l2.0
`Hz) ppm.
`Mass Spec (FAB. -I-ions) rule 689 (M+I-1); (FAB. —ions)
`II!/C 335 (M-2(C9HnN)+H)-
`
`83 of 93
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`
`

`
`5,712,396
`
`165
`Anal. Ca1c'd for C35H,30-,N,PS+1.00 H20: C. 61.17; H.
`7.84: N. 3.96; P. 4.38‘. S. 4.54. Found: C. 61.26; H. 7.90; N.
`4.00; P. 4.27; S. 4.74.
`Regeneration of Metal Salt
`Title salt (60 mg. 0.08 mmol) was stirred with 1.5 J:nL of
`Ag50—X8 ion exchange refin (2.5 meq. IC’ form) for2 1: in
`3 mL of water and 1 mL of methanol (pH=7). The rnixnue
`was slowly eluted through an additional oolurnn ofAg50-X8
`ion exchange resin (1.5 mL. 2.5 meq. K"' form) with 1:1
`methanolfwater. Product containing fractions were pooled.
`the methanol was removed under reduced pressure and the
`aqueous solution lyophilized to provide 38 mg (95%) of the
`lripotassium salt as a white lyophilate.
`Chiral HPLC analyis of enantiomeric excess was per-
`formed on a Chrom"Iech u-acid glycoprotein (ctl-AGP)
`column eluted with isocratic 85% 0.1M KH2P0_,. 15%
`cH.c1-I. pH 4.5.
`For this sample.
`Example 181 (S)-isomer: retention tirne=9.5 min. 98%
`Example 180 (R)-isomer: retention time==19.0 min. 2%.
`lhuefore a 96% enantiomeric excess of the (S)-isomer.
`EXAMPLE 132
`
`(S)-(—)—3-Phenoxy-( 1-
`phosphonobenzenebutanesulfonic acid. (S)-(I-
`methylbenzylamine (1:2) salt
`
`A sample of the (—)-isomer (Example 175) (70 mg. 0.14
`mmol) was stirred with 3 g of Ag50-X8 ion exchange resin
`(7.5 meq.H*fornr)for 1 h in 5 rnLo:Ewarerand3 mLof
`methanol. The mixttn-e was slowly eluted through an addi-
`tional column of Ag50—X8 ion exchange resin (1 g, 2.5 meq.
`H+ form) with 1:1 methanolfwater. Approximately 3 ml.
`fi-actions were collected. Fractions #2 to 7 were pooled. the
`methanol was removed under reduced pressure and the
`aqueous solution lyophilized to provide 54 mg ( 100%) of the
`free acid form of the title salt as a thin him. The free acid was
`used without further clraracterization.
`The free acid in 3 ml. of a 1:1 metlianol/wan: solution
`was treated with 36 UL (0.28 mmoL 2 eq) of (S)-(—)-(1-
`methylbenzylarnine under argon. The mixture was stirred for
`0.5 h and concentrated to an oiL Recrystallization from 3 ml.
`of hot acetonhrile and 3 drops of water followed by slow
`evaporation to dryness provided 60 mg (73%) of title
`diamine salt as needles. mp 160“—163° C.
`[ot1D‘°=-8.0° (methanol, t.-=1)
`IR (KBr) 3447. 3050. 3038. 2938. 2762. 1613. 1582,
`1566.14-89.1242. 1213. 1182. 1163. 1072. 1044,1022. 924.
`702 cm”.
`
`Mass Spec (FAB. -I-ions) mile 629 (M+H)2 (FAB. —-ions)
`We 385 (M—2(C3I-I“N)+H).
`‘H NMR (3:l DMSCI:CD._..0D. 300 MHz): 5'}'.S8—'7.30
`(m. 12H) 7.25 (t. 1H. .1=8.0 Hz) 7.10 (t. 1H. .I'=8.0 Hz) 7.00
`(d. 31-I. J=9.0 Hz) 6.85 (m. 11-1) 6.75 (dd. 1H. .l=7.0. 2.0 Hz)
`4.40 (q. 2H. J=6.5 Hz) 2.80 (d1. 11-1. .1:-19.0. 5.8 1-12) 2.57 (in.
`21-1) 1.80 (m. 41-1) 1.55 (I1. 61-1. I=6.5 Hz) ppm.
`The needles were subjected to X-ray aystallograpliic
`studies. which demonstrated that the (—)-isoma had the
`(S)-stqeochernistry at the ot-carbon.
`EXAMPLE 183
`
`(S)-ot-[Bis[(2.2-dimethy1-1-oxopnopoxy)rnethoxy]
`phosphinyl]—3-phenoxybenzenebutanesulfonic acid.
`nronopotassium salt
`
`(S)-3-Phenoxy-ct-phosphonobenzenebutanesulfonic
`A.
`acid. lrisilver salt
`A solution of Example 175 product (1.66 g. 332 mmol)
`in watu (17 mL) was added over 30 min via syringe pump
`
`166
`
`to a vigorously stirred solution of silver nitrate (2.02 g. 11.9
`mmol)inwater(17 mL) underargon atRTinthe d.ar1t.A
`white precipitate resulted irnrnediatcly upon addition. Fol-
`lowing addition. additional water (5 mL) was added to aid
`stirring. and the thick slmzry was stirred vigorously at RT for
`15 min then filtered through aporosity D (10-20 pm) glass
`frilxed funnel. The solid was washed with water {2x40 mL)
`and diethyl ether (2x40 mL) then air-dried for 15 min. The
`product was further dried by pumping under high vacuum in
`the dark overnight to give title compound (2.28 g. 97%) as
`a beige solid.
`B.
`(S)—o‘.-[Bis[(2.2-dimethyl-l-oxopropoxy)methoxy]
`phosphinyl]-3-phenoxybenzenchutanesulfonic acid. mono-
`polassium salt
`A suspension of PartA compound (2.12 g. 3.00 mlnol)
`and activated 4A molecular sieves (2.1 g) in CI-I,Cl, (25
`mL) was stirred at ET in the dark under argon for 45 min.
`Anhydrous arrisole (1.6 ml... 15.0 mmol) was added and the
`reaction was placed in a 20° C. water bath. To the suspension
`was added a solution of 2.2-dimethylpropanoic acid. iodoIn-
`ethyl ester (2.18 g. 9.00 mmol) in CH,C1, (5 mL) dropwise
`slowly over 15 min via syringe pump ensuring that the
`reaction temperature remained below 30° C. The reaction
`tinned bright yellow during addition. The heterogeneous
`reaction was stirred vigorously at ET in the dark for 40 min.
`then filtered through Celite with the aid of CI-1,C12 (200
`mL). Evaporation of the filtrate gave 3.3 g of the crude
`triester ot-[bis[(2.2-dimethy1-1-oxopropoxy)methoxy]
`phosphinyl]-3-phenoxybenzenebutanesulfonic acid.
`(2.2-
`dimeahyl-1-oxopropoxy)methyl ester as a yellow liquid.
`The crude triester was dissolved in CH3CNfwaicr (4: 1. 40
`mL) to give an opaque solution containing a small amount
`of yellow precipitate. The reaction was stirred at RI‘ and
`progress of the solvolysis was monitored by ‘H NMR
`(disappearance of the t-BuCO,CH,-sulfonate signal at 5.8
`ppm [in d6-DMS01). When no sulfonate ester remained (8
`h) the reaction was partitioned between Et0Ac (150 mL)
`and saturated KC! (20 mL). The resultant biphasic mixttm:
`was filtered to remove the yellow precipitate. The organic
`layer was washed with 1M potassium phosphate (pH=6.0.
`2X20 mL) and saturated KC] (5 mL). then dried over
`anhydrous KCL Evaporation followed by pumping under
`high vacuum for 1.5 h gave 2.0 g of a colorless oil.
`C1-IP20? gel was stirred with 0.5M potassium phosphate
`buifer (pl-I=5.0. 1000 mL) for 4 h. then packed (5305 cm
`column) and flushed with water (500 mL). The column was
`equililrrated with 5:95 CH,C.Nfwater (1.5 L).
`The crude product was dissolved in Cl-I3CN (5 mL). then
`water (10 mL) was added. The solution was adjusted to pH
`5.0 with 1M potassium phosphate buifer (pH='?.0). The
`product solution was clrronratographed on CEOP gel
`above (25 rnL fractions). eluted with 5:95 CH,CNl‘
`1-110 (250 ml.) followed b