5,712,396
`
`69
`mmol) of hromotrimethylsilane. After 72 h.. the resulting
`clear solution was evaporated at 25° C. and the redue
`dissolved in 5 mL of 'I'l-IF. To this stirred solution was added
`180 mg (1.1 mmol) of dried. finely groundpotassium iodide
`and 3 mg (0.01 mmol) of 18-crown-6. The resulting slurry
`was heated to reflux for 20 h. evaporated and then stirred for
`1 h with 8 mL (4 mmol) of 0.5M potassium hydroxide
`solution. The solution was lyophilized and then purified by
`MIPLC (2.5>-:20 cm column of Mitsubishi Kasei Sepadbeads
`SP-20788 resin): 11.5 mL Emotions. 7 mill-nin flow rate.
`eluted with 200 ml. of water and ‘then a gradient prepared
`from 400 ml. of water and 450 mL of 2:1 aoetonitrilelwater).
`Fractions 20-34 were collected and lyophilized to give title
`salt as a white solid. 505 mg. 85% yield.
`IR (KBr pellet) 3422. 2959. 2930. 2870. 1653. 1497.
`1202. 1080. 968 cm“.
`1}! NMIR (D20. 400 MHZ) 57.45 (:1. 2H. l=8.6 Hz) 7.43
`(d. 2H. ls-8.6 1-1z)'}'.39 (d. 2H. I=8.1 Hz) 7.15 (d. 2H. I-—-8.]
`Hz) 6.44 (m. 2H) 2.98 (dm. 1H. .l=13.2 Hz) 2.87 (In. 11-1,
`l=13.6 Hz) 2.68 (m. 1H) 2.44 (t. 2H. J=6.0 Hz) 1.4-6(dq.2H.
`J=6.0 Hz) 0.73 (t. 311. J=6.0 Hz) ppm.
`Anal. Calc’d for C19!-l,oK3O,,PS.2.2 H._.O: C. 40.45; H.
`4.36: P. 5.49‘. S. 5.68 Found: C. 40.11; H. 4.70; P. 5.18; S.
`5.95.
`MS (FAB. +ions) rule 563 (M+!(). 525 (M-I-H). 487
`(M--K+2H).
`
` 7
`
`ot—Pho sphono—4‘—Propy1[ l.1'—bipheny1]—4—
`butanwulfonic acid. uipotassium salt
`
`o‘.-( Diet]: oxypho sphi nyl )-4'—propyl[ 1.1'-biphenyl]-4-
`A.
`butanesulfonic acid. cyclohexyl ester
`To a 11itrogen—p-urged solution of 1.30 mg (2.3? mmol) of
`Example6PartBoompoundin50ml.ofethylaoet.ateina
`500 mL one-neck round bottom flask was attached a
`hydrogen-filled rubber bladder of approximately 1 L capac-
`ity. The reaction mixuire was vigorously stirred for 16 11.
`purged with nitrogen. filtered through Celite and the filtrate
`evaporated. The oily residue was redissolved in
`dichlormethane. filtered through a 0.7511 (micron) filter and
`re-evaporated to give title compound as a colorless oil. [.28
`g. 98% yield. The product was used without further purifi-
`cation.
`B. ct-Pliosphono-4'-propy1[ 1. 1‘-biphenyl]-4-butanesulfonic
`acid. tr1potas' 5:il.l.l'l1 salt
`To a stirred solution of 1.14 g (2.06 mmol) of Part A
`compound in 10 ml. of didrloromethane under argon at
`room ternperaune was added 1.10 mL (8.3 mmol) of bro-
`motrimethylsilane. After 24 h. the resulting clear solution
`was evaporated at 25° C. and the residue dissolved in 101111.
`of THIF. To this stirred solution was added 340 mg (2.1
`mmol) of dried. finely ground potassium iodide and 5 mg
`(0.02 mmol) of l8—crown-6. The resulting sltury was heated
`to reflux for 24 h. evaporated and then stirred for 1 h with
`8 mL (8 mmol) of 1.051 potassium hydroxide solution. The
`solution was lyophilized and then purified by MPLC (2.S><
`20 cm column of Mitsubishi Kasei Sepadbeads SPZOCFSS
`resin): 11.5 mL fractions. 7 ml..!'min flow rate. eluted with
`200rnLofwater and then agradientpreparedfrom4-00ml..
`of water and 450 ml. of 1:1 aoetonitIilc:'waI:er). Fractions
`27-31 were collected and lyophilized to give title compound
`as a white solid. 450 mg. 39% yield.
`IR (KBr pellet) 3432, 2957. 2930. zsro. 1636. 1499.
`1198. 1080. 1049. 966 car‘.
`‘H NMR (D,0. 400 MHz) 87.47 (cl. 2H. J.-.75 Hz) 1.46
`(d. 2H. .l=7.3 Hz) 7.28 (cl. 2H. J-7.5 Hz) 7.21 (d. 2H. .l=7.3
`
`70
`Hz) 2.86 (dnl. 1H. J=18.4 Hz) 2.58 (In. 2H) 2.49 (t. 2H.
`J=7.2 Hz) 1.35 (In. 4H) 1.50 (In. 2H) 0.78 (t. 31-1. I=6.0 Hz)
`ppm.
`Anal. Calc‘d fa" C,,H,,K,o.,1>s.1.9 11.0: C. 40.68; 1-1.
`4.64‘. P. 5.52: S. 5.72 Found: C. 40.69: H. 5.00; P. 5.46; S.
`6.00.
`MS (ion spray. -I-ions) rule 495 (M—3K-H‘-H+2CH,CN).
`492 (M—2K+3H~lCH3CN). 489 (M—-K+2H). 454 (M—3K+
`4H-I-Cl-l3CN). 451 (M—2K+3H). 413 (M—3K+-4H),
`EXAMPLES
`
`10
`
`4-(2-Plienylethoxy)-co
`phosphonobenzenebulanesulfonic acid. dipotassium
`salt
`
`A. 4«-(2-Phenylethoxy)benzenepropanoi-2 acid.
`2-phenylethyl ater
`To a stirred solution of 5.00 g (30.1 mmol) of
`4-hydroxybenzenepropanoic acid. 8.0 ml. of
`2-phenylothanol
`(67 mmol) and 16.3 g (61 mmol) of
`triphenyl-phosphine in 50 mL of Tl-[F at —-10° C. under
`argon was added a solution 12.0 mL (61 mmol) of d.iiso-
`propyl diazodicarboxylate in 50 ml. or TBIF over the course
`of 4 hours. The resulting light yellow solution was allowed
`to warm to room temperature. stirred 16 h and then evapo-
`rated. The oily residue was uiuirated in 500 ml. of hot
`hexane until a precipitate formed. The solids were filtered
`oif and treated with an additional 100 mL of hot hexane. The
`filtrates were combined and concentrated. Purification of the
`residue by flash chromatography (5><20 cm column. 3:2
`didaloromethanefhexanes as elutent) gave 6.51 g. 58% yield.
`of title compound as a colorless oil.
`13. 1-(3~Iodo1'.a‘opyl)-4-(2-pheny1ethoxy)benzene
`To a stirred solution of 6.20 g (16.6 mmol) of Part A
`compound in 50 ml. of THF at room temperature under
`argon was added a 1M solution of lithium aluminum hydride
`(9.0 ml.. 2.2 equivalents) in THF. After 2 h. the reaction was
`quenched with 1M sodium potassium tarlrate solution and
`extracted twice with ether. The organic extracts were dried
`(MgSO,,) and evaporated.
`The residue was stirred in 25 mL of did-dorornethane at 0
`° C. under argon with 2.8 mL (20 mmol) of n-iethyl amine.
`To this solution was added. over 20 min. 1.3 ml. (17 mmol)
`of methanesulfonyl chloride. After an additional 20 min. the
`reaction mixttue was diluted with dichlorornethane and
`washed twice with 10% citric acid. The organic extracts
`were dried (MgS0,) and evaporated
`The resulting yellow oil was stirred at reflux under argon
`in a solution of 25 mL of acetone oontaining 3 g (20 mmol)
`of sodium iodide. After 16 h. the reaction mixture was
`cooled and diluted with an iwd solution of 5% aqueous
`sodium bisulfite. Afiet two extractions with hexane.
`the
`extracts were dried (MgSO,) and evaporated. Ptrifrcation on
`silica gel (520.0 cm column. 1:? diehloromedranelhexanes as
`elutent) gave 4.13 g. 68%. of Part 15 compound from Part A
`compound
`C.
`ot—( DiethoxyphosphinyI)—4-(2 -p henylethox y)
`benzenebutanesulfonic acid. cyclohexyl ester
`To a stirred slurry of 120 mg (3.0 mmol. 60% mineral oil
`dispasion) of sodium hydride in 3 ml. of DMF under argon
`at -20° C. was added a solution of 1.12 g (3 .56 Inmol. 1.3
`equiv.) of Example 1A. Part B sulfonale in 1 mL of DMF.
`After addition was complete. the reaction was warmed to
`room temperature and stirred for 30 min. To the resulting
`solution was added a solution of 1.00 g (2.73 mmol) of Part
`B compound in 1 mL of DMF. The reaction was stirred for
`16 h. diluted with ether and washed once with 10% citric
`
`45
`
`55
`
`60
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`36 of 93
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`
`

`
`71
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`5 ,7 12.396
`
`72
`
`10
`
`acid and thrice with water. The organic phase was dried
`(MgS04) and evaporated. Purification by chromatography
`on silica gel (5>Q0 cm column) eluted with 1:19 ether!
`dichlorornethaue gave title compound as a colorless oil. 935
`mg. 62% yield.
`D. 4{2-Phenylechoxy)-ct-phosphonohenzenebutanesulfouic
`acid. dipotassium salt
`To a stirred solution of 648 mg (1.2 mrnol) of Part C
`compound in 5 mL of dichlorornethane under argon at room
`temperature was added 620 ml. (3.0 mmol) of his
`(u-imethylsilyl)uifluoroacetamide and then 620 mL (6.9
`mmol) of bromotrirnethylsilane. After 16 h. the resulting
`clear solution was evaporated at 25° C. and the residue
`dissolved in 6 mLoEl"I'l-IF. To this stirred solution was added
`250 mg (1.5 mmol) of dried. finely ground potassium iodide
`and 3 mg (0.01 mmol) of 18—crown-6. The resulting slurry
`was heated to reflux for 24h. evaporated and then stirred for
`1 h with 8 mL (4 mmol) of 0.5M potassium hydroxide
`solution. The solution was Iyophilized and then purified by
`W (2.5x20 cm column of Mitsubishi Kasei Sepadbeads
`HP-20 resin): 11.5 mL fractions. 7 mumin flow rate. eluted
`with 200 ml. of water and then a gradient prepared firom 400
`ml. of water and 450 mL of 2:1 acetonitrilefwata}. Fractions
`25-32 were collected and lyophilized to give title salt as a
`white solid. 385 mg. 57% yield.
`IR (lCBr pellet) 3434. 3088. 2936. 2868. 1636. 1512.
`1198. 1076. 966 cm".
`in NMR (D20. 400 MHz) 87.21 (m. 5H) 7.09 (:1. 211.
`J=8.6 Hz.) 6.76 (d. 2H. .l=8.6 I-1z)4.15 (t. 2H. J=6.4 Hz) 2.91
`(t. 21-1. J=6.4 Hz) 2.77 (dm. 1H. .l=18.0 Hz) 2.44 (m. 2H)
`1.6? (in. 2H) ppm.
`Anal. Calc’d for C,3H:,l(2O.,PS.3.'75 H,0: C. 38.73‘. H.
`5.15; P. 5.55: S. 5.74 Found: C. 38.73; H. 5.10; P. 5.24; S.
`5.51.
`MS (FAB. -I-ions) rule 567 {M+2K-—H). 529 (M-I-K).
`EXAMPLE9
`
`45
`
`6-(Hexyloxy)-ct-phosphono-2
`naphtlialenebttanesulfonic acid, dipotassium salt
`A. 2-Brorno-6-(hexyloxymaphthalene
`To a stirred solution of 4.46 g (20.0 mmol) of 6-t!l'0l'l'|0—
`2-naphthalenol (obtained from Aldrich Chemical Company
`(#B'}.340-6) and used without purification). in 20 mL of
`DMF at room ternpaatuzre under argon was added 480 mg
`(20 mmol) of 95% sodium hydride over the course of 15
`min. The resulting fight yellow solution was stirred 30 min
`and 3.5 ml. (22 mmol) of 1-bromohexane was added- The
`reaction was heated to 50° C. and stirred for 60 min. The
`reaction was quenched with ice water. the resultings solids
`filtered. washed with water and dried in vacuo at 60“ C.
`Purilication of the residue by chromatography on silica gel
`[5><20 cm column. hexanes as elutant) gave 5.00 g. 81%
`yield. of title compound as a colorless oil.
`B. tr-Edie nyl-(r(hexyloxy)-2—naphthalenem.etl1anoI
`To a stirred solution of 2.23 g (7.25 mruo1)ofPart A
`compound in 25 mL of THF under argon at —'.'8° C. was
`added a
`solution of 8.5 ml. (145 mmol) of 1.7M
`t-butyllitblum in pentaue over 10 min. After 15 min. a
`yellow slurry had formed. This was warmed to 0“ C. and the
`resulting organic solution was stirred for 30 min. To this
`reaction mixture was added 550 ml. (9.5 mmol. 1.3
`equivalents) of freshly distilled acrolein at a rate to keep the
`tempu-ature below 5“ C. After an additional 30 min. the
`reaction was quenched with saturated ammonium chloride
`solution. extracted twice with ethu. dried (MgS0.,) and
`evaporated Recrystallization from hexanes gave title com—
`pound as a white solid. mp 47°—48° C.. 1.83 g. 89%.
`
`C. :1-Ethenyl-6-(hexyloxy)-2-naphthalenemethanol. acetate
`ester
`
`To a solution of 1.43 g (5.0 mmol) of Part B compound
`and1.1m1.(8 rnmol) cf triethylamine in 15 ml. of CHECL,
`at room teinperaune under argon was added 0.’? ml. (6.6
`mmol) of acetic anhydeide and 20 mg (0.16 mmol) of
`4-diruethylaminopyridine. After 10 min. the reaction mix-
`ture was evaporated. diluted with ether. washed once with
`10% citric acid. once with water. once with saturated sodium
`bicarbonate solution. dried [MgS04) and evaporated to give
`title compound as a colorless oil. 1.54 g. 94%. The com-
`pound was used without further puri.fication for the subse-
`quent reaction.
`D.
`(E)-1—(Diethoxyphosp11inyl)-4-[6-(hexyloxy)-2~
`naphthalenyll-3-butenesulfonic acid. cyclohexyl ester
`To a stirred solution of 1.47 g (4.5 mmol) of Part C
`compound. 1.55 ml.
`(6.6 mmol. 1.5 equiv.) of his
`(u-irnethylsilynacetarnide. 1.85 g (5.85 mmol. 1.3 equiv.) of
`Example 1A. Part B sulionate and 125 mg (0.5 mmol) of
`triphenylphosphine in 10mLofT1-IF unda argon was added
`270 mg (0.24 mmol) of tetraltis(tripheny1phosphine)
`palladium. The resulting mixttne was heated to reflux for 1
`hour. The reaction was cooled. evaporated. diluted with
`ether and washed once with 10% citric acid and thrice with
`water. The organic phase was dried (MgSO4) and evapo—
`rated. Purifica—tion by flash chromatography on silica gel
`(5><20 cm column) eluted with 1:24 ether:-‘dichlororuethane
`gave title compound as a colorless oil. 1.06 g. 41% yield
`E. ct-(Diethcxyphosphiny1)-6-(hexyloxy)-2-
`naphthalenebutanesulfonic acid. cyclohestyl ester
`To an argon-purged solution of 965 mg (1.66 mrnol) of
`Part D compound and 100 mg of10% palladium-on-carbon
`in 15 ml. of ethyl acetate in a 500 ml. one-neck round
`bottom flask was attached a hydrogen-filled rubber bladda
`of approximately 1 L capacity. The reaction mixture was
`vigorously stirred for 16 h. purged with nitrogen. filtered
`through Celite and the filtrate evaporated. The oily residue
`was redissolved in dichlormethane. filtered through a 0.75;:
`(micron) filter and re-evaporated to give title compound as
`a colorless oil. 950 mg. 98% yield. The product was used
`without fu1't.’ner purification.
`F. 6—{Hexylouty)-on-phosphono-2—naphthalenehutanesul:fonic
`acid. dipotassium salt
`To a md solution of 885 mg (1.52 mmol) of Part E
`cornpotlnd in 10 ml. of dichloromethane under argon at
`room temperature was added 800 ill. (8.9 mmol) of bromot~
`rimethylsilane. After 18 h. the resulting clear solution was
`eva
`at 25° C. and the residue dissolved in 15 ml. of
`THF. To this stirred solution was added 320 mg (1.9 mmol)
`of dried. finely ground potassium iodide and 3 mg (0.01
`mmol) of 18-crown-6. The resulting slurry was heated to
`reflux for 24h. evaporated andthen stirred for 1 h with 9 ml.
`(4.5 mtnol) of 0.5M potassium hydroxide solution. The
`solution was lyop-hilined and then purified by MPLC (2.5x
`20 cm column of Mitsubishi Kasei Sepadbeads C1-{P-20P
`resin): 11.5 ml. fractions. 7 mllrnin flow rate. eluted with
`200 ml. of water and then a gradient prepared from 400 ml.
`of water and 450 mL of 1:1 acetonitrilefwater). Fractions
`44-52 were colleotedand lyophilized to give title compound
`as a white solid. 475 mg. 53% yield.
`IR (KB: pellet) 3434. 3057. 2932. 2361. 1653. 1605.
`1181. HT76. 966 cm“.
`‘H NMR (D20. 400 MHZ) 87.60 (d. 1H. J=9 Hz) 7.56 (5.
`1H) 7.52 ((1. 11-1. J=8.3 Hz) 7.32 (d. 1H. .l=8.3 Hz) 7.00 (s.
`1H) 6.94 (d. 1H. .l=9.0 Hz) 3.78 (t. 2H. J=6.4 1-12) 2.83 (dm.
`1H. l=l8.0 Hz) 2.65 (m 2H) 1.89 (m 4-H) 1.48 (m 2H) 1.16
`(I'll 2H) 1.07 (in 41-1) 0.67 (t 2H. I=5.5 Hz) ppm.
`
`37 of 93
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`

`
`5,712,396
`
`73
`Anal. Calc’d for CNH-,.7K¢O-,PS.3.81 H20: C. 40.76; H.
`5.92: P. 5.26; S, 5.44 Found: C. -10.76; H. 5.81; P. 5.35; S.
`5.35.
`MS (FAB. -I-ions) me 559 (M+K). 521 (M+H).
` 10
`
`4-[(5-Methyl-4—hexeny1)oxy]-ob
`phosphonobenzenebutanesulfonic acid. tripotassiurn
`salt
`
`A. 5-Methyl-4-hexenoic acid, 1.1-dimetlrylethyl ester‘
`To a stirred solution of 20.0 mL(1-12 mmol) of diiscpro
`pylarnine in 160 ml. of THF under argon at —10° C. was
`added a
`solution of 56 ml.
`(140 Iurncl) of 2.5M
`n-butyllilhium in hexane at a rate to keep the temperature
`below 0° C. The resulting light yellow solution was stirred
`15 min and to this reaction mixture was added 20rul..(115
`mmol) d HMPA. After an additional 10 min. the reaction
`was cooled to —75° C. and 18.8 ml. (140 mmol) of 1.1-
`d.i.methyle‘thanol. acetate ester was added at a rate to keep the
`temperattne below —60° C. ‘The resulting colorless solution
`was stirred for 3-0 min and 20 g (134 mmol) of 4-bromo-2-
`methyl-2-butcne was added over 10 min. The reaction was
`stirred at —75° C.
`for 6 h and then warmed to room
`temperature. After 16 h. the reaction was quenched with
`saturated ammonium chloride solution. extracted twice with
`ether. dried 043504) and evaporated. Plnification by distil-
`lation (‘b.p. 64°-67° C. @6mmHg) gave title compound as
`a colorless oil. 20.1 g. 82% yield.
`13. 5-Methyl-4-hcxcn-1-o1
`To a stirred slun-y of 1.71 g (45.1 mmol) of lithium
`aluminum hydride in 50 ml. of ether under nitrogen at 0° C.
`was added a solution of 15.5 g (84 mmol) of Part A
`compound in 20 mLof ether over 20 rn1'n.'I‘hereaction was
`warmedtoro0mtemperatt1reandst:'n'ed.Afier24l1,tl1e
`reaction was quenched with 1M sodium potassium tartrate
`solution. extracted twice with 50 mL portions of ether. dried
`(M3504) and filtered. The extract was distilled at atmo-
`spheric pressure through a 10 cm Vigreau column until the
`head tempcrattnereached 80“ C. The residue was purified by
`vacuum distillation (l1.p. '76°—77° C. @143 mrnllg) to give
`title compound as a colorless oil. 9.06 g. 94% yield.
`C. 4-[(5-Merltyl-4-he1eny1)oxy]benzeneptropanoic acid.
`ethyl ester
`To a stirred solution of 1.14 g (10.0 mmol} of Part B
`compound. 1.94 g (10.0 mmol) of ethyl 4-hyd.roxyphcnyl-
`3-propanoate and 2.62 g (10.0 mmol) of m'phenyIpI1cs1:tu'ne
`in 20 ml. of'I'I-[F at —l0° C. under nitrogen was added a
`solution 2.0 mL (10 mmol) of diisopropyl diazodicarboxy-
`latein20mLofTHFovert'nccourseof2hotrrs.'[‘he
`resulting light yellow solution was allowed to warm to room so
`temperature. stirred 16 h and then evaporated. The oil)‘
`residuexvasn-inn-a1edin500mLofhothe3rancun1:ila
`precipitate formed. The solids were filtered oil’ and treated
`with an additional 100 ml. of hot hexane. The filtrates were
`combined and concentrated. Plrrification of the residue by
`flash chromatography (5x15 cm column. 1:1
`dichlorranethanefhexanes as elutent) gave 2.58 g. 89% yield.
`of title compound as a colorless oil.
`D. 4-[(5-Methyl-4-hexeny1)oxy |benzenepropanol
`To a stirred solution of 2.28 g (7.85 mmol) of Part C
`compound in 15 mL of THF at room ternperauue under
`nitrogen was added a 1M solution of lithium aluminum
`hydride (4.5 mL. 2.4 equivalents) in T1-IF. After 20 min. the
`reaction was quenched with 1M sodium potassilnn Iartraae
`solution and extraded twice with ether. The organic extracts
`were dried (MgS0.,) and evaporated twice from hexanes to
`give 1.88 g of title compound. 96% yield. as a colorless oil.
`
`74
`E. 1-(3-lodopropyl)-4-[(5-methyl-4—hexeny1)oxy]benzene
`To a stirred solution of 1.86 g (7.5 mmol) of Part D
`compound. 1.96 g (7.5 mmol) of triphenylphosphine and
`1.13 g (16.5 mmsol)o1"1.midazo1e in 25 mL of'I‘1IF at room
`temperatme under nitrogen was added 1.91 g (7.5 mmol) of
`solid iodine. portionwise. over 30 min. Afro: an additional
`10 min. the reaction mixture was diluted with hexanes and
`washed once with saturated sodium bisulflte solution. The
`organic extracts were dried (MgS0..) and evaporated. Puri-
`fication by flash chromatography (5x12 cm column. 1:4
`dichlctomethanefhexanes as clutent) gave 226 g. 84%. of
`title compound
`F. o‘.~(Diethoxyphosphinyl)—4—[(5—methyl—4—hexeny1)oxyJ
`benzencbutanesulfonic acid. Cyclohexyl ester
`'1b a stirred slurry of 120 mg (3.0 mmoL 60% mineral oil
`dispersion) of sodium hydride in 3 ml. of DMF under argon
`at —l0° C. was added a solution of 1.12 g (3.56 mmol. 1.3
`equiv.) Example 1A. Part}! sulfonate in 1mLof DMF. Afler
`addition was complete. the reaction was warmed to room
`temperature and stirred for 30 min. 'I‘o the resulting solution
`was added a solution of 1.00 g (2.79 mmol) of Part E
`compoundin1mL of DMF. The reaction was stirred for 16
`h. diluted with ether and washed once with 10% citric acid
`and thrice with watu. The organic phase was dried (M3804)
`and evapcrated. Purification by flash chromatography on
`silica gel
`(5><20 crn column) eluted with 3:4’? ether)‘
`dlchlorornethane gave title compound as a colorless oil. 685
`mg. 45% yield.
`G.
`4-[(5-Methyl-4-hexenyl)oxyJ-cr-
`phosphonobenzenebutanesulfonic acid. tripotassiurn. salt
`A solution of 680 mg (1.25 mmol) of Part F compound in
`10 mL of rnetlranol under argon at room temperauue was
`saturated with amnlorlia gas. The flask containing the reac-
`tion mixture was scaled and heated to 75° C. After 16 h. the
`reaction was cooled to room tenperature and evaporated
`under dry conditions. The residue was dissolved in 10 mL of
`dichloromethane and 1.7 mL (6.4 mmol} of his
`(I1'imethy1sily1)o-ifluomacetainide and then 670 pl. (5.0
`mmol) of 1:uromotrimethylsilane was added. After 24 11. the
`resulting clear solution was evaporated at 25° C. and then
`stin'edfor1hwit118mL(4mrnol)of0.5Mpotassium
`hydroxide solution. The solution was lyophilized and then
`purified by MPLC (2.5><20 urn column of Mitsubishi Kasei
`Sepadbeads HP-20 resin): 11.5 mLf1'actions. 7 mlJmin flow
`rate. eluted with 200 mL of water and then a gradient
`prepared from 400 mL of water and 450 mL of 3:1
`acetonitriletwater). Fractions 25-31 were collected and lyo-
`philizcd to give title salt as a white solid. 504 mg. 74% yield.
`IR (1-{Br pellet) 3432. 2963. 2928, 2866. 1636. 1512.
`1242. 1202. 1080. 966 cm“.
`‘H NMR (1)20. 400 MHZ) 57.09 ((1. 2H. J=8.5 Hz) 6.77
`(d. 2H. J=8.5 Hz) 5.06 (t. 1H. J-6.7 Hz) 3.85 (t. 1H. .l=6.4
`Hz) 2.79 {ddd. Ill. J=-4.3. 6.0. 18.0 Hz) 2.45 (m 2H) 1.98 (m
`2H) 1.77 (m 4H) 1.61 (In 2H) 1.52 (s 3H) 1.43 (s 3H) ppm.
`Anal. Calc'd for C 1-,H2,,K3O7PS.1.33 H10: C. 37.49; H.
`4.93; P. 5.69; S. 5.89 Found: C. 37.48; H. 5.28; P. 5.62; S.
`5.64.
`MS (FAB. +ions)mfe 559 (M+1(). 521 (M+H). 483
`(M—K+2H).
`
`EK.A.MPl..E 11
`
`l-Phosphono-1-pentadecanesulfonic acid.
`tripotassium salt
`(Diethoxyphosphinyl)methanesu1fonic acid.
`A.
`1-methylethyl ester
`To a rapidly stirred solution of 8.28 g (60 mmol) of
`isopropyl me1hanesul:fona1e in 150 mL of THIF at —73° C.
`
`38 of 93
`
`PENN EX. 2205
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`75
`
`5,712,396
`
`76
`
`Mass Spec (FAB. +ions) rule 525 (M+K). 437 (mu).
`Anal. Calc’d for c,,11,.,o.,1r.,1>s+2. 19 11,0: C. 3424; H.
`5.59; p. 5.39; s. 6.09 Found: c. 34.03; H. 6.88: P. 5.57; s.
`6.02.
`
` 12
`
`(E)-10.14-Di.methyl-l-phosphono-9.13-
`pentadecadiene-1-sulfonic acid. dipotassium salt
`
`A. Dichloi-o[p-[1-hexanolato(2-3-C6:O,]]diJnagnesiurn
`To a stirred solution of 11.00 g (80.0 mmol) of 6-chloro-
`l-propanol (Aldrich) in 20 ml. of THF at —20° C. was added
`27.0 mL (81.0 mrnol) of 3.0M methylmagnesium chloride in
`THF dropwise over 25 nn'.nutes. After 0.5 hours at —-20° C..
`the reaction was allowed to warm to room ternperatine and
`2.88 g (118.0 mmol) of magnesiurn turnings were added and
`the reaction was heated to reflux. The reaction was
`by adding a few crystals of iodine at the start of reflux and
`after 1 hour ofheating. After 2 hours at reflux the reaction
`was cooled to room temperature providing the Grignard
`solution. The rnolarity of the reaction mixture was deter-
`mined by titration: 5.20 mL (2.60 mmol) of a 0.5M solution
`of 2-propanol in benzene was slowly added to a blood red
`solution of 2—2'~biquinoline (indicator) in benzene and 2.0
`ml. of the freshly prepared Grlgnard solution. The endpoint
`color was light green and tire molarity was determined to be
`1.3M.
`
`I0
`
`25
`
`(internal temp.) was added 25 ml. (60 mmol) of 2.4M
`n-buryllithium dropwise over 20 min. The internal tempera-
`u.Ire was not allowed to rise above —69° C. throughout the
`course of the addition. After an additional 15 min., 5.17 g
`(30 mmol) of freshly distilled diethyl chlorophosphate was
`added at a rate to lreep the solution temperature below —69°
`C. The reaction rnixture was stirred for 0.3 h at —'!3° C. and
`for 0.5 h at —40° C. when it was quenched with 125 mL of
`saturated N'H..Cl solution. The reaction mass was warmed to
`room temperature and the TI-IF removed undu reduced
`pressure. The remainder was partitioned between methylene
`chloride and water (3><75 mL). The extracts were dried
`(Na,S0‘), concentrated. and purified by flash chromatogra-
`phy (350 g silica gel] eluting with l:l methylene chloride‘
`ether to provide 5.20 g (67%) of title compound as a
`colorless oil.
`TLC Silica gel (l:l methylene cI1loride.(ethcr) R,=0.3'.".
`‘H NMR (cDC1,. 270 MHz) 55.05 (sept. 1H. J=6.0 Hz)
`4.20 (quint. 411. J=7.0 Hz.) 3.75 (d. 211. 1:1‘.-.5 Hz) 1.50 (d.
`6H. J=6.0 Hz) 1.40 (t. 6H. J=’?.5 Hz) ppm.
`B. 1-(Diethoxyphosphiny1)pentadecanesu1fonic acid.
`1-rnethylethyl ester
`To a suspension of 0.10 g (4.38 mmol) of Nah’. in 7 mL
`of dry DMF at 0° C. under argon was added 1.20 g (4.38
`mmol) of Part A compound over 5 min. to give a yellow
`solution. The reaction was allowed to warm to room tem-
`perature and stir for 0.5 h when 0.55 g (2.00 mmol) of
`tetradecanyl bromide was added in one portion. The reaction
`mixture was stirred for 24 h when it was quenched with 20
`ml, of saturated Nacl solution and diluted with 50 ml. of
`ether. The layers were separated.
`the organics dried
`(Na,S04) and evaporated to provide a crude oil. Flash
`chromatography was performed on 100 g of silica gel
`eluting with 3:7 ethyl acetatefhexane to provide 0.30 g
`(31%) of title compound in the fonn of a pale yellow oil.
`TLC Silica gel (l:l ethyl aeetatefhexanes)
`.50.
`IR (film) 2924. 2853. 1466. 1358. 1260. 1177. 1053.
`1024. 930 cm“.
`‘H NMR (CDCl,. 300 MHz) 85.05 (sep(.. 1H. l=6.0 Hz)
`4.20 (In. 4H) 3.35 (dr. 1H. .l=20.0. 6.4 Hz) 2.10 (m. 2H) 1.45
`(in. 21-1) 1.40 (£1. 6H. l=6.5 Hz) 1.30 (L 6H. J=7.3 Hz) 1.20
`(In. 2211) 0.85 (t. 311. J=6.5 Hz) ppm.
`Mass spec (CI. +-ions) me 433 (M-1-N11,). 471 (M+H).
`34? (M+H—S03CgHa).
`C. 1-Phosphono-1-pentadecanesulfonic acid.
`salt
`To a stirred solution of 0.25 g (0.53 rnmol) of Part B
`eornpoundin5mLofdichlo:romethane at0° C. andinthe
`darkwas added 4.24 g (2.12 mmol) of iodotritnethylsflane.
`The reaction was allowed to stir for 16 h when the solvent
`was evaporated and the semisolid residue pumped (==1 mm
`pressure) for 0.5 h. The residue was dissolved by adding 3
`ml. of 1M (3.0 mmol) KOH solution and freeze dried to
`provide an of white solid. The solidwas purified by MPLC
`on a column of CHP20P gel (25 cm di.arn.xl5 cm height]
`eluting with water (100 mL) followed by a gradient created
`by the gradual addition of 400 mL of acetonitrile to a
`reservoir of 250 ml. of water. Approximately '1 tnLfract:ions
`were collected. The acetonin-ile was removed under reduced
`pressure and the aqueous solution was lyophilized to provide
`0.15 g (62%) of title salt as a white lyophilate.
`TLC Silica gel (6:3:1 n-propanollconc. amt-noniatwater)
`R,=0.40.
`IR (KBr) 3443. 2920. 2851. 1653. 1468. 1215. 1163.
`10-45. 966 cm".
`‘H NMR (D20. 300 MHz) 52.80 (dt. III. J=19.0. 6.0 Hz)
`1.85 (In. 2H) 1.50 (m. 2H) 1.20 (In. 2211) 0.90 (1. 3H. I--6.0
`Hz) ppm.
`
`tripotassium
`
`B. (E)-9.13-Dimethyl-8.12-tetradecadiene-1-ol
`A solution of 21.5 mL (28.0 mmol) of 1.3M Part A
`Grignard reagent in THF and 5.0 ml. of KMPA at 0° C. was
`treated dropwise with 1.21 g (7.0 mmol) of geranyl chloride
`in 7 mL of THF over 7 minutes. After the addition the
`reaction was allowed to warm to room temperature and stir
`for 2 hours. at which point the reaction was diluted with
`ether and quenched with 50 mi. (50.0 mmol] of 1M I-[Cl
`solution. The organic layer was washed two times with
`N'H,Cl solution. dried over MgS0¢ and evaporated to pro-
`vide a crude oil. Flash chromatography was performed on
`125 g of silica gel packed. loaded and eluted with 1:4 ethyl
`acetatefhexanes to provide 1.10 (66%) of title alcohol as an
`amber oil.
`TLC Silica gel (1:9 ethyl acetatezhexancl R,=0.20.
`IR; (CC1. solution) 3636. 2923. 2854, 1450. 137?. 1055
`cm .
`‘H NMR (CDC13. 270 MHz): 55.40 (q. 2H. J='?.0 Hz).
`3.69 (t. 21-1,J=7.0 Hz). 2.25-1.85 (m. SH). 1.75 (s. H). 1.70
`(s. 61!). 1.65 (In. 21-1). 1.39 (s. 7H) ppm.
`MS (CI. N1"-I3. +ions) 256 (M+NH4].
`C. (E)-9.13-Dimethyl-8.12—tct:1'adecad.ien-1-yl iodide
`To a stirred solution of 1.10 g (4.62 mmol) of Part 13
`alcohol and 1.40 mL (10.00 mmol) of trlethyrlarnine in 10
`mL of methylene chloride at 0° C. was added 0.37 ml. (4.80
`name!) of methanesulfonyl chloride dropwise over 15 min-
`utes.Afta1hour at 0° C. the reaction was t|.ilutedw1'th ether
`and washed with aqueous solutions of NH4Cl. NaHCO,. and
`brine. The organic layer was dried (MgS04) and concen-
`trated under reduced pressure to provide 1.42 g (~45 mmol)
`of the crude mesylate. The residual oil was dissolved in 25
`mL of acetone and treated with 3.00 g (20.0 mmol) of NaI.
`The resulting suspension was heated to reflux for 4 hotns
`and diluted with ether. washed with hrine. dried over
`MgS0,_. and concentrated to provide a yellow oil. Hash
`chromatography was performed on 100 g of silica gel
`packed. loaded and eluted with hexanes to provide 1.10 g
`(68% overall yield) of title iodide in the form of a colorless
`oil.
`TUC Silica gel (hexanes) R,-=0.45.
`
`45
`
`65
`
`39 of 93
`
`PENN EX. 2205
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,712,396
`
`77
`
`IR (CC14 solution) 2962. 2%8. 2854. 1450. 1375. cm-‘‘‘.
`‘H NMR (CDC1,, 270 MHz): 55.41 (q. 2H. I='.’.0 Hz).
`3.47 (t. 2H. J=7.0 Hz). 2.40—12.20(In. 6H). 2.11 (quint.. 2H.
`J=7.0 Hz). 1.97 (5. 31-1), 1.89 (s. 6H}. 1.60 (In. SH} ppm.
`MS (CI. NI-1,. -I-ions) 366 (M+N'H.,). 348 (M).
`D.
`(E)-ct-(biethyoxyphosphiny1)-10.14-dimethyl-9.13-
`pentadecadiene-1-sulfonic acid. cyclohexyl ester
`To a stirred suspension of 191 mg (4.77 mol. 2 151;.) of
`soditlmhydride (as a 60% mineral oil dispersion) in 2 mL of
`dry dirnethylformatnide (DMF) at 0° C. was added a solu-
`tion of 1.50 g (4.7? mmol. 2 eq.) of Example IA Part B
`sulfonate in 3 ml. of DMF dropwise over 7 min. The solution
`was warmed to RI‘ and stirred for 50 min. To the resulting
`clear yellow solution was added a solution of 831 mg (2.39
`Inrnol.1eq.)ofPartCiodide 1113 1nLofdryDM§Fdropwise
`over5min.There-action was stirreda.tR1'for ltihdiluted
`with ether (100 mL) and washed with water (50 mL). The
`aqueous layer was extracted with ether (2)610 mL) and the
`combined organic layers were washed with brine. dried
`(MgSCl,,). and concentrated to afiord 1.7? g of a yellow oil.
`Flash chromatography was performed on 300 g of silica gel
`eluting with 30% ethyl acetate in hexanes. Fractions (40 ml.
`cacti) containing clean product by TLC were pooled and
`concentrated to afford, after high vac (0.25 mmflg) removal
`of solvent remnants. 782 mg (61%) of title compound as a
`dear yellow oil.
`TLC Silica gel (10% ether in CH,Cl§): R_,0.50.
`E. (E)-10.l4—Dime£hyl-1-phosphono-9.13-pentadecadiene-
`1-sulfonic acid, dipotasium salt
`1 eq.) of Part D
`To a solution of 515 mg (0.96 mol.
`compound in 10 ml. of methanol at 0° C. was bubbled
`ammonia until the solution was saturateti The reaction tube
`was then sealed and heated at 75° C. for 16 h. The reaction
`mixture was allowed to cool to RI‘ and th concentrated.
`The oily residue was dried by coevaporation with toluene
`(2x). High vac (0.25 rn.I:nHg) removal of solvent remnants
`afforded 480 mg of light yellow oil.
`To a solution of the yellow oil in 4 ml. of dry dichlt»
`romethane at RT was adduil 636 |iL (4.81 11111101. 5 eq.) of
`2.4.6-collidine all at once. To the resulting clear light yellow
`solution was added 890 11L (6.74 mmol. 7 eq.) of biomet-
`n'.r|r:thyl.silane (TMSBr) dropwise over 3 min. As the
`TMSBr was added a white precipitate formed and upon
`completion of TMSBI addition. 1 In]. of dichlorornethane
`was added to the thiclrneaction mixture to facilitate stirring.
`Afier 17 h at R1‘ the reaction was concentrated and the
`resulting semisolid was placed on high vac (0.25 mm Hg)
`for 1 h. The residue was dissolved by adding 4.8 mL (5 eq.)
`of 1M potassium hydroxide followed by 10 ml. of water and
`lyophilizod to afford an olf-white lyophilate. The lyophilate
`was purified by MPLC on a column of CI-IP20P (2.5 cm:a<25
`cm) eluting
`with 150 ml. of water followed by a
`gradient formed by the gradual addition of 400 mL cf 30%
`acetonitrile in water to a reservoir containing 400 mL of
`10% acetonitrile in water. Fractions containing dean prod-
`uct by HPLC (Method 8) were pooled and concentrated. The
`semisolid residue was taken up in wata. filtered. concen-
`trated and finally triturated with acetone to afford. afterhigh
`vac (0.025 mm Hg) removal of acetone remnants. 207 mg
`(43%) of title salt in the form of a white solid.
`TLC silica gel (5:4:l n-propanolmrnmonium
`hyd.roxide:wa.ter): Rf 0.39
`Iii (KBr) 3450(br). 2920. 2851. 1462, 1215. 1080. 1040
`cm‘ .
`
`‘H NMR (D20. 300 MHz) 55.01 (t. 1H. .l=7.6 Hz) 4.96
`(t. 111. J=7.0 1{z)2.8'? (dt. 1H. J=18.l. 5.4 Hz) 1.90 (m. 2H)
`- 1.82 (111. 611) 1.4-9(s. 3H) 1.43 (m. 2H) 1.42 (s. 6H) 1.15 (bs.
`3H)PPm-
`
`35
`
`78
`"C NMR 03,0. 75.6 MHZ) 5135.7 132.7 125.5 124.7
`61.0 (d. Jc,.= 126 Hz) 39.4 29.6 29.4 292 (d. J,,,=7 Hz) 29.1
`29.1 23.1 272 263 25.3 17.4 15.6 ppm
`MS (FAB. +ions) ml: 473 (M+H). 511 (M+K). 549
`(M—H+K).
`Anal. Calc‘d for C,-,.l{,,05PSK,.1.4 11,0: c. 41.01; 11.
`6.84; s. 6.44; P. 6.22 Found: C. 41.19; 11. 6.52; s. 6.30; P.
`5.95
`
` 13
`
`(E.E)-6.10.l4—'I1'i.Inet.hy1-1-phosphono-5.9.13-
`pentadecatriene-1-sulfonic acid. phenyl ester.
`dipotassiurn salt
`
`A. Methanesulfonic acid, phenyl ester
`To a solution of 4-0.0 g (0.42 mol. 1 sq.) of phenol in 250
`rnLofdicl1lorornethane at 0° C. was added 250 mL (1.8 11101.
`4.2 54;.) of triethylamine. After 5 min. 49.3 mL (0.64 11101. 1.5
`sq.) of methanesulfonyl chloride was added dropwise over
`20min. Theresulting cloudy yellow solution was warmed to
`RT and stirred for 14 h. The reaction was partitioned
`between ether (250 n:IL) and water (100 mL) and the
`resulting organic layer was washed with cold 6N hydrochlo-
`ric acid {2><200 mL). The combined aqueous layers were
`extracted with etha (2)-<50 mL) and the combined organic
`layers were washed with water (100 mL). saturated sodiuin
`bicarbonate (211) mL). la-ine (200 mL). dried (MgS04) and
`concentrated. Recrystallization of the orange solid from
`isopropanol a1fcrded4-4.94 g (61%) ofthe title compound as
`light yellow crystals; mp 58.0°—58.5° C.
`TLC Silica gel (25% ethyl acetate in hexanes): Rf 0.29.
`B. (Dieti|oxy'phosphinyl)methanesu1fonic acid. phenyl ester
`To a turbid solution of 174 ml. (0.174 mol. 1 eq.) of
`potassium bis(t::imet11ylsily1)arnide (20% by weight in tet-
`rahydrofuran (THY) from Callory Chem.) at -83° C.
`(inte