NZ224734A

NZ224734A - Organophosphorus hmg-coa reductase inhibitors, and pharmaceutical compositions

Info

Publication number: NZ224734A
Application number: NZ224734A
Authority: NZ
Inventors: Michael Joseph Sofia; Donald Steven Karanewsky; Michael Christopher Badia; Scott Adams Biller; Eric Michael Gordon
Original assignee: Squibb & Sons Inc
Priority date: 1987-05-22
Filing date: 1988-05-20
Publication date: 1991-04-26
Also published as: IE63715B1; GB2205838A; FI87927B; PL157761B1; PT87540B; DK277388D0; FR2615516B1; AU1650288A; PH25581A; FR2615516A1; CH675582A5; FI882385A0; IL86463A; SE9201588D0; CN1030761A; PH26578A; GB2205838B; GB8811931D0; NO882219D0; HUT47123A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £24734 22473 DRAWII Priority PatefsjL P7... 2), ority PatefsiL Complete Specification Filsdi^Q.' Class: C6] .Vrfjl 3o.. 5>.?f bh....... Publication Date: .... .E6.APfl.t93l... P.O. Journal, No: No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION "PHOSPHOHUS-CCNT&INING HMG-CcA REDUCTASE INHIBITORS, ' INTERMEDIATES AND METHOD" 31/We, E R SQUIBB & SONS INC, a corporation of Delaware, USA, of Lawrenceville-Princeton Road, Princeton, New Jersey, USA c. hereby declare the invention for which X / we pray that a patent may be granted toXHX/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page 1A.) 224734 O -lA- HXlOb 15 20 . 25 PHOSPHORUS-CONTAINING HMG-CoA REDUCTASE INHIBITORS, NEW INTERMEDIATES AND METHOD The present invention relates to new phosphorus-containing compounds which inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and thus are useful in inhibiting cholesterol biosynthesis, to hypocholesterolemic compositions containing such compounds, to new intermediates formed in the preparation of such compounds and to a method of using such compounds for such purposes. F. M. Singer et al., Proc. Soc. Exper. Biol♦ Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.. *1 224 7 3 4 HXlOb -2- 10 15 20 25 30 Endo et al in U. S. Patents Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin I. 1165 (1976)) to have a complex mevalonolactone structure. GB 1,586,152 discloses a group of synthetic compounds of the formula in which E represents a direct bond, a C1_3 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents. The activity reported in the U.K. patent is less than 1% that of compactin. U. S. Patent No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic ■compounds having the structure a^fV 35 2 2 4 7 HXlOb -3- wherein A is H or methyl; E is a direct bond, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH=CH-; R2 and R3 are each selected from H, halogen, C1-4 alkyl> C1-4 haloalkyl, phenyl, phenyl substituted by halogen, C1-4 alkoxy, C2_8 alkanoyloxy, C^_4 alkyl, or C1-4 haloalkyl, and 0R4 in which R4 is H, C2_8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C^_3 alkyl, alkyl, cinnamyl, C1-4 haloalkyl, allyl, cycloalkyl-C1-3-alkyl, adameuityl-C1_3-alkyl, or substituted phenyl C1_3-alkyl in each of which the substituents are selected from halogen, C^_4 alkoxy, C1-4 alkyl, or C1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C1-3-alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula. WO 84/02131 (PCT/EP83/00308) (based on U. S. application Serial No. 443,668, filed November 22, 1982, and U. S. application Serial No. 548,850, filed November 4, 1983), filed in the name of Sandoz AG discloses heterocyclic analogs of mevalono lactone and derivatives thereof having the structure a, n / *7 LL*\! HXlOb -4 R "4 wherein one of R and R_ is and the o R, 5 R 5a other is primary or secondary C1_6 alkyl, C3_6 cycloalkyl or phenyl-(CH2)m~, wherein R4 is hydrogen, alkyl, C1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5 is hydrogen, alkyl, cr_3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5a is hydrogen, C1_2 alkyl, C1_2 alkoxy, fluoro or chloro, and m is 1, 2 or 3, with the provisos that both R^ and R^a must be hydrogen when R4 is hydrogen, R5a must be hydrogen when Rg is hydrogen, not more than one of R- and Rc is trifluoromethyl, not more than one of % o R4 and R5 is phenoxy and not more than one of R4 and R5 is benzyloxy, R2 is hydrogen, C1-4 alkyl, C3_6 cycloalkyl, C1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R3 is hydrogen, C1_3 alkyl, C^_3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R3 must be hydrogen when R2 is hydrogen, not more than one of R2 and R3 is trifluoromethyl, not more than one of R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy. OA f 1 £ L 4 / HXlOb -5- X is -<CH2>n- or -CH=CH- (n=0, 1, 2 or 3), I* 5 4 3 2 1 Z is -CH-CH-—C—CHo-C00H II I 2 I 2 5 OH OH wherein R& is hydrogen or C1-3 alkyl in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a 6 lactone thereof or in salt form. 10• GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure Me ^ ^Me 15 20 30 wherein = 1-3C alkyl; Z is a gp. of formula Z^ or -CHCH.CHCH-COOR_ A 2 4 2 7 25 OH OH (zx) (z2) R7 = H, a hydrolysable ester gp. or a cation. 9 9 7 L "T / HXlOb -6- European Patent No. 164-698-A discloses preparation of lactones useful as anti-hyper-cholesterol emic agents by treating an amide with an organic sulphonyl halide R5SC>2X, then removing the protecting group Pr. fw 10 R i PrO "tT^3R4 R5S02X H°trr 15 20 wherein X = halo; Pr = a carbinol-protecting group; R1 = H or CH3; R3, R4 = H, 1-3C alkyl or phenyl-(l-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo; 2 R = a group of formula (A) or (B): 25 (B) 30 Q = R5—C- or R6-CH ; ^ I ! 1 CH- . r\ O /. 7 jL ^ / HXlOb -7- o 10 15 20 25 30 R = H or OH; R = H or CH3; a, b, c and d = optional double bonds; 7 R = phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo; R®, = 1-3C alkyl or halo; R^ = 1-3C alkyl, phenyl or mono- or di-(l-3C alkyl)phenyl. Anderson, Paul Leroy, Ger. Offen. DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure -CHCH-CHCH-CO-R A OH i OH 2 2 wherein R is alkyl, Z = Q, Q ; R = H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment df atherosclerosis. WO 8402-903 (based on U.S. application Serial No. 460,600, filed January 24, 1983) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure 35 r\ HXlOb -8- wherein the two groups Ro together form a radical of formula 8 7 6 5 C = C - C = C or -<CH2)4- 10 15 20 25 30 wherein R2 is hydrogen, alkyl, C^_4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R3 is hydrogen, C1-3 alkyl, C1-l3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R2 and R3 is trifluoromethyl, not more than one of R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy, Rj^ is hydrogen, C1_g alkyl, fluoro, chloro or benzyloxy, R4 is hydrogen, C1-4 alkyl, C1_4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, Re- is hydrogen, C^_3 alkyl, C^_3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5a is hydrogen, C-^-2 alkyl, C1_2 alkoxy, fluoro or chloro, and with the provisos that not more than one of R4 and R5 is trifluoromethyl, not more than one of R4 and R5 is phenoxy and not more than one of R4 and Rg is benzyloxy, X is -(CH2)n-, \ ;CH2»9 c = c -<ch2)^ \ i o 22 HXlOb 34 -9- wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, Z is l 6 5 4 3 2 1 -CH-CH0—C-CH„-C00H I 2 I 2 OH OH II wherein Rg is hydrogen or C1-3 alkyl, with 10 the general proviso that -X-Z and the bearing phenyl group are ortho to each other; in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a 6 lactone thereof or in salt form. 15 U. S. Patent No. 4,613,610 to Wareing (assigned to Sandoz) discloses a series of 7-pyrazolo-3,5-dihydrohept-6-enoic acid HMG-CoA reductase inhibitors of the structure W 20 25 X-Z 30 wherein R.^ is C1_galkyl not containing an asymmetric carbon atom, each of R2 311(1 Rs is independently hydrogen, C-^alkyl, n-butyl, i-butyl, t-butyl, i 4 >w' 10 15 20 v 22 4 7 3 4 HXlOb -10- C1_3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy, each of R3 and R& is independently hydrogen, C1-3alkyl, C^^alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, each of R4 and R7 is independently hydrogen, C^_2alkyl, C^_2alkoxy, fluoro or chloro, with the provisos that not more than one of R2 and R3 is trifluoromethyl, not more than one of R2 and R3 is phenoxy, not more than one of R2 and R3 is benzyloxy, not more than one of Rg and R& is trifluoromethyl, not more than one of R$ and Rg is phenoxy, and not more than one of Rg and Rg is benzyloxy, X is -(CH2)m-, -CH=CH-, -CH=CH-CH2- or -CH2-CH=CH-, wherein m is 0, 1, 2 or 3, and Z is ?10 •CH-CHo-C-CHo-C00R.. t I i | c li. OH OH -CH or \ OH R. 10 0 CH_ 2 II O wherein R1Q is hydrogen or C1-3alkyl, and R1;l is hydrogen, R12 or M, wherein R12 is a physiologically acceptable and hydrolyzable ester group, and M is a cation, with the provisos that (i) the -X-Z group is in the 4- or 5-position of the pyrazole ring, o w o 10 22 4 7 3 4 HXlOb -11- and (ii) the group and the -X-Z group are ortho to each other. WO 8607-054A (Sandoz-Erfindungen) discloses imidazole analogues of mevalonolactone, useful for treating hyperlipoproteinaemia and atherosclerosis, which have the formula (I) 15 R1 = alkyl, cycloalkyl, adamantyl-1 or R4, Rg, Rg-substituted phenyl (gp. A); R2 = alkyl, cycloalkyl, adamantyl-1 or R?/ Rg, Rg-substituted phenyl (gp. B); R3 = h, alkyl, cycloalkyl, adamantyl-1, 20 styryl or R1Q, R^, R12~substituted phenyl (gp, c); x = -(ch2)m-, -ch=ch-, -ch=ch-ch2- or -ch2-ch=ch-; m =•0-3; z = -ch(oh)-ch2-c(r13)(oh)-ch2-coor14 (gp. 25 a), -q-ch2-c(r13)(oh)-ch2-coor14 (gp. c) or a gp. of formula (b): 22 4 7 3 4 -12- HXlOb "•Vf» i U 10 15 20 25 30 CH„ / \ •CH OH \ 13 ) CH, \ / ' C li o Q = CO or -C(0R15)2-; R15 = primary or sec. alkyl; each R15 being the same; or R1S + R1S = (CH2)2 or <CH2)3; 13 = H or 1-3C alkyl; R14 = H' R16 or M? R^g = ester gp.; M = cation; provided that Z may be gp. (c) only when X is CH=CH or CH2-CH=CH and/or when R13 = 1-3C alkyl; R4, R7 and R1q = 1-3C alkyl, n-, i- or t-butyl, 1-3C alkoxy, n- or i-butoxy, CF3, F, CI, Br, phenyl, phenoxy or benzyloxy; R5, Rq and R1;l = H, 1-3C alkyl, 1-3C alkoxy, CF3, F, CI, Br, COOR17, N(Rlg)2, phenoxy or benzyloxy; R^7 H, Rjg or M; 18 = 1-3C alkyl, n, i- or t-butyl or benzyl; R19 = alkyl; Rg, Rg and R12 = H, 1-2C alkyl, 1-2C alkoxy, F or CI; provided that © 22 4 7 HXlOb -13- (1) not more than one substituent of each 5 O 10 15 20 O 25 6 of gps. A, B and C is CF^, not more than one substituent of each of gps. A, B and C is phenoxy, and not more than one substituent of each of gps, A, B and C is benzyloxy; (2) when Z is gp. (c; Q = C(0R15)2), the compound is in free base form and either (i) is R16 and each R17 is independently Rlg or (ii) R14 is M and each R17 is independently Rlg or M; and (3) when *14 and/or at least one R^7 is M, the compound is in free base form. Unless otherwise stated, all "alkyl" gps. are 1-6C and do not contain an asymmetric C; and "cycloalkyl" has 3-7C. WO 8603-488-A (Sandoz AG) discloses indene analogues of mevalolactone, useful as hypolipoproteinaemia and anti-atherosclerotic agents, in free acid form or in the form of an ester or delta-lactone or in salt form which have the formula 2 30 R = H or primary or secondary 1-6C alkyl; R^ = primary or secondary 1-6C alkyl; or R + R1 = (CH_ ) or (Z)-CH_-CH=CH-CH- ; 12 m 2 2 22 4 7 ; HXlOb -14- m = 2-6; Rq = 1-6C alkyl, 3-7C cycloalkyl or R4, R5, Rg-substituted phenyl; R2' R4 = H/ 1""4C 1-4C alkoxy (except 5 t-butoxy), CFg, F, CI, phenoxy or benzyloxy; R3 and R5 = H, 1-3C alkyl, 1-3C alkoxy, £) CF3, F, CI, phenoxy or benzyloxy; Rg = H, 1-2C alkyl, 1-2C alkoxy, F or CI; provided that there may only be one each of 10. CF3, phenoxy or benzyloxy on each of the phenyl and indene rings; X = (CH2)n or -(CH2)q-CH=CH(CH2)q-; n = 1-3; both q's = 0, or one is 0 and the other is 15 1; Z = -Q-CH2-C(R10)(OH)-CH2COOH, in free acid form or in the form of an ester or delta-lactone or salt; Q = CO, -C(OR?)2- or CHOH; 20 R1?s = the same primary or secondary 1-6C Q alkyl, or together are (CE^^ (CH2^3; R10 = H or 1-3C alkyl; provided that Q may be pther than CHOH only when X is CH=CH or CH2-CH=CH and/or R1Q is 1-3C 2 5 alkyl. U. S. Patent No. 4,647,576 to Hoefle et al (Warner Lambert) discloses new C- and N-substituted pyrrole(s), useful as hypolipidaemic and hypocho-lesterolaemic agents, which have the formula o r* -15- 22 4 7 3 4 HXlOb o o H. vOH (I) G • G 10 15 20 25 30 H .OH COOH (II) X = -CH2-, -CH2CH2- or -CH(CH3)CH2-; = 1- or 2-naphthyl; cyclohexyl; norbornenyl; phenyl optionally substituted by F, CI, OH, CF3, 1-4C alkyl, 1-4C alkoxy or 2-8C alkanoyloxy; 2-, 3- or 4-pyridinyl or their N-oxides; or -O Rc.hal e / 5 R& = 1-4C alkyl; hal = chloride, bromide or iodide; R2 and R3 = H, CI, Br, CN, CF3, phenyl, 1-4C alkyl, 2-8C carboalkoxy, -CH20Rg or -CH2OCONHR?; Rg = H or 1-6C alkanoyl; -16- HXlOb R7 = alkyl or phenyl optionally substituted by CI, Br or 1-4C alkyl; or R2 and R3 together = -(CH2)^~' -CH2OCH2-, -CON(Rg)CO- or -CON(R9)N(R10)CO-; n = 3 or 4; R8 = H, 1-6C alkyl, phenyl or benzyl; Rg and R10 = H, 1-4C alkyl or benzyl; R4 = 1-4C alkyl, cyclopropyl, cyclobutyl or CF3. European patent application 0 221 025 Al (Sandoz AG) discloses heterocyclic analogs of mevalonolactone and derivatives thereof having the formula Rc Rb wherein Ra is a group -X-Z, Rb is R2, Rc is R3, Rd is R^ and Y is a group -N- or K Ra is R^ Rb is a group -X-Z, Rc is R2, Rd is R3 and Y is O, S or a group -^T-; R4 Rx, R2, R3 and R4 independently are C1_4 alkyl not containing an asymmetric carbon atom, C3_7cycloalkyl or a ring 22 4 7 34 -17- HXlOb O o 10 15 20 25 30 or in the case of R3 and R^ additionally hydrogen or for Rg when Y is 0 or S \ /R18 /C = R17 R19 whereby R17 is hydrogen or C1-3alkyl and Rlg and Rig are independently hydrogen, C1-3alkyl or phenyl; each R5 is independently hydrogen, C1<_3alkyl, n-butyl, i-butyl, t-butyl, C1_3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy; each R^ is independently hydrogen, C^_3alkyl, C^_3alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy and each R7 is independently hydrogen, C^_2alkyl' C^_2alkoxy, fluoro or chloro with the proviso that there may only be one each of trifluoromethyl, phenoxy or benzyloxy in each ring A present. X is (CH2)m or (CH,)_CH=CH(CH,)_, m is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1. b Z is -CH-CH_-C-CH_-COOH I 2 | 2 OH OH wherein Rg is hydrogen or C^^alkyl, in free acid form or in the form of an ester of 0-lactone thereof or in salt form as appropriate © Lu HXlOb 2 4 7 -18- o which compounds are indicated for use as hypolipo-proteinemic and anti-atherosclerotic agents. Tetrahedron Letters, 29, 929, 1988, discloses the synthesis of a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor of the structure O o 10 15 20 25 where R is Na or C2H5, European patent application 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5-thia-w-aryl-alkanoic acids having the structural formula: HO I OX S(0) I E I z n wherein Z is: HXlOb 19 R r' 3 2 R f R 4 R R' 5 n is 0, 1 or 2; e is -ch2—, -ch2-ch2-, -ch2-ch2-ch2-, -CH=CH-CH2-; or -CH2-CH=CH-; R^, R2 and R3 are, e.g., hydrogen, chloro, bromo, fluoro, C^-alkyl, phenyl, substituted phenyl or 0R7 in which R7 is, e.g., hydrogen, C2_8alkanoyl, benzoyl, phenyl, substituted phenyl, C1_galkyl, cinnamyl, C^^aloalkyl, allyl, cycloalkyl-C1-3alkyl, adamantyl-C1_3-alkyl, or phenyl C,3 alkyl; R , R5 and R6 are hydrogen, chloro, bromo, fluoro or C^_3 alkyl; and X is, e.g., hydrogen, C1-3 alkyl, a cation derived from an alkali metal or is ammonium. Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity. French patent application 2,596,393 A filed on April 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: © -20- 22 HXlOb >. ■ o £ k S 3 o o h $/or3 Rt00C-CH,-C-CHo-P 1 2 I \ OH 0R4 5 wherein and R2 = H, lower alkyl or optionally substituted aralkyl; R3 and R4 = H, lower alkyl or optionally substituted aryl or aralkyl. 10 These comounds are disclosed as giving greater reductions in cholesterol/ triglyceride and phospholipid levels than meglutol. European patent application 142,146-A (Merck & Co., Inc) discloses mevinolin-like compounds of 15 the structural formula: HO ^ 0 .1 20 V"V OR' V^O wherein: 25 R1 is, e.g., hydrogen or C1_4alkyl; E is -CH2CH2, -CH=CH-, or -(CH2)r-; and Z is 1) 22 4 7 3 4 HXlOb -21- i O o o 10 15 20 25 9 9 wherein X is -o- or -NR wherein R is hydrogen or C1_3alkyl; R7 is C- Qalkyl; and a R is hydrogen or CH3; 2) 10 11 12 wherein R , R and R are independently, e.g., hydrogen, halogen or C1_4alkyl; 3) I rsfc-1 o 22 4 7 3 4 O 4> HXlOb -22- 14 . wherein n is 0-2 and R is halo or C^^alkyl; or 10 These compounds are HMG-CoA reductase inhibitors. 15 In accordance with the present invention, there is provided phosphorus-containing compounds 20 which inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA Reductase) and thus are useful as hypocholesterolemic agents and include the following moiety 25 O (< -P-CH0 -CH-CH0 -CO- ^ i 24h 2 Z 30 wherein X is -(CH2)a~, -CH=CH-, -C=C- or -CH20- (where O is linked to Z), "a" is 1, 2 or 3, and Z is an "hydrophobic anchor". The term hydrophobic anchor as employed herein refers to a lipophilic group which when o 22 4 7 3 4 HXlOb -23- linked to the HMG-like upper side chain of the molecule by the appropriate linker ("X"), binds to a hydrophobic pocket of the enzyme not utilized in binding the substrate HMG CoA, resulting in 5 enhanced potency relative to compounds where Z=H. In preferred embodiments, the compounds of (^) the invention have the formula I 0 ^ 10 i r-p-ch~-c-ch_-c0orx 1 2 | 2 2 x oh i wherein R is OH or lower alkoxy; 15 Rx is H or lower alkyl; x is ch2, -ch2ch2-, -ch2ch2ch2-, -ch=ch-, —C= C— or -CH20- (where O is linked to Z); Z is a hydrophobic anchor; and including pharmaceutically acceptable 20 salts thereof. The terms "salt" and "salts" refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts like, lithium, sodium and potassium salts 25 (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, such as amine like salts, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino 30 acids like arginine, lysine and the like. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product. O '/ O / -^47 O 20 HXlOb -24- Examples of hydrophobic anchors which may be included in accordance with the present invention include, but are not limited to 10 15 O 25 'tij R*° -N \ -=-N rio * Ilk? Ik o 20 -25- hxlob O o Rv ,12 ra rb 10 15 3 4 R'V^N^ R fs r16 r23a c=c \ 22 > r ,23a o 25 or alkyl m £ c 4 / HXlOb -26- wherein the dotted lines represent optional double bonds, for example, O o o 10 IS 20 25 alkyl alkyl alkyl or J uii-bl* 22 4 7 -27- HXlOb n n alkyl O kJ 10 15 20 25 1 O wherein R , R , R and R may be the same or different and are each independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or OR^ wherein R^ is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl. Where Z is alkyl 30 5 5' R and R are the same or different and are H, lower alkyl or OH; n ^ / *? 1 c c 4 / 5 HXlOb -28- O 0 °, 6 H »' R is lower alkyl-C such as CR.-CH^-C-C-, i V" \ 7 CH3 R or arylCH,-; R is lower alkyl, hydroxy, oxo or halogen; q is 0, 1, 2 or 3, and 7 R is H or lower alkyl. 10 15 Where Z is O. 20 I, N —N o 25 30 or eVnVr4 K 22 4 7 3 4 HXlOb -29- ,3 „4 R13 14 R is hydrogen, lower alkyl, lower alkoxy, 14a . R is hydrogen, lower alkyl, lower one of R and R is —v and R14a the other is lower alkyl, cycloalkyl or phenyl-(CH,) -, p is 0, 1, 2, 3 or 4; ™ 13 wherein R as hydrogen, lower alkyl, lower alkoxy, (except t-butoxy), halogen, phenoxy or benzyloxy; R14 halogen, phenoxy or benzyloxy; 14a . R is hydrogen alkoxy, or halogen; and 14 14a with the provisos that both R and R must be hydrogen when R13 is hydrogen, R14a must be 14 hydrogen when R is hydrogen, not more than one of 13 14 . R and R is trifluoromethyl, not more than one of 13 14 . 13 R and R is phenoxy and not more than one of R 14 . and R is benzyloxy; Q R is hydrogen, alkyl, C3_6 cycloalkyl, C1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; Q R is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or g benzyloxy, with the provisos that R must be O hydrogen when R is hydrogen, not more than one 8 9 of R and R is trifluoromethyl, not more than 22 4 7 3 4 HXlOb tit 1 ! , -30- 8 9 one of R and R is phenoxy, and not more than 8 9 one of R and R is benzyloxy. R10 and R11 are independently selected from hydrogenalkyl, cycloalkyl, adamantyl-1 or O 10 -<CH2>g .14 R 13 14 14a where R , R and R are as defined above and q=0, 1, 2, 3 or 4. 15 . Y is 0, S or N-R Where Z is 10 20 .12 o 25 R is H or primary or secondary 1-6C alkyl; Rb is primary or secondary 1-6C alkyl; or Ra + Rb is (CH2)r or (cis)-CH2-CH=CH-CH2 ; r = 2, 3, 4, 5 or 6; o 20 22 4 7 3 4 HXlOb -31- I . „12 R is lower alkyl, cycloalkyl or /—v r13 -J/ .14 \±Ar" R 10 wherein R8, R9, R13, R14 and R14a are as defined above. When Z is 15 r3 : R4 A E16 ,15 „16 R and R are both H, CI, Br, CN, CF3, phenyl, ^ 1-4C alkyl, 2-8C alkoxycarbonyl, -CH-OR17 or i a -CH-OCONHR ; 17 R is H or 1-6C alkanoyl; 18 25 R is alkyl or phenyl optionally substituted by F, CI, Br or 1-4C alkyl; ^ or R15 and R16 taken together are -(CH^) 1 <4 90 ?1 -CH2OCH2-, -CON(RX*)CO-, or -CON(Rzu)N(R*X)CO-; £ HXlOb 2 4 7 34 -32- S = 3 or 4; ,19 _ R"1"' = H, 1-6C alkyl, phenyl or benzyl; 90 PI R and R are H, 1-4C alkyl or benzj with the added proviso that when Z is 10 X can only be -CH^-, -CE^CB^- or -C^CHgCHg' Where Z is 15 20 O 25 r™ c=C \22 ,23a 22 4 7 3 4 HXlOb -33- O .22 is lower alkyl, cycloalkyl, adamantyl-1 or -(CH2)t-<(5) O 5 t = 1, 2, 3 or 4; R23 and R23a are the same or different and are each independently selected from hydrogen, lower alkyl, lower alkoxyl (except t-butoxy), halogen, phenoxy or benzyloxy; and 23a 10 with the provisos that R must be 23 . hydrogen when R is hydrogen, not more than one of R23 and R23a is trifluoromethyl, not more than 23 23a one of R and R is phenoxy, and not more than 23 23a one of R and R is benzyloxy. 15 Where X is -CHjO- (carbon attached to P and 0 attached to Z), the hydrophobic anchor Z will be a phenyl or naphthalene type anchor such as Q 20 or ,2b 25 o 25 kJ 22 4 7 3 4 HXlOb -34- Thus, the compounds of formula I encompass 0 ii v la R-P-CH0-CH-CH~-C00R 1 2 * 2 2 C OH in C I z 0 |l v lb R-P-CH„-gH-CH„-C0oR 1 2 £ 2 2 10 ch oh II I C] II CH (cis) 0 I' x 15 ic r-p-ch2-ch-ch2-co2rx ch oh li ch (trans) 1 z 20 O " x ^ Id R-P-CH2-CH-CH2-C02R ^ CH0 OH I 2 CH I 2 z f OhMI ^ 47 HXlOb -35- 0 " x Ie r-p-ch2-ch-ch2-c02r CH0 5H , 1 2 z 0 If R-P-CH.-CH-CH«-C0oRX 1 2 = 2 2 (p2)3 OH Z 0 I' x Ig . R-P-CHo-CH-CHo-C0oR , | 2. a Z /L CH0 OH 1 ^ 0 1 z The term "lower alkyl" or "alkyl" as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 12 carbons in the normal chain, preferably 1 to 7 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl-pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including a halo-substituent, such as F, Br, CI or I or CFg, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent, an alkyl-cycloalkyl substituent, hydroxy, and alkylamino substituent, an alkanoylamino substituent, an aryl-carbonylamino substituent, a nitro substituent, a 9 o / "j & 7 HXlOb -36- cyano substituent, a thiol substituent or an alkylthio substituent. The term "cycloalkyl" as. employed herein alone or as part of another group includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be substituted with 1 or 2 halogens, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 alkanoyl-araino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups, and/or 1 or 2 alkyl-thio groups. The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be 1, 2 or 3 lower alkyl groups, halogens (CI, Br or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy group, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3 haloalkyl groups, 1, 2 or 3 halophenyl groups, 1, 2 or 3 allyl groups, 1, 2 or 3 cyclo-alkylalkyl groups, 1, 2 or 3 adamantylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoyl-amino groups, 1, 2 or 3 arylcarbonylamino groups, 1, 2 or 3 amino groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, 1, 2 or 3 thiol groups, and/or -37- 22 4 7 HXlOb 1, 2 or 3 alkylthio groups with the aryl group preferably containing 3 substituents. The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein alone or as part 5 of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl. The term "lower alkoxy", "alkoxy", or "aryloxy" or "aralkoxy" as employed herein alone or 10 as part of another group includes any of the above lower alkyl, alkyl, aralkyl or aryl groups linked to an oxygen atom. The term "lower alkylthio", "alkylthio", "arylthio" or "aralkylthio" as employed herein alone 15 or as part of another group includes any of the above lower alkyl, ' alkyl, aralkyl or aryl groups linked to a sulfur atom. The term "lower alkylamino", "alkylamino", "arylamino", "arylalkylamino" as employed herein 20 alone or as part of another group includes any of the above lower alkyl, alkyl, aryl or arylalkyl groups linked to a nitrogen atom. The term "alkanoyl" as used herein as part of another group refers to lower alkyl linked to a 25 carbonyl group. The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, iodine and CF3, with chlorine or fluorine being preferred. Preferred are those compounds of formula I 30 which have the following structure 22 4 7 3 4 HXlOb -38- II R 0 CH, H CH, \ i' / 2\l/ 2\ x P C CO„R I - 2 x - Z OH wherein R is OH, OLi or CH30; Rx is Li or H; x is -ch2-, -ch2ch2-, -ch2ch2ch2, -ch=ch-, 10 R R* wherein R"*" is phenyl or phenyl which includes an alkyl and/or halo substitutent, 15 30 R1 is cycloalkylalkyl such as or R1 is benzyloxy which includes a halo 2 2a R and R are the same and are hydrogen, cyclohexylmethyl, or R1 20 substituent; R2 ar halogen or lower alkyl; Z may also preferably be 25 1 2 wherein R and R are as defined immediately above with respect to the compound of formula II; r3 Z may be also preferably be ^ 35 R4 a 2? tUM £xju HXlOb -39- 10 wherein R is substituted phenyl, lower alkyl, cycloalkyl or phenylalkyl and R is substituted phenyl, lower alkyl, such as isopropyl, cycloalkyl or phenylalkyl; or „6 Z may also preferably be /N/W wherein R^ is H, CH^ or OH and is 15 r or (substituted)phenylmethyl • ' CH, R' wherein R is H or CH3. Z may also preferably be 20 u 25 ? u 30 3 4 wherein at least one of R and R are phenyl or 3 4 . substituted phenyl and the remaining R or R is lower alkyl. The compounds of formula I of the invention may be prepared according to the following reaction sequence and description thereof. O ' o o o Reaction Sequence A. Preparation of Compounds of Formula I where X is -CH=CH-?6H5 OSi-C(CH3)3 I C6H5 P(Oalkyl) III 0 ii I-CH2-CH-CH2-C02alkyl A Arbuzov Reaction alkyl0-P-CH2-CH-CH2-C02alkyl ^ 1 JL t Oalkyl Ssi-C (CH-,) C6H5 C6H5 IV 1- (CH3)3SiBr, CH2C12 2. H20 O II Phosphorus ester cleavage ■> H0-^-CH2-CH-CH2-C02alkyl OH 0 f Si-C(CH A)o / \ 33 C6H5 C6H5 IV alkanol-DCC pyridine * O I alkyl0-P-CH2-CH-CH2C02alkyl OH 0 1 Si-CtO^ C6H5 C6H5 V « X t—1 o cr ro {X3 VI "vvj o o o o > o VI 1. 2. (CH3)3SiN(C2H5)2(TMSNEt2) (COCl)2; CH2C12 (Acid CI Formation) » o II alkyl0-P-CH2-CH-CH2C02alkyl CI O I Si-C(CH^) X \ C6»5 C6H5 VII CHO I Z VIII CBr Ph3P 4' Wittig -> CH=CBr-I 2 Z IX Dehydrohalogenation > 1) n-BuLi 2) H20 C=CH I Z I t—' I 1) Li anion formation (n-BuLi, THF) X 2) Condensation with phosphono-chloridate VII 0 II alkyl0-P-CH2-CH-CH2-C02alkyl ' 0 I CEC i Z ^ Si-C(CH-)o C6H5 C6»5 XI w X M o or ?v> to 04 o o O ' o xi 1) Silyl ether cleavage (n-C4H9)4NF, CH3COOH, THF 2) Hydrolysis (LiOH, dioxane^ 0 it h0-p-cho-ch-choc0oh | 2 » 2 2 c 5h ill c 1 z IA XI Selective reduction H2, 10% Pd-C MeOH, 1 atm ^ alkyl0-P-CH»-CH-CH9C09alkyl 1 2 _ . ch 0 ^ I z-ch (cis) Si-C(CH,)^ / \ 33 C6«5 C6H5 1) Silyl ether cleavage 2) Hydrolysis > O ii H0-P-CH2_CH-CH2-C02H . CH OH // Z-CH XII (cis) IB G C) O S" XII Reduction H2, 10% Pd-C MeOH, 50 psi 0 ii alky10-P-CHo-CH-CHo-C0oalkyl .. c., , .. , \ 2 ~ 2 2 ■* 1) Silyl ether cleavage /H2 ^ 2) Hydrolysis CH, I ii-C(CH-) 0 / \ 33 C6«5 C6H5 XIII 0 II H0-P-CHo-CH-CH_C0oH 1 2 = 2 2 /H2 OH CH- I 2 ID o o o 0 # Reaction Sequence B. Preparation of compounds I where X linkage (-CH=CH-) is trans, that is 0 il H0-P-CH2-CH-CH2C02H .CH OH // CH (trans) I Z IC H I C HI <r Hydrostannation (n-C4H9)3SnH AIBN, 120 C -» // CH I Z Sn(n-C4H9)3 CH XV Iodination I2, Et20 * // CH I Z I I CH XVI 1) n-C4H9Li (Metallation) 2) VII (Condensation) l I cg X 9 ro ro 4^ 04 o M AlkylO-P-CH2 ^CH (trans) — CH-CH2C02alkyl OSi-C(CH^), / \ *3 C6»5 C6H5 1.) silyl ether cleavage > 2.) LiOH, Dioxane (Hydrolysis) XVII 0 l» H0-P-CH2-CH-CH2C02H CH 5H CH (trans) Z IC Reaction Sequence C. Alternative Preparation of Compound I where X linkage (-CH=CH-) is trans, that isf compound IC- CHO I z VIII XXI Condensation HO LiCH2P(Oalkyl)2 — > THF, -78 C V |(Oalkyl) Hydrolysis aqueous LiOH dioxane * CH-CH~ I 2 Z XX ?• -a%10-P-0H ^CH CH I Z (trans) XXII H^)Elimination p-TsOH benzene . A Acid Cl formation 1. (CH3)3SiN(C2H5)2 (TMSNEt2) 2. (COCl)2, Cat. DMF CH2C12 ^ CH I Z 0 n P-(Oalkyl)2 CH (trans) XXI 0 II alkylo-P-Cl 'J* (*H (trans) Z XXI11 » 'c> » »»1" fV| rll f'**1 l-M.'l/fc'.U-Av/J*-*! V i . u*i<*ujw « o o o • f XXIII Condensation C«2 oe oe I I C CH Oalkyl O O t> II alkylO-P-CH2-C-CH2-C02alkyl Reduction • NaBH, ^CH CH I THP, -78 C XXIV c2h5oh O OH o OH alkylp-P-CH2-CH-CH2C02alkyl Hydrolysig H0-P-CH2-CH-CH2C02H i ,CH OH" J: H ' CH 7 CH I dioxane L z i z IC1 IC ro to as £ 4^ * t o-J o o o 9 Reaction Sequence D. Preparation of Compounds of Formula I where X is -CH2-, -CH2CH2" or -CH2CH2CH2" CHO I z VIII CI Wa (a is 1, .2 or 3) xxv (Alky10)^P III J A 0 II AlkylO-P-Cl 4H2>a Z XXVII CH, ?9 f c / c ^ X ^ \ CH Oalkyl -> coupling THF, -78°C O II P(Oalkyl)2 <(fH2»a Z XXVI 0 II 1. OH 2. 3. TMSNEt, (C0Cl)o, Cat. DMF (Acid Chloride Formation) alkyl0-P-CH9-C-CHo-C0oalkyl I ^ |l * * Wa 0 XXVIII Reduction NaBH. C_HcOH Z D ■> I 00 I X M O tr ro ro CM 4^ lm^ ... .1 ■ ■■ .j. ...——.i. i.u,...,.,iji» 0 o 0 OH it I alkyl0-P-CH2-CH-CH2C02alkyl Hydrolysis^ ^^2^3 aqueous OH Z ID1 (a=2) IE1 (a=l) IF1 (a=3) O 0 OH M I HO-P-CHj-CH-CH^OjH «fH2)a Z ID (a=2) IE (a=l) IF (a=3) A u> I ro 4N , Vl Cm els*** o G O Reaction Sequence E. Preparation of Compounds of Formula I where X is -CH^O CHO » Z VIII 1. Baeyer-Villiger Oxidation (MCPBA) 2. Base Hydrolysis OH I Z XXIX Alkylation TsO-CH,-PO(Oalkyl), ^ XXX _ Base > PO(Oalkyl)2 /H2 Hydrolysis aqueous LiOH > dioxane XXXI 0 II alkylO-P-OH /H2 0 1 Z Acid CI formation 1) TMSNEt2 2) (C0C1)2 Cat. DMF, CHC12 XXXII o G o o o ii alkyl-O-^-Cl /CH2 ? Z XXXIII Condensation 0 6 ? e > . c , c * \ * \ CH, CH Oalkyl THP, -78°C O O I! Ii ilkyl0-^-CH2-C-CH2C02alkyl /CH2 ? z XXXIV Reduction NaBH. c2h5.oh 0 OH II ?H t ?H alkyl0-y-CH2-CH-CH2C02alkyl Hydrolysis H0-^-CH2-CH-CH2C02H C / CH2 _OH ^ CH2 CJ 22. 4 7 3 4 HXlOb -52- As seen in the above Reaction Sequence "A", compounds of Formula I may be prepared by subjecting iodide A to an Arbuzov reaction by heating iodide A 5 ?6H5 n O-Si-C(CH-), ft 33 C6H5 10 15 I-CH,-C-CH,-CO,alkyl 2k and phosphite III III P(Oalkyl)3 employing standard Arbuzov conditions and procedures to form the phosphonate IV 0 n IV alkylO-P CH2 CH-CH2-C02 alkyl Oalkyl OSi-C(CH-), C£h C6H5 20 (a novel intermediate) 25 Phosphonate IV is then subjected to a phosphorus ester cleavage by treating a solution of phosphonate IV in an inert organic solvent, such as methylene chloride, sequentially with 30 bis(trimethylsilyl)trifluoroacetamide (BSTFA) and trimethylsilyl bromide, under an inert atmosphere such as argon, to form the phosphonic acid V 22 47 HXlOb -53- O II V H0-P-CH2-CH-CH2-C02alkyl OH O I .Si-C(CH-)- =s<Vs (a novel intermediate) Phosphonic acid V is esterified by treating V in dry pyridine with a lower alkyl alcohol (such as methanol) and dicyclohexyl carbodiimide and the resulting reaction mixture is stirred under an inert atmosphere, such as argon, to form phosphonic monoalkyl ester VI (a novel intermediate). Phosphonic monoester VI is then dissolved in an inert organic solvent, such as, methylene chloride, benzene or tetrahydrofuran (THF) and treated with trimethylsilyldiethylamine and stirred under an inert atmosphere such as argon, the mixture is evaporated and then dissolved in methylene chloride (or other appropriate inert organic solvent). The resulting solution is cooled to a temperature within the range of from about -10°C to about 0°C, treated with oxalyl chloride and catalytic dimethyl-formamide and then evaporated to give crude phosphonochloridate VII (a novel intermediate). The phosphonochloridate VII is dissolved in inert organic solvent such as methylene chloride, benzene, pyridine or THF, the solution is cooled to a temperature within the range of from about -90°C to about 0°C and preferably from about -85°C to 22 4 7 -54- HXlOb about -30°C and treated with a cooled (same range (3 as solution of phosphonochloridate VII) solution of the lithium anion of acetylene X formed by treating with a lithium source such as n-butyllithium in 5 hexane or other inert solvent, O X C=CH Z 10 employing a molar ratio of VII:X of within the range of from about 3:1 to about 1:1 and preferably from about 1.5:1 to about 2:1 to form the acetylenic phosphinate XI 15 0 ii XI alkylO-P CH2 CH-CH2-C02alkyl C O ill l C S1-C(CH3)3 2 C6H5 C6H5 20 (^) (a novel intermediate) Acetylenic phosphinate XI may then be employed to prepare the various compounds of the 25 present invention as follows. o Acetylenic phosphinate XI is converted to acetylenic phosphinate IA^" by subjecting XI to silyl ether cleavage by treating XI in an inert organic solvent such as tetrahydrofuran, with 30 glacial acetic acid and tetrabutylammonium fluoride to form ester IA1 t o 22 4 7 3 A O HXlOb -55- • 0 0 IAa alkyl0-P-CH2-CH-CH2-C02alkyl C OH in 5 C I Z which may then be hydrolyzed to the corresponding basic salt or acid, that is, where Rx is Rxa which 10 is ammonium, alkali metal, alkaline earth metal, an amine and the like, by treatment with strong base such as lithium hydroxide in the presence of dioxane, tetrahydrofuran or other inert organic solvent under an inert atmosphere such as argon, at 15 25°C, employing a molar ratio of base:ester IA1 of | within the range of/from about 1:1 to about 1.1:1 j to form the corresponding basic salt 1. ] i O 1 2 " xa 20 IA alkylO-^-CH2-CH-CH2-C02-R I o c °H 01 III c I z 2 25 Compound IA may then be treated with strong acid such as HC1 to form the corresponding acid IA3 22 4 7 HXlOb -56- 0 IA3 alkyl0-^-CH2-CH-CH2-C02H C OH Hi c 1 Z The ester IA1 may be converted to the corresponding di-basic salt by treating ester IA1 with strong base at 50-60°C employing a molar ratio of base:ester IA1 of within the range of from about 4 2:1 to about 4:1 to form IA 0 IA4 ■ RXa0-P-CHo-CH-CHo-C0oRXa 1 2 = 2 2 c oh in C I Z 4 The dibasic salt IA may be converted to the corresponding acid by treatment with strong acid. such as HC1 to form acid IA. Phosphinate compounds of the invention where X is (cis) -CH=CH-, that is, IB are formed by subjecting acetylenic phosphinate XI to selective reduction, for example by treating XI with H2 in the presence of a reduction catalyst such as palladium on carbon, palladium on barium carbonate and an inert organic solvent such as methanol to form the silyl ether XII * 22 4 7 3 4 %lgw o o o HXXOb -57- 0 XII alkylO-P-CH2—CH-CH2C02-alkyl CH . 0 CH Si-C(CH3)3 C6H5 C6H5 (a novel intermediate) 10 Silyl ether XII may then be subjected to silyl ether cleavage and hydrolysis as described above to form the ester IB1 0 15 IB1 alkyl0-P-CH2-CH-CH2-C02-alkyl CH OH II (cis) CH Z 2 20 the basic salt IB 0 O H Ya IB alkyl0-P-CH2-CH-CH2-C02Rxa CH OH II 25 (cis) CH Z the acid IB3 © ^2 4 7 3 4 HXlOb -58- n • o - H IB alkylO-^-CH2-QH-CH2-C02H .Os '-U CH OH II (Cis) CH 4 the dxbasic metal salt IB 10 0 IB4 RXa0-|-CH2-CH-CH2-C02RXa CH 5H ii (cis) CH Z 15 and the corresponding diacid IB. phosphinate compounds of the invention where X is -CH2-CH2~, that is, ID are formed by subjecting acetylenic phosphinate. XII to catalytic 20 reduction, for example by treating XII with H2 in £2) the presence of a reduction catalyst such as palladium on carbon and an inert organic solvent such as methanol at' 50 psi to form the silyl ether XIII 25 O o II XIII alkylO-P-CH2—CH-CH2C02-alkyl CH0 O • 1 I CR2 ^Si-C(CH3)3 30 Z C6H5 C6H5 (a novel intermediate) 22 4 7 3 4 o 'w- i I O 10 HXlOb -59- Silyl ether XIII may then be subjected to silyl ether cleavage and hydrolysis as described above to form the ester ID1 0 ID1 alkyl0-P-CH2-CH-CH2-C02-alkyl ch2 oh ch2 Z 2 the basic salt ID 0 ID2 alkyl0-t-CH2-CH-CH2-C02Rxa , 15 CH, 5H 1 ^ CH, I 2 z 3 20 25 the acid ID 0 3 11 ID alkyl0-P-CH2-CH-CH2-C02H CH, OH 1 2 CH2 4 the dibasic salt ID 0 30 id4 rxa0-p-ch2-ch-ch2-c02rxa <j:h2 oh CH0 O r>t 22 4 7 34 HXlOb -60- and the corresponding diacid ID. Referring now to Reaction Sequence "B", compounds of Formula I wherein the X linking group between the phosphorus atom and the hydrophobic 5 anchor Z is (trans) -CH=CH- may be prepared by treating a mixture of acetylene X and n-C4HgSnH with a radical initiator such as azobisiso-butyrylnitrile (AIBN), hydrogen peroxide, benzoyl peroxide and the like, and heating the resulting 10 solution to a temperature of within the range of from about 100 to about 140°C under an inert atmosphere such as argon to form the vinyl stannane XV 15 Sn(n-C4Hg)3 XV CH CH I Z 20 Vinyl stannane XV dissolved in an organic solvent such as ethyl ether, methylene chloride or chloroform is treated with iodine and stirred under an inert atmosphere such as argon to form vinyl iodide XVI 25 I XVI CH CH I Z 30 •A cooled solution of vinyl iodide XVI (-78 to -40°C) in dry organic solvent such as tetra-hydrofuran, or ethyl ether is treated with a 61- HXlOb metallating agent such as n-butyllithium in an inert organic solvent such as hexane and the mixture is cooled at a temperature of from -78 to -40°C under an inert atmosphere such as argon. The anion is added to a cooled (-78 to -40°C) solution of phosphonochloridate VII at a molar ratio of XVI:VII of within the range of from about 1:1 to about 2:1 and preferably from about 1:1 to about 1.5:1 in dry inert organic solvent such as tetrahydrofuran, or ethyl ether to form the silyl ether XVII O tl XVII alkylO-^-CH2-CH-CH2-C02 alkyl (trans) CH 6si-C(CH")- s*— v o j C6H5 C6H5 Z (a novel intermediate) The silyl ether XVII is subjected to silyl ether cleavage by treating a solution of XVII in an inert organic solvent such as tetrahydrofuran, or acetonitrile with glacial acetic acid and a solution of (n-C4Hg)4NF in an inert organic solvent such as tetrahydrofuran to form the hydroxy diester IC1 0 1 '' ICX alkyl0-P-CH2-CH-CH2-C02alkyl (trans) CH OH CH I Z C u j *■* L. / HXlOb -62- Diester IC1 may then be hydrolyzed as described above to form the basic salt IC2, O IC2 .alkyl0-P-CH2-CH-CH2C02Rxa (trans )^CH OH ^ CH 0 k €) 10 the acid IC3 O 3 '' ICJ alkyl0-^>-CH2-CH-CH2-C02H CH OH s? 15 CH I Z 4 the basic salt IC 20 O IC4 RXa0-P-CH2-CH-CH2-C02RXa CH OH CH I Z 25 and the corresponding diacid IC 0 It IC HO-P-CH--CH-CH,-CO-H | 2 — 2 2 30 CH OH // HC i 22 4 7 HXlOb -63- In an alternative process, as shown in Reaction Sequence "C", compounds of Formula I wherein the X linking group between the phosphorus atom and tJie hydrophobic anchor Z is (trans)-CH=CH- may be prepared by subjecting aldehyde VIII CHO VIII Z to a condensation reaction with a cooled (-90 to 0°C) solution of dialkyl methylphosphonate and butyl lithium (LiCH2PO(alkyl)2) in the presence of an organic solvent such as tetrahydrofuran or ethyl ether to form the p-hydroxyphosphonate XX 0 P(Oalkyl)2 XX H0-CH-CHo I 2 Z The 3-hydroxyphosphonate XX is then treated with p-toluenesulfonic acid in the presence of benzene or toluene while heating to a temperature within the range.of from about 50 to about 120°C, preferably at reflux, to eliminate water and form the trans-olefin XXI 0 il P(Oalkyl)2 XXI (trans) ^CH CH I Z which is hydrolyzed by treating with aqueous alkali metal hydroxide, such as LiOH, in the / *7 t / HXlOb -64- presence of dioxane or other inert organic solvent and then with acid such as hydrochloric acid to form the monoacid ester XXII 0 5 alkylO-j?-OH XXII (trans) ^CH CH I Z 10 A solution of the monoacid ester XXII in dry methylene chloride is treated with trimethyl-silyldiethylamine. The mixture is evaporated and the resulting oil is taken up in dry methylene chloride cooled to 0°C and treated with oxalyl 15 chloride and a catalytic amount of dimethyl formamide under an inert atmosphere such as argon to form phosphonochloridate XXIII 0 alkylO-t-Cl 20 XXIII (trans) ^.CH © CH I Z Phosphonochloridate XXIII is condensed with 25 an alkyl acetoacetate dianion such as methyl acetoacetate dianion in the presence of an inert organic solvent such as tetrahydrofuran at reduced temperature of -90 to -40°C employing a molar ratio of phosphonochloridate:dianion of within the range 30 of from about 1:1 to about 0.75:1 to form the ketophosphonate XXIV n r-s L L / *~3 4 / HXlOb -65- 0 0( XXIV alkylO-P-CH2-C-CH2-C02alkyl (trans) ^.CH CH I 5 Z (a novel intermediate) o which is reduced by treatment with a reducing agent such as sodium borohydride in the presence of 10 an alkaxiol such as ethanol to form the phosphinate IC1 O 1 •' IC alkyl0-P-CH2-CH-CH2-C02alkyl (trans) CH OH 15 CH I 20 O • Diester IC may then be hydrolyzed as described 2 above to form the basic salt IC , 0 2 ll »a IC* alkyl0-^>-CH2-CH-CH2C02RXd (trans )^CH OH CH 25 Z the acid IC3 O 30 IC3 alkyl0-P-CH2-CH-CH2-C02H (trans )^CH OH CH I Z r) / "7 c l. 4 / o HXlOb -66- 4 the basic salt IC 0 IC4 RXa0-P-CHo-CH-CHo-C0oRXa 1 2 | 2 2 (trans) ^,CH OH CH and the corresponding diacid IC. 10 Referring to Reaction Sequence D(, compounds of Formula I wherein X is -(CH2)a- and a is 1, 2 or 3, that is -CH2-, -CH2CH2- or -CH2CH2CH2- may be prepared starting with aldehyde VIII which is converted to halide Villa using conventional 15 procedures. For example, the aldehyde VIII may be reduced with NaBH^ in the presence of ethanol and ether to form the corresponding alcohol Villa CH-OH l 2 20 2 which is treated with mesyl chloride in the presence of an organic base such as triethylamine and a solvent such as methylene chloride to form the chloride XXV (a=l). 25 The chloride XXV is subjected to a conden sation reaction where XXV is treated with phosphite III employing a molar ratio of III:XXV of within the range of from about 1:1 to about 10:1 and a temperature within the range of from 30 about 100 to about 150°C to form phosphonate diester XXVI. A solution of the phosphonate diester XXVI in a solvent such as dioxane is treated with a strong base such as an alkali metal hydroxide, for example, LiOH, to form a corre- V 9 ^ 1 T c L i 0 HXlOb -67- sponding monoester which is treated with oxalyl chloride in the presence of an inert organic solvent such as dimethylformamide to form the corresponding phosphonochloridate XXVII. XXVII is 5 condensed with an alkyl acetoacetate dianion such as methylacetoacetate dianion in the presence of an fpwiy inert organic solvent such as tetrahydrofuran at reduced temperatures of from about -90 to about -40°C employing a molar ratio of phosphono-10 chloridate XXVII:dianion of within the range of from about 1:1 to 0.75:1 to form the ketophos-phinate XXVII which is a novel intermediate. Ketophosphinate XXVII may then be reduced to the 11 1 corresponding phosphinate ID , IE and IF which 15 may be hydrolyzed to form the corresponding diacids ID, IE and IF following procedures as described with respect to Reaction Sequence C. Referring to Reaction Sequence E, compounds of formula I wherein X is -CH20- may be prepared 20 starting with aldehyde VIII which is subjected to a Baeyer-Villiger oxidation by reacting VIII with meta-chloroperbenzoic acid (MCPBA) in the presence of an inert organic solvent such as methylene chloride and followed by a strong base such as an 25 alkali metal hydroxide like KOH or NaOH and a solvent such as tetrahydrofuran to form the corresponding alcohol XXIX. The alcohol XXIX is alkylated by treating XXIX with sodium hydride in the presence of an inert organic solvent such as 30 dimethyl formamide under an inert atmosphere such as argon and a solution of a dialkyl tosyloxymethyl-phosphonate XXX employing a molar ratio of XXX:XXIX of within the range of from about 1:1 to about 3:1 to form the corresponding dialkyl ester XXXI. The 0 o h 7 dL zL, i / 0 HXlOb -68- remainder of the synthesis described in Reaction Sequence E that is forming the monoester XXXII, chloride XXXIII, ketophosphinate XXXIV (a new intermediate), diester IG* and diacid.IG is similar to that set out hereinbefore with respect to in Reaction Sequence D. The acetylene starting material X may be prepared from the corresponding aldehyde VIII 10 VIII CHO Z by subjecting VIII to a Wittig reaction, for example, by treating a cooled solution of VIII 15 (-25°C to 0°C) in triphenylphosphine, and an inert organic solvent such as methylene chloride, with a solution of tetrabromomethane (CBrA) in an inert organic solvent such as T » 20 methylene chloride to form vinyl dibromide IX IX CH=CBr0 I 2 Compound IX is subjected to dehydrohalogenation by 25 treatment with n-butyllithium in an inert organic solvent such as hexane under an inert atmosphere to give X. Alternatively, aldehyde VIII may be converted directly to acetylene X by treatment 30 with dimethyl diazomethylphosphonate in the presence of potassium t-butoxide in an inert solvent such as tetrahydrofuran (-78°C to 25°C) under an inert atmosphere. The iodide starting material A may be 35 prepared starting with the bromide C 22 4 7 34; HXlOb -69- 9 OH I C Br-CH2-CH-CH2C02alkyl 5 (which is prepared by employing procedures as described in Tetrahedron Lett. 26, 2951 (1985)) which is dissolved in solution in dimethylformamide 10 (DMF) with imidazole, and 4-dimethylamino pyridine and the resulting solution is treated with t-butyldiphenyl silyl chloride under an inert atmosphere such as argon to form the silyl ether D 15 C6\5/C6H5 j)Si-C(CH3)3 D Br-CH2-CH-CH2C02alkyl A solution of silyl ether D in an inert organic 20 solvent such as methyl ethyl ketone or DMF is treated with sodium iodide under an inert atmosphere such as argon, to form iodide A. The starting aldehyde compounds VIII, that is 25 VIII CHO I Z are known compounds. 30 The various intermediates IV, V, VI, VII, XI, XII, XIII, XVII and XXIV also are part of the present invention. These novel intermediates may be represented by the following generic formulae: 22 4 7 HXlOb -70- 1 " XXXV Rr-P-CH^-CH-CHL-CO,, alkyl a |, 2 | 2 2 J R£ OSi-C(CH3)3 5 C6H5 C6H5 including all stereoisomers thereof, wherein R1 is -w -i a alkoxy or hydroxy and R^ is alkoxy, hydroxy, ci, -ch2-z, -ch2ch2ch2-z, -ch2o-z, -c=c-z, -ch=ch-z, 10 -ch2ch2-z, wherein z is a hydrophobic anchor as defined above; provided that where R^ is hydroxy, R1 is preferably hydroxy or alkoxy; and 0 II XXXVI alkyl0-P-CH2-C-CH2-C02alkyl 15 X O 1 z wherein Z is as defined above, including all stereoisomers thereof. 20 The compounds of the invention may be prepared as racemic mixtures and may later be resolved to obtain the S-isomer which is preferred. However, the compounds of the invention may be prepared directly in the form of 25 their S-isomers as described herein and in the working examples set out hereinafter. The compounds of the invention are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and thus are useful in 30 inhibiting cholesterol biosynthesis as demonstrated by the following tests. o -71- 22 4 7 3 4 HXlOb 1) Rat: Hepatic HMG-CoA Reductase Rat hepatic HMG-CoA reductase activity is ''TO- measured using a modification of the method described by Edwards (Edwards, P.A., et al., 5 J. Lipid Res. 20:40, 1979). Rat hepatic microsomes, are used as a source of enzyme, and the enzyme activity is determined by measuring the 14 conversion of the C-HMG-CoA substrate to 14, O o C-mevalonic acid. 10 a. Preparation of Microsomes Livers are removed from 2-4 cholestyramine-fed, decapitated, Sprague Dawley rats, and homogenized in phosphate buffer A 15 (potassium phosphate, 0.04 M, pH 7.2; KCl, 0.05 M; sucrose, 0.1 M; EDTA, 0.03 M; aprotinin, 500 KI units/ml). The homogenate is spun at 16,000 x g for 15 minutes at 4°C. The supernatant is removed and recentrifuged under the same conditions a 20 second time. The second 16,000 x g supernatant is spun at 100,000 x g for 70 minutes at 4°C. Pelleted microsomes are resuspended in a minimum volume of buffer A (3-5 ml per liver), and homogenized in a glass/glass homogenizer. 25 Dithiothreitol is added (10 mM), and the preparation is aliquoted, quick frozen in acetone/dry ice, and stored at -80°C. The specific activity of the first microsomal preparation was 0.68 nmole mevalonic acid/mg 30 protein/minute. 2 4 7 Ms' O HXlOb -72- b. Enzyme Assay The reductase is assayed in 0.25 ml which contains the following components at the indicated final concentrations: 5 0.04 M Potassium phosphate, pH 7.0 0.05 M KC1 0.10 M Sucrose 0.03 M EDTA 10 0.01 M Dithiothreitol 3.5 mM NaCl 1% Dimethylsulfoxide 50-200 |jg Microsomal protein 100 MM I4c-[DL]HMG-CoA (0.05 |jCi, 15 30-60 mCi/mmole) 2.7 mM NADPH (nicotinamide adenine dinucleotide phosphate) Reaction mixtures are incubated at 37°C. Under 20 conditions described, enzyme activity increases ^ linearly up to 300 per microsomal protein per reaction mixture, and is linear with respect to incubation time up to 30 minutes. The standard incubation time chosen for drug studies is 20 25 minutes, which results in 12-15% conversion of HMG-CoA substrate to the mevalonic acid product. [DL-]HMG-CoA substrate is used at 100 pM, twice the concentration needed to saturate the enzyme under the conditions described. NADPH is used in 30 excess at a level 2.7 times the concentration required to achieve maximum enzyme velocity. o r\ © " ~ HXlOb -73- Standardized assays for the evaluation of inhibitors are conducted according to the following procedure. Microsomal enzyme is incubated in the presence of NADPH at 37°C for 15 5 minutes. DMSO vehicle with or without test compound is added, and the mixture further incubated for 15 minutes at 37°C. The enzyme 14 assay is initiated by adding C-HMG-CoA substrate. After 20 minutes incubation at 37°C 10 the reaction is stopped by the addition of 25 pi of 33% KOH. 3H-mevalonic acid (0.05 pCi) is added, and the reaction mixture allowed to stand at room temperature for 30 minutes. Fifty pi 5N HCl is added to lactonize the mevalonic acid. 15 Bromophenol blue is added as a pH indicator to monitor an adequate drop in pH. Lactonization is allowed to proceed for 30 minutes at room temperature. Reaction mixtures are centrifuged for 15 minutes at 2800 rpm. The supernatants are 20 layered onto 2 grams AG 1-X8 anion exchange resin (Biorad, formate form) poured in 0.7 cm (id) glass ( - j columns, and eluted with 2.0 ml HgO- The first 0.5 ml is discarded, and the next 1.5 ml is collected and counted for both tritium and carbon 25 14 in 10.0 ml Opti-fluor scintillation fluid. Results are calculated as nmoles mevalonic acid produced per 20 minutes, and are corrected to 100% recovery of tritium. Drug effects are expressed as I5Q values (concentration of drug producing 50% 30 inhibition of enzyme activity) derived from composite dose response data with the 95% confidence interval indicated. 0 HXlOb -74- Conversion of drugs in lactone form to their sodium salts is accomplished by solubilizing the lactone in DMSO, adding a 10-fold molar excess of NaOH, and allowing the mixture to stand at room temperature for 15 minutes. The mixture is then partially neutralized (pH 7.5-8.0) using IN HCl, and diluted into the enzyme reaction mixture. 2) Cholesterol Synthesis in Freshly Isolated Rat Hepatocytes Compounds which demonstrate activity as inhibitors of HMG-CoA reductase are evaluated for 14 their ability to inhibit C-acetate incorporation into cholesterol in freshly isolated rat hepatocyte suspensions using methods originally described by Capuzzi et al. (Capuzzi, D.M. and Margolis, S., Lipids, 6:602, 1971). a. Isolation of Rat Hepatocytes Sprague Dawley rats (180-220 grams) are anesthetized with Nerobutol (50 mg/kg). -The abdomen is opened and the first branch of the portal vein is tied closed. Heparin (100-200 units) is injected directly into the abdominal vena cava. A single closing suture is placed on the distal section of the portal vein, and the portal vein is canulated between the suture and the first branching vein. The liver is perfused at a rate of 20 ml/minute with prewarmed (37°C), oxygenated buffer A (HBSS without calcium or magnesium containing 0.5 mM EDTA) after severing the vena cava to allow drainage of the effluent. The liver is additionally perfused with 200 ml of o 22 47 HXlOb -75- prewarmed buffer B (HBSS containing 0.05% bacterial collagenase). Following perfusion with buffer B, the liver is excised and decapsulated in 60 ml Waymouth's medium allowing free cells to 5 disperse into the medium. Hepatocytes are isolated by low speed centrifugation for 3 minutes at 50xg at room temperature. Pelleted hepatocytes are washed once in Waymouth's medium, counted and assayed for viability by trypan blue exclusion. 10 These hepatocyte enriched cell suspensions routinely show 70-90% viability. 14 b. C-Acetate Incorporation into Cholesterol 15 Hepatocytes are resuspended at 5xl06 cells per 2.0 ml in incubation medium (IM) [0.02 M Tris-HCl (pH 7.4), 0.1 M KC1, 3.3 mM sodium citrate, 6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate]. 20 Test compounds are routinely dissolved in DMSO or DMS0:H20 (1:3) and added to the IM. Final DMSO concentration in the IM is <_ 1.0%, and has no significant effect on cholesterol synthesis. Incubation is initiated by adding 14 25 C-acetate (58 mCi/mmol, 2 |jCi/inl), and placing the cell suspensions (2.0 ml)' in 35 ram tissue culture dishes, at 37°C for 2.0 hours. Following incubation, cell suspensions are transferred to glass centrifuge tubes and spun at 50xg for 3 30 minutes at room temperature. Cell pellets are resuspended and lysed in 1.0 ml B^O, and placed in an ice bath. -•/ I o o 22 4 7 3 4 HXlOb -76- Lipids are extracted essentially as described by Bligh, E. G. and W. J. Dyer, Can. J. Biochem. and Physiol., 37:911, 1959. The lower organic phase is removed and dried under a stream 5 of nitrogen, and the residue resuspended in (100 pi) chloroform:methanol (2:1). The total sample is spotted on silica gel (LK6D) thin-layer plates ^ and developed in hexane:ethyl ether:acetic acid (75:25:1). Plates are scanned and counted using a 10 BioScan automated scanning system. Radiolabel in the cholesterol peak (RF 0.28) is determined and expressed at total counts per peak and as a percent of the label in the total lipid extract. Cholesterol peaks in control cultures routinely 15 contain 800-1000 cpm, and are 9-20% of the label present in the total lipid extract; results compatable with Capuzzi, et al., indicating 9% of extracted label in cholesterol. Drug effects (% inhibition of cholesterol 20 synthesis) are determined by comparing % of label <~\ in cholesterol for control and drug treated cultures. Dose response curves are constructed from composite data from two or more studies, and results are expressed as I5Q values with a 95% 25 confidence interval. 3) Cholesterol Synthesis in Human Skin Fibroblasts Compound selectivity favoring greater inhibitory activity in hepatic tissue would be an 30 attribute for a cholesterol synthesis inhibitor. Therefore, in addition to evaluating cholesterol synthesis inhibitors in hepatocytes, these compounds are also tested for their activity as 22 4 7 HXlOb -77- inhibitors of cholesterol synthesis in cultured fibroblasts. a. Human Skin Fibroblast Cultures 5 Human skin fibroblasts (passage 7-27) are grown in Eagles* minimal essential medium (EM) (^) containing 10% fetal calf serum. For each experiment, stock cultures are trypsonized to disperse the cell monolayer, counted, and plated 10 in 35 mm tissue culture wells (5xl05 cells/2.0 ml). Cultures are incubated for 18 hours at 37°C in 5% C02/95% humidified room air. Cholesterol biosynthetic enzymes are induced by removing the serum containing medium, washing the cell 15 monolayers, and adding 1.0 ml of EM containing 1.0% fatty acid free bovine serum albumin, and incubating the cultures an additional 24 hours. 14 b. C-Acetate Incorporation into 20 Cholesterol O Induced fibroblast cultures are washed with EMEMioo (Earle's minimal essential medium). Test compounds are dissolved in DMSO or DMSO:EM (1:3) (final DMSO concentration in cell cultures <_ i.0%), 25 added to the cultures, and the cultures preincubated for 30 minutes at 37°C in 5% C02/95% humidified room air. Following preincubation with 14 drugs, [1- C]Na acetate (2.0 pCi/ml, 58 mCi/mmole) is added, and the cultures reincubated for 4 hours. 30 After incubation, the culture medium is removed, and the cell monolayer (200 pg cell protein per culture) is scraped into 1.0 ml of HjO. Lipids in the lysed cell suspension are extracted into 22 47 HXlOb -78- chloroform:methanol as described for hepatocyte suspensions. The organic phase is dried under nitrogen, and the residue resuspended in chloro form: methanol (2:1) (100 (Jl), and the total sample spotted on silica gel (LK6D) thin-layer plates, and analyzed as described for hepatocytes. Inhibition of cholesterol synthesis is determined by comparing the percent of label in the cholesterol peak from control and drug-treated cultures. Results are expressed as I5Q values, and are derived from composite dose response curves from two or more experiments. A 95% confidence interval for the I5Q value is also calculated from the composite dose response curves. A further aspect of the present invention is a pharmaceutical composition consisting of at least one of the compounds of formula I in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles of diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, such dosage forms containing from 1 to 2000 mg of active compound per dosage, for use in the treatment. The dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient. It 4 7 HXlOb -79- The compounds of formula I may be administered in a similar manner as known compounds suggested for use in inhibiting cholesterol biosynthesis, such as lovastatin, in mammalian species such as humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in an amount from about 4 to 2000 mg in a single dose or in the form of individual doses from 1 to 4 times per day, preferably 4 to 200 mg in divided dosages of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4 times daily or in sustained release form. 224734 HXlOb -80- The following working Examples represent preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are expressed in degrees' Centigrade. Flash 5 chromatography was performed on either Merck 60 or Whatmann LPS-I silica gel. Reverse phase chromatography was performed on CHP-20 MCI gel O resin supplied by Mitsubishi, Ltd. "••aw As used in the following Examples, the 10 abbreviations "E^O", "EtOAc", "MeOH" and "EtOH" refer to ethyl ether, ethyl acetate, methanol and ethanol, respectively. ■ Exanple 1. (S)-4-[[2-(4'-Fluoro-3,3',5-tnmethyl- [1,1* -biphenyl ] -2 -y 1 ] ethyl ] methoxyphos - phinyl]-3-hydroxybutanoic acid, methyl ester ' 15 (S)-4-[[[41-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]- 2-yl]methoxy]methoxyphosphinyl]-3-hydroxy-butanoic acid, monolithium salt A. N-(2,4-Dimethylbenzylidene)benzeneamine % Ref. Merck U. S. Patent No. 4,375,475, pg. 39. 20 A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich, 6.97 ml, 50 mmole) and distilled aniline (Aldrich, 4.56 ml, 50 mmole) in dry toluene (80.0 ml) was refluxed for « 3.0 hours under argon in a flask equipped with a 25 Dean-Stark apparatus. The mixture was cooled, then evaporated in vacuo to a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm Hg, 160-180°C) to give 8.172 g (78.1%) of desired title benzeneimine as a light yellow o} 30 which crystallized on standing to a low melting solid. TLC (4:1) Hex-acetone, Rf=0.67 and 0.77 (geometric isomers), U.V. and I2. -81- 22 4 7 3 4 HXlOb O o O B. 10 Ref. Merck U.S. Patent No. 4,375,475, pg. 39. A mixture of Part A benzeneimine (6.0 g, 28.7 mmol) in glacial HOAc (144 ml) was treated with palladium (II) acetate (6.44 g, 28.7 mmole) and the clear, red homogeneous solution refluxed 15 under argon for one hour. The resulting turbid mixture was filtered warm through a packed V bed of Celite into 900 ml of H20. Precipitated orange solid was collected by filtration and dried in vacuo at 65®C over F2°5 for 16 hours to give 20 10.6 g (85.5%) of desired title palladium complex as an orange solid with m.p. = 194°-196°C. (Literature m.p. of a recrystallized analytical sample = 203°-205°C). ! O 25 C. 4'-Fluoro-3,3',5-trimethyl[l,l'- biphenyl1-2-carboxaldehyde (1) Bromo[4-fluoro-3-methylphenyl]- magnesium Ref. Merck U. S. Patent No. 4,375,475, pp. 37 and 30 38. The title Part C(1) Grignard reagent was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmole, Fairfield Chemical Co.) dropwise o o 5 Q 10 15 20 o 25 O 2,'n. a ***) Z 9 / HXlOb -82- at a rate sufficient to maintain the reaction at reflux to stirred magnesium turnings (1.35 g, 55.4 mmole, 8.0 eq.) in dry Et20 (70.0 ml). The reaction was initiated in an ultrasound device. After bromide addition was complete, the mixture was stirred for one hour under argon at room temperature, refluxed for 15 minutes and then allowed to cool to room temperature. (2) 4'-Fluoro-3,3',5-trimethyl- f1,11-biphenyl1-2-carboxaldehyde In a second flask, a mixture of the- Part B dipalladium complex (3.0 g, 6.92 mmole) and triphenylphosphine (14.52 g, 55.4 mmole, 8.0 eq.) in dry benzene (100 ml) was stirred at room temperature under argon for 30 minutes. Freshly prepared and filtered (glass wool plug) Part C (1) Grignard reagent was then added in one portion by means of a cannula to this solution and the mixture was stirred for 1.5 hours at room temperature under argon. 6.0 N HCl (35 ml) was added, , the mixture stirred an additional hour at room temperature, then filtered through packed Celite (V1 bed). The filtrate was extracted with Et2o (250 ml), the extract washed with brine (2 x 100 ml), dried over anhydrous MgSO^ and evaporated in vacuo to give 13.35 g of a viscous orange oil which crystallized on standing. The crude orange solid was purified by flash chromatography on silica gel (700 g) eluting with hexane, followed by (95:5) hexane-Et20. Product fractions were combined and evaporated to give 1.507 g (89.9%) of desired title aldehyde as a light yellow solid with 83- HXlOb m.p. = 72°-75°C) (Literature reports m.p. = 73°-74°C). TLC: (95:5) Hex-Et20f Rf = 0.40, U.V. and PMA. D. 2-(2,2-Dibromoethenyl)-41-fluoro-3,3',5-trimethyl\1,11-biphenyl1 A cooled (-10°C, salt/ice bath) solution of the Part C biphenyl aldehyde (242 mg, 1.0 mmole) and triphenylphosphine (787 mg, 3.0 mmole, 3.0 eq) in dry CH2C12 (10 ml) was treated dropwise with a solution of CBr4 (497 mg, 1.5 mmole, 1.5 eq) in CH2C12 (5.0 ml) over a 5 minute period. After 30 minutes at 0°C the red-orange solution was partitioned between CH2C12 and saturated NaHCO^. The organic phase was washed with saturated NaHCOg and brine, then dried over anhydrous Na2S04 and evaporated to give 1.478 g of a light brown solid. The crude solid was purified by flash chromatography on silica gel (50:1) eluting with (9:1) Hex-CH2C12. Product fractions were combined and evaporated to give 392 mg (99%) of pure title vinyl dibromide as a pale yellow oil. TLC (95:5) Hex-EtOAc, Rf = 0.51, UV and PMA. E. 2-Ethynyl-41-fluoro-3,3', 5-trimethyl-[1,11-biphenyl] A -78°C (dry ice/acetone) solution of the Part D vinyl dibromide (336 mg, 0.844 mmole) in dry THF (5 ml) was treated dropwise via syringe with a 1.6 M solution of n-BuLi in hexanes (1.06 ml, 1.7 mmole, 2.0 eq) and the mixture stirred at -78°C under argon for one hour. During the n-BuLi addition color changes from colorless to deep rs j HXlOb -84- yellow to pale yellow to deep blue-purple were evident. The mixture was quenched at -78°C by the dropwise addition of saturated NH^Cl (4 ml), allowed to warm to room temperature, extracted with Et20, the ethereal layer washed with brine, dried over anhydrous MgS04 and evaporated to give 191 mg of a green oil. The crude oil was purified by flash chromatography on LPS-1 silica gel (60:1) eluting with hexanes. Product fractions were combined and evaporated to give 185 mg (92%) of desired.title acetylene as a colorless oil which eventually turned deep blue on standing at -20°C under argon. TLC hexane, Rf = 0.18 UV and PMA. F. (S )-3-[[(1,1-Dimethy1ethyl)diphenyl- silyl]oxy]-4-(chloromethoxyphosphinyl)-butanoic acid, methyl ester (1) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester (1)(a) [R-(R*,R*)]-2,3,4-trihydroxy-butanoic acid, calcium salt, hydrate Ref. Carbohydrate Research 72, pp. 301-304 (1979). Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid (44.0 g, 250 mmol) in H20 (625 ml), the suspension cooled to 0°C (ice bath) and treated portionwise with 30% H202 (100 ml). The mixture, was stirred at 30°-40°C (oil bath) for 30 minutes. Darco (10 g) was added and the black suspension heated on a steam bath until evolution of 02 ceased. The suspension was filtered through Celite, evaporated in vacuo (bath O HXlOb -85- temperature 40°C). The residue was taken up in H20 (50 ml), warmed on a steam bath and CH3OH was added until the solution was turbid. The gummy precipitated solid was collected by filtration and air dried to give 30.836 g (75.2%) of desired calcium salt as a powdery white solid. TLC (7:2:1) iPrOH-NH40H-H20, Rf = 0.19, PMA. (1)(b) [ S- (R*, S *) ] -2,4-Dibromo-3- hydroxybutanoic acid, methyl ester Ref. Bock, K. et al., Acta Scandinavica (B) 37, pp. 341-344 (1983) Part (l)(a) calcium salt (30 g) was dissolved in 30-32% HBr in acetic acid (210 ml) and stirred at room temperature for 24 hours. Methanol (990 ml) was then added to the brown solution and it was stirred overnight. The mixture was evaporated to an orange oil, taken up in CH30H (75 ml), refluxed for 2.0 hours and evaporated. The residue was partitioned between EtOAc (100 ml) and H20, the organic phase washed with H20 (2x) and brine then dried over anhydrous Na2S04 and evaporated to give 22.83 g (90.5%) of crude dibromide as a light orange oil. TLC (1:1) EtOAc-Hex, Rf = 0.69, UV & PMA. (1)(c) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester Ref. the same as for preparation of (l)(b). An argon purged solution of the dibromide (20.80 g, 75.4 mmol) and anhydrous NaOAc (21.0 g) in EtOAc (370 ml) and glacial HOAc (37 ml) was OH / "7 £» 1L 4 / HXlOb -86- treated with 5% Pd/C (1.30 g) and the black suspension stirred under of H^ (1 atm) while monitoring H2 uptake. After 2.0 hours H2 uptake was complete, the mixture was 5 filtered through Celite, the filtrate washed with saturated NaHCOg and brine then dried over anhydrous MgSO. and evaporated to give crude dibromoester as a brown oil. The crude oil was combined with another batch (starting from 36.77 g 10 of the dibromide) and vacuum distilled to give 25.77 g (61.3%) of desired title bromoester as a colorless oil with b.p. = 79°-80°C (1.0 mm Hg) TLC (1:1) EtOAc-Hex, Rf = 0.44, PMA. 15 Anal Calcd for C5Hg03Br: C, 30.48; H, 4.60; Br, 40.56 Found: C, 29.76; H, 4.50; Br, 39.86 (2) (S)-4-Bromo-3-[[(1,1-dimethylethyl)-20 diphenylsilyl]oxy]butanoic acid, methyl ester O " o A solution of part F(l) bromohydrin (4.0 g, 20.4 mmol), imidazole (6.94 g, 5.0 eg.), and 4-dimethylamino pyridine (4-DMAP) (12 mg, 0.005 25 eq.) in dry DMF (40 ml) was treated with t-butyl-diphenylsilyl chloride (5.84 ml, 1.1 eq.) and the homogeneous mixture stirred overnight under argon at room temperature. The mixture was partitioned between 5% KHS04 and EtOAc, the organic phase 30 washed with H20 and brine, dried over anhydrous Na2S04 and evaporated to give 9.32 g (100%) of crude silyl ether as a colorless, viscous oil. 0 0 /, C. jL -S1 HXlOb -87- TLC (3:1) Hex-EtOAc, Rf silyl ether = 0.75, U.V. and PMA. (3) (S)-4-Iodo-3-[[(1,1-dimethylethyl)-diphenylsilyl]oxy]butanoic acid, methyl ester A solution of the crude Part F(2) bromide (9.32 g, 201 mmole) in methyl ethyl ketone (60 ml, dried over 4A sieves) was treated with sodium iodide (15.06 g, 100.5 mmole, 5.0 eq.) and the yellow suspension refluxed for 5.0 hours under argon. The mixture was cooled, diluted with EtOAc, filtered, the filtrate washed with dilute NaHS03 (until colorless) and brine then dried over anhydrous Na2S04 and evaporated in vacuo to give 10.17 g of a yellow oil. The crude oil was purified by flash chromatography on silica gel (600 g) eluting with (3:1) Hexane-CH2C12. Product fractions were combined and evaporated to give 7.691 g (74.2%, overall yield for both steps) of desired title iodide as a clear, colorless, viscous oil. TLC (3:1) Hex-EtOAc, product. Rf = 0.75, U.V. and PMA. (Note: product iodide co-spots with starting bromide). (4) (S)-4-(Diethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-butanoic acid, methyl ester A solution of the iodide (7.691 g) in triethyl phosphite (20 ml) was heated at 155°C (oil bath) for 3.5 hours under argon. The mixture was cooled and excess phosphite distilled off in vacuo (0.5 mm Hg, 75°C) to leave a yellow oil O / -=3 o, c / -r / HXlOb -88- (•v-8.0 g). The crude oil was purified by flash r*) chromatography on silica gel (400 g) eluting with (4:1) Hexane-acetone. Product fractions were evaporated to give 3.222 g (41.1%) of desired title 5 phosphonate as a clear, colorless, viscous oil. TLC (1:1) Hex-acetone, Rf = 0.51, U.V. and PMA. Additionally 2.519 g (61.1% corrected yield) of starting Part (3) iodide was recovered. 10 (5) (S)-3-[[(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-phosphonobutanoic acid, methyl ester A solution of the Part F(4) phosphonate (9.85 g, 20.0 mmole) in dry CH2C12 (20 ml) was 15 treated sequentially with bistrimethylsilyltri- . fluoroacetamide (BSTFA) (5.31 ml, 32.0 mmole, 1.6 eq.) and trimethylsilyl bromide (TMSBr) (6.60 ml 50.0 mmole, 2.5 eg.) and the clear mixture stirred overnight under argon at room temperature. O 5% 20 KHSO^ (80 ml) was added and the mixture was extracted with EtOAc. The aqueous phase was saturated with NaCl and re-extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and evaporated 25 in vacuo to give crude title phosphonic acid as a viscous oil. TLC (7:2:1) iPrOH-NH.0H-H.,0, Rf = ft z 0.30, U.V. and PMA. (6) (S)—3—[[(1,1-Dimethylethyl)diphenyl-30 silyl]oxy]-4-(hydroxymethoxyphosphinyl)- butanoic acid, methyl ester Part F(5) crude phosphonic acid (~20.0 mmole) in dry pyridine (25 ml) was treated with dried 22 4 HXlOb -89- CHgOH (over 3A sieves, 1.62 ml, 40.0 mmole, 2.0 eq.) and dicyclohexyl carbodiimide (DCC) (4.54 gm, 22.0 mmole, 1.10 eq.) and the resulting white suspension stirred under argon at room temperature overnight. Pyridine was removed in vacuo, then azeotroped with benzene (2 x 15 ml). The residual oil was dissolved in EtOAc, filtered and washed with 1.0 N HCl and brine, dried over anhydrous Na2S04 and evaporated in vacuo to give 8.272 g of crude title ester as an oil containing a small amount of precipitated dicyclohexyl urea (DCU). TLC (7:2:1) iPrOH-NH4-OH H20, Rf = 0.60, U.V. and PMA. (7) (S)-3-[ [(1-Dimethylethyl)diphenylsilyl]-oxy ] -4- (chloromethoxyphosphinyl) - butanoic acid, methyl ester Part F(6) crude phosphonic acid mono methyl ester (6.595 gm, ~14.7 mmole) was dissolved in dry CH2C12 (30 ml), treated with distilled trimethyl-silyldiethylamine (5.60 ml, 29.4 mmole, 2.0 eq.) and stirred under argon at room temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo. The light yellow viscous oil was dissolved in dry CH2C12 (30 ml) and DMF (dried over 4A sieves, 2 drops), the clear solution cooled to -10°C (salt/ice bath) and treated dropwise via syringe with distilled oxalyl chloride (1.41 ml, 16.2 mmole, 1.1 eq.). Vigorous gas evolution was evident and the solution became deeper yellow in color. The mixture was stirred under argon at -10°C for 15 minutes then allowed to stir at room -90- HXlOb temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo to give crude phosphonochloridate as a yellow oil. G. (S)—4—[[2-[41-Fluoro-3,31,5-trimethyl-[1,1'-biphenyl]-2-yl]ethynyl]methoxy-phosphinyl]-3-t-butyldiphenylsilyloxy- butanoic acid, methyl ester A -78°C (C02/acetone) solution of the Part E acetylene (2.678 g, 11.2 mmole) in dry THF (20 ml) was treated dropwise with a 1.6 M solution of n-BuLi in hexanes (7 ml, 11.2 mmole, 1.0 eq). The purple mixture was stirred under argon at -78°C for one hour, briefly warmed to 0°C, recooled to -78°C, transferred by cannula into an addition funnel and added dropwise to a -78°C (CC^/acetone) solution of the Part F phosphonochloridate (8.27 g, 18.4 mmole, 1.6 eq) in dry THF (20 ml). After one hour at -78°C the mixture was quenched with saturated NH4C1, then allowed to warm to room temperature and extracted with Et20. The ethereal layer was washed with saturated NaHC03 and brine then dried over anhydrous MgS04 and evaporated to give 11.705 g of a brown oil. The crude oil was purified by flash chromatography on silica gel eluting with (7:3) Hex-EtOAc. Product fractions were combined and evaporated to give 4.246 g (56%) of desired title acetylenic phosphinate as a light brown oil. Additionally, 457 mg (68% corrected yield) of Part E biphenyl acetylene was recovered. TLC (7:3) Hex-Acetone, Rf = 0.20, UV and PMA. 22 4 7 HXlOb -91- H. (S)-4-[(2-[4*-Fluoro-3",35-trimethyl-[1,1'-biphenyl]-2-yl]ethyl]methoxyphos-phinyl]-3-t-butyldiphenylsilyloxy- butanoic acid, methyl ester An argon purged solution of the Part G acetylenic phosphinate (333 mg) in CH3OH (5 ml) was treated with 10% Pd/C (121 mg, 36% by weight) and shaken on a Parr apparatus under H2 (40 psi) for 30 hours. Catalyst was removed by filtration through packed Celite and the filtrate evaporated to a pale yellow oil. The crude oil was purified by flash chromatography on silica gel eluting with (1:1) EtOAc-Hex. Product fractions were evaporated to give 250 mg (75%) of the title saturated phosphinate as a clear oil. TLC (4:1) EtOAc-Hex, Rf = 0.33, UV and PMA." J. (S)-4-[[2-(4'-Fluoro-3,3l,5-trimethyl-[1,1* -biphenyl ] -2 -yl ] ethyl ] methoxyphos-phinyl]-3-hydroxybutanoic acid, methyl ester A solution of the Part H silyl ether (330 mg, 0.489 mmole) in dry THF (6 ml) was treated with glacial HOAc (115 pi, 1.96 mmole, 4.0 eq) followed by a 1.0 M tetrabutylammonium fluoride solution in THF (1.47 ml, 1.47 mmole, 3.0 eq) and the resulting mixture stirred overnight at room temperature under argon. The mixture was diluted with 10 ml of ice water and extracted with EtOAc (2X). The organic phase was washed with saturated NaHC03 and brine then dried over anhydrous Na2S04 and evaporated to give 364 mg of a pale yellow oil. The crude oil was purified by flash £ 'i 4 7 3 4 HXlOb -92- chromatography on silica gel eluting with (6:4) OAcetone-Hexane. Product fractions were evaporated * to give 205 mg (96%) of desired title free alcohol as a clear oil which slowly crystallized on 5 standing. TLC (7:3) Acetone-hexane, Rf = 0.28,"UV and PMA. O Example 2 (S)-4-[[2-[4'-Fluoro-3, 31,5-trimethyl]1,1 * -10 b ipheny 1 ] - 2 -yl. ] &thy 1 ] hydr oxypho sphinyl ] - 3 -hydr oxy- butanoic acid, dilithium salt A solution of the Example 1 diester (187 mg, 0.429 mmole) in dioxane (5 ml) was treated with a 1.0 N LiOH solution (1.29 ml, 1.29 mmole, 15 3.0 eg) and the mixture heated at 55°C (oil bath) under argon for 2.5 hours. The mixture was cooled, diluted with H20, filtered and evaporated in vacuo. The residue was dissolved in a minimum amount of H20 and chromatographed on HP-20 20 resin (25 mm column diameter, ^15 cm bed) eluting with H20 followed by a (1:1) CH30H-H20 mixture. Collected product fractions were evaporated, dissolved in H20 (50 ml), filtered, and lyophilized to give 175 mg (91%, based on hydrate weight) of 25 desired title dilithium salt as a white, electrostatic solid. TLC (8:1:1) CH2Cl2-CH30H-H0Ac, Rf = 0.1, UV and PMA and (7:2:1) iPr0H-NH40H-H2O, Rf = 0.45, UV and PMA. o 30 Microanalysis for C21H2405FPLi2 and 1.7 moles H20 (MW 450.90) ► I 9 9 A 7 * HXlOb -93- Calcd: C, 55.93; H, 6.13; F, 4.21," P, 6.87 fN Found: C, 55.91; H, 5.84; F, 3.92; P, 6.89 k«f*n»u * ^H-NMR (400 MHz, CD30D 5 61.34 - 1.56 ppm (4H, multiplet) 2.22 - 2.31 ppm (2H, multiplet) 2.25 + 2.37 ppm (6H, two singlets) 2.29 ppm (3H, doublet, Jg_F = 1.4 Hz) 2.75 ppm (2H, multiplet) 10 4.13 ppm (1H, multiplet) 6.73 - 7.10 ppm (5H, multiplet) Example 3 (S)-4-[[2-[4'-Fluoro-3,3',5-trimethyl[1,1'-15 biphenyl ] -2-yl ] ethynyl ]methoxyphosphinyl ] -3- hydroxybutanoic acid, methyl ester A mixture of the Example 1 Part G silyl ether (455 mg, 0.678 mmole) and glacial acetic acid (155 |jl, 2.71 mmole, 4.0 eq.) in dry THF (7 20 ml) was treated with a 1.0 M tetrabutylammonixun U— fluoride solution in THF (2.0 ml, 2.0 mmole, 3.0 eq.) and the resulting solution stirred overnight under argon at room temperature. The mixture was poured into ice cold H20 (10 ml) and extracted 25 with EtOAc (2X). The organic phase was washed with saturated NaHC03 and brine, then dried over ^ anhydrous Na2S04 and evaporated to give 498 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with 30 (3:2) Hexane-Acetone. Product fractions were evaporated to give 217 mg (74%) of title alcohol as a colorless oil. TLC (7:3) Hexane-Acetone, Rf = 0.10, U.V. and PMA. 22 47 3 4 HXlOb -94- Example 4 (S)-4-[[2-[41-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt A mixture of the Example 3 diester (203 mg, 0.469 mmole) in dioxane (6 ml) was treated with a 1.0 N LiOH (1.6 ml, 1.6 mmole, 3.5 eq.) and the solution heated at 55° (oil bath) under argon for 30 minutes. The mixture was cooled, diluted with H20, filtered, evaporated, taken up in H20 (30 ml) and lyophilized. The white lyophilate was dissolved in a minimum amount of H20 and chromatographed on HP-20 resin (25 mm diameter column, 10 cm resin bed), eluting with H20 followed by (50:50) H20-CH30H. Product fractions were combined and evaporated, the residue taken up in H20 (30 ml) and lyophilized to give 199 mg (97%, based on hydrate, MW = 435.36) of the title di-lithium salt as a whi.te solid. TLC (8:1:1) CH2Cl2-CH30H-H0Ac, Rf = 0.13, U.V. and PMA. Microanalysis for C21H2Q05FPLi2 + 1.06 moles H20 (MW 435.36) Calcd: C, 57.93; H, 5.12; F, 4.36; P, 7.11 Found: C, 57.91; H, 4.89; F, 4.22; P. 6.89 1H NMR (400 MHZCD30D): 61.76-1.82 ppm (2H, multiplet) 2.32 (3H, doublet, JRF=1.8 Hz) 2.34 (3H, singlet) 22 4 7 HXlOb -95- 2 .37 (1H, dd, J=8.4 Hz) 2 .41 (1H, dd, J=4.1 Hz) 2 .49 (3H, singlet) 4 .27 (1H, multiplet) 6.98-7 .37 (5H, m) Example 5 (S,Z)-4-[[2-[41-Fluoro-3, 31,5-trimethyl[1,1'-biphenyl]-2-yl]ethenyl]methoxyphosphinyl]-3- hydroxybutanoic acid, methyl ester A. (S,Z)-4-[[2-[4'-Fluoro-3,3',5- trimethyl[1,1'-biphenyl]-2-yl]ethenyl]-methoxyphosphinyl]-3-t-butyldiphenyl-silyloxy-butanoic acid, methyl ester A degassed solution of the Example 1 Part G acetylenic phosphinate (498 mg, 0.742 mmole) in CHgOH (10 ml) was treated with 10% Pd/C (50 mg, 10% by weight) and the black suspension stirred under an H2 atmosphere (1 a tin) for 2 hours. Catalyst was removed by filtration through Celite and the filtrate evaporated to give 500 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (3:2) Hexane-EtOAc. Product fractions were combined and evaporated to give 498 mg (100%) of desired olefin as a colorless oil. TLC (4:1) EtOAc-Hexane, Rf diastereomers = 0.44 and 0.51, U.V. and PMA. 22 4 7 HXlOb -96- B. (S,Z)-4-[[2-[41-Fluoro-3,31,5- trimethyl [1,1' -biphenyl ] -2 -yl ] ethenyl ] -methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester A solution of the Part A silyl ether (498 mg,'0.74 mmole) in dry THF (6 ml) was treated with glacial acetic acid (170 (jl, 2.96 mmole, 4.0 eq. ) followed by a 1.0M tetrabutylammonium fluoride solution in THF (2.2 ml, 2.2 mmole, 3.0 eq.) and the clear, colorless mixture stirred at room temperature under argon for 16 hours. TLC indicated a small amount of remaining starting material. Additional HOAc (40 pi, 1.0 eq.) and n-Bu4NF (0.74 ml, 1.0 eq.) were added and stirring continued for 6 more hours. The mixture was diluted with ice cold H20 (10 ml) and extracted with EtOAc (2X). The combined extracts were washed with saturated NaHCO^ and brine, dried over anhydrous Na2S04 and evaporated to give 468 mg of a pale yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (7:3) Hexane-Acetone. Product fractions were combined and evaporated to give 243 mg (76%) of title alcohol as a colorless oil. TLC (7:3) Hexane-Acetone, Rf = 0.19, U.V. and PMA. Example 6 (S,Z)-4-[[2-[41-Fluoro-3,3',5-trimethyl[1,11 -biphenyl]-2-yl]ethenyl]hydroxyphosphinyl ] -3 - hydroxybutanoic acid, dilithium salt A solution of the Example 5 diester (240 mg, 0.552 mmole) in dioxane (7 ml) was treated with a 1.0 N LiOH solution (1.9 ml, 1.9 mmole, 3.5 eq.) 97 HXlOb arid the stirred mixture heated under argon at 50° (oil bath) for 3 hours. A white precipitate was evident. The mixture was cooled, diluted with HgO, filtered and evaporated in vacuo to a white solid. The crude solid was dissolved in a minimum amount of H20 and chromatographed on HP-20 resin, eluting with H20 followed by (50:50) H20:CH30H. Product fractions were combined and evaporated, taken up in H20 (50 ml), filtered, and lyophilized to give 255 mg (100%, based on hydrate weight, MW 457.58) of title di-lithium salt as a white electrostatic solid. TLC (8:1:1) CH2Cl2-CH3OH-HOAc, Rf = 0.26, U.V. and PMA. Microanalysis for C21H2205FPLi2 +2.18 moles H20 (457.58): Calcd: C, 55.12; H, 5.81; F, 4.15; P, 6.77 Found: C, 55.35; H, 5.68; F. 4.27; P, 7.09 XH NMR (400 MHz, CD3OD): 61.24 ppm (2H, multiplet) 2.09 (2H, doublet, J=6.2 Hz) 2.27 (3H, doublet, J^l.8 Hz) 2.30 (3H, singlet) 2.38 (3H, singlet) 4.06 (1H, multiplet) 5.87 (1H, d doublet, ^=12,4 Hz, JHp=14.3 HZ) 6.87 (1H, s) 6.91 (1H, d doublet, ^=43.4 Hz) 6.98 (2H, triplet) 7.22 (2H, multiplet) 0 22 4 7 3 4 HXlOb -98- Example 7 (S)-4-[[2-[3-(4-Fluorophenyl)-l-(1-methylethyl)-lH-indol-2-yl]ethyl]methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester 5 A. 2-[(4-Fluorophenyl)methyl]-3- oxobutanoic acid, ethyl ester Sodium pellets (8.31 g, 362 mmole) were dissolved with mechanical stirring in absolute EtOH (1 liter) and distilled ethyl acetoacetate 10 (47 g, 362 mmole, 1 eq.) was added to the clear solution "under argon. The pale yellow mixture was refluxed for 1 hour, cooled to room temperature, treated with 4-fluorobenzyl bromide (75 g, 398 mmole, 1.1 eq.) and the light orange mixture 15 stirred under argon at room temperature for 2.5 hours.* The mixture was concentrated in vacuo. The residue was partitioned between EtOAc-I^O, the organic phase washed with H20 (2X) and brine, dried over anhydrous Na2S04 and evaporated to 20 give an orange oil. The crude product was purified by vacuum distillation (5 mm Hg) to give 46.47 g (54%) of alkylated product as a clear, colorless liquid with b.p. 142°-144°C. TLC (7:3) Hex-Et20, Rf product = 0.31. 25 1H NMR (CDC13): 61.20 (3H, t), 2.19 (3H, s), 3.13 (2H, d), 3.73 (1H, t), 4.14 (2H, q), 6.95 (2H, t), 7.13 (2H, m) ppm. 30 13C NMR (CD3CN): 614.4, 29.7, 33.7, 62.1, 62.3, 115.3, 116.8, 131.4, 131.9, 145.1 (JC_F=284 Hz), 170.1, 203.5 ppm. cy / ./ HXlOb -99- 34 B. 3-(4-Fluorophenyl)-lH-indole-2-CD carboxylic acid, ethyl ester Ref- Chemical Abstracts Vol. 33^ p, 587 Ref. Helmuth R. et al. J. Chem. Society pp. 6-7, 5 (1927) Ref. Preparative Organic Chemistry 4th Ed. p. 582 O (1972) A solution of the Part A ester (46.4 g, 195 mmole) in absolute EtOH (290 ml) at 0°C (ice bath) 10 was. treated with an aqueous NaOH solution (23.4 g, in 58 ml H20), then treated immediately with a' benzenediazonium chloride solution (Prep. Org. Chem, 4th Ed. p. 582 (1972) prepared from aniline (17.8 ml), conc HCl (88 ml), H20 (98 ml) and NaN02 15 (13.5 g)) to give a deep orange-red biphasic solution. The mixture was stirred for 1 hour at room temperature, poured into ice cold H20 (500 ml) and extracted with EtOAc (3 x 300 ml). The organic phase was washed with brine, (500 ml), dried over 20 anhydrous Na2S04 and evaporated in vacuo to give 55.62 g of crude hydrazone intermediate as an orange oil. TLC (7:3) Hex-Et20, Rf hydrazone = 0.22, UV and PMA. Crude material was used as is for subsequent Fischer cyclization. 25 A solution of the hydrazone in absolute ^ EtOH (200 ml) was treated with gaseous, bubbling HCl for 30 minutes with intermittent ice bath cooling. The brownish mixture was poured into ice cold H20 (600 ml) and extracted with EtOAc (3X). 30 The organic phase was washed with H20 (2X) and brine, dried over anhydrous Na2S04 and evaporated in vacuo to a brownish-tan solid. Trituration with ice cold hexane and filtration afforded 26.74 g / o HXlOb -100- (49%) of desired title indole as tan, granular crystals with m.p. = 129°-130°C. 'V TLC (7:3) Hex-Et20, Rf = 0.26,. U.V. and PMA. 5 Microanalysis for C17H^4FN02:" Calcd: C, 72.07; H, 4.98; F, 6.71; N, 4.94 Found: C, 72.38; H, 5.05; F, 6.87'; N, 5.01 1H NMR (CDC13): 61.22 ppm (3H, t), 4.29 (2H, q), 10 7.10-7.62 (8H, m), 9.21 (1H, bs) ppm. 13C NMR (CDC13): 614.1, 60.9, 111.8, 114.5, 114.8, 120.9, 121.4, 122.9, 123.1, 125.9, 127.9, 129.5, 132.2 (JC_F=7.6 Hz), 135.7, 162.0, 162.2 (Jc_p=244 Hz) ppm. 15 C. 3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indole-2-carboxylic acid, ethyl ester Ref. Sandoz International Patent #158675 p. 35 (1984) A solution of the Part B indole (26.74 g, 20 94.4 mmole) in dry, distilled dimethyl acetamide (100 ml) at 0°C (ice bath) was treated portionwise (vigorous gas evolution) with 60% NaH dispersion in mineral oil (4.53 g, 113.3 mmole, 1.2 eq.) and the mixture stirred under argon at 0°C for 1 hour. 25 2-Iodopropane (85 g, 500 mmole, 5.3 eq.) was added and the mixture allowed to warm to room temperature under argon and stirred for 1 hour. The mixture was re-cooled to 0°C, treated with another 1.2 eq. of NaH, allowed to stir at room terperature for 1 30 hour. This procedure was repeated two more times. The final mixture was cooled to 0°C (ice bath) and excess NaH quenched by careful dropwise addition of absolute EtOH (30 ml). The mixture was diluted *3 ^ / / / 4 / -a n HXlOb -101- with EtOAc, washed with 5% KHSO^, the aqueous phase back extracted once with EtOAc', the combined EtOAc layers washed with H20, and brine (2X), dried over anhydrous Na2S04 and evaporated to give 38.54 g of 5 a brown solid. The solid was taken up in hot CH2C12 and starting indole crystallized out with (-o/' t*16 addition of hexane. 13.88 g of the starting indole was recovered. The mother liquor was evaporated in vacuo to give 22.32 g of a brown oil. 10 The crude product was purified by flash chromatography on silica gel eluting with hexane followed by (95:5) Hex-Acetone. Product fractions were evaporated to give 6.55 g (21%) (62% corrected yield) of desired title N-isopropyl 15 indole as a yellow oil. TLC (4:1) Hexane-Acetone, Rf = 0.57, U.V. and PMA. XH NMR (CDC13): 61.04 (3H,t), 1.20 (6H, d), 4.17 20- (2H, q), 5.40 (1H, m), 7.10-7.7 (8H, m) ppm. n G 13c NMR (CDC13): 613.6, 21.5, 48.7, 53.3, 60.8, 112.7, 114.5, 114.8, 120.3, 121.4, 122.4, 124.3, 125.9, 127.6, 130.8, 131.7 (Jc_p=7.5 Hz), 136.2, 25 162.3 (JC_F=144 Hz), 163.0 ppm. D. 3-(4-Fluorophenyl)-l-(l-methylethyl)- lH-indole-2-methanol Lithium aluminum hydride (1.12 g, 29.6 30 mmole, 1.5 eq.) was carefully added to a 0°C (ice bath) solution of dry, distilled Et20 (30 ml). The resulting suspension was treated dropwise over 10 minutes with an ethereal solution of the Part C 0 - / -* O 4 7 HXlOb -102- indole ester (6.42 g, 19.7 mmole in 20 ml of Et20) ^5 After stirring for 30 minutes at 0°C under argon, the mixture was quenched by sequential dropwise addition of H20 (1.1 ml), 15% NaOH (1.1 ml) and 5 H20 (3.4 ml). The resulting suspension was filtered through packed Celite, dried over ✓-V anhydrous MgSO^ and evaporated in vacuo to give 5.1 g of a yellow foam. The crude product was purified by flash chromatography on silica 10 gel eluting with (85:15) Hex-Acetone to give 5.08 < (91%) of pure title alcohol as a pale yellow foam. TLC (7:3) Hex-Acetone, Rf= 0.38, U.V. and PMA. A small sample was crystallized from hexanes to give 15 the title alcohol as white crystals with m.p. = 101°-103°C. Microanalysis for C18H17NOF: Calcd: C, 76.30; H, 6.40; F, 6.71; N, 4.94 20 Found: C, 76.49; H, 6.46; F, 6.84; N, 4.88 XH NMR (CDC13): 6 1.60 (1H, t), 1.69 (6H, d), 4.76 25 (2H, d), 4.93 (1H, m), 7.05-7.62 (8H, m) ppm. 13, (0 •LJC NMR (CDC13): 6 20.9, 47.3, 54.8, 113.0, 115.9, 116.3, 116.6, 120.2, 120.6, 122.9, 128.5, 131.6, 132.4, 135.1, 135.7, 163.0 (Jc_p=245 Hz) ppm. 30 E. 3-(4-Fluorophenyl)-l-(l-methylethyl)-lH- indole-2-carboxaldehyde A solution of Dess-Martin periodinane (5.9 g, 13.9 mmole, 1.2 eq.) in dry, CH2C12 (30 ml) was o 22 4 7 HXlOb -103- treated with dry t-butanol (1.3 ml, 13.9 mmole, 1.2 eq.) and the mixture stirred at room temperature under argon for 15 minutes. Part D indole alcohol (3.28 g, 11.6 mmole, 1 eq) in dry 5 CH2C12 (12 ml) was added dropwise over 5 minutes and the yellow mixture stirred under argon at room temperature for 1 hour. The reaction mixture was added to a stirred solution of sodium thiosulfate (15.3 g, 97 mmol, 7 eq.) in freshly 10 prepared 1.0N NaHCO^ (40 ml) and the resulting mixture stirred vigorously for 5 minutes. The organic phase was separated, washed with 1.0N NaHC03, H20 and brine, dried over anhydrous Na2SC>4 and evaporated to give 3.69 g of a yellow 15 oil. The crude product was purified by flash chromatography on silica gel eluting with (40:1) Hexane-Et20 to give 2.7 g (83%) of pure title aldehyde as a white crystalline solid with m.p. = 88°-89°C. 20 TLC (7:3) Hex-Acetone, Rf = 0.56, U.V. and PMA. Microanalysis for C^gH^gFNO: 25 Calcd: C, 76.85; H, 5.73; N, 4.98; F. 6.75 Found: C, 76.91; H, 5.71; N, 4.95; F, 6.76 1H NMR (CDC13): 61.69 (6H, d), 5.92 (1H, m), 7.10-7.70 (8H, m), 9.80 (1H, s) ppm. 30 13C NMR (CDC13): 621.4, 48.0, 112.5, 113.2, 115.4, 115.7, 120.8, 122.1, 126.9, 127.0, 132.0, 132.6 (JC_F=7.5 Hz), 183.6 ppm. w o / 7 HXlOb -104- F. 3-(4-Fluorophenyl)-l-(l-methylethyl)-2- C^) (2,2-dibromoethenyl)-lH-indole A cooled (-15°C, ice/salt bath) solution of the Part E indole aldehyde (1.84 g, 6.54 mmole) 5' and triphenylphosphine (5.14 g, 19.6 mmole, 3 eq.) in dry CH2C12 (30 ml) was treated dropwise over 5 minutes with a dry CH2Cl2 (10 ml) solution of CBr^ (3.25 g, 9.8 mmole, 1.5 eq.) and the yellow mixture stirred at 15°C under argon for 15 10 minutes. The mixture was partitioned between saturated NaHC03 and CH2C12, the organic phase washed with saturated NaHC03 and brine, dried over anhydrous Na2S04 and evaporated to give 9.44 g of a brown oil. The crude product was purified 15 by flash chromatography on silica gel eluting with (95:5) Hexane-CH2Cl2. Product fractions were evaporated to give 2.87 g (100%) of desired title vinyl dibromide as a yellow oil which crystallized on standing. One recrystallization from ethyl 20 ether gave 2.46 g (86%) of purified product as pale yellow, granular crystals with m.p. 135-137°C. u J?**1"®*- o TLC (7:3) Hex-CH.Cl,, Rf = 0.45, U.V. and PMA. 25 Microanalysis for C^gH^gNF Br2: Calcd: C, 52.20; H, 3.69; N, 3.20; Br, 36.56 Found: C, 52.25; H, 3.68; N, 3.20; Br, 36.58 30 XH NMR (CDC13): 6 1.15 (6H, d), 4.67 (1H, m), 7.10-7.70 (9H, m) ppm. 22 4 7 HXlOb -105- 13C NMR (CDC13): 5 21.9, 48.6, 98.6, 111.6, 115.3, 115.6, 115.9, 119.9 (JC_F=7.6 Hz), 122.4, 127.5, 129.3, 130.5, 130.7, 130.9, 135.2, .161.5 (Jc_p=246 Hz) ppm. G. 3—(4-Fluoropheny1)-1-(1-methylethyl)-2- ethynyl-lH-indole A -78°C solution (dry ice/acetone) of the Part F vinyl dibromide (2.395 g, 5.48 mmole) in dry THF (10 ml) under argon was treated dropwise with a 1.6M solution of n-BuLi in hexanes (6.9 ml, 10.96 mmole, 2 eg.). The resulting mixture was stirred at -78°C for 1 hour then quenched by dropwise addition of saturated NH4C1 (5 ml). The mixture was allowed to warm to room temperature then extracted with Et20 (2X). The ethereal layers were washed with brine, dried over anhydrous MgS04 and evaporated in vacuo to give 1.893 of a dark brown oil. The crude product was purified by flash chromatography on silica gel (80:1) eluting with (200:1) Hexane-Et20 to give 1.12 g of purified product as a (3.3:1) mixture of acetylene to terminal olefin. This mixture was separated by chromatography on alumina (neutral, activity = II) column eluting with (200:1) Hexane-Et20. Evaporation of product fractions gave 900 mg of off-white crystals. One. recrystallization from hot hexane gave 700 mg (46%) of purified title acetylene as white needles with m.p. = 105-106°C. TLC (95:5) Hex-Et20, Rf acetylene = 0.44, Rf olefin = 0.49, U.V. and PMA. 22 4 7 HXlOb -106- Microanalysis for CigH16NF: Calcd: C, 82.28; H, 5.81; N, 5.05; F, 6.85 Found: C, 82.70; H, 5.85; N, 5.10; F, 6.62 XH NMR (CDC13): 61.70 (6H, d), 3.5 (1H, s), 5.06 (1H, m), 7.10-7.75 (8H, m) ppm. H. (S)-4—[£2—[3—(4-Fluorophenyl)-1—(1-methylethyl)-lH-indol-2-yl]ethynyl]-methoxyphosphinyl]-3-(t-butyldiphenyl-silyloxy)butanoic acid, methyl ester A -78°C (dry ice/acetone) solution of the Part G acetylene (678 mg, 244 mmole, 1.0 eq.) in dry THF (6 ml) under argon was treated dropwise with a. 1. 6M solution of n-BuLi in hexanes (1.53 ml, 2.44 mmole, 1.0 eq.). After 30 minutes at -78°C, the mixture was transferred by cannula to a -78°C solution of Example 1 Part F phosphonochloridate (^4.3 mmole, 1.75 eq.) in dry THF (5 ml). The dark brown mixture was stirred at -78°C for 30 minutes then quenched by dropwise addition of saturated NH4C1 (5 ml) and allowed to warm to room temperature- The mixture was extracted with Et20 (2X), washed with saturated NH4C1 and brine, dried over anhydrous MgSC>4 and evaporated in vacuo to give 2.567 g of a brown-red oil. The crude oil was purified by flash chromatography on silica gel eluting with (3:2) Hexane-EtOAc to give 756 mg (44%) of desired title acetylenic phosphinate as a dark yellow oil. TLC (7:3) Hex-Acetone, Rf = 0.27, U.V. and PMA. O -107 22 4 7 34 HXlOb 1H NMR (CDC13): 6 1.0 (9H, s), 1.64 (6H, d), (3 2.10-2.90 (4H, m), 3.56 (3H, s), 3.58 (3H, dd), 4.6 (1H, bm), 4.90 (1H, m), 7.05-7.55 (18H, m) ppm. 5 13C NMR (CDC13): 6 14.2, 19.1, 21.0, 26.7, 27.8, 37.5, 39.2, 42.2, 45.1, 49.2, 51.4, 51.9, 60.3, Q 65-5 <Jc_p=15.1 Hz), 88.1, 91.2, 98.3, 111.3, 115.3, 115.6, 120.8 (J=5.7 Hz), 122.3, 124.9, 125.9, 126.4, 127.6, 129.2, 130.7, 133.0, 135.7, 10 136.1, 170.9 ppm. J. (S) —4— [ [2-[3-(4-Fluorophenyl)-l-(l-methylethyl )-lH-indol-2-yl] ethyl] -methoxyphosphinyl ] -3- (t-butyl diphenyl-15 silyloxy)butanoic acid, methyl ester An argon purged solution of the Part H acetylenic phosphinate (422 mg) in CH^OH (9 ml) was treated with 10% Pt/C (420 mg) and the resulting mixture shaken on a Parr apparatus for 20 2 hours under 40 psi of hydrogen. Catalyst was removed by filtration through Celite and the filtrate evaporated to give 380 (90%) of title indole phosphinate as a yellow foam. TLC (4:1) EtOAc-Hex, Rf = 0.27 U.V. and PMA. 25 Q 1H NMR (CDC13): 5 1.00 (9H, s), 1.63 (6H, d), 1.5-2.0 (2H, m), 2.20 (1H, m), 2.58-3.00 (5H, m), 3.44 (3H, dd, JH_p=10.6 Hz), 3.61 (3H, s), 4.52 (2H, m), 7.07-7.66 (18H, m) ppm. 30 1 o 22 4 7 34 HXlOb -108- 13C NMR (CDC13): 612.6, 16.8, 17.2, 19.1, 21.5, O" 26.7, 36.0, 42.1, 47.2, 50.9, 51.4, 65.8; 111.8, 115.3, 119.1, 121.1, 127.7, 128.3, 129.9, 131.2, 131.3, 132.8, 133.4, 134.3, 134.8, 135.7, 171.3 5 ppm. 'w' K. (S)-4-[[2-[3-(4-FluorophenylJ-l-fl- methylethyl )-lH-indol-2-yl]ethyl]-methoxyphosphinyl]-3-hydroxybutanoic 10 acid, methyl ester A solution of the Part J silyl ether (379 mg, 0.531 mmole) in dry THF (5 ml) was treated successively with glacial HOAc (120 h1/ 2.12 mmole, 4 eq.) and a 1.0M tetrabutylammonium 15 fluoride solution in THF (1.6 ml, 1.6 mmole, 3 eq.) and the resulting solution stirred overnight under argon at room temperature. The mixture was diluted with ice cold ^0 (10 ml), extracted with EtOAc (2X), the organic phase washed with saturated 20 NaHCOg and brine then dried over anhydrous Na2S0^ £) and evaporated to give 408 mg of a yellow oil.. The crude product was purified by flash chromatography on silica gel eluting with (7:3) Acetone-Hexane. Product fractions were evaporated to give 197 mg 25 (78%) of desired title alcohol as a white foam. TLC (1:1) Hexane-Acetone, Rf = 0.09 U.V and PMA. XH NMR (CDC13): 6 1.68 (6H, d), 1.80-2.0 (2H, m), 30 2.10 (2H, m), 2.58 (2H, m), 3.08 (2H, m),.3.63 (3H, dd, JH_p=10.1 Hz), 3.70 (3H, d), 3.96 (1H, t), 4.35 + 4.49 (1H, 2 broad multiplets), 4.67 (1H, m), 7.0-7.6 (8H, m) ppm. © 22 47 HXlOb -109- 13C NMR (CDC13): 617.6, 17.7, 21.4, 29.2, 29.4, rV • 33.2, 33.3, 34.6, 41.6, 41.8, 42.0, 42.2, 47.3, W 50.9, 51.7, 63.4, 111.8, 113.5, 115.2, 115.5, 119.0, 119.4, 121.1, 128.3, 131.3, 131.5, 134.2, 5 134.8, 161.5 Jc_p=244.1 Hz), 172.1 ppm. .O) Example 8 (S)-4-[[2-[3-(4-Fluorophenyl)-l-(l-methylphenyl)-lH-indol-2-yl ] ethyl ] hydroxyphosphinyl ] -3-hydroxy- 10 butanoic acid, dilithium salt A stirred solution of the Example 7 diester (197 mg, 0.414 mmole) in dioxane (5 ml) was treated with l.ON LiOH (1.45 ml, 3.5 eq.) and the resulting white suspension was heated at 55°C (oil 15 bath) under argon for 40 minutes. The mixture was cooled, diluted with H20, filtered, evaporated in vacuo. The residue was taken up in a minimum amount of H20 and chromatographed. on HP-20 resin, eluting with H20 followed by (50:50) H20-CH30H. 20 Product fractions were combined and evaporated. The glassy residue was taken up in H90 (50 ml), filtered and lyophilized to give 178 mg (85%, based on hydrate weight) of pure title di-lithium salt as a white solid. 25 Microanalysis for C23H25NFP«2Li + 2.52 moles H20 (MW 504.71): Calcd: C, 54.73; H, 6.00; N, 2.78; F, 3.76; P, 6.14 Found: C, 54.62; H, 5.67; N, 2.90; F, 3.61; P, 6.06 30 g 10 224734 HXlOb -110- XH NMR (400 MHz, CDC13): 1 .69 ppm (6H, dd, J=5.8 Hz) 1 .71 (2H, multiplet) 1 .93 (2H, multiplet) 2 .38 (2H, multiplet) 3 .06 (2H, quartet) 4 .32 (1H, multiplet) 4 .87 (1H, multiplet) 6 .97 (1H, dt, J=0.7 Hz) 7 .07 (1H, dt, J=1.1 Hz) 7 .16 (2H, t) 7 .41 (3H, m) 7, .57 (1H, 1/2 AB quarte 15 Example 9 (S )-4- [[2-[[l,l! -Biphenyl ] -2 -yl ] ethyl ] methoxyphosphinyl] -3 -hydroxybutanoic acid, methyl ester A. Biphenyl-2-carboxaldehyde Dess-Martin periodinane (27.64 g, 65.2 20 mmol) was stirred under argon atmosphere with 150 ml of CH2C12. Dry t-BuOH (8.0. ml) was added to the stirring solution, and this mixture was stirred for 10 minutes at room temperature. A. CH2C12 solution (20 ml) of biphenyl-2-methanol (10 25 g, 54.3 mmol) was added dropwise over 15 minutes. After the addition was complete, the reaction was allowed to stir at room temperature. After stirring for 1 hour at room temperature, 600 ml of Et20 (anhydrous) was added to the reaction 30 followed by IN NaOH (225 ml). After 10 minutes, the resulting slurry was filtered, and the filter cake was washed with Et20. The filtrate was washed 2X with 250 ml portions of IN NaOH. The 99 4 7 CM HXlOb -111- organic layer was dried over MgS04 and filtered to give a yellow oil (10 g) after solvent removal. Purification by flash (silica gel, l:10/Et20:Hexane) provided title aldehyde (9.58 g, 97%) as a colorless oil. TLC (1/9 EtOAc/Hexane, silica gel) Rf = 0.29 IR (film) 3065, 3025, 2850, 2760, 1685, 1700, 1600, 1470, 1450, 1395 cm"1 NMR (270 MHZ) (CDClg) 68.00 (d, 1, J=70. Hz), 7.60 (m, 1), 7.40 (m, 7). Mass Spec m/e 183 (M++H). B. 2 - (2,2 -Dibromoe thenyl) - f 1,1' -biphenyl ] A solution of Part A aldehyde (2.0 g, 11 mmol) in CH2C12 (60 ml) was placed under argon atmosphere and cooled to -10°C. Triphenylphosphine (9.21 g, 35 mmol) was added, and this mixture was stirred until all of the solid dissolved. To the resulting solution at -10°C was added over 15 minutes a CH2Cl2 (40 ml) solution of CBr4 (5.5 g, 16.5 mmol). The reaction was stirred at -10°C for 1 hour 15 minutes, and then it was quenched at -10°C with 50 ml of saturated aqueous NaHC03 solution. The CH2C12 and aqueous layers were separated and the aqueous layer was extracted IX with CH2C12. The combined CH2C12 extracts were washed IX with saturated aqueous NaHC03 solution and IX with saturated aqueous NaCl solution. The CH2C12 extract was dried over Na2S04 and evaporated to dryness. The crude product was <r^. 22 4 7 3 4 HXlOb -112- purified by flash chromatography eluting with (, > ... hexane to give the title dibromide as an off white solid (2.45 g, 66%). 5 TLC (5 :95/EtOAc:Hexane silica gel) Rf = 0.47. IR (CHC13) 3064, 3011, 1596, 1473, 1450, 1435, I 889, 860, 702 cm"1 10 "^H NMR (270 MHz) (CDCl3) 67.75 (m, 1), 7.35 (m., 8), 7.20 (s, 1) 13C NMR (67.0 MHz) (CDCl3) 6141.06, 140.08, 137.49, 133.83, 129.81, 129.45, 15 129.17, 128.61, 128.22, 127.50, 127.08, 90.78 Mass Spec m/e 337/339/341 (M++H) C. 2-Ethynyl-I" 1,1'-biphenyl] 20 A THF (35 ml) solution of Part B vinyl dibromide (2,31 g, 6.9 mmol) was cooled to -78°C under an argon atmosphere. With stirring at -78°C, n-BuLi (5.52 ml of 2.5 M solution in hexane) was added over 10 minutes to the vinyl 25 dibromide. On completion of the n-BuLi addition, ' S W the reaction mixture became deep purple. After stirring at -78°C for 2 hours 45 minutes, the reaction was quenched with saturated aqueous NH4C1 solution. After the quenched reaction was warmed 30 to room temperature, the THF was removed from the reaction mixture and the resulting material was diluted with H20 and extracted 3X with : Et20/hexane. The organic extract was dried over « 22 4 7 HXlOb -113- MgS04 and filtered to give 1.3 g of a yellow oil. Purification by flash chromatography eluting with 1% Et20/hexane provided the desired title acetylene (1.04 g, 88%). 5 TLC (100% Hexane, silica gel) Rf = 0.16 IR (film) 3287, 3061, 3026, 1474, 1449, 1432, 1008, 775, 758, 738 cm'1 10 XH NMR (270 MHZ) (CDC13) 6 7.68 (m, 3), 7.35 (m, 6), 3.00 (s, 1) 13C NMR (67.8 MHz) (CDCl3) 15 6144.40, 140.22, 133.83, 129.56, 129.20, 128.92, 127.95, 127.49, 126.94, 120.44, 83.08, 80.15 Mass Spec m/e 179 (M++H). 20 D. (S)-4-[[2-[[1,11-Biphenyl]-2-yl]- ^ ethynyl]methoxyphosphinyl]-3-(t-butyl- dipehnylsilyloxy)butanoic acid, methyl ester Part C acetylene (0.332.g, 1.86 mmol) was 25 stirred at -78°C (under argon atmosphere and in 10 ml of THF. Over 5 minutes, n-BuLi (0.75 ml of a 2.5 M solution in hexane) was added to the acetylene solution. The reaction was stirred at -78°C for 1 hour warmed to 0°C and stirred for 10 30 minutes and then recooled to -78°C. The acetylenic anion solution was then added dropwise over 8 minutes to a 10 ml THF solution of the Example 1 Part F phosphonochloridate (2.98 mmol) 22 4 7 HXlOb -114- which had been cooled to -78°C under an argon atmosphere. After the addition was complete, the reaction was stirred at -78°C for 1 hour and then quenched by the addition of saturated aqueous NH^Cl 5 solution. The quenched reaction was warmed to room temperature, diluted with half-saturated aqueous NaCl solution and extracted 3X with Et20. The combined Et20 extracts were washed with saturated aqueous NaHCO^ and saturated aqueous NaCl 10 solutions. The Et20 layer was dried over MgSO^ and evaporated to give 1.5 g of a yellow oil: Purification by flash chromatography eluting with 5:1:4 hexane:toluene:EtOAc gave the title acetylenic phosphinate (0.543 g, 48%). 15 TLC (5:1:4 hexane:toluene:EtOAc, silica gel) Rf = 0.20. IR (CHC13) 3070, 3053, 3035, 3000, 2952, 2934, 20 2896, 2859, 2178, 1735, 1474, 1448, 1436, 1429 cm"1 © ■'■H NMR (270 MHZ) CDCl3) 67.65 (m, 3), 7.65-7.28 (m, 16), 4.55 (m, 1), 3.55 (d, 3), 3.40 (dd, 3), 2.80 (m, 1), 2.55 (m, 1), 2.35 25 (m, 1) 2,08 (m, 1), 1.00 (s, 9) 13C (67.8 Mz) (CDC13) 6170.83, 145.29, 145.19, 139.22, 135.95, 135.59, 133.86, 133.75, 133.16, 132.86, 130.57, 129.56, . 30 129.34, 128.81, 127.92, 127.75, 127.44, 127.39, 126.94, 117.90, 100.91, 100.38, 100.18, 84.51, 22 4 7 3 4 HXlOb -115- 81.60, 65.53, 65.42, 60.06, 51.61, 51.50, 51.11, 42.07, 41.90, 38.86, 37.16, 26.56, 20.75, 18.97, 13.97 5 Mass Spec m/e 611 (M++H) E. (S)-4-[ [2-[ [1,1'-Biphenyl]-2-yl]ethyl]-methoxyphosphinyl ] - (t-butyldiphenyl-silyloxy)butanoic acid, methyl ester 10 Argon was bubbled through a methanol (8 ml) solution of Part D acetylenic phosphinate (0.515 g, 0.85 mmol) for 10 minutes. Addition of 10% Pd/C (0.190 g) to the acetylene solution was followed by Parr hydrogenation at 43 psi. After 15 shaking for 25 hours at 43 psi, the methanol solution was filtered through Celite and the filtrated evaporated to give the title phosphinate (0.510 g, 98%) as a colorless oil. 20 TLC (4:1 EtOAc: hexane) Rf = 0.21 IR (CHClg) 3071, 3054, 2998, 2954, 2934, 2902, 2859, 1734, 1477, 1462, 1448, 1438, 1428 cm"1 25 2H NMR (270 MHz) (CDCl3) 67.65 (m, 3), 7.55-7.00 (m, 16), 4.45 (m, 1), 3.58 (s, 3), 3.30-3.20 (2 doublets, 3, J = 11 Hz), 2.88 (m, 1), 2.60 (m, 3), 2.17-1.80 (m, 1), 1.80-1.30 (m, 1), 1.00 (s, 3). W 30 13C NMR (67.8 MH) (Diagnostic peaks) (CDC13) 6171.33, 65.78, 51.36, 42.24, 26.75 « 22 4 7 3 4 HXlOb -116- Mass Spec m/e 615 (M++H) QC ■ F. (S)-4-[2-[[1,l1-Biphenyl]-2-yl]ethyl]-, . methoxyphosphinyl]-3-hydroxybutanoic 5 acid, methyl ester A THF (10 ml) solution of Part E phosphinate (0.500 g, 0.82 mmol) was stirred under an argon atmosphere with HOAc (0.19 ml, 3.3 mmol). At room temperature, nBu4 NF (2.45 ml, 1.0 10 M solution THF) was added dropwise. The reaction was stirred at room temperature for 23 hours and then quenched with 15 ml of ice water. The aqueous layer was extracted 3X with EtOAc. The combined organic solutions were washed 2X with 15 saturated aqueous NaHC03 solution and IX with saturated aqueous NaCl solution. The organic layer was dried over Na2S04 and evaporated to give 0.437 g of a colorless oil. Purification by flash chromatography eluting with 7:3 20 acetone:hexane gave the title alcohol (0.247 g, 81%) as a colorless oil. TLC (7:3 acetone:hexane, silica gel) Rf = 0.22 25 IR (CHC13) 3600-3171 (br), 3064, 3009, 2954, 1731, 1479, 1439, 1237, 1180, 1042, 999 cm"1 1H NMR (270 MHz) (CDClg) 6 7.50-7.10 (m, 9), 4.50-4.15 (m, 1), 3.70 (s, 3), 30 3.53 & 3.50 (2 doublets, 3, J=ll Hz), 2.88 (m, 2), 2.50 (m, 2), 2.00-1.60 (m, 4) 22 4 HXlOb -117- 13c NMR (67.8 MHz) (CDCl3) 6171.55, 171.49, 141.39, 141.00, 138.10, 137.88, 129.95, 128.81, 128.06, 127.53, 26.83, 126.22, 63.08, 63.02, 62.85, 51.39, 50.58, 50.-47, 42.35., 42.15, 42.07, 41.87, 34.31, 33.06, 33.00, 30.77, 30.52, 29.49, 29.21, 25.41 Mass Spec m/e 377 (M++H) Example 10 (S)-4-[2-[1,1'-Biphenyl-2-yl]ethyl]hydroxyphos-phinyll-3-hydroxybutanoic acid, dilithium salt Example 9 diester (0.239 g, 0.64 mmol) was stirred in dioxane (6.5 ml) under argon atomsphere. At room temperature, 1.9 ml of 1.0 M LiOH solution was added. This mixture was stirred at 55°C. After stirring for 2.5 hours, the reaction was cooled to room temperature, and the dioxane and most of the H20 were removed by rotary evaporation. Purification by HP-20 chromatography (18 cm x 2.5 cm) eluting first with 100% H20 and then with 1:1 Me0H:H20 gave the title dilithium salt (0.180 g, 79%) as a white solid. TLC (8:1:1 CH2Cl2:MeOH:AcOH) Rf = 0.16 (7:2:1 nPrOH:NH3:H20) Rf = 0.37 22 4 7 3 4 HXlOb -118- Example 11 (R)-4-[[(E)-2-[4'-Fluoro-3,3\5-trimethyl[l,l'-biphenyl]-2-yl]ethenyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt 5 A. (E)-Tributyl[2-[41-fluoro-3,3',5- triraethyl[1,1*-biphenyl]-2-yl]ethenyl]- Q tin Ref. Miftakov, M.A. et al. Synthesis (Comm.) pp. 496-499 (1985). A mixture of 2-ethynyl-4'-10 fluoro-3,3',5-trimethyl[1,1'-biphenyl] (1.7 g, 7.13 mmole) and (n-C^Hg^SnH (2.9 ml, 10.7 mmole, 1.5 eg.) was treated with AIBN (7.0 mg, 0.426 mmole) and the solution heated rapidly to 120°C (oil bath) under argon. After 15 minutes at 120°C an 15 additional quantity of (n-C^g^SnH (0.39 ml, 1.43 mmole, 0.2 eq.) was added and heating continued for a total of 3 hours. The yellow mixture was cooled and purified by Kugelrohr distillation at 0.1 mmHg, 240°C to give 3.073 g (81%) of title vinyl stannane 20 as a colorless liquid. TLC hexane, R^ product =0.45, UV & PMA. Product is unstable on silica gel (streaks to baseline). 13C NMR (67.5 MHz, CDClg): 9.5, 13.6, 14.5, 20.9, 25 21.1, 27.2, 27.6, 114.0, 114.3, 123.6, 123.9, 128.8, 130.4, 133.0, 135.6, 136.1, 138.1, 140.0, 144.4, 160.3 (Jcf=244 H2) ppm. 22 4 7 3 4 HXlOb -119- 1H NMR: 60.8-1.5 ppm (27 H, m, Sn(Bu)3) 2.27, 2.31, 2.36 (9H, 3 singlets, aromatic ch31s) 6.05 (1H, d, J=20 Hz, PhCH=CHSn) 6.68 (1H, d, J=20 Hz, PhCH=CHSn) 6.90-7.13 (5H, m, aromatic protons) B. (E)-4'-Fluoro-2-(2-iodoethenyl)-3,3', 5- trimethylf1,11-biphenyl 1 A solution of the Part A vinyl stannane (1.537 g, 2.89 mmole) in dry Et20 (20 ml) was treated with iodine (734 mg, 2.9 nunole, 1 eq.) and the brownish solution stirred at room temperature under argon for 2 hours. The mixture was washed with saturated sodium thiosulfate, 10% NH^OH and brine, dried over anhydrous MgSO^ and evaporated to give 1.639 g of a yellow oil. The crude product was purified by flash chromatography on silica gel (160 gm) eluting with hexane. Combined product fractions gave 832 mg (65%) of desired pure title trans vinyl iodide as a pale yellow oil which slowly crystallized on standing, m.p. 53-55°C. TLC (hexane) R^ trans olefin =0.31, (R^ cis olefin = 0.26), UV & PMA 1H NMR (270 MHZ): 62.30 & 2.32 ppm (9H, 2 singlets, aromatic methyls) 6.05 (1H, d, J=15 Hz, -HC=CHI) 6.92-7.10 (5H, m, aromatic H's) 7.24 (1H, d, J=15 Hz, PhCH=CHI) -120- 22 4 7 HXlOb 13C NMR (67.5 MHz): 14.6, 21.0, 21.1, 81.0 O (=CH-1), 114.4, 114.7, 124.2, 124.5, 128.5, 128.7, 130.5, 132.7, 132.. 8, 133.2, 135.8, 137.2, 140.1, 143.1 (PhCH=CHI), 161.0 (Jcp=244 Hz) ppm. 5 Note: An XH NMR (CDC1,, 270 MHz) on mixed J ... fractions indicated the close running impurity to be the cis vinyl iodide. 66.54 ppm (1H, d, JWaHh = 7.9 Hz (PhCH^CH^I)) 10 C. (R)-3-[[(l,l-Dimethylethyl)diphenyl- silyl]oxy]-4-[ [. (E)-2 - [41 -fluoro-3,3', 5-trimethyl[1,1'-biphenyl]-2-yl]ethenyl]-methoxyphosphinyl]butanoic acid, methyl 15 ester A -78°C (dry ice/acetone) solution of the Part B vinyl iodide (812 mg, 2.22 mmole) in dry THF (6 ml) was treated dropwise via syringe with a 1.6 M n-BuLi solution in hexanes (1.4 ml, 2.2 20 mmole, 1 eq.) and the pale yellow mixture stirred (pp under argon at -78°C for 45 minutes. The anion- was then transferred by cannula dropwise over 10 minutes directly into a -78°C solution of the Example 1 Part F phosphonochloridate (^3.5 mmole, 25 1.58 eq) in dry THF (6 ml). The yellow mixture was stirred for 30 minutes at -78°C then warmed to room temperature. The mixture was quenched at room temperature by the addition of saturated NH^Cl (5 ml). The mixture was diluted with Et20, 30 the ethereal layer washed with saturated NH^Cl and brine, then dried over anhydrous MgSO^ and evaporated to give 2.083 g of a yellow oil. The crude product was purified by flash chromatography 22 4 7 3 4 HXlOb -121- on silica gel eluting with (85:15) Hex-acetone. Product fractions were combined and evaporated to give 249 mg (17%) of the desired trans olefinic phosphinate as a pale yellow oil. NMR indicated 5 approximately at (1:1) mixture of diastereomers at phosphorus. TLC (7:3) Hex-acetone, Rf = 0.35, UV & O PMA. *H NMR: 10 0 63.27 ppm (3H, d, Jg_p =11.6 Hz, -P0CH3) 3.57 & 3.60 (3H, 2 singlets, diastereomers, -co2ch3) 4.33 & 4.50 (1H, 2 multiplets, diastereomers, 15 -CH2CH(0SiR3)CH2-) 4.84 & 5.25 (1H, 2 dd's, diastereomers, JHaHb = 17,9 Hz' JHa-P=25*3 Hz' 0 II 20 PhCHb=CHa-P-) D. (R)-4-[[(E)-2-[4'-Fluoro-3,31,5- trimethyl[1,1'-biphenyl]-2-yl]ethenyl]-methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester 25 A solution of the Part C silyl ether (249 mg, 0.370 mmole) in THF (5.0 ml) was treated successively with glacial HOAc (85 pi, 1.48 mmoles, 4.0 eq.) and a 1.0 M (n-CjHg)4NF solution in THF (1.1 ml, 1.1 mmole, 3.0 eq) and the yellow 30 mixture was stirred overnight at room temperature under argon. The mixture was diluted with cold H20 (10 ml) and extracted with EtOAc. The organic phase was washed with saturated NaHC03 and brine c 4 7 HXlOb -122- then dried over anhydrous Na2SC>4 and evaporated to give 243 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (55:45) Hex-acetone. Product fractions were combined and evaporated to give 121 mg (75%) of desired title hydroxy diester as a colorless viscous oil. TLC (6:4) Acetone-Hex, = 0.26, UV & PMA. 1H NMR; 0 It 51.8-2.06 ppm (2H, m, CH^O-PCTU-) 1 2.30, 2.35, 2.40 (9H, 3 singlets, aromatic CH3's) 2.40-2.60 (2H, m, -CH(OH)CH2CC>2CH3) 3.50+3.55 (3H, 2 doublets, diastereomers, 0 II -P0CH3, JH_p=12 Hz) 1 3.64 (3H, s, -C02CH3) 3.77+3.84 (1H, 2 doublets, • diastereomers, -CH(OH)-) 4.28+4.38 (1H, 2 broad multiplets, -CH(OH)-) 5.52 (1H, 2 dd's, diastereomers Jgjj coupling & Jgp coupling, O ii PhCH=CH-P(OCH3)-) 22 4 7 3 4 HXlOb -123- 6.90-7.10 (5H, aromatic protons) 7.50 (1H, multiplet, diastereomers & Jggj coupling 5 JHP coupling, 0 0 PhCH=CH-F(OCH3)-) 1 E. (R)-4-[[(E)-2-[4'-Fluoro-3,31,5-. 10 trimethyl[1,1'-biphenyl]-2-yl]ethenyl]- hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt A solution of Part D hydroxy diester (121 mg, 0.279 mmole) in dioxane (2 ml) was treated 15 with excess 1.0 N LiOH (0.98 mg, 0.98 mmole, 3.5 eq) and the clear pale yellow mixture stirred under argon at 50°C (oil bath) for 1.5 hours. The mixture was cooled, diluted with H20, filtered and evaporated in vacuo. The residue was taken up in 20 a minimum amount of H20 and chromatographed on HP-20 resin (8 cm bed, 25 mm column diameter) eluting sequentially with H20 (200 ml), (80:20) H20-CH30H, and finally (60:40) H20-CH30H. Product fractions were evaporated in vacuo, taken up in 25 H20 (50 ml) and lyophilized to give 91 mg of pure fv-H title dilithium salt product as a hygroscopic, white lyophilate. TLC (8:1:1) CH2CH2-CH30H-H0Ac, Rf = 0.19, UV & PMA. 34 O HXlOb -124- Examples 12 to 24 Following the procedures as outlined heretofore and as described in the previous working Examples, the following additional 5 compounds may be prepared. o OH v J II I II I Y R-P-CH2-C-CH2-C02-R X OH I 10 z 224/34 - 125- HXlOb o o o o Ex. no. 12. OH 13. C2H5° 14. OH 15. OLi 16. OH 17. OLi :h. -ch2ch2- h -CH=CH- CH. -C=C- H -CH.CH - Li 2 2 -CH=CH- H -C=C- Li - 126- HX10 b o O Ex. no. r 18. och. -ch2ch2- ch3 19. OK c.h.-ch 2 5 I c=0 I o ch. ch. -ch=ch- ok } 5 3 i 20. ONa <oHv iS£r —c=c- c2h5 Na 1 21. oh <2> ch2-0 -«r- H -cilch - h 2 2 o 22 4 7 3 4 - 127- HXlOb ex. no. r z • x r* c_h -c c o 22. OH / \ o -CH2CH2- H CH CH. I 3 3 ^C H 2n5 OH 23. CH30 (P/ -CH«CH- CH3 O 22 4 7 HXlOb -128-Example 25 (S)-4- (Hydroxymethoxyphosphinyl)-3-[[(1,1-di-methylethyl)diphenylsilyl]oxy]butanoic acid, methyl ester, dicyclohexylamine (1:1) salt A. (S )-4-Diisopropyloxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl] oxyl-butanoic acid, methyl ester The Example 1, Part F(2) iodide (45.1 mmol., 21.70 g) was stirred under high vacuum for 30 minutes. Freshly distilled triisopropyl phosphite (0.451 mol., 93.92 g, 113.37 ml.) was added in one portion and the reaction mixture was stirred under argon and heated in a 155°C oil bath for 16.5 hours. The mixture was then cooled to room temperature. Excess triisopropyl phosphite and volatile reaction products were removed by short path distillation (10 mm Hg) followed by Kugelrohr distillation (0.50 nun Hg, 100°C, 8 hours). The product was further purified via flash chromatography (95 mm diam. column, 6"/Merck silica gel, 6/3/1 Hexane/acetone/toluene eluent, 2"/min flow rate, 50 ml fractions) to afford 17.68 g (33.96 mmol, 75% yield) of the title isopropylphosphonate as a clear viscous oil. TLC: Silica gel Rf=0.32 (6:3:1 Hexane/acetone toluene) ^hnmr: (270 mh^, cdclj) 6 7.70-7.65 (m,4H) 7.45-7.35 (m,6H) 4.57-4.44 (m,3H) 3.59 (s,3H) 2.94 and 2.88 (2xd, 1H J=3.7 Hz) 22 4 HXlOb -129- 2.65 and 2.60 (2xd, 1H J=7.4 Hz) 2.24-1.87 (Series of m, 2H) 1.19 and 1.12 (2xd, 12H J=6.3 Hz) 1.01 (s, 9H) B. (S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]-oxy]butanoic acid, methyl ester, dicyclohexylamine (1:1) salt The Part A isopropyl phosphonate (30.5 mmol, "10.66 g) was stirred under argon, at room temperature, in 80 ml of dry C^C^- This solution was treated dropwise (5 min) with bistrimethylsilyltrifluoroacetamide (BSTFA) (32.8 mmol, 8.44 g, 8.71 ml), followed by dropwise addition (10 min) of trimethylsilylbromide (TMSBr) (51.3 mmol, 7.84 g, 6.75 ml). After stirring at room temperature for 20 hours, the reaction mixture was quenched with 200 ml of 5% aqueous KHSO. and stirred vigorously for 15 minutes. The aqueous layer was extracted 3 times with ethylacetate. The organic extracts were combined, washed once with brine, dried over Na2S04 and concentrated in vacuo♦ The residue was azeotroped 2 times with 50 ml of toluene. The precipitate which formed was suspended in toluene and filtered. The filtrate was concentrated and the azeotrope/filter process repeated. The resulting filtrate was evaporated in vacuo and then pumped under high vacuum for 5 hours. The resulting viscous clear oil was stirred under argon, at room temperature, in 50 ml of dry pyridine. This solution was treated in one portion with M o cc h i HXlOb -130- dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g), followed by addition of methanol (41.0 mmol, 1.31 g, 1.67 ml). After stirring at room temperature for 20 hours, the reaction mixture was filtered 5 through a celite pad in a sintered glass funnel. The celite was washed with ethyl acetate and the (0 combined filtrates were evaporated in vacuo. The residue was redissolved in ethyl acetate and washed 2 times with 5% aqueous KHS04 and once with 10 brine.- The organic extract was dried over Na2S04, filtered, the filtrate concentrated and azeotroped 2 times with toluene, suspended in toluene and filtered. The resulting filtrate was again concentrated, azeotroped, filtered and the 15 filtrate evaporated in vacuo and placed under high vacuum for 6 hours to afford the phosphonate monoester as a clear viscous oil (10.2 g, >100% yield). TLC: silica gel Rf=0.50 (7:2:1 nPr0H/NH40H/H20). The phosphonate monoester 20 [1.21 g was pumped under high vacuum for 4 hours, (V) affording 1.16 g (2.57 mmol)] was dissolved in 10 | ml of dry ethyl ether and treated dropwise with | dicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml). I The resulting homogeneous solution sat at room j 25 temperature for 7 hours resulting in significant | crystal formation. The mixture was stored at | -20°C for 16 hours and then warmed to room temperature and filtered. The crystals were washed with cold, dry ethyl ether and then pumped 30 under high vacuum over ?2°5 ^or hours. The crystals were subsequently pumped under high vacuum at 45°C for 4 hours, affording 1.25 g (1.98 22 4 7 HXlOb -131- mmol, 77% yield) of the title dicyclohexylamine salt as a white powdery solid, m.p. 155-156°C. TLC: Silica gel Rf=0.57 (20% MeOH/CH2Cl2) 'H NMR:' (270 MH2, CDC13) 6 7.71-7.65 (m, 4H) 7.40-7.32 (ra, 6H) 4.02 (m, 1H) 3.52 (s, 3H) 3.28 and 3.22 (m, 1H) 3.11 (d, 3H J=ll Hz) 2.77-2.64 (m, 2H) 2:62-2.56 (m, 1H) 1.92-1.08 (Series of m, 22H) 1.00 (S, 9H) Mass Spec: (FAB) 632 (M&H)+ IR:(KBr) 3466-3457 (broad) 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051, 82 0 CM-1 Anal.Calcd for C22H31 OgPSi-C12H23N: C,64.63; H,8.61; N,2.22 Found: C, 64.51; H, 8.49; N, 2.18 25 Example 26 (E)-4-[[2-[4'-Fluoro-3,31,5-trimethyl[1,11-biphenyl]-2-yl]ethenyl]hdroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt A. [2-[4'-Fluoro-3,31,5-trimethyl[1,1'-30 biphenyl]-2-yl]-2-hydroxyethyl]- phosphonic acid, dimethyl ester A -78°C (C02/acetone) solution of dimethylmethylphosphonate (1.8 ml, 16.5 mmole, 1.6 H 5 O 10 15 20 22 4 1 3 4 HXlOb -132- eq) in dry THF (20 ml) was treated dropwise over 20 minutes with a 1.6 M n-butylithium solution in hexanes (9.7 ml/ 15.5 mmole, 1.5 eq) and the resulting white suspension stirred under argon at 5 -78°C for 60 minutes. Example 1, Part C biphenyl aldehyde (2.5 g, 10.3 mmole, 1 eq) in dry THF (10 f*} ml) was then added dropwise over 15 minutes at W -78°C to give a pale orange suspension. After 30 minutes at -78°C, the mixture was quenched by 10 dropwise addition of sat'd NH^Cl (10 ml) and allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and H20, the organic phase washed with brine, dried over anydrous Na2S04 and evaporated in vacuo to give 15 4.127 g of a yellow oil which slowly crystallized on standing. The crystals were triturated with hexanes to give after filtration and drying in vacuo 3.38 g (89.4%) of pure title hydroxy phosphonate as white needles with mp = 98°-100°C. 20 An additional 233 mg (3.613 g total, yield = 95.6%) of pure title compound was recovered by a flash chromatography of the mother liquor (603 mg) on LPS-1 silica gel (40:1) eluting with (7:3) hexane-acetone. TLC (1:1) hexane-acetone, 25 Rf=0.33, UV + PMA. Anal Calcd for C^gH2404PF: C, 62.29; H, 6.60; F, 5.19; P, 8.45 Found: C, 62.66; H, 6.56; F, 5.03; P, 8.68 O a 22 4 7 HXlOb -133- B. [2-[4'-Fluoro-3,31,5-trimethyl[1,11-biphenyl] -2-yl]ethenyl]phosphonic acid, dimethyl ester A solution of the Part A hydroxy 5 phosphonate (3.513 g, 9.6 mmole) in dry (4A sieves) toluene (15 ml) was treated with pTsOH'l O H20 (91 mg, 0.48 mmole, 0.05 eq) and refluxed through a Soxhlet apparatus containing 4A sieves for 16 hours under argon. Additional pTs0H*H20 10 was added during the course of the reaction at the following time intervals: 3.5 hours (91 mg), 5.0 hours (91 mg), and 6.5 hours (91 mg). The mixture was cooled, diluted with ethyl acetate and washed with sat'd NaHCO^ to give an aqueous phase, an 15 organic phase and an oily layer between phases. The aqueous phase and oily layer were collected, washed with ethyl acetate, the ethyl acetate layer washed with sat'd NaHC03 and put aside. The 2 bicarbonate washes were acidified with conc. HCl, 20 extracted with ethyl acetate, the organic phase washed with brine, dried over anhydrous Na2S04 and evaporated to give 520 mg of recovered phosphonic acid, mono methyl ester. The diester was regenerated by dissolving the oil in trimethyl 25 orthoformate (5 ml) and refluxing the mixture under argon for 4 hours. Excess formate was removed in vacuo to give a yellow.oil which was taken up in ethyl acetate and combined with the original neutral organic phase. The ethyl acetate 30 layer was washed with brine, dried over anhydrous Na2S04 and evaporated to give 3.396 g of a yellow oil. The crude oil was purified by flash chromatography on LPS-1 silica gel (40:1) eluting 22 4 7 3 HXlOb -134- with (75:25) Hexane-acetone. Product fractions O were evaporated to give 2.987 g (89.4%) of the title trans-vinyl dimethyl phosphonate as a golden oil. TLC (1:1) Hex-acetone, = 0.44, UV & PMA. 5 XH NMR (CDC13): 6 2.27 (3H, d, Jh_f=1.6 Hz) 0 2.33 (3H, s) 2.39 (3H, s) 3.61 (6H, d, jh_p= 11 Hz) 10 5.51 (1H, dd, JH_H = 18 Hz, JH_p = 20.6 Hz) 6.95-7.09 (5H, m) 7.48 (1H, dd, JH_H = 17.9 Hz, JR_p=23.7 Hz) ppm. 15 ' 13 C NMR (CDC13): 6 14.4, 20.9, 52.0 (Jc_p=5.7 Hz) 114.4, 114.7, 119.2 (Jc_p=185.5 Hz) 124.3, 124.5, 128.4, 128.5 129.0 130.6 20 130.9 132.6, 132.7, 134.6, 137.1, 141.0, 0 148.2, 148.2 (Jc_p=5.7 Hz) 160.5 (JC_F = 244.1 Hz) C. [2-[4*-Fluoro-3,31,5-trimethyl[1,11-25 biphenyl]-2-yl]ethenyl]phosphonic acid, monomethyl ester A solution of Part E vinyl dime thy lphosphonate (2.895 g, 8.31 mmole) in dioxane (20 ml) was treated with a 1.0 N LiOH 30 solution (12.5 ml, 12.5 mmole, 1.5 eq) and the resulting mixture stirred at 75°C (oil bath) for 70 minutes under argon. After 15 minutes of heating, the mixture became homogeneous. The mixture was 2 0 / I 4 / HXlOb -135- cooled to room temperature, acidified to pH 1 with O1.0 N HCl (~15 ml), extracted (2X) with ethyl . acetate, the organic phase washed with brine, dried over anhydrous Na2S04 and evaporated in 5 vacuo to give 2.663 g (95.8%) of desired title monomethyl ester as a clear, colorless oil. TLC: Q (8:1:1) CH2Cl2-CH3OH-HOAc, Rf=0.57, UV & PMA. Mass Spec (M+H+=335+ observed). XH NMR (CDC13): 10 6 2.25 (3H, d, JH_F = 1.6 Hz) 2.33 (3H, s) 2.39 (3H, s) 3.53 (3H, d, JH_p = 11 Hz) 5.61 (1H, dd, JH_H = 18 Hz, JH_p=20.6 Hz) 15 6.90-7.12 (5H, m) 7.38 (1H, dd, Jh_h=18 Hz, JN_p= 24 Hz) ppm. D. 4-[[2-[4'-Fluoro-3,3',5-trimethyl[1,11-biphenyl ] -2-yl ] ethenyl ] methoxyphosphinyl ] 20 3-oxobutanoic acid, methyl ester Distilled methyl acetoacetate (420 pi, 3.9 mmole, 1.3 eq) was added dropwise over 15 minutes to a stirred suspension of 60% NaH dispersion in mineral oil (168 mg, 4.2 mmole, 1.4 eq) in dry THF 25 (10 ml) at 0°C (ice bath) under argon. The resulting clear solution was stirred 15 minutes at 0°C, then treated, with 1.6 M n-butyllithium solution in hexanes (2.25 m, 3.6 mmole, 1.2 eq) over 10 minutes. The yellow dianion solution was 30 stirred for 15 minutes at 0°C, then cooled to -78°C in preparation for treatment with phosphonochloridate. O 22 4 7 HXlOb -136- Phosphonochloridate was prepared from title Part C mono methyl ester according to the following method. A solution of the Part C phosphonic mono methyl ester (960 mg, 2.87 mmole) in dry CH2C12 (8 5 ml) was treated with distilled trimethylsilyl-diethylamine (750 m1* 5.98 mmole, 2 eq) and the clear mixture stirred under argon at room temperature for 1 hour. The mixture was evaporated in vacuo, azeotroped with benzene (2 x 15 ml) and 10 the viscous oil left on the vacuum pump for 15 minutes. The oil was taken up in dry CH2C12 (8 ml) and dry DMF (1 drop), cooled to 0°C (ice bath) and treated with distilled oxalyl chloride (290 jjI, 3.3 mmole, 1.1 eq) dropwise over 5 minutes under 15 argon. After 15 minutes at 0°C, the mixture was stirred at room temperature for 45 minutes then evaporated in vacuo. The crude oil was azeotroped with dry benzene (2 x 15 ml) to give after evaporation and drying on the vacuum pump for 15 20 minutes crude phosphonochloridate as a pale yellow oil. Phosphonochloridate (^2.9 mmole, 1 eq) in dry THF (8 ml) at -78°C was transferred via cannula dropwise over 30 minutes to a -78°C 25 solution of methyl acetoacetate dianion. After 30 minutes at -78°C the orange brown reaction mixture was quenched by dropwise addition of saturated NH^Cl (8 ml) and allowed to warm to room temperature. The mixture was diluted with ethyl 30 acetate, washed with sat'd NaHCO^ and brine, then dried over anhydrous Na2S04 and evaporated in vacuo to give 1.481 g of an orange oil. The crude oil was purified by flash chromatography on Merck -137- 22 4 7 HXlOb silica gel eluting with (9:1) Hexane-Acetone, followed by (1:1) Hexane-Acetone. Product fractions were combined and evaporated to give 813 mg (62.9%) of desired title vinyl phosphinic 5 diester as a viscous, pale yellow oil. TLC (1:1) Hex-Acetone, Rf=0.42, UV & PMA. 1H NMR (CDC13): S 2.28 (3H, s) 2.34 (3H, s) 10 2.40 (3H, s) 3.15 (2H, dd, Jh_h=4.7 Hz, JH_p=18.2 Hz) 3.54 (3H, d, JH_p = 11.6 Hz) 3.63 (2H, s) 3.72 (3H, s) 15 5.57 (1H, dd', JH_H=17.9 Hz, JH_p 25.3 Hz) 6.95-7.09 (5H, m) 7.52 ppm. 7.52 (1H, dd, JH_H=17.9 Hz, JH_p=22.7 Hz) 20 13NMR (CDC13): 6 14.0 (Jc_p=3.9 Hz), 20.6, 45.3 (Jc-p=85.9 Hz), 49.6, 50.9 (Jc_p=5.8 Hz), 5.18, 113.6, 115.0 121.4 (Jc_p=128.9 Hz), 25 123.6, 124.7, 128, 187.7, 129.5, 130.3, 130.8, 132.1, 132.4, 136.4, 136.8, 138.2, 140.7, 149.2 (Jc_p=4.9 Hz), 160.3 (JC_F=245.1 Hz), 166.7, 194.4 (Jc_p=4.9 Hz) ppm. 30 22 4 HXlOb -138- E. (E)-4-[[2-[4!-Fluoro-3,3•,5-trimethyl-[1,11-biphenyl]-2-yl]ethenyl]methoxyphosphinyl ]-3-hydroxybutanoic acid, methyl ester 5 A 0°C (ice bath) solution of the Part D, ketone (585 mg, 1.35 mmole) in dry THF (4 ml) was treated with solid NaBH^ (51 mg, 1.35 mmole, 1 molar eq. ) followed by dropwise addition of dry CH3OH (1 ml, 3A sieves) and the yellow mixture 10 stirred under argon at 0°C for 30 minutes. The . mixture was quenched at 0°C by addition of reagent acetone (6.5 ml) followed by addition of CC-4 silica gel (500 mg). The suspension was warmed to room temperature, filtered through sintered glass, 15 rinsed with ethyl acetate and evaporated in vacuo to give 607 mg of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel (30:1) eluting with neat ethyl aqetate. Product fractions were evaporated to give 340 mg 20 (57.6%) of desired title alcohol as a pale yellow oil. TLC (neat EtOAc), Rf=0.19, UV + PMA. M< 1, Mass Spec (M+H+=435 observed) H NMR (CDC13): 25 6 1.90 (2H, m) 2.27 + 2.28 (3H, 2 singlets) 2.34 (3H, s) 2.39 + 2.40 (3H, singlets) 2.56 (2H, d), 30 3.52 (3H, d, JH-p=ll.l Hz) 3.69 + 3.70 (3H, 2 singlets) 3.79 + 3.90 (1H, 2 doublets) 5.52 + 5.54 (1H, 2dd, JH_H=18 Hz, JH_p=2.48 Hz) 2 'i H j HXlOb O o -139- 6.95 - 7.02 (5H, m) (JJJ 7.52 - 7.54 (1H, 2dd, JR_H=18 Hz, JR_p=21.6 Hz) ppm. 13 C NMR (CDC13)(R,S mixture) 6 14.3 (Jc_p=3.9 Hz) 20.8, 35.4 + 35.8 (Jc_p=100.6 Hz) 0 42.0 (Jc_p=12.7 Hz) 50.7 (Jc_p=6.8 Hz) 56.5, 63.2 (Jc-p=3.9 Hz) 10 113.8, 115.3, 122.9 + 123.2 (Jc_p=122.1 Hz) 123.8, 128.2, 128.7, 129.0, 130.4, . 131.4,. 132.3, 132.7, 136.6, 137.0, 138.2, 140.8, 148.2 + 148.8 (Jc-p=4.9 Hz) 160.5 (Jc-p=245.1 Hz) 15 171.8 ppm- F. (E)-4-[[2-[4'-Fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl]ethenyl]hydroxy-phosphinyl]-3-hydroxybutanoic acid, 20 dilithium salt A solution of the Part E diester (339 mg, 0.781 mmole) in dioxane (8 ml) was treated with excess 1.0 N LiOH (2.3 ml, 2.3 mmole, 3 eg) and the mixture heated at 50°C (oil bath) for 1.5 25 hours under argon. A white precipitate was evident after 15 minutes. While still warm, the mixture was diluted with H20 until all solids dissolved then filtered. The filtrate was evaporated in vacuo, taken up in a minimum amount 30 of H20 and chromatographed on HP-20 resin eluting with a neat H20 •* neat CH^OH linear gradient. Product fractions were evaporated, the white 22 4 7 HXlOb -140- residue taken up in H20 (50 ml), filtered and lyophilized to give 270 mg (82.7%) of desired) title dilithium salt as a hygroscopic, white lyophilate. TLC (8:1:1) CH2Cl2-CH3OH-HOAc, Rf=0.33, UV + PMA. Anal for C^H^O^FP*2Li + 0.63 moles H20 (MW 429.57): Calcd: C, 58.71; H, 5.46; F, 4.42; P, 7.21 Found: C, 58.71; H, 5.70; F, 4.18, P, 6.96 1H NMR (CDC13) 6 1.59 (2H, multiplet) 2.24-2.37 (2H, 3 multiplet, JH_H=8.5 Hz + 4.4 Hz) 2.28 (3H, doublet, JH_F=1.8 Hz) 2:30 + 2.39 (6H, 2 singlets) 4.14 (1H, multiplet) 5.78 (1H, JH_H=17.9 Hz, JH_p=20.5 Hz) 6.88-7.21 (6H{ multiplet) Example 27 4-[[2-[41-Fluoro-3,3',5-trimethyl[1,11-biphenyl]-2-yl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt ■ A. 4-[[2-[4'-Fluoro-3,3'-trimethyl[1,1'- biphenyl]-2-yl]ethyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester An argon purged solution of the Example 6 Part E trans vinyl phosphinate (297 mg) in CH3OH (6 ml) was treated with 10% Pd/c (74 mg, 25% by weight) and the black suspension shaken on a Parr apparatus under 40 psi H2 for 3 hours. Catalyst was removed by filtration through packed Celite and the filtrate evaporated in vacuo to an oil. II kl HXlOb -141- The oil crystallized from hexanes giving, after filtration and drying in vacuo, 267 mg (89.5%) of title saturated phosphinate as a white crystalline solid. TLC (EtOAc), Rf=0.20, UV + PMA. 1H NMR (CDC1,, 270 MHz), IR (KBr pellet) + + Mass Spec (M+H =437 observed). 1H NMR (CDC13): 6 1.55-1.87 (4H, m) 2.29 + 2.30 + 2.31 (6H, 3 singlets) 2.35 (3H, d, JH-F=2.1 Hz) 2.52 (2H, m) 2.78 (2H, m) 3.50 + 3.55, (3H, 2 doublets JH-p=4.3 Hz) 3.71 (3H,s) 3.86 + 3.91 (1H, 2 singlets) 4.25 + 4.39 (1H, 2 broad multiplets) ppm. B. 4-[[2-[4'-Fluoro-3,3',5-trimethyl[1,11-biphenyl ] -2 -yl ] ethyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt • A solution of the Part A diester (250 mg, 0.573 mmole) in dioxane (6 ml) was treated with excess 1.0 N LiOH (1.72 ml, 3 eq) and the mixture heated at 50°C (oil bath) under argon for 1.5 hours. A white precipitate was evident after 15 minutes. The mixture was diluted with H20, while still warm until all solids dissolved and then filtered. The filtrate was evaporated in vacuo, the white residue dissolved in a minimum amount of H20 and chromatographed on HP-20 resin, eluting with neat H20 (until neutral), followed by neat CHgOH. Product fractions were evaporated in vacuo to a white solid which was azeotroped (2X) with 22 4 7 HXlOb -142- CH3CN and dried in vacuo to give 131 mg (55%) of desired title dilithium salt as a white solid. TLC (8:1:1) CH2Cl2-CH30H-acetic acid, Rf=0.34, Uv + PMA. Anal Calcd for C21H2405FPLi2 + 0.95 moles H20 (MW 437.30): C, 57.67; H, 5.97; F, 4.34; P, 7.08 Found: C, 57.67; H, 5.90; F, 3.92; P. 7.39 XH NMR (CD30D + D20): 6 1.39-1.57 (4H, multiplet) ppm 2.22-2.37 (2H, multiplet) 2.26 + 2.38 (6H, 2 singlets) 2.31 (3H, doublet, JH_F=1.8 Hz) 2.71-2.77 (2H, multiplet) 4.13-4.20 (1H, multiplet) 6.73-7.11 (5H, multiplet, aromatic H's) Example 28 (E)-4- [ [2-[3-(4-Fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]ethenyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt A. [2-[3-(4-Fluorophenyl)-l-(l- methylethyl)-lH-indol-2-yl]-2-hydroxyethyl]phosphonic acid, dimethyl ester A -78°C (acetone/C02) solution of methyl dimethylphosphonate (1.35 ml, 12.42 mmole, 1.6 eq.) in dry THF (20 ml) was treated dropwise over 15 minutes with a 1.6 M n-BuLi solution in hexanes (7.3 ml, 11.6 mmole, 1.5 eq.) and the resulting white suspension stirred under argon at -78°C for 1 hour. The Example 7 Part E indole aldehyde (2.183 g, 7.76 mmole) in dry THF (8 ml) was added dropwise over 10 minutes to the anion at -78°C and -143- 22 4 7 3 HXlOb O the resulting light orange suspension stirred for 30 minutes at -78°C. The mixture was quenched by 'w dropwise addition of saturated NH4C1 (10 ml), warmed to room temperature, partitioned between 5 H20 and ethyl acetate, the organic phase washed with brine, dried over anhydrous Na2S04 and evaporated to give 3.19 g of a white solid. The crude solid was triturated with warm hexane to give 2.967 g (94.3%) of pure title hydroxy 10 phosphonate as a white solid with m.p.=161-162°C. TLC (1:1) Hex-Acetone, Rf=0.29, UV + PMA. Anal Calcd for C21H2504NPF: C, 62.21; H, 6.22; N, 3.46; F, 4.69; P. 7.64 Found: C, 62.34; H, 6.32; N, 3.30; F, 4.61; P. 7.32 15 LH NMR (CDC13): 6 1.69 + 1.74 (6H, 2 doublets) 2.18 + 2.56 (2H, 2 multiplets) 3.61 (1H) 3.67 + 3.71 (6H, 2 doublets, JH_p=ll Hz) O O 48.3, 52.6 + 52.7 (Jc_p=5.7 Hz) 62.1 (Jc_p=3.8 Hz) 112.5, 114.3, 115.1, 115.4, 119.5, 120, 30 122, 128.1, 130.6, 131.9, 132.0/ 134.8, 134.9, 135.2, 161.8 (Jc_p=246.1 Hz) ppm. 20 5.32 (1H, m) 5.50 (1H, m) 7.04-7.25 (4H, m) 7.33-7.39 (2H quartet) 7.52 (2H, AB quartet) ppm. 25 13C NMR (CDC13): 6 21.1, 21.3, 33.1 (Jc_p=136.3 Hz) o 2247 HXlOb -144- B. (trans)-[2-[3-(4-Fluorophenyl)-1-*0 (1-methylethyl) -lH-indol-2-yl ] - ethenyl]phosphonic acid, dimethyl ester 5 The Part A hydroxy phosphonate (2.60 g, 6.43 mmole) dissolved in warm benzene (20 ml) was treated with pTs0H*H20 (122 mg, 0.1 eq.) and the mixture refluxed through a Soxhlet containing 4a sieves for 1 hour under argon. The yellow 10 . solution was cooled, diluted with ethyl acetate, the organic phase washed with saturated NaHC03 (2X) and brine then dried over anhydrous Na2S04 and evaporated to give 2.47 g of crude olefin as a yellow solid. One recrystallization from ethyl . 15 acetate-hexanes gave 2.238 g (89.9%) of pure title trans vinyl phosphonate as pale yellow plates with m.p.=153-155°C. TLC (1:1) Hex-Acetone, Rf =0.33, UV + PMA Mass Spec (M+H+388+ observed). 20 Anal Calcd for C21H2303PNF: C, 65.11; H, 5.98; 0 N, 3.62; F, 4.90; P. 7.99 * Found: C, 65.27; H, 6.03; N, 3.48; F, 5.11; P. 7.98 XH NMR(CDC13): 6 1.67 (6H, doublet) 25 3.68 (6H, d, JH_p=11.6 Hz) 0 • 4.90 (1H, septet) 5.73 (1H, dd, JH_H(trans)=18 Hz, JH_p=18.2 Hz) 7.05-7.56 (8H, m) 7.64 (1H, dd, JH_H=17.9 Hz, JR_p=23.7 Hz) 30 ppm. o 22 4 7 HXlOb -145- 13C NMR (CDClg): 6 21.1, 47.8, 52.2 (Jc_p=5.7 Hz) 111.8, 115.4, 115.7, 118.5 (Jc_p=43.5 H) 120.1, 120.2, 123.4, 128.2, 130.5, 130.7, 131.1, 131.7, 135.9, 137.9 (Jc_p=7.6 Hz) 161.9 (Jc_p=246 Hz) ppm. C. (trans)-[2-[3-(4-Fluorophenyl)-l-(1-methylethyl)-lH-indol-2-yl]-10 ethenyl]phosphonic acid, .monomethyl ester The Part B vinyl dimethylphosphonate (1.787 g, 4.61 mmole) was dissolved in warm dioxane (12 ml), treated with 1.0 N LiOH (6.9 ml, 6.9 mmole, 15 1.5 eq.) and heated at 75°C (oil bath) under argon for 30 minutes. The mixture was cooled, acidified with 1.0 N HCl (8 ml), extracted with ethyl acetate (2X), washed with H20 (2X\ and brine, dried over anhydrous Na2S04 and evaporated to give 1.859 g of 20 a yellow oil. The oil was dissolved in warm hexane, cooled, and crystallized to give 1.657 g (96.1%) of mono acid as a pale yellow solid with m.p.=181-183°C. Anal Calcd for C20H2103PNF: C, 64.02; H, 5.70; 25 N, 3.73; F, 5.06; P, 8.25 O Found: C, 64.02; H, 5.87, N, 3.64, F, 5.26, P. 7.90 TLC (20:1:1) CH2Cl2-CH3OH-acetic acid, Rf =0.26, UV + PMA XH NMR (CDC13): 30 6 1.66 (6H, doublet) 3.64 (3H, doublet, JH-p=11.6 Hz) 4.89 (1H, septet) 0 o / *■■*> £4 4 / HXlOb -146- 5.81 (1H, dd, Jh_h=17.9 Hz, JH_p=18.5 Hz) 7.06 -7.64 (9H, multiplet) ppm. 13C NMR (CDC13): 6 21.8, 47.9, 52.1 (Jc_p=5.7 Hz) 112.0, 115.5, 115.8, 116.1, 119.0 (Jc_p=9.5 Hz) 120.2, 120.4, 123.5, 128.3, 130.4, 130.8, 131.2, 131.8, 131.9, 136.2, 136.8 (Jc_p=7.6 HZ) 161.9 (Jc_f=246 Hz) ppm. D. 4-[[2-[3-(4-Fluorophenyl)-l-(l-methyl-ethyl)-lH-indol-2-yl]ethenyl]methoxyphosphinyl] -3 -oxobutanoic acid, methyl ester Phosphonochloridate was prepared according to the following method. A solution of Part C phosphonic mono methyl ester (1.564 g, 4.19 mmole, 1 eg) in dry CH2C12 (10 ml) was treated with distilled diethylamino trimethylsilane (1.05 ml, 8.38 mmole, 2 eq) and the mixture stirred under argon at room temperature for 1 hour. The mixture was evaporated in vacuo, taken up in benzene (20 ml), evaporated in vacuo and the viscous oil left on the vacuum pump for 15 minutes. A solution of the crude silylated acid in dry CH2C12 (10 ml) and dry DMF (1 drop) was cooled to 0°C, treated dropwise with distilled (C0C1)2 (400 ml, 4.61 mmole, 1.1 eq), stirred 15 minutes at 0°C, then at room temperature for 45 minutes under argon. The yellow mixture was evaporated in vacuo, taken up in benzene (20 ml), evaporated in vacuo and left on the vacuum pump O O '■ £ & H / HXlOb -147- for 15 minutes to give crude phosphonochloridate as a viscous yellow oil. A solution of the phosphonochloridate in dry THF (8 ml) at -78°C was transferred by cannula dropwise over 20 minutes to a -78°C solution of the methyl acetoacetate dianion prepared as described in Example 26 from methyl acetoacetate(590 pi, 5.45 mmole, 1.3 eq), 60% NaH oil dispersion (235 mg, 5.87 mmole, 1.4 eq), 1.6 M n-butyllithi\m (3.1 ml, 5.03 mmole, 1.2 eq), THF (10 ml). The orange reaction mixture was stirred 30 minutes at -78°C then quenched by dropwise addition of saturated NH4Cl and allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and H20, the organic phase washed with saturated NaHCO^ and brine then dried over andhydrous Na2S04 and evaporated to give 2.080 g of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (7:3) CH2Cl2~EtOAc. Product fractions were combined and evaporated to give 519 mg (26.3%) of desired title trans phosphinate as a light yellow oil. TLC (1:1) .Hex-Acetone, Rf=0.48, UV + PMA. Mass Spec (M+H+=472+ observed). XH NMR (CDC13): 5 1.66 + 1.71 (6H, 2 doublets) 1.68 (2H, m) 3.23 (2H doublet) 3.54 (3H, d) * 3.72 (3H, s) 4.90 (1H, septet) 5.76 (1H, dd, Jh_h=18 Hz) 22 4 7 HXlOb -148- 7.10-7.58 (8H, m) 7.66 (1H, dd, J„ =18 Hz) ppm. 13 AJC NMR (CDC13): 6 21.8, 45.7 (Jc_p=87.1 Hz) 47.9, 50.0, 51.5 (Jc_p=5.7 Hz) 52.3, 111.9, 115.5, 118.8 (Jc_p=104.1 Hz) 119.8, 120.2, 120.3, 123.6, 128.2, 130.4, 130.8, 131.8, 131.9, 136.1, 139.2 (Jc_p=5.6 HZ) 161.9 (Jc_p=246 HZ) 167.0, 194.6 (J{,_p=3.8 Hz) ppm. E. (E)-4-[[2-[3-(4-Fluorophenyl)-l-(1-methylethyl) -lH-indol-2-yl ] ethenyl ] -methoxyphosphinyl ] -3 -hydroxybutanoic acid, methyl ester A -15°C (salt/ice bath) solution of the Part D ketone (519 mg, 1.1 mmole) in dry absolute EtOH (3A sieves, 8 ml) was treated with solid NaBH4 (42 mg, 1.1 mmole) and the yellow mixture stirred under argon at -15°C for 20 minutes. The mixture was quenched by addition of acetone (0.5 ml) followed by CC-4 silica gel (500 mg). The mixture was warmed to room temperature, filtered, rinsed with ethyl acetate and evaporated in vacuo to give 512 mg of a yellow foam. The crude foam was purified by flash chromatography on Merck silica gel eluting with (4:1) ethyl acetate-acetone followed by neat acetone. Product fractions were evaporated to give 317 mg (60.9%) of desired title alcohol as a yellow oil. TLC (4:1) EtOAc-Acetone, Rf=0.21, UV + PMA. 2r\ /, n L H / HXlOb -149- Mass Spec (M+H+=4.74+ observed) XH NMR (CDC13): 6 1.68 (6H, doublet) 1.97 (2H, m) 5 2.58 (2H, d) 3.61 (3H, d, JH_p=ll Hz) 3.68 (3H, s) 3.95 +4.04 (1H, 2 doublets) 4.40 (1H, bm) 10 4.95 (1H, septet) 5.78 (1H, dd, JH_H=17.4 Hz, JH_p=23.2 Hz) 7.05-7.77 (9H, m) ppm. 'C NMR (CDC13): 6 21.7, 34.9 + 36.3 (Jc_p=20.8 Hz) 15 42.0 (Jc_p=13.2 Hz) 47.8, 50.8 (Jc_p=5.6 Hz) 51.6, 63.1 (Jc_p=15.1 Hz) 111.8, 115.4, 115.7, 118.6, 119.9 + 121.8 (Jc_p=18.9 Hz) 120.1, 123.4, 128.2, 20 130.6, 130.7, 131.1, 131.7, 131.9, 135.8, 138.0 + 138.5 (Jc_p=5.7 Hz) 161.8 (JC_F=246.1 Hz) 171.7, 171.8 ppm. 13, 25 F. (E)-4-[[2-[3-(4-Fluorophenyl)-l-(1- methylethyl)-lH-indol-2-yl]ethenyl]-hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A stirred solution of the Part E hydroxy 30 diester (264 mg, 0.558 mmole) in dioxane (6 ml) was treated with 1.0 N LiOH (1.95 ml, 3.5 eq) and heated at 70°C (oil bath) for 20 minutes under argon. The mixture was allowed to cool, diluted -150- HXlOb with H2O, filtered, evaporated in vacuo, taken up in a small amount of H20 (1-2 mis) and chromatographed on HP-20 eluting with H20 (until neutral, 3-4 column volumes) followed by (75:25) CH3OH-H20. Product fractions were evaporated, taken up in H20 (50 ml), filtered and lyophilized to give 217 mg (85.1%) of desired title dilithium salt as a white lyophilate. TLC (8:1:1) CH2Cl2-CH3OH-acetic acid, Rf0.08, UV + PMA Anal Calcd for C23H2305NPF*2 Li + 1.62 moles H20 (MW 486.46): C, 56.78; H, 5.44; N, 2.88; F, 3.91; P, 6.37 Found: C, 56.76; H, 5.64; N, 2.58; F, 3.60; P, 6.77 1H NMR (400 MHz, CDC13): 6 1.67 (6H, doublet) 1.73 (2H, multiplet) 2.38 (2H, doublet of AB quartet, >1^=15 Hz, J^x=8 Hz, Jbx=4.8 Hz) 4.24 (1H, multiplet) . 5.06 (1H, septet) 6.09 (1H, Jhh=17.6 Hz, ^=19.4 Hz) 7.02-7.61 (9H, multiplet) Example 29 (S)-4-[[2-[l-(4-Fluorophenyl)-3-(l-methylethyl)-lH-indol-2-yl]ethyl]hydroxyphosphinyl]-3-hydroxy- butanoic acid, dilithium salt A. 4-Methyl-2-oxopentanoic acid, ethyl ester 4-Methyl-2-oxopentanoic acid, sodium salt (25 g) was dissolved in a minimum amount of H20, acidified to pH 1 with concentrated HCl and then 22 hi HXlOb -151- extracted several times with CH2C12. The aqueous phase was saturated with NaCl and back extracted (2X) with CH2C12. The combined organic phases were washed with brine, dried over anhydrous 5 Na2S04 and evaporated to give 17.7 g of the free acid as a viscous oil. A mixture of the acid (17.7 g, 136 mmole) in dry benzene (200 ml) was treated with diazabicycloundecane (DBU) (20.4 ml, 136.2 mmole, 10 1 eq.) giving an exothermic reaction and a gel-like crystalline salt formed. The mixture was treated with ethyl iodide (10.9 ml, 1 eq.) and mechanically stirred under argon for 3 hours. Precipitated salts were removed by filtration, the filtrate 15 washed once with a small amount of H20 (50 ml) and brine then dried over anhydrous Na2S04. Benzene was removed by distillation at atmospheric pressure and the yellow liquid remaining was vacuum distilled to give 6.46 g (35.1%) of desired title 20 ester as a clear, pale yellow liquid with bp = 65-66°C (5 mmHg). TLC (9:1) Hexane-acetone, Rf=0.55, PMA (pale blue) Mass Spec (M+H+=159+ observed). 25 B. 4-Methyl-2-(2-phenylhydrazono)- pentanoic acid, ethyl ester A solution of the Part A ethyl ester (5 g, 31.6 mmole) in dry CH2C12 (30 ml) was treated with phenylhydrazine (3.3 ml, 33.2 mmole, 1.05 eq) 30 dropwise over 5 minutes and the resulting yellow mixture stirred under argon at room temperature over 4A sieves for 3 hours. The mixture was dried over anhydrous Na2S04, filtered and evaporated 22 47 34 HXlOb -152- in vacuo to give 8.105 g of an orange oil. The CD oil was purified by flash chromatography on LPS-1 silica gel eluting with Hexane-ethyl acetate. Product fractions were, evaporated to give 6.8 g 5 (86.7%) of pure title hydrazone and 848 mg (10.8%) of the geometrical isomer of the title hydrazone. (3 Total yield=97.5% TLC (9:1) Hexane-Acetone, geometrical isomers=0.42 + 0.64, UV + PMA 10 Mass Spec (M+H+=249+ observed). C. 3-(l-Methylethyl)-lH-indole-2- carboxylic acid, ethyl ester Gaseous HCl was bubbled (gas dispersion 15 tube) into an absolute ethanolic (50 ml, over 3 a sieves) solution of the Part B hydrazone (6.8 g, 27.4 mmole) for 30 minutes at room temperature. The exothermic reaction was characterized by color changes from yellow to red to deep green followed 20 by precipitation of NH.Cl. The suspension .•"""■v. * ' was stirred an additional 20 minutes under Drierite, then dumped into ice cold Ho0 (50 ml). Z » Ethanol was removed in vacuo and the residue partitioned between ethyl acetate and ^0. The 25 aqueous layer was extracted with ethyl acetate (2X), the combined organic phases washed with H20 and brine, then dried over anhydrous MgS04 and evaporated to give 4.969 g of a green solid. The crude solid was dissolved in hot hexane, treated 30 with Darco, filtered through packed Celite, concentrated to a 30-50 ml volume and the yellow solution allowed to crystallize. Precipitated crystals were collected by filtration, rinsed with 22 4 / HXlOb -153- cold hexane and dried to give 4.34 g (68.5%) of pure title indole as white needles with mp80-81°C and with consistent ^H NMR (CDClg, 270 MHz). TLC (9:1) Hexane-Acetone, R^ = 0.42, UV + PMA. Note: Rf of hydrazone and indole are identical but • • + indole has bright purple fluorescence. (M+H = 232 observed). Anal Calcd for ci4H17N02: C' 72.70; H, 7.41, N, 6.06 Found: C, 72.67; H, 7.57; N, 6.00 D. l-(4-Fluorophenyl-3-(l-methylethyl)-lH-indole-2-carboxylic acid, ethyl ester A solution of the Part C indole (3.937 g, 17 mmole) and l-bromo-4-fluorobenzene 9.34 ml, 85 mmole, 5 eq) in dry DMF (15 ml) was treated with cuprous oxide (245 mg, 1.7 mmole, 0.1 eq) and refluxed under argon for 17 hours. Additional bromide (9.34 ml, 5 eq) and Cu20 (245 mg, 0.1 eq) were added, refluxing continued for 6 hours, more Cu20 added (730 mg, 5.1 mmole) and refluxing continued for 60 more hours. DMF and excess bromide were distilled off in vacuo and the orange residual oil taken up in ethyl acetate, filtered through packed Celite, washed with saturated NaHCO^ and brine then dried over anhydrous Na2S04 and evaporated to give 5.385 g (97.2%) of desired crude title indole as an orange oil. TLC (9:1) Hexane-Acetone, Rf=0.29, UV + PMA. 22 4 HXlOb -154- E. l-(4-Fluorophenyl)-3-(l-methylethyl)-lH-indole-2-methanol To cold (0°C, ice bath) dry ether (24 ml) under argon was added solid LiALH^ (907 mg, 23.9 5 mmole, 1.5 molar equivalent) followed by dropwise addition of the Part D indole ester (5.185 g, 15.9 (?) mmole) in dry Et20 (10 ml) over 10 minutes. The mixture was stirred for 1 hour at 0°C, then quenched at 0°C by sequential dropwise addition of 10 H20 (910 mD/ 15% NaOH (910 pi) and H20 (2.73 ml). The suspension was filtered through anhydrous MgSO^ over packed Celite and the filtrate evaporated to a clear, colorless oil. The oil gradually crystallized from hexane to give in 2 15 crops (3.771 g + 0.333 g) 4.10 g (90.9%) of pure title indole alcohol as white, granular crystals with mp = 81-82°C. Mass Spec (M+H+=284+ observed). Anal Calcd for C18HlgN0F: C, 76.30; H, 6.40; 20 N, 4.94; F, 6.71 Q Found: C, 76.59; H, 6.31; N, 4.93; F, 6.49 F. l-(4-Fluorophenyl)-3-(l-methylethyl)-lH-indole-2-carboxaldehyde 25 A solution of Dess-Martin periodinane (6.46 (0 9/ 15.24 mmole) in dry CH2C12 (30 ml) was treated with dry t-butanol (4A sieves, 1.44 ml, 15.24 mmole, 1 eq.) and the mixture stirred under- argon for 15 minutes at room temperature. A solution of 30 the Part E indole alcohol (3.599 g, 12.7 mmole) in dry CH2C12 (13 ml) was added dropwise over 10 minutes and the pale yellow mixture stirred under argon at room temperature for 30 minutes. The 22 47 HXlOb -155- reaction mixture was added to a solution of sodium thiosulfate (14.06 g, 89 mmole, 7 eq) in freshly prepared IN NaHCO^ (40 ml) and stirred for 10 minutes. The aqueous phase was drawn off, the 5 organic phase washed with 1.0 N NaHCO^ (2X), H20 and brine, then dried over anhydrous Na2S04 and (2) evaporated to give 3.877 g of a yellow oil. The crude oil was purified by flash chromatography on LPS-1 silica gel eluting with (40:1) 10 Hexane-ether. Product fractions were evaporated to give 3.118 g (87.3%, crude yield) of crude product. One recrystallization from hot hexane gave 2.643 g (74%) of pure title aldehyde as white fluffy needles with mp = 114-116°C. 15 Mass Spec (M+H+=282+ observed). TLC (7:3) Hex-Et20, Rf=0.51, UV + PMA Anal Calcd for C1QN16N0F: C, 76.85; H, 5.73; N, 4.98; F, 6.75 Found: C, 76.87; H, 5.63; N, 4.89; F, 6.88 20 £2) G. . 2-(2,2-Dibromoethenyl)-l-(4-fluoro- phenyl)-3-(1-methylethyl)-lH-indole A -15°C (salt/ice bath) solution of the Part F aldehyde (1.615 g, 5.74 mmole) and 25 triphenylphosphine (4.52 g, 17.22 mmole, 3 eq) in dry CH2C12 *25 m1^ was treated dropwise over 10 minutes with a CBr4 (2.86 g, 8.61 mmole, 1.5 eq) solution in dry CH2C12 (10 ml) and the resulting dark orange red solution stirred under argon at 30 -15°C for 15 minutes. The mixture was quenched at -15°C by the addition of saturated NaHC03, diluted with CH2C12, the organic phase washed with saturated NaHC03 and brine then dried over 22 4 7 3 HXlOb -156- anhydrous Na2S04 and evaporated to give 8.9 g of a red solid. The crude solid was purified by flash chromatography on LPS-1 silica gel eluting with (100:1) Hexane-ether. Product fractions were evaporated to give 2.017 g (80.6%) of pure title vinyl dibromide as pale yellow crystals with mp=123°-124°C . TLC (9:1) Hexane-ether, Rf = 0.67, UV & PMA. + +■ Mass Spec (M&H =438 observed). Anal Calcd for CigH16NFBr2: C, 52.20; H, 3.69; N, 3.20; F, 4.35; Br, 36.56 Found: C, 52.25; H, 3.69; N, 3.18; F, 4.24; Br, 36.59 H. 2-Ethynyl-l-(4-fluorophenyl)-3-(1- methylethyl)-1H-indole A -78°C (C02/acetone) solution of dry THF (10 ml) was treated with a 1.6 M n-butyl lithium solution in hexanes (5.5 ml, 8.8 mmole, 2.2 eq) and a solution of Part G vinyl dibromide (1.749 g, 4 mmole) in dry THF (10 ml) was added dropwise over 15 minutes under argon. The yellow mixture was stirred 20 minutes at -78°C, then quenched by the addition of sat'd. NH4C1 (10 ml). After warming to room temperature, the mixture was diluted with ethyl acetate, the organic phase washed with sat'd. NH4Cl and brine, then dried over anhydrous Na2S04 and evaporated to give 1.216 g of a dark green-brown oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (300:1) Hexane-ether. Product fractions were evaporated to give 1.084 g (97.5%) o 22 4 7 HXlOb -157- of title indole acetylene as a fluorescent green oil. NMR (CDClg, 270, MHZ) indicated an (18:1) mixture of desired acetylene to undesired terminal olefin. TLC (50:1) Hex-E^O, R^.=0.55, 5 UV & PMA. s~-"1 j. (s)-4-[ [2-[l-(4-Fluorophenyl)-l- (1-methylethyl)-lH-indol-2-yl]-ethynyl]methoxyphosphinyl]-3-10 [[(1,1-dimethylethyl)diphenylsilyl]- oxylbutanoic acid, methyl ester Phosphonochloridate was prepared from the Example 25 phosphonic mono methyl ester, dicylohexylamine salt by the following procedure.. 15 The free acid was regenerated from, the dicyclohexylamine salt (4.32 g, 6.83 mmole, 1.75 eq) by partitioning between 1.0 N HCl and ethyl acetate, washing the organic phase with 1.0 N HCl (2X) and brine then drying over anydrous Na2S04 and ^ 20 evaporating in vacuo to give the free acid (6.8 mmole) as a clear, viscous oil. The phosphonic acid, mono methyl ester (6.8 mmole) in dry CH^Cl^ (10 ml) was treated with distilled trimethylsilyl diethylamine (1.72 ml, 13.7 mmole, 2 eq) and the 25 clear solution stirred under argon at room temp, u for 1 hour. The mixture was evaporated in vacuo, chased with dry benzene (2 X 20 ml) and left on the vacuum pump for 15 minutes. The crude silylated acid in dry CH2C12 (10 ml) and dry DMF 30 (1 drop) was cooled to 0°C (ice bath) and treated dropwise over 5 minutes with distilled (C0C1)2 (655 |jl, 7.5 mmole, 1.1 eq). The yellow mixture was stirred at 0°C for 15 minutes and 45 minutes at 22 4 7 HXlOb -158- room temp, under argon. The mixture was evaporated in vacuo, chased with benzene (2 x 20 ml) and left on the vacuum pump for 15 minutes giving crude phosphonochloridate as a yellow, viscous oil. A -78°C solution (C02/acetone) of the Part H indole acetylene (1.084 g, 3.90 mmole, 1 eg) in dry THF (10 ml) was treated dropwise over 10 minutes with a 1.6 M n-butyllithium in hexanes solution (2.44 ml, 3.9 mmole, 1 eq) and the purple suspension stirred under argon at -78°C for 30 minutes. The anion was added dropwise via cannula over 30 minutes at -78°C to a -78°C solution of the phosphonochloridate in dry THF (10 ml). The dark brown mixture was stirred at t78°C for 30 minutes then quenched by dropwise addition of sat'd NH^Cl (10 ml). The mixture was warmed to room temperature, partitioned between ethyl acetate, and sat'd NH4C1, washed with brine, dried over anhydrous Na2S04 and evaporated to give 1.968 g (71.1%) of title acetylenic phosphinate as a light yellow oil. TLC (7:3) Hexane-Acetone, Rf=0.25, UV & PMA. + + Mass Spec. (M+H =710 observed). K. (S)—3—[[(1,1-DimethylethylJdiphenyl- silyl]oxy]-4-[[2-[l-(4-fluorophenyl)-3-(1-methylethyl)-lH-indol-2-yl]ethyl]-methoxyphosphinyl]butanoic acid, methyl ester An argon purged solution of Part J acetylene (950 mg) in CHgOH (10 ml) was treated with 10% Pt/C (238 mg, 25% by weight) and the 2^ *"? C 4 / HXlOb -159- black suspension stirred under an H2 atmosphere (1 C"*) atm) overnight. Catalyst was removed by filtration through a Millipore polycarbonate filter (0.4 |jm) and prefilter and the filtrate 5 evaporated in vacuo to a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (8:2) Hexane-ethyl acetate. Product fractions were evaporated to give 915 mg (86.7%) of pure title saturated 10 phosphinate as a white foam. TLC (4:1) EtOAc-Hexane, = 0.39, UV + PMA. Mass Spec (M+H+=714+ observed). L. (S)-4- [ [2-[l-(4-Fluorophenyl)-3-(l-15 methylethyl)-lH-indol-2-yl]ethyl]- methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester A solution of the Part K silyl ether (915 mg, 1.22 mmole) in THF (10 ml) was treated 20 successively with glacial acetic acid (280 pi, 4.88 mmole, 4 eq) and a 1.1 M n-C^HgNF solution in THF (3.3 ml, 3.66 mmole, 3 eq) and the mixture stirred under argon at room temperature overnight. Ice cold H20 (8 ml) was added, the mixture extracted 25 with ethyl acetate, the organic phase washed with 5% KHS04 (2X), saturated NaHC03 and brine then dried over anhydrous Na2S04 and evaporated in vacuo to give 955 mg of a yellow oil. The crude oil was purified by flash chromatography on 30 Merck silica gel eluting with (1:1) Hexane-Acetone. Product fractions were evaporated to give 521 mg (85.5%) of desired title alcohol as a pale yellow oil. HXlOb -160- TLC (3:2) Acetone-Hexane, Rf=0.21, UV + PMA. + + Mass Spec (M+H =476 observed). M. (S )-4-[[2-[l-(4-Fluorophenyl)-3-(1-methylethy1)-lH-indol-2-yl]ethyl]-hydroxyphosphinyl[-3-hydroxybutanoic acid, dilithium salt A solution of Part L diester (505 mg, 1.06 mmole) in dioxane (10 ml) was treated with excess 1.0 N LiOH (3.7 ml, 3.7 mmole, 3.5 eq) and the mixture heated at 65°C (oil bath) under argon for 1.5 hours. The mixture was diluted with H20, filtered, and evaporated in vacuo to a light yellow solid. The crude solid was suspended in a small amount of H20 and chromatographed on HP-20 resin (15 cm bed, 25 mm dia. column) eluting with H20 until neutral followed by CH3OH. Product fractions were combined, evaporated, taken up in H20 (50 ml) and lyophilized to give 484 mg (95.4%) of desired title dilithium salt as a white lyophilate. TLC (8:1:1) CH2Cl2-CH3OH-acetic acid, Rf=0.39, UV + PMA. Anal Calcd for C23H25N05FP-2Li +1.03 moles H20 (MW=477.91): C, 57.80; H. 5.72; N, 2.93; F, 3.97; P, 6.48 Found: C, 57.80; H, 6.01, N. 3.01; F, 3.93, P, 6.41 n f-, • £ H J *5 & HXlOb -161- Example 30 t(S) -4- [ [2- [ 1- (4-Fluorophenyl) -3- (1-methylethyl) - lH-indol-2-yl]ethynyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt 5 A. (S)-4-[[2-[l-(4-Fluorophenyl)-3-(l- methylethyl)-lH-indol-2-yl]ethynyl]-methoxyphosphinyl ] -3-hydroxybutanoic acid, methyl ester A solution of the Example 30 Part J silyl 10 ether (987 mg, 1.39 mmole) in dry THF (12 ml) was treated successively with glacial acetic acid (320 pi, 5.6 mmol, 4 eg) followed by a 1.1 M n-C4HgNF solution in THF (3.8 ml, 4.17 mmole, 3 eq) and the mixture stirred overnight under argon at room 15 temperature. The mixture was diluted with ice cold H^O (10 ml) and extracted with ethyl acetate. The organic phase was washed with 5% KHS04 (3X), saturated NaHC03 and brine then dried over anhy'drous Na2S04 and evaporated to give 1.0 g 20 .of a yellow oil. TLC indicated formation of some mono acid which was converted back to the methyl ester by treatment with ethereal solution of CH2N2. Excess CH2N2 was quenched with glacial acetic acid and the mixture evaporated in vacuo to 25 give 1.012 g of a brown oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (8:2) Hexane-Acetone (600 ml) followed by (1:1) Hexane-Acetone. Product fractions were evaporated to give 516 mg (78.7 %) 30 of free title alcohol as a light brown oil. TLC (9:1) CH2C12-CH30H, Rf=0.41, UV + PMA. Mass Spec (M+H+=472+ observed). T HXlOb -162- B. (S)-4-[[2-[l-(4-Fluorophenyl)-3-(l-methylethyl)-lH-indol-2-yl]ethynyl ]-hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt ; A solution of the Part A diester (516 mg, 1.09 mmole) in dioxane (10 ml) was treated with a 1.0 N LiOH solution (3.8 ml, 3.8 mmole, 3.5 eq) and the clear mixture heated and stirred at 60°C (oil bath) for 1.5 hours under argon. The mixture was diluted with H20, filtered, evaporated in vacuo, the residual oil taken up in a minimum amount of H20 and chromatographed on HP-20 resin (15 cm bed, 25 mm column diameter) eluting with neat H20 (until neutral) followed by (1:1) H20-CH30H. Product fractions were evaporated in vacuo, taken up in H20 (50 ml), filtered and lyophilized to give 447 mg (82.3%) of desired title di-lithium salt as a white lyophilate. TLC (8:1:1) CH2Cl2-CH3OH-acetic acid, Rf=0.39, UV + PMA. Anal Calcd for C23H2105PNF-2Li+2.27 moles H20 (MW 496.19): C, 55.67; H, 5.19; N, 2.82; F, 3.83; P. 6.24 Found: C, 55.69; H, 5.37; N, 2.82;, F, 3.85; P, 6.19 Example 31 (S)-4-[[[2,4-Dimethyl-6-[(4-fluorophenyl)methoxy]-phenyl ] ethynyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt A. 1- (Methoxymethoxy )-3,5-dimethylbenzene A THF solution. (12 ml) of 3,5-dimethylphenol (10.42 g, 85.3 mmol) was added dropwise over 10 <*5 / **"» "7 £ H / 5 HXlOb -163- minutes to a suspension of NaH (85.3 mmol) (prewashed with pentane) in THF, (150 ml) under an argon atmosphere and cooled to 0°C. After completion of the addition of the phenol, the 5 reaction was stirred at 0°C for 10 minutes warmed to room temperature and stirred for 20 minutes. To the alkoxide solution was added 42 ml of dry DMF followed by the slow addition of a 10 ml THF solution of bromomethyl methyl ether (11.19 g, 89.6 10 mmol). A white precipitate formed. After stirring for 2.5 hours at room temperature, the reaction was quenched by the slow addition of 25 ml of IN NaOH. The THF was removed from the reaction mixture by rotary evaporation and the resulting solution was 15 diluted with saturated NaCl solution and then extracted 3 times with ether. The combined ether extracts were dried over Na2S04 and filtered. Solvent removal gave an orange oil. Purification by flash chromatography eluting with 5% 20 ether/hexanes gave the title methoxymethyl (MOM) ether (12.0 g, 85% yield) as a clear oil. TLC Rf=0.45 (15% Et20/Hexane, silica gel) Mafes Spec m/e 166 (M+), 165 (M+-H)~ 25 B. 2-(Methoxymethoxy)-4,6-dimethyl- benzaldehyde Tetramethylethylenediamine (7.70 g, 79.45 mmol) was added slowly to a solution of n-butyllithium (26.5 ml, of a 2.5 M solution of 30 hexane) in cyclohexane (30 ml) under argon atmosphere. The solution was cooled to 0°C and the Part A MOM-ether (11.00 g, 66.21 mmol) was added dropwise over 20 minutes. After the HXlOb -164- addition was complete, the reaction was stirred at 0°C for 30 minutes, warmed to room temperature and stirred for 10 minutes. The anion was then added via addition funnel to a 100 ml dry cyclohexane solution of DMF (5.81 g, 79.45 mmol) under argon atmosphere and at room temperature. The reaction was stirred at room temperature for 2 hours then quenched with methanol. The reaction solvent was removed on the rotavap, and the resulting orange oil was dissolved in a 1:1 ether/water mixture. The water layer was extracted 3 times with ether and the combined ether extracts were dried over MgSC>4. Filtration and solvent removal gave an orange oil. Purification of the oil by flash chromatography eluting with 20% ether/Hexane gave the desired title aldehyde (7.7 g, 60%) as a clear oil. TLC Rf=0.14 (15% Et20/Hexane, silica gel). Mass Spec, m/e 195 (M+H)+, 179 (M-CH3)+, 163 (M-OCH3)+, 149 (M-02CH5)+ C. 2-Hydroxy-4,6-dimethylbenz aldehyde A IM HCl solution (35.5 ml) was added to a dioxane (130 ml) solution of the Part B MOM-ether (6.89 g, 35.5 mmol) at room temperature. The reaction was warmed to a gentle reflux and stirred for 30 minutes. The reaction was cooled to room temperature, and the dioxane was removed via rotary evaporation. The resulting aqueous solution was diluted with H2<D and extracted with ether. The aqueous layer was then saturated with NaCl and reextracted 2 times with ether. The ether extracts were combined and then dried over / L f / & %} HXlOb -165- Y<ws/ MgS04. Filtration and solvent removal gave a greenish solid which was purified by recrystallizati'on from hexane (4.01 g, 75%). TLC Rf=0,48 (25% Et20/Hexane, silica gel) mp 5 46-48°C. Mass Spec, m/e 151 (M+H)+, 135 (M-CH3)+ D. 2-[(4-Fluorophenyl)methoxy]-4,6- dimethylbenzaldehyde A solution of the Part C phenol (4.0 g, 10 26.7 mmol) and dry DMF (30 ml) was stirred under argon atmosphere. At room temperature, solid K2C03 (4.43 g, 32 mmol) was added to the phenol solution and then warmed to 60°C for 35 minutes. The resulting orange solution was cooled to room 15 temperature and the p-fluorobenzyl bromide (5.55 g, 29.3 mmol) was added. The reaction was warmed to 60°C and stirred for 2 hours. The reaction mixture was poured into 50 ml of ice water and this mixture was extracted several times with 20 ether. The combined ether extracts were dried over MgSO^ and filtered to give a yellow solid after solvent removal. Purification by flash chromatography eluting with 15% ether/Hexane gave the title benzyl ether (4.48 g, 60%) as a white 25 solid. TLC R^=0.34 (25% Et20/Hexane, silica gel) Mass Spec, m/e 259 (M+H)+, 231 (M-CHO)+, 109 (m-c7h6f)+ 30 E. l-(2,2-Dibromoethenyl)-2,4-dimethyl-6- (phenylmethoxy)benzene A 170 ml dry CH2C12 solution of the Part D aldehyde (4.42 g, 17.13 mmol) under argon -166- 22 4 7 HXlOb atmosphere was cooled in an ice-salt bath. To the cooled solution was added triphenyl phosphine (14.4 g, 55.0 mmol) and the mixture was stirred until all of the solid dissolved. A 50 ml CH2C12 solution of CBr^ (8.52 g, 25.7 mmol) was added via an addition funnel over a 12 minute period. After the addition was complete, the orange reaction solution was stirred at 0°C for 1 hour 15 minutes. The reaction was quenched with 60 ml of saturated aqueous NaHC03 solution and stirred vigorously. The aqueous layer was removed and extracted 2 times with CH2C12. The combined CH2Cl2 solutions were washed once with saturated aqueous NaHC03 solution, dried over MgSO^ and filtered to give the title dibromide in the form of a tan solid (13 g). The title dibromide was purified by flash chromatography eluting with 2% ether/hexane providing 5.49 g, 77% yield of the title dibromide. TLC R^=0.28 (2% Et20/Hexane, silica gel). Mass Spec, m/e 413 (M+H) + , 333, 335 (M-Br)+, 317 (M-C6H4F), 109 (M-C10HgOBr2)+. F. l-Ethynyl-2- [ (4-fluorophenyl )methoxy] -4,6-dimethylbenzene A 70 ml THF solution of the Part E dibromide (5.48 g, 13.3 mmol) under argon atmosphere was cooled to -78°C. n-Butyllithium (10.5 ml of a 2.5 M solution in hexane, 26.5 mmol) was added to the dibromide solution over 10 minutes. The reaction was stirred at -78°C for 1 hour and then quenched at -78°C with saturated aqueous NH4C1 solution. After the reaction was 22 4 7 3 4 HXlOb -167- warmed to room temperature, it was diluted with 60 ml of H20, and the aqueous layer was extracted 2 times with ether. All of the organic layers were combined and dried over MgS04. Filtration and solvent removal gave 3.8 g of title benzyloxyacetylene in the form of a yellow solid. The title benzyloxyacetylene was purified by flash chromatography eluting with 3% ether/hexane. Title acetylene was obtained in 85% yield (2.76 g) as a white solid. TLC Rf=0.17 (2% Et20/Hexane, silica gel) Mass Spec, m/e 255 (M+H)+, 159 (M-C.H4F)+, 109 <M-C10h9°)+ G. (S)-4- [ [ [2;4-Dimethyl-6-[(4-fluoro- pheny 1) me thoxy ] phenyl ] ethynyl ] hydroxy-phosphinyl ] -3- (t-butyl diphenylsilyloxy )-butanoic acid, dilithium salt A 40 ml THF solution of the Part F acetylene (2.76 g, 11 mmol) under argon atmosphere was cooled to -78°C. At -78°C, n-butyllithium (4.4 ml of a 2.5 M solution in hexane) was added over 8 minutes. The reaction was stirred at -78°C for 40 minutes. The Example 25 phosphonylchloridate (17.4 mmol), in 60 ml of THF and under argon atmosphere was cooled to -78°C. The above generated acetylenic anion was then added over 8 minutes. After stirring for 1 hour at -78°C, the reaction was quenched at -78°C with saturated aqueous NH^Cl solution and allowed to warm to room temperature. The aqueous layer was diluted with H20 and extracted 2 times with ether. The THF was removed 22 4 7 HXlOb -168- from the THF reaction layer, and the resulting orange oil was taken up in ether. All of the ether solutions were combined and washed once with saturated aqueous NaHC03 solution and once with saturated NaCl solution. The organic layer was dried over MgSC>4 and filtered leaving 9.4 g of title acetylenic phosphinic acid in the form of an orange gum after solvent removal. The title acetylenic phosphinic acid was purified by flash chromatography by eluting with a 5/1/4 hexane/toluene/ethyl acetate mixture. Title acetylenic phosphinic acid (4.23 g) was obtained in 56% yield as a clear gum. TLC Rf=0.28 (5/1/4 Hexane/toluene/ethylacetate silia gel) Mass Spec, m/e 609 (M+H-C6H5)+, 255 (C14HigSiO)+ H. (S)-4-[[[2,4-Dimethyl-6-[(4-fluoro- phenyl )methoxy ] phenyl ] ethynyl ] methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester Part G acetylenic phosphinate (0.455 g, 0.66 mmol) was stirred in 10 ml of THF under argon atmosphere. Acetic acid (0.16 g, 2.66 mmol) was added at room temperature followed by the dropwise addition over 5 minutes of n-C^HgNF (1.8 ml of a 1.1 M THF solution, 2.0 mmol). After stirring for 24 hours at room temperature, the reaction was quenched by the addition of 30 ml of ice-water. The aqueous layer was removed and extracted 2 times with ethyl acetate. The THF was removed from the reaction organic layer, and the resulting oil was dissolved in ethyl acetate and combined O 9 / "? C. L, / o HXlOb -169- with the extracts of the aqueous layer. This ethyl acetate solution was washed 2 times with saturated aqueous NaHC03 solution and once with saturated NaCl solution and then dried over 5 Na2S04. Filtration and solvent removal gave 0.40 g of title hydroxy acetylenic phosphinate in the form of an oil. The title hydroxy acetylenic phosphinate was purified by flash chromatography eluting with 100% ethyl acetate. Title hydroxy 10 acetylenic phosphinate was obtained in 79% yield. TLC Rf=0.56 (7:3 acetone/Hexane, silica gel). . Mass Spec, m/e 449 (M+H)+, 431 (M-OH)+, 417 (m-och3)+ 15 'J. (S)-4-[[[2,4-Dimethyl-e-[(4-fluoro- phenyl ) methoxy ] phenyl ] ethynyl ] hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt To a 6.0 ml dioxane solution of Part H 20 acetylenic phosphinate (0.191 g, 0.43 mmol) at room temperature was added 1.4 ml of IN LiOH solution. The reaction was warmed to 55°C and stirred for 2 hours. The reaction was cooled to room temperature and evaporated to dryness to 25 obtain the title compound. The title compound was purified on a 130 mm x 30 mm diameter column of HP-20 eluting first with 100 ml of H20 then with a 1:1 Me0H/H20 mixture. Title compound was obtained in 91% yield (0.170 g) as a white lyophilate. 30 TLC Rf=0.37 (7:2:1 nPr0H/NH40H/H2O, silica gel). Mass Spec (FAB) m/e 421 (M+H)+, 427 (M+Li)+, 433 (M+2Li)+ O: HXlOb -170- "t / Anal Calcd for C21H2QOgFPLi2* 1.4 HjO: C, 55.09; H' 4.98; F, 4.15; P, 6.78 Found: C, 55.13; H, 5.25; F, 4.08; P, 6.91 5 Example 32 (S)-4-[[[2,4-Dimethyl-6-[(4-fluorophenyl)methoxy]-phenyl]ethyl]hydroxyphosphinyl]-3-hydroxy- butanoic acid, dilithium salt A. (S)-3-[ [(1,1-Dimethylethyl)diphenyl-10 silyl]oxy]-4-[[2-[2-[(4-fluorophenyl)- methoxy]-4,6-dimethylphenyl]ethyl]-methoxyphosphinyl]butanoic acid, methyl ester The Example 31 of Part G acetylenic 15 phosphinate (1.34 g, 1.95 mmole) was stirred in methanol (12 ml) and Pt02 (0.040 g) was added Hydrogen gas was bubbled through the methanol solution for 10 minutes and then a H2(g) atmosphere was maintained with a balloon. After 5 20 hours, 15 minutes at room temperature, the (^) reaction was complete and argon was bubbled through the reaction solution. The reaction was filtered through a celite pad in a fine sintered glass funnel, and the catalyst was washed with 25 methanol. Solvent was removed from the filtrate to give 1.4 g of a title saturated phosphinate in the form of a clear gum. The title saturated phosphinate was purified by flash chromatography eluting with 60% ethyl acetate/hexane and then 30 rechromatographing material from slightly impure fractions with 6/2.5/1.5 hexane/acetone/toluene. Title saturated phosphinate was obtained in 86% yield (1.17 g). rv 22 4 7 3 4 HXlOb -171- t ; TLC R^=.045 (80% ethyl acetate/hexane, silica gel) Mass Spec, m/e 691 (M+H)+, 659 (M-OCH3)+, &35 (M-CgHigOSi)+ B. (S)-4-[[[2,4-Dimethyl-6-[(4-fluoro-pheny1)methoxy]phenyl]ethyl]methoxyphosphinyl ]-3-hydroxy-butanoic acid, methyl ester The Part A phosphinate (1.16 g, 1.68 mmol) 10 was stirred in THF (25 ml) under argon atmosphere and at room temp. Glacial acetic acid (0.40 ml) was added dropwise to the phosphinate solution, and then n-C^NgNF (4.6 ml of a 1.1 M THF solution) was added dropwise over 5 minutes. The reaction 15 was stirred at room temperature overnight (18 hours) and then quenched with 50 ml of ice-water. After stirring for several minutes, sat'd NaCl solution was added, and the layers were separated. The organic layer was rotary evaporated to remove the 20 THF, and the resulting residue was dissolved in (£*) ethyl acetate. The aqueous layer was extracted 2 times with ethyl acetate, and all of the ethyl acetate solutions were combined and washed 2 times with sat'd aqueous NaHCO^ solution and once with 25 sat'd NaCl solution, then dried over Na2SO^. Filtration and solvent removal gave 1.13 g of title hydroxy phosphinate in the form of a clear oil. The title hydroxy phosphinate was purified by flash chromatography eluting with 100% ethyl acetate and 30 gave the title hydroxy phosphinate as a clear oil in 83% yield. TLC Rf = 0.27 (6:4 Acetone/hexane, silica, gel). Mass Spec, m/e 453 (M+H)+, 343 (M-C?H6F)+ 22 4 7 HXlOb -172- C. (S)-4-[[[2,4-Dimethyl-6-[ (4- fluorophenyl)methoxy]phenyl]ethyl]-hydroxyphosphinyl]-3-hydroxy-butanoic acid, dilithium salt The Part B phosphinate (0.594 g, 1.3 mmole) was stirred in 19 ml of dioxane at room temperature IN LiOH (4.0 ml) was added with stirring at room temp, and the reaction was warmed to 55°C. After 20 minutes at 55°C, a white thick precipitate formed and 4.0 ml of dioxane was added, and the resulting suspension was stirred at 55°C. After 2.5 at 55°C, 3 ml of H20 were added and the reaction mixture became clear. After 3 hours at 55°C, the reaction was cooled to room temperature, and the dioxane and water were removed by rotary evaporation leaving title diacid in the form of white solid which was placed under high vacuum for 15 minutes. The title diacid was purified by HP-20 chromatography eluting first with 100 ml of H20 followed by elution with 1:1 Me0H/H20 solution. Title diacid was obtained as a white lyophilate in 67% yield. TLC Rf=0.36 (7:2:1 n-propanol/NH4OH/H20, silica gel). Mass Spec, m/e (FAB), 425 (M+H)+, 437 (M+H+2 Li)+. Anal Calcd for C21H2405FP-1.15 H20: C, 55.19; H, 5.80; F., 4.16; P, 6.78 Found: C, 55.19; H, 5.80; F, 4.29; P. 6.83 -173- h JL2 4 Example 33 (S)-4-[ [2- [ [1,11-Biphenyl]-2-yl]ethynyl] hydroxyphosphinyl ] -3 -hydr oxybutanoic acid, dilithium salt A. (S)-4-[[2-[[1,1'-Biphenyl]-2-yl]- ethynyl]hydroxy-phosphinyl]-3-hydroxy butanoic acid, methyl ester The Example 9, Part D phosphinate (1.61 mmole, 0.985 g) was stirred under argon, at room temperature in 19.6 ml of dry THF. This solution was treated dropwise with glacial acetic acid (6.44 mmol, 0.386 g, 0.368 ml), followed by dropwise addition (8 min) of n-C^HgNF (4.84 mmol, 4.40 ml of a 1.1 M solution in THF). After stirring at room temp, for 18 hours, the reaction . mixture was quenched with 30 ml of ice water. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed 2 times with saturated aqueous NaHCOg, once with brine, dried over MgS04, filtered and evaporated. The product was isolated via flash chromatography (50 mm column, 6" Merck silica gel, 40% acetone/hexane eluent, 2"/min flow rate). Product fractions were concentrated, azeotroped with toluene, and evaporated in vacuo to afford (0.369 g, 0.991 mmol, 62% yield) of the title alcohol as a viscous yellow oil. (Also obtained 0.098 g, 0.263 mmol, 16% of slightly impure product) TLC: Silica gel = 0.35 (50% acetone/hexane). Mass Spec. CI m/e 373 (M+H)+ HXlOb -174- B. (S)-4-[[2-[[1,1'-Biphenyl]-2-yl]-ethynyl ] hydroxyphosphinyl ] -3 -hydroxybutanoic acid, dilithium salt The Part A diester (0.739 mmol, 0.275 g) was stirred under argon in 7.57 ml of dioxane and treated with IM LiOH (2.22 mmol, 2.22 ml). This cloudy reaction mixture was heated in a 55°C oil bath for 45 minutes. The mixture was cooled to room temp. The solvents were removed via rotary evaporation and high vacuum (90 minutes). The resulting yellow foam was dissolved in 4 ml of distilled H20 and eluted through an HP-20 chromatography column (2.5 cm x 19 cm), collecting 10 ml .fractions every 1.4 minutes. The column was eluted with H20 until 15 fractions were collected (no longer basic) and then elution with 45/55 methanol/H20 afforded (after lyophilization (2X) and high vacuum pump over P2°5 ^or 16 hours) 0.231 g (0.649 mmol, 88% yield) of the title diacid as a white lyophilate TLC: Silica gel Rf=0.55 (7:2:1 n-propanol/NH40H/H20) Mass Spec. (FAB m/e 345 (M+H)+, 351 (M+Li)+, 357 (M+2 Li) + . Anal Calcd for C18H1505PLi2 + 1.42 moles H20 MW=381.75: C, 56.63; H, 4.71; P, 8.07 Found: C, 56.62; H, 4.70; P, 8.07 n n i r «M= HXlOb -175- T '$ / %J o u o Example 34 (S)-4-[[2-[3,5-Dimethyl[1,1'-biphenyl]- 2-yl]-ethyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt 5 A. 3,5-Dimethyl[1,1'-biphenyl]-2- carboxaldehyde Phenylmagnesium bromide was obtained from Aldrich (Cat. No. 17, 156-5) as a 3M solution in ethyl ether. 10 A mixture of Example 1, Part B dipalladium complex (4.48 mmol, 3.35 g) and triphenylphosphine (35.85 mmol, 9.40 g)' was stirred at room temperature under argon in 67.2 ml of anhydrous toluene for 30 minutes. This reaction mixture was cooled to 0°C 15 and phenylmagnesium bromide Grignard reagent (Aldrich) (35.84 mmol, 11.95 ml of a 3M solution in ether was added portionwise (quickly). The resulting mixture was stirred at room temp, for 1.5 hours. The mixture was then cooled at 0° and 20 treated in one portion with 22.4 ml of 6.0 N HCl, and stirred at room temp, for 1 hour. The aqueous layer was separated and extracted with ether. The organic extracts were combined, filtered through Celite (washed with ether) and the filtrate washed 25 with brine, azeotroped with toluene, and evaporated in vacuo to afford a yellow solid. Attempted product purification via (2X) flash chromatography (95 mm diameter column, 6" Merck silica gel, 100% Hexane -> 3% ether/Hexane eluent, 30 2"/min flow rate afforded 2.95 g of a yellow solid (1.88 g, 8.96 mmol 100% yield of the title aldehyde and 1.06 g of triphenylphosphine). This compound mixture was used directly in the o 22 4 7 34 HXlOb -176- preparation of the Part B compound. TLC: Silica ^ gel, Rf=0.30 (5% ether/Hexane) ***' Mass Spec. (CI) m/e 211 (M+H)+, 263 (M2+H) + , 473 (m1+m2+h)+ 5 M^= Part A aldehyde, M2 = triphenylphosphine. B. 2-(2,2-Dibromoethenyl)-3,5-dimethyl- T1,1'-biphenyl) A mixture of Part A aldehyde (8.96 mmol, 10 "1.88 g") and triphenylphosphine (26.4 mmol, 6.90 g) was stirred in 88 ml of dry CH2CL2 at -5°C for 10 minutes. This reaction mixture was maintained at -5°C as a solution of CBr4 (13.2 mmol, 4.38 g) in 32 ml of dry CH2C12 was added dropwise (20 15 min). The resulting reaction mixture was stirred at -5°C for 1 hour and became progressively darker orange with time. The mixture was then quenched with 85 ml of saturated aqueous NaHCO^ • The aqueous layer was extracted with CH2C12. The 20 organic extracts were combined, washed once with saturated NaHC03 (aqueous), and once with brine, dried over MgS04, filtered and evaporated in vacuo. The product was purified by preabsorbing the crude product in CH2C12 onto 25 g of Merck 25 silica gel and applying this to a flash Q chromatography column (50 mm diameter, 6" Merck silica gel, 4% CH2C12/Hexane eluent, 2"/min flow rate), affording 2.18 g (5.96 mmol, 68% yield) of the title vinyl dibromide as a viscous colorless 30 oil. TLC: Silica gel Rf=0.37 (4% CH2C12, Hexane) Mass Spec. (CI) m/e 365/367/369 (M+H) r,..'* * • ?•. "** J -= i f HXlOb -177- o C. 3,5-Dimethyl-2-(l-propynyl)[1,1'-biphenyll . A solution of the Part B vinyl dibromide (5.74 mmol, 2.10 g) in 29.11 ml of anhydrous THF 5 was stirred under argon and cooled to -78°C. This solution was treated dropwise (20 minutes) with n-butyllithium (11.47 mmol, 4.59 ml of a 2.5 M solution in hexanes) resulting in a deep purple solution. After stirring at -78°C for an 10 additional hour, the reaction mixture was quenched at -78°C with 25 ml of saturated NH^Cl (aqueous), warmed to room temp, diluted with ^0, and the aqueous layer extracted with 1:1 ether/hexane. The organic extracts were combined, dried over 15 MgS04, filtered, and evaporated in vacuo. The product was isolated via flash chromatography (50 mm column, 6" Merck silica gel, 1% ether/hexane eluent) to afford 1.08 g (5.23 mmol, 91% yield) of the title acetylene as a colorless oil which 20 became blue when stored 16 hours at -20°C. TLC: r-~v Silica gel R^=0.32 (100% hexane). ^ Mass spec. (CI) m/e 207 (M+H)+. D. (S)-3-[[(1,1-Dimethylethyl)diphenyl-25 silyl]oxy]-4-[[2-[3,5-dimethyl[1,l1- biphenyl ] -2-yl ] methoxyphosphinyl ] - w ' butanoic acid, methyl ester A solution of the Part C acetylene (4.61 mmol, 0.950 g) in 27.3 ml of dry THF was stirred 30 under argon and cooled to -78°C. n-Butyllithium (4.61 mmol, 1.84 ml of a 2.5 M solution in hexanes) was added dropwise (20 min) resulting in a dark purple/brown solution. The reaction ^ $ *? ^ 4 ^ 'V/ r» HXlOb -178- mixture was stirred at -78°C for 1 hour (reaction mixture became a slurry) warmed to 0°C and stirred 15 min. (reaction mixture returned to a dark purple homogeneous solution) and finally recooled 5 to -40°C (remained homogeneous). This acetylenic anion solution at -40°C was then added dropwise (25 min) to a solution of the Example 1, Part F phosphinyl chloridate (8.12 mmol) in 27.3 ml of dry THF which had been cooled to -78°C as it was 10 stirred under argon. After the addition of the acetylenic anion solution to the phosphinyl chloridate solution was complete, the dark orange reaction mixture was stirred at -78°C for 1 hour and then quenched at -78°C with 50 ml of saturated 15 NH^Cl, warmed to room temp, and diluted with ^0. The aqueous layer was extracted with ether. The organic extracts were combined, washed once with saturated NaHCOg (aqueous), once with brine, dried over MgS04, filtered and evaporated in vacuo. The 20 product was isolated via flash chromatography (50 (^) mm diameter column, 6" Merck silica gel, 50% ethyl acetate/hexane eluent, 2"/min flow rate) to afford 0.609 g (0.945' mmol, 21%) of the title phosphinate as a golden orange oil. 25 TLC: Silica gel Rf=0.32 (50% ethyl acetate/Hexane) Q) Mass Spec. (CI) m/e 639 (M+H)+ E. (S)-4-[[2-[3,5-Dimethyl[1,1'-biphenyl]-2-yl]ethyl]hydroxyphosphinyl]-3-(t-30 butyldiphenylsilyloxy)butanoic acid, dilithium salt Argon was bubbled through a methanol (13 ml) solution of the Part D acetylenic phosphinate rf*a f. * j1 * /* £• c,. -t / HXlOb -179- (1.37 mmol, 0.876 g) for 10 minutes. 10% Pd/C (0.315 g) was added and the reaction' mixture was subjected to Parr hydrogenation "at 40 psi. After shaking for 24 hours, the reaction mixture was filtered through a Celite pad in a sintered glass funnel. The Celite was washed with methanol and the filtrate was evaporated in vacuo to afford 0.896 g of a yellow oil which was purified via flash chromatography (50 mm diameter column, 6" Merck silica gel, 40% -* 50% ethyl acetate/Hexane eluent) to afford 0.680 g (1.06 mmol, 77% yield) of the title saturated phosphinate as a pale yellow foam. Stripping the flash column by eluting with methanol produced an additional 0.087 g of slightly impure product. TLC: =0.27, Silica gel (50% acetone/hexane). Mass Spec. (CI) m/e 643 (M+H)+. F. (S)-4-[[2-[3,5-Dimethyl[1,1'-biphenyl]-2-yl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt The Part E phosphinate (1.03 mmol, 0.66 g) was stirred under argon at room temp, in 12.65 ml of dry THF. This solution was treated dropwise with glacial acetic acid (4.12 mmol, 0.247 g, 0.236 ml), followed by dropwise addition of n-C^N^NF (3.09 mmol, 2.81 ml of a 1.1M solution of THF). After stirring at room temperature for 16 hours, the reaction mixture was quenched with 25 ml of ice water. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed 2 times with saturated aqueous ^ FS / s © ^ / 3 HXlOb -180- NaHC03, once with brine, dried over MgS04, /"""n filtered and evaporated in vacuo. The product was purified via flash chromatography (40 mm column, 6" Merck silica gel, 50% acetone/Hexane eluent) to 5 afford 0.363 g (0.898 mmole, 87% yield) of the title alcohol as a white solid. TLC: Silica gel, O Rf=0.30 (50% acetone/Hexane). Mass Spec (FAB) m/e 405 (M+H)+. 10 G. (S)-4-[ [2-[3,5-Dimethyl[1,1'-biphenyl]- 2 -yl ] ethyl ] hydroxyphosphinyl ] -3 -hydroxybutanoic acid, dilithium salt The Part F diester (0.878 mmol, 0.355 g) 15 . was stirred under argon in 9 ml of dioxane and treated with IM LiOH (2.63 mmol, 2.63 ml). This homogeneous reaction mixture was heated in a 55°C oil bath. After stirring at 55°C for 10 minutes, the reaction mixture became a white suspension. 20 An additional 9 ml of dioxane and 2 ml of H,0 were added, and the suspension was heated at 55°C for 45 minutes, then cooled to room temperature. The solvents were removed by rotary evaporation and high vacuum (1 hour). The resulting white solid 25 was eluted through an HP-20 chromatography column (18 cm x 2.5 cm). 10 ml fractions were collected every 1.4 minutes. The column was eluted with H20 until 15 fractions were collected and then elution with 1:1 methanol/^O afforded [after lyophiliza-30 tion (3X) and high vacuum pump over P2°5 (4x8 • hours)] 0.289 g (0.744 mmol, 85% yield) of the title diacid as a white lyophilate. O £C H / s 0 0 /. 7 HXlOb -181- TLC: silica gel, Rf=0.56 (7:2:1, n-propanol/NH4OH/H26). " Anal Calcd for C20H23O5PLi2 + 0.34 moles of H20 M.W.=394.31: C, 60.92; H, 6.05 5 Found: C, 60.95; H, 6.18 Mass Spec. (FAB) m/e 389 (M+H)+. o Example 35 (S)-4-[[2-[41-Fluoro-3,5-dimethyl[1,1*-biphenyl]-2-10 yl] ethyl] hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A. Bromo(4-fluorophenyl)magnesium Magnesium metal turnings (44.35 mmol, 1.08 g) were flame dried, then stirred under argon in 15 40 ml of anhydrous ether. With vigorous stirring, l-bromo-4-fluorobenzene (40.3 mmol) was added dropwise to the magnesium. The reaction was initiated in an ultrasound device and then the halide was added dropwise at a rate sufficient to 20 maintain reflux. After addition of the bromide was complete, the reaction mixture was stirred at room temperature for 20 minutes, then heated to reflux and finally cooled to room temperature. This procedure yielded a golden orange transparent 25 Grignard solution containing 40.32 mmol of title Grignard as a 0.91 M solution in ether. B. 41-Fluoro-3,5-dimethyl[1,1'-biphenyl]-2-carboxaldehyde 30 Reference: Stockker et al, Journal of Med. Chem., 29, 170-181 (1986). A mixture of the Example 26 Part B . palladium complex (4.35 mmol, 3.20 g) and 0 o / "?■ © s~ **0 HXlOb -182- triphenylphosphine (40.32 mmol, 10.58 g) was stirred at room temperature under argon in 67.2 ml of anhydrous toluene for 30 minutes. Then this reaction mixture was cooled to 0°C and the Part A 5 Grignard reagent (40.32 mmol, 44.43 ml) was added portionwise (quickly). The resulting mixture was (^) stirred at room temperature for 1.5 hours. The mixture was then cooled to 0°C and treated in one portion with 21.75 ml of 6.0 N HCl and stirred at 10 room temperature for 1 hour. The aqueous layer was separated, extracted with ether and the combined organic extracts filtered through Celite. The celite was washed with ether and the combined filtrates were washed with brine, 15 azeotroped 2 times with toluene, and stripped, to afford an orange-yellow solid. Attempts at isolating the title aldehyde by flash chromatography using a 95 mm diameter column, 6" Merck silica gel, hexane eluent followed by 3% 20 Et,0/hexane eluent, 2"/min flow rate, resulted in Ct ) a final reaction product mixture of the desired title aldehyde and triphenylphosphine as a pale yellow solid (3.70 g - assume this contains 8.7 mmol, 1.99 g, 100% yield of title aldehyde + 1.70 25 g of triphenylphosphine). This compound mixture O was used directly in the preparation of Part C compound. TLC: silica gel R^=0.25 (5% ether/Hexane) 1H NMR: (270 MHz, CDClg) 30 n 9 / Ss> HXlOb -183- C. 2-(2,2-Dibromoethenyl)-4'-fluoro-3,5- C) dimethyl[1,1'-biphenyl ] A mixture of the Part B aldehyde (8.70 mmol, "1.99 g") and triphenylphosphine (26.1 mmol, 5 6.85 g) was stirred in 87 ml of dry CH2C12 at -5°C for 10 minutes. This reaction mixture was o maintained at -5°C as a solution ofCBr^ (13.05 mmol, 4.33 g) in 43 ml of dry CH2C12 was added dropwise over 25 minutes. The resulting reaction 10 mixture was stirred at -5°C for 1 hour producing a dark orange solution which was then quenched with 80 ml of saturated aqueous NaHCO^. The aqueous layer was extracted 4 times with CH2C12. The combined organic extracts were washed once with 15 saturated aqueous NaHC03 and once with brine. The CH2C12 extract was dried over MgS04, filtered and the filtrate combined with 25 g of Merck silica gel. The solvent was evaporated and the preabsorbed product was purified via flash 20 chromatography (50 mm diameter column, 6" Merck silica gel, 4% CH2C12/Hexane -eluent, 2"/min flow rate) to afford 2.32 g (6.04 mmol, 69% yield) of the title vinyl dibromide as a colorless oil. TLC: silica gel, Rf=0.43 (5% CH2C12/Hexane). 25 Mass Spec. (CI) m/e 383/385/387 (M+H)+. o D. 4'-Fluoro-3,5-dimethyl-2-(1-propynyl)- fl,!1-biphenyl] A solution of the Part C vinyl dibromide 30 (5.99 mmol, 2.30 g) in 33 ml of anhydrous THF was stirred under argon and cooled to -78°C. This solution was treated dropwise (25 minutes) with n-butyllithium (11.97 mmol, 4.79 ml of a 2.5 M 1 J ' '5*^^ O 9o /,-y x r Cc. h / o 4 HXlOb -184- solution in hexanes), resulting in a deep purple solution. After stirring at -78°C for an additional hour, the reaction mixture was quenched | at -78°C with 25 ml saturated aqueous NH4C1, 5 warmed to room temperature and diluted with 25 ml j of H_0. The aqueous layer was extracted 4 times i ^ i with 1:1 ether/hexane. The organic extracts were I j combined, dried over MgSO^, filtered and ' evaporated. The product was isolated via flash | 10 chromatography (50 mm column, 6" Merck silica gel, | 0.50% ether/hexane eluent, 2"/mm flow rate) to ! afford 1.25 g (5.57 mmol, 93% yield) of the title j acetylene, as a colorless oil which turns blue | when stored at 20°C. | 15 TLC: silica gel, R^=0.25 (100% hexane) I Mass Spec. (CI) m/e 225 (M+H)+. E. (S)-4-[[2-[41-Fluoro-3,5-dimethyl- [1,1*-biphenyl]-2-yl]ethynyl]hydroxy-20 phosphinyl]-3-(t-butyldiphenylsilyloxy) • butanoic acid, methyl ester A solution of the Part D acetylene (5.24 mmol, 1.18 g) in 28 ml of dry THF was .stirred under argon and cooled to -78°C. n-Butyllithium 25 (5.24 mmol, 2.10 ml of a 2.5 M solution in hexane) was added dropwise( 25 min) as the reaction mixture became dark purple/brown. The reaction mixture was then stirred at -78°C for 1 hour, warmed to 0°C, stirred for 10 minutes, and 30 recooled to -78°C. This acetylenic anion solution at -78°C was then added dropwise (20 minutes) to a solution of the Example 1 Part F phosphinyl chloridate (8.32 mmol) in 28 ml of anhydrous THF 0 /, "7 n U / HXlOb -185- which had been cooled to -78°C as it was stirred ' under argon. After the addition was complete, • the dark orange reaction mixture was stirred at -78°C for 1 hour and then quenched at -78°C with 5 saturated aqueous NH4C1, warmed to room temperature and diluted with H20. The aqueous layer was extracted 4 times with ether. The organic extracts were combined and washed once with saturated aqueous NaHCO^, once with brine, dried over MgSO^, filtered, and evaporated. The product was isolated via flash chromatography (50 mm diameter column, 6" Merck silica gel, 40% ethyl acetate/hexane eluent, 2"/min flow rate) to afford 0.730 g (1.11 mmol, 21% yield) of the title 15 acetylenic phosphinate as a green viscous oil. TLC: silica gel Rf=0.36 (50% ethyl acetate/hexane) / 10 Mass Spec (CI) m/e 657 (M+H)+ F. (S)-4-[[2-[4*-Fluoro-3,5-dimethyl-20 [1,1*-biphenyl]-2-yl]ethyl]hydroxy- phosphinyl] -3- (t-butyldiphenylsilyloxy.)- butanoic acid, methyl ester Argon was bubbled through a methanol 9.9 ml solution of the Part E acetylenic phosphinate 25 (1.04 mmol, 0.685 g) for 10 minutes. 10% Pd/C 0.239 g was added and the reaction mixture was subjected to Parr hydrogenation at 40 psi. After shaking for 24 hours, the reaction mixture was filtered through a Celite pad in a sintered glass 30 funnel, the Celite was washed with methanol, and the filtrate was evaporated to afford 0.638 g of a green oil. . The product was purified via flash chromatography (40 mm diameter column, 6" Merck r , O j ^ ^ *■ f! ' .£ - -? / o HXlOb -186- silica gel, 45% ethyl acetate/hexane eluent, /-"n 2"/min flow rate) to afford 0.530 g (0.802 mmol J 77% yield) of the title saturated phosphinate as a pale yellow foam. Also obtained 0.09 g (0.136 5 mmol, 13%) of slightly impure product. TLC: silica gel. Rf=0.30 (50% ethyl acetate/hexane) Mass spec. (CI) m/e 661 (M+H)+ G. (S)-4-[[2-[41-Fluoro-3,5-dimethyl-10 [1,11 -biphenyl] -2-yl] ethyl] methoxy phosphinyl ]-3-hydroxybutanoic acid, methyl ester The Part F phosphinate (0.794 mmol, 0.525 g) was stirred under argon at room temperature in 15 9.74 ml of anhydrous THF. This solution was treated dropwise with glacial acetic acid (3.18 mmol, 0.191 g, 0.182 ml), followed by dropwise addition of n-C^HgNF (2.38 mmol, 2.17 ml of a 1.1 M solution in THF). After stirring at room 20 temperature for 16 hours, the reaction mixture was quenched with 15 ml of ice water. The aqueous layer was extracted 3 times with ethyl acetate. The organic extracts were combined, washed 2 times with saturated aqueous NaHC03, 1 time with brine, 25 dried over MgS04, filtered and evaporated. The product was purified via flash chromatography (40 mm diameter column, 6" Merck silica gel, 50% acetone/hexane eluent, 2"/min flow rate). Product fractions were concentrated and azeotroped 30 to dryness with toluene to afford 0.281 g (0.665 mmol, 84% yield) of the title alcohol as a white solid. An impurity visible by 270 MHz "^H NMR was not separable/visible in various TLC systems. 22 47 34 HXlOb -187- TLC: Silica gel, Rf=G.31 (50% acetone/hexane) XH NMR: (270 MHz, CDC13). Mass Spec- (CI) m/e 423 (M+H)+ H'. (S) 74- [ [2- [41 -Fluoro-3, 5-dimethyl-[1,1'-biphenyl]-2-yl]ethyl]hydroxyphosphinyl ]-3-hydroxybutanoic acid, dilithium salt The Part G diester (0.473 mmol, 0.20 g) was stirred under argon in dioxane (4.84 ml) and treated with IM LiOH (1.42 mmol, 1.42 ml). This homogeneous reaction mixture was heated in a 55°C oil bath. After stirring at 55°C for 10 minutes, the reaction mixture became a white suspension. The mixture was maintained at 55°C for an additional 45 minutes, then cooled to room temperature. The solvents were removed by rotary evaporation and high vacuum (1 hour). The resulting white foam was dissolved in 4 ml of distilled H20 and eluted through an HP-20 chromatography column (16 cm x 2.5 cm). 10 ml fractions were collected every 1.4 minutes. The column was eluted with ^O until 15 fractions were collected and then elution with 1:1 methanol/^O afforded (after lyophilization (2X) and high vacuum pump over F2°5 ^or ^ h°urs) 0-158 g (0.389 mmol,.82% yield) of the title diacid as a white lyophilate. TLC: silica gel R^=0.59 (7:2:1, n-propanol/NH^OH/^O) Mass Spec (FAB) m/e 395 (M+H)+ Anal Calcd for C2QH22F05PLi2+0.39 moles H20 ~ J 1 \ ^ ^ HXlOb -188- MW=413.25: C, 58.12; H, 5.56 Found: C, 58.14; H, 6.09 Example 36 (S)-4-[[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-phenyl-lH-pyrazol-4-yl]ethynyl]methoxyphosphinyl]- 3-hydroxybutanoic acid/ methyl ester A. 4-Fluoro-p-oxobenzenepropanoic acid, ethyl ester 60% Sodium hydride in mineral oil (17.4 g, 0.43 mmole) was washed twice with dry hexane, dried in vacuo then treated with neat diethylcarbonate (44.3 ml, 0.36 mmole) followed by the dropwise addition of p-fluoro-acetophenone (22 ml, 0.18 mole). After about 10% of the ketone had been added, 4 drops of ethanol was added to initiate refluxing and the remainder of the p-fluoro-acetophenone was added over 1.0 hour at a rate that maintained reflux conditions. The yellow solid which formed was slurried in dry ether (250 ml) and refluxed for an additional 3.0 hours under argon. The reaction mixture was cooled in an ice \ bath, diluted with ether (200 ml) and treated slowly with water (1.3 liters) until all the solids dissolved. The aqueous phase was separated from the organic phase, acidified with 12N HCl (32 ml) to pH 1.0 and extracted with ether (2 x 500 ml). The combined organic extracts were washed with brine (200 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness. The crude product (44.0 g) was distilled under reduced pressure (3.5 mm) to give title compound as a homogeneous oil _ 2? 4 7 HXlOb -189- (24.88 g, 65.J ^ TLC: Rf 0.46 (Silica gel; CH2C12:hexane-4:l}. B. 4-Fluoro-a-(2-methyl-1-oxopropyl)-p-5 oxobenzenepropanoic acid, ethyl ester 60% Sodium hydride in mineral oil (10.3 g, 0.26 mmole) was washed twice with dry hexane, dried in vacuo, suspended in dry tetrahydrofuran (245 ml) and cooled down to 0° (ice water bath) 10 under argon. The suspension was treated dropwise with Part A compound (24.5 g, 0.12 mole) over a 20-minute period, warmed to room temperature and stirred for.another 30 minutes. The reaction mixture was cooled down to 0° (ice water bath), 15 treated dropwise with isobutyryl chloride (18.62 g, 0.17 mole), warmed to room temperature and stirred for 3.0 hours. The mixture was cooled down to 0° (ice water bath), quenched with water (200 ml) to produce a homogeneous solution and 20 evaporated on a rotary evaporator to remove most of the tetrahydrofuran. The aqueous phase was acidified with 10% HCl (37 ml) to pH 1.0 and extracted with ether (3 x 100 ml). The combined organic extracts were washed with brine (50 ml), 25 dried (anhydrous MgS04), filtered and evaporated to dryness, to give an oil (36.85 g) which was a mixture of starting material and two other products. 30 TLC: Rf 0.46, 0.33, 0.20 (Silica gel; CH2C12:hexane-4:1, UV). 0 0 L 7 L, L, H 3 HXlOb -190- C. 5-(4-Fluorophenyl)-3-(1-methylethyl)-1-phenyl-lH-pyrazole-4-carboxylic acid, ethyl ester. Crude Part B compound (36.85 g, ^ 0-12 mole) was dissolved in glacial acetic acid (151 ml), treated portionwise with 97% phenylhydrazine (18.1 ml, 0.18 mole) under nitrogen and stirred at room temperature for 19 hours. The reaction mixture was poured into water (350 ml), extracted with ether (3 x 100 ml) and the combined organic extracts were washed with saturated NaHC03 until the aqueous layer was basic, brine (500 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The dark orange oil was evaporated once from petroleum ether (300 ml) to obtain a yellow solid. This crude product was triturated with petroleum ether (100 ml) to give a crude product (15.3 g) which in turn was chromatographed on a silica gel column (LPS-1), eluting the column with CH2C12:hexane (2:1) to give 11.53 g of pure product. The mother liquor (26.4 g) on chromatography on a silica gel column (LPS-1) and trituration of the compound obtained gave an additional 7.12 g of desired product (total yield: 18.65 g or 44.1%). A small amount of title compound was recrystallized from Et20:hexane to give homogeneous solid, m.p. 92-93°C. TLC: Rf 0.35 (Silica gel: CH2Cl2:hexane-4:l) Anal Calcd: C, 71.57; H, 6.01; N, 7.95; F, 5.39 Found: C, 71.62; H, 5.99; N, 7.91; F, 5.54. -191- HXlOb D. 5-(4-Fluorophenyl)-3-(1-methylethyl)-1-phenyl-lH-pyrazole-4-methanol A solution of Part C compound (11.53 g, 32.7 mmole) in anhydrous ether (142 ml) was added dropwise over a period of 1.5 hours to a cooled (0°; ice-salt bath) suspension of lithium aluminum hydride (3.67 g, 96.7 mmoles) in anhydrous ether (70 ml) under argon. The greenish suspension was allowed to warm up to room temperature over a period of 1.5 hours, cooled back down to 0° (ice-salt bath) and quenched by the dropwise addition of water (20 ml) until gas evolution ceased. The thick slurry was diluted with ether (100 ml) and filtered, washing the precipitates well with ethyl acetate (3 x 150 ml). The combined organic extracts were washed with brine (50 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness to give a cream-colored solid (10.3 g, 100% crude yield). 100 mg of the crude product was recrystallized from Et20:hexane to .give title compound (58 mg) as white crystals, m.p. 138-140°. TLC: Rf 0.01 (Silica gel; CH2Cl2) Anal Calcd: C, 73.52; H, 6.17; F, 6.12; N, 9.03 Found: C, 73.16; H, 6.15; F, 6.12; N, 8.90 MS (M+H)+=311 E. 5-(4-Fluorophenyl)-3-(1-methylethyl)-■l-phenyl-lH-pyrazole-4-carboxaldehyde A solution of crude Part D compound (10.2 g, ~32.7 mmole) in dry dichloromethane (85 ml) was added rapidly to a solution of pyridinium chlorochromate (21.23 g, 98.4 mmoles) in dry 192- HXlOb dichloromethane (125 ml) and the resulting dark brown solution was stirred at room temperature under nitrogen for 4.0 hours. The mixture was diluted with ether (750 ml) and stirred for 10 minutes. The supernatant solution was decanted from the tar-like residue and the residue was triturated with dichloromethane (2 x 100 ml). The dichloromethane extracts were diluted with ether (750 ml) and the combined extracts filtered through a silica gel pad. The clear filtrate was evaporated to dryness to give a crude product (10.0 g). The crude product was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the' column with CH2C12:hexane (4:1) to give title compound as a solid (9.6 g, 95.2%). An analytical sample (72 mg, m.p. 108-110°) was obtained by recrystallizing 100 mg from hexane. TLC: Rf 0.58 (silica gel; CH2C12>- UV). Anal Calcd: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 74.10; H, 5.52; N, 9.12; F, 6.29 MS (M+H)+=309 F. 4-(2,2-Dibromoethenyl)-5-(4-fluoro-phenyl)-3-(1-methylethyl)-1-phenyl-lH-pyrazole A mixture of Part E compound (2.0 g, 6.48 mmole) and triphenylphosphine (5.10 g, 19.2 mmoles) in dry dichloromethane (30 ml) was cooled down to -5° to -10° (ice-salt bath) under argon and treated dropwise over a period of 5 minutes with a solution of carbon tetrabromide (3.22 g, 9.61 mmoles) in dry dichloromethane (10 ml). The f"-' / •"» © £ *: *i- / 0 HXlOb -193- reaction mixture was stirred at 15°-20° for 15 minutes then poured onto saturated NaHC03 (10 ml) ^ and extracted with dichloromethane (3 x 50 ml). The combined organic extracts were washed with 5 saturated NaHC03 (10 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product mixture (9.33 g) was chromatographed on a silica gel column (LPS-1) 10 eluting the column with CH2Cl2:hexane mixtures (1:9, 1:1; 4:1) to give title compound as a solid (2.75 g, 91.6%). Recrystallization of a small sample of title compound gave white crystals, m.p. 88-90°. 15 TLC: Rf 0.85 (silica gel; CH2C12:hexane-4:1) Anal Calcd: C, 51.75; H, 3.69; N, 6.04; F, 4.09; Br, 34.43 Found: C, 51.96; H, 3.51; N, 5.97; F, 4.22; Br, 34.77 {J 20 MS (M+H)+=465. G. 4-Ethynyl-5-(4-fluorophenyl)-3-(1- methylethyl)-1-phenyl-lH-pyrazole A solution of Part F compound (2.64 g, 5.67 25 mmole) in dry tetrahydrofuran (10.5 ml) was cooled ) down to -78° (dry ice-acetone) under argon and treated dropwise with 1.6M n-BuLi/hexane (7.16 ml, 11.37 mmoles). The" resulting suspension was stirred at -78° for 1 hour and 20 minutes, 30 quenched by the dropwise addition of 25% NH4C1 (10 ml) and allowed to warm up to room temperature. The reaction mixture was extracted with ether (3 x 50 ml) and the combined organic extracts were D r* r} .<■ L, L HXlOb -194- washed with brine (20 ml), dried.(anhydrous MgS04), filtered and evaporated to dryness to give title compound as a light brown solid (1.79 g). The crude product was chromatographed on a 5 silica gel column, eluting the column with Et20:hexane (5:95) to give title compound as a light gold-colored solid (1.08 g, 97.4%). Recrystallization of a small sample from hexane gave white, fluffy crystals, m.p. 106-108°. TLC: Rf 0.70 (silica gel; Et20:hexane-1:9; developed 2X). Anal Calcd: C, 78.92; H, 5.63; N, 9.21; F, 6.24 Found: C, 79.22; H, 5.53; N, 9.28; F, 6.23 < j 10 MS (M+H)+=305 15 H. (S)-3-[[(l,1-Dimethylethyl)diphenyl-silyl]oxy]-4-[[[5-(4-fluorophenyl)-3-(1-methylethyl)-l-phenyl-lH-pyrazol-4-yl]ethynyl]methoxyphos-20 phinyllbutanoic acid, methyl ester A mixture of the crude Example 1- Part F phosphonic monomethyl ester (2.77 g, 5.55 mmoles) and trimethylsilyldiethylamine (2.1 ml, 11.05 . mmoles) in dry dichloromethane (10 ml) was 25 stirred at room temperature under argon for 1.0 hour. The mixture was evaporated to dryness, azeotroped with dry benzene (20 ml) and dried in vacuo (pump) for 15 minutes. The viscous oil was re-dissolved in dry dichloromethane (10 ml), 30 treated with one drop of DMF, cooled down to -10° (ice-salt bath) and treated dropwise with oxalyl chloride (530 pi, 6.08 mmoles). Vigorous gas evolution was observed and the dark yellow r\ r-, f £ L 4 / HXlOb -195- solution was stirred at -10° .for 15 minutes, then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with benzene (20 ml) and dried in vacuo. 5 A solution of Part G compound (1.12 g, 3.67 mmoles) in dry tetrahydrofuran (9.0 ml) was cooled O down to -78° (dry ice-acetone) under argon and treated with 1.6M n-BuLi/hexane (2.3 ml, 3.67 mmoles) and stirred at -78° for 30 minutes. The 10 above phosphochloridate was dissolved in dry tetrahydrofuran (6.5 ml), cooled down to -78° (dry ice-acetone) under argon and treated dropwise by cannula with the solution of the acetylene anion, both solutions being kept at -78° 15 throughout the addition. The reaction mixture was stirred at -78° for 30 minutes, quenched by the dropwsie addition of 25% NH^Cl (6.0 ml) then warmed to room temperature. The mixture was extracted with ether (3 x 100 ml) and the combined 20 organic extracts were washed with 25% NH4C1 (10 (^) ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product mixture (^4.2 g) was chromatographed on a silica gel column, 25 eluting the column with hexane:acetone (9:1) to give title compound as a light brown oil (1.54 g, 57.0%). TLC": Rf 0;33 (silica gel; hexane:acetone-7:3 ) 30 I. (S)-4-[[2-[5-(4-Fluorophenyl)-3- (1-methylethyl)-l-phenyl-lH-pyrazol-4-yl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester HXlOb -196- A solution of Part H compound (593.9 mg; 0.81 mmole) in dry tetrahydrofuran (8.0 ml) was treated successively with glacial acetic acid (190 Ml, 3.24 mmoles) and IM Bu^NF (2.54 ml, 2.54 mmoles) and stirred overnight at room temperature under argon. The reaction mixture was cooled down to 0°C (ice water bath), treated with 5% KHS04 (8.5 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extracts were washed with 5% KHS04 (10 ml), brine (20 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product was dissolved in a mixture of ether (14 ml) and dry tetrahydrofuran (10 ml), cooled down to 0° (ice-salt bath), treated with excess diazomethane in ether and stirred at 0° for 3.0 hours. The reaction mixture was quenched by the dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column eluting the column with acetone:hexane (1:2) to give title compound as a semi-solid (325.6 mg, 80.6% yield). Example 37 (S)-4-[[2-[5-(4-Fluoropheny1)-3-(1-methylethyl) -1 -phenyl-lH-pyrazol-4-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A solution of Example 36 compound (325 mg, 0.65 mmole) in dioxane (7.7 ml) was treated with IN LiOH (2.25 ml, 2.25 mmole) stirred at 55° (oil bath) under nitrogen for 1.5 hours then at room temperature for 16 hours. The reaction'mixture O O. it *■'-* fl a £=, 4, HXlOb -197- was evaporated to dryness and dried in vacuo. The /—•n crude product was chromatographed on an HP-20 column (1" x 5"), eluting the column with steam-distilled water (400 ml) and 50% aqueous 5 CH30H (500 ml). The desired fractions were combined, evaporated to dryness and dried 0 in vacuo. The solid product was dissolved in steam-distilled water and lyophilized to give title product as a fluffy solid lyophilate (317.1 10 mg, 96.4%). TLC: Rf 0.33 (silica gel; i-Pr0H:NH40H:H20-8:l:l). Anal Calcd for C24H22FN205P*2 Li-1.3 H20 (Eff. Mol. Wt.=505.861): C, 56.99, H, 4.90;, N, 5.54; F, 3.75; P, 6.12 15 Found: C, 56.98; H, 5.17; N, 5.46; F, 3.90; P, 6.26 H^-NMR Spectrum (400 MHz, CD3OD): 6 1.40 (d, 6H, J=7 Hz) 1.81-1.98 (m, 2H) 20 2.35 (dd, 1H, J=9, 15 Hz) Q) 2.48 (dd, 1H, J=4, 15 Hz) 3.35 (septet, 1H, J=7 Hz) 4.42 (m, 1H) vj 7.08-7.41 (m, 9H). 25 IR(KBr): 2173 cm"1 (C=C). Example 38 (E)-4-[[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1-phenyl-lH-pyrazol-4-yl]ethenyl]methoxyphosphinyl]-3-30 hydroxybutanoic acid, methyl ester 22 4 7 3 HXlOb -198- . " A. [2-[5-(4-Fluorophenyl)-3-(l-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]-2-hydroxyethyl]phosphonic acid, dimethyl ester A -78°C (C02/acetone) solution of dimethyl methylphosphonate (2.81 ml, 25.9 mmole) in dry THF (50 ml) was treated with a 1.6M n-BuLi solution in hexanes (15.2 ml, 24.3 mmole) dropwise over 15 minutes and the white suspension (after ~15 minutes) stirred under argon at -78°C for one hour. Example 36 Part E pyrazole aldehyde (5.0 g, 16.2 mmole) in dry THF (15 ml) was added dropwise over 10 minutes and the yellow mixture stirred at -78°C for 30 minutes. The mixture was quenched with saturated NH4C1 (20 ml) and allowed to warm to room temperature. The mixture was partitioned between H20 and EtOAc, the organic phase washed with brine, dried over anhydrous Na2S04 and evaporated to give 7.158 g of crude title p-hydroxyphosphonate as a yellow foam. A small sample was crystallized from hexanes to give pure title compound as white crystals with m.p. = 126°-128°C. TLC (1:1) hexane-acetone, = 0.27. + + Mass Spec. (M+H =433 observed). Anal Calcd for C22H2604N2PF: C, 61.10; H, 6.06; N, 6.48; F, 4.39; P, 7.16-Found: C, 60.95; H, 6.06; N, 6.41; F, 4.22; P, 7.27 u n. t- .» CC H / HXlOb "9 -199- 10 LH NMR (CDC13): 6 1.42 (6H, d) 1.94-2.40 (2H, m) 3.29 (1H, septet) ■ 3.62+3.63 (2 doublets, JH_p=ll.l Hz) 3.91 (1H, s) 5.11 (1H, bm) 6.90-7.30 (9H, m) ppm. 13C NMR (CDC13): 6 22.6, 26.5, 32.8 (Jc-p=136.3 Hz), 52.1 (Jc_p=5.7 Hz), 60.8, 115.0, 115.4, 119.3, 119.5, 124.7, 126.3, 126.6, 128.5, 132.2, 132.3, 139.4, 139.5, 156.7, 164.5 (Jc-p=265 Hz) ppm. 15 B. (E)—[2—[5-(4-Fluorophenyl)-3-(1- methylethyl)-1-phenyl-lH-pyrazo1-4-yl]ethenyl]phosphonic acid, dimethyl 20 ester A solution of the crude Part A hydroxy phosphonate (7.158 g) in dry benzene (40 ml) was treated with pTs0H*H20 (304 mg, 1.6 mmole) and the mixture refluxed through a Dean Stark trap 25 containing 4A sieves for 2 hours under argon. The Q mixture was cooled, diluted with EtOAc, the organic phase washed with saturated NaHC03 (2X) and brine then dried over anhydrous Na2S04 and evaporated in vacuo to give 6.893 g of a yellow 30 oil. The crude oil was triturated with hexane to give 5.692 g of nearly pure vinyl phosphonate as off-white crystals. One recrystallization from EtOAc-hexane gave in 2 crops 5.655 g (84.2%, total o HXlOb -200- yield from aldehyde) of pure title trans vinyl phosphonate as white needles with m.p. 143-144°C. TLC (1:1) hexane-acetone, "= 0.40 + + Mass. Spec. (M+H = 415 observed). 5 Anal Calcd for C22H2403PN2F: C, 63.76; H, 5.84; N, 6.76; F, 4.58, P, 7.47. Found: C, 63.99; H, 5.95; N, 6.76; F, 4.54; P, 7.31. 1H NMR (CDC13): 10 6 1.42 (6H, d) 3.27 (1H, septet) 3.70 (6H, d, JH_p=11.0 Hz) 5.67 (1H, dd, JgH=18.4 Hz, ^=18.5 Hz) 7.02-7.30 (9H, m) 15 7.34 (1H, dd, JgH=18 Hz, ^=24.3 Hz) ppm. 13C NMR (CDC13): 621.8, 27.1, 52.1 (Jc_p=5.7 Hz), 110.4 (Jc_p=193.1 Hz), 114.7 (Jc_p=24.6 Hz), 115.9, 116.2, 122.2, 124.9, 125.5, 127.3, 128.8, 132.0, 139.2, 140.2 (Jc_p=7.6 Hz), 142.1, 158.0, 20 163.4 (JC_F=249.8 Hz) ppm. C. (E)-[2-[5-(4-Fluorophenyl)-3-(l-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]-25 ethenyl]phosphonic acid, monomethyl ester . A solution of the Part B dimethylphosphonate (2.0 g, 4.83 mmole) in dioxane (15 ml) was treated with l.ON LiOH (7.3 ml) and the mixture refluxed 30 for one hour under argon. The mixture was cooled to room temperature, acidified to pH 1 with l.ON HCl, extracted with EtOAc (2X), the organic phase washed with l.ON HCl and brine then dried over -201- 22 4 7 3 HXlOb anhydrous Na2S04 and evaporated in vacuo to give crude mono acid which slowly crystallized on r-^j standing from hexane. Crystals were collected by filtration and dried in vacuo to give 1.918 (99%) 5 of title mono acid as a white crystalline solid with m.p. 168-170°C. An analytical sample was prepared by recrystallization from EtOAc-hexane. ( l 20 O TLC (8:1:1) CH^Cl2-CH3OH-HOAc, Rf=0.40. Mass Spec (M+H =401+ observed). 10 Anal Calcd for C21H2203N2PF: C, 62.99; H, 5.54; N, 7.00; F, 4.75; P. 7.74 Found: C, 62.95; H, 5.57; N, 6.87; F, 4.58; P, 7.58 2H NMR (CDC13): 6 1.40 (6H, d) 15 3.26 (1H, septet) 3.65 (3H, d, JH_p=11.6 Hz) 5.74 (1H, dd, JH_H=17.9 Hz, JH_p=19.5 Hz) 7.00-7.36 (10H, m) 8.65 (1H, bs) ppm. 13C NMR (CDC13): 6 21.8, 27.0, 51.8 (Jc_p=6.3 Hz), 111.7 (Jc_p=198.7 Hz), 114.6 (Jc_p=24.6 Hz); 115.8, 116.2, 124.9, 125.4, 127.3, 128.7, 131.9, 132.1, 138.8 (Jc_p=7.6 Hz), 139.2, 142.0, 157.9, 25 162.9 (JC_F=249.8 Hz) ppm. ^ D. (E)-4- [ [2-[5-(4-Fluorophenyl.)-3-(l- me thy 1 e thy 1)-1-phenyl - lH-pyr az o 1 - 4-yl ] ethenyl ] methoxyphosphinyl ] -3 - 30 oxobutanoic acid, methyl ester The dianion of methyl acetoacetate was prepared according to the method described in Example 26 using the following quantities: methyl acetoacetate (815 pi, 7.53 9 9 /.3 1 X A Z- T / o T" HXlOb -202- mmole) 60% NaH dispersion in oil (324 mg, 8.11 mmole), 1.6 M N-BuLi in hexanes (4.3 ml, 6.95 mmole), THF (15 ml). A solution of phosphonic monomethyl ester (2.317 g, 5.79 mmole) and trimethylsilyldiethylamine (TMSDEA) (1.45 ml, 11.6 mmole) in CH2C12 (15 ml) was stirred at room temperature for 1 hour. The mixture was evaporated to dryness, chased with benzene (20 ml) and dried in vacuo. The residue was taken up in dry CH2Cl2 (15 ml) treated with (COCl)2 (555 |jl, 6.37 mmole) and DMF (1 drop), and stirred at room temperature for 1 hour. The mixture was evaporated to dryness, chased with benzene (20 ml) and dried in vacuo. A -78°C (C02/acetone) solution of the above phosphonochloridate in dry THF (10 ml) was transferred dropwise via cannula over 20 minutes to a -78°C solution of the methyl acetoacetate dianion in dry THF (15 ml). The brown mixture was stirred for 30 minutes at -78°C then quenched by dropwise addition of saturated NH4C1 (10 ml) and allowed to warm to room temperature. The mixture was partitioned between H20 and EtOAc, the aqueous phase back-extracted with EtOAc, the combined organic phases washed with saturated NaHC03 and brine then dried over anhydrous Na2S04 and evaporated in vacuo- to give 3.080 g of an orange foam. The crude product was purified by flash chromatography on Merck silica gel eluting with (5:3:2) hexane-acetone-toluene. The product fractions were combined and evaporated to give 1.247 g (43.2%) of the desired title 0-ketophosphonate as a pale yellow oil. TLC (4:4:2) acetone-hexane-toluene, R^=0.29. Mass Spec (M+H+=499+ observed). -203- HXlOb XH NMR (CDC13): 6 1.42&1.43 (6H, 2 doublets) 3.24 (2H, m) 3.27 (1H, septet) 3.63 (2H, m) 3.66&3.67 (3H, 2 doublets, JH_p=11.6 Hz) 3.72 (3H, s) 5.72 (1H, dd, Jjjn=18.7 Hz, ^=24.3 Hz) 7.08-7.30 (9H, m) 7.37 (1H, dd, Jgg=18.0 Hz, Jgp-22.7 Hz) ppm. 13C NMR (CDC13): 621.8, 27.1, 46.1 (Jcp=84.1 Hz), 50.0, 51.2 (Jc_p=5.9 Hz), 52.3, 112.6 (Jcp=135.0 Hz), 114.5 (Jcp=23.5 Hz), 116.0, 116.3, 124.9, 125.4, 127.4, 128.8, 132.0, 132.1, 139.1, 141.4 (Jcp=5.9 Hz), 142.5, 158.2, 163.1 (JCF=250.4 Hz), 167.1, 194.9, 195.0 ppm. E. (E)-4-[[2-[5-(4-Fluorophenyl)-3-(1- methylethyl)-l-phenyl-lH-pyrazol-4-yl]-ethenyl]methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester A -15° (salt/ice bath) solution of the Part D ketone (1.304 g, 2.62 mmole) in absolute EtOH (15 ml) was treated with NaBH^ (100 mg, 2.62 mmole) and the mixture stir.red for 15 minutes under argon at -15°C. The reaction was quenched by addition of reagent acetone (0.3 ml) followed by CC-4 silica gel (600 mg), allowed to warm to room temperature, diluted with EtOAc, filtered and evaporated in vacuo to give 1.46 g of a yellow foam. The crude product was purified by flash -204- HXlOb chromatography on Merck silica gel eluting with (85:15) EtOAc-acetone. Product fractions were evaporated to give 388 mg of pure title alcohol as a white foam plus 228 mg of slightly impure product. Total yield was 616 mg (47%). TLC.(7:3) EtOAc-acetone, Rf = 0.31. + + Mass Spec. (M+H =501 observed). NMR (CDC13): 6 1.42 (6H, d) 2.00 (2H, m) 2.60 (2H, d) 3.27 (1H, d) 3.64 (3H, d, ^=11.1 Hz) 3.69 (3H, s) 3.93&4.02 (1H, 2 doublets) 4.42 (1H, 2 broad singlets) 5.72 (1H, dd, Jhh=18.0 Hz, JH_p23.2 Hz) 7.04-7.47 (10H, m) ppm. 13C NMR (CDC13): 6 21.8, 27.1, 35.7 & 36.5 (Jcp=100.3 Hz), 42.0, 42.2, 50.8 (Jcp=5.7 Hz), 51.6, 63.4 (Jcp=20.8 Hz), 114.2 & 114.4 (Jcp=128.7 Hz), 114.6 (Jcp=20.8 HZ), 115.9, 116.3, 124.9, 125.4, 127.3, 128.8, 131.9, 132.1, 139.1, 140.1&140.6 (Jcp=5.7 HZ), 142.1, 158.0, 163.0 (Jcp=251.6 Hz), 171.2, 171.9 ppm. Example 39 (S)-4-[[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1 -phenyl - lH-pyr azo 1 -4-y 1 ] ethenyl ] hydroxyphosphinyl ] 3-hydroxybutanoic acid, dilithium salt A solution of the Example 38 diester (487 mg, 0.973 mmole) in dioxane (10 ml) was treated 1 n i o O ^ - • HXlOb -205- 34 with 1. ON LiOH (3.4 ml, 3.4 mmole) and' the resulting mixture was heated and stirred at 70°C for 30 minutes.' The mixture was cooled, diluted with H20, filtered and evaporated in vacuo- to an 5 off-white solid. The crude product was dissolved in a minimum amount of H20 and chromatographed on HP-20 resin (15 cm bed, 25 mm diameter column) eluting with H20 followed by (1:1) CH30H-H20. Product fractions were evaporated in vacuo, 10 dissolved in 75 ml of H20, filtered and lyophilized to give 429 mg (87.3%) of pure title dilithium salt as a fluffy, white lyophilate. TLC (8:1:1) CH2Cl2-CH30H-H0Ac, Rf=0.14 Anal Calcd for C24H24°5N2PF L^2 + 1,16 moles H20 15 (MW 505.233): C, 57.05; H, 5.25; N, 5.55; F, 3".76; P, 6.13 Found: C, 57.05; N, 5.18; N, 5.75; F, 3.89; P, 6.47 1H NMR (400 MHz, CD3OD): 6 1.39 (6H, doublet) 20 1.71 (2H, m) ; 0 2.35 (2H, m) | 3.36 (1H, septet) 4.24 (1H, m) 6.00 (1H, dd 25 7.07-7.35 (10H, m) 6.00 (1H, dd, Jjjjj-17 .6 Hz, ^=19.4 Hz) Example 40 (E)-4—[[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]methoxyphosphinyl]-3-30 hydroxybutanoic acid, methyl ester -206- HXlOb A. (S)-3-[[(l,1-Dimethylethyl)diphenyl-s ilyl]oxy]-4-[[2-[5-(4-fluorophenyl)- 3-(1-methylethyl)-1-phenyl-lH-pyrazol- 4-yl]ethyl]methoxyphosphinyl]butanoic acid, methyl ester A solution of Example 36 Part H compound (912.0 mg, 1.24 mmole) in dry methanol (50 ml) was treated with 10% Pd/C and hydrogenated at 50 psi on a Parr hydrogenator overnight. The suspension was filtered through Celite and the filtrate was evaporated to dryness and dried in vacuo to give title compound as a homogeneous oil (908.3 mg, 99.1%). TLC: Rf 0.23 (silica gel; Hexane:Acetone-7:3). B. (S)-4-[[2-[5-(4-Fluorophenyl)-3-(l-methylethyl)-l-phenyl-lH-pyrazol-4-yl]-ethyl] methoxyphosphinyl]-3-hydroxy-butanoic acid, methyl ester A solution of Part A compound (908.3 mg, 1.23 mmole) in dry tetrahydrofuran (12 ml) was stirred under argon at room temperature and treated successively with glacial acetic acid (0.29 ml, 4.94 mmoles) and 1.0 M Bu4NF/hexane (3.89 ml, 3.89 mmoles). The reaction mixture was stirred at room temperature for 20 hours, diluted with ice water (25 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated NaHCC>3 (15 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product mixture (1.0 g) was chromatographed on a silica gel column (LPS-1; 1" " 7 ' tf S "^1 i / 3 HXlOb -207- x 9.5"), .eluting the column wtih EtOAc:Hexane mixtures (4:1; 9:1), EtOAc and acetone to give . J title compound as an oil (529.1 mg, 85.6% yield). TLC: Rf 0.17 (silica gel; EtOAc:hexane-4:1). 5 Example 41 (S)-4-[[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt 10 A solution of Example 40 compound (529.0 mg, 1.05 mmoles) in dioxane (12.5 ml) was treated with 1.0 N LiOH (3.7 ml, 3.7 mmoles) and stirred at 55°C (oil bath) under nitrogen for 3.0 hours then at room temperature for 20 hours. The reaction 15 mixture was evaporated to dryness and dried in' vacuo. The crude product was chromatographed on an HP-20 column (1" x 6"), eluting the column with steam-distilled water (750 ml), 10% agueous CHgOH (500 ml), 20% aqueous CH^OH (500 ml) and 50% 20 aqueous CH^OH (500 ml). The desired fractions were 0) combined, evaporated to dryness and dried in vacuo. The solid obtained was dissolved in steam-distilled water (35 ml) and lyophilized to give title compound as a fluffy white solid (510.0 mg, 92.4%). 25 TLC: Rf 0.38 (silica gel; i-Pr0H:NH40H: H20-8:l:l). Q Anal Calcd for C24H26FLi2N205P-2.2 H20 (Eff. Mo. Wt. = 525.899): C, 54.81; H, 5.83; N, 5.33; F, 3.61; P, 5.88 Found: C, 54.81; H, 5.61; N, 5.53; F, 4.06; P, 5.80 30 IR (KBr) (1596 cm"1, C=0 of COO"). -208- HXlOb H^NMR Spectrum (400 MHz, CD3OD): 6 1.36 (d, 6H, 3=1) 1.60-1.72 (m, 4H) 2.32 (m, 2H) 2.74 (m, 2H) 3.21 (septet, 1H, J=7) 4.23 (m, 1H) 7.06-7.32 (m, 9H). Example 42 (S)-4-[[2-[3-(4-Fluorophenyl)-5-(l^methylethyl)-1-phenyl-lH-pyrazol-4-yl]ethynyl]methoxyphosphinyl]-3 hydroxybutanoic acid, methyl ester A. 4-Fluorobenzoic acid, 2-phenylhydrazide A mixture of phenylhydrazine (25 ml, 0.25 mmole) and triethylamine (35 ml, 0.25 mmole) in anhydrous ether (500 ml) was cooled down to -5° to -10°C (ice-salt bath) under nitrogen and treated dropwise, over a 30 minute period, with 4-fluorobenzene carbonyl chloride (30 ml, 0.25 mole). The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then filtered, washing the solids well with ether (200 ml). The solids were dissolved in dichloromethane (600 ml), stripped to near dryness, suspended in hexane (600 ml) and filtered. The'clear filtrate was evaporated to dryness, triturated with tetrahydrofuran (700 ml) and filtered, washing the solids well with tetrahydrofuran (100 ml). The filtrate was evaporated to dryness and dried in vacuo to give a crude product (34.6 g) contaminated with two other components. ' J, * ^ Jl *a'' f * - '"V j HXlOb -209- 3 The crude product was recrystallized from {—\ acetone to give title compound as white crystals (22.36 g, 38.8%), m.p. 182-184°C. The' filtrate and mother liquor were 5 combined, chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the column with EtOAc(1:9) to give an additional 9.78 g of title compound (55.8%). TLC: Rf 0.63 (silica gel: EtOAc:CH2C12-1:4). 10 Anal Calcd for C^H^F^O: c, 67.81; H, 4.82; N, 12.17, F, 8.25. Found: C, 67.86; H, 4.88; N, 12.14; F, 8.10 MS (M+H)+=231. 15 B. 4-Fluoro-N-phenylbenzenecarbohydrazo- noyl chloride A solution of Part A compound (6.16 g, 26.8 mmole) in anhydrous ether (46 ml) was treated with phosphorus pentachloride (6.6 g, 31.7 mmoles) 20 and the reaction mixture was refluxed under 0) nitrogen for 16.0 hours. The reaction mixture was cooled to room temperature, treated with a solution of phenol (11.5 g, 122.2 mmoles) in ether (15 ml), stirred for 5 minutes then treated 25 dropwise with methanol (11.4 ml). The mixture was concentrated at ^75° in a rotary evaporator and the resulting oil cooled at 5°. The solid obtained was triturated with 5% aqueous acetone (20 nil) and filtered, washing the precipitates 30 well with 5% aqueous acetone (30 ml). The precipitates were dried in vacuo to give title compound as a solid (2.2 g), m.p. 118-120°. 4 7 3 HXlOb -210- The clear filtrate was evaporated to (^) dryness and the product mixture chromatographed twice on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the column with CH2C12:Hexane 5 mixtures (1:3; 1:1), to give more title compound (total amount = 5.66 g of 85%). TLC: Rf 0.90 (silica gel; CH2Cl2:Hexane-4:l) . Anal Calcd for C13H10FN2C1: C, 62.78; H, 4.05; N, 11.27; F, 7.64; CI, 14.26 10 Found: C, 62.87; H, 3.97; N, 11.34; F, 7.51; CI, 13.95 MS (M+H)+=249. C. 3-(4-Fluorophenyl)-5-(1-methylethyl)-15 l-phenyl-lH-pyrazole-4-carboxylic acid, ethyl ester A solution of sodium ethoxide (from 0.28 g of 12 mmoles of sodium metal and 40 ml of absolute ethanol) is treated dropwise under nitrogen with 20 ethyl isobutyrylacetate (2.0 ml, 12 mmoles), stirred for 15 minutes at room temperature then treated with Part B compound (3.0 g, 12 mmoles). The mixture was stirred at room temperature for 4.0 hours, quenched with 10% HCl (10 ml), evaporated 25 to dryness and the resulting solid triturated with ether (3 x 100 ml). The combined organic extracts were washed with brine (25 ml), dried (anhydrous MgSC>4), filtered and evaporated to dryness. The crude product (4.3 g) was chromatographed on a 30 silica gel-column, eluting the column with CH2C12:hexane (1:1) to give title compound as a reddish-brown syrup (3.27 g, 77.3%). TLC: Rf 0.42 (silica gel; CH2C12:hexane-4:l). C a x o ■' L L •' •* -> HXlOb -211- D. 3-(4-Fluorophenyl)-5-(1-methylethyl)-l- phenyl-lH-pyrazole-4-methano1 A solution of Part C compound (3.26 g, 9.25 mmoles) in dry ether (22 ml) was added to a cooled 5 (0°, ice-salt bath) suspension of lithium aluminum hydride (0.71 g; 18.7 mmoles) in dry ether (32 ml) and the reaction mixture was stirred at 0° under nitrogen for 3.0 hours. The mixture was quenched at 0° by the dropwise addition of ethyl acetate .10 (5.0 ml), followed by 10% HCl (11 ml), decanted and the residue triturated with ether (2 x 100 ml). The combined organic extracts were washed with brine (20 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness to give title 1.5 compound (2.87 g, 94.4%). 100 mg of title compound was recrystallized from ether to afford an analytical sample (57 mg, m.p. 145-147°). TLC: Rf. 0.17 (silica gel; CI^C^:hexane-4:1; 20 developed 2X). Anal Calcd for CigH19FN20: C, 73.52; H, 6.17; N, 9.03; F, 6.12 Found: C, 73.26; H, 6.11; N, 8.96; F, 6.09 MS (M+H)+=311, 25 O E. 3-(4-Fluorophenyl)-5-(1-methylethyl)-l-phenyl-lH-pyrazole-4-carboxaldehyde A solution of Part D compound (2.59 g, 8.34 mmoles) in dry dichloromethane (22.0 ml) was added 30 rapidly to a stirred suspension of pyridinium chlorochromate (5.41 g, 25.1 mmoles) in dry dichloromethane (32 ml) and stirred at room HXlOb -212- temperature under nitrogen for 4.0 hours. The reaction mixture was diluted with ether (190 ml), stirred for 20 minutes then decanted. The tarry residue was triturated with ether (100 ml) and dichloromethane (30 ml) and the combined organic extracts were filtered through a silica gel pad. The clear filtrate was evaporated to dryness and the crude product chromatographed on a silica gel column (Baker, 60-200 mesh, 300 ml) eluting the column with CH2C12:hexane (4:1) to give title compound (2.40 g, 93.4%) as a solid product. 100 mg of title compound was recrystallized from hexane to give an analytical sample (50 mg, m.p. 103-105°). TLC: Rf 0.67 (silca gel; CH2C12). Anal Calcd for CigH17FN20: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 74.18; H, 5.35; N, 9.11; F, 6.12 MS (M+H)+=309. F. 4-(2,2-Dibromoethenyl)-3-(4-fluoro-phenyl)-5-(1-methylethyl)-1-phenyl-lH-pyrazole A mixture of Part E compound (2.296 g, 7.45 mmoles) and triphenylphosphine (5.86 g, 22.1 mmoles) in dry dichloromethane (35.0 ml) was cooled down to -5° to -10°C (ice-salt bath) under argon, treated dropwise, over a 5 minute period, with a solution of carbon tetrabromide (3.70 g, 11.0 mmoles) in dry dichloromethane (12 ml) and stirred at -10° for 20 minutes. The reaction mixture was warmed up to room temperature, poured into saturated NaHC03 (12 ml) and extracted with r* 22 4 7 3 4 V HXlOb -213- dichloromethane (3 x 60 ml). The combined organic extracts were washed with saturated NaHCC>3 (12 ml), brine (10 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. 5 The crude product (11.0 g, solid) was •chromatographed on a silica gel column, eluting the column with CH2C12:hexane mixtures (1:1, 4:1) to give title compound (2.96 g, 96.0% corrected yield) and unreacted starting material 10 (250.6 mg). 100 mg of title compound was recrystallized from Et20:hexane to give an analytical sample (36.5 mg, m.p. 93.5°). TLC: Rf 0.57 (silica gel; CH2Cl2:hexane-4:l). 15 Anal Calcd for C20H17Br2FN2: C, 51.75; H,. 3.69; N, 6.04; Br, 34.43; F, 4.09 Found: C, 51.78; H, 3.54; N, 6.07; Br, 34.40; F, 3.92 MS (M+H)+=465 20 q>.. G. 4-Ethynyl-3-(4-fluorophenyl)-5-(l- methylethyl)-1-phenyl-lH-pyrazole A solution of Part F compound (2.87 g, 6.18 mmoles) in dry tetrahydrofuran (11.44 ml) was 25 cooled down to -78° (dry ice-acetone), treated dropwise with 1.6 M n-BuLi/hexane (11.7 ml, 18.6 mmoles) under argon then stirred at -78° for 2. hours and 20 minutes. The reaction mixture was quenched at -78° with 25% NH4C1 (16.5 ml), wanned 30 up to room temperature and extracted with ether (3 x 60 ml). The combined organic extracts were washed with brine (22 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The rs j —3 £. L H 7 t~\ m.p. 117-118°). r\ SD HXlOb -214- crude product (1.9 g) was chromatographed on a silica gel column, eluting the column with EtgO:hexane (5:95). The desired fractions were combined and evaporated to dryness to give title compound (1.88 g, 100% yield) as a solid product. 100 mg of title compound was recrystallized from hexane to give an analytical sample (63.5 mg, TLC: Rf 0.37 (silica gel; Et20:hexane-1:9). 10 Anal Calcd for C20H17FN2: C, 78.92; H, 5.63; F, 6.24; N, 9.21 Found: C, 79.12; H, 5.60; F, 6.02; N, 9.12 MS (M+H)+=305. 15 H. (S)-3-[[(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-[[[3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-lH-pyrazo1-4-yl]ethynyl]methoxyphosphinyl]butanoic acid, methyl ester 20 A solution of (S)-3-[[(1,1-dimethylethyl)- diphenylsilyl]oxy]-4-(hydroxymethoxyphosphinyl)- ij "■PK butanoic acid, methyl ester (prepared in Example 1 Part F) (2.77 g, 5.55 mmoles) in dry dichloromethane (10 ml) was treated with 25 trimethylsilyldiethylamine (2.1 ml) and stirred at room temperature for 1.0 hour under argon. The reaction mixture was evaporated to dryness, azeotroped with dry benzene (20 ml) and dried in vacuo. The syrup was re-dissolved in dry 30 dichloromethane (10 ml), cooled down to -10° (ice-salt bath), treated with 1 drop of DMF followed by the dropwise addition of oxalyl chloride (530 pi), stirred at -10° for 15 minutes a O' o 22 4 7 3 HXlOb -215- then at room temperature for 1.0 hours. The mixture was evaporated to dryness, azeotroped with benzene (20 ml) and dried in vacuo. Part G compound (1.12 g, 3.67 mmoles), was 5 dissolved in dry tetrahydrofuran (9.0 ml), cooled down to -78° (dry ice-acetone bath), treated with 1.6 M n-BuLi/hexane (2.3 ml, 3.68 mmoles) under argon and stirred at -78° for 45 minutes. The above phosphonochloridate was dissolved in dry 10 tetrahydrofuran (6.5 ml), cooled to -78° and treated dropwise, by cannula, with the solution of the acetylene anion both solutions being kept at -78° throughout the addition. The reaction mixture was stirred at -78° for 30 minutes then 15 quenched by the dropwise addition of 25% NH4C1 (6.0 ml) and allowed to warm up to room temperature. The mixture was extracted with ether (3 x 100 ml) and the combined organic extracts were washed with 25% NH4C1 (10 ml), brine (25 ml), 20 dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product mixture (4.0 g) was chromatographed on a silica gel column, eluting the column with acetone:hexane mixtures (1:9; 3:7) 25 to give title compound (1.76 g, 65.2%) as an oil. TLC: Rf 0.40 (silica gel; hexane:acetone-7:3). I. (S)-4-[[2-[3-(4-Fluorophenyl)-5-(1- methylethyl)-l-phenyl-lH-pyrazol-4-yl]-30 ethynyl]methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester - ^ is "**? °T A a z i: ^ y 3 4 HXlOb tv -216- A solution of Part H compound (700 mg, 0.95 mmoles) in dry tetrahydrofuran (9 ml) was treated successively with glacial HOAc (224 pi, 3.82 mmoles) and 1.0 M (C4Hg)4NF (3.0 ml, 3.0 5 mmoles) and stirred overnight at room temperature under argon. The solution was cooled down to 0° (ice-salt bath), treated dropwise with 5% KHS04 (10 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extracts were washed 10 with 5% KHS04 (10 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product (890 mg) was dissolved in a mixture of ether (16 ml) and tetrahydrofuran 15 (12 ml), cooled down to 0° (ice-salt bath) and treated with excess diazomethane in ether. The reaction mixture was stirred at 0° for ^3 hours, quenched by the dropwise addition of glacial acetic acid and evaporated to dryness. The crude 20 product mixture (764 mg) was chromatographed on a silica gel column, eluting the column with EtOAc:hexane mixtures (1:1; 4:1; 9:1) to give title compound as a semi-solid (347 mg/ 73.2%). TLC: Rf 0.28 (silica gel; EtOAc:hexane-4:1). o 25 Example 43 (S)-4-[[2-[3-(4-Fluorophenyl)-5-(1-methylethyl)-1-phenyl-lH-pyrazol-4-yl] ethynyl] hydroxyphosphinyl ] -3- hydroxybutanoic acid, dilithium salt 30 A solution of Example 42 compound (347 mg, 0.7 mmoles) in dioxane (8.3 ml) was treated with 1.0 N LiOH (2.4 ml, 2.4 mmoles) and stirred at 55°C (oil bath) under nitrogen for 45 minutes. 3\ / •' •' / V t i? J i If O' 7 3 HXlOb -217- The reaction mixture was evaporated to dryness and dried in vacuo. The resulting semi-solid was chromatographed on an HP-20 column (1" x 3"), eluting the column with steam-distilled water (350 5 ml), 50% aqueous methanol (250 ml). The desired fractions were combined, evaporated to dryness and dried in vacuo. The product was dissolved in steam-distilled water and lyophilized to give title compound as a white solid lyophilate (338 10 mg, 97.5%). TLC: Rf 0.50 (silica gel; i-Pr0H:NH40H:H20-7:2:l). Anal Calcd for C24H22FLi2N205P-1.95 H20: C, 55.71; H, 5.04; N, 5.42; F, 3.67; P, 5.99 Found: C, 55.90; H, 5.46; N, 5.30; F, 3.95; P, 5.96, 15 H^-NMR Spectrum (400 MHz, CD3OD): 6 1.45 (d, 6H, J=7) 1.89-2.05 (m, 2H) 2.38 (dd, 1H, J=9, 15) 2.52 (dd, 1H, J=4, 15) 20 3.06 (septet, 1H, J=7) 4.48 (m, 1H) 7.16-8.11 (ra, 9H) Example 44 25 (S)-4-[[2-[3-(4-Fluorophenyl)-5-(1-methylethyl)- l-phenyl-lH-pyrazol-4-yl ] ethyl ] methoxyphosphinyl ] - 3-hydroxybutanoic acid, methyl ester A. (S)-3-[[(l,l-Dimethylethyl)diphenyl-silyl]oxy]-4-[[2-[3-(4-fluorophenyl)~ 30 5-(1-methylethyl)-1-phenyl-lH-pyrazole- 4-yl ] ethyl ] methoxyphosphinyl ] butanoic acid, methyl ester a 5 O" 10 15 20 25 ^ £ "7 t; C L 4 / 0 HXlOb -218- A solution of Example 42 Part I compound (1.0 gm, 1.36 mmole) in dry methanol (72 ml) was treated with 10% Pd/C (250 mg) and hydrogenated in a Parr hydrogenator overnight at *>-40 psi. The reaction mixture was filtered through Celite and the clear filtrate was evaporated to dryness to give title compound as a homogeneous oil (1.0 gm, 100% crude yield). TLC: Rf 0.27 (silica gel; hexane:acetone - 7:3). B. (S)-4-[[2-[3-(4-Fluorophenyl)-5-(1- methylethyl)-l-phenyl-lH-pyrazol-4-yl] ■ ethyl]methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester A solution of Part A compound (1.05 g, 1.41 mmoles) in dry tetrahydrofuran (14.0 ml) was treated successively with glacial acetic acid (334 Ml, 5.83 mmoles) and 1.0 M (C4Hg)4NF/THF (4.46 ml, 4.46 mmoles) and stirred at room temperature under argon for *^19 hours. The reaction mixture was diluted with ice-water (28 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated NaHC03 (15 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product mixture (1.14 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 150 ml), eluting the column with EtOAc:hexane mixtures (2:1; 4:1, 9:1), ethyl acetate and acetone to give title compound as a semi-solid (623.5 mg, 88.0%). TLC: Rf 0.18 (silica gel; EtOAc:hexane -4:1). » -219- 22 47 34 HXlOb 6' © Example 45 (S)-4-[[2—[3—(4-Fluorophenyl)-5-(1-methylethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt 5 A solution of Example 44 compound (623.5 mg, 1.24 mmoles) in dioxane (14.7 ml) was treated with 1.0 N LiOH (4.28 ml, 4.27 mmoles) under nitrogen, heated at 55°C (oil bath) for 2 hours then stirred at room temperature for ~20 hours. 10 The reaction mixture was evaporated to dryness, dried in vacuo and chromatographed on an HP-20 column (1" x 6"), eluting the column with steam-distilled water (750 ml), 10% aqueous CH3OH, 20% aqueous CHgOH (500 ml) and 50% aqueous CH3OH 15 (500 ml). The desired fractions were combined and evaporated to dryness to give the desired product (560 mg, 92.8%). TLC: Rf 0.42 (silica gel; i-PrOH:NH40H:H20 - 8:1:1). Anal Calcd for C24H26FLi2N205P-l ..16 H20: (Eff. 20 M.W*. = 507.197): C, 56.83; H, 5.62; N, 5.52; F, 3.74; P, 6.11 Found: C, 56.83; H, 5.80; N, 5.76; F, 3.46; P, 6.19 H^-NMR Spectrum (400 MHz, CD30D): 6 1.30 (d, 6H, 25 1 00 9 I—1 1 o KD (d, 4H) 2.36 (m, 2H) 2 .96-2.99 (m, 2H) 3.14 (m, 1H) 4.26 (m, 1H) 30 7 .14-7.68 (m, 9H) 22 4 7 * -f HXlOb -220- o= w Example 46 (S) -4-[[[4-(4-Fluorophenyl)-l-(1-methylethyl)-3-phenyl-lH-pyrazol-5-yl]ethynyl]methoxyphosphinyl]- 3-hydroxybutanoic acid, methyl ester 5 A. 2-(4-Fluorophenyl)-1-phenylethanone A suspension of magnesium turnings (928 mg, 38 mmoles) in dry ether (38 ml) under argon was treated dropwise with 4-fluorobenzylbromide (5.3 ml, 42 mmoles) over a period of 45 minutes at a 10 rate maintaining gentle reflux. When addition was completed, the mixture was refluxed for another 30 minutes, cooled down to room temperature and treated with a solution of benzonitrile (2.96 ml, 29 mmoles) in dry ether (5 ml). The mixture was 15 stirred at room temperature for 4.5 hours, poured slowly into cold 10% HCl (40 ml) and the resulting suspension was extracted with ether (5 x 50 ml) and ethyl acetate (2 x 100 ml). The combined organic extracts were washed with saturated NaHC03 20 (50 ml), brine (50 ml), dried (anhydrous MgS04), Q\ filtered and evaporated to dryness. The crude product (9.8 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the column with 25 C^C^:hexane mixtures (1:4, 1:2). The desired fractions were combined and evaporated to dryness to give title compound as a white solid (3.29 g, m.p. 106-8°). (An additional 2.60 g was obtained from other fractions containing a trace of 30 starting material to give a total yield of 94.8%.) TLC: Rf 0.60 (silica gel; CH2C12:hexane - 1:1). ^ o /, 7 L I H ' HXltfb -221- Anal Calcd for C^H^FO: C, 78.49; H, 5.18; F, 8.87 Found: C, 78.22; H, 5.22; F, 9.21 MS (M+H)+=215 B. 2-(4-Fluorophenyl)-1-phenylethanone, (1-methylethyl)hydrazone A solution of Part A compound (4.45 g, 21 mmoles) in a mixture of 95% ethanol (34 ml) and glacial acetic acid (0.74 ml) was treated with isopropylhydrazine (3.63 ml, ~42 mmoles) and heated at 80°(oil bath) under N2 for 1.4 hours. Thin layer chromatography indicated that some starting material was still present so the reaction mixture was treated with additional isopropylhydrazine (2.0 ml, ~23 mmoles) and heated at 80° (oil bath) for another hour. The reaction mixture vjas cooled down to room temperature, evaporated in a rotary evaporator to remove most of the solvent then diluted with dichloromethane (200 ml). The organic solution was washed with brine (25 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness. The yellow oil obtained was evaporated once from toluene (150 ml) to give title compound as a crude product (5.63 g) contaminated with some starting material and traces of two other components. TLC: Rf 0.28 (silica gel; CI^C^:hexane-l: 1). Isopropylhydrazine was prepared as follows: Iodopropane (10.3 ml, 0.10 mole) was added over a period of 2.0 hours to hydrazine hydrate (48.4 ml, 1.0 mole) under N2. The mixture was then stirred at 60° (oil bath) under N2 for 3 hours, cooled and extracted with ether (250 ml) 22 4 7 HXlOb -222- for 20 hours (liquid-liquid extractor). The ethereal extract was evaporated to give isopropylhydrazine (5.63 ml or 5.3 g). C. Acetic acid, 2-[2-(4-fluorophenyl)-l-phenylethylidene]-1-(1-methylethyl)- hydrazide A mixture of crude Part B compound (5.63 g, =21 mmoles) and triethylamine (5.85 ml, 42 mmoles) in dry toluene (210 ml) was cooled down to 0° (ice-salt bath) under N2 and treated with acetyl chloride (1.86 ml, 26.3 mmoles). The reaction mixture was stirred with gradual warming to room temperature for 1.5 hours, diluted with ether (700 ml) and filtered. The clear filtrate was dried (anhydrous Na2S04), filtered, evaporated to dryness and evaporated once from toluene (300 ml). The semi-solid obtained (7.1 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the column with CH2C12:hexane mixtures (1:1, 2:1), CH2C12 and CH2C12:CH30H (9:1) to give title compound as a crude product (4.11 g). The crude product was rechromatographed on another silica gel column, eluting the column with EtOAc:hexane (4:1). The desired fractions were combined and evaporated to dryness to give title compound as a thick yellow oil (3.89 g). TLC:Rf 0.47 (silica gel:EtOAc:hexane-l:1). 22 4 7 HXlOb -223- % D. 4-(4-Fluorophenyl)-5-methyl-l-(1-methyl-ethyl)-3-phenyl-lH-pyrazole A solution of Part C compound (1.50 g, 4.80 mmoles) in bis (2-methoxyethyl)ether (48 ml) was treated with solid potassium hydroxide (615 mg, 10.96 mmoles) and heated at 80° (oil bath) under N2 for 2.0 hours. The reaction mixture was treated with a second batch of potassium hydroxide (700 mg, 12.5 mmoles), heated at 80° for 2 hours and then stirred at room temperature for 16 hours. The mixture was poured into water (300 ml) and extracted successively with ether (3 x 150 ml) and ethyl acetate (200 ml). The organic solutions were combined, washed with cold 3% HCl (500 ml), brine (2 x 100 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product (3.5 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 500 ml), eluting the column with EtOAc:hexane (1:4) to give title compound as a cream-colored solid (1.33 g, 94.3%), m.p. 135-7°. TLC: Rf 0.63 (silica gel; EtOAc:hexane - 1:4). E. 4-(4-Fluorophenyl)-1-(1-methylethyl)-3-phenyl-lH-pyrazole-5-carboxaldehyde A mixture of CuS04*5H20 (2.21 g, 8.85 mmoles) and potassium persulfate (9.53 g, 35.3 mmoles) in acetonitrile (65 ml) and water (39 ml) was heated to 65° (oil bath) under N2 and treated with Part D compound (2.6 g, 8.83 mmoles). The bath temperature was slowly raised to 75°, kept at 75° for 40 minutes then cooled to room temperature, using a water bath. The reaction mixture was n 47 HXlOb -224- C) o diluted with dichloromethane (45 ml), stirred for 10 minutes and decanted, extracting the aqueous suspension with more dichloromethane (3 x 45 ml). The combined organic extracts were washed with 5 brine (2 x 30 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness. The crude product (2.75 g) was chromatographed on a silica gel column (LPS-1), eluting the column with EtOAc:hexane (1:9) to give title compound as a 10 solid (1.57 g, 57.7%). TLC: Rf 0.72 (silica gel; EtOAc;hexane - 1:4). F. 5-(2,2-Dibromoethenyl)-4-(4-fluoro-phenyl)-1-(1-methylethyl)-3-phenyl- 15 IH-pyrazole A mixture of Part E compound (1.75 g, 5.68 mmoles) and triphenylphosphine "(4.6 g, 16.8 mmoles) in dry dichloromethane (27.0 ml) was cooled down to -5° to -10° (ice-salt bath) under 20 argon, treated dropwise, over a 5 minute period • with a solution of carbon tetrabromide (2.82 g, 8.42 mmoles) in dry dichloromethane (9 ml) and stirred at -10° for 20 minutes. The reaction mixture was warmed up to room temperature, poured 25 onto saturated NaHCOg (9.0 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic extracts were washed with saturated NaHCO^ (10 ml), brine (10 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. 30 The crude product was chromatographed on silica gel eluting with CH2C12:hexane "mixtures O 20 22 4 7 3 4 HXlOb -225- (1:0, 1:4). The desired fractions were combined to give, title compound (2.35 g, 91.4%) as an oil. TLC:Rf 0.32 (silica gel:CH2C12:hexane - 1:1). 5 G. 5-Ethynyl-4-(4-fluorophenyl)-l-(l- methy1ethyl)-3-phenyl-lH-pyrazole A solution of Part F compound (1.89 g, 4.08 mmoles) in dry tetrahydrofuran (7.6 ml) was cooled down to -78° (dry ice-acetone), treated dropwise 10 with 1.6 M BuLi/hexane (5.2 ml, 8.18 mmoles, 2 eg.) under argon and stirred at -78° for 1 hour and 20 minutes. The reaction mixture was quenched at -78° with 25% NH^Cl (11.0 ml), warmed up to room temperature and extracted with dichloromethane (3 15 x 50 ml). The combined organic extracts were washed with brine (15 ml), dried (anhydrous MgSC>4), filtered and evaporated to dryness. The crude product (1.77 g) was chromatographed on a * silica gel column, eluting the column with CH2C12:hexane mixtures (1:4; 1:1) to give title compound (648 mg) along with mixed fractions containing title compound and Part F compound. The mixed fractions were combined with the product from another run (490 mg from 1.1 mmoles of Part F 25 compound) and chromatographed on a second column, eluting the column with CH2C12:hexane (1:9). The desired fractions were combined and evaporated to dryness to give title compound as an oil (1.02 g, 71.5% corrected for recovered 30 starting material). r ^ 22 4 7 HXlOb -226- H. (S)-3-[[(l,l-Dimethylethyl)diphenyl-silyl]oxy]-4-[[[4-(4-fluorophenyl)-l-(1-methylethyl)-3-phenyl-lH-pyrazol-5-yl ] ethynyl ] methoxyphosphinyl ] butanoic 5 acid, methyl ester A solution of the Example 1 Part F phosphonic monomethyl ester (2.341 g, 5.01 mmoles) and trimethylsilylethylamine (1.90 ml, 10 mmoles) in dry dichloromethane (9.5 ml) was stirred at 10 room temperature under argon for 1 hour. The mixture was evaporated to dryness, azeotroped with dry benzene (15 ml) and dried in vacuo. The viscous oil was re-dissolved in dry dichloromethane (9.5 ml), treated with one drop of 15 DMF, cooled down to -10 to 0° (ice-salt bath) and treated dropwise with oxalyl chloride (480 |jl, 5.47 mmoles). Vigorous gas evolution was observed and the dark yellow solution was stirred at -10° to 0° for 15 minutes then at room temperature for 20 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with benzene (18 ml) and dried in vacuo. A solution of Part G compound (1.016 g, 3.34 mmoles) in dry tetrahydrofuran (8 ml) was 25 cooled down to -78° (dry ice-acetone) under argon (0 and treated with 1.6 M n-BuLi/hexane (2.1 ml, 3.36 mmoles) and stirred at -78° for 1.0 hour. The above phosphonochloridate was dissolved in dry tetrahydrofuran (8 ml), cooled down to -78° (dry 30 ice-acetone) under argon and treated dropwise by cannula with the solution of the acetylene anion both solutions being kept at -78° throughout the addition. The reaction mixture was stirred at 2 2 4 7 n HXlOb -227- -78° for 1.0 hour, quenched by the dropwise addition of 25% NH4C1 (9 ml) then warmed up to room temperature. The mixture was extracted with ether (3 x 100 ml) and the combined organic 5 extracts were washed with 25% NH^Cl (10 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product was chromatographed on a silica gel column, eluting the column with 10 acetone:hexane mixtures (1:9, 1:4) to give title compound as an oil (1.595 g, 64.8%). TLC: Rf 0.43 (silica gel; acetone:hexane - 3:7). I. . (S)-4-[[[4-(4-Fluorophenyl)-l-(l-15 methylethyl)-3-phenyl-lH-pyrazol-5-yl ]- ethynyl ] methoxyphosphinyl ] -3-hydroxy- butanoic acid, methyl ester A solution of Part H compound (1.0 g, 1.36 mmoles) in dry tetrahydrofuran (13 ml) was 20 treated successively with glacial acetic acid (320 \il, 5.46 mmoles) and 1 M (C4Hg)4NF (4.26 ml, 4.26 mmoles) and stirred overnight at room temperature under argon. The reaction mixture was cooled down to 0° (ice-salt bath), treated with 5% KHS04 (15 25 ml) and extracted with ethyl acetate (3 x 125 ml). The combined organic extracts were washed with 5% KHS04 (2 x 25 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. 30 The crude product (1.06 g) was dissolved in a mixture of ether (23 ml) and tetrahydrofuran (18 ml), cooled down to 0° (ice-salt bath), treated with excess diazomethane in ether and c v L 1 C & / HXlOb -228- j stirred at 0° for 4 hours. The reaction mixture was1 quenched by the dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed 5 on a silica gel column, eluting the column with acetone:hexane (1:2). The desired fractions were combined and evaporated to dryness to give title compound as an oil (330 mg, 48.7%). TLC: Rf 0.23 (silica gel; EtOAc:hexane - 4:1). 10 Example 47 (S)—4—[[[4-(4-Fluorophenyl)-l-(1-methylethyl)-3-phenyl-lH-pyrazol-5-yl]ethynyl]hydroxyphosphinyl)- 3-hydroxybutanoic acid, dilithium salt 15 A solution of Example 46 compound (330 mg, 0.66 mmole) in dioxane (7.8 ml) was treated with IN LiOH (2.29 ml, 2.29 mmole) stirred at 55° (oil bath) under argon for 1.5 hours then at room temperature for 16 hours. The reaction mixture was 20 evaporated to dryness and dried in vacuo. The crude product was chromatographed on' an HP-20 column (1" x 10"), eluting the column with steam-distilled water (750 ml), 10% aqueous CH^OH (500 ml), 20% aqueous CH^OH (500 ml) and 50% aqueous 25 CHgOH (500 ml). The desired fractions were combined, evaporated to dryness and dried in vacuo. The solid product was dissolved in steam-distilled water and lyophilized to give title compound as a fluffy solid lyophilate (275 mg, 30 99.5%). TLC: Rf 0.57 (silica gel; i-PrOH;NH4OH:H20 -8:1:1) . vj 22 4 7 34' HXlOb -229- Anal Calcd for C24H22FLi2N205P«2.28 (Eff. mol. wt = 523.310): C, 55.08; H, 5.11; N, 5.35; F, 3.63; P, 5.92 Found: C, 55.08; H, 4.98; N, 5.47; F, 3.66; P, 5.99 IR (KBr): 2172 cm"1 (C=C) H^-NMR spectrum (400 MHz, CD^OD): 6 1.57 (d, 6H, J=7 Hz) 1.86-2.01 (m, 2H) 2.37 (dd, 1H, J=8) 2.50 (dd, 1H, J=4) 4.40 (m, 1H) 5.01 (septet, 1H, J=7) 7.04-7.39 (m, 9H) Example 48 (S) -4-[[2-[4-(4-Fluorophenyl)-1-(1-methylethyl)-3-phenyl-lH-pyrazol-5-yl]ethyl]methoxyphosphinyl)-3- hydroxybutanoic acid, methyl ester A. (S)-3-[[(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-[[2-[4-(4-fluorophenyl)-l-(1-methylethyl)-3-phenyl-lH-pyrazol-5-yl]ethyl]methoxyphosphinyl]butanoic acid, methyl ester A solution of Example 46, Part H compound (608 mg, 0.85 mmole) in dry methanol (63 ml) was treated with 10% Pd/C (155 mg) and hydrogenated at room temperature on a Parr hydrogenator at ~40 psi overnight. The suspension was diluted with methanol (50 ml) and filtered through a celite pad in a millipore unit, washing the pad well with methanol. The clear filtrate was evaporated to dryness and dried in vacuo to give title compound © 22 4 7 3 4" HXlOb -230- © •'snr?x as a homogeneous oil (559 mg, 90.9%) with 1 13 consistent H -NMR and C -NMR spectral data. RC: Rf 0.20 (silica gel:acetone: hexane 3:7; UV). 5 B. (S)-4-[[2-[4-(4-Fluorophenyl)-l-(1- methylethyl)-3-phenyl-lH-pyrazol~5-yl]-jc-n ethyl ] methoxyphosphinyl ] -3-hydroxy- butanoic acid,methyl ester A solution of Part A compound (559 mg, 0.75 10 mmole) in dry tetrahydrofuran (7.5 ml) was treated successively with glacial acetic acid (176 nl, 3.0 mmoles, 4 eq) and 1.0 M (C4Hg)4 NF/hexane (2.34 ml, 2.34 mmoles, 3.1 eq) under nitrogen and stirred at room temperature for ~20 hours. The reaction 15 mixture was diluted with ice-water (20 ml), . extracted with ethyl acetate (3 x 70 ml), and the combined organic extracts were washed with saturated NaHCO^ (10 ml), brine (20 ml), dried (•anhydrous MgSO^), filtered and evaporated to 20 dryness. The crude product (580 mg) was 0 . chromatographed on a silica gel column, eluting the column with EtOAc:hexane (1:4), EtOAc and acetone:hexane (4:1). The desired fractions were combined, evaporated to dryness and dried in vacuo 25 to give title compound as a homogeneous oil (337 Q mg, 89.4%). TLC: Rf 0.18 (silica gel; acetone-.hexane - lil; UV). -231- HXlOb Example 49 (S)-4-[[2-[4-(4-Fluorophenyl)-1-(1-methylethyl)-3-phenyl-lH-pyrazol-5-yl]ethyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt A solution of Example 48 compound (337.0 mg, 0.67 mmole) in dioxane (8.0 ml) was treated with 1.0 N LiOH (2.32 ml, 3.5 eq) under argon, stirred at 55° (oil bath) for 3.0 hours then at room temperature for 20 hours. The reaction mixture was evapprated to dryness and dried in vacuo (pump) for 1.0 hour. The crude product was chromatographed on an HP-20 column (l"x8"), eluting the column With steam-distilled water (500 ml), 10% aqueous CH3OH (500 ml), 20% aqueous CH3OH (500 ml) and 50% aqueous CH3OH. The desired fractions were combined, evaporated to dryness and dried in vacuo. The resulting solid was dissolved in steam-distilled water, frozen and lyophilized overnight to give title compound as a fluffy white lyophilate (280.4 mg, 82.4%) with consistent analytical, mass spectrum, IR and H^-NMR spectral data. TLC: Rf 0,45 (silica gel; i-PrOH: NH^OH: H20 -8:1:1; UV). An additional 24 mg of slightly impure product was obtained from other fractions. Anal Calcd for C24H26FLi2N205P*1.19 H20 (Effective mol weight) = 507.733: C, 56.77; H, 5.63; N, 5.51; F, 3.74; P, 6.10 Found: C, 52.77; H, 5.69; N, 5.49; F, 3.91; P, 6.50 IR (KBr) #69377 (1589 CM-1, C=0 of COO") 4 7 34' -232- H1-NMR Spectrum (400 MHz, CD30D): ^ 6 1.55 (d, 6H, J=7, Hj) 1.64-1.84 (m, 4H, Hc + Hd) 2.34 (m, 2H, -, H ) a 5 2.91 (pseudo quartet, 2H, He) 4.25 (m, 1H, -, Hg) 4.77 (septet, 1H, partially buried under HOD signal, -, H^) 7.05-7.32 (m, 9H, aromatic protons) 10 . Example 50 (S)-4-[[[1-(4-Fluorophenyl)-4-(1-methylethyl)-2-phenyl-lH-imidazol-5-yl]ethynyl]methoxyphosphinyl]- 3-hydroxybutanoic acid, methyl ester 15 A. N-Benz oylvaline A solution of valine (20 g, 0.17 mole) in tetrahydrofuran (20 ml) and 2 N NaOH (111 ml) was cooled down to 10° (ice-water bath) under nitrogen and treated dropwise with benzoyl chloride (23.8 20 ml, 0.21 mole). The reaction mixture was warmed up (~j to room temperature, stirred for 3.0 hours then cooled back down to 0° (ice-salt bath) and treated with concentrated sulfuric acid (8.0 ml). The mixture was extracted with ethyl acetate (3 x 200 25 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness to give title compound as a solid (41.97 g, 100% crude yield). 30 A small amount (260 mg) of the product was recrystallized from ethyl acetate and petroleum ether to give title compound as an analytical sample (205 mg, m.p. 132-3°). i i L^J c 22 4 7 3 f HXlOb -233- TLC: Rf 0.10 (silica gel; acetone:hexane - 1:1) Anal Calcd: C, 65.14; N, 6.83; N, 6.33 Found: C, 64.81; N, 6.79; N, 6.29 MS (M+H)+=222 B. N- (l-Acetyl-2-methylpropyl )benzamide A mixture of Part A compound (41.7 g, =0.17 mole) and triethylamine (47.3 ml, 0.34 mole) in acetic anhydride (48 ml) was treated with two 10 portions of 4-dimethylaminopyridine (2.07 g, 0.017 mole) and stirred at ropm temperature for 16 hours under nitrogen. The reaction mixture was cooled down to 0° (ice-salt bath), quenched with methanol and stirred for 30 minutes. The light brown 15 precipitates that formed were filtered off, washed well with water (1.1 1.) and re-dissolved in dichloromethane (750 ml). The solution obtained was dried (anhydrous MgS04), filtered and evaporated to dryness to give a crude product 20 (35.9 g). The crude product was dissolved in ether (1.3 1.), filtered to remove the insoluble solids and the clear filtrate was concentrated down to a volume of ^300 ml and cooled in an ice-bath. 25 Title compound in the form of a cream colored 0 precipitate (21.35 g, m.p. 88-90°) was filtered off. Purification of the solid obtained by evaporation of the filtrate on a silica gel column (Baker, 600-200 mesh, 600 ml), eluting the column 30 with EtOAc:hexane mixtures (1:7, 1:4) gave an additional 4.77 g of title compound. A small amount of title compound was recrystallized from ether, m.p. 88-89°C. 22 A 7 3 4 HXlOb -234- TLC: Rf 0.75 (silica gel; acetone:hexane - 1:1). Anal Calcd: C, 70.20; H, 7.81; N, 6.39 Found: C, 70.79; H, 7.68; N, 6.31 MS (M+H)+=220. C. N-[1-[1-[(4-Fluorophenyl)imino]ethyl]-2-methylpropyl1benz amide A solution of Part B compound (25.0 g, 0.114 mole) in dry toluene (250 ml) was treated with 4-fluoroaniline (12 ml, 0.127 mole, 1.11 eq.) and p-toluenesulfonic acid hydrate (.125 mg) and the reaction mixture was refluxed under N2 with a Dean-Starke distilling receiver for 20 hours. The reddish-brown solution was cooled down to -10°C (ice-salt bath) and used as is"for the next step in the sequence. D. 1-(4-Fluorophenyl)-5-methyl-4-(1-methylethyl)-2-phenyl-1H-imidazole The cooled solution of Part C compound (=0.114 mole) was diluted at -10° (ice-salt bath) with dry dichloromethane (200 ml) and treated portionwise with phosphorus pentachloride (47.5 g, 0.228 mole). The cream-colored slurry was warmed up, refluxed for 2.5 hours under N2, cooled down to room temperature and poured slowly into a mixture of ice (400 g) and 50% NaOH (105 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 200-ml). The combined organic extracts were washed with brine (2 x 100 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness. D G r ~, n /, "7 L L 1 ' HXlOb -235- The crude product mixture (35.0 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 600 ml), eluting with EtOAcihexane mixtures (1:9, 1:4) to give title compound as 5 white needles (29.24 g, m.p. 146-8°, 87%). TLC: Rf 0.40 (silica gel; EtOAc:hexane - 1:4) Anal Calcd: C, 77.52; H, 6.51; N, 9.52; F, 6.45 Found: C, 77.48; H, 6.69; N, 9.40, F, 6.45 MS (M+H)+ = 295 10 E. 1-(4-Fluorophenyl)-4-(1-methylethyl)- 2-phenyl-lH-imidazole-5-carboxaldehvde A mixture of cupric sulfate hydrate (8.50 g, 34.0 mmoles) and potassium persulfate (36.8 g, 15 0.136 mole) in a solvent mixture of acetonitrile (250 ml) and water (150 ml) was heated to 65° (oil bath) under N2 and treated with Part D compouund (10 g, 34.0 mmoles). The reaction mixture was slowly heated up to 75°, kept there for 40 minutes 20 then cooled to room temperature. The solution was decanted from the solids, extracting both aqueous phase and solid with dichloromethane (3 x 200 ml). The combined organic extracts were washed with brine (2 x 100 ml), dried (anhydrous MgSO^), 25 filtered and evaporated to dryness. The crude product (17.0 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 600 ml) eluting the column with EtOAc:hexane mixtures (5:95, 1:7) to give title compound as a solid (6.27 g, 59.8%). 30 200 mg of title compound was recrystallized from Et20:hexane to give an analytical sample (76 mg, m.p. 160-1°). rh »"L / "7 J / l\ / Ft S af HXlOb -236- TLC: Rf 0.34 (silica gel; EtOAc:hexane -1:4). Anal Calcd: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 73.98; H, 5.68; N, 9.04; F, 6.09 MS (M+N+)=309 F. 5-(2,2-Dibromoethenyl)-l-(4-fluoro-phenyl) -4- (1-methylethyl) -2-phenyl- C j w 1H-imidazole A solution of Part E compound (1.75 g, 5.68 10 mmoles) and triphenylphosphine (4.46 g, 16.8 mmoles) in dry dichloromethane (27.0 ml) was cooled down to -5° to -10° (ice-salt bath) under argon and treated dropwise over a period of 5 minutes with a solution of carbon tetrabromide 15 (2.82 g, 8.42 mmoles) in dry dichloromethane (9 ml). The mixture was stirred at -10° for 20 minutes then poured onto saturated sodium bicarbonate (9.0 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic 20 extracts were washed with saturated NaHC03 (10 0 ml), brine (10 ml), dried (anhydrous MgSO^), filtered and evaporated to dryness. The crude product (8.07 g) was chromatographed on a silica gel column, eluting the column with C^C^:hexane 25 mixtures (1:7; 1:4) to give title compound as a 0 solid (2.35 g, 91.4%). 100 mg of Part F compound was recrystallized from Et20:hexane to give an analytical sample (49 mg, m.p. 164-5°). 30 TLC: Rf0.32 (silica gel; CH2C12:hexane - 1:1). Anal Calcd: C, 51.75; H, 3.69: N, 6.04; F, 4.09; Br, 34.43 Found: C, 51.80; H, 3.71; N, 6.02; F, 4.08; r> 2 2 4 7 HXlOb -237- Br, 34.25 MS (M+H)+ = 465. G. 5-Ethynyl-l- (4-fluorophenyl)-4-(1-5 methylethyl)-2-phenyl-lH-imidazole A solution of Part F compound (3.065 g, ^ 6.60 mmoles) in dry tetrahydrofuran (12.5 ml) was cooled down to -78° (dry ice-acetone) and treated with 1.6 M n-BuLi/hexane (8.4 ml, 13.4 mmoles) 10 under argon. The reaction mixture was stirred at -78° for 1 hour and 20 minutes, quenched by the dropwise addition of 25% NH4C1 (18 ml), warmed up to room temperature and extracted with ether (3 x 100 ml). The combined organic extracts were washed 15 with brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product (2.08 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the column with EtOAc:hexane mixtures (1:9,. 1:4). 20 The desired fractions were combined and evaporated to dryness to give title compound as a solid (1.97 g, 97.8%). 92 mg of Part G compound was recrystallized. from hexane to give an analytical sample (59 mg, 25 m.p. 148-150°). ^ TLC: Rf 0.60 (silica gel; EtOAc:hexane - 1:4). Anal Calcd: C, 78.92; H, 5.63; N, 9.21; F, 6.24 Found: C, 78.95; H, 5.83; N, 9.07; F, 6.63 MS (M-H)~ =303. 30 G 22 4 7 o HXlOb -238- H. (S)-3-[ [ (1, l-Dimethylethyl^iphenyl-silylJoxy]^-[ [ [1-(4-fluorophenyl)- 4-(1-methylethyl)-2-phenyl-lH-imidazol- 5-yl ] ethynyl ] raethoxyphosphinylbutanoic 5 acid, methyl ester A mixture of the Example 1 Part F crude phosphonic monomethyl ester (3.54 g, 7.86 mmoles) and trimethylsilyldiethylamine (2.70 ml, 14.21 mmoles) in dry dichloromethane was stirred at room 10 temperature under argon for 1.0 hour. The mixture was, evaporated to dryness, azeotroped with dry benzene (26 ml) and dried in vacuo. The viscous oil was re-dissolved in dry dichloromethane (14 ml), treated with 2 drops of DMF, cooled down to 15 -10° (ice-salt bath) and treated dropwise with oxalyl chloride (0.68 ml, 7.79 mmoles). Vigorous gas evolution was observed and the yellowish brown solution was stirred at -10° for 15 minutes then at room temperature for 1.0 hours. The reaction 20 mixture was evaporated to dryness, azeotroped with dry benzene (26 ml) and dried in vacuo. A solution of Part G compound (1.43 g, 4.7 mmoles) in dry tetrahydrofuran (11.5 ml) was cooled down to -78° (dry ice-acetone) under argon 25 and treated with 1.6 M n-BuLi/hexane (2.94 ml, 4.7 mmoles) and stirred at -78° for 30 minutes. The above.phosphonochloridate was dissolved in dry tetrahydrofuran (11.5 ml), cooled down to -78° (dry ice-acetone) under argon and treated dropwise 30 by cannula with a solution of the acetylenic anion, both solutions being kept at -78° throughout the addition. The reaction mixture was stirred at -78° for 30 minutes, quenched by the o ° 22 4 7 HXlOb -239- y \ dropwise addition of.25% NH4C1 (13 ml), allowed to ^ warm up to room temperature then extracted with ^ ether (3 x 130 ml). The combined organic extracts were washed with 25% NH4C1 (15 ml), brine (30 ml), 5 dried (anhydrous MgSO^), filtered and evaporated to dryness. The crude product mixture (4.3 g) was w chromatographed on a silica gel column, eluting the column with acetone:hexane mixtures 10 (5:95; 1:4). The desired fractions were combined and evaporated to dryness to give title compound as a light brown, syrup (2.18 g, 62.9%) TLC: Rf 0.13 (silica gel; hexane:acetone - 7:3). 15 I. (S)-4-[[[1-(4-Fluorophenyl)-4-(1- methylethyl)-2-phenyl-lH-imidazol-5-yl] ethynyl]methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester A solution of Part H compound (974 mg, 1.32 20 mmoles) in dry tetrahydrofuran (13.0 ml) was treated successively with glacial acetic acid (310 pi, 5.29 mmoles) and 1 M (C4Hg)4NF (4.14 ml, 4.14 mmoles) and stirred overnight at room temperature under argon. The reaction mixture was cooled down 25 to 0° (ice-water bath), treated with 5% KHS04 (14 ml) and extracted with ethyl acetate (3 x 125 ml). The combined organic extracts were washed with 5% KHS04 (16 ml), brine (35 ml), dried (anhydrous MgS04), filtered and evaporated to 30 dryness. The crude product (1.48 g) was dissolved in a mixture of ether (22 ml) and dry tetrahydrofuran (17 ml), cooled down to 0° (ice-water bath)-, 12 k HXlOb -240- treated with excess diazomethane in ether arid stirred at 0° for 4.0 hours. The reaction mixture was quenched by the. dropwise addition of glacial acetic acid, evaporated to dryness and dried In vacuo. The crude product was chromatographed on a silica gel column, eluting the column with EtOAc:hexane mixtures (1:1; 4:1). The desired fractions were combined to give title compound as a solid (304 mg, 46.2%). TLC: Rf 0.33 (silica gel; EtOAc:hexane - 4:1) Example 51 (S)-4-[[[1-(4-Fluorophenyl)-4-(1-methylethyl)-2-phenyl-lH-imidazol-5-yl]ethynyl]hydroxyphosphinyl] 3-hydroxybutanoic acid, dilithium salt A solution of Example 50 compound (304 mg, 0.6 mmole) in dioxane (7.1 ml) was treated with 1 N LiOH (2.03 ml, 2.08 mmoles), stirred at 55° (oil bath) under argon for 1.5 hours then at room temperature for 24 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on an HP-20 column (1" x 7"), eluting the column'with steam-distilled water (750 ml), 10% aqueous CHjOH (500 ml), 20% aqueous CH30H (500 ml) and 50% aqueous CH^OH (500 ml). The desired fractions were combined, evaporated to dryness and dried in vacuo. The solid product was dissolved in steam-distilled water and lyophilized to give title comopund as a fluffy solid lyophilate (257 mg, 84.1 %). Other fractions: TLC: Rf 0.38 (silica gel; i-Pr0H:NH40H:H20 - 8:1:1). -241- 22 4 7 3 ? HXlOb Anal Calcd for C24H22FLi2N205P-1.52 H20: C, 56.56; H, 4.95; N, 5.49; F, 3.73; P, 6.08 Found: C, 56.56; H, 4.94; N, 5.32; F, 3.89; P, 5.99. H^-NMR spectrum (400 MH2, CDgOD): 6 1.37 (d, 6H, J=7 Hz) 1.79 (m, 2H) 2.31 (dd, 1H, J=9.15 Hz) 2.43 (dd, 1H, J=4.15 Hz) 3.24 (septet, 1H, J=7 Hz) 4.26 (m, 1H) 7.17-7.35 (m, 9H). . IR(KBr) 2163 (ChC), 1590 (C=0) cm-1. Example 52 (S)-4-[[2-[l-(4-Fluorophenyl)-4-(1-methylethyl)-2-phenyl-lH-imidazol-5-yl]ethyl ] methoxyphosphinyl]-3- hydroxybutanoic acid, methyl ester A. (S)-3-[[(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-[[2-[l-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazol-5-yl]ethyl]methoxyphosphin-ylbutanoic acid, methyl ester A solution of Example 50 Part H compound (839 mg, 1.14 mmoles) in dry methanol (86 ml) was treated with 10% Pd/C (213 mg) and hydrogenated at room temperature on a Parr hydrogenator overnight at ^40 psi. The suspension was filtered through celite, the clear filtrate was evaporated to dryness and dried in vacuo to give title compound as a thick syrup (853 mg, 100% yield). TLC: Rf 0.17 (silica gel; hexane:acetone - 7:3). HXlOb -242- 22 4 7 3* B. (S)-4-[[2-[l-(4-Fluorophenyl)-4-(1- methylethyl)-2-phenyl-lH-imidazol-5-yl]-ethyl]methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester A solution of Part A compound (853 mg, ~1.14 mmoles) in dry tetrahydrofuran (11.0 ml) was treated successively with glacial acetic acid (270 Ml, 4.60 mmoles) and 1.0 M (C4Hg)4NF/hexane (3.62 ml, 3.62 mmoles) and stirred overnight at room temperature under argon. The reaction mixture was diluted with ice-water (25 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated NaHCC>3 (15 ml), brine (25 ml), dried (anhydrous MgS04), filtered and evaporated to dryness. The crude product (958 mg) was chromatographed on a silica gel column, eluting the column with acetone:hexane mixtures (1:1, 4:1). The desired fractions were combined, eyaporated to dryness and dried in vacuo to give title compound as a solid (443 mg, 77.0%). TLC: Rf 0.13 (silica gel; acetone:hexane - 1:1). Example 53 (S)—4—[[2-[l-(4-Fluorophenyl)-4-(1-methylethyl)-2-phenyl - 1H- imidazol- 5 -yl ] ethyl ] hydroxyphosphinyl ] - 3 - hydroxybutanoic acid, dilithium salt A solution of Example 52 compound (443 mg, 0.88 mmole) in dioxane (10.5 ml) was treated with 1.0 N LiOH ('3.05 ml, 3.09 mmoles) and stirred at 55° (oil bath) under argon for 3.0 hours then at room temperature for ^20 hours. The reaction mixture was evaporated to dryness and dried o C 2,2 4 7 HXlOb -243- in vacuo. The crude product was chromatographed on an HP-20 column (1" x 8"), eluting the column with steam-distilled water (750 ml), 10% aqueous CH30H (500 ml), 20% aqueous CH3OH (500 ml) and 50% 5 aqueous CH30H. The desired fractions were combined and evaporated to dryness. The resulting £) solid was dissolved in steam-distilled water (30 ml) and lyophilized to give title compound as a fluffy white solid (376.4 mg, 83.9%). 10 TLC: Rf 0.40 (silica gel; i-Pr0H:NH40H:H20 - 8:1:1) Anal Calcd for C24H26FLiH2N205P-0.84 H20 (Eff. mol. wt.=501.46): C, 57.43; H, 5.76; N, 5.69; F, 3.99; P, 6.08 Found: C, 57.48; N, 5.56; N, 5.59; F, 3.79; P, 6.18 15 IR(KBr) (1587 cm"1, C=0 COO") HX-NMR spectrum (400 MHz, CD3OD): 6 1.33 (d, 6H, J=7 Hz) 1.46-1.61 (m, 4H) 2.30 (m, 2H) 20 2.76 (m, 2H) 3.13 (septet, 1H, J7 Hz) 4.14 (m, 1H) 7.17-7.30 (m, 9H). 25 Example 54 (S)-4-[[[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]-ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A. N-(2,4-Dimethylbenzylidene)benzeneamine 30 Ref. Merck U. S. Patent No. 4,375,475, pg. 39. The title compound was prepared as described in Example 1 Part A. 22 4 7 3 4 -244- B. Ref. Merck U.S. Patent No. 4,375,475, pg. 39, The title Pd-complex was prepared as described in Example 1 Part B. C. 2-[(Cyclohexylmethyl)-4,6-dimethylbenz- aldehyde Magnesium turnings (1.44 g, 59.45 mmol) under argon atmosphere were covered with 15 ml of dry Et20 and sonicated for 5 minutes. Cyclohexylmethylbromide (1.5. ml) was added to the Mg°-turnings and sonication was continued (refluxing began within minutes). Simultaneously via addition funnel 60 ml of dry Et20 and a 5 ml Et20 solution of the remainder of the cyclohexylmethylbromide was added with continued sonication (a total of 9.12 ml, 65.3 mmole of cyclohexylmethylbromide was added). After addition was complete, sonication was continued for 15 minutes and then the reaction was refluxed for 40 minutes. This Grignard reagent was cooled to room temperature and then added via cannula to a solution of the Part B Pd-complex (5.55 g, 7.43 mmol) and triphenylphosphine (15.59 g, 59.45 mmol) which had been stirring for 30 minutes under argon atmosphere and at room o ZZ <\ I 3 4 HXlOb -245- temperature. Upon the addition of the Grignard f"*) reagent the reaction became green and a precipitate formed. This reaction solution was stirred at room temperature for 2 hours followed by the addition of 5 37 ml of 6N HCl. This mixture was stirred for 1 hour and then filtered through a celite pad in a sintered glass funnel in order to remove solids. f - o The solid was washed with Et20 and the filtrate was rotavapped to remove volatiles. The resulting 10 residue was stirred in Et20 and filtered as above. The filtrate was washed once with saturated NaCl solution, and the organic layer was dried over MgSO^; 14.5 g of a brown oil was obtained. Purification by flash chromatography, eluting with 15 4% Et20/hexane gave 1.70 g of a clear oil, 99% yield. TLC: Rf=0.30 (5% Et20/hexane, silica gel). IR (CHC1-) 3030, 3008, 2926, 2853, 1679, 1606, -1 20 G 25 30 1448, 1147 cm H NMR (270 MHz "cdclg) 10.51 (s , 1) 6.90 (s, 1) 6.85 (s, 1) 2.80 (d, 2, J = 2.55 (s, 3) 2.30 (s, 3) 1 o 00 rH ■1.55 (m, 5) 1.55- ■1.30 (m, 1) 1.30- ■0.80 (m,. 5) Mass Spec (CI) m/e 231 (M+H)+ 22 4 7 3 n HXlOb -246- D. l-(Cyclohexylmethyl)-2-(2,2-dibromo- ethenyl) -3,5-dimethylbenzene ■ Part C aldehyde (1.68 g, 7.30 mmol) in 65 ml of dry CH2C12 under argon atmosphere was cooled to 0°C. To this solution was added triphenylphosphine (6.13 g, 23.4 mmol) and the solution was At d) stirred until all of the solid was dissolved. 0°C, CBr4 (3.63 g, 11.0 mmol) was added as a 20 ml CH2C12 solution. The reaction solution became 10 orange. The reaction was stirred at 0°C for 1.5 hours, then quenched with saturated NaHC03 solution and stirred vigorously. The aqueous layer was removed and extracted 2 times with CH2C12. The organic solutions were combined, washed once with 15 saturated NaHCO^ solution, and dried over MgSO^. Filtration and solvent removal gave 9.6 g of a brown solid. Purification by flash chromatography eluting with 100% hexane gave 2.52 g, 90% yield, of a clear oil. 20 TLC 0.62 (5% Et20/hexane, silica gel) PMA. IR (CHC13) 2925, 2852, 1608, 1472, 869 cm"1 1HNMR (270 MHz, CDC13) 6 7.39 (s, 1) 6.87 (s, 1) 25 6.80 (s, 1) Q) 2.37 (d, 2, J=6.3 Hz) 2.27 (s 3) 2.24 (s, 3) 1.70 (m, 5) 30 1.45 (m, 1) 1.38-1.10 (m, 3) 0.90 (m, 2) 22a&7 5 -247- Mass. Spec. (CI) m/e 387 (M+H) + E. l-(Cyclohexylmethyl)-2-ethynyl-3,5- dimethylbenzene The Part D vinyl dibromide (2.51 g, 6.5 mmol) under argon atmosphere was stirred with THF (30 ml) and cooled to -78°C. To the dibromide solution at -78°C was added n-butyllithium (5.20 ml of 2.5 M solution in Hexane) over 3 minutes. The resulting pink reaction mixture was stirred at -78°C. After 1..5 hours at -78°C, the reaction was quenched with saturated aqueous NH^Cl solution and then warmed to room temperature. The aqueous layer was removed and extracted twice with Et20 and once with hexane. All of the organic layers were combined and dried over MgS04 to give 1.65 g of a brown oil after filtration and solvent removal. Purification by flash chromatography eluting with hexane gave 1.39 g, 95% yield, of title acetylene. TLC 0.50 (5% toluene/hexane, silica gel), PMA. IR (CHC13) 3305, 3007, 2924, 2852, 2096, 1607, 1470, 1448 cm"1. XH NMR (270 MHz, CDC13) 6 6.86 (s, 1) 6.79 (s, 1) 3.39 (s, 1) 2.63 (d, 2, J=6.9 Hz) 2.63 (m, 6) 1.20 (m, 3) 1.00 (m, 2) Mass Spec (CI) m/e 227 (M+H)+- 22 4 7 3 4" HXlOb -248- F. (S)-4-[[[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]ethynyl]raethoxyphos-phinyl]-3-[[(1,1-dimethylethyl)diphenyl-sily1]oxy1butanoic acid, methyl ester Part E acetylene (1.36 g, 6.0 mmol) in 30 ml of dry THF under argon atomosphere was cooled to -78°C. To this solution was added n-BuLi (2.4 ml, of 2.5 M solution in hexane); the reaction solution became a burgundy color, stirred for 1 hour at -78°C. Example 1 Part F phosphonochloridate (4.68 g, 9.6 mmol) was stirred with 30 ml of dry THF and cooled to -78°C. The acetylenic anion was then cannulated into the phosphonochloridate solution over 15 minutes. After the transfer was complete, the reaction was stirred at -78°C for 1 hour, then quenched with saturated aqueous NH4C1 and wanned to room temperature. The THF was removed from the reaction mixture, and the resulting material was dissolved with Et20 and ^O. The aqueous layer was extracted 3 times with Et20. All the Et20 extracts were combined and washed once with saturated NaHCOg solution and once with brine, then dried over MgS04- Filtration and solvent removal gave an orange oil which was purified by flash chromatography eluting with 3.5:5.5:1/-EtOAc:Hexane:toluene. The title acetylenic phosphinate (2.80 g, 70% yield) was obtained as a clear oil. TLC Rf=0.37 (5:1:4/Hexane:toluene:EtOAc, silica gel) PMA. n 22 4 7 3 4" HXlOb -249- U O 10 15 20 IR (CHC13) 3025, 3001, 2929, 2856, 2164, 1736( 1607, 1240, 1112, 1039, 823 cm 1H NMR (270 MHz , CDC13) 5 7.66 (m, 4) 7.30 (m, 6), 6.87 (s, 1), 6.81 (s, 1) 4.66 (m, 1) 3.70&3.66 (d1 5, 3, J—14.3 Hz) 3.56 (s, 3) 2.95 (m, 1) 2;69 (m, 1) 2.50 (m, 3) 2.32 (m, 2) 2.30 (s, 3) 2.27 (s, 3) 1.60 (m, 6) 1.03 (m, 3) 1.02 (s, 9) 0.95 (m, 2) Mass Spec (CI) m/e 659 (M+H) G. (S)-4-[[[2-(Cyclohexylmethyl)-4,6-dime thy lphenyl ] ethynyl ] me thoxyphos -25 phinyl]-3-hydroxybutanoic acid, methyl ester The Part F acetyleneic phosphinate (0.633 g, 0.96 mmol) was stirred under argon atmosphere at room .temperature with 14.0 ml of dry THF. 30 Glacial acetic acid (0.22 ml, 3.84 mmol) was added to the phosphinate solution followed by the dropwise addition over 5 minutes of n-Bu^NF (2.62 ml of 1.1 M THF solution). After stirring for 19 c U 47 34 HXlOb -250- hour s at room temperature, the reaction was O quenched with ice water, and the aqueous layer was extracted 3 times with EtOAc. The combined organic solutions were washed 2 times with 5 saturated aqueous NaHC03 solution and once with saturated NaCl solution. The organic layer was 's 1 dried over Na2S0^ and filtered to give a yellow gum (0.658 g) after solvent removal. Purification by flash chromatography eluting with EtOAc 10 provided the title alcohol (0.23 g, 65%) as a clear oil. TLC Rf=0.51 (6:4 Acetone/hexane, silica gel) PMA IR (CHC13) 3450 (br), 3005, 2926, 2852, 2164, 1733, 1607, 1448, 1439, 1039 cm-1. 15 XH NMR (270 MHz, CDC13) 6 6.89 (s, 1) 6.82 (s, 1) 4.63 (m, 1) 3.88&3.87 (2d's, 3, J=12 Hz) 20 3.69 (s, 3) O 2.70 (s, 2) 2.62 (d, 2, J=6.3 Hz) 2.43 (s, 3) 2.32 (s, 3) 25 2.27 (m, 2) O . 1.65 (m, 6) 1.19 (m, 3) 1.00 (m, 2) Mass Spec (CI) m/e 421 (M+H)+ 30 C 22 4 7 3 4" n y.. j HXlOb -251- H. (S)-4-[[[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]ethynyl]hydroxyphos-phinyl]-3-hydroxybutanoic acid, dilithium salt 5 The Part G diester (0.212 g, 0.51 mmol) was stirred in dioxane (7 ml) and 1.5 ml of IN LiOH (1.5 mmol) was added at room temperature. The reaction was warmed to 55°C and after 20 minutes the resulting orecipitate was solubilized by adding 5 10 ml of dioxane and 4 ml of H20. After 2 hours 30 minutes at 55°C, the reaction was cooled to room temperature, the solvent was removed under reduced pressure, and the resulting white solid was placed under vacuum for 15 minutes. The product was 15 purified on a 3.0 x 19 cm column of HP-20 resin eluting first with 100 ml of H20 followed by 1:1 Me0H/H20. Lyophilization of product gave 0.145 g (71%) of a white lyophilate Rf = 0.39 (7:2:1 nPrOH/NH^H/HjO, silica gel) PMA. 20 IR (KBr) 3700-3100 (br), 2922, 2850, 2167, 1590, © 1447, 1179, 1076 cm"1. H NMR (400 MHz , D20) 5 6.99 (s, 1) 6 .94 (s, 1), 25 4.53 (m, 1), 2 .64 (m, 1), 6.22 (d, 2, J=6.2 Hz) 2 .39 (s, 3) 2.37 (m, .1) 30 2.26 (s, 3) 22 4 7 3 4 HXlOb -252- 2.02 (m, 2) 1.60 (m, 6) 1.14 (m, 3) 1.00 (m, 2) Spec (FAB) m/e )9 (M+H)+, 397 (M-2 Li + H)+ Anal Calcd for C2iH27°5P L^2*1,72 H20: C' 57,96; H, 7.05; P, 7.12 Found: C, 57.96; H, 7.18; P, 6.96 Example 55 4-[[2-[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]-ethenyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A. (E)-[2-[2-(Cyclohexylmethyl)-4,6-dimethy lphenyl ] ethenyl ] phosphonic acid, dimethyl ester Dimethylmethylphosphonate (1.64 g, 13.2 mmol) in dry THF (20 ml) under argon atmosphere was cooled to -78°C. To this solution at -78°C was added n-butyl lithium (5.0 ml, 2.5 M solution in hexane, 12.4 mmol) over 5 minutes. After the addition was complete, the milky white reaction mixture was stirred for 1 hour. To the anion solution at -78°C, a 10 ml THF solution of the Example 54 Part A aldehyde (1.9 g, 8.26 mmol) was added via addition funnel over 10 minutes. After-stirring for 35 minutes at -78°C, the reaction was quenched with saturated aqueous NH4C1 (8 ml) and then allowed to warm to room temperature. The organic layer was removed and the aqueous layer was extracted 3 times with EtOAc. The organics were combined and washed once with brine and dried 22 4 7 HXlOb -253- over Na2S04. Filtration and solvent removal gave 3.25 g of a yellow oil. The above yellow oil (3.25 g) was dissolved in dry toluene and refluxed through a soxhlet extractor containing 4A molecular sieves. p-Toluenesulfonic acid-^O (0.080 g, 0.42 mmol) was added at time 0, 3.5 and 18 hours. After 22 hours at reflux, the reaction was cooled to room temperature, and the toluene was removed in vacuo. The resulting yellow residue, in EtOAc was washed twice with saturated NaHC03 solution, dried over Na2S04 and filtered to give a yellow oil (A) after solvent removal. The aqueous solution was acidified with concentrated HCl, extracted 3 times with EtOAc, dried over MgS04, filtered and solvent removed to give 0.535 g of a yellow oil. This yellow oil was then refluxed in 6.0 ml of HC(OCH)3 for 24 hours followed by removal of excess HC(OCH3)3 under vacuum. This material was combined with yellow, oil (A) and purified by flash chromatography eluting with 80% EtOAc/hexane. The title vinyl phosphonate (2.07 g, 73%) was obtained as a white solid. TLC Rf=0.45 (1:1 Acetone/hexane, silica gel) PMA. IR(KBr) 2921, 2851, 1623, 1447, 1243, 1186, 1060, 1027 cm"1. XH NMR (270 MHz, CDC13) 6 7.65 (dd, 1, J=23.6 Hz, 18.1 Hz) 6.88 (s, 1) 6.82 (s, 1) 5.80 (dd, 1, J=21.0 Hz, 18.1 Hz) 3.79 (d, 6, J=ll.5 Hz) © 22 4 7 HXlOb -254- 2.49 (d, 2, J=7.2 Hz) O 2.29 (s, 3) 2.28 (s, 3) 1.65 (m, 5) 5 1.45 (m, 1) 1.25-0.80 (m, 5) Mass Spec (CI) m/e 337 (M+H) + B. (E)-[2-[2-(Cyclohexylmethyl)-4,6-10 dimethylphenyl]ethenyl]phosphonic acid, methyl ester " Part A vinyl phosphonate (2.07 g, 6.16 mmol) was stirred with 14 ml of dioxane at room temperature. To this solution was added 1.0 N 15 LiOH (9.24 ml, 9.24 mmol), and this mixture was warmed to 75°C. After 3.5 hours at 75°C, the reaction was cooled to room temperature, and the dioxane was removed in vacuo. The resulting residue was stirred with H20 and acidified to pH^2 20 with IN HCl. The aqueous solution was extracted 3 0 times with EtOAc, dried over Na2S04, filtered and solvent removed to give 1.95 g of off-white solid. TLC Rf = 0.58 (8:l:l/CH2Cl2:CH3OH:AcOH, silica gel), PMA. 25 XH NMR (270 MHz, CDC13) 0 5 12.11 (s,l) 7.61 (dd, 1, J=24.17 Hz, 17.58 Hz) 6.87 (s, 1) 6.81 (s, 1) 30 5.88 (dd, 1, J=21.43 Hz, 17.58 Hz) 3.78 (d, 3, J=ll.54 Hz) 2.47 (d, 2, J=6.6 Hz) 2.29 (s, 3) -255- 22 4 7 3? HXlOb 2 .28 (s, 3) 1 .65 (m, 5) 1 .45 (m, 1) 1 .15 (m, 3) 0 .95 (m, 2) C. (E)-4-[[2—[2 — (Cyc1ohexylmethy1)-4,6-dimethylphenyl]ethenyl]methoxyphos-phinyl]-3-oxobutanoic acid, methyl ester . The Part B monomethyl phosphonate (1.95 g, 6.06 mmol) in 50 ml of dry CH2C12 was stirred at room temperature under argon atmosphere with (C2H5)2NSi(CH3)3 (1.76 g, 12.1 mmol) for 1 hour 25 minutes. The CH2C12 wa£ removed in vacuo, and the resulting yellow oil was azeotroped once with benzene and placed under high vacuum for 20 minutes. This oil was then dissolved in dry CH2C12 (50ml) under argon atmosphere and cooled to 0°c. Two drops of dry DMF were, added followed by slow dropwise addition of oxalylchloride (0.92 g, 7.27 mmol):gas evolution was observed. The reaction was stirred for 15 minutes at 0°C then warmed to room temperature and stirred for 1 hour. The CH2C12 was removed in vacuo from the reaction mixture, and the resulting orange oil was azeotroped twice with dry benzene and pumped under high vacuum for 1 hour thus giving the phosphonochloridate. The dianion of methylacetoacetate was prepared as follows. Pentane washed NaH (0.25 g oil dispersion, 8.7 mmol) in dry THF (10 ml) under argon atmosphere was cooled to 0°C. Methyl o 11 hi^ ®*" &>«»■ ». j n 'V HXlOb -256- acetoacetate (0.92 g, 7.9 mmol) was added to the NaH suspension as a 10 ml THF solution and stirred for 20 minutes, and then n-butyllithium (2.90 ml, 2.5 M in hexane, 7.3 mmol) was added 5 followed by stirring for 45 minutes. The dianion solution was cooled to -78°C and a 10 ml THF solution of the above prepared phosphonochloridate was cooled to -78°C and added to the dianion solution over 15 minutes. After stirring at -78°C 10 for 30 minutes, the reaction was quenched with saturated aqueous NH4C1 solution and warmed to room temperature. The THF was removed from the reaction mixture, and the resulting orange oil was taken up in 1:1 EtOAc/T^O. The aqueous layer was 15 extracted 3 times with EtOAc. The combined EtOAc extracts were combined and washed 2 times with saturated NaHCO^ solution and once with saturated NaCl solution, then dried over Na2S04. Purification of the crude product (2.75 g) by 20 flash chromatography eluting with EtOAc gave the d) title keto ester (0.97 g, 42%) as a yellow oil. TLC Rf = 0.24 (EtOAc, silica gel) PMA. 1H NMR (270 MHz, CDCl3) 6 7.71 (dd, 1, J=22.52 Hz, 18.13 Hz) 25 6.89 (s, 1) O 6-83 (s, 1) 5.89 (dd, 1, J=26.37 Hz, 17.58 Hz) 3.79 (s, 2) 3.73 (s(br), 6) 30 3.36 (dd, 2, J=18.68 Hz, 5.5 Hz) 2.50 (m, 2) 2.30 (s, 3) 2.29 (s, 3) 22 4 7 3 4" HXlOb -257- 1.70 (m, 5) 1.45 (m, 1) 1.10-0.80 (m, 5) D. 4-[[2-[2-(Cyclohexylmethyl)-4,6- dimethylphenyl ]"ethenyl ] methoxyphosphinyl]-3-hydr oxybutanoic acid, methyl ester The Part C 0-keto phosphonate (0.97 g, 2.31 mmol) was stirred in THF (10 ml) under argon atmosphere and cooled to 0°C. Solid NaBH^ (0.087 g, 2.31 mmol) was added to the THF solution followed by the dropwise addition of 2 ml of CHgOH; gas evolution resulted. After stirring for 50 minutes at 0°C,.the reaction was quenched with 2 ml of acetone followed by the addition of CC-4 silica gel. The reaction was warmed to room temperature and filtered through sintered glass. The solvent was removed from the filtrate to give a yellow oil which was purified by flash chromatography eluting with EtOAc. The title alcohol was obtained as a clear oil (0.65 g, 66%). TLC Rf = 0.29 (50% Acetone/hexane, silica gel), PMA. M.P. 80-83°C. IR (KBr) 3282 (br), 2923, 2918, 2848, 1743, 1614, 1450, 1442, 1080, 1045 cm"1. XH NMR (270 MHZ, CDC13) ■6 7.68 (m, 1) 6.88 (s, 1) 6.82 (s, 1) 5.89 (m, 1) A 7 HXlOb -258- 4.50 (m, 1) 4.00 (m, 1) 3.77&3.74 (2 d's, 3, J=11.0 Hz) 3.69&3.68 (2 s's, 3) 2.65 (d, 2, J=6.0 Hz) 2.50 (m, 2) 2.30 (S(br),3) 2.28 (s, 3) 2.15 (m, 2) 1.68 (m, 5) 1.45 (m, 1) 1.30 to 0.80 (m, 5) Mass Spec (CI) m/e 423 (M+H)+ E. 4-[[2-[2-(Cyclohexylmethyl)-4,6- dimethylphenyl]ethenyl]hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt Part D diester (0.565 g, 1.33 mmol) was stirred with 14 ml of dioxane until all of the solid went into solution. 1.0 N LiOH (4.0 ml) was added and the solution warmed to 55°C.- After 30 minutes, the reaction became turbid. After 2 hours at 55°C, the reaction was cooled to room temperature, and the solvent was removed on the rotavap to give a white solid. The crude product was purified on a 3.0 x 15 cm column of HP-20 resin eluting first with 100 ml of H20 followed by 75% MeOH/HjO. Lyophilization of product fractions gave title compound in the form of a white lyophilate (0.524 g, 98%). 22 4 7 3 4 HXlOb -259- TLC Rf = 0.41 (7:2:1 nPr0H/NH40H/H20, silica gel) PMA. IR (KBr) 3700-3100 (br), 2921, 2851, 1591, 1446, • 1222, 1195, 1161, 1051 cm"1. 5 1H NMR (400 MHz, D20) 6 7.25 (dd, 1, J=18.68 Hz) 6.98 (s, 1) 6.94 (s, 1) 6.00 (dd, 1, J=17.95 Hz) 10 4.33 (m, 1) 2.53 (dd, 1, J=15.0 Hz, 4.4 Hz) 2.49 (d, 2, J=7.0 Hz) 2.36 (dd, 1, J=15.0 Hz, 8.43 Hz) 2.27 (s, 3) 15 2.25 (s, 3) 1.89 (dd, 2, J=14.3 Hz, 6.6 Hz) 1.60 (m, 5) 1.45 (m, 1) 1.13 (m, 3) 20 0.95 (m, 2) Mass Spec. (FAB) m/e 407 (M+H)+, 347 (M+-2 Li+ + 2H) Anal Calcd for C21H2g05PLi2*0.38 H20: C, 61.03; H, 7.45; P, 7.49 Found: C, 61.03; H, 7.63; P, 7.66 25 Example 56 (S)-4-[[2-[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]-ethyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt 30 A. 4-[[[2-(Cyclohexylmethyl)-4,6-dimethyl- phenyl]ethyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-butanoic acid, methyl ester I," t ,/ HXlOb -260- O ! o j . 10 15 20 25 30 Argon was bubbled through a 45 ml methanol solution of Example 54 Part F acetylenic phosphinate (1.33 g, 2.02 mmol) for 10 minutes. To this methanol solution in a Parr bottle was added 10% Pd/C (0.34 g). Hydrogenation on a Parr apparatus at 40 psi for 20 hours gave 1.39 g of an oil after filtration through a celite pad in a sintered glass funnel. Purification by flash chromatography eluting with 1:1 EtOAc/hexane gave the title phosphinate (1.25 g, 94%) as a clear oil TLC Rf = 0.21 (5/4/1 Hexane/EtOAc/toluene, silica gel) PMA. IR (CHC1«) 3600-3200 (br), 3003, 2925, 2853, 1731, -1 1448, 1440, 1247, 1233 , 1179, 1044 "hi NMR (270 MHz, CDC13 ) 6 6.83 (s, 1) 6.78 (s, 1) 4.50 (m, 1) 3.80&3.77 (2 d's , 3, J=6 .3 Hz) 3.72&3.71 (2 s 1 s , 3) 3.38 (m, 1) 2.87 (m, 1) 2.60 (m, 2) 2.45 (d, 2, J=6 .9 Hz) 2. 29&2.28 (2 s 1 s , 3) 2.25 (s, 3) 2.00 (m, 4) 1.70 (m, 6) 1.45 (m, 1) 1.30-0.90 (m, 6) Mass Spec (EI) m/e 424 (M) rf r 3 HXlOb -261- B. (S)-4-[[2-[2-(Cyclohexylmethyl)-4,6-O dimethylphenyl ] ethyl ] methoxyphosphinyl ] 3-hydroxybutanoic acid, methyl ester A solution of the Part A silyl ether (1.2 5 g, 1.8 mmol) in THF (20 ml) was stirred under argon atmosphere at room temperature. To this f") solution was added sequentially 0.41 ml of glacial acetic acid and n-Bu^NF (5.0 ml of a 1.1 M THF soluiton, 5.44 mmol) which was added dropwise over 10 5 minutes. After stirring for 23 hours at room temperature, the reaction was quenched with 50 ml of ice water and stirred vigorously. The THF was removed in vacuo, and the resulting material was diluted with water and extracted 3 times with 15 EtOAc. The EtOAc extract was washed- 2 times with saturated NaHCO^ solution and once with brine then dried over Na2S04- Filtration and solvent removal gave a clear oil (1.3 g). The product was purified by flash chromatography with 100% EtOAc 20 to give the title alcohol (0.55 g, 72%) as a clear oil. R.£=0.22 (EtOAc, silica gel) PMA IR (CHC13) 2999, 2950, 2929, 2856, 1734, 1244, 1195, 1183, 1112, 1105, 1065, 1043 cm"1. 25 XH NMR (270 MHz, CDCl3) 8 7.65 (m, 4) 7.28 (m, 6) 6.81 (s, 1) 6.76 (s, 1) 30 4.51 (m, 1) 3.62&3.60 (2 d's, 3, J=5.3 Hz) 3.49&3.46 (2 s's, 3) o 22 4 7 3 HXlOb -262- 2.97 (m, 1) 2.65 (m, 2) 2. 35&2.33 (2 d's, 2, 2 .25 (2 s's, 3) 2.16 (2 s's, 3) 1.84 (m, 1) 1.68 (m, 6) 1.55 (m, 1) i—» 00 (m, 2) 1.15 (m, 3.) 1.00&0.99 (2 s's, 9) 0.91 (m, 2) Mass Spec (CI) m/e 663 (M+H)+ C. (S)-4-[[2-[2-(Cyclohexylmethyl)-4,6- dimethylphenyl]ethyl]hydroxyphosphinyl] 3-hydroxybutanoic acid, dilithium salt . Part B diester (0.552 g, 1.3 mmol) was stirred in 14 ml of dioxane at room temperature. To this solution was added l.ON LiOH (3.9 ml, 3.9 mmol) and then the reaction was warmed to 55°C. After stirring for 30 minutes a cake-like precipitate formed which was solubilized by adding 5 ml of H20. After 2 hours 15 minutes at 55°C, the reaction was cooled to room temperature, and the volatiles were removed in vacuo leaving a white solid. The product was purified on a 3.0 x 30 cm HP-20 column eluting first with 100 ml of H20 followed by 1:1 CHgOH/^O. Product fractions were lyophilized to give 0.482 g, 92% yield of white lyophilate. TLC Rf=0.36 (7:2:1 n-PrOH/NH4OH/H20, silica gel) PMA. o 22 4 7 HXlOb -263- IR (KBr) 3700-3100 (br), 2923, 2852, 1588, 1446, •1410, 1159, 1132, 1048 cm"1. XH NMR (400 MHz, D20) 6 6.93 (s, 1) 5 6.91 (s, 1) 4.34 (m, 1) 2.80 (m, 2) 2.50 (dd, 1, J=14.7 Hz, 4.4 Hz) 2.48 (d, 2, J=5.12 Hz) 10 2.38 (dd, 1, J=15.0 Hz, 6.6 Hz) 2.29 (s, 3) 2.26 (s, 3) 1.84 (m, 2) 1.65 (m, 7) 15 1.48 (m, 1) 1.15 (m, 3) 1.00 (m, 2) Mass Spec (FAB) m/e 397 (M+H-2L+) + , 409 (M+H) + Anal Calcd for C21H3105PLi2«0.76 H20: C, 59.76; 20 H, 7.77; P, 7.34 Found: C, 59.76; H, 7.91; P, 7.53 Example 57 4—[[[[41-Fluoro-3,31,5-trimethyl[1,1*-biphenyl]-25 2 -yl ] oxy ] methyl ] hydroxyphosphinyl ] -3-hydroxy's butanoic acid, dilithium salt A. 4' -Fluoro-3,3 15-trimethyl [1,1*- biphenyl1-2-carboxaldehyde Ref. Merck U. S. Patent No. 4,375,475, pp. 37 and 30 38. The title compound was prepared as described in Example 1 Parts A to C. f*) 0 f. O c c * 7 3 4 HXlOb -264- B. 4'-Fluoro-3, 3',5-trimethyl[1,1'- /—v (w- biphenyl ] -2 -methanol Part A aldehyde (1.03 g, 4.26 mmol) was stirred in 30 ml of dry CH2C12 under argon 5 atmosphere. A 20 ml CH2C12 solution of m-Cl-perbenzoic acid (1.06 g, 5.11 mmol) was added dropwise over 15 minutes to the aldehyde solution at room temperature. After stirring for 58 hours at room temperature, the reaction mixture was 10 rotavapped to dryness, and the resulting yellow solid was dissolved in THF and treated with 6.4 ml of 2N KOH. This mixture was stirred at room temperature for 5.5 hours, then the THF was removed from the reaction. The resulting residue 15 was diluted with H20 and the aqueous solution was extracted 3 times with Et20 which was then dried over MgSO^. The crude yellow oil obtained after filtration and solvent removal was purified by flash chromatography eluting with 5% Et20/hexane. 20 The title phenol was obtained as white solid Q (0.843 g, 100%). TLC Rf = 0.37 (10% Et20/hexane, silica gel) PMA M.P. 83-86°C. IR (KBr) 3512, 3500 (br), 2950, 1504, 1482, 1238, -1 25 1231, 1215 cm It, 30 (270 MHz , cdci3) 7.20 (m, 2) 7.07 (t, 1, j=9.0 Hz) 6.92 (s, 1) 6.82 (s, 1) 4.95 (s, 1) 2.31 (s, 3) 2.25 (s, 6) 22 4 7 HXlOb -265- Mass Spec (CI) m/e 231 (M+H)+ C. [[[41-Fluoro-3,31,5-trimethyl[1,1'-biphenyl]-2-yl]oxy]methyl]phosphonic acid, diethyl ester A suspension of pentane washed NaH (0.30 g 80% oil disp, 10.3 mmol) in 15 ml of dry DMF under argon atmosphere was cooled in an ice bath. A 10 ml DMF solution of the Part B phenol (2.36 g, 10.3 mmol) was added to the NaH suspension over 15 min:gas evolution was observed. After the addition was complete, the reaction was warmed to room temperature and stirred for 35 minutes. At room temperature, an 11 ml DMF solution of the diethyl tosyloxy methylphosphonate (3.31 g, 10.26 mmol, for prep, see Holy, A., Rosenberg, I., Collection Czechoslovak Chem. Commun., Vol. 47, 1982) was added dropwise over 10 minutes. After 22 hours at room temperature, the reaction was quenched with saturated aqueous NH^Ci solution and the DMF was removed in vacuo. The resulting solid was dissolved in EtOAc and H20, and the aqueous layer was washed 2 times with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaHCO^ solution and brine then dried over MgS04> Filtration and solvent removal gave 4.3 g of crude title ether compound which was purified by flash chromatography eluting with 70% EtOAc/hexane. The title ether (3.2 g, 82%) was obtained as a clear oil. TLC 0.52 (50% Acetone/hexane, silica gel) PMA. IR (Film) 2983, 2925, 2910, 1504, 1474, 1213, 1032, 971 cm"1. n r*. ZZ 4 7 3 4 HXlOb -266- *1 6 NMR (270 MHZ , CDC13) 7.33 (m, 2) 7.01 (t, 1, J=10.0 Hz) 6.96 (s, 1) 6.91 (s, 1) 4.07 (m, 4) 3.69 (d. 2, J=9.3 Hz) 2.34 (s, 3) 2.31 (d, 3, J=1.7 Hz) 2.29 (s, 3) 1.31 (t, 6, J=7.0 Hz) 10 1.31 (t, 6, J=7.0 Hz] Mass Spec (CI) m/e 381 (M+H)+, 242 (M+-C4H10PO3)+ D. [ [ [41-Fluoro-3,3,51-trimethyl[1,11-15 biphenyl] -2-yl] oxy] methyl] phosphonic acid, monoethyl ester Part C diester (3.21 g, 8.45 mmol) in 40 ml of dioxane was stirred with 12.7 ml of IN LiOH (12.67 mmol) at 70°C. After 3 hours at 70°C, the 20 reaction was cooled to room temperature and the dioxane was removed in vacuo. The aqueous solution was diluted with H20 and cooled in an ice bath, then acidified to pH^l with 6N HCl leaving a milky white solution. This solution was then 25 extracted 3 times with EtOAc; the EtOAc extract ©i was dried over MgSO^ and filtered to give 3.12 g of a clear gum. TLC Rf=0.20 (9/0.5/0.5 CH2Cl2/AcOH/MeOH, silica gel) PMA 30 1H NMR (270 MHz, CDC13) 6 10.26 (s, 1) 7.35 (2) 6.96 (m, 3) 22 4 7 34 \. HXlOb -267- 4.05 (dq, 2, J=7.14 Hz, 14.8 Hz) 3.63 (d, 2, J=9.34 Hz) 2.31 (s, 3) 2.29 (s, 3) 5 2.28 (d, 3, J=2.2 Hz) 1.28 (t, 3, J=7.14 Hz) E. 4-[Ethoxy[[[4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl]oxy]methyl]phos-10 phinyl]-3-oxobutanoic acid, methyl ester The Part D phosphonic acid (2.96 g, 8.42 mmol) in 75 ml of dry CH2C12 under argon atmosphere was stirred at room temperature with (C2H5)2Si(CH3)3 (2.44 g, 16.84 mmol). After 15 stirring for 1 hour 10 min, the CH2C12 was removed in vacuo and the resulting oil was azeotroped once with benzene, then placed under high vacuum for 15 minutes. This oil was dissolved in 75 ml of dry CH2Cl2 and cooled to 0°C under argon atmosphere. 20 Three drops of dry DMF were added to the cooled solution followed by dropwise addition of oxalyl chloride (1.18 g, 9.26 mmol). The reaction was stirred at 0°C for 20 minutes, warmed to room temperature and stirred for an additional hour. 25 The reaction solvent was removed in vacuo and the maroon oil phosphonochloridate was azeotroped 2 times with benzene then placed under high vacuum for 1 hour. The dianion of methylacetoacetate was 30 prepared as described in Example. 55 Part C [methylacetoacetate (1.27 g, 10.95 mmol), NaH (0.350 g oil disp., 12.05 mmol), n-butyllithium (4.0 ml of 22 t 7 2£i. HXlOb -268- 2.5 M solution in hexane, 10.07 mmol), THF (35 ml)]. The above prepared phosphonochloridate in 10 ml of THF, cooled to -78°C, was added dropwise 5 over 20 minutes to the dianion solution also at -78°C. After stirring at -78°C for 40 minutes, the reaction was quenched at -78°C with saturated aqueous NH^Cl and allowed to warm to room temperature. The THF was removed in vacuo, and 10 the resulting residue was dissolved in EtOAc and H20. The aqueous layer was extracted 2 times with EtOAc, and all of the EtOAc solutions were combined and washed once with saturated NaHC03 solution and once with brine then dried over 15 Na2S04. Crude title phosphinate was obtained as an orange oil (4.0 g) which was purified by flash chromatography eluting with 75% EtOAc/hexane. Title phosphinate (1.4 g, 42%) was obtained as a yellow oil. 20 TLC Rf=0.25 (75% EtOAc/hexane, silica gel), PMA. IR(CHC13) 3004, 2954, 2925, 1744, 1718, 1643, 1541, 1503, 1472, 1449, 1438, 1425, 1236, 1037 cm-1. XH NMR (270 MHz, CDCl3) 25 6 7.30 (m, 2) ' 6.95 (m, 3) 4.05&3.90 (2 m's, 2) 3.75 (m, 2) 3.73&3.66 (2 s's, 3) 30 3.55 (m, 1) 3.25 (m, 1) 2.33&2.29 (2 s's (br), 9) 22473 HXlOb -269- 1.28&1.12 (2 tfS, 3, J=7.1 Hz) Mass Spec (CI) m/e 451 (M+H)+ ester F. 4-[[[[41-Fluoro-3,31,5-trimethyl[1,l1-biphenyl]-2-yl]oxy]methyl]ethoxyphos-phinyl]-3-hydroxybutanoic acid, methyl A solution of Part E ketone (1.39 g, 3.09 mmol) in THF (15 ml) under argon atmosphere was 10 cooled to 0°C. To the cooled solution was added NaBH4 (0.12 g, 3.09 mmol) followed by slow dropwise addition of CHgOH (2.8 ml). After 1 hour at 0°C, the reaction was guenched with acetone followed by 1.4 g of CC-4 silica gel and then 15 warmed to room temperature. The reaction was filtered, and the filtrate was rotavapped to give a yellow oil. The oil was flash chromatographed eluting with 90% EtOAc/hexane and product containing fractions were combined and solvent was 20 removed in vacuo. The resulting yellow oil was crystallized from Et20/hexane and the resulting crystals were triturated with EtjO/hexane to give white crystals (0.320 g) of title alcohol. TLC Rf=0.38 (90% EtOAc/hexane, silica gel) PMA. • 25 M.P. 116-119°C. IR (KBr) 3288 (br), 3000, 2950, 2920, 1735, 1503, 1473, 1440, 1311, 1232, 1195 cm"1. XH NMR (270 MHz, CDC13) 6 7.28 (m, 2) 30 7.05 (t, .1, J=6.0 Hz) 6.98 (s, 1) 6.90 (s, 1) 4.42 (m, 1) 22 4 7 3- HXlOb 10 -270- 4.05&3.85 (m, 2) 3.75 (d, 2, J=6 .0 Hz) 3.70 (s, 3) 2.55 (m, 2) 2.32 (s, 6) 2.30 (s, 3) 2.00 (m, 2) 1.30 (t, 3, J=7 .0 HZ) Mass Spec (CI) m/e 453 (M+H)+, 435 (M-H20) + G. 4-[[[[4*-Fluoro-3,31,5-trimethyl[1,1'-diphenyl]-2-yl]oxy]methyl]hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt 15 At room temperature IN LiOH (2.0 ml) was added to a 13 ml dioxane solution of Part F diester (0.293 g, 0.65 mmol). The reaction mixture was warmed to 55°C and stirred for 1 hour 45 minutes, then cooled to room temperature. The 20 reaction mixture was rotavapped to dryness and gave a'white solid which was then placed under high vacuum for 10 minutes. The crude product was purified by chromatography on a 15 cm x 3.0 cm column of HP-20 eluting first with 100 ml of H20 25 followed by elution with 50% CH30H/H20. Pure title dilithium salt was obtained as a white lyophilate (0.295 g, 88%). TLC Rf=0.38 (7:2:1 n-PrOH/NH4OH/H20, silica gel) PMA 30 IR (KBr) 3400 (br), 3021, 3011, 2981, 2958, 2924, 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175, 1087 cm"1. 22 4 7 34 HXlOb -271- XH NMR (270 MHz * D20) 6 7.20 (m, 2) 7.07 (d, 1, J=9.9 Hz) 7.03 (s, 1) 6.86 (s, 1) 4.03 (m, 1) 3.40 (d, 2, J=8.3 Hz) 2.24 (s, 3) 2.21 (s, 3) 2.20 (m, 2) 2.17 (s, 3) 1,45 (m, 2). Mass Spec (FAB) m/e 423 (M+H) Anal Calcd for C^H^OgFPLi^ 0.95 H20:C, 54.67; H, 5.48; F, 4.32; P, 7.05 Found: C, 54.37; H, 5.03; F, 4.31; P, 7.55 Example 58 4-[[[41-Fluoro-3,3',5-trimethyl[1,11-biphenyl]-2-yl]methyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A. 41-Fluoro-3,31,5-trimethyl[1,1*— biphenyl ] -2 -methanol To a 9 ml EtOH (Abs) solution of NaBH^ (0.12 g, 3.18 mmol) was added the Example 57 Part A aldehyde (0.70 g, 2.89 mmol) as an Et20-Et0H (4.5 ml/3.0 ml) solution. This reaction mixture was stirred at room temperature for 2 hours and then quenched with saturated NH4C1 solution. The resulting solid precipitate was removed by filtration. The filtrate was rotavapped to dryness and the resulting solid was dissolved in Et20 and H20. The aqueous layer was washed 2 times with 22 4 7 34 HXlOb -272- Et20, and the combined Et20 solutions were dried over MgS04> After filtration and solvent removal 0.70 g of a white solid was obtained. The solid was purified by flash chromatography eluting with 33% Et20/hexane giving 0.675 g (100% yield) of title alcohol. TLC 0.11 (15% Et20/hexane, silica gel) PMA. M.P. 101-102°C. IR (KBr) 3351, 3293, 3267, 3260, 3024, 3016, 2980, 2939, 2921, 1605, 1601, 1502, 1451, 1355, 1243, 1236, 1228, 1189, 1118, 999 cm"1. 1H NMR (270 MHz, CDC13) 6 7.15 (m, 2) 7.03 (m, 2) 6.90 (s, 1) 4.55 (d, 2, J=6.0 Hz) 2.48 (s, 3) 2.33 (s, 6) Mass Spec (CI) m/e 244 (M+), 227 (M+-0H) B. [[41-Fluoro-3,31,5-trimethyl[1,1'- biphenyl]-2-yl]methyl]phosphonic acid, diethyl ester A 50 ml CH2C12 solution of Part A alcohol (1.94 g, 7.95 mmol) under argon atm. was cooled to 0°C. To this cooled solution was added Et^N (0.965 g, 9.54 mmol) followed by dropwise addition of MsCl (1.00 g, 8.75 mmol). The reaction was stirred at 0°C for 30 minutes and then warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaHC03 solution and stirred vigorously. The organic ZZ 4 7 3 HXlOb -273- layer was washed with saturated NaHC03 solution and then dried over MgSO^. Filtration and solvent removal gave 2.1 g of 2-(chloromethyl)-4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl] as a clear oil. 5 TLC Rf = 0.68 (50% Et20/hexane, silica gel) PMA. 1H NMR (270 MHz, CDC13) 6 7.22 (m, 2) 7.03 (m, 2) 6.90 (s, 1) 10 4.50 (s, 2) 2.48 (s, 3) 2.33 (s, 6) Without further purification the above chloride (2.1 g) was stirred with P(0C2H5)3 (30 ml) 15 at 150°C under argon atomosphere for 3 hours. The reaction was cooled to room temperature and the excess P(OC2H5)3 was removed by distillation. The crude product was purified by flash chromatography eluting with 70% EtOAc/hexane. Title phosphonate 20 (2.40 g, 83%) was obtained as a clear oil. £*™s TLC Rf = 0.37 (70% EtOAc/hexane, silica gel) PMA.. IR(CHC13) 2992, 2928, 2909, 1501, 1474, 1455, 1443, 1392, 1245, 1239, 1119, 1053, 1029, 970, 963 cm"1. 25 1H NMR (270 MHz, CDC13) 6 7.15 (m, 2) 7.00 (m, 2) 6.83 (s, 1) 3.83 (m, 4) 30 3.22 (d, 2, J=22.52 Hz) . 2.47 (s, 3) 2.29 (s, 6) 1.16 (t, 6, J=7.14 Hz) U 4 7 34 HXlOb -274- Mass spec (CI) m/e 365 (M+H)+ C. [ [4'-Fluoro-3,3',5-trimethyl[1,1'- biphenyl]-2-yl]methyl]phosphonic acid, 5 monoethyl ester Part B phosphonate diester (2.40 g, 6.59 t v mmol) was stirred in 30 ml of dioxane at room temperature. To this dioxane solution was added IN LiOH (9.9 ml) and the reaction was warmed to a 10 reflux. Additional IN LiOH (9.9 ml) was added at each of the 18 hour and 44 hour time points. After 55 hours at reflux the reaction was cooled to room temperature and the dioxane was removed on the rotavap. The resulting aqueous solution was 15 diluted with H20 and extracted 2 times with Et20 to remove any remaining diester. The aqueous layer was then cooled in an ice bath and acidified to pH-v-l with 6N HCl. The milky white solution was extracted 3 times with EtOAc, the EtOAc extract was dried over MgSO^, filtered, and the solvent was removed to give 1.89 g, 85% yield of a clear oil. TLC Rf = 0.26 (9/0.5/0.5, CH2Cl2/MeOH/AcOH, silica gel) PMA. 20 25 IR (CHC13) 3029, 3023, 3005, 2983, 2925, 1710, 1605, 1500, 1234, 1042, 988 cm"1. XH NMR (270 MHZ, CDCI3) 6 11.07 (s, 1) 7.05 (m, 2) 30 6.95 (m, 2) 6.80 (s, 1) 3.71 (dq, 2, J=7.15 Hz, 14.83 Hz) 3.13 (d, 2, J=23.0) II 4 7 3 4' HXlOb -275- 2-38 (s, 3) 2.27 (s, 6) 1.13 (t, 3, J=7.2 Hz). Mass Spec (CI) m/e 337 (M+H)+ D. 4-[Ethoxy[ [4* -fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl]methyl]phosphinyl ]-3-oxobutanoic acid, methyl ester A 50 ml C^C^ solution of Part C half acid (1.85 g, 5.50 mmol) under argon atmosphere was ' stirred with (C2H5)2NSi(CH3)3 (1.60 g, 11.0 mmol) at room temperature for 1 hour 15 minutes. The CH2CI2 was removed from the reaction mixture arid the resulting yellow oil was azeotroped once with benzene and placed under high vacuum for 20 minutes. This oil under argon atmosphere was dissolved in 50 ml of dry CH2C12 and cooled to 0°C. Two drops of dry DMF were added to the cooled solution followed by the dropwise addition of oxalyl chloride (0.768 g, 6.06 mmol):gas evolution was observed. The reaction was stirred at 0°C for 20 minutes, warmed to room temperature and stirred for an additional 1 hour 40 minutes; •the reaction turned deep burgundy. The CH2Cl2 was removed from the reaction and the resulting oil was azeotroped 2 times with dry benzene then placed under high vacuum for 1 hour. The dianion of methylacetoacetate was prepared as described in Example 57 Part E [methylacetoacetate (0.830 g, 7.16 mmol); NaH (0.230 g oil disp., 7.88 mmol); n-BuLi (2.64 ml of 2.5 M solution in hexane, 6.59 mmol); 20 ml of THF]. HXlOb 4734 -276- The above prepared phosphonochloridate in (8^. 10 ml of dry THF cooled to -78°C was added via cannula over 20 minutes to the dianion solution cooled to -78°C. After stirring for 40 minutes at 5 -78°C, the reaction was quenched at -78°C with saturated NH4C1 solution, and warmed to room temperature; the reaction mixture was diluted ^ with H20 in order to dissolve solids and the THF was removed on the rotavap. The resulting mixture 10 was extracted 3 times with EtOAc. The EtOAc extract was washed once with saturated NaHCOg, once with brine, dried over MgS04 and filtered to give 2.6 g of crude orange oil after solvent removal. The crude product was purified by flash 15 chromatography eluting with 75% EtOAc/hexane. The Part D ketone (0.43 g, 23%) was obtained as an orange foam. TLC Rf=0.32 (50% acetone/hexane, silica gel), PMA. IR (KBr) 2952, 2925, 1739, 1718, 1654, 1529, 1503, 20 1472, 1234, 1206, 1166, 1119, 1035 cm"1. 2H NMR (270 MHz, CDC13) 6 7.20-6.70 (aromatic H's, 5) 4.00-3.70 (m, 2) 3.70&3.55 (2 s's, 3) 25 3.35 (m, 2) 3.35 (d, 2, J=15 Hz) 2.92 (m, 1) 2.45&2.35 (2 s's, 3) 2.25 (s, 6) 30 1.15&0.95 (2 t's, 3, J=7.0 Hz) Mass Spec (CI) m/e 435 (M+H)+ 22 4 7 3 4 HXlOb -277- E. 4-[Ethoxy[[4•-fluoro-3,31,5-trimethyl-[.1,1' -biphenyl ] -2-yl ] methyl ] phosphinyl ] -3-hydroxybutanoic acid, methyl ester Solid NaBH4 (0.035 g, 0.92 mmol) was added to a 5 ml THF solution of the Part D ketone (0.40 g, 0.92 mmol) under argon atmosphere. Methanol (0.80 ml) was added to the THF solution at room temperature. After 1 hour at room temperature, the reaction was quenched with acetone followed by the addition of 0.4 g of CC-4 silica gel. The reaction mixture was filtered and the solvent was removed. The reaction product still retained some ketone starting material; therefore, the above reaction product was resubjected to the identical reduction conditions described above; however, C02 (g) was bubbled through the solution prior to the addition of the NaBH^. Workup as before gave 0.250 g of a yellow oil which was purified by flash chromatography eluting with EtOAc. Pure title alcohol was obtained as a clear oil. TLC R.£=0.26 (50% acetone/hexane, silica gel) PMA. ""■H NMR (270 MHz, CDCI3) 6 7.10 (m, 2) 7.00 (m, 2) 6.85 (s, 1) 4.28&4.03 (2 m's, 1) 4.10-3.70 (m, 2) 3.67 (s, 3) 3.33 (m, 2) 2.47 (s, 3) 2.40 (m, 2) 2.30 (s, 6) « 11 4 7 3 HXlOb -278- 1.63 (m, 2) 1.17 (t, 3, J=6.6 Hz) 5 F. 4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'- biphenyl ] -2-yl] methyl ] hydroxyphosphinyl ] ■ 3-hydroxybutanoic acid, dilithium salt Part E diester (0.110 g, 0.252 mmol) in dry CH2C12 (5.5 ml) under argon atmosphere was cooled 10 to 0°C and treated with collidine (0.046 g, 0.38 mmol) followed by dropwise addition of trimethylsilyl iodide (TMSI) (0.182 g, 0.88 mmol). The reaction was stirred at 0°C for 2 hours then warmed to room temperature. After 24 15 hours an additional aliquot of both collidine (0.023 g) and TMSI (0.091 g) was added. After stirring for 48 hours at room temperature, the CH2C12 was removed, and 6 ml of dioxane was added to the oil followed by 1.7 ml of IN LiOH. This 20 mixture was refluxed for 16 hours, cooled to room temperature and the dioxane was removed to leave an orange gum. The gum was dissolved in HjO and filtered through sintered glass to remove a solid. The filtrate was lyophilized to give an 25 off-white lyophilate which was purified on a 1.5 cm x 15 cm column of HP-20. The column was eluted first with 150 ml of H20 then with 50% Me0H/H20. Product fractions were lyophilized to give title compound in the form of a white lyophilate (88. mg, 30 80%) TLC Rf=0.38 (7:2:1 n-PrOH/NH4OH/H20, silica gel), PMA. IR (KBr) 3700-3100 (br), 2923, 1591, 1501, 1234, 'w o 22 4 7 $ HXlOb -279- 1147 cm"1. 1H NMR (270 MHz, D20) 6 7.20-7.00 (m, 4) .6.82 (s, 1) 3.76 (m, 1) 3.11 (m, 2) 2.35 (s, 3) 2.22 (s, 3) 2.21 (s, 3) 2.05 • (m, 2 ) 1.16 (dd, 2, J=12.32 Hz, 6.45 Hz) Mass Spec (FAB) m/e 407 (M+H)+. Anal Calcd for C20H22FO5PLi2*0.80 H20: C, 57.11; H, 5.65; F, 4.52; P. 7.36 Found: C, 57.11; H, 6.63; F, 4.44; P, 7.70 Example 59 (S)-4-[[[l-(4-Fluorophenyl)-3-methyl-2-naphtha-lenyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A. l-Methoxy-2-naphthalene carboxylic acid Reference: J. Organomet. Chem., 20 (1969) p. 251-252.n-BuLi (208.60 mmol, 83.44 ml of a 2.5 M solution in hexane, Aldrich) was stirred under argon in 42 ml of dry cyclohexane. This solution was cooled to 0°C and treated dropwise (10 min.) with distilled tetramethylethylenediamine (TMEDA) (208.6 mmol, 24.24 g, 31.48 ml). The resulting slurry was stirred at 0°C for 30. minutes, then treated dropwise (20 minutes) with a solution of 1-methoxynaphthalene (208.60 mmol, 33 g, 30.28 ml) (Aldrich Chem. Co., used without further purification) in 84 ml of dry cyclohexane. The 4 7 34 HXlOb -280- resulting bright red homogeneous reaction mixture was warmed to room temperature and stirred fbr 2 hours. The reaction mixture was cooled to 0°C and added portionwise over 30 minutes via cannula to a -78°C solution of dry Et20 (250 ml) saturated with C02 (g) (C02 pellets sublimed through drying tube containing Si02, bubbled into dry Et20 at -78°C). The resulting white slurry was warmed to *^0° over 45 minutes and then treated with 450 ml of 5% HCl (aqueous). The Et20 layer was separated and the aqueous layer extracted three times with Et20.. The organic extracts were combined and extracted with 3 x 150 ml saturated NaHCO^ (aqueous). The aqueous layer was filtered through a sintered glass funnel to remove insolubles and the filtrate was cooled to 0°C and acidified slowly with concentrated HCl until pH=l. The resulting precipitate was filtered, azeotroped with 2 x 150 ml of toluene, dried under high vacuum at 50°C for 5 hours to afford 32.52 g (0.161 mol, 77% yield) of the l-methoxy-2-naphthalene carboxylic acid as an off-white powder, m.p. 118-121.5°C. TLC: Silica gel, Rf=0.35 94:5:l/CH2Cl2:Me0H:CH3C02H ^H NMR: (270 MHz, CDCl^) consistent 1^C NMR: (67.8 MHz, CDCl^) consistent Mass Spec: CI m/e 203+(M+H)+ IR: KBr consistent. B. N-(2-Hydroxy-1,1-dimethylethyl)-l- methoxy-2-naphthalenecarboxamide The l-methoxy-2-naphthalene carboxylic acid (155.22 mmol, 31.4 g) was stirred under argon in 155 ml of dry CH2C12. The solution was then n o G 4 734' HXlOb -281- treated with. SOCl2 (310.44 mmol, 36.94 g, 22.65 ml). The reaction mixture was stirred at room f*) temperature for 45 minutes then heated to reflux in a 55°C oil bath for 45 minutes. The reaction 5 mixture was cooled to room temperature and treated with an additional amounts (18.47 g, 11.32 ml) of thionyl chloride'and again heated to reflux for 45 minutes. The reaction mixture was cooled to room temperature, the excess S0C12 and CH2C12 10 removed via rotary evaporation at 35°C (venting to argon atmosphere) and the resulting mustard yellow solid dissolved under argon in 155 ml dry CH2Cl2. This solution was transferred via cannula to an' addition funnel and added dropwise (40 minutes) to 15 a solution of 2-amino-2-methyl propanol (310.44 mmol, 27.67 g) in 155 ml dry CH2C12 which had been stirring under argon at 0°C. The resulting reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture 20 was then filtered, the precipitate washed with CH2C12, the filtr-ate evaporated in vacuo. The residue was redissolved in 350 ml EtOAc and washed with 1 x 250 ml H20, 1 x 250 ml 5% HCl, 1 x 250 ml 5% NaOH and 1 x 250 ml brine. The aqueous 25 extracts were each back-extracted once with EtOAc. The organic extracts were combined, dried over MgSO^, filtered, and evaporated in vacuo to afford an orange oil which was azeotroped with 250 ml toluene and pumped under high vacuum at 55°C 30 for 8 hours to afford 38.2 g (139.76 mmol, 90% yield) of the title naphthalamide as a light yellow solid. o 22 4 7 3 HXlOb -282- TLC: Silica •hi NMR (270 gel MHz , Rf — 0. , CDC13) 65 100% EtOAc 6 8.19 (s, br, 1H) 8.14 (m, 1H) 8.03 <d, 1H, J=8. 7 Hz) 7.83 (m, 1H) 7.66 (d, 1H, J=8. 7 Hz) 7.55 (m, 2H) 4.00 (s, 3H). 3.74 (s, 2H) 1.47 (S, 6H) 10 Mass Spec: CI m/e 274 (M+H)+ IR: (CHC13 solution) 3365, 3063, 3024, 3005, 2971, 2938, 2873, 1641, 15 1597, 1540, 1456, 1446, 1387, 1371, 1344, 1291, 1256, 1238, 1223, 1210, 1199, 1183, 1168, 1145, 1079, 981, 833 cm"1. C. 4,5-Dihydro-2-(l-methoxy-2-naphthalenyl) 20 4,4-dimethyloxazole The Part B naphthalamide (139 mmol, 38.2 g) was stirred under argon and cooled to 0°C as thionyl chloride (0.556 mol, 66.15 g, 40.56 ml) was added dropwise (15 minutes). The resulting 25 dark brown oil was stirred at room temperature for 45 minutes. Dry Et2<3 (500 ml) was added, and the reaction mixture was stirred mechanically for 2.5 hours. The resulting yellow crystalline precipitate was filtered, washed with Et20 and 30 then suspended in 250 ml Et20. The suspension was cooled to 0°C and basified with ~200 ml 10% NaOH. The aqueous layer was extracted 3 times with Et20 and once with EtOAc. The organic extracts were ££1/3 * v •***$' HXlOb -283- combined, washed once with brine, concentrated, dried over MgS04 and filtered. The filtrate was azeotroped with toluene in vacuo and the residue pumped under high vacuum at 55°C for 8 hours to 5 afford 32.10 g (0.126 mol, 90% yield) of the title oxazoline as a golden powder. o TLC: silica gel R.=0.37 50% EtOAC H NMR: (270 MHz, CDC13) 6 8.25 (m, 1H) 10 7.84 (d, 1H, J=8.7 Hz) 7.84 (m, 1H) 7.60 (d, 1H, J=8.7 Hz) 7.54 (m, 2H) 4.19 (s, 2H) 15 4.04 (s, 3H) 1.46 (s, 6H) Mass Spec: CI m/e 256 (M+H)+ IR: 2969, 2935, 2896, 1642, 1465, 1447, 1386, -1 1372, 1349, 1255, 1109, 1074, 991 cm 20 O D. 2-[1-(4-Fluorophenyl)-2-naphthalenyl)]- 4,5-dihydro-4,4-dimethyloxazole The Part C oxazoline (117.52 mmol/ 30.0 g) was stirred under argon in 352.5 ml of dry THF. 25 This solution was warmed to 45°C in an oil bath. The heat source was removed and a 2M solution of 4-fluorophenyl magnesium bromide in Et20 (Aldrich) (158.65 mmol, 79.33 ml) was added dropwise (30 minutes) at a rate sufficient to maintain the 30' reaction temperature at ^45°C. After addition was complete, the reaction temperature was maintained at 45°C as the reaction mixture was stirred for 18 hours. The reaction mixture was cooled to 0°C and nhu V_- HXlOb -284- quenched with 200 ml saturated NH4C1 (aqueous), r°\ diluted with 200 ml H~0 and 200 ml EtOAc. The w 2 aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, concentrated, 5 dried over MgS04 and filtered. The filtrate was evaporated in vacuo to afford 39 g of a dark ^ golden solid. The product was purified via flash chromatography (95 mm diameter column, 7" Merck silica gel, 25% EtOAc/hexane eluent, 2"/min flow 10 rate) to afford 30.42 g (95.25 mmol, 81% yield) of the title 4-fluorophenyl substituted naphthalene as a pale yellow solid, m.p. 94-96°C. Also obtained was 3.38 g (10.58 mmol, 9%) of slightly impure product. 15 TLC: silica gel Rf=0.45 50% EtOAc/hexane XH NMR: (270 MHz, CDC13) 6 7.93-7.13 (aromatic, 10H) 3.77 (s, 2H) 1.27 (s, 6H) c 20 Mass Spec: CI m/e 320 (M+H)+ IR:(KBr) 3060, 2966, 2927, 2884, 1667, 1603, 1508, 1462, 1383, 1354, 1335, 1293, 1219, 1185, 1160, 1119, 1083, 978, 842, 830 cm-1. 0 25 E. 2-[1-(4-Fluorophenyl)-3-methyl-2- naphthalenyl)]-4,5-dihydro-4,4- dimethyloxazole The Part D l-4-fluorophenyl-2-oxazoline-naphthyl compound (87.67 mmol, 28 g) was stirred 30 under argon in 585 ml dry Et20. This solution was cooled to -25°C and treated dropwise (1 hour) with n-BuLi (140.27 mmol, 56.1 ml of a 2.5 M solution in hexane). The reaction mixture transformed 22 4 7 34" HXlOb -285- during this hour long addition from a yellow homogeneous solution to a dark red/orange solution to an orange/green solution with a precipitate. The reaction mixture was stirred at -25°C for an additional 2.5 hours and was then treated with iodomethane (263.01 mmol, 37.33 g, 16.4 ml) added dropwise over 15 minutes. The resulting dark burgundy solution was stirred at -25°C for 4.5 hours, warmed to 0°c and stirred for 16 hours and finally warmed to room temperature and stirred for 7 hours. The resulting yellow transparent solution was quenched with 500 ml of ice cold brine. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, concentrated, dried over MgSO^ and filtered through Florisil (300 ml glass sintered funnel 2/3 full). The Florisil was washed with . The filtrate was concentrated, azeotroped with toluene and evaporated in vacuo and pumped under high vacuum at 55°C for 3 hours to afford 30.32 g ("90.94 mmol", 100% yield) of the title methylated naphthalene as a yellow solid. TLC: Silica gel R£=0.50 50% EtOAc/hexane ■""H NMR: (270 MHz, CDC13) 6 7.79-7.07 (aromatic, 9H) 3.80 (s, 2H) 2.54 (s, 3H) 1.13 (s, 6H) Mass Spec: CI m/e 334 (M+H)+ ' IR: (CHClg solution) 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513, 1497, 1461, 1299, 1280, 1235, 1190, 1158, 1041, 965, 841 cm"1. 22 4 7 HXlOb -286- F. 2-[1-(4-Fluorophenyl)-3-methyl-2-naphthalenyl) ] -4,5-dihydro-3,4,.4-trimethyloxazolium Iodide The Part E oxazoline (87.67 mmol, 29.23 g) was stirred under argon in 140.28 ml nitromethane. This solution was treated in one portion with iodomethane (0.789 mol, 112 g, 49.2 ml). The resulting brown reaction mixture was heated in a 60°C oil bath for 1 hour 20 minutes in the absence of light. The iodomethane was removed via simple distillation. The. nitromethane was removed via rotary evaporation followed by pumping under high vacuum for 45 minutes. The resulting burgundy solid was stirred mechanically in 250 ml dry Et20 for 1 hour. The red filtrate was decanted and the solid was again triturated from Et20 as above. The resulting yellow solid was filtered and pumped under high vacuum for 4 hours (in the absence of light) to afford the title oxazolinium iodide 44 g ("92.63" mmol, 100% yield) as a mustard yellow solid. The title compound was stored in the absence of light at -30°C for 18 hours and was then used directly in the preparation of the Part G compound. TLC:Silica gel Rf=0.30 10% MeOH/CH2Cl2. G. 1- (4-Fluorophenyl )-3-methyl-2-naphthalenecarboxaldehyde The Part F oxazolinium iodide (87.67 mmol, 41.67 g) was stirred under argon in 526 ml of dry THF and 210 ml absolute EtOH (dried over 4A molecular sieves). This solution/suspension was cooled to -15°C and treated protionwise with NaBH4 -287- 22 4 734' HXlOb over a one hour period. After addition was C**"' complete, the reaction solution was stirred at vy.'"' -10°C to —15°C for 2.5 hours. Then, the solution was diluted with 210 ml absolute EtOH and the 5 reaction mixture stirred at -15°C as 2N HCl (438 ml, 876 mmol) was added dropwise over 45 minutes (add very slowly initially). After addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. Then, 10 dilution with 500 ml H20 was followed by aqueous extraction with Et20. The organic extracts were combined, concentrated, dried over MgSO^, filtered, concentrated, azeotroped with toluene (2 x 120 ml) and stripped in vacuo to afford 12.9 g, 15 (48.81 mmol, 56% yield) of the title aldehyde as a pale yellow solid. TLC: Silica gel Rf=0.66 50% EtOAc/hexane XH NMR: (270 MHz, CDClg ) 6 10.0 (s, 1H) 20 7.83-7.18 (aromatic, 9H) 2.81 (s, 3H) C Mass Spec: CI m/e 265 (M+H)+ IR: (CHClg solution) 1685, 1512, 1422, 1237, 862 cm"1, 25 H. 2-(2,2-Dibromoethenyl)-l-(4-fluoro- phenyl)-3-methylnaphthalene The Part G aldehyde (11.35 mmol, 3.0 g) was stirred under argon in 113.5 ml dry CH2C12. This 30 solution was cooled to 0°C and then treated in one portion with triphenylphosphine (36.32 mmol, 9.53 g). The reaction mixture was stirred at 0° for 20 minutes and then treated dropwise (20 min) with a 22 4 7 IC 1 ' w t HXlOb -288- solution of carbon tetrabromide (18.16 mmol, 6.02 g) in 41 ml dry CH2C12. The resulting dark orange solution became dark burgundy as it was stirred at 0°C for 1% hours. Then the reaction mixture was quenched with 150 ml saturated NaHC03 (aqueous). The aqueous layer was extracted 4 times with CHjC^ * T^e or9anic extracts were combined, concentrated in vacuo, washed once with brine, dried over MgS04 and filtered. The filtrate was preabsorbed onto Merck silica gel (^28 g) and then applied to a 50 mm diameter flash chromatography .column containing 6" Merck silica gel and eluted with 7% EtOAc/hexane eluent, 2"/min flow rate to afford 4.23 g of the title dibromo-olefin as a slightly impure pale yellow solid. Subsequent recrystallization from hexane afforded 3.68 g (8.77 mmol, 77% yield) of the title dibromo-olefin as a white powdery solid, m.p. = 134.5-135.5. TLC: silica gel Rf=0.60 20% EtOAc/hexane XH NMR: (270 MHz, CDC13) 6 7.79-7.11 (aromatic olefinic, 10H) 2.48 (s, 3H) Mass Spec: CI m/e 419/421/423 (M+H)+ IR: (CHC13 solution) 3016, 1604, 1512, 1496, 1234, 1220, 1208, 1158, 886, 858 cm'1. I. 2-Ethynyl-l-(4-fluorophenyl)-3- methylnaphthalene The Part H dibromo olefin (8.7 mmol, 3.69 g) was stirred under argon in 47.9 ml dry THF. This solution was cooled to -78°C and then treated dropwise (15 min) with n-BuLi (17.4 mmol, 6.96 ml U i?34 ' W , HXlOb -289- of a 2.5 M solution in hexane - Aldrich). The reaction mixture was stirred at -78°C for 1 hour and then was quenched with 40 ml saturated NH^Cl (aqueous). After warming to 0°C,' the reaction mixture was diluted with 40 ml of H20 and 40 ml of Et20. The aqueous phase was extracted 2 times with Et20 and once with EtOAc. The organic extracts were combined, dried over MgS04, filtered and the solvent evaporated in vacuo. Initial purification via flash chromatography (50 mm . diameter column, 6" Merck silica gel, 7% EtOAc/hexane eluent, 2"/min flow rate) afforded 2.32 g of a green oil/solid. 270 MH2 1H NMR evidenced impure product. Repurification via flash chromatography (75 mm diameter column, 6" Merck silica gel, 1% EtOAc/hexane eluent, 2"/min flow rate) afforded 2.11 g (8.11 mmol, 93% yield) of the title acetylene as a pale blue solid (pumped under high vacuum 8 hours) m.p. = 91.5-94.5. TLC: Silica gel, PMA Rf = 0.56 20% EtOAc/hexane 1H NMR: (270 MHz, CDClg) 6 7.77-7.13 (aromatic, 9H) 3.18 (s., 1H) 2.62 (s, 3H) Mass Spec: CI m/e 260 M+ IR: (CH2C12 film) 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150, 1092, 884, 871, 853, 825 cm"1. J. (S)-3-[[(1,1-Dimethylethyl)diphenyl-silyl]oxy]-4-[[[1-(4-fluorophenyl)-3-methyl-2-naphthalenyl]ethynyl]methoxy-phosphinyl]hutanoic acid, methyl ester 22 4 73 HXlOb -290- 4 The Example 25 dicyclohexylamine salt (8.82 mmol, 5.57 g) was partitioned between a 1:1 mixture of EtOAc/5% KHS04 (150 ml ea.) and shaken vigorously. The layers were separated and the EtOAc layer was washed with 2 x 100 ml fresh 5% KHS04< Finally, the organic phase was dried over MgS04, filtered and the solvent removed in vacuo. The resulting residue was azeotroped with 2 x 120 ml benzene, evaporated and pumped under high vacuum for 2 hours to afford "4i33 g""109%" yield, of the phosphonate monoester as a viscous pale yellow oil. This oil was stirred under argon in 24.8 ml dry CH2C12 and treated dropwise (8 minutes) with distilled diethyltrimethylsilyl amine (17.64 mmol, 2.56 g, 3.34 ml). This splution was stirred at room temperature for 2 hours. Then, the volatiles were removed on the rotavap (vent to argon) and the resulting residue azeotroped with 1 x 60 ml dry benzene, evaporated in vacuo and pumped under high vacuum for 45 minutes. The . residue was then stirred under argon in 24.8 ml of dry CH2C12. Two drops of DMF were added and the solution cooled to 0°C. Oxalyl chloride (10.58 mmol, 1.34 g, 0.923 ml) was added dropwise (10 min). The resulting amber solution was stirred at 0°C for 30 minutes, warmed to room temperature and stirred for 2 hours. The volatiles were removed, the residue azeotroped and pumped under high vacuum as above. Finally, the residue was stirred under argon in 27.7 ml dry THF. This solution was cooled to -78°C and treated dropwise (15 minutes) with a -78°C THF solution of the acetylenic anion 224 7 j, HXlOb -291- formed and added to the phosphonochloridate as follows. The Part I acetylene (5.19 irnnol, 1.35 g) was stirred under argon in 27.7 ml of dry THF and 5 cooled to -78°C. This solution was treated dropwise (10 minutes) with n-BuLi (5.19 mmol, 2.08 ml of a 2.5 M solution in hexane). The resulting green solution was stirred at -78°C for 1.5 hours, warmed to 0°C for 15 minutes and recooled to 10 -78°C. This solution was maintained at -78°C as it was transferred portionwise to an addition funnel and added dropwise to the -78°C THF solution of the phosphonochloridate formed above. After completion of addition, the reaction mixture 15 was stirred at -78°C for 1 hour, then quenched with 50 ml saturated NH4C1 (aqueous) and warmed to 0°C. The reaction mixture was then diluted with 40 ml H20 and 40 ml Et20. The aqueous layer was extracted with 4 x 50 ml Et20. The organic 20 extracts were combined, concentrated, dried over MgS04> filtered, and the solvent removed in vacuo. The product was isolated via flash chromatography (75 mm diameter column, 6" Merck silica gel, 5:4:1 hexane:EtOAc:toluene eluent, 25 2"/min flow rate) to afford 1.53 g (2.21 mmol 43% yield) of the title acetylenic phosphinate as a yellow foam. Also recovered 0.589.g of impure starting material. TLC:Silica gel, PMA Rf=0.26 5:4:1 3 0 Hexane:EtOAc:toluene -292- 22 47 3* HXlOb o 5 C 10 15 20 25 O ■hi'NMR: (270 MHz, CDC1,) 6 7.82-7.09 (aromatic, 19H) 4.52 (m, 1H) 3.60&3.59 (2 x s, 3H) 3.36&3.31 (2 x d, 3H, J=11.5 Hz) 2.54&2.49 (2 x s, 3H) 2.87-2.73 (m, 1H) 2.61-2.56 (m, 1H) 2.39-2.22 (m, 1H) 2.12-2.00 (m, 1H) 1.02 (s, 9H) Mass Spec: CI m/e 693 (M+H)+ IR:(CHCl^ solution) 3004, 2951, 2932, 2858, 2164, 1735, 1605, 1512, 1494, 1472, 1437, 1427., 1237, 1197, 1182, 1158, 1151, 1138, 1110, 1105, 1093, 1038, 1017, 951, 885, 834 cm"1. K. (S)-4-[[[1-(4-Fluorophenyl)-3-methyl-2-naphthalenyl ] ethynyl ] methoxyphosphinyl ]-3-hydroxybutanoic acid, methyl ester The Fart J acetylenic phosphinate (0.866 mmol, 0.60 g) was stirred under argon in 10.5 ml dry THF and treated with glacial acetic acid (3.46 mmol, 0.208 g, 0.198 ml) followed by dropwise addition of tetrabutylammonium fluoride (2.60 mmol, 2.36 ml of a 1.1 M solution in THF). The reaction mixture was stirred at room temperature for 24 hours, then quenched with 25 ml ice water and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The organic extracts were combined, washed once with saturated o 22 4 7 HXlOb -293- NaHC03 (aqueous) and once with brine, dried over MgS04, filtered and evaporated in vacuo. The product was purified via flash chromatography using a 30 mm diameter column; 35:1 Merck silica 5 gel, 100% EtOAc eluent, 2"/min flow rate to afford 0.267 g (0.588 mmol; 68% yield) of the title p-hydroxyphosphinate as a pale yellow foam. TLC:Silica gel, PMA Rf=0.28 100% EtOAc XH NMR: (270 MHz, CDC13) 10 6 7.81-7.18 (aromatic, 9H) 4.38 (m, 1H) 3.71 (s, 3H) 3.59&3.58 (2 x d, 3H, J=12 Hz) 2.66&2.65 (2 x s, 3H) 15 2.62-2.52 (m, 2H) 2.19-1.92 (m, 2H) Mass Spec: CI m/e 455 (M+H)+ IR: (film) 3380 (broad), 3065, 3048, 2993, 2951, 2166, 1738, 20 1604, 1513, 1495, 1457, 1438, 1423, 1401, 1385, 1378, 1334, 1299, 1222, 1179, 1160, 1138, 1095, 1035, 951, 887, 836 cm"1 L. (S)-4-[[[1-(4-Fluorophenyl)-3-methyl-2-25 naphthalenyl]ethynyl]hydroxyphosphinyl]- 3-hydroxybutanoic acid, dilithium salt The Part K diester (0.583 mmol, 0.265 g) was stirred under argon in 6 ml dioxane and treated with IN LiOH (1.75 mmol, 1.75 ml). The 30 reaction mixture was heated in a 70°C oil bath for 45 minutes. The reaction mixture was cooled to room temperature. The solvents were removed via rotary evaporation followed by pumping under high o O 22 4 5 HXlOb -294- vacuum for 1 hour. The resulting white solid was (^; dissolved in 4 ml of distilled H20 and applied to an HP-20 chromatography column (2.5 cm x 17.0 cm, equilibrated with H20). The column was eluted 5 with 250 ml H20 followed by eluting with 45:55 Me0H:H20. Fractions were collected every 1.3 m (^10 ml). Product fractions were evaporated in vacuo at 35°C, lyophilized, and pumped under high vaccum over P2°5 for 8 hours to afford 0.237 10 g (0.541 mmol, 93% yield) of the title phosphinic acid dilithium salt as a white lyophilate. TLC:Silica gel, PMA Rf=0.40 7:2:1 n-C3H70H/NH40H/H20 XH NMR: (400 MHz, D20) 6 7.88 (d, 1H, J=8.43 Hz) 15 . 7.80 (s, 1H) 7.58-7.29 (aromatic, 7H) 4.14-4.05 (m, 1H) 2.61 (s, 3H) 2.43 (dd, 1H, J=3.67, J=15.39) 20 2.21 (dd, 1H, J=9.16, J=15.39) 1.84-1.67 (m, 2H) Mass Spec: FAB m/e 439 (M+2 Li)+ IR:(KBr) 3443-3260 (broad), 3066, 2164, 1594, 1512, 1495, 1434, 1222, 1183, 1160, 1071, 834 cm"1, 25 Anal Calcd for C23H^gFOgPLi2+0.66 moles H20 M.W.=450.14: C, 61.38; H, 4.33; F, 4.22; P, 6.88 Found: C, 61.38; H, 4.07; F. 4.42; P, 6.80 22 4 7 34 HXlOb -295-Example 60 (E)-4-[[2-[1-(4-Fluorophenyl)-3-methy1-2-naphthai enyl ] ethenyl ] hydroxyphosphinyl ] -3 -hydroxy- butanoic acid, dilithium salt 5 A. [2-[1-(4-Fluorophenyl)-3-methyl-2- naphthalenyl]-2-hydroxyethyl]phosphonic acid, dimethyl ester Dimethyl methyl phosphonate (24.21 mmol, 3.0 g, 2.62 ml) was stirred under argon in dry THF 10 (47 ml). This solution was cooled to -78°C and then treated dropwise (15.min) with n-BuLi (22.70 mmol, 9.08 ml of a 2.5 M solution in hexane). This reaction mixture was stirred at -78°C for 1.5 hours and then the resulting milky solution was 15 treated dropwise (15* minutes) with a solution of the Example 59 Part G aldehyde (15.13 mmol, 4.0 g) in dry THF (14 ml). This reaction mixture was stirred at -78°C for 45 minutes. Finally, the reaction mixture was quenched with saturated NH^Cl 20 (aqueous) (50 ml), warmed to room temperature, diluted with H20 (50 ml) and EtOAc (50 ml). The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO^, filtered, concentrated, azeotroped 2 times 25 with toluene, evaporated in vacuo, and pumped under high vacuum to afford 5.90 g (15.13 mmol, 100% yield) of the title phosphonate as a yellow solid which was used directly in the preparation of Part B compound. 30 TLC:Silica gel, PMA Rf=0.37 50% acetone/hexane :2 4 7 HXlOb -296- B. (E)-[2-[l-(4-Fluorophenyl)-3-methyl-2-O naphthalenyl]ethenyl]phosphonic acid, dimethyl ester The Part A p-hydroxyphosphonate (14.16 5 mmol, 5.5 g) was stirred under argon in 66.5 ml of dry toluene. This solution was treated with C paratoluene sulfonic acid monohydrate (Ts0H«H2O) (3.54 mmol, 0.673 g). The reaction mixture was heated to reflux in a 135°C oil bath. The 10 condensate was passed through a soxhlet containing dry 4A molecular sieves. After 16 hours at reflux additional TsOH-I^O (2.12 mmol, 0.404 g) was added and the reaction mixture heated as above for an additional 8.5 hours. The reaction mixture was 15 cooled to room temperature and diluted with 100 ml of EtOAC. The mixture was then washed with 100 ml of saturated NaHCOg (aqueous). The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO^, filtered 20 . and evaporated in vacuo to afford 4.22 g of crude vinyl phosphonate as a brown solid. The aqueous layer was acidified with 5% HCl and then extracted 3 times with EtOAc. The organic extracts were combined, dried over MgSO^, filtered and 25 evaporated to afford 1.4 g ("3.92 mmol") of the O vinyl phosphonate monoester as a light brown solid. This solid was stirred under argon in trimethyl orthoformate (15 ml) and heated to reflux in a 120°C oil bath for 16 hours. The 30 reaction mixture was cooled to room temperature. The excess trimethyl orthoformate was removed in vacuo and the residue combined with the 4.22 g of crude vinyl phosphonate (above). The product -297- Z? 4 7 HXlOb was purified via flash chromatography (75 mm diameter column, 6" Merck silica gel, 100% EtOAc eluent, 2"/min flow rate) to afford 3.70 g (9.99 mmol, 71% yield) of the title vinyl phosphonate as a peach solid. TLC:Silica gel, PMA Rf=0.48 100% EtOAc 1H NMR:(270 MHz, CDC13) 6 7.79 (d, 1H, J=8.4 Hz) 7.72 (s, 1H) 7.56-7.13 (m, 8H) 5.54 (dd, 1H, J=17.93 Hz, J=20.6 Hz) 3.57 (d, 6H, J=ll Hz) 2.54 (s, 3H) Mass Spec: CI m/e 371 (M+H)+ IR:(CHClg solution) 3016, 2956, 2857, 1617, 1521, 1500, 1245, 1188, 1162, 1071, 1047, 834 cm"1. C. (E)-[2-[1-(4-Fluorophenyl)-3-methyl-2-naphthalenyl ] ethenyl]phosphonic acid, monomethyl ester The Part B vinyl phosphonate (9.72 mmol, 3.60 g) was stirred under argon in dioxane (23.5 ml) and treated with IN LiOH (23.32 mmol, 23.32 ml). The reaction mixture was heated in a 75°C oil bath for 1 hour. Then, the reaction mixture was cooled to room temperature and the solvents removed in vacuo. The resulting residue was diluted with 15 ml of H20, cooled to 0°C and acidified to pH=l with 5% HCl (aqueous). The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO^, filtered, concentrated, azeotroped 2 times 2?4 7.H « W J HXlOb -298- with benzene and evaporated in vacuo to afford 0 3.38 g (9.48 mmol, 98% yield) of the title phosphonate monoester as a peach solid. TLC:Silica gel, PMA Rf=0.41 10:1:1 5 CH2Cl2/MeOH/CH3C02H 1H NMR: (270 MHz, CDC13) 0 6 7.76 (d, 1H, J=8.4 Hz) 7.68 (s, 1H) 7.47-7.09 (m, 8H) 10 5.61 (dd, 1H, J=18.47 Hz, J=20.58 Hz) 3.48 (d," 3H, J=10.96 Hz) 2:52 (s, 3H) Mass Spec: FAB m/e 357 (M+H)+ IR: (CHC13 solution) 15 3025, 3008, 2951, 1614, 1605, 1511, 1494, 1235, 1210, 1188, 1158, 1050, 987, 833 cm"1. D. (E)-4-[[2-[l-(4-Fluorophenyl-3-methyl-2-naphthalenyl]ethenyl]methoxyphosphinyl]- 20 3-oxobutanoic acid, methyl ester 0; The Part C phosphonate monoester (9.12 mmol, 3.29 g) was stirred under argon in dry CH2C12 (60 ml) and treated dropwise (10 minutes) with trimethylsilyldiethyl amine (TMSDEA) (18.24 25 mmol, 2.65 g, 3.45 ml, distilled). The reaction 0} mixture was stirred at room temperature for 1.5 hours. The volatiles were removed.on the. rotavap (vent to argon) and the residue pimped under high vacuum 40 minutes. Then, the residue was stirred 30 under argon in dry CH2C12 (25 ml). This solution was cooled to 0°C, treated with 2 drops of dry DMF, followed by dropwise addition (15 minutes) of oxalyl chloride (10.94 mmol, 1.39 g, 0.955 mol). 2247 34 HXlOb -299- The reaction mixture was stirred at 0°C for 20 C*) minutes then warmed to room temperature and stirred for 1 hour.. The volatiles were removed and the residue pumped as above. Finally, the residue was 5 stirred under argon in dry THF (25 ml), cooled to -78°C and maintained at -78°C as this solution was transferred via cannula to an addition funnel and added dropwise (20 minutes) to a -78°C THF solution of the dianion of methyl acetoacetate. This 10 dianion was generated in the following manner: NaH (13.22 mmol, 0.317 g, 0.397 g of 80% mineral oil dispersion) was washed once with pentane, dried under an argon stream, and then stirred under argon in dry THF (20 ml). This suspension was cooled to 15 0°C and treated dropwise (10 minutes) with a solution of methylacetoacetate (12.31 mmol, 1.43 g, 1.33 ml) in dry THF (10 ml). The resulting clear solution was stirred at 0°C for 20 minutes and was then treated dropwise (10 20 minutes) with n-BuLi (11.40 mmol, 4.56 ml of a 2.5 M solution in hexane). The resulting yellow solution was stirred at 0°C for 45 minutes then cooled to -78°C and treated dropwise with the -78°C THF solution of the phosphonochloridate 25 formed above. After the addition was complete, the reaction mixture was stirred at -78°C for 45 minutes. Then, the reaction was quenched with saturated NH4C1 (aqueous) (50 ml), warmed to room temperature, diluted with H20 (50 ml) and EtOAc 30 (50 ml). The aqueous layer was extracted 3 times with NaHCOg (aqueous) and once with CI^C^. The organic extracts were combined, washed 3 times with saturated NaHC03 (aqueous) and once with brine, • HXlOb -300- dried over MgSO^, filtered and evaporated in vacuo to afford 4.0 g of a rust colored foam. Initial purification via flash chromatography (40 mm diameter column, 20:1 Merck silica gel, 100% EtOAc eluent, 2"/min flow rate) afforded 2.0 g of slightly impure title keto-phosphinate as an orange oil. Subsequent chromatography (30 mm diameter column, 25:1 Merck silica gel, 95% EtOAc/hexane eluent, 2"/min flow rate) afforded 1.95 g (4.29 mmol 47% yield) of the title ketophosphinate as an orange foam. TLC:Silica gel, PMA Rf=0.29 100% EtOAc XH NMR:(270 MHz, CDC13) 6 7.78-7.13 (aromatic, olefinic, 10H) 5.62 (dd, 1H; J=17.93 Hz, J=25.84 Hz) 3.71 (s, 3H) 3.63 (s, 2H) 3.48 (d, 3H, J=ll.6 Hz) 3.14&3.13 (2 x d, 2H, J=18.46 Hz) 2.44 (s, 3H) Mass Spec: CI m/e 455 (M+H)+ IR:(film) 1749, 1717, 1623, 1614, 1604, 1511, 1328, 1223, 1159, 1031, 834 cm"1 E. (E)-4-[[2-[l-(4-Fluorophenyl)-3-methyl-2-naphthalenyl.] ethenyl ] methoxyphosphinyl]-3-hydroxy-butanoic acid, methyl ester The Part D ketophosphonate (2.82 mmol, 1.28 g) was stirred under argon in dry THF (12 ml). This solution was cooled to 0°C and treated with NaBH^ (2.82 mmol, 0.107 g), followed by dropwise 22 4 7 34 HXlOb -301- addition of methanol (2.45 ml, dried over 4a molecular sieves). The reaction mixture was stirred at 0°C for 1 hour, then quenched with 2.5 ml of acetone. 1.3 g of CC-4 silica gel (Mallinckrodt) were added and the reaction mixture was stirred as it was warmed to room temperature. Finally, the suspension was filtered through a fritted funnel, washed 2 times with EtOAc and 2 times with CH2C12. The filtrate was evaporated in vacuo to afford 1.3 g of an orange foam which crystallized upon addition of EtOAc. The product was purified via flash chromatography (30 mm diameter column 30:1 Merck silica gel, 3% MeOH/CH2Cl2 eluent, 2"/min flow rate). Product fractions were combined, evaporated, and azeotroped one time with benzene to afford 0.653 g (1.43 mmol, 51% yield) of the title hydroxyphosphinate as a pale yellow solid. ^ This pure product was triturated from 7:3 EtOAc/hexane to afford 0.516 g of the hydroxyphosphinate as a white solid, m.p.=132-134.5°C TLC:Silica gel, PMA Rf=0.38 4% Me0H/CH2Cl2 1H NMR:(270 MHz, CDC13) 6 7.79-7.16 (aromatic, olefinic, 10H) 5.59 (2 x dd, 1H, J=17.94 Hz, J=24.27 Hz) 4.35&4.24 (2 x m, 1H) 3.70 (s, 3H) 3.49&3.47 (2 x d, 3H, J=ll Hz) 2.58-2.53 (m, 2H) 2.54&2.53 (2 x s, 3H) 2.01-1.74 (m, 2H) Mass Spec:CI m/e 457 (M+H)+ ^ 224734 o n HXlOb -302- IR: (KBr) 3422-3382, 3062, 3051, 2951, 2926, 2913,"1738, 1613, 1604, 1511, 1494, 1457, 1438, 1399, 1373, 1330, 1311, 1307, 1286, 1220, 1194, 1177, 1160, 5 1092, 1077, 1035, 883, 833 cm"1. F. (E)-4-[[2-[1-(4-Fluorophenyl)-3-methyl-2 -naphthaleny 1 ] ethenyl ] hydroxyphos -phinyl]-3-hydroxy-butanoic acid, 10 dilithium salt The Part E diester (1.1 mmol, 0.50 g) was stirred under argon in dioxane (10.45 ml) and treated with IN LiOH (3.3 mmol, 3.3 ml). The reaction mixture was heated in a 70°C oil bath for 15 45 minutes. The resulting white slurry was dissolved in ^100 ml 9:1 H20/Me0H and rotavapped to dryness at 35°C. The white solid was pumped under high vacuum for 1 hour, then redissolved in 100 ml 9:1 H20/Me0H and rotavapped to a volume of 20 ^8 ml. This turbid solution was applied directly to an HP-20 chromatography column (17.5 cm x 2.5 cm, equilibrated with H20) and eluted with 250 ml of ^0, followed by 45:55 Me0H/H20. Fractions were collected every 1.3 minutes (^10 ml). 25 Product fractions were combined, rotavapped at 35 °C, redissolved in H20, lyophilized 16 hours and pumped under high vacuum over ?205 for 16 hours to afford 0.449 g, 1.02 mmol, 93% yield of the title dilithium salt as a white lyophilate. 30 TLC:Silica gel, PMA Rf=0.49 7:2:1 (n-C3H?0H/NH40H/H20) 22 4 7 HXlOb -303- 1H NMR:(400 MHz, D20) O 6 7*73 <d' 1H' J=8-06 Hz) 7.64 (s, 1H) 7.43-7.39 (m, 1H) 5 7.25-7.13 (m, 4H) 7.05-6.95 (ra, 3H) 0 5.62 (dd, 1H, J=17.96 Hz, J=21.2 Hz) ' 2.43 (s, 3H) 2.38 (dd, 1H, J=4.03 Hz, J=15.39 Hz) 10 2.22 (dd, 1H, J=9.16 Hz, J=15.39 Hz) 1.59-1.51 (m, 2H) Mass Spec:FAB m/e 429 (M+H) + , 435 (M+Li)+, 441 (M+2Li)+ IR:(KBr) 15 3431 (br), 1603, 1593,- 1511, 1494, 1423, 1221, 1158, 1050 cm"1 Anal calcd for C23H20FO5PLi2•0.87 moles H20 M.W.= 455.94: C, 60.60; H, 4.80; F, 4.17; P, 6.79 Found: C, 60.60; H, 4.73; F, 4.24; P, 6.82 20 Example 61 (S)-4-[[2-[1-(4-Fluorophenyl)-3-methyl-2-naphth-alenyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt 25 A. (S)-3-[[(l,l-Dimethylethyl)diphenyl- silyl]oxy]-4-[[2-[1-(4-fluorophenyl)-3-methyl-2-naphthalenyl]ethynyl]methoxy-phosphinyllbutanoic acid, methyl ester The Example 59 Part J acetylenic 30 phosphinate (0.974 mmol, 0.675 g) was dissolved in methanol (14.3 ml). Argon was bubbled through this solution for 10 minutes, then 10% Pd/C (0.270 g) was added and the reaction mixture was shaken i.Z 4 7 HXlOb -304- on a Parr hydrogenator at 40 psi H2 for 24 hours. The reaction mixture was filtered through a celite pad, washed through with methanol, and the filtrate evaporated in vacuo to afford a white foam. The product was purified via flash chromatography (50 mm diameter column, 4.5" Merck silica gel, 70% EtOAc/hexane eluent, 2"/min flow rate) to afford 0.556 g (0.798 mmol, 82% yield) of the title saturated phosphinate as a white foam. Elution of the column with methanol afforded an additional 0.101 g, (0.145 mmol, 15%) of product. TLC:Silica gel, PMA Rf=0.24 60% EtOAc/hexane XH NMR:(270 MHz, CDCl3) 6 7.78-7.14 (aromatic, 19H) 4.44 (m, 1H) 3.61 (s, 3H) 3. 35&3.23 (2 x d, 3H, J=10.6 Hz) 2.92-2.83 (m, 1H) 2.63-2.54 (m, 3H) 2.21-1.27 (m, 4H) 2. 45&2.42 (2 x s, 3H) 1.00 (s, 9H) Mass Spec: CI m/e 697 (M+H)+' IR:(CHClg solution) 3028, 3019, 3007, 2997, 2953, 2933, 2859, 1735, 1510, 1497, 1472, 1463, 1439, 1428, 1378, 1364, 1314, 1236, 1197, 1157, 1142, 1112, 1091, 1073, 1065, 1043, 823 cm™1. 2 47 HXlOb -305- B. (S)-4-[[2-[l-(4-Fluorophenyl)-3-methyl- 2-naphthalenyl ] ethyl ] methoxyphosphinyl ] ■ 3-hydroxybutanoic acid, methyl ester The Part A silyl ether (0.775 mmol, 0.540 5 g) was stirred under argon in 9.45 ml of dry THF and treated with glacial acetic acid (3.10 mmol, 0.186 g, 0.177 ml), followed by dropwise addition of tetrabutylammonium fluoride (2.33 mmol, 2.1 ml of a 1.1 M solution in THF). The reaction mixture 10 was stirred at room temperature for 16 hours. The reaction mixture was quenched with 30 ml of ice water and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The organic extracts were combined, washed once with saturated 15 NaHCOg (aqueous), one time with brine, dried over MgSO^, filtered and evaporated in vacuo. Initial purification via flash chromatography (40 mm diameter column, 6" Merck silica gel, 4% MeOH/CH2Cl2 eluent, 2"/min flow rate afforded 0.40 20 g of a white solid. This solid was triturated from 100% hexane, filtered and pumped under high vacuum (8 hours) to afford 0.317 g (0.691 mmol, 89% yield) of the title hydroxyphosphinate as a white solid, m.p.=120-122°C. 25 TLC:Silica gel Rf=0.12 2% MeOH/CH2Cl2 O LH NMR:(270 MHz, CDCl3) 6 7.76 (d, 1H, J=7.9 Hz) 7.69 (s, 1H) 7.42-7.16 (m, 7H) 30 4.42&4.26 (2 x m, 1H) 3.92&3.84 (2 x d, 1H, J=3.16 Hz) 3.72 (s, 3H) ; r, 224 7 HXlOb -306- 3.58&3.54 (2 x d, 3H, J=3.69 Hz) 0 2.89-2.76 (m, 2H) 2.56 (s, 3H) 2.63-2.41 (m, 2H) 5 1.92-1.61 (m, 4H) Mass Spec:CI m/e 459 (M+H)+ Q IR: (KBr) 3428 (br), 3287 (br), 3064, 3050, 3017, 2989, 2952, 2921, 1737, 1603, 1510, 1497, 1458, 1438, 10 1234, 1221, 1191, 1175, 1159, 1042, 826 cm"1. C. (S)-4-[[2-[1-(4-Fluorophenyl)-3-methyl- 2-naphthalenyl ] ethyl ] hydroxyphosphinyl ] ■ 3-hydroxybutanoic acid, dilithium salt 15 The Part B diester (0.687 mmol, 0.315 g) was stirred under argon in dioxane (6.9 ml). The solution was treated with IN LiOH (2.06 mmol, 2.06 ml). The reaction mixture was heated in a 70°C oil bath for 45 minutes. The reaction mixture was 20 cooled to room temperature. The solvents were removed on' the rotavap at 35°C and the resulting, white solid pumped under high vacuum for 1 hour. Then, the solid was dissolved in ~8 ml of distilled H20 and applied to an HP-20 25 chromatography column (16 cm x 2.5 cm equilibrated with H20). The column was eluted with 250 ml of H20 followed by 45:55 MeOH/H20. Fractions were collected every 1.4 minutes (~10ml). Product fractions (37-47) were combined, evaporated on the 30 rotavap at 35°C, lyophilized 16 hours, and pumped under high vacuum over P20g for 8 hours to afford 0.286 g (0.647 mmol, 94% yield) of the title dilithium salt as a white lyophilate. o o G mob 22 4 7 3 4 TLC: silica gel, PMA Rf=0.42 7:2:1 . (n-C3H?0H/NH40H/H20) "^H NMR: (400 MHz, D20) 6 7.82 (d, 1H, J=8.06 Hz) 5 7.76 (s, 1H) 7.46-7.42 (m, 1H) 7.30-7.25 (m, 3H) 7.18-7.13 (m, 3H) 4.06 (m, 1H) 10 2.72-2.66 (m, 2H) 2.54 (s, 3H) 2.34 (dd, 1H, J=4.4 Hz, J=15.22 Hz) 2.22 (dd, 1H, J=8.43 Hz, J=15.02 Hz) 1.59-1.51 (m,. 2H) 15 1.44-1.39 (m, 2H) Mass Spec: FAB m/e 443 (M+H)+ IR:(KBr) 3451-3426 (br), 3151, 3124, 1620, 1593, 1509, 1439, 1422, 1403, 1218, 1159, 1050 cm"1. 20 Anal Calcd for C25H22F05PLi2*0.60 moles H20 M.W. =453.09: C, 60.96; H, 5.16; F, 4.19; P, 6.83 Found: C, 60.96; H, 5.29; F, 4.12; P, 6.82 Example 62 25 4-[[3-[4'-Fluoro-3,31,5-trimethyl[1,1'-biphenyl]-2-' yl]propyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt A. 3-[4'-Fluoro-3,315-trimethyl[1,1'-biphenyl]-2-yl]-2-propenoic acid, 30 ethyl ester Sodium hydride (4.96 mmol, 0.119 g, 0.149 g of an 80% mineral oil dispersion) was washed under argon once with hexane and dried under an argon r n V HXlOb -308- O 22 4 7 stream. Then, the NaH was stirred under argon in dry THF (9.1 ml). This suspension was cooled to 0°C and treated dropwise (5 minutes) with a solution of triethylphosphonoacetate (4.96 mmol, 5 1.11 g, 0.983 ml) in dry THF (2.2 ml). The resulting clear solution was stirred at 0°C for 15 (3) minutes, then warmed to room temperature and stirred for 30 minutes. Finally, a solution of Example 1 Part C aldehyde (4.13 mmol, 1.0 g) in dry 10 THF (2.5 ml) was added dropwise (8 minutes). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with H20 and the aqueous layer extracted 2 times with EtOAc and 2 times with Et20. The organic extracts were 15 combined, washed once with brine, dried over MgSO^, filtered and evaporated in vacuo. The product was purified via flash chromatography (50 mm diameter column, 6" Merck silica gel, 6% EtOAc/hexane eluent, 2"/min flow rate) to afford 20 1.19 g (3.79 mmol, 92% yield) of the title vinylic (^) • ester as a pale yellow foam. TLC:Silica gel, PMA R^=0.22 4% EtOAc/hexane 1H NMR (270 MHz, CDC13) 6 7.64 (d, 1H, J=16.35 Hz) 25 7.09-6.93 (m, 5H) 5.81 (d, 1H, J=16.35 Hz) 4.17 (q, 2H, J=7.12 Hz) 2.42 (s, 3H) 2.33 (s, 3H) 30 2.28 (s, 3H) 1.25 (t, 3H, J=7.12 Hz) Mass Spec: CI m/e 313 (M+H)+ a o HXlOb -309- 22 4 7 3 4 B. 41-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-butanoic acid, ethyl ester The Part A vinylic ester (3.68 mmol, 1.15 ; 5 g) was dissolved in absolute EtOH (36 ml). Argon was bubbled through the solution for 10 minutes. • O 10% Pd/C (230 mg) was added and H2(g) was bubbled through the solution for 10 minutes. The reaction mixture was stirred under an atmosphere of H2 for 10 2 hours. The reaction mixture was diluted with EtOH and filtered through a V Celite pad in a 60 ml fritted funnel. The Celite was washed with EtOH. The filtrate was evaporated in vacuo to \ afford 1.12 g (3.56 mmol, 97% yield) of the title 15 saturated ester as a white solid. TLC:Silica gel, PMA Rf=0.29 5% EtOAc/hexane j 1H NMR (270 MHZ, CDC13) j 5 7.09-6.97 (m, 4H) 6.84 (s, 1H) 20 4.06 (q, 2H, J=7.12 Hz) j O • 2.90-2.84 (m, 2H) ; 2.37 (s, 3H) : 2.30 (2 x s, 6H) 2.32-2.27 (m, 2H) j 25 1.20 (t, 3H, J=7.12 Hz) \ O Mass Spec: CI m/e 315 (M+H)+ C. 41-Fluoro-3,3',5-trimethyl[1,11- I biphenyl 1-2-propanol ) 30 Lithium aluminum hydride (3.5 mmol, 0.133 | g) was stirred under argon in dry Et20 (3.5 ml). This suspension was cooled to 0°C and treated . dropwise (8 minutes) with a solution of the Part B G HXlOb -310- I , • V J 22 4 7 10 ester (3.5 mmol, 1.1 g) in dry Et20 (3.5 ml). The reaction mixture was stirred at 0°C for 15 minutes, then warmed to room temperature and stirred for- 45 minutes. The mixture was again cooled to 0°C and treated dropwise with 0.133 ml of H20, followed by 0.133 ml of 15% NaOH and finally 0.399 ml of H20. The suspension was warmed to room temperature over 30 minutes. The resulting white powdery solid was filtered and washed with dry Et20. The filtrate was concentrated, azeotroped once with benzene and stripped in vacuo to afford 0.950 g of alcohol which was purified via flash chromatography (50 mm diameter column, 6" Merck silica gel, 35% 15 EtOAc/hexane eluent, 2"/min flow rate) to afford 0.906 g (3.33 mmol, 95% yield) of the title alcohol as a colorless oil. TLC:Silica gel, PMA Rf=0.18 20% EtOAc/Hexane XH NMR (270 MHz, CDC13) 20 6 7.08-6.93 (m, 4H) Q 6.82 (s, .1H) 3.45-3.40 (m, 2H) 2.60-2.54 (m, 2H) 2.34 (s, 3H) 25 2.28 (2 x s, 6H) 1.63-1.52 (m, 2H) Mass Spec: CI m/e 273 (M+H)+ D. 2-(3-Bromopropyl)-4'-fluoro-3,3',5- 30 trimethylF1,1'-biphenyl 1 A solution of triphenylphosphine (10.1 mmol, 2.65 g) in dry THF (27.5 ml) was cooled to 0°C and treated dropwise with a solution of carbon 2T%7 tetrabromide (10.71 mmol, 3.55 g) in dry THF (5.5 ml). The resulting yellow/white slurry was stirred at 0°C for 2 hours. The complex was treated dropwise with a solution of the Part C alcohol (4.04 mmol, 1.1 g) in dry THF (8.2 ml). The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred 16 hours. The reaction mixture was diluted with Et20, filtered through a fritted funnel and the precipitate washed with Et20. The filtrate was washed once with brine, dried over MgS04, filtered, and evaporated in vacuo. The product was purified via flash chromatography (50 mm diameter, 6" Merck silica gel, 2% EtOAc/hexane eluent, 2"/min flow rate) to afford 1.35 g (4.05 mmol, 100% yield) of the title bromide as a pale yellow oil. TLC:Silica gel, PMA Rf=0.22 100% hexane LH NMR (270 MHz, CDC13) 6 7.07-6.99 (m, 4H) 6.82 (s, 1H) 3.22 (m, 2H) 2.69-2.63 (m, 2H) 2.36 (s, 3H) 2.30 (s, 3H) 2.28 (s, 3H) 1.90-1.80 (ia, 2H) Mass Spec: CI m/e 235 (M+H)+ _HXlOb -312- 22 4 7 34 E. [3-[4'-Fluoro-3,3',5-trimethyl[1,11 -0* biphenyl]-2-yl]propyl]phosphonic acid, dimethyl ester The Part D bromide (3.88 mmol, 1.3 g) was 5 stirred under argon in trimethylphosphite (38.8 ml). The reaction mixture was heated to reflux in 0! a 135°C oil bath for 36 hours. The excess (CHgOJ^P was removed via short path distillation and the residue pumped under high vacuum at 100°C for 1 10 hour. The resulting yellow oil was subjected to flash chromatography purification (50 mm diameter column, 6" Merck silica gel, 85% EtOAc/hexane eluent, 2"/min flow rate) to afford 1.13 g (3.10 mmol, 80% yield) of the title dimethylphosphonate 15 as a colorless oil. TLC:Silica gel, PMA, Rf=0.28 100% EtOAc 1H NMR (270 MHz, CDC13) 6 7.08-6.97 (m, 4H) 6.81 (s, 1H) 20 3.65 (d, 6H, J=ll Hz) Q 2.63-2.56 (m, 2H) 2.34 (S, 3H) • 2.30 (2 x s, 3H) 2.28 (s, 3H) 25 1.68-1.50 (m, 4H) Mass Spec: CI m/e 365 (M+H) F. [3-[41-Fluoro-3,31,5-trimethyl[1,11-biphenyl]-2-yl] propyl.] phosphonic 30 acid, monomethyl ester The Part E phosphonate (3.43 mmol, 1.25 g) was stirred under argon in dioxane (8.23 ml). This solution was treated with IN LiOH (5.15 mmol, n HXlOb -313- 22 4 7 34" n 5.15 ml) and heated in a 95°C oil bath. After 1 hour, an additional 3.43 mmol of LiOH were added and the reaction mixture again heated to 95°C for 3.5 hours. The reaction mixture was cooled to 5 room temperature. The solvents were removed in vacuo. The white solid residue was diluted 0) with 25 ml of H20, the slurry cooled to 0°C and acidified to pH=l with 5% HCl (aqueous). The aqueous layer was extracted 4 times with EtOAc. 10 The organic extracts were combined, dried over MgSO^, filtered, and the filtrate concentrated. The residue was azeotroped 2 times with benzene and the resulting viscous oil pumped under high vacuum for 4 hours to afford 1.18 g (3.37 mmol, 15 98% yield) of the phosphonate mono-methyl ester as a yellow oil. TLC:Silica gel, PMA, Rf=0.46 10:1:1 CH2Cl2/MeOH/CH3C02H XH NMR (270 MHz, CDCl3) 20 5 7.06-6.95 (m, 4H) Q 6.81 (s, 1H) 3.56 (d, 3H, J=ll Hz) 2.62-2.53 (m, 2H) 2.32 (s, 3H) 25 2.27 (2 x s, 6H) O 1.69-1.48 (m, 4H) Mass Spec: FAB m/e 351 (M+H)+ G. 4-[[3-[41-Fluoro-3,31,5-trimethyl[1,11 -3 0 biphenyl ] -2 -yl ] propyl ] methoxyphosphinyl ] - 3-oxobutanoic acid, methyl ester The Part F phosphonate monoester (3.22 mmol, 1.13 g) was stirred under argon in dry HXlOb -314- 22 4.7 3.4 CH2CI2 (12.9 ml). This solution was treated dropwise (8 minutes) with TMSDEA (6.44 mmol, 0.918 g, 1.20 ml freshly distilled). This solution was stirred at room temperature for 1.5 hours. The 5 volaties were removed in vacuo (venting to argon). The residue was azeotroped once with 70 0 ml of dry benzene and evaporated in vacuo (venting to argon). Finally, the residue was pumped under high vacuum for 50 minutes. Then, the residue was 10 stirred under argon in dry CH2C12 (12.9 ml). Two drops of dry DMF were added and the solution cooled to 0°C and treated dropwise (8 minutes) with oxalyl chloride (3.70 mmol, 0.470 g, 0.323 ml). This reaction mixture was stirred at 0°C for 15 20 minutes, then warmed to room temperature and stirred for 1-3/4 hours. The volatiles were removed, the residue azeotroped and pumped under high vacuum as above. The rust colored oil was then stirred under argon in dry THF (9-0 ml). 20 This solution was cooled to -78°C and maintained at -78°C as it was added dropwise (20 minutes) to a -78°C THF solution of the dianion of methylacetoacetate generated in the following manner: Sodium hydride (4.85 mmol, 0.116 g, 0.145 25 g of an 80% mineral oil dispersion) was washed once with hexane and dried under a stream of argon. The solid was then stirred under argon in dry THF (7.1 ml )• and this suspension was cooled to 0°C. A solution of methyl acetoacetate (4.36 30 mmol, 0.506 g, 0.471 ml) in dry THF (3.6 ml) was added dropwise (8 minutes) and the resulting clear solution stirred at 0°C for 25 minutes. Then, the reaction mixture was treated dropwise (10 minutes) -3is- 2 7 3 with n-BuLi (4.04 mmol, 1.62 ml of a 2.5 M solution in hexane, Aldrich). The resulitng yellow solution was stirred at 0°C for 35 minutes, then cooled to -78°C and treated dropwise (20 min) with the -78°C THF solution of the phosphonochloridate formed above. The reaction mixture was stirred at -78°C for 1 hour, then quenched with saturated NH4C1 (aqueous) (45 ml) and warmed to room temperature. The mixture was diluted with H20 (45 ml) and EtOAc. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, washed once with saturated NaHC03 (aqueous) and once with brine, dried over MgS04, filtered and evaporated in vacuo to afford 2.0 g of a rust oil. The product was isolated via flash chromatography (40 mm diameter column, 35:1) Merck silica gel, 100% EtOAc to 5% MeOH/CH2Cl2 eluent, 2 "/min flow rate to afford 0.220 g (0.491 mmol, 15% yield) of the title p-ketophosphinate as a rust oil. TLC: Silica gel, PMA Rf=0.19 100% EtOAc ■'•H NMR (270 MHz, CDC13) 6 7.08-6.98 (m, 4H) 6.81 (s, 1H) 3.73 (s, 3H) 3.65 (d, 3H, J=ll Hz) 3.64 (s, 2H) 3.10 (dd, 2H, J=5.27 Hz, J= =17.41 Hz) 2.67-2.57 (m, 2H) 2.35 (s; 3H) 2.30&2.28 (2 x s, 3H) 2.29 (s, 3H) HXlOb -316- 22-47 3-4 1.72-1.56 (m, 4H) Mass Spec: CI m/e 449 (M+H) + H. 4-[[3-[4'-Fluoro-3,3 *,5-trimethyl[1,11 -b ipheny 1 ] -2 -y 1 ] propyl ] methoxypho sphiny 1 ] - 3-hydroxybutanoic acid, methyl ester The Part G 0-ketophosphinate (0.223 mmol, 0.10 g) was stirred under argon in dry THF (1.9 ml). This solution was cooled to 0°C and then treated with NaBH4 (0.223 mmol, 0.008 g), followed by dropwise addition of MeOH (0.194 ml, dried over 4A mol sieves). The reaction mixture was stirred at 0°c for 1 hour, then quenched with acetone (0.194 ml) followed by 0.10 g of CC-4 silica gel (Mallinckrodt). The suspension was stirred as it was warmed to room temperature, then filtered through a fritted funnel. The silica was washed with EtOAc. The filtrate was evaporated in vacuo to afford 0.108 g of a golden oil. Two reaction products were isolated via flash chromatography (10 mm diameter column, 35:1 Merck silica gel, 4% MeOH/CH2Cl2 eluent, 2"/min flow .rate). The desired title p-hydroxyphosphinate was obtained in 58% yield (0.058 g, 0.129 mmol) as a pale yellow oil. Also obtained were 0.019 g (0.043 mmol 20% yield) of the 1,3-butandiol phosphinate. TLC:Silica gel PMA Rf =0.19 3.5% Me0H/CH2Cl2 1H NMR (270 MHZ, CDC13) 6 7.08-6.98 (m, 4H) 6.82 (s, 1H) 4.44&4.32 (2 x m, 1H) 3.63 &3.62 (2 x d, 3H, J=10.55 Hz) rrS; HXlOb -317- 22 4 7 34 3.70 (s, 3H) O 2.65-2.50 (m, 4H) 2.35 (s, 3H) 2.30 (2 x s, 3H) 5 2.29 (s, 3H) 1.89-1.76 (m, 2H) Q 1.71-1.59 (m, 4H) Mass Spec: CI m/e 451, (M+H)+ 10 I. 4-[[3-[4*-Fluoro-3,3',5-trimethyl[1,1'- biphenyl ] -2-yl ]propyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt The Part H diester (0.122 mmol, 0.055 g) was stirred under argon in dioxane (2 ml) and 15 treated with IN LiOH (0.366 mmol, 0.366 ml). The reaction mixture was heated in a 80°C oil bath for 45 minutes. The reaction mixture was cooled to room temperature and the solvents were removed on the rotavap. The resulting yellow solid was 20 pumped under high vacuum for 2 hours to afford the (0 title dilithium salt as a yellow solid. TLC:Silica gel, PMA R.£=0.29 8:1:1 CH2Cl2/MeOH/CH3C02H 1I 25 6 30 • NMR (270 MHz ' °2 CO o • -7.05 (m, 4H) 6.80 (s, 1H) 4.13 (m, 1H) 2.54' -2.47 (m, 2H) GO CO CM -2.28 (m, 2H) 2 .30 (s, 3H) 2.22 (s, 3H) 2.20 (s, 3H) 0 HXlOb -318- rs j 22 4 7 34 1.59-1.50 (m, 2H) O- 1.42-1.29 (m, 4H) Example 63 5 [IS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-4-[[2—[8—(2,2— Dimethyl-1-oxobutoxy)decahydro-2-methyl-1-naphtha-lenyl]ethyl]hydroxyphosphinyl]-3-hydroxy butanoic acid, dilithium salt A. [IS-(l<a,2<a,4a<b,8<b,8a<a)]-8-[[(1,1-10 Dimethylethyl)dimethylsilyl]oxy]- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-l- naphthalenemethanol . To dry Et20 (5 ml) at 0°C (ice bath) was added lithium aluminum hydride (132 mg, 1 molar 15 eg) followed by the dropwise addition of [IS—(l<a,2<a,4a<b,8<b,8a<a)]-8-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-1,2,4a,5,6,7,8,8a-octahydro-2-methyl-l-naphthalenecarboxylic, acid, methyl ester, R. L. Funk et al., Tetrahedron Lett. 25, 1655 20 (1984) (1.175 g, 3.47 mmole) in dry Et_0 (5 ml) and C- ) the resulting grey suspension stirred overnight under argon at room temperature. The mixture was quenched by the sequential dropwise addition of H20 (130 |jl), 15% NaOH (130 (jl) and H20 (390 mD-25 Precipitated salts were removed by filtration through anhydrous MgSO^ over packed Celite. Evaporation in vacuo gave 1.112 g of a clear oil which was purified by flash chromatography on silica gel eluting with (95:5) Hexane-EtOAc to give 30 902 mg (85.7%) of desired title alcohol as a clear oil which crystallized on standing, m.p. = 79-81°C. TLC (9:1) Hexane-EtOAc, Rf=0.21. w ■ HXlOb n -319- 22 4 7 3 4 Anal Calcd for C1QH3402Si: C, 69.61; H, 11.04 Found: C, 69.64; H, 11.04 1T 6 10 15 H NMR (CDCl,) 0.00 (s, 6H) 0.82 (s, 9H) 0.83 (d, 3H) 0.94-1.05 (m, 2H) 1.18 (s, 1H) 1.2-1.42 (m, 2H) 1.67 (m, 3H) 1.89 (m, 1H) 2 .2 5&2 .3 7 (2H, 2 multiplets) 3.42 (bt, 1H) 3.80 (dd, 1H) 3.93 (bs, 1H) 5.29 (d, 1H) 5.48 (dq, 1H) ppm. B. [lS-(l<a,2<a,4a<b,8<b,8a<a)]-8-[[(1,1-20 DimethylethylJdimethylsilyl]oxy]- (Q) 1,2,4a,5, 6,7,8,8a-octahydro-2-methyl-l- naphthalenecarboxaldehyde A solution of Dess-Martin periodinane (895 mg, 2.11 mmole) in dry CH2C12 (6 ml) was treated 25 with dry t-CAHQ0H (200 |jl) and the white suspension stirred under argon at room temperature for 15 minutes. A solution of the alcohol (596 mg, 1.92. mmole) in dry CH2C12 (6 ml) was added dropwise over 5 minutes and the mixture stirred under argon 30 at room temperature for 20 minutes. The mixture was added to a solution of sodium thiosulfate (2.12 g) in 1.0 N NaHCO^ (12 ml) and the resulting mixture stirred until, all solids dissolved. The -320- HXlOb 4 7 3 41 © ■V ' C Q 10 organic phase was washed with saturated NaHCOg, HjO and brine then dried over anhydrous Na2SO^ and evaporated in vacuo to give 1.005 g of a colorless oil. The crude product was combined with a smaller run (1.306 g total) and then purified by flash chromatography on silica gel eluting with (98:2) hexane-EtOAc. Product fractions were evaporated in vacuo to give 667 mg (75.7%) of desired title aldehyde as a colorless oil. TLC (7:3) Hexane-EtjO, Rf=0.70 PMA 1H NMR (CDC13): 5 0.07 (s, 3H) 0.00 (s, 3H) 0.85 (s, 9H) 15 0.89 (d, 3H) 0. 93-1.10 (m, 2H) 1. 38-1.52 (m, 2H) 1. 58-1.78 (m, 4H ) 2.31 (m, 1H) 20 2.66 (m, 1H) 2.78 (m, 1H) 4.30 (s, 1H) 5.40 (d, 1H) 5.50 (m, 1H) 25 9.74 (d, 1H) C. [lS-(l<a,2<a,4a<b,8<b,8a<a)]-l-(2; 2- Dibromoethenyl)-8-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-1,2,4a,5,6,7,8,8a- 30 octahydro-2-methylnaphthalene A -15°C (salt/ice bath) solution of the Part B aldehyde (667 mg, 2.16 mmole) and triphenylphosphine (1.7 g, 6.48 mmole) in dry HXlOb -321- 22 4 7 3 f CH2C12 (10 ml) was treated dropwise over 5 minutes with a CH2Cl2 (5 ml) solution of carbon tetrabromide (1.7 g, 6.48 mmole) and the deep reddish brown mixture stirred under argon at -15°C for 30 minutes, at 0°C for 2 hours and finally overnight at room temperature. The mixture was recooled to 0°C, treated with additional triphenylphosphine (567 mg, 216 mmol) followed by CBr4 (358 mg, 1.08 mmole) and stirred for 4 hours at room temperature. The mixture was quenched with saturated NaHC03 (10 ml), diluted with CH2CI2, the organic phase filtered through sintered glass, washed with saturated NaHCOg and brine, dried over anhydrous Na2S04 and evaporated in vacuo to give 3.578 g of a brown solid. The crude product was purified by flash chromatography on silica gel eluting with neat hexanes. Product fractions were evaporated to give 677 mg (67.3%) of pure title vinyl dibromide as a colorless oil. TLC (9:11 Hexane-acetone, R^=0.73 UV+PMA). 1h nmr (cdc13) 6 0.08&0.10 (2 singlets, 6H) 0.85 (d, 3H) 0.90 (s, 9H) 0.98 (m, 2H) 1.25-2.52 (m, 5H) 1.74 (m, 1H) 1.82 (m, 1H) 2.39 (m, 1H) 2.56 (m, 1H) 2.66 (m, 1H) 3.95 (s, 1H) 5.48 (d, 1H) o HXlOb -322- o o 22 4.7 5$ 5.52 (m, 1H) 6.37 (d, 1H) ppm. D. [lS-(l<a,2<a,4a<b,8<b,8a<a)]-8-[[(1,1-5 Dimethylethyl)dimethylsily1]oxy]-1- ethynyl-1,2,4a,5,6,7,8,8a-octahydro-2- methylnaphthalene A -78°C (dry ice/acetone) solution of the Part C vinyl dibromide (495 mg, 1.07 mmole) in dry 10 THF (6 ml) was treated dropwise over 5 minutes with a 1.6 M n-BuLi in hexanes solution (1.34 ml, 2.14 mmole) and the. clear, colorless mixture stirred for 30 minutes under argon at -78°C. The mixture was quenched at -78°C by addition of 15 saturated NH^Cl (5 ml), allowed to warm to room temperature, diluted with EtOAc, the organic phase washed with brine, dried over anhydrous Na2S04 and evaporated in vacuo to give 291 mg (89.6%) of crude title acetylene as a colorless oil. 20 TLC hexanes Rf=0.43, UV + PMA Q XH NMR (CDC13) 6 0.08&0.12 (2 singlets, 6H) 0.90 (s, 9H) 0.99 (m, 1H) 25 1.09 (d, 3H) 1.19 (m, 1H) 1.46 (m, 2H) 1.74 (m, 3H) 2.12 (d, 1H) 30 2.30 (m, 1H) 2.41 (m, 1H) 2.71 (m, 1H) 4.37 (m, 1H) -323 5.38 (d, 1H) 5.55 (m, 1H) ppm. E. (S)-4-(Chloromethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]-oxylbutanoic acid, methyl ester Phosphonochloridate was prepared from the Example 25 Part B dicyclohexylamine salt by the following procedure. The free acid was regenerated by partitioning the dicyclohexyl amine salt (1.3 g, 2.05 mmole) between EtOAc and 5% KHS04, the organic layer was washed with 5% KHSO^ (4 times) and brine then dried over anhydrous Na2S04 and evaporated in vacuo to give the free acid as a clear viscous oil. The phosphonic acid monomethyl ester (2.05 mmole) was taken up in dry CH2C12 (5 ml), treated with distilled N,N-diethyltrimethylsilylamine (515 Ml, 4.1 mmole) and the clear, colorless solution stirred at room temperature under argon for 1 hour. Excess reagent and solvent was removed in vacuo, the residual oil chased with benzene (2 x 10 ml). The crude silyl ester (^2.05 mmole) in dry CH2C12 (5 ml) and dry DMF (1 drop) was cooled to 0°C (ice bath) and treated dropwise with distilled oxalyl chloride (195 pi/ 2.26 mmole) and the yellow mixture stirred under argon at 0°C for 15 minutes and at room temperature for 45 minutes. The mixture was evaporated in vacuo, chased with dry benzene (2 x 10 ml) to give crude title phosphonochloridate as a viscous yellow oil. HXlOb 22 4 7J 4' -324- HXlOb 224 7 3 4 F. [lS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-4-[[[8— C[(1,1-dimethylethyl)dimethyl-silyl]oxy]-1,2,4a,5,6,7,8,8a-octahydro-2-methyl-l-naphthalenyl] ethynyl] -methoxyphosphinyl]-3-[[(1,1-dimethyl-ethyl)diphenylsilyl]oxy]butanoic acid, methyl ester A -78°C solution of the Part D acetylene (356 mg, 1.17 mmole) in dry THF (5 ml) was treated dropwise with a 1.6 M n-BuLi in hexanes solution (730 pi, 1.17 mmole) and the clear mixture stirred under argon at -78°C for 30 minutes. The acetylenic anion was then transferred via cannula dropwise over 15 minutes to a -78°C solution of the Part E phosphonochloridate in dry THF (6 ml). The yellow mixture was stirred 30 minutes at -78°C then quenched by dropwise addition of saturated NH4C1 (5 ml) and allowed to warm to room temperature. The mixture was partitioned between EtOAc and H20, the organic phase washed with brine, dried over anhydrous Na2S04 and evaporated in vacuo to give 1.282 g of a pale yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (7:3) hexane-EtOAc. Product fractions were evaporated to give 624 mg (72.4%) of title acetylenic phosphinate as a colorless glass. TLC (7:3) Hexane-acetone, R£=0.49, UV + PMA. HXlOb -325- _ 22 fylJf G. [IS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-4-[ [2-[8-[[(1,1-Dimethylethyl)dimethylsilyl]-oxy]decahydro-2-methyl-l-naphthalenyl]-ethyl]methoxyphosphinyl]—3-[[(1,1— dimethylethyl)diphenylsilyl]oxy]butanoic acid, methyl ester A solution of Part F acetylene phosphinate (498 mg) in CHgOH (6 ml) was treated with 10% Pt/C (200 mg) and the black suspension shaken on a Parr apparatus under H2 (40 psi) for 48 hours. The catalyst was removed by filtration through Celite, the reaction mixture charged with new catalyst (150 mg) and shaken on the Parr apparatus under H2 (40 psi) for an additional 24 hours. Catalyst was removed by filtration through Celite and the filtrate evaporated in vacuo to give 448 mg of a clear glass. The crude product was purified by flash chromatography on silica gel eluting with (8:2) Hexane-EtOAc. Product fractions were evaporated in vacuo to give 334 mg (66.5%) of title compound as a colorless glass. TLC (7:3) EtOAc-Hexane, 3 diastereomers as one spot=0.42, Rf 4th diastereomer as one spot=0.49, UV + PMA. H. [IS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-4- [[2-(Decahydro-8-hydroxy-2-methyl-l-naphthalenyl)ethyl]methoxyphosphinyl] -3-[[(1,1-dimethylethyl )diphenylsilyl]- oxy]butanoic acid, methyl ester A solution of Part G compound (248 mg, 0.334 mmole) in CH^CN (4 ml) was treated with 48% HF in H20 (36 pi, 1 mmole) and the mixture stirred -326- 22 for 6.5 hours under argon at room temperature. The mixture was partitioned between EtOAc and saturated NaHCO^, the organic phase washed with brine, dried over anhydrous Na2SO^ and evaporated in vacuo to give 227 mg of a colorless glass. The crude product was purified by flash chromatography on silica gel eluting with (4:1) Hexane-EtOAc followed by neat EtOAc. Product fractions were evaporated in vacuo to give 159 mg (75.8 %) of pure title mono alcohol as a colorless oi!L. TLC (7:3) Acetane-Hexane, Rf=0.5 (UV (weak) + PMA. I. [IS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-3- [[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4— [[2—[S—(2,2 -dimethyl -1-oxobu.toxy) -decahydro-2-methyl-l-naphthalenyl]ethyl]-methoxyphosphinyl]butanoic acid, methyl ester A solution of the Part H alcohol (147 mg, 0.234 mmole) in dry pyridine (1.5 ml) was treated, with 2,2-dimethylbutyryl choride (160 |jl, 1.17 mmole, 5 eq.) followed by 4-dimethylaminopyridine (3 mg, 0.1 eq) and the pale yellow mixture heated at 100°C under argon for 4 hours. The mixture was cooled, partitioned between 1.0 N HCl and EtOAc, the organic phase washed with l.ON HCl (2 times) and brine, dried over anhydrous Na2S04 and evaporated to give 255 mg of a pale, yellow brown oil. The crude product was purified by flash chromatography on silica gel eluting with (55:45) Hexane-EtOAc. Product fractions were evaporated in vacuo to give 112 mg (65.9%) of desired title dimethyl butyryl ester as a colorless oil. HXlOb HXlOb 22 4 7 34 Hexane-acetone, Rf=0.62, UV + PMA. J. [IS-[l<a(R*),2<a,4a<b,8<b, 8a<a]]-4-[[2-[8-(2,2-Dimethyl-1-oxobutoxy)-decahydro-2-methyl-l-naphthalenyl]ethyl]-methoxyphosphinyl]-3-hydroxy-butanoic acid, methyl ester A solution of the Part I silyl ester (130 mg, 0.179 mmole) in THF (2 ml) was treated successively with glacial acetic acid (HOAc) (41 pi, 0.716 mmole) and a 1.1 M (n-C4Hg)4NF solution in THF (490 pi, 0.537 mmole) and the mixture stirred overnight under argon. The mixture was partitioned between EtOAc and 5% KHS04, the organic phase washed with H20 and brine, dried over anhydrous Na2S04 and evaporated in vacuo to give 115 mg of a colorless oil. The crude product was purified by flash chromatography on silica gel eluting with (1:1) hexane-acetone. Product fractions were evaporated in vacuo to give 72 mg (82.4%) of desired title alcohol as a colorless oil. TLC (1:1) Hexane-acetone, Rf=0.20, UV + PMA. K. [lS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-4-[[2-[8-(2,2-Dimethyl-1-oxobutoxy)-decahydro-2-methyl-l-naphthalenyl]ethyl]-hydroxyphosphinyl ] -3-hydroxy-butanoic acid, dilithium salt A solution of Part J alcohol (72 mg, 0.147 mmole) in dioxane (1.5 ml) was treated with 1.0 N LiOH (0.52 ml) and the mixture heated at 55°C (oil bath) under argon for 1.5 hours. The mixture was cooled, diluted with H20, filtered and evaporated HXlOb -328- 224734 in vacuo to an oil. The crude product was chromatographed on HP-20 resin (3 cm bed, 15 nun diameter column) eluting with H20 followed by (70:30) ^O-CH^OH. Product fractions were evaporated in vacuo, dissolved in H20 (20 ml) and lyophilized to give 55 mg (74%) of desired title dilithium salt as a white solid. TLC (8:1:1) CH2Cl2-CH2OH-CH3COOH, Rf=0.05, PMA. Anal Calcd for C23H3g07PLI2+1.78 moles H20 (MW 504.53): C, 54.75; H, 8.50; P, 6.14 Found: C, 54.75; H, 8.64; P, 5.93 Example 64 (S)—4—[[[31 -(4-Fluorophenyl)spiro[cyclopentane-1,1'-[1H]indene]-2-yl]ethynyl]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt A. 3-(4-Fluorophenyl)-lH-indene To a solution of solution of 4-fluorophenyl-magnesium bromide (prepared from 6.43 ml of 4-fluorobromobenzene and 1.71 g of Mg in 50 ml of ether) at room temperature under argon was added dropwise over 40 minutes a solution of 1-indanone (6.61 g, 50 mmole) in dry ether (20 ml). After stirring at room temperature for 1 hour, the reaction was quenched by the dropwise addition of saturated NH4C1 solution (15 ml). The mixture was diluted with Et20, washed with saturated NaCl solution, dried (MgS04) and evaporated. The residue was taken up in glacial acetic acid (15 ml) and refluxed under argon for 30 minutes. The acetic acid was evaporated off and chased twice with toluene. The residue (9.45 g) was purified by flash chromatography on silica gel HXlOb -329- 22 4 7 34 eluting with hexane to give title compound (8.174 g, 78%) as a colorless oil which crystallized on standing,- m.p. 38-40°C TLC (hexane) Rf=0.21. B. 31 -(4-Fluorophenyl)spiro[cyclopentane-l,l'-riH]indene] To a solution of Part A compound (10.676 g, 50.8 mmole) in dry THF (90 ml) at 0°C under argon was added, in portions, solid potassium t-butoxide (12.2 g, 109 mmole).. After stirring at 0°C for 30 minutes, 1,4-dibromobutane (6.50 ml, 101 mmole) was added dropwise. The resulting mixture was allowed to warm to room temperature, stirred for 2 hours, then partitioned between EtOAc-5% KHSO^ (150 ml each). The organic phase was washed with saturated NaCl solution, dried (Na2S04) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with hexane to give title compound (9.43g, 70%) as a colorless oil. TLC (Et20-hexane; 1:9) Rf=0169 (Rf of Part A compound = 0.63). C. 31 -(4-Fluorophenyl)spiro[cyclopentane-!,!'-[ 1H]indene]-2'-carboxaldehyde To a solution of Part B compound (9.30 g, 35.2 mmole) in dry CH2C12 (50 ml) at 0°C under argon was added a 1.0 M solution of TiCl^ in CH2C12 (70 ml, 70 mmole). The resulting dark green solution was treated dropwise with 1,1-dichloromethyl methyl ether (3.50 ml, 38.7 mmole). After stirring at 0°C for 1 hour and at room temperature for 1 hour, the mixture was poured onto cold, saturated NaHCO^ solution. The HXlOb -330- 22 4 7 34 organic phase was separated, dried (Na2S04) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with Et20-hexane (5:95) to give title 5 compound (8.233 g, 80%) as a yellow oil. Crystallization of the oil from hexane gave pure title compound (6.778 g, 66%) as pale yellow crystals, 116-117°C. TLC (Et20-hexane; 15:85) Rf=0.56. 10 Anal Calqd for C2oH17°*": C' 82.17; H, 5.86; F, 6.50 Found: C, 83.13; H, 5.82; F, 6.29 D. 2'-Ethynyl-3'-(4-fluorophenyl)spiro- f cyclopentane-1,11-[1H1indene 15 Tq a solution of potassium t-butoxide (0.672 g, 6.00 mmol) in dry THF (8 ml) at -78°C under argon was added dropwise a solution of dimethyl diazomethylphosphonate (0.960 g, 6.40 mmole, prepared as in J. Org. Chem. 36, 1379 20 (1971)) in THF (4 ml). After stirring at -78°C for 5 minutes, a solution of Part C compound (1.168 g, 4.00 mmole) in THF (8 ml) was added dropwise over 10 minutes. After stirring at -78°C for 3 hours, -45°C for 1.5 hour and at room temperature for 1 25 hour, the mixture was diluted with hexane (50 ml) and washed with 5% KHS04 solution. The organic phase was washed with saturated NaCl solution, dried (Na2S04) and concentrated to a small volume (not to dryness). The yellow solution was flash 30 chromatgraphed on silica gel eluting with hexane. The product containing fractions were combined, treated with butylated hydroxytoluene (BHT) (0.080 g, 0.36 mmole) and concentrated to a small volume HXlOb -331- 11 4 7 34 (5-10 ml) which was used immediately as a solution for the next step. TLC (Et20-hexane; 1:9) Rf=0.57. ^"H NMR (270 MHz, CDC13) using BHT as an internal standard (1.45 ppm, 18H, s) shows the presence of 3.10 mmoles (77.5% yield) of the desired acetylene (3.32 ppm, 1H, s). E. (S)-4-(Chloromethoxyphosphinyl)-3- [[(1,1-dimethylethyl)diphenylsilyl]-oxy1butanoic acid, methyl ester Title phosphonochloridate was prepared from the Example 25 Part B dicyclohexylamine salt (3.44 g, 54.4 mmole) as described in Example 29, Part J using the following guantities; trimethylsilyldiethylamine (1.36 ml, 10.85 mmole), CH2Cl2 (15 ml); oxalyl choride (0.50 ml, 5.73 mmole), DMF (1 drop), CH2C12 (15 ml). F. (S)-3—[[(1,1-Dimethylethyl)diphenylsilyl] oxy] -4- [[[31-(4-fluorophenyl)-spiro[cyclopentane-1,1'-[1H]indene] -2 -yl]ethynyl]methoxyphosphinyl]butanoic acid, methyl ester . The hexane solution of the Part D acetylene (3.10 mmole + 0.36 mmole of BHT) was diluted with dry THF-(15 ml) and cooled to -78°C under argon. The solution was then treated with a 1.6 M solution of n-BuLi in hexane (2.16 ml, 3.46 mmole) dropwise via syringe. After stirring at -78°C for 45 minutes, the anion solution was transferred via cannula to a -78°C solution of Part E phosphonochloridate (54.4 mmole) in dry THF (15 ml). After stirring at -78°C for 1 hour, the reaction was quenched by the HXlOb 2 2 4 7 3 4- dropwise addition of saturated NH^Cl (15 ml) and allowed to warm to room temperature. The mixture was extracted with EtOAc, the extracts washed with 5% KHS04, saturated NaHC03 and saturated NaCl solutions, dried (Na2S04) and evaporated to dryness. The .crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexane (25:75) to give title compound (1.781 g, 80% based on Part D compound) as a pale yellow glass. TLC (acetone-hexane; 1:1) Rf=0.46. G. (S)-4-[[[3'-(4-Fluorophenyl)spiro[cyclo-pentane-1,1'-[1H]indene]-2-yl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester To a solution of Part F compound (1.00 g, 1.39 mmole) in dry THF (5 ml) at room temperature under argon was added glacial acetic acid (0.32 ml, 5-.59 mmole) and a 1.1 M solution of (n-C4Hg)4NF in THF (3.80 ml, 4.18 mmole). After stirring at room temperature for 18 hours, the mixture was diluted with EtOAc (50 ml) washed successively with IN HCl (3 x 30 ml) and saturated NaCl solutions, dried (Na2S04) and evaporated to dryness. The residue was taken up in Et20 (20 ml), cooled in an ice bath and treated with excess etheral diazomethane. The residue obtained by evaporation of the ether was purified by flash chromatography on silica gel eluting with acetone-hexane (3:7) to give title compound (0.595 g, 89%) as a colorless glass. TLC (acetone-hexane; 1:1) =0.29. -333- HXlOb 22 4 7 3 H. (S) -4-[[[3'-(4-Fluorophenyl) spiro-[cyclopentane-1,11 -[1H]indene]-2-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt To a solution of Part G compound (0.580 g, 1.20 mmole) in dioxane (6 ml) at room temperature under argon was added IN LiOH solution (4.2 ml, 4.2 mmole). After stirring at room temperature for 3 hours, the mixture was diluted with acetonitrile (20 ml), the white preciiptate was collected, washed with acetonitrile and dried in vacuo to give crude title product (0.670 g) as a white solid. The crude product was suspended in water (10 ml) and applied to a short pad of HP-20 (15 ml bed volume, 1 inch diameter), eluted with water (300 ml) followed by MeOH (300 ml). The product containing fractions were combined and evaporated to dryness. The solid residue was triturated with acetonitrile to give pure title product (0.550 g, 98%) as a white solid, mp 301-303°C (decomp). TLC (i-C3H?OH-concentrated NH40H-H20; 7:2:1) Rf=0.' HXlOb -334- Ljl Examples 65 to 122 Following the procedures as outlined heretofore and as described in the previous working Examples, the following additional compounds may be prepared. 0 H il i v R-P-CH2-C-CH2-C02-R X OH 1 z 7 ho *89 h -d5d- Vo TO t 'hd ho *99 L*ill qoixH "ON •xa -see- o t1 -3hd2h02hd- "hd eHD tio * L9 O id £ Z Z tho -hd-hd- 'hoo *59" o © SEZD 0- hd -hd- *N0 * ZL "hd hd h so -hd- . O 0=d I s z hd- h d Z ' hd XO * XL o £hd -zhdzhdzhd- 3. HP® *hd-hd "hdo *0l 11 -zhdzhdshd- *r<LL*iZZ E Z hd hd t10 * 69 h *on •xg sT\ O qOTXH -9ee- h zhdzhd h -0 hd- "hd - hd- V h -zhdzhozhd- ho *9 L 0 hd 'SL ho 'bl h -zhdzhd- ho 'ZL £ £ [_*! ZZ h *°n •xa qoixH -Z.EE _ 338- Ex. No. HXlOb 22 4 7 3 4 78. oh c H3C CH3 -CH=CH- H 0 Ex. No. 82. HO 83. NaO 339- CH ch3 ch3 HXlOb 22 4 7 34 -C=C- -C5C- Na 84. CH3° -CH=CH- H 85. ch3o -CH2CH2- NH4 A h 340- Ex. No. R HXlOb 224734 86. HO CH. 87. 0 3 -CH2- K -CH2CH2CH2- ca C-CH H 3 C 88. CH30 /CH 3 V / -CH=CH- Na ^-CH„ 89. H T3 C-CH. H - -CH_- H - 341- Ex. No. HXlOb <.73* R 90. CH30 C -CH=CH- C1 # - 342- HXlOb Ex. No. 22 4 7 3 4- 94. ko O i*H3 c-ch. h - -ch2ch2- k ch. "w c c Ex. No. P 98. LiO " 343- HXlOb i£ 4 1 ch. ch ■ CH, N~< o -c=c- 99. LiO <sxjgr sK i ch / N CH3 CH3 "CH - y*®*\ W-' 100. HO ch. > ch3 -CH„ - o 101. ho CI CI ch . / ch. ch3 -ch2ch2- ehd —t D20eHD £ Z Z hd - hd hd- *VhD OeHD •SOI "hd "hd —hd * -zhd- t1 -3hd3hd- *n -3hd-zho- d3o£hd oh "froi ott *e0i OBN "SOI t ^ % qoixH -m _ •on •xg /I hd — hd h -zhdzhd- jg jg OH * 601 'hd x -zhd3hd- TD ID OS *801 O 'hd / 'hd — hd h -zhdzhdzhd- ID ID OH *101 'hd hd — hd -N h -zhdzhd- oh *901 o L II qoixH -SfrC _ •on Q (3 n V_> O 346- ~H*10b 22 4 7 Ex. No. R Z ' X RX 110. LiO -CH=CH— Li in. ko rvo -ch2ch2- k 112. LiO irv -CH=CH- Li >c JOi ^ f ch 113. CH30 -CH=CH- CH3 © Ex. No. I 114; OH 347- CH. HXlOb 22 47 34 -CH2- H 115. • LiO CH. /CH3 -C=C- CH •CH. Li 116. LiO F CH CH . CH3 -CH2CH2" Li 'CH_ o 117. LiO -CSC- Li 118. LiO /CH3 -CH2CH2- Li ® NCH3 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> iiA±OD -349- © r\ O WHAT WE CLAIM IS: 1. A comDound•having the formula 0 H |l I yr R-P-CHo-C-CHo-C0oR 1 2 | 2 2 X OH. I z wherein R is OE or lower alkoxy; Rx is H or lower alkyl; x is ch2, -ch2ch2-, -ch2ch2ch2-, -ch=ch-., -C=C- or -CH20- (where O is linked to Z); and Z is a hydrophobic anchor which is ? 24734 o /o N __ N A 224734 HXlOb -35 0- 1 o o a o v\ wherein R , R , R and R are the same or different and are each independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl wherein the substituents are as herein defined, or OR^, wherein is H, C?-Ci2 alkanoyl, benzoyl, phenyl, halophenyl,phenyl-lower alkyl, lower alkyl,cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl •wherein the subtituents are as herein defined; where 2 is r -351 - 224734 0 R5 and R5' are the same or different and are E, lower alkyl or OH; O 6 " R is lower alkyl-C or arylC^-; and R6a is lower alkyl', hydroxy, oxo or halogen; g is 0, 1, 2 or 3; -353- HXlOb or * VN K. one of R3 and R4 is and the other is lower alkyl, cycloalkyl or phenyl-(CBL) -, p is 0, 1, 2, 3 or 4; P 13 wherein R is hydrogen, lower alkyl, lower alkoxy, (except t-butoxy), halogen, phenoxy or benzyloxy; R14 is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy; R^4a is hydrogen, lower alkyl, lower alkoxy, or halogen; and 14 14a with the provisos that both R and R must 13 14a be hydrogen when R is hydrogen, R must be 14 hydrogen when R is hydrogen, not more than one of R13 and R14 is trifluoromethyl, not more than one of R13 and R14 is phenoxy and not more than one of R1-3 14 and R is benzyloxy; Q R is hydrogen, alkyl, C3_6 cycloalkyl, C1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R^ is hydrogen, al^yl, ^1-3 alk°xy' trifluoromethyl, fluoro, chloro, phenoxy or -353- HXlOb 224734 9 benzyloxy, with the provisos that R must be Q hydrogen when R is hydrogen, not more than one 8 9 of R and R is trifluoromethyl, not more than 8 9 one of R and R is phenoxy, and not more than 8 9 one of R and R is benzyloxy; R10 and R11 are independently selected from hydrogen, Ci~Ct? alkyl, cycloalkyl, adamantyl-1 or 13 14 14a where R , R and R are as defined above and q=0, 1, 2, 3 or 4; and - Y is 0, S or N-R10; where Z is Ra is H or primary or secondary 1-6C alkyl; R*5 is primary or secondary 1-6C alkyl; or Ra + Rb is (CH2)r or (cis )-CH2-^S<^H-CH2 ; r = 2, 3, 4, 5 or 6; and ^ HXlOb -35^ - R12 is lower alkyl, cycloalkyl or ,13 Jl4a wherein R8, R9, R13, R14 and R14a are as defined, above; where Z is 3 I «■ 8vnv5 16 R~ R wherein R"3 and R4 are as defined above, R15 and R16 are both H, CI, Br, CN, CF_, phenyl,- 17

1-4C alkyl, 2-8C alkoxycarbonyl, -CH,OR or -CH20C0NHRiO; R17 is H or 1-6C alkanoyl; R 18 is Ci—Ci2 alkvl or ohenvl ootionallv substituted by F, CI, Br or 1-4C alkyl; or R15 and R16 taken together are -(CH,) 1Q 70 21 -CH2OCH2-, -CON(R)CO-, or -CON(R )N(R )CO-; S = 3 or 4; 19 R = H, 1-6C alkyl, phenyl or benzyl; and R21 are H, 1-4C alkyl or benzyl; ,20 and X is -CE2~, -CH2CH2- or -CE^CHjCH^, where Z is -355- HXlOb E23a C=C —^ \22 *23a 22 R xs lower alkyl, cycloalkyl, adamantyl-1 or -<CH2)t-<g>. ; t = 1, 2, 3 or 4; R and R are the same or different and are each independently selected from hydrogen, lower alkyl, lower alkoxy (except t-butoxy), halogen, phenoxy or benzyloxy; and 23a with the provisos that R must be . 23 hydrogen when R is hydrogen, not more than one of R23 and R23a is trifluoromethyl, not more than 23 23a one of R and R is phenoxy, and not more than 23 23a one of R and R is benzyloxy; and where X is -CH20- (carbon attached to P and 0 attached to Z), the hydrophobic anchor Z will be -356- HXlOb -<<7? or wherein Rl, r2, R2a an(j R2b are as defined above; and wherein the term "lower alk.yl" throuqhout this claim is as defined on page 35 herein; in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or in salt form. 2. A compound as defined in Claim 1 wherein X is -CH=CH- or -C=C-, R is OH or alkoxy, and Z is

2 3 •R R v. .. JC 4 °r 15 R R R and wherein rl, r2, R2a, r3, r4, rjL0, r15, r16 and and Y are as defined as above. ' 3. The compound as defined in Claim 1 r— having the name (S)-4-[[(E)-2-[4,-fluoro-3/3',5-trimethyl [1,1' -biphenyl ] -2-yl ] ethenyl ] hydroxyphosphinyl ]-3-hydroxybutanoic acid or its dilithium salt; (S)-4-[ [2-[41 -fluoro-3 ;31,5-tr imethyl— [1,1' -biphenyl ] -2-yl ] ethyl ] hydroxyphosphinyl f-3-hydroxybutanoic acid, methyl ester or mono4 or di-alkali metal salts thereof; (S)-4-[[[41-fluoro-3,3',5-trimethyl-[ 1,1' -b iphenyl ] - 2 -y 1 ] e thyny 1 ] me thoxyphosphinyl ] - 224734 HXlOb -357-

3-hydroxybutanoic acid or the methyl ester (~^ thereof; (5Z)-4-[[2-[4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, methyl esters thereof; (S)-4-[[2-[3-(4-fluorophenyl)-l-(l-methyl-ethyl) -lH-indol-2-yl]ethyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl esters; (S)-4-[[2-[[1,1'-biphenyl]-2-yl]ethyl]-methoxyphosphinyl-3-hydroxybutanoic acid, methyl ester;. (S)-4-[[2-[4•-fluoro-3,3',5-trimethyl-[1,1* -biphenyl] -2-yl ] ethyl] hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt; (S)-4-[[2-[4'-fluoro-3,3',5-trimethyl-[1,1* -biphenyl] -2-yl ] ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt; (5Z) -4- [ [2- [41 -fluoro-3,3 1,5-trimethyl-[1,1' -biphenyl ] -2 -yl ] ethenyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt; {S)-4-[[2-[3-(4-fluorophenyl)-l-(l-methyl-ethyl) -lH-indol-2-yl ] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; {S)-4-[[2-[(1,1'-biphenyl]-2-yl]ethyl]-hydroxyphosphinyl]-3-butanoic acid, dilithium^ salt; (S) -4- [ [2- [1- (4-fluorophenyl)-3-(lj^methyl-ethyl)-l-indol-2-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; HXlOb -358- (S)-4-[[2-[l-(4-fluorophenyl)-3-(l-methyl-ethyl) -lH-indol-2-yl ] ethyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (E)-4-[[2—[3—(4—f luorophenyl)-1-(1 -methyl-ethyl) -lH-indol-2-yl ] ethenyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid or its dilithium salt' or methyl ester thereof; 4-[[2-[41-fluoro-3, 31,5-trimethyl[1,11 -biphenyl ] -2 -yl ] ethyl ] hydroxyphosphinyl ] -3 -hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (E)-4-[[2-[41-fluoro-3,31,5-trimethyltl,!1-biphenyl ] -2 -yl ] ethenyl ] hydroxyphosphinyl ] -3 -hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S)-4-[ [ [2,4-dimethyl-6-[(4-fluorophenyl>-methoxy] phenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S)-4-[ [ [2,4-dimethyl-6-[ (4-fluorophenyl)-methoxy ] phenyl ] ethynyl ] hydroxyphosphinyl ] -3 -hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S)-4-[[2-[3,5-dimethyl[1,1*-biphenyl)-2-yl ] ethyl) hydroxyphosphinyl ] -3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S )-4- [ [2- [41 -fluoro-3,5-dimethyl [1,1'-biphenyl ] -2-yl ] ethyl ] hydroxyphosphinyl ] -3-rKvv_ hydroxybutanoic acid of its dilithium salt or methyl ester thereof; b 224734 HXlOb -35*)- (S)-4-[[2- [[1,1'-biphenyl]-2-yl]ethynyl]-hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S)—4—[[2-(5-(4-fluorophenyl)-3-{l-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethynyl]me'thoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[2-[5-(4-fluorophenyl)-3-(l-methyl-• ethyl)-l-phenyl-lH-pyrazol-4-yl]ethynyl]hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt; (E)-4-[[2-[5-(4-fluoropheny1)-3-(1-methy1-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethenyl ] me thoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (E)-4-[[2-[5-(4-fluorophenyl) -3 - (1-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethenyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S)—4—[[2-[5-(4-fluorophenyl)-3-(1-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[2-[5-(4-fluorophenyl)-3-(1-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]hydroxyphosphinyl ]•- 3 -hydroxybutano ic acid, dilithium salt; (S)-4-[[2-[3-(4-fluorophenyl)-5-<l-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[2-[3-(4-fluoropheny1)-5-{1-methyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S)-4-[[2-[3-(4-fluorophenyl)-5-(1-methy1-ethyl)-l-phenyl-lH-pyrazol-4-yi]ethynyl]methoxy- . phosphinyl]-3-hydroxybutanoic acid, methylester; "x * v 224734 HXlOb -360- (S) -4- [ [2-[3-(4-f luorophenyl)-5-(1-me thyl-ethyl)-l-phenyl-lH-pyrazol-4-yl]ethynyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S)-4-[[[4-(4-fluorophenyl)-l-(1-methyl-ethyl)-3-phenyl-lH-pyrazol-5-yl]ethynyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[[4-(4-fluorophenyl)-l-(l-methyl-ethyl)-3-phenyl-lH-pyrazol-5-yl]ethynyl]hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt; (S)-4-[ ^-[^-^-fluorophenylj-l^l-methyl-ethyl )-3-phenyl-lH-pyrazol-5-yl] ethyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[2-[4-(4-fluorophenyl)-1-(1-methyl-ethyl)-3-phenyl-lH-pyrazol-5-yl ] ethyl ] hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt; (S)-4-[[[1-(4-fluorophenyl)-4-(1-methyl-ethyl)-2-phenyl-lH-imidazole-5-yl]ethynyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[ [ [l-(4-fluorophenyl)-4-(l-methyl-ethyl)-2-phenyl-lH-imidazol-5-yl]ethynyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[2— C1—(4-fluorophenyl)-4-(1-methyl-ethyl)-2-phenyl-lH-imidazol-5-yl]ethyl]methoxy-phosphinyl]-3-hydroxybutanoic acid, methyl ester; (S)-4-[[2-[1-(4-fluorophenyl)-4-(1-methyl-ethyl)-2-phenyl-lH-imidazol-5-yl]ethyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S)-4-[[[2-(eyelohexyImethyl)-4,6-dimethyl-phenyl]ethynyl]hydroxyphosphinyl]r3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; 4-[[2-[2-(cyclohexyImethyl)-4,6-dimethyl-phenyl ] ethenyl ] hydroxyphosphinyl ] -3-hydroxybutanoic acid or its dilithium salt or methylr"ester thereof; 22473 HXlOb -361 - (S) -4- [ [2- [2- (cyclohexylmethyl) -4,6-dimethyl-phenyl]ethyi]hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; 4-[[[[4*-fluoro-3,3',5-trimethyl[l,l'-biphenyl]-2-yl]oxy]methyl]hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; 4-[[[4'-fluoro-3, 3',5-trimethyl[1,1*-biphenyl]-2-yl]methyl]hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S)-4-[[[1-(4-fluorophenyl)-3-methyl-2-naphthalenyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (E)-4-[[2-[l-(4-fluorophenyl)-3-methyl-2-naphthalenyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoic acid or its dilithium salt or methyl ester thereof; (S)-4-[[2-[1-(4-fluorophenyl)-3-methyl-2-naphthalenyl]ethyl]hydroxyphosphinyl]-3"hydroxybutanoic acid or its dilithium salt or methyl ester thereof; 4-[[3-[41-fluoro-3,31,5-trimethyl[1,1'-biphenyl]-2-yl]propyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester; 4-[[3-[4*-fluoro-3,3',5-trimethyl[l,l'-biphenyl]-2-yi]propyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt; [IS-[l<a(R*),2<a,4a<b,8<b,8a<a]]-4-[[2-[8-(2,2-dimethyl-l-oxobutoxy)decahydro-2-methyl-l-naphthaleny 1 ] ethyl ] methoxyphosphinyl ] -3 -hydroxy^ ^ butanoic acid, methyl ester; -362- HXlOb 224734 9 [IS-[l<a(R*), 2<a,4a<b,8<b,8a<a]]-4-[[2-[ 8 - (2,2 -dimethyl-1-oxobutoxy)decahydro-2-methyl-1-naphthalenyl]ethyl]hydroxyphosphinyl]-3-hydroxy-butanoic acid, dilithium salt; (S)—4—[[[3'-(4-fluorophenyl)spiro]cyclo-pentane-1,1'-[1H]indene]-2-yl]ethynyl]methoxyphosphinyl] -3-hydroxybutanoic acid, methyl'ester; or (S)-4-[[ [3'-(4-fluorophenyl)spiro]cyclo-pentane-1,11-[1H]indene]-2-yl]ethynyl]hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt.

4- An intermediate having the structure 0 1 M Rt-P-CHo-CH-CHo-C0, alkyl a | 2 J 2 2 osi-c(cH3)3 C6H5 C6H5 including all stereoisomers thereof, wherein R^ is C1-C12 1 alkoxy or hydroxy; R^ is hydroxy, CI, -CeC-Z, -CH2-2, -CH2CH2CH2-Z, -CH20-Z, tCH=CH-Z or -CH0CH_-Z, wherein Z is a hydrophobic anchor, as defined in claim 1, 1 1 . provided that where is hydroxy, is hydroxy or Ci-C-j 2 alkoxy or an intermediate having the structure 0 II alky10-P-CHo -C-CEL - CO., alkyl , 1 2 m .2 2 > f i Z wherein in the structural formula 'alkyl' is defined as having from 1 to 12 carbon atoms, including all stereoisomers thereof wherein X is (CH_)_, -CH=CH-, -C=C—, or -CH90- and a is 1, 2 or cl 6 fm>' 3 and Z is a hydrophobic anchor. iiA-LUD -383- 724734

5. A method for preparing an intermediate of Claim 4 wherein is Oalkyl wherein alkyl is defined as having from 1 to 12 carbon atoms, and R^ is. -CH=CH-Z, wherein Z is as defined in claim 1, which comprises treating the vinyl (trans) iodide I J™ fE ' z with a metallating.agent in the presence of an inert organic solvent, and reacting the resulting anion with a cooled solution of a phosphonochloridate of the structure o alkyl0-!p-CH2-ai-CH2C02 alkyl Cl <p Si-C(CH3)3 C6H5 C6H5 / wherein in the structural formula alkyl is defined as having from 1 to 12 carbon atoms, in the presence of an inert organic solvent. "6. A method for preparing an intermediate as defined in Claim 4 having the structure C -II alkyl0-P-CH2-C-CH2-C02alkyl, J* ° CH I Z wherein in the structural formula alkyl is defined as having from 1 to 12 carbon atoms, which comprises treating a cooled solution of a phosphonochloridate having the structure </div>