SE9201587A0 - Phosphorus-containing HMG-CoA reductase inhibitors, novel intermediates and method - Google Patents

Abstract

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Description

NAME OF THE INVENTION PHOSPHORIC IIMG-COA REDUCTUAL 1131 TORES, NEW INTERMEDIATES AND METHOD.

APPLICANT (name, domicile and address.

If a representative is missing, state aver) telephone number.

Sakes patent ay fkra common, stated if nigon at- them that tnsedd VI for all received notices from the patent office) B E. R.SQUIB & SONS, INC.

Lawrenceville-Princeton Road Princeton, New Jersey, USA INVENTED ARE Man and address) According to appendix AGENT (name, domicile, address and telephone number) r - 1 Signed. sokande befullmiktigar harmed.nedansdende upptagtsa svenska on-thud att.

AL — I prefer 1 alit as the root of this patent application and 1 alit as the root of any the patent.

BE1 Saande authorizes the following Swedish agents by separate power of attorney.

Dr. Ludwig Brann PatentbyrAB Box 171 9 2 104 62 Stockholm REQUEST FOR PRIORITY (date, country and origin of number) 22 May 1987, USA, No. 53 238 Oct 19, 1987, USA, No. 109 681 ON DEPOSIT OF MICROORGANISM Depositary authority: Deposit date • Deposit number: IN THE EVENT OF A DIVISIONED OR EXTENDED APPLICATION Master application number: 880.19.04-7 Begardiapdag: 20 maj1988 APPENDICES CS Description, claims and summary in ire copiesStockholm on May 20, 1992 0 drawings iexemplarOtt, date iii Surrender Act (copy a) t3 Power of attorney, i 0151 F4) .W.Ilfrioverribor, 1991: A FEE4or the basic figure SEK 1,600 EN Grindavgitt: t-400 kronorUndenkriftEVaKik i gtly / 0Tiftiggsavgift, 100 hr hit- each patent claim in addition to rio: hr 12 Fee (Or copies of news item SEK 300 0 Diary certificate: kronor Payment: 0 postal giro0 check0 cash ••• •••• • • • •• • •• 0 • • • • • • S • • • • ••• • • ••• • • • • • • • •• • • • id • • sr> .: 14 ••• ‘1. eS. 0:10 • S. Its • 00.e. 44.

Inventors' names and addresses: DONALD STEVEN KARANEWSKY, 8 Charred Oak Lane, East Windsor, New Jersey, A.f.s.

MICHAEL CHRISTOPHER BADIA, 116 Glenview Drive, Lawrenceville, New Jersey, A.f.s.

SCOTT ADAMS PICTURES, 136 Nancy Lane, Ewing, New Jersey, A.f.s.

ERIC MICHAEL GORDON, 126 Laning Avenue, Pennington, New Jersey, A.f.s.

MICHAEL JOSEPH SOFIA, 502 White Pine Circle, Lawrenceville, New Jersey, A.f.s. • ••• O • •• • • • • • • •• • • •• • R. SQUIBB & SONS, INC. Divided from p.ans. 88 01904-7 Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method.

The present invention relates to novel phosphorus-containing compounds which inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase and thus are useful in the inhibition of cholesterol biosynthesis, agents for hypocholesterolemia containing such compounds, novel intermediates formed in the preparation of such compounds and av fOreningarna for sgdana dndamal.

M. Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) state that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.

Endo et al., In U.S. Patent No. 4,049,495, 4,137,322 and 3,983,140 a fermentation product which is active in inhibiting cholesterol biosynthesis. This product is called compactin and was reported by Brown et al. (J. Chem. Soc.

• • • PerkinI.116 (1976)) have a complex mevalonolactone structure.

• • • • • • GB 1586152 describes a group of synthetic compounds with • • • • • the formula • • • • • • • • • • • • • • • • • • • • • • * • 4. • • • • • • • • • • • * • • • 2 in which E represents a direct bond, a C 1-3 alkylene bridge or a vinylene bridge and the different R substituents represent a plurality of different substituents.

The activity reported in the UK patent is less than 1% of that of compactin.

U.S. Patent No. 4,375,475 to Willard et al. Discloses hypocholesterolemic and hypolipemic compounds having the structure ••• •••• • • • • •• • •• • 0 • • . • • e S • • • • • ••• • • ••• • • • 4 • • •• • • • • ■ • • • wherein A is H or methyl; E is a direct bond, -CH 2 -, -Cl 2 - 2CH 2 -, -CH 2 -CH 2 -CH 2 - or -CH = CH-; 1, R 2 and R 3 are each selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, phenyl, phenyl substituted by halogen, C 1-4 alkoxy, C 2-8 alkanoyloxy, C 1-4 alkyl or C 1-4 haloalkyl and OR 4, in which R 4 is H, C 2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl-C 1-4 , C 1-9 alkyl, cinnamyl, C 1-4 haloalkyl, allyl, cycloalkyl-C 1-3 alkyl, adamantyl-C 1-3 alkyl or substituted phenyl-C 1-3 alkyl, the substituents in each of these being selected from halogen, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring and the pharmaceutically acceptable salts of said acids and with C 1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C 1-3 alkyl esters of the dihydroxy acids; wherein all the compounds Sr enantiomers with a 4 R configuration in the tetrahydropyran moiety the transracate shown in the above formula.

WO 84/02131 (PcT / EP83 / 00308) (based on p5 U.S. Patent Application Serial No. 443,668, filed November 22, 1982 and U.S. Patent Application Serial No. 548,850, filed November 4, 1983), filed in the name of Sandoz AG, discloses heterocyclic analogs of mevalonolactone and derivatives thereof with the structure X-2 used in one of R and Ro Sr and the other Sr : • • •••• R5a primary or secondary C 1-6 alkyl, C 3-6 cycloalkyl or phenyl- (CH 2) m -, van in R 4 Sr vate, C 1-4 alkyl, C 1-4 alkoxy (excluding t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R 1 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine,} dor, phenoxy or benzyloxy, • • •• 0. •• • • • • • • • • 4 • ••• 0 • 119 • 0 • r •• IP ••• I • • • • 4 R 5a is hydrogen, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine and m 1, 2 or 3 with the proviso that both Roch R5a must be hydrogen when R is hydrogen 'R5a must be hydrogen when Rär is hydrogen, no more than one of R4 and R is trifluoromethyl, no more than one of R4 and R is phenoxy and no more than one of R and Rar benzyloxy, R 2 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy (excluding t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R 3 is hydrogen, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, with the proviso that R 3 must be hydrogen when R 2 is free, no more than one of R 2 and B 3 is trifluoromethyl, no more than one of R 2 and R 3 is phenoxy and no more than one of R 2 and R 3 is benzyloxy.

X ar - (CH2) n- el. -CH = CH- (n = 0, 1, 2el. 3), R6 5 4 31 2 I is -CH-CH --C - CH2-COOHII 2 OHOH van in R6 is vate or C1-3i form of free acid or in in the form of a physiologically hydrolysable and acceptable ester or em 4i-lactone thereof or in salt form. 00 • .41, • • • • • • • • • 0 ••• • • SOO • • ••• /YES* • • 4 • 0 GB 2162-179-A discloses naphthyl analogs of mevalolactone which are useful as cholesterol biosynthesis inhibitors with the structure MeMe of i R 1 = 1-3 C-alkyl; Z is a group of the formula Z1 or Z2: -CHCH CHCH COOR & 2427 OH OH 0 (Z2) R7 = H, a hydrolysable ester group or a cation.

European Patent No. 164-698-A discloses the preparation of lactones which are useful as agents for hypercholesterolemia by treating an amide with an organic sulfonyl halide RSO2X and subsequently removing the protecting group Pr. vani X = halogen; Pr = a carbinol protecting group; = H or CH • 3 ' R 3, R 4 = H, 1-3C-alkyl or phenyl- (1-3C-alkyl), wherein phenylene is optionally substituted with 1-3 C-alkyl, 1-3 C-alkoxy or halogen; R2 = a group of formula (A) or (B): 1. 4 2 R2 R1 R 0SO2X R3R4 -> HO OH Pro 000 44100 •• • I •• • • • • • • • • • • • ••• • • 060 3 • • • • • • • •• • ■ • ••• • • • • • • po oyes p se two o.0. 6 CH (A) Q = R6-y- or CH3 R6 = H or OH; R = H or CH • 3 ' a, b, c and d = arbitrary double bonds; R7 = phenyl or benzyloxy, the ring in each case being arbitrarily substituted with 1 to 3 C-alkyl or halogen; R 8, R 9 = 1-3 C-alkyl or halogen; R = 1-3 C-alkyl, phenyl or mono- or di (1-3C-alkyl) -phenyl.

In the German publication DE 3 525 256, Paul Leroy Anderson describes naphthyl analogs of mevalonolactones with the structure ••• •••• • -CHCH21 CHCH2 CO2 R7 •• • C Ci NH • 0 • • • • • • • • IS.

••• • OH OH OH • ••• 0 • ••• • 0 • •• • 1 of. R is alkyl, Z = Q, Q1; R7 = H or a hydrolysable ester group, which can be used as inhibitors of cholesterol •• • • • • • 7 biosynthesis and in the treatment of atherosclerosis.

WO 8402-903 (based on U.S. Patent Application Serial No. 460,600, filed January 24, 1983), filed in the name of Sandoz AG, discloses mevalonolactone analogs useful as hypolipoproteinemic agents having the structure wherein the two groups Re together form a radical of the formula 1.8 7 6 5 C = C- C = C R2R3 or • 041 • •••• • • • • •• 0 •• • • • • • • • • • • ••• • • ••• • 0 ••• • 0 • • •• • ••• • • So R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy (excluding t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R3 is 'C1-3' -alkyl C1-3 -alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, with the proviso that no more than one of R 2 and R 3 is trifluoromethyl, no more than one of R 2 and R 3 is phenoxy and no more than one of R 2 and R 3 is benzyloxy, R 1 is C 1-6 alkyl, fluorine, chlorine or benzyloxy, R 4 is radical, C 1-4 alkyl, C 1-4 alkoxy (excluding t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, R anvate, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, 8 R 5a is C 1-4 alkyl, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine the proviso that no more than one of R and R is trifluoro- 4 methyl, no more than one of R4 and R is phenoxy and no more than one of R4 and R is benzyloxy, H / (CH2) q \ X is - (CH 2) n -, C = C ,, / \.in - (CH2) q van i n an 0, 1, 2 eller 3 och b & da q'na dr 0 eller den ena an 0 and the other an 1, Z an R6 5 431 21 -CH-CH2 - C-CH2 -COOHII 3 (1111 OH used in R 6 or C 1-3 alkyl, with the general proviso that -X-Z and the R 4 bearing a phenyl group are in orthoposition to each other; In the free acid form or in the form of a physiologically hydrolysable and acceptable ester or a .beta.-lactone thereof or in salt form.

U.S. Patent No. 4,613,610 to Wareing (OverlAten to Sandoz) discloses a series of 7-pyrazolo-3,5-dihydrohept-6-enoic acid HMG-CoA reductase inhibitors having the structure •••• • • I •• • II • • • • • • II. • • • ••• • • ••• • • ••• ••• • • • 4 9 wherein R 1 is C 1-6 alkyl which does not contain 115 asymmetric carbon atoms, each of R 2 and R 3 is independently C 1-3 alkyl, n-butyl, isobutyl, t-butyl, C 1-3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenyl, phenoxy or benzyloxy, each and one of R 3 and R 6 is independently hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, each of R 4 and R 7 is independently vate, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine, with the proviso that no more than one of R 2 and R 3 is trifluoromethyl, no more than one of R 2 and R 3 is phenoxy, no more than one of R 2 and R 3 is benzyloxy, no more than one of Roch R 6 is trifluoromethyl , no more than one of Roch R6 is phenoxy and no more than one of Roch R6 is benzyloxy, X ar - (CH 2) m -, -CH = CH-, -CH = CH-Cl 11 - or -CH 2 -CH = CH-, van in ar (), 1, 2 or 3 and Z is / CH2 \ / OH R -CHC 1 -CH-CH -C-CH -COORellerII \ f2 1211 OHOH0CH 2 0 •••• • vani • •• R 10 is vate or C 1-3 alkyl and R 11 is vate, R 12 or M, •• • whereby • • • • 0.R12 to a physiologically acceptable and hydrolyzable ester group • • • • • ••• • and • ••• • • ••• * • •• • ••• • • • M ar a cation, with the proviso that the (1) -X-Z group is present in 4- or 10 ' 10 • • • .0.0 • S , • I.0 • • • • • • $ 0 • If 0 • • • • 00. •• •• • 0 0.0 • • • • The 5-position of the pyrazole ring and (ii) the P1 group and the -X-Z group are in orthoposition to each other.

WO 8607-054A (Sandoz inventions) discloses imidazole analogs of mevalonolactone, which are useful for the treatment of hyperlipoproteinemia and atherosclerosis and have the formula R 1 = alkyl, cycloalkyl, adamantyl-1 or R 4, R, R 6 -substituted phenyl (group A); R 2 = alkyl, cycloalkyl, adamantyl-1 or R 7, R 8, R 9 -substituted phenyl (group B); R 3 = H, alkyl, cycloalkyl, adamantyl-1, styryl or R 10, R 11, R 12 -substituted phenyl (group C); X = - (CH2) m-, -CH = CH-, -CH = CH-C112- or -CH2-CH = CH-; m = 0 - 3; Z = -CH (OH) -Cl12-C (R13) (OH) -CH2-000R14 (group a), -Q-CH2-C (R13) (OH) -CH2-000R14 (group c) or a group with formula (b): CH 2 7, OH --- CH I N3 11 Q = CO or R = primary or secondary alkyl; each R is the same; or also Hr RR = (CH2) 2 or (CH2) 3; R13 = H or 1-3 C-alkyl; R14 = H, R16 or M; R16 = ester group; M = cation; provided that Z may be group (c) only dA X Hr CH = CH or CH 2 -CH-CH and / or when R 13 = 1-3 C-alkyl; R 7 and R 6 = 1-3 C-alkyl, n-, iso- or t-butyl, 1-3 C-alkoxy, n- or isobutoxy, CF 3, F, Cl, Br, phenyl, phenoxy or benzyloxy; R 8 and R 11 = H, 1-3 C-alkyl, 1-3 C-alkoxy, CF 3, F, Cl, Br, COR 17 'N (R 19) 2' phenoxy or benzyloxy; R17 = H, R18 or M; R18 = 1-3 C-alkyl, n-, iso- or t-butyl or benzyl; R19 = alkyl; R 6, R 9 and R 12 = H, 1-2 C-alkyl, 1-2 C-alkoxy, F or Cl; provided that ••• •••• Q = CO or R = primary or secondary alkyl; each R is the same; or also Hr RR = (CH2) 2 or (CH2) 3; R13 = H or 1-3 C-alkyl; R14 = H, R16 or M; R16 = ester group; M = cation; provided that Z may be group (c) only dA X Hr CH = CH or CH 2 -CH-CH and / or when R 13 = 1-3 C-alkyl; R 7 and R 6 = 1-3 C-alkyl, n-, iso- or t-butyl, 1-3 C-alkoxy, n- or isobutoxy, CF 3, F, Cl, Br, phenyl, phenoxy or benzyloxy; R 8 and R 11 = H, 1-3 C-alkyl, 1-3 C-alkoxy, CF 3, F, Cl, Br, COR 17 'N (R 19) 2' phenoxy or benzyloxy; R17 = H, R18 or M; R18 = 1-3 C-alkyl, n-, iso- or t-butyl or benzyl; R19 = alkyl; R 6, R 9 and R 12 = H, 1-2 C-alkyl, 1-2 C-alkoxy, F or Cl; provided that ••• •••• (1) no more than one substituent in each of the groups •.

•. •• A, B and C Mr CF3, no more An a substituent in each • • • of groups A, B and C Hr phenoxy and no more than one sub- stituent in each of groups A, B and C Hr benzyloxy; • • ea • • ••• • • ••• • • • •• 0 ••• • • • • (2) when Z Hr group (c; Q = C (011) 2), Hr fOreningen i fri base form and either (i) R 14 is R 16 and each R 17 is Hr independently R 18 or (ii) R 14 is Hr M and each R 17 is Hr 12 R18 or M; and (3) when R 14 and / or at least one R 17 M, is the compound free bass form.

Unless otherwise indicated, all "alkyl" groups have 1 to 6 ° C (Doh does not contain flake asymmetric C; and "cycloalkyl" has 3 - 7 ° C).

WO 8603-488-A (Sandoz AG) discloses internal analogs of mevalolactone, which are useful as hypolipoproteinic agents () and anti-atherosclerotic agents in free acid form or in the form of an ester or delta-lactone or in salt form, having the formula (IN) R = H or primary or secondary 1-6 C-alkyl; R = primary or secondary 1-6 C-alkyl; or R + R1 = (CH2) m or (Z) -C112-CH = CH-C112 • ' m = 2 - 6; Ro = 1-6 C-alkyl, 3-7 C-cycloalkyl or R4, R, R6-sub- substituted phenyl; R 2, R 4 = H, 1-4 C-alkyl, 1-4 C-alkoxy (excluding t-butoxy), CF 3, F, Cl, phenoxy or benzyloxy; ••• . ".

R3 and R = H, 1-3 C-alkyl, 1-3 C-alkoxy, CF3, F, Cl, 0 phenoxy or benzyloxy; R 6 = H, 1-2 C-alkyl, 1-2 C-alkoxy, F or Cl; provided that there is only one of each of CF3 'phenoxy or benzyloxy in each of the phenyl and inner rings; X = (CH2) 1. or - (CH2) q-CH = CH (CH2) q - ' n = 1 - 3; bathe q'en = 0 or also at one 0 and the other 1; = -4-CH 2 -C (R) (OH) -CH 2 COOH, in free acid form or in the form of •• • •• • • 1 • • • • • • • • ••• • • ••• 0 • ••• • • • •• 111 • ••• • 0 • 0 • 13 an ester or delta-lactone or salt; Q = CO, -C (OR 7) 2 - or CHOH; R'7 = the same primary or secondary 1-6 C-alkyl or together are (CH2) 2 or (CH2) 3 • ' R. H or 1-3 C-alkyl; provided that Q may be something other than CHOH only cid X ar CH = CH or CH2-CH = CH and / or 1-3 C-alkyl.

R U.S. Patent No. 4,647,576 to Hoefle Flora (Warner Lambert) discloses novel C- and N-substituted pyrrole (s) useful as hypolipidemic and hypocholesterolemic agents, which have the formula COOH • 0/0 • •••• • • • • •• • •• • • • • • 0 • • * • • ••• • X = -CH 2 -, -CH 2 CH 2 - or -CH (CH 3) CH 2 -; R 1 = 1- or 2-naphthyl; cyclohexyl; norbornenyl; phenyl, optionally substituted with F, Cl, OH, CF 3, 1-4 C-alkyl, 1-4 C-alkoxy or 2-8 C-alkanoyloxy; 2-, 3- or 4-pyridinyl or their N-oxides; or .hale HE: 2: T • ••• • •••• • • * • 4 • ••• • ••• • • ••• 14 R 5-14 C-alkyl; hal = chloride, bromide or iodide; R 2 and R 3 = H, Cl, Br, CN, CF 3, phenyl, 1-4 C-alkyl, 2-8 C-carboalkoxy, -CH 2 OR 6 or -CH 2 OCONHR 7; R6 = H or 1-6 C-alkanoyl; R 7 = alkyl or phenyl, optionally substituted with C 1, Br or 1-4 C-alkyl; or R 2 and R 3 together are the same -CH 2 OCH 2 -, -CON (R 8) CO- or -CON (R 9) N (R) CO-; n = 3 or 4; R8 = H, 1-6 C-alkyl, phenyl or benzyl; R 9 and R = H, 1-4 C-alkyl or benzyl; R4 = 1-4 C-alkyl, cyclopropyl, cyclobutyl or CF3.

European Patent Application 0 221 025 A1 (Sandoz AG) discloses heterocyclic analogs of mevalonolactone and derivatives thereof of the formula wherein Ra is a group -X-Z, Rb is R2, RC is R3, Rd is R4 and Y is a group -N- or R1 also Ra is R1, Rb is a group -X-Z, Rc is R2, Rd is R3 and Y is 0, S or a group -N-; 4 R 1, R 2, R 3 and R 4 are independently C 1-4 alkyl which do not contain flagon asymmetric carbon atom, C 3-7 cycloalkyl or a ring . • • ••• • ••• • • • • • • • • ■■■ • • •• • • • •• it •• • • • a • • • • • •• • ••• 0 ••• • • ••• •• ..6 • 5 • ••••• or ask if R3 and R4 are additionally vate or for R3 when Y is 0 or S ,, R18 c = c / • R17R19 vane in R 17 independently or C 1-3 alkyl and R 18 and R 19 independently, C 1-3 alkyl or phenyl; each R 3 is independently, C 1-3 alkyl, n-butyl, isobutyl, t-butyl, C 1-3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy; each R 4 is independently hydrogen, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, bromine, phenoxy or benzyloxy and each R 7 independently represents hydrogen, C 1-2 alkyl, C 1-2 alkoxy, fluorine or chlorine with the proviso that there may be only one of each trifluoromethyl, phenoxy or benzyloxy present in each ring A. X Mr (CH 2) 1 or (CH 2) g CH = CH (CH 2) q, m is 0, 1, 2 or 3 and had q 'an 0 or also one 0 and the other 1. 9 Z at -CH-CH 2 -C-CH 2 -COOH 1 OHOH • e •• • •••• • .

• Si • • • 0 • * 0 • • • • • ••• 0 used in R9 an or C 1-3 alkyl, in the form of a free acid or in the form of an ester of β-lactone thereof or in salt form as appropriate, which compounds can be used as hypolipoproteinemic and anti-atherosclerotic average.

Tetrahedron Letters, 29, 929, 1988 describes the synthesis of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor having the structure • . •: • ..

:: S S .. *. it Mire • •••• 16 van in R an Na or C211.

European Patent Application 127,848-A (Merck & Co. Inc.) discloses derivatives of 3-hydroxy-5-thia-LU-aryl alkanoic acids having the structural formula of i Z ar: HO n is 0, 1 or 2; E is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 '-CH = CH-CH 2 - or -CH 2 -CH = CH-; R 1, R 2 and R 3 are, for example, hydrogen, chlorine, bromine, fluorine, O 1 -alkyl, phenyl, substituted phenyl or OR 7, in which R 7 is, for example, hydrogen, • 0O • 0 0. 17 C 2-8 alkanoyl, benzoyl, phenyl, substituted phenyl, C 1-9 alkyl, cinnamyl, C 1-4 haloalkyl, allyl, cycloalkyl-C 1-3 alkyl, adamantyl-C 1-3 alkyl or phenyl-C 1-3 alkyl: 46 R, R and R are hydrogen, chlorine, bromine, fluorine or C 1-3 alkyl; and X is, for example, hydrogen, C 1-3 alkyl, a cation derived from an alkali metal or ammonium.

These compounds have antihypercholesterolemic activity due to their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and fungicidal activity.

French Patent Application 2,596,393 A, filed April 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propanephosphonic acid derivatives including salts thereof, which are useful as hypolipemic agents and have the formula: R1 00C-CH2 -C-CH2 -P OH NOR 4 van in R and R 2 = H, lower alkyl or optionally substituted aralkyl17 R 3 and R 4 = H, lower alkyl or optionally substituted aryl or aralkyl.

These compounds are said to have greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol. European Patent Application 142 146-A (Merck & Co., Inc.) discloses mevinoline-like compounds of the structural formula: I '• • • * • • e • • • • • ••• • ••• • • ••• 18 HO vani R 1 is, for example, water or C 1-4 alkyl; E is -CH 2 CH 2, -CH = CH- or - (CH 2) r -; and Z ar van in X is -O- or -NR 9, van, R ar or rate or C 1-4 alkyl; R7 is C2-8 and 8. - R dr vate or CH • 3 ' R1 R12 • • • 0 • • • .A1 wherein R 13iR 1 and R 12 are independently, for example, vate, halogen or C 1-4 alkyl; • • • • • ••• • •• • • ••• 19 ) n van i n is 0-2 and R 14 is halogen or C 1-4 alkyl; or These compounds are HMG-CoA reductase inhibitors.

According to the present invention there are provided phosphorus-containing compounds which inhibit the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase) and are useful as hypocholesterolemic agents and include the following moieties 0 -P-CH -CH-CH -CO- I22 XOH of i X an - (CH2) a- '-CH = CH-, -CC- or -C1120- (of i 0 • ••• is bound to Z), "a" is 1, 2 or 3 and Z is a "hydro- • •••• fobt anchor ".

•• • •• The term "hydrophobic anchor" as used in a lipophilic group which binds to the HMG-like boron side chain in the molecule by means of the exemplary linker ("X") binds to a hydrophobic pocket of the enzyme which is not being used. for binding the substrate HMG CoA, which • • • • • • • • • • • ••• • • ••• • • ••• • 0 • GO • ••• 0 .0 • • 0 • • • • • • • • • • • 0 • • • • • • • : 5 *.; * " • ••• • ••• • • • •• :, • • . • • S ••• •. • • ; 0; • •• •••• • •• •••• •••• •• results in increased potency in relation to compounds in which Z = H.

In preferred embodiments, the compounds of the invention have formula I 0 IR-P-CH2 -C-CH2 -CO2 Rx XOH vani R is OH or lower alkoxy; Rx is H or lower alkyl; X dr CH 2, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH = CH-, -CC- or -CH 2 O- (van in O dr attached to Z); Z an hydrophobic anchor; and includes pharmaceutically acceptable salts ddrav.

The terms "salt" and "salts" refer to basic salts which are formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts, such as lithium, sodium and potassium salts, (which are preferred), salts of alkaline earth metals, such as calcium and magnesium salts, salts with organic bases, such as amine-like salts, e.g. dicyclohexylamine salt, benzatin, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids, such as arginine, lysine oct. similar. The non-toxic, pharmaceutically acceptable salts are preferred, while other salts are also useful, for example in isolating or purifying the product.

Examples of hydrophobic anchors which may be included in the invention include but are not limited to 'S •• • • Of • 21 IN N ...... N R (0 t r f • • alb • • • 11 0 • • • • • • • f •• a • •••• • • e •• ••• 6 • • • • • 1 R16 alkyl a or 22 R6 • • • •• • •• • IS. • * • 0 • 0 • • • • • ••• 0 • • o • • • ••• :::; • :: Li •: : ■ •• re. ••• • •• 6. • • •••• 455 • I. 6 • oa • •• 23 van in the dotted lines represents arbitrary double bonds, for example alkyl alkyl 6 R6 R6 alkyl or (R R6 • • a • • • • OS • 24 wherein R 1, R 2, R 2a and R 2b may be the same or different and each is independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or OR of R 1 is H 1 alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl- lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl.

Da z R6 alkyl • ••• • R and R 5 'are the same or different and are H, lower alkyl or OH; 00 0 R6 contains alkyl-Cs such as CH3-CH2-C-C-i N., 7 CH3 R or arylCH 2 -; R6a are lower alkyl, hydroxy, oxo or halogen; q an 0, 1, 2 or 3 and R 7 is H or lower alkyl. •••• • • • • •• • • • • • • • • 4, • • • • ••• • • ••• • • 000 •• • •• •••• • •• Since Z is R3 R R11 R is one of R 3 and R 4 and the other is lower alkyl, cycloalkyl or phenyl- (CH2) p-1 p is 0, 1, 2, 3 slier 4; . ". van in R13 an vate, lower alkyl, lower alkoxy (with the exception of "t-butoxy), halogen, phenoxy or benzyloxy; 14.

Rdr vate, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy; R14a is hydrogen, lower alkyl, lower alkoxy or halogen; and • • • S * • • • • • • • • • • • • • • • • • 4 • • • 6 •• • • * • 26 with the provisos that both RI4 and R14a must be hydrogen when RI3 is hydrogen, R14a Waste be hydrogen when R14 is hydrogen, not more than one of R13 and R14 is trifluoromethyl, not more than one of R14 ar R13 and R14 are phenoxy and no more than one of R13 and benzyloxy; R 8 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy (excluding t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy; chlorine, phenoxy or benzyloxy, with the provisos that R 9 must be hydrogen or R 8 is hydrogen, no more than one of R 8 and R 9 is trifluoromethyl, no more than one of R 8 and R 9 is phenoxy and no more than one of R 8 and R 9 is benzyloxy.

" Roch and R 11 are independently selected from the radical, alkyl, cycloalkyl, adamanty1-1 or R 9 is hydrogen, C 1-3 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoro, -3 - (CH2) q used in R13, R14 and R14a has the meaning given above and q = 0, 1, 2, 3 or 4.

Y dr 0, S or N-R.

DA Z ar ". • . ". R12 • • • • •• • •• • • • • • 111 • • • • •• • • ••• • • ••• * •• 4 ••• • • • • Ra is H or primary or secondary 1-6 C-alkyl; b - R is primary or secondary 1-6 C-alkyl; 27 or also Rb (CH) or (cis) -CH 2 -CH = CH-C [12; 2 r r = 2, 3, 4, 5 or 6; 12 Lower alkyl, cycloalkyl or R13 R14 . of]. R 8R, R 13, R 14 and R 14a have the meaning given above part. DA Z dr _ ar Roch R16 bAda H, Cl, Br, CN, CF3, phenyl, 1-4 C-alkylf 2-8 C-alkoxycarbonyl, -CH 2 OR 17 or -CH 2 OCONHR 18; 17 -.

R 1 is H or 1-6 C-alkanoyl; 18.

Rk alkyl or phenyl optionally substituted with F, Cl, S ••• • •••• • • • •• • •• • •• 6.

• • * • •• •••• • • Iik • * Br or 1-4 C-alkyl; 16 or also Roch Rtagna together, - (CH2) s -CH22 AND -'- CON (R19) CO- or -CON (R) N (1121) CO-; S = 3 or 4; R19 I - 6 C-alkyl, phenyl or benzyl; 21 Roch Ran IL, 1-4 C-alkyl or benzyl; ••• • • • • 49 • 4 * 0 • • • • with the additional condition that dA Z dr 28 R 22 is lower alkyl, cycloalkyl, adamantyl or -1 (CH 2) t t. 1, 2, 3 or 4; R23 and R23a are the same or different and are each selected from hydrogen, lower alkyl, lower alkoxyl (with the exception of t-butoxy), halogen, phenoxy or benzyloxy; 1 X can only be -CH2 'DA Z ar R16 -C112C112- or -CH2CH2CH2. 23 R23a R2 R23a . ". more than one of R23 and R23a 4r phenoxy and not More than one of ••• and with the proviso that R23a must be hydrogen when R23 is hydrogen, into one of R23 and R23a is trifluoromethyl, not D5 X is -CH, O- (carbon bound at P and 0 bound at Z), lir dot 4 the hydrophobic anchor Z is a phenyl or naphthalene anchor, such as R23 and R23a are benzyloxy. • •• • . 4 • IP • S • • • ••• • ••• • • ••• • • * •• • 1 • • •• I • I • •••. • • : ••• 41: ••: ••:: • • • • • • S.C. • •• .11 0 ••••• 29 el ler The compounds of formula I thus include 0 IaR-F-CH2-CH-CH2-CO2Rx OH III 1 0 0 lbR-P-CH2 -QH-CH2 -CO2 Rx 1r.

CH OH CH (cis) 0 If IcR-P-CH -CH-CH -CO Rx 2s 2 2 CH 5H CH (trans) 0 0 IdR-P-CH2 -CH-CH2 -CO2 Rx 13 CH2 OH 6CH 2 • ; 60 • 00 • • • 9 • • • 0 • • • • ••• • • * 0004 • 064 • 6 0.0 0 leR-T.-CH2-CH'C} 12-CO2Rx CH2 OH :: •••••• •: •• • •••• •••• * i: •• ••••••• : 0 IfR-T-CH2-.93-CH2-CO2Rx (FH2) 3 81.1 0 IgR-P-CH2 -CH-CH2 -CO2 Rx 12 CH2 OH 0 The term "lower alkyl" or "alkyl" as used herein alone or as part of another group includes both straight and branched chain hydrocarbons which contain 1 to 12 carbon atoms in the normal chain, preferably 1 to 7 carbon atoms, such as methyl , ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various isomers of which branched chain and the like and such groups which include Fa halogen substituent such as F, Br, Cl or I or CF 3, an alkoxy substituent, an aryl substituent, an alkyl aryl substituent, a haloaryl substituent, a cycloalkyl substituent, an alkyl cycloalkyl substituent alkanoylamino substituent, and arylcarbonylamino substituent, ennitro substituent, a cyano substituent, a thiol substituent tuent or an alkylthio substituent.

The term "cycloalkyl" as used herein includes alone or as part of another group of matt cyclic carbonate groups which contain 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctyl, cyclooctyl and cyclododecyl, these groups being substituted by 2 halogen atoms, 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 groups. : ::: La, • 't :: • • 1: g 61, ** • ** OS * •• * 01 * 6 * 31 amino 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 alkylthio groups.

The term. "aryl" or "Ar" as used herein denote monocyclic or bicyclic aromatic groups containing from 6 to 10 carbon atoms in the ring moiety, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, the substituent on either phenyl or naphthyl may be 1, or 3 lower alkyl groups, halogens (Cl, 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 groups, 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 cycloalkylalkyl groups, 1, 2 or 3 adamantylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoylamino 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 1, 2 or 3 alkylthio groups, the aryl group preferably containing three substituents.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein alone or as part of another group denotes lower alkyl groups which have been discussed above with an aryl substituent, e.g. benzyl.

The term "lower alkoxy", "alkoxy" or "aryloxy1" or "aralkoxy" as used herein alone or as part of another group includes any of the above groups lower alkyl, alkyl, aralkyl or aryl, attached to an acid atom.

The term "lower alkylthio", "alkylthio", "arylthio" or "aralkylthio" as used herein alone or as part of another group includes any of the above uses. More alkyl, alkyl, aralkyl or aryl, • •• 411 • •• •• • • • •• • •• • 1 0 • • • • • • • • ••• • • ••• • 0 ••• • • • • • • •• aII • • • ••• • ••• :: •• f ••• • 11: •• • •• "1 • t • I •• 11 •• t • •••• .11 •••• 32 bound to a sulfur atom.

The term "lower alkylamino", "alkylamino", "arylamino", "arylalkylamino" as used herein alone or as part of another group includes any of the above groups lower alkyl, alkyl, aryl or arylalkyl, attached to a kvdveatom.

The term "alkanoyl" as used herein as part of another group denotes lower alkyl attached to a carbonyl group.

The term "halogen" as used herein denotes chlorine, bromine, fluorine, iodine or CF3, with chlorine or fluorine being preferred.

The compounds of formula I are preferred which have the following structure iiR 0 CH, H CH, -..., 4 -... 1 ./e4-k \ ,. p. ''s CCO2Rx X_ _ - :. 6H van in R is OH, OLi or CH 3 '0. Rx an Li or H; X and -CH 2 - CH 2 Cl 2 - CH 2 CH 2 CH 2 '-CH.CH-, -Cr: C- or -CH2 '0-. and Z an R1R2 \ iJvan i R1 Ar phenyl eller phenyl, which includes one C) alkyl and / or halogenated substituent, R2a . • ••• • ••• • • • • • • ••• 0 • • • * • - R 1 is cycloalkylalkyl, such as cyclohexylmethyl, or R 1 also includes benzyloxy, which includes a halogen substituent; : • •• ••• - • •• •••• • •• ••• ••••• •• 33 R 2 and R 2a are the same and are hydrogen, halogen or lower alkyl; Z can also preferably be vane in R 1 and R 2 has the meaning given above with reference to the compound of formula II; Z can therefore preferably be .3 substituted phenyl, lower alkyl, cycloalkyl or _ phenylalkyl and R 4 are substituted phenyl, lower alkyl, sasom isopropyl, cycloalkyl or phenylalkyl; or ocks & kan z Aven forretAdesvis varaR6 No van in R is H, CH 3 or OH and R 6 an CH2 .in••• • ••• • • • • e • CH3 • • • • • ••• • ••• • • • • or (substituted) phenylmethyl, van in R 7 an H or CH 3.

Z may also preferably be 34 R4 R3 or R at least one of R 3 and R 4 is phenyl or substituted phenyl () and the remaining R 3 or R 4 is lower alkyl.

The compounds of formula I according to the invention can be prepared according to the following reaction sequence and description. •• se • •• • •••• •• •••• • • ■ •• o • S0 S • •• • • ••• 0 •• • • •••• • • • ••• • •••• • 1 • •• • 0 ••• • • • • •••• • Reaction sequence A. Preparation of compounds of formula I, van i X an -CH = CH OSi-C (CH) P (Oalkyl) 30 113 30 C6HIIIalkyl10-P-CH2-CH-CH2-OO2alkyl i + + I-CH2-CH-CH2-CO2alkylOalkyl 5Si-C (CH3) 3 A Arbuzov's reaction AC6HC6H _ IV IV I. (ai) 3 2. H 2 O CH 2 Cl 2 0 It HOI-CH2-cH-CH2-OO2alkyl OH alkanol-DCC phosphoric ester Si-C (CH3) 3 splitting \ C6HC6H V 0 alky10-P-CH2-CH-CH2CO2alkyl1 i OH 6 Si-C (CH3) 3 C6HC6H pyridine WE We S • •• •• • i ••• •• ••• • • ••• • • • •• • • • 0 • • • • • • •• •• • • •• 0 • •• ••• • • • •• • e • 111 ••• • •• 0 • •••• 0 WE I. (CH 3) 3 SiN (C 2 H) 2 (TMSNEt 2) 2. (COCl) 2; CH2Cl2 (Acid chloride formation) 0 alkyl10-P-CH2 -CH-CH2CO2alkyl 2 CI0 Si-C (CH3) 3 V C6HC6H VII CHO VIII CBr4 'Ph3P Wittig CH = CBr2 dehydrohalogenation CECH n-BuLi H20 IX X 1) Li anion formation (n-BuLi, THF) X 2) Condensation with phosphonochloridate VII 0 II alkyl10-P-CH2-p-CH2-OO2alkyl 0 CEC Si-C (CH3) 3 Z V N C6HC6H XI 100.1 • • • 00 • • • S • • • 00. • 041 • • • .000 • O0O0 0000 1000 000 00 • • XI 0 it HO-P-CH -CH-CH2CO2H 2 m OH lei Silyl ether splint (n-C4H9) 4NF, CH3COOH, THF Hydrolysis (LiOH, dioxane) IA XI selective reduction.

H2 '10% Pd-C MeOH, 1 atm 0 alkyl10-P-CH2 -9H-CH2CO2alkyl1) Silylene cleavage 4% CH 82) Hydrolysis i - 1 Zr-CHSi-C (CH3) 3 (cis) V N% C6HC6H XII 0 HO-f-CH21H-CH2-CO2H CHOH Z-CH (cis) IB 00 S • OAP • • .0 • • 06 Sat " • 06 • * 6.00 • • • ••• • • • Al "O. • 00" • • 00 6 4.0411. • 01 • OIDO • 00. • 00 • e OM • Reduction 0 $ 1 alkyl10-1 ,, - CH2-CH-CH2-0O2aalkyl CH 0 / 2 1 1 .--- C (CH3) 3 Cu // N \ 1 2 Z C6HC6HSilyl ether cleavage Hydrolysis XII H2 '10% Pd-C MeOH, 50 psi XIII 0 st HO-P-CH2 -CH-CH2CO2H i s CH of 2 OH CH2 1 Z ID 0. ... 0. 0 00.0 00 8.00 • V • • • • O. 4 • • • • ... • • • • 0 • • • • ... 0 • O.

• • . BOOS • ... 0 464 • • • • • • fa • • • 0 • Reaction Sequence B. Preparation of Compounds I, accustomed to the X bond (-CH = CH-) and trans, i.e. 0 H0-P-CH2 -CH-CH2 CO2 H = ) 7H0-H 4, CH (trans) IC HSn (h-C4H9) 3I1) n-C4H9Li 1II C Hydrostannatj.onCHjoderingCH (Metallation) titA% 4% C (n-CH9) 3SnHCHI2 Et2OCH 1I 'I2) VII Z ----- '> Z ----) Z0 <ondensation) AIBN, 1 ° C XVXVI 041, 0 O.p. • 41.0 00 • • • 0 • • • 041 • • • •• • 00 • • 00O 0600 • .00 • 000 04 0 * • 00 41180O • • • • .06414 • • • GOO. • 0 Alky10-P-CH 2CH-CH 2 CO 2 alkyl CHOSi-C (CH3) 3 γH (trans) C6HC6H XV II 0 HO-r-CH2-CH-CH2CO2H CH 6H CH (trans) 1 silyl ether cleavage IAOH, Dioxane (Hydrolysis) IC W0 • 41of • 0 0 • • 00 WOO * 0 • O. • 0.00 4.40 • • • * ADO 06 • • • • 4 •• • 4, "• •• • ••• s •• • • •• • • 000.

Reaction sequence C. Alternative preparation of compound I, used in the X bond (-CH = CH-) Ar trans, i.e. association IC.

CHOXondensationqHpEliminering0 0 P 1LiCH2? (Oalky1) 2 HO (Oalky1) 2 ■ CH-CH- (Oalkyl) 2 2p-Ts0H1 CH ./..% Z VIIIbenzene, ACH (trans) THF, -78 ° CXXi Z XXI XXI Hydrolysis water LiOH 0Acuric chloride formation 0 - 10-P-OH1. (CH 3) 3 SiN (C 2 H) 2 1 (TMSNEt2) 0 CHfi 2. (COCl) 2, Cat. DMFalky10-p-C1 CH1 I (trans), CH ZCH2Cl2CH XXIIi (trans) Z dioxane • O •• • SO • • • • •••• • 0 • •• • •• • • ••• •• S. 0 •• a ••• CP • • •• • •• ••••• • • • s ••• • • • •••• • XXI II K ondensation00 8elu 0oe a lky 10-P-CH 2 -C-CH 2 -O 2 alkylReduction fIINaBH4 .... riC, ....,: ...- C ,,., H ./ CH2-CHOa lky I., > THF, -78 ° C C2H0H XXIV OH 0I0OH alkyl-Q-P-CH -CH-CH2CO2alkylO1 i2HydrolysisHO-P-CH2 -CH-CH 2CO 2ii , CHOH-, H Arfi HCH C 1dioxanI z IC1z IC •• • •• • • •• • • ■ • •••• • •• • •••• • 0 ••• a • • 0 ••• •• • •••• 0 • •• • lb. "• •• • ••• • ••• • db. • $ ••••• Reaction sequence D. Preparation of compounds of formula I, used in X ar -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - 0 0 p (Oalky1) 2 (CH) 2 a (a and 1, 2 or 3) XXVXXVI 1. OH TMSNEt2 (COCl) 1, Cat. DMF (Acid Chloride Formation) CHO VIII Cl (CH) 2 a Z (Alky10) 3P III oe ooe 1o HiH Alky10-P-C1C49 /, ... 0 ".. alky10-P-CH2 -C-CH2 -CO2 alkyl Reduction .1ii (CH) 2 αCH 2 CH 2 alkyl (F12) and NaBH 4 1 Z> Z XXVII coupling C2HOH XXVIII THF, -78 ° C 0. '0,01,0 •• •••• a •• • • • 0 • • 0 ••• •• •• • • • • 41 • WO ••• •••••••• 0OH tiI alkyl10-P-CH2-CH-CH2CO2alkylHydrolysis in (CH2) dewatering 1 Containing 0OH III HO-P-CH2-CH-CH2CO2H I _ OH (j "2) a Z ID1 (a = 2) 1E1 (a = 1) IF1 (a = 3) ID (a = 2) IE (a = 1) IF (a = 3) 4111 00 SO • 4 06 • 0 SO 6000 • S. . 1160041 • 4 V 000 • • • w • • 0 04. 0 • 44 • • 0 044.0 • WOO. 00 0000 00 O0 0 • 0 00 • • Reaction sequence E. Preparation of compounds of formula I, used in X is -CH 2 O- Baeyer-Villiger Oxidation (MCPBA) 2. Bas Hydrolysis OHAlky1ering z1TsO-CH2-PO (Oalkyl) 2 XXIXBas CHO VIII XXX 0 Hydrolysis water LiOHalky10-P-OH / pi2 0 xxxl xxxii Acid chloride formation TMSNEt2 (COCl) 2) Cat. DMF, CHCl 2 P0 (Oalky1) 2 1 / pH2 0 1 dioxane • •• •• •• • s • • • •••• • • ••• • • l • • • • •• • • •• Al • •• • •••• • e • 0 a, * • •• • • • •• a 01,111 ••• • • •• • • •••• • 0 a1ky1-0-y-C1 CH / 2 2 ondensation no 0 CC ';' " CH2 CH2 alkyl 00 0 alkyl-10-y-CH2-C-CH2CO2alkyl / C H2 Reduction NaBH4 C2HOH XXXII'THF, -78 ° C2 XXXIV 0OH alkyl-f-CR2-CH-CH2CO2alkyl Cu / 2 Hydro Lys OH- 9OH HO-P-CH2 -CH-CH2CO2H 1 / CH2 dioxane IG121G •• - •••• • - •• - ••• '• •; •• •••••• 47 As can be seen from the above reaction sequence "A", compounds of formula I can be prepared by iodide A subjected to an Arbuzov reaction by heating iodide A A C H 16 O-Si-C (CH 3) 3 6H I-CH -C-CH -CO alkyl 2 2 2 and phosphite III IIIP (Oalky1) 3 using standardized Arbuzov conditions and phosphonate IV preparation procedures 0 it IV a1ky10-13 --- CH2 --- CH-CH2-0O2aly1 alkyloSi-C (CH3), C6HC6H (a new intermediate).

Phosphonate IV is then subjected to a phosphoric ester cleavage by treating a solution of phosphonate IV in an inert organic solvent, such as methylene chloride, then with • e • • • • • • • 8 0 • • • I • • • • • • • 0 • • • • • I • • • • • • • • • • • • • • • Bis (trimethylsilyl) trifluoroacetamide (BSTFA) and trimethylsilyl bromide under an inert atmosphere, such as argon, to form phosphonic acid V 0 VHO-P-CH2 -cH-CH2 -CO2 alkyl .

OH6 .Si-c (cH3) 3 C6HC6H (a new intermediate). 48 Phosphonic acid V is esterified by treating V in dry pyridine with a lower alkyl alcohol (such as methanol) and dicyclohexylcarbodiimide and the resulting reaction mixture is stirred under an inert atmosphere, such as argon, to give the phosphono monoalkyl ester VI (a new intermediate). Phosphone 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 suitable inert organic solvent). The resulting solution is cooled to a temperature in the range of about -0 ° C to about 0 ° C, treated with oxalyl chloride and catalytic dimethylformamide and then evaporated to give crude phosphonochloridate VII (a new intermediate). The phosphonochloride VII is dissolved in inert organic solvent, such as methylene chloride, benzene, pyridine or THF, the solution is cooled to a temperature in the range of from about -90 ° C to about 0 ° C and preferably from about -8 ° C to about -0 ° C and treated with a cooled (same interval as the solution of phosphonochloridate VII) solution of the lithium anion of acetylene X formed by treatment with a lithium cold, such as n-butyllithium in hexane or other inert solvent, XCECH using a molar ratio VII: X of the range 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 • 0 It XIalky10-P ---- CH2 ---- 0-cH2-co2alkyl 1 8 IIII Si-C (CH3) 3 \ C6HCCH (a new intermediate)., •• • •• 0 • I • • • • • • • • • ••• • • ••• 0 ••• • • ••• • • • •• • • • • • 49 Acetylenic phosphinate XI can then be used to prepare the various compounds of the present invention in the following manner.

Acetylenic phosphinate XI is converted to acetylenic phosphinate IA1 by subjecting XI to silyl ether cleavage by treating XI in an inert organic solvent, such as tetrahydrofuran, with glacial acetic acid and tetrabutylammonium fluoride to give ester IA1. 0 IA1alky10-P-CH2-SH-CH2-CO2alkyl 6H 14 1 which can then be hydrolyzed to the corresponding basic salt or acid, i.e. da Rx is Rxa, which 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 any other inert organic solvent under an inert atmosphere, such as argon, at 0 C, using a molar ratio of base: ester IA1 in the range of from about 1: 1 to about 1.1: 1 to give the corresponding basic salt. 0 IA2alky10-13-CH2-pi-CH2-0O2-Rxa 511 41 • 1 O.

• •• • • • • • • Compound IA2 can then be treated against strong acid, such as HCl to give the corresponding acid IA • 6 • • • ••• • • 4.0 • • .06 .66 • 6 0 • : ":" .. • •. • 1.1 • •• Si •••• • •• 11111, • ••• 1 • IA3 0 a1ky104-CH21H-CH2-CO2H II OH Estern IA1 can be transferred to the corresponding dibasic salt by treating ester IA1 with a strong base at 50 to 60 ° C using a molar ratio base: ester IA1 in the range from about 2: 1 to about 4: 1 to form IA4 0 IA4RxaO-P-CH2 -CH-CH2 -CO-Rxa 1 OH Hi z The dibasic salt IA4 can be transferred to the corresponding acid by treatment with strong acid, such as HCl to form acid IA.

Phosphinate compounds of the invention, van in X 5r (cis) -CH = CH-, i.e. IB is 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-pA-carbon, palladium-O-barium carbonate and an inert organic solvent, such as methanol, to give the silyl ether XII 0 alkyl10-P-CH2 --CH-CH2 CO2 -alkyl CH0 f. yH 7 "Cels, COis XII • • • • • • •• • 0 • 604 • • 646 (a new intermediate). 51 Silyl ether XII can then be subjected to silyl ether cleavage and hydrolysis as described above to give the ester IB1 0 IB1alky-p-CH2-cH-CH2-OO2-alkyl CHOH (cis) CH the basic salt I132 0 IB2alky-CH2-CH-CH2-0O2Rxa CH 6 H (i (cis) CH syran III3 0 a1ky.1-CH2-CH-CH2-CO2H CH 6H (cis) CH the dibasic metal salt I134 0 ••• IB4Rxa0-C111-CH-CH2-CO2Rxa •• e • I4.

' CHOH.

If •• • (cis) CH •• 1 . . • • • • • • • • • • ••• • • •• 0 • ••• and the corresponding diacid IB.

••• S I • • •• ▪ •• • 41 •• • 000. ..7. • • ":" • 000. ••: 0. f • • OAP 000. • 0 .. 000 • 000. 4.0 52 Posfinate compounds of the invention, van in X an -CH 2 -CH 2 -, i.e. ID is formed by subjecting acetylenic phosphinate XII to catalytic reduction, for example by treating XII with H2 in the presence of a reduction catalyst such as palladium-pa-carbon and an inert organic solvent such as methanol at 50 psi to give the silyl ether XIII XIII 0 alkyl10-P-CH2 --CH-CH2 CO2 -alkyl CH 1 2 , Si-C (CH) / 3 3 Z C6HC6H (a new intermediate).

Silyl ether XIII can then be subjected to silyl ether cleavage and hydrolysis as described above to give the ester ID1 0 ID1 alkyl10.1-CH2-gi-CH2-OO2-alkyl1 CH OH 1 2 CH 2 the basic salt ID2 0 0 TD2alky10-P-CH2 -CH-CH2-CO2Rxa, i - CH811 1 2 • • • • • • • • • • • • • • 0 • • • •• • • • • • • • • • • • 0 . ••• CH 2 • .0 • • w ••• ••• • •••:. • •• 0.; • •. ••• •••• • •• ••• • •••• •• 53 syran ID3 0 ID3alky10-11, -CH2-CH-CH2-CO2H CH2 OH 1 CH 2 the dibasic salt ID4 0 xa ID4R 0-1) -CH -CH-CH -CO Rxa 2 2 2 qH2 6H CH 2 and the corresponding diacid ID.

Referring to Reaction Sequence "B", compounds of Form 'I, used in the X bonding group between the phosphorus atom and the hydrophobic anchor Z are (trans) -CH = CH-, can be prepared by treating a mixture of acetylene X and n-C4H9SNH with a radical initiator, such as azobisisobutyrylnitrile (AIBN), hydrogen peroxide, benzoyl peroxide and the like, and heating the resulting solution to a temperature in the range of about 100 to about 10 ° C under an inert atmosphere, such as argon, to form the vinyl column XV Sn (n-C4H9) 3 XVCH • CH •• • • e • • 0 • • • • • • • • • ••• • • ••• • • • • • 00 • •• I • • • • • Vinyl stann 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. ••• •••• • •• ••• • ••••••• - 59 XVICH CH A cooled solution of vinyl iodide XVI (-78 to - ° C) in dry organic solvent such as tetrahydrofuran or ethyl ether is treated with a metallate-forming agent such as n-butyllithium in an inert organic solvent such as hexane and the mixture is cooled to a temperature of -78 ° C. to -0 ° C under an inert atmosphere, such as argon. The anion was added to a cooled (-78 to - ° C) solution of phosphonochloride VII at a molar ratio of XVI: VII in the range of from about 1: 1 to about 2: 1 and preferably from about 1: 1 to about 1.5: 1. dry, inert, organic solvent such as tetrahydrofuran or ethyl ether to give silyl ether XVII 0 XVIIaalkyl10-CH2-CH-CH2-OO2alkyl (trans) CH) i-C (CH) 3 CEz: CH C6HC6H (a new 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-C4H9) 4NF in an inert organic solution. agents such as tetrahydrofuran to form hydroxydi- / estern IC1 0 Clalky10-p-CH2-cH-CH2-OO2alkyl (trans) CHOH CH • •• •••• • • • • IN. • 00 0 0 • • 10 • • • • 1 • • / •• • • • 1 •••• • • • 1 • ••• • 1 • • •• 4 • • 11 • • • 5 Diester IC1 can then be hydrolyzed in the manner described above to give the basic salt IC2. 0 IC2I1 alkyl10-p-CH2-CH-CH2CO2Rxa (trans) 4CH (5H Cu syran IC3 IC3 0 0 alkyl1013-CH2-cH-CH2-CO2H CH OH CH the basic salt IC4 0 xa " IC4 R O-P-CH -CH-CH -CO2 Rxa 4pi 5H CH and the corresponding diacid IC 0 II ICHO-P-CH2 -CH-CH2 -CO2 H 7, CH OH HC O • •• • • • • • • • • • • a o ••• 4 • ••• • • ••• • • • *IN; $ ••• • It 9 5 56 In an alternative process, as shown in reaction sequence "C", compounds of formula I in which the X-bonding group between the phosphorus atom and the hydrophobic anchor Z is (trans) -CH = CH-, r1-may be assembled by aldehyde VIII CHO VIII7, subjected to a condensation reaction with a cooled (-90 DEG to 0 DEG C.) solution of dialkylmethylphosphonate and butyllithium (LiCH2PO (alkyl1) 2) in the presence of an organic solvent such as tetrahydrofuran or ethyl ether to give the hydroxyphosphonate XX 0 it T (Oalky1) 2 XXHO-CH-CH2 The p-hydroxyphosphonate XX is then treated with p-toluenesulfonic acid in the presence of benzene or toluene while heating to a temperature in the range of about 50 to about 1 ° C, preferably under AterflOde to eliminate water and form the trans-olefin XXI 0 it P (Oalkyl) 2 XXI (trans) 2CH CH ... •• • ••••in Z • •• • GI. • • • • • • • • ••• • which is hydrolysed by treatment with aqueous alkali metal hydroxide, such as LioH, in the presence of dioxane or something other inert organic solvent and then with acid, such as hydrochloric acid, to give the monoacid ester XXII • • • • • • ••• • • • e • • •• • • • • • •• • - : ". •• ■ •• •: :: • • • I • 5S "55 • •• ••• • •••• •• XXII 0 alky10-V-OH (trans) CH /% CH 1Z 57 A solution of the monoacid ester XXII in dry methylene chloride is treated with trimethylsilyldietylamine. The mixture is evaporated and the resulting oil is taken up in dry methylene chloride, cooled to 0 DEG C. and treated with oxalyl chloride and a catalytic amount of dimethylformamide under an inert atmosphere, such as argon, to give phosphonochloride XXIII XXIII 0 alkyl10-ILC1 (trans) 42CH CH z1 Phosphonochloridate XXIII is condensed with an alkyl acetoacetate dianion, such as methyl acetoacetate dianion in the presence of an inert organic solvent, such as tetrahydrofuran, at a gentle temperature from -90 to-° C using a molar ratio of phosphonochloride: 1 to about 0. : 1 to form the ketophosphonate XXIV . " • XXIVaalkyl-γ-CH 2 -C-CH 2 -OO 2 alkyl (tr ans) CH CH " z1 •• 00 isIt • • • • • • • • • • • • • • It • • • st (a new intermediate) which is reduced by treatment with a reducing agent, such as sodium borohydride in the presence of an alkanol, such as ethanol, during 1 formation of the phosphinate IC 58 •• • •• • • • •• • • tI • • • • 0 IC1 alkyl10-f-CH2-fH-CH2-OO2alkyl (trans) CH OH CH Diester IC1 can then be hydrolyzed in the manner described above to give the basic salt IC2. 0 0 IC2 alkyl10-T-CH2-CH-CH2CO2Rxa (trans) 4FHOH CH syran IC3 IC3 0 If alkyl10-f-CH2-H-CH2-0O2H (trans) CH OH Cu the basic salt IC4 0 xa IC4R O-P-CH -CH-CH2-CO2Rxa 2 (trans) CH OH 4 CH and the corresponding diacid IC.

Referring to reaction sequence D, compounds of formula 1 in which X is - (CH 2) a - and a are 1, 2 or 3, i.e. -CH2-, -CH2CH2- or -CH2CH2CH2-, are prepared starting from aldehyde VIII, which is Converted to halide Villa with f, "•;" "t • tet t • ::;. • - ea • • • • t: • s: • ••. •• ::: 0e • •••• • •• ••• • •••• •• 59 use of conventional procedures. For example, the aldehyde VIII can be reduced with NaBH 4 in the presence of ethanol and ether to give the corresponding alcohol. Villa CH2 OH , which is treated with mesyl chloride in the presence of an organic base, such as triethylamine, and a lasing agent, such as methylene chloride, to give chloride XXV (a = 1).

The chloride XXV is subjected to a condensation reaction, XXV being treated with phosphate III using a molar ratio of III: XXV in the range of from about 1: 1 to about 10: 1 and a temperature in the range of from about 100 to about 1 ° 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, e.g. LiOH, to give a corresponding monoester, which is treated with oxalyl chloride in the presence of an inert organic solvent such as dimethylformamide to give the corresponding phosphonochloridate XXVII. XXVII is condensed with an alkyl acetoacetate dianion, such as methyl acetoacetate dianion in the presence of an inert organic solvent, such as tetrahydrofuran, at temperatures ranging from about -90 to about-° C using a molar ratio of phosphonochloride to about 1. , 75: 1 to form ketophosphinate XXVII, which is ••• •••• a new intermediate. Ketophosphinate XXVII can then be reduced • • • • • reaction sequence C.

-. • • • • • •• • • • • •• • • • By referring to reaction sequence E, compounds of formula I, used in X ar -CH 2 O-, can be prepared starting from aldehyde VIII, which is subjected to a Baeyer-Villiger oxidation. • formed during the formation of the corresponding diacids ID, IE and IF • • e • • •• according to the procedures described with reference to I • • • ••• • ••• • • 60 by reacting VIII with meta-chloroperbenzoic acid (MCPBA) in the presence of an inert organic reading agent, such as methylene chloride, and then with a strong base, such as an alkali metal hydroxide such as KOH or NaOH and a solvent, such as tetrahydrofuran, to give 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 dimethylformamide under an inert atmosphere, such as argon, and a solution of a dialkyltosyloxymethylphosphonate XXX using a molar moiety XXX: XXIX in the range: 1 to about 3: 1 to give the corresponding dialkyl ester XXXI. The remainder of the synthesis described in reaction sequence E, i.e. preparation of the monoester XXXII, the chloride XXXIII, the ketophosphinate XXXIV (a new intermediate), diester IG1 and diacid 1G is similar to that previously indicated with reference to reaction sequence D.

The acetylene starting material X can be prepared from the corresponding aldehyde VIII VIIICHO by subjecting VIII to a Wittig reaction, for example by treating a cooled solution of VIII (- ° C to 00 ° C) in triphenylphosphine and an inert organic solvent, such as methylene chloride, with a solution of tetrabromomethane (C13r4) in an inert organic solvent , such as methylene chloride, to give vinyl dibromide IX CH = CBr2 IX •• • 041 • • • • • • * • • • • 9 ••• • Formulation IX is subjected to dehydrohalogenation by treatment with n-butyllithium in an inert organic solvent, such as hexane, under an inert atmosphere to give X.

• ••• • • O• dr • • 1 / •• • •• 0 • * • 61 • 1, •• • • 41 • • • • •• • •• • • * • • • a • • • • • • • • • •• • • O• • • • • • • a • • • • • Alternatively, aldehyde VIII can be transferred directly to acetylene X by treatment with dimethyldiazomethylphosphonate in the presence of potassium t-butoxide in an inert solvent such as tetrahydrofuran (-78 ° C to ° C) under an inert atmosphere.

The iodide release material A can be prepared starting from the bromide C OH Br-CH 2 -CH-CH 2 CO 2 alkyl (which is prepared using procedures as described in Tetrahedron Letters 26, 2951 (1985)) dissolved in dimethylformamide (DMF) with imidazole and 4-dimethylaminopyridine and the resulting solution is treated with t-butyldiphenylsilyl chloride under an inert atmosphere such as argon, to form the silyl ether D Ce415,, C6H? Si-C (CH3) 3 Br-CH2-CH-CH2 CO2 alkyl A solution of silyl ether D in an inert organic solvent such as methyl ethyl ketone or DMF is treated with sodium iodide under an inert atmosphere, such as argon, to give jodid A.

Those using the aldehyde compounds VIII, i.e. ar kanda associations.

The various intermediates IV, V, VI, VII, XI, XTI, XIII, 00: •: • 0 • •• •••• ••• • • •• ■ • • ••• 7 • 62 • • • • •• • • • • •• • I • • • • 7 • • • IN• I • • • • • • • , O • • • • • • •• • R • XVII and XXIV also form part of the present invention. These new intermediates can be represented by the following general formulas: 0 1 " XXXVR -P-CH -CH-CH-CO2alkyl a 122 R1 bOSi-C (CH3) 3 C6HC6H 1 which includes all stereoisomers thereof, van in Ra is alkoxy 1 or hydroxy and R b is alkoxy, hydroxy, Cl, -CH-Z, -CH 2 CH 2 CH 2 -Z, -CH 2 O-Z, -CH = CH-Z, -CH 2 CH 2 -Z, van i Z an a hydrophobic anchor s & as defined above; provided that when R1 is hydroxy, R1 is preferably hydroxy or alkoxy; and 0 if XXXVI alkyl10-P-CH -C-CH -CO alkyl 22 -CO. , alkyl 0 van i Z has the meaning given above, including all stereoisomers thereof.

The compounds of the invention may be prepared as racemic mixtures and may later be partitioned to give the preferred S-isomer. However, the compounds of the invention may be prepared directly in the form of their S-isomers as described herein and in the working examples set forth below. The compounds of the invention in inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) are reduced and are thus useful in inhibiting cholesterol biosynthesis, as shown by the following tests: • 441 04600 5 0 $ 41110 • 05.0 -0 63 • ••• 0 •••• • • • • •• • •• • • • • • • • • • • • • ••• • 1) Hepatic HMG-CoA is reduced in rats Hepatic HMG-CoA reductase activity in rats is assessed using a modification of the method described by Edwards (P. A. Edwards, et al., J. Lipid Res. 20:40, 1979). Rat hepatic microsomes were used as an enzyme source and the enzyme activity was determined by feeding the transfer of the 14C-HMG-CoA substrate to 14C-mevalonic acid.

Preparation of microsomes The liver is degraded from 2-4 with cholestyramine-fed, decapitated Sprague Dawley rats and homogenized in phosphate buffer A (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 centrifuged at 16,000 x g for 15 minutes at 40 ° C. The supernatant is deposited and centrifuged under the same conditions a second time. The other 16,000 x g supernatant is centrifuged at 100,000 x g for 70 minutes at 40 ° C. Pelletized microsomes are resuspended in a minimum volume of buffer A (3-5 ml per liver) and homogenized in a glass / glass homogenizer. Ditiotreitol was added (10 mmol) and the preparation was divided into equal parts, quickly frozen in acetone / dry ice and stored at -80 ° C. The specific activity of the first microsomal preparation was 0.68 nmol mevalonic acid / mg protein / minute.

Enzyme analysis The reductase is analyzed in 0.25 ml containing the following components at the indicated final concentrations: 64 0.04 molk potassium phosphate, pH 7.0 0.05 molKCl 0.10 moles of sucrose 0.03 molEDTA 0.01 molditiotreito1 3.5 mmolNaCl 1% dimethyl sulfoxide 50-200 lug microsomal protein 100 / moil 14C- / DL / 1jMG-CoA (0.05 / uCi, 30-60 mCi / mmol) 2.7 mmolNADPH (nicotinamide adenine dinucleotide phosphate) The reaction mixtures are incubated at 370 DEG C. Under the conditions described, the enzyme activity increases linearly up to 300 microsomal protein per reaction mixture and is linear with respect to incubation time up to 1 minute. The standardized incubation time chosen for drug studies is 20 minutes, resulting in a 12 to 15% transfer of HMG-CoA substrate to the mevalonic acid product. / DL / HMGCoA substrate was used at 100 μmol twice the concentration required to matte the enzyme under the conditions described. NADPH was used in Excess at a level 2.7 times the concentration required to achieve maximum enzyme rate.

Standardized assays for inhibitor evaluation are performed according to the following procedure. Microsomal enzyme is incubated in the presence of NADPH at 370 ° C for 15 minutes. DMSO vehicle with or without test compound was added and the mixture was incubated for an additional 15 minutes at 37 ° C. The enzyme assay is initiated by the addition of 14 C-HMG-CoA substrate. After 20 minutes of incubation at 37 DEG C., the reaction is quenched by the addition of .mu.l of 33% KOH. 311-Mevalonic acid (0.05 / Xi) was added and the reaction mixture was allowed to stand at room temperature for 30 minutes. 5 N HCl was added to lactonize the mevalonic acid. Bromophenol leaf was added as a pH indicator to monitor an adequate lowering of the pH value. Lactonize 6 ••• • •••• • • • • •• • •• • • • • • • 0 • • • • • • ••• • ring fir fortg5 30 minutes Yid room temperature. The reaction mixtures are centrifuged for 15 minutes Yid 2800 vary per minute. The overlying water shoes are layered on 2 g of AG I-X8 anion exchange resin (Biorad, formate form) held in 0.7 cm (inner diameter) glass columns and eluted with 2.0 ml of H 2 O. The first volume of 0.5 ml is discarded and the next 1.5 ml is collected and shaved for bide tritium and carbon 14 in 10.0 ml of Opti-fluoro scintillation syringe. The results are calculated as nmol of mevalonic acid produced per 20 minutes and corrected to 100% recovery in tritium. Drug effects are expressed as the value (concentration of drug that provides 50% inhibition of enzyme activity) derived from the compound dose-response yard with a stated 95% certainty. Transfer of lactic acid drugs to their sodium salts is by solubilizing the lactone in DMSO and adding a ten-fold molar excess of NaOH, after which the mixture is allowed to stand at room temperature for 15 minutes. The mixture is then partially neutralized (pH 7.5 - 8.0) using 1 N HCl and diluted in the enzyme reaction mixture. 2) Cholesterol1 synthesis in newly isolated.priL92EalLoallr_ Compounds which show activity as inhibitors of HMG-CoA reductase are valued for their ability to inhibit 14 C-acetate satin deposition in cholesterol in suspensions of newly isolated rat hepatocytes using methods originally described by Capuzzi et al. (D: M. Capuzzi and S. Margolis, Lipids, 6: 602, 1971) a.Isolation of steering wheel hepatoytes Sprague Dawley rAttor (180 - 220 g) is anesthetized with Nembutol (50 mg / kg). The abdomen is opened and the first branch of the intraocular vein (portal vein) is tied so that it closes. Heparin (100 - 200 units) is injected directly into the hAlven (vena caya) 66 in the abdomen. A single occlusive suture is placed on the distal section of the intradesven and the intradesven is cannulated between the suture and the first bifurcated vein. The liver is perfused at a rate of 20 ml / minute with preheated (370 ° C) oxygenated buffer A (HBSS without calcium or magnesium containing 0.5 mmol EDTA) after separation of vein to allow drainage of the effluent. The liver is further perfused with 200 ml of preheated buffer B (HBSS containing 0.05% bacterial collagenase). Following perfusion with buffer B, the liver is excised and decapsulated in 60 ml of Waymouth's medium to allow free cell dispersion in the medium. Hepatocytes are isolated by centrifugation at 1Ag speed for 3 minutes at 50 x g at room temperature. Pelletized hepatocytes are washed one Ong in Waymouth's medium, shaved and analyzed for viability by excluding trypan blat. These hepatocyte-enriched cell suspensions usually show 70-90% viability. b.Inforlivnialay 14C-acetate in cholesterol Hepatocytes Atersuspended in an amount of 5 x 6 cells per 2.0 ml of incubation medium (1M) / 0.02 M tris-HCl (pH 7.4), 0.1 M KCl, 3.3 mmol sodium citrate, 6.7 mmol nicotinamide, 0.23 mmol NADP, 1.7 mmol glucose-6-phosphate /.

The test experiences are routinely dissolved in DMSO or DMSO: H 2 O (1: 3) and added to the incubation medium. Final DMSO ". tration in the incubation medium is less than or equal to 1.0% • •••• and does not have a significant effect on cholesterol synthesis. • •• • •• • • • • • • • • • • Incubation is initiated by the addition of 14C-acetate (58 mCi / mmol, 2 μl / ml) and placement of the cell suspensions (2.0 ml) in 35 mm tissue culture scales at 37 ° C for 2.0 hours. After incubation, the cell suspensions are transferred to glass centrifuges and centrifuged at 50 g for 3 minutes at room temperature. Cell pellets are resuspended and lysed in 1.0 ml of 1120 and placed in an ice bath. ••• • • 0 •• • • • •• • ••• • • • • • •• • •••• • 00 ••• • ••••• •• 67 Lipids are extracted essentially as described by E. G. Bligh and W. J. Dyer, Can. J. Biochem. and Physiol., 37: 911, 1959. The lower organic phase is removed and dried under a nitrogen stream and the residue is resuspended in (100 μl) chloroform: methanol (2: 1). The total sample is usually placed on silica gel (LK6D) thin layer plates and developed in hexane: ethyl ether: acetic acid (75: 25: 1). Tiles are scanned and shaved using an automated scanning system of the BioScan type. The amount of radioactive markers in the cholesterol peak (RF 0.28) is determined and expressed at the total number (counts) per peak and as a percentage of the markers in the total lipid extract. Cholesterol peaks in iron cultures usually contain 800 - 1000 cpm and make up 9 - 20% of the markers present in the total lipid extract; the results are consistent with Capuzzi et al indicating 9% extracted moles in cholesterol.

Drug effects (percentage inhibition of cholesterol synthesis) are determined by comparing the percentage of markers in cholesterol for comparison with drug-treated cultures. Dose-response curves are compiled from composite data from two or more studies and the results are expressed as I-value with a 95% certainty. 3) Cholesterol synthesis in human skin fibroblasts Association selectivity that promotes inhibitory activity in hepatic political armament would be a distinguishing feature of a ". sterol synthesis inhibitor. In addition to the evaluation of cholesterol1- . ". a. • synthesis inhibitors in hepatocytes are therefore tested in these compounds "also regarding its activity as inhibitors of cholesterol- • appeared in cultured fibroblasts. • • • • • • • • a) Human skin fibroblast cultures • • • • • S • • • • Human skin fibroblasts (passages 7 - 27) are grown in the Eagles' mini- • • • • • Pt • • grind essential medium (EM) containing% fetal calf IP • • 68 serum. For each experiment, broth cultures were trypsonized to disperse the cell monolayer, determine the number, and transfer them into 35 mm tissue culture wells (5 x cells / 2.0 ml). Cultures are incubated for 18 hours at 37 ° C in 5% CO2 / 9% humidified room air. Cholesterol biosynthetic enzymes are induced by removing the serum-containing medium, washing the cell monolayers and adding 1.0 ml of EM, which contains 1.0% of free fatty acid, bovine serum albumin and incubating the cultures for a further 24 hours. b) Incorporation of 14C-acetate into cholesterol S ••• • •••• Induced fibroblast cultures are washed with EMEM100 (Eagle's minimal essential medium). Test results are dissolved in DMSO or DMSO: EM (1: 3) (final DMSO concentration in cell cultures less than or equal to 1.0%) and added to the cultures and the cultures are preincubated for 30 minutes at 37 ° C in 5% CO 2! 95% humidified room air. After preincubation with drug, / 1-14C / Na-acetate (2.0 / uCi / ml, 58 mCi / mmol) was added and the cultures are incubated again for 4 hours. After incubation, the culture medium is removed and the cell monolayer (200 .mu.g of cell protein per culture) is triturated in 1.0 ml of H2O. Lipids in the lysed cell suspension are extracted into chloroform: methanol as described for hepatocyte suspensions. The organic phase is dried under nitrogen and the residue is resuspended in chloroform: methanol (2: 1) (100 .mu.l) and the total sample is applied in layers to silica gel (LK6D) thin layer plates and analyzed as described for hepatocytes.

• Inhibition of cholesterol synthesis is determined by comparison of • "The percentage of markers in the cholesterol peak from the comparison • • • • • cultures and cultures treated with drugs. The results • 6 • • is expressed as the I-value and is derived from compound doses e • ••• • response curves from two or more experiments. A 95 percent. . ••• The safety value is also calculated from the combined • ". • set the dose-response curves. . • •• • 060 0 • * 9 A further aspect of the present invention is a pharmaceutical : 0: 01i • .44 '• 4.0 4.4a 69 a pharmaceutical composition comprising at least one of the compounds of formula I together with a pharmaceutical. vehicle or diluent. The pharmaceutical composition may be formulated using conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type suitable for the desired route of administration. The compounds can be administered orally, for example in the form of tablets, capsules, granules or powders or they can also be administered parenterally in the form of injectable preparations, which dosage forms contain from 1 to 2000 mg of active compound per dosage for use in the treatment. The dose to be administered depends on the unit dose, the symptoms and the age and body weight of the patient.

The compounds of formula I may be administered in the same manner as known compounds proposed for use in inhibiting cholesterol biosynthesis, such as lovastatin, in such mammalian species as humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in an amount of from about 4 to 2000 mg in a single dose or in the form of individual doses from 1 to 4 times a day, preferably 4 to 200 mg in divided doses of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4 times daily or in continuous release form.

The following embodiments represent preferred embodiments of the present invention. If nothing else Specifically, all temperatures are expressed in degrees 40. .400 Celsius. Flash chromatography was performed on either Merck 60 or Whatmann LPS-I silica gel. Chromatography in reverse phase . . .. conducted on CHP-20 MCI gel resin from Mitsubishi Ltd. the • • • 0 The abbreviations "Et 2 O", "EtOAc", "MeOH" and "EtO11" used in the following examples refer to ethyl ether, ethyl acetate, methanol and ethanol, respectively. • • • 40 1.0 • II 404 • • 00. 1.4 • • 0 • • • • • OE * 0.4 • 44 Pee • 0, fe, 70 Example 1 (S) -4- // 2- (4'-fluoro-3,3 ', 5-trimethyl- [1,11-biphenyl] -2-yl] -ethyl / methoxyphosphinyl] -3-hydroxybutanoic acid: methyl ester A.N- (2,4-dimethylbenzene, liden) benzeneimine Ref. Merck U.S. Patent No. 4,375,475 page 39.

A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich, 6.97 mL, 50 mmol) and distilled aniline (Aldrich, 4.56 mL, 50 mmol) in dry toluene (80.0 mL) was heated under reflux for 3.0 hours. under argon in a flask equipped with a Dean-Stark apparatus. The mixture was cooled and then evaporated in vacuo to a yellow oil. The crude oil was purified by color distillation (0.5 frame Hg, 160 - 180 ° C) and gay 8.172 g (78.1%) of the desired title benzeneimine in the form of a light yellow oil, which crystallized but it was allowed to stand to a solid with a melting point of 15 g. TLC (4: 1) hex-acetone, Rf = 0.67 and 0.77 (geometric isomers), UV and 2.

B.

•••••••• H3Pd- 0 OCCH 3 ••• ° •••• CII3 ••• ■■ • • •• 2 Ref. Merck U.S. Patent No. 4,375,475, page 39 A mixture of the benzeneimine of Part A (6.0 g, 28.7 mmol) in glacial acetic acid (144 mL) was treated with palladium (II) acetate (6.44 g, 28.7 mmol) and the clear, red, homogeneous solution. heated under reflux under argon for one hour. The resulting cloudy • • • • • 4 • • • • • •• • • • • • • • • • • • • • • O 0 • • • • ; "." • • • • * • 71 • 00 •••• II • S • • • .1 ee I • • • • • • • • • • •• 0 ••• • • • • the mixture was filtered hot through a packed bath Celite in 900 ml of 1120. Precipitated orange solid was collected by filtration and dried in vacuo at 6 ° C over P2016 hours and gay 10.6 g (85.5%) of the desired title palladium complex in the form of an orange solid with the melting point 194 - 1960 C (melting point given in the literature of a recrystallized analytical sample = 203 - 20o C).

C. 4t-Fluoro-3,3 ', - trimethyl / 1,1'-biphenyl / -2-carboxaldehyde (1) 11.I2L1114-211112172: 172YILtLELTalATTalitE.1,21, Ref. Merck U.S. Patent No. 4,375,475 p. 37 (Doh 38.

The Grignard reagent classified in Part C (1) was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmol), Fairfield Chemical Co.) dropwise at a rate sufficient to sustain the reaction at Aterflode. to stirred magnesium turnings (1.35 g, 55.4 mmol, 8.0 equivalents) in dry Et 2 O (70.0 mL). The reaction was initiated in an ultrasound device. When the bromide addition was complete, the mixture was stirred for one hour under argon at room temperature, boiled for minutes under reflux and then allowed to cool to room temperature. (2) 4'-flur-3,3 ', 5-tzimethyl / 1,1'-biphenyl / -2-carboxaldehyde In a second flask was stirred a mixture of the dipalladium complex of Part B (3.0 g, 6.92 mmol) and triphenylphosphine (14.52 g, 55.4 mmol, 8.0 eq.) In dry benzene (100 mL) at room temperature under argon for 30 minutes. Freshly prepared and filtered (glass wool stopper) grignard reagent from Part C (1) was then added in one portion using 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 and the mixture was stirred for an additional hour at room temperature and then filtered 72 through packed Celite (1 "bath). The filtrate was extracted with Et 2 O (250 mL), the extract was washed with brine (2 x 100 mL), dried over anhydrous MgSO 4 and evaporated in vacuo and gay 13.35 g of a viscous orange oil, which The crude orange solid was purified by flash chromatography on silica gel (700 g) and eluted with hexane and then with (95: 5) hexane-Et 2 O. Product fractions were combined and evaporated to give 1.507 g (89.9%). of the desired title aldehyde in the form of a light yellow solid, m.p. 72 DEG-70 DEG C. (in the literature, the melting point is stated to be 73 DEG-740 DEG C.).

TLC: (95: 5) hex-Et 2 O, Rf = 0.40, UV and PMA.

D.2- (2,2-dibromoethyl) -41-fluoro-3,3 ', 5-trimethyl- / 1,1'-biphenyl / A cooled (-0 ° C, salt / ice bath) solution of the biphenyl aldehyde Part C (242 mg, 1.0 mmol) and triphenylphosphine (787 mg, 3.0 mmol, 3.0 eq) in dry CH 2 Cl 2 (10 mL) was treated dropwise with a solution of C8r4 (497 mg, 1.5 mmol, 1.5 eq) in CH 2 Cl 2 (5.0 mL) over a 5 minute period. After 30 minutes at 0 ° C, the red-orange solution was partitioned between CH 2 Cl 2 and matt NaHCO 3. The organic phase was washed with matt NaHCO 3 and brine, then dried over anhydrous Na 2 SO 4 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-CH 2 Cl 2. Product fractions were combined and evaporated. . • . and bile 392 mg (99%) of the pure title vinyl the dibromide in the form of a light yellow oil.

TLC (95: 5) hex-EtOAc, Rf = 0.51, UV and PMA. • • • • • • 0 • IN• • ••• • E. 2-Ethynyl-4'-fluoro-3,3 ', 5-trimeth 1 / 1,11.7111enylL • ft Oef • •.

A -78 ° C (dry ice / acetone) reading of the vinyl dibromide in Part D 0100 • * • • RE * • O..

• • (336 mg, 0.844 mmol) in dry THP (5 mL) was treated dropwise by syringe with a 1.6 M solution of n-BuLi in hexanes 73 • ••• • •••• • • • • O • •• • 0 • • •• • * • • • • ••• • ••• • • ••• • • • •• • ••• • • • • (1.06 mL, 1.7 mmol, 2.0 eq) and the mixture was stirred at -78 ° C under argon for one hour. During the n-BuLi addition, clear color changes occurred from color yellow to dark yellow to light yellow to dark blue-purple. The mixture was quenched at -78 ° C by dropwise addition of saturated NH 4 Cl (4 mL), allowed to warm to room temperature and extracted with Et 2 O and the ether layer was washed with brine, dried over anhydrous MgSO 4 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 the desired title acetylene in the form of a colored oil which was gradually darkened to 15 DEG C. under argon.

TLC hexane, Rf = 0.18 UV and PMA.

F. (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4- (chloro- methoxyphosphinyl) -butanoic acid, methyl ester 000.0.0.0060 • 000 (1) (S) -4-bromo-3-112, b1LtahlyIELeIy.lester (1) (a) / R- (R *, R *) / - 2,3,4-trihydroxybutanoic acid, calcium salt, hydrate Ref. Carbohydrate Research 72, p. 301-304 (1979) Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid (44.0 g, 250 mmol) in H 2 O (625 mL), the suspension was cooled to 0 ° C (ice bath) and treated portionwise with 30% 11202 (100 mL) . The mixture was stirred at 30 DEG-0 DEG C. (oil bath) for 30 minutes. Darco (10 g) was added and the black suspension was heated on an Angbad until the evolution of O 2 ceased. The suspension was filtered through Celite and evaporated in vacuo (bath temperature 0 ° C). The remainder was taken up 1120 (50 ml), heated on an steam bath and continued with CH 3 OH until the solution was cloudy. The rubbery precipitate was collected by filtration and air dried IN ; • • • • •• • - • s; • ••. " • •• ■ •; • • os o • o • • •; • es., 74 gay 30.836 g (75.2%) of the desired calcium salt in the form of a powdery white solid.

TLC (7: 2: 1) iPrOH-N114011-H 2 O, 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, p. 341-344 (1983).

Calcium salt (30 g) from Part (1) (a) was dissolved in 30 - 32% HBr 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, which was taken up in CH 3 OH (75 ml) and heated under reflux for 2.0 hours and evaporated. The residue was partitioned between EtOAc (100 mL) and 1120, the organic phase was washed with 1120 (two Ongs) and brine and then dried over anhydrous Na 2 SO 4 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 and PMA. (1) (c) (S) -4-bromo-3-hydroxybutanoic acid, methyl ester Ref. same as for the preparation 1 (1) (b).

••• An argon-purged solution of the 41 bromide (20.80 g, 75.4 mmol) and anhydrous NaOAc (21.0 g) in EtOAc (370 ml) And glacial acetic acid (37 ml) were treated with 5% Pd / C (1.30 g) and • • •• The black suspension was stirred under H2 (1 atm.) While • •• • • H2 uptake was ever monitored. After 2.6 hours, H 2 uptake was • • • ••• • the mixture was completed, the mixture was filtered through Celite, • • •• • • ••• • •• •• • •• 0 • 0 The filtrate was washed with matt NaHCO 3 and brine and then dried over anhydrous MgSO 4 and evaporated to give a crude dibromester as a brown oil. The crude oil was combined with another seat (starting from 36.77 q of di- ••• '•; •.' 7 bromide) and vacuum distilled to give 25.77 g (61.3%) of the desired title bromine ester as a colorless oil, b.p. 79 DEG-800 DEG C. (1.0 mm Hg).

TLC (1: 1) EtOAc-hex, Rf = 0.44, PMA.

Analysis. Calculated for cH903Br: C 30.48; H 4.60; Br 40.56 Found: C 29.76; H 4.50; Br 39.86 (S) -4-bromo-3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] - butansra, iety__ A solution of bromohydrin from Part F (1) (4.0 g, 20.4 mmol), imidazole (6.94 g, 5.0 eq.) And 4-dimethylaminopyridine (4-DMAP) (12 mg, 0.005 eq. .) in dry DMF (40 ml) was treated with t-butyl diphenylsilyl chloride (5.84 ml, 1.1 eq.) and the homogeneous mixture was stirred over the surface under argon at room temperature. The mixture was partitioned between 5% KHSO 4 and EtOAc and the organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 9.32 g (100%) of crude silyl ether as a colorless, viscous oil.

TLC (3: 1) hex-EtOAc, Rf silyl ether = 0.75, UV and PMA (S) -4-Iodo-3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] - butanoic acid, methyl ester ••• ■ • ■ ••• ■ A solution of crude bromide from Part F (2) (9.32 g, 201 mmol) ••• • Treated in methyl ethyl ketone (60 ml, dried Over 4A sieves) •••• with sodium iodide (15.06 g, 100.5 mmol, 5.0 eq.) and the • •• • •• • • • • • • • ••• • ••• • • • • • • The yellow suspension was heated under Aterflode for 5 hours under argon. The mixture was cooled, diluted with EtOAc and filtered. and the filtrate was washed with dilute NaliSO 3 (until was color load) and saline and then dried over anhydrous Na 2 SO 4 and evaporated in vacuo and gay 10.17 g of a • • t • • • • •• • • • • • • yellow oil. The crude oil was purified by flash chromatography on silica gel (600 g) and eluted with (3: 1) hexane-Cl 2 Cl 2. Product fractions were combined and evaporated and gay ••• •••• •••• r •• •••• •••• • • •• ..:. • •• ■■ • • :•••'Smile •• • •• 0 •••• • • • to • •••• • ••••; •• 76 7.691 g (74.2%, total yield for the bathing steps) of% the thinned Liteljodide in the form of a clear, colorless, viscous oil. TLC (3: 1) hex-EtOAc, product. Rf = 0.75. UV and PMA. (Note: the product iodide has coincident flakes with the starting bromide.) (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 150 DEG C. (oil bath) for 3.5 hours under argon. The mixture was cooled and an excess of phosphite was distilled off in vacuo (0.5 mm Hg, 7 ° C) leaving a yellow oil ("/ 8.0 g). The crude oil was purified by flash chromatography on silica gel (400 g) and eluted with (4: 1) hexane-acetone Product fractions were evaporated and bile, 3.222 g (41.1%) of the desired title phosphonate as a clear, colorless, viscous oil.

TLC (1: 1) hex-acetone, Rf = 0.51, UV and PMA.

An additional 2.519 g (61.1% corrected yield) of the iodide starting from Part (3) was used as the starting material.

(S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4-phosphonobutanoic acid, methyl ester A solution of the phosphonate from Part F (4) (9.85 g, 20.0 mmol) in dry CH 2 Cl 2 (20 mL) was treated successively with bistrimethylsilyltrifluoroacetamide (BSTFA) (5.31 mL, 32.0 mmol, 1 , 6 eq.) And trimethylsilyl bromide (TMSBr) (6.60 mL, 50.0 mmol, 2.5 eq.) And the clear mixture was stirred over the surface under argon at room temperature. 5% KHSO 4 (80 mL) was added and the mixture was extracted with EtOAc. The aqueous phase was quenched with NaCl and re-extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give the gall / crude title phosphonic acid as a viscous oil.

TLC (7: 2: 1) iPrOH-NH 4 OH-H 2 O, Rf = 0.30, UV and PMA. : • '0 •• - • - •• •••• • •• ••• • •••• •• 77 (S) -3 - // (1,1-dimethylethyl) diZenylsilyl / oxy / -4- hydroxymethoxyphosphinyl) -butanoic acid methyl ester Crude phosphonic acid from Part F (5) (20.0 mmol) in dry pyridine (25 mL) was treated with dried CH 3 OH (over 3A sieves, 1.62 mL, 40.0 mmol, 2.0 eq.) And dicyclohexylcarbodiimide (DCC) (4.54 g, 22.0 mmol, 1.10 eq.) And the resulting white suspension was stirred under argon at room temperature above the surface. The pyridine was stripped off in vacuo and then azeotroped with benzene (2 x 15 ml). The residual oil was dissolved in FtOAc, filtered and washed with 1.0 N HCl and brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo and gay 8.272 g of the crude title ester as an oil containing ).

TLC (7: 2: 1) iPrOH-NH 4 -OH, Rf = 0.60, UV and PMA.

(S) -3 - // (1-dimethylethyl) diphenylsilyl / oxy / -4- (J.Lilest91_ • Crude phosphonic acid monomethyl ester from Part F (6) (6.595 g, 1.14.7 mmol) was dissolved in dry C 12 Cl 2 (30 mL), treated with distilled trimethylsilyldiethylamine (5.60 mL, 29.4 mmol, 2.0 eq.) And stirred under argon at room temperature for one hour. The mixture was evaporated in vacuo, taken up in benzene (1 x 30 ml) and dried in vacuo. The light yellow viscous oil was dissolved in dry CH 2 Cl 2 (30 mL) and DMF (dried Over 4A sieves, 2 drops). • pair) and the clear glaze was cooled to - ° C (salt / ice bath) ••• • •••• • • • •• and treated dropwise via syringe with distilled oxalyl chloride (1.41 mL, 16.2 mmol, 1.1 eq.) Rapid gas evolution was observed and the reading became more dark yellow in color. Among- • • • • The mixture was stirred under argon at - ° C for 15 minutes and stirred. • • • O• ese • • • • was then heated at room temperature for one hour. The mixture is evaporated • was taken up in vacuo, taken up in benzene (1 x 30 ml) and dried in • • ••••• vacuum and impure phosphonochloridate in the form of a yellow oil. • • ••• 78 • • • • • • • • e • • • • • • • •• • • • • • • • • (S) -4- [2- [4'-fluoro-3,3 ', 5-trimethyl- [1,11-biphenyl] -2-yl] ethynyl] methoxyphosphinyl] -3-t-butyldiphenylsilyloxybutanoic acid, methyl ester A -78 ° C (CO 2 / acetone) solution of the acetylene in Part E (2.678 g, 11.2 mmol) in dry THF (20 mL) was treated dropwise with a 1.6 M solution of n-BuLi in hexanes (7 mL, 11.2 mmol, 1.0 eq.). The purple mixture was stirred under argon at -78 DEG C. for one hour, heated briefly to 0 DEG C., cooled to -78 DEG C., cooled by cannulae in an addition funnel and added dropwise to a -78 DEG C. (CO2 / acetone) solution. of the phosphonochloridate in Part F (8.27 g, 18.4 mmol, 1.6 eq.) in dry THF (20 mL). After one hour at -78 ° C, the mixture was quenched with saturated NH 4 Cl, then allowed to warm to room temperature and extracted with Et 2 O. The ether layer was washed with matt NaHCO 3 and brine and then dried over anhydrous M00 4 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 the desired title acetylenic phosphinate as a light brown oil. In addition, 457 mg (68% corrected yield) of the biphenylacetylene was recovered in Part E.

TLC (7: 3) hex-acetone, Rf. 0.20, UV and PMA.

(S) -4 - [(2- [4 * -fluoro-3,31,5-trimethyl- [1,11-biphenyl] -2-yl] ethyl] methoxyphosphinyl] -3-t-butyldiphenylsilyloxybutanoic acid, methyl ester An argon-purged solution of the acetylenic phosphinate in Part G (333 μg) in CH 3 OH (5 mL) was treated with 10% Pd / C (125 mg, 36 wt%) and shaken on a Parr apparatus under H (40 psi ) 30 hours. The catalyst was removed by filtration through packed Celite and the filtrate was evaporated to a light yellow oil. The crude oil was purified by flash chromatography on silica gel eluting with (1: 1) EtOAc-hex. Product fractions were evaporated and gay 250 mg (75%) of the crude 79 matte phosphinate in the form of a clear oil. TLC (4: 1) EtOAc-hex, Rf = 0.33, UV and PMA.

J. (S) -4-1 / 2- (4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] - 2-Wetyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the silyl ether in Part H (330 mg, 0.489 mmol) in dry THF (6 mL) was treated with glacial acetic acid (11.96 mmol, 4.0 eq.) And then with a 1.0 M tetrabutylammonium fluoride solution in THF (1.47 mL, 1.47 mmol, 3.0 eq.) And the resulting mixture was stirred over the surface at room temperature under argon. The mixture was diluted with 10 mL of ice water and extracted with EtOAc (2 times). The organic phase was washed with matt NaHCO 3 and brine and then dried over anhydrous Na 2 SO 4 and evaporated to give 364 mg of a pale yellow oil. The arena oil was purified by flash chromatography on silica gel eluting with (6: 4) acetone-hexane. Product fractions were evaporated and gay 205 mg (96%) of the desired title free alcohol was in the form of a clear oil, which crystallized slowly on standing.

TLC (7: 3) acetone-hexane, Rf = 0.28, UV and PMA.

Example 2 (S) -4 - // 2- [4g-fluoro-3,3 ', 5-trimethyl] -1,1-biphenyl / -2-ethyl] - dilitium salt • ••• • A solution of the diester in Example 1 (187 mg, 0.429 mmol) Dioxane (5 ml) was treated with a 1.0 N L10H solution (1.29 ml, • 1.• mmol, 3.0 eq.) And the mixture was heated at 5 ° C • • • • • (oil bath) under argon 2.5 hours. The mixture is cooled, • • • Spit with 11201, filtered and evaporated in vacuo. Ater- . The residue was dissolved in a minimum amount of 1120 and chromatographed ••• • pA 1IP-20 resin (25 mm c ion diameter, 1.15 cm bath) and • ••• • •• was triturated with 11 and then with a (1: 1) CH 3 OH-H • • • ••• ning. Collected product fractions were evaporated, IOstes in . • • ••. *: •• •••• • •• ••• I •••• •• 80 H 2 O (50 mL), filtered and lyophilized and gay 175 mg (91%, calculated on hydrate weight) of the desired title di- the lithium salt in the form of a white electrostatic solid TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAc, Rf = 0.1, UV and PMA and (7: 2: 1) iPrOH-NH 4 O 11 -H 2 O, Rf = 0, 45, UV and PMA.

Microanalysis for C211-1240FPL12 and 1.7 moles of H2 O (molecular weight 450.90) Berdknat: C, 5193; H, 6113; F, 4.21; P, 6.87 Found: C, 55.91; H, 5.84; F, 3192; P, 6189 1 H-NMR (400 MHz, CD 3 OD) 61.34 - 1.56 ppm (4H, multiplet) 2.22 - 2131 ppm (2H, multiplet) 2,2,37 ppm (61 !, tvA singlets) 2.29 ppm (31 !, doublet, jH-F = 1'4 Hz) 2.7ppm (21 !, multiplet) 4.13 ppm (1g, multiplet) 6.73 - 7.10 ppm (51 !, multiplet) Example 3 (S) -4 - // 2- / 4'-fluoro-3,3 ', - trimethyl / 1,11-biphenyl / -2-yl / ethynylimethoxyphosphinyl / -3-hydroxistezine A mixture of the silyl ether from Example 1, Part G (455 mg, 0.768 mmol) and glacial acetic acid (155 μL, 2.71 mmol, 4.0 eq.) Of dry THF (7 mL) was treated with a 1.0 M tetrabutylammonium fluoride solution in TI -IF (2.0 mL, 2.0 mmol, 3.0 eq.) And the resulting solution was stirred over the surface under argon at room temperature. The mixture was halided in ice-cold H 2 O (10 mL) and extracted with EtOAc (2X). The organic phase was washed with saturated NaHCO 3 and brine, then dried over anhydrous Na 2 SO 4 and evaporated to give 498 mg of a yellow oil. The crude product was purified by flash chromatography silica gel and eluted with (3: 2) hexane-acetone. Product shipping f * • • •• • • I • 0 • IN• / • • I • • l • • • t •••• • ••• • • 611.

• • •• • ID • I • D • • 00 0 • * 0 .4.0 • •• 1.64 • 0Ogo 00 81 ions were evaporated and gay 217 mg (74%) of the title alcohol as a colorless oil.

TLC (7: 3) hexane-acetone, Rf = 0.10, UV and PMA.

Example1 4 (S) -4 - // 2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / ethynyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A mixture of the diester of Example 3 (203 mg, 0.469 mmol) in dioxane (6 mL) was treated with a 1.0 N LiOH (1.6 mL, 1.6 mmol, 3.5 eq.) And the solution was heated at 50 ° C. (oil bath) under argon for 30 minutes. The mixture was cooled, diluted with H 2 O, filtered, evaporated, taken up in H 2 O (30 mL) and lyophilized. The white lyophilate was dissolved in a minimal amount of 1120 and chromatographed on HP-20 resin (25 mm diameter column, 10 cm resin bath) and eluted with 1120 and then with (50:50) H 2 O-CH 3 OH. Product fractions were combined and evaporated, the residue was taken up in H 2 O (30 mL) and lyophilized to give 199 mg (97%, shaved pA hydrate, molecular weight = 435.36) of the title dilitium salt as a white solid.

TLC (8: 1: 1) CH 2 Cl 2 -C 1130H-HOAc, Rf = 0.15, UV and PMA.

Microanalysis for C21110FPL121.06 mol 1120 (molecular weight 435.36) Calcd: C, 57.93; H, 5.12; F, 4736; P, 7.11 • ••• ••• • Found: C, 57.91; H, 4.89; F, 4.22; P. 6.89 1 H NMR (400 MHzCD 3 OD): •• Δ 61.76-1782 ppm (2H, multiplet) • •. • • 2132 (3H, doublet, 3HF = 1/8 Hz) • • • 2.34 (3H, singlet) •. • • ... • 2737 (1H, dd, 3 = 8.4 Hz) a • • • 2.41 (1H, dd, J = 4, 1 Hz) • •• • 2149 (3H, singlet) •• . • • . .4.27 (1H, multiplet) . ... • • .6198-7.37 (5 H, m) • 9 82 Example (S, Z) -4 - // 2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / ethylmethoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester (S, Z) -4 - // 2- [4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl] -2-yl / ethenyl / methoxyphosphinyl] -3-t-butyldiphenylsilyloxybutanoic acid, methyl ester A gas-free solution of the acetylenic phosphinate in Example 1, Part G (498 mg, 0.742 mmol) in CH 3 OH (10 mL) was treated with 10% Pd / C (50 mg, 10% by weight) and the black suspension was stirred under an H2 atmosphere (1 atm) for 2 hours. The catalyst was removed by filtration through Celite and the filtrate was 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 the desired clef but in the form of a colorless oil.

TLC (4: 1) EtOAc-hexane, Rf diastereomers = 0.44 and 0.51, UV and PMA.

(S, Z) -4 - // 2- [4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl] -2-yl / ethenyl / methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A solution of the silyl ether in Part A (498 mg, 0.74 mmol) in dry THF (6 mL) was treated with glacial acetic acid (170 μL, 2.96 mmol, 4.0 eq.) And then with a 1.0 M tetrabutylammonium fluoride solution. in THF (2.2 mL, 2.2 mmol, 3.0 eq.) and the clear, colored mixture is stirred at room temperature under argon for 16 hours. TLC indicated a small amount of residual starting material. Additional HOAc (p1 1.0 eq.) And n-Bu4NF (0.74 mL, 1.0 eq.) Were added and stirring was continued for 6 hours. The mixture was diluted with fresh cold H 2 O (10 mL) and extracted with EtOAc (2X). The combined extracts were washed with matt NaHCO 3 and brine, dried over i ***: -: •• "'i 7 — s • •• -: I • •••• 111.1 • •• ••• • @ Ill. & .09 83 anhydrous Na2 SO4 and oh evaporated and gay 468 mg light 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 the title alcohol as a colorless oil. TLC (7: 3) hexane-acetone, Rf = 0.19, UV and PMA.

Example 6 (S, Z) // 2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / ethenyl / hydL_oxiLT_flliy_1, L_3-ty.dr2Llbut_a_ns.ua, dilithium salt A solution of the diester in Example 5 (240 mg, 0.552 mmol) in dioxane (7 mL) was treated with a 1.0 N LiOH solution (1.9 mL, 1.9 mmol, 3.5 eq.) And the stirred the mixture was heated under argon at ° (oil bath) for 3 hours. Fn white fall was clear. The mixture was cooled, diluted with 1120, filtered and evaporated in vacuo to a white solid. The crude solid was added to a minimal amount of 1120 and chromatographed on HP-20 resin, eluting with 1120 and then with (50:50) H 2 O: CH 3 OH. Product fractions were combined and evaporated, taken up in 1120 (50 ml), filtered and lyophilized and gay 255 mg (100%, stripped of hydrate weight, molecular weight 457.58) of the title dilitium salt as a white electrostatic solid.

TLC (8: 1: 1) CH 2 Cl 2 -CH 3 O 11 -HOAc, R f = 0.26, UV and PMA.

Microanalysis for C21 "22 °" Li2 4. 2.18 mol 14 (457.58): Berdknat: c, 55.12; H, 5.81; F, 4.15; P, 6.77 Found: C, 5/35; H, 168; F. 4127; E, 7.09 ::: ** ••• • ••• ••••••••• •• 0 •• ••: ‘0. • •• 0 ••• • 4 * ••••••• e • 84 1 H NMR (400 MHz, CD 3 OD): 51 (24 ppm (2H, multiplet) 2109 (211, Cubblett, J = 6.2 Hz) 2/27 (311, doublet, jHF = 1'8 112) 27 (311, singlet) 2.38 (3H, singlet) 4.06 (1H, multiplet) 787 (111, d doublet, JHH = 12.4 Hz, JHp = 14.3 Hz) 6787 (111, s) 691 (111, d dubb1ett, JHp = 43/4 Hz) 6198 (211, triplet) 7/22 (211, multiplet) Example 7 (S) -4 - // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -1- ethyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A. 2 - [(4-fluorophenyl) methyl] -3-oxobutanesyalcyl] ester • •• • •••• • • • • •• • •• • • • • el • • • • 44 • ••• • • ••• • • • •• • ••• • 4 4 4 • Sodium pellets (8.31 g, 362 mmol) were dissolved under mechanical stirring in absolute EtOH (1 liter) and distilled ethyl acetate (47 g; 362 mmol, 1 eq.) Was added to the clear solution under argon. The light yellow? the mixture was boiled under reflux for one hour, cooled to room temperature, treated with 4-fluorobenzyl bromine, 98 mmol, 1.1 eq.) and the The light orange mixture was stirred under argon at room temperature for 2.5 hours. The mixture was concentrated in vacuo. The residue was partitioned between EtOAc and H 2 O, the organic phase was washed with 11 (2X) and brine, dried over anhydrous Na 2 S 94 and evaporated to 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 at a boiling point of 142 DEG-144 DEG C.

TLC (7: 3) hex-Et 2 O, Rf-pro (odor), 31. in.•••• ••; ••• • 1 • • •••••• • :: •. •: • • ••• * • ••••• •••• • •• ••• ■ • •••• 04, 8 1 H NMR (CDCl 3): 61.20 (311, t), 2.19 (311, s), 3.13 (211, d), 3.73 (111, t), 4.14 (211, q), 60.95 (211, t), 7013 (211, M) PPM. 13 C NMR (CD 3 CN): 614.4, 29.7, 33.7, 62.1, 62/3, 103, 116.8, 131.4, 131.9, 145.1 (Jc-F = 284 Hz), 170 (1, 2035, ppm).

B.3- (4-fluorophenyl) -1H-indole-2-carboxylic acid, ethyl ester Male reference: Chemical Abstracts, volume 33, page 587 Male reference: R. Helmuth et al., J. Chem. Society p. 6 - 7 (1927) Male reference: Preparative Organic Chemistry, fourth edition, p. 582 (1972).

A solution of the ester in Part A (46.4 g, 195 mmol) in absolute EtOH (290 mL) at 0 ° C (ice bath) was treated with an aqueous NaOH solution (23.4 g, in 58 mL 1120). immediately with a benzene diazonium chloride solution (Prep. Org. fourth edition, p. 582 (1972) prepared from aniline (17.8 ml), conc. HCl (88 ml), 1120 (98 ml) and NaNO2 (13.5 g)) and gay a dark orange-red biphasic solution. The mixture was stirred for one hour at room temperature, halided in ice-cold 11 (500 ml) and extracted with EtOAc (3 x 300 ml). The organic phase was washed with brine (500 mL), dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 55.62 g of crude hydrazone intermediate as an orange oil. TLC (7: 3) hex-Et 2 O, Rf hydrazone =, 0.22, UV and PMA.

. • • Crude material was used as it was for the following Fischer . . cyclization.

• •• • • • • II • A solution of the hydrazone in absolute EtOH (200 mL) was treated with gaseous, bubbling HCl for 30 minutes with intermediate cooling in an ice bath. The brown active mixture is halided in the ice edge ••• ■ • • •• 86 H 2 O (600 mL) and extracted with EtOAc (3X). The organic phase was washed with H 2 O (2X) and brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to a tan red solid. Trituration with ice-cold hexane and filtration gay 26.74 g (49%) of the desired title indole in the form of reddish-brown, granular crystals with a melting point = 129 - 10 ° C.

TLC (7: 3) hex-Et 2 O, Rf = 0.26, UV and PMA Microanalysis for C17H14FNO2: Berdknat: C 72.07; H 4.98; F 6.71; N 4.94 Found: C 72.38, H 5.05; F 6.87; F 5.01 1 H NMR (CDCl 3): 61.22 ppm (3H, t), 4129 (2H, q), 7.10-7.62 (8H, m), 9.21 (18, bs) ppm. 13 C NMR (CDCl 3): δ 14.1, 60.9, 111.8, 11415, 114) δ, 120.9, 121.4, 122.9, 123.1, 125.9, 127.9, 129, Δ, 132.2 (Jc_F-7.6 Hz), 135.7, 162.0, 162.2 (Jc_F = 244 Hz) ppm.

C.3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole-2-carboxylic acid acid, ethyl ester Manual: Sandoz International Patent No. 158675, p. 35 (1984) A solution of the indole in Part B (26.74 g, 94.4 mmO1) in dry, distilled dimethylacetamide (100 ml) at 0 DEG C. (ice bath) was treated portionwise (strong gas evolution) with 60% Nail dispersion in mineral oil (4, 53 g, 113.3 mmol, 1.2 eq.) And the mixture was stirred under argon at 0 ° C for one hour. 2-Iodopropane (85 g, 500 mmol, 5.3 eq.) Was added and the mixture was allowed to warm to room temperature under argon and stirred for one hour. The mixture was cooled Anyo to 0 ° C, treated with an additional 1.2 eq. Nail and stirred at room temperature for one hour. This procedure was repeated further tv5 ginger. The final •• ••• • •. • ••: ••• : •• 3 :: • • • • ••• ••: ••••••••. • •• • • • • 9 ••• •••• • • • •• • • I 87 The mixture was cooled to 0 DEG C. (ice bath) and the excess of NaH was waved by careful dropwise addition of absolute EtOH (30 mL). The mixture was diluted with EtOAc, quenched with 5% KHSO 4, the aqueous phase was back-extracted once with EtOAc, the combined EtOAc layers were washed with H 2 O and brine (2X), dried over anhydrous Na . The solid was taken up in hot CH 2 Cl 2 and the like The starting material using the indole was crystallized by adding hexane. 13.88 g of the starting material used as the starting material were recovered. The mother liquor was evaporated in vacuo and gay 22.32 g of a brown oil. The crude product was purified by flash chromatography on silica gel eluting with hexane and then with (95: 5) hex-acetone. Product fractions were evaporated to give the gay 6.55 g (21%) (62% corrected yield) of the desired title N-isopropylindole as a yellow oil.

TLC (4: 1) hexane-acetone, Rf = 0.57, UV and PMA 1 H NMR (CDCl 3): 61104 (3H, t), 1.20 (6H, d), 4.17 (21 !, q), (40 (11 !, m), 7710-7.7 (81 !, m) ppm. 13 C NMR (CDCl 3): δ 13.6, 21/5, 4817, 5373, 6078, 11277, 11475, 114,8, 120 „3, 121 (4, 122 (4, 12413, - 119, 127.6, 130.8, 131.7 (jC-F775 Hz), 136.2: 162.3 (Jc-F = 144 Hz), 16370 ppm.

D. 3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole-2-methanol Lithium aluminum hydride (1.12 g, 29.6 mmol, 1.5 eq.) Was added . • gently to a 00 C (ice bath) solution of dry, distilled • • • Et 2 O (30 mL). The resulting suspension was treated dropwise • • • .for 10 minutes with an ether loading of the indole ester in Part C. .. ••• • (6.42 g, 19.7 mmol in 20 mL of Et 2 O). After stirring 30 minutes • at 0 ° C under argon, the mixture was quenched by the following .. 0 • • 0 • dropwise addition of H 2 O (1.1 mL), 15% NaOH (1.1 mL) • • " . . "and 1120 (3.4 ml). Part of the suspension was filtered through ••• ••• • ••• ••• • ••• ••• • •• ••• • ••• 88 packed Celite, dried over anhydrous MgSO 4 and evaporated in vacuo and gay 5.1 g of a yellow foam. The crude product was purified by flash chromatography on silica gel eluting with (85:15) hex-acetone and gay 5.08 g (91%) of pure title alcohol as a pale yellow foam.

TLC (7: 3) hex-acetone, Rf = 0.38, UV and PMA.

A small sample was crystallized from hexanes and gay the title alcohol in the form of white crystals with a melting point = 101 - 103 ° C.

Microanalysis for C1017NOF: Calcd: C 76.30, H 6.40; F 6.71; N 4.94 Found: C 76.49, H 6.46; F 6.84; N 4.88 111 NMR (CDCl 3): δ 1.60 (1H, t), 1) 69 (6H, d), 4.76 (2H, d), 4.93 (1H, m), 7) 05-7.62m) PPm. 13 C NMR (CDCl 3): δ 20.9, 47.3, 54.8, 113.10, 115.9, 116.3, 116.6, 120.2, 11.6, 12209, 128.5, 13106, 132.4, 135.1, 13517, 16300 (jc .... F = 245 Hz) ppm.

E.3- (4-fluorophenyl) d • • OS • A solution of Dess-Martin periodinane (5.9 g, 13.9 mmol, 1.2 eq.) In dry Cl 2 Cl 2 (30 mL) was treated with dry t-butanol (1.3 mL, 13.9 mmol, 1 mL). , 2 eq.) And the mixture was stirred at room temperature under argon for 15 minutes. The indole alcohol of Part D (3.28 g, 11.6 mmol, 1 eq.) In dry CH 2 Cl 2 (12 mL) was added dropwise over 5 minutes and the yellow mixture was stirred under argon at room temperature for one hour. The reaction mixture was added to a stirred solution of sodium tir, 11fat (15.3 g, 97 mmol, 7 eq.) In the novel 1.0 N FLO 3 (40 mL) and the resulting mixture was stirred vigorously with S-linter. The organic form was separated, washed with Sri, N NaHCO 1120 and brine, dried over anhydrous Na 2 SO 4 and IS 4 9 • • 0 • • • • • • ••• 0 89 evaporated and gay 3.69 g of yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (40: 1) hexane-Et 2 O and gay 2.7 g (83%) of pure title aldehyde as a white crystalline solid, m.p. = 88-89 ° C.

TLC (7: 3) hex-acetone, Rf 0.56, UV and PMA.

Microanalysis for cieljNo: Berdknat: C76.85; H5.73; N 4.98; F 6.7 Found: C76.91; H5.71; N4.95; F 6.76 1 H NMR (CDCl 3): 61.69 (6H, d), 592 (1H, m), 7.10-7170 (8H, m), 9.80 (1H, s) ppm. 13 C NMR (CDCl 3): 621.4, 48.0, 112.5, 113.2, 115.4, 1r7, 120, .8, 122r1, 126.9, 127r0, 132r0, 132.6 (JC-F = 7/5 Hz), 183.6 ppm.

F.3- (4-fluorophenyl) -1- (1-methylethyl) -2- (2,2-dibromoethyl) - 1H-indole A cooled (- ° C, ice / salt bath) solution of the indolaldehyde in Part E (1.84 g, 5.54 mmol) and triphenylphosphine (5.14 g, 19.6 mmol, 3 eq.) In dry CH 2 Cl 2 (30 mL) were treated dropwise for 5 minutes with a dry CH 2 Cl 2 (10 mL). solution of cBr4 (3.25 g, 9.8 mmol, 1.5 eq.) and the yellow mixture is stirred at ° C under argon for 15 minutes. The mixture was distributed between • ••• • •••• • . •• • •• • • • Late matte NaHCO3 and CH2Cl2, and the organic phase was washed with matte NaHCO3 and brine, dried over anhydrous Na2SO4 and evaporated to give 9.44 g of brown oil. The arena product was purified by flash chromatography on silica gel V • • • . And eluted with (95: 5) hexane-CH 2 Cl 2. Product fractions included • 0 • 0 • • evaporated and gay 2.87 g (100%) of the desired title • • • • the yinyl dibromide in the form of a yellow oil, which crystallized • 0 •• • •• • • • • dA den tick stA. A recrystallization from ethyl ether gay 2.46 g (86%) of purified product as light yellow granular crystals 90 with a melting point of 135 - 137 ° C.

TLC (7: 3) hex-CH 2 Cl 2, Rf = 0.45, UV and PMA Microanalysis for C19H16NF Br2: Calculated: 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 1 H NMR (CDCl 3): δ 1.15 (6H, d), 4167 (1H, m), 7.10-7.70 (9H, m) ppm. 13 C NMR (CDCl 3): δ 21e9, 48.6, 98/6, 11116, 113, 115.6, 119, 119.9 (3C-F = 7 to 6 Hz), 122.4, 127/5, 129 / 3, 1) 1 130.7, 130.9, 1/2, 161/5 (Jc_F = 246 Hz) ppm.

G.3- (4-fluorophenyl) -1- (1-methylethyl) -2-ethynyl-1H-indole A -78 ° C solution (dry ice / acetone) of the vinyl dibromide in Part F (2.395 g, 5.48 mmol) in dry THF (10 mL) under argon was treated dropwise with a 1.6 M solution of n-BuLi in hexanes ( 6.9 mL, 10.96 mmol, 2 eq.). The resulting mixture was stirred at -78 ° C for one hour and then quenched by dropwise addition of matt NH 4 Cl (5 mL). The mixture was allowed to warm to room temperature and then extracted with Et 2 O (2X). The ether layers were washed with brine, dried over anhydrous MgSO 4 and evaporated in vacuo and gay 1.893 g of dark brown oil. The crude product was purified by flash chromatography on silica ••• gel (80: 1) and eluted with (200: 1) hexane-Et 2 O and gay •••• 1.12 g of purified product in the form of a (3.3: 1) mixture of • by chromatography on alumina (neutral, activity = II) - • 9 • • •• Column and eluted with (200: 1) hexane-Et 2 O. Evaporation of • e • • • product fractions gay 900 mg yellowish-white crystals. A recrystalline -. • . • ▪lization from hot hexane gay 700 mg (46%) purified heading • • acetylene in the form of white needles with a melting point = 10-106o C. • ••• • • acetylene and final olefin. This mixture was separated • • • O• IN.

I • • • TLC (95: 5) hex-Et 2 O, Rf acetylene = 0.44, Rf olefin = 0.49, UV and PMA. 91 Microanalysis for C191116NF: Calculated: C 82.28, H 5.81; N 5.05, F 6.8 Found: C 82.70, H 5.85; N 5.10, F 6.62 1 H NMR (CDCl 3): δ1.70 (6H, d), 3. (1H, s), 5.06 (1H, m), 7.10-7.75 (8H, m) PPm.

H. (S) -4- // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethynyl / methoxyphosphinyl] -3- (t-butyldiphenylsilyloxy) - butanoic acid, methyl ester A -780 ° C (dry ice / acetone) solution of the acetylene in Part G (678 mg, 244 mmol, 1.0 eq.) In dry THF (6 mL) under argon was treated dropwise with a 1.6 M solution of n-BuLi in hexanes (1.53 mL, 2.44 mmol, 1.0 eq.). After 30 minutes at -78 ° C, the mixture was transferred via cannula to a -78 ° C solution of the phosphonium chloride in Example 1, Part F (about 4.3 mmol, 1.75 eq.) ± dry THF (5 mL). The dark brown mixture was stirred at -78 ° C for 30 minutes, then quenched by dropwise addition of matt NH 4 Cl (5 mL) and allowed to warm to room temperature. The mixture was extracted with Et 2 O (2X), washed with saturated NH 4 Cl and brine, dried over anhydrous MgSO 4 and evaporated in vacuo to give 2.567 g of a tan oil. The crude oil was purified by flash chromatography on silica gel eluting with (3: 2) hexane-EtOAc and gay 756 mg (44%) of the desired title acetylenic phosphinate • • • • • In the form of a dark yellow oil.

TLC (7: 3) hcx-acetone, Rf = 0.27, UV and PMA.

• • • • IH NMR (CDCl 3): 6110 (9H, s), 1.64 (6H, d), • • 3 •• 2410-2 / 90 (4H, ‘m), 3.56 (3H, s), 3758 (3H, dd), • • 0 46 (1H, mm), 4790 (1H, m), 7.05-7.5 (18a, m) ppm. • • ••• ••• 92 13C UNR (CDCl 3): 61412.19 / 1,21,0,26 / 7,278, 3715.39 / 2.42 / 2.45, 1.49 / 2.51 / 4.51 / 9.60.3, 67 (Jc_p = 71 Hz), 88 (1, 91, .2, 98; 3, 111) 31 115.3, 17.6, 118 (J = 5.7 Hz), 122.3, 124 (9, 125.9, 126.4, 127.6, 129.2, 130.7, 133.0.1; 7, 13611, 170.9 ppm. (s) -4-1 / 2-13- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol2-yl] ethyl / methoxyphosphinyl] -3- (t-butyldiphenylsilyloxy) butanoic acid, methyl ester An argon-purged solution of the acetylenic phosphinate The part of Part H (422 mg) in CH 3 OH (9 ml) was treated with 10% Pt / C (420 mg) and the resulting mixture was shaken on a Parr apparatus for 2 hours at 40 psi. The catalyst was removed by filtration through Celite and the filtrate was evaporated to give 380 mg (90%) of the title indole phosphinate as a yellow foam.

TLC (4: 1 EtOAc-hex, Rf = 0.27, UV () and PMA. 1 H NMR (CDCl 3): δ 1100 (91L s), 1.63 (6H, d), 1.5-2.0 (2H, m), 2.20 (1H, m), 2158-3100 (5H, m), 3/44 (3H, dd, JH_p = 10 „6 Hz), 3.61 (3H, s), (2H, m), 7 (07-71.66 (18H, m) PPm- 13 C NMR (CDCl 3): δ12 / 6.16, 8.17) 2.19.1, 2677,36,0,42 / 1,47,2,50.9,5114,678; 4.52 2175, 111 „8 ,. 115.3, 119.1, 121.1, 127.7, 128.3, 12919, 131.2, 13113, 132.8, 133.4, 134.3, 134.8, 135.7, 171.3 ppm.

(S) -4 - // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl. / met "if ° sfiralL: IIIIIIEDIILaLaaaIai_TP113-ester •• • • • • • 0 0 • • • ••• • A solution of the silyl ether in Part J (379 mg, 0.531 mmol) in dry 04 • • • THF (5 ml) was treated successively with glacial acetic acid (1 . ". • 2.12 mmol, 4 eq.) And a 1.0 M tetrabutylammonium fluoride 10 • : T • 11111 • •••• • * 6: I I: * • * • • •• I • I • IS •••• • •••• • • 11 • 111 •• • 93 in THF (1.6 mL, 1.6 mmol, 3 eq.) and the resulting Stirred over the surface under argon at room temperature. The mixture was diluted with ice-cold H 2 O (10 mL), extracted with EtOAc (2X), and the organic phase was washed with saturated NaHCO 3 and brine and then dried over anhydrous Na 2 SO 4 and evaporated to give 408 mg of 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 (78%) of the desired title alcohol as a white foam.

TLC (1: 1) hexalletacetone, Rf0.09 UV and PMA. 111 NMR (CDCl 3): δ 1/68 (611, d), 1.80-210 (2H, m), 2710 (211, m), 2.58 (211, m), 3108 (211, m), 3.63 (311, dd, J = 10 1 HHz), 3.70 (311, d), 3.96 (1H, -P7 t), 414/49 (111, 2 broad multiplets), 4.67 (111, m), 770-776 (811, m) ppm. 13 C NMR (CDCl 3): 617.6, 177.7, 21.4, 29.2, 29.4, 33.2, 33/3, 34.6, 41 (61 41/8, 42/0, 42.2, 4773, 50.9, 511.7, 6314, 111 (8, 11315, 1 (2, 115.5, 119.0, 119.4, 1214, 128.3, 131.3, 131 „5, 134.2, 134.8, 161/5 3C-F = 244r1 Hz), 172.1 ppm.

Example 8 (S) -4 - // 2- [3- (4-fluorophenyl) -1- (1-methylphenyl) -1H-indol-2-yl] - ethyl / hydroxyphosphinyl] .3-hydroxydyrate A stirred solution of the diester in Example 7 (197 mg, 0.414 mmol) in dioxane (5 mL) was treated with 1.0 N LiOH (1.45 mL, 3.5 eq.) And the resulting white suspension was heated at 50 ° C ( oil bath) under argon for 40 minutes. The mixture was cooled, diluted with H 2 O, filtered and evaporated in vacuo.

The residue was taken up in a minimal amount of 1120 and chromatographed. rades p5 1IP-20 resin. and eluted with 1 (20 and then with • • • • I • • • • • • 0 oloo • • I • • • • • • 0 • • • • • 0 • I • • ••• I • • • • ; ; V.4.0 • -4 ... et. S ** le 94 (50:50) H 2 O-CH 3 OH. Product fractions were combined and evaporated. The vitreous residue was taken up in H 2 O (50 mL), filtered and lyophilized to give 178 mg (85%, by weight hydrate) of pure title dilithium salt as a white solid.

Microanalysis for C2311NF13.2Li + 2.52 mol H2O (molecular weight 504.71): Berdknat: 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 1 H NMR (400 MHz, CDCl 3): Δ 1169 ppm (6H, dd, J = 5.8 Hz) 1.71 (2 H, multiplet) 1/93 (2H, multiplet) 2.38 (2H, multiplet) 3106 (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 (2 H, t) 7.41 (3 H, m) 7.57 (1H, 1/2 AB quartet) Example 9 (S) -4 - // 2 - // 1,1'-biphenyl / -2-yl / ethyl / methoxyphosphinyl / -3-hydroxybutanes ra, with ester A. Biphenyl-2-carboxaldehyde Dess-Martin periodinane (27.64 g, 65.2 mmol) was stirred under an argon atmosphere with 150 mL of cH 2 Cl 2. Dry t-BuOH (8.0 mL) was added to the solution with stirring and this mixture was stirred for 10 minutes at room temperature. After stirring for one hour at room temperature, 600 ml of Et 2 O (anhydrous) was added to the reaction medium. 9 • •• • • • • • • • • • • • • • • •• • • • ••• • ••• • • • •• • •• II • II • • • the mixture and then 1 N NaOH (225 mL). After 10 minutes, the resulting slurry was filtered and the filter cake was washed with Et 2 O. The filtrate was washed 2X with 250 mL portions of 1 N NaOH. The organic layer was dried over MgSO 4 and filtered to give a yellow oil (10 g) after removal of the solvent. Purification by flash chromatography (silica gel, 1:10 / Et 2 O: hexane) to give the 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, -1 1600, 1470, 1450, 1395 cm 1 H NMR (270 MHz) (CDCl 3) 68.00 (d, 1.3 = 70. Hz), 7.60 (m, 1), 7.40 (m, 7).

Mass spectrum rule 183 (M + 411) B.2- (2,2-Dibromoethyl) - / 1,1'-biphenyl / A solution of the aldehyde in Part A (2.0 g, 11 mmol) in CH 2 Cl 2 (60 mL) was placed under an argon atmosphere and cooled to-° C. Triphenylphosphine (9.21 g, 35 mmol) was added and the mixture was stirred until all solids had loads. To the resulting solution was added at - ° C for about 15 minutes a CH 2 Cl 2 (40 mL) solution of CBr 4 (5.5 g, 16.5 mmol). The reaction mixture was stirred at-° C for one hour and 15 minutes and then quenched at-° C with 50 mL of saturated aqueous NaHCO 3 solution. The CH 2 Cl 2 and aqueous layers were separated and the aqueous layer was extracted once with CH 2 Cl 2. The combined CH 2 Cl 2 extracts: one was added with an aqueous solution of NaHCO 3 and a gel with an aqueous solution of NaCl. The C112Cl2 extract was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with hexane and gay the title dibromide as an off-white solid (2.45 g, 66%). ie .. ** 4 ":. • •: :: • s • • •; • • •• tf ••••• •• ••• ••••• •• 96 TLC (5: 95 / EtOAc: hexane silica gel) Rf = 0.47 IR (CHCl 3) 3064, 3011, 1596, 1473, 1450, 1435, 889, 860, 702 cm-1 1 H NMR (270 MHz) (CDCl 3) 87.75 (m, 1), 7/35 (m, 8), 7/20 (s, 1) 13 C NMR (67.0 MHz) (CDCl 3) 6141.06, 1/08, 137/49, 13383, 129.81, 129/45, 129.17, 128.61, 128 / .22, 127/50, 127.08, .90r78 Mass spectrum m / e 337/339/341 (M + + H) C.2-ethynyl- / 1,11-biphenyl / A THF (35 mL) solution of the vinyl dibromide in Part B (2.31 g, 6.9 mmol) was cooled to -78 ° C under an argon atmosphere. While stirring at -78 ° C, n-BuLi (5.52 mL of a 2.5 M solution in hexane) was added to the vinyl dibromide for 10 minutes. When the addition of n-BuLi was complete, the reaction mixture turned markedly purple. After stirring at -78 ° C for 2 hours and 45 minutes, the reaction is quenched with a slow solution of NH 4 Cl in water. D. the reaction was stopped, the reaction mixture was warmed to room temperature, THF was removed from the reaction mixture and the resulting material was diluted with 1120 and extracted three times with Et 2 O / hexane. The organic extract was dried over MgSO 4 and filtered and • 4411 • •• • Gay 1.3 g qui oil. Purification by flash chromatography eluting with 1 ?; Et 2 O / hexane gave the desired title acetylene (1.04g, 88%).

•• • • • • TLC (100% hexane, silica gel) Rf = 0.16 • • • • ••• • IR (film) 3287, 3061, 3026, 1474, 1449, 1432, . ••• -1 I ••• 1008,775,758,738 cm t 4..5. • • 4 .. • •• 1: •• 1. $ •• •••• .4 ••• • IS 97 000 • 0000 • • • • • • • • COO • • 111 NMR (270 MHz) (CDCl 3) δ 7.68 (m, 3), 7.35 (m, 6), 3.00 (s, 1) 13 C NMR (67.8 MHz) (CDCl 3) 6144.40, 1/221 133.83, 129.56, 129.20, 128/92, 127.95, 127/49, 126/94, 1/44, 83/08, 80, Mass spectrum m / e 179 (M + + H) D. (S) --4-1 / 2 - // 1,11-biphenyl / -2-ylethynyl / methoxyphosphinyl / - 3- (t-butyldiphenylsil The acetylene in Part C (0.332 g, 1.86 mmol) was stirred at -78 ° C (under argon atmosphere and 10 ml PHI?). mom 5 minutes was set n-BuLi (0.75 ml of a 2.5 M solution in hexane) to the acetylene solution. The reaction mixture was stirred at -78 ° C for one hour, warmed to 0 ° C and stirred for 10 minutes and then cooled to -78 ° C. The acetylenic anion solution was then added dropwise within 8 minutes to 10 ml of a THF solution of the phfonochloridate of Example 1. Part F (2.98 mmol) which had been cooled to -78 ° C under an argon atmosphere. Nat * until the addition was complete, the reaction mixture was stirred at -780 ° C for one hour and the reaction was then quenched by the addition of a saturated solution of NH 4 Cl in water. The reaction mixture was warmed to room temperature, diluted with half-matted solution of NaCl in water and extracted 3X with Et 2 O. The combined Et 2 O extracts were washed with saturated aqueous solutions of NaHCO 3 and NaCl. The Et 2 O layer was dried over MgSO 4 and evaporated to give 1.5 g of a yellow oil. Reflux by flash chromatography eluting with 5: 1: 4 hexane: toluene: EtOAc gay dot the title acetylenic phosphinate (0.543 g, 48%).

PLC (5: 1: 4 hexane: toluene: EtOAc, silica gel) Rf = 0.20.

Often. • • ••• .1 I; 1.-i ijilt • rV ... I .24 .. a. 1, e'eta a .2. • 98 2896, 2859, 2178, 1735, 1474, 1448, 1436, 1429 cm-1 1 H NMR (270 MHz) CDCl 3) 67/65 (m, 3), 7.65-7.28 (m, 16), 4.55 (m, 1), 3155 (d, 3), 3.40 (dd, 3), 280 (m , 1), 2155 (m, 1), 2.35 (m, 1) 2/08 (m, 1), 1100 (s, 9) 13C (67.8 Mz) (CDCl 3) .5170,83, 1/29, 1119, 139,22, 1195, 1/59, 13386, 133.75, 133.16, 132186, 130.57, 129.56, t 129.34, 128181, 127.92, 127/75, 127.44, 127739, 126.94, 117.90, 100.91, 100138, 100.18, 84.51, 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 Mass spectrum m / e 611 (M1-4-1) E. (S) -4 - // 2 - // 1,1 * -biphenyl / -2-yl / ethyl / methoxyphosphinyl / - (t-butyldiphenylsilyloxy) butanes.yfa, methyl ester va., * Argon was bubbled through a methanol (8 mL) solution of the acetylenic phosphinate in Part D (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 shaking for 25 hours at 43 psi, the methanol solution was filtered ••• •••• • • • 0 • •• • through Celite and the filtrate were evaporated and gay nets were classified the phosphinate (0.510 g, 98%) as a fArglbs oil.

TLC (4: 1EtOAc: hexane) 17f.0.21 •• •• IR (CHCl 3) 3071, 3054, 2998, 2954, 2934, 2902, • •• -1 •• •••• 2859,1734, 1477, 1462, 1448, 1436, 1428 cm • • ••• * • • ••• • •• it • ••• •• 0 • IR (CHCl 3) 3070, 3053, 3035, 3000, 2952, 2934, 99 1 H NMR (270 MHz) (CDCl 3) 67165 (m, 3), 7155-7100 (m, 16), 4145 (m, 1), 3158 (s, 3), 3730-31 / 20 (2 doublets, 3, J = 11 Hz), 2188 (m , 1), 2160 (m, 3), 2117-1180 (m, 1), 1 / 80-1 / 30 (m, 1), 1700 (s, 3). 13 C NMR (67.8 MH) (diagnostic peaks) (CDCl 3) 6171133, 65.78, 51.36, 42.24, 2617 Mass spectrum m / e 615 (M + + H) F. (S) -4- [2- // 1,1'-biphenyl / -2-yl / ethyl / methoxyphosphinyl] hydroxybutanoic acid, methyl ester A THF (10 mL) solution of the phosphinate in Part E (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 M solution in THF) was added dropwise. The reaction mixture 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 a matt solution of NaHCO 3 in water and 1X with a matt solution of NaCl in water. The organic layer was dried over Na 2 SO 4 and evaporated to give 0.437 g of a stained glass of oil. Purification by flash chromatography eluting with 7: 3 acetone: - hexane gay the title alcohol (0.247 g, 81%) as a colorless oil. • • • • • • • • 08 TLC (7: 3 acetone: hexane, silica gel) Rf = IR (CHCl 3) 3600-3171 (br), 3064.3009, -1 0.22 2954,1731, • 1479,1439,1237,1180,1042,999 cm • O • •• OS 1 H NMR (270 MHz) (CDCl 3) • • • 67.50-7, (m, 9), 4, L-4, (m, 1), 3/70 (s, 3), • 3.53 & 3, (2 doublets, 3, J = 11 Hz), 2188 (m, 2), • •• 9 • 111 • 21 (m, 2), 2100-1160 (m, 4) • • •• O•• 100 13 C NMR (67.8 MHz) (CDCl 3) 6171,55, 171,49, 141,39,141,00, 138110,137,88, 129.95, 128.81, 128706, 127.53, 26 / .83, 126, .22, 63108, 63702, 62.85, 51.39, / 58, 50.47, 4235, 42/15, 42/07, 41.87, 34.31, 33.06, 33/00, 30.77, / 52, 29149, 29.21, 25.41 Mass spectrum m / e 377 (le + H) Example (S) -4- [2- [1,1'-biphenyl-2-yl] ethyl / hydroxyphosphinyl] -3-hydroxybutanoic acid, dialithium salt The diester in Example 9 (0.239 g, 0.64 mmol) was stirred in dioxane (6.5 mL) under an argon atmosphere. At room temperature, 1.9 ml of 1.0 M LiOH-18 solution was added. This mixture was stirred at 50 DEG C. After stirring for 2.5 hours, the reaction was cooled to room temperature and the dioxane and most of the water were removed by evaporation on a rotary evaporator. Purification by HP-20 chromatography (18 cm x 2.5 cm), eluting first with 100% H 2 O and then with 1: 1 MeOH: 1120 gay the title dilitium salt (0.180 g, 79%) as a white solid.

TLC (8: 1: 1 CH 2 Cl 2: MeOH: AcOH) Rf = 0.16 (7: 2: 1 nPrOH: NH 3: H 2 O) Rf = 0.37 Example 11 0 • • (R) -4 - // (E) -2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl / ethenyl / hydroxyphosphinyl / -3-hydroxybutane ra di1itium salt • • 0 • • 0 100, * • 1 • O • k0. i0 •• 496 - 499 (1985). A mixture of 2-ethynyl-4'-fluoro-3,3 ', 5- •• • • • • A. (E) -tributyl / 2- / 41-fluoro-3,3 ', -trimethyl / 1,1' • biphenyl / -2-yl / ethenyl / tin Male reference: M. A. Miftakov with flora, Synthesis (Comm.) P. 101 trimethyl / 1,1'-biphenyl / (1.7 g, 7.13 mmol) and (n-C 4 H 9) 3 SnH (2.9 mL, 10.7 mmol, 1.5 eq.) were treated with AIBN (7, 0 mg, 0.426 mmol) and the solution was rapidly heated to 10 ° C (oil bath) under argon. After 15 minutes at 10 ° C, an additional amount of (n-C 4 H 9) 3 SnI (0.39 mL, 1.43 mmol, 0.2 eq.) Was added and heating was continued for a total of 3 hours. The yellow mixture was cooled and purified by color distillation at 0.1 mm Hg and 2 ° C and gay 3.073 g (81%) of the title vinyl tan in a colorless liquid.

TLC hexane, Rf product = 0.45, UV and PMA. The product is unstable on silica gel (streaks to baseline). 13 C NMR (67r5 MHz, CDCl 3): 9.5, 13.6, 14/5, 79, 2111, 27/2, 2716, 1141.0, 114.3, 123/6, 123.9, 128.8, 130 , 4, 133/0, 135, .6, 136.1, 138.1, 140.0, 144/4, 160.3 (3cF = 244 H2) ppm.

1 H NMR: 4 / 8-1 / 5 ppm (27 H, m, Sn (Bu)) 2127, 2, .31, 2.36 (9H, 3 singlets, aromatic CH3) 6.05 (1H, d, 3 = 20 Hz, PhCH = CHSn) 6.68 (1H, d, 3 = 20 Hz, PhCH = CHSn) 600-713 (5H, m, aromatic protons) B. (E) -4'-fluoro-2- (2-iodoethylene) -3,3 ', 5-trimethyl- / 1,1'-biphenyl / •• A solution of the vinyl stannane in Part A (1.537 g, 2.89 mmol) of dry Et 2 O (20 mL) was treated with iodine (734 mg, 2.9 mmol, 1 eq.) And the brown solution was stirred at room temperature under argon. 2 hours. The mixture was washed with matt sodium thiosulfate, 10% NH 4 OH and brine, dried over anhydrous MgSO 4 and evaporated to give 1.639 g of a yellow oil.

•• The crude product was purified by flash chromatography pA silica gel (160 g) and eluted with hexane. : ••• •? 0 •• • •••• •••• • 102 fractions gay 832 mg (65%) of the desired pure classified trans-vinyl iodide in the form of a light yellow oil, which crystallizes slowed down when it was allowed to stand, melting point 53 - 50 C.

TLC (hexane) Rf trans-olefin = 0.31, (Rf cis-olefin = 0.26), UV and PMA.

1 H NMR (270 MHz): 62.30 & 2.32 ppm (9H, 2 singletr.pharomatic methyl groups) 6.0 (1H, d, J = H2, -HC = CHI) 6.92-7. (5H, m, aromatic H) 7.24 (1H, d, J = 15 Hz, PhCH = CHI) 13 C NMR (67.5 MHz): 14.6, 21.0, 21.1, 81.0 (= CH-I), 114.4, 114.7, 12412, 124.5, 128.5, 128.7, 130.5, 132.7, 132.8, 133.2, 135.8, 137.2, 1f1, 143.1 (PhCH = CH1), 161.0 1 Note: 1 H NMR (CDCl 3, 270 MHz) p5 mixed fractions depi that the adjacent contaminant was the cis-vinyl iodide. 66.54 ppm (IN, d, HaEb = 7.9 Hz (PhCHb = CHa-I)) C. (R) -3 - // 1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // (E) - 2- [4 * -fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl] ethenyl / methoxyphosphinyl / butanoic acid, methyl ester • • 2.2 mmol, 1 eq.) And the light yellow mixture was stirred under . • ••• by means of needles for 10 minutes directly in a -780 C solution • • of the phosphonochloridate In Example 1, Part F (approximately 3.5 mmol, • 1.58 eq.) In dry THF (6 ml). The yellow mixture was stirred .30 minutes at -78 ° C and then warmed to room temperature. . . . 4 0. • •••lucky. The reaction was quenched at room temperature by addition . •.

•. (JcF = 244 Hz) ppm.

A -78 ° C (dry ice / acetone) solution of the vinyl iodide in Part E1 (812 mg, 2.22 mmol) in dry THF (6 mL) was treated dropwise by syringe with a 1.6 M n-BuLi solution in hexanes (1.4 ml, 0 • ••• •••• • •• ••• • • 6 103 • ••• • •••• • • • •• • tl • • • • • • • S it • • ••• • • •• • • 0 •• • • • e • • ••• • • • • of matt NH4Cl (5 ml). The mixture was diluted with Et 2 O, the ether layer was washed with saturated NH 4 Cl and brine, then dried over anhydrous MgSO 4 and evaporated to give 2.083 g of yellow oil. The crude product was purified by flash chromatography 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 at about (1: 1) mixture of diastereomers at phosphorus.

TLC (7: 3) hex-acetone, Rf = 0.35, UV and PMA.

NMR: 0 63.27 ppm (3H, d, = 11.6 Hz, -POCH 3) 3.57 & 3.60 (3H, 2 singlets, diastereomers, -CO, CH 2) 4.33 & 4.50 (1H, 2 matiplets, diastereomers, -CH 2 CH (OSiR 3) CH 2 -) 4.84 & 5.25 (1H, 2 dd, diastereomers Halib = 17.9 Hz, JHa-P25'3 Hz, J 0 PhCHb = 2Ha-P-) D.00-4 - // (E) -2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / - 2-yl / ethenyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the silyl ester in Part C (249 mg, 0.370 mmol) in THF (5.0 mL) was treated successively with glacial acetic acid (85 μl, 1.48 mmol, 4.0 eq.) And a 1.0 M (n-C4H9) 4NF solution in THF (1.1 mL, 1.1 mmol, 3.0 eq.) and the yellow mixture is stirred overnight at room temperature under argon. The mixture was diluted with cold H 2 O (10 mL) and extracted with EtOAc. The organic phase was washed with matt NaHCO 3 and brine and then dried over anhydrous Na 2 SO 4 and evaporated to give 243 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (55745) : .. ": .. '•; • • • • •• •• 0 •• • • •• • •••• • •• •• • • ••• 104 hex-acetone. Product fractions were combined and evaporated to give 121 mg (75%) of the desired title hydroxide ester as a colorless viscose oil.

TLC (6: 4) acetone-hex, Rf = 0.26, UV and PMA. 1HNMR: 61.8-2.06ppm (2H, m, CH 3 O-PCH 2 -) 2.30, 2.35, 2, (9H, 3 singlets, aromatic CH3) 2040-2.60 (2H, m, -CH (OH) CH 2 CO 2 CH 3) 3.50 + 315 (3H, 2 doublets, caastereoner 0 -POCH3 (J HP = 12 Hz) --- 3.64 31'77 + 3.84 4.28 + 4.38 5.52 (3H, s, -co203) (1H, 2 doublets diastereomers, -CH (OH) -) (1H, 2 broad multiplets, -CH (OH) -) (1H, 2 dd's, diastereomers coupling HH & J HP connector 0 PhCH = CH-P (0CH3) -) ••• . ": • 6190-7, • "7 • 0 • • • • • • • • • • •• • • • • • • ••• (5H, aromatic protons) (1H, multip1ett, diastereomers Jch coupling HH clutch HP 0 pholl = m- (0cH3) -) •• •• • •• 41 ••• • •• ••• • •••• 10 E. (R) -4-1 / (E) -2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / - 2-yl / ethenyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A solution of the hydroxide diester in Part D (121 mg, 0.279 mmol) in dioxane (2 mL) was treated with an excess of 1.0 N LiOH (0.98 mg, 0.98 mmol, 3.5 eq.) And the clear light yellow the mixture was stirred under argon at 0 ° C (oil bath) for 1.5 hours. The mixture was cooled, diluted with H 2 O, filtered and evaporated in vacuo. The residue was taken up in a minimal amount of H 2 O and chromatographed on HP-20 resin (8 cm bath, 25 mm column diameter) and eluted successively with H 2 O (200 mL), (80:20) H 2 O-CH 3 OH and finally with (60: 40) H 2 O-CH 3 OH. Product fractions were evaporated in vacuo, taken up in 1120 (50 ml) and lyophilized to give 91 mg of pure title dilitium salt as a hygroscopic white lyophilate.

TLC (8: 1: 1) CH 2 CH 2 -CH 3 OH-HOAc, Rf = O) 19, UV and PMA. Examples 12 to 24 Following the procedures outlined earlier and described in the foregoing embodiments, the following additional compounds can be prepared. 0 fi R-P-CH2 -C-CH2 -CO2 -Rx XOH 1 101. • •••• • •••. • tO • • • •• • ••• 0 • • • ••• •••• •••• S •••• 106 Ex. n r X Rx OH C2H0CH - CH -CH2CH2- CH3 -C = C- Cl -CH2CH2-Li -CH = CH- OH OLi OH • • • 0 • • 0 • • • • • • •• • • 17.OLi Li ••••• • ••• • * • ••• •• • • • • 107 Ex. nrR 18.OCH3 -CH2CH2 - CH3 CH 3 I 19.OKC2 H -CH 1 CO I 0 -CliggCH- OK CH3 CH 3 20.ONa Na H 3 -CH 2 CH 2 -H • 0 0 • • • • • • •• • ••• • IN ••• s • ••• • 9 • •• • I1 •• • • 0 • • •: •• • ** 0 oll ••••: •• 108 Rx H -C — C —0 22.C OH CH3 CH3 -CH2CH2- OH 23.CH3 ° -CHAITCH-CH3 24.OH -CEC- Example (S) -4- (hydroxymethoxyphosphinyl) -3 - // (1,1-dimethylethylidiphenylsilyl / oxy / butanoic acid, methyl ester, dicyclohexylanine (1: 1) salt A. (S) -4-Diisopropyloxyphosphinyl) -3 - // (1,1-dimethylethyl) -di- • phenylsilyl / oxy / butanoic acid, methyl ester • The iodide in Example 1, Part F (2) (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 15 ° C oil bath for 16.5 hours. The mixture was then cooled to room temperature. excess triisopropyl phosphite 6 • • • • • • • • • • • • • • • • • • • • • • • 109 • 1114.9 , 00.11 • 1 •• 11 • • • • • • • 01, • • •••• It •••• • ••• ••• • • • and volatile reaction products were removed by short-wave distillation (10 mm Hg) and subsequent color distillation (0.50 mm Hg, 1000 C, 8 hours). The product was further purified by flash chromatography (95 mm diameter column, 6 "/ Merck silica gel, 6/3/1 hexane / acetone / toluene as eluent, 2" / minute flow rate, 50 ml fractions) and gay 17.68 g (33.96 mmol, 75% yield) of the title isopropyl phosphonate as a clear viscous oil.

TLC: silica gel Rf - 0.32 (6: 3: 1 hexane / acetone / toluene) 1 HNMR: (270 MHz 'CDCl 3) 67.70-7.65 (m, 4H) 7) 45-7.35 (m, 6H) 4.57-4.44 (m, 3 H) 3.59 (s. 3H) 2.94 and 2.88 (2xd, 1H J = 3.7 Hz) 2.650ch 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 isopropyl phosphonate in Part A (30.5 mmol, 10.66 g) was stirred under argon at room temperature in 80 mL of dry CH 2 Cl 2. This solution was treated dropwise (5 minutes) with bistrimethylsilyltrifluracetamide (BSTFA) (32.8 mmol, 8.44 g, 8.71 mL) and thereafter by dropwise addition (10 minutes) of trimethylsilyl bromide (TMSBr) (51.3 mmol, 7.84 g, 6.75 mL). After stirring at room temperature for 20 hours, the reaction was quenched with 200 mL of 5% KHSO 4 in water and the reaction mixture was stirred vigorously for 15 minutes. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried :: ••• •: •• • 1 • • • • ••• • • • • • •• • •• • • • • 0 • • • • • • v • • • • •O, • • • ••• • • • 0 • • 9 DI, • • • • over Na 2 SO 4 and concentrated in vacuo. The residue was azeotroped twice with 50 ml of toluene. The resulting formation was suspended in toluene and filtered. The filtrate was concentrated and the azeotropic distillation and filtration were repeated. The resulting filtrate was evaporated in vacuo and then pumped under high vacuum for 5 hours. The resulting viscose clear oil was stirred under argon at room temperature in 50 ml of dry pyridine. This solution was treated in one portion with dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g) and then added with methanol (41.0 mmol, 1.31 g, 1.67 mL). After stirring at room temperature for 20 hours, the reaction mixture was filtered through a pad of Celite into a sintered glass funnel. The celite was washed with ethyl acetate and the combined filtrates were evaporated in vacuo. The residue was redissolved in ethyl acetate and washed twice with 5% solution of KHSO4 in water and once with brine. The organic extract was dried over Na 2 SO 4 and filtered, the filtrate was concentrated and azeotroped twice with toluene, suspended in toluene and filtered. The resulting filtrate was concentrated Anyo, distilled azeotropically and filtered, and the filtrate was evaporated in vacuo and placed under high vacuum for 6 hours to give the phosphonate monoester as a clear viscous oil (10.2 g,> 100% yield). TLC: silica gel Rf = 0, (7: 2: 1 nPrOH / NH 4 OH / 1120). The phosphonate monoester / 1.21 g was pumped under high vacuum for 4 hours and gay 1.16 g (2.57 mmol) / 10 was dissolved in 10 ml of dry ethyl ether and treated dropwise with dicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml). The resulting homogeneous solution was allowed to stand at room temperature for 7 hours, resulting in significant crystal formation. The mixture was stored at -0 ° C for 16 hours and then warmed to room temperature and filtered. The crystals were washed with cold, dry ethyl ether and then pumped under high vacuum Over P2018 hours. The crystals were then pumped under high vacuum at 0 c 4 hours and gay 1.25 g (1.98 mmol, 77% yield) of the title dicyclohexylamine salt as a powdered solid, m.p. 155 DEG-156 DEG C. • * • 00 Os ** 0 • S 111 TLC: silica gel Red / 57 (20% MeOH / CH 2 Cl 2) 1 H NMR: (270 MH2 'CDCl3) 67771-7165 (m, 4H) 7140-7.32 (m, 6H) 4.02 (m, 1 H) 3152 (s, 3 H) 3728 and 3.22 (m, 1 H) 311 (d, 311 J = 11 Hz) 2.77 - 2.64 (m, 2H) 2162-2) 56 (m, 111) 1792-1108 (Series of M, 22H) 1.00 (s, 9H) Mass spectrum: (FAB) 632 (M&H) 4 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, 820 CM -1 Analysis. Calculated for C22H31 06PSi .C12 3N: C 64.63; H 8.61; N - .22 Found: C 64.51; H 8.49; N 2.18 Example 26 • ••• • ••• ■ • • • • • •• • •• 40 •• • 0 • 0 • V • •• •••• • ft A.

One ml, (E) -4 - // 2- / 4'-fluoro-3.3, or / hydroxyphosphinyl / -3-hydroxybulyra. -trimethyl / 1,1'-biphenyl / -2-yl / - dilitium salt [2- [4'-fluoro-3,31,5-trimethyl] -1,1'-biphenyl] -2-yl] -2-hydroxyethyl] ionosonic acid, dimethyl ester -78 ° C (CO2 / acetone) -16 Solution of dimethylmethylphosphonate (1.8 16.5 mmol, 1.6 eq.) Of dry THF (20 mL) was treated dropwise over 20 minutes with a 1.6 M n-butyllithium solution hexanes (9.7 mL, 15.5 mmol / 1.5 eq.) and the resultant The white suspension was stirred in dry argon at -78 DEG C. for 60 minutes. ••••• • ••• • • ft •• • ••• 0 • • • • • 112 Biphenylaldehyde in Example 1, Part C (2.5 g, 10.3 mmol, 1 eq.) In dry Ti-IF (10 mL) was then added dropwise over 15 minutes at -78 DEG C. and a light orange suspension was added. After 30 minutes at -78 ° C, the reaction was quenched by the dropwise addition of matt NH 4 Cl (10 mL) and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and H 2 O and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo and gay 4.127 g of a qui oil which crystallized slowly on dA Lick st5. The crystals were triturated with hexanes and after filtration and drying In vacuo 3.38 g (89.4%) of pure title hydroxyphosphonate in the form of white nAlar with melting point = 98 - 100 ° C. Additional 233 mg (3.613 g in total, yield 95.6%) pure title compound was recovered by rapid chromatography of the mother liquor (603 mg) on LPS-1 silica gel (40: 1) and eluting with (7; 3) hexane-acetone. TLC (1: 1) hexane-acetone, Rf = 0.33, UV 4-PMA.

Analysis. Bergknat for C19 - .., H 24 ° 4PF: C 62.29; H 6.60; F 5.19; P 8, Found: C, 62.66; H 6.56, F 5.03; P 8.68 3./2-/4-fluoro-3,31,5-trimethyl / 1,11-biphenyl / -2-yl / etenyl.s1imet- A solution of the hydroxyphosphonate in Part A (3.513 g, 9.6 mmol) of dry (4 A sieve) toluene (15 ml) was treated with pTsO (91 mg, 0.48 mmol, 0.05 eq.) And boiled under AterflOde. by on SoxhInt apparatus containing 011 4 A sieves 16 hours under argon. Additional pTsOH-1120 was added during the reaction. The course at the following time intervals: 3.5 hours (91 mg), •. • 5.0 hours (91 mg) and 6.5 hours (91 mg). The mixture is cooled, • t • u was washed with ethyl acetate and washed with matt NaHCO 3 ••• and gay an aqueous phase, an organic phase and an oily layer between the phases. The aqueous phase and the oil layer were collected and . •• was washed against ethyl acetate and the ethyl acetate layer was washed with mod 4 4 4 6mattened NaHCO and set aside 5h. he b5da vatocarbonattvatt- 3 •••••• •• • •••• •••• • 01 113 The liquids were acidified with concentrated HCl and extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to give 520 mg of recovered phosphonic acid, monomethyl ester. The diester was regenerated by dissolving the oil in trimethyl orthoformate (5 ml) and boiling under reflux of the mixture under argon for 4 hours. Excess formate was removed in vacuo and gay a yellow oil taken up in ethyl acetate and combined with the original neutral organic phase. The ethyl acetate layer was washed with solution, dried over anhydrous Na 2 SO 4 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) and eluted with (75:25) hexane-acetone. Product fractions were evaporated and 2.987 g (89.4%) of the title the vinyl dimethyl phosphonate in the form of a gold-colored oil.

TLC (1: 1) hex-acetone, Rf = 0.44, UV and PMA.

1 H NMR (CDCl 3): Δ 2.27 (3H, d, Ja_F = 1.6 Hz) 2.33 (3 H, s) 2.39 (3 H, s) 3.61 (6H, d, J / 1-11 = 11 Hz) 151 (1H, dd, = 18 Hz, JH..p = 20.6 Hz) 6.95 - 7.09 (5H, m) 7148 (1H, dd, J11-11 = 17.9 Hz, JH_p = 231.7 Hz) PPm. 13 C NMR (CDCl 3): 614.4, /9, 52.0 (Jc_p = 5.7 Hz) 114.4, 114.7, 11912 (Jc_p = 185.5 Hz) 124.3, 12415, 128.4, 128/5 12910 130.6 130.9 132.6, 13217, 13416, 137.1, 141 , 0, 148.2, 148/2 (Jc_p = 5.7 Hz) 160/53 "C-F = 244E1 Hz) 114 • ••• S II • 0 • • • • •• • • • • • • • • • • 0 • • ••• • • ••• • • 110.

• • • •• • IS • • • [2- [4'-fluoro-3,3 ', 5-trimethyl] -1,1'-biphenyl] -2-yl] ethenyl / phosphonic acid, monomethyl ester A solution of vinyl dimethylphosphonate in Part E (2.895 g, 8.31 mmol) ± dioxane (20 mL) was treated with a 1.0 N LiOH solution (12.5 mL, 12.5 mmol, 1.5 eq.) And the resulting mixture was stirred at 7 ° C (oil bath) for 70 minutes under argon. After heating for 15 minutes, the mixture became homogeneous. The mixture was cooled to room temperature, acidified to pH 1 with 1.0 N HCl (ca. 15 mL) and extracted (2X) with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous Na .8%) of the desired title monomethyl ester in the form of a clear, colorless oil.

TLC: (8: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAc, Rf = 0.57, UV and PMA. Mass spectrum (M + H + = 3+ observed). 1 H NMR (CDCl 3): 62125 (3H, d, = 1/6 Hz) 2/33 (3H, s) 2139 (3H, s) 3.53 (3H, d, = 11 Hz) 5.61 (1H, dd, J / 4-11 = 18 Hz, JH_P = 16 Hz) 6 / 90-7.12 (51 !, m) 7/38 (11 !, dd, j1! _1! = 18 Hz, SN-P 24 Hz) ppm. 4- // 2- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / ethenyl / methoxyphosphinyl / -372x2IL Distilled methyl acetoacetate (420) 111, 3.9 mmol, 1.3 eq.) Was added dropwise over 15 minutes to a stirred suspension of 60% NaH dispersion in mineral oil (168 mg, 4.2 mmol, 1.4 eq.) In dry THF (ml) at 0 ° C (ice bath) under argon. The resulting clear reading was now titrated for 15 minutes at 0 ° C, then treated with 1.6 M n-butyllithium solution in hexanes (2.25 mg, 3.6 mmol, 1.2 eq.) for 10 minutes. The yellow The dianion solution was stirred for 15 minutes at 0 DEG C. and cooled 1 • • to • • • • • 0 • 4I • •••• • ••• • • ••• I0 • • IN• .00 0 • • then to -78 ° C in preparation for treatment with phosphonochloridate.

Phosphonochloride was prepared from the title monomethyl ester of Part C according to the following method. A solution of the phosphonomethyl ester in Part C (960 mg, 2.87 mmol) in dry CH 2 Cl 2 (8 mL) was treated with distilled trimethylsilyldiethylamine (750 μl, 5.98 mmol, 2 eq.) And the clear mixture was stirred under argon at room temperature an hour. The mixture was evaporated in vacuo, azeotroped with benzene (2 x 15 ml) and the viscous oil was left in the vacuum pump for 15 minutes. The oil was taken up in dry CH 2 Cl 2 (8 mL) and dry DMF (one drop), cooled to 0 ° C (ice bath) and treated with distilled oxalyl chloride (290 μl, 3.3 mmol, 1.1 elcv.) Dropwise over 5 minutes under argon. After 15 minutes at 0 DEG C., the mixture was stirred at room temperature for 45 minutes and then evaporated in vacuo. The crude oil was azeotroped with dry benzene (2 x 15 ml) and gay after evaporation and drying in a vacuum pump for 15 minutes crude phosphonochloridate as a pale yellow oil.

Phosphonochloridate (approximately 2.9 mmol, 1 eq.) ± dry THF (8 mL) at -78 ° C Transferred dropwise via cannula within 30 minutes to a -78 ° C solution of methylacetoacetate dianion. After 30 minutes at -78 DEG C., the reaction was quenched by adding the orange-brown reaction mixture dropwise with saturated NH 4 Cl (8 mL) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with matt NaHCO 3 and brine, then dried over anhydrous Na 2 SO 4 and evaporated in vacuo and gay 1.481 g of an orange oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with m-ki (9: 1) hexane-acetone and then with (1: M hexane-acetone. Product fractions were combined and evaporated and gay 813 mg (62.9%) of the desired the title vinyl phosphine diester is viscous, light yellow oil TLC (1: 1): lex-acetone, Rf 0.42, UV and PMA. , 1, • * 'es! • I' • si.I •• 444 • 4 44 444 ° 0 4044 ft 116 1 H NMR (CDCl 3): 62.28 (311, s) 2.34 (311, s) 2.40 (311, s) 315 (211, dd, H-H = 4i7 Hz, JH = 18 2 Hz) -P 3.54 (311, d, J / i_p = 11.6 Hz) 3.63 (211, s) 3.72 (311, s) 5.57 (111,, dd, JII_11 = 1719 Hz, H25.3 Hz) -P 6.95-7.09 (511, m) 7.52 (111, dd, J11_11 = 1719 Hz, J11_p = 22.7 Hz) 13 NMR (CDCl 3): 614.0 (3c-F = 3.9 Hz), 16, 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 = 12819 Hz), 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 (3c-F = 245.1 Hz), 166.7, 194.4 (Jr_p = 4 „9 Hz) ppm.

E. (E) -4 - // 2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] illetenyl / methoxyphosphinyl / -3-hydroxybutanoic acid, mglal2aLtE A 0 ° C (ice bath) loading of the ketone in Part D, (585 mg, 1, initial) in dry THF (4 mL) was treated with solid NaBH 4 (51 mg, 1.35 mmol, 1 mol.) And then continued dropwise with dry CH 3 O 11 (1 mL, 3 Å sieve) and the yellow mixture was stirred under argon at 0 ° C for 30 minutes. The reaction was quenched by mixing the mixture at 0 DEG C. with reagent acetone (6.5 ml) and then with CC-4 silica gel (500 mg). The suspension was warmed to room temperature, filtered through sintered glass, separated with ethyl acetate and evaporated in vacuo and gay 607 mu qul •• •• V 00 "•• -II • •• V • •• • •• • • • • •• ••• • •••• ••• •••• ••••• • • •• •• ::: •••• •• • ••• •: •• • •• ••• • • - ■■ •• 117 oil. The arena oil was purified by flash chromatography on Merck silica gel (30: 1) and eluted with pure ethyl acetate. Product fractions were evaporated and gay 34e mg (57.6%) ay the desired title alcohol as a pale yellow oil. TLC (pure EtOAc), Rf = 0.19, UV + PMA.

Mass spectrum (M + 114- = 435 observed) 1 H NMR (CDCl 3): 61.90 (2 H, m) 2.27 + 2.28 (3H, 2 singlets) 2134 (3H, s) 2/39 + 2.40 (3H, singlets) 2.56 (2H, d), 3.52 (3H, d, Jii-p = 11.1 Hz) 3169 + 3.70 (3H, 2 singlets) 3.79 + 3.90 (1H, 2 eubblets) 5.525.54 (1H, 2dd, Jii-H18 Hz, JH-P = 2.48 Hz) •• • • 6.95 - 7102 (5H, m) 7.52 - 7154 (1H, 2dd, 3H-H = 18 Hz, J = 21 6 H-P / Hz) ppm. 13 C NMR (CDCl 3) (R, S mixture): 1413 (jC-F = 319 Hz) 20.8, 35.4 + 18 (Jc_p = 100.6 Hz) 42.0 (Jc_p = 1217 Hz) 17 (Jc_p = 648 Hz) 56: 5, 63/2 (Jc_p = 3.9 Hz) 113.8, 1/3, 122/9 + 123/2 (Jc_p = 12211 Hz) 123.8, 12812, 128.7, 129.0, 130.4, 13114, 132/3, 13217, 136.6, 137/0, 13812, 140.8, 148.2 + 148.8 (J = 49 Hz) C-P 160.5 (Jc-F = 245.1 Hz) 171/8 ppm. • • ••• • • • • • • 410.0 • I • • • * • • • • • • 1 • • • • •• • • • • • •• • • •• ••• • • • • • •• • 1. •• • • ••••: • • •: • • •: • • ••• • • • • • • ••• ■ 118 F. (E) -4 - // 2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] yl / ethenyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A solution of the diester in Part E (339 mg, 0.781 mmol) in dioxane (8 mL) was treated with an excess of 1.0 N LiOH (2.3 mL, 2.3 mmol, 3 eq.) And the mixture was heated at 0 ° C. C (oil bath) 1.5 hours under argon. A white fall was evident after 15 minutes. While still in vacuo, the mixture was diluted with H 2 O until all solids had dissolved and then filtered. The filtrate was evaporated in vacuo, taken up in a minimal amount of H 2 O and chromatographed on HP-20 resin and eluted with a pure 11 -3 pure CH 3 OH lines gradient. Product fractions were evaporated and the white oxygen residue was taken up in H 2 O (50 mL), filtered and lyophilized and gay 270 mg (82.7%) of the desired title dilitium salt as a hygroscopic white lyophilate.

TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OH-HOAc, Rf = 0.33, UV + PMA Analysis for C 20 2 20 FP-2Li + 0.63 mol 11 (molecular weight 429.57): Calculated: 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 1 H NMR (CDCl 3) ••• •••• 4.4 Hz) • • 2.28 (3H, doublet, JH_F = 1.8 Hz) 61.59 (2H, multiplet) 2124-2.37 (211, 3 multiplet, J11_11 = 815 Hz + • 2.30 + 2.39 (6H, 2 singlets) • 4.14 (1H, multiplet) . . . . • . • • 5.78 (111, J11_H = 17.9 Hz, J11_p = t5 Hz) ".. 6.88 - 7.21 (6H, multiplet) • • • • • • • • • : ••• • • • : *** •• • ••• • • • •••,; 9 • • • • ••:. • •• • • • • • • • • •••• 119 Example 27 4- [2- [4-fluoro-3,3 ', 5-trimethyl] -1,1-biphenyl] -2-yl] ethyl] hydroxyphosphinycisal 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 trans-vinyl phosphinate of Example 61, Part E (297 mg) in CH 3 OH (6 mL) was treated with 10% Pd / C (74 mg, 25 wt%) and the black suspension was shaken on a Parr. device under 40 psi 112 3 hours. The catalyst was removed by filtration gel-1 ° m packed Celite and the filtrate was evaporated in vacuo to an oil. The oil crystallized from hexanes and gay after filtration and drying in vacuo 267 mg (89.5%) of the title saturated phosphinate as a white crystalline solid. TLC (EtOAc), Rf = 0.20, UV + PMA, 1 H NMR (CDCl 3, 270 MHz), IR (KBr pellet) Mass spectrum (M + H + = 437+ observed) 1 H NMR (CDCl 3): o1155-1.87 (411, m) 2/29 + 21 + 2131 (611.3 singlets) 2 / (311, d, Ja_F = 2.1 Hz) 2152 (211, m) 278 / (211, m) : • 31+ 315 (311.2 doubles JH_p = 4.3 Hz) •• 3.71 ($ 311) • • • 3186 + 3.91 (111.2 singlets) b • • •• 4+ 4.39 (11112 wide multipletters) ppm. • 41, IN,•• • • • 8 •••• B. 4- [2- [4-fluoro-3,3 ', - trimethyl] -1,1'-biphenyl] -2-yl] ethyl] - • •••• • • .11ydr -sfinyl / -3-hydroxybutanoic acid, dilitium salt • • • A solution diester in Part A (250 mg, 0.573 mmol) in dioxane (6 ml) was treated with an excess of 1.0 N LION (1.72 ml, • • . * • i • • •••• • •• VI * • 1111 •• 4 1 3 eq.) And the mixture was heated at 0 ° C (oil bath) under argon for 1.5 hours. A white fanning was evident after 15 minutes. The mixture was diluted with H 2 O while still hot until all solids had dissolved and then filtered. The filtrate was evaporated in vacuo and the white residue was dissolved in a minimal amount of H 2 O and chromatographed on HP resin and eluted with pure H 2 O (to neutral) and then with pure CH 3 OH. The product fractions were evaporated in vacuo to a white solid which was azeotroped (twice) with CH 3 CN and dried in vacuo to give 131 mg (55%) of the desired title dilitium salt as a white solid.

TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OH-acetic acid, Rf = 0.34, UV + PMA. Analysis. Calculated for C20240FPLi2 + 0.95 mol H2O (molecular weight 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 1 H NMR (oD 3 OD + D 2 O): 1139-1157 (411, multiplet) .ppm 2122-2.37 (211, multiplet) 2/26 + 2/38 (611, 2 singlets) 2/31 (3H, dilibblett., J /. / ... F = 1.8 Hz) 2171-2 / 77 (2H, multiplet) 4113-4 / 20 (111, multiplet) 6.73-7111 (5H, multiplet aromatic H) Example 28 (E) -4 - // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanesyrilinium salt A. [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] dimethyl ester A -78 ° C (acetone / CO2) solution of methyl dimethylphosphonate (1.35 mL, 12.42 mmol, 1.6 eq.) In dry PHI? (20 ml) was treated dropwise within 15 minutes with a 1.6 M n-BuLi solution •• • • 6. • • - - • go. •: 7 "" • • • I •• •• • I •••.

•• •••• •••• I • • •• •• • • ••• •• •• • 4 • ••• •••• • •• ••• • ••• 121 hexanes (7.3 mL, 11.6 mmol, 1.5 eq.) and the resulting white suspension was stirred under argon at -78 ° C for one hour. Indol- the aldehyde in Example 7, (8 ml) was added dropwise and the resulting light for 30 minutes at -780 ° C. Part E (2.183 g, 7.76 mmol) in dry THF within 10 minutes to the anion at -78 ° C the orange suspension was stirred. The reaction was stopped by dropwise NH 4 Cl (10 mL) and the reaction mixture was warmed to room temperature and partitioned between 1120 and ethyl acetate and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to give 3.19 g of a white solid. The arena solid was triturated with hot hexane and gay 2.967 g (94.3%) of pure title hydroxyphosphonate as a white solid, mp 161-162 ° C.

TLC (1: 1) hex-acetone, Rf = 0.29, UV + PMA Analysis. Calculated for C21H04NPF: C 62.21, H 6.22, N 3.46; Found: t: C 62.34, H 6.32; N 3; 30; 1 H NMR (CDCl 3): a1.69 + 1.74 (611, 2dUblets) F 4.69; P 7.64 F 4.61, P 7.32 2.18 3.61 3.67 132 5, -4- 2.56 (211, 2 multiples) (1H) + 3.71 (611, 2 doublets, H-P = 11 Hz) (1H, m) (1H, m) 7 04-7 25 (411, m) 7133 ° 7/39 (2H quartet) 7.52 (211, AB quartet) PPm 13 C NMR (CDCl 3): 621.1, 21.3, 33.1 (Jc_p = 136.3 Hz) 48.3, 52.6 + 5287 (Jc_ = 5.7 Hz) (Jc_p = 3.8 Hz) 112.5, 114.3, 115.1, 115.4, 119.5, 120, 122, 128.1, 130.6, 131.9, 132.0, 134.8, 134.9, 135.2, 161.8 (Jc_F = 246.1 Hz) ppm. •• • •• • • 0 0 • • • • 0 • 41 • • • • • • • • • • * • • • • • • • • • • S • • . • ..0 1. •••• • -1eve '• 0:60 ** 0 122 B. (trans) - [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole] 2-yl / ethenyl / phosphonic acid, dimethyl ester The hydroxyphosphonate in Part A (2.60 g, 6.43 mmol) dissolved in hot benzene (ml), treated with pTsOH.H 2 O (122 mg, 0.1 eq.) And the mixture was boiled under & terflode through a Soxhlet containing 4 A-sieves 1 hour under argon. The yellow solution was cooled and diluted with ethyl acetate and the organic phase was washed with matt NaHCO 3 (2X) and brine and then dried over anhydrous Na 2 SO 4 and evaporated to give 2.47 g of crude olefin as a yellow solid. Recrystallization from ethyl acetate-hexanes gay 2.238 g (89.9%) of pure title trans-vinyl phosphonate in the form of light yellow plates, m.p. 153 DEG-15 DEG.

TLC (1: 1) hex-acetone, Rf = 0.33, UV + PMA.

Mass spectrum (M + H + 388 + observed) Analysis. Calculated for C21H2303PNF: C 65.11, H 5.98; 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 1 H NMR (CDCl 3): α1; 67 (6H, doublet) 3) 68 (61 !, d, J1! _P = 1116 Hz) 4.90 (1H, septet) ; 73 (11 !, dd, J1! _1! (Trans) = 18 Hz, JHP = 18f 2 Hz) - 7; 05-7.56 (81 μm) 7/64 (11 !, dd, J1! _1! = 17.9 Hz, JH1 = 23 7 Hz) -P PPm.

••• • NIP 13 C NMR (CDCl 3): 21/7, 4718, 52.2 (Jc_p = 5.7 Hz) 111.8, 115.4, 115.7, 118.5 (Jc_p = 43.5 H) 111, 120.2, 123.4, 12812, 1/5, 130.7, 0. • 13111, 13117, 1; 9, 13719 (Jc_p = 7.6 Hz) . "161.9 (Jc-F = 246 Hz) ppm. •• •• 0 • • •• a •• •••• •• ••• • • •• • • • • • •• • • I •••: ••• ••: ••:: •••••:: • ••• •• •• • •• • • ••• •• •• • •• ••• • •••• •• 123 C. (trans) - [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole] nonometlester The vinyl dimethylphosphonate in Part B (1.787 g, 4.61 mmol) was dissolved in hot dioxane (12 mL), treated with 1.0 N LiOH (6.9 mL, 6.9 mmol, 1.5 eq) and heated at 70 ° 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 H 2 O (2X) and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 1.859 g of yellow oil. The oil was dissolved in hot hexane, cooled and crystallized to give 1.657 g (96.1%) of monoacid as a light yellow solid, m.p. 181 DEG-183 DEG.

Analysis. Calculated for C112103PNF: C 64.02; H 5.70; N 3.73; F 5.06; P 8, Found: C 64.02; H 5.87; N 3.64; F 5.26; P 7.90 TLC (20: 1: 1) CH 2 Cl 2 -CH 3 OH-acetic acid, R = 0 26 f UV + PMA 1 H NMR (CDCl 3): 61.66 (611, doublet) 3.64 (311, doublet ,, T11_F = 11.6 Hz) 4.89 (1H, septet) 5.81 (111, dd, J11_11 = 17.9 Hz, J11_1) = 18.5 Hz) 7.06 -7.64 (911, multiplet) ppn. 13 C NMR (CDCl 3): 621.8, 47.9, 52.1 (Jc_p = 5.7 Hz) 112.0, 115.5, 115, .8, 116.1, 119.0 Hz) 120.2, 120.4, 123.5, 128.3, 130.4, 1 131.2, 131.8, 13119, 136.2, 136.8 (Jc_p = 7.6 Hz) 161.9 (Jc-F = 246 Hz) ppm. .:: * • :: ••• • 000 • • I., ••• • I • • • a • • • I • • • • •• 11, •• • •• •••• •••• •• 124 D. 4- [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethenyl] methoxyphosphinyl] -3-oxobutanoic acid, methyl ester Phosphonochloride was prepared according to the following method. In los- of the phosphonomonomethyl ester of Part C (1.564 g, 4.19 mmol, 1 eq.) in dry CH 2 Cl 2 (10 mL) was treated with distilled diethylaminotrimethylsilane (1.05 mL, 8.38 mmol, 2 eq.) and the mixture was stirred under argon at room temperature one hour. The mixture was evaporated in vacuo, taken up in benzene (20 ml) and evaporated in vacuo and the viscous oil remained in the vacuum pump for 15 minutes. A solution of the crude silylated acid in dry CH 2 Cl 2 (10 mL) and dry DMF (1 drop) was cooled to 0 ° C, treated dropwise with distilled (COCl) 2 (400 mL, 4.61 mmol, 1.1 eq.) And was stirred for 15 minutes at 0 ° C and 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 in the vacuum pump for 15 minutes and gay 'pure phosphonochloridate as a viscous yellow oil. A solution of the phosphonochloridate in dry THF (8 ml) at -78 ° C was transferred by means of needles dropwise over 20 minutes to a -780 ° C solution of the methyl acetoacetate dianion, prepared in the manner described in Example 26, of methyl acetate (590 , 45 mmol, 1.3 eq.), 60% Nail oil dispersion (235 mg, 5.87 mmol, 1.4 eq.), 1.6 M n-butyllithium (3.1 mL, 5.03 mmol, 1 , 2 eq.) And THF (10 ml). The orange reaction mixture was stirred for 30 minutes at -78 ° C. Then the reaction was quenched by the dropwise addition of matt NH 4 Cl and the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and 1120, the organic phase was washed with matt NaHCO 3 and was then dried over anhydrous Na 2 SO 4 and evaporated to give 2,080 g of yellow oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (7: 3) CH 2 Cl 2 -EtOAc. Product fractions were combined and evaporated to give 519 mg (26.3%) of the desired title transphosphinate as a pale yellow oil.

TLC (1: 1) hex-acetone, R = 0.48, UV + PMA ; ;. ;; ; •: •• II 106s •• * :: • ■ ••: • • ft • ••• • •••• • • to ••• • •••• •• • • • • IN• ••• • • • • 1 Mass spectrum 472f observed) 1 H NMR (CDCl 3): 61166 4- 1771 (611, 2 duplicates) 1168 (2 H, m) 3123 (2H dubbed) 3.54 (3 H, d) 3.72 (311, s) 4.90 (1H, septet) 176 (111, dd, JH.4477-18 Hz) 7110-7758 (8H, m) 7.66 (1H, dd, JR_H = 18 Hz) ppm. 13 C NMR (CDCl 3): 62118, 17 (Jc_p = 87.1 Hz) 4719, 50.0, 51.5 (Jc_pt --- 17 Hz) 52/3, 111/9, 1 / .5, 118, .8 (Jc_p = 104/1 Hz) 119.8, 1/2, 113, 123.6, 128.2, 1/4, 130.8, 13178, 131.9, 136.1, 13912 (Jc_p = 5.6 Hz) 161/9 (Jc-F = 246 Hz) 16710, 19416 (Jc_p = 3.8 Hz) ppm.

E. (E) -4- // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole- 2-yl / ethenyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A -0 C (salt / ice bath) solution of the ketone in Part D (519 mg, 1.3 mmol) in dry absolute EtOH (3 A-sieve, 8 mL) was treated with solid Na13114 (42 mg, 1.1 mmol) and the (-pia mixture) was stirred under argon at -0 ° C for 20 minutes - was prepared by adding acetone (0.5 ml) and then CC-4 silica gel (500 mg). The mixture was warmed to room temperature, filtered, partitioned with ethyl acetate and evaporated in vacuo to give 312 mg of a yellow foam. The impure foam. was purified by flash chromatography on Merek / silica gel eluting with (4: 1) ethyl acetate-acetone and then with pure acetone. rioduct fractions were evaporated and (jay 317 my (60.9%) of the desired 126 classified alcohol in the form of a qui oil.

TLC (4: 1) EtOAc-acetone, Rf0.21, UVPMA.

Mass spectrum (M-441 + = 4.74+ observed) 1 H NMR (CDCl 3): 61168 (6H, doublet) 1.97 (21L m) 2.58 (2 H, d) 3.61 (3H1 d, JH_p = 11 Hz) 3.68 (311, s) 3195 + 4104 (1H, 2 doublets) 4140 (1H, bin) 4195 (111, septet) 5.78 (1H, dd, J11_H = 1714 Hz, J23.2 Hz) 7.05 - 7.77 (9H, m) 13 C NMR (CDCl 3): 62117, 3419 + 36/3 (Jc_p = 20.8 Hz) 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 + 12118 (Jc_p = 1819 Hz) 171, 12314, 12812, 130.6, 117, 131/1, 131.7, 131.9, 118, 138.0 + 138.5 (Jc_p = 5.7 Hz) 161.8 (J C-F = 246.1 Hz) 17117, 171.8 ppm.

F. (E) -4 - // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole- 2-yl / ethenyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt ••• 0 •• 0 I • 0 0 • • • • 6 • ••• IN• 1001 I •• A stirred solution of the hydroxide diester in Part E (264 mg, 0.558 mmol) in dioxane (6 mL) was treated with 1.0 N 1.1011 (1.9 F mL, 3.5 eq.) And heated at 70 ° C (oil bath). ) 20 minutes under argon. The mixture was allowed to cool, diluted with 1120 /. filtered, evaporated in 1st vacuum, taken up in a small amount of 1120 (1 to 2 ml) and chromatographed on HP and clue-radon with H 0 (to neutral reaction, 3 - 4 column volumes) • O.S * • •• • ••• •••• •• ••• • •••• •• 127 and then with (75:25) CH 3 OH-H 2 O. Product fractions were evaporated, taken up in H 2 O (50 mL), filtered and lyophilized to give 217 mg (85.1%) of the desired title dilitium salt as a white lyophilate.

TLC (8: 1: 1) CH 2 Cl 2 -C 1130 11 acetic acid, Rf 0.08, UV + PMA. Analysis. Calculated for C2311230NPF.2 Li + 1.62 mol H2 O (molecular weight 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 1 H MMR (400 MHz, CDCl 3): 1767 (6H, doublet) 173 (2H, multiplet) t 2/38 (2H, doublet of AB quartet; JAB = 15 HZ, J = 8 Hz, JBX = 4.8 Hz) AX 4124 (1H, mule full) ) 06 (1H, septet) 6.09 (1H, JHH = 17.6 Hz, JHp = 19.4 Hz) 7.02-7 / 61 (9H, multiplet) Example 29 (S) -4 - // 2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] ethylinhydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt A.4-methyl-2-oxopentanoic acid, ethyl ester 4-Methyl-2-oxopentanoic acid, sodium salt (25 g) was dissolved in a minimal amount of H 2 O, acidified to pH 1 with concentrated HCl and then extracted several times with CH 2 Cl 2. The aqueous phase was quenched with NaCl and back-extracted (2X) with CH 2 Cl 2. The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to give gay 17.7 g of the free acid as a viscous oil.

• • • • • • . • • • • • • • • A mixture of the acid (17.7 g, 136 mmol) in dry benzene (200 mL) was treated with diazabicycloundecane (NW) (20.4 mL, O00 SOO 00 :: IP se. • • • •• • 4, -; ; • s •• * • SS 0404. • 0 • OS * 4.04 / • 11406 me 128 136.2 mmol, 1 eq.) And gay an exothermic reaction and a gel-like crystalline salt were formed. The mixture was treated with ethyl iodide (10.9 ml, 1 eq.) And stirred mechanically under argon for 3 hours. Precipitated salts were removed by filtration, the filtrate was washed once with a small amount of 1120 (50 ml) and brine and then dried over anhydrous Na 2 SO 4 °. %) of the desired title ester in the form of a clear, light yellow liquid with a boiling point of 65 - 66 ° C (5 mm Hg).

TLC (9: 1) hexane-acetone, Rf = 0.55, PMA (light blue).

Mass spectrum (M + H + = 159+ observed).

B.4-Methyl-2- (2-phenylhydrazono) -pentanoic acid, ethyl ester A solution of the ethyl ester in Part A (5 g, 31.6 mmol) in dry CH 2 Cl 2 (30 mL) was treated with phenylhydrazine (3.3 mL - 33.2 mmol, 1.0 eq.) Dropwise over 5 minutes and the resulting yellow mixture stirred under argon at room temperature over 4 A sieves for 3 hours. The mixture was dried over anhydrous Na 2 SO 4, filtered and evaporated in vacuo to give 8.105 g of an orange oil. The 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 (86.7%) of pure title hydrazone and 848 mg (10.8%) of the geometric isomer of the title hydrazone.

Total yield = 97.5% •• TLC (9: 1) hexane-acetone, Rf geometric isomers = 0.42 + 0.64, uV + PMA.

Mass spectrum (M + H + = 249+ observed). • • • .1 e • C3- (1-methyl and U-1H-indole-Dentra et 'ester •• • I • Gaseous Hcl was bubbled (gas dispersions) into a solution of absolute ethanol (50 ml, over 3 A sieves) of part of the hydrazone in Part B (6.8 g, 27.4 mmol) for 30 minutes at room temperature. • 14 --4 44; 11lee4 404.; ; 44: 10 129 The exothermic reaction is characterized by color changes from quit to root to dark green and faulty invention of NH4Cl. The suspension was stirred for an additional 20 minutes under Drierite and then halided in ice-cold water (50 ml). Ethanol was removed in vacuo and the residue was partitioned between ethyl acetate and H 2 O. The aqueous layer was extracted with ethyl acetate (2X) and the combined organic phases were washed with H 2 O and brine, then dried over anhydrous MgSO 4 and evaporated to give 4.699 g of a spruce solid. The crude solid was dissolved in hot hexane, treated with Darco, filtered through packed Celite and concentrated to a volume of 30-50 ml and the yellow solution was allowed to crystallize. Precipitated crystals were collected by filtration, rinsed with cold hexane and dried to give 4.34 g (68.5%) of pure title indole in the form of white needles, m.p. TLC (9: 1) hexane-acetone, Rf. 0.42, UV + PMA.

Note: Rf for hydrazone and indole are identical but indole has bright purple fluorescence. (M + H + = 232+ observed). Analysis. Calculated for C141117NO2: C 72.70, H 7.41; N 6.06 Found: C 72.67, H 7.57; N 6.00 D. 1- (4-Fluorophenyl-3- (1-methylethyl) -1H-indole-2-carboxylic acid, ethyl ester A solution of the indole in Part C (3.937 g, 17 mmol) and 1-bromo- 4-fluorobenzene (9.34 mL, 85 mmol, 5 eq.) In dry DMF (15 mL) .. • •••• was treated with copper (I) oxide (245 mg, 1.7 mmol, 0.1 eq.) and boiled under reflux under argon for 17 hours. Ytterli. • • •• Bromide (9.34 ml, 5 eq.) And Cu 2 O (245 mg, 0.1 eq.) • •. . • • was added and cooking under Aterflode was continued for 6 hours, •. •. . • • • Additional Cup was added (730 mg, 5.1 mmol) and boiling . • under reflux continued for another 60 hours. DMF and • • excess bromide was distilled off in vacuo and the orange - • • • •• The remaining residue was taken up in ethyl acetate and filtered • e • , • by packed Celite, washed with mNttatoch salt- • 1 solution, then dried over anhydrous Na 2 SO 4 and evaporated and gay 5.385 g (97.2%) of the desired arena was labeled indole in the form of an orange oil.

TLC (9: 1) hexane-acetone, Rf. 0.29, UV + PMA. 1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-methanol To cold (0 ° C, ice bath) dry ether (24 mL) under argon was added LiALH 4 (907 mg, 23.9 mmol, 1.5 molar equivalent) and then the indole ester in Part D (51185 g, 15.9 mmol) was added dropwise. ) in dry Et 2 O (10 mL) for 10 minutes. The mixture was stirred for one hour at 0 DEG C., then quenched at 0 DEG C. by dropwise addition of H2 O (910 .mu.l) of 15% NaOH (910721) and 11 (2.73 ml). The suspension was filtered through anhydrous MgSO 4 over packed Celite and the filtrate was evaporated to a clear, stained glass oil. The oil crystallized slowly from hexane and gay on TV.5. harvests (3.771 g + 0.333 g) 4.10 g (90.9%) of pure classified indole alcohol in the form of white granular crystals, m.p. 81 DEG-82 DEG C.

Mass spectrum (M + H = 284+ observed) Analysis. Calculated for C18 Hi8NOF: C 76.30; H 6.40; N 4.94; F 6.71 Found: C 76.59; H 6.31; N 4.93, F 6.49 1- (4-fluorophenyl) A release of Dess-Martin periodinane (6.46 g, 15.24 mmol) dry CH22 Cl. (30 ml) was treated with dry t-butanol (4 A-sec. tar, 1.44 ml, 15.24 mol, 1 eq.) and the mixture was stirred •• under argon minutes at room temperature. A solution of 0 • • 00 • the indole alcohol in Part E (3.599 g, 12.7 mmol) dry C112Cl2 (13 ml) was added dropwise with mom for 10 minutes and the light yellow - • • - " The mixture was stirred under argon at room temperature for a minimum. ter. The reaction mixture was added to a solution of sodium. 000 thiosulfate (14.06 g, 89 mmol, 7 eq.) in freshly prepared 1 N NaHCO 3 • •• • (40 ml) and stirred for 10 minutes. The water phase avdTevs and the :: •• ••• e • •••• • •• ••• • 611. • 131 The organic phase was washed with 1.0 N NaHCO 3 (2X), 1120 and brine, then dried over anhydrous Na 2 SO 4 and 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) hexane-ether. Product fractions were evaporated and gay 3.118 g (87.3%, crude yield) of crude product. One from hot hexane gay 2.643 g (74%) of the title aldehyde in the form of white fluffy needles, m.p. 114 DEG-116 DEG C.

Mass spectrum (M + H + = 2824 'observed).

TLC (7: 3) hex-Et 2 O, Rf = 0.51, UV + PMA.

Analysis. Calculated for C1016N0F: C 76.85, H 5.73; N 4.98; F 6.7 Found: C 76.87; H 5.63; N 4.89; F 6.88 G.2- (2,2-dibromoethyl) -1- (4-fluorophenyl) -3- (1-methylethyl) - 1H-indole A - ° C (salt / ice bath) log of the aldehyde in Part F (1.615 g, 5.74 mmol) and triphenylphosphine (4.52 g, 17.22 mmol, 3 eq.) In dry CH 2 Cl 2 (25 mL) was treated dropwise For 10 minutes with a CBr 4 (2.86 g, 8.61 mmol, 1.5 eq.) - 18 Solution In dry Cl 2 Cl 2 (10 mL) and the resulting dark orange-red solution was stirred under argon at -0 ° C for 15 minutes. The reaction was quenched at-° C by the addition of matt NaHCO 3, the mixture was diluted with CH 2 Cl 2 and the organic phase was washed with NaHCO 3 and brine, then dried over anhydrous Na 2 SO 4 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 and 2,017 g (80.6%) of the title vinyl dibromide were formed in the form of light yellow crystals, m.p. 123 DEG-124 DEG C.

TLC (9: 1) hexane-ether, Rf = 0.67, UV and PMA.

Mass spectrum (M + 11 + = 438+ observed). 132 Analysis. Calculated for C19H16NFBr2: 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. (4-f luor_f_e_n A -78 ° C (CO 2 / acetone) solution of dry THF (10 mL) was treated with a 1.6 M n-butyllithium solution in hexanes (5.5 mL, 8.8 mmol, 2.2 eq.) And a solution of the vinyl dibromide in Part G (1.749 g, 4 mmol) in dry THF (10 mL) was added dropwise at 15 minutes under argon. The yellow mixture was stirred for 20 minutes at -78 ° C and the reaction was then quenched by the addition of matt NH 4 Cl (10 mL). After warming to room temperature, the mixture was diluted with ethyl acetate and the organic phase was washed with matt NH 4 Cl and brine, then dried over anhydrous Na 2 SO 4 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 and gay 1.084 g (97.5%) of the title indolacetylene as 1 a fluorescent green oil. 1 H NMR (CDCl 3, 270, MHz) showed pA a mixture of undesired acetylene and undesired final olefin in the ratio 18: 1.

TLC (50: 1) hex-Et 2 O, Rf = 0.55, UV and PMA.

J. (S) -4 - // 2- [1- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole η 5 -ethynyl / methoxyphosphinyl / -3 - // (1,1-dimethylethyl) diphenyl- • The phosphonium chloride was prepared starting from phosphonomonomethyl- , • ester, the dicyclohexylamine salt of Example 25 as follows • •• P * 0 • , • • • 0 PII • • P • SO • • 111 ••• •• 00 • Procedure. The free acid was regenerated from the dicyclohexylamine salt (4.32 g, 6.83 mmol, 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. , following drying Over anhydrous Na 2 SO 4 and evaporation In vacuo as gay the free acid (6.8 mmol) in the form of a clear, viscous oil. Phosphonic 133 acid, the monomethyl ester (6.8 mmol) in dry CH 2 Cl 2 (10 mL) was treated with distilled trimethylsilyldiethylamine (1.72 mL, 13.7 mmol, 2 eq.) and the clear charge was stirred under argon at room temperature for one hour. The mixture was evaporated in vacuo, taken up in dry benzene (2 x 20 ml) and left in the vacuum pump for 15 minutes. The crude silylated acid in dry CH 2 Cl 2 (10 mL) and dry DMF (1 drop) was cooled to 0 ° C (ice bath) and treated dropwise within 5 minutes with distilled (COCl) 2 (655/111 7.5 mmol, 1.1 eq. .). The yellow mixture was stirred at 0 ° C for 15 minutes and 45 minutes at room temperature under argon. The mixture was evaporated in vacuo, taken up in benzene (2 x 20 ml) and left in the vacuum pump for 15 minutes and gay crude phosphonochloridate as a yellow viscous oil.

A -78 ° C solution (CO 2 / acetone) of the indole acetylene in Part H (1.084 g, 3.90 mmol, 1 eq.) In dry THF (10 mL) was treated dropwise over 10 minutes with a 1.6 M n-butyllithium solution. in hexanes (2.44 mL, 3.9 mmol, 1 eq.) and the purple suspension was stirred under argon at -78 ° C for 30 minutes. The anion was added dropwise by cannulae over 30 minutes at -78 ° C to a -78 ° C solution of the phosphonochloride in dry THF (10 mL). The dark brown mixture was stirred at -78 ° C for 30 minutes and the reaction was then quenched by the dropwise addition of matt NH 4 Cl (10 mL). The mixture was warmed to room temperature, partitioned between ethyl acetate and matt NH 4 Cl, matted with brine, dried over anhydrous Na 2 SO 4 and evaporated to give 1.968 g (71.1%) of the title acetylenic phosphinate as a pale yellow oil.

TLC (7: 3) hexane-acetone, Rf = 0.25, UV and PMA.

Mass spectrum (M-411 + = 7+ observed).

K. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // 2- [1- (4- fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl / ethyl / methoxyphosphinyl / butanoic acid, methyl ester • • • An argon flush solution of acetylene in Part J (9) 134 mg) in CH 3 OH (10 mL) was treated with 10% Pt / C (238 mg, 25 wt%) and the black suspension was stirred under an H 2 atmosphere (1 atmosphere) overnight. The catalyst was removed by filtration through a Millipore polycarbonate filter (0.4 .mu.m) and pre-filter and the filtrate was 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 and gay 9mg (86.7%) was purely labeled matt phosphinate in the form of a white foam.

TLC (4: 1) EtOAc-hexane, Rf0.39, UV and PMA.

Mass spectrum (M + 1-14- = 714+ observed).

L. (S) -4 - // 2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole- 2-yl / ethyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester 0 • ••• • • • • •• It • •• IL • • 0 • • • • • 0 • 0 * • •• 0 • ••• • • • • • • • • • • • • A solution of the silyl ether in Part K (915 mg, 1.22 mmol) in THE '(10 mL) was treated successively with glacial acetic acid (280 μl, 4.88 mmol, 4 eq.) And a 1.1 M -C 4 H 9 NF-10 solution in THF (3.3 mL, 3.66 mmol, 3 eq.) And the mixture was stirred under argon at room temperature overnight. Ice-cold H 2 O (8 mL) was added, the mixture was extracted with ethyl acetate and the organic phase was washed with 5% KHSO 4 (2X), saturated NaHCO 3 and brine and then dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 955 mg of a yellow oil. The arena oil was purified by flash chromatography on Merck silica gel eluting with (1: 1) hexane-acetone. Product fractions were evaporated and gay 521 mg (85.5%) of the desired title alcohol in the form of a light yellow oil.

TLC (3: 2) acetone-hexane, Rf = 0.21, UV + PMA.

Mass spectrum (M-4-H + = 476+ observed).

M. (5) -4 - // 2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole-2- yl / ethyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A solution of the diester in Part L (505 mq, 1.06 mmol) in dioxane 1 (10 mL) was treated with an excess of 1.0 N LiOH (3.7 mL, 3.7 mmol, 3.5 eq.) And the mixture was heated at 6 ° C (oil bath) under argon for 1.5 hours. The mixture was diluted with H 2 O, filtered and evaporated in vacuo to a light yellow solid. The crude solid was suspended in a small amount of H 2 O and chromatographed on HP-20 resin (15 cm bath, 25 mm diameter column) and eluted with H 2 O until neutral and then with CH 3 OH. Product fractions were combined, evaporated, taken up in H 2 O (50 mL) and lyophilized to give 484 mg (95.4%) of the desired crude dilitium salt as a white lyophilate. TLC (8: 1: 1) C 12 Cl 2 -CH 3 OH acetic acid, Rf = 0.39, UV + PMA. Analysis. Calculated for C23H200FP * 2L1 + 1.03 mol 11 (molecular weight = 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 Example (S) -4 - // 2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] - ethynyl / hydroxyphosphinyl / -3-hydroxybutane crude dilitium salt A. (S) -4 - // 2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole- 2-ylethynylimethoxyphosphinyl-3-hydroxybutanoic acid, methyl ester • . • . • • • ••• ••• .

• • ". • The mixture was diluted with ice-cold H 2 O (10 mL) and extracted . • • line with ethyl acetate. The organic phase was washed with 5% .KHSO4 (3X), food NaHCO3 and brine and then dried . 4 • Over anhydrous Na2SO4 and evaporated and gay 1.0 g yellow • • oil. TLC tycide formation of a certain amount of monoacid, which . • The .111 methyl ester was reconverted by treatment with an ether • ••• • •••• • • • • • • A solution of the silyl ether of Example 30, Part 3 (987 mg, 1.39 mmol) in dry THP (12 mL) was treated successively with glacial acetic acid (35.6 mmol, 4 eq.) and with a 1.1 M n-C4H9NF solution in THF (3.8 mL, 4.17 mmol, 3 eq.) and mixed • ** 0640 • 00- *** - • Of ** 136 release of cH2N2. An excess of CH 2 N 2 was quenched with glacial acetic acid and the mixture was evaporated in vacuo and gay 1.012 g of brown oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (8: 2) hexane-acetone (600 ml) and then with (1: 1) hexane-acetone. Product fractions were evaporated and gay 516 mg (78.7%) of the free classified alcohol as a light brown oil.

TLC (9: 1) CH 2 Cl 2 -CH 3 OH, Rf = 0.41, UV + PMA.

Mass spectrum (M + H + = 472 + observed).

B. (S) -4 - // 2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole yl / ethynyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A solution of the diester in Part A (516 mg, 1.09 mmol) in dioxane (10 mL) was treated with a 1.0 N L 10 H solution (3.8 mL, 3.8 mmol, 3.5 eq.) And the clear mixture was heated and stirred at 60 ° C (oil bath) for 1.5 hours under argon. The mixture was diluted with H 2 O, filtered and evaporated in vacuo and the residual oil was taken up in a minimal amount of H 2 O and chromatographed on HP-20 resin (15 cm bath, column diameter 25 mm) and eluted with pure H 2 O (until neutral) and then with (1: 1) 1120-CH 3 OH. Product fractions were evaporated in vacuo, taken up in H 2 O (50 mL), filtered and lyophilized to give 447 mg (82.3%) of the desired title dilitium salt as a white lyophilate.

TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OH acetic acid, Rf = 0.39, UV + PMA.

Analysis. Calculated for C23H210PNF.2Li2.27 mol H2O (molecular weight 496.19): C 55.67; H 5.19; N 2.82; F 3183; • 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- [1- (4-fluorophenyl) methoxy] phenyl] ethynyl] - : - ••• •: •• • ••• • k • • 137 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 minutes to a suspension of NaH (85.3 mmol) (washed initially with pentane) in THF (150 ml) under an argon atmosphere and cooled to 0 DEG C. When the addition of the phenol was complete, the reaction mixture was stirred at 0 DEG C. for 10 minutes, warmed to room temperature and stirred for 20 minutes. The alkoxide solution was continued with 42 mL of dry DMF and then slowly with 10 mL of THF-16 solution of bromomethyl methyl ether (11.19 g, 89.6 mmol). A white fanning was formed. After stirring for 2.5 hours at room temperature, the reaction was quenched by the initial addition of 25 mL of 1 N NaOH. The THF was removed from the reaction mixture by a rotary precursor and the resulting solution was washed with saturated NaCl solution and then extracted three times with ether. The combined ether extracts were dried over Na 2 SO 4 and filtered. WHEN the solvent was removed, an orange oil was obtained. Purification by flash chromatography eluting with 5% ether-hexanes to give the title methoxymethyl (MOM) ether (12.0 g, 85% yield) as a clear oil.

TLC Rf = 0.45 (15% Et 2 O / hexane, silica gel) Mass spectrum m / e 166 (M +), 165 (M4 - H) - B. 2- (methoxymethoxy) -4,6-dimethylbenzaldehyde 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 . hexane) in cyclohexane (30 ml) under an argon atmosphere. •• The solution was cooled to 0 ° C and the MOM ether in Part A (11.0 g, • • •, • • • 66.21 mmol) was added dropwise over 20 minutes. When to- • . • • • the setting was complete, the reaction mixture was stirred ••• • at 00 ° C for 30 minutes, warmed to room temperature and • rOrdes 10 minutes. The anion was then added via • • funnel to a 100 ml dry cyclohexane solution of DMP (5.81 g, •• . • . 79.45 mmol) under an argon atmosphere and at room temperature. Reactive • • The mixture was stirred at room temperature for 2 hours and ▪0. 00, s • So Sea • 410 •• 138 D • • • • • 0 • e • ••• 0 • •••• • ••• • • •• • ••• • • a the reaction is then quenched with methanol. The reaction solvent was deposited on a rotary evaporator and the resulting orange oil was dissolved in a 1: 1 ether / water mixture. The aqueous layer was extracted three times with ether and the combined ether extracts were dried over MgSO 4. Filtration and removal of solvent gay an orange oil. Purification of the oil by flash chromatography eluting with 20% ether / hexane to give the desired title aldehyde (7.7 g, 60%) as a clear oil.

TLC Rf = 0.14 (15% Et 2 O / hexane, silica gel).

Mass spectrum. m / e 195 (M + H) &lt; + &gt;, 179 (M-CH3) + 163 (M-OCH 3) +, 149 (M-02CH) + 2-hydroxy-4,6-dimethylbenzaldehyde A 1 M HCl solution (35.5 mL) was added to a dioxane (130 mL) solution of the MOM ether in Part B (6.89 g, 35.5 mmol) at room temperature. The reaction mixture was heated to weak Aterflode and stirred for 30 minutes. The reaction mixture was cooled to room temperature and the oxane was deposited on a rotary evaporator. The resulting aqueous solution was diluted with H 2 O and extracted with ether. the aqueous layer was then quenched with NaCl and extracted again with ginger with ether. The ether extracts were combined and then dried over MgSO 4. Filtration and removal of solvent gay a granular solid which was purified by recrystallization from hexane (4.01 g, 75%).

TLC Rf = 0.48 (25% Et 2 O / hexane, silica gel) m.p. 46 - 48 ° C. Mass spectrum. m / e 151 (M411) +, 135 (M-CH 3) +. 2 - [(4-Chlorophenyl) methoxy] -4,6-dimethylbenzaldehyde A solution of the phenol in Part C (4.0 g, 26.7 mmol) and dry DMF (30 mL) was stirred under an argon atmosphere. At room temperature, K 2 CO 3 (4.43 g, 32 mmol) was added to the phenol solution and then heated to 60 ° C for 35 minutes. The resulting orange solution was cooled to room temperature and p-fluorine. 1_39 the benzyl bromide (5.55 g, 29.3 mmol) was added. The reaction mixture was heated to 60 DEG C. and stirred for 2 hours. The reaction mixture was halided in 50 ml of ice water and this mixture was extracted several times with ether. The combined ether extracts were dried over Mg4 and filtered to give a yellow solid when the solvent had been removed. Purification by flash chromatography eluting with 15% ether / hexane to give the title benzyl ester (4.48 g, 60%) as a white solid.

TLC Rf. 0.34 (25% Et 2 O / hexane, silica gel).

Mass spectrum. m / e 259 (M441) +, 231 (M-CHO) +, 109 (M-C7H6F) E.1- (2,2-th.bromoethyl) -2,4-dimethyl-6- (phenylmethoxy) benzene 170 ml of dry CH 2 Cl 2 16 solution of the aldehyde in Part D (4.42 g, 17.13 mmol) under an argon atmosphere was cooled in an ice-salt bath. To the cooled solution was added triphenylphosphine (14.4 g 55.0 mmol) and the mixture was stirred until all solids had been dissolved. 50 ml of C112 Cl2 solution of CBr4 (8.52 g, 25.7 mmol) was added immediately to the addition funnel over a period of 12 minutes. When the addition was complete, the orange reaction solution was stirred at 0 DEG C. for one hour and 15 minutes. The reaction was quenched with 60 mL of a lukewarm solution of NaHCO 3 in water and stirred vigorously. The aqueous layer was removed and extracted twice with CH 2 Cl 2. The combined CH 2 Cl 2 solutions were washed once with saturated NaHCO 3 solution in water, dried over MgSO 4 and filtered to give the title dibromide as a reddish brown solid (13 g). The title dibromide was purified by • • • • * • • • • • • • 0 • • • • • • ft • • • 0 • • • • • • • • • • • • • Flash chromatography eluting with 2% ether-hexane and gay 5.49 g, 77% yield of the title dibromide.

TLC Rf-0.28 (2% Et 2 O / hexane, silica gel).

Mass spectrum.m / e413 (M + H) 4,333.3 (M-Hr) 4, 317 (M-C6 H4 'F) 109 (M-C11 9013r2) ' F.ketyny17.22 / (4-11uprfeyfl) methoxy / 1416.: Dib „Ilbensen • 70 ml THF solution of the dibromide in Part E (5.48 q, 13.3 mot) 1 • • • • • 0 • • • • • •• • 0 • • • • • • • • ••• • • • • • n • 4I • t.) • • ft • under an argon atmosphere was cooled to -78 ° C. n-Butyllithium (10.6 mL of a 2.5 M solution in hexane, 26.5 mmol) was added to the dibromide solution over 10 minutes. The reaction mixture was stirred at -780 ° C for one hour and then quenched at -78 ° C with a quenched solution of NH 4 Cl in water. When the reaction mixture was warmed to room temperature, it was diluted with 60 ml of H 2 O and the aqueous layer was extracted twice with ether. All organic layers were combined and dried over m004. Filtration and loading of solvent 3.8 g of the title benzyloxyacetylene as a yellow solid. The title benzyloxyacetylene was purified by flash chromatography eluting with 3% ether / hexane. The title acetylene is obtained in a yield of 85% (2.76 g) as a white solid.

TLC Rf = 0.17 (2% Et 2 O / hexane, silica gel).

Mass spectrum. m / e 255 (M + H), 159 (M-C 6 H 4 F), 109 (N-C101190) 4 G. (S) -4 - /// 2,4-dimethyl-6- - [(4-fluorophenyl) methoxy] phenyl] - Ethynyl / hydroxyphosphinyl / -3- (t-butyldiphenylsilyloxy) - butanoic acid, dilitium salt 40 ml of THF-10 solution of the acetylene in Part F (2.76 g, 11 mmol) under an argon atmosphere was cooled to -78 ° C. At -78 ° C, n-bsityllithium (4.4 ml of a 2.5 M 10 solution in hexane) for 8 minutes. The reaction mixture was stirred at -780 ° C for 40 minutes.

The phosphonyl chloride in Example 25 (17.4 mmol) in 60 mL of THF was cooled under an argon atmosphere to -78 ° C. The acetylenic anion formed as above was then added over 8 minutes. After stirring for one hour at -78 DEG C., the reaction was quenched at -78 DEG C. with a slurry solution of NH4Cl in water and the reaction mixture was allowed to warm to room temperature. The aqueous layer was diluted with 1120 and extracted twice with ether. PEW was removed from the T1IF 'reaction layer and the resulting orange oil was taken up in ether. All ether solutions were combined and quenched with a medium solution of Na 2 CO 2 in water and an Ong mod of NaCl solution. Dot the organic layer 141 dried over MgSO 4 and filtered, leaving 9.4 g of the title acetylenic phosphinic acid as an orange gum when the solvent was removed. The title acetylenic phosphinic acid was purified by flash chromatography eluting with a 5/1/4 hexane / toluene / ethyl acetate mixture. The title acetylenic phosphinic acid (4.23 g) is obtained in 56% yield as a clear gum.

TLC R = 0.28 (5/1/4 hexane / toluene / ethyl acetate silica1). Mass spectrum. m / e 609 (M + H-C 6 H) +, 255 (C 14 H 19 SiO) * H. (S) -4 - /// 2,4-dimethyl-6- - [(4-fluorophenyl) methoxy] phenyl] - ethynyl / methoxyphosphine1 / -3-hydroxybiara, n The acetylenic phosphinate in Part G (0.455 g, 0.66 mmol) was stirred in 10 mL of THF under an argon atmosphere. Attic acid (0.16 g, 2.66 mmol) was added at room temperature and then n-C 4 H 9 NF (1.8 mL of a 1.1 M THF solution, 2.0 mmol) was added dropwise over 5 minutes. After stirring for 24 hours at room temperature, the reaction is quenched by the addition of 30 ml of ice water. The aqueous layer was removed and extracted twice with ethyl acetate. THF was removed from the organic layer of the reaction mixture and the resulting oil was dissolved in ethyl acetate and combined with the extracts from the aqueous layer. This ethyl acetate solution was washed twice with a quenched solution of NaHCO 3 in water and once with a quenched NaCl 4 slurry and then dried over Na 2 SO 4. Filtration and removal of solvent gay 0.40 g of the title hydroxyacetylenic phosphinate in the form of an oil. The title hydroxyacetylenic phosphinate was purified by flash chromatography eluting with 100% ethyl acetate. The title hydroxyacetylenic phosphinate is obtained in a yield of 79%.

TLC Rf = 0.56 (7: 3 acetone / hexane, silica gel).

Mass spectrum. m / e 449 (M + H) +, 431 (M-OH) +, 417 (M-OCH 3) +. 142 J. (S) -4 - /// 2,4-dimethyl-6- - [(4-fluorophenyl) methoxy] phenyl] - ethynyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt 6.0 mL of dioxane solution of the acetylenic phosphinate in Part H (0.191 g, 0.43 mmol) was added at room temperature with 1.4 mL of 1 N LiOH solution. The reaction mixture was heated to 5 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness to give the title compound. The title compound was purified on a column of HP-20 which was 130 mm high and had a diameter of mm and was eluted first with 100 ml of 1120 and then with a 1; 1 MeOH / H 2 O mixture. The title compound is reset in 91% yield (0.170 g) as a white lyophilate.

TLC Rf = 0.37 (7: 2: 1 nPrOH / N1-140H / H2O silica gel).

Mass spectrum (FAB) m / e 421 (M + H) +, 427 (M + Li) +, 433 (M4-2Li): Analysis. Calculated for C2006FPL12.1,4 H20: 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 Example 32 (S) -4 - /// 2,4-dimethyl-6- [1- (4-fluorophenyl) methoxy] phenyl] ethyl] hiS-11210 / 2aflaY111: 12112Y.L212Laca, dilitium salt A. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // 2- / 2- / (4-fluorophenyl) methoxy / -4,6-dimethylphenyl / ethyl / methoxyphosphinyl / butanoic acid, with ester The Acetylenic Phosphinate In Example 31 Part G (1.34 g, 1.95 mmol) was stirred in methanol (12 mL) and PtO 2 (0.040 g) was added. Hydrogen gas was bubbled through the methanol solution for 10 minutes and then a 112 gaseous atmosphere was created by means of a balloon. After 5 hours and 15 minutes at room temperature, the reaction was complete and argon was allowed to bubble through the reaction. • 0 0 • co • 143 solution solution. The reaction mixture was filtered through a pad of celite into a lens sintered glass funnel and the catalyst was washed with methanol. The solvent was removed from the filtrate to give 1.4 g of a title saturated phosphinate as a clear gum. The title matte phosphinate was purified by flash chromatography eluting with 60% ethyl acetate / hexane and then the chromatographed material was purified from slightly contaminated fractions with 6 / 2.5 / 1.5 hexane / acetone / toluene. The title saturated phosphinate obtained 86% yield (1.17 g).

TLC Rf. 0.045 (80% ethyl acetate / hexane, silica gel). Mass spectrum. m / e 691 (M + H) f, 659 (M-OCH 3), 635 (M-C 9 H 19 OSi) B. (S) -4 - /// 2,4-dimethyl-6- - [(4-fluorophenyl) methoxy] phenyl] - y11, methoxyphosphinyl / -3-hydroxy-butEllna, ITIL / Lester The phosphinate in Part A (1.16 g, 1.68 mmol) was stirred in THF (25 mL) under an argon atmosphere and at room temperature. Glacial acetic acid (0.40 mL) was added dropwise to the phosphinate solution and then n-C 4 N 9 NF (4.6 mL of a 1.1 M THF solution) was added dropwise over 5 minutes. The reaction mixture was stirred at room temperature overnight (18 hours) and then quenched with 50 ml of ice-water. After stirring for several minutes, matt NaCl solution was added and the layers were separated. The organic layer was evaporated on a rotary precursor to remove THF and the resulting residue was dissolved in ethyl acetate. The aqueous layer was extracted twice with ethyl, acetate and all ethyl acetate solutions were combined and washed twice with matt solution of NaHCO 3 in water and once with matt NaCl solution and then dried over Na 2 SO 4. Filtration and removal of solvent Gay 1.13 g of the title hydroxyphosphinate in the form of a clear oil. The title hydroxyphosphinate was purified by flash chromatography eluting with 100% ethyl acetate and gay the title hydroxyphosphinate as a clear oil in 83% yield. TLC Rf. 0.27 (6: 4 acetone / hexane, silica gel). 4.

ManspekLrum. m / e 453 (M411), 343 (M-C7H6P). •• • • ••• • • • • • 6 • O• • • • • 416.4.1% **% • ' 144 (S) -4 - /// 2,4-dimethyl-6- [1- (4-fluorophenyl) methoxy] phenyl] ethyl] hydroxyphosphinyl] 22,1hydroxybutanoic acid, dilitium salt The phosphinate in Part B (0.594 g, 1.3 mmol) was stirred in 19 mL of dioxane at room temperature, 1 N LiOH (4.0 mL) was added with stirring at room temperature and the reaction mixture was warmed to 5 ° C. After 20 minutes at 5 ° C a white thick formation formed and 4.0 ml of dioxane was added and the resulting suspension was stirred at 50 ° C. After 2.5 hours at 50 ° C 3 ml of H 2 O were added and the reaction mixture became clear. After 3 hours at 5 ° C, the reaction mixture was cooled to room temperature and the dioxane and water were removed by a rotary evaporator leaving the title diacid in the form of a 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 H70 and then with 1: 1 MeOH / H2 O solution. The title diacid is obtained in the form of a white lyophilate in a yield of 67%. TLC Rf = 0.36 (7: 2: 1 n-propanol / NH 4 OH / H 2 O, silica gel). Mass spectrum. m / e (FAB), 425 (M + H) +, 437 (M + H + 2) Analysis. Calculated for C202406FP.1.15 H2O: 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 Example 33 (S) -4 - // 2 - // 1,1'-biphenyl / -2-ylmyl / nyl: oxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A. (S) -4 - // 2 - // 1,1'-biphenyl / -2-yl / ethynyl / hydroxy-phosphinyl / - 3-hydroxybutanoic acid, methyl ester The phosphinate in Example 9, Part D (1.61 mmol, 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) and then continued dropwise over 8 minutes with n-C 4 H 9 NF (4.84 mmol, 4.40 mL of a 1.1 M solution in THP). : ••: •• , •• • •• , •• • • • 4 se '04d, • * •• a. 000 • 00011 1 After stirring at room temperature for 18 hours, the reaction mixture was continued with 30 ml of ice water. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed twice with a matt solution of NaHCO 3 in water and once with brine, dried over MgSO 4, filtered and evaporated. The product was isolated by flash chromatography (50 mm cyclone, 6 "Merck silica gel, 40% acetone / hexane as eluent, 2" / minute flow rate). Product fractions were concentrated, azeotroped with toluene and evaporated in vacuo to give the title alcohol (0.379 g, 0.991 mmol, 62% yield) as a viscous yellow oil. (0.098 g, 0.263 mmol, 16% of a slightly contaminated product was also obtained.) TLC: silica gel Rf = 0.35 (50% acetone / hexane).

Mass spectrum. CI m / e 373 (M + H) &lt; + &gt;. B. (S) -4 - // 2 - // 1,1'-biphenyl / -2-yl / ethynyl / hydroxyphosphinyl / - 3-hydroxybutanoic acid, dilitium salt The diester in Part A (0.739 mmol, 0.275 g) was stirred under argon in 7.57 mL of dioxane and treated with 1 M LiOH (2.22 mmol, 2.22 mL). This cloudy reaction mixture was heated in a 50 ° C oil bath for 45 minutes. The mixture was cooled to room temperature. The readings were deposited on a rotary evaporator and at high vacuum (90 minutes). The resulting yellow foam was dissolved in 4 ml of distilled 11 and eluted through an HP-20 chromatography column (2.5 cm x 19 cm) and 10 ml fractions were collected after each time period of 1.4 minutes. The column was eluted with H 2 O until 15 fractions were collected (no longer basic) and subsequent elution with 45/55 methanol / H 2 O gay (after lyophilization (2X) and high vacuum pump over P 2 O for 16 hours) 0.231 g (0.649 mmol, 88% yield) of the the title diacid in the form of a white lyophilate.

TLC: silicon Rf = 0.55 (7: 2: 1 n-propanol / NH 3 OH / 1120).

Mass spectrum (FAB m / e 345 (M + H) +, 351 (M + Li) +, 357 (M + 2 Li) 4, „„ 7 i f -; • 01, 664 • 00 004 0 146 Analysis. Calculate for C1e1sOPLi2 + 1.42 mol H2 molecular weight. 381.75: C 56.63; H 4.71; P 8.07 Found: C 56.62; H 4.70; p 8.07 Example 34 (S) -4- [2- [3,5-dimethyl] -1,1-biphenyl] -2-yl] ethyl / hydroxyphosphinyl] -2: 3L-hydroxybutanoic acid, dilitium salt A.3,5-dimethyl / 1,1'-biphenyl / -2-carboxaldehyde Phenylmagnesium bromide is obtained from Aldrich (Cat. No. 17, 156-5) in the form of a 3 M solution in ethyl ether.

A mixture of the dipalladium complex of Example 1, Part B (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 DEG C. and phenylmagnesium bromide-grignard reagent (Aldrich) (35.84 mmol, 11.95 ml of a 3 M solution in ether was added dropwise (rapidly)). The resulting mixture was stirred at room temperature for 1.5 hours. The mixture was then cooled to 0 DEG C. and treated in one portion with 22.4 ml of 6.0 N HCl and stirred at room temperature for one hour. The aqueous layer was separated and extracted with ether. The organic extracts were combined, filtered through Celite (washed with ether) and the filtrate was washed with brine, azeotrophically distilled ••• whipped with toluene and evaporated in vacuum and gay a yellow solid. Try to clean the product with (2X) quick release • IN In •• matography (95 mm diameter column, 6 ”Merck silica gel, 100% , • hexane -43% ether / hexane as eluent, 2 "/ minute river , • • 4 I • 0 • speed gay 9.5 g of a yellow solid (1.88 g 8.96 IN • • mmol, 100% yield of the title aldehyde and 1.06 g. • • • triphenylphosphine). This compound mixture was used directly • ••• . • in the presentation of the association 1 Part B.

• IN•• • TLC: silica gel, Rf - 0.30 (5 in ether / hexane). •, • 0 +.

Mass spectrum, (CI) m / L 211 (M + H) 4-, 263 (M2 + H), 473 1M M2 + 11) •• .:. • .t • i •••• •. •• • .. • 0 •• •• O •••• • •• •••. ••••. • 147 M1 = the aldehyde in Part A, M2triphenylphosphine.

B.2- (2,2-Dibromoethyl) -3,5-dimethyl / 1,11-biphenyl / A mixture of the aldehyde of Part A (8.96 mmol, "1.88 g") and triphenylphosphine (26.4 mmol, 6.90 g) was stirred in 88 mL of dry CH 2 Cl 2 at -0 ° C for 10 minutes. This reaction mixture was kept at-° C while a solution of C8r4 (13.2 mmol, 4.38 g) in 32 mL of dry CH 2 Cl 2 was added dropwise (20 minutes). The resulting reaction mixture was stirred at-° C for one hour and gradually became darker orange. The reaction is then quenched with 85 mL of a molten solution of NaHCO 3 in water. The aqueous layer was extracted with CH 2 Cl 2. The organic extracts were combined, washed once with a matt solution of NaHCO 3 in water and once with brine, dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by pre-absorbing the arena product in cH 2 Cl 2 on 25 g of Merck silica gel and then passed to a flash chromatography column (50 mm diameter, 6 "Merck silica gel, 4% CH 2 Cl 2 / - hexane as eluent, 2" / minute flow rate) gay 2 , 18 g (5.96 mmol, 68% yield) of the title vinyl dibromide as a viscous colorless oil.

TLC: silica gel Rf = 0.37 (4% CH 2 Cl 2, hexane) Mass spectrum. (CI) m / e 365/367/369 (M + H): 3,5-dimethyl-2- (1-propyryl) / 1,11-biferalL • • • • • • A solution of the vinyl dibromide in Part B (5.74 mmol, 2.10 g) in 29.11 ml of anhydrous THF were stirred under argon and cooled to -78 ° C. This solution was treated dropwise (20 minutes) with • • • • •• n-butyllithium (11.47 mmol, 4.4 ml of a 2.5 M solution in • - • hexanes) and gay a dark purple solution. After omro-- • ring at -78 ° C for another hour, the reaction is stopped at • .41-78 ° C with 25 ml of a matt solution of NH4Cl in water, • • •• . The reaction mixture was warmed to room temperature and -. • •• was diluted with 11 and the aqueous layer was extracted mod 1: 1 ether / hexane. The organic extracts were combined, dried 148 over MgSO 4, filtered and evaporated in vacuo. The product was isolated by flash chromatography (50 mm column, 6 "Merck silica gel, 1% ether / hexane as eluent) and gay 1.08 g (5.23 mmol, 91% yield) of the title acetylene to form a colorless oil, which was db it was stored for 16 hours at -0 ° C.

TLC: silica gel Rf = 0.32 (100% hexane).

Mass spectrum. (CI) m / e 207 (M + H) + D. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxl / -4 - // 2- / 3,5- dimethyl / 1,1'-biphenyl / -2-yl / methoxyphosphinyl / butanoic acid, methyl ester • ••• • •••• • • t • • • • e • • • • ••• • A reading of the acetylene in Part C (4.61 mmol, 0.950 g) in 27.3 mL of dry TI-IF was stirred 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 minutes) to give a dark purple / brown solution. The reaction mixture was stirred at -78 ° C for one hour (the reaction mixture became a slurry), warmed to 0 ° C and stirred for 15 minutes (the reaction mixture & returned to a market purple homogeneous solution) and finally cooled to - ° C (remained homogeneous). This acetylenic anion solution at -0 DEG C. was added dropwise (25 minutes) to a solution of the phosphinyl chloride in Example 1, Part F (8.12 mmol) in 27.3 ml of dry THF, which had been cooled to -78 DEG C. while stirring. under argon. When the addition of the acetylenic anion solution to the phosphinyl chloride solution was complete, the dark orange reaction mixture was stirred at -78 ° C for one hour and then quenched at -78 ° C with 50 mL of matt NH 4 Cl, warmed to room temperature and diluted with H 2 O. the aqueous layer was extracted with ether. The organic extracts were combined, washed with a molten solution of NaHCO 3 in water and an Ong with brine, dried over MgSO 4, filtered and evaporated in vacuo. The product was isolated by flash chromatography (50 mm diameter column, 6 "Merck silica gel, 50% ethyl acetate / hexane as eluent, 149 • ••• 0 • • 2 "/ minute flow rate) and gamma 0.609 g (0.945 mmol, 21%) of the title phosphinate as a guide yellow-orange oil.

TLC: silica gel Rf = 0.32 (50% ethyl acetate / hexane). Mass spectrum. (CI) m / e 639 (m + B) + E. (S) -4 - // 2- [3,5-Dimethyl] -1,1'-biphenyl / 2-yl / ethyl / hydroxy- phosphinyl / -3- (t-butyldiphenylsilyloxy) butanoic acid, dilitium salt Argon was bubbled through a methanol (13 mL) solution of the acetylenic phosphinate in Part D (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 pad of Celite in a funnel of sintered glass. The celite was washed with methanol and the filtrate was evaporated in vacuo to give 0.896 g of a yellow oil, which was purified by flash chromatography (50 mm diameter column, 6 "Merck silica gel, 40% 50% ethyl acetate / hexane as eluent) and gay 0.680 g (1.06 mmol, 77% yield) of the title matte foinate as a pale yellow foam. Elution of the column with methanol gave an additional 0.087 g of slightly contaminated product.

TLC: Rf. 0.27, silica gel (50% acetone / hexane).

Mass spectrum: (CI) m / e 643 (M + H) 4-.

F. (S) -4 - // 2- [3,5-Dimethyl] -1,1'-biphenyl / -2-yl / ethyl / hydroxy- phosphinyl / -3-hydroxybutanoic acid, dilitium salt •• • •• • • • • • The phosphinate in Part E (1.03 mmol, 0.66 g) was stirred under argon at room temperature 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) and then added dropwise with n-C4H3NF (3.09 mmol, 2.81 ml of 1.1 M solution of THF). After stirring at At room temperature for 16 hours, the reaction mixture was continued with 25 ml of ice water. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed twice • • ilk • • 0 •• • • 0 1 with a saturated solution of NaHCO 3 in water and a slurry of brine, dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by flash chromatography (40 mm column, 6 "Merck silica gel, 50% acetone / hexane as eluent) and gay 0.363 g (0.898 mmol, 87% yield) of the title alcohol as a white solid. TLC: silicon Rr = 0.30 (50% acetone / hexane) Mass spectrum. (FAB) m / e 405 (M + H) +.

G. (S) -4- [2- [3,5-dimethyl] -1,1-biphenyl] -2-yl] ethyl / hydroxy- phosphinyl / -3-hydroxybutanoic acid, dilitium salt The diester in Part F (0.878 mmol, 0.355 g) was stirred under argon in 9 mL of dioxane and treated with 1 M LiOH (2.63 mmol, 2.63 mL). This homogeneous reaction mixture was heated in a 50 ° C oil bath. After stirring at 50 ° C for 10 minutes, the reaction mixture became a white suspension. An additional 9 mL of dioxane and 2 mL of H 2 O were added and the suspension was heated at 5 ° C for 45 minutes and then cooled to room temperature. The solvents were deposited on a rotary evaporator and at high vacuum (one hour). The resulting white solid was eluted through an HP-20 chromatography column (18 cm x 2.5 cm). 10 ml fractions were collected after each period of 1.4 minutes. The column was eluted with H 2 O until 15 fractions were collected and elution with 1: 1 methanol / H 2 O gay then S •••• • • • •• • •• • / after lyophilization (3X) and hag vacuum pump over P20 (4 x 8 hours) / 0.289 g (0.744 mmol, 85% yield) of it the title diacid in the form of a white lyophilate.

TLC: silica gel, Rr. 0.56 (7: 2: 1, n-propanol / NH 4 OH / H 2 O). • 0 •• Analysis. Berdknat for C20230PLi2 +0.34 mol H2O •• • Molecular weight = 394.31: C 60.92, H 6.0 •• •• •••• Found: C 60.95, H 6.18 0 Mass spectrum (FAB) m / e 389 (M + H) +. ••• • 0 • ••• 0 • • •• • 000 •• •• •• ••• • • • • ••:. •; •• ' •• •••• • g • 151 Example „3.

(S) // 2- [4'-fluoro-3,5-dimethyl / 1,11-biphenyl] -2-ylmethyl] -h hydroxyphosphine / 73-h BroM (4-fluorophenyl) magnesium Magnesium metal pan (44.35 mmol, 1.08 g) was flame dried and then stirred under argon in 40 ml of anhydrous ether. With vigorous stirring, 1-bromo-4-fluorobenzene (40.3 mmol) was added dropwise to the magnesium. The reaction was initiated in an ultrasonic device and then the halide was added dropwise at a rate sufficient to maintain reflux. When the 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 gal, a golden orange transparent grignard solution containing 40.32 mmol of the title grignard as a 0.91 M solution in ether. 4'-Fluoro73457dimethyll14.1! -B, phenyl / 72-carboxal4ehyd Male reference: Stockker et al., Journal of Med. Chem. 29, 170 - 181 (1986).

A mixture of the palladium complex of Example 26 Part B (4.35 mmol, 3.20 g) and 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 grignard reagent (40.32 mmol, 44.43 ml) was added portionwise (rapidly). The resulting mixture was stirred at room temperature for 1.5 hours. The mixture was then cooled to 0 DEG C. and treated in a portion with 21.75 ml of 6.0 N HCl and stirred at room temperature for one hour. The aqueous layer was separated and extracted with ether and the combined organic extracts were filtered through Celite. The celite was washed with ether and the combined filtrates were washed with salt: • • •••• • • • • 06 • •• ••••• • • • • • • ••• 0 • ••• a g ••• • 9 • • •• • •• • • • • • 152 azotropically distilled two ginger with toluene and evaporated and gay an orange-yellow solid. Attempts to isolate the title aldehyde by flash chromatography using a 95 ml diameter column, 6 "Merck silica gel and with hexane as eluent and then 3% Etphexan as eluent and a flow rate of 2" / min resulted in a final reaction product mixture of the desired the title aldehyde and triphenylphosphine as a pale yellow solid (3.70 g - it is assumed to contain 8.7 mmol, 1.99 g, 100% yield of the title aldehyde 4. 1.70 g of triphenylphosphine). This compound mixture was used directly in the preparation of the compound of Part C.

TLC: silica gel Rf = 0.25 (5% ether / hexane), 1 H NMR: (270 MHz, CDCl 3).

C.2- (2,2-dibron-f_1 = -21.5-diyaifs_n_xli A mixture of the aldehyde of Part 13 (8.70 mmol, "1.99 g") and triphenylphosphine (26.1 mmol, 6.85 g) was stirred in 87 mL of dry CH 2 Cl 2 Yid -5 C for 10 minutes. This reaction mixture was maintained at Yid - ° C while a solution of CBr 4 (13.05 mmol, 4.33 g) 43 ml of dry CH 2 Cl 2 was added dropwise within 25 minutes. The resulting reaction mixture was stirred at -c C for one hour and gay a market orange solution which was then quenched with 80 ml ay a matt solution of NaHCO 3 in water. The aqueous layer was extracted with four gins with C112Cl2. The combined organic extracts were washed once with a matt solution NaHCO3 in water and one went with saline. The C112C12 extract • dried over MgSO 4 and filtered and the filtrate combined . • • • . • 0 • •• ■ • • •••• • ••• • • ••• • • •• • Dissolve with 25 g of Merck silica gel. The solvent was evaporated and the precursor product was purified by flash chromatography (50 mm diameter column, 6 "Merck silica gel, 4% C112c12 / hexane as eluent, 2" / minute flow rate) and gay 2.32 g (6.04 mmol, 69% yield) ay of the title vinyl dibromide in the form of a colorOs oil.

TLC: silica gel, Rf 0.43 (5% C 12 Cl 2 / hexane).

Mass spectrum. (Cl) m / e 383/385/387 (M + 11) • 153 4'-Fluoro-3,5-dimethyl-2- (1-propynyl) - / 1,1'-bi, phenyl / A solution of the vinyl dibromide in Part C (5.99 ml, 2.30 g) The 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 M solution of hexanes) to give a dark purple solution. After stirring at -78 ° C for an additional hour, the reaction mixture was quenched at -78 ° C with 25 mL of a lukewarm solution of NH 4 Cl in water, warmed to room temperature and diluted with 25 mL of H 2 O. The aqueous layer was extracted with four ginger with 1: 1 ether / hexane. The organic extracts were combined, dried over MgSO 4, filtered and evaporated. The product was distilled by flash chromatography (50 mm column, 6 "Merck silica gel, 0.50% ether / hexane as eluent, 2n / mm flow rate) and gay 1.25 g (5.57 mmol, 93% yield) of the title acetylene as of a colorless oil, which becomes, inter alia, when stored at o C.

TLC: silica gel, Rf = 0.25 (100% hexane) Mass spectrum. (CI) m / e 225 (M + 11) 4.

(S) -4- [2- [4'-fluoro-3,5-dimethyl- [1,1'-biphenyl] -2-yl] -ethynyl] hydroxyphosphinyl] -3- (t-butyldiphenylsilyloxy) -butanoic acid , methyl ester A solution of the acetylene in Part D (5.24 mol, 1.18 g) in 28 ml of dry THE was stirred under argon and cooled to -78 ° C. lithium (5.24 mmol, 2.10 mL of a 2.5 M solution in hexane) was added dropwise (25 minutes) to the reaction mixture markt purpurfArgad / brown. The reaction mixture was stirred • •• Then at -780 ° C for one hour, warmed to 0 ° C, stirred • • • • minutes and cooled Anyo to -780 ° C. This acetylenic . ••. • ionic solution at -780 ° C was then added dropwise (20 minutes) • to a solution of the phosphinyl chloride ± Example 1, Part F . " . • • (8.32 mol) in 28 ml of anhydrous THE which was cooled to -78 ° C " . (15 it was stirred under argon. When the addition was complete ". .. • boarded, the dark orange reaction mixture was stirred • • . • S •• 4 • 4 •••••• t: af • 154 at -78 ° C for one hour and then quenched at -78 ° C with a saturated solution of NH 4 Cl in water, warmed to room temperature and diluted with H 2 O. The aqueous layer was extracted four times with ether. The organic extracts were combined and washed once with a matt solution of NaHCO 3 in water and one Ong with brine, dried over MgSO 4, filtered and evaporated. The product was isolated by flash chromatography (50 mm diameter column, 6 "Merck silica gel, 40% ethyl acetate / hexane as eluent, 2" / min flow rate) and gay 0.730 g (1.11 mmol, 21% yield) of the title acetylenic phosphinate as a spruce viscous oil.

TLC: silica gel Rf = 0.36 (50% ethyl acetate / hexane) Mass spectrum. (CI) m / e 657 (M41) 4- F. (s) -4 - // 2- [4'-fluoro-3,5-dimethyl- [1,1'-biphenyl] -2-yl] - ethyl / hydroxyphosphinyl / -3- (t-butyldiphenylsilyloxy) butane methyl ester Argon was bubbled through a methanol (9.9 mL) solution of the acetylenic phosphinate in Part E (1.04 moles 0.685 g) for 10 minutes. 0.239 g of 10% Pd / C 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 pad of Celite into a sintered glass funnel, the celite was washed with methanol and the filtrate was evaporated to give 0.638 g of a spruce oil. The product was purified by flash chromatography (40 mm diameter column, 6 "Merck silica gel, 45% ethyl acetate / hexane as eluent, 2" / min flow rate) and gay 0.530 g (0.802 mmol, 77% yield) of the title matte phosphinate as a light yellow foam. 0.09 g (0.136 mol 13%) of slightly contaminated product were also obtained. TLC: silica gel. Rf = 0.30 (50% ethyl acetate / hexane) Mass spectrum. (CI) m / e 661 (M + H) 4, • • • • • It • • •• • • •••• IP • 15 • ••• f • •• • 0 • • • • • • • • , ••• • 11 ••• I, •• • • • (S) -4 - // 2- [4-fluoro-3,5-dimethyl- [1,11-biphenyl] -2-yl] -ethyl] methoxyphosphinyl] ethyl ester The phosphinate in Part F (0.794 mmol, 0.525 g) was stirred under argon at room temperature in 9.74 mL of anhydrous THF. This solution was treated dropwise with glacial acetic acid (3.18 mmol, 0.191 g, 0.182 mL) and then by dropwise addition of n-C 4 H 9 NF (2.38 mmol, 2.17 mL of a 1.1 M solution in THF). After stirring at room temperature for 16 hours, the reaction mixture was quenched with 15 ml of ice water. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed twice with quenched solution of NaHCO 3 in water and once with brine, dried over MgSO 4, filtered and evaporated. The product was purified by flash chromatography (40 mm diameter column, 6 "Merck silica gel, 50% acetone / hexane as eluent, 2" / min flow rate). Product fractions were concentrated and azeotroped to dryness with toluene and gay 0.281 g (0.665 mmol, 84% yield) of the title alcohol as a white solid. An impurity visible at 270 MHz 1 H NMR was not separable / visible in different TLC systems.

TLC: silica gel, Rf = 0.31 (50% acetone / hexane) 11 H NMR: 270 MHz, CDCl 3).

Mass spectrum. (CI) m / e 423 (M + H) + ..

(S) -4 - // 2- [4'-fluoro-3,5-dimethyl- [1,1'-biphenyl] -2-yl] -ethibutanstium salt The diester in Part G (0.473 mmol, 0.20 g) was stirred under argon in dioxane (4.84 mL) and treated with 1 M LiOH (1.42 mmol, 1.42 mL). This homogeneous reaction mixture was heated in a 50 ° C oil bath. After stirring at 50 ° C for 10 minutes, the reaction mixture became a white suspension. The mixture was kept at 5 ° C for another 45 minutes and then cooled to room temperature. The solvents were deposited on a rotary evaporator and at high vacuum (I Unite). The resulting white foam was dissolved in 4 ml of distillate H 2 O and eluted through an HP 156 chromatography column (16 cm x 2.5 cm). 10 ml fractions were collected after each period cm 1.4 minutes. The column was cleaved with H 2 O until 15 fractions were collected and then gay elution with 1: 1 methanol / H 2 O (after lyophilization (2X) and high vacuum pump Over P 2 O for 11 hours) 0.158 g (0.389 mmol, 82% yield) of the title diacid in the form of a white 1yophilate.

TLC: silica gel Rf = 0.59 (7: 2: 1, n-propanol / NH 4 OH / H 2 O) Mass spectrum (FAD) m / e 395 (14-01) 4- Analysis. Calculated for CH22 - FO514 Li 0.39 mo1 H2O - molecular weight = 413.25: C 58.12; H 5.56 Found: C 58.14; H 6.09 Example 36 (5) -4- [2 - [(4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, with ester A.4-fluoro-tb-oxobenzenepropanoic acid, ethyl ester 60% sodium hydride in mineral oil (17.4 g, 0.43 mmol) was washed twice with dry hexane, dried in vacuo and then treated with pure diethyl carbonate (44.3 mL, 0.36 mmol), then p-fluoroacetophenone (22 ml, 0.18 mol) was added dropwise. When about 10% of the ketone had been added, ••• • 4 drops of ethanol were added to initiate the Aterflod and res- • The p-fluoroacetophenone was added at about 1.0 hour at a rate that maintained reflux conditions. The yellow • . ••• solid that formed was slurried dry ether • 6 (250 ml) and heated under & terflode another 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 had dissolved. The aqueous phase was separated from the organic phase, acidified with 12 N HCl • • • • • • • • •• •• I; ia • • 157 (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 4), filtered and evaporated to dryness. The crude product (44.0 g) was distilled under gentle pressure (3.5 mm) and the gay title compound as a homogeneous oil (24.88 g, 65.8%).

TLC: Rf = 0.46 (silica gel; C1212 Cl2: hexane-4: 1).

B.4-fluoro-ok (2-methyl-1-oxopropyl) -oxobenzenepropanoic acid, ethyl ester 60% sodium hydride in mineral oil (10.3 g) (0.26 mmol) was washed twice with dry hexane, dried in vacuo, suspended in dry tetrahydrofuran (245 ml) and cooled to 0 ° (ice-water bath) under argon. The suspension was treated dropwise with the compound of Part A (24.5 g, 0.12 mol) over a 20 minute period, warmed to room temperature and stirred for a further 30 minutes. The reaction mixture was cooled to 0 ° C (ice-water bath), treated dropwise with isobutyryl chloride (18.62 g, 0.17 mol), warmed to room temperature and stirred for 3.0 hours. The mixture was cooled to 0 ° (ice-water bath), continued with water (200 ml) so that a homogeneous solution was formed and evaporated on a rotary evaporator so that most of the tetrahydrofuran was removed. 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), dried (anhydrous M004), filtered and evaporated to dryness to give an oil (36.85 g), which was a mixture of starting materials and two other products.

TLC: Rf 0.46, 0.33, 0.20 (silica gel; CH 2 Cl: hexane - 4: 1, UV).

C. 5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole 4-carbouluryl ester • • • • : • • The crude compound from Part B (36.85 g, 1.12 .mu.l) of 16 parts of glacial acetic acid (151 ml) was treated portionwise with 97% of phenyl. •• •••• • •• •• Il • •••• 158 hydrazine (18.1 ml, 0.18 mol) under nitrogen and stirred at room temperature for 19 hours. The reaction mixture was halided in water (350 mL) and extracted with ether (3 x 100 mL) and the combined organic extracts were washed with saturated NaHCO 3 until the aqueous layer was basic, and brine (500 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness .

The pale orange oil was evaporated to an Ong from petroleum ether (300 ml) to give a yellow solid. This crude product was triturated with petroleum ether (100 ml) and gay a crude product (15.3 g) which was in turn chromatographed on a silica gel column (LPS-1) and the column was eluted with CH 2 Cl 2: hexane (2: 1) and gay 11, 53 g pure product. The mother liquor (26.4 g) after chromatography on a silica gel column (LPS-1) and trituration of the obtained compound gay an additional 7.12 g of the desired product (total yield: 18.65 g or 44.1%). A small amount of the title compound was recrystallized from Et 2 O: hexane to give a homogeneous solid, m.p. 92 DEG-930 DEG.

TLC: Rf 0.35 (silica gel: CH 2 Cl 2: hexane-4: 1).

Analysis. Calculated: 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.

D. 5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole-4-methanol ••• • •• es • • • • •• .

•• • • • • • • • S.

• • • • • •IN• 4 • • •• 0 • • • • • • ••• • • • • A solution of the compound of Part C (11.53 g, 32.7 mmol) 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 mmol) in anhydrous ether (70 mL) under argon. The greenish suspension was allowed to warm to room temperature over a period of 1.5 hours, cooled again to 0 DEG (ice-salt bath) and quenched by the dropwise addition of water (20 ml) until the gas evolution ceased. The thick solution was diluted with ether (100 ml) and filtered, and the precipitates were washed selectively with ethyl acetate (3 x 150 ml). 159 The combined organic extracts were washed with brine (50 ml), dried (anhydrous M00 4), filtered and evaporated to dryness to give a pale solid (10.3 g / 100% crude yield). 100 mg of the crude product were recrystallized from Et 2 O: hexane and gay 58 mg of the title compound as white crystals, m.p. 138 DEG-10 DEG.

TLC: Rt 0.01 (silica gel; CH 2 Cl 2) Analysis.

Calculated: 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-1-11) + = 311 E. 5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1HPYrazole-4-carboxaldehyde A solution of crude compound of Part D (10.2 g, 32.7 mmol) dry dichloromethane (85 ml) was quickly added to a solution of pyridinium chlorochromate (21.23 g, 98.4 mmol) in dry 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 overlying 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 pad of silica gel. The clear filtrate was evaporated to dryness and gay an unclean product (10.0 g).

The crude product was chromatographed on a silica gel column •• (Baker, 60 - 200 mesh, 400 ml), the column was eluted with CH 2 Cl 2: • hexane (4: 1) and gay title compound as a solid (9.6 g, 95.2%). An analytical sample (72 mg, m.p. 108 - •• C) is obtained by recrystallization of 100 mg of hexane.

TLC: Rf 0.58 (silica gel; CH 2 Cl 2; UV).

Analysis.

Berdknat: C 74.01; H 5.56; N 9.09; F 6.16 Found: C 74.10, H 5.52; N 9.12; F 6.29 160 Ms (M + H) 4 = 309.

F.4- (2,2-Dibromoethyl) -5- (4-fluorophenyl) -3- (1-methylethyl) - 1-phenyl-1H-pyrazole A mixture of the compound of Part E (2.0 g, 6.48 mmol) and triphenylphosphine (5.10 g, 19.2 mmol) in dry dichloromethane (30 mL) was cooled to -5 to - ° (ice-salt bath). ) under argon and treated dropwise over a period of 5 minutes with a reading of carbon tetrabromide (3.22 g, 9.61 mmol) in dry dichloromethane (10 ml). The reaction mixture was stirred at 15 DEG-0 DEG C. for 15 minutes and then halide pA matt NaHCO3 (10 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic extracts were washed with matt NaHCO 3 (10 mL) and brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product mixture (9.33 g) was chromatographed on a silica gel column (LPS-1) and eluted with CH 2 Cl 2: hexane mixtures (1: 9, 1: 1, 4: 1) and gay title compound as a solid ( 2.75 g, 91.6%). Recrystallization of a small sample title compound gay white crystals, m.p. 88-900 .

TLC: Rf 0.85 (silica gel; CH 2 Cl 2: hexane-4: 1) Analysis.

Beraknat! 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 MS (M + H) &lt; + &gt;. = 465. •• •• •• • • • 0 • • • • • • • • ••• • • ••• • • II • • G. 4-Ethynyl-5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl] H-pyrazole A compound of Part F (2.64 g, 5.67 mmol) in dry tetrahydrofuran (10.5 mL) was cooled to -78 ° (dry ice-acetone) under argon and treated dropwise with 1.6 M n-BuLi. / hexane (7.16 mL, 11.37 mmol). The resulting suspension was stirred at -78 ° for 1 hour and 20 minutes, quenched by dropwise addition. : •• •% O. •••• • *Smile • ••• • •••• • • • 00 • •• • • •• • • 0 • • 4 • 050 • •• • • 0 • •• $ • • • take• • ••• • • • 161 25% NH 4 Cl (10 mL) and allowed to warm to room temperature. The reaction mixture was extracted with ether (3 x 50 ml) and the combined organic extracts were washed with brine (20 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness and gay title compound as a light brown solid (1.79 g) .

The crude product was chromatographed on a silica gel column, eluting with Et 2 O: hexane (5:95) and gay title compound as a light gold solid (1.08 g, 97.4%). Recrystallization from a small sample of hexane gay white, fluffy crystals, m.p. 106-108 °.

TLC: RE 0.70 (silica gel; Et 2 O: hexane-1: 9; developed tv5 ginger) Analysis.

Berdknat: 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 MS (M-141) + = 305.

H. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - /// 5- (4- fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl / methoxyphosphinyl / butanoic acid, methyl ester A mixture of crude phosphonomonomethyl ester from Part F of Example 1 (2.77 g, 5.55 mmol) and trimethylsilyldiethylamine (2.1 mL, 11.05 mmol) in dry dichloromethane (10 mL) was stirred at room temperature under argon for 1.0 h. The mixture was evaporated to dryness, azeotroped with dry benzene (20 ml) and dried in vacuo (pump) for 15 minutes. The viscose oil was redissolved in dry dichloromethane (10 mL), treated with a drop of DMF, cooled to-° (ice-salt bath) and treated dropwise with oxalyl chloride (5 μl, 6.08 mmol). Strong gas evolution was observed and the dark yellow solution was stirred at -15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with benzene (20 ml) and dried in vacuo.

A solution of the compound in Part G (1.12 g, 3.67 mmol) in dry • • • • •• ••• • 41 "- • •• • • •• •••• • •••• • • • ••• •• •• • • 0 • •••• •••• • •• ••• • •••• 162 tetrahydrofuran (9.0 mL) was cooled to -78 ° (dry isacetone) under argon and treated with 1.6 M n-BuLi / hexane (2.3 mL, 3.67 mmol) and stirred at -78 ° C for 30 minutes. . The above phosphochloridate was dissolved in dry tetrahydrofuran (6.5 ml), cooled to -78 ° (dry ice-acetone) under argon and treated dropwise with needles with the dissolution of the acetylene anion, keeping both solutions at -78 ° during the addition. The reaction mixture was stirred at -780 minutes, quenched by dropwise addition of 25% NH 4 Cl (6.0 mL) and then warmed to room temperature. The mixture was extracted with ether (3 x 100 mL) and the combined organic extracts were washed with 25% NH 4 Cl (10 mL) and brine (25 mL) / dried (anhydrous MgSO 4). filtered and evaporated to dryness.

The crude product mixture (about 4.2 g) was chromatographed p5 a silica gel column, the column was eluted with hexane: acetone (9: 1) and gay title association in the form of a light brown oil (1.54 g, 57.0%).

TLC: Rf 0.33 (silica gel; hexane: acetone-7: 3) I. (S) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl / ethynyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester • A solution of the compound of Part H (593.9 mg, 0.81 mmol) in dry tetrahydrofuran (8.0 ml) was treated successively with isatic (190) μl, 3.24 mmol) and 1 M Bu4NF (2.54 mL, 2.54 64 •• ..mmol) and stirred over the surface at room temperature under argon.

• • • • • • • • • • • The reaction mixture was cooled to 0 ° C (ice-water bath), treated with 5% KHSO 4 (8.5 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were washed with 5% KHSO 4 (10 mL) and brine (20 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product was immersed in a mixture of ether (14 ml) and dry tetrahydrofuran (10 ml), cooled to 0 ° (ice) ••• • • • • • • • • • • •• • • • 0 • 11--111 • ••• ....- • • ••• : .0; • _ • V ••••• • ••• • • 11 ... • • •• • • . ••• • • • * • • ir ".. w 0.00. • • •• • •••• • • • ••• • •••• 163 salt bath), was treated with an excess of diazomethane in ether and stirred at 3.0 hours. The reaction mixture was quenched by dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column, eluting with acetone: hexane (1: 2) and gay title compound as a semi-solid (325.6 mg, 80.6% yield).

Example 37 (S) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt A solution of the compound of Example 36 (325 mg, 0.65 mmol) dioxane (7.7 mL) was treated with 1 N LiOH (2.25 mL, 2.25 mmol) and stirred at 50 (oil bath) under nitrogen for 1.5 hours and then at room temperature for 16 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on an HP column (1 "x 5") and the column was eluted with distilled water (400 ml) and 50% loading of CH 3 OH in water (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 and gay title product as a fluffy solid lyophilate (317.1 mg, 96.4%).

• •••• TLC: Rf 0.33 (silica gel; i-PrOH: NH 4 OH: H 2 O- 8: 1: 1).

• Analysis. Calculated for C2 Li-1.3 H2O 24H22FN2 ° 1). • •• (effective molecular weight = 505,861): • • C 56.99; H 4.90; N 5.54; F 3.75; P 6.12 • • • Found: C 56.98, H 5.17; N 5.46; F 3.90; P 6.26 • • • • ••• • • • • • 0 •• • • • 1 H-NMR Spectrum 61, (d, 1 / 81-1.98 (m, (400 6H, 2H) 164 MHz, CD300): J = 7 Hz) 2) (dd, 1H, 3 = 9, 15 Hz) 2.48 (dd, 1H, δ = 4.15 Hz) 31 (septet, 1H, J = 7 Hz) 4/42 (m, 111) 7 / 08-7.41 (m, 911).

IR (KBr): 2173 cm (CC).

Example 38 (E) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl) ethenylimethoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A. [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol4-yl] -2-hydroxyethyl] phosphonic acid, dimethyl ester A -78 ° C (CO2 / acetone) solution of dimethyl methylphosphonate (2.81 mL, 25.9 mmol) in dry THE '(50 mL) was treated with a 1.6 M n-BuLi solution in hexanes (15.2 mL, 24.3 mmol) dropwise over 15 minutes and the the white suspension (after about 15 minutes) was stirred under argon at -78 ° C for one hour. Pyrazolaldehyde from Example 36 Part E (5.0 g, 16.2 mmol) in dry THF (15 mL) was added dropwise over 10 minutes and the quid mixture was stirred at -780 ° C for 30 minutes. The mixture was quenched with matt NH 4 Cl (20 mL). The mixture was partitioned between H 2 O and EtOAc and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated to give 7.158 g of crude title phydroxyphosphonate as a yellow foam, a small sample and crystallized from hexanes. title compound in the form of white crystals, m.p. 126 DEG-128 DEG C.

TLC (1: 1) hexane-acetone, Rf = 0.27.

Mass spectrum (M4-H-F = 433 observed). • • • e • IN.• • • • 1 I • • • I • ft • • • • If, • • • II • 4.4 i •• - •••• - • - • - •• r . ..: •. • : I: •• •••• • •• ••• e • 16 Analysis. Calculated for C 22-26H 0 4N2PF: 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 1 H NMR (CDCl 3): 61.42 (6H, d) 1.94 - 2.40 (2H, m) 3.29 (1H, septet) 3.62 + 3.63 (2 doublets, JH_p = 11.1 Hz) 3.91 (1 H, s) 5.11 (1 H, bm) 6.90-7.30 (9H, m) ppm. 13 C NMR (CDCl 3): δ 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.

B. (E) - [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-y.1 / ethylene A solution of the crude Part A (7.158 g) crude hydroxyphosphonate (7.158 g) was treated with pTsOH.H 2 O (304 mg, 1.6 mmol) and the mixture was refluxed through a Dean Stark trap containing hours under argon. The mixture was cooled and diluted with EtOAc and the organic phase was quenched with saturated NaHCO 3 (2X) and brine and then dried over anhydrous Na 2 SO 4 and evaporated. vacuum and gay 6.893 g of a yellow oil. The crude oil was triturated with hexane to give 5.692 g of almost pure vinyl phosphonate as off-white crystals. A recrystallization from EtOAchexane gay in tv & harvests 5.655 g (84.2%, total yield from aldehyde) of pure classified trans-vinylphosphonate in the form of white needles with a melting point of 143-144 ° C.

TLC; 1: 1) hexane-acetone, RfO, • qv.t3 * •: • • I "• • :: 7. •• •. 0. •••• • •• •••• • •••• 166 4- Mass spectrum (M411 + 415 observed) Analysis. Calculated for C 22 H 24 O 3 "1F: 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 1 H NMR (CDCl 3): 61.42 (6H, a) 3.27 (1H, septet) 3.70 (6H, d, J / 1.4) = 11.0 Hz) 5.67 (1H, dd, .7 = 1814 Hz, Jlip = 1815 Hz) 7102-7.30 (9H, m) 7.34 (1H, dd, JHH = 18 Hz, Jim = 24.3 Hz), pm. 13 C NMR (CDCl 3): 621.8, 27.1, 5211 (J = .517 Hz), 110.4 (Jc_p = 19311 Hz), 114.7 (Jc_p, = 24.6 Hz), 115.9, 116.2, 12212, 124.9, 125.5, 127.3, 128.8, 132.0, 13912, 1.2 (Jc_p = 7.6 Hz), 142.1, 158.0, 163, 4 (Jc-F = 249.8 Hz) ppm.

C. (E) - [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl] -1H- pyrazol-4-yl / ethenyl / phosphonic acid, monomethyl ester • e • A solution of the dimethylphosphonate in Part 11 (2.0 g, 4.83 mmol) in dioxane (mL) was treated with 1.0 N LiOH (7.3 mL) and the mixture was boiled under AterflOde for one hour under argon. The mixture was cooled to room temperature, acidified • • pH 1 with 1.0 N HCl and extracted with EtOAc (2X) and the •• The organic phase was washed with 1.0 N HCl and brine a • • • • • • 0 • • The anhydrous Na 2 SO 4 was then dried and evaporated vacuum and gay crude monoacid, which crystallized slowly from hexane when allowed to stand. The crystals were collected by filtration and dried in vacuo to give 1.918 g (99%) of the title monoacid as a white crystalline solid, m.p. 168 DEG-1700 DEG C. After analytical prayer, it was prepared by recrystallization from EtOAc-hexane.

TLC (8: 1: 1) CH 2 Cl 2 -CH 3 OR-HOAc, RfO, • .. • • • • •• • • • • • • • ••• 0 • • . • ••• •••• • •• ••• • •••• I 167 Mass spectrum (Mi-H + = 401+ observed) Analysis. Heraknat for C H 0PF: 21 22 3'N 2 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 NMR (CDCl 3): 61.40 (6 H, d) 3.26 (1H, septet) 3.6 (3H, d, Ju_p = 11.6 Hz) 5.74 (1H, dd, Jii_H = 17f9 Hz, J = 19Hz) H-P 1'9 7.00-7.36 (10 H, m) 8.65 (111, bs) ppm. 13 C NMR (CDCl 3): δ 21.8, 27.0, 51.8 (Jc_p = 6/3 Hz), 411.11; 7 (1c_p = 198.7 Hz), 114.6 (Jc_p = 24e6 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, 16219 3c_p = 249.8 Hz) ppm.

D. (E) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yliethenyl / methoxyphosphinyli-3-oxutanoic acid, yeer The dianion of methyl acetoacetate was prepared according to the method described in Example 26 using the following amounts: methyl acetoacetate (8? A, 7.53 mol, 60% NaH dispersion in oil (324 mg, 8.11 mmol), 1.6 M n-BuLi 1 hexanes (4.3 mL, 6.95 mmol), THF (15 mL). • • ft • • • • • • t ••• • • 00 • '• • ••• • • ••• • • • • • • •• 0 • • A solution of phosphonomonomethyl ester (2.317 g, 5.79 mmol) and trimethylsilyldethylamine (TMSDEA) (1.45 mL, 11.6 mmol) CH 2 Cl 2 (15 mL) was stirred for one hour at room temperature. The mixture was evaporated to dryness, taken up in benzene (20 ml) and dried in vacuo. The residue was taken up in dry CH 2 Cl 2 (15 mL) and treated with (COCl) 2 (555 μl, 6.37 mmol) and IMF (one drop) and stirred at room temperature for one hour. • ••• • •••• • • • • in• • •• 168 The mixture was evaporated to dryness, taken up in benzene (20 ml) and dried in vacuo.

A -78 ° C (CO 2 acetone) solution of the above phosphonochloridate in dry TI-IF (10 ml) was transferred dropwise by cannulae within 20 minutes to a -78 ° C solution of the methyl acetoacetate dianion in dry THF (15 ml). The brown mixture was stirred at -78 DEG C. for 30 minutes and then quenched by dropwise addition of matt NH 4 Cl (10 mL) and allowed to warm to room temperature. The mixture was partitioned between 1120 and EtOAc, the aqueous phase was back-extracted with EtOAc, the combined organic phases were washed with saturated NaHCO 3 and brine and then dried over anhydrous Na 2 SO 4 and evaporated. vacuum and gay 3,080 yielded orange foam. The unclean the 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 title compound (b-ketophosphonate) as a pale yellow oil.

TLC (4: 4: 2) acetone-hexane-toluene, Rf = 0.29 • ••• S •• • • • •• • • • • • a ••• • Oa, Mass spectrum (M + 111- 1 H NMR (CDCl 3): Δ 1 42 & 1 43 (6H, 3.24 (2H, 3.27 (1H, 3.63 (2H, 3.66 & 3.57 (3H, 3.72t3H, 5.72 (1H, 7.0877, (9H, 7.37 (1H, = 499+ observed) 2 duplicates) m) septet) m) 2 doubles, J11_p = 11.6 Hz) s) dd, jHH = 18.7 Hz, JHp = 24.3 Hz) m) dd, J = 18, 0 Hz, .14-22.7 Hz) PPIn • S • •• •• • • V 169 13 C NMR (CDCl 3): δ 21/8, 2711, 46.1 (Jcp = 8411 Hz), 50.0, 51.2 (Jc_p = 5.9 Hz), 52.3, 112.6 (Jcp = 110 Hz ), 11415 (Jcp = 23.5 Hz), 11610, 116.3, 124.9, 114, 12714, 12818, 13210, 13211, 139/1, 141.4 (Jcp = 19 Hz), 142.5, 158.2, 16311 (Jcp = 250.4 Hz), 167.1, 194.9, 1950, ppm.

E. (E) -4 - // 2 - [(4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl / ethenyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A - ° (salt / ice bath) solution of the ketone in Part D (1.304 g, 2.62 mmol) in absolute EtOH (15 mL) was treated with NaBH 4 (100 mg, 2.62 mmol) and the mixture was stirred for 15 minutes under argon. at - ° C. The reaction was quenched by the addition of reagent acetone (0.3 mL) and then CC-4 silica gel (600 mg) and the reaction mixture was 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 chromatography on Merck silica gel eluting with (85:15) EtOAc-acetone. Product fractions were evaporated and gay 388 mg of pure classified alcohol in the form of a white foam and 228 mg of slightly herbal product. The total yield of 616 mg (47%).

••• TLC (7: 3) EtOAc-acetone, Rf = 0.31 ••• Mass spectrum. (M + 114. = 501+ lactated) • •• 0 • • • • al • •• 0 • ••• • • ••• • • •• • • • • ••• • • • iz • e. : • • * • • •••• •• I •••• * IP 170 111 NMR (CDCl 3): 1.42 (611, d) 2.00 (211, m) 2.60 (2 H, d) 3.27 (111, d) 3.64 (311, d, JHp = 11.1 Hz) 3.69 (311, s) 3.93 & 4.02 (111, 2 duplicates) 4.42 (111, 2 wide singlets) 5.72 (111, dd, JHH = 18.0 Hz, J11.p23.2 Hz) 7.04-7.47 (1011, m) ppm. 13 C NMR (CDCl 3): δ 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 (JcF = 251.6 Hz ), 171.2, 171.9 ppm.

Example 39 (S) -4 - // 2 - [(4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl / ethenyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, * dilitium salt A solution of the diester in Example 39 (487 mg, 0.973 mmol) • dioxane (ml) was treated with 1.0 N LiOH (3.4 ml, 3.4 mmol) and the resulting mixture was heated and stirred at • 70o C 30 minutes. The mixture was cooled, diluted with H 2 O, filtered and evaporated in vacuo to an off-white solid. • substance. The crude product was unloaded in a minimal amount 11 • and chromatographed on HP-20 resin (15 cm bath, 25 mm diameter column) eluting with 11 and then with. (1: 1) CH 3 OH-H 2 O. Product fractions were evaporated in vacuo, 18 h 171 75 ml of 1120 'were filtered and lyophilized and gay 429 mg (87.3%) of pure title dilitium salt as a fluffy white lyophilate.

TLC (8: 1: 1) CH 2 Cl 2 -C 113011-HOAc, Rf = 0.14 Analysis. Calculated for C 24 H 24 N 2 PF Li 2 + 1.16 mol 1120 (molecular weight 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 1 H NMR (400 MHz, CD 3 OD): 61.39 (6H, doublet) 1.71 (2 H, m) 2.35 (2 H, m) 3.36 (18, septet) 4.24 (1 H, m) 6.00 (1H, dd, JHH = 17.6 Hz, J / Ip = 19.4 Hz) 7.07-7.35 (10H, m) Example (E) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl / methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // 2- / 5- (4- fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl-ethyl-riciphosphutanoic acid, methyl ester.

A solution of the compound of Example 36 Part H (912.0 mg, 1.24 mmol) in dry methanol (50 mL) was treated with 10% Pd / C and hydrogenated at 50 psi with a Parr hydrogenator overnight. The suspension was filtered through Celite and the filtrate was evaporated to dryness and dried in vacuo and gay title compound as a homogeneous oil (908.3 mg, 99.1%).

TLC: Rf 0.23 (silica gel; hexane: acetone-7: 3) eq. • • 1, •• • IP • i •• •• • O •• •••• • •• •• • • •••• •• 172 B. (S) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl / ethyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the compound of Part A (908.3 mg, 1.23 mmol) in dry tetrahydrofuran (12 mL) was stirred under argon at room temperature and treated successively with glacial acetic acid (0.29 mL, 4.94 mmol) and 1.0 M Bu4NF / hexane (3.89 mL, 3.89 mmol). 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 NaHCO 3 (15 mL) and brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The arena product mixture (1.0 g) was chromatographed on a silica gel column (LPS-1; 1 "x 9.5") and the column was eluted with EtOAc: hexane mixtures (4: 1; 9: 1), EtOAc and acetone and gay title compound in form of an oil (529.1 mg, 85.6% yield). TLC: Rf 0 '17 (silica gel; EtOAc: hexane-4: 1).

Example 41 (S) -4-1 / 2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt A solution of the compound of Example 40 (529.0 mg, 1.05 mmol) ° •• in dioxane (12.5 mL) was treated with 1.0 N LiOH (3.7 mL, 3.7 Mmol) and stirred at 5 ° C (oil bath) under nitrogen for 3.0 hours ••• and then at room temperature for 20 hours. The reaction mixture • evaporated to dryness and dried in vacuo. The unclean ••• The product was chromatographed on an HP-20 column (1 "x 6"). •• and column eluted, 7 with Anga-distilled water (750 ml), a 10% solution of CH 3 OH in water (500 ml), a 20% • • percent solution of CH 3 OH in water (500 mL) and a 50% cent solution of CH 3 OH in water (500 ml). De Onskade frak- 173 • • • •• fr • • • •• 0 • •• • • • • • • •• • • •• •• • 0 ••• • •• • * • ••• • • •• • • • • 0 • • the ions were combined, evaporated to dryness and dried vacuum. The resulting solid was dissolved in Angdistilled water (35 ml) and lyophilized to give the title compound as a fluffy white solid. (510.0 mg, 92.4%).

TLC: Rf 0.38 (silica gel; i-PrOH: NH 4 OH: H 2 O- 8: 1: 1).

Analysis. Calculated for C24 H26FL1 2N2O1: 2.2 1190 (effective molecular weight = 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 -1 IR (KBr) (1596 cm -1, C = O in COO).

1 H-NMR Spectrum (400 MHz, CD 3 OD): 61136 (d, 6H, 3 = 7) 1.60 - 1.72 (m, 4H) 2.32 (m, 211) 2.74 (m, 211) 3121 (septet, 1H, J = 7) 4.23 (m, 111) 7.06 - 7.32 (m, 9H).

Example 42 (S) -4- [2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A.4-fluorobenzoic acid, 2-phenylhydrazide A mixture of phenylhydrazine (25 mL, 0.25 mmol) and triethylamine (35 mL, 0.25 mmol) in anhydrous ether (500 mL) was cooled to - ° to - ° C (ice-salt bath) under nitrogen and treated dropwise. over a 30 minute period with 4 fluorobenzenecarbonyl chloride (30 mL, 0.25 mol). The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then filtered and the solids washed with ether (200 ml). The solids were dissolved in dichloromethane (600 ml), almost evaporated to dryness, suspended in hexane (CO ••••• ■ •••••••• 174 ml) and filtered. The clear filtrate was evaporated to dryness, triturated with tetrahydrofuran (700 ml) and filtered and the solids washed with tetrahydrofuran (100 ml). The filtrate was evaporated to dryness and dried in vacuo to give a crude product (34.6 g) which was contaminated with TV & other components.

The crude product was recrystallized from acetone and the gay title compound as white crystals (22.36 g, 38.8%), mp 182-184 ° C.

The filtrate and mother liquor were combined, chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml) and the column eluted with EtOAc: CH 2 Cl 2 (1: 9) and gay an additional 9.78 g of the title compound (55.8%).

TLC: Rf 0.63 (silica gel; EtOAc: CH 2 Cl 2-1: 4) Analysis. Calculated for C131111FN20: C 67.81, H 4.82; N 12.17; F 8, Found: C 67.86; H 4.88; N 12.14; F 8.10 MS (M4-1 -) 4. = 231.

B.4.-Lifluoro: N-fendrazono chloride A solution of the compound of Part A (6.16 g, 26.8 mmol) in water Ten-free ether (46 ml) was treated with phosphorus pentachloride (6.6 g, 31.7 mmol) and the reaction mixture was boiled under ". reflux during nitrogen 16.0 hours. The reaction mixture is cooled. e • to room temperature, treated with a solution of phenol • (11.5 g, 122.2 mmol) in ether (15 mL), and stirred for 5 minutes • • • • • was then treated dropwise with methanol; 11.4 ml). Among- • The concentration was concentrated at about a rotating extender . • ••• ". • and the obtained oil was cooled at °. The obtained fixed sub. The punch was triturated with 5% solution of acetone ▪ • • e • • • •• . with 5% acetone water (30 ml). The precipitate was dried (2.2 g), m.p. 118-1 ° C. •••• 4OO 9.6 in vacuum and gay title compound in the form of a solid 17 The clear filtrate was evaporated to dryness and the product mixture was chromatographed on a silica gel column (Baker, 60 - 200 mesh, 400 ml) and the column was eluted with CH 2 Cl 2: hexane mixtures (1: 3; 1: 1) and gay title compound (total amount = 5.66 g corresponding to 85%).

TLC: Rf 0.90 (silica gel; C112Cl2: hexane-4: 1) Analysis. Calculated for C 13 H 18 N 2 Cl: C 62.78; H 4.05; N 11.27, F 7.64, Cl 14.26 Found: C 62.87; H 3.97; N 11.34; F 7.51; Cl 13.95 MS (M44) +. 249.

C.3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole --- A solution of sodium ethoxide (from 0.28 g of 12 mmol sodium metal and 40 ml of absolute ethanol) is treated dropwise under nitrogen with ethyl isobutyryl acetate (2.0 ml, 12 mmol), stirred for 15 minutes at room temperature and then treated with the compound of Part B ( 3.0 g, 12 mmol). The mixture was stirred at room temperature for 4.0 hours. The reaction was quenched with 10% HCl (10 mL), the mixture was evaporated to dryness and the resulting solid was triturated with ether (3 x 100 mL). The combined organic extracts were washed with brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (4.3 g) chromium a silica gel column was tographed and the column was eluted with • •••• CH 2 Cl 2: hexane (1: 1) and the gay title compound as a reddish brown syrup (3.27 g, 77.3%). • D.3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole 4-methanol • • R • • • •• • 0 A solution of the compound of Part C (3.26 g, 9.25 mmol) in dry ether (22 mL) was added to a cooled (0 °, ice-salt bath) suspension of lithium aluminum hydride (0.71 g, 18 mL). 7 mmol) in dry ether (32 ml) and the reaction mixture was stirred at 0 DEG C. under nitrogen •• • It • • • I • RI • • 0 • • • ••• • • 176 3.0 hours. The mixture was quenched at 0 DEG by dropwise addition of ethyl acetate (5.0 mL), then with 10% HCl (11 mL) and decanted and the residue triturated with ether (2 x 100 mL). The combined organic extracts were washed with brine (20 mL), dried (water-free MgSO 4), filtered and evaporated to dryness to give the title compound (2.87 g, 94.4%). 100 mg of the title compound were recrystallized from ether and gay an analytical sample (57 mg, m.p. 145-147 ° C).

TLC: Rf 0.17 (silica gel; CH 2 Cl 2: hexane-4: 1; developed twice).

Analysis. Calculated for C19H19FN2O: 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 (M + H) + = 311 E.3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole 4-carboxaldehyde A solution of the compound of Part D (2.59 g, 8.34 mmol) in dry dichloromethane (22.0 mL) was quickly added to a stirred suspension of pyridinium chlorochromate (5.41 g, 25.1 mmol) in dry dichloromethane ( 32 ml) and stirred at room temperature under kvaye 4.0 hours. The reaction mixture was diluted with ether (190 ml), ••• • •••• stirred for 20 minutes and then decanted. The tar-like one • the residue was triturated with ether (100 ml) and dichloromethane • •• • (30 ml) and the combined organic extracts were filtered • • • • • • • • • a a • ••• 0 through a silica gel pad. The clear filtrate was evaporated to dryness and the crude product was chromatographed on a silica gel column (Baker, 60-200 mesh, 300 ml) and the column was eluted with CH 2 Cl 2: hexane (4: 1) and the gay title compound (2.40 g, 93.4 %) in the form of a solid product. 100 mg of the title compound were recrystallized from hexane and gay an analytical sample (50 mg, m.p. 103-10 ° C).

• ••• ••• • • •• ••• •••• •• •• •• • ••• •• • • •• • •• ••• • • C • 4 • • • • •• •• • •• • • •• • 0 • I. OLIO • • * •. • • • • • • •• • ••• e • • ••• 177 TLC: Rt 0.67 (silica gel, CH 2 Cl 2). Analysis. Calculated for Cl9H17FN20: C 74.01; H 5.56; N 9.09; 6.16 Found: C 74.18; H 5.35; N 9.11; F 6.12 MS (M + H) -1 = 309.

F. 4- (2,2-Dibromoethyl) -3- (4-fluorophenyl) -5- (1-methylethyl) - A mixture of the compound of Part E (2.296 g, 7.45 mmol) and triphenylphosphine (5.86 g, 22.1 mmol) in dry dichloromethane (35.0 mL) was cooled to -5 to-° C (- salt bath) under argon, treated dropwise over a 5-minute period with a solution of carbon tetrabromide (3.70 g, 11.0 mmol) in dry dichloromethane (12 mL) and stirred at - ° 20 minutes. The reaction mixture was warmed to room temperature, halided in matt NaHCO 3 (12 mL) and extracted with dichloromethane (3 x 60 mL). The combined organic extracts were washed with matt NaHCO 3 (12 mL), brine (10 mL), dried (anhydrous Mg 4) and filtered and evaporated to dryness.

The crude product (11.0 g, solid) was chromatographed on a silica gel column and the column was eluted with CH 2 Cl 2: hexane mixtures (1: 1, 4: 1) and gay title compound (2.96 g, 96.0% corrected yield) and starting materials that did not have reagent-4 / rat (250.6 mg). 100 mg of title compound was recrystallized from Et 2 O: hexane and gay an analytical sample (36.5 mg, m.p. 93 °). TLC: Rf 0.57 (silica gel; CH 2 Cl 2: hexane-4: 1) Analysis. Calculated for C4u --H1, Br FN: 7 2 2 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) &lt; + &gt; = 465. •• • ••• ••••• • • •• •• : • • • • 1 •• • •• • • ••• • • • LIVI 178 G.4-Ethynyl-3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H- p / ra.zol A solution of the compound of Part F (2.87 g, 6.18 mmol) in dry tetrahydrofuran (11.44 mL) was cooled to -78 ° C (torrisacetone), treated dropwise with 1.6 M n-BuLi / hexane. (11.7 mL, 18.6 mmol) under argon and then stirred at -80 ° C for 2 hours and 20 minutes. The reaction mixture was quenched at -78 ° C with 25% N1-14Cl (16.5 mL), warmed to room temperature and extracted with ether (3 x 60 mL). The combined organic extracts were washed with brine (22 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (1.9 g) was chromatographed on a silica gel column and the column was eluted with Et 2 O: hexane (5:95). The desired fractions were combined and evaporated to dryness and gay title compound (1.88 g, 100% yield) as a solid product. 100 mg of title compound were recrystallized from hexane and gay an analytical sample (63.5 mg, m.p. 117-118 ° C).

TLC: Rf 0.37 (silica gel: Et 2 O: hexane-1: 9) Analysis. Calculated for C20 / 7FN2: 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) 4. = 305.

• • • • • • H. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - /// 3- (4- 9 • Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl / ethynyl / methoxyphosphinyl / butanoic acid, methyl ester 0 • • • 0 • • • • A solution of (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy [-4- (hydroxymethoxyphosphinyl) -butanoic acid, methyl ester (prepared in Example I, Part F) (2.77 g, 5, 55 mmol) in dry dichloromethane (10 ml) was treated with trimethylsilyldiethylamine (2.1 ml) and stirred at room temperature for 1.0 hour under argon. The reaction mixture was evaporated to dryness, distilled 0 • • • • ID & • • • • • • • • • • • 0 • • • • • 0 • • • ••• • • ••• • • • •• • ••• • ••• • • •• •• • •• • • • ■ ••• • fp, • • I a • • % • • • • • • • ••• •, : ** •: ••• • t: • • 11 • •••• • • • •• 0 •••• • ••. 179 azeotrope with dry benzene (20 ml) and dried in vacuo. The syrup was redissolved in dry dichloromethane (10 ml), cooled to - ° C (ice-salt bath) treated with a drop of DMF and then by dropwise addition of oxalyl chloride (530 id), stirred at - ° 15 minutes and then at room temperature 1, 0 hours. The mixture was evaporated to dryness, azeotroped with benzene (20 ml) and dried in vacuo.

Compound from Part G (1.12 g, 3.67 mmol) was dissolved in dry tetrahydrofuran (9.0 mL), cooled to -78 ° C (tri-acetone bath), treated with 1.6 M n-BuLi / hexane. (2.3 mL, 3.68 mmol) under argon and stirred at -780 ° C for 45 minutes. The above phosphonochloride was dissolved in dry tetrahydrofuran (6.5 ml), cooled to -78 ° C and treated dropwise with needles with the solution of the acetylene anion, keeping the solutions at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ° C for 30 minutes and then quenched by dropwise addition of 25% NH 4 Cl (6.0 mL) and allowed to warm to room temperature. The mixture was extracted with ether (3 x 100 mL) and the combined organic extracts were washed with 25% NH 4 Cl (10 mL) and brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product mixture (4.0 g) was chromatographed on a silica gel column and the column was eluted with acetone: hexane mixtures (1: 9; 3: 7) and gay title compound (1.76 g, 65.2%) as an oil. .

TLC: Rf 0.40 (silica gel; hexane: acetone-7: j) I. (S) -4 - // 2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl / ethynyl / methoxyphosphinyl / -3-hydroxybutanoic acid, ester An 18 g of the compound in Part H (700 mg, 0.95 mmol) in dry tetrahydrofuran (9 ml) was treated successively with ice. ! .. ': .. • :: I ..: * S .: • t "*.,' . • .. • .. • •• • . • •• .... • 41 $ $ 11, • O. 180 • 0 • 0 • •••• 0 attic (HOAc) (2243.82 mmol) and 1.0 M (c 4 H 9) 4 NF (3.0 mL, 3.0 mmol) and stirred over the surface at room temperature under argon. The solution was cooled to 0 DEG (ice-salt bath), treated dropwise with 5% RHSO4 (10 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic extracts were washed with 5% KHSO 4 (10 mL) and brine (25 mL), dried (anhydrous M00 4), filtered and evaporated to dryness.

The crude product (890 mg) was immersed in a mixture of ether (16 ml) and tetrahydrofuran (12 ml), cooled to 0 DEG (ice-salt bath) and treated with an excess of diazomethane I. ether. The reaction mixture was stirred at 0 DEG C. for about 3 hours, quenched by dropwise addition of glacial acetic acid and evaporated to dryness. The crude product mixture (764 mg) was chromatographed on a silica gel column and the column was eluted with EtOAc: hexane mixtures (1: 1; 4: 1; 9: 1) and gay title compound as a semi-solid (347 mg, 73.2%). ).

TLC: Rf 0.28 (silica gel; EtOAc: hexane-4: 1).

(S) -4- [2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl] -1H-pyrazol-4-yl] ethynyl / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt • 41 • IS • 0 • • • • • • I • ••• • • •• • e 4 • Of • 4, • • •• • ••• • • • • A solution of the compound of Example 42 (347 mg, 0.7 mmol) of dioxane (8.3 mL) was treated with 1.0 N LiOH (2.4 mL, 2.4 mmol) and stirred at 50 ° C (oil bath) under simmer 45 minutes. 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"), and the column was eluted with 5-distilled water (350 ml), and 50% methanol in water (250 ml). The desired fractions were combined, evaporated to dryness and dried in vacuo. The product dissolved in steam distilled water and 17 S • S • II • at •••••• • •• •• ■ • • •••• 181 compound in the form of a white solid lyophilate (338 mg, 97.5%). TLC: Rf 0.50 (silica gel; i-PrOH: NH 4 OH: H 2 O-7: 2: 1) Analysis. Calculated for FL 2 N 2 O 2 • 1.95 H 2 O: - 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; P 3.95; P 5.96 1 H-NMR Spectrum (400 MHz, CD 3 OD): 1145 (d, 6H, J = 7) 1189-2.05 (m, 2 H) 2138 (dd, 1H, J = 9, 15) 2152 (dd, 1H, J = 4, 15) 3.06 (septet 111, J = 7) 4.48 (m, 1H) 7.16-8111 (m, 91!) Example 44 (8) -4- [2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1HPyrazol-4-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, with ester A. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // 2- / 3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl / ethyl / methoxyphosphinyl / butanoic acid, methyl ester A solution of the compound of Example 42, Part I (1.0 g, 1.36 mmol) in dry methanol (72 mL) was treated with 10% Pd / C (250 mg) and hydrogenated in a Parr hydrogenator. about 40 psi. The reaction mixture was filtered through Celite and the clear filtrate was evaporated to dryness and gay title compound as a homogeneous oil (1.0 g, 100% crude yield).

TLC: Rf 0.27 (silica gel; hexane: acetone - 7: 3) • • • • • • • • IN I. I • I • • • • I • • • I • • • 11, • • P.0011.1 • • • 1 • • •••••• •• • •• IS •• I •• • • ••••• • ••• • • : .. *: .. • "..::" '... *: •• • •• • • • • •••• • • •• • •••• • •••• 182 B. (S) -4 - // 2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl / ethyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the compound of Part A (1.05 g, 1.41 mmol) in dry tetrahydrofuran (14.0 mL) was treated successively with glacial acetic acid (334 μl, 5.83 mmol) and 1.0 M ( C 4 H 9) 4NF / THE (4.46 mL, 4.46 mmol) and stirred at room temperature under argon for about 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 matt NaHCO 3 (15 mL) and brine (25 mL) was dried (anhydrous MgSO 4), 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 with EtOAc: hexane mixtures (2: 1, 4: 1, 9: 1), ethyl acetate and acetone. and gay title compound as a semi-solid (623.5 mg, 88.0%).

TLC: Rf 0.18 (silica gel; EtOAc: hexane - 4: 1).

Example (S) -4 - // 2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl / hydroxyphosphinyl] -3-hydrox: butanoic acid, dilitiumsalt0 A solution of the compound of Example 44 (623.5 mg, 1.24 mmol) dioxane (14.7 mL) was treated with 1.0 N LiOH (4.28 mL, 4.27 mmol) under nitrogen, heated at 50 ° C (oil bath) for 2 hours and then stirred at room temperature for about 20 hours. The reaction mixture was evaporated to dryness, dried in vacuo and chromatographed on an HP column (1 "x 6") and the column was eluted with distilled water (750 ml), 10% loading of CH 3 OH in water, 20% dissolving CH 3 OH in water (500 ml) and 50% solution of CH 3 OH in water (500 ml). The desired fractions were combined, evaporated to dryness and gay the desired product 183 (560 mg, 92.8%).

TLC: Rf 0.42 (silica gel; i-PrOH: NH 4 OH: H 2 O - 8: 1: 1) Analysis. Calculated for C24H26FLi2N2011.16 H2O: (effective molecular cooling weight = 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 1 NMR Spectrum (400 MHz, CD 3 OD): 61, (d, 6H, J = 7) 1.60 - 1.78 (d, 4H) 2.36 (m. 2H) 2.96 - 2.99 (m, 2H) 3.14 (m. 1H) 4.26 (m. 1H) 7.14 - 7.68 (m, 9H) Example 46 (S) -4- [1- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H- pyrazol-yl / ethynyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A. 2- (4-fluorophenyl) -1-phenylethanone ••• flood for a further 30 minutes, cooled to room temperature and treated with a solution of benzonitrile (2.96 ml, 29 . • in dry ether (5 m1). The mixture was stirred at room temperature. ••• • • • mm temperature 4.5 tiar, halides slowly in cold 10% HCl . e • O .00 • (40 ml) and the resulting suspension was extracted with ether • . "(5 x 50 ml) and ethyl acetate (2 x 100 ml). They combined ••• The organic extracts were washed with matt NaHCO 3 (50 mL) and • • I • Saline (50 ml) and dried (anhydrous M004), filtered ••• •. • • and evaporated to dryness.

A suspension of magnesium turnings (928 mg, 38 mmol) in dry ether (38 mL) under argon was treated dropwise with 4-fluorobenzyl bromide (5.3 mL, 42 mmol) over a period of 45 minutes at a rate that maintained gentle reflux. Da till- • • e • • • 0 •, •• ft ... ••• •••• •••••• ftt • •, : ••• •••• • •• ••• • 04 • • • • • • • • • • 0 • • • • • • • • • • 0 ^) • 184 The crude product (9.8 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml) and the column was eluted with CH 2 Cl 2: hexane mixtures (1: 4; 1: 2). The desired fractions were combined and evaporated to dryness and the gay title compound as a white solid (3.29 g, mp 106-108 ° C). (An additional 2.60 g was obtained from other fractions containing savings of starting material and gay a total yield of 94.8%).

TLC: Rr 0.60 (silica gel; CH 2 Cl 2: hexane - 1: 1) Analysis. Calculated for C141111F0: C 78.49; H 5.18; F 8.87 Found: C 78.22; H 5.22; F 9.21 MS (M41) 4- = 215.

B.2- (4-fluorophenyl) -1-phenylethanone, (1-methylethyl) hydrazone A solution of the compound of Part A (4.45 g, 21 mmol) in a mixture of 95% ethanol (34 mL) and glacial acetic acid (0.74 mL) was treated with isopropylhydrazine (3.63 mL, about 42 mmol) and was heated at 80 ° C (oil bath) under N 2 for 1.4 hours. Thin layer chromatography showed that a certain amount of starting material was still present so that the reaction mixture was treated with additional isopropylhydrazine (2.0 mL, about 23 mmol) and heated at 80 ° C (oil bath) for an additional hour. The reaction mixture was cooled to room temperature, evaporated on a rotary evaporator to remove most of the solvent and then diluted with dichloromethane (200 ml). The organic solution was washed with brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The yellow oil obtained was evaporated once from toluene (150 ml) and gay title compound as a crude product (5.63 g), contaminated with a certain amount of starting material and traces of two other components.

TLC: Rf 0.28 (silica gel; Cl 2 Cl 2: hexane - 1: 1) Isopropylhyd, zazine was prepared ph following Witt: iodopropane * .` •• • I I •• •••• 0 •• ••• • •• 18 • •• • •••• • • • • •• • •• • * • • • • • • • • • •• • • • ■ •• • • •• • 0 • • • 0 • •• II • • • • (10.3 mL, 0.10 mol) was added over a period of 2.0 hours to hydrazine hydrate (48.4 mL, 1.0 mol) under N 2. The mixture was then stirred at 600 ° C (oil bath) under N 2 for 3 hours, cooled and extracted with ether (250 ml) for 20 hours (Otske water spoon extractor). The ether extract was evaporated and the gay isopropyl hydrazine (5.63 ml or 5.3 g).

C. Acetic acid, 2- [2- (4-fluorophenyl) -1-phenylethylidene] (1-methylethyl 1) h drazide A mixture of the crude compound of Part B (5.63 g, 2.t21 mmol) and triethylamine (5.85 mL, 42 mmol) in dry toluene (210 mL) was cooled to 0 ° (ice-salt bath) under N with α: ethyl chloride (1.86 mL, 26.3 mmol). The reaction mixture was stirred with gradual heating to room temperature for 1.5 hours, diluted with ether (700 ml) and filtered. The clear filtrate was dried (anhydrous Na 2 SO 4), filtered, evaporated to dryness and evaporated once from toluene (300 ml). The resulting semi-solid (7.1 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml) and the column was eluted with CH 2 Cl 2: hexane mixtures (1: 1, 2: 1), CH 2 Cl 2 and CH 2 Cl 2: CH 3 OH (9: 1) and gay title compound as a crude product (4.11 g). The crude product was chromatographed on another silica gel column and the column was eluted with EtOAc: hexane (4: 1). The desired fractions were combined and evaporated to dryness and gay title compound as a thick yellow oil (3.89 g). TLC: Rf 0.47 (silica gel: EtOAc: hexane - 1: 1).

D.4- (4-fluorophenyl) -5-methyl-1- (1-methylethyl) -3-phenyl-1H- pyrazole A solution of the compound of Part C (1.50 g, 4.80 mmol) in bis (2-methoxyethyl) ether (48 mL) was treated with solid potassium hydroxide (615 mg, 10.96 mmol) and heated at 80 ° C ( oil bath) under N2 2.0 hours. The reaction mixture was treated with a second batch of potassium hydroxide (700 mg, 12.5 mmol), : ••• 4 • 11 • 186 was heated at 800 DEG C. for 2 hours and then stirred at room temperature for 16 hours. The mixture was halided in 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) and brine (2 x 100 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (3.5 g) was chromatographed on a silica gel column (Baker, 60 - 200 mesh, 500 ml) and the column was eluted with EtOAc: hexane (1: 4) and gay title burning as a graduated solid (1.33 g, 94.3%) m.p. 135-137 ° C.

TLC: Rf 0.63 (silica gel; EtOAc: hexane 1: 4).

E. 4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazole-5-carboxaldehyde A mixture of CuSO 4 -5H 2 O (2.21 g, 8.85 mmol) and potassium persulfate (9.53 g, 35.3 mmol) in acetonitrile (65 mL) and water (39 mL) was heated to 6 ° C (oil bath) under N 2 and treated with the compound of Part D (2.6 g, 8.83 mmol). The bath temperature was slowly raised to 70 DEG C., cooled at 70 DEG C. for 40 minutes and then lowered to room temperature using a water bath. The reaction mixture was diluted with dichloromethane (45 ml), stirred for 10 minutes and decanted and the aqueous suspension was extracted with more dichloromethane (3 x 45 ml). The combined organic extracts were washed with brine (2 x 30 mL), dried (aqueous MgSO 4), filtered and evaporated to dryness. The crude product (2.75 g) was chromatographed on a silica gel column (LPS-1) and the column was eluted with EtOAc: hexane (1: 9) and gay title compound. in the form of a solid, 57.7%).

TLC: Rf 0.72 (silica gel; EtOAc: hexane - 1: 4).

F.5- (2,2-dibromoethyl) -4- (4-fluorophenyl) -1- (1-methylethyl) - 3-phenyl-1H-pyrazole A mixture of the compound of Part E (1.75 g, 5.68 mmol) and 1 • 1 • • 1 • 1 •• • • 0 “ • ••• 1 • • ••• • 0 • IN•• • 110 • • 1 • • • .10 • * Of f • 0 w • 4541 0 • II • • Feb 4 • 0 • • Oa * • fa • • • f fa .. f * • 0 0 • • 0 • * of * Of • * • $ • * • • Ogee 187 triphenylphosphine (4.6 g, 16.8 mmol) in dry dichloromethane (27.0 mL) was cooled to -5 to - ° C (ice-salt bath) under argon, treated dropwise over a 5 minute period with a solution of carbon tetrabromide (2.82 g, 8.42 mmol) in dry dichloromethane (9 mL) and stirred at-° C for 20 minutes. The reaction mixture was warmed to room temperature, halided in mat NaHCO 3 (9.0 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with carpet NaHCO 3 (10 mL) and brine (10 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product was chromatographed on silica gel eluting with CH 2 Cl 2: hexane mixtures (1: 0, 1: 4). The desired fractions were combined and gay title compound (2.35 g, 91.4%) as an oil.

TLC: Rf 0.32 (silica gel: C 12 Cl 2; hexane - 1: 1).

G.-Ethynyl- 4- (4-fluorophenyl) -1- (1-methylethyl) - 3-phenyl-1H-pyrazole • ••• • A solution of the compound of Part F (1.89 g, 4.08 mmol) in dry tetrahydrofuran (7.6 mL) was cooled to -78 ° C (torrisacetone), treated dropwise with 1.6 M BuLi / hexane (5.2 mL, 8.18 mmol, 2 eq.) under argon and stirred at -78 ° C for one hour and 20 minutes. The reaction mixture was quenched at -78 ° C with 25% NH 4 Cl (11.0 mL), warmed to room temperature and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with brine • •• •• was evaporated to dryness. The arena product (1.77 g) chromium f • • • • was tographed on a silica gel column and the column was eluted with • • • • CH2Cl2: hexane mixtures (1: 4; 1: 1) and gay title compound . • • boo • • s •••• • ••• • • ••• • • 0 •• • •• 11 • II • • • (648 mg) together with mixed fractions containing the title compound and the compound of Part F. The mixed fractions were combined with the product from another process (490 mg from 1.1 mmol of the compound of Part F) and chromatographed on a second column and the column was eluted with C (15 ml), dried (anhydrous MgSO 4), filtered and filtered ":. •. *.

:: *. • St •••• • •• ••• • •• ■■ • 188 hexane (1: 9). The desired fractions were combined and evaporated to dryness and gay title compound as an oil (1.02 g, 71.5%, corrected for starting material).

H. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - /// 4- (4- fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl / p-ylyl-1-ylmethoxyphosphinyl butyl, methyl ester A solution of the phosphonomonomethyl ester of Example 1, Part F (2.341 g, 5.01 mmol) and trimethylsilylethylamine (1.90 mL, 10 mmol) in dry dichloromethane (9.5 mL) was stirred at room temperature under argon for one hour. The mixture was evaporated to dryness, azeotroped with dry benzene (15 ml) and dried in vacuo. The viscous oil was redissolved in dry dichloromethane (9.5 ml), treated with a drop of DMF, cooled to -10 DEG to 0 DEG C. (ice-salt bath) and treated. dropwise with oxalyl chloride (4805.47 mmol). Powerful gas evolution was observed and the dark yellow glaze was stirred at -0 ° C to 0 ° C for 15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with benzene (18 ml) and dried in vacuo.

A solution of the compound of Part G (1.016 g, 3.34 mmol) in dry tetrahydrofuran (8 mL) was cooled to -78 ° C (dry ice-acetone) under argon and treated with 1.6 M n-BuLi / hexane ( 2.1 ml, 3.36 mmol) and stirred at -780 ° C for 1.0 hour. The above phosphonochloride was dissolved in dry tetrahydrofuran (8 ml), cooled to -78 ° C (dry ice-acetone) under argon and treated dropwise with needles with the solution of the acetylene anion, keeping the solutions at -78 DEG C. throughout the addition. The reaction mixture was stirred at -78 ° C for 1.0 h, quenched by dropwise addition of 25% NH 4 Cl (9 mL) and then warmed to room temperature. The mixture was extracted with ether (3 x 100 mL) and the combined organic extracts were washed with 25% NH 4 Cl (10 mL) • •• • • 1 ••• • • • • PO I • • • • I • • • IN• • I • • I • • • 0.8.1 111.1: •• • •• • • • •• • NS 0 • • * att -t • ' ••• •••• • 59 ••• d yea * 189 and brine (25 mL) and dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product was chromatographed on a silica gel column and the column was eluted with acetone: hexane mixtures (1: 9, 1: 4) and gay title compound as an oil (1.595 g, 64.8%).

TLC: Rf 0.43 (silicon; acetone: hexane - 3: 7).

I. (S) -4 - /// 4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H- pyrazol-5-yl / ethynyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the compound in Part H (1.0 g, 1.36 mmol) in dry tetrahydrofuran (13 mL) was treated successively with glacial acetic acid (320 μl, 5.46 mmol) and 1 M (C 4 H 9) 4 NF ( 4.26 ml, 4.26 mmol) and stirred overnight at room temperature under argon. The reaction mixture was cooled to 0 ° C (ice-salt bath), treated with 5% KHSO 4 (15 mL) and extracted with ethyl acetate (3 x 125 mL). The combined organic extracts were washed with 5% KHSO 4 (2 x 25 mL) and brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product (1.06 g) was dissolved in a mixture of ether (23 ml) and tetrahydrofuran (18 ml), cooled to 0 ° C (ice-salt bath), treated with an excess of diazomethane ether and stirred at . The reaction mixture was quenched by dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column and eluted with acetone: hexane (1: 2). The desired fractions were combined and evaporated to dryness and gay title compound in the form of • • • an oil (3mg, 48.7%).

• S .. 9 TLC: R f 0.23 (silica gel; EtOAc: hexane -4: 1). • 400 f • * 00 O • • • • 0 • • • • ••• ••• • • •• ••• •••• •• •• • •• • • •• • • e t • •• •• ••• • ••• •• • ••• ••••• • # ••• :: •••• •• •• • •• •••• • •• ••• • ••• 190 Example 47 (S) -4 - /// 4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl / ethynyl / hydroxyphosphinyl) -3-hydroxybutanoic acid, dilitium salt A solution of the compound of Example 46 (330 mg, 0.66 mmol) of dioxane (7.8 mL) was treated with 1 N LICH (2.29 mL, 2.29 mmol), stirred at 50 ° C (oil bath) under argon 1 , 5 hours and then at room temperature 16 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on an HP-20 column (1 "x 10") and the column was eluted with distilled water (750 ml), 2% solution of CH 3 OH in water (500 ml), 20% solution of CH 3 OH in water (500 ml). ml) and 50% dissolution of CH 3 OH in water (500 ml). The desired fractions were combined, evaporated to dryness and dried in vacuo. The solid product was charged to Angio distilled water and lyophilized and gay title compound as a fluffy solid lyophilate (275 mg, 99.5%).

TLC: RE 0.57 (silica gel; i-PrOH: NH 4 OH: H 2 O - Analysis. Calculated for C24H22FLi 2N2 OP • 2.28 (effective molecular weight = 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 -1 IR (KBr): 2172 cm (CC) 1 H-NMR sr, ectrum (400 MHz, CD 3 OD): ••• 1.57 (d, 6H, J = 7Hz) •••• 1.86 - 2.01 (m, 2H). • -2137 (dd, 1H, J = 8) 2150 (dd, 1H, J = 4) • • 0 4.40 (m. 1H) . • •• 5.01 (septet, 1H, J = 7) • • • • • • • •• • • • 0 • ••• 7.04-7.39 (m, 9H) • ••• •• •• • 00. 4.0 • ..O. * Ale '• .40.1 .41 191 Example 48 IS) -4 - // 2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-yl / ethyl / methoxyphosphinyl) -3-hydroxybutanoic acid, methyl ester (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // 2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazole -5- / methoxyphosphyl / butanes, methyl ester A solution of the compound of Example 46, Part H (608 mg, 0.85 mmol) in dry methanol (63 mL) was treated with 10% Pd / C (155 mg) and hydrogenated at room temperature with a Parr hydrogenator at about 40 ° C. psi overnight. The suspension was diluted with methanol (50 ml) and filtered through a pad of Celite in a millipore unit and the pad was washed selectively with methanol. The clear filtrate was evaporated to dryness and dried in vacuo and gal / title compound as a homogeneous oil (559 mg, 90.9%) with consistent H 1 NMR and C 13 NMR spectral data.

RC: Rf 0.20 (silica gel: acetone: hexane 3: 7; UV).

(S) -4- [2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl] -1H-pyrazol-5-yl] ethyl / methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A solution of the compound in Part A (559 mg, 0.75 mmol) in dry tetrahydrofuran (7.5 Al) was treated in turn with. ". •• 9 at room temperature about 20 hours. The reaction mixture is 0 . . 4 0 • It was diluted with ice-water (20 ml) and extracted with ethyl acetate . ". •... (3 x 70 ml) and the combined organic extracts were washed • with matt NaHCO 3 (10 mL) and brine (20 mL), dried . •••• . • • . . -.

The crude product (580 mg) was chromatographed on a silica gel. ••• • gel column and the column was eluted with EtOAc: hexane (1: 4), 192 EtOAc and acetone: hexane (4: 1). The desired fractions were combined, evaporated to dryness and dried in vacuo and gay title compound as a homogeneous oil (337 mg, 89.4%). TLC: Rf 0.18 (silica gel; acetone: hexane - 1: 1, UV).

Example 49 (S) -4 - // 2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-yl] ethyl / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt A solution of the compound of Example 48 (337.0 mg, 0.67 mmol) dioxane (8.0 mL) was treated with 1.0 N LiOH (2.32 mL, 3.5 eq.) under argon, stirred at 5 ° (oil bath) for 3.0 hours and then at room temperature for 20 hours. The reaction mixture was evaporated to dryness and dried in vacuo (pump). 1.0 hour. The crude product was chromatographed on an HP-20 column (1 "x 8") and the column was eluted with distilled water (500 ml), a 10% solution of CH3OH in water (500 ml), a 20% solution of CH3OH in water (500 mL) and a 50% solution of CH 3 OH in water. The desired fractions were combined, evaporated to dryness and dried in vacuo. The resulting solid was dissolved in Angdistilled water, frozen and lyophilized over the surface and gay title compound as a fluffy white lyophilate (280.4 mg, 82.4%) with consistent analytical data and mass. IR and H1 NMR spectral data.

•••• • TLC: Rf 0.45 (silica gel; i-PrOH; NH 4 OH: 11 - 8: 1: 1, UV).

• •• An additional 24 mg of slightly contaminated product is recovered from • •• other factions. . • • 0 • e •Analysis. Calculated for C241126FLi2N20P- 1.19 H2O (effective • ••• • molecular weight = 507,733): 6.0 0 C 56.77; H 5.63; N 5.51; F 3.74; P 6, . " • Found: C 52.77; H 5.69; N 5.49; F 3.91; P 6, ••• • . • IR (KHr) 0.69377 (1589 cm-1, in COO). •• • ••• 0 • 0 • 193 H1-NR Spectrum (400 MHz, CD30D): 61.55 (d, 611, J = 7, Hi) 1.64-1 / 84 (m, 4H, -, Hc + Hd) 2/34 (m, 2H, -, Ha) 2.91 (pseudo quartet, 211, -, He) 425 (m, 1H, -, 116) 4.77 (septet, 111, partially hidden below HOD signal, -, mi) 7.05-7132 (m, 911, aromatic protons).

EemPL9.1_ (S) -4 - /// 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-pyrazol-ylmethynyl / methoxyphosphinyl / -3-hydroxybutyric acid, methyl ester A. N-benzoylvaline • 41041 • .0.111 • • • • 0 lb be • • • • • • 0 • • • • • ••• • • • F * • • 0 • • • 00 • 0 • • • • A solution of valine (20 g, 0.17 mol) in tetrahydrofuran (20 ml) and 2 N NaOH (111 ml) was cooled to 0 ° C (ice-water bath) under nitrogen and treated dropwise with benzoyl chloride (23.8 ml, 0 ml). 21 mol). The reaction mixture was warmed to room temperature, stirred for 3.0 hours and then cooled again to 0 DEG (ice-salt bath) and treated with concentrated sulfuric acid (8.0 ml). The mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with water (1u) ml) and brine (50 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness and gay title compound as a solid (41.97 g, 100% crude yield) .

A small amount (260 mg) of the product was recrystallized from ethyl acetate and petroleum ether and gay title compound as an analytical sample (205 mg, m.p. 132 DEG-133 DEG C.). TLC: Rf 0.10 (silica gel; acetone: hexane - 1: 1) Analysis. Calcd C 65.14; N 6.83; N 6.33 Punnot: C 64.81; N 6.79; N 6.29 S-- ": •" •., •• g •• •• 50 • •• Ste • ••••• I 194 MS (M4-1) 4- = 222- B.N- (1-Acetyl-2-methylpropyl) benzamide A mixture of the compound of Part A (41.7 g, 0.7 mol) and triethylamine (47.3 ml, 0.34 mol) in acetic anhydride (48 ml) was treated with two portions of 4-dimethylaminopyridine (2.07 g). 0.017 mol) and stirred at room temperature for 16 hours under nitrogen. The reaction mixture was cooled to 0 ° C (ice-salt bath), quenched with methanol and stirred for 30 minutes. The light brown precipitates that formed were filtered off, washed selectively with water (1.1 liters) and redissolved in dichloromethane (750 ml). The resulting solution was dried (anhydrous M004), filtered and evaporated to dryness to give a crude product (35.9 g).

The crude product was poured into ether (1.3 liters), filtered to remove the soluble solids and the clear filtrate was concentrated to a volume of about 300 ml and cooled in an ice bath. Title compound in the form of a degree-colored formation (21.35 g, m.p. 88-90 ° C) was filtered off. Purification of the resulting solid by evaporation of the filtrate on a silica gel column (Baker, 60-200 mesh, 600 ml), eluting the column with EtOAc: hexane mixtures (1: 7, 1: 4) to give a further 4.77 g of the title compound. A small amount of title compound was recrystallized from ether, m.p. 88-89 ° C.

TLC: Rf 0.75 (silica gel; acetone: hexane - 1: 1).

Analysis. Calculated: C 70.20; H 7.81; N 6.39 Found: c 70.79; H 7.68; N 6.31 • • • • MS (M + H) 4- = 220.

. • . • • • • • • ••• • • • • • •• • • • • Oil • I • • C.N- / - / (4-fluorophenyl) -1_11411 ’21,9ethyl / -2-trattylacylbenzamide A solution of the compound of Part B (25.0 g, 0.114 mol) in dry toluene (250 ml) was treated with 4-fluoroaniline (12 ml, 0.127 mol, 1.13 eq.) And p-toluenesulfonic acid hydrate (125 mg) and 19 the reaction mixture was boiled under Aterflode under N 2 with a Dean-Stark distillation receiver for 20 hours. The reddish brown solution was cooled to - ° C (ice-salt bath) and used as the side for the next step I sequence.

D.1- (4-fluorophenyl) -5-methyl- 4- (1-methylethyl) -2-phenyl-1H- imidazole The cooled solution of the compound in Part C (V-0.114 mol) was diluted at-° C (ice-salt bath) with dry dichloromethane (200 ml) and treated portionwise with phosphorus pentachloride (47.5 g, 0.228 mol). The grade slurry was heated, boiled under Sterflode for 2.5 hours under N 2, cooled to room temperature and slowly halided in a mixture of ice (400 g) and 50% NaOH (105 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 x 200 ml). The combined organic extracts were washed with brine (2 x 100 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product mixture (35.0 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 600 ml), the column was eluted with EtOAc: hexane mixtures (1: 9, 1: 4) to give white title compound. nalar (29.24 g, m.p. 146 DEG-140 DEG C. 87%).

TLC: Rf 0.40 (silica gel; EtOAc: hexane - 1: 4) Analysis. Calculated: C 77.52; H 6.51; N 9.52; F 6, Found: C 77.48, H 6.69; N 9.40; F 6.1 MS (M + H) 4 = 295.

E. 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazole-5-carboxaldehyde ▪A mixture of copper (II) sulphate hydrate (8.50 g, 34.0 mmol) and potassium persulfate (36.8 g, 0.136 mol) in a solvent mixture of acetonitrile (250 ml) and water (150 ml) . heated to 6 ° C (oil bath) under N 2 and treated with • • ••• •••• • •• 196 ••• •••• • • •• • •• • • • • 0 • • • • • • • 0 ••• • • ••• • • ••• • •• •• • ••• • • • • the compound of Part D (10 g, 34.0 mmol). The reaction mixture was heated successively to 7 ° C, h011s days at 40 minutes and then cooled to room temperature. The solution was decanted from the solid and the aqueous phase and the solid were extracted with dichloromethane (3 x 200 ml). The ferrous organic extracts were washed with brine (2 x 100 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (17.0 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 600 ml) and the column was eluted with EtOAc: hexane mixtures (5:95, 1: 7) and gay title compound as a solid. substance (6.27 g, 59.8%). 200 mg of the title compound were recrystallized from Et 2 O: hexane and gay an analytical sample (76 mg, m.p. 160-161 ° C). TLC: Rf 0.34 (silica gel; EtOAc: hexane - 1: 4).

Analysis. Calculated: 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. - (2,2-Dibromoethyl) -1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazole A solution of the compound of Part E (1.75 g, 5.68 mmol) and triphenylphosphine (4.46 g, 16.8 mmol) in dry dichloromethane (27.0 mL) was cooled to -5 to - ° C (ice-salt bath) under argon and treated dropwise over 5 minutes with a solution of carbon tetrabromide (2.82 g, 8.42 mmol) in dry dichloromethane (9 mL) . The mixture was stirred at - ° C for 20 minutes and then halinated on sodium bicarbonate (9.0 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic extracts were washed with matt NaHCO 3 (10 mL) and brine (10 mL) was dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (8.07 g) was chromatographed on a silica gel column and the column was eluted with CH 2 Cl 2: hexane mixtures (1: 7, 1: 4) and gay title compound as a solid (2.35 g, 91.4%). . t ••• ••••. ■ .60. ••••• if •• ••• • ■ • ei • e; sea; 3 i ••• 34.I • i : 3 •: •: .6. 3 •• ••• • * lbw •• 197 100 mg of the compound of Part F was recrystallized from Et 2 O: hexane and gay an analytical sample (49 mg, m.p. 164-16 ° C).

TLC: Rf 0.32 (silica gel; CH 2 Cl 2: hexane 1: 1).

Analysis. 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; Br 34, MS (M + H). 1- = 465.

G. 5-Ethynyl-1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1Himidazole A thaw of the compound of Part F (3.065 g, 6.60 mmol) in dry tetrahydrofuran (12.5 mL) was cooled to -78 ° C (dry ice-acetone) and treated with 1.6 M n-BuLi / hexane (8 , 4 mL, 13.4 mmol) under argon. The reaction mixture was stirred at -78 ° C for one hour and 20 minutes, quenched by dropwise addition of 25% NH 4 Cl (18 mL), warmed to room temperature and extracted with ether (3 x 100 mL). The combined organic extracts were washed with brine (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (2.08 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml) and the column was eluted with EtOAc: hexane mixtures (1: 9, 1: 4). The desired fractions were combined and evaporated to dryness and the title compound (1.97 g, 97.8%). : • • •: • • •• • • • •••• -e • • a : ••• • I •• • e • •• •: •• e • • 92 mg of the compound of Part G was recrystallized from hexane and gay an analytical sample (59 mg, mp 148-1 ° C). TLC: Rf 0.60 (silica gel; EtOAc: hexane - 1: 4) Analysis. Calculated: 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.

H. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - /// 1- (4- fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethynyl / methoxyphosphinylbutanoic acid methyl ether A mixture of the arena phosphon monomethyl ester Example 1 Aip * • oSso 11 * 4 : •: lb • I • • • " I) • • •• g •: • •• ••. .. °. .. • ... •. . • .. • • • 198 Part F (3.54 g, 7.86 mmol) and trimethylsilyldiethylamine (2.70 mL, 14.21 mmol) in dry dichloromethane were stirred at room temperature under argon for 1.0 h. The mixture was evaporated to dryness, azeotroped with dry benzene (26 ml) and dried in vacuo. The viscous oil was redissolved in dry dichloromethane (14 mL), treated with 2 drops of DMF, cooled to -16 ° C (ice-salt bath) and treated dropwise with oxalyl chloride (0.68 mL, 7.79 mmol). Strong gas evolution was observed and the yellow-brown solution was stirred at-° C for 15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with dry benzene (26 ml) and dried in vacuo.

A solution of the compound of Part G (1.43 g, 4.7 mmol) in dry tetrahydrofuran (11.5 mL) was cooled to -78 ° C (dry ice-acetone) under argon and treated with 1.6 M n-BuLi / hexane (2.94 mL, 4.7 mmol) and stirred for 30 minutes at -780 ° C. The above phosphonochloride was dissolved in dry tetrahydrofuran (11.5 ml), cooled to -78 ° C (dry ice-acetone) under argon and treated dropwise with needles with a solution of the acetylenic anion, keeping both solutions at -78 ° C during the addition. The reaction mixture was stirred at -78 ° C for 30 minutes and quenched by dropwise addition of 25% NH 4 Cl (13 mL), allowed to warm to room temperature and then extracted with ether (3 x 130 mL). The combined organic extracts were washed with 25% NH 4 Cl (15 mL) and brine (30 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product mixture (4.3 g) was chromatographed on a silica gel column and the column was eluted with acetone: hexane mixtures (5:95; 1: 4). The desired fractions were combined and evaporated to dryness and the gay title compound as a light brown syrup (2.18 g, 62.9%).

TLC: Rf 0.1.3 (silica gel; hexane: acetone 7: 3). • 04 • ** 41 • • • • • • • • • • • • • • ••• 4,011 S •• • 5 • 4000 •• •• • •• • to • • • . * •:: *** • •• 1 ••• .. i •••• •: •• • •••• • a • * • •;: e 199 I. (S) -4 - /// 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H- imidazol -5-yl / ethynyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the compound of Part H (974 mg, 1.32 mmol) in dry 7-tetrahydrofuran (13.0 mL) was treated successively with glacial acetic acid (310 / L11, 5.29 mmol) and 1 M (C 4 H 9) 4 NF ( 4.14 mL, 4.14 mmol) and stirred overnight at room temperature under argon. The reaction mixture was cooled to 0 ° C (ice-water bath), treated with 5% KHSO 4 (14 mL) and extracted with ethyl acetate (3 x 125 mL). The combined organic extracts were washed with 5% Cl 2 SO 4 (16 mL) and brine (35 mL), dried (anhydrous MO 4), filtered and evaporated to dryness.

The crude product (1.48 g) was dissolved in a mixture of ether (22 ml) and dry tetrahydrofuran (17 ml), cooled to 0 DEG (ice-water bath), treated with an excess of diazomethane in ether and stirred at 0 DEG C. hours. The reaction mixture was quenched by dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column and the column was eluted with EtOAc: hexane mixtures (1: 1, 4: 1). The uninjured the fractions were combined and gay title compound as a solid (306 mg, 46.2%).

TLC: RI 0.33 (silica gel; EtOAc: hexane - 4: 1).

Example 51 (S) -4 - /// 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl / ethynyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt 0 • • • • • A reading of the compound of Example 50 (304 mg, 0.6 mmol) in • 60. * 0 • dioxane (7.1 mL) was treated with 1 N LiOH (2.03 mL, 2.08 mmol), • • stirred at 50 ° C (oil bath) under argon for 5 hours and • . . then at room temperature for 24 hours. Reak ‘_All mixtures in. .0 4 * was evaporated to dryness and dried in vacuo. The 6-year-old pro- . . 0 : ••• ; •; O • vo 0 Of 000 0 41000 200 • 008 • 0000 • • • • • • • 0 * 04 • • • IN• 4100 • • • • O • 00 II, 0 • The product was chromatographed in an HP-20 column (1 "x 7"), the column was distilled with Angdistilled water (750 ml), 10% solution of CH 3 OH in water (500 ml), 20% solution of CH 3 OH in water (500 ml ) and 50% solution of CH 3 OH in water (500 ml). The desired fractions were combined, evaporated to dryness and dried in vacuo. The solid product was dissolved in Angdistilled water and lyophilized and gay title compound as a fluffy solid lyophilate (257 mg, 84.1%).

Other fractions: TLC: Rf 0.38 (silica gel; i-PrOH: NH 4 OH: H 2 O 8: 1: 1).

Analysis.

Calculated for C24 H22 FLi2 N2 0P- ° .1 52 1120: 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 1 H-NMR spectrum (400 MHz, CD 3 OD): 6137 (d, 6H, 3 = 7 Hz) 179 (m. 2H) 2.31 (dd, 111, J = 9.15 Hz) 2.43 (dd, 1H, J = 4.15 Hz) 3.24 (septet 1H, 3 = 7 Hz) 4.26 (m. 1H) 7.17 - 7.35 (m, 9H).

IR (KBr) 2163 (CC), 1590 (C = 0) cm-1.

Example 52 (S) -4 - // 2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1Himidazol-5-yl] ethyl / methoxyphosphinyl] -3-hydroxybutanoic acid, me_tylester A. (S) -3 - // (1,1-dimethylethyl) diphenylailyl / oxy / -4 - // 2- / 1- (4- fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl / methoxyphosphinylbutanoic acid, methyl ester A solution of the compound of Example 50 Part H (839 mg, 1.14) 201 • 911.1 • 1000 • • • • 1 • 1 •• • 1 • • 1 0 • • 1 • 1 9 11 I • • 111P. • • 1 • 11011, • ••• 1 • 1 • ••• 1111 1 • • 1 0 • mmol) in dry methanol (86 ml) was treated with 10% Pd / C (213 mg) and hydrogenated at room temperature on a surface Parr hydrogenator at about 40 psi. The suspension was filtered through Celite and the clear filtrate was evaporated to dryness and dried in vacuo and gay title compound as a thick syrup (853 mg, 100% yield).

TLC: Rf 0.17 (silica gel; hexome: acetone - 7: 3).

B. (S) -4 - // 2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl- 1H-imidazol-5-yl / ethyl / methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the compound of Part A (853 mg, about 1.14 mmol) in dry tetrahydrofuran (11.0 mL) was treated successively with glacial acetic acid (270 μL, 4.60 mmol) and 1.0 M (C 4 H 9). 4NF / hexane (3.62 mL, 3.62 mmol) and stirred over the surface at room temperature under argon. The reaction mixture was diluted with ts-water (25 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated NaHCO 3 (15 mL) and brine (25 mL), dried (anhydrous Mg 4), filtered and evaporated to Dryness.

The crude product (958 mg) was chromatographed on a silica gel column and the column was eluted with acetone: hexane mixtures (1: 1, 4: 1). The desired fractions were combined, evaporated to dryness and dried in vacuo to give the title compound (443 mg, 77.0%). TLC: Rf 0.13 (silica gel; acetone: hexane - 1: 1).

Example 53 (B) -4 - // 2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1Himidazol-5-yl] ethyl / hydroxyphosphinyl] -3-hydroxybutanoic acid, dilitium salt A solution of the compound of Example 52 (443 mg, 0.88 mmol) 202 00.4 11.1141 • • la I • I • • II • I • • a IN• • 1 • • • • , •• .0 • • • 1111 • • 4 0 •• • 4 • 41 • . • in dioxane (10.5 mL) was treated with 1.0 N LiOH (3.05 mL, 3.09 mmol) and stirred at 5 ° C (oil bath) under argon for 3.0 hours and then at room temperature for about 20 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on an HP-20 column (1 "x 8") and the column was eluted with Angdistilled Water (750 ml), 10% solution of CH 3 OH in water (500 ml), 20% solution of CH 3 O 1 in water (500 ml) and 50% solution. of CH 3 OH in water. The desired fractions were combined and evaporated to dryness. The resulting solid was dissolved in Angdistilled water (30 ml) and lyophilized and gay title compound as a fluffy white solid (376.4 mg, 83.9%).

TTC: Rf 0.40 (silica gel; i-PrOH: NH 4 OH: H 2 O - 8: 1: 1) Analysis. Calculated for C ... zqH26FLill 2N205P-0.84 1120 (effective molecular weight = 501.46): C 57.43; H 5.76; N 5.69; F 3.99; P 6.08 Found: C 57.48; H 5.56; N 5.59; F 3.79; P 6.18 IR (KBr) (1587 cm-1, C = 0 C00-) 111 NMR Spectrum (400 MHz, CD 300): 1.33 (d, 611, J = 7Hz) 1.46-1.61 (m, 411) 2.30 (m, 211) 2.76 (m, 211) 3.13 (septet, 111, J7 Hz) 4.14 (m, 111) 7.17-7.30 (m, 911).

Example 54 (S) -4-7 / 72- (cyclohexylmethyl) -4,6-dimethylphenyl / ethynyl / hydroxy- phosphinyl / -3-hydroxybutanoic acid, dilitium salt A.N- (2,4-dimethylbenzylidene) benzenamine Reference to Merck U.S. Patent No. 4,375,475, p. 39. The title association was presented in the manner described 203 Example 1, Part A.

B. Cl.

[N r "-1.

H C IPd- 3 • ,,, "• - .. 11 0 OCH3 CH3 Reference to Merck, U.S. Patent No. 4,375,475, p. 39.

The title Pd complex was prepared as described in Example 1, Part B.

C.2- (cyclohexylmethyl) -4,6-dimethylbenzaldehyde Magnesium span (1.44 g, 59.45 mmol) under argon atmosphere was charged with 15 mL of dry Et 2 O and sonicated for 5 minutes. Cyclohexylmethyl bromide (1.5 ml) was added to the Me-span and sonication was continued (boiling under Aterflode began with a few minutes). Through an addition funnel, 60 ml of dry Et 2 O and 5 ml of Et 2 O solution of the remainder of the cyclohexylmethyl bromide were added simultaneously with continued sonication (a total of 9.12 ml, 65.3 mmol of the cyclohexylmethyl bromide were added). When the addition was pine board, sonication was continued for 15 minutes and then the reaction mixture was boiled under Aterflode for 40 minutes. This Grignard reagent was cooled to room temperature and then cannulated to a solution of the Pd complex in Part B (5.55 g, 7.43 mmol) and triphenylphosphine (15.59 g, 59.45 mmol) which had been stirred for 30 minutes under argon atmosphere and at room temperature. After the addition of the grignard reagent, the reaction mixture became spruce and a mold was formed. This reaction solution was stirred at room temperature for 2 hours after which 37 ml of 6 N HCl was added. This mixture was stirred for one hour and then filtered through a pad of Celite into a sintered glass funnel to give off solid 2 : 00 ': O.': 0 '• "'" 0 • • 0.1 • • i: .0. 40 • • .4, ** Of • 40, ••• 4 WI * 204 substances. The solid was washed with Et 2 O and the filtrate was evaporated on a rotary evaporator to remove volatiles. The resulting residue was stirred with Et 2 O and filtered as above. The filtrate was washed one Ong with matt NaCl solution and the organic layer was dried over MgSO 4; 14.5 g of a brown oil are obtained. Purification by flash chromatography eluting with 4% Et 2 O-hexane gay 1.70 g of a clear oil, 99% yield.

TLC: Rf = 0.30 (5% Et 2 O / hexane, silica gel).

IR (CHCl 3) 3030, 3008, 2926, 2853, 1679, 1606 -1 1448, 1147 cm 1 H NMR (270 MHz-CDCl 3) 151 (s, 1) 6190 (s, 1) 6.85 (s, 1) 2.80 (d, 2, J = 610 Hz) 2155 (s, 3) 2/30 (s, 3) 1180-1.55 (m, 5). 1.55-1 / 30 (m, 1) 1.30-0.80 (m, 5) Mass Spec (CI) m / e 231 (M + H) -1.

D. 1- (Cyclohexylmethyl) -2- (2,2-dibromoethyl) -3,5-dimethylbenzene The aldehyde in Part C (1.68 g, 7.3 in 65 mL of dry CH 2 Cl 2) ••• "00cooled to 0 ° C une - food atmospheres. To this point triphenylphosphine (b, L3 g, 23.4 mmol) was added and the solution • •• stirred until all solids had dissolved. At 00 ° C • • • CBra (3.63 g, 11.0 mmol) was added as a 20 ml CH 2 Cl 2 solution. • • • • • • ning. The reaction solution turned orange. Reaction mixture ••• • The mixture was stirred at 0 DEG C. for 1.5 hours, then quenched with food. ". • NaHCO3 solution and stirred vigorously. The water layer . 00 • was charged and extracted twice with CH 2 Cl 2. The organic ... ". • The mixtures were combined, washed once with matte . . . • • 20 NaHCO 3 solution and dried over MgSO 4. Filtration and removal of solvent 9.6 g of a brown solid. Purification by flash chromatography eluting with 100% hexane gay 2.52 g, 90% yield, of a clear oil.

TLC 0.62 (5% Et 2 O / hexane, silica gel) PMA. -1 IR (CHCl 3) 2926, 2852, 1608, 1472, 869 cm -1 1HN4R (270 MHz, CDCl3) 67.39 (s, 1) 6.87 (s, 1) 6.80 (s, 1) 2.37 (d, 2, J = 6.3 Hz) 2.27 (s 3) 2.24 (s, 3) 1.70 (m, 5) 1145 (m, 1) 1138-1110 (m, 3) 0.90 (m, 2) Mass. Bacon. (CI) m / e 387 (M + H) + E. 1- (Cyclohexylmethyl) -2-ethynyl-3,5,5-dimethylbenzene ••• • The vinyl dibromide in Part D (2.51 g, 6.5 mmol) under an acron atmosphere was stirred with THF (30 mL) and cooled to -78 ° C. To the dibromide solution was added at -78 ° C n-butyllithium (5, ml of a 2.5 M solution in hexane) for 3 minutes. The resulting pink reaction mixture was stirred at -78 ° C. After 1.5 hours at -78 ° C, the reaction was quenched with a slow thawing of • NH 4 Cl in water and the reaction mixture was then heated . • . "" To room temperature. The aqueous layer was removed and extracted. • • • • • • row twice with Et 2 O and once with hexane. All the organic layers were combined and dried over MgSO 4 and gay 1.65 g of a brown oil after filtration and removal of solvent. Purification by flash chromatography and cloning with hexane gay 1.39 g, 95% yield, of the title acetylene. • • • • • 0 • • 11 • •• • • ••• • • • 60 • ••• • • • • 206 TLC 0/50 (5% toluene / hexane, silica) PMA.

IR (CHCl 3) 3305, 3007, 2924, 2852, 2096, 1607, 1470, 1448 cm-1. 1 H NMR (270 MHz, CDCl 3) 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) 10.00 (m, 2) Mass Spe, k (CI) m / e 227 (M4-11) 4-- F. (S) -4 - /// 2- (cyclohexylmethyl) -4,6-dimethylphenyl / ethynyl / - methoxyphosphinyl / -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / - butanoic acid, methyl ester Acetylene from Part E (1.36 g, 6.0 mmol) in ml dry THF under argon atmosphere 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 was burgundy and stirred for an hour at -780 ° C. The phosphonochloride in Example 1, Part F (4.68 g, 9.6 mmol) was stirred with ml of dry THF and cooled to -780 ° C. within minutes. When the transfer was complete, the reaction mixture was stirred at -78 ° C for one hour and then diluted with a slow solution of Nti4Cl in water and warmed to room temperature. THF was removed from the reaction mixture and the resulting material was loaded with Et 2 O and H 10. Water- 4 the layer was extracted 3 Ongs with Et 2 O. The Alia Et 2 O extracts were combined and washed once with saturated NaHCO 3 solution and one Ong with brine and then dried over MgSO 4. Filtration and removal of solvent to give 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 (I, 70% yield) is obtained in the form •• • •• 4 '• • • S • • • 0 0 • • ••• • • 4. • • • ••• 0 • • • •• • •• II a • 207 of a clear oil.

TLC Rf., -, 0.37 (5: 1: 4 / hexane: toluene: EtOAc, silica gel) PMA.

IR (CHCl 3) 3025, 3001, 2929 2856, 2164, 1736, 1607, 1240, 1112, 1039, 823 cm-1. 1H NR (270 MHz, CDCl 3) 7166 (m, 4) 7.30 (m, 6), 687 (s, 1), 6.81 (s, 1) 4166 (m, 1) 3.70 & 3166 (d's, 3, J = 14/3 Hz) 3156 (s, 3) 2195 (m, 1) 2169 (m, 1) 2150 (m, 3) 2132 (m, 2) 2.30 (s, 3) 2127 (s, 3) 1160 (m, 6) 1.03 (m, 3) 1.02 (s, 9) 0.95 (m, 2) Mass Spe.k. (CI) m / e 659 (M4.1) 4 G. (S) -4 - /// 2- (cyclohexylmethyl) -4,6-dimethylphenylethynyl / - met9) 4phosphinyl / -37hydroxybutanaya, The acetylenic phosphate in Part F (0.633 g, 0.96 mmol) • Stir under argonate at 14.0 ml at room temperature dry THF. Glacial acetic acid (0.22 mL, 3.84 mmol) was added to the phosphinate solution and then n-Bu4NF (2.62 mL of 1.1 M THF-1 solution) was added dropwise within 5 minutes. After stirring for 19 hours at room temperature, the reaction mixture was quenched against ice water and the aqueous layer was extracted three times with EtOAc. The combined organic solutions were washed twice with a quenched solution of NaHCO 3 in water and once with a quenched NaCl solution. The organic layer was dried over Na24 and filtered. •• • •• • 0 • • • • • 0 • • • it • ft * • • ••• • • ••• • • 6 66 • SG 6 • • • • • 208 O • 4.8 • • • • • 0 • • • • • SOO • • 000.4. • .6.0. • $ 410. • • • •• 4 rades and gay a quit rubber (0.658 g) after removal of solvent. Purification by flash chromatography and clarification with EtOAc gal / the title alcohol (0.23 g, 65%) as a clear oil.

TLC Rf 0.51 (6; 4 acetone / hexane, silica gel) PMA IR (CHCl 3) 3450 (br), 3005, 2926, 2852, 2164, 1733, 1607, 1448, 1439, 1039 1 H NMR (270 MHz, CDCl 3) 66.89 (s, 1) 6.82 (s, 1) 4.63 (m, 1) 3.88 & 3.87 (2d, .3, 3 = 12 Hz) 3.69 (s, 3) 2.70 (s, 2) 2.62 (d, 2, 3 = 6/3 Hz) 2.43 (s, 3) 2/32 (s, 3) 2.27 (m, 2) 1.65 (m, 6) 1.19 (m, 3) 1.00 (m, 2) Mass spectrum (CI) m / e 421 (M + H) 4.

H. (S) -4 - /// 2- (cyclohexylmethyl) -4,6-dimethylphenyl / ethynyl / - hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt The diester in Part G (0.212 g, 0.51 mmol) was stirred in dioxane (7 mL) and 1.5 mL of 1 N LiOH (1 mmol) was added at room temperature. The reaction mixture was heated to 50 DEG C. and after 20 minutes the resulting precipitate was solubilized by adding 5 ml of dioxane and 4 ml of H2 O. After 2 hours and 30 minutes at 50 DEG C., the reaction mixture was cooled to room temperature and the solvent was removed under gentle pressure and the resulting white solid was placed under vacuum for 15 minutes. The product was purified on a 3.0 x 19 cm column of HP-20 resin and eluted first with 100 ml of 1120 and then with 1: 1 MeOH / H 2 O. Lyophilization of the product gay 209 0.145 g (71%) of a white lyophilate.

Rf = 0.39 (7: 2: 1 nPrOH / NH 4 OH / H 2 O, silica gel)? MA.

IR (KBr) 3700-3100 (br), 2922, 2850, 216, 1590, 1447, 1179, 1076 cm-1.

1 H NMR (400 MHz, D 2 O) 6 6/99 (s, 6.94 (s, 1); 4153 (m, 1), 2/64 (m, 1), • 6.22 (d, 2, J = 6 2 Hz) 2/39 (s, 3) 2/37 (m, 2.26 (s, 3) 2.02 (m, 1160 (m, 6) 1114 (m, 1.00 (m, Mass spectrum (FAB) m / e 409 (M + H) + 397 (M-2 Li + H) Analysis. Calculated for C2111270P Li2-1.72 H2O C 57.96; H 7.05; P 7.12 Found: C 57.96; H 7.18; P 6.96 Example 5 4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl / ethenyl / hydroxyphosphate] III: 12 / hydroxybutanoic acid, dilitium salt • • • • •• • •• • • • 6 • 0 • !IN• ••• • ••• • ••• • • • • • • • • • • A. (E) - [2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] / - phosphonic acid, dimethyl ester Dimethyl methylphosphonate (1.64 g, 13.2 mmol) in dry THF (20 mL) under an argon atmosphere was cooled to -78 ° C. For this solution was added at -78 ° C n-butyllithium (5.0 ml, 2.5 M solution in hexane, 12.4 mmol) within 5 minutes. When the addition is wet r completed, the milky white reaction mixture was stirred one time. The anion solution fo ° was reacted at -78 DEG C. with 10 ml of THF solution. ••••••••• ••••: ••••••• • •• ••• 11 •••• • Is •••• •••: •• •: • ••: : ••••• •••• • • • •• • • •••• • 2 Example 54, Part A (1.9 g, 8.26 mmol) through an addition funnel for about 10 minutes. After stirring for 35 minutes at -78 DEG C., the reaction mixture was quenched with a matt solution of NH4Cl in water (8 ml) and then allowed to warm to room temperature. The organic layer was removed and the aqueous layer was extracted three times with EtOAc. The organic layers were combined and washed with brine and dried over Na 2 SO 4. Filtration and removal of solvent Gay 3.25 g of a yellow oil.

The above yellow oil (0.25 g) was dissolved in dry toluene and refluxed through a soxhlet extractor containing 4 A molecular sieves. p-Toluenesulfonic acid H 2 O (0.080 g, 0.42 mmol) was added at time 0 and after 3.5 and 18 hours, respectively. After 22 hours at reflux, the reaction mixture was cooled to room temperature and the toluene was removed in vacuo. The resulting yellow residue in EtOAc was washed twice with matt NaHCO3 solution, dried over Na2SO4 and filtered and gay a yellow oil (A) after removal of solvent.

The aqueous solution was acidified with concentrated HCl, extracted three times with EtOAc, dried over MgSO 4 and filtered and the solvent was removed and 0.535 g of a yellow O • ••• • • • • • • • • • • • • • • • • • • • •• • • • • • • • • • 0 • lit • • • • • • • • • • • • • • • • • • • • • oil. This yellow oil was then boiled under reflux in 6.0 ml of HC (AND) 3 for 24 hours after which the excess HC (AND) 3 was removed under vacuum. This material was combined with yellow oil (A) and purified by flash chromatography eluting with 80% EtOAc / hexane. The title vinyl phosphonate (3.07 g, 73%) is obtained in the form of a white solid.

TLC R = 0, (1: 1 acetone / hexane, silica gel) PMA IR (KBr) 2921,2851,1623,1447,1243,1186,1060, -1 1027 cm.

1 H NMR (270 MHz, CDCl 3) 7.6 (dd, 1, J = 23r6 Hz, 18/1 Hz) 6188 (s, 1) 6.82 (s, 1) • • •••••• •• * silo • • •• ••• • • • 11 211 5.80 (dd, 1, J = 21.0 Hz, 18.1 Hz) 3.79 (d, 6, J = 14.5 Hz) 2/49 (d, 2, J = 7.2 Hz) 2.29 (s, 3) 2; 28 (s, 3) 1.6 (m, 5) 1, (m, 1) 1.25-0 / 80 (m, 5) Mass spectrum (CI) m / e 337 (M.441) 4 " B. (E) - [2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] - .9.I2RylifostallaseA, methyl ester The vinyl phosphonate in Part A (2.07 g, 6.16 mmol) was mixed with 14 mL of dioxane at room temperature. To this solution was added 1.0 N LiOH (9.24 mL, 9.24 mmol) and this mixture was heated to 7 ° C. After 3.5 hours at 70 ° C, the reaction mixture was cooled to room temperature and the dioxane was removed. vacuum. The resulting residue was stirred with H 2 O and acidified to pH about 2 with 1 N HCl. The aqueous solution was extracted three times with EtOAc, dried over Na 2 SO 4 and filtered and the solvent was removed to give 1.95 off-white solids.

TLC Rf = 0.58 (8: 1: 1 / CH 2 Cl 2: CH 3 OH: AcOH, silica gel), PMA.

1 H NMR (270 MHz, CDCl 3) • • • • 612.11 (s, 1) •• 7161 (dd, 1, J24317 Hz, 17158 Hz) • •• • 0 • 6/87 (s, 1) •• • 0 6.81 (s, I) • •• •• •••• 5.88 (dd, 1, J = 21.43 Hz, 17.58 Hz) • 3.78 (d, 3, J = 11.54 Hz) ••• • • ••• 2147 (0.2, J = „6 Hz) • •• •• 2.29 (s, 3) • ••• •• a • IIe • •••• • •• ••• • •••• 212 2.28 (s, 3) 1.6 (m, 5) 11 (m, 1, (m, 3) 019 (m, C. (E) -4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] - Ethenyl / methoxyphosphinyl / -3-oxobutanoic acid, methyl ester The monomethylphosphonate in Part 13 (1.95 g, 6.06 mmol) in 50 mL of dry CH 2 Cl 2 was stirred at room temperature under an argon atmosphere with (C 2 H) 2 NSi (C 11 3) 3 (1.76 g, 12.1 mmol) for one hour and 25 minutes. C12 Cl2 was 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 CH 2 Cl 2 (50 mL) under an argon atmosphere and cooled to 0 ° C. TWO drops of DMF were added and then oxalyl chloride (0.92 g, 7.27 mmol) was added slowly and dropwise. Gas evolution was observed. The reaction mixture was stirred for 15 minutes at 0 ° C and then warmed to room temperature and stirred for one hour. CH 2 Cl 2 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 one hour to give the saline phosphorus chloride.

••• • •••• The dianion of methyl acetoacetate was prepared as follows true. Pentane washed NaH (0.25 g oil dispersion, 8.7 •• • . .mmol) in dry THF (10 ml) under an argon atmosphere was cooled ... . • . " 0 0 • • •• •• •. • • . • • 00 ° C Methyl acetoacetate (0.92 g, 7.9 mmol) was added to NaH the suspension in the form of ml of THF solution and stirred minutes and then n-butyllithium (2.90 ml, 2.5 ml in hexane, 7.3 mmol) and the mixture is stirred minutes. The dianion solution was cooled to -78 ° C and 10 ml of THF solution of the phosphonium chloride prepared as above cooled to -78 ° C and added to the dianion solution mom 213 15 minutes. After stirring at -78 DEG C. for 30 minutes, the reaction was quenched with the quenched solution of NH4Cl in water and the reaction mixture was warmed to room temperature. THF was removed from the reaction mixture and the resulting orange oil was taken up in 1: 1 EtOAc / H 2 O. The aqueous layer was extracted three times with EtOAc. The combined EtOAc extracts were combined and washed twice with saturated NaHCO 3 solution and once with matt NaCl solution and then dried over Na 2 SO 4. Purification of the crude product (2.75 g) by flash chromatography eluting with EtOAc gay the title keto ester (0.97 g, 42%) as a yellow oil.

TLC Rf = 0.24 (EtOAc, silica gel) PMA. 1 H NMR (270 MHz, CDCl 3) 67171 (dd, 1, J = 22.52 Hz, 18/13 Hz) 6.89 (s, 1) 6.83 (s, 1) ; 89 (dd, 1, J = 26.37 Hz, 17158 Hz) 3.79 (s, 2) 3173 (s (br), 6) 3.36 (dd, 2, J = 18168 Hz, 5.5 Hz) 2.50 (m, 2) 2130 (s, 3) 2129 (s, 3) 1170 (m, 5) 1.45 (m, 1) 1110-0.80 (m, 5) D.4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] - rnet-LIY-1 c) -ketophosphonate. In Part C (0.97 g, 2.31 mmol), THF (10 mL) was stirred under an argon atmosphere and cooled to 0 DEG C. Solid NaBH 4 (0.87 g, 2.31 mmol) was added to the THF solution and then added dropwise. 2 ml CH 3 OH; this resulted in gas evolution. After stirring for 50 minutes at 0 DEG C., the reaction was quenched with 2 ml of acetone and then CC-4 silica gel was added. The reaction mixture was warmed to room temperature. 214 and filtered through sintered glass. The solvent was removed from the filtrate and a yellow oil was purified by flash chromatography eluting with EtOAc. The title alcohol is obtained as a clear oil (0.65 g, 65%).

TLC Rf = 0.29 (50% acetone / hexane, silica gel), PMA.

Mp "80-83 ° C.

IR (KBr) 3282 (br), 2923, 2918, 2848, 1743, 1614, 1450, 1442, 1080, 1045 cm-1. 1 H NMR (270 MHz, CDCl 3) 67168 (m, 1) 6188 (s, 1) 6182 (s, 1) 189 (m, 1) 450 (m, 1) 4.00 (m, 1) 3.776.3174 (2 d; 3, J = 11.0 Hz) 3.69 & 3168 (2 SI3) 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) 1168 (m, 5) 1.45 (m, 1) 1.30 to 0.80 (m, 5) Mass spectrum (CI) m / e 423 (M + H) ± E. 4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] - hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt The diester in Part D (0.565 g, 1.33 mmol) was stirred with 14 mL of dioxane until all solids had Ott in solution. 1.0 N 2 • •• • • ••• • • • • •• • •• • 0 • • • • • • • • • ••• • • 5 * 0 • • • LiOH (4.0 mL) was added and the solution was heated to 50 ° C. After 30 minutes, the reaction mixture became cloudy. After 2 hours at 50 DEG C., the reaction mixture was cooled to room temperature and the solvent was deposited on a rotary evaporator and a white solid. The crude product was purified on a 3.0 x 15 cm column of HP-20 resin and eluted first with 100 ml of 11 and then with 75% MeOH / H 2 O. Lyophilization of product fraction is a gay title compound as a white lyophilate (0.524 g, 98%).

TLC Rf = 0.41 (7: 2: 1 nPrOH / NH 4 OH / H 2 O, silica gel) PMA.

IR (KBr) 3700-3100 (br), 2921, 2851, 1591, 1446, -1 1222, 1195, 1161, 1051 cm. 1 H NMR (400 MHz, D 2 O) 67.25 (dd, 1.3 = 18.68 Hz) 6.98 (s, 1) 6.94 (s, 1) 6.00 (dd, 1.3 = 17.95 Hz) 4.33 (m, 1) 2.53 (dd, 1, J = 15.0 Hz, 4.4 Hz) 2.49 (d, 2, 3 = 710 Hz) 2.36 (dd, 1.3 = 15.0 Hz, 8.43 Hz) 2.27 (s, 3) 2.25 (s, 3) 1.89 (dd, 2, J = 1413 Hz, 6.6 Hz) 1.60 (m, 5) 1.45 (m, 1) 1.13 (m, 3) 0.95 (m, 2) Mass spectrum (FAB) m / e 407 (M + H) +, 347 (M4-2 Li + + 211). Anaiys. Calculated for C202905PLi2 ° 0.38 1120: C 61.03; H 7.45, P 7.49 Found: C 61.03; H 7.63; P 7.66 216 Example 56 (S) -4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl / hydroxy phosphinyl / -3-hydroxybutanoic acid, dilitium salt A.4 - /// 2- (cyclohexylmethyl) -4,6-dimethylphenyl / ethyl / methoxy- phosphinyl / -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / butanoic acid, methyl ester Argon was bubbled through 45 ml of methanol solution of the acetylenic phosphinate in Example 54, Part F (1.33 g, 2.02 mmol) for 10 minutes. To this methanol solution in a Parr flask was added 10% Pd / C (0.34 g). Hydrogenation in a Parr apparatus at 40 psi 20 hours gay 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 to give 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 (CHCl 3) 3600-3200 (br), 3003, 2925, 2853; 1731, 1448, 1440, 1247, 1233, 1179, 1044 cm-1. 1 H NMR (270 MHz, CDCl 3) • ••• • •••• • • • • 0 •• S • • •• 10 • ••• ••• • • • ••• • • • • 6.83 (s, 1) 6.78 (s, 1) 4.50 (m, 1) 3.80 & 3.77 (2 d, 3, J = 613 Hz) 3.72 & 3171 (2s, 3) 3.38 (m, 1) 2.87 (m, 1) 2.60 (m, 2) 2.45 (d, 2, J = 6.9 Hz) 2.29 & 2128 (2s, 3) 2.25 (s, 3) 2.00 (m, 4) 1.70 (m, 6) 1.45 (m, 1) 1.30-0.90 (m, 6) Mass spectrum (EI) m / e 424 (M) 217 B. (S) -4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] - methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester A solution of the silyl ether in Part A (1.2 g, 1.8 mmol) in THF (20 mL) was stirred under an argon atmosphere at room temperature. To this solution was added, in turn, 0.41 ml of glacial acetic acid and n-Bu4NF (5.0 ml of a 1.1 M THF solution, 5.44 mmol) which was added dropwise within 5 minutes. After stirring for 23 hours at room temperature, the reaction was quenched with 50 ml of ice water and the reaction mixture was stirred vigorously. THF was removed vacuum and the resulting material was diluted with water and three gels were extracted with EtOAc. The EtOAc extract was washed twice with matt NaHCO3 solution and once • • • • • • a • • • • • • • •• • • I, • • • • • • • • • • • • • • • • • • • • • • • • With brine and then dried over Na 2 SO 4. Filtration and removal of gay solvent a clear oil (1.3 g).

The product 4 was purified by flash chromatography with 100% EtOAc and gay the title alcohol (0.55 g, 72%) as a clear oil.

Rf = 0 „22 (Et0Ac, silica gel) PMA IR (CHCl 3) 2999, 2950, 2929, 2856, 1734, 1244, 1195,1183,1112,1105,1065,1043 cm-1.

1 H NMR (270 MHz, CDCl 3) 6.7.6 (m, 4) 7.28 (m, 6) 6.81 (s, 1) 6.76 (s, 1) 4.51 (m, 1) 3.62 & 3.60 (2 di3, J = 5.3 Hz) 3.49 & 3146 (2Si3) 2.97 (m, 1) 2.6 (m, 2) 2.35 & 2.33 (2 d, 2, J = 6.9 Hz) 2, (2s, 3) 2.16 (2s, 3) 1.84 (m, 1) 1.68 (m, 6) • 218 1.5 (m, 148 (m, 1r (m, 1100 & 0199 (2S, 9) 0.91 (m, 2) Mass spectrum (CI) m / e 663 (M + H) 4- C. (S) -4 - // 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] - hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt The diester in Part B (0.552 g, 1.3 mmol) was stirred in 14 mL of dioxane at room temperature. To this solution was added 1.0 N LiOH (3.9 mL, 3.9 mmol) and then the reaction mixture was heated to 50 ° C. After stirring for 30 minutes, a cake-like formation was formed which was solubilized by adding 5 mL of H 2 O. After 2 hours and 15 minutes at 5 ° C, the reaction mixture was cooled to room temperature and the volatiles were removed in vacuo to leave a white solid. Product ••• • • • •• • IS • IN •• •• 9 • • •• S • ••••• • • ••• $ • ••• • •• 00 • Idea • The mixture was purified on a 3.0 x 30 cm HP-20 column which was eluted first with 100 ml of H 2 O and then with 1: 1 C 11 3 OH / H 2 O. Product- fractions were lyophilized and gay 0.482 g, 92% yield, white lyophilate.

TLC Rf = O / 36 (7: 2: 1 n-PrOH / NH 4 OH / H 2 O, silica gel) .

PMA.

IR (KBr) 3700-3100 (br), 2923, 2852, 1588, 1446, -1 1410,1159,1132,1048 cm.

1 H NMR (400 MHz, D 2 O) 66.93 (s, 1) 6.91 (s, 1) 4.34 (m, 1) 2/80 (m, 2) 2, (dd, 1, J = 14/7 Hz, 4.4 Hz) 2.48 (d, 2, J = 5.12 Hz) 2.38 (dd, 1, J = 15.0 Hz, 6.6 Hz) 2.29 (s, 3) 2.26 (s, 3) 11: ••:., 1 ••: ••••• ••• •• ••• •: •• • .7. •• •••• • •: •••• 219 lb q km, 2) 1.65 (m, 7) 1748 (m, 1) 1.15 (m, 3) 1.00 (m, 2) Mass spectrum (FAB) m / e 397 (M + H-21, +) +, 409 (M + H) 4 * Analysis. Calculated for C20310PLi2 • 0.76 H2O: C 59.76, H 7.77; P 7.34 Found: C 59.76; U 7.91; P 7.53 Example 57 4 - //// 4'-Fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / oxy / methyl / hydroxyphosphinyl / -3-hydroxybutanes ra, dilitium salt 4'-Fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-carboxaldehyde HA Reference to Merck U.S. Patent No. 4,375,475 p. 37 and 38.

The title compound was prepared as described in Example 1, Parts A to C. 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-methanol The aldehyde in Part A (1.03 g, 4.26 mmol) was stirred in 30 mL of dry CH 2 Cl 2 under an argon atmosphere. 20 ml of CH 2 Cl 2 solution of m-Cl-perbenzoic acid (1.06 g, 5.11 mmol) was added dropwise within 15 minutes to the aldehyde solution at room temperature. After stirring for 58 hours at room temperature, the reaction mixture was evaporated to dryness on a rotary evaporator and the resulting yellow solid was dissolved in THF and treated with 6.4 ml of 2 N KOH. This mixture was stirred at room temperature for 5.5 hours, after which the THF was removed from the reaction. The resulting residue was diluted with H 2 O and the aqueous solution was extracted three times with Et 2 O which was then dried over MgSO 4. The crude yellow oil obtained after filtration 2 and eluent, purified by flash chromatography eluting with 5% Et 2 O / hexane. The title phenol is obtained as a white solid (0.843 g, 100%).

TLC Rf = 0.37 (10% Etphexan, silica gel) PM) '. Melting point 83 - 860 ° C.

IR (KBr) 3512, 3500 (br), 2950, 1504, 1482, 1238, -1 1231, 1215 cm. 1 H NMR (270 MHz, CDCl 3) 67.20 (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 (3, 6) Mass spectrum (CI) m / e 231 (M4-1) 4 C.///4'-fluoro-3,3',5-trimethyl1/1,1'- biphenyl/-2-yl/oxyi- methyl / phosphonic acid, diethyl ester A suspension of pentane-washed Nall (0.30 g, 80% oil dispersion, 10.3 mmol) in 15 ml of dry DMF under an argon atmosphere was cooled in an ice bath. 10 ml of DMF solution of the phenol in Part B (2.36 g, 10.3 mmol) was added to the Nail suspension over 15 minutes; gas evolution was observed. When the addition was complete, the reaction mixture was warmed to room temperature and stirred for 35 minutes. At room temperature, 11 ml of DMF solution of the diethyltosyloxymethylphosphonate (3.31 g, 10.26 mmol, for preparation Cilining see A. Holy, I. Rosenberg, Collection Czechoslovak Chem. Commun., Vol. 47, 1982) was added dropwise over 10 minutes. After 22 hours at room temperature, the reaction was quenched with a slow solution of NH 4 Cl in water and the DMF was removed in vacuo. The resulting solid was dissolved in EtOAc and 1120 and the aqueous layer was washed twice with EtOAc. The combined EtOAc extracts were washed with nil t-- • ••• • •• 1114 • 1 • •• 0 * • • it • • • • • • • •• 0 • •• • • •• se • • • • * • •••• • • • • ••• • ■ ••• • •• 221 • 10 •• • •••• • O• 6 •• • • • • • aa • • • • ••• • •••••• • ••• • • ••• 11 •IN 41 solution of NaHCO3 in water and brine and then dried over MgSO4. Filtration and removal of solvent 4.3 g of the crude title ether compound, which was purified by flash chromatography eluting with 70% EtOAc / hexane. The title tern (3.2 g, 82%) is 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 1 H NMR (270 MHz, CDCl 3) 67.33 (m, 2) 7.01 (t, 1, J = 10.0 Hz) 6.96 (s, 1) 6.91 (s, 1) 407 (m, 4) 3.69 (d, 2, J = 913 Hz) 2/34 (s, 3) 2131 (d, 3, J = 1/7 Hz) 2.29 (s, 3) 1/31 (t, 6, J = 710 Hz) Mass spectrum (CI) m / e 381 (M + H) +, 242 (m + -C 4 HPO 3) + D.///4'- fluoro-3,3,5'- trimethyl1/1,1'- biphenyl/-2-yl/oxyi- metY1112112alaL The diester in Part C (3.21 g, 8.45 mmol) in 40 mL of dioxane was stirred with 12.7 mL of 1 N LiOH (12.67 mmol) at 70 ° C. After 3 hours at 700 ° C, the reaction mixture was cooled to room temperature and the dioxane was evaporated in vacuo. The aqueous solution was diluted with 1120 and cooled in an ice bath, then acidified to pH about 1 with 6 N HCl and leaving a milky white solution. This solution was then extracted three times with EtOAc; The EtOAc extract was dried over M004 and filtered to give 3.12 g of a clear gum. 0:04, • ..s. Oeo. • 444, e 222 TLC Re0.20 (9 / 0.5 / 0.5 CH 2 Cl 2 / AcOH / MeOH, silica gel) PMA 1 H NMR (270 MHz, CDCl 3) 610.26 (s, 1) 7.35 (2) 6.96 (m, 3) 4.05 (dq, 2.3 = 7.14 Hz, 14.8 Hz) 3.63 (d, 2, J = 9.34 Hz) 2.31 (s, 3) 2.29 (s, 3) 2.28 (d, 3.3 = 2.2 Hz) 1.28 (t, 3.3 = 7.14 Hz) E.4- / ethoxy /// 41-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / oxy / methyl / phosphinyl / -3-oxobutanoic acid, methyl ester Phosphonic acid in Part D (2.96 g, 8.42 mmol) 75 ml dry CH 2 Cl 2 under argon atmosphere was stirred at room temperature with (C 2 H) 2 Si (CH 3) 3 (2.44 g, 16.84 mmol). After stirring for one hour for 10 minutes, CH 2 Cl 2 was removed in vacuo and the resulting oil was azeotroped with benzene once and then placed under high vacuum for 15 minutes. This oil was dissolved in 75 mL of dry CH 2 Cl 2 and cooled to 0 ° C under an argon atmosphere. Three drops of dry DMP were added to the cooled solution and then oxalyl chloride (1.18 g, 9.26 mmol) was added dropwise. The reaction mixture was stirred at 0 DEG C. for 20 minutes, warmed to room temperature and stirred for a further hour. The reaction solvent was removed in vacuo and the reddish brown oil phosphonium chloride was azeotrophically distilled ". whipped with benzene twice and then placed under Mgt • • • • vacuum and hour. 0 • • The dianion of methyl acetoacetate was prepared as follows • • • • described in Example 55, Part C / methyl acetoacetate (1.27g, • • • • 10.95 mmol), NaH (0.350 g oil dispersion, 12.0 mmol), n- • • 000 butyllithium (4.0 ml 2.5 M loading in hexane, 10.07 mmo), • • • • ••• • • THF (35 ml) /. • • • • • • • • 0 • • • • ;; •• •% mt .. SA ,. • 4.0 223 The phosphonochloridate prepared above in 10 ml of THF, cooled to -78 ° C, was added dropwise within 20 minutes to the dianion solution, then at -78 ° C. After stirring at -78 ° C for 40 minutes, the reaction was stopped at -78 ° C. C with a saturated solution of NH 4 Cl in water and the reaction mixture was allowed to warm to room temperature. The THF was precipitated in vacuo and the resulting residue was dissolved in EtOAc and H 2 O. The aqueous layer was extracted twice with EtOAc and all the EtOAc solutions were combined and washed once with saturated NaliCO3-18 solution and one Ong with brine and then dried over Na2SO4. Crude title phosphinate was obtained as an orange oil (4.0 g) which was purified by flash chromatography eluting with 75% EtOAc / hexane. The title phosphinate (1.4 g, 42%) is obtained as a yellow oil.

TLC Rf = 0.25 (75% EtOAc / hexane, silica gel) PMA.

IR (CHCl 3) 3004, 2954, 2925, 1744, 1718, 1643, 1541, 1503, 1472, 1449, 1438, 1425, 1236, 1037 -1 cm. 1 H NMR (270 MHz, CDCl 3) 7.30 (m, 2) 6.95 (m, 3) 4.05 & 3.90 (2 in2) 3.75 (m, 2) 3.73 & 3.66 (2 s, 3) 3.55 (m, 1) 3.25 (m, 1) 2.33 & 2.29 (2s, (br), 9) 1.28 & 112 (2 h, 3, J = 7.1 Hz) Mspectrum (CI) m / e 451 (M + H) + F.4 - //// 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / oxy / - methyl ester • • • • • 0 • • • ••• • • • • • 0 • A solution of the ketone in Part E (1.39 g, 3.09 mmol) in THF (15 mL) under an argon atmosphere was cooled to 0 ° C. To the cooled solution was added NaBH 4 (0.12 g, 3.09 mmol) and then slowly and dropwise C113011 (2.8 ml). After one hour at 0 ° C, discontinue 4. ••• • ID * 4. / • S • •: •• 224 the reaction with acetone and then 1.4 g of CC-4 silica gel and then the reaction mixture was warmed to room temperature. The reaction mixture was filtered and the filtrate was evaporated on a rotary evaporator and a yellow oil. The oil was flash chromatographed eluting with 90% EtOAc / hexane and fractions containing product were combined and the solvent was added in vacuo. The resulting yellow oil was crystallized from Et 2 O / hexane and the resulting crystals were triturated with Et 2 O / hexane and gay white crystals (0.320 g) of the title alcohol.

TLC R = 0.38 (90% EtOAc / hexane, silica gel) PMA.

Mp 116-119 ° C.

IR (K8r) 3288 (br), 3000, 2950, 2920, 1735, 1503, - 1473,1440,1311,1232,1195 cm1. 1 H NMR (270 MHz, CDCl 3) Δ 7.28 (m, 2) 7.0 (t, 1, J = 6/0 Hz) 6.98 (s, 1) 6.90 (s, 1) 4.42 (m, 4.05643.8 (m, 3.7 (d, 2, 3 = 6.0 Hz) 3.70 (s, 3) 2.5 (m, 2) 2.32 (s, 6) 2, (s, 3) 2.00 (m, 2) • •• • • 1, (t, 3, J = 7/0 Hz) ••• Mass spectrum (CT) m / e 453 (M4-H) 4-, 435 (M-1120) + 1 • • • 1 • • • • • • 41, • • • • ••• • • 11 • 11 • 1 • • I •• • * • 0 6 G.4 - //// 4'-Fluoro-3,3 ', 5-trimethyl / 1,11-diphenyl / -2-yl / oxy / - methyl / hiciroxyphosphiltyllroxybutariaLELdilitium salt At room temperature, 1 N LiOH (2.0 mL) was added to 13 mL of dioxane solution of the diester in Part F (0.293 g, 0.65 mmol). The reaction mixture was heated to 50 ° C and stirred for one hour 2 minutes and then cooled to room temperature. The reaction mixture was evaporated to dryness on a rotary passenger and 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 and eluted first with 100 ml of H 2 O and then with 50% CH 3 OH / H 2 O. The pure title dilitium salt is obtained as a white lyophilate (0.295 g, 88%).

TLC R1 = 0.38 (7: 2: 1 n-PrOWNH4OH / H2O, silica gel) PMA.

IR (KBr) 3400 (br), 3021, 3011, 2981, 2956, 2924, 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175, 1087 cm-1. 1 H NMR (270 MHz, D 2 O) 67.20 (m, 2) 7.07 (d, 1. J = 9.9 Hz) 7.03 (s, 1) 6.86 (s, 1) 4.03 (m, 1) 3740 (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 spectrum (FAB) m / e 423 (M + H) + Analysis. Calculated for C112206FPL12 * 0.91120: ••• C 54.67; H 5.48; F 4.32, P 7.0 • ••. • Found: C 54.37, H 5.03; F 4.31, P 7.5 •• • •O • • • 1 • • • Example1 58 •• • • • • ••• • 4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-ylimethyl / - h hydroxyphosphine 1 / -2-hydroxybutanes ra, dilitium salt ••• • • ••• • • 0 •• • ••• • • • • A.4'-Fluoro-3,31,5-trimethyl / 1,1-biphenyl-14-methanol • ••• •••• * ••• - • • • ■ •• - ••• 226 To 9 mL of NaBH 4 solution (0.12 g, 3.18 mmol) in absolute ethanol was added the aldehyde of Example 57, Part A (0.70 g, 2.89 mmol) as an Et 2 O-EtOH (4.5 m1 / 3.0 m1) solution. This reaction mixture was stirred at room temperature for 2 hours and then quenched with matt NH 4 Cl solution. The resulting solid precipitate was removed by filtration. The filtrate was evaporated to dryness on a rotary evaporator and the resulting solid was dissolved in Et 2 O and 1120. The aqueous layer was washed twice with Et 2 O and the combined Et 2 O solutions were dried over MgSO 4.

After filtration and removal of solvent, 0.70 g of a white solid was obtained. The solid was purified by flash chromatography and el, eluting with 33% Et 2 O / hexane and gay 0.675 g (100% yield) of the title alcohol.

TLC 0/11 (15% Et 2 O / hexane, silica gel) PM / h.

M.p. 101-102 ° C.

IR (101) 3351, 3293, 3267, 3260, 3024, 3016, 2980, 2939, 2921, 1605, 1601, 1502, 1451, 1355, 1243, -1 1236, 1228, 1189, 1118, 999 cm.

1 H NMR (270 MHz, CDCl 3) 67/15 (m, 2) 7/0 ?, (m, 2) 6190 (s, 1) 4.55 (d, 2, J = 610 Hz) 2/48 (s, 3) 233 (s, 6) Mass spectrum ACI) m / e 244 (e), 227 (Mt-OH) B.//4'-Fluoro-3,3',5-trimethyl1/1,1*-biphenyl/-2-yl/methyl/- phosphonic acid, diethyl ester 50 ml of CH 2 Cl 2 solution of the alcohol in Part A (1.94 g, 7.95 mmol) under an argon atmosphere was cooled to 0 ° C. To this cooled solution was added Et 3 N (0.965 g, 9.54 mmol) and then dropwise MsCl (1 .00 g, 8.75 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and then warmed to room temperature and ••• 0 • II • • • • II • e 'Fp • • ••• •• •• •• • •••• ••••• •• ••• * •••• • 227 stirred over the flat. The reaction mixture was quenched with fed NaHCO 3 solution and stirred vigorously. The organic layer was washed with matt NaHCO 3 solution and then dried over MgSO 4. Filtration and removal of solvent 2.1 g of 2- (chloromethyl) -4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / in the form of a clay oil.

TLC Rf = 068 (50% Et 2 O / hexane, silica gel) PMA. 1 H NMR (270 MHz, CDCl 3) 67.22 (M, 2) 7.03 (m, 2) 6190 (s, 1) 4150 (s, 2) 4) 48 (s, 3) 2.33 (s, 6) Without further purification, the above chloride (2.1 g) was stirred with P (CO 2 H) 3 (30 mL) at 1 ° C under an argon atmosphere for 3 hours. The reaction mixture was cooled to room temperature and the excess P (OC 2 H 5) 3 was removed by distillation. The arena product was purified by flash chromatography eluting with 70% EtOAc / hexane. The title phosphonate (2.40 g, 83%) is obtained as a clear oil.

TLC Rf = 0137 (70% EtOAc / hexane, silica gel) PMA.

IR (CHCl 3) 2992, 2928, 2909, 1501, 1474, 1455, ••• •• • , • • . •. ° • • ,., • , ". . „• . • 1443, -1 cm. 1 H NMR δ 1392, 1245, 1239, 1119, 1053, 10929,970,963 (270 MHz, CDCl 3) 71 (m, 2) 7100 (m, 2) 6.83 (s, 1) 3/83 (m, 4) 3.22 (d, 2, J = 22.52 Hz) 2.47 (s, 3) 2.29 (s, 6) 1.16 (t, 6, J = 7.14 Hz) IN•• • • 0 ••• : ••• :.:, • *. : •• :: lo • ': • : •••• :: .. 0 * ': ••• • ••• • • •• ••• • • • • • • • * • • • • • • 66 •••• • ••• •• • • •••• 228 Mass spectrum (CI) m / e 365 (M-1-11) + C.//4'-fluorine-3,3',5-trimethyl1/1,11-biphenyl/-2-yl/methyl/- phosphonic acid, monoethyl ester The phosphonate diester in Part 13 (2.40 g, 6.59 m-lol) was rearranged in 30 ml of aioxane at room temperature. To this dioxane solution was added 1 N LiOH (9.9 mL) and the reaction mixture was heated to reflux. An additional 1 N LiOH (9.9 mL) was added both after 18 hours and after 44 hours. After 55 hours of refluxing, the reaction mixture was cooled to room temperature and the dioxane was deposited on the rotary evaporator. The resulting aqueous solution was diluted with H 2 O and extracted twice with Et 2 O to remove any residual diester. The aqueous layer was then cooled in an ice bath and acidified to pH about 1 with 6 N HCl. The milk-like white solution was extracted three times with EtOAc, the EtOAc extract was dried over MgSO 4 and filtered and the solvent was removed and gay 1.89 g, 85% yield of a clear oil.

TLC Rf = .0.26 (9 / 0.5 / 0.5, CH 2 Cl 2 / MeOH / AcOH, silica gel) prIT1- • ••• •••• • •• • • • •• •• • 9 •• •• • •• • • • IR (CHCl 3) 3029, 3023, 3005, 2983, 2925, 1710, 1605,1500,1234,1042,988 cm-1. 1 H NMR (270 MHz, CDCl 3) 611.07 (s, 1) 7.0 (m, 2) 6.9 (m, 2) 6.80 (s, 1) 3.71 (dq, 2, J = 7/15 Hz, 14.83 Hz) 3.13 (d, 2, J = 23r0) 2.38 (s, 3) 2.27 (s, 6) 1.13 (t, 3, J = 7 / 2Hz). mass spectrum (CI) m / e 337 (Mi./1) 4 ' ••• • • "• • ••• • • ••• : ••• • ••• : • ••• 000 • • : •• • • ••: •• •• II • . * • ••••• • • • ell •••• 00 ••• 1, C 1 IN • 111.1. 229 D.4- / ethoxy // 4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2- yl / methyl / phosphinyl / -3-oxobutanoic acid, methyl ester 50 ml of CH 2 Cl 2 solution of the half acid in Part C (1.85 g, 5.50 mmol) under an argon atmosphere was stirred with (C 2 H) 2 NSI (CH 3) 3 at room temperature for one hour and 15 minutes. CH 2 Cl 2 was removed from the reaction mixture and the resulting yellow oil was azeotroped with benzene once and placed under high vacuum for 20 minutes. This oil under an argon atmosphere was dissolved in 50 mL of dry Cl 2 Cl 2 and cooled to 0 ° C. Two drops of dry DMF were added to the cooled solution and then oxalyl chloride (0.768 g, 6.06 mmol) was added dropwise; gas evolution was observed. The reaction mixture was stirred at 0 DEG C. for 20 minutes, warmed to room temperature and stirred for a further hour and 40 minutes; the reaction mixture Lick a dark burgundy color. CH 2 Cl 2 was removed from the reaction mixture and the resulting oil was azeotroped twice with dry benzene and then placed under high vacuum for one hour.

The dianion of methyl acetoacetate was prepared as described in Example 57, Part E / methyl acetoacetate (0.830 g, 7.16 mmol); NaH (0.230 g oil dispersion, 7.88 mmol); n-BuLi (2.64 mL of 2.5 M solution in hexane, 6.59 mmol); 20 ml THF /. The above phosphone chloride in 10 ml of dry THF, cooled to -78 ° C, was added by cannulae for 20 minutes. to the dianion solution, cooled to -78 ° C ". For 40 minutes at -78 ° C, the reaction mixture was quenched at -78 ° C •••• With saturated NH 4 Cl solution and warmed to room temperature. • • • •lucky; the reaction mixture was diluted with H 2 O to dissolve • . • • solids and THF were deposited on the rotating • • •. . . ••• • • • anclaren. The resulting mixture was extracted three times with Et0Ac. The EtOAc extract was washed once with mhttat • • • • •• ••• • • II • "• O • •••• • ••••••• •• e 2 • 0 • • • • • • • • • •• • • • • • •• 6 * NaHCO 3, once with brine, was dried over MgSO 4 and filtered to give 2.6 g of crude orange oil after removal of solvent. The crude product was purified by flash chromatography eluting with 75% EtOAc / hexane. The ketone in Part D (0.43 g, 23%) is recovered as an orange foam.

TLC Rf = 0.32 (50% acetone / hexane, silica gel), PMA.

IR (KBr) 2952, 2925, 1739, 1718, 1654, 1529, 1503, 1472, 1234, 1206, 1166, 1119, 1035 cm.

1 H NMR (270 MHz, CDCl 3) 6.20-6.70 (aromatic H, 5) 4 / 00-370 (m, 2) 3.70 & 3.55 (2s, 3) 3.35 (m, 2) 3.35 (d, 2, 3 = 15 Hz) 2.92 (m, 1). 2.45 & 2135 (2 Si3) 2., 25 (s, 6) 1115 / A0.95 (2 h, 3, J = 7.0 Hz) MasSpect. (CI) m / e 435 (M + H) &lt; + &gt;. E.4- / ethoxy // 41-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] - methyl / phosphinyl / -3-hydroxybutanoic acid, methyl ester Solid NaBH 4 (0.035 g, 0.92 mmol) was added to 5 mL of THF solution of the ketone in Part D (0.40 g, 0.92 mmol) under an argon atmosphere. Methanol (0.80 mL) was added to the THF solution at room temperature. After one hour at room temperature, the reaction mixture was quenched with acetone and subsequent addition of 0.4 g of CC-4 silica gel. The reaction mixture was filtered and the solvent was removed. The reaction product still retains a certain amount of the ketone starting material; therefore, the above reaction product Anyo was subjected to reduction conditions identical to those described above; however, CO2 (gaseous) was bubbled through the solution before NaBH 4 was added. Processing as before gay 0.250 g of •• 0 1 ••. ••• ••••••• ., .. .rift. • .. : •••• loS •: • 5p • • •••• •• • 0 • II • ••• • •: •• • •• •• • • • 0 .. C. 231 a yellow oil, son was purified by flash chromatography eluting with EtOAc. Pure labeled alcohol is obtained in the form of a clear oil.

TLC R0.26 (50% acetone / hexane, silica gel) PMA. 1 H NMR (270 MHz, CDCl 3) 6.7,10 (m, 2) 7.00 (m, 2) 6.85 (s, 1) 4.28 & 4 „03 (2 m, 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) 1.63 (m, 2) 1.17 (t, 3, J = 6.6 Hz) F.4 - /// 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / methyl / - hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt The diester in Part E (0.110 g, 0.252 mmol) in 1 dry CH 2 Cl 2 (5.5 mL) under an argon atmosphere was cooled to 0 ° C and treated with collidine (0.046 g, 0.38 mmol) and then continued dropwise with trimethylsilyl iodide (TMSI) ( 0.182 g, 0.88 mmoT). The reaction mixture was stirred at 0 DEG C. for 2 hours and then heated to room temperature. After 24 hours, an additional amount of bidide collidine (0.023 g) and TMSI (0.091 g) were added. After stirring for 48 hours at room temperature, CH 2 Cl 2 was removed and 6 ml of dioxane was added to the oil and then 1.7 ml of 1 N LiOH. This mixture was boiled under Aterflode for 16 hours and cooled to room temperature and the dioxane was removed to give an orange gum. The rubber was dissolved in H 2 O and filtered through sintered glass to remove a solid. The filtrate was lyophilized to give an off-white lyophilate, which was purified in a 1.5 cm x 15 cm column of HP-20. •••! ... * • i is ": • 232 The column was eluted first with 150 ml of 1120 and then with 50% Me0H / H2O. Product fractions were lyophilized and gay titles the compound in the form of a white lyophilate (88 mg, 80%).

TLC Rf = 0.36 (7: 2: 1 n-PrOH / NH 4 OH / H 2 O, silica), PMA.

IR (KBr) 3700-3100 (br), 2923, 1591, 1501, 1234, -1 1147 cm. 1 H NMR (270 MHz, D 2 O) to 7.20-7.00 (m, 4) 6/82 (s, 1) 3.76 (m, 1) 3.11 (m, 2) 2.35 (s, 3) 2722 (s, 3) 2721 (s, 3) 2.05 (m, 2) 1.16 (dd, 2, ..1 = 12132 Hz, 6E45 Hz) ilasspect. (FAB) m / e 407 (M + H) +.

Analysis. Calculated for C. 10H22M5PLi2. 0.80 1120: 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 - /// 1- (4-fluorophenyl) -3-methyl-2-naphthalenyl / ethynyl] -hysl = phosphinyl] • • A. 1-Methoxy-2-naphthalene-carboxylic acid • •• Male reference: J. Organomet. Chem., 20 (1969) p. 251 - 252. n-Buld (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 minutes) with partitioned tetramethylethylenediamine (TMEDA) (208.6 mmol, 24.24 g, 31.48 mL). The • AThAllan slurry is stirred • • • • • • t 1. • • • • , •• • • •• . ; •••• • IN •• •••• • •• ••• • •: •• 44 233 • • • • •• • • • • • • • • • • •• • • ••• • • ••• • I • • • • • •• 0 • • • • at 30 DEG 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 dry cyclohexane. The resulting light red homogeneous reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 DEG C. and added portionwise over 30 minutes by means of needles to a -78 DEG C. solution of dry Et 2 O (250 mL) fed with CO 2 (gaseous) CO 2 pellets sublimed by drying tubes containing 611 SiO -78 ° C). The resulting white slurry was heated to about 0 DEG C. for minutes and then treated with 450 ml of 5% HCl (aqueous). The Et 2 O layer was separated and the aqueous layer was extracted three times with Et 2 O. The organic extracts were combined and extracted with 3 x 150 mL of saturated NaHCO 3 (aqueous). The aqueous layer was filtered through a sintered glass funnel to remove insoluble matter and the filtrate was cooled to 0 DEG C. and slowly acidified with concentrated HCl to pH = 1. The resulting precipitate was filtered, azeotroped with 2 x 150 ml of toluene and dried under high vacuum at 0 DEG C. 5 hours and gay 32.52 g (0.161 mol, 77% yield) of the 1-methoxy-2-naphthalenecarboxylic acid as an off-white powder, m.p. 118 DEG-121 DEG.

TLC: silica gel, Rf = 0.35 94: 5: 1 / CH 2 Cl 2: MeOH: CH 3 CO 2 H 1 1 H NMR: (270 MHz, CDCl 3) or Variable 13 C NMR: (67.8 MHz, CDCl 3) or Variable Mass Spectrum: CI m / e 203+ (M + H) + IR: KBr variable B.-1,1-12-ethylethyl) -1-methoxy-2-naphthalenecarboxamide The 1-methoxy-2-naphthalenecarboxylic acid (155.22 mmol, 31.4 g) was stirred under argon in 155 mL of dry CH 2 Cl 2. The solution was then treated with SOCl 2 (310.44 mmol, 36.94 g, 22.65 mL). The reaction mixture was stirred at room temperature for 45 minutes and stirred • •• • "• • • • • • •• •: •. • • 234 was then heated to reflux in a 50 ° C oil bath for 45 minutes. The reaction mixture was cooled to room temperature and treated with an additional amount (18.47 g, 11.32 ml) of thionyl chloride and heated Snyo to reflux for 45 minutes. The reaction mixture was cooled to room temperature, the excess SOCl 2 and CH 2 Cl 2 were removed, evaporated by evaporation on a rotary evaporator at 0 ° C (vented to argon atmosphere) and the resulting mustard yellow solid was dissolved under argon in 155 ml of dry CH 2 Cl 2. This solution was cannulated into an addition funnel and added dropwise (40 minutes) to a solution of 2-amino-2-methylpropanol (310.44 mmol, 27.67 g) in 155 mL of dry CH 2 Cl 2 which had been stirred under argon at 0 ° C. ° C. The resulting reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was then filtered, the precipitate was washed with CH 2 Cl 2 and the filtrate was evaporated in vacuo. The residue was redissolved in 350 mL of EtOAc and washed with 1 x 250 mL H 2 O, 1 x 250 mL 5% HCl, 1 x 250 mL 5% NaOH and 1 x 250 mL brine. Each of the aqueous extracts was back-extracted once with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated in vacuo to give an orange oil, which was azeotroped with 250 ml of toluene and pumped under Mgt vacuum at 50 ° C for 8 hours. • •• • • 11 •• • • • • • • • • • • • • • • • • in• • • • • • • • • • II to give 38.2 g (139.76 mmol, 90% yield) of the crude naphthalamide in the form of a light yellow solid.

TLC: silica gel, Rf = 0.65 100% EtOAc 1 H NMR (270 MHz, CDCl 3) 8.19 (s, br. 1H) 8.14 (m, 1 H) 8.03 (d, 1H, J = 8.7 Hz) 7.83 (m. 1H) 7.66 (d, 111, J -. = 8.7Hz) 7.5 (m, 2H) 4.00 (s. 3H) 3.74 (S, 211) 147 (s, 611) Hasspektr.CI m / e 274 (M141) 4.

IR: (CHCl 3 solution) 3365,3063,3024,3005,2971, 1597,1540,1456,1446,1387, 1256,1238,1223,1210,1199, -1 1079,981,833 cm. 2 2938, 1371, 1183, 2873, 1344, 1168, 1641, 1291, 1145, C,4,5-dihydro-2- (1-methoxy-2-naphthalenyl) -4,4-dimethyl- oxazole The naphthalamide in Part B (139 mmol, 38.2 g) was stirred under argon and cooled to 0 ° C while thionyl chloride (0.556 mol, 66.15 g, 40.56 ml) was added dropwise (15 minutes). The resulting dark brown oil was stirred at room temperature for 45 minutes. Dry Et70 (500 mL) was added and the reaction mixture was stirred mechanically for 2.5 hours. The resulting yellow crystalline precipitate was filtered, washed with Et 2 O and then suspended in 250 mL of Et 2 O. The suspension was cooled to 0 ° C and basified with about 200 ml of -percent NaOH. The aqueous layer was extracted three times with Et 2 O and once with EtOAc. The organic extracts were combined, washed once with brine, concentrated, dried over MgSO 4 and filtered. The filtrate was azeotroped with toluene in vacuo and the residue was pumped under high vacuum at 50 DEG C. for 8 hours to give 32.10 g (0.126 mol, 90% yield) of the title oxazoline as a golden yellow powder. • • •• • • • • • • • • • ••• • •• • • ••• • • • • •• 0 • • • • • • • • • • • 0 • TLC: silica gel, Re-0.3750% EtOAC 1 H NMR: (270 MHz, CDCl 3) 8 / (L, 1h) 7.84 (d, 111, J = 8.7 Hz) 7.84 (m, 111) 7.60 (d, 111, J = 8.7 Hz) 7.54 (m, 211) 4.19 (s, 211) ••: • •• •••• • ••• ••• • •••• 4. 236 404 (s, 311) 1.46 (s, 611) Mass spectrum: CI m / e 256 (M + H) + IR: 2969, 2935, 2896, 1642, 1465, 1447, 1386, 1372, 1349, 1255, 1109, 1074, 991 cm (1.

D.2-11- (4-fluorophenyl) -2-naphthalenyl) [4,5-dihydro- The oxazoline in Part C (117.52 mmol, 30.0 g) was stirred under argon in 352.5 mL of dry THF. Clay solution was heated to ° C in an oil bath. The heating medium was removed and a 2 M solution of 4-fluorophenylmagnesium bromide in Et 2 O (Aldrich) (158.65 mmol, 79.33 ml) was added dropwise (30 minutes) at a rate sufficient to bring the Walla reaction temperature to about ° C. was completed, the reaction temperature was maintained at 0 DEG C. when the reaction mixture was stirred for 18 hours. The reaction mixture was cooled to 0 ° C and quenched with 200 mL of saturated NH 4 Cl (aq), diluted with 200 mL of H 2 O and 200 mL of EtOAc. The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, concentrated, dried over M00 4 and filtered. The filtrate was evaporated in vacuo to give 39 g of a dark golden yellow solid. The product was purified by flash chromatography (95 mm diameter column, 7 "Merck silica gel, 25% EtOAc / hexane as eluent, 2" / minute flow rate) and vial 30.42 g (95.25 mmol, 81% yield) of the title 4 -fluorophenyl substituted the naphthalene in the form of a light yellow solid, m.p. 94 DEG-960 DEG C. 3.38 g (10.58 mmol, 9%) slightly contaminated product.

TLC: kielgelRf = 014.5 50% EtOAc / hexaa 111 NMR: (270 MHz, CDCl 3) Δ 7.93-7.13 (aromatic, 10H) 3.77 (s, 211) 1.27 (s. 6H) Mass spectrum: C1 m / e 320 (M + H) • I • • • 1 • • • • • • 237 • • • 0 • • •• • • • IR: (KBr) 3060, 2966, 2927, 2884, 1667, 1603, 1508, 1462, 1383, 1354, 1335, 1293, 1219, 1185, 1160, -1 1119, 1083, 978, 842, 830 cm.

E.2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl)] - 4,5- dihydro-4,4-dimethyloxazole The 1-4-fluorophenyl-2-oxazoline naphthyl compound of Part D (87.67 mmol, 28 g) was stirred without argon in 585 mL of dry Et 2 O. This solution was cooled to-° C and treated dropwise (one hour) with n-BuLi (140.27 mmol, 56.1 mL of a 2.5 M solution in hexane). The reaction mixture was converted during this hour-long addition from a yellow homogeneous solution to a ground red / orange solution to an orange / green solution with a fanning. The reaction mixture was stirred at - ° C for an additional 2.5 hours and then treated with iodomethane (263.01 mmol, 37.33 g, 16.4 mL), added dropwise over 15 minutes. The resulting market burgundy solution was stirred at - ° 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 clear solution was quenched with 500 ml of ice-cold saline. The aqueous layer was extracted with four ginger with EtOAc. The organic extracts were combined, concentrated, dried over M004 and filtered through Florisil (300 ml glass sintered funnel 2/3 full). Florisilen was washed with CH 2 Cl 2. The filtrate was concentrated, azeotroped with toluene and evaporated in vacuo and pumped under high vacuum at 50 DEG C. for 3 hours to give 30.32 g ("90.94 mmol", 100% yield) of the title methylated naphthalene as a yellow solid. subs tans. ••• ••• • • • • • •• • • • • 238 TLC: silica gel Rf = 0.50 50% EtOAc / hexane 1 H NMR: (270 MHz, CDCl 3) 7.79 - 7.07 (aromatic, 9H) 3.80 (s, 211) 2754 (s, 3 H) 1., 13 (s, 61!) mass spectrum: CI m / e 334 (M + H) + IR: (CHCl 3 solution) 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513, 1497, 1461, 1299, 1280, 1235, 1190, 1158, 1041, 965, 841 cm-1.

F.2-11- (4-fluorophenyl) -3-methyl-2-naphthalenyl) / - 4,5- dihydro-3,4,4-trimethyloxazolium iodide The oxazoline in Part E (87.67 until, 29.23 g) was stirred under argon in 140.28 ml of 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 one hour 20 minutes ± in the absence of light. The iodomethane was removed by simple distillation. The nitromethane was removed by evaporation on a rotary evaporator and then subjected to pumping under high vacuum for 45 minutes. The resulting burgundy solid was mechanically stirred in 250 ml of dry Et 2 O for one hour. The red filtrate was decanted and the solid was triturated Anyo from Et 2 O as above. The resulting yellow solid was filtered and pumped under high vacuum for 4 hours (in French, of light) and the title oxazolinium iodide 44 g (92.63 "mmol, 100% yield) as a mustard yellow solid. The title compound was removed in the absence. of light Yid - ° C 18 hours and then used directly in the preparation of the compound of Part G.

TLC ':. silica gel Rf = 0.30 10% MeOH / CH 2 Cl 2. • ••• ••• • • • • • • •• • • • • • • •• • • •••• • ••• 0 •• • II • • • • • • • • ••• • • ••• • ••• 239 G.1- (4-fluorophenyl) -3-methyl naphthalenecarboxaldehyde The oxazolinium iodide in Part F (87.67 mmol, 41.67 g) was stirred under argon in 526 mL of dry THF and 210 mL of absolute EtOH (dried over 4 Å molecular sieves). This lasing / suspension was cooled to -o C and treated portionwise with NaBH 4 for one hour. When the addition was complete, the reaction was allowed to proceed at - ° C to - ° C for 2.5 hours. Then the solution was diluted with 210 ml of absolute EtOH and the reaction mixture was stirred to - ° C while 2 N 1-IC1 (438 ml, 876 mmol) was added dropwise over 45 minutes (added very slowly initially). When the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. Dilution with 500 ml H 2 O was then followed by water extraction with Et 2 O. The organic extracts were combined, concentrated, dried over MgSO 4, filtered, concentrated, azeotroped with toluene (2 x 120 mL) and evaporated in vacuo to give 12.9 g (48.81 mmol, 56% yield) of the title aldehyde in form of a light yellow solid.

TLC: silica gel Re0.66 50% EtOAc / hexane 1 H NMR: (270 MHz, CDCl 3) 610.0 (s, 1 H) 7.83-7.18 (aromatic, 9H) 2.81 (s. 3H) Mass Spectrum: Cl m / e 265 (M-441) 4.

IR: (CHCl 3 solution) 1685, 1512, 1422, 1237, 862 cm-1.

H.2- (2,2-dibromoethyl) -1- (4-fluorophenyl) - 3-methylnaphthalene The aldehyde in Part G (11.35 mmol, 3.0 g) was stirred under argon in 113.5 mL of dry CH 2 Cl 2. This solution was cooled to 0 ° C and 2 was then treated in one portion with triphenylphosphine (36.32 mmbi in 9.53 g). The reaction mixture was stirred at 0 ° C for 20 minutes and then treated dropwise (20 minutes) with a solution of carbon tetrabromide (18.16 mmol, 6.02 g) in 41 mL of dry CH 2 Cl 2. The resulting markt orange solution became markt bourgognePargad when it was stirred at 00 ° C for 1.25 hours. Sed-q1 was quenched the reaction mixture with 150 mL of matt NaHCO 3 (aqueous). The aqueous layer was extracted four times with CH 2 Cl 2. The organic extracts were combined, concentrated in vacuo, washed once with brine, dried over MgSO 4 and filtered. The filtrate was pre-absorbed on Merck silica gel (about 28 g) and then passed to a 50 mm diameter flash chromatography column containing 6 "Merck silica gel and eluted with 7% EtOAc-hexane as eluent, flow rate 2" / minute to give 4.23 g of the title dibromolefin in the form of a slightly contaminated light yellow solid. After recrystallization from hexane, 3.68 g (8.77 mmol, 77% yield) of the title dibromolefin are obtained as a white powdered solid, m.p. = 134.5 - 135.5.

TLC: silica gel Rf = 0160 20% EtOAc / hexane 1 H NMR: (270 MHz, CDCl 3) 6 7r79-7.11 (aromatic carbon finic 10H) 2.48 (s. 3H) Mass spectrum: CI m / e 419/421/423 (M + H) 4 " IR: (CHCl 3 reading). 3016, 1604, 1512, 1496, 1234, 1220, 1208, 1158, -1 886, 858 cm.

1,2-Ethynyl-1- (4-fluorophenyl) -3-methylnaphthalene The dibromolefin in Part H (8.7 mmol, 3.69 g) was stirred under argon in 47.9 mL of dry THF. This solution was cooled to -78 ° C and then treated dropwise (15 minutes) with n-BuLi (17.4 mmol, 6.96 mL of a 2.5 M solution hexane - Aldrich). 241 ••• •• • • •• • •• O • • The reaction mixture was stirred at -78 ° C for one hour and then quenched with 40 mL of saturated NH 4 Cl (aq). After heating to 0 DEG C., the reaction mixture was diluted with 40 ml of H2 O and 40 ml of Et2 O. The aqueous phase is extracted twice with Et 2 O and once with Et 2 OAc. The organic extracts were combined, dried over MO 4 and filtered and the solvent was evaporated in vacuo. Initial purification by flash chromatography (50 mm diameter column, 6 "Merck silica gel, 7% EtOAc / hexane as eluent, flow rate 2" / minute) gay 2.32 g of a green oil / solid. 270 MH2 1 H NMR showed contaminated product. Renewed purification by flash chromatography (75 mm diameter column, 6 "Merck silica gel, 1% EtOAc / hexane as eluent, flow rate 2" / minute) gay 2.11 g (8.11 mmol, 93% yield) of the title acetylene in the form of a light blue solid (pumped under high vacuum for 8 hours) melting point = 91.5 - 94.5.

TLC: silica gel, PMA Rf - 0.56 20% EtOAc / hexall 1 H NMR: (270 MHz, CDCl 3) Δ 7.77-7.13 (aromatic, 9H) 3.18 (s, 111) 2.62 (s. 3H) Mass spectrum: CI m / e 260 M IR: (CH 2 Cl 2 film) 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150, -1 1092, 884, 871, 853, 825 cm.

J. (S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - /// 1- (4- fluorophenyl) -3-methyl-2-naphthalenyl / ethynyl / methoxyphosphinyl / butanoic acid, methyl ester The diecyclohexylamine salt of Example 25 (8.82 mmol, 5.57 g) was partitioned between a 1: 1 mixture of EtOAc / 5% KHSO 4 (150 mL each) and shaken vigorously. The layers were separated and the EtOAc layer was washed with 2 x 100 mL fresh 5% KHSO 4. Finally, the organic phase was dried over MgSO 4 and filtered and the solvent was removed in vacuo. The erh511- 242 4 • a • • V '• • 94, • • , 44100 0 a. Oa. O • fa • 00 • 4 • • The residue was azeotroped with 2 x 120 ml of benzene, evaporated and pumped under vacuum for 2 hours to give 4.33 g, 109% yield of the phosphonate monoester as a viscous light yellow oil. This oil was stirred under argon in 24.8 mL of dry CH 2 Cl 2 and treated dropwise (8 minutes) with distilled diethyltrimethylsilylamine (17.64 mmol, 2.56 g, 3.34 mL). This solution was stirred at room temperature for 2 hours. Then the volatiles IDA the rotary evaporator (vented to argon) were removed and the resulting residue was 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 CH 2 Cl 2. TV A drops of DMF were added and the solution was cooled to 0 ° C. Oxalyl chloride (10.58 mmol, 1.34 g, 0.923 mL) was added dropwise (10 minutes). The resulting amber solution was stirred at 0 DEG C. for 30 minutes, warmed to room temperature and stirred for 2 hours. The volatiles were removed, the residue was azeotroped and pumped under high vacuum as above. The residue was finally stirred under argon in 27.7 ml of dry THF. This solution was cooled to -78 ° C and treated dropwise (15 minutes) with a -78 ° C THF solution of the acetylenic anion formed and added to the phosphonochloride on the following set.

The acetylene in Part I (5.19 mmol, 1.35 g) was stirred under argon in 27.7 mL of dry THF and cooled to -78 ° C. This solution was treated dropwise (10 minutes) with n-Buld (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, heated to 0 ° C for 15 minutes and cooled to -78 ° C. This loading was maintained at -78 ° C when it was transferred portionwise to an addition funnel and added dropwise thereto. above, the THF-16 solution of the phosphonochloridate formed at -78 ° C. DA the addition was complete, the reaction mixture was stirred at -780 ° C for one hour, then quenched with 50 ml of matt NH 4 Cl (aqueous) and heated to 0 ° C. The reaction mixture was diluted •• •••• • •• •••• • 0; 4 243 then with 40 mL of H 2 O and 40 mL of Et 2 O. the aqueous layer was extracted with 4 x 50 mL Et 2 O. The organic extracts were combined, concentrated, dried over Mg 4 and filtered and the solvent was removed in vacuo. The product was isolated by flash chromatography (75 mm diameter column, 6 "Merck silica gel, 5: 4: 1 hexane: EtOAc: toluene as eluent, 2" / minute flow rate) and gay 1.53 g (2.21 mmo1, 43% yield) of the title acetylenic phosphinate in the form of a yellow foam. 0.589 g of crude starting material were also recovered.

TLC: silica gel, PMA Rf = 0.26 5: 4: 1 hexane: EtOAc: toluene 1 H NMR: (270 MHz, CDCl 3) (7.82-7.09 (aromatic, 19H) 4.52 (m. 1H) 3760 & 3.59 (2 x s, 311) 3.36 & 301 (2 x d, 3H, J = 11.5 Hz) 2754 & 2r49 (2 x s, 311) 21.87-2.73 (m, 111) 2761-2 56 (m, 111) 7 2739-2122 (m, 111) . 2.12-2100 (m, 111) 17.02 (s, 911) Mass Spectrum: Cl m / e 693 (14-141) + IR: (CHCl 3 -1Eisning) 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 / - methoxyphosphilly.1 / -3-h droxibutans ra with ester The acetylenic phosphinate in Part J (0.866 mmol, 0.60 g) was stirred under argon in 10.5 ml of dry THE 'and treated with 0 IP • • 0 0 000 0 • c.o .. O 4114 • • 000 • 0 e 4, 00 4 000 0 • • • 244 glacial acetic acid (3.46 mmol, 0.208 g, 0.198 mL) and then continued dropwise with tetrabutylammonium fluoride (2.60 mmol, 2.36 mL of a 1.1 M solution in TI-IF). The reaction mixture was stirred at room temperature for 24 hours, then quenched with 25 mL of ice water and diluted with EtOAc. The aqueous layer was extracted three times with EtOAc. The organic extracts were combined, washed once with matt NaHCO 3 (aqueous) and once with brine, dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by flash chromatography using a 1 mm diameter column; 35: 1 Merck silica gel, 100% EtOAc as eluent, 2n / minute flow rate and gay 0.267 g (0.588 mmol, 68% yield) of the title 1-hydroxyphosphinate as a pale yellow foam.

TLC: silica gel, PM A Re0.28 100% EtOAc 1 H NMR: (270 MHz, CDCl 3) 6.81-7.18 (aromatic, 911) 4.38 (m, 111) 3.71 (s, 311) 3.590758 (2 x d, 311, J = 12 Hz) 2166 & 2.65 (2 x s, 311) 2.62-2.52 (m, 211) 2.19-1.92 (m, 211) Mass spectrum: C1 m / e 455 (M + H) + IR: (film) 3380 (broad), 3065, 3048, 2993, 2951, 2166, 1738, ••• 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-naphthalenyl / ethynyl / hydroxyphosphinyl / -3-hydroxybutanoic acid dilitium salt The diester in Part K (0.583 mmol, 0.265 g) was stirred under argon in 6 mL of dioxane and treated with 1 N LiOH (1.75 mmol, 1.7 mL). The reaction mixture was heated in a 70 ° C oil bath •• • •• • a • • • • • • • • • • ••• • • ••• • • * 4 * • • • •• • ••• • • • • 2 4 45 minutes. The reaction mixture was cooled to room temperature. The release agent was removed by trapping on a rotary evaporator and then by pumping under high vacuum for one hour. The resulting white solid was dissolved in 4 mL of distilled H 2 O and passed to an HP-20 chromatography column. (2.5 cm x 17.0 cm, equilibrated with H 2 O). The column was eluted with 250 mL of H 2 O and then with 45:55 MeOH: H 2 O. Product fractions were evaporated in vacuo at 0 ° C, lyophilized and pumped under high vacuum Over P 2 O for 8 hours and gay 0.237 g (0.541 mmol, 93% yield) of the title phosphinic acid radilitium salt as a white lyophilate.

TLC: silica gel, pMA Rf = 0.40 7: 2: 1 n-C 3 H 7 OH / NH 4 OH / H 2 O 1 H NMR: (400 MHz, D 2 O) 67.88 (d, 1H, J = 8.43 Hz) 7.80 (s. 1H) 7.58-7.29 (aromatic, 7H) 4.14 - 4.05 (m, 1H) 2.61 (s, 311) 2.43 (dd, 111, J = 3.67, J = 739) 2.21 (dd, 111, J = 9.16, J = 15.39) 1.84-1.67 (m, 211) Mass spectrum: FAB m / e 439 (M + 2 Li) + IR: (10r) 3443-3260 (broad), 3066, 2164, 1594, - 1512, 1495, 1434, 1222, 1183, 1160, 1071, 834 cm1.

Analysis. Calculated for C23H18F05PIA240.66 mol H2O molecular weight 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 Example 60 (E) -4 - // 2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] hydroxyphosphinex1] -3-ladroxybutanoic acid, dilitium salt 246 N, N, N- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] hydroxyethyl / phosphonic acid, dimethyl ester Dimethyl methylphosphonate (24.21 mmol, 3.0 g, 2.62 mL) was stirred under argon in dry TI-IF (47 mL). This solution was cooled to -78 ° C and then treated dropwise (15 minutes) 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 treated dropwise (15 minutes) with a solution of the aldehyde in Example 59 Part G (15.13 mmol, 4.0 g) in dry THF (14 ml). ). The reaction mixture was stirred at -78 ° C for 45 minutes. Finally, the reaction mixture was quenched with matt NH 4 Cl (aq) (50 mL), warmed to room temperature, diluted with H 2 O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted four times with Anglo. The organic extracts were combined, dried over MtO 4, filtered, concentrated, azeotroped with toluene twice as long, evaporated in vacuo and pumped under high vacuum to give 5.90 g. (15.13 mmol, 100% yield) of the title phosphonate In the form of a yellow solid, which was used directly in the preparation of the compound of Part B.

TLC: silica gel, PMA RE = 0.37 50% acetone / hexane B. (E) - [2-O- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] - phosphonic acid, dimethyl ester • 000 • 0900 The hydroxyphosphonate in Part A (14.16 mmol, 5.5 g) was stirred • 09 • • 0 • 0 • • . • , ". • • " 0 0 . • • • under argon in 66.5 ml of dry toluene. des with pat, itoluenesulfonic acid monohydrate (TsOH • 1120) (3.54 mmol, 0.673 g). The reaction mixture was heated to flood in a 1 ° C oil bath. The condensate was passed through a soxhlet containing dry 4 A molecular sieves. After 16 hours at 5 ° C, additional was added • 0 OO01120 (2.12 mmol, 0.404 g) and the reaction mixture was heated. • 0 0 • • ••• : ••• : • .; • •• tit : • • •••• :. • ° ••• i ••• • •••• • • • :: ••• ••• 4110 • ••• ••• • 247 as above for an additional 8.5 hours. The reaction mixture was cooled to room temperature and diluted with 100 mL of EtOAc. The mixture was then washed with 100 mL of matt NaHCO 3 (aqueous). The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated in vacuo to give 4.22 g of crude vinyl phosphonate as a brown solid. The aqueous layer was acidified with 5% HCl and then extracted three times with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated to give 1.4 g (3.92 mmol) of the vinyl phosphonate monoester as a light brown solid. This solid was stirred under argon in trimethyl orthoformate (15 mL) and heated to Aterflode in a 1 ° C oil bath for 16 hours. The reaction mixture was cooled to room temperature. The excess trimethyl orthoformate was removed in vacuo and the residue was combined with the above 4.22 g of crude vinyl phosphonate. The product was purified by flash chromatography (75 mm diameter column, 6 "Merck silica gel, 100% EtOAc as eluent, 2" / minute flow rate) and gay 3.70 g (9.99 mmol, 71% yield) of the title vinyl phosphonate as a peach-colored solid. ". 7.56-7.13 (m. 8H) • 5.54 (dd, 1H, J = 17.93 Hz, J = 20.6 Hz) 3.57 (d, 6H, J = 11Hz) 2.54 (s. 3H) Nasp .: CI m / e 371 (M + H) + . • "• ..

IR: (CHCl . " • 3016, 2956, 2857, 1617,1521, - 1 1500,1245,1188, • 1162, 1071, 1047, 834 cm.

•• • • • • • •• •• TLC: ki5e1ge1 „PMA Rf = 0748 100% EtOAc 1 H NMR: (270 MHz, CDCl 3) 7.79 (d, 1 H, J = 8.4 Hz) 7.72 (s. 1H) ; •• -; ••• • e • • • • • • • • •• • •••• • • • •• • ••• • • 248 C. (E) - [2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] - ethenyl / phosphonic acid, monomethyl ester The vinyl phosphonate in Part B (9.72 mmol, 3.60 g) was stirred under argon in dioxane (23.5 mL) and treated with 1 N LiOH (23.32 mmol, 23.32 mL). The reaction mixture was heated in a 70 ° C oil bath for one hour. Then the reaction mixture was cooled to room temperature and the solvents were removed in vacuo. The resulting residue was diluted with 15 mL of H 2 O, cooled to 0 ° C and acidified to pH = 1 with 5% HCl (aqueous). The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered, concentrated, azeotroped twice with benzene and evaporated in vacuo to give 3.38 g (9.48 mmol, 98% yield) of the title phosphonate monoester as a peach solid. .

NMR: (270 MHz, CDCl 3) 67.76 (d, 1H, J = 814 Hz) 7.68 (s. 1H) 7747-7.09 (m. 8H) 761 (dd, 1H, J = 18747 Hz, 3 = 20.58 Hz) 3148 (d, 3H, 3 = 10.96 Hz) 2.52 (s. 3H) Mass spectrum FAB m / e 357 (M + H) 4 "IR: (CHCl 3 solution) II • • • 3025, 3008, 2951, 1614, 1605, 1511, 1494, 1235, -1 1210, 1188, 1158, 1050, 987, 833 cm.

•• • • • • D, (E) -4 - // 2- [1- (4-fluorophenyl] -3-methyl-2-naphthalenyl] - ethenyl / methoxyphosphinyl / -3-oxobutanoic acid, methyl ester Il • • • • • •• * The phosphonate monoester in Part C (9.12 mmol, 3.29 g) was stirred under argon in dry C TLC: silica gel, PMA Rf = 0.41 10: 1: 1 CH2Cl2 / MeOH / CH3CO2H i2 • • • • • • • • • • • •••• •••• • •• ••• • : .. "«; •••; S •;; p • • a S. • •• •• 249 • ••• S •••• • • • • •• • •• • • • • • II • • • • • • ••• • • ••• • • • • • * 6 • •• 11 0 • • • • with trimethylsilyldiethylamine (TMSDEA) (18.24 mmol, 2.65 g, 3.45 mL, distilled). The reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were deposited on the rotary evaporator (vented to argon) and the residue was pumped under high vacuum for 40 minutes. The residue was then stirred under argon in dry CH 2 Cl 2 (25 mL). This solution was cooled to 0 DEG C., treated with two drops of dry DMF and then continued dropwise over 15 minutes with oxalyl chloride (10.94 mmol, 1.39 g, 0.955 .mu.m). The reaction mixture was stirred at 0 DEG C. for 20 minutes and then warmed to room temperature and stirred. The volatiles were removed and the residue was pumped as above.The residue was finally stirred under argon in dry THF (25 ml), cooled to -78 ° .0 and ball at -78 ° C dA this solution was transferred by means of needles to an addition funnel and was added dropwise over 20 minutes to a -78 ° C THF solution of the dianion of methyl acetoacetate, this dianion was formed as follows NaH (13.22 mmol, 0.317 g, 0.397 g of 80% mineral oil dispersion) was washed once with pentane, dried under a stream of argon and then stirred under argon in dry THF (20 mL) This suspension was cooled to 0 ° C and treated dropwise (10 minutes) with a solution of methyl acetoacetate (12.31 mmol, 1.43 g, 1.33 mL) in dry THF (10 ml) The clear solution was stirred at 0 DEG C. for 20 minutes and then treated dropwise (10 minutes with n-BuLi). (11.40 mmol, 4.56 mL of a 2.5 M solution of 1. hexane). The resulting yellow solution was stirred at 0 ° C for 45 minutes and then cooled to -78 ° C and treated dropwise with the THF solution of the phosphonochloride formed above at -780 ° C. When the addition was complete, the reaction mixture was stirred at -78 ° C for 45 minutes. The reaction mixture was then quenched with matt NH 4 Cl (aq) (50 mL), warmed to room temperature and diluted with H 2 O (50 mL) and EtO 1 C (50 mL). The aqueous layer was extracted three times with NaHCO 3 (aqueous) and once with CH 2 Cl 2. The organic extracts were combined, washed three times with saturated NaHCO t •• :. • 0 •• •• • • • I • •••• • •• •• • • •••• 2 • • and once with brine, dried over MgSO 4, filtered and evaporated in vacuo to give 4.0 g of a stainless steel foam. Initial purification by flash chromatography (40 mm diameter carbon, 20; 1 Merck silica gel, 100% EtOAc as eluent, 2 "/ minute flow rate) gay 2.0 g slightly contaminated labeled ketophosphinate in the form of an orange oil. Following chromatography (30 mm diameter column, 25: 1 Merck silica gel, 95% EtOAc / hexane as eluent, 2 "/ minute flow rate) gay 1.95 g (4.29 mmol, 47% yield) of the title ketophosphinate as an orange stain.

TLC: silica gel, PMA Rf = 0.29 100% EtOAc 1 H NMR: (270 MHz, CDCl 3) Δ 7E78-7.13 (aromatic, olefinic, 10H) 5.62 (dd, 1H, J = 17.93 Hz, J = r84 Hz) 3.71 (s, 3 H) 3763 (s 2 H) 3.48 (d, 3H, J = 1116 Hz) 3.14643713 (2 x d, 2H, J = 18146 Hz) 244 (s, 3 H) Mass spectrum: CI m / e 455 (M + H) .4.

IR: (film) 1749, 1717, 1623, 1614, 1604, 1511, 1328, 1223, 1159, 1031, 834 cm-1 E. (E) -4-1 / 2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] - ethylene 1 / methoxyphosphinyl / -3-hydroxy-butanoic acid methyl ester The ketophosphonate in Part D (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 4 (2.82 mmol, 0.107 g) after which methanol was added dropwise (2.45 mL, dried over 4 A molecular sieves). The reaction mixture was stirred for one hour at 0 DEG C. and then quenched with 2.5 ml of acetone. 1.3 g of CC-4 silica gel (Mallinckrodt) was added and the reaction mixture was stirred while warming to room temperature. Finally, the suspension was filtered through a frying funnel, washed with water (Vinger mod • ••• •••• • •• - 0. • - • • ir 251 EtoAc and twice with CH2Cl2. The filtrate was evaporated in vacuo to give 1.3 g of an orange foam which crystallized on addition of EtOAc. The product was purified by flash chromatography (30 mm diameter column 30: 1 Merck silica gel, 3% MeOH / CH 2 Cl 2 eluent, 2n / minute node rate). Product fractions were combined, evaporated and azeotroped with benzene an Ong and gay 0.653 g (1.43 mmol / l, 51% yield) of the title hydroxyphosphinate as a light yellow solid. This pure product was triturated from 7: 3 EtOAc / hexane and gay 0.516 g of the hydroxyphosphinate as a white solid, m.p. 132 DEG-134 DEG.

TLC: silica gel, PMA Rf = 0.38 4% MeOH / CH 2 Cl 2 111 NMR: (270 MHz, CDCl 3) Δ 7.79-7.16 (aromatic, oJefinic, 10H) 759 (2 x dd, 1H, J = 17.94 Hz, J = 24.27 Hz) 4735 & 4.24 (2 x m, 1H) 3470 (s, 3 H) 3749 & 3147 (2 x d, 3H, J = 11Hz) 2758-2753 (m, 2H) 2.54 & 2753 (2 x s, 3H) 2.01 - 1.74 (m, 2H) Mass spectrum: CI m / e 457 (M + H) + IR: (KBr) 3422-3382, 3062, 30b1,2951,2926, 2913, 1738 ,. 1613, 1604, 1511, 1494, 1457, 1438, 1399, 1373, • 01 O ... 1330, 1311, 1307, 1286,1220,1194, 1177, 1160, • -1 • • 1092, 1077, 1035, 883,833 cm.

• F. (E) -4 - // 2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] - hydroxyphosSildlansyEal_Allitium salt I • • I • • I .. • 00000 0 000 • • • • • • • The diester in Part E (1.1 mmol, 0.50 g) was stirred under argon in dioxane (10.45 mL) and treated with 1 N LiOH (3.3 mmol, 3.3 m1). The reaction mixture was heated in a 70 ° C oil bath minutes. The resulting white slurry was dissolved in about 100 ml 252 9: 1 H 2 O / MeOH and evaporated to dryness on a rotary evaporator at 0 ° C. The white solid was pumped under high vacuum for one hour and then redissolved in 100 ml of 9: 1 H 2 O / MeOH and evaporated on a rotary evaporator to a volume of about 8 ml. This cloudy solution was passed directly to an HP-20 chromatography column (17.5 cm x 2.5 cm, equilibrated with 1120) and eluted with 250 ml of 1120 and then with 45:55 MeOH / H 2 O. Fractions were collected every 1.3 minutes (approximately 10 ml). Product fractions were combined, evaporated on a rotary evaporator at 0 DEG C., redissolved in H2 O, lyophilized for 16 hours and pumped under high vacuum over P2 O for 16 hours to give 0.449 g, 1.02 mmol / l, 93% yield of the title dilitium salt as a white lyophilate.

TLC :, silica gel, PMA Rf = 0/49 7: 2: 1 (n-C 3 H 7 OH / NH 4 OH / H 2 O) 1 H NMR: (400 MHz, b 2 O) 67.73 (d, 1H, J = 8.06 Hz) 7.64 (s. 1H) 7.43 - 7.39 (m, 1 H) 7.25 - 7.13 (m, 4H) 7.05-6.95 (m. 3H) 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) 2722 (dd, 1H, J = 9.16 Hz, J = 15.39 Hz) 1.59-1.51 (m. 2H) Mass Spectrum: FAB m / e 429 (M + H) +, 435 (141-41, W, 441 (M + 2Li) .1- IR: (KBr) 3431 (br), 16'3, 1593, 1511, 1494, 1423, 1221, 1158, 1050 cm, 1 Analysis. Calculated for C I0.87 mol 11202312or ° 5PLi2. molecular weight. 455.94 C 60.60; H 4.80; F 4.17; P 6.79 Found: C 60.60; 11 4.73; F 4.24; P 6.82 253 Example 61 (S) -4 - // 2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] - hydroxyphosphineY1 / -12 !, 191IalL_ALLLLLTIL _______ A. (S) -3-1 / (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - // 2- / 1- (4-fluorophenyl) -3-methyl-2-naphthalenyl / ethynyl / methoxyphosphinyl / butanoic acid, methyl ester The acetylenic phosphinate of Example 59, Part J (0.974 mmol, 0.675 g) was dissolved in methanol (14.3 mL). Argon Lick bubble through this solution for 10 minutes. Then 10% Pd / C (0.270 g) was added and the reaction mixture was shaken on a Parr hydrogenator for 24 hours at 40 psi H 2. The reaction mixture was filtered through a pad of Celite and washed selectively with methanol and the filtrate was evaporated in vacuo to give a white foam. The product was purified by flash chromatography (50 mm diameter column, 4.5 "Merck silica gel, 70% EtOAc / hexane as eluent, 2" / minute flow rate) and gay 0.556 g (0.798 mmol, 82% yield) of the title matte phosphinate in the form of a white foam. Elution of the column with methanol gay further 0.101 g (0.145 mmol, 15%) of product.

TLC: silica gel, AMA ReOe24 60% EtOAc / hexane 111 NMR: (270 MHz, CDCl 3) Δ 7.78-7.14 (aromatic, 19H) 4.44 (m, 1H) ••• 3.61 (s, 3 H) •••• 3.35 & 3.23 (2 x d, 311, J = 10.6 Hz) • • •• 2.92-2.83 (m, 1H) • ••. • . • • • 2.63-2.54 (m, 311) • • • . • 2.21-1.27 (m, 411) • • • • ••• • 2.45 & 2142 (2 x s, 311) 000 •• 0.6Nasspect .: CI m / e 697 (14-4) + • • • • 11 • ••• • • • • . 1.00 (s, 911) 254 IR: (CHCl 3-18 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.

B. (S) -4 - // 2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] - methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester The silyl ether in Part A (0.775 mmol, 0.5 g) was stirred under argon in 9.45 ml of dry THE 'and treated with glacial acetic acid (3.10 mmol, 0.186 g, 0.177 ml) and then added dropwise with tetrabutylammonium fluoride (2.33 mmol). , 2.1 ml of a 1.1 M solution in THF). The reaction mixture 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 three times with EtOAc. The organic extracts were combined, washed once with matt NaHCO 3 (aqueous) and one brine, dried over MgSO 4, filtered and evaporated in vacuo. Initial purification by flash chromatography (40 mm diameter column, 6 "Merck silica gel, 4% MeOH / - CH 2 Cl 2 as eluent, 2" / min flow rate) gay 0.40 g of a white solid. This solid was triturated from 100% hexane, filtered and pumped under high vacuum (8 hours) to give 0.317 g (0.691 mmol, 89% • •• • • • • • 0 • . • • • • • • • • • 1 • • • Exchange) of the title hydroxyphosphinate in the form of a white solid, melting point = 120 - 1220 ° C.

TLC: silica gel, Re: 0112 2% MeOH / CH 2 Cl 2 111 NMR: (270 MHz, CDCl 3) 7.76 (d, 1 H, J = 7.9 Hz) 7.69 (s, 111) 7.44.-7.16 (m, 711) 4.42 & 4.26 (2x m, 111) 3.92 & 3.84 (2x d, 111, J = 3.16 Hz) 3.72 (s, 311) • • • • •• ••: 100 00 0000011.9 • • •• I 0 • I. • •• •• • • ••• •••• • e • ••• • 25 3.58 & 3.54 (2 x d, 3H, J = 3.69 112) 2.89 - 2/76 (m, 2H) 2156 (s, 3 H) 2.63 - 211 (m, 2H). 1.92 - 161 (m, 4H) Mass spectrum: CI m / e 459 (M + H) + IR: (KBr) 3428 (br), 3287 (br), 3064, 3050, 3017, 2989, 2952, 2921, 1737, 1603, 1510, 1497, 1458, 1438, 1234, 1221, 1191, 1175, 1159, 1042, 826 cm-1.

(S) -4 - // 2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl / 11Y21E2? Ilf_ciEflIalL22: 12Y.S.111911tanaIAL_SWILLTIALL The diester in Part B (0.687 mmol, 0.315 g) was stirred under argon dioxane (6.9 ml). The solution was treated with 1 N 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 cooled to room temperature. The solvents were deposited on the rotary evaporator at 0 DEG C. and the resulting white solid was pumped under high vacuum for one hour. The solid was then dissolved in about 8 ml of distilled H 2 O and fed to an HP-20 chromatography column (16 cm x 2.5 cm, equilibrated with H 2 O). The column was eluted with 250 mL of H 2 O and then 45:55 MeOH / H 2 O. The fractions collected were 1.4 ml. • *. • •••• • • • • IDS nut (about 10 ml). Product fractions (37-47) were combined, evaporated on a rotary evaporator at 0 ° C, lyophilized for 16 hours and pumped under high vacuum over P and gay 0.286 g (0.647 mmol, 94% yield) of the title • 060 • The dilithium salt in the form of a white lyophilate. •• •• • • •• 0 • O•• • • • a • • •• * • •• • • 0 •• •• el • 11, •• 11 •• • i a a.

I • •• • S •• • •• /01.0 0 • or ••• • 4104 256 TLC: silica gel PMA Rf = 0.42 7: 2: 1 (n-C 3 H 7 OH / NH 4 OH / H 2 O) 1 H NMR: (400 MHz, 1) 20) 7.82 (d, 1 H, J = 8.06 Hz) 7.76 (s, 1H) 7 / 46-7.42 (m, 1 H) 7.30 - 7.7 (m, 3H) 7.18 - 7.13 (M, 3H) 4.06 (m, 1H) 2.7272.66 (m. 2H) 2154 (s, 3 H) 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) 1.44 - 1.39 (m, 2H) Mass Spectrum: FAB m / e 443 (M-1 + IR: (KBr) 3451-3426 (br), 3151, 3124, 1620, 1593, 1509, 1439, 1422, 1403, 1218, 1159, 1050 cm-1.

Analysis. Calculated for C2022170PLi2 • 0.60 mol H2 O Molecular weight = 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 4 - // 3- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / propyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A.3- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / - 2-yl] -27propenoic acid, ethyl ester Sodium hydride (4.96 mmol, 0.119 g, 0.149 g of an 80% mineral oil dispersion) was washed under argon and Ong with hexane and dried under a stream of argon. Then it was stirred 4 ••• V0 • • : ■ ••• CCC9 :IN O. va : • cc * SC • • 04 24111 • I • ! 4.0 00 •• 0 .. : 0 4000 257 the sodium hydride under argon in dry ThF (9.1 ml). This suspension was cooled to 0 DEG C. and treated dropwise (5 minutes) with a solution of triethylphosphonoacetate (4.96 mmol, 1.11 g, 0.983 mL) in dry THF (2.2 mL). The resulting clear solution was stirred at 0 DEG C. for 15 minutes, then warmed to room temperature and stirred for 30 minutes. Finally, a solution of the aldehyde in Example 1, Part C (4.13 mmol, 1.0 g) in dry TI-IF (2.5 ml) was added dropwise (8 minutes). The reaction mixture was stirred at room temperature for one hour. The mixture was quenched with H 2 O and the aqueous layer was extracted twice with EtOAc and twice with Et 2 O. The organic extracts were combined, washed once with brine. dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by flash chromatography (50 mm diameter column, 6 "Merck silica gel, 6% EtOAc / hexane as eluent, 2" / min flow rate) and gay 1.19 g (3.79 mmol, 92% yield) of the title vinyl ester in form of a light yellow foam.

TLC: silica gel,. PMA Rf = 0.22 4% EtOAc / hexane NMR (270 MHz, CDCl 3) 7.64 (d,: 7, J = 16.35 Hz) 7.09 - 6.93 (m, 5H) 5.81 (d, .H, J = 16.35 Hz) 4.17 (q, 2H, J = 7.12 Hz) 2.42 (s, 2.33 (s. 3H) 2.28 (s. 3H) . " 1.25 (t, 3H, J = 7.12 Hz) Mass spectrum: CI m / e 313 (M + H) + B.4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / butanoic acid, ethyl ester The vinyl ester in Part A (3.68 mmol, 1.15 g) was dissolved in absolute EtOH (36 mL). Argon was bubbled through the solution for 10 minutes. 10% Pd / C (230 mg) was added and 1120 (gaseous) was bubbled. •• • • • • • • • • • 0 • o • e • • • • e • • • , • • • • 9, • • • • • • • 0 • • • ••• • • ••• ••• • • ••• : • • • • 7 • 1.4 • ••• • • oil • • •••• • • • • • • • • • •• •• •••• • ••• • • •••• 258 nom the solution 10 minutes. The reaction mixture was stirred under an atmosphere of H 2 for 2 hours. The reaction mixture was diluted with EtOH and filtered through a 4 "Celite pad in a 60 mL fried funnel. The Celite pad was washed with BUM. The filtrate was evaporated in vacuo and gay 1.12 g (3.56 mmol, 97% yield) of the title matte ester in the form of a white solid.

TLC: silica gel, PMA R1 = 0.29 δ% 1 H NMR (270 MHz, CDCl 3) EtOAc / hexane 6 7.09-6.97 6.84 4.06 2.90-2.84 2.37 2, 2.32-2.27 1, (m, 4H) (S. 1H) (q, 2H, J = 7.12 Hz) (m, 2H) 3H) (2 x s, 611) (m, 211) 3H, J = 7.12 Hz) 000 • 0000 e • 11 • • • • • • • • 0 041 • • 0, 4 • • * NO * • • •• • no • • 4 0 4 Mass Spectrum: CI m / e 315 (14-4-H) + C. 4t-Fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-propanol Lithium aluminum hydride (3.5 mmol, 0.133 g) was stirred under argon in dry Et 2 O (3.5 mL). Donna suspension was cooled to 0 DEG C. and treated dropwise (8 minutes) with a solution of the ester in Part B (3.5 mmol, 1.1 g) in dry Et 2 O (3.5 mL). The reaction mixture was stirred at 0 ° C for 15 minutes, then extended to room temperature and stirred for 45 minutes. Bnnd-. The solution was cooled to 0 DEG C. and treated dropwise with 0.133 ml of 1120 and then with 0.133 ml of 15% NaOH and finally with 0.399 ml of 1120. The suspension was warmed to room temperature for 30 minutes. The resulting white powdered solid was filtered and washed with dry Et 2 O. The filtrate was concentrated, azeotroped with benzene once and evaporated in vacuo to give 0.950 g of alcohol which was purified by flash chromatography ( ••• •••••••••. •• .. •: ••• •: .. • 11 • •• •••• • * SS • ••••• •• •• ••. ’,: A • • ••• .1 •• • 44.1 259 mm diameter column, 6 "Merck silica gel, 35% EtOAc / hexane as eluent, 2" / min flow rate) and gay 0.906 g (3.33 mmol, 95% yield) of the title alcohol as a colorless oil.

TLC: silica gel, PMA R. = 0.18 20% EtOAc / Hexane 111 UMR (270 MHz, CDCl 3) 6 7.08-6.93 (m, 411) 6.82 (s, 111) 3.45-3, (M, 211) 2.60-2.54 (M, 211) 2.34 (s. 3H) 2.28 (2 x s, 6H) 1: 63-1.52 (m, 211) Ni spectrum: CI m / e 273 (M4-1.) 4.

D.z: 11:, p_r_TITI.2py1ll4 '-fluoro-3,3' -trimethyl1 / 1 f 11 '.43if enYll • • • • •• • • • • • • • II • • • 10 • 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 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 alcohol of Part C (4.04 mmol, 1.1 g) in dry THF (8.2 mL). The reaction mixture was stirred for one hour at 0 ° C, then warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with Et 2 O and filtered through a frying funnel and the precipitate was washed with Et 2 O. The filtrate was washed one Ong with filtration, dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by flash chromatography (50 mm diameter, 6 "Merck silica gel, 2% EtOAc / hexane as eluent, 2" / min flow rate) to give 1.35 g (4.05 mmol, 100% yield) of the title bromide as of a light yellow oil.

• • • • • • • • • S • • s • • • • • • • • ••• • • ••• • • • •• s SOO • • • I • •• • ••• • • •• •• • 0 • • • • • • IN •• • ••• •• • • ••• • • • • 4.1 • • • •• • 111 • • •••• • • ••. .14 260 TLC: silica gel, PMA Re0.22 100% hexane 1 H NMR (270 MHz, CDCl 3) δ 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 (m, 2H) b..aspect .: CI m / e 235 (M + H) + E./3-/4'- fluoro-3,3',5-trimethyl1/1,11-biphenyl/-2-y1/- The bromide in Part D (3.88 mmol, 1.3 g) was stirred under argon in trimethyl phosphite (38.8 ml). The reaction mixture was heated to Aterflode in a 1 ° C oil bath for 36 hours. The surplus of (CH30) 3P was removed by short-wave distillation and the pellet was pumped under Mgt vacuum at 1000 C for one hour. The the obtained yellow oil was subjected to flash chromatography purification (50 mm diameter column, 6 "Merck silica gel, 85% EtOAc / hexane as eluent, 2 "/ min river velocity) and gay 1.13 g (3.10 mol 80% yield) of the title dimethylphosphonate in the form of a colorless oil.

TLC: silica gel, PMA, Rf = 0.28 100% EtOAc 1 H NMR (270 MHz, CDCl 3) Δ 7.08-6.97 (m. 4H) 6.81 (s, 111) 3.65 (d, 6H, J = 11Hz) 2.63 - 2.56 (m, 2H) 2.34 (s. 3H) 2.30 (2 x s, 3H) 2.28 (s. 3H) 1168-1.50 (m. 4H) Mass spectrum: CI m / e 365 (M + H) 4- e "• ;; • 06 f000 • 00 000 • * II 261 F./3-/4'- fluorine-3,3',5-trimethyl1/1,1.-biphenyl/-2-y1/- propyl / phosphonic acid, monomethyl ester The phosphonate in Part E (3.43 mmol, 1.25 g) was stirred under argon in dioxane (8.23 mL). This solution was treated with 1 N LiOH (5.15 mmol, 5.15 mL) and heated in a 9 ° C oil bath. After one hour, an additional 3.43 mmol of LiOH was added and the reaction mixture was heated at 9 ° C for 3.5 hours. The reaction mixture was cooled to room temperature. The solvents were removed in vacuo. The white solid iterate was diluted with 25 mL of H 2 O and the slurry was cooled to 0 ° C and acidified to pH = 1 with G 5% HCl (aqueous). The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, dried over MgSO 4 and filtered and the filtrate was concentrated. The residue was azeotropically distilled twice with benzene and the viscous oil was pumped under high vacuum for four hours to give 1.18 g (3/37 mmol, 98% yield) of the phosphonate monomethyl ester as a yellow oil.

TLC: silica gel, PMA, Rf = 0.46 10: 1: 1 CH2Cl2 / MeOH / CH3CO2H 1 H NMR (270 MHz, CDCl 3) 7.06-6; 95 (m, 4H) 6.81 (s. 1H) 3.56 (d, 3H, J = 11Hz) 2.62-2 / 53 (m. 2H) 2.32 (s. 3H) 2.27 (2 x s, 6 H) 1.69-1.48 (m. 4H) Axis spectrum: FAB m / e 351 (M + H) + •••• • ••• °° .9: 9 ° •: S: ••: 40 * 900 4 OS 004 • 41.90 262 G.4 - // 3- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / propyl / methoxyphosphinyl / -3-oxobutanoic acid, methyl ester The phosphonate monoester in Part F (3.22 mmol, 1.13 g) was stirred under argon in dry CH 2 Cl 2 (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 volatiles were removed in vacuo (ventilated to argon). The residue was azeotroped once with 70 ml of dry benzene and evaporated in vacuo (vented to argon). The residue was finally pumped under high vacuum for 50 minutes. Then the residue was stirred under argon in dry CH 2 Cl 2 (12.9 mL). Tv A drops of dry DMF were added and the solution was 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 20 minutes, then warmed to room temperature and stirred for 1 3/4 hours. The volatiles were removed, the residue was azeotroped and pumped under high vacuum as above. The rust-colored oil was then stirred under dry In dry THF (9.0 mL). This solution was cooled to -78 ° C and at -780 ° C IA it was added dropwise (20 minutes) To a -78 ° C THF solution of the dianion of methyl acetoacetate formed as follows: sodium hydride (4.85 mmol, 0.116 g, 0.145 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 mmol, 0.506 g, 471 ml) In dry THF (3.6 ml) was added dropwise (8 minutes) and the resulting clear solution was stirred at 0 ° C for 25 minutes. Then the reaction mixture was treated dropwise (10 minutes) with n-BuLi (4.04 mmol, 1.62 mL of a 2.5 M solution in hexane, Aldrich). The resulting yellow solution was stirred for 35 minutes at 0 ° C, then cooled to -78 ° C and treated dropwise (20 minutes) with the THF formed above. : V ••• 117 ■ •• • 263 the solution of the phosphonium chloride at a temperature of -78 ° C. The reaction mixture was stirred at -78 ° C for one hour and then quenched with matt NH 4 Cl (aqueous) (45 ml) and warmed to room temperature. The mixture was diluted with H 2 O (45 mL) and EtOAc. The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, washed once with matt NaHCO 3 (aqueous) and once with brine, dried over MO 4, filtered and evaporated in vacuo to give 2.0 g of a rust-colored oil. The product was isolated by flash chromatography (40 mm diameter column, 35: 1 Merck silica gel, 100% EtOAc to 5% MeOH / CH 2 Cl 2 as eluent, 2 "/ min flow rate) and gay 0.220 g (0.491 mai, 15% yield) of the title p -ketophosphinate in the form of a rust-colored oil.

TLC: silica gel, PMA Rf = 0.19 100% EtOAc 1 H NMR (270 MHz, CDCl 3) Δ 7.08-6.98 (m. 4H) 6.81 (s. 1H) 3.73 (s, 311) 3165 (d, 3H, J = 11Hz) 3.64 (s, 211) 3.10 (dd, 211, J = 5.27 Hz, J = 17.41 Hz) 2 / 67-2.57 (m, 211) 2.35 (s, 311) 2.30 & 2.28 (2 x s, 311) 2.29 (s, 311) 1.72-1.56 (m, 411) Mass spectrum CI m / e 449 (m41) 1- ••• • H.4 - // 3- / 4'-fluoro-3,3 ', 5-trimethyl / 1,11-biphenyl / -2-yl / - • • • • Propyl / methoxyphosphinyl / -3-hydroxybutyl / methyl ester The ketophosphinate in Part G (0.223 mol, 0.10 g) was stirred under argon in dry THF (1.9 mL). This mixture was cooled to 0 DEG C. and • 264 • ••• • •••• • • •, •• • • .00.06 • •••.

• • •• • O• • • • was then treated with NaBH 4 (0.223 mmol, 0.008 g) and then continued dropwise with MeOH (0.194 mL, dried over 4 A molar sieves). The reaction mixture was stirred for one hour at 0 DEG C., then quenched with acetone (0.194 ml) and then with 0.10 g of CC-4 silica gel (Mallinckrodt). The suspension was stirred while warming to room temperature and then filtered through a fried funnel. The silica gel was washed with EtOAc. The filtrate was evaporated in vacuo to give 0.108 g of a pale yellow oil. TVS. reaction products were isolated by flash chromatography (10 mm diameter column, 35: 1 Merck silica gel, 4% MeOH / CH 2 Cl 2 as eluent, 2 "/ min flow rate). The desired title p-hydroxyphosphinate was obtained in 58% yield (0.058 g, 0.129 mmol). 0.019 g (0.043 mmol, 20% yield) of the 1,3-butanediol phosphinate were also obtained in the form of a light yellow oil.

TLC: silica gel, PMA Rf = 0.19 3.5% MeOH / CH 2 Cl 2 1 H NMR (270 MHz, CDCl 3) Δ 7.08-6.98 (m. 4H) - 6.82 (s. 1H) 4.446 (4.32 (2 x m, 1H) 3.63 & 3p62 (2 x d, 3H, J = 10.55 Hz) 3.70 (s. 3H) 2.65 - 2.50 (m, 4H) 2735 (s, 3 H) 2.30 (2 x s, 3h) 2.29 (s. 3H) 1.89-1776 (m. 2H) 1771-11.59 (m, 4 H) Mass spectrum: CI m / e 451, (M441) 4 " I.4 - // 3- / 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl propyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt The diester in Part H (0.122 mmol, 0.055 g) was stirred under argon 26 in dioxane (2 mL) and treated with 1 N LiOH (0.366 mmol, 0.366 mL). The reaction mixture was heated in an 800 ° C oil bath for 45 minutes. The reaction mixture was cooled to room temperature and the solvents were removed on a rotary evaporator. The resulting yellow solid was pumped under high vacuum for 2 hours and the title dilute salt was yellow solid.

TLC: silica gel, PMA Re0.29 8: 1: 1 CH2Cl2 / MeOH / CH3CO2H 1 H NMR (270 MHz, D 2 O) Δ 7.08-7.05 (m, 4H) 6.80 (s, 1H) 4.13 (m, 1H) 2.54 - 2.47 (m, 2H) 2.38 - 2.28 (m, 2H) 2.30 (s, 3H) 2.22 (s, 3H) 220 (s, 311) 1.59-1.50 (m, 211) 1.42-1; 29 (m, 411) Example 63 1S-11 <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-hydroxybutanoic acid, dilitium salt A./1S-(1<a,2<a,4a<b,8<b,8a<a)/-8-//(1,1-dimethylethyl)di- methylsilyl / oxy / -1,4,4a, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenemethanol To dry Et 2 O (5 mL) at 0 ° C (isbt1) was added lithium aluminum hydride (132 114g, 1 mol.) And then added dropwise / 1S- (1 ) - - 8 - // (1,1-dimethylethyl) dimethylsilyl / oxy / -1,2,4a, 5,6,7,8,8a-octahydro-2-methyl • • • •• * • •••• • ••• • ••• • • •• • ••• • • • ; 60 '40 1: Sea S I V00.

II s I I 040 • I V0 f • 0 Sof fee. • •• sae • 266 naphthalene carboxylic acid, methyl ester, R. L. Funk and others, Tetrahedron Lett. 25, 1655 (1984) (1.175 g, 3.47 mmol) in dry Et 2 O (5 mL) and the resulting rub suspension was stirred over the surface under argon at room temperature. The mixture was quenched by dropwise addition in turn H 2 O (130 / al 15% NaOH (11 μl) and H 2 O (390 μl) Precipitated salts were removed by filtration through anhydrous MgSO 4 Over packed Celite. Evaporation in vacuo gay 1.112 g of a clear oil which was purified by flash chromatography silica gel and elution with (95: 5) hexane-EtOAc and gay 902 mg (85.7%) of the desired title alcohol in the form of a clear oil, which crystallized and was allowed to stand. Melting point = 79 - 81 ° C.

TLC (9: 1) hexane-EtOAc. Rf = 0.21.

Analysis. Calculated for C 18 H 34 O 2 S 1: C 69.61; H 11.04 Found: C 69.64; H 11.04 1 H NMR (CDCl 3) Δ 0.00 (s, 6H) 0.82 (s, 9H) 0.83 (d, 3 H) 0.94-1.0 (m. 2H) 1.18 (s. 1H) 1.2-1.42 (m. 2H) 1.67 (m. 3H) • ••• 1.89 (m, 1H, • •••• • 2.25 & 2137 (2H, 2 multipletterl • • • •• 3142 (bt, 1H) • a • Δ 3.80 (dd, 1 H) • • 0 • IP • 3.93 (bs, 1H) • •• • • •• 129 (d, 1H) • 5.48 (dq, 1H) ppm.

• • . • • • Of • • • : •••• •••• • •• ••• • ••• ■ 267 B./1S-(1<a,2<a,4a<b,8<b,8a<a)/-8-//(1,1-dimethylethyl)di- methylsilyl / oxy / 1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenecarboxaldehyde A solution of Dess-Martin periodinane (895 mg, 2.11 mmol) in dry CH 2 Cl 2 (6 mL) was treated with dry t-C 4 H 9 OH (200 μl) and the white suspension was stirred under argon at room temperature for 15 minutes. A loading of the alcohol (596 mg, 1.92 mmO1) in dry C12 Cl2 (6 mL) was added dropwise within 5 minutes and the mixture was stirred under argon at room temperature for 20 minutes. The mixture was added to a solution of sodium thiosulfate (2.12 g) in 1.0 N NaHCO 3 (12 ml) and the resulting mixture was stirred until all solids had dissolved. The organic phase was washed with matt NaHCO 3, H 2 O and brine and then dried over anhydrous Na 2 SO 4 and evaporated in vacuo and gay 1.005 g of a colorless oil. The crude product was combined with a small amount (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 and gay 667 mg (75.7%) of the desired title aldehyde as a colorless oil.

TLC (7: 3) Hexane - Et 2 O, Re 0.70 PMA 1 H NMR (CDCl 3): S ••• • • • IN•• IN• • • IN• • • 0 • •• 1 •• 11 5 • 4.0 • • •• 0.07 0.00 0.85 0.89 0.93-1, 1.38-1.52 1.58-1.78 2.31 2.66 2.78 4, (s, (s, (s, (d, (m,), m, (m, (m,), m, (m, (s)) , 3H) 3H) 9H) 3H) 2H) 2H) 4H) 1H) 111) 1H) 1H) •• 0 268 5, (d, 1 H) 5, (m, 1 H) 974 (d, 1 H) C./1S-(1<a,2<a,4a<b,8<b,8a<a)/-1-(2,2-dibrometeny1) // (1,1-dimethylethyl) -dimethylsilyl / oxy / -1,2,4a, 16,7,8,8a-octahydro-2-methylnaphthalene A - ° C (salt / ice bath) solution of the aldehyde in Part B (667 mg, 2.16 mmol) and triphenylphosphine (1.7 g, 6.48 mmol) in dry CH 2 Cl 2 (10 mL) was treated dropwise over 5 minutes with a CH 7 Cl 2 (5 mL) solution of carbon tetrabromide (1.7 g, 6.48 mmol) and the dark reddish brown mixture were stirred under argon at - ° C for 30 minutes, at 0 ° C for 2 hours and finally over the surface at room temperature. The mixture was cooled to 0 DEG C., treated with additional triphenylphosphine (567 mg, 216 mmol) and then with CBr4 (358 mg, 1.08 mmol) and stirred for 4 hours at room temperature. The mixture was quenched with matt NaHCO 3 (10 mL) and diluted with CH 2 Cl 2 and the organic phase was filtered through sintered glass, washed with matt NaHCO 3 and brine, dried over anhydrous Na 2 SO 4 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 pure hexanes. Product fractions were evaporated and gay 677 mg (67.3%) of pure title vinyl dibromide in the form of one color oil.

TLC (9:11 Hexane-T-acetone R1 = 0.73 UV + PMA). 1 H NMR (CDCl 3) o 0.08 & 0, (2 singlets, 6H) 0185 (d, 3H) 0190 (s, 911) 0.98 (m, 211) 1.25-2152 (m, 511) 1.74 (m, 111) 1182 (m, 111) 269 2.39 (m, 1H) 2.56 (m, 1H) 2.66 (m, 1H) 3195 (s, 1H) 5.48 (d, 1H) 5.52 (m, 1H) 6.37 ( d, 11!) ppm.

D./1S-(1<a,2<aitia<b,8<bi8a<a)/-8-//(1,1-dimethylethyl)di- methylsilyl / oxy / -1-ethynyl-1,2,4a, 5,6,7,8,8a-octahydro-anethylnaltalene A -78 ° C (dry ice / acetone) solution of the vinyl dibromide in Part C (495 mg, 1.07 mmol) in dry THF (6 mL) was treated dropwise over minutes with a 1.6 M n-BuLi in a solution of hexanes (1.34 mL, 2.14 mmol) and the clear colorless mixture was stirred for 30 minutes under argon at -780 ° C. The mixture was quenched at -78 ° C by the addition of matt NH 4 Cl (5 mL), allowed to warm to room temperature and diluted with EtOAc and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 291 mg (89.6%) of crude title acetylene as a colorless oil.

TLC hexanes R = 0 43UV + PMA f ' 111 NMR (CDCl 3) Δ 0.08 & 0.12 (2 singlets, 6H) 0.90 (s, 911) • • 0.99 (m, 1 H) ••• 0 • 1.09 (d, 311) • • IN. 1.19 (m, 111) •• • 1.46 (m, 211) • • • • 1.74 (m, 311) , •• IN•• ••• 2.12 (d, 111) • , 000 2.30 (m, 1H) 2.41 (m, 1H) 2.71 (m, 1H) 4.37 (m, 1H) 5.38 (d, 1H) 5.55 (m, 1H) ppm. 270 •••• 0 • • •• • • • • 0 • E. (S) -4- (chloromethoxyphosphinyl) -3 - // (1,1-dimethylethyl) - diphenylsilyl / oxy / butanes ra, with ester The phosphonochloride was prepared from the dicyclohexylamine salt of Example 25, Part B according to the following procedure. The free acid was regenerated by partitioning the dicyclohexylamine salt (1.3 g, 2.05 mmol) between EtOAc and 5% KHSO 4, the organic layer was washed with 5% KHSO 4 (four times) and solution and then dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give the free acid as a clear viscous oil.

The phosphonic acid monomethyl ester (2.05 mmol) was taken up in dry CH 2 Cl 2 (5 mL), treated with distilled N, N-diethyltrimethylsilylamine (5 μl, 4.1 mmol) and the clear colorless solution was stirred at room temperature under argon for one hour. Excess reagents and solvents were removed in vacuo and the remaining solution was taken up in benzene (2 x 10 ml).

The crude silyl ester (about 2.05 mol) in dry CH 2 Cl 2 (5: 1) and dry DMF (1 drop) was cooled to 0 ° C (ice bath) and treated dropwise with distilled oxalyl chloride (195 μl, 2.26 mmol) and the yellow mixture was stirred under argon at 0 ° C for 15 minutes and at room temperature 45 minutes. The mixture was evaporated in vacuo, taken up in dry benzene (2 x 10 ml) and gay crude labeled phosphonochloridate as a yellow oil. 271 • • • • • • • • • • • • • • • • 0 • • • • • • • • • • 0 0 0 • • • • • • • • • • • • • • • 6 • • • 41 F. methylethyl) dimethylsilyl / oxy / -1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenyl / ethynyl / methoxyphosphinyl / -3- // (1,1-dimethylethyl) diphenylsilyl / oxy / butanoic acid, methyl ester A -780 ° C solution of the acetylene in Part D (356 mg, 1.17 mmol) in dry THF (5 mL) was treated dropwise with a 1.6 M n-BuLi in a solution of hexanes (71.17 mmol) and the clear the mixture was stirred under argon at -780 ° C for 30 minutes. The acetylenic anion was then transferred via cannula dropwise over 15 minutes to a -78 ° C solution of the phosphonium chloride in Part E in dry THF (6 mL). The yellow mixture was stirred for 30 minutes at -78 ° C and then quenched by dropwise addition of matt NH 4 Cl (5 mL) and allowed to warm to room temperature. The mixture was partitioned between EtOAc and H 2 O, the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give 1.282 g of a light yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (7: 3) hexane-EtOAc. Product fractions were evaporated and gay 624 mg (72.4%) of the title acetylenic phosphinate shape of a colorless glass.

TLC (7: 3) hexane-acetone, Rf = 0.49, UV + PMA.

G./15/1<a(R*),2<a,4a<b,8<b,8a<a//-4-//2-/8-//(1,1-di- methylethyl) dimethylsilyl / oxy / decahydro-2-methyl naphthalenyl / ethyl / methoxyphosphinyl / -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / butanoic acid, methyl2Att..y A solution of the acetylene phosphinate in Part F (498 mg) in C113O11 (6 ml) was treated with 10% Pt / C (200 mg) and the black suspension was shaken on a Parr apparatus for 112 (40 psi) for 48 hours. The catalyst was removed by filtration through Celite and the reaction mixture was charged with new catalyst. r. V. • Stf ••• • • •• • •••••• • •• 00 272 (1mg) and shaken in the Parr apparatus under H2 (40 psi) for another 24 hours. The catalyst was removed by filtration through Celite and the filtrate was evaporated in vacuo to give 448 mg of a clear glass. The arena 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 the title compound as a colorless glass.

TLC (7: 3) EtOAc-hexane, Rf 3 diastereomers as a flack = 0.42, Rf fourth diastereomer as a flack = 0.49, UV + PMA.

H./1S-/1<a(R*)2<a,4a<b,8<b,8a<a//-4-//2-(dekahydro hydroxy-2-methyl-1-naphthalenyl) ethyl / methoxyphosphinyl / -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / butanoic acid, yes A solution of the compound in Part G (248 mg, 0.334 mmol) of CH The mixture was partitioned between EtOAc and saturated NaHCO 3 and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and evaporated in vacuo and gay 227 mg of a colored glass. The crude product was purified by flash chromatography on silica gel eluting with (4: 1) hexane-EtOAc and then with pure EtOAc. Product fractions were evaporated in vacuo and gay 159 mg (75.8%) cv of the pure title monoalcohol in the form of a colorless ••• ▪ • • oil. • a. s • • • • • • • • 0 • S • • • II • • TLC (7: 3) acetone-hexane R = 0.5 (UV (weak) + PMA) f ••• • • ••• • • • • • • 273 ••• ••••• • • • • •• I 0 •• • • • • • • • • 0 • • • ••• • • ••••• 0 ••• •.

• • • ••• • • • • I./1S-/1<a(R*)2<a,4a<b,8<b,8a<a//-3-//(1,1-dimety1ety1)- diphenylsilyl / oxy / -4 - // 2- [8- (2,2-dimethyl-1-oxobutoxy) -decahydro-2-methyl-1-naphthalenyl] ethyl / methoxyphosphinyl A solution of the alcohol of Part H (147 mg, 0.234 mmol) in dry pyridine (1.5 mL) was treated with 2,2-dimethylbutyryl chloride (160 μL, 1.17 mmol, 5 eq.) And then with 4-dimethylaminopyridine ( 3 mg, 0.1 eq.) And the light yellow mixture was heated at 1000 DEG C. under argon for 4 hours. The mixture was cooled, partitioned between 1.0 N HCl and EtOAc, the organic phase washed with 1.0 N HCl (two ginger) and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 255 mg of a light tan oil. The crude product was purified through flash chromatography on silica gel eluting with (55:45) hexane-EtOAc. Product fractions were evaporated in vacuo and gay 112 mg (65.9%) of the desired title dimethylbutyryl ester as a colorless oil.

Hexane-acetone, Rf = 0.62, UV 4- PMA.

J./1S-/1<a(R*)2<a,4a<13,8<b,8a<a//-4-//2-/8-(2,2-dimety1- 1-Oxobutoxy) -decahydro-2-methyl-1-naphthalenyl / ethyl / methoxyphosphinyl / -3-hydroxyalanyl metal ester .....: _ A solution of the silyl ester in Part I (130 mg, 0.179 mmol) THF (2 mL) was treated successively with glacial acetic acid (HOAc) (41 μl, 0.716 mmol) and a 1.1 M (n-C 4 H 9) 4NF-145 solution in THF (490) 11, 0.537 mmol) and the mixture was stirred. over the flat under argon. The mixture was partitioned between EtOAc and 5% KHSO 4, the organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 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 and gay 72 mg (82.4%) of the desired title alcohol as a dye oil. • •• - •••• • •• ••• • 274 TLC (1: 1) hexane-acetone, Rf = 0.20, UV + PMA.

K./1S-/1<a(R*)2<a,4a<b,8<b,8a<a//-4-//2-/8-(2,2-di- Methyl-1-oxobutoxy) -decahydro-2-methyl-1-naphthalenyl / ethyl / hydroxyphosphinyl / -3-hydroxy-butanoic acid, dilitium salt A solution of the alcohol of Part J (72 mg, 0.147 mmol) in dioxane (1.5 mL) was treated with 1.0 N LiOH (0.52 mL) and the mixture was heated at 50 ° C (oil bath) under argon for 1.5 hours. . The mixture was cooled, diluted with 11201, filtered and evaporated in vacuo to an oil. The crude product was chromatographed on HP-20 resin (3 cm bath, 15 mm diameter column) and eluted with 1120 and then with (70:30) H 2 O CH 3 O-J. Product fractions were evaporated in vacuo, read in 1120 (20 ml) and lyophilized and gay 55 mg (74%) of the desired title dilitium salt as a white solid.

TLC (8: 1: 1) CH 2 Cl 2 -CH 2 OH-CH 3 COOH Rf = 0.05, PMA. Analysis. Calculated for C23H3907PLi2 + 1.78 mol 1120 (molecular weight 504.53): C 54.75, H 8.50; P 6.14 Found: C 54.75; H 8.64; P 5.93 Example 64 (5) -4 - /// 3 '- (4-fluorophenyl) spiro / cyclopentane-1,1' - / 1H / - indene-2-yl / ethynyl / hydroxyphosphinyl / -3-hydroxybutanoic acid, dilitium salt A. 1111.1111.121.111) -111-111deaI __________ a • • • • • 41 e • • • • a • • • • • IN• 1 •• • To a solution of 4-fluorophenylmagnesium 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 under 40 mifluter a solution of 1-indanone (6.61 g, 50 mmol) in dry ether • • • • 6 • S • 27 (20 ml). After stirring at room temperature for one hour, the reaction mixture was quenched by the dropwise addition of matt NH 4 Cl solution (15 ml). The mixture was diluted with Et 2 O, washed with saturated NaCl solution, dried (MgSO 4) and evaporated.

The residue was taken up in glacial acetic acid (15 ml) and boiled under reflux under argon (30 minutes). The acetic acid was evaporated and taken up twice with toluene. The residue (9.45 g) was purified by flash chromatography on silica gel eluting with hexane and the gay title compound (8.174 g, 78%) as a colorless oil which crystallized on standing. Melting point 38 - o C TLC (hexane) Rf = 0.21.

B. „32: L (.zj.t_Lo._r_fLe_L.ro / cNasloentan_p-1,1'- 1H / inden / To a solution of the compound of Part A (10.666 g, 50.8 mmol) in dry THF (90 mL) at 0 ° C under argon was added to portions of solid potassium t-butoxide (12.2 g, 109 mmol). After stirring at 0 DEG C. for 30 minutes, 1,4-dibromobutane (6.50 ml, 101 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature, stirred for 2 hours and then partitioned between EtOAc and 5% KHSO 4 (150 mL each). The organic phase was washed with saturated NaCl solution, dried (Na 2 SO 4) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with hexane and the title compound (9.43 g, 70%) in •••• form of a colorless oil. TLC (Et 2 O-hexane; 1: 9) Rf = 0.69 (Rf for the LO cleaning in Part A = 0.63). •• • •• • 0 • • • C.31- (4-fluorophenyl) spiro / cyclopentane-1,1s- / 1H / indene / - 2'-carboxaldehyde • • • • lo ••• • ••• • To a solution of the compound in Part B (9.30 g, 35.2 mot) in dry CH 2 Cl 2 (50 mL) at 0 ° C under argon was added a 1.0 M solution of TiCl 4 in CH 2 Cl 2 (70 mL). , 70 moil. The erh511na • • • 0 • ••• • • 0 • • 276 000 • • 00 • •• • • • • • • • • • • • • O. & • • see • ••• 0 • • 1 •• * 0 ••• • • S • • the dark green solution was treated dropwise with 1,1-dichloromethyl methyl ether (3.50 mL, 38.7 mmol). After stirring at o C for one hour and at room temperature for one hour halides the mixture in cold, saturated NaHCO 3 solution. The organic phase was separated, dried (Na 2 SO 4) and evaporated to dryness. The arena product was purified by flash chromatography on silica gel eluting with Et 2 O-hexane (5:95) and the gay title compound (8.233 g, 80%) as a yellow oil. Crystallization of the oil from hexane gay pure title compound (6.778 g, 66%) as light yellow crystals, 116 DEG-117 DEG C.

TLC (Et 2 O-hexane; 15:85) Rf = 0.56.

Analysis. Calculated for C11170F: C 82.17; H 5.86; F 6, Found: C 83.13; H 5.82; F 6.29 D.2'-ethyl% 1-3 '- (4-fluorophenyl) spiro- / cyclopentane- 1.1'-1H / ind To a solution of potassium t-butoxide (0.672 g, 6.00 mmol) in dry THF (8 mL) at -78 ° C without argon was added dropwise a solution of dimethyldiazomethylphosphonate (0.960 g, 6.40 mmol, prepared as in J. Org. Chem. 36, 1379 (1971)) and TI-IF (4 ml). After stirring at -78 ° C for 5 minutes, a solution of the compound in Part C (1.168 g, 4.00 mmol) of I. THF (8 mL) was added over 10 minutes. After stirring at -78 ° C for 3 hours, -0 ° C for 1.5 hours and at room temperature for one hour, the mixture was diluted with hexane (50 mL) and washed with 5% KHSO 4. The organic f-3 was washed with matt NaCl solution, dried (Na 2 SO 4) and concentrated to a small volume (not to dryness). The yellow solution was flash chromatographed on silica gel eluting with hexane. The product-containing fractions were combined, treated with butylated hydroxytoluene (BHT) (0.080 g, 0.36 mmol) and concentrated to a small volume (5 - 10 mL) which was used immediately as you. solution for the following stay.

TLC (Et 2 O-hexane; 1: 9) Rf 0.57. 1 H NMR (270 MHz, CDCl 3) 277 .00 • 41.0 • 0 • • • • 410 • 0. • • • 1 • • • • • • • • ••• • • O * 0 • • 000 I • • 1 * a • SOO • • • • using BHT as an internal standard (1.45 ppm, 18H, s) shows the narvaron of 3.10 mmol (77.5% yield) of the desired acetylene (3.32 ppm, 111, s).

(S) -4- (chloromethoxyphosphinyl) -3 - // (1,1-dimethylethyl) - - The title phosphonochloride was prepared from the dicyclohexylamine salt of Example 25, Part B (3.44 g, 54.4 mmol) as described in Example 29, Part J using the following amounts: trimethylsilyldiethylamine (1.36 mL, 10.85 mmol), CH 2 Cl 2 (15 mL); oxalyl chloride (0.50 mL, 5.73 mmol), DMF (one drop), CH 2 Cl 2 (15 mL).

(S) -3 - // (1,1-dimethylethyl) diphenylsilyl / oxy / -4 - /// 3'- (4-fluorophenyl) -spiro [cyclopentane-1,11- / 1H / inden / -2- yl / ethynyl / methoxyphosphinyl / butanoic acid, methyl ester The hexane solution of the acetylene in Part D (3.10 mmol + 0.36 mmol BHT) was diluted with dry THF (15 mL) and cooled to -780 ° C under argon. The solution was then treated with a 1.6 M solution of n-BuLi in hexane (2.16 mL, 3.46 mmol) dropwise by syringe. After stirring at -78 ° C for 45 minutes, the anion solution was transferred by cannulae to a -78 ° C solution of the phosphonium chloride in Part E (54.4 mmol) in dry THF (15 mL). After stirring at -78 ° C for one hour, the reaction mixture was quenched by dropwise addition of matt NH 4 Cl (15 mL) and allowed to warm to room temperature. The mixture was extracted with EtOAc and the extracts were washed with 5% KHSO 4, matt NaHCO 3 and matt NaCl solution, dried (Na 2 SO 4) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexane (25:75) and gay title compound (1.781 g, 80% stripped on the compound in Part D) as a light yellow glass.

TLC (acetone-hexane; 1: 1) Rf = 0.46. 278 4160 0 * • • • 4.4 " • 00 • • • • • • 0 • • • • • ••• • ••• • • 00. 4 4 • • • 40 I •••• • • • • (S) -4 - /// 3 '- (4-fluorophenyl) spiro / cyclopentane-1,1'- [1H] indene-2-yl] ethynyl / methoxyphosphinyl] -3-hydroxy- 1211L4LlaIIIL_EflYlster To a solution of the compound of Part F (1.00 g, 1.39 mmol) in dry THF (5 mL) at room temperature under argon was added glacial acetic acid (0.32 mL, 5.59 mmol) and a 1.1 M solution of (n-C4H9) 4NF in THF (3.80 mL, 4.18 mmol). After stirring at room temperature for 18 hours, the mixture was diluted with EtOAc (50 mL) and washed successively with 1 N HCl (3 x 30 mL) and saturated NaCl 10 solutions, dried (Na 2 SO 4) and evaporated to dryness. The residue was taken up in Et 2 O (20 mL), cooled in an ice bath and treated with an excess of diazomethane in ether. The residue obtained by lining the ether was purified by flash chromatography on silica gel eluting with acetone-hexane (3: 7) and gay title compound (0.595 g, 89%) as a colorless glass.

TLC (acetone-hexane; 1: 1) Rf = 0.29.

(S) -4 - /// N- (4-fluorophenyl) spiro / cyclopentane-1,11- [1H] indene-2-yl] ethynyl / hydroxyphosphinyl] -3-hydroxy butanoic acid, dilitium salt To a solution of the compound in Part G (0.580 g, 1.20 mmol) dioxane (60 mL) at room 7, temperature under argon was added 1 N LiOH solution (4.2 mL, 4.2 mmol). After stirring at room temperature for 3 hours, the mixture was diluted with acetonitrile (20 ml) and the white precipitate was collected, washed with acetonitrile and dried in vacuo to give the crude title product (0.670 g) as a white solid. The crude product was suspended in water (10 ml) and fed to a short pad with HP-20 (15 ml bath volume, diameter 1 "), eluted with water (300 ml) and then with MeOH (300 ml). product was combined and 279 evaporated to dryness. The solid residue was triturated with acetonitrile and gay pure title product (0.550 g, 98%) as a white solid, mp 301-303 ° C (probing).

TLC (1-C 3 H 7 O 11 -concentrated NH 4 OH-H 2 O; 7: 2: 1) Rf = 0.48. Examples 65 to 122 According to the procedures outlined above and described in the foregoing embodiments, the following additional compounds may be prepared. 0 R-P-CH2 -C-CH2 -CO2 -R 1 Xoff ••• • • a • ••• ••• :. • •• •• ! • : ••• 0 ••• • ••• • 11 •• •• 11. • I • • • • •• •••• • • •••• ......... ■■ • ■ • ■■■■ • ■■■ 1111.71 280 Ex. n r 65.OCH3 -CH2-CH2-CH3 Cl 66.OH Cl 67.OLi -CH2CH2CH2-Li CH3 S ••• • •••• • • • • • • • • • • • ••• • 68.OH -CH20- • • 41 * • S ••• • • 0 94 • ••• I • • I • • ••• a • :. • • ••• • • '4..4, • • • • . •: • •• • • ••• • •• •• • • • • •••• • • : • • • •: •• ■ • •••• • •• • : a •••• • 0 .11 VP * X 281 Lx. 69.OLi -CH2CH2CH2-Li CH3 CH3 70.OCH3 -CH2CH2CH2- CH3 CH3 71.OKC2 H -CH-CH2-OK C = 0 H3 CH 3 7 2 .ONa -CH2 - Na • PP. • • IP • • P. • • • • • OP • • • iP • • IP • • • • • 4P0 '. 4.00 • -00. ' Odle- • 6; 00 Ex. No. 282 X Rx •••••• 11 / .11 • 1 ...... • ■ ••• 73.OH CH3 -CH2CH2- OHC2H CH3 CH3 HO -CH2CH2CH2-H CH 3 O -CH 2 ° CH 3 76.OH -CH2O- 77.OH CH2CH2 a •• • • • 283 Ex. No. Rx mosn • ■ ••••••• ■ • ■ OH OH / CH3-CH2CH2- -CH H3 Na0 0 • • • • / CH3-CH = CH-Na H -CH3 Ca • • • o • • • • • • • • • • • •• • • •••• to 0 • • 0 • • • • I • • n 6 • I. • I • • • • 1.I ••• • • • •• • • •••• 284 n rr4x 82.HO -CZC- a • • • • It 0 : •• , 6 'at * • • * 0 00 • 0 CH CH3 CH3 C1.130CH3 H 3r -CH = CH- CH / 3 H 3 CH3 -CH2CH2-NH4 Cti30 CHNa / 3 C-CU S H Na0 :: ••• ••••• • ••••• • Ex. II r 28 86.HO Cu CH-CH- 32 C-CH H 87.0 -CH2CH2CH2-Ca CH / 3 C -CH H 3 88.CH30 Na 89. CH3 C -CH 3 H • If • • • • ••• 4 ••• • * 0 • 60 4 • • 6 • • •• • ••• • a • •• •• V •• • • • • •••• • •• IN • •• • ••• •• • • ••• • • • I f • ••• • • • • •• • • ••• • ern • • 0 • • •••• • •••• 286 Ex. no 90.CH30 -CH = CH- 91.HO IH3 C-CH 3 -CH = CH- CH3 92.CH30 CH / 3-CH2-CH3 C- CH 3 93.Li0 0.

• Oa • • • • 0 • • S • • • • • • • • • CH3 C-CH, H -CH2CH2CH-2- 4.1411 • • .1. • • o 0 • 0 • II • • a • • Cl 0. • w • V Oe:. • •! I ...IN. • .0 • • .0: 000 00 00 • • • * lb 0000 • S. 000 • OW 287 Ex. No. Rx 94. KO -CH CH - 2 2 CH3 9HO -CH = CH- 96. HO CH / 3-CEC- C-CH H 3 • • 97. HO CH3 CH • CH3 • • CH / CH 0 • • CH3 . •. . • • • • • • • • • • 288 CH 98.Li0I 3 CH I.

CH3 -CSC-Li 99.Li0 -012-Li CH CH3 CH3 L00. HO -CH2 -11 101. HO CI -C H2CH2- CH CH3 CH3 : ":". 1st: • • • ":." ::: •. ° S. 04.60 • 0411 0Se 0 SOO •••. • . ••• • 105. CH30 •• • 0 •• • w • • • 0 • • • • • • •• • • • 0 • • •• • • • • • • •• 0 • • • • 0 Li0 HO Rx -Cii2-CH2-Na x -CH2CH2- -CH2- Li hrs Ex. nrR —_ 102. Na0 CH302 CH302C CH - CH 3 / CH3 F 71— CHi CH3 F CH— CH3 / CH3 289 vooloa *.

CH302 CH302C CH— CH3 / CH3 -CH2CH2CH3 "-:." i :: * a •• • 9 • •• • • • * a It • • • Ex. no _ 290 x RX 106.HO -CH 2 CH 2 -H CH - * CH3 / CH3 107. HO Cl Cl Cl -CH2CH2CH2- H CH - CH3 / CH3 108. KO Cl Cl Cl -CH2CH2-K CH3 109. HO -CH2CH2-H . 0 • • • • • CH -4 .-- CH CH 2 291 Ex. nrRzX -CH = CH -Li C = C Li0 i-C3H7 i-C3H7 COW C = C -CH2CH2- 112.Li0 tr-C C2H-CH = CH-Li CH3 113.C / 130 CH 30 -CH = CH-CH3 CH3 • • • ••• • • ••• • • •• •• 1 • • • smile. • Tile • • "" ••• ••••• • atofl 292 Ex. n r 114.OH -CH2- 115.Li0 CH 3 CH CH3 -CBC-Li 116.Li0 .CH3-CH2CH2-Li CH CH3 CH3 117.Li0 , CH3 CH CH3 '\ CH 3 -CSC-Li • 1.6111 • • CH3 CH NCH3 118. Li0 -CH2CH2-Li •• • • a *.

Ex. 293 LiO CH3-C = C-Li CH CH3 : 0 •••• 122.

IN.

• • • • • • • • • • • • • ••• • CH CH3Li CH3 • # • ••• • • Of • • o •• • ••• • I 6 • CH30 Li 121. Li0 -CRC CH Li0 ..0 "CH3-CH2CH2-Li CH . *% `• CH3

Claims (12)

CLAIM 1. Intermediate having the structure O 2 alkyl10-P-CH 2 -C-CH 2 -CO 2 alkyl g including all stereoisomers thereof, van in X an (CH 2) 8, -CH = CH-, -CC- or -CH 2 O- and a an 1, 2 or 3, and an hydrophobic anchor. A method of preparing an intermediate according to claim 1 having the structure O 0 alkyl-f-CH 2 -C 2 -CH 2 -O 2 alkyl CHO CH which method comprises treating a cooled solution of a phosphonochloridate having the structure 0 aalkyl-P-C 1 Z% CH CH with a dianion with the structure 1. • 2. • 9 0OG 1 CC N \\ Oalkyl CH2CH 3. 0 • 4. • • I • I 5. • in the presence of an inert organic solvent. 6. • 7. • • 8. • 9. • 10. • 11. • • 12. • Summary Intermediate with the structure O II alkyl-P-CH C CH 2 -CO 2 alkyl g. Including all stereoisomers thereof, van in X ar (CH 2) 8, -CH = CH-, -CC- or -CH 2 O- and a or 1, 2 or 3, and Z is a hydrophobic anchor; as well as a method for producing them.