NL8801331A - PHOSPHORUS-INHIBITING HMG-COA REDUCTASE INHIBITORS, NEW INTERMEDIATES, AND METHOD OF APPLICATION THEREOF. - Google Patents

Description

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Phosphorus-containing HMG-CoA reductase inhibitors, novel intermediates and method for their use.

This invention relates to novel phosphorus-containing compounds that inhibit the action of 3-hydroxy-3-methylglutaryl coenzyme A reductase and thus are useful for inhibiting cholesterol biosynthesis; the invention further relates to hypercholesterolemic preparations containing such compounds, new products resulting from the preparation of these compounds, and a method of using these compounds for those purposes.

F.M. Singer et al. In Proc. Soc. Exper.

10 Biol. Med. 102 (1959) 370 and F.H. Hulcher in Arch. Biochem.

Biophys. 146 (1971) 422 that certain mevalonate derivatives inhibit cholesterol biosynthesis.

Endo et al., U.S. Patent Nos. 4,049,495, 4,137,322, and 3,983,140 disclose a fermentation product which is effective in inhibiting cholesterol biosynthesis. That product is called "compactin," and Brown et al. Report in J. Chem. Soc. Perkin I (1976) 1165 that it has a complex mevalonolactone structure.

GB 1,586,152 describes a group of synthetic compounds according to formula 1, in which E represents a direct bond, a C 1-6 alkylene bridge or a vinylene bridge and the various Rs represent different substituents. The activity mentioned in this British patent is weaker than 1% of that of compactine.

US Patent 4,375,475 describes hypocholesterolemic and hypolipemic compounds of formula 2, wherein AH or methyl, E is a direct bond, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH = CH- R 2, R 3 and R 3 independently of one another is H, halo, C 1-6 alkyl, C 1-6 halo-alkyl, phenyl, halo-substituted phenyl, -alkoxy, C 2-8 alkanoyloxy, C 1-6 alkanoyloxy alkyl or C 1 -haloalkyl or OR 2 where R 2 H, C 2 -G alkanoyl, benzoyl, phenyl, halo-phenyl, phenyl-C 1-8 alkyl, C 1-8 alkyl, cinnamyl, C 1-8 halogen- 8801331 1: 2 "represents" 2 "alkyl, allyl, cycloalkyl-C 1 -alkyl, adamantyl-C 2 -alkyl or substituted phenyl-C 2 -alkyl wherein the substituents are selected under halogen, C 1 -6 -alkoxy,--alkyl and--haloalkyl, as well as the corresponding dihydroxy acids resulting from hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of those acids, and the alk-alkyl esters substituted with phenyl, dimethylamino or acetylamino der d ihydroxy acids; in all these compounds, the tetrahydropyran portion has the 4R configuration.

WO 84/02131 (PCT / EP83 / 003Q8) (based on the

U.S. Patent Applications Nos. 443,668 and 548,850 of November 22, 1982 and November 4, 1983, respectively, in the name of Sandoz AG describe heterocyclic analogues of mevalono-N * lactone and derivatives thereof of formula 3, wherein 15 of R and Rq are one one with R ^, R ,. and R 1 is substituted phenyl group and the other primary or secondary C 1 -alkyl, C-10-j-b cycloalkyl or phenyl- (CH 2) m-1, where R 1 is hydrogen, C 1 -alkyl, -— alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy 20, R 1 is hydrogen, -alkyl, ^ - ^ koxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R, - ^ hydrogen, 2_a ^ yl>

Cj is 2 ~ alkoxy, fluorine or chlorine and where m is 1, 2 or 3, with the limitations that R 1. and R ^ a both must be hydrogen if R ^ is hydrogen, R5a must be hydrogen if R ^ is hydrogen, of R ^ and R. there is no more than one trifluoromethyl, phenoxy or benzyloxy, wherein R 2 is hydrogen, C 1 -3-alkyl, C-3-cycloalkyl, C-3-alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or 30 is benzyloxy,

Rg is hydrogen, C 1 -alkyl, C 1 -2 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the limitations that R 2 must be hydrogen if R 2 is hydrogen, and that of R 2 and R 2 no more than one is trifluoromethyl, phenoxy or benzyloxy, wherein X is - (CH 2 - or -CH = CH- (n * 0, 1, 2 or 3), Z is a group of formula 4, wherein R 9 is hydrogen or C 2 -alkyl, in the form of the free acid or of a physiologically hydrolysable and acceptable ester or in the form of a δ-lactone or in the form of a salt.

,, 8301331 - 3 - * 5 Η λ GB 2.162.179-Α and DE 3.525.256-Α describe naphthyl analogues of mevalolactone useful as inhibitors of cholesterol biosynthesis, having the structure of formula 5, wherein 3 ~ alkyl and Z is a group of formula 5 6a or 6b, wherein hydrogen represents a hydrolysable ester group or a cation.

European Patent Application No. 164,698-A describes the preparation of lactones of formula 7, useful as anticholesterolemia agents, by treating an amide of formula 8 with an organic sulfonyl halide R-SO-X and then removing the protecting group Pr, in which formulas X is halogen, Pr is a carbinol protecting group and R 1 H or CH 3, R 3 and R 1 H, C 1-3 alkyl or phenyl (C 1-3 alkyl), which phenyl optionally is substituted by g-alkyl, C 1 -3 -alkoxy or halogen, wherein is a group of formula 9a or 9b, the dotted lines between A and B and between C and D indicate any double bonds, Q is a carbon atom optionally a carries hydroxy or methyl substituent, is RH or CH 3, R 1 is phenyl or benzyloxy the ring of which is optionally substituted with C 1 -3 alkyl or halogen, R 8 and R 1 C 3 -3 alkyl and / or halogen, R ,. 3-alkyl, phenyl or phenyl substituted once or twice with 3-25 alkyl and X represents a halogen atom.

WO 8402-903 (based on U.S. Patent Application No. 460,600 of January 24, 1983) to Sandoz AG lists mevalolactone analogs useful as agents that lower the lipoprotexes content, having a structure of Formula 10, wherein the two groups Rq together form a tetramethylene bridge or a bridge of formula 11, wherein R 2 is hydrogen, C 1 -alkyl, C 1 -6 -alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy and R 3 hydrogen, C 3 -3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the limitations that of R 2 and R 3 there is no more than one trifluoromethyl, phenoxy or benzyloxy, wherein R 1 is hydrogen, alkyl, fluoro, chloro or benzyloxy, R ^ is hydrogen, ^ -alkyl, ^ -alkoxy (except t-butoxy), c 8 80 1 331 £ fz - 4 - trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R ,. hydrogen, C 1 -alkyl, C 1 -alkoxy, trifluoromethyl, fluoro, chloro, phenoxy, or benzyloxy, R 1 a is hydrogen, C 1 -alkyl, C 1 -2 alkoxy, fluorine or chlorine, 5 with the limitations that of R ^ and R ,. there is no more than one trifluoromethyl, phenoxy or benzyloxy, wherein X is - (CH0) - or trans- (CH0) -CH = CH- (CH2) -, where Zn Z q Z qn 0, 1, 2 or 3 and of both q's one is 0 and the other is 1, wherein Z is a group of formula 12, wherein Rg represents hydrogen 10 or -alkyl, with the general limitation that -XZ and the phenyl group bearing R ^ ortho to one another in the form of the free acid or of a physiologically hydrolyzable and acceptable ester or δ-lactone or in the form of a salt.

Sandoz U.S. Patent No. 4,613,610 discloses a series of substances that inhibit the 7-pyrazolo-3,5-di-hydroheptoic acid HMG-CoA reductase, having the structure of formula 13, wherein 20 R 1 -alkyl without asymmetric carbon atom, R 2 and R 2 independently of each other is hydrogen, alkyl, n-butyl, isobutyl, t-butyl, 2-alkoxyl, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenyl, phenoxy or benzyloxy, Rg and Rg are independently hydrogen, ^ -alkyl, ^ -25 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R ^ and R ^ are independently hydrogen, C1-2 alkyl, alkoxy, fluoro or chlorine, with the limitations that of R2 and R2 there is no more than one trifluoromethyl, there is no more than one phenoxy and there is no more than one benzyloxy, and that of Rg and Rg there are no more than one trifluoromethyl, not is more than one phenoxy and not more than one benzyloxy, where X is - (CHJ -, -CH = CH-, -CH = CH-CH0- or -CH -CH = CH-, zmzz where m is 0.1, Is 2 or 3, and where 3 Z is a group of formula 14 or 15, wherein R ^ q is hydrogen or ^ -alkyl and R ^ represents hydrogen, R ^ or M, wherein R ^ is a physiologically acceptable and hydrolyzable ester group, and wherein M represents a cation , with the limitations that (i) the group -XZ in the 4 or 5 position, 8 80 1 3 3 f - 5 - 'ϊ? ·; λ is on the pyrazole ring and (ii) that the group and the -X-Z group are ortho to each other.

WO 8607-054A (from Sandoz) describes imidazole analogs of mevalonolactone useful for the treatment of hyperlipoproteinaemia and atherosclerosis, having the structure of formula 16, wherein

R 1 alkyl, cycloalkyl, adamantyl-1 or with R 1, R 1. and Rg is substituted phenyl (group A),

Rg is alkyl, cycloalkyl, adamantyl-1 or phenyl substituted with R 1, Rg and Rg (group B),

Rg hydrogen, alkyl, cycloalkyl, adamantyl-1, styryl or with

R 10, R n and R ^ g is substituted phenyl (group C), X - (CH 2) -, -CH = CH-, -CH = CH-CH 2 - or -CHo-0H = CH-, imilm 0 t / m 3 may be 15 Z -CEKOHj-CHg-CiR ^ g) (OH) -CHg-COORj ^ (group A), a group according to formula 15 (group B) or -Q-CHg-C (R ^ g) is (OH) -CHg-COORj ^ (group C), where Q represents CO or -C (0R ^ g) g-,

Rgg is primary or secondary alkyl and both Rgg are identical or together represent ethylene or trimethylene, Rgg is hydrogen, Rgg or M and Rgg represents an ester group and M represents a cation with the limitations that Z can only be a group (C) if X is -CH = CH- or -CHg-CH = CH- and / or if R ^ q g-alkyl, where R ^, Rg and R ^ qg-alkyl , n-, i- or t-butyl, g-25 alkoxy, n- or i-butoxy, CFg, F, Cl, Br, phenyl, phenoxy and / or benzyloxy,

Rg, Rg and Rg hydrogen, Cgg alkyl, Cgg alkoxy, CFg, F, Cl,

Br, COOR ^ y, NiRjgJg, phenoxy and / or benzyloxy can be,

R 12 is hydrogen, R ^ g or M, where R ^ g represents C 1-6 alkyl, n-, i- or 30-t-butyl or benzyl, R ^ g is alkyl and R 9, R 9 and R 6 represents hydrogen, C 12 g-alkyl, C 1 -g-alkoxy, F and / or Cl, with the limitations that (1) on groups A, B and C are not more than one CFg substituent, not more than one phenoxy substituent and not has more than one benzyl oxy substituent, (2) when Z is a group (C) the compound is in the free base form and either (i) R ^ is equal to R ^ g and each R ^ y is independent of the other R ^ g or either (ii) R ^ ^ M and each R ^ is independent of the other R ^ g or M, and 860 133 1. "- 6 - (3) that if and / or at least one of the M is the compound in the form of a free base.

Unless otherwise indicated, all alkyl groups have 1 to 6 carbon atoms but do not have an asymmetric carbon atom and an eycloalkyl group has 3 to 7 carbon atoms.

WO 8603-488-A of Sandoz describes mevalonolactone indene analogues useful as agents for lowering blood levels of lipoproteins and against atherosclerosis, in the form of the free acid, a salt, a 10-lactone or an ester of formula 16a wherein R is hydrogen or a primary or secondary g-alkyl group and R 1 is a primary or secondary g-alkyl group, or

where R and R together form (CH „) or (Z) -CH„ -CH = CH-CH „, where-1 Z m Z Z

at m 2 to 6 may be R 15 is C 1-6 alkyl, C 1-6 cycloalkyl or phenyl substituted with R 1, R 7 and R 8, wherein R 2 and R 6 is hydrogen, C 1-6 alkyl, -Alkoxy (except t-butoxy), CF ^, F, Cl, phenoxy and / or benzyloxy, R ^ and hydrogen, C 1-3 alkyl, C 1-4 alkoxy, CF ^, F, Cl, phenoxy or benzyloxy and Rg may be hydrogen, C1-2alkyl, C1-6alkoxy, F and Cl, with the limitation that the phenyl and indene rings may contain only one CF1, phenoxy and / or benzyloxy, in which X is - (CH „) - or - (CH„) -CH = CH (CH „) - where η 1 to 3 Zn can be Z q Z q 25 and both q's are 0 or one is 0 and the other 1, wherein Z is -Q-CH 2 -C (R 1 q) (0H) -CH 2 CO 2 H, in the form of the free acid, a salt, an ester or a δ-lactone, where Q is for —CO—, - C (ORy) 2_ or -CHOH- state and the two groups R ^ are the same primary or secondary C ^ _g -alkyl group or together form 30 - (CH2> 2 or - (CH2) 3-), and where R ^ q is hydrogen or C 1-3 alkyl, with the limitation that Q can only be other than CHOH if X is -CH = CH- or -CH 2 - CH = CH- and / or R ^ is a C1-3 alkyl.

U.S. Patent No. 4,647,576 to Warner Lambert describes new C- and N-substituted pyrroles useful as agents for lowering blood levels of lipids and cholesterol, according to formulas 17 and 18, wherein X -CH2- CH 2 CH 2 - or -CH (CH 3) CH 2 - is, 6601331 4 - 5 - 7 - '

Or R-naphthyl, cyclohexyl, norbornenyl, optionally with F,

Cl, OH, CF 9, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkanoyloxy substituted phenyl or 2-, 3- or 4-pyridyl, an N-oxide thereof or an N-alkylpyridinium group, And Rg may be H, Cl, Br, CN, CFg, phenyl, C 1 -C 4 alkyl, C 2 -C 8 carbonalkoxy, -CHgORg and / or -C 2 OCONHR-, where Rg is H or C 8 -alkanoyl and R 1 alkyl or phenyl substituted optionally with C 1, Br or C 1 alkyl, or wherein R 4 and R 6 together - (CH 2) -, -CH 2 OCH 2, -CO 2 (Ro) CO- or Z 3 Zn zzo 10 -C0N (Rg) N (R ^ Q) CO2 forms, where n is 3 or 4, Rg is H, C 1-8 alkyl, phenyl or benzyl, Rg and R ^ q are H, C 1-4 alkyl or benzyl and R 1 is C 1 -C 20 alkyl, cyclopropyl, cyclobutyl or CFg.

European patent application 221,025 to Sandoz describes heterocyclic analogues of mevalonolactone and its derivatives according to formula 19, wherein R 1 is a group -XZ, R 1 = R 2, R 1 = R 1, R 1 = R 1 and Y 1 a group -N (Rj) -, or where R & = R ^, R ^ = a group -XZ, Rc = R2, R, R ,, and Y is 0, S or a group -N (R.) -,

Cl J H

wherein R ^, R2, Rg and R ^ independently of each other are C ^ _ ^ alkyl 20 without asymmetric carbon atom, C ^ _ ^ cycloalkyl or with Rg,

Rg and Ry are substituted phenyl, wherein Rg and R ^ may additionally be hydrogen, and if Y is 0 or S Rg may also be a group of the formula -C (Rj2) = C (Rj | g) (R ^ g) wherein R 4 represents hydrogen or C 1-6 alkyl and R 4 g and R 4 independently are hydrogen, C 1-6 alkyl or phenyl, and R 8 hydrogen, C 1-6 alkyl, n-butyl , i-butyl, t-butyl, C 1-8 -alkoxy, n-butoxy, i-butoxy »trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy, Rg represents hydrogen, C 1-6 -alkyl, C 1 -g -alkoxy, trifluoromethyl, fluorine, chlorine, bromine, phenoxy or benzyloxy and R 1 represents hydrogen, C 1 -alkyl, C 1 -2 alkoxy, fluorine or chlorine, with the limitation that only one trifluoromethyl on each ring A , only one phenoxy and only one benzyloxy may be present. Furthermore, X is (CH „) or (CH_) CH = CH (CH„), where m is 0, 1, 2 or 3 and Z m Z q Z q 35 are both q's 0 or one 0 and the other 1. Z is a group -CH (0H) -CH 2 -C (Rg) (OHj-CHg-COOH, in the form of the free acid, of a salt, of an ester or of a lactone, where Rg is hydrogen or C1-alkyl These compounds would be useful as agents for reducing blood levels of 8801331 s * at - 8 - on lipoproteins and against atherosclerosis.

Tetrahedron Letters 29 (1988) 929 describes the synthesis of a retimer of 3-hydroxy-2-methylglutaryl coenzyme A reductase of formula 20, wherein R is Na or C 2 H 5.

European Patent Application No. 127,848 to Merck & CO. Ine. describes derivatives of 3-hydroxy-5-thia-1-aryl alkanoic acids of the formula wherein X is hydrogen, a C 1-8 alkyl group, an alkali cation or the ammonium ion, n 0, 1 or 2 is, e is -ch2-, -ch2-ch2-, -ch2-ch2-ch2-, -ch = ch-ch2- or -ch2-ch = ch-, Z is optionally substituted with 1, 2 or 3 substituents phenyl group or an α-naphthyl group optionally substituted at positions 2, 4 and / or 7.

These compounds act against hypercholesterolaemia by inhibiting HMG-CoA reductase and also acting against fungi.

French Patent Application No. 2,596,393 A of April 1, 1986 describes 3-carboxy-2-hydroxypropane phosphonic acid derivatives, including their salts, which are useful as hypolipemic agents, according to formula 2.1, wherein R 1, R 2, Rg and R hydrogen, lower alkyl and optionally substituted aralkyl, and R8 and R1 may additionally be substituted aryl. These compounds are said to lower the levels of cholesterol, triglycerides and phospholipids more than the meglutol.

European Patent Application No. 142,146 discloses 30 mevinolin-like compounds of formula 22, wherein

R 1 is, for example, hydrogen or -alkyl and E is ethylene, polymethylene or vinylene, and wherein Z

1) is a group of formula 23 wherein X is -O- or -NR ^ -, wherein R ^ represents hydrogen or g-alkyl, R ^ is C2-alkyl, and Rg is H or CHg, or 2) optionally with 1 , 2 or 3 substituents substituted phenyl group or 3) an optionally substituted α-naphthyl group, 4) a group of formula 23a.

. J) et al. Compounds are inhibitors of HMG-CoA reductase.

“8801331 S l S \ 3- - 9 -

This invention now provides phosphorus-containing compounds that inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and thus are useful as hypocholesterolemic agents and are characterized by the group of formula 17, wherein X is - (CH7) -CH = CH-, -C = C- or -CH2 O- (where the oxygen is on Z), a is 1, 2 or 3 and Z is a "hydrophobic anchor".

The term "hydrophobic anchor" used herein stands for a lipophilic group which, when attached to the HMG-like core group by an appropriate bridge ("X") 10, binds to a hydrophobic pit in the enzyme which is not used for binding of the substrate HMG-CoA, which, compared to compounds in which Z = H, leads to compounds with enhanced adhesion.

In preferred embodiments, the compounds of the invention are of formula 25, wherein R is OH or lower alkoxy,

Rx is H or lower alkyl, x -ch2-, -ch2ch2-, -ch2ch2ch2-, -ch = ch-, -esc- or -ch2o is 20 (where oxygen is in Z) and Z is a hydrophobic anchor, as well as the pharmaceutically acceptable salts thereof.

The term "salt" refers here to salts with inorganic and organic bases. These include the ammonium, alkali metal and alkaline earth metal salts (including the preferred lithium, sodium and potassium salts) and the salts of organic bases such as dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine and amino acids such as arginine, lysine, etc. The non-toxic, pharmaceutically acceptable salts are preferred, although other salts are sometimes also useful, for example, in isolating and purifying the product.

Examples of hydrophobic anchors that can occur according to this invention are (not exhaustive list) groups of formulas 26, 27, 28, 29a, 29b, 29c, 30, 31, 35, 32, 33, 34 and 35, in which the dotted lines are any double bonds for example, groups of formulas according to formulas 35a, 35b, 35c, 35d, 35e, 35f and 35g, wherein R, R ', R' and Rn, L La Ld independently of one another are hydrogen, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or R 4, where 1, 2, atomic, lower alkyl, haloalkyl, allyl, cycloalkyl-3β-; - lower alkyl * alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, cinnamyl or is adamantyl-lower alkyl.

If Z is a group of formula 35, R 5 and R 5 are independently hydrogen, lower alkyl or hydroxy, R 6 is lower alkanoyl, for example CH 2 -CH 2 -CKCHg) (R 1) -CO- or arylmethyl with R 1 is hydrogen or lower alkyl, and q is 0, 1, 2 or 3.

If Z is a group of formula 28, 29a, 29b, 10 29c, 30, 31 or 33, of R 1 and R 1 there is one with R 1, R, and 34 13 14 R 1 a substituted phenyl and the other lower alkyl, cycloalkyl or phenyl- (CH-) - with p is 0, 1, 2, 3 or 4, zp where R 1 is hydrogen, lower alkyl, lower alkoxy (except t-butoxy), halogen, phenoxy or is benzyloxy, R 15 is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy, or benzyloxy, is 14a hydrogen, lower alkyl, lower alkoxy, or halogen, with the limitations that if R 1 is hydrogen R 1 and R 2 a that should also be that if R ^ is hydrogen R ^ a it should be 20, and that of R ^ and R ^ there is no more than one trifluoromethyl, no more than one phenoxy and no more than one benzyloxy wherein Rg is hydrogen, -alkyl, Cg -cycloalkyl, -alkoxy (except t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,

Rg is hydrogen, C 1-8 alkyl, g-alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the restriction that if Rq is hydrogen RQ must also be and that of R0 and Royoy there are not more than one trifluoromethyl , not more than one phenoxy and 30 not more than one benzyloxy, R10 and R1 are independently hydrogen, alkyl, cycloalkyl, adamantyl-1 or phenylalkyl having 0, 1, 2, 3 or 4 carbon atoms in the alkylene bridge and with 0, 1, 2 or 3 substituents, 35 and Y is 0, S or NR ^ q.

If Z is a group of formula 32, R fl is hydrogen or primary or secondary g-alkyl, R g is primary or secondary C 1-8 alkyl,

or form R and R, together - (CEL) - or cis -CH «-CH = CH-CH0-, with a D Zr Z Z

8801331 3, - 11 - r is 2, 3, 4, 5 or 6, R 12 is lower alkyl, cycloalkyl or phenyl substituted with 0, 1, 2 or 3 substituents.

If Z is a group of formula 33, R ^.

5 and R ^ g are both H, Gl, Br, CW, CF ^, phenyl, C ^ _ ^ -alkyl, C2_g-alkoxycarbonyl, -CH2 OR ^ or -d ^ OCONHR ^ g, where R ^ is H or C -alkanoyl and R10 is alkyl or optionally with F, Cl, Br or 1-10

C 1-4 alkyl substituted alkyl, or R 4, and R 4 g together form "(cVs" - -CH2 OCH2-, -con (r19) co- or -con (r20) n (r21) co-, 10 where s is 3 or 4, R ^ is H, C 1-8 alkyl, phenyl or benzyl and R 20 and R ^ is H, C 1-6 alkyl or benzyl, with the limitations that X is only -CH., -, -CH2CH2- or -CH2CH2CH2- can be.

If Z is a group of formula 34, R22 is lower alkyl, cycloalkyl, adamantyl-1 or phenylalkyl having 1, 2, 3, 15 or 4 carbon atoms in the alkylene bridge and R 4 and R 22a are hydrogen, lower alkyl, independently of one another. lower alkoxy (except t-butoxy), halogen, phenoxy or benzyloxy, with the limitations that if R ^ is hydrogen R ^ a should be too and that of R ^ and R23a there should be no more than one trifluoromethyl, no more than one phenoxy, and is no more than one benzyloxy.

If X is -CH 2 O- (with the carbon on the phosphorus and the oxygen on the group Z), the hydrophobic anchor Z will be of the phenyl or naphthalene type, according to formula 26 or formula 27.

Thus, the compounds of formula 25 include those of formulas 25a, 25b, 25c, 25d, 25e, 25f, and 25g.

The terms "alkyl" and "lower alkyl" used by themselves or as part of another group herein refer to both branched and straight chain hydrocarbon chains, 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 and dodecyl, the various branched isomers thereof, as well as these handles with the halogen substituents F, Br, Cl, J and CF ^, the alkoxy, aryl, alkylaryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol and alkylthio substituents.

The term "cycloalkyl" used herein alone or as part of another group refers to saturated cyclic, 8801331; 1 to 12 hydrocarbon radicals having 3 to 12, preferably 3 to 8, carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclodode-cyl, all of which may be substituted with 1 or 2 halogens , 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 10 t8801331-13 * * 1 alkanoylamino 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 terms "aryl" and "Ar" used herein refer to 5 monocyclic and bicyclic aromatic groups having 6 to 10 ring carbon atoms, such as phenyl, naphthyl, substituted phenyl and substituted naphthyl, the substituents of which are both phenyl and naphthyl 1,2 or 3 lower alkyl groups halogen atoms (Cl, Br and F), 1, 2 or 3 lower alkoxy groups, 10 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 15 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, preferably an aryl group having three substituents.

The terms "aralkyl", "arylalkyl" and "aryl-lower alkyl", by themselves or as parts of other groups, here refer to lower alkyl groups as discussed above and having an aryl substituent such as benzyl,

The terms "lower alkoxy", "alkoxy", "aryloxy" and "aralkoxy", by themselves or as parts of other groups, herein refer to the above-mentioned alkyl, aryl and aralkyl groups attached to an oxygen atom.

The terms "lower alkylthio", "alkylthio", "aryl-thio" and "aralkylthio", alone or as parts of other groups, here refer to the above-mentioned alkyl, aralkyl and aryl groups attached to a sulfur atom.

The terms "lower alkylamino", "alkylamino", "arylamino" and "arylalkylamino", by themselves or as parts of other groups, herein refer to the above-mentioned alkyl, aryl-35 and arylalkyl groups attached to a nitrogen atom.

The term "alkanoyl", by itself or as part of another group, here refers to a lower alkyl group attached to a carbonyl group.

The term "halogen" here refers to chlorine, bromine, 8001331 * 1 '- 14 - fluorine, iodine and trifluoromethyl, with preference for chlorine and fluorine.

Preferred are the compounds of formula 36 wherein R = HO, LiO or CH „0, R = Li or Η, X = -CH9-, -CH0CH„ -, -5 -CE ^ CE ^ CE ^, -CH = CH- -C = C- or -C 2 O-, and wherein Z is a group of formula 26 wherein R 1 is phenyl with optionally an alkyl and / or halogen substituent or cycloalkylalkyl such as cyclohexylmethyl or benzyloxy with optionally a halogen substituent, and wherein R 1 and R 1 a are the same and represent halogen or lower alkyl. Z may also preferably be a group of formula 26a in which R 1 and R 2 have the meanings just given or a group of formula 28a in which R 1 is substituted phenyl, lower alkyl, cycloalkyl or phenylalkyl and R 1 is substituted phenyl, lower alkyl ( e.g. isopropyl), cyclo-15alkyl or phenylalkyl.

Z may also preferably be a group CH 2 CH 2 CCCH 2) (R 2) CO 2 wherein R 1. = H, CH 2 or OH and R 2 is a group of formula 25 or substituted benzyl, where R 2 represents H or CH 2.

Z may also preferably be a group of formula 29a, 29b or 29c wherein of R 1 and R 1 at least one is phenyl or substituted phenyl and the other is lower alkyl,

The compounds of the invention can be prepared by the following series of reactions, which are now described.

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8801331 - 18 - 1, Γ i t

As can be seen, compounds of formula 25 can be prepared by subjecting the iodide of formula 37 to the Arbuzov reaction by heating the iodide (37) with a trialkyl phosphite, using standard 5 Arbuzov conditions and methods, whereby the phosphonate (38) creates a new intermediate product.

The phosphonate (38) then undergoes a phosphoric acid ester cleavage by successively treating a solution of compound (38) in an inert organic solvent such as methylene chloride under an inert atmosphere such as argon with bis (trimethylsilyl) trifluoroacetamide (BSTFA) and trimethyl -silyl bromide, which creates the phosphonic acid (39), a new intermediate. This phosphonic acid (39) is then esterified by treating it in dry pyridine with an alcohol (such as methanol) and dicyclohexylcarbodiimide and stirring the resulting reaction mixture under an inert atmosphere, such as argon, to give the phosphonic acid monoalkyl ester of formula 40 (a new intermediate product). This phosphonic acid monoester (40) is then treated with trimethylsilyl diethylamine under argon in an inert solvent such as methylene chloride, benzene or tetrahydrofuran. The reaction mixture is evaporated to dryness and the residue is taken up in methylene chloride (or other suitable inert organic solvent), and after cooling to a temperature between -10 ° and 0 °, oxalyl chloride and dimethylformamide as catalyst are added, which after evaporation to dryness. the phosphonic acid chloride of formula 41 (a new intermediate). The phosphonic acid chloride (41) is dissolved in an inert organic solvent, such as methylene chloride, benzene, pyridine or THF, and after cooling to a temperature between 30 -90 ° and 0 °, preferably between -85 ° and -30 °, a solution of the lithium salt of the acetylene of formula 44 cooled to approximately the same temperature is added, using a molar ratio of (41) to (44) between 3: 1 and 1: 1, preferably between 1.5: 1 and 2: 1 to give the acetylene phosphinate of formula 45 (a new intermediate).

The acetylene phosphinate (45) can then serve to prepare various compounds of the invention as follows. The acetylene phosphinate (45) can be subjected to silyl ether cleavage by treating (45) in an inert organic solvent such as tetrahydrofuran with glacial acetic acid and tetrabutyl ammonium fluoride to give a compound of formula 25a R = alkoxy and R = alkyl. This can then be done

X

5 the corresponding monoester of formula 25a, wherein R = alkoxy and = H are hydrolyzed by treating it in dioxane under an inert atmosphere with a strong base, with a molar ratio of base to ester (45) from 1: 1 to 1.1 : 1.

That compound can then be converted into the corresponding acid with a strong acid such as HCl.

By treating the ester (45) with a strong base at 50-60 ° using a base to ester (45) molar ratio between 2: 1 and 4: 1, the salt of the acid of formula 25a wherein R = HO and = H. This can again be converted into the free acid by treatment with strong acid such as HCl.

Compounds of the invention in which X is cis-CH = CH- are formed by subjecting the acetylene phosphinate (45) to selective reduction, for example, by (45) in an inert organic solvent such as methanol and in the presence of a catalyst such as palladium- treating on-carbon with hydrogen; this then gives the ester of formula 46 (a new intermediate). It can undergo a silyl ether cleavage in the manner as already described above, giving a compound of formula 25b in which R = alkoxy and R =

X

alkyl. It can be hydrolyzed in the manner already described above to salts of the monoalkyl ester and of the free acid, which are liberated when acidifying with a strong acid. Compounds of the invention in which X is -C 1 Cl 2 - i.e., compounds of formula 25d, are formed by catalytically reducing an acetylene phosphinate (46), for example in an inert organic solvent such as methanol in the presence of a catalyst such as palladium-op coal with, for example, 3¾ atmosphere of hydrogen; this gives a silyl ether according to formula 35 47 (a new intermediate). This compound (47) can then undergo a silyl ether cleavage and hydrolysis as described above to give a dialkyl ester, a monoalkyl ester or the free acid of formula 25d or a corresponding salt.

.8801331 - 20 - ï 1 * f

The series of reactions "B" leads to compounds of formula 25 wherein the bridge between the phosphorus atom and the hydrophobic anchor Z is trans-CH = CH-. These can be prepared by treating a mixture of the acetylene of formula 44 and (nC ^ Hg ^ SnH 5 with a radical initiator such as azobisisobutyronitrile (AIBN), hydrogen peroxide, benzoyl peroxide, etc. and the reaction mixture under inert atmosphere such as argon to a temperature between Heating to 100 ° and 140 °, resulting in the formation of the vinyl stannane of formula 45. This vinyl Ι -stannane (45) is treated with iodine in an organic solvent such as ethyl ether, methylene chloride or chloroform to form the vinyl iodide of formula 46. The vinyl iodide (46) is treated in a dry organic solvent such as tetrahydrofuran or ethyl ether under an inert atmosphere at a temperature between -78 ° and -40 ° with a metallating agent such as n-butyl lithium, and at the same A solution of the phosphonic acid chloride (41) is added at a low temperature, with a molar ratio of (46) :( 41) between 1: 1 and 2: 1, preferably between 1: 1 and 1.5: 1. results in the compound of formula 47 (a new intermediate). The compound (47) then undergoes silyl ether cleavage by treating (47) in an inert organic solvent such as tetrahydrofuran or acetonitrile with acetic acid and (nC ^ Hg) ^ NF to give a dialkyl ester of formula 25c wherein R = Alkoxy and Rx = alkyl.

This diester can then be converted into monoalkyl ester and free acid or corresponding salt in the manner previously described.

In another approach, represented in the series 30 reactions "C", compounds of formula 25, wherein the X bridge between the carbon atom and the hydrophobic anchor Z trans-CH = CH- are prepared by the aldehyde of formula 42 in the presence of allowing an organic solvent such as tetrahydrofuran or diethyl ether to condense at low temperature (-90 ° to 0 ° C) with LiCS 4 PO (alkyl) itself formed in solution from dialkylmethylphosphonate and butyl lithium; this leads to a β-hydroxyphosphonate according to formula 51.

This β-hydroxyphosphonate (51) is then treated in benzene or toluene with p-toluenesulfonic acid, at a temperature between 50 ° and 120 ° C (preferably under reflux), whereby, 88 0 1331 - 21 - ί · £ * ι * water is split off and the trans-olefin according to formula 52 is formed, which is hydrolysed in dioxane or another inert organic solvent with an alkali metal hydroxide such as LiOH; this gives the monoalkyl ester of formula 53.

Trimethylsilyldiethylamine is added to a solution of the monoalkyl ester (53) in dry methylene chloride, and after evaporation to dryness, the residue is taken up in dry methylene chloride and cooled to 0 ° C, after which oxalyl chloride and a catalytic amount of dimethylform-10 amide are added under an inert atmosphere. adds; this produces the phosphonic acid chloride according to formula 54.

The phosphonic acid chloride (54) is condensed in an inert organic solvent such as tetrahydrofuran, at a temperature between -90 ° and -40 °, with the dianion of methyl acetoacetate of formula 55, with a molar ratio of (54) :( 55) between 1 : 1 and 0.75: 1; this produces the ketophosphonate of formula 56 (a new intermediate) which is reduced in an alcohol such as ethanol with sodium borohydride to the phosphate of formula 57.

This diester (57) can be hydrolyzed to mono alkyl ester and to free acid or corresponding salt in the manner previously described.

According to the series of reactions "D", compounds of formula 25 wherein X is -CH 2 -, -C 1 CH 2, or -C 1 CH 3 CH 3 - can be prepared starting from the aldehyde (42) which is known in a known technique. halide of formula 58 turnover. For example, the aldehyde (42) in an alcohol with NaBH4 is reduced to the corresponding alcohol, which is then treated with mesyl chloride in the presence of a solvent such as methylene chloride and an organic 3G base such as triethylamine, whereby the chloride according to formula 59 (a = 1 ) arises.

This chloride (59) is reacted with a trialkyl phosphite at a temperature between 100 ° and 150 ° in a molar ratio between 1: 1 and 10: 1 to give a phosphonic acid diester of formula 60. A solution of the phosphonate (60) in a solvent such as dioxane is treated with a strong base such as LiOH to give the corresponding monoester which is treated with oxalyl chloride in the presence of an organic solvent such as dimethylformamide to yield the corresponding 8001 ^ 31 - 22 - τ ».

Strong phosphonic acid chloride according to formula 61 is formed.

This acid chloride is then allowed to condense with the dianion of an alkyl acetoacetate of formula 55 in a molar ratio of (61) :( 55) between 1 in the presence of an inert organic solvent such as tetrahydrofuran at reduced temperatures between -90 ° and -40 °. : 1 and 0.75: 1 to give the ketophosphinate of formula 62 (a new intermediate). This ketophosphinate (62) can then be reduced to the corresponding phosphinate of formula 25d (R = alkoxy and R =

X

10) which can then be hydrolyzed to the free acid in the manner previously indicated.

According to the series of reactions "E", compounds of formula 25 wherein X -C 2 O- is prepared can be prepared from the aldehyde of formula 42, which undergoes a Bayer-Villiger-15 oxidation by (42) in the presence of an inert organic solvent such as methylene chloride with m-chloro-perbenzoic acid and then with a strong base such as KOH or NaOH and a solvent such as tetrahydrofuran to give a Nor alcohol of formula 63. The alcohol (63) is alkylated by first treating it in an inert organic solvent such as dimethyl formamide with sodium hydride under an inert atmosphere and then with a solution of a dialkyltosyloxymethyl phosphonate of formula 64, with a molar ratio of (63) :( 64) between 1: 1 and 1: 3 to give the corresponding dialkyl ester of formula 65. The rest of the synthesis according to series reactions "E", ie the formation of the monoester of formula 66, of the acid chloride of formula 67, the ketophosphinate of formula 68 (a new intermediate) and the diester of formula 25g (R = alkoxy and Rx = alkyl) and the corresponding free acid (R = HO and R = H) is equal to that

X

from series reactions "D".

The starting material of formula 44 can be prepared starting from the corresponding aldehyde of formula 42, 35 by subjecting (42) to a Wittig reaction, for example, by applying a cooled (-25 ° to 0 ° C) solution of (42) and add triphenylphosphine in an inert organic solvent such as methylene chloride tetrabromomethane in an inert solvent such as methylene chloride to give the vinyl dibromide, 8801331-23 * 4 * of formula 43. This compound (43) then undergoes dehydrohalogenation by treatment with n-butyl lithium in an inert organic solvent such as hexane to yield the acetylene (44).

But also the aldehyde (42) can be directly converted into the acetylene (44) by being in an inert solvent such as tetrahydrofuran under inert atmosphere at a temperature between -78 ° and 25 ° C in the presence of potassium t-butylate with react dimethyldiazomethane phosphonate.

The starting material of formula 37 can be prepared starting from the bromide of formula 69, which is itself obtained by the methods described in Tetrahedron Letters 26 (1985) 2951). (69) is dissolved together with imidazole and 4-dimethyl-aminopyridine in dimethylformamide and t-butyldiphenylsilyl chloride is added under this inert atmosphere to give the bromide corresponding to the compound (37). A bromine / iodine exchange is applied to this by boiling the bromine compound in butanone with sodium iodide.

The aldehydes of formula 42 are known compounds.

The intermediates of formulas 38, 39, 40, 41, 45, 46, 47, 50 and 56 are also an aspect of this invention. These new intermediates, including all stereoisomers thereof, can be represented by the general formulas 70 and 71, wherein R 'is alkoxy or hydroxy and R' is alkoxy, hydroxy, Cl, -CH2-Z, -CH2CH2CH2-Z, - CH2O-Z, -C2 CZ, -CH = CH-Z and -CH2CH2-Z.

The compounds of the invention can be formed as racemic mixtures and can be split to yield the preferred S isomer. However, the compounds according to the invention can also be obtained directly in the form of S isomers, as will be explained below.

The compounds of the invention are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are thus useful for inhibiting cholesterol biosynthesis, as shown in the following experiments.

- 8801331 - 24 - J * a t 1) HMG-CoA reductase from the rat liver

The activity of the rat liver HMG-CoA reductase was measured by a modification of the method described by Edwards (P. A. Edwards et al. In J. Lipid. Res. 20 (1979) 40). Rat liver microsomes were used as a source of enzyme and the enzyme activity was determined by measuring the conversion of 14 14 C-HMG-CoA to C-mevalonic acid.

a. Preparation of the microsomes

Livers were decapitated from 2 to 10 4 Chragerylamine fed Sprague-Dawley rats and homogenized in phosphate buffer A (0.04 M potassium phosphate (pH 7.2), 0.05 M KCl, 0.1 M sucrose, 0.03 M EDTA and 500 KI units / ml aprotinin). The homogenate was centrifuged at 16,000 g at 4 ° C for 15 minutes. The supernatant was removed and centrifuged a second time under the same conditions.

This second supernatant was then centrifuged at 100,000 g at 4 ° C for 70 minutes. The sedimented microsomes were suspended in a minimum volume of buffer A (3-5 ml per liver) and homogenized in a glass / glass homogenizer. 10 mM dithiothreitol was added, and known portions of the preparation were quickly frozen in acetone / carbonic acid and stored at -80 ° C. The specific activity of the first microsome preparation was 0.68 nmol mevalonic acid per mg protein per minute.

25 b. Enzyme determination

The reductase was determined in 0.25 ml of liquid containing the following ingredients at the indicated final concentrations: 0.04 M potassium phosphate, pH = 7.0 30 0.05 M KCl 0.10 M sucrose

0.03 M EDTA

0.01 M Dithiethreitol 3.5 mM NaCl 35 1% Dimethyl sulfoxide 50-200 yug Microsomal protein 100 µM 14C - / "DL_7hMG-CoA (0.05 µCi,> 30-60 mCi / mmol) 2.7 mM NADPH ( nicotinamide adenine dinucleotide phosphate), -980 1 331 - 25 -

i X

* a>

The reaction mixtures were incubated at 37 ° C.

Under the conditions described, the enzyme activity increases directly with the amount of protein, up to 300% microsomal protein per reaction mixture, and the conversion is also proportional to time for at least 30 minutes. The standard incubation time chosen for this study was 20 minutes, resulting in 12-15% conversion of the substrate to the product mevalonic acid.

The substrate (DL-) HMG-CoA was used in 100 yuM, twice the concentration required to saturate the enzyme under the conditions described. NADPH was used in excess, 2.7 times the concentration required to reach the maximum enzyme rate.

Standard tests for evaluating the inhibitors were done as follows. Microsome enzyme was incubated at 37 ° C in the presence of NADPH for 15 minutes. The DMSO, with or without test substance, was added and then the mixture was incubated at 37 ° C for an additional 15 minutes. The enzyme test started with the addition of the substrate C-HMG-CoA. After 20 minutes at 37 ° C, the reaction was stopped by adding 25 µl of 33% KOH.

0.05 µCi H-mevalonic acid was added and the reaction mixture was allowed to stand at room temperature for 30 minutes. Then 50 µl 5N HCl was added to lactonize the mevalonic acid. Bromophenol blue was added as a pH indicator to monitor the drop in pH. Lactonization was allowed to proceed at room temperature for 30 minutes. The reaction mixtures were then centrifuged at 2800 rpm for 15 minutes. The supernatants were placed on 2 g of anion exchanger AG 1-X8 (from Biorad, in the formate form) which was poured into 0.7 cm inner diameter glass columns and eluted with 2.0 ml of water. The first 0.5 ml was discarded and the next 1.5 ml collected and in 10.0 ml "Opti-Fluorine" scintillation fluid both tritium and C14 were counted. The mevalonic acid (in nanomoles) formed in 20 minutes was calculated from this with a correction to 100% of the tritium. From the composite dose / response data, the effects of the test substances were calculated as ED ^ values (concentration of the substance that inhibits enzyme activity by 50%) with the 95% confidence limits.

Conversion of the test substances from the lactone form to <BSD 1331 ir -26-- their sodium salts was done by solubilizing the lactone in DMSO, adding a 10-fold excess of NaOH and the reaction mixture at 15 minutes room temperature.

The reaction mixture was then partially neutralized with 1N HCl (to pH 7.5-8.0) and diluted in the enzyme reaction mixture.

2) Cholesterol synthesis in freshly isolated rat hepatocytes

Compounds exhibiting inhibitory action on the HMG-CoA reductase were evaluated for their ability to inhibit the incorporation of 14 C acetate into cholesterol in 10 freshly isolated rat hepatocyte suspensions, by methods initially described by Capuzzi et al. (DM Capuzzi and S Margolis in Lipids 6 (1971) 602).

a. Isolation of rat hepatocytes Sprague-Dawley rats of 180-220 grams were anesthetized with 50 mg / kg Nembutal. The abdominal cavity was opened and the first branch of the portal vein was tied off. 100-200 units of heparin were directly indicated in the hollow vein of the abdomen. A single sealing suture was placed on the distal end of the portal vein and a cannula was placed between that suture and the first branch vein. The liver was flushed at 20 ml / min at 37 ° C pre-warmed oxygen-aerated buffer A (HBSS without calcium or magnesium but with 0.5 mM EDTA) after the hollow vein 25 had been cut to allow effluent to drain.

In addition, the liver was flushed with 200 ml of pre-warmed buffer B (HBSS with 0.05% bacterial collagenase). After the perfusion with buffer B, the liver was excised and encapsulated in 60 ml of Waymouth medium so that free cells could disperse in the medium. Hepatocytes were isolated by centrifugation at low speed, i.e., 50 g, for 3 minutes at room temperature. The sedimented hepatocytes were washed once with Waymouth medium, counted and tested for viability with trypan blue (should be left out). These hepatocyte-enriched cell suspensions routinely exhibited a life force of 70-90%.

14 b. Incorporation of C-acetate into cholesterol

Hepatocytes were suspended to a concentration of 5 x 10 cells per 2.0 ml in incubation medium (IM) (0.02 6, 8801331 3t 'Ji - 27 - M Tris.HCl (pH = 7.4), 0.1H KC1, 3.3 mM sodium citrate, 6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate).

As a routine, the test substances were dissolved in DMSO or DMSO / water 1: 3 and added to the IM. The final concentration of the DMSO in the IM was £ 1.0%, which has no significant influence on cholesterol synthesis.

14

Incubation was initiated by adding C acetate (58 mCi / mmol, 2 µCi / ml) and holding 2.0 ml cell suspension in 35 mm tissue culture dishes at 37 ° C for 2.0 hours. After incubation, the cell suspensions were transferred to glass centrifuge tubes and spun at 50 g at room temperature for 3 minutes.

The sedimented cells were resuspended and lysed with 1.0 ml water and then placed in an ice bath.

The extraction of the lipids was essentially done as described by E.G. Bligh and W.J. Dyer described in Can. j.

Biochem. and Physiol. 37 (1959) 911. The lower organic phase was removed and dried with a stream of nitrogen and the residue was resuspended in 100 µl chloroform / methanol 2: 1. The total sample was placed on silica gel thin layer plates (LK6D) and developed with hexane / diethyl ether / acetic acid 75: 25: 1. The plates were automatically scanned and counted with a BioScan device. The radioactivity of the cholesterol peak (R = 0.28) was measured and expressed in total count per liter. peak and as percent of the brand in the total lipid extract. Routinely, the cholesterol peaks from the blank samples contained 800-1000 cpm and 9-20% of the total lipid extract brand, results comparable to that of Capuzzi et al., About 9% of the radioactivity in the cholesterol.

Effects of the test substances (% inhibition of cholesterole synthesis) were determined by determining% of the radioactivity in cholesterol in test-treated and blank incubations. Dose / response curves were drawn from the figures of two or more studies and calculated ED values with 95% confidence limits.

35 3) Cholesterol synthesis in human skin fibroblasts

Selectivity of a substance with more inhibition of the liver tissue will be a favorable attribute of an inhibitor of cholesterol synthesis. Therefore, these compounds were tested not only for inhibition of cholesterol synthesis in hepatocytes, but also in fibroblast cultures.

a. Cultivation of human skin fibroblasts

Human skin fibroblasts (generations 5 7-27) were grown in the minimal essential medium of

Eagles (EM) containing 10% fetal calf serum. For each run, stock cultures were trysonized to disperse the monolayer of the cells and the cells were counted and plated in 35 mm tissue culture plates (5 x 10 "cells in 2.0 ml). Cultures were maintained at 37 ° for 18 hours. C incubated under a mixture of 5% CO 2 and 95% humidified ambient air.

The enzymes of the cholesterol biosynthesis were induced by removing the serum-containing medium, washing the cell mono-layers and adding 1.0 ml EM containing 1.0% of fatty acid liberated bovine serum albumin and then 24 an hour to grow.

14 b. Incorporation of C-acetate into cholesterol

EMEM

Induced fibroblast cultures were washed with 100 (Earle minimal essential medium). The test substances were dissolved in DMSO or in DMSO / EM 1: 3 (final concentration in DMSO in the cell cultures ^ 1.0%) and thus added to the cultures, which were preincubated for 30 minutes at 37 ° C under a mixture of 5% CO 2 and 95% humidified ambient Z-14 air. After pre-incubation with the test substance, / 1 C / Na acetate was added (2.0 µCi / ml, 58 mCi / mgmol) and the cultures were incubated for an additional 4 hours. The culture medium was then removed and the cell monolayer (200 µg of cell protein per culture) was scraped and suspended in 1.0 ml of water. The lipids were extracted from the lysed cell suspensions with chloroform / methanol as described for the hepatocyte suspensions. The organic phase was dried with nitrogen and the residue resuspended in 100 µl chloroform / methanol 2: 1, and the total sample was loaded onto silica gel thin layer plates (LK6D) and analyzed in the same manner as in the hepatocytes.

Inhibition of cholesterol synthesis was determined by comparing percentages of radioactivity in the blank cholesterol peak and test cultures. The results are expressed in the ED ^ Q values, which were derived from dose-res-40 punch curves from two or more experiments. The .8801351 - 29 - 4 i *, 95% confidence limits were also calculated from this.

Another aspect of this invention is a pharmaceutical product containing at least one compound of formula 5 18 in combination with a pharmaceutical carrier or diluent. The pharmaceutical preparation can be formulated with the usual solid and liquid carriers and diluents and pharmaceutical auxiliaries according to the nature of the intended mode of administration. The compounds can be administered orally, for example in the form of tablets, capsules, granules and powders, but also parenterally in the form of injectable preparations containing 1 to 2000 mg of active substance per unit dose. The dose to be administered depends on the patient's symptoms, age and body weight.

The compounds of formula 18 can be administered in a similar manner to known compounds which have been proposed for inhibiting cholesterol biosynthesis, such as lovastatin, to mammals including humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in a single dose of 4 to 2000 mg or in multiple doses administered 1 to 4 times a day, preferably 4 to 200 mg over single doses of 1 to 100 mg, suitably 0 .5 to 50 mg in 2 to 4 individual doses, or else in a delayed action form.

The following examples illustrate preferred embodiments of this invention. Unless otherwise stated, all temperatures are in ° C. Chromatography was done on silica gel "Merck 60" or "Whatmann LPS-1". Reversed phase chromatography was done on the gel "CHP-20-MCI" from Mitsubishi Ltd.

In these examples, the abbreviations "Et20", "EtOAc", "MeOH" and "EtOH" represent respectively. diethyl ether, ethyl acetate, methanol and ethanol.

Example I

(S) -4 - [/ '' Z-r4, -fluoro-3,3 ', 5-trimethylbiphenylyl-2 J-ethyl J-methoxyphosphinyl J-3-hydroxybutyric acid, monolithium salt A. K- (2,4- dimethylbenzylidene) aniline 40 See page 39 of U.S. Patent No. 4,375,475.

.8801331 T t "1 - 30 -

A solution of 6.97 ml (50 mgmol) of freshly distilled 2,4-dimethylbenzaldehyde (from Aldrich) and 4.56 ml (50 mgmol) of distilled aniline (also from Aldrich) in 80 ml of dry toluene was refluxed for 3 hours under argon 5 boiled in a flask equipped with Dean and Stark water trap. The mixture was cooled and evaporated to a yellow oil under vacuum. The crude was purified by distillation through a Kugelrohr (0.5 mm Hg, 160-180 ° C) to give 8.172 g (78.1%) of the desired benzalaniline as pale yellow oil which crystallized to a low melting solid upon storage. dust. TLC with hexane / acetone 4: 1 gave R = 0.67 and 0.77 (geometric isomers). UV spectrum and ^ consumption were correct.

B. Palladium derivative (according to formula 46)

See page 39 of U.S. Patent 4,375,475.

A mixture of 6.0 g (28.7 mg mol) benzalaniline of Part A and 144 ml glacial acetic acid was treated with 6.44 g (28.7 mg mol) palladium (II) acetate and the clear, red, homogeneous solution was 1 refluxed for an hour under argon.

The resulting cloudy mixture was filtered warm through 13 mm Celite and the filtrate dropped into 900 ml water. The precipitated orange solid was collected by filtration and dried over vacuum at 65 ° C for 16 hours to give 10.627 g (85.5%) of the desired palladium derivative, an orange mp. 194-196 ° C (literature melting point of a recrystallized analytical sample: 203-205 ° C).

C. 4'-Fluoro-2-formyl-3,3 ', 5-trimethylbiphenyl (1) (4-fluoro-3-methylphenyl) magnesium bromide

See pages 37 and 38 of U.S. Patent 4,375,475. The title Grignard reagent was prepared by stirring 22.5 g (60.9 mg mol) 5-bromo-2-fluorotoluene (from Fairfield Chemical Co.) to 1.35 g (55.4 mg mol) add magnesium shavings in 70 ml dry Et ^ O, at a rate fast enough to keep the mixture boiling. The reaction was initiated with an ultrasonic device. After all the bromide was added, the mixture was stirred at room temperature for 1 hour under argon, boiled for 15 minutes and then cooled back to room temperature.

(2) 4'-Fluoro-Z-formyl-3,3 ', 5-trimethylbiphenyl

In a second flask, a mixture of 3.0 g of 8801331 * i * · »- 31 - (6.92 mg mol) dipalladium compound and 14.52 g (55.4 mg mol) of triphenylphosphine in 100 ml of dry benzene was added for 30 minutes stirred under argon at room temperature. The freshly prepared C (1) Grignard reagent of glass wool filtered through a plug of glass wool was then suddenly added via a cannula and the mixture was stirred at room temperature under argon for 1 hour. After 35 ml of 6.0 N HCl was added, the mixture was stirred for an additional hour at room temperature and then filtered through 13 mm of Celite. The filtrate was extracted with 250 ml Et 2 O and the extract washed with 2 x 100 ml brine, dried over MgSO 4 and evaporated in vacuo to give 13.35 g of a viscous orange oil which crystallized on storage. The crude orange solid was purified by chromatography on 700 g of silica gel, first with hexane and then with hexane / Et 2 O 95: 5. The product fractions were combined and evaporated to dryness to give 1.507 g (89.9%) of the desired aldehyde, a pale yellow substance, m.p. 72-75 °.

(In literature mp. 73-74 ° C). TLC with hexane / ^ i ^ O 95: 5:

Rp = 0.40, UV and PMA.

D. 2- (2,2-dibromoethenyl) -4 * -fluoro-3,31,5-trimethylbiphenyl 20 At 242 mg (1.0 mgmol) solution (ice / salt bath) cooled to -10 ° C biphenylaldehyde of part C and 787 mg (3.0 mgmol, 3.0 eq.) triphenylphosphine in 10 ml dry CH 2 Cl 2 was dissolved in 497 mg (1.5 mgmol, 1.5 eq.) CBr over 5 minutes. ^ drop into 5.0 ml. After 30 minutes at 0 °, the red-orange solution was partitioned over saturated NaHCO 2. The organic phase was washed with saturated NaHCO4 and with brine, dried over Na2SO4 and evaporated to give 1.488 g of a light brown substance. This crude was purified by chromatography with hexane / 9: 1 on silica gel. The product fractions were combined and evaporated to dryness to give 392 mg (99%) of the title vinyl vibromide, a pale yellow oil. TLC with hexane / EtOAc 95: 5: R5. = 0.51, UV and PMA.

E. 2-vinyl-4'-fluoro-3,3 T, 5-trimethylbiphenyl

At -78 ° (C 2 / acetone), a solution of 35 336 mg (0.844 mgmol) of vinyl dibromide of Part D in 5 ml of dry THE with a syringe made 1.06 ml of 1.6 M (1.7 mgmol, 2.0 eq.) n-BuLi dropwise into hexane and the mixture was stirred at -78 ° under argon for an additional hour. While adding the, 8801331 T, t * - 32 - n-BuLi, the solution turned dark yellow and light yellow into deep purple blue. The mixture was quenched at -78 ° by dripping 4 ml of saturated NH 2 Cl solution, then allowed to warm to room temperature, extracted with Et 2 O 5 and washed the ether layer with brine, dried over MgSO 2 and evaporated to dryness ; this gave 191 mg of green oil. The crude oil was purified by chromatography with hexane on silica gel LPS-1. The product fractions were combined and evaporated to dryness to give 185 mg (92%) of the desired acety-lene as a colorless oil which faded to dark blue when stored under argon at -20 °. For DLC with hexane:

Rp = 0.18, UV and PMA.

F. Methyl ester of (S) -3-t-butyldiphenyloxy-4- (chloromethoxyphosphinyl) butyric acid 15 (1) Methyl ester of (S) -4-bromo-3-hydroxybutyric acid (1) (a) Calcium salt, hydrate of £ R- (R *, R *) J-2,3,4-trihydroxybutyric acid

See Carbohydrate Research 12, (301) 301-304.

To a suspension of 44.0 g (250 mgmol) of D-iso 25 25 35, 8801331 - 33 - s * * ascorbic acid in 625 ml of water was added 50 g of calcium carbonate and the suspension was added in an ice bath to 0 ° C cooled and then portionwise treated with 100 ml of 30%. The mixture was stirred at 30-40 ° C for 30 minutes (oil bath). 10 g of Darco was added and the black slurry was heated on a steam bath until the O 2 development ceased. The suspension was filtered through Celite, evaporated to dryness under vacuum (bath temperature 40 ° C). The residue was taken up in 50 ml of water and heated on a steam bath and methanol was added until the solution was cloudy. The gummy precipitate was collected by filtration and air dried to give 30.836 g (75.2%) of the desired calcium salt as a white solid powder. DLG with iPr0H-NH40H-H20 7: 2: 1: Rp = 0.19, PMA.

(1) (b) Methyl ester of CS - (R *, S *) J-2,4-dibromo-3-hydroxy-15 butyric acid

See K. Bock et al. In Acta Scandinavica (B) 37 (1983) 341-344.

30 g of calcium salt of part (1) (a) were dissolved in 210 ml of 30-32% HBr in acetic acid and stirred at room temperature for 24 hours. To the brown solution, 990 ml of methanol was added and it was stirred overnight. The mixture was evaporated to an orange oil, which was taken up in 75 ml of methanol and refluxed for 2 hours and evaporated to dryness again. The residue was partitioned between 100 ml EtOAc and water and the organic phase was washed twice with water and then brine and dried over Na 2 SO 4 and evaporated to dryness, yielding 22.83 g (90.5%) crude dibromide as light orange gave oil. TLC with EtOAc / hexane 1: 1: R = 0.69, UV and PMA.

(L) (c) Methyl ester of (S) -4-bromo-3-hydroxybutyric acid Same literature as for section (1) (b).

To an argon-flushed solution of 20.80 g (75.4 mg mol) dibromide and 21.0 g anhydrous NaOAc in 370 ml EtOAc and 37 ml HOAc was added 1.30 g 5% Pd / C and the black suspension hydrogen was stirred with 1 atmosphere while following gas consumption. After 2.0 hours, the hydrogen-35 uptake was complete. The mixture was filtered through Celite and the filtrate washed with saturated NaHCO 2 and brine then dried over MgSO 2 and evaporated to give the crude dibromo ester as brown oil. The crude oil was combined with another batch (from 36.77 g of dibromide) and distilled under vacuum, 8801331 - Τ - 34 34 34 34 34 - - - - - wat wat wat wat wat wat wat wat wat wat gaf 25 25 25 25 volgens volgens volgens volgens volgens volgens; volgens;;; title by title; a colorless oil with bp. = 79-80 ° at 1.0 mm Hg. TLC with EtOAc-Hex R = 0.44. PMA.

Γ

Elemental analysis: C 29.76, H 4.50, Br 39.86%; 5 Calculated for C ^ O ^ Br; C 30.48, H 4.60, Br 40.56%.

(2) Methyl ester of (S) -4-bromo-3- (t-butyldiphenylsilyloxy) butyric acid

To a solution of 4.0 g (20.4 mg mol) of bromohydrin of Part E (1), 6.94 g (5.0 eq.) Of imidazole and 12 mg of 10 (0.005 eq.) Of 4-dimethylaminopyridine (DMAP ) in 40 ml of dry DMF

5.84 ml (1.1 eq.) of t-butyldiphenylsilyl chloride was added, and the homogeneous mixture was stirred at room temperature overnight under argon. The mixture was partitioned between 5% KHSO 2 solution and EtOAc, the organic phase was washed with water and brine, dried on 2% and evaporated to give 9.32 g (100%) of the crude silyl ether as clear, viscous oil. TLC with Hex / EtOAc 3: 1: Rp = 0.75, ÜV and PMA.

(3) Methyl ester of (S) -4-iodo-3- (t-butyldiphenylsilyloxy) -butyric acid 20 To a solution of 9.32 g (201 mg mol) of crude bromide of Part E (2) in 60 ml of butanone (which a molecular sieve of 4% was dried), 15.06 g (100.5 mgmol, 5.0 eq.) of sodium iodide were added and the yellow suspension was refluxed for 5 hours. The mixture was cooled, diluted with EtOAc and filtered, and the filtrate was washed with dilute NaHSO 2 solution (until colorless) and brine then dried over Na 2 SO 4 and evaporated in vacuo to give 10.17 g of yellow oil gave. The crude oil was purified by chromatography with hexane / C 1 -C 3 3: 1 over 600 g of silica gel. The product fractions were combined and evaporated to dryness to give 7.691 g (74.2% total over both steps) of the desired iodide as a clear, colorless, viscous oil. TLC with hexane / EtOAc 3: 1: Rp = 0.75, UV and PMA.

(Note: iodide and starting bromide gave the same stain at DLC).

(4) Methyl ester of (S) -4- (diethoxyphosphinyl-3- (t-butyldiphenylsilyloxy) butyric acid

A solution of 7.691 g of the iodide in 20 ml of triethyl phosphite was heated at 155 ° C in an oil bath under argon for 3 h. The mixture was cooled and the excess phosphite 8801331 -35-42 distilled in vacuo (0.5 mm Hg, 75 ° C) leaving <8.0 g of yellow oil. The crude oil was purified by chromatography on 400 g of silica gel with 4: 1 hexane / acetone as the running liquid. The product fractions were evaporated to dryness to give 3.222 g (41.1%) of the desired phosphonate, a colorless clear, viscous oil. At DLG with hexane / acetone 1: 1:

Rp * 0.51? UV and PMA. In addition, 2.519 g (61.1% after correction) of the starting iodide of part (3) were recovered.

(5) Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4-phosphono-butyric acid

To a solution of 9.85 g (20.0 mg mol) of phosphonate of part E (4) in 60 ml of dry CH 2 Cl 2 was successively 5.31 ml (32.0 mg mol, 1.6 eq.) Of bistrimethylsilyltrifluoroacetamide (BSTFA) and 6.60 ml (50.0 mg mol, 2.5 eq.) Of trimethyl-15-silyl bromide (TMSBr) were added and the clear mixture was stirred at room temperature under argon overnight. 80 ml 5% KHSO4 was added and that mixture was extracted with EtOAc. The water phase was saturated with NaCl and extracted again with EtOAc. The organic phases were washed together with brine, dried over Na 2 SO 4 and evaporated in vacuo to give the title crude phosphonic acid as a viscous oil.

At DLC with iPr0H-NH40H-H20 7: 2: 1: * 0.30, ÜV and PMA.

(6) Methyl ester of (S) -3- (t-butyldiphenylsllyloxy) -4- (hydroxy-methoxyphosphinyl) butyric acid. 25 To the crude phosphonic acid of part E (5) (-20.0 mgmol) in 25 ml dry pyridine 1 62 ml (40.0 mg mol, 2.0 eq.) Over molecular sieve of dried methanol 2 and 4.54 g (22.0 mg mol, 1.10 eq.) Dicyclohexylearbodiimide (DCC) were added and this suspension was left overnight at room temperature stirred under argon. Pyridine was removed in vacuo and the residue was azeotroped twice with 15 ml of benzene. The residual oil was dissolved in EtOAc, filtered and washed with 1.0 N HCl and with brine, dried over Na 2 SO 4 and evaporated again under vacuum to give 8.272 g of crude title ester, an oil slightly precipitated dicyclohexylurea. In TLC with iPrOH-NH.OH-H-O 7: 2: 1: R '= 0.60. UV and PMA.

8801331-36-, r <r (7) Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4-chloromethoxyphosphinyl) butyric acid

To 6.595 g (* 14.7 mg mol) of the crude phosphonic acid monomethyl ester of part F (6) dissolved in 30 ml of dry C 1 C 5 3.5 was added 5.60 ml (29.4 mg mol, 2.0 eq trimethylsilyldiethylamine was added and it was stirred at room temperature under argon for 1 hour. The mixture was evaporated to dryness under vacuum, azeotroped once with 30 ml of benzene and dried under vacuum. The pale yellow, viscous oil was dissolved in 30 ml dry with 10 drops of DMF (which had been dried on a 4 & 7 molecular sieve).

The clear solution was cooled to -10 ° with a salt / ice bath and 1.41 ml of 816.2 mgmo, 1.1 eq.) Of distilled oxalyl chloride was added dropwise with a syringe. Obviously there was a violent gas evolution and the solution turned a deeper yellow in color. Under argon, the mixture was stirred at -10 ° for 15 minutes and then at room temperature for 1 hour. The mixture was evaporated in vacuo, azeotroped once with 30 ml of benzene and dried in vacuo to give the crude chlorophosphonic ester as a yellow oil.

20 G. Methyl ester of (S) -4- / ~ /% - (4-fluoro-3,3,5-trimethylbiphenyl-2) ethynyl Jmethoxyphosphinyl J-3- (t-butyldiphenylsilyloxy) butyric acid

At -78 ° ((^ / acetone), a solution of 2.688 g (11.2 mgmol) of acetylene in part E in 20 ml of dry THF was added to 7 ml of 1.6 M (11.2 mgmol, 1.0 eq. n-BuLi dropwise into hexane.

The purple mixture was stirred at -78 ° under argon for 1 hour, warmed briefly to 0 ° C, cooled again to -78 °, and transferred into a dropping funnel with a cannula from which it was added dropwise to a solution of C 2 / acetone -78 ° cooled solution of 8.27 g (18.4 mg mol, 1.6 eq.) Of phosphonic acid chloride of part F in 20 ml of dry THF. After 1 hour at -78 ° C, the mixture was quenched with saturated NH 4 Cl, and extracted with £ί θ 1 after warming to room temperature. The ether layer was washed with saturated NaHCO4 and brine, dried over MgSO4 ^ 35 and evaporated to give 11.705 g of brown oil. The crude oil was purified by chromatography with hexane / EtOAc 7: 3 on silica gel. The product fractions were evaporated together to give 4.246 g (56%) of the desired acetylene phosphinate as a light brown oil. In addition, 457 mg (after correction, 8801531 of 37-68 Z) of the biphenylacetylene of Part E was recovered. At TLC with hexane / acetone 7: 3: R = 0.20, UV and PMA.

H. Methyl ester of (S) -4 / [[2- (4L-fluoro-3,31,5-trimethyl-biphenylyl-1-2) ethyl] methoxyphosphinyl-7-3- (t-butyl-5-phenylsilyloxy) -putyric acid

121 mg (36% of 333 mg) of 10% Pd / C was added to an argon-rinsed solution of 333 mg acetylene phosphinate of part G in 5 ml methanol, which was shaken with 2.8 ato in a Parr apparatus for 30 hours. The catalyst was removed by filtration over a layer of Celite and the filtrate was evaporated to a pale yellow oil. This crude oil was purified by chromatography on silica gel with EtOAc / hexane 1: 1. The product fractions were concentrated to dryness to give 250 mg (75%) of the title saturated phosphinate as a clear oil. At TLC with EtOAc / hexane 4: 1: R 2 = 0.33, UV and PMA.

Γ J. Methyl ester of (S) -4- [[2- (41-fluoro-3,3 ', 5-trimethyl-biphenylyl-2) ethyl] methoxyphosphinyl J-3-hydroxybutyric acid

To a solution of 330 mg (0.489 mgmol) silyl ether of part H in 6 ml dry THF was first added 115 µl (1.96 20 mgmol, 4.0 eq.) Glacial acetic acid and then 1.47 ml 1.0 M

(3.0 eq.) Tetrabutyl ammonium fluoride in THF, and this mixture was stirred at room temperature overnight under argon. The mixture was diluted with 10 ml of ice water and extracted twice with EtOAc. The organic phase was washed with saturated NaHCO 2 and brine and dried over Na 2 SO 4 and evaporated to give 364 mg of pale yellow oil. The crude oil was purified by chromatography with acetone / hexane 6: 4 on silica gel. The product fractions were evaporated to dryness to give 205 mg (96%) of the desired free alcohol as a clear oil which slowly crystallized on storage. At TLC with acetone / hexane 7: 3:

Rp - 0.28, UV and PMA.

Example II

Dilithium salt of (5) -4 - / ^ C 2- (4T-fluoro-3,3l, 5-trimethylbi-phenyly1-2) ethyl Jhydroxyphosphinyl J-3-hydroxybutyric acid 35 To a solution of 187 mg (0.429 mgmol) Diester of Example I in 5 ml dioxane 1.29 ml 1.0 N (1.29 mg mol, 3.0 eq.) LiOH solution was added and the mixture was heated at 55 ° C in an oil bath under argon for 1 hour. After cooling, the mixture was diluted with water, filtered and evaporated to dryness under vacuum. The residue was taken up in a minimum amount of water and chromatographed on a column of HP-20 (bed about 15 cm long, inner diameter 25 mm) eluting first with water and then 1: 1 with methanol / water. The product fractions were evaporated to dryness and the residue was taken up in 50 ml of water, filtered and freeze-dried to give 175 mg (91%, calculated as hydrate) of the desired dilithium salt, a white electrostatic solid.

TLC with CH2Cl2 / CH3OH / HOAc: R ^ = 0.1, with iPrOH / NH ^ OH / ^ 0.10 Rp = 0.45. UV and PMA.

Elemental analysis: C 55.91, H 5.84, F 3.92, P 6.89%;

Calculated for C 1 H 30 O FPL 4 with 1.7 mol H 2 O (MG 450.90): C 55.93, H 6.13, F 4.21, P 6.87%.

1 H-NMR (400 MHz, CD ^ D), 6 = 15 1.34-1.56 ppm (4H, multiplet) 2.22-2.31 ppm (2H, multiplet) 2.25 + 2.37 ppm ( 6H, two singlets) 2.29 ppm (3H, doublet, J = 1.4 Hz) rt-r 2.75 ppm (2H, multiplet) 20 4.13 ppm (1H, multiplet) 6.73-7, 10 ppm (5H, multiplet).

Example III

Methyl ester of (S) -4- / ~ [2- (4 ^ 11 ^ ^ - 3,31,5-trimethyl-biphenylyl-2) ethynyl J methoxyphosphinyl J-3-hydroxybutyric acid 25 To a mixture of 455 mg (0.678 mgmol) silyl ether of Example I part G, 155 µl 1 (2.71 mg mol, 4.0 eq.) glacial acetic acid and 7 ml dry THF became 2.0 ml 1.0 M (2.0 mg mol, 3.0 eq. tetrabutyl ammonium fluoride in THF was added and that mixture was stirred at room temperature overnight under argon.

The mixture was then poured into 10 ml of ice cold water and extracted twice with EtOAc. The organic phase was washed with saturated NaHCO 2 and brine, dried over Na 2 SO 4 and evaporated to give 498 mg of yellow oil. The crude product was purified by chromatography with hexane / acetone 3: 2 on silica gel. The product fractions were evaporated to dryness to give 217 mg (74%) of the title alcohol as a colorless oil.

TLC with hexane / acetone 7: 3: R ^ = 0.10, UV and PMA.

Example IV

Dilithium salt of (S) -4- [[2- (4 ^^^^ 3,3 *, 5-trimethylbor8801331 _ ί *. Ϊ́ - 39 - * phenylyl-2) ethynylhydroxyphosphinyl J-3-hydroxybutyric acid

To a mixture of 203 mg (0.469 mgmol) diester of Example III and 6 ml of dioxane, 1.6 ml of 1.0 N (1.6 mgmol, 3.5 eq.) Of LiOH was added and the solution was stirred under argon for 30 minutes heated at 55 ° C in an oil bath. After cooling, the mixture was diluted with water, filtered and evaporated to dryness; the residue was taken up in 30 ml of water and freeze-dried. The white lyophilization was taken up in a minimum amount of water and chromatographed on HP-20 (10 cm length column with 25 ml internal diameter, eluting with water and then 1: 1 with water / methanol. The product fractions were evaporated together and the residue taken up in 30 ml of water and lyophilized to give 199 mg of the title dilithium salt as a white matter (yield 97%, calculated as hydrate, MG = 435.36).

15 TLC with CH2Cl2 / CH3OH / HOAc 8: 1: 1: Rp = 0.13, UV and PMA.

Elemental analysis: C 57.91, H 4.89, F 4.22, P 6.89%;

Calculated for C 3 H O O FPld 1 + 1.06 mol H 2 O: C 57.93, H 5.12, F 4.36, P 7.11 Z.

XH NMR (400 MHz, CD30H), δ in ppm: 20 1.76-1.82 (2H, multiplet) 2.32 (3H, doublet, J - 1.8 Hz) rir 2.34 (3H, singlet) 2.37 (1H, dd, J - 8.4 Hz) 2.41 (1H, dd, J «4.1 Hz) 25 2.49 (3H, singlet) 4.27 (1H, multiplet) 6.98 -7.37 (5H, m)

Example V

Methyl ester of (S, Z) -4 - / * [2- (4 ^ 1 ^ ^ 3,3 ^ 5- ^ 11 ^ 117 161-30 phenyl-2) ethenyl J methoxyphosphinyl J-3-hydroxybutyric acid A. Methyl ester of (S (Z) -4- / ~ / '2- (4T-fluoro-3,3,5,5-trimethyl-biphenylyl-2) ethenyl] methoxyphosphinyl J-3- (t-butyldiphenyl-silyloxy) butyric acid

To a degassed solution of 498 mg (0.742 mgmol) of acetylene phosphinate of Example I part G in 10 ml of methanol, 50 mg of 10 Z Pd / C was added and the black suspension was stirred under 1 atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration over Celite and the filtrate was evaporated to give 500 mg of yellow oil. The crude product was purified by chromatography with hexane / EtOAc 3: 2 on silica gel at 880 1331-40 V A V 4. The product fractions were evaporated to dryness to give 498 mg (100%) of the desired olefin as a colorless oil.

TLC with EtOAc / hexane 4: 1: R = 0.44 and 0.51. UV and PMA.

B. 5 B. Methyl ester of (5, Ζ) -4-Ζ ~ [2- (4-fluoro-3,3, 5-trimethyl-biphenylyl-2) ethenyl] methoxyphosphinyl 7-3-hydroxybutyric acid To a solution of 498 mg (0.74 mgmol) silyl ether of part A in 6 ml dry THF was first added 170 µl (2.96 mgmol, 4.0 eq.) Glacial acetic acid and then 2.2 ml 1.0 M (2.2 10 mgmol, 3.0 eq.) tetrabutyl ammonium fluoride in THF, and the clear colorless mixture was stirred at room temperature under argon for 16 hours. TLC showed a small amount of starting material.

An additional 40 µl (1.0 eq.) Glacial acetic acid and 0.74 ml (1.0 eq.) N-Bu 2 NF were added and stirring was continued for another 6 hours.

The mixture was diluted with 10 ml of ice cold water and extracted twice with EtOAc. The extracts were washed together with saturated NaHCOg and with brine, dried over Na 2 SO 4 and evaporated to give 468 mg of pale yellow oil. The crude product was purified by chromatography with hexane / acetone 7: 3 on silica gel. The product fractions were evaporated to dryness to give 243 mg (76 Z) of the title alcohol as a colorless oil.

TLC with hexane / acetone 7: 3: R '= 0.19, UV and PMA.

Γ

Example VI

Dilithium salt of (S, Z) -4- / ~ Γ 2- (4l-fluoro-3,3t, 5-trimethyl-25-biphenylyl-2) ethenyl. Hydroxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 240 mg (0.552 mgmol) diester of Example V in 7 ml dioxane, 1.9 ml 1.0 N (1.9 mgmol, 3j5 eq.) LiOH solution was added and the stirred mixture was stirred for 3 hours under argon kept at 50 ° (oil bath). A white precipitate 30 was clearly visible. The mixture was cooled, diluted with water, filtered and evaporated in vacuo to a white matter. The crude was taken up in a minimum amount of water and chromatographed on HP-20, eluting with water and then 1: 1 with water / methanol. The product fractions were evaporated to dryness and the residue was taken up in 50 ml of water; this was filtered and lyophilized to give 255 mg of title dilithium salt, a white electrostatic. Yield 100 Z (calculated as dihydrate).

TLC with CH2Cl2 / CH3OH / HOAc 8: 1: 1: Rp = 0.26, UV and PMA.

, 8801331 4 i- * - 41 -

Elemental analysis: C 55.35, H 5.68, F 4.27, P 7.09%;

Calcd for C 21 H 22 ° 5 F 2 Li 2 + 18 mol H 2 O (457.58): C 55.12, H 5.81, F 4.15, P 6.77%.

1H-NHR (400 MHz in CD30D), δ in ppm: 5 1.24 (2H, multiplet) 2.09 (2H, doublet, J = 6.2 Hz) 2.27 (3H, doublet, J__ = 1, 8 Hz) no 2.30 (3H, singlet) 2.38 (3H, singlet) 10 4.06 (1H, multiplet) 5.87 (1H, d doublet, JHH = 12.4 Hz, JHp = 14.3 Hz) 6.87 (1H, s) 6.91 (1H, d doublet, JUT) = 43.4 Hz) no 6.98 (2H, triplet) 15 7.22 (2H, multiplet)

Example VII

Methyl ester of (S) -4- ^ C 2 -C 3- (4-fluorophenyl) -1-isopropyl-1H-indolyl-2-methyl. Methoxyphosphinyl 7-3-hydroxybutyric acid A. Ethyl ester of 2- (4-fluorobenzyl) - 3-oxobutyric acid 8.31 g (362 mgmol) of sodium was dissolved in 1 liter of absolute alcohol, and 47 g (362 mgmol, 1 eq.) Of distilled ethyl acetetoate were added to the clear solution under argon. The pale yellow mixture was refluxed for 1 hour and after cooling to room temperature, 75 g (398 mgmol, 1.1 eq.) Of 4-fluorobenzyl bromide were added. The light orange mixture was stirred at room temperature under argon for 2 hours and then evaporated to dryness under vacuum. The residue was partitioned between ethyl acetate and water, and the organic phase was washed twice with water and brine, dried over Na 2 SO 4 and evaporated to an orange oil. The crude product was purified by vacuum distillation (bp = 142-144 ° at 5 mm Hg) to give 46.47 g (54%) of the alkylated product as a clear, colorless liquid.

At TLC with hexane / diethyl ether 7: 3: R = 0.31.

1 * 35 H-NMR (in CDCl ^, δ in ppm: 1.20 (3H, t), 2.19 (3H, s), 3.13 (2H, d), 3.73 (1H, t), 4 , 14 (2H, q), 6.95 (2H, t), 7.13 (2H, m) 13 C-NMR (in CD3CN), δ in ppm: 14.4, 29.7, 33.7, 62.1 , 62.3, 115.3, 116.8, 131.4, 131.9, 145.1 (JC_F = 284 Hz), 170.1, .8B013 ^ Y 'Τ. V, - χ i - 42 - Ethyl ester of 3- (4-fluorophenyl) -1H-indole-2-carboxylic acid See Chemical Abstracts 33, p. 587, reference by R. Helmuth et al in J. Chem. Soc. (1927) 6-7.

β

See also Preparative Organic Chemistry (4 edition, 1972) 5 biz. 582.

A solution of 23.4 g of NaOH in 58 ml of water was added to a solution of 46.4 g (195 mgmol) of the ester of part A in 290 ml of absolute ethanol at 0 ° C (ice bath), and a benzenediazonium chloride solution immediately after which according to 10 biz. 582 of Prep. Org. Chem. from 17.8 ml of aniline in 88 ml of conc. HCl and 98 ml of water had been prepared with 13.5 g of NaNO 2 this gave a deep orange-red biphasic solution. The mixture was stirred for an additional 1 hour at room temperature and then poured into 500 ml ice-cold water and extracted with 3 x 300 ml EtOAc. The organic phase was washed with 500 ml of brine, dried over 100% and evaporated in vacuo to give 55.62 g of crude hydrazone as orange oil. At TLC with hexane / diethyl ether 7: 3: R 2 = 0.22, UV and PMA. This raw material was used as such for the subsequent Fischer ring closure. HCl gas was bubbled for 30 minutes through a solution of the hydrazone in 200 ml of absolute ethanol, with intermediate cooling in an ice bath. The brownish mixture was poured into 600 ml of ice-cold water and extracted three times with EtOAc. The organic phase was washed twice with water and once with brine, dried over Na 2 SO 4 and evaporated in vacuo to a light brown solid. Stirring with ice-cold hexane and filtration gave 26.74 g (94%) of the expected indole as light brown, granular, m.p. crystals. 129-130 °.

30 TLC with hexane / Et 2 O 7: 3: R 2 = 0.26, UV and PMA.

Elemental analysis: C 72.38, H 8.05, F 6.87, N 5.01%;

Calcd for C 10 H 18 FN 10: 17 14 C 72.07, H 4.98, F 6.71, N 4.94%.

1 H NMR (in CDCl 3), δ in ppm: 1.22 (3H, t), 4.29 (2H, q), 7.10-7.62 (8H, m), 9.21 (1H, bs) 13C-MR (in CDC13), δ in ppm: 14.1, 60.9, 111.8, 114.5, 114.8, 120.9, 121.4, 122.9, 123.1, 125.9, 127.9, 129.5, 132.2 (JC_F = 7.6 Hz), 135.7, 162.0, 162.2 (JC_F = 244 Hz).

C. Ethyl ester of 3- (4-fluorophenyl) -1-isopropyl-1 H -indole-2-carboxylic acid 8801331?. c - 43 -

See International Patent Application No. 158,675 to Sandoz, (1984) p. 35.

To a solution of 26.74 g (94.4 mgmol) of part B indole in 100 ml of dry distilled dimethylacetamide 5 was added in portions at 0 ° C (ice bath) 4.53 g of 6Q% (113.3 mgmol, 1, 2 eq.) NaH in mineral oil added (violent gas evolution) and the mixture was stirred at 0 ° C for an additional 1 hour under argon.

85 g (500 mg mol, 5.3 eq.) Of 2-iodopropane were then added and the mixture was allowed to warm to room temperature under argon under stirring for 1 hour. The mixture was cooled again to 0 ° C and again with 1.2 eq. NaH treated, followed by stirring at room temperature for 1 hour. This treatment was repeated two more times. The final mixture was cooled to 0 ° C (ice bath) and excess NaH was rendered harmless by carefully adding 30 ml of absolute EtOH. The mixture was diluted with EtOAc and washed with 5% KHSO4; the aqueous phase was backwashed once with EtOAc and the EtOAc extracts were washed together with water and twice with brine, dried over Na 2 SO 4 and evaporated to give 38.54 g of brown matter. This was dissolved in hot CH 2 Cl 2 and the hexane crystallized on addition of hexane; 13.88 g of this was recovered. The mother liquor was evaporated to dryness under vacuum to give 22.32 g of brown oil. This crude product was purified by silica gel chromatography, first with hexane and then with hexane / acetone 95: 5.

The product fractions were concentrated to dryness to give 6.55 g (21%) (corrected yield 62%) of the desired N-isopropyl indole as yellow oil.

TLC with hexane / acetone 4: 1: R = 0.57, UV and PMA.

1 * H-NMR (in CDCl3), δ in ppm: 1.04 (3H, t), 1.20 (6H, d), 4.17 (2H, q), 5.40 (1H, m) 7.10-7.7 (8H, m) 13 C-NMR (in CDCl 3), 6 in ppm: 13.6, 21.5, 48.7, 53.3, 60.8, 112.7, 114.5m 114.8, 120.3, 121.4, 122.4, 124.3, 125.9, 127.6, 130.8, 131.7 (JC_F = 7.5 Hz), 136.2, 162.3 ( JC_F = 144 Hz), 163.0.

35 D. 2- (hydroxymethyl) -3- (4-fluorophenyl) -1-isopropyl-1H-indole

1.12 g (29.6 mg mol, 1.5 eq.) Of lithium aluminum hydride were dissolved in 30 ml of dry, freshly distilled ether at 0 ° C (ice bath). An ethereal solution of 6.42 g (19.7 mg mol) of indole ester. 8801331-44 - t was added to this suspension over 10 minutes. τ; Dropped part C in 20 ml diethyl ether. After stirring for an additional 30 minutes under argon at 0 ° C, the reaction mixture was quenched by adding 1.1 ml water, 1.1 ml 15% NaOH and 3.4 ml water successively. The resulting suspension was filtered through a 5 layer Celite, dried over MgSO 4 and evaporated in vacuo to give 5.1 g of yellow foam. The crude product was purified by chromatography with hexane / acetone 85:15 on silica gel to give 5.08 g (91%) of the pure title alcohol as a pale yellow foam.

10 TLC with hexane / acetone 7: 3: R = 0.38, UV and PMA.

Γ

A small sample was recrystallized from hexane to give the title alcohol as white crystals, m.p. 101-103 ° C. Elemental Analysis: C 76.49, H 6.46, F 6.84, N 4.88%;

Calcd for C 19 H 15 NOF: C 76.30, H 6.40, F 6.71, N 4.94%.

^ H-NMR (in CDClg), δ in ppm: 1.60 (1H, t), 1.69 (6H, d), 4.76 (2H, d), 4.93 (1H, m), 7 .05-7.62 (8H, m) 13 C-NMR (in CDClg), 6 in ppm: 20.9, 47.3, 54.8, 113.0, 115.9, 116.3, 116.6 , 120.2, 120.6, 122.9, 128.5, 131.6, 132.4, 135.4, 135.1, 135.7, 163.0 (J. = 245 Hz).

0 "r E. 2-formyl-3- (4-fluorophenyl) -1-isopropyl-1H-indole

To a solution of 5.9 g (13.9 mgmol, 1.2 eq.) Periodinane of Dess-Martin in 30 ml dry, 1.3 ml (13.9 mgmol, 1.2 eq.) Dry t-butanol and the mixture was stirred at room temperature under argon for 15 minutes. About

A solution of 3.28 g (11.6 mg mol, 1 eq.) Of indole alcohol of part D was added dropwise for 5 minutes and the yellow mixture was stirred at room temperature under argon for 1 hour. The reaction mixture was now poured into a freshly prepared solution of 15.3 g (97 mg mol, 7 eq.) Sodium thiosulfate in 40 ml 1.0 N

NaHCOg and that mixture was stirred vigorously for 5 minutes. The organic phase was separated, washed with 1.0 N NaHCO 2 solution, with water and brine, dried over Na 2 SO 4 and evaporated to give 3.69 g of yellow oil. The crude product was purified by chromatography with hexane / Et 2 O 40: 1 on silica gel to give 2.7 g (83%) of the pure title aldehyde as white crystals with mp. 88-89 °.

TLC with hexane / acetone 7: 3: R '= 0.56, UV and PMA.

8 .880 133 f - 45 - * '

Elemental analysis: C 76.91, H 5.71, N 4.95, F 6.76%;

Calcd for C 19 H 15 g FNO: C 76.85, H 5.73, N 4.98, F 6.75%.

1H-HMR (in CDCl3): δ in ppm: 1.69 (6H, d), 5.92 (1H, m), 5 7.10-7.70 (8H, m), 9.80 (1H, s).

13 C-NMR (in CDCl3): δ in ppm: 21.4, 48.0, 112.5, 113.2, 115.4, 115.7, 120.8, 122.1, 126.9, 127, 0.12.0, 132.6 (JC_F = 7.5 Hz), 183.6.

F. 2- (2,2-dibromoethenyl) -3- (4-fluorophenyl) -1-isopropyl-1H-10 indole

In a solution (ice with salt) cooled to -15 ° of 1.84 g (6.54 mgmol) indolealdehyde of part E and 5.14 g 819.6 mgmol, 3 eq.) Triphenylphosphine in 30 ml was dried over 5 a solution of 3.25 g (9.8 mg mol, 15 1.5 eq.) of CBr 1 in 10 ml was dripped dry in minutes and the yellow mixture was stirred at 15 ° C under argon for 15 minutes. The mixture was then partitioned between saturated NaHCO 3 and the organic phase washed with saturated NaHCO 2 and brine, dried over Na 2 SO 4 and evaporated to give 9.44 g of brown oil.

The crude product was purified by chromatography with hexane / CH 2 Cl 2 95: 5 on silica gel. The product fractions were evaporated together to give 2.87 g (100%) of the desired dibromovinyl indole, a yellow oil which crystallized on storage. Recrystallization from diethyl ether once gave 2.46 g (86%) of the purified product as pale yellow, granular crystals with m.p.

135-137 °.

TLC with hexane / C 2 C 7: 3: 0.45, UV and PMA.

Elemental analysis: C 52.25, H 3.68, N 3.20, Br 36.58%;

Calcd for C 11 H 21 NF B 3 O: C 52.20, H 3.69, N 3.20, Br 36.56%.

1 H NMR (in CDCl 3), δ in ppm: 1.15 (6H, d), 4.67 (1H, m), 7.10-7.70 (9H, m).

13 C-NMR (in CDCl3), δ in ppm: 21.9, 48.6, 98.6, 111.6, 115.3, 115.6, 115.9, 119.9 (JC_F = 7.6 Hz ), 122.4, 127.5, 129.3, 35, 130.5, 130.7, 130.9, 135.2, 161.5 (J 1, = 246 Hz).

G. 2-ethynyl-3- (4-fluorophenyl) -1-isopropyl-1H-indole

To the solution of 2.395 g (5.48 mgmol) of dibromo-vinyl compound of part F in 10 ml of dry THF was added under argon at -78 ° (carbonic acid with acetone) 6.9 ml of 1.6 M (10.96 mgmol , 8801331 τ - «c * * J - 46 - 2 eq.) N.BuLi dripped in hexane. The resulting mixture was stirred at -78 ° for 1 hour and then quenched by adding 5 ml of a saturated NH 2 Cl solution. The reaction mixture was allowed to warm to room temperature and then extracted twice with diethyl ether. The ether layers were washed with brine, dried over MgSO4 and evaporated in vacuo to give 1.893 g of dark brown oil. The crude product was purified by chromatography with a J% diethyl ether in hexane on silica gel to give 1.12 g of purified product as a 3.3: Ι-ΙΟ mixture of acetylene and olefin terminal. This mixture was separated by chromatography using a | % Et 2 O in hexane over neutral alumina (activity no. 2). Evaporation of the product fractions gave 900 mg of off-white crystals. Recrystallization from hot hexane gave 700 mg (46%) of purified acetylene of the title as white needles, m.p. 105-106 ° C.

TLC with hexane / Et 2 O 95: 5: 0.44 (the acetylene) and R 4 0.49 (the olefin), UV and PMA.

Elemental analysis: C 82.70, H 5.85, N 5.10, F 6.62%;

Calculated for Cir.H .., NF: 19 16 20 C 82.28, H 5.81, N 5.05, F 6.85%.

^ H-NMR (in CDCl ^), 6 in ppm: 1.70 (6H, d), 3.5 (1H, s), 5.06 (1H, m), 7.10-7.75 (8H , m).

H. Methyl ester of (S) -4 - / * C 2 - / * 3- (4-fluorophenyl) -1-iso-propyl-1 H -indolyl-2-methyl-7-methoxyphosphinyl, 7-3- (t-butyl-diphenylsilyloxy) ) butyric acid

To a solution of 678 mg (244 mgmol, 1.0 eq.) Acetylene of part G in 6 ml dry THF was added dropwise 1.53 ml 1.6 M (2.44 mgmol) under argon at -78 ° (carbonic acid / acetone) 1.0 eq.) N-BuLi in hexane. After 30 minutes at -78 ° 30, the mixture was transferred by cannula to the -78 ° cooled solution of 0.3 mg mol (1.75 eq.) Phosphonic acid chloride of Example I, part F in 5 ml dry THF. The dark brown mixture was stirred at -78 ° for 30 minutes and then quenched by adding 5 ml of saturated NH 4 Cl, followed by warming to room temperature. The mixture was extracted twice with Et 2 O and washed with saturated NH 2 Cl and brine, dried over MgSO 2 and evaporated in vacuo to give 2.567 g of brownish red oil. The crude oil was purified by chromatography with hexane / EtOAc 3: 2 on 40 silica gel to give 756 mg (44%) of the desired acetylene phosphine 880 1 331-47 * * * nate as dark yellow oil.

TLC with hexane / acetone 7: 3: Ry = 0.27, UV and PMA.

^ -NMR (in CDCl3), δ in ppm: 1.0 (9H, s), 1.64 (6H, d), 2.10-2.90 (4H, m), 3.56 (3H, s ), 3.58 (3H, dd), 4.6 (1H, bm), 4.90 (1H, m), 7.05-7.55 (18H, m) 13C-HMR (in CDCl3), δ in ppm: 14.2, 19.1, 21.0, 26.7, 27.8, 37.5, 39.2, 42.2, 45.1, 49.2, 51.4, 51, 9.60.3, 65.5 (Jc_p = 15.1 Hz), 88.1, 91.2, 98.3, 111.3, 115.3, 115.6, 120.8 (J = 5, 7 Hz), 122.3, 124.9, 125.9, 126.4, 127.6, 129.2, 130.7, 133.0, 135.7, 136.1, 170.9.

J. Methyl ester of (S) -4 - / * [2--3- (4-fluorophenyl) -1-isopropyl-1H-indolyl-2-Methyl] methoxyphosphinyl 7-3- (t-butyl-diphenylsilyloxy) butyric acid

To an argon-rinsed solution of 422 15 mg of acetylene phosphinate from part H in 9 ml of methanol, 420 mg of 10% Pt / C was added and that mixture was shaken with 2.8 ato of hydrogen in a Parr apparatus for 2 hours. The catalyst was filtered over Celite and the filtrate was evaporated to dryness to give 380 mg (90%) of the expected indole phosphinate as yellow foam.

TLC with EtOAc / hexane 4: 1: R - 0.27, UV and PMA.

1 * H NMR (in CDCl3), δ in ppm: 1.00 (9H, s), 1.63 (6H, d), 1.5-2.0 (2H, m), 2.20 (1H , m), 2.58-3.00 (5H, m), 3.44 (3H, dd, J * 10.6 Hz), 3.61 (3H, s), 4.52 (2H, m) , 7.07-7.66 (18H, m), 25 C-NMR (in CDCl 3) δ in ppm: 12.6, 16.8, 17.2, 19.1, 21.5, 26.7, 36.0, 42.1, 47.2, 50.9, 51.4, 65.8, 111.8, 115.3, 119.1, 121.1, 127.7, 128.3, 129, 9, 131.2, 131.3, 132.8, 133.4, 134.3, 134.8, 135.7, 171.3.

K. Methyl ester of (S) -4- / ~ f2 ~ C 3- (4-fluorophenyl) -1-iso-30 propyl-1H-indolyl-2-methyl-7-methoxyphosphinyl] -3-hydroxybutyric acid

To a solution of 379 mg (0.531 mgmol) silyl ether of part J in 5 ml dry THF were successively 120 ƒ11 (2.12 mgmol, 4 eq.) Glacial acetic acid and 1.6 ml 1.0 M (1.6 mgmol) .35 eq.) Tetrabutyl ammonium fluoride in THF was added and the resulting solution was stirred at room temperature overnight under argon. The mixture was diluted with 10 ml of ice cold water and extracted twice with EtOAc; the organic phase was washed with saturated NaHCO3 and brine and dried over Na2SO4-8801331 1 t-f48- and evaporated to give 408 mg of yellow oil. The crude product was purified by chromatography with acetone / hexane 7: 3 on silica gel. The product fractions were concentrated to dryness to give 197 mg (78%) of the desired alcohol as a white foam.

TLC with hexane / acetone 1: 1: = 0.09, UV and PMA.

1 H-NMR (in CDCl 3), δ in ppm: 1.68 (6H, dj, 1.80-2.0 (2H, m), 2.10 (2H, m), 2.58 (2H, m) , 3.08 (2H, m), 3.63 (3H, dd, JD _ = 10.1 Hz), 3.70 (3H, d), 3.96 (1H, t), 4.35 + 4 , 49 (1H, ft-r 10 2 broad multiplets), 4.67 (1H, m), 7.0-7.6 (8H, m) 13 C-NMR (in CDCl 3), d in ppm: 17.6 , 17.7, 21.4, 29.2, 29.4, 33.2, 33.3, 34.6, 41.6, 41.8, 42.0, 42.2, 47.3, 50 , 9, 51.7, 63.4, 111.8, 113.5, 115.2, 115.5, 119.0, 119.4, 121.1, 128.3, 131.3, 131.5 , 134.2, 134.8, 161.5, J (244.1 Hz), 172.1.

L-r

Example VIII

Dilithium salt of (S) -4- / ~ [2- / Γ 3- (4-fluorophenyl) -1-isopropyl-1H-indolyl-2,7ethyl-hydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of 197 mg (0.414 mgmol) diester according to example VII in 5 ml dioxane was added 1.45 20 ml 1.0 N (3.5 eq.) LiOH with stirring and the white suspension was stirred for 40 minutes under argon on a olei bath heated to 55 ° C. After cooling, the mixture was diluted with water, filtered and evaporated in vacuo. The residue was taken up in a minimum amount of water and chromatographed on HP-20, eluting with water and then 1: 1 with water / methanol. The product fractions were evaporated to dryness. The glassy residue was taken up in 50 ml of water, filtered and freeze-dried to give 178 mg (85%, calculated as hydrate) of pure dilithium salt as white matter.

Elemental analysis: C 54.62, H 5.67, N 2.90, F 3.61, P 6.06%;

Calculated for ^ 23Η25ΝΪΊ> 2Li + 2.52 mol ^ 0 (MG = 504.71): C 54.73, H 6.00, N 2.78, F 3.76, P 6.14%.

^ -NMR (400 MHz, in CDCl3): δ 1.69 ppm (6H, dd, J = 5.8 Hz) 35 1.71 (2H, multiplet) 1.93 (2H, multiplet) 2.38 (2H , multiplet) 3.06 (2H, quartet) 4.32 (1H, multiplet) 8801331® s' - 49 - 4.87 (1Η, multiplet) 6.97 (1H, dt, J - 0.7 Hz) 7 .07 (1H, dt, J = 1.1 Hz) 7.16 (2H, t) 5 7.41 (3H, m) 7.57 (1H, 1/2 AB quartet).

Example IX

Methyl ester of CS) —4— [[1-Z (biphenylyl-2) ethyl, 7-methoxy-phosphinyl-7-3-hydroxybutyric acid 10 A. 2-formylbiphenyl

Diss-Martin 27.64 g (65.2 mgmol) of periodinane were taken up in 150 ml of CE ^ C ^. 8.0 ml of dry t-BuOH was added with stirring and this mixture was stirred at room temperature for an additional 10 minutes. Over 15 minutes, a solution of 10 g (54.3 mg mol) of 2- (hydroxymethyl) biphenyl in 20 ml was added dropwise. When all was added, the reaction mixture was allowed to come to room temperature with stirring. After stirring at room temperature for 1 hour, 600 ml of dry ether were added, followed by 225 ml of 1N NaOH. After 10 minutes, the suspension was filtered and the filter cake washed with ether. The filtrate was washed with 2 x 250 ml 1 N NaOH, dried over MgSO 4 and evaporated to give 10 g of yellow oil. Purification by chromatography with diethyl ether / hexane 1:10 over silica gel gave 9.58 g (97%) of the aldehyde of the title as a colorless oil.

TLC with EtOAc / hexane 1: 9 over silage gel: R @ 0.29 IR (film) 3065, 3025, 2850, 2760, 1685, 1700, 1600, 1470, 1450, 1395 cm -1.

1 H NMR (270 MHz in CDCl 3), δ in ppm: 8.00 (d, 1, J = 7.0 Hz), 7.60 (m, 1), 7.40 (m, 7).

Mass spectrum: m / e = 183 (M ++ H).

B. 2- (2,2-dibromoethenyl) biphenyl

A solution of 2.0 g (11 mg mol) aldehyde of part A in 60 ml was cooled to -10 ° C under argon.

With stirring, 9.21 g (35 mgmol) of trxphenylphosphine was added and that mixture was stirred until all solid was dissolved. To this solution was added a solution of 5.5 g (16.5 mgmol) CBrr in 40 ml C ^ Clg at -10 ° over 15 minutes. After stirring at -10 ° for 1 hour and 15 minutes, the reaction mixture was quenched at -10 ° with 50 ml of saturated NaHCO 2 solution.

, a8o 1331 r * - 50 -

Water and organic layers were separated and the water layer extracted once with CH 2 Cl 2. The combined CH 2 Cl 2 extracts were washed once with saturated NaHCO 2 solution and once with saturated NaCl solution, dried over Na 2 SO 2, and evaporated to dryness. The crude product was purified by chromatography with hexane to give 2.45 g (66%) of the title dibromide as off-white.

TLC with EtOAc / hexane 5:95 over silica gel: R ^ = 0.47.

IR (CHCl 3) 3064, 3011, 1596, 1473, 1450, 1435, 889, 860, 10 702 cm-1 1 H-NMR (270 MHz in CDCl3) δ 7.75 (m, 1), 7.35 (m, 8), 7.20 (s, 1) 13 C-NMR (67.0 MHz in CDCl 3), δ in ppm: 141.06, 140.08, 137.49, 133.83, 129.81, 129.45 , 129.17, 128.61, 128.22, 127.50, 127.08, 80.78

Mass spectrum m / e = 337/339/341 (M ++ H).

C. 2-ethynyl biphenyl

A solution of 2.31 g (6.9 mgmol) of vinyl dibromide from part B was cooled to -78 ° under argon. With stirring, 5.52 ml of 2.5 M n-BuLi in hexane was added dropwise at -78 ° over 10 minutes. When all n-BuLi was added, the reaction mixture turned dark purple. After stirring for 2 hours at -78 °, the reaction mixture was quenched with saturated NH 2 Cl solution. After warming up to room temperature, the THF was removed from the quenched mixture and the residue was diluted with water and extracted 1: 1 with Et2O / hexane three times.

The organic extracts were dried together on MgSO4, filtered and evaporated to give 1.3 g of yellow oil. Purification by chromatography with 1% Et 2 O in hexane gave 1.04 g (88%) of the desired acetylene.

TLC with 100% hexane over silica gel: R = 0.16.

E

IR (film) 3287, 30.61, 3026, 1474, 1449, 1432, 1008, 775, 758 and 738 cm -1 of 1 H NMR (270 MHz in CDCl3) 35 δ 7.68 (m, 3), 7, 35 (m, 6), 3.00 (s, 1) 13 C-NMR (67.8 MHz in CDCl 3), δ in ppm: 144.40, 140.22, 133.83, 129.56, 129.20 , 128.92, 127.95, 127.49, 126.94, 120.44, 83.08, 80.15 Mass spectrum m / e = 179 (m "* + H).

40 D. Methyl ester of (S) -4-Z ~ C 2-f (biphenylyl-2) ethynyl J-8801331 - 51 - * * * methoxyphosphinyl ^ -3- (t-butyldiphenylsilyloxy) butyric acid

0.332 g (1.86 mgmol) of the acetylene from Part C was stirred in 10 ml of THF at -78 ° under argon over 10 minutes. Over 5 minutes, 0.75 ml of 2.5 M n-BuLi in hexane was added to this solution. The mixture was stirred at -78 ° for 1 hour, then warmed to 0 ° C and then stirred for 10 minutes and then cooled back to -78 °. The solution of the acetylene anion was then added dropwise under argon to a solution of 2.98 mg mol phosphonic acid chloride of Example I part F cooled to -78 ° C over 8 minutes. When all was added, the mixture was stirred at -78 ° for an additional 1 hour and then quenched by adding saturated NH 2 Cl solution. After warming up to room temperature, the quenched reaction mixture was diluted with half saturated NaCl solution and extracted three times with diethyl ether. The combined Et 2 O extracts were washed with saturated NaHCO 2 solution and saturated NaCl solution, dried over MgSO 4 and evaporated to give 1.5 g of yellow oil. Purification by chromatography with hexane / toluene / EtOAc 5: 1: 4 gave 0.543 g (48%) of the title acetylene phosphinate.

20 TLC with hexaaii / toluene / EtOAc 5: 1: 4 over silica gel: R = 0.20.

1 H-NMR (270 MHz in GDGl ^) δ in ppm: 7.65 (m, 3), 7.65-7.28 (m, 16), 4.55 (m, 1), 3.55 (d , 3), 3.40 (dd, 3), 2.80 (m, 1), 2.55 (m, 1), 2.35 (m, 1), 2.08 (m, 1), 1 0.00 (s, 9) 25 13 C-NMR (67.8 M 2 in CDCl 2), d in ppm: 170.83, 145.29, 145.19, 139.22, 135.95, 135.59, 133, 86, 133.75, 133.16, 132.86, 130.57, 129.56, 129.34, 128.81, 127.92, 127.75, 127.44, 127.39, 126.94, 117.90, 100.91, 100.38, 100.18, 84.51, 81.60, 65.53, 65.42, 60.06, 51.61, 51.50, 51.11, 30 42 , 07, 41.90, 38.86, 37.16, 26.56, 20.75, 18.97, 13.97,

Mass spectrum: m / e = 611 (M ++ H).

E. Methyl ester of (S) -4-r [2- [(biphenyly1-2) ethyl 7methoxy-phosphinyl] (2-butyldiphenylsilyloxy) butyric acid

Argon was bubbled through a solution of 0.515 g (0.85 mgmol) acetylene phosphinate according to part D for 10 minutes. After addition of 0.190 g 10% Pd / C, hydrogenation was carried out in a Parr apparatus at 3.0 ato. After shaking at 3.0 atmospheres for 25 hours, the methanol solution was filtered through Celite and the filtrate was evaporated to give 0.510 g (98%) of title phosphinate 8801331 * τ * - 52 - as a colorless oil.

TLC with EtOAc / hexane 4: 1: R = 0.21.

IR (CHC13) 3071, 3054, 2998, 2954, 2934, 2902, 2859, 1734, 1477, 1462, 1448, 1438, 1428 cm-1 5 ^ -NMR (270 MHz in CDC13), δ in ppm: 7.65 (m, 3), 7.55-7.00 (m, 16), 4.45 (m, 1), 3.58 (s, 3), 3.30-3.20 (2 doublets, 3, J = 11 Hz), 2.88 (m, 1), 2.60 (m, 3), 2.17-1.80 (m, 1), 1.80-1.30 (m, 1), 1.00 (s, 3).

1 C-NMR (67.8 MH) (Diagnostic peaks, in CDCl 3), δ in ppm: 10 171.33, 65.78, 51.36, 42.24, 26.75.

Mass spectrum: m / e = 615 (m "*" + H).

F. Methyl ester of (S) -4-Z * 2- / ~ (biphenyly 1-2) ethyl Jmethoxy-phosphinyl J3-hydroxybutyric acid

A solution of 0.500 g (0.82 mgmol) of phosphinate 15 of part E in 10 ml of THF was stirred with 0.19 ml (3.3 mgmol) of HOAc under argon. At room temperature, 2.45 ml of 1.0 M nBu ^ NF in THF was added dropwise. The mixture was stirred at room temperature for 23 hours and then quenched with 15 ml of ice water. The water layer was extracted three times with EtOAc. The combined organic solutions were washed twice with saturated NaHCO 2 solution and once with saturated NaCl solution.

The organic layer was dried over Na 2 SO 4 and evaporated to dryness to give 0.437 g of a colorless oil. Chromatography with acetone / hexane 7: 3 gave 0.247 g (81%) of the title alcohol as a colorless oil.

TLC with acetone / hexane 7: 3 over silica gel: R 0.22.

IR (in CHC13) 3600-3171 (br), 3064, 3009, 2954, 1731, 1479, 1439, 1237, 1180, 1042, and 999 cm -1 1 H NMR (270 MHz in CDC13) δ in ppm: 7.50 -7.10 (m, 9), 4.50-4.15 (m, 1), 3.70 (s, 3), 3.53 & 3.50 (2 30 doublets, 3, J = 11 Hz ), 2.88 (m, 2), 2.50 (m, 2) 2.00-1.60 (m, 4) 13 C-NMR (67.8 MHz) (in CDClg) δ in ppm: 171, 55, 171.49, 141.39, 141.00, 138.10, 137.88, 129.95, 128.81, 128.06, 127.53, 26.83, 126.22, 63.08, 63.02, 62.85, 51.39, 50.58, 35 50.47, 42.35m 42.15, 42.07, 41.87, 34.31, 33.06, 33.00, 30, 77, 30.52, 29.49, 29.21 and 25.41.

Mass spectrum: m / e = 377 (M ++ H).

.8801331 • fc ^ * - 53 -

Example X.

Dilithium salt of (S) -4- £ 2- (biphenyly1-2) ethyl Jhydroxyphosphinyl-73-hydroxybutyric acid

While stirring and under argon, a solution of 0.239 g (0.64 mg mol) of the diester of Example IX in 6.5 ml of dioxane was added to 1.9 ml of 1.0 M LiOH. The mixture was stirred at 55 ° for 2 hours. After cooling to room temperature, the dioxane and most of the water were removed in a rotary evaporator.

Purification by chromatography on a column of HP-20 (18 cm x 10 2.5 cm) eluting first with 100% water and then 1: 1 with methanol / water gave 0.180 g (79%) of the title dilithium salt , a white matter.

TLC with CH2Cl2 / Me0H / Ac0H 8: 1: 1: Rp = 0.16

with nPrOH / NH4 / water 7: 2: 1: R = 0.37. j F

Example XI

Dilithium salt of (R) -4 - / * C (E) -2- (4 ^ 11110 ^ 3,31,5-trimethylbiphenylyl-2-ethylene) hydroxyphosphinyl -7-3-hydroxybutyric acid A. (E) -tributyl / ~ 2- (4 ^ 11 ^ ^ 3,31,5-trimethylbiphenylyl-2> -20 ethenyl 7tin

See M.A, Miftakov et al. In Synthesis (Comm.) (1985) biz.

496-499.

To a mixture of 1.7 g (7.13 mgmol) of 2-ethynyl-4'- £ 1ηοΓ-3,3 ', 5-trimethylbiphenyl and 2.9 ml (10.7 mgmol, 1.5 eq.) 25 (nC ^ Hg) .jSnH, 7.0 mg (0.426 mgmol) AIBN was added and the solution was quickly heated to 120 ° C in an oil bath under argon. After 15 minutes at 120 ° C, 0.39 ml (1.43 mg mol, 0.2 eq.) (N-C ^ Hg) ^ SnH was added and heating was continued for a total of 3 hours. The yellow mixture was cooled and purified by distillation through a Kugelrohr (240 ° / 0.1 mm Hg) to give 3.073 g (81 Z) of the title vinyl stannane as a colorless liquid.

TLC with hexane: R4 = 0.45, UV and PMA. The product is unstable on silica gel (long stripes from the base).

35 13 C-NMR (67.5 MHz in CDCl 3) δ in ppm: 9.5, 13.6, 14.5, 20.9, 21.1, 27.2, 27.6, 114.0, 114, 3, 123.6, 123.9, 128.8, 130.4, 133.0, 135.6, 136.1, 138.1, 140.0, 144.4, 160.3 (J__ = 244 H .)

, onion? Z.

H-NMR δ in ppm: 0.8-1.5 (27H, m, Sn (Bu) 3> 40 2.27, 2.31, 2.36 (9H, 3 singlets, aromatic CH3) 8 80 1 3 36 f5 (1H'd'J = 20 Hz * phCHsCHSn) - 54 - r _ rx> 6.68 (1H, d, J = 20 Hz, PhCH = CHSn) 6.90-7.13 (5H, m, aromatic protons).

B. (E) -41-Fluoro-2- (2-iodoethenyl) -3,3 ', 5-trimethylbiphenyl

To a solution of 9.537 g (2.89 mg mol) vinyl-5 stannane of part A in 20 ml dry Et 2 O was added 734 mg (2.9 mg mol, 1 eq.) Iodine and the brown solution was stirred for 2 hours argon stirred at room temperature. The mixture was washed with a saturated sodium thiosulfate solution, with 10% ammonia and with brine, dried over MgSO 4 and evaporated to give 1.639 g of yellow oil. The crude product was purified by chromatography with hexane on 160 g of silica gel. The combined product fractions gave 832 mg (65%) of the desired trans-vinyl iodide as pale yellow oil which slowly crystallized on storage; mp. 53-55 ° C.

TLC with hexane: = 0.31 for the trans-olefin (for the cis-olefin R1 = 0.26), UV and PMA.

1 H-NMR (270 MHz): δ in ppm: 230 & 2.32 (9H, 2 singlets, aromatic methyl) 6.05 (1H, d, J = 15 Hz, -HC = CHI) 20 6.92-7 .10 (5H, m, aromatic H) 7.24 (1H, d, J = 15 Hz, PhCH = CHI) 13 C-NMR (67.5 MHz) 6 in ppm: 14.6, 21.0, 21, 1.81.0 (= CH-I), 114.4, 114.7, 124.2, 124.5, 128.5, 128.7, 130.5, 132.7, 132.8, 133, 2,135.8, 137.2, 140.1, 143.1 (PhCH = CHI), 161.0 (Jcf-244Hz).

Note. 1 H-NMR (in CDCl 2 at 270 MHz) of the mixed fractions showed that the nearly equally fast impurity was the cis-vinyl iodide. δ = 6.54 ppm (1H, d, JRaHb = 7.9 Hz (PhCH ^ CH ^ I)).

30 C. Methyl ester of (R) -3- / ~ [(t-butyldiphenylsilyloxy) -4- C (£) -2- (4 ^ ^^^ 3,31,5-trimethylbiphenylyl-2) ethenyl J-methoxyphosphinyl Jbutyric acid

To a solution of 812 mg (2.22 mgmol) of vinyl iodide of Part B in 6 ml of dry THF was injected at -78 ° (carbonic acid / acetone) with a syringe 1.4 ml tbsp, 6 M (2.2 mgmol , 1 eq.) N-BuLi in hexane and the pale yellow mixture was stirred at -78 ° under argon for 45 minutes. The anion was then dripped with a cannula over 10 minutes in a solution cooled to -78 ° of about 3.5 mgmol (1.58 eq.) Of phosphonic acid chloride of 8801331 Λ τ * - 55 - example I part F in 6 ml dry THF . After stirring at -78 ° for 30 minutes, the yellow mixture was allowed to warm to room temperature. It was then quenched at room temperature by adding 5 ml of saturated NH 2 Cl. The mixture was diluted with diethyl ether and the ether layer was washed with saturated NH 2 Cl solution and brine, dried over MgSO 2 and evaporated to give 2.083 g of yellow oil. The crude product was purified by chromatography with hexane / acetone 85:15 on silica gel. The product fractions were evaporated to dryness to give 249 mg (17%) of the desired trans-olefin phosphinate as pale yellow oil. NMR showed it to be an approximately 1: 1 mixture of diastereomers on the phosphorus. At TLC with hexane / acetone 7: 3: R @ 0.35, UV and PMA.

^ H-NMR: δ in ppm: 3.27 (3H, d, J_ Ώ = 11.6 Hz, -P (0) 0CH_> n-ir δ 3.57 & 3.60 (3H, 2 singlets, diastereomers, -CX ^ CH ^) 4.33 & 4.50 (1H, 2 multiplets, diastereomers -CH2CH (OSiR3) CH2-) 4.84 & 5.25 (1H, d dd'n, diastereomers, 17.9 Hz, 20 JRa-p = 25.3 Hz, PhCHb = CHa-P (0) -).

D. Methyl ester of (R) -4-CC (E) -2- (4t-fluoro-3,3t, 5-trimethyl-biphenylyl-2) ethenyl-7-methoxyphosphinyl 7-3-hydroxybutyric acid To a solution of 249 mg (0.370 mgmol) Silyl ether of Part C in 5.0 ml THF was successively 85 µl 25 (1 48 mg mol, 4.0 eq.) glacial acetic acid and 1.1 ml 1.0 M (1.1 mg mol, 3.0 eq.) ( nC ^ Hg) ^ NF in THF and the yellow mixture was stirred at room temperature overnight under argon. The mixture was diluted with 10 ml of cold water and extracted with EtOAc.

The organic phase was washed with saturated NaHCO solution and pe-boulder and dried over Na 2 SO 4 and evaporated to give 243 mg of yellow oil. The crude product was purified by chromatography with hexane / acetone 55:45 on silica gel. The product fractions were evaporated to dryness to give 121 mg (75%) of the desired hydroxydester, a colorless viscous oil. At TLC with acetone / hexane 6: 4: R = 0.26, UV and PMA.

1 * H-NMR: δ in ppm: 1.8-2.06 (2H, m, CH30-P (0) CH2-) 2.30, 2.35, 2.40 (9H, 3 singlets, aromatic CH3 ), 8801331 * τ * τ - 56 - 2.40-2.60 (2Η, m, -CH (0H) CH2CO2CH3) 3.50 + 3.55 (3Η, 2 doublets, diastereomers, -P (0) 0CH3 , JH_p = 12 Hz) 3.64 (3H, s, -CO 2 CH 3) 5 3.77 + 3.84 (1H, 2 doublets, diastereomers, -CH (OH) -) 4.28 + 4.38 (1H, 2 broad multiplets, -CH (OH) -) 5.52 (1H, 2 dd'n, diastereomers, J coupling nn & J_ coupling, PhCH = CH-P (0) (OCH -) -) rlJr Ó 10 6, 90-7.10 (5H, aromatic protons) 7.50 (1H, multiplet, diastereomers & JHH k ° PPeling 'JHP coupling PhCH = CH-P (0) (0CH3) -) E. Dilithium salt of (R) -4-CC (E) -2- (4t-fluoro-3,3t, 5-15 trimethylbiphenylyl-2) ethenyl Jhydroxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 121 mg (0.279 mgmol) hydroxy-diester of part D in 2 ml of dioxane, 0.98 ml of 1.0 N (0.98 mgmol, 3.5 eq.) Of LiOH was added and the clear yellow mixture was added | stirred under argon in an oil bath at 50 ° C. The mixture was cooled, diluted with water, filtered and evaporated under vacuum. The residue was taken up in a minimum amount of water and chromatographed on resin HP-20 (bed of 8 cm length and 25 mm diameter), successively with 200 ml of water, 25 with water / methanol 80:20 and finally with water / methanol 60 : 40 was eluted. The product fractions were evaporated together under vacuum and the residue was taken up in 50 ml of water and freeze-dried to give 91 mg of pure dilithium salt as hygroscopic white freeze-dried.

At TLC with CH 2 Cl 2 / CH 3 OH / HOAc 8: 1: 1: R 1 = 0.19, ÜV and PMA.

Examples XII through XXIV

The following compounds can also be prepared by the methods described above as worked out in the previous examples: 35, 8801331 Λ) r- * - 57 - 1

Compounds of formula 25

Ex. R Z X R

x no .__

XII OH 2-benzyloxy-4-chloro-6-methylphenyl -C2 CS4 -H

5 XIII 2-phenyl-4-methylbiphenyl -CH = CH-CH 2

XIV OH 4-chloro-2- (3-chloro-4-methylphenyl) -C-C-H

6-ethylphenyl XV LiO 1-benzyloxy ~ 3-methylnaphthyl-2 -C ^ CHg- Li

XVI HO 1,3-diphenylnaphthyl-2 -CH = CH-H

10 XVII LiO 1-benzyl-3-phenylindolyl-2 -C = C- Li XVIII OCHg 3-cyclopentyl-1-phenylindolyl-2 -CH2CH2-CH ^

XIX CH 2 O 2,6-dimethyl-8- (2'-methylbutyryl- -CH-CH-K

oxy) -1,2,3,4,6,7,8,8a-ethahydronaphthyl-1 15 XX NaO 8-benzyloxy-2-ethyl-1,2,4a, 5,6,7, -C = C- Na 8,8a-octahydronaphthyl-1

XXI HO 8-benzyloxy-6-hydroxy-2-methyl- -CH 2 CH-H

1,2,6,7,8,8a-hexahydronaphthyl-1

XXII HO 8- (2,2-dimethylbutyryloxy) - -CH-CH-- H

2-ethyl-6-hydroxy-1,2,4a, 5,6,7,8,8a-octahydronaphthyl-1 XXIII CH30 phenyl -CH = CH-CH3

XXIV HO 2,4,6-triphenylphenyl -C = C-H

Example XXV

Dicyclohexylammonium salt of the methyl ester of (S) -4- (hydroxy-methoxyphosphnyl) -3- (t-butyldiphenylsilyloxy) butyric acid A. Methyl ester of (S) -4- (diIsopropyloxyphosphinyl) -3- (t-butyl-diphenylsilyloxy) ) butyric acid

21.70 g (45.1 mgmol) of the iodide of Example I, Part F (2) was stirred under high vacuum for 30 minutes. To this was added 113.37 ml (93.92 g, 451 mgmol) of freshly distilled triisopropyl phosphite and the mixture was heated at 155 ° C for 15 hours under argon and with stirring in an oil bath. After cooling to room temperature, the excess of triisopropylphosphite and the volatile reaction products were removed by short-way distillation (at 10 mm Hg), followed by distillation by a Kugelrohr (at 0.50 mm Hg, 100 ° C, 8 hours).

The product was further purified by chromatography with hexane / acetone / toluene 6: 3: 1 on a column of silica gel of Merck 40 with an internal diameter of 95 mm with a running liquid at 5 cm per minute, 50 ml fractions were collected. Thus, 17.68 g (33.96 mgmol, 75%) of the title isopropylphosphonate, 8601331 - T t '- 58 - are obtained as a clear, viscous oil.

At TLC with hexane / acetone / toluene 6: 3: 1 over silica gel: R = 0.32.

* H-NMR: (270 MHz, in CDCl 3) 6 in ppm: 5 7.70-7.65 (m, 4H) 7.45-7.35 (m, 6H) 4.57-4.44 ( m, 3H) 3.59 (s, 3H) 2.94 and 2.88 (2xd, 1H J - 3.7 Hz) 10 2.65 and 2.60 (2xd, 1H, J = 7.4 Hz) 2.24-1.87 (series m'n, 2H) 1.19 and 1.12 (2xd, 12H, J = 6.3 Hz) 1.01 (s, 9H) B. Dicyclohexylammonium salt of the methyl ester of (S) -4-15 (hydroxymethoxyphosphinyl) -3- (t-butyldiphenylsilyloxy) - butyric acid

10.66 g (30.5 mgmol) of the isopropyl phosphonate of Part A was stirred in 80 ml under argon at room temperature. 8.71 ml of 20 (8.44 g, 32.8 mg mol) bis (trimethylsilyl) trifluoroacetamide (BSTFA) was added dropwise to this solution over 5 minutes, followed by 6.75 ml (7.84 g, 51.3 mgmol) trimethylsilyl bromide (TMSBr) over 10 minutes. After stirring at room temperature for 20 hours, the reaction mixture was quenched with 200 ml of 5% KHSO4 solution with vigorous stirring for 15 minutes.

The water layer was extracted three times with ethyl acetate. The organic extracts were washed together once with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was azeotroped twice with 50 ml of toluene. The resulting precipitate was filtered from the toluene. The filtrate was concentrated and the azeotroping and filtration was repeated.

That filtrate was evaporated to dryness under vacuum and kept under high vacuum for 5 hours.

The resulting viscous clear oil was stirred in 50 ml of dry pyridine at room temperature under argon. To this solution was suddenly added 4.65 g (22.6 mg mol) dicyclohexyl carbodiimide, followed by 1.67 ml (1.31 g, 41.0 mg mol) methanol. After stirring at room temperature for 20 hours, the reaction mixture was filtered through a pad of Celite on a sintered glass filter. The Celite was washed with ethyl acetate and 40 filtrate and washings were evaporated to dryness together under vacuum.

.8801331 * * * r - 59 -

The residue was taken up again in ethyl acetate and washed twice with 5% KHSO2 solution and once with brine. The organic extract was dried over Na 2 SO 4, filtered and evaporated to dryness and azeotroped the residue twice with toluene. That residue was taken up in toluene and filtered. That filtrate was again concentrated, azeotroped, filtered and evaporated to dryness under vacuum and the latter residue was kept under high vacuum for 6 hours to give 10.2 g (> 100% yield) of phosphonic acid monoester as a clear, viscous oil. At TLC with nPrOH / NH ^ OH / H ^ O 10 7: 2: 1: * 0.50.

1.21 g of this phosphonic acid monoester was kept under high vacuum for 4 hours to give 1.16 g (2.57 mg mol) which was dissolved in 10 ml of dry diethyl ether and 0.528 ml (0.481 g, 2, 65 mgmol) dicyclohexylamine dropwise at 15. The homogeneous solution was left at room temperature and a significant amount of crystals formed in 7 hours. The mixture was then kept at -20 ° C for an additional 16 hours and filtered after warming to room temperature. The crystals were washed with dry cold diethyl ether and then kept under high vacuum, above for 18 hours and then at 45 ° C for 4 hours. This gave 1.25 g (1.98 mg mol, 77%) of the title dicyclohexylammonium salt as a white powder, m.p. 155-156 °.

TLC with 20% methanol in C 1 C 3 Rp = 0.57.

25 ^ H-NMR (270 Mhz, in CDCl ^), δ in ppm: 7.71-7.65 (m, 4H) 7.40-7.32 (m, 6H) 4.02 (m, 1H) 3.52 (s, 3H) 30 3.28 and 3.22 (m, 1H) 3.11 (d, 3H J = 11 Hz) 2.77-2.64 (m, 2H) 2.62-2 .56 (m, 1H) 1.92-1.08 (series m'n, 22H) 35 1.00 (s, 9H)

Mass spectrum: (FAB) 632 (M&H) + IR: (in KBr): 3466-3457 (wide), 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051 and 820 cm 1.

, 8801331 T. t -ν - 60 -

Calculated for ^ 22 ^ 31 ^ 6 ^^^ 12 ^ 23 ^ 5 C 64.63, H 8.61, N 2.22%;

Elemental analysis: C 64.51, H 8.49, N 2.18%.

Example XXVI

5 Dilithium salt of (E) - 4 - Z - '- fluoro - S (1,5 - trimethyl - biphenylyl - 2 - Jethenyl) hydroxyphosphinyl J - 3 - hydroxybutyric acid A. Dimethyl ester of [2 - 4t - fluoro -3,3t, 5-trimethylbiphenylyl-2 7-2-hydroxyethyl-1phosphonic acid

To a solution of 1.8 ml (16.5 mg mol, 1.6 eq.) Of 10 dimethylmethylphosphonate in 20 ml of dry THF of -78 ° (CO 2 / acetone) was added dropwise 9.7 ml of 1.6 M over 20 minutes (15.5 mgmol, 1.5 eq.) N-butyl lithium in hexane was added and the resulting white suspension was stirred at -78 ° under argon for 60 minutes. Then, 2.5 g (10.3 mg mol, leq.) Of bi-15 phenylaldehyde of Example I part C was added dropwise over 15 minutes at -78 ° C to give a pale orange suspension. After 30 minutes at -78 °, the mixture was quenched by adding 10 ml of saturated NH 2 Cl.

After warming to room temperature, the mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 4.127 g of a yellow oil which slowly crystallized on storage.

The crystals were stirred with hexane to give 3.38 g (89.4%) of pure hydroxyphosphonate as title after filtration and drying under vacuum, white needles, m.p. 98-100 °.

An additional 223 mg of pure title compound was obtained by chromatography of the mother liquor (603 mg) on silica gel LPS-1 with hexane / acetone 7: 3. Total yield 3.613 g (95.6%).

At TLC with hexane / acetone 1: 1: R 3 = 0.33, UV and PMA. Elemental analysis: C 62.66, H 6.56, F 5.03, P 8.68%; Calculated for C 25 E 25 PF: C 62.29, H 6.60, F 5.19, P 8.45%.

B. 2- (4 ^ 1 ^ 0 ^ 3,31,5-trimethylbiphenylyl-2) ethenylphosphonic acid dimethyl ester

91 mg (0.48 mgmol, 0.05 eq.) Of p-toluenesulfonic acid was added to a solution of 3.513 g (9.6 mg mol) of hydroxy-35 phosphonate of part A in 15 ml on molecular sieves of 4 l of dried toluene. monohydrate and boiled under argon in a Soxhlet apparatus containing 4 lb molecular sieve for 16 hours. Supplemental pTsOH.l ^ O Was after reaction times 3 | hours, 5 hours and 6 hours 40, each time 91 mg. Finally, the mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCO 2 solution to give three phases: an aqueous phase, an organic phase and in an oil therebetween. The water phase and oil were drained and both washed with ethyl acetate; the ethyl acetate was washed with saturated NaHCO 2 and set aside. Both bicarbonate washings were acidified with concentrated HCl and extracted with ethyl acetate; that organic phase was washed with brine, dried over Na 2 SO 4 and evaporated to give 520 mg of recovered phosphonic acid monomethyl ester.

The diester was regenerated by taking the oil in 5 ml of trimethyl orthoformate and refluxing the mixture for 4 hours. Excess formate was removed in vacuo to give a yellow oil which was taken up in ethyl acetate and combined with the original neutral organic phase. This ethyl acetate was washed with brine, dried over Na 2 SO 4 and evaporated to give 3.396 g of yellow oil. This was purified by chromatography with hexane / acetone 75:25 on silica gel LPS-1. The product fractions were evaporated to dryness to give 2.987 g (89.4%) of trans-vinyl dimethyl-20-phosphonate as gold oil. At TLC with hexane / acetone 1: 1: R * 0.44, UV and PMA.

1F

H-NMR (in CDCl3), δ in ppm: 2.27 (3H, d, Jfl_F = 1.6 Hz) 2.33 (3H, s) 25 2.39 (3H, s) 3.61 (6H, s) d, JH_p = 11 Hz) 5.51 81H, dd, J_ = 18 Hz, J 1 - 20.6 Hz) fi-nn-r 6.95-7.09 (5H, m) 7.48 (1H , dd, JH_H = 17.9 Hz, J0_p = 23.7 Hz) 30 C NMR (in CDCl3), δ in ppm: 14.4, 20.9, 52.0 (Jc_p = 5.7 Hz) 114.4, 114 .7 119.2 (Jc_p = 185.5 Hz) 124.3, 124.5, 128.4, 128.5, 129.0, 130.6, 130.9, 132.6, 132.7, 134 , 6, 137.1, 141.0, 148.2, 148.2 (Jc_p * 5.7 Hz), 35 160.5 (J 1 - 244.1 Hz).

u C. R Monomethyl ester of C 2 (4-fluorine-3,3 *, 5-trimethylbiphenyl-2-yl) ethenylphosphonic acid

To a solution of 2.895 g (8.31 mgmol) of vinyl dimethylphosphonate of part E in 20 ml of dioxane was added 12.5 ml of 8801331

L T T

62-1.0 N (1.5 eq.) LiOH solution was added and that mixture was stirred in an olei bath at 75 ° C for 70 minutes under argon. After heating for 15 minutes, the mixture was homogeneous. The mixture was cooled to room temperature, acidified to about pH 15 with 1.0 N HCl, and extracted twice with ethyl acetate; the organic phase was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 2.663 g (95.8%) of the desired monomethyl ester as a clear, colorless oil. At TLC with CH 2 Cl / CH_OH / HOAc 8: 1: 1: IL = 0.57, UV and PMA.

10 Mass spectrum (M + H = 335 observed).

^ H-NMR (in CDCl ^), δ in ppm: 2.25 (3H, d, JH_p = 1.6 Hz) 2.33 (3H, s) 2.39 (3H, s) 15 3.53 ( 3H, d, JL = 11 Hz) 5.61 (1H, dd, JH_H = 18 Hz, JH_p = 20.6 Hz) 6.90-7.12 (5H, m) 7.38 (1H, dd, JH_R = 18 Hz, JN_p = 24 Hz).

D. Methyl ester of h- [[2- (4-fluoro-3,3t, 5-trimethylbiphenylyl-20 2) ethenyl J methoxyphosphinyl J-3-oxobutyric acid

With a stirred suspension of 168 mg of 60% (4.2 mg-mol, 1.4 eq.) NaH in 10 ml of dry THF, 420 µl (3.9 mgmol, 1.3 eq.) Was added under argon at 0 ° C. distilled methyl acetoacetate. The resulting clear solution was stirred at 25 ° for 15 minutes and then 2.25 ml of 1.6 M was added over 10 minutes

(3.6 mg mol, 1.2 eq.) N-butyl lithium in hexane when dripped.

The yellow dianion solution was stirred at 0 ° for 15 minutes and then cooled to -78 ° C before the reaction with phosphonic acid chloride.

The phosphonic acid chloride was prepared from the monomethyl ester of part C in the following manner. To a solution of 960 mg (2.87 mgmol) of phosphonic acid monomethyl ester according to Part C in 8 ml dry, 750 µl (5.98 mgmol, 2 eq.) Of distilled trimethylsilyldiethylamine was added and the clear mixture was stirred for 1 hour under argon stirred at room temperature. The mixture was evaporated to dryness under vacuum and azeotroped twice with 15 ml of benzene and the viscous oil remaining was kept on the vacuum pump for 15 minutes. The oil was now taken up in 8 ml of dry C ^C ^ with one drop of dry DMF.

, 8801331

4 r X

- 63 -

After cooling to 0 ° C (ice bath), distilled oxalyl chloride was added dropwise over 5 min under argon under argon (3.3 mg mol). After 15 minutes at 0 ° C, the mixture was evaporated to dryness under vacuum. The crude oil was azeotroped twice with 15 ml of benzene to give the crude phosphonic acid chloride as pale yellow oil after evaporation to dryness and drying on the vacuum pump for 15 minutes.

Using a cannula, about 2.9 mg mol (1 eq.) Of phosphonic acid monochloride in 8 ml of dry THF of -78 ° was transferred into a solution of the dianion of the methyl acetoacetate, also of -78 °. After 30 minutes at -78 °, the orange-brown reaction mixture was quenched by adding 8 ml of saturated NH 2 Cl solution to it and allowing it to warm to room temperature, the mixture was diluted with ethyl acetate, with saturated NaHCO 4 and with brine washed and then dried on ^ 80 ^ and evaporated to dryness under vacuum to give 1.481 g of orange oil. The crude was purified by Merck silica gel chromatography, first with hexane / acetone 9: 1 and then with hexane / acetone 1: 1.

The product fractions were concentrated to dryness to give 813 mg of 20 (62.9%) of the desired vinyl phosphonic acid diester as a viscous, pale yellow oil. TLC with hexane / acetone 1: 1: R = 0.42, UV and PMA.

1 H NMR (in CDCl 3> .6 in ppm: 2.28 (3H, s) 25 2.34 (3H, s) 2.40 (3H, s) 3.15 (2H, dd, JH_H - 4.7 Hz, J0_p * 18.2 Hz) 3.54 (3H, d, J0_p - 11.6 Hz) 3.63 (2H, s) 30 3.72 (3H, s) 5.57 (1H, dd, JH_H = 17.9 Hz, J0_p = 25.3 Hz) 6.95-7.09 (5H, m) 7.52 (1H, dd, JR_H = 17.9 Hz, J0_p = 22.7 Hz).

* ^ C-NMR (in CDCl ^), δ in ppm 35 14.0 (JC_F = 3.9 Hz), 20.6, 45.3 (Jc_p = 8.5.9 Hz) 49.6, 50.9 (Jc_p = 5.8 Hz) 5.18, 113.6, 115.0, 121.4 (Jc_p = 128.9 Hz), 123.6, 124.7, 128, 187.7, 129.5, 130.3, 130 , 8, 40 132.1, 132.4, 136.4, 136.8, 138.2, 140.7, 149.2 8801331 - 64 - τ τ »X. Λ (Jc_p - 4.9 Hz), 160.3 (JC_F = 245.1 Hz), 166.7, 194.4 (JG_p = 4.9 Hz).

E. Methyl ester of (E) -4-Z * C 2- (4l-fluoro-3,3,5,5-trimethyl-5-biphenylyl-2) ethenyl J7methoxyphosphinyl J-3-hydroxybutyric acid

To a solution of 585 mg (1.35 mgmol) ketone of part D in 4 ml dry THF cooled to 0 ° C, 51 mg (1.35 mgmol, 1 eq.) Of solid NaBH4 was added, followed dropwise by 1 ml on molecular sieves of 3 & dried CH 2 OH, and the yellow mixture was stirred at 0 ° C for 30 minutes under argon.

The mixture was quenched at 0 ° by adding 7.5 ml of acetone followed by 500 mg of silica gel CC-4. The suspension was allowed to warm to room temperature and then filtered through sintered glass, which was rinsed with ethyl acetate; the filtrate was evaporated in vacuo to 607 mg of yellow oil.

The crude oil was purified by Merck chromatography with ethyl acetate over silica gel. The product fractions were concentrated to dryness to 340 mg (57.6%) of the desired alcohol, a pale yellow oil. TLC (with EtOAc): R = 0.19, UV and PMA.

+ ^ 20 Mass spectrum: (M + H = 435, observed).

1 H-NMR (in CDClg), δ in ppm 1.90 (2H, m) 2.27 + 2.28 (3H, 2 singlets) 2.34 (3H, s) 25 2.39 + 2.40 (3H , singlets) 2.56 (2H, d) 3.52 (3H, d, JR_p «11.1 Hz) 3.69 + 3.70 (3H, 2 singlets) 3.79 + 3.90 (1H, 2 doublets) 30 5.52 + 5.54 (1H, 2dd, J = = 18 Hz, J_ = 2.48 Hz) n-ri-r 6.95-7.02 (5H, m) 7.52 -7.54 (1H, 2dd, J_ = 18 Hz, J__ _ - 21.6 Hz) 1 λ n-ri η-Jr C-NMR (in CDCl ^) (R, S mixture), δ in ppm: 14.3 (JC_F = 3.9 Hz) 35 20.8, 35.4 + 35.8 (J_ _ = 100.6 Hz) L “Jr 42.0 (Jc_p = 12.7 Hz) 50.7 ( Jc_p = 6.8 Hz) 56.5, 63.2 (Jc_p = 3.9 Hz) 113.8, 115.3, 122.9 + 123.2 (J = 122.1 Hz) vj ~ ir, 8801331 Λ ζ, * - 65 - ΐ 123.8, 128.2, 128.7, 129.0, 130.4, 131.4, 132.3, 132.7, 136.6, 137.0, 138, 2,140.8, 148.2 + 148.8 (Jc_p4.9 Hz) 160.5 (JC_F = 245.1 Hz) 5 171.8 ppm.

F. Dilithium salt of (E) -4 [2- (4t-fluoro-3,3t, 5-trimethyl-biphenylyl-2) ethenyl-7-hydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of 339 mg (0.781 mgmol) diester of part E in 8 ml dioxane, 2.3 ml 1.0 N LiOH was added (2.3 mg mol, 3 eq., An excess) and the mixture was stirred for 1 h heated at 50 ° C in an olei bath under argon. A white precipitate was clearly visible after 15 minutes. The mixture was diluted with water while still warm until all the solid was in solution, then filtered. The filtrate was evaporated in vacuo and the residue was taken up in a minimum amount of water and chromatographed on resin HP-20 with a linear gradient from water to methanol. The product fractions were evaporated to dryness and the residue was taken up in 50 ml of water, filtered and freeze-dried to give 270 mg (82.7 Z) of the desired dilithium-20 salt as a hygroscopic white matter. At TLC with C 1 Cl 2 / CH 2 OH / H 2 Ac 8: 1: 1: R '= 0.33, UV and PMA.

Elemental analysis: C 58.71, H 5.70, F 4.18, P 6.96 Z;

Calculated for ^ - ^ 22 ^ 5 ^ '2Li + 0.63 mol ^ 0 (MG = 429.57): W (in CDC1J? 58'71> S 5'46' F 4'42> P 7'21 25 δ in ppm: 1.59 (2H, multiplet) 2.24-2.37 (2H, 3 multiplets, J „= 8.5 Hz + 4.4 Hz) xi-n 2.28 (3H, doublet, J P = 1.8 Hz) n-r 2.30 + 2.39 (6H, 2 singlets) 30 4.14 (1H, multiplet) 5.78 (1H, JH_H = 17.9 Hz, JH_p = 20, 5 Hz) 6.88-7.21 (6H, multiplet.

Example XXVII

Dilithium salt of k- [Γ 2- (4 ^ 1100 ^ 3,31,5-trimethylbipheny-35-ly1-2) ethyl] hydroxyphosphinyl ^ 7-3-hydroxybutyric acid A. Methyl ester of h- [[2- (41-fluoro- 3,3'-trimethylbiphenylyl-2) -ethyl-methoxyphosphinyl7-3-hydroxybutyric acid

To an argon-rinsed solution of 297 mg trans-vinyl phosphinate of Example VI part E in 6 ml CH 2 OH was added 74 mg 10 Z Pd / 0 and the black suspension was dissolved. 8801331 * τ * '- 66 - a Parr device shaken with 2.8 ato for 3 hours. The catalyst was removed by filtration through a pack of Celite and the filtrate was evaporated to an oil in vacuo. With some hexane, that oil crystallized, and after filtration and drying, 267 mg (89.5%) of the title saturated phosphinate was white crystalline. TLC with EtOAc: R = 0.20, UV and PMA.

H-NMR (in CDC1,, 270 MHz), IR (in a KBr pellet) J ++

Mass spectrum: M + H = 437 observed) 10 1 H NMR (in CDCl 3): δ in ppm: 1.55-1.87 (4H, m) 2.29 + 2.30 + 2.31 (6H, 3 singlets) ) 2.35 (3H, d, JH_F = 2.1 Hz) 2.52 (2H, m) 15 2.78 (2H, m) 3.50 + 3.55 (3H, 2 doublets, JH_p = 4, 3 Hz) 3.71 (3H, s) 3.86 + 3.91 (1H, 2 singlets) 4.25 + 4.39 (1H, 2 wide multiplets).

20 B. Dilithium salt of k- [C 2— (41-fluoro-3,31,5-trimethyl-biphenylyl-2) ethyl] -hydroxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 250 mg (0.573 mgmol) diester of Part A in 6 ml of dioxane, 1.72 ml of 1.0 N (3 eq., Excess) LiOH was added and the mixture was stirred in an oil bath for 1 hour under argon. Heated to 50 ° C. A white precipitate was clearly visible after 15 minutes. The mixture was diluted with water while still warm until all the substance was dissolved, then filtered. The filtrate was evaporated in vacuo and the white residue was taken up in a minimum amount of water and chromatographed on resin HP-20, eluting with water (to neutral), then with undiluted methanol. The product fractions were evaporated in vacuo to a white matter, which was azeotroped twice with acetonitrile and dried in vacuo; this gave 131 mg (55%) of the desired dilithium salt as a white matter.

35 TLC with C 1 / C 2 / CH 2 OH / acetic acid 8: 1: 1: R 3 0.34, UV and PMA.

Elemental analysis: C 57.67, H 5.90, F 3.92, P 7.39%;

Calculated for ^ 22 ^ 24 ^ 5 ^ ^ 2 + 0.95 mol ^ 0 (MG = 437.30): C 57.67, H 5.97, F 4.34, P 7.08%.

1 H-NMR (in CD ^ D + D20), δ in ppm: .8001331 * t * i - 67 - 1.39-1.57 (4H, multiplet) 2.22-2.37 (2H, multiplet) 2 , 26 + 2.38 (6H, 2 singlets) 2.31 (3H, doublet, J_ - 1.8 Hz) π - J? 5 2.71-2.77 (2H, multiplet) 4.13-4.20 (1H, multiplet) 6.73-7.11 (5H, multiplet, aromatic H).

Example XXVIII

Dilithium salt of (E) -4-Z ~ C 2- / 3- (4-fluorophenyl) -1-isopropyl-10H-indolyl-2-Jethenyl-hydroxyphosphinyl J-3-hydroxybutyric acid A. Dimethyl ester of [2 ~ C 3- (4-fluorophenyl) -1-isopropyl-1H-indolyl-2 J7-2-hydroxyethylphosphonic acid

At a temperature of -78 ° (acetone / CX ^), a solution of 1.35 ml (12.42 mg mol; 1.6 eq.) Of dimethyl methane phosphonate in 20 ml of dry THF over 15 minutes gave 7.3 ml 1.6 M (11.6 mgmo, 1.5 eq.) N-BuLi were dropped into hexane and the resulting white suspension was stirred at -78 ° under argon for 1 hour.

Over 10 minutes, at -78 °, 2.183 g (7.76 mgmol) of indole-aldehyde of Example VII part E was added dropwise in 8 ml of dry THF and the light orange suspension was stirred at -78 ° for 30 minutes. The mixture was then quenched by adding 10 ml of saturated NH 2 Cl; after warming up to room temperature was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over Na 2 SO 4 and evaporated to give 3.19 g of white matter. This was stirred with warm hexane to give 2.967 g (94.3%) of the title pure hydroxyphosphonate, a white substance with m.p. 161-162 ° G.

TLC with hexane / acetone 1: 1: 0.29, UV and PMA.

Elemental analysis: C 62.34, H 6.32, N 3.30, F 4.61, P 7.32%; Calculated for ColHoc O, NPF: 21 25 C 62.21, H 6.22, N 3.46, F 4.69, P 7.64%.

1 H NMR (in CDCl 3>: δ in ppm: 1.69 + 1.74 (6H, 2 doublets) 2.18 + 2.56 (2H, 2 multiplets) 35 3.61 (1H) 3.67 + 3 .71 (6H, 2 doublets, J1 = 11 Hz) rr-r 5.32 (1H, m) 8801331 - 68 -

4. "i T

5.50 (1H, m) 7.04-7.25 (4H, m) 7.33-7.39 (2H, quartet) 7.52 (2H, ΔΒ quartet), 5 13 C-NMR (in CDCl3) : δ in ppm: 21.2, 21.3, 33.1 (Jc_p = 136.3 Hz) 48.3, 52.6 + 52.7 (Jc_p = 5.7 Hz) 62.1 (Jc_p = 3.8 Hz) 112.5, 114.3, 115.1, 115.4, 119.5, 120, 122, 128.1, 10 130.6, 131.9, 132.0, 134.8, 134.9, 135 2.161.8 (Jc_p = 246.1 Hz).

B. Dimethyl ester of trans- 2- (3- (4-fluorophenyl) -1-iso-propyl-1H-indolyl-2-ethylphenylphosphonic acid

2.60 g (6.43 mgmol) of the hydroxyphosphonate of Part A were dissolved in 20 ml of warm benzene and 122 mg (0.1 eq.) Of p-TsOH. 2 O was added thereto and the mixture was stirred for 1 hour. argon cooked in a Soxhlet apparatus containing a 4 lb molecular sieve. The yellow solution was cooled and diluted with ethyl acetate; the organic phase was washed twice with saturated NaHCO 2 and with brine, dried and evaporated to give 2.47 g of crude olefin as a yellow substance. After recrystallization from ethyl acetate / hexane, 2.238 g (9.9%) of pure trans vinyl phosphonate by title were presented as pale yellow platelets with m.p. 153-155 °. TLC with hexane / acetone 1: 1: 25 R = 0.33, UV and PMA.

* + +

Mass spectrum: M + H 388 (observed).

Elemental analysis: C 65.27, H 6.03, N 3.48, F 5.11, P 7.98%; Calculated for ^ 1 ^ 23 ^ 3 ^ 1 ^ C 66.11, H 5.98, N 3.62, F 4.90, P 7.99%.

30 1 H NMR (in CDCl 3): δ in ppm: 1.67 (6H, doublet) 3.68 (6H, d, JH_p = 11.6 Hz) 4.90 (1H, septet) 5.73 (1H, dd, J ( trans) = 18 Hz, J = 18.2 Hz) nn n-r 35 7.05-7.56 (8H, m) 7.64 (1H, dd, JH_H = 17.9 Hz, J0_p = 23.7 Hz) 13 C-NMR (in CDCl3): δ in ppm: 21.7, 47.8, 52.2 (Jc_p = 5.7 Hz) 111.8, 115.4, 115.7, 118.5 (Jc_p = 43.5 Hz) 8 Ö 0 1 S δ 1 £ - * - - 69 - 14 120.1, 120.2, 123.4, 128.2, 130.5, 130.7 131.1, 131.7, 135 9, 137.9 (Jc_p = 7.6 Hz) 161.9 (JC_F = 246 Hz).

C. Monomethyl ester of trans- / * 2- / ~ 3- (4-fluorophenyl) -1-iso-5-propyl-1H-indolyl-2-ethenylphosphonic acid

To a solution of 1.787 g (4.61 mgmol) of vinyl dimethylphosphonate of part B in 12 ml of warm dioxane, 6.9 ml of 1.0 N (6.9 mgmol, 1.5 eq.) Of LiOH was added and this was added. heated to 75 ° in an oil bath under argon for minutes. After cooling, the mixture was acidified with 8 ml 1N HCl and extracted twice with ethyl acetate; the extract was washed twice with water and brine, dried over Na 2 SO 4 and evaporated to dryness to give 1.859 g of yellow oil which was taken up in warm hexane. On cooling, the monoacid crystallized out, yield 1.657 g (96.1%) of pale yellow substance with m.p. 181-183 °.

Elemental analysis: C 64.02, H 5.87, N 3.64, F 5.26, P 7.90%; Calcd for C 22 H 21 Cl 3: P 64.02, H 5.70, N 3.73, F 5.06, P 8.25%.

TLC with CH 2 Cl / CH 2 OH / acetic acid 20: 1: 1: R = 0.26, UV and PMA.

- Z L j J? 20 H-NMR (in CDCly): δ in ppm: 1.66 (6H, doublet) 3.64 (3H, doublet, Jg_p = Hz) 4.89 (1H, septet) 5.81 (1H, dd, JM »17.9 Hz, JR_p = 18.5 Hz) 25 7.06-7.64 (9H, multiplet) 13 C NMR (in CDCl 3): δ in ppm: 21.8, 47.9, 52.1 ( J „Ώ = 5.7 Hz) L * ™ Jr 112.0, 115.5, 115.8, 116.1, 119.0 (Jc_p * 9.5 Hz) 120.2, 120.4, 123, 5, 128.3, 130.4, 130.8, 30 131.2, 131.8, 131.9, 136.2, 136.8 (Jc_p = 7.6 Hz) 161.9 (JC_F = 246 Hz ).

D. Methyl Ester of A ~ [[2- [3- (4-Fluorophenyl-1-isopropyl-1H-indolyl-2-ethylenyl-7-methoxyphosphinyl] -3-oxobutyric acid

The required phosphonic acid chloride was prepared as follows: To a solution of 1.564 g (4.19 mg mol, 1 eq.) Of phosphonic acid monomethyl ester according to Part C in 10 ml of dry CH 2 Cl 2 was 1.05 ml (8.38 mgmol, 2 eq.) distilled diethylamino-trimethylsilane and the mixture was stirred at room temperature under argon for 1 hour and then evaporated to dryness under vacuum.

8801331 * r * '- 70 -

The residue was taken up in 20 ml of benzene, evaporated to dryness under vacuum and the residue was kept on the vacuum pump for a further 15 minutes. A solution of the crude silylated acid in 10 ml dry and one drop of dry DMF was cooled to 0 ° and 400 µl (4.61 mgmol, 1.1 eq.) Was freshly distilled (COCl) 2 added. After stirring at 0 ° for 15 minutes and then at room temperature for 45 minutes, always under argon, the yellow mixture was evaporated to dryness under vacuum. The residue was taken up in 20 ml of benzene, evaporated to dryness under vacuum and kept in the vacuum pump for an additional 15 minutes to give the crude phosphonic acid chloride as a viscous yellow oil.

The solution of the phosphonic acid chloride cooled to -78 ° in 8 ml of dry THF was transferred dropwise with a cannula over 20 minutes into a solution of the methyl acetoacetate dianion cooled to -78 °, which was prepared according to example XXVI from 590 ƒ11 (5 .45 mg mol, 1.3 eq.) Methyl acetoacetate, 235 mg 60% NaH (5.87 mg mol, 1.4 eq.), 3.1 ml 1.6 M (5.03 mg mol, 1.2 eq.) n-butyl lithium and 10 ml THF. The orange reaction mixture was stirred at -78 ° for 30 minutes and then quenched by dripping saturated NH 4 Cl and allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with saturated NaHCO 4 and brine, dried over Na 2 SO 4 and evaporated to give 2.080 g of yellow oil. The crude oil was purified by chromatography with C 1 / C 4 / EtOAc 7: 3 over silica gel from Merck. The product fractions were combined and evaporated to dryness to give 519 mg (36.3%) of the title title transphosphinate as a pale yellow oil. TLC with hexane / acetone 1: 1: Rp - 0.48, DV and PMA.

Mass spectrum: M + H * ~ 472 (observed).

^ -NME (in CDCl3): <5 in ppm: 1.66 + 1.71 (6H, 2 doublets) 1.68 (2H, m) 3.23 (2H, doublet) 35 3.54 (3H, d ) 3.72 (3H, s) 4.90 (1H, septet) 5.76 (1H, dd, Ju_ = 18 Hz) li-ri 7.10-7.58 (8H, m) 40 7.66 (1H, dd, Ju = 18 Hz) ii-n <8801331 - 71 - * * * ΐ 13C-HMR (in CDC13): δ in ppm: 21.8, 45.7 (J ^ p = 87.1 Hz ) 47.9, 50.0, 51.5 (Jc_p = 5.7 Hz) 52.3, 111.9, 115.5, 118.8 (J__ = 104.1 Hz) Ur 5 119.8, 120.2, 120.3, 123.6, 128.2, 130.4, 130.8, 131.8, 131.9, 136.1, 139.2 (Jc_p = 5.6 Hz), 161, 9 (Jc_p = 246 Hz), 167.0, 194.6 (Jc_p = 3.8 Hz).

E. Methyl ester of (E) -4-f [2- [3- (4-fluorophenyl) -1-isopropyl-1 H -indolyl-2-ethylenyl] -methoxyphosphinyl, 7-3-hydroxyhydroxy-butyric acid

To a solution of 519 mg (1.1 mgmol) ketone of part D in 8 ml absolute ethanol (dried on a 3x molecular sieve) 42 mg (1.1 mgmol) NaBH at -15 ° (salt / ice bath) ^ and the yellow mixture was stirred at -15 ° C for 20 minutes under argon 15. The mixture was quenched by adding 0.5 ml of acetone followed by 500 mg of silica gel CC-4 After warming to room temperature, the mixture was filtered the residue was rinsed with ethyl acetate and the filtrate was evaporated to dryness under vacuum to give 512 mg of yellow foam The crude foam was purified by silica gel chromatography.

Merck, first with ethyl acetate / acetone 4: 1 and then with pure acetone. The product fractions were evaporated to dryness to give 317 mg (60.9%) of the desired alcohol as a yellow oil. At TLC with EtOAc / acetone 4: 1: R = 0.21, UV and PMA.

+ + * 25 Mass spectrum (M + H = 4.74 observed) 1 H NMR (in CDCl 3): δ in ppm: 1.68 (6H, doublet) 1.97 (2H, m) 2.58 (2H, d ) 30 3.61 (3H, d, JH_p = 11 Hz) 3.68 (3H, s) 3.95 + 4.04 (1H, 2 doublets) 4.40 (1H, bm) 4.95 (1H, septet) 35 5 .78 (1H, dd, Ju _ = 17.4 Hz, J_ _ = 23.2 Hz) n-tl xi Jr 7.05-7.77 (9H, m) 13 C NMR (in CDCl 3): .8801331 j. 1 i '- 72 - δ in ppm: 21.7, 34.9 + 36.3 (Jq p “20.8 Hz) 42.0 (Jc_p = 13.2 Hz) 47.8, 50 1.8 (Jc_p = 5.6 Hz) 51.6, 63.1 (Jc_p = 15.1 Hz) 5 111.8, 115.4, 115.7, 118.6, 119.9 + 121.8 ( Jc_p = 18.9 Hz), 120.1, 123.4, 128.2, 130.6, 130.7, 131.7, 131.9, 135.8, 138.0 + 138.5 (Jc_p = 5, 7 Hz) 161.8 (JC_F = 246.1 Hz) 171.7, 171.8.

10 F. Dilithium salt of (E) -4- / / 2- / 3- (4-fluorophenyl) -1-isopropyl-1H-indolyl-2 / ethenyl / hydroxyphosphinyl / -3-hydroxy-butyric acid

A mixture of 264 mg (0.558 mgmol) hydroxydester of part E in 6 ml dioxane and 1.95 ml 1.0 N (3.5 eq.) LiOH was heated at 70 ° under argon and stirring in an olei bath for 15 minutes. . After cooling, the mixture was diluted with water, filtered and evaporated in vacuo; the residue was taken up in 1-2 ml of water and chromatographed on HP-20, first with water (to neutral, 3-4 column volumes) and then with CH 2 OH / 20 water 75:25. The product fractions were evaporated to dryness and the residue taken up in 50 ml of water, filtered and lyophilized to give 217 mg (85.1%) of the desired dilithium salt as a white lyophilization. At TLC with C ^ C ^ / CH ^ OH / acetic acid 8: 1: 1:

Rp = 0.08, UV and PMA.

Elemental analysis: C 56.76, H 5.64, N 2.58, F 3.60, P 6.77%;

Calculated for ^ gl ^ O ^ NPF ^ Li + 1.62 mol ^ 0 (MG = 486.46): C 56.78, H 5.44, N 2.88, F 3.91, P 6.37% .

1 H NMR (400 MHz, in CDCl 3): δ in ppm: 1.67 (6H, doublet) 30 1.73 (2H, multiplet) 2.38 (2H, doublet of an AE quartet, J = 15 Hz, Aü JAX 8 = JBX - 4'8 Hz) 4.24 (1H, multiplet) 5.06 (1H, septet) 35 6.09 (1H, JHH = 17.6 Hz, = 19.4 Hz) 7, 02-7.61 (9H, multiplet).

Example XXIX

Dilithium salt of (S) -4 - / * [2- [1- (4-fluorophenyl) -3-isopropyl-1 H -indolyl-2 Methyl] hydroxyphosphinyl J-3-hydroxybutyric acid, $$ 01331 * f. - - 73 - A. Ethyl ester of 4-methyl-2-oxovaleric acid

25 g of sodium salt of 4-methyl-2-oxovaleric acid was dissolved in a minimum amount of water, and after acidification with concentrated HCl to pH = 1, it was extracted several times with 5. The water phase was saturated with NaCl and extracted twice more with CK ^ C ^. The organic phases were washed together with brine, dried over Na 2 SO 4 and evaporated to give 17.7 g of free acid as a viscous oil.

To the mixture of this 17.7 g (136 mg mol) acid 10 and 200 ml dry benzene, 20.4 ml (136.2 mg mol, 1 eq.) Diaza bicycloundecane was added to give an exothermic reaction in which a gel-like, crystalline salt was created. To this mixture was added 10.9 ml (1 eq.) Of ethyl iodide and then it was stirred under argon for 3 hours. The precipitated salts were removed by filtration and the filtrate was washed once with a little (50 ml) water and brine, then dried over Na 2 SO 4. The benzene was removed by distillation under normal pressure and the yellow liquid remaining was distilled under vacuum, yielding 6.46 g (35.1% of the desired ester as a clear, pale yellow liquid, bp = 65-66 ° / 5 mm Hg.

At TLC with hexane / acetone 9: 1: R 4 = 0.55, PMA (pale blue).

+ F

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

B. Ethyl ester of 4-methyl-2-phenylhydrazonovaleric acid

To a solution of 5 g (31.6 mg mol) ethyl ester 25 of part A in 30 ml dry was added 3.3 ml (33.2 mg mol, 1.05 eq.) Phenylhydrazine over 5 minutes and the yellow mixture was added for 3 hours stirred under argon at room temperature with molecular sieves of 4 &. The liquid was dried over ^ 280 ^, filtered and evaporated in vacuo to give 8.105 g of orange oil. The oil was purified by chromatography with hexane / ethyl acetate over silica gel LPS-1. The product fractions were concentrated to dryness to give 6.8 g (86.7%) of the hydrazone of the title and above 848 mg (10.8%) of the isomer of that hydrazone. So total yield 97.5%.

35 At TLC with hexane / acetone 9: 1: = 0.42 and 0.64, UV and PMA.

Mass spectrum: M + H + = 249 (observed).

C. Ethyl ester of 3-isopropyl-1H-indole-2-carboxylic acid

HCl gas was passed for 30 minutes through a solution of 6.8 g (27.4 mg mol) of part B hydrazone in 50 ml of absolute ethanol (dried on molecular sieves. 8801331 -74-, r * τ of 3%). The exothermic reaction was accompanied by a color shift from yellow via red to dark green, after which NH 2 Cl precipitated. The suspension was stirred for an additional 20 minutes under exclusion of moisture and then poured into 50 ml of ice cold water. The ethanol was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted two more times with ethyl acetate and the combined organic phases were washed with water and brine, dried over MgSO4 and evaporated to give 4.969 g of green matter. The crude was dissolved in hot hexane, treated with Darco, filtered through a pad of Celite and concentrated to a volume of 30-50 ml and the yellow solution allowed to crystallize. The precipitated crystals were collected by filtration, rinsed with cold hexane and dried to give 4.34 g (68.5%) of the desired indole, white needles with m.p. 80-81 ° whose ^ H-NMR spectrum (in CDCl ^, at 270 MHz)

knocked. At TLC with hexane / acetone 9: 1: R = 0.42, UV and PMA

£ (Note: The R_ of the hydrazone and of the indole were the same, but the indole shows a bright blue fluorescence).

"f" 20 Mass spectrum: M + H = 232.

Elemental analysis: C 72.67, H 7.57, N 6.00%;

Calculated for C 14 H 14 NO: 14 17 2 C 72.70, H 7.41, N 6.06%.

D. Ethyl ester of 1- (4-fluorophenyl) -3-isopropyl-1H-indole-2-25 carboxylic acid

To a solution of 3.937 g (17 mg mol) of indole of part C and 9.34 ml (85 mg mol, 5 eq.) Of 1-bromo-4-fluorobenzene in 15 ml of dry DMF was added 245 mg (1.7 mg mol, 0.05 ml). 1 eq.) Cuprous oxide was added and it was boiled under argon and reflux for 17 hours. 9.34 ml (5 eq.) Of bromide and 245 mg (0.1 eq.) Of Ch 2 O were added and boiling was continued for 6 hours, after which an additional 730 mg (5.1 mg mol) of C 2 O was added and cooking was continued for 60 hours. DMF and excess bromide were distilled off in vacuo and the orange oil remaining was taken up in ethyl 35 acetate, filtered through a pad of Celite, washed with saturated NaHCO 2 and brine, dried at 80 lb and evaporated to dryness 5.385 g (97 .2%) of the title title crude indole as orange oil. At TLC with hexane / acetone 9: 1: R = 0.29, UV and PMA.

F

, 8861331 *. * - 75 - E. 1- (4-Fluorophenyl) -2- (hydroxymethyl) -3-isopropyl-1H-indole In 24 ml dry ether, it was 0 ° C (ice had) 907 mg (23.9 mgmol, 1. 5 eq.) LiAlH 2, and then 5.185 g (15.9 mgmol) indole ester of part D in 10 ml dry Et 2 O was added dropwise over 10 minutes. The mixture was stirred at 0 ° for an additional 1 hour and then quenched at 0 ° by successively adding 910 µl water, 910 µl 15% NaOH and 2.73 ml water. The suspension was filtered through a layer of anhydrous MgSO4 on Celite and the filtrate evaporated to a clear, colorless oil. The oil gradually crystallized from hexane, yielding in total two portions (3.771 g and 0.333 g) 4.10 g (90.9%) of pure indole alcohol as white, granular crystals, m.p. 81-82 °. Mass spectrum: M + H + = 284 (observed).

Elemental Analysis: C 76.59, H 6.31, N 4.93, F 6.49%;

Calcd for C 19 H 15 NOF: C 76.30, H 6.40, N 4.94, F 6.71%.

F. 1- (4-fluorophenyl) -2-formyl-3-isopropyl-1H-indole

To a solution of 6.46 g (15.24 mg mol) per-20 iodinane of Dess-Martin in 30 ml dry CH 2 Cl 2 was added 1.44 ml (15.24 mg mol, 1 eq.) T-butanol which was dried with 4% molecular sieve, and that mixture was stirred at room temperature under argon for 15 minutes. A solution of 3.599 g (12.7 mg mol) of indole alcohol of part E 25 in 13 ml of dry CH 2 Cl 2 was now added dropwise over 10 minutes and the pale yellow mixture was stirred at room temperature for another 30 minutes under argon. The reaction mixture was poured into a freshly prepared solution of 14.06 g (89 mg mol, 7 eq.) Of sodium thiosulfate in 40 ml 1N NaHCO2 and stirred for 10 minutes. The aqueous phase was drawn off and the organic phase was washed twice with 1 N NaHCO 2 solution, with water and with brine, dried over Na 2 SO 2 and evaporated to give 3.877 g of yellow oil. The crude oil was purified by chromatography with hexane / ether on silica gel LFS-1. Evaporation of the product fractions gave 3.118 g (87.3%) of crude product. One recrystallization from hot hexane gave 2.643 g (74%) of pure title aldehyde as white fluffy needles with mp. 114-116 °.

Mass spectrum: M + H + = 282 (observed).

At TLC with hexane / diethyl ether 7: 3: R '= 0.51, UV and PMA.

1? 8801331 * τ ί "- 76 -

Elemental Analysis: C 76.87, Η 5.63, Ν 4.89, F 6.88%;

Calculated for C ^ gN ^ gNOF: C 76.85, Η 5.73, Ν 4.98, F 6.75%.

G. 2- (2,2-dibromoethenyl) -1- (4-fluorophenyl) -3-isopropyl-1H-5 indole

To a solution of 1.615 g (5.74 mgmol) aldehyde of part F and 4.52 g (17.22 mgmo, 3 eq.) Of triphenylphosphine in 25 ml of dry CI ^ C ^ was added at -15 ° over 10 minutes a solution of 2.86 g (8.61 mgmol, 1.5 eq.) of CBr4 in 10 ml of dry drop, and the resulting dark orange-red solution was stirred under argon at -15 ° for 15 minutes. The mixture was quenched at -15 ° by adding a saturated NaHCO 2 solution and after dilution with, the organic phase was washed with saturated NaHCO 2 and with brine, dried over Na 2 SO 4, and evaporated to dryness 8.9 g of red gave dust. The crude was purified by chromatography with hexane / ether 100: 1 on silica gel. Evaporation of product fractions gave 2.017 g (0.6%) of pure vinyl dibromide by title as pale yellow crystals with m.p. 123-124 °.

At TLC with hexane / ether 9: 1: R = 0.67, UV and PMA.

+ ^

Mass spectrum: M + H = 438 (observed).

Elemental analysis: C 52.25, H 3.69, N 3.18, F 4.24, Br 36.59%;

Calculated for C.H. -NFBrO: 19 16 2 C 52.20, H 3.69, N 3.20, F 4.35, Br 36.56%.

25 H. 2-ethyny1-1- (4-fluorophenyl) -3-isopropyl-1H-indole

To 10 ml of dry THF, 5.5 ml of 1.6 M (8.8 mg mol, 2.2 eq.) N-butyl lithium in hexane was added at -78 ° (CC2 / acetone), then 1,749 under argon over 15 minutes g (4 mgmol) of vinyl dibromide from part G in 10 ml of dry THF. The yellow mixture was stirred at -78 ° for 20 minutes and then quenched by adding 10 ml of saturated NH 2 Cl solution. After warming to room temperature, the mixture was diluted with ethyl acetate and the organic phase was washed with saturated NH 4 Cl and with brine, dried over Na 2 SO 4 and evaporated to give 1.216 g of a dark green-brown oil. The crude oil was purified by chromatography with hexane / ether 300: 1 on Merck silica gel. Evaporation of product fractions gave 1.084 g (97.5%) of ethynyl indole by title as a fluorescent green oil. 1 H-NMR (in CDCl 2, at 270 MHz) showed that this was an 18: 1 mixture, 880155i - 77 - * * * "of the desired acetylene and the unwanted terminal olefins. At TLC with hexane / Et 2 O 50: 1: R 2 = 0.55, UV and PMA.

J. Methyl ester of (S) -4-Z * C 1- [1- (4-fluorophenyl) -1-isopropyl-1H-indolyl-2-jethynyl. -Methoxyphosphinyl J-3- (t-butyl-5-phenylsilylyloxy) -butyric acid

The acid chloride was prepared as follows from the dicyclohexylammonium salt of the phosphonic acid monomethyl ester of Example XXV. The acid was liberated from 4.32 g (6.83 mgmol, 1.75 eq.) Of dicyclohexylammonium salt by distributing it over 1.0 HCl and ethyl acetate, the organic phase twice with 1.0 HCl and with wash brine, dry at 80 ° and evaporate under vacuum; this gave 6.8 mg mole of free acid as a clear, viscous oil, which was taken up in 10 ml of dry C 2 C 4. To this was added 1.72 ml (13.7 mg mol, 2 eq.) Of distilled trimethylsilyldiethylamine and the clear mixture was stirred at room temperature under argon for 1 hour. After evaporation to dryness, the residue was azeotroped twice with 20 ml of benzene and the residue was kept on the vacuum pump for 15 minutes. To the crude silylated acid in 10 ml dry and one drop of DMF 20 was added 655 µl (7.5 mg mol, 1.1 eq.) Distilled oxalyl chloride at 0 ° C (ice bath) over 5 minutes. The yellow mixture was stirred at 0 ° C and 45 minutes at room temperature under argon and then evaporated to dryness under vacuum.

The residue was azeotroped twice with 20 ml of benzene and the residue was kept for 15 minutes on the vacuum pump to give the crude phosphonic acid chloride as a yellow viscous oil.

At -78 ° C, a solution of 1.084 g (3.90 mgmol, 1 eq.) Of indole acetylene according to part H in 10 ml of dry THF over 10 minutes yielded 2.44 ml of 1.6 M (3.9 mgmol, 1 eq. n-butyl-30 lithium dropwise into hexane and the purple suspension was stirred at -78 ° under argon for 30 minutes. The solution of this lithium salt was added dropwise to a solution of the phosphonic acid chloride in 10 ml of dry THF of -78 °. The dark brown mixture was stirred at -78 ° for 30 minutes and then quenched dropwise with 10 ml of saturated NH 2 Cl. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and saturated NH 2 Cl. The organic phase was washed with brine, dried over Na 2 SO 4 and evaporated to give 1.968 g (71.1%) of the title acetylene phosphinate as a light-40 yellow oil. At TLC with hexane / acetone: R ^ = 0.25, UV and PMA.

, 8801331, * ί = · - 78 -

Mass spectrum: Μ + Η + = 710 (observed).

Κ. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4-CC 2 - / * 1- (4-fluorophenyl) -3-isopropyl-1H-indolyl-2 J-ethyl-methoxyphosphinyl-butyric acid 5 To an argon-flushed solution of 950 mg acetylene of part J in 10 ml CH 2 OH, 238 mg 10% Pt / C was added and the black suspension was stirred overnight under 1 atmosphere of hydrogen. The catalyst was removed by filtration through a 0.4 µm 10 polycarbonate filter "Millipore" (with pre-filter) and the filtrate was evaporated to dryness in a yellow oil. The crude was purified by Merck chromatography with hexane / ethyl acetate over silica gel. From the product fractions, 915 mg (86.7%) of the pure saturated phosphinate of the title were obtained by dry evaporation as a white foam. At TLC with EtOAc / hexane 4: 1: R = 0.39, UV and PMA.

+ *

Mass spectrum: M + H = 714 (observed).

L. Methyl ester of (S) -4 - / * [2-C 1- (4-fluorophenyl) -3-isopropyl-1 H -indolyl-2 Methyl J'-methoxyphosphinyl J-3-hydroxybutyric acid

To a solution of 915 mg (1.22 mgmol) silyl-20 ester according to part K in 10 ml THF were successively 280 µl (4.88 mgmol, 4 eq.) Glacial acetic acid and 3.3 ml 1.1 M (3 .63 mgmol, 3 eq.) (NC ^ Hg) ^ NF in THF and that mixture was stirred at room temperature overnight under argon. 8 ml of ice cold water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with 5% KHSO 2 solution, once with saturated NaHCO 2 solution and brine, dried over Na 2 SO 4 and evaporated in vacuo to give 955 mg of yellow oil. The crude oil was purified by chromatography with hexane / acetone 1: 1 on Merck silica gel. Evaporation of the product fractions gave 521 mg (85.5%) of the desired alcohol as a pale yellow oil. At TLC with acetone / hexane 3: 2; ^ = 0.21, UV and PMA.

Mass spectrum: M + H + = 476 (observed).

M. Dilithium salt of (S) -4- [~ -C- (4-fluorophenyl) -3-isopropyl-1H-indolyl-2-methyl-7-hydroxyphosphyl-7-3-hydroxy- butyric acid

To a solution of 505 mg (1.06 mgmol) diester of part L in 10 ml dioxane, 3.7 ml 1.0 N (3.7 mgmol, 3.5 eq.) Of LiOH was added and that mixture was left under argon, 8801531 * τ 1 - 79 - heated in an oil bath at 65 ° C. The mixture was diluted with water, filtered and evaporated under vacuum to a pale yellow substance. The crude was suspended in a small amount of water and chromatographed on a 15 cm length, 25 mm diameter HP-20 column, rinsing first with water to neutral and then with methanol. The product fractions were combined and evaporated to dryness and the residue was taken up in 50 ml of water and lyophilized to give 484 mg (95.4%) of the desired dilithium salt as a white lyophilization.

At TLC with CH2Cl2 / CH3OH / acetic acid 8: 1: 1: = 0.39, UB and PMA.

Elemental Analysis: C 57.80, H 6.01, N 3.01, F 3.93, F 6.41% j Calculated for C23H25N05FP.Li2 +1.03 Η £ 0 (MG = 477.91): C 57.80, H 5.72, N 2.93, F 3.97, P 6.48 1.

Example XXX

15 Dilithium salt of (S) -4 ~ C [1-C 1- (4-fluorophenyl) -3-isopropyl-1 H -indolyl-2 Jethynyl, 7hydroxyphosphinyl J-3-hydroxybutyric acid A. Methyl ester of (S) -4 - / ~ [2-C 1- (4-fluorophenyl) -3-isopropyl-1H-indolyl-2 Jethynyl J methoxyphosphinyl J-3-hydroxybutyric acid

To a solution of 987 mg (1.39 mgmol) of silyl ether 20 according to Part J of Example XXX in 12 ml of dry THF were successively 320 µl (5.6 mgmol, 4 eq.) Of glacial acetic acid and 3.8 ml of 1.1 M (4.17 mg mol, 3 eq.) (NC2 -Hg) ^ NF in THF was added and that mixture was stirred at room temperature overnight under argon. The mixture was diluted with 10 ml of ice cold water and extracted with ethyl acetate. The organic phase was washed three times with 5% KHSO4, with saturated NaHCO3 and with brine, and dried over Na2SO4 and evaporated to give 1.0 g of yellow oil. TLC showed the formation of some monoacid which was converted back into the methyl ester by treatment with an ethereal solution of diazomethane. Excess diazomethane was destroyed with glacial acetic acid and the mixture was evaporated in vacuo to 1.012 g of brown oil. The crude oil was purified by Merck silica gel chromatography, first with 600 ml of hexane / acetone 8: 2 and then with hexane / acetone 1: 1. Evaporation to dryness of the product fractions gave 516 mg (78.7 Z) of the title alcohol as a light brown oil. At TLC with CH2Cl2 / CH30H: Rp = 0.41, UV and PMA. Mass spectrum: M + H + = 472 (observed).

8801331 r 1 r '- 80 - B. Dilithium salt of (S) -4-CC 2 -1 / 1- (4-fluorophenyl) -3-isopropyl-1H-indolyl-2-jethynyl-7-hydroxyr-phosphinyl J- 3-hydroxybutyric acid

To a solution of 516 mg (1.09 mgmol) diester 5 of part A in 10 ml dioxane was 3.8 ml 1.0 N (3.5 eq.) LiOH

and the clear mixture became 1 | kept in an oil bath at 60 ° under argon for an hour. The mixture was diluted with water, filtered and evaporated to dryness under vacuum, the residual oil was taken up in a minimum amount of water and chromatographed on a column of HP-20 15 cm long and 25 mm in diameter, first with pure water until neutral and then with water / methanol 1: 1. The product fractions were evaporated in vacuo and the residue was taken up in 50 ml of water, filtered and freeze-dried to give 447 mg (82.3%) of the desired dilithium salt as white vires dryness. At TLC with C 1 / C 2 / CH 2 OH / acetic acid 8: 1: 1: R * 0.39, UV and PMA.

J Γ

Elemental analysis: C 55.69, H 5.37, N 2.82, F 3.85, P 6.19%; Calculated for ^ 23 ^ 21 ^ 5 ^^^ 2 + 2.27 mol ^ 0 (MG = 496.19): C 55.67, H 5.19, N 2.82, F 3.83, P 6, 24%.

Example XXXI

Dilithium salt of (S) -4- / ~ CC 2,4-dimethyl-6- / r (4-fluorobenzyl oxy) phenyl Jethynyl Jhydroxyphosphinyl, 7-3-hydroxybutyric acid A. 1- (methoxymethoxy) -3.5 dimethylbenzene

A solution of 10.42 g (85.3 mgmol) of 3,5-di-25 methylphenol in 12 ml of THF was dripped under argon over a 10 minute period in a suspension of 85.3 mgmol pre-washed with pentane NaH in 150 ml of THF , with cooling to 0 ° C. When all was added, the mixture was stirred at 0 ° for an additional 10 minutes and stirred for an additional 20 minutes after warming to room temperature. 42 ml of dry DMF was added to the phenylate solution and then slowly a solution of 11.19 g (89.6 mgmol) of methyl bromomethyl ether in 10 ml of THF. A white precipitate formed. After stirring at room temperature for 2 hours, the reaction mixture was quenched by slowly adding 25 ml of 1N NaOH. In a rotary evaporator, the THF was removed from the reaction mixture and the leftover solution was diluted with saturated NaCl solution and then extracted three times with ether. The ether extracts were dried together over Na 2 SO 4, filtered and evaporated to dryness. The residual orange oil was purified by chromatography with 5% ether in hexane, 8801331 * 81-81 - * to give 12.0 g (85%) of the title methoxymethyl ether as a clear oil. At TLC with 15% Et 2 O in hexane: = 0.45.

Mass spectrum: m / e = 166 (M +) and 165 (M-H).

B. 2- (methoxymethoxy) -4,6-dimethylbenzaldehyde 5 To a mixture of 26.5 ml of 2.5 M n-butyl lithium in hexane and 30 ml of cyclohexane was slowly added 7.70 g (79 g) under an atmosphere of argon .45 mg mol) of tetramethyl ethylene diamine. The mixture was cooled to 0 ° and 11.00 g (66.21 mg mol) of methoxymethyl ether of Part A were added dropwise over 20 minutes. When all was added, the reaction mixture was stirred at 0 ° C for 30 minutes and an additional 10 minutes after warming to room temperature. This solution was brought through a dropping funnel under argon and at room temperature in a solution of 5.81 g (79.45 mg mol) DMF in 100 ml dry cyclohexane. The mixture was stirred at room temperature for 2 hours and then quenched with methanol. The solvent was removed in a rotary evaporator and the residual orange oil was taken up in a 1: 1 mixture of ether and water. The water layer was extracted three times with ether and the ether extracts were dried together on MgSO4, filtered and evaporated to dryness. The residual orange oil was purified by chromatography with 20% ether and hexane to give 7.7 g (60%) of the desired aldehyde as a clear oil. At TLC with 15% Et 2 O in hexane over 4 4 silica gel: R = 0.14. Mass spectrum: m / e * 195 (M + H), 179 + * + + 25 (M-CH3), 163 (M-0CH3) and 149 (M-OC ^).

C. 2-hydroxy-4,6-dimethylbenzaldehyde

To a solution of 6.89 g (35.5 mg mol) of methoxymethyl ether of part B in 130 ml of dioxane was added 35.5 ml of 1 M HCl at room temperature. The mixture was gently boiled under stirring and reflux for 30 minutes and then cooled to room temperature. The dioxane was removed in a rotary evaporator. The residual aqueous solution was diluted with water and extracted with ether. The water layer was then saturated with NaCl and extracted two more times with ether. The ether extracts were dried together on MgSO 4, filtered and evaporated to give a greenish substance; after recrystallization from hexane 4.01 g (75%). At TLC with Et 2 O / hexane 1: 3 over silica gel: R 0.48; mp. 46.48 °; mass spectrum: m / e = 151 + *. + (M + H) and 135 (M-CH. ^).

8801331 * t τ · - 82 - D. 2-C (4-fluorophenyl) methoxy _7 ~ 4,6-dimethylbenzaldehyde

To a solution of 4.0 g (26.7 mgmol) phenol of Part C in 30 ml dry DMF was added with stirring and under argon 4.43 g (32 mgmol) solid 1 CO 2 and the mixture was then 35 heated to 60 ° for minutes. The resulting orange solution was cooled to room temperature and 5.55 g (29.3 mg mol) p-fluorobenzyl bromide was added. After this, it was heated to 60 ° with stirring for 2 hours. The reaction mixture was now poured into 50 ml of ice water and this mixture was extracted several times with ether. The combined ether extracts were dried over MgSO 4, filtered and evaporated to give a yellow substance. Purification by chromatography with 15% ether in hexane gave 4.48 g (60%) benzyl ether by title as a white matter. At TLC with EtoO / hexane 1: 3: IL = 0.34; mass spec-

X ^ X. ^ X

Trum: m / e - 259 (M + H), 231 (M-CHO) and 109 (M-C-, H, F).

E. 1- (2,2-dibromoethenyl) -2,4-dimethyl-6- (phenylmethoxy) benzene

To a solution 4.42 g (17.13 mgmol) aldehyde of part D in 170 ml dry CH2 Cl2 was added with cooling in an ice / salt bath 14.4 g (55.0 mgmol) triphenylphosphine and the mixture was stirred until all the solid was dissolved. Now 8.52 g (25.7 mgmol) CBr 2 in 50 ml CH 2 Cl 2 was added dropwise via a dropping funnel over 12 minutes. When all was added, the orange solution was stirred at 0 ° C for an additional 15 hours and then the reaction mixture was quenched with 60 ml of saturated NaHCO 2 solution under vigorous stirring. The water layer was drained and pulled out twice more. The C 1 -C 2 extracts were washed once with saturated NaHCO 2 solution, dried over MgSO 2, filtered and evaporated to give 13 g of a light brown substance. The title dibromide was purified by chromatography with 2% ether in hexane to give 5.49 g (77%) of title dibromide.

At TLC with 2% Et 2 O in hexane over silica gel: IL = 0.28. Mass spectrum: m / e = 413 (M + H) +, 333, 335 (M-Br), 317 (M-C6H4F) and 109 (M-C1 () H9OBr2) +.

35 F. 1-ethynyl-2-Z * (4-fluorophenyl) methoxy J-b, 6-dimethylbenzene

To a solution of 5.48 g (13.3 mgmol) of dibromide of part G in 70 ml THF cooled to -78 °, 10.6 ml of 2.5 M (26.5 mgmol) n-butyl was added under argon over 10 minutes. lithium in hexane added. The mixture was stirred at -78 ° 880 1 53.1 * -1-83 - for 1 hour and then quenched at -78 ° with saturated NH 4 Cl solution. After warming up to room temperature, the mixture was diluted with 60 ml of water and extracted twice with ether. All organic extracts were combined and dried over MgSO4.

Filtration and removal of the solvent gave 3.8 g of the title benzyl oxyacetylene as a yellow substance.

This was purified by chromatography with 3% ether in hexane to give 2.76 g (85 Z) of acetylene as the title white matter. At TLC with 2% Et2 O in hexane over silica gel: R10 0.17. Mass spectrum: m / e = 255 (M + H) +, 159 (M-CgH ^ F) + and 109 (m-c10h9o) +.

G. Dilithium salt of (S) -4-f [2,4-dimethyl-6- (4-fluoro-benzyloxy) phenyl-jethynyl-7-hydroxyphosphinyl J-3- (t-butyl-diphenylsilyloxy) butyric acid 15 To one to - 78 ° cooled solution of 2.76 g (11 mgmol) acetylene of part E in 40 ml THF was added over 8 minutes 4.4 ml 2.5 M n-butyl lithium in hexane, followed by stirring at -78 ° for another 40 minutes .

17.4 mg mol in 60 ml THF of the phosphonic acid chloride according to Example XXV 20 was cooled to -78 ° under argon.

The acetylene solution described above was then added over 8 minutes. After stirring for an additional 1 hour at -78 °, the reaction mixture was quenched at -78 ° with saturated NH 2 Cl solution. After warming up to room temperature, the water layer was diluted with water and extracted twice with ether. THF was removed from the organic layer and the residual orange oil was taken up in ether. All ether solutions were combined, washed once with saturated NaHCO 2 and once with saturated NaCl solution, dried over MgSO 4, filtered and evaporated to give 9.4 g of title acetylene phosphinic acid in the form of an orange gum.

The acetylene phosphinic acid was purified by chromatography with hexane / toluene / ethyl acetate 5: 1: 4. Thus, 4.23 g (56%) of the title acetylene phosphinic acid were obtained as colorless gum. At TLC with hexane / toluene / ethyl acetate (5: 1: 4) over silica gel: R - 0.28. Mass spectrum: m / e = 609 + ^ + (WtH-C6H5) and 255 (C14H19Si0).

H. Methyl ester of (S) -4- / ~ [[2,4-dimethyl-6- (4-fluorobenzyloxy) phenyl] ethynyl-7-methoxyphosphinyl-7-3-hydroxybutyric acid 40 To a solution of 0.455 g (0.66 mgmol) acetyl-.8801331 * ri-84 - boron phosphinate of part G in 10 ml of THF was added under argon at room temperature 0.16 g (2.66 mgmol) acetic acid and then over 5 minutes 1.8 ml 1.1 M (2, 0 mgmol) (nC ^ Hg) ^ NF in THF. After stirring at room temperature for 24 hours, the reaction mixture was quenched by adding 30 ml of ice water. The water layer was drained and extracted twice with ethyl acetate. The THF was removed from the organic layer and the residual oil was taken up in ethyl acetate and combined with the extracts of the water layer. This combination was made twice with saturated NaHCO2 solution and once with saturated

NaCl solution washed and dried over Na2SO4. Filtration and removal of the solvent gave 0.40 g of the title acetylene phosphinate in the form of an oil. This was purified by chromatography with pure ethyl acetate. The hydroxyacety-15 loan phosphinate of the title was obtained in a yield of 79%.

At TLC with acetone / hexane 7: 3 over silica gel: R = 0.56.

+ + * + Mass spectrum: m / e = 449 (M + H), 431 (M-OH), 417 (M-OCH ^) J. Dilithium salt of (S) -4 - / * [C 2, 4-dimethyl-6- (4-fluoro-benzyloxy) phenyl Jethynyl-7hydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of 0.191 g (0.43 mg mol) of acetylene phosphate of part H in 6.0 ml of dioxane was added 1.4 ml of 1 N LiOH at room temperature. The mixture was heated to 55 ° with stirring for 2 hours. After cooling to room temperature, it was evaporated to dryness. The title compound thus obtained was purified by chromatography on a 130 mm x 30 mm column HP-20, first with 100 ml of water and then with water / methanol 1: 1. 0.170 g (91% yield) was obtained as white lyophilized 30 g. At TLC with nPrOH / NH ^ OH / ^ O 7: 2: 1 over silica gel:

Rp = 0.37. Mass spectrum: m / e is 421 (M + H) +, 427 (M + Li) + and 433 (M + 2Li) +.

Elemental analysis: C 55.13, H 5.25, F 4.08, P 6.91%;

Calculated for ^ 21 ^ 20 ^ 6 ^^ 2 '^ 0: 35 C 55.09, H 4.98, F 4.15, P 6.78%.

Example XXXII

Dilithium salt of (S) -4-Z ~ [[2,4-dimethyl-6- (4-fluorobenzyloxy) phenyl-7-ethyl-7-hydroxyphosphinyl, 7-3-hydroxybutyric acid A. Methyl ester of (S) -3- (t- butyldiphenylsilyloxy) -4- / 'Cl-' 8801331 - 85 - * C 2- (4-fluorobenzyloxy) -4,6-dimethylphenyl 7ethyl-7-methoxy-phosphinyl butyric acid

While stirring, a solution of 1.34 g (1.95 mg mol) of acetylene phosphinate of Example XXXI part G in 5 12 ml of methanol was added to 40 mg of mgίθθ and hydrogen was bubbled through for 10 minutes, after which the hydrogen atmosphere was ballooned was maintained. After 5 hours and 15 minutes at room temperature, the reaction was complete and argon was bubbled through the reaction mixture. The mixture was then filtered through a layer of Celite on a glass filter and the catalyst was washed with some methanol. The solvent was removed from the filtrate to give 1.4 g of the title saturated phosphinate as a clear gum. This was purified by chromatography with ethyl acetate / hexane 60:40 and then the still slightly impure fractions were re-chromatographed with hexane / acetone / toluene 60:25:15. Thus, 1.17 g (86%) of the saturated phosphinate of the title were obtained.

TLC with ethyl acetate / hexane 80:20 over silica gel = 0.45.

Mass spectrum: m / e = 691 (M + H) +, 659 (M-OCH2) + and 635 (M-C9H19OSi) +.

B. Methyl ester of (S) -4- / ~ C Γ2,4-dimethyl-6- (4-fluorobenzyloxy) phenyl Jethyl] methoxyphosphinyl-7-3-hydroxybutyric acid

Under argon and with stirring, 1.16 g (1.68 mgmol) of phosphinate according to Part A in 25 ml of THF were added 0.40 ml of ice-25 vinegar and then over 4.6 min. H9) NF

in THF. The mixture was stirred at room temperature overnight (18 hours) and then quenched with 5 ml ice water. After stirring for several minutes, saturated NaCl solution was added, and the phases separated. The THF was removed from the organic layer in a rotary evaporator and the residue was taken up in ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and all ethyl acetate solutions were washed together twice with saturated NaHCO 2 solution and once with saturated NaCl solution, dried over Na 2 SO 4, filtered and evaporated to dryness. This gave 1.13 g of the title hydroxy phosphinate in the form of a clear oil.

This hydroxyphosphinate was purified by chromatography with 100% ethyl acetate to give the pure product as a clear oil in 83% yield. At TLC with ace-, 8801331 T f f "* - 86 - ton / hexane 6: 4 over silica gel: R = 0.27. Mass spectrum: + m / e = 453 (M + H) and 343 (M-C ^ F).

C. Dilithium salt of (S) -A- ££ [2,4-dimethyl-6- (4-fluorobenzyl-oxy) phenyl] methyl-7-hydroxyphosphinyl J-3-hydroxybutyric acid 5 To a solution of 0.594 g (1.3 mgmol) of phosphinate of part B in 19 ml of dioxane was added at room temperature with stirring 4.0 ml of 1 N LiOH and that mixture was heated to 55 °. After 20 minutes at 55 °, a thick precipitate had formed and a further 4.0 ml of dioxane was added. That suspension was stirred for an additional 2 hours at 55 ° C and then 3 ml of water was added to clarify the reaction mixture. After an additional 3 hours at 55 ° C, the reaction mixture was cooled to room temperature and the dioxane and water were removed in a rotary evaporator, leaving the dilithium salt in the form of a white matter, which was kept under high vacuum for 15 minutes. The title lithium salt was purified by chromatography on HP-20, first with 100 ml of water and then with MeOH / 2 O 1: 1. The dilithium salt was obtained in a yield of 67% as a white lyophilization. TLC with nPrOH / NH4OH / water 7: 2: 1 over silica gel: = 0.36. Mass spectrum: m / e = 425 + '+ (M + H) and 437 (M + H + 2 Li).

Elemental analysis: C 55.19, H 5.80, F 4.29, P 6.83%;

Calculated for Co1Ho / O, FPL10.1.15 HoO: 21 24 6 2 2 C 55.19, H 5.80, F 4.16, P 6.78%.

Example XXXIII

Dilithium salt of (S) -4- / TC 2- / f (biphenylyl-2) ethynyl-7-hydroxy-phosphinyl J-3-hydroxybutyric acid A. Methyl ester of (S) -4- £ * ζ 2- £ (biphenylyl-2 ethynyl-7-hydroxy-phosphinyl, 7-3-hydroxybutyric acid. To a solution of 0.985 g (1.61 mg mol) phosphinate of Example IX part D in 19.6 ml dry THF at room temperature was 0.368 ml (0.386 g, 6.44 mgmol) glacial acetic acid added, followed over 8 minutes by 4.40 ml of 1.1 M (nC ^ Hg) ^ NF in THF.

After stirring for an additional 18 hours at room temperature, the reaction mixture was quenched with 30 ml of ice water. The water layer was extracted with ethyl acetate. The organic extracts were washed together twice with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated to dryness. The product was isolated by chromatography on a 15 cm length, 50 mm diameter silica gel column 8801331 from Merck at a rate of 5 cm per minute acetone / hexane 40:60. The product fractions were evaporated to dryness. and the residue is azeotroped with toluene and dried under vacuum. This gave 0.369 g (0.991 mg mol, 62% yield) of the title alcohol as a viscous yellow oil. (98 mg (0.263 mgmol, 16%) of a slightly less pure product were also obtained). At DLG with acetone / hexane 1: 1 over silica gel: R ^ 0.35. Mass spectrum: m / e = 373 (M + H) +.

B. Dilithium salt of (S) -4- / ~ Γ2-C (biphenylyl-2) ethynyl J-10 hydroxyphosphinyl J7-3-hydroxybutyric acid

From the diester of part A, 0.275 g (0.739 mg mol) in 7.57 ml dioxane was treated with argon and stirring with 2.22 ml 1 N LiOH under stirring. The cloudy reaction mixture was heated to 55 ° in an oil bath for 45 minutes and then cooled to room temperature. The solvents were removed in a rotary evaporator and kept under high vacuum for 90 minutes.

The resulting yellow foam was dissolved in 4 ml of distilled water and rinsed through a 19 cm x 25 mm column HP-20, collecting 10 ml fractions every 1.4 minutes.

First, 15 fractions were collected with pure water (now no longer basic) and then with methanol / water 45:55; the product fractions thereof were evaporated to dryness and kept on top of a high vacuum pump for 16 hours; this gave the title dilithium salt as a white lyophilization.

At TLC with nPrOH / NH4 OH / ^ O 7: 2: 1 over silica gel: = 0.55.

Mass spectrum: m / e = 345 (M + H) +, 351 (M + Li) + and 357 (M + 2 Li) +. Elemental analysis: C 56.62, H 4.70, P 8, Q7%;

Calcd for C 19 H 10 O P 11 + 1.42 mole O (MG = 381.75): C 56.63, H 4.71, P 8.07%.

Example XXXIV

Dilithium salt of (S) -4- [[2- (3,5-dimethyl-bisphenylyl-2) -ethyl-7-hydroxyphosphinyl] -3-hydroxybutyric acid A. 2-formyl-3,5-dimethylbiphenylyl

Phenylmagnesium bromide was purchased from Aldrich 35 (Cat. No. 17, 156-5) as a 3M solution in diethyl ether.

A mixture of 3.35 g (4.48 mg mol) dimer palladium complex of Example I part B and 9.40 g (35.85 mg mol) triphenylphosphine in 67.2 ml dry toluene was stirred at room temperature under argon for 30 minutes. After cooling to 0 ° C, 8801331 "1 - 88 - 11.95 ml of 3 M Grignard reagent from Aldrich was added rapidly in portions. That mixture was still 1 stirred at room temperature for an hour. After cooling to 0 ° C, 22.4 ml of 6.0 HCl were suddenly added, followed by stirring at room temperature for 1 hour more. The water layer was separated and extracted with ether.

The organic extracts were filtered together through Celite (which was rinsed with ether) and the filtrate was washed with brine and evaporated to dryness. The residue was azeotroped with toluene and dried under vacuum to give a yellow substance.

An attempt at purification by double chromatography on a column of Merck silica gel of 15 cm length and 95 mm diameter, first with 100% hexane and then with 3% diethyl ether in hexane (running speed 5 cm / min.) Gave 2.95 g of yellow substance, which was a mixture of 1.88 g (8.96 mg mol, 100% yield) of the aldehyde of the title and 1.06 g of triphenylphosphine. This mixed product was used as such in the preparation of Part B.

At TLC with 5% diethyl ether in hexane over silica gel: R + + + 0.30. Mass spectrum: m / e m 211 (M + H), 263 (M2 + H) and 473 20 (Mj + M2 + H) +. (M ^ = desired aldehyde and M2 = triphenylphosphine).

B. 2- (2,2-dibromoethenyl) -3,5-dimethylbiphenyl

A mixture of the product of Part A (containing 8.96 mgmoles of aldehyde) and 6.90 g (26.4 mgmoles) of triphenylphosphine in 88 ml of dryness was stirred at -5 ° for 10 minutes, and then stirred over 20 minutes a solution of 4.38 g (13.2 mgmol) of CBrmol in 32 ml of dry CE mlCl ^ cooled to -5 ° when dripped. The reaction mixture was stirred at -5 ° for 1 hour and gradually turned dark orange. Then it was quenched with 85 ml of saturated NaHCO 2 solution. The water layer was extracted with CE2 Cl2.

The organic extracts were combined once with saturation

NaHCO 2 solution and washed once with brine, dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by first absorbing 25 g silica gel from Merck from the top, placing it at the top of a column of 35 cm Merck silica gel, 15 cm in length and 50 mm in diameter, and eluting with 4% CH 2 Cl 2 in hexane (running speed 5 cm / cm). min.). This gave 2.18 g (5.96 mg mol, 68% yield) of the title vinyl vibromide as a viscous colorless oil. At TLC with 4% CHOC10 in hexane over silica gel: R1 = 0.37. Mass spectrum: 11 + * m / e = 365, 367 and 396 (M + H).

8801331 - 89 - Λ - Λ -Τ C. 3,5-dimethyl-2- (1-propynyl) biphenyl

A solution of 2.10 g (5.74 mgmol) of vinyl dibold part of Part B in 29.11 ml of dry THF was cooled to -78 ° under argon and with stirring. 4.59 ml of 2.5M (11.47 mgmol) n-butyl lithium was added dropwise over 20 minutes in hexane, through which the liquid turned deep purple. After stirring for an additional hour at -78 °, the reaction mixture was quenched at -78 ° with 25 ml of saturated NH 2 Cl solution and after warming to room temperature, it was diluted with water and extracted 1: 1 with ether / hexane. The organic extracts were dried together over MgSO 4, filtered and evaporated in vacuo. The product was isolated after chromatography with 1% ether and hexane on a Merck silica gel column (15 cm long, 50 mm diameter) to give 1.08 g (5.23 mg mol, 91% yield) of the title acetylene as 15 colorless oil which was colored blue at -20 ° after 17 hours of storage.

At TLC with 100% hexane over silica gel: R = 0.32. Mass + * spectrum: m / e = 207 (M + H).

D. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4 - / * C 2-20 (3,5-dimethylbiphenylyl-2) methoxyphosphinyl-7-butyric acid

A solution of 0.950 g (4.61 mg mol) of acetylene from part C in 27.3 ml of dry THF was cooled to -78 ° with stirring and under argon. Over 20 minutes, 1.84 ml of 2.5 M (4.61 mgmol) n-butyl lithium in hexane was added dropwise, whereby the solution turned dark purple brown. The mixture was stirred at -78 ° for an additional 1 hour (making it a slurry) and stirred for a further 15 minutes after warming to 0 ° C (the mixture was now a dark purple, homogeneous solution) and finally cooled again to -40 ° ( remained homogeneous). This -40 ° 30 saline was dripped over 25 minutes at a cooling to -78 ° solution of 8.12 mg mole of phosphonic acid chloride according to Example I part F in 27.3 ml of dry THF. When all was added, the dark orange reaction mixture was stirred at -78 ° for 1 hour and then quenched at -78 ° with 50 ml of saturated NH 4 Cl. After heating to room temperature, it was diluted with water. The water layer was extracted with ether and the organic extracts were washed together once with saturated NaHG2 and once with brine, dried over MgSO4, filtered and evaporated in vacuo.

The product was isolated by chromatography with ethyl 40 acetate / hexane 1: 1 on a Merck silica gel column of 8801331 - 'τ - 90 - cm in length and 50 mm in diameter (running speed 5 cm / min.) Containing 0.609 g ( 0.945 mgmol, 21% yield) of the title phosphinate as orange yellow oil.

At TLC with ethyl acetate / hexane 1: 1 over silica gel: R = 0.32.

Mass spectrum: m / e = 639 (M + H) +.

E. Dilithium salt of (S) -4-Z-f2- (3,5-dimethyl-biphenylyl-2) -ethyl, hydroxyphosphinyl J-3- (t-buty] diphenylsilyloxy) butyric acid

Under argon, to a solution of 0.876 g (1.37 mgmol) of acetylene phosphinate according to Part D in 13 ml of methanol-0.315 g of 10% Pd / C was added and that mixture was hydrogenated in a Parr apparatus with 2.8 ato of hydrogen . After shaking for 24 hours, the reaction mixture was filtered through a pad of Celite in a glass filter. The Celite was rinsed with methanol and the filtrates were evaporated to dryness together under vacuum to give 0.896 15 g of yellow oil, which was purified by chromatography on a column of Merck silica gel 15 cm in length and 50 mm in diameter, with 40% * 50% ethyl acetate in hexane; this gave 0.680 g (1.06 mg mol, 77% yield) of saturated title phosphinate as a pale yellow foam, rinsing the column with pure methanol gave 87 mg of a slightly crude product.

At TLC with acetone / hexane 1: 1 over silica gel: R 2 0.27. Mass spectrum: m / e = 643 (M + H) +.

F. Dilithium salt of (S) -4-ζ C 2- (3,5-dimethylbiphenylyl-2) -ethyl, 7-hydroxyphosphinyl, 7-3-hydroxybutyric acid 25 In a solution of 0.66 g (1.03 mg mol) phosphinate of part E in 12.65 ml dry THF, while stirring under argon at room temperature, first drop 0.236 ml (0.247 g, 4.12 mgmol) ice vinegar and then 2.81 ml 1.1 M (3.09 mgmol) (nC ^ Hg) ^ NF in THF. After stirring at room temperature for 16 hours, the reaction mixture was quenched with 25 ml of ice water. The water layer was extracted with ethyl acetate. The organic extracts were combined, washed twice with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated in vacuo. The product was purified by chromatography with acetone / hexane 1: 1 on a column of Merck silica gel 15 cm in length and 40 mm in diameter to give 0.363 g (0.898 mgmol, 87% yield) of the title alcohol as a white matter.

At TLC with acetone / hexane 1: 1 over silica gel: R @ 0.30. Mass spectrum: m / e = 405 (M + H) +.

c 8801331 ji - λ; - 91 - G. Dilithium salt of (S) -4-CC 2- (3,5-dimethylbiphenylyl-2) -ethyl J7hydroxyphosphinyl 7-3-hydroxybutyric acid

Under argon, 0.355 g (0.878 mgmol) of the diester of part F in 9 ml of dioxane was treated with 2.63 ml of 1 M LiOH. The homogeneous reaction mixture was heated to 55 ° in an oil bath.

After stirring at 55 ° for 10 minutes, the reaction mixture had become a white suspension. An additional 9 ml of dioxane and 2 ml of water were added and the suspension was heated to 55 ° for 45 minutes, then cooled to room temperature. The solvents were removed in a rotary evaporator 10, after which vacuum was maintained for 1 hour under high pressure. The leftover white matter was purified by chromatography on a column of HP-20 (18 cm x 25 mm). A fraction of 10 ml was collected every 1.4 minutes. First 15 fractions were collected with pure water and then eluted with methanol / water 1: 1. From this was obtained (after freeze-drying and 8 hours under high vacuum over 20 ^ 0.289 g (0.744 mgmol, 85% yield) dilithium salt according to the title as white freeze-dried.

TLC with nPrOH / NH 4 OH / 7 7: 2: 1 over silica gel: R 0.56.

Elemental analysis: C 60.95, H 6.18%;

Calculated for c20H2305PL12 + 0.34H20 (MG = 394.31): C 60.92, H 6.05%.

• j-

Mass spectrum: m / e = 389 (M + H).

Example XXXV

25 Dilithium salt of (S) -4-ζ / * 2- (4'-fluoro-3,5-dimethyl-biphenylyl-2) ethyl, / hydroxyphosphinyl J-3-hydroxybutyric acid A. 4-fluorophenylmagnesium bromide 1, 08 g (44.35 mgmol) of magnesium shavings were dried by flambering and then stirred in 40 ml of dry ether under argon. While stirring vigorously, 40.3 mg mole of 1-bromo-4-fluoro-benzene was added to the magnesium. The reaction was started with ultrasonication and then the halide was added dropwise at such a rate that the mixture kept to a boil. When all was added, the mixture was stirred at room temperature for an additional 20 minutes, heated to boiling and finally cooled to room temperature. This gave a golden orange, transparent Grignard solution containing 40.32 mg mol of Grignard reagent (0.91 M in ether).

.8801331 - 92- * 1 * r B. 2-formyl-4 * -fluoro-3,5-dimethyl-biphenyl

See Stockker et al. In Journal of Med. Chem. 2 lb (1986) 170-181.

A mixture of 3.20 g (4.35 mgmol) palladium complex of Example XXVI part B and 10.58 g (40.32 mgmol) 5-triphenylphosphine in 67.2 ml dry toluene was stirred at room temperature under argon for 30 minutes. Then this mixture was cooled to 0 ° C and the 40.32 mg mol Grignard reagent of Part A was added (rather quickly). The resulting mixture was stirred at room temperature for 1 h and after cooling to 10 ° C, 21.75 ml of 6.0 N HCl was added. After stirring at room temperature for 1 hour, the water 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 washed with brine and evaporated to dryness. The residue was azeotroped twice with toluene to give an orange-yellow substance.

Attempts to isolate the aldehyde by chromatography on a column of silica gel 15 cm in length and 95 mm in diameter, first with hexane and then with 3% Et 2 O in hexane (5 cm per minute), eventually resulted in a mixture of the desired aldehyde with triphenylphosphine as a pale yellow substance (3.70 g - it may be assumed that it contained 8.7 mg mol, ie 100% yield, i.e. 1.99 g of title aldehyde and 1.70 g of triphenylphosphine). This mixture was used directly for the preparation of Part C.

At TLC with 5% ether and hexane over silica gel: R = 0.25.

1 F H-NMR (at 270 MHz in CDCl3).

C. 2- (2,2-dibromoethenyl) -41-fluoro-3,5-dimethylbiphenyl

A mixture of the crude reaction product of Part B (containing 8.70 mg mol aldehyde), 6.85 g (26.1 mg mol) triphenylphosphine and 87 ml dry was stirred at -5 ° for 10 minutes. While the mixture was kept at -5 °, a solution of 4.33 g (13.05 mg mol) of CBr 2 in 43 ml dry over 25 minutes was added. That mixture was stirred at -5 ° for an additional 1 hour to give a dark orange solution which was then quenched with 80 ml of saturated NaHCO 2 solution. The water layer was extracted four times. The combined organic extracts were washed once with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and combined with 25 g of Merck silica gel. The solvent was evaporated and the pre-absorbed product was purified by chromatography on a column of silica gel 15 cm in length and 50 mm in diameter, with 4% Cl 2 C 4 in hexane, 5 cm / min. This gave 2.32 g (6.04 mgmol, 69% yield) of vinyl-5 dibromide by title as a colorless oil.

At TLC with 5% in hexane over silica gel: = 0.43.

Mass spectrum: m / e = 383, 385 and 387 (M + H) +.

D. 4 * -fluoro-3,5-dimethyl-2- (1-propynyl) biphenyl

A solution of 2.30 g (5.99 mgmol) of vinyldi-10 bromide of part C in 33 ml of dry THF was cooled to -78 ° under argon and 4.79 ml of 2.5 M (11. Dropped 97 mg mol) of n-butyl lithium in hexane to give a dark purple solution. After stirring for an additional hour at -78 °, the reaction mixture was quenched at -78 ° with 25 ml of saturated 15 NH 2 Cl solution and diluted with 25 ml of water after warming to room temperature. The water layer was extracted 4 times with ether / hexane 1: 1. The organic extracts were dried together on MgSO 4, filtered and evaporated to dryness. The product was purified by chromatography with 1% ether in hexane over a 20 column Merck silica gel of 15 cm length and 50 mm diameter (5 cm / min.) Yielding 1.25 g (5.57 mg mol, 93% yield). of the title gave acetylene, a colorless oil which turned blue when stored at 20 °.

In TLC with hexane over silica gel: R = 0.25. Mass spectrum: + * 25 m / e = 225 (M + H).

E. methyl ester of (S) -4- / / 2- (4f-fluoro-3,5-dimethyl-biphenyl-2-ethynyl / hydroxyphosphinyl / -3- (t-butyldiphenyl-silyloxy) butyric acid

With a solution of 1.18 g of 30 (5.24 mgmol) acetylene of part D in 28 ml of dry THF cooled to -78 °, 2.10 ml of 2.5 M (5.24 mgmol) of n-butyllithium were added in argon dripped hexane causing the mixture to turn dark purple-brown. After stirring for an additional hour at -78 °, it was allowed to warm to 0 ° C, stirred for 10 minutes and then cooled back to -78 °.

At -78 ° and under argon, a solution of 8.32 mg mole of phosphinyl chloride according to Example I part F in 28 ml of dry THF was cooled to -78 ° to this solution of the acetylene anion over 20 minutes. When all was added, the dark orange reaction mixture was stirred at -78 ° for an additional 1 hour and then quenched with a saturated NH 2 Cl solution at -78 ° 8801331 -L 1 x '- 94. After warming up to room temperature, it was diluted with water and extracted four times with ether. The organic extracts were washed together once with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated to dryness. The product was isolated by chromatography with ethyl acetate / hexane 40:60 on silica gel to give 0.730 g (1.11 mg mol, 21% yield) of the title acetylene phosphinate as green viscous oil.

At TLC with ethyl acetate / hexane 1: 1 over silica gel: R = 0.36.

Mass spectrum: m / e = 657 (M + H) "*".

F. Methyl ester of (S) -4- / ~ C 2- (4l-fluoro-3,5-dimethylbipheny-ly1-2) ethyl J hydroxyphosphinyl-7-3- (t-butyldiphenylsilyloxy) -butyric acid 15 By a solution of 0.685 g (1.04 mgmol) acetylene phosphinate according to part E in 9.9 ml methanol was bubbled argon for 10 minutes. 0.239 g of 10% Pd / C was now added and the mixture was hydrogenated in a Parr apparatus with 2.8 atoms of hydrogen. After shaking for 24 hours, the reaction mixture was filtered through a layer of Celite in a glass filter, which Celite was rinsed with methanol, and the filtrate was evaporated to give 0.638 g of green oil.

The product was purified by chromatography with ethyl acetate / hexane 45:55 on Merck silica gel (5 cm / 25 min.) To give 0.530 g (0.802 mgmol, 77%) of the title saturated phosphate as a pale yellow foam. Also 90 mg (0.136 mg mol, 13%) of a slightly impure product were obtained.

At TLC with ethyl acetate / hexane 1: 1 over silica gel: E = 0.30.

Mass spectrum: m / e = 661 (M + H) +.

G. Methyl ester of (S) -4- [[2- (4T-fluoro-3,5-dimethyl-biphenylyl-2-methyl-methoxyphosphinyl J-3-hydroxybutyric acid)

To a solution of 0.525 g (0.794 mgmol) of phosphinate of part F in 9.74 ml of dry THF was added dropwise 0.182 ml (0.191 g, 3.18 mgmol) of ice vinegar at room temperature under argon, followed by 2, 17 ml 1.1 M (2.38 mgmol) (nC ^ Hg) ^ NF in THF. After stirring at room temperature for 16 hours, the reaction mixture was quenched with 15 ml of ice water. The water layer was extracted three times with ethyl acetate and the combined. Organic extracts were washed twice with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated to dryness.

The product was purified by chromatography 5 with acetone / hexane 1: 1 on Merck silica gel (5 cm / min). The product fractions were evaporated to dryness and azeotroped with toluene to give 0.281 g (0.665 mgmol, 84% yield) of the title alcohol as a white matter. A contamination visible in the 1 H NMR spectrum at 270 MHz was not visible in various DLC systems 10 and thus could not be separated.

TLC with acetone / hexane 1: 1 over silica gel = 0.31. ^ H-NMR

(270 MHz, in CDCl ^). Mass spectrum: m / e = 423 (M + H) +.

H. Dilithium salt of (S) -4 - / * [2- (4T-fluoro-3,5-dimethyl-phenylyl-1-2) -ethyl] -hydroxyfisfinyl J-3-hydroxybutyric acid 15 to 0.20 g (0.473 mgmol) diester of Part G in 4.84 ml of dioxane was added with stirring and under argon 1.42 ml of 1 M LiOH. The homogeneous reaction mixture was heated to 55 ° in an oil bath. After stirring at 55 ° for 10 minutes, the reaction mixture had become a white suspension. This was kept at 55 ° for an additional 45 minutes and then cooled to room temperature. The solvents were removed in a rotary evaporator under high vacuum (1 hour). The leftover white foam was dissolved in 4 ml of water and chromatographed through a column of HP-20. A fraction of 10 ml was collected every 1.4 minutes. The column 25 was rinsed with water until 15 fractions were collected and then 1: 1 with methanol / water. After freeze-drying twice and under high vacuum for 11 hours, 0.158 g (0.389 mgmol, 82% yield) of the desired salt as white freeze-dried material is added.

TLC with nPrOH / NH 4 OH / 7 7: 2: 1 over silica gel: R 0.59.

"i *

Mass spectrum: m / e = 395 (M + H).

Elemental analysis: C 58.14, H 6.09%;

Calculated for 020 ^ 2 ^ 0 ^ 112 + 0.39 ^ 0 (MG = 413.25): C 58.12, H 5.56%.

35 Example XXXVI

Methyl ester of (S) -4- [[2-C 5- (4-fluorophenyl) -3-isopropyl-1-phenyl-1H-pyrazolyl-4 Jethynyl J methoxyphosphinyl J-3-hydroxybutyric acid A. Methyl ester of β- (4 -fluorophenyl) - / * -oxopropionic acid 40 17.4 g 60% sodium hydride (0.43 mol) in mineral, 8801331 - 96 - r τ x χ oil was washed twice with dry hexane and dried under vacuum, followed by 44 .3 ml (0.36 mol) of diethyl carbonate, followed dropwise by 22 ml (0.18 mol) of p-fluoroacetophenone. After about 10% of the ketone was added, 4 drops of ethanol were added to initiate the reaction and the remainder of the p-fluoroacetophenone was added over 1 hour at such a rate that the mixture was left to boil. The resulting yellow precipitate was boiled for 3 hours under argon in 250 ml dry ether.

After the reaction mixture had cooled in an ice bath and diluted with 200 ml ether, 1.3 liters of water were slowly added until all the substance was dissolved. The aqueous phase was separated, acidified to pH 1.0 with 32 ml of 12 N HCl and extracted with 2 x 500 ml of ether. The combined organic extracts were washed with 200 ml of brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product (44.0 g) was distilled under reduced pressure (3.5 mm) to give 24.88 g of 865.8% title compound as a homogeneous oil. At TLC with C 1 / C 4 / hexane 4: 1 over silica gel: Rp = 0.46.

B. Ethyl ester of 2- (4-fluorobenzoyl) -4-methylvaleric acid 10.3 g of 60% sodium hydride (0.26 mol) in mineral oil was washed twice with dry hexane, dried under vacuum and suspended in 245 ml of dry tetrahydrofuran. After cooling to 0 ° C, a solution of 24.5 g (0.12 mol) of Part A compound was added dropwise under argon over 20 minutes, and stirring was continued for 30 minutes after warming to room temperature. The mixture was then cooled again to 0 ° (ice water bath) and 18.62 g (0.17 mol) isobutyryl chloride was added dropwise. After warming to room temperature, stirring was continued for 3 hours. After cooling to 0 ° C, the mixture was quenched with 200 ml of water, which was freed from most tetrahydrofuran in a rotary evaporator. The water phase was now acidified to pH 1.0 with 37 ml 10% HCl and extracted with 3 x 100 ml ether. The combined organic extracts were washed with 50 ml of brine, dried over MgSO 4, filtered and evaporated to give 36.85 g of oil which was a mixture of the desired product with two other compounds.

At TLC with C 1 / C 4 / hexane 4: 1 over silica gel: Rp = 0.46, 0.33 and 0.20 (UV).

, 8801331 - 97 - * 3 * C. Ethyl ester of 1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazole-4-carboxylic acid

The crude product of part B (36.85 g, 0.12 mol) was dissolved in 151 ml glacial acetic acid and 18.1 ml (0.18 mol) 97 Z phenylhydrazine was added under nitrogen with 5 bits »

After stirring at room temperature for 19 hours, the reaction mixture was poured into 350 ml of water and extracted with 3 x 100 ml of ether. The combined organic extracts were washed with saturated NaHCO 2 until the water layer remained basic and then with 500 ml of brine, then dried over MgSO 4, filtered and evaporated to dryness.

The dark orange oil was mixed once with 300 ml of petroleum ether and evaporated to dryness to give a yellow solid. This crude product was stirred with 100 ml of petroleum-15 ether to give 15.3 g of crude product which was in turn chromatographed on a column of silica gel LPS-1 with CH 2 Cl 2 / hexane 2: 1, yielding 11.53 g pure product. An additional 7.12 g of the desired product were obtained from the 26.4 g of mother liquor by chromatography on a column of silica gel LPS-1; total yield 20 18.65 g = 44.1 Z. A small sample of this substance was taken out

Et 2 O / hexane recrystallized to give a homogeneous solid with m.p. 92-93 °.

In TLC with CR 2 Cl 4 / hexane 4: 1 over silica gel: R 0.3 0.35. Elemental analysis: C 71.62, H 5.99, N 7.91, F 5.54 Z; Calculated: C 71.57, H 6.01, N 7.95, F 5.39 Z.

D. 1-phenyl-5- (4-fluorophenyl) -4- (hydroxymethyl) -3-isopropyl-1H-pyrazole

A solution of 11.53 g (32.7 mg mol) of Part C compound in 142 ml of dry ether was taken over 1 µl dropwise for 30 hours in a suspension of 3.67 g (96.7 mg mol) of lithium aluminum hydride in 70 ml of ether. The greenish suspension was allowed to warm to room temperature over 1 hour. After cooling to 0 ° again, it was quenched by adding 20 ml of water until gas evolution ceased. The thick suspension was diluted with 100 ml of ether and filtered and the precipitates were washed well with 3 x 150 ml of ethyl acetate. The organic extracts were washed together with 50 ml of brine, dried over MgSO 4, filtered and evaporated to give 10.3 g (100 Z crude) of cream. 100 mg of Et20 / 8801331 - 98 - of the crude product

* 1 X

recrystallized from hexane to give 58 mg of the title compound as white crystals, m.p. 138-140 °.

At DLG with C & ^ Cl ^ over silica gel: R ^ 0.01.

Elemental Analysis: C 73.16, H 6.15, F 6.12, N 8.90 Calculated: C 73.52, H 6.17, F 6.12, N 9.03%.

Mass spectrum: (M + H) = 311.

E. 1-phenyl-5- (4-fluorophenyl) -4-formyl-3-isopropyl-1H-pyrazole

A solution of 10.2 g (* / 32.7 mgmol) of crude product of Part D in 85 ml of dry dichloromethane was quickly added to a solution of 21.23 g (98.4 mgmol) of pyridinium chlorochromate in 125 ml of dry dichloromethane and the dark brown solution were stirred at room temperature under nitrogen for 4 hours. The mixture was now diluted with 750 ml ether and stirred for an additional 15 minutes. The above solution was decanted from the tar residue and the residue was stirred with 2 x 100 ml of dichloromethane. The dichloromethane extracts were diluted with 750 ml ether and the combined extracts filtered through a layer of silica gel. The clear filtrate was evaporated to dryness to give 10.0 g of crude product.

The crude product was chromatographed on a column of 400 ml Baker silica gel (100-150 µm) with C1-4 / hexane 4: 1; this gave 9.6 g (95.2%) of the title compound as a solid. By recrystallizing 100 mg from hexane, an analytical sample of 72 mg was obtained; mp. 108-110 °.

At TLC with CH0Cl1 over silica gel: R = 0.58 (UV). δ 1 F

Elemental analysis: C 74.10, H 5.52, N 9.12, F 6.29%;

Calculated: C 74.01, H 5.56, N 9.09, F 6.16%.

Mass spectrum: (M + H) "*" - 309.

30 F. 4- (2,2-dibromoethenyl) -1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazole

A mixture of 2.0 g (6.48 mgmol) of compound of part E and 5.10 g (19.2 mgmol) of triphenylphosphine in 30 ml of dry dichloromethane 35 was cooled under argon to a mixture cooled to between -5 ° and -10 °. A solution of 3.22 g (9.61 mgmol) CBr 1 in 10 ml was dropped for 5 minutes. After the mixture was stirred at 15-20 ° for 15 minutes, it was poured into 10 ml of saturated NaHCOg solution and extracted with 3 x 50 ml. The combined organic extracts. 8801331 * i. Λ - 99 - * were washed with 10 ml of saturated NaHCO 4 and 25 ml of brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product mixture (9.33 g) was chromatographed on a column of silica gel LPS-1, first with C 1 / C 5 / hexane 1: 9, then 1: 1, then 4: 1. This gave 2.75 g (91.6%) of the title compound as a solid. Recrystallization of a small sample gave mp white crystals. 88-90 °.

At TLC with CH 2 Cl 4 / hexane 4: 1 over silica gel: R 0.85.

Elemental analysis: C 51.96, H 3.51, N 5.97, F 4.22, Br 34.77%;

Calculated: C 51.75, H 3.69, N 6.04, F 4.09, Br 34.43%.

Mass spectrum: (M + H) = 465.

G. 4-ethynyl-1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazole 15 A solution of 2.64 g (5.67 mgmol) of Part F compound in 10.5 ml of dry tetrahydrofuran was cooled to -78 ° under argon and 7.16 ml of 1.6 M n-BuLi in hexane was added dropwise. This suspension was stirred at -78 ° for 1 hour for 2 hours and then quenched by adding 10 ml of 25% 20 NH 2 Cl. After warming to room temperature, the mixture was extracted three times with 50 ml of ether and the combined organic extracts were washed with 20 ml of brine, dried over MgSO 4, filtered and evaporated to give 1.79 g of the title compound as a light brown substance.

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

30 At TLC with Et 2 O / hexane 1: 9 over silica gel (developed twice)

Rp - 0.70.

Elemental Analysis: C 79.22, H 3.53, N 9.28, F 6.23%;

Calculated: C 78.92, H 5.63, N 9.21, F 6.24%.

Mass spectrum: (M + H) + = 305.

H. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4- / ~ E [\ - phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4, 7-ethyl, 7-methoxyphosphinyl] butyric acid

A mixture of 2.77 g (5.55 mg mol) crude phosphonic acid monomethyl ester of Example I part F and 2.1 ml (11.05 .8801331 * Γ ΐ * - 100 mg mol) of trimethylsilyldiethylamine in 10 ml of dry dichloro -methane was stirred at room temperature under argon for 1 hour. The mixture was evaporated to dryness and the residue azeotroped with 20 ml of benzene and kept on the vacuum pump for 15 minutes. The viscous oil was taken up again in 10 ml of dry dichloromethane and cooled after addition of 1 drop of DMF to -10 °, after which 530 µl (6.08 mgmol) of oxalyl chloride was added dropwise. Violent gas evolution was observed and the solution was stirred at -10 ° for 15 minutes and then at room temperature for 1 hour. The reaction mixture was then evaporated to dryness and the residue azeotroped with 20 ml of benzene and dried under vacuum.

A solution of 1.12 g (3.67 mgmol) of Part G compound in 9.0 ml of dry tetrahydrofuran was cooled to -78 ° under argon and 2.3 ml of stirred at -78 ° 15 over 30 minutes with stirring .6 M (3.67 mgmol) n-BuLi in hexane when dripped. This solution was dropped by cannula at -78 ° into a pre-cooled to -78 ° solution of the above phosphonic acid chloride in 6.5 ml of dry tahydrofuran. The mixture was then stirred at -78 ° for an additional 30 minutes and quenched by dripping 6.0 ml of 25% NH 4 Cl, thereafter, and allowed to warm to room temperature. The mixture was extracted with 3 x 100 ml ether and the combined organic extracts were washed with 10 ml 25% NH 4 Cl and 25 ml brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product mixture (~ 4.2 g) was chromatographed on a column of silica gel with hexane / acetone 9: 1 to give 1.54 g (57.0%) of the title compound as a light brown oil.

At TLC with hexane / acetone 7: 3 over silica gel: R = 0.33.

F

I. Methyl ester of (S) -4- / ~ [2- [1-phenyl-5- (4-fluorophenyl) -3-30 isopropyl-1 H -pyrazolyl-4-jethynyl 7methoxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 593.9 mg (0.81 mgmol) of Compound H in 8.0 ml of dry tetrahydrofuran, 190 xx1 (3.24 mgmol) of glacial acetic acid and 2.54 ml of 1 M 35 Bu ^ NF in THF were successively dropped. and it was stirred at room temperature overnight under argon. After cooling to 0 ° C, 8.5 ml of 5% KHSO 2 solution was added and extracted with 3 x 75 ml of ethyl acetate. The combined organic extracts were washed with 10 ml of 5% KHSO4 solution and with 20 ml of brine, dried on MgSO4, filtered and evaporated to dryness.

The crude product was taken up in a mixture of 14 ml ether and 10 ml dry tetrahydrofuran and cooled to 0 ° C, after which excess diazomethane and ether were added. After stirring at 0 ° C for 3 hours, the reaction mixture was quenched by dripping glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of silica gel with acetone / hexane 1: 2 to give 325.6 mg (80.6% yield) of the title compound as a semisolid.

Example XXXVII

Dilithium salt of (S) -4-C C 2 -C 1 -phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4-ethynyl-hydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of 325 mg (0.65 mgmol) of compound XXXVI in 7.7 ml of dioxane was added 2.25 ml of 1 N

LiOH was added and it was stirred under nitrogen in an oil bath at 55 ° C for 1 hour and then at room temperature for another 16 hours.

The reaction mixture was evaporated to dryness under vacuum and dried.

The crude product was chromatographed on a column of HP-20 (15 cm length and 25 mm diameter), first with 400 ml of distilled water and then with 500 ml of water / methanol 1: 1. The desired fractions were evaporated to dryness and dried under vacuum. The solid product was taken up in distilled water and lyophilized to give 317.1 mg (96.4%) of title product 25 as a fluffy white lyophilization.

In TLC with iPrOH / NH ^ OH / H ^ O 8: 1: 1 over silica gel: R ^ 0.33. Elemental Analysis: C 56.98, H 5.17, N 5.46, F 3.90, P 6.26%; Calculated for H 2 O (HG = 505.861): C 56.99, H 4.90, N 5.54, F 3.75, P 6.12%.

30 ^ H-NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.40 (d, 6H, J = 7 Hz), 1.81-1.98 (m, 2H) 2.35 (dd , 1H, J = 9.15 Hz) 2.48 (dd, 1H, J = 4.15 Hz) 3.35 (seper, 1H, J = 7 Hz) 35 4.42 (m, 1H) 7.08-7 .41 (m, 9H) IR (in KBr): 2173cm -1 (<> C).

Example XXXVIII

Methyl ester of (E) -4- / ~ [2- / ~ 1-phenyl-5- (4-fluoro-phenyl) -3-40 isopropyl-1H-pyrazolyl-4-Jethenyl-Methoxyphosphinyl J-3-hydroxy-. 8801331-102 - X. > ί. + butyric acid A. Dimethyl ester of [2-f 1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4 7-2-hydroxyethyl-7-phosphonic acid

At -78 °, 15.2 ml of 1.6 M (24.3 mg mol) n-BuLi 5 in hexane was dripped over 15 minutes into a solution of 2.81 ml (25.9 mg mol) of dimethyl methane phosphonate in 50 ml of dry THF and the white suspension was stirred at -78 ° under argon for 1 hour.

Over 10 minutes, a solution of 5.0 g (16.2 mg mol) of pyra-

sole aldehyde according to example XXXVI part E in 15 ml dry THF

10 was added dropwise and the yellow mixture was stirred at -78 ° for 30 minutes. After quenching with 20 ml of saturated NH 2 Cl, it was allowed to warm to room temperature. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed with brine, dried over Na 2 SO 4 and evaporated to dryness to give 7.158 g of crude title β-hydroxyethyl phosphonate, a yellow foam. A small sample was recrystallized from hexane to give the pure title compound as white crystals, m.p. 126-128 °.

At TLC with hexane / acetone 1: 1: R = 0.27.

Mass spectrum: 433 (M + H, observed).

Elemental analysis: C 60.95, H 6.06, N 6.41, F 4.22, P 7.27%;

Calculated for Co 4 Ho, N 4 PF: 22 26 4 2 C 61.10, H 6.06, N 6.48, F 4.39, P 7.16%.

1 H NMR (in CDCl3): δ in ppm: 1.42 (6H, d) 25 1.94-2.40 (2H, m) 3.29 (1H, septet) 3.62 + 3.63 (2 doublets, J1 = 11.1 Hz) r1-r 3.91 (1H, s) 5.11 (1H, bm) 30 6.90-7.30 (9H, m) 13 C-NMR (in CDCl3): δ in ppm: 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).

B. Dimethyl ester of (E) - / “2- [1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4-ethylphenyl 7-phosphonic acid

To a solution of 7.158 g of crude hydroxyphosphonate of Part A in 40 ml of dry benzene, 304 mg (1.6 mg mol) of p-TsOH. 2 O was added and that mixture was boiled under argon for 2 hours 8801331-103 Dean and Stark water reflux in the presence of a molecular sieve of 4. After cooling, the mixture was diluted with EtOAc and the organic phase was washed twice with saturated NaHCO 2 and with brine, dried over 5 Na 2 SO 4 and evaporated in vacuo to 6.893 g gave yellow oil. This crude oil was stirred with hexane to give 5.692 g of nearly pure vinyl phosphonate as off-white crystals. Recrystallization of a mala from EtOAc / hexane in two aliquots gave 5.655 g (84.2% total, based on aldehyde) of 10 pure trans vinyl phosphonate by title as white needles with m.p. 143-144 °.

At TLC with hexane / acetone: R = 0.40. Mass spectrum: 415 + * (M + H, observed).

Elemental analysis: C 63.99, H 5.95, N 6.76, F 4.54, P 7.31%; Calculated for C20Ho / OPNoF: 22 24 3 2 C 73.76, H 5.84, N 6.76, F 4.58, P 7.47%. ^ -NMR (in CDCl3): δ in ppm: 1.42 (6H, d) 3.27 (1H, septet) 20 3.70 (6H, d, J = 11.0 Hz) il-r 5.67 (1H, dd, JHH = 18.4 Hz, JHp = 18.5 Hz) 7.02-7.30 (9H, m) 7.34 (1H, dd, JRH = 18 Hz, JHp = 24.3 Hz 13 C-NMR (in CDCl3): δ in ppm: 21.8, 27.1, 52.1 (Jc_p = 5.7 Hz), 110.4 (Jc_p = 193.1 Hz), 114.7 ( Jc_p = 24.6 Hz), 115.9, 116.2, 122.2, 124.9, 125.5, 127.3, 128.8, 132.0, 139.2, 140.2 (Jc_p = 7.6 Hz), 142.1, 158.0, 163.4 (Jc_p = 249.8 Hz).

C. Monomethyl ester of (E) - / T 2- [1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1 H -pyrazolyl-4-ethylenylphosphonic acid 30 To a solution of 2.0 g (4.83 mgmol) dimethyl phosphonate of part B in 15 ml dioxane, 7.3 ml 1.0 N LiOH was added and the mixture was refluxed for 1 hour under argon. The mixture was cooled to room temperature, acidified with 1N HCl to pH = 1 and extracted twice with EtOAc 35. The organic phase was washed with 1N HCl and with brine, dried over Na 2 SO 4 and evaporated in vacuo to give the crude monoacid which slowly crystallized out upon storage in hexane. The crystals were collected by filtration and dried in vacuo to give 1.918 g (99%) of the monoacid. 8801331, r-104- as white crystalline with mp. 168-170 °. An analytical sample was obtained by recrystallization from EtOAc / hexane.

TLC with CHoCl_ / CHo0H / H0Ac 8: 1: 1: R_ = 0.40.

Z Z 5 i? Mass spectrum: 401 (M + H (observed)).

Elemental analysis: C 62.95, H 5.57, N 6.87, F 4.58, P 7.58%; Calculated for iH22 ° 3N2PF: C 62.99, H 5.54, N 7.00, F 4.75, P 7.74%.

1H MR (in CDC13) 10 δ in ppm: 140 (6H, d) 3.26 (1H, septet) 3.65 (3H, d, JH_p = 11.6 Hz) 5.74 (1H, dd, JH_H = 17.9 Hz, JR_p = 19.5 Hz) 7.00-7.36 (10H, m) 15 8.65 (1H, bs) 13C-MR (in CDC13): δ in ppm: 21.8, 27 , 0.51.8 (Jc_p = 6.3 Hz), 111.7 (Jc_p = 198.7 Hz), 114.6 (Jc_p = 24.6 Hz), 115.8, 116.2, 124.9 , 125.4, 127.3, 128.7, 131.9, 132.1, 138.8 (Jc_p = 7.6 Hz), 139.2, 142.0, 157.9, 162.9 (J (= 249.8 Hz).

20 D. Methyl ester of (E) -4 - / * [2- 1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4-ethylenyl methoxyphosphinyl J-3-ketobutyric acid

Methyl acetoacetate in its dianion was reacted in the manner described in Example XXVI, starting from 815 µl (7.53 mg mol) methyl acetoacetate, 324 mg 60% (8.11 mg mol) NaH dispersion in oil, 4.3 ml 1 .6 M (6.95 mgmol) n-BuLi in hexane and 15 ml THF.

A solution of 2.317 g (5.79 mg mol) of phosphonic acid monomethyl ester and 1.45 ml (11.6 mg mol) of trimethylsilyldiethylamine in 15 ml was stirred at room temperature for 1 hour.

The mixture was evaporated to dryness, azeotroped with 20 ml of benzene and dried under vacuum. The residue was taken up in 15 ml dry and 555 µl (6.37 mgmol) (COCl 2) and 1 drop DMF were added thereto, followed by stirring at room temperature for 1 hour. The mixture was evaporated again, azeotroped with 20 ml benzene and dried under vacuum.

At -78 °, a solution of this phosphonic acid chloride in 10 ml of dry THF was dripped through a cannula over 20 minutes into a solution at -78 ° of the above mentioned 8801331-105 * * * Li-methyl-acetoacetate in 15 ml of dry THF. The brown mixture was stirred at -78 ° for 30 minutes and then quenched by dripping 10 ml of saturated NH 2 Cl, and allowed to warm to room temperature. The mixture was partitioned between water and EtOAc 5 and the aqueous phase was back-extracted with EtOAc, the combined organic phases were washed with saturated NaHCO 2 and with brine, dried at <RTI ID = 0.0> 0 ^ </RTI> and evaporated in vacuo to give 3.080 g of orange foam . The crude product was purified by chromatography with hexane / acetone / toluene 5: 3: 2 over Merck silica gel.

The product fractions were evaporated to dryness to give 1.247 g (43.2%) of the desired 8-ketophosphonate as pale yellow oil. At TLC with acetone / hexane / toluene: R = 0.29.

+ *

Mass spectrum: 499 (M + H (observed)).

15 1 H NMR (in CDCl3): δ in ppm: 1.42 & 1.43 (6H, 2 doublets) 3.24 (2H, m) 3.27 (1H, septet) 3.63 (2H, m) 20 3.66 & 3.67 (3H, 2 doublets, J1 = 11.6 Hz) rL-r 3.72 (3H, s) 5.72 (1H, dd, JRH = 18.7 Hz, JHp = 24.3 Hz) 7.08-7.30 (9H, m) 7.37 (1H, dd, JHH = 18.0 Hz, JHp = 22.7 Hz) 25 13 C NMR (in CBC13): δ in ppm: 21 , 8, 27.1, 46.1 (Jcp «84.1 Hz), 50.0, 51.2 (Jc_p = 5.9 Hz), 52.3, 112.6 (Jcp = 135.0 Hz), 114 .5 (Jcp = 23.5 Hz), 116.0, 116.3, 124.9, 125.4, 127.4, 128.8, 132.0, 132.1, 139.1, 141.4 (Jcp = 5.9 Hz), 142.5, 158.2, 163.1 (Jcp = 250.4 Hz), 167.1, 194.9, 195.0.

30 E. Methyl ester of (E) -4- / ~ C 2 -ph-1-phenyl-5- (4-fluorophenyl) -3- isopropyl-1H-pyrazolyl-4-Jethenyl, 7-methoxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 1.304 g (2.62 mgmol) ketone of part D in 15 ml absolute EtOH kept at -15 ° was added 100 35 mg (2.62 mgmol) NaBH4 and the mixture was heated at -15 for 15 minutes under argon Stirred. After quenching the reaction mixture with 0.3 ml of reagent grade acetone, 700 mg of CC-4 silica gel was added and allowed to warm to room temperature. It was diluted with EtOAc, filtered and the filtrate 8801331 evaporated 1 1 - 106 under vacuum to give 1.46 g of yellow foam.

The crude product was purified by chromatography with EtOAc / acetone 85:15 on Merck silica gel. The product fractions gave, on evaporation to dryness, 388 mg of pure alcohol according to the title as white foam, and also 228 mg of slightly impure product.

Total yield 616 mg (47%).

At TLC with EtOAc / acetone: 7: 3: R = 0.31.

Mass spectrum: 501 (M + H + (observed)).

1 H NMR (in CDCl 3): 10 S in ppm: 1.42 (6H, d) 2.00 (2H, m) 2.60 (2H, d) 3.27 (1H, d) 3.64 (3H , d, JHp = 11.1 Hz) 15 3.69 (3H, s) 3.93 & 4.02 (1H, 2 doublets) 4.42 (1H, 2 broad singlets) 5.72 (1H, dd, JRH = 18.0 Hz, J ^ p = 23.2 Hz) 7.04-7.47 (10H, m) 20 13 C-NMR (in CDCl 3: δ in ppm: 21.8, 27.1, 35 .7 & 36.5 (Jcp = 110.3 Hz), 42.0, 42.2, 50.8 (Jcp = 5.7 Hz), 51.6, 63.4 (J = 20.8 Hz) , 114.2 & 114.4 (JnO = 128.7 Hz), 114.6

Lr LJr (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 (Jnw = 251.6 Hz), 171.2, 171.9.

Lr

Example XXXIX

Dllithium salt of (8) -4 - / ^ C 2- / ~ 1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4. Methyl Jhydroxyphosphinyl J-3-hydroxybutyric acid 30 On a solution of 487 mg (0.973 mgmol) diester of Example XXXVIII in 10 ml dioxane, 3.4 ml 1.0 N LiOH was added and the mixture was stirred at 70 ° for 30 minutes. After cooling, the mixture was diluted with water, filtered and evaporated in vacuo to an off-white. The crude product was taken up in a minimum amount of water and chromatographed on a HP-20 column (15 cm length, 25 mm diameter), first with pure water and then with methanol / water 1: 1. The product fractions were concentrated to dryness under vacuum and the residue was taken up in 75 ml of water, filtered and. 88 0 1 33 1

X., J

- 107 - lyophilized to give 429 mg (87.3%) of pure title dilithium salt as a fluffy white lyophilization.

At TLC with CH2Cl2 / CH3OH / HOAc 8: 1: 1: ^ = 0.14.

Elemental Analysis: C 57.05, H 5.18, N 5.75, F 3.89, P 6.47%; Calculated for ^ 24 ^ 24 ^ 5¾ Li2 + ®2 ° = ^ 05.233): C 57.05, H 5.25, N 5.55, F 3.76, P 6.13%. 1H-MMR (400 MHz, in CD30D): δ in ppm: 1.39 (6H, doublet) 1.71 (2H, m) 10 2.35 (2H, m) 3.36 (1H, septet) 4, 24 (1H, m) 6.00 (1H, dd, JHH = 17.6 Hz, = 19.4 Hz) 7.07-7.35 (10H, m).

15 Example XL

Methyl ester of (E) -4- / ~ [2- / Γ 1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4 Methyl] methoxyphosphinyl, 7-3-hydroxybutyric acid A. Methyl ester of ( S) -3- (t-butyldiphenylsilyloxy) -4- / T C2-20 C 1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4 J-ethyl-7-methoxyphosphinyl-butyric acid

To a solution of 912.0 mg (1.24 mgmol) compound of Example XXXVI part H in 50 ml dry methanol, 10% Pd / C was added and this was hydrogenated in a Parr apparatus overnight with 3.5 atoms of hydrogen. The suspension was passed through

Celite was filtered and the filtrate was evaporated in vacuo and dried to give 908.3 mg (99.1%) of the title compound as a homogeneous oil.

At TLC with hexane / acetone 7: 3 over silica gel: = 0.23.

B. Methyl ester of (S) -4 - / * [2- [1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4-ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid

To a solution of 908.3 mg (1.23 mgmol) of Part A compound in 12 ml of dry tetrahydrofuran, 0.29 ml (4.94 mgmol) of glacial acetic acid and 3.89 ml of 1, were stirred successively under argon at room temperature. 0 M Bu ^ NF in hexane was added. The reaction mixture was stirred at room temperature for 20 hours and then diluted with 25 ml of ice water and extracted with 3 x 100 ml of ethyl acetate. The combined organic extracts, 8801331 r-108, were washed with 15 ml of saturated NaHCO 2 and 25 ml of brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product mixture (1.0 g) was chromatographed on a column of silica gel LPS-1 (24 cm length, 25 mm diameter), first with EtOAc / hexane 4: 1, then with EtOAc / hexane 9: 1 and finally with a mixture of EtOAc and acetone; this gave 529.1 mg (85.6% yield) of the title compound as oil.

At TLC with EtOAc / hexane 4: 1 over silica gel: R 0.17.

Example XLI

10 Dilithium salt of (S) -4- / ~ C 2- [1-phenyl-5- (4-fluorophenyl) -3-isopropyl-1H-pyrazolyl-4-ethylethylhydroxyphosphinyl] -S-hydroxybutyric acid

To a solution of 529.0 mg (1.05 mgmol) of the compound of Example XL in 12 I ml of dioxane 3.7 ml of 1.0 N 15 LiOH were added and this was kept under stirring under nitrogen in an oil bath at 55 ° for 3 hours and then at room temperature for 20 hours. The reaction mixture was evaporated to dryness under vacuum and dried.

The crude product was chromatographed on a column of HP-20 (15 cm length, 25 mm diameter), first with 750 ml of distilled water, then with methanol / water 1: 9, then with 500 ml methanol / water 2: 8 and finally with 500 ml of methanol / water 5: 5. The desired fractions were evaporated together under vacuum and dried. The resulting solid was taken up in 35 ml of distilled water and freeze-dried to give 510.0 mg (92.4%) of the title-25 compound as a white fluff.

At TLC with iPrOH / NH.OH / water 8: 1: 1 over silica gel: R = 0.38.

Η Γ

Elemental analysis: C 54.81, H 5.61, N 5.53, F 4.06, P 5.80%; Calculated for C24H26FL12N2 ° 5P'2.2 H2O (MG = 525.899): C 54.81, H 5.83, N 5.33, F 3.61, P 5.88%.

IR (in KBR): 1596 cm (C = O of carboxylate).

PH-NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.36 (d, 6H, J = 7) 1.60-1.72 (m, 4H) 2.32 (m, 2H ) 2.74 (m, 2H) 3.21 (septet, 1H, J = 7) 4.23 (m, 1H) 7.06-7.32 (m, 9H).

Example XLII

40 Methyl ester of (S) -4- / ~ [2- (1-phenyl-3- (4-fluorophenyl) -5-iso. 8801331-109 * * *, propyl-1H-pyrazolyl-4-ethynyl-7-methoxyphosphinyl-7-3 -hydroxy-butyric acid A. 4-fluorobenzoic acid-2-phenylhydrazide

To a mixture of 5 ml (0.25 mol) phenylhydrazine, 35 ml (0.25 mol) triethylamine and 500 ml dry ether cooled to -5 ° to -10 °, 30 ml (0.25) under nitrogen over 30 minutes mol) of 4-fluorobenzoyl chloride. The mixture was stirred for 3 hours while allowed to warm to room temperature and then filtered, the solid residue was washed well with 200 ml of ether. The solid was dissolved in 600 ml of dichloromethane and again almost evaporated to dryness; this residue was suspended in 600 ml hexane and filtered again.

The clear filtrate was evaporated to dryness and that residue was stirred with 700 ml of tetrahydrofuran and filtered, washing the solid well with 100 ml of tetrahydrofuan. The filtrate was evaporated to dryness and dried under vacuum to give 34.6 g of a crude product, containing two more by-products.

The crude product was recrystallized from acetone to give 22.36 g (38.8%) of the title compound as white crystals, m.p. 182-184 °.

Filtrate and mother liquor were evaporated to dryness and the residue was chromatographed on a 400 ml column of silica gel from Baker with EtOAc / C 2 C 1: 9; this gave 9.78 g of the title compound (55.8% in total).

At TLC with EtOAc / C 1 C 4 1: 4 over silica gel = 0.63.

Elemental analysis: C 67.86, H 4.88, N 12.14, F 8.10%;

Calcd for C 21 H 19 JF NO 3: C 67.81, H 4.82, N 12.17, F 8.25%.

Mass spectrum: 231 (M + H) *.

B. N- (g-chloro-4-fluorobenzylidene) phenylhydrazine

To a solution of 6.16 g (26.8 mgmol) of Part A compound in 46 ml of dry ether, 6.6 g (31.7 mgmol) of phosphorus pentachloride was added and that mixture was refluxed for 16 hours under nitrogen. After cooling to room temperature, a solution of 11.5 g (122.2 mg mol) phenol in 15 ml ether was added to the mixture, and after 5 minutes stirring also 11.4 ml methanol. The mixture was then concentrated in a rotary evaporator at 75 ° and the residual oil cooled to 5 °. The solid obtained was mixed with 20 ml of 5% 8801331-110. * - * aqueous acetone was stirred and filtered, and the precipitate was washed well with 30 ml of 5% aqueous acetone. The precipitate was dried under vacuum to give 2.2 g of solid with m.p.

5 gave 118-120 °.

The clear filtrate was evaporated to dryness and the residue was chromatographed twice through a 400 ml column of Baker silica gel, first with C 1 / C 2 / hexane 1: 3 then with C 1 / C 2 / hexane 1: 1 to give even more of the substance became; Total yield 5.66 g (85%).

TLC with C 4/4 / hexane 4: 1 over silica gel: Rp = 0.90. Elemental analysis: C 62.87, H 3.97, N 11.34, F 7.51, Cl 13.95%; Calcd for C 1 H 25 F C 1 Cl: C 62.78, H 4.05, N 11.27, F 7.64, Cl 14.26%.

Mass spectrum: 249 (M + H).

C. Ethyl ester of 1-phenyl-3- (4-fluorophenyl) -5-isopropyl-1H-pyrazole-4-carboxylic acid

To a solution of sodium ethylate (from 0.28 g (12 mg mol) sodium metal and 40 ml absolute ethanol) was added dropwise 2.0 ml (12 mg mol) ethyl isobutyrylacetate under nitrogen under nitrogen, and after stirring at room temperature for 15 minutes, 3 . 0 g (12 mgmol) of the compound of Part B are added. The mixture was stirred at room temperature for 4 hours, quenched with 10 ml of 10% HCl and evaporated to dryness, and the residue was stirred three times with 100 ml of ether. The combined organic extracts were washed with 25 ml of brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product was chromatographed on a column of silica gel with C 1 / C 2 / hexane 1: 1 to give 3.27 g (77.3%) of the title compound as red brown syrup.

At TLC with C 1 / C 4 / hexane 4: 1 over silica gel: R 4 0.42.

D. 1-phenyl-3- (4-fluorophenyl) -4- (hydroxymethyl) -5-isopropyl-1H-pyrazole

A solution of 3.26 g (9.25 mg mol) of compound 35 of part C in 22 ml of dry ether was added to a suspension of 0.71 g (18.7 mgmol) of lithium aluminum hydride in 32 ml of dry ether cooled to 0 ° and that mixture was stirred at 0 ° C under nitrogen for 3 hours. After the mixture was quenched at 0 ° by dripping with 5.0 ml of ethyl acetate and then 11 ml of 10% HCl, the mixture was evaporated to dryness and the residue was added with 2 x 100 ml of 8801331-III. % t * * ether pulled out. The combined organic extracts were washed with 20 ml of brine, dried over MgSO 4, filtered and evaporated to give 2.87 g (94.4%) of the title compound.

100 mg of this material were recrystallized from ether to give 57 mg of the analytical sample, m.p. 145-147 °.

At DLG with CH 2 Cl / hexane 4: 1 over silica gel (developed twice)

Rp = 0.17.

Elemental Analysis: C 73.26, H 6.11, N 8.96, F 6.09%;

Calcd for C 18 H 15 GF 2 O: 10 C 73.52, H 6.17, N 9.03, F 6.12%.

Mass spectrum: 311 (M + H) +.

E. 1-phenyl-3- (4-fluorophenyl) -4-formyl-5-isopropyl-1H-pyrazole A solution of 2.59 g (8.34 mgmol) of Part D compound in 22 ml of dry dichloromethane was added quickly 15 to a stirred suspension of 5.41 g (25.1 mg mol) of pyridinium chlorochromate in 32 ml of dry dichloromethane and stirred at room temperature under nitrogen for 4 hours. After diluting with 190 ml of ether and stirring for an additional 20 minutes, the liquid was decanted. The tar residue was extracted with 100 ml of ether and with 30 ml of dichloromethane and the combined organic extracts were filtered through a layer of silica gel.

The clear filtrate was evaporated to dryness and the crude product was chromatographed on a 300 ml column of Baker silica gel with CH 2 Cl 2 / hexane 4: 1 to give 2.40 g (93.4%) of the title compound as a solid.

100 mg of this material was recrystallized from hexane to give a 50 mg analytical sample with m.p. 103-105 °.

For DLG with over silica gel: Rp = 0.67.

Elemental analysis: C 74.18, H 5.35, N 9.11, F 6.12%;

Calcd for C 7 H 20 F: C 74.01, H 5.56, N 9.09, F 6.16%.

Mass spectrum: 309 (M + H) +.

F. 4— (2,2-dibromoethenyl) -1-phenyl-3- (4-fluorophenyl) -5-iso-35 propyl-1H-pyrazole

A mixture of 2.296 g (7.45 mgmol) of Part E compound and 5.86 g (22.1 mgmol) of triphenylphosphine in 35 ml of dry dichloromethane was cooled to between -5 ° and -10 ° under argon and over 5 minutes a solution of 3.70 g. 8801331 tr * τ - 112 - (11.0 mgmol) CBr ^, dripped in 12 ml dry, followed by stirring at -10 ° for 20 minutes * After warming to room temperature, the reaction mixture was 12 ml of saturated NaHCO 2 solution was poured out and extracted three times with 60 ml of C 1 C 1 C 5. The combined organic extracts were washed with 12 ml of saturated NaHCO 4 and 10 ml of brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product (11.0 g, solid) was chromatographed on a silica gel column, first with hexane 1: 1 and then with C 1 / C 4 / hexane 4: 1, correcting 2.96 g (96.0%) yield). title compound and 250.6 mg of unchanged starting material.

100 mg of the title compound was recrystallized from Et 2 O / hexane, yielding 36.5 mg of the analytical sample, m.p. 93.5 ° 15.

At TLC with / hexane 4: 1 over silica gel: R = 0.57.

Elemental Analysis: C 51.78, H 3.54, N 6.07, Br 34.40, F 3.92%;

Calcd for ^ 20 ^ 17 ^ 2 ^ 2: C 51.75, H 3.69, N 6.04, Br 34.43, F 4.09%.

Mass spectrum: 465 (M + H).

G. 4-ethynyl-1-phenyl-3 "(4-fluorophenyl) -5-isopropyl-1H-pyrazole To a solution of 2.87 g (6.18 mgmol) of component F in 11 cooled to -78 ° 44 ml of dry tetrahydrofuran was added dropwise under argon 11.7 ml of 1.6 M (18.6 mgmol) n-BuLi 25 in hexane, followed by stirring at -78 ° for an additional 2 hours and 20 minutes. The reaction mixture was quenched at -78 ° with 16 mL of 25% NH 4 Cl and extracted with 3 x 60 mL of ether after warming to room temperature. The combined organic extracts were washed with 22 ml of brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product (1.9 g) was chromatographed on silica gel with Et 2 O / hexane 5:95. The desired fractions were evaporated to dryness to give 1.88 g (100% yield) of the title compound as a solid.

100 mg of this material was recrystallized from hexane, yielding 63.5 mg of the analytical sample with m.p. 117-118 °.

At TLC with Et 2 O / hexane 1: 9 over silica gel: R = 0.37.

Z Γ

Elemental Analysis: C 79.12, H 5.60, F 6.02, N 9.12%;

Calculated for C 78.92, H 5.63, F 6.24, N 9.21%.

, 8801331 * i. * - 113 -

Mass spectrum: 305 (M + H) +.

H. Methyl ester of (S) -3- (t-butyldlphenylsllyloxy) -4- [[C 1-phenyl-3- (4-fluorophenyl) -5-isopropyl-1H-pyrazolyl-4-methylphenyl-7-methoxyphosphinyl-7-butyric acid 5 To a solution of 2 77 g (5.55 mgmol) methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4- (hydroxymethoxyphosphinyl) butyric acid (prepared according to Example I part F) in 10 ml dry dichloromethane became 2.1 ml trimethylsilyldiethylamine was added and it was stirred at room temperature for 1 hour under argon. The reaction mixture was evaporated to dryness and the residue azeotroped with 20 ml of benzene and dried under vacuum. The residue was redissolved in 10 ml of dry CH 2 Cl 2 and after cooling to -10 °, one drop of DMF was added and then 530 µl oxalyl chloride. After stirring at -10 ° for 15 minutes and then at room temperature for 1 hour, the reaction mixture was evaporated to dryness and the residue azeotroped with 20 ml of benzene and dried under vacuum.

To a solution of 1.12 g (3.67 mgmol) of part G in 9.0 ml of dry tetra-20 hydrofuran cooled to -98 °, 2.3 ml of 1.6 M (3.68 mgmol) were added under argon. n-BuLi in hexane was added and stirred at -78 ° for 45 minutes. This solution was added dropwise via a cannula to a solution of the above phosphonic acid chloride in 6.5 ml of dry tetrahydrofuran, both liquids being kept at -78 ° each time. After stirring at -78 ° for 30 minutes, the reaction mixture was quenched by dripping 6.0 ml of 25% NH 2 Cl, and allowed to warm to room temperature. The mixture was extracted three times with 100 ml ether and the combined organic extracts were washed with 10 ml 25% NH 2 Cl and 25 ml brine, dried over MgSO 2, filtered and evaporated.

The crude product mixture (4.0 g) was chromatographed on a column of silica gel, first with acetone / hexane 1: 9 and then with acetone / hexane 3: 7; this gave 1.76 g (65.2%) of the title compound as oil.

TLC with hexane / acetone 7: 3 over silica gel: R = 0.40.

F

I. Methyl ester of (S) -4-Γ [1-C 1-phenyl-3- (4-fluorophenyl) -5-isopropyl-1H-pyrazolyl-4-methylphenyl-7-methoxyphosphinyl J-3-hydroxybutyric acid

To a solution of 700 mg (0.95 mgmol), compound <8801331 τ. τ - 114 - part H in 9 ml dry tetrahydrofuran was added successively 224 µl (3.82 mgmol) glacial acetic acid and 3.0 ml 1.0 M (C ^ Hg) ^ NF in THF and that mixture was left overnight argon stirred at room temperature. After cooling to 0 °, 5 ml of 5% KHSO4 were added dropwise and extracted with 3 x 75 ml of ethyl acetate. The combined organic extracts were washed with 10 ml 5% KHSO 4 and 25 ml brine, dried over MgSO 4, filtered and evaporated.

Excess diazomethane in ether was added to a solution of the crude product (890 mg) cooled to 0 ° in a mixture of 16 ml ether and 12 ml tetra hydrofuran. The mixture was stirred at 0 ° for about 3 hours and then quenched by dripping glacial acetic acid and evaporated to dryness. The crude product mixture (764 mg) was chromatographed on a 15 column silica gel with EtOAc / hexane mixtures (1: 1, 4: 1, and 9: 1) to give 347 mg (73.2%) of the title compound as a semisolid. .

At TLC with EtOAc / hexane 4: 1 over silica gel: R 0.2 0.28.

Example XLIII

Dilithium salt of (S) -4-Z ~ [2-C 1-phenyl-3- (4-fluorophenyl) ~ 20 5-isopropyl-1H-pyrazolyl-4-ethynyl-7-hydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of 347 mg (0.7 mgmol) Compound of Example XLII in 8.3 ml dioxane, 2.4 ml 1.0 N LiOH was added and this was stirred under nitrogen in an oil bath at 55 for 45 minutes. ° held. The reaction mixture was evaporated to dryness under vacuum and dried. The semisolid obtained was chromatographed on a column of HP-20 (75 mm length, 25 mm diameter), first with 350 ml of distilled water and then with 250 ml of methanol / water 1: 1. The desired fractions were combined, evaporated to dryness and dried under vacuum. The product was dissolved in distilled water and freeze-dried to give 338 mg (97.5%) of the title compound as a white solid freeze-dried.

At TLC with iPrOH / NH4H / ^ 7: 2: 1 over silica gel: Rp = 0.50.

Elemental analysis: C 55.90, H 5.46, N 5.30, F 3.95, P 5.96%;

Calcd for 02 ^ 22 ^ 12 ^ 0 ^ 1.95 ^ 0: C 55.71, H 5.04, N 5.42, F 3.67, P 5.99%.

8801331 * ΐ * τ - 115 - * H NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.45 (d, 6H, J «7) 1.89-2.05 (m, 2H) 2.38 (dd, 1H, J = 9.15) 5 2.52 (dd, 1H, J = 4.15) 3.06 (septet, 1H, J = 7) 4.48 (m, 1H 7.16-8.11 (m, 9H).

Example XLIV

10 Methyl ester of (S) -4-CC 2-Z-1-phenyl-3- (4-fluorophenyl) -5-isopropyl-1H-pyrazolyl-4-Methyl] -methoxyphosphinyl-3-hydroxybutyric acid A. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4 - / * C 2 -C 1-phenyl-3- (4-fluorophenyl) -5-isopropyl-1H-pyrazolyl-4 J -ethyl ethyl methoxyphosphinyl-7-butyric acid

A solution of 1.0 g (1.36 mgmol) of the compound of Example XLII part I in 72 ml of dry methanol was hydrogenated with 250 mg of 10% Pd / C in a Parr apparatus overnight with ca 2.8 ato of hydrogen. The reaction mixture was filtered through Celite 20 and the clear filtrate evaporated to give 1.0 g (crude yield 100%) of the title compound as homogeneous oil.

TLC with hexane / acetone 7: 3 over silica gel: R 0.27.

B. Methyl Ester of (S) -4- [2-C 1-phenyl-1-3- (4-fluorophenyl) -5-isopropyl-1H-pyrazolyl-4-methylmethoxyphosphinyl] -3-hydroxybutyric acid

To a solution of 1.05 g (1.41 mgmol) of compound of Part A in 14.0 ml of dry tetrahydrofuran were sequentially 334 ynl (5.83 mgmol) glacial acetic acid and 4.46 ml 1.0 M (C ^ Hg) NF in THF was added and it was stirred at room temperature under argon for 19 hours. After diluting with 28 ml of ice water, the reaction mixture was extracted with 3 x 100 ml of ethyl acetate.

The combined organic extracts were washed with 15 ml of saturated NaHCOg and with 25 ml of brine, dried over MgSO4, filtered and evaporated to dryness. The crude product mixture (1.14 g) was chromatographed over a 150 ml Baker silica gel column with EtOAc / hexane mixtures, first 2: 1, then 4: 1, then 9: 1, giving 623.5 mg (88.0%) of the title compound as a semi-solid.

At TLC with EtOAc / hexane 4: 1 over silica gel: Rj = 0.18.

. 880133.1 - 116 - r * y *

Example XLV

Dilithium salt of (S) -bf 2- 2- l l-phenyl-3- (4-fluorophenyl) ~ 5-lsopropyl-1H-pyrazolyl-4-ethyl-hydroxyphosphinyl-3-hydroxy-butyric acid 5 To a solution of 623.5 mg (1.24 mgmol) compound of Example XLIV in 14.7 ml of dioxane was added under Nitrogen 4.28 ml of 1.0 N LiOH, while stirring under argon in an oil bath at 55 ° for 2 hours and about 20 hours kept at room temperature and then evaporated to dryness under vacuum. The residue was chromatographed on a column of HP-20 (15 cm length, 25 mm diameter), first with 750 ml of distilled water, then with 500 ml of 10% aqueous methanol, then with 500 ml of 20% aqueous methanol and finally with 500 ml 50% aqueous methanol. The desired fractions were combined and evaporated to dryness to give 560 mg (92.8%) of the desired product.

In TLC with iPrOH / NH ^ OH / ^ O 8: 1: 1 over silica gel: = 0.42.

Elemental analysis: C 56.83, H 5.80, N 5.76, F 3.46, P 6.19%; Calculated for ^^ E ^ gFI ^^ Oi-P. 1.16 ^ 0 (MG = 507.197): C 56.83, H 5.62, N 5.52, F 3.74, P 6.11%.

20 ^ H-NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.30 (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 XLVI

Methyl ester of (S) -4-r [C 3-phenyl-4- (4-fluorophenyl) -1-isopropyl-30 H -pyrazolyl-5 Jethynyl J methoxyphosphinyl J-3-hydroxybutyric acid A. a- (4-fluorophenyl) acetophenone

To a suspension of 928 mg (38 mgmol) of magnesium curls in 38 ml of dry ether was added 5.3 ml (42 mgmol) of 4-fluorobenzyl bromide under argon over 45 minutes at a rate such that the mixture continued to boil gently. When all was added, the mixture was refluxed for an additional 30 minutes and after cooling to room temperature, a solution of 2.96 ml (29 mg mol) benzonitrile in 5 ml dry ether was added. That mixture was stirred at room temperature for 4 hours and then poured slowly into 40 ml cold 10% HCl. That suspension was extracted with 5 x 50 ml ether and with 2 x 100 ml ethyl acetate. The combined organic extracts were washed with 50 ml of saturated NaHCO 2 and 50 ml of brine * 5 on MgSO 4, dried, filtered and evaporated to dryness.

The crude product (9.8 g) was chromatographed on a 400 ml baker's silica gel column, first with CH 1 Cl 2 / hexane 1: 4 and then with C 1 Cl 2 / hexane 1: 2. The desired fractions were evaporated to dryness, yielding 3.29 g of the title compound as white matter, m.p. 106-108 °. (From other fractions, an additional 2.60 g was obtained containing a trace of starting material; total yield 94.8%).

At TLC with hexane 1: 1 over silica gel: R = 0.60.

elemental analysis: C 78.22, H 5.22, F 9.21%; Calculated for C 8 H 10 FO: 14 11 C 78.49, H 5.18, F 8.87%.

Mass spectrum: 215 (M + H) +.

B. Isopropylhydrazone of α- (4-fluorophenyl) acetophenone

A mixture of 4.45 g (21 mgmol) compound of 20 part A, 0.74 ml glacial acetic acid and 3.63 ml (ca 42 mgmol) isopropylhydrazine in 34 ml 95% ethanol was stirred in nitrogen for 1.4 hours under a oil bath heated to 80 °. Thin layer chromatography showed that some starting material was still present, so 2.0 ml (ca 23 mgmol) isopropylhydrazine was added to the reaction mixture and heated in an oil bath at 80 ° for an additional hour.

After cooling to room temperature, the reaction mixture was stripped of most of the solvent in a rotary evaporator and the residue was diluted with 200 ml of dichloromethane. The organic solution was washed with 25 ml of brine, dried over MgSO 4, filtered and evaporated to dryness. A yellow oil was left over, which was taken up once in 150 ml of toluene and evaporated to dryness again; this gave 5.63 g of crude product which was contaminated with some starting material and with traces of two other materials.

At TLC with C 1 / C 3 / hexane 1: 1 over silica gel: R 2 0.28.

The isopropylhydrazine was prepared as follows:

Over 2 hours, 10.3 ml (0.10 mol) of iodopropane was added to 48.4 ml (1.0 mol) of hydrazine hydrate under nitrogen. The mixture was kept in an oil bath at 60 ° under nitrogen for 3 hours, cooled and extracted with 250 ml of ether in a perforator for 20 hours.

8801331 '* - 118 -

The ether extract was evaporated to give 5.63 ml (5.3 g) of isopropylhydrazine.

C. N1-acetyl-NZ "1-pheny1-2- (4-fluorophenyl) ethylideepy-N * -isopropylhydrazine 5 To a mixture of 5.63 g (ca 21 mgmol) of crude product of parts B and 5 cooled to 0 ° 85 ml (42 mgmol) of triethylamine in 210 ml of dry toluene were added under nitrogen 1.86 ml (26.3 mgmol) of acetyl chloride The mixture was stirred for 1 hour with gradual warming to room temperature and then 700 ml of ether were diluted and filtered The clear filtrate was dried over Na 2 SO 4, filtered and evaporated to dryness, and azeotroped another 300 ml of toluene.

The 7.1 g semisolid thus obtained was chromatographed on a 400 ml column of Baker silica gel, first with C 1 / C 2 / hexane 1: 1, then with C 1 / C 2 / hexane 2: 1, with and then with C ^ C ^ / CH ^ OH 9: 1. This gave 4.11 g of crude title product. This crude product was further chromatographed on another column of silica gel with EtOAc / hexane 4: 1. The desired fractions were evaporated to dryness to give 3.89 g of the title compound 20 as a thick yellow oil.

At TLC with EtOAc / hexane 1: 1 over silica gel: = 0.47.

D. 3-phenyl-1-isopropyl-4- (4-fluorophenyl) -5-methyl-1H-pyrazole

A mixture of 1.50 g (4.80 mgmol) of compound 25 of part C in 48 ml of bis (2-methoxyethyl) ether and 615 mg (10.96 mgmol) of solid KOH was added under nitrogen in an oil bath at 80 ° for 2 hours. heated. Now a second portion of 700 mg (12.5 mg mol) KOH was added and heating was continued at 80 ° C for 2 hours, followed by stirring at room temperature for 16 hours. The mixture was poured into 300 ml of water and extracted successively with 3 x 150 ml of ether and with 200 ml of ethyl acetate. The organic extracts were washed together with 500 ml of 3% HCl and with 2 x 100 ml of brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product (3.5 g) was chromatographed 1: 4 with EtOAc / hexane on a 500 ml column of Baker silica gel to give 1.33 g (94.3%) of the title compound as cream, m.p.

135-7 °.

TLC with EtOAc / hexane 1: 4 over silica gel: R = 0.63.

8. 8801331 - 119 - * * 'E. 3-phenyl-4- (4-fluorophenyl) -5-formyl-1-isopropyl-1H-pyrazole

To a mixture of 2.21 g 8.85 mg mol) CuSO 2 SO 4 and 9.53 g (35.3 mg mol) potassium persulfate in 65 ml acetonitrile and 39 ml water heated to 65 ° under nitrogen 5 2 6 g (8.83 mgmol) of Part D compound are added. The bath temperature was slowly raised to 75 ° and held at 75 ° for 40 minutes. Then it was cooled to room temperature with a water bath. The reaction mixture was diluted with 45 ml of dichloromethane, stirred for 10 minutes and decanted, and the aqueous suspension was extracted with an additional 3 x 45 ml of dichloromethane. The combined organic extracts were washed with 2 x 30 ml brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product (2.75 g) was chromatographed on a column of silica gel LPS-1 with EtOAc / hexane 1: 9 to give 1.57 g (57.7%) of the title-15 compound as a solid.

At TLC with EtOAc / hexane 1: 4 over silica gel: R = 0.72.

r F. 5- (2,2-dibromoethenyl) -3-phenyl-4- (4-fluorophenyl) -1-iso-propyl-1H-pyrazole

A mixture of 1.75 g (5.68 mg mol), 4.6 g (16.8 mg mol) of triphenylphosphine and 27.0 ml of dry dichloromethane was cooled to between -5 ° and -10 ° under argon, and over 5 minutes a solution of 2.82 g (8.42 mgmol) of CBr2 in 9 ml was added dropwise, followed by stirring at -10 ° for an additional 20 minutes.

After warming to room temperature, the reaction mixture was poured into 9.0 25 ml of saturated NaHCO 2 and extracted with 3 x 50 ml of CH 2 Cl 2. The combined organic extracts were washed with 10 ml saturated NaHCO 4 and 10 ml brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product was chromatographed on silica gel, first with CH 2 Cl 1 / hexane 1: 1 and then with CH 2 Cl 1 hexane 1: 4. The desired fractions were evaporated to dryness to give 2.35 g (91.4 Z) of the title compound as oil.

At TLC with C 1 / C 3 / hexane 1: 1 over silica gel: R 3 0.32.

G. 5-ethynyl-3-phenyl-4- (4-fluorophenyl) -1-isopropyl-1H-pyrazole 35 With a solution of 1.89 g (4.08 mgmol) of part F cooled to -78 ° in 7.6 ml of dry tetrahydrofuran was dripped under argon 5.2 ml of 1.6 M (8.18 mg mol) BuLi in hexane, followed by stirring at -78 ° for an additional 1 hour and 20 minutes. The mixture was quenched at -78 ° with 11 ml 25 Z NH 4 Cl 8801331 * 120 - and extracted with 3 x 50 ml dichloromethane after warming to room temperature. The combined organic extracts were washed with 15 ml of brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product (1.77 g) was chromatographed on a column of silica gel, first with Cl 2 / hexane 1: 4 and then with Cl 2 / hexane 1: 1 to give 648 mg of the title compound, together with mixed fractions containing the title compound together with the starting material of Part F. The mixed fractions were combined with the product of another preparation (490 mg from 1.1 mol of compound of Part F) and chromatographed on a second column, now with C 1 / C 4 / hexane 1: 9.

The desired fractions were combined and evaporated to dryness to give 1.02 g of the title compound as an oil. Yield 71.5% after correction for recovered starting material.

At TLC with CHOCl / hexane 1: 1 over silica gel: R = H. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4-CCC 3-phenyl-4-fluorophenyl-1-isopropyl-1H-pyrazolyl- 5-Ethynyl-Methoxyphosphinyl-Butyric Acid 20 A solution of 2.341 g (5.01 mg mol) of phosphonic acid monomethyl ester according to Example I part F and 1.90 ml (10 mgmol) of trimethylsilyldiethylamine in 9.5 ml was stirred at room temperature for 1 hour under argon and then evaporated to dryness. the residue was azeotroped with 15 ml of benzene and dried under vacuum. The viscous oil was taken up again in 9.5 ml dry with one drop of DMF and after cooling to between 0 ° and -10 °, 480 µl (5.47 mg mol) of oxalyl chloride was added dropwise. Violent gas evolution was observed and the dark yellow solution was stirred between -10 ° and 0 ° 30 for 15 minutes and then at room temperature for an additional 1 hour. Then the reaction mixture was evaporated to dryness and the residue azeotroped with 18 ml of benzene and dried under vacuum.

Under argon, a solution of 1.016 g (3.34 mgmol) of Part G compound in 8 ml dry tetrahydrofuran was cooled to 35 -78 ° and 2.1 ml 1.6 M (stirred at -78 ° over 1 hour) was stirred. 3.36 mgmol) n-BuLi in hexane when dropped.

The above-mentioned phosphonic acid chloride was dissolved in 8 ml of tetrahydrofuran and after cooling to -78 °, the solution of the aforementioned lithium-.8801331 * -f * - 121 -acetylene was added dropwise under argon via a cannula, the two liquids being - Were kept at 78 °. The reaction mixture was stirred at -78 ° for an additional 1 hour and then quenched with 9 ml 25% NH 2 Cl. After warming up to room temperature, the mixture was extracted with 3 x 100 ml ether and the combined organic extracts were washed with 10 ml 25% NH 2 Cl and 25 ml brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product was chromatographed on a column of silica gel, first with acetone / hexane 1: 9 and then with 10 acetone / hexane 1: 4 to give 1.595 g (64.8%) of the title compound as oil.

At TLC with acetone / hexane 3: 7 over silica gel: R = 0.43.

Γ I. Methyl ester of (S) -4-Z-C C 3-phenyl-4- (4-fluorophenyl) -1-isopropyl-1H-pyrazolyl-5-Jethynyl-methoxyphosphinyl] -15 3-hydroxybutyric acid

To a solution of 1.0 g (1.36 mgmol) of Compound H in 13 ml of dry THF was added successively 320 µl of 1 (5.46 mgmol) glacial acetic acid and 4.26 ml of 1 M (C ^ Hg) ^ NF and the mixture was stirred at room temperature under argon overnight. After cooling to 0 °, 15 ml of 5% KHSO4 was added and extracted with 3 x 125 ml of ethyl acetate.

The combined organic extracts were washed with 2 x 25 ml 5% KHSO 4 and 25 ml brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product (1.06 g) was dissolved in a mixture of 23 ml ether and 18 ml tetrahydrofuran, and after cooling to 0 °, excess diazomethane in ether was added, followed by stirring at 0 ° C for 4 hours. The reaction mixture was quenched by dripping glacial acetic acid, then evaporated to dryness and dried under vacuum. The crude product was chromatographed on a column of silica gel with acetone / hexane 1: 2. The desired fractions were evaporated to dryness to give 330 mg (48.7%) of the title compound as an oil.

At TLC with EtOAc / hexane 4: 1 over silica gel: R 2 0.23.

35 Example XLVII

Dilithium salt of (S) -4- / T C C 3-phenyl-4- (4-fluorophenyl) -1-isopropyl-1H-pyrazolyl-5-ethynyl-hydroxyphosphinyl 7-3-hydroxybutyric acid

Under argon was added to a solution of 330 mg of .8801331 1. T xr - 122 - (0.66 mgmol) compound of Example XLVI in 7.8 ml of dioxane 2.29 ml of 1 N LiOH, then left in an oil bath for 1 h. 55 ° and then stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness under vacuum and dried, and the crude product was chromatographed on a column of HP-20 (25 cm in length and 25 mm in section), first with 750 ml of distilled water, then with 500 ml of 10% aqueous CH 2. OH, with 500 ml of 20% aqueous CH 2 OH and finally with 500 ml of 50% aqueous CH 2 OH. The desired fractions were evaporated together under vacuum and dried.

The solid product was dissolved in distilled water and freeze-dried to give 275 mg (99.5%) of the title compound as a fluffy white lyophilization.

At TLC with iPrOH / NH ^ OH / ^ O 8: 1: 1 over silica gel: R ^ = 0.57. Elemental analysis: C 55.08, H 4.98, N 5.47, F 3.66, P 5.99%; Calculated for C24H22FL12N2O5P.2.28 H2O (MG = 523.31): C 55.08, H 5.11, N 5.35, F 3.63, P 5.92%.

IR (in KBr): 2172 cm -1 (C = C) 1 H NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.57 (d, 6H, J = 7 Hz) 20 1, 86-2.01 (m, 2H) 2.37 (dd, 1H, J = 8) 2.50 (dd, 1H, J «4) 4.40 (m, 1H) 5.01 (septet, 1H, J = 7) 7.04-7.39 (m, 9H).

Example XLVIII

Methyl ester of (S) -4-Z ~ ƒ * 2- £ * 3-phenyl-4- (4-fluorophenyl) -1-iso-propyl-1H-pyrazolyl-5 J ethyl J-methoxyphosphinyl J-3-hydroxy- butyric acid 30 A. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4- / 7 C 2- C 3-phenyl-4- (4-fluorophenyl) -1-isopropyl-1H-pyrazolyl-5 J-ethyl methoxyphosphinyl J / butyric acid

A solution of 608 mg (0.85 mg mol) compound of Example XLVI part H in 63 ml dry methanol was hydrogenated with ca 155 mg 10% Pd / C in a Parr apparatus at room temperature with ca 2.8 ato hydrogen. After shaking overnight, the suspension was diluted with 50 ml of methanol and filtered through a layer of Celite, after which this filter was rinsed well with methanol. The clear filtrate was evaporated to dryness under vacuum, 8801331-123 - * ¥ * and dried to give 559 mg (90.9%) of the title compound as 1 13 homogeneous oil, with H-NMR and C-NMR spectra that were good knocked.

At TLC with acetone / hexane 3: 7 over silica gel: R * 0.20 (UV).

B. 5 B. Methyl ester of (S) -4- / ~ C 2 -C 3-phenyl-4- (4-fluorophenyl) -1-isopropyl-1H-pyrazolyl-5-methyl / methoxyphosphinyl] -3-hydroxybutyric acid

To a solution of 559 mg (0.75 mgmol) of Part A compound in 7 ml of dry tetrahydrofuran under nitrogen, 176 µl (3.0 mg mol, 4 eq.) Of glacial acetic acid and 2.34 ml of 1.0 M ( C 1 Hg) N N in hexane and that mixture was stirred at room temperature for about 20 hours. After quenching with 20 ml of ice water, the reaction mixture was extracted with 3 x 70 ml of ethyl acetate and the combined organic extracts were washed with 10 ml of saturated NaHCO 2 and 20 ml of brine, dried over MgSO 2, filtered and evaporated to dryness. The crude product (580 mg) was chromatographed on a column of silica gel, first with EtOAc / hexane 1: 4 and then with EtOAc / hexane 4: 1. The desired fractions were evaporated together under vacuum and dried to give 337 mg (89.4%) of the title compound as a homogeneous oil.

At TLC with acetone / hexane 1: 1 over silica gel: R = 0.18 (UV). Example XLIX

Dilithium salt of (S) -4-C C 2- / Γ 3-phenyl-4- (4-fluorophenyl) -1-25 isopropyl-1H-pyrazolyl-5-ethyl, .hydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of 337.0 mg (0.67 mgmol) compound of Example XLVIII in 8.0 ml of dioxane was added 2.32 ml of 1.0 N LiOH under argon and this was in an oil bath at 55 ° C for 3 hours and then stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness under vacuum and kept on the vacuum pump for 1 hour. This crude product was chromatographed on a column of HP-20 (20 cm length and 25 mm diameter), first with 500 ml of distilled water, then with 500 ml of 10% aqueous methanol, then with 500 ml of 20% aqueous methanol and finally with 50% aqueous methanol. The desired fractions were evaporated together under vacuum and dried, the resulting solid was dissolved in distilled water, frozen and lyophilized overnight to give 280.4 mg (82.4%) of the title compound, a, 8801331 ir ί - 124 - fluffy white lyophilization of which the mass spectrum and the IR and * H NMR spectra were correct.

At TLC with iPr0H / NH40H / H20 8: 1: 1 over silica gel: Rp = 0.45 (UV). An additional 24 mg of slightly impure product was recovered from other fractions.

Elemental analysis: C 52.77, H 5.69, N 5.49, F 3.91, P 6.50%; Calculated for c24H26FL12N2 ° 5P · 1.19H 2 O (MG = 507.733): C 56.77, H 5.63, N 5.51, F 3.74, P 6.10%.

IR (in KBr): 1589 cm @ 1 (C = O of carboxylate).

10 '*' H NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.55 (d, 6H, J = 7, H ^) 1.64-1.84 (m, 4H, -, H, + Hd) 2.34 (m, 2H, -, H) α 2.91 (pseudo quartet, 2H, -, Ηβ) 15 4.25 (m, 1H, -, Hg) 4.77 ( septet, 1H, partially covered by the HOD signal, H ^) 7.05-7.32 (m, 9H, aromatic protons).

Example L

20-Methyl ester of (S) -4- [£] [2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-S-methylphenyl / methoxyphosphinyl, 7-3-hydroxybutyric acid A. N -benzoylvaline

To a solution of 20 g of 25 (0.17 mol) valine in a mixture of 20 ml of tetrahydrofuran and 111 ml of 2 N NaOH, cooled to 10 °, was added dropwise under nitrogen 23.8 ml (0.21 mol) of benzoyl chloride. After warming to room temperature, the reaction mixture was stirred for an additional 3 hours at room temperature, and after cooling to 0 ° C, 8.0 ml of concentrated sulfuric acid was added. It was then extracted with 3 x 200 ml ethyl acetate and the organic extracts were washed with 100 ml water and 50 ml brine, dried over MgSO 4, filtered and evaporated to give 41.97 g (crude yield 100%) of the title compound as solid gave dust.

A small amount of product (260 mg) was recrystallized from ethyl acetate and petroleum ether to give 205 mg of the analytical sample with m.p. 132-3 °.

At TLC with acetone / hexane 1: 1 over silica gel: R = 0.10.

8 t 880 1 331 - 125 -

Elemental Analysis: C 64.81, H 6.79, N 6.29%;

Calculated: C 65.14, H 6.83, N 6.33%.

Mass spectrum: 222 (M + H) +.

B. N- (1-acetyl-2-isopropyl) benzamide 5 To a mixture of 41.7 g (ca 0.17 mol) of Part A compound, 47.3 ml (0.34 mol) of triethylamine and 48 ml acetic anhydride was added 2.07 g (17 mgmol) 4-dimethylaminopyridine in two portions under nitrogen and stirred at room temperature for 16 hours. After cooling to 0 ° C, the mixture was quenched with methanol and stirred for an additional 30 minutes.

The light brown precipitate which formed was filtered off, washed thoroughly with 1.1 liters of water and taken up again in 750 ml of dichloromethane. This solution was dried over MgSO4, filtered and evaporated to give 35.9 g of crude product.

This crude product was dissolved in 1.3 liters of ether and filtered to remove an insoluble residue, and the clear filtrate was concentrated to about 300 ml and cooled in an ice bath. A cream-colored precipitate formed which was filtered off; yield 21.35 g with m.p. 88-90 °. The filtrate was evaporated to dryness and that residue was chromatographed on a 600 ml column of Baker silica gel, first with EtOAc / hexane 1: 7 and then with EtOAc / hexane 1: 4; this gave another 4.77 g of the title compound. A small amount of the title compound was recrystallized from ether, m.p. 88-89 °.

DLG with acetone / hexane 1: 1 over silica gel: R 2 - 0.75.

Γ

Elemental analysis: C 70.79, H 7.68, N 6.31%;

Calculated: C 70.20, H 7.81, N 6.39%.

Mass spectrum: 220 (M + H) +.

C. N-C1 -C 1- (4-fluorophenyl) iminoethyl-7-2-methylpropyl J-benzamide

In a reflux condenser flask with Dean & Stark water trap, a mixture of 25.0 g (0.114 mol) of Part B compound in 250 ml of dry toluene, 12 ml (0.127 mol) of 4-fluoroaniline and 125 mg of p-toluenesulfonic acid hydrate Refluxed under nitrogen for 20 hours. The reddish brown solution was cooled to -10 ° and used as such for the next step.

D. 2-phenyl-1- (4-fluorophenyl) -4-isopropyl-5-methyl-1H-imidazole

The cooled solution of the product of part C.

8801331 r - 126 - (ca 0.114 mol) was diluted at -10 ° with 200 ml of dry C 1 Cl 4 and in bits 47.5 g (0.228 mol) of PCI- was added.

t * o

The creamy slurry was warmed, refluxed under nitrogen for 2 hours, cooled to room temperature and slowly in a mixture of 400 g of ice and 105 ml of 50 Z NaOH

donated. The organic phase was drawn off and the water phase was extracted with 2 x 100 ml of C 1 -C 4. The combined organic extracts were washed with 2 x 100 ml brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product mixture (35.0 g) was chromatographed on a 600 ml column of Baker silica gel, first with EtOAc / hexane 1: 9 and then with EtOAc / hexane 1: 4 to give 29.24 g (87%) of the title compound in the form of white needles, m.p. 146-8 °.

At TLC with EtOAc / hexane 1: 4 over silica gel: Rp = 0.40.

Elemental analysis: C 77.48, H 6.69, N 9.40, F 6.45 Z;

Calculated: C 77.52, H 6.51, N 9.52, F 6.45%.

Mass spectrum: 295 (M + H).

E. 2-phenyl-1- (4-fluorophenyl) -5-formyl-4-isopropyl-1H-imidazole 20 A mixture of 8.50 g (34.0 mgmol) CuSO4. SH4 O and 36.8 g (0.136 mgmol) K2S2 ^ 8 in 150 ml of water and 250 ml of acetonitrile was heated to 65 ° in an oil bath under nitrogen and then 10 g (34.0 gmol) of Part D compound was added. The mixture was slowly heated to 75 °, held for 40 minutes and then cooled to room temperature. The solution was decanted from the solids and both the aqueous phase and the solids were extracted with 3 x 200ml. The combined organic extracts were washed with 2 x 100 ml brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product (17.0 g) was chromatographed on a 600 ml baker's silica gel column, first with EtOAc / hexane 5:95, then with EtOAc / hexane 1: 7; this gave 6.27 g (59.8 Z) of the title compound as a solid.

200 mg of this was recrystallized from Et2 O / hexane, yielding 76 mg of the analytical sample, m.p. 160-1 °.

TLC with EtOAc / hexane 1: 4 over silica gel: R = 0.34.

Γ

Elemental Analysis: C 73.98, H 5.68, N 9.04, F 6.09 Z;

Calculated: C 74.01, H 5.56, N 9.09, F 6.16 Z.

Mass spectrum: 309 (M + H) +, 8801331 - 127 -? F. 5- (2,2-dibromoethenyl) -2-phenyl-1- (4-fluorophenyl) -1H-imidazole

A solution of 1.75 g (5.68 mgmol) of the compound of part E and 4.46 g (16.8 mgmol) of triphenylphosphine in 27.0 ml of dry Cl 2 Cl 4 was stirred between -5 (F and Cooled to -10 ° and a solution of 2.82 g (8.42 mgmol) of CBr ^ in 9 ml was added dropwise over 5 minutes.

The mixture was stirred at -10 ° for 20 minutes and then poured into 9.0 ml of saturated NaHCO 2 solution; this was extracted with 3 x 10 50 ml CH 2 Cl 2. The combined organic extracts were washed with 10 ml of saturated NaHCO 2 solution and 10 ml of brine, dried over MgSO 2, filtered and evaporated to dryness.

The crude product (8.07 g) was chromatographed on a column of silica gel, first with C 1 / C 2 / hexane 1: 7 then with C 1 / C 2 / hexane 1: 4; this gave 2.35 g (91.4%) of the title compound as a solid.

Of this, 100 mg was recrystallized from Et2 O / hexane to give a 49 mg analytical sample with m.p. 164-5 °.

TLC with C 1 / C 3 / hexane 1: 1 over silica gel: R 3 0.32.

Elemental analysis: C 51.80, H 3.71, N 6.02, F 4.08, Br 34.25 Z;

Calculated: C 51.75, H 3.69, N 6.04, F 4.09, Br 34.43%.

+

Mass spectrum: 465 (M + H).

G. 5-ethynyl-2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazole To a solution of 3.065 g of 25 (6.60 mgmol) compound of part F in 12 cooled to -78 °, 5 ml of dry tetrahydrofuran was added under argon 8.4 ml of 1.6 M (13.4 mg mol) n-BuLi in hexane. The mixture was stirred at -78 ° for an additional 1 hour and 20 minutes and then quenched by dripping 18 ml of 25% NH 4 Cl, thereafter warmed to room temperature and extracted three times with 100 ml of ether. The combined organic extracts were washed with 25 ml of brine, dried over MgSO 4, filtered and evaporated to dryness. The crude product (2.08 g) was chromatographed on a 400 ml Baker silica gel column, first with EtOAc / hexane 1: 9 then with EtOAc / hexane 1: 4.

The desired fractions were combined and evaporated to dryness to give 1.97 g (97.8%) of the title compound as a solid.

Of this, 92 mg was recrystallized from hexane to give an analytical sample of 59 mg, mp. 148-150 °.

TLC with EtOAc / hexane 1: 4 over silica gel: R = 0.60.

8. 8801331

X £ X

- 128 -

Elemental analysis: C 78.95, H 5.83, N 9.07, F 6.63%;

Calculated: C 78.92, H 5.63, N 9.21, F 6.24%.

Mass spectrum: 303 (M-H).

H. Methyl ester of (S) -3- (t-butyldiphenylsllyloxy) -4-5 CCC 2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-5-Jethynyl-methoxyphosphinyl-butyric acid

A mixture of 3.54 g of 87.86 mg mol) of crude phosphonic acid monomethyl ester according to Example I part F and 2.70 ml (14.21 mg mol) of trimethylsilyldiethylamine in dryness was stirred under argon for 10 h and then evaporated to dryness. The residue was azeotroped with 26 ml of benzene and dried under vacuum.

The viscous oil was taken up again in 14 ml dry with 2 drops of DMF and cooled to -10 °, and 0.68 ml (7.79 mgmol) of oxalyl chloride was added dropwise. Violent gas evolution was observed and the golden brown solution was stirred at -10 ° for 15 minutes and then at room temperature for 1 hour. The reaction mixture was evaporated to dryness, azeotroped with 26 ml of benzene and dried under vacuum.

To a solution of 1.43 g of 20 (4.7 mg mol) of part G in 11.5 ml of dry tetrahydrofuran cooled to -78 ° solution, 2.94 ml of 1.6 M (4.7 mgmol) was added under argon. n-BuLi in hexane was added and it was stirred at -78 ° for 30 minutes. The above phosphonic acid chloride was dissolved in 11.5 ml of dry tetrahydrofuran and cooled to -78 ° under argon, and the newly prepared solution of lithium acetylene was added dropwise with a cannula, keeping both liquids at -78 ° were. The mixture was stirred at -78 ° for an additional 30 minutes and quenched by dripping 13 ml of 25% NH 2 Cl. After warming to room temperature, it was extracted with 3 x 130 ml ether. The combined organic extracts were washed with 15 ml 25% NH 2 Cl and 30 ml brine, dried over MgSO 2, filtered and evaporated to dryness.

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

At TLC with hexane / acetone 7: 3 over silica gel: R = 0.13.

8801331 * i * * - 129 - I. Methyl ester of (S) -4-Z * C C 2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-5-Jethynyl Jmethoxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 974 mg (1.32 mgmol) of compound H in 13.0 ml of dry tetrahydrofuran were successively 310 µl x (5.29 mgmol) glacial acetic acid and 4.14 ml 1 M (C 2 Hg) NF added and that mixture was stirred at room temperature overnight under argon. After cooling to 0 ° G, 14 ml of 5% KHSO4 was added and the 3 x 125 ml of ethyl acetate was extracted. The combined organic extracts were washed with 16 ml of 5 Z KHSO 4 and with 35 ml of brine, dried over MgSO 4, filtered and evaporated to dryness.

The crude product (1.48 g) was dissolved in a mixture of 22 ml ether and 17 ml tetrahydrofuran, and after cooling 15 to 0 ° C, excess diazomethane in ether was added and stirred at 0 ° C for 4 hours. The reaction mixture was quenched by dripping glacial acetic acid, evaporated in vacuo and dried.

The crude product was chromatographed on a 20 column silica gel, first with EtOAc / hexane 1, 1 then with EtOAc / hexane 4: 1. The desired fractions were combined and evaporated to dryness to give 304 mg (46.2%) of the title compound as a solid. TLC with EtOAc / hexane 4: 1 over silica gel: R = 0.33.

Γ

Example LI

Ditlithium salt of (S) -4- / ~ * [1 2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-5-ethynyl] -hydroxyphosphinyl 7-3-hydroxybutyric acid.

2.03 ml of 1 N LiOH was added to a solution of the 304 mg (0.6 mgmol) product of Example L in 7.1 ml of dioxane and stirred under an argon in an oil bath at 55 ° for 1 hour and then at room temperature for 24 hours. The reaction mixture was evaporated to dryness under vacuum and dried. The crude product was chromatographed on a column of HP-20 (18 cm in length and 25 mm in diameter), successively with 750 ml of distilled water, with 500 ml of 10% aqueous CH 2 OH, with 500 ml 20% aqueous CH 2 OH and with 500 ml of 50% aqueous CH 2 OH. The desired fractions were evaporated in vacuo and dried. The solid product was dissolved in distilled water and freeze-dried to give 257 mg (84.1%) of the title compound as a fluffy freeze solid. 8801331 IT-130-TLC with other fractions: with iPrOH / NH 4 OH / 8: 1: 1 over silica gel: Rj = 0.38.

Elemental analysis: C 56.56, H 4.94, N 5.32, F 3.89, P 5.99%; Calcd for 0: 5 C 56.56, H 4.95, N 5.49, F 3.73, P 6.08%.

^ H-NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.37 (d, 6H, J = 7 Hz) 1.79 (m, 2H) 2.31 (dd, 1H, J = 9.15 Hz) 10 2.43 (dd, 1H, J = 4.15 Hz) 3.24 (septet, 1H, J = 7 Hz) 4.26 (m, 1H) 7.17-7.35 (m, 9H) IR (in KBr) 2163 (<> C), (0 = 0) cm -1.

Example LII

Methyl ester of (S) -4- [[1- [2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-5 J ethyl-7-methoxyphosphinyl J-3-hydroxybutyric acid A. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4-Z 'C 2- ζ 2-20 phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-5 J-ethyl.Jmethoxyphosphinyl J7butyric acid

To a solution of 839 mg (1.14 mgmol) of the compound of Example L part H in 86 ml of dry methanol, 213 mg of 10% Pd / C was added and this was hydrogenated in a Parr apparatus overnight with ca 2.8 ato of hydrogen. . The suspension was filtered through Celite and the clear filtrate was evaporated in vacuo and dried to give 853 mg (100% yield) of the title compound as a thick syrup.

At TLC with hexane / acetone 7: 3 over silica gel: R = 0.17.

30 B. Methyl ester of (S) -4- [Γ 2- β-2-phenyl-1- (4-fluorophenyl) -4-lsopropyl-1H-imidazolyl-5-ethyl-methyl methoxyphosphinyl 7-3-hydroxybutyric acid

To a solution of 853 mg (about 1.14 mgmol) of Part A compound in 11.0 ml of dry tetrahydrofuran, 270 µl (4.60 mgmol) of glacial acetic acid and 3.62 ml of 1.0 M were successively added.

(C ^ Hg ^ NF in hexane was added and that mixture was stirred at room temperature overnight under argon. Then 25 ml of ice water was added and extracted with 3 x 100 ml of ethyl acetate. The combined organic extracts were extracted with 15 ml. α.

- 131 - τ saturated NaHCO 2 solution and 25 ml brine, dried over MgSO 2, filtered and evaporated.

The crude product (958 mg) was chromatographed on a silica gel column, first with acetone / hexane 1: 1 and then 5 with acetone / hexane 4: 1. The desired fractions were evaporated together under vacuum and dried to give 443 mg (77.0%) of the title compound as a solid.

In TLC with acetone / hexane 1: 1 over silica gel: R @ 0.13. Example LUI

10 Dilithium salt of (S) -4-f [2-f 2-phenyl-1- (4-fluorophenyl) -4-isopropyl-1H-imidazolyl-5 J ethyl Hydroxyphosphinyl J-3-hydroxy butyric acid

To a solution of 443 mg (0.88 mgmol) compound of Example Lil in 10.5 ml of dioxane, 3.05 ml of 1.0 N 15 LiOH was added and this was argon in an oil bath at 55 ° for 3 hours and then ca Stirred at room temperature for 20 hours. The reaction mixture was now evaporated to dryness under vacuum and dried. The crude product was chromatographed on a column of HP-20 (20 cm in length and 25 mm in diameter), first with 750 ml of distilled water, then with 500 ml of 10% aqueous methanol, with 500 ml of 20% aqueous methanol and finally with 50% aqueous methanol.

The desired fractions were combined and evaporated to dryness. The resulting solid was dissolved in 30 ml of distilled water and freeze-dried to give 376.4 mg (83.9%) of the title compound as a white fluff.

At TLC with iPr0H / NH40H / H20 8: 1: 1 over silica gel: Rp = 0.40. Elenment analysis: C 57.43, H 5.76, N 5.69, F 3.99, P 6.08%; Calculated for Co, H 4, No CFLiP 0.84 Ho0 (MG = 501.46): Z4 Su 4 µL C 57.43, H 5.76, N 5.69, F 3.99, P 6.08% .

30 IR (in KBr) (1587 cm -1, C = 0 of C00 ~) ^ NMR spectrum (400 MHz, in CD ^ OD): δ in ppm: 1.33 (d, 6H, J = 7 Hz ) 1.46-1.61 (m, 2H) 2.30 (m, 2H) 35 2.76 (m, 2H) 3.13 (septet, 1H, J = 7 Hz) 4.14 (m, 1H) 7.17 -7.30 (m, 9H).

r8801331 - 132 - τ τ i- *

Example LIV

Dilithium salt of (S) -4- (C 2 -Cyclohexylmethyl) -4,6-dimethyl-phenyl Jethynyl Jhydroxyphosphinyl, 7-3-hydroxybutyric acid A. N- (2,4-dimethylbenzylidene) aniline 5 See biz. 39 of U.S. Patent 4,375,475.

The title compound was prepared as described in Part A of Example I.

B. Palladium complex of formula 72

See biz. 39 of U.S. Patent 4,375,475.

This palladium complex was prepared as described in Part B of Example I.

C. 2- (cyclohexylmethyl) -4,6-dimethylbenzaldehyde

Under argon, 1.44 g (49.45 mgmol) of magnesium shavings were covered with 15 ml of ether and subjected to ultrasonication for 5 minutes. 1.5 ml of cyclohexylmethyl bromide was added and ultrasonication was continued (within a few minutes the mixture started to boil). At the same time, dropping funnels were added 60 ml of dry ether and 5 ml of ether solution of the remainder of the cyclohexylmethyl bromide (in total 9.12 ml (65.3 mgmol) of cyclohexylmethyl bromide). When everything was added, ultrasonication was continued for 15 minutes and the reaction mixture was refluxed for 40 minutes. This Grignard reagent was cooled to room temperature and then 5.55 g (7.43 mgmol) of Pd complex of 25 part B and 15.59 g (59.45 mgmol) of triphenylphosphine were added which had been under argon for 30 minutes at stirred at room temperature. On this addition, the reaction mixture turned green and a precipitate formed. This mixture was stirred at room temperature for 2 hours, after which 37 ml 6N HCl was added. After stirring for an additional 30 hours, the mixture was filtered through a pad of Celite in a glass funnel and the solid residue was washed with ether. The volatiles were removed from the filtrate in a rotary evaporator. The residual residue was stirred with ether and filtered again. That filtrate was washed once with saturated NaCl solution and dried over MgSO4 and evaporated to dryness; 14.5 g of brown oil were obtained. Purification by chromatography with 4% in hexane gave 1.70 g (99% yield) of clear oil.

At TLC with 5% Et 2 O in hexane over silica gel: R = 0.30.

Z r c 880 133 1 - 133 - * 1 a - IR (in CHCl 3) 3030, 3008, 2926, 2853, 1679, 1606, 1448 and 1147 cm -1.

1 H-NMR (270 MHz in CDCl 3> δ in ppm: 10.51 (s, 1) 5 6.90 (s, 1) 6.85 (s, 1) 2.80 (d, 2, J = 6, 0 Hz) 2.55 (s, 3) 2.30 (s, 3) 10 1.80-1.55 (m, 5) 1.55-1.30 (m, 1) 1.30-0, 80 (m, 5)

Mass spectrum m / e = 231 (M + H) +.

D. 1- (cyclohexylmethyl) -2- (2,2-dibromoethenyl) -3,5-dimethyl-15 benzene

To a solution of 1.68 g (7.30 mgmol) aldehyde of part C in 65 ml dry to 0 ° C, dry was added under argon 6.13 g (23.4 mgmol) triphenylphosphine and stirred until all dust dissolved used to be. Now 3.63 g (11.0 mgmol) CBr 2 in 20 ml was added at 20 ° C. The reaction mixture turned orange. The mixture was stirred at 0 ° C for 1 hour and then quenched with saturated NaHCO 3 solution under vigorous stirring. The water layer was drained and extracted twice with CH 2 Cl 2. The organic solutions were combined, washed once with saturated NaHCO 2 solution and dried over MgSO 2. Filtration and removal of the solvent gave 9.6 g of brown matter. Purification by chromatography with 100% hexane gave 2.52 g (90% yield) of clear oil.

At TLC with 5% Et £ 0 in hexane over silica gel: 30 Rp * 0.62 (PMA).

IR (in CHCl 3) 2925, 2852, 1608, 1472, and 869 cm -1 of 1 H NMR (270 MHz in CDCl 3) δ in ppm: 7.39 (s, 1) 6.87 (s, 1) 35 6, 80 (s, 1) 2.37 (d, 2, J = 6.3 Hz) 2.27 (s, 3) 2.24 (s, 3) 1.70 (m, 5) 8801331 r ί * - 134 - 1.45 (m, 1) 1.38 - 1.10 (m, 3) 0.90 (m, 2)

Mass spectrum: m / e = 387 (M + H) +.

5 E. 1- (cyclohexylmethyl) -2-ethynyl-3,5-dimethylbenzene

A solution of 2.51 g (6.5 mg mol) of vinyl dibromide of part D in 30 ml of THF was cooled to -78 ° under argon and with stirring, and 5.20 ml of 2.5 M n- was added over 3 minutes. butyl lithium in hexane. The pink reaction mixture was stirred at -78 ° for 1 hour and then quenched with saturated NH 2 Cl solution and allowed to warm to room temperature. The water layer was drained and extracted twice with ether and once with hexane. All the organic layers were dried together on MgSO4, filtered and evaporated to give 1.65 g of brown oil. Purification by chromatography with hexane gave 1.39 g (95% yield) of the title acetylene.

At TLC with 5% toluene in hexane over silica gel: R '= 0.50 (PMA).

IR (in CHCl 3) 3305, 3007, 2924, 2852, 2096, 1607, 1470 and 1448 cm-1.

20 ^ H-NMR (270 MHz in CDCl 3) 6 in ppm: 6.86 (s, 1) 6.79 (s, 1) 3.39 (s, 1) 2.63 (d, 2, J = 6 , 9 Hz) 25 2.63 (m, 6) 1.20 (m, 3) 1.00 (m, 2)

Mass spectrum m / e = 227 (M + H) +.

F. Methyl Ester of (S) -4- / ƒ * f2- (cyclohexylmethyl) -4,6-dimethyl-30-phenyl-ethynyl-methoxyphosphinyl 7-3- (t-butyldiphenylsilyloxy) -butyric acid

To a solution of 1.36 g (6.0 mg mol) of acetylene of part E in 3Q ml of dry THF cooled to -78 °, 2.4 ml of 2.5 M n-BuLi in hexane were added; the reaction solution 35 turned red as burgundy. After stirring at -78 ° for 1 hour, a solution of 4.68 g (9.6 mg mol) of phosphonic acid chloride, cooled to -78 °, of Example I part F in 30 ml of dry THF was added via a cannula over 15 minutes. When everything was transferred, the mixture was stirred at -78 ° for 1 hour more and then quenched with saturated NH 2 Cl solution. After warming to room temperature, the THE was removed from the reaction mixture and the remaining material was partitioned between diethyl ether and water. The water layer was extracted three times with carbon dioxide. All 5 Et 2 O extracts were washed together once with saturated NaHCO 2 solution and once with brine and dried over MgSO 2. Filtration and removal of the solvent gave an orange oil which was purified by chromatography with EtOAc / hexane / toluene 35:55:10. This gave 2.80 g (70% yield) of acetylene-10 phosphinate as a clear oil.

At TLC with hexane / toluene / EtOAc 5: 1: 4 over silica gel: R 0.3 0.37 (PMA).

IR (in CHCl 3) 3025, 3001, 2929, 2856, 2164, 1736, 1607, 1240, 1112, 1039 and 823 cm -1.

15 1 H-NMR (270 MHz in CDCl3) δ in ppm: 7.66 (m, 4) 7.30 (m, 6) 6.87 (s, 1) 6.81 (s, 1) 20 4.66 (m , 1) 3.70 & 3.66 (d's, 3, J = 14.3 Hz) 3.56 (s, 3) 2.95 (m, 1) 2.69 (m, 1) 25 2.50 (m, 3) 2.32 (m, 2) 2.30 (s, 3) 2.27 (s, 3) 1.60 (m, 6) 30 1.03 (m, 3) 1.02 (s, 9) 0.95 (m, 2)

Mass spectrum: m / e = 659 (M + H) +.

G. Methyl Ester of (S) -4-C [C 2- (cyclohexylmethyl) -4,6-di-35-methylphenyl-ethynyl] methoxyphosphinyl, 7-3-hydroxybutyric acid

To a solution of 0.633 g (0.96 mgmol) acetylene phosphinate of part F in 14.0 ml dry THF was added 0.22 ml (3.84 mgmol) glacial acetic acid under argon at room temperature, then 2 minutes over 2 min. 62 ml 1.1 M n-Bu ^ NF in THF.

8801331, ΐ *? - 136 -

After stirring at room temperature for 19 hours, the reaction mixture was quenched with ice water and the water layer was extracted three times with EtOAc. The combined organic solutions were washed twice with aqueous NaHCO 2 solution and once with saturated NaCl solution, dried over Na 2 SO 2 and filtered to give 0.658 g of yellow gum after removal of the solvents. Purification by chromatography with EtOAc gave 0.23 g (65%) of the title alcohol as a clear oil.

TLC with acetone / hexane 6: 4 over silica gel: R ^ = 0.51 (PMA).

IR (in CHCl 3) 3450 (br), 3005, 2926, 2852, 2164, 1733, 1607, 3 -1 1448, 1439 and 1039 cm.

^ H-NMR (270 MHz in CDCl3) <5 in ppm: 6.89 (s, 1) 6.82 (s, 1) 15 4.63 (m, 1) 3.88 & 3.87 (2 d's , 3, J = 12 Hz) 3.69 (s, 3) 2.70 (s, 2) 2.62 (d, 2, J = 6.3 Hz) 20 2.43 (s, 3) 2.32 (s, 3) 2.27 (m, 2) 1.65 (m, 6) 1.19 (m, 3) 25 1.00 (m, 2)

Mass spectrum: m / e = 421 (M + H), H. Dillthium salt of (S) -4-Z ~ 1 [2- (cyclohexylmethyl) 4,6-dimethylphenyl] methylynhydroxyphosphinyl J7-3-hydroxybutyric acid

To a solution of 0.212 g (0.51 mgmol) of di-ester of part G in 7 ml of dioxane was added 1.5 ml of 1 N LiOH at room temperature. The mixture was heated to 55 ° C for 20 minutes and the resulting precipitate was dissolved by adding 5 ml of dioxane and 4 ml of water. After 2 hours and 30 minutes at 55 °, the mixture was cooled to room temperature, the solvent was removed under reduced pressure and the leftover white matter was kept under vacuum for 15 minutes.

The product was purified by chromatography on a column of HP-20 (19 cm length and 30 mm diameter), first with 100 ml of water and then with MeOH / water 1: 1. Freeze-drying of the pro-40 pressure fractions gave 0.145 g (71%) of white freeze-dried.

8801331 * * * - 137 -

Rp with nPrOH / NH4 OH / H4 O 7: 2: 1 over silica gel: Rp * 0.39 (PMA).

IR (in KBr) 3700-3100 (br), 2922, 2850, 2167, 1590, 1447, 1179 and 1076 cm -1.

^ H-NMR (400 MHz in D20) 5 δ in ppm: 6.99 (s, 1) 6.94 (s, 1) 4.53 (m, 1) 2.64 (m, 1) 6.22 (d, 2, J = 6.2 Hz) 10 2.39 (s, 3) 2.37 (m, 1) 2.26 (s, 3) 2.02 (m, 2) 1.60 (m , 6) 15 1 »14 (m, 3) 1.00 (m, 2)

Mass spectrum: m / e = 409 M + H) + and 397 (M-2Li + H) +.

Elemental analysis: C 57.96, H 7.18, P 6.96%;

Calcd for C 11 H 14 OpPL 10 1.72 H O: 21 11 o z z 20 C 57.96, H 7.05, P 7.12%.

Example LV

Dilithium salt of k- [β- [2- (cyclohexylmethyl) -4,6-dimethyl-phenyl-Jethenyl-7-hydroxyphosphinyl] -3-hydroxybutyric acid A. Dimethyl ester of (E) -jf 2-C 2- (cyclohexylmethyl) -4,6 -di-25 methylphenyl Jethenyl Phosphonic Acid

To a solution of 1.64 g (13.2 mgmol) of dimethylmethane phosphonate in 20 ml of dry THF cooled to -78 °, 5.0 ml of 2.5 M n-butyl lithium in hexane was added over 5 minutes. When all was added, the milky white reaction-30 mixture was stirred at -78 ° for 1 hour and then, still at -78 °, a solution of 1.9 g (8.26 mgmol) of aldehyde was added through a dropping funnel over 10 minutes. according to example LIV part A in 10 ml THF. After stirring at -78 ° for 35 minutes, the reaction mixture was quenched with 8 ml of saturated NH 2 Cl solution and allowed to warm to room temperature. The organic layer was drained and the water layer was extracted three times with EtOAc.

The organic extracts were washed together once with brine and dried over Na 2 SO 4. Filtration and removal of the solvent gave 3.25 g of yellow oil.

8801331, * t t ”- 138 -

This 3.25 g of yellow oil was dissolved in dry toluene and refluxed in a Soxhlet apparatus containing 4 µ molecular sieve. at t = 0 and after 3J and 18 hours, 80 mg (0.42 mgmol) of p-toluenesulfonic acid hydrate was added each time. After boiling for 22 hours, the reaction mixture was cooled to room temperature and the toluene was removed in vacuo. The leftover yellow residue was washed twice with saturated NaHCO 2 solution in EtOAc, dried over 80 ml and filtered to give a yellow oil (A) after removing the solvent.

The aqueous solution was acidified with concentrated HCl and extracted three times with EtOAc; those extracts were dried over MgSO 4, filtered and evaporated to give 0.535 g of yellow oil. This yellow oil was then refluxed with 6.0 ml of HC (OCH) 2 for 24 hours, after which the excess orthoformate was removed under vacuum. This material was combined with the yellow oil A and purified by chromatography with EtOAc / hexane 80:20. This gave 2.07 g (73%) of the title vinyl vinyl phosphonate as a white matter.

At TLC with acetone / hexane 1: 1 over silica gel: R = 0.45 (PMA).

IR (in KBr) 2921, 2851, 1623, 1447, 1243, 1186, 1060 and 1027 cm -1.

1 H-NMR (270 MHz in CDCl3) δ in ppm: 7.65 (dd, 1.1 J = 23.6 Hz, 18.1 Hz) 25 6.88 (s, 1) 6.82 (s, 1) 5.80 (dd, 1, J = 21.0 Hz, 18.1 Hz) 3.79 (d, 6, J = 11.5 Hz) 2.49 (d, 2, J = 7.2 Hz) 30 2.29 (s, 3) 2.28 (s, 3) 1.65 (m, 5) 1.45 (m, 1) 1.25-0.80 (m, 5) 35 Mass spectrum: m / e = 337 (M + H) +.

B. Methyl ester of (Ε) -Γ 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl. Ethylenyl phosphonic acid

To the 2.07 g (6.16 mg mol) of vinyl phosphonate of Part A in 14 ml of dioxane was added 9.24 ml of 1.0 8801331-139-1 N * LiOH at room temperature, and that mixture was heated to 75 °. After 3 hours at 75 °, the mixture was cooled to room temperature and the dioxane was removed in vacuo. The residual residue was stirred with water and extracted three times with EtOAc after acidification with 1 N HCl to 5 pH-2. The extracts were dried together over Na 2 SO 4, filtered and evaporated to give 1.95 g of off-white matter.

At TLC with CH2Cl2 / CH3OH / AcOH 8: 1: 1 over silica gel: Rp = 0.58 (PMA).

10 1 H-NMR (270 MHz in CDCl3) δ in ppm: 12.11 (s, 1) 7.61 (dd, 1, J = 24.17 Hz, 17.58 Hz) 6.87 (s, 1) 6.81 (s, 1) 15 5.88 (dd, 1, J = 21.43 Hz, 17.58 Hz) 3.78 (d, 3, J = 11.54 Hz) 2.47 (d, 2, J = 6.6 Hz) 2.29 (s, 3) 2.28 (s, 3) 20 1.65 (m, 5) 1.45 (m, 1) 1.15 (m, 3) 0.95 (m, 2).

C. Methyl ester of (E) -4-f C2-C 2- (cyclohexylmethyl) -4,6-dimethylphenyl / ethenyl] methoxyphosphinyl 7-3-ketobutyric acid

A mixture of 1.95 g (6.06 mg mol) of monomethyl phosphonate from Part B, 50 ml of dry CH 2 Cl 2 and 1.76 g (12.1 mg mol) of trimethylsilyldiethylamine was stirred under argon for 1 hour. The CH2 Cl2 was removed under vacuum and the leftover yellow oil was azeotroped once with benzene and held under high vacuum for 20 minutes. This oil was then dissolved in 50 ml of dry CH2 Cl2 and cooled to 0 ° C under argon.

Two drops of dry DMF were added, then 0.92 g (7.27 mgmol) of oxalyl chloride dropwise: gas evolution was observed. The mixture was stirred at 0 ° C for an additional 15 minutes and for 1 hour after warming to room temperature.

The CH2 Cl2 was then removed from the reaction mixture under vacuum and the residual orange oil was azeotroped twice with benzene and held under high vacuum for 1 hour to give the 8801331 1 * -140 phosphonic acid chloride.

The dianion of methyl acetoacetate was prepared as follows. Under argon, 0.25 g (8.7 mg mol) of NaH in oil was washed with pentane and then suspended in 10 ml of dry THF.

After cooling to 0 ° C, 0.92 g (7.9 mg mol) of methyl acetoacetate in 10 ml of THF was added and after stirring for 20 minutes, 2.90 ml of 2.5 M (7.3 mg mol) n-butyl lithium in hexane was added and stirred for another 45 minutes. The dianion solution was cooled to -78 ° and a solution of the above phosphonic acid chloride in 10 ml THF was added over 15 minutes. After stirring at -78 ° for 30 minutes, the reaction mixture was quenched with saturated NH 2 Cl solution, and after warming to room temperature, the THF was removed. The leftover orange oil was taken up in EtOAc / water 1: 1. The water layer 15 was extracted three times with EtOAc. The combined EtOAc extracts were washed twice with saturated NaHCO 2 solution and once with saturated NaCl solution and dried over Na 2 SO 4. Purification of the crude product (2.75 g) by chromatography with EtOAc gave 0.97 g (42%) of the title 20 ketoester as yellow oil.

In TLC with EtOAc over silica gel: R @ 0.24 (PMA).

& in ppm: 7.71 (dd, 1, J = 22.52 Hz, 18.13 Hz) 6.89 (s, 1) 6.83 (s, 1) 25 5.89 (dd, 1, J = 26.37 Hz, 17.58 Hz) 3.79 (s, 2) 3.73 (s (br), 6) 3.36 (dd, 2. J - 18.68 Hz, 5.5 Hz) 2.50 (m, 2) 30 2.30 (s, 3) 2.29 (s, 3) 1.70 (m, 5) 1.45 (m, 1) 1.10-0.80 (m , 5).

35 D. Methyl ester of 4 ° C C 2- 2 - 2- (cyclohexylmethyl) -4,6-dimethylphenyl Jethenyl J ^ methoxyphosphinyl 7-3-hydroxybutyric acid

A solution of 0.97 g (2.31 mgmol) β-keto-phosphonate of part C in 10 ml THF was cooled to 0 ° C under argon and with stirring. Now 87 mg (2.31 mg mol) of solid NaBH ^ .88D1331-141 * 5 * was added to the solution, followed dropwise by 2 ml of methanol; there was gas development. After stirring at 0 ° C for 50 minutes, the reaction mixture was quenched with 2 ml of acetone, followed by adding silica gel GC-4. After warming to room temperature, the mixture was filtered through a sintered glass filter. The solvent was removed from the filtrate to give an orange oil which was purified by chromatography with EtOAc. There was thus obtained 0.65 g (66 Z) of the title alcohol as a clear oil.

At TLC with acetone / hexane 1: 1 over silica gel: R ^ 0.29 (PMA).

Mp. 80-83 ° C.

IR (in KBr) 3282 (br), 2923, 2918, 2848, 1743, 1614, 1450, 1442, 1080 and 1045 cm XH-NMR (270 MHz in CDCl3) 15 δ in ppm: 7.68 (m, 1) 6.88 (s, 1) 6.82 (s, 1) 5.89 (m, 1) 4.50 (m, 1) 20 4.00 (m, 1) 3.77 & 3.74 (2 d'n, 3, J = 11.0 Hz) 3.69 & 3.68 (2 s'n, 3) 2.65 (d, 2, J = 6.0 Hz) 2.50 (m, 2) 25 2.30 (s ( br), 3) 2.28 (s, 3) 2.15 (m, 2) 1.68 (m, 5) 1.45 (m, 1) 30 1.30 to 0.80 (m, 5)

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

E. Dilithium salt of h- [f 2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] hydroxyphosphinyl J-3-hydroxybutyric acid 0.565 g (1.33 mgmol) diester of part D was added with 35 Stirred 14 ml of dioxane until everything had dissolved. 4.0 ml of 1.0 N LiOH was now added and the solution was heated to 55 °. After 30 minutes, the mixture turned cloudy. After 2 hours at 55 °, the reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator to give an 8801331. r * - 142 - gave white matter. The crude product was purified on a column of HP-20 (15 cm length, 30 mm diameter) first with 100 ml of water and then with methanol / water 3: 1. Freeze drying of the product fractions gave 0.524 g (98%) of the title compound as a white lyophilization. At TLC with nPrOH / NH4 OH / ^ O 7: 2: 1 over silica gel: R4 = 0.41 (PMA).

IR (in KBr) 3700-3100 (br), 2921, 2851, 1591, 1446, 1222, 1195, 1161, and 1051 cm -1.

^ -NMR (400 MHz in D20): 10 δ in ppm: 7.25 (dd, 1, J = 18.68 Hz) 6.98 (s, 1) 6.94 (s, 1) 6.00 ( dd, 1, J = 17.95 Hz) 4.33 (m, 1) 15 2.53 (dd, 1, J = 15.0 Hz, 4.4 Hz) 2.49 (d, 2, J - 7.0 Hz) 2.36 (dd, 1, J = 15.0 Hz, 8.43 Hz) 2.27 (s, 3) 2.25 (s, 3) 20 1.89 (dd, 2, J = 14.3 Hz, 6.6 Hz) 1.60 (m, 5) 1.45 (m, 1) 1.13 (m, 3) 0.95 (m, 2) 25 Mass spectrum: m / e = 407 (M + H) + and 347 (M + -2Li ++ 2H).

Elemental analysis: C 61.03, H 7.63, P 7.66%;

Calcd for 0: C 61.03, H 7.45, P 7.49%.

Example LVI

30 Dilithlum salt of (S) -hC [2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] methylhydroxyphosphinyl 7-3-hydroxybutyric acid A. Methyl ester of 4-Z * £ 2 - (cyclohexylmethyl) - 4,6-dimethyl-phenyl-methyl-1'-methoxyphosphinyl ^ 7-3- (t-butyldiphenylsilyl-oxy) butyric acid 35 A solution of 1.33 g (2.02 mgmol) of acetylene phosphinate according to example LIV part F in 45 ml of methanol bubbled with argon for 10 minutes and then 0.34 g of 10% Pd / C was added in a Parr bottle. After hydrogenation with 2.8 atoms of hydrogen, filtration and evaporation to dryness, 1.39 g of 8801331 were obtained

* ï r 'T

- 143 - oil. Purification by chromatography with EtOAc / hexane 1: 1 gave 1.25 g (94%) of the title phosphinate as clear oil.

At TLC with hexane / EtOAc / toluene 5: 4: 1 over silica gel: R 2 0.21 (PMA).

IR (in CHCl 3) 3600-3200 (br), 3003, 2925, 2853, 1731, 1448, 1440, 1247, 1233, 1179, and 1044 cm-1.

1 H-NMR (270 MHz in CDCl3) ύ in ppm: 6.83 (s, 1) 6.78 (s, 1) 10 4.50 (m, 1) 3.80 & 3.77 (2 d , 3, J = 6.3 Hz) 3.72 & 3.71 (2 s'n, 3) 3.38 (m, 1) 2.87 (m, 1) 15 2.60 (m, 2) 2.45 (d, 2, J = 6.9 Hz) 2.29 & 2.28 (2 s'n, 3) 2.45 (s, 3) 2.00 (m, 4) 20 1.70 (m, 6 ) 1.45 (m, 1) 1.30-0.90 (m, 6)

Mass spectrum: me. - 424 (M) +.

B. Methyl Ester of (S) -4- t 2- [2- (cyclohexylmethyl) -4,6-dimethyl-methylphenyl] -ethyl methoxyphosphinyl J-3-hydroxybutyric acid

A solution of 1.2 g (1.8 mg mol) of part A silyl ether in 20 ml of THF was stirred at room temperature under argon, followed by successively 0.41 ml of glacial acetic acid and 5.0 ml of 1.1 M n-Bu NF in THF added (over 5 minutes). After stirring at room temperature for 30 hours, the reaction mixture was quenched with 50 ml of ice water and stirred vigorously. The THF was removed in vacuo and the remaining material diluted with water and extracted three times with EtOAc. The EtOAc extracts were washed twice with saturated NaHCOg solution and once with brine, then dried over Na 3 SO 4. Filtration and removal of the solvent gave 1.3 g of a clear oil. This product was purified by chromatography with 100% EtOAc to give 0.55 g (72%) of the title alcohol as a clear oil.

In TLC with EtOAc over silica gel: R 0.2 0.22 (PMA).

.8801331 - 144 -

i r * Y

IR (in CHCl 3) 2999, 2950, 2929, 2856, 1734, 1244, 1195, 1183, 1112, 1105, 1065 and 1043 cm -1.

1 H-NMR (270 MHz in CDCl3) δ in ppm: 7.65 (m, 4) 5 7.28 (m, 6) 6.81 (s, 1) 6.76 (s, 1) 4.51 ( m, 1) 3.62 & 3.60 (2 d'n, 3, J = 5.3 Hz) 10 3.49 & 3.46 (2 s'n, 3) 2.97 (m, 1) 2.65 (m, 2) 2.35 & 2.33 (2 d'n, 2, J = 6.9 Hz) 2.25 (2, s'n, 3) 15 2.16 (2 s' n, 3) 1.84 (m, 1) 1.68 (ut, 6) 1.55 (m, 1) 1.18 (m, 2) 20 1.15 (m, 3) 1.00 & 0 .99 (2 s'n, 9) 0.91 (m, 2)

Mass spectrum: m / e = 663 (M + H) +.

C. Dilithium salt of (S) -4- / ~ [2-C 2- (cyclohexylmethyl) 4.6-25 dimethylphenyl Jethyl, 7hydroxyphosphinyl J-3-hydroxybutyric acid

The 0.552 g (1.3 mgmol) diester of Part B was stirred with 14 ml of dioxane at room temperature. 3.9 ml of 1.0 N LiOH was added to this solution and that mixture was heated to 55 °. After stirring for 30 minutes, a precipitate cake had formed, which was dissolved by adding 5 ml of water. After 2 hours and 15 minutes at 55 °, the reaction mixture was cooled to room temperature and the volatiles were removed in vacuo to leave a white substance. The product was purified by chromatography on a column of HP-20 (length 30 cm, diameter 30 mm), first with 100 ml of water and then with methanol / water 1: 1. The product fractions were lyophilized to give 0.482 g (92% yield) off-white freeze-dried.

At TLC with nPrOH / NH4 OH / ^ O 7: 2: 1 over silica gel: R ^ 0.36 (PMA).

.8801331 - 145 - * '* * IR (in KBr) 3700-3100 (br), 2923, 2852, 1588, 1446, 1410, 1159, 1132 and 1048 cm * 1.

1H-i3MR (400 MHz in D20) δ in ppm: 6.93 (s, 1) 5 6.91 (s, 1) 4.34 (m, 1) 2.80 (m, 2) 2.50 ( dd, 1, J = 14.7 Hz, 4.4 Hz) 2.48 (d, 2, J = 5.12 Hz) 10 2.38 (dd, 1, J = 15.0 Hz, 6.6 Hz) 2.29 (s, 3) 2.26 (s, 3) 1.84 (m, 2) 1.65 (m, 7) 15 1.48 (m, 1) 1.15 (m, 3 ) 1.00 (m, 2)

Mass spectrum: m / e = 397 (M + H-2L +) + and 409 (M + H) +.

Elemental analysis: C 59.76, H 7.91, F 7.53%; Calculated for C 14 H 10 P 10 P 10 O H 2 O: C 59.76, H 7.77, P 7.34%.

Example LVII

Dilithium salt of 4-CC (4 * -fluoro-3,3 ', 5-trimethylbiphenylyl-2-) oxymethyl ^ hydroxyphosphinyl 7 ~ 3-hydroxybutyric acid 25 A. 41-fluoro-2-formyl-3,3', 5 trimethyl biphenyl

See pages 37 and 38 of U.S. Patent 4,375,475.

This compound was prepared as described in Parts A through C of Example I.

B. 41-fluoro-2- (hydroxymethyl) -3,3f, 5-trimethylbiphenyl

1.30 g (4.26 mg-mol) of the aldehyde of part A was stirred with 30 ml of dry CH 2 Cl 2 under argon. A solution of 1.06 g (5.11 mg mol) m-chloroperbenzoic acid in 20 ml CH2 Cl2 was added dropwise over 15 minutes. After stirring at room temperature for 58 hours, the reaction mixture was concentrated in a rotary evaporator and the leftover yellow substance was dissolved in THF and 6.4 ml of 2N KOH was added. This mixture was stirred at room temperature for 5 hours after which the THF was removed. What was left was diluted with water and this solution was extracted three times with ether, which extract 8801331-146-I.

were dried over MgSO4. After filtering and removing the solvent, a yellow oil was left which was purified by chromatography with 5% ether in hexane. Thus, 0.843 g (100% yield) of the title phenol was obtained as a white matter.

At TLC with 10% Et 2 O in hexane over silica gel: R 3 0.37 (PMA). Mp. 83-86 °.

IR (in KBr) 3512, 3500 (br), 2950, 1504, 1482, 1238, 1231 and 1215 cm -1.

10 ^ -NMR (270 MHz in CDCl3) δ in ppm: 7.20 (m, 2) 7.07 (t, 1, J = 9.0 Hz) 6.92 (s, 1) 6.82 (s , 1) 15 4.95 (s, 1) 2.31 (s, 3) 2.25 (s, 6)

Mass spectrum: m / e = 231 (M + H) +.

C. Diethyl ester of [(4'-fluoro-3,3, ', 5-trimethyl-biphenylyl-2) -20-oxymethyl-1-phosphonic acid

A suspension of 0.30 g of 80% (10.3 mg mol) of pentane-washed NaH in 15 ml of dry DMF was cooled in an ice bath under argon. Over 15 minutes, 2.36 g (10.3 mgmol) of Part B phenol was added: gas evolution was observed. When all was added, the mixture was warmed to room temperature and stirred for 35 minutes. A solution in 11 ml DMF of 3.31 g (10.26 mg mol) diethyltosyloxymethane phosphonate was added over 10 minutes at room temperature. (For its preparation, see A. Holy and I. Rosenberg in Collection Czechoslovak Chem. Commun. 47 (1982). After 22 hours at room temperature, the reaction mixture was quenched with saturated NH 2 Cl solution and the DMF was removed in vacuo. The residue was partitioned between EtOAc and water and the aqueous phase was extracted twice with EtOAc The combined EtOAc extracts were washed with saturated NaHCO 2 solution and brine and dried over MgSO 2, filtration and solvent removal gave 4.3 g of the above ether, which was purified by chromatography with EtOAc / hexane 70:30, yielding 3.2 g (82%) of the ether as titled 8801331-147-1 * * , oil.

At TLC with acetone / hexane 1: 1 over silica gel: R = 0.52 (PMA).

IR (as film) 2983, 2925, 2910, 1504, 1474, 1213, 1032 and 971 cm -1.

5 1 H-NMR (270 MHz in CDCl3) δ in ppm: 7.33 (m, 2) 7.01 (t, 1, J = 10.0 Hz) 6.96 (s, 1) 6.91 (s, 1 ) 10 4.07 (m, 4) 3.69 (d, 2, J = 9.3 Hz) 2.34 (s, 3) 2.31 (d, 3, J - 1.7 Hz) 2.29 (s, 3) 15 1.31 (t, 6, J = 7.0 Hz)

Mass spectrum: m / e = 381 (M + H) + and 242 (M + -C ^ H ^ qPO3) +.

D. Monoethyl ester of [(4-fluoro-3,3,5l-trimethylbiphenylyl-2) -oxymethylphosphonic acid

The 3.21 g (8.45 mgmol) diester of part C in 40 ml of dioxane was stirred with 12.7 ml of 1 N LiOH at 70 °. After 3 hours at 70 ° C, the reaction mixture was cooled to room temperature and the dioxane was removed under vacuum. The remaining solution was diluted with water, cooled in an ice bath and acidified to pH 1 with 6N HCl to give a milky white emulsion. This was extracted three times with EtOAc; the

EtOAc extracts were dried together over MgSO 4, filtered and evaporated to give 3.12 g of clear gum.

In TLC with CE ^ Cl ^ / AcOH / MeOH over silica gel: R ^ 0.20 (PMA). 1 H-NMR (270 MHz, in CDCl3) 30 δ in ppm: 10.26 (s, 1) 7.35 (2) 6.96 (m, 3) 4.05 (dq, 2, J = 7.14 Hz, 14, 8 Hz) 3.63 (d, 2, J = 9.34 Hz) 35 2.31 (s, 3) 2.29 (s, 3) 2.28 (d, 3, J = 2.2 Hz) 1.28 (t, 3, J = 7.14 Hz).

8801331 i. f t - 148 - E. Methyl ester of 4- [ethoxy / * - ^ - fluoro-S ^ ', 5-trimethyl-biphenylyl-2) oxymethylphosphinyl J-3-keto butter

Of the phosphonic acid of part D, 2.96 g (8.42 mgmol) in 75 ml of dry C 2 Clg under argon was stirred at room temperature with 2.44 g (16.84 mgmole (H 2 N 2 N 3 CHg)). .

After stirring for 1 hour and 10 minutes, it was removed under vacuum and the residual oil azeotroped with benzene once and then held under high vacuum for 15 minutes. This oil was taken up in 75 ml dry and after cooling to 0 ° under 10 argon, first three drops of dry DMF were added and then 1.18 g (9.26 mgmol) oxalyl chloride dropwise. After stirring at 0 ° C for 20 minutes, the reaction mixture was warmed to room temperature and then stirred for an additional hour. The solvent was removed under vacuum and the phosphonic acid chloride (a chestnut oil) azeotroped twice with benzene and then kept under high vacuum for 1 hour.

The dianion of methyl acetoacetate was prepared as described in Part C of Example LV (from 1.27 g (10.95 mg mol) methyl acetoacetate, 0.350 g (12.05 mg mol) NaH suspension, 4.0 ml 2.5 M n -butyl lithium in hexane and 35 ml of THF).

The solution of the dianion was added dropwise over 20 minutes to a solution of the thus prepared phosphonic acid chloride in 10 ml of THF cooled to -78 °, also at -78 °. After stirring at -78 ° for 40 minutes, the reaction mixture was quenched with saturated NH 2 Cl solution. After warming to room temperature, the THF was removed under vacuum and the residual material was partitioned between EtOAc and water. The water layer was extracted twice with EtOAc and all EtOAc solutions were washed together once with saturated NaHCO 2 solution and once with brine and dried over Na 2 SO 4. 4.0 g of crude phosphinate by title as an orange oil was obtained, which was purified by chromatography with EtOAc / hexane 75:25.

This gave 1.4 g (42%) of the title phosphinate as a yellow oil.

At TLC with EtOAc / hexane 3: 1 over silica gel: R = 0.25 (PMA).

IR 35 IR (CHCl 3) 3004, 2954, 2925, 1744, 1718, 1643, 1541, 1503, 1472, 1449, 1438, 1425, 1236, 1037 cm-1.

^ -NMR (270 MHz in CDC13): δ in ppm: 7.30 (m, 2) 6.95 (m, 3), 8601331 - 149 - * · -r * 4.05 & 3.90 (2 m'n , 2) 3.75 (m, 2) 3.73, 3.66 (2 s'n, 3) 3.55 (m, 1) 5 3.25 (m, 1) 2.33 & 2.29 (2 s'n (br), 9) 1.28 & 1.12 (2 t's, 3, J = 7.1 Hz)

Mass spectrum: m / e * 451 (M + H) +.

F. 4- / ~ C methyl ester (4t-fluoro-3,3t, 5-trimethylbiphenylyl-102) oxymethyl Jethoxyphosphinyl-7-3-hydroxybutyric acid

To a solution of 1.39 g (3.09 mgmol) ketone of part E in 15 ml THF cooled to 0 ° C, 0.12 g (3.09 mgmol) NaBH4 was added, followed slowly and dropwise by 2.8 ml of methanol. After 1 hour at 0 ° C, the reaction mixture was quenched with acetone, followed by 1.4 g of silica gel CC-4, then allowed to warm to room temperature. The mixture was filtered and the filtrate evaporated to a yellow oil in a rotary evaporator. This was chromatographed with EtOAc / hexane 90:10 and the solvent was removed from the product fractions under vacuum. The leftover yellow oil was crystallized from Et 2 O / hexane, and the resulting crystals were stirred with Et 2 O / hexane to give 0.320 title alcohol as white crystals.

At TLC with EtOAC / hexane 9: 1 over silica gel: R 0.3 0.38 (PMA).

Mp. 116-119 °.

IR (in KBr) 3288 (br), 3000, 2950, 2920, 1735, 1503, 1473, 1440, 1311, 1232 and 1195 cm -1.

1 H-NMR (270 MHz in CDCl3) δ in ppm: 7.28 (m, 2) 30 7.05 (t, 1, J = 6.0 Hz) 6.98 (s, 1) 6.90 (s , 1) 4.42 (m, 1) 4.05 & 3.85 (m, 2) 35 3.75 (d, 2, J = 6.0 Hz) 3.70 (s, 3) 2.55 (m, 2 ) 2.32 (s, 6) 2.30 (s, 3) 2.00 (m, 2), 8801331 τ, r '- 150 - 1.30 (t, 3, J = 7.0 Hz)

Mass spectrum: m / e = 453 (M + H) "*", 435 (M-H20) "*".

G. Dilithium salt of 4 - / - ((- - fluoro-S ^ 1,5-trimethylbiphenylyl-2-) oxymethyl Jhydroxyphosphinyl J-3-hydroxybutyric acid. 2.0 ml 1N LiOH was added at room temperature to a solution of 0.293 g (0.65 mgmol) diester of part F in 13 ml of dioxane. After stirring at 55 ° for 1 hour, the reaction mixture was cooled to room temperature and evaporated to dryness on a rotary evaporator. This gave a white substance which was kept under high vacuum for 10 minutes. The crude product was purified by chromatography on a column of HP-20 (15 cm length and 30 mm diameter), first with 100 ml of water and then 1: 1 with methanol / water. 0.295 g (88%) of pure dilithium salt by title were obtained as white lyophilization.

At TLC with nPr0H / NH40H / H 2 O 7: 2: 1 over silica gel: Rp = 0.38 (PMA).

IR (in KBr) 3400 (br), 3021, 3011, 2981, 2958, 2924, 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175 and 1087 cm -1.

1 H-NMR (270 MHz, in D20) δ in ppm: 7.20 (m, 2) 20 7.07 (d, 1, J = 9.9 Hz) 7.03 (s, 1) 6.86 (s, 1) 4.03 (m, 1) 3.40 (d, 2, J - 8.3 Hz) 25 2.24 (s, 3) 2.21 (s, 3) 2.20 (m, 2) 2, 17 (s, 3) 1.45 (m, 2). Mass spectrum: m / e = 423 (M + H) +.

Elemental analysis: C 54.37, H 5.03, F 4.31, P 7.55%;

Calculated for C 20 H 22 O 8 FPLi 2 · 0.95 H 2 O: C 54.67, H 5.48, F 4.32, P 7.05%.

Example LVIII

Dilithium salt of 4- / ~ [(4 * -fluoro-3,3 ', 5-trimethylbiphenylyl-2) -methyl-7-hydroxyphosphinyl J-3-hydroxybutyric acid A. 4'-fluoro-2- (hydroxymethyl) -3, 3 *, 5-trimethylbiphenyl

To a solution of 120 mg (3.18 mgmol) NaBH4 in 9 ml absolute ethanol, 700 mg (2.89 mgmol) aldehyde according to .8801331

S '> ® V

- 151 - 'example LVII part A added. The mixture was stirred at room temperature for 2 hours and then quenched with saturated NH 2 Cl solution. The resulting precipitate was filtered off.

The filtrate was evaporated to dryness on a rotary evaporator and the residual matter was dissolved in ether and water. The water layer was extracted twice with ether and the combined ether solutions were dried over MgSO4. After filtration and removal of the solvent, 700 mg of white matter was obtained. This was purified by chromatography with Et 2 O / hexane 1: 2 to give 675 mg of 10 (100% yield) of title alcohol.

At TLC with 15% Et 2 O in hexane over silica gel: R 2 0.11 (PMA). Mp. 101-102 °.

IR (in KBr) 3351, 3293, 3267, 3260, 3024, 3016, 2980, 2939, 2921, 1605, 1601, 1502, 1451, 1355, 1243, 1236, 1228, 1189, 15 1118, and 999 cm 1 H-NMR ( 270 MHz, in CDCl3) δ in ppm: 7.15 (m, 2) 7.03 (m, 2) 6.90 (s, 1) 20 4.55 (d, 2, J = 6.0 Hz) 2.48 ( s, 3) 2.33 (s, 6)

Mass spectrum: m / e = 244 (M +) and 227 (M + -OH).

B. Diethyl ester of C 1 -fluoro-B 1, 1,5-trimethylbiphenylyl-2) -25 methylphosphonic acid

Under argon, to a solution of 1.94 g (7.95 mgmol) of alcohol according to Part A, cooled to 0 ° C, was added 0.965 g (9.54 mgmol) Et 2 N, then 1.00 g dropwise (8.75 mg mol) mesyl chloride. After stirring at 0 ° C for 30 minutes and warming to room temperature, stirring was continued overnight. The reaction mixture was quenched with saturated NaHCO 2 solution under vigorous stirring. The organic layer was saturated with

NaHCO 2 solution and dried over MgSO 2. Filtration and removal of the solvent gave 2.1 g of 2- (chloromethyl) -351-fluoro-3,3,5,5-trimethylbiphenyl as clear oil.

At TLC with Et 2 O / hexane 1: 1 over silica gel: R = 0.68 (PMA).

1 z t H-NMR (270 MHz, in CDCl3) 6 in ppm: 7.22 (m, 2) 7.03 (m, 2) 6.90 (s, 1) 880 1 33 1.

x τ * - 152 - 4.50 (s, 2) 2.48 (s, 3) 2.33 (s, 6)

Without further purification, this 2.1 g of chloride 5 was mixed with 30 ml of triethyl phosphite and heated at 150 ° under argon for 3 hours. The mixture was cooled to room temperature and the excess P (0C2H3) 3 was removed by distillation. The crude product was purified by chromatography with EtOAc / hexane 70:30. Thus, 2.40 g (83%) of the title phospho-10nate as a clear oil were obtained.

At TLC with EtOAc / hexane 70:30 on silica gel: R = 0.37 (PMA).

IR (in CHCl 3) 2992, 2928, 2909, 1501, 1474, 1455, 1443, 1392, 1245, 1239, 1119, 1053, 1029, 970, and 963 cm -1.

1 H-NMR (270 MHz in CDCl3) 15 δ in ppm: 7.15 (m, 2) 7.00 (m, 2) 6.83 (s, 1) 3.83 (m, 4) 3.22 (d, 2, J = 22.52 Hz) 20 2.47 (s, 3) 2.29 (s, 6) 1.16 (t, 6, J = 7.14 Hz)

Mass spectrum: m / e = 365 (M + H).

C. Monoethyl ester of .beta.-fluoro-S4-, 5-trimethylbiphenylyl-2) -25 methyl-7-phosphonic acid

At room temperature, stirring was added to the 2.40 g (6.59 mg mol) phosphonic acid diester of Part B in 30 ml of dioxane 9.9 ml of 1 N LiOH and the mixture was refluxed. After 18 hours and after 44 hours, an additional 9.9 ml of 1 N LiOH was added. After boiling for a total of 55 hours, the mixture was cooled to room temperature and the dioxane was removed in the rotary evaporator. The resulting aqueous solution was diluted with water and extracted twice with diethyl ether to remove any diester residues. The water layer 35 was then cooled in an ice bath and acidified with 6 N HCl to pH * / l. The milky white emulsion was extracted three times with EtOAc and that extract was dried over MgSO4, filtered and evaporated to dryness. This gave 1.89 g (85%) of a clear oil.

At TLC with C 1 / C 2 / MeOH / AcOH 90: 5: 5 over silica gel: R 2 0.26 40 (PMA).

8ÖG1331 Γ "ϊ * τ - 153 - τ IR (in CHC13) 3029, 3023, 3005, 2983, 2925, 1710, 1605, 1500, 1234, 1042 and 988 cm -1.

1 H-NMR (270 MHz, in CDCl3) δ in ppm: 11.07 (s, 1) 5 7.05 (m, 2) 6.95 (m, 2) 6.80 (s, 1) 3.71 (dq, 2, J = 7.15 Hz, 14.83 Hz) 3.13 (d, 2, J = 23.0) 10 2.38 (s, 3) 2.27 (s, 6) 1.13 (t, 3, J = 7.2 Hz)

Mass spectrum: m / e = 337 (M + H) +.

D. Methyl ester of 4 - / - / ethoxy (4, -fluoro-3,3l, 5-trimethylbife-15-nylyl-2) methylphosphinyl, 7-3-ketobutyric acid

To a solution of 1.85 g (5.50 mgmol) of part C semiester in 50 ml was added with stirring and under argon 1.60 g (11.0 mgmol) 1 H 2 N 2 NS 3 C 3. After 1 hour and 15 minutes, the (H 2 Clg was removed from the reaction mixture and the remaining yellow oil was azeotroped once with benzene and kept under high vacuum for 20 minutes. This oil was dissolved in 50 ml dry under argon and to 0 ° C

chilled. Two drops of DMF were added first and then 0.768 g (6.06 mg mol) oxalyl chloride; gas evolution was observed. The reaction mixture was kept at 0 ° C for an additional 20 minutes

stirred and after warming to room temperature an additional 1 hour 40 minutes, the mixture turning to a deep burgundy red.

It was removed from the mixture and the residual oil was azeotroped twice with dry benzene and then kept under high vacuum for 1 hour.

The dianion of methyl acetoacetate was prepared as described in Part E of Example LVII (from 830 mg (7.16 mg mol) methyl acetoacetate, 230 mg (7.88 mg mol) NaH dispersion, 2.64 ml 2.5 M n-BuLi in hexane and 20 ml THF).

To a solution of the above phosphonic acid chloride in 10 ml of dry THF cooled to -78 °, the dianion solution cooled to -78 ° was added via cannula over 20 minutes. After stirring at -78 ° for 40 minutes, the mixture was quenched at -78 ° with saturated NH 4 Cl solution; after warming to room temperature 8801331 * 154 - the mixture was diluted with water (so that all solids dissolved) and the THF was removed in the rotary evaporator. The remaining mixture was extracted three times with EtOAc. The EtOAc extracts were washed once with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated to give 2.6 g of orange oil. The crude product was purified by chromatography with EtOAc / hexane 3: 1. Thus, as an orange foam, 430 mg (23%) of the title ketone was obtained.

10 TLC with acetone / hexane 1: 1 over silica gel: R = 0.32 (PMA).

IR (in KBr) 2952, 2925, 1739, 1718, 1654, 1529, 1503, 1472, 1234, 1206, 1166, 1119 and 1035 cm -1.

1 H-NMR (270 MHz in CDCl3) δ in ppm: 7.20-6.70 (aromatic H, 5) 15 4.00-3.70 (m, 2) 3.70 & 3.55 (2 s 'n, 3) 3.35 (m, 2) 3.35 (d, 2, J = 15 Hz) 2.92 (m, 1) 20 2.45 & 2.35 (2 s'n, 3) 2.25 ( s, 6) 1.15 & 0.95 (2 t's, 3, J = 7.0 Hz) • j

Mass spectrum: m / e = 435 (M + H).

E. Methyl ester of 4-Cethoxy [(4'-fluoro-3,3 ', 5-trimethyl 1-25 biphenylyl -2) methyl, 7-phosphinyl. J-3-hydroxybutyric acid

To a solution of 400 mg (0.92 mgmol) ketone of part D in 5 ml THF was added 35 mg (0.92 mgmol) solid NaBH4 under argon, then 0.80 ml methanol. After 1 hour at room temperature, the reaction mixture was quenched with acetone, followed by 400 mg of CC-4 silica gel. The reaction mixture was filtered and the solvent was removed. The crude reaction product still contained some ketone starting material, therefore this reaction product was again subjected to the same reduction conditions, except that now CO2 was also bubbled through the solution before adding the NaBH. Work-up as above gave 250 mg of yellow oil which was purified by chromatography with EtOAc. The title pure alcohol was obtained as a clear oil.

At TLC with acetone / hexane 1: 1 over silica gel: R ^ = 0.26 (PMA).

8801331 * ί · ·>> - 155 - * H-NMR (270 MHz, in CDC13) δ in ppm: 7.10 (m, 2) 7.00 (m, 2) 6.85 (s, 1) 5 4.28 & 4.03 (2 m's, 1) 4.10-3.70 (m, 2) 3.67 (s, 3) 3.33 (m, 2) 2.47 (s, 3) 10 2.40 (m, 2) 2.30 (s, 6) 1.63 (®, 2) 1.17 (t, 3, J = 6.6 Hz).

F. Diphasic salt of 4- / ~ Z * (4t-fluoro-3,3t, 5-trimethylbiphenylyl-2) - 15 methyl] 7hydroxyphosphinyl, 7-3-hydroxybutyric acid

Under argon was added to a solution of 110 mg (0.252 mgmol) diester of part E cooled to 0 ° C in 5.5 ml of dry CH 2 Cl 2 46 mg (0.38 mgmol) collidine, then dropwise 182 mg (0.88 mgmol) trimethylsilyl iodide. After stirring at 0 ° C for 2 hours, the reaction mixture was allowed to warm to room temperature. After 24 hours, an additional 23 mg of collidine and an additional 91 mg of trimethylsilyl iodide were added. After standing at room temperature for 48 hours, the CH2 Cl2 was removed and 6 ml of dioxane and 1.7 ml of 1 N LiOH were added successively.

This mixture was refluxed for 16 hours. After cooling to room temperature, the dioxane was removed to leave an orange gum. This gum was dissolved in water and filtered through sintered glass to remove a residual solid. The filtrate was lyophilized to an off-white matter which was purified on a column of HP-20 (15 cm length and 15 mm diameter). The column was first eluted with 150 ml of water and then 1: 1 with methanol / water. The product fractions were lyophilized to give 88 mg (80%) of the title compound as white lyophilization.

At TLC with nPr0H / NH40H / H 2 O 7: 2: 1 over silica gel: Rp = 0.38 (PMA).

IR (in KBr) 3700-3100 (br), 2923, 1591, 1501, 1234, 1147 cm-1.

^ -NMR (270 MHz, in D20) δ in ppm: 7.20-7.00 (, 4) 8801331 1. T t - 156 - 6.82 (s, 1) 3.76 (m, 1) 3 .11 (m, 2) 2.35 (s, 3) 5 2.22 (s, 3) 2.21 (s, 3) 2.05 (m, 2) 1.16 (dd, 2, J = 12.32 Hz, 6.45 Hz)

Masa spectrum: m / e = 407 (M + H), Elemental analysis: C 57.11, H 6.63, F 4.44, P 7.70%;

Calculated for ^ qI ^ FO ^ H ^ .OjSO ^ 0: C 57.11, H 5.65, F 4.52, P 7.36 1.

Example LIX

Dilithium salt of (S) -4-jf [C 1- (4-fluorophenyl) -3-methyl-15-naphthyl-2-ethynyl] -hydroxyphosphinyl J-3-hydroxybutyric acid A. 1-methoxynaphthalene-2-carboxylic acid See J. Organomet. Chem. 20 (1969) 251-252.

To a mixture of 83.44 ml of 2.5 M (208.6 mgmol) n-BuLi in hexane and 42 ml of dry cyclohexane under argon at 20 ° C over 10 minutes, 31.48 ml (24.24 g, 208 .6 mg mol) of tetramethyl ethylene diamine. The resulting suspension was stirred at 0 ° C for 30 minutes and then a solution of 30.28 ml (33 g, 208.6 mg mol) of 1-methoxynaphthalene (from Aldrich Chem. Co., without further purification) was used over 20 minutes. dropwise in 84 ml of dry cyclohexane. The resulting bright red, homogeneous reaction mixture was allowed to warm to room temperature and stir for an additional 2 hours. The mixture was then cooled again to 0 ° C and dropped through a cannula into 250 ml of dry diethyl ether held at -78 ° C and kept saturated with carbon dioxide (lumps of carbon dioxide were bubbled through a dry tube of S102 by dry Et2 kept at -78 °). The resulting white suspension was warmed to about 0 ° over 45 minutes and then 450 ml of 5% HCl in water was added. The ether layer was separated and the water layer was extracted three times with ether. The organic extracts were extracted together with 3 x 150 ml of saturated NaHCO 2 solution and this water layer was filtered through a sintered glass filter to remove some insoluble residue. The filtrate was cooled again to 0 ° C and slowly acidified with concentrated HCl to .8801331 - 157 - * 4 * * pH * 1. The resulting precipitate was filtered off, azeotroped twice with 150 ml of toluene and at 50 ° under high vacuum for 5 hours. dried, yielding 32.52 g (0.161 mol, 77% yield) of 1-methoxy-naphthalene-2-carboxylic acid as an off-white powder, m.p.

5 118-12li ° C.

At TLC with CH 2 Cl / MeOH / AcOH 94: 5: 1 over silica gel: R = 0.35.

1 ^ 1 13 F

The H-NMR spectrum (at 270 MHz in CDCl 2) and the C-NMR spectrum (at 67.8 MHz, in CDCl 2) and the IR spectrum (in KBr) in accordance with the expected structure.

Mass spectrum: m / e = 203 (M + H) +.

B. N- (2-hydroxy-1,1-dimethylethyl) -1-methoxynaphthalene-2-carboxamide

To a solution of 31.4 g (155.22 mg mol) of 1-methoxynaphthalene-2-carboxylic acid in 155 ml of dry CH 2 Cl 2, was added 22.65 ml (36.94 g, 310.44 mg mol) of SQCl 2 under argon. .

The mixture was first stirred at room temperature for 45 minutes and then in an oil bath at 55 ° C for 45 minutes. After cooling to room temperature, 15 g of thionyl chloride was added to the mixture and refluxed for 45 minutes. After cooling to room temperature, excess SO 2 Cl 2 and CR 2 Cl 2 were removed in a rotary evaporator at 35 ° C (in contact with argon atmosphere) and the resulting mustard yellow substance was dissolved in 155 ml of dry CH 2 Cl 2 under argon. This solution was transferred into a dropping funnel with a cannula and dropped over 25 40 minutes with stirring and argon in a solution of 27.67 g (310.4 mgmol) of 2-amino-2-methylpropanol in 155 ml of dry CH 2 Cl 2 of Q ° C. This reaction mixture was allowed to warm to room temperature and after stirring for 18 hours it was filtered, the precipitate washed with CH 2 Cl 2 and the filtrate evaporated in vacuo. The residue was taken up in 350 ml EtOAc and washed once with 250 ml water, once with 250 ml 5% HCl, once with 250 ml 5% NaOH and once with 250 ml brine. The aqueous extracts were backwashed once with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated in vacuo to an orange oil which was azeotroped with 250 ml of toluene and kept at 55 ° C under high vacuum for 8 hours. This gave 38.2 g (139.76 mg mol, 90% yield) of the title naphthalene amide as a pale yellow solid.

8801331-158 - i τ l 'DLC with 100% EtOAc over silica gel: R = 0.65.

^ -NMR (270 MHz, in CDCl3) δ in ppm: 8.19 (s, br, 1H) 8.14 (m, 1H) 5 8.03 (d, 1H, J = 8.7 Hz) 7.83 ( m, 1H) 7.66 (d, 1H, J = 8.7 Hz) 7.55 (m, 2H) 4.00 (s, 3H) 10 3.74 (s, 2H) 1.47 (s, 6H)

Mass spectrum: m / e = 274 (M + H) * IR (solution in CHCl 3): 3365, 3063, 3024, 3005, 2871, 2938, 2873, 1641, 1597, 1540, 15 1456, 1446, 1387, 1371, 1344, 1291, 1256, 1238, 1223, 1210, 1199, 1183, 1168, 1145, 1079, 981 and 833 cm -1.

C. 2- (1-methoxynaphthyl-2) -4,4-dimethyl-4,5-dihydrooxazole

The 38.2 g (139 mg mol) naphthalene amide of Part B was cooled to 0 ° C while dripping 40.56 ml (66.15 g, 556 mg mol) thionyl chloride over 5 minutes with argon and stirring. The resulting dark brown oil was stirred at room temperature for 45 minutes, and stirred for an additional 2 hours after adding 500 ml of dry ether. The resulting yellow crystalline precipitate was filtered off, washed with ether and suspended in 250 ml of ether. This ether was cooled to 0 ° C and

made basic with ca 200 ml 10% NaOH. The water layer was extracted three times with ether and once with EtOAc. The organic extracts were washed together once with brine, dried over MgSO 4, filtered and concentrated. The residue was azeotroped with toluene for 30 hours and at 55 ° C under high vacuum for 8 hours

kept. This gave 32.10 g (126 mg mol, 90% yield) of the title oxazoline as a gold colored powder.

At TLC with 50% EtOAc over silica gel: R = 0.37.

1 * H-NMR (270 MHz, in CDCl3) 35 δ in ppm: 8.25 (m, 1H) 7.84 (d, 1H, J = 8.7 Hz) 7.84 (m, 1H) 7.60 (d, 1H, J = 8.7 Hz) 7.54 (m, 2H) 40 4.19 (s, 2H). 8801 311 - 159 - * 1 * τ 4.04 (s, 3H) 1.46 (s, 6H )

Mass spectrum: m / e = 256 (M + H) + IR: 2969, 2935, 2896, 1642, 1465, 1447, 1386, 1372, 1349, 5 1255, 1109, 1074 and 991 cm-1.

D. 2-C 1- (4-fluorophenyl) naphthyl-2 J-4,4-dimethyl-4,5-dihydro-oxazole

Under argon, 30.0 g (117.52 mg mol) of oxazoline of Part C was stirred in 352 ml of dry THF. This solution was heated at 45 ° C in an oil bath. The heat source was removed and 79.33 ml of 2 M (158.65 mg mol) 4-fluoro-phenylmagnesium bromide in Et 2 O (from Aldrich) was added dropwise over 30 minutes at a rate sufficient to bring the reaction temperature to about 45 ° to keep. When everything was added, the mixture was kept at 45 ° with stirring for an additional 18 hours. After cooling to 0 ° C, the reaction mixture was quenched with 200 ml of saturated NH 2 Cl solution and diluted with 200 ml of water and 200 ml of ethyl acetate. The water layer was extracted four more times with EtOAc. The organic extracts were dried together on MgSO4, filtered and concentrated. This gave 39 g of a dark gold colored solid.

This product was purified by chromatography with EtOAc / hexane 1: 3 on a Merck silica gel column (18 cm length, 95 mm diameter) at a flow rate of 5 cm / min. This gave 30.42 g (95.25 mg mol, 81% yield) of the title 4-fluoro-25-phenyl substituted naphthalene, a pale yellow substance, m.p. 94-96 °.

3.38 g (10.58 mg mol, 9%) of slightly impure product were also obtained.

At TLC with EtOAc / hexane 1: 1 over silica gel: = 0.45.

30 1 H NMR: (270 MHz, in CDCl3) δ in ppm: 7.93-7.13 (aromatic, 10H) 3.77 (s, 2H) 1.27 (s, 6H)

Mass spectrum: m / e = 320 (M + H) + 35 IR (in KBr) 3060, 2966, 2927, 2884, 1667, 1603, 1508, 1462, 1383, 1354, 1335, 1293, 1219, 1185, 1160, 1119 , 1083, 978, 842 and 830 cm E. 2-C 1- (4-fluorophenyl) -3-methylnaphthyl-2 J-4,4-dimethyl-4,5-di-hydrooxazole 8801331 * - 160 -

Under argon, 28 g (87.67 mg mol) of naphthyloxazoline according to Part D were stirred in 585 ml of dry ether. This solution was cooled to -25 ° and 56.1 ml of 2.5 M (140 mgmol) n-BuLi in hexane was added dropwise over 1 hour. During this prolonged addition, the homogeneous yellow solution went through dark red orange to an orange-green solution with precipitate.

The mixture was stirred at -25 ° for an additional 2 hours and then 16.4 ml (37.33 g, 263 mgmol) of iodomethane was added dropwise over 15 minutes. The dark burgundy red solution was stirred at -25 ° for an additional 10 hours and after heating to 0 ° C for another 16 hours and finally at room temperature for another 7 hours. The resulting yellow transparent solution was quenched with 500 ml of ice cold brine. The water layer was extracted four times with EtOAc.

The organic extracts were concentrated together, dried over MgSO4 / 15 and filtered through Florisil (two thirds volume glass filter beaker). The Florisil was washed with. The filtrates were evaporated to dryness and azeotroped with toluene and kept at 55 ° for a further 3 hours under high vacuum. This gave 30.32 g (100% yield) of methylated naphthalene as a yellow substance.

At TLC with EtOAc / hexane 1: 1 over silica gel: R ^ = 0.50.

1 H NMR: (270 MHz, in CDCl3) <$ in ppm: 7.79-7.07 (aromatic, 9H) 3.80 (s, 2H) 25 2.54 (s, 3H) 1.13 (s , 6H)

Mass spectrum: m / e = 334 (M + H) + IR: (solution in CHCl 3): 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513, 1497, 1461, 30 1299, 1280, 1235, 1190 , 1158, 1041, 965, and 841 cm -1.

F. 2-C 1- (4-fluorophenyl) -3-methylnaphthyl-2J-3,4,4-trimethyl-4,5-dihydrooxazolium iodide

To 29.23 g (87.67 mg mol) oxazoline of part E in 140.28 ml nitromethane was added 49.2 ml (112 g, 789 mg mol) iodomethane with stirring and under argon 35. The brown reaction mixture was kept at 60 ° in an oil bath for 1 hour and 20 minutes in the absence of light. The iodomethane was easily removed by distillation and the nitromethane in a rotary evaporator, followed by 45 minutes under high vacuum.

»8801331 - 161 - 4 * *»

The resulting burgundy red substance was stirred with 250 ml of dry ether for 1 hour. The red filtrate was decanted and the solid extracted again in the same manner. The leftover yellow matter was filtered off and kept under high vacuum for 4 hours in the absence of light. This gave 44 g (100% yield) of oxazolinium iodide according to the title, a mustard yellow substance.

This substance was stored at -30 ° in the dark for 18 hours and as such was used directly for the preparation of Part 10 G.

TLC with 10% methanol in CH 2 Cl 2 over silica gel: R 3 = 0.30.

G. 1- (4-Fluorophenyl) -2-formyl-3-methylnaphthalene

Under argon, 41.67 g (87.67 mg mol) oxazolinium iodide of part F was stirred in 210 ml absolute (dried on molecular sieve of 4 & 15) ethanol. This solution / suspension was cooled to -15 ° and NaBH4 was added in bits over 1 hour. When everything was added, the mixture was stirred at -10 ° to -15 ° for an additional 2 hours. The solution was then diluted with 210 ml of absolute alcohol and 20 438 ml of 2 N HCl was added dropwise with stirring over 45 minutes (very slowly at first).

When all was added, the reaction mixture was allowed to warm to room temperature while stirring for an additional 4 hours. Then it was diluted with 500 ml of water and extracted with ether. The ether extracts were dried together over MgSO 4, filtered and concentrated and the residue was azeotroped twice with 120 ml of toluene and kept under vacuum. This gave 12.9 g (48.8 mg mol, 56% yield) of aldehyde according to the title as a pale yellow substance.

At TLC with EtOAc / hexane 1: 1 over silica gel: R = 0.66.

1 F 30 H NMR: (270 MHz, in CDCl3) δ in ppm: 10.0 (s, 1H) 7.83-7.18 (aromatic, 9H), 2.81 (s, 3H)

Mass spectrum: m / e = 265 (M + H) "*" IR: (solution in CHGl ^): 35 1685, 1512, 1422, 1237 and 862 cm -1.

H. 2- (2,2-dibromoethenyl) -1- (4-fluorophenyl) -3-methylnaphthalene

To a solution of 3.0 g (11.35 mg mol) aldehyde of part G in 113 ml of dryness was added at 0 ° and under argon suddenly 9.53 g (36.32 mg mol) triphenylphosphine. After stirring at 0 ° C for 8 minutes, a solution of 6.02 g (18.16 mgmol) of CBr 2 in 41 ml of dry CH 2 Cl 2 was added dropwise over 20 minutes.

The now dark orange solution turned to dark burgundy red during stirring at 0 ° C for 1 hour. Then the reaction mixture was quenched with 150 ml of saturated NaHCO 2 and the water layer was extracted four times with C 1 -C 2. The organic extracts were evaporated slightly, washed once with brine, dried over MgSO4 and filtered. The filtrate was pre-absorbed on 28 g of Merck's silica and placed in a chromatography column already containing 15 cm of silica gel; this was increased by 7%

EtOAc eluted in hexane (5 cm / min.); this gave 4.23 g of the title dibromo-olefin as slightly impure pale yellow substance.

Recrystallization from hexane gave 3.68 g (8.77 mg mol, 77%) of dibromolefine by title as white powder, m.p.

15 134 ^ -135J °.

At TLC with EtOAc / hexane 1: 4 over silica gel: R = 0.60.

1 F H-NMR (270 MHz in CDCl3) δ in ppm: 7.79-7.11 (aromatic olefin, 10H), 2.48 (s, 3H) Mass spectrum: m / e = 419, 421 and 423 (M + H) + 20 IR: (solution in CHCl 3): 3016, 1604, 1512, 1496, 1234, 1220, 1208, 1158, 886 and 858 cm-1.

I. 2-Ethynyl-1- (4-fluorophenyl) -3-methylnaphthalene

To a solution of 3.69 g (8.7 mg mol) of dibromolefine of part H in 47.9 ml of dry THE was stirred with stirring and under argon at -78 ° over 15 minutes 6.96 ml of 2.5 M (17, 4 mgmol) n-BuLi dropwise into hexane. After stirring for an additional 1 hour at -78 °, the reaction mixture was quenched with 40 ml of saturated NH 2 Cl solution. After warming to 0 ° C, the reaction mixture was diluted with 40 ml of water and 40 ml of ether. The water phase was drawn off and extracted twice more with 3030 and once with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated to dryness.

A first purification by chromatography with 7% EtOAc in hexane on a Merck silica gel column (15 cm length, 50 mm diameter) gave 2.32 g of green material, half oil, half solid.

1 H-NMR at 270 MHz showed an impure product. Purification once more by chromatography on a column of silica gel (15 cm length, 75 mm diameter), now with 1% EtOAc in hexane (5 cm / min.) Gave 2.11 g (8.11 mg mol, 93%) of acetylene according to the title as 40 pale blue dust (held under high vacuum for 8 hours), m.p.

9S01331-163 - * 4 * * 91i-94 °.

At TLC with EtOAc / hexane 1: 4 over silica gel: R = 0.56 (PMA).

1 * H NMR: (270 MHz, in CDCX3) δ in ppm: 7.77-7.13 (aromatic, 9H), 3.18 (s, 1H), 5 2.62 (s, 3H)

Mass spectrum: m / e = 260 M + IR: (CH2Cl2 film): 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150, 1092, 884, 871, 853 and 825 cm-1.

10 J. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4- Γ [Γ 1- (4-fluorophenyl-3-methylnaphthyl-2-jethynyl] methoxy-phosphinyl] butyric acid

With vigorous shaking, 5.57 g (8.82 mg mol) of dicyclohexylammonium salt of Example XXV was distributed between 75 ml of EtOAc and 75 ml of 5% KHSO4 and water. The layers were separated and the EtOAc layer was washed with 2 x 100 ml of fresh 5% KHSO4, dried over MgSO4, filtered and evaporated in vacuo. The residue was azeotroped with 120 ml of benzene twice and kept under high vacuum for 2 hours to give 4.33 g of 20 ("109%") phosphonic acid monoester as a viscous pale yellow oil.

This oil was taken up in 24.8 ml of dry CH2 Cl2 and 3.34 ml (2.56 g, 17.64 mg mol) of distilled diethyl trimethylsilylamine was added dropwise. After stirring for 2 hours at room temperature, the volatiles were removed in rotary evaporator (connection to argon) and the residue was azeotroped once with 60 ml of benzene and kept under high vacuum for an additional 45 minutes.

The residue was taken up in 24.8 ml of dry CH 2 Cl 2 under argon and with stirring. Two drops of DMF were added

and the solution was cooled to 0 ° C. Over 10 minutes, 0.923 ml (1.34 g, 10.58 mg mol) of oxalyl chloride were added dropwise. The amber solution was stirred at 0 ° C for an additional 30 minutes and stirred for an additional 2 hours after warming to room temperature. The volatiles were removed and the residue azeotroped as above and kept under high vacuum. Finally, the residue was taken up in 27.7 ml of dry THF under argon and after cooling to -78 ° C, the lithium acetylene solution was added dropwise over 15 minutes, which was added as follows: 0801331-164-1V v1. * makes wax.

1.35 g (5.19 mg mol) of the acetylene of Part I were taken up in 27.7 ml of dry THF under argon and after cooling to -78 °, 2.08 ml of 2.5 M (5 ml) were added over 10 minutes. 19 mg mol) n-BuLi 5 in hexane when dropped. The now green solution was stirred at -78 ° for 1 hour, kept at 0 ° C for 15 minutes after heating and then cooled back to -78 °. At that temperature, it was dropped in portions from a dropping funnel into the above-mentioned solution of the phosphonic acid chloride cooled to -78 °.

When everything was added, the mixture was stirred at -78 ° for an additional 1 hour and quenched with 50 ml of saturated NH 2 Cl solution. After warming to 0 ° C, the reaction mixture was diluted with 40 ml of water and 40 ml of ether. The water layer was extracted four more times with 50 ml of ether. The organic extracts were concentrated together, dried over MgSO4, filtered and evaporated in vacuo. The product was isolated by chromatography with hexane / EtOAc / toluene 5: 4: 1 on a Merck silica gel column (15 cm in length and 75 mm in diameter) to give 1.53 g (2.21 mgmol, 43%) of acetylene phosphate according to the title as a yellow foam.

A further 589 mg of crude starting material were also recovered.

At TLC with hexane / EtOAc / toluene 5: 4: 1 over silica gel: R ^ = 0.26 (PMA).

^ -NMR: (270 MHz, in CDCl3) 6 in ppm: 7.82-7.09 (aromatic, 19H), 4.52 (m, 1H) 25 3.60 & 3.59 (2 xs, 3H) 3.36 & 3.31 (2 xd, 3H, J = 11.5 Hz) 2.54 & 2.49 (2 xs, 3H) 2.87-2.73 (m, 1H) 2.61-2 .56 (m, 1H) 30 2.39-2.22 (m, 1H) 2.12-2.00 (m, IH) 1.02 (s, 9H)

Mass spectrum: m / e = 693 (M + H) + IR (solution in CHCl 3): 35 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 and 834 cm -1.

K. Methyl ester of (S) -4-jf C C 1- (4-fluorophenyl) -3-methylnaphthyl-2-jethynyl-methoxyphosphinyl J-3-hydroxybutyric acid 8801331-165.

> τ

To a solution of 600 mg (0.866 mgmol) acetylene phosphinate according to part J in 10.5 ml dry THF was added 0.198 ml (208 mg, 3.46 mgmol) glacial acetic acid with argon and stirring then 2.36 ml dropwise 1.1 M 5 (2.60 mg mol) tetrabutyl ammonium fluoride in THF. The reaction mixture was stirred at room temperature for 24 hours, then quenched with 25 ml of ice water and diluted with EtOAc. The water layer was extracted three times with EtOAc. The organic extracts were washed together once with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated in vacuo. The product was purified by chromatography with 100% EtOAc over a Merck silica gel column (30 mm diameter, 5 cm / min) to give 267 mg (0.588 mgmol, 68%) of β-hydroxyphosphinate as the pale yellow foam.

At TLC with 100% EtOAc over silica gel: R = 0.28 (PMA).

1 * H-NMR: (270 MHz, in CDClg) δ in ppm: 7.81-7.18 (aromatic, 9H) 4.38 (m, 1H) 3.71 (s, 3H) 20 3.59 & 3.58 (2 xd, 3H, J = 12 Hz) 2.66 & 2.65 (2 xs, 3H) 2.62-2.52 (m, 2H) 2.19-1.92 (m, 2H )

Mass spectrum: m / e = 455 (M + H) + 25 IR (film): 3380 (wide), 3065, 3048, 2993, 2951, 2166, 1738, 1604, 1513, 1495, 1438, 1423, 1401, 1385, 1378, 1334, 1299, 1222, 1179, 1160, 1138, 1095, 1035, 951, 887 and 836 cm-1.

L. Dilithium salt of (S) -4 ~ ZT CC 1- (4-fluorophenyl) -3-methyl-naphthyl-2-jethynyl-7-hydroxyphosphinyl, 7-3-hydroxybutyric acid 30 To 265 mg (0.583 mgmol) diester of Part K in 6 ml of dioxane was added under argon and with stirring 1.75 ml of 1 N LiOH. The mixture was heated to 70 ° in an oil bath for 45 minutes and then cooled. The solvents were removed in a dry evaporator and kept under high vacuum for an additional 1 hour. The leftover white matter was taken up in 4 ml of distilled water and placed on a chromatography column HP-20 (17.0 cm length, 25 mm diameter, equilibrated with water). The column was first eluted with 250 ml of water and then 45:55 with methanol / water. Every 1.3 minutes, a fraction of ca IQ ml was collected. The product fractions were evaporated together under vacuum at 35 ° C and freeze-dried and kept under high vacuum for 8 hours. This gave 237 mg (0.541 mg mol, 93%) dilithium salt as the title as white lyophilization.

At TLC with nPr0H / NH40H / H 2 O 7: 2: 1 over silica gel: Rp = 0.40 (PMA).

1 H-NMR: (400 MHz, in D20) δ in ppm: 7.88 (d, 1H, J = 8.43 Hz) 7.80 (s, 1H) 10 7.58-7.29 (aromatic, 7H ) 4.14-4.05 (m, 1H) 2.61 (s, 3H) 2.43 (dd, 1H, J = 3.67, J = 15.39) 2.21 (dd, 1H, J = 9.16, J = 15.39) 1.84-1.67 (m, 2H)

Mass spectrum: m / e = 439 (M + 2Li) + IR: (in KBr) 3443-3260 (wide), 3066, 2164, 1594, 1512, 1495, 1434, 1222, 1183, 1160, 1071 and 834 cm-1 .

Elemental analysis: C 61.38, H 4.07, F 4.42, P 6.80%; Calculated for c23Hi8F05PLi2 + 0.66H20 (MG - 450.14): C 61.38, H 4.33, F 4.22, P 6.88%.

Example LX

Dilithium salt of (E) -4-Z * [2- / 1- (4-fluorophenyl) -3-methyl-naphthyl-2-jethenyl 7-hydroxyphosphinyl 7-3-hydroxybutyric acid 25 A. Dimethyl ester of ƒ * 2- [1- (4-fluorophenyl) -3-methylnaphthyl-2J-2-hydroxyethyl7phosphonic acid

To a solution of 2.62 ml (3.0 g, 24.2 mg mol) dimethyl methane phosphonate in 47 ml dry THF was added 9.08 ml 2.5 M (22.7) under argon and stirring at -78 ° over 15 minutes. 30 mg mol) n-BuLi dropwise into hexane. The reaction mixture was

Stirred at -78 ° for an hour and then a solution of 4.0 g (15.13 mgmol) of aldehyde according to Example LIX part G in 14 ml of dry THF was dripped on the milky emulsion over 15 minutes.

The reaction mixture was stirred at -78 ° for 45 minutes and then quenched with 50 ml of saturated NH 2 Cl solution. After warming to room temperature, it was diluted with 50 ml of water and 50 ml of EtOAc. The water layer was extracted four times with EtOAc. The organic extracts were dried together over MgSO4, filtered and evaporated to dryness, and the residue was azeop twice with toluene azeo-8801331-167-1 * 1 and then kept under high vacuum to give 5.90 g (15.13 mgmol). ), 100% yield) of the title phosphonate as a yellow substance, which as such was used directly for Preparation B.

5 At TLC with acetone / hexane 1: 1 over silica gel: = 0.37 (PMA).

B. Dimethyl ester of (E) - ^ 2-C 1- (4-fluorophenyl) -3-methylnaphthyl-2-J-ethenyl-Phosphonic acid

To a solution of 5.5 g (14.16 mgmol) (3-hydroxy-phosphonate according to part A in 66.5 ml of dry toluene) was added 673 mg (3.54 mgmol) of p-toluenesulfonic acid monohydrate (TsOH) under argon.

^ 0) added. The reaction mixture was heated to reflux at 135 ° in an oil bath; however, the condensate was passed through a Soxhlet apparatus containing a 4X molecular sieve. After refluxing for 16 hours, a further 404 mg (2.12 mg mol) of TsOH. 2 O was added and another 8 | cooked for an hour. The reaction mixture was now cooled to room temperature and diluted with 100 ml EtOAc. That mixture was washed with 100 ml of saturated NaHCO 2 solution and the water 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 substance. The water layer was acidified with 5% HCl and extracted three times with EtOAc. The organic extracts were dried together on MgSO 4, filtered and evaporated to give 1.4 g (n 3.92 mgmol ") of vinyl phosphonic acid monoester as a light brown substance. The latter was taken up in 15 ml of trimethyl orthoformate under argon and 16 heated in an oil bath at 120 ° for an hour.

After cooling to room temperature, the excess trimethyl orthoformate was removed from the reaction mixture in vacuo and the residue was combined with the above 4.22 g of crude vinyl phosphate. The product was purified by chromatography with 100 L EtOAc over a Merck silica gel column (15 cm length, 5 cm / min.) Yielding 3.70 g (9.99 mg mol, 71% yield) of vinyl phosphonate as peach colored title. gave dust.

35 TLC with 100% EtOAc over silica gel: R = 0.48 (PMA).

XH-NMR: (270 MHz, in CDCl3) δ in ppm: 7.79 (d, 1H, J = 8.4 Hz) 7.72 (s, 1H) 7.56-7.13 (m, 8H) 8801331 .r. > 1 i - 168 - 5.54 (dd, 1H, J = 17.93 Hz, J = 20.6 Hz) 3.57 (d, 6H, J = 11 Hz) 2.54 (s, 3H)

Mass spectrum: m / e = 371 (M + H) + 5 IR (solution in CHCl 3): 3016, 2956, 2857, 1617, 1521, 1500, 1245, 1188, 1162, 1071, 1047 and 834 cm C. Monomethyl ester of (E) -ƒ * 2- [1- (4-Fluorophenyl) -3-methyl-naphthyl-2-ethylenyl.phosphonic acid

10 to 3.60 g (9.72 mgmol) of vinyl phosphonate from part B.

in 23.5 ml of dioxane was added with stirring and under argon 23.32 ml of 1 N LiOH. The mixture was heated at 75 ° in an oil bath for 1 hour. After cooling to room temperature, the solvents were removed under vacuum. The residual residue 15 was diluted with 15 ml of water and, after cooling to 0 ° C, acidified to pH = 1 with 5% aqueous HCl. The water layer was extracted four times with EtOAc. The organic extracts were dried together over MgSO 4, filtered and evaporated to dryness, and the residue was azeotroped twice with benzene and kept under vacuum. This gave 3.38 g (98% yield) of the phosphonic acid monoester by title as a peach substance.

At TLC with CH2Cl2 / MeOH / AcOH 10: 1: 1 over silica gel: Rp = 0.41 (PMA).

1 H NMR: (270 MHz, in CDCl3) 25 δ in ppm: 7.76 (d, 1H, J = 8.4 Hz) 7.68 (s, 1H) 7.47-7.09 (m, 8H ) 5.61 (dd, 1H, J = 18.47 Hz, J = 20.58 Hz) 3.48 (d, 3H, J = 10.96 Hz) 30 2.52 (s, 3H)

Mass spectrum: m / e = 357 (M + H) + IR (solution in CHCl 3): 3025, 3008, 2951, 1614, 1605, 1511, 1494, 1235, 1210, 1188, 1158, 1050, 987 and 833 cm " 1.

35 D. Methyl ester of (Ε) -4-Γ [2- [1- (4-fluorophenyl) -3-methyl-naphthyl-2-jethenyl] methoxyphosphinyl 7-3-ketobutyric acid

To a solution of 3.29 g (9.12 mg mol) of phosphonic acid monoester of Part C in 60 ml of dry CH2 Cl2 was added 3.45 ml (2.65 g, 18.24 mg mol) under argon and with stirring over 10 minutes, 8801331>> r - 169 - distilled trimethylsilyldiethylamine distilled. After stirring at room temperature for 1 hour, the volatile components were removed from the reaction mixture in a rotary evaporator and the residue was kept under high vacuum for 40 minutes. Then that residue was taken up in 25 ml of dry C 1 -C 4 and after cooling to 0 ° C, two drops of dry DMF were added, followed dropwise over 15 minutes by 0.955 ml (1.39 g, 10.94 mgmol) oxalyl chloride . The reaction mixture was stirred at 0 ° C for 20 minutes and for another 10 hours after warming to room temperature. Again the volatiles were removed and kept from the residue under high vacuum. Finally, the residue was taken up in 25 ml of dry THF under argon and after cooling to -78 °, the solution was transferred to a dropping funnel with a cannula and then dripped from there into a solution of dilithium methyl acetoacetate in THF kept at 15 -78 ° for 20 minutes.

(That solution was made up of 397 mg 80% (13.22 mgmol)

NaH in mineral oil, once washed with pentane, dried with a stream of argon and taken up in 20 ml of THF, to which was added 1.33 ml (1.43 g, 12.31 mg mol) of methyl acetoacetate in 10 ml of dry THF.) After the above-mentioned phosphonic acid chloride solution was added at -78 °, stirring was continued at -78 ° for 45 minutes. After quenching with 50 ml of saturated NH 2 Cl solution and warming to room temperature, it was diluted with 50 ml of water and 50 ml of EtOAc. The water layer was extracted once with CH 2 Cl 2 25 and the organic extracts were washed together three times with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated in vacuo to give 4.0 g of a rust-colored foam.

Initial purification by chromatography with 100% EtOAc over Merck silica gel (40 mm diameter column, 5 cm / min.) Gave 2.0 g of slightly crude ketophosphinate as the title orange oil. A further chromatography with EtOAC / hexane 95: 5 on a column of silica gel (30 mm diameter, 5 cm / min.) Gave 1.95 g (4.29 mg mol, 47% yield) of ketophosphinate according to the title as orange foam.

At TLC with 100% EtOAc over silica gel: R = 0.29 (PMA).

1 F H-NMR: (270 MHz, in CDCl3) δ in ppm: 7.78-7.13 (aromatic, olefinic, 10H) 5.62 (dd, 1H, J = 17.93 Hz, J = 25, 84 Hz) βSO 1 33 ί .11 r * A - 170 - 3.71 (s, 3H) 3.63 (s, 2H) 3.48 (d, 3H, J = 11.6 Hz) 3.14 & 3.13 (2 xd, 2H, J = 18.46 Hz) 5 2.44 (s, 3H)

Mass spectrum: m / e = 455 (M + H) + IR; (film): 1749, 1717, 1623, 1614, 1604, 1511, 1328, 1223, 1159, 1031, 834 cm-1.

E. Methyl Ester of (E) -4-C 1- 2- [1- (4-Fluorophenyl) -3-methyl-10-naphthyl-2-Jethenyl-Methoxyphosphinyl J-3-Hydroxybutyric Acid

To 1.28 g (2.82 mgmol) of ketophosphinate according to Part D in 12 ml of dry THF was added 107 mg (2.82 mgmol) of NaBH 4 under argon at 0 ° C, followed dropwise by 2.45 ml of methanol, which was added to 4 lb molecular sieve was dried. The reaction mixture was stirred at 0 ° C for 1 hour and then quenched with 2 ml of acetone. An additional 1.3 g of silica gel CC-4 (from Mallinckrodt) was also added and the reaction mixture was stirred while warming to room temperature. Finally, the suspension was filtered through a sintered glass filter, which was washed twice with EtOAc and twice with post-wash. The filtrates were concentrated to dryness under vacuum to give 1.3 g of an orange foam which crystallized on addition of EtOAc. The product was purified by chromatography with 3% MeOH in a Merck silica gel column (diameter 30 mm, 5 cm / min.).

The product fractions were evaporated to dryness and the residue azeotroped once with benzene to give 653 mg (1.43 mg mol, 51% yield) of the title hydroxyphosphinate as pale yellow. This product was stirred with EtOAc / hexane 7: 3 to give 516 mg of pure hydroxyphosphinate as white matter, m.p. 132-30 134¾0.

At TLC with 4% MeOH in C 2 Cl 4 over silica gel: Rp = 0.38 (PMA). 1 H NMR: (270 MHz, in CDCl3) δ in ppm: 7.79-7.16 (aromatic, olefin, 10H) 5.59 (2 x dd, 1H, J = 17.94 Hz, J = 24, 27 Hz) 35 4.35 & 4.24 (2 xm, 1H) 3.70 (s, 3H) 3.49 & 3.47 (2 xd, 3H, J = 11 Hz) 2.58-2.53 (m, 2H) 2.54 & 2.53 (2 xs, 3H) 40 2.01-1.74 (m, 2fi) 8801331.4, τ - 171 -

Mass Spectrum 457 (M + H) + IR (in KBr): 3422-3382, 3062, 3051, 2951, 2926, 2913, 1738, 1613, 1604, 1511, 1494, 1457, 1438, 1399, 1373, 1330 , 1311, 1307, 1286, 5 1220, 1194, 1177, 1160, 1092, 1077, 1035, 883 and 833 cm-1.

F. Dilithium salt of (E) -4- / "[2- [1- (4-fluorophenyl) -3-methyl-naphthyl-2-jethenyl] -hydroxyphosphinyl, 7-3-hydroxybutyric acid

To 500 ml (1.1 mgmol) of diester of part E in 10.45 ml of dioxane, 3.3 ml of IN LiOR were added under argon. After stirring for 45 minutes at 70 °, the resulting white suspension was dissolved in approx. 100 ml water / methanol 9: 1 and evaporated to dryness in a rotary evaporator at 35 °. The white matter was kept under high vacuum for an additional 1 hour, redissolved in 100 ml water / methanol 9: 1 and concentrated to about 8 ml in a rotary evaporator. This cloudy solution was applied directly to a column of HP-20 (17.5 cm length, 25 mm diameter, equilibrated with water) and eluted first with 250 ml water and then 45:55 with methanol / water. A fraction of about 10 ml was collected every 1.3 minutes. The product fractions were evaporated together in a rotary evaporator at 35 ° C and the residue was taken up in water, freeze-dried for 16 hours and kept at high vacuum for 16 hours. This gave 449 mg (1.02 mg mol, 93% yield) of title lithium dilithium salt as white lyophilization.

At TLC with nPrOH / NH ^ OH / ^ O 7: 2: 1 over silica gel: R ^, = 0.49 (PMA), 25 1 H-NMR: (400 MHz in D20) δ in ppm: 7.73 (d , 1H, J = 8.06 Hz) 7.64 (s, 1H) 7.43-7.39 (m, 1H) 7.25-7.13 (m, 4H) 30 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) 2.22 (dd, Iff, J = 9.16 Hz, J = 15.39 Hz) 35 1.59-1.51 (m, 2H)

Mass spectrum: m / e = 429 (M + H) +, 435 (M + Li) + and 441 (M + 2Li) +.

IR: (in KBr): 3431 (br), 1603, 1593, 1511, 1494, 1423, 1221, 1158 and 1050 cm 8801331 λ * „- 172 -

Elemental Analysis: C 60.60, Η 4.73, F 4.24, Ρ 6.83%;

Calculated for C22H2qFO2 PL ± 2.0.87 1 ^ 0 (MG = 455.94): C 60.60, H 4.80, F 4.17, P 6.79%.

Example LXI

5 Dollthium salt of (S) -Af C 2 -JT 1- (4-fluorophenyl) -3-methyl-naphthyl-2-methylhydroxyphosphinyl, 7-3-hydroxybutyric acid A. Methyl ester of (S) -3- (t- butyldiphenylsilyloxy) -4- [C 2 -C 1- (4-fluorophenyl) -3-methylnaphthyl-2-methynyl] -methoxyphosphinyl] butyric acid 10 Argon was bubbled for 10 minutes through a solution of 675 mg (0.974 mgmol) of acetylene phosphate according to Example LIX. then 270 mg of 10% Pd / C was added and the reaction mixture was shaken with 2.8 ato of hydrogen in a Parr apparatus for 24 hours. The reaction mixture was filtered through a layer of Celite, which was washed with methanol, and the filtrate was evaporated in vacuo to a white foam. The product was purified by chromatography with EtOAc / hexane 70:30 on a Merck silica gel column (13 cm length, 50 mm diameter, 5 cm / min) saturating 556 mg (0.798 mgmol, 82%) of the title phosphinate as white foam.

Elution of the column gave another 101 mg (0.145 mg mol, 15%) of product.

At TLC with EtOAc / hexane 6: 4 over silica gel: R @ 0.24 (PMA). 1 H-NMR: (270 MHz, in CDCl 3) 6 in ppm: 7.78-7.14 (aromatic, 19H) 4.44 (m, 1H) 3.61 (s, 3H) 3.35 & 3, 23 (2 xd, 3H, J = 10.6 Hz) 2.92-2.83 (m, 1H) 30 2.63-2.54 (m, 3H) 2.21-1.27 (m, 4H ) 2.45 & 2.42 (2 xs, 3H) 1.00 (s, 9H)

Mass spectrum: m / e = 697 (M + H) 35 IR (solution in CHCl 3): 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 and 823 cm-1.

8801331 - 173 - * * ί τ Β. Methyl ester of. (S) -4-C C 2- [1- (4-fluorophenyl) -3-methyl-naphthyl-2-methyl-methoxyphosphinyl] -3-hydroxybutyric acid

To 540 mg (0.775 mg mol) of silyl ether according to Part A in 9.45 ml of dry THF was added 0.177 ml (0.186 g, 3.10 mg mol) of glacial acetic acid under argon, and then 2.1 ml of 1.1 Μ (2, 33 mg mol) tetrabutyl ammonium fluoride in THF. The reaction mixture was stirred at room temperature for 16 hours and then quenched with 30 ml of ice water and diluted with EtOAc. The water layer was extracted three more times with EtOAc. The organic extracts were washed together once with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and evaporated in vacuo.

A first purification by chromatography with 4%

MeOH over a Merck silica gel column (15 cm length, 40 mm diameter, 5 cm / min) gave 400 mg of white matter. This material was stirred with 100% hexane, filtered and held under high vacuum for 8 hours to give 317 mg (0.691 mgmol, 89%) of the title hydroxy phosphinate as a white matter, m.p. 120-122 °.

TLC with 2% MeOH in CH 2 ^ on silica gel: R 2 0.12.

20 1 H NMR: (270 MHz, in CDCl 3) δ in ppm: 7.76 (d, 1H, J = 7.9 Hz) 7.69 (s, 1H) 7.42-7.16 (m, 7H ) 4.42 & 4.26 (2 xm, 1H) 25 3.92 & 3.84 (2 xd, 1H, J = 3.16 Hz) 3.72 (s, 3H) 3.58 & 3.54 (2 xd, 3H, J = 3.69 Hz) 2.89-2.76 (m, 2H) 2.56 (s, 3H) 30 2.63-2.41 (m, 2H) 1.92- 1.61 (m, 4H)

Mass spectrum: m / e = 459 (M + H) + IR: (in KBr): 3428 (br), 3287 (br), 3064, 3050, 3017, 2989, 2952, 2921, 35 1737, 1603, 1510, 1497 , 1458, 1438, 1234, 1221, 1191, 1175, 1159, 1042, 826 cm-1.

C. Dilithium salt of (S) -4-f [2- - * 1- (4-fluorophenyl) -3-methylnaphthyl-2-methylhydroxyphosphinyl, 7-3-hydroxybutyric acid To 315 mg (0.687 mgmol) diester of part B in 6.9 0801331 J * X τ - 174 ml dioxane was added 2.06 ml 1 N L10H under argon and with stirring. The reaction mixture was heated in an oil bath at 70 ° C for 45 minutes and then cooled to room temperature. The solvents were removed in a rotary evaporator at 35 ° C and the residual white matter was kept under high vacuum for 1 hour. The substance was now dissolved in about 8 ml of distilled water and placed on a column of HP-20 (16 cm length, 25 mm diameter and equilibrated with water). The column was first eluted with 250 ml of water and then with methanol / water 55:55.

A fraction of about 10 ml was collected every 1.4 minutes.

The product fractions 37 to 47 were combined and evaporated to dryness in a rotary evaporator at 35 ° C, then lyophilized for 16 hours and finally kept under high vacuum over P2O2 Se_ for 8 hours. There was thus obtained 286 mg (0.647 mg mol, 94%) of di-15 lithium salt as title white freeze-dried.

At TLC with nPrOH / NH.0H / HoO 7: 2: 1 over silica gel: R_ = 0.42 (PMA).

1 4 L Γ ^ H-NMR: (400 MHz, in D20) δ in ppm: 7.82 (d, 1H, J = 8.06 Hz) 7.76 (s, 1H) 20 7.46-7, 42 (m, 1H) 7.30-7.25 (m, 3H) 7.18-7.13 (m, 3H) 4.06 (m, 1H) 2.72-2.66 (m, 2H) 2.54 (s, 3H) 2.34 (dd, 1H, J = 4.4 Hz, J = 15.22 Hz) 2.22 (dd, 1H, J = 8.43 Hz, J = 15, 02 Hz) 1.59-1.51 (m, 2H) 1.44-1.39 (m, 2H) 30 Mass spectrum: m / e = 443 (M + H) *

Ir: (in KBr): 3451-3426 (br), 3151, 3124, 1620, 1593, 1509, 1439, 1422, 1403, 1218, 1159, 1050 cm -1.

Elemental analysis: C 60.96, H 5.29, F 4.12, P 6.82%; Calculated for C25H22FO5PL1 2 * 0.6 ° H 2 O (MG = 453.09): C 60.96, H 5.16, F 4.19, P 6.83%.

8801331 -¾, ï.

- 175 - Example LXII

Dilithium salt of h- [[3- (4 * -fluoros-3,3 ', 5-trimethyl-bipheny-lyl-2) -propyl] -hydroxyphosphinyl, 7-3-hydroxybutyric acid A. Ethyl ester of 3- (4 * -fluoro-3 , 3 ', 5-trimethylbiphenylyl-2) -5 acrylic acid

Under argon, 149 mg of 80% sodium hydride in mineral oil (119 mg pure, 4.96 mg mol) was washed once with hexane and dried with a stream of argon. 9.1 ml of dry THF was then added. This suspension was cooled to 0 ° C and a solution of 0.983 ml (1.11 g, 4.96 mgmol) of triethylphosphonoaeetate in 2.2 ml of dry THF was added over 5 minutes. The resulting clear solution was stirred at 0 ° C for 15 minutes and an additional 30 minutes after warming to room temperature. Finally, 1.0 g (4.13 15 mgmol) aldehyde of part C in 2.5 ml THF was added dropwise over 8 minutes. The reaction mixture was stirred at room temperature for 1 hour and then quenched with water; the water layer was washed twice with EtOAc in twice with 100 ml. The organic extracts were washed together once with brine, dried over MgSO4, filtered and evaporated in vacuo. The product was purified by chromatography with 6% EtOAc in hexane on a Merck silica gel column (50 mm diameter, 5 cm / cm xn.) To give 1.19 g (3.79 mg mol, 92%) of the vinyl ester as pale yellow foam gave.

At TLC with 4% EtOAc in hexane over silica gel: R 2 0.22.

1 H NMR (270 MHz, in CDCl 3) 6 in ppm: 7.64 (d, 1H, J - 16.35 Hz) 7.09-6.93 (m, 5H) 5.81 (d, 1H, J = 16.35 Hz) 30 4.17 (q, 2H, J = 7.12 Hz) 2.42 (s, 3H) 2.33 (s, 3H) 2.28 (s, 3H) 1.25 ( t, 3H, J = 7.12 Hz). Mass spectrum: m / e = 313 (M + H) +.

B. Ethyl ester of β- (41-fluoro-3,3F, 5-trimethylbiphenylyl-2) -propionic acid

Argon was bubbled through a solution of 1.15 g (3.68 mgmol) of vinyl ester of part A in 8801331 λ · r 1 - 176 - 36 ml of absolute ethanol for 10 minutes. Then 230 mg of 10% Pd / C was added and hydrogen was bubbled through the solution for 10 minutes.

This mixture was stirred for an additional 2 hours under a hydrogen atmosphere and then diluted with alcohol and filtered through 13 ml of Celite in a glass funnel beaker. The Celite was washed with ethanol. The filtrates were evaporated together under vacuum to give 1.12 g (3.56 mg mol, 97% yield) of the saturated ester of the title as a white solid.

At TLC with 5% EtOAc in hexane over silica gel: R 2 0.29 (PMA). 10 ^ -NMR (270 MHz, in CDCl3) δ in ppm: 7.09-6.97 (m, 4H) 6.84 (s, 1H) 4.06 (q, 2H, J = 7.12 Hz) 2.90-2.84 (m, 2H) 15 2.37 (s, 3H) 2.30 (2 xs, 6H) 2.32-2.27 (m, 2H) 1.20 (t, 3H, J = 7.12 Hz)

Mass spectrum: m / e = 315 (M + H).

C. 4'-fluoro-2- (3-hydroxypropyl) -3,31,5-trimethylbiphenyl

Under argon a solution of 1.1 g (3.5 mgmol) ester of part B in 3 was added over 8 minutes to a suspension of 133 mg (3.5 mgmol) lithium aluminum hydride in 3.5 ml dry Et30 cooled to 0 ° C. .5 ml of dry Et30 were dropped. The reaction mixture was stirred at 0 ° C for 15 minutes and an additional 45 minutes after warming to room temperature. After the mixture was again cooled to 0 ° C, 0.133 ml of water was added dropwise, then 0.133 ml of 15% NaOH and finally 0.399 ml of water. The suspension was allowed to warm to room temperature over 30 minutes.

The resulting solid was filtered off and washed with dry ether. The filtrate was concentrated and the residue azeotroped once with benzene and dried under vacuum to give 950 mg of alcohol, which was purified by chromatography with EtOAc / hexane 35:65 on a column of silica gel of Merck 35 (15 cm length, 50 mm diameter, 5 cm / min.) To give 906 mg (3.33 mg mol, 95%) of the title alcohol as a colorless oil.

At TLC with EtOAc / hexane 1: 4 over silica gel: Rp = 0.18 (PMA). 1 H-NMR (270 MHz, in CDCl3) δ in ppm: 7.08-6.93 (m, 4H) - 8801331 - 177 - 1 »τ 6.82 (s, 1Η) 3.45-3.40 (m , 2H) 2.60-2.54 (m, 2H) 2.34 (s, 3H) 5 2.28 (2 xs, 6H) 1.63-1.52 (m, 2H)

Mass spectrum; m / e = 273 (M + H) + D. 2- (3-bromopropyl) -4T-fluoro-3,31,5-trimethylbiphenyl

To a solution of 2.65 g of 10.810.1 mg mol) of triphenylphosphine in 27.5 ml of dry THF cooled to 0 ° C, a solution of 3.55 g (10.71 mgmol) of CBr ^ in 5.5 ml of dry THF dripped. The resulting yellowish-white suspension was stirred at 0 ° C for 2 hours. A solution of 1.1 g (4.04 mg mol) of alcohol of part C in 8.2 ml of dry THF was now added dropwise to the complex. The reaction mixture was stirred at 0 ° C for 1 hour and for another 16 hours after warming to room temperature. The mixture was then diluted with ether and filtered through a sintered glass filter. The precipitate was washed with ether and the filtrates were washed together once with brine, dried over MgSO 4, filtered and evaporated in vacuo. The product was purified by chromatography with 2% EtOAc in hexane on a Merck silica gel column (15 cm length, 50 mm diameter, 5 cm / min.) To give 1.35 g (4.05 mg mol, 100% yield). title bromide as pale yellow oil.

At TLC with 100% hexane over silica gel: Rw = 0.22 (PMA).

1 * H NMR (270 MHz in CDCl3) δ in ppm: 6.99 (m, 4H) 6.82 (s, 1H) 3.22 (m, 2H) 30 2.69-2.63 (m, 2H) 2.36 (s, 3H) 2.30 (s, 3H) 2.28 (s, 3H) 1.90-1.80 (m, 2H) 35 Mass spectrum: m / e = 235 (M + H) + .

E. Dimethyl ester of [3- (4 * -fluoro-3,3 ", 5-trimethylbiphenyl-2-yl) propylphosphonic acid

A mixture of 1.3 g (3.88 mgmol) of bromide of Part D and 38.8 ml of trimethyl phosphite was refluxed in an oil bath at 135 ° C under argon and under 40 reflux for 36 hours. The 8801331

-f I

- 178 - excess of trimethylphosphite was removed by short-way distillation and the residue was kept at 100 ° C for 1 hour under high vacuum. The leftover yellow oil underwent purification by chromatography with EtOAc / hexane 85:15 on a column of Merck silica gel 5 (length 15 cm, diameter 50 mm, 5 cm / min.), Giving 1.13 g (3.10 mgmol, 80%). yield) dimethylphosphonate by title as a colorless oil.

At TLC with 100% EtOAc over silica gel: R @ 0.28 (PMA).

XH-NMR (270 MHz, in CDCl3) 106 in ppm: 7.08-6.97 (m, 4H) 6.81 (s, 1H) 3.65 (d, 6H, J = 11 Hz) 2.63- 2.56 (m, 2H) 2.34 (s, 3H) 15 2.30 (2 xs, 3H) 2.28 (s, 3H) 1.68-1.50 (m, 4H)

Mass spectrum: m / e = 365 (M + H) +.

F. Monomethyl ester of Γ S - ^ '- fluoro-SjS', 5-trimethylbiphenyly 1-2) -20 propylphosphonic acid

To 1.25 g (3.43 mgmol) of phosphonate according to Part E in 8.23 ml of dioxane, 5.15 ml of 1 N LiOH was added under argon, followed by heating in an oil bath at 95 °. After 1 hour, a further 3.42 mgmol LiOH was added and boiling was continued for 3 hours.

The reaction mixture was then cooled to room temperature and the solvents were removed from it. The solid white residue was diluted with 25 ml of water and after cooling the suspension was acidified to pH = 1 with 5% HCl in water. The water layer was extracted four times with EtOAc and the organic extracts were dried together over MgSO4, filtered and concentrated.

The residue was azeotroped twice with benzene and the residual viscous oil was kept under high vacuum for 4 hours. This gave 1.18 g (3.37 mg mol, 98%) of phosphonic acid monoethyl ester as a yellow oil.

At TLC with CHoClo / Me0H / Ac0G 10: 1: 1 over silica gel: R = 0.46 Z Z r (PMA).

^ -NMR (270 MHz, in CDCl ^ δ in ppm: 7.06-6.95 (m, 4H) 6.81 (s, 1H) ^ 3.56 (d, 3H, J = 11 Hz) 8801331 - 179 - *. ·. * Τ 2.62-2.53 (m, 2H) 2.32 (s, 3H) 2.27 (2 xs, 6H) 1.69-1.48 (m, 4H) 5 Mass spectrum: m / e = 351 (M + H) +.

G. Methyl ester of 4 - / * C 3- (4-Fluoro-3,3 ', 5-trimethylbiphenylyl-2-2) propyl methoxyphosphinyl 7-3-ketobutyric acid

To 1.13 g (3.22 mgmol) of phosphonic acid monoester of part F in 12.9 ml of dry CÜC1 Cl ^ was added 1.20 ml (918 mg, 6.44 mgmol) of freshly distilled trimethylsilyl under argon over 8 minutes. - drop diethylamine. After stirring at room temperature for 1 hour, the volatiles were removed under vacuum (contact with argon) and the residue was azeotroped once with 70 ml of dry benzene (vacuum removed with argon). Finally, the residue was kept under high vacuum for 50 minutes.

Now the residue was stirred under argon with 12.9 ml of dry CH 2 Cl 2, 2 drops of dry DMF were added and, after cooling to 0 ° C over 8 minutes, 0.323 ml (0.470 g, 3.70 mg mol) of oxalyl chloride became when dripped. The reaction mixture was stirred at 0 ° C for 20 minutes and an additional 105 minutes after warming to room temperature. The volatiles were removed and the residue was azeotroped as above and kept under high vacuum.

The rust-colored oil was then stirred under argon with 9.0 ml of dry THF and after cooling to -78 °, a solution of the dianion of methyl acetoacetate of -78 ° was added dropwise over 20 minutes. (This solution was prepared according to Part D of Example LX from 0.471 ml (506 mg, 4.36 mg mol) methyl acetoacetate, 145 mg 80% NaH and 10 ml THF.) The reaction mixture was stirred at -78 ° for 1 hour and then with 45 ml of saturated NH 2 Cl solution quenched. After warming up to room temperature, it was diluted with 45 ml of water and with EtOAc. The water layer was extracted four times with EtOAc. The extracts were washed together once with saturated NaHCO 2 solution and once with brine, dried over MgSO 2, filtered and dried in vacuo to give 2.0 g of rust oil. The product was isolated by chromatography on a Merck silica gel column (diameter 40 mm, 5 cm / min.) First with 100% EtOAc and then with 5% MeOH in C 2 Cl 2 - This gave 220 mg (0.491 mgmol, 8801331). t * t - 180 - 15%) β-ketophosphinate according to the title as a rust-colored oil.

At TLC with 100% EtOAc over silica gel: R_ = 0.19 (PMA).

1 F H-NMR (270 MHz, in CDCl3) δ in ppm: 7.08-6.98 (m, 4H) 5 6.81 (s, 1H) 3.73 (s, 3H) 3.65 (d , 3H, J - 11 Hz) 3.64 (s, 2H) 3.10 (dd, 2H, J = 5.27 Hz, J = 17.41 Hz) 10 2.67-2.57 (m, 2H ) 2.35 (s, 3H) 2.30 & 2.28 (2 xs, 3H) 2.29 (s, 3H) 1.72-1.56 (m, 4H) 15 Mass spectrum: m / e = 449 (M + H) +.

H. Methyl ester of k- [[3- (4-fluoro-3,3l, 5-trimethylbiphenylyl-2) -propyl] methoxyphosphinyl J-3-hydroxybutyric acid.

Under stirring and argon, 8 mg of 20 (0.223 mgmol) of NaBH 4 was added to 100 mg (0.223 mgmol) of β-ketophosphinate of Part G in 1.9 ml of dry THF at 0 ° C, followed by 0.194 ml of methanol passed through a molecular sieve of Was dried 4%. After stirring at 0 ° C for 1 hour, the reaction mixture was quenched with 0.194 ml of acetone, to which 100 mg of silica gel CC-4 (from Mallinckrodt) was then added. The suspension was allowed to warm to room temperature with stirring, which was then filtered through a sintered glass filter. Silica was washed with EtOAc. The filtrates were evaporated in vacuo to give 108 mg of golden oil. Chromatography with 4% MeOH in a Merck silica gel column (diameter 10 mm, 5 cm / min.) Isolated two reaction products from it: 58 mg (0.129 mgmol, 58%) 8-hydroxyphosphinate as title pale yellow oil and 19 mg (0.043 mg mol, 20%) of 2,4-dihydroxy-butane phosphinate.

At TLC with 3.5% MeOH in over silica gel: Rp = 0.19 (PMA).

1 H-NMR (270 MHz, in CDCl3) δ in ppm: 7.08-6.98 (m, 4H) 6.82 (s, 1H) 4.44 & 4.32 (2 xm, 1H), 8801331 - 181 - * '' τ 3.63 & 3.62 (2 xd, 3H, J = 10.55 Hz) 3.70 (s, 3H) 2.65-2.50 (m, 4H) 2.35 ( s, 3H) 5 2.30 (2 xs, 3H) 2.29 (s, 3H) 1.89-1.76 (m, 2H) 1.71-1.59 (m, 4H)

Mass spectrum: m / e = 451 (M + H) * 10 I. Dilithium salt of 4 - / * C 3 - (41-fluoro-3,3 *, 5-trimethyl-biphenylyl-1-2) propylhydroxyphosphinyl] -3-butyric acid

Under argon was added to 55 mg (0.122 mgmol) diester of part H in 2 ml dioxane 0.366 ml 1 N LiOH. The reaction mixture was heated to 80 ° C under argon and with stirring in an oil bath for 45 minutes. After cooling to room temperature, the solvents were removed in a rotary evaporator. The leftover yellow matter was kept under high vacuum for 2 hours to give the title dilithium salt as yellow matter.

At TLC with (H 2 Cl 2 / MeOH / AeOH 8: 1: 1 over silica gel: = 0.29 (PMA).

1 H-NMR (270 MHz, in D20) δ in ppm: 7.08-7.05 (m, 4H) 6.80 (s, 1H) 4.13 (m, 1H) 25 2.54-2.47 (m, 2H) 2.38-2.28 (m, 2H) 2.30 (s, 3H) 2.22 (s, 3H) 2.20 (s, 3H) 30 1.59-1.50 ( m, 2H) 1.42-1.29 (m, 4H).

Example LXIII

Dilithium salt of lS-f l <a (R *), 2 <a, 4a <b, 8 <b, 8a <a 7 J-4-f28- (2,2-dimethyl-1-oxobutoxy) decahydro -2-methylnaphthyl-1J-35 ethyl Jhydroxyphosphinyl-3-hydroxybutyric acid A. 1S- (1 <a, 2 <a, 4a <b, 8 <b, 8a <a) -8- (t-butyldimethylsilyloxy) -1- hydroxymethyl-2-methyl-1,2,4a, 5,6,7,8,8a-octahydro-naphthalene

To 132 mg (1 mol.eq.) of lithium aluminum hydride in 8601331 4 J <- 182 - 5 ml of dry Et ^ 0 at 0 ° C (ice bath) 1.175 g (3.47 mgmol) of methyl ester of / lS- (1 <a .2 <a, 4a <b, 8 <b, 8a <a) / "/ / (1,1-dimethylethyl) -dimethylsilyl 7oxy 7-2-methyl-1,2,4a, 5,6,7 8.8a-octahydro-naphthalene-1-carboxylic acid (see RL Funk et al in 5 Tetrahedron Lett. 25 (1984) 1655) in 5 ml dry Et 2 O and the gray suspension was stirred under argon overnight. The mixture was quenched by adding successively 130 µl water, 130 µl 15% NaOH and 390 µl water. The precipitated salts were removed by filtering over MgSO4 10 on a pad of Celite. Evaporation to dryness under vacuum gave 1.112 g of a clear oil which was purified by chromatography with 5% EtOAc in hexane on silica gel to give 902 mg (85.7%) of the desired alcohol as a clear oil which crystallized on storage, m.p. 79-81 °.

At TLC with hexane / EtOAc 9: 1: R i = 0.21.

Elemental analysis: C 69.64, H 11.04%;

Calculated for C 16 H 16 Si: C 69.61, H 11.04%.

1 H NMR (in CDCl 3) 20 δ in ppm: 0.00 (s, 6H) 0.82 (s, 9H) 0.83 (d, 3H) 0.94-1.0.5 (m, 2H) 1, 18 (s, 1H) 25 1.2-1.42 (m, 2H) 1.67 (m, 3H) 1.89 (m, 1H) 2.25 & 2.37 (2H, 2 multiplets) 3, 42 (bt, 1H) 30 3.80 (dd, 1H) 3.93 (bs, 1H) 5.29 (d, 1H) 5.48 (dq, 1H).

B. 1-formyl - / * 1S - (1 <a, 2 <a, 4a <b, 8 <b, 8a <a) J-8- (t-butyldimethyl-35 silyloxy) -2-methyl-1, 2.4a, 5,6,7,8,8a-octahydronaphthalene

To a solution of 895 mg (2.11 mgmol) perjdinane of Dess-Martin in 6 ml dry was added 200 µl dry t-C 1 H 2 OH and the white suspension was stirred at room temperature under argon for 15 minutes. Over 5 minutes, a solution of 596 mg (1.92 mgmol) in 6 ml was dripped dry and the mixture was stirred at room temperature for another 20 minutes under argon. Now the mixture was poured into

a solution of 2.12 g of sodium thiosulfate in 12 ml of 1.0 N

NaHCOg and that mixture was stirred until all dust had dissolved. The organic phase was drained and washed with saturated NaHCO 2 solution, with water and brine, dried over Na 2 SO 4 and evaporated in vacuo to give 1.005 g of colorless oil.

The crude product was combined with a smaller portion of 10 previously obtained (1.306 g in total) and then purified by chromatography with 2% EtOAc in hexane on silica gel.

The product fractions were evaporated to dryness under vacuum to give 667 mg (75.7%) of the title aldehyde as a colorless oil.

TLC with hexane / Eto7 7: 3: R = 0.70 (PMA).

1 2 F

15 H NMR (in CDCl ^ δ in ppm: 0.07 (s, 3H) 0.00 (s, 3H) 0.85 (s, 9H) 0.89 (d, 3H) 20 0.93-1 .10 (m, 2H) 1.38-1.52 (m, 2H) 1.58-1.78 (m, 4H) 2.31 (m, 1H) 2.66 (m, 1H) 25 2, 78 (m, 1H) 4.30 (s, 1H) 5.40 (d, 1H) 5.50 (m, 1H) 9.74 (d, 1H) 30 C. [lS- (l <a, 2 <a, 4a <b, 8 <b, 8a <a) 7 ~ 1 ~ (2,2-dibromoethenyl) -8- (t-butyldimethylsilyloxy) -2-methyl-1,2,4a, 5,6,7 , 8,8a-octahydronaphthalene

In a solution of the 767 mg (2.16 mg mol) aldehyde of part B and 1.7 g (6.48 mg mol) of triphenylphosphine in 10 ml, a solution of 1.7 g (6.48 mg mol) was dried over 5 minutes. 5 ml dropwise and the deep reddish brown solution was stirred at -15 ° C for 30 minutes under argon, then at 0 ° C for 2 hours and finally at room temperature overnight. After cooling again to 0 ° C, an additional 567 mg (2.16 mg mol) 8801351 X 'J was added.

184 triphenylphosphine and 358 mg (1.08 mg mol) CBrr were added, followed by stirring at room temperature for 4 hours. The mixture was quenched with 10 ml of saturated NaHCO4, diluted and filtered through sintered glass. The organic phase was washed with 5 saturated NaHCO 2 and with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 3.578 g of a brown solid. The crude product was purified by pure hexane chromatography on silica gel. From the product fractions, 677 mg (67.3%) of pure vinyl dibromide of the title was obtained as a colorless oil by evaporation to dryness.

At TLC with hexane / acetone 9:11: R ^ 0.73 (UV and PMA).

^ -NMR (in CDClj) δ in ppm: 0.08 & 0.10 (2 singlets, 6H) 0.85 (d, 3H) 15 0.90 (s, 9H) 0.98 (m, 2H) 1 .25-2.52 (m, 5H) 1.74 (m, 1H) 1.82 (m, 1H) 20 2.39 (m, 1H) 2.56 (m, 1H) 2.66 (m, 1H) 3.95 (s, 1H) 5.48 (d, 1H) 5.52 (m, 1H) 6.37 (d, 1H).

D. C 1S- (1 <a, 2 <a, 4a <b, 8 <b, 8a <a) 7-8- (t-butyldimethylsilyloxy) -1-ethynyl-2-methyl-1,2,4a, 5,6,7,8,8a-octahydronaphthalene At -78 °, 1.34 ml of 1.6 M (2.14 mg mol) n-BuLi 30 in hexane was added dropwise to the solution of 495 mg (1.07 mgmol) vinyl dibromide of part C in 6 ml of dry THF and the clear, colorless mixture was stirred at -78 ° under argon for 30 minutes and then quenched by adding 5 ml of saturated NH 2 Cl. After warming to room temperature, the EtOAc was diluted and the organic phase was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 291 mg (89.6%) of crude acetylene of the title as colorless oil.

At TLC with hexane: R = 0.43 (UV and PMA).

1 F H-NMR (in CDC13), 8801331 - 185 - * '' f δ in ppm: 0.08 & 0.12 (2 singlets, 6H) 0.90 (s, 9H) 0.99 (m, 1H ) 1.09 (d, 3H) 5 1.19 (m, 1H) 1.46 (m, 2H) 1.74 (m, 3H) 2.12 (d, 1H) 2.30 (m, 1H) 2.41 (m, 1H) 2.71 (m, 1H) 4.37 (m, 1H) 5.38 (d, 1H) 5.55 (m, 1H).

15 E. Methyl ester of (S) -4- (chloromethoxyphosphinyl) -3- (t-butyldiphenylsilyloxy) butyric acid

Phosphonic acid chloride was prepared from the dicyclohexylammonium salt of Example XXV Part B as follows. The acid was liberated from 1.3 g (2.05 mgmol) of dicyclohexylammonium salt by distributing it between EtOAc and 5% KHSO 2 solution, washing the organic layer four times with 5% KHSO 2 and with brine and then dry on ^ £ 80 ^ and evaporate to dryness. The phosphonic acid monomethyl ester (2.05 g mgmol, a clear viscous oil) was taken up in 5 ml dry and to this was added 515 µl (4.1 mgmol) distilled N, N-diethyl trimethylsilylamine at room temperature under argon 25. After stirring for 1 hour, excess reagent and solvent were removed under vacuum and the residual oil was azeotroped twice with 10 ml of benzene.

At 0 ° C was added to this ca 2.05 mg mole crude silyl ester 30 in 5 ml dry GH 2 Cl 4 and one drop of dry DMF 195 11 11 (2.26 mg mol) distilled oxalyl chloride and the yellow mixture was heated to 0 for 15 minutes under argon ° C and then at room temperature for 45 minutes. The mixture was evaporated to dryness under vacuum and azeotroped twice with 10 ml of benzene to give the crude phosphonic acid chloride as a viscous yellow oil.

F. Methyl ester of C IS - / * 1 a (R *), 2 <a, 4a <b, 8 <b, 8a <a7J-4-Z ^ Z ~ 8- (t-butyl dimethylsilyloxy) -2-methyl- 1,2,4a, 5,6,7,8,8a-octahydro-naphthyl-1-ethynyl-methoxyphosphinyl-S-Ct-butylsilyloxy-butter “acid 40 At -78 °, 730 1111 1.6 M (1.17 mgmol) n -BuLi in 8801331 * Λ * - 186 - hexane was dropped into a solution of 356 mg (1.17 mg mol) acetylene of part D in 5 ml of dry THF and the clear mixture was stirred at -78 ° under argon for 30 minutes. The acetylene salt was then dropped by cannula over a 15 minute solution of the phosphonic acid chloride of Part E in 6 ml of dry THF held at -78 °. The yellow mixture was stirred at -78 ° for 30 minutes and then quenched by dripping 5 ml of saturated NH 2 Cl, and allowed to warm to room temperature. The mixture was partitioned between EtOAc and water and the organic phase 10 was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 1.282 g of pale yellow oil. The crude product was purified by chromatography with hexane / EtOAc 7: 3 on silica gel. The product fractions were evaporated to dryness to give 624 mg (72.4%) of the title acetylene phosphinate as colorless glass.

At TLC with hexane / acetone 7: 3: = 0.49 (UV and PMA).

G. Methyl ester of C IS-C 1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a J (8-t-butyldimethylsilyloxy) -2-methyldecahydronaphthyl-1 J -ethyl ^ methoxyphosphinyl J-3- (t-butyldiphenylsilyloxy) butyric acid 20 To a solution of 498 mg of acetylene phosphinate of part F in 6 ml of methanol was added 200 mg of 10% Pt / C and the black suspension in a Parr apparatus with 28 atoms of hydrogen for 48 hours. shaken. The catalyst was filtered over Celite, the reaction mixture was given 150 mg of fresh catalyst and shaken with 2.8 atmospheres for another 24 hours in the Parr apparatus.

The catalyst was filtered through Celite and the filtrate evaporated to dryness under vacuum to give 448 mg of clear glass. This crude product was purified by chromatography with hexane / EtOAc 8: 2 on silica gel. The product fractions gave, on evaporation in vacuo, 334 mg (66.5%) of the title compound as a colorless gas.

On TLC with EtOAc / hexane 7: 3, three diastereomers gave a single spot with R = 0.42; a fourth diastereomer had a Γ R = 0.49 (UV and PMA).

Γ H. Methyl ester of ζ lS-jT 1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a J J-4- 35 CC 2- (8-hydroxy-2-methyl decahydronaphthyl- l) ethyl Jmethoxyphosphinyl J-3- (t-butyldiphenylsilyloxy) butyric acid

To a solution of 248 mg (0.334 mgmol) compound of Part G in 4 ml of acetonitrile was added 36 µl of 48% HF in ^ 0 (1 mgmol) and that mixture was stirred under argon at 8801331 - 187 - * * * τ for 6 hours. stirred at room temperature. The mixture was then partitioned between EtOAc and saturated NaHCO 2 and the organic phase was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 227 mg of colorless glass. The crude product was purified by silica gel chromatography, first with hexane / EtOAc 4: 1 and then with pure EtOAc. The product fractions gave, under vacuum drying, 159 mg (75.8%) of pure monoalcohol as the title as a colorless oil.

At TLC with acetone / hexane 7: 3: R ^ = 0.5 (weak under UV, also f10 with PMA).

I. Methyl ester of [IS - / - 1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a J J-3- (t-butyldiphenylsilyloxy) -4 - / * [Ï- C 8- (2,2-dimethyl-1-oxo-butoxy) -2-methyl-decahydronaphthyl-1-methyl-7-methoxyphosphinyl-7-butyric acid 15 To a solution of 147 mg (0.234 mgmol) of Part H alcohol in 1.5 ml of dry pyridine, 160 - 1 x (1.17 mg mol, 5 eq.) 2,2-dimethylbutyryl chloride was added, then 3 mg (0.1 eq.) 4-dimethylaminopyridine, and the pale yellow mixture was heated to 100 ° C under argon for 4 hours. After cooling, the mixture was partitioned between 1 N HCl and EtOAc, and the organic phase was washed twice with 1 N HCl and brine, dried at 50 ^ and evaporated to give 255 mg of pale tan oil.

The crude product was purified by chromatography with hexane / EtOAc 55:45 on silica gel. Evaporation of product fractions under vacuum gave 112 mg (65.9%) of dimethylbutyric acid ester by title as colorless oil.

At TLC with hexane / acetone: Rp = 0.62 (UV and PMA).

J. Methyl ester of? IS - / * l <a (R *), 2 <a, 4a <h, 8 <b, 8a <aJ J-4- [C 2 ~ C 8- (2,2- dimethyl-1-oxobutoxy) -2-methyl-decahydro-30-naphthyl-1 J ethyl-7-methoxyphosphinyl, 7-3-hydroxybutyric acid

To a solution of 130 mg (0.179 mgmol) of silyl ester according to Part I in 2 ml of THF were added 41 µl (0.716 mgmol) glacial acetic acid and 490 µl 1.1 M (0.537 mgmol) (nC ^ H ^) ^ NF in succession. THF was added and that mixture was stirred under argon overnight. Then the mixture was partitioned between EtOAc and 5% KHSO 2 solution and the organic phase was washed with water and brine, dried over Na 2 SO 4 and evaporated in vacuo to give 115 mg of colorless oil. The crude product was purified by chromatography with hexane / acetone 1: 1 on silica gel. Drying vapors 880133.1 1 '-1' - 188 - of the product fractions gave 72 mg (82.4%) of the alcohol as title colorless oil.

TLC with hexane / acetone 1: 1: = 0.20 UV and PMA).

K. Dilithium salt of C IS - / "1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a J J-4-5 [C 2- [8- (2, 2-dimethyl-1-oxobutoxy) -2-methyldecahydronaphthyl-1-7ethyl Jhydroxyphosphinyl J-3-hydroxybutyric acid

To a solution of the 72 mg (0.147 mg mol) alcohol of Part J in 1.5 ml of dioxane, 0.52 ml of 1.0 N LiOH was added and that mixture was heated at 55 ° for 1 hour under argon in an oil bath. After cooling, the water was diluted, filtered and evaporated to an oil in vacuo. The crude product was chromatographed on a column of HP-20 (length 3 cm, diameter 15 mm), first with pure water and then with water / methanol 7: 3. Evaporation of the product fractions under vacuum, redissolving in 20 ml of water and lyophilization gave 55 mg (74%) of the desired dilithium salt as white matter.

At TLC with CH2Cl2 / CH3OH / AcOH 8: 1: 1: Rj = 0.05 (PMA). Elemental analysis: C 54.75, H 8.64, P 5.93%;

Calculated for c23H3907PLi2 · 1.78 H2O (MG = 504.53); C 54.75, H 8.50, P 6.14%.

Example LXIV

Dilithium salt of (S) -4-yd CC 3, - (4-fluorophenyl) -spiro-C cyclopentane (1,1) indenyl-2-ethynylhydroxyphosphinylJ-3-hydroxybutyric acid 25 A. 3- (4-fluorophenyl) - 1H-indene

Under argon and at room temperature, a solution of 4-fluorophenylmagnesium bromide (made up of 6.43 ml of 4-fluorobromobenzene and 1.71 g of magnesium in 50 ml of ether) was dissolved over 40 minutes in a solution of 6.61 g (50 mgmol) of indanone. 1 in 30 ml of dry ether are added. After stirring for 1 hour at room temperature, the reaction mixture was quenched by dripping 15 ml of saturated NH 2 Cl solution. The mixture was diluted with ether, washed with saturated NaCl solution, dried over MgSO 4 and evaporated to dryness.

The residue was taken up in 15 ml glacial acetic acid and refluxed for 30 minutes under argon. The acetic acid was evaporated and what was left was azeotroped twice with toluene. The 9.45 g of residue was purified by chromatography with hexane on silica gel to give 8.174 g (78%). 8801337-189-4 "title compound as a colorless oil which crystallized on storage; mp 38-40 °.

In TLC with hexane: R = 0.21.

B. S-3-Fluorophenyl-spiro / * cyclopentane (1.1) indene 7 5 To a solution of 10.676 g (50.8 mgmol) of Compound A in 90 ml of dry THF was added under argon and at 0 ° C 12.2 g (109 mgmol) of solid potassium t-butylate were added in portions. After stirring at 0 ° C for 30 minutes, 6.50 mg (101 mg mol) of 1,4-dibromobutane was added dropwise. This mixture was stirred for 2 hours while warming to room temperature, then it was partitioned between 150 EtOAc and 150 ml 5 Z KHSO 2 solution. The organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and evaporated to dryness. The crude product was purified by chromatography with hexane on silica gel to give 9.43 g (70%) of the title compound as a colorless oil.

DLC with Eto0 / hexane 1: 9: R_ = 0.69 (the R of the starting material Δf Γ is 0.63).

C. 3l- (4-fluorophenyl-21-formylspiro- / cyclopentane (1,1) indene J

To a solution of 9.30 g (35.2 mgmol) compound of part B in 50 ml dry was added under argon and 70 ml 1.0 M TiCl 2 at 0 ° C. To the now dark green solution, 3.50 ml (38.7 mgmol) of methyl 1,1-dichloromethyl ether was added dropwise. After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the mixture was poured into cold saturated NaHCO 2 solution. The organic phase was separated, dried over Na 2 SO 4 and evaporated to dryness. The crude product was purified by chromatography with 5 Z Et 2 O in hexane on silica gel to give 8.233 g (80 Z) of the title compound as yellow oil. Crystallizing the oil from hexane gave 6.778 g (66 Z) of pure title compound as pale yellow crystals with m.p. 116-117 °.

At TLC with Et 2 O / hexane 15:85: R = 0.56.

L i?

Elemental Analysis: C 83.13, H 5.82, F 6.29 Z;

Calculated for C ^ qH ^^ OR: 35 C 82.17, H 5.86, F 6.50 Z.

D. 2T-ethynyl-3 * - (4-fluorophenyl) spiro-C cyelopentane-1,1 '- [1H. 7indene.7

In a solution of 0.960 g (6.40 mgmol) of dime thyldiazomethane phosphonate (prepared as described in J. Org.

6 8 0 1 3 3 1 1 * - 190 -

Chem. 36 (1971) 1379) in 4 ml THF was dripped under argon at -78 ° into a solution of 0.672 g (6.00 mgmol) potassium t-butylate in 8 ml dry THF. After stirring at -78 ° for 5 minutes, a solution of 1.168 g (4.00 mgmol) compound of Part C in 8 ml THF was added dropwise over 10 minutes. After stirring at -78 ° for 3 hours, at -45 ° for 1 hour and at room temperature for 1 hour, the reaction mixture was diluted with 50 ml of hexane and washed with 5% KHSO 2 solution. The organic phase was washed with saturated NaCl solution, dried over Na 2 SO 4 and evaporated to a small volume (not evaporated to dryness). The yellow solution was placed on a column of silica gel and chromatographed on hexane. The product fractions were combined and after addition of 80 mg (0.36 mg mol) of butylated hydroxytoluene (BHT) concentrated to a small volume (5-10 ml), which as such was used directly for the next step.

At TLC with Et2O / hexane 1: 9: = 0.57.

1 H-NMR (at 270 MHz, in CDCl 3) with BHT as the internal standard (1.45 ppm, 18H, s) showed the presence of 3.10 mg mol (77.5% yield) of the desired acetylene (3, 32 ppm, 1H, s).

20 E. Methyl ester of (S) -4- (chloromethoxyphosphinyl) -3- (t-butyl disilyloxy) butyric acid

In accordance with Example XXIX part J, the phosphonic acid chloride was prepared from the dicyclohexylammonium salt of Example XXV part B, using the following amounts: 3.44 g (54.4 mgmol) dicyclohexylammonium salt, 1.36 ml (10.85 mgmol). trimethylsilyldiethylamine, 15 ml of 0.50 ml (5.73 mg mol) of oxalyl chloride, one drop of DMF and 15 ml of C 2 C 4.

F. Methyl ester of (S) -3- (t-butyldiphenylsilyloxy) -4- / "[31 - (4-fluorophenyl) spiro / cyclopentane (1,1) indenyl-2. Methynyl J-30 methoxyphosphinyl Jbutyric acid

The solution of the acetylene of part D (3.10 mg mol + 0.36 mg mol BHT) was diluted with 15 ml THF and cooled to -78 ° under argon. Then 2.16 ml of 1.6 M (3.46 mgmol) n-BuLi in hexane was added dropwise with a syringe.

After stirring at -78 ° for 45 minutes, the anion solution was transferred by cannula to a solution of the phosphonic acid chloride of part E (54.4 mgmol in 15 ml dry THF) cooled to -78 °. After stirring at -78 ° for 1 hour, the reaction mixture was quenched by dripping 15 ml of saturated NH 2 Cl, and allowed to warm to 8801331 - 1, 1 -1 - room temperature. The mixture was extracted with EtOAc and the extracts were washed with 5% KHSO 2, saturated NaHCO 2 and saturated NaCl solutions, dried at 80 μg and evaporated to dryness. The crude product was purified by chromatography with EtOAc / hexane 1: 3 on silica gel to give 1.781 g (80%, based on compound of part D) title compound as pale yellow glass.

At TLC with acetone / hexane 1: 1: = 0.46.

G. Methyl ester of (S) -4-f [S '- ^ - fluorophettylspiro / cyclo-10 pentane (1,1) indenyl-2-jethynyl-methoxyphosphinyl J-3-hydroxybutyric acid

To a solution of 1.00 g (1.39 mgmol) of Part F compound in 5 ml of dry THF was first added 0.32 ml (5.59 mgmol) of glacial acetic acid under argon at room temperature and then 3.80 ml of 1, 1 M (4.18 mgmol) (nC ^ H ^) ^ NF in THF. After stirring at room temperature for 18 hours, the reaction mixture was diluted with 50 ml EtOAc and washed successively three times with 30 ml 1N HCl and with saturated NaCl solution, dried over Na 2 SO 4 and evaporated to dryness. The residue was taken up in 20 ml Et 2 O, and after cooling in an ice bath, an excess of ethereal diazo methane was added. The residue left by evaporation of the ether was purified by chromatography with acetone / hexane 3: 7 on silica gel to give 0.595 g (89%) of the title compound as a colorless glass.

At TLC with acetone / hexane 1: 1: R = 0.29.

H. Dilithium salt of (S) -4-C C S -H-fluorophenyl-spiro-cyclo-pentane (1,1) indenyl-2-methyl-hydroxyphosphinyl-7-3-hydroxybutyric acid

To a solution of 0.580 g (1.20 mgmol) of compound G in 6 ml of dioxane was added 4.2 ml of 1 N LiOH at room temperature under argon. After stirring at room temperature for 3 hours, the mixture was diluted with 20 ml of acetonitrile and the white precipitate was collected, washed with acetonitrile and dried in vacuo to 0.670 g of crude title product, a white solid.

The crude product was suspended in 10 ml of water and placed on a short column of HP-20 (15 ml, 25 mm diameter), which was eluted first with 300 ml of water and then with 300 ml of methanol. The product fractions were evaporated to dryness 880 1 53 t '- 192 -. The residue was stirred with acetonitrile to give 550 mg of 898% pure title product as a white matter, m.p. 301-303 ° (dec.).

TLC with iPr0H / NH40H / H20 7: 2: 1: 0.48.

Examples LXV to CXXII

With the previously outlined methods as described in the previous examples, the following compounds can also be prepared:

Compounds of formula 25

Ex. R Z X R

x nr._ LXV 0CH „2,4-dichloro-6- (4-fluorobenzyl- -CH„ -CH „- CH_oxy) phenyl

LXVI OH 3 ', 5-dichloro-3-ethyl-4, -C-C-H

methyl biphenylyl-2 LXVII OLi 3-methyl-1- (3,5-dimethyl -CH „CH„ CH „- Li phenyl) naphthyl-2

LXVIII OH 2- (4-fluorophenyl) -1-naphthyl -CH 2 ° "H

LXIX OLi 3- (4'-fluorophenyl) -1-iso- -CH_CH "CH" - Li propylindolyl-2 LXX OCH 1- (4-fluorophenyl) -3-iso- -CH CH-CH-CH, propylindolyl- 2

LXXI 0K 2,6-dimethyl-8- (2-methyl-CH-K

butyryloxy) -1,2,3,4,6,7,8,8a-octahydronaphthyl-1 LXXII ONa 8- (benzyloxy) -2-ethyl- -CH2 ~ Na 1,2,4a, 5,6,7, 8,8a-octahy-dronaphthyl-1

LXXEI OH 8- (benzyloxy) -6-hydroxy- -CH "CH" - H

2-methyl-1,2,6,7,8,8a-hexahydronaphthyl

LXXIV OH 8- (2,2-dimethylbutyryloxy) - -CH „CH„ CH „- H

2-ethyl-6-hydroxy-1,2,4a, 5,6,7, 8,8a-octahydronaphthyl-1 LXXV CH30 phenyl -CH2-CH3

LXXVI OH 2,4,6-triphenylphenyl -CH2 ° "H

LXXVII OH 3- (4-fluorophenyl) -spiro-CH 2 CH 2 H

Cyclopentane-1,1'-indenyl-2-7

LXXVIXI OH 3- (3,5-dimethylphenyl) -spiro-CH-CH-H

~ ~ Cyclopentane-1,1-indeny1-2 ^ 7

LXXIX OH 5-pheny1-1- (4-fluorophenyl) -CH2CH2-H

3- isopropylpyrrolyl-2 LXXX NaO 5-phenyl-3- (4-fluorophenyl) - -CH = CH- Na 1- isopropylpyrrolyl-2 LXXXI 0 5-phenyl-4- (4-fluorophenyl) - -C = C— Ca 2-isopropylfuryl-3 .8801331 - 193 - ''

Ex. R Z X R

x no. _____________

LXXXII HO 5-phenyl-4- (4-fluoro--C = C-H

phenyl) -2-isopropyl) -thienyl-3 LXXXIII NaO 4- (4-fluorophenyl) -2,5-di- -C ^ C- Na isopropylthienyl-3

LXXXIV CH30 4- (3,5-dimethylphenyl) - -CH = CH- H

5-phenyl) -2-isopropyl-thienyl-3 LXXXV CH30 4- (3,5-dimethylphenyl) - -CH2CH2- NH ^ 5-phenyl-2-isopropylthienyl-3

LXXXVI HO 5-phenyl-2-isopropyl- -CH2- K

4- (4-methoxyphenyl) -thienyl-3 LXXXVII 0 5-phenyl-2-isopropyl- -CH2CH2CH2- Ca 4- (3-trifluoromethyl-phenyl) thienyl-3 LXXXVIII CH30 4- (biphenylyl-4) -5-phenyl - -CH = CH- Na 2-isopropylthienyl-3

LXXXIX H 4-cyclopentyl-5-phenyl-CH 2 -H

2-isopropylthienyl-3

XC CH30 4,5-diphenyl-2-iso -CH = CH-H

propylthienyl-3

XCI HO 4- (4-fluorophenyl) -2-iso -CH = CH-H

propy1-5- (4-methylphenyl) -thienyl-3 XCII CH30 4- (4-fluorophenyl) -2-iso- “CH2 ~ CH3 propyl-5- (4-methoxyphenylthienyl-3 XCIII LiO 5- (4- chlorophenyl) -4- (4- -CH2CH2CH2- Li • fluorophenyl) -2-isopropylthienyl-3

XCIV KO 4- (4-fluorophenyl) -2-iso -CH2CH2-K

propyl-5-methyl-thienyl-3

XCV HO 5- (2 »2-dimethylvinyl) - -CH = CH- H

4- (4-fluorophenyl) -2-iso -propylthienyl-3

XCVI HO 5-cyclopentyl-4- (4-fluoro- -C = C-H

phenyl) -2-isopropyl-thienyl-3

XCVII HO 3- (4-fluorophenyl) -2,5-di- -C 1 C-H

isopropylimidazolyl-4 XCVIII LiO 2-cyclopentyl-3- (4-fluoro--C = C-Li phenyl) -5-imidazolyl-4 XCIX LiO 5-pheny1-4- (4-fluorophenyl) - -CH2- Li 2- isopropylpyrazolyl-3 8 8 0 1 3 3 t-194

Ex. R Z X R

X

No._

CHO 1-phenyl-5- (4-fluorophenyl) -CH2 “H

3-isopropylpyrazolyl-4

Cl HO 3,4-dichloro-2- (4-fluoro--CH2CH2-H

phenyl) -5-isopropylpyrrolyl-1 CII NaO 2- (4-fluorophenyl) -5-iso -C 1 -C 2 - Na propyl-3,4-di (methoxycarbonyl) -pyrrolyl-1 CIII L10 3, 4-dibromo-2- (4-fluoro--CH2CH2-Li-phenyl) -4-isopropylpyrrolyl-1

CIV HO idem -C ^ - H

CV CH ^ O 2- (4-fluorophenyl) -5-iso -CH2CH2-CH ^ propyl-3,4-di (methoxy-carbonyl) pyrrolyl-1

CVI HO 2- (4-fluorophenyl) -5-iso -CH 2 CH 2 -H

propylpyrrolyl-1

CVII HO 3,4-dichloro-2- (4-fluoro--CH2CH2CH2-H

phenyl) -5-isopropylpyrrolyl-1

CVIII KO 3,4-dichloro-2- (4-fluoro--CH2CH2-K

phenyl) -5-methylpyrrolyl-1

CIX HO 3,4-dibromo-5-cyclopropyl--CH2CH2-H

2- (4-fluorophenyl) pyrrolyl-1 CX LiO 2,2-di (4-fluorophenyl) -1-iso -CH = CH- Li propylvinyl

CXI KO 2,2-diphenyl-1-isopropyl- -CH "CH" "K

vinyl CXII LiO 2,2-di (4-fluoro-3-methyl- -CH = CH- Li phenyl) -1-ethylvinyl CXIII CH „0 2- (4-methoxyphenyl) -1-methyl- -CH = CH- CH 2 - (4-methylphenyl) vinyl

CXIV OH 4, -fluoro-3'-methylbi- -CH 2 -H

phenylyl-2 CXV LiO 1- (4-fluoro-3-methylphenyl) - -C = C- Li 3- isopropylindolyl-2 CXVI LiO idem -CH2CH2- Li CXVII LiO 1- (3,5-dimethylphenyl) -3- - C = C- Li isopropylindolyl-2 CXVIII LiO idem -C ^ C ^ - Li CXIX LiO 2,3-di- (4-fluorophenyl) -5- -C = C- Li isopropylimidazolyl-4 CXX LiO idem -C ^ C ^ - Li CXXI LiO 2- (biphenylyl-4) -3- (4-fluoro- -C = C-Li phenyl) -5-isopropylimidazolyl-4 CXXII LiO 3- (4-fluorophenyl) -5-isopropyl- -C = C-Li 2- (4-methoxyphenyl) imidazolyl-3

Claims (10)

1. A '-Looo-2-7 -ethyl / hydroxyphosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester, (E) -4- / / 2- / 3- (4-fluorophenyl) -1- (1-methylthyl) 1H-indol-2 / ethenyl / hydroxyphosphinyl-3-hydroxybutyric acid or its dilithium salt or methyl ester, 4- / 2- (4-fluoro-3,3 ', 5-trimethylbiphenylyl-2) ethyl / hydroxy-phosphinyl 7-3-hydroxybutyric acid and its dilithium salt or methyl ester, (E) -4- / / 2- (4 ^ 1 ^ ^ - 3,31,5-trimethylbiphenylyt-2) ethenyl 7-10 hydroxyphosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester, (S) -4- / ~ / "/ ~ 2,4-dimethyl-1-6- ((4-fluorophenyl) methoxy-7-phenyl-7-ethyl-7-hydroxyphosphinyl / -3-hydroxybutyric acid or dilithium salt or its methyl ester, 15 (S) -4 - / - / - / 2,4-dimethyl-6- / (4-fluorophenyl) methoxy-7-phenyl-7-ethynyl / hydroxy-phosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester, (S) -4- / / 2- (3,5-dimethyl / 1,1'-biphenyl7-2-yl 7ethyl) hydroxyphosphinyl 7-3-hydroxybutyric acid or the dilithium salt or methyl-20 e star thereof, (S) -4- / / 2- (4'-fluoro-3,5-dimethyl / 1,1'-biphenyl 7-2-yl 7-ethyl 7hydroxyphosphinyl-7-3-hydroxybutyric acid or dilithium salt or methyl ester thereof, (S) -4- / / 2- / / 1,1,1-biphenyl_7-2-yl_7ethynyl_7hydroxyphosphinyl_7-25, 3-hydroxybutyric acid or its dilithium salt or methyl ester, (S) -4- / / 2- (5- (4-Fluorophenyl) -3- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4-ethynyl-7-methoxyphosphinyl-7-3-hydroxybutyric acid, its methyl ester, 30 (S) -4- / / 2- / 5- (4- fluorophenyl) -3- (1-methylethyl) -1-pheny1-1H-pyrazolyl-4 / ethynyl 7hydroxyphosphinyl 7-3-hydroxybutyric acid, as dilithium salt thereof, (E) -4- / / 2- / 5- (4-fluorophenyl ) -3- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4-ethylenyl-7-methoxyphosphinyl-7-3-hydroxybutyric acid, its methyl ester, (E) -4- / / 2- / 5- (4-fluorophenyl ) -3- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4 / ethenyl / hydroxyphosphinyl 7-3-hydroxybutyric acid, as dilithium salt thereof, (S) -4 - / - / - 2- / ~ 5- ( 4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazolyl-4 / ethyl / methoxyphosphinyl / -3-hy droxybutyric acid, «8801331 its methyl ester, (S) -4 - / - / ~ 2- / 5- (4-fluorophenyl) -3- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4 / ethyl / hydroxyphosphinyl / -3-Hydroxybutyric acid, as dilithium salt, 5 (S) -4- / / 2- / 3- (4-fluorophenyl) -5- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4 / ethyl-7-methoxyphosphinyl / -3-Hydroxybutyric acid, its methyl ester, (S) -4- / / 2- / 3- (4-fluorophenyl) -5- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4 / ethyl / hydroxyphosphinyl_ / -3-hydroxybutyric acid, 10 as dilithium salt, (S) -4- / 2- / 3- (4-fluorophenyl) -5- (1-methyl-ethyl) -1-phenyl-1H-pyrazolyl-4-ethynyl-7-methoxyphosphinyl-7-3- hydroxybutyric acid, its methyl ester, (S) -4 - / "/ ~ 2- / 3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-15H-pyrazolyl-4 / ethynyl 7hydroxyphosphinyl_7 ~ 3 -hydroxybutyric acid as dilithium salt, (S) -4- / / / 4- (4-fluorophenyl) -1- (1-methyl-ethyl) -3-phenyl-1H-pyrazolyl-5 / ethynyl-7-methoxyphosphinyl / -3-hydroxybutyric acid, de methyl ester thereof, 20 (S) -4- / / / 4- (4-fluorophenyl) -1- (1-methyl-ethyl) -3-phenyl-1H-pyrazolyl-5-ethynyl / hyd roxyphosphinyl 7-3-hydroxybutyric acid, as dilithium salt, (S) -4- / / 2- / 4- (4-fluorophenyl) -1- (1-methyl-ethyl) -3-phenyl-1H-pyrazolyl-5 / ethyl-7-methoxyphosphinyl 7- 3-hydroxybutyric acid, its methyl ester, (S) -4- / 2- / 4- (4-fluorophenyl) -1- (1-methyl-ethyl) -3-phenyl-1H-pyrazolyl-5 / ethyl / hydroxyphosphinyl 7 -3-hydroxybutyric acid as dilithium salt, (S) -4- / / / l- (4-fluorophenyl) -4- (1-methyl-ethyl) -2-phenyl-1H-30 imidazolyl-5-ethynyl / methoxyphosphinyl 7-3-hydroxybutyric acid, the methyl ester thereof, (S) -4- / / / 1- (4-fluorophenyl) -4- (1-methyl-ethyl) -2-phenyl-1H-imidazolyl-5 / ethynyl / methoxyphosphinyl 7-3-hydroxybutyric acid, the methyl ester thereof, 35 (S) -4- / / 2- / 1- (4-fluorophenyl) -4- (1-methyl-ethyl) -2-phenyl-1H-imidazolyl-5 / ethyl / / methoxyphosphinyl 7-3-hydroxybutyric acid, the methyl ester thereof, (S) -4- / 2- / 1- (4-fluorophenyl) -4- (1-methyl-ethyl) -2-phenyl-1H-imidazolyl-5 / ethyl / hydroxyphosphinyl-3-hydroxybutyric acid 40 as dilithium salt,, 8801331 I> i '- * © o- (S) -4- / / / 2- (cyclohexylmethyl) -4,6-dimethylphenyl_7 ethynyl J-hydroxyphosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester, 4- / / 2- / 2- (cyclohexylmethyl) -4,6-dimethylphenyl_7ethenyl 7-5 hydroxyphosphinyl 7-3-hydroxybutyric acid or dilithium salt or methyl ester thereof, (S) -4- / / 2- / 2- (cyclohexylmethyl) -4,6-dimethylphenyl 7ethyl-7-hydroxyphosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester, 10 4- / / / (4'- fluoro-3,3 ', 5-trimethylbiphenylyl-2) oxy / methyl / hydroxyphosphinyl-7-3-hydroxybutyric acid or its dilithium salt or methyl ester, 4- / / (4'-fluoro-3,3', 5-trimethylbiphenylyl- 2) methyl-7-hydroxy-phosphinyl / -3-hydroxybutyric acid or its dilithium salt or its methyl ester, (S) -4- / / / 1- (4-fluorophenyl) -3-methyl-2-naphthalenyl_7-hydroxyphosphinyl 7-3-hydroxybutyric acid or the dilithium salt or the methyl ester thereof, (E) -4- / / 2- / 1- (4-fluorophenyl) -3-methyl-2-naphthalenyl_7ethenyl -1/20 hydroxyphosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester , (S) —4— / / 2- / 1- (4-Fluorophenyl) -3-methyl-2-naphthalenyl 7ethyl 7-hydroxyphosphinyl 7-3-hydroxybutyric acid or its dilithium salt or methyl ester, 4- / / 3- (4'-fluoro-3,3 ' 5-trimethylbiphenylyl-2) propyl J-methoxyphosphinyl 7-3-hydroxybutyric acid, its methyl ester, 4- / -3- (4-fluoro-3,3 ', 5-trimethylbiphenylyl-2) propyl-7-hydroxyphosphinyl 7- 3-hydroxybutyric acid as dilithium salt, flS-fl <a (R *), 2 <a, 4a <b, 8 <b, 8a <a_7_7-4 - / "/" 2 - / "8- (2,2-di -30 methyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl-7ethyl-7-methoxyphosphinyl 7-3-hydroxybutyric acid, its methyl ester, / - S - / "1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a_7_7-4 - / "/" 2 - / "8- (2,2-dimethyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl_7ethyl-7-hydroxyphosphinyl 7-3-hydroxybutyric acid as dilithium salt, 35 (S) -4- / 1/3 '- (4-fluorophenyl) spiro 7cyclopentane-1,1' - / 1H-7-indene 7-2-yl 7ethynyl / methoxyphosphinyl-7-3-hydroxybutyric acid, or its methyl ester S) -4- / / / Ι '- ^ - ίΙυοΓίβ ^ Ι ^ ρΐΓο / ^ αΙορβηίηηη-Ι, Ι' - / 1H ^ 7-indene 7-2-yl_7ethynyl_7hydroxyphosphinyl 7-3-hydroxybote acid as its dilithium salt. -8801331 -201- 4 * τ 1. A compound useful for inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which has a group 5 of formula 24 wherein X -CH ^ -, -CH ^ CH ^ - »-CH = CH -, -CH2CH2CH2- * -C = C- or -CH2O- (where the oxygen is on Z) and where Z is a hydrophobic anchor. 2. A compound according to claim 1, the hydrophobic anchor of which is a lipophilic group which, when linked to the HMG-like core group by an appropriate bridge, binds to a hydrophobic pit in the enzyme which is not used to bind the substrate. HMG-CoA, which, compared to compounds in which Z = H, leads to a stronger bond. A compound according to claim 1 of formula 25, wherein R is OH or lower alkoxy, Rx is H or lower alkyl, X is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH = CH-, -C-C- or -CH2 O- is 20 (where the oxygen is on Z) and wherein Z is a hydrophobic anchor of formula 26, 27, 28, 29a, 29b, 29c, 30, 31, 32, 33, 34 or 35, where R ^, R 2> and R 2 independently of each other are hydrogen, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl, or R 2, where R 1 is hydrogen, lower alkyl, haloalkyl, allyl, cycloalkyl-lower alkyl, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, cinnamyl or adamantyl-lower alkyl, wherein when Z is a group of formula R 1 and R 2 'are independently hydrogen, lower alkyl or hydroxy, Rg is lower alkanoyl such as CH2 -CH2C1CH2) (R?) -C0 or arylmethyl with for R6 hydrogen or lower alkyl and q is 0, 1, 2 or 3, if Z is a group of formula 28, 29a , 29b, 29c, 30, 31, or 33 thereof, R ^ and R ^ is one with R ^, R ^ and R ^ 4a Substituted phenyl and the other is lower alkyl, cycloalkyl or phenyl- (CH2) -, 35 with p = 0, 1, 2, 3 or 4, where R 1 is hydrogen, lower alkyl, lower alkoxy (except t-butoxy), halogen, phenoxy or benzyloxy, R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy R 11 is a hydrogen, lower alkyl, lower alkoxy or halogen, with the limitation that when R 1 is hydrogen R 8801331 • '*' -, a 'and R'. that should also be that if R 1 is hydrogen R. 14a J 14 14a it should also be and that R. and R no more than one 13 14 trifluoromethyl, no more than one phenoxy and no more than one benzyloxy, where R0 is hydrogen, C1 -alkyl, CL, -cyclo-1-4-yl-alkyl, ^ -alkoxy (except t -butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, wherein Rg is hydrogen, g-alkyl, C 1-8 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the restriction that if Rg is hydrogen Rg is also should be and that of Rg and Rg there is no more than one trifluoromethyl, no more than one phenoxy and no more than one benzyloxy, where R ^ q and R ^ independently of each other are hydrogen, alkyl, cycloalkyl, adamantyl- 1 or phenylalkyl with 0, 1, 2, 3 or 4 carbon coming into the alkylene bridge and having 0, 1, 2 or 3 substituents, and where Y is 0, S or NR ^ g, where if Z is a group according to formula 32 R is hydrogen 8l or primary or secondary g-alkyl and Rg is primary or secondary g-alkyl or wherein R & and Rg then together form ° f cis-CE ^ -CEhCH-CK ^ -, with for r 2, 3, 4, 5 or 6, and m et for R 2 lower alkyl, cycloalkyl or phenyl substituted with 0, 1, 2 or 3 substituents, where if Z is a group of formula 33 R 2 g and R 2 g are both H, Cl, Br, CN, C 25 -phenyl, -alkyl, C 2-8 -alkoxycarbonyl, -C 1-4 OR ^ or -C 1-4 OCONHR ^ g, wherein R 1 H or C 1 -g alkanoyl and R 1 g alkyl or optionally with F, Cl, Br or C 1 -6 -alkyl is substituted alkyl or in which R 1-2 and R 2 -g together - (Cl 2 -g, -CH 2 OCH 2 -, -C0N (Rgg) C0- or -C0N (R2q) N (R 2 ^) ) C0- forms, with for s 3 or 4, for R ^ g H, C ^ g -alkyl, phenyl or benzyl and for R2q and R2 ^ H, C ^ ^ -alkyl or benzyl, with the limitation that X then only -CB ^ - »-C ^ C ^ - or -CH2CH2CH2-, where if Z is a group of formula 34 R22 is lower alkyl, cycloalkyl, adamantyl-1 or phenylalkyl having 1, 2, 3 or 4 carbon atoms in the alkylene bridge and R22 and R23a are independently hydrogen, lower alkyl, lower alkoxy (except t-butoxy), halogen, phenoxy or benzyloxy, with the restrictions that if R22 is hydrogen & must be da t of R22 and n: - et is more than trifluoromethyl, not more than one phenoxy and not more than one benzyloxy, where if X is -Cl ^ O- (with the carbon on the phosphorus and the oxygen on the group Z ) the hydrophobic anchor is of the phenyl-8801331 -97-K-naphthalene type, that is to say according to formula 26 or formula 27, in the form of the free acid, of a salt or of a physiological hydrolyzable and acceptable ester. The compound of claim 3, wherein X The following compounds according to claim 1: (S) -4- / / (E) -2- (4'-fluoro-3,3 ', 5-trimethyl-biphenylyl-2) -ethyl-7-hydroxyphosphinyl-3-hydroxybutyric acid and the dilithium salt thereof, (S) -4 / / 2- (4ι-ί1ηοΓ-3,3τ, 5-trimethylbiphenylyl-2) ethyl 7-hydroxyphosphinyl 7-3-hydroxybutyric acid, the methyl ester or the mono- or dialkali metal salts thereof, (S) -4- / / (4'-fluoro, 3,3 ', 5-trimethylbiphenylyl-2) ethynyl 7-15 methoxyphosphinyl / -3-hydroxybutyric acid or its methyl ester, (5Z) -4- / / 2- (4T-fluoro-3,3 ', 5-trimethyl-biphenylyl-2) -ethenyl-hydroxy-phosphinyl-7-3-hydroxybutyric acid, its methyl esters, (S) -4- / 2- / 3- (4-fluorophenyl) - 1- (1-Methyl-ethyl) -1H-indolyl-2 / ethyl / methoxyphosphinyl 7-3-hydroxybutyric acid, its methyl esters 20, (S) -4- / / 2- / / 1,1'-biphenyl 7-2- yl 7ethyl 7-methoxyphosphinyl-3-hydroxybutyric acid, its methyl ester, (S) -4- / / 2- / / l, 1T-biphenyl 7-yl 7ethyl-7-methoxyphosphinyl-3-hydroxybutyric acid, its methyl ester, (S) -4- / / 2- (4, -fluoro-3,3, 5-trimethylbiphenylyl-2) et hyl-7-hydroxyphosphinyl-7-3-hydroxybutyric acid as dilithium salt, (S) -4- / / 2- (4T-fluoro-3,3, 5-trimethylbiphenylyl-2) ethynyl _ / - hydroxyphosphinyl 7-3-hydroxybutyric acid as dilithium salt, (5Z ) -4- / / 2- (4'-fluoro-3,3 ', 5-trimethylbiphenylyl-2) ethenyl / - 30 hydroxyphosphinyl 7-3-hydroxybutyric acid as dilithium salt, (S) -4/2/3 - (4-Fluorophenyl) -1- (1-methylethyl) -1H-indolyl-2 7-ethyl7hydroxyphosphinyl 7-3-hydroxybutyric acid as dilithium salt, (S) -4 / / 2- / (1,1-biphenyl_7-) 2-yl_7ethyl_7hydroxyphosphinyl_7-3 butyric acid as dilithium salt, 35 (S) -4- (hydroxymethoxyphosphinyl) -3- (t-butyldiphenylsilyloxy) butyric acid, the methyl ester or the dicyclohexylamine salt (1: 1), (S) —4 - / / 2- / 1- (4-fluorophenyl) -3- (1-methylethyl) -1-indolyl-2-ethynyl / hydroxyphosphinyl / 3-hydroxybutyric acid or its dilithium salt or methyl ester, 40 CS) —4— / / 2-1 1- (4-fluorophenyl) -3- (1-methyl-ethyl) -1H-indolyl- 8801331 5 is -CH = CH- or CSC-, R is hydroxy or alkoxy and Z is a group according to formula 26, formula 31 or formula 33. 6. Intermediate of structure of formula 70, including all stereoisomers thereof, wherein R 'is alkoxy or hydroxy and R "is hydroxy, Cl, -C = CZ, -CH 2 -Z, -C 1 Cl 2 -Z, -CH 2 O -Z, -CH = CH-Z, or -CH 2 CH 2 -Z, where Z represents a hydrophobic anchor, and structured intermediates of formula 71, including all stereoisomers thereof, wherein X - (CH 2) -, -CH = CH-, C = C- or -CH-O-, a is 1, 2 or 3 and Z za Z represents a hydrophobic anchor. 7. Process for preparing the intermediate according to claim 6, wherein R 'is alkoxy and R "-CH = CH-Z, consisting of using the trans-vinyl iodide of formula 46 in an inert organic solvent with a metalle- reactant and the formed anion is reacted in an inert organic solvent with a cooled solution of a phosphonic acid chloride of formula 47. 8. Process for preparing an intermediate of formula 25c wherein R is alkoxy and R alkyl, consisting of reacting a cooled solution of a phosphonic acid chloride of formula 53 in an inert organic solvent with a dianion of formula 55. A hypocholesterolemic or hypolipemic composition containing a compound according to claim 3 and a pharmaceutically acceptable carrier therefor. 10. Use of a compound according to claim 3 for inhibiting the biosynthetic of cholesterol. -o-o-o-o-. 8801331