CH675582A5 - - Google Patents

Description

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CH 675 582 A5

Description

The present invention relates to novel phosphorus-containing compounds which inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase, and are therefore useful for inhibiting the biosynthesis of cholesterol and hypocholesterolemic compositions containing these compounds.

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

Endo et al., In US Pat. Nos. 4,049,495.4 137,322 and 3,983,140, describe a fermentation product which inhibits the biosynthesis of cholesterol. This product is called compactin, and Brown et al. fJ. Chem. Soc. Perkin. 1.1165 (1976)) indicated that it had the structure of a complex mevalonolac-tone.

GB Patent No. 1,586,152 describes a group of synthetic compounds of the formula in which E represents a direct bond, a C1-3 alkylene bridge or a C1-3 vinylene bridge, the different radicals R representing different substituents.

The activity indicated in the British patent is less than 1% of that of compactin. US Patent No. 4,375,475 to Villard et al. presents hypocholesterolemic and hypolipemic compounds having the structure a ^ V

in which A is H or the methyl radical; E is a direct bond, -CH2-, -CH2-CH2, -CH2-CH2-CH2- or -CH = CH-; R1, R2 and R3 are each selected from the group consisting of H, halogens, C1-4 alkyl, C1-4 haloalkyl, phenyl, halogen substituted phenyl, C1-4 alkoxy, C2-8 alkanoyloxy, C1-4alkyl C1-4 or C1-4 haloalkyl, and OR4 where R4 is H, a C2-8 alka-nucleus, benzoyl, phenyl, halophenyl, phenyl- (C1-3 alkyl), C1-9 alkyl, cinnamyl, haloalkyl C1-4, allyl, cycloalkyl- (C1-3 alkyl), adamantyl- (C1-3 alkyl), or substituted phenyl- (C1-3 alkyl), the substituents in each of the above compounds being selected among halogens, C1-4 alkoxy, C1-4 alkyl or C1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic decyclization of the lactone, and the pharmaceutically acceptable salts of these acids, and the C1-3 alkyl esters, substituted by C1-3 alkyl radicals and phenyl, dimethylamino or acetylamino, dihydroxy acids; all the compounds being

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CH 675 582 A5

enantiomers having a 4 R configuration in the tetrahydropyran fragment of the trans racemate presented in the above formula.

WO 84/02131 (PCT / EP / 83/00308) (which is based on the US patent application filed under the serial number 443 668 on November 22, 1982 and on the US patent application filed under the serial number 548 850 November 4, 1983), and filed on behalf of Sandoz AG, describes heterocyclic analogs of mevalonolactone and its derivatives, having the structure and the other is a primary or secondary C1-6 alkyl radical, cycloalkyl in C3-6 or phenyl- (CH2) m-,

in which R4 is hydrogen, a C1-4alkyl, C1-4alkoxy (except the tert-butoxy radical), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy radical,

R5 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Rsa is hydrogen, C1-2 alkyl, C1-2 alkoxy, fluoro or chloro, and m is 1, 2 or 3,

provided that the two radicals R5 and Rsa are hydrogen when R4 is hydrogen, that Rsa is hydrogen when R5 is hydrogen, that at most one of the radicals R4 and R5 is the trifluoromethyl radical, that at plus one of the radicals R4 and R5 is the phenoxy radical, and at most one of the radicals R4 and R5 is the benzyloxy radical,

R2 is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy (except tert-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R3 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, provided that R3 is hydrogen when R2 is hydrogen, that at most one of radicals R2 and R3 is the trifluoromethyl radical, at most one of the radicals R2 and R3 is the phenoxy radical, and at most one of the radicals R2 and R3 is the benzyloxy radical,

X is - (CH2) n- or -CH = CH- (n = 0,1, 2 or 3),

^ 6

Z is -CH-CHo-C-CHo-COOH

I I

OH OH

II

where R6 is hydrogen or a C1-3 alkyl radical, in the free acid form or in the form of a physiologically hydrolysable and acceptable ester of one of their 8-lactones, or in the form of a salt.

GB 2162-179-A describes naphthyl analogs of mevalonolactone, which can be used as inhibitors of cholesterol biosynthesis, having the formula

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CH 675 582 A5

Me

Me z

1

in which Ri is an alkyl radical having 1 to 3 carbon atoms; Z is a group of formula Zi or Z2:

H

| 0H

H

-CHCH 2 CHCH2 COOR7 OH OH

O

(Zi)

<Z2)

R7 is H, a hydrolyzable ester group or a cation.

European patent n ° 164-698-A describes the preparation of lactones which can be used as anti-hypercholesterolimic agents, by treatment of an amide with an organic sulphonyl halide RsSO2X, then elimination of the protective group Pr.

where X = halogen;

Pr = a carbinol-protecting group;

Ri = H or CHs;

R3, R4 = H, alkyl with 1 to 3 carbon atoms, or phenyl (alkyl with 1 to 3 carbon atoms), the phenyl radical being optionally substituted by an alkyl radical with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon or halo atoms;

r2 = a group of formula (A) or (B):

B-

, 1

R

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CH 675 582 A5

Q = R6-Ç- or R6-CH;

. i 1

CH3

R6 = H or OH;

R = H or CH3;

a, b, c and d = optional double bonds;

R7 = phenyl or benzyloxy, the nucleus, in each case, optionally being able to be replaced by an alkyl group having from 1 to 3 carbon atoms, or halo;

R8, R9 = alkyl with 1 to 3 carbon atoms, or halo;

R5 = alkyl having 1 to 3 carbon atoms, phenyl, or mono- or di- (alkyl having 1 to 3 carbon atoms) - phenyl.

Anderson, Paul Leroy, Ger. Offen. From 3,525,256 describes naphthyl analogs of structural mevalonolactones

-CHCH, CHCH, CO, R

i 2 to 2 2

Vy

OH

OH OH

Y

Q '

in which Ri is an alkyl radical, Z = Q, Q1; R7 = H or a hydrolyzable ester group, which can be used as inhibitors of cholesterol biosynthesis and in the treatment of atherosclerosis.

WO 8402-903 (which is based on the US patent application filed under the serial number 460 600 on January 24, 1983), filed in the name of Sandoz AG, describes analogs of mevalonolactones which can be used as hypolipoproteinemic agents having the structure

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CH 675 582 A5

8

C = C - C = C -

I

or - "34) 4-

where R2 is hydrogen, a C-m alkyl radical, C1-4 alkoxy (except tert-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R3 is hydrogen, a C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy radical, provided that at most one of the radicals R2 and R3 is the trifluoromethyl radical, that at most one of the radicals R2 and R3 is the phenoxy radical, and at most one of the radicals R2 and R3 is the benzyloxy radical,

Ri is hydrogen, C1-6 alkyl, fluoro, chloro or benzyloxy,

R4 is hydrogen, C1-4 alkyl, C1-4 alkoxy (except tert-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R5 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Rsa is hydrogen, a C1-2 alkyl, C1-2 alkoxy, fluoro or chloro radical, and provided that at most one of the radicals R4 and R5 is the trifluoromethyl radical, at most one radicals R4 and R5 is the phenoxy radical, and at most one of the radicals R4 and R5 is benzyloxy,

X is - <CH2) n-,

- <Œ2> a

\ ✓ C = C

- {CH2> q where n is worth 0,1, 2 or 3 and the two indices Q are each worth 0 or one is worth 0 and the other is worth 1, Zest

5 4 3 2 1

-ÇH-CH, —C-CH -COOE H

i - "s i 2

OH OH

where R6 is hydrogen or a C1-3 alkyl radical, with the general condition that the group -X-Z- and the phenyl group carrying the radical R4 are in the ortho position relative to each other;

in the free acid form or in the form of a physiologically hydrolyzable and acceptable ester, or of one of their lactones, or in the salt form.

US Patent No. 4,613,610 to Wareing (assigned to Sandoz) describes a series of HMG-CoA-reductase inhibitors of the 7-pyrazolo-3,5-dihydroheptenoic-6 acid type, with a structure

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CH 675 582 A5

in which

Ri is a C1-6 alkyl radical not containing an asymmetric carbon atom,

each of the radicals R2 and R5, independently of one another, is hydrogen, a C1-3 alkyl radical, n-butyl, isobutyl, tert-butyl, C1-3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy,

each of the radicals R3 and R6, independently of the other, is hydrogen, a C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy radical,

each of the radicals R4 and R5, independently of the other, is hydrogen, a C1-2 alkyl, C1-2 alkoxy, fluoro or chloro radical, provided that at most one of the radicals R2 and R3 is the trifluoromethyl radical, that at most one of the radicals R2 and R3 is the phenoxy radical, that at most one of the radicals R2 and R3 is the benzyloxy radical, that at most one of the radicals R5 and R6 either the trifluoromethyl radical, that at most one of the radicals R5 and R6 is the phenoxy radical, and that at most one of the radicals R5 and R6 is the benzyloxy radical,

X is - (CH2) m-, -CH = CH-, -CH = CH-CH2- or -CH2-CH = CH-, where m is 0.1, 2 or 3, and Z is

/ 0H

ho - "? f \

-CH-CH2-Ç-CH2-COOR1; l or | • J R10>

OH OH O yCS2

C II O

where R10 is hydrogen or a C1-3 alkyl radical, and Ru is hydrogen, R12 or M, where R12 is a physiologically acceptable and hydrolyzable ester group, and M is a cation,

provided that (i) the group -X-Z- is in position 4 or 5 of the pyrazole ring, and (ii) that the group Ri and the group -X-Z are in position ortho to each other.

WO 8607-054A (Sandoz-Erfindungen) describes imidazolic analogs of mevalonolactone, which can be used to treat hyperlipoproteinemia and atherosclerosis, and which have the following formula:

N N-R- (I)

"3

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CH 675 582 A5

Ri = alkyl, cycloalkyl, adamantyl-1 or phenyl substituted by a radical R4, Rs, R6 (group A);

R2 = alkyl, cycloalkyl, adamantyl-1 or phenyl substituted with a radical R7, Rs, R9 (group B);

R3 = H, alkyl, cycloalkyl, adamantyl-1, styryl or phenyl substituted by a radical R10, Ru, R12 (group

VS);

X = - (CH2) m-, -CH = CH-, -CH = CH-CH2- or -CH2-CH = CH-;

m = 0—3;

Z = -CH (OH) -CH2-C (Ri3) (OH) -CH2-COORi4 (group a), -Q-CH2-C (Ri3) (OH) -CH2COORi4 (group c) or a group of formula ( b):

THIS-

/ \ / 0H

CH C

O CH0

\ /

VS

! l O

Q = CO or —C (ORis) 2—;

R15 = primary or secondary alkyl; the two R15 being the same;

or R15 + R15 = (CH2) 2 or (CH2) 3

R13 = H or C1-3 alkyl;

R14 = H, R16 or M;

R16 = an ester group;

M = a cation;

provided that group Z can only be group (c) when X is CH = CH or CH2 = CH = CH and / or when R13 = C1-3 alkyl;

R4, R7 and R10 = C1-3 alkyl, n-, iso- or tert-butyl, C1-3 alkoxy, n- or isobutoxy, CF3, F, Cl, Br, phenyl, phenoxy or benzyloxy;

Rs, Rs and R11 = H, C1-3 alkyl, C1-3 alkoxy, CF3, F, Cl, Br, COORt7, N (Ri9) 2, phenoxy or benzyloxy; R17 = H, Ris or M;

Ris = C1-3 alkyl, n-, iso- or tert-butyl, or benzyl;

Rig = alkyl

Rß, R9 and R12 = H, C1-2 alkyl, C1-2 alkoxy, F or Cl; on the condition of

(1) at most one substituent from each of the groups A, B and C or CF3, at most one substituent from each of the groups A, B and C is the phenoxy radical, and at most one substituent from each of the groups A, B and C is the benzyloxy radical;

(2) when Z is the group (c; Q = C (ORis) 2), the compound is in the form of a free base, and either (i) R14 or R16 and each R17, independently of each other , either Rib or (ii) R14 or M, and each radical R17, independently of the others, either Ris or M; and

(3) when R14 and / or at least one of the radicals R17 is M, the compound is in the form of a free base.

Unless otherwise stated, all "alkyl" groups have 1 to 6 carbon atoms and do not contain asymmetric carbon; and the "cycloalkyl" radicals have from 3 to 7 carbon atoms.

WO 8603-488-A (Sandoz AG) describes indenic analogs of mevalonolactone, which can be used as anti-lipoproteinemic and anti-atherosclerotic agents, in the free acid form or in the form of an ester or of a delta-iactone, or in the form of a salt, and having the formula

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CH 675 582 A5

R.

3

R

o

(I)

X-Z

R,

R, R

1

2

R = H or primary or secondary C1-6 alkyl;

Ri = C1-e alkyl, primary or secondary;

or R + Ri = (CH2) m or (Z) -CH2-CH = CH-CH2;

m = 2-6;

Ro = C1-6 alkyl, C3-7 cycloalkyl, or phenyl substituted by a radical R4, Rs, Rö!

R2, R4 = H, C1-4 alkyl, C1-4 alkoxy (except tert-butoxy), CF3, F, Cl, phenoxy or benzyloxy;

R3 and Rs = H, C1-3 alkyl, C1-3 alkoxy, CF3, F, Cl, phenoxy or benzyloxy;

R6 = H, C1-2 alkyl, C1-2 alkoxy, F or Cl;

provided that there can be only one of each of the radicals CF3, phenoxy or benzyloxy on each of the phenyl and indene rings;

X (CH2) n or - (CH2) g-CH = CH (CH2) q-;

n = 1-3;

the two indices q = 0, or one is worth 0 and the other is worth 1;

Z = -Q-CH2-C (Rio) (OH) -CH2COOH, in the free acid form or in the form of an ester or a del-ta-lactone or a salt;

Q - CO, -C (OR7) 2- or CHOH.

The radicals R'7 are C1-6 alkyl radicals, primary, or secondary, identical, or together form (CH2) 2 or (CH2) 3;

R10 = H or C1-3 alkyl;

provided that Q can only be different from CHOH if X is CH = CH or CH2-CH = CH and / or that Rio is C1-3 alkyl.

U.S. Patent No. 4,647,576 to Hoefle et al. (Warner Lambert) describes new C- and N-substituted pyrrays, which can be used as hypolipidemic and hypocholesterolemic agents, which have the formula

X = -CH2-, -CH2CH2- or -CH (CH3) CH2-;

Ri = 1 or 2-naphthyl; cyclohexyl; norbornenyl; phenyl optionally substituted with F, Cl, OH, CF3, C1-4 alkyl, C1-4 alkoxy or C2-8 alkanoyloxy; 2-, 3- or 4-pyridinyie or their N-oxides; or

H OH

% "K *

H OH V. ”v

COOH

(II)

'4

g

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CH 675 582 A5

Rs = C1-4 alkyl;

hai = chloride, bromide or iodide;

R2 and R3 = H, CI, Br, CN, CF3, phenyl, C1-4alkyl, carbo (C2-8alkoxy), -CH2OR6 or

-CH2OCONHR7;

R6 = H or C-i-alkanoyl;

R7 = alkyl or phenyl optionally substituted with Cl, Br or C1-6 alkyl;

or R2 and R3, together = - (CH2) n-, -CH2OCH2-, -CON (Rs) CO- or -CON (R9) N (Rio) CO-;

n = 3 or 4;

Rs = H, C1-6 alkyl, phenyl or benzyl;

Rg and R10 = H, C1-4alkyl or benzyl;

R4 = C1-4 alkyl, cyclopropyl, cyclobutyl or CF3.

European patent application No. 0 221 025 AI (Sandoz AG) describes heterocyclic analogs of mevalonolactone, and its derivatives, having the formula in which

Ra is a group -X-Z, Rb is R2, Re is R3, Rd is R4 and Y is a group

-NOT-

)

R1

or

Ra is R-i, Rb is a group -X-Z, Re is R2, Rd is R3 and Y is O, S or a group

-NOT-

I

R4

Ri, R2, R3 and R4, independently of each other, are each C1-4 alkyl radicals containing no asymmetric carbon atom, C3-7 cycloalkyl or a nucleus or, moreover, in the case of R3 and R4, a hydrogen, or, for R3, when Y is O or S

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CH 675 582 A5

17

* 18

19

where Ri7 is hydrogen or a C1-3 alkyl radical, and Ris and Rig, independently of each other, are each hydrogen, C1-3 alkyl or phenyl; each radical Rs, independently of the others, is hydrogen, a C1-3 alkyl radical, n-butyl, iso-butyl, tert-butyl, C1-3 alkoxy, n-butoxy, iso-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy; each of the radicals R4, independently of the others, is a hydrogen, an alkyl radical in C1-3, alkoxy in C1-3, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each radical R7, independently of the others, is a hydrogen, a C1-2 alkyl, C1-2 alkoxy, fluoro or chloro radical, provided that there is in each ring A only one of each of the trifluoromethyl, phenoxy or benzyloxy radicals. X is (CH2) m or (CH2) qCH = CH (CH2) q, m is 0, 1, 2 or 3, and the two indices q each are 0, or one is 0 and the other is 1,

Z is -CH-CH2-C-CH2-COOH OH OH

where R9 is hydrogen or a C1-3 alkyl radical, in the free acid form or in the form of an ester or a β-lactone thereof, or in the salt form, as appropriate, these compounds being indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.

Tetrahedron Letters, 29, 929, 1988, describes the synthesis of an inhibitor of 3-hydroxy-3-methylgluta-ryl-coenzyme A-reductase, of formula in which R is Na or C2H5.

European patent application No. 127 848-A (Merck and Co, Inc.) describes derivatives of 3-hy-droxy-5-thia-cû-aryl-alkanoic acids having the following structure

HO

Y ~ V

I ox s (O)

I

E

I

Z

where Z is:

not

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CH 675 582 A5

R

R '

3

2

R

f

R

, 4

R "

R '

5

n is 0.1 or 2;

E is —CHa-, —CH2 — CH2 — î —CHa — CHa — GHa—, —CH = CH — CHa—; or —CHa — CH = CH—;

Ri, R2 and R3 are each, independently of each other, for example hydrogen, chloro, bromo, fluoro, C1-alkyl, phenyl, substituted phenyl or ORz, where R7 is for example hydrogen,

C2-8 alkanoyie, benzoyie, phenyl, substituted phenyl, C1-9 alkyl, cinnamyl, C1-4 haloalkyl, allyl, cycloalkyl- (C1-3 alkyl), adamantyl- (C1-3 alkyl) or phenyl- (C1 alkyl Ci_3);

R4, R5 and R6 are each hydrogen, chloro, bromo, fluoro or C1-3 alkyl; and X is for example hydrogen, a C1-3 alkyl radical, a cation derived from an alkali metal or ammonium.

These compounds exhibit antihypercholesterolemic activity due to their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) -reductase, as well as antifungal activity.

French patent application No. 2,596,393 A, filed April 1, 1986 (Sanofi SA) describes derivatives of 3-carboxy-2-hydroxy-propane-phosphonic acid, as well as the salts thereof, which can be used as lipid-lowering agents, and which have the following formula:

wherein R1 and R2 = H, lower alkyl or optionally substituted aralkyl;

R3 and R4 = H, lower alkyl or aryl or aralkyl optionally substituted.

It says that these compounds provide a reduction in cholesterol, triglyceride and phospholipid levels greater than meglutol.

European patent application No. 142 146-A (Merck and Co., Ine) presents compounds of the mevinoline type, of structural formula:

E

Z

in which:

Ri is, for example, hydrogen or a C1-6 alkyl radical; E is -CHaCHa, -CH = C-, or - (CHa) r-; and Z is 1)

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CH 675 582 A5

where X is -O- or -NR9 where R9 is hydrogen or a C1-3 alkyl radical; R7 is a C2-8 alkyl radical; and R8 is hydrogen or CH3;

2)

where R10, R11 and R12, independently of each other, are each for example hydrogen, halogen or a C1-4 alkyl radical;

3)

where n is 0-2 and R14 is a halogen or a C1-4 alkyl radical; or 4)

These compounds are inhibitors of HMG-CoA-reductase.

In accordance with the present invention, there are provided phosphorus compounds which inhibit the enzyme 3-hydroxy-3methylglutaryl-coenzyme A-reductase (HMG-CoA-reductase), and are therefore useful as cholesterol lowering agents and which include the moiety following

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CH 675 582 A5

0

-P-CH2-CH-CH2-CO-

X OH

1

Z

in which X is - (CH2) a-, -CH = CH-, -OC- or -CH2O- (where O is linked to Z), "a" is 1, 2 or 3, and Z is a "hydrophobic anchor "

The term "hydrophobic anchor", as used herein, refers to a lipophilic group which, when linked to the upper side chain of the HMG of the molecule using the appropriate bond ("X"), binds to a hydrophobic pocket of the enzyme, not used to bind the HMG-CoA substrate, which gives increased activity compared to the compounds where Z = H.

In preferred embodiments, the compounds of the invention have the formula I

It î

I R-P-CH2-C-CH2-C02Rx

Ì OH

!

Z

wherein R is OH or a lower alkoxy radical;

Rx is H or a substituted or unsubstituted lower alkyl radical;

X is CH2, -CH2CH2-, -CH2CH2CHa-, -CH = CH-, -C = C- or -CH20- (where O is attached to Z);

Z is a hydrophobic anchor;

and include their pharmaceutically acceptable salts.

The terms "salt" and "salts" denote basic salts, formed by organic and inorganic bases. These salts include ammonium salts, alkali metal salts, such as lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts, such as calcium and magnesium salts, salts obtained with organic bases, such as the amine type salts, for example the dicyclohexylamine salt, the benzathine, N-methyl-D-glucamine, hydrabamine salts, the salts obtained with amino acids such as arginine , lysine and the like. Non-toxic, pharmaceutically acceptable salts are preferred, although other salts can also be used, for example to isolate or purify the product.

Examples of hydrophobic anchors which can be incorporated according to the present invention include, but are not limited to, the following compounds:

14

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CH 675 582 A5

15

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OR

alkyl ir v *; 'q where dashed lines represent optional double bonds, for example,

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CH 675 582 A5

alkyl alkyl alkyl or where Ri, R2, R2a and R2b may be the same or different and are each, independently of one another, chosen from H, halogens, trifluoromethyl radicals, substituted or unsubstituted lower alkyl, halogenoalkyl, phenyl, substituted phenyl or ORy, or Ry is H or an alkanoyie, benzoyie, phenyl, halogenophenyl, phenyl- (substituted or unsubstituted lower alkyl), substituted or unsubstituted lower alkyl, cinnamyl, haloalkyl, allyl, (substituted or unsubstituted cycloalkyl -killed- (substituted or unsubstituted lower alkyl), adamantyl- (substituted or unsubstituted lower alkyl) or substituted phenyl- (substituted or unsubstituted lower alkyl);

when Z is R

17

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CH 675 582 A5

alkyl

(R)

R5 and R5 'are the same or different and are each H, a substituted or unsubstituted lower allyl radical or OH;

R4 is a radical (substituted or unsubstituted lower alkyl)

o

-fi such

O

CH3-CH2 "C-C-.

y s. 7 CBj H7

or arylCH2-;

R6a is a substituted or unsubstituted lower alkyl, hydroxy, oxo, halo or trifluoromethyl radical; q is 0,1,2 or 3, and

R7 is H or a substituted or unsubstituted lower alkyl radical;

when Z is

18

CH 675 582 A5

and the other is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or phenyl - (CH2) P- radical, p is 0,1,2,3 or 4;

where R13 is hydrogen, a substituted or unsubstituted lower alkyl, lower alkoxy (except tert-butoxy), halo, trifluoromethyl, phenoxy or benzyloxy radical;

R14 is hydrogen or a substituted or unsubstituted lower alkyl, lower alkoxy, halo, trifluoromethyl, phenoxy or benzyloxy radical;

Ri4a is hydrogen, substituted or unsubstituted lower alkyl, lower alkoxy, halo or trifluoromethyl; and under the conditions that the two radicals R14 and R14a are both hydrogen when R13 is a hydrogen, that the radical R14a is a hydrogen when R14 is a hydrogen, that at most one of R13 and R14 is the radical trifluoromethyl , that at most one of R13 and R14 is the phenoxy radical, and that at most one of R13 and R14 is the benzyloxy radical;

R® is hydrogen or a substituted or unsubstituted C1-4 alkyl radical, substituted or unsubstituted C3-6 cycloalkyl, C1-4 alkoxy (except tert-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy;

R9 is hydrogen or substituted or unsubstituted C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, provided that R9 is hydrogen when R8 is hydrogen, at most one of R8 and R® is the trifluromethyl radical, that at most one of the radicals R8 and R9 is the phenoxy radical, and that at most one of R8 and R9 is the benzyloxy radical;

rio and R11, independently of one another, are each chosen from the group comprising hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, adamantyl-1 or where R13, R14 and R14a are as defined above and q = 0.1, 2.3 or 4; Y is O, S or N-R10.

When Z is

Ka Rb

Ra is H or a substituted or unsubstituted primary or secondary C1-6 alkyl radical;

Rb is a substituted or unsubstituted primary or secondary C1-6 alkyl radical;

or Ra + Rt> form (CH2V or (cis) -CH2-CH = CH-CH2;

r = 2, 3, 4, 5 or 6;

R12 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl radical or

19

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

R '

13

R

14

where R8, R9, R13, R14 and R14a are as defined above. When Z is

R "

3

R

4

R

]

R '

16

R23 and R23a are the same or different and are each, independently of the other, chosen from the group comprising hydrogen, substituted or unsubstituted lower alkyl, lower alkoxy (except tert-butoxy), halo, trifluoromethyl, phenoxy radicals or benzyloxy; and on the conditions that R23a is hydrogen when R23 is hydrogen, that at most one of the radicals R23 and R23a is the trifluoromethyl radical, that at most one of the radicals R23 and R23a is the phenoxy radical, and that qu 'at most one of the radicals R23 and R23a is the benzyloxy radical.

When X is -CH2O- (carbon attached to P and O attached to Z), the hydrophobic anchor Z is an anchor of the phenyl or naphthalene type, as R15 and R16 are each H, Cl, Br, CN, CF3 or a radical phenyl, substituted or unsubstituted C1-C1 alkyl, (C2-8 alkoxy) carbonyl, -CH2OR17 or -CH2OCONHRI8;

R17 is H or a C1-C alkanoyl radical;

Ris is a substituted or unsubstituted alkyl radical or phenyl optionally substituted by F, Cl, Br or by a substituted or unsubstituted C1-C6 alkyl radical;

or R1s and R16, taken together, form - (CH2) s-, -CH2OCH2-, -CON (R19) CO-, or -CON-R20) N (R21) CO-;

s = 3 or 4;

R19 is H or a substituted or unsubstituted C1-6 alkyl radical, phenyl or benzyl;

R20 and R21 are each H, a substituted or unsubstituted C1-4 alkyl radical or benzyl; with the additional condition that when Z is

X can only be -CH2-, -CH2CH2-, -CH2CH2CH2-. When Z is

20

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

R23a C = C

- \ 22

23a

R "

R22 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, adamantyl-1 or t = 1, 2, 3, or 4;

- <cH2) t- <§>

Y

"2a or o o-

Thus, the compounds of formula I include

21

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

0

H y la R-P-CH- -CH-ŒL, -CO-R

1 2 s 2 2

"C OH m C I

Z

0

Ib R-P-Π- CH-CH-- CO-RX

1 2 i 2 2

CH OH •

"

CH (eis)

• Z

O

"- x

IC R-P-CH2-ÇH-CH2-C02Rx

CH OH

II

CH (trans)

Z

OH

Id R-P-CH - CH-CH - CO-R

x

ÇH2 OH

I

THIS

CH-I 2 Z

2; 2

OH

R-P-CH2-ÇH-CH2-C02R 'CH- ÔH

l 2 Z

X

22

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

O

If R-P-CH - ÇH-CH_-CO-RX

(P2) 3 OH

Z

0

"*

Ig R-P-CH- -CH-CH - CO-R,

/ 2 Ä 2 2

CH- ÒH

1 2

O

I.

Z

The terms "substituted or unsubstituted lower alkyl" or "substituted or unsubstituted alkyl", as used herein, alone or as part of another group, include straight or branched chain hydrocarbons containing from 1 to 12 atoms carbon in the straight chain and preferably from 1 to 7 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl radicals, octyl, 2,2,4-trimethylpentyle, no-nyle, décyle, undécyle, dodécyle, their various isomers with branched chain, as well as the hydrocarbon chains quoted previously carrying halogen substituents, like F, Br, Cl or I or CF3, an alkoxy substituent, an aryl substituent, an alkylaryl substituent, a halogenaryl substituent, a substituted or unsubstituted cycloalkyl substituent, an alkylcycloalkyl, hydroxy substituent, and an alkylamino substituent, a substituent t alkanoylamino, an arylcarbonylamino substituent, a nitro substituent, a cyano substituent, a thiol substituent or an alkylthio substituent.

The term "substituted or unsubstituted cycloalkyl", as used herein, alone or as part of another group, includes saturated cyclic hydrocarbon groups containing from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and which include cyclopropyl, cyclobu-tyle, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, each of these hydrocarbon groups may be substituted by one or two halogen or trifluoromethyl atoms, one or two lower alkyl groups, substituted or unsubstituted, one or two lower alkoxy groups, one or two hydroxy groups, one or two alkylamino groups, one or two alkanoylamino groups, one or two arylcarbonylamino groups, one or two amino groups, one or two nitro groups, one or two groups cyano, one or two thiol groups and / or one or two alkylthio groups.

The terms "aryia" or "Ar", as used herein, refer to monocyclic or bicyclic aromatic groups containing 6 to 10 carbon atoms in the cyclic moiety, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, substitution can be 1, 2 or 3 substituted or unsubstituted lower alkyl groups, halogens (Cl, Br or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups , 1, 2 or 3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups, 1,2 or 3 haloalkyl groups, 1,2 or 3 halophenyl groups, 1,2 or 3 allyl groups, 1,2 or 3 cycloalkylaikyl groups , 1,2 or 3 adamantylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoylamino groups, 1,2 or 3 arylcarbonylamino groups, 1,2 or 3 amino groups, 1, 2 or 3 nitro groups, 1 , 2 or 3 cyano groups, 1, 2 or 3 thiol groups and / or 1, 2 or 3 alkylthio groups, the aryan group preferably containing 3 substituents.

The terms "aralkyl", "arylalkyl" or "aryl- (substituted or unsubstituted lower alkyl)", as used herein, alone or as part of another group, denote substituted or unsubstituted lower alkyl groups, such as discussed above, and comprising an aryan substituent, for example benzyl.

The terms "lower alkoxy", "alkoxy" or "aryloxy" or "aralcoxy", as used herein, alone or as part of another group, include any of the substituted or unsubstituted lower alkyl, alkyl substituted or unsubstituted, aralkyl or aryie above, attached to an oxygen atom.

The terms "lower alkylthio", "alkylthio", "arylthio" or "arafkylthio", as used herein, alone or as part of another group, include any of the substituted or unsubstituted lower alkyl, alkyl substituted or unsubstituted, aralkyl or aryie above, attached to a sulfur atom.

The terms "lower alkylamino", "alkylamino", "arylamino", "arylalkylamino", as used herein, alone or as part of another group, include any of the groups aryie, substituted or unsubstituted alkyl, aryie or arylalkyl substituted or unsubstituted above, attached to a nitrogen atom.

23

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

The term "alkanoyie" as used herein as part of another group means a substituted or unsubstituted lower alkyl radical attached to a carbonyl group.

The terms "halogen" or "halo", as used herein, denote chlorine, bromine, fluorine and iodine, chlorine and fluorine being preferred.

The compounds of formula I having the following structure are preferred:

n R O CH- H CH2

i r z x ~

i -

Z: oh

wherein R is OH, OLi or CH3O; R * is Li or H;

X is —CH2—, —OH2CH2—1 —CH2CH2CH2—, —GH = GH-, —C ^ C— or —CH2O—; and

Z is where R1 is the phenyl radical, or a phenyl radical bearing an alkyl and / or halogen and trifluoromethyl substituent,

R1 is a cycloalkylalkyl radical, such as cyclohexylmethyl,

or else R1 is the benzyloxy radical, comprising a halogen or trifluoromethyl substituent;

R2 and R2a are identical and are each hydrogen, halogen, trifluoromethyl or a substituted or unsubstituted lower alkyl radical;

Z can also preferably be:

where R1 and R2 are as defined immediately above with respect to the compound of formula 11;

Z can also be, preferably

R3

at?

'r4

where R3 is a substituted phenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or phenylalkyl radical, and, R4 is a substituted phenyl radical, substituted or unsubstituted lower alkyl, such as isopropyl, substituted or unsubstituted cycloalkyl or phenyiaikyl; or Z can also be preferably

24

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

, A / W

where R5 is H, CH3 or OH, and R6 is

0 * 3

or a phenyl (substituted) -methyl radical, where R7 is H or CH3.

Z can also be preferably

CH.

'X>

TT T \ /

CH3 R

R '

or where at least one of the radicals R3 and R4 is a phenyl or substituted phenyl radical, the other radical R3 or R4 being a substituted or unsubstituted lower alkyl radical.

The compounds of formula I according to the invention can be prepared by the following reaction sequence, and the corresponding description.

25

Yes

O)

o

Ol

Ol

Ol o

Ol

4 * o co

Ol co o

N »Ol

IO

o

Sequence of reactions A. Preparation of compounds of formula I, in which X is -CH = CH-

OSi-C (CH3) 3

I-CH2-CH-GH2-C02alkyl

P (Oalkyl) 3 III

O II

alkyl0-P-CH2-CH-CH2-C02alkyl

^ Oalkyl '5si-C (CH3) 3

Arbuzov's reaction \

C6H5 C6H5

ro o

1. (CH3) 3SiBr, CH2C12 0

2. H20 H0 - ^ - CH2-eH-CH2-C02alkyl

Cleavage of the phosphonic ester

* '

OH 0 "

Si-C (CH,) -

/ \ 33

C6H5 C6H5

IV

Alcanol-DCC

Pyridine

•>

O

I have it

00

N)>

01

V

O | l alkyl0-P-CH2-ÇH-CH2C02alkyl

OH Ö i

Si-C (CH,)

/ \ 33

C6H5 C6HS

VI

4 ^ O

ro o

VI

1. (CH3) 3SiN (C2H5) 2 (TMSNEt2)

2. (C0C1) 2; CH2C12

(Formation of diacid chloride)

O

alkyl0-P-CH2-CH-CH2C02alkyl Cl O

Si-C (CHt) ~ / \

C6H5 C6H5 VII.

CHO I

Z

VIII

CBr ^, ph3P Wittig

->

CH = CBr0

I 2

Z

IX

Dehydrohalogenation>

1) n-BuLi

2) H20

C = CH I

Z

1) Formation of the Li anion (n-BuLi, THF)

2) Condensation with phosphono-chloride VII

OH

alkyl0-P-CH2-ÇH-CH2-C02alkyl

CEC? Z ^ 81 ^ (^ 3) 3

C6H5

C6H5

XI

CD O

Ol

Ol

Ol o

Ol

• £> o

CO

Ol

CO

o

N> Ol ro o

1) Cleavage of the silylether

XI (n-C4H9) 4NF # CH3COOH, THF

2) Hydrolysis (LiOH / dioxane)

0 II

ho-p-ch0 ~ ch ~ ch0co0h

1 2 at £ £

C ÖH

Iii C I

z

XA

XI

Selective reduction

H2, 10% Pd-C MeOH, 1 atra

0 he

H0-P-CH2-ÇH-CH2-C02H

. CH OH //

Z-CH

0 Ii

-) alkyl0-P-CH2-CH-CH2C02alkyl

.CH 0 ^ I

Si-C (CH.,),

/ \ 33

Z-CH (eis)

C6H5 C6H5 XII

1) Cleavage of the silylether

2) Hydrolysis

; ^

(eis)

IB

Ol Ol

Ol o

-P "

Ol o

N> Ol

N> O

xii

Reduction

H2 # 10% Pd-C MeOH, 350 kPa

O II

alkyl0-P-CH2-CH-CH2-C02alkyl ^ cleavage of silylether

/

ch,

CH.

ï k-

C6H5

c (ch3) 3 C6H5

2) Hydrolysis

0 II

HO-P-CHn-CH-CH0CQ0H

1 2 = 2 2

/ H2 OH ch2

xiii

ID

CD

Ol

Yes

O

Ol

Ol

Ol

O

Ol

■ fc. o

CO

Ol

CO

o ro

Ol ro o

co o

Sequence of reactions B. 'Preparation of compounds X in which the bond X (-CH = CH-) is

H I

C Hi

î

X

trans, that is to say

Hydros tanning (n-C4H9) 3SnH

AIBN, 120 C

// CH I

Z

XV

O II

H0-P-CH2 ~ ÇH-CH2C02H

yCH OH //

CH (trans)

? Z

IC

Sn (h-C4H9) 3 CH

lodation I0, Et00

CH I

Z

I I

CH

XVI

1) n-C4HgLi (Metallation)

2) VII

(Condensation)

0 X ci ci

01 09

N)>

Ol

in co o ro in ro o

o m

AlkylO-P-CH2-

: h ch

(trans)

ÇH-CH2C02alkyl ÔSi-C (CH ^) o

C6H5

C6H5

1 ") Cleavage of silylether ^

2.) LiOH, Dioxanne (hydrolysis)

xvii

0 h

ho-p-ch2 ~ çh-ch2co2h ch öh ch (trans)

Z

ic

O)

o

Cl Ol

Ol o

O!

O

CO

Ol co o

IO Ol ro o

Sequence of reactions C. Another mode of preparation of compound I in which the bond X

(-CH = CH ~) is trans, that is to say of the compound IC.

CHO!

Z

VIII

XXI

Condensation

LiCH2P (Oalkyl) 2

5—>

THF, -78 C

H0 dd> (Oalkyl) H ^) Elimination V ™, L, A p-TsOH

LiOH aqueous hydrolysis

dioxane

CH-CH "I 2

Z '

XX

? l • alç ^ lO-p-OH

^ CH

CH.

I (trans)

Z

XXII

benzene A

Acid chloride formation 1. (CH3) 3SiN (C2H5) 2 <TMSNEt2)

2. (C0C1) 2, Cat. DMF

O

H

P- (Oalkyl) 2 ^ CH

ÇH (trans)

Z

XXI

O II

ch2ci2

alkylo-P-Cl CH

I (trans) Z

XXIII

Ol Ol

Ol o

4 *. Ol o

CO Ol ro

Ol

Condensation Q

0

XXIII oe oe alkvl0-P-CHo-c! -CH9-C09alkyl Reduction

I I * I. 2 * * NaBH.

sCH

CH2 CH Oalkyl CH

■>

o 'Z

THF, -78 C

XXIV

, c2h5oh

0 OH o OH

alkyl (> P-CH2-CH-CH2C02alkyl Hydrolysis H0-P-CH2-CH-CH2C02H

ch 0h ch t! '^ 9h

✓

I dioxane •

n Z

IC1 IC

O)

o

Ol

Ol

Ol o

Ol

• fx o

CO

Ol

CO

o

Ol

N> O

Sequence of reactions D. Preparation of compounds of formula X in which X is -CH ,.

-ch2ch2- or -ch2ch2ch2- 1

CHO I

z viii

Cl

• K '«

z

(a is 1, 2 or 3)

xxv

0 m

AlkylO-P-Cl z

xxvii

(AlkylO) 3P iii.

AT

, e

e o

CH0 CH Oalkyl _>

THF coupling, -78 ° C

S

P (Oalkyl) 2

"PVa z

xxvi

1. OH

2. TMSNEt,

3. (C0C1) 2, Cat. DMF

(Formation of acid chloride)

Ô

alkyl0 - ^ - CH2-C-CH2 ~ C02alkyl Reduction

(çii2) a 0

xxviii

NaBH j c2h5oh

->

4 * in co CJì

0 OH

H t ilkyl0-P-CH2-CH-CH2C02alkyl Z

ID1 (a = 2)

IE1 (a = l)

IF1 (a = 3)

ro

Ol ro o

O OH

-, II I

Hydrolysis HO-P-CHo-CH-CH ^ CO-H

-: ^ i 2 2 2 o

/ _ ICH I I

aqueous OH lY 2'a o>

Z al ai

ID (a = 2) 5

>

IE (a "l)

IF (a = 3)

O)

o

Ol in

Ol o

4 *. Ol

O

CO

Ol

CO O

N) Ol ro o

Sequence of reactions E. Preparation of the compounds of formula I in which X is -CH

CHO I

Z

VIII

1. Oxidation of

Baeyer-Villiger (MCPBA) |

OH

2. Basic hydrolysis

XXIX

Alkylation TsO-CH2-PO (Oalkyl) 2

XXX

Based

PO (Oalkyl) -I 4

/ H2

Aqueous hydrolysis (LiOH)

dioxane

XXXI

O II

alkylO-P-OH "2

0

1

Z

XXXII

Acid chloride formation

1) TMSNEt2

2) (C0Cl) o

- »

Cat. DMF, CHC12

Ol o

Ol o

CO

o

IO Ol ro o

0 II

alkyl-O - ^ - Cl CH,

Î

Z

/ 2

XXXIII

Condensation f îe ^ c \

CH,

CH Oalkyl

THF, -78 ° C

0 ii alkyl0 - ^ "- CH2-C-CH2C02alkyl

/ Cfl2

?

z

XXXIV

NaBH reduction.

c2h5oh

0 ii

OH

I

alkyl0 - ^ - CH2-CH-CH2C02alkyl

?

CH0 / 2

OH hydrolysis "

dioxane

IG

->

R

T

CH,

Î

H

ho - ^> - ch2-ch-ch2co2h

/ 2

î

Z

IG

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

As seen in the reaction sequence "A" above, the compounds of formula I can be prepared by subjecting iodide A to an Arbuzov reaction, by heating iodide A

? 6H5

O-Si-CfCH ^

C6H5

I-CH2-C-CH2-C02alkyl i

and phosphite III III P (Oalkyl) 3

using standard Arbuzov reaction conditions and procedures to form phosphonate IV

O

IV alkylO-P CH2 CH-CH2-CC> 2 alkyl

Oalkyl OSi-C (CH3) 3

C6H5

(a new intermediary).

Then phosphonate IV is subjected to cleavage of the phosphoric ester, by treatment of a solution of phosphonate IV in an inert organic solvent, such as methylene chloride, then subsequently with bis (trimethylsilyl) trifluoroacetamide (BSTFA) and trimethylsilyl bromide, under an inert atmosphere, for example argon, to form phosphonic acid V

O M

V. H0-P-CH2-ÇH-CH2-C02alkyl OH Ô

(Si-C (CH3) 3

(a new intermediary).

Phosphonic acid V is esterified by treating compound V, in dry pyridine, with a lower alkyl alcohol (such as methanol) and dicyclohexyl-carbodiimide, then the reaction mixture obtained is stirred under an inert atmosphere, for example d 'argon, to form the mo-noalkyl phosphonic ester VI (a new intermediate). The phosphonic monoester VI is then dissolved in an inert organic solvent, such as methylene chloride, benzene or tetrahydrofuran (THF), and treated with trimethylsilyidiethylamine, and stirred under an inert atmosphere, for example of argon, then the mixture is evaporated and then dissolved in appropriate methylene chloride (or other inert organic solvent). The solution obtained is cooled to a temperature between about -10 and about 0 ° C, treated with oxalyl chloride and catalytic dimethylformamide, then evaporated to give the crude phosphonochloridate VII (a new intermediate). Phosphonochloridate VII is dissolved in an inert organic solvent, such as methylene chloride, benzene, pyridine or THF, the solution is cooled to a temperature between about -90 and about 0 ° C, and preferably between about - 85 and about -30 ° C and treated with a cooled solution (over the same temperature range as the phosphonochloridate solution VII) of the lithinated acetylene anion X, formed by treatment using a source of lithium, such as N-butyllithium in hexane or another inert solvent,

38

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

X C — CH

I

using a mole ratio, between compounds VII and X, of between approximately 3: 1 and approximately 1: 1, preferably between approximately 1.5: 1 and approximately 2: 1, to form acetylenic phosphinate XI

XI alkylO-P CH2 ÇH-CH2-C02 alkyl

5

Si-C (CH3) 3.

C6H5

(a new intermediary)

One can then use acetylenic phosphinate XI to prepare the various compounds of the present invention, as follows.

Acetylenic phosphinate XI is converted into acetylenic phosphinate IA1 by subjecting compound XI to cleavage of the silylether, by treatment of compound XI in an inert organic solvent, such as t-trahydrofuran with glacial acetic acid and tetrabutylammonium fluoride, to form the IA1 ester

0

IA1 alkyl0-P-CH2-ÇH-CH2-C02alkyl

C ÔH

m C

1

Z

which can then be hydrolyzed to the corresponding salt or basic acid, i.e. when Rx is Rxa, which represents ammonium, an alkali metal, an alkaline earth metal, an amine and the like, by treatment with a strong base such as lithium hydroxide, in the presence of dioxane, tetrahydro-furan or another inert organic solvent, under an inert atmosphere, for example of argon, at 25 ° C., using a ratio of moles between the base and the ester IA1 of between approximately 1: 1 and approximately 1.1: 1, to form the corresponding basic salt

0

2 'I

IA alkyl0- |> -CH2-CH-CH2-C02-Rxa

C ÔH lll

VS

1

Z

The compound IA2 can then be treated with a strong acid, such as HCl, to form the corresponding acid IA3

IA3 alkyl0 - ^ - CH2-ÇH-CH2-C02H

C OH

Iii

VS

39

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

The IA1 ester can be converted into the corresponding dibasic salt, by treatment of the IA1 ester with a strong base at 50-60 ° G, with a molar ratio, between the base and the IA1 ester, of between approximately 2 : 1 and about 4: 1, to form compound IA *

0

IA4 RXa0-P-CH2-ÇH-CH2-C02RXa

C ÔH

ut

VS

1

Z

The dibasic salt IA4 can be converted to the corresponding acid, by treatment with a strong acid, such as HCl, to form the acid IA.

The phosphinate compounds of the invention, in which X is (cis) -CH = CH-, that is to say IB, are formed by subjecting acetylenic phosphinate XI to a selective reduction, for example by treating compound XI with H2 in the presence of a reduction catalyst, for example palladium on charcoal, palladium on barium carbonate and an inert organic solvent, such as methanol, to form silylether XII

O

XII alkyÎO-P-CH2 — ÇH-CH2 C02 - alkyl

CH O

ÇH k-C (CH3) 3 2 C6H5 C6H5

(a new intermediary)

Silylether XII can then be subjected to cleavage of the silylether and to hydrolysis, as described above, to form the ester IB1

0

1 11

IB alkyl0-P-CH2-ÇH-CH2-C02-alkyl

CH ÔH u

(eis) CH

1

Z

0

If i alkylO-P-CH2-ÇH-CH2-C02R,

CH ÖH

M

(eis) CH

1

Z

1B3 acid

IB2 basic salt

IB2

40

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

0

IB3 alkyl0 - ^ - CH2-ÇH-CH2-C02H

CH ÔH H

(cis) CH

1

Z

IB4 dibasic metal salt

O

Iß4 RXa0- | -CH2-ÇH-CH2-C02RXa

CH ÔH H

(eis) ÇH Z

and the corresponding diacid IB.

The phosphinate compounds of the invention are formed in which X is -CH2-CH2-, that is to say ID, by subjecting acetylenic phosphinate XII to a catalytic reduction, for example by treating compound XI with H2 in the presence a reduction catalyst, such as palladium on carbon, and in an inert organic solvent, such as methanol, under a pressure of 350 kPa (50 psi), to form silylether XIII

0

II

XIII alkylO-P-CH2 — CH-CH2CO2-alkyl

CH- Ö

1 2 t.

CH- ^ Sl-C (CH -) -

f 2 \ 3 '3

Z CcH- C, Hc 6 5 6 5

(a new intermediary)

Silylether XIII can then be subjected to cleavage of the silylether and to hydrolysis as described above, to form the ester ID1.

0

alkyl0-P-CH2-CH-CH2-C02-alkyl

CH- ÔH

1 2

CH-l 2 Z

ID1

ID2 basic salt

O

ID2 alkylO-j? -CH - CH-CH - CO-RXa,

2 r

ÇH2 ÔH

CH-I 2

Z

ID3 acid

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CH 675 582 A5

O d alkylO-P-CH2-ÇH-CH2-C02H

CH- OH {2

P2

Z

0

ID4 RXaO-P-CH - CH-CH - CO-RXa

1 2 z 2 2

? H2 ÖH

CH-f 2

Z

and the corresponding diacid ID.

Referring now to the sequence of reactions B, one can prepare compounds of formula I, in which the linking group X between the phosphorus atom and the hydrophobic anchor Z is (trans) -CH = CH - By treating a mixture of acetylene X and nC ^ SnH with a radical promoter, such as azobisisobutyronitrile (AIBN), hydrogen peroxide, benzoyl peroxide and the like, and heating the solution obtained to a temperature between approximately 100 and approximately 140 ° C., under an inert atmosphere, for example of argon, to form vinylstannane XV

SnCn-C ^ Hç) 3

XV CH

//

CH i

Z

Vinylstannane XV, dissolved in an organic solvent, for example ethyl ether, methylene chloride or chloroform, is treated with iodine and stirred under an inert atmosphere, for example argon, to form iodide of vinyl XVI

ï

XVI CH

//

CH i

Z

A cooled solution of vinyl iodide XVI (-78 to -40 ° C) in a dry organic solvent, such as tetrahydrofuran or ethyl ether, is treated with a metallization agent, such as N-butyllithium, in a inert organic solvent such as hexane, and the mixture is cooled to a temperature of -78 to -40 ° C under an inert atmosphere, for example of argon. The anion is added to a cooled solution (-78 to -40 ° C) of phosphonochlorurate VII, in a molar ratio, between compound XVI and compound VII, comprised between approximately 1: 1 and approximately 2: 1, and preferably between about 1: 1 and about 1.5: 1, in a dry inert organic solvent such as tetrahydrofuran or ethyl ether, to form silylether XVII

ID3

dibasic salt ID *

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CH 675 582 A5

O

XVII alkylO - ^ - CH2-ÇH-CH2-C02 alkyl

<trans) jm ^ Oßi-C (CH ^) 3

CH C, Ht.XsCÄHe;

I 6 5 6 5

Z

(a new intermediary).

Silylether XVII is subjected to cleavage of silylether by treatment of a solution of compound XVII in an inert organic solvent, such as tetrahydrofuran or acetonitrile, with glacial acetic acid and a solution of (nC ^ g ^ NF in an organic solvent such as tetrahydrofuran, to form the hydroxy diester IC1

O

IC ^ alkyl0-P-CH2-ÇH-CH2-C02alkyl

{trans) ^ CH OE

CH »

Z

The diester IC1 can then be hydrolyzed as described above, to form the basic salt IC2,

O

9 11 go

IC ^ .alkyl0-P-CH2-CH-CH2C02RÂa

(trans) CH OH ■ r

CH '

IC3 acid

Z

O

3 ''

IC alkyl0-î-CH2-ÇH-CH2-C02H

CH ÔH

CH I

Z

basic salt IO

O

IC4 RXa0-P-CH2-ÇH-CH2-C02RXa y /

CH

f

Z

and the corresponding diacid IC

CH ÖH

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CH 675 582 A5

O

ic. ho-p-ch - ch-ch - co-h | 2 - 2 2

ch öh hc k

In another process, as represented by the reaction sequence “C”, the compounds of formula I can be prepared, in which the linking group X between the phosphorus atom and the hydrophobic anchor Z is (trans) - CH = CH-, subjecting the aldehyde VIII

CHO 1

VIII Z

a condensation reaction with a cooled solution (-90 to 0 ° C) of dialkyl methylphosphonate and butyllithium (LiCH2PO (alkyl) 2) in the presence of an organic solvent such as tetrahydrofuran or ethyl ether, to form ß-hydroxyphosphonate XX

O 11

xx ho-ch-ch2

P (Oalkyl) 2

I

Then the ß-hydroxyphosphonate XX is treated with p-toluene sulfonic acid in the presence of benzene or toluene, while heating to a temperature between approximately 50 and approximately 120 ° C., preferably at reflux, to remove the water and form the XXI trans-olefin

O

P (Oalkyl) 2 XXI (trans) CH

y /

CH I

Z

which is hydrolyzed by treatment with an alkali metal hydroxide in aqueous solution, such as LiOH, in the presence of dioxane or another inert organic solvent, then with an acid such as hydrochloric acid, to form the ester of monoacid XXII

O 11

alkylO-P-OH

XXII (trans) CH

CH i z

A solution of the monoacid ester XXII in dry methylene chloride is treated with trimethylsilyidiethylamine. The mixture is evaporated, and the oil obtained is taken up in dry methylene chloride cooled to 0 ° C., and treated with oxalyl chloride and a catalytic amount of dimethylform-amide, under an inert atmosphere, for example of argon, to form phosphonochloridate XXIII

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CH 675 582 A5

O 11

alkylO-P-Cl XXIII (trans) ^ CH

CH

23

The phosphonochloridate XXIII is condensed with an alkyl acetoacetate dianion, such as the methyl acetoacetate dianion, in the presence of an inert organic solvent such as tetrahydrofuran, at a reduced temperature, from -90 to -40 ° C., using a mole ratio between phosphonochloridate and dianion of between about 1: 1 and about 0.75: 1, to form the ketophosphate XXIV

O O

II (I

XXIV alkylO-P-CH, -C-CH2-C02 alkyl

(trans) CH &

CH i

Z

(a new intermediary)

which is reduced by treatment with a reducing agent such as sodium borohydride in the presence of an al-canol such as ethanol, to form the phosphinate IC1

O

1 "

IC1 alkylO-P-CH2 -CH-CH2 -C02 alkyl

(trans) ^ CH OH

CH l

Z

The diester IC1 can then be hydrolyzed as described above, to form the basic salt IC2,

O

IC2 alkylO-P-CH ^ -CH-CH2 C02 Rx a}

(trans) CH OH //

CH i

Z

IC3 acid

O

x w

IC3 alkylO-P-CH2 -ÇH-CHj -C02 H J

(trans) CH OH

CH 1

z basic salt IC4

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CH 675 582 A5

O

NOT

ic4 rx a o-p-ch2 -ch-ch2 -co2 rx 3

(trans) ch oh

CH ^

i z

and the corresponding diacid IC.

By reference to the reaction sequence D, it is possible to prepare compounds of formula I in which X is - (CH2) a-, and a is 1, 2 or 3, i.e. -CH2-, -CH2CH2 - or -CH2CH2H2-, starting from aldehyde VIII which is converted into the Villa halide by conventional techniques. For example, aldehyde VIII can be reduced with NaBm in the presence of ethanol and ether, to form the corresponding alcohol

Villa this, oh

Z

which is treated with mesyl chloride in the presence of an organic base, such as triethylamine, and a solvent such as methylene chloride, to form chloride XV (a = 1).

Chloride XV is subjected to a condensation reaction, during which compound XV is treated with phosphite III using a mole ratio between compounds III and XXV of between approximately 1: 1 and approximately 10: 1, and at a temperature between about 100 and about 150 ° C, to form the phosphonate diester XXVI. A solution of the phosphonate diester XXVI in a solvent, such as dioxane, is treated with a strong base, such as an alkali metal hydroxide, for example LiOH, to form the corresponding monoester, which is treated with oxalyl chloride in the presence of 'An inert organic solvent, such as dimethylformamide, to form the corresponding phosphonochloridate XXVII. Compound XXVII is condensed with an alkyl acetoacetate dianion, such as methyl acetoacetate dianion, in the presence of an organic solvent such as tetrahydrofuran, at reduced temperatures, from about -90 to about -40 ° C, using a molar ratio between phosphonochloridate XXVII and dianion of between about 1: 1 and 0.75: 1, to form ketophosphinate XXVII, which is a new intermediate. Then cetophosphinate XXVII can be reduced to the corresponding phosphinate ID1, IE1 and IP, which can be hydrolyzed to form the corresponding diacids ID, IE and IF, using techniques as described in connection with the reaction sequence C.

With reference to reaction sequence E, compounds of formula I can be prepared, in which X is -CH2O-, starting from aldehyde VIII, which is subjected to Baeyer-Villi-ger oxidation, by reaction of compound Vili on meta-chloroperbenzoic acid (MCPBA) in the presence of an inert organic solvent, such as methylene chloride, then on a strong base, such as an alkali metal hydroxide, for example KOH or NaOH, and d 'a solvent such as tetrahydrofuran, to form the corresponding alcohol XXIX. Alcohol XXIX is alkylated by treating compound XXIX with sodium hydride in the presence of an inert organic solvent, such as dimethylformamide, under an inert atmosphere, for example argon, and a solution of a dialkyl tosyloxymethylphosphonate XXX, using a mole ratio between compounds XXX and XXIX of between about 1: 1 and about 3: 1, to form the corresponding dialkyl ester XXXI. The rest of the synthesis, described in reaction sequence E, which forms the monoester XXXII, the chloride XXXIII, the ketophosphinate XXXIV (a new intermediate), the diester IG1 and the diacid IG, is analogous to what is said above. above about the reaction sequence D.

Acetylene starting material X can be prepared from the corresponding aldehyde VIII

viii cho

)

z by subjecting compound VIII to a Wittig reaction, for example by treating a cooled solution of compound VIII (-25 to 0 ° C) in triphenylphosphine, and an inert organic solvent such as methylene chloride, with a solution of tetrabromomethane (CBu) in an inert organic solvent such as methylene chloride, to form vinyl dibromide IX

ix ch = CBr2

I

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CH 675 582 A5

Compound IX is subjected to dehydrohalogenation, treating it with N-butyllithium in an inert organic solvent, such as hexane, under an inert atmosphere, to give compound X.

Alternatively, aldehyde VIII can be converted directly to acetylene X, by treatment with dimethyl diazomethylphosphonate in the presence of potassium tert-butoxide in an inert solvent such as tetrahydrofuran (-78 to 25 ° C) under inert atmosphere.

The iodide A starting material can be prepared starting from the bromide Ç

10 oh

ç Br-CH2 -CH-CIL, C02 alkyl

(which are prepared using the techniques described in Tetrahedron Lett. 26, 2951 (1985)),

which is dissolved in a solution in dimethylformamide (DMF) with imidazole and 4-dimé-15-thylamino-pyridine, and the solution obtained is treated with tert-butyldiphenyl-silyl chloride, under an inert atmosphere, for example argon, to form silylether D

20

C6 ^ C6H5

OSi-C (CHj) 3 D Br-CH2 -CH-CH2 C02 alkyl

A solution of silylether D in an inert organic solvent, such as methyl ethyl ketone or DMF, is treated with sodium iodide under an inert atmosphere, for example argon, to form iodide A.

The starting aldehyde compounds VIII, i.e.

30

VIII CHO

!

Z

are known compounds.

The various intermediaries IV, V, VI, VII, XI, XII, XIII, XVII and XXIV also come within the scope of the present invention. These new intermediaries can be represented by the following general formulas:

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XXXV o

XXXV R ^ -P-CH2-ÇH-CH2-C02alkyl

OSi-C (CH3) 3

C6H5 C6H5

including all their stereoisomers, where R1 is an alkoxy or hydroxy radical, and R1 is an alkoxy, hydroxy, Cl, -CH2-Z, -CH2CH2CH2-Z, -CH20-Z, -C = CZ, -CH = CH radical -Z, -CH2CH2-Z, where Z is a hydrophobic anchor as defined above; provided that when R1 is a hydroxy radical, R1 is preferably a hydroxy or alkoxy radical; and

0 \

XXXVI alkylO-P-CH, -C-CH, -CO, alkyl

1 2 »2 2

X O!

z where Z is as defined above, including all of its stereoisomers.

The compounds of the invention can be prepared in the form of racemic mixtures, and can be subsequently split to give the S isomer, which is preferred. However, the compounds of the invention

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CH 675 582 A5

can be directly prepared in the form of their S isomers, as described in the present invention and in the examples presented below.

The compounds of the invention are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) -reductase, and are useful for inhibiting the biosynthesis of cholesterol, as will be demonstrated by tests below.

1) HMG-CoA-reductase from rat liver

The activity of rat liver HMG-CoA-reductase is measured using a variant of the method described by Edwards (Edwards, P.A. et al., J. Lipid Res. 20:40, 1979). As the enzyme source, hepatic microsomes from rats are used, and the enzyme activity is determined by measuring the conversion of the substrate C-HMG-CoA to 14C-mevalonic acid.

at. Preparation of microsomes

The livers of 2-4 Sprague Dawley rats, decapitated, fed with cholestyramine are taken and homogenized in a phosphate A buffer (potassium phosphate, 0.04 M, pH 7.2; KCl, 0.05 M; sucrose, 0.1 M; EDTA, 0.03 M; aprotinin, 500 KfU units / ml). The homogenate is centrifuged at 16,000 g for 15 min. at 4 ° C. The supernatant is removed and recentrifuged under the same conditions a second time. The 16,000 g supernatant is centrifuged at 100,000 g for 70 min. at 4 ° C. The microsome pellet is resuspended in a minimum volume of buffer A (3-5 ml / liver), and homogenized in a glass / glass homogenizer. Add dithiothreitol (10 mM), take aliquots of the preparation, freeze it in acetone / dry ice, then store it at -80 ° C. The specific activity of the first microsomal preparation was 0.68 nmole of mevalonic acid / mg protein / min.

bi Enzyme analysis

The reductase is analyzed in a volume of 0.25 ml, containing the following components, at the final concentrations indicated:

0.04 M Potassium phosphate, pH 7.0 0.05 M KCl 0.10 M Sucrose 0.03 M EDTA 0.01 M Dithiothreitol 3.5 mM NaCI 1% Dimethyl sulfoxide 50-200 jig Microsomal protein 100 (ig 14C - [DL] HMG-CoA (0.05 pg Ci, 30-60 mCi / mmole)

2.7 mM NADPH (nicotinamide-adenine-dinucleotide-phosphate)

The reaction mixtures are incubated at 37 ° C. Under the conditions described, the activity of the enzyme increases linearly up to 300 ng of microsomal protein per reaction mixture, and it is linear compared to the incubation time, up to 30 min. The standard incubation time chosen for the drug studies is 20 min., Which gives a conversion rate of 12-15% of the HMG-CoA substrate into the mevalonic acid product. The substrate [DL-] HMG-CoA is used at 100 nM or twice the concentration necessary for the saturation of the enzyme under the conditions described. NADPH is used in excess, at a concentration 2.7 times higher than the concentration required to obtain a maximum speed of the enzyme.

The calibrated analyzes, used for the evaluation of the inhibitors, are carried out according to the following procedure. The microsomal enzyme is incubated in the presence of NADPH at 37 ° C for 15 min. The DMSO vehicle is added, with or without the test compound, and the mixture is further incubated for 15 min. at 37 ° C. The enzymatic analysis is triggered by adding the substrate wC-HMG-CoA. After 20 min. incubation at 37 ° C, the reaction was stopped by the addition of 25 µl of 33% KOH. 3H-mevalonic acid (0.05 jiCi) is added, and the reaction mixture is allowed to stand at room temperature for 30 min. 50 μl of 5N HCl are added to lactonize the mevalonic acid. Bro-mophenol blue is added as a pH indicator to monitor the proper drop in pH. The lactonization is allowed to continue for 30 min. at room temperature. The reaction mixtures are centrifuged for 15 min. at 2800 rpm. The supernatants are deposited on 2 g of an anion exchange resin AG 1-X8 (Biorad, formate form), poured into glass columns of 0.7 cm (internal diameter), the elution being carried out with 2, 0 ml of H2O. The first 0.5 ml is thrown away, and the following 1.5 ml are collected and counted with tritium and carbon-14 in 10.0 ml of an opti-fluorine scintillation fluid. The results are calculated in nmoles of mevalonic acid produced in 20 min., And they are corrected to 100% recovery of tritium. Drug effects are expressed as I50 (drug concentration leading to 50% inhibition of enzyme activity), which is obtained from responses to a composite dose, with the 95% confidence interval indicated.

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CH 675 582 A5

The conversion of the drugs in lactone form to their sodium salts is carried out by solubilization of the lactone in DMSO, addition of a 10-fold molar excess of NaOH, the mixture then being able to stand at room temperature for 15 min. Then the mixture is partially neutralized (pH 7.5-8.0) using 1N HCl and diluted in the enzymatic reaction mixture.

2) Synthesis of cholesterol in the hepatocytes of freshly isolated rats

The ability of compounds exhibiting activity as HMG-CoA-reductase inhibitors to inhibit the incorporation of 14C-acetate into cholesterol from suspensions of freshly isolated rat hepatocytes was evaluated by the use of methods initially described by Capuzzi et al. (Capuzzi, D.M. and Margolis, S., Lipids, 6: 602.1971).

at. Isolation of rat hepatocytes

Sprague Dawley rats (180-220 g) are anesthetized with Nembutol (50 mg / kg). We open the abdomen, and we ligate the first branch of the portal vein. Heparin (100-200 units) is injected directly into the abdominal vena cava. A single closure suture is placed in the distal section of the portal vein, and the portal vein is cannulated between the suture and the first branch. The liver is perfused at a rate of 20 ml / min. with an oxygenated buffer A preheated to 37 ° C (HBSS without calcium or magnesium containing 0.5 mmol EDTA), after having sectioned the vena cava to allow evacuation of the ef-fluent. In addition, an infusion of the liver is carried out with 200 ml of preheated buffer B (HBSS containing 0.05% bacterial collagenase). After perfusion with buffer B, the liver is excised and decapsulated in 60 ml of Waymouth medium, the free cells then being able to disperse in the medium. The hepatocytes are isolated by centrifugation at low speed for 3 min. at 50 g at room temperature. The hepatocyte pellet is washed once with Waymouth medium, counted, then subjected to a viability analysis by exclusion with trypan blue. These cell suspensions, enriched in hepatocytes, usually have a viability of 70 to 90%.

b) Incorporation of 14C-acetate into cholesterol

The hepatocytes are resuspended, at a rate of 5 × 10 6 cells per 2.0 ml, in the incubation medium (IM) [0.02 M tris-HCl (pH 7.4), 0.1 M KCl, 3.3 mM sodium citrate, 6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate].

The test compounds are systematically dissolved in DMSO or DMSO: H2O (1: 3), and added to the IM medium. The final concentration of DMSO in the IM medium is <1.0%, and has no significant effect on the synthesis of cholesterol.

Incubation is started by adding i4C-acetate (58 mCi / mmol, 2 dxCi / ml), and placing the cell suspensions (2.0 ml) in 35 mm tissue culture dishes at 37 ° C for 2 0 hours. After incubation, the cell suspensions are transferred to glass centrifuge tubes, and centrifuged at 50 g for 3 min. at room temperature. The cell pellets are resuspended and lysed in 1.0 ml of H2O, then placed in an ice bath.

The lipids are extracted essentially as described by Bligh, E.G. and W.J. Dyer, Can. J. Biochem. and Physiol., 37: 911, 1959. The lower organic phase is removed and dried under a stream of nitrogen, and the residue is resuspended in 100 µl of a 2: 1 mixture of chloroform and methanol. The entire sample is applied to silica gel plates (LK6D) for thin layer chromatography, and developed in a 75: 25: 1 mixture of hexane: ethyl ether: ethyl acetate. Detection and counting is carried out using an automatic BioScan system. The radiolabelling in the cholesterol peak (RF 0.28) is determined and expressed by the total number of counts per peak, and as a percentage of the radioactivity of the total lipid extract. The cholesterol peaks of the control cultures usually contain from 800 to 1000 cpm, and account for 9 to 20% of the radioactivity present in the total lipid extract; these results are compatible with those of Capuzzi et al., which indicate 9% of the radioactivity extracted in cholesterol.

The effects of the drug (% inhibition of cholesterol synthesis) are determined by comparison of the percentage of radioactivity in cholesterol, for the control cultures and the cultures treated with the drug. Dose / response curves are constructed from composite data from at least two studies, and the results are expressed by the I50 with a 95% confidence interval.

3) Synthesis of cholesterol in human skin fibroblasts

The selectivity of the compound, which would promote better inhibitory activity in liver tissue, should be a feature of an inhibitor of cholesterol synthesis. Consequently, in addition to the evaluation of inhibitors of the synthesis of cholesterol in hepatocytes, these compounds are also the subject of tests, relating to their activity as inhibitors of the synthesis of cholesterol in fibroblasts in culture.

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CH 675 582 A5

a) Cultures of fibroblasts of human skin

Human skin fibroblasts (passages 7-27) are cultured on minimal Eagles (EM) essential medium containing 10% fetal calf serum. For each experiment, the mother cultures are trypsonized to disperse the cell monolayer, counted and placed in 35 ml reservoirs for cell cultures (5 × 10 5 cells / 2.0 ml). The cultures are incubated for 18 hours at 37 ° C. in ambient air humidified to 95% and containing 5% of CO2. Cholesterol biosynthesis enzymes are induced by eliminating the medium containing the serum, washing the cell monolayers and adding 1.0 ml of the EM medium containing 1.0% of fatty acid-free bovine serum albumin, and the cultures are incubated for another 24 hours.

b) Incorporation of i4C-acetate into cholesterol

The cultures of induced fibroblasts are washed with the minimal essential medium of Earle EMEM100. Test compounds are dissolved in DMSO or DMSO: EM (1: 3) (final concentration of DMSO in cell cultures less than or equal to 1.0%), added to cultures, and cultures are preincubated for 30 min. at 37 ° C in ambient air humidified to 95% and containing 5% of CO2. After preincubation with the drugs, [1-14G] sodium acetate (2.0 µCi / ml, 58 mCi / mmol) is added, and the cultures are reincubated for 4 hours. After incubation, the culture medium is eliminated and the cell monolayer (200 ng of cellular protein per culture) is transferred by scraping into 1.0 ml of H2O. The lipids present in the lysed cell suspension are extracted into chloroform: methanol, as described with regard to the hepatocyte suspensions. The organic phase is dried under nitrogen, and the residue is resuspended in chloroform: methanol (2: 1) (100 µl), and the entire sample is applied to silica gel plates (LK6D) to Thin layer chromatography, and analyzed as described for hepatocytes.

The inhibition of cholesterol synthesis is determined by comparing the radioactivity in the cholesterol peak, in the control cultures and the cultures treated with the drug (in%). The results are expressed by the I50, and are derived from composite dose / response curves from at least two experiments. We also calculate, from the composite dose / response curves, a 95% confidence interval for the Iso-

Another subject of the present invention relates to a pharmaceutical composition comprising at least one of the compounds of formula I, in combination with a pharmaceutical excipient or diluent. The pharmaceutical composition can be formulated using conventional solid or liquid excipients or diluents, and pharmaceutical additives of a type suitable for the desired mode of administration. The compounds can be administered orally, for example in the form of tablets, capsules, granules or powders, or they can be administered parenterally in the form of injections, these dosage forms containing from 1 to 2000 mg active ingredient per dose, for use in treatment. The dose to be administered depends on the unit dose, the symptoms, and the patient's age and body weight.

The compounds of formula I can be administered in a manner analogous to that of known compounds, the use of which is proposed for inhibiting the biosynthesis of cholesterol, such as lovastatin, in mammalian species such as man, dog, cat and the like. Thus, the compounds of the invention can be administered in an amount of between approximately 4 and 2000 mg in a single dose, or in the form of individual doses, 1 to 4 times per day, preferably from 4 to 200 mg in divided doses. from 1 to 100 mg, preferably from 0.5 to 50 mg 2 to 4 times a day, or in a delayed form.

The following examples represent preferred embodiments of the present invention. Unless otherwise stated, all temperatures are in degrees Celsius. Flash chromatography was performed on Merck 60 or Whatmann LPS-1 silica gel. Reverse phase chromatography was performed on a CHP-20 MCI gel resin, supplied by Mitsubishi, Ltd.

When used in the examples below, the abbreviations "Et20", "EtOAc", "MeOH" and "EtOH" represent ethyl ether, ethyl acetate, methanol and ethanol respectively.

Example 1

Methyl acid ester (SV4-rf2-f4 / -fluoro-3.3'.5-trimethvin.1, -biphénvn-2-vnethvnméthoxvDhosphinvn-3-hvdroxvbutanoïaue

A. N-f2.4-Dimethvlbenzlvidènetoenzene-amine

Ref. Merck U.S. Patent No. 4,375,475, p. 39.

A freshly distilled solution of 2,4-dimethylbenzaldehyde (Aldrich, 6.97 ml, 50 mmol) was heated at reflux for 3.0 hours under an argon atmosphere, in a flask fitted with a Dean-Stark apparatus. distilled aniline (Aldrich, 4.56 ml, 50 mmol) in dry toluene (80.0 ml). The mixture was cooled, then evaporated in vacuo to give a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm Hg, 160-180 ° C) to give 8.172 g (78.1%) of the title benzeneimine, researched

50

CH 675 582 A5

chée, in the form of a light yellow oil, which crystallized on standing to give a solid with a low melting point. TLC (4: 1) Hex-acetone, Rf = 0.67 and 0.77 (geometric isomers), U.V. and k.

Ref. Merck, U.S. Patent No. 4,375,475, p. 39.

A mixture of benzeneimine A (6.0 g, 28.7 mmol) in glacial HOAC (144 ml) was treated with palladium (II) acetate (6.44 g, 28.7 mmol). and the clear red homogeneous solution was heated at reflux under argon for 1 hour. The cloudy mixture obtained was filtered hot through a 12.7 mm packed bed of Celite in 900 ml of H2O. The precipitated solid, orange, was collected by filtration and dried under vacuum at 65 ° C over P2O5 for 16 hours to give 10.6 g (85.5%) of the title palladium complex, in the form a solid orange, pf = 194-196 ° C (m.p. from the literature for a recrystallized analytical sample: 203-205 ° C).

30 C. 4'-Fluoro-3.3'.5-trimethviï1.1'-biDhénvl1-2-carboxaldéhvde

(1Ì Bromor4-fluoro-3-methvlphénvnmaanèse

Ref. Merck, U.S. Patent No. 4,375,475, p. 37 and 38.

The Grignard reagent C (1) of the title was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmol, Fairfield Chemical Co.), dropwise and at a rate sufficient to maintain the reaction at reflux, with magnesium turns with stirring (1.35 g, 55.4 mmol, 8.0 eq.) in dry Et20 (70.0 ml). The reaction was started in an ultrasonic device. After the addition of the bromide was complete, the mixture was stirred for 1 hour under an argon atmosphere at room temperature, heated at reflux for 15 min., Then allowed to stand at room temperature.

(2) 4 / -Fluoro-3.3 / .5-trimethviï1.1'-biDhénvn-2-carboxaldéhvde

In a second flask, a mixture of the dipalladium complex from part B (3.0 g, 6.92 mmol) and triphenylphosphine ( 14.52 g, 55.4 mmol, 8.0 eq.) In dry benzene (100 ml). Then to this solution was added, in one portion, by means of a cannula, the Grignard reagent C (1), freshly prepared and filtered through a glass wool pad, and the mixture was stirred for 1.5 hour at room temperature under an argon atmosphere. HCl 6, ON (35 ml) was added, and the mixture was stirred for a further 1 hour at room temperature, then filtered through a packed Celite filter (12.7 mm bed). The filtrate was extracted with Et20 (250 ml), the extract was washed with brine (2 x 100 ml), dried over anhydrous MgSO4 and evaporated in vacuo to give 13.35 g of a viscous orange oil , which crystallized at rest. The crude orange solid was purified by flash chromatography on silica gel (700 g), eluting using hexane, then a 95: 5 mixture of hexane and Et2O. The fractions obtained were combined and evaporated to give 1.507 g (89.9%) of the title aldehyde, in the form of a light yellow solid, m.p. 72-75 ° C (the literature gives a mp of 73-75 ° C).

TLC: (95: 5) Hex-Et20, Rf = 0.40, U.V. and PMA.

D. 2- (2.2-Dibromoethénv0-4'-f [uoro-3.3'.5-triméthvl-f1.1'-biphénvll

60

Was treated dropwise with a solution of CBr4 (497 g, 1.5 mmol, 1.5 eq.) In CH2Cl2 (5.0 ml) over a period of 5 min., A cooled solution (-10 ° C, salt / ice bath) of biphenylaldehyde C (242 mg, 1.0 mmol) and triphenylphosphine (787 mg, 3.0 mmol, 3.0 eq.) In dry CH2Cl2 (10 ml). After 30 min. at 0 ° C., the orange-red solution was partitioned between CH2Cl2 and NaHCOs satu-65 re. The organic phase was washed with saturated NaHCOs and brine, then dried over Na2SO4

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anhydrous and evaporated to give 1.478 g of a light brown solid. The crude solid was purified by flash chromatography on silica gel (50: 1), eluting with a 9: 1 mixture of hexane and CH2CÌ2. The fractions obtained were combined and evaporated to give 392 mg (99%) of the title vinyl dibromide, in the form of a pale yellow oil. TLC (95: 5) Hex-EtOAc, Rf = 0.51, U.V. and PMA.

E. 2-Ethvnvl-4 / -fluoro-3.3'.5-trimethvlH.1 / -biphénvll

A 1.6 M solution of n-BuLi in hexanes (1.06 ml, 1.7 mmol, 2.0 eq.) Was treated dropwise with a syringe. -78 ° C (dry ice / acetone) of dibromide devi-nyie D (336 mg, 0.844 mmol) in dry THF (5 ml), and the mixture was stirred at -78 ° C under an argon atmosphere for 1 hour. During the addition of n-BuLi, color changes were observed, changing from colorless to deep yellow, pale yellow and deep purple blue. The mixture was blocked at -78 ° C by dropwise addition of saturated NH4Cl (4 ml), allowed to warm to room temperature, extracted with EtaO, then the ethereal layer was washed with brine, dried over anhydrous MgSO4 and evaporated to give 191 mg of a green oil. The crude oil was purified by flash chromatography on LPS-1 silica gel (60: 1), eluting with hexanes. The fractions obtained were combined and evaporated to give 185 mg (92%) of the title acetylene, in the form of a colorless oil, which finally turned deep blue at rest at -20 ° C under atmosphere argon.

TLC hexane, Rf = 0.18, U.V. and PMA.

F. Methyl ester of acid (SÎ-3-fiï1.1-diméthvléthvndiphénvlsilvnoxv1-4- (chlorométhoxvphosphinvlV butanoïaue d) Methvlia ester of acid fSV4-bromo-3-hvdroxvbutanoïue

(1) (a) Calcium salt of the acid rR- (R * -. R * -ïï-2.3.4-trihvdroxvbutanoïaue hvdraté

Ref. Carbohydrate Research 72, pp. 301-304 (1979)

Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid (44.0 g, 250 mmol) in H2O (625 ml), the suspension was cooled to 0 ° C (ice bath ) and treated in portions with 30% H2O2 (100 ml). The mixture was stirred at 30-40 ° C (oil bath) for 30 min. 10 g of Darco were added, and the black suspension was heated on a steam bath until the evolution of 02 was stopped. The suspension was filtered through Celite, evaporated in vacuo (bath temperature 40 ° C). The residue was taken up in 50 ml of H2O, heated on an oil bath, and CH3OH was added until the solution became cloudy. The gummy precipitated solid was collected by filtration and air dried to give 30.836 g (75.2%) of the desired calcium salt, in the form of a white powdery solid.

TLC (7: 2: 1) iPr0H-NH40H-H20, Rf = 0.19, PMA.

(1) (b) Methyl ester of rS-fR * -. S * -ïï-2,4-dibromo-3-hvdroxvbutanoïaue acid.

Ref. Bock et al., Acta Scandinavica (B) 37, pp. 341-344 (1983).

30 g of the calcium salt (1) (a) were dissolved in 30-32% HBr in 210 ml of acetic acid, and stirred at room temperature for 24 hours. Then 990 ml of methanol was added to the brown solution, and stirred overnight. The mixture was evaporated to give an orange oil, taken up in 75 ml of CH3OH, heated at reflux for 2.0 hours and evaporated. The residue was partitioned between 100 ml of EtOAC and H2O, the organic phase was washed twice with H2O and brine, then dried over anhydrous Na2SO4 and evaporated to give 22.83 g (90.5%) of dibromide raw, in the form of a light orange oil. TLC (1: 1) EtOAC-Hex, Rf = 0.69, UV and PMA.

(1) (c) Methyl ester of fSV4-bromo-3-hvdroxvbutanoïaue acid

Ref. as for the preparation of compound (1) (b).

An argon purged solution of 20.80 g (75.4 mmol) of the dibromide and 21.0 g of anhydrous NaOAC in 370 ml of was treated with 1.30 g of Pd 5% / C EtOAC and 37 ml of glacial HOAC, and the black suspension was stirred under hydrogen pressure of 1 atmosphere, while monitoring the absorption of hydrogen. After 2.0 hours, the absorption of H2 was complete, the mixture was filtered through Celite, the filtrate was washed with saturated NaHCO3 and brine, then dried over anhydrous MgSO4 and evaporated to give the crude dibromoester in the form of a brown oil. The crude oil was combined with another batch (obtained from 36.77 g of said bromide), and distilled under vacuum to give 25.77 g (61.3%) of the title bromoester, in the form a colorless oil, PE = 79-80 ° C (1.0 mm Hg). TLC (1: 1) EtOAC-Hex, Rf = 0.44, PMA.

Analysis: calculated for CsHgOsBr:

C, 30.48; H, 4.60; Br, 40.56 Found: C, 29.76; H, 4.50; Br, 39.86.

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CH 675 582 A5

(2) Methyl acid ester (Sl-4-bromo-3-nY1.1-dimethvlethvfldiPhénvlsilvlloxv1butanoïaue

Was treated with 5.84 ml (1.1 eq.) Of tert-butyldiphenylsilyl chloride a solution of 4.0 g (20.4 mmol) of hydrobromine F (1), 6.94 g (5, 0 eq.) Of imidazole, and 12 mg (0.005 eq.) Of 4-dimethylamino-pyridine in 40 ml of dry DMF, and the homogeneous mixture was stirred overnight under an argon atmosphere at temperature. ambient. The mixture was partitioned between 5% KHSO4 and EtOAC, the organic phase was washed with H2O and brine, dried over anhydrous Na2SO4 and evaporated to give 9.32 g (100%) of crude silylether, under form of a colorless viscous oil. TLC (3: 1) Hex-EtOAC, Rf silyltether = 0.75, U.V. PMA.

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(3) Methyl acid ester (S) -4-iodo-3-lïï1.1-diméthvléthvfldiphénvlsilvnoxv1butanoïaue

15.06 g (100.5 mmol, 5.0 eq.) Of sodium iodide were treated with a solution of 9.32 g (201 mmol) of the crude bromide F (2) in 60 ml of methyl ethyl ketone ( dried over 4 A molecular sieve, and the yellow suspension was heated at reflux for 5.0 hours under an argon atmosphere. The mixture was cooled, diluted with EtOAC, then filtered, the filtrate was washed with dilute NaHS03 (until it became colorless) and brine, then dried over anhydrous Na2SO4 and evaporated under vacuum to give 10.17 g of a yellow oil. The yellow oil was purified by flash chromatography on 600 g of silica gel, the eluent being a 3: 1 mixture of hexane-CH2Cl2. The fractions obtained were combined and evaporated to give 7.691 g (74.2%, overall yield for the two stages) of the title iodide, in the form of a viscous, colorless and clear oil ( note: the iodide produced gives spots with the starting bromide).

(4) Methyl acid ester (SM-fdiethoxphosphinvh-25 3-ff {1.1 -diméthvléthvndiphénvlsilvnoxvlbutanoïaue

A solution of 7.691 g of iodide in 20 ml of triethyl phosphite was heated at 155 ° C. (oil bath) for 3.5 hours under an argon atmosphere. The mixture was cooled, and the excess phosphite was distilled off in vacuo (0.5 mm Hg, 75 ° C) to leave a yellow oil (8.0 g). The crude oil was purified by flash chromatography on 400 g of silica gel, eluting with a 4: 1 mixture of hexane-acetone. The fractions obtained were evaporated to give 3.222 g (41.1%) of the title phosphonate in the form of a viscous, colorless and clear oil. TLC (1: 1) Hex-acetone, Rf = 0.51, U.V. and PMA. In addition, 2.519 g (corrected yield 61.1%) of the starting iodide (3) were recovered.

35 (5) Methyl ester of acid (SV3-lïï1.1-diméthvndiphénvlsilvnoxvl-4-phosphonobutanoïaue

Treated with 5.31 ml (32.0 mmol, 1.6 eq.) Of bistrimethylsilyltrifluroacetamide (BSTFA) and 6.60 ml (50.0 mmol, 2.5 eq.) With trimethylsilyl bromide (TMSBr) a solution of 9.85 g (20.0 mmol) of phosphonate F (4) in 20 ml of dry CH2Cl2, and the clear mixture was stirred overnight under an argon atmosphere at room temperature. 80 ml of 5% KHSO4 was added, and the mixture was extracted using EtOAc. The aqueous phase was saturated with NaCl, and extracted again using EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude phosphonic acid of the title as a viscous oil. TLC (7: 2: 1) iPr0H-NH40H-H20, Rf = 0.30, U.V. and PMA.

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(6) Methyl ester of acid (SV3-rr (1.1-dimethvlethvndiphénvlsilvnoxvl-4- (hvdroxvmethoxvohosphinvl) butanoïaue

About 20.0 mmol of crude phosphonic acid F (5) in 25 ml of dry pyridine was treated with 1.62 ml (40.0 mmol, 2.0 eq.) Of dried CH3OH over molecular sieve. 3 Å, and 4.54 g (22.0 mmol, 1.10 eq.) Of dicyclohexyl-carbodiimide (DCC), and the white suspension obtained was stirred under an argon atmosphere at room temperature overnight. The pyridine was removed in vacuo and then used to make an azeotrope with benzene (2x15 ml). The residual oil was dissolved in EtOAC, filtered and washed with 1.0 N HCl and brine, dried over Na2SO4 an-55 hydro and evaporated in vacuo to give 8.272 g of the crude ester of the title under the form of an oil containing a small amount of precipitated dicyclohexylurea (DCU). TLC (7: 2: 1) iPrOH-NH4-OH H2O, Rf = 0.60, U.V. and PMA.

(7) Methyl ester of acid (SÎ-3-lïï1-diméthvléthvhdiphénvlsilvrioxvl-4- (chlorométhoxvphosphinvh-60 butanoïaue

6.595 g (approximately 14.7 mmol) of the monomethyl ester of crude phosphonic acid F (6) were dissolved in 30 ml of dry CH2Cl2, treated with 5.60 ml (29.4 mmol, 2.0 eq .) of distilled trimethylsilyidiethylamine, and stirred under an argon atmosphere at room temperature for 1 hour. The mixture was evaporated in vacuo, removed with 1 x 30 ml of benzene and dried in vacuo. Light yellow viscous oil

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CH 675 582 A5

was dissolved in 30 ml of dry CH2Cl2 and two drops of DMF (dried on a 4 A molecular sieve), the clear solution was cooled to -10 ° C (salt / ice bath) and treated dropwise, with water. Using a syringe, with 1.41 ml (16.2 mmol, 1.1 eq.) of distilled oxalyl chloride. A strong gas evolution was observed, and the solution took on a deeper yellow color. The mixture was stirred under an argon atmosphere at -10 ° C for 15 min., Then allowed to stir at room temperature for 1 hour. The mixture was evaporated in vacuo, removed with 1 x 30 ml of benzene and dried in vacuo to give the crude phosphonochloridate as a yellow oil.

G. acid methvlia ester fSV4-rr2.r4'-fluoro-3.3, .5-trimethvin.1 / -biDhénvn-2-vnéthvnvnméthoxvphosphinvn-3-t-butvldiphénvlsilvloxvbutanoìaue

A solution at -78 ° C (CO2 / acetone) of 2.678 g was treated dropwise with a 1.5 M solution of n-BuLi in hexanes (7 ml, 11.2 mmol, 1.0 eq.) (11.2 mmol) of acetylene E in 20 ml of dry THF. The purple mixture was stirred under an argon atmosphere at -78 ° C for one hour, rapidly heated to 0 ° C, cooled to -78 ° C, transferred using a cannula to a funnel for addition, and added dropwise to a solution at -78 ° C (CXVacetone) of 8.27 g (18.4 mmol, 1.6 eq.) of phosphonochloridate F in 20 ml of THF. After one hour at -78 ° C, the mixture was blocked with saturated NH4Cl, then allowed to warm to room temperature, and extracted with Et20. The ethereal layer was washed with saturated NaHCOs and brine, then dried over anhydrous MgSO4 and evaporated to give 11.705 g of a brown oil. The crude oil was purified by flash chromatography on silica gel, the eluent being a 7: 3 mixture of hexane and EtOAc. The fractions obtained were combined and evaporated to give 4.246 g (56%) of the acetylenic phosphinate of the title, in the form of a light brown oil. In addition, 457 mg (corrected yield 68%) of biphenylacetylene E was recovered.

TLC (7: 3) Hex-acetone, Rf = 0.20, U.V. and FMA.

H. acid ester fSV4-rf2-r4, -fluoro-3.3 / .5-trimethvin.1, -biphénvn-2-vlléthvllméthoxvphosphinvll-3-t-butvldiphénvlsilvloxvbutanoTaue

A solution purged with argon of 330 mg of acetylenic phosphinate G in 5 ml of CH3OH was treated with Pd at 10% / C (121 mg, 36% by weight) and shaken on a Parr apparatus under a pressure of 280 kPa (40 psi) hydrogen for 30 hours. The catalyst was removed by filtration on a filter packed with Celite, and the filtrate was evaporated to give a pale yellow oil. The crude oil was purified by flash chromatography on silica gel, the eluent being a 1: 1 EtOAcHex mixture. The product fractions were evaporated to give 250 mg (75%) of the title's saturated phosphinate, as a clear oil.

TLC (4: 1) EtOAc-Hex, Rf = 0.33, UV and PMA.

J. Methyl ester of fSV4-iï2- (4 / -fluoro-3.3, .5-trimethvin.1'-biphenvn-2-vnéthvnméthoxvphosphinvn-3-hvdroxvbutanoïaue acid

A solution of 330 mg (0.489 mmol) of silylether H in 6 ml of dry THF was treated with 115 μl (1.96 mmol, 4.0 eq.) Of glacial HOAc, then a solution of tetrabutylammonium fluoride 1.0 M in

1.47 ml (1.47 mmol, 3.0 eq.) Of THF, and the resulting mixture was stirred overnight at room temperature under an argon atmosphere. The mixture was diluted with 10 ml of ice water, and extracted twice with EtaAc. The organic phase was washed with saturated NaHCOs and brine, then dried over anhydrous Na2SO4 and evaporated to give 364 mg of a pale yellow oil. The crude oil was purified by flash chromatography on silica gel, the eluent being a (6: 4) acetone-hexane mixture. The fractions obtained were evaporated to give 205 mg (96%) of the desired free alcohol of the title, in the form of a clear oil, which slowly crystallized on standing.

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

Example 2

FSV4-iï2-r4'-fluoro-3.3'.5-trimethvni.1'-biphenvn-2-vnéthvnhvdroxvphosphinvn-3-hvdroxvbutanoïue acid dilithium salt

A solution of 187 mg (0.429 mmol) of the diester of Example 1 in 5 ml of dioxane was treated with 1.29 ml (1.29 mmol, 3.0 eq.) Of a solution of LiOH, 1, 0N, and the mixture was heated to 55 ° C (oil bath) under an argon atmosphere for 2.5 hours. The mixture was cooled, diluted with water, filtered and evaporated in vacuo. The residue was dissolved in a minimum quantity of H2O and chromatographed on an HP-20 resin (25 mm diameter column, bed approximately 15 cm), eluting with H2O, then a 1: 1 mixture of CH3OH-H2O. The collected fractions were evaporated, dissolved in 50 ml of H2O, filtered and lyophilized to give 175 mg (91% relative to the weight of the hydrate) of the dilithium salt of the title, in the form of a white solid , electrostatic.

TLC (8: 1: 1) CH2CI2-CH3OH-HOAC, Rf = 0.1, UV and PMA, and (7: 2: 1) iPr0H-NH40H-H20, Rf = 0.45, UV and PMA.

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CH 675 582 A5

Microanalysis for G21H24O5FPLÌ2 and 1.7 moles of H2O (molecular weight 450.90).

Calculated: C, 55.93; H, 6.13; F, 4.21; P, 6.87 Found: C, 55.91; H, 5.84; F, 3.92; P, 6.89.

1 H NMR (400 MHz, CD3OD)

81.34-1.56 ppm (4H, multiplet)

2.22-2.31 ppm (2H, multiplet)

2.25 + 2.37 ppm (6H, two singlets)

2.29 ppm (3H, doublet, Jh-f = 1.4 HZ)

2.75 ppm (2H, multiplet)

4.13 ppm (1H, multiplet)

6.73-7.10 ppm (5H, multiplet)

Example 3

Methyl ester of CSf-4-ff2-f4 / -fluoro-3.3 / .5-trimethvlf1.1, -biphénvn-2-vlléthvnvnméthoxvphosphinvll-3-hvdroxvbutanoïue acid

A mixture of 455 mg (0.678 mmol) of silylether G from Example 1 and 155 n '(2.71 mmol, 4.0 eq.) Of glacial acetic acid in 7 ml of dry THF was treated with 2 0.0 ml (2.0 mmol, 3.0 eq.) Of a solution of 1.0 M tetrabutylammonium fluoride in THF, and the solution obtained was stirred overnight under argon atmosphere at temperature ambient. The mixture was poured into 10 ml of ice water, and extracted twice with EtOAc. The organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to give 498 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel, eluting with a 3: 2 mixture of hexane and acetone. The fractions obtained were evaporated to give 217 mg (74%) of the title alcohol, in the form of a colorless oil.

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

Example 4

Acid dilithium salt (SV4-iï2-r4'-fluoro-3.3'.5-trimethviï1 .l'-biphenvll-2-vnéthvnvnhvdroxvphosphinvn-3-hvdroxvbutanoTaue

A mixture of 203 mg (0.469 mmol) of the diester of Example 3 in 6 ml of dioxane was treated with 1.6 ml (1.6 mmol, 3.5 eq.) Of 1.0 N LiOH, and the solution was heated to 55 ° C (oil bath) under an argon atmosphere for 30 minutes. The mixture was cooled, diluted with water, filtered, evaporated, taken up in 30 ml of H2O and lyophilized. The white lyophilisate was dissolved in a minimum quantity of H2O and chromatography on an HP-20 resin (25 mm diameter column, 10 cm resin bed), eluting with water and then with a 50:50 Hg mixture. CHsOH. The fractions obtained were combined and evaporated, and the residue was taken up in 30 ml of H2O and lyophilized to give 199 mg (97% relative to the hydrate, molecular weight 435.36), of the dilithium salt of the titled, in the form of a white solid.

TLC (8: 1: 1) CH2CI2-CH3OH-HOAC, Rf = 0.13, UV and PMA.

Microanalysis for C21H20O5FPLÌ2 +1.06 mole of H2O (molecular mass 435.36)

Calculated: C, 57.93; H, 5.12; F, 4.36; P, 7.11 Found: C, 57.91; H, 4.89; F, 4.22; P, 6.89

1 H NMR (400 MHz CD3OD):

81.76-1.82 ppm (2H, multiplet)

2.32 (3H, doublet, Jhf = 1.8 Hz)

2.34 (3H, singlet)

2.37 (1H, dd, J = 8.4 Hz)

2.41 (1H, dd, J = 4.1Hz)

2.49 (3H, singlet)

4.27 (1 H, multiplet)

6.98-7.37 (5H, m)

Example 5

FS.ZV4-rr2-f4, -fluoro-3.3, .5-trimethvin.1'-biphenvn-2-vlléthénvnméthoxvphosphinvn-3-hvdroxvbutanoïue acid methvlia ester

A: Methyl acid ester (S.ZV4-fr2-r4'-fluoro-3.3'.5-trimethvlf1.1'-biphenvll-2-vnéthénvnméthoxvphosphinvn-3-t-butvldiphénvlsiloxv-butanoiaue

A degassed solution of 498 mg (0.742 mmol) of acetylene phosphinate G of Example 1 in 10 ml

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CH 675 582 A5

of CH3OH was treated with 10% Pd / C (50 mg, 10% by weight), and the black suspension was stirred under a hydrogen atmosphere under a pressure of 1 atm. during 2 hours. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to give 500 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel, eluting with a 3: 2 mixture of hexane and EtOAc. The fractions obtained were combined and evaporated to give 498 mg (100%) of the desired olefin, in the form of a colorless oil.

TLC (4: 1) EtOAc-hexane, Rf diastereoisomers = 0.44 and 0.51 ", U.V. and PMA.

B: Methyl ester of acid fS.ZV4-rr2-r4, -fluoro-3.3'.5-trimethvin.1'-biDhénvn-2-vnéthénvnméthoxvphosphinvl1-3-hvdroxvbutanoïaue

A solution of 498 mg (0.74 mmol) of silylether A in 6 ml of dry THF was treated with 170 μl (2.96 mmol, 4.0 eq.) Of glacial acetic acid, then a solution 1.0 M of tetrabutylammonium fluoride in THF (2.2 ml, 2.2 mmol, 3.0 eq.), And the colorless and clear mixture was stirred at room temperature under an argon atmosphere for 16 hours. A CCM indicated that a small amount of the starting material remained. A further 40 µl (1.0 eq.) Of HOAc and 0.74 ml (1.0 eq.) Of n-Bu4NF were added, and stirring was continued for a further 6 hours. The mixture was diluted with 10 ml of ice water, and extracted twice with EtOAc. The combined extracts were washed with saturated NaHCOs and brine, dried over anhydrous Na2SO4 and evaporated to give 468 mg of a pale yellow oil. The crude product was purified by flash chromatography on silica gel, eluting with a 7: 3 mixture of hexane and acetone. The fractions obtained were combined and evaporated to give 243 mg (76%) of the title alcohol, in the form of a colorless oil.

■ TLC (7: 3) hexane-acetone, Rf = 0.19, U.V. and PMA.

Example 6

Acid dilithium salt (S.ZV4-rr2-r4'-fluoro-3.3'.5-trimethviï1.1'-biphénvn-2-vnéthénvl1hvdroxvphosphinvll-3-hvdroxvbutanoïue

A solution of 140 mg (0.552 mmol) of the diester of Example 5 in 7 ml of dioxane was treated with 1.9 ml (1.9 mmol, 3.5 eq.) Of a 1.0 LiOH solution N, and the stirred mixture was heated under an argon atmosphere at 50 ° C (oil bath) for 3 hours. We could see a white precipitate. The mixture was cooled, diluted with water, filtered and evaporated in vacuo to give a white solid. The crude solid was dissolved in a minimum quantity of H2O and chromatographed on an HP-20 resin, eluting with water, then a 50:50 H20: CH3OH mixture. The fractions obtained were combined and evaporated, taken up in 50 ml of H2O, filtered and lyophilized to give 255 mg (100% relative to the weight of the hydrate, molecular mass 457.58) of the dilithium salt of the title, in the form of a white electrostatic solid. TLC (8: 1: 1) CH2CI2-CH3OH-HOAC, Rf: 0.26, U.V. and TMA.

Microanalysis for C21H22O5FPLÌ2 + 2.18 moles H2O (457.58):

Calculated: C, 55.12; H, 5.81; F, 4.15; P, 6.77 Found: C, 55.35; H, 5.68; F, 4.27; P, 7.09

1 H NMR (400 MHz, CD3OD):

81.24 ppm (2H, multiplet)

2.09 (2H, doublet, H = 6.2 Hz)

2.27 (3H, doublet, Jhf = 1.8 Hz)

2.30 (3H, singlet)

2.38 (3H, singlet)

4.06 (1 H, multiplet)

5.87 (1 H, d doublet, Jhh = 12.4 Hz, JHp = 14.3 H)

6.87 (1 H, s)

6.91 (1 H, double, Jhp = 43.4 Hz)

6.98 (2H, triplet)

7.22 (2H, multiplet)

Example 7

Methyl ester of acid (SV4-IT2-r3-f4-fluorophénvfl-1- (1-méthvléthvn-1H-indol-2-vnéthvllméthoxvphosphinvn-3-hvdroxv-butanoïaue

A: Ethyl ester of 2-iï4-fluorophénvfl-méthvn-3-oxobutanoïue acid

Sodium pellets (8.31 g, 362 mmol) were dissolved with mechanical stirring in 1 l of absolute EtOH, and 47 g (362 mmol, 1 eq.) Were added to the clear solution, under an argon atmosphere. ) distilled ethyl acetoacetate. The pale yellow mixture was heated at reflux for 1 hour, cooled to

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room temperature, treated with 75 g (398 mmol, 1.1 eq.) 4-fluorobenzyl bromide, and the light orange mixture was stirred under an argon atmosphere at room temperature for 2.5 hours. The mixture was concentrated in vacuo. The residue was partitioned between EtOAc and H2O, the organic phase was washed twice with water, then with brine, dried over anhydrous Na2SO4 and evaporated to give an orange oil. The crude product was purified by vacuum distillation (5 mm Hg) to give 46.47 g (54%) of the alkyl product in the form of a colorless and clear liquid, having a boiling point of 142-144 ° vs.

TLC (7: 3) Hex-Et20, Rf product = 0.31

1 H-NMR (CDCIs): 5 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) ppm.

RMN-13C (CD3CN): 5 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, 203.5 ppm.

B: Ethyl ester of 3-IY4-fluorophenvP-1 H-indole-2-carboxylic acid

Ref. Chemical Abstracts Vol. 33, p. 587

Ref. Helmuth R. et al. J. Chem. Society pp. 6-7, (1927)

Ref. Preparative Oraanic Chemistrv 4th ed. p. 582 (1972).

A solution of 46.4 g (195 mmol) of ester A in 290 ml of absolute EtOH at 0 ° C (ice bath) was treated with 23.4 g of an aqueous solution of NaOH in 58 ml of H2O, then immediately treated with a benzenediazonium chloride solution (Prep. Org. Chem., 4th ed., P. 582 (1972), prepared from 17.8 ml of aniline, 88 ml of concentrated HCl, 98 ml of H2O and 13.5 g of NaNOa)), to give a deep orange-red biphasic solution. The mixture was stirred for 1 hour at room temperature, poured into 500 ml of ice water and extracted with 3 x 300 ml of EtOAc. The organic phase was washed with 500 ml of brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 55.62 g of a crude hydrazone intermediate, as an orange oil. TLC (7: 3) Hex-Et20, Rf hydra-zone = 0.22, U.V. and PMA. The crude product was used as it was for the subsequent Fischer cyclization.

A solution of hydrazone in absolute EtOH (200 ml) was sparged with HCl gas for 30 min., With intermittent cooling in an ice bath. The brownish mixture was poured into 600 ml of ice water and extracted 3 times with EtOAc. The organic phase was washed twice with water and then with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give a brownish-tan solid. Trituration with ice-cold hexane and filtration gave 26.74 g (49%) of the title indole as yellow-brown granular crystals, Pf = 129- 130 ° C.

TLC (7: 3) Hex-EtaO, Rf = 0.26, U.V. and PMA.

Microanalysis for C17H14FNO2:

Calculated: C, 72.07; H, 4.98; F, 6.71; N, 4.94 Found: C, 72.38; H, 5.05; F, 6.87; N, 5.01

1 H NMR (CDCI3): 8 1.22 ppm (3H, t), 4.29 (2H, q), 7.10-7.62 (8H, m), 9.21 (1H, bs) ppm.

RMN-13C: s 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) ppm.

C. Ethyl acid ester 3- (4-fluorophenvn-1- (methvlethvn-1H-indole-2-carboxvliaue

Ref. Sandoz International patent n ° 158 675, p. 35 (1984).

A solution of 26.74 g (94.4 mmol) of indole B in 100 ml of dry distilled dimethylacetamide at 0 ° C (ice bath) was treated in portions (violent evolution of gas) with a dispersion of NaH at 60% in mineral oil (4.53 g, 113.3 mmol, 1.2 eq.), and the mixture was stirred under an argon atmosphere at 0 ° C for 1 hour. 85 g (500 mmol, 5.3 eq.) Of 2-iodopropane was added, and the mixture was allowed to rise to room temperature under an argon atmosphere, then stirred for 1 hour. The mixture was again cooled to 0 ° C, treated with a new amount of 1.2 eq. of NaH, and then stirred at room temperature for 1 hour. This procedure was repeated twice more. The final mixture was cooled to 0 ° C (ice bath), and the excess NaH was blocked by the dropwise, gentle addition of 30 ml of absolute EtOH. The mixture was diluted with EtOAc, washed with 5% KHSO4, the aqueous phase was reextracted once with EtOAc, the combined EtOAc layers were washed with water and brine (twice), dried over anhydrous Na2SO4 and evaporated to give 38.54 g of a brown solid. The solid was taken up in hot CH2Cl2, and the starting indole separated by crystallization after addition of hexane. 13.88 g of the starting indole were recovered. The mother liquor was evaporated in vacuo to give 22.32 g of a brown oil. The crude product was purified by flash chromatography on silica gel, the eluent being hexane, then a 95: 5 mixture of hexane and acetone. The fractions obtained were evaporated to give 6.55 g (21%) (corrected yield 62%) of the desired N-isopropylindole, the title, in the form of a yellow oil.

TLC (4: 1) Hexane-acetone, Rf = 0.56, U.V. and PMA.

1 H-NMR (CDCIs): 5 1.04 (3H, t), 1.20 (6H, d), 4.17 (2H, q), 5.40 (1H, m), 7.10-7, 7 (8H, m) ppm.

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CH 675 582 A5

13C-NMR (CDCI3): 8 13.6, 21.5, 48.7, 53.3, 60.8, 112.7, 114.5, 114.8, 120.3, 121.4, 122.4, 124.3, 125.9, 127, 6,130.8,131.7 (Pc-F = 7.5 Hz), 136.2,162.3 (Pc-F = 144 Hz), 163.0 ppm.

D. 3- (4-Fluorophenvh-1 - (1-methvlethvlV1 H-indole-2-methanol

1.12 g (29.6 mmol, 1.5 eq.) Of lithium aluminum hydride were carefully added to a solution at 0 ° C (ice bath) of 30 ml of dry distilled Et2O. The suspension obtained was treated dropwise in 10 min. with a solution of 6.42 g (19.7 mmol) of indole ester C in 20 ml of Et20. After stirring for 30 min. at 0 ° C under argon, the mixture was blocked by adding dropwise, successively, 1.1 ml of H 2 O, 1.1.1 ml of 15% NaOH and 3.4 ml of H2O. The suspension obtained was filtered through a filter packed with Celite, dried over anhydrous MgSO4 and evaporated in vacuo to give 5.1 g of a yellow foam. The crude product was purified by flash chromatography on silica gel, eluting with an 85:15 mixture of hexane and acetone, to give 5.08 g (91%) of the pure alcohol of the title, in the form of a pale yellow foam.

TLC (7: 3) Hexane-acetone, Rf = 0.38, U.V. and PMA. A small sample was recrystallized from hexanes to give the title alcohol as white crystals, mp = 101-103 ° C.

Microanalysis for CteH ^ NOF:

Calculated: C, 76.30; H, 6.40; F, 6.71; N, 4.94 Found: C, 76.49; H, 6.46; F, 6.84; N, 4.88

1 H-NMR (CDCIs): S 1.60 (1H, t), 1.69 (6H, d), 4.76 (2H, d), 4.93 (1H, m), 7.05-7, 62 (8H, m) ppm.

RMN-13C (CDCIs): 820.9.47.3, 54.8,113.0,115.9,116.3,116.6,120.2,120.6,122.9,128.5,131.6,132.4, 135.1,135.7,163.0 (Jc-F = 245 Hz) ppm.

E. 3- (4-Fluorophenvn-1 - (1 -methvlethvll-1 H-indole-2-carboxaldehyde)

A solution of 5.9 g (13.9 mmol, 1.2 eq.) Of Dess-Martin periodinane in 30 ml of dry CH2Cl2 was treated with 1.3 ml (13.9 mmol, 1.2 eq. ) of dry tert-butanol, and the mixture was stirred at room temperature under an argon atmosphere for 15 min. It was added dropwise over 5 min. 3.28 g (11.6 mmol, 1 eq.) Of indole alcohol D in 12 ml of dry CH2Cl2, and the yellow mixture was stirred under an argon atmosphere at room temperature for 1 hour. The reaction mixture was added to a solution, with stirring, of 15.3 g (97 mmol, 7 eq.) Of sodium thiosulfate in 40 ml of freshly prepared 1.0 N NaHCOs, and the mixture obtained was vigorously stirred for 5 min. The organic phase was separated, washed with 1.0 N NaHCOs, H2O and brine, dried over anhydrous Na2SO4 and evaporated to give 3.69 g of a yellow oil. The crude product was purified by flash chromatography on silica gel, the eluent being a 40: 1 mixture of hexane and Et 2 O, to give 2.7 g (83%) of the pure aldehyde of the title, as a white crystalline solid, mp: 88-89 ° C.

TLC (7: 3) Hex-acetone, Rf = 0.56, U.V. and PMA.

Microanalysis for C18H16FNO:

Calculated: C, 76.85; H, 5.73; N, 4.98; F, 6.75 Found: C, 76.91; H, 5.71; N, 4.95; F, 6.76

1 H-NMR (CDCIs): 8 1.69 (6H, d), 5.92 (1H, m), 7.10-7.70 (8H, m), 9.80 (1H, s) ppm

RMN- “C (CDCI3): 8 21.4.48.0,112.5,113.2,115.4,115.7,120.8,122.1,126.9,127.0,132.0,132.6 (Jc-F = 7.5 Hz), 183.6 ppm

F. 3- (4-Fluorophénvn-1 -f 1 -méthvléthvh-2- (2.2-dibromoéthénvn-1 H-indole

A cooled solution (-15 ° C, ice and salt bath) of 1.84 g (6.54 mmol) of indole-aldehyde E and 5.14 g (19.6 mmol, 3 eq.) of triphenylphosphine in 30 ml of dry CH2Cl2 was treated dropwise in 5 min. with 10 ml of a solution, in dry CH2Cl2, of 3.25 g (9.8 mmol, 1.5 eq.) of CBr4, and the yellow mixture was stirred at 15 ° C for 15 min. under an argon atmosphere. The mixture was partitioned between saturated NaHCOs and CH2Cl2, the organic phase was washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and evaporated to give 9.44 g of a brown oil. The crude product was purified by flash chromatography on silica gel, eluting with a 95: 5 mixture of hexane and CH2Cl2. The fractions obtained were evaporated to give 2.87 g (100%) of the title vinyl dibromide, in the form of a yellow oil which crystallized on standing. Recrystallization from ethyl ether gave 2.46 g (86%) of the purified product as pale yellow granular crystals, mp = 135-137 ° C.

TLC (7: 3) Hex-CH2Cl2, Rf = 0.45, U.V. and PMA.

Microanalysis for C19H16NF Br2:

Calculated: C, 52.20; H, 3.69; N, 3.20; Br, 36.56 Found: C, 52.25; H, 3.69; N, 3.20; Br, 36.58

1 H-NMR (CDCIs): 8 1.15 (6H, d), 4.67 (1H, m), 7.10-7.70 (9H, m) ppm.

NMR- "C (CDCI3): 8 21.9.48.6.98, 8.6111.6, 115.3, 115.6, 115.9, 119.9 (Jc-F = 7.6 Hz), 122.4, 127.5, 129.3, 130 , 5,130.7,130.9,135.2,161.5 (Jc-F = 246 Hz) ppm

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G. 3-f4-Fluorophenvfl-1 (1 -methvlethvl) -2-ethvnvl-1 H-indole

A solution at -78 ° C (dry ice / acetone) of 2.395 g (5.48 mmol) of vinyl dibromide F in 10 ml of dry THF under an argon atmosphere was treated dropwise with a 1.6 solution M of n-BuLi in hexanes (6.9 ml, 10.96 mmol, 2 eq.). The resulting mixture was stirred at -78 ° C for

1 hour, then blocked by the dropwise addition of 5 ml of saturated NH4Cl. The mixture was allowed to return to room temperature, then extracted twice with Et2O. The ethereal layers were washed with brine, dried over anhydrous MgSO4 and evaporated in vacuo to give 1.893 g of a dark brown oil. The crude product was purified by flash chromatography on silica gel (82: 1), the eluent being a 200: 1 hexane-Et20 mixture, to give 1.12 g of a purified product, in the form of a 3.3: 1 mixture of acetylene and the terminal olefin. This mixture was separated by alumina column chromatography (neutral, activity = II), eluting with a 200: 1 hexane-Et20 mixture. Evaporation of the fractions obtained gave 900 mg of off-white crystals. Recrystallization from hot hexane gave 700 mg (46%) of the purified acetylene of the title, as white needles, mp = 105-106 ° C.

TLC (95: 5) Hex-Et20, Rf acetylene = 0.44, Rf olefin = 0.49, U.V. and PMA.

Microanalysis for C19H16NF:

Calculated: C, 82.28; H, 5.81; N, 5.05; F, 6.85 Found: C, 82.70; H, 5.85; N, 5.10; F, 6.62.

1 H-NMR (CDCIs): 8 1.70 (6H, d), 3.5 (1H, s), 5.06 (1H, m), 7.10-7.75 (8H, m) ppm

H. Methyl ester of CSV4-lT2-r3-f4-fluorophenvD-1 -f1 -methvlethvn-1 H-indol-2-vllethvnvll-methoxvDhosDhinvn-3- (tert-butvldiDhenvlsilvloxvibutanoïue)

A solution at -78 ° C (dry ice / acetone) of 678 mg (244 mmol, 1.0 eq.) Of acetylene G in 6 ml of dry THF under an argon atmosphere was treated dropwise with a 1.6 M solution of n-BuLi in hexanes (1.53 ml, 2.44 mmol, 1.0 eq.). After 30 min. at -78 ° C, the mixture was transferred to the cannula in a solution at -78 ° C of approximately 4.3 mmol (1.75 eq.) of phosphonochloridate F of Example 1 in 5 ml of dry THF . The dark brown mixture was stirred at -78 ° C for 30 min., Then blocked by the dropwise addition of 5 ml of saturated NH4Cl, then allowed to return to room temperature. The mixture was extracted with 2 times Et 2 O, washed with saturated NH 4 Cl and a brine, dried over anhydrous MgSO 4 and evaporated in vacuo to give 2.567 g of a red brown oil. The crude oil was purified by flash chromatography on silica gel, the eluent being a 3: 2 hexane-EtOAc mixture, to give 756 mg (44%) of the title acetylenic phosphinate as an oil. dark yellow.

TLC (7: 3) Hex-acetone, Rf = 0.27, U.V. and PMA.

1 H-NMR (CDCIs): 8 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) ppm.

RMN-13C (CDCIs): S 14.2, 19.1.21.0, 26.7, 27.8, 37.5, 39.0, 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 ppm.

J. Methyl ester of acid (SV4-IT2-r3- (4-fluoroDhénvlV1 - (1 -méthvléthvn-1 H-indol-2-vnéthvn-méthoxvphosDhinvn-3-ftert-butvldiphénvlsilvloxv) butanoïaue

A solution, purged with argon, of 422 mg of acetylenic phosphinate H in 9 ml of CH3OH was treated with 420 mg of Pt at 10% / C, and the mixture obtained was shaken on a Parr apparatus for

2 hours under a hydrogen pressure of 280 kPa (40 psi). The catalyst was removed by filtration through Celite, and the filtrate was evaporated to give 380 mg (90%) of the title indole phosphinate, as a yellow foam.

TLC (4: 1) EtOAc-Hex, Rf = 0.27 U.V. and PMA.

1 H-NMR (CDCIs): 8 1.00 (9H, s), 1.63 (6H, d), 1.5-2.0 (2H, m), 2.20 (1H, m), 2, 58-3.00 (5H, m), 3.44 (3H, dd, Jh-p = 10.6 Hz), 3.61 (3H, s), 4.52 (2H, m), 7.07 -7.66 (18H, m) ppm.

RMN-13C (CDCI3): 5 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 ppm.

K. Acid methvlia ester ^ S) -4-iï2-f3-M-fluorophénvl) -1 - (1 -méthvléthvl) -1 H-indol-2-vl1éthvn-méthoxvphosphinvn-3-hvdroxvbutanoïue

A solution of 379 mg (0.531 mmol) of silylether J in 5 ml of dry THF was treated successively with 120 (il (2.12 mmol, 4 eq.) Of glacial HOAc and a solution of tetrabutylammonium fluoride

1.0M in THF (1.6 ml, 1.6 mmol, 3 eq.), And the solution obtained was stirred overnight under an argon atmosphere at room temperature. The mixture was diluted with 10 ml of ice water, extracted twice with ETOAc, the organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to give 408 mg of an oil yellow. The gross product

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CH 675 582 A5

was purified by flash chromatography on silica gel, the eluent being a 7: 3 mixture of acetone and hexane. The fractions obtained were evaporated to give 197 mg (78%) of the title alcohol, in the form of a white foam.

TLC (1: 1) Hexane-acetone, Rf = 0.09 U.V. and PMA.

1 H-NMR (CDCI3): S 1.68 (6H, d), 1.80-2.0 (2H, m), 2.10 (2H, m), 2.58 (2H, m), 3, 08 (2H, m), 3.63 (3H, dd, Jh-P = 10.1 Hz), 3.70 (3H, d), 3.96 (1H, t), 4.35 + 4.49 (2 broad multiplets), 4.67 (1H, m), 7.0-7.6 (8H, m) ppm.

RMN-13C (CDCIs): 8 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, 51.7,63.4,111.8,113.5,115.2,115.5,119.0,119.4,121.1,128.3,131.3,131.5,134.2,134.8,161.5Jc-F = 244.1 Hz), 172.1 ppm.

Example 8

(S) -acid dilithium salt -4 - [[2- [3- (4-fluoroohenvl) -1-f1-methvlDhenvl) -1H-indol-

2-vnéthvnhvdroxvphosphinvl1-3-hvdroxvbutanoïaue

A solution, with stirring, of 197 mg (0.414 mmol) of the diester of Example 7 in 5 ml of dioxane was treated with 1.45 ml (3.5 eq.) Of 1.0N LiOH, and the white suspension obtained was heated to 55 ° C (oil bath) under an argon atmosphere for 40 min. The mixture was cooled, diluted with water, filtered and evaporated in vacuo. The residue was taken up in a minimum quantity of H2O and chromatographed on an HP-20 resin, eluting with water and then with a 50:50 mixture of H2O-CH3OH. The fractions obtained were combined and evaporated. The glassy residue was taken up in 50 ml of H2O, filtered and lyophilized to give 178 mg (85%, relative to the weight of the hydrate) of the pure dilithium salt of the title, in the form of a white solid .

Microanalysis for C23H25NFP.2LÌ + 2.52 moles H2O (molecular weight 504.71):

Calculated: C, 54.73; H, 6.00; N, 2.78; F, 3.76; P, 6.14 Found: C, 54.62; H, 5.67; N, 2.90; F, 3.61; P, 6.06

1 H NMR (400 MHz, CDCI3):

81.69 ppm (6H, dd, J = 5.8 Hz)

1.71 (2H, multiplet)

1.93 (2H, multiplet)

2.38 (2H, multiplet)

3.06 (2H, quadruplet)

4.32 (1 H, multiplet)

4.87 (1 H, multiplet)

6.97 (1 H, dt, J = 0.7 Hz)

7.07 (1 H, dt, J = 1.1 Hz)

7.16 (2H, t)

7.41 (3H, m)

7.57 (1H, 1/2 AB quadruplet)

Example 9

FSV4-rr2-rri.1 acid methvlia ester, -biphenvn-2-vnéthvllméthoxvphosphinvn-

3-hvdroxvbutanoïaue

A. Biphénvl-2-carboxaldéhvde

27.64 g (65.2 mmol) of Dess-Martin periodinane were stirred under an argon atmosphere with 150 ml of CH2Cl2. 8.0 ml of dry tert-BuOH was added to the solution with stirring, and this mixture was stirred for 10 min. at room temperature. It was added dropwise over 15 min. 20 ml of a solution, in CH2CI2, of 10 g (54.3 mmol) of biphenyl-2-methanol. When the addition was complete, stirring of the reaction mass was continued at room temperature. After stirring for 1 hour at room temperature, 600 ml of anhydrous Et2O were added to the reaction mass, then 225 ml of 1N NaOH. After 10 min., The suspension obtained was filtered, and the filter cake was washed with Et20. The filtrate was washed twice with 250 ml portions of 1N NaOH. The organic layer was dried over MgSO4 and filtered to give 10 g of a yellow oil, after removal of the solvent. Purification by flash chromatography (silica gel, 1: 10 / Et 2 O: hexane) gave 9.58 g (97%) of the title aldehyde, as a colorless oil.

TLC (1/9 EtOAc / hexane, silica gel) Rf = 0.29

IR (film) 3065, 3025,2850, 2760,1685,1700,1600,1470,1450,1395 cm "i RMN-1H (270 MHz) (CDCI3)

8 8.00 (d, 1, J = 70 Hz), 7.60 (m, 1), 7.40 (m, 7).

Mass spectrometry m le 183 (M ++ H).

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CH 675 582 A5

B. 2- (2.2-Dibromoethénvh-H.1'-biphénvlel

A solution of 2.0 g (11 mmol) of aldehyde A in 60 ml of CH2Cl2 was placed under an argon atmosphere and cooled to -10 ° C. 9.21 g (35 mmol) of triphenylphosphine was added, and this mixture was stirred until all of the solids dissolved. It was added in 15 min. to the solution obtained, at -10 ° C, a solution, in 40 ml of ChfeC ^, of 5.5 g (16.5 mmol) of CBr4. The reaction was stirred at -10 ° C for 1 hour 15 min., Then fixed at -10 ° C using 50 ml of a saturated aqueous solution of NaHCO3. The CH2CI2 and aqueous layers were separated, and the aqueous layer was extracted once with CH2CI2. The combined CH2CI2 extracts were washed once with a saturated aqueous solution of NaHCOs and once with a saturated aqueous solution of NaCI. The CH2Cl2 extract was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography, the eluent being hexane, to give the title dibromide as an off-white solid (2.45 g, 66%).

TLC (5: 95 / EtOAc: hexane, silica gel) Rf = 0.47.

15 IR (CHCI3) 3064, 3011,1596,1473,1450,1435, 889, 860, 702 cm "i.

1 H NMR (270 MHz) (CDCI3)

6 7.75 (m, 1), 7.35 (m, 8), 7.20 (s, 1)

NMR-13C (67.0 MHz) (CDCI3) 8,141.06,140.08,137.49,133.83,129.81,129.45,129.17 17,128.61,128.22,127.50,127.08, 90.78. 20 Mass spectrometry m / e 337/339/341 (M ++ H)

C. 2-Ethvnvl- [1.1 / -biphénvle1

A solution in THF (35 ml) of 2.31 g (6.9 25 mmol) of vinyl dibromide B was cooled to -78 ° C. under an argon atmosphere, while stirring at -78 ° C. added in 10 min. with vinyl dibromide of n-BuLi (5.52 ml of a 2.5M solution in hexane). After completion of the addition of n-BuLi, the reaction mixture took on a dark purple hue. After stirring at -78 ° C for 2 hours 45 min., The reaction was fixed with the aid of a saturated aqueous NH4Cl solution. After heating the fixed reaction to room temperature, the THF was removed from the reaction mixture, and the product obtained was diluted with H2O and extracted 3 times with an Et 2 O / hexane mixture. The organic extract was dried over MgSO4 and filtered to give 1.3 g of a yellow oil. Purification by flash chromatography, the eluent being a 1% Et 2 O / hexane mixture, gave the title acetylene (1.0 g, 88%).

TLC (100% hexane, silica gel) Rf = 0.16

IR (film) 3287, 3061, 3026,1474,1449,1432,1008, 775, 758, 738 cm ~ i 35 1 H NMR (270 MHz) (CDCI3)

8 7.68 (m, 3), 7.35 (m, 6), 3.00 (s, 1)

RMN-13C (67.8 MHz) (CDCI3) S 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 spectrometry m / e 179 (M ++ H).

40

D. Methyl ester of acid (SÎ-4-iï2-rri.1'-biDhénvn-2-vl1éthvnvl1méthoxvphosphinvn-3-tert-butvldiphénvlsilvloxv) butanoïaue

0.332 g (1.86 mmol) of 45 C acetylene was stirred at -78 ° C, under an argon atmosphere and in 10 ml of THF. Over a period of 5 min., The solution was added to the solution. n-BuLi acetylene (0.75 ml of a 2.5M solution in hexane). The reaction was stirred at -78 ° C for 1 hour, heated to 0 ° C and stirred for 10 min., Then cooled to -78 ° C. The acetylenic anionic solution was then added dropwise over 8 min. To a solution, in 10 ml of THF, of 2.98 mmol of the phosphonochloridate F of Example 1, which had been cooled to -78 ° C under an atmosphere of argon. After completion of the addition, the reaction mass was stirred at -78 ° C for 1 hour, then the reaction was quenched by the addition of a saturated aqueous Na4Cl solution. The fixed reaction was heated to room temperature, the reaction mass was diluted with an aqueous NaCl solution at 50% saturation and extracted 3 times with EtzO. The combined Et20 extracts were washed with a saturated aqueous solution of NaHCOs and a saturated aqueous solution of NaCl. The Et20 layer was dried over MgSO4 and evaporated to give 1.5 g of a yellow oil. Purification by flash chromatography, the eluent being a 5: 1: 4 mixture of hexane: toluene-EtOAc gave the title acetylenic phosphinate (0.543 g, 48%).

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

IR (CHCI3) 3070, 3053, 3035, 3000, 2952, 2934, 2896, 2859, 2178, 1735,1474, 1448,1436,1429 cm-1.

1 H NMR (270 MHz) (CDCI3)

60 8 7.65 (m, 3), 7.65-7.28 (m, 116), 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), 1.00 (s, 9)

NMR-13C (67.8 MHz) (CDCI3) S 170.83.145.29.145.19.139.22.135.95.135.59.133.86, 133.75,133.1116.132.86.130.57.129.56.129.34, 128.81.127.92.127,127.12 , 94,117.90,100.91,100,38,100,18,84,51,81,60,65,53, 65,42, 65 60.06, 51.61, 51.50, 51.11, 42.07, 41, 90, 38.86, 37.16, 26.56, 20.75, 18.97, 13.97.

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Mass spectrometry m / e 611 (M ++ H)

E. Methyl acid ester (SV4-iï2-rri.1 / -biDhénvH-2-vlléthvnméthoxvphosphinvn-tert-butvldiphénvlsilvloxvibutanoïaue

Argon was bubbled for 10 min. in a solution, in 8 ml of methanol, of 0.515 g (0.85 mmol) of acetylene phosphinate D. The addition of 0.190 g of Pd at 10% / C to the acetylene solution was followed by hydrogenation of Parr under 296 kPa (43 psi). After shaking for 25 hours at 296 kPa (43 psi) the methanol solution was filtered through Celite, and the filtrate was evaporated to give 0.510 g (98%) of the title phosphinate, as colorless oil.

TLC (4: 1 EtOAc: hexane) Rf = 0.21

IR (CHCIs) 3071,3054,2998,2954,2934, 2902,2859,1734,1477,1462,1448,1438,1428 cm "i 1 H-NMR (270 MHz) (CDCIs)

S 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 Mz), 2.88 (m, 1), 2.60 (m, 3), 2.17-1.80 (m, 1), 1.80-1.30 (m , 1), 1.00 (s, 3).

NMR-13C (67.8 MHz) (diagnostic peaks) (CDCI3)

8 171.33, 65.78, 51.36, 42.24, 26.75 Mass spectrometry m / e 615 (M ++ H)

F. Acid methvlia ester (SÎ-4-r2-rn.1'-biphenvfl-2-vnéthvnméthoxvphosphinvn-3-hvdroxvbutanoïaue

A solution in THF (10 ml) of 0.500 g (0.82 mmol) of phosphinate E was stirred under an argon atmosphere with 0.19 ml (3.3 mmol) of HOAc. At room temperature, nBu4NF (2.45 ml, 1.0M solution in THF) was added dropwise. The reaction mixture was stirred at room temperature for 23 hours, then the reaction was quenched with 15 ml of ice water. The aqueous layer was extracted 3 times with ETOAc. The combined organic solutions were washed twice with a saturated aqueous solution of NaHCOs and once with a saturated aqueous solution of NaCl. The organic layer was dried over NaaSO 4 and evaporated to give 0.437 g of a colorless oil. Purification by flash chromatography, the eluent being a 7: 3 mixture of acetone and hexane, gave 0.247 g (81%) of the title alcohol, as a colorless oil.

TLC (7: 3 acetone: hexane, silica gel) Rf = 0.22

IR (CHCI3) 360-3171 (br), 3064, 3009, 2954,1731,1479,1439,1237,1180,1042, 999 cm ~ i 1 H-NMR (270 MHz) (CDCIs)

5 7.50-7.10 (m, 9), 4.50-4.15 (m, 1), 3.70 (s, 3) 3.53 and 3.50 (2 doublets, 3, J = 11 Hz), 2.88 (m, 2), 2.50 (m, 2), 2.00-1.60 (m, 4)

NMR-13C (67.8 MHz) (CDCIs) 8,171.55,171.49,141.39,141.00,138,10,137.88,129.95,128.81,128.06 6.127.53.26.83.126.22.63.08.63.02, 62, 85, 51.39, 50.58, 50.47, 42.35, 42.15, 42.07, 41.87, 34.31, 33.06, 33.00, 30.77, 30.52, 29.49, 29.21, 25.42

Mass spectrometry m / e 377 (M ++ H)

Example 10

FSV4-f2-ri.1 / -biphenvl-2-vnéthvnhvdroxvphosphinvl1-3-hvdroxvbutanoïue dilithium salt

0.239 g (0.64 mmol) of the diester of Example 9 was stirred in 6.5 ml of dioxane under an argon atmosphere. At room temperature, 1.9 ml of a 1.0 M LiOH solution was added. This mixture was stirred at 55 ° C. After 2.5 hours of stirring, the reaction mixture was cooled to room temperature, and the dioxane and most of the water were removed by evaporation on a rotary evaporator. Purification by chromatography on HP-20 resin (18 cm x 2.5 cm), eluting first with 100% H2O and then with a 1: 1 MeOH: H2O mixture, gave the dilithium salt of the title (0.180 g, 79%) as a white solid.

TLC (8: 1: 1 CH2Cl2: MeOH: AcOH) Rf = 0.16 (7: 2: 1 nPr0H: NH3: H2O) Rf = 0.37

Example 11

Acid dilithium salt (RV4-rrfEV2-r4 / -fluoro-3.3 / .5-trimethvin.1'-biphenvll-2-vnethénvll-hvdroxvphosphinvn-3-hvdroxvbutanoïue

A. rEVTributvir2-r4 / -fluoro-3.3'.5-trimethviri.1'-biphénvn-2-vnéthénvnétain

Ref. Miftakov; M.A. et al., Synthesis (Comm.) Pp. 496-499 (1985)

A mixture of 1.7 g (7.13 mmol) of 2-ethynyl-4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl] and 2.9 ml (10.7 mmol , 1.5 eq.) Of (n-C4H9) 3SnH was treated with 7.0 mg (0.426 mmol) of AIBN, and the solution was

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CH 675 582 A5

was quickly heated to 120 ° C (oil bath) under an argon atmosphere. After 15 min. at 120 ° C, an additional amount of (n-C4H9) 3SnH (0.39 ml, 1.43 mmol, 0.2 eq.) was added, and heating was continued for a total of 3 hours. The yellow mixture was cooled and purified by distillation of Kugel-rohr under 0.1 mm Hg and at a temperature of 240 ° C to give 3.73 g (81%) of the title vinyl stannane, in the form d 'a colorless liquid.

TLC hexane, Rf product = 0.45, U.V. and PMA. The product is unstable on silica gel (bands on the baseline).

NMR-13C (67.5 MHz, CDCI3): 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 (Jcf = 244 H2) ppm.

1 H NMR:

8 0.8-1.5 ppm (27 H, m, Sn (Bu) s)

2.27, 2.31, 2.36 (9H, 3 singlets, aromatic CH3 radicals)

6.05 (1H, d, J = 20 Hz, PhÇH = CHSn)

6.68 (1 H, d, J = 20 Hz, PhCH = CHSn)

6.90-7.13 (5H, m, aromatic protons)

B. (E) -4'-Fluoro-2-C2-iodoethénvl) -3.3'.5-trimethvlf1.1 '-biphénvll

A solution of 1.537 g (2.89 mmol) of vinyl stannane A in 20 ml of dry Et 2 O was treated with 734 mg (2.9 mmol, 1 eq.) Of iodine, and the brownish solution was stirred with room temperature under an argon atmosphere for 2 hours. The mixture was washed with saturated sodium thiosulfate, 10% NH4OH and brine, dried over anhydrous MgSC> 4 and evaporated to give 1.639 g of a yellow oil. The crude product was purified by flash chromatography on 160 g of silica gel, the eluent being hexane. The fractions obtained, combined, gave 832 mg (65%) of the pure trans transvinyl iodide of the title, in the form of a pale oil, which slowly crystallized on standing, m.p. = 53-55 ° C.

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

1 H NMR (270 MHz)

8 2.30 and 2.32 ppm (9H, 2 singlets, aromatic methyl radicals)

6.05 (1H, d, J = 15 Hz, -HC = ÇHI)

6,927.10 (5H, m, aromatic H)

7.24 (1 H, d, J = 15 Hz, PhCH = CHI)

RMN-13C (67.5 MHz): 14.6, 21.0, 21.1, 81.0 (= ÇH-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 (PhÇH = CHI), 161,0 (Jcf = 244 Hz) ppm.

Note: 1 H-NMR (CDCl3, 270 MHz) on mixed fractions indicated that the impurity corresponding to the closest fraction was cis-vinyl iodide.

8 6.54 ppm (1H, d ÜHaHb = 7.9 Hz (PhCHb = ÇHa-l))

C. Methyl ester of acid (RÌ-3-nT1.1-dimethvlethvndiphenvlsilvnoxvl-4-nYE) -2-r4'-fluoro-3.3'.5-trimethviri.1'-biDhénvri-2-vnéthénvnméthoxvDhosDhinvllbutanoïue

A solution at -78 ° C (dry ice / acetone) of 812 mg (2.22 mmol) of vinyl iodide B in 6 ml of dry THF was treated dropwise using a syringe, with a 1.6 M solution of n-BuLi in hexanes (1.4 ml, 2.2 mmol, 1 eq.), and the pale yellow mixture was stirred under an argon atmosphere at -78 ° C for 45 min. Then the anion was transferred dropwise using a cannula, over a period of 10 min., Directly into a solution at -78 ° C of the phosphono chioridate F of Example 1 (approximately 3.5 mmol, 1.5 eq.) in 6 ml of dry THF. The yellow mixture was stirred for 30 min. at -78 ° C, then brought back to room temperature. The reaction was fixed at room temperature by the addition of 5 ml of saturated NH4Cl. The mixture was diluted with Et2O, the ethereal layer was washed with saturated NH4Cl and brine, then dried over anhydrous MgSC> 4 and evaporated to give 2.083 g of a yellow oil. The crude product was purified by flash chromatography on silica gel, the eluent being an 85:15 mixture of hexane and acetone. The fractions obtained were combined and evaporated to give 249 mg (17%) of the desired trans olefinic phosphinate, in the form of a pale yellow oil. NMR indicated an approximately 1: 1 mixture of diastereoisomers at the phosphorus level. TLC (7: 3) hexane-acetone, Rf = 0.35, UV and PMA.

1 H NMR:

8 3.27 ppm (3H, d, Jh-p = 11.6 Hz,

O

he

—POÇHj

3.57 and 3.60 (3H, 2 singlets, diastereoisomers, -COpCHsI

4.33 and 4.50 (1H, 2 multiplets, diastereoisomers, -CHpCWOSiRsiCHg-)

4.84 and 5.25 (1 H, 2 dd, diastereoisomers, JHaHb = 17.9 Hz, ÜHa-P = 25.3 Hz,

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CH 675 582 A5

O

II

phch. = ch -p-

□ "—a

D. Methyl ester of fRM-nTEÎ-2-r4, -fluoro-3.3 / .5-trimethviï1.1'-biphenvn-2-vnéthénvnméthoxvDhosphinvn-3-hvdroxvbutanoïue acid

A solution of 249 mg (0.370 mmol) of silylether C in 5.0 ml of THF was treated successively with 85 μl (1.48 mmol, 4.0 eq.) Of glacial HOAC and a 1.0M solution of (n -C4Hg) 4NF in THF (1.1 ml, 1.1 mmol, 3.0 eq.), And the yellow mixture was stirred overnight at room temperature under an argon atmosphere. The mixture was diluted with 10 ml of cold H2O and extracted with EtOAc. The organic phase was washed with saturated NaHCOs and brine, then dried over anhydrous Na2SO4 and evaporated to give 243 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel, the eluent being a 55:45 mixture of hexane and acetone. The fractions obtained were combined and evaporated to give 121 mg (75%) of the title hydroxy-diester, in the form of a colorless viscous oil.

TLC (6: 4) acetone-hexane, Rf: 0.26, UV and PMA.

1 H NMR 81.8-2.06 ppm

O

(2h, m, ch, o-pchl, -)

2.30, 2.35, 2.40 (9H, 3 singlets, aromatic CH3 radicals)

2.40-2.60 (2H, m, -CH (0H) ÇH2C02CH3)

3.50 + 3.55 (3H, 2 doublets, diastereoisomers,

O 11

-poçh3,

Jh-p = 12 Hz)

3.64 (3H, s, -CO2ÇH3)

3.77 + 3.84 (1 H, 2 doublets, diastereoisomers, -CH (OH) -)

4.28 + 4.38 (1 H, 2 large multiplets, -CH (OH) -)

5.52 (1 H, 2 dd, diastereoisomers, Jhh coupling and Jhp coupling

O

II

phch = ch — pfoch,) -)

6.90-7.10 (5H, aromatic protons)

7.50 (1H, multiplet, diastereoisomers and Jhh coupling, Jhp coupling

O II

phçh = ch-p- (och3) -)

E. Acid dilithium salt (RV4-riïEÎ-2-r4'-fluoro-3.3 / .5-trimethvlf1.1 / -biphénvll-2-vl1éthénvn-hvdroxvphosDhinvll-3-hvdroxvbutanoTaue

A solution of 121 mg (0.279 mmol) of hydroxydiester D in 2 ml of dioxane was treated with an excess of 1.0N LiOH (0.98 mg, 0.98 mmol, 3.5 eq.), And the Light pale yellow mixture was stirred under an argon atmosphere at 50 ° C (oil bath) for 1.5 h. The mixture was cooled, diluted with H2O, filtered and evaporated in vacuo. The residue was taken up in a minimum quantity of H2O and chromatographed on an HP-20 resin (bed 8 cm, column diameter 25 mm), eluting successively with 200 ml of H2O, an 80:20 mixture H2O-CH3OH, and finally a 60:40 mixture H2O-CH3OH. The fractions obtained were evaporated in vacuo, taken up in 50 ml of H2O and lyophilized to give 91 mg of the pure dilithium salt product of the title, in the form of a hygroscopic white lyophilisate.

TLC (8: 1: 1) CH2CH2-CH3OH-HOAC, Rf = 0.19, UV and PMA.

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CH 675 582 A5

Examples 12 to 24

The following additional compounds can be prepared by following the procedures indicated above, and described in the previous working examples.

x oh

I

Z

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CH 675 582 A5

ex. No.

r

-12. Oh

13.

c2s5 °

14. OH

15. olì

16. oh

17. olì

-ch2ch2- h

-ch = ch- ch.

-c = c- h

-ch2ch2- li

-ch = ck- h

-c5c-

Li

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CH 675 582 A5

Ex.

NO. L

18. "OCH,

19. OK

f3

C.H.-CH 2 5 I

C = 0 I

O

H

THIS_-

-CH2CH2- CH3

-CH = CS- OK

CH.

20. ONa

: H2-O

-C = C- Na

C2H5

21. OH

-CH CH.- H 2 2

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CH 675 582 A5

Sx. NO.

X

.x

21.

OH

c.h -c

2? \

ch3 ch3

-ch2ch2- h

23.

ch3O

© ~

-ch = ch-

ch.

Example 25

Dicvclohexvlamine salt f1: 1> of the acid methvlia ester (SM- (hvdroxvmethoxvDhosphinvn-3-fiï1.1-di-méthvléthvndiphénvlsilvnoxvlbutarioïaue

A. Acid methvlia ester (SM-diisopropyloxv-phosphinvIV 3-rr Cl.l'-diméthvléthvndiphénvlsilvlloxvl-butanoïaue

It was stirred under high vacuum for 30 min. 21.70 g (45.1 mmol) of iodide F (2) from Example 1. 93.92 g (0.451 mol, 113.37 ml) of freshly distilled triisopropyl phosphite was added in one portion , and the reaction mixture was stirred under an argon atmosphere and heated in an oil bath at 155 ° C for 16.5 hours. Then the mixture was cooled to room temperature. Excess triisopropyl phosphite, as well as volatile reaction products, were removed by short path distillation (10 mm Hg), followed by Kugelrohr distillation (0.50 mm Hg, 100 ° C, 8 hours) . The product underwent further purification by flash chromatography (column diameter 95 mm, 152 mm (6 inches) / silica gel, eluent 6/3/1 hexane / acetone / toluene flow rate 5.1 mm (2 inches) per min ., 50 ml fractions), to give 17.68 g (33.96 mmol, yield 75%) of the isopropylphosphonate of the title, in the form of a viscous oil.

TLC: silica gel Rf = 0.32 (6: 3: 1 hexane / acetone / toluene).

1 H NMR: (270 MHz, CDCIs)

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 (2x d, 1H J = 3.7 Hz)

2.65 and 2.60 (2x d, 1H J = 7.4 Hz)

2.24-1.87 (Series of m, 2H)

1.19 and 1.12 (2xd, 12H J = 6.3 Hz)

1.01 (s, 9H)

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CH 675 582 A5

B. Dicvclohexvlamine salt (1: 1i of the acid methyl ester (SÌ-4- (HvdroxvméthoxvphosphinvD-3-rr (1.1-diméthvléthvndiphénvlsilvn-oxvlbutanoïaue)

10.66 g (35.5 mmol) of isopropyl phosphonate A were stirred under an argon atmosphere at room temperature in 80 ml of dry CH2Cl2. This solution was treated (5 minutes) dropwise with 8.44 g (32.8 mmofes, 8.71 ml) of bistrimethylsilyftrifluoracetamide (BSTFA), operation followed by dropwise addition, in 10 minutes, of 7 , 84 g (51.3 mmol, 6.75 ml) of trimethylsilyl bromide (TMSBr). After stirring at room temperature for 20 hours, the reaction was fixed with 200 ml of KHSO4 in 5% aqueous solution, and the reaction mixture was vigorously stirred for 15 minutes. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed once with brine, dried over Na2SC> 4 and concentrated in vacuo. The residue was mixed twice with 50 ml of toluene to obtain an azeotrope. The precipitate which formed was suspended in toluene and filtered. The filtrate was concentrated, and the process of preparing an azeotrope / filtrate was repeated. The filtrate obtained was evaporated in vacuo, then pumped under high vacuum for 5 hours. The clear viscous oil obtained was stirred under an argon atmosphere at room temperature in 50 ml of dry pyridine. This solution was treated at once with 4.65 g (22.6 mmol) of dicyclohexylcarbodiimide, followed by the addition of 1.31 g (41.0 mmol, 67 ml) of ethanol. After stirring at room temperature for 20 hours, the reaction mixture was filtered through a pad of Celite in a sintered glass funnel. The Celite was washed with ethyl acetate, and the combined filtrates were evaporated in vacuo. The residue was redissolved in ethyl acetate and washed twice with a 5% aqueous solution of KHSO4 and once with brine. The organic extract was dried over Na2SO4, filtered, and the filtrate was concentrated, an azeotrope of this filtrate was formed twice with toluene, resuspended in toluene and filtered . The filtrate obtained was again concentrated, put into the form of an azeotrope, filtered, and the filtrate was evaporated in vacuo and placed under high vacuum for 6 hours to give the phosphonate monoester in the form of a clear viscous oil (10.2 g, yield> 100%). TLC: silica gel Rf = 0.50 (7: 2: 1 nPr0H / NH40H / H2O). The phosphonate monoester [1.21 g was pumped under high vacuum for 4 hours to give 1.16 g (2.57 mmol)] was dissolved in 10 ml of dry ethyl ether and treated dropwise with 0.481 g (2.65 mmol, 0.528 ml) of dicyclohexylamine. The homogeneous solution obtained was left at room temperature for 7 hours, which led to a significant formation of crystals. The mixture was stored at -20 ° C for 16 hours, then brought to room temperature and filtered. The crystals were washed with dry and cold ethyl ether, then pumped under high vacuum over P2O5 for 18 hours. The crystals were then pumped under high vacuum at 45 ° C. for 4 hours, to give 1.25 g (1.98 mmol, yield 77%) of the title dicyclohexylamine salt in the form of a white powdery solid. . P.f. 155-156 ° C. TLC: silica gel Rf = 0.57 (20% MeOH / CH2Cl2).

1 H NMR: (270 MHz, CDCIs)

8 7.71-7.65 (m, 4H)

7.40-7.32 (m, 6H)

4.02 (m, 1H)

3.52 (s, 3H)

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 (m series, 22H)

1.00 (s, 9H)

Mass spectrometry: (FAB) 632 (M & H) +

IR: (KBr) 3466-3457 (large)

3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736, 1449,1435,1426,1379, 1243,1231, 1191, 1107, 1074,1061, 1051, 820 Cm -1)

Analysis: calculated for C22H31O6PSLC12H23 N:

C, 64.63; H, 8.61; N, 2.22 Found: C, 64.51; H, 8.49; N, 2.18

Example 26

Acid dilithium salt (EV4-rr2-r4'-fluoro-3.3'.5-trimethviï1.1'-biphénvn-2-vlléthénvnhvdroxvphosphinvn-3-hvdroxvbutanoïue

A. Dimethyl acid ester r2-r4 / -fluoro-3.3, .5-trimethvin.1 / -biphénvll-2-vll-2-hvdroxvéthvll-phosphonîaue

A solution at -78 ° C (CO2 / acetone) of 1.8 ml (16.5 mmol, 1.6 eq.) Of dimethyl methyl phosphonate in 20 ml of dry THF was treated dropwise in 20 minutes with 1.6 M solution of n-butyl-

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CH 675 582 A5

lithium in hexanes (9.7 ml, 15.5 mmol, 1.5 eq.), and the white suspension obtained was stirred under an argon atmosphere at -78 ° C for 60 minutes. Then, dropwise was added over 15 minutes at -78 ° C., to obtain a pale orange suspension, 2.5 g (10.3 mmol, 1 eq.) Of the biphenylaldehyde C of Example 1, in 10 ml of THF sec. After 30 minutes at -78 ° C, the reaction was fixed by the dropwise addition of 10 ml of saturated NH4Cl solution, then the reaction mixture was allowed to return to room temperature. The mixture was partitioned between ethyl acetate and H2O, the organic phase was washed with brine, dried over anhydrous NazSCU and evaporated in vacuo to give 2.127 g of a yellow oil, which slowly crystallized at rest. The crystals were triturated with hexanes to give, after filtration and drying under vacuum, 3.38 g (89.4%) of the title's pure hydroxyphosphonate in the form of white needles, m.p. 98-100 ° C. An additional 233 mg (total 3.613 g, yield = 95.6%) of the pure title compound was recovered by flash chromatography of 603 mg of the mother liquor on LPS-1 silica gel (40: 1) eluting with a mixture (7: 3) of hexane and acetone.

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

Analysis: Calculated for C19H24O4PF:

C, 62.29; H, 6.60; F, 5.19; P, 8.45 Found: C, 62.66; H, 6.56; F, 5.03; P, 8.68

B. Dimethyl acid ester r2-r4Mluoro-3.3, .5-trimethviri.1 / -biDhénvn-2-vlléthénvllphosphoniaue

A solution of 3.513 g (9.6 mmol) of hydroxyphosphonate A in 15 ml of dry toluene (4 A molecular sieve) was treated with 91 mg (0.48 mmol, 0.05 eq.) Of pTsOH.1 H2O, and heated to reflux in a Soxhlet apparatus containing a 4 Å molecular sieve, under an argon atmosphere for 16 hours. Additional amounts of pTsOH.FteO were added during the reaction at the following times: 3.5 hours (91 mg), 5.0 hours (91 mg) and 6.5 hours (91 mg). The mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCOs to give an aqueous phase, an organic phase and an oily layer between the phases. The aqueous phase and the oil layer were collected, washed with ethyl acetate, the ethyl acetate layer was washed with saturated NaHCO3 and set aside. The two bicarbonate washing waters were acidified with concentrated HCl, extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated to give 520 mg of the monomethyl ester of phosphonic acid recovered. The diester was regenerated by dissolving the oil in 5 ml of trimethyl orthoformate and heating the mixture at reflux under argon for 4 hours. The excess formate was removed in vacuo to give a yellow oil, which was taken up in ethyl acetate and combined with the original neutral organic phase. The ethyl acetate layer was washed with brine, dried over anhydrous Na2§04 and evaporated to give 3.396 g of a yellow oil. The crude oil was purified by flash chromatography on LPS-I silica gel (40: 1), the eluent being a mixture (75:25) of hexane and acetone. The fractions obtained were evaporated to give 2.987 g (89.4%) of the trans-vinyl dimethyl phosphonate of the title in the form of a golden oil.

TLC (1: 1) hex-acetone, Rf = 0.44 UV & PMA 1 H NMR (CDCI3):

S 2.27 (3H, d, Jh-f = 1.6 Hz 2.33 (3H, s)

2.39 (3H, s)

3.61 (6H, d, Jh-p = 11 Hz)

5.51 (1 H, dd, Jh-H = 18 Hz, Jh-p = 20.6 Hz)

6.95-7.09 (5H, m)

7.48 (1H, dd, Jh-h H = 17.9 Hz, Jh-p = 23.7 Hz) ppm

RMN-13C (CDCI3):

814.4, 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, 132.6, 132.7, 134.6, 137.1, 141.0,

148.2,148.2 (Jc-p = 5.7 Hz)

160.5 (Jc-f = 244.1 Hz)

C. F2-r4, -fluoro-3.3, .5-trimethvir-1.1, -biphenvll-2-vnethenvllphosphonic acid ester

A solution of 2.895 g (8.31 mmol) of vinyl dimethyl phosphonate E in 20 ml of dioxane was treated with 12.5 ml (12.5 mmol, 1.5 eq.) Of a 1.0 N solution of LiOH and the mixture obtained was stirred at 75 ° C (oil bath) for 70 minutes under an argon atmosphere. After 15 minutes of heating, the mixture became homogeneous. The mixture was cooled to room temperature, acidified to pH 1 with about 15 ml of 1.0 N HCl, extracted twice with ethyl acetate, then the organic phase was washed with

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CH 675 582 A5

brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 2.663 g (95.8%) of the title monomethyl ester, as a clear colorless oil.

TLC: (8: 1: 1) CH2Cl2-CH3OH-HOAc, Rf = 0.57, UV & PMA.

Mass spectrometry (M + H + = 335+ observed)

RMNiH (CDCI3):

s 2.25 (3H, d, Jh-f = 1.6 Hz)

2.33 (3H, s)

2.39 (3H, s)

3.53 (3H, d, Jh-p = 11 Hz)

5.61 (1H, dd, Jh-h = 18 Hz, Jh-p 20.6 Hz)

6.90-7.12 (5H, m)

7.38 1 H, dd, Jh-h = 18 Hz, Jn-p 24 Hz) ppm

D. Methyl ester of 4-i'4'-fluoro-3.3'.5-trimethviï1.1'- biphenvll-2-vnéthénvnméthoxv-phosphinvl1-3-oxobutanoïue acid

420 [d (3.9 mmol, 1.3 eq.) Of distilled methyl acetoacetate was added dropwise over 15 minutes to a suspension, with stirring, to a dispersion of 60% NaH in 168 mg (4 , 2 mmol, 1.4 eq.) Of a mineral oil, in 10 ml of dry THF, at 0 ° C. (oil bath) and under an argon atmosphere. The clear solution obtained was stirred for 15 minutes at 0 ° C, then treated for 10 minutes with a 1.6 M solution of n-butyilithium in hexanes (2.25 m (?), 3.6 mmol, 1, 2 eq.). The yellow dianionic solution was stirred for 15 minutes at 0 ° C, then cooled to -78 ° C, in preparation for treatment with phosphonochloridate.

The phosphonochloridate was prepared from the monomethyl ester C, by the following method. A solution of 960 mg (2.87 mmol) of the monomethyl ester of phosphonic acid C in 8 ml of dry CH2Cl2 was treated with 750 μl (5.98 mmol, 2 eq.) Of distilled trimethylsilyidiethylamine, and the mixture clear was stirred under argon for 1 hour at room temperature. The mixture was evaporated in vacuo, mixed with benzene (2 x 15 ml) to form an azeotrope, and the viscous oil remained on the vacuum pump for 15 minutes. The oil was taken up in 8 ml of dry CH2Cl2 and a drop of dry DMF, cooled to 0 ° C. (ice bath) and treated with 290 μl (3.3 mmol, 1.1 eq.) Of chloride. distilled oxalyl, drop by drop, in five minutes under an argon atmosphere. After 15 minutes at 0 ° C, the mixture was stirred at room temperature for 45 minutes, then evaporated in vacuo. The crude oil was mixed with dry benzene (2x15 ml) to form an azeotrope and to give, after evaporation and drying on the vacuum pump for 15 minutes, the crude phosphonochloridate in the form of a pale yellow oil.

About 2.9 mmol (1 eq.) Of phosphonochloridate in 8 ml of dry THF at -78 ° C was transferred dropwise using a cannula in 30 minutes, in a solution at -78 ° C methyl acetoacetate dianion. After 30 minutes at -78 ° C, the orange-brown reaction mixture was fixed by dropwise addition of 8 ml of saturated NH4Cl and allowed to return to room temperature. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.481 g of an orange oil. The crude oil was purified by flash chromatography on Merck silica gel, the eluent being a 9: 1 mixture of hexane and acetone, then a 1: 1 mixture of hexane and acetone. The fractions obtained were combined and evaporated to give 813 mg (62.9%) of the vinylphosphinic diester of the title, in the form of a pale yellow, viscous oil.

TLC (1: 1) Hex-acetone, Rf = 0.42, UV & PMA.

1 H NMR (CDCL3).

Ô 2.28 (3H, s)

2.34 (3H, s)

2.40 (3H, s)

3.15 (2H, dd, Jh-h = 4.7 Hz, Jh-p 18.2 Hz)

3.54 (3H, d, Jh-p = 11.6 Hz)

3.63 (2H, s)

3.72 (3H, s)

5.57 (1 H, dd, Jh-h = 1 7.9 Hz, Jh-p 25.3 Hz 6.95-7.09 (5H, m)

7.52 (1H, dd, Jh-h = 17.9 Hz, Jh-p 2.7 Hz) ppm

RMN-13C (CDCI3)

S 14.0 (Jc-f = 3.9Hz)

20.6, 45.3 (Jc-p = 85.9 Hz)

49.6, 50.9 (Jc-p = 5.8 Hz)

5.18, 113.6, 115.0, 121.4 (Jc-p = 128.9 Hz)

123.6, 124.7, 128.187.7, 129.5, 130.3, 130.8.132.1, 132.4, 136.4, 136.8, 138.2, 140.7, 149.2 (Jc-p = 4, 9 Hz)

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160.3 (Jc-f = 245.1 Hz),

166.7.194.4 (Jc-p = 4.9 Hz) ppm.

E. Methyl ester of fEÎ-4-iï4'-fluoro-3.3'.5-trimethvl-iï1.1y-biDhénvll-2-vl1éthénvnmethoxv-phosphinvll-3-hvdroxvbutanoïue acid.

A solution at 0 ° C (ice bath) of 585 mg (1.35 mmol) of ketone D, in 4 ml of dry THF, was treated with 51 mg (1.35 mmol, 1 mol eq.) Of Solid NaBH4, treatment followed by the dropwise addition of 1 ml of dry CH3OH (3 A molecular sieve), and the yellow mixture was stirred under an argon atmosphere at 0 ° C for 30 minutes. The reaction was set at 0 ° C by addition of 6.5 ml of the acetone reagent, followed by the addition of 500 mg of CC-4 silica gel. The suspension was brought to room temperature, filtered through sintered glass, rinsed with ethyl acetate and evaporated in vacuo to give 607 mg of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel (30: 1), elution being carried out with pure ethyl acetate. The fractions obtained were evaporated to give 340 mg (57.6%) of the title alcohol in the form of a pale yellow oil.

TLC (pure EtOAc), Rf = 0.19, W + PMA Mass spectrometry (M + H + = 435 observed)

1 H NMR (CDCI3):

8 1.90 (2H, m)

2.27 + 2.28 (3H, 2 singlets)

2.34 (3H, s)

2.39 + 2.40 (3H, singlets)

2.56 (2H, d)

3.52 (3H, d, Jh-p = 11.1 Hz)

3.69 + 3.70 (3H, 2 singlets)

3.79 + 3.90 (1 H, 2 doublets)

5.52 + 5.54 (1 H, 2dd, Jh-h = 18 Hz, Jh-p = 2.48 Hz)

6.95-7.02 (5H, m)

7.52-7.54 (1H, 2dd, Jh-H = 18 Hz, Jh-P = 21.6 Hz) ppm.

RMN-13C (CDCIs) (mixture R, S)

S 14.3 (Jc-f = 3.9 Hz)

20.8, 35.4 + 35.8 (Jc-p = 100.6 Hz)

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 (Jc-p = 122.1 Hz)

123.8, 128.2,128.7,129.0,130,4,131,4,132,3,132,7,136,6,137,0,138,2,140,8,

148.2 + 148.8 (Jc-p = 4.9 Hz)

171.8 ppm

F. acid dilithium salt fEV4-rr2-r4 / -fluoro-3.3, .5-trimethvl-n.1 / -biphénvn-2-vl1éthénvn-hvdroxv-phosphinvn-3-hvdroxvbutanoïue

A solution of 339 mg (0.781 mmol) of diester E in 8 ml of dioxane was treated with an excess of 1.0 N LiOH (2.3 ml, 2.3 mmol, 3 eq.) And the mixture was heated at 50 ° C (oil bath) for 1.5 hours under an argon atmosphere. A white precipitate was observed after 15 minutes. Still hot, the mixture was diluted with H2O until all the solids dissolved, then filtered. The filtrate was evaporated in vacuo, taken up in a minimum quantity of H2O and chromatographed on an HP-20 resin, eluting according to a linear gradient pure H2O - »pure CH3OH. The fractions obtained were evaporated, the white residue was taken up in 50 ml of H2O, filtered and lyophilized to give 270 mg (82.7%) of the dilithium salt of the title in the form of a white, hygroscopic lyophilisate .

TLC (8: 1: 1) CH2Cl2-CH3OH-HOAC, Rf = 0.33, UV + PMA.

Analysis for C21H22O5FP.2LÌ + 0.63 mole H2O (molecular weight 429.57):

Calculated: C, 58.71; H, 5.46; F, 4.42; P, 7.21 Found: C, 58.71; H, 5.70; F, 4.18; P, 6.96

1 H NMR (CDCIs)

8 1.59 (2H, multiplet)

2.24-2.37 (2H, 3 multiplets, Jh-h = 8.5 Hz + 4.4 Hz)

2.28 (3H, doublet, Jh-f = 1.8 Hz 2.30 + 2.39 (6H, 2 singlets)

4.14 (1H, multiplet)

5.78 (1 H, Jh-h = 17.9 Hz, Jh-p = 20.5 Hz)

6.88-7.21 (6H, multiplet)

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Example 27

4-IT2-4'-fluoro-3.3 / .5-trimethviri acid dilithium salt ■ 1, -biphenvn-2-vl1éthvnhvdroxvphosphinvll-3-hvdroxvbutanoïue

A. 4-rf2-r4, -fluoro-3.3 / -trimethvlf1.1, -biphenvlI-2-vnethvnmethoxv-phosphinvn-3-hvdroxvbutanoic acid methvlia ester

An argon purged solution of 297 mg of the trans vinyl phosphinate E of Example 6 in 6 ml of CH3OH was treated with 74 mg (25% by weight) of Pd at 10% / C, and the suspension black was shaken on a Parr apparatus under 276 kPa (40 psi) hydrogen pressure for 3 hours. The catalyst was removed by filtration through a filter packed with Celite and the filtrate was evaporated in vacuo to give an oil. The oil crystallized from hexanes to give, after filtration and drying in vacuo, 267 mg (89.5%) of the title's saturated phosphinate as a white crystalline solid.

TLC (EtOAc), Rf = 0.20, UV + PMA 1 H NMR (CDCIs, 270 MHz), IR (KBr pellet)

Mass spectrometry: (M + H + = 437+ observed)

1 H NMR (CDCIs):

1.55-1.87 (4H, m)

2.29 + 2.30 + 2.31 (6H, 3 singlets)

2.35 (3H, d, Jh-f = 2.1 Hz)

2.52 (2H, m)

2.78 (2H, m)

3.50 + 3.55 (3H, 2 doublets Jh-p = 4.3 Hz)

3.71 (3H, s)

3.86 + 3.91 (1 H, 2 singlets)

4.25 + 4.39 (1H, 2 broad multiplets) ppm.

B. Acid dilithium salt 4-fr2-r4, -fluoro-3.3'.5-trimethvlH.1 / -biphénvn-2-vnéthvllhvdroxv-phosphinvn-3-hvdroxvbutanoVaue

A solution of 250 mg (0.573 mmol) of diester A in 6 ml of dioxane was treated with an excess of 1.0N LiOH (1.72 ml, 3 eq.) And the mixture was heated to 50 ° C (bath oil) under an argon atmosphere for 1.5 hours. A white precipitate was observed after 15 minutes. The mixture was diluted with H2O, still hot, until all the solids dissolved, then it was filtered. The filtrate was evaporated in vacuo, the white residue was dissolved in a minimum quantity of H2O and chromo-tographed on an HP-20 resin, eluting with pure H2O (until neutral), then with pure CH3OH. The fractions obtained were evaporated in vacuo to give a white solid, which was mixed with CH3CN (2 times) to form an azeotrope, and was dried in vacuo to give 131 mg (55%) of the dilithium salt of l titled, in the form of a white solid.

TLC (8: 1: 1) CH2Cl2-CH3OH-acetic acid, Rf = 0.34, UV + 20 PMA

Analysis: Calculated for C21H24O5FPLÌ2 + 0.95 mole H2O (molecular mass 437.30):

C. 57.67, H, 5.97; F, 4.34; P, 7.08 Found: C, 57.67; H, 5.90; F, 3.92; P, 7.39

1 H NMR (CD3OD + D2O):

S 1.39-1.57 (4H, multiplet) ppm 2.22-2.37 (2H, multiplet)

2.26 + 2.38 (6H, 2 singlets)

2.31 (3H, doublet, Jh-f = 1.8 Hz)

2.71-2.77 (2H, multiplet)

4.13-4.20 (1H, multiplet)

6.73-7.11 (5H, multiplet, Aromatic H)

Example 28

Acid dilithium salt (E1-4-iï2-r3- (4-fluoro- phenvh 1 -M -méthvléthvl) -1 H-indol-2-vnéthénvllhvdroxv-phosDhinvn-3-hvdroxvbutanoïue

A. r2-r3- (4-fluororohenvO-1-M-methvlethvO-1H-indol-2-vl1-2-hvdroxvethvnphosphoniaue acid dimethvlia ester

A solution at -78 ° C (acetone / CO 2) of 1.35 ml (12.42 mmol, 1.6 eq.) Of methyl dimethylphosphonate in 20 ml of dry THF was treated dropwise in 15 minutes with a 1.6 M solution of n-BuLi in hexanes (7.3 ml, 11.6 mmol, 1.5 eq.), and the white suspension obtained was stirred under atmo73

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argon sphere at -78 ° C for 1 hour. 2.183 g (7.76 mmol) of the indoie-aldehyde E of Example 7 in 8 ml of dry THF was added dropwise over a period of 10 minutes to the anion at -78 ° C. and the light orange suspension obtained was stirred for 30 minutes at -78 ° C. The reaction was fixed by dropwise addition of 10 ml of saturated NH4Cl, then the reaction mixture was brought to room temperature and partitioned between H2O and ethyl acetate, the organic phase was washed with brine , dried over anhydrous Na2SO4 and evaporated to give 3.19 g of a white solid. The crude solid was triturated with hot hexane to give 2.967 g (94.3%) of the title pure hydroxyphosphonate, as a white solid, m.p. = 161-162 ° C.

TLC (1: 1) Hex-acetone, Rf = 0.29, UV + PMA Analysis - Calculated for C2iH2s04NPF:

C, 62.21; H, 6.22; N, 3.46; F, 4.69; P, 7.64 Found: C, 62.34; H, 6.32; N, 3.30; F, 4.61; P, 7.32

1 H NMR (CDCI3)

51.69 +1.74 (6H, 2 doublets)

2.18 + 2.56 (2H, 2 multiplets)

3.61 (1 H)

3.67 + 3.71 (6H, 2 doublets, Jh-P = 11 Hz)

5.32 (1 H, m)

5.50 (1H, m)

7.04—7.25 (4H, m)

7.33-7.39 (2H, quadruplet)

7.52 (2H, AB quadruplet) ppm

RMN-13C (CDCIs)

8 21.1, 21.3, 33.1 (Jc-p = 136.3 Hz)

48.3, 52.6 + 52.7 (Pc-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, 130.6, 131.9, 132.0, 134.8, 134.9, 135.2, 161.8 (Jc-f = 246.1 Hz) ppm.

B. Dimethyl acid ester ftransH2-r3- (4-fluorophenvn-1 -1 1 -methvlethvlH H-indol-2-vll-ethenvll-DhosDhoniaue

2.60 g (6.43 mmol) of hydroxyphosphonate A dissolved in 20 ml of hot benzene were treated with 122 mg (0.1 eq.) Of pTs0H.H20, and the mixture was heated to reflux in a Soxhlet containing a 4 Â molecular sieve, for one hour under an argon atmosphere. The yellow solution was cooled, diluted with ethyl acetate, the organic phase was washed twice with saturated NaHCO3, and brine, then dried over anhydrous Na2SO4 and evaporated to give 2.47 g of Polefin raw, in the form of a yellow solid. Recrystallization from ethyl acetate-hexanes gave 2.238 g (89.9%) of the pure trans vinyl phosphonate of the title as light yellow slides, m.p. 153-155 ° C. TLC (1: 1) Hex-acetone, Rf = 0.33, UV + PMA Mass spectrometry (M + H + 388+ observed)

Analysis - calculated for C21H23O3 PNF:

C, 65.11; H, 5.98; N, 3.62; F, 4.90; P, 7.99 Found: C, 65.27; H, 6.03; N, 3.48; F, 5.11; P, 7.98

1 H NMR (CDCIs):

81.67 (6H, doublet)

3.68 (6H, d, Jh-p = 11.6 Hz)

4.90 (1 H, septuplet)

5.73 (1 H, dd, Jh-h (trans) = 18 Hz, Jh-p = 18.2 Hz)

7.05-7.56 (8H, m)

7.94 (1H, dd, Jh-h = 17.9 Hz, JH-p 23.7 Hz) ppm

RMN13C (CDCIs)

8 21.7, 47.8, 52.2 (Jc-p = 5.7 Hz)

111.8,115.4,115.7,118.5 (Jc-p = 43.5 Hz)

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) ppm

C. Monomethyl ester of ftransH2-r3- (4-fluorophénvli-1-n-méthvléthvl'l-1H-indol-2-vll-éténénn-phosphoniaue acid

1.787 g (4.61 mmol) of vinyl dimethyl phosphonate B was dissolved in 12 ml of hot dioxane, treated with 6.9 ml (6.9 mmol, 1.5 eq.) Of 1.0 N LiOH and heated at 75 ° C (oil bath) under an argon atmosphere for 30 minutes. The mixture was cooled, acidified with 8 ml of 1.0 N HCl, extracted with

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twice with ethyl acetate, washed twice with water, then brine, dried over anhydrous Na2SO4 and evaporated to give 1.859 g of a yellow oil. The oil was dissolved in hot hexane, cooled and crystallized to give 1.657 g (96.1%) of monoacid, as a pale yellow solid, m.p. 181-183 ° C.

Analysis: calculated for C20H21O3PNF:

C, 64.02; H, 5.70; N, 3.73; F, 5.06; P, 8.25;

Found: C, 64.02; H, 5.87; N, 3.64; F, 5.26; P, 7.90;

TLC (20: 1: 1) CH2Cl2-CH30H-acetic acid, Rf = 0.26, UV + PMA 1 H NMR (CDCI3):

S1.66 (6H, doublet)

3.64 (3H, doublet, Jh-p = 11.6 Hz)

4.89 (1 H, septuplet),

5.81 (1 H, dd, Jh-H = 17.9 Hz, Jh-p 18.5 Hz)

7.06-7.64 (9H, multiplet) ppm

RMN-13C (CDCI3)

8 21.8.47.9.52.1 (Jc-p = 5.7 Hz)

112,0,115,5,115,8,116,1,119,0 (Jc-p = 9,5 Hz)

120,2,120,4,123,5,128,3,130,4,130,8,131,2,131,8,131,9,136,2,136,8 (Jc-p = 7,6 Hz)

161.9 (Jc-f = 246 Hz) ppm

D. 4-ff-2-f3- (4-fluoro-phenvn-1- (1-methvlethvlV1H-indol-2-vll-ethenvn-methoxvDhosphinvl] -3-oxobutanoic acid ester)

A phosphonochloridate was prepared by the following method. A solution of 1.564 g (4.19 mmol, 1 eq) of the monomethyl ester of phosphonic acid C in 10 ml of dry CH2Cl2 was treated with 1.05 ml (8.38 mmol, 2 eq.) Of distilled diethylamino-trimethylsilane, and the mixture was stirred under an argon atmosphere at room temperature for one hour. The mixture was evaporated in vacuo, taken up in 20 ml of benzene, evaporated in vacuo and the viscous oil was left on the vacuum pump for 15 minutes. A solution of crude sylated acid in dry CH2Cl2 (10 ml) and dry DMF (one drop) was cooled to 0 ° C, treated dropwise with 400 ml (4.61 mmol, 1.1 eq. ) of (COCI) 2 distilled, stirred for 15 minutes at 0 ° C, then at room temperature for 45 minutes under an argon atmosphere. The mixture obtained was evaporated in vacuo, taken up in 20 ml of benzene, evaporated in vacuo and left on the vacuum pump for 15 minutes to give a crude phosphonochloridate in the form of a viscous yellow oil. A solution of phosphonochloridate in 8 ml of dry THF at -78 ° C was transferred using a cannula, drop by drop, in 20 minutes, in a solution at -78 ° C of the methyl acetoacetate dianion, prepared as described in Example 26 from 590 ni (5.45 mmol, 1.3 eq.) of methyl acetoacetate, from 235 mg (5.87 mmol, 1.4 eq.) of a dispersion 25 of 60% NaH in an oil, 3.1 ml (5.03 mmol, 1.2 eq.) of 1.6 M n-butyllithium and 10 ml of THF. The orange reaction mixture was stirred for 30 minutes at -78 ° C, then the reaction was quenched by the dropwise addition of saturated NH4Cl, and the reaction mixture was allowed to return to room temperature. The mixture was partitioned between ethyl acetate water, the organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to give 2.080 g of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel, eluting with a 7: 3 CfaCk-EtOAc mixture. The fractions obtained were combined and evaporated to give 519 mg (26.3%) of the trans phosphinate of the title, in the form of a light yellow oil.

TLC (1: 1) Hex-acetone, Rf = 0.48, UV + PMA.

Mass spectrometry (M + H + = 472+ observed

1 H NMR (CDCIs)

81.66 + 2.71 (6H, 2 doublets)

1.68 (2H, m)

3.23 (2H, doublet)

3.54 (3H, d)

3.72 (3 | H, »s)

4.90 (1 H, septuplet)

5.76 (1H, dd, Jh-H = 18Hz)

7.10-7.58 (8H, m)

7.66 (1 H, dd, Jh-h = 18 Hz) ppm

RMN-13C (CDCI3)

8 21.8.45.7 (Jc-p = 5.7 Hz)

1 52.3, 111.9, 115.5, 118.8 (Jc-p = 104.1 Hz)

119.8, 120.2, 120.3, 123.6, 128.2, 130.4,

130.8,131.8,131.9,136.1,139.2

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(Jc-p = 5.6 Hz)

161.9 (Jc-f = 246 Hz)

167.0.194.6 (Jc-p = 3.8 Hz) ppm

E. Methyl acid ester Œ) -4-iï2-r3-fluoroDhénvn-1 - (1 -méthvléthvh-1 H-indol-2-vlléthénvn-méthoxvphosphinvll-3-hvdroxlbutanoïue

A solution at -15 ° C (salt and ice bath) of 519 mg (1.1 mmol) of ketone D in 8 ml of dry absolute EtOH (molecular sieve 3 Â) was treated with 42 mg (1, 1 mmol) of solid NaBH *, and the yellow mixture was stirred under argon at -15 ° C for 20 minutes. The reaction was fixed by adding 0.5 ml of acetone, then 500 mg of CC-4 silica gel. The mixture was brought to room temperature, filtered, rinsed with ethyl acetate and evaporated in vacuo to give 512 mg of a yellow foam. The crude foam was purified by flash chromatography on Merck silica gel, using a 4: 1 mixture of ethyl acetate and acetone as eluent, then pure acetone. The fractions obtained were evaporated to give 317 mg (60.9%) of the title alcohol, in the form of a yellow oil.

TLC (4: 1) EtOAc-acetone, Rf = 0.21, UV + PMA Mass spectrometry (M + H + = 474+ observed)

1 H NMR (CDCI3)

8 1.68 (6H, doublet)

1.97 (2H, m)

2.58 (2H, d)

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 (1 H, septuplet)

5.78 (1H, dd, Jh-h = 17.4 Hz, Jh-p = 23.2 Hz)

7.05-7.77 (9H, m) ppm.

"C NMR (CDCI3)

5 21.7, 34.9+ 36.3 (Jc-p = 20.8 Hz)

42.0 (Jc-p = 13.2 Hz)

47.8, 50.8 (Jc-p = 5.6 Hz)

51.6, 63.1 (Jc-p = 15.1 Hz)

111,8,115,4,115,7,118,6,119.9 + 121.8 (Jc-p = 18.9 Hz) 120,1,123,4,128,2,130,6,130,7,131,1,131,7,131,9, 135,8,138,0 + 138 , 5 (Jc-p = 5.7 Hz)

161.8 (Jc-f = 246.1 Hz)

171.7, 171.8 ppm.

F. Acid dilithium salt (E) -4-iï2-f3-f-4-fluoroDhénvn-1-f1-méthvléthvn-1H-indol-2-vnéthénvl1-hvdroxvphosphinvl1-3-hvdroxvbutanoïue.

A solution, with stirring, of 264 mg (0.558 mmol) of the hydroxy-diester E in 6 ml of dioxane was treated with 1.95 ml (3.5 eq.) Of 1.0 N LiOH, and heated to 70 ° C (oil bath) for 20 minutes under an argon atmosphere. The mixture was allowed to cool, then it was diluted with H2O, filtered, evaporated under vacuum, taken up in a small amount of H2O (1 to 2 ml) and chromatographed on 3 an HP-20 resin, eluting with H2O (up to neutrality, 3 to 4 column volumes), followed by a 75:25 CH3OH-H2O mixture. The fractions obtained were evaporated, taken up in 50 ml of H2O, filtered and lyophilized to give 217 mg (85.1%) of the dilithium salt of the title, in the form of a white lyophilisate.

TLC (8: 1: 1) CH2Cl2-CH3OH-acetic acid, Rf 0.08, UV + PMA Analysis - calculated for C23H23O5NPF.2 Li +1.62 moles H2O (Molecular mass 486.46):

C, 56.78; H, 5.44; N, 2.88; F, 3.91; P, 6.37 Found: C, 56.76; H, 5.64; N, 2.58; F, 3.60; P, 6.77

1 H NMR (400 MHz, CDCI3):

8 1.67 (6Ht doublet)

1.73 (2H, multiplet)

2.38 (2H, doublet of quadruplet AB, Jab = 15 Hz,

Jax = 8 Hz, Jbx = 4.8 Hz)

4.24 (1 H, multiplet)

5.06 (1 H, septuplet)

6.09 (1H, Jhh = 17.6Hz, JHp = 19.4Hz)

7.02-7.61 (9H, multiplet)

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Example 29

Acid dilithium salt (SM-rr2-M- (4-fluorophénvn-3- (1-méthvléthvlHH-indol-2-vnéthvllhvdroxv-phosphinvll-3-hvdroxvbutanoïue

A. Ethyl ester of 4-methvl-2-oxopentanoic acid

25 g of the sodium salt of 4-methyl-2-oxopentanoic acid were dissolved in a minimum quantity of H2O, acidified to pH 1 with concentrated HCl, then extracted several times with CH2Cl2. The aqueous phase was saturated with NaCl, then extracted again (twice) with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SC> 4 and evaporated to give 17.7 g of the free acid as a viscous oil.

A mixture of 17.7 g (136 mmol) of the acid in 200 ml of dry benzene was treated with 20.4 ml (136.2 mmol, 1 eq.) Of diazabicyclo-undecane (DBU), which gave result in an exothermic reaction and the formation of a gel-like crystalline salt. The mixture was treated with 10.9 ml (1 eq.) Of ethyl iodide, and was mechanically stirred for 3 hours under an argon atmosphere. The precipitated salts were removed by filtration, the filtrate was washed once with a small amount of H2O (50 ml) and brine, then dried over anhydrous Na2SC> 4. Benzene was removed by distillation under atmospheric pressure, and the remaining yellow liquid was distilled in vacuo to give 6.46 g (35.1%) of the title ester as a yellow liquid pale clear PE = 65-66 ° C (5 mm Hg).

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

Mass spectrometry (M + H + = 159+ observed)

B. Ethyl ester of 4-methvl-2-f2-phenvl-hvdrazonoi-pentanoic acid

A solution of 5 g (31.6 mmol) of ethyl ester A in 30 ml of dry CH2Cl2 was treated with 3.3 ml (33.2 mmol, 1.05 eq.) Of phenylhydrazine, dropwise for 5 minutes, and the yellow mixture obtained was stirred under an argon atmosphere at room temperature on a 4 A molecular sieve for three hours. The mixture was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give 8.105 g of an orange oil. The oil was purified by flash chromatography on silica gel LPS-1, the eluent being a mixture of hexane and ethyl acetate. The fractions obtained were evaporated to give 6.8 g (86.7%) of the pure hydrazone of the title and 848 mg (10.8%) of the geometric isomer of the hy-drazone of the entitled. Total yield = 97.5% TLC (9: 1) hexane-acetone, Rf geometric isomers = 0.42 + 0.64, UV + PMA

Mass spectrometry (M + H + = 249+ observed)

C. Ethyl acid ester 3- (1-methvlethvh-1 H-indole-2-carboxylate

HCl gas was bubbled (gas dispersion tube) for 30 minutes at room temperature in a solution in absolute ethanol (50 ml, on 3 A molecular sieve) of hydrazone B (6.8 g, 27.4 mmol). The exothermic reaction was characterized by a change in color, from yellow to red, then to dark green, followed by precipitation of NH4CI. The suspension was stirred for another 20 minutes under Drierite and then transferred to 50 ml of ice-cold H 2 O. The ethanol was removed in vacuo, and the residue was partitioned between ethyl acetate and H2O. The aqueous layer was extracted twice with ethyl acetate, the combined organic phases were washed with H2O and brine, then dried over anhydrous MgSO4 and evaporated to give 4.969 g of a green solid. The crude solid was dissolved in hot hexane, treated with Darco, filtered through a filter packed with Celite, concentrated to a volume of 30-50 ml, and the yellow solution was 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 title's pure indole in the form of white needles, PF 80-81 ° C and a coherent 1 H NMR spectrum (CDCI3.270 MHz).

TLC (9: 1) hexane-acetone, Rf = 0.42, UV + PMA.

Note: The Rf of hydrazone and indole are identical, but the indole has a bright purple fluorescence (M + H + = 232+ observed).

Analysis - calculated for C14H17NO2:

C, 72.70; H, 7.41; N, 6.06 Found: C, 72.67; H, 7.57; N, 6.00

D. Ethyl acid ester 1 - (4-fluorophenvl-3- (1-methvlethvli-1 H-indole-2-carboxvliaue

A solution of 3.937 g (17 mmol) of indole C and 9.34 ml (85 mmol, 5 eq.) Of 1-bromo-4-fluoro-benzene in 15 ml of dry DMF was treated with 245 mg (1.7 mmol, 0.1 eq.) Of cuprous oxide, and heated under reflux under an argon atmosphere for 17 hours. Additional amounts of bromide (9.34 ml, 5 eq.) And CU2O (245 ml, 0.1 eq.) Were added, heating under reflux was continued for 6 hours, another 730 mg was added ( 5.1 mmol) of CU2O, and heating was continued under reflux pen77

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CH 675 582 A5

for another 60 hours. DMF and excess bromide were removed by vacuum distillation, and the residual orange oil was taken up in ethyl acetate, filtered through a filter packed with Celite, washed with saturated NaHCC> 3 and brine , then dried over anhydrous Na2SO4 and evaporated to give 5.385 g (97.2%) of the crude indole of the title, in the form of an orange oil.

TLC (9: 1) hexane-acetone, Rf = 0.29, UV + PMA

E. 1 -f4-fluoroDhenvn-3-f1-methvlethvh-1 H-indole-2-methanol

Was added to 24 ml of dry and cold ether (0 ° C, ice bath), under an argon atmosphere, 907 mg (23.9 mmol, 1.5 mol eq.) Of solid LÌAIH4, then added dropwise over 10 minutes, 5.185 g (15.9 mmol) of the indole ester D in 10 ml of dry Et2O. The mixture was stirred for 1 hour at 0 ° C, then the reaction was fixed at 0 ° C by successive dropwise addition of 910 μl of H2O, 910 μl of 15% NaOH and 2.73 ml of H2O. The suspension was filtered through anhydrous MgSO4, through a filter packed with Celite, and the filtrate was evaporated to give a clear colorless oil. The oil gradually crystallized in hexane, to give, in two harvests (3.771 g + 0.333 g) 4.10 g (90.9%) of the pure indole alcohol of the title, in the form of white granular crystals, mp = 81-82 ° C.

Mass spectrometry (M + H + = 284+ observed)

Analysis - calculated for CisHisNOF:

C, 76.30; H, 6.40; N, 4.94; F, 6.71 Found: C, 76.59; H, 6.31; N, 4.93; F, 6.49

F. 1 -f4-fluorophenvn-3-f 1 -methvlethvfl-1 H-indole-2-carboxaldehyde

A solution of 6.46 g (15.24 mmol) of Dess-Martin periodinane in 30 ml of dry CH2Cl2 was treated with 1.44 ml (15.24 mmol, 1 eq.) Of dry tert-butanol (sieve molecular 4 4), and the mixture was stirred under an argon atmosphere for 15 minutes at room temperature. A solution of 3.599 g (12.7 mmol) of indole alcohol E in 13 ml of dry CH2Cl2 was added dropwise over 10 minutes, and the pale yellow mixture was stirred under an argon atmosphere at temperature room for 30 minutes. The reaction mixture was added to a solution of 14.06 g (89 mmol, 7 e) of sodium thiosulfate in 40 ml of freshly prepared 1 N NaHCO3, then stirred for 10 minutes. The aqueous phase was removed, the organic phase was washed twice with 1.0 N NaHCO3, then H2O and brine, then dried over anhydrous Na2SO4 and evaporated to give 3.877 g of a yellow oil. The crude oil was purified by flash chromatography on silica gel LPS-1, eluting with a 40: 1 mixture of hexane and ether. The fractions obtained were evaporated to give 3.118 g (87.3%, crude yield) of the crude product. Recrystallization from hot hexane gave 2.643 g (74%) of the title pure aldehyde, in the form of fluffy needles, m.p. 114-116 ° C

Mass spectrometry (M + H + = 282+ observed).

TLC (7: 3) hex-Et20, Rf = 0.51, UV + PMA

Analysis calculated for CmNisNOF:

C, 76.85; H, 5.73; N, 4.98; F, 6.75 Found: C, 76.87; H, 5.63; N, 4.89; F, 6.88

G. 2- (2.2-dibromoethénvn-1 - (4-fluoroDhénvn-3- (1-méthvléthvn-1 H-indole

A solution at -15 ° C (salt and ice bath) of 1.615 g (5.74 mmol) of aldehyde F and 4.52 g (17.22 mmol, 3 eq.) Of triphenylphosphine in 25 ml of dry CH2Cl2 was treated dropwise over 10 minutes with a solution of 2.86 g (8.61 mmol, 1.5 eq.) of CBr4 in 10 ml of dry CH2Cl2, and the resulting dark orange red solution was stirred under an argon atmosphere at -15 ° C for 15 minutes. The reaction was fixed at -15 ° C by addition of saturated NaHCO3, the reaction mixture was diluted with CH2Cl2, the organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to give 8 , 9 g of a red solid. The crude solid was purified by flash chromatography on silica gel LPS-1, the eluent being a 100: 1 mixture of hexane and ether. The fractions obtained were evaporated to give 2.017 g (80.6%) of the pure vinyl dibromide of the title in the form of pale yellow crystals, m.p. 123-124 ° C.

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

Mass spectrometry (M & H + = 438+ observed)

Analysis: calculated for CigHi6NFBr2:

C, 52.20; H, 3.69; N, 3.20; F, 4.35; Br, 36.56 Found: C, 52.25; H, 3.69; N, 3.18; F, 4.24; Br, 36.59

H. 2-éthvnvl-1-f4-fluoroDhénvn-3-f1-méthvléthvl \ -1 H-indole

A solution at -78 ° C (CCVacetone) of 10 ml of dry THF was treated with a solution of 1.6 M n-butyl lithium in hexanes (5.5 ml, 8.8 mmol, 2.2 eq .), and added dropwise over 15 minutes

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CH 675 582 A5

under an argon atmosphere a solution of 1.749 g (4 mmol) of vinyl dibromide G in 10 ml of dry THF. The yellow mixture was stirred for 20 minutes at -78 ° C, then the reaction was quenched by the addition of 10 ml of saturated NH4Cl. After bringing the mixture to room temperature, diluted with ethyl acetate, the organic phase was washed with saturated NH4Cl and brine, then dried over anhydrous Na2SC> 4 and evaporated to give 1.216 g of a dark green-brown oil. The crude oil was purified by flash chromatography on Merck silica gel, eluting with a 300: 1 mixture of hexane and ether. The fractions obtained were evaporated to give 1.084 g (97.5%) of the title acetylene acetylene, in the form of a fluorescent green oil. 1 H NMR (CDCl3, 270 MHz) a indicates an 18: 1 mixture of the desired acetylene and the undesirable terminal olefin.

TLC (50: 1) hex-EtaO, Rf = 0.55, UV & PMA.

J. Acid methvlia ester (SV4-IT2-r 1 -M-fluorophénvh-l (1 -méthvléthvO-1 H-Indol-

2-vn-éthvnvnméthoxvphosphinvn-3-1U1.1-diméthvléthvndiDhénvlsilvn-oxv1-butanoïaue

A phosphonochloridate was prepared from the dicyclohexylamine salt of the monomethyl ester of phosphonic acid of Example 25, by the following procedure.

The free acid was regenerated from the dicycloxylamine salt (4.32 g, 6.83 mmol, 1.75 eq.) By partitioning between 1.0 N HCl and ethyl acetate, washing of the organic phase twice with 1.0 N HCl and brine, then drying over anhydrous Na2SO4 and evaporation in vacuo to give 6.8 mmol of the free acid in the form of a viscous and clear oil. 6.8 mmol of the monomethyl ester of phosphonic acid in 10 ml of dry CH2Cl2 were treated with 1.72 ml (13.7 mmol, 2 eq.) Of distilled trimethylsilyl-diethylamine, and the clear solution was stirred under an argon atmosphere at room temperature for 1 hour. The mixture was evaporated in vacuo, removed with 2 x 20 ml of dry benzene and left on the vacuum pump for 15 minutes. The crude silylated acid in dry CH2Cl2 (10 ml) and a drop of dry DMF was cooled to 0 ° C (ice bath) and treated dropwise in 5 minutes with 655 n '(7.5 mmol, 1 , 1 eq.) Of (COCI) 2 distilled. The yellow mixture was stirred at 0 ° C for 15 minutes and 45 minutes at room temperature under an argon atmosphere. The mixture was evaporated in vacuo, removed with 2 x 20 ml of benzene, and left on the vacuum pump for 15 minutes, to give the crude phosphonochloridate as a yellow viscous oil.

A solution at -78 ° C (CO 2 / acetone) of 1.084 g (3.90 mmol, 1 eq.) Of indol-acetylene H in 10 ml of dry THF was treated dropwise in 10 minutes with 2, 44 ml (3.9 mmol, 1 eq.) Of 1.6 M n-butyllithium in hexanes, and the purple suspension was stirred under an argon atmosphere at -78 ° C for 30 minutes. The anion was added dropwise using a cannula over 30 minutes at -78 ° C, to a solution, at -78 ° C, of phosphonochloridate in 10 ml of dry THF. The dark brown mixture was stirred at-78 ° C for 30 minutes, then the reaction was fixed by dropwise addition of 10 ml of saturated NH4Cl. The mixture was brought to room temperature, partitioned between ethyl acetate and saturated NH4Cl, washed with brine, dried over anhydrous Na2SO4 and evaporated to give 1.968 g (71.1%) of acetylene phosphinate. the title, in the form of a light yellow oil.

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

Mass spectrometry (M + H + = 710+ observed).

K. Acid methvlia ester (SV3-fiï1 ■ 1-dimethvléthvndiphénvlsilvlloxvl-4-ri2-M- (4-fluorophénvn-

3-M -methvlethvn-1 H-indol-2-vn-ethvll-methoxvhosphinvlbutanoïaue

A solution, purged with argon, of 950 mg of acetylene J in 10 ml of CH3OH was treated with 238 mg (25% by weight) of Pt at 10% / C and the black suspension was stirred under atmosphere of hydrogen, under a pressure of one atmosphere, overnight. The catalyst was removed by filtration through a Millipore polycarbonate filter (0.4 nm) and a prefilter, and the filtrate was evaporated in vacuo to give a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel, the eluent being an 8: 2 mixture of hexane and ethyl acetate. The fractions obtained were evaporated to give 915 mg (86.7%) of the pure saturated phosphinate of the title, in the form of a white foam.

TLC (4: 1) EtOAc-hexane, Rf = 0.39 UV + PMA.

Mass spectrometry (M + H + = 714+ observed)

L. Acid methvlia ester (SÌ-4-ff2-M- (4-fluorophénvh-3-f1-méthvléthvn-1 H-indol-2-vnéthvn-méthoxvphosphinvn-3-hvdroxvbutanoïue

A solution of 915 mg (1.22 mmol) of silyltéher K in 10 ml of THF was successively treated with 280 n '(4.88 mmol, 4 eq.) Of glacial acetic acid and a solution of n-C4HgNF 1 , 1 M in THF (3.3 ml, 366 mmol, 3 eq.) And the mixture was stirred under an argon atmosphere at room temperature overnight. 8 ml of ice-cold water was added, the mixture was extracted with ethyl acetate, then the organic phase was washed twice with 5% KHSO4, saturated NaHCO3 and brine , then dried over anhydrous Na2SO4 and evaporated in vacuo to give 955 mg of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel, the eluent being

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CH 675 582 A5

a 1: 1 mixture of hexane and acetone. The fractions obtained were evaporated to give 521 mg (85.5%) of the title alcohol, in the form of a pale yellow oil.

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

Mass spectrometry (M + H + = 476+ observed).

M. Acid dilithium salt (SM-rr2-ri- (4-fluoro-phenvli-3- (1-méthvléthvn-1H-lndol-2-vlléthvll-hvdroxv-phosphinvn-3-hvdroxvbutanoTaue

A solution of 505 mg (1.06 mmol) of diester L in 10 ml of dioxane was treated with an excess of 1.0N-LiOH (3.7 ml, 3.7 mmol, 3.5 eq.), And the mixture was heated to 65> C (oil bath) under an argon atmosphere for 1.5 h. The mixture was diluted with water, filtered and evaporated in vacuo to give a light yellow solid. The crude solid was suspended in a small amount of H2O and chromatographed on an HP-20 resin (bed 15 cm, column diameter 25 mm), eluting with H2O until neutral, then with CH3OH. The fractions obtained were combined, evaporated, taken up in 50 ml of H2O and lyophilized to give 484 mg (95.4%) of the dilithium salt of the title, in the form of a white lyophilisate. TLC (8: 1: 1) CH2Cl2-CH30H-acetic acid, Rf = 0.39 UV + PMA.

Analysis: calculated for C23H25NO5FP.2LÌ + 1.03 mole H2O (Molecular mass = 477.91): C, 57.80; H, 5.72; N, 2.93; F, 3.97; P, 6.48 Found: C, 57.80; H, 6.01; N, 3.01; F, 3.93; P, 6.41

Example 30

Acid dilithium salt (S1-4-iï2-n- (4-fluoro-phenvn-3- (1-méthvléthvn-1 H-indol-2-vnéthvnvnhvdroxv-phosphinvl1-3-hvdroxvbutanoïaue

A. f5M-rr2-ri- (4-fluoro-phenvfl-3- (1-méthvléthvlV1H-indol-2-vnéthvnvnméthoxv-phosphinvn-3-hvdroxvbutanoïue) acid methvlia ester

A solution of 987 mg (1.39 mole) of the silylether J of Example 30 in 12 ml of dry THF was treated successively with 320 μl (5.6 mmol, 4 eq.) Of glacial acetic acid, then a 1.1 M solution of nC ^ gNF in THF (3.8 ml, 4.17 mmol, 3 eq.), and the mixture was stirred overnight under an argon atmosphere at room temperature. The mixture was diluted with 10 ml of ice-cold H2O and extracted with ethyl acetate. The organic phase was washed three times with 5% KHSO4, saturated NaHCC> 3 and brine, then dried over anhydrous NO2SO4 and evaporated to give 1.0 g of a yellow oil. A TLC indicated the formation of a certain amount of monoacid, which was converted back to the methyl ester by treatment with a solution of CH2N2 in ether. The excess CH2N2 was fixed using glacial acetic acid, and the mixture was evaporated in vacuo to give 1.12 g of a brown oil. The crude oil was purified by flash chromatography on Merck silica gel, eluting with 600 ml of an 8: 2 mixture of hexane and acetone, then a 1: 1 mixture of hexane and acetone . The fractions obtained were evaporated to give 516 mg (78.7%) of the free alcohol of the title, in the form of a light brown oil.

TLC (9: 1) CH2Cl2-CH3OH, Rf = 0.41, UV + PMA.

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

B. Acid dilithium salt (SV4-iï2-ri- (4-fluoro-phenvlV3-M-méthvléthvn-1 H-indol-2-vnéthvnvnhvdroxv-phosohinvll-3-hvdroxvbutanoTaue

A solution of 516 mg (1.09 mmol) of diester A in 10 ml of dioxane was treated with 3.8 ml (3.8 mmol, 3.5 eq.) Of a solution of 1.0N LiOH, and the clear mixture was heated and stirred at 60 ° C (oil bath) for 1.5 h under an argon atmosphere. The mixture was diluted with H2O, filtered, evaporated under vacuum, the residual oil was taken up in a minimum quantity of H2O and chromatographed on an HP-20 resin (bed 15 cm, column diameter 25 mm), eluting with Pure H2O until neutral, then with a 1: 1 mixture H2O-CH3OH. The fractions obtained were evaporated in vacuo, taken up in 50 ml of H2O, filtered and lyophilized to give 447 mg (82.3%) of the dilithium salt of the title in the form of a white lyophilisate.

TLC (8: 1: 1) CH2Cl2-CH3OH-acetic acid, Rf = 0.39, UV + PMA.

Analysis: calculated for C23H21O5PNF. 2Li + 2.27 moles H2O (molecular weight 496.1):

C. 55.67; H, 5.19; N, 2.82; F, 3.83; P, 6.24 Found: C, 55.69; H, 5.37; N, 2.82; F, 3.85; P, 6.19

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Example 31

Acid dilithium salt (5i-4-lïï2.4-dimethvl-6-

iï4-fluorophénvnméthoxvlphénvnéthvnvllhvdroxvphosphinvn-3-hvdroxvbutanoïaue

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A. 1 (-Methomethoxv) -3.5-dimethvlbenzene

12 ml of a THF solution of 10.42 g (85.3 mmol) of 3,5-dimethylphenol was added dropwise over 10 min. to a suspension of 85.3 mmol of NaH (prewashed with pentane) in 50 ml of THF under an atmosphere of argon, and cooled to 0 ° C. After completion of the addition of phenol, the reaction mixture was stirred at 0 ° C for 10 min., Warmed to room temperature and stirred for 20 min. 42 ml of dry DMF was added to the alkoxide solution, then a solution, in 10 ml of THF, of 11.19 g (89.6 mmol) of bromomethyl methyl ether was added slowly. A white precipitate has formed. After stirring at room temperature for 2.5 h, the reaction was quenched by the slow addition of 25 ml of 1N NaOH. The THF was removed from the reaction mixture by evaporation on a rotary evaporator, and the solution obtained was diluted with a saturated NaCl solution, then extracted 3 times with ether. The combined ether extracts were dried over Na2SO4 and filtered. Removal of the solvent gave an orange oil. Purification by flash chromatography, eluting with 5% ether / hexanes, gave the title methoxymé-thyl (MOM) -ether (12.0 g, 85% yield) as a clear oil .

20 CCM Rf = 0.45 (15% EfeO / hexane, silica gel)

Mass spectrometry m / e 166 (M +), 165 (M + -H) ~

B. (2-Methoxvmethoxvi-4.6-dimethvlbenzaldéhvde

7.70 g (79.45 mmol) of tetramethylethylenediamine was added slowly to a solution of n-bu-tyllithium (26.5 ml in a 2.5 M solution in hexane) in 30 ml of cyclohexane in an atmosphere argon. The solution was cooled to 0 ° C, and 11.00 g (66.21 mmol) of MOM-ether A was added dropwise over 20 min. After completion of the addition, the reaction mixture was stirred at 0 ° C for 30 min., Warmed to room temperature and stirred for 10 min. Then the anion was added via a funnel to a solution, in 100 ml of dry cyclohexane, of 5.81 g (79.45 mmol) of DMF under an argon atmosphere and to the ambient temperature. The reaction mixture was stirred at room temperature for 2 h, then the reaction was fixed with methanol. The solvent used for the reaction was removed on a rotary evaporator, and the orange oil obtained was dissolved in a 1: 1 mixture of ether and water. The aqueous layer was extracted three times with ether, and the combined ethereal extracts were dried over MgSO4. Filtration and removal of the solvent gave an orange oil. Purification of the oil by flash chromatography, eluting with 20% ether / hexane, gave 7.7 g (60%) of the title aldehyde, as a clear oil.

TLC Rf = 0.14 (15% Et20 / hexane, silica gel).

Mass spectrometry m / e 195 (M + H) +, 179 (M-CH3) 4 ", 163 (M-OCH3) +, 149 (M-02CHs) +

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C. 2-Hvdroxv-4.6-dimethvlbenzaldéhvde

35.5 ml of a 1M HCl solution was added to a solution, in 130 ml of dioxane, of 6.89 g (35.5 mmol) of MOM-ether B, at room temperature. The reaction mixture was heated to moderate reflux, and stirred for 30 min. The reaction mixture was cooled to room temperature, and the dioxane was removed by evaporation on a rotary evaporator. The aqueous solution obtained was diluted with water and extracted with ether. The aqueous layer was then saturated with NaCl, and reextracted twice with ether. The ethereal extracts were combined and then dried over MgSO4. Filtration and removal of the solvent gave a greenish solid, which was purified by recrystallization from hexane 50 (4.01 g, 75%).

TLC Rf = 0.48 (15% Et20 / hexane, silica gel) m.p. 46-48 ° C.

Mass spectrometry m / e 151 (M + H) +, 135 (M-CH3) +

D. 2-IY4-Fluorophénvnméthoxvl-4.6-diméthvlbenzaldéhvde

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A solution of 4.0 g (26.6 mmol) of phenol C and 30 ml of dry DMF was stirred under an argon atmosphere. At room temperature, 4.43 g (32 mmol) of solid K2CO3 was added to the phenol solution, then heated to 60 ° C for 35 min. The orange solution obtained was cooled to room temperature, and 5.55 g (29.3 mmol) of p-fluorobenzyl bromide was added. The reaction-60 mixture was heated to 60 ° C and stirred for 2 h. The reaction mixture was poured into 150 ml of ice water, and this mixture was extracted several times with ether. The combined ether extracts were dried over MgSO4 and filtered to give a yellow solid after removal of the solvent. Purification by flash chromatography, eluting with 15% ether / hexane, gave the title benzylether (4.48 g, 60%) as a white solid.

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TLC Rf = 0.34 (25% EtaO / Hexane, silica gel)

Mass spectrometry m / e 259 (M + H) +, 231 (M-CHO) +, 109 (M-C? H6F) +

E. 1- (2.2-Dibromoethénvh-2.4-diméthvl-6-fohénvl-méthoxvtoenzène

A solution, in 170 ml of dry CH2Cl2, of 4.42 g (17.13 mmol) of the aldehyde D under an argon atmosphere, was cooled in an ice and salt bath. To the cooled solution was added 14.4 g (55.0 mmol) of triphenylphosphine, and the mixture was stirred until all of the solids dissolved. A solution of 8.52 g (25.7 mmol) of CBr4 in 50 ml of CH2Cl2 was added using a funnel over a period of 12 min. After completion of the addition, the orange reaction solution was stirred at 0 ° C for 1 h 15 min. The reaction was fixed with 60 ml of a saturated aqueous solution of NaHCO3, and the reaction mass was vigorously stirred. The aqueous layer was removed, and extracted twice with CH2Cl2. The combined solutions in CH2Cl2 were washed once with a saturated aqueous solution of NaHCOs, dried over MgSO4 and filtered to give the title dibromide as a yellow brown solid (13 g). The title dibromide was purified by flash chromatography, eluting with 2% ether / hexane, to give 5.49 g (77% yield) of the title dibromide.

TLC Rf = 0.28 (2% Et20 / Hexane, silica gel).

Mass spectrometry m / e 413 (M + H) +, 333, 335 (M-Br) +, 317 (M-C6H4F), 109 (M-CioHgOBr2) +.

F. 1-Ethvnvl-2-rf4-fluorophenvhmethoxv1-4.6-dimethvl-benzene •

A solution, in 70 ml of THF, of 5.48 g (13.3 moles) of dibromide E was cooled to -78 ° C. under an argon atmosphere. It was added in 10 min. with the n-butyllithium dibromide solution (10.6 ml of a 2.5 M solution in hexane, 26.5 mmol). The reaction mixture was stirred at -78 ° C for 1 h, then the reaction was set at -78 ° C with a saturated aqueous NH4Cl solution. After bringing the reaction mixture to room temperature, it was diluted with 60 ml of H2O, and the aqueous layer was extracted twice with ether. All of the organic layers were combined and dried over MgSO4. Filtration and removal of the solvent gave 3.8 g of the title benzyloxyacetylene as a yellow solid. The title benzyloxyacetylene was purified by flash chromatography, eluting with 3% ether / hexane. The title acetylene was obtained in 85% yield (2.76 g) as a white solid.

TLC Rf = 0.17 (2% Et20 / hexane, silica gel)

Mass spectrometry m / e 255 (M + H) +, 159 (M-C6H4F) +, 109 (M-CioHgO) +

G. Acid dilithium salt (SV4-flf2.4-dimethvl-

6-IY4-fluoroDhénvnméthoxvlDhénvHéthvnvnhvdroxvDhosDhinvll-3-ftert-butvldiphénvlsilvloxvibutanoïaue

A solution, in 40 ml of THF, of 2.76 g (11 mmol) of acetylene F under an argon atmosphere was cooled to -78 ° C. At -78 ° C, added in 8 min. n-butyllithium (4.4 ml of a 2.5M solution in hexane). The reaction mass was stirred at -78 ° C for 40 min.

17.4 mmol of the phosphonylchloridate of Example 25 were cooled to -78 ° C in 60 ml of THF and under an argon atmosphere. The acetylene anion obtained above was then added in 8 min. After 1 h of stirring at -78 ° C, the reaction was set at -78 ° C with saturated aqueous NH4Cl solution, and the reaction mass was allowed to return to room temperature. The aqueous layer was diluted with H2O and extracted twice with ether. THF was removed from the THF reaction layer, and the orange oil obtained was taken up in ether. All the solutions in ether were combined and washed 1 time with a saturated aqueous solution of NaHCOs and 1 time with a saturated solution of NaCl. The organic layer was dried over MgSO4 and filtered to leave 9.4 g of the acetylenic phosphinic acid of the title, in the form of an orange gum after removal of the solvent. The acetylenic phosphinic acid of the title was purified by flash chromatography, eluting with a 5/1/4 mixture of he-xane / toluene / ethyl acetate. 4.23 g of the acetylenic phosphonic acid of the title were obtained in the form of a clear gum, with a yield of 56%.

TLC Rf = 0.28 (5/1/4 hexane / toluene / ethyl acetate, silica gel)

Mass spectrometry m / e 609 (M + H-C6H5) 4 *, 255 (Ct4Hi9SiO) +

H. Methyl acid ester (5V4-iïr2.4-dimethvl-

6-r (4-fluoroDhénvflméthoxvlDhénvnéthvnvnméthoxvDhosDhinvll-3-hvdroxvbutanoïaue

0.455 g (0.66 mmol) of acetylene phosphinate G was stirred in 10 ml of THF under an argon atmosphere. 0.16 g (2.66 mmol) of acetic acid was added at room temperature, then added dropwise over 5 min. n-C4HgNF (1.8 ml of a 1.1 M solution in THF, 2.0 mmol). After 24 h of stirring at room temperature, the reaction was fixed by adding 30 ml of ice water. The aqueous layer was removed and extracted twice with ethyl acetate. THF has been removed from the diaper

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CH 675 582 A5

organic reaction, and the oil obtained was dissolved in ethyl acetate and combined with extracts from the aqueous layer. This ethyl acetate solution was washed twice with a saturated aqueous solution of NaHCOs and once with a saturated solution of NaCl, then dried over Na2SO4. Filtration and removal of the solvent gave 0.40 g of the title acetylated 5-hydroxyphosphinate hydroxide as an oil. The acetylenic hydroxy phosphinate of the title was purified by flash chromatography, eluting with 100% ethyl acetate. The acetylenic hydroxy phosphinate of the title was obtained with a yield of 79%.

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

Mass spectrometry m / e 449 (M + H) +, 431 (M-OH) +, 417 (M-OCH3) +.

10

J. Acid dilithium salt (SV4-nT2.4-dimethvl-

6-f (4-fiuorophénvhméthoxv1phénvnéthvnvnhvdroxvphosphinvll-3-hvdroxvbutanoTaue

1.4 ml of a 1N LiOH solution was added to a solution, in 6.0 ml of dioxane, 0.191 g (0.43 mmol) of acetylene phosphinate H at room temperature. The reaction mass was heated to 55 ° C and stirred for 2 h. The reaction mass was cooled to room temperature and evaporated to dryness to give the title compound. The title compound was purified on a column 130 mm x 30 mm in diameter from an HP-20 resin, eluting first with 100 ml of H2O, then a 1: 1 mixture of MeOH / H2O. The title compound was obtained with a yield of 91% (0.170 g) as a white lyophilisate.

TLC Rf = 0.37 (7: 2: 1 nPr0H / NH40H / H2O, silica gel)

Mass spectrometry (FAB) m / e 421 (M + H) +, 427 (M + Li) +; 433 (M + 2Li) +

Analysis: Calculated for C2iH2o06FPLÌ2.1.4 H2O:

C, 55.09; H, 4.98; F, 4.15; P, 6.78 Found: C, 55.13; H, 5.25; F, 4.08; P, 6.91

Example 32

Acid dilithium salt (SÌ-4IIT2.4-dimethvl-30 6-r (4-fluorophénvhméthoxvllphénvlléthvnhvdroxvphosphinvn3-hvdroxvbutanoïue

A. Acid methvlia ester (SV3-lïï1.1'-dimethvl-éthvndiphénvlsilvnoxv1-4-lf2-r2-f (4-fluorophénvnméthoxvl-4.6-diméthvlphénvnéthvnméthoxvphosphinvnbutanoTaue

1.34 g (1.95 mmol) of acetylenic phosphinate G of Example 31 were stirred in 12 ml of methanol, and 0.040 g of PtO 2 was added. Hydrogen gas was bubbled through the methanol solution for 10 min., Then an atmosphere of hydrogen was maintained in a vial at a pressure of 1 atmosphere. After 5 h and 15 min. at room temperature, the reaction was complete, and argon was bubbled through the reaction solution. The reaction mass was filtered through a pad 40 of Celite in a fine sintered glass funnel, and the catalyst was washed with methanol. The solvent was removed from the filtrate to give 1.4 g of a saturated phosphinate of the title, in the form of a clear gum. The saturated phosphinate of the title was purified by flash chromatography, eluting with 60% ethyl acetate / hexane, then rechromatographing the materials coming from the slightly impure fractions, with a 6 / 2.5 / 1 mixture, 5 of hexane / acetone / toluene. The title saturated phosphinate was obtained with a yield of 86% (1.17 g).

TLC Rf = 0.045 (80% ethyl acetate / hexane, silica gel)

Mass spectrometry m / e 691 (M + H) +, 659 (M-OCHs) +, 635 (M-CgHigOSi) +

B. Methyl ester of acid fS) -4-fff2.4-dimethvl-

50 6-IY4-fluorophénv0méthoxv1phénvnéthvnméthoxvphosphinvn-3-hvdroxv-butanoïaue

1.16 g (1.68 mmol) of phosphinate A was stirred in 25 ml of THF at room temperature and under an argon atmosphere. 0.40 ml of glacial acetic acid was added dropwise to the phosphinate solution, then added dropwise over 5 min. 4.6 ml of a 1.1 M solution of n-C4HgNF in THF. The reaction mixture was stirred at room temperature overnight (18 h), then the reaction was fixed with 50 ml of ice water. After several min. stirring, saturated NaCl solution was added, and the layers separated. The organic layer was evaporated on a rotary evaporator to remove the THF, and the residue obtained was dissolved in ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and all the solutions in ethyl acetate were combined and washed twice with a saturated aqueous solution of NaHCOs and once with a saturated solution NaCl, then dried over Na2SO4. Filtration and removal of the solvent gave 1.13 g of the title hydroxyphosphinate as a clear oil. The title hydroxyphosphinate was purified by flash chromatography, the eluent being 100% ethyl acetate, to give the title hydroxyphosphinate as a clear oil, with a yield of 83. %.

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CH 675 582 A5

TLC Rf = 0.27 (6: 4 acetone / hexane, silica gel).

Mass spectrometry m / e 453 (M + H) +, 343 (M-C? H6F) +

C. Acid dilithium salt (SÎ-4-lïï2.4-diméthvl-6-

iï4-fluorophénvnméthoxvlDhénvnéthvnhvdroxvDhosDhinvn-3-hvdroxv-butanoïaue

0.594 g (1.3 mm) of phosphinate B was stirred in 19 ml of dioxane at room temperature. 4.0 ml of 1 N LiOH was added while stirring at room temperature, and the reaction mixture was heated to 55 ° C. After 20 min. at 55 ° C, a thick white precipitate formed, and 4.0 ml of dioxane was added, and the resulting suspension was stirred at 55 ° C. After 2.5 h at 55 ° C, 3 ml of H2O was added, which made the reaction mixture clear. After 3 h at 55 ° C, the reaction mixture was cooled to room temperature, and the dioxane and water were removed by evaporation on a rotary evaporator, leaving the diacid of the title in the form of a white solid, which was placed under high vacuum for 15 min. The title acid was purified by chromatography on an HP-20 resin, eluting first with 100 ml of H2O, then with a 1: 1 solution of MeOH / H2O. The diacid of the title was obtained in the form of a white lyophilisate with a yield of 67%.

TLC Rf = 0.36 (7: 2: 1 n-propanol / NH40H / H2O, silica gel).

Mass spectrometry m / e (FAB), 425 (M + H) +, 437 (M + H + 2 Li) +.

Analysis: calculated for C2iH240sFP.1.15 H2O:

C, 55.19; H, 5.80; F, 4.16; P, 6.78 Found: C, 55.19; H, 5.80; F, 4.29; P, 6.83

Example 33

FSV4-rr2-rri.1 / -biphenvn-2-vnethvnvllhvdroxvphosphinvl-3-hvdroxvbutanoTaue dilithium salt

A. fSV4-i2-rH.1'-biphenvl1-2-vnethvnvnhvdroxvphosphinvn-3-hvdroxv butanoic acid methvlia ester

0.985 g (1.61 mmol) of the phosphinate D of Example 9 was stirred under an argon atmosphere at room temperature in 19.6 ml of dry THF. This solution was treated dropwise with 0.386 g (6.44 mmol, 0.368 ml) of glacial acetic acid, treatment followed by 8 min. dropwise addition of n-C4H9NF (4.84 mmol, 4.40 ml of a 1.1 M solution in THF). After 18 h of stirring at room temperature, the reaction was fixed with 30 ml of ice water. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed twice with NaHCO3 in saturated aqueous solution, once with brine, dried over MgSO4, filtered and evaporated. The product was isolated by flash chromatography (column 50 mm, 15.2 cm Merck silica gel, eluent 40% acetone / hexane, flow rate 51 mm (2 inches) per min.). The fractions obtained were concentrated, mixed with toluene to form an azeotrope, and evaporated under vacuum to give 0.369 g (0.991 mmol, yield 62%) of the alcohol of the title in the form of a viscous yellow oil ( 0.098 g (0.263 mmol, yield 16%, of a slightly impure product) was also obtained.

TLC: silica gel, Rf = 0.35 (50% acetone / hexane).

Mass spectrometry Cl m / e 373 (M + H) +

B. acid dilithium salt fSÌ-4-rr2-fri.1, -biphénvl1-2-vnéthvnvnhvdroxvphosphinvn-3-hvdrpxvbuta-noïaue

0.739 mmol (0.275 g) of diester A was stirred under an argon atmosphere in 7.57 ml of dioxane and treated with 2.22 ml (2.22 mmol) of 1 M LiOH. This cloudy reaction mixture was heated for 45 mins. in an oil bath at 55 ° C. The mixture was cooled to room temperature. The solvents were removed by evaporation on a rotary evaporator and under high vacuum for 90 min. The yellow foam obtained was dissolved in 4 ml of distilled H2O and eluted on a 2.5 cm x 19 cm chromatographic column on an HP-20 resin, 10 ml fractions being collected every 1.4 min. The column was eluted with H2O until 15 fractions had been collected (until they were no longer basic), then elution using a 45/55 mixture of methanol and H2O gave (after 2 lyophilization and application on a high vacuum pump on P2O5 for 16 h) 0.231 g (0.649 mmol, yield 88%) of the title acid, in the form of a white lyophilisate.

TLC: silica gel Rf = 0.55 (7: 2: 1 n-propanol / NH40H / H2O)

Mass spectrometry (FAB m / e 345 (M + H) +, 351 (M + Li) +, 357 (M + 2 Li) +.

Analysis: calculated for C18H15O5PLÌ2 + 1.42 mole H2O,

molecular weight = 381.75: C, 56.63; H, 4.71; P, 8.07 Found: C, 56.62; H, 4.70; P, 8.07

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CH 675 582 A5

Example 34

Acid dilithium salt (SÎ-4-iï2-r3.5-dimethvl-n .1'-biphenvn-2-vHéthvnhvdroxvphosphinvl1-

3-hvdroxvbutanoïaue

5

A. 3.5-Dimethvin. 1'-biphenvn-2-carboxaldehyde

Phenylmagnesium bromide was obtained from Aldrich (Art. No. 17,156-5) in the form of a 3M solution in ethyl ether.

A mixture of 3.35 g (4.48 mmol) of the dipalladium B complex of Example 1 and 9.40 g (35.85 mmol) of triphenylphosphine was stirred at room temperature under an argon atmosphere for 30 min. in 67.2 ml of anhydrous toluene. This reaction mixture was cooled to 0 ° C, and a Grignard reagent based on phenylmagnesium bromide (Aldrich) (35.84 mmol, 11.95 ml of 3M solution) was quickly added in portions. in ether). The resulting mixture was stirred at room temperature for 1.5 h. Then the mixture was cooled to 0 ° C and treated in one portion with 22.4 ml of HCl 6, ON, and stirred at room temperature for 1 h. The aqueous layer was separated and extracted with ether. The organic extracts were combined, filtered through Celite (washed with ether), and the filtrate was washed with brine, mixed with toluene to form an azeotrope, and evaporated in vacuo to give a yellow solid. An attempt to purify the product by double flash chromatography (column diameter 20 95 mm, 15.2 cm Merck silica gel, eluent 100% hexane -> 3% ether / hexane, flow rate 51 mm (2 inches) per min.) gave 2.95 g of a yellow solid (1.88 g, 8.96 mmol, 100% aldehyde yield of the title, and 1.06 g of triphenylphosphine). This mixture of compounds was used directly for the preparation of compound B.

TLC: silica gel, Rf = 0.30 (5% ether / hexane)

25 Mass spectrometry (Cl) m / e 211 (M + H) +, 263 (M2 + H) +; 473 (M1 + M2 + H) +

Mi = aldehyde A, M2 = triphenylphosphine

B. 2- (2.2-Dibromoethénvfl-3.5-diméthvlH, 1'-biphenvl1

A mixture of 1.88 g (8.96 mmol) of aldehyde A and 6.90 g (26.4 mmol) of triphenylphosphine was stirred for 10 min. at -5 ° C in 88 mi of dry CH2CI2. This reaction mixture was kept at -5 ° C, and added dropwise over 20 min. a solution of 4.38 g (13.2 mmol) of CBm in 32 ml of dry CH2Cl2. The reaction mixture obtained was stirred at -5 ° C for 1 h, and gradually took a dark orange color over time. The mixture was then fixed with 85 ml of a saturated aqueous solution of NaHCOs. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed once with saturated aqueous NaHCO3 solution and once with brine, dried over MgSO4, filtered and evaporated in vacuo. The product was purified by pre-absorption of the crude product in CH2Cl2 on 25 g of Merck silica gel, and application of this product on a column for flash chromatography (diameter 50 mm, Merck silica gel 15.2 cm eluent 4% 40 CH2Cl2 / hexane, flow rate 51 mm (2 inches) per min.), To give 2.18 g (5.96 mmol, yield 68%) of the title vinyl dibromide in the form of a viscous colorless oil.

TLC: silica gel Rf = 0.37 (4% CH2CI2, hexane)

Mass spectrometry (Cl) m / e 365/367/369 (M + H) +.

45 C. 3.5-Dimethvl-2-f 1 -propvnvlïïl. 1 '- biphenyl

A solution of 2.10 g (5.74 mmol) of vinyl dibromide B in 29.11 ml of anhydrous THF was stirred under an argon atmosphere and cooled to -78 ° C. This solution was treated dropwise for 20 min. with n-butyllithium (11.47 mmol, 4.59 ml of a 2.5M solution in hexanes), to give a dark purple solution. After another 1 h of stirring at -78 ° C, the reaction was fixed at -78 ° C with 25 ml of a saturated aqueous solution of NaH4Cl, the reaction mixture was warmed to room temperature, diluted with H2O, and the aqueous layer was extracted with a 1: 1 mixture of ether and hexane. The organic extracts were combined, dried over MgSO4, filtered and evaporated in vacuo. The product was isolated by flash chromatography (column 50 mm, Merck silica gel 15.2 cm, eluting 1% 55 ether / hexane) to give 1.08 g (5.23 mmol, 91% yield) of 1 acetylene of the title in the form of a colorless oil, which turned blue after storage for 16 h at -20 ° C.

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

Mass spectrometry (Cl) m / e 207 (M + H) +

60 D. Methyl acid ester (S1-3-FIY1.1 -dimethvl-éthvndiphénvlsilvlloxvl-

4-ir2-f3.5-dimethvlf1.1 '-biphénvll-2-vnméthoxvphosphinvl butanoïaue

A solution of 0.950 g (4.61 mmol) of acetylene C in 27.3 ml of dry THF was stirred under an argon atmosphere and cooled to -78 ° C. It was added dropwise over 20 min. To obtain a solution.

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CH 675 582 A5

dark purple / brown, 1.84 ml (4.61 mmol) of a 2.5M solution of n-butyllithium in hexanes. The reaction mixture was stirred at -78 ° C for 1 h (the reaction mixture became a suspension), heated to 0 ° C and stirred for 15 min. (the reaction mixture again became a homogeneous dark purple solution), and it was finally cooled to -40 ° C. while remaining homogeneous. This acetylenic anionic solution at -40 ° C. was then added dropwise over 25 min. to a solution of 8.12 mmol of the phosphinylchloridate F of Example 1 in 27.3 ml of dry THF, which had been cooled to -78 ° C when it was mixed under an argon atmosphere. After completion of the addition of the acetylenic anion solution to the phosphinylchloridate, the dark orange reaction mixture was stirred at -78 ° C for 1 h, then set at -78 ° C with 50 ml of saturated NH4Cl, brought to room temperature and diluted with H2O. The aqueous layer was extracted with ether. The organic extracts were combined, washed once with saturated aqueous NaHCO3 solution, once with brine, dried over MgSCU, filtered and evaporated in vacuo. The product was isolated by flash chromatography (50 mm diameter column, 15.2 cm Merck silica gel, eluent 50% ethyl acetate / hexane, flow rate 51 mm (2 inches) per min., To give 0.609 g (0.945 mmol, 21%) of the title phosphinate in the form of a golden orange oil.

TLC: silica gel Rf = 0.32 (50% ethyl acetate / hexane)

Mass spectrometry (Cl) m / e 639 (M + H) +

E. Acid dilithium salt (SÎ-4-ff2-r3.5-dimethvl-ri.1, -biDhénvn-2-vnéthvllhvdroxvphosDhinvn-3-ftert-butvl-diphenvlsilvloxvibutanoTaue

Argon was bubbled into a solution, in 13 ml of methanol, of 0.876 g (1.37 mmol) of acetylene phosphinate D for 10 min. 0.315 g of 10% Pd / C was added, and the reaction mixture was subjected to Parr hydrogenation at 276 kPa (40 psi). After shaking for 24 h, the reaction mixture was filtered through a pad of Celite in a sintered glass funnel. The Celite was washed with methanol, and the filtrate was evaporated in vacuo to give 0.896 g of a yellow oil, which was purified by flash chromatography (column 50 mm in diameter, 15.2 cm Merck silica gel, eluent 40% -> 50% ethyl acetate / hexane) to give 0.680 g (1.06 mmol, yield 77%) of the saturated phosphinate of the title in the form of a pale yellow foam. Purification of the flash chromatography column by elution with methanol gave an additional 0.087 g of a slightly impure product.

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

Mass spectrometry (Cl) m / e 643 (M + H) +

F. acid dilithium salt fSV4-rr2-r3.5-dimethvl-f1.1'-biohénvll-2-vnéthvnhvdroxvohinvn-3-hvdroxvbutanoïue

0.66 g (1.03 mmol) of phosphinate E was stirred under an argon atmosphere at room temperature in 12.65 ml of dry THF. This solution was treated dropwise with 0.247 g (4.12 mmol, 0.236 ml) of glacial acetic acid, treatment followed by the addition, dropwise, of n-C4HgNF (3.09 mmol, 2.81 ml of a 1.1 M solution in THF). After 16 h of stirring at room temperature, the reaction was fixed with 25 ml of ice water. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed twice with NaHCOs in saturated aqueous solution, once with brine, dried over MgSO4, filtered and evaporated in vacuo. The product was purified by flash chromatography (40 mm column, 15.2 cm Merck silica gel, eluent 50% acetone / he-xane) to give 0.363 g (0.898 mmol, 87% yield) of the alcohol. the title, in the form of a white solid.

TLC: silica gel, Rf = 0.30 (50% acetone / hexane).

Mass spectrometry (FAB) m / e 405 (M + H) +

G. Acid dilithium salt (SÎ-4-rr2-r3.5-dimethvl-ri.1'-biDhénvn-2-vl1éthvllhvdroxvphosDhinvll-3-hvdroxv-butanoïaue

0.355 g (0.878 mmol) of diester F was stirred under an argon atmosphere in 9 ml of dioxane, and treated with 2.63 ml (2.63 mmol) of 1M LiOH. This homogeneous reaction mixture was heated in an oil bath at 55 ° C. After 10 min. stirring at 55 ° C, the reaction mixture became a white suspension. A further 9 ml of dioxane and 2 ml of H2O were added, and the suspension was heated at 55 ° C for 45 min., Then cooled to room temperature. The solvents were removed by evaporation on a rotary evaporator, and under vacuum for 1 hour. The white solid obtained was eluted on an HP-20 resin chromatography column (18 cm x 2.5 cm). 10 ml fractions were collected every 1.4 min. The column was eluted with H2O until 15 fractions had been collected, then an elution with a 1: 1 mixture of methanol and water gave (after 3 lyophilizations, and application on a high vacuum pump on P2O5 (4 times 8 h)), 0.289 g (0.744 mmol, yield 85%) of the title acid in the form of a white lyophilisate.

TLC: silica gel, Rf: 0.56 (7: 2: 1, n-propanol / NH40H / H2O).

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CH 675 582 A5

Analysis: calculated for C20H23O5PLÌ2 + 0.34 mole of H20,

molecular weight = 394.31: C, 60.92; H, 6.05 Found: C, 60.95; H, 6.18

Mass spectrometry: (FAB) m / e 389 (M + H) +

Example 35

Acid dilithium salt (SV4-IT2-r4'-fluoro-3.5-dimethviri.1'-biphenvn-2-vnéthvllhvdroxvphosphinvn-3-hvdroxvbutanoïue

A. Bromo (4-fluorophenvnmaanesium

1.08 g (44.35 mmol) of metallic magnesium turnings was flame dried, then stirred under an argon atmosphere in 40 ml of anhydrous ether. With vigorous stirring, 40.3 mmol of 1-bromo-4-fluorobenzene was added dropwise to the magnesium. The reaction was started by an ultrasonic device, then the halide was added dropwise at a rate sufficient to maintain the reflux. After completion of the addition of bromide, the reaction mixture was stirred at room temperature for 20 min., Then heated to reflux, and finally cooled to room temperature. This procedure gave a transparent, orange-golden Grignard solution containing 40.32 mmol of the Grignard reagent of the title, in the form of a 0.91 M solution in ether.

B. 4'-Fluoro-3.5-dimethvlM .l'biphénvll-2-carboxaldéhvde

Ref .: Stockker et al., Journal of Med. Chem. 29.170-181 (1986).

A mixture of 3.20 g (4.35 mmol) of the palladium B complex of Example 26 and 10.58 g (40.32 mmol) of triphenylphosphine was stirred at room temperature under an argon atmosphere for 30 min. in 67.2 ml of anhydrous toluene. This reaction mixture was then cooled to 0 ° C., and 44.43 ml (40.32 mmol) of Grignard reagent A was rapidly added in portions. The mixture obtained was stirred at room temperature for 1 hour, 5 a.m. Then the mixture was cooled to 0 ° C and treated in one portion with 21.75 ml of HCl 6, ON and stirred at room temperature for 1 h. The aqueous layer was separated, extracted with ether, and the combined organic extracts were filtered through Celite. The Celite was washed with ether, and the combined filtrates were washed with brine, mixed twice with toluene to form an azeotrope, and rectified to give an orange-yellow solid. Attempts to isolate the aldehyde from the title by flash chromatography using a column 95 mm in diameter, 15.2 cm Merck silica gel, a hexane eluent followed by a 3% Et 2 O / hexane eluent, with a flow rate of 51 mm (2 inches) per min., gave a final mixture of reaction products consisting of the title aldehyde and triphenylphosphine, in the form of a pale yellow solid (3.70 g - assuming that this quantity contains 8.7 mmol, 1.99 g, 100% yield of the aldehyde of the title +1.70 g of triphenylphosphine). This mixture of compounds was used directly for the preparation of compound C.

TLC: silica gel Rf = 0.25 (5% ether / hexane).

1 H NMR: (270 MHz, CDCI3).

C. 2-f2.2-DibromoethénvD-4 / -fluoro-3.5-diméthvl-H.1 / -biphénvle1

A mixture of 1.99 g (8.70 mmol) of aldehyde B and 6.85 g (26.1 mmol) of triphenylphosphine was stirred for 10 min. at -5 ° C in 87 ml of dry CH2Cl2. This reaction mixture was kept at -5 ° C, and added dropwise over 25 min. a solution of 4.33 g (13.05 mmol) of CBr4 in 43 ml of dry CH2CI2. The reaction mixture obtained was stirred at -5 ° C for 1 h, and gave a dark orange solution, which was then fixed with 80 ml of a saturated aqueous solution of NaHCOs. The aqueous layer was extracted 4 times with GH2Cl2. The combined organic extracts were washed once with a saturated aqueous solution of NaHCOs and once with brine. The CH2Cl2 extract was dried over MgSO4, filtered, and the filtrate was combined with 25 g of Merck silica gel. The solvent was evaporated, and the pre-absorbed product was purified by flash chromatography (column 50 mm in diameter, Merck silica gel 15.2 cm, eluent 4% CH2Cl2 / hexane, flow rate 51 mm (2 inches) per min.) to give 2.32 g (6.04 mmol, yield 69%) of the title vinyl dibromide, as a colorless oil.

TLC: silica gel, Rf: 0.43 (5% CHgC 4 / hexane).

Mass spectrometry (Cl) m / e 383/385/387 (M + H) +

D. 4'-Fluoro-3.5-dimethvl-2- (1 -propvnvh-H. 1 '-biohénvlel

A solution of 2.30 g (5.99 mmol) of vinyl dibromide C in 33 ml of anhydrous THF was stirred under an argon atmosphere and cooled to -78 ° C. The solution was treated dropwise for 25 min. with n-butyllithium (11.97 mmol, 4.79 ml of a 2.5M solution in hexanes), which gave a

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dark purple solution. After another 1 h of stirring at -78 ° C, the reaction mixture was fixed at -78 ° C with 25 ml of NH4Cl in saturated aqueous solution, heated to room temperature and diluted with 25 ml of H2O. The aqueous layer was extracted 4 times with a 1: 1 mixture of ether and hexane. The organic extracts were combined, washed over MgSO4, filtered and evaporated. The product was isolated by flash chromatography (50 mm column, 15.2 cm Merck silica gel, eluent 0.50% ether / hexane, flow rate 51 mm (2 inches) per min.), To give 1.25 g (5.57 mmol, yield 93%) of the acetylene of the title, in the form of a colorless oil which turns blue after storage at 20 ° C.

TLC: silica gel, Rf = 0.25 (100% hexane)

Mass spectrometry (Cl) m / e 225 (M + H) +

E. fSÎ-4-iï2-r4'-fluoro-3.5-dimethvl-H-1'-biDhénvn-2-vlléthvnvllhvdroxvphosphinvn-3- (t-butvldiDhénvlsilvloxv) butanoic acid methvlia ester

A solution of 1.18 g (5.24 mmol) of acetylene D in 28 ml of dry THF was stirred under an argon atmosphere and cooled to -78 ° C. While the reaction mixture became dark purple / brown in color, 2.10 ml (5.24 mmol) of a 2.5M solution of n-butyllithium in hexane was added dropwise over 25 min. . Then the reaction mixture was stirred at -78 ° C for 1 h, heated to 0 ° C, stirred for 10 min. and cooled to -78 ° C. This acetylenic anion solution at -78 ° C was then added dropwise over 20 min. to a solution of 8.32 mmol of phosphinylchloridate F of Example 1 in 28 ml of anhydrous THF, which had been cooled to -78 ° C while it was stirred under an argon atmosphere. After the addition was complete, the dark orange reaction mixture was stirred at -78 ° C for 1 h, then set at -78 ° C with a saturated aqueous NH4Cl solution, warmed to room temperature and diluted with water. The aqueous layer was extracted 4 times with ether. The organic extracts were combined and washed once with a saturated aqueous solution of NaHCOs and once with brine, dried over MgSO4, filtered and evaporated. The product was isolated by flash chromatography (50 mm diameter column, 15.2 cm Merck silica gel, eluent 40% ethyl acetate / hexane, flow rate 51 mm (2 inches) per min.) To give 0.730 g (1.11 mole, yield 21%) of the acetylenic phosphinate of the title, in the form of a viscous green oil.

TLC: silica gel, Rf = 0.36 (50% ethyl acetate / hexane).

Mass spectrometry (Cl) m / e 657 (M + H) +

F. fSÎ-4-iï2-r4'-fluoro-3.5-dimethvl-H.1'-biohénvn-2-vnéthvnhvdroxvphosDhinvn-3- (t-butvldiphenvlsilvloxvibutanoïue acid)

Argon was bubbled into 9.9 ml of a solution, in methanol, of 0.685 g (1.04 mmol) of acetylene phosphinate E for 10 min. 0.239 g of Pd 10% / C was added, and the reaction mixture was subjected to hydrogenation of Parr under a pressure of 276 kPa (40 psi). After 24 h of stirring, the reaction mixture was filtered through a pad of Celite in a sintered glass funnel, the Celite was washed with methanol, and the filtrate was evaporated to give 0.638 g of a green oil. The product was purified by flash chromatography (40 mm diameter column, 15.2 cm Merck silica gel, eluting 45% ethyl acetate / hexane, flow rate 51 mm (2 inches) per min.) To give 0.530 g (0.802 mmol, yield 77%) of the saturated phosphinate of the title in the form of a pale yellow foam. There was also obtained 0.09 g (0.136 mmol, 13%) of slightly impure product.

TLC: silica gel. Rf = 0.30 (50% ethyl acetate / hexane).

Mass spectrometry (CI) m / e 661 (M + H) +

G. Methyl acid ester i'S) -4-iï2-r4 / iffluoro-3.5-diméthvl-ri.1 / -biphénvl1-2-vlléthvHméthoxvDhosphinvn-3-hvdroxvbutanoïaue

0.525 g (0.794 mmol) of phosphinate F was stirred under an argon atmosphere at room temperature in 9.74 ml of anhydrous THF. This solution was treated dropwise with 0.191 g (3.18 mmol, 0.182 ml) of glacial acetic acid, this treatment being followed by the dropwise addition of 2.17 ml (2.38 mmol) of a solution of 1.1 M n-CUHgNF in THF). After 16 h of stirring at room temperature, the reaction mixture was fixed with 15 ml of ice water. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed twice with saturated aqueous NaHCO3 solution and once with brine, dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography (40 mm diameter column, 15.2 cm Merck silica gel, eluent 50% acetone / hexane, flow rate 51 mm (2 inches) per min.). The fractions obtained were concentrated, and mixed with toluene to form an azeotrope to dryness, to give 0.281 g (0.665 mmol, yield 84%) of the title alcohol in the form of a white solid . An impurity, visible by 1 H NMR 270 MHz, was not isolable / visible in different TLC systems.

TLC: silica gel, Rf = 0.31 (50% acetone / hexane)

1 H NMR: (270 MHz, CDCIs).

Mass spectrometry (Cl) m / e 423 (M + H) +

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H. Acid dilithium salt (SV4-iï2-f4'-fluoro-3.5-dimethvl-ri.1 / -biphénvn-2-vl1éthvnhvdroxvphosDhinvn-3-hvdroxvbutanoTaue

0.20 g (0.473 mmol) of diester G was stirred under an argon atmosphere in 4.84 ml of dioxane and treated with 1.42 ml (1.42 mmol) of 1M LiOH. This homogeneous reaction mixture was heated in an oil bath at 55 ° C. After 10 min. stirring at 55 ° C, the reaction mixture became a two-way suspension. The mixture was kept at 55 ° C for another 45 min, then cooled to room temperature. The solvents were removed by evaporation on a rotary evaporator and under vacuum for 1 h. The bianche foam obtained was dissolved in 4 ml of distilled H2O, and eluted in a chromatographic column, on HP-20 resin, 16 cm x 2.5 cm. 10 ml fractions were collected every

I, 4 min. The column was eluted with H2O until 15 fractions were collected, then an elution using a 1: 1 mixture of methanol and water gave (after 2 lyophilizations and installation on a high vacuum pump on P2O5 for 11 h) 0.158 g (0.389 mmol, yield 82%) of the title acid in the form of a white lyophilisate.

TLC: silica gel, Rf: 0.59 (7: 2: 1, n-propanol / NH40H / H2O)

Mass spectrometry (FAB) m / e 395 (M + H) +

Analysis: calculated for C2oH22FOsPLÌ2 + 0.39 mole H2O Molecular mass = 413.25: C, 58.12; H, 5.56 Found: C, 58.14; H, 6.09

Example 36

Methyl ester of the acid (SÌ-4-ff2-r5- (4-fluoro-ohénvlì-3-f1-méthvléthvh-1-Dhénvl-1H-pvrazol-4-vnéthvnvn-méthoxvphosphinvll-3-hvdroxvbutanoïue

A. Ethyl ester of 4-fluoro-B-oxobenzene-propanoic acid

17.4 g (0.43 mole) of 60% sodium hydride in mineral oil was washed twice with dry hexane, dried under vacuum and then treated with 44.3 ml (0.36 mole) pure diethyl carbonate, this treatment being followed by the dropwise addition of 22 ml (0.18 mole) of p-fluoro-acetophenone. After adding approximately 10% of the ketone, 4 drops of ethanol were added to trigger reflux, and the rest of the p-fluoro-acetophenone was added over 1.0 h, at a rate ensuring the conditions of the reflux. The yellow solid which formed was suspended in 250 ml of dry ether and heated under reflux for a further 3.0 h under an argon atmosphere.

The reaction mixture was cooled in an ice bath, diluted with 200 ml of ether and slowly treated with 1.3 l of water until all the solids dissolved. The aqueous phase was separated from the organic phase, acidified with 32 ml of 12N HCl at pH 1.0 and extracted with 2 x 500 ml of ether. The combined organic extracts were washed with 200 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. 44.0 g of the crude product was distilled under reduced pressure (3.5 mm Hg) to give the title compound as a homogeneous oil (24.88 g, 65.8%).

TLC: Rf 0.46 (silica gel); CH2Cl2: hexane-4: 1).

B. Ethyl ester of 4-fluoro-a- (2-methvl-1 -oxopropvn-B-oxobenzenepropanoic acid)

10.3 g (0.26 mole) of 60% sodium hydride in mineral oil was washed twice with dry hexane, dried in vacuo, suspended in 245 ml of dry tetrahydrofuran and cooled to 0 ° C (ice water bath) under an argon atmosphere. The suspension was treated dropwise with 24.5 g (0.12 mole) of compound A over a period of 20 min., Brought to room temperature and stirred for a further 30 min. The reaction mixture was cooled to 0 ° C (ice-water bath), treated dropwise with 18.62 g (0.17 mole) of isobutyryl chloride, brought to room temperature and stirred for 3.0 h. The mixture was cooled to 0 ° C (ice-water bath), fixed with 200 ml of water to produce a homogeneous solution, and evaporated on a rotary evaporator to remove most of the tetrahydrofuran. The aqueous phase was acidified to pH 1.0 with 37 ml of 10% HCl, and extracted with three times 100 ml of ether. The combined organic extracts were washed with 50 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 36.85 g of an oil, which was a mixture of the starting material and two others products.

TLC: Rf 0.46, 0.33, 0.20 (silica gel; CH2Cl2: hexane 4: 1, UV).

C. Ethyl acid ester 5- (4-fluorophenvh-3- (1-methvlethvh-1-phenvl-1 H-pvrazole-4-carboxvliaue

36.85 g (approx. 0.12 mole) of crude compound B was dissolved in 151 ml of glacial acetic acid, treated in portions with 18.1 ml (0.18 mole) of 97% phenylhydrazine under a d atmosphere nitrogen, and stirred at room temperature for 19 h. The reaction mixture was poured into 350 ml of water, extracted with three times 100 ml of ether, and the combined organic extracts were washed with NaHCO3 saturated jus89

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CH 675 582 A5

until the aqueous layer becomes basic, then with 500 ml of brine, dried over anhydrous MgS04, filtered and evaporated to dryness.

The dark orange oil was evaporated once in 300 ml of petroleum ether to give a yellow solid. This crude product was triturated with 100 ml of petroleum ether to give 15.3 g of a crude product, which, in turn, was chromatographed on a column of LPS-1 silica gel, the column being eluted with a 2: 1 mixture of CH2Cl2 and hexane, to give 11.53 g of the pure product. 26.4 g of the mother liquor, chromatographed on a column of silica gel LPS-1, and trituration of the compound obtained, gave another 7.12 g of the desired product (total yield 18.65 g, or 44.1 %). A small amount of the title compound was recrystallized from an EtaO: hexane mixture to give a homogeneous solid, m.p. 92—93 ° C.

TLC: Rf0.35 (silica gel: CH2CI2: hexane-4: 1)

Analysis: Calculated: C, 71.57; H, 6.01; N, 7.95; F, 5.39 Found: C, 71.62; H, 5.99, N, 7.91; F, 5.54

D. 5-f4-Fluorophenvfl-3- (1 -methvlethvh-l -phenvl-1 H-pvrazole-4-methanol

A solution of 11.53 g (32.7 mmol) of compound C in 142 ml of anhydrous ether was added dropwise over 1.5 h to a suspension, cooled to 0 ° C in an ice-cold bath. salt, 3.67 g (96.7 mmol) of double lithium aluminum hydride in 60 ml of anhydrous ether under an argon atmosphere. The greenish suspension was allowed to warm to room temperature in 1.5 h, then it was cooled to 0 ° C in an ice and salt bath and fixed by dropwise addition of 20 ml of water until the release of gas. The thick suspension was diluted with 100 ml of ether and filtered, the precipitates being washed well with 3 times 150 ml of ethyl acetate. The combined organic extracts were washed with 50 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 10.3 g (crude yield 100%) of a cream-colored solid. 100 mg of the crude product was recrystallized from an Et2O: hexane mixture to give 58 mg of the title compound in the form of white crystals, m.p. 138-140 ° C.

TLC: Rf 0.01 (silica gel; CH2CI2)

Analysis: Calculated: C, 73.52; H, 6.17; F, 6.12; N, 9.03 Found: C, 73.16; H, 6.15; F, 6.12; N, 8.90

MS (M + H) + = 311.

E. 5- (4-FluorophenvB-3-f 1 -methvlethvB-1 -phenvl-1 H-pvrazole-4-carboxaldehyde

10.2 g (approx. 32.7 mmol) of the crude compound D in 85 ml of dry dichloromethane was quickly added to a solution of 21.23 g (98.4 mmol) of pyridinium chlorochromate in 125 ml of dry dichloromethane , and the dark brown solution obtained was stirred at room temperature under nitrogen for 4.0 h. The mixture was diluted with 750 ml of ether and stirred for 10 min. The supernatant solution was decanted from the tarry residue, and the residue was triturated with 2 times 100 ml of dichloromethane. The dichloromethane extracts were diluted with 750 ml of ether, and the combined extracts were filtered through a pad of silica gel. The clear filtrate was evaporated to dryness to give 10.0 g of a crude product.

The crude product was chromatographed on a column of silica gel (Baker, 60-200 mesh (particle size corresponding to a mesh opening of 0.250 to 0.074 mm), 400 ml), the column being eluted with a 4: 1 mixture of CH2Cl2 and hexane, to give 9.6 g (95.2%) of the title compound as a solid. 72 mg of an analytical sample, m.p., were obtained by recrystallization of 100 mg of the product from hexane. 108-110 ° C.

TLC: Rf 0.58 (silica gel; CH2Cl2; UV).

Analysis: Calculated: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 74.10; H, 5.52; N, 9.12; F, 6.29

SM (M + H) + = 309

F. 4- (2.2-Dibromoethénvn-5- (4-fluorophénvn-3- (1 -méthvléthvlil -phénvl-1 H-pvrazole

A mixture of 2.0 g (6.48 mmol) of compound E and 5.10 g (19.2 mmol) of triphenylphosphine in 30 ml of dry dichloromethane was cooled to a temperature of -5 to -10 ° C on an ice and salt bath under an argon atmosphere, and treated dropwise over a period of 5 min. with a solution of 3.22 g (9.61 mmol) of carbon tetrabromide in 10 ml of dry dichloromethane. The reaction mixture was stirred at 15-20 ° C for 15 min., Then poured onto 10 ml of saturated NaHCO3 and extracted with 3 x 50 ml of dichloromethane. The combined organic extracts were washed with 10 ml of saturated NaHCOs, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

9.33 g of the mixture of crude products was chromatographed on a column of silica gel (LPS-1), the column being eluted with 1: 9.1: 1 and 4: 1 mixtures of CH2Cl2 and hexane to give the title compound as a solid (2.75 g, 91.6%). Recrystallization of a small sample of the title compound gave white crystals, m.p. 88-90 ° C.

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CH 675 582 A5

TLC: Rf 0.85 (silica gel); CH2CI2: hexane-4: 1)

Analysis:

Calculated: C, 51.75; H, 3.69; N, 6.04; F, 4.09; Br, 34.43 Found: C, 51.96; H, 3.51; N, 5.97; F, 4.22; Br, 34.77 5 MS (M + H) + = 465.

G. 4-Ethvnvl-5- (4-fluorophenvn-3- (1-methvlethvD1 -phenvl-1 H-pyrazole

A solution of 2.64 g (5.67 mmol) of compound F in 10.5 ml of dry tetrahydrofuran was cooled to -78 ° C (dry ice-acetone) under an argon atmosphere and treated dropwise drop with 7.16 ml (11.37 mmol) of a solution of 1.6M n-BuLi in hexane. The suspension obtained was stirred at -78 ° C for 1 h and 20 min., Fixed by dropwise addition of 10 ml of 25% NH 4 Cl, then it was allowed to return to room temperature. The reaction mixture was extracted three times with 50 ml of ether, and the combined organic extracts were washed with 20 ml of brine, dried over anhydrous MgSC> 4, filtered and evaporated to dryness to give the compound of the title as a light brown solid (1.79 g).

The crude product was chromatographed on a column of silica gel, the eluent being a 5:95 mixture of Et 2 O and hexane, to give the title compound as a solid of light golden color ( 1.08 g, 97.4%). Recrystallization of a small sample from hexane gave white and fluffy crystals, m.p. 106-108 ° C.

TLC: Rf 0.70 (silica gel; Et2Ü: hexane-1.9; 2 developments.

Analysis:

Wedge: C, 78.92; H, 5.63; N, 9.21; F, 6.24 Found: C, 79.22; H, 5.53; N, 9.28; F, 6.23 25 SM (M + H) + = 305

H. Methyl ester of acid (SV3-FIY1 ■ 1-dimethvl-ethvhdiphenvlsilvnoxv1-4-rrr5-f4-fluorophenvli-3- (1-methvlethvD-1-phenvl-1H-pvrazol-4-vnethvnvnimethbutanophosphin

A mixture of 2.77 g (5.55 mmol) of the crude phosphonic monomethyl ester F of Example 1 and 2.1 ml (11.05 mmol) of trimethylsilyidiethylamine in 10 ml of dry dichloromethane was stirred at room temperature under an argon atmosphere for 1.0 h. The mixture was evaporated to dryness, mixed with 20 ml of dry benzene to form an azeotrope, and dried under vacuum (vacuum pump) for 15 min. The viscous oil was dissolved again in 10 ml of dry dichloromethane, treated with a drop of DMF, cooled to -10 ° C (ice and salt stick) and treated dropwise with 530 μl (6.08 mmol) of oxalyl chloride. Strong gas evolution was observed, and the dark yellow solution was stirred at -10 ° C for 15 min., Then at room temperature for 1.0 h. The reaction mixture was evaporated to dryness, mixed with 20 ml of benzene to form an azeotrope, and dried in vacuo.

A solution of 1.12 g (3.67 mmol) of compound G in 9.0 ml of dry tetrahydrofuran was cooled to 40 ° C. at -78 ° C. (dry ice-acetone) under an argon atmosphere, and treated with 2.3 ml (3.67 mmol) of a solution of 1.6 M n-BuLi in hexane, and stirred at -78 ° C for 30 min. The above phosphonochloridate was dissolved in 6.5 ml of dry tetrahydrofuran, cooled to -78 ° C (dry ice-acetone) under an argon atmosphere and treated dropwise with a cannula, with the solution of the acetylene anion, the two solutions being maintained at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ° C for 30 min., Fixed by dropwise addition of 6.0 ml of 25% NH4Cl, then brought to room temperature. The mixture was extracted with 3 x 100 ml of ether, and the combined organic extracts were washed with 10 ml of 25% NH4Cl, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness .

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

TLC: Rf 0.33 (silica gel; hexane: acetone-7: 3)

I. fSÌ-4-lf2-r5- (4-fluoro-phenvh-3-f1-méthvléthvlV1-phenvl-1 H-Pvrazol-4-55 vlléthvnvn-méthoxvohosphinvn-3-hvdroxvbutanoïa acid methvlia ester of fSÌ-4-lf2-r5-

A solution of 593.9 mg (0.81 mmol) of compound H in 8.0 ml of dry tetrahydrofuran was treated successively with 190 n '(3.24 mmol) of glacial acetic acid and 2.54 ml (2.54 mmol) of BU4NF1M, and stirred overnight at room temperature under an argon atmosphere. The reaction mixture was cooled to 0 ° C (ice-water bath), treated with 8.5 ml of 5% KHSÓ4 and extracted with 3 x 75 ml of ethyl acetate. The combined organic extracts were washed with 10 ml of 5% KHSO4, 20 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product was dissolved in a mixture of 14 ml of ether and 10 ml of dry tetrahydrofuran, cooled to 0 ° C (ice and salt bath), treated with an excess of diazomethane in ether and stirred at

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0 ° C for 3 h. The reaction mixture was fixed by dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of silica gel, the eluent being a 1: 2 mixture of acetone and hexane, to give the title compound as a semi-solid (325 , 6 mg, yield 80.6%).

Example 37

Acid dilithium salt (SV4-rr2-r5- (4-fluoro-phenvn-3- (1-méthvléthvfl-1 -phenénl-1 H-ovrazol-4-vlIéthvnvn-hvdroxvphosphinvn-3-hvdroxvbutanoiQue

A solution of 325 mg (0.65 mmol) of the compound of Example 36 in 7.7 ml of dioxane was treated with 2.25 ml (2.25 mmol) of 1N LiOH and stirred at 55 ° C (bath oil) under a nitrogen atmosphere for 1.5 h, then at room temperature for 16 h. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of HP-20 resin (1 "x 5", 25.4 x 127 mm), the column being eluted with 400 ml of a vapor-distilled water mixture and 500 ml of CH3OH in 50% aqueous solution. The desired fractions were combined, evaporated to dryness and dried under vacuum. The solid product was dissolved in steam-distilled water and lyophilized to give the title product as a fluffy solid lyophilisate (317.1 mg, 96.4%).

TLC: Rf 0.33 (silica gel; i-Pr0H: NH40H: H20-8: 1: 1).

Analysis calculated for C24H22FN2O5P.2 Li.1.3 H2O (effective molecular mass = 505,861):

C, 56.99; H, 4.90; N, 5.54, F, 3.75; P, 6.12 Found: C, 56.98; H, 5.17; N, 5.46; F, 3.90; P, 6.26

1 H NMR spectrum (400 MHz, CD3OD):

51.40 (d, 6H, J = 7 Hz)

1.81-1.98 (m, 2H)

2.35 (dd, 1 H, J = 9.15 Hz)

2.48 (dd, 1 H, J = 4.15 Hz)

3.35 (Septuplet, 1 H, J = 7 Hz)

4.42 (m, 1H)

7.08-7.41 (m, 9H)

IR (KBr): 2173 cm-1 (C = C)

Example 38

Œ) -4-rr2-r5-f4-fluorophenvn-3-f1 -methvlmethvli-1 -phenvl-1 H-pvrazol-4-vn-ethenvnmethoxvphosphinvll-3-hvdroxvbutanoic acid ester

A. Dimethyl ester of r2-r5-C4-fluorophenvn-3-f 1 -methvlethvn-1 -phenvl-1 H-pyrazol-4-vn-2-hvdroxvethvnphosphoniaue acid

A solution, at -78 ° C (CO 2 / acetone) of 2.81 ml (25.9 mmol) of dimethyl methylphosphonate in 50 ml of dry THF was treated with 15.2 ml (24.3 mmol) of a solution of 1.6 M n-BuLi in hexanes, dropwise over 15 minutes, and the white suspension (after about 15 minutes) was stirred under an argon atmosphere at -78 ° C for 1 hour . 5.0 g (16.2 mmol) of pyrazole-aldehyde E of Example 36 in 15 ml of dry THF were added dropwise over 10 minutes, and the yellow mixture was stirred at -78 ° C for 30 minutes. The mixture was fixed with 20 ml of saturated NH4Cl and allowed to warm to room temperature. The mixture was partitioned between H2O and EtOAc, the organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated to give 7.158 g of the title crude β-hydroxyphosphonate, as a yellow foam. A small sample was recrystallized from hexanes to give the pure title compound as white crystals, m.p. 126-128 ° C. TLC (1: 1) hexane-acetone, Rf = 0.27 Mass spectrometry (M + H + = 433+ observed)

Analysis: calculated for C22H26O4N2PF:

C, 61.10; H, 6.06; N, 6.48; F, 4.39; P, 7.16 Found: C, 60.95; H, 6.06; N, 6.41; F, 4.22; P, 7.27

1 H NMR (CDCIs):

51.42 (6H, d)

1.94-2.40 (2H, m)

3.29 (1 H, septuplet)

3.62 + 3.63 (2 doublets, Jh-p = 11.1 Hz)

3.91 (1 H, s)

5.11 (1H, bm)

6.90-7.30 (9H, m) ppm.

NMR "C (CDCI3): 6 22.6, 26.5, 32.8 (Jc-p = 136.3 Hz), 52.1 (Jc-p = 5.7 Hz), 60.8, 115, 0, 115.4, 119.3, 119.5, 124.7, 126.3, 126.6, 128.5, 132.2, 132.3, 139.4, 139.5, 156.7, 164.5 (Jc-p = 265 Hz) ppm

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B. Dimethyl acid ester (EH2-r5- (4-fluorophenvh-3- (1-methvlethvfl-1-phenvl-1H-pyrazol-4-vll-ethénvnphosphoniaue.

A solution of 7.158 g of crude hydroxyphosphonate A in 40 ml of dry benzene was treated with 304 mg (1.6 mmol) of PTsOH.HaO, and the mixture was heated to reflux in a Dean Stark apparatus containing a sieve molecular weight of 4 A, for 2 hours under an argon atmosphere. The mixture was cooled, diluted with EtOAc, the organic phase was washed twice with saturated NaHCOs and brine, then dried over anhydrous Na2SO4 and evaporated in vacuo to give 6.893 g of a yellow oil. The crude oil was triturated with hexane to give 5.692 g of almost pure vinyl phosphonate, in the form of off-white crystals. Recrystallization from an EtOAc-hexane mixture gave in two harvests 5.655 g (total yield from aldehyde 84.2%) of the pure trans vinyl phosphonate of the title in the form of white needles, PF 143-144 ° C.

TLC (1: 1) hexane-acetone, Rf = 0.40

Mass spectrometry (M + H + = 415+ observed)

Analysis calculated for C22H24O3PN2F:

C, 63.76; H, 5.84; N, 6.76; F, 4.58; P, 7.47 Found: C, 63.99; H, 5.95; N, 6.76; F, 4.54; P, 7.31

1 H NMR (CDCIs):

51.42 (6H, d)

3.27 (1H, septuplet)

3.70 (6H, d, Jh-p = 11.0 Hz)

5.67 (1 H, d, Jh h = 18.4 Hz, Jh p = 18.5 Hz)

7.02-7.30 (9H, m)

7.34 (1 H, dd, Jh h = 18 Hz, Jh P = 24.3 Hz) ppm

RMN13C (CDCIs): 5 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-F = 249.8 Hz) ppm

C. Monomethyl ester of acid (EW2-r5-f4-fluorophenvn-3- (1-methvlethvB-1-phenvl-1H-pvrazol-4-vll-ethénvnphosphoniaue

A solution of 2.0 g (4.83 mmol) of dimethylphosphonate B in 15 ml of dioxane was treated with 7.3 ml of 1.0 N LiOH, and the mixture was heated at reflux for 1 hour under an atmosphere of 'argon. The mixture was cooled to room temperature, acidified to pH 1 with 1.0 N HCl, extracted twice with EtOAc, the organic phase was washed with 1.0 N HCl and brine, then dried over Anhydrous Na2SO4 and evaporated in vacuo to give the crude monoacid which slowly crystallized on standing in hexane. The crystals were collected by filtration and dried in vacuo to give 1.918 mg (99%) of the title monoacid, as a white crystalline solid, m.p. 168-170 ° C. An analytical sample was prepared for recrystallization from an EtOAc-hexane mixture.

TLC (8: 1: 1) CH2CI2-CH3OH-HOAC, Rf = 0.40

Mass spectrometry (M + H + = 401+ observed)

Analysis: calculated for C21H22O3N2PF:

C, 62.99; H, 5.54; N, 7.00; F, 4.75; P, 7.74 Found: C, 62.95; H, 5.57; N, 6.87; F, 4.58; P, 7.58

1 H NMR (CDCIs):

S 1.40 (6H, d)

3.26 (1 H, septuplet)

3.65 (3H, d, Jh-p = 11.6 Hz)

5.74 (1H, dd, Jh-h = 17.0 Hz, Jh-p = 19.5 Hz)

7.00-7.36 (10H, m)

8.65 (1H, bs) ppm

RMN13C (CDCIs): 8 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 (Jc-F = 249 , 8 Hz) ppm.

D. OME-rr2-r5- (4-fluorophenvn-3- (1-methvlethvD-1-phenvl-1 H-ovrazol-4-vnethenvnmethoxvphosphinvn-3-oxobutanoic acid ester)

The methyl acetoacetate dianion was prepared by the method described in Example 26, using the following quantities: methyl acetoacetate (815 nl, 7.53 mmol), dispersion of 60% NaH in an oil (324 mg, 8.11 mmol), 1.6 M n-BuLi in hexanes (4.3 ml, 6.95 mmol), THF (15 ml).

A solution of 2.317 g (5.79 mmol) of the monomethyl ester of phosphonic acid and 1.45 ml (11.6 mmol) of trimethylsilyidiethylamine was stirred for one hour at room temperature.

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(TMSDEA) in 15 ml of CH2CI2. The mixture was evaporated to dryness, mixed with 20 ml of benzene and dried in vacuo. The residue was taken up in 15 ml of dry CH2Cl2, treated with 555 μl (6.37 mmol) of (COCI} 2 and a drop of DMF, and stirred at room temperature for one minute. The mixture was evaporated to to dryness, mixed with 20 ml of benzene and dried under vacuum.

A solution, at -78 ° C (CCVacetone) of the above phosphonochloridate in 10 ml of dry THF was transferred dropwise using a cannula in 20 minutes in a solution at -78 ° C of the acetoacetate dianion methyl in 15 ml of dry THF. The brown mixture was stirred for 30 minutes at -78 ° C, then fixed by the dropwise addition of 10 ml of saturated NH4Cl, and allowed to return to room temperature. The mixture was partitioned between H2O and EtOAc, the aqueous phase was extracted again with EtOAc, the combined organic phases were washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated in vacuo to give 3.080 g an orange moss. The crude product was purified by flash chromatography on Merck silica gel, eluting with a 5: 3: 2 mixture of hexane-acetone-toluene.

The fractions obtained were combined and evaporated to give 1.247 g (43.2%) of the title p-ketophos-phonate in the form of a pale yellow oil.

TLC (4: 4: 2) acetone-hexane-toluene, Rf = 0.29.

Mass spectrometry (M + H + = 499+ observed).

1 H NMR (CDCIs):

51.42 & 1.43 (6H, 2 doublets)

3.24 (2H, m)

3.27 (1 H, septuplet)

3.63 (2H, m)

3.66 & 3.67 (3H, 2 doublets, Jh-p = 11.6 Hz)

3.72 (3H, s)

5.72 (1 H, dd, Jh h = 18.7 Hz, JH p = 24.3 Hz)

7.08-7.30 (9H, m)

7.37 (1 H, dd, Jh h = 18.0 Hz, Jh P = 22.7 Hz) ppm

RMN13C (CDCIs): S 21.8, 27.1, 46.1 (JC p = 84.1 Hz), 50.0, 51.2 (Jc-p = 5.9 Hz), 52.3,112.6 (I p = 135.0 Hz), 114.5 (I p = 23.5 Hz), 116.0, 116.3, 124.9, 125.4, 127.4, 128.8, 132.0 , 132.1, 139.1, 141.4 (Je p = 5.9 Hz), 142.5,158.2,163.1 (Je f = 250.4 Hz), 167.1,194.9 195.0 ppm

E. Methyl ester of acid (EÌ-4-IT2-r5- (4-fluoroohenvn-3- (1-methvlethvfl-1 -phenvl-1 H-ovrazol-4-vl1-ethenvl1methoxvphosphinvn-3-hvdroxvbutanoïaue.

A solution at -15 ° C (salt / ice bath) of 1.304 g (2.62 mmol) of ketone D in 15 ml of absolute EtOH was treated with 100 mg (2.62 mmol) of NaBH4, and the mixture was stirred for 15 minutes under an argon atmosphere at -15 ° C. The reaction was fixed by adding 3.0 ml of reactive acetone and then 600 mg of CC-4 silica gel, the reaction mass was allowed to return to room temperature, then it was diluted with EtOAc, filtered and evaporated in vacuo to give 1.46 g of a yellow foam. The crude product was purified by flash chromatography on Merck silica gel, eluting with an 85:15 mixture of EtOAc and acetone. The fractions obtained were evaporated to give 388 mg of the pure alcohol of the title, in the form of a white foam, plus 228 mg of a slightly impure product. The total yield was 616 mg (47%).

TLC (7: 3) EtOAc-acetone, Rf = 0.31 Mass spectrometry (M + H + = 501+ observed)

1 H NMR (CDCIs):

S 1.42 (6H, d)

2.00 (2H, m)

2.60 (2H, d)

3.27 (1 H, d)

3.64 (3H, d, Jhp = 11.1 Hz)

3.69 (3H, s)

3.93 & 4.02 (1 H, 2 doublets)

4.42 (1 H, 2 wide singlets)

5.72 (1 H, dd, Jh h = 18.0 Hz, Jh-p = 23.2 Hz)

7.04-7.47 (10H, m) ppm

RMN13C (CDCI3): 8 21.8, 27.1, 35.7 & 36.5 (Je p = 100.3Hz) 42.0, 42.2, 50.8 (Je p = 5.7 Hz), 51.6, 63.4 (I p = 20.8 Hz), 114.6 (I p = 20.8 Hz), 114.2 & 114.4 (I p = 128Hz), 114.6 (I p = 20.8 Hz), 115.9,116.3, 124.9, 125.4, 127.3, 128.8, 131.9,132.1, 139.1, 149.1 & 140.6 (I p = 5.7 Hz), 142.1, 158.0, 163.0 (Je f = 251.6 Hz), 171.2,171.9 ppm.

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Example 39

Acid dilithium salt (SV4-rr2-r5- (4-fluoro-phenvh-3- (1-méthvléthvh-1-phenvl-1 H-pvrazol-4-vll-éténénvl1-hvdroxvphosphinvl-3-hvdroxvbutanoi'aue .

A solution of 487 mg (0.973 mmol) of the diester of Example 38 in 10 ml of dioxane was treated with 3.4 ml (3.4 mmol) of LiOH 1, ON, and the mixture obtained was heated and stirred at -70 ° C for 30 minutes. The mixture was cooled, diluted with H2O, filtered and evaporated in vacuo to give an off-white solid. The crude product was dissolved in a minimum quantity of H2O and chromatographed on an HP-20 resin (bed 15 cm, column diameter 25 mm), eluting with H2O then a 1: 1 CH3OH-H2O mixture. The fractions obtained were evaporated in vacuo, dissolved in 75 ml of H2O, filtered and lyophilized to give 429 mg (87.3%) of the pure dilithium salt of the title in the form of a fluffy white lyophilisate.

TLC (8: 1: 1) CH2 CI2-CH3 OH-HOAc, Rf = 0.14

Analysis: calculated for C24 H24O5N2PF Lfe + 1.16 moles H20 (Molecular mass 505, 233):

C, 57.05; H, 5.25; N, 5.55; F, 3.76; P, 6.13 Found: C, 57.05; H, 5.18; N, 5.75; F, 3.89; P, 6.47

1 H NMR (400 MHz, CD3OD):

S 1.39 (6H, doublet)

1.71 (2H, m)

2.35 (2H, m)

3.36 (1 H, septuplet)

4.24 (1 H, m)

6.00 (1H, dd, Jh h = 17.6 Hz, JH p = 19.4 Hz)

7.07-7.35 (10H, m)

Example 40

Methyl ester of acid (EV4-i2-r5- (4-fluoro-phenvB-3- (1-methvlethvh-1 -phenvl-1 H-pvrazol-4-vlléthvn-methoxvphosphinvn-3-hvdroxvbutanoïue

A. Acid methvlia ester (S-3-iï 1.1-dimethvl-ethvndiphénvlsilvlloxvl-4-iï2-r5- (4-fluorophénvli-

3- (1 -methvlethvlH -phenvl-1 H-pvrazol-4-vllethvllmethoxv-phosphinvllbutanoïaue

A solution of 912.0 mg (1.24 mmol) of compound H of Example 36 in 50 ml of dry methanol was treated with 10% Pd / C and hydrogenated under a pressure of 345 kPa (50 psi) in a Parr hydrogenator overnight. The suspension was filtered through Celite, and the filtrate was evaporated to dryness and dried in vacuo to give the title compound as a homogeneous oil (908.3 mg, 99.1%) TLC: Rf 0.23 (silica gel; hexane: acetone - 7: 3)

B. Methyl acid ester (SM-ff2-r5- (4-fluorophenvn-3- (1-methvlethvh-1 -phenvl-1 H-pvrazol-

4-vll-éthvnméthoxvphosphinvn-3-hvdroxvbutanoiaue.

A solution of 908.3 mg (1.23 mmol) of compound A in 12 ml of dry tetrahydrofuran was stirred under an argon atmosphere at room temperature, and treated successively with 0.29 ml (4.94 mmol). glacial acetic acid and 3.89 ml (3.89 mmol) of 1.0 M BU4NF / hexane. The reaction mixture was stirred at room temperature for 20 hours, diluted with 25 ml of ice water and extracted with three times 100 ml of ethyl acetate. The combined organic extracts were washed with 15 ml of saturated NaHCO3, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

1.0 g of the crude product mixture was chromatographed on a silica gel column (LPS-1; 25.4 mm x 241.3 mm) (1 "x 9.5"), the column being eluted with 4: 1 and 9: 1 mixtures of EtOAc and hexane, EtOAc and acetone to give the title compound as an oil (529.1 mg, 85.6% yield).

TLC: Rf 0.17 (silica gel; EtOAc: hexane - 4: 1).

Example 41

Acid dilithium salt (S) -4-fr2-r5- (4-fluoroohenvli-3-f1-methvlethvl) -1 -phenvl-1 H-pyrazol-4-vnethvllhvdroxv-phosphinvll-3-hvdroxvbutanoïue

A solution of 529.0 mg (1.05 mmol) of the compound of Example 40 in 12.5 ml of dioxane was treated with 3.7 ml (3.7 mmol) of 1.0 N LiOH and stirred at 55 ° C (oil bath) under nitrogen atmosphere for 3.0 hours, then at room temperature for 20 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on a resin column

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HP-20 (25.4 mm x 152 mm) (1 "x 6"), the column being eluted with 750 ml of a steam-distilled water mixture, 500 ml of a 10% aqueous solution of CH3OH, 500 ml of a 20% aqueous solution of CH3OH and 500 ml of a 50% aqueous solution of CH3OH. The desired fractions were combined, evaporated to dryness and dried under vacuum. The solid obtained was dissolved in 35 ml of distilled steam-water and lyophilized to give the title compound as a fluffy white solid (510.0 mg, 92.4%).

TLC: Rf 0.38 (silica gel; i-Pr0H: NH40H: H20-8: 1: 1).

Analysis: calculated for C24H26FLÌ2N205P.2,2H20 (effective molecular weight = 525,899):

C, 54.81; H, 5.83; N, 5.33; F, 3.61; P, 5.88 found: C, 54.81; H, 5.61; N, 5.53; F, 4.06; P, 5.80

IR (KBr) (1596 cm- \ C = O of COO).

1 H NMR spectrum (400 MHz, CD3OD):

5 1.36 (d, 6H, J = 7)

1.60-1.72 (m, 4H)

2.32 (m, 2H)

2.74 (m, 2H)

3.21 (septuplet, 1 H, J = 7)

4.23 (m, 1 H)

7.06-7.32 (m, 9H)

Example 42

FS1-4-iï2-r3- (4-fluoro-phenvli-5- (1-méthvléthvn-1-phenvl-1 H-Pvrazol-4-vn-éthvnvllmethoxvphosphinvl1-3-hvdroxvbutanoïue acid)

A. 4-Fluorobenzoic acid. 2-phenvlhvdrazide

A mixture of 25 ml (0.25 mmol) of phenylhydrazine and 35 ml (0.25 mmol) of triethylamine in 500 ml of anhydrous ether was cooled to a temperature of -5 to -10 ° C (ice bath and salt) under a nitrogen atmosphere and treated dropwise over a period of 30 minutes, with 30 ml (0.25 mmol) of 4-flurobenzenecarbonyl chloride. The reaction mixture was brought to room temperature, stirred for 3.0 hours, then filtered, the solids being washed well with 200 ml of ether.

The solids were dissolved in 600 ml of dichloromethane, rectified almost to dryness, suspended in 600 ml of hexane and filtered. The clear filtrate was evaporated to dryness, triturated with 700 ml of tetrahydrofuran and filtered, the solids being washed well with 100 ml of tetrahydrofuran. The filtrate was evaporated to dryness and dried in vacuo to give 34.6 g of a crude product contaminated with two other components.

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

The filtrate and the mother liquor were combined, chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 400 ml), the column being eluted with a 1: 9 EtOAc: CH2Cl2 mixture, to give another 9.78 g of the title compound (55.8%).

TLC: Rf 0.63 (silica gel: EtOAc: CH2CI2-1: 4)

Analysis: Calculated for G13H11FN2O: C, 67.81; H, 4.82; N, 12.17; F, 8.25 Found: C, 67.86; H, 4.88; N, 12.14; F, 8.10

SM (M + H) + = 231

B. 4-Fluoro-N-phenvlbenzenecarbohvdrazonovle chloride

A solution of 6.16 g (26.8 mmol) of compound A in 46 ml of anhydrous ether was treated with 6.6 g (31.7 mmol) of phosphorus pentachloride, and the reaction mixture was heated to reflux under nitrogen for 16.0 hours. The reaction mixture was cooled to room temperature, treated with a solution of 11.5 g (122.2 mmol) of phenol in 15 ml of ether, stirred for 5 minutes and then treated dropwise with 11.4 ml of methanol. The mixture was concentrated to about 75 ° C in a rotary evaporator, and the oil obtained was cooled to 5 ° C. The solid obtained was triturated with 20 ml of a 5% aqueous acetone solution and filtered, the precipitates being washed well with 30 ml of a 5% aqueous acetone solution. The precipitates were dried in vacuo to give the title compound as a solid (2.2 g), m.p. 118-120 ° C.

The clear filtrate was evaporated to dryness and the product mixture was chromatographed twice on a column of silica gel (Baker, 50-200 mesh = 0.250-0.074 mm, 400 ml), the column being eluted with 1: 3 and 1: 1 mixtures of CH2Cl2 and hexane, which again gave the compound of the entity (total amount = 5.66 g, 85%).

TLC: Rf 0.90 (qel of silica; CHaCfe: hexane-4: 1)

Analysis: Calculated for C13H10FN2CI: C, 62.78; H, 4.05 N, 11.27; F, 7.64; Cl, 14.26

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Found: C, 62.87; H, 3.97; N, 11.34; F, 7.51; Cl, 13.95

SM (M + H) + = 249

C. Ethyl acid ester 3- (4-fluorophenvli-5- (1-methvlethvfl-1 -phenvl-1 H-pvrazole-4-carboxvliaue

5

A solution of sodium ethoxide (obtained from 0.28 g, 12 mmol, metallic sodium and 40 ml of absolute ethanol) was treated dropwise under nitrogen with 2.0 ml (12 mmol) of ethyl isobutyrylacetate, stirred for 15 minutes at room temperature, then treated with 3.0 g (12 mmol) of compound B. The mixture was stirred at room temperature for 4.0 hours, fixed 10 with 10 ml of 10% HCl, evaporated to dryness, and the solid obtained was triturated with 3 x 100 ml of ether. The combined organic extracts were washed with 25 ml of brine, dried over anhydrous MgSC> 4, filtered and evaporated to dryness. 4.3 g of the crude product were chromatographed on a column of silica gel, eluted with a 1: 1 mixture of CH2Cl2 and hexane, to give the title compound in the form of a reddish brown syrup ( 3.27 g, 77.3%).

TLC: Rf 0.42 (silica gel; CH2Cl2: hexane-4: 1)

D. 3- (4-Fluorophenvh-5- (1 -methvlethvh-1 -phenvl-1 H-pvrazole-4-methanol

A solution of 3.26 g (9.25 mmol) of compound C in 22 ml of dry ether was added to a suspension, cooled to 0 ° C in an ice and salt bath, of 0, 71 g (18.7 mmol) of lithium aluminum hydride in 32 ml of dry ether, and the reaction mixture was stirred at 0 ° C under nitrogen for 3.0 hours. The mixture was fixed at 0 ° C. by adding dropwise 5.0 ml of ethyl acetate, then 11 ml of 10% HCl, then decanted, and the residue was triturated with 2 × 100 ml ether. The combined organic extracts were washed with 20 ml of brine, dried over anhydrous MgSC> 4, filtered and evaporated to dryness to give 2.87 g (94.4%) of the title compound .

100 mg of the title compound was recrystallized from ether to give an analytical sample (57 mg, mp 145-147 ° C).

TLC: Rf 0.17 (silica gel; CH2Cl2-hexane-4: 1; 2 developments).

Analysis: Calculated for G19H19FN2O: C, 73.52; H, 6.17; N, 9.03; F, 6.12 Found: C, 73.26; H, 6.11; N, 8.96; F, 6.09

SM (M + H) + = 311

E. 3-M-FluoroDhenvlV5- (1 -methvlethvn-1 -phenvl-1 H-Pvrazole-4-carboxaldehyde

A solution of 2.59 g (8.34 mmol) of compound D in 22.0 ml of dry dichloromethane was quickly added to a suspension, with stirring, of 5.41 g (25.1 mmol) of chlorochromate pyridinium in 32 ml of dry dichloromethane, and stirred at room temperature under a nitrogen atmosphere for 4.0 hours. The reaction mixture was diluted with 190 ml of ether, stirred for 20 minutes, then decanted. The tarry residue was triturated with 100 ml of ether and 30 ml of dichloromethane, and the combined ex-40 organic extracts were filtered through a pad of silica gel. The clear filtrate was evaporated to dryness, and the crude product was chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 300 ml), eluted with a 4: 1 mixture CH2Cl2 and hexane to give 2.40 g (93.4%) of the title compound as a solid.

100 mg of the title compound was recrystallized from hexane to give 50 mg of an analytical sample, m.p. 103-105 ° C.

TLC: Rf 0.67 (silica gel; CH2Cl2).

Analysis: Calculated for CigHi7FN20: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 74.18; H, 5.35; N, 9.11; F, 6.12

SM (M + H) + = 309

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F. 4-f2.2-DibromoethénvlV3-f4-fluorophénvn-5- (1-méthvléthvh-1-phenvl-1 H-pyrazole

A mixture of 2.296 g (7.45 mmol) of compound E and 5.86 g (22.1 mmol) of triphenylphosphine in 35.0 ml of dry dichloromethane was cooled to a temperature of -5 to -10 ° C (ice and 55 salt bath) under an argon atmosphere, treated dropwise in 5 minutes with a solution of 3.70 g (11.0 mmol) of carbon tetrabromide in 12 ml of dry dichloromethane, and stirred at -10 ° C for 20 minutes. The reaction mixture was brought to room temperature, poured into 12 ml of saturated NaHCCte and extracted with 3 x 60 ml of dichloromethane. The combined organic extracts were washed with 12 ml of saturated NaHCOs, 10 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product (11.0 g, solid) was chromatographed on a column of silica gel, eluting with 1: 1 and 4: 1 mixtures of CH2Cl2 and hexane to give the title compound (2 , 96 g, corrected yield 96.0%), and 250.6 mg of the unreacted starting material.

100 mg of the title compound were recrystallized from an Et 2 O: hexane mixture to give 36.5 g 65 of an analytical sample, m.p. 93.5 ° C.

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TLC: Rf 0.57 (silica gei; CH2CÌ2: hexane-4: 1)

Analysis: Calculated for C2oHi7Br2FN2: C, 51.75; H, 3.69; N, 6.04; Br, 34.43; F, 4.09 Found: C, 51.78; H, 3.54; N, 6.07; Br, 34.40; F, 3.92

SM (M + H) + = 465

G. 4-Ethvnvl-3-f4-fluoroDhénvn-5- (1 -methvlethvli-1 -phenvl-1 H-ovrazole

A solution of 2.87 g (6.18 mmol) of compound F in 11.44 ml of dry tetrahydrofuran was cooled to -78 ° C (dry ice-acetone), treated dropwise with 11.7 ml (18 , 6 mmol) of 1.6 M n-BuLi / hexane under an argon atmosphere, then stirred at -78 ° C for 2 hours and 20 minutes. The reaction mixture was fixed at -78 ° C with 16.5 ml of 25% NH 4 Cl, brought to room temperature and extracted with 3 x 60 ml of ether. The combined organic extracts were washed with 22 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. The crude product (1.9 g) was chromatographed on a column of silica gel, eluting the column with a 5:95 mixture of Et 2 O and hexane. The desired fractions were combined and evaporated to dryness to give 1.88 g (100% yield) of the title compound as a solid product.

100 mg of the title compound was recrystallized from hexane to give 63.5 mg of an analytical sample, m.p. 117-118 ° C.

TLC: Rf 0.37 (silica gel; Et20: hexane-1: 9)

Analysis: Calculated for C20H17FN2: C, 78.92; H, 5.63; F, 6.24; N, 9.21 Found: C, 79.12; H, 5.60; F, 6.02; N, 9.12

SM (M + H) + = 305

H. Acid methvlia ester (SV3riï1.1-diméthvléthvndiphénvlsilvlloxvl-4-lfr3-f4-fluoroDhénvh-5- (1 -méthvlethvn-1 -ohénvl-1 H-pvrazol-4-vlléthvnvnméthoxbutanophvin)

A solution of 2.77 g (5.55 mmol) of the methyl ester of (S) -3 [[(1,1-dimethylethyl) -diphenyl-silyl] oxy] -4- (hydroxymethoxyphosphinyl) butanoic acid (prepared in Example 1, part F) in 10 ml of dry dichloromethane, was treated with 2.1 ml of dimethylsilyldiethylamine and stirred at room temperature for 1.0 hour under an argon atmosphere. The reaction mixture was evaporated to dryness, mixed with 20 ml of dry benzene to form an azeotrope, and dried in vacuo. The syrup was dissolved again in 10 ml of dry dichloromethane, cooled to -10 ° C. in an ice and salt bath, treated with a drop of DMF, then 530 μl or oxalyl chloride were added dropwise , and stirred the syrup at -10 ° C for 15 minutes, then at room temperature for 1.0 hour. The mixture was evaporated to dryness, mixed with 20 ml of benzene to form an azeotrope, and dried in vacuo.

1.12 g (3.67 mmol) of compound G was dissolved in 9.0 ml of dry tetrahydrofuran, cooled to -78 ° C (dry ice-acetone bath), treated with 2.3 ml (3.68 mmol) of 1.6 M n-BuLi / hexane under an argon atmosphere, and stirred at -78 ° C for 45 minutes. The above phosphonochloridate was dissolved in 6.5 ml of dry tetrahydrofuran, cooled to -78 ° C and treated dropwise with a cannula with the solution of the acetylene anion, the two solutions being maintained at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ° C for 30 minutes, then fixed by dropwise addition of 6.0 ml 25% NH4Cl, and allowed to warm to room temperature. The mixture was extracted with 3 x 100 ml of ether, and the combined organic extracts were washed with 10 ml of 25% NH4Cl, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

4.0 g of the crude product mixture was chromatographed on a column of silica gel, eluting with 1: 9 and 3: 7 mixtures of acetone and hexane to give 1.76 g (65.2% ) of the title compound in the form of an oil.

TLC: Rf 0.40 (silica gel; hexane: acetone-7: 3)

I. fSV4-rr2-r3- (4-fluorophenvh-5- (1-methvlethvlV1-ohénvl-1 H-ovrazol-4-vnethvnvnmethoxvphosphinvll-3-hvdroxvbutanoTaue acid methvlia ester)

A solution of 700 mg (0.95 mmol) of compound H in 9 ml of dry tetrahydrofuran was treated successively with 224 (il (3.82 mmol) of glacial HOAc and 3.0 ml (3.0 mmol) of ( C4Hg) 4NF 1.0 M. and stirred overnight at room temperature under an argon atmosphere The solution was cooled to 0 ° C. (ice and salt bath), treated dropwise with 10 ml of 5% KHSO4 and extracted with 3 x 75 ml of ethyl acetate The combined organic extracts were washed with 10 ml of 5% KHSO4, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

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

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

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Example 43

Acid dilithium salt (SV4-rr2-r3-M - fluorophenvli-5-n-methvlethvD-1 -phenvl-1 H-pyrazol-4-vnéthvnvnhvdroxvphosphinvl1-3-hvdrpxvbutanoïue

A solution of 347 mg (0.7 mmol) of the compound of ex. 42 in 8.3 ml of dioxane was treated with 2.4 ml (2.4 mmol) of 1.0 N LiOH and stirred at 55 ° C (oil bath) under nitrogen for 45 minutes. The reaction mixture was evaporated to dryness and dried in vacuo. The semi-solid obtained was chromatographed on a column of HP-20 resin (25.4 x 76.2 mm, 1 "x 3"), eluting the column with steam-distilled water (350 ml) and 250 ml of methanol in 50% aqueous solution. The desired fractions were combined, evaporated to dryness and dried under vacuum. The product was distilled in a distilled steam-water mixture and lyophilized to give the title compound as a white solid lyophilizer (338 mg, 97.5%).

TLC: Rf 0.50 (silica gel; i-Pr0H: NH40H: H20-7: 2: 1)

Analysis: Calculated for C24H22FLi2N205P-1.95 H2O: C, 55.71; H, 5.04; N, 5.42; F, 3.67; P, 5.99 Found: C, 55.90; H, 5.46; N, 5.30; F, 3.95; P, 5.96

1 H NMR spectrum (400 MHz, CD3OD):

1.45 (d, 6H, J = 7)

1.89-2.05 (m, 2H)

2.38 (dd, 1H, J = 9.15)

2.52 (dd, 1H, J = 4.15)

3.06 (septuplet, 1 H, J = 7)

4.48 (m, 1H)

7.16-8.11 (m, 9H)

Example 44

Methyl acid ester (SV4-rf2- [3- (4-fluorophenvn-5- (1-methvlethvh-1-phenvl-1 H-pyrazol-

4-vnéthvnméthoxvphosphinvin-3-hvdroxvbutanoïaue

A. fSV3-rr (1.1-dimethvlethvndiphenvisilvlloxv1-4-rf2-r3- (4-fluorophenvn-) acid methvlia ester

5-f1 -methvlethvli-l -phenvl-1 H-pvrazole-4-vnethvnmethoxvphosphinvllbutanoïaue

A solution of 1.0 g (1.36 mmol) of compound I of Example 42 in 72 ml of methanol was treated with 250 mg of 10% Pd / C and hydrogenated in a Parr hydrogenator overnight under a pressure of approximately 276 kPa (40 psi). The reaction mixture was filtered through Celite, and the clear filtrate was evaporated to dryness to give the title compound as a homogeneous oil (1.0 g, 100% crude yield).

TLC: Rf 0.27 (silica gel; hexane: acetone - 7: 3)

B. Methyl ester of acid (SÏ-4-rr2-r3- (4-fluorophénvli-5- (1-méthvléthvn-1 -phénvl-1 H-pyrazol-4-vlléthvnméthoxvphosphinvn-3-hvdroxvbutanoïue

A solution of 1.05 g (1.41 mmol) of compound A in 14.0 ml of dry tetrahydrofuran was treated successively with 334 (il (5.83 mmol) of glacial acetic acid and 4.46 ml (4 , 46 mmol) of (C4H9) 4NF 1.0 M / THF, and stirred at room temperature under an argon atmosphere for about 19 hours The reaction mixture was diluted with 28 ml of ice water and extracted with 3 x 100 ml of ethyl acetate The combined organic extracts were washed with 15 ml of saturated NaHCO3, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. mixture of crude products was chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 150 ml), eluting with mixtures 2: 1, 4: 1 and 9: 1 of EtOAc and of hexane, ethyl acetate and acetone, to give the title compound as a semi-solid (623.5 mg, 88.0%). TLC: Rf 0 , 18 (silica gel; EtOAc: hexane - 4: 1).

Example 45

FSV4-rf2-r3- (4-fluorophenvn-5- (1 -methvlethvO-1-phenvl-1 H-pyrazol-4-vllethvllhvdroxvphosphinvll-3-hvdroxvbutanoïue acid dilithium salt

A solution of 623.5 mg (1.24 mmol) of the compound of Example 44 in 14.7 ml of dioxane was treated with 4.28 ml (4.27 mmol) of 1.0 N LiOH under an atmosphere of nitrogen, heated to 55 ° C (oil bath) for 2 hours, then stirred at room temperature for about 20 hours. The reaction mixture was evaporated to dryness, dried under vacuum and chromatographed on a column of HP-20 (25.4 x 152 mm, 1 "x 6"), eluting the column with 750 ml of steam-water distilled, 500 ml of a solution

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CH 675 582 A5

aqueous 10% CH3OH, 500 ml of a 20% aqueous solution of CH3OH and 500 ml of a 50% aqueous solution of CH3OH. The desired fractions were combined and evaporated to dryness to give the desired product (560 mg, 92.8%).

TLC: Rf 0.42 (silica gel; i-Pr0H: NH40H: H2O - 8: 1: 1)

Analysis: Calculated for C24H26FLÌ2N20sP-1.16 H2O: (Effective molecular weight 507.197):

C, 56.83; H, 5.62; N, 5.52; F, 3.74; P, 6.11 Found: C, 56.83; H, 5.80; N, 5.76; F, 3.46; P, 6.19

1 H NMR spectrum (400 MHz, CD3OD):

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, 1 H)

4.26 (m, 1H)

7.14 - 7.68 (m, 9H)

Example 46

Acid methvlia ester (SV4-iïr4- (4-fluorophénvl) -1 - (1 -méthvléthvn-3-phenvl-l H-Pvrazol-5-vnéthvnvnméthoxv-phosphinvn-3-hvdroxvbutanoïue

A. 2-f4-FluoroDhenvli-1-phenvlethanone

A suspension of 928 mg (38 mmol) of magnesium turnings in 38 ml of dry ether under an argon atmosphere was treated dropwise with 5.3 ml (42 mmol) of 4-fluorobenzyl bromide over a period of 45 minutes, at a rate ensuring moderate reflux. When the addition was complete, the mixture was heated at reflux for a further 30 minutes, cooled to room temperature and treated with a solution of 2.96 ml (29 mmol) of benzonitrile in 5 ml of dry ether. The mixture was stirred at room temperature for 4.5 hours, poured slowly into 40 ml of cold 10% HCl, and the suspension obtained was extracted with 5 x 50 ml of ether and 2 x 100 ml of acetate ethyl. The combined organic extracts were washed with 50 ml of saturated NaHCOs, 50 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

9.8 g of the crude product were chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 400 ml), the column being eluted with 1: 4 and 1: 2 mixtures of CH2CÌ2 and hexane. The desired fractions were combined and evaporated to dryness to give the title compound as a white solid (3.29 g, mp 106-108 ° C). (Another 2.60 g was obtained from other fractions, containing a trace of the starting material, to reach a total yield of 94.8%).

TLC: Rf 0.60 (silica gel; CH2Cl2: hexane -1: 1).

Analysis: Calculated for Ci4HiiFO: C, 78.49; H, 5.18; F, 8.87 Found: C, 78.22; H, 5.22; F, 9.21

SM (M + H) + = 215

B. 2-f4-Fluorophenvn-1 -phenvlethanone. (1 -methvlethvhhvdrazone

A solution of 4.45 g (21 mmol) of compound A in a mixture of 34 ml of 95% ethanol and 0.74 ml of glacial acetic acid was treated with 3.63 ml (approximately 42 mmol) isopropylhydrazine and heated to 80 ° C (oil bath) under nitrogen for 1.4 hours. Thin layer chromatography showed that part of the starting material was still present, so that the reaction mixture was treated with another 2.0 ml (about 23 mmol) of isopropylhydrazine, and heated to 80 ° C (oil bath) for another 1 hour. The reaction mixture was cooled to room temperature, evaporated on a rotary evaporator to remove most of the solvent, then diluted with 200 ml of dichloromethane. The organic solution was washed with 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. The yellow oil obtained was evaporated once in 150 ml of toluene to give the title compound as a crude product (5.63 g) contaminated with a little of the starting material and traces of two other components.

TLC: Rf 0.28 (silica gel; CH2CÌ2: hexane-1: 1).

Isopropylhydrazine was prepared as follows: 10.3 ml (0.10 mole) of iodopropane was added over 2.0 hours to 48.4 ml (1.0 mole) of hydrazine hydrate under a d atmosphere 'nitrogen. The mixture was then stirred at 60 ° C. (oil bath) under a nitrogen atmosphere for 3 hours, cooled and extracted with 250 ml of ether for 20 hours (liquid-liquid extractor). The ether extract was evaporated to give 5.63 ml, or 5.3 g, of isopropylhydrazine.

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C. Acetic acid. 2-f2- (4-fluorophenvfl-1 -phenvl-ethvlidènel-1 -f1 -methvlethvhhvdrazide

A mixture of 5.63 g (about 21 mmol) of the crude compound B and 5.85 ml (42 mmol) of triethylamine in 210 ml of dry toluene was cooled to 0 ° C (ice and salt bath) under nitrogen atmosphere and treated with 1.86 ml (26.3 mmol) of acetyl chloride. The reaction mixture was stirred, while gradually heating to room temperature for 1.5 hours, diluted with 700 ml of ether and filtered. The clear filtrate was dried over anhydrous Na2SC> 4, filtered, evaporated to dryness and evaporated once in toluene (300 ml). The semi-solid obtained (7.1 g) was chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 400 ml), eluting the column with 1: 1.2 mixtures : 1 of 10 CH2CI2 and hexane, CH2CI2 and a 9: 1 mixture of CH2CI2: CH3OH, to give the title compound as a crude product (4.11 g). The crude product was rechromatographed on another column of silica gel, eluting the column with a 4: 1 mixture of EtOAc and hexane. The desired fractions were combined and evaporated to dryness to give the title compound as a thick yellow oil (3.89 g).

TLC: Rf 0.47 (silica gel: EtOAc: hexane-1: 1).

D. 4-M-Fluorophenvfl-5-methvl-1 - (1 -methvlethvh-3-phenvl-1 H-pvrazole

A solution of 1.50 g (4.80 mmol) of compound C in 48 ml of bis (2-methoxyethyl) ether was treated with 615 mg (10.96 mmol) of solid potassium hydroxide and heated at 80 ° C (oil bath) under nitrogen atmosphere for 2.0 hours. The reaction mixture was treated with a second batch of potassium hydroxide (700 mg, 12.5 mmol), heated at 80 ° C for 2 hours, then stirred 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 200 ml of ethyl acetate. The organic solutions were combined, washed with 500 ml of cold 3% HCl, 2 x 100 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. 3.5 g of the crude product were chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 500 ml), eluting the column with a 1: 4 mixture of EtOAc and hexane to give the title compound as a cream-colored solid (1.33 g, 94.3%), mp 135-137 ° C.

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

E. 4- (4-Fluorophenvl) -1 - (1 -methvlethvn-3-phenvl-1 H-pvrazole-5-carboxaldehyde

A mixture of 2.21 g (8.85 mmol) of CUSO45H2O and 9.53 g (35.3 mmol) of sodium 35-persulfate in 65 ml of acetonitrile and 39 ml of water was heated to 65 ° C (oil bath) under a nitrogen atmosphere and treated with 2.6 g (8.83 mmol) of compound D. The temperature of the bath was slowly raised to 75 ° C, maintained at 75 ° C for 40 minutes then brought back to room temperature using a water bath. The reaction mixture was diluted with 45 ml of dichloromethane, stirred for 10 minutes and decanted, the aqueous suspension being extracted with a further 3 x 45 ml of dichloromethane. The combined organic extracts were washed with 2 x 30 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. 2.75 g of the crude product was chromatographed on a column of LPS-1 silica gel, eluting the column with a 1: 9 mixture of EtOAc and hexane, to give the title compound in the form of '' a solid (1.57 g, 57.7%).

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

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F. 5- (2.2-DibromoethénvlV4- (4-fluorophénvn-1 -l 1 -méthvléthvh-3-phenvl-1 H-pvrazole

A mixture of 1.75 g (5.68 mmol) of compound E and 4.6 g (16.8 mmol) of triphenylphosphine in 27.0 ml of dry dichloromethane was cooled to a temperature of -5 to -10 ° C (ice and salt bath) 50 under an argon atmosphere, treated dropwise in 5 minutes with a solution of 2.82 g (8.42 mmol) of carbon tetrabromide in 9 ml of dry dichloromethane, and stirred at -10 ° C for 20 minutes. The reaction mixture was brought to room temperature, poured onto 9.0 ml of saturated NaHCO3 and extracted with 3 x 50 ml of dichloromethane. The combined organic extracts were washed with 10 ml of saturated NaHCO3, 10 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to sic-55.

The crude product was chromatographed on silica gel, eluting with 1: 0 and 1: 4 mixtures of CH2Cl2 and hexane. The desired fractions were combined to give the title compound (2.35 g, 91.4%) as an oil.

TLC: Rf 0.32 (silica gel; CH2Cl2: hexane -1: 1).

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G. 5-Ethvnvl-4-f4-fluorophenvlV1 - (1 -methvlethvn-3-ohénvl-1 H-pvrazole

A solution of 1.89 g (4.08 mmol) of compound F in 7.6 ml of dry tetrahydrofuran was cooled to -78 ° C (dry ice-acetone), treated dropwise with 5.2 ml (8 , 18 mmol, two equiva

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slow) of BuLi 1.6 M / hexane under an argon atmosphere, and stirred at -78 ° C for 1 hour and 20 minutes. The reaction mixture was fixed at -78 ° C with 11.0 ml of 25% NH 4 Cl, brought to room temperature and extracted with 3 x 50 ml of dichloromethane. The combined organic extracts were washed with 15 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. 1.77 g of the crude product was chromatographed on a column of silica gel, eluting with 1: 4 and 1: 1 mixtures of CH2Cl2 and hexane to give 648 mg of the title compound, at the same time as mixed fractions containing the title compound and compound F. The mixed fractions were combined with the product from another passage (490 mg from 1.1 mmol of compound F) and chromatographed on a second column, eluting the column with a 1: 9 mixture of CH2Cl2 and hexane. The desired fractions were combined and evaporated to dryness to give the title compound as an oil (1.02 g, yield 71.5%, corrected to take account of the starting material recovered ).

H. Acid methvlia ester (SÎ-3nY1.1-dimethvlethvfldiDhénvlsilvlloxv1-4-nT4-f4-fluorophénvn-1 - (1 -méthvléthvl1-3-Dhénvl-1 H-Dvrazol-5-vnéthvnvllhininvhvnhvnhvnv

A solution of 2.341 g (5.01 mmol) of the phosphonic acid monomethyl ester F of Example 1 and 1.90 ml (10 mmol) of trimethylsilylethylamine in 9.5 ml of dry dichloromethane was stirred at room temperature under an argon atmosphere for 1 hour. The mixture was evaporated to dryness, mixed with 15 ml of dry benzene to form an azeotrope, and dried under vacuum. The viscous oil was redissolved in 9.5 ml of dry dichloromethane, treated with a drop of DMF, cooled to a temperature of -10 to 0 ° C (ice and oil bath) and treated dropwise with 480 ni (5.47 mmol) of oxalyl chloride. Strong gas evolution was observed, and the dark yellow solution was stirred at -10 to 0 ° C for 15 minutes, then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, mixed with 18 ml of benzene to form an azeotrope, and dried in vacuo.

A solution of 1.016 g (3.34 mmol) of compound G in 8 ml of dry tetrahydrofuran was cooled to -78 ° C (dry ice-acetone) under an argon atmosphere and treated with 2.1 ml (3.36 mmol) of 1.6 M n-BuLi / hexane, and stirred at -78 ° C for 1.0 hour. The above phosphonochloridate was dissolved in 8 ml of dry tetrahydrofuran, cooled to -78 ° C (dry ice-acetone) under an argon atmosphere, and treated dropwise with a cannula with the solution of the acetylene anion, the two solutions being maintained at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ° C for 1.0 hour, fixed by dropwise addition of 9 ml of 25% NH4Cl, and then brought to room temperature. The mixture was extracted with 3 x 100 ml of ether, and the combined organic extracts were washed with 10 ml of 25% NH4Cl, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

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

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

I. Acid methvlia ester (S) -4-iïr4- (4-fluorophénvn-1 - (1 -méthvléthvli-3-phenvl-1 H-pvrazol-5-vlléthvnvnméthoxvphosDhinvn-3-hvdroxvbutanoïue

A solution of 1.0 g (1.36 mmol) of compound H in 13 ml of dry tetrahydrofuran was treated successively with 320 μl (5.46 mmol) of glacial acetic acid and 4.26 ml (4.26 mmol ) of 1 M (C4Hg) 4NF and stirred overnight at room temperature under an argon atmosphere. The reaction mixture was cooled to 0 ° C (ice and salt bath), treated with 15 ml of 5% KHSO4 and extracted with 3 x 125 ml of ethyl acetate. The combined organic extracts were washed with 2 x 25 ml of 5% KHSO4, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

1.06 g of the crude product was dissolved in a mixture of 23 ml of ether and 18 ml of tetrahydrofuran, cooled to 0 ° C (ice and salt bath), treated with an excess of diazomethane in ether and stirred at 0 ° C for 4 hours. The reaction mixture was fixed by dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of silica gel, eluting the column with a 1: 2 mixture of acetone and hexane. The desired fractions were combined and evaporated to dryness to give the title compound as an oil (330 mg, 48.7%).

TLC: Rf 0.23 (silica gel; EtOAc: hexane-4: 1).

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CH 675 582 A5

Example 47

FSV4-iïr4-C4-fluoroDhenvn-1 -d -methvlethvh-3-phenvl-1 acid dilithium salt fSV4-iïr4-h-ovrazol-5-vnéthvnvnhvdroxvphosphinvn-3-hvdroxvbutanoïue

A solution of 330 mg (0.66 mmol) of the compound of Example 46 in 7.8 ml of dioxane was treated with 2.29 ml (2.29 mmol) of 1 N LiOH, stirred at 55 ° C ( oil bath) under an argon atmosphere for 1.5 hours, then at room temperature for 16 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of HP20 (25.4 x 254 mm, 1 "x 10"), eluting the column with 750 ml of distilled steam-water, 500 ml of CH3OH in 10% aqueous solution, 500 ml of CH3OH in 20% aqueous solution, and 500 ml of CH3OH in 50% aqueous solution. The desired fractions were combined, evaporated to dryness and dried under vacuum. The solid product was dissolved in a steam-distilled water mixture, and lyophilized to give the title compound as a fluffy solid lyophilisate (275 mg, 99.5%).

TLC: Rf 0.57 (silica gel; i-PrOH; NH4OH: H2O - 8: 1: 1).

Analysis: Calculated for C24H22FLÌ2N20sP- 2.28 H2O (Effective molecular weight 523.310): C, 55.08; H, 5.11; N, 5.35; F, 3.63; P, 5.92 Found: C, 55.08; H, 4.98; N, 5.47; F, 3.66; P, 5.99

IR (KBr): 2172 cm-i (C-C)

1 H NMR spectrum (400 MHz, CD3OD):

1.57 (d, 6H, J = 7 Hz)

1.86-2.01 (m, 2H)

2.37 (dd, 1H, J = 8)

2.50 (dd, 1 IH, J = 4)

4.40 (m, 1H)

5.01 (septuplet, 1H, J = 7)

7.04-7.39 (m, 9H)

Example 48

Methyl ester of acid (SÎ-4-iï2-r4- (4-fluorophénvn-1 - (1 -méthvléthvn-3-phenvl-1 H-pyrazol-5-vnéthvl1méthoxv-phosphinvB-3-hvdroxvbutanoïue

A. Acid methvlia ester (SÎ-3-lïï1.1-diméthvléthvldiphénvlsiivnoxv1-4-rr2-r4- (4-fluorophénvh-1-f1-méthvléthvn-3-phenvl-1H-pvrazol-5-vnéthvllmétbutoxvosphin

A solution of 608 mg (0.85 mmol) of compound H of Example 46 in 63 ml of dry methanol was treated with 155 mg of Pd at 10% / C and hydrogenated at room temperature on a Parr hydrogenator up to '' overnight under pressure of approximately 276 kPa (40 Psi). The suspension was diluted with 50 ml of methanol and filtered through a pad of Celite in a Millipore unit, the pad being washed well with methanol. The clear filtrate was evaporated to dryness and dried in vacuo to give the title compound as a homogeneous oil (559 mg, 90.9%), 1 H NMR and 13 C NMR spectra being compatible.

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

B. Acid methvlia ester (SÌ-4-ir2-r4- (4-fluorophénvn-1- (1-méthvléthvh-3-phenvl-1H-Pvrazol-5-vnéthvnméthoxvphosphinvll-3-hvdroxv-butanoïue

A solution of 559 mg (0.75 mmol) of compound A in 7.5 ml of dry tetrahydrofuran was treated successively with 176 μl (3.0 mmol, 4 equivalents) of glacial acetic acid 3 and 2.34 μl (2 , 34 mmol, 3.1 equivalents) of (C4Hg) 4 NF 1.0M / hexane under a nitrogen atmosphere, and stirred at room temperature for about 20 hours. The reaction mixture was diluted with 20 ml of ice water, extracted with 3 x 70 ml of ethyl acetate, and the combined organic extracts were washed with 10 ml of saturated NaHCOs, 20 ml of brine, dried on anhydrous MgS04, filtered and evaporated to dryness. 580 mg of the crude product were chromatographed on a column of silica gel, eluting the column with a 1: 4 mixture of EtOAc and hexane, then EtOAc and a 4: 1 mixture of acetone and hexane. The desired fractions were combined, evaporated to dryness and dried in vacuo to give the title compound as a homogeneous oil (337 mg, 89.4%).

TLC: Rf 0.18 (silica gel; acetone: hexane -1: 1; UV).

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Example 49

Acid dilithium salt (SM-iï2-14- (4-f [uoro-phér) vh-1- (1-méthvléthvn-3-Dhénvl-1H-Pvrazol-5-viréthvll-hvdroxvphosphinvll-3-hvdroxvbutanoïue

A solution of 337.0 mg (0.67 mmol) of compound 48 in 8.0 ml of dioxane was treated with 2.32 ml (3.5 eq.) Of 1.0N LiOH under argon atmosphere, stirred at 55 ° C (oil bath) for 3.0 h, then at room temperature for 20 h. The reaction mixture was evaporated to dryness and dried under vacuum (at the pump) for 1.0 h. The crude product was chromatographed on a HP-20 column (25.4 x 203.2 mm (1 "x 8"), eluting the column with 500 ml of distilled steam-water, 500 ml of CHsOH in aqueous solution at 10%, 500 ml of CH3OH in 20% aqueous solution and 500 ml of CH3OH in 50% aqueous solution The desired fractions were combined, evaporated to dryness and dried under vacuum. The solid obtained was dissolved in a mixture of steam and distilled water, frozen and lyophilized overnight to give the title compound as a white, fluffy lyophilisate (280.4 mg, 82.4%), with analytically compatible data, mass spectrometry, IR spectrum and 1 H NMR spectrum.

TLC: Rf 0.45 (silica gel; i-PrOH: NH4OH: H2O - 8: 1: 1; UV). An additional 24 mg of a somewhat impure product was obtained from other fractions.

Analysis: calc. for C24H26FLÌ2N20sP-1.19 H2O (effective molecular weight 507,733):

C, 56.77; H, 5.63; N, 5.51; F, 3.74; P, 6.10 Found: C, 52.77; H, 5.69; N, 5.49, F, 3.91, P, 6.50

R (KBr) no 69377 (1589 crtH, C = 0 COO ").

1 H NMR spectrum (400 MHz, CD3OD):

5 1.55 (d, 6H, J = 7, Hj)

1.64-1.84 (m, 4H, -, Ho + Hd)

2.34 (m, 2H, -, Ha)

2.91 (pseudo quadruplet, 2H, -, He 4.25 (m, 1H, -, H6)

4.77 (septuplet, 1 H, partially hidden under the sign HOD, -, Hj)

7.05-7.32 (m, 9H, aromatic protons)

Example 50

FSV4-iïri- (4-fluoro-phenvn-4- (1-méthvléthvB2-phenvl-1 H-imidazol-5-vnéthvnvnméthoxvphosphinvn-3-hvdroxvbutanoïue acid ester)

A. N-Benzovlvaline

A solution of 20 g (0.17 mole) of valine in 20 ml of tetrahydrofuran and 111 ml of 2N NaOH was cooled to 10 ° C. (ice-water bath) under a nitrogen atmosphere and treated dropwise with 23 , 8 ml (0.21 mole) of benzoyl chloride. The reaction mixture was brought to room temperature, stirred for 3.0 h, then cooled again to 0 ° C (ice and salt bath), and treated with 8.0 ml of concentrated sulfuric acid . The mixture was extracted with 3 x 200 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of water, 50 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give the title compound as a solid (41.97 g, 100% gross yield).

A small amount (260 mg) of the product was recrystallized from ethyl acetate and petroleum ether to give the title compound as an analytical sample (205 mg, mp 132- 133 ° C).

TLC: Rf 0.10 (silica gel, acetone: hexane -1: 1).

Analysis: Wed .: C, 65.14; Hf 6.83; N, 6.33 Found: C; 64.81; H, 6.79, N, 6.29

SM (M + H) + = 222

B. N-f1 -Acétvl-2-méthvlpropvDbenzamide

A mixture of 41.7 g (approx. 0.17 mole) of compound A and 47.3 ml (0.34 mole) of triethylamine in 48 ml of acetic anhydride was treated with 2 portions of 2.07 g (0.017 mole) of 4-dimethylaminopyridine, and stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to 0 ° C (ice and salt bath), fixed with methanol and stirred for 30 min. The light brown precipitates which formed were separated by filtration, washed well with water (1.1 l) and redissolved in 750 ml of dichloromethane. The solution obtained was dried over anhydrous MgSO4, filtered and evaporated to dryness to give 35.9 g of a crude product.

The crude product was dissolved in 1.3 l ether, filtered to remove insoluble solids, and the

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CH 675 582 A5

Clear filtrate was concentrated to a volume of about 300 ml and cooled in an ice bath. The title compound was filtered off as a cream-colored precipitate (21.35 g, mp 88-90 ° C). Purification of the solid materials obtained, by evaporation of the filtrate on a column of silica gel (Baker, 60-200 mesh (0.250-0.074 mm, 600 ml), elution using 1: 7 and 1: 4 mixtures of EtOAc and hexane gave an additional 4.77 g of the title compound A small amount of the title compound was recrystallized from ether, mp 88-89 ° C.

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

Analysis: wedge: C, 70.20; H, 7.81; N, 6.39 Found: C, 70.79; H, 7.68; N, 6.31

MS (M + H) + = 220.

C. N-f1 -H -r (4-Fluorophénvniminléthvll2-méthvl-propvl1benzamide

A solution of 25.0 g (0.114 mole) of compound B in 250 ml of dry toluene was treated with 12 ml (0.127 mole, 1.11 eq.) Of 4-fluoroaniline and 125 mg of p-toluene sulfonic acid hydrated, and the reaction mixture was heated to reflux under nitrogen using a Dean-Stark distillation apparatus for 20 h. The reddish-brown solution was cooled to -10 ° C (ice and salt bath) and used as such for the next step in the reaction sequence.

D. 1 - (4-Fluorophenvli-5-methvl-4- (1 -methvlethvh-2-phenvl-1 H-imidazole

The cooled solution of compound C (approx. 0.114 mole) was diluted to -10 ° C (ice and salt bath) with 200 ml of dry dichloromethane, and treated in portions with 47.5 g (0.228 mole) of pentachloride phosphorus. The cream-colored suspension was heated, brought to reflux for 2.5 h under a nitrogen atmosphere, cooled to room temperature and slowly poured onto a mixture of 400 g of ice and 105 ml of 50% NaOH . The organic phase was separated and the aqueous phase was extracted with 2 x 200 ml of dichloromethane. The combined organic extracts were washed with 2 x 100 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product mixture (35.0 g) was chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 600 ml), eluting with 1: 9 and 1: 4 mixtures. EtOAc and hexane, to give the title compound as white needles (29.24 g, mp 146-148 °, 87%).

TLC: Rf 0.40 (silica gel; EtOAc: hexane -1: 4)

Analysis: calc: C, 77.52; H, 6.51; N, 9.52; F, 6.45 Found: C, 77.48; H, 6.69; N, 9.40; F, 6.45

SM (M + H) + = 295

E. 1 - (4-FluoroDhénvlV4- (1 méthvléthvli-2-Dhénvl-1 H-imidazole-5-carboxaldéhvde

A mixture of 8.50 g (34.0 mmol) of hydrated cupric sulfate and 36.8 g (0.136 mol) of potassium persulfate in a solvent mixture consisting of 250 ml of acetonitrile and 150 ml of water was heated to 65 ° C (oil bath) under nitrogen and treated with 10g (34.0 mmol) of compound D. The reaction mixture was slowly heated to 75 ° C, maintained at this temperature for 40 min., then cooled to room temperature. The solution was decanted from the solids, extracting both the aqueous phase and the solids with 3 x 200 ml of dichloromethane. The combined organic extracts were washed with 2 x 100 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. The crude product (17.0 g) was chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 600 ml), eluting the column with mixtures 5:95 and 1: 7 EtOAc and hexane to give the title compound as a solid (6.27 g, 59.8%).

200 mg of the title compound were recrystallized from an Et 2 O: hexane mixture to give an analytical sample (76 mg, mp 160-161 ° C).

TLC: Rf 0.34 (silica gel; EtOAc: hexane -1: 4).

Analysis: wedge: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 73.98; H, 5.68; N, 9.04; F, 6.09

SM (M + H) + = 309

F. 5- (2.2-Dibromoethénvlì-1 - (4-fluoroDhénvli-4-C 1 -méthvléthvD-2-phenvl-1 H-imidazole

A solution of 1.75 g (5.68 mmol) of compound E and 4.46 g (16.8 mmol) of triphenylphosphine in 27.0 ml of dry dichloromethane was cooled to a temperature of -5 to -10 ° C (ice and salt bath) under an argon atmosphere and treated dropwise in 5 min. with a solution of 2.82 g (8.42 mmol) of carbon tetrabromide in 9 ml of dry dichloromethane. The mixture was stirred at -10 ° C for 20 min. then poured onto 9.0 ml of sodium bicarbonate in saturated solution, and extracted with 3 x 50 ml of dichloromethane. The combined organic extracts were washed with 10 ml of saturated NaHCO3, 10 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness. 8.07 g pro105

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CH 675 582 A5

crude product was chromatographed on a column of silica gel, eluting the column with 1: 7 and 1: 4 mixtures of CH2Cl2 and hexane, to give the title compound as a solid ( 2.35 g, 91.4%).

100 mg of compound F were recrystallized from an Et 2 O: hexane mixture to give an analytical sample (49 mg, mp 164-165 ° C).

TLC: Rf 0.32 (silica gel; CH2Cl2: hexane -1: 1).

Analysis: Wed .: C, 51.75; H, 3.69; N, 6.04; F, 4.09; Br, 34.43 Found: C, 51.80; H, 3.71; N, 6.02; F, 4.08; 3 Br, 34.25

MS (M + H) +: 465.

G. 5-Ethvnvl-1 - (4-fluoroohénvli-4- (1 -méthvléthvn-2-phenvl-1 H-imidazole

A solution of 3.065 g (6.60 mmol) of compound F in 12.5 ml of dry tetrahydrofuran was cooled to -78 ° C (dry ice-acetone) and treated with 8.4 ml (13.4 mmol) of n-BuLi 1.6M / hexane under an argon atmosphere. The reaction mixture was stirred at-78 ° C for 1 h and 20 min., Fixed by dropwise addition of 18 ml of 25% NH4Cl, brought to room temperature and extracted with 3 x 100 ml of ether. The combined organic extracts were washed with 25 ml of brine, dried over anhydrous MgSCU, filtered and evaporated to dryness. 2.08 g of the crude product were chromatographed on a column of silica gel (Baker, 60-200 mesh = 0.250-0.074 mm, 400 ml), eluting the column with 1: 9 and 1: 4 mixtures of EtOAc and hexane. The desired fractions were combined and evaporated to dryness to give the title compound as a solid (1.97 g, 97.8%).

92 mg of compound G were recrystallized from hexane to give an analytical sample (59 mg, mp 148-150 ° C).

TLC: Rf 0.60 (silica gel; EtOAc: hexane -1: 4)

Analysis: Wed .: C, 78.92; H, 5.63; N, 9.21; F, 6.24 Found: C, 78.95; H, 5.83; N, 9.07; F, 6.63

MS (M-H) - = 303.

H. Acid methvlia ester (SV3-rr (1.1-dimethvl-éthvndiphénvlsilvnoxv1-4-nT1- (4-fluorophénvn-

4- (1-methvlethvn-2-Dhénvl-1H-imidazol-5-vnéthvnvnméthoxv-phosphinvlbutano'faue

A mixture of 3.54 g (7.86 mmol) of the crude phosphinic acid mono-methyl ester F of Example 1 and 2.70 ml (14.21 mmol) of trimethylsilyidiethylamine in dry dichloromethane has was stirred at room temperature under an argon atmosphere for 1.0 h. The mixture was evaporated to dryness, mixed with 26 ml of dry benzene to form an azeotrope, and dried in vacuo. The viscous oil was redissolved in 14 ml of dry dichloromethane, treated with 2 drops of DMF, cooled to -10 ° C (ice and salt bath) and treated dropwise with 0.68 ml (7.79 mmol ) of oxalyl chloride. A strong gas evolution was observed, and the yellowish brown solution was stirred at -10 ° C for 15 min., Then at room temperature for 1.0 h. The reaction mixture was evaporated to dryness, mixed with 26 ml of dry benzene to form an azeotrope, and dried in vacuo.

A solution of 1.43 g (4.7 mmol) of compound G in 11.5 ml of dry tetrahydrofuran was cooled to -78 ° C (dry ice-acetone) under an argon atmosphere and treated with 2.94 ml (4.7 mmol) of 1.6M n-BuLi / hexane and stirred at -78 ° C for 30 min. The above phosphonochloridate was dissolved in 11.5 ml of dry tetrahydrofuran, cooled to -78 ° C (dry ice / acetone) under an argon atmosphere and treated dropwise, using a cannula, with a solution of the acetylene acetate, the two solutions being maintained at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ° C for 30 min., Fixed by dropwise addition of 13 ml of 25% NH4Cl, it was allowed to return to room temperature, then extracted with 3 x 100 ml of 'ether. The combined organic extracts were washed with 15 ml of 25% NH4Cl, 30 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product mixture (4.3 g) was chromatographed on a column of silica gel, the eluent consisting of 5:94 and 1: 4 mixtures of acetone and hexane. The desired fractions were combined and evaporated to dryness to give the title compound as a light brown syrup (2.18 g, 62.9%).

TLC: Rf 0.13 (silica gel; hexane: acetone-7: 3).

I. Acid methvlia ester (S ^ -4-rm-f4-fluoro-phenvl ') - 4-C1 -méthvléthvh2-phenvl-1 H-imidazoi-

5-vn-éthvnvn-méthoxvphosphinvll-3-hvdroxv-butanoïaue

A solution of 974 mg (1.32 mmol) of compound H in 13.0 ml of dry tetrahydrofuran was treated successively with 310 μl (5.29 mmol) of glacial acetic acid and 4.14 ml (4.14 mmol ) of 1 M (C4H9) 4NF, and stirred overnight at room temperature under an argon atmosphere.

The reaction mixture was cooled to 0 ° C (ice-water bath), treated with 14 ml of 5% KHSO4 and ex106

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CH 675 582 A5

treated with 3 x 125 ml of ethyl acetate. The combined organic extracts were washed with 16 ml of 5% KHSO4, 35 ml of brine, then dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product (1.48 g) was evaporated in a mixture of 22 ml of ether and 17 ml of tetrahydrofuran seCi cooled to 0 ° C (ice water bath), treated with an excess of diazomethane in ether, and stirred at 0 ° C for 4.0 h. The reaction mixture was fixed by dropwise addition of glacial acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of silica gel, eluting the column with 1: 1 and 4: 1 mixtures of EtOAc and hexane. The desired fractions were combined to give the title compound as a solid (304 mg, 46.2%).

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

Example 51

Acid dilithium salt (S) -4-lïï1- (4-fluoro-phenvfl-4- (1-méthvléthvlV2-phenvl-1H-imidazol-5-vn-éthvnvnhvdroxvphosphinvn-3-hvdroxvbutanoïue

A solution of 304 mg (0.6 mmol) of compound 50 in 7.1 ml of dioxane was treated with 2.03 ml (2.08 mmol) of 1N LiOH, stirred at 55 ° C (oil bath) under an argon atmosphere for 1.5 h, then at room temperature for 24 h. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of HP-20 (25.4 x 177.8 mm = 1 "x 7"), eluting the column with 750 ml of distilled steam-water, 500 ml of CH3OH in aqueous solution at 10%, 500 ml of CH3OH in 20% aqueous solution and 500 ml of CH3OH in 50% aqueous solution. The desired fractions were combined, evaporated to dryness and dried under vacuum. The solid was dissolved in steam-distilled water, and lyophilized to give the title compound as a fluffy solid lyophilisate (257 mg, 84.1%).

Other fractions: TLC: Rf 0.38 (silica gel; i-Pr0H: NH40H: H2O - 8: 1: 1)

Analysis: Wedge, for C24H22FLi2N205P-1.52 H2O: C, 56.56, H, 4.95, N, 5.49; F, 3.73; P, 6.08 Found: C, 56.56; H, 4.94; N, 5.32; F, 3.89, P, 5.99

1 H NMR spectrum (400 MHz, CD3OD):

51.37 (d, 6H, J = 7 Hz)

1.79 (m, 2H)

2.31 (dd, 1H, J = 9.15 Hz)

2.43 (dd, 1 H, J = 4.15 Hz)

3.24 (septuplet, 1 H, J = 7 Hz)

4.26 (m, 1H)

7.17-7.35 (m, 9H).

IR (KBr) 2163 (C = C), 1590 (C = 0) cm ~ i

Example 52

Methyl ester of acid (Si-4-12-H- (4-fluorophenvim-d -methvlethvn-2-phenvl-1 H-imidazol-5-vnethvll-methoxvDhosphinvll-3-hvdroxvbutanoïue

A. Acid methvlia ester (SV3-nT1.1-dimethvl-éthvlidiDhénvlsilvlloxvl-4-rr2-H- (4-fluorophénvn-

4- (1 -methvlethvli-2-phenvl-1 H-imidazol-5-vnéthvllméthoxvphosphin-vlbutanoïaue

A solution of 839 mg (1.14 mmol) of compound H of Example 50 in 86 ml of dry methanol was treated with 213 mg of Pd at 10% / C and hydrogenated at room temperature on a Parr hydrogenator until '' overnight under pressure of approximately 276 kPa (40 psi). The suspension was filtered through Celite, the clear filtrate was evaporated to dryness and dried in vacuo to give the title compound as a thick syrup (853 mg, 100% yield).

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

B. Acid methvlia ester (SV4-rf2-ri- (4-fluoro-phenvn-4- (1-méthvléthvli-2-phenvl-1H-imidazol-

5-vn-éthvll-méthoxvDhosphinvll-3-hvdroxvbutanoïaue

A solution of 853 mg (approx. 1.14 mol) of compound A in 11.0 ml of dry tetrahydrofuran was treated successively with 270 μl (4.60 mmol) of glacial acetic acid and 3.62 ml (3, 62 mmol) of (C4H9) 4NF 1.0M / hexane, and stirred overnight at room temperature under argon. The reaction mixture was diluted with 25 ml of ice water and extracted with 3 x 100 ml of ethyl acetate. The combined organic extracts were washed with 15 ml of saturated NaHCO3, 25 ml of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product (958 mg) was chromatographed on a column of silica gel, eluting with mixtures.

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CH 675 582 A5

1: 1 and 4: 1 swaddles of acetone and hexane. The desired fractions were combined, evaporated to dryness and dried in vacuo to give the title compound as a solid (443 mg, 77.0%)

TLC = Rf 0.13 (silica gel; acetone: hexane -1: 1).

FSV4-iï2-ri-f4-fluoro- phenvIM-f 1 -methvlethvn-2-phenvl-1 H-imidazol-5-vnethvn-hvdroxvphosphinvn-3-hvdroxvbutanoic acid dilithium salt

A solution of 443 mg (0.88 mmol) of the compound of Example 52 in 10.5 ml of dioxane was treated with 3.05 ml (3.09 mmol) of LiOH 1, ON and stirred at 55 ° C (oil bath) under an argon atmosphere for 3.0 h, then at room temperature for about 20 h. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on a column of HP-20 (25.4 x 203.2 mm, 1 "x 8"), eluting the column with 750 ml of distilled steam-water, 500 ml of 30 CH3OH in solution 10% aqueous, 500 ml of CH3OH in 20% aqueous solution and 500 ml of CH3OH in 50% aqueous solution. The desired fractions were combined and evaporated to dryness. The solid obtained was dissolved in 30 ml of distilled steam-water and lyophilized to give the title compound as a fluffy white solid (376.4 mg, 83.9%).

TLC: Rf 0.40 (silica gel; i-Pr0H: NH40H: H2O - 8: 1: 1)

Analysis: calc. for C24H26FLiH2N205P-0.84 H20 (effective molecular weight 501.46):

C, 57.43; H, 5.76; N, 5.69; F, 3.99; P, 6.08 Found: C, 57.48; H, 5.56; N, 5.59; F, 3.79 P, 6.18 IR (KBr) (1587 cm-1, C = 0 COO ")

1 H NMR spectrum (400 MHz, CD3OD):

8 1.33 (d, 6H, J = 7 Hz)

1.46-1.61 (m, 4H)

2.30 (m, 2H)

2.76 (m, 2H)

3.13 (septuplet, 1 H, J = 7 Hz)

4.14 (m, 1H)

7.17-7.30 (m, 9H).

Example 54

Acid dilithium salt (SH4-fir2- (cvclohexvl- méthvH-4.6-diméthvlPhénvnéthvnvnhvdroxvphosphinvll-3-hvdroxvbutanoïue

A. N-f2.4-Dimethvlbenzvlideneibenzene-amine

Ref. Merck, U.S. Patent No. 4,375,475, p. 39.

The title compound was prepared as described in Part A of Example 1.

Example 53

b.

not

O ° SŒ3

O

Œ3

2

Ref. Merck, U.S. Patent No. 4,375,475, p. 39.

The Pd complex of the title was prepared as described in part B of Example 1.

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CH 675 582 A5

C. 2-iïCvclohexvlméthvh-4.6-diméthvlbenzaldéhvde1

Magnesium turnings (1.44 g, 59.45 mmol), under an argon atmosphere, were covered with 15 ml of dry Et 2 O and subjected to ultrasound for 5 min. 1.5 ml of cyclohexylmethyl bromide was added to the Mg turnings, and the application of ultrasound continued (reflux starting after a few minutes). Simultaneously, and via a funnel, 60 ml of dry Et2 and 5 ml of a solution, in Et2O, of the remainder of cyclohexylmethyl bromide were added, while continuing the application of the ultrasound (we have added altogether 9.12 ml, 65.3 moles, cyclohexylmethyl bromide). After completion of the addition, the ultrasound was continued for 15 min., Then the reaction mass was brought to reflux for 40 min. This Grignard reagent was cooled to room temperature, then added, using a cannula, to a solution of 5.55 g (7.43 mmol), of the Pd B complex and 15.59 g (59.45 mmol) of triphenylphosphine, which had been stirred for 30 min. under an argon atmosphere and at room temperature. After addition of Grignard's reagent, the reaction mass turned green, and a precipitate formed. This reaction solution was stirred at room temperature for 2 h, then 37 ml of 6N HCl was added. This mixture was stirred for 1 h, then filtered through a pad of Celite in a sintered glass funnel to remove solids. The solids were washed with Et20, and the filtrate was evaporated on a rotary evaporator to remove the volatiles. The residue obtained was stirred in Et20 and filtered as above. The filtrate was washed once with saturated NaCl solution, and the organic layer was dried over MgSO4. 14.5 g of a brown oil were obtained. Purification by flash chromatography, eluting with 4% EfeO / hexane, gave 1.70 g of a clear oil, 99% yield:

TLC: Rf = 0.30 (5% Et20 / hexane, silica gel).

IR (CHCI3) 3030, 3008, 2926, 2853,1679,1606,1448,1147 cm ~ i 1 H NMR (270 MHz-CDCIs)

25 6 1 0.51 (s, 1)

6.90 (s, 1)

6.85 (s, 1)

2.80 (d, 2, J = 6.0 Hz)

2.55 (s, 3)

30 2.30 (s, 3)

1.80-1.55 (m, 5)

1.55-1.30 (m, 1)

1.30-0.80 (m, 5)

Mass spectrometry (Cl) m / e 231 (M + H) +

35

D. 1- (Cvclohexvlmethvh-2- (2.2-dibromoethénvn-3.5-dimethvlbenzene

1.68 g (7.30 mmol) of aldehyde C in 65 ml of dry CH2Cl2 were cooled to 0 ° C under an argon atmosphere. To this solution was added 6.13 g (23.4 mmol) of triphenylphosphine, and the solution was stirred until all of the solids dissolved. At 0 ° C, 3.63 g (11.0 mmol) of CBr4 was added as a solution of 20 ml in CH2Cl2. The reaction solution became orange. The reaction mixture was stirred at 0 ° C for 1.5 h, then fixed with saturated NaHCO3 solution and vigorously stirred. The aqueous layer was removed and extracted twice with CH2Cl2. The organic solutions were combined, washed once with saturated NaHCO3 solution, and dried over 45 MgSO4. Filtration and removal of the solvent gave 9.6 g of a brown solid. Purification by flash chromatography, eluting with 100% hexane, gave 2.52 g (90% yield) of a clear oil.

TLC: Rf 0.62 (5% EfeO / hexane, silica gel) PMA.

IR (CHCI3) 2925, 2852,1608,1472, 869 cm "i 50 1 H NMR (270 MHz, CDCI3)

5 7.39 (s, 1)

6.87 (s, 1)

6.80 (s, 1)

2.37 (d, 2, J = 6.3 Hz)

55 2.27 (s, 3)

2.24 (s, 3)

1.70 (m, 5)

1.45 (m, 1)

1.38-1.10 (m, 3)

60 0.90 (m, 2)

Mass spectrometry (Cl) m / e 387 (M + H) +

E. 1 - (Cvclohexvlméthvh-2-éthvnvl-3.5-diméthvlbenzène

65 2.51 g (6.5 mmol) of vinyl dibromide D, under an argon atmosphere, were stirred with 30 ml of

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CH 675 582 A5

THF and cooled to -78 ° C. It was added in 3 min. to the solution of dibromide, at -78 ° C, 5.20 ml of a solution of 2.5M n-butyllithium in hexane. The pink reaction mixture obtained was stirred at -78 ° C. After 1.5 h at -78 ° C, the reaction was fixed with a saturated aqueous NH4Cl solution, then warmed to room temperature. The aqueous layer was removed and extracted twice with Et20 and once with hexane. All organic layers were combined and dried over MgSO4 to give

1.65 g of a brown oil after filtration and removal of the solvent. Purification by flash chromatography, eluting with hexane, gave 1.39 g, 95% yield, of the title acetylene.

TLC: Rf 0.50 (5% toluene / hexane, silica gel), PMA.

IR (CHCI3) 3305,3007, 2924, 2852, 2096,1607,1470,1448 cm "i 1 H NMR (270 MHz, CDCI3)

8 6.86 (s, 1)

6.79 (s, 1)

3.39 (s, 1)

2.63 (d, 2, J = 6.9 Hz)

2.63 (m, 6)

1.20 (m, 3)

1.00 (m, 2)

Mass spectrometry (Cl) m / e 227 (M + H) +.

F Methyl ester of feV4-riï2- acid (cvclohexvl-méthvlV

4.6-dimethvlphénvnéthvnvnméthoxvphosphinvn-3-riï1.1-diméthvléthvndiphénvlsilvnoxvlbutanoïaue

1.36 g (6.0 mmol) of acetylene E in 30 ml of dry THF under an argon atmosphere was cooled to -78 ° C. To this solution was added 2.4 ml of a 2.5M solution of n-BuLi in hexane; the reaction solution took on a burgundy hue, and was stirred for 1 h at -78 ° C. 4.68 g (9.6 mmol) of the phosphonochloridate F of Example 1 were stirred with 30 ml of dry THF and cooled to -78 ° C. The acetylene anion was then introduced using a cannula into the phosphonochloridate solution over 15 min. After completion of the transfer, the reaction mass was stirred at -78 ° C for 1 h, then fixed with a saturated aqueous NH4Cl solution and brought to room temperature. THF was removed from the reaction mixture, and the product obtained was dissolved in Et20 and H2O. The aqueous layer was extracted three times with EfeO. All of the Et20 extracts were combined and washed once with saturated NaHCO3 solution and once with brine, then dried over MgSO4. Filtration and removal of the solvent gave an orange oil, which was purified by flash chromatography, the eluent being a 3.5: 5.5: 1 EtOAc: hexane: toluene mixture. It was obtained in the form of a clear oil

2.80 g (yield 70%) of the acetylenic phosphinate of the title.

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

IR (CHCI3) 3025, 3001, 2929, 2856, 2164,1736,1607,1240,1112,1039, 823 cm-l 1 H-NMR (270 MHz, CDCI3)

8 7.66 (m, 4)

7.30 (m, 6)

6.87 (s, 1)

6.81 (s, 1)

4.66 (m, 1)

3.70 & 3.66 (d, 3, J = 14.3 Hz)

3.56 (s, 3)

2.05 (m, 1)

2.69 (m, 1)

2.50 (m, 3)

2.32 (m, 2)

2.30 (s, 3)

2.27 (s, 3)

1.60 (m, 6)

1.03 (m, 3)

1.02 (s, 9)

0.95 (m, 2)

Mass spectrometry (Cl) m / e 65 9 (M + H) +

G. fSl-4-iïr2-fcvclohexvl-méthvn-4.6-diméthvlphénvlléthvnvnméthoxvphosphinvll-3-hvdroxvbutanoiaue methvlia acid ester

0.633 g (0.96 mmol) of acetylene phosphinate F was stirred under an argon atmosphere at room temperature with 14.0 ml of dry THF. 0.22 ml (3.84 mmol) of glacial acetic acid was added to the phosphinate solution, followed by addition dropwise over 5 min. 2.62 ml of a 1M solution of n-BU4NF in THF. After 19 h of stirring at room temperature, the reaction was fixed with ice water, and the aqueous layer was extracted three times with EtOAc. Combi110 organic solutions

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born were washed twice with saturated aqueous NaHCOs solution, and once with saturated NaCl solution. The organic layer was dried over Na2SC> 4 and filtered to give a yellow gum (0.658 g) after removal of the solvent. Purification by flash chromatography, eluting with EtOAc, yielded 0.23 g (65%) of the title alcohol, as a clear oil.

TLC: Rf = 0.51 (6: 4 acetone / hexane, silica gel) PMA

IR (CHCI3) 3450 (br), 3005, 2926, 2852, 2164,1733, 1607, 1448, 1439,1039 cm ~ i 1 H NMR (270 MHz, CDCI3)

5 6.89 (s, 1)

6.82 (s, 1)

4.63 (m, 1)

3.88 & 3.87 (2d, 3, J = 12 Hz)

3.69 (s, 3)

2.70 (s, 2)

2.62 (d, 2, J = 6.3 Hz)

2.43 (s, 3)

2.32 (s, 3)

2.27 (m, 2)

1.65 (m, 6)

1.19 (m, 3)

1.00 (m, 2)

Mass spectrometry (Cl) m / e 421 (M + H) +

H. Acid dilithium salt (SV4-fiï2 (-cvclohexvl-méthvn-4.6-diméthvlDhénvlléthvnvllhvdroxvDhosDhinvll-3-hvdroxvbutanoïaue

0.212 g (0.51 mmol) of diester G was stirred in 7 ml of dioxane, and 1.5 ml (1.5 mmol) of 1N LiOH was added at room temperature. The reaction mixture was heated to 55 ° C and, after 20 min., The precipitate obtained was dissolved by adding 5 ml of dioxane and 4 ml of H2O. After 2 h and 30 min. at 55 ° C, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the white solid obtained was placed in vacuo for 15 min. The product was purified on a 3.0 x 19 cm column of HP-20 resin, eluting first with 100 ml of H2O, then with a 1: 1 MeOH / H2O mixture. Lyophilization of the product obtained gave 0.145 g (71%) of a white lyophilisate.

TLC: Rf = 0.39 (7: 2: 1 n-Pr0H / NH40H / H2O, silica gel), PMA.

IR (KBr) 3700-3100 (br), 2922, 2850, 2167,1590,1447,1179,1076 cm-1.

1 H NMR (400 MHz, DaO)

5 6.99 (s, 1)

6.94 (s, 1)

4.53 (m, 1)

2.64 (m, 1)

6.22 (d, 2, J = 6.2 Hz)

2.39 (s, 3)

2.37 (m, 1)

2.26 (s, 3)

2.02 (m, 2)

I, 60 (m, 6)

1.14 (m, 3)

1.00 (m, 2)

Mass spectrometry (FAB) m / e 409 (M + H) +, 397 (M-2 Li + H) + = Analysis: Wedge, for C21H27O5P LÌ2-1.72 H2O:

C, 57.96; H, 7.05; P, 7.12 Found: C, 57.96; H, 7.18; P, 6.96

Example 55

4-IT2-r2-cvclohexvlmethvn-4.6-dimethvlphenvllethenvnhvdroxvphosphinvri-3-hvdroxv-butanoic acid dilithium salt

A. Dimethyl acid ester (EH2-r2- (cvclohexvl-méthvn-4.6-diméthvlphénvlléthénvllphosphoniaue

1.64 g (13.2 mmol) of dimethyl methylphosphonate in 20 ml of dry THF were cooled to -78 ° C. under an argon atmosphere. To this solution was added at -78 ° C, over 5 min., 5.0 ml (12.4 mmol) of a solution of 2.5M n-butyllithium in hexane. After completion of the addition, the milky white reaction mixture was stirred for 1 h. To the anionic solution at -78 ° C was added, using a funnel and over 10 min., A solution, in 10 ml of THF, of 1.9 g (8.26 mmol) of the aldehyde A of Example 54. After 35 min. of stirring at -78 ° C., the reaction was fixed with 8 ml of NH 4 Cl in saturated aqueous solution, and

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CH 675 582 A5

allowed the reaction mass to return to room temperature. The organic layer was removed, and the aqueous layer was extracted three times with EtOAc. The organic layers were combined and washed once with brine and dried over Na2SO4. Filtration and removal of the solvent gave 3.25 g of a yellow oil.

3.25 g of the above yellow oil was dissolved in dry tolene and heated to reflux in a soxhlet extractor containing a 4 Å molecular sieve. 0.080 g (0.42 mmol) of p-toluene sulfonic acid was added at times 0, 3.5 and 18 h. H2O. After 22 h at reflux, the reaction mass was cooled to room temperature, and the toluene was removed in vacuo. The yellow residue obtained, in EtOAc, was washed twice with saturated NaHCOs solution, dried over Na2SO4 and filtered to give a yellow oil (A) after removal of the solvent.

The aqueous solution was acidified with concentrated HCl, extracted three times with EtOAC, dried over MgSO4, filtered, and the solvent was removed to give 0.535 g of a yellow oil. This yellow oil was then heated to reflux in 6.0 ml of HC (OCH3) 3 for 24 h, then the excess HC (OCH3) 3 was removed in vacuo. This product was combined with yellow oil (A) and purified by flash chromatography eluting with 80% EtOAc / hexane. The title vinyl phosphonate (2.07 g, 73%) was obtained as a white solid.

TLC Rf = 0.45 (1: 1 acetone / hexane, silica gel) PMA.

IR (KBr) 2921, 2851,1623,1447,1243,1186,1060,1027 cm "i.

1 H NMR (270 MHz, CDCI3)

8 7.65 (dd, 1, J = 23.6 Hz, 18.1 Hz)

6.88 (s, 1)

7.82 (s, 1)

5.80 (dd, 1, J = 21.0 Hz, 18.1 Hz)

2.49 (d, 2, J = 7.2 Hz)

2.29 (s, 3)

2.28 (s, 3)

1.65 (m, 5)

1.45 (m, 1)

1.25-0.80 (m, 5)

Mass spectrometry (Cl) m / e 337 (M + H) +

B. Acid methvlia ester (EH2-r2- (cvclohexvl-méthvfl-4.6-diméthvlphénvlélthénvriphosphoniaue

2.07 g (6.16 mmol) of vinyl phosphonate A was stirred with 14 ml of dioxane at room temperature. 9.24 ml (9.24 mmol) of LiOH 1, ON was added to this solution, and this mixture was heated to 75 ° C. After 3.5 h at 75 ° C, the reaction mass was cooled to room temperature, and the dioxane was removed in vacuo. The residue obtained was stirred with H2O and acidified to pH approx. 2 with 1N HCl. The aqueous solution was extracted three times with EtOAc, dried over Na2SO4, filtered, and the solvent was removed to give 1.95 g of an off-white solid.

TLC Rf = 0.58 (8: 1: 1 / CH2Cl2: CH30H: AcOH, silica gel), PMA.

1 H NMR (270 MHz, CDCI3)

812.11 (s, 1)

7.61 (dd, 1, J = 24.17 Hz, 17.58 Hz)

6.87 (s, 1)

6.81 (s, 1)

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)

1.65 (m, 5)

1.45 (m, 1)

1.15 (m, 3)

0.95 (m, 2)

C. Methyl ester of acid (EM-12-l2-fcvclo-hexv [methvh-4.6-dimethvlphenvllethenvl1methoxvDhosphinvn-3-oxobutanoïaue

1.95 g (6.06 mmol) of the monomethyl phosphonate B in 50 ml of dry CH2Cl2 were stirred at room temperature under an argon atmosphere with 1.76 g (12.1 mmol) of (C2H5) 2NSi (CH3 ) 3, for 1 h and 25 min. The CH2Cl2 was removed in vacuo and the yellow oil obtained was mixed once with benzene to form an azeotrope, and placed in high vacuum for 20 min. Then this oil was dissolved in 50 ml of dry CH2CÌ2 under an argon atmosphere and cooled to 0 ° C. 2 drops of dry DMF were added, then 0.92 g (7.27 mmol) of oxalyl chloride was added slowly and dropwise: evolution of gas was observed. The reaction mixture was stirred for 15 min. at 0 ° C, then heated to

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CH 675 582 A5

room temperature and stirred for 1 hr. The CH2Cl2 was removed in vacuo from the reaction mixture, and the orange oil obtained was mixed twice with dry benzene to form an azeotrope, and pumped under high vacuum for 1 h to give the phosphonochloridate.

The dianion of methyl acetoacetate was prepared as follows. NaH washed with pentane (0.25 g of an oil dispersion, 8.7 mmol) in 10 ml of dry THF was cooled to 0 ° C under an argon atmosphere. 0.92 g (7.9 mmol) of methyl acetoacetate was added to the NaH suspension, in the form of a solution in 10 ml of THF, and stirred for 20 min., Then 2 was added, 90 ml (7.3 mmol) of 2.5M n-butyllithium in hexane, then stirred for 45 min. The dianion solution was cooled to -78 ° C, and a solution, in 10 ml of THF, of the phosphonochloridate prepared above was cooled to -78 ° C and added to the dianion solution. 15 min. After 30 min. with stirring at -78 ° C, the reaction was fixed using a saturated aqueous NH4Cl solution, and heated to room temperature. The THF was removed from the reaction mixture, and the orange oil obtained was taken up in a 1: 1 EtOAc / HaO mixture. The aqueous layer was extracted three times with EtOAc. The combined EtOAC extracts were combined and washed twice with saturated NaHCOs solution and once with saturated NaCl solution, then dried over Na2SO4. Purification of the crude product (2.75 g) by flash chromatography eluting with EtOAc gave the title keto ester (0.97 g, 42%) as a yellow oil.

TLC Rf = 0.24 (EtOAc, silica gel) PMA.

1 H NMR (270 MHz, CDCI3)

20 ô 7.71 (dd, 1, J = 22.52 Hz, 18.13 Hz)

6.89 (s, 1)

6.83 (s, 1)

5.89 (dd, 1, J = 26.37 Hz, 17.58 Hz)

3.79 (s, 2)

25 3.73 (s (br), 6)

3.36 (dd, 2, J = 18.68 Hz, 5.5 Hz)

2.50 (m, 2)

2.30 (s, 3)

2.29 (s, 3)

30 1.70 (m, 5)

1.45 (m, 1)

1.10-0.80 (m, 5)

D. 4-IT2-r2- acid methvlia ester (cvclohexvl-methvh-35 4.6-diméthvlphénvlléthénvllméthoxvphosDhinvl1-3-hvdroxvbutanoïaue

0.97 g (2.31 mmol) of p-ketophosphonate C was stirred in 10 ml of THF under an argon atmosphere and cooled to 0 ° C. 0.087 g (2.31 mmol) of solid NaBH4 was added to the THF solution, then 2 ml of CH3OH was added dropwise; this resulted in gas evolution. After 50 min. of stirring at 40 ° C., the reaction mass was fixed with 2 ml of acetone, fixing followed by the addition of silica gel CC-4. The reaction was warmed to room temperature and filtered through sintered glass. The solvent was removed from the filtrate to give a yellow oil, which was purified by flash chromatography eluting with EtOAc. The alcohol of the title was obtained in the form of a clear oil (0.65 g, 66%). TLC Rf = 0.29 (50% acetone / hexane, silica gel), PMA.

45 p.F. 80-83 ° C

IR (KBr) 3282 (br), 2923, 2918, 2848,1743,1614,1450,1442,1080,1045 cm ~ i 1 H-NMR (270 MHz, CDCI3)

5 7.68 (m, 1)

6.88 (s, 1)

50 6.82 (s, 1)

5.89 (m, 1)

4.50 (m, 1)

4.00 (m, 1)

3.77 & 3.74 (2d, 3, J = 11.0 Hz)

55 3.69 & 3.68 (2s, 3)

2.65 (d, 2, J = 6.0 Hz)

2.50 (m, 2)

2.30 (s (br), 3)

2.28 (s, 3)

60 2.15 (m, 2)

1.68 (m, 5)

1.45 (m, 1)

1.30 to 0.80 (m, 5)

Mass spectrometry (Cl) m / e 423 (M + H) +

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CH 675 582 A5

E. 4-i2-r2-fcvclohexvl-methvn-4.6-dimethvlDhénvnéthénvnhvdroxvphosDhinvn-3-hvdroxvbutanoïa acid dilithium salt

0.565 g (1.33 mole) of diester D was stirred with 14 ml of dioxane until all of the solids dissolved. 4.0 ml of 1.0N LiOH was added, and the solution was heated to 55 ° C. After 30 min, the reaction mass became cloudy. After 2 h at 55 ° C, the reaction mass was cooled to room temperature, and the solvent was removed on a rotary evaporator to leave a white solid. The crude product was purified on a 3.0 x 15 cm column of HP-20 resin, eluting first with 10 ml of H2O, then 75% MeOH / H2O. Lyophilization of the product fractions obtained gave the title compound as a white lyophilisate (0.524 g, 98%).

TLC: Rf = 0.41 (7: 2: 1 nPr0H / NH40H / H2O, silica gel) PMA.

IR (KBr) 3700-3100 (br), 2921.2851,1591,1446,1222,1195,1161,1051 cm ~ i 1 H NMR (400 MHz, D20) 8 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)

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)

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)

Mass spectrometry (FAB) m / e 407 (M + H) +, 347 (M + -2 Li + + 2H).

Analysis: Wedge, for C2iH290sPLÌ2.0.38 H2O:

C, 61.03; H, 7.45; P, 7.49 Found: C, 61.03; H, 7.63; P, 7.66

Example 56

FSV4-iï2-r2- dilithium salt (cvclohexvl-méthvn-4.6-diméthvlphénvnéthvnhvdroxvphosDhinvn-3-hvdroxvbutanoïue

A. 4-iïr2-fcvclohexvl-methvli- acid methvlia ester

4.6-dimethvlphénvnéthvnméthoxvphosphinvn-3-riï1.1-diméthvléthvndiphénvlsilvnoxv1butanoi'aue

Argon was bubbled for 10 min. in a solution, in 45 ml of methanol, of 1.33 g (2.02 mmol) of acetylenic phosphinate F of Example 54. In a Parr apparatus, 0.34 g was added to this solution in methanol of Pd at 10% / C. Hydrogenation on a Parr hydrogenator at 276 kPa (40 psi) for 20 h gave 1.39 g of an oil, after filtration through a pad of Celite in a sintered glass funnel. Purification by flash chromatography, eluting with a 1: 1 EtOAc / hexane mixture, gave a clear oil 1.25 g (94%) of the title phosphinate.

TLC Rf = 0.21 (5/4/1 hexane / EtOAc / toluene, silica gel), PMA.

IR (CHCI3) 3600-3200 (br), 3003,2925, 2853,1731,1448,1440,1247,1233,1179,1044cm "i 1H NMR (270 MHz, CDCI3)

86.83 (s, 1)

6.78 (s, 1)

4.50 (m, 1)

3.80 & 3.77 (2 d, 3, J = 6.3 Hz)

3.72 & 3.71 (2 s, 3)

3.38 (m, 1)

2.87 (m, 1)

2.60 (m, 2)

2.45 (d, 2, J = 6.9 Hz)

2.29 & 2.28 (2 s, 3)

2.25 (s, 3)

2.00 (m, 4)

1.70 (m, 6)

1.45 (m, 1)

1.30-0.90 (m, 6)

Mass spectrometry (El) m / e 424 (M) +

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CH 675 582 A5

B. Acid methvlia ester (SV4-fr2-r2- (cvclo-hexvlméthvfl-4.6-diméthvlphénvnéthvnméthoxvphosphinvn-3-hvdroxvbutanoïue

A solution of 1.2 g (1.8 mmol) of silylether A in 20 ml of THF was stirred under an argon atmosphere at room temperature. 0.41 ml of glacial acetic acid and 5.0 ml (5.44 mmol) of a 1.1 M solution of n-Bu4NF in THF were added to this solution in order. 'was added dropwise over 5 min. After 23 h of stirring at room temperature, the reaction was fixed with 50 ml of ice water, and the reaction mass was vigorously stirred. The THF was removed in vacuo, and the product obtained was diluted with water and extracted three with EtOAc. The EtOAc extract was washed twice with saturated NaHCO3 solution and once with brine, then dried over Na2SO4. Filtration and removal of the solvent gave 1.13 g of a clear oil. The product was purified by flash chromatography with 100% EtOAc to give 0.55 g (72%) of the title alcohol, as a clear oil. TLC Rf = 0.22 (EtOAc, silica gel) PMA

IR (CHCI3) 2999, 2950, 2929, 2856,1734,1244,1195,1183,1112,1105,1065,1043 cm "i.

1 H NMR (270 MHz, CDCIs)

8 7.65 (m, 4)

7.65 (m, 6)

6.81 (s, 1)

6.76 (s, 1)

4.51 (m, 1)

3.62 & 3.60 (2 d, 3, J = 5.3 Hz)

3.49 & 3.46 (2 s, 3)

2.97 (m, 1)

2.65 (m, 2)

2.35 & 2.33 (2 d, 2, J = 6.9 Hz)

2.25 (2 s, 3)

2.16 (2 sec, 3)

1.84 (m, 1)

1.68 (m, 6)

1.55 (m, 1)

1.18 (m, 2)

1.15 (m, 3)

1.00 & 0.99 (2 s, 9)

0.91 (m, 2)

Mass spectrometry (Cl) m / e 663 (M + H) +

C. Acid dilithium salt (SM-iï2-r2- (cvclohexvlméthvD-4.6-diméthvlphénvnéthvlllhvdroxvphosphinvl-3-hvdroxvbutanoïue

0.552 g (1.3 mmol) of diester B was stirred at room temperature in 14 ml of dioxane. 3.9 ml (3.9 mmol) of 1.0N LiOH were added to this solution, then heated the reaction mass to 55 ° C. After 30 min. from agitation, a cake-type precipitate is formed, which was dissolved by adding 5 ml of H2O. After 2 h 15 min. at 55 ° C, the reaction mass was cooled to room temperature, and the volatiles were removed in vacuo leaving a white solid. The product was purified on a 3.0 x 30 cm column of HP-20 resin, eluting first with 100 ml of H2O, then with a 1: 1 CH3OH / H2O mixture. The product fractions obtained were lyophilized to give 0.482 g, 92% yield, of a white lyophilisate.

TLC Rf = 0.36 (7: 2: 1 n-Pr0H / NH40H / H2O, silica gel), PMA.

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

1 H NMR (400 MHz, DaO)

8 6.93 (s, 1)

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)

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)

1.48 (m, 1)

1.15 (m, 3)

1.00 (m, 2)

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CH 675 582 A5

Mass spectrometry (FAB) m / e 397 (M + H-2L +) +, 409 (M + H) +

Analysis: Wedge, for C2iH3iOsPLÌ2.0.76 H2O:

C, 59.76; H, 7.77; P, 7.34 Found: C, 59.76; H, 7.91; P, 7.53

Example 57

Dilithium salt of 4-fnT4'-fluoro-3.3, .5-trimethviï1.1, -biphénvn-2-vnoxvlméthvnhvdroxvohosohinvll-3-hvdroxvbutanoïaue acid

A. 4'-Fluoro-3.3'.5-trimethvlf1.1 '-biphénvn-2-carboxaldéhvde Ref. Merck, U.S. Patent No. 4,375,475, pp. 37 and 38.

The title compound was prepared as described in Parts A to C of Example 1.

B. 4, -Fluoro-3.3'.5-trimethviï1 .1'-biphenvn-2-methanol

Was stirred in 30 ml of dry CH2Cl2 under an argon atmosphere 1.03 g (4.26 mmol) of aldehyde A. A solution, in 20 ml of CH2Cl2, of 1.06 g (5.11 mmol) m-CI-perbenzoic acid was added dropwise over 15 min. to the aldehyde solution at room temperature. After stirring for 58 h at room temperature, the reaction mixture was evaporated on a rotary evaporator to dryness, and the yellow solid obtained was dissolved in THF and treated with 6.4 ml of 2N KOH. This mixture was stirred at room temperature for 5.5 h, then the THF was removed from the reaction mass. The residue obtained was diluted with H2O, and the aqueous solution was extracted three times with Et20, then was dried over MgSO4. The crude yellow oil obtained after filtration and removal of the solvent was purified by flash chromatography eluting with 5% Et 2 O / hexane. The title phenol was obtained as a white solid (0.843 g, 100%).

TLC Rf = 0.37 (10% Et2O / hexane, silica gel) PMA m.p. 83-86 ° C.

IR (KBr) 3512, 3500 (br), 2950,1504,1482,1238, 1231,1215 crrri.

1 H NMR (270 MHz, CDCIs)

8 7.20 (m, 2)

7.07 (t, 1, J = 9.0 Hz)

6.92 (s, 1)

6.82 (s, 1)

4.95 (s, 1)

2.31 (s, 3)

2.25 (s, 6)

Mass spectrometry (Cl) m / e 231 (M + H) +

C. Diethyl ester of rfr4 acid, -fluoro-3.3 / .5-trimethviri.1, -biphénvl1-2-vnoxv1méthvnphosphoniaue

A suspension of NaH washed with pentane (0.30 g, 80% oil dispersion, 10.3 mmol) in 15 ml of dry DMF under an argon atmosphere was cooled in an ice bath. A solution, in 10 ml of DMF, of 2.36 g (10.3 mmol) of phenol B was added to the NaH suspension over 15 min., And a gas evolution was observed. After completion of the addition, the reaction mass was warmed to room temperature and stirred for 35 min. At room temperature, it was added dropwise over 10 min. a solution, in 11 ml of DMF, of 3.31 g (10.26 mmol) of diethyl tosyloxymethylphosphonate (for its preparation, see Holy, A., Rosenberg, I., Collection Czechoslovak Chem. Commun., vol. 47, 1982). After 22 h at room temperature, the reaction was quenched with a saturated aqueous NH4Cl solution, and the DMF was removed in vacuo. The solid obtained was dissolved in EtOAc and H2O, and the aqueous layer was washed twice with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaHCO3 solution and brine, then dried over MgSO4. Filtration and removal of the solvent gave 4.3 g of the crude ether of the title, which was purified by flash chromatography eluting with 70% EtOAc / hexane. The ether of the title (3.2 g, 80%) was obtained in the form of a clear oil.

TLC Rf = 0.52 (50% acetone / hexane, silica gel) PMA.

IR (Film) 2983, 2925, 2910,1504,1474,1213,1032, 971 cm ~ i RM-1H (270 MHz, CDCIs)

8 7.33 (m, 2)

7.01 (t, 1, J = 10.0 Hz)

6.96 (s, 1)

6.91 (s, 1)

4.07 (m, 4)

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CH 675 582 A5

3.69 (d, 2, J = 9.3 Hz)

2.34 (s, 3)

2.31 (d, 3, J = 1.7 Hz)

2.29 (s, 3)

1.31 (t, 6, J = 7.0 Hz)

Mass spectrometry (Cl) m / e 381 (M + H) +, 242 (M + -C4HioP03) +

D. Monoethyl ester of fff4'-fluoro-3.3.5, -trimethvlH.1'-biphenvll-2-vnoxvlméthvnphosphoniaue acid

Stirred with 12.7 ml (12.67 mmol) of 1N LiOH, 3.21 g (8.45 mmol) of dies ter C in 40 ml of dioxane. After 3 h at 70 ° C, the reaction mixture was cooled to room temperature, and the dioxane was removed in vacuo. The aqueous solution was diluted with water and cooled in an ice bath, then acidified to pH approx. 1 with HCl 6N, leaving a milky white solution. This solution was then extracted three times with EtOAc; the EtOAc extract was dried over MgSO4 and filtered to give 3.12 g of a clear gum.

TLC Rf = 0.20 (9 / 0.5 / 0.5 CH2Cl2 / AcOH / MeOH, silica gel) PMA 1 H NMR (270 MHz, CDCI3 S 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)

2.31 (s, 3)

2.29 (s, 3)

2.28 (d, 3, J = 2.2 Hz)

1.28 (t, 3, J = 7.14 Hz)

E. 4-fethoxvrir4, -fluoro-3.3.5, -trimethvlF1.1, -biphenvll-2-vnoxvlmethvnphosphinvn-3-oxobutanoic acid methvlia acid ester

2.96 g (8.42 mmol) of phosphonic acid D in 75 ml of dry CH2Cl2 was stirred at room temperature under an argon atmosphere with 2.44 g (16.84 mmol) of ( C2Hs) 2Si (CH) 3. After 1 h 10 min. stirring, CH2CI2 was removed in vacuo, and the oil obtained was mixed once with benzene to form an azeotrope, then placed under high vacuum for 15 min. This oil was dissolved in 75 ml of dry CH2Cl2 and cooled to 0 ° C under an argon atmosphere. 3 drops of dry DMF were added to the cooled solution, then 1.18 g (9.26 mmol) of oxalyl chloride was added dropwise. The reaction mass was stirred at 0 ° C for 20 min., Warmed to room temperature, and stirred for another 1 hr. The reaction solvent was removed in vacuo, and the phosphonochloridate, as a brown oil, was mixed twice with benzene to form an azeotrope, then placed under high vacuum for 1 h.

The methyl acetoacetate dianion was prepared as described in part C of Example 55 [(methyl acetoacetate (1.27 g, 10.95 mmol), NaH (0.350 g, oil dispersion, 12, 05 mmol), n-butyllithium (4.0 ml of a 2.5M solution in hexane, 10.07 mmol), THF (35 ml)].

The phosphonochloridate prepared as above, in 10 ml of THF, and cooled to -78 ° C, was added dropwise over 20 min. to the dianion solution, also at -78 ° C. After 40 min. with stirring at -78 ° C, the reaction was set at -78 ° C with NH 4 Cl in saturated aqueous solution, and allowed to return to room temperature. The THF was removed in vacuo, and the residue obtained was dissolved in EtOAc and H2O. The aqueous layer was extracted twice with EtOAc, and all of the solutions in EtOAc were combined and washed once with saturated NaHCO3 solution and once with brine, then dried over Na2SO4. The title crude phosphinate was obtained as an orange oil (4.0 g), which was purified by flash chromatography, eluting with 75% EtOAc / he-xane. The title phosphinate (1.4 g, 42%) was obtained as a yellow oil.

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

IR (CHCI3) 3004, 2954, 2935,1744,1718,1643,1541,1503,1472,1449,1438,1425,1236,1037 cm "i. 1 H-NMR (270 MHz, CDCI3)

5 7.30 (m, 2)

6.95 (m, 3)

4.05 & 3.90 (2 m, 2)

3.75 (m, 2)

3.73 & 3.66 (2 s, 3)

3.55 (m, 1)

3.25 (m, 1)

2.33 & 2.29 (2 s (br), 9)

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CH 675 582 A5

1.28 & 1.12 (21.3, J = 7.1 Hz)

Mass spectrometry (Cl) m / e 451 (M + H) +

F. Methyl ester of acid 4-rrfr4, -fluoro-3.3, .5-trimethvin.1, -biphénvll-2-vnoxv1méthvnéthoxvDhosphinvn-3-hvdroxvbutarioïaue

A solution of 1.39 g (3.09 mmol) of ketone E in 15 ml of THF was cooled to 0 ° C. under an argon atmosphere. 0.12 g (3.09 mmol) of NaBH4 was added to the cooled solution, then 2.8 ml of CH3OH was added slowly dropwise. After 1 hour at 0 ° C, the reaction was quenched with acetone, then 1.4 g of CC-4 silica gel, and the reaction mass was warmed to room temperature. The reaction mass was filtered, and the filtrate was evaporated on a rotary evaporator to give a yellow oil. The oil was subjected to flash chromatography, the eluent being 90% EtOAc / hexane, and the fractions containing the product were combined, and the solvent was removed in vacuo. The yellow oil obtained was crystallized from an EfeO / hexane mixture, and the crystals obtained were triturated with an EtaO / hexane mixture to give 0.320 g of white crystals of the alcohol of the title.

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

M.p. 116-119 ° C

IR (KBr) 3288 (br), 3000, 2950, 2920,1735,1503,1473,1440,1311,1232,1195 cm ~ \

1 H NMR (270 MHz, CDCI3)

8 7.28 (m, 2)

7.05 (t, 1, J = 6.0 Mz)

6.98 (s, 1)

6.90 (s, 1)

4.42 (m, 1)

4.05 & 3.85 (m, 2)

3.75 (d, 2, J = 6.0 Hz)

3.70 (s, 3)

2.55 (m, 2)

2.32 (s, 6)

2.30 (s, 3)

2.00 (m, 2)

1.30 (t, 3, J = 7.0 Hz)

Mass spectrometry (Cl) m / e 453 (M + H) +, 435 (M-H2O) -1-

G. Dilithium salt of 4-iïiï4-f [uoro-3.3'.5-trimethviï1.1 '-diphenvll-2-vlloxvlméthvnhvdroxvDhosphinvn-3-hvdroxvbutanoïue

At room temperature, 2.0 ml of 1N LiOH was added to a solution, in 13 ml of dioxane, of 0.293 g (0.65 mmol) of diester F. The reaction mixture was heated to 55 ° C and stirred for 1 h 45 min., then cooled to room temperature. The reaction mixture was evaporated on a rotary evaporator to dryness, and gave a white solid, which was then placed under high vacuum for 10 min. The crude product was purified by chromatography on a 15 cm x 3.0 cm column of HP-20 resin, eluting first with 100 ml of H2O, then with 50% CH3OH / H2O. The pure dilithium salt of the title was obtained in the form of a white lyophilisate (0.295 g, 88%).

TLC Rf = 0.38 (7: 2: 1 n-Pr0H / NH40H / H2O, silica gel) PMA

IR (KBr) 3400 (br), 3021, 3011, 2981, 2958, 2924, 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175, 1087 cm-1

1 H NMR (270 MHz, D2O)

87.20 (m, 2)

7.07 (d, 1, J = 9.9 Hz)

7.03 (s, 1)

6.86 (s, 1)

4.03 (m, 1)

3.40 (d, 2, J = 8.3 Hz)

2.24 (s, 3)

2.21 (s, 3)

2.20 (m, 2)

2.17 (s, 3)

1.45 (m, 2)

Mass spectrometry (FAB) m / e 423 (M + H) +

Analysis: Wedge, for C2oH2206FPLÌ2.0.95 H2O:

C, 54.67 H, 5.48; F, 4.32; P, 7.05 Found: C, 54.37; H, 5.03; F, 4.31; P, 7.5

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CH 675 582 A5

Example 58

4-flT4 / -fluoro-3.3 / .5-trimethviri.1 / -biphénvl-2-vl1méthvl1hydroxyphosphinvlI-3-hvdroxvbutanoïue acid dilithium salt

5

A. 4, -Fluoro-3.3, .5-trimethvin .1 / -biphenvll-2-methanol

To a solution, in 9 ml of absolute EtOH, of 0.12 g (3.18 mmol) of NaBH 4, 0.70 g (2.89 mmol) of the aldehyde A of Example 57 was added under the as a solution in Et20-Et0H (4.5 ml / 3.0 ml). This reaction mixture was stirred at room temperature for 2 h, then fixed with saturated NH4Cl solution. The solid precipitate obtained was removed by filtration. The filtrate was evaporated on a rotary evaporator to dryness, and the solid obtained was dissolved in Et20 and H2O. The aqueous layer was washed twice with Et2O, and the solutions in Et2O, combined, were dried over MgSO4.

After filtration and removal of the solvent, 0.70 g of a white solid was obtained. The solid was purified by flash chromatography, eluting with 33% Et2O / hexane, to give 0.675 g (100% yield) of the title alcohol.

TLC Rf = 0.11 (15% Et20 / hexane, silica gel) PMA.

M.p. 101—102 ° C

IR (KBr) 3351,3293,3267,3260,3024,3016,2980,2939,2921,1605,1601,1502,1451,1355,1243,1236, 20 1228,1189,1118, 999 cm-1.

1 H NMR (270 MHz, CDCI3)

8 7.15 (m, 2)

7.03 (m, 2)

6.90 (s, 1)

25 4.55 (d, 2, J = 6.0 Hz)

2.48 (s, 3)

2.33 (s, 6)

Mass spectrometry (Cl) m / e 244 (M +), 227 (M + -OH)

30 B. Diethyl acid ester IT4'-fluoro-3.3'.5- trimethvlH .1'-biDhénvn-2-vHméthvnphosDhoniaue

A solution, in 50 ml of CH2Cl2, of 1.94 g (7.95 mmol) of alcohol A was cooled to 0 ° C under an argon atmosphere. To this cooled solution was added 0.965 g (9.54 mmol) of Et3N, then 1.00 g (8.75 mmol) of MsCl was added dropwise. The reaction mass was stirred at 0 ° C for 30 min., Then warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaHCOs solution, and the reaction mass was vigorously stirred. The organic layer was washed with saturated NaHCO3 solution, then dried over MgSO4. Filtration and removal of the solvent gave as a clear oil 2.1 g of 2- (chloromethyl) -4'-fluoro-3,3 ', 5-trimethyl [1,1' -bipheny the].

40 CCM Rf = 0.68 (50% Et20 / hexane, silica gel) PMA.

1 H NMR (270 MHz, CDCIs)

8 7.22 (m, 2)

7.03 (m, 2)

6.90 (s, 1)

45 4.50 (s, 2)

2.48 (s, 3)

2.33 (s, 6)

Without carrying out another purification, the above chloride (2.1 g) was stirred for 3 h under an argon atmosphere at 150 ° C with 30 ml of P (OC2Hs) 3. The reaction mass was cooled to room temperature, and the excess P (OC2Hs) 3 was distilled off. The crude product was purified by flash chromatography, eluting with 70% EtOAc / hexane. 2.40 g (83%) of the title phosphonate was obtained in the form of a clear oil.

TLC Rf = 0.37 (70% EtOAc / hexane, silica gel) PMA.

IR (CHCh) 2992, 2928, 2909,1501,1474,1455,1443,1392,1245,1239,1119,1053,1029, 970, 963 cm ~ i. 55 1 H NMR (270 MHz, CDCI3)

8 7.15 (m, 2)

7.00 (m, 2)

6.83 (s, 1)

3.83 (m, 4)

60 3.22 (d, 2, J = 22.52 Hz)

2.47 (s, 3)

2.29 (s, 6)

1.16 (t, 6, J = 7.14 Hz)

Mass spectrometry (Cl) m / e 365 (M + H) +

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CH 675 582 A5

C. Monoethyl ester of acid [T4'-f [uoro-3.3'.5-trimethvl ri.1 / -biDhénvl1-2-vilméthvllDhosphoniaue

2.40 g (6.59 mmol) of the phosphonate diester B were stirred in 30 ml of dioxane at room temperature. 9.9 ml of 1 N LiOH were added to this solution in dioxane, and the mass reaction was heated to reflux. A further 9.9 ml of 1 N LiOH was added at 18 h and 44 h. After 55 h at reflux, the reaction mass was cooled to room temperature, and the dioxane was removed on a rotary evaporator. The aqueous solution obtained was diluted with water and extracted twice with Et2O to remove any residual diester. The aqueous layer was then cooled in an ice bath and acidified to pH approx. 1 with 6N HCl. The milky white solution was extracted three times with EtOAc, the EtOAc extract was dried over MgSO4, filtered, and the solvent was removed to give 1.89 g of a clear oil, with a yield of 85%.

TLC Rf = 0.26 (9 / 0.5 / 0.5, CH2Cl2 / MeOH / AcOH, silica gel) PMA.

IR (CHCI3) 3029, 3023, 3005, 2983, 2925,1710,1605,1500,1234,1042, 988 cm ~ i

1 H NMR (270 MHz, CDCI3)

8 11.07 (s, 1)

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)

2.38 (s, 3)

2.27 (s, 6)

1.13 (t, 3, J = 7.2 Hz).

Mass spectrometry (Cl) m / e 337 (M + H) +

D. 4-Rethoxvrr4, -fluoro-3.3'.5-trimethviri.1'-biphenvn-2-vnmethvnphosphinvn-3-oxobutanoic acid methvlia ester

A solution, in 50 ml of CH2Cl2, of 1.85 g (5.50 mmol) of half acid C under an argon atmosphere was stirred at room temperature for 1 h 15 min. with 1.60 g (11.0 mmol) of (C2Hs) 2NSi (CH3) 3. The CH2Cl2 was removed from the reaction mixture, and the yellow oil obtained was mixed once with benzene to form an azeotrope, and placed under high vacuum for 20 min. This oil, under an argon atmosphere, was dissolved in 50 ml of dry CH2Cl2 and cooled to 0 ° C. 2 drops of dry DMF were added to the cooled solution, then 0.768 g (6.06 mmol) of oxa-lyl chloride was added dropwise: evolution of gas was observed. The reaction mass was stirred at 0 ° C for 20 min., Warmed to room temperature and stirred for another 1 h 40 min .; the reaction took on a dark burgundy hue. The CH2Cl2 was removed from the reaction, and the oil obtained was mixed twice with dry benzene to form an azeotrope, then placed under high vacuum for 1 h.

The methyl acetoacetate dianion was prepared as described in part E of Example 57. Methyl acetoacetate (0.830 g, 7.16 mmol); NaH (0.230 g, oil dispersion, 7.88 mmol); n-BuLi (2.64 ml of a 2.5M solution in hexane, 6.59 mmol); 20 ml of THF.

The phosphonochloridate prepared above, in 10 ml of dry THF cooled to -78 ° C, was added using a cannula, in 20 min., To the solution of the dianion, cooled to -78 ° C. After 40 min. stirring at -78 ° C, the reaction was set at -78 ° C with saturated NH4Cl solution, and the reaction mass was warmed to room temperature; the reaction mixture was diluted with water to dissolve the solids, and the THF was removed on a rotary evaporator. The mixture obtained was extracted three times with EtOAc. The EtOAc extract was washed once with saturated NaHCOs, once with brine, dried over MgSO4 and filtered to give 2.6 g of crude orange oil after removal of the solvent. The crude product was purified by flash chromatography, eluting with 75% EtOAc / hexane. 0.43 g (23%) of ketore D was obtained in the form of an orange foam.

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

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

1 H NMR (270 MHz, CDCI3)

7.20-6.70 (Aromatic H, 5)

4.00-3.70 (m, 2)

3.70 & 3.55 (2 s, 3)

3.35 (m, 2)

3.35 (d, 2, J = 15 Hz)

2.92 (m, 1)

2.45 & 2.35 (2 s, 3)

2.25 (s, 6)

1.15 & 0.95 (21.3, J = 7.0 Hz)

Mass spectrometry (Cl) m / e 435 (M + H) +

120

CH 675 582 A5

E. Methyl ester of 4-rethoxviT4'-fluoro-3.3'.5-trimethvl-ri.1 / -biphénvn-2-vnméthvllphosphinvll-3-hvdroxvbutanoïue acid

0.035 g (0.92 mmol) of solid NaB1-U was added to a solution, in 5 ml of THF, of 0.40 g (0.92 5 mmol) of ketone D under an argon atmosphere. 0.80 ml of methanol was added to the THF solution at room temperature. After 1 h at room temperature, the reaction was fixed with acetone, then 0.4 g of CC-4 silica gel was added. The reaction mixture was filtered, and the solvent was removed. The reaction product still contained some of the starting ketone; therefore, the above reaction product was again subjected to the same reduction conditions described above; however, gaseous CO2 was bubbled through the solution before addition of NaBH4. Treatment as above gave 0.250 g of a yellow oil, which was purified by flash chromatography, eluting with EtOAc. The pure title alcohol was obtained in the form of a clear oil.

TLC Rf = 0.26 (50% acetone / hexane, silica gel) PMA.

1 H NMR (270 MHz, CDCI3)

15 5 7.10 (m, 2)

7.00 (m, 2)

6.85 (s, 1)

4.28 & 4.03 (2 m, 1)

4.10-3.70 (m, 2)

20 3.67 (s, 3)

3.33 (m, 2)

2.47 (s, 3)

2.40 (m, 2)

2.30 (s, 6)

25 1.63 (m, 2)

1.17 (t, 3, J = 6.6 Hz)

F. 4-iïr4'-fluoro-3.3'.5-trimethviï1.1'-biphenvn-2-vnméthvnhvdroxvphosphinvn-3-hvdroxvbutanoïue acid dilithium salt

30

0.110 g (0.252 mmol) of diester E in 5.5 ml of dry CH2Cl2 under an argon atmosphere was cooled to 0 ° C and treated with 0.046 g (0.38 mmol) of collidine, then added dropwise 0.182 g (0.88 mmol) of trimethylsilyl iodide (TMSI). The reaction mass was stirred at 0 ° C for 2 h, then warmed to room temperature. After 24 h, an additional aliquot was added, both collidine (0.023 g) and TMSI (0.091 g). After 48 h of stirring at room temperature, the CH 2 Cl 2 was eliminated, and 6 ml of dioxane and then 1.7 ml of 1N LiOH were added to the oil. This mixture was heated under reflux for 16 h , cooled to room temperature, and the dioxane was removed to leave an orange gum. The gum was dissolved in H2O and filtered through sintered glass to remove the solid. The filtrate was lyophilized to give an off-white lyophilisate, which was purified on a 1.5 cm x 40 cm column of HP-20. The column was eluted first with 150 ml of H2O, then with 50% MeOH / HaO. The product containing fractions were lyophilized to give the title compound as a white lyophilisate (88 mg, 80%).

TLC Rf = 0.38 (7: 2: 1 n-Pr0H / NH40H / H2O, silica gel), PMA.

IR (KBr) 3700-3100 (br), 2923,1591,1501,1234,1147 cm "i 45 1H NMR (270 MHz, DzO)

7.20-7.00 (m, 4)

6.82 (s, 1)

3.76 (m, 1)

3.11 (m, 2)

50 2.35 (s, 3)

2.22 (s, 3)

2.21 (s, 3)

2.05 (m, 2)

1.16 (dd, 2, J = 12.32 Hz, 6.45 Hz)

55 Mass spectrometry (FAB) m / e 407 (M + H) +

Analysis: Calculated for C2oH22FOsPLÌ2-0.80 H20: C, 57.11;

H, 5.65; F, 4.52 P, 7.36 Found: C, 57.11; H, 6.63; F, 4.44; P, 7.70

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CH 675 582 A5

Example 59

Acid dilithium salt (Si-4-iïri-f4-fluorophénv0-3-méthvl-2-naphtalénvnethvrivllhvdroxvphosphinvn-3-hvdroxv-butanoïue

A. Acid 1 -methoxv-2-riaphtaiènecarboxvliaue Reference: J. Organomet. Chem., 20 (1969) p. 251-252.

The mixture was stirred under an argon atmosphere in 42 ml of dry cyclohexane 83.4 ml (208.60 mmol) of a 2.5 M solution of n-BuLi in hexane, Aldrich. This solution was cooled to 0 ° C and treated dropwise (10 minutes) with 24.4 g (208.6 mmol, 31.48 ml) of distilled tetramethylethylenediamine (TMEDA). The suspension obtained was stirred at 0 ° C for 30 minutes, then treated dropwise in 20 minutes with a solution of 33 g (208.60 mmol, 30.28 ml) of 1-methoxynaphthalene (Aldrich Chem. Co., used without further purification) in 84 ml of dry cyclohexane. The homogeneous brilliant red reaction mixture obtained was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C. and added in portions, over 30 minutes and using a cannula, to a solution, at -78 ° C., of 250 ml of dry Et 2 O saturated with CO2 gas (pellets of CO2, sublimated through a dryer tube containing SÌO2, bubbling in dry Et2Û at -78 ° C). The white suspension obtained was heated to about 0 ° C for 45 minutes, then treated with 450 ml of a 5% aqueous HCl solution. The EtzO layer was separated, and the aqueous layer was extracted three times with Et20. The organic extracts were combined and extracted with 3 x 150 ml of a saturated aqueous solution of NaHCO3. The aqueous layer was filtered through a sintered glass funnel to remove the insolubles, and the filtrate was cooled to 0 ° C and slowly acidified to pH 1 with concentrated HCl. The precipitate obtained was filtered, mixed with 2 x 150 ml of toluene to form an azeotrope, dried under high vacuum at 50 ° C for 5 hours to give 32.52 g (0.161 mole, 77% yield) of the acid 1 -methoxy-2-naphtha! encarboxylic in the form of an off-white powder, mp 118-121.5 ° C.

TLC: silica gel, Rf = 0.35 94: 5: 1 / CH2Cl2: Me0H: CH3C02H 1 H NMR: (270 MHz, CDCI3) NMR-13C compatible: (67.8 MHz, CDCIs) compatible Mass spectrometry: Cl m / e 203+ (M + H) +

IR: Br compatible

B. N-f2-Hvdroxv-1.1 -dimethvlethvlV1 -methoxv-2-naphthalenecarboxamide

Stirred under an argon atmosphere in 150 ml of dry CH2Cl2 31.4 g (155.22 mmol) of 1-methoxy-2-naphthalenecarboxylic acid. The solution was then treated with 36.94 g (310.44 mmol, 22.65 ml) of SOCI2. The reaction mixture was stirred at room temperature for 45 minutes, then heated to reflux in an oil bath at 55 ° C for 45 minutes. The reaction mixture was cooled to room temperature and treated with an additional amount (18.47 g, 11.32 ml) of thionyl chloride, then it was again heated at reflux for 45 minutes. The reaction mixture was cooled to room temperature, the excess CH2Cl2 and SOCI2 were removed by evaporation on a rotary evaporator at 35 ° C (purge with argon atmosphere), and the mustard yellow solid obtained was dissolved under an argon atmosphere in 155 ml of dry CH2Cl2. This solution was transferred using a cannula into an addition funnel, and added dropwise over 40 minutes to a solution of 27.67 g (310.44 mmol) of 2-amino-2-methyl. -propanol in 150 ml of dry CH2Cl2, which had been stirred under an argon atmosphere at 0 ° C. The reaction mixture obtained was warmed to room temperature and stirred for 18 hours. Then the reaction mixture was filtered, the precipitate was washed with CH2Cl2 and the filtrate was evaporated in vacuo. The residue was redissolved in 350 ml of EtOAc and washed with 1 x 250 ml of H2O, 1 x 250 ml of 5% HCl, 1 x 250 ml of 5% NaOH and 101 x 250 ml of brine. The aqueous extracts were each re-extracted once with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and evaporated in vacuo to give an orange oil, which formed an azeotrope with 250 ml of toluene and which was pumped under high vacuum at 55 ° C for 8 hours to give 38.2 g (139.76 mmol, 90% yield) of the title naphthalamide as a light yellow solid.

TLC: silica gel, Rf = 0.65 100% EtOAc 1 H NMR (270 MHZ, CDCI3)

8 8.19 (s, br, 1H)

8.14 (m, 1H)

8.03 (d, 1H, J = 8.7 Hz)

7.83 (m, 1H)

7.66 (d, 1H, J = 8.7 Hz)

7.55 (m, 2H)

4.00 (s, 3H)

3.74 (s, 2H)

1.47 (s, 6H)

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CH 675 582 A5

Mass spectrometry: Cl m / e 274 (M + H) +

IR: (solution in CHCI3) 3365, 3063, 3024, 3005, 2971, 2938, 2873, 1641, 1597, 1540, 1456, 1446, 1387, 1371,1344, 1291,1256,1238,1223, 1210,1199,1183 , 1168, 1145.1079, 981, 833 cm "i

C. 4.5-Dihvdro-2- (1-methoxv-2-naphthalenvli-4.4-dimethvloxazole

Stirred under an argon atmosphere and cooled to 0 ° C, while adding dropwise over 15 minutes 66.15 g (40.56 ml) of thionyl chloride, 38.2 g (139 mmol) of naphthalamide B The dark brown oil obtained was stirred at room temperature for 45 minutes. 500 ml of dry E 4 O were added, and the reaction mixture was subjected to mechanical stirring for 2.5 hours. The yellow crystalline precipitate obtained was filtered, washed with Et20 and then suspended in 250 ml of Et2O. The suspension was cooled to 0 ° C and basified with about 200 ml of 10% NaOH. The aqueous layer was extracted 3 times with Et20 and once with EtOAc. The organic extracts were combined, washed once with brine, concentrated, dried over MgsO4 and filtered. The filtrate formed an azeotrope with toluene under vacuum, and the residue was pumped under high vacuum at 55 ° C for 8 hours to give 32.10 g (0.126 mole, 90% yield) of the title oxazoline in the form of a golden powder.

TLC: silica gel Rf = 0.37 50% EtOAc

1 H NMR: (270 MHz, CDCIs)

S 8.25 (m, 1H)

7.84 (d, 1H, J = 8.7 Hz)

7.84 (m, 1H)

7.60 (d, 1 H, J = 8.7 Hz)

7.54 (m, 2H)

4.19 (s, 2H)

4.04 (s, 3H)

1.46 (s, 6H)

Mass spectrometry: Cl m / e 256 (M + H) +

IR: 2969, 2935, 2896,1642,1465,1447,1386,1372,1349,1255,1109,1074, 991 cm ~ i

D. 2-ri- (4-FluoroDhénvli-2-naphtalénvlYI-4.5-dihvdro-4.4-dimethvloxazole

Stirred under an argon atmosphere in 252.5 ml of dry THF 30.0 g (117.52 mmol) of oxazoline C. This solution was heated to 45 ° C in an oil bath. The heat source was removed, and a 2M solution of 4-fluorophenylmagnesium bromide in EtaO (Aldrich) (158.65 mmol, 79.33 ml) was added dropwise over 30 minutes, at a rate sufficient to maintain at about 45 ° C the reaction temperature. After completion of the addition, the reaction temperature was maintained at 45 ° C while stirring the reaction mixture for 18 hours. The reaction mixture was cooled to 0 ° C and fixed with 200 ml of a saturated aqueous NH4Cl solution, and diluted with 200 ml of H2O and 200 ml of EtOAc. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, concentrated, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give 39 g of a dark gold solid. The product was purified by flash chromatography (95 mm diameter column, 7 "Merck silica gel (178 mm), eluent 25% EtOAc / hexane, flow rate (51 mm) 2" / minute) to give 30.42 g ( 95.25 mmol, yield 81%) of the 4-fluorophenyl-substituted naphthalene of the title in the form of a pale yellow solid, mp 94-96 ° C. There was also obtained 3.38 g (10.58 mmol, 9%) of a somewhat impure product.

TLC: silica gel Rf = 0.45 50% EtOAc / hexane

1 H NMR: (270 MHz, CDCI3)

8 7.93-7.13 (aromatic, 10 H)

3.77 (s, 2H)

1.27 (s, 6H)

Mass spectrometry: Cl m / e 320 (M + H) +

IR: (KBr) 3060,2966,2927,2884,1667,1603,1508,1462,1383,1354,1335,1293,1219,1185,1160,1119, 1083, 978, 842, 830 cm-1

E. 2-ri-f4-Fluorophenvn-3-methvl-2-naohtalénvffl-4.5-dihvdro-4.4-dimethvloxazole

Stirred under an argon atmosphere in 585 ml of dry Et 2 O 28 g (87.67 mmol) of compound 1-4-fluorophenyl-2-oxazoline-naphthyl D. This solution was cooled to 25 ° C. and treated dropwise. drop in 1 hour with 56.1 ml (140.27 mmol) of a 2.5 M solution of n-BuLi in hexane. The reaction mixture is passed, during this addition of one hour, from a homogeneous yellow solution to an orange / dark red solution, then to an orange / green solution, with precipitation. The reaction mixture was stirred at -25 ° C for an additional 2.5 hours, then it was treated with 37.33 g (263.01 mmol, 16.4 ml) of iodomethane added dropwise over 15 minutes. The dark burgundy solution obtained was stirred at -25 ° C for 4.5 hours, heated to 0 ° C and stirred for 16 hours, finally being heated to room temperature and stirred for 7 hours. The yellow transparent solution obtained was fixed with 500 ml

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CH 675 582 A5

brine at ice temperature. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, concentrated, dried over MgSO4 and filtered through Florisil (sintered glass funnel, 300 ml, 2/3 filled). Florisil was washed with CH2CI2. The filtrate was concentrated, mixed with toluene to form an azeotrope and evaporated in vacuo, then pumped under high vacuum at 55 ° C for 3 hours to give 30.32 g (90.94 mmol, 100% yield) of the methylated naphthalene of the title, in the form of a yellow solid.

TLC: silica gel Rf = 0.50 50% EtOAc / hexane 1 H NMR: (270 MHz, CDCI3)

S 7.79-7.07 (aromatic, 9H)

3.80 (s, 2H)

2.54 (s, 3H)

1.13 (s, 6H)

Mass spectrometry: Cl m / e 334 (M + H) +

IR: (solution in CHCI3)

3013, 2967, 2931, 2895, 2870,1667,1605,1513,1497,1461,1299,1280,1235,1190,1158,1041, 965, 841 cm ~ i

F. 2-H -f4-fluoroDhenvlV3-methvl-2-naDhtalénvlïl-4.5-dihvdro-3.4.4-trimethvloxazolium lodide

Stirred under an argon atmosphere in 140.28 ml of nitromethane 29.23 g (87.67 mmol) of oxazoline E. This solution was treated in one portion with 112 g (0.789 mole, 49.2 ml ) iodomethane. The brown reaction mixture obtained was heated in an oil bath at 60 ° C for 1 hour 20 minutes protected from light. The iodomethane was removed by simple distillation. The nitromethane was removed by evaporation on a rotary evaporator, followed by pumping under high vacuum for 45 minutes. The burgundy solid obtained was mechanically stirred for 1 hour in 250 ml of dry Et20. The red filtrate was decanted, and the solids were again triturated in PEt20, as above. The yellow solid obtained was filtered and pumped under high vacuum for 4 hours (protected from light) to give 44 g (92.63 mmol, 100% yield) of the title oxazolinium iodide, in the form of a solid mustard yellow. The title compound was stored protected from light at -30 ° C for 18 hours,

then it was directly used for the preparation of compound G.

TLC: silica gel Rf = 0.30 10% MeOH / CH2CI2

G. 1 -C4-FliJoroDhénvl) -3-méthvl-2-naphtalènecarboxaldéhvde

41.67 g (87.67 mmol) of oxazolinium iodide F were stirred under an argon atmosphere in 526 ml of dry THF and 210 ml of absolute EtOH (dried on a 4A molecular sieve). This solution / suspension was cooled to -15 ° C and treated in portions with NaBH4 for one hour. After completion of the addition, the reaction solution was stirred for 2.5 hours at a temperature of -10 to -15 ° C.

Then the solution was diluted with 210 ml of absolute EtOH, and the reaction mixture was stirred at -15 ° C, while adding dropwise over 45 minutes (very slow addition at the start) 438 ml (876 mmol )

of 2N HCl. After completion of the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. Then the dilution with 500 ml of H2O was followed by an aqueous extraction with Et20. The organic extracts were combined, concentrated, dried over MgSO4, filtered, concentrated, mixed with 2 x 120 ml of toluene to form an azeotrope, and rectified under vacuum to give 12.9 g (48.81 mmol, yield 56% ) of the title aldehyde as a pale yellow solid.

TLC: silica gel Rf = 0.66 50% EtOAc / hexane 1 H NMR: (270 MHz, CDCIs)

510.0 (s, 1 H)

7.83-7.18 (aromatic, 9H)

2.81 (s, 3H)

Mass spectrometry: CI m / e 265 (M + H) +

IR: (solution in CHCI3)

1685.1512.1237, 862 cm-1

H. 2- (2.2-Dibromoethénvn-1 - (4-fluoroDhénvh-3-méthvlnaphtalène

The mixture was stirred under an argon atmosphere in 113.5 ml of dry CH2Cl2 3.0 g (11.35 mmol) of aldehyde G.

This solution was cooled to 0 ° C, then treated in one portion with 9.53 g (36.32 mmol) of triphenylphosphine. The reaction mixture was stirred at 0 ° C for 20 minutes, then treated dropwise in 20 minutes with a solution of 6.02 g (18.16 mmol) of carbon tetrabromide in 41 ml of dry CH2Cl2. The dark orange solution obtained took on a dark burgundy shade after stirring for 1 hour 1/4 at 0 ° C. Then the reaction mixture was fixed with 150 ml of a saturated aqueous solution of NaHCOs. The aqueous layer was extracted 4 times with CH2Cl2. The organic extracts were combined, concentrated in vacuo, washed once with brine, dried over MgSCU and filtered. The filtrate was

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CH 675 582 A5

pre-absorbed on about 28 g of Merck silica gel, then it was applied to a 50 mm flash chromatography column containing 6 "Merck silica gel (152 mm), the eluent being 7% EtOAc / hexane, flow rate (51 mm) 2 "/ minute, to give 4.23 g of the title dibromoolefin as a slightly impure pale yellow solid. Subsequent recrystallization from hexane gave 3.68 g (8.77 mmol, 77% yield) of the title dibromoolefin as a white powdery solid, m.p. 134.5-135.5 ° C.

TLC: silica gel Rf = 0.60 20% EtOAc / hexane 1 H NMR: 270 MHz, CDCI3)

8 7.79-7.11 (aromatic olefinic, 10H)

2.48 (s, 3H)

Mass spectrometry: Cl m / e 419/421/423 (M + H) + IR: (solution in CHCI3)

3016, 1604.1515, 1496.1234, 1220, 1208, 1158, 886, 858 cm-1

I. 2-Ethvnvl-1- (4-fluorophénvn-3-méthvlnaDhtalène

Stirred under an argon atmosphere in 47.9 ml of dry THF 3.69 g (8.7 mmol) of dibromeo-olefin H. This solution was cooled to -78 ° C, then treated dropwise. drop in 15 minutes with 6.96 ml (17.4 mmol) of a 2.5 M solution of n-BuLi in hexane - Aldrich. The reaction mixture was stirred at -78 ° C for 1 hour, then it was fixed with 40 ml of a saturated aqueous NH4Cl solution. After heating to 0 ° C, the reaction mixture was diluted with 40 ml of H2O and 40 ml of Et20. The aqueous phase was extracted twice with Et20 and once with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and the solvent was evaporated in vacuo. Initial purification by flash chromatography (50 mm diameter column, 6 "Merck silica gel (152 mm), eluent 7% EtOAc / hexane, flow rate (51 mm) 2" / minute) gave 2.32 g of a solid green oil. 270 MHz H-NMR showed that it was an impure product. A repurification by flash chromatography (column of diameter 75 mm, Merck silica gel 6 "(152 mm), eluting 1% EtOAc / hexane, flow rate (51 mm) 2" / minute) gave 2.11 g (8, 11 mmol, yield 93%) of the acetylene of the title in the form of a pale blue solid (pumping under high vacuum for 8 hours), pf 91.5-94.5 ° C.

TLC: silica gel, PMA, Rf = 0.56 20% EtOAc / hexane 1 H NMR: (270 MHz, CDCIs)

8 7.77-7.13 (aromatic, 9H)

3.18 (s, 1 H)

2.62 (s, 3H)

Mass spectrometry: CI m / e 260 M +

IR: (CH2CI2 film)

3291,1604,1512,1494,1383,1222,1158,1150,1092, 884, 871, 853, 825cm-i

J. fSi-3-iï (1.1-dimethvl-ethvndiphénvlsilvnoxvI-4-iïri-f4-fluorophénvn-3-methvl-2-naphthalenvnethvnvnmethoxvphosphinvllbutanoïa acid methvlia ester

5.57 g (8.82 mmol) of the dicyclohexylamine salt of Example 25 was partitioned between a 1: 1 mixture of 5% Et0Ac / KHS04 (150 ml each) and vigorously shaken. The layers were separated, and the EtOAc layer was washed with 2 x 100 ml of fresh 5% KHSO4. Finally, the organic phase was dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue obtained was mixed with 2 x 120 ml of benzene to form an azeotrope, evaporated and pumped under high vacuum for 2 hours to give 4.33 g (yield 109%) of the phosphonate monoester in the form of a pale yellow oil viscous. This oil was stirred under an argon atmosphere in 24.8 ml of dry CH2Cl2 and treated dropwise over 8 minutes with 2.56 g (17.64 mmol, 3.34 ml) of distilled diethyltrimethylsilylamine. This solution was stirred at room temperature for 2 hours. Then the volatiles were removed on a rotary evaporator (argon purge), and the residue obtained was mixed with 1 x 60 ml of dry benzene to form an azeotrope, evaporated in vacuo and pumped under high vacuum for 45 minutes. The residue was then stirred under an argon atmosphere in 24.8 ml of dry CH2Cl2. Two drops of DMF were added, and the solution was cooled to 0 ° C. 1.34 g (10.58 mmol, 0.923 ml) of oxalyl chloride was added dropwise over 10 minutes. The solution obtained was stirred at 0 ° C for 30 minutes, warmed to room temperature and stirred for 2 hours. The volatiles were removed, the residue formed an azeotrope, and it was pumped under high vacuum as above. Finally, the residue was stirred under an argon atmosphere in 27.7 ml of dry THF. This solution was cooled to -78 ° C and treated dropwise in 15 minutes with a solution at -78 ° C, in THF, of the acetylene anion formed, and added as follows to the phosphonochloridate.

Stirred under an argon atmosphere in 27.7 ml of dry THF and cooled to -78 ° C, 1.35 g (5.19 mmol) of acetylene I. This solution was treated dropwise in 10 minutes with 2.08 ml (5.19 mmol) of a 2.5M solution of n-BuLi in hexane. The green solution obtained was stirred at -78 ° C for 1.5 hours, heated to 0 ° C for 15 minutes and cooled to -78 ° C. This solution was kept at -78 ° C while being poured in portions into an addition funnel, and added dropwise to the solution.

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CH 675 582 A5

at -78 ° C, in THF, of the phosphonochloridate formed above. After completion of the addition, the reaction mixture was stirred at -78 ° C for 1 hour, then fixed with 50 ml of a saturated aqueous NH4Cl solution and heated to 0 ° C. Then the reaction mixture was diluted with 40 ml of H2O and 40 ml of Et2 <D. The aqueous layer was extracted with 4 x 50 ml of Et2O. The organic extracts were combined, concentrated, dried over MgSCU, filtered and the solvent was removed in vacuo. The product was isolated by flash chromatography (75 mm diameter column, 6 "Merck silica gel (152 mm), eluent 5: 4: 1 hexane: EtOAc: toluene, flow rate (51 mm) 2" / minute) to give 1.53 g (2.21 mmol, yield 43%) of the acetylenic phosphinate of the title in the form of a yellow foam. 0.589 g of an impure starting material were also recovered.

TLC: silica gel, PMA, Rf = 0.26.5: 4: 1 hexane: EtOAc: toluene

1 H NMR: (270 MHz, CDCI3)

8 7.82-7.0.9 (aromatic, 19H)

4.52 (m, 1H)

3.60 & 3.59 (2 x s, 3H)

3.36 & 3.31 (2 x d, 3H, J = 11.5 Hz)

2.54 & 2.49 (2 x s, 3H)

2 2.87-2.73 (m, 1H)

2.61-2.56 (m, 1H)

2.39-2.22 (m, 1H)

2.12-2.00 (m, 1H)

1.02 (s, 9H)

Mass spectrometry: CI m / e 693 (M + H) +

IR: (solution in CHCI3)

3004.2951.2932.2858.2164,1735,1605,1512,1494,1472,1437,1427,1237,1197,1182,1158,1151,1138, 1110,1105,1093, 1038,1017, 951, 885, 834 cm ~ i

K. fSV4-iïri -C4-fluoro-DhenvlV3-methvl-2-naphthalenvnethvnvHmethoxv-phosDhinvn-3-hvdroxvbutano'faue acid methvlia ester

0.60 g (0.866 mmol) of acetylene phosphinate J was stirred under argon in 10.5 ml of dry THF and treated with 0.208 g (3.46 mmol, 0.198 ml) of glacial acetic acid, this treatment being followed by a dropwise addition of 2.36 ml (2.60 mmol) of a solution of 1.1M tetrabutyiammonium fluoride in THF. The reaction mixture was stirred at room temperature for 24 hours, then fixed with 25 ml of ice water and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The organic extracts were combined, washed once with saturated aqueous NaHCO3 solution and once with brine, dried over MgSO4, filtered and evaporated in vacuo. The product was purified by flash chromatography using a 30 mm diameter column; Merck 35: 1 silica gel, 100% EtOAC eluent and a flow rate of (51 mm) 2 "/ minute to give 0.267 g (0.588 mmol, yield 68%) of the title ß-hydroxyphosphinate, in the form a pale yellow foam.

TLC: silica gel, PMA Rf = 0.28 100% EtOAc

1 H NMR: (270 MHz, CDCI3)

8 7.81-7.18 (aromatic, 9H)

4.38 (m, 1H)

3.71 (s, 3H)

3.59 & 3.58 (2 x d, 3H, J = 12 Hz)

2.66 & 2.65 (2 x s, 3H)

2.62-2.52 (m, 2H)

2.19-1.92 (m, 2H)

Mass spectrometry: Cl m / e 455 (M + H) + IR: (film)

3380 (wide), 3065, 3048, 2993, 2951, 2166,1738,1604,1513,1495,1457,1438,1423,1401,1385,1378, 1334,1299,1222, 1179,1160,1138,1095,1035 , 951, 887, 836 cirH

L. acid dilithium salt fSM-HI-f4-fluoro-phenvh-3-methvl-2-naphthalenvnethvnvnhvdroxv-phosphinvn-3-hvdroxvbutanoi'aue

0.265 g (0.583 mmol) of diester K was stirred under an argon atmosphere in 6 ml of dioxane and treated with 1.75 ml (1.75 mmol) of 1N LiOH. The reaction mixture was heated in a water bath. oil at 70 ° C for 45 minutes. The reaction mixture was cooled to room temperature. The solvents were removed on a rotary evaporator, then pumped under high vacuum for 1 hour. The white solid obtained was dissolved in 4 ml of distilled water and applied to an HP-20 resin chromatography column (2.5 cm x 17.0 cm, equilibrated with H2O). The column was eluted with 250 ml of Î-feO, then with a 45:55 10 MeOH: H2O mixture. The fractions were collected every 1.3 minutes (about 10 ml). The product-containing fractions were evaporated in vacuo at 35 ° C, lyophilized and pumped under high vacuum over P2O5 for 8 hours to give 0.237 g (0.541 mmol, yield 93%) of the dilithium salt of phosphinic acid of titled, in the form of a white lyophilisate.

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CH 675 582 A5

TLC: silica gel, PMA Rf = 0.40 7: 2: 1 n-C3H70H / NH40H / H2O

1 H NMR: (400 MHz, D20)

8 7.88 (d, 1 H, J = 8.43 HZ)

7.80 (s, 1 H)

7.58-7.29 (aromatic, 7H)

4.14-4.05 (m, 1H)

2.61 (s, 3H)

2.43 (dd, 1 H, J = 3.67, J = 15.39)

2.21 (dd, 1 H, J = 9.16, J = 15.39)

1.84-1.67 (m, 2H)

Mass spectrometry: FAB m / e 439 (M + 2 Li) + IR: (KBr) 3443-3260 (large), 3066, 2164, 1594, 1512, 1495, 1434,1222, 1183,1160, 1071, 834 cm "i

Analysis: Calculated for C23Hi8F05PLÌ2 + 0.66 mole H20 Molecular mass = 450.14: C, 61.38; H, 4.33; F, 4.22; P, 6.88 Found: C, 61.38; H, 4.07; F, 4.42; P, 6.80

Example 60

FEÌ-4-ff2-ri- (4-fluorophenvli-3-methvl-2-naphthalenvllethenvllhvdroxvDhosphinvll-3-hvdroxv-butanoic acid dilithium salt

A. 2-1 - (4-fluorophenvlV3-methvl-2-naphthalenvll-2-hvdroxvethvn-phosphoniaue acid dimethvlia ester of 2-1 acid

Stirred under argon in 47 ml of dry THF 3.0 g (24.21 mmol, 2.62 ml) of dimethyl methylphosphonate. This solution was cooled to -78 ° C, then treated dropwise over 15 minutes with 9.08 ml (22.70 mmol) of a 2.5 M solution of n-BuLi in hexane. This reaction mixture was stirred at -78 ° C for 1.5 hours, then the milky solution obtained was treated dropwise in 15 minutes with a solution of 4.0 g (15.13 mmol) of aldehyde G of Example 59 in 14 ml of dry THF. This reaction mixture was stirred at -78 ° C for 45 minutes. Finally, the reaction mixture was fixed with 50 ml of a saturated aqueous NH4Cl solution, heated to room temperature, diluted with 50 ml of H20 and 50 ml of EtOAc. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, concentrated, mixed twice with toluene to form an azeotrope, evaporated in vacuo and pumped under high vacuum to give 5.90g (15.13 mmol, yield 100%) phosphonate of the title as a yellow solid, which was directly used in the preparation of compound B.

TLC: silica gel, PMA Rf = 0.37 50% acetone / hexane

B. Dimethyl acid ester (EH2-H- (4-fluoro-phenvfl-3-méthvl-2-naphtalénvHéthénvHphosDhoniaue

It was stirred under an argon atmosphere in 66.5 ml of dry toluene 5.5 g (14.16 mmol) of ß-hydroxyphosphonate A. This solution was treated with 0.673 g (3.54 mmol) of para acid -toluenesulfonic monohydrate (TsOH- H2O). The reaction mixture was heated to reflux in an oil bath at 135 ° C. The condensate was passed through a soxhlet containing a dry 4 Å molecular sieve. After 16 hours at reflux, another 0.404 g (2.12 mmol) of TsOH-H2O was added, and the reaction mixture was heated as above for another 8.5 hours. The reaction mixture was cooled to room temperature and diluted with 100 ml of EtOAc. Then the mixture was washed with 100 ml of a saturated aqueous solution of NaHCOs. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and evaporated in vacuo to give 4.22 g of crude vi-nylphosphonate as a brown solid. The aqueous layer was acidified with 5% HCl, then extracted 3 times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and evaporated to give 1.4 g (3.92 mmol) of the vinyl phosphonate monoester as a light brown solid. This solid was stirred under an argon atmosphere in 15 ml of trimethyl orthoformate and heated to reflux in an oil bath at 120 ° C for 16 hours. The reaction mixture was cooled to room temperature. The excess trimethyl orthoformate was removed in vacuo, and the residue was combined with 4.22 g of crude vinylphosphonate (above). The product was purified by flash chromatography (75 mm diameter column, 6 "Merck silica gel (152 mm), eluent 100% EtOAC, flow rate (51 mm) 2" / minute) to give 3.70 g (9 , 99 mmol, yield 71%) of the vinyl phosphonate of the title, in the form of a peach-colored solid.

TLC: silica gel, PMA Rf = 0.48 100% EtOAc

1 H NMR: (270 MHz, CDCI3)

8 7.79 (d, 1H, J = 8.4 Hz)

7.72 (s, 1 H)

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7.56-7.13 (m, 8H)

5.54 (dd, 1H, J = 17.93 HZ, J = 20.6 Hz)

3.57 (d, 6H, J = 11 Hz)

2.54 (s, 3H)

Mass spectrometry: CI m / e 371 (M + H) +

IR: (solution in CHCI3)

3016, 2956, 2857,1617,1521,1500,1245,1188,1162,1071,1047, 834cm "i

C. Monomethyl ester of acid (EVr2-H- (4-fluoroDhénvn-3-méthvl-2-naphtalénvnéthenvnDhosphoniaue

3.60 g (9.72 mmol) of the vinylphosphonate were stirred under an argon atmosphere in 23.5 ml of dioxane and treated with 23.32 ml (23.32 mmol) of 1N LiOH. The reaction mixture was heated in an oil bath at 75 ° C for 1 hour. Then the reaction mixture was cooled to room temperature, and the solvents were removed in vacuo. The residue obtained was diluted with 15 ml of water, cooled to 0 ° C and acidified to pH 1 with a 5% aqueous HCl solution. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, concentrated, mixed twice with benzene to form an azeotrope, and evaporated in vacuo to give 3.38 g (9.48 mmol, yield 98%) of the phosphonate monoester of the title in the form of a solid peach. TLC: silica gel, PMA, Rf = 0.41 10: 1: 1 CH2Cl2 / Me0H / CH3C02H 1 H NMR: (270 MHz, CDCI3)

8 7.76 (d, 1 H, J = 8.4 Hz)

7.68 (s, 1 H)

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)

2.52 (s, 3H)

Mass spectrometry: FAB m / e 357 (M + H) +

IR: (solution in CHCI3)

3025, 3008, 2951,1614,1605,1511,1494,1235,1210,1188,1158,1050, 987, 833 cm "i

D. Methyl ester of fEÎ-4-iï2-H- (4-fluoroDhénvl-3-méthvl-2-naphtalénvlléthénvnméthoxvDhosphinvn-3-oxobutanoïaue acid

3.29 g (9.12 mmol) of monoesterphosphonate C were stirred under an argon atmosphere in 60 ml of dry CH2Cl2 and treated dropwise in 10 minutes with 2.65 g (18.24 mmol, 3.45 ml , distilled) of trimethylsilyidiethylamine (TMSDEA). The reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed on a rotary evaporator (purge with argon atmosphere), and the residue was pumped under high vacuum for 40 minutes. The residue was then stirred under an argon atmosphere in 25 ml of dry CH2Cl2. This solution was cooled to 0 ° C., treated with 2 drops of dry DMF, this treatment being followed by a dropwise addition over 15 minutes of 1.39 g (10.94 mmol, 0.955 ml) of chloride. oxalyl. The reaction mixture was stirred at 0 ° C for 20 minutes, then warmed to room temperature and stirred for 1 hour. The volatiles were removed, and the residue was pumped out as above. Finally, the residue was stirred under an argon atmosphere in 25 ml of dry THF, cooled to -78 ° C and kept at -78 ° C, while this solution was transferred using a cannula into a addition funnel and added dropwise for 20 minutes to a solution at -78 ° C, in THF, of dianion of methyl acetoacetate. This dianion was produced in the following way: 0.317 g (13.22 mmol, 0.317 g of an 80% dispersion in mineral oil) of NaOH was washed once with pentane, dried under a stream of argon , then stirred under an argon atmosphere in 20 ml of dry THF. This suspension was cooled to 0 ° C and treated dropwise for 10 minutes with a solution of 1.43 g (12.31 mmol, 1.33 ml) of methyl acetoacetate in 10 ml of dry THF. The clear solution obtained was stirred at 0 ° C for 20 minutes, then treated dropwise for 10 minutes with 4.56 ml (11.40 mmol) of a suspension of 2.5 M n-BuLi in 1 'hexane. The yellow solution obtained was stirred at 0 ° C for 45 minutes, then cooled to -78 ° C and treated dropwise with the solution at -78 ° C, in THF, of the phosphonochloridate formed above. After completion of the addition, the reaction mixture was stirred at -78 ° C for 45 minutes. Then the reaction was fixed with 50 ml of a saturated aqueous NH4Cl solution, heated to room temperature, diluted with 50 ml of H2O and 50 ml of EtOAc. The aqueous layer was extracted 3 times with an aqueous solution of NaHCO 3 and once with CH 2 Cl 2. The organic extracts were combined, washed 3 times with saturated aqueous NaHCO 3 solution and once with brine, dried over MgSO 4, filtered and evaporated in vacuo to give 4.0 g of a rust-colored foam. Initial purification by flash chromatography (40 mm diameter column, Merck 20: 1 silica gel, eluent 100% EtOAc, flow rate (51 mm) 2 "/ minute) gave 2.0 g of the title ketophosphinate, somewhat impure, in the form of an orange oil. Subsequent chromatography (column 30 mm in diameter, silica gel

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Merck 25: 1, eluting 25% EtOAc / hexane, flow rate (51 mm) 2 "/ minute) gave 1.95 g (4.29 mmol, yield 47%) of the title keto-phosphinate, under the form of an orange moss.

TLC: silica gel, PMA Rf = 0.29 100% EtOAc 1 H NMR: (270 MHz, CDCIs)

5 8 7.78-7.13 (aromatic, olefinic, 10H)

5.62 (dd, 1H, J = 17.93 Hz, J = 25.84 Hz)

3.71 (s, 3H)

3.63 (S, 2H)

3.48 (d, 3H, J = 11.6 Hz)

10 3.14 & 3.13 (2 x d, 2H, J = 18.46 Hz)

2.44 (s, 3H).

Mass spectrometry: Cl m / e 455 (M + H) +

IR: (film)

1749, 1717,1623, 1614,1604, 1511,1328, 1223,1159, 1031,834 cm-1

15

E. Methyl ester of the acid (EI-4-i2-ri- (4-fluorophenvn-3-methvl-2-naphthalenvl1ethenvn-methoxvphosphinvn-3-hvdroxv-butanoïoue

It was stirred under an argon atmosphere in 12 ml of dry THF 1.28 g (2.82 mmol) of ketophosphinate D. This solution was cooled to 0 ° C. and treated with 0.107 g (2.82 mmol) of NaBH4, this treatment being followed by a dropwise addition of 2.45 ml of dried methanol on a 4 Å molecular sieve. The reaction mixture was stirred at 0 ° C for 1 hour, then fixed with 2.5 ml of acetone. 1.3 g of CC-4 silica gel (Mallinckrodt) was added, and the reaction mixture was stirred while being warmed to room temperature. Finally, the suspension was filtered through a sintered funnel, washed twice with 25 EtOAc and twice with CH2Cl2. The filtrate was evaporated in vacuo to give 1.3 g of an orange foam, which crystallized after addition of EtOAC. The product was purified by flash chromatography (column 30 mm in diameter, Merck silica gel 30: 1, eluent 3% MeOH / CH2Cl2, flow rate (51 mm) 2 "/ minute). The fractions containing the product were combined , evaporated and mixed once with benzene to form an azeotrope, to give in the form of a pale yellow solid 0.653 g (1.43 mmol, yield 51%) of the hydroxyphosphinate of the title. was triturated in a 7: 3 mixture of EtOAC and hexane to give 0.516 g of the hydroxyphosphinate in the form of a white solid, mp 132-134.5 ° C.

TLC: silica gel, PMA Rf = 0.38 4% MeOH / CH2CI2 1 H NMR: (270 MHz, CDCI3)

8 7.79-7.16 (aromatic, olefinic, 10H)

35 5.59 (2 X dd, 1 H, J = 17.94 Hz, J = 24.27 Hz)

4.35 & 4.24 (2 x m, 1H)

3.70 (s, 3H)

3.49 & 3.47 (2 x d, 3H, J = 11 Hz)

2.58-2.53 (m, 2H)

40 2.54 & 2.53 (2 x s, 3H)

2.01-1.74 (m, 2H)

Mass spectrometry: Cl m / e 457 (M + H) +

IR: (KBr)

3422-3382,3062,3051,2951,2926,2913,1738,1613,1604,1511,1494,1457,1438,1399,1373,1330,1311, 45 1307,1286,1220, 1194,1177, 1160,1092 , 1077.1035, 883.833 cm "i

F. Acid dilithium salt (EÌ-4-ff2-f1- (4-fluorophénvn-3-méthvl-2-naphtalénvnéthénvn-hvdroxvDhosphinvll-3-hvdroxv-butanoïue

50.50 g (1.1 mmol) of diester E was stirred under an argon atmosphere in 10.45 ml of dioxane, and treated with 3.3 ml (3.3 mmol) of 1N LiOH. The mixture The reaction was heated in an oil bath at 70 ° C for 45 minutes. The white suspension obtained was dissolved in approximately 100 ml of a 9: 1 mixture of H2O / MeOH, and evaporated on a rotary evaporator until dryness at 35 ° C. The white solid was pumped under high vacuum for 1 hour, then redissolved in 100 ml of a 9: 1 mixture of H2O / MeOH and evaporated on a rotary evaporator to a volume of approximately 8 ml. This cloudy solution was directly applied to an HP-20 resin chromatography column (17.5 cm x 2.5 cm, equilibrated with H2O) and eluted with 250 ml of H2O and then a 45:55 MeOH / H2O mixture. The fractions were collected every 1.3 minutes (about 10 ml). The fractions containing the product were combined, evaporated on a rotary evaporator at 35 ° C, redissolved in H2O, lyophilized for 16 hours and pumped under high vacuum over P2O5 for 16 hours, to give 0.449 g (1.02 mmol, yield 93%) of the dilithium salt of the title, in the form of a white lyophilisate.

TLC: silica gel, PMA Rf = 0.49 7: 2: 1 (n-C3H70H / NH40H / H2O)

1 H NMR: (400 MHz, DzO)

8 7.73 (d, 1 H, J = 8.06 Hz)

65

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CH 675 582 A5

7.64 (s, 1 H)

7.43-7.39 (m, 1H)

7.25-7.13 (m, 4H)

7.05-6.95 (m, 3H)

5.62 (dd, 1 H, J = 17.96 Hz, J = 21.2 Hz)

2.43 (s, 3H)

2.38 (dd, 1 H, J = 4.03 HZ, J = 15.39 HZ)

2.22 (dd, 1H, J = 9.16 Hz, J = 15.39 Hz)

1.59-1.51 (m, 2H)

Mass spectrometry: FAB m / e 429 (M + H) +, 435 (M + Li) +, 441 (M + 2Li) +

IR: (KBr)

3431 (large), 1603,1593,1511,1494,1423,1221,1158,1050 cm ~ i

Analysis: Calculated for C23H2oFOsPLÌ2-0.87 mole H2O molecular mass = 455.94: C, 60.60; H, 4.80; F, 4.17; P, 6.79 Found: C, 60.60; H, 4.73; F, 4.24; P, 6.82

Example 61

Acid dilithium salt fSV4-iï2-f1-f4-fluoroDhénvn-3-méthvl-

2-naphthalenvl1ethvnhvdroxvphosphinvl-3-hvdroxvbutanoïaue

A. Methyl ester of acid (SÎ-3-nY1.1-dimethvl-ethvndiphénv [silvfloxvl-4-iï2-ri- (4-fluoro-ohénvn-

3-methvl-2-naphthalenvllethvnvnmethoxv-phosphinvnbutanoïaue

0.675 g (0.974 mmol) of acetylenic phosphinate J of Example 59 was dissolved in 14.3 ml of methanol. Argon was bubbled through this solution for 10 minutes, then 0.270 g of Pd was added. 10% / C, and the reaction mixture was shaken on a Parr hydrogenator under a hydrogen pressure of 276 kPa (40 Psi) for 24 hours. The reaction mixture was filtered through a pad of Ceiite, thoroughly washed with methanol, and the filtrate was evaporated in vacuo to give a bianche foam. The product was purified by flash chromatography (50 mm diameter column, 4.5 "Merck silica gel (11.4 mm), eluent 70% EtOAc / hexane, flow rate (51 mm) 2" / minute) to give 0.556 g (0.798 mmol, yield 82%) of the title's saturated phosphinate, in the form of a white foam. Election of the column with methanol gave a further 0.101 g (0.145 mmol, 15%) of the product.

TLC: silica gel, PMA Rf = 0.24 60% EtOAc / hexane 1 H NMR: (270 MHz, CDCI3)

5 7.78-7.14 (aromatic, 19H)

4.44 (m, 1 H)

3.61 (s, 3H)

3.35 & 3.23 (2 x d, 3H, J = 10.6 Hz)

2.92-2.83 (m, 1H)

2.63-2.54 (m, 3H)

2.21-1.27 (m, 4H)

2.45 & 2.42 (2 x s, 3H)

1.00 (s, 9H)

Mass spectrometry: Cl m / e 697 (M + H) +

IR: (solution in CHCI3)

3028, 3019, 3007, 2997, 2953, 2933, 2859, 1735, 1510,1497, 1472, 1463, 1439, 1428, 1378, 1364, 1314, 1236,1197,1157,1142,1112,1091,1073,1065, 1043, 823 cm-1

B. Methyl ester of fSÎ-4-iï2-H-f4-fluoroDhénvh-3-méthvl-2-naphtalénvnéthvn-méthoxvphosphinvll-3-hvdroxvbutanoïue

0.540 g (0.775 mmol) of silylether A was stirred under an argon atmosphere in 9.45 ml of dry THF, and treated with 0.186 g (3.10 mmol, 0.177 ml) of glacial acetic acid, this treatment being followed the dropwise addition of 2.1 ml (2.33 mmol) of a solution of 1.1 M tetrabutylammonium fluoride in THF. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was fixed with 30 ml of ice water and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The organic extracts were combined, washed once with a saturated aqueous solution of NaHCOs, once with brine, dried over MgSO4, filtered and evaporated in vacuo. Initial purification by flash chromatography (40 mm diameter column, 6 "Merck silica gel (152 mm), eluent 4% MeOH / CbizClz, flow rate (51 mm) 2" / minute) gave 0.40 g of a white solid. This solid was triturated in 100% hexane, filtered and pumped under high vacuum for 8 hours, to give 0.317 g (0.691 mmol, yield 89%) of the hydroxyphosphinate of the title, in the form of a solid white, pf 120—122 ° C.

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CH 675 582 A5

TLC: silica gel Rf = 0.12 2% MeOH / CH2CI2 1 H NMR: (270 MHz, CDCIs)

5 7.76 (d, 1H, J = 7.9 Hz)

7.69 (s, 1 H)

7.42-7.16 (m, 7H)

4.42 & 4.26 (2 x m, 1 H)

3.92 & 3.84 (2 x d, 1 H, J = 3.16 Hz)

3.72 (s, 3H)

3.58 & 3.54 (2 x d, 3H, J = 3.69 Hz)

2.89-2.76 (m, 2H)

2.56 (s, 3H)

2.63-2.41 (m, 2H)

1.92-1.61 (m, 4H)

Mass spectrometry: CI m / e 459 (M + H) +

IR: (KBr)

3428 (wide), 3287 (wide), 3064, 3050, 3017,2989,2952, 2921,1737,1603,1510,1497,1458,1438,1234, 1221,1191,1175,1159,1042, 826 cm "i

C. Dilithium salt of the acid (SÌ-4-rr2-ri- (4-fluorophenvlì-3-méthvl-2-naphtalénvflethvn-hvdroxvDhosphinvll-3-hvdroxvbutanoïaue

Stirred under an argon atmosphere in 6.9 ml of dioxane 0.315 g (0.687 mmol) of diester B. The solution was treated with 2.06 ml (2.06 mmol) of 1N LiOH. The reaction mixture was was heated in an oil bath at 70 ° C for 45 minutes. The reaction mixture was cooled to room temperature. The solvents were removed on a rotary evaporator at 35 ° C, and the white solid obtained was pumped under high vacuum for 1 hour. The solids were then dissolved in about 8 ml of distilled water, and applied to an HP-20 resin chromatography column (16 cm x 2.5 cm, equilibrated with H2O). The column was eluted with 250 ml of H 2 O, then a 45:55 NaOH / H 2 O mixture. The fractions were collected every 1.4 minutes (about 10 ml). The fractions containing product 20 (37-47) were combined, evaporated on a rotary evaporator at 35 ° C, lyophilized for 16 hours, and pumped under high vacuum over P2Os for 8 hours to give 0.286 g (0.647 mmol, yield 94%) of the title dilithium salt, in the form of a white lyophilisate.

TLC: silica gel, PMA, Rf = 0.42.7: 2: 1 (n-CsH70H / NH40H / H2O)

1 H NMR: (400 MHz, DzO)

5 7.82 (d, 1H, J = 8.06 Hz)

7.76 (s, 1 H)

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, 1 H, J = 8.43 Hz, J = 15.02 Hz)

1.59-1.51 (m, 2H)

1.44-1.39 (m, 2H)

Mass spectrometry: FAB m / e 443 (M + H) + IR: (KBr)

3451-3426 (wide), 3151, 3124,1620,1593,1509,1439,1422,1403,1218,1159,1050 cm ~ i

Analysis: Calculated for C2sH22FOsPLÌ2 • 0.60 mole H20 Molecular mass = 453.09: C, 60.96; H, 5.16; F, 4.19; P, 6.83 Found: C, 60.96; H, 5.29; F, 4.12; P, 6.82

Example 62

4-iï3-r4'-fluoro-3.3'.5-trimethvll1.1'-biphenvl-2-vripropvl hvdroxvphosphinvll-3-hvdroxvbutanoïue acid dilithium salt

A. Ethyl ester of 3-l4'-fluoro-3.3'5-trimethviri acid. 1'-biphenvll-2-vll-2-Dropenoic acid

0.119 g (4.96 mmol, 0.149 g of an 80% dispersion in mineral oil) of sodium hydride was washed once with hexane under an argon atmosphere, and dried under a stream of argon . The NaH was then stirred under an argon atmosphere in 9.1 ml of dry THF. This suspension was cooled to 0 ° C. and treated dropwise over 5 minutes with a solution of 1.11 g (4.96 mmol, 0.983 ml) of phosphonoacetate.

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CH 675 582 A5

of triethyl in 2.2 ml of dry THF. The clear solution obtained was stirred at 0 ° C for 15 minutes, then warmed to room temperature and stirred for 30 minutes. Finally, a solution of 1.0 g (4.13 mmol) of the aldehyde C of Example 1 in 2.5 ml of dry THF was added dropwise over 8 minutes. The reaction mixture was stirred at room temperature for 1 hour. The mixture was fixed with H2O, and the aqueous layer was extracted 2 times with EtOAc and 2 times with EfeO. The organic extracts were combined, washed once with brine, dried over MgSO4, filtered and evaporated in vacuo. The product was purified by flash chromatography (50 mm diameter column, 6 "Merck silica gel (152 mm), eluent 6% EtOAc / hexane, flow rate (51 mm) 2" / minute) to give 1.19 g (3.79 mmol, yield 92%) of the vinyl ester of the title in the form of a pale yellow foam.

TLC: silica gel, PMA Rf = 0.22 4% EtOAc / hexane 1 H NMR (270 MHz, CDCI3)

8 7.64 (d, 1H, J = 16.35 Hz)

7.09-6.93 (m, 5H)

5.81 (d, 1H, J = 16.35 HZ)

4.17 (q, 2H, J = 7.12 Hz)

2.42 (s, 3H)

2.33 (s, 3H)

2.28 (s, 3H)

1.25 (t, 3H, J = 7.12 Hz)

Mass spectrometry: CI m / e 313 (M + H) +

B. Ethyl acid ester 4, -fluoro-3.3 / .5-trimethvlH .1 '-biDhénvn-2-butanoïaue

1.15 g (3.68 mmol) of vinyl ester A were dissolved in 36 ml of absolute EtOH. Argon was bubbled through the solution for 10 minutes. 230 mg of 10% Pd / C was added, and hydrogen gas was bubbled through the solution for 10 minutes. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was diluted with EtOH, and filtered through a 1/2 "(12.7 mm) Celite pad in a 60 mmm sintered funnel. The Celite was washed with EtOH. The filtrate was evaporated under vacuum to give 1.12 g (3.56 mmol, yield 97%) of the saturated ester of the title, in the form of a white solid.

TLC: silica gel, PMA Rf = 0.29 5% EtOAc / hexane 1 H NMR (270 MHz, GDCI3)

8 7.09-6.97 (m, 4H)

6.84 (s, 1H)

4.06 (q, 2H, J = 7.12 Hz)

2.90-2.84 (m, 2H)

2.37 (s, 3H)

2.30 (2 x s, 6H)

2.32-2.27 (m, 2H)

1.20 (t, 3H, J = 7.12 Hz)

Mass spectrometry: Cl m / e 315 (M + H) +

C. 4, -Fluoro-3.3'.5-trimethvl n.1'-biphenvl 1-2-propanol

The mixture was stirred under an argon atmosphere in 3.5 ml of dry Et 2 O 0.133 g (3.5 mmol) of lithium aluminum hydride. This suspension was cooled to 0 ° C and treated dropwise for 8 minutes with a solution of 1.1 g (3.5 mmol) of ester B in 3.5 ml of dry Et2O. The reaction mixture was stirred at 0 ° C for 15 minutes, then warmed to room temperature and stirred for 45 minutes. The mixture was again cooled to 0 ° C. and treated dropwise with 0.133 ml of H2O, then 0.133 ml of 15% NaOH and finally 0.399 ml of H2O. The suspension was warmed to room temperature for 30 minutes. The white powdery solid obtained was filtered and washed with dry Et2O. The filtrate was concentrated, mixed once with benzene to form an azeotrope, and rectified in vacuo to give 0.950 g of the alcohol, which was purified by flash chromatography (column diameter 50 mm, Merck 6 "silica gel (152 mm), eluent 35% EtOAc / hexane, flow rate (51 mm) 2 "/ minute) to give 0.906 g (3.33 moles, 95% yield) of the alcohol of the title, in the form d 'a colorless oil.

TLC: silica gel PMA Rf = 0.18 20% EtOAc / hexane 1 H NMR (270 MHz, CDCI3)

5 7.08-6.93 (m, 4H)

6.82 (s, 1H)

3.45-3.40 (m, 2H)

2.60-2.54 (m, 2H)

2.34 (s, 3H)

2.28 (2 x s, 6H)

1.63-1.52 (m, 2H)

Mass spectrometry: Cl m / e 273 (M + H) +

132

CH 675 582 A5

D. 2-f3-BromoDroDvh-4'-fluoro-3.3'.5-trimethviri .1 '-biphénvle

A solution of 2.65 g (10.1 mmol) of triphenylphosphine in 27.5 ml of THF was cooled to 0 ° C and treated dropwise with a solution of 3.55 g (10.71 mmol) of tetrabromide of carbon in 5.5 ml 5 of dry THF. The yellow / white suspension obtained was stirred at 0 ° C for 2 hours. The complex was treated dropwise with a solution of 1.1 g (4.04 mmol) of alcohol C in 8.2 ml of dry THF. The reaction mixture was stirred at 0 ° C for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with Et2O, filtered through a sintered funnel, and the precipitate was washed with Et2 <D. The filtrate was washed once with brine, dried over MgSC> 4.10, filtered and evaporated in vacuo. The product was purified by flash chromatography (diameter 50 mm, Merck silica gel 6 "(152 mm), eluent 2% EtOAc / hexane, flow rate (51 mm) 2" / minute) to give 1.35 g (4, 05 mmol, 100% yield) of the title bromide, in the form of a pale yellow oil.

TLC: silica gel, PMA Rf = 0.22 100% hexane 1 H NMR (270 MHz, CDCIs)

15 8 7.07-6.99 (m, 4H)

6.82 (s, 1 H)

3.22 (m, 2H)

2.69-2.63 (m, 2H)

2.36 (s, 3H)

20 2.30 (s, 3H)

2.28 (s, 3H)

1.90-1.80 (m, 2H)

Mass spectrometry: Cl m / e 235 (M + H) +

25 E. Dimethyl ester of r3-r4 / -fluoro-3.3 / .5-trimethvin.1 / -biphenvl1-2-vl1propvl phosphonic acid

Stirred under an argon atmosphere in 38.8 ml of trimethyl phosphite 1.3 g (3.88 mmol) of bromide D. The reaction mixture was heated to reflux in an oil bath at 135 ° C for 36 hours. The excess (CH30) 3P was removed by short path distillation, and the residue was pumped under high vacuum at 100 ° C for 1 hour. The yellow oil obtained was subjected to purification by flash chromatography (column 50 mm in diameter, silica gel Merck 6 "(152 mm), eluent 85% EtOAc / hexane, flow rate (51 mm) 2" / minute ) to give 1.13 g (3.10 mmol, yield 80%) of the title dimethyl phosphonate, in the form of a colorless oil.

TLC: silica gel, PMA, Rf = 0.28 100 EtOAc 35 1 H NMR (270 MHz, CDCI3)

8 7.08-6.97 (m, 4H)

6.81 (s, 1 H)

3.65 (d, 6H, J = 11 Hz)

2.63-2.56 (m, 2H)

40 2.34 (s, 3H)

2.30 (2 x s, 3H)

2.28 (s, 3H)

1.68-1.50 (m, 4H)

Mass spectrometry: Cl m / e 365 (M + H) +

45

F. Monomethyl ester of r3-f4, -fluoro-3.3, -5-trimethvlf1.1 / -biphénvn-2-ynoropyllphosphoniaue acid

The mixture was stirred under an argon atmosphere in 8.23 ml of dioxane 1.25 g (3.43 mmol) of phosphonate E. 50 This solution was treated with 5.15 ml (5.15 mmol) of 1N LiOH and heated in an oil bath at 95 ° C. After 1 hour, a further 3.43 mmol of LiOH was added, and the reaction mixture was again heated at 95 ° C for 3.5 hours. The reaction mixture was cooled to room temperature. The solvents are removed in vacuo. The white solid residue was diluted with 25 ml of H2O, the suspension was cooled to 0 ° C and acidified to pH 1 with a 5% aqueous HCl solution. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and the filtrate was concentrated. The residue was mixed 2 times with benzene to form an azeotrope, and the viscous oil obtained was pumped under high vacuum for 4 hours to give 1.18 g (3.37 mmol, 98% yield) of the ester monomethyl phosphonic acid in the form of a yellow oil. TLC: silica gel, PMA, Rf = 0.46 10: 1: 1 60 CH2CI2 / Me0H / CH3C02H 1 H NMR (270 MHz, CDCI3)

8 7.06-6.95 (m, 4H)

6.81 (s, 1H)

3.56 (d, 3H, J = 11 Hz)

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CH 675 582 A5

2.62-2.53 (m, 2H)

2.32 (s, 3H)

2.27 (2 x s, 6H)

1.69-1.48 (m, 4H)

Mass spectrometry: FAB m / e 351 (M + H) +

G. Methyl ester of 4- rr3-r4 acid, -fluoro-3.3, .5-trimethviri.1 / -biDhénvn-2-vnpropvllméthoxv-phosphinvl] -3-oxobutanoïue

It was stirred under an argon atmosphere in 12.9 ml of dry CH2Cl2 1.13 g (3.22 mmol) of the phosphonate F ester. This solution was treated dropwise in 8 minutes with 0.918 g (6.44 mmol , 1.20 ml freshly distilled) of TMSDEA. This solution was stirred at room temperature for 1.5 hours. The volatile substances were removed under vacuum (purging in the atmosphere of argon). The residue was mixed once with 70 ml of dry benzene to form an azeotrope, and evaporated in vacuo (purge in the atmosphere of argon). Finally, the residue was pumped under high vacuum for 50 minutes. The residue was then stirred under an argon atmosphere in 12.9 ml of dry CH2CÌ2. Two drops of dry DMF were added, and the solution was cooled to 0 ° C and treated dropwise for 8 minutes with 0.470 g (3.70 mmol, 0.323 ml) of oxalyl chloride. This reaction mixture was stirred at 0 ° C for 20 minutes, then warmed to room temperature and stirred for 1 3/4 hours. The volatiles were removed, the residue formed an azeotrope and it was pumped under high vacuum as above. The rust-colored oil was then stirred under an argon atmosphere in 9.0 ml of dry THF. This solution was cooled to -78 ° C and kept at -78 ° C, while being added dropwise over 20 minutes to a solution at -78 ° C, in THF, of methyl acetoacetate dianion, obtained in the following manner: 0.116 g (4.85 mmol, 0.145 g of an 80% dispersion in a mineral oil) of sodium hydride was washed once with hexane, and dried under a current of 'argon. The solids were then stirred under an argon atmosphere in 7.1 ml of dry THF, and this suspension was cooled to 0 ° C. A solution of 0.506 g (4.36 mmol, 0.471 ml) of methyl acetoacetate in 3.6 ml of dry THF was added dropwise over 8 minutes, and the resulting clear solution was stirred at 0 ° C for 25 minutes. Then the reaction mixture was treated dropwise for 10 minutes with 1.62 ml (4.04 mmol) of a solution of 2.5 M n-BuLi in hexane, Aldrich. The yellow solution obtained was stirred at 0 ° C for 35 minutes, then cooled to -78 ° C and treated dropwise for 20 minutes with the solution at -78 ° C, in THF, of phosphonochloridate form above. The reaction mixture was stirred at -78 ° C for 1 hour, then fixed with 45 ml of a saturated aqueous NH4Cl solution, and warmed to room temperature. The mixture was diluted with 45 ml of H2O and EtOAc. The aqueous layer was extracted 4 times with EtOAc. The organic extracts were combined, washed once with saturated aqueous NaHCO3 solution and once with brine, dried over MgSO4, filtered and evaporated in vacuo to give 2.0 g of a rust-colored oil. The product was isolated by flash chromatography (40 mm diameter column, Merck 35: 1 silica gel, eluent of 100% 5% EtOAC MeOH / CH2Cl2, flow rate (51 mm) 2 "/ minute) to give 0.220 g ( 0.491 mmol, yield 15%) of the title p-cephosphinate, in the form of a rust-colored oil.

TLC: silica gel, PMA Rf = 0.19 100% EtOAc

1 H NMR (270 MHz, CDCIs)

S 7.08-6.98 (m, 4H)

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)

2.67-2.57 (m, 2H)

2.35 (s, 3H)

2.30 & 2.28 (2 x s, 3H)

2.29 (s, 3H)

1.72-1.56 (m, 4H)

Mass spectrometry: Cl m / e 449 (M + H) +

H. 4-iï3-r4'-fluoro-3.3 'acid methvlia ester.

5-trimethviri. 1'-biphenvn-2-vnpropvnmethoxv-Dhosphinvn-3-hvdroxvbutanoïue

Stirred under an argon atmosphere in 1.9 ml of dry THF 0.10 g (0.223 mmol) of p-ketophosphinate G. This solution was cooled to 0 ° C. and then treated with 0.008 g (0.223 mmol) of NaBH4, this treatment being followed by the dropwise addition of 0.194 ml of dried MeOH on a 4 Å molecular sieve. The reaction mixture was stirred at 0 ° C for 1 hour, then fixed with 0.194 ml of acetone, then 0.10 g of CC-4 silica gel (Mallinckrodt). The suspension was stirred while being heated to am134

CH 675 582 A5

biante, then filtered through a sintered funnel. The silica was washed with EtOAc. The filtrate was evaporated in vacuo to give 0.108 g of a golden oil. Two reaction products were isolated by flash chromatography (10 mm diameter column, Merck 35: 1 silica gel, eluent 4% MeOH / CH2Cl2, flow rate (51 mm) 2 "/ minute). desired hydroxyphosphinate, title, with a yield of 588% (0.058 g, 0.129 mmol) as a pale yellow oil. Also obtained was 0.019 g (0.043 mmol, 20% yield) of 1.3 -butanediol-phosphinate.

TLC: silica gel PMA Rf = 0.19 3.5% MeOH / CH2CI2 1 H NMR (270 MHz, CDCI3)

8 7.08-6.98 (m, 4H)

10 6.82 (s, 1 H)

4.44 & 4.32 (2 x m, 1H)

3.63 & 3.62 (2 x d, 3H, J = 10.55 Hz)

3.70 (s, 3H)

2.65-2.50 (m, 4H)

15 2.35 (s, 3H)

2.30 (2 x s, 3H)

2.29 (s, 3H)

1.89-1.76 (m, 2H)

1.71-1.59 (m, 4H)

20 Mass spectrometry: Cl m / e 451, (M + H) +

Ì. 4-lT3-r4 acid dilithium salt, -fluoro-3.3 '. 5-trimethviri.1'-biphenvH-2-vllpropvllhvdroxv-phosphinvl-3-hvdroxvbutanoTaue

0.055 g (0.122 mmol) of diester H was stirred under an argon atmosphere in 2 ml of dioxane and treated with 0.366 ml (0.366 mmol) of 1N LiOH. The reaction mixture was heated in an oil bath. 80 ° C for 45 minutes. The reaction mixture was cooled to room temperature, and the solvents were evaporated on a rotary evaporator. The yellow solid obtained was pumped under high vacuum for 2 hours, to give the dilithium salt of the title, in the form of a yellow solid. 30 TLC: silica gel, PMA Rf = 0.29 8: 1: 1 CH2CI2 / Me0H / CH3C02H 1 H NMR (270 MHz, D20)

8 7.08-7.05 (m, 4H)

6.80 (s, 1 H)

4.13 (m, 1H)

35 2.54-2.47 (m, 2H)

2,382.28 (m, 2H)

2.30 (s, 3H)

2.22 (s, 3H)

2.20 (s, 3H)

40 1.59-1.50 (m, 2H)

1.42-1.29 (m, 4H)

Example 63

45 PIS-H dilithium salt <ai, R * i.2 <a.4a <b.8 <b.8a <an-4-iï2-F8 - (, 2.2-dimethvl-

1-oxobutoxv ^ décahvdro-2-méthvl-1-naphtaiénvl1éthvllhvdroxvphosphinvn-3-hvdroxvbutanoïaue

A. f1 S-f1 <a.2 <a.4a <b.8 <b.8a <ai1-8-riï1.1-diméthvl-éthvndiméthvlsilvnoxv1-1,2.4a.5.6.7.8.8a-octahvdro-2- methvl-1-naphthalene methanol

50

132 mg (1 molar equivalent) of lithium aluminum hydride were added to 5 ml of dry Et20 at 0 ° C (ice bath), then 1.175 g (3.47 mmol) were added dropwise of the methyl ester of the acid [1 S (1 <a, 2 <a, 4a <b, 8 <b, 8a <a)] - 8 - [[(1,1-dimethyl-ethyl) dimethylsilyl] oxy] -1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenecarboxylic, RL Funk et al., Tetrahedron Lett. 25, 1655 (1984) in 5 ml of dry Et 2 O, and the gray suspension obtained was stirred overnight under an argon atmosphere at room temperature. The mixture was fixed by adding dropwise, in order, 130 µl of H2-0, 130 µl of 15% NaOH and 390 µl of H2O. The precipitated salts were removed by filtration, through anhydrous MgSO4, on a filter packed with Celite. Evaporation in vacuo gave 1.112 g of a clear oil, which was purified by flash chromatography on silica gel, eluting with a 95: 5 mixture of hexane and 60 of EtOAc to give 902 mg (85.7 %) of the alcohol of the title in the form of a clear oil, which crystallized at rest, mp. 79-81 ° C. TLC (9: 1) hexane-EtOAc,

Rf = 0.21

Analysis: calculated for CisH3402Si: C, 69.61; H, 11.04 Found: C, 69.64; H, 11.04

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CH 675 582 A5

1 H NMR (CDCIs)

5 0.00 (s, 6H)

0.82 (s, 9H)

0.83 (d, 3H)

0.94-1.05 (m, 2H)

1.18 (s, 1H)

1.2-1.42 (m, 2H)

1.67 (m, 3H)

1.89 (m, 1H)

2.25 & 2.37 (2H, 2 multiplets)

3.42 (bt, 1H)

3.80 (dd, 1H)

3.93 (bs, 1H)

5.29 (d, 1H)

5.48 (dq, 1 H) ppm

B. H Sf 1 <a.2 <a.4a <b.8 <b.8a <aYl-8-lïï1.1 -diméthvl-éthvhdiméthvlsilvnoxvl-1.2.4a.5.6.7.8.8a-octahvdro-2-méthvl- 1-naphthalenecarboxaldehyde

A solution of 895 mg (2.11 mmol) of Dess-Martin periodinane in 6 ml of CH2Cl2 was treated with 200 l of dry tert-C ^ gOH, and the white suspension was stirred under an argon atmosphere to the room temperature for 15 minutes. A solution of 596 mg (1.92 mmol) of alcohol in 6 ml of dry CH2Cl2 was added dropwise over 5 minutes, and the mixture was stirred under an argon atmosphere at room temperature for 20 minutes. The mixture was added to a solution of 2.12 g of sodium thiosulfate in 12 ml of 1.0 N NaHCOs, and the mixture obtained was stirred until all of the solids dissolved. The organic phase was washed with saturated NaHCO3, water and brine, then dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.005 g of a colorless oil. The crude product was combined with the product of a smaller test (total 1.306 g), then purified by flash chromatography on silica gel, eluting with a 98: 2 mixture of hexane and EtOAc. The product-containing fractions were evaporated in vacuo to give 667 mg (75.7%) of the title aldehyde as a colorless oil.

TLC (7: 3) hexane-Et20, Rf = 0.70 PMA

1 H NMR (CDCIs)

5 0.07 (s, 3H)

0.00 (s, 3H)

0.85 (s, 9H)

0.89 (d, 3H)

0.93-1.10 (m, 2H)

1.38-1.52 (m, 2H)

1.58-1.78 (m, 4H)

2.31 (m, 1H)

2.66 (m, 1H)

2.78 (m, 1 H)

4.30 (s, 1 H)

5.40 (d, 1 H)

5.50 (m, 1H)

9.74 (d, 1 H)

C. n SM <a.2 <a.4a <b.8 <b.8a <al-1 - (2.2-dibromo-ethhenvlV8-nY1.1 -dimethvlethvn-dimethvlsilvn-oxvl-1.2.4a.5.6.7.8. 8a-octahvdro-2-methvl-naphthalene

A solution at -15 ° C (ice and salt bath) of 667 mg (2.16 mmol) of aldehyde B and 1.7 g (6.48 mmol) of triphenylphosphine in 10 ml of CH2Cl2 was treated dropwise for 5 minutes with 5 ml of a solution, in CH2Cl2, of 1.7 g (6.48 mmol) of carbon tetrabromide, and the dark reddish brown mixture was stirred under an argon atmosphere. -15 ° C for 30 minutes, at 0 ° C for 2 hours and finally overnight at room temperature. The mixture was again cooled to 0 ° C, treated with an additional 567 mg (216 mmol) of triphenylphosphine, then 358 mg (1.08 mmol) of CBr4, and stirred for 4 hours at room temperature. The mixture was fixed with 10 ml of saturated NaHCOs, diluted with CH2Cl2, the organic phase was filtered through a sintered glass, washed with saturated NaHCOs and brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 3.578 g of a solid brown. The crude product was purified by flash chromatography on silica gel, eluting with pure hexanes. The product containing fractions were evaporated to give 677 mg (67.3%) of the title pure vinyl dibromide as a colorless oil.

TLC (9:11 hexane-acetone, Rf = 0.73 UV + PMA).

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CH 675 582 A5

1 H NMR (CDCIs)

5 0.08 & 0.10 (2 singlets, 6H)

0.85 (d, 3H)

0.90 (s, 9H)

5 0.98 (m, 2H)

1.25-2.52 (m, 5H)

1.74 (m, 1H)

1.82 (m, 1H)

2.39 (m, 1H)

10 2.56 (m, 1 H)

2.66 (m, 1H)

3.95 (s, 1H)

5.48 (d, 1H)

5.52 (m, 1H)

15 6.37 (d, 1 H) ppm

D. H S-f1 <a.2 <a.4a <b.8 <b.8a <aïl-8-ff (1.1 -diméthvléthvndiméthvlsilvnoxvl-1-éthvnvl-1.2.4a.5.6.7.-8.8a-octahvdro -2-methvlnaphthalene

A solution at -78 ° C (dry ice / acetone) of 495 mg (1.07 mmol) of vinyl dibromide C in 6 ml of dry THF was treated dropwise for 5 minutes with 1.34 ml (2 , 14 mmol) of a 1.6 M solution of n-BuLi in hexanes, and the clear colorless mixture was stirred for 30 minutes under an argon atmosphere at -78 ° C. The mixture was fixed at -78 ° C by addition of 5 ml of saturated NH4Cl, it was allowed to return to room temperature, then diluted with EtOAc, the organic phase was washed with brine, dried over NaaSO * anhydrous and evaporated under vacuum to give 291 mg (89.6%) of the raw acetylene of the title in the form of a colorless oil.

TLC hexanes Rf = 0.43, UV + PMA

1 H NMR (CDCI3)

8 0.08 0.12 (2 singlets, 6H)

30 0.90 (s, 9H)

0.99 (m, 1H)

1.09 (d, 3H)

1.19 (m, 1H)

1.46 (m, 2H)

35 1.74 (m, 3H)

2.12 (d, 1H)

2.30 (m, 1H)

2.41 (m, 1H)

2.71 (m, 1H)

40 4.37 (m, 1 H)

5.38 (d, 1H).

5.55 (m, 1 H) ppm

E. Methyl ester of acid (SM-fchloromethoxv-phosDhinvn-S-lïïl.l'-45 diméthvléthvhdiphénvlsilvlloxvl-butano'iue

A phosphonochloridate was prepared by the procedure according to the dicyclohexylamine B salt of example 25. The free acid was regenerated by partitioning the dicyclohexylamine salt (1.3 g, 2.05 mmol) between EtOAc and 5% KHSO4, the organic layer was washed four times with 5% KHSO4 and brine, then dried over anhydrous Na2SO4 and evaporated in vacuo to give the free acid as a clear viscous oil.

The phosphethyl acid monomethyl ester (2.05 mmol) was taken up in 5 ml of dry CH2CÌ2, treated with 515 ni (4.1 mmol) of distilled N, N-dimethyltrimethylsiiylamine, and the clear colorless solution was stirred at room temperature under an argon atmosphere for 1 h. The reagent and the ex-55 solvent were removed in vacuo, and the residual oil was mixed with twice 10 ml of benzene.

About 2.05 mmol of the crude silyl ester in 5 ml of CH2CÌ2 and one drop of dry DMF were cooled to 0 ° C in an ice bath and treated dropwise with 195 µl (2.26 mmol) of chloride of distilled oxalyl, and the yellow mixture was stirred under an argon atmosphere at 0 ° C for 15 min. and at room temperature for 45 min. The mixture was evaporated in vacuo, mixed with twice 10 ml of dry benzene, to give the crude phosphonochloridate of the title as a viscous oil.

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CH 675 582 A5

F. Methyl ester of HSH acid <a / R *). 2 <a.4a <b.8 <b.8a <aH-4-iïf8-fiï 1 -

diméthvléthvndiméthvlsilvlloxv1-1.2.4a.5.6.7.8a-octahvdro-2-méthvl-1-naDhtalénvnéthvrivnméthoxv-phosDhinvn-3-nY1.1-diméthvléthvndiDhénvlsilvnoxv'lbutano''

A solution at -78 ° C of 356 mg (1.17 mmol) of acetylene D in 5 ml of dry THF was treated dropwise with 730 μl (1.17 mmol) of a solution of n-BuLr pl, 6M in hexanes, and the clear mixture was stirred under an argon atmosphere at -78 ° C for 30 min. The acetylene anion was then transferred using a cannula, drop by drop in 15 min., In a solution at -78 ° C of the phosphonochloridate in 6 ml of dry THF. The yellow mixture was stirred for 30 min. at -78 ° C, then the reaction was quenched by the dropwise addition of 5 ml of saturated NH4Cl, and the reaction mass was allowed to return to room temperature. The mixture was partitioned between EtOAc and H2O, the organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.282 g of a pale yellow oil. The crude product was purified by flash chromatography on silica gel, eluting with a 7: 3 mixture of hexane and EtOAc. The product-containing fractions were evaporated to give 624 mg (72.4%) of the title acetylenic phosphinate, as a colorless glass.

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

G. Acid methvlia ester f1 SH <afR * ^. 2 <a.4a <b.8 <b.8a <an-4-rr2-r8-riY1.1 -diméthvléthvhdiméthvlsilvlloxv1décahvdro-2-méthvl-1-naphtalénvlléthvl1méthoxvosphin -3-IT (1.1-dimethvlethvndiphénvlsilvlloxvlbutanoïaue

A solution of 498 mg of acetylenic phosphinate F in 6 ml of CH3OH was treated with 200 mg of Pt at 10% / C, and the black suspension was stirred on a Parr apparatus under a hydrogen pressure of 276 kPa ( 40 psi) for 48 h. The catalyst was removed by filtration through Celite, the reaction mixture was added with fresh catalyst (150 mg) and shaken on the Parr apparatus under a hydrogen pressure of 276 kPa (40 psi) for a further 24 h. The catalyst was removed by filtration through Celite, and the filtrate was evaporated in vacuo to give 440 mg of a clear glass. The crude product was purified by flash chromatography on silica gel, eluting with an 8: 2 mixture of hexane and EtOAc. The product containing fractions were evaporated in vacuo to give 334 mg (66.5%) of the title compound as a clear glass.

TLC (7: 3) EtOAc-hexane, Rf 3 diastereoisomers, one spot = 0.42, Rf, 4th diastereoisomers, one spot = 0.49, UV + PMA.

H. Acid methvlia ester of HS-r <a (R * i.2 <a. 4a <b. 8 <b. 8a <an-4-iï2- (décahvdro-8-hvdroxv-2-méthvl-1 -naDhtalénvhéthvllméthoxvDhosphinvn-3-rff 1.1 -diméthvléthvn-diphénvlsilvlloxvlbutanoïaue

A solution of 248 mg (0.334 mmol) of compound G in 4 ml of CH3CN was treated with 36 μl (1 mmol) of 48% HF in H2O, and the mixture was stirred for 6.5 h under an atmosphere of argon at room temperature. The mixture was partitioned between EtOAc and saturated NaHCOs, the organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 227 mg of a colorless glass. The crude product was purified by flash chromatography on silica gel, eluting with a 4: 1 mixture of hexane and EtOAc, then pure EtOAc. The product fractions were evaporated in vacuo to give 159 mg (75.8%) of the title pure monoalcohol as a colorless oil.

TLC (7: 3) acetone-hexane, Rf = 0.5 (UV (weak) + PMA).

I. Methyl ester of nS-H acid <a (R * i.2 <a.4a <b.8 <b. 8a <aH-3-nT1.1-diméthvléthvndiphénvlsilvlioxvi-4-IT2-r8-fê. 2-dimethvl-1-oxobutoxv} -décahvdro-2-méthvl-1-naphtalénvnethvllméthoxvDhosphinvIlbutanoïaue

A solution of 147 mg (0.234 mmol) of alcohol H in 1.5 ml of dry pyridine was treated with 160 μl (1.17 mmol, 5 eq.) Of 2,2-dimethylbutyryl chloride, then with 3 mg (0.1 eq.) of 4-dimethylaminopyridine, and the pale yellow mixture was heated at 100 ° C. under an argon atmosphere for 4 h. The mixture was cooled, partitioned between 1.0 N HCl and EtOAc, the organic phase was washed twice with 1.0N HCl and brine, dried 3 over anhydrous Na2SO4 and evaporated to give 255 mg of a pale yellow-brown oil. The crude product was purified by flash chromatography on silica gel, eluting with a 55:45 mixture of hexane and EtOAc. The product-containing fractions were evaporated in vacuo to give 112 mg (65.9%) of the title dimethyl butyryl ester, as a colorless oil.

TLC hexane-acetone, Rf = 0.62, UV + PMA.

J. F1S-f1 acid methvlia ester <a (R * i.2 <a.4a <b.8 <b.8a <a1l-4-iï2-r8- (2.2-dimethvl-1-oxobutoxv ') -décahvdro-2-méthvl-1-naphtalénvnéthvnméthoxvphosphinvn-3-hvdroxv-butanoïaue

A solution of 130 mg (0.179 mmol) of silyl ester I in 2 ml of THF was treated successively with 41 μl (0.716 mmol) of glacial acetic acid (HOAc) and 490 μl (0.537 mmol) of a solution of

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CH 675 582 A5

(n-C4Hg) 1.1 M 4NF in THF, and the mixture was stirred overnight under an argon atmosphere. The mixture was partitioned between EtOAc and 5% KHSO4, the organic phase was washed with water and brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 115 mg of a colorless oil. The crude product was purified by flash chromatography on silica gel, eluting with a 1: 1 mixture of hexane and acetone. The product fractions were evaporated in vacuo to give 72 mg (82.4%) of the title alcohol as a colorless oil.

TLC (1: 1) hexane-acetone, Rf = 0.20, UV + PMA.

K. Acid dilithium salt f1S-f1 <aCR * V2 <a.4a <b.8 <b.8a <aH-4-iï2-r8-C2.2-dimethvl-1-oxobutoxv) -10 decahvdro -2-méthvl-1-naDhtalénvlléthvnhvdroxvohosDhinvl1-3-hvdroxv-butanoïaue

A solution of 72 mg (0.147 mmol) of alcohol J in 1.5 ml of dioxane was treated with 0.52 ml of 1.0N LiOH, and the mixture was heated to 55 ° C (oil bath ) under an argon atmosphere for 1.5 h. The mixture was cooled, diluted with water, filtered and evaporated in vacuo to give an oil. The crude product was chromatographed on an HP-20 resin (3 cm bed, column with a diameter of 15 mm), eluting with H2O then with a 70:30 H2O-CH3OH mixture. The product-containing fractions were evaporated in vacuo, dissolved in 20 ml of H2O and lyophilized to give 55 mg (74%) of the title dilithium salt as a white solid.

TLC (8: 1: 1) CH2CI2-CH2OH-CH3COOH, Rf = 0.05, PMA 20 Analysis: Wedge, for C23H3g07PLi2 + 1.78 moles H2O (molecular weight 504.53):

C, 54.75; H, 8.50; P, 6.14 Found: C, 54.75; H, 8.64; P, 5.93

Example 64

25

Acid dilithium salt (SM-fiïS'-M-fluoro-Dhénvnspirorcvclopentanel.l'-nHlindènel-2-vnéthvnvn-hvdroxvphosphinvn-3-hvdroxvbutanoïaue

A. 3- (4-Fluorophenvh-1 H-indene

30

A solution of 6.61 g (50 mmol) of 1-indanone in 20 ml of dry ether was added dropwise over 40 min. At room temperature and under an argon atmosphere to a bromide solution. 4-fluorophenylmagnesium (prepared from 6.43 ml of 4-fluorobromobenzene and 1.71 g of Mg in 50 ml of ether). After 1 hour of stirring at room temperature, the reaction was fixed by adding dropwise -35 drop of 15 ml of a saturated NH4Cl solution. The mixture was diluted with Et 2 O, washed with saturated NaCl solution, dried over MgSO 4 and evaporated.

The residue was taken up in 15 ml of glacial acetic acid and heated under reflux under a nitrogen atmosphere for 30 min. The acetic acid was removed by evaporation, and mixed twice with toluene. The residue (9.45 g) was purified by flash chromatography on silica gel, eluting with hexane, to give 8.174 g (78%) of the title compound, as an oil colorless which crystallized at rest, pf 38-40 ° C. TLC (hexane) Rf = 0.21.

B. 3, -f4-Fluorophénvnspirorcvclopentane-1.1, -ri Hl-indènel

45 Was added in portions, at 0 ° C under an argon atmosphere, to a solution of 10.676 g (50.8 mmol) of compound A in 90 ml of dry THF, 12.2 g (109 mmol) of tert- solid potassium butoxide. After 30 min. of stirring at 0 ° C., 6.50 ml (101 mmol) of 1,4-dibromobutane was added dropwise. The resulting mixture was allowed to warm to room temperature, stirred for 2 h, then partitioned between EtOAc and 5% KHSO4 (150 ml each). The organic phase was washed with a saturated 50 NaCl solution, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with hexane to give 9.43 g (70%) of the title compound, as a colorless oil. TLC (Et20-hexane; 1: 9), Rf = 0.69 (Rf of compound  = 0.63).

C. 3 / -f4-fluorophénvnsDirolcvclopentane-1.1 / - f1 H1- indènel-2-carboxaldéhvde

55

Was added at 0 ° C under an argon atmosphere, to a solution of 9.30 g (35.2 mmol) of compound B in 50 ml of dry CH2Cl2, a 1.0M solution of TiCU in CH2Cl2 (70 ml , 70 mmol). The dark green solution obtained was treated dropwise with 3.50 ml (38.7 mmol) of 1,1-dichloromethyl-methyl-ether. After stirring at 0 ° C for 1 h and at room temperature for 1 h, the mixture was poured into a cold saturated NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with a 5:95 mixture of Et2O-hexane to give 8.233 g (80%) of the title compound, as a yellow oil. Crystallization of the oil from hexane gave 6.778 g (66%) of the pure title compound, as pale yellow crystals, m.p. 116-117 ° C.

65

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CH 675 582 A5

TLC (Et20-hexane; 15:85) Rf = 0.56.

Analysis: Wedge, for C20H17OF: C, 82.17; H, 5.86; F, 6.50 Found: C, 83.13; H, 5.82; F, 6.29

D. 2'-Ethvnvl-3'-f4-fluorophénvlisDirorcvclooentane-1 .1'-H Hlindènel

Was added dropwise at -78 ° C under an argon atmosphere, to a solution of 0.672 g (6.00 mmol) of potassium tert-butoxide in 8 ml of dry THF, a solution of 0.960 g (6, 40 mmol) of dimethyl diazo-methylphosphonate, prepared as indicated in J. Org. Chem. 36.1379 (1971) in 4 ml of THF. After 5 min. stirring at -78 ° C, added dropwise over 10 min. a solution of 1.168 g (4.00 mmol) of compound C in 8 ml of THF. After stirring at -78 ° C for 3 h, at -45 ° C for 1.5 h and at room temperature for 1 h, the mixture was diluted with 50 ml of hexane and washed with a 5% KHSO4 solution. The organic phase was washed with saturated NaCl solution, dried over Na2SO4 and concentrated to a small volume (but not to dryness). The yellow solution was subjected to flash chromatography on silica gel, the eluent being hexane. The fractions containing the product were combined, treated with 0.080 g (0.36 mmol) of butylated hydroxytoluene (BHT), and concentrated to a low volume (5-10 ml), which was immediately used as a solution for the next step. TLC (Et20-hexane; 1: 9) Rf = 0.57. 1 H-NMR (270 MHz, CDCb), using BHT as internal standard (1.45 ppm, 18H, s) shows the presence of 3.10 mmol (yield 77.5%) of the acetylene sought (3, 32 ppm, 1 H, s).

E. Methyl acid ester (SV4-chloromethoxv-phosphinvn-3-liï1.1-diméthvléthvlkliphénvlsilvnoxv'l-butanoïaue

The title phosphonochloridate was prepared from 3.44 g (54.4 mm) of the dicyclohexylamine B salt of Example 25, as described in Part J of Example 29, using the following amounts : trimethysilyldiethylamine (1.36 ml, 10.85 mmol), CH2Cl2 (15 ml), oxalyl chloride (0.50 ml, 5.73 mmol), DMF (1 drop), CH2Cl2 (15 ml).

F. Acid methvlia ester fSÎ-3-rrf1.1-dimethvl-éthvndiDhénvlsilvnoxv1-4-rrr3 / - (4-fluoroDhénvnspiro-rcvclopentane-1.1'-H H1indène12-vnéthvnvnmethoxvphosphinbut

The solution, in hexane, of acetylene D (3.10 mmol + 0.36 mmol of BHT) was diluted with 15 ml of dry THF and cooled to -78 ° C under an argon atmosphere. The solution was then treated dropwise, using a syringe, with 2.16 ml (3.46 mm) of a 1.6M solution of n-BuLi in hexane. After 45 min. with stirring at -78 ° C, the anion solution was transferred using a cannula into a solution at -78 ° C of 54.4 mmol of phosphonochloridate E in 15 ml of dry THF. After 1 hour of stirring at -78 ° C, the reaction was quenched by the dropwise addition of 15 ml of saturated NH4Cl, and allowed to return to room temperature. The mixture was extracted with EtOAc, the extracts were washed with 5% KHSO4 solution, saturated NaHCOs solution and saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with a 25:75 mixture of EtOAc-hexane to give the title compound (1.781 g, 80% based on compound D) as d 'a pale yellow glass.

TLC (acetone-hexane; 1: 1) Rf = 0.46.

G. fSV4-nT3 acid methvlia ester, - (4-fluoro-phenvnspirorcvclopentane-1.1 / -riHlindene'l-2-vnéthvnvl1-méthoxvphosphinvn-3-hvdroxvbutanoïue

Was added at room temperature and under an argon atmosphere to a solution of 1.00 g (1.39 mmol) of compound F in 5 ml of dry THF, 0.32 ml (5.59 mmol) of glacial acetic acid and a 1.1M solution of (n-C4Hg) 4NF in THF (3.80 ml, 4.18 mmol). After 18 h of stirring at room temperature, the mixture was diluted with 50 ml of EtOAc, washed successively with 3 × 30 ml of 1N HCl and saturated NaCl solutions, dried over Na2SO4 and evaporated to dryness . The residue was taken up in 20 ml of Et 2 O, cooled in an ice bath and treated with excess ethereal diazomethane. The residue obtained by evaporation of the ether was purified by flash chromatography on silica gel, the eluent being a 3: 7 mixture of acetone and hexane, to give the title compound (0.595 g, 89 %) in the form of a colorless glass.

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

H. acid dilithium salt fSÎ-4-fiï3 '- (4-fluoro-phenvnsDirorcvcloDentane-1.1'-f1Hlindène1-2-vlléthvnvn-hvdroxvphosphinvn-3-hvdroxvbutano' ['aue

4.2 ml (4.2 mmol) of a solution of 1N LiOH was added at room temperature and under an argon atmosphere to a solution of 0.580 g (1.20 mmol) of compound G in 6 ml of dioxane . After 3 h of agita140

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CH 675 582 A5

tion at room temperature, the mixture was diluted with 20 ml of acetonitrile, the white precipitate was collected, washed with acetonitrile and dried under vacuum to give 0.670 g of the crude product of the title, in the form of 'a solid white. The crude product was suspended in 10 ml of water and applied to a pad of thin HP-20 resin (bed volume 15 ml, diameter 25.4 mm (1 inch)), eluted with 300 ml of water then 300 ml of MeOH. The product-containing fractions were combined and evaporated to dryness. The solid residue was triturated with acetonitrile to give the pure product of the title (0.550 g, 98%) as a white solid, m.p. 301-303 ° C with decomp.).

TLC (Ì-C3H7OH-NH4OH concentrated-H2O; 7: 2: 1) Rf = 0.48.

Examples 65 to 122

The following additional compounds can be prepared by respecting the procedures as presented above and described in the previous working examples.

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CH 675 582 A5

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35

40

45

50

55

60

65

CH 675 582 A5

Ex. No.

X

73. OH

-CH = CH- H

79. OH

-ch2CH2- a

80. NaO

-CH = CH- Na

81. o

-C3C-

It

145

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

146

m

S9

09

SV Z8S SZ9 HO

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

148

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

Ex. No.

X

94. KO

-CH2CV K

95. HO

/ CH3

-CH.

H

dC

CH //

Sh

3 3

-CH = CH- H

96. HO

/ 3

C-CH, H 3

-C = C-

H

97. HO

CH, J

CH

3

^ erO-

4 "= ^

-CSC- H

/ CH>

CH-

CH.

149

5

10

15

20

25

30

35

40

45

50

55

CH 675 582 A5

Ex. NO.

X

9a. Lio

/

CH-

CH.

I

CH

"" b

-CSC- Li

99. LiO

-CH.- Li

100. HO

-CH. - H

101- HO

Cl-

Cl

-CH2CH2- H

CH.

/ CH

CH3

150

l-SL

S9

gv Z85 919 HO

ESI

S9

H -ZEDZBD-

OH * 901

• on • xa gv 289 gz9 HO

CH 675 582 A5

Ex.

No. R_

110. LiO

10

15

20

25

111. kb

—CH = CH - Li

-ch2ch2- k

30

35

40

112. LiO

C2H5

-ch = ch- Li ch.

45

50

55

113. CH30

ch3o

Your.

CH.

c = c

\

O

CH.

-ch = ch- ch.

60

65

153

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

Ex-No.

114. OH

CH.

-ch2- h

115. LiO

116. LiO

117. LiO

118. LiO

SCE3 -C = C-

Li

CH, -CH-CH-— Li

E 3

^ CHg

-CEC- Li

-CH2CH2- Li

154

CH 675 582 A5

10

15

20

25

30

35

40

45

50

55

60

Ex • No.

119. LiO

120. LiO

121. LiO

122. LiO

i ^ ch

-C = C- Li t.

"CH2CH2 ~ Li

P

-esc -

\ CH,

CH

# 3

CH30

Li

• CH3 -CEC- Li

65

155

5

10

15

20

25

30

35

40

45

50

55

60

65

CH 675 582 A5

Claims (5)

Claims 1. A compound intended to inhibit the enzyme 3-hydroxy-3-methylglutaryicoenzyme A-reductase, comprising the fragment 0 -p-ch2-ch-ch2co- x oh 1 z where X is —CH2—, —CH2 - CH2--, —CH = CH—, —CH2CH2CH2—, —C — C— or —CH2O—, where O is linked to Z and Z is a lipophilic group. 2. Compound according to claim 1, having the formula 0 a.m. ( r-p-ch2-c-ch2e02Rx x oh 1 z in which the R is OH or a lower alkoxy radical; Rx is H or a substituted or unsubstituted lower alkyl radical; X is —GH2—, —CH2CH2--, -CH2CH2CH2 "-, -CH = CH—, —C = C— or —CH2O—, where O is linked to Z; Z is a lipophilic group, which is 156 5 10 15 20 25 30 35 40 45 50 55 CH 675 582 A5 157 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 675 582 A5 NyS4 XJl laugh , 16 r »23a c * c \ R ' >> R23a R ' 22 alfcyl or where the dotted lines represent the optional double bonds, or R1, R2, R2a and R25 are identical or different and are each, independently of the others, chosen from H, halo, trifluoromethyl, substituted or unsubstituted lower alkyl, haloalkyl , phenyl, substituted phenyl or ORy, where Ry is H or an alkanoyie, benzoyie, phenyle, halophnéyle, phenyl- (substituted or unsubstituted lower alkyl), substituted or unsubstituted lower alkyl, cinnamyl, haloalkyl, allyl, (substituted cycloalkyl or unsubstituted- (substituted or unsubstituted lower alkyl), adamantyl- (substituted or unsubstituted lower alkyl) or substituted phenyl- (substituted or unsubstituted lower alkyl); when Z is alkyl R5 and RS 'are the same or different and are each H or a substituted or unsubstituted lower alkyl radical or OH; R6 is a radical (substituted or unsubstituted lower alkyl) - such 158 CH 675 582 A5 0 " 5 ch3-ch2h = -c-, ch3 r7 10 or arylChte-; R6a is a substituted or unsubstituted lower alkyl, hydroxy, oxo, halo or trifluoromethyl radical; q is 0,1,2 or 3, and R7 is H or a substituted or unsubstituted lower alkyl radical; when Z is 15 20 25 30 35 at R R * 6- R one of the two radicals R3 and R4 is or V'v "' XX R Vs 45 and the other is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or phenyl - (CH2) P-, p is 0.1, 2, 3 or 4; where R13 is hydrogen, a substituted or unsubstituted lower alkyl, lower alkoxy (except tert-butoxy), halo, trifluoromethyl, phenoxy or benzyloxy radical; R14 is hydrogen or substituted or unsubstituted lower alkyl, lower alkoxy, halo-50 geno, trifluoromethyl, phenoxy or benzyloxy; Ri4a is hydrogen, substituted or unsubstituted lower alkyl, lower alkoxy, halo or trifluoromethyl; and provided that R14 and R14a are each hydrogen when R13 is hydrogen, that R14a is hydrogen when R14 is hydrogen, that at most one of R13 and R14 is the trifluoromethyl radical, that at most one of R13 and R14 is the phenoxy radical, and that at most one of R13 and R14 55 is the benzyloxy radical; R8 is hydrogen or substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C3-6 cycloalkyl, C1-6 alkoxy (except tert-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; 60 R9 is hydrogen or substituted or unsubstituted C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, provided that R9 is hydrogen when R8 is hydrogen, than plus one of R8 and R9 is the trifluromethyl radical, at most one of R8 and R9 is the phenoxy radical, and at most one of R8 and R9 is the benzyloxy radical; rio and R11 are, independently of one another, each chosen from hydrogen and the substituted or unsubstituted alkyl 65, substituted or unsubstituted cycloalkyl, adamantyl-1 or 159 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 675 582 A5 where R13, R14 and R14a are as defined above and q = 0,1,2,3 or 4; Y is O, S or N-R10; when Z is R 8 R 12 Ra is H or a substituted or unsubstituted primary or secondary C-i-e alkyl radical; Rb is a substituted or unsubstituted primary or secondary C1-6 alkyl radical; or Ra + Rb form (CH2) r or (cis) -CH2-CH = CH-CH2; r = 2, 3,4,5 or 6; r12 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or r15 and Ris are each H, Cl, Br, CN, CF3 or a phenyl radical. substituted or unsubstituted C1-4 alkyl, (C2-8 alkoxy) carbonyl, -CH2OR17 or -CH2OCONHR18; R17 is H or a C1-C alkanoyl radical; Ris is a substituted or unsubstituted alkyl radical or phenyl optionally substituted by F, Cl, Br or by a substituted or unsubstituted C1-4 alkyl radical; or R15 and R16, taken together, form - (CH2) s-, -CH2OCH2-, -CON (R19) CO-, or -CON-R20) N (R21) CO-; s = 3 or 4; R19 is H or a substituted or unsubstituted C1-6 alkyl radical, phenyl or benzyl; R20 and R21 are each H, a substituted or unsubstituted C1-6 alkyl radical or benzyl; and X is -CH2—, —CH2CH2—, —CH2CH2CH2—; when Z is where R8, R9, R ", ru and ri4a are as defined above; when Z is 4 " 160 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 675 582 A5 OC r - ^ „22 .23 " R22 is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, adamantyl-1 or t = 1,2, 3 or 4; R23 and R23a are the same or different and are each, independently of the other, chosen from hydrogen and the substituted or unsubstituted lower alkyl, lower alkoxy (except tert-butoxy), halo, trifluoromethyl, phenoxy or benzyloxy radicals; and under the conditions that R23a is hydrogen when R23 is hydrogen, that at most one of R23 and R23a is the trifluoromethyl radical, that at most one of R23 and R23a is the phenoxy radical, and that at plus one of R23 and R23a is the benzyloxy radical; when X is -CH2O (carbon atom attached to P and oxygen atom attached to Z), the lipophilia group Z will be , 2a 00 O Ojt 2b K where Rx is hydrogen or a substituted or unsubstituted lower alkyl radical, the compound having in free acid form, or in the form of a physiologically hydrolysable and acceptable ester, or in the form of a salt. 3. A compound according to claim 2, in which X is -CH = CH- or -C = C-, R is OH or an alkoxy radical, and Z is 'R2 R \ ^ ■ - XI r2a or Y '-r4 4. Compound according to claim 1, having the following designations: acid (S) -4 - [[(E) -2- [4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl] -2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic or its dilithium salt; (S) -4 - [[2- [4'-fluoro-3,3 ', 5'-trimethyl [1,1'-bi-phenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, its methyl ester or its mono- or di- (alkali metal) salts; (S) -4 - [[[4'-fluoro-3,3 ', 5-trimethyi [1,1' -biphenyl] -2-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, or its methyl ester; 161 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 675 582 A5 (5Z) -4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl [1,1' biphenyl] -2-yI] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, its methyl esters; (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] -methoxyphosphinyl] -3-hydroxybutanoic acid methyl esters ; (S) -4 - [[2 - [[1,1'-biphenyl] -2-yl] ethylmethoxyphosphinyl-3-hydroxybutanoic acid methyl ester; dilithium salt of acid (S) -4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3 -hydroxybutanoic; dilithium salt of (S) -4 - [[2- [4'-fluoro-3I3 ', 5-trimethyl [1,1, -biphenyl] -2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid ; dilithium salt of acid (5Z) -4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl] -2-yl] ethenyl] hydroxyphosphinyl] -3 - hydroxybutanoic; (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid dilithium salt ; dilithium salt of (S) -4 acid - [[2 - [(1,1'biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-butanoic acid (S) -4 methyl ester - (hydroxymethoxy-phosphinyl) -3 - [[(1,1'-dimethylethyl) diphenylsilyl] oxy] butanoic or its dicyclohexylamine salt (1: 1); (S) -4 - [[2- [1 - (4-fluorophenyl) -3- (1-methylethyl) -1-indol-2-yl] ethynyi] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt, or its methyl ester; (S) -4 - [[2- [1 - (4-fluorophenyl) -3- (1-methylethyl) -1 H-indol-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (E) -4 - [[2- [3- (4-fluorophenyl) -1 - (1-methylethyl) -1 H-indol-2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; 4 - [[2- [4'-fluoro-3,3,, 5-trimethyl] [1,1'-biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester ; (E) -4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl [1,1' -biphenyl] -2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its salt dilithium or its methyl ester; (S) -4 - [[[2,4-dimethyl-6-f (4-fluorophenyl) -methoxy] phenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[[2,4-dimethyl-6 - [(4-fluorophenyl) -methoxy] phenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[2- [3,5-dimethylI [1,1'-biphenyl] -2-yl] -ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[2- [4'-fluoro-3,5-dimethyl [1,1 '-biphenyl] -2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[2 - [[1,1 '-biphenyl] -2-yl] ethynyl] -hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1 H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] methyl ester -3-hydroxybutanoic; dilithium salt of acid (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic; (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethenyl] methoxyphosphinyl] methyl ester -3-hydroxybutanoic; dilithium salt of acid (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-ylj-ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic; (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1 H-pyrazol-4-yl] ethyl] -methoxyphosphinyl acid methyl ester ] -3-hydroxybutanoic; (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] -hydroxyphosphinyl acid dilithium salt ] -3-hydroxybutanoic; (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1 H-pyrazol-4-yi] ethyl] -methoxyphosphinyl acid methyl ester ] -3-hydroxybutanoic; (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] -hydroxyphosphinyl acid dilithium salt ] -3-hydroxybutanoic; (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethynyl] methoxyphosphinyl] methyl ester -3-hydroxybutanoic; dilithium salt of (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methyl! ethyl) -1-phenyl-1H-pyrazol-4-yl] -ethynyl acid ] hydroxyphosphinyl] -3-hydroxybutanoic; (S) -4 - [[[[4- (4-fluorophenyl) -1- (1-methylethyl-3-phenyl-1H-pyrazol-5-yl] -ethynyl] methoxyphosphinyl) -3 methyl ester -hydroxybutanoic; dilithium salt of (S) -4 - acid [[[[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -ethynyl] hydroxyphosphinyl] - 3-hydroxybutanoic; (S) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1 H-pyrazol-5-yl] ethyl] -methoxyphosphinyi acid methyl ester ] -3-hydroxybutanoic; (S) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] -hydroxyphosphinyl acid dilithium salt ] -3-hydroxybutanoic; 162 5. A cholesterol-lowering or lipid-lowering composition comprising a compound according to claim 2 and a pharmaceutically acceptable excipient for this compound. 163 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 675 582 A5 (S) -4 - [[[1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1 H-imidazol-5-yl] -ethynyl] methoxyphosphinyl] methyl ester 3-hydroxybutanoic; (S) -4 - [[[1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1 H-imidazol-5-yl] -ethynyl] methoxyphosphinyl] methyl ester 3-hydroxybutanoic; (S) -4 - [[2- [1 - (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1 H-imidazol-5-yl] ethyl] methoxyphosphinyl acid methyl ester -3-hydroxybutanoic; (S) -4 - [[2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] hydroxyphosphinyl] dilithium salt -3-hydroxybutanoic; (S) -4 - [[[2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; 4 - [[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; 4 - [[[[4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl] -2-yl] oxy] methyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its ester methyl; 4 - [[[4'-fluoro-3,3 ', 5-trimethyl [1,1' -biphenyl] -2-yl] methyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[[1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (E) -4 - [[2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; (S) -4 - [[2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or its methyl ester; 4 - [[3- [4'-fluoro-3,3 ', 5-trimethyl [1,1' -biphenyl] -2-yl] propyl] methoxyphosphinyl] -3-hydroxybutanoic acid methyl ester; dilithium salt of 4 - [[3- [4'-fluoro-3,3 ', 5-trimethyl [1,1'-biphenyl] -2-yl] propyl] hydroxyphosphinyl] -3-hydroxybutanoic acid; [1S- [1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a] acid methyl ester - 4 - [[2- [8- (2,2- dimethyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic; dilithium salt of acid [1S- [1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a]] - 4 - [[2- [8- (2,2 -dimethyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic; (S) -4 - [[[3 '- (4-fluorophenyl) spiro] cyclopentane-1,1' - [1H] indene] -2-yl] ethynyl] -methoxyphosphinyl] methyl ester hydroxybutanoic; or dilithium salt of acid (S) -4 - [[[3 '- (4-fluorophenyl) spiro] cyclopentane-1,1' - [1H] indene] -2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic.