FI87927B - FOERFARANDE FOER FRAMSTAELLINING AV NYA FOSFORHALTIGA HMG-COA-REDUCTASINHIBITORER OCH NYA MELLANPRODUKTER - Google Patents

Description

1,57927

The present invention relates to the preparation of novel phosphorus-containing compounds which reduce the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and are thus useful in the preparation of novel phosphorus-containing compounds. in the inhibition of cholesterol biosynthesis, in particular as components in blood cholesterol lowering compositions, novel intermediates in the preparation of such compounds and methods for their preparation.

F. M. Singer et al., Proc. Soc. Exper. Biol. Med. 102 (1959) 370, and F. H. Hulcher, Arch. Biochem. Biophys. 15,146 (1971) 422, have disclosed some mevalonate derivatives which inhibit cholesterol biosynthesis.

Endo et al. have disclosed in U.S. Patent 4,049,495, 4,137,322 and 3,983,140 a fermentation product which is effective in inhibiting cholesterol biosynthesis.

20 This product is termed compactin and is described by Brown et al. (J. Chem. Soc. Perkin I 1976, 1165) complex mevalonolactone structure.

: GB Patent 1,586,152 discloses a group of synthetic compounds corresponding to the formula

i'V 25 CH

VYR

Sr n ”*’ ·; ··· where E represents a direct bond, a C 1-4 alkylene bridge 35 or a vinylene bridge and different Rs denote different substituents. The activity reported in this GB patent publication is 2 87927, less than 1% of the activity of the compactin.

U.S. Patent No. 4,375,475 to Willard et al. Discloses blood cholesterol and lipid lowering compounds having a structure of

Xi? 3

E

10 I

6r ^ S2 r, 1H ”1 2 4 * 3 wherein A is H or methyl, E is a direct bond, -CH2-, -CH2-CH2-, -CH2-CH2-CH2- or -CH = CH- and R 2 and R 3 are each H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, phenyl, halogen, C 3-4 alkoxy, C 2-8 alkanoyloxy, C 1-4 alkyl or C 1-4 haloalkyl substituted phenyl or OR 4, wherein R 4 is H, C 2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl-C 1-3 alkyl, C 1-8 alkyl, cinnamyl, C 1-4 haloalkyl, allyl, cycloalkyl-C 1-3 alkyl,: " : Adamantyl-C 1-3 -alkyl or (substituted phenyl) -C 1-4 -alkyl, in which each of the substituents may be halogen, C 1-4 -alkoxyl, C 1-4 -alkyl or C 1-4 -haloalkyl, and the corresponding dihydroxy acids formed upon opening the lactone ring hydrolytically, and pharmaceutically acceptable salts of said acids and C 1-3 alkyl, phenyl and (dimethyl- * amino- or acetylamino-substituted) -C 1-3 alkyl esters of all of said compounds. en being ”• * 5 enantiomers having the 4R- ·“ ”· ^ configuration in the tetrahydropyran moiety of the trans racemate shown in formula 35 above.

3,87927

Patent application WO 84/02131 (PCT / EP83 / 00308) filed in the name of Sandoz AG, based on U.S. Patent Application 443,668, filed November 22, 1982, and U.S. Patent Application 548,850, filed November 4, 1982. 1983, heterocyclic compounds analogous to mevalonolactone and their derivatives corresponding to the formula? 10 ς 5 \ IL / r "xz 6 4 15 wherein one of the substituents R and Rq is - //, T R5 R5a wherein 4 20 R is hydrogen, C1-4 alkyl, C1-4 alkoxyl (except t-butoxyl), trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy,: R 5 is hydrogen, C 1-3 alkyl, C 1-6 alkoxyl, trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy and R 5a is hydrogen. , C 1-4 alkyl, C 1-2 alkoxyl, fluorine or chlorine, provided that R 1 and R 2 are both hydrogen, with R 4 being hydrogen, R 1 - is hydrogen and R 1 is hydrogen. - in the case of hydrogen, at most one of the substituents R 4 and R 1 is trifluoromethyl, at most one of the substituents R 4 and R 8 is phenoxyl and at most one of the substituents R 4 and R 2 is benzyloxy, and the other is primary or secondary C,

'! * ‘\ 1“ O

35 alkyl, C 3-8 cycloalkyl or phenyl- (CH 2) -, where m is 1, 2 or 3, 4,87927 R 2 is hydrogen, C 3-8 alkyl, C 3-8 cycloalkyl, 4-alkoxyl (excluding t-butoxyl) , trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy and R 3 is hydrogen, C 1-3 alkyl, C 1-3 alkoxyl, trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy provided that R 3 is hydrogen R 2: when n is hydrogen, at most one of R 2 and R 3 is trifluoromethyl, at most one of R 2 and R 3 is phenoxyl and at most one of R 2 and R 3 is benzyloxy, X is - (CH 2) -, where n is 0, 1, 2 or 3, or -CH = CH- and R, 54 3 2 1

Z is -CH-CH--C-CH 2 -COOH II

I ^ I 2 OH OH

wherein R 9 is hydrogen or C 1-3 alkyl; and in the form of the free acid, in the form of its hydrolysable and physiologically acceptable ester or 6-lactone or in the form of a salt under physiological conditions.

GB Patent 2,162,197A discloses: naphthyl analogs of mevalonolactone useful as inhibitors of cholesterol biosynthesis and having the structure 30 1 R 1 wherein R 1 is C 1-4 alkyl and Z is a group corresponding to 35 formula Z . ^ or Z2, 5 07927 -chch0chch-coor7 * y \ γ ·· Η k 2k * '1

OH OH OsV

0 5 (Ζχ) (Z2) «wherein in the first formula R1 is hydrogen, a hydrolysable ester group or a cation.

EP 164 698A discloses the preparation of lactones useful as high blood cholesterol lowering agents by treating the amide with an organic sulfonyl halide R SO 2 X and then removing the protecting group Pr.

15 1 R

protp! ° R4 8 ° tjr ° 20 R * 1.2 where: X is halogen,

Pr is a carbinol protecting group, R1 is H or CH-,

3.4 J

.25 R and R are each independently H, C 1-3 alkyl or phenyl-C 1-3 alkyl, where phenyl is possible; ; C 1-6 alkyl, C 1-4 alkoxyl- or halogen-substituted, 2 R is a group corresponding to formula A or B, β 87927.

0

J J

CH3 'H f 7 f a

5 0¾¾ ^ ¾ ^ IsjJ

(A) T, (B)

R

where Q is

1 I

Q = R6-C- or R6-CH; 1 CH 3 wherein R 1 is H or CH 2, R is H or CH 2, a, b, c and d are optionally double bonds, R 7 is phenyl or benzyloxy, the ring being in each case optionally substituted by C 1-3 alkyl or halogen, and R 8 and R 2 are each independently C 1-3 alkyl or halogen; and R 1 is C 3-3 alkyl, phenyl or mono- or; di (C 1-3 alkyl) phenyl.

. DE-A-3,525,256 (Paul Leroy: * ·. 25 Anderson) discloses a naphthyl analog of mevalonolactone; geja with structure so ί Ηγ ^ γ0Η en 2i 2 2 • - L 11 yA n oh oh £ Q ’

....: I

7,37927 in which the formulas are alkyl, Z is a group corresponding to the formula Q or Q1 and R7 is H or a hydrolyzable ester group; and which are useful as inhibitors of cholesterol biosynthesis and in the treatment of atherosclerosis.

Patent application WO84 / 02903, filed in the name of Sandoz AG and based on U.S. Patent Application No. 460,600, filed January 24, 1983, discloses compounds analogous to mevalonolactone and useful as blood cholesterol lowering agents having the structure χ-ζ r5

XfY

wherein both RQs together form a group corresponding to the formula 8 7 6 5 --C = C- C = C or - (CH2) 4-

::: L I I

Γ * ': 25 R R

R 2 where R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxyl (except t-butoxyl), trifluoromethyl, fluorine,. . Chlorine, phenoxyl or benzyloxy and • R 1 is hydrogen, C 1-4 alkyl, C 1-4 alkoxyl, trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy, provided that no more than one substituent is present; - of the substituents R 2 and R 2 is trifluoromethyl, at most one of the substituents R 2 and R 2 is phenoxyl and at most one of the substituents R 2 and R 2 is benzyloxy; β 07927 R 1 is hydrogen, C 1-6 alkyl, fluoro, chloro or benzyloxy, R 4 is hydrogen, C 1-6 alkyl, C 1-4 alkoxyl (except t-butoxyl), trifluoromethyl, fluoro, chloro, phenoxyl or benzyloxy and

R 9 is hydrogen, C 1-6 alkyl, C 1-4 alkoxyl, trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy, provided that at most one of the substituents and R 1. is trifluoromethyl, up to one of the substituents R 1 and R 8 is phenoxyl and at most one of the substituents R 1 and R 2 is benzyloxy, R 1a is hydrogen, C 1-2 alkyl, C 1-4 alkoxy, fluorine or chlorine, H CH2) q

C = C

15 x is “^ CH2} n” or - (CH2 \ where n is 0, 1, 2 or 3 and both q are 0 or one is 0 and the other is 1, and Z is 20 * 6 5 4 3 | 2 1

. . -CH-CH-C-CH-COOH II

::: I 2 I 2

; V OH OH

: Wherein R 9 is hydrogen or alkyl, with the general proviso that the phenyl group containing the -X-Z and the R 1 substituent is in the ortho position relative to each other; and which are in the form of the free acid, hydrolysable under its physiological conditions and physiologically. : 30 ti in the form of an acceptable ester or (β-lactone or in the form of a salt.

U.S. Patent 4,613,610 (Wareing), assigned to Sandoz AG, discloses a number of 7-pyrazolo-3,5-dihydrohept-6 useful as HMG-CoA reductase inhibitors. -eenihappojoh -____. derivatives having the structure 9 37927 R 6 R 5 -T 1 -R 7 r 2 R 1 wherein R 10 is C 1-6 alkyl which does not contain an asymmetric carbon atom, each of R 2 and R 8 is independently hydrogen, C 1-3 alkyl, n -butyl, isobutyl, t-butyl, C 1-4 alkoxyl, n-butoxyl, isobutoxyl, trifluoromethyl, fluoro, chloro, phenyl, phenyl or benzyloxy, each of R 1 and R 8 is independently hydrogen, C 1-2 alkyl, C 1-4 alkoxyl, trifluoromethyl, fluoro, chloro, phenoxyl or benzyloxy and each of R 4 and R 7 is independently hydrogen, C 1-2 alkyl, C 1-4 alkoxyl, fluorine or chlorine provided that not more than one of the substituents R 2 and R 3 is phenoxyl, not more than one of the substituents R 2 and R 2 is benzyloxy, not more than one of the substituents R 8 and R 8 is trifluoromethyl, | at most one of Rg and Rg is phenoxyl and at most one of Rg and Rg is * - benzyloxy, X is wherein m is 0, 1, 2 or 3, -CH = CH-, -CH = CH-CH2 or -CH2CH = CH- and * · Z is 6 / oh ·: ·? f 10 -CH <\ 35 -CH-CH2-C-CH2-COOR11 or I R10 · ..i: OH OH O CH- xc / 2

II

o wherein 10 8 7927 R 10 is hydrogen or C 1-3 alkyl and is hydrogen, R 1 or M, of which R 2 is a physiologically acceptable ester group which is hydrolysable under physiological conditions and M is a cation; provided that (i) the group -X-Z- is located in the 4- or 5-position of the pyrazole ring and (ii) the groups R 1 and -X-Z are in the ortho position relative to each other.

WO 86/07054A (an invention of Sandoz AG) discloses imidazole compounds analogous to mevalonolactone which are useful in the treatment of hyperlipoproteinemia and atherosclerosis and which correspond to formula I,

R, X-Z

M

H N-R, (I) v

20 I

R 3 wherein: R 1 is alkyl, cycloalkyl, Adamant-1-yl or R 4 --5 - / R 5 -substituted phenyl (group A),; * · *: 25 is alkyl, cycloalkyl, Adamant-1-yl li or: * ·. · R1-, R8-, R8-substituted phenyl (group B), R1 is hydrogen, alkyl, cycloalkyl, Adamant-1-yl, styryl or R1Q-, R11-, R12-substituted ° phenyl (group C); . . X is - (CH_) -, where m is 0-3, -CH = CH-, ... zm -CH = CH-CH2- or -CII2CH = CH-, Z is -CH (OH) -CH2- C (R13) (OH) -CH2-COOR14 (group A), -Q-CH2-C (R33) (OH) -CH2-COOR14 (group c) or a group corresponding to formula (b),

II

n 87927 CH,

/ \ / 0H

-CH C

I XR

I K13 5 0 CH0 \ / c | 10 0 wherein Q is CO or -C (OR3g) 2 ~, where R1g is primary or secondary alkyl, each R1gt is the same or both R1g2 together form a group - (CH 2) 2 - or - (CH 2> 3 -, R 13 is hydrogen or C 1-6 alkyl and R 1-4 is hydrogen, R 6g or M, wherein R 1g is an ester group and M is a cation; provided that Z is a group (c) only when X is -CH = CH- or -CH 2 -CH = CH- and / or when R 13 is C 3-3 alkyl, R 1, R 2 and R 2 -q are each independently C 3-3 alkyl, n-butyl, isobutyl, t-butyl, C 1-3 alkoxy, n-butoxyl, isobutoxyl, CF 3, F, Cl, Br, phenyl, phenyl, or benzyloxy,: ·: 25 Rg, R8 and R1-4 are each independently hydrogen, C1-3 alkyl, C3-3 alkoxyl, CF3, F, Cl, Br, COOR2, V (N (R19) 2, phenoxyl or benzyloxy in which R 1 is hydrogen.

R 18 'is C 1-3 alkyl, n-butyl, isobutyl, t-butyl or benzyl, or M and R 18' are alkyl, and. . Rg, Rg and R32 are each independently hydrogen,; / C 1-2 alkyl, C 3-2 alkoxyl, F or Cl provided that (1) at most one substituent in each of A, B and C is CF 3, at most one substituent in each of Λ, B and C is phenoxyl and at most one substituent in each of A, B and C is benzyloxy, 12 87927 (2) wherein Z is group (c) wherein Q is -C (OR15) 2-, the compound is in the form of the free base and either ( i) on

R 9 and each R 7 are independently R 8 or (ii) R 14 is M and each R 7 is independently R 8 or M and 5 (3) R 7 and / or at least one R 7 is M

the compound is in the form of the free base.

All alkyl groups are C 1-6 alkyl and do not contain an asymmetric carbon atom, and all cycloalkyl groups contain from 3 to 7 carbon atoms, unless otherwise indicated.

WO 86/04848A (Sandoz AG) discloses indene derivatives analogous to mevalono-Ikton in free acid form, in ester or delta-alkton form or in salt form, which are useful as blood lipoprotein lowering and anti-atherosclerotic agents and which correspond to formula I, fe:

- :. (: * 2 R: R

: Wherein R is hydrogen or primary or secondary C 1-6 alkyl and R 6 is primary or secondary alkyl or R and together form a group - (CH 2) m - if -m 3 is 6-6, or (Z ) -CH 2 CH = CH-CH 2,

Rq is C1-8 alkyl, C3-7 cycloalkyl or 1 * 4 "f * ·" 'R5-' R-6-substituted phenyl R2 and R4 are each independently hydrogen, C1-4 alkyl, C1-4 alkyl, C1-4 ~ alkoxyl (except t-butoxyl), CF 3, F, Cl, phenoxyl or benzyloxy, * 13 07927 R 3 and R 5 are each independently hydrogen, C 3-3 alkyl, C 1-3 alkoxyl, CF 3, F, Cl, phenoxyl or benzyloxy and

R 9 is hydrogen, C 1-2 alkyl, C 1-6 alkoxyl, F and Cl; 5 with the proviso that each phenyl and indene ring may have only one of each of the substituents CF 3, phenoxyl or benzyloxy, X is - (CH-) - or - (CH) -CH = CH- (CHO) -, where n is 1 to 3 and both qs are 0 or one q is 0 and the other q is 1, Z is -Q-CH 2 -C (R 10) (OH) -CH 2 COOH, which may be in the form of the free acid, ester or delta-lactone or in the form of a salt and wherein Q is CO 2 - (OR 2+- → wherein R 2 are the same primary or secondary C 3-8 alkyls or together form a group - (^ 2 ^ - or - (CH 2) 2 -, or -CHOH and R 1 q is hydrogen or C 3-3 alkyl with the proviso that Q can be other than CHOH only when X is -CH = CH- or -CH 2 -CH = CH- and / or R 6g is C 3-3 ~ alkyl.

U.S. Patent No. 4,647,576 to Hoefle et al., Issued to Warner Lambert, discloses novel C- and N-substituted pyrroles useful as blood lipid and cholesterol lowering agents, corresponding to formulas I and II, 25

H OH

ί Λ ^ H '(I)

• · 30 R "“ S

: R3 r4

H kOH ^ Λν ^ / COOH

35 R2'Y # 1vn- ^ x ": ^ oh <h> R3 R4 wherein i4 87927 X is -CH2-, -CH2CH2- or -CH (CH-j) CH2-, is 1- or 2-natyl, cyclohexyl , norborne-yl, phenyl optionally substituted with F, Cl, OH, CF 9, C 1-6 alkyl, C 1-6 alkoxyl or C 2-8 alkanoyloxy, 2-, 3- or 4-pyridinyl or their N-oxide or __® / ^ 5'hal ^ 10 wherein

R 9 is C 1-4 alkyl and halo 9 is chloride, bromide or iodide; R 2 and R 2 are each independently hydrogen, Cl, Br, CN, CF 3, phenyl, C 1-4 alkyl, C 2-8 carboalkoxyl, -CH 2 OR 8 or -CH 2 OCONHR 7, wherein R 8 is hydrogen or C 1-8 alkanoyl and R 6 is alkyl or phenyl optionally substituted with C1-, Br- or C1-4-alkyl, or R2 and R3 together form a group - (CH2) n-> -CH2OCH2-, -CON (Rg) CO- or -CON (Rg) N (R1Q) CO-, where n. . is 3 or 4, R 9 is hydrogen, C 1-4 alkyl, phenyl or benzyl and R 9 and R 9 q are each independently hydrogen, C 1-4 alkyl or benzyl, and R 4 is C 1-4 alkyl, cyclopropyl , cyclobutyl or CF ,.

• * J

In EP-A-0 221 025 A1 (Sandoz AG):; Compounds analogous to mevalonolactone and their derivatives corresponding to formula 30 are shown.

Rc Rb

ϊ, M

... Rd Ra is 37927 where

Ra is a group -XZ, Rb is R2, Rc is R1, Rd is R1 and Y is a group -N- or R1 Ra is R1, Rb is a group -XZ, Rc is R2, Rd is R1 and Y is O, S or -N-, R 1, R 2, R 1 and R 2 are each independently C 1-6 alkyl which does not contain an asymmetric carbon atom, C 3-7 cycloalkyl or a ring corresponding to the formula f " = jh · ^ R? 15 wherein each R 1 is independently hydrogen, C 1-4 alkyl, n-butyl, isobutyl, t-butyl, C 1-4 alkoxyl, n-butoxyl, isobutoxyl, trifluoromethyl, fluorine, chlorine, bromo, phenyl, phenoxyl or benzyloxy, each R 9 is independently hydrogen, C 1-4 alkyl, C 1-3 alkoxyl, trifluoromethyl, fluoro, chloro, bromo, phenoxyl or benzyloxy, or each R 1 is independently: hydrogen, C 1-2 alkyl , C 1-2 alkyl, fluorine or chlorine with the proviso that each ring A may have: only one of each of the substituents trifluoromethyl, phenoxyl and benzyloxy;

'* R 1 and R 2 may further be hydrogen and, when Y

· * · · Is O or S, R 2 may be a group ™ X / R 18

30 / C-C

V *: R 17 R 19 · .. wherein R 1 is hydrogen or C 1-3 alkyl, and R 1 and R 9 are each independently hydrogen, C 1-3 alkyl or phenyl; X is or ( CH 2) CH = CH (CH) -, where m is 0, 1, 2 or 3 and both qs * ^ 'd are 0 or one q is 0 and the other 1, and ie 87927

OF

Z is -CH-CH, -C-CH, -COOH

I 2 I 2

OH OH

Wherein R 9 is hydrogen or C 1-6 alkyl and which may be in the form of the free acid, in the form of an ester or β-lactone or in the form of a salt, as appropriate; and which are said to be suitable for use as blood lipoprotein lowering and anti-atherosclerotic agents.

Tetrahedron Letters 29 (1988) 929 discloses a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor having the structure

F

OH OH o 20 JJ a a.

H3C2CH3: 'wherein R is Na or synthesis.

EP-A-127 848A (Merck & Co., Inc.) 25 discloses the derivative of 3-hydroxy-5-thia-α-arylalkanoic acids. : derivatives with the structural formula 'V ho _ o I ox 30 ^ S (O). : I n

'· *' · E

· ** ·: I

2 • · «• · · ··« *> - m * · »· i.

17 37927 where Z is, * xo6 / ’

R3 I

R 5 wherein 1 2 3 R # R and R are each independently, for example, hydrogen, chlorine, bromine, fluorine, C 1-4 alkyl, phenyl, substituted phenyl or OR 7, wherein Ry is, for example, hydrogen, C 2-8 alkanoyl, benzoyl, phenyl , substituted phenyl, C 1-9 alkyl, cinnamyl, C 1-3 haloalkyl, allyl, cycloalkyl-C 1-3 alkyl, adamantyl-C 1-3 alkyl or phenyl-C 1-3 alkyl, and R 4, R 5 and R 6 are each independently hydrogen, chlorine , bromine, fluorine or C 1-3 alkyl; n is 0, 1 or 2, E is -CH 2 -, -CH 2 CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH = CH-CH 2 ~ 20 or -CH 2 -CH = CH- and X is, for example, hydrogen, C 1-3 ~ alkyl or alkali metal cation or ammonium.

These compounds have a high blood cholesterol-lowering effect due to their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A: (HMG-CoA) reductase, and antifungal activity.

FR patent application 2,596,393A (Sanofi? A), X filed April 1, 1986, discloses 3-carboxy-2 '' hydroxypropanephosphonic acid derivatives including salts corresponding to the formula h, V ° R3

R-OOC-CH - C-CH, -P

ie R 1 and R 2 are each independently H, lower alkyl or optionally substituted aralkyl and 18,07927 and are each independently H, lower alkyl or optionally substituted aryl or aralkyl; and are useful as blood lipid lowering agents.

5 These compounds are reported to lower cholesterol, triglycerides and phospholipids more than meglutole.

EP-A-142 146A (Merck & Co., Inc.) discloses mevinoline-like compounds having the structural formula H0 0

15 E

z wherein R 1 is, for example, hydrogen or C 1-6 alkyl, E is -CH 2 -CH 2 -, -CH = CH- or "(CH 2) r - and Z is a group υ o

25 R7- ^ X

a1ch3

R g '^ S ^ S ^ J

•. 30 wherein: .9.9 I .. * X is -O- or -NR-, wherein R is hydrogen or C 1-8 alkyl, ... 7: R is C 2-8 alkyl and ·; ··· R® is hydrogen or CH 2; R 12 wherein R 3, R 1 and R 2 are each independently, for example, hydrogen, halogen or C 1-4 alkyl;

3) I

Wherein 1 is 0 to 2 and R is halogen or C 1-4 alkyl; or

4) O

R7kk0: H - 20 II I 3 (r15). . m: A: These compounds are HMG-CoA reductase inhibitors.

This invention relates to a process for the preparation of novel phosphorus-containing compounds which inhibit HMG-CoA reductase and are thus useful as blood cholesterol lowering agents and which contain a group of

. . 30 O

: I »-P-CHo-CH-CHo-CO- - 12. 2

X OH

Cl · i

35 wherein X is “(C ^ a” '-CH = CH-, -C = C- or -CH 2 O- (where O

is attached to Z), a is 1, 2 or 3 and Z is a "hydro-" 'phobic anchor ".

20 97927

The term "hydrophobic anchor" as used herein means a lipophilic group which, when attached via a linking group ("X") to the upper HMG-like side chain of the molecule, binds to the hydrophobic "pocket" of the enzyme, which is not utilized by HMG-CoA binding, resulting in increased potency compared to compounds where Z is H.

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

I R-P-CH., - C-CHo-CO., RX

t 2 | 2 2

X OH

£ 15 wherein R is OH or lower alkoxyl,

Rx is hydrogen or lower alkyl, X is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH = CH-, -C * C- or -CH2O- (where O is attached to Z) and Z is hydrophobic anchor; and said compounds include pharmaceutically acceptable salts thereof.

V. "The term" salt "and" salts "refer to the inorganic and organic bases formed by the compounds: · .: such salts as 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 with organic bases such as amine salts, for example dicyclohexylamine, benzathine, N-methyl-D-glucamine and hydrabamine salts, salts with amino acids such as arginine and lysine salts, etc. Non-toxic, pharmaceutically acceptable salts are preferred, although other salts are useful, for example, in isolating or purifying the product.

2i 37927

Examples of hydrophobic anchors useful in accordance with this invention include, but are not limited to, the following: R2a R1

VM

> 10 k * "

15 R® I

R «

20 R3'N ^ \ r-R <«-N

y N - N »Ym N 'N

: / ° R ^ V

ri ”* yM‘ «vV *’ v_v ,! m H, -y / p & · * R r9 R- Rb 30 S '' γγ * '· ^, .. v> R23a 22 87 927 R6

0 I

JL >> alkyl or 5 '| rs "** 6 *), where in the latter dashed lines denote possible double bonds, for example 10 R6 R6 Γ l

0 0 I

15 MM r5 + «·%. R - R «, r“ '<. .....

R * · <**% r5 (r>, 07 r6 r6 ΙΌ 25 Iq {, alkyl alkyl JOO, · M1 or R5 C * '\ R 1B> q

. . 30 H

: ·: «E: 7: i 0 ^ Vy ^ V ^ alkyl 35 23 37 927 i 2 2 ci 2 b and wherein R, RT, κ and R may be the same or different and are each independently H, halogen, lower alkyl , haloalkyl, phenyl, substituted phenyl or OR 4, where R 1 is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl (lower alkyl), lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl (lower alkyl), adamantyl - (lower alkyl) or (substituted phenyl) - (lower alkyl).

Z is group 10 R6

O

15

r5 -—JL. JL J

R 5 5 51 20 R and R may be the same or different and are each independently hydrogen, lower alkyl or OH,

O

• · * · c n: R is (lower alkyl) -C-, such as

v .: O

i V 25 CH, -CH9-C-C-, or aryl-CH9-,. . J \ 7 Δ

ch3 R

R is lower alkyl, OH, oxo or halogen, q is 1, 2 or 3 and. : R 7 is hydrogen or lower alkyl.

When Z is a group R® r3 t - 24 87927 * vy * νν. · Γν

N — N '\ = - N' X = _N

5 / o R ™ Rl “r3-J \ / R4 r ^ A ^ r4" Vv'1 XJ.> _ / -> 4 R10 RU R ° ^ * 1β 3 4 15 one of the substituents R and R is —— \ i > v.R14 R14a and the other is lower alkyl, cycloalkyl or phenyl-20 (CH2) p-, wherein p is 0, 1, 2, 3 or 4, wherein R is hydrogen, lower alkyl, lower alkoxyl (except t-butoxyl) ), halogen, phenoxyl • · · * * ·>. *: or benzyloxy,

R 14 is hydrogen, lower alkyl, lower alkoxyl, halo, phenoxyl or benzyloxy and; R * a is hydrogen, lower alkyl, lower alkoxyl or halogen with the proviso that when R-Xn is hydrogen both R1 and R1a must be hydrogen, when R14 is * * 1 hydrogen R: n must be hydrogen, not more than one substituent, ·. ; And R 1 may be trifluoromethyl, at most one of R 1 and R 2 may be phenoxy, and at most one of R 1 and R 2 may be benzyloxy; • f: R 8 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxyl (excluding t-butoxyl), trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy and R 87927 9 R is hydrogen, C 1-3 alkyl , C 1-3 alkoxyl, trifluoromethyl, fluorine, chlorine, phenoxyl or benzyloxy, with the proviso that when R is hydrogen R is

g Q

be hydrogen, not more than one of the substituents R and R

5 may be trifluoromethyl, at most one of the substituents R9 and R9 may be phenoxyl and at least one of the substituents R9 and R9 may be benzyloxy, R1 and R * ^ are each independently hydrogen, alkyl, cycloalkyl, yl or group 10

R 14a is wherein R 1, R 4 -4 and R 4a are as defined above and q is 0, 1, 2, 3 or 4, and Y is O, S or NR 10.

When Z is group 20 B '

: ·: 25 R R R

: Y: Ra is hydrogen or primary or secondary C1-6 alkyl and R * 3 is primary or secondary C1-6 alkyl, or R and Rd together form a group - (CH2) r, where r is 2 , 3, 4, 5 or 6, or cis-CHO-CH = CH-CHO-, · - · 12 μl R is lower alkyl, cycloalkyl or a group

1 - - & C

14a 26 07927 and, R 1, R 2, R 2 and R 2a are as defined above.

When Z is a group 5 R 3 I R 4 x x 15 R 15 R 16 15 16 10 R and R are each hydrogen, Cl, Br, CN, CF 2, phenyl, C 1-4 alkyl, C 2-8 alkoxycarbonyl, -CH 2 OR 17 or -CH 2 OCONHR Wherein R 1 is hydrogen or C 1-6 alkanoyl 18 and R is alkyl or phenyl, which is optionally

F- * Cl-, Br- or C 1-4 alkyl-substituted, or 15 is 2.S

R and R together form a group - (CH9) -, and -CH2OCH-, CON (R *) CO- or -CON (R) N (R) CO-, wherein ^ 19 s is 3 or 4, R is hydrogen, C 1-6 alkyl, phenyl or benzyl and R and R are each independently hydrogen, C 1-4 alkyl or benzyl, with the additional proviso that Z 1 4 that when Z is a group 3 I 4 • y 25 T / x can only be -CH2- # -CH2CH2- or -CH2CH2CH2-.

When Z is a group «” £? ·: „J £ \

R23a C-C

X 35 r - <X \ 22 R 23 »27 37927 22 R is lower alkyl, cycloalkyl, adamant-1-yl or - (CH 2) t - (^) ^; wherein t is 1, 2, 3 or 4, and R 2 and R 2 may be the same or different and are each independently hydrogen, lower alkyl, lower alkoxyl (except t-butoxyl), halogen, phenoxy or benzyloxy with the proviso that when R is hydrogen R 2a must be hydrogen, at most one of R 2 and R 2a is trifluoromethyl, at most one of R and R is phenoxyl 23a and at most one of the substituents R and R is benzyloxy.

When X is -C 2 O (carbon bound to P and oxygen to Z), the hydrophobic anchor is an anchor of the phenyl or naphthalene type, such as group-15

V - M

20 La R2b R2

K

Compounds of formula I thus include compounds of formulas Ia to Ig.

25 O

Ia R-P-CH2-CH-CH2-CO2RX

C OH

ml

C

of 30 0

Ib R-P-CH2-gH-CH2-CO2RX

. · * · CH OH

· ... li CH (cis) 1

Z

28 37927

O

Ie R-P-CH2-CH-CH2-CO2RX

CH OH

II

CH (trans) 5 k 0

Id R-P-CH2-? H-CH2-CO2RX

CH, OH

1 2 10 CH, i 2 z 0 Work 11 x

Ie R-P-CH, -CH-CH, -CO, Rx 1 2 s 2 2

15 CH2 OH

Z

O

If R-P-CH2-CH-CH2-CO2RX

20 (^ 2 ^ 3 ° H

Z

V ;: O

\ v Ig R-P-CH, -CH-CH, -CO, RX /

* V 25 CH, OH

* O

• · .1

Z

• a * · ·

The terms "lower alkyl" and "alkyl", which-. . As used herein either alone or as part of another group, both straight and branched chain hydrocarbon groups containing 1 to 12 carbon atoms in the normal chain, preferably 1 to 7 carbon atoms, such as methyl, ethyl, propyl, 35 isopropyl, butyl, -butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-di-293727 methylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, their various branched isomers and the like as well as groups containing a halogen substituent, such as an F, Br, Cl, I or CF 2 substituent, or an alkoxyl, aryl, alkylaryl, haloaryl, cycloalkyl, hydroxyl, alkylamino, alkanoyl -amino, arylcarbonylamino, nitro, cyano, thiol or alkylthio substituent.

The term "cycloalkyl" as used herein, either alone or as part of another group, refers to saturated cyclic hydrocarbon groups containing from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cycloedecyl and cyclododecyl, any of which may be 1 or 2 halogen, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxyl groups, 1 or 2 hydroxyl groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino groups, Substituted by 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups and / or 1 or 2 alkylthio groups.

* 25 The term "aryl" or "Ar" as used herein means mono- or bicyclic aromatic groups containing from 6 to 10 carbon atoms in the ring moiety, such as phenyl, naphthyl, substituted phenyl and substituted naphthyl in which phenyl or naphthyl may have 1, 2 or 3 lower alkyl groups, 1, 2 or 3 halogens (Cl, Br or F) as substituents, 1, 2 or 3 lower alkoxyl groups, 1, 2 or 3 hydroxyl groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups, 1, 35 2 or 3 haloalkyl groups, 1, 2 or 3 halogenated groups. - a phenyl group, 1, 2 or 3 allyl groups, 1, 2 or 3 cycloalkyl groups, 1, 2 or 3 adamantyl 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 5 cyano groups, 1, 2 or 3 thiol groups and / or 1, 2 or 3 alkylthio groups, the aryl group preferably containing 3 substituents.

The terms "aralkyl", "arylalkyl" and "aryl (lower alkyl)" as used herein, either individually or as part of another group, refer to lower alkyl groups as defined above containing an aryl substituent such as benzyl.

The terms "lower alkoxyl", "alkoxyl", "aryloxy" and "aralkoxyl" as used herein, either alone or as part of another group, mean (lower alkyl), alkyl, aralkyl or aryl groups as defined above which are bound to an oxygen atom.

The terms "(lower alkyl) thio", "alkyl-20-thio", "arylthio" and "aralkylthio", used herein either alone or as part of another group, mean (lower alkyl; alkyl) as defined above. , aralkyl or aryl groups attached to a sulfur atom.

. * 25 The terms "(lower alkyl) amino", "alkylamino", "arylamino" and "arylalkylamino" are used herein, either alone or in the presence of another group; means (lower alkyl), alkyl, aryl or arylalkyl as defined above. : 30 l groups attached to a nitrogen atom.

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

1 The term "halogen" as used herein means chlorine, bromine, fluorine, iodine and CF 3, with chlorine and fluorine being preferred.

I.

31 37 927

Preferred compounds are those compounds of formula I having the following structure: II R 0 CH., H CH- \ 1 '/ 2 \ I / 2 \ x 5 P c co2rx x 5

2 OH

wherein R is OH, OL 1 or CH 3 O, RX is Li or H, X is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH = CH-, -C * C- or -CH 2 O- and Z is a group R 1 R 2 R 20a wherein: R 1 is phenyl or alkyl- and / or halogen-substituted phenyl, cycloalkylalkyl, such as, for example, cyclohexylmethyl, or halogen-substituted benzyloxy and • · "2 2a::: R and R are the same and are hydrogen, halogen, Y or lower alkyl.

Z may also preferably be a group 30 R1 1 © k,

12 R

Wherein R and R are as defined above in connection with the compound of formula II; 32 87927 or group CSX?

5 I

R 4 is wherein R is substituted phenyl, lower alkyl, cycloalkyl or phenylalkyl and R is substituted phenyl, lower alkyl such as isopropyl, cycloalkyl or phenylalkyl; or group H6

OF

R 5 is wherein R 2 is hydrogen, CH 2 or OH and R 2 is; :: r ': v. 25 •. · 7. . wherein R is hydrogen or CH 2 / or (substituted phenyl) -1-methyl.

Z may also preferably be a group 30 f: W -yS'1 '* vV' N —N '\ = _ N ^ \ - m as & · £ *> «···· I, 33 87 92 7 3 4 where at least one of the substituents R 1 and R 2 is phenyl or substituted phenyl and the other is lower alkyl.

The analogous process according to the invention for the preparation of the novel compounds of the formula I and their salts is characterized by what is stated in the characterizing part of claim 1.

The compounds of the invention corresponding to formula I can be prepared according to the following reaction series 10 and the related description: • 87 •

M

d -ρ tn

•B

* «Τ ', j? υ - ρ υ

ι τ Q

a * η "· η

U -Γ * Tr, · Η C

11 R aT * Η -Η * V Μ Ο · Η y {Ν'- in S 'Η χ u s S τ1 5 ι · η ^ υ>> ·

° s CO M «CU

* o »iiio \

* I H \ m -H

, rt N rl \ S Tl.

‘U” »v \ Λ> Ί“ ο δ O> 1 H I M *

3 O-O, rH -H

.0 I (O * e π O «n n _ -H O -» - rH U ^

S> 1 IS

$> i ™ u jp, S sn 3 rtJ / s i> “UlllO'-w 'Γΐ _ ι V m S 2 (N \ s 5 T m S \ us

> <-H 4J O U

• · _ 1—1 X IS

: · G> i «oscu— o

• p * u A

r::> h i. g ««>: *. o m o:. · £ - m n -h

. . 52 CU M. VJ 3 (N yfs, rH

... JÖ and rH ^ XW> 1 ·. :> p u d> i <CM -P Λ *::: H SO ή • η O -n «n. . «RH (N -;::«> 1 Λ O rn • *>> 1 us «^ * C cm o in

«Ή p -r | E w S

US o «β m CJ o vo: r cm -h (u ι ι u ·· ·· m OW 4J S -H> r <in s in um tn UmO-w.:. Susi -v <u ι \« nm. * «e-« m -Τ 'o' -rl CM \ s> n U — UU S g PM HS \ Ά

Ρ ι U <1 ä K O U U

• - «—H I * 4H IS

··· «m S tn OsCU — o O o · ^ ·” U · ·, o ι

- - -H I rH cm pn O

P CM -H

M S rH

·; «U>, O l>>,

• S M M M

'***! rH

ro 35 87927 H ^

£ S

(0 ro CN - <0 O «Ό 04 ro U X O - * 04 U> n o ro

X ~ X IX

CJ Cj vo m 04 U m I I U M X X x.

X -H /> U υΟ'Λ

UimO — w ^ m x I I> o

I V 1Λ U-N X -H / M

04 \ X Uwo-M 'X

X \ VO I. m

U U 04 \ X

I <—I X \ ve o = .cu_u u u

I I

Ο -H OiO.-U

• H + J / K I "I

H is CJ-ea> 1 -H.

> · O T? • X C £ Η Φ -. C 'ftJ φ Cl, ^

0 ffi "J

rH H m 10 1 · Η „> o g ή c /« ον

M ^ ^ -H

β Ό Ο O 3 4J

\: I - «ro j = - = s'" fa: *:: £ 3 S - - £ 5 WM rl 04 t,; ···: II -.35 1 I. S5 ·.: 04 6 04 ° e • *. - »« N cun (2: · - mm X 9, V, Xu ra υ 2 £ nj OI g II X ε o U x £ XM ^

2 U Ο υ “ΝΙ .S -H

5 .. 3 Ό + *. . tn 04 7; -ri c <e * · * ro -N 5 Cu / N Γ1 'H ω' · '· ~ m n O' M1 2 2

·. · Ro cj B4 JS-H -PtOC

::: x o 2 S-u <uc «tj

• cj U ^ 4J W <D X

- w ^. -h * g

. "·.„ £ I C H

* * · · I. Ή O I — I

. M 04 (33 J X i> ·: * ·: u Λ __

. * H <N

* M

'OM

* M X M

> u — n> x 36 87927

C/O

-P

0 • n (Ö Λ

C

B

P

(U

-P

+ J -H

CU. C/O

0)> i

• H> i r "H f — I

> 1 O> 1 P r-ί T3 32 Ή

·% CO X

O ~ ~

U iH CN

CN

S I

u ^ 1 •> 1 SS> 1

UrnO <M

I M »H

CN (0 PO

S CN -S

U O n

_ i O X

O-Oi — Or O-esi CN u «Λ I S'-®

O O O VO

S I I yO H

S -H / M

umO-cn 'X

1. m cn \ x

S \ VO

~ u o

. -H I S

· .: Ö / 1N o-0, -0. . HJ I A -.

6, rö g \ X 0) • CO s CO rH O Ή

= 1 ^ Λί> 1 l O

. ·: -P o>, n ~

• · O'-H CO M

. : n 5 ό>, -h. <d 2 + J (d Λ o. co • U-, X -H ^ S.

c -Τ 'o λ;

• H = -H H

• ·. : P υ J <u <υ - o, ...

jj * s P fc -H C -f <u z co oi u p.

: 0) J * ·>, C 's. e V

3 <* S> S ^ ™ i®, o Λ «g, η1 u ii Tj f— (i

-H I si, £ O SS

•: co £ k ai ^ -Γ pn, ° ®

a - o CN

r ·: ~ $ (NO) s

^ <N w X s O

I X

ο = ο.-υ - i 'N.x en M m O Nu -h x x x i o

Csi ^ I: 37 87927 to

P

P

• ° / N

(O

a c

•B

p <u

-P

-P -H

Q) to <1)> i

• H> i r — I r — I

> 1 O> i P η 'd • Η ί> ι w a

rH CM

*B

I-I

λ;

I — I t0 (N

o - 0 t * i 1 a m cn u a a ^ vo u u u

I I / M

a ή / m

Uh * 0 —tn in m I \ a x

<N \ VO

a υ

CJ fM

0 = 04- U <N

: I \ a:. :: o o— n «. * «" T

• · * I — I

* * ’·> 1> 1

: ·: M

rH

: * d • - · τ ·

P ~ fM

U to o ^ λ υ ... T3 cn ": to (¾ a

> 1 U Q

::: -P up m ι m • to o a a

• · Η t — I »CJimO

. "·. M a ι

· Ι — I »O (N

<U (N 0) ~ - ^ a, a 2 cj <n ι a on-u <N ι \ a "M o U- ··· * M 23 ....: x • 38 8 7927 1s o Ή Ή

4J + J

c e <ο ο m η Ο η: g J H c 6 αχ ι — t υ £ 33 (Ο Ό

^ * ί -Ρ M G

^ CJ β) μ Ο • μ ι ε> «: (0 ^ _ + * ιΗ γί tn Η τ3 Ä« χ> 1 3 CM S Η _ + J o M-CJ> (0 ιη υ Λ, χ χ m -Η <Ν χυ — Ν w ε χ

Ρ ή U CJ

0 3 ι ^ Μ / Κ • ro> χ, χ co θ · ΙΙθ C Ο

'1 (β CN

GO CN Ρ W 4J

OJ h χ .ρ 3 Μ Ό Ο w <β • HC ι χ Ό »<υ ω o-ο * —υν ο μ -Ρ Ό t <Χχ ^ Μ m -η Ο υ — ν H a) χ Ό - Ρ χ ω t> 1 -rl ΓΟ Ό • · G, e α ^::: a>> ι χ • · · · · Η> · υ • · to tn ι> • '(0 + j, cx.. -Ρ w • · tn ι ex to x trt — uv • · ·> U '^ x

II XU-N

MX

::: u (0 1

3 tn O / K

• ·> e -π

<0 (0 + J

(0 M ro _ “» g c o e w o ω H - °::: (0 tn ^ ^

ι-. O

• ρ p «β £ V 5 0 x 5 ~

• · -P

λ: · ': · $ x-u = cj-N x x 39 87927 tn 2

O -IV

• m (0 Λ

B

c c -H (0 P (Ö ^ 0) tn -h • P M tn -P O> i 0) -H> 1

O) t) H

-Ρ O

-H * U

> i 5 'Ö> i O>,

Ή XJ

P M ^ C / 0 • «

rH (N

'; 'Ή

• - · -) —I

- ·> 1: -> i ^ _: ·. ·. h ^ - - '' Kl ro - - OS m: '· new * · CM -> to

. ·. ·. MOUTH

V V

. ‘· - E to. m

U "iO \ S

\ to

U S

CN

O

-.H U

tn m (N

c> s · «3 X U r ~ <n u i tn SP s s c ·“ 'U UHIO fl IS I u u

O = 04-Uv rt | 4-1 H

• - -. i v s s -

Q U-tSJ U

• p I I

^ o — en- u.

^ I \\ E

> 1 O X U — tS5 .... * rn rH ^ fÖ 40 87927

CN

H (—I

> i ~

> i CO

MG _ C r-t <a m 0 ·· rt P r ·

M O -P M K

X G 7 ^ w x S

»» O = i-5 * 3 £ s 1 e Va o = i-3 5

> 1 h U — N I Λ. M

H «Q

> * U — NJ

JfO Ή> G> i aö OJ> i PC Ai tn -H tn ^ • P O 2 (0 Ό -P .j> .5, * Q ϊ! ^ «2» i-, m £ 2 10

w -p ^ G ^ -P

g 5 * a ^ E cf * °> OO C Ci Ai „> - · en - · ρ 55 * - cj e ^ e! 5 · * p ·· <n e · i_j c 1 c Η (Λ · Ρ—.

S ·· α <u P oo ω ΙΓ -rtC 0 03 O - Z n J * • h ® sT * "£ af3 g O um fl ^ en Γ. S um S® ~ SS, H £ - g .S 5 ~ Λ O, u T3 co flj p§ * ·

JK -H t! 35 ^ «N

* V, S

: Λ 8 S Ϊ ::: ·: s »s« 1.

* '·' 5 ^ 0 = 0 <-0 X E 2: *. 2 * «x -o 2 • ·" uj 1 S _ 1 33 - m ffl E .U “N ° - ^ tU m.

: · .:> u / I \\ ·> <• · 11 o 9 vk x

H K S tN I

υ ~, Η fÖ I ^

. - (0 CO Q

-. ·. > e ^> K

(0 <Ö Of? ^ / S «JM -H * rt X -p -p ^ O ™ - -« J «o -Hl! '." ·· Cd O go CO d) • · U co ~ r- > 1> C 0 = 0, 1> 1 co

... rt (U (N r-t e O

• n T3 K * O ·· C

P C CJ & P K -H

- (0 O -H a; Ό O · —I

'. - - CO X kj Γη> ί -H -H

O Kpm

*! ' -B

-p M

<Ö _ M

...: 0) O M

OS = M S

....; U -N> £ 4i 87927

✓K

tn

P

tn s • h o M S m

Ή E S

a> <rs cn ft z o

E

• H tN

• H O

> 4 U

> 1 ™

2 S

iti I

cn SS U

O 0-0 m

0 I

1 m

ΓΊ S

s o

0> IS

1 M OSft — O

o = u x i ss.s

I X O X0 — N

S * => s 0 1 s

No-U-ft

O N U-N -H

::: -h tn '> -h

·· - rH> lL C

> 1> 1 5 (ö

• · ·> 1 -H pH ^ ttJ

λ; pH o tn:. ή> 1 p λ; • - <0>, ό o

... Ή SO

'. nj -H

p t

: V: -2 ®θ-υ S

"Ιο Λ o ^

2 VI o <N

3 u Q0 o “/ r * a: · .: S Φ / 1 <n * - $ 0-0 s: -r: | V a = Ϊ ^ O E- · 0-0

• * I H

<N <J

X M

..... 0

I S

M Olft-O

'M ά · ^ o — n

X

rH

rd · ": *> i 42 87927

UI

5 '' N

»« O> i / N ό ^ 2 .S ®

Cl, G ^ N · O

se ί X in Q „^ cq s

G n] «3 CN

• -H Λ Z U

-P Ό, nj -H ^ X p O £ «. ^ Λ> 1 Γ4 ^ n Ή cn -P - O ro

X U rH a ™ CN

CJ Z CJ ft o I CO O G u

c X s U -G I

o o H - - CN

23

χ. V

(Q cH (N CO CJ32.O

G * _ H

U) ™ 10> ._j rj £ ^ v O'- U CN 5 2, «-h I M *

G Ή 0 = -0, -O — N

-p> 1 I -

e M> 1 O

S 3 -H

rri e G Ifl H

H d «-> 1 ai? O CN M> 1

ij> - X> .X

dj 0 = 0, - CJ-N X H

• h ι "- x * S ^ 3> 1 Π> 1 ^ UCM / S> 1 f, X * ^:: ': -h 0 d: ..: ί cn o,«

£ x en O

• * 2 V o </ 1 φ / o u Γ ··: S „3 <J ° - \ i i

. . : ^ -p> 1 \ 's (d I

h X, u ai

I / G

• · · „<CN (13 Φ f n) Cl, S« ° - ° «£

. . ·. > U Λ G

‘$ X ™ \ CN

sv - g "H« "§ S 5

• · * ° O-CJ-N X

" (IS

^ <0. ‘‘ F-1 <—c -—

£ / fs U CN

.. „<0 1 30 _::“ 0 = 0, —cj — n £ ... g> - £

3 S I

x M H X

J O M> 1 •; - 9, X M> 1 ...: 05 u —n> • ..... (0 43 87927 as

(OF

0 u

<n

as u s *. n h n o — u II || || 1 <0 nj «3

CN Π3 ^ <^ r W

X - υ <N Q w fe

_ *. M H M

Ο, Λ-CJ-N

o as

/OF

Ή * H

CO CO., LTD

> i Φ> i>

rH

0 C co

H ·· O

::: t3 I 3 - as ή. . as o m

'-' -H

· * · IH

* ':> 1 * *> 1: λ: *. : ή. . φ

... (M

'. ·. · O • - u ::: cn • as u as as Λ Λ Ä

. '. : O-CJ (N rH (H

'· "'« 1 11 11 11 · - ^ 1,3 (0 fl 'U ΓΜ ^' r · "-r * IS rH rH i — t. ·· *. O = 04-U-nj qw & 4 0 ~ mmm

•B

«I ~ H

•> Ί *: *> i ....

• »H

'F; (ΰ 44 87927 en 3 -μ tn tn 'd 3 6 -m

1-1 W / K

rt O

> Ό

i 6 S

»" -S G

V -h 'O

1 rH H fsi (M Cu

C> 4 n ** Λ S

n> 4 O ω Ή Q

0 AC Tl 2 O

* H * w O

* rt S £ υ + J

rt SX cu ^ ~ 3 g -HOX 5 ^ - • h ϋ® · χΒ * - ™ .2, Ή 1Ί 5 π os ε HU «C> 4 '1-¾» 1 ° = ΐ- ° ν, 3 OO - «m 'rd Ή x Ό Ί x

• 2>, X

> 4 33 X C

C ° ”N S * rt * 'd • h * rt ::: - 2 / tv .... rt

. . -P

:: - m <-h 1 - rt μ oq tn a) -h: *. > oj eu -h> i> e crej tn> i tn rt '· H -HS> 4 H C o rt i — iw> ^ o ·· 3 tn ·. ·: Rt -4 r-ι μ ® -h a:

,. rt -AO T) O H O

• · ·>> tn μ> ί · η · η -h '. ·. · Rt i 3 -rt »Pltn-ö rt μ -P> i * *: X o q) x; > i CU tn ·· rt to: rt <n w 5Λ e -

ffl I W -H

. *. : m h ·: • '“i> i ... μ · ·> i ... rt <-4 tN a:

• 'tn rH

o rt ... -H O m:: -P - · tN x a: m o s x ....: rt o m o. — cjl x rt = M \

«U-CSJ> o —N

/ 1 \ 45 87927 m> 1

P

CO SC • H m · O M E m

-H 03 X

CL) «J (S

a z o _

HM

CN

• H O

^ o> 1 -Τ 'S v g% 0-0 o 1 O ™

f \ J X

s O (N

0 | a 1 0 = 04— u ° = V> i Xo- «(N 2 35

x C

v "X

I X

0 = 04— u / K

I \ 'N

O 'o — N .H

• <-i en

T *> 1 -H

> 4> 1 G

> 1 Ή (0 • X O fö

* 8'a jS

.2:. ·. / Φν x tj · .:: o · • · Ή O,::: -p ® / o 2 n) 0—0 o 7 * 10 * »h tn ^ X r-> 4 C O l. . : ω φ / Tl • · T) 0—0 ~ <0 •. e Λ <N Cm «Ί

... O VX X O

M OH O

iN

... X

O

XX.

. . ° -V O

- r * fM M

CJ CN X

IX O <N

0 = 04- u. £ „'= i \ £ o = (V-o O O— n [T I \„:; i 5 ö o— n H C - "f' '> 4 ^ 4> 4 * *

... «H H

...: to <e 46 46 87927

As shown in Reaction Series A above, compounds of formula I can be prepared by the Arbuzov reaction of iodide A by heating iodide A

0-Si-C (CH3) 3

A I C6HS

I 'CH 2 CH 2 C "C02alkyyli

and phosphite III

III P (Oalkyl) 3 under standard Arbuzov reaction conditions and using conventional procedures to form phosphonate IV: O IV alkylO-β-CH2-CH-C1-4-C1-4alkyl O3-C6H5 (new intermediate ) * »· * * M

Phosphonate IV is then cleaved off with phosphorus. 25 ester groups by treating a solution containing phospho-] · -phonate IV in an inert organic solvent. as in methylene chloride, under an inert atmosphere such as argon with bis (trimethylsilyl) trifluoroacetamide (BSTFA) and trimethylsilyl bromide in succession to form phosphonic acid V: * »

O

Il ..

H0-P-CH_-CH-CHo-COalkyl. I z Z Z

• * * * · y OH O

'... · I

^^ S ^ i-C (CH3) 3 35 = 6¾ 'C6H5 *** # (new intermediate) 47 S 7 92 7

Phosphonic acid V is esterified by treatment in dry pyridine with a lower alkyl alcohol (such as methanol) and dicyclohexylcarbodiimide and stirring the resulting reaction mixture under an inert atmosphere such as argon to form phosphonic acid monoalkyl ester VI (new intermediate). The phosphonic acid monoester VI is then dissolved in an inert organic solvent such as methylene chloride, benzene or tetrahydrofuran (THF) and treated with trimethylsilyldiethylamine, the mixture is stirred under an inert atmosphere such as argon and then evaporated to give in a suitable, inert, organic solvent). The resulting solution is cooled to about -10 to 0 ° C, oxalyl chloride and a catalytic amount of dimethylformamide are added to the solution, and the mixture is then evaporated, yielding crude phosphonochlorididate VII (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 of about -90 to 0 ° C, preferably about -85 to -30 ° C, and treated with a cooled (same temperature) solution. -

than phosphonochloridate solution VII): ·: 25 of ethylene X

: V: x C * CH

• - I

: Y: Z

. ·. : a solution of the resulting lithium acetylide formed by treating acetylene X with a lithium source such as n-butyllithium, hexane or another inert solvent using compounds VII and V in an approximately 3: 1 to 1: 1 molar ratio, preferably 35 in an approximately molar ratio of 1.5: 1 to 2: 1 to give acetylenic phosphinate XI: 48 87927 0

II

alkylO-P-CH2-CH-CH2-CO2alkyl

XI CO

m i C .Si-C (CH 2).

1 \ 3 3 5 Z C6H5 C6H5 (new intermediate)

Acetylene phosphinate XI can then be used to prepare various compounds of this invention in the following manner. The acetylene phosphinate XI is converted to the acetylene phosphinate IA * by cleavage of the silyl ether group of XI by treatment with glacial acetic acid and tetrabutylammonium fluoride in an inert organic solvent such as tetrahydrofuran to form the ester IA *, 0 1 P-CH 2 alkyl-CH 2 -C02alkyyli

C OH

III

20 C

l

Z

: which can then be hydrolysed to the corresponding base ... I Xcl •. a salt, i.e. a compound in which R is R which is .1 l of ammonium, an alkali metal, an alkaline earth metal, an amine or ·. corresponding, by treatment in dioxane, tetrahydrofuran or other inert organic solvent under an inert atmosphere such as argon at 25 ° C with a strong base such as lithium hydroxide using a base and ester IA * in an approximate molar ratio 1: 1 to 1.1: 1 to form 2:; ; corresponding base salt IA: 0.7 ': IA2 alkyl O- | -CH2-CH-CH2-CO2-Rxa 35 c 5h m ·: · c i

·: ··: Z

i · 2 49 87927

Compound IA can then be treated with a strong acid, 3

such as HCl, IA of the corresponding acid

0

5 IA3 alkylO-CH2-CH-CH2-CO2H

C ÖH

to form m c z 10.

The ester IA1 can be converted to the corresponding base salt by treating the ester at 50-60 ° C with a strong base using base and ester IA1 in an approximately 4 molar ratio of 2: 1 to 4: 1 to give IA: 15 0 IA RxaO-P-CH, -CH-CH, -CO, RÄel | 2 s 2 2

C OH

III

C

20 Z

4

The base salt IA can be converted to the corresponding ha-; by treating it with a strong acid such as HCl, for example to form acid IA.

; The phosphinate compounds of the invention wherein • X is cis-CH = CH-, i.e. compounds IB, are formed by selective reduction of acetylene phosphinate XI, for example, by treating compound XI with H2 over a reduction catalyst such as carbon support or barium. -30 in the presence of palladium on a carbonate support, and and in the presence of an inert organic solvent such as methanol to form silyl ether XII: 50 87927

0 H

XII alkylO-P-CH2-CH-CH2CO2-alkyl CH611.

5 CH Sl-C (CH., K

1 c £ 'cA

(new intermediate) jQ The silyl ether group of compound XII can then be cleaved and the compound can be hydrolyzed as described above to give the alkyl-O-P-CH2-CH-CH2-CO2-alkyl of the ester IB1, 0 1 11 IB.

CH ÖH

li

(cis) CH Z

2 base salts IB, 20

O

p | (except IB alkylO-P-CH2-CH-CH2-CO2R,

CH ÖH

: M

(cis) CH

: 25 z: 3; / acid IB,

O

30 IB3 alkyl O-^ -CH2-gH-CH2-CO2H

Oi CH ÖH

::: (cis) CH

O ·. Z

____: 4

• · 35 diemassalt IB

si 87927 o IB4 RXa0 - ^> - CH2-CH-CH2-CO2RXa CH OH li

(cis) CH

5 Z

and to form the corresponding diacid IB.

The phosphinate compounds of the invention wherein X is -CH 2 -CH 2 -, i.e., compounds ID, are formed by reducing the acetylene phosphinate XII catalytically, for example, by treating compound XII with H 2 under a reduction catalyst such as palladium on carbon and an inert organic solvent. methanol in the presence of 3.4 bar of silyl ethers-15 ter XIII

0

II

XIII alkylO-P-CH2 "-CH-CH2CO2" alkyl

ch2 O

2 ° CH2 Z C6H5 CgHg: (new intermediate) ·· - 25.

The silyl ether group of compound XIII i can then be cleaved and the compound hydrolyzed as described above for ester ID1, 1

O

0? ID1 alkylio-P-CH2-CH-CH2-CO2-alkyl, CH-OH I 2 CH0 · ... · I 2 z * 35 '2 base salt ID, 52 37927 0 ID alkylO-P-CH2-CH-CH2- C02Rxa,

CH, ÖH

1 2 CH, I 2

5 Z

3 acid ID,

O

ID3 alkylO-P-CH2-qH-CH2-CO2H

CH, OH

I 2 CH,

• I 2 Z

4

15 ID of salt

0 ID4 RXa0-P-CH2-CH-CH2-CO2RXa

CH, ÖH

20 CH-

1 2 Z

r and to form the corresponding diacid ID.

As for Reaction Series B, the corresponding compounds of formula I having a phosphorus atom and a hydrophobic. : the linking group X between the anchor Z is trans-CH = CH-, • 'can be prepared by adding acetylene X and n-C ^ HgSnHsn! ! a mixture of a radical initiator such as azo-bisobutyronitrile (AIBN), hydrogen peroxide, benzoyl peroxide or the like, and heating to give the resultant. *: the resulting mixture at a temperature of about 100 to 140 ° C under an inert atmosphere such as argon, where. * ··. formed of vinyl stannane XV: 35 XV Sn (n-C4Hg) 3 ch *

* ": CH

z 53 87927

Vinyl stannane XV dissolved in an organic solvent such as ethyl ether, methylene chloride or chloroform is treated with iodine and the mixture is stirred under an inert atmosphere such as argon to form vinyl iodide XVI: XVI ch

CH

After cooling to a solution (-78 to -40 ° C) containing vinyl iodide XVI in a dry organic solvent such as tetrahydrofuran or ethyl ether, a metallizing agent such as n-butyllithium in an inert organic solvent such as hexane is added, and the mixture is maintained at -78 to -40 ° C under an inert atmosphere such as argon. The anion is added 2q to a cooled solution (-78 to -40 ° C) containing phosphonochloridate VII in a dry inert organic solvent such as tetrahydrofuran f or ethyl ether in an amount such that the molar ratio of compounds XVI and VII is approximately 1: 1 to 2: 1. 3a is preferably about 1: 1 to 1.5: 1 to form the silyl ether XVII: ::: 0: XVII alkyl and O-CH2-CH-CH2-CO2alkyl (trans and CH2-C3h5c6h5).

: T: Z

(new intermediate) 1

From the silyl ether XVII, the silyl ether group is cleaved by treating compound XVII dissolved in an inert organic solvent, such as tetrahydrofuran or acetonitrile, with glacial acetic acid and a solution of (nC 2 Hg) NF in an inert organic solvent such as tetrahydrofuran, forms the hydroxy ester IC1: 0. II IC1 alkylO-P-CH2-5H-CH2-CO2alkyl (trans) CH OH //

10 CH

z

The diester IC1 can then be hydrolyzed as described above with the base salt IC, 15

O

IC2 alkyl.O-P-CH2-CH-CH2CO2RXa

(trans) CH OH

• s /

CH

20 k acid IC3,

O

. I 25 IC3 alkylO-1-CH2-CH-CH2-CO2H

CH OH

. . : s /

CH

Z

4 diemal salt IC 30

V-: O

IC4 RxaO-P-CH2-CH-CH2-CO2RXa

.1. CH OH

: · // p * 35 z »» * «.

87927

and the corresponding diacid IC

0 IC ho-p-ch2-ch-ch2-co2h

5 CH OH

//

HC

i to form.

In an alternative process described in Reaction Series C, compounds of formula I wherein the linking group X between the phosphorus atom and the hydrophobic anchor Z is trans-CH = CH- can be prepared by aldehyde Vili

15 CHO

VIII Z

and a cooled (-90 to 0 ° C) solution of dialkyl methylphosphonate and butyllithium / LiCH 2 PO (alkyl) 2-7 in which the solvent is an organic solvent such as tetrahydrofuran or ethyl ether by a condensation reaction to form N-hydroxyphosphonate; 25 XX ^ (Oalkyl) 2 HO-CH-CH- I 2 • 2 β-hydroxyphosphonate XX is then treated with p-toluene-30 sulfonic acid in the presence of benzene or toluene

and while heating the mixture at about 50 to 120 ° C, preferably at reflux temperature, to remove water and remove the trans-olefin XXI.

O

: Il 35 XXI P (Oalkyl) 2

(trans) ^ CH

CH

to form which olefin XXI is hydrolyzed by treating it with an aqueous solution of an alkali metal hydroxide such as LiOH in the presence of dioxane or another inert organic solvent followed by an acid such as hydrochloric acid to form the monoacid ester XXII: 0

XXII alkylio-P-OH

10 (trans) CH

CH

J

Z

Monoacid-15 ester XXII dissolved in dry methylene crodide is treated with trimethylsilyldiethylaraine. The mixture is evaporated and the residual oil is dissolved in dry methylene chloride cooled to 0 ° C and treated under an inert atmosphere such as argon with oxalyl chloride and a catalytic amount of dimethylformamide to form phosphonochloride XXIII:

: O

XXIII alkyl O-1 R -Cl

* '· *: 25 (trans) CH

CH

. I

Z

Phosphonochloridate XXIII is condensed with an alkyl acetate acetate dione, such as methyl acetoacetate dianion, in an inert organic solvent such as tetrahydrofuran at reduced temperature. (-90 to 40 ° C) using phosphonochloridate and dianion in an approximately molar ratio of 1: 1 to 0.75: 1 to give the ketophosphonate XXIV, 87927 57 N alkyl O-P-Cl 2 -C-Cl 2. -CC ^ alkyl

(trans) ^ CH

ς CH

3 I

z (novel intermediate) which is reduced by treatment with a reducing agent such as sodium borohydride in the presence of an alkanol such as ethanol to form a phosphinate IC3: 0 IC1 alkyl O-P-CH2-CH-CH2-CO2-alkyl

15 (trans) CH OH

CH

k

The diester IC1 can then be hydrolyzed as described above for the base salt IC10. ie2 alkyliio - ^> - cH2.cH-cH2co2Rxa

(trans) ^ pH OH 25 CH

\ 2 acid IC3,

30 O

ic3 a1kyl.oJp.CH0-CH-CH - C00H

... i 2 I Z Z

: <trans> ^, CH OH

CH

'···; 2 4 0 58 87927

diemassaltan IC

IC RXaO-P-CH - CH-CH, -CO, RXa, I 2 I 2 2

5 (trans) ^ CH OH

CH

z and to form the corresponding diacid IC, For reaction series D, compounds of formula I wherein X is - (CH-) -, wherein a is 1, 2 or 3, i.e. X is -C 1-4 -, or can be selected from using aldehyde VIII as the starting material, which is converted to the halide Villa using standard procedures. For example, aldehyde VIII can be reduced with NaBH 4 in the presence of ethanol and ether to give the corresponding alcohol VIIIa,

Villa CH90H

I * 20 s which is treated with mesyl chloride in the presence of an organic • base such as triethylamine and a solvent such as methylene chloride to give chloride XXV (a = 1).

*. Chloride XXV is condensed by treatment with phosphite at a temperature of about 100 to 150 ° C using compounds III and XXV in an approximately molar ratio of 1: 1 to 10: 1 to form phosphonate diester XXVI. Phosphonate I diester XXVI dissolved 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 monoester is treated with oxalyl chloride in the presence of an inert organic solvent such as dimethylformamide. to form the corresponding phosphonochloridate XXVII.

59 37927

Phosphonochloridate XXVII is condensed with an alkyl acetoacetate dianion, such as methyl acetoacetate dianion, in an inert organic solvent, such as tetrahydrofuran, at reduced temperature (about -90 to 40 ° C) using phosphonochloridate 1 to about - 0.75: 1 to give ketophosphinate XXVII, a new intermediate. The ketophosphinate XXVII can then be reduced to the corresponding phosphinate ID, IE or IF, which can be hydrolyzed according to the procedures described above for Reaction Series C to form the corresponding diacid ID, IE or IF.

As for Reaction Series E, compounds of formula I wherein X is -C 1-10 can be prepared using aldehyde VIII as a starting material, which is subjected to Baeyer-Villiger oxidation by reacting it with meta-chloroperbenzoic acid (MCPBA) in an inert organic solvent. , such as methylene chloride, followed by an alkali metal hydroxide, such as KOH or NaOH, in the presence of a solvent, such as tetrahydrofuran, to form the corresponding alcohol XXIX. The alcohol XXIX is manually alkylated by treatment with sodium hydride under an inert atmosphere such as argon and in the presence of an inert organic solvent such as dimethylformamide. : and a solution of dialkyl tosyloxyphosphonate XXX using compounds XXX and XXIX in an approximately molar ratio of * · 1: 1 to 3: 1 to form the corresponding dialkyl ester XXXI. The remainder of the synthesis described in Reaction Series E, i.e., the formation of monoester XXXII, chloride XXXIII, ketophosphinate XXXIV (new intermediate), diester IG1, and diacid IG, proceeds in the same manner as described above for Reaction - "r Series D.

The acetylene starting material X can only be prepared from the aldehyde VIII

60 87927

VIII CHO

z

Wittig reaction, for example by treating a cooled solution (-25 to 0 ° C) containing aldehyde VIII in triphenylphosphine and a tetrabromomethane dissolved in an inert organic solvent such as methylene chloride in an inert organic solvent such as methylene chloride. ^), from which vinyl bromide IX: IX CH = CBr f ^ is formed

Z

Compound IX is dehydrohalogenated by treating it under an inert atmosphere with n-butyllithium in an inert organic solvent such as hexane to give compound X.

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

V. Iodide starting material A can be prepared using

; 25 bromidia C as active ingredient

• * »oh c Br-CH 2 -CH-CH 2 CO 2 alkyl 1 2 3 4 5 6 (prepared using the procedures described in Tetrahdedron Lett. 26 2 (1985) 2951), which 3 ·“. is dissolved in a solution of imidazole and 4-dimethylaminopyridine in 4 dimethylformamide (DMF), and the resulting solution is treated with t-butyldiphenyl-6-silyl chloride under an inert atmosphere such as argon to form silyl ether D: no 8792 7 C6 ^ C6H5 j> Si-C (CH3) 3 D Br-CH2-CH-CH2CO2alkyl

Silyl ether D dissolved in an inert organic solvent such as methyl ethyl ketone or DMF is treated under an inert atmosphere such as argon with sodium iodide to form iodide A: Aldehyde compounds VIII, i.e. compounds

15 VIII CHO

f

Z

are known compounds.

Various intermediates IV, V, VI, VII, XI, XII, XIII, XVII and XXIV are also part of this invention. These new intermediates can be represented by the following general formulas: V: 25 °: V XXXV R1-P-CH_-CH-CH_-COalkyl. . a i, 2 i - ^: ·: r £ OSi-C (CH3) 3 ö: = / \.

t t “O

wart, hydroxyl. Cl, -CH 2 -Z, -CH 2 CH 2 CH 2 -Z, -CH 2 O-Z, 1 • m · · -C = CZ, -CH = CH-Z or -CH 2 CH 2 -Z, wherein Z is a hydrophobic as defined above. an anchor, provided that when R * is hydroxyl R 1 is preferably hydroxyl or alkoxyl; and O 5 XXXVI alkylO-β-CH, -C-CH 0 -C 0 alkyl I Z li Δ / X 0 2 10 wherein X is as defined above and which includes all stereoisomers.

The compounds of the invention may be prepared as racemic mixtures, and their resolution to give the preferred S-isomer may be carried out at a later date. However, the compounds of the invention may be prepared directly in the form of their S-isomers as described herein and in the working examples below.

The compounds of the invention are inhibitors of 3-hydroxy-3-20 methylglutaryl coenzyme A (HMG-Coa) reductase and thus useful in inhibiting cholesterol biosynthesis, as shown by the following:. experiments: "IV 1) Rat liver HMG-CoA reductase. 1 I 25 Rat liver HMG-CoA reductase activity is measured using a modification of the method described by Edwards et al. / PA Edwards et al. ., J. Lipid

Res. 20 (1979) 4-7. Rat V. · liver microsomes are used as the source of the enzyme, and enzyme activity is determined by measuring the conversion of the HMG-CoA substrate to mevalonic acid.

; V; a) Preparation of microsomes in 2-4 Sprague-Dawley rats fed and decapitated cholestyramine, 35 livers are removed and homogenized in phosphate buffer A (potassium phosphate, 0.04 M, pH 7.2, KCl, 0.05 M, sucrose.

63 87927 0.1 M; EDTA 0.03 M; aprotinin, 500 IU / ml). The homogenate is centrifuged (16,000 x g) for 15 minutes at 4 ° C. The supernatant is removed and recentrifuged under the same conditions. The second supernatant separated after centrifugation at 16,000 x g is centrifuged at 100,000 x g for 70 minutes at 4 ° C. The microsome pellets are resuspended in as little phosphate buffer A as possible (3-5 ml / liver) and homogenized in a glass-glass homogenizer. Dithiothreitol (10 mM) is added and the preparation is aliquoted, rapidly frozen in an acetone-carbonic acid ice bath and stored at -80 ° C. The specific activity of the first microsome apparatus was 0.68 nmol mevalonic acid / mg protein / minute.

15 b) Enzyme assay

The reductase is determined from 0.25 ml of a mixture containing the following constituents in the declared final concentrations:

Potassium phosphate, pH 7.0 0.04 M

20 KCl 0.05 M

Sucrose 0.10 M

EDTA 0.03 M

· ,:; Dithiothreitol 0.01 M

NaCl 3.5 mM

Dimethyl sulfoxide 1%) Microsomal protein 50 - 200 pg / “14c7 (DL) -HMG-CoA (0.05 pCi, 30 -

60 mCi / mmol 100 pM

NADPH (nicontinamide adenine dinucleo-.. 30 thidiphosphate) 2.7 mM

The reaction mixtures are incubated at 37 ° C. Under the conditions shown, the enzyme activity increases linearly up to the limit of 300 pg microsomal protein / reaction mixture, and the linear increase lasts for 30 minutes. The typical incubation time in drug studies is 20 minutes, resulting in a conversion of the HMG-CoA substrate to mevalonic acid 64,87927 of about 12-15%. The (DL-) HMG-CoA substrate is used at 100 pM, which is twice the concentration required to satisfy the enzyme under the conditions shown. NADPH is used in excess so that its concentration is 2.7 times that required to achieve the maximum rate of the enzyme reaction.

Standardized tests to evaluate inhibitors are performed according to the following procedure. The microsomal enzyme is incubated for 15 minutes at 37 ° C in the presence of 10 NADPH. DMSO medium with or without test compound is added and the mixture is incubated for another 15 minutes at 37 ° C. Enzyme assay -14 - is started by adding / C / HMG-CoA substrate.

After incubation for 20 minutes at 37 ° C, the reaction is stopped by the addition of 25 μl of 33% KOH.

- 3 -

Add / H / mevalonic acid (0.05 pCi) and allow the reaction mixture to stand at room temperature for 30 minutes. Add 50 5 N HCl to convert mevalonic acid to the lactone. Bromophenol blue is added as a pH indicator to detect a sufficient decrease in pH. The lactone mud precipitation reaction is allowed to proceed for 30 minutes at room temperature. The reaction mixtures are centrifuged at 15 ml minutes at 2800 rpm. The supernatants are applied to glass columns with an inner diameter of 0.7 cm over poured AG 1-X8 anion exchange resin (Biorad, formate form; 2 g) and eluted with 2.0 ml of H 2 O. The first 0.5 ml of eluate is discarded, • and the next 1.5 ml is collected and both tritium and carbon-14 in 10 ml of Opti-fluoroscintil-30 lation liquid are counted. The results are calculated as the amount of mevalonic acid (nmol) formed over 20 minutes * and corrected to correspond to 100% tritium recovery. The effects of the drugs are expressed as I-values (concentration of drug that causes a 50% reduction in enzyme activity) obtained from the pooled dose-response data with a 95% confidence interval.

li 65 87927

Conversion of lactone drugs to sodium salts is accomplished by dissolving the lactone in DMSO, adding a 10-fold molar excess of NaOH to the solution, and allowing the mixture to stand at room temperature for 15 mL to 5 minutes. The mixture is then partially neutralized (to pH 7.5-8.0) with 1N HCl and then diluted to an enzyme reaction mixture.

2) Cholesterol synthesis in freshly isolated rat hepatocytes 10 Investigate the activity of compounds with HMG--14 -

As inhibitors of CoA, the ability to inhibit / C / acetate incorporation into cholesterol in suspensions prepared from freshly isolated rat hepatocytes using the procedure originally described by Capuzzi et al. / 5. M.

15 Capuzzi and S. Margolis, Lipids 6 (1971) 602 /. a) Isolation of rat heptocytes Sprague-Dawley rats (180-220 g) are anesthetized with nembutol (50 mg / kg). The abdomen is opened and the first branch of the portal vein is tied. Heptrin (100 to 200 units) is injected directly into the abdominal intravenous vein, one occluding suture is placed in the distal portion of the portal vein, and a cannula is placed in the portal vein between the suture and the first branch vein. The liver is perfused, ’: after the vena cava has been severed to allow drainage * · 25, with preheated (37 ° C) oxidized. : buffer A: 11a (HBSS, which does not contain calcium or magnesium but contains 0.5 pmol EDTA / a / ml) at a rate of 20 ml / minute. The liver is further perfused 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's medium, allowing the cells to be dispersed in the medium. Hepatocytes are isolated by centrifugation at 3 x 50 g for 3 minutes. Hepatocyte pellets are washed once with Waymouth's medium and counted, and their 66 87 927 viability is determined by trypan blue exclusion. The viability of these hepatocyte-rich cell suspensions is normally 70-90%.

-14 - b) / C / acetate incorporation into cholesterol Hepatocytes were resuspended in incubation medium (1M) (Tris-HCl, 0.02 M, pH 7.4; KCl, 0.1 M; sodium citrate, 3.3 mM; nicotinamide, 6.7 mM, NADP, 0.23 mM, glucose-6-phosphate, 1.7 mM) to a cell concentration of 5 x 10 ° cells / 2.0 ml.

Test compounds are normally dissolved in DMSO or DMSO-H 2 O (1: 3) and listed in IM.

The final concentration of DMSO in IM is up to 1.0% and has no significant effect on cholesterol synthesis.

-14 -

Incubation is initiated by the addition of / C / acetate 15 (58 mCi / mmol, 2 uCi / ml) and placement of cell suspensions (2.0 ml) in 35 mm tissue culture dishes; the incubation time is 2.0 hours at 37 ° C. After incubation, the cell suspensions are transferred to glass centrifuge tubes and centrifuged at 50 x g for 3 minutes at room temperature. The cell pellets are resuspended in 1.0 ml of Orta, lysed and placed in an ice bath.

f] Lipids are extracted essentially as described by E. G. Bligh and W. J. Dyer, Can. J.

I '·': 25 Biochem. and Physiol. 37 (1959) 911. The lower organic phase is separated and dried under a stream of nitrogen, and the residue is resuspended in 100 of chloroform-methanol (2: 1). The total sample is spotted onto thin-layer plates (silica gel LK6D), and the plates are developed in hexane-ethyl ether-acetic acid (75: 25: 1). Widths are scanned using an automatic BioScan scanning system. The radioactive tracer ____ contained in the cholesterol peak (Rf 0.28) is determined and the result is expressed as the total amount of scintillation per 35 peaks and as a percentage of the tracer - · - · in the total lipid extract. In reference systems, the radioactivity contained in the cholesterol I: 67 3 7 927 peaks is usually 800 to 1000 scintillations / minute and the amount of tracer in the total lipid extract is 9 to 20%; the results are consistent with those of Capuzzin et al. (9% extracted 5 tracers in cholesterol).

The effects of the drugs (percentage inhibition of cholesterol synthesis) are determined by comparing the percentage of tracers in the cholesterol of the control cultures and the treated cultures.

Dose-response curves are generated from pooled data from two or more studies, and results are expressed as I ^ ^ values with a 95% confidence interval.

3) Cholesterol synthesis in human skin fibroblasts

The selectivity of a compound that results in a greater inhibitory effect on liver tissue would be a hallmark of an inhibitor of cholesterol synthesis. Therefore, in addition to studying cholesterol synthesis inhibitors in hepatocytes, the activity of these compounds as cholesterol synthesis inhibitors is also being studied in cultured fibroblasts. f ·: a) Prepared from human skin fibroblasts: cultures 25 Human skin fibroblasts are cultured in Eagle's minimal medium (EM) containing 10% fetal bovine serum. In each experiment, trypsin is added to stock cultures to disperse the monolayer, counted, and the cells are transferred to tissue culture dishes in 35 mm diameter wells "(5 x 10 5 cells / 2.0 ml). The cultures are incubated with 5% CO 2 and 95 % in humid humidity for 18 hours at 37 ° C. Enzymes involved in cholesterol biosynthesis are activated by removing serum-containing medium, rinsing monolayers, adding * 1.0 ml EM containing 1.0% fatty acid-free bovine serum sublime, and incubating the cultures for an additional 24 hours.

-14 - b) Addition of / C / acetate to cholesterol

Activated fibroblast cultures are rinsed with 5 ENEM ^ 0Q (Earle's minimal medium). Test compounds are dissolved in DMSO or DMSO-EM (1: 3) is added to the cultures (final DMSO retention solution in cell cultures is up to 1.0%), and the cultures are preincubated in 5% CO 2 and 95% humidified air. at 37 ° C for 30 minutes. After pre-incubation with drugs, sodium chloride (2.0 pCi / ml, 58 mCi / mmol) is added and the cultures are re-incubated for 4 hours. After incubation, the medium is removed and the monolayer (200 μg cell protein / 15 culture) is scraped into 1.0 ml I 2. The lipids contained in the lysed cell suspension are extracted into their chloroform-methanol mixture as described for hepatocyte suspensions. The organic phase is dried under nitrogen, the residue is resuspended in 100 of chloro-20-formi-methanol (2: 1), and the total sample is spotted onto thin-layer plates (silica gel LK6D) and analyzed as described for hepatocytes.

Inhibition of cholesterol biosynthesis is determined by comparing the percentage of tracer to the relative amount. ; licensing and drug treatment of the culture pe- i. cholesterol peaks. The results are expressed as Ig values and are obtained from dose-30 response curves pooled from two or more experiments. 95% confidence interval for I ^ Q values ·. * also calculated from combined dose-response curves.

* A: For use, a pharmaceutical composition comprising at least one compound of formula I, respectively, in association with a pharmaceutical medium or diluent may be prepared.

The pharmaceutical composition may be formulated using conventional solid or liquid media or diluents and pharmaceutical excipients of a type suitable for the desired route of administration. The compounds may be administered orally, for example, in the form of tablets, capsules, granules or powders, or may be administered in the form of parenterally injectable preparations containing from 1 to 2000 mg of active compound per therapeutic dose. The dose to be given depends on the unit dose, the symptoms and the age and body weight of the patient.

Compounds of formula I may be administered in a manner similar to those known compounds (such as lovastatin) which have been proposed for use as inhibitors of cholterol biosynthesis in mammals, such as humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in an amount of about 4 to 200 mg, either as a single dose or in separate doses 1 to 4 times a day, preferred! 4 to 200 mg in sub-doses of 1 to 100 mg, preferably 0.5 to 50 mg, 2 to 4 times a day or in a sustained release form.

The following working examples represent preferred: embodiments of the present invention. All temperatures are in degrees Celsius unless otherwise indicated. Flash chromatography treatments were performed either,. * Merck 60 or Whatman LSP-1 silica gel. Reverse phase chromatography treatments were performed on CHP-20 MCI gel resin supplied by Mitsubishi, Ltd.

The abbreviations "Et 2 O", "EtOAc", "MeOH" and "EtOH" as used in the following examples refer to ethyl ester, ethyl acetate, methanol and ethanol, respectively.

70 87 92 7

Example 1 (S) -4- (774'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) -methoxymethoxyphosphinyl] -3-hydroxybutanoic acid, monolithium salt 5 A) N- (2,4-dimethyl benzylidene) benzenamine

Reference: U.S. Patent 4,375,475 (Merck), p. 39 A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich; 6.97 mL, 50 mmol) and distilled aniline (Aldrich; 4.56 mL, 50 mmol). mmol) in dry toluene 10 (80.0 mL) was refluxed under argon for 3.0 h under Dean-

In a bottle with a Stark water separator. The mixture was cooled and then evaporated under reduced pressure to a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mmHg, 160-180 ° C) to give 8.172 g (78.1%) of the desired title benzenimine as a pale yellow oil which crystallized on standing to melt at low temperature. TLC (hexane-acetone, 4: 1): Rf = 0.67 and 0.77 (geometric isomers), UV and 20 i- · _ (O)

B. N

f * H3Vk, M-; ·; · 25 [Ojops V: · _ _2

Reference: U.S. Patent 4,375,475 (Merck), p. 39 30 To a mixture of the benzeneimine prepared in Part A (6.0 g, 28.7 mmol) in glacial acetic acid (144 mL). palladium (II) acetate (6.44 g, 28.7 mmol) was added, and the clear, red, homogeneous solution was refluxed under argon for 1 hour. The resulting cloudy mixture * · * 35 was filtered in a warm, tightly packed,} - ··· through diatomaceous earth layer into water (900 mL). The precipitated orange solid was collected by filtration and dried under reduced pressure at 65 ° C under P 2 O 5 for 16.0 hours to give 10.627 g (85.5%) of the desired title palladium complex as an orange solid, m.p. 194-196 ° C (m.p. 203-205 ° C for a recrystallized analytical sample reported in the literature).

C. 4'-Fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-carboxaldehyde 10 (1) Bromine (4-fluoro-3-methylphenyl) magnesium

Reference: U.S. Patent 4,375,475 (Merck), pp. 37 and 38

The title Grignard reagent from Part C (1) was prepared by adding 5-bromo-2 to magnesium turnings (1.35 g, 55.4 mmol, 8.0 eq.) Stirred in dry Et 2 O (70.0 mL). -fluorotoluene (Fairfield Chemical Co .; 22.5 g, 60.9 mmol) dropwise at a rate sufficient to keep the reaction mixture refluxing. The reaction was started on an ultrasonic device. After the addition of bromide was complete, the mixture was stirred under argon for 1 hour at room temperature and refluxed for 15 minutes, after which it was allowed to cool to room temperature.

* ·· (2) 4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-carboxaldehyde and 25 In a second flask, a mixture containing the dipalladium complex prepared in Part B was stirred. (3.0 g, 6.92 mmol) and triphenylphosphine (14.52 g, 55.4 mmol, 8.0 eq) in dry benzene (100 mL) at room temperature under argon for 30 minutes. Then, to this solution, Grignard reagent, freshly prepared and filtered (glass wool filling) according to Part C (1), was added to this solution in one portion in 1 batch, and the mixture was stirred for 1.5 hours at room temperature under argon. . below. 6.0 N HCl (35 mL) was added and the mixture was stirred for another hour at room temperature, followed by. it was filtered through tightly packed diatomaceous earth (i inch 72 87 92 7 layer). The filtrate was extracted with Et 2 O (250 mL), and the extraction solution was washed with saturated NaCl solution (2 x 100 mL), dried over anhydrous MgSO 4 and evaporated under reduced pressure to give 13.35 g of a viscous orange oil which crystallized on standing. The crude orange solid was purified by flash chromatography using silica gel (700 g) as adsorbent and hexane as eluent followed by hexane-Et 2 O (95: 5). The product fractions were combined and evaporated to give 1.507 g (89.9%) of the desired title aldehyde as a pale yellow solid, m.p. 72-75 ° C (m.p. 73-74 ° C reported in the literature). TLC (hexane-Et 2 O, 95: 5): Rf = 0.40, UV and PMA.

D) 2- (2,2-dibromoethenyl) -4'-fluoro-3,31,5-trimethyl-1,11-biphenyl In a cooled (-10 ° C, salt-ice bath) solution containing the biphenylaldehyde prepared in Part C (242 mg, 1.0 mmol) and triphenylphosphine (787 mg, 3.0 mmol, 3.0 eq.) in dry CH 2 Cl 2 (10 mL) were added dropwise over 5 minutes to a solution of CBr 4 (497 mg , 1.5 mmol, 1.5 eq.) In CH 2 Cl 2: (5.0 mL). After keeping the mixture at 0 ° C for 30 minutes, the red-orange solution was partitioned between CH 2 Cl 2 and saturated NaHCO 2. The organic phase was washed with saturated NaHCO 3 and sat. . NaCl, then dried over anhydrous Na 2 SO 4; ; and evaporated to give 1.478 g of a light brown solid. The solid crude product was purified by flash chromatography using silica gel as adsorbent. ·; gel (50: 1) and hexane CH2Cl2 V-: (9: 1) as eluent. The product fractions were combined and evaporated to give · ···. 392 mg (99%) of the title vinyl bromide were obtained as a pale yellow oil. TLC (hexane-EtOAc-35 95: 5): Rf = 0.51, UV and PMA.

73 3792 7 E) a solution of 2-ethynyl-4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl at -78 ° C (carbonic acid-ice-acetone bath) containing the vinyl dibromide prepared in Part D. 5 slides (336 mg, 0.844 mmol) in dry THF (5 mL) were added dropwise via syringe a solution of 1.6 M n-BuLi in hexane (1.06 mL, 1.7 mmol, 2.0 eq), and the mixture was stirred at -78 ° C under argon for 1 hour. through the addition of n-BuLi to deep blue or purple. Saturated NH 4 Cl (4 mL) was added dropwise at 10-78 ° C, allowed to warm to room temperature and extracted with Et 2 O, and the ether layer was washed with saturated NaCl solution, dried over anhydrous MgSO 4 and evaporated to give 191 mL. mg of green oil. The crude oil was purified by flash chromatography using LPS-1 silica gel (60: 1) as absorbent and hexane as eluent. The product fractions were combined and evaporated to give 185 mg (92%) of the desired title acetylene as a colorless oil which eventually turned deep blue on standing at -20 ° C under argon. TLC (hexane): Rf = 0.18, UV and PMA.

F) (S) -3- [7T (1-dimethylethyl) diphenylsilyl] -oxyoxy-4- (chloromethoxyphosphinyl) butanoic acid, methyl:. * V ester | 25 (1) (S) -4-Bromo-3-hydroxybutanoic acid, methyl ester: (1) (a) / R- (R *, R *) γ-2,3,4-trihydroxybutanoic acid, calcium salt, hydrate

Reference: Carbohydrate Research 72 (1979) 301-304 To a solution of D-isoascorbic acid (44.0 g, 250 mmol) in water (625 mL) was added calcium carbonate (50 g) and the suspension was cooled to 0 ° C. *: (ice bath), and 30% CH 2 Cl 2 (100 mL) was added dropwise. The mixture was stirred at 30-40 ° C for 35 (oil bath) for 30 minutes. Activated carbon (Darco, 10 g) was added and the black suspension was heated on a 74 37 927 steam bath until the evolution of Cl 2 ceased. The suspension was filtered through diatomaceous earth and evaporated under reduced pressure (bath temperature 40 ° C). The residue was taken up in water (50 mL), the solution was heated on a steam bath, and CH 2 OH was added until the solution was vortexed. The fibrous precipitate was collected by filtration and imaged in air to give 30.836 g (75.2%) of the desired calcium salt as a white powder.

TLC (iPrOH-NH 4 OH-1 2 O 7: 2: 1): Rf = 0.01, 10 PMA.

(1) (b) [S- (R *, S *)] - 2,4-Dibroin-3-hydroxybutanoic acid, methyl ester

Reference: K. Book et. ai., Acta Scandinavica (B) 37 (1983) 341-344 The calcium salt prepared in part (1) (a) (30 g) was dissolved in 30-32% acetic acid solution of HBr (210 ml), and the solution was stirred at room temperature. at 24 hours. Methanol (990 ml) was then added to the brown solution, and the mixture was stirred overnight. The mixture was evaporated to an orange oil which was dissolved in CH 2 Cl 2 (75 ml), the solution was refluxed for 2.0 hours and evaporated. The residue was partitioned between EtOAc (100 ml) and CH 2 Cl 2, and the organic phase was washed with water (twice) and saturated NaCl solution, then dried over anhydrous Na 2 SO 4 and evaporated to give 22. 83 g (90.5%) of purified

: untreated dibromide as a light orange oil. TLC

(EtOAc-hexane mixture 1: 1): Rf = 0.69, UV and PMA.

30 (l) (c) (S) -4-Bromo-3-hydroxybutanoic acid, λ-methyl ester

Reference: Same as in the preparation of compound (1) (b)

To an argon purged solution of the dibromide prepared in part (1) (b) (20.80 g, 75.4 35 mmol) and anhydrous NaOAc (21.0 g) in EtOAc (370 mL) and glacial acetic acid (37 mL), 5% Pd / C catalyst (1.30 g) was added and the black suspension was stirred under H 2 (1 bar) while monitoring the uptake of H 2.

H 2 consumption ceased after 2 h, the mixture was filtered through diatomaceous earth, and the filtrate was washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous MgSO 4 and evaporated to give the crude dibromoester as a brown oil. The crude oil was combined with another batch (starting from 36.77 g of dibromide) and distilled under reduced pressure to give 25.77 g (61.3%) of the desired title bromoester as a colorless oil boiling in the range of 79-80 ° C (1 mmHg). ). TLC (1: 1 EtOAc-hexane): Rf = 0.44, PMA. Elemental analysis (C 9 H 9 O 3 Br) Calculated: C, 30.48; H, 4.60; Br, 40.56 Found: C, 29.76; H, 4.50; Br, 39.86 (2) (S) -4-Bromo-3 - [((1,1'-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester

To a solution of bromohydrin (4.0 g, 20.4 mmol) prepared in Part F (1), imidazole (6.94 g, 5.0 eq.) And 4-dimethylaminopyridine (4-DMAP) (12 mg, 0.005 eq.) In dry DMF (40 ml), t-butyl · · * * lidiphenylsilyl chloride (5.84 ml, 1.1 eq.) Was added, and the homo- V .: the gene mixture was stirred under argon at room temperature. 25 modes overnight. The mixture was partitioned between 5%: KHSO 4 and EtOAc, and the organic phase was washed with: V: water and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give 9.32 g ( 100%) crude silyl ether colorless ...; 20 as a viscous oil. TLC (hexane-EtOAc 3: 1): silyl ether Rf = 0.75, UV and PMA.

76 37927 (3) (S) -4-Iodo-3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester

To a solution of the crude bromide (9.32 g, 201 mmol) prepared in Part F (2) in methyl 5-ethyl ketone (60 mL, dried over 4 A molecular sieves) was added sodium iodide (15.06 g, 100 mL). 5 mmol, 5.0 eq.), And the yellow suspension was refluxed for 5 hours under argon. The mixture was cooled, diluted with EtOAc and filtered, and the filtrate was washed with dilute NaHSO 4 (colorless) and saturated NaCl solution, then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 10.17 g of a yellow oil. The crude oil was purified by flash chromatography on silica gel (600 g) as an adsorbent and hexane-CH 2 Cl 2 (3: 1) as eluent. The product fractions were combined and evaporated to give 7.691 g (74.2% total yield of both steps) of the desired title iodide as a clear, colorless, viscous oil. TLC (hexane-EtOAc 3: 1): product Rf = 0.75, UV and PMA (note: iodide product spots in addition to bromine starting spots).

(4) (S) -4- (Diethoxyphosphinyl) -3- (1,1'-1,1-dimethylethyl) diphenylsilyl / oxy / butanoic acid, methyl ester

A solution of the iodide prepared in Part F (3) (7.691 g) in triethyl phosphite (20 ml) was heated at 155 ° C (oil bath) under argon for 3 hours.

The mixture was cooled and the excess phosphite was distilled off under reduced pressure (0.5 mmHg, 75 ° C) to leave a yellow oil (ca. 8.0 g). The crude oil was purified by flash chromatography using ab- · "silica gel (400 g) as sorbent and hexane-acetone (4: 1) as eluent. The product fractions were evaporated to give 3.222 g (41.1%) of the desired title phosphonate as a clear, colorless, viscous oil.

77 87 9 7 7 TLC (hexane-acetone 1: 1): Rf = 0.51, UV and PMA. In addition, 2.519 g of the iodide starting material prepared in Part F (3) were recovered (corrected yield 61.1%).

5 (5) (S) -3- (7H / 1-Dimethylethyl) diphenylsilyloxy] -4-phosphonobutanoic acid, methyl ester

To a solution of the phosphonate prepared in Part F (4) (9.85 g, 20.0 mmol) in dry Cl 2 Cl 2 (20 mL) was added sequentially bistrimethylsilyl-10 trifluoroacetamide (BSTFA) (5.31 mL, 32, 0 mmol, 1.6 eq.) And trimethylsilyl bromide (TMSBr) (6.60 mL, 50.0 mmol, 2.5 eq.), And the clear mixture was stirred under argon at room temperature overnight. 5% KHSO 4 (80 mL) was added and the mixture was extracted with EtOAc.

The aqueous phase was saturated with NaCl and re-extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give crude title phosphonic acid as a viscous oil. TLC (iPrOH-NH 4 OH-1 2 O 7: 2: 1): Rf = 0.30, UV and PMA.

(6) (S) -3- [771,1-Dimethylethyl) diphenyl- · silyl] oxy-4- (hydroxymethoxyphosphinyl) butanoic acid, methyl ester 25 to the crude phosphonic acid prepared in Part F (5) (about 20.0 mmol) mixed with pyridine (25 ml) was added dried. . (With 3 A molecular melts) CH 2 OH (1.62 mL, 40.0 mmol, 2.0 eq) and dicyclohexylcarbodiimide (DCC). . 30 (4.54 g, 22.0 mmol, 1.10 eq.), And the resulting; the white suspension was stirred under argon at room temperature

temperature overnight. The pyridine was removed under reduced pressure and then azeotroped with benzene (2 x 15 ml) by distillation. The residual oil was dissolved in EtOAc and the solution was filtered, washed with 1.0 N

HCl and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 8.272 g of crude title ester as an oil containing a small amount of precipitated dicyclohexylurea (DCU). TLC (iPrOH-NH 4 OH-1 O 2 in 7: 2: 1): Rf = 0.60, UV and PMA.

(7) (s) -3 - [(1-dimethylethyl) diphenylsilyl] oxy] -4- (chloromethoxyphosphinyl) butanoic acid, methyl ester

The crude phosphonic acid 10-monomethyl ester prepared in Part F (6) (6.595 g, ca. 17.7 mmol) was dissolved in dry CH 2 Cl 2 (30 mL), and distilled trimethylsilyldiethylamine (5.60 mL, 29.4 mmol, 2, 0 eq.), And the mixture was stirred under argon at room temperature for 1 hour. The mixture was evaporated under reduced pressure and then again with benzene (1 x 30 ml) and dried under reduced pressure. The pale yellow viscous oil was dissolved in dry CH 2 Cl 2 (30 mL) containing DMF (dried on 4 A molecular sieves, 2 drops), the clear solution was frozen at -10 ° C (salt-20 ice bath), and added dropwise. syringe distilled oxalyl chloride (1.41 mL, 16.2 mmol, 1.1 eq). Strong evolution of gas was observed, and the solution turned deeper yellow in color. The mixture was stirred under argon at -10 ° C for 15 minutes and then at room temperature for 1 hour. The mixture was evaporated; under reduced pressure and then again with benzene (1 x 30 ml) and dried under reduced pressure to give the crude phosphonochloridate as a yellow oil.

G) (S) -4 - [[2- (4'-fluoro-3,31,5-trimethyl-1,1'-; biphenyl-2-yl) ethynyl] methoxyphosphinyl] -3- (t-butyl) - • To a solution of diphenylsilyloxybutanoic acid methyl ester in a -78 ° C (CO 2 -acetone bath) containing acetylene prepared in Part E (2.678 g, 35 11.2 mmol) in dry THF (20 mL) was added dropwise - a 1.6 M solution of n-BuLi in hexane (7 ml, 11.2 mmol, li 79 87927 1.0 eq.). The purple mixture was stirred under argon at -78 ° C for 1 h and briefly warmed to 0 ° C, recooled to -78 ° C and transferred via tube to a dropping funnel from which it was added dropwise to -78 ° C: (CO 2 -acetone bath) containing the phosphonochloridate prepared in Part F (8.27 g, 18.4 mmol, 1.6 eq.) in dry THF (20 mL). After 1 h at -78 ° C, saturated NH 4 Cl was added, the mixture was allowed to warm to room temperature and extracted with Et 2 O. The ether layer was washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous MgSO 4 and evaporated to give 11.705 g of a brown oil. The crude oil was purified by flash chromatography on silica gel using adsorbent and hexane-EtOAc (7: 3) as eluent. The product fractions were combined and evaporated to give 4.246 g (56%) of the desired title acetylene phosphinate as a light brown oil. In addition, 457 mg of the biphenylacetylene prepared in Part E were recovered (corrected yield 68%). TLC (hexane-acetone 7: 3): Rf = 0.20, UV and PMA.

H) (S) -4- [72- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-: ":"; biphenyl-2-yl) ethyl] methoxyphosphinyl-3- (t-butyl- 25 diphenylsilyloxy) butanoic acid, methyl ester. : To an argon-flushed solution containing the acetylene phosphinate prepared in Part G (333 mg)! In CH 3 OH (5 mL), 10% Pd / C catalyst * (121 mg, 36 wt%) was added, and the mixture was shaken on a Parr apparatus under H 2 (2.8 bar) for 30 h. The catalyst ether was removed by filtering the mixture through a tightly packed diatomaceous earth, and the filtrate was evaporated to a light. to a ketal oil. The crude oil was purified by flash chromatography on silica gel with absorbent and EtOAc-hexane (1: 1) as eluent. The product fractions were evaporated to give 250 mg (75%) of oto 37927 saturated phosphate as a clear oil. TLC (EtOAc-hexane 4: 1): Rf = 0.33, UV and PMA.

J) (S) -4 - [(4-Fluoro-3,3 ', 5-trimethyl-1,1'-5-biphenyl-2-yl) methoxy] methoxyphosphinyl] -3-hydroxybutanoic acid, monolithium salt

To a solution of the silyl ether prepared in Part H (330 mg, 0.489 mmol) in dry THF (6 mL) was added glacial acetic acid (115, 1.96 mmol, 4.0 eq) followed by 1.0 M THF solution of tetrabutylammonium fluoride (1.47 mL, 1.47 mmol, 3.0 eq), and the resulting mixture was stirred at room temperature under argon overnight. The mixture was diluted with ice water (10 mL) and extracted with EtOAc (twice). The organic phase was washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated to give 364 mg of a pale yellow oil. The crude oil was purified by flash chromatography on silica gel using adsorbent and acetone-Toni-hexane (6: 4) as eluent. The product fractions were evaporated to give 205 mg (96%) of the desired free alcohol as a clear oil which crystallized slowly on standing. TLC (acetone-hexane 7: 3): γ: Rf = 0.28, UV and PMA.

: \. 25 Example 2. ; (S) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-n-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutane; nic acid, dilithium salt

To a solution of the di-ester of Example 1 (187 mg, 0.429 mmol) in dioxane (5 mL) was added a 1.0 N solution of LiOH (1.29 mL, 1.29 mmol, 3.0 eq). .), ·. · - and the mixture was heated at 55 ° C (oil bath) under argon for 2.5 hours, cooled, diluted with water, filtered and evaporated under reduced pressure. to a minimum of water and chromatographed on HP-20 resin (column si 87927 diameter 25 nun, layer thickness about 15 cm) using water as eluent and then a mixture of CH 2 OH-1 2 O (1: 1). the residue was dissolved in water (50 mL), and the solution was filtered and lyophilized to give 175 mg (91%, based on the mass of the hydrate) of the desired title dilithium salt as a white electrostatic solid TLC (CH 2 Cl 2 -CH 2 OH-HOAc mixture relative to 8: 1: 1): Rf = 0.1, UV and PMA, and TLC (iPrOH-NH 2 OH-1 2 O 7: 2: 1): R f = 10 0.45, UV and PMA.

Microanalysis for C 21 H 24 O 5 FPL * 2 + 1.7 mol H 2 O, M = 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; Δ, 6.89 1 H-NMR (400 MHz, CD 3 OD): δ 1.34 - 1.56 ppm (4 H, mul-15 doublet), 2.22 - 2.31 ppm (2 H, multiplet), δ , 25 and 2.37 ppm (6 H, two singlets), 2.29 ppm (3 H, doublet, JH_F = 1.4 Hz), 2.75 ppm (2 H, multiplet), 4.13 ppm (1H, multiplet, 6.73 - 7.10 ppm (5H, multiplet).

Example 3 (S) -4- [2- (4'-Fluoro-3,3 ', 5-trimethyl-1,1-biphenyl-2-yl) ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester: ·] To a mixture of the silyl ether of Example 1, Part G (455 mg, 0.678 mmol) and glacial acetic acid ”· *: 25 (155 μL, 2.71 mmol, 4.0 eq.) In dry THF (7 mL ),. : A 1.0 M solution of tetrabutylammonium fluoride in THF (2.0 mL, 2.0 mmol, 3.0 eq.) was added, and the resulting solution was stirred under argon at room temperature overnight. The mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (twice). The organic phase was washed with saturated NaHCO 3 and saturated NaCl and evaporated to give 498 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel using hexane-35 acetone (3: 2) as adsorbent. The product fractions were evaporated to give 217 mg (74%) of the title alcohol as a colorless oil, TLC (hexane-acetone 7: 3):

Rf = 0.10, UV and PMA.

Example 4 (S) -4 - [[2- (4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt

To a mixture of the diester of Example 3 (203 mg, 0.469 mmol) in dioxane (6 mL) was added 1.0 N LiOH (1.6 mL, 1.6 mmol, 3.5 eq.) And the solution was heated to reflux. -10 at 55 ° C (oil bath) under argon for 30 minutes. The mixture was cooled, diluted with water, filtered and evaporated, the residue dissolved in water (30 ml) and the solution lyophilized. The white freeze-drying product was dissolved in as little water as possible and chromatographed on HP-20 resin (column diameter 25 mm, resin layer thickness 20 cm) using water as eluent and then a mixture of I 2 O-CH 2 OH (50:50). . The product fractions were combined and evaporated, the residue dissolved in water (30 ml) and the solution lyophilized to give 199 mg (97%, based on hydrate, M = 435.36) of the title dilithium salt as a white solid. TLC (Cl 2 Cl 2 -CH 2 OH-HOAc 8: 1: 1): Rf = 0.13, UV and PMA.

: Y: Microanalysis (C 21 H 20 O 5 FBLi 2 + mol H 2 O · M = 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, CD 3 OD): δ 1.76 - 1.82 ppm (2 H, multi-i: pipette), 2.32 (3 H, doublet, JflF = 1 , 8 Hz), 2.34 (3 H, singlet), 2.37 (1H, dd, J = 8.4 Hz), 2.41 (1H, dd, 30 J = 4.1 Hz) , 2.49 (3H, singlet), 4.27 (1H, multiplet V), 6.98-7.37 (5H, m).

83 87927

Example 5 (S, Z) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester 5 A) (S, Z) -4 - [[2- (4'-fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] methoxyphosphinyl] -3- (t-butyl-diphenylsilyloxy ) butanoic acid, methyl ester

To a degassed solution of acetylene phosphinate 10 (498 mg, 0.742 mmol) in Part G of Example 1 in CH 2 OH (10 mL) was added 10%

Pd / C catalyst (50 mg, 10% by weight) and the black suspension was stirred under N 2 atmosphere (1 bar) for 2 hours. The catalyst was removed by filtering the mixture through diatomaceous earth, and the filtrate was evaporated to give 15,500 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel using adsorbent and hexane-EtOAc (3: 2) as eluent. The product fractions were combined and evaporated to give 498 mg (100%) of the desired olefin as a colorless oil.

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

B) (S, Z) -4 - [[2- (4 · -Fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester 25 To a solution of the silyl ether prepared in Part A (498 mg, 0.74 mmol) in dry THF! . (6 mL), glacial acetic acid (170 μL, 2.96 mmol,;; 4.0 eq.) Was added followed by a 1.0 M solution of tetrabutylammonium fluoride in THF (2.2 mL, 2.2 mmol, 3, 0 eq.), And the clear colorless mixture was stirred at room temperature under argon for 16 hours. TLC showed a small amount of V * remaining in the mixture. Additional HOAc (40, 1.0 eq) and n-Bu 2 NF (0.74 mL, 1.0 eq) were added and stirring was continued for an additional 6 hours.

The mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (twice). The combined extracts were washed with saturated NaHCO 3 and saturated NaCl, dried over anhydrous Na 2 SO 4 and evaporated to give 468 mg of a pale yellow oil. The crude product was purified by flash chromatography on silica gel using hexane-acetone (7: 3) as adsorbent. The product fractions were combined and evaporated to give 243 mg (76%) of the title alcohol as a colorless oil. TLC (hexane-acetone 7: 3): Rf = 0.19, UV and PMA.

Example 6 (S, Z) -4 - [[2- (4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid , dilithium salt

To a solution of the di-15 ester of Example 5 (240 mg, 0.552 mmol) in dioxane (7 mL) was added a 1.0 N LiOH solution (1.9 mL, 1.9 mmol, 3.5 eq). and the mixture was heated with stirring at 50 ° C (oil bath) under argon for 3 hours. A white precipitate was observed. The mixture was cooled, diluted with water, filtered and evaporated under reduced pressure to a white solid. The crude solid was dissolved in as little water as possible and chromatographed on HP-20 resin using water: V: followed by H 2 O-CH 3 OH (50:50) as eluent. The product fractions were combined and evaporated, the residue being dissolved in water. : (50 ml), and the solution was filtered and lyophilized to give 255 mg (100%, based on the mass of hydrate, M = 457.58) of the title dilithium salt as a white electrostatic solid. TLC (CH 2 Cl 2/30 CH 2 OH-HOAc 8: 1: 1): Rf = 0.26, UV and: - PMA.

"Microanalysis for C 2 H 2 O 2 • FPl 2 + 2.18 mol H 2 O, M = 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, CD 3 OD): δ $ 1.24 ppm (2 H, multiplet), 2.09 (2 H, doublet, J = 6.2 Hz), 2.27 (3 H, doublet, li es 37927

Jhf = i'8 Hz) / 2.30 (3H, singlet), 2.38 (3H, singlet), 4.06 (1H, multiplet), 5.87 (1H, double doublet) , JHH = 12.4 Hz, JHp = 14.3 Hz), 6.87 (1H, s), 6.91 (1H, double doublet, JHp = 43.4 Hz), 6.98 (2H, 5 triplets), 7.22 (2H, multiplet).

Example 7 (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester 10 A) 2- [ T4-fluorophenyl) methyl-3-oxobutanoic acid, ethyl ester

Sodium granules (8.31 g, 362 mmol) were dissolved in absolute EtOH (1 L) with mechanical stirring, and ethyl acetoacetate (47 g, 362 mmol, 1 eq.) Distilled under argon was added to the clear solution. The pale yellow mixture was refluxed for 1 hour, cooled to room temperature, and 4-fluorobenzyl bromide (75 g, 398 mmol, 1.1 eq.) Was added, and the pale orange mixture was stirred at room temperature under argon for 2.5 hours. The mixture was evaporated under reduced pressure. The residue was partitioned between EtOAc and water, and the organic phase was washed with water (twice) and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to an orange oil.

The crude product was triturated by vacuum distillation (5 mmHg). : to give 46.47 g (54%) of the alkylated product as a clear, colorless liquid with a boiling point of 1,142-144 ° C. TLC (hexane-Et 2 O 7: 3): Rf = 0.31.

1 H-NMR (CDCl 3: δ 1.20 (3 H, t), 2.19 (3 H, s), 3.13 (2 H, V "d), 3.73 (1H, t), 4.14 (2H, q), 6.95 (2H, t), 7.13: (2H, m) ppm.

13 C-NMR (CD 3 CN): 614.4, 29.7, 33.7, 62.1, 62.3, 115.3, 116.8, 131.4, 131.9, 145.1 (J = 284 Hz), 170.1, 203.5.

86 87927 B) 3- (4-Fluoro-phenyl) -1H-indole-2-carboxylic acid, ethyl ester

References: Chemical Abstracts 33, p. 587; Preparative Organic Chemistry, 4th ed., 1972, p. 582.

To a solution of the ester prepared in Part A (46.4 g, 195 mmol) in absolute EtOH (290 mL) at 0 ° C (ice bath) was added aqueous NaOH (23.4 g, 50 mL). in water immediately) followed by dibenzenediazonium chloride solution 10 (Prep. Org. Chem., 4th ed., 1972, p. 582) prepared from aniline (17.8 mL), concentrated HCl (88 mL), water ( 98 ml) and NaNO 2 (13.5 g) to give a deep orange-red biphasic solution.

The mixture was stirred at room temperature for 1 hour and poured into ice-cold water (500 ml) and extracted

With EtOAc (3 x 300 mL). The organic phase was washed with saturated NaCl solution (500 ml), dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 55.62 g of crude hydrazone intermediate as an orange oil. TLC (hexane-Et 2 O 7: 3): hydrazone Rf = 0.22, UV and PMA. The crude material was used as such in the subsequent addition of Fischer.

Y: To a solution of hydrazone in absolute EtOH (200 mL) was added gaseous HCl below the surface for 30 minutes with occasional cooling in an ice bath. The brownish mixture was poured into ice-cold water (600 mL) and extracted with EtOAc (3 x). The organic phase was washed with water (twice) and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to a brownish golden solid. Trituration with ice-cold hexane and filtration afforded 26.74 g (49%) of the desired title indole as golden brown granular crystals with a melting point of - · - 129 - 130 ° C. TLC (hexane-Et 2 O 7: 3):

Rf = 0.26, UV and PMA.

87 87927

Microanalysis (C ^ H ^ FNC ^):

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 (CDCl 3): tfl, 22 (3 H, t), 4.29 (2 H, q), 7.10-5 7.62 (8 H, m); 9.21 (1H, bs) ppm.

13 C-NMR (CDCl 3): 414.1, 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_p = 7.6 Hz), 135.7, 162.0, 162.2 (JC_F = 244 Hz) ppm.

C) 3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-10 indole-2-carboxylic acid, ethyl ester

Reference: International Patent Publication 158,635 (1984) in the name of Sandoz, p. 35.

To a solution of the indole prepared in Part B (26.74 g, 94.4 mmol) in dry distilled di-15-methylacetamide (100 mL) at 0 ° C (ice bath) was gradually added (gas evolution from heat) 60% of a mineral oil dispersion of NaH (4.53 g, 113.3 mmol, 1.2 eq.), and the mixture was stirred under argon at 0 ° C for 1 h. 2-Iodopropane-20 (85 g, 500 mmol, 5.3 eq) was added and the mixture was allowed to warm to room temperature under argon and stirred for 1 hour. The mixture was recooled to 0 ° C another 1.2 eq. NaH, and the mixture was stirred at room temperature for 1 hour. This procedure • 25 was repeated twice more. The final mixture is cooled. to 0 ° C (ice bath), and excess NaH was destroyed by careful dropwise addition of abs. 1 L of EtOH (30 mL). The mixture was diluted with EtOAc and washed with 5% KHSO 4, the aqueous phase was back-extracted once with EtOAc, and the combined EtOAc; the layers were washed with water and saturated NaCl solution (twice), dried over anhydrous Na 2 O 4 and evaporated to give 38.54 g of a brown solid. The solid was dissolved in hot CH 2 Cl 2 and the indole starting material was crystallized by the addition of hexane.

• 13.88 g of indole starting material were recovered. The mother liquor ββ 87927 was evaporated under reduced pressure to give 22.32 g of a brown oil. The crude product was purified by flash chromatography on silica gel using hexane followed by hexane-5 acetone (95: 5) as adsorbent. The product fractions were evaporated to give 6.55 g (21%, corrected yield 62%) of the desired title N-isopropylindole as a yellow oil.

TLC (4: 1 hexane-acetone): Rf = 0.57, UV and PMA.

1 H-NMR (CDCl 3): δ, 04 (3 H, t), 1.20 (6 H, d), 4.17 (2 H, q), 5.40 (1H, m), 7, 10-7.7 (8H, m) ppm 13 C-NMR (CDCl 3): δ 3.6, 21.5, 48.7, 53.3, 60.8, 112.7, 114.5, 114.8, 120.3, 121.4, 122.4, 124.3, 125.9, 127.6, 130.8, 131.7 (JC_F = 7.5 Hz), 136.2, 162.3 (Jc_p = 15 144 Hz), 163, 0 ppm D) 3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole-2-methanol at 0 ° C (ice bath) in dry distilled Et 2 O (30 ml) lithium aluminum hydride 20 (1.12 g, 29.6 mmol, 1.5 eq.) was carefully added. To the resulting suspension was added dropwise over 10 minutes an ethereal solution of the indole ester prepared in Part C (6.42 g, 19.7 mmol, in 20 mL of Et 2 O). After the mixture was stirred at 0 ° C under argon for 30 minutes, water (1.1 mL), 15% NaOH (1.1 mL) and water (3 mL) were added dropwise. 4 ml). The resulting suspension was filtered through tightly packed diatomaceous earth, and the filtrate was dried over anhydrous MgSO 4 and evaporated under reduced pressure to give 5.1 g of a yellow foam. The crude product was purified by flash chromatography on silica gel using hexane-acetone (85:15) as eluent to give 5.08 g (91%) of pure title alcohol as a pale yellow foam. TLC (hexane-acetone 5: 3): Rf = 0.38, UV and PMA. A small sample was crystallized from hexane to give the title alcohol as white crystals, m.p. was 101-103 ° C.

es 87927

Microanalysis (CH 2 Cl 2 / 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 (CDCl 3): 61.60 (1H, t), 1.69 (6H, d), 4.76 (2H, d), 4.93 (1H, m), 7.05-7.62 (8 H, m) ppm 13 C-NMR (CDCl 3): (δ 20.9, 47.3, 54.8, 113.0, 115.9, 116.3, 116.6, 120.2, 120.6, 122.9, 128.5, 131.6, 132.4, 135.1, 135.7, 163.0 (Jc_p = 245 Hz) PPm E) 3- (4-fluorophenyl ) -1- (1-methylethyl) -1H-10 indole-2-carboxaldehyde

To a solution of Dess-Martin eriodinane (5.9 g, 13.9 mmol, 1.2 eq) in dry Cl 2 Cl 2 (30 mL) was added dry t-butanol (1.3 mL, 13 .9 mmol, 1.2 eq.), And the mixture was stirred at room temperature under argon for 15 minutes. The indole alcohol prepared in Part D (3.28 g, 11.6 mmol, 1 eq.) In dry Cl 2 Cl 2 (12 mL) was added dropwise over 5 minutes, and the yellow mixture was stirred under argon at room temperature for 1 hour. The reaction mixture was added to a solution of sodium thiosulfate (15.3 g, 97 mmol, 7 eq.) In freshly prepared 1.0 N NaHCO 3 (40 mL) and stirred, and the resulting mixture was stirred vigorously: 'simmer for 5 minutes. The organic phase was separated, washed with 1.0 N NaHCO 3, water and saturated NaCl, dried over anhydrous Na 2 SO 4 and evaporated to give 3.69 g of a yellow oil. The crude product was purified by flash chromatography using silica gel II as the adsorbent and hexane-Et 2 O (40: 1) as eluent to give 2.7 g (83%) of the pure title aldehyde as a white crystalline solid, m.p. was 88-89 ° C. TLC (hexane-acetone 7: 3): Rf = 0.56, UV and PMA.

Microanalysis (C 18 H 28 FFO). Calculated: C, 76.85; H, 5.73; N, 4.98; F, 6.75 Found: C, 76.91; 11, 5.71; N, 4.95; F, 6.76 9 ° 87927 1 H-NMR (CDCl 3): d 6, 69 (6 H, a), 5.92 (1H, m), 7.10 - 7.70 (8 H, m), 9, 80 (1H, s) ppm 13 C-NMR (CDCl 3): δ 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), δ 183.6 ppm F) 3- (4-fluorophenyl) -1- (1-methylethyl) -2- (2, 2-Dibromoethenyl) -1H-indole To a cooled (-15 ° C, ice-salt bath) solution of the indole aldehyde prepared in Part E (1.84 g, 6.54 mmol) and triphenylphosphine (5.14 g, 19.6 mmol, 3 eq.) in dry CH 2 Cl 2 (30 mL), a solution of CBR 2 (3.25 g, 9.8 mmol, 1.5 eq.) in dry CH 2 Cl 2 was added dropwise over 5 minutes. (10 mL), and the yellow mixture was stirred at 15 ° C under argon for 15 minutes. The mixture was partitioned with sat

Between NaHCO 3 and CH 2 Cl 2, and the organic phase was washed with saturated NaHCO 3 and saturated NaCl, dried over anhydrous Na 2 SO 4 and evaporated to give 9.44 g of a brown oil. The crude product was purified by flash chromatography on silica gel using hexane-CH 2 Cl 2 (95: 5) as adsorbent. The product fractions were evaporated to give 2.87 g (100%): ['the desired title vinyl dibromide as a yellow • Y: oil which crystallized on standing. One recrystallization from ethyl ether gave 2.46 g (86%) of purified product as pale yellow granular crystals, m.p. 135-137 ° C. TLC (hexane-CH 2 Cl 2 7: 3): Rf = 0.45 UV and PMA.

Microanalysis (C 39 H 18 NFBr 2): Calculated: C, 52.20; H, 3.69; N, 3.20; Br, 36.56 Found: C, 52.25; H, 3.68; N, 3.20; Br, 36.58 Y! 1 H-NMR (CDCl 3): δ 1.15 (6 H, d), 4.67 (1H, m), 7.10 - 7.70 (9 H, m) ppm 13 C-NMR (CDCl 3): δ 21, 9, 48.6, 98.6, 111.6, 1 15.3, 35 115.6, 115.9, 119.9 (J_ = 7.6 Hz), 122.4, 127.5, 129 .3, 130.5, 130.7, 130.9, 135.2, 161.5 (J "= 246 Hz) • L *" r ppm 91 87 92 7 G. 3- (4-fluorophenyl) -1 - (1-methylethyl) -2-ethynyl-1H-indole in a solution of -78 ° C (carbonic acid-ice-acetone bath) containing vinyl dibromo-5 dia (2.395 g, 5.48 mmol) prepared in Part F in dry THF (10 ml) under argon, a 1.6 M solution of n-BuLi in hexane (6.9 mL, 10.96 mmol, 2 eq.) was added dropwise. The resulting mixture was stirred at -78 ° C for 1 h, after which saturated NH 4 Cl (5 mL) was added dropwise.

The mixture was allowed to warm to room temperature and then extracted with Et 2 O (twice). The ether layers were washed with saturated NaCl solution, dried over anhydrous MgSO 4 and evaporated under reduced pressure to give 1.893 g of a dark brown oil. The crude product was purified by flash chromatography on silica gel (80: 1) as adsorbent and hexane-Et 2 O (200: 1) as eluent to give 1.12 g of purified product as a 3.3: 1 mixture of acetylene and terminal olefin. . This mixture was separated into its components by chromatography on an alumina column (neutral alumina, activity class II) using hexane-Et 2 O (200: 1) as eluent. Evaporation of the product fractions r: gave 90 mg of off-white crystals. One recrystallization from hot hexane gave 700 mg (46%) of purified title acetylene. . : as needle needles with a melting point of 105-106 ° C.

TLC (hexane-Et 2 O in suture 95: 5): Rf = I 0.44 for acetylene and Rf = 0.49 for olefin, UV and PMA.

Microanalysis (C 18 H 18 N 2 NF): 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 V 1 H-NMR (CDCl 3): 01.70 (6H, d), 3.5 (1H, s), 5.06 (1H, m), 7.10 - 7.75 (8H, m) ppm * · · · * 92 87 92 7 H. (S) -4 - // 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indole 2-yl-ethynyl-7-methoxyphosphinyl-3- (t-butyldiphenylsilyloxy) butanoic acid, methyl ester in a solution of 5-78 ° C (carbonic acid-ice-acetone bath) containing acetylene prepared in Part G (678 mg, 2.44 mmol, 1, 0 eq.) In dry THF (6 mL) under argon, a 1.6 M solution of 1.6 M n-BuLin in hexane (1.53 mL, 2.44 mmol, 1.0 eq.) Was added dropwise. After 30 minutes at -78 ° C, the mixture was transferred via tube to a -78 ° C solution containing the phosphonium chloride of Example 1, Part F (ca. 4.3 mmol, 1.75 eq. ) in dry THF (5 mL). The dark brown mixture was stirred at -78 ° C for 30 minutes to 15 minutes, after which saturated NH 4 Cl (5 mL) was added dropwise and allowed to warm to room temperature. The mixture was extracted with Et 2 O (twice), and the extract solution was washed with saturated NH 4 Cl and saturated NaCl, dried over anhydrous MgSO 4 and evaporated under reduced pressure to give 2.567 g of a brown oil. The crude oil was purified by flash chromatography on silica gel using hexane-EtOAc (3: 2) as adsorbent to give 756 mg (44%) of the desired title acetylpheninate as a dark yellow oil.

: TLC (hexane-acetone 7: 3): Rf = 0.27, UV

and PMA.

1 H-NMR (CDCl 3): 61.0 (9H, s), 1.64 (6H, d), 2.10-2.90 (4H, m), 3.56, 3H, s), 3.58 (3H, dd), 4.6 (1H, 30bm), 4.90 (1H, m), 7.05-7.55 (18H, m) ppm; 13 C-NMR (CDCl 3): 614.2, 19.1, 21.0, 26.7, 27.8, 37.5, 39.2, 42.2, 45.1, 49.2, 51.4 , 51.9, 60.3, 65.5 (Jc_p = 15.1 Hz), 88.1, 91.2, 98.3, 111.3, 115.3, 115.6, 120.8. 7: (J = 5.7 Hz), 122.3, 124.9, 125.9, 126.4, 127.6, 129.2, 35 130.7, 133.0, 135.7, 136, 1,170.9 ppm 93,37927 J) (S) -4 - [[2- (3-4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] methoxyphosphinyl] -3- (t-butyldi -phenylsilyloxy) butanoic acid, methyl ester

To an argon-purged solution of acetylphosphinate (422 mg) prepared in Part H in CH 2 Cl 2 (9 mL) was added 10% Pt / C catalyst (420 mg), and the resulting mixture was stirred on a Parr apparatus for 2 h under hydrogen (2 mL). 8 bar) below. The catalyst was removed by filtering the mixture through diatomaceous earth and the filtrate was evaporated to give 380 mg (90%) of the title indole phosphinate as a yellow foam. TLC (EtOAc-hexane 4: 1): Rf = 0.27, UV and PMA.

1 H-NMR (CDCl 3): dl (00H, s), 1.63 (6H, d), 1.5-15 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 (18 H, m) ppm 13 C-NMR (CDCl 3): (δ 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, 20 121.1, 127.7, 128.3, 129 , 9, 131.2, 131.3, 132.8, 133.4, 134.3, 134.8, 135.7, 171.3 ppm K) (S) -4 - // 2- / 3- (4-fluorophenyl) -1- (1-methyl-ethyl) -1H-indol-2-yl-ethyl-methoxyphosphinyl-3-hydroxyl; : sibutanoic acid, methyl ester To a solution of the silyl ether prepared in Part J (379 mg, 0.531 mmol) in dry THF (5 mL) was added sequential glacial acetic acid (120, 2.12 mmol, 4 eq.) and 1 .0 M THF solution of tetrabutylammonium fluoride (1.6 mL, 1.6 mmol, 3 eq.), And the resulting. . The resulting mixture was stirred under argon at room temperature overnight. The mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (twice), and the organic phase was washed with saturated NaHCO 3 and saturated. NaCl, then dried over anhydrous Na 2 SO 4 and evaporated to give 408 mg of a yellow oil, The crude product was purified by flash chromatography on silica gel using silica gel as adsorbent and acetone-hexane as eluent ( The product fractions were evaporated to give 197 mg (78%) of the desired title alcohol as a white foam TLC (1: 1 hexane-5 acetone): Rf = 0.09, UV and PMA.

1 H-NMR (CDCl 3): δ $ 1.68 (6 H, d), 1.80 - 2.0 (2 H, m), 2.10 (2 H, m), 2.58 (2 H, m ), 3.08 (2H, m), 3.63 (3H, dd, JH_p = 10.1 Hz), 3.70 (3H, d), 3.96 (1H, t), 4 , 35 + 4.49 (1H, 2 broad multiplets), 4.67 (1H, 10 m), 7.0-7.6 (8 H, m) ppm 13 H-NMR (CDCl 3): δ 17, 6, 17.7, 21.4, 29.2, 29.4, 33.2, 33.3, 34.6, 41.6, 41.8, 42.0, 42.2, 47.3, 50, 9, 51.7, 63.4, 111.8, 113.5, 115.2, 115.5, 119.0, 119.4, 121.1, 128.3, 131.3, 131.5, 134, 2, 134.8, 161.5 (J = 244.1 15 Hz), 172.1 ppm

Example 8 (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt. containing the diester of Example 7 (197 mg, 0.414 mmol) in dioxane (5 mL) and stirred, 1.0 N LiOH (1.45 mL, 3.5 eq.) was added, and the resulting white suspension was heated. At 55 ° C (oil bath) under argon for 40 minutes. The mixture was cooled, diluted with water, filtered and. : evaporated under reduced pressure. The residue was dissolved in as little water as possible and treated with HP-20 resin. Using water followed by H 2 O-CH 3 OH (50:50) as eluent. The glassy residue was dissolved in water (50 ml), and the solution was filtered and lyophilized to give 178 mg (85%, based on hydrate: mass) of the pure title dilithium salt as a white solid.

Microanalysis (C23H23NFp. 2Li + 2.52 mol Η20, M = 504.71):. 35 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 95 37 927 1 H-NMR (400 MHz, CDCl 3): (fl, 69 ppm (6 H, dd, J = 5.8 Hz), 1.71 (2 H, multiplet), 1, 93 (2H, multiplet), 2.38 (2H, multiplet), 3.06 (2H, quartet), 4.32 (1H, multiplet), 4.87 (1H, multiplet), 6, 97 (1H, dt, δ J = 0.7 Hz), 7.07 (1H, dt, J = 1.1 Hz), 7.16 (2H, t), 7.41 (3H, m), 7.57 (1H, 1/2 AB quartet)

Example 9 (S) -4 - [[2- (1,1'-Biphenyl-2-yl) ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester 10 A) Biphenyl-2-carboxaldehyde

Dess-Martin periodinane (27.64 g, 65.2 mmol) was stirred (150 mL) under argon. To the stirred solution was added dry t-BuOH (8.0 mL), and this mixture was stirred at room temperature for 10 minutes. A solution of biphenyl-2-methanol (10 g, 54.3 mmol) in CH 2 Cl 2 (20 mL) was added dropwise over 15 minutes. After the addition was complete, the reaction mixture was stirred at room temperature. After stirring at room temperature for 1 hour, anhydrous was added to the reaction mixture

Et 2 O (600 mL) followed by 1 N NaOH (225 mL).

After 10 minutes, the resulting suspension was filtered and the filter cake was washed with Et 2 O. The filtrate was washed with 1 N

::: With NaOH (2 x 250 mL). The organic layer was dried over 25 MgSO 4 and filtered to give a yellow oil (10 g) after removal of the solvent. Purification by flash chromatography (silica gel, Et 2 O-hexane 1:10) afforded the title aldehyde (9.58 g, 97%) as a colorless oil. TLC (silica gel, 1: 9 EtOAc-hexane): Rf = 0.29.

IR (film): 3065, 3025, 2850, 2760, 1685, 1700, 1600, 1470, 1450, 1395 cm -1 1 H-NMR (270 MHz, CDCl 3: δ 8.00 (d, 1H, J = 7.0 Hz), 7.60 (m, 1H), 7.40 (m, 7H) ppm 35 Mass spectrum (m / e): 183 (M + + H) 96 87927 B) 2- (2, 2-Dibromoethenyl) -1,11-biphenyl A solution of the aldehyde prepared in Part A (2.0 g, 11 mmol) in CH 2 Cl 2 (60 mL) was placed under argon and cooled to -10 ° C. triphenylphosphine (9.21 g, 35 mmol) was added and the mixture was stirred until the solid was completely dissolved, and a solution containing CBr 2 was added over 15 minutes to the resulting solution at -10 ° C ( 5.5 g, 16.5 mmol) in CH 2 Cl 2 (40 mL) The reaction mixture was stirred at -10 ° C for 1 h 15 min, then saturated aqueous NaHCO 3 (-10 ° C) was added. The CH 2 Cl 2 layer and the aqueous layer were separated, and the aqueous layer was extracted once with CH 2 Cl 2 The combined CH 2 Cl 2 extraction solutions were washed with saturated NaHCO 3 water. solution (once) and saturated aqueous NaCl (once). The CH 2 Cl 2 extraction solution was dried over Na 2 SO 4 and evaporated to dryness. The crude product was purified by flash chromatography using hexane as eluent to give the title dibromide as an off-white solid (2.45 g, 66%). TLC (silica gel, EtOAc-hexane 5:95): Rf = 0.47.

IR (CHCl 3): 3064, 3011, 1596, 1473, 1450, 1435, 889, i 860, 702 cm -1. · 1. 1 H-NMR (270 MHz, CDCl 3): 67.75 (m, 1H), 7.35 (m, 8H), λmax 7.20 (s, 1H) ppm 13 C-NMR (67.0 MHz, CDCl 3): δ 41.06, 140.08, 137.49, δ 133.83, 129.81, 129.45, 129.17, 128.61, 128.22, 127.50, 1! 127.08, 90.78 ppm • * Mass spectrum (m / e) 337, 339, 341 (M + + H) 30 C) 2-Ethynyl-1,1'-biphenyl ·. *: A solution of the vinyl dibromide prepared in Part B (2.31 g, 6.9 mmol) in THF (35 mL). ), cooled to -78 ° C under argon, and n-BuLi (5.52 ml) was added to the vinyl dibromide over 10 minutes at 35-78 ° C with stirring. 2.5 M hexane solution) After the addition of n-BuLi was complete, the reaction mixture became deep purple, and after stirring at -78 ° C for 2 h 45 min, saturated NH 4 Cl was added. After the quenched reaction mixture was warmed to room temperature, the THF was removed. And the resulting material was diluted with water and extracted with Et20 heksaaniseoksel-la (three times). The organic extraction solution was dried over MgSO 4 and filtered to give 1.3 g of a yellow oil. Purification by flash chromatography using 1% Et 2 O in hexane as eluent afforded the desired title acetylene (1.04 g, 88%). TLC (silica gel, 100% hexane): Rf = 0.16.

IR (film): 3287, 3061, 3026, 1474, 1449, 1432, 1008, 775, 758, 738 cm -1 1 H-NMR (270 MHz, CDCl 3): δ 57.68 (m, 3 H), δ , 35 (m, 6 H), 3.00 (s, 1H) 13 C-NMR (67.8 MHz, CDCl 3): δ * 144.40, 140.22, 133.83, 129.56, 129.20, 128.92, 127.95, 127.49, 126.94, 120.44, 83.08, 80.15 Mass spectrum (m / e): 179 (M + + H) D) (S) -4 - [2- (1,1'-Biphenyl-2-yl) ethynyl] methoxyphosphinyl] -3- (t-butyldiphenylsilyloxy) butanoic acid, methyl ester: ': *: Acetylene prepared in Part C (0.332 g, 1.86 mmol) was stirred in THF (10 mL) at -78 ° C. and under an argon atmosphere To the acetylene solution was added n-BuLi (0.75 mL of a 2.5 M hexane solution) over 5 minutes. ).

! The reaction mixture was stirred at -78 ° C for 1 hour, warmed to 0 ° C and stirred for 10 minutes, then cooled again to -78 ° C.

The acetylene anion solution was then added dropwise over 8 minutes to a solution of the phosphonochloridate of Example 1, Part F (2.98 mmol) in THF (10 mL) cooled to -78 ° C under argon. At the end of the addition, the reaction mixture was stirred at -78 ° C for 1 h, after which 98 37927 saturated aqueous NH 4 Cl solution was added, the quenched reaction mixture was warmed to room temperature, diluted with half-saturated aqueous NaCl solution and extracted. The combined Et 2 O extracts were washed with saturated aqueous NaHCO 3 and saturated aqueous NaCl, the Et 2 O layer was dried over MgSO 4 and evaporated to give 1.5 g of a yellow oil. hexane-toluene-EtOAc (5: 1: 4) as eluent to give acetylene phosphinate (0.543 g, 48%).

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

IR (CHCl 3): 3070, 3053, 3035, 3000, 2952, 2934, 2896, 2859, 2178, 1735, 1474, 1448, 1436, 1429 cm -1 1 H-NMR (270 MHz, CDCl 3): δ 7.65 (m, 3H), 7.65 - 7.28 (m, 16H), 4.55 (m, 1H), 3.55 (d, 3H), 3.40 (dd, 3H) , 2.80 (m, 1H), 2.55 (m, 1H), 2.35 (m, 1H), 2.08 (m, 1H, 1.00 (s, 9H) 13 C 1 H NMR (67.8 MHz, CDCl 3): (5170.83, 145.29, 145.19, δ 139.22, 135.95, 135.59, 133.86, 133.75, 133.16, 132 , 86 130.57, 129.56, 129.34, 128.81, 127.92, 127.75, 127.44, 127.39, 126.94, 117.90, 100.91, 100.38, 100.18, 84.51, f ft 81.60, 65.53, 65.42, 60.06, 51.61, 51.50, 51.11, 42.07: V: 41.90, 38, 86, 37.16, 26.56, 20.75, 18.97, 13.97 Mass spectrum (m / e): 611 (M + + H): E) (S) -4 - // 2- (1 , (1'-Biphenyl-2-yl) ethyl] methoxyphosphinyl-7- (t-butyldiphenylsilyloxy) butanoic acid, methyl ester

A solution of the acetylene phosphinate prepared in Part D (0.515 g, 0.85 mmol) dissolved in methanol (8 mL) was purged with argon: 10 minutes. To the acetylene solution was added 10%

Pd / C catalyst (0.190 g), followed by hydrogenation on a Parr apparatus at 3.0 bar.

After shaking the methanol solution for 25 minutes at 3.0 bar, it was filtered through diatomaceous earth through 99,37927 and the filtrate was evaporated to give the title phosphinate (0.510 g, 98%) as a colorless oil. TLC (EtOAc-hexane 4: 1):

Rf = 0.21.

Δ IR (CHCl 3): 3071, 3054, 2998, 2954, 2934, 2902, 2859, 1734, 1477, 1462, 1448, 1438, 1428 cm -1 1 H-NMR (270 MHz, CDCl 3): δ $ 7.65 (m , 3H), 7.55-7.00 (m, 16H), 4.45 (m, 1H), 3.58 (s, 3H), 3.30-3.20 (2 doublets, 3 H, J = 11 Hz), 2.88 (m, 1H), 2.60 (m, 3 3 H), 2.17 - 1.80 (m, 1H), 1.80 - 1, Δ (m, 1H), 1.00 (s, 3H) 1 H-NMR (67.8 MHz, CDCl 3) (characteristic peaks): δ fl71.33, 65.78, 51.36, 42.24 , 26.75 Mass spectrum (m / e): 615 (M + + H) 15 F) (S) -4- [2- (1,1'-Biphenyl-2-yl) ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester

A solution of the phosphinate prepared in Part E (0.500 g, 0.82 mmol) in THF (10 mL) was stirred with HOA (0.19 mL, 3.3 mmol) under an argon atmosphere. NBu 2 NF (2.4 mL of a 1.0 M THF solution) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at room temperature for 23 hours, after which ice water (15 ml) was added. The aqueous layer was extracted three times with EtOAc. The combined organic solutions were washed with saturated aqueous NaHCO 3; (twice) and saturated aqueous NaCl 7 7 (once). The organic layer was dried over Na 2 SO 4 and; ; evaporated to give 0.437 g of a colorless oil. Purification by flash chromatography using 30 acetone-hexane (7: 3) as eluent gave the title. (0.247 g, 81%) as a colorless oil.

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

77; IR (CHCl 3): 3600-3171 (broad), 3064, 3009, 2954, 1731, 35 1479, 1439, 1237, 1180, 1042, 999 cm -1 1100 87 927 1 H-NMR (270 MHz, CDCl 3): δ $ 7 , 50-7.10 (m, 9H), 4.50-4.15 (m, 1H), 3.70 (s, 3H), 3.53-3.50 (2 doublets, 3H) , J = 11 Hz), 2.88 (m, 2 H), 2.50 (m, 2 H), 2.00 - 1.60 (in, 4 H) δ 13 C-NMR (67.8 MHz, CDCl 3): <$ 171.55, 171.49, 141.39, 141.00, 138.10, 137.88, 129.95, 128.81, 128.06, 127.53, 126.83, 126.22, 63.08, 63.02, 62.85, 51.39, 50.58, 50.47, 42.35, 42.15, 42.07, 41.87, 34.31, 33, 06, 33.00, 30.77, 30.52, 29.49, 29.21, 25.41 Mass spectrum (m / e): 377 (M + + H)

Example 10 (S) -4- [2- (1,1'-Biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt

The diester of Example 9 (0.239 g, 0.64 mmol) was stirred in dioxane (6.5 mL) under argon. 1.0 M LiOH solution (1.9 mL) was added at room temperature. This mixture was stirred at 55 ° C. After stirring for 2.5 hours, the reaction mixture was cooled to room temperature and the dioxane and most of the water were removed on a rotary evaporator. Purification by chromatography on an HP-20 resin column (18 cm x 2.5 cm) using first water alone and then MeOH-H 2 O as eluent · (1: 1) gave the title dilithium salt.

'(0.180 g, 79%) as a white solid. TLC

25 (CH 2 Cl 2 -MeOH-AcOH 8: 1: 1): Rf = 0.16; : TLC (nPrOH-NH 3 -H 2 O 7: 2: 1): Rf = 0.37.

... Example 11 (R) -4 - [(7e) -2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxy- . . 30 Butanoic acid, dilithium salt '* (A) (E) -tributyl / 2- (4'-fluoro-3,3', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl

Reference: MA Miftakov et al. Synthesis (Comm.) 1985, 496-499 35 To a mixture containing 2-ethynyl-41-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl (1.7 g, 7.13 mmol) and ιοί 87927 (nCl 2 Hg) 2 SnH (2.9 mL, 10.7 mmol, 1.5 eq.), AIBN (7.0 g, 0.426 mmol) was added. , and the solution was heated rapidly to 120 ° C under argon (oil bath). After keeping the solution at 120 ° C for 15 minutes, more (nC 2 H 2 O) • SnH (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 Kugelrohr distillation at 0.1 mmHg at 240 ° C to give 3.073 g (81%) of the title vinyl stannane as a colorless liquid. TLC (hexane): product Rf = 0.45, UV and PMA. The product is unstable on silica gel (streaks towards the baseline).

13 C-NMR (67.5 MHz, CDCl 3): rf 9.5, 13.6, 14.5, 20.9, 21.1, 27.2, 27.6, 114.0, 114.3, 123 , Δ, 123.9, 128.8, 130.4, δ 133.0, 135.6, 136.1, 138.1, 140.0, 144.4, 160.3 (JC_F = 244 Hz) ppm 1 H-NMR: rf 0.8 - 1.5 ppm (27 H, m, Sn (Bu> 3), 2.27, 2.31, 2.36, (9 H, 3 singlets, aromatic CH 3)) , 6.05 (1H, d, J = 20 Hz, PhCH = CHSn), 6.68 (1H, d, J = 20 Hz, PhCH = 20 CHSn), 6.90 - 7.13 (5 H , m, aromatic protons) B) (E) -4'-fluoro-2- (2-iodoethenyl) -3,3 ', 5-trimethyl-1,11-biphenyl

To a solution of the vinyl stannane prepared in Part A (1.537 g, 2.89 mmol) in dry Et 2 O * <25 (20 mL) was added iodine (734 mg, 2.9 mmol, 1 eq.), and the brownish solution was stirred at room temperature under argon for 2 hours. The mixture was washed with saturated sodium thiosulfate, 10% NH 4 OH and saturated NaCl, dried over anhydrous magnesium sulfate. . 30 la and evaporated to give 1.639 g of a yellow oil. The crude product was purified by flash chromatography on silica gel (160 g) as adsorbent and hexane as eluent. The combined product fractions gave 832 mg (65%) of the desired, pure, vinyl iodide 35 as a pale yellow oil which crystallized on standing. mp. 53-55 ° C. TLC (hexane: 102 87927 trans-olefin Rf = 0.31 (cis-olefin Rf = 0.26), UV, PMA.

1 H-NMR (270 MHz): c (2.30 & 2.32 ppm (9 H, 2 singlets, aromatic methyls), 6.05 (1H, d, J = 5 Hz, -HC = CHI), δ 6.92-7.10 (5H, m, aromatic Hs), 7.24 (1H, d, J = 15 Hz, PhCH = CHI) 13 C-NMR (67.5 MHz): δ14 , 6, 21.0, 21.1, 81.0, (= CH-I), 114.4, 114.7, 124.2, 124.5, 128.5, 128.7, 130.5, 132.7, 132.8, 133.2, 135.8, 137.2, 140.1, 143.1 (PhCH = CHI), 10 161.0 (J = 244 Hz) ppm

Note: The 1 H-NMR spectrum (270 MHz, CDCl 3) run from the mixed fractions shows the cis-vinyl iodide of the nearby mobile impurity, 66.54 ppm (1H, d, JHaHk = 7.9 Hz (PHCH, = CH-I)) D cl C) (R) -3- [7- (1,1-dimethylethyl) diphenylsilyl] oxy-7- (7TE) -2- (4'-fluoro-3,3 ', 5'-trimethyl-1,1' -bi-phenyl-2-yl) ethenyl7-methoxyphosphinyl-7-butanoic acid, methyl ester to -78 ° C (carbonic acid-ice-acetone bath) containing a solution of vinyl iodide prepared in Part B (812 mg, 2.22 mmol) in dry THF (6 ml), a 1.6 M solution of n-BuLi in hexane (1.4 mL, 2.2 mmol, 1 eq.) was added dropwise via syringe, and the pale yellow mixture was stirred under argon at -78 ° C for 45 minutes. The anion was then transferred via a droplet over 10 minutes directly to a -78 ° C solution containing the pre-; / phosphonochloridate of mark 1, part F (ca. 3.5 "/ · 'mmol, 1.58 eq.) in dry THF (6 ml). The yellow ·'. mixture was stirred at -78 ° C for 30 minutes, then It was warmed to room temperature and saturated NH 4 Cl (5 mL) was added to the mixture at room temperature.

The mixture was diluted with Et 2 O, and the ether layer was washed with ... saturated NH 4 Cl and saturated NaCl, then dried over anhydrous MgSO 4 and evaporated to give 2.083 g of a yellow oil. The crude product # was purified by flash chromatography using 103 8 7 927

silica gel as absorbent and hexane-acetone (85:15) as eluent. The product fractions were combined and evaporated to give 249 mg (17%) of the desired trans-olefin phosphinate as a pale yellow oil. NMR showed a ratio of di-5 astereomers (for phosphorus) in the mixture of about 1: 1. TLC (hexane-acetone 7: 3): Rf = 0.35, UV and PMA. O

1 H-NMR: (J 3.27 ppm (3 H, d, J H_p = 11.6 Hz, -POCH 3), 3.57 & 3.60 (3 H, 2 singlets, diastereomers, δ 4.33 & 4.50 (1H, 2 multiplets, diastereomers, -CH 2 CH (OSirj) CH 2 -), 4.84 & 5.25 (1H, 2 double doublets, diastereomers, = 17.9 Hz, JHa_p = 25.3 Hz,

O

PhCH, = CH (P-) 15 D) (R) -4 - [(7e) -2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl7-methoxyphosphinyl7-3-hydroxybutanoic acid, methyl ester

To a solution of the silyl ether from Part C (249 mg, 0.370 mmol) in THF (5.0 mL) was added sequential glacial acetic acid (5 and 1, 1.48 mmol, 4.0 eq) and A solution of 1.0 M (nCl 2 Hg) 2 NNF in THF (1.1 mL, 1.1 mmol, 3.0 eq) and the yellow mixture was stirred at room temperature under argon overnight. The mixture was diluted with cold water (10 mL) and extracted with EtOAc. The organic phase was washed with saturated NaHCO 3 and saturated *. NaCl, then dried over Na 2 SO 4 and evaporated to give 243 mg of a yellow oil.

The crude product was purified by flash chromatography on silica gel using adsorbent and hexane-acetone blocker (55:45) as eluent. The product fractions were combined: · and evaporated to give 121 mg (75%) of the desired title hydroxide ester as a colorless viscous oil. TLC (acetone-hexane 6: 4): 35 Rf = 0.62 UV and PMA.

104 37927 o 1 H-NMR: 41.8 - 2.06 ppm (2 H, m, CH 2 O-PCH 2 -), 2.30, 2.35, 2.40 (9 H, 3 singlets, aromatic CH 3: t), 2.40 - 2.60 (2H, m, -CH (OH) CH 2 Cl 2> CH 3), 3.50 and 3.55 (3H, O

II

5 2 doublets, diastereomers, -POCH0, J n = 12 Hz),

1 j rl-F

3.64 (3H, s, -CO 2 CH 3), 3.77 and 3.84 (1H, 2 doublets, diastereomers, -CH (OH) -), 4.28 and 4.38 (1H, 2 broad multiplet, -CH 2 (OH) -), 5.52 (1H, 2 double doublets, diastereomers, JHH coupling & JHp coupling,

10 O

PhCH = CH-P (OCH) -), 6.90 - 7.10 (5 H, aromatic protons), 7.50 (1H, multiplet, diastereomers)

O

coupling, PhCH = CH-P (OCH3) -) (E) (R) -4 - // (E) -2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl- 2-yl) ethenyl7-hydroxyphosphinyl7-3-hydroxybutanoic acid, dilithium salt

To a solution of the hydroxide ester prepared in Part D (121 mg, 0.279 mmol) in dioxane 20 (2 mL) was added an excess of 1.0 N LiOH (0.98 mg, 0.98 mmol, 3.5 eq) / and the bright pale yellow mixture was stirred under argon at 50 ° C (oil bath) 1.5:. hours. The mixture was cooled, diluted with water and filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in as little water as possible and chromatographed on HP-20 resin (8 cm), column diameter 25 mm, using water (200 ml) as eluent, then H 2 O-CH 3 OH. mixture (80:20) and finally H 2 O-CH 3 OH (60:40). The product fractions were evaporated under reduced pressure, the residue was dissolved in water. (50 ml), and the solution was lyophilized to give 91 mg of pure title dilithium salt as a hygroscopic white lyophilization product. TLC (CH 2 Cl 2 -CH 3 OH-HOAc 8: 1: 1): Rf = 0.19, UV and PMA.

I; 105 87927

Examples 12 to 24

Following the procedures outlined above and described in the previous working examples, the following additional compounds can be prepared: 5

0 H

Il | χ

The R-P-C-CH2-CH2-C02-R

X OH

z 106 37927

Eg x

No. R _Z_. x R

12. OH -CH2 -CH2CH2- h 0 3 13. c2h5o chT \ Q / -ch-ch- ch3 CH *, 3 L C1

14. OH (qY “C = C- H

cih ^ v C2H5 15- OLi φ-ΟΙ, -Ο -CH2CH2- Li; ΐ: ®k ,,

·: 16 · OH [θ '] -CH-CH- H

: .0 (o} oX "» * · • a »17 · 0Li föj -CSC- Li = h2 ^ Ö) 107 3 7 92 7

Eg X

No. R __2__ _1- -S

18. och3 (~) -ch2ch2- ch3

19. OK C.H.-CH -CH-CH- ° K

2 5 | C-0

O

- £ 0- “· CH3 20. OM (ÖVcHj-O -CK-“ a is όότ'Α: V: 21. OH (ÖVcH, -O -CH2; H2- ”

w IL

-ώ! τ ·

. ·. : H

· • 1,108,37527

Eg n * No. _s_ _ £ _-- i- —-- CH -C-C-0

22. OH 2 ^ \ O \ -CH 2 CH 2 "H

OH

23. CH 3 O (O) -CSma! - CH 3

24. OH (oy {oy- -CSC- H

T§) 109 879 2 7

Example 25 (S) -4- (Hydroxymethoxyphosphinyl) -3- [1,1'-dimethylethyl) diphenylsilyl] oxy7-butanoic acid, methyl ester, dicyclohexylamine salt (1: 1) 5 A) (S) -4- (Diisopropyloxyphosphinyl) ) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester

The iodide from Example 1, Part F (2) (45.1 mmol, 21.70 g) was stirred under high vacuum for 30 minutes. Freshly distilled triisopropyl phosphite (0.451 mol, 93.92 g, 113.37 mL) was added in one portion, and the reaction mixture was stirred under argon and heated in a 155 ° C oil bath for 16.5 hours. The mixture was then cooled to room temperature. Excess tri-15 isopropyl phosphite and volatile reaction products were removed by short path distillation (10 mmHg) followed by Kugelrohr distillation (0.50 mmHg, 100 ° C, 8 hours). The product was further purified by flash chromatography (column diameter 95 mm, 15 cm layer of 20 Merck silica gel, eluent hexane-acetone-toluene 6: 3: 1, flow rate 5 cm / min, fraction size 50 ml) to give 17.68 g (33.96: mmol; 75% yield) of the title isopropylphosphonate as a clear viscous oil. TLC (silica gel, hexane-acetone-toluene 6: 3: 1): Rf = 0.32.

·. ·. 1 NMR (270 MHz, CDCl 3): δ 7.70 - 7.65 (m, 4 H), 7.45 - 7.35 (m, 6 H), 4.57 - 4.44 (m, 3 H), 3.59 (s, 3 H), 2.94 and 2.88 (2 xd, 1 HJ = 3.7 Hz), 2.65 and 2.60: · (2 xd, 1 HJ = 7.4 Hz) ), 2.24 to 1.87 (set of m, 2 H), 30 1.19 and 1.12 (2 xd, 12 HJ = 6.3 Hz), 1.01 (s, 9 H) B (S) -4- (hydroxymethoxyphosphinyl) -3- [1,1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, .alpha.-methyl ester, dicyclohexylamine salt (1: 1)

The isopropyl phosphonate 35 prepared in Part A (30.5 mmol, 10.66 g) was stirred in dry CH 2 Cl 2 (80 mL) under argon at room temperature. To this solution 37927 was added dropwise over 5 minutes bistrimethylsilyl trifluoroacetamide (BSTFA) (32.8 mmol, 8.44 g, 8.71 mL) followed by dropwise addition over 10 minutes of trimethylsilyl bromide (TMSBr) (51.3 mmol, 7.84 g, δ 6.75 mL). After the reaction mixture was stirred at room temperature for 20 hours, 5% aqueous KHSO 4 solution (200 ml) was added thereto, and the mixture was stirred vigorously for 15 minutes. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed once with saturated NaCl solution, dried over Na 2 SO 4 and concentrated in vacuo. The residue was azeotroped twice with benzene (50 ml). The precipitate formed was suspended in toluene, and the suspension was filtered. The filtrate was concentrated and the azeotropic distillation and filtration process was repeated. The resulting filtrate was evaporated under reduced pressure and then kept under high vacuum with a pump for 5 hours. The resulting viscous clear oil was stirred in dry pyridine (50 mL) under argon at room temperature. To this solution was added in one portion dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g) followed by methanol (41.0 mmol, 1.31 g, 1.67 mL). After stirring at room temperature for 20 hours, the reaction mixture was filtered through a pad of diatomaceous earth formed on a glass sinter. The diatomaceous earth was washed with ethyl acetate, and the combined filtrates were evaporated under reduced pressure. The residue was redissolved in ethyl acetate and the solution was washed twice with 5% aqueous KHSO 4 and once with saturated NaCl solution. The organic extraction solution was dried over Na 2 SO 4 and filtered, the filtrate was concentrated and azeotroped twice with toluene, the residue was suspended in toluene and filtered. The resulting filtrate was reconcentrated, azeotroped and filtered, and the filtrate was evaporated under reduced pressure and placed under high vacuum for 6 hours to give the phosphonate monoester as a clear viscous oil (10.2 g, yield> 100.2 g, yield). ). The phosphonate monoester / 1.21 g portion was maintained under high vacuum under pump for 4 hours to give 1.16 g (2.57 mmol) of the substance / dissolved in dry ethyl ether (10 mL), and di was added dropwise to the solution. -cyclohexylamine (2.65 mmol, 0.481 g, 0.528 mL). The resulting homogeneous solution was allowed to stand at room temperature for 7 hours, resulting in significant crystal formation. The mixture was stored at -20 ° C for 16 hours, after which it was warmed to room temperature and filtered. The crystals were washed with cold dry ethyl ether and then kept under high vacuum on P 2 O 3 for 18 hours. The crystals were then kept under high vacuum in a pump at 45 ° C for 4 hours to give 1.25 g (1.98 mmol; 77% yield) of the title dicyclohexylamine salt as a white powder, m.p. 155-156 ° C. TLC (silica gel-20 L, 20% MeOH in CH 2 Cl 2): R f = 0.57.

1 H-NMR (270 MHz, CDCl 3): 61.71 - 7.65 (m, 4 H), 7.40 - 7.32 (m, 6 H), 4.02 (m, 1H), 3, 52 (s, 3 H) 3.28 and 3.22 • (m, 1H), 3.11 (d, 3 HJ = 11 Hz), 2.77 - 2.64 (m, 2 H), 2, 62 - 2.56 (m, 1H), 1.92 - 1.08 (set of m, 22 H), 25 1.00 (S, 9 H) *. Mass spectrum (FAB): 632 (M + H) + "IR (KBr): 3466-3457 (broad), 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736 , 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 30 1061, 1051, 820 cm-1 Elemental analysis (C22H31O6PS1Cl2H23N *: * 'Calculated: C, 64.63; H, 8, 61, N, 2.22

Found: C, 64.51; H, 8.49; N, 2.18 112 37927

Example 26 (E) -4 - [[2- (4'-Fluoro-3,3 ', 5-trimethyl-1,1'-bi-phenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) [2- (4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) -2-hydroxyethyl] phosphonic acid, dimethyl ester to -78 ° C (CC 4 acetone bath) To a solution of dimethyl methylphosphonate (1.8 mL, 16.5 mmol, 1.6 eq.) in dry THF (20 mL) was added a 1.6 M solution of n-butyllithium in hexane dropwise over 20 minutes ( 9.7 mL, 15.5 mmol, 1.5 eq.), And the resulting white suspension was stirred under argon at -78 ° C for 60 minutes. The biphenylaldehyde from Example 1, Part C (2.5 g, 10.3 mmol, 1 eq.) In dry THF (10 mL) was then added dropwise over 15 minutes to give a pale orange suspension. After the mixture was kept at -78 ° C for 30 minutes, saturated NH 4 Cl (10 mL) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 4.127 g of a yellow oil which slowly crystallized on standing. The crystals were triturated with hexane to give, after filtration and drying under reduced pressure, 3.38 g (89.4%) of pure title hydroxyphosphonate as white needles with a melting point of 98-100 ° C. An additional 233 mg (3.613 g, 95.6% yield) of the pure title compound was recovered by flash chromatography of the mother liquor (603 mg) on LPS-1 silica gel (40: 1) using hexane-acetone as eluent ( 7: 3). TLC (hexane-acetone 1: 1): Rf = 0.33, UV and PMA.

Elemental analysis (c 19 H 24 O 4 PF 3: Calculated: C, 62.29; H, 6.60; F, 5.19; P, 8.45 - Found: C, 62.66; H, 6.56; F, 5.03; P, 8.68 113 87927 B) / 2- (4-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl / phosphonic acid, dimethyl ester

To a solution of the hydroxyphosphonate prepared in Part A (3.513 g, 9.6 mmol) in dry (dried over 5 4 A molecular sieves) in toluene (15 mL) was added pTsOH · 1H 2 O (91 mg, 0.48 mmol, 0.05 eq.), And the mixture was refluxed through a 4 A Soxhlet with molecular sieves under argon for 16 hours. During the reaction, additional pTsOH'1 was added at the following intervals: 3.5 hours (91 mg), 5.0 hours (91 mg) and 6.5 hours (91 mg). The mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCO 3 to give the aqueous phase and the organic phase and an oily layer between phases. The aqueous phase and the oily layer were collected and washed with ethyl acetate, and the ethyl acetate layer was washed with saturated NaHCO 3 and set aside. Both bicarbonate washes were acidified with concentrated HCl and extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give 520 mg of phosphonic acid monoester. The diester was reconstituted by dissolving the oil in trimethyl orthoformate (5 mL) and refluxing the mixture under argon for 44 hours. Excess formate was removed under vacuum. 25 to give a yellow oil which dissolved. in ethyl acetate and combined with the original neutral organic phase. The ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give 3.396 g of a yellow oil. The crude oil was purified by flash chromatography using LPS-1 silica gel (40: 1) as adsorbent and hexane-gun, λ ton (75:25) as eluent. The product fractions were evaporated to give 2.987 g (89.4 L) of the title trans-vinyl '35 dimethylphosphonate as a golden oil. TLC (1: 1 hexane-acetone): Rf = 0.44 UV and PMA.

114 37927 1 H-NMR (CDCl 3): (52.27 (3 H, d, JR_p = 1.6 Hz), 2.33 (3 H, s), 2.39 (3 H, s), 3.61 (6 H, d, JR_p = 11 Hz), 5.51 (1H, dd, JR_R = 18 Hz, JR_p = 20.6 Hz), 6.95 - 7.09 (5 H, m), 7, 48 (1H, dd, JR_R = 17.9 Hz, JR_p = 23.7 Hz) ppm.

13 C-NMR (CDCl 3): (514.4, 20.9, 52.0 (Jc_p = 5.7 Hz), 114.4, 114.7, 119.2 (Jc_p = 185.5 Hz), 124.3 , 124.5, 128.4, 128.5, 129.0, 130.6, 130.9, 132.6, 132.7, 134.6, 173.1, 141.0, 148.2, 148.2 (Jc_p = 5.7 Hz), 160.5 (Jc_p = 244.1 Hz) C) / 2- (4'-fluoro-3,31,5-trimethyl-1,1'-biphenyl-ΙΟ 2-yl ) ethenyl / phosphonic acid, monomethyl ester

To a solution of the vinyl dimethyl phosphonate prepared in Part E (2.895 g, 8.31 mmol) in dioxane (20 mL) was added a 1.0 N solution of LiOH (12.5 mL, 12.5 mmol, 1.5 eq.), and the resulting mixture was stirred at 75 ° C (oil bath) under argon for 70 minutes.

After heating for 15 minutes, the mixture became homogeneous. The mixture was cooled to room temperature, adjusted to pH 1 with 1.0 N H 2 O (ca. 15 mL) and extracted with ethyl acetate (twice), and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 2.663 g (95.8%) of the desired title monomethyl ester as a clear colorless oil.

*. . TLC (CH 2 Cl 2 -CH 3 OH-HOAc 8: 1: 1): Rf = 0.75, /. 25 UV and PMA.

. Mass spectrum: 335 (M + H) + (observed) 1 H-NMR (CDCl 3): d 2.25 (3 H, d, JR_p = 1.6 Hz), 2.33 (3 H, s), 2.39 ( 3 H, s), 3.53 (3 H, d, JR_p = 11 Hz), 5.61 (1H, dd, JR_R = 18 Hz, JR_p = 20.6 Hz), 6.90 -30 7, 12 (5 H, m), 7.38 (1H, dd, JR_R = 18 Hz, JN_p = 24 Hz) ppm * · D) 4 - // 2- (4'-fluoro-3,3 ', 5 -trimethyl-1,1'-biphenyl-2-yl) ethenyl] methoxyphosphinyl / oxobutanoic acid, methyl ester 35 To a suspension of 60% NaH mineral oil dispersion (168 mg, 4.2 mmol, 1.4 eq.) in dry THF (10 mL) and stirred at 0 ° C (ice bath) under argon, methyl acetoacetate (420 μL, 3.9 mmol, 1.3 mL) was added dropwise over 15 minutes. equiv.). The resulting clear solution was stirred at 0 ° C for 15 minutes, after which a 1.6 M solution of n-butyllithium in hexane (2.25 mL, 3.6 mmol, 1.2 eq) was added over 10 minutes. The yellow di-anion solution was stirred at 0 ° C for 15 minutes, after which it was cooled to -78 ° C in preparation for the addition of phosphonochloridate.

The phosphonochloridate was prepared from the title monomethylethyl ester of Part C according to the following procedure. To a solution of the phosphonic acid monomethyl ester from Part C (960 mg, 2.87 mmol) in dry Cl 2 Cl 2 (8 mL) was added distilled trimethylsilyldiethylamine (750 μL, 5.98 mmol, 2 eq). and the clear mixture was stirred under argon at room temperature for 1 hour. The mixture was evaporated under reduced pressure and azeotroped again with benzene (2 x 15 ml), and the viscous oil was left connected to a vacuum pump for 15 minutes, the oil dissolved in dry Cl 2 Cl 2 (8 ml) containing dry THF (1 drop). , the solution was cooled to 0 ° C (ice bath), and oxalyl chloride (290 μL, 3.3 mmol, 1.1 eq.) distilled under argon was added dropwise over 5 minutes. After: keeping the mixture at 0 ° C for 15 minutes, it was stirred at room temperature for 45 minutes and then evaporated under reduced pressure. The crude oil was azeotroped with dry benzene (2 x 15 mL). : 30 to give, after drying for 15 minutes on a vacuum pump, crude phosphonochloridate as a pale yellow oil.

Phosphonochloridate (ca. 2.9 mmol, 1 eq.) Dissolved in Dry THF (8 mL) at -78 ° C was added dropwise from the tube battery over 30 minutes to -78 ° C methyl acetoacetate. - 116 87927 to the anionic solution. After maintaining the reaction mixture at -78 ° C for 30 minutes, saturated NH 4 Cl (8 mL) was added dropwise to the orange-brown mixture and allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with saturated NaHCO 3 and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 1.481 g of an orange oil. The crude oil was purified by flash chromatography using Merck silica gel as adsorbent and hexane-acetone (9: 1) followed by hexane-acetone (1: 1) as eluent. The product fractions were combined and evaporated to give 813 mg (62.9%) of the desired title vinylphosphinic acid diester as a viscous pale yellow oil. TLC 15 (1: 1 hexane-acetone): Rf = 0.42, UV and PMA.

1 H-NMR (CDCl 3): δ 2.28 (3H, s), 2.34 (3H, s), 2.40 (3H, s), 3.15 (2H, dd, JH_H = 4, 7 Hz, JR_p = 18.2 Hz), 3.54 (3H, d, JH_p = 11.6 Hz), 3.63 (2H, s), 3.72 (3H, s), 5, 57 20 (1H, dd, JR_H = 17.9 Hz, JR_p 25.3 Hz), 6.95 - 7.09 (5H, m), 7.52 (1H, dd, JR_R = 17.9 Hz, JR_p = 22.7 Hz) ppm 13 NMR (CDCl 3): 614.0 (JC_F = 3.9 Hz), 20.6, 45.3 (Jc_p = '; V 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,: 25 130.3, 130.8, 132.1, 132.4, 136.4, 136.8, 138.2, 140.7, Vi 149.2 (Jc_p = 4.9 Hz), 160.3 (Jc_p = 245.1 Hz), 166.7,: 194.4 (Jc_p = 4.9 Hz) ppm.

E) (E) -4 - [[2- (4'-fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] methoxyphosphinyl] -3-hydroxy-. : 30 Butanoic acid, methyl ester _ ··· 0- ° C (ice bath) to a solution of the ketone prepared in Part D (585 mg, 1.35 mmol) in dry THF (4 mL) , solid NaBH 4 (51 mg, 1.35 mmol, 1 molar equivalents) was added followed by dropwise addition. 35% CH 3 OH (1 mL, dried over 4 A molecular sieves), and the yellow mixture was stirred under argon at 0 ° C at 117,37927 for 30 minutes. Reagent grade acetone (6.5 mL) was added to the mixture at 0 ° C followed by CC-4 silica gel (500 mg). The suspension was warmed to room temperature, filtered through sintered glass, washed with ethyl acetate and evaporated under reduced pressure to give 607 mg of a yellow oil. The crude oil was purified by flash chromatography using Merck silica gel (30: 1) as adsorbent and ethyl acetate alone as eluent. The product fractions were evaporated to give 340 mg (57.6%) of the desired title alcohol as a pale yellow oil. TLC (ethyl acetate):

Rf = 0.19, UV and PMA.

Mass spectrum: 435 (M + H) + (observed) 1 H-NMR CDCl 3): 0.90 (2H, m), 2.27 and 2.28 (3H, 2 singlets), 2.34 ( 3 H, s), 2.39 and 2.40 (3 H, singlets), 2.56 (2 H, d), 3.52 (3 H, d, JR_p = 11.1 Hz), 3.69 and 3.70 (3 H, 2 singlets) 3.79 and 3.90 (1H, 2 doublets), 5.52 and 5.54 (1H, 2 double doublets, J n = 18 Hz, rl-n JH_p = 2.48 Hz), 6.95-7.02 (5H, m), 7.52-7.54 (1H, 2 2dd, JR_R = 18 Hz, JR_p = 21.6 Hz) ppm.

13 C NMR (CDCl 3) (R, S mixture): $ 14.3 (JC_F = 3.9 Hz), 20.8, 35.4 and 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 and 123.2 (Jc_p = 122, 1 Hz), 123.8, 128.2, | V 25 128.7, 129.0, 130.4, 131.4, 132.3, 132.7, 136.6, 137.0, 138.2, 140.8, 148.2 and 148.8 ( Jc_p = 4.9 Hz), 160.5: V: (JC-F = 245.1 Hz), 171.8 ppm.

F. (E) -4 - [[2- (4, -fluoro-3,3,5,5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxy-: butanoic acid , dilithium salt · To a solution of the diester prepared in Part E (339 mg, 0.781 mmol) in dioxane (8 mL) was added 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) under argon for 1.5 h. After 15 minutes, a white ‘precipitate appeared. The mixture was diluted while warm by adding 118,37927 water until all the solid had dissolved, after which it was filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in as little water as possible and chromatographed on HP-20 resin 5 eluting with a linear solvent gradient from water alone to CH 2 OH alone. The product fractions were evaporated, the white residue was dissolved in water (50 ml), and the solution was filtered and lyophilized to give 270 mg (82.7%) of the desired title dilithium-10 salt as a hygroscopic white lyophilisate. TLC (Cl 2 Cl 2 -CH 2 OH-HOAc 8: 1: 1): Rf = 0.33, UV and PMA.

Elemental analysis (C 21 H 22 O 5 FP * 2Ij * + 0/63 mol ^ O, M = 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; Δ, 6.96 1 H-NMR (CDCl 3): δ 59 (2 H, multiplet), 2.24 - 2.37 (2 H, 3 multiplets, J = 8.5 Hz + 4.4 Hz ), 2.28 rl ”xl (3 H, doublet, J„ „= 1.8 Hz), 2.30 and 2.39 (6 H, 2 ri” r 20 singlets), 4.14 (1H, multiplet), 5.78 (1H, JH-H = 17.9 Hz 'JH-P = 20.5 Hz' 6'88 "7.21 (6 H 'multiplet) ·; ·: Example 27 4- / [2- (4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl: 2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt -: A) 4 - // 2 - (4'-Fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl) ethyl] methoxyphosphinyl / -3-hydroxybutanoic acid, methyl ester ·.: 30 To an argon-rinsed solution containing Example 6 trans-vinyl phosphinate of Part E (297 mg) in CH 3 OH (6 mL), 10% Pd / C catalyst (74 mg, 25 wt%) was added, and the black suspension was shaken on a Parr apparatus under H 2 (2, 8 bar) under 3 35 hours The catalyst was removed by filtering the mixture through tightly packed diatomaceous earth and the filtrate was evaporated. under reduced pressure to an oil, the oil was crystallized from hexane to give, after filtration and drying under reduced pressure, 267 mg (89.5%) of the title saturated phosphinate as a white crystalline solid. TLC (EtOAc): δ Rf = 0.20, UV and PMA.

Mass spectrum: 437 (M + H) + (observed) 1 H-NMR (270 MHz, CDCl 3): ($ 1.55 - 1.87 (4 H, m), 2.29 and 2.30 and 2.31 ( 6 H, 3 singlets), 2.35 (3 H, d, Ju = n — r 2.1 Hz), 2.52 (2 H, m), 2.78 (2 H, m), 3, 50 and 3.55 10 (3 H, 2 doublets JH_p = 4.3 Hz), 3.71 (3 H, s), 3.86 and 3.91 (1H, 2 singlets), 4.25 and 4 .39 (1H, 2 broad multiplets) ppm.

B) 4- [72- (4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxy-15-butanoic acid, dilithium salt

To a solution of the diester prepared in Part A (250 mg, 0.573 mmol) in dioxane (6 mL) was added an excess of 1.0 N LiOH (1.72 mL, 3 eq.) And the mixture was heated at 50 ° C (oil bath). argon al-20 la 1.5 hours. After 15 minutes, a white precipitate appeared. The mixture was diluted while warm by the addition of: water until all the solid had dissolved, after which it was filtered. The filtrate was evaporated under reduced pressure; and the white residue was dissolved in as little water as possible and chromatographed on HP-20 resin using water alone (until the eluate was neutral) as eluent and then CH 2 CH 2 alone. The product fractions were evaporated under reduced pressure to a white solid from which any residual solvent was removed by azeotropic distillation twice with CH 2 Cl 2 and dried under reduced pressure to give 131 mg (55%) of the desired dilithium salt as a white solid. as a solid TLC (CH 2 Cl 2 -CH 3 OH-HOAc 8: 1: 1): 35 Rf = 0.34, UV and PMA.

• »» t.

120 8 7 927

Elemental analysis (C 21 H 24 O 5 FPL; * - 2 + 0.95 mol H 2 O, M = 437.30)

Calculated: 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 δ 1 H-NMR (CD 3 OD + D 2 O): J 39, 1.57 (1.5 H, multiplet) ppm, 2.22 - 2.37 (2 H, multiplet), 2.26 and 2 .38 (6 H, 2 singlets), 2.31 (3 H, doublet, J „„ = 1.8 Hz), n * “I? 2.71 - 2.77 (2H, multiplet), 4.13 - 4.20 (1H, multiplet, 6.73 - 7.11 (5H, multiplet, aromatic-10 set Hs))

Example 28 (E) -4- [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt 15 A) / 2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -2-hydroxyethyl] phosphonic acid, dimethyl ester in a -78 ° C (acetone-CO 2 bath) solution containing methyl dimethyl phosphonate (1.35 mL, 12.42 mmol, 1.6 eq.) in dry THF (20 mL) was added dropwise over 15 minutes a solution of 1.6 M n-BuLi in hexane (7.3 mL, 11.6 mmol, 1.5 eq.) And the resulting white suspension was stirred under argon at -78 ° C for 1 h. To the anion maintained at -78 ° C was added dropwise over 10 minutes the indole aldehyde of Example 7: Part E (2.183 g, 7.76 mmol) in dry THF (8 mL) and the resulting the light orange suspension was stirred at -78 ° C for 30 minutes. Saturated NH 4 Cl was added dropwise to the mixture. . 30 (10 ml), the mixture was warmed to room temperature and partitioned between water and ethyl acetate, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give 3.19 g of a white solid. The crude solid was triturated with warm hexane to give 2.967 g (94.3%) of pure title I; m 87927 hydroxyphosphonate as a white solid, m.p. 161-162 ° C. TLC (hexane-acetone 1: 1): Rf = 0.29, UV and PMA. Elemental analysis (C 21 H 25 ° 4NFF); Δ Calculated: 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 (CDCl 3): δ $ 1.69 and 1.74 (6 H, 2 doublets), 2.18 and 2.56 (2 H, 2 multiplets), 3.61 (1H) , 3.67 and 3.71 (6H, 2 doublets, JH_p = H Hz), 5.32 (1H, m), 5.50 (1H, m), 7.04-7.25 ( 4 H, m), 7.33 - 7.39 (2 H, quartz), 7.52 (2 H, AB quartet) ppm 13 C NMR (CDCl 3): δ J21.1, 21.3, 33, 1 (Jc_p = 136.3 Hz), 48.3, 52.6 and 52.7 (Jc_p = 5.7 Hz), 62.1 (Jc_p = 3.8 Hz), 112.5, 114.3, 115.1, 115.4, 119.5, 120, 122, 128.1, 15 130.6, 131.9, 132.0, 134.8, 134.9, 135.2, 161.8 JC_F = 246.1 Hz) ppm B) Trans- [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethenyl] phosphonic acid, dimethyl ester 20 to the hydroxyphosphonate prepared in Part A (2 , 60 g, 6.43 mmol) dissolved in warm. . to benzene (20 mL), pTSO 3 * H 2 O (122 mg, I '. 0.1 eq.) was added, and the mixture was refluxed through a 4 A molecular sieve under argon · 25 h . The yellow solution was cooled and diluted with ethyl acetate, and the organic phase was washed with saturated NaHCO 3 (twice) and saturated NaCl, then dried over anhydrous Na 2 O 4 and evaporated to give 2.238 g (89.9%). ) of pure title trans-vinylphosphonate as pale yellow plate-like crystals with a melting point of 153-155 ° C. TLC (hexane-acetone 1: 1): Rf = 0.33, UV and PMA.

: Mass spectrum: 388 (M + H) + (observed) 35 Elemental analysis (CH 2 Cl 2 -NPNF):

Calculated: 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, 7.98 122 87927 1 H-NMR (CDCl 3): 61.67 (6H, doublet), 3.68 (6H, d, JH_p = 11.6 Hz), 4.90 (1H, septet) , 5.73 (1H, dd, JH-H 2 transS 2 = Hz 1 H-P = 1 · 2 Hz) / 7.05 - 7.56 (8 H, m), 7.64 (1H , dd, JH_H = 17.9 Hz, JH_p = 23.7 Hz), ppm δ 13 C-NMR (CDCl 3): δ21.7, 47.8, 52.2, (Jc_p = 5.7 Hz), 111, Δ, 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_p = 246 Hz) ppm C) Trans- [2- / 3- (4-fluorophenyl) -1- (1 -methyl-10-ethyl) -1H-indol-2-yl-ethenyl-phosphonic acid, monomethyl ester

The dimethyl phosphonate prepared in Part B (1.787 g, 4.61 mmol) was dissolved in warm dioxane (12 mL), 1.0 N LiOH (6.9 mL, 6.9 mmol, 1.5 eq.) Was added to the solution, and the mixture was heated at 75 ° C (oil bath) under argon for 30 minutes. The mixture was cooled, acidified with 1.0 N HCl (8 ml) and extracted with ethyl acetate (twice), the organic phase washed with water (twice) and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give 1.859 g of a yellow solid. oil, the oil was dissolved in warm hexane, the solution was cooled, and the product was allowed to crystallize to give 1.657 g (96.1%); monoacid as a pale yellow solid with a melting point of 181-183 ° C.

. Elemental analysis (C 20 H 21 O 3 PNF 3: V. Calculated: 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 (CH 2 Cl 2 -CH 3 OH-HOAc 20: 1: 1): Rf =

'30 0.26, UV and PMA

. ···. 1 H-NMR (CDCl 3): 61.66 (6 H, doublet), 3.64 (3 H, doublet, J = 11.6 Hz), 4.89 (1H, septet), 5.81 ( 1H,. * * '. Ri “and dd, JH_H = 17.9 Hz, JH_p = 18.5 Hz), 7.06 - 7.64 (9H, multiplet) ppm' · 35 13 C-NMR (CDCl 3 ): d'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), I: 123 37927 120.2, 120.4, 123.5, 128.3, 130.4, 130.8, 131.2, 131.8, 131.9, 136.2, 136.8 (Jc_p = 7.6 Hz), 161.9 (JC_F = 246 Hz) ppm D) 4- [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -5H-indol-2 -yl7-ethenyl7-methoxyphosphinyl-3-oxobutanoic acid, methyl ester

The phosphonic chloride was prepared according to the following procedure: To a solution of the phosphonic acid monomethyl ester prepared in Part C (1.564 g, 4.19 mmol, 1 eq) in dry CH 2 Cl 2 (10 mL) was added distilled (diethylamino) triemethylsilane (1.05 mL, 8.38 mmol, 2 eq.), And the mixture was stirred under argon at room temperature for 1 hour. The mixture was evaporated under reduced pressure, the residue was dissolved in benzene (20 ml), the solution was evaporated under reduced pressure and the viscous oil was left connected to a vacuum pump for 15 minutes. A solution of crude silylated acid in dry CH 2 Cl 2 (10 mL) containing dry DMF (1 drop) was cooled to 0 ° C and 20 (COCl) 2 (400 mL, 4.61 mmol, 1.1 eq.), And the mixture was stirred under argon at 0 ° C for 15 minutes and its •. after room temperature for 45 minutes. The yellow mixture was evaporated under reduced pressure, the residue was dissolved in benzene; so (20 ml), and the solution was evaporated under reduced pressure and left in a vacuum pump for 15 minutes to give the crude phosphonochloridate V. 'as a viscous yellow oil. A solution of phosphonochloridate in dry THF (8 mL) at -78 ° C was added dropwise via tube over 20 minutes to a solution of methyl acetoacetate dianion prepared in Example 26 as -78 ° C; from methyl acetoacetate (590, 5.45 mmol, 1.3 eq.), 60% NaH oil dispersion (235 mg, 5.87 mmol, 1.4 eq.), 1.6 M from n-butyllithium (3.1 mL, 5.03 mmol, 1.2 eq) and THF (10 mL).

____ The orange reaction mixture was stirred at -78 ° C for 30 minutes to 124,37927 minutes, then saturated NH 4 Cl was added dropwise and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated to give 2.080 g of a yellow oil. The crude oil was purified by flash chromatography using Merck silica gel as adsorbent and EtOAc (7: 3) as eluent. The product fractions were combined and evaporated to give 519 mg (26.3%) of the desired title trans-phosphinate as a pale yellow oil. TLC (1: 1 hexane-acetone): Rf = 0.48 UV and PMA. Mass spectrum: 472 (M + H) + (observed) 1 H-NMR (CDCl 3): (f 1.66 + 1.71 (6 H, 2 doublets), 1.68 (2 H, m), 3.23 (2H, doublet), 3.54 (3H, d), 3.72 (3H, s), 4.90 (1H, septet), 5.76 (1H, dd, JH_H = 18 Hz ), 7.10 - 7.85 (8H, m), 7.66 (1H, dd, JH_H = 18 Hz) ppm δ 13 C-NMR (CDCl 3): tf21.8, 45.7 (Jc_p = 87 , 1 Hz), 47.9, 50.0, 51.5 (Jc_p = 5.7 Hz), 52.3, 111.9, 115.5, 118.8 (Jc_p = 104.1 Hz), 119 Δ, 120.2, 120.3, 123.6, 128.2, 130.4, 130.8, 131.8, 131.9, 136.1, 139.2 (Jc_p = 5.6 Hz), 161.9 (JC_F = 246 Hz), 167.0, 194.6 (Jc_p = 3.8 Hz) ppm 25 E) (E) -4 - // 2- [3- (4-fluorophenyl) -1- (1-Methyl-ethyl) -1H-indol-2-yl-ethenyl-7-ethoxy-phosphinyl-3-yl-hydroxybutanoic acid, methyl ester to -15 ° C (salt-ice bath) solution containing the ketone prepared in Part D (519 mg, 1.1 · 30 in dry absolute EtOH (8 mL, depicted on 3 A molecular sieves), solid NaBH 4 (42 mg, 1.1 mmol) was added, and the yellow mixture was stirred under argon at -15 ° C for 20 h. min uuttia. Acetone (0.5 ml) was added to the mixture, followed by CC-4 silica gel 35 (500 mg). The mixture was warmed to room temperature, filtered, washed with ethyl acetate and evaporated under reduced pressure to give 512 mg of a yellow foam. The crude foam was purified by flash chromatography using Merck silica gel as adsorbent and first ethyl acetate-acetone (4: 1) followed by acetone alone as eluent. The product fractions were evaporated to give 317 mg (60.9%) of the desired title alcohol as a yellow oil. TLC (EtOAc-acetone 4: 1): Rf = 0.21, UV and PMA.

Mass spectrum: 474 (M + H) + (observed) 1 H-NMR (CDCl 3): 61.68 (6 H, doublet), 1.97 (2 H, m), 2.58 (2 H, d), 3.61 (3H, d, JR_p = 11 Hz), 3.68 (3H, s), 3.95 + 4.04 (1H, 2 doublets), 4.40 (1H, bm), 4.95 (1H, specific), 5.78 (1H, dd, JH_H = 17.4 Hz, JH_p = 23.2 Hz), 7.05 - 7.77 (9H, m) ppm 1 H NMR (CDCl 3): cf21.7, 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 and 138.5 (Jc_p = 5.7 Hz) , 161.8 (JC_F = 246.1 Hz), 171.7, 171.8 ppm F) (E) -4- [2- [3- (4-fluorophenyl) -1- (1-methylin ethyl) -1H-Indol-2-yl-ethenyl-hydroxyphosphinyl-7-hydroxybutanoic acid, dilithium salt To a stirred solution of the hydroxide ester prepared in Part E (264 mg, 0.558 mmol) in dioxane (6 mL) was added 1.0 N LiOH. (1.95 mL, 3.5 eq.), and the mixture was heated to 70 ° C sa (oil bath) under argon for 20 minutes. The mixture was allowed to cool, diluted with water, filtered and evaporated under reduced pressure, and the residue was dissolved in a small amount of water (1-2 ml) and chromatographed on HP-20 resin first using hydrogen as eluent ( until the eluate was neutral, 3-4 times the column volume) followed by CH 2 H 2 O (75:25).

The product fractions were evaporated, the residue was dissolved in water 126 (50 ml), and the solution was filtered and lyophilized to give 217 mg (85.1%) of the desired title dilithium salt as a white lyophilization product. TLC (Cl 2 Cl 2 -CH 2 OH-HOAc 8: 1: 1): Rf = 0.08, UV and PMA.

Elemental analysis (C23H23®5NFF * + 1.62 mol H2O):

Calculated: 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, CDCl 3): δ, 67 (6H, doublet), 1.73 (2H, 10 multiplets), 2.38 (2H, AB quartet doublet, JAB = 15 Hz, J = 8 Hz, J_.v = 4.8 Hz), 4.24 (1H, multiplet

AX DA

ti), 5.06 (1H, septet), 6.09 (1H, = 17.6 Hz, rl rl JUT.) 19.4 Hz), 7.02 - 7.61 (9H, multiplet) rir

Example 29 (S) -4 - [[2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indolin-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) 4-methyl 2-Oxopentanoic acid, ethyl ester The sodium salt of 4-methyl-2-oxopentanoic acid (25 g) was dissolved in as little water as possible, the pH of the solution was adjusted to 1 with concentrated HCl, and then the solution was extracted several times with CH 2 Cl 2. The water phase; The mixture was saturated with NaCl and back-extracted twice with CH 2 Cl 2. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give 17.7 g of the free acid as a viscous oil.

To a mixture of acid (17.7 g, 136 mmol) in dry benzene (200 mL) was added diazabicyclo. . Undecane (DBU) (30.4 mL, 136.2 mmol, 1 eq), giving; this resulted in an exothermic reaction and the formation of a gel-like crystalline salt. Ethyl iodide (10.9 mL, 1 eq.) Was added to the mixture and stirred mechanically under argon for 3 hours. The precipitated salts were removed by filtration, and the filtrate was washed once with a small amount of water (50 ml) and saturated NaCl-127 87 927 solution, and then dried over anhydrous Na 2 SO 4. Benzene was removed by distillation at atmospheric pressure, and the remaining yellow liquid was distilled under reduced pressure to give 6.46 g (35.1%) of the desired title ester as a clear pale yellow liquid boiling at 65-66 ° C (5 mmHg). TLC (hexane-acetone 9: 1): Rf = 0.55, PMA (light blue).

Mass spectrum: 159 (M + H) + (observed) 10 B) 4-Methyl-2- (2-phenylhydrazono) pentanoic acid, ethyl ester

To a solution of the ethyl ester prepared in Part A (5 g, 31.6 mmol) in dry Cl 2 Cl 2 (30 mL) was added phenyl-hydrazine (3.3 mL, 33.2 mmol, 1 mL) dropwise over 5 minutes. 05 eq.), And the resulting yellow mixture was stirred under argon at room temperature for 3 hours on 4 A molecular sieves. The mixture was dried over anhydrous Na 2 SO 4, filtered and evaporated under reduced pressure to give 8.105 g of an orange oil, the oil was purified by flash chromatography using LPS-1 silica gel as adsorbent and hexane-ethyl acetate as eluent; mixture. The product fractions were evaporated to give 6.8 g (86.7%) of pure title hydrazone and 848 g: 25 (10.8%) of the geometric isomer of the title hydrazone. The overall yield was 97.5%. TLC (hexane-acetone 9: 1): Rf = 0.42 for geometric isomers; r j a 0.6 4, U V j a PMA.

Mass spectrum: 249 (M + H) + (observed): 30 C) 3- (1-methylethyl) -1H-indole-2-carboxylic acid, ethyl ester

To a solution of the hydatosin prepared in Part B (6.8 g, 27.4 mmol) in absolute ethanol (50 mL, dried through 3 A molecular sieves) was added gaseous HCl for 30 minutes at room temperature. . The exothermic reaction was characterized by a color change of 128,87927 from yellow through red to deep green, followed by precipitation of NH 4 Cl. The suspension was stirred for a further 20 minutes under Drierite, after which it was poured into ice-cold water (50 ml). Ethanol 5 was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice), and the combined organic phases were washed with water and saturated NaCl solution, then dried over anhydrous MgSO 4 and evaporated to give 4.969 g of a green solid. The crude solid was dissolved in hot hexane, the solution treated with activated carbon (Darco), filtered through tightly packed diatomaceous earth and concentrated to a volume of 30-50 ml, and the product allowed to crystallize from a yellow solution. The precipitated crystals were collected by filtration, rinsed with cold hexane and dried to give 4.34 g (68.5%) of pure title indole as white needles with a melting point of 80-81 ° C and appropriate 1 H-NMR. spectrum (270 MHz, CDCl 3). TLC (hexane-acetone 9: 1):

Rf = 0.42, UV and PMA.

Note: Hydrazone and indole have the same Rf value, but indole has a bright purple fluorescence.

·: Mass spectrum: 232 (M + H) + (observed)

Elemental analysis (C ^ H ^ NC ^):

Calculated: C, 72.70; H, 7.41; N, 6.06 Found: C, 72.67; H, 7.57; N, 6.00 •. D) 1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole-2-carboxylic acid, ethyl ester

To a solution of the indole prepared in Part C (3.937 g, 17 mmol) and 1-bromo-4-fluorobenzene (9.34 mL, 85 mmol, 5 eq.) In dry DMF (15 mL). Copper (I) oxide (245 mg, 1.7 mmol, 0.1 eq) was added and the mixture was refluxed under argon for 17 hours. 1, 129 37927 more bromide (9.34 mL, 5 eq.) And Cu 2 O (245 mg, 0.1 eq.) Were added, and reflux was continued for 6 h, more Cu 2 O (730 mg, 5.1 eq.) Was added. mmol), and reflux was continued for an additional 60 hours. DMF and excess bro-5 mide were distilled off under reduced pressure, the remaining orange oil was dissolved in ethyl acetate, and the solution was filtered through tightly packed diatomaceous earth, washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated. to give 5.385 g (97.2%) of the desired crude title indole as an orange oil. TLC (hexane-acetone 9: 1): Rf = 0.29, UV and PMA.

E) 1- (4-fluorophenyl) -3- (1-methylethyl) -1H-15 indole-2-methanol

To cold (0 ° C, ice bath) dry ether (24 mL) kept under argon was added solid LiAlH 2 (907 mg, 23.9 mmol, 1.5 mmol eq) followed by dropwise addition over 10 minutes in Part D 20 prepared indole esters (5.185 g, 15.9 mmol) in dry Et 2 O (10 mL). The mixture was stirred at 0 ° C for 1 hour, after which water (910 μΐ), 15% NaOH (910 μl) and water (2.73 ml) were added dropwise at 0 ° C dropwise. The suspension was filtered tightly Through anhydrous MgSO 4 placed on top of 25 packed diatomaceous earth, and the filtrate was evaporated to a clear colorless oil, the oil gradually crystallized from hexane to give 4.10 g (3.771 g + 0.333 g, 90.9 %) of pure title indole alcohol in the form of white granules with a melting point of 81-82 ° C.

Mass spectrum: 284 (M + H) + (observed): Elemental analysis (C 18 H 28 NOF):

Calculated: C, 76.30; H, 6.40; N, 4.94; F, 6.71 Found: C, 76.59; H, 6.31; N, 4.93; F, 6.49 130 87927 F) 1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole-2-carboxaldehyde

To a solution of Dess-Martin periodinane (6.46 g, 15.24 mmol) in dry Cl 2 Cl 2 (30 mL) was added dry t-butanol (1.44 mL, 15.24 mmol, 1 eq.); dried on 4 A molecular sieves), and the mixture was then stirred at room temperature under argon for 15 minutes. A solution of the indole alcohol 10 prepared in Part E (3.599 g, 12.7 mmol) in dry CH 2 Cl 2 (13 mL) was added dropwise over 10 minutes, and the pale yellow mixture was stirred at room temperature under argon for 30 minutes. The reaction mixture was added to a solution of sodium thiosulfate (14.06 g, 89 mmol, 7 eq.) In freshly prepared 1 N NaHCO 3 (40 mL) and the mixture was stirred for 10 minutes. The aqueous phase was separated and the organic phase was washed with 1.0 N NaHCO 3 (twice), water and saturated NaCl solution, then dried over anhydrous Na 2 SO 4 and evaporated to give 3.877 g of a yellow oil. The crude oil was purified by flash chromatography using LPS-1 silica gel as adsorbent and hexane as eluent. . ether mixture (40: 1). The product fractions were evaporated, yielding; 3.118 g (87.3%, crude yield) of crude product were obtained. Recrystallization from hot hexane once gave 2.643 g (74%) of pure title aldehyde as white fluffy needles, m.p. 114-116 ° C Mass spectrum: 282 (M + H) + (observed) TLC (hexane-Et 2 O 7: 3): Rf = 0.51, UV and PMA.

. ·. : 30 Elemental analysis (C 18 H 28 NOF):

Calculated: C, 76.85; H, 5.73; N, 4.98; F, 6.75

Found: C, 76.87; H, 5.63; N, 4.89; F, 6.88 131 87927 G) 2- (2,2-dibromoethenyl) -1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole at -15 ° C (salt-ice bath) To a solution of the aldehyde prepared in Part F (4.52 g, 17.22 mmol, 5 3 eq.) in dry CH 2 Cl 2 (25 mL) was added dropwise over 10 minutes CBr 2 (2.86 g, 8.61 mmol, 1.5 eq.) Dissolved in dry Cl 2 Cl 2 (10 mL), and the resulting dark orange-red solution was stirred under argon at -15 ° C for 15 minutes. Saturated NaHCO 3 was added to the mixture at -15 ° C, the resulting mixture was diluted with Cl 2 Cl 2, and the organic phase was washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated to give 8.9 g of a red solid were obtained. The crude solid was purified by flash chromatography using LPS-1 silica gel as adsorbent and hexane-ether (100: 1) as eluent. The product fractions were evaporated to give 2.017 g (80.6%) of pure title vinyl dibromide as pale yellow crystals, m.p. 123-124 ° V. TLC (hexane-ether 9: 1): Rf = 0.67, UV and PMA.

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

Elemental analysis (C 18 H 28 N 2 N 2 O 2): Calculated: C, 52.20; H, 3.69; N, 3.20; F, 4.35; Br, 36.56: V 25 Found: C, 52.25; H, 3.69; N, 3.18; F, 4.24; Br, 36.59 H) 2-Ethynyl-1- (4-fluorophenyl) -3- (1-methyl-N '-ethyl) -1H-indole to -78 ° C (CC 4 acetone bath) in dry THF (10 ml) was added 1.6 M n-butyllithium under argon. Hexane solution (5.5 mL, 8.8 mmol, 2.2 eq) and a solution of vinyl dibromide prepared in Part G (1.749 g, 4 mmol) in dry THF (10 mL) was added dropwise over 5 minutes. . The yellow mixture was stirred at -78 ° C for 20 minutes, then saturated NH 4 Cl (10 mL) was added. After warming to room temperature ____, the mixture was diluted with ethyl acetate and the organic phase was washed with saturated NH 4 Cl and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated to give 1.216 g of a dark green-brown oil. The crude oil was purified by flash chromatography using Merck silica gel as adsorbent and hexane-ether (300: 1) as eluent. The product fractions were evaporated to give 1.084 g (97.5%) of the title indole acetylene as a fluorescent green oil. 1 H-NMR spectrum (CDCl 3, 10 270 MHz) showed the oil to be a mixture of the desired acetylene and the undesired terminal olefin in a ratio (18: 1). TLC (hexane-Et 2 O (50: 1): Rf = 0.55, UV and PMA.

J) (S) -4 - [[2- [2- (4-fluorophenyl) -1- (methyl-ethyl) -1H-indol-2-yl] ethynyl] methoxyphosphinyl] -3- (771/1-dimethylethyl) diphenylsilyl] oxy] butanoic acid , methyl ester

The phosphonochloridate was prepared from the dicyclohexyl-20-amine salt of the phosphonic acid monomethyl ester of Example 25 by the following procedure: The dicyclohexylamine salt (4.32 g, 6.83 mmol, 1.75 eq.) Was reconstituted with the free acid by partitioning; ; : Between 1.0 N HCl and ethyl acetate, washing the organic phase with 1.0 N HCl (twice) and saturated NaCl solution, drying over anhydrous Na 2 SO 4 and evaporating the solvent under reduced pressure to give • :: free acid (6.8 mmol) as a clear viscous oil.

To phosphonic acid monomethyl ester (6.8 mmol) dissolved in dry CH 2 Cl 2 (10 mL) was added distilled (trimethylsilyl) diethylamine (1.72 mL, 13.7 mmol, 2 eq). .), and the clear solution was stirred under argon at room temperature for 1 hour. The mixture was evaporated under reduced pressure and again with dry benzene (2 x 20 ml) and left in a vacuum pump for 15 minutes. A solution of crude silylated acid in dry CH 2 Cl 2 (10 mL), 133 8 7 9 2 7 containing dry DMF (1 drop) was cooled to 0 ° C (ice bath) and 5 drops were added dropwise. distilled (COCl) 2 (655 μΐ, 7.5 mmol, 1.1 eq.) per minute. The yellow mixture was stirred under argon at 50 ° C for 15 minutes and at room temperature for 45 minutes. The mixture was evaporated under reduced pressure and again with Bentene (2 x 20 ml) and left connected to a vacuum pump for 15 minutes to give the crude phosphonochloridate as a yellow viscous oil.

To a 10-78 ° C solution (CC 4 acetone bath) containing the indole acetylene prepared in Part H (1.084 g, 3.90 mmol, 1 eq.) In dry THF (10 mL) was added dropwise over 10 minutes 1 , A 6 M solution of n-butyllithium in hexane (2.44 mL, 3.9 mmol, 1 eq), and a purp-15 purple suspension was stirred under argon at -78 ° C for 30 minutes. The anion was added dropwise via tube over 30 minutes at -78 ° C to a solution of phosphonochloridate in dry THF (10 mL) at -78 ° C. The dark brown mixture was stirred at -78 ° C for 30 minutes, then saturated NH 4 Cl (10 mL) was added dropwise.

:. ·. The mixture was warmed to room temperature and partitioned between ethyl acetate and saturated NH 4 Cl; and the organic phase was washed with saturated NaCl. 25 solution, dried over anhydrous Na 2 O 4 and evaporated to give 1.968 g (71.1%) of the title compound. strip of acetylene phosphinate to a pale yellow oil. TLC (hexane-acetone 7: 3): Rf = 0.25, UV and PMA.

Mass Spectrum: 710 (M + H) + (observed) K) (S) -3 - [(1,1-dimethylethyl) diphenylsilyloxy] -4 - // 2- [1- (4-fluorophenyl-3- ( 1-Methyl- (ethyl) -1H-indol-2-yl] ethyl] methoxyphosphinyl-7-butanoic acid, methyl ester • to a solution of acetone (950 mg) prepared in Part J in CH 3 OH 134 87927 (10 mL) , 10% Pt / C catalyst (238 mg, 25 wt%) was added and the black suspension was stirred under N 2 atmosphere (1 bar) overnight The catalyst was removed by filtration of a mixture of Millipore polycarbonate filter 5 (0.4 μm) and pre-filter. The crude oil was purified by flash chromatography using Merck silica gel as adsorbent and hexane-ethyl acetate (8: 2) as eluent to give 915 mg (86.7%) of pure product fractions. TLC (EtOAc-hexane 4: 4) to give the saturated phosphate as a white foam. : 1): Rf = 0.39, UV and PMA. Mass spectrum: 714 (M + H) + (observed) L) (S) -4 - [[2- (N- (4-fluorophenyl) -3- (1-methyl-ethyl) -1H-indol-2- yl7ethyl7methoxyphosphinyl7-3-hydroxybutanoic acid, methyl ester

To a solution of the silyl ether prepared in Part K (915 mg, 1.22 mmol) in THF (10 mL) was added sequential glacial acetic acid (280 μL, 4.88 mmol, 4 eq.) And 1.1 M nCl 2 HgNF. THF solution (3.3 mL, 3.66 mmol, 3 eq), and the mixture was stirred under argon; . ·. overnight. Ice-cold water (8 mL) was added, the mixture was extracted with ethyl acetate, and the organic phase was washed with 5% KHSO 4 (twice), saturated NaHCO 3 and saturated NaCl, dried; then with anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 955 mg of a yellow oil. The crude oil was purified by flash chromatography using Merck silica gel as adsorbent and hexane-acetone (1: 1) as eluent. The product fractions were evaporated to give 521 mg (85.5%) of the desired ot. alcohol as a pale yellow oil.

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

·; · 35 Mass spectrum: 476 (M + H) + (observed) 135 87 927 M) (S) -4 - [[2- [N- (4-fluorophenyl) -3- (1-methylethyl) - 1H-indol-2-yl-ethyl-7-hydroxyphosphinyl-3-hydroxybutanoic acid, dilithium salt

To a solution of the 5 diesterM prepared in Part L (505 mg, 1.06 mmol) in dioxane (10 mL) was added an excess of 1.0 N LiOH (3.7 mL, 3.7 mmol, 3.5 eq.), And the mixture heated at 65 ° C (oil bath) under argon for 1.5 hours. The mixture was diluted with water, filtered and evaporated under reduced pressure to a pale yellow solid. The crude solid was suspended in a small amount of water and chromatographed on HP-20 resins (15 cm layer, column diameter 25 mm) using water as eluent until the eluate was neutral, followed by CH 2 OH.

The product fractions were combined and evaporated, the residue dissolved in water (50 ml) and the solution lyophilized to give 484 mg (95.4%) of the desired title dilithium salt as a white lyophilisate. TLC (Cl 2 Cl 2 -CH 2 OH-HOAc 8: 1: 1): Rf = 0.39, UV and PMA.

Elemental analysis (C 23 H 25 NO 5 FP '+ · * · Ό3 mol 1 ^ 0, M = 477.91) Calculated: C, 577.80; 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: · 25 Example 30 (S) -4 - [[2- [N- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] ethynyl] hydroxyphosphinyl] -3- * hydroxybutanoic acid, Dithithium salt A) (S) -4 - [[2- [N- (4-fluorophenyl) -3- (1-methyl-ethyl) -1H-indol-2-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester

To a solution of the silyl ether of Example 30, Part J (987 mg, 1.39 mmol) in dry THF (12 mL) was added sequential glacial acetic acid (35 μL, 5.6 mmol, 4 eq.) And its after 1.1 M

in THF (3.8 mL, 3.17 mmol, 3 eq.), and 136 87927 was stirred under argon at room temperature overnight. The mixture was diluted with ice-cold water (10 ml) and extracted with ethyl acetate. The organic phase was washed with 5% KHSO 4 (three times), saturated NaHCO 3 and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated to give 1.0 g of a yellow oil. TLC showed the formation of some monoacid which was converted back to the methyl ester by treatment with ethereal ether. The excess was destroyed with glacial acetic acid and the mixture evaporated under reduced pressure to give 1.012 g of a brown oil. The crude oil was purified by flash chromatography using Merck silica gel as adsorbent and hexane-acetone (8: 2) (600 mL) as eluent and then 1: 1. The product fractions were evaporated to give 516 mg (78.7%) of the free title alcohol as a light brown oil. TLC (9: 1 mixture of Cl 2 Cl 2 -CH 2 OH): Rf = 0.41, UV and PMA.

Mass spectrum: 472 (M + H) + (observed) B) (S) -4- [2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2- yl7ethynyl7hydroxyphosphinyl7-3-: hydroxybutanoic acid, dilithium salt

To a solution of the di-: V ester from Part A (516 mg, 1.09 mmol) in dioxane (10 mL) was added a 1.0 N solution of LiOH (3.8 mL, 3.8 mmol, 3 , 5 eq.), And the clear mixture was heated and stirred at 60 ° C (oil bath) under argon for 1.5 h. The mixture was diluted with water, filtered and evaporated under reduced pressure, and the residual oil was dissolved in as little water as possible and chromatographed on HP-20 resin (15 cm layer, column diameter 25 mm) using as eluent only water f: (until the eluate was neutral) and then a mixture of I 2 O- 35 CH 2 OH (1: 1). The product fractions were evaporated under reduced pressure, the residue dissolved in water (50 ml), and the solution 137,87927 was filtered and lyophilized to give 447 mg (82.3%) of the desired title dilithium salt as a white lyophilisate. TLC (CH 2 Cl 2 -CH 2 OH-HOAc 8: 1: 1): Rf = 0.39, UV and PMA.

Elemental analysis (m / z O 2 PNF 3 Li + 2.27 mol H 2 O, M = 496.19)

Calculated: C, 55.67; H, 5.19; N, 2.82; F, 3.83; P, 6.34 Found: C, 55.69; H, 5.37; N, 2.82; F, 3.85; P, 6.19

Example 31 10 (S) -4 - [(2,4-Dimethyl-6- (4-fluorophenyl) methoxy] phenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) 1- (methoxymethoxy) -3,5-dimethylbenzene Solution containing 3,5-dimethylphenol (10.42 g, 85.3 mmol) in THF (12 mL) was added dropwise over 10 mL to a suspension of NaH (85.3 mmol, prewashed with pentane). In THF (150 mL) and kept under argon cooled to 0 ° C. After the addition of phenol was complete, the reaction mixture was stirred at 0 ° C for 10 minutes to 20 minutes, warmed to room temperature and stirred for 20 minutes. To the alkoxide solution was added dry DMF (42 mL) followed slowly by a solution of bromomethyl methyl ether (11.19 g, 89.6 mmol). . In THF (10 mL). A white precipitate formed. After the reaction mixture was stirred at room temperature for 2.5 hours, 1 N NaOH (25 mL) was slowly added to the mixture. The THF was removed from the reaction mixture on a rotary evaporator, and the resulting solution was diluted with saturated NaCl solution and then extracted three times. ; 30 with ether. The combined ether extracts were dried

Na 2 SO 4 and filtered. Removal of the solvent gave an orange oil. Purification by flash chromatography using 5% ether in hexane as eluent afforded the title methoxymethyl ether 35 (MOM ether) (12.0 g, 85% yield) as a clear oil.

138 87927 TLC (15% Et 2 O in hexane, silica gel):

Rf = 0.45.

Mass spectrum (m / e): 166 (M +), 165 (M - H) B) 2- (methoxymethoxy) -4,6-dimethylbenzaldehyde To a solution of n-butyllithium (26.5 mL, 2.5 M in hexane). ) in cyclohexane (30 mL) under argon, tetramethylethylenediamine (7.70 g, 79.45 mmol) was added slowly. The solution was cooled to 0 ° C and MOM ether prepared in Part A (11.0 g, 66.21 mmol) was added dropwise over 20 minutes. After the addition was complete, the reaction mixture was stirred at 0 ° C for 30 minutes, warmed to room temperature, and stirred for 10 minutes. The anion was then added via addition funnel to a solution of DMF (5.81 g, 79.45 mmol) in dry cyclohexane (100 mL) and kept under argon at room temperature. The reaction mixture was stirred at room temperature for 2 hours, after which methanol was added. The solvent used in the reaction section was removed on a rotary evaporator, and the resulting orange oil was dissolved in ether-water (1: 1). The aqueous layer was extracted three times with ether, and the combined ether extracts were dried over MgSO 4. Filtration and removal of the solvent gave an orange oil. Purification of the oil by flash chromatography using 20% ether in hexane as eluent gave the desired title aldehyde (7.7 g, 60%) as a clear oil. TLC (15% Et 2 O in hexane, silica gel): Rf = 0.14.

. . Mass spectrum (m / e): 195 (M + H) +, 179 (m - CH 2) +, 163 (M - OCH 3) +, 149 (M - O 2 CH 5) + C) 2-hydroxy-4,6- dimethylbenzaldehyde: To a solution containing the one prepared in Part B; · MOM ether (6.89 g, 35.5 mmol) in dioxane (130 mL), 1 M HCl solution (35.5 mL) was added at room temperature. The reaction mixture was gently heated to reflux and stirred for 30 minutes. The reaction mixture was cooled to room temperature and the dioxane was removed on a rotary evaporator. The resulting aqueous solution was diluted with water and extracted with ether. The aqueous layer was then saturated with NaCl and re-extracted twice with ether. The ether extraction solutions were combined and then dried over MgSO 4. Filtration and removal of the solvent gave a greenish solid which was purified by recrystallization from hexane (4.01 g, 75%). TLC (25% Et 2 O in hexane, silica gel): Rf = 0.48.

Sp. 46-48 ° C.

Mass spectrum (m / e): 151 (M + H) +, 135 (m - CH 2) + D) 2- (4-fluorophenyl) methoxy] -4,6-dimethyl-15-benzaldehyde

A solution of the phenol prepared in Part C (4.0 g, 26.7 mmol) and dry DMF (30 mL) was stirred under argon. To the phenol solution was added solid K 2 CO 2 (4.43 g, 32 mmol) at room temperature, and the mixture was then heated to 60 ° C for 35 minutes. The resulting orange solution was cooled to room temperature and added to p-fluorobenzyl bromide (5.55 g, 29.3 mmol). The reaction mixture was heated to 60 ° C and stirred for 2 hours. The reaction mixture: V 25 was poured into ice water (50 ml), and this mixture was extracted: several times with ether. The combined ether extracts were imitated with MgSO 4 and filtered to give a yellow solid after removal of the solvent. Purification by flash chromatography using 15% ether in hexane as eluent afforded the title benzyl ether (4.48 g, 60%) as a white solid. TLC (25% Et 2 O in hexane, silica gel): Rf = 0.34.

: Mass spectrum (m / e): 259 (M + H) +, 231 (M - CHO) +, 35 109 (M - C 7 H 6 F) + 140 37927 E) 1- (2,2-dibromoethenyl) -2,4- dimethyl-6- (phenylmethoxy) benzene

A solution of the aldehyde prepared in Part D (4.42 g, 17.13 nunol) in dry CH 2 Cl 2 (170 mL) under argon was cooled in an ice-salt bath. To the cooled solution was added triphenylphosphine (14.4 g, 55.0 mmol), and the mixture was stirred until all solids had dissolved. A solution of CBr 2 (8.52 g, 25.7 mmol) in Cl 2 Cl 2 (50 mL) was added to the mixture via addition funnel over 12 minutes.

After the addition was complete, the reaction solution was stirred at 0 ° C for 1 hour 15 minutes. Saturated aqueous NaHCO 3 (60 mL) was added to the reaction mixture, and the mixture was stirred vigorously. The aqueous layer was removed and extracted with CH 2 Cl 2. The combined Cl 2 Cl 2 solutions were washed once with saturated aqueous NaHCO 3, dried over MgSO 4 and filtered to give the title dibromide as a tan solid (13 g). The title dibromide was purified by flash chromatography using 2% ether in hexane as eluent to give 5.49 g (77% yield) of the title dibromide. TLC (2% Et 2 O 'in hexane, silica gel): Rf = 0.28.

Mass spectrum (m / e): 413 (M + H) +, 333.335 (M - Br) +,: V 25 317 (M - C 6 H 4 F) +, 109 (M - C 10 H 9 OBr 2) + F) 1-ethynyl-2- / T4-fluorophenyl) methoxy--4,6-::: dimethylbenzene

A solution of the dibromide prepared in Part E (5.48 g, 13.3 mmol) in THF (70 mL) under argon. : 30 perimeter, cooled to -78 ° C. To the dibromide solution was added n-butyllithium (10.6 mL, 2.5 M hexane, 26.5 mmol) over 10 minutes. The reaction mixture was stirred at -78 ° C for 1 h, after which a saturated solution of NH 4 Cl in water was added at -78 ° C. After warming to room temperature, the reaction mixture was diluted with water (60 ml) and the aqueous layer was extracted twice with ether. All organic layers were combined and dried over MgSO 4. 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 using 3% ether in hexane as eluent. The title acetylene was obtained as a white solid (2.76 g, 85% yield). TLC (2% Et 2 O in hexane, silica gel): Rf = 0.17.

Mass spectrum (m / e): 255 (M + H) +, 159 (M-C 6 H 4 F) +, 109 (M-C 10 H 9 O) + G) (S) -4 - [/ 2,4-dimethyl-6-] (4-fluoro-phenyl) -methoxy? phenyl7ethynyl7hydroxyphosphinyl7-3- (t-15 butyldiphenylsilyloxy) butanoic acid, dilithium salt

A solution of the acetylene prepared in Part F (2.76 g, 11 mmol) in THF (40 mL) under argon was cooled to -78 ° C. To the solution was added n-butyllithium 20 (4.4 mL, 2.5 M hexane solution) at -78 ° C over 8 minutes. The reaction mixture was stirred at -78 ° C for 40 minutes.

. . The phosphonyl chloride of Example 25; * '(17.4 mmol) dissolved in THF (60 mL) was cooled to -78 ° C under argon. The acetylene anion formed above was then added over a period of 8 minutes. After the reaction mixture was stirred at -78 ° C for 1 hour, saturated aqueous NH 4 Cl solution was added at -78 ° C and the mixture was allowed to warm to room temperature. The aqueous layer was diluted with water and extracted twice with ether. The THF was removed from the THF layer, and the remaining orange oil was dissolved in ether. All ether solutions were combined and washed once with saturated aqueous NaHCO 3 and once with saturated NaCl solution. The organic layer was dried over MgSO 4 and filtered to give -____ after removal of the solvent 9.4 g of acetylphenic acid of the title compound as an orange gum. The title acetylenephosphinic acid was purified by flash chromatography-1M using hexane-toluene-ethyl acetate-5 (5: 1: 4) as eluent. The title acetylenic phosphinic acid was obtained as a clear gum (4.23 g, 56% yield). TLC (hexane-toluene-ethyl acetate 5: 1: 4, silica gel): Rf = 0.28. Mass spectrum (m / e): 609 (M + H - C 9 H 8 -) +, 255 (C 1 H 3 H 2 SiO) + 10 H) (S) -4- [7 / 2,4-dimethyl-6- / 74 (fluorophenyl) methoxy7phenyl7ethynyl7methoxyphosphinyl7-3-hydroxybutanoic acid, methyl ester

The acetylene phosphinate prepared in Part G (0.455 g, 0.66 mmol) was stirred in THF (10 mL) under an argon atmosphere. Acetic acid (0.16 g, 2.66 mmol) was added dropwise at room temperature, followed by dropwise addition of n-CH 2 HNNF (1.8 mL of a 1.1 M THF solution, 2.0 mmol) over 5 minutes. After the reaction mixture was stirred at room temperature for 24 hours, ice water (30 ml) was added thereto. The aqueous layer was removed and extracted twice with ethyl acetate. The THF was removed. . from the organic layer, and the resulting oil * was dissolved in ethyl acetate and combined with the aqueous extraction solutions. This ethyl acetate solution was washed twice with saturated aqueous NaHCO 3 solution and once with saturated NaCl solution and then dried over Na 2 SO 4. Removal of the title compound gave 0.40 g of the title hydroxyacetylene phosphinate as an oil The hydroxyacetylene phosphate of the title compound was purified by flash chromatography using 100% ethyl acetate as eluent. The yield of the title hydroxyacetylene phosphinate was 79%. TLC '**' (acetone-hexane 7: 3, silica gel): 35 Rf = 0.56.

____ Mass spectrum (m / e): 449 (M + H) +, 431 (M - OH) +), 4.17 (M - OHC 3) + i 143 87927 J) (S) -4 - /// 2, 4-dimethyl-6- (T4-fluorophenyl) methoxy? phenyl / ethynyl / hydroxyphosphinyl-3-hydroxy-butanoic acid, dilithium salt

To a solution of the acetyl-5-ethylene phosphinate prepared in Part H (0.191 g, 0.43 mmol) in dioxane (6 mL) was added 1 N LiOH solution (1.4 mL) at room temperature. The reaction mixture was heated to 55 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness to give 10 title compound. The title compound was purified on an HP-20 resin column measuring 130 mm x 30 mm using first water (100 ml) and then MeOH-f 2 O (1: 1) as eluent. The title compound was obtained as a white lyophilization product (0.170 g, yield-15 to 91%). TLC (nPrOH-NH 4 OH-1 2 O 7: 2: 1, silica gel): Rf = 0.37.

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

Elemental analysis (C 21 H 20 O 6 FPL * 2 · 1.4H 2 O) Calculated: C, 55.09; H, 4.98; F, 4.15; P, 6.78 Found: C, 55.13; H, 5.25; F, 4.08; P, 6.91

Example 32 (S) -4 - [(2,4-Dimethyl-6- [74-fluorophenyl) thiothotoxyl phenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) (S) -3 - // (1,1- dimethylethyl) diphenylsilyl-oxy-4- [2- (2- (4-fluorophenyl) methoxy] -4,6-dimethylphenyl] ethyl / methoxyphosphinyl] butanoic acid, methyl ester: from the acetylene phosphine of Example 31, Part G. ·. sodium (1.34 g, 1.95 mmol) was stirred in methanol (12 mL) and PtO 2 (0.040 g) was added. Hydrogen gas was blown through the methanol solution for 10 minutes, after which the H 2 atmosphere was maintained with a balloon. After the reaction mixture was kept at room temperature for 5 hours and 15 minutes, the reaction was complete with 144,87927 and argon was blown through the reaction solution. The reaction mixture was filtered through a pad of diatomaceous earth formed on fine glass sinter, and the catalyst was washed with methanol. The solvent was removed from the filtrate to give 1.4 g of the title saturated phosphinate as a clear gum. The title saturated gum was purified by flash chromatography using ethyl acetate-hexane (60:40) as eluent and then the slightly crude fractions were rechromatographed using hexane-acetone-toluene (6: 2.5: 1) as eluent. 5). The yield of the title saturated phosphinate was 86% (1.17 g). TLC (80:20 ethyl acetate-hexane, silica gel): Rf = 0.45.

Mass spectrum (m / e): 691 (M + H) +, 659 (M - OCH.j) +> 635 (M - C9H19OSi) + B) (S) -4 - [/ 2,4-dimethyl- 6- (T4-fluorophenyl) methoxy? phenyl7ethyl7methoxyphosphinyl-3-hydroxybutanoic acid, methyl ester The phosphinate prepared in Part A (1.16 g, 1.68 mmol) was stirred in THF (25 mL) at room temperature under argon. Glacial acetic acid (0.40 mL) was added dropwise to the phosphinate solution, followed by dropwise addition of n-CH 2 Cl 2 (4.6 mL, 1.1 M THF solution) over 5 minutes. The reaction mixture was stirred at room temperature overnight (18 hours), and then ice water (50 ml) was added thereto. After stirring for a few minutes, saturated NaCl solution was added and the layers were separated. The organic layer was removed on a rotary evaporator with 30-30 THF, and the resulting residue was dissolved in ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and all ethyl acetate solutions were combined and washed twice with saturated aqueous NaHCO 3 solution and once with saturated NaCl solution, and then dried over Na 2 SO 4. Filtration and removal of the solvent gave 1.13 g of the title 145,87927 hydroxyphosphinate as a clear oil. The title hydroxyphosphinate was purified by flash chromatography using 100% ethyl acetate as eluent to give the title hydroxy-5-phosphinate as a clear oil (83% yield). TLC (6: 4 acetone-hexane, silica gel): Rf = 0.27. Mass spectrum (m / e): 453 (M + H) +, 343 (M - C 7 H 9 F) + C) (S) -4 - [(2,4-dimethyl-6- (4-fluorophenyl) methoxy)? phenyl7ethyl7hydroxyphosphinyl7-3-hydroxy-10 butanoic acid, dilithium salt

The phosphinate prepared in Part B (0.594 g, 1.3 mmol) was stirred in dioxane (19 mL) at room temperature, 1 N LiOH (4.0 mL) was added at room temperature with stirring, and the reaction mixture was heated to 55 ° C. C. After holding the mixture at 55 ° C for 20 minutes, a white thick precipitate formed, dioxane (4.0 ml) was added to the mixture, and the resulting suspension was stirred at 55 ° C. The suspension was then kept at 55 ° C for 2.5 hours, water (3 ml) was added and the reaction mixture became clear. After 3 hours at 55 ° C, the mixture was cooled to room temperature and the dioxane and water were removed on a rotary evaporator to leave the diacid as a white solid which was placed under high vacuum for 15 minutes.

The title diacid was purified by chromatography on HP-20 resin using water (100 mL) as eluent followed by MeOH-1 O (1: 1). The title diacid was obtained as a white freeze-dried product (yield 67%). TLC (n-propanol-NH 4 OH-t 2 O- ... 7: 2: 1, silica gel): Rf = 0.36.

Mass spectrum (FAB, m / e): 425 (M + H) +, 437 (M + H + 2Li) + *: · *: Elemental analysis 1.151 ± 0): 35 Calculated: C, 55.19; H, 5.80? F, 4.16; P, 6.78 Found: C, 55.19; H, 5.80; F, 4.29; P, 6.83 146 87927

Example 33 (S) -4- [2- (1,1'-Biphenyl-2-yl) ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) (S) -4 - // 2- (1,1 ' -biphenyl-2-yl) ethynyl7-hyd-5-hydroxyphosphinyl-3-hydroxybutanoic acid, methyl ester

The phosphinate from Example 9, Part D (1.61 mmol, 0.985 g) was stirred in dry THFr 5 S (19.6 mL) at room temperature under argon. To this solution was added dropwise glacial acetic acid (6.44 mmol, 0.386 g, 0.368 mL) followed by dropwise addition of n-CH 2 Cl 2 over 8 minutes.

(4.84 mmol, 4.40 mL of 1.1 M THF solution). After the reaction mixture was stirred at room temperature for 18 hours, ice water (30 ml) was added thereto. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed twice with saturated aqueous NaHCO 3 and once with saturated NaCl, dried over MgSO 4, filtered and evaporated. The product was isolated by flash chromatography (column diameter 50 mm, 15 cm layer of Merck silica gel, eluent 40% acetone in hexane, flow rate 5 cm / min). The product fractions were concentrated, azeotroped with toluene and evaporated under reduced pressure to give the title alcohol (0.369 g, 0.991 mmol, 62% yield) as a viscous yellow oil. 0.098 g, 0.263 mmol (16%) of a slightly crude product or TLC (silica gel, acetone-hexane 1: 1) were also obtained: Rf = 0.35.

Mass spectrum (CI, m / e): 373 (M + H) + B) (S) -4 - [[2- (1,1'-biphenyl-2-yl) ethynyl] -. . 30 hydroxyphosphinyl-7-hydroxybutanoic acid, dilithium; salt

The diester prepared in Part A (0.739 mmol, 0.275 g) was stirred in dioxane (7.57 mL) under argon and 1 M LiOH (2.22 mmol, 2.22 mL) was added. This cloudy reaction mixture was heated in an oil bath at 55 ° C for 45 minutes. The mixture was cooled to 147,87927 room temperature. The solvents were removed on a rotary evaporator under high vacuum (90 minutes). The resulting yellow foam was dissolved in distilled water (4 mL) and eluted through an HP-20 chromatography column 5 (2.5 x 19 cm) collecting 10 mL fractions at 1.4 minute intervals. The column was eluted with water until 15 fractions (no longer basic) were collected, and then elution with methanol-water (45:55) afforded (after two freeze-drying and high vacuum suction pumps 10 after 16 hours of drying over P 2 O 2) 0.231 g (0.946 mmol, 88% yield) of the title diacid as a white lyophilization product. TLC (silica gel, n-propanol-NH 4 OH-H 2 O 7: 2: 1): Rf = 0.55.

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

Elemental analysis (C 19 H 18 Cl 2 N 2 O 2 + 1.42 mol H 2 O, M = 381.75) Calculated: C, 56.63; H, 4.71; P, 8.07 Found: C, 56.62; H, 4.70; P, 807 Example 34 (S) -4 - [[2- (3,5-dimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; A) 3,5-dimethyl-1,11-biphenyl-2-carboxaldehyde; . Phenylmagnesium bromide was purchased from Aldrich (Cat. No. 17, 156-5) as a 3 M ethyl ether solution::: The dipalladium complex of Example 1, Part B

A mixture of sin (4.48 mmol, 3.35 g) and triphenylphosphine (35.85 mmol, 9.40 g) was stirred in anhydrous toluene (67.2 mL) at room temperature under argon for 30 minutes. This reaction mixture was cooled to 0 ° C and phenylmagnesium bromide - * ... · Grignard reagent (Aldrich) (35.84 mmol, 11.95 mL of 3 M

ethereal). The resulting mixture was stirred at 35 room temperature for 1.5 hours. The mixture is then cooled to -____; to 0 ° C, 148,87927 6.0 N HCl (22.4 mL) was added in one portion and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and extracted with ether. The organic extracts were combined and filtered through diatomaceous earth (washed with ether), and the filtrate was washed with saturated NaCl solution, azeotroped with toluene and evaporated under reduced pressure to give a yellow solid. Attempt to purify the product by two flash chromatography treatments (column diameter 95 mm, 15 cm layer 10 Merck silica gel, eluent 100% hexane

followed by 3% ether in hexane, flow rate 5 cm / minute) afforded 2.95 g of a yellow solid / 1.88 g, 8.96 mmol (100% yield), the title aldehyde and 1.06 g of triphenylphosphine. 15 nia7. This compound mixture was used directly in Part B.

for the preparation of a compound according to TLC (silica gel, 5% ether in hexane): Rf = 0.30.

Mass spectrum (CI, m / e): 211 (M + H) +, 263 (M2 + H) +, 473 (M1 + M- + H) + 20 M aldehyde according to Part A, M2 = triphenylphosphine B) 2- ( 2,2-dibromoethenyl) -3,5-dimethyl-1,1'-·. biphenyl IV In Part A, a mixture of aldehyde (8.96 mmol,; "1.88 g") and triphenylphosphine (26.4 mmol, 6.0 g) was stirred in dry Cl 2 Cl 2 (88 mL) -5 ° C. at 10 minutes. This reaction mixture was maintained at -5 ° by the dropwise addition over 20 minutes of a solution of CBr 2 (13.2 mmol, 4.38 g) in dry Cl 2 Cl 2 (32 mL). The resulting reaction mixture was stirred at -5 ° C for 1 hour and turned darker and darker orange over time. Saturated aqueous NaHCO 3 (85 mL) was then added to the mixture. The aqueous layer was extracted with Cl 2 Cl 2. The organic extracts were combined, washed once with saturated NaHCO 3 (a) solution and once with saturated

NaCl solution, dried over MgSO 4, filtered and evaporated under reduced pressure. The product was purified by pre-soaking the crude product in CH 2 Cl 2 on Merck silica gel (25 g) and transferring to a flash chromatography column (column diameter 50 mm, 15 cm layer of Merck 5 silica gel, eluting with 4% Cl 2 Cl 2). hexane, flow rate 5 cm / minute) to give 2.18 g (5.96 mmol, 68% yield) of the title vinyl bromide as a viscous colorless oil. TLC (silica gel, 4% Cl 2 Cl 2 in hexane: Rf = 0.37.

Mass spectrum (CI, m / e): 365, 367, 369 (M + H) + C) 3,5-Dimethyl-2- (1-ethynyl) -1,1'-biphenyl A solution containing the compound prepared in Part B -nyl bromide (5.74 mmol, 2.10 g) in anhydrous THF (29.11 mL) was stirred under argon and cooled to -78 ° C. To this solution was added n-butyllithium (11.47 mmol, 4.59 mL of a 2.5 M hexane solution) dropwise over 20 minutes, resulting in a dark purple solution. After the reaction mixture was stirred at -78 ° C for an additional 1 h, a saturated (aqueous) solution of NH 4 Cl (25 mL) was added at -78 ° C, the mixture was warmed to room temperature and diluted with water. and the aqueous layer was extracted with ether-hexane; sell (1: 1). The organic extracts were combined, dried over MgSO 4, filtered and evaporated under reduced pressure. The product was isolated by flash chromatography (column diameter 50 mm, 15 cm layer • Merck silica gel, 1% ether in hexane as eluent) to give 1.08 g (5.23 mmol). , yield to 91%) of the title acetylene as a colorless oil which turned blue on storage at -20 ° C for 16 hours. TLC (100% hexane, silica gel): Rf = 0.32.

Mass spectrum (CI, m / e): 207 (M + H) + • · · ·.

150 87927 D) (S) -3- (771,1-Dimethylethyl) diphenylsilyl-7-oxy-4- [2- (3,5-dimethyl-1,1'-biphenyl-2-yl) ethynyl] methoxyphosphinyl butanoic acid, methyl ester

A solution of the acen-5 ethylene prepared in Part C (4.61 mmol, 0.950 g) in dry THF (27.3 mL) was stirred under argon and cooled to -78 ° C. N-Butyllithium (4.61 mmol, 1.84 mL of a 2.5 M hexane solution) was added dropwise over 20 minutes to give a dark purple / brown solution. The reaction mixture was stirred at -78 ° C for 1 h (the reaction mixture turned into a suspension), warmed to 0 ° C and stirred for 15 minutes (the reaction mixture turned into a dark purple homogeneous solution), and finally cooled again to -40 ° C ( the mixture remained homogeneous). This solution of acetylenic anion, maintained at -40 ° C, was then added dropwise over 25 minutes to a solution of the phosphinyl chloride of Example 1, Part F (8.12 mmol) in dry THF (27.3 mL) which was cooled to -78 ° C while stirring under argon. After the addition of the acetylenic anion solution to the phosphinyl chloride solution was complete, the dark orange reaction mixture was stirred at -78 ° C for 1 h, then saturated NH 4 Cl (50 mL) was added at -78 ° C, and the mixture was added. heated room ·. * to temperature and diluted with water. The aqueous layer was extracted with ether. The organic extracts were combined, washed once with saturated (aqueous) NaHCO 3 solution and once with saturated NaCl solution, dried over MgSO 4. : 30 was filtered and evaporated under reduced pressure. The product was isolated by flash chromatography (column diameter 50 mm, 15 cm layer of Merck silica gel, eluent 1: 1 ethyl acetate-hexane, flow rate 5 cm / minute) to give 0.609 g 35 (0.945 mmol, yield 21 %) of the title phosphinate as a gold-orange oil. TLC (ethyl acetate-hexam 87927 1: 1, silica gel): Rf = 0.32. Mass spectrum (CI, m / e): 639 (M + H) + E) (S) -4 - [[2- (3,5-dimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3- (t-butyldiphenyl-silyloxy) butanoic acid

To a solution of the acetylene phosphinate prepared in Part D (1.37 mmol, 0.876 g) in methanol (13 mL) was purged with argon for 10 minutes. 10% Pd / C catalyst 10 (0.315 g) was added and the reaction mixture was hydrogenated on a Parr apparatus at 2.8 bar. After shaking for 24 hours, the reaction mixture was filtered through a pad of diatomaceous earth formed on sintered glass. The diatomaceous earth was washed with methanol and the filtrate was evaporated under reduced pressure to give 0.896 g of a yellow oil which was purified by flash chromatography (50 mm column diameter, 15 cm layer of Merck silica gel, eluting first with 40% and then 50% ethyl acetate in hexane). ) to give 0.680 g (1.06 mmol, 77% yield) of the title saturated phosphinate as a pale yellow foam. Emptying the column eluting with methanol gave additional. . 0.087 g of slightly impure product.

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

• Mass spectrum (CI, m / e): 643 (M + H) + F) (S) -4- [2- (3,5-dimethyl-1,1'-biphenyl-2-yl) -ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt

The phosphinate prepared in Part E (1.03 mmol, * 0.66 g) was stirred in dry THF (12.65 mL). temperature under argon. To this solution was added dropwise glacial acetic acid (4.12 mmol, 0.247 g, 0.236 mL) followed by dropwise addition of n-CH 2 Cl 2 (3.09 mmol, 2.81 mL of a 1.1 M THF solution). After the reaction mixture was stirred at room temperature for 16 hours, ice water (25 ml) was added. The aqueous layer was extracted with 152,87927 ethyl acetate. The organic extracts were combined, washed twice with saturated aqueous NaHCO 3 and once with saturated NaCl, dried over MgSO 4, filtered and evaporated under reduced pressure. The product was purified by flash chromatography (column diameter 40 mm, 15 cm layer of Merck silica gel, eluent acetone-hexane 1: 1) to give 0.363 g (0.898 mmol, 87% yield) of the title alcohol as a white solid. as a solid. TLC (silica gel-10 L, acetone-hexane 1: 1): Rf = 0.30. Mass spectrum (FAB, m / e): 405 (M + H) + G) (S) -4- [2- (3,5-dimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl? -3-hydroxybutanoic acid, dilithium salt The diester prepared in Part F (0.878 mmol, 0.355 g) was stirred in dioxane (9 mL) under argon and 1 M LiOH (2.63 mmol, 2.63 mL) was added.

This homogeneous reaction mixture was stirred in an oil bath at 55 ° C. After stirring at 55 ° C for 10 minutes, the reaction mixture turned to a white suspension. Additional dioxane (9 mL) and water (2 mL) were added, and the suspension was heated at 55 ° C for 45 minutes and then cooled to room temperature. The solvents were removed on a rotary evaporator under high pressure (1 hour). The resulting white solid was eluted through an HP-20 chromatography column (18 cm x 2.5 cm). 10 ml fractions were collected every 1.4 minutes. The column was eluted with water until 15 fractions were collected, followed by: 30 elution with methanol-water (1: 1) product / three freeze-drying and high vacuum suction pump? 2θ ^: η drying (4x8 hours) · ... · 'After? to give 0.289 g (0.744 mmol, 85% yield) of the title diacid as a white lyophilization product. TLC (silica gel, n-propanol-NH 4 OH-1 2 O 7: 2: 1): Rf 0.56.

i 153 3792 7

Elemental analysis (C20H23 ° 5PL ^ 2 + O »34 mol I ^ O, M = 394.31)

Calculated: C, 60.92; H, 6.05 Found: C, 60.95; H, 6.18 Mass spectrum (FAB, m / e): 389 (M + H) +

Example 35 (S) -4 - [[2- (4'-Fluoro-3,5-dimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt 10 A) Bromo- (4- fluorophenyl) magnesium

The magnesium metal chips (44.35 mmol, 1.08 g) were dried with a flame and then stirred in anhydrous ether (40 mL) under argon. 1-Bromo-4-fluorobenzene (40.3 mmol) was added dropwise to the magnesium dropwise with vigorous stirring. The reaction was started on an ultrasonic device, and then the halide was added at a sufficient rate to maintain reflux. After the addition of bromide was complete, the reaction mixture was stirred at room temperature for 20 minutes and then refluxed and finally cooled to room temperature. This procedure resulted in a gold-orange, clear Grignard solution containing 40.32 mmol of the title Grignard reagent as a 0.91 M ether solution.

:. B) 4'-Fluoro-3,5-dimethyl-1,1'-biphenyl-2-carboxaldehyde: Reference: Stockker et al., Journal of Med. Chem.

: Y: 29 (1986) 170-181

Palladium complex according to Part 26 of Example 26. : 30 (4.35 mmol), 3.20 g) and a mixture of triphenylphosphine (40.32 mmol, 10.58 g) in anhydrous toluene (67.2 mL) were stirred at room temperature under argon for 30 minutes. . This reaction mixture was then cooled to 0 ° C and Grignard reagent prepared in Part A (40.32 mmol, 44.43 mL) was added gradually (rapidly). The resulting mixture was stirred at room temperature 154,87927 for 1.5 hours. The mixture was then cooled to 0 ° C, and 6.0 N HCl (21.75 mL) was added in one portion and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and extracted with ether, and the combined organic extracts were filtered through diatomaceous earth. The diatomaceous earth was washed with ether, and the combined filtrates were washed with saturated NaCl solution, azeotroped twice with toluene, and evaporated under reduced pressure to give an orange-yellow solid. Attempts to isolate the title aldehyde by flash chromatography using a 95 mm diameter column, a 15 cm layer of Merck silica gel and first hexane followed by Et 2 O-hexane at a flow rate of 15 5 cm / minute gave a final reaction mixture containing the desired title aldehyde and triphenylphosphine, as a pale yellow solid / 3.70 g - assumed to contain 8.7 mmol, 1.99 g (100% yield) of the title aldehyde and 1.70 g of triphenylphosphine? · This compound mixture was used directly for the preparation of the compound of Part C.

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

1 H-NMR (270 MHz, CDCl 3) δ c) 2- (2,2-dibromoethenyl) -4'-fluoro-3,5-dimethyl-1,1'-biphenyl

A mixture of the aldehyde prepared in Part B (8.70 mmol, "1.99 g") and triphenylphosphine (26.1 mmol, 6.85 g) was stirred in dry Cl 2 Cl 2 (87 mL) -5 ° At C for 10 minutes. This reaction mixture was kept at -5 ° C by the addition dropwise over 25 minutes of a solution of CBr 2 (13.05 · ... mmol, 4.33 g) in dry Cl 2 Cl 2 (43 mL). The resulting reaction mixture was stirred at -5 ° C for 1 hour to give a dark orange solution to which was added; then saturated aqueous NaHCO 3 (80 mL). The aqueous layer was extracted four times with CH 2 Cl 2. The combined organic extracts were washed once with saturated aqueous NaHCO 3 and once with saturated NaCl. The CH 2 Cl 2 extraction solution was dried over MgSO 4 and filtered, and the filtrate was combined with Merck silica gel (25 g). The solvent was evaporated off and the pre-absorbed product was purified by flash chromatography (column diameter 50 mm, 15 cm layer of Merck silica gel, eluent 4). Hexane containing% CH 2 Cl 2, flow rate 10 cm / min) to give 2.32 g (6.04 mmol, 69% yield) of the title vinyl borimide as a colorless oil. TLC (silica gel, hexane containing 5% CH 2 Cl 2): Rf = 0.43.

Mass spectrum (CI, m / e): 383, 385, 387 (M + H) + 15 D) 4'-fluoro-3,5-dimethyl-2- (1-ethynyl) -1,1'-biphenyl

A solution of the vinyl bromide prepared in Part C (5.99 mmol, 2.30 g) in anhydrous THF (33 mL) was stirred under argon and cooled to 20-78 ° C. To this solution was added n-butyllithium (11.97 mmol, 4.79 mL of a 2.5 M hexane solution) dropwise over 25 minutes to give a deep purple solution. After the reaction mixture was stirred at -78 ° C for an additional 1 h, saturated aqueous NH 4 Cl (25 mL) was added at -78 ° C, and the mixture was warmed to room temperature and diluted. with water (25 mL). The aqueous layer was extracted four times with V: ether-hexane (1: 1). The organic extracts were combined, dried over MgSO 4, filtered. : 30 and evaporated. The product was isolated by flash chromatography (column diameter 50 mm, 15 cm layer

Merck silica gel, hexane containing 0.50% ether as eluent, flow rate 5 cm / minute) to give 1.25 g (5.57 mmol, 93% yield) of the title acetylene as a colorless oil which turned blue. . when stored at 20 ° C. TLC (silica gel, 100% hexane) Rf = 0.25.

Mass spectrum (CI, m / e): 225 (M + H) + 156 37927 E) (S) -4- [72- (4'-fluoro-3,5-dimethyl-1,1-biphenyl-2-yl) ) ethynyl7-hydroxyphosphinyl-3- (t-butyldiphenylsilyloxy) butanoic acid, methyl ester A solution of 5 acetylene (5.24 mmol, 1.18 g) prepared in Part D in dry THF (28 mL) was stirred under argon and cooled to -78 ° C. N-Butyllithium (5.24 mmol, 2.10 mL of a 2.5 M hexane solution) was added dropwise over 25 minutes as the reaction mixture turned dark purple or brown. The reaction mixture was then stirred at -78 ° C for 1 hour, warmed to 0 ° C. This solution of the acetylene anion at -78 ° C was then added dropwise over 20 minutes to a solution of the phosphinyl chloride of Example 1, Part F (8.32 mmol) in anhydrous THF (28 mL) cooled to - To 78 ° C while stirring under argon. After the addition was complete, the dark orange reaction mixture was stirred at -78 ° C for 1 h, then saturated aqueous NH 4 Cl was added at -78 ° C and the mixture was warmed to room temperature and diluted with water. The aqueous layer was extracted four times with ether. The organic extracts were combined, washed once with saturated aqueous NaHCO 3 and once with saturated NaCl, dried over MgSO 4, filtered and evaporated. The product was isolated by flash chromatography

(column diameter 50 mm, 15 cm layer of Merck silica gel, eluent 40% ethyl acetate in hexane, flow rate 5 cm / minute) to give 0.730 g (1.11 mmol, 21% yield) of the title acet. . 30 linen phosphinates as a green viscous oil. TLC

(silica gel, 1: 1 ethyl acetate-hexane): Rf 0 0.36.

:: Mass spectrum (CI, m / e): 657 (M + H) + I: 15? 87927 F) (S) -4 - [[2- (4'-fluoro-3,5-dimethyl-1,11-bi-phenyl-2-yl) ethyl] hydroxyphosphinyl] -3- (t-butyl-diphenylsilyloxy) butanoic acid, methyl ester

To a solution of the acetylene phosphinate prepared in Part E (1.04 mmol, 0.685) in methanol (9.9 mL) was purged with argon for 10 minutes. 10% Pd / C catalyst (0.239 g) was added and the reaction mixture was hydrogenated on a Parr apparatus at 2.8 bar. After shaking for 24 hours, the reaction mixture was filtered through a pad of diatomaceous earth formed on sintered glass, the diatomaceous earth 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 (column diameter 40 mm, 15 cm layer of Merck silica gel, eluent 45% ethyl acetate in hexane, flow rate 5 cm / minute) to give 0.530 g (0.802 mmol, 77% yield) of the title compound. saturated phosphinate as a pale yellow foam. 0.09 g (0.136 mmol, 13%) of slightly impure product was also obtained. TLC (silica gel, ethyl acetate-oxane 1: 1): Rf = 0.30.

Mass spectrum (CI, m / e): 661 (M + H) + ·: G) (S) -4 - [2- (4'-fluoro-3,5-dimethyl-1,1'-• ' · Biphenyl-2-yl) ethyl] methoxyphosphinyl-β-hydroxy-butanoic acid, methyl ester. The phosphinate prepared in Part F (0.794 mmol, 0.525 g) was stirred in anhydrous THF (9.74 mL) at room temperature under argon. To this solution was added dropwise glacial acetic acid (3.18 mmol, 0.191 g, 0.182 mL) followed by dropwise addition of n-CH 2 HNNF (2.38 mmol, 2.7 mL of 1.1 M THF). After stirring at room temperature for 16 hours, ice water (15 ml) was added. The aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, washed twice with saturated aqueous NaHCO 3 and once with saturated NaCl, dried over MgSO 4, filtered and evaporated. The product was purified by flash chromatography (column diameter 40 mm, 15 cm layer of Merck silica gel, eluent acetone-hexane 5 1: 1, flow rate 5 cm / minute). The product fractions were concentrated and azeotroped with toluene to dryness to give 0.281 g (0.665 mmol, 84% yield) of the title alcohol as a white solid. In the 270 MHz 1 H-NMR spectrum, the ha-10-claimed impurity was not separable / ha-detectable in different TLC systems. TLC (silica gel, acetone-hexane 1: 1): Rf = 0.31. 1 H-NMR (270 MHz, CDCl 3)

Mass spectrum (CI, m / e): 423 (M + H) + 15 H) (S) -4 - [[2- (4'-fluoro-3,5-dimethyl-1,1'-biphenyl- 2-yl) ethyl7-hydroxyphosphinyl / -3-hydroxy-butanoic acid, dilithium salt

The diester prepared in Part G (0.473 mmol, 0.20 g) was stirred in dioxane (4.84 mL) under argon al-20 Ia, and 1 M LiOH (1.42 mmol, 1.42 mL) was added. This homogeneous reaction mixture was heated in an oil bath at 55 ° C. After stirring at 55 ° C for 10 minutes, the reaction mixture turned to a white suspension. The mixture was kept at 55 ° C for another 45 minutes and then cooled to room temperature.

The solvents were removed on a rotary evaporator and under high vacuum (1 hour). The resulting white foam was dissolved in distilled water (4 mL) and eluted through an HP-20 chromatography column (16 cm x 2.5 cm). The collected. . 10 ml fractions were added every 1.4 minutes. The column was eluted with water until 15 fractions were collected, and then elution with methanol-water (1: 1) afforded:: (after two freeze-drying with high vacuum suction pump over 11 hours of P303). ) gave 0.158 g (0.389 mmol, 82% yield) of the title diacid as a white freeze-dried product. TLC (silica gel, n-propanol-NH 4 OH-t 2 O 7: 2: 1): Rf = 0.59.

Mass spectrum (FAB, m / e): 395 (M + H) +

Elemental analysis (C20H22FO5PL22 + ^ '^ 9 mol H2O, M = 5 413.25)

Calculated: C, 58.12; H, 5.56 Found: C, 58.14; H, 6.09

Example 36 (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -10 1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A) 4-Fluoro-4-oxobenzenepropanoic acid, ethyl ester

A 60% mineral oil dispersion of sodium hydride (17.4 g, 0.43 mmol) was washed twice with dry hexane and dried under reduced pressure, followed by the addition of bare diethyl carbonate (44.3 mL, 0.36 mmol) and then dropwise p- fluoroacetophenone (22 mL, 0.18 mol). After the addition of about 10% ketone-20, 4 drops of ethanol were added to initiate reflux, and the remainder of the p-fluoroacetophenone was added over a period of 1.0 hour at such a rate that refluxation remained. The resulting yellow solid was slurried in dry ether (250 mL), and the slurry was refluxed for an additional 3.0 h under argon.

: ’; The reaction mixture was cooled in an ice bath and diluted with ether (200 mL) and water (1.3 L) was added slowly until all solids had dissolved. The aqueous phase was separated from the organic phase, its pH. : 30 was adjusted to 1.0 with 12 N HCl (32 mL) and extracted with ether (2 x 500 mL). The combined organic extracts were washed with saturated NaCl solution (200 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (44.0 g) was distilled under reduced pressure (3.5 mmHg) to give the title compound as a homogeneous oil (24.88 g, 160,87927 65.8%). TLC (silica gel, CH 2 Cl 2: 4: 1):

Rf = 0.46.

B) 4-Fluoro-cis - (2-methyl-1-oxopropyl) -p-oxobenzenepropanoic acid, ethyl ester 5 A 60% mineral oil dispersion of sodium hydride (10.3 g, 0.26 mmol) was washed twice with dry hexane. , dried under reduced pressure, suspended in dry tetrahydrofuran (245 ml) and cooled to 0 ° C (ice-water bath) under argon. The compound prepared in Part A (24.5 g, 0.12 mol) was added portionwise over 20 minutes to the suspension, the mixture was warmed to room temperature, and stirred for an additional 30 minutes. The reaction mixture was cooled to 0 ° C (ice water bath), isobutyryl chloride (18.62 g, 0.17 mol) was added dropwise, the mixture was warmed to room temperature and stirred for 3.0 hours. The mixture was cooled to 0 ° C (ice water bath), water (200 ml) was added to give a homogeneous solution, and evaporation on a rotary evaporator was performed to remove most of the tetrahydrofuran. The aqueous phase was adjusted to pH 1.0 with 10% HCl (37 mL) and extracted with ether (3 x 100 mL). The combined organic extracts were washed with saturated NaCl solution V (50 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness to give an oil (36.85 g) which was the starting material and two other products. mixture.

TLC (silica gel, CH 2 Cl 2 4: 1, UV): 0.46, 0.33 and 0.20.

C) 5- (4-Fluorophenyl-3- (1-methylethyl) -1-. 30-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester

The crude compound prepared in Part B (36.85 g, ca. 0.12 mol) was dissolved in glacial acetic acid (151 mL), and 97% phenylhydrazine (18.1 mL, 0 mL) was gradually added to the solution under nitrogen. , 18 mol), and the mixture was stirred at room temperature for 19 hours. Reaction mixture '. poured into water (350 ml) and extracted with ether (3 x 161 87927 100 ml), and the combined organic extracts were washed with saturated NaHCO 3 (until the aqueous layer was basic) and saturated NaCl (500 ml), dried (anhydrous MgSO 4), filtered and filtered. evaporated to dryness.

The dark orange oil was stirred in petroleum ether (300 ml) and the solvent evaporated to give a yellow solid. This crude product was triturated with petroleum ether (100 ml) to give the crude product (15.3 g) which was in turn chromatographed on a silica gel column (LPS-1) eluting the column with Cl 2 Cl 2 -hexane (2: 1) to give 11.53 g of pure product were obtained. The mother liquor (26.4 g) was chromatographed on a silica gel column (LPS-1) and triturated to give an additional 7.12 g of the desired product (total yield 18.65 g or 44.1%). A small amount of the title compound was recrystallized from E 2 O-hexane to give a homogeneous solid, mp 92-93 ° C. TLC (silica gel, CH 2 Cl 2 -hexane 4: 1): Rf = 0.35.

20 Elemental analysis:

Calculated: C, 71.57; H, 6.01; N, 7.95; F, 5.39 Found: C, 71.62; H, 5.99; N, 7.91; F, 5.54 · D] 5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole-4-methanol; To a cooled (0 ° C, ice-salt bath) suspension of lithium aluminum hydride (3.67 g, 96.7 mmol): in anhydrous ether (70 mL) under argon was added dropwise over 1.5 hours a solution which contained the compound prepared in Part C (11.54 g, 32.7 mmol) in water. : 30 in dry ether (142 ml). The greenish suspension was allowed to warm to room temperature over 1.5 hours, cooled back to 0 ° C (ice-salt bath) and water (20 ml) was added dropwise until gas evolution ceased. The thick slurry was diluted with ether (100 mL) and filtered, and the precipitate was washed well with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with saturated NaCl solution (50 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness to give a cream solid (10.3 g, 100% crude yield).

5,100 mg of the crude product was recrystallized from Et 2 O-hexane to give the title compound (58 mg) as white crystals, m.p. 138-140 ° C. TLC (silica gel, CH 2 Cl 2): Rf = 0.01. Elemental 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

Mass spectrum: 311 (M + H) + E) 5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole-4-carboxaldehyde To a solution containing pyridinium chloroformate (21.23 g, 98.4 mmol) in dry dichloromethane (125 mL), a solution of the crude compound from Part D (10.2 g, ca. 32.7 mmol) in dry dichloromethane (85 mL) was added rapidly, and the resulting dark brown solution was stirred at room temperature under nitrogen for 4.0 hours. The mixture was diluted with ether (750 mL) and stirred for 10 minutes. The supernatant solution was decanted off the usual residue, and the residue was triturated with dichloromethane (2 x 100 mL). The dichloromethane extracts were diluted with ether (750 mL) and the combined extracts were filtered through a pad of silica gel. Clear: the filtrate was evaporated to dryness to give the crude product (10.0 g).

. ·. : 30 The crude product was purified by chromatography on silica. on a silica gel column (Baker, mesh 60-200, 400 ml) eluting the column with CH 2 Cl 2 -hexane (4: 1) to give the title compound as a solid: (9.6 g, 95.2 tt). An analytical sample (72 mg, melting point 35 108-110 ° C) was obtained by crystallization of 200 mg of the compound. again from hexane. TLC (silica gel, CH 2 Cl 2, UV:

Rf = 0.58.

163 8 7 927

Elemental 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

Mass spectrum: 309 (M + H) + 5 F) 4- (2,2-dibromoethenyl) -5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole

A mixture of the compound prepared in Part E (2.0 g, 6.48 mmol) and triphenylphosphine (5.10 g, 19.2 mmol) in dry dichloromethane (30 mL) was cooled to -5 to -10 ° C. (ice-salt bath) under argon, and a solution of carbon tetrabromide (3.22 g, 9.61 mmol) in dry dichloromethane (10 mL) was added dropwise over 5 minutes. The reaction mixture was stirred at 15-20 ° C for 15 minutes, after which it was poured into saturated NaHCO 3 (10 mL) and extracted with chloromethane (3 x 50 mL). The combined organic extracts were washed with saturated NaHCO 3 (10 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product mixture (9.33) was chromatographed on a silica gel column (LPS-1) eluting with Cl 2 Cl 2 -hexane mixtures (1: 9, 1: 1 and 4: 1) to give the title compound as a solid (2.75 g, 91.6%). Recrystallization of a small aliquot of the title compound gave white crystals: · -; you, sp. 88-90 ° C. TLC (silica gel, CH 2 Cl 2: hexane: V: 4: 1): Rf = 0.85.

Elemental analysis:

Calculated: C, 51.75; H, 3.69; N, 6.04; F, 4.09; Br, 34.43 ...: 30 Found: C, 51.96; H, 3.51; N, 5.97; F, 4.22; Br, 34.77

Mass spectrum: 465 (M + H) + G) 4-ethynyl-5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole

A solution of the compound from Part F (2.64 g, 5.67 mmol) in dry THF (10.5 mL) was cooled to -78 ° C in a dry ice-acetone bath) under argon (164,87927), and a 1.6 M solution of n-BuLi in hexane (7.16 mL, 11.37 mmol) was added dropwise. The resulting suspension was stirred at -78 ° C for 1 h 20 min, 5% NH 4 Cl (10 mL) was added dropwise, and the mixture was allowed to warm to room temperature. The reaction mixture was extracted with ether (3 x 50 ml) and the combined organic extracts were washed with saturated NaCl solution (20 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness to give the title compound as a light brown solid (1.79 g). ).

The crude product was purified by column chromatography on silica gel eluting with Et 2 O-hexane (5:95) to give the title compound 15 as a light golden solid (1.08 g, 97.4%). Recrystallization of a small aliquot of hexane gave white useful crystals, m.p. 106-108 ° C. TLC (silica gel, Et 2 O-hexane 1: 9; elution twice): Rf = 0.70.

20 Elemental analysis:

Calculated: 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; Mass spectrum: 305 (M + H) + H) (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] -2'-oxy] -4- [5- (4-fluorophenyl) -3- ( 1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl7-methoxyphosphinyl / N, butanoic acid, methyl ester::: A mixture of crude phosphonic acid monomethyl ester of Example 1, Part F (2.77 g,: 30). , 55 mmol) and trimethylsilyldiethylamine (2.1 mL, 11.05 mmol) in dry dichloromethane (10 mL) were stirred at room temperature under argon for 1.0 h.

The mixture was evaporated to dryness, re-evaporated: azeotropically with dry benzene (20 ml) and dried under reduced pressure (pump, 15 minutes). The viscous oil was redissolved in dry dichloromethane (165 mL) (10 mL), DMF (1 drop) was added, the mixture was cooled to -10 ° C (ice-salt bath), and oxalyl chloride (530 μL, 6.08) was added dropwise. mmol). Strong gas evolution was observed, and the dark yellow solution was stirred at -10 ° C for 15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, re-evaporated azeotropically with benzene (20 ml) and dried under reduced pressure.

A solution of the compound prepared in Part G (1.12 g, 3.67 mmol) in dry tetrahydrofuran (9.0 mL) was cooled to -78 ° C (dry ice-acetone bath) under argon, 1 , 6 M n-BuLi in hexane (2.3 mL, 3.67 mmol), and the mixture was stirred at -78 ° C for 30 minutes. The phosphonochloridate prepared above was dissolved in dry tetrahydrofuran (6.5 mL), the solution was cooled to -78 ° C (carbon dioxide-acetone bath) under argon, and a solution of acetylene anion was added dropwise via tube, keeping both solutions at -78- ° C: as fathers throughout the addition. The reaction mixture was stirred at -78 ° C for 30 mL. . minutes, then 25% was added dropwise; · NH 4 Cl (6.0 mL), and then the mixture was warmed to room temperature. The mixture was extracted with ether (3 x 100 mL), and the combined organic extracts were washed with 25% NH 4 Cl (10 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude mixture (ca. 4.2 g) was chromatographed on a silica gel column eluting with hexane-acetone (9: 1) to give the title compound as a light brown oil (1.54 g, 57.5%). TLC (silica gel, hexane-acetone 7: 3): Rf = 0.33.

166 87 927 I) (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3- hydroxybutanoic acid, methyl ester

To a solution of the compound from Part H (593.3 mg, 0.81 mmol) in dry tetrahydrofuran (8.0 mL) was added sequential glacial acetic acid (190 μL, 3.24 mmol) and 1 M Bu NF (2.54 mL, 2.54 mmol), and the mixture was stirred at room temperature under argon overnight. The reaction mixture was cooled to 0 ° C (ice water bath), 5% KHSO 4 (8.5 mL) was added, and the mixture was extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were washed with 5% KHSO 4 (10 mL) and saturated NaCl (20 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product was dissolved in a mixture of ether (14 ml) and dry tetrahydrofuran (10 ml), the mixture was cooled to 0 ° C (ice-salt bath), excess diazomethane in ether was added, and the mixture was stirred at 0 ° C for 3.0 hours. Pisa-20 was added portionwise to the reaction mixture, and the mixture was evaporated to dryness and dried under reduced pressure. The crude product was purified by chromium. . chromatographed on a silica gel column eluting with acetone-1 · ni-hexane (1: 2) to give the title compound as a semi-solid (325.6 mg,: 80.6% yield).

Example 37; · (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl] -1-phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt: To a solution of the compound of Example 36 (325 mg, 0.65 mmol) in dioxane (7.7 mL) was added 1 N LiOH (2.25 mL, 2.25 mmol). and the mixture was stirred at 55 ° C (oil bath) under nitrogen for 1.5 hours and then at room temperature for 16 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure.

____: The crude product was purified by chromatography on an HP-20 resin 167 8 7 9 2 7 column (2.5 cm x 12.5 cm) eluting the column with steam distilled water (400 ml) and water-methanol (1: 1). The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The solid product was dissolved in steam-distilled water and the solution was lyophilized to give the title product as a fluffy solid freeze-dried product (317.1 mg, 96.4%).

TLC (silica gel, iPrOH-NH 4 OH-H 2 mixture 8: 1: 1): Rf 0 0.33.

10 Elemental analysis (C24H22FN2 ° 5P''1.3H2O, effective molecular weight = 505,861)

Calculated: 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 (400 MHz, CD 3 OD): 61.40 (d, 6H, J = 7 Hz), 1.81 - 1.98 (m, 2H), 2.35 (dd, 1H , J = 9.15 Hz), 2.48 (dd, 1H, J = 4.15 Hz), 3.35 (specific, 1H, J = 7 Hz), 4.42 (m, 1H), 7 .08 - 7.41 (m, 9H), IR (KBr): 2173 cm-1 (C = C).

Example 38 (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] methoxy]. . phosphinyl-3-hydroxybutanoic acid, methyl ester A) [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -2-hydroxyethyl] phosphonic acid, dimethyl ester · / -: To a solution of -78- ° C (CC> 2-acetone bath) containing dimethyl methylphosphonate (2.81 mL, 25.9: mmol) in dry THF (50 mL) was added 1.6 M drop of a hexane solution of n-BuLi (15.2 mL, 24.3 mmol) in 15 mL. · Over 30 minutes, and the white suspension (formed after about 15 minutes) was stirred under argon at -78 ° C for 1 hour. Pyrazole: aldehyde from Example 36, Part E (5.0 g, 16.2 mmol) in dry THF (15 mL) was added dropwise over 10 minutes, and the yellow mixture was stirred at -78 ° C for 30 minutes. Saturated NH 4 Cl (20 mL) was added to the mixture, and 168,87927 was allowed to warm to room temperature. The mixture was partitioned between water and EtOAc, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to give the title β-hydroxyphosphonate as a yellow foam. A small aliquot was crystallized from hexane to give the title compound as white crystals, m.p. 126-128 ° C. TLC (hexane-acetone 1: 1). Rf = 0.27.

10 Mass spectrum: 433 (M + H) + (observed)

Elemental analysis (C ~~ H „, Ο.Ν-PF) 11 22 26 4 2

Calculated: C, 61.10; H, 6.06; N, 6.48; F, 4.39; P, 7.16

Found: C, 60.95; H, 6.06; N, 6.41; F, 4.22; P, 7.27 1 H-NMR (CDCl 3): δ 1.42 (6 H, d), 1.94 - 2.40 (2 H, m), 3.29 (1H, septet), δ , 62 + 3.63 (2 doublets, JH_p = 11.1 Hz), 3.91 (1H, s), 5.11 (1H, bm), 6.90 - 7.30 (9H, m) ppm .

13 C-NMR (CDCl 3): δ $ 22.6, 26.5, 32.8 (Jc_p = 136.3 Hz), 52.1 (Jc_p = 5.7 Hz), 60.8, 115.0, 115.4, 119.3, 119.5, 20 124.7, 126.3, 126.6, 128.5, 132.2, 132.3, 139.4, 139.5, 156.7, 164.5 (J ^ _p = 265 Hz) ppm.

. . B) (E) - [2- [5- (4-fluorophenyl) -3- (1-methyl-ethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] phosphonic acid, dimethyl ester

: · 25 To the solution containing the crude in Part A

: prepared hydroxyphosphinate (7.158 g) in dry benzene (40 mL), pTSO 4 * H 2 O (304 mg, 1.6 mmol) was added, and the mixture was refluxed through a 4 A Dean-Stark trap containing molecular sieves. through argon for 2 to 30 hours. The mixture was cooled and diluted with EtOAc. and the organic phase was washed with saturated NaHCO 3 (twice) and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 6.893 g of a yellow oil. The crude 35 oil was triturated with hexane to give 5.692 g of nearly pure vinyl phosphonate as off-white white crystals. Recrystallization once from EtOAc-hexane gave in two portions 5.655 g (84.2% overall yield based on aldehyde) of pure title trans-vinylphosphonate 5 as white needles with a melting point of 143-144 ° C. TLC (hexane-acetone 1: 1): Rf = 0.40.

Mass spectrum: 415 (M + H) + (observed)

Elemental analysis (C22H24O3PN2F2: 10 Calculated: C, 63.76; H, 5.84; N, 6.76; F, 4.58; P, 7.47

Found: C, 63.99; H, 5.95; N, 6.76; F, 4.54; P, 7.31 1 H-NMR (CDCl 3): δ 1.42 (6H, d), 3.27 (1H, septet), 3.70 (6H, d, JH_p = 11.0 Hz), δ , 67 (1H, dd, JHH = 18.4 Hz, JHp = 18.5 Hz), 7.02 - 7.30 (9H, m), 7.34 (1H, 15 dd, JHH = 18 Hz, JHp = 24.3 Hz) ppm.

13 C-NMR (CDCl 3): (f 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 δ (Jc-F = 249.8 Hz) ppm.

C) (E) - [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] phosphonic acid, monomethyl ester

To a solution of the dimethyl phosphonate prepared in Part B: 2.0 g, 4.83 mmol in dioxane (15 mL) was added 1.0 N LiOH (7.3 mL), and the mixture was refluxed under argon for 1 hour. . The mixture was cooled to room temperature, adjusted to pH 1 with 1.0 N HCl, and extracted with EtOAc (twice). . The 30-phase phase was washed with 1.0 N HCl and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give crude mono-: acid which crystallized slowly from hexane on standing.

The crystals were collected by filtration and dried under reduced pressure to give 1.918 g (99%) of the title monoacid as a white crystalline solid having a melting point of 168-170 ° C. An analytical sample was prepared by recrystallization from EtOAc-hexane. TLC (8: 1: 1 CH 2 Cl 2 -CH 3 OH-HOAc): Rf = 0.40.

Mass spectrum: 401 (M + H) + (observed) 5 Elemental analysis (C21H22 ° 3N2PF ^

Calculated: 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; Δ, 7.58 1 H-NMR (CDCl 3): cfl, 40 (6 H, d), 3.26 (1H, septet), 3.65 (3 H, d, JH_p = 11.6 Hz), δ , 74 (1H, dd, JR_H = 10 17.9 Hz, JH_p = 19.5 Hz), 7.00 - 7.36 (10 H, m), 8.65 (1H, bs) ppm 13 C- NMR (CDCl 3): δ $ 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, Δ 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_p = 249.8 Hz) ppm D) (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1- Phenyl-1H-pyrazol-4-yl] ethenyl] methoxyphosphinyl-3-oxobutanoic acid, methyl ester The methyl acetoacetate dianion was prepared by the method described in Example 26 using the following amounts: methyl acetoacetate (815 μL, 7.53 mmol), 60% NaCl oil: (324 mg, 8.11 mmol), 1.6 M n-BuLi in hexane (4.3 mL, 6.95 mmol), THF (15 mL).

A solution of phosphonic acid monomethyl ester (2.317 g, 5.79 mmol) and trimethylsilytyldi; ethylamine (TMSDEA) (1.45 mL, 11.6 mmol) in CH 2 Cl 2 • (15 mL) was stirred at room temperature for 1 h.

The mixture was evaporated to dryness and again with benzene (20 ml) and dried under reduced pressure. Residue V: was dissolved in dry CH 2 Cl 2 (15 mL), (COCl) 2 (555 μL, 6.37 mmol) and DMF (1 μl ____; Sara) were added to the solution, and the mixture was stirred at room temperature. 1 35 hours. The mixture was evaporated to dryness and again with benzene (20 ml) and dried under reduced pressure.

A solution of 171 87927 -78 ° C (CCl 4 acetone bath) containing the phosphonochloridate prepared above in dry THF (10 mL) was transferred dropwise via tube over 20 minutes to a -78 ° C solution containing 5 contained methyl acetoacetate dianion in dry THF (15 mL). The brown mixture was stirred at -78 ° C for 30 minutes, after which saturated NH 4 Cl (10 mL) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was partitioned between 10 H2 (I) and EtOAc, the aqueous phase was reversed

EtOAc, and the combined organic phases were washed with saturated NaHCO 3 and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 3.080 g of an orange foam. The crude 15 product was purified by flash chromatography using Merck silica gel as adsorbent and hexane-acetone-toluene (5: 3: 2) as eluent.

The product fractions were combined and evaporated to give 1.247 g (43.2%) of the desired title [S] ketophosphonate as a pale yellow oil. TLC (acetone-hexane-toluene 4: 4: 2): Rf = 0.29.

: Mass spectrum: 499 (M + H) + (observed) 1 H-NMR (CDCl 3): δ 1.42 & 1.43 (6 H, 2 doublets), 3.24 (2 H, m), 3.27 (1H, specific), 3.63 (2H, m), 3.66 & 3.67 (3H, 2 doublets, JH_p = 11.6 Hz), 3.72 (3H, s), . 5.72 (1H, dd, JHH = 18.7 Hz, JHp = 24.3 Hz), 7.08 - 7.30 (9H, m), 7.37 (1H, dd, JRH = 18 .0 Hz, JRp -2 2.7 Hz) ppm δ 13 C-NMR (CDCl 3): t $ 21.8, 27.1, 46.1 (Jcp = 84.1 Hz), 50.0, 51.2 ( Jc_p = 5.9 Hz), 52.3, 112.6 (Jcp = 135.0 Hz), 114.5 (Jcp = 23.5 Hz), 116.0, 116.3, 124.9, 125, 4, 127.4, 128.8, 132.0, 132.1, 139.1, 141.4 (JCp = 5.9 Hz), 142.5, 158.2, 163.1 (J__ = 250.4 Hz) , 167.1, 194.9, ..... 1 195.0 ppm 172 87927 E) (E) -4 - // 2- [5- (4-fluorophenyl) -3- (1-methylethyl) ) -1-phenyl-1H-pyrazol-4-yl-ethenyl-methoxy-phosphinyl-3-hydroxybutanoic acid, methyl ester to a solution of -15 ° C (salt-ice bath) containing the ketone prepared in Part D (1.304 g, 2.62 mmol) ) in absolute EtOH (15 mL), NaBH 4 (100 mg, 2.62 mmol) was added, and the mixture was stirred at -15 ° C under argon for 15 minutes. Reagent grade acetone (0.3 mL) was added to the reaction mixture followed by CC-4 silica gel (600 mg), allowed to warm to room temperature, diluted with EtOAc, filtered and evaporated under reduced pressure to give 1.46 g of a yellow foam. The crude product was purified by flash chromatography using Merck silica gel as absorbent and EtOAc-acetone (85:15) as eluent. The product fractions were evaporated to give 388 mg of pure title alcohol as a white foam and 228 mg of slightly impure product. The total yield was 616 mg (47%). TLC (EtOAc-20 acetone 7: 3): Rf = 0.31.

Mass spectrum: 501 (M + H) + (observed) 1 H-NMR (CDCl 3): 01.42 (6 H, d), 2.00 (2 H, m), 2.60: (2 H, d), 3.27 (1H, d), 3.64 (1H, d, JHp = 11.1 Hz), VV 3.69 (3H, s), 3.93 & 4.02 (1H, 2 doublet), 4.42 (1H, 2 broad singlets), 5.72 (1H, dd, = 18.0 Hz, JH_p 23.2 Hz), 7.04 to 7.47 (10 H, m ) ppm · 13 · 13 C-NMR (CDCl 3): δ S21.8, 27.1, 35.7 S> 36.5 (jcp = 100.3 Hz), 42.0, 42.2, 50.8 (Jcp = 5.7 Hz), 51.6, 63.4 (Jcp = 20.8 Hz), 114.2 & 114.4 (Jcp = 128.7 Hz), 114.6. . 30 (Jcp = 20.8 Hz), 115.9, 116.3, 124.9, 125.4, 127.3, V 128.8, 131.9, 132.1, 139.1, 140.1 & 140.6 (Jcp = ·; 5.7 Hz), 142.1, 158.0, 163.0 (Jcp = 251.6 Hz), 171.2,: 171.9 ppm 173 8 7 927

Example 39 (S) -4- [72- / 5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt 5 To a solution of the diester of Example 38 (487 mg, 0.973 mmol) in dioxane (10 mL) was added 1.0 N LiOH (3.4 mL, 3.4 mmol), and the resulting mixture was heated and stirred at 70 °. At C for 30 minutes. The mixture was cooled, diluted with water, filtered and evaporated under reduced pressure to an off-white solid. The crude product was dissolved in as little water as possible and chromatographed on HP-20 resin (15 cm layer, column diameter 25 mm) using water as eluent and then CH 2 OH-O 2 (1: 1). The product fractions were evaporated under reduced pressure, the residue dissolved in water (75 ml), and the solution filtered and lyophilized to give the pure title lithium salt as a useful white lyophilisate. TLC (CH 2 Cl 2 -CH 2 OH-20 HOAc 8: 1: 1): Rf = 0.14.

Elemental analysis (C24H24O5N2PFL * 2 + 1/6 mol I0.0, M = 505.233): Calculated: 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, CD 3 OD): δ 1.39 (6 H, doublet), 1.71 (2 H, m), 2.35 (2 H, m), 3.36 (1H, sepetetti), 4.24 I. (1H, m), 6.00 (1H, dd, JHH = 17.6 Hz, JHp = 19.4 Hz), 7.07 - 7.35 (10H, m) * * Example 40 (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4- yl7ethyl7methoxy-phosphinyl7-3-hydroxybutanoic acid, methyl ester ···. A) (S) -3- [7,1-dimethylethyl) diphenylsilyl] oxy-4- [2- [5- (4-fluorophenyl) -3- (1-methyl-35-ethyl) -1-phenyl- 1H-pyrazol-4-yl-ethyl-methoxy-phosphinyl-butanoic acid, methyl ester · To a solution of the compound of Example 36, Part H (912.0 mg, 1.24 mmol) in dry methanol (50 mL) was added 10% Pd. A / C catalyst, and the mixture was hydrogenated in a Parr hydrogenator at 3.4 bar overnight. The suspension was filtered through diatomaceous earth, and the filtrate was evaporated to dryness and dried under reduced pressure to give the title oil as a homogeneous oil (908.3 mg, 99.1%). TLC (silica gel, hexane-acetone 7: 3): Rf = 0.23.

B) (S) -4- [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] methoxy-10-phosphinyl] -3-hydroxybutanoic acid, methyl ester

A solution of the compound prepared in Part A (908.3 mg, 1.23 mmol) in dry tetrahydrofuran (12 mL) was stirred at room temperature under argon and glacial acetic acid (0.29 mL, 4.94 mmol) was added sequentially. ) and a 1.0 M solution of Bu 2 N in hexane (3.89 mL, 3.89 mmol). The reaction mixture was stirred at room temperature for 20 hours and diluted with ice-water (25 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with saturated NaHCO 3 (15 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

: The crude mixture (1.0 g) was chromatographed on a silica gel column (LPS-1; 2.5 cm x 24 cm) eluting with EtOAc-hexane mixtures (4: 1 and 9: 1), EtOAc and acetone to give 1. The title compound was obtained as an oil (529.1 mg, yield 85.6%).

TLC (silica gel, EtOAc-hexane 4: 1): Rf = 0.17.

30 Example 41 ·. ’; (S) -4- [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt To a solution of the compound of Example 40 (529.0 mg, 1.05 mmol) in dioxane (12.5 mL) was added 1.0 N LiOH (3.7 mL, 3.7 mmol), and the mixture was i.

175 87 927 was stirred at 55 ° C (oil bath) under nitrogen for 3.0 hours and then at room temperature for 20 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromatographed on an HP-20 5 resin column (2.5 cm x 15 cm) eluting with steam distilled water (750 mL) and aqueous CH 2 OH mixtures (90:10, 500 mL; 80:20, 500 mL). and 50:50, 500 ml). The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The resulting solid was dissolved in 10 steam-distilled water (35 mL) and the solution was lyophilized to give the title compound as a useful white solid (510.0 mg, 92.4%).

TLC (silica gel, iPrOH-NH 4 OH-H 2 OH 8: 1: 1): Rf = 0.38.

Elemental analysis (C24H26FL * 2N2 ° 5P * 2.2H2O, effective molecular weight = 525,899)

Calculated: 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; Δ, 5.80 IR (KBr): 1596 (CCl 2 CO 2 O) cm -1 1 H-NMR (400 MHz, CD 3 OD): δ 1.36 (d, 6 H, J = 7), 1.60 - 1.72 (m, 4H), 2.32 (m, 2H), 2.74 (m, 2H), 3.21 (septet, 1H, J = 7), 4.23 (m , 1H), 7.06-7.32 (m, 9H).

Example 42: (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methyl- [ethyl] -1-phenyl-1H-pyrazol-4-yl] ethenyl] methoxy]: V: phosphinyl-3-hydroxybutanoic acid, methyl ester; A) 4-Fluorobenzoic acid, 2-phenylhydrazide

A mixture of phenylhydrazine (25 mL,: 0.25 mmol) and triethylamine (35 mL, 0.25 mmol) in anhydrous ether (500 mL) was cooled to -5-10 ° C (ice-salt bath) under nitrogen. below and 4-fluorobenzenecarbonyl chloride (30 mL, 0.25 mol) was added dropwise over 30 minutes. The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then filtered and the solid (176,87927) was washed well with ether (200 mL). The solid was dissolved in dichloromethane (600 ml), the solution evaporated to near dryness, the residue suspended in hexane (600 ml) and the suspension filtered. The clear filtrate was evaporated to dryness, the residue triturated with tetrahydrofuran (700 ml) and filtered, and the solid washed well with tetrahydrofuran (100 ml). The filtrate was evaporated to dryness and dried under reduced pressure to give a crude product (34.6 g) which contained the other two components in impurity.

The crude product was recrystallized from acetone to give the title compound as white crystals (22.16 g, 38.8 *), mp 182-184 ° 0.

The filtrate and mother liquor were combined and chromatographed on a silica gel column (Baker, mesh 60-200, 400 mL) eluting with EtOAc-CH 2 Cl 2 (1: 9) to give an additional 9.78 g of the title compound (total yield 55.8 %). TLC (silica gel, EtOAc-CH 2 Cl 2 1: 4): Rf = 0.63.

20 Elemental analysis (C ^ H ^ Fl ^ O):

Calculated: 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

Mass spectrum: 231 (M + H) + B) 4-Fluoro-N-phenylbenzenecarbohydrazone-: 25 chloride

To a solution of the compound prepared in Part A - (6.16 g, 26.8 mmol) in dry ether - (46 mL) was added phosphorus pentachloride (6.6 g, 31.7 mmol), and the reaction was refluxed under nitrogen. .0 hours. The reaction mixture was cooled to room temperature, phenol (11.5 g, 122.2 mmol) dissolved in ether (15 ml) was added, the mixture was stirred for 5 minutes, and then methanol (11 ml) was added dropwise. The mixture was concentrated on a rotary evaporator at about 75 ° C and the resulting oil was kept at 5. The solid was triturated i.

177 8 7 927 with 5% acetone in water (20 ml) and filtered, and the precipitate was washed well with 5% acetone in water (30 ml). The precipitate was dried under reduced pressure 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 silica gel column (Baker, mesh number 60-200, 400 ml) eluting with a column of Cl 2 Cl 2 -hexane mixtures (1: 3 and 1: 1) to give An additional 10 mg of the title compound was obtained (total amount 5.66 g, 85% yield). TLC (silica gel, CH 2 Cl 2 -hexane 4: 1): Rf = 0.90. Elemental analysis (ci3HigFN2C ^:

Calculated: C, 62.78; H, 4.05; N, 11.27; F, 7.64; Cl, 14.26 Found: C, 62.87; H, 3.97; N, 11.34; F, 7.51; Cl, 13.95 Mass spectrum: 249 (M + H) + C) 3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester

To a solution of sodium ethoxide (prepared from 0.28 g of 20 (12 mmol) sodium metal and 40 mL of absolute ethanol) was added dropwise under nitrogen nitrogen-ethyl isobutyryl acetate (2.0 mL, 12 mmol), stirring; was carried out at room temperature for 15 minutes, after which the compound prepared in Part B was added; 25 (3.0 g, 12 mmol). The mixture was stirred at room temperature for 4.0 h, 10% HCl (10 mL was added), the mixture was evaporated to dryness, and the resulting solid was triturated with ether (3 x: 100 mL). the extracts were washed with saturated NaCl solution (25 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness The crude product (4.3 g) was chromatographed on a silica gel column eluting with a CH 2 Cl 2 -hexane mixture ( 1: 1) to give the title compound as a reddish brown syrup (3.27 g, 77.3%).

TLC (silica gel, 4: 1 CH 2 Cl 2 -hexane):

Rf = 0.42.

178 87 927 D) 3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole-4-methanol In a cooled (0 ° C, ice-salt bath) suspension containing lithium aluminum hydride (0, 71 g, 18.7 g) in dry ether (32 mL), a solution of the compound prepared in Part C (3.26 g, 9.25 mmol) in dry ether (25 mL) was added, and the reaction mixture was stirred at 0 ° C: under nitrogen for 3.0 hours. Ethyl acetate (5.0 mL) was added dropwise at 0 ° C followed by 10% HCl (11 mL), the mixture was decanted and the residue was triturated with ether (2 x 100 mL). The combined organic extracts were washed with saturated NaCl solution (20 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness to give the title compound (2.87 g, 94.4%).

100 mg of the title compound was recrystallized from ether to give an analytical sample (57 mg), mp 145-147 ° C. TLC (silica gel, Cl 2 Cl 2 -hexane 4: 1, development twice): 20 Rf = 0.17.

Elemental analysis (C ^ gH ^ gF ^ O):

Calculated: 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 Mass spectrum: 311 (M + H) + 25 E) 3- (4-fluorophenyl) -5- (1-methylethyl) -1- '· phenyl-1H-pyrazole-4-carboxaldehyde •: For suspension containing pyridinium chlorochlorochloromate (5.41 g, 25.1 mmol) in dry dichloromethane (32 mL) and stirred, a solution of the compound prepared in Part D (2.59 g, 8.34 mmol) in dry dichloromethane (22.0 mL), and the mixture was stirred at room temperature under nitrogen for 4.0 hours. The reaction mixture was diluted with ether (190 ml), stirred for 20 minutes and then decanted. The tarry residue was triturated with ether (100 mL) and dichloromethane 179,87927 (30 mL), and the combined 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 silica gel column (Baker, mesh 5 60-200, 300 ml) eluting the column with C 1 -C 4 hexane (4: 1) to give the title compound (2.40 g). , 93.4%) as a solid product.

100 mg of the title compound was recrystallized from hexane to give analytical sample 10 (50 mg), m.p. 103-105 ° C. TLC (silica gel, CH 2 Cl 2): Rf = 0.67.

Elemental analysis (C ^ Hj ^ FN20):

Calculated: 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 Mass spectrum: 309 (M + H) + F) 4- (2,2-dibromoethenyl) -3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole

A mixture of the compound prepared in Part E (2.296 g, 7.45 mmol) and triphenylphosphine 20 (5.86 g, 22.1 mmol) in dry dichloromethane (35.0 mL) was cooled to -5 to -10 ° C. (ice-salt bath) under argon, was added dropwise over 5 minutes; · A solution of carbon tetraborimide (3.70 g, 11.0 mmol) in dry dichloromethane (12 mL) and the mixture; The mixture was stirred at -10 ° C for 20 minutes. The reaction mixture was warmed to room temperature, poured into saturated NaHCO 2 (12 mL) and extracted into dichloromethane (3 x 60 mL). The combined organic extracts were washed with saturated NaHCO 3 (12 mL) and saturated NaCl (10 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product (11.0 g, solid) was chromatographed on a silica gel column eluting with CH 2 Cl 2 / hexanes (1: 1 and 4: 1) to give the title compound (35.96, corrected yield 96). 0%) and unreacted starting material (250.6 mg).

180 87 927 100 mg of the title compound were recrystallized from Et 2 O-hexane to give an analytical sample (36.5 mg), mp 93.5 ° C. TLC (silica gel, CH 2 Cl 2 / hexane 4: 1): Rf = 0.57.

5 Elemental analysis (C20H17Br2FN2 ^:

Calculated: 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

Mass spectrum: 465 (M + H) + G) 4-ethynyl-3- (4-fluorophenyl) -5- (1-methyl-10-ethyl) -1-phenyl-1H-pyrazole

A solution of the compound prepared in Part F (2.87 g, 6.18 mmol) in dry tetrahydrofuran (11.44 mL) was cooled to -78 ° C (carbonic acid-acetone bath), and 1.6 M n-BuLi was added dropwise. 15 in hexane (11.7 mL, 18.6 mmol) under argon and then stirred at -78 ° C for 2 h 20 min. To -78 ° C, 25% NH 4 Cl (16.5 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and extracted with ether (3 x 60 mL). The combined organic extracts were washed with saturated NaCl solution (22 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (1.9 g) was purified:. chromatographed on a silica gel column eluting the column

Et 2 O-hexane (5:95). The desired fractions are combined-. 25 and evaporated to dryness to give the title compound (1.88 g, 100% yield) as a solid; ’· As a product.

100 mg of the title compound was crystallized. · Again from hexane to give analytical sample 30 (63.5 mg), melting point 117-118 ° C. TLC (silica: gel, Et 2 O-hexane 1: 9): Rf = 0.37.

Elemental analysis (C20H17FN22:

Calculated: 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 35 Mass spectrum: 305 (M + H) +, 181 87927 H) (S) -3- [71,1-dimethylethyl) diphenylsilyl] oxy-4- [3- (4-fluorophenyl) ) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl / ethynyl] methoxyphosphinyl-7-butanoic acid, methyl ester (hydroxymethylphosphinyl) butanoic acid methyl ester (prepared in Example 1, Part F) (2.77 g, 5.55 mmol) in dry dichloromethane (10 mL), trimethylsilyldiethylamine (2.1 mL) was added and the mixture was stirred at room temperature. at room temperature under argon for 1.0 hour. The reaction mixture was evaporated to dryness and re-azeotropically with dry benzene (20 ml) and dried under reduced pressure. The syrup was redissolved in dry dichloromethane (10 ml), the solution was cooled to -10 ° C (ice-salt bath), DMF (1 drop) was added followed by dropwise addition of oxalyl chloride (530), and the mixture was stirred. At 10 ° C for 15 minutes and then at room temperature for 1.0 hour. The mixture was evaporated to dryness and re-azeotroped with benzene (20 ml) and dried under reduced pressure.

Compound prepared in Part G (1.12 g, 3.67 mmol); dissolved in dry tetrahydrofuran (9.0 ml), the solution cooled to -78 ° C (dry ice-acetone bath); To this was added a 1.6 M solution of n-BuLi in hexane (2.3 mL, 3.68 mmol) under argon, and the mixture was stirred.

• * * Q

At -78 ° C for 45 minutes. The phosphonochloro-W ridate prepared above was dissolved in dry tetrahydrofuran V .: (6.5 mL) and cooled to -78 ° C, and the acetylene anion solution was added dropwise via tube, keeping both solutions at -78 ° C throughout. during the addition. The reaction mixture was stirred at -78 ° C for 30 mi-; 25% NH 4 Cl (6.0 mL) was added dropwise and the mixture was allowed to warm to 35 room temperature. The mixture was extracted with ether (3 x - 100 mL), and the combined organic extracts were washed with 25% NH 4 Cl (10 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4). ^), filtered and evaporated to dryness.

The crude mixture (4.0 g) was chromatographed on a silica gel column eluting with acetone-hexane mixtures (1: 9 and 3: 7) to give the title compound (1.76 g, 65.2%) as an oil. TLC (silica gel, hexane-acetone 7: 3): Rf = 0.40.

I) (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methyl-ethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxy-phosphinyl] -3- hydroxybutanoic acid, methyl ester

To a solution of the compound prepared in Part H (700 mg, 0.95 mmol) in dry tetrahydrofuran (9 mL) was added sequential glacial acetic acid (224 μL, 3.82 mmol) and 1.0 M (CH 2 Cl 2). NF (3.0 mL, 3.0 mmol), and the mixture was stirred at room temperature under argon overnight. The solution was cooled to 0 ° C (ice-salt bath), 5% KHSO 4 (10 mL) was added dropwise, and the mixture was extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were washed with 5% KHSO 4 (10 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated. . dryness.

The crude product (890 mg) was dissolved in a mixture of ether (16 ml) and tetrahydrofuran (12 ml), the solution was cooled to 0 ° C (ice-salt bath) and an excess of diazomethane in ether was added. The reaction mixture was stirred at 0 ° C for about 3 hours, glacial acetic acid was added dropwise, and the mixture was evaporated to dryness.

The crude product mixture (764 mg) was chromatographed. : on a silica gel column eluting with EtOAc-hexane (1: 1, 4: 1 and 9: 1) to give the title compound as a semi-solid (347 mg, -73.2%). TLC (silica gel, EtOAc-hexane 4: 1): Rf = 0.28.

183 8 7927

Example 43 (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3- hydroxybutanoic acid, dilithium salt To a solution of the compound of Example 42 (347 mg, 0.7 mmol) in dioxane (8.3 mL) was added 1.0 N LiOH (2.4 mL, 2.4 mmol), and the mixture was stirred at 55 ° C (oil bath) under nitrogen for 45 minutes. The reaction mixture was evaporated to dryness and dried under reduced pressure. The resulting semi-solid was chromatographed on an HP-20 resin column (2.5 cm x 7.5 cm) eluting with steam distilled water (350 ml) and water-methanol (50:50, 250 ml). The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The product was dissolved in steam distilled water and the solution was lyophilized to give the title compound as a white solid by freeze-drying (338 mg, 97.5%). TLC (silica gel, iPrOH-NH 4 OH- 2 O 7: 2: 1): 20 Rf = 0.50.

Elemental analysis (C24H22FL2N2O5 * 1'95H2 ° *:

Calculated: 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 (400 MHz, CD 3 OD): δ 1.45 (d, 6H, J = 7 Hz), δ 1.89 - 2.05 (m, 2H), 2.38 ( dd, 1H, J = 9.15 Hz), 2.52 (dd, 1H, J = 4.15 Hz), 3.06 (septet, 1H, J = 7 Hz), 4.48 (m , 1H), 7.16 - 8.11 (m, 9 H)

Example 44 (S) -4- [2- [3- (4-fluorophenyl) -5- (1-methyl-ethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid , methyl ester; T: A) (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4 - [[2- (3- (4-fluorophenyl) -5- (1-methylethyl) -1- phenyl-1H-pyrazol-4-yl-ethyl / methoxyphosphinyl-35-butanoic acid, methyl ester - *: · To a solution of the compound of Example 42, Part I (1.0 g, 1.36 mmol) in dry methanol (184,87927) ( 72 ml), 10% Pd / C catalyst (250 mg) was added, and the mixture was hydrogenated in a Parr hydrogenator at a pressure of about 2.8 bar overnight. The reaction mixture was filtered through diatomaceous earth, and the clear filtrate was evaporated to dryness to give the title compound as a homogeneous oil (1.0 g, 100% crude yield). TLC (silica gel, hexane-acetone 7: 3):

Rf = 0.27.

B) (S) -4H-2- [3- (4-fluorophenyl) -5- (1-methyl-10-ethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid , methyl ester

To a solution of the compound prepared in Part A (1.05 g, 1.41 mmol) in dry tetrahydrofuran (14.0 mL) was added sequential glacial acetic acid 15 (334 μL, 5.83 mmol) and 1.0 M (C (Hg) THF in NF (4.46 mL, 4.46 mmol), and the mixture was stirred at room temperature under argon for about 19 hours. The reaction mixture was diluted with ice water (28 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with saturated NaHCO 3 (15 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. Crude product mixture: (1.14 g) was chromatographed on silica gel. on a column (Baker, mesh 60-200, 150 ml) eluting with 25 columns of EtOAc-hexane mixtures (2: 1, 4: 1 and 9: 1), ethyl acetate and acetone to give the title compound; as a semi-solid (623.5 g, 88.0%). TLC (silica gel, EtOAc-hexane 4: 1): Rf = 0.18.

Example 45 (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] hydroxy] phosphinyl] -3 -hydroxybutanoic acid, dilithium salt

To a solution of the compound of Example 44 (623.5 mg, 1.24 mmol) in dioxane (14.7 mL) was added 1.0 N LiOH (4.28 mL, 4.27 mmol) under nitrogen, I: 185 87 927 and the mixture was heated at 55 ° C (oil bath) for 2 hours and then stirred at room temperature for about 20 hours. The reaction mixture was evaporated to dryness, dried under reduced pressure and chromatographed on an HP-20 resin-5 column (2.5 cm x 15 cm) eluting the column with steam-distilled water (750 ml) and aqueous CH 2 OH mixtures (90:10, 500 ml; 80:20, 500 ml; and 50:50, 500 ml). The desired fractions were combined and evaporated to dryness to give the desired product (560 mg, 92.8%). TLC (si-10 silica gel, iPrOH-NH 4 OH-O 2 mixture 8: 1: 1): Rf = 0.42.

Elemental analysis (C24H26FLi2N2 ° 5P'1'16H20 'effective M = 507.197)

Calculated: 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 (400 MHz, CD 3 OD): δ 1.30 (d, 6 H, J = 7 Hz), 1.60 - 1.78 (d, 4 H), 2.36 (m , 2H), 2.96-2.99 (m, 2H), 3.14 (m, 1H), 4.26 (m, 1H), 7.14-7.68 (m, 9H) ) Example 46 (S) -4 - [[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester: A) 2- (4-fluorophenyl) -1-phenyl-ethanone

For a suspension containing magnesium turnings:. 25 (928 mg, 38 mmol) in dry ether (38 mL) argon. below, 4-fluoro was added dropwise over 45 minutes. . ribenzyl bromide (5.3 mL, 42 mmol) with no-; ; that the mixture boiled gently under reflux. After the addition was complete, the mixture was refluxed for an additional 30 minutes, cooled to room temperature: and a solution of benzonitrile (· 2.96 mL, 29 mmol) in dry ether (5 mL) was added. The mixture was stirred at room temperature for 4.5 hours, slowly poured into cold 10% HCl (40 mL), and the resulting suspension was extracted with ether (5 x 50 mL) and ethyl acetate (2 x 100 mL). The combined organic extracts were washed with saturated NaHCO 3 (50 mL) and saturated NaCl (50 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product (9.8 g) was purified by chromatography on a silica gel column (Baker, mesh number 60-200, 400 ml) eluting the column with Cl 2 Cl 2 -hexane mixtures (1: 4 and 1: 2). The desired fractions were combined and evaporated to dryness to give the title compound 10 as a white solid (3.29 g), mp 106-108 ° C. (2.60 g of additional product was obtained from other fractions containing some starting material to give a total yield of 94.8%). TLC (silica gel, CH 2 Cl 2 -hexane 1: 1): Rf = 0.60.

15 Elemental analysis (C ^ H ^ FO):

Calculated: C, 78.49? H, 5.18; F, 8.87 Found: C, 78.22; H, 5.22; F, 9.21

Mass spectrum: 215 (M + H) + B) 2- (4-fluorophenyl) -1-phenylethanone, (1-20 methylethyl) hydrazone

To a solution of the compound prepared in Part A (4.45 g, 21 mmol) in a mixture of 95% ethanol (34 mL): and glacial acetic acid (0.74 mL) was added isopropylhydrazine (3.63 mL, ca. 42 mmol), and the mixture was heated at 80 ° C (oil bath) under N 2 for 1.4 h.

\ TLC showed some starting material; . further isopropylhydrazine (2.0 mL, ca. 23 mmol) was added to the reaction mixture and the mixture was heated at 80 ° C (oil bath) for an additional 1 to 30 hours. The reaction mixture was cooled to room temperature, evaporated on a rotary evaporator to remove most of the solvent and then diluted with dichloromethane (200 ml). The organic solution was washed with saturated NaCl solution (25 mL), imaged (anhydrous MgSO 4), filtered and evaporated to dryness. The resulting yellow oil was dissolved in toluene (150 ml) and the solvent evaporated to give the title compound as a crude product (5.63 g) containing some starting material and very small amounts of the other two ingredients as impurities. TLC (silica gel, 1: 1 mixture of Cl 2 Cl 2 -hexane-5): Rf = 0.28.

Isopropylhydrazine was prepared as follows: To hydrazine hydrate (48.4 mL, 1.0 mol) kept under H 2 was added iodopropane (10.3 mL, 0.10 mol) over 2.0 h. The mixture was stirred at 60 ° C (oil bath) for 3 hours, cooled and extracted with ether (250 ml) for 20 hours (liquid-liquid extractor). The ether extraction solution was evaporated to give isopropylhydrazine (5.63 ml or 5.3 g).

15 C) Acetic acid, 2- [2- (4-fluorophenyl) -1-phenylethylidene] -1- (1-methylethyl) hydrazide

A mixture of the crude compound prepared in Part B (5.63 g, ca. 21 mmol) and triethylamine (5.85 mL, 42 mmol) in dry toluene 20 (210 mL) was cooled to 0 ° C (ice-salt bath). ) and acetyl chloride (1.86 mL, 26.3 mmol) was added. The reaction mixture was stirred for 1.5 hours to give:. while gradually warming to room temperature, it was diluted with ether (700 mL) and filtered.

The clear filtrate was dried (anhydrous Na 2 SO 4), filtered and evaporated to dryness, the residue was dissolved in toluene (300 ml) and the solution was evaporated. The resulting semi-solid (7.1 g) was chromatographed on a silica gel column (Baker, mesh 60-200, 400 ml) eluting with 30 column C 1 -C 4 hexane mixtures (1: 1 and 2: 1). 1 H and CH 2 Cl 2 -CH 2 -OH (9: 1) to give the title compound as a crude product (4.11 g). The crude product was rechromatographed on a second silica gel column eluting column 35 with EtOAc-hexane (4: 1). The desired fractions were combined and evaporated to dryness to give the title compound as a thick yellow oil (3.89 g). TLC (silica gel, EtOAc-hexane 1: 1): Rf = 0.47.

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

To a solution of the compound prepared in Part C (1.50 g, 4.80 mmol) in bis (2-methoxyethyl) ether (48 mL) was added solid potassium hydroxide (615 mg, 10.96 mmol), and the mixture was heated. At 80 ° C (oil bath) for 2.0 hours. Another portion of potassium hydroxide (700 mg, 12.5 mmol) was added to the reaction mixture, and the mixture was heated at 80 ° C for 2 hours and then stirred at room temperature for 16 hours. The mixture was poured into water (300 ml) and extracted successively with ether (3 x 150 ml) and ethyl acetate (2 x 100 ml). The organic solutions were combined, washed with cold 3% H 2 (500 mL) and saturated NaCl (2 x 100 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product 20 (3.5 g) was purified by chromatography on a silica gel column (Baker, mesh 60-200, 500 ml) eluting the column with EtOAc-hexane (1: 4) to give the title compound as a cream solid (1.33 g). , 94.3%), mp 135-137 ° C.

TLC (silica gel, EtOAc-hexane 1: 4):

Rf = 0.63.

E) 4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazole-5-carboxaldehyde

A mixture of CuSO 4 · 5 ^ 0 (2.21 g, 8.85 mmol) and potassium persulfate (9.53 g, 35.3 mmol) in acetonitrile (65 mL) and water (39 mL) , was heated to 65 ° C (oil bath) under and added. the compound prepared in Part D (2.6 g, 8.83 mmol) was adjusted. The temperature of the bath was slowly raised to 35 to 75 ° C, the mixture was kept at 75 ° C for 40 minutes, and then cooled to room temperature using a water-189,87927 bath. The reaction mixture was diluted with dichloromethane (45 mL), stirred for 10 minutes and decanted, and the aqueous suspension was extracted with dichloromethane (3 x 45 mL). The combined organic extracts were washed with saturated NaCl solution (2 x 30 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (2.75 g) was chromatographed on a silica gel column (LPS-1) eluting with EtOAc-hexane (1: 9) to give the title compound as a solid (1.57 g, 57.7%). TLC (silica gel, 1: 4 EtOAc-hexane):

Rf = 0.72.

F) 5- (2,2-Dibromoethenyl) -4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazole A mixture containing the compound prepared in Part E (1.75 g). , 5.68 mmol) and triphenylphosphine (4.6 g, 16.8 mmol) in dry dichloromethane (27.0 mL), cooled to -5 to -10 ° C (ice-salt bath) under argon, added dropwise. a solution of α1-20 chicken containing carbon tetraborimide (2.82 g, 8.42 mmol) in dry dichloromethane (9 mL) and stirred at -10 ° C for 20 minutes. Reaction mixture:,. warmed to room temperature, poured into sat

NaHCO 3 (9.0 mL) and extracted with dichloromethane! 25 (3 x 50 mL). The combined organic extracts were washed with saturated NaHCO 3 (10 mL) and saturated NaCl (10 mL), dried (anhydrous MgSO 4), filtered and evaporated.

The crude product was chromatographed on silica gel using C1-C4-hexane mixtures (1: 0 and 1: 4) as eluents. The desired fractions were combined to give the title compound (2.35 g, 91.4%) as an oil. TLC (silica gel, 1: 1 CH 2 Cl 2 -hexane): Rf = 0.32.

1 ,. 87927 G) 5-Ethynyl-4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazole

A solution of the compound prepared in Part F (1.89 g, 4.08 mmol) in dry tetrahydrofuran 5 (7.6 mL) was cooled to -78 ° C (carbonic acid-acetone bath), and 1.6 M was added dropwise under argon. A hexane solution of M n-BuLi (5.2 mL, 8.18 mmol, 2 eq), and the mixture was stirred at -78 ° C for 1 h 20 min. At -78 ° C, 25% NH 4 Cl (11.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with saturated NaCl (15 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (1.77 g) was chromatographed on a silica gel column eluting with CH 2 Cl 2 -hexane (1: 4 and 1: 1) to give the title compound (648 mg) and mixed fractions containing the title compound and Part F prepared compound. The mixed fractions 20 were combined with the product from the second batch (490 mg of the compound prepared in 1.1 mmol of Part F) and chromatographed on a second column eluting with CH 2 Cl 2 -hexane (1: 9). The desired fractions were combined and evaporated to dryness to give the title compound as an oil (1.02 g, recovered starting material with a corrected yield of 71.5%).

‘! H) (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4- (7Z4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H- Pyrazol-5-yl-ethynyl7-methoxyphosphinyl-7-butanoic acid, methyl ester

A solution of the phosphonic acid monomethyl ester (2.341 g, 5.01 mmol) of Example 1, Part F and trimethylsilylethylamine (1.90 mL, 10 mmol) in dry dichloromethane (9.5 mL) was stirred at room temperature. at room temperature under argon for 1 hour. The mixture was evaporated to dryness and re-azeotropically with dry benzene (15 ml) and dried under reduced pressure. The viscous oil was redissolved in dry dichloromethane (9.5 mL), DMF (1 drop) was added to the solution, and cooled to -10 to 0 ° C (ice-salt bath), and oxalyl chloride (480 μL) was added dropwise. , 5.47 mmol). Strong gas evolution was observed, and the dark yellow solution was stirred at -10 to 0 ° C for 15 minutes and then at room temperature for 10 hours. The reaction mixture was evaporated to dryness and re-azeotroped with benzene (18 ml) and dried under reduced pressure.

A solution of the compound prepared in Part G (1.016 g, 3.34 mmol) in dry tetrahydrofuran (8 mL) was cooled to -78 ° C under argon (carbonic acid-ice-acetone bath), 1.6 M was added. A hexane solution of n-BuLi (2.1 mL, 3.36 mmol), and the mixture was stirred at -78 ° C for 1.0 h. The phosphono-chloridate prepared above was dissolved in dry tetrahydrofuran (8 mL) and cooled to -78 ° C under argon (carbonic acid-ice-acetone bath), and a solution of acetylene anion was added dropwise via tube, keeping both; solutions at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ° C for 1.0 h, 25% NH 4 Cl (9 mL) was added dropwise, and then the mixture was warmed to room temperature. The mixture was extracted with ether (3 x 100 mL), and the combined organic extracts were washed with 25% NH 4 Cl (10 mL) and saturated NaCl (25 mL), dried. . 30 (anhydrous MgSO 4), filtered and evaporated to dryness.

; : The crude product was chromatographed on a silica gel column eluting with acetone-hexane (1: 9 and 1: 4) to give the title compound as an oil (1.595 g, 64.8%). TLC (silica gel, 3: 7 acetone-hexane): Rf = 0.43.

192 8 7 927 I) (S) -4 - [[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid , methyl ester

To a solution of the 1-diacet prepared in Part H (1.0 g, 1.36 mmol) in dry tetrahydrofuran (13 mL) was added sequential glacial acetic acid (320 μL, 4.46 mmol) and 1 M (CH 2 Cl 2). ) NF (4.26 mL, 4.26 mmol), and the mixture was stirred at room temperature under argon overnight. The reaction mixture was cooled to 0 ° C (ice-salt-10 bath), 5% KHSO 4 (15 mL) was added, and the mixture was extracted with ethyl acetate (3 x 125 mL). The combined organic extracts were washed with 5% KHSO 4 (2 x 25 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product (1.06 g) was dissolved in a mixture of ether (23 ml) and tetrahydrofuran (18 ml) and cooled to 0 ° C (ice-salt bath), excess diazomethane in ether was added and the mixture was stirred at 0 ° C for 4 hours. . Glacial acetic acid was added dropwise to the reaction mixture, and the mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromatographed on a silica gel column eluting with acetone-hex. with a slurry mixture (1: 2). The desired fractions were combined and evaporated to dryness to give the title compound as an oil (330 mg, 48.7%). TLC (silica gel, EtOAc-hexane 4: 1): Rf = 0.23.

Y; Example 47 (S) -4- [4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethynyl] hydroxyphosphinyl. . 30 3-hydroxybutanoic acid, dilithium salt

To a solution of the compound of Example 46 (330 mg, 0.66 mmol) in dioxane (7.8 mL) was added 1 N LiOH (2.29 mL, 2.29 mmol), and the mixture was stirred. - stirred at 55 ° C (oil bath) under argon for 1.5 hours to 35 hours and then at room temperature for 16 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure.

193 87927

The crude product was chromatographed on an HP-20 resin column (2.5 cm x 25 cm) eluting with steam distilled water (750 mL) and aqueous CH 2 OH (90:10, 500 mL; 80:20, 500 ml, and 50:50, 500 ml). The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The solid product was dissolved in steam-distilled water and the solution was lyophilized to give the title compound as a volatile solid freeze-dried product (275 mg, 99.5%). TLC (silica gel, iPrOH-10 NH 4 OH-H 2 O 8: 1: 1): Rf = 0.57.

Elemental analysis (effective molecular weight of C24H22FLi2N2 ° 5P * 2.28H2O = 523.310)

Calculated: 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; Δ, 5.99 δ and (KBr): 2172 (C .01 (m, 2 H), 2.37 (dd, 1H, J = 8 Hz), 2.50 (dd, 1H, J = 4 Hz), 4.40 (m, 1H), .01 (septet, 1H, J = 7 Hz), 7.04-7.39 (m, 9H) Example 48 (S) -4- / 72- / 4- (4-fluorophenyl) -1- (1-Methyl-ethyl) -3-phenyl-1H-pyrazol-5-yl-ethyl-7-methoxy-phosphinyl-3-hydroxybutanoic acid, methyl ester • A) (S) -3- [771,1-dimethylethyl) -diphenylsilyl] -:: 25 oxy7 -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] methoxyphosphinyl] butanoic acid, methyl ester

To a solution of the compound of Example 46, Part H (608 mg, 0.85 mmol) in dry methanol. . In 30 l (63 mL), 10% Pd / C catalyst was added; (155 mg), and the mixture was hydrogenated in a Parr hydrogenator at room temperature and about 2.8 bar overnight. The suspension was diluted with methanol (50 ml) and filtered through a pad of diatomaceous earth using a Millipore filter. washed well with methanol. The clear filtrate was evaporated to dryness and dried under reduced pressure to give the title compound as a homogeneous oil (559 mg, 90.9%) having the appropriate 1.1.1 H-NMR and C-NMR spectral data. TLC (silica gel, acetone-hexane 3: 7, UV): Rf = 0.20.

5 B) (S) -4H-2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester

To a solution of the compound prepared in Part A (559 mg, 0.75 mmol) in dry tetrahydrofuran (7.5 mL) was added sequential glacial acetic acid (176 μΐ, 3.0 mmol, 4 eq.) And 1.0 M A hexane solution of (C 4 H 9) 2 NF (2.34 mL, 2.34 mmol, 3.1 eq.) Under nitrogen was stirred at room temperature for about 20 hours. The reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (3 x 70 mL), and the combined organic extracts were washed with saturated NaHCO 3 (10 mL) and saturated NaCl (20 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (580 mg) was chromatographed on a silica gel column eluting with EtOAc-hexane (1: 4), EtOAc and acetone-hexane (4: 1). The desired fractions were combined, evaporated to dryness and dried under reduced pressure to give the title compound as a homogeneous oil (337 mg, 89.4%). TLC (silica gel, acetone: hexane 1: 1, UV): Rf = 0.18.

: Example 49: Y (S) -4H- [2- [4- (4-fluorophenyl) -1- (1-methyl-ethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt. . To a solution of the compound of Example 48 (337.0 mg, 0.67 mmol) in dioxane (8.0 mL) was added 1.0 N LiOH (2.32 mL, 3, 5 eq.), And the mixture was stirred at 55 ° C (oil bath) for 3.0 hours and then at room temperature for 20 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure (pump, 1 hour). The crude product was chromatographed on an HP-20 resin column (2.5 cm x 20 cm) eluting with steam distilled water (500 mL) and aqueous CH 3 OH mixtures (90:10, 500 mL; 80:20, 500 mL; and 50:50, 500 mL). The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The resulting solid was dissolved in steam-distilled water, the solution was frozen and lyophilized overnight to give the title compound as a fluffy white freeze-dried product (280.4 mg, 82.4%) having the appropriate analytical, mass spectral, IR spectral and 1 H-NMR spectral data. TLC (silica gel, iPrOH-NH OH-H O mixture 8: 1: 1, UV: Rf = 0.45. In addition, 24 g of slightly impure product were obtained from the other fractions.

Elemental analysis (C24H26FLi2N2O5P * 1.19H2O, effective molecular weight = 507.733)

Calculated: C, 56.77; H, 5.63; N, 5.51; F, 3.74; P, 6.10 Found: C, 52.77; H, 5.69; N, 5.49; F, 3.91; P, 6.50 IR (KBr, No. 69377): 1589 (C = O of COO_) 1 H-NMR (400 MHz, CD 3 OD): δ 1.55 (d, 6 H, J = 7, H ), 1.64 - 1.84 (m, 4 H, -, Hc + Hd), 2.34 (m, 2 H, -, H), 2.91 (pseudoquartet, 2 H, -, He) , 4.25 (m, 1H, -, Hg), 4.77 (septet, 1H, partially masked by HOD signal: HOD below, -, H 2), 7.05 - 7.32 (m, 9 H, aromatic protons): ·: 25 Example 50 (S) -4 - [(N- (4-fluorophenyl) -4- (1-methylethyl) -: 2-phenyl-1H-imidazol-5-yl] ethenyl] methoxyphosphinyl ·. 17-3-hydroxybutanoic acid, methyl ester A) N-benzoylvaline. . A solution of valine (20 g, 0.17 mol) in tetrahydrofuran (20 mL) in 2 N NaOH (111 mL) was cooled to 10 ° C under nitrogen (ice water bath) and benzoyl chloride was added dropwise. (23.8 ml, · 0.21 mol). The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then cooled back to 0 ° C (ice-salt bath) and concentrated sulfuric acid (8.0 ml) was added dropwise.

The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water (100 ml) and saturated NaCl (50 ml), dried (anhydrous 5 MgSO 4), filtered and evaporated to dryness to give the title compound as a solid (41.97 g, 100% crude yield). . A small amount (260 mg) of the product was recrystallized from ethyl acetate and petroleum ether to give the title compound as an analytical sample (205 mg), m.p. 132-133 ° C. TLC (silica gel, acetone-hexane 1: 1): Rf = 0.10.

Elemental analysis:

Calculated: C, 65.14; N, 6.83; N, 6.33 Found: C, 64.81; N, 6.79; N, 6.29

Mass spectrum: 222 (M + H) + B) N- (1-Acetyl-2-methylpropyl) benzamide To a mixture of the compound prepared in Part A (41.7 g, about 0.17 mol) and triethylamine 20 (47.3 ml, 0.34 mol) in acetic anhydride (48 ml), 4-dimethylaminopyridine (2.07 g, 0.017 mol) was added in two portions, and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was cooled to 0 ° C (ice-salt bath), methanol was added, and the mixture was stirred for 30 minutes. The light brown precipitate formed was filtered off, washed well with water (1.1 L) and redissolved in dichloromethane (750 mL). The resulting solution was dried (anhydrous MgSO 4), filtered and evaporated to dryness. 30 crude product (35.9 g) was obtained.

The crude product was dissolved in ether (1.3 L), the solution was filtered to remove insoluble solids, and the clear filtrate was concentrated to a volume of about 300 mL and cooled in an ice bath. The cream-colored title compound (21.35 g, melting point 88-90 ° C) was isolated by filtration. Purification of the solid obtained by evaporation of the filtrate on a silica gel column (Baker, mesh number 60-200, 600 ml) eluting the column with EtOAc-hexane mixtures (1: 7 and 1: 4) gave an additional 4.77 g. title yh-5. A small amount of the title compound was recrystallized from ether, m.p. 88-99 ° C.

TLC (silica gel, acetone-hexane 1: 1):

Rf = 0.75.

Elemental Analysis: Calculated: C, 70.20; H, 7.81; N, 6.39 Found: C, 70.79; H, 7.68; N, 6.31 Mass spectrum: 220 (M + H) + C) N- (1- (1- (T4-fluorophenyl) imino) ethyl] -2-methylpropyl] benzamide 15 To a solution of the compound prepared in Part B (25.0 g, 0.114 mol) in dry toluene (250 ml), 4-fluoroaniline (12 ml, 0.127 mol, 1.11 eq.) And p-toluenesulfonic acid hydrate (125 mg) were added, and the reaction mixture was refluxed under N 2 under a Dean-Stark trap. 20 using 20 hours. The reddish brown solution was cooled to -10 ° C (ice-salt bath) and crystallized as such in the next step of the reaction series.

:: D) 1- (4-fluorophenyl) -5-methyl-4- (1-methylethyl) -2-phenyl-1H-imidazole:: 25 A cooled solution of the compound prepared in Part C (about 0.114 mol) was diluted to -10 At 0 ° C (ice-salt: bath) with dry dichloromethane (200 mL) and phosphorus pentachloride (47.5 g, 0.228 mol) was added dropwise. The cream-colored suspension was heated, refluxed under N 2 for 2.5 hours, cooled to room temperature and slowly poured into a mixture of ice (400 g) and 50% NaOH (105 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 x 200 ml). The combined organic extracts were washed with saturated NaCl solution (2 x 100 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

198 87927

The crude mixture (35.0 g) was chromatographed on a silica gel column (Baker, mesh 60-200, 600 ml) using EtOAc-hexane mixtures (1: 9 and 1: 4) as eluent to give the title compound 5 as white needles (29 , 24 g, 87%), mp 146-148 ° C. TLC (silica gel, EtOAc-hexane 1: 4): Rf = 0.40.

Elemental analysis:

Calculated: 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 Mass spectrum: 295 (M + H) + E) 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazole-5-carboxaldehyde

A mixture of copper (I) sulfate hydrate 15 (8.50 g, 34.0 mmol) and potassium persulfate (36.8 g, 0.136 mol) in a mixed solvent of acetonitrile (250 mL) and water (150 mL) was heated to 65 ° C. (oil bath) under N, and the compound prepared in Part D (10 g, 34.0 mmol) was added. The reaction mixture was slowly heated to 75 ° C and maintained at that temperature for 40 minutes, after which it was cooled to room temperature. The solution was separated from the solids by decantation, and both the aqueous phase and the solid were extracted with dichloromethane (3 x 200 mL). The combined: organic extracts were washed with saturated NaCl solution (2 x 100 mL), dried (anhydrous MgSO 4), filtered. The crude product (17.0 g) was purified by chromatography on a silica gel column (Baker, mesh 60-200, 600 ml) eluting with column: 30 EtOAc-hexanes (5:59 and 1: 7) to give the title compound. compound as a solid (6.27 g, 59.8%).

200 mg of the title compound was recrystallized from Et 2 O-hexane to give an analytical sample (76 mg), mp 160-161 ° C. TLC (silica gel, EtOAc-hexane 1: 4): Rf = 0.34.

i 199 8 7 927

Elemental analysis:

Calculated: C, 74.01; H, 5.56; N, 9.09; F, 6.16 Found: C, 73.98; H, 5.68; N, 9.04; F, 6.09 Mass spectrum: 309 (M + H) + 5 F) 5- (2,2-dibromoethenyl) -1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazole

A solution of the compound prepared in Part E (1.75 g, 5.68 mmol) and triphenylphosphine (4.46 g, 16.8 mmol) in dry dichloromethane (27.0 mL) was cooled to -5-10 ° C. C (ice-salt bath) under argon, and a solution of carbon tetrabromide (2.82 g, 8.42 mmol) in dry dichloromethane (9 mL) was added dropwise over 5 minutes. The mixture was stirred at -10 ° C for 20 minutes, then poured into saturated sodium bicarbonate (9.0 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with saturated NaHCO 3 (10 mL) and saturated NaCl (10 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (8.07 g) was purified by chromatography on a silica gel column eluting with column mixtures of CH 2 Cl 2 / hexane (1: 7 and 1: 4) to give the title compound as a solid (2.35 g, 91.4%). ).

100 mg of the compound ki- prepared in this Part F; 25 was recrystallized from Et 2 O-hexane to give an analytical sample (49 mg), mp 164-165 ° C. TLC (silica gel, 1: 1 CH 2 Cl 2 -hexane): Rf = 0.32.

Elemental analysis:. . Calculated: C, 51.75; H, 3.69; N, 6.04; F, 4.09; Br, 34.43 Found: C, 51.80; H, 3.71; N, 6.02; F, 4.08; Br, 34.25 Mass spectrum: 465 (M + H) + G) 5-ethynyl-1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazole 35 Solution containing The compound prepared in Part F (3.065 g, 6.60 mmol) in dry tetrahydrofuran 200 87927 (12.5 mL) was cooled to -78 ° C (carbonic acid-ice-acetone bath) and added under argon. 6 M hexane solution of n-BuLi (8.4 mL, 13.4 mmol). The reaction mixture was stirred at -78 ° C for 1 h 20 min, 25% NH 4 Cl (18 mL) was added dropwise, and the mixture was warmed to room temperature and extracted with ether (3 x 100 mL). The combined organic extracts were washed with saturated NaCl solution (25 ml), dried (anhydrous MgSO 4), filtered and evaporated to dryness. The crude product (2.08 g) was purified by chromatography on a silica gel column (Baker, mesh 60-200, 400 ml) eluting the column with EtOAc-hexane (1: 9 and 1: 4). 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 the compound prepared in this Part G was recrystallized from hexane to give an analytical sample (59 mg), m.p. 148-150 ° C. TLC (silica gel, EtOAc-hexane 1: 4): Rf = 20 0.60.

Elemental analysis:

Calculated: C, 78.92; H, 5.63; N, 9.21; F, 6.24 Found: C, 78.95; H, 5.83; N, 9.07; F, 6.63 Mass spectrum: 303 (M-H) -25H) (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4- [7H- (4-fluorophenyl) -4- (1-Methylethyl) -2-phenyl-1H-imidazol-5-yl-ethynyl7-methoxyphosphinyl-7-butanoic acid, methyl ester

A mixture of crude phosphonic acid monomethyl ester from Example 1, Part F (3.54 g, 7.86 mmol) and trimethylsilyldiethylamine (2.70 mL, 14.21 mmol) in dry dichloromethane was stirred at room temperature under argon for 1.0 h. The mixture was evaporated to dryness and re-azeotropically with dry benzene (26 ml) and dried under reduced pressure. The viscous oil was redissolved in dry dichloro-201,87927 methane (14 ml), DMF (2 drops) was added to the solution, the mixture was cooled to -10 ° C (ice-salt bath), and oxalyl chloride (0.68 ml, 7.79 mmol). Strong gas ke-5 incorporation was observed and the yellowish brown solution was stirred at -10 ° C for 15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness and re-azeotroped with dry benzene (826 ml) and dried under reduced pressure.

A solution of the compound prepared in Part G (1.43 g, 4.7 mmol) in dry tetrahydrofuran (11.5 mL) was cooled to -78 ° C (carbon dioxide-ice-acetone bath) under argon, 1.6 A hexane solution of M n-BuLi (2.94 mL, 4.7 mmol) and soes was stirred at -78 ° C for 30 minutes. The phosphonochloridate prepared above was dissolved in dry tetrahydrofuran (11.5 mL) and cooled to -78 ° C (dry ice-acetone bath) under argon, and a solution of acetylenic anion was added dropwise via tube, keeping both solutions at -78 ° C. : as fathers throughout the addition. The reaction mixture was stirred at -78 ° C for 30 minutes, 25% NH 4 Cl (13 mL) was added dropwise and allowed to warm to room temperature, then extracted with ether (3 x 130 mL). The combined organic extracts were washed with 25% NH 4 Cl (15 mL) and saturated NaCl (30 mL), dried (anhydrous MgSO 4), filtered and evaporated under reduced pressure.

The crude mixture (4.3 g) was chromatographed on a silica gel column eluting with acetone-hexane (5:95 and 1: 4). 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 (silica gel, hexane-acetone-35 7: 3): Rf = 0.13.

202 87927 X) (S) -4- [7 / 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester

To a solution of the compound h-5 prepared in Part H (974 mg, 1.32 mmol) in dry tetrahydrofuran (13.0 mL) was added sequential glacial acetic acid (310 μΐ, 5.29 mmol) and 1 M (CH 2 Cl 2). ) NF (4.14 mL, 4.14 mmol), and the mixture was stirred at room temperature under argon overnight. The reaction mixture was cooled to 0 ° C (ice water-10 bath), 5% KHSO 4 (14 mL) was added, and the mixture was extracted with ethyl acetate (3 x 125 mL). The combined organic extracts were washed with 5% KHSO 4 (16 mL) and saturated NaCl (35 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product (1.48 g) was dissolved in a mixture of ether (22 ml) and dry tetrahydrofuran (17 ml), the solution was cooled to 0 ° C (ice-water bath), excess diazomethane in ether was added and the mixture was stirred at 0 ° C 4. 0 hours. Glacial acetic acid was added dropwise to the reaction mixture, and the mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromatographed on a silica gel column eluting with EtOAc-hexane mixtures (1: 1 and 4: 1). The desired fractions were combined to give the title compound as a solid (304 mg, 46.2%). TLC (silica gel, EtOAc-hexane 4: 1): Rf = 0.33.

·. ' : Example 51 (S) -4- [7H- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-4-yl] ethynyl] hydroxyphosphinyl-30-7-3-hydroxybutanoic acid, dilithium salt

To a solution of the compound of Example 50 (304 mg, 0.6 mmol) in dioxane (7.1 mL) was added 1 N LiOH (2.03 mL, 2.08 mmol), and the mixture was stirred at 55 ° C: (oil bath) under argon for 1.5 hours 35 and then at room temperature for 24 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure.

203 87927

The crude product was chromatographed on an HP-20 resin column (2.5 cm x 18 cm) eluting with steam-distilled water (750 ml) and aqueous CH 2 OH (90:10, 500 ml; 80:20, 500 ml, and 50:50, 500 ml). The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The solid product was dissolved in steam distilled water and lyophilized to give the title compound as a useful solid freeze-dried product (257 mg, 84.1%). Other fractions: TLC silica gel, 10 iPrOH-NH 4 OH- (O: 8: 1: 1): Rf = 0.38.

Elemental analysis (£ 24Η22ΡΙ ^ 2Ν205Ρ * ^ '52 ^ 0)

Calculated: 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 (400 MHz, CD-iOD): δ 1.37 (d, 6 H, J = 7 Hz), δ 1.79 (m, 2 H), 2.31 (dd , 1H, J = 9.15 Hz), 2.43 (dd, 1H, J = 4.15 Hz), 3.24 (septet, 1H, J = 7 Hz), 4.26 (m, 1H), 7.17-7.35 (m, 9H) IR (KBr) 2163 (C + C), 1590 (C = O) cm -1 Example 52 20 (S) -4 - // 2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester A) (S) -3- [71/1-dimethylethyl) . butanoic acid, methyl ester

To a solution of the ferrous compound of Example 50 Part H (839 mg, 1.14 mmol) in dry methanol (86 mL) was added 10% Pd / C catalyst (213 mg), and the mixture was hydrogenated. at room temperature Parr hydrogenation. : in the appliance at a pressure of approx. 2.8 bar overnight. The suspension was filtered through diatomaceous earth, and the clear filtrate was evaporated to dryness and dried under reduced pressure to give the title compound as a thick syrup (853 mg, 100% yield). TLC (silica gel, hexane-acetone 7: 3): Rf = 0.17.

204 87927 B) (S) -4- [4- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid , methyl ester

To a solution of the compound prepared in Part A (853 mg, ca. 1.14 mmol) in dry tetrahydrofuran (11.0 mL) was added sequential glacial acetic acid (270 μL, 4.60 mmol) and 1.0 M (CH 2 Cl 2). Hg) • NF in hexane (3.62 mL, 3.62 mmol), and the mixture was stirred at room temperature under argon overnight. The reaction mixture was diluted with ice (25 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with saturated NaHCO 3 (15 mL) and saturated NaCl (25 mL), dried (anhydrous MgSO 4), filtered and evaporated to dryness.

The crude product (958 mg) was chromatographed on a silica gel column eluting with acetone-hexane (1: 1 and 4: 1). The desired fractions were combined, evaporated to dryness and dried under reduced pressure to give the title compound as a solid (443 mg, 77.0%). TLC (silica gel, acetone-hexane 1: 1): Rf = 0.13.

Example 53 '(S) -4 - [[2- [N- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] hydroxy] N-phosphinyl] -3- hydroxybutanoic acid, dilithium salt To a solution of the compound of Example 52 (443 mg, 0.88 mmol) in dioxane (10.5 mL) was added 1.0 N LiOH (3.05 mL, 3.09 mmol). , and the mixture was stirred at 55 ° C (oil bath) under argon. . 30 3.0 hours and then at room temperature for about 20 'hours. The reaction mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromatographed on an HP-20 resin column (2.5 cm x 20 cm) eluting with column-distilled water (750 mL) and aqueous CH 2 OH (90:10, 500 mL; 80:20). The desired chips were combined and evaporated to dryness to give 205 87927 of a solid which was dissolved in steam distilled water (30 ml) and the solution was freeze dried to give the title compound as a fluffy white solid (376.4 mg, 83, 9%) TLC (silica gel, iPrOH-NH 4 OH-5 I / O 8: 1: 1): Rf = 0.40.

Elemental analysis (C24H26FL1H2N2 ('> 5P * 0.841 ^ 0, effective molecular weight = 501.46)

Calculated: C, 57.43; H, 5.76; N, 5.69; F, 3.99; P, 6.08 Found: C, 57.48; H, 5.46; N, 5.59; F, 3.79; Ν, 6.18 δ IR (KBr): 1587 (C = O C = 0) cm -1 1H-NMR (400 MHz, CD 3 OD): δ (1.33 (d, 6 H, J = 7 Hz) , 1.46-1.61 (m, 4H), 2.30 (m, 2H), 2.76 (m, 2H), 3.13 (septet, 1H, J = 7 Hz), 4 .14 (m, 1H), 7.17-7.30 (m, 9H) Example 54 (S) -4 - [[2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethynyl] hydroxyphosphinyl] -3- hydroxybutanoic acid, dilithium salt A) N- (2,4-dimethylbenzylidene) benzeneamine Reference: U.S. Patent 4,375,475 (Merck), p. 39

The title compound was prepared as described in Example 1, Part A.

s, Φ I

: 25 B. N

f *

Oi "VV4": V: 1 ° JY3. .30 CH3 2 - -

Reference: U.S. Patent 4,375,475 (Merck), p. 39 ____: The title Pd complex was prepared as described in Example 1, Part B.

206 87 927 C) 2- (cyclohexylmethyl) -4,6-dimethylbenzaldehyde

Magnesium chips (1.44 g, 59.45 mmol) kept under argon were covered with dry Et 2 O 5 (15 mL) and sonicated for 5 minutes. Cyclohexylmethyl bromide (1.5 mL) was added to the Mg (O) chips, and sonication was continued (reflux began within 5 minutes). While continuing the sonication, dry Et 2 O (60 mL) and the remainder of the cyclohexylmethyl bromide dissolved in Et 2 O (5 mL) were added via addition funnel (a total of 9.12 mL, 65.3 mmol, cyclohexylmethyl bromide) was added. At the end of the addition, the sonication was continued for 15 minutes, after which the reaction mixture was refluxed for 40 minutes. This Grignard reagent was cooled to room temperature and then added via tube to a solution of the Pd complex prepared in Part B (5.55 g, 7.43 mmol) and triphenylphosphine (15.59 g, 59.45 mmol) at 20 ° C. stirred under an argon atmosphere at room temperature for 30 minutes. Upon addition of the Grignard reagent, the reaction mixture turned green and a precipitate formed. This solution was stirred at room temperature for 2 hours, after which 6 N HCl (37 mL) was added. This mixture was stirred for 1 hour and then filtered through a pad of diatomaceous earth formed on sintered glass to remove solids. The solid was washed with Et 2 O and the filtrate was treated on a rotary evaporator to remove volatiles. The resulting residue 30 was stirred in Et 2 O and the mixture was filtered as above. The filtrate was washed once with saturated NaCl solution, and the organic layer was dried over MgSO 4 to give 14.5 g of a brown oil. Purification by flash chromatography using 4% Et 2 O in hexane 35 as eluent gave 1.70 g of a clear oil (99% yield). · TLC (5% Et 2 O: 51 hexane, silica gel): Rf = 0.30.

207. 37927 IR (CHCl 3: 3030, 3008, 2926, 2853, 1679, 1606, 1448, 1147 cm -1 1H-NMR (270 MHz, CDCl 3): δ 10.51 (s, 1), 6.90 (s, 1 ), 6.85 (s, 1), 2.80 (d, 2, J = 6.0 Hz), 2.55 (s, 3), δ 2.30 (s, 3), 1.80 - 1.55 (m, 5), 1.55 - 1.30 (m, 1), 1.30 - 0.80 (m, 5)

Mass spectrum (CI, m / e): 231 (M + H) + D) 1- (cyclohexylmethyl) -2- (2,2-dibromoethenyl) -3,5-dimethylbenzene 10 Solution containing the alde prepared in Part C. - hyd (1.68 g, 7.30 ramol) in dry CH 2 Cl 2 (65 ml) under argon, cooled to 0 ° C. To this solution was added triphenylphosphine (6.13 g, 23.4 mmol) and the solution was stirred until all solids had dissolved. CBr 2 (3.63 g, II, 0 mmol) dissolved in CH 2 Cl 2 (20 mL) was added at 0 ° C. The reaction solution turned orange. The reaction mixture was stirred at 0 ° C for 1.5 h, after which saturated NaHCO 3 solution was added and the mixture was stirred vigorously. The aqueous layer was removed and extracted twice with CH 2 Cl 2. The organic solutions were combined, washed once with saturated NAHCO 3 solution and dried over MgSO 4. -.1 f Filtration and removal of the solvent gave 9.6 g of a brown solid. Purification by flash chromatography-25 using 100% hexane as eluent. yielded 2.52 g (90% yield) of a clear oil.

TLC (5% Et 2 O in hexane, silica gel):

Rf = 0.62, PMA.

IR (CHCl 3): 2925, 2852, 1608, 1472, 869 cm -1 1H-NMR (270 MHz, CDCl 3): δ 7.39 (s, 1), 6.87 (s, 1), 6.80 ( s, 1), 2.37 (d, 2, J = 6.3 Hz), 2.27 (s, 3),: 2.24 (s, 3), 1.70 (m, 5), 1 .45 (m, 1), 1.38 - 1.10 (m, 3), 0.90 (m, 2)

Mass spectrum (CI, m / e): 387 (M + H) + 208 87927 E) 1- (cyclohexylmethyl) -2-ethynyl-3,5-dimethylbenzene

The vinyl dibromide prepared in Part D (2.51 g, 6.5 nunol) was stirred in THF (30 mL) under argon, and the solution was cooled to -78 ° C. To a dibromide solution maintained at -78 ° C was added n-butyllithium (5.20 mL of a 2.5 M hexane solution) over 3 minutes. The resulting pink reaction mixture was stirred at -78 ° C. After the reaction mixture was kept at 10-78 ° C for 1.5 hours, saturated aqueous NH 4 Cl solution was added thereto, and the mixture was then warmed to room temperature. The aqueous layer was removed and extracted twice with Et 2 O and once with hexane. All organic layers were combined and dried over MgSO 4 to give, after filtration and removal of the solvent, 1.65 g of a brown oil. Purification by flash chromatography using hexane as eluent gave 1.39 g (95% yield) of the title acetylene. TLC (5% toluene in hexane, silica gel): Rf = 0.50 PMA.

IR (CHCl 3): 3305, 3007, 2924, 2852, 2096, 1607, 1470, 1448 cm -1 1H-NMR (270 MHz, CDCl 3): δ 6.86 (s, 1), 6.79 (s, 1 ),: 3.39 (s, 1), 2.63 (d, 2, J = 6.9 Hz), 2.63 (m, 6), • V. 1.20 (m, 3) , 1.00 (m, 2) 25 Mass spectrum (CI, m / e): 227 (M + H) +. ·, F) (S) -4- [2- (cyclohexylmethyl) -4.6 -di- 1. methylphenyl7ethynyl7methoxyphosphinyl7-3- / 7Tl, 1-; ; dimethylethyl) diphenylsilyl-7-oxybutanoic acid, methyl ester A solution of the acetyl-V'-lene prepared in Part E (1.36 g, 6.0 mmol) in dry THF (30 mL) ar-; :: under a gas atmosphere, cooled to -78 ° C. Here. ···. To the solution was added n-BuLi (2.4 mL of 2.5 M hexane).

solution), the reaction solution turned burgundy, and. It was stirred at -78 ° C for 1 hour, Part F of Example 1

Phosphonochloridate (4.68 g, 9.6 mmol) was stirred in dry THF (30 mL) and the solution was cooled to -78 ° C. The acetylene anion was then transferred via tube over 15 minutes to the phosphono-chloride solution. At the end of the transfer, the reaction mixture was stirred at -78 ° C for 1 hour, after which saturated NH 4 Cl was added and the mixture was warmed to room temperature. The THF was removed from the reaction mixture, and the residue was dissolved in Et 2 O and Et 2 O. The aqueous layer was extracted three times with Et 2 O. All Et 2 O extracts were combined, washed once with saturated NaHCO 3 solution and once with saturated NaCl solution, and then dried over MgSO 4. Filtration and removal of the solvent gave an orange oil which was purified by flash chromatography using EtOAc-hexane-toluene (3.5: 5: 1) as eluent. The title acetylene phosphinate (2.80 g, 70% yield) was obtained as a clear oil. TLC (hexane-toluene-EtOAc 5: 1: 4, silica gel): Rf = 0.37, PMA.

IR (CHCl 3): 3025, 3001, 2929, 2856, 2164, 1736, 1607, 1240, 1112, 1039, 823 cm -1 1 H-NMR (270 MHz, CDCl 3): δ J, 66 (m, 4) , 7.30 (m, 6), 6.87 (s, 1), 6.81 (s, 1), 4.66 (m, 1), 3.70 & 3.66 (doublets, 3, J = 14.3 Hz), 3.56 (s, 3), 2.95 (m, 1), 2.69 (m, 1), 2.50 (m, 3), 2.32 (m, 2), 2.30 (s, 3), 2.27 (s, 3), 1.60 (m, 6), 1.03 (m, 3), 1.02 (s, 9), 0 .95 (m, 2)

Mass spectrum (CI, m / e): 659 (M + H) + G) (S) -4 - [[2- (cyclohexylmethyl) -4,6-di-30-methylphenyl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester V : The acetylene phosphinate prepared in Part F (0.633 g, 0.96 mmol) was stirred in dry THF (14.0 mL) under argon at room temperature.

To the phosphinate solution was added glacial acetic acid (0.22 mL, 3.84 mmol) followed by dropwise addition of 210,87927 n-Bu 2 NF (2.62 mL of a 1.1 M THF solution) over 5 minutes. After stirring the reaction mixture at room temperature for 19 hours, ice water was added and the aqueous layer was extracted three times with EtOAc. The combined organic solutions were washed twice with saturated NaHCO 3 solution and once with saturated NaCl solution. The organic layer was dried over Na 2 SO 4 and filtered to give, after removal of the solvent, a yellow gum (0.658 g). Purification by flash chromatography using EtOAc as eluent gave the title alcohol (0.23 g, 65%) as a clear oil. TLC (acetone-hexane 6: 4, silica gel): Rf = 0.51, PMA.

IR (CHCl 3): 3450 (broad), 3005, 2926, 2852, 2164, 1733, 1607, 1448, 1439, 1039 cm -1 1 H-NMR (270 MHz, CDCl 3): ¢ 6.89 (s, 1), 6.82 (s, 1), 4.63 (m, 1), 3.88 & 3.87 (2 doublets, 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) 20 +

Mass spectrum (CI, m / e): 412 (M + H) H) (S) -4- [7 / 2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethynyl] hydroxyphosphinyl] -3-hydroxy; butanoic acid, dilithium salt. The diester prepared in Part G (0.212 g, 0.51 mmol) was stirred in dioxane (7 mL) and 1 N LiOH (1.5 mL) was added at room temperature.

. ' The reaction mixture was heated to 55 ° C, and 20 minutes; ; the resulting precipitate was dissolved by the addition of dioxane (5 ml) and water (4 ml). After keeping the reaction mixture at 55 ° C for 2 hours 30 minutes, it was warmed to room temperature, the solvent was removed: under reduced pressure and the resulting solid. was placed under reduced pressure for 15 minutes. The product was purified on an HP-20 resin column (3.0 cm x 19 cm) 35 using water (100 ml) as eluent and then MeOH-1 O (1: 1). Freeze-drying of the product gave 0.145 g (71%) of a white freeze-drying product. TLC (nPrOH-NH 4 OH-O 2 7: 2: 1, silica gel): Rf = 0.39, PMA.

IR (KBr): 3700-31300 (broad), 2922, 2850, 2167, 1590, δ 1447, 1179, 1076 cm -1 1H-NMR (400 MHz, D 2 O): δ $ 6.99 (s, 1), δ .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), 1.60 (in, 6), 1.14 (m, 3), 1.00 ( m, 2) Mass spectrum (FAB, m / e): 409 (M + H) +, 397 M - 2Li + H) +

Elemental analysis (C21H2705PLi2 1.722 ^ 0):

Calculated: C, 57.96; H, 7.05; P, 7.12 Found: C, 57.96; H, 7.18; P, 6.96 Example 55 4- [3- [2- (Cyclohexylmethyl) -4,6-dimethyl-phenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) (E) - [2- [2- (cyclohexylmethyl) ) -4,6-dimethyl-20-phenyl-ethenyl-phosphonic acid, dimethyl ester

A solution of dimethyl methylphosphonate (1.64 g, 13.2 mmol) in dry THF (20 mL) under argon was cooled to -78 ° C. To this solution, which was maintained at -78 ° C, was added 25 n-butyllithium (5.0 mL of a 2.5 M hexane mixture, 12.4 mol) over 5 minutes. At the end of the addition, the milky white reaction mixture was stirred for 1 hour. To a -78- ° C anion solution was added a solution of the aldehyde of Example 54, Part A (3-9 g, 8.26 mmol) in THF (10 mL) over 10 minutes via addition funnel. After ; the reaction mixture was stirred at -78 ° C for 35 minutes, saturated aqueous NH 4 Cl (8 mL) was added, and the mixture was then allowed to warm to room temperature. The organic layer was removed and the aqueous layer was extracted 33 times with EtOAc. The organic phases were combined, washed once with saturated NaCl solution and dried over Na 2 SO 4. Filtration and removal of the solvent gave 3.25 g of a yellow oil.

The yellow oil prepared above (3.25 g) was dissolved in dry toluene, and the solution was refluxed through a Sochlet extractor containing 4 A molecular sieves. P-Toluenesulfonic acid monohydrate was added at 0, 3.5 and 18 hours. After refluxing for 22 hours, the reaction mixture was cooled to room temperature and the toluene was removed under reduced pressure. The yellow residue obtained as a result was dissolved in EtOAc, and the solution was washed twice with saturated NaHCO 3 solution, dried over Na 2 SO 4 and filtered to give, after removal of the solvent, a yellow oil (A).

The aqueous solution was acidified with concentrated HCl, extracted three times with EtOAc, dried over MgSO 4 and filtered, and the solvent was removed to give 0.535 g of a yellow oil. This yellow oil was then refluxed in HCl (OCH 3) 3 (6/0 mL) for 24 hours, after which time excess HClO 2 O 3 was removed under reduced pressure. This material was combined with the yellow oil (A) and purified by flash chromatography using EtOAc-hexane (80:20) as eluent. The title vinyl phosphonate (2.07 g, 73%) was obtained as a white solid. TLC (acetone-hexane 1: 1, silica gel): Rf = 0.45, PMA.

IR (KBr): 2921, 2851, 1623, 1447, 1243, 1186, 1060, 1027 cm -1: 1 H-NMR (270 MHz, CDCl 3): δ 7.65 (dd, 1 J = 23.6 Hz , 18.1 Hz), 6.88 (s, 1), 6.82 (s, 1), 5.80 (dd, 1, J = 30 21.0 Hz, 18.1 Hz), 3.79 (d, 6, J = 11.5 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 spectrum (CI, m / 3): 337 (M + H) + 213 87927 B (E) - [2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] phosphonic acid, methyl ester The vinyl phosphonate prepared in Part A (2.07 g, 6.16 mmol) was stirred in dioxane (14 mL) at 5 room temperature. to the solution was added 1.0 N LiOH (2.24 mL, 9.24 mmol), and this mixture was warmed to 75. After maintaining the reaction mixture at 75 for 3.5 h, it was cooled to room temperature and The resulting residue was stirred with H 2 O and the pH of the mixture was adjusted to approximately 2 with 1 N HCl. The aqueous solution was extracted three times with EtOAc. Cr 2, dried over Na 2 SO 4 and filtered, and the solvent was removed to give 1.95 g of an off-white solid. TLC (CH 2 Cl 2 -CH 2 OH-AcOH 8: 1: 1, silica gel) Rf = 0.58, PMA.

1 H-NMR (270 MHz, CDCl 3): 612.11 (s, 1), 7.61 (dd, 1, J = 24.17 Hz, 17.58 Hz), 6.87 (s, 1), δ .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) (E) -4 - [[2 / 2- (cyclohexylmethyl) -4,6-di-. methylphenyl7ethenyl7methoxyphosphinyl7-3-oxo-. 25 butanoic acid, methyl ester

The monomethylphosphonate prepared in Part B; · (1.95 g, 6.06 mmol) dissolved in dry CH 2 Cl 2 (50 mL) was stirred with (C 2 H 3) 2 NSi (CH 2) 3 (1.76 g, 12.1 mmol) at room temperature. at room temperature under ar-30 for 1 hour 25 minutes. The CH 2 Cl 2 was removed under reduced pressure, and the residual yellow oil was once azeotroped with benzene ... and placed under high vacuum for 20 minutes. This oil was then dissolved in dry CH 2 Cl 2 (50 mL) under argon and cooled to 0 ° C. To the solution was added dry DMF 214,37927 (2 drops) followed slowly by dropwise addition of oxalyl chloride (0.92 g, 7.27 mmol); gas evolution was observed. The reaction mixture was stirred at 0 ° C for 15 minutes, after which it was warmed to room temperature and stirred for 1 hour. CH 2 Cl 2 was removed from the reaction mixture under reduced pressure, the resulting orange oil was azeotroped twice with dry benzene, and maintained under high vacuum under pump for 1 hour to give the phosphonochloridate.

The methyl acetoacetate dianion was prepared as follows: Pentane-washed NaH (0.25 g of an oil dispersion, 8.7 mmol) suspended in dry THF (10 mL) and kept under argon was cooled to 150 ° C. To the NaH suspension was added methyl acetoacetate (0.92 g, 7.9 mmol) dissolved in THF (10 mL), the mixture was stirred for 20 minutes, and then n-butyllithium (2.90 mL of 2.5 M hexane) was added. solution, 7.3 mmol) and the mixture was then stirred for 45 minutes. The dianion solution and a solution of the phosphonochloridate prepared above in THF (10 mL) were cooled to -78 ° C and the latter solution was added to the dianion solution over 15 minutes. After the reaction mixture was stirred at -78 ° C for 30 minutes, saturated aqueous NH 4 Cl and the mixture were added. heated to room temperature. THF was removed; . from the reaction mixture, and the remaining orange oil was dissolved in EtOAc-H 2 O (1: 1). The aqueous layer was extracted three times with EtOAc. The EtOAc extracts were combined, washed twice with saturated NaHCO 3 solution and once with saturated NaCl solution and dried over Na 2 SO 4. Purify by flash chromatography of the crude product (2.75 g) using EtOAc as eluent. gave the title keto ester (0.97 g, 35 42%) as a yellow oil. TLC (EtOAc, silica gel):

Rf = 0.24, PMA.

215 87927 1 H-NMR (270 MHz, CDCl 3): δ $ 7.71 (dd, 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), 3.73 (broad s), 6), 3.36 (dd, 2, J = 18.68 Hz, 5.5 Hz), 2.50 (m, 2), δ 2.30 (s, 3), 2.29 (s, 3), 1.70 (m, 5), 1 .45 (m, 1), 1.10-0.80 (m, 5) D) 4- [2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester The β-ketophosphonate prepared in Part C (0.97 g, 2.31 mmol) was stirred in THF (10 mL) under argon and the solution was cooled to 0 ° C. To the THF solution was added solid NaBH 4 (0.087 g, 2.31 mmol) followed by dropwise addition of CH 2 OH (2 mL): gas evolution resulted. The reaction mixture was then stirred at 0 ° C for 50 minutes, acetone (2 ml) was added, followed by CC-4 silica gel. The reaction mixture 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 using EtOAc as eluent. The alcohol under the heading | as a clear oil (0.65 g, 66%). TLC (acetone / hexane 50:50, silica gel): Rf = 0.29, melting point = 80-83 ° C.

7 /. IR (KBr): 3282 (broad), 2923, 2918, 2848, 1743, 1614, *; 7 1450, 1442, 1080, 1045 cm-1 V; 1 H-NMR (270 MHz, CDCl 3): δ 7.68 (m, 1), 6.88 (s, 1), 6.82 (s, 1), 5.89 (m, 1), 4.50 (m, 1), 4.00 (m, 1), 3.77 & 3.74 (2 doublets, 3, J = 11.0 Hz), 3.69 & · '. * ·: 3.68 (2 singlets, 3), 2.65 (d, 2, J = 6.0 Hz), V2.50 (m, 2), 2.30 (broad s, 3), 2.28 (s, 3) , 2.15 / · -. (m, 2), 1.68 (m, 5), 1.45 (m, 1), 1.30 - 0.80 (m, 5)

Mass spectrum (CI, m / e): 423 (M + H) + 216 87927 E) 4- [2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt

The diester prepared in Part D (0.565 g, 1.33 nunol) was stirred in dioxane (14 mL) until all solids had dissolved. 1.0 N LiOH (4.0 mL) was added and the solution was heated to 55 ° C. After 30 minutes, the reaction mixture became cloudy. After maintaining the reaction mixture at 55 ° C for 2 hours, it was cooled to room temperature and the solvent was removed on a rotary evaporator to give a white solid. The crude product was purified on an HP-20 resin column (3.0 cm x 15 cm) using first water (100 mL) and then MeOH-H'20 (75:25) as eluent. Freeze-drying of the T-15 fractions gave the title compound as a white freeze-drying product (0.524 g, 98%). TLC (nPrOH-NH 4 OH-H 2 7: 2: 1): R f = 0.41, PMA.

IR (KBr): 3700-31300 (broad), 2921, 2851, 1591, 1446, 201222, 1195, 1161, 1051 cm -1 1H-NMR (400 MHz, D2 O): δ $ 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 spectrum (FAB, m / e): 407 (M + H) +, 347 (M + - 2Li + + · '* 2H) δ Elemental analysis (C 2 H 2 O 2 • PLi 2 · 0.38H 2 O):

Calculated: C, 61.03; H, 7.45; P, 7.49 V ': Found: C, 61.03; H, 7.63; P, 7.66 217 87927

Example 56 (S) -4 - [[2 / 2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt 5 A) 4 - [[2- (cyclohexylmethyl) -4.6 -Dimethylphenyl7ethyl7methoxyphosphinyl-3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester

A solution of acetylene phosphinate from Example 54, Part F (1.33 g, 2.02 mmol) in methanol (45 mL) was purged with argon for 10 minutes. To this methanol solution in a Parr flask was added 10% Pd / C catalyst (0.34 g). Hydrogenation on a Parr apparatus at 2.8 bar for 20 hours, after filtration through a layer of diatomaceous earth formed on glass sinter, yielded 1.39 g of oil. Purification by flash chromatography using EtOAc-hexane (1: 1) as eluent gave the title phosphinate (1.25 g, 94%) as a clear oil. TLC (hexane-EtOAc-toluene 5: 4: 1, silica gel): Rf = 0.21, PMA.

IR (CHCl 3): 3600-3200 (broad), 3003, 2925, 2853, 1731, 1448, 1440, 1247, 1233, 1179, 1044 cm -1 1 H-NMR (270 MHz, CDCl 3): 66.83 (s , 1), 6.78 (s, 1), 4.50 (m, 1), 3.80 & 3.77 (2 doublets, 3, J = 6.3 Hz), 3.72 & 3, 71 (2 singlets, 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 - · singlets, 3), 2.25 (s, 3), 2.00 (m, 4), 1.70 (m, 6), V: 1.45 ( m, 1), 1.30 - 0.90 (m, 6)

Mass spectrum (EI, m / e): 424 (M) + 30 B) (S) -4 - [[2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester. ·· *. A solution of the-: lyyl ether prepared in Part A (1.2 g, 1.8 mmol) in THF (20 mL) was stirred at room temperature under argon. To this solution were sequentially added glacial acetic acid 218,37927 (0.41 mL) and n-Bu 2 NF (5.0 mL, 1.1 M THF solution, 5.44 mmol) which was added dropwise over 5 minutes. After the reaction mixture was stirred at room temperature for 23 hours, 5 ice water (50 ml) was added thereto, and the mixture was stirred vigorously. The THF was removed under reduced pressure, and the residue was diluted with water and extracted three times with EtOAc. The EtOAc extract solution was washed twice with saturated NaHCO 3 solution and once with saturated NaCl solution and then dried over Na 2 SO 4. Filtration and removal of the solvent gave a clear oil (1.3 g). The product was purified by flash chromatography eluting with 100% EtOAc to give the title alcohol (0.55 g, 72%) as Kirk-15 as an oil. TLC (EtOAc, silica gel): Rf = 0.22, PMA.

IR (CDCl 3): 2999, 2950, 2929, 2856, 1734, 1244, 1195, 1183, 1112, 1105, 1065, 1043 cm -1 1 H-NMR (270 MHz, CDCl 3): δ $ 7.65 (m, 4) , 7.28 (m, 6), δ 6.81 (s, 1), 6.76 (s, 1), 4.51 (m, 1), 3.62 & 3.60 (2 doublets, 3 , J = 5.3 Hz), 3.49 & 3.46 (2 singlets, 3), 2.97 (m, 1), 2.65 (m, 2), 2.35 & 2.33 j ·: (2 doublets, 2, J = 6.9 Hz), 2.25 (2 singlets, 3),: ·: 2.16 (2 singlets, 3), 1.84 (m, 1), 1 .68 (m, 6), 25 1.55 (m, 1), 1.18 (m, 2), 1.15 (m, 3), 1.00 & 0.99.... (2 singles .9), 0.91 (m, 2)

Mass spectrum (CI, m / e): 663 (M + H) + C) (S) -4 - [[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethyl] hydroxyphosphinyl] -3-hydroxybisobutanoic acid, dilithium salt

The diester prepared in Part B (0.552 g, 1.3 mmol) was stirred in dioxane (14 mL) at room temperature. To this solution was added 1.0 N LiOH (3.9 mL, 3.9 mmol), and then the reaction mixture was warmed to 55 ° C. After stirring for 30 minutes, a cake precipitate formed which was dissolved by the addition of water 219 37927 (5 ml). After maintaining the reaction mixture at 55 ° C for 2 hours 15 minutes, it was allowed to warm to room temperature and the volatiles were removed under reduced pressure to leave a white solid. The product was purified on an HP-20 resin column (3.0 cm x 30 cm) using first water (100 ml) and then CH 2 OH-O 2 (1: 1) as eluent. The product fractions were lyophilized to give 0.482 g (92% yield) of a white freeze-dried product. TLC 10 (7: 2: 1 nPrOH-NH 4 OH- 2 O, silica gel):

Rf = 0.36, PMA.

IR (Kbr): 3700-31100 (broad), 2923, 2852, 1588, 1446, 1410, 1159, 1132, 1048 cm -1 1H-NMR (400 MHz, D2 O): δ 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) Mass spectrum ( FAB, m / e): 397 (M + H - 2L +) +, 409 (M + 20 H) +

Elemental analysis H20):

Calculated: C, 59.76; H, 7.77; P, 7.34: Found: C, 59.76; H, 7.91; P, 7.53

Example 57 4- [7774'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) oxy] methyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) 4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-carboxaldehyde Reference: U.S. Patent 4,375,475 (Merck), pp. 37 and 38

The title compound was prepared as described in Example 1, Parts A to C.

220 37927 B) 4'-Fluoro-3,3 '-, 5-trimethyl-1,1'-biphenyl-2-methanol

The aldehyde prepared in Part A (1.03 g, 4.26 mmol) was stirred in dry Cl 2 Cl 2 (30 mL) under argon. To a solution of the aldehyde kept at room temperature was added dropwise over 15 minutes a solution of m-chloroperbenzoic acid (1.06 g, 5.11 mmol) in Cl 2 Cl 2 (20 mL). After stirring at room temperature for 58 hours, the reaction mixture was evaporated to dryness on a rotary evaporator, the resulting yellow solid was dissolved in THF and 2N KOH (6.4 mL) was added to the solution. This mixture was stirred at room temperature for 5.5 hours, after which the THF was removed from the reaction mixture.

The resulting residue was diluted with water, and the aqueous solution was extracted three times with Et 2 O, which was then dried over MgSO 4. The crude yellow oil obtained after filtration and removal of the solvent was purified by flash chromatography using 5% hexane in 5% Et 2 O as eluent. The title phenol was obtained as a white solid (0.843 g, 100%). TLC (10% Et 2 O in hexane, silica gel): Rf = 0.37, PMA, melting point = 83-86 ° C.

: Y: IR (KBr): 3512, 3500 (broad), 2950, 1504, 1482, 1238, 251231, 1215 cm -1 1 H-NMR (270 MHz, CDCl 3): δ 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 spectrum (CI, m / e): 231 (M + H) + 30 C) / 7741-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl- [2-yl) oxy] methyl] phosphonic acid, diethyl ester r Suspension , which was washed with pentane

NaHrta (0.30 g of 80% oil dispersion, 10.3 mmol) in ____: dry DMF (15 mL) under argon was cooled in an ice bath. To the NaH suspension was added over 15 minutes a solution of the phenol prepared in Part B (2.36 g, 10.3 mmol) in DMF (10 mL); 221 87927 gas evolution was avoided. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 35 minutes. At room temperature, a solution of diethyl tosyloxymethylphosphonate / 3.31 g, 10.26 mmol was added dropwise over 10 minutes; as to its preparation, see A. Holy and I. Rosenberg, Collection Czechoslovak Chem. Commun. After keeping the reaction mixture at room temperature for 22 hours, saturated aqueous NH 4 Cl was added and the DMF was removed under reduced pressure, the remaining solid was dissolved in EtOAc and water, and the aqueous layer was washed twice with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaHCO 3 and saturated NaCl 15 and then dried over MgSO 4 Filtration and removal of the solvent gave 4.3 g of crude title ether which was purified by flash chromatography eluting with flash chromatography. EtOAc-hexane (70:30) The title ether-20 ter (3.2 g, 82%) was obtained as a clear oil: TLC (50:50 acetone-Toni-hexane, silica gel: Rf = 0.52, PMA).

IR (film): 2983, 2925, 2910, 1504, 1474, 1213, 1032, 971 cm -1 1 H-NMR (270 MHz, CDCl 3): δ 57.33 (m, 2), δ, 01 (t, 1.1, · J = 10.0 Hz, 6.96 (s, 1), 6.91 (s, 1), 4.07 (m, 4), 3.69 (d, 2, J = 9.3 Hz), 2.34 (s, 3), 2.31 (d, 3, :: J = 1.7 Hz), 2.29 (s, 3), 1.31 ( t, 6, J = 7.0 Hz)

Mass spectrum (CI, m / e): 381 (M + H) +, 242 (M + - 30 C 4 H 10 PO 3) + '·: D) / 774'-fluoro-3,31,5-trimethyl-1,1'-bi -:. · Phenyl-2-yl) oxy7methyl7phosphonic acid, monoethyl ester

A solution of the diester prepared in Part C (3.21 g, 8.45 mmol) in dioxane (40 mL) was stirred with 1 N LiOH (12.7 mL, 12.67 mmol) at 70 ° C. . After maintaining the reaction mixture at 222,87927 at 70 ° C for 3 hours, it was cooled to room temperature and the dioxane was removed under reduced pressure. The aqueous solution was diluted with water and cooled in an ice bath, after which its pH was adjusted to approximately 1 with 6 N HCl to leave a milky white solution. This solution was then extracted three times with EtOAc, and the EtOAc extraction solution was dried over MgSO 4 and filtered to give 3.12 g of a clear gum. TLC (CH 2 Cl 2 -AcOH-MeOH 9: 0.5: 0.5, silica gel): Rf = 0.20, PMA.

1 H-NMR (270 MHz, CDCl 3): cfl0.26 (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- (ethoxy // T4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl -2-yl) oxy7methyl7 phosphinyl7-3-oxobutanoic acid, methyl ester

A solution of the phosphonic acid prepared in Example D (2.96 g, 8.42 mmol) in dry CH 2 Cl 2 (75 mL) was stirred with (C 2 H 5) 2 Si (CH 3) 3 (2.44 g, 16 , 84 mmol) at room temperature under argon. After stirring for 1 h 10 min, CH 2 Cl 2; was removed under reduced pressure, and the resulting oil was once azeotroped with benzene. 25 and then placed under high vacuum for 15 minutes. This oil was dissolved in dry CH 2 Cl 2 (75 mL) and cooled to 0 ° C under argon. To the cooled solution was added dry DMF (3 drops) followed by dropwise addition of oxalyl chloride (1.18 g, 9.26 mmol). The reaction mixture was stirred at 0 ° C for 20 minutes, warmed to room temperature, and stirred for an additional 1 hour.

, ··. The reaction solvent was removed under reduced pressure, and chestnut ____; the brown oily phosphonochloridate was azeotroped twice with benzene and then placed under high vacuum for 1 hour.

223 37 927

The methyl acetoacetate dianion was prepared as described in Example 55, Part C / methyl acetoacetate (1.27 g, 10.95 mmol), NaH (0.350 g oil dispersion, 12.05 mmol), n-butyllithium (4.0 mL 2.5 M 5 hexane solution, 10.7 mmol) and THF (35 mL) y.

The phosphonochloridate prepared above was added dropwise to THF (10 mL) and cooled to -78 ° C dropwise over 20 minutes in a dianion solution, which was also maintained at -78 ° C. After the reaction mixture was stirred at -78 ° C for 40 minutes, saturated aqueous NH 4 Cl solution was added at -78 ° C and the mixture was allowed to warm to room temperature. The THF was injected under reduced pressure, and the resulting residue was dissolved in EtOAc and water. The aqueous layer was extracted twice with EtOAc, and all EtOAc extracts were combined, washed once with saturated NaHCO 3 solution and once with saturated NaCl solution, and then dried over Na 2 SO 4. The title crude phosphinate was obtained as an orange oil (4.0 g) which was purified by flash chromatography using eluent as eluent.

EtOAc-hexane (75:25). The title phosphinate (1.4 g, 42%) was obtained as a yellow oil. TLC :: (EtOAc-hexane 75:25, silica gel):

Rf = 0.25, PMA.

f ··; IR (CHCl 3): 3004, 2954, 2925, 1744, 1718, 1643, 1541, 1503, 1472, 1449, 1438, 1425, 1236, 1037 cm -1 1H-NMR (270 MHz, CDCl3): δ 7.30 ( m, 2), 6.95 (m, 3),: - 4.05 & 3.90 (2 multiplets, 2), 3.75 (m, 2), 3.73 & 3.66 (2 singlets, 3), 3.55 (m, 1), 3.25 (m, 1), 30 2.33 & 2.29 (2 broad singlets, 9), 1.28 & 1.12 (2 triplets, 3, J = 7.1 Hz)

Mass spectrum (CI, m / e): 451 (M + H) + F) 4- (7774'-fluoro-3 ', 3'-5-trimethyl-1,1'-bi-phenyl-2-yl) oxy] methyl] ethoxyphosphinyl] -3- hydroxy-35 butanoic acid, methyl ester

A solution of the ketone prepared in Part E (1.39 g, 3.09 mmol) in THF (15 mL) under argon was cooled to 0 ° C. To the cooled solution was added NaBH 4 (0.12 g, 3.09 mmol) followed slowly by dropwise addition of CH 2 Cl 2 (2.8 mL).

After the reaction mixture was kept at 0 ° C for 5 hours, acetone and then CC-4 silica gel (1.4 g) were added thereto, and then the mixture was warmed to room temperature. The reaction mixture was filtered and the filtrate was evaporated on a rotary evaporator to give a yellow oil, the oil was purified by flash chromatography-EtOAc-hexane (90:10) as eluent, the product fractions were combined and the solvent removed under reduced pressure. The resulting yellow oil was crystallized from Et 2 O-hexane and the resulting crystals were triturated with Et 2 O-hexane to give the title alcohol as white crystals (0.320 g). TLC (EtOAc-hexane 90:10, silica gel: Rf = 0.38, PMA. Melting point = 116-119 ° C.

IR (KBr): 3288 (broad), 3000, 2950, 2920, 1735, 1503, 20 1473, 1440, 1311, 1232, 1195 cm -1 1H-NMR (270 MHz, CDCl3): ¢ 7.28 (m, 2), 7.05 (t, 1, J = 6.0 Hz), 6.98 (s, 1), 6.90 (s, 1), 4.42 (m, 1), 4.05 & 3.85 (m, 2), 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), δ 1.30 (t, 3, J = 7.0 Hz) - · - Mass spectrum (CI, m / e): 453 (M + H) +, 435 (M - H 2 O) + G) 4- (7774'-fluoro-3,3 ', 5-trimethyl-1,1-biphenyl-2-yl) oxy] methyl] hydroxyphosphinyl-7-hydroxybutanoic acid, dilithium salt To a solution of the diester prepared in Part F (0.293 g, 0.65 mmol) in dioxane (13 mL) was added 1 N LiOH (2.0 mL) at room temperature, and the reaction mixture was warmed to 55 ° C and stirred. After 1 hour 45 minutes, after which it was cooled to room temperature, the reaction mixture was evaporated to dryness on a rotary evaporator to give a white solid (225,87927), which was then placed under high vacuum for 10 ml. The crude product was purified by chromatography on an HP-20 resin column (15 cm x 3.0 cm) using first water (100 ml) and then CH 2 OH-O 2 (50:50) as eluent. The pure title dilithium salt was obtained as a white freeze-dried product (0.295 g, 88%). TLC (nPrOH-NH 4 OH-H 2 O 7: 2: 1): Rf = 0.38, PMA.

IR (KBr): 3400 (broad), 3021, 3011, 2981, 2958, 2924, 10 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175, 1087 cm -1 1H-NMR (270 MHz, D2 O) : 47.20 (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, 15 2), 2.17 (s, 3), 1.45 (m, 2)

Mass spectrum (FAB, m / e): 423 (M + H) +

Elemental analysis (C2QH22 ° gFPIji2 0'9ϊ> H2O):

Calculated: C, 54.67; H, 5.48; F, 4.32; P, 7.05 Found: C, 54.37; H, 5.03; F, 4.31; P, 7.55 Example 58 4- (ZZ4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) methyl] hydroxyphosphinyl] -3-hydroxybutane -: acid, dilithium salt * A) 4'-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-methanol

To a solution of NaBH 4 (0.12 g, 3.18 mmol) in absolute EtOH (9 mL) was added the aldehyde of Example 57, Part A (0.70 g, 2.89 mmol) in Et 2 O. (4.5 mL) and EtOH (3.0 mL) dissolved in 30 mL. This reaction mixture was stirred at room temperature.

sa for 2 hours, after which a saturated NH4Cl solution was added. The resulting solid precipitate was removed by filtration to:: **. The filtrate was evaporated to dryness on a rotary evaporator, and the remaining solid was dissolved in Et 2 O and water. The aqueous layer was washed twice with Et 2 O, the combined Et 2 O solutions were dried over MgSO 4.

226 879 2 7

After filtration and removal of the solvent, 0.70 g of a white solid was obtained. The solid was purified by flash chromatography using 33% Et 2 O in hexane as eluent to give 0.675 g (100% yield) of the title alcohol. TLC (15% Et 2 O in hexane, silica gel): Rf = 0.11, PMA. Melting point = 101-102 ° C.

IR (KBr): 3351, 3293, 3267, 3260, 3024, 3016, 2980, 2939, 2921, 1605, 1601, 1502, 1451, 1355, 1243, 1236, 10 1228, 1189, 1118, 999 cm-1 1H- NMR (270 MHz, CDCl 3): 07.15 (m, 2), 7.03 (m, 2), 6.90 (s, 1), 4.55 (d, 2, J = 6.0 Hz), δ .48 (s, 3); 2.33 (s, 6)

Mass spectrum (CI, m / e): 244 (M +), 227 (M + - OH) 15 B) (T 4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) methylphosphonic acid, diethyl ester

A solution of the aldehyde prepared in Part A (1.94 g, 7.95 mmol) in CH 2 Cl 2 (50 mL) under argon was cooled to 0 ° C. To this solution was added Et 2 N (0.965 g, 9.54 mmol) followed by dropwise addition of MsCl (1.00 g, 8.75 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes, after which it was warmed to room temperature and stirred overnight. Saturated NaHCO 3 solution was added to the reaction mixture and the mixture was stirred vigorously.

The organic layer was washed with saturated NaHCO 3 solution and then dried over MgSO 4. Filtration and removal of the solvent gave 2.1 g of 2- (chloromethyl) -4'-fluoro-3,3 ', 5'-trimethyl-1,11-biphenyl as a clear oil. TLC (Et 2 O-hexane 50:50, silica gel): Rf = 0.68, PMA.

1 H-NMR (270 MHz, CDCl 3): δ 7.22 (m, 2), 7.03 (m, 2), 6.90 (s, 1), 4.50 (s, 2), 2.48 (s, 3), 2.33 (s, 6)

The chloride prepared above (2.1 g) was stirred in the crude state with P (OC2H, -) 3: (30 ml) ···· at 150 ° C under argon for 3 hours.

227 37927

The reaction mixture was cooled to room temperature, and excess PiOCl 2 H 2 O was removed by distillation. The crude product was purified by flash chromatography using EtOAc-hexane (70:30) as eluent. The phosphonate of Search-5 con (2.40 g, 83%) was obtained as a clear oil. TLC (EtOAc-hexane 70:30, silica gel): Rf = 0.37, PMA.

IR (CHCl 3): 2992, 2928, 2909, 1501, 1474, 1455, 1443, 1392, 1245, 1239, 1119, 1053, 1029, 970, 963 cm -1 1 H-NMR (270 MHz, CDCl 3): δ, 15 (m, 2), 7.00 (m, 2), 6.83 (s, 1), 3.83 (m, 4), 3.22 (d, 2, J = 22.52 Hz), 2.47 (s, 3), 2.29 (s, 6), 1.16 (t, 6, J = 7.14 Hz) Mass spectrum (CI, m / e): 365 (M + H) + C (74'-fluoro-3,31,5-trimethyl-1,11-biphenyl-2-yl) methyl] phosphonic acid, monoethyl ester The phosphonate diester prepared in Part B (2.40 g, 6.59 mmol) was stirred in dioxane (30 mL). To this dioxane solution was added 1 N LiOH (9.9 mL), and the reaction mixture was heated to reflux 20. Additional 1 N LiOH (9.9 mL) was added both at 18 hours and at 44 hours. After refluxing for 55 hours: the reaction mixture was cooled to room temperature and the di- •: oxane was removed on a rotary evaporator The resulting aqueous solution was diluted with water and extracted twice with Et 2 O, possibly trace. to remove the diester. The aqueous layer was then cooled in an ice bath and its pH was adjusted to approximately 1 with 6 N HCl. The milky white solution was extracted. . 30 times with EtOAc, the EtOAc extraction solution was dried; · MgSO 4 and filtered, and the solvent was removed to give 1.89 g (85% yield) of a clear oil.

TLC (CH 2 Cl 2 -MeOH-AcOH 9: 0.5: 0.5, silica gel): Rf = 0.26, PMA.

IR (CHCl 3): 3029, 3023, 3005, 2983, 2925, 1710, 1605, 1500, 1234, 1042, 988 cm -1 1H-NMR (270 MHz, CDCl 3): ¢ 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 spectrum (CI, m / e): 337 (M + H) + D) 4- (ethoxy) -4'-fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl) methyl ? phosphinyl? -3-oxobutanoic acid, methyl ester

A solution of the 10 half-acids (1.85 g, 5.50 mmol) prepared in Part C in CH 2 Cl 2 (50 mL) under argon was stirred with (C 2 H 2) 2 NSO 4 (CH 2) 3 (1.60 g, 11.0 mmol) at room temperature for 1 hour 15 minutes. CH 2 Cl 2 was removed from the reaction mixture, and the resulting yellow oil was azeotroped once with benzene once and placed under high vacuum for 20 minutes. This oil was dissolved in dry ΟΗ2012: θβη (50 mL) under argon and cooled to 0 ° C. To the cooled solution was added dry DMF (2 drops) followed by pi-20 dropwise oxalyl chloride (0.768 g, 6.06 mmol); gas evolution was observed. The reaction mixture was stirred at 0 ° C for 20 minutes, warmed to room temperature, and stirred for an additional 1 hour 40 minutes; the reaction mixture became a deep vine, 0-2012 was removed from the reaction mixture and the residual oil was azeotroped twice with dry benzene and placed under reduced pressure for 1 hour.

Methyl acetoacetate dianion was prepared as described in Example 57, Part E / methyl acetoacetate (0.830 g, 7.16 mmol); NaH (0.230 g oil dispersion, 7.88 mmol); n-BuLi (2.64 mL of a 2.5 M hexane mixture, 6.59 mmol) and THF (20 mL).

____ The phosphonochloridate prepared above was added to 35 dry THF (10 mL) dissolved and cooled to -78 ° C via tube over 20 minutes to -78 ° C 229 87927 cooled via tube over 20 minutes to a solution of dianion cooled to -78 ° C . After the reaction mixture was stirred at -78 ° C for 40 minutes, saturated NH 4 Cl solution was added at -78 ° C and warmed to room temperature, the reaction mixture was laminated with water to dissolve the solid, and the THF was removed on a rotary evaporator. . The resulting mixture was extracted three times with EtOAc. The EtOAc extract solution was washed once with saturated NaHCO 3 and once with saturated NaCl, dried over MgSO 4 and filtered to give 2.6 g of crude orange oil after removal of the solvent. The crude product was purified by flash chromatography using EtOAc-hexane (75:25) as eluent. The ketone from Part D (0.43 g, 23%) was obtained as an orange foam. TLC (acetone-hexane ratio (50:50, silica gel)): Rf = 0.32, PMA.

IR (KBr): 2952, 2925, 1739, 1718, 1654, 1529, 1503, 1472, 1234, 1206, 1166, 1119, 1035 cm -1 1H-NMR (270 MHz), CDCl3): {> 1.20 - 6.70 (aromatic 20 Hs, δ), 4.00 to 3.70 (m, 2), 3.70 & 3.55 (2 singlets, 3), 3.35 (m, 2), 3 .35 (d, 2, J = 15 Hz), 2.92 (m, 1), 2.45 & 2.35 (2 singlets, 3), 2.25 (s, 6), 1.15 & 0 , 95; (2 triplets, 3, J = 7.0 Hz:: Mass spectrum (CI, m / e): 435 (M + H) + 25 E) 4- / ethoxy / T4 1-fluoro-3.3 ', 5 -trimethyl-1,1'-[(biphenyl-2-yl) methyl] phosphinyl] -3-hydroxybutanoic acid, methyl ester

To a solution of the ketone prepared in Part D (0.40 g, 0.92 mmol) in THF (5 mL) under argon. . 30 h, solid NaBH 4 (0.035 g,; 0.92 mmol) was added. To a THF solution maintained at room temperature was added methanol (0.80 mL). After: after keeping the reaction mixture at room temperature for 1 hour, acetone was added followed by CC-4 35 silica gel (0.4 g). The reaction mixture was filtered and the solvent was removed. However, 230 37927 of the starting ketone remained in the reaction product, so that the reaction product obtained above was reduced again under the same conditions as above, but CCl 2 (g) was blown through the solution before the addition of NaBH 4. Treatment of isolation-5 in the same manner as above gave 0.250 g of a yellow oil which was purified by flash chromatography using EtOAc as eluent. The pure title alcohol was obtained as a clear oil. TLC (50:50 acetone-hexane, silica gel-10 L): Rf = 0.26 PMA.

1 H-NMR (270 MHz, CDCl 3): 87.10 (m, 2), 7.00 (m, 2), 6.85 (s, 1), 4.28 & 4.03 (2 multiplets, 1) , 4.10 - 3.70 (m, 2), 3.67 (s, 3), 3.33 (m, 2), 2.47 (s, 3), 2.40 (m, 2), 2.30 (s, 6), 1.63 (m, 2), 1.17 (t, 3, 15 J = 6.6 Hz) F) 4- [774'-fluoro-3,3'-5 -trimethyl-1,1'-bi-phenyl-2-yl) methyl] hydroxyphosphinyl-3-hydroxybutanoic acid, dilithium salt

To a solution of the 20 diesters prepared in Part E (0.110 g, 0.252 mmol) in dry CH 2 Cl 2 (5.5 mL) under argon was cooled to 0 ° C and collidine (0.046 g, 0.38 mmol) was added. and:: then dropwise trimethylsilyl iodide (TMSI) V: (0.182 g, 0.88 mmol). The reaction mixture was stirred at 0 ° C for 2 hours, after which it was warmed to room temperature. After 24 hours, an additional portion of both collidine (0.023 g) and TMSI (0.091 g) was added. After the mixture was stirred at room temperature for 48 hours, dioxane (6 mL) was removed and 1N LiOH (1.7 mL) was added to the oil. This mixture was refluxed for 16 hours, cooled to room temperature and the dioxane removed to leave an orange gum. The gummy substance was dissolved in water, and the solution was filtered through sintered glass to remove 35 fines. The filtrate was lyophilized to give an off-white freeze-drying product, 231 87 92 7, which was purified on an HP-20 resin column (1.5 cm x 15 cm). The column was eluted first with water (150 mL) and then with MeOH-1 O 2 (50:50). The product fractions were freeze-dried to give the title compound 5 as a white freeze-dried product (88 mg, 80%). TLC (nPrOH-NH 4 OH-1 2 O 7: 2: 1, silica gel):

Rf = 0.38, PMA.

IR (KBr): 3700-31100 (broad), 2923, 1591, 1501, 1234, 1147 cm -1 1 H-NMR (270 HHz, D 2 O): δ 7.20 - 7.00 (m, 4), δ , 82 (s, 1), 3.76 (m, 1), 3.11 (m, 2), 2.35 (s, 3), 2.22 (s, 3), 2.21 (s, 3), 2.05 (m, 2), 1.16 (dd, 2, J = 12.32 Hz, 6.45 Hz)

Mass spectrum (FAB, m / e): 407 (M + H) + 15 Elemental analysis ^ 2 (^ 22 ^ 5 ^^ 2 '®' ^ H2O ^ 5

Calculated: C, 57.11; H, 5.65? F, 4.52; P, 7.36

Found: C, 57.11; H, 6.63; F, 4.44; P, 7.70

Example 59 (S) -4 - [(N- (4-fluorophenyl) -3-methyl-2-naphth-20-talenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) 1-methoxy-2-naphthalenecarboxylic acid. Reference: J. Organomet. Chem. 20 (1969) 251-252: n-BuLi (208.60 mmol), 83.44 ml of a 2.5 M hexane solution; Aldrich) was stirred in dry cyclohexane (42 mL) under argon. This solution was cooled to 0 ° C and distilled tetramethylethylenediamine (TMEDA) (208.6 mmol, 24.24 g, 31.48 mL) was added dropwise over 10 minutes.

The resulting suspension was stirred at 0 ° C for 30 minutes, after which a solution of 1-methoxynaphthalene (208.60 mmol, 33 g, 30.28 mL) (Aldrich Chem. Co., Ltd.) was added dropwise over 20 minutes. , was used in more detail in Purified-35 tomato) in dry cyclohexane (84 ml). The resulting bright red homogeneous reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C and added dropwise via tube over 30 minutes to -78 ° C dry Et 2 O (250 mL) saturated with CO 2 5 (g) (CO 2 "pellets sublimed with Siesta). through a drying tube and blown into dry Et 2 O cooled to -78 ° C.) The resulting white suspension was warmed to about 0 ° C over 45 minutes and then treated with 5% HCl (water). The Et 2 O layer was separated and the aqueous layer was extracted three times with Et 2 O. The organic extracts were combined and extracted with saturated NaHCO 3 (aq) (3 x 150 mL) and the aqueous layer was filtered through sintered glass to remove insoluble components, and the filtrate was cooled to 0 ° C and the pH was slowly adjusted to 1 with concentrated HCl, and the resulting precipitate was filtered off with additional toluene (2 x 150 mL), which was evaporated off azeo-20 tropically, and dried over a large portion. under reduced pressure at 50 ° C for 5 hours to give 32.52 g (0.161 mol yield 77%) of 1-methoxy-2-naphthalenecarboxylic acid as an off-white powder, m.p. 118-121.5 ° C. TLC (CH 2 Cl 2 / MeOH-CH 2 Cl 2 / H 2: 94: 5: 1, silica gel): Rf = 0.35.

1 H-NMR (270 MHz, CDCl 3): appropriate 1 H-NMR (67.8 MHz, CDCl 3): appropriate. Mass spectrum (CI, m / e): 203 (M + H) +; IR (KBr): appropriate 30 B) N- (2-Hydroxy-1,1-dimethylethyl) -1-methoxy-2-naphthalenecarboxamide 1-Methoxy-2-naphthalenecarboxylic acid (155.22 mmol, 31.4 g) was stirred in dry In CH 2 Cl 2 (155 mL), ···. under argon. SOCL 2 (310.44 mmol, 36.94 g, 22.65 mL) was then added to the solution. The reaction mixture was stirred at room temperature for 45 minutes and then refluxed in a 55 ° C oil bath for 45 minutes 233 8792 7 and then refluxed in a 55 ° C oil bath for 45 minutes. The reaction mixture was cooled to room temperature, an additional portion (18.47 g, 11.32 mL) of thionyl chloride was added, and it was refluxed again for 45 minutes.

The reaction mixture was cooled to room temperature, excess SOCl 2 and Cl 2 Cl 2 were removed on a rotary evaporator at 35 ° C (purge under argon), and the resulting mustard yellow solid was dissolved in dry Cl 2 Cl 2 under argon (155 mL). This solution was transferred via a dropping funnel to a dropping funnel and added dropwise over 40 minutes to a solution of 2-amino-2-methylpropanol (310.44 mmol, 26.67 g) in dry CH 2 Cl 2 (155 mL) stirred at 0 ° C. ° C under argon. The resulting reaction mixture was warmed to 15 room temperature and stirred for 18 hours. The reaction mixture was then filtered, the precipitate was washed with CH 2 Cl 2, and the filtrate was evaporated under reduced pressure. The residue was redissolved in EtOAc (350 mL), and the solution was washed with water (1 x 250 mL), 5% HCl (1 x 250 mL), 5% NaOH (1 x 25 mL), ml) and saturated NaCl (1 x 250 ml). The aqueous extraction solutions were each back-extracted once with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated; under reduced pressure to give an orange oil, [* · '; 25 which was azeotroped with toluene (250 ml). and kept 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 pale yellow solid. TLC 30 (100% EtOAc, silica gel): Rf = 0.65.

1 H-NMR (270 MHz, CDCl 3): ($ 8.19 (broad s, 1H), 8.14 (m, 1H), 8.03 (d, 1H, J = 8.7 Hz), δ, 83 (m, 1H), 7.66 (d, 1H, J = 8.7 Hz), 7.55 (m, 2H), 4.00 (s, 3H), 3.74 (s , 2 H), 1.47 (s, 6 H) 35 Mass spectrum (CI, m / e): 274 (M + H) + 234 87 927 IR (CHCl 3 solution): 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 -1 4,5-Dihydro-2- (1-methoxy-2-naphthalenyl) -4,4-dimethyloxazole

The naphthalamide prepared in Part B (139 mmol, 38.2 g) was stirred under argon and cooled to 0 ° C by the dropwise addition of 10 thionyl chloride (0.556 mol, 66.15 g, 40.56 mL) over 15 minutes. The resulting dark brown oil was stirred at room temperature for 45 minutes. Dry Et 2 O (500 mL) was added and the reaction mixture was stirred mechanically for 2.5 hours. The resulting yellow crystalline precipitate was filtered off, washed with Et 2 O and then suspended in Et 2 O (250 mL). The suspension was cooled to 0 ° C and basified with 10% NaOH (ca. 200 mL). The aqueous layer was extracted with three portions of Et 2 O and once with EtOAc. The organic extracts were combined, washed once with saturated NaCl solution, concentrated, dried over MgSO 4 and filtered. The filtrate was azeotroped with toluene under reduced pressure, and the residue was kept under high vacuum at 55 ° C for 25 hours to give 32.10 g (0.126 mol, yield: 90%) of the title oxazoline as a golden powder. TLC (50% EtOAc, silica gel): Rf = I. 0.37.

1 H-NMR (270 MHz, CDCl 3): 68.25 (m, 1H), 7.84 (d, 1H, J = 8.7 Hz), 7.84 (m, 1H), 60 (d, 1H, J = 8.7 Hz), 7.54 (m, 2H), 4.19 (s, 2H), 4.04 (s, 3H), 1.46 (s , 6 H)

Mass spectrum (CI, m / e): 256 (M + H) + IR: 2969, 2935, 2896, 1642, 1465, 1447, 1386, 1372, 35 1349, 1255, 1109, 1074, 991 cm -1; 235 8792 7 D) 2- [N- (4-fluorophenyl) -2-naphthalenyl] -4,5-dihydro-4,4-dimethyloxazole

The oxazoline prepared in Part C (117.52 mmol, 30.0 g) was stirred in dry THF (352.5 mL) under Argo-5. This solution was heated in an oil bath to 45 ° C. The heat source was removed and a 2 M solution of 4-fluorophenylmagnesium bromide in Et 2 O (Aldrich; 158.65 mmol, 79.33 mL) was added dropwise (30 min) at such a rate that the reaction temperature remained at 45 ° C. After the addition was complete, the reaction temperature was maintained at 45 ° C while stirring the reaction mixture for 18 hours. The reaction mixture was cooled to 0 ° C, saturated NH 4 Cl (aq) (200 mL) was added, and the mixture was diluted with water (200 mL) and EtOAc (200 mL). The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, concentrated, dried over MgSO 4 and filtered. The filtrate was evaporated under reduced pressure to give 39 g of a dark golden solid. The product was purified by flash chromatography-20 (95 mm column diameter, 18 cm layer of Merck silica gel, eluent 25% EtOAc in hexane, flow rate 5 cm / min) to give::: 30.42 g (95, 25 mmol, yield 81%) of the title 4-: Y; fluorophenyl-substituted naphthalene as a pale yellow solid, m.p. 94-96 ° C. Also obtained. 3.38 g (10.58 mmol, 9%) of a slightly crude product.

TLC (silica gel, EtOAc-hexane 50:50): Rf = 0.45.

1 H-NMR (270 MHz, CDCl 3): 67.93 - 7.13 (aromatic 30 Hs, 10 H), 3.77 (s, 2 H), 1.27 (s, 6 H) • 1 Mass spectrum : (CI, m / e): 320 (M + H) + Y: IR (KBr): 3060, 2966, 2927, 2884, 1667, 1603, 1508; 1462, 1383, 1354, 1335, 1293, 1219, 1105, 1160, 1119, 1083, 978, 842, 830 cm-1 236 87 927 Ε) 2- [Ϊ- (4-fluorophenyl) -3-methyl-2- naphthalene-nyyli7-4,5-dihydro-4,4-Dimethyl

The 1- (4-fluorophenyl) -4-oxazoline naphthyl compound prepared in Part D (87.67 mmol, 28 g) was stirred in dry EHO (585 mL) under argon. This solution was cooled to -25 ° C and n-BuLi (140.27 mmol, 56.1 mL of 2.5 M hexane solution) was added dropwise over 1 hour. During this hour-long addition, the reaction mixture changed from a homogeneous yellow solution through a dark red / orange solution to an orange / green solution in which a precipitate had formed. The reaction mixture was stirred at -25 ° C for an additional 2.5 h, after which iodomethane (263.01 mmol, 37.33 g, 16.4 mL) was added dropwise over 15 min. The resulting dark burgundy solution was stirred at -25 ° C for 4.5 hours, warmed to 0 ° C and stirred for 16 hours, and finally warmed to room temperature and stirred for 7 hours. To the resulting yellow translucent solution 20 was added ice-cold saturated NaCl solution (500 mL). The aqueous layer was extracted four times with EtOAc. The organic extraction solutions were combined, concentrated, dried over MgSO 4 and filtered through Florisil (300 mL glass sinter to 2/2; V; filled). Florisil was washed with CH 2 Cl 2. The filtrate was concentrated, azeotroped with toluene and evaporated under reduced pressure and kept I. under high vacuum at 55 ° C * for 3 hours to give 30.32 g ("90, 94 mmol", yield to 100%) of the title methylated naphthalene as a yellow solid. TLC (silica gel, EtOAc-: hexane 50:50): Rf = 0.50.

1 H-NMR (270 MHz, CDCl 3): δ 7.79 - 7.07 (aromatic Hs, 9 H), 3.80 (s, 2 H), 2.54 (s, 3 H), 1.13 (s, 6 H) ____: Mass fraction (Cl, m / e): 334 (M + H) + 35 IR (CHCl 3 solution): 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513 1497, 1461, 1299, 1280, 1235, 1190, 1158, 1041, 965, 841 cm-1: 237 3 7 92 7 F) 2- [N- (4-fluorophenyl) -3-methyl-2-naphthalenyl -li7 ~ 4,5-dihydro-3,4,4-trimetyylioksatsoliumjodidi

The oxazoline prepared in Part E (87.67 mmol, 29.23 g) was stirred in nitromethane (140.28 mL) under Argo-5. To this solution was added iodomethane (0.789 mol, 112 g, 49.2 mL) in one portion. The resulting brown reaction mixture was stirred in a 60 ° C oil bath for 1 hour 20 minutes protected from light. Iodime-tane was removed by simple distillation. The nitro-10 methane was removed on a rotary evaporator and the residue was kept under high vacuum provided by the pump for 45 minutes. The resulting burgundy solid was stirred in dry Et 2 O (250 mL) for 1 h. The red filtrate was separated by decantation, and the solid was re-triturated with Et 2 O as above. The resulting yellow solid was filtered off and kept under high vacuum on a pump for 4 hours (protected from light) to give the title oxazolium iodide 20 g ("92, 63 mmol", 100% yield) as a mustard yellow solid. The title compound was stored protected from light at -30 ° C for 18 hours and then used directly in the preparation of the compound of Part G. TLC (silica gel, 10% MeOH in CH 2 Cl 2): R f = 0.30.

. ·. : G) 1- (4-Fluorophenyl) -3-methyl-2-naphthalene-carboxaldehyde The oxazolium iodide prepared in Part F (87.66 mmol, 41.67 g) was stirred in dry THF (526 mL) 30 and absolute. In a mixture of EtOH (210 mL, in dry 4 A Mole screens) under argon. This solution / suspension was cooled to -15 ° C and NaBH 4 was gradually added over 1 hour. At the end of the addition, the reaction solution was stirred at -10 to 15 ° C for 2.5 hours.

The solution was then diluted with absolute EtOH (210 mL), and the reaction mixture was stirred at -15 ° C, 238,87927 miles, when 2 N HCl (438 mL, 876 mmol) was added dropwise over 45 minutes (initial addition very slowly). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After diluting the Seu-5 wrist with water (500 mL), the aqueous mixture was extracted with Et 2 O. The organic extracts were combined, concentrated, dried over MgSO 4, filtered, concentrated, azeotroped with toluene (2 x 120 mL) and evaporated under reduced pressure to give 12.9 g (48.81 mmol, 56% yield). ) the title aldehyde as a pale yellow solid. TLC (silica gel, EtOAc-hexane 50:50): Rf = 0.66.

1 H-NMR (270 MHz, CDCl 3): 610.0 (s, 1H), 7.83-7.18 (aromatic Hs, 9H), 2.81 (s, 3H),

Mass spectrum (CI, m / e): 265 (M + H) + IR (CHCl 3 solution): 1685, 1512, 1422, 1237, 862 cm -1 1H) 2- (2,2-dibromoethenyl) -1- ( 4-Fluorophenyl) -3-methylnaphthalene The aldehyde prepared in Part G (11.35 mmol, 3.0 g) was stirred in dry CH 2 Cl 2 (113.5 mL) under argon. This solution was cooled to 0 ° C and triphenylphosphine (36.32 mmol, 9.53 g) was then added in one portion. The reaction mixture was stirred at 0 ° C for 20 minutes, then a solution of carbon tetraboride (18.16 mol, 6.01 g) in dry CH 2 Cl 2 (41 mL) was added dropwise over 20 minutes.

1; The resulting dark orange solution turned dark burgundy when stirred at 0 ° C for 1.5-30 hours. Saturated NaHCO 3 (aq) solution (150 mL) was then added to the reaction mixture. The aqueous layer was extracted. · ‘Four times ^ 20 ^: 11¾. The orthane extracts were combined, concentrated in vacuo, washed once with saturated NaCl solution, dried over MgSO 4 and filtered. The filtrate was pre-soaked in Merck silica gel (ca. 28 g) and then transferred to flash 239 P 79. 7 columns (50 mm diameter) containing a 15 cm layer of Merck silica gel and eluted with 7% EtOAc in hexane at a flow rate of 5 cm / min 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 powder, m.p. 134.5-135.5 ° C. TLD (silica gel 10, 20% EtOAc in hexane): Rf = 0.60. 1 H-NMR (270 MHz, CDCl 3): (δ 7.79 - 7.11 (aromatic and olefinic Hs, 10 H), 2.48 (s, 3 H),

Mass spectrum (CI, m / e): 419, 421, 423 (M + H) + IR (CHCl 3 solution): 3016, 1604, 1512, 1496, 1234, 1220, 15208, 1158, 886, 858 cm -1 I) 2-ethynyl-1- (4-fluorophenyl) -3-methyl-naphthalene

The dibromoolefin prepared in Part H (8.7 mmol, 3.69 g) was stirred in dry THF (47.9 mL). This solution was cooled to -78 ° C and then N-BuLi (17.4 mmol, 6.96 mL of a 2.5 M hexane solution; Aldrich) was added dropwise over 15 minutes.

:: · The reaction mixture was stirred at -78 ° C for 1 hour, after which a saturated solution of NH 4 Clin (aq) (40 ml) was added. After warming to 0 ° C, the reaction mixture was extracted twice with Et 2 O and once with EtOAc. The organic! The extracts were combined, dried over MgSO 4 and filtered, and the solvent was removed under reduced pressure. The first flash chromatography purification (column diameter 50 mm, 15 cm layer of Merck silica gel, hexane containing 7% EtOAc as eluent, flow rate 5 cm / min) gave 2.32 g of a green oil. / solid. A 270 MHz 1 H-NMR separator showed - the product to be impure. Further purification by flash chromatography (column diameter 75 mm, 15 cm layer of Merck silica gel, hexane containing 1% EtOAc as eluent, 240 87927 flow rate 5 cm / min) gave 2.11 g (8.11 mmol, yield 93 %) of the title acetylene as a light blue solid (maintained under high vacuum in the pump for 8 hours), melting point 91.5-94.5 ° C. TLC (silica gel, 20% EtOAc in hexane): Rf = 0.56, PMA.

1 H-NMR (270 MHz, CDCl 3): (δ 7.77 - 7.13 (aromatic Hs, 9 H), 3.18 (s, 1H), 2.62 (s, 3 H),

Mass spectrum (CI, m / e): 260 (M +) δ IR (CH 2 Cl 2 film): 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150, 1092, 884, 871, 853, 825 cm -1 ) (S) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] -4- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethynyl] methoxyphosphinyl / butanoic acid, methyl 15 ester

The dicyclohexylamine salt of Example 25 (2.82 mmol, 5.57 g) was partitioned by shaking vigorously in a mixture of EtOAc and 5% KHSO 4 (1: 1, 150 mL each). The layers were separated, and the EtOAc layer was washed with fresh 5% KHSO 4 (2 x 100 mL). Finally, the organic phase was dried over MgSO 4 and filtered, and the solvent was removed under reduced pressure. The resulting residue was azeotroped with benzene (2 x 120 ml) and evaporated, and kept in a pumped mouth. under reduced pressure for 2 hours to give "4.33 g" - ·. (yield "109%") phosphonate monoester as a viscous pale yellow oil. This oil was stirred in dry CH 2 Cl 2 (24.8 mL) under argon, and distilled diethyltrimethylsilylamine (17.64 mmol, 2.56 g, 3.34 mL) was added dropwise over 8 minutes. This solution was stirred at room temperature for 2 hours. The volatile components were then removed round. on an evaporator (removal under argon), and the resulting residue 35 was azeotroped with dry benzene (1 x 60 ml) and evaporated under reduced pressure, and 241,87927 was maintained under high vacuum with a pump for 45 minutes. The residue was then stirred in dry CH 2 Cl 2 (24.8 mL) under argon. DMF (2 drops) was added and the solution was cooled to 0 ° C.

Oxalyl chloride (10.58 mmol, 1.34 g, 0.923 mL) was added dropwise to the solution over 10 minutes. The resulting amber solution was stirred at 0 ° C for 30 minutes, warmed to room temperature, and stirred for 2 hours. The volatiles were removed, the residue was azeotroped and kept under high vacuum as above. The residue was finally stirred in dry THF (27.7 mL) under argon. This solution was cooled to -78 ° C, a solution of the acetylenic anion formed in Pisa-15 over 15 minutes, cooled to -78 ° C, was added portionwise, and the mixture was added to the phosphonochloridate as follows:

The acetylene prepared in Part I (5.19 mmol, 1.35 g) was stirred in dry THF (27.7 mL) under argon and the solution was cooled to -78 ° C. To this solution was added n-BuLi (5.19 mmol, 2.08 mL of a 2.5 M hexane solution) dropwise over 10 minutes. The resulting green solution was stirred at -78 ° C for 1.5 ° C, warmed to 0 ° C for 15 minutes and re-cooled to -78 ° C. This solution was kept at -78 ° C when gradually transferred to a dropping funnel and added dropwise to a solution of the phosphonochloridate formed above in THF maintained at -78 ° C. At the end of the addition, the reaction mixture. . After stirring at -78 ° C for 1 h, saturated NH 4 Cl (aq) solution (50 mL) was added and the mixture was warmed to 0 ° C. The reaction mixture was diluted with water (40 mL) and Et 2 O (40 mL). The aqueous layer was extracted with EHO (4 x 50 mL). The organic extracts were combined, concentrated, dried over MgSO 4 and filtered, and the solvent removed under reduced pressure. The product 242 87927 was isolated by flash chromatography (column diameter 75 nun, 15 cra layer of Merck silica gel, eluent hexane-EtOAc-toluene 5: 4: 1, flow rate 5 cm / min) to give 1.53 g (2, 21 5 mmol, yield 43%) of the title acetylene phosphinate as a yellow foam. 0.589 g of crude starting material was also recovered. TLC (silica gel, hexane-EtOAc-toluene 5: 4: 1): Rf = 0.26. 1 H-NMR (270 MHz, CDCl 3): δ 7.82 - 7.09 (aromatic Hs, 10 19 H), 4.52 (m, 1H), 3.60 & 3.59 (2x, 3 H), 3.36 & 3.31 (2 xd, 3 H, J = 11.5 Hz), 2.54 & 2.49 (2 x, 3 H), 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 spectrum (CI, m / e): 693 (M + H) + IR (CHCl 3 solution): 3004, 2951, 2932, 2858, 2164, 1735, 1605, 1512, 1494, 1472, 1437, 1427, 1237, 1197, 1182, 1158, 1151, 1138, 1110, 1105, 1093, 1038, 1017, 951, 885, 834 cm-1 K) (S) -4- [N- (4-fluorophenyl) -3-methyl-2 -20 Naphthalenyl7-ethynyl7-methoxyphosphinyl7-3-hydroxy-butanoic acid, methyl ester

The acetylene phosphinate from Part J (0.866 mmol, 0.60 g) was stirred in dry THF (10.5 mL) under argon, and glacial acetic acid (3.46 mmol, 0.208 g, 0.198 mL) was added and after drops; tetrabutylammonium fluoride (2.60 mmol, 2.36 mL of a 1.1 M THF solution). The reaction mixture was stirred at room temperature for 24 hours, then 25 mL of ice water was added and the mixture was diluted with EtOAc. The organic. . The extracts were combined, washed once with saturated NaHCO 3 (aq) solution and once with saturated NaCl solution, dried over MgSO 4, filtered and evaporated under reduced pressure. The product was purified by flash chromatography on a column with a diameter of 30 mm, Merck silica gel (35: 1), eluent 100% EtOAc and a flow rate of 5 cm / min, 243 87927 to give 0.267 g (0.588 nunol). , yield 68%) of the title N-hydroxyphosphinate as a pale yellow foam. TLC (silica gel, 100% Et) Ac): Rf = 0.28, PMA.

1 H-NMR (270 MHz, CDCl 3): δ 7.81 - 7.18 (aromatic Hs, 9 H), 4.38 (m, 1H), 3.71 (s, 3 H), 3.59 & 3.58 (2 xd, 3 H, J = 12 Hz), 2.66 & 2.65 (2 xs, 3 H), 2.62 - 2.52 (m, 2 H), 2 , 19 - 1.92 (m, 2H)

Mass spectrum (CI, m / e): 455 (M + H) + 10 IR (film): 3380 (broad), 3065, 3048, 2993, 2951, 2166, 1738, 1604, 1513, 1495, 1457, 1438, 1423 , 1401, 1385, 1378, 1334, 1299, 1222, 1179, 1160, 1138, 1095, 1035, 951, 887, 836 cm -1 L) (S) - 4- [7 / 1- (4-fluorophenyl) - 3-Methyl-2-naphthalenyl7-ethynyl7-hydroxyphosphinyl-3-hydroxybutanoic acid, dilithium salt

The diester prepared in Part K (0.583 mmol, 0.265 g) was stirred in dioxane (6 mL) under argon, and 1 N LiOH (1.75 mmol, 1.75 mL) was added.

The reaction mixture was heated in a 70 ° C oil bath for 45 minutes. The mixture was cooled to room temperature. The solvents were removed on a rotary evaporator, after which the residue was kept under high vacuum with a pump for 1 hour. The resulting white solid was dissolved in distilled water (4 mL) and transferred to an HP-20 resin column (2.5 cm x 17 cm, equilibrated with H 2 O). The column was first eluted with water (250 mL) followed by elution with MeOH-H 2 O (45:55). Fractions were collected every 1.3 minutes (approximately 30 ml). The product fractions were evaporated under reduced pressure at 35 ° C and freeze-dried, and the material thus obtained was kept: * under high vacuum under P 2 O 8 for 8 hours to give 0.237 g (0.541 mmol, yield 93%) of the title phosphinic acid lithium-35. salt as a white freeze-dried product. TLC (silica gel, n-CH 2 H 2 OH-NH 3 OH-O 2: 7: 2: 1): Rf = · -: 0.40, PMA.

244 g7927 1 H-NMR (400 MHz, D 2 O): 67.88 (d, 1H, J = 8.43 Hz), 7.80 (s, 1H), 7.58-7.29 (aromatic Hs: t) 7 H), 4.14 - 4.05 (m, 1H), 2.61 (s, 3 H), 2.43 (dd, 1H, J = 3.67, J = 15.39 ), 2.21 (dd, 1H, J = 9.16, J = δ 15.39), 1.84 - 1.67 (m, 2 H)

Mass spectrum (FAB, m / e): 439 (M + 2Li) + IR (KBr): 3443-3260 (broad), 3066, 2164, 1594, 1512, 1495, 1434, 1222, 1183, 1160, 1071, 834 cm -1 Elemental analysis (C23H18F05PLi2 + 0.66 mol H 2 O, M = 10,450.14)

Calculated: C, 61.38; H, 4.33; F, 4.22; P, 6.88 Found: C, 61.38; H, 4.07; F, 4.42; P, 6.80

Example 60 (E) -4H-2- [N- (4-fluorophenyl) -3-methyl-2-15 naphthalenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) [2- (1- (4-fluorophenyl)) -3-Methyl-2-naphthalenyl / -2-hydroxyethyl-7-phosphonic acid, dimethyl ester

Dimethyl methyl phosphonate (24.21 mmol, 3.0 g, 2.62 mL) was stirred in dry THF (47 mL) under argon. This solution was cooled to -78 ° C, then n-BuLi (22.70 mmol, 9.08 mL of a 2.5 M hexane solution) was added dropwise over 15 minutes. This reaction mixture was stirred at -78 ° C for 1.5 h, and to the resulting milky solution was then added dropwise over 15 minutes a solution of the aldehyde of Example 59, Part G (15.13 mmol, 4.0 g). in dry THF (14 mL). This reaction mixture was stirred at -78 ° C for 45 minutes. Finally, a saturated solution of NH 4 Cl (aq) (50 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and diluted with water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered, concentrated, azeotroped twice with toluene and evaporated under reduced pressure, and the resulting mixture was kept under high vacuum with a pump (5.90 g). , 13 nunol, yield 100%) of the title phosphonate as a yellow solid which was used directly in the preparation of compound 5 of Part B. TLC (silica gel, acetone-hexane 50:50): Rf = 0.37, PMA.

B) (E) - [2- [N- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] phosphonic acid, dimethyl ester The N-hydroxyphosphonate 10 prepared in Part A (14.16 mmol, 5.5 g) was stirred in dry toluene (66 .5 ml) under argon. To this solution was added para-toluenesulfonic acid monohydrate (TsOH * H 2 O) (3.54 mmol, 0.673 g). The reaction mixture was heated to reflux in a 135 ° C oil bath. Condensate-15 ti was derived containing dry 4 A molecular sieves

Through a Soxhlet extractor. After 16 h at reflux, additional TsOH-H 2 O (2.12 mmol, 0.404 g) was added and the reaction mixture was heated for an additional 8.5 h as described above. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). The mixture was then washed with saturated NaHCO 3 (aq) solution (100 mL). The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated under reduced pressure to give 4.22 g of crude vinyl phosphonate as a brown solid; as a solid. The aqueous layer was acidified with 5% HCl and then extracted three times with EtOAc. The organic extracts were combined, dried over MgSO 4, filtered and evaporated to give. . 1.4 g ("3.92 mmol") of vinyl phosphonate monoester were added; as a light brown solid. This solid was stirred in trimethyl orthoformate (15 mL) under argon and refluxed in a 120 ° C oil bath for 16 hours. The reaction mixture was cooled to room temperature. Excess trimethyl orthoformate was removed under reduced pressure, and the residue was combined with 4.22 g of 246,37927 crude vinyl phosphonate (above). The product was purified by flash chromatography (column diameter 75 mm, 15 cm layer of Merck silica gel, eluent 100% EtOAc, flow rate 5 cm / min) to give 3.70 g (9.99 mmol, 71% yield). ) the title vinyl phosphonate as a peach solid. TLC (silica gel, 100% EtOAc): Rf = 0.48, ΡΜΛ.

1 H-NMR (270 MH +, CDCl 3): δ 7.79 (d, 1H, J = 8.4 Hz), δ 7.72 (s, 1H), 7.56 - 7.13 (m, 8 H), 5.54 (dd, 1H, J = 17.93 Hz, J = 20.6 Hz), 3.57 (d, 6 H, J = 11 Hz), 2.54 ( s, 3 H)

Mass spectrum (CI, m / e): 371 (M + H) + IR (CHCl 3 solution): 3016, 2956, 2857, 1617, 1521, 1500, 15 1245, 1188, 1162, 1071, 1047, 834 cm -1 C) (E) - [2- [N- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] phosphonic acid, monomethyl ester The vinyl phosphonate prepared in Part B (9.72 mmol, 3.60 g) was stirred in dioxane (23.5 mL). Under Argo-20n, 1 N LiOH (23.82 mmol, 23.32 mL) was added and the reaction mixture was heated in a 75 ° C oil bath for 1 h, then cooled to room temperature and the solvents removed under reduced pressure. The resulting residue was diluted with water (15 mL) and cooled to 0 ° C, and the pH was adjusted to 1 with 5% HCl (aq) .The aqueous layer was extracted four times with EtOAc. MgSO 4, filtered, concentrated, azeotroped twice with benzene and evaporated under reduced pressure to give 3.38 g (9.48 mmol, to 98%) of the title phosphonate monoester as a peach solid. TLC (silica gel, CH 2 Cl 2 -MeOH-CH 3 CO 2 H 10: 1: 1): Rf = 0.41, PMA.

247 87927 1 H-NMR (270 MHz, CDCl 3): δ 7.76 (d, 1H, J = 8.4 Hz), 7.68 (s, 1H), 7.47-7.09 (m, 8 H), 5.61 (dd, 1H, J = 18.47 Hz, J = 20.58 Hz), 3.48 (d, 3 H, J = 10.96 Hz), 2.52 (s , 3 H) Mass spectrum (FAB, m / e): 357 (M + H) + IR (CHCl 3 solution): 3025, 3008, 2951, 1614, 1605, 1511, 1494, 1235, 1210, 1188, 1158 , 1050, 987, 833 cm -1 D (E) -4 - [[2- (1- (4-fluorophenyl) -3-motyl-2-naphthalenyl] ethenyl] methoxyphosphinyl] -3-oxobutane-10 acid, methyl ester

The phosphonate monoester prepared in Part C (9.12 mmol, 3.29 g) was stirred in dry CH 2 Cl 2 (60 mL) under argon, and trimethylsilyldiethylamine 15 (TMSDEA) (18.24 mmol, 2 .65 g, 3.45 ml, distilled). The reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed on a rotary evaporator (removal to argon), and the residue was pumped at high pressure for 40 minutes. The residue was then stirred in dry CH 2 Cl 2 (25 mL) under argon. This solution was cooled to 0 ° C and dry DMF (2 drops) was added followed by oxalyl chloride (10.94 mmol, 1.39 g, 0.955 mL) dropwise over 15 minutes: The reaction mixture was stirred at 0 ° C: after 20 minutes, after which it was warmed to room temperature and stirred for 1 hour. The volatiles were removed and the residue was kept connected to a vacuum pump as above. Finally, the residue was stirred in dry THF (25 mL) under Argo-30, cooled to -78 ° C, and kept at -78 ° C while transferring this solution through a tube to a dropping funnel and added dropwise over 20 minutes. To a THF solution of methyl acetoazotate dianion cooled to -78 ° C. This dianion 35 was formed as follows: NaH (13.22 mmol, 0.317 g, 0.397 g, 80% mineral oil dispersion) 248 87 927 was washed once with pentane and dried under a stream of argon, then stirred in dry THF (20 mL). under argon. This suspension was cooled to 0 ° C and a solution of methyl acetoacetate (12.31 mmol, 1.43 g, 1.33 mL) in dry THF (10 mL) was added dropwise over 10 minutes. The resulting clear solution was stirred at 0 ° C for 20 minutes, after which n-BuLi (11.40 mmol, 4.56 mL of a 2.5 M hexane solution) was added dropwise over 10 minutes. The resulting yellow solution was stirred at 0 ° C for 45 minutes, after which it was cooled to -78 ° C, and a THF solution of the phosphonochloride formed above cooled to -78 ° C was added dropwise. After the addition was complete, the reaction mixture was stirred at -78 ° C for 45 minutes. Saturated NH 4 Cl (aq) solution (50 mL) was then added to the reaction mixture, and the mixture was warmed to room temperature and diluted with water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted three times with NaHCO 3 (a) solution and once with CH 2 Cl 2. The organic extracts were combined, washed three times with saturated NaHCO 3 (aq) solution and once with saturated NaCl solution, dried over MgSO 4, filtered and evaporated under reduced pressure to give 4.0 g of a rusty foam. The first flash chromatography purification (column diameter 40 mm, Merck silica gel 20: 1, eluent 100% EtOAc, flow rate 5 cm / min) gave 2.0 g of slightly impure title ketophosphinate as an orange oil. Subsequent chromatographic treatment (column diameter 30 mm, Merck silica gel 25: 1, EtOAc in 5% hexane as eluent, flow rate 5 cm / min) afforded 1.95 g (4.29 mmol, 47% yield) of the title compound. ketophosphate in orange foam. TLC (silica gel, 100% EtOAc): Rf = 0.29, PMA.

249 δ 7 9 2 7 1 H-NMR (270 MHz, CDCl 3): δ 7.78 - 7.13 (aromatic Hs, olefinic Hs, 10 H), 5.62 (dd, 1H, J = 17.93 Hz, J = 25.84 Hz), 3.71 (s, 3 H), 3.63 (s, 2 H), 3.48 (d, 3 H, J = 11.6 Hz) , 3.14 & 3.13 (2x, 2H, J = 18.46 Hz), δ 2.44 (s, 3H)

Mass spectrum (CI, m / e): 455 (M + H) + IR (film): 1749, 1717, 1623, 1614, 1604, 1511, 1328, 1223, 1159, 1031, 834 cm-1E) (E) -4 - [[2- [N- (4-fluorophenyl) -3-methyl-2-10 naphthalenyl] ethenyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester

The ketophosphonate prepared in Part D (2.82 mol, 1.28 g) was stirred in dry THF (12 mL) under argon. This solution was cooled to 0 ° C and treated with NaBH 4 (2.82 mmol, 0.107 g) followed by dropwise addition of methanol (2.45 mL, dried over 4 A molecular sieves). The reaction mixture was stirred at 0 ° C for 1 hour, after which acetone (2.5 ml) was added. CC-4 silica gel (Mallinckrodt) was added and the reaction was stirred while warming to room temperature. Finally, the suspension was filtered through a sintered funnel and washed twice with EtOAc and twice with CH 2 Cl 2. The filtrate was evaporated under reduced pressure to give 1.3 g of an orange foam which crystallized on addition of EtOAc. The product was purified by flash chromatography (column diameter 30 mm, Merck silica gel 30: 1, CH 2 Cl 2 containing 3% MeOH as eluent, flow rate 5 cm / min). The product fractions were combined, evaporated and azeotroped once with benzene to give 0.653 g (1.43 mmol, 51% yield) of the title hydroxyphosphinate as a pale yellow solid.

This pure product was triturated with EtOAc-hexane (7: 3) to give 0.516 g of hydroxy-35 phosphininate as a white solid, mp 132-134.5 ° C. TLC (silica gel, 4% MeOH in CH 2 Cl 2): Rf = 0.38, PMA.

250 87 927 1 H-NMR (270 MHz, CDCl 3): δ 7.79 - 7.16 (aromatic Hs, olifinic Hs, 10 H), 5.59 (2 x dd, 1H, J = 17, 94 Hz, J = 24.27 Hz), 4.35 & 4.24 (2 x m, 1H), 3.70 (s, 3 H), 3.49 & 3.47 (2 x d, 3 H, J = 11 Hz), δ 2.58 - 2.53 (m, 2 H), 2.54 & 2.53 (2 xs, 3 H), 2.01 - 1.74 (m, 2 H)

Mass spectrum (CI, m / e): 457 (M + H) + IR (KBr): 3422-3382, 3062, 3051, 2951, 2926, 2913, 1738, 1613, 1604, 1511, 1494, 1457, 1438, 1399 , 1373, 1330, 10 1311, 1307, 1286, 1220, 1194, 1177, 1160, 1092, 1077, 1035, 883, 833 cm-1 F) (E) -4 - // 2- / 1- (4- fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt The diester prepared in Part E (1.1 mmol, 0.50 g) was stirred in dioxane (10.45 mL) under argon and 1 N LiOII (3.3 mmol, 3.3 mL). The reaction mixture was heated in a 70 ° C night bath for 45 minutes. The resulting white slurry was dissolved in 20 H 2 O-MeOH (9: 1, ca. 100 mL) and the solution was evaporated to dryness on a rotary evaporator at 35 ° C. The white solid was kept under high vacuum on the pump for 1 hour, after which it was redissolved in N-MeOH (9: 1, 100 mL) and the solution *. · 25 was concentrated on a rotary evaporator to a volume of about 8 ml.

This same solution was applied directly to a chromatographic column containing HP-20 resin (17.5 cm x 2.5 cm, equilibrated with water), which was eluted first with water (250 ml) and then with MeOH. ^ O mixture 30 (45:55). Fractions were collected every 1.3 minutes (approximately 10 mL). The product fractions were combined, evaporated on a rotary evaporator at 35 ° C, redissolved in water and lyophilized (16 hours), and the material thus obtained was kept under high vacuum created by a pump. 35 P 2 O 4 for 16 hours to give 0.449 g (1.02 mmol, 93% yield) of the title dilithium salt as a dry freeze-dried product. TLC (silica gel, η - (λmax-NH 4 OH-H 2 O 7: 2: 1): Rf = 0.49, PMA.

1 H-NMR (400 MHz, D 2 O): 67.73 (d, 1H, J = 8.06 Hz), 7.64 (s, 1H), 7.43 - 7.39 (m, 1H) , 7.25 - 7.13 (m, 5 4 H), 7.05 - 6.95 (m, 3 H), 5.62 (dd, 1H, J = 17.96 Hz, J = 21, 2 Hz), 2.43 (s, 3 H), 2.38 (dd, 1H, 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, 2 H)

Mass spectrum (FAB, m / e): 429 (M + H) +, 435 (M + LI) +, 10 441 (M + 2Li) + IR (KBr): 3431 (broad), 1603, 1593, 1511, 1494 , 1423, 1221, 1158, 1050 cm -1

Elemental analysis (C23H20FO5PL12 '87H2O' M = 455.94) Calculated: 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 (S) -4 - [[2- [1- (4-Fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt 20 A) (S) -3- [1H-dimethylethyl ) diphenylsilyl-7-oxy-4- [2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethynyl] methoxyphosphinyl] butanoic acid, methyl ester The acetylene phosphinate of Example 59, Part J (0.974 mmol, 0.675 g) was dissolved in methanol V 25 (14.3 mL). Argon V was blown through this solution for 10 minutes, after which 10% Pd / C catalyst (0.270 g) was added and the reaction mixture was shaken in a Parr hydrogenator at 2.8 bar H 2 for 24 hours. The reaction mixture was filtered through a pad of diatomaceous earth, which was rinsed with methanol, and the filtrate was evaporated; under reduced pressure to give a white foam.

The product was purified by flash chromatography (column diameter 50 mm, 11.5 cm layer of Merck / silica gel, eluent EtOAc-hexane in a ratio of ·: ·· 35 70:30, flow rate 5 cm / min) to give 0.556 g (0.798 mmol). , yield 82%) of the title saturated 252 87927 phosphinate as a white foam. Elution of the column with methanol further afforded 0.101 g (0.145 mmol, 15%) of product. TLC (silica gel, EtOAc-hexane 60:40): Rf = 0.24, PMA.

Δ δ-ΝΜΚ (270 MHz, CDCl 3): 67.78-7.14 (aromatic Hs, 19 H), 4.44 (m, 1H), 3.61 (s, 3 H) , 3.35 & 3.23 (2 xd, 3 H, J = 10.6 Hz), 2.92 - 2.83 (m, 1 II), 2.63 - 2.54 (m, 3 H) , 2.21 - 1.27 (m, 4 H), 2.45 & 2.42 (2x, 3 H), 1.00 (s, 9 H) Mass spectrum (CI, m / e): 697 (M + H) + IR (CHCl 3 solution): 3028, 3019, 3007, 2997, 2953, 2933, 2859, 1735, 1510, 1497, 1472, 1463, 1439, 1428, 1378, 1364, 1314, 1236, 1197 , 1157, 1142, 1112, 1091, 1073, 1065, 1043, 823 cm-1 B) (S) -4 - [[2- [N- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] methoxyphosphinyl] -3 -hydroxybutanoic acid, methyl ester

The silyl ether from Part A (0.775 mmol, 0.540 g) was stirred in dry THF (9.45 mL) under argon, and glacial acetic acid (3.10 mmol, 0.186 g, 0.177 mL) was added followed by dropwise addition of tetrabutylammonium fluoride ( 2.33 mmol, 2.1 mL of 1.1 M THF solution). The reaction mixture was stirred at room temperature for 16 hours. Ice water (30 mL) was added to the reaction mixture, and the mixture was diluted with EtOAc. The aqueous layer was extracted three times with EtOAc. The organic extracts were combined, washed once with saturated NaHCO 3 (aq) and once with saturated NaCl, dried over MgSO 4, filtered and evaporated under reduced pressure. The first flash chromatography purification (column diameter 40 mm, 15 cm layer of Merck silica gel, eluent 4% MeOH CH 2 Cl 2r flow rate 5 cm / min) gave 0.40 g white: solid. This solid was triturated with 100% hexane, filtered and maintained under high vacuum of 253,87927 (8 hours) to give 0.317 g (0.691 mmol, 89% yield) of the title hydroxyphosphinate as a white solid, mp 120 - 122 ° C. TLC (silica gel, 2%, CHOH-Me- containing MeOH): Rf = δ 0.12.

1 H-NMR (270 MHz, CDCl 3): δ $ 7.76 (d, 1H, J = 7.9 Hz), 7.69 (s, 1H), 7.42 - 7.16 (m, 7 H), 4.42 & 4.26 (2x, 1H), 3.92 & 3.84 (2x, 1H, J = 3.16 Hz), 3.72 (s, 3H), 3.58 & 3.54 (2 xd, 3 H, J = 3.69 Hz), 2.89-10 2.76 (m, 2 H), 2.56 (s, 3 H), 2.63 - 2.41 (m, 2 H), 1.92 - 1.61 (m, 4 H)

Mass spectrum (CI, m / e): 459 (M + H) + IR (KBr): 3428 (broad), 3287 (broad), 3064, 3050, 3017, 2989, 2952, 2921, 1737, 1603, 1510, 1497 , 1458, 1438, 15 1234, 1221, 1191, 1175, 1159, 1042, 826 cm-1 (C) (S) -4 - [[2- [N- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] hydroxyphosphinyl] -3-hydroxy-butanoic acid, dilithium salt

The diester prepared in Part B (0.687 mmol, 0.315 g) was stirred in indioxane (6.9 mL) under argon. To the solution was added 1 N LiOH (2.06 mmol, 2.06 mL). The reaction mixture was heated in a 70 ° C oil bath for 45 minutes. The reaction mixture was cooled to room temperature. The solvents were removed on a rotary evaporator at 35 ° C, and the resulting white solid was kept under high vacuum on the pump for 1 hour. The solid was then dissolved in distilled water (ca. 8 mL) and transferred to a chromatography column containing HP-20 'resin (16 cm x 30 2.5 cm, equilibrated with water). The column was eluted with water (250 mL) followed by MeOH-O (45:55). The residue was collected at 1.4 minute intervals (approximately \ 10 mL). The product fractions (37-47) were combined, evaporated on a rotary evaporator at 35 ° C and lyophilized at 35 ° C (16 hours) and kept under high vacuum at -20 ° C for 8 hours to give 254,87927. 0.286 g (0.647 mmol, 94% yield) of the title dilithium salt as a white freeze-dried product.

TLC (silica gel, n-Cl 2 H 2 OH-NH 3 OH 2 OH- 2 O 7: 2: 1): Rf = 0.42, PMA.

1 H-NMR (400 MHz, D 2 O): δ 7.82 (d, 1H, J = 8.6 Hz), 7.76 (s, 1H), 7.46 - 7.42 (m, 1 H), 7.30 - 7.25 (m, 3 H), 7.18 - 7.13 (m, 3 H), 4.06 (m, 1H), 2.72 - 2.66 (m , 2 H), 2.54 (s, 3 H), 2.34 (dd, 1 H, J = 4.4 Hz, J = 15.22 Hz), 2.22 (dd, 1H, J = 8.43 Hz, J = 15.02 Hz), 1.59 - 1.51 (m, 2 H), 1.44 - 1.39 (m, 2 H)

Mass spectrum (FAB, m / e): 443 (M + H) + IR (KBr): 3451-3426 (broad), 3151, 3124, 1620, 1593, 1509, 1439, 1422, 1403, 1218, 1159, 1050 cm Elemental analysis (025 ^ 2 ^ 5 ^ - ^ 2 '® M = 453.09) Calculated: C, 60.96; H, 5.16; F, 4.19; P, 6.83

Found: C, 60.96, H, 5.29; F, 4.12; P, 6.82

Example 62 4- [3- (4'-Fluoro-3,3 ', 5'-trimethyl-1,1'-biphenyl-2-yl) propyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt A) 3- (41 -fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl) -2-propenoic acid, ethyl ester:: Sodium hydride (4.96 mmol, 0.119 g, 0.149 g of an 80% mineral oil dispersion) rinsed under Argo-25. This suspension was cooled to 0 ° C, and. ; a solution of triethylphosphonoacetate (4.96 mmol, 1.1 g, 0.983 mL) in dry THF (2.2 mL) was added dropwise over 5 minutes. The resulting clear solution was stirred at 0 ° C for 30 minutes, then warmed to room temperature and stirred for 30 minutes. Finally, V: a solution was added dropwise over 8 minutes, which. * ··. contained the aldehyde of Example 1, Part C (4.13 ____: mmol, 1.0 g) in dry THF (2.5 mL). The reaction mixture was stirred at room temperature for 1 hour. Water was added to the mixture, and the aqueous layer was extracted twice with 255 87 927

EtOAc and twice with Et 2 O. The organic extracts were combined, washed once with saturated NaCl solution, dried over MgSO 4, filtered and evaporated under reduced pressure. The product was purified by flash chromatography-5 (column diameter 50 mm, 15 cm layer of Merck silica gel, 6% EtOAc in hexane, flow rate 5 cm / min) to give 1.19 g (3.79 mmol, yield 92%) of the title vinyl ester as a pale yellow foam. TLC 10 (silica gel, 4% EtOAc in hexane): Rf = 0.22, PMA.

1 H-NMR (270 MHz, CDCl 3): 07.64 (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, 3 H), 1.25 (t, 3 H, J = 7.12 Hz)

Mass spectrum (CI, m / e): 313 (M + H) + B) (4'-Fluoro-3,3 ', 5-trimethyl-1,11-biphenyl-2-yl) butanoic acid, ethyl ester

The vinyl ester prepared in Part A (3.68 mmol, 1.15 g) was dissolved in absolute EtOH (36 mL). Argon was blown through the solution for 10 minutes. 10% Pd / C catalyst (230 mg) was added and H 2 (g) was blown through the solution for 10 minutes. The reaction mixture was stirred under an atmosphere of H 2 for 2 h. The reaction mixture was diluted with EtOH and filtered through a 1.3 cm pad of diatomaceous earth into a 60 mL sintered funnel. The diatomaceous earth was washed with EtOH. The filtrate was evaporated under reduced pressure to give 1.12 g (3.56 mmol, 97% yield) of the title compound. . 30 as a white solid. TLC (silica gel, 5% EtOAc in hexane): Rf = 0.29, PMA.

1 H-NMR (270 MHz, CDCl 3): δ 7.09 - 6.97 (m, 4 H), 6.84 (s, 11 H), 4.06 (q, 2 H, J = 7.12 Hz ), 2.90-2.84 (m, 2H), 2.37 (s, 3H), 2.30 (2x, 6H), 2.32 - ". 2.27 (m , 2 H), 1.20 (t, 3 H, J = 7.12 Hz)

Mass spectrum (CI, m / e): 315 (M + H) + 256 87 927 C) (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) propanol

Lithium aluminum hydride (3.5 mmol, 0.133 g) was stirred in dry Et 2 O (3.5 mL) under argon. This suspension was cooled to 0 ° C and a solution of the ester prepared in Part B (3.5 mmol, 1.1 g) in dry Et 2 O (3.5 mL) was added dropwise over 8 minutes. The reaction mixture was stirred at 0 ° C for 15 minutes, then warmed to room temperature and stirred for 45 minutes. The mixture was re-cooled to 0 ° C and water (0.133 mL) was added dropwise, followed by 15% NaOH (0.133 mL) and finally water (0.399 mL). The suspension was warmed to room temperature over 30 minutes. The resulting white powder was filtered off and washed with dry Et 2 O. The filtrate was concentrated, azeotroped once with benzene and evaporated under reduced pressure to give 0.950 g of alcohol, which was purified by flash chromatography (50 mm column diameter, 15 cm layer of Merck silica gel, eluting with 35% EtOAc in 35% EtOAc). , flow rate: 5 cm / min) to give the title alcohol as a colorless oil. TLC (silica gel, 20% EtOAc in hexane): Rf = 0.18, PMA.

1 H-NMR (270 MHz, CDCl 3): δ 7.08 - 6.93 (m, 4 H), 6.82 (s, 1H), 3.45 - 3.40 (m, 2 H), 2.60-2.54 (m, 2H), 2.34 (s, 3H), 2.28 (2x, 6H), 1.63-1.52 (m, 2H) ). . Mass spectrum (CI, m / e): 273 (M + H) + D) 2- (3-bromopropyl) -41-fluoro-3,31,5-tri- ·] methyl-1H-biphenyl: *: A solution of triphenylphosphine (10.1 mmol, 2.65 g) in dry THF (27.5 mL) was cooled to 0 ° C and a solution of carbon tetraborimide (10 mL) was added dropwise. 71 mmol, 257,87927 (3.55 g) in dry THF (5.5 mL). The resulting yellow / white suspension was stirred at 0 ° C for 2 hours. A solution of the alcohol prepared in Part C (4.04 mmol, 1.1 g) in dry THF (8.2 mL) was added dropwise to the complex. 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 EHO. The filtrate was washed once with saturated NaCl solution, dried over 10 MgSO 4, filtered and evaporated under reduced pressure. The product was purified by flash chromatography (column diameter 50 mm, 15 cm layer of Merck silica gel, eluent 2% EtOAc in hexane, flow rate 5 cm / min) to give 1.35 g (4.05 15 mmol, yield 100%) of the title bromide as a pale yellow oil. TLC (silica gel, 100% hexane): Rf = 0.22, PMA.

1 H-NMR (270 MHz, CDCl 3): 67.07 - 6.99 (m, 4 H), 6.82 (s, 1H), 3.22 (m, 2 H), 2.69 - 2, 63 (m, 2 H), 2.36 (s, 3 H), 2.30 (s, 3 H), 2.28 (s, 3 H), 1.90 - 1.80 (m, 2 H); B)

Mass spectrum (CI, m / e): 235 (M + H) + E) / 3- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-bi-phenyl-2-yl) ) propylphosphonic acid, dimethyl ester The bromide prepared in Part D (3.88 mmol, 1.3 g) was stirred in trimethyl phosphite (38.8 mL) under argon. The reaction mixture was refluxed in a 135 ° C oil bath for 36 hours. Excess (CH 3 O) 3 P was removed by short path distillation, and the residue was kept under high vacuum at 100 ° C for 1 hour. The resulting yellow oil was purified by flash chromatography (column diameter 50 mm, 15 cm layer of Merck silica gel, eluent EtOAc-hexane 85:15, flow rate 35 5 cm / min) to give 1.13 g (3.10 mmol). , yield • 80 5) the title dimethyl phosphonate as a colorless 258 8792 7 oil. TLC (silica gel, 100% EtOAc): Rf = 0.28, PMA.

1 H-NMR (270 MHz, CDCl 3): (δ 7.08 - 6.97 (m, 4 H), 6.81 (s, 1H), 3.65 (d, 6 H, J = 11 Hz), 2.63 - 2.56 δ (m, 2 H), 2.34 (s, 3 H), 2.30 (2 x, 3 H), 2.28 (s, 3 H), 1.68 - 1.50 (m, 4H)

Mass spectrum (CI, m / e): 365 (M + H) + F) / 3- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) propyl] phosphonic acid, monomethyl ester 10 The phosphonate prepared in Part E (3.43 mmol, 1.25 g) was stirred in dioxane (8.23 mL) under argon. To this solution was added 1 N LiOH (5.15 mmol, 5.15 mL), and the mixture was heated in a 95 ° C oil bath. After 1 h, more LiOH (3.43 mmol) was added and the reaction mixture was reheated to 95 ° C for 3.5 h. The reaction mixture was cooled to room temperature. The solvents were removed under reduced pressure. The white solid residue was diluted with water (25 mL), the suspension was cooled to 0 ° C, and the pH was adjusted to 1 with 5% HCl (aq). The aqueous layer was extracted four times with EtOAc. The organic extraction solutions were combined, dried over MgSO 4 and filtered, and the filtrate was concentrated. The residue was azeotroped twice with benzene, and the remaining: 25 viscous oil remaining was kept under high vacuum with a pump for 4 hours, 1.18 g (3.37 mmol, 98% yield) of phosphonate monomethyl ester as a yellow oil TLC (silica gel, CH 2 Cl 2 -MeOH-CH 3 CO 2 H 10: 1: 1): Rf = 0.46, PMA .

. . 1 H-NMR (270 MHz, CDCl 3): δ $ 7.06-6.95 (m, 4 H), 6.81 (s, 1H), 3.56 (d, 3 H, J = 11 Hz) ), 2.62 - 2.53 (m, 2 H), 2.32 (s, 3 H), 2.27 (2 x, 6 H), 1.69 - 1.48: m 4 H) ·· Mass spectrum (FAB, m / e): 351 (M + H) + 1 ί 259 87927 G) 4 - // 3- (41-fluoro-3,3 ', 5-trimethyl-1,11 -bi-phenyl-2-yl) propyl / methoxyphosphinyl-3-oxobutanoic acid, methyl ester

The phosphonate monoester M 5 prepared in Part F (3.22 mmol, 1.13 g) was stirred in dry CH 2 Cl 2 (12.9 mL) under argon. To this solution was added TMSDEA (6.44 mL, 0.918 g, 1.20 mL, freshly distilled) dropwise over 8 minutes. This solution was stirred at room temperature for 1.5 hours. The volatiles were removed under reduced pressure (removal under argon). The residue was once azeotroped with dry benzene (70 ml) and evaporated under reduced pressure (removal under argon). Finally, the residue was kept under high vacuum with the pump for 50 minutes. The residue was then stirred in dry CH 2 Cl 2 (12.9 mL) under argon. DMF (2 drops) was added, the solution was cooled to 0 ° C, and oxalyl chloride (3.70 mmol, 0.470 g, 0.323 mL) was added dropwise over 8 minutes. The reaction mixture was stirred at 0 ° C for 20 ml to 20 minutes, then warmed to room temperature and stirred for 1 hour 45 minutes. The volatiles were removed, the residue was azeotroped and maintained under high vacuum with a pump as above. The rusty oil) was then stirred in dry THF (9.0 mL) under argon. This solution was cooled to -78 ° C and kept at -78 ° C and kept at -78 ° C while dropwise addition of methyl acetoacetate di- formed in the following manner over 20 minutes. To a THF solution of 30 anions cooled to -78 ° C:

Sodium hydride (4.85 mmol, 0.116 g, 0.145 g of an 80% mineral oil dispersion) was rinsed once with hexane and dried under a stream of argon. The solid was then stirred in dry THF (7.1 mL) under argon and this suspension was cooled to 0 ° C. A solution of methyl acetoacetate (4.36 mmol, 0.506 g, 0.471 mL) in dry THF (3.6 mL) was added dropwise over 8 minutes and the resulting clear solution was stirred at 0 ° C for 25 minutes. . N-BuLi (4.04 mmol, 1.62 mL of a 2.5 M hexane solution; Aldrich) was then added dropwise to the reaction mixture over 5 minutes. The resulting yellow solution was stirred at 0 ° C for 35 minutes, then cooled to -78 ° C and a THF solution of the phosphono-10 chloride formed above cooled to -78 ° C was added dropwise over 20 minutes. The reaction mixture was stirred at -78 ° C for 1 h, after which a saturated solution of NH 4 Cl (aq) (45 mL) was added and the mixture was warmed to room temperature. The mixture was diluted with water (45 mL) and EtOAc. The aqueous layer was extracted four times with EtOAc. The organic extracts were combined, washed once with saturated NaHCO 3 (a) solution and once with saturated NaCl solution, dried over MgSO 4, filtered and evaporated under reduced pressure to give 2.0 g of a rusty oil.

The product was isolated by flash chromatography (column diameter 40 mm, Merck silica gel 35: 1, eluent first 100% EtOAc and then CH 2 Cl 2 containing 5% MeOH, flow rate 5 cm / min) to give 0.220 g (0.491 mmol , yield 15%) of the title i: 25 p> -ketophosphinate as a rusty oil. TLC (silica gel: 100% EtOAc): Rf = 0.19, PMA.

1 H-NMR (270 MHz, CDCl 3): δ 7.08 - 6.98 (m, 4 H), 6.81 (s, 1H), 3.73 (s, 3 H), 3.65 (d , 3 H, J = 11 Hz), 3.64 (s, 2 H), 3.10 (dd, 2 H, J = 5.27 Hz, J = 17.41 Hz), 2.67 - 2.57 (m, 2H), 2.35 (s, 3H), 2.30 & 2.28 (2x, 3H), 2.29 (s, 3H), 1.72-1 .56 (m, 4H)

Mass spectrum (CI, m / e): 449 (M + H) + 261 87927 H) 4- [3- (4'-Fluoro-3,315-trimethyl-1,11-bi-phenyl-2-yl) propyl] methoxyphosphinyl] - 3-Hydroxy-butanoic acid, methyl ester

The β-ketophosphinate prepared in Part G (0.223 5 mmol, 0.10 g) was stirred in dry THF (1.9 mL) under argon. This solution was cooled to 0 ° C, then NaBH 4 (0.223 mmol, 0.008 g) was added followed by dropwise addition of MeOH (0.194 mL, dry with 4 A molecular sieves). The reaction mixture was stirred at 10 ° C for 1 hour, after which acetone (0.194 ml) was added followed by CC-4 silica gel (Mallinckrodt; 0.10 g). The suspension was stirred while warming to room temperature and then filtered through a sintered funnel. The Si-15 silica gel was washed with EtOAc. The filtrate was evaporated under reduced pressure to give 0.108 g of a golden oil. Flash chromatography (column diameter 10 mm, Merck silica gel 35: 1, CH 2 Cl 2 in 4% MeOH as eluent, flow rate 5 cm / min) isolated two reaction products. The desired title p-hydroxyphosphinate was obtained in 58% yield (0.058 g, 0.129 mmol) as a pale yellow oil. 0.19 g (0.043 mmol, 20% yield) of 1,3-butanediol phosphinate was also obtained. TLC (silica gel, 3.5% MeOH in CH 2 Cl 2): R f = 0.19, PMA.

1 H-NMR (270 MHz, CDCl 3): δ $ 7.08 - 6.98 (m, 4 H), 6.82 (s, 1H), 4.44 & 4.32 (2 x m, 1H), 3.63 & 3.62 (2x, 3 H, J = 10.55 Hz), 3.70 (s, 3 H), 2.65 - 2.50 (m, 4 H), 2.35 (s, 3H), 2.30 (2x, 3H), 2.29 (s, 3H), 1.89 -. . 1.76 (m, 2H), 1.71-1.59 (m, 4H)

Mass spectrum (CI, m / e): 451 (M + H) + + · 3- (3-) (4'-fluoro-3,3 ', 5-trimethyl-1,1'-bi-): phenyl-2-yl) propyl-hydroxyphosphinyl-3-hydroxy-2-butanoic acid, dilithium salt The diester prepared in Part H (0.122 mmol, · "0.055 g) was stirred in dioxane (2 ml) under argon, 262 37 927 and 1 N LiOH was added: (0.366 mmol, 0.366 mL) The reaction mixture was heated in an oil bath at 80 ° C for 45 minutes, cooled to room temperature, and the solvents were removed on a rotary evaporator The resulting yellow solid was kept under high vacuum on a pump for 2 hours to give the title compound. TLC (silica gel, Cl 2 Cl 2 -MeOH-CH 2 Cl 2 H 2: 1: 1): Rf = 0.29, PMA.

1 H-NMR (270 MHz, D 2 O): (δ 7.08 - 7.05 (m, 4 H), 6.80 (s, 1H), 4.13 (m, 1H), 2.54 - 2.47 (m, 2 H), 2.38 - 2.28 (m, 2 H), 2.30 (s, 3 H), 2.22 (s, 3 H), 2.20 (s , 3 H), 1.59 - 1.50 (m, 2 H), 1.42 - 1.29 (m, 4 H)

Example 63 15 / 1S- / I <a (R *), 2 <a, 4a <b, 8 <b, 8a <a / 7-4 - // 2- [8- (2,2-dimethyl-1 -oxobutoxy) decahydro-2-methyl-1-naphthalenyl / ethyl / hydroxyphosphinyl-7-hydroxybutanoic acid, dilithium salt A) / IS- (1 <a, 2 <a, 4a <b, 8 <b, 8a <a) 7-8- [(1,1-di-20-methylethyl) dimethylsilyl] oxy-1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenemethanol

To dry 0 ° C (ice bath) in Et 2 O (5 mL) was added lithium aluminum hydride (132 mg, 1 molar equivalents) followed by dropwise addition of / Is- (1 <a, 2 <a, 4a <b, 8 <b , 8a <a) (7-8-25 (T1 (1-dimethylethyl) dimethylsilyloxy) -1,2,4a, 5,6,7, ·. 8α-Octahydro-2-methyl-1-naphthalenecarboxylic acid methyl ester / R. L. Funk et al., Tetrahdedron Lett. 25 (1984) 16557 (1.175 g, 3.47 mmol) in dry Et 2 O (5 mL), and the resulting gray suspension was stirred. - 30 were tested at room temperature under argon overnight.

Water (130 μΐ), 15% NaOH (130 μl) and water (390 μΐ) were added successively dropwise to the mixture.

-: The precipitated salts were positioned by filtering the mixture through anhydrous MgSO 4 placed diagonally on packaged diatomaceous earth. Evaporation under reduced pressure gave 1.112 g of a clear oil which was purified by flash chromatography on silica gel using hexane-EtOAc (95: 5) as adsorbent to give 902 mg (85.7%) of the desired title alcohol as a clear oil. , which crystallized on standing; Melting point 79-81 ° C. TLC (hexane-EtOAc 9: 1): Rf = 0.21.

Elemental analysis (CH 2 Cl 2 / CH 2 Si):

Calculated: C, 69.61; H, 11.04 Found: C, 69.64; H, 11.04 1 H-NMR (CDCl 3): δ> 0.00 (s, 6 H), 0.82 (s, 9 H), 0.83 (d, 3 H), 0.94 - 1 .05 (m, 2H), 1.18 (s, 1H), 1.2-1.42 (m, 2H), 1.67 (m, 3H), 1.89 (m, 1H), H), 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, 1H) ppm 15 B) / IS- (l <a, 2 <a, 4a <b, 8 <b, 8a <a) / - 8- / (1,1'-dimethylethyl) dimethylsilyl] oxy-1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenecarboxaldehyde

To a solution of Dess-Martin periodinane (895 mg, 2.11 mmol) in dry Cl 2 Cl 2 (6 mL) was added dry CH 2 Cl 2 (200 μL) and the white suspension was stirred at room temperature. under argon for 15 minutes. A solution of alcohol (596 mg, 1.92 mmol) in dry Cl 2 Cl 2 (6 mL) was added dropwise over 5 minutes and the mixture was stirred at room temperature. At 25 under argon for 20 minutes. The mixture was added - to a solution of sodium thiosulfate (2.12 g) in 1.0 N NaHCO 3 (12 mL), and the resulting mixture * was stirred until all solids had dissolved.

The organic phase was washed with saturated NaHCO 3, water and saturated NaCl, then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 1.005 g of a colorless oil. The crude product was combined in a smaller batch (1.306 g in total) and then purified by flash chromatography on silica gel using hexane-EtOAc (98: 2) as adsorbent. The product fractions were evaporated under reduced pressure to 264,37927 to give 667 mg (75.7%) of the desired title aldehyde as a colorless oil. TLC (hexane-EtOAc 7: 3): Rf = 0.70, PMA.

1 H-NMR (CDCl 3): 60.07 (s, 3 H), 0.00 (s, 3 H), 0.85 δ (s, 9 H), 0.89 (d, 3 H), 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, 1H), 4.30 (s, 1H), 5.40 (d, 1H), 5.50 (m, 1H), 9.74 (d, 1H) C) / IS- (1 <a, 2 <a, 4a <b, 8 <b, 8a <a) yl- (2,2-dibromo-10 ethenyl) -8- // t1.1-dimethylethyl) dimetyylisilyl7oksi7-1,2,4a, 5,6,7,8,8a-octahydro-2-methylnaphthalene

To a solution of the aldehyde prepared in Part B (667 mg, 2.16 mmol) and triphenylphosphine (1.7 g, 6.48 mmol) in dry CH 2 Cl 2 (10 mL) and kept at -15 ° C (salt ice bath), a solution of carbon tetrabromide (1.7 g, 6.48 mmol) in CH 2 Cl 2 (5 mL) was added dropwise over 5 minutes, and the deep reddish brown mixture was stirred under argon at -15 ° C. 30 minutes, at 0 ° C for 2 hours 20 and finally at room temperature overnight. The mixture was re-cooled to 0 ° C, more triphenylphosphine (567 mg, 216 mmol) was added followed by CBr 2 (358 mg, 1.08 mmol), and the mixture was stirred at room temperature for 4 hours. To the mixture was added saturated NaHCO 3 (10 mL) and diluted with CH 2 Cl 2, and the organic phase was filtered through sintered glass, washed with saturated NaHCO 3 and saturated NaCl, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. to give 3.578 g of a brown solid. The crude product was purified by flash chromatography on silica gel using adsorbent and hexane alone as eluent. The product fractions were evaporated to give 677 mg (67.3%) of pure title vinyl dibromide as a colorless oil.

TLC (hexane-acetone 9:11): Rf = 0.73, UV and PMA.

265 87927 1 H-NMR (CDCl 3): ¢ $ 0.08 & 0.10 (2 singlets, 6 H), 0.85 (d, 3 H), 0.90 (s, 9 H), 0.98 (m , 2 H), 1.25 - 2.52 (m, 5 H), 1.74 (m, 1H), 1.82 (m, 1H), 2.39 (m, 1H), 2 , 56 (m, 1H), 2.66 (m, 1H), 3.95 (s, 1H), δ 5.48 (d, 1H), 5.52 (m, 1H), 6.37 (d, 1H) ppm.

D) / IS- (1 <a, 2 <a, 4a <b, 8 <b, 8a <a) γ-8- [771,1-dimethylethyl) dimethylsilyloxy] -1-ethynyl-1,2,4a , 5,6,7,8,8a-octahydro-2-methylnaphthalene

To a solution of 10 vinyl dibromide (495 mg, 1.07 mmol) prepared in Part C in dry THF (6 mL) and kept at -78 ° C (carbonic acid-acetone bath) was added dropwise 1.6 M over 5 minutes. A hexane solution of n-BuLi (1.34 mL, 2.14 mmol), and the clear colorless mixture was stirred at -78 ° C under argon for 30 minutes. Saturated NH 4 Cl (5 mL) was added to the mixture at -78 ° C, the mixture was allowed to warm to room temperature and diluted with EtOAc, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. 291 mg (89.6%) of crude title acetylene were obtained as a colorless oil. TLC (hexane): Rf = 0.43, UV and PMA. 1 H-NMR (CDCl 3): δ 0.08 & 0.12 (2 singlets, 6 H), 0.90 (s, 9 H), 0.99 (m, 1H), 1.09 (d, 3 H), 1.19 (m, 1H), 1.46 (m, 2H), 1.74 (m, 3H), 2.12 (d, 1H),. 2.30 (m, 1H), 2.41 (m, 1H), 2.71 (m, 1H), 4.37 (m, 1H), 5.38 (d, 1H) ), 5.55 (m, 1H) ppm; · E) (S) -4- (chloromethoxyphosphinyl) -3- [1,1'-dimethylethyl) diphenylsilyl] oxy7-butanoic acid, methyl ester • '/ • f The phosphonochloridate was prepared according to Example 25'. from the dicyclohexylamine salt of Part B by the following procedure: The free acid was formed by partitioning the dicyclohexylamine salt (1.3 g, 35 2.05 mmol) between EtOAc and 5% KHSO 4, and the organic the layer was washed with 5% KHSO 4 (4 x 266 87927 and saturated NaCl), then dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give the free acid as a clear viscous oil. Phosphonic acid monomethyl ester (2.05 mmol) was taken up in dry Cl 2 Cl 2 (5 mL), distilled N, N-diethyltrimethylsilylamine (515 μL, 4.1 mmol) was added, and the clear colorless solution was stirred at room temperature under argon for 1 h. The excess reagent and solvent were removed under reduced pressure, and the remaining oil was re-evaporated with Benzene (2 x 10 mL).

A solution of crude silyl ester (ca. 2.05 mmol) in dry CH 2 Cl 2 (5 mL) and dry DMF (1 drop) was cooled to 0 ° C (ice bath), and distilled oxalyl chloride was added dropwise ( 195 μl, 2.26 mmol), and the yellow mixture was stirred under argon at 0 ° C for 15 minutes and at room temperature for 45 minutes. The mixture was evaporated under reduced pressure and again with dry benzene (2 x 20 ml) to give the crude title phosphonochloridate as a viscous yellow. . as an oil.

:; VF) flS - / 'l <a (R *), 2 <a, 4a <b, 8 <b, 8a <a77-4- / 77B- / f (1,1-dime style) dime ethylsilyl / oxy-1,2,4a, 5,6,7,8,8a- • 25 octahydro-2-methyl-1-naphthalenyl-ethynyl-methoxy-·: phosphinyl-3- (1H-1-dimethylethyl) diphenylsilyl-7 oxy7butanoic acid, methyl ester

To a solution of the acetylene prepared in Part D (356 mg, 1.17 mmol) in dry THF (5 mL) and maintained at -78 ° C was added dropwise a 1.6 M solution of n-BuLi in hexane (730 μL). , 1.17 mmol), and the clear mixture was stirred at -78 ° C under argon for 30 minutes. The acetylene anion was then transferred dropwise via tube over 15 minutes to a solution of the phosphonochloridate prepared in Part E in dry THF (6 mL) at -78 ° C. The yellow mixture 267 87927 was stirred at -78 ° C for 30 minutes, after which saturated NH 4 Cl (5 mL) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was partitioned between EtOAc and water, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 1.282 g of a pale yellow oil. The crude product was purified by flash chromatography on silica gel using hexane-EtOAc (7: 3) as eluent. The product fractions were evaporated to give 624 mg (72.4%) of the title acetylene phosphinate as a colorless glass. TLC (hexane-acetone 7: 3):

Rf = 0.49, UV and PMA.

15 G) (Is- / I <a (R *), 2 <a, 4a <b, 8 <b, 8a <a (7-4 - // 2- (8- [7 (1,1-dimethylethyl) dimethylsilyloxy] decahydro) 2-Methyl-1-naphthalenyl-ethyl-7-ethoxy-phosphinyl-3 - [(1,1-dimethylethyl) -diphenylsilyl] oxy-butanoic acid, methyl ester 20 To a solution of the acetylene phosphinate prepared in Part F (498 mg) in CH 2 OH (6 mL) was added % Pt / C catalyst (200 mg), and the black: suspension was shaken on a Parr apparatus under H 2 (2.8 bar) for 48 hours. The catalyst was removed by filtering the mixture through diatomaceous earth, a new catalyst (150 mg) was added to the reaction mixture, and the suspension was shaken on a Parr I. * Under H 2 (2.8 bar) for a further 24 hours.

1; The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated under reduced pressure to give 448 mg of a clear glass. The crude product was purified by flash chromatography using silica gel as adsorbent and hexane-EtOAc as eluent. mixture (8: 2). The product fractions were evaporated under reduced pressure,]. to give 334 mg (66.5%) of the title compound as a colorless glass. TLC (EtOAc-hexane 7: 3): 3 diastereomer as a single spot,

Rf = 0.42; fourth diastereomer as a single spot, Rf = 0.49; UV and PMA.

268 87927 H) / Is- / I <a (R *), 2 <a, 4a <b, 8 <b, 8a <a ^ 7-4- (E2-decahydro-8-hydroxy-2- methyl 1-naphthalenyl) ethyl7-methoxy-phosphinyl-3- (1,1'-dimethylethyl) diphenylsilyl-7-oxybutanoic acid, methyl ester 5 To a solution of the compound prepared in Part G (248 mg, 0.334 mmol) in CH 2 CN (4 mL) was added 48- % aqueous HF (36, 1 mmol), and the mixture was stirred at room temperature under argon for 6.5 hours. The mixture was partitioned between EtOAc and saturated NaHCO 3, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 227 mg of a colorless glass. The crude product was purified by flash chromatography on silica gel using adsorbent and hexane-EtOAc (4: 1) as eluent followed by EtOAc alone. The product fractions were evaporated under reduced pressure to give 159 mg (75.8%) of pure title monoalcohol as a colorless oil. TLC (acetone-hexane 7: 3): Rf = 0.5, UV (weak) and PMA.

I) (1S- / 1 <a (R *), 2 <a, 4a <b, 8 <b, 8a <a (7-3- (7,1,1-dimethylethyl) diphenylsilyloxy] -4 - [2- 8- (2,2-Di-: methyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl

Ethyl 7 methoxyphosphinyl 7 butanoic acid, methyl ester To a solution of the alcohol prepared in Part H (174 mg, 0.234 mmol) in dry pyridine; (1.5 ml), 2,2-dimethylbutyryl chloride was added; (160 μL, 1.17 mmol, 3 eq.) Followed by 4-dimethylaminopyridine (3 mg, 0.1 eq.), And the pale yellow mixture was heated at 100 ° C under argon for 4 h. The mixture was cooled, partitioned between 1.0 N HCl and EtOAc, and the organic phase was washed with 1.0 N HCl (twice) and saturated NaCl solution, dried over anhydrous Na 2 SO 4. and evaporated to give 255 mg of a pale tan oil.

The crude product was purified by flash chromatography i.

269 87927 using silica gel as adsorbent and hexane-EtOAc (55:45) as eluent. The product fractions were evaporated under reduced pressure to give 112 mg (65.9%) of the desired title dimethylbutyryl ester as a colorless oil. TLC (hexane-acetone): Rf = 0.62, UV and PMA.

J) / 1S- / I <a (R *), 2 <a, 4a <b, 8 <b, 8a <a / 7-4 - // 2- [8- (2,2-dimethyl-1- oxobutoxy) decahydro-2-methyl-1-naphthalenyl7-ethyl7-methoxyphosphinyl-3-hydroxy-10-butanoic acid, methyl ester

To a solution of the silyl ester prepared in Part I (130 mg, 0.179 mmol) in THF (2 mL) was added sequential glacial acetic acid (HOAc) (41 μL, 0.716 mmol) and 1.1 M (nCl 2 Hg) NF. THF solution (490 μΐ, 0.537 mmol), 15 and the mixture were stirred under argon overnight. The mixture was partitioned between EtOAc and 5% KHSO 4, the organic phase was washed with water and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 115 mg of a colorless oil. The crude product was purified by flash chromatography using silica gel as adsorbent and hexane-acetone (1: 1) as eluent. The product fractions • were evaporated under reduced pressure to give 72 mg (82.4%) of the desired title alcohol as a colorless oil. TLC (hexane-acetone 1: 1): Rf = 0.20, UV and PMA.

. K) / 1S- / I <a (R *), 2 <a, 4a <b, 8 <b, 8a <a77-4 - // 2- / 8-; ; (2,2-Dimethyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenyl] ethyl7-hydroxyphosphinyl-3-hydroxy-30-butanoic acid, dilithium salt

To a solution of the alcohol prepared in Part J: alcohol (72 mg, 0.147 mmol) in dioxane (1.5 mL) was added. 1.0 N LiOH (0.52 mL) was adjusted, and the mixture was heated at 55 ° C (oil bath) under argon for 1.5 h. The mixture was cooled, diluted with water, filtered and evaporated in vacuo to an oil. The crude product was purified by chromatography on 270 87927 HP-20 resin columns (3 cm layer, column diameter 15 mm) using water as eluent and then a mixture of O 2 -CH 2 OH (70:30). The product fractions were evaporated under reduced pressure, the residue dissolved in water (20 ml), and the solution lyophilized to give 55 mg (74%) of the desired title dilithium salt as a white solid. TLC (CH 2 Cl 2 -CH 2 OH-CH 2 COOH 8: 1: 1): Rf = 0.05, PMA.

Elemental analysis (C 23 H 39 O 7 Pl 2 O 2 + 1/78 mol H 2 O, M = 504.53) Calculated: C, 54.75; H, 8.50; P, 6.14 Found: C, 54.75; H, 8.64; P, 5.93

Example 64 (S) -4- [7/3 '- (4-Fluorophenyl) spiro / cyclopentane-1,1'- (1H-inden) -7-yl] ethynyl] hydroxyphosphinyl] -3-15 hydroxybutanoic acid, dilithium salt A) 3- ( 4-Fluorophenyl) -1H-indene To a solution of 4-fluorophenylmagnesium bromide (prepared from 6.43 ml of 4-fluorobromobenzene and 1.71 g of Mg in 50 ml of ether) kept at room temperature under argon was added a solution of 1-indanone (6.61 g, 50 mmol) in dry ether (20 mL) dropwise over 40 minutes. After the reaction · *; the mixture was stirred at room temperature for 1 hour, saturated NH 4 Cl solution I '·' was added dropwise; 25 (15 ml). The mixture was diluted with Et 2 O, washed with saturated: NaCl solution, dried (MgSO 4) and evaporated.

The residue was dissolved in glacial acetic acid (15 mL), and the solution was refluxed under argon for 30 minutes. The acetic acid was evaporated off and the evaporation was repeated twice with the aid of toluene. The residue (9.45 g) was purified by flash chromatography on silica gel using adsorbent and hexane as eluent to give the title compound (8.174 g, 78%) as a colorless oil which crystallized on standing. mp 35-40 ° C. TLC (hexane): Rf = 0.21.

271 87927 B) 3 '- (4-fluorophenyl) spiro / cyclopentane-1,1'- (1H-indene) -7

To a solution of the compound prepared in Part A (10.676 g, 50.8 mmol) in dry THF (90 mL) 5 and maintained at 0 ° C under argon was added solid potassium t-butoxide (12.2) in several portions. g, 109 mmol). After the mixture was stirred at 0 ° C for 30 minutes, 1,4-dibromobutane (6.50 mL, 101 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 2 h, then partitioned between EtOAc and 5% KHSO 4 (150 mL each). The organic phase was washed with saturated NaCl solution, dried (Na 2 SO 4) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using adsorbent and hexane as eluent to give the title compound (9.43 g, 70%) as a colorless oil. TLC (Et 2 O-hexane 1: 9):

Rf = 0.69 (Rf = 0.63 for the compound prepared in Part A).

20 C) 31- (4-fluorophenyl) spiro / cyclopentane-1,1'- (1H-indene) γ-2'-carboxaldehyde

To a solution of the compound prepared in Part B (9.30 g, 35.2 mmol) in dry Cl 2 Cl 2 (50 mL) and maintained at 0 ° C under argon was added 1.0 M TiCl 2. Cl 2 Cl 2 solution (70 mL, 70 mmol).

/ / / To the resulting dark green solution was added dropwise 1,1-dichloromethyl methyl ether (3.50 mL, 38.7 mmol). After the mixture was stirred at 0 ° C for 1 hour and at room temperature for 1 hour, it. . 30 was poured into cold saturated NaHCO 3 solution. The organic phase was separated, dried (Na 2 SO 4) and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using adsorbent and Et 2 O-hexane war (5:95) as eluent to give the title compound. Compound (8.233 g, 80%) as a yellow oil Crystallization of the oil from hexane gave 272 8 7 92 7 of pure title compound (6.778 g, 66%) as pale yellow crystals, mp 116-117 ° C.

TLC (Et 2 O-hexane 15:85); Rf = 0.56. Elemental analysis (C 20 H 17 OF 3: δ Calculated: C, 82.17; H, 5.86; F, 6.50 Found: C, 83.13; H, 5.82; F, 6.29

D) 2'-Ethynyl-3 '- (4-fluorophenyl) spiro / cyclopentane-1,1'- (1H-indene)

To a solution of potassium t-butoxide 10 (0.672 g, 6.00 mmol) in dry THF (8 mL) at -78 ° C under argon was added dropwise a solution of dimethyldiazomethylphosphonate (0.960 g, 6.40 mmol). mmol) / prepared in J. Org. Chem. 36 (1971) 1379 / in THF (4 ml). After the mixture was stirred at -78 ° C for 5 minutes, a solution of the compound prepared in Part C (1.168 g, 4.00 mmol) in THF (8 mL) was added dropwise over 10 minutes. 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 hexane (50 mL) and washed with 5% KHSO 4. solution. The organic phase was washed with saturated NaCl solution, * dried (Na 2 SO 4>) and concentrated to a small volume ... (not dry). The yellow solution was flash chromatographed on silica gel using silica gel as the adsorbent and hexane as the eluent. was combined, treated with butylated hydroxytoluene (BHT (0.080 g, 0.36 mmol)) and concentrated to a small volume (5-10 mL), which was used immediately as a solution in the next step. TLC (Et-O-hexane: 1 λ.: 1: 9): Rf 0.57. 1 H-NMR spectrum (270 MHz, V CDCl 3) using BHT as an internal standard (1.45 ppm,. ···. 18 H, s) showed it to contain 3.10 ml (yield 77.5%) of the desired acetylene. (3.32 ppm, 1H, s).

273 37927 E) (S) -4- (Chloromethoxyphosphinyl) -3 - [(1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester

The title phosphonochloridate was prepared from the dicyclohexylamine salt of Example 25, Part B (3.44 g, 54.4 mmol) as described in Example 29, Part J using the following amounts: trimethylsilyldiethylamine (1.36 mL, 10.85 mmol), CH 2 Cl 2 (15 mL), oxalyl chloride (0.50 mL, 5.73 mmol), DMF (1 drop) and CH 2 Cl 2 (15 mL).

F) (S) -3- [(1,1-dimethylethyl) diphenylsilyloxy] -4- [7,3- (4-fluorophenyl) spiro] cyclopentane-1,1 '- (1H-indene) -7- 2-yl-7-ethynyl-ethoxy-phosphinyl-7-butanoic acid, methyl ester A solution of the acetylene prepared in Part D (3.10 mmol + 0.36 mmol BHT) in hexane was diluted with dry THF (15 mL) and cooled to -78 ° under argon. C. To the solution was then added dropwise a 1.6 M n-BuLi hexane solution (2.16 mL, 3.46 mmol) via syringe. After stirring at -78 ° C for 45 minutes, the anion solution was transferred via tube to a solution of -78 ° C containing the phosphonochloridate prepared in Part R: (54.4 mmol) in dry THF (15 mL). After the reaction mixture was stirred at -78 ° C for 1 h, saturated NH 4 Cl (15 mL) was added dropwise and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc, and the extracts were washed with 5% KHSO 4, saturated NaHCO 3 and saturated NaCl, dried (Na 2 SO 4) and evaporated to dryness. The crude product is *. was flash chromatographed using silica gel as adsorbent and EtOAc-hexane (25:75) as eluent to give the title compound (1.781 g, 80% based on the compound of Part D) as a pale yellow glass. TLC (acetone-hexane 1: 1): Rf = 0.46.

274 37927 G) (S) -4 - [[3- (4-fluorophenyl) spiro] cyclopentane-1,1 '- (1H-indene) -2-2-yl] ethynyl / methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester

To a solution of the compound of Part F prepared in Part F (1.00 g, 1.39 mmol) in dry THF (5 mL) under argon at room temperature was added glacial acetic acid (0.32 mL, 5.59 mmol) and 1 , 1 M in THF solution (3.80 mL, 4.18 mmol). After stirring at room temperature for 18 h, the mixture was diluted with 10 EtOAc (50 mL), washed successively with 1 N HCl solution (3 x 30 mL) and saturated NaCl solution, dried (Na 2 SO 4) and evaporated. dryness. The residue was dissolved in Et 2 O (20 mL), the solution was cooled in an ice bath, and excess diazomethane in ether was added. The residue obtained by evaporation of the ether was purified by flash chromatography using silica gel as adsorbent and acetone-hexane (3: 7) as eluent to give the title compound (0.595 g, 89%) as a colorless glass.

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

H) (S) -4- [3 '- (4-fluorophenyl) spiro / cyclopentane-1,1' - (1H-inden) -2-2-yl] ethynyl] hydroxyphosphinyl-3-hydroxybutanoic acid, dilithium salt • To solution containing the compound from Part G (0.580 g, 1.20 mmol) in dioxane (6 mL) under argon at room temperature was added 1 N LiOH solution (4.2 mL, 4.2 mmol). After stirring at room temperature for 3 hours, the mixture was diluted with acetonitrile (20 mL) and a white precipitate. , 30 were collected, washed with acetonitrile and dried; / under reduced pressure to give the crude title product (0.670 g) as a white solid. The crude product was suspended in water (10 ml) and * - · - transferred to a chromatography column containing a small layer of HP-20 resin (layer volume 15 ml, column diameter 25 mm) eluted with water 275 87927 (300 ml) and then with MeOH (300 mL). The product-containing fractions were combined and evaporated to dryness. The solid residue was triturated with acetonitrile to give the pure title product 5 (0.550 g, 98%) as a white solid, mp 301-303 ° C (dec) TLC (a mixture of CH 2 Cl 2, concentrated NH 4 OH and water). in a ratio of 7: 2: 1): Rf = 0.48. Examples 65 -122

In addition, following the procedures outlined above and described in the 10 previous working examples, the following compounds can be prepared:

0 H

Il I x R-P-CHo-C-CH ~ -C0 ~ -R 15 i 2 s 2 *

X OH

z 276 87927

Eg, No. B _J_- -—- --- 65. OCH3 r-Y ^ -CVCV CH3 cv ° ^ rcl

Cl Γ "3

66. OH _C2C ‘H

4 C2H5 · 3 TAl -CH.CH.CH - Li: 67. OLi KJJ 2 2 2

©ν '© SX

ch3 1

OH (ojoj ^ F

27? 87927

E.g.

No. r _z_ x Rx

F

69 · OLi (OJ -CH2CH2CH2- Li (o ^ y CH3 CH3 \ K3 CH-CH3 70. OCHj -CH2CH2CH2- CH3 φ

F

? H3

: · '- 71. OK C.H.-CH -CH - OK

..:. 2 5 | 2 C = 0 o £: <r- 'CH3 ”· 0Na <ÖVc„, - 0 s iJC- - 278 87927

E.g.

n rn R _Z_ _X_ R

73 * 0H / 0VCH2- ° "CH2CH2" H

B

74 · OH C2H5 ^ (f-O "CH2CH2CH2" H

'' O

CH- CH 2. & R 75. CH 3 O (oy -CH 2 - CH 3

76. OH -CH 2 O- H

!:; IO)

: F

77 · 0H (¾} ch2ch2 h (o ^ y-

Eg x No. R _Z_ _X_ ^ 279 87927

78. OH H, C CH, -CH = CH- H

w

79. OH- 'VTl I, CH3 -CVV H

H 3

F

I5, 1 C H

80. NaO LII I / 3 -CH = CH- Na 81 * O "N ^ N rH -C = C- Ca ·. ·; L.jL i / 3

^ —C-H

A ° 'c * 2

Eg x No. R__2 _ _ £ ---- 280 87927

82. HO F. -CIO H

(o) F>.

83. NaO Γΐΐ CH, -C30 Na k 7 V ^ V-C-CH, λ__ S H 3 / n! CH3 CH3

84. CH 3 O CH 3 -CH = CH- H

A cH ^ JSLa / CH3 0 ·: | H3 85. CH30 jAt i / H3 “CH2CH2 'NH4 CH3 isr H 3

Eg χ

No. R _Z_ _X R

281 87 927

CH Q

86. HO 3 LOl 1 / CH3 "CH2" K

lss’XT7 “- C-CH_ n-s H 3

OF

87. O "I" -CH2CH2CH2- Ca foKL / 3

C-CH

V-S H 3 ~ r- \. / CH3 88. CH3O (m-VO / sA-c CH -CH * CH- Na wis H 3

89. H / ^] I / 3 -CH - H

Oops: 0: 0

Eg χ

No. R _ 2__ _x R

282 87927 90. cho / h3 -ch = ch- h

C-CH

Jyr H 3

91. HO FV> I / FH3 ‘CH * CH’ H

WVC'CH, JL S H 3 W * CH3 92. CH O 7 3 "CH2" CH3> - C- CH 'V- S H 3; <S)

ICV

* CH

93 · Li0 L / 3 -cwv ti ^ V> ~ c-ch •; 'V S H 3: ...: ci l

Eg χ,

No. R _Z_ _x R

283 87 927

94. KO Li] 1 -CH2CH2 ~ K

c-ch y- S H 3 CH3

95. HO i CH. -CH = CH- H

yi *

CH

//

/ CS

Ch3 CH3

Fv> v

96. HO Π I, CH 3 -C = C- H

Jp "S'CH3 '. *. F1 * 3,

: 97. HO CH 1 f = \ -CS> H

'0 ~ F

ch3 N = ^ W

: CH

/ Vh CH3 CH3

Eg „x no R __Z_ ___ ___ 284 8 7 927 CH, - 98. LiO | -C * C- Ll

04 "S

L1 ° (o) Jdf *

CH

/ N

CH3 CH3 f3

100. HO CH -CH2- H

M <s> '

F

101 · H0 / - ~ CH2CH2 * H

Clx ^ K __

C ^ X

; - CH.

/ ch3 ch3 i

Eg χ No. R _Z_ _X 8 285 87927

F

102. NaO, -Λ. -CH -CH - Na

If VS 2 2 αΗ3 ° 2θ \

CHOC

ch-ch / CH3

F

103. LiO rfL · "CH2CH2" Li

Brv_X

Yv '

Br - CH3 CH3

F

104. HO / -CH2- H

(J%

Br n: Brx \: V:. CH— CH,: / 3: V ch3

‘F

I: 105. ch3o rj \. '-ch2ch2- ch3 CH3 ° 2

"V" CH O C

J CH— CH

/ CH3 286 87927

E.g.

No. R _ Z_ _X R

106. HO yF -CH2CH2- H

KV

ζ ^ Ν-

CH— CH

/ CH3

F

107. HO J -CH_CH_CH - H

ÄVV lii

Cl

|> A

C ^ \

CH CH

/ CH3

F

108. KO r ~ L -CH2CH2- k cl ^ (: cr ^ \ ch3

^ / F

:: 109 · H0 / Tss -ch2ch2- h

Br · * / .; Br "^

V: CH "CH

'/ ... · ch2 287 37 927

Ex. „X RX

O it __ ____ 'pro £ ---, Λ —CH = CH - Li 110. LiO i [C) l gf ν "λ

F

111. KO -ch2ch2- k CH3 F cf. -CH = CH- Li 112 · Ll ° xgl ys- CH3 * 1 1 »· · *: CH q 3 -CH = CH- CH.

II3. ch3o hit 3

OC

: ‘M ch3» 1 · · 288 87 927

E.g.

No. R _2_ x 1 Rx

F

114 ° H XC T) | -CH - H

L 2 CH 3 ^ ns. Lio ^ CoX I ch ^ ch3 -chc- Li CH3 lT ^ CH3 (o) 116 · Li0 FNTol I ✓CH -CH CH - Li 3 I_J ^ CH, <2> 3 Γ3 117 · Ll ° fAv CH -C = C - Li I: ·: NA ^ (3: S © ·: ° Γ3 118 'Ll ° | <Ol -CH CH - Li L ^ CH3

CH V N ^ v ^ CH J

2 © N “· * ·» ·.

• Λ «289 8 7927. Eg x

No. R _Z_ _X R

119. LiO '' tOl / CH -C = C- Li 120. LiO Ifilv i / CH -CH CH - Li> H ^ CH3 β F.

121. LiO Ύθ1 / CH -CsC - Li

L ^ J \ i.CH

\ CH.

/ N J

'' · 122. LiO F> TOl ^ CH3 “C = C- Li

N CH

: v · @ ch o

• J

Claims (51)

290 37927 1 I 10 alkyl-O-P-CH2-C-CH2-CO2-alkyl, CHO I 2 0 Z 15 The ketophosphonate is reduced to form the diester phosphinate of formula 0 II alkyl-O-P-CH2-CH-CH2 -CO2-alkyl, 20 CH0 OH I 2 0. . Z and, if desired, the diester are converted into a base salt of formula 0 II xa alkyl-O-P-CHo-CH-CHo-CO 2> R 1 | 2 | Z £ CH- OH. ·. : 30 A. Z to an acid of formula 1 307 3 7 927 0 alkyl-O-P-CH2-CH-CH2-CO2H, CHO OH I 2 0 5 Z to the base salt of formula 0 | 10 RXa-O-P-CHo-CH-CHo-CORXa | 2 | 2 2 CH0 OH I 2 0 Z 15 or a diacid of the formula O II HO-P-CHn-CH-CH_-CO "H. i2 | 2 2 H2 0H 20 1. Z-O 5 is condensed with an alkyl acetoacetate dianion to form a ketophosphonate of formula 0 O 1 Z | z z (trans) ^ CH OH: '· CH z 25 to an acid of formula? alkyl-O-P-CH 2 -CH-CH 2 -CO 2 H, (trans) .CH OH • / 30 CH Z to a base salt of formula 1 304 3792 7 o RXa-O-P-CHo-CH-CHo-CORXa, | Z | Z 2 .CH OH Z-CH (trans) 5 or a diacid of formula 0 II HO-P-CH 0 -CH-CH 0 -COOH; I 2 | 2 2 10 .CH OH Z-CH (trans) (F) X is -CH2-, -CH2CH2- or -CH2CH2CH2- phosphonochloridate of formula 15 O alkyl-OP-Cl4H2> az 20 wherein a is 1, 2 or 3, condensed with an alkyl acetoacetate anion anion to form a ketophosphonate of formula V 25 O II alkyl-O-P-CH_-C-CH_-CO - alkyl, I z μ zz (fVa 0 Z : The ketophosphonate is reduced to form a diester of formula 0 II alkyl-OP-CH 2 -CH-CH 2 -CO 2 -alkyl, I z IZ z 35 (CHO) OH | Z d Z i 305 3 7 927 and if desired, the diester is converted into a base salt of the formula 0 R x a 5 alkyl-O-P-CH 2 -CH-CH 2 -CO 2 R, ° H 2 to an acid of the formula 10 0 H alkyl-O-P-CH 2 -CH-CH 2 -CO 2 H , «FVa ° H z 15 as a basic salt of formula 0 RXa-O-P-CH CH-CH CO pXa | 2 | 2 2 20 (CH2) OH I 2 az or diacid of formula: 25 0 II H0 -P-CH 0 -CH-CH 0 -COOH; IZ IZ 2 OH (f> 2> a Z: 30; ·: · and (G) X is -CH 2 O- phosphonochloridate of formula 35 306 87927 0 II alkyl-O-P-Cl CH0 1. CH-I 2 5 Z (D) X is trans-CH = CH- from silyl ether of formula 10 0 H alkyl-O-P-CH 2 -CH-CH 2 -CO 2 -alkyl (trans), CH OSi-C (CH-) - // / \ JJ CH C, Hc C, Hc I 6 5 6 5 The Z silyl ether group is cleaved to form a hydroxide ester of the formula 20 O II alkyl-O-P-CH2-CH-CH2-CO2-alkyl: (trans) .CH OH ✓ CH: · Z25 and, if desired, the hydroxide ester is converted into a base salt of formula O 11 alkyl-O-P-CH - CH-CH - CO-Rxa, | Z | 2 2 (trans) ^ CH OH CH Z - ·· 35 to an acid of formula 302 37 92 7 0 alkyl-O-P-CH2-CH-CH2-CO2H, .CH OH CH 5 Z to a base salt of formula 0 RXa-O-P-CH2- <j: H-CH2-CO2Rxa, (trans) ^ j, CH OH CH Z 15 or the corresponding diacid of formula 0 HO-J-CHO-CH-CHO-C00H; I 2, 2 2 (trans) ^ CH OH 20 JH (E) X is trans-CH = CH- phosphonochloridate of formula 25 O II alkyl-O-P-Cl -CH CH (trans), · I 30 Z is condensed with an alkyl acetoacetate dianion to form a ketophosphonate of the formula -35-H-alkyl-O-P-CH2-C-CH2-CO2-alkyl, (trans) CH CH The 5 Z ketophosphonate is reduced to form the diester phosphinate of formula 10-alkyl-O-P-CH2-CH-CH2-CO2-alkyl, (trans) ^, CH OH CH Z 15 and, if desired, the diester is converted to the base salt of formula 0 H va 20 alkyl-O-P-CHO-CH-CH 0 -COOR, 1. I / / CH OH (Cis) CH I 5 Z or as a basic salt of formula 0 10 RXa-O-P-CH9-CH-CHo-CORXa; I Z | Δ Δ CH OH I (cis) CH 2 15 (C) X is -CH 2 -CH 2 - silyl ether of formula 0 II alkyl-O-P-CH 2 -CH-CH 2 -CO 2 alkyl 20 .CH 0 SI Z-CH (cis) SiC (CH3) 3 c6 ^ \ h5 is reduced to give a silyl ether of formula:. 0 alkyl-O-P-CH2-CH-CH2-CO2-alkyl CH9 0 I 2 I - 30 CH0 SiC (CH9) 0 I 2 / \ 33 Z C6H5 C6H5 from this silyl ether is cleaved by a silyl ether group to form a diester of the formula · '35 300 37 927 0 II alkyl-O-β-CH 2 -CH-CH 2 -CO 2 -alkyl, CHO OH 1 2 ΪΗ 2 5 Z and, if desired, the diester is converted into a base salt of formula 10 0 III xa alkyl-O-P-CH2-CH-CH2-CO2R, CH-OH I 2 0Ho I 2 Z 15 to an acid of formula 0 II alkyl-O- P-CH2-CH-CH2-CO2H, 20 <J: h2 OH CH0 I 2::: Z to a basic salt of formula: 25 0 RXa-O-P-CH0-CH-CH_-CORXa, | Z | L Z CH- OH I 2 CH_ | 2 30 Z or diacid of the formula • '35 i. 301 87927 0 II H0-P-CHo-CH-CHo-COH; | Z | Z 2 CH- OH 1. I 2 2 '10 c = c OH Z as a basic salt of formula 15 0 RXa-O-P-CH2-CH-CH2-CO2RXa, Z-C = C 4h or a diacid of formula 20 0. - H H0-P-CHo-CH-CHo-COOH; | 2 | 2 2 ΟξΟ OH: ·. Z '25 (B) X is cis-CH = CH-acetylene phosphinate of formula O 30 alkyl-O-P-CH 2 -CH-CH 2 -CO 2 -alkyl V: CsC 0 IIZ ^ - SiC (CH -) _ c6 <X „533 - 35 is reduced to give a silyl ether of formula 3 7 9 ^ 7 298 ^ / ytt 0 alkyl-O-P-CH2-CH-CH2-CO2-alkyl,> f Z-CH (OIS) / S1C'CH3 »3 The C6H5 C6H5 silyl ether is cleaved with a silyl ether group to form a diester of the formula 10 O-alkyl-O-P-CH2-CH-CH2-CO2-alkyl, (cis) CH OH K CH Z 15 and, if desired, the diester is converted to a monoester of formula 0 alkyl-O-1> -CH2-CH-CH2-CO2H, XCH OH:. . Z-CH (cis) to a base salt of formula -; 25 o H xa alkyl-O-P-CH2-CH-CH2-CO2R, CH OH II (cis) CH 30 Z to the acid of formula 35 299 8 7 927 0 N HO-P-CH 2 -CH-CH 2 -COOH A process for the preparation of novel therapeutically useful compounds of formula 5 0 H 1. x R-P-CHo-C-CH_-CO 0R | Δ | Δ Δ X OH Z 10 wherein R is OH or lower alkoxy, Rx is hydrogen or lower alkyl, X is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH = CH-, -C = C-15 or -CH2O - (where 0 is attached to Z) and Z is a hydrophobic anchor which is a group having one of the following formulas: “V 'M' ^ R 1« ;; ·: 25 rVVr4 »vV · 4 N ') = H - \ =. J / ° R ^ ° ^ 30 1 R Ra Rb 3 7 92 7 291 * 'Vr * j £) \ - 5 R 22 * R23 * 10 0 I and JL. alkyl R 5 <R 6a, q wherein R 1, R 2, R 2a and R 2b may be the same or different and are each independently H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or ORT, · wherein Ry is H , alkanoyl, benzoyl, phenyl, halo-phenylphenyl, phenyl- (lower alkyl), lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl- (lower alkyl), adamantyl- (lower alkyl) or (substituted phenyl) - (lower alkyl); R 2 and R 5 may be the same or different and are each independently hydrogen, lower alkyl or OH, O 0, "" R is (lower alkyl) ) -C-, such as CH3-CH2pp-C-, CH 3 R 7 or aryl-CH 2 -, R 6 'is lower alkyl, OH, oxo or halogen, q is 0, 1, 2 or 3 and R 7 is hydrogen or lower alkyl; 10 Z is r8 15 R9 I R4 „W * yy. -VV ° N - N ': ^ 10 p7 ° r10 25 rI «V ^ r4 r3V'Y ^ r4 Tj, ~ YJ r10 RU R °» “30 one of the substituents R3 and R * is a group of formula 293 8792 7 b13 -ας 5 Τ «· and the other is lower alkyl, cycloalkyl or phenyl- (CH2) p-, wherein p is 0, 1, 2, 3 or 4; Wherein R 13 is hydrogen, lower alkyl, lower alkoxy (excluding t-butoxy), halogen, phenoxy or benzyloxy, R 14 is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy and R 14 * is hydrogen, lower alkyl, lower alkoxy or halogen, provided that when R13 is hydrogen both R14 and R14a must be hydrogen, when R14 is hydrogen R14a must be hydrogen, not more than one of R13 and R14 may be trifluoromethyl, not more than one substituent -20 of the substituents R13 and R14 may be phenoxy and at most one of the substituents R13 and R14 may be benzyloxy; : R 8 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-6 al- · *:: coke (excluding t-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, and: R 9 is hydrogen , C 1-6 alkyl, C 1-3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, provided that when R 8 is hydrogen R 9 must be hydrogen, at most one of the substituents R 8 and R 9 may be trifluoromethyl, at most one of R8 and •: R9 may be phenoxy and at most one of R8 and R9 may be benzyloxy, R10 and Ru are each independently hydrogen, alkyl, cycloalkyl, Adamant-1-yl or 294 0 7 9 2 7 5 V wherein R 13, R 14 and R 14a are as defined above and q is 0, 1, 2, 3 or 4, and Y is O, S or NR 10; When Z is r8 Λ I n, ίκ 'H9 Ra Rb R "is hydrogen or primary or secondary C1-4 alkyl and Rb is primary or secondary C1-6 alkyl or R * and Rb together form a group having kaaa; · Va - (CH2) r-, where r is 2, 3, 4, 5 or 6, or cis-CH2-CH = CH-CH2-,: R12 is lower alkyl, cycloalkyl or V .: / -r13 R14 - 30 and: R8, R9, R13, R14 and R14a have the same meaning as above; 35 Z is 29s 3 7 92 7 3 '.4 p · ^ R Ä R15 and R16 are each hydrogen, Cl, Br, CN, CF3, phenyl-10, C1-4-alkyl, C2-8-alkoxycarbonyl, - CH 2 OR 17 or -CH 2 OCONHR 18 wherein R 17 is hydrogen or C 1-6 alkanoyl and R 18 is alkyl or phenyl optionally substituted with F, Cl, Br or C 1-4 alkyl, or R 15 and R 16 together form a group having Formula - (CH 2) -, -CH 2 OCH 2 -, -CO (R 19) CO - or -CON (R 20) N (R 21) CO-, wherein s is 3 or 4, R 19 is hydrogen, C 1-6 alkyl, phenyl or benzyl and R 20 and R 21 are each independently hydrogen, C 1-4 alkyl or benzyl, and X is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; 20 When Z is E, Ä -:. C * C v R23a R22 is lower alkyl, cycloalkyl, Adamant-1-yl or - (CH2) t-^ Q2, where t is 1, 2, 3 or 4, and ·· .: 35 R23 and R23a may be the same or different and are each independently hydrogen, lower alkyl, lower alkoxy (excluding t-butoxy), halogen, phenoxy or benzyloxy, provided that when R23 is hydrogen R23a must be hydrogen, not more than one of the substituents R23 and R23a are phenoxy and at most one of the substituents R23 and R23a is benzyloxy; and when X is -CH 2 O- (carbon bound to P and oxygen to Z) Z is 8. r 2 8 νγ · / 10 l ° J or Γο ^ Λ- Ύ · »! and physiologically acceptable salts thereof, characterized in that (A) X is a -C * C- acetylene phosphinate distate of the formula O 20 alkyl-O-P-CH 2 -CH-CH 2 -CO 2 - alkyl CeC 0: (Cl 2 CH 2) 53:25 cleaves the silyl ether group to form a diester of the formula O n alkyl-O-P-CH 9 -CH-CH 0 -C 0 alkyl, ί Δ · 30 C = C OH z ____: and, if desired, the diester is converted into a monoester of formula 35 297 37 92 7 O II alkyl-O-P-CH2-CH-CH2-CO2H, C = C OH IZ 5 base salt with is the formula 0 alkyl-O - CH2-CH-CH2-CORxa, Process according to Claim 1, characterized in that X is -CH = CH- or -C 1 -C- R is OH or alkoxy and Z is r. 25 riA / 2 ^ * 3V "V * 4 T ° X ·“ ... M ,,. R2a .30 Process according to Claim 1, characterized in that a compound which is (S) -4 - [[(E) -2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'- biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxy-35-butanoic acid or its dilithium salt; 308 3792 7 (S) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutane- acid or a methyl ester or mono- or dialkali metal salt thereof; 5 (S) -4 - [[(4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid or its methyl ester; (5Z) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; (S) -4 - [[2- (1,1'-Biphenyl-2-yl) ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; (S) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt ; (5Z) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt ; (S) -4 - [[2- (1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-butanoic acid, dilithium salt; •] 30 (S) -4- (hydroxymethoxyphosphinyl) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] butanoic acid, methyl ester, or its dicyclohexylamine salt (1: 1); (S) -4 - [[2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxy-35-oxybutanoic acid or a dilithium salt or methyl ester thereof; 309 8 7 92 7 (S) -4 - [[2- [1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] ethyl] hydroxyphosphinyl] -3- hydroxybutanoic acid or its dilithium salt or methyl ester; (E) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl-5H) -1H-indol-2-yl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; 4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid 10 or its dilithium salt or methyl ester; (E) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt, or methyl ester; (S) -4 - [[[2,4-dimethyl-6 - [(4-fluorophenyl) methoxy-15] phenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[[2,4-dimethyl-6 - [(4-fluorophenyl) methoxy] phenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[2- (3,5-dimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[2- (4'-fluoro-3,5-dimethyl-1,1'-biphenyl-2-yl) ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid '25 or a dilithium salt or methyl ester thereof; (S) -4 - [[2- (1,1'-Biphenyl-2-yl) ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3 -hydroxybutanoic acid, methyl ester; (S) -4- [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; ... 35 310 37927 (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] methoxyphosphine -nyl] -3-hydroxybutanoic acid, methyl ester; (E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethenyl] hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt; (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl-yl) -l-phenyl-lH-pyrazol-4-yl] ethyl] metoksifosfinyy-phenyl] -3- hydroxybutanoic acid, methyl ester; (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] hydroxyphosphinyl] -3 -hydroxybutanoic acid, dilithium salt; (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] methoxyphosphinyl-15] -3 -hydroxybutanoic acid, methyl ester; (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethyl] hydroxyphosphinyl] -3- hydroxybutanoic acid, dilithium salt; (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] methoxyphosphinyl] -3 -hydroxybutanoic acid, methyl ester; . . (S) -4 - [[2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ethynyl] hydroxyphosphinyl] -3- hydroxybutanoic acid, dilithium salt; (S) -4 - [[[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; (S) -4 - [[[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethynyl] hydroxyphosphinyl-30-yl] -3-hydroxybutanoic acid, dilithium salt ; (S) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; (S) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] ethyl] hydroxyphosphine; nyl] -3-hydroxybutanoic acid, dilithium salt; 311 3,792 7 (S) -4 - [[[1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid , methyl ester; (S) -4 - [[[1- (4-fluorophenyl) -4- (1-methylethyl) -5-phenyl-1H-imidazol-5-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; (S) -4 - [[2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; 10 (S) -4 - [[2- [1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] ethyl] hydroxyphosphinyl ] -3-hydroxybutanoic acid, dilithium salt; (S) -4 - [[[2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; 4 - [[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[2- [2- (cyclohexylmethyl) -4,6-dimethyl-phenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or 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 methyl ester; 4 - [[(4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) methyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[[1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethynyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or a dilithium salt or methyl ester thereof; (E) -4 - [[2- [1- (4-fluorophenyl) -3-methyl-2-naphthalenyl] ethenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; (S) -4 - [[2- [1- (4-fluorophenyl) -3-methyl-2-naphtha-. Lenyl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid or its dilithium salt or methyl ester; 312 3 7 92 7 4 - [[3- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-yl) propyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; 4 - [[3- (4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-5-yl) propyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; [IS [l <a (R *), 2 <a, 4a <b, 8 <b, 8a <a]] - 4 - [[2- [8- (2,2-di-1-metyy1i oxobutoxy i) decahydro-2-methyl-1-naphthalenyl] ethyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; [IS [l <a (R *), 2 <a, 4a <b, 8 <b, 8a <a]] - 4 - [[2- [8- (2,2-di-methyl-L- oxobutoxy) decahydro-2-methyl-1-naphthalenyl-1-yl] ethyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, dilithium salt; (S) -4 - [[[3 '- (4-fluorophenyl) spiro [cyclopentane-1,1' - (ΙΗ-inden)) - 2-yl] ethynyl] methoxyphosphinyl] -3-hydroxybutanoic acid, methyl ester; or (S) -4 - [[[3 '- (4-fluorophenyl) spiro [cyclopentane-1,1' - (ΙΗ-inden)] - 2-yl] ethynyl] hydroxyphosphinyl] -3-20 hydroxybutanoic acid, dilithium salt . 4. An intermediate including all stereoisomers thereof, characterized in that said intermediate has the formula 25, R 1 -P-CH 2 -CH-CH 2 -CO 2 -alkyl R e 2, 08 1 -O (3) 3 C 6 H 5 NC 6 H 5 wherein R 1, is alkoxy or hydroxy and r e is hydroxy, Cl, -CsC-Z, -CH 2 -Z, -CH 2 CH 2 CH 2 -Z, -CH 2 O-Z, -CH = CH-Z or -CH 2 CH 2 -Z, wherein Z is a hydrophobic anchor; or formula O. 35 alkyl-O- * * -CH -C-CH9-C00-alkyl X 0 ..... IZ 313 37927 wherein X is - (CH2) a-, -CH = CH-, -C = C- or - CH 2 O-, a is 1, 2 or 3 and Z is a hydrobic anchor. A process for the preparation of an intermediate according to claim 4, wherein R a is O-alkyl and r e is trans-CH = CH-Z, characterized in that the vinyl iodide of formula> CH 2 is treated with a metallating agent in the presence of an inert organic solvent and the resulting anion is reacted with a phosphonochloridate of formula 0 II alkyl-O-P-CH 2 -CH-CH 2 -CO 2 -alkyl C 10 I 20 Si-C (CH 3) 3 C6H5 ^ C6H5 with a cooled solution in the presence of an inert organic solvent. A process for the preparation of an intermediate product according to claim 4 of formula 0 II alkyl-O-P-CH 9 -C-CH 0 -C 0 9 alkyl I 2 II z 2. 30 o CH z characterized in that the phosphonochloridate having. . 35 formula 314 37927 o II alkyl-O-P-Cl .CH CH The 5 Z cooled solution is treated with a dianion of formula 10 0Θ 0Θ I I /.C v .c. CH2 CHO-alkyl in the presence of an inert organic solvent. 15,315,37927