DD281605A5 - METHOD FOR PRODUCING PHOSPHORUS-BASED HMG-COA REDUCTASE INHIBITORS OF GENERAL FORMULA I - Google Patents

Abstract

The invention relates to a process for the preparation of phosphorus-containing compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase and are thus suitable as hypocholesterolemic agents. The compounds of the present invention have the following formula in which R represents a hydroxyl group or a salt thereof or a lower alkoxy group, Rx represents a hydrogen atom or an alkyl group, X represents one of (CH 2) a, CHCH, CC or CH 2 O (wherein the O is bound to the radical Z), a has the value 1, 2 or 3 and Z represents a hydrophobic anchor. Formula {HMG-CoA reductase inhibitors; Cholesterol biosynthesis; phosphorus-containing compounds; Medicine; Cholesterol; lowering agents, lipid level lowering agents; Method}

Description

The application of the present invention is in the field of medicine in the inhibition of the activity of 3-hydroxy-3-methylg] .utaryl-coenzyme A reductase and thus the inhibition of the biosynthesis of cholesterol.

Characteristic of the known state of the art

F.M. Singer et al., Proc. Soc. Exper. Biol. Med., Vol. 102 U959), p. 370 and F. H = Hulcher, Arch. Biochem. Biophys., Vol. 146 (1971), p. 422, report that certain mevalonate

Derivatives inhibit the biosynthesis of cholesterol.

Endo and Mitarb, U.S. Patents 4,049,495, 4,137,322, and 3,983,140, report a fermentation product which effects the inhibition of cholesterol biosynthesis. This pro-

The term dukt is referred to as compactin, and Erown and Mitarb report in J. Chem. Soc. Perkin I (1976), p. 1165, that it has a complex tievalonolactone structure.

GB-A-1,586,152 discloses a group of synthetic

binc.ungen the formula

-z

in which E is a direct bond, an alkylene bridge having 1 to 3 carbon atoms or a vinylene bridge and the various radicals R denote a plurality of substituents. The activity reported in the GB patent is less than 1 % of that of COmpactin.

In US-A-4,375,4 ⁿ 5 are hypocholesterolemic and hypolipemic compounds of the structure

described, in which A is a Wasserstoffatcm Eire or methyl group, E is a direct bond or one of the groups -CH ₀ -, -CH _{0 n} -CH -, -CH -CH _{0 0 0} -CH - or -CH = CH- , R _1, R ₀ and R .. each a hydrogen or halogen atom, a C ₁ _ ₄ alkyl, C ₁ _ ₄ haloalkyl, phenyl, halogen substituted phenyl, C alkoxy, alkanoyloxy C , C 1 -C 4 -alkyl or C-haloalkyl radical or the radical OR. in which R, a hydrogen atom, a C 1-8 alkanoyl, snzoyl,

4 / C-O

Phenyl, halo-phenyl,

-C ₁ _ ₃ alkyl-

-3-

Cinnamyl, C ₁ -haloalkyl, allyl, CyClOalkVl-C ₁ -alkyl, adamantyl-C. _ ^ - alkyl or a substituted phenyl-C. __- alkyl radical, where the substituents are each halogen, C ₁ _.- alkoxy, C.. -alkyl or C.. -haloalkyl radicals. Furthermore, the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring are described. The US patent further describes the pharmaceutically acceptable salts of these acids and the C ₁ -C 4 alkyl and the phenyl, dimethylamino or acetylamino substituted C ₁ alkyl esters of the dihydroxy acids. All of these compounds are enantiomers having a 4 R configuration in the tetrahydropyran unit of the trans racemate of the above formula.

WO 84/02131 (PCT / EP83 / 00308) describes heterocyclic analogues of mevalolactone and derivatives thereof of the structure

in the one of the radicals R and R is a radical of the formula

and the other represents a primary c of the secondary ^c -j_g-alkyl, C-cycloalkyl or phenyl- (CH ₂ ) _m -P.sub.est wherein R _{4 is} a hydrogen atom, a C 1-6 alkyl, C _{1 -4} -alkoxy (with the exception of the tert-butoxy radical), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy radical,

-4-

R ₅ represents a hydrogen atom, a C. --Alkyl-, C ₁ alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Rg represents a hydrogen atom, a C. --Alkyl-, c._ means ₂ alkoxy, fluoro or chloro, and m has the value 1, 2 or 3,

with the provisos that both radicals R ₁ . and R_ is hydrogen must be atoms when R. is a hydrogen atom, R ₅ must be a hydrogen atom when R ₅ is a hydrogen atom i _s t, not more than one of R and R ₅ represent a trifluoromethyl group, not more than one of the radicals R and R ₅ denote a phenoxy group and not more than one of the radicals R. and R represents a benzyloxy group, R "is a hydrogen atom, a C.-alkyl, C-, -cycloalkyl, C,. -Alkoxy (excluding the tert-butoxy group), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy group,

R _{3 represents} a hydrogen atom, a C 1 -C 12 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy group, with the provisos that R 1 must be a hydrogen atom, when R "is a hydrogen atom, not more than one of R" and R ^ is a trifluoromethyl group, not more than one of R_ and R ^ represents a phenoxy group, and not more than one of R "and R, a benzyloxy

25 group represents,

X is one of the radicals - (CH ^ - or -CH = CH- (n = 0, 1, 2

or 3), Z is a radical of the formula

CH-CH ₂ -C-CH ₂ -COOH II OH OH

means

where R, a hydrogen atom or a C _1. , - alkyl radical in the form

the free acid or in the form of a physiologically hydrolyzable and compatible ester or an o-lactone thereof or

Represents -5-in the form of a salt thereof.

GB-A-2-162-179 describes naphthyl analogs of mevalolactone which are useful as inhibitors of cholesterol biosynthesis and the structure

in which R _{1 represents} a C ₁ "-alkyl radical Z represents a radical of the formulas Z ₁ or Z_:

-CHCH ₂ CHCH ₂ COOr ₇ OH OH

(Z ₁ )

(Z ₂ )

and R represents a hydrogen atom, a hydrolyzable ester group or a cation.

EP-A-164-698 describes the preparation of lactones which are useful as antihypercholesterolemic agents by treating an amide with an organic sulfonyl halide of the formula R SO ₉ X _{1 followed} by removal of the protecting group Pr. The reaction proceeds according to the following reaction equation 1 ι

J H Jr3r4 ¹ S _n L-OH

-6-

where X is a halogen atom,

Pr represents a carbinol protecting group, R represents a hydrogen atom or a methyl group,

3 4 R and R are each a hydrogen atom, a C ₃ ~ C alkyl or phenyl. --alkylrest represent, wherein the phenyl group ₃ alkoxy group or a halogen atom can be optionally substituted by a C. --Alkyl-, C. _,

2 R is a radical of the formulas (A) or (B)

CH

X ο J

(A)

Q is a radical of the formula

R ⁶ -C-ι

I CH,

or

R ⁶ is -CH

represents,

R is a hydrogen atom or a hydroxyl group, R is a hydrogen atom or a methyl group, a, b, c and d are optionally double bonds,

7 R is a phenyl or benzyloxy group, wherein the ring is in each case optionally substituted by a C ₁ _, - alkyl radical or a halogen atom,

Q Q

R and R are each a C. ..- Alkyirest or a halogen atom,

R represents a C alkyl, phenyl or a mono- or di (C ^ alkyl) phenyl radical.

8 16 0

-7-

In DE-A-35 25 256 are naphthyl analogues of mevalolactones of the structure

-CHCH-CHCH ₀ CO ₀ R '

A ² I ^{2 2}

OH OH

described in which R is an alkyl radical, the radical Z

1 7

represents one of the radicals Q or Q and R represents a hydrogen atom or a hydrolyzable ester radical, which are suitable as inhibitors of cholesterol biosynthesis and for the treatment of atherosclerosis.

In WO-84/02903 are suitable as hypolipoproteinemische agents mevalolactone analogues of the formula

X-Z

described in which the two radicals Ro together a remainder of the formulas

8 7 6 5

C = C-C = C

I i

R- R-,

or -

35 mean, where

R "is a hydrogen atom, a C ^^ j-alkyl, C ^ ₄ -Aikoxy- (

-δι taken tert-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy represents,

R _{3 represents} a hydrogen atom, a C ₃ alkyl, C _1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R "and R ₃ denotes a trifluoromethyl group, not more than one of the radicals R "and R _{3 represents} a phenoxy group and not more than one of the radicals R» and R ₃ denotes a benzyloxy group,

R _{1 represents} a hydrogen atom, a C._galkyl, fluorine, chlorine or benzyloxy radical,

R _{4 denotes} a hydrogen atom, a C 1-4 -alkyl, C 1-4 -alkoxy (excluding tert-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy radical,

15 K _{5 is} a hydrogen atom, a C., -alkyl, C .. -alkoxy,

Trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy

represents,

R represents a hydrogen atom, a C.sub.10 "alkyl or C.sub.1" alkoxy group, a fluorine or chlorine atom, with the provisos that not more than one of R.sup.1 and R.sup.2 represents a trifluoromethyl group, not more than one of the radicals R and R represents a phenoxy group and not more than one of the radicals R. and R- is a benzyloxy group, X is a radical of the formulas

²⁵ \

C =

- < ^CH 2> q

where π is 0, 1, 2 or 3 and both q are 0 or one is 0 and the other is 1, Z is a radical of the formula

^R 6

5 4

-CH-CH, -C-CH - COOH II I ι * OH OH

8 16

-9-

wherein Rg represents a hydrogen atom or a C, -alkyl radical, with the general proviso that -X-Z and the phenyl group carrying the radical R are in ortho position to one another

 5

The compounds are described in the form of the free acid or in the form of a physiologically hydrolyzable and compatible ester or an O-lactone thereof or in the form of a salt

 10

US-A-4,613,610 describes a series of 7-pyrazolo-3,5-dihydrohept-6-enoic acid HMG-CoA reductase inhibitors of the structure

R

R.sup.1 represents a C.sub.1.sup _fi -alkyl radical which does not contain an asymmetric carbon atom,

each of R "and R ₁ . independently a hydrogen atom, a C 1-4 alkyl, η-butyl, i-butyl, tert-butyl, C 1, alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro - represents chlorine, phenyl, phenoxy or benzyloxy, each of R ^ and R dec radicals _fi independently a hydrogen atom, a C.-alkyl., C, -. alkoxy, Trif luormethyl-, fluoro, chloro Represents phenoxy or benzyloxy, each of R * and R- independently represents a hydrogen atom, a C "alkyl or C 1-6 alkoxy group, a fluorine or chlorine atom, with the provisos that at most one of the radicals R "and R_. a trifluoromethyl group means at most one of R "and R-. represents a phenoxy group,

-10-

at most one of R ₂ and R-. a benzyloxy group, at most one of the radicals R ₁ . and R _{fi represents} a trifluoromethyl group, at most one of R ₁ . and R _{fi represents} a phenoxy group and at most one of Rj and R _{fi represents} a benzyloxy group, X represents one of the groups ^--Cii ₂ ⁾ _m - '- ^{CH = CH} - * - ^{CH =CH} - CH ₂ - or --CH ₂ -CH = CH-, where m is 0, 1, 2 or 3 and Z is one of the radicals

.CH ^ OH R, - / Λ

· "10 -CH C

-CH-CH ₀ -C-CH ₀ -COOR _1. , Or I 2 ι 2 11

^{0H 0H} 0 CH

^R 10 '

Il

where R _{10 is} a hydrogen atom or a

C. _- represents alkyl radical and R _{11 represents} a hydrogen atom, the radical R ₁₀ or M, where

R ₁ P is a physiologically acceptable and hydrolyzable ester group and

^{M represents} a cation,

with the provisos that (i) the radical -XZ is in the 4- or 5-position of the pyrazole ring and (ii) the radical R ₁ and the radical -XZ are in ortho position to one another.

WO-A-86/07054 describes imidazole analogs of mevalonolactone which are useful in the treatment of hyperlipoproteinemia and atherosclerosis and the formula

R ₁ XZ

N NR ₂ (I)

^R 3

in which R is an alkyl, cycloalkyl, adamantyl-1

-11-

or one by R

R ₅ or

., R ₅ or R _{5 is} substituted phenyl radical (group A),

R is an alkyl, cycloalkyl, adamantyl-1 or a phenyl radical substituted by R ₇ , R _fi or R "(group B), R 1 is a hydrogen atom, an alkyl, cycloalkyl, adamantyl-1 , styryl or a "substituted by R. _fl) R ₁₁ or phenyl radical R. (group C),

X is a group of the formulas - ( ^CH ₂ ) _m - <-CH = CH-, -CH = CH-CH ₂ - or -CH ₂ -CH = CH-, m has a value of 0 to 3,

Z is one of the radicals -CH (OH) -CH ₂ -C (R ₁₃ ) (OH) -CH ₂ -COOR ₁₄ (group a), -Q-CH ₂ -C (R ₁₃ ) (OH) -CH ₂ - COOR ₁₄ (group c) or a group of formula (b)

CH

• CH

\ / ^0H

₁₃

CH

25 Q represents one of the radicals -CO or -C (OR _1t .) "-,

R ₁ J. represents a primary or secondary alkyl radical, wherein the radicals R. are the same, or

^R 15 ^{+ R} 15 is ^{one of Gru} PP ^en ~ ^ ^CH 2 ^ 2 ^or " ^CH 2 ^ 3 ~ ^b e ^is -R _{1 is} a hydrogen atom or a C ₁ ..- alkyl radical,

30 R ₁ . represents a hydrogen atom, the radical R _lfi or M, R ₁ , represents an ester group, and M is a cation,

with the proviso that Z can only be the group (c) when X represents one of the groups -CH = CH- or -CH ₂ -CH = CH- and / or when R _ represents a C ₁ , -alkyl radical, R ., R ₇ and R _{Q is} a C., -, alkyl radical, an n-, i- or tert.-

23 1605

-12-

Butyl group, a C ₁ alkoxy group, an η- or i-butoxy group, a trifluoromethyl group, a fluorine, chlorine or bromine atom, a phenyl, phenoxy or benzyloxy group, R ₅ , Rg and R represent a hydrogen atom, a C ., -Alkyl or

C., - alkoxy, a Trif luormethylgruppe, a fluorine, chlorine or bromine atom, one of the radicals -COOR ₁₇ or N (R ₁ ") _, or a phenoxy or benzyloxy group, R _{17 is} a hydrogen atom, the radical R. . "represents OAER M, 18 ^ ^e ^ ^NEN __- C ₁ alkyl group, an n-, i- or tert-butyl or a benzyl group, R ₁ O represents an alkyl radical,

R _ß , Rq and R ₁ "is a hydrogen atom, a C." alkyl or C ₁ "alkoxy, a fluorine or chlorine atom, with the

^ 5 proviso that

(1) at most one substituent of each of the groups A, B and C is a trifluoromethyl group, at most one substituent of each of the d ^ r groups A, B and C represents a phenoxy group and at most one substituent of each of the groups

20 P ^en A. B ^{un <} 3 C represents a benzyloxy group,

(2) when Z is selected from the group (c) and Q is a radical -C (OR ₁ J.) ", the compound is in the form of the free base and either (i) R ₁ , the radical R ₁ , and ever-

14 Io

the radical R ₁₇ is independently R ₁ "or M, or (ii) R _{14 is} the radical M and each R ₁₇ is independently R .. _g or M, and

(3) if R ₁₄ and / or at least one radical R _{17 has} the meaning M, the compound is in the form of the free base.

Unless otherwise indicated, all alkyl radicals have 1 to 6 C atoms and contain no asymmetric C atom and the cycloalkyl radicals have 3 to 7 C atoms.

WO-A-86/04848 describes indole analogues of mevalolactone, which are useful as hypolipoproteinemic and anti-atherosclerotic agents, in the form of the free acid or in the form of a

Esters or ole-lactones, or in salt form. The compounds have the formula

(I)

the in / R is a hydrogen atom or a primary or secondary

C, g-alkyl radical means,

R _{1 represents} a primary or secondary C 1-6 alkyl radical,

or R 4 R ₁ together form one of the groups - (CH ₀ ) - or l 2. m

- (Z) -CH ₂ -CH = CH-CH ₂ -,

15 m has a value of 2 to 6,

R represents a C 1-6 alkyl, C 1-6 cycloalkyl or a phenyl radical substituted by R, R ₅ and R, R "and R represents a hydrogen atom, a C 1-4 alkyl, C 1-4 alkoxy (except tert-butoxy), trifluoromethyl, fluoro,

20 is chlorine, phenoxy or benzyloxy,

R and R ₁ . a hydrogen atom, C. _ _r) -Alkyi-, C .._- alkoxy, trifluoromethyl, fluorine constitute, chloro, phenoxy or benzyloxy

 R, a hydrogen atom, a C. "-alkyl or C." -alkoxy

25 denotes a fluorine or chlorine atom,

with the proviso that only one trifluoromethyl, phenoxy or benzyloxy group is located on each of the phenyl and indole rings,

X represents one of the radicals - (CH _n ) or - (CH-) -CH = CH (CH-) -,

2 η 2 q 2 q

30 η has a value of 1 to 3,

the two indices q are 0 or Gjner is 0 and the other has the value 1,

Z is the radical -Q-CH, -C (R _Q ) (OH) -CH ₂ COOH- in the form of the free acid or in the form of an ester, o-lactone or salt.

35 ^tet -

Q denotes one of the radicals -CO, -C (OR-) · or -CHOH,

-14-

the radicals R _{7 represent} the same primary or secondary C 17 radical or together form one of the groups - (CH -) - or - (CH ₂ J ₃ -,

R _{10 represents} a hydrogen atom or a C 1-4 alkyl radical provided that Q has a meaning other than -CHOH- only when X represents one of the groups -CH = CH- or -CH "-CH = CH- and / or R ~ is a C.sub.1-6 alkyl radical.

US-A-4,647,576 discloses novel C- and N-substituted pyrroles which are useful as hypolipidemic and hypocholesterolemic agents and which are of the formulas

(D

H _v 0H

COOH

(II)

where ^u > ei

X is one of the groups -CH ₂ -, -CH ₂ CH-- or -CH (CH ₃ ) CH ₂ -, R.sup.1 imitates 1- or 2-naphthyl, cyclohexyl, norbornenyl, etc., by fluorine or chlorine atom, a hydroxyl,

Trifcuryl, C ₁ -alkyl,

^ Alkoxy or C ₂ _ _Q alkanoyl

oxygrujpe substituted phenyl group, a 2-, 3- or 4-Pyric'.i nylgruppe or an N-oxide thereof or a radical of the formula

R _c .hai

-15-

1 means R ₁ . represents a C.sub.1-6 alkyl radical, hai being a chloride, broinide or iodide ion,

R "and R is a hydrogen, chlorine or bromine atom, a cyano, trifluoromethyl, phenyl, C,. Alkyl, C" _ _R -Carboalkoxygruppe or one of the radicals -CH ₀ -OR- or -CH ₀ OCONHR -, - mean

Zo al

Rg represents a hydrogen atom or an alkanoyl c._ _g, R_ is an alkyl group or an optionally by a chlorine or bromine atom or a C.. Alkyl substituted phenyl

10 group means

or R "or R ₃ together form one of the groups - (CH ₂ ) -, -CH-OCH--,

-CON (R ₀ ) CG- or -CON (R ₀ ) N (R _1n ) CO-, η is the value J or 4, R _{fl is} a hydrogen atom, a C ₁ , - alkyl, phenyl or -C

15 represents denzyl radical,

Rg and R .. represent a hydrogen atom, a C.- alkyl or ßenzylrest, and

F. Represents a C 1-4 alkyl, cyclopropyl, cyclobutyl or trifluoromethyl radical.

EP-A-221 025 discloses heterocyclic analogues of Mevalo®.

lactone and derivatives thereof having the formula

30 described in the

Ra is a radical of the formula -XZ, Rb is the radical R ", Rc is the radical R ₃ , Rd is the radical R, and Y is the radical -N-, or

R.

Ί radical R ", Rd represents the radical R ₃ and Y represents an oxygen radical

Ra is the radical R, Rb is the radical -XZ, Rc is the radical

Represents -16- or sulfur atom or the radical -N-,

wherein R, RR, and R are independently C ..- alkyl groups containing no asymmetric carbon atom, C ₃ _ ₇ cycloalkyl or a ring of formula

fs

R.

R ₇ 10 ⁷

or in the case of R and R represent hydrogen atoms or R_ when Y is an oxygen or sulfur atom, the rest of the formula

N / ^R i8

^R 17 ^R 19

where R ₁₇ denotes a hydrogen atom or a C ₁ -C 4 -alkyl radical and R ₁₈ and R ₁ 'independently of one another

Substituents, C, _- represent alkyl or phenyl radicals, δ υ ι - j

the radicals R ₁ . independently hydrogen atoms, C ,, - alkyl, n-Buty.li-butyl, tert. -Butyl, C. __.- alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy or benzyloxy,

"_ The radicals R, independently of each other hydrogen atoms, C ₁ _- 2b 4 l -ο

Alkyl, C ₁ - alkoxy, trifluoromethyl, fluorine, chlorine, bromine, phenoxy or benzyloxy, and the radicals R_ are independently hydrogen, ^C i ₂ ~ alkyl or C alkoxy, fluoro or Chlorine atoms, provided that at least one trifluoromethyl, phenoxy or benzyloxy group is present in each ring A, X is one of the radicals - (CH) - or - (CH) -CH = CH (CH) - -

2 m 2 q 2 q

provides,

m is 0, 1, 2 or 3 and both indices q are 0 or one

is and the other has the value 1, 35

Z is a radical of the formula

-1 7-

-CH-CH ₉ -C-CH ₉ -COOH OH OH

means

wherein Rg represents a hydrogen atom, a C. __- alkyl radical wherein the radical Z is in the form of the free acid or in the form of an ester or o-lactone thereof or in the form of a salt.

The compounds should be suitable for use as hypolipoproteinemic and anti-atherosclerotic agents.

In Tetrahedron Letters Vol. 29 (1988), p. 929, the synthesis of a β-hydroxy-S-methylglutaryl-coenzyme A reductase inhibitor of the structure

OH OH 0

in which R represents a sodium ion or an ethyl group.

In EP-A-127,848 are derivatives of 3-hydroxy-5-thia-W-arylalkanoic acids of the structural formula

HO

OX S (O)

-18-described, in the Z a remainder of the formulas

-, CH ₂ -CH ₂ -, -

means that η is 0, 1 or 2 E is one of the groups -CH = CH-CH ₂ - or -CH ₂ -CH = CH-, R, R ₂ and R _3, for example, hydrogen, chlorine, bromine or Fluorine atoms, C 1-4 -alkyl, phenyl or substituted phenyl radicals, or the radical --OR--, in which R _{7 is,} for example, a hydrogen atom, a C 1-8 -alkanoyl, benzyl, phenyl, substituted phenyl, Cg Alkyl, cinnamyl, C. _. Haloalkyl, allyl, cycloalkyl-C. _ ₃ alkyl, adamantyl-c '_ ~ ₃ alkyl or phenyl-C. represents --alkyl,

λc ? a

R, R and R are hydrogen, chlorine, bromine or fluorine atoms

one or / C. --Alkyl, and

X e.g. represents a hydrogen atom, a C 1 - alkyl group, a cation derived from an alkali metal atom, or an ammonium ion.

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

3Q FR-A-2,596,393 discloses S-carboxy-Z-hydroxyoropanphosphonic acid derivatives and salts thereof which are useful as hypolipidemic agents and the formula

q I 2 | i

R ₁ OOC-CH ₀ -C-CH ₀ -POH

0R

-19-

in which R ₁ and R represent hydrogen atoms, lower alkyl radicals or optionally substituted Aralkylrestebedeuten, R, and R are hydrogen atoms, lower alkyl or optionally substituted aryl or aralkyl radicals.

These compounds are said to give a greater reduction in cholesterol, glyceride and phospholipid levels than meglutol.

In EP-A-142,146 mevinolinartige compounds of the formula

HO ^ ο, 1

described in the

R is, for example, a hydrogen atom or a C 1-4 alkyl

rest means

E one of the groups -CH ₂₂ and

Z 1) is a radical of the formula

-, - CH = CH- or -

- represents

9

in which X represents -O- or -NR -, where R represents a hydrogen atom or a C 1-4 -alkyl radical,

7 "

R is a C "" alkyl radical, and

/ L - ö

-20-

R represents a hydrogen atom or a methyl group, 2) a radical of the formula

where R, R and R independently of one another denote, for example, hydrogen or halogen atoms or C 1 - = -alkyl radicals,

3) a radical of the formula

15

20 25

1 4, where η is 0 to 2 and R is a halogen atom or

represents a C.-alkyl radical, or 4) a radical of the formula

represents.

These compounds are HMG-CoA reductase inhibitors

35

- 20a -

Object of the invention

The aim of the present invention is to provide novel phosphorus-containing compounds which contain the enzyme 3-hydroxy-3-

methylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibit 5

and thus are suitable as hypocholesterolemic agents.

Explanation of the essence of the invention

The object of the invention is to make available new phorphoriferous jQ HMG-CoA reductase inhibitors.

The invention thus provides a process for the preparation of compounds of general formula I.

0 H

15 Il I χ

RP-CH ₀ -C-CH ₀ CO ₀ R (I)

1 ² I 2 2 X OH

in which R represents a hydroxyl group or a lower alkoxy radical, X represents one of the groups -CH ₂ -, -CH ₂ CH ₂ -, --CH ₂ CH ₂ CH ₂ -, -CH = CH-, -C = C- or -CH ₂ O- (where 0 is attached to the radical Z),

Z represents a hydrophobic anchor, and

R ^{x represents} a hydrogen atom or a lower alkyl radical, in the form of the free acid or in the form of a physiologically hydrolyzable and compatible ester or salt, characterized in that (A) when X denotes the group -CH = CH-,

an acetylenic phosphinate of formula 30

alk-1-O-P-CHo-CK-CHo-CO ₂ alkyl

I ChC 0

Z SiC (CH ₃ ) 3 35 ^C ^ ^{N (V} " ⁵

a silyl ether cleavage to produce a diester

- 20b -

the formula

alkylO-P-CH, -CH-CH _n -CO, alkyl

C = C

I ~

subjects and, if desired, the diester to the monoester of the formula

alkylO-P-CHO-CH-CH ₂ -COOH,

'' '

C = COH

the basic salt of the formula

alkylO-P-CH ₂ -CH-CH ₂ CO ₂ R ^Xa

C = COH

the dibasic salt of formula 0

R ^Xa 0 -? - CH 9 -CH-CHo-CO ₂ R ^Xa

I "I Z-CnC OH

or in the diacid of the formula

HO-P-CH ₂ -CH-CH ₂ -CO ₂ H

c = c Oh

converting;

(B) when X is the group -CH = CH- (ice), · 2ίη acetylenic phosphinate of the formula

alkvlO-P-CHo-CH-CHO-COO alkvl

I 'I "C = C 0 I Z SiC (CH ₃ ) ₃

C ^ VH

C ₆ H ₅ C ₆ H ₅

- 20c -

to the silyl ether of the formula

alkylO-P-CH ₂ -CH-CH ₂ CO ₂ alkyl,

CH // j

^Z ~ ^CE (cis) SiC ₁ C

C ₆ H ₅ C ₆ H ₅

reduced, the silyl ether of a Silyläthei.-cleavage to prepare the diester of the formula

O-

Il alky10-P-CH ₂ -CH-CH ₂ -CO ₂ -alkyl,

(ice) CH OH Il

CH ι Z

and, if desired, the diester in the mono-

ester of the formula

O-alky10-P-CH ₂ -CH-CH ₂ -CO ₂ H,

, CH OH

Z-CH (ice)

the basic salt of the formula

Il _xa

alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ R,

CH OH Il (ice) CH

QQ the acid of the formula

0 Il

HO-P-CH ₂ -CH-CH, -COO H ι

OH

Il (ice) CH z

- 20d - ·

or the dibasic salt of the formula

R ^{CC ±} 0 -? - CHo -CH-CHo-COo Κ ^Λ ;

, CH OF.

^b Il

{ice cream) CH

converting;

(C) when X is the group -CH ₂ -CH--, the silyl ether of the formula

alkylO -? - CHo-CH-CHoCO ₂ alkyl

I "1 CH 0 4

4 1

Z-CH (ice) SiC (CH ₃ ) ₃

T ^N C _O H ₅

to the silyl ether of the formula

II alkylO-P-CHo-CH-CHoCO ₂ alkyl CHo

I CHO SiC (CH ₃ ) 3

Z ~ / ^X

C ₆ H ₅ C ₀ H ₅

reduced, and the silyl ether of a silyl ether cleavage to produce a diester of the formula

0 alkylO-P-CHO-CH-CH ₂ -CO ₂ -alkyl,

CHo OH

CHO

I, ~

and, if desired, place the diester in the alkaline salt of the formula

0 alkylO-P-CHo. -CH-CH ₂ -CO ₂ R ^xa ,

CHo OH

CHo I "Z

- 2Oe -

the acid of the formula

alk-1-O-P-CH ₂ -CH-CHo-COoH,

I ι CH ₂ OH

CH ₂ Z is the dibasic salt of the formula

t Ii XS

R ^ CP-CHo-CH-CH ₂ -CO ₂ R '

l '' I CH, OH I "CHo I" Z

or the causes of Formula 15

0 I! HO-P-CHo-CH-CHo-COoH;

"I" CHo OH "CH ₂

^Z

converting;

(D) when X is the group -CH = CH- (trans), a silyl ether of the formula

_{9 (} - 0

I,

alkylO-P-CHO-CH-CHO-COO alkvl

"l" (trans) CH

CH C ₆ Ii ₅

30 a silyl ether cleavage to produce the Hydrcxydiesters the formula

Il ,,

alkylO -? - CHO-CH-CHO-COO alkyl,

"1" {trans) , CH OH ην

I Z

- 20f -

and, if desired, subjecting the hyuroxy diester to the basic salt of the formula

alkvlO -? - CHo-CH-CH, CO ₂ R

I ' (trans) CH OH

CH

a

the acid of the formula • 0

alk-1-O-P-CH, -CH-CHo-CO ₂ H, I "1 CH OH

CH

the basic salt of formula 0

^Xa

R 0-P-CHO-CH-CH ₂ -CO ₂ R,

"I (trans) CH OH

CH

or the corresponding diacid of the formula

HO-P-CH ₂ -CH-CH ₂ -CO ₂ H

Il (trans) CH OH

HC I Z

(E) when X is the group of the formula -CH = CiI- (trans), a Phosphonochloridat do> - formula

0 Il

aikylO-P-Cl

CH {trans)

- 20g -

with an alkyl acetoacetate dianion to a ketophosphonate of the formula

O '

Il. , alky10-P-CH ₂ -C-CH ₂ -CO ₂ alkyl,

(trans) CH CH Z

condenses, the ketophosphonate to Diesterphosphinat

the formula

0 Ii alky10-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl,

(trans) CH OH

reduced, and if desired, the diester in the dibasic salt of the formula

alkylO-P-CHo-CH-CH ₂ COoR

I "( trans) CH OH

CH

xa

the acid of the formula

alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ H, (trans) CH OH CH

the basic salt of the forms ¹ .

0 R ^Xa O -? - CH ₂ -CH-CH ₂ -CC-., R ^Xa

Z-CH (crans)

- 20h -

or the diacid of the formula

KO-P-CH ₂ -CH-CHo-COoH;

Z-CH ( trans)

converting;

(F) when X is one of the groups -CH ₂ -, -CH ₂ CH ₂ - or

a phosphonochloridate of the formula

(CH ₂ ) _a

where a is 1, 2 or 3 with an alkyl acetoacetate dianion to the ketophosphonate of the formula

0 "ΊΙ alky10-P-CH ₂ -C-CH ₂ -CO ₂ alkyl,

(CHO)

I

condenses, the ketophosphonate to the diester of the formula

0 is alkylO-P-CHO-CH-CH ₂ -CO ₂ alkyl,

(CH ₂ ) _a OH

reduced, and if desired, the diester in the basic salt of the formula

alkvlO -? - CH ₂ -CH-CH ₁ COOR "

I '"(CHo) OH

I " ^a Z

the acid of the formula

alky10-P-CH ₂ -CH-CH ₂ -CO ₂ H,

OH

- 20i -

the dibasic salt of the formula

R ^X5 OP-CH ₂ -CH-CH ₂ -CO ₂ R I I ) OH

x a

or the diacid of the formula

0 Il HO-P-CH ₂ -CH-CH ₂ -CO ₂ H

(CH ₂ ) _a OH

converting; and

(0) when X is the group - (CH ₂ O) -, a phosphonochioridate of the formula

• II alkylO-P-Cl

Z-O

with an alkyl acetoacetate dianion to the ketophosphonate of the formula

0

Il Μ _Ί1 , alkylO-P-CHo-C-CH ₂ -CO ₂ alkyl

condensed,

I 0

the ketophosphonate to the diester phosphinate of the formula

alkvlO -? - CH ₂ -CH-CHO-COO alkyl ι "ι CHo OH ι

0 ι Z

and, if desired, the diester into the basic salt of the molds.

- 21 -

O

alkylO -? - CKo-CH-CH ₂ CO ₂ R ^Xa I "CH, OK I" O I Z

the acid of the formula

O, alkylO -? - CH ₂ -CH-CH ₂ -CO ₂ H,

CH ₂ OH

O Z the dibasic salt of the formula

0 R ^Xa 0 -? - CH ₂ -CH-CH ₂ -CO ₂ R ^Xa

CHo OH

I Z

or the diacid of the formula

0

HO-P-CH ₂ -CH-CH ₂ -CO ₂ HZO-CH ₂ OH

converts

 25

The term "hydrophobic anchor" refers to a lipophilic moiety that, when attached to the HMG-like upper side chain of the molecule through a suitable bridging member ("X"), joins to a hydrophobic stall ("pocket") of the enzyme , which is not used for binding the substrate HMG CoA. This leads to an increased efficiency compared to compounds in which Zein means hydrogen atom.

-22-

The term "salt" refers to basic salts with inorganic and organic bases. Such salts include the ammonium salts and alkali metal salts such as the lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts such as the calcium and magnesium salts, organic base salts such as amine-type salts, e.g. Dicyclohexylamine, benzathine, N-methyl-D-glucamine and hydrabamine salts, salts with amino acids such as arginine and lysine. The non-toxic pharmaceutically acceptable salts are preferred, although other salts may also be useful, for example for the separation and purification of the product.

Examples of hydrophobic anchoring groups which may be present in the compounds prepared according to the invention are (without being limited thereto) radicals of the formulas:

/O

vv

N _ N / V ^ N

ii

RV ^ N ^ / R

23

^23a

R-- C = C

22

, 23a

or

alkyl

-24-

The dashed lines indicate the possible presence of double bonds, for example in terms of the formulas

alkyl

or

alkyl

In the pre-tenend listed formulas, R, R, R and R may be the same or different and are independently hydrogen, halogen, lower alkyl, HaIogenalkyl-, phenyl or substituted phen ¹ Ireste or radicals of the formula OR ^, wherein R "is a Hydrogen atom, an alkanoyl,

-25-

Benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl, lower alkyl, adamantyl, lower alkyl or substituted phenyl-lower alkyl.

If Z is the rest of the formula

, 6

¹⁰ JL X, alkyl

ς 5 ', the radicals R "and R are the same or different and denote hydrogen atoms, lower alkyl radicals or hydroxyl groups, O

6 "I ¹

R is lower alkyl-C, for example CH - CH ₀ -CC-,

^{3 1} S \ 7 20 or ArylCH ₂ - CH ₃ R

R ^{a represents} a lower alkyl group, a hydroxy or oxo group or a halogen atom, g represents 0, 1, 2 or 3, and R represents a hydrogen atom or a lower alkyl group.

If Z is one of the radicals

-26-

N -Ν

⁴ Rl ^ Nv R ⁴

represents one of the radicals R and R is the radical of the formula

, 14a

and the other is a lower alkyl, cycloalkyl or phenyl (CH ₉ ) radical, ρ is 0, 1, 2, 3 or 4, wherein

1 3 ^p R is a hydrogen atom, a lower alkyl, lower alkoxy (except tert-butoxy), halogen, phenoxy or benzyloxy

rest means

R 1 represents a hydrogen atom, a lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy radical, R represents a hydrogen atom, a lower alkyl or lower alkoxy radical or a halogen atom,

with the provisos that R ** and R ^a must be hydrogen when R is hydrogen, R is hydrogen

1 4 atom must be, if R is a hydrogen atom, at most

13 14 one of the radicals R and R signifies a trifluoromethyl group.

13 14 tet, at most one of the radicals R and R is a phenoxy group

13 14 pe, and at most one of the remainder · =? R and R one

-27-

1 benzyloxy group means

R represents a hydrogen atom, a c._.-Alkyl, C, _fi cycloalkyl, C., alkoxy (except t-butoxy), tri-

fluoromethyl, fluoro, chloro, phenoxy or benzoyl, 9 F. means a hydrogen atom, a C., -alkyl, C, _-

Alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

9 • with the provisos that R must be a hydrogen atom, if

8 fl

• R is a hydrogen atom, at most one of the radicals R and ^R 9 is a trifluoromethyl group, at most one of

8 9 radicals R and R represents a phenoxy group and at most

8 9 one of the radicals R and R denotes a benzyloxy group,

R and R independently of one another are hydrogen atoms, alkyl, cycloalkyl or adamantyl-1 radicals or radicals of the formula

R ^14a

13 14 ι 4 _a wherein R, R and R are as defined above and q

0, 1, 2, 3 or 4,

Y is an oxygen or sulfur atom or group 25

-NR ¹⁰ -.

If Z is a remainder of the formula

,8th

R is a hydrogen atom or a primary or

secondary C 1 -, -alkyl radical

R is a primary or secondary C.sub.1-6 alkyl radical;

-28-

or R and R together are one of the groups - (CH ₂ ) - or (CiS) -CH ₀ -CH = CH-CH ₂ -,

r is 2, 3, 4, 5 or 6,

12 R 'represents a lower alkyl or cycloalkyl radical or

a remainder of the formula

'R ¹³

Jua 10

wherein R and R, R, R and R ^{a are} as defined above

are.

When Z is a radical of formula 15

R and R are hydrogen, chlorine or bromine, cyano, trifluoromethyl, phenyl, C ₁ alkyl or

17 C_ "-Alkoxycarbonylreste or radicals of the formulas -CH ₀ OR

1fl 25 or -CH ₀ OCONHR -,

17 R is a hydrogen atom or a C, --alkanoyl- '

rest,

1 8 R represents an alkyl or an optionally through

a fluorine, chlorine or bromine atom or a C ₁ -alkyl radical-substituted phenyl group,

or R and R together are one of the groups - (CH ₀ ) -,

1Q? 0

-CH ₂ OCH ₂ -, -CON (R) C0- or -CON (Px VN (R) CO-,

s is 3 or 4,

1 9 R is a hydrogen atom, a C. _ _fi alkyl, phenyl or

35 benzyl radical,

20 R and R represent hydrogen atoms, C ..- alkyl or benzyl

-29-

rest,

with the additional proviso that X can represent only one of the radicals -C-CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ - when Z is a radical of the formula

represents.

If Z is a remainder of the formula

means

22 R is a lower alkyl, cycloalkyl or adamantyl-1 radical

or a remainder of the formula

- <CH ₂ ) _t - @

30 t is 1, 2, 3 or 4,

R and R ^a are the same or different and each independently represent hydrogen atoms, lower alkyl, lower alkoxy (excluding tert-butoxy), halogen, phenoxy or benzyloxy radicals,

35 with the provisos that R ^a must be a hydrogen atom,

23 when R is a hydrogen atom, at most one of the radicals

-30-

23 23a R and R is a trifluoromethyl group, at most one of the radicals R and R represents a phenoxy group, ur.d at most one of the radicals R and R is a benzyloxy group.

When X represents the group -CH-O- (the carbon atom attached to P and the oxygen atom attached to Z), the hydrophobic anchor Z is an anchor of the phenyl or naphthalene type, for example of the formula

.The compounds of general formula I thus comprise the following structures:

Il χ

a RP-CH ₂ -CH-CH ₂ -CO ₂ R

C ÖH

III C I Z

ib

0 R-i-

CH ₂ -QH-CH ₂ -CO ₂ R CH OH CH (ice)

0 U

Ic RP-CH ₀ -CH-CH, -C0, R

I 2 s ZZ

CH ÖHIl CH (trans)

_Id RP-CH ₂ -QH-

CH, OH I ^z CH ₀

Il j

Ie RP-CH ₂ -QH-CH ₂ -CO ₂ R

10 CH ₀ OH

2

0 If RP-CH ₂ -gH-CH ₂ -CO ₂ R ^X

16 (fVa ° ^H

Ig RP-CH ₂ -CH-CH ₂ -CO ₂ R ^X 20 CH ₀ OH

I *

0 z

The terms "lower alkyl" or "alkyl", alone or as part of another group, refer to straight or branched chain hydrocarbon radicals containing 1 to carbon atoms in the normal chain, preferably 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl , Butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4'-dimethylpentyl, octyl, 2,2 _? 4-trimethylpantyl, nonyl, decyl, undecyl and dodecyl group, the various branched-chain isomers thereof, and also those groups having a halogen substituent, such as a fluorine, bromine, chlorine or iodine atom or a trifluoromethyl group, an alkoxy, Aryl, alkylaryl, haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino, alkanoyl

amino, arylcarbonylamino ·, nitro, cyano, thiol or alkylthio substituents.

The term "cycloalkyl radical", alone or as part of another group, denotes saturated cyclic hydrocarbon radicals having 3 to 12, preferably 3 to 8, carbon atoms. These include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, each containing 1 or 2 halogen atoms, 1 or 2 lower alkyl, 1 or 2 lower alkoxy, 1 or 2 hydroxy , 1 or 2 alkylamino, 1 or 2 alkanoylamino, 1 or 2 arylcarbonylamino, 1 or 2 amino, 1 or 2 nitro, 1 or 2 cyano, 1 or 2 thiol and / or 1 or 2 alkylthio substituted can be.

The term "aryl radical" refers to monocyclic or bicyclic aromatic radicals having 6 to 10 carbon atoms in the ring moiety, such as the phenyl, naphthyl, substituted phenyl or substituted naphthyl group, wherein the phenyl or naphthyl group has 1, 2 or 3 lower alkyl radicals, halogen atoms (Cl , Br or F), 1, 2 or 3 lower alkoxy radicals, 1, 2 or 3 hydroxyl groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy radicals, 1, 2 or 3 benzyloxy groups, 1, 2 or 3 haloalkyl radicals, 1, 2 or 3 halophenyl radicals, 1, 2 or allyl groups, 1, 2 or 3 cycloalkylalkyl radicals, 1,2 or 3 adamantylalkyl radicals, 1, 2 or 3 alkylamino radicals, 1, 2 or 3 alkanoylamino radicals, 1, 2 or 3 arylcarbonylamino radicals, 1, 2 or 3 3 amino groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, 1, 2 or 3 thiol groups and / or 1, 2 or Alkylbhioreste may have, wherein the aryl radical preferably contains three substituents.

The terms "arylalkyl", "arylalkyl" or "aryl-lower alkyl" refer, by themselves or as part of another group, to lower alkyl groups as described above having an aryl substituent, such as the benzyl group.

-33-

The terms "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" refer, by themselves or as part of another group, to the lower alkyl, alkyl, aralkyl or aryl groups described above attached to an oxygen atom.

The terms "lower alkylthio radical", "alkylthio radical", "arylthio radical" or "aralkylthio radical", by themselves or as part of another group, signify one of the lower alkyl, alkyl, aralkyl or aryl radicals described above attached to a sulfur atom.

The terms "lower alkylamino", "alkylamino", "arylamino", "arylalkylamino", alone or as part of another group, refer to one of the loweralkyl, alkyl, aryl or arylalkyl radicals described above attached to a nitrogen atom.

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

The term "halogen atom" refers to chlorine, bromine, fluorine and iodine atoms as well as trifluoromethyl groups, with the chlorine and fluorine atoms being preferred.

Preferred compounds of the formula I have the following structure:

30 II R 0 CH, H CH,

CO ₀ R ²

X;

Z OH

in which R is -OH, -OLi or CH ₃ O, R ^{X is} Li or H dar-. provides,

-34-

X is one of the groups -CH--, -CH_C - C = C- or -CH_O-, and Z is a radical of the formula

"1

2 8 UO 5

-, - CH = CH-,

  '

wherein R represents a phenyl group or a phenyl group which contains an alkyl and / or a halogen substituent,

R is a cycloalkylalkyl radical, such as the cyclohexylmethyl group, or R is a benzyloxy group which has a halogeno group;

contains substituents,

2 2a R and R are the same and are a hydrogen or halogen atom or a lower alkyl radical:

Z may preferably also be a radical of the formula

O O

1 2

wherein R and R are as immediately above defined in connection with the compounds of formula II sine; Z may preferably also be a radical of the formula

-35-

in which R is a substituted phenyl, lower

4 is alkyl, cycloalkyl or phenylalkyl and R is a substituted phenyl, lower alkyl, e.g. Isopropyl, cycloalkyl or phenylalkyl; or Z may preferably also be a radical of the formula

where R is a hydrogen atom, a methyl or hydroxyl group and R is a radical of the formula O.

, CH, CH-,

or a substituted phenylmethyl group, wherein

7 R represents a hydrogen atom or a methyl group.

Z may preferably also be a radical of the formula

3 4, wherein at least one of the radicals R and P represents a phenyl or substituted phenyl group and the remaining radical R or R represents a lower alkyl radical.

The compounds of general formula I of the invention can be prepared as follows.

Reaction Sequence A. Preparation of Compounds of Formula I ₄ wherein X is -CH = CH-

fe ^H 5

P (Oalkyl) ₃

OSi-C (CH ₃ J ₃

C ₆ H ₅

III

I-CH ₂ -CH-CH ₂ -CO ₂ alkyl Arbuzov reaction

alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl ' oalkyl 5si-C (CH "K

^C 6 ^H 5 ^C 6 ^H 5

1. (CH ₃ J ₃ SiBr,

2. H-O

Phosphorester cleavage

K HO-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl

OH Ö

Si-C (CH-), ³

^C 6 ^H 5 ^C 6 ^H 5IV

A ^ Kanol DCC

pyridine

1 u>.

"Ti I

| i alkylO-P-CH ₂ -QH-CH ₂ CO ₂ alkyl

OH Ö

^ Si-C (CH ₃ ) 3

^C 6 ^H 5 ^ 6 ^H 5 VI

1. (CH ₃ J ₃ SiN (C ₂ H ₅ ) 2 (TMSNEt ₂ )

2. (COCl) ₂ ; CH ₂ Cl ₂

(Acid chloride formation 5

Il

alkylO-P-CH ₂ -CH-CH ₂ CO ₂ alkyl

Cl ^C 6 ^H 5

Si-C (CH ₄ J \ ^J

^C 6 ^E 5 VII

CBr ₄ , Ph ₃ P Wittig

CH = CBr ₂ Z

IX

Dehydrohalogenation ^

1) n-BuLi

2) H ₂ O

C = CH I

1) Li-anion formation (n-BuLi, THF)

2) condensation with. Phosphonochloridate VII

alkylO-P-CH - CH-CH - CO_alkyl ι · * - 2 & J.

C = Cι

² / NOI

^C 6 ^H 5

1) Silyl ether cleavage

_χΙ (nC ₄ H ₉ ) ₄ NF, CH ₃ COOH, THP

2) hydrolysis (LiOH, dioxane ·)

Il

HO-P-CH ₀ -CH-CH ₀ CO ₀ HI 2 at 2

C OH ill

Selective reduction

H _2, 10% Pd-C MeOH, 1 atm

HO-P-CH ₂ -CH-CH ₂ -CO ₂ H

CH OH Z-CH (ice) IB

I Z

IA

alkylO-P-CH ₂ -CH-CH ₂ CO ₂ alkyl 1) silyl ether cleavage

.CH Ö .2) hydrolysis Z-CH Si-C (CH.),

(ice)

^C 6 ^H 5 ^C 6 ^H 5

XII

co

reduction

H ₂ , 10% Pd-C MeOH, 3.5% b

alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl _{±) silyl} ä _ _{ther cleavage}

/ CH ₂

CH ₂ O

^C 6 ^H 5 ^C 6 ^H 5

2) hydrolysis

XIII

HO-P-CH ₀ -CH-CH ₀ CO ₀ H 2 = 2 2

(CH ₂ OH

ID

Reaction sequence B. Preparation of compounds I in which the X bond (-CH = CH-)

trans is, that is 0 '

il

CH (trans)

, IC

H C III Hydros tending CH I SnCn-C ₄ Hg) ₃ pH iodination CH I ι 1) nC ₄ HgLi (metallation) ^ ί Cn-C ₄ Hg) ₃ SnH Z I ₂ , Et ₂ O Z 2) VII Z AIBN, 120 ⁰ C. (Condensation)

XV

XVI

O Il

Alky10-P-CH ₂ CH-CH ₂ CO ₂ alkyl 1.) Silyl ether cleavage

OSi-C (CH ₃₎

CH (trans) C..H ,. C _fi H _q 2.) LiOH, dioxane

ο a o D (hydrolysis)

XVII

0 H

"f ~ ^H 2 ~ =" 22 CH OH

CH (trans) Z

IC

Reaction sequence C. Alternative preparation of compounds I in which the X bond

(-CH = CH-) trans, that is, of compounds 1C

Condensation Q

HO | f (Oalkyl) ₂ (Oalkyl) ₂ ^V CH-CH.

HJD elimination p-TsOK

THF, -78 "C

Hydrolys e aqueous LiOH

Dioxane.

XX

3

alkyJO-P-OH

benzene

-. Δ

{Trans)

XXII

Acid chloride formation

1. (CH ₃ ) ₃ SiN (C ₃ H ₅ ) ₂ (TMSNEt ₂ )

2. (COCl) ₂ , Cat. DMF

CH ₂ Cl ₂

CH Z

OK

P- (Oalkyl) ₂

(Trans)

XXI

1.1 "

alkylo-P-Cl I

CH Z

(Trans)

XXIII

condensation

YYTTT

Oh!

0 *

C.

oo

l 'Il

alkylO-P-CH_-C-CH, -CO-alkyl reduction

CH ₂

OAlkyl

THF, -78 "" 'C

XXIV

C ₂ H ₅ OH

j? ^OH

alkylO-P-CH ₂ -CH-CH ₂ C0 ₂ alkyl _hydrolys

CH I

IC

dioxane

OH

PCCH

CH I

IC

Reaction Sequence D. Preparation of compounds of the formula I in which X is -CH.-,

-CH-CH-- or -CH-CH-CH ₀ -

, Cl <f ^H 2> a

(a isl, 2 or 3)

XXV

0 II alkylO-P-Cl

<f ^H 2> a Z

XXVII

(AlkylO) ^ P III

CH

OAlkyl

clutch

THF, -78 ° C

P (Oalkyl) ₂

^(CH 2 ^J a Z

XXVI OH

2. TMSNEt.

3. · (COCl) ₂ , cat. DMF

(Acid chloride formation)

alkylO-P-CH ₂ -C-CH ₂ -CO ₂ alkyl reduction «fV a ° Z

NaBH

C ₂ H ₅ OH

XXVIII

O OH il I alkylO-P-CH ₂ -CH-CH ₂ CO ₂ alkyl 2> a hydrolysis 0 II HO-P-CH OH ₂ -CH-CH ₂ CO ₂ H (CH.I.Z (A = 2) / L aqueous OH (CH ₂ ) Z a ID ¹ (A = l) ID (A = 2) IE ¹ ία = 3) IE (A = l) IP ¹ IF (A = 3)

Reaction Sequence E. Preparation of Compounds of Formula I wherein X is -CH ₂ O-

VIII

1 ". Baeyer-Villiger Oxidation (MCPBA)

2nd base, hydrolysis

OH I Z

XXIX

Alkylation TsO-CH ₀ -PO (Oalkyl) _o

'_ _ * XXX

base

PO (OAlkyl)

Hydrolysis of aqueous LiOH

dioxane

XXXI

O-alkyl-O-P-OH

O Z

Acid chloride formation

1) TMSNEt ₂

2) (COCl) ₂

Cat. DMF, CHCl ₂

XXXII

O alkyl-0-P-Cl reduction

IT alkylO-P-CH ₂ -C-CH ₂ CO ₂ alkyl ^MaBH 4

.CH- C ₇ HcOH

₂ W ₂ CH Oa Iky I

XXXIII ^THF '- ⁷⁸ ° ^cz xxxiv

? ? ^H 'β? ^H ι

alkylO-P-CH ₂ -CH-CH ₂ CO ₂ alkyl hydrolysis e-

OH ^ ^ H ₂

dioxane

1 i ^IG

IG ¹ Z

ι.

'-48-

* 'Ίΐι

K; According to the above reaction sequence "A", compounds "'of the formula I can be prepared by subjecting the iodide A f / to an Arbuzov reaction. For this purpose, the iodide A is

5? 6 ^H 5

0-Si-C (CH ₃ J ₃

j ^C 6 ^H 5 A I-CH ₂ -C-CH ₂ -CO ₂ alkyl

' H

10

and a phosphite of the formula III

III, P (Oalkyl) ₃

heated using standard Arbuzov conditions and methods. The result is the phosphonate of formula IV

¹⁵

IV alkylO-p ¹ CH ₂ CH-CH ₂ -CO ₂ alkyl

Oalkyl ^ OSi-C (CH ₃ ) ₃

^{: 6H5}

'/ -Hr- C, -Hr

(a new intermediate).

The phosphonate IV is then subjected to a phosphoric ester cleavage. For this purpose, a solution of the phosphonate IV in an inert organic solvent, such as methylene chloride, successively treated with bis (trimethylsilyl) trifluoroacetamide (BSTFA) and trimethylsilyl bromide under an inert atmosphere, such as argon. The result is the phosphonic acid V

0 V H0-P-CH _O -CH-CH, -C0, alkyl

on I *

OH 0

.Si-C (CH-)

^C 6 ^H 5 ^C 6 ^H 5

(a new intermediate). 35

The phosphonic acid V is obtained by treatment in dry pyridine.

28 160

-49-

din esterified with a lower alkyl alcohol (such as methanol) and dicyclohexylcarbodiimide. The resulting reaction mixture is stirred under an inert atmosphere, such as argon, to give the phosphonic monoalkyl ester VI (a novel intermediate). The phosphoric monoester VI is then dissolved in an inert organic solvent such as mathylene chloride, benzene or tetrahydrofuran (THF) and treated with trimethylsilyl diethylamine and stirred under an inert atmosphere such as argon. The mixture is then evaporated and then dissolved in methylene chloride or another suitable inert organic solvent. The resulting solution is cooled to a temperature in the range of about -10 to 0 ⁰ C, treated with oxalyl chloride and a catalytic amount of dimethylformamide and then evaporated. The crude phosphonochloridate VII (a new intermediate) is obtained. The Phosphonochloridat VII is dissolved in an inert organic solvent such as methylene chloride, benzene, pyridine or THF, at a temperature dieyLösung ir the range of about -90 to about 0 ⁰ C, preferably about -85 to -30 ⁰ C, cooled, and a cooled (same range as the solution of phosphonochloridate VII) solution of the lithium anion of acetylene X treated. This is prepared by treating a lithium source, such as n-butyllithium, in hexane or other inert solvent,

χ ChCH

wherein a molar ratio of VII: X in the range of about 3: 1 to 1: 1, preferably from about 1.5: 1 to about 2: 1, is used. It becomes the acetylenic phosphinate XI

O It

XI alkylO-P CH ₂ CH-CH ₂ -CO ₂ alkyl

Λ, CO

^d5 III I

^C 6 ^H 5 ^C 6 ^H 5

-50- (a new intermediate).

The acetylenic phosphinate XI can then be used to prepare the various compounds of the invention as described below.

The acetylenic phosphinate XI is converted to the acetylenic phosphinate IA. For this purpose, XI is subjected to silyl ether cleavage, to which XI is reacted in an inert organic solvent, such as tetrahydrofuran, with glacial acetic acid and tetrabutylammonium fluoride. The result is the ester IA

1 'Ii

IPT 31! CyIO-P-CH ₂ -CH-CH ₂ -CO ₂ Pil

C OH

_1R III

15 _c

I Z

which can then be hydrolyzed to the corresponding basic salt or acid, i. to compounds in which R

R ^xa has the meaning which may be an ammonium, alkali metal or alkaline earth metal ion, an amine or the like. For this purpose, IA is treated with a strong base, such as lithium hydroxide, in the presence of dioxane, tetrahydrofuran or another inert organic solvent, under an inert atmosphere, such as argon, at 25 ° C. There is a molar ratio of base: ester IA in the range of etva 1: 1 to about 1.1:

1 used. The corresponding basic salt IA is obtained.

0 ³⁰ IA ² alkylO- | -CH ₂ -CH-CH ₂ -CO ₂ -R ⁵ "

C OH

• Ul

2 Compound IA can then be treated with a strong acid, such as

-51-

HCl, to give the corresponding acid IA.

IA ³ alkylO - ^ - CH ₂ -CH-CH ₂ -CO ₂ H

C OH

III

The ester IA can also be converted to the corresponding dibasic salt by treatment with a strong base at 50 to 60 ^° C. For this purpose, a molar ratio of base: ester IA in the range of about 2: 1 to 4: 1 is used. It is

4 is a compound of the formula IA.

IA ⁴ R ^{xa O} -P-CH, -CH-CH ₀ -CO, R ^Xa

C OH

III

C z

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

Phosphinate compounds of the invention in which X represents the group (cis) -CH = CH-, i. Compounds of formula IB are obtained by subjecting the acetylenic phosphinate XI to selective reduction, for example by treatment with hydrogen in the presence of a reduction catalyst, such as palladium on carbon or palladium on barium carbonate, in an inert organic solvent like methanol. It becomes the silyl ether XII

₃₅ XII Sikyl-P-CH ₂ -QH-CH ₂ CO ₂ -

CH 0

Si-C (CH ₃ ) ₃ H CH

C ₆ H ₅ C ₆ H ₅

8 16 0 5 · ^;

-52-j (a new intermediate).

The silyl ether XII can then undergo silyl ether cleavage and hydrolysis as described above. 5 The following are obtained: the ester IB

O IB ¹ alkylO-P-CH 2 CH-CH ² CO 3 alkyl

CH OH (ice) CH Z

2 the basic salt IB

0 IB ² alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ R ^xa ,

'CH OH

Il (ice) CH

3 the acid IB

0 IB ^{3 3} ICYLOP

CH OH Il (ice) CH

Z

4 the dibasic metal salt IB

0 IB ⁴ R ^Xa OP-CH, -CH-CH ₉ -C0 _o R ^Xa

CH OH (ice) CH Z.

and the corresponding diacid IB.

-53-

Phosphinate compounds of the invention in which X represents the group -CH_-CH ₂ -, ie compounds of formula ID, are obtained by subjecting the acetylenic phosphinate XII to catalytic reduction, for example by treatment with hydrogen in the presence of a reduction catalyst such as palladium on carbon, in an inert organic solvent, such as methanol, at a pressure of about 3.5 bar. It becomes the silyl ether XIII

.ίο ^s · ti

XIII 3 Ikyl-P-CH ₂ -CH-CH ₂ CO ₂ -silyl

CH ₀ 0 l ^ί I CH ₀

6 ^C 6 ^H 5 ^C 6 ^H 5 15

(a new intermediate).

The silyl ether XIII can then be subjected to silyl ether cleavage and hydrolysis as described above. The ester ID ^{1 is obtained}

1 "

ID 3-alkyl-P-CH ₂ -CH-CH ₂ -CO ₂ -alkyl,

CH ₂ OH

²⁵ f ^H 2

Z.

the basic salt ID

30 ₀

2 Μ xa ID 3 Ikyl-P-CH ₀ -CH-CH ₀ -CO ₀ R,

CH ₂

OH

the acid ID

-54-3 ·

CH ₀ OH I 2

f ^H 2

the dibasian salt ID

O. ID ⁴ · R ^Xa O-P-CH ₂ -CH-CH ₂ -CO ₂ R ^Xa

CH ₂ . OH

'2 15

and the corresponding diacid ID.

With reference to the reaction sequence "B", compounds of the formula I in which the bridging group X between the phosphorus atom and the hydrophobic anchor Z represents the group (trans J-CH = CH-, by treating a mixture of the acetylene X and nC .HqSnH with a radical initiator, such as azo

bisisobutylnitrile (AIBN), hydrogen peroxide or benzoyl peroxide, and heating the resulting solution to a temperature in the range of about 100 to 140 ^° C under an inert atmosphere such as argon. The vinylstannane XV is obtained.

30.

SnU-C ₄ H ₉ ) ₃

XV CH 's

CH

I '. , , ,

The vinylstannane XV is dissolved in an organic solvent such as diethyl ether, methylene chloride or chloroform and treated with iodine and stirred under an inert atmosphere such as argon. The result is the vinyl iodide XVx.

5 '

XVI CH

S /

CH Z

10

A cooled solution of the vinyl iodide XVI (-78 to -40 ° C) in,. a dry organic solvent such as tetrahydrofuran or diethyl ether is treated with a metallizing agent such as n-butyllithium in an inert organic solvent such as hexane. The mixture is cooled to a temperature of -78 to -40 ⁰ C under an inert atmosphere such as argon, *. The anion is added to a cooled to -78 to ⁰ C cooled solution of the -4o Phosphonochloridats VII in an MOI ratio XVI: VII within the range of about 1: 1 to 2: 1,

dry

preferably from about 1: 1 to about 1.5: 1, in an inert organic solvent such as tetrahydrofuran or diethyl ether. The result is Silyläther XVII

XVII alkylO - ^ - CH ₂ -CH-CH ₂ -CO ₂ alkyl 25 (trans) ^ CH 5βi-C (CH ₃ ) ₃

CH C ₆ H ₅ ^ C ₆ H ₅ Z

(a new intermediate).

30

Silyl ether XVII is subjected to silyl ether cleavage. For this purpose, a solution of XVII in an inert organic solvent, such as tetrahydrofuran or acetonitrile, with glacial acetic acid and a solution of (nC.HgJ.NF in an inert

erten organic solvents such as tetrahydrofuran treated. The result is the hydroxydiester IC.

28 160

-56-

1 "

I (3) alkyl-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl

, (trans) CH OH

CH

The diester IC can then be hydrolyzed as described above. The result is:

2 ₁₀ the basic salt IC

IC ² alkylO-P-CHj-CH-CH ₂ CO ₂ R ^xa (trans ) _y CH OH CH

the acid IC

3 "

IC alkylO-P-CH ,, -CH-CH ₀ -CO ₀ H 20 12 = 22

^ CH OH

4 the basic salt IC

IC ⁴ R ^Xa 0-P-CH _o -CH-CH _o . -C0 _o R ^Xa

jm oh

CH J

and the corresponding diacids IC

O ³⁵ IC HO-P-CH ₂ -CH-CH ₂ -CO ₂ H

^ CH OH HC

28 160

-57-

In an alternative process, according to reaction sequence "C", compounds of the formula I in which the bridging radical X between the phosphorus atom and the hydrophobic anchor Z represents the group (trans) -CH = CH- can be prepared thereby

5 that an aldehyde VIII

VIII CHO

a condensation reaction with a cooled to -90 to 0 ⁰ C solution of a Dialkylmethylphosphonats and Butyllithium (LiCH ₂ PO (alkyl) ₂ ) in the presence of an organic solvent such as tetrahydrofuran or ethyl ether is subjected. The result is the ß-hydroxyphosphonate XX.

0 ¹⁵ ^

XX HO-CH-CH ₂

The ß-hydroxyphosphonate XX is then treated with p-toluenesulfonic acid in the presence of benzene or toluene with heating at a temperature in the range of about 50 to 120 ⁰ C, preferably under reflux. The water is driven off and a trans-olefin XXI obtained,

²⁵ ^ (Oalkyl) ₂

XXI (trans) ^ CH

CH Z

30 by treatment with an aqueous alkali metal eye,

such as LiOH, in the presence of dioxane or other inert organic solvent, and then hydrolyzed with an acid such as hydrochloric acid. The result is the monoacid ester XXII.

-58-

alkylo-P-OH (trans) CH

CH

A solution of the mono acid ester XXII in dry methylene chloride is treated with trimethylsilyldiäthylamin. The jQ mixture is evaporated and the resulting oil taken up in dry methylene chloride, which is cooled to 0 ⁰ C. Then the solution is treated with oxalyl chloride and a catalytic amount of dimethylformamide under an inert atmosphere such as argon. The result is phosphonochloridate XXIII.

15 o

alkylO-t-Cl

XXIII (trans) CH

CH

The Phosphonochloridat XXIII is in an alkyl acetoacetate dianion such as, treated methyl acetoacetate dianion in the presence of an inert organic solvent such as tetrahydrofuran at reduced temperature from -90 to -40 ⁰ C. For this purpose, a molar ratio of phosphonochloridate: dianion in the range of about 1: 1 to 0.75: 1 is used. The result is the ketophosphonate XXIV

⁰ I ° l XXIV alkylO-P-CH, -C-CH ₉ -CO ₉ alkyl

^όΌ (trans) ^ CH

CH Z

(a novel intermediate) which is reduced by treatment with a reducing agent such as sodium borohydride in the presence of an alkanol such as ethanol. The result is the phos-

-59-

phinate IC ¹ .

O IC ^{1 3} Ikyl-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl (trans) CH OH Clf

The diester IC can then be hydrolyzed as described above. The result is: the basic salt IC

'0

IC ² alkylO-P-CH ₂ -CH-CH ₂ CO ₂ R ^xa "(trans) CH OH CH Z

3 the acid IC.

'0

IC ³ alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ H (trans) ^, CH OH

CH Z

4 the basic salt IC

(trans) CH OH

R ^Aa OP-CH ₂ -CH-CH ₂ -CO ₂ R OH

F ¹

Z

and the corresponding diacid IC.

With reference to reaction sequence D, compounds of formula I in which X represents the group - (CH -) -, where a is 1, 2 or 3, i. Groups of formulas -CH_-,

-60-

-CK-CH-- or -CH-CH-CH--, starting from aldehyde VIII, which is converted by conventional methods into the halide Villa. For example, the aldehyde VIII can be reduced with sodium borohydride in the presence of ethanol and ether. The result is the corresponding alcohol villa

Villa CH ₉ OH

which is treated with mesyl chloride in the presence of an organic base such as triethyiamine and a solvent such as methylene chloride to give the chloride XXV (a = 1).

The chloride XXV is subjected to a condensation reaction, including XXV with the phosphite 'Τ.ΪΙ using a molar ratio of III: XXV in the Bt region of about 1: 1 to 10: and at a temperature in the range of about 100 to 150 ⁰ C. is treated. The result is the Phosphonatrdiester XXVI. A solution of Phosphonac diestar XXVI. in a solvent such as dioxane is treated in a strong base such as an alkali metal hydroxide, eg LiOH, to give a corresponding monoester which is reacted with oxalyl chloride in the presence of an inert organic solvent such as dimethylformamide to give the corresponding phosphonochloridate XXVII. The compound XXVII is condensed with a Alkylacetoacetatdianion as methyl acetoacetate dianion in the presence of an inert organic solvent such as tetrahydrofuran, at a reduced temperature of about -90 to -40 ⁰ C, with a molar ratio of Phosphonochloridat XXVII: dianion of within the range of about 1: 1 to 0.75: 1 is used.

The result is the ketophosphinate XXVIII, which represents a new intermediate. The ketophosphinate XXVIII can then be reduced to the corresponding phosphinate ID, IE and IF, which are added to the corresponding diacids ID, IE and IF according to the reaction sequence C mentioned above.

35 conditions can be hydrolyzed.

  · -61-

After the reaction sequence E, compounds of the formula I ₁ in which X is the group -CH_O-, starting from the aldehyde VIII, can be prepared. For this purpose, the aldehyde VIII is a Bayer-Villiger oxidation by reaction with m-chloroperbenzoic acid (MCPBA) in the presence of an inert organic solvent such as methylene chloride, and then with a strong base such as an alkali metal hydroxide, for example KOH or NaOH, in a solvent, such as tetrahydrofuran. The resulting alcohol XXIX is formed which is alkylated by treatment with sodium hydride in the presence of an inert organic solvent such as dimethylformamide in an inert atmosphere such as Argen and a solution of a dialkyl tosyloxymethylphosphonate XXX wherein a molar ratio of XXX: XXIX is in the range of about 1: 1 to 3: 1 is used. The corresponding dialkyl ester XXXI is obtained. The remainder of the synthesis described in Reaction Sequence E, ie the production of the monoester XXXII, the chloride XXXIII, the ketophosphinate XXXIV (a new intermediate), the diester IG and the diacid IG proceed similarly as described above with reference to reaction sequence D.

The starting acetylenic compound X can be prepared from the corresponding aldehyde VIII

 VIII CHO

For this, the aldehyde VIII is subjected to a Wittig reaction, for example by treatment of a cooled solution of

VIII (-25 0 of about ⁰ C) and triphenylphosphine in an inert organic solvent such as Ksthylenchlorid, with a solution of carbon tetrabromide (CBr.) In an inert organic solvent such as methylene chloride. It becomes the vinyl dibromide

IX received

IX CH = CBr

35 z

by treatment with n-butyl-lithium in an inert or-

-62-

ganic solvent, such as hexane, is subjected to dehydrohalogenation under an inert atmosphere. This creates the connection X.

In another embodiment, the aldehyde VIII may be by treatment with dimethyl-diazomethylphosphonat in the presence of potassium tert-butoxide in an inert solvent such as tetrahydrofuran, at -78 to 25 ^0C under an inert atmosphere to be converted directly into the acetylene X.

The Jo'iid starting material A can, starting from the bromide C

OH C Br-CH ₂ -CH-CH ₂ C0 ₂ alkyl

which is prepared according to the method described in Tetrahedron Letters Vol. 26 (1985), p. 2951. The compound C is dissolved in a solution in dimethylformamide (DMF) with imidazole and 4-dimethylaninopyridine and the resulting solution treated with tert-butyldiphenylsilyl chloride under an inert atmosphere such as argon. The result is silyl ether D.

OSi-C (CH ₃ J ₃ ²⁵ D Br-CH ₂ -CH-CH ₂ CO ₂ alkyl

A solution of the silyl ether D in an inert organic solvent such as methyl ethyl ketone or DMF is reacted with sodium iodide under an inert atmosphere, such as argon, for the iodide A.

The starting aldehyde compounds VIII VIII CHO

35 ^z

are known compounds.

28 1 60

-63-

The various intermediates IV, V, VI, VII, XI, XII, XIII, XVII and XXIV form part of the present invention. These novel intermediates can be represented by the following general formulas:

XXXV R 1 -P-CH ₂ -CH-CH ₂ -CO ₂ alkyl

OSi-C (CH ₃ J ₃

^C 6 ^H 5 ^C 6 ^H 5 10

including all stereoisomers thereof, wherein R is a

Alkoxy radical or a hydroxyl group and R, an alkoxy radical, a hydroxyl group, a chlorine atom or a radical of the formulas -CH ₂ -Z, -CH ₂ CH ₂ CH ₂ -Z, -CH ₃ OZ, -ChC-Z, -CH = CH-Z,

-CH ₃ CH ₂ -Z

wherein Z 'is a hydrophobic anchor as defined above, with the proviso that R represents preferably a hydroxyl group or an alkoxy group when R represents a hydroxyl group; and

0 XXXVI alkylO-] f -CH ₂ -C -CH ₂ -CO ₂ alkyl

X 0

in which Z is as defined above, including all

Stereoisomers thereof.

The compounds of the invention can be prepared as racemic, and later separated to obtain the S-isomer, which is preferred. On the other hand, the compounds of the invention may also be formulated directly in the form of their S-isomers as described above and in the examples.

The compounds of the invention are inhibitors of 3-hydroxy

V, ^1. "·

-64-

3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. They are therefore valuable drugs for inhibiting cholesterol biosynthesis. This is shown by the following tests.

1) Rat liver HMG-CoA reductase The activity of HMG-CoA reductase from rat liver is determined using a modification of the method described by Edwards (PA Edwards and Mitarb., J. Lipid Res, Vol. 20 (1979), P. 40). Rat liver microsomes are used as an enzyme source. The enzyme activity is determined by measuring the Umwan «.

14 14

the conversion of C-HMG-CoA substrate into C-mevalonic acid

a) Preparation of microsomes

From 2 to 4 cholestyramine-fed, decapitated Sprague Dawley rats, the liver is removed and homogenized in phosphatidifferent A (0.04M potassium phosphate, pH 7.2, 0.05M KCl, 0.1M sucrose, 0.03M EDTA, 500 KI units / ml aprotinin). The homogenate is centrifuged for 15 minutes at 4 ° C and 16,000 g. The supernatant is removed and centrifuged a second time under the same conditions. The second supernatant at 16,000 g is centrifuged for 70 min ¹ at 4 ° C at 100,000 g. The pelleted microsomes are resuspended in a minimal volume of buffer A (3 to 5 ml per liver) and homogenized in a glass / glass homogenizer. 1mM Di: hiotreitol is added and the preparation divided into aliquots, rapidly frozen in acetone / dry ice and stored at -80 ° C. The specific activity of the first microsome preparation is 0.68 nM mevalonic acid / mg protein / minute.

b) enzyme assay

The reductase is tested in 0.25 ml quantities containing the following components in the indicated final concentrations:

-65- 0.04 M Potassium phosphate, pH 7.0 0.05 M KCl 0.10 M sucrose 0.03 M EDTA 0.0! M dithiothreitol 3.5 raM NaCl 1 % dimethyl sulfoxide 50-200 ug Microsomal protein 100 μM ¹⁴ C-PdLIHMG-CoA (0.05

10 "30-60 mCi / mmol)

2.7 mM NADPH (nicotinamide adenine dinucleotide phosphate)

The reaction mixtures are incubated at 37.degree. Under the conditions described, the enzyme activity increases linearly to 300 μg of microsomal protein per reaction mixture and is linear with respect to the incubation time up to 30 minutes. The standard incubation time chosen for drug testing is 20 minutes. This results in a 12 to 15 % conversion of the HMG-CoA substrate into the product mevalonic acid. Q) LJ HMG-CoA substrate is used at a concentration of 100 μΜ, ie twice the concentration required to saturate the enzyme under the conditions described. NADPH is used in a 2.7-fold excess of the concentration needed to achieve the highest enzyme rate.

Standardized tests are carried out to test the inhibitors according to the following procedure. The microsomal enzyme is incubated at 37 ° C for 15 minutes in the presence of NADPH. Then DMSO is added as a carrier with or without a test compound and the mixture is incubated at 37 ^° C. for an additional 15 minutes. The enzyme assay is started by adding C-HMG-CoA as a substrate. After 20 minutes incubation at 37 ° C, the reaction is stopped by the addition of 25 μΐ 33 % KOH. 0.05 μCi of H-Mevalonic Acid is added and the reaction mixture is stirred for 30 min.

-66-

allowed to stand at room temperature. Then 50 μΐ 5N HCl are added for lactonization of mevalonic acid. As a pH indicator, bromophenol blue is added to monitor a corresponding drop in pH. The lactonization is allowed to proceed for 30 minutes at room temperature. Then the reaction mixture is allowed to stand for 15 minutes at 2800 rpm. centrifuged. The supernatants are applied to 2 g of AG 1-X8 anion exchange resin (Biorad, Format-Form), which is in 0.7 cm glass columns, and eluted with 2.0 ml of H 2 O.

The first 0.5 ml are discarded. The next 1.5 ml are collected and tested for tritium and carbon 14 in 10.0 ml of Opti-fluor Scintillation Fluid. The results are calculated as nmol mevalonic acid generated per 20 minutes and corrected for 100 % tritium recovery. The drug effect is expressed as the value IC ₅ Q (concentration of drug giving 50 % inhibition of enzyme activity), which is derived from the 95% certainty average values of the dose response curve.

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

2) Cholesterol synthesis in freshly isolated rat hepatocytes

Compounds which have activity as inhibitors of the HMG-CoA receptor

1 4 ductase are tested for their ability to inhibit C-acetate incorporation into cholesterol in freshly isolated rat hepatocyte suspensions. For this purpose, methods are used which were originally described by Capuzzi and Mitarb (D.M. Capuzzi and S. Margolis, Lipids, Vol. (1971), p. 602).

-67-

1 a) Isolation of rat hepatocytes

Sprague Dawley rats weighing 180 to 220 g are anesthetized with 50 mg / kg nembutol. Then the abdomen is opened and the first branch of the vena porta sealed. 100 to 200 units of heparin are injected directly into the abdominal vena cava. A single occlusive suture is applied directly to the distal portion of the vena porta and the vena porta is inserted between the suture and the suture

the first branching vein is cannulated. The liver / in an amount of 20 ml / minute with 37 ° C preheated, oxygenated buffer A (HBSS without calcium or magnesium, containing 0.5 mM EDTA) soaked / after the vena cava a siphon has been attached to drainage to allow the outflow. The liver is additionally soaked with 200 ml prewarched buffer B (HBSS containing 0.05 % bacterial collagenase). After the buffers with Buffer B, the liver is removed and decapsulated in 60 mL of Waymouth's medium / with the free cells dispersed in the medium. The hepatocytes are separated by centrifugation at low speed for 3 minutes at 50 g and room temperature. The pelleted hepatocytes are washed once in Waymouth medium, counted and checked for viability by trypan blue exclusion. These cell suspensions are protected against hepatocytes

25 usually show a viability of 70 to 90 %.

1 4 b) C-acetate incorporation into cholesterol

The hepatocytes are resuspended in an amount of 5x10 cells per 2.0 ml in incubation medium (IM) [θ, Ο2Μ Tris-HCl (pH 7.4), 0.1 M KCl, 3.3 mM sodium citrate, 6.7 mM nicotinamide , 0.23 mM NADP, 1.7 mM glucose-6-phosphate].

The test compounds are routinely dissolved in DMSO or DMSO: H "O (1: 3) and added to the IM. The final DMSO concentration in IM is <1.0% and has no significant effect on cholesterol synthesis.

-68-

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

The lipids are essentially as described by

YQ EG Bligh and WJ Dyer, Can. J. Biochem. and Physiol., Vol. 37 (1959), p. 911. The lower organic phase is removed and dried under a stream of nitrogen. The residue is resuspended in 100 μL chloroform: methanol (2: 1). The entire sample is on silica gel (LK6D)

each applied to thin-layer plates and developed in hexane: diethyl ether: acetic acid (75: 25: 1). The plates are scanned with an automated BioScan scanning system and the radioactivity measured. The radiolabelling in the cholesterol peak (RF 0.28) is determined and expressed as the total count per peak and as the percentage of label in the total lipid extract. Cholesterol peaks in control cultures are usually 800 to 1000 cpm and represent 9 to 20 % of the label present in the total lipid extract. With Capuzzi and Mitarb, consistent

25 de results show 9 % of the extracted label in cholesterol.

Drug effects (% inhibition of cholesterol synthesis) are determined by comparing the percentage labeling in cholesterol of control cultures and drug-treated cultures. Dose response curves are obtained from data from at least two studies. The results are expressed as IC ₅ Q values with 95 % confidence.

-69-

3) Cholesterol Synthesis in Human Skin Fibroblasts Selectivity of a compound for greater inhibitory activity in liver tissue would be considered as an indication of an inhibitor of cholesterol synthesis. Therefore, in addition to being evaluated as cholesterol synthesis inhibitors in hepatocytes, the compounds are also tested for their effectiveness as inhibitors of cholesterol synthesis in cultured fibroblasts.

jQ a) human skin fibroblast cultures

Human skin fibroblasts (passage 7 to 27) are cultured in Eagle minimal medium (EM) containing 10% fetal calf serum. For each experiment, stock cultures are trypsinized to disperse the cell monolayer,

jg counted and applied to 35 mm tissue culture plates (5 x 10 cells / 2.0 ml). The cultures are incubated for 18 hours at 37 ^° C. in 5% CO ₂ /95 % humidified room air. The enzymes of cholesterol biosynthesis are stimulated by removing the serum-containing medium, washing the cell monolayers and adding 1.0 ml of EM containing 1.0 % fatty acid-free bovine serum albumin and incubating the cultures for a further 24 hours.

b) C-acetate incorporation into cholesterol

The induced fibroblast cultures are washed with EMEM. "(Earle minimal medium). The test compounds are dissolved in DMSO or DMSO: EM (1: 3) (final DMSO concentration in the cell cultures <1.0 %) added to the cultures and the cultures humidified for 30 minutes at 37 ° C in 5 5ί CO ₂ /95 % room air

go preincubated. After preincubation with the drug, add | c7Na-acetate (2.0 μCi / ml, 58 mCi / mmol) is added and the cultures are incubated again for 4 hours. After incubation, the culture medium is removed and the cell monolayer (200 μg of cell protein per culture) is introduced into 1.0 ml of H-O.

The lipids in the lysed cell suspension are described as for the hepatocyte suspensions, in chloroform: methanol

2 3 1605

extracted. The organic phase is dried under nitrogen and the residue is resuspended in 100 μL chloroform: methanol (2: 1). The entire sample is applied to silica gel (LK6D) thin-layer plates and, as for the hepato-

5 described analyzed.

Inhibition of cholesterol synthesis is determined by comparing the percent label in the cholesterol peak of control and drug-treated cultures. The results are expressed as ICcq values and are derived from average dose response curves from at least two experiments. A 95% security for the values of IC ₅₀ is also calculated from the average dose-response curves.

Another object of the present invention are pharmaceutical compositions containing at least one compound of formula I together with a pharmaceutical carrier or diluent. The pharmaceutical compositions can be formulated using conventional solid or liquid carriers or diluents, as well as with pharmaceutical additives suitable for the desired mode of administration. The compounds may be given orally, for example in the form of tablets, capsules, granules or powders. They may also be administered parenterally in the form of injectables. "Such dosage forms contain from 1 to 2000 mg of active ingredient per dosage for use in the treatment The dose to be administered will depend on the patient's unit dose, symptoms, age and body weight.

The compounds of formula I can be administered to mammals such as humans, dogs and cats in a manner similar to the known compounds proposed for use in inhibiting cholesterol biosynthesis, such as lovastatin. Thus, the compounds of the invention may be present in an amount of about 4 to 2000 mg in a single fluid or in the form

-71-

from sub-doses 1 to 4 times a day, preferably in an amount of 4 to 200 mg in divided doses of 1 to 100 mg and especially 0.5 to 50 mg 2 to 4 times a day. Also administration in preparations with delayed active substance

Discharge is possible.

The examples illustrate the invention. Flash chromatography is performed with either Merck 60 or Whatmann LPS-I silica gel. Reverse phase chromatography is performed on CHP-20 MCI gel (Mitsubishi). The abbreviations "Et ₂ O", "EtOAc", "MeOH" and "EtOH" refer to the ethyl ether, ethyl acetate, methanol and ethanol. ¹¹ in numbers means "inch" (2.54 cm); Grain size "60-200 mesh" = 75-250 μm; "Flash chromatography" is flash chromatography.

embodiments

example 1

(S) -4 - [[2- (4'-fluoro-S ₁ S ^1, 5-trimethyl- [i, 1 '-biphenyl] -2-yl] -20-ethyl 3 methoxyphosphinylJ-S-hydroxy-methyl butyrate

A. N- (2,4-dimethylbenzylidene) -benzenamine (US-A-4,375,475, p. 39) "25.

A solution of 6.97 ml (50 mmol) of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich) and 4.56 ml (50 mmol) of distilled aniline (Aldrich) in 80.0 ml of dry toluene is added under argon for 3.0 hours heated under reflux with a flask equipped with a Dean-Stark apparatus. The mixture is then cooled and evaporated under reduced pressure to a yellow oil. The crude oil is purified by Kugelrohr distillation (0.5 mm Hg, 160 to 180 ⁰ C), 8.172 g (78.1%) of the desired Benzolimin-title compound as a light yellow oil which on standing to give a solid with crystallized low melting point. TLC (4: 1) Hex-acetone, Rf = O, 67 and 0.77 (geometric isomers), UV and I.

8 16 0 5;

-72-

B.

(US-A-4,375,475, p. 39)

A mixture of 6.0 g (28.7 mmol) of Part B A in 144 ml of glacial acetic acid is treated with 6.44 g (28.7 mmol) of palladium (II) acetate. The clear, red homogeneous solution is refluxed for 1 hour under argon. The resulting turbid mixture is filtered warm through 1/2 ^N diatomaceous earth in 900 ml H_O. The precipitated orange solid is filtered off and under reduced pressure for 16 hours at 65 ⁰ C over PO ₁ .

dried. Yield: 10.6 g (85.5 %) of the desired palladium complex (title compound) as an orange solid of mp 194 to 196 ^° C. (mp. A recrystallized analytical sample according to the literature: 203 to 205 ⁰ C).

c. 4'-fluoro-3,3 ', 5-trimethyl- [i, 1'-biphenyl] -2-carboxaldehyde "

(1) Bromo- [J'-fluoro-3-methylphenyl] -magnesium (US-A-4,375,475, p. 37 and 38)

The Grignard reagent (title compound of part C (T)) is added dropwise by addition of 22.5 g (60.9 mmol) of 5-bromo-2-fluorotoluene (Fairfield Chemical Co.) to 1.35 g (55 , 4 mmol, 8.0 eq.) Of magnesium turnings in 70.0 ml of anhydrous F.c_O at a rate sufficient to reflux the reaction. The reaction is started in an ultrasound facility. After complete

-73-

constant bromide addition, the mixture is stirred for 1 hour at room temperature under argon, boiled for 15 minutes under reflux and then allowed to cool to room temperature.

5 (2) 4'-fluoro-3,3 ', 5-trimethyl-Q, 1'-biphenyl] -2-carboxaldehyde

In a second flask, a mixture of 3.0 g (6.92 mmol) of the dipalladium complex of Part B and 14.52 g (55.4 mmol, 8.0 eq.) Of triphenylphosphine in 100 ml of anhydrous benzene is added for 30 minutes stirred at room temperature under argon. Then freshly prepared and filtered (glass wool plug) Grignard reagent of part C (1) is added in an amount through a cannula to this solution and the mixture is stirred at room temperature under argon for 1.5 hours. Then 35 ml

15 6, ON HCl added, the mixture for an additional hour at

Stirred at room temperature and then filtered through diatomaceous earth (1/2 "bed) The filtrate is extracted with 250.ml Et-O, the extracts washed twice with 100 ml of brine, dried over anhydrous MgSO4 and evaporated under reduced pressure The crude orange solid is purified by flash chromatography on 700 g of silica gel and eluted with hexane followed by hexane-Et-O (95: 5) to yield 13.35 g of viscous orange oil Yield: 1.507 g (89.9 %) of the desired aldehyde title compound as a light yellow solid of mp 72-75 ° C (literature: 73-75 ° C).

TLC: (95: 5) HeX-Et ₃ O, Rf = 0.40, UV and PMA.

D. 2- (2,2-Dibromoethyl) -4'-fluoro-3,3 ', 5-trimethyl-Q, 1'-biphenylTJ

A cooled to -10 ⁰ C in saline / ice bath solution of 2.42 mg (1.0 mmol) biphenyl-Adlehyd from Part C and 787 mg (3.0 mmol, 3.0 eq.) Of triphenylphosphine in 10 ml anhydrous CH ₇ Cl ₉ is added dropwise within 5 minutes with a

28 1 60

Solution of 497 mg (1.5 mmol, 1.5 eq.) CBr ₄ in 5.0 mL CH ₂ Cl ₂ . After 30 minutes at 0 ⁰ C, the red-orange solution between CH ₂ Cl and saturated NaHCO. solution is divided. The organic phase is washed with saturated NaHCO 3 solution and brine, then over anhydrous Na ₂ SO ₄ . dried and evaporated to give 1.478 g light brown solid. The crude solid is purified by flash chromatography on silica gel (50: 1) and eluted with HeX-CH ₂ Cl ₂ (9: 1). The product fractions are combined and evaporated. Yield: 392 mg (99 %) of pure vinyl dibromide title compound as a pale yellow oil. TLC (95: 5) Hex-EtOAc, Rf = 0.51, UV and PMA.

E. 2-Ethinyl-4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl]

A solution of 336 mg (0.844 mmol) of vinyldibtomide from Part D in 5 ml of anhydrous THF cooled to -78 ° ^C. in the dry ice / acetone bath is added dropwise by syringe with a 1.6M solution of n-BuLi in hexanone (1, 06 ml, 1.7 mMol, 2.0 eq.) And the mixture was stirred at -78 ° C for 1 hour under argon. During n-BuLi addition, the color changes from colorless to deep yellow and pale yellow to deep purple to purple. The mixture is quenched at -78 ° C by the dropwise addition of 4 mL of saturated NH.Cl solution, warmed to room temperature and extracted with EtO. The ether layer is washed with brine, over anhydrous MgSO 4. dried and evaporated to 191 mg of green oil. The crude oil is purified by flash chromatography on silica gel LPS-1 (60: 1) and eluted with hexanes. The product fractions are combined and evaporated. Yield: 185 mg (92%) of the desired acetylene-title compound as a colorless oil which discolored upon standing at -20 ⁰ C under argon after deep blue

 TLC hexane, Rf = 0.18 UV and PMA.

-75-

Methyl 1-dimethyhyl) diphenylsilyr-oxy-4- (chloromethoxyphosphinyl) butyrate (1) Methyl (S) -4-bromo-3-hydroxybutyric acid (1) (a) [R- (R *, R *)] - 2,3,4-trihyric hydroxybutyrate hydrate calcium salt

(Carbohydrate Research, Vol. 72 (1979), pp. 301 to 304)

50 g of potassium carbonate are added to a solution of 44.0 g (250 mmol) of D-isoascorbic acid in 625 ml of H 2 O. The solution is cooled in an ice bath at 0 ⁰ C and treated batchwise with 100 ml of 30 % H ₂ O ₂ . The mixture is then stirred for 30 minutes in an oil bath at 30 to 40 ^° C. Then 10 g of Darco was added and heated the black suspension on the steam bath until the (^ evolution ceases. The suspension is filtered through diatomaceous earth and concentrated under reduced pressure at a bath temperature of 40 ^c C evaporated. The residue is taken up in 50 ml H_O, heated on a steam bath

-. - - and with CH-OH added until the solution becomes cloudy. The precipitated rubbery solid is filtered off and dried in air. Yield: 30.836 g (75.2 %) of the desired calcium salt e.sub.l as a powdery white solid. TLC (7: 2: 1) 1PrOH-NH ₄ OH-H ₂ O, R f = 0.19, PMA.

(1) (b) [s- (R *, S *)] - 2,4-dibromo-3-hydroxybutyric acid methyl ester

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

30 g of calcium salt of part M) ν a) are dissolved in 210 ml of 30 to 32 % HBr in acetic acid and stirred for 24 hours at room temperature. Then 990 ml of methanol are added to the brown solution and they are stirred overnight. The mixture is evaporated to an orange oil, taken up in 75, Λ CH-OH, refluxed for 2.0 hours and then evaporated. The residue is partitioned between 100 ml EtOAc and H ₃ O, the organic phase is extracted twice with H ₂ O and saline.

-76-

washed and then over anhydrous Na ₂ SO. dried and evaporated. Yield: 22.83 g (90.5 %) of crude dibromide as a light orange oil

 TLC (1: 1) EtOAc-Hex, Rf = 0.69, UV and PMA.

(1) (c) (S) -4-bromo-3-hydroxybutyric acid methyl-

ester (Ref. as (1Hb))

IQ An argon-purged solution of 20.80 g (75.4 mmol) of the dibromide and 21.0 g of anhydrous NaOAc in 370 mL EtOAc and 37 mL glacial acetic acid is treated with 1.30 g 5 % Pd / C and the black suspension stirred under hydrogen at a pressure of 1 bar. The hydrogen uptake is monitored.

After 2.0 hours, the hydrogen uptake is complete and the mixture is filtered through diatomaceous earth. The filtrate is washed with saturated NaHCO3, brine and then dried over anhydrous MgSO4 and evaporated to the crude dibromoester as a brown oil *. The crude oil is combined with another batch (starting from 36.77 g of dibromide) and distilled under reduced pressure. . Yield: 25.77 g (61.3%) of the desired Bromester-title compound as a colorless oil, bp 79 to 8O ⁰ C (1.0 mm Hg). TLC (1: 1) EtOAc-Hex, Rf = 0.44, PMA.

Analysis for C ₅ HgO ₃ Br:

ber .: gef. :

(2) (S) -4-bromo-3 - [[(1,1-dimethylethyl) diphenyl]

silyl] -oxy] -butyric acid methyl ester

A solution of 4.0 g (20.4 mmol) of bromohydrin from part F (1), 6.94 g (5.0 eq) of imidazole and 12 mg (0.005 eq) of 4-dimethylaminopyridine (4-DMAP) in 40 ml of anhydrous DMF is treated with 5.84 ml (1.1 eq.) Of tert-butyl-diphenylsilyl chloride

C 4 H br 56 30 48 4 60 40 86 29 , 76 50 39,

• -77-

1 and the homogeneous mixture under argon at room temperature

Stirred for 15 hours. The mixture is between 5 % KHSO. split and EtOAc, the organic phase washed with H 2 O and brine, over anhydrous Na ₂ SO. dried and evaporated. Yield: 9.32 g (100 %) of crude silyl ether as a colorless viscous oil

 TLC (3: 1) Hex-EtoAc, Rf Silyl Ether = 0.75, U.V. and PMA.

(3) (S) -4-iodo-3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -butyric acid methyl ester

A solution of 9.32 g (201 mmol) of crude bromide from part F (2) in 60 mL of methyl ethyl ketone (dried over 4 S sieve) is added 15.06 g (100.5 mmol, 5.0 eq) of sodium iodide treated. The yellow suspension is refluxed for 5 hours under argon. The mixture is cooled, diluted with EtOAc, filtered and the filtrate washed with dilute NaHSO ₃ solution until it is colorless. It is then washed with brine, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give 10.17 g of yellow oil. The crude oil is purified by flash chromatography on 600 g of silica gel and eluted with hexane-CH-Cl "(3: 1). The product fractions are combined and evaporated. Yield: 7.691 g (74.2% overall yield for both steps) of the desired iodide title compound as a clear, colorless, viscous oil. TLC (3: 1) Hex-EtOAc, product. Rf = 0.75, UV and PMA. (Note: the iodide product gives a spot in the same place as the bromide starting material.)

(4) (S) -4- (diethoxyphosphinyl) -3- [£ (1,1-dimethyl-

ethyl) diphenylsilyl] oxy] butyric acid methylester

A solution of 7.691 g of the iodide in 20 ml of triethyl phosphite is heated under argon in an oil bath at 155 ° C for 3.5 hours. The mixture is cooled and excess phosphorus

8 16

-78-

distilled off under reduced pressure of 0.5 mm Hg at 75 °. There remain about 8.0 g of yellow oil. The crude oil is purified by flash chromatography on 400 g of silica gel and eluted with hexane-acetone (4: 1). The product fractions are evaporated. Yield: 3.222 g (41.1 %) of the desired phosphonate title compound as a clear, colorless, viscous oil.

TLC (1: 1) Hex-acetone, Rf = 0.51, UV and PMA. In addition, 2.519 g (61.1 % corrected yield) of the starting iodide of part (3) was recovered.

(5) (S) -3- [[(1,1-dimethylethyl) -diphenylsilyljoxy ] -4-phosphono-butyric acid, F, methyl ester

A solution of 9.85 g (20.0 mmol) of phosphoant of part F (4) in 20 mL of CH ₂ Cl ₂ is added sequentially with 5.31 mL (32.0 mmol, 1.5 eq) of bistrimethylsilyltrifluoroacetamide (BSTFA). and 6.60 ml. (50.0 mmol, 2.5 eq.) .Trimethylsilylbromide (TMSBr) and the clear mixture was stirred at room temperature under argon for about 15 hours. Then 80 ml of 5 % KHSO. added and the mixture extracted with ETOAc. The aqueous phase is saturated with NaCl and back-extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Na 2 SO 4. dried and evaporated under reduced pressure to the crude phosphonic acid title compound as a viscous oil

TLC / 7: 2: 1) 1PrOH-NH ₄ OH-H ₂ O, R f = 0.30, UV and PMA.

(6) (S) -3- [[(1,1-dimethylethyl) -diphenylsilyl-oxy] -4- (hydroxymethoxyphosphinyl) -butyric acid-methyl-

ester

About 20.0 mmol of crude phosphonic acid from part F (5) in 25 mL of dry pyridine are charged with 1.62 mL (40.0 mmol, 2.0 eq) of CH ₃ OH dried over 3A sieve and 4.54 g (22.0 mmol, 1.10 eq.) Of dicyclohexylcarbodiimide (DDC). The obtained

-79-

white Suspensi.on is stirred under argon at room temperature for about 15 hours. Then the pyridine is distilled off under reduced pressure and the mixture is then azeotroped with 2 times 15 ml of benzene. The residual oil is dissolved in EtOAc, filtered and washed with 1.0N HCl and brine, over anhydrous Na ₂ SO ₄ . dried and evaporated under reduced pressure. Yield: 8.272 g of crude ester-title compound as an oil containing a small amount of precipitated dicyclohexylurea (DCU).

TLC (7: 2: 1) 1PrOH-NH ₄ OH H ₃ O, R f = 0.60, UV and PMA.

(7) (S) -3 - [[(1-dimethylethyl) diphenylsilyl] oxy] -4- (chloromethoxyphosphinyl) -butyric acid methyl ester

6 _# 595 g (about 14.7 mmol) of crude phosphonic acid monomethyl ester. of Part F (6) are dissolved in 30 ml of dry CH ₃ Cl ₂ , treated with 5.60 ml (2y, 4 mmol, 2.0 eq.) of distilled trimethylsilyl diethyl ester and stirred for 1 hour under argon at room temperature. Then the mixture is evaporated under reduced pressure, taken up with 30 ml of benzene and dried under reduced pressure. The pale yellow viscous oil is in

30 ml of CH ₂ Cl ₂ and 2 drops of 4 Α sieve-dried DMF, the clear solution is in a salt / ice bath to -10 ⁰ C cooled and treated dropwise (via syringe with 1.41 ml 16.2 mmol, 1.1 eq.) Distilled oxalyl chloride. It shows strong gas evolution and the solution gets a more yellow color. The mixture is stirred under argon for 15 minutes at -10 ⁰ C and then stirred at room temperature for 1 hour. Then the mixture is evaporated under reduced pressure, taken up with 30 ml of benzene, re-evaporated and dried under reduced pressure to give crude phosphonochloridate as a yellow oil. 35

•. -80-

G. (S) -4- [2- [4'-F: ioror -3, 3 ', 5-trimethyl- [ΐ, 1'-biphenyl] * 2-ylJ-eth inyl] -methoxyphosphinyl] -3 t-butyldiphenylsilyloxy-butyric acid methylester

A solution of 2.678 g (11.2 mmol) of Part E acetylene in 20 mL of anhydrous THF cooled in C0 ₂ / acetone to -78 ° C is added dropwise with 7 mL (11.2 mmol, 1.0 eq) 1, 6M solution of n-BuLi treated in hexanes. The purple mixture was stirred under argon for 1 hour at -78 ^e C, warmed briefly to 0 ⁰ C, cooled to -78 ⁰ C and then transferred via cannula to a dropping funnel and added dropwise to a in C0 ₂ / acetone to -78 ° C cooled solution of 8.27 g (18.4 mmol, 1.6 eq.) Phosphonochloridat of Part F in 20 ml of anhydrous THF. After 1 hour at -78 ° C, the mixture is quenched with saturated NH.Cl solution, then warmed to room temperature and extracted with Et-O. The ether layer is washed with saturated NaHCO 3 solution and brine, then dried over anhydrous MgSO 4, and dried

-ri.- · to 11, 705 g of brown oil evaporated. The crude oil is purified by flash chromatography on silica gel and eluted with hex-EtOAc (7: 3). The product fractions are combined and evaporated. Yield: 4.246 g (56 %) of the desired acetylenic phosphinate-Ti 'el compound as a light brown oil. In addition, 457 mg (68 % corrected

25% yield) of biphenylacetylene recovered from part E. TLC / 7: 3) Hex-acetone, Rf = 0.20, UV and PMA.

H. (S M-D 2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] 2-yl] -ethyl] -methoxyphosphinyl] -3-t-butyldiphenylsilyloxy-butyric acid methyl ester

An argon-purged solution of 333 mg of Part II acetylenic phosphinate in 5 ml of CH-OH is treated with 121 mg (36% by weight) of 10 % Pd / C and pressurized for 30 hours in a Parr apparatus under water Shaken from about 2.8 bar. The catalyst is filtered through diatomaceous earth

2 8 1 6C ί

-81-

and the filtrate evaporated to a pale yellow oil. The crude oil is purified by flash chromatography on silica gel and eluted with EtOAc-Hex (1: 1). The product fractions are evaporated. Yield: 250 mg (75 %) of the saturated

5 Phosphinate title compound as a clear oil. TLC (4: 1) EtOAc-Hex, Rf = 0.33, UV and PMA.

j. (S) -4 - [[2- (4'-fluoro-3,3 ', 5-trimethyl-1,2'-biphenyl] -2-yl-3-ethyl) -methoxyphosphinyl-3-hydroxybutyric acid methyl ester

A solution of 330 mg (0.489 mmol) of Part H silyl ether in 6 ml of anhydrous THF is added with 115 μΐ (1.96 mmol, 4.0 Ag) of glacial acetic acid and then with 1.47 ml (1.47 mmol, 3, 0 eq.), 1.0M tetrabutylammonium fluoride solution. The resulting mixture is stirred for about 15 hours in argon at room temperature. The mixture is diluted with 10 ml of ice water and. .. extracted 2 times with EtOAc. The ^ organic layer with overall -. · Washed .sättigter NaHCO, solution and brine, dried over anhydrous Na ₂ SO. dried and evaporated to 361 mg pale yellow oil. The crude oil is purified by flash chromatography on silica gel and eluted with acetone-hexane (6: 4). The product fractions are evaporated. Yield: 205 mg (96 %) of the desired free alcohol title compound as

25 clear oil, which slowly crystallises on standing. TLC / 7: 3) acetone-hexane, Rf = 0.28, UV and PMA.

Example 2

(S) -4 - [[2- [4'-Fluoro-3,3 ', 5-trimethyl] -1, 1'-biphenyl-2-yl] -ethyl Q-hydroxyphosphinyl-3-hydroxybutyric acid dilithium salt

A solution of 187 mg (0.499 mmol) of the diester of Example 1 in 5 ml of dioxane is treated with 1.29 ml (1.29 mmol, 3.0 equiv) of 1.0N LiOH solution and the mixture is dissolved in oil bath 2, 5 hours

2 8 ί

-82-

heated to 55 ⁰ C under argon. The mixture is then cooled, diluted with H 2 O, filtered and evaporated under reduced pressure. The residue is dissolved in the lowest possible amount of H.sub.10 and chromatographed on resin HP-20 (25 mm column diameter, about 15 cm bed) with H_0 and

then eluted with a mixture of CH ₃ OH-H ₂ O (1: 1). The collected fractions are evaporated, dissolved in 50 ml H ₂ O, filtered and lyophilized. As a repeat: 175 mg (91 % by weight of the hydrate) of the desired dilithium salt title compound as a white electrostatic solid.

TLC (8: 1: 1). CH ₂ Cl-CH ₃ OH-HOAc, R f = 0.1, UV and PMA and (7: 2: 1) 1 PrOH-NH ₄ OH-H ₂ O, R f = 0.45, UV and PMA.

IQ microanalysis for C ₂₁ H ₂₄ O ₅

and 1.7 moles of H ₂ O (MW 450.90)

About:

^'1 H-NMR (400 MHz, CD ₃ OD)

ί1.34 - 1.56 ppm (4H, multiplet)

2.22 - 2.31 ppm (? .H, multiplet)

2.25 + 2.37 ppm (6H, two singlets)

2.29 ppm (3H, doublet, J _u _ = 1.4 Hz)

2.75 ppm (2H, multiplet)

4.13 ppm (1H, multiplet)

6.73 - 7.10ppm (5H, multiplet)

gO example3

1S) -4-j] [2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -äthinyl ^ -methoxyphosphinyl]] -3-hydroxybutyric acid methylester

A mixture of 455 mg (0.678 mmol) of silyl ether of Example 1, part G, and 155 μΐ (2.71 mmol, 4.0 Xq.) Of glacial acetic acid in 7 ml

C 6 H 4 F 6 P 55 , 93 5 .13 3 .21 6 , 87 55 .91 , 84 , 92 , 89

28 160

-83-

anhydrous THF is treated with 2.0 ml (2.0 mmol, 3.0 equiv.) of 1.0 M tetrabutylammonium fluoride solution in THF and the resulting solution is stirred under argon at room temperature for about 15 hours. The mixture is poured into 10 ml of ice-cold H "0 and extracted 2MaJ with EtOAc. The organic phase is washed with saturated NaHCO 3 solution and brine, over anhydrous Na ₂ SO ₄ . dried and evaporated to 498 mg of yellow oil. The crude product is purified by flash chromatography on silica gel and eluted with hexane-acetone (3: 2). The product fractions are evaporated. Yield: 217 mg (74 %) of the title alcoholic compound as a colorless Cl

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

Example 4

(S) -4 - [[2- ^[4-fluoro-1 3.3 ^L, 5-trimethyl- [1, 1 '-biphenyl] -2-yl] - · - ethynyl] -hydroxyphosphinyl ·] - S-hydroxybutyric acid dilithium

salt. "0

A mixture of 203 mg (0.469 mmol) of the diester from Example 3 in 6 ml of dioxane is treated with 1.6 ml (1.6 mmol, 3.5 eq.) Of 1N LiOH and the solution in an oil bath under argon at 55 ° for 30 minutes C heated. The mixture is cooled, diluted with H ₂ O, filtered, evaporated, taken up in 30 ml H ₂ O and lyophilized. The white lyophilate is dissolved in the minimum amount of H ₂ O and chromatographed on Hrz HP-20 (25 ml column diameter, 10 cm resin bed) and eluted with H ₂ O and then with H ₂ O-CH-OH (50:50). The product fractions are combined and evaporated, the residue taken up in 30 ml H_0 and lyophilized. Yield: 199 mg (97 % by hydrate, MW = 435.36) of the dilithium salt title compound as a white solid. TLC (8: 1: 1) CH ₂ Cl ₂ -CH ₃ OH-HOAd ₁ Rf = 0.13, UV and PMA.

28 ί 60S

-84 microanalysis for C ₉₁ H _9n O

+1.06 mole H ₂ O (MW 435.36)

36) 57 C 5 H 4, F 7 P About: 57 , 93 4 12 4, 36 6 , 11 gef. : 91 , 89 22 , 89

¹ H NMR (400 MHzCD ₃ OD):

£ i, 76 - 1.82 ppm (2H, multiplet)

2.32 (3H, Doublet, J _HF = 1.8 Hz) 2.34 (3H, singlet) 2.37 (1H, dd, J = 8.4 Hz) 2.41 (1H, dd, J = 4.1 Hz) 2.49 (3H, singlet) 4.27 (1H, Multiplet) 6.98 - 7,37 (5H, m)

Example 5

(S, Z) -4 - [[^ 2- [4-fluoro-3,3 ^{1 1,} 5-trimethyl-Q, 1 '-biphenyl] -2-YLJ-äthenyl3-methoxyphosphinyl] -3-hydroxybutyric acid-2Q methylester

A. (S, Z) -4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -äthenyl3-methoxyphosphinyl] -3- t-butyldiphenylsilyloxy-butyric acid methylester

A degassed solution of 498 mg (0.742 mmol) of acetylenic phosphinate from Example 1, Part G, in 10 mL of CH ₃ OH is treated with 50 mg (10% by weight) of 10 % Pd / C and the black solution is allowed to settle for 2 hours Hydrogen at a pressure of 1 bar stirred. The catalyst is filtered through diatomaceous earth.

QQ trated and the filtrate evaporated to 500 mg of yellow oil. The crude product is purified by flash chromatography on silica gel and eluted with hexane-EtOAc (3: 2). The product fractions are combined and evaporated. Yield: 498 mg (100:56) of the desired olefin as a colorless oil.

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

-85-

B. (S, Z) -4 - [[2- [4'-fluoro-3,3 ^l, 5-trimethyl- (j, 1 '-biphenyl] -2-YL3-äthenylj -methoxyphosphinylj -3-hydroxybutyrate

A solution of 498 mg (0.74 mmol) of Silyl Ether of Part A in 6 mL of anhydrous THF is added with 170 μΐ (2.96 mmol, 4.0 eq) of glacial acetic acid and then with 2.2 mL (2.2 mmol, 3.0 eq.) 1.0M tetrabutylammonium fluoride solution in THF. The kJ.are, colorless mixture is stirred at room temperature for 16 hours under argon. The TLC shows a small amount of residual starting compound. 40 μΐ (1.0 eq.) Of additional acetic acid and 0.74 ml (1.0 eq.) Of n-Bu.NF are added, and the mixture is stirred for a further 6 hours. Then the mixture is diluted with 10 ml of ice-cold HjO and extracted twice with EtOAc. The combined extracts are washed with saturated NaHCO ₃ solution and brine, over anhydrous Na ₂ SO ₄ . dried and evaporated to 468 mg pale yellow oil. The crude product is through

•. Flash chromatography 'on silica gel and eluted with hexane-acetone' - '{7: 3)'. The product fractions are combined and evaporated. Yield: 243 mg (76 %) of the title alcoholic compound as a colorless oil

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

25 Example6

(S, Z) -4- [[2- [4'-fluoro-3, 3, 5-trimethylsilyl-D, 1'-biphenyl] -2-yl] ethynyl] hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

A solution of 240 mg (0.552 mmol) of diester from Example 5

in 7 ml of dioxane is treated with 1.9 ml (1.9 mmol, 3.5 eq.) of 1, ON LiOH solution and the mixture is heated under stirring and under argon for 3 hours in an oil bath at 50 ⁰ C. It shows a white precipitate. The mixture is cooled, diluted with H ₂ O, filtered and evaporated under reduced pressure to a white solid. The crude solid is in the lowest

Dissolved the possible amount of H ₂ O and chromatographed on resin HP-20 and eluted with H ₂ O followed by H ₂ O: CH-OH (50:50). The product fractions are combined and evaporated, taken up in 50 ml H 2 O, filtered and lyophilized.

5 siert. Yield: 255 mg (100 % by weight of the hydrate, MW 457.58) of the dilithium salt title compound as a white electrostatic solid

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

20 microanalysis for C ₂₁ H ₃ 2.18 mol H ₂ O (457.58):

55 C 5 H 4 F 6 P About: 55 12 5 , 81 4 15 7 77 gef. : 35 , 68 , 27 , 09

¹ H NMR (400 MHz, CD ₃ OD): 15 <Si, 24 ppm (2H, multiplet)

= 1.8 Hz)

, .2,30 (3H, singlet) - -,: · · 2,38 (3H, singlet) 20

_HH = 12.4 Hz)

2:09 (2H, Doublet, J = 2ί, .2 7. (3H, Doublet, J HF 2.30 (3H, singlet) 2.38 (3H, singlet) 4.06 (1H, Multiplet) 5.87 (1H, d doublet, J ^J HP = 14.3 Hz) 6.87 (1H, s) 6.91 (1H ₁ d doublet, H 6.98 (2H, triplet) 7.22 (2H, Multiplet)

_Hp = 43.4 Hz)

Example 7

30 (S) -4 - [[2- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid methyl ester A 2-Q4-fluorophenyl) -methyl] -3-oxobutyric acid ethyl ester

8.31 g (362 mmol) of sodium cube are dissolved with mechanical stirring in 1 L of anhydrous EtOH. The clear solution is distilled under argon with 47 g (362 mmol, 1 Ag.)

2 8 ί

-87-

, 1 ethyl acetoacetate added. The pale yellow mixture is refluxed for 1 h, cooled to room temperature, treated with 75 g (398 mmol, 1 Xq) of 4-fluorobenzyl bromide, and the bright orange mixture stirred under argon for 2.5 h at room temperature. The mixture is evaporated under reduced pressure. The residue is partitioned between EtOAc-H2 O, the organic phase washed twice with H2 O and brine, over anhydrous Na _. SO. dried and evaporated to an orange oil. The crude product is purified by distillation under reduced pressure (5 ml Hg). Yield: 46.47 g (54 %) of alkylated product as a clear colorless liquid of bp. 142 to 144 ° C.

TLC (7: 3) HeX-Et ₂ O, Rf product = 0.31

¹ H NMR (CDCl ₃ ): 1.20 (3H, t), 2.19 (3H, s), 3.13 (2H, d),

3.73 (1H, t), 4.14 (2H, q), 6.95 (2H, t), 7.13 (2H, m) ppm.

¹³ C NMR (CD ₃ CN): 14, '4 / 29.7, '33, "7v 62.1, 62.3, 115.3, 116, 131, -4, 131.9 / 145.1 ( J. - - = 284 Hz), 170.1, 203.5 ppm.

B. 3- (4-fluorophenyl) -1H-indole-2-carboxylic acid ethyl ester (Chemical Abstracts, Vol. 33, page 587; R. Helmuth and co-workers, J. Chem. Society (1927), p. 6 - 7; Preparative Organic Chemistry, 4th ed. (1972), p. 582)

A solution of 46.4 g (195 mmol) of ester from Part A in anhydrous 290 ml of EtOH is in an ice bath at 0 ⁰ C with sodium hydroxide solution (23.4 g) in 58 ml H_O and treated immediately with a Benzoldiazoniumchloridlösung, in accordance with Preg , Org.

30 Chem, 4th ed. (1972), p. 582, from 17.8 ml aniline, '88 ml

cone. HCl, 98 ml H-O and 13.5 g NaNO. A deep orange-red two-phase solution is obtained. The mixture is stirred for 1 hour at room temperature, then poured into 500 ml ice cold H_0 and extracted with 3 times 300 ml EtOAc. The organic phase is washed with 500 ml brine, over anhydrous Na, SO. dried and under

-88-

reduced pressure to 55.62 g of crude hydrazone intermediate as an orange oil.

TLC (7: 3) HeX-Et ₂ O, Rf hydrazone = 0.22, US and PMA.

The crude material is used in the subsequent Fischer cyclization.

A solution of the hydrazone in 200 ml of anhydrous EtOH is treated with gaseous HCl for 30 minutes with intermittent cooling in an ice bath. The brownish mixture is then poured into 600 ml of ice-cold H 2 O and extracted 3 times with EtOAc. The organic phase is washed twice with H 2 O and brine, over anhydrous Na 2 SO 4. dried and evaporated under reduced pressure to a brownish tan solid. Trituration with ice-cold hexane and filtering yields 26.74 g (49%) of the desired indole-title compound in the form of buff-colored granular crystals melting at 129-130 ⁰ C.

TLC (7: 3) HeX-Et ₂ O, R f = 0.26, UV and PMA.

Microanalysis for C ₁₇ H ₁₄ FNO ₂ : CHFN

: 72.07 4.98 6.71 4.94 F .: 72.38 5.05 6.87 5.01

25 ¹ H NMR (CDCl ₃ ): i, 22 ppm (3H, t), 4.29 (2H, q), 7.10 7.62 (8H, m), 9.21 (1H, bs) ppm ,

¹³ C NMR (CDCl ₃ ): 514.1, 60.9, 111.8, 114.5, 114.8, 120.9, 121.4, 122.9, 123.1, 125.9, 127, 9, 129.5, 132.2 U _C _ _F = 7.6 Hz), 135.7, 162.0, 162.2 (J_ = 244 Hz) ppm. '

C. 3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indole-2-carbon

acid ethyl ester (Sandoz International Patent No. 158,675 (1984), p. 35)

A solution of 26.74 g (94.4 mmol) of indole from part B in

2 β Ι

-89-

100 ml of dry distilled dimethylacetamide is treated in an ice bath at ⁰ ° C., with vigorous evolution of gas, with 4.53 g (113.3 mmol, 1.2 eq.) 60 % dispersion of NaH in mineral oil and the mixture is stirred at 0 for 1 hour under argon ⁰ C stirred. Then, 85 g (500 mmol, 5.3 eq.) Of 2-iodopropane are added and the mixture is warmed to room temperature under argon and stirred for 1 hour. The mixture is then cooled again to 0 ^° C., with a further 1.2 ×q. NaH treated and stirred for a further hour at room temperature. This procedure is repeated twice more. The final mixture is cooled to ⁰ ° C. in an ice-bath and excess NaH is destroyed by careful dropwise addition of 30 ml of anhydrous EtOH. The mixture is diluted with EtOAc, washed with 5 % KHSO.-solution, the aqueous phase is back-extracted once with EtOAc, the combined EtOAc layers are washed with H ₂ O and brine twice, dried over anhydrous Na ₃ SO ₄ and added to 38, 54 g brown solid evaporated. The solid is taken up in white CH "C1_ and the indole starting material is crystallized out by addition of hexane.

^There are recovered 13.88 g indole starting compound. The mother liquor is evaporated under reduced pressure to give 22.32 g of brown oil. The crude product is purified by flash chromatography on silica gel eluted with hexane and then with hexane-acetone (95: 5).

The product fractions are evaporated. Yield: 6.55 g (21 %) (62 % corrected yield) of the desired N-isopropylindole title compound as a yellow oil. TLC (4: 1) hexane-acetone, Rf = 0.57, UV and PMA

¹ H NMR _(CDCl3): ^ 1.04 (3H, t), 1.20 (6H, d), 4.17 (2H, q), 5 ₍₄₀ (1H, m), 7.10 to 7 , 7 (8H _1m ) ppm.

¹³ CNMR (CDCl ₃ ): <S 1 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

(J _CF = 7.5 Hz), 136.2, 162.3 (J _ _{c p} = 144 Hz), 163.0 ppm. 35

•. -9α-

D. 3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indole-2-methanol

1.12 g (29.6 mmol, 1.5 eq.) Lithium aluminum hydride are anhydrous carefully to a cooled in an ice bath to 0 ⁰ C solution of 30 ml of distilled Et-O. The resulting suspension is added dropwise over 10 minutes with an ethereal solution of 6.42 g (17.9 mmol in 20 ml Et-O) of Part C indole. After stirring for 30 minutes at 0 ^° C. under argon, the mixture is quenched by successive dropwise addition of 1.1 ml H ₃ O, 1.1 ml 15 % NaOH and 3.4 ml HpO. The resulting suspension is filtered through diatomaceous earth, over anhydrous MgSO 4. dried and evaporated under reduced pressure to 5.1 g of yellow foam. The crude product is purified by flash chromatography on silica gel.

15 and eluted with hex-acetone (85:15). Yield:

5.08 g (91 %) of pure alcohol title compound as pale yellow

Foam. :

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

A small sample is recrystallized from hexane to give the alcohol title compound as white crystals, mp 101-103 ⁰ C.

Microanalysis for C ₁₈ H ₁₇ NOF *. CHF. N °: 76.30 6.40 6.71 4.94

F .: 76.49 6.46 6.84 4.88

¹ H NMR (CDCl ₃ ): 51, 60 (1H, t), 1.69 (6H, d), 4.76 (2H, d), 4.93 (1H, m), 7.05-7, 62 (8H, m) ppm.

¹³ CNMR (CDCl ₃ ): S 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 (J "" = 245 Hz) ppm.

E. 3- (4-Fluorophenyl) -1- (1-ethylethyl) -1H-indole-2-carboxaldehyde

2 8i60 5

• · -91-

A solution of 5.9 g (13.9 mmol, 1.2 Ag.) Of Dess-Martin-Perjodinan in 30 ml of anhydrous QH "C1_ is anhydrous with 1.3 ml (13.9 mmol, 1.2 Ag.) treated tert-butanol and the mixture stirred for 15 minutes at room temperature under argon. Then 3.20 g (11.6 mmol, 1 Xg.) Of indole alcohol of Part D in 12 ml of anhydrous CH ₂ Cl _{2 are added} dropwise over 5 minutes and the yellow mixture is stirred under argon at room temperature for 1 hour. The reaction mixture is added with stirring to a solution of 15.3 g (97 mmol, 7 Xg.) Of sodium thiosulfate in 40 ml of freshly prepared 1.0N NaHCO ^ solution and the resulting mixture stirred vigorously for 5 minutes. The organic phase is separated, washed with 1.0N NaHCO ₃ solution, H ₂ O and brine, over anhydrous Na ₂ SO 4. dried and evaporated to 3.69 g of yellow oil. The crude product is purified by flash chromatography on silica gel and eluted with hexane-Et 2 O (40: 1). Yield: _2: 7 g (83%) of pure aldehyde title compound as a white crystalline solid, mp 88-89 ° C. TLC (7: 3) Hex-acetone, Rf = 0.56, UV and PMA.

Microanalysis of C ₁₀ H ₁ -FNO: CHNF

Io Ib

Calculated: 76.85 5.73 4.98 6.75 Found: 76.91 5.71 4.95 6.76

¹ H NMR (CDCl ₃ ): ¹ , 69 (6H, d), 5.92 (1H, m), 7JO - 7.70

(8H, m), 9.80 (1H, s) ppm.

¹³ C NMR (CDCl ₃ ): 21.4, 48.0, 112.5, 113.2, 115.4, 115.7, 120.8, 122.1, 126.9, 127.0, 132 , 0, 132.6 (J _C _ _F = 7.5 Hz) ppm. 30

F. 3- (4-Fluorophenyl) -1- (1-methylethyl) -2- (2,2-dibromoethenyl) -1H-indole

A cooled in ice / salt bath to -15 ° C solution of 1.84 g (6.54 mmol) of indole-aldehyde of Part E and 5.14 g (19.6 mmol, '3 Xg.) Triphenylphosphine in 30 ml of anhydrous CH_C1_

28160

-92-

Dropwise over 5 minutes with 3.25 g. (9.8 mmol, 1.5 eq.) CBr. solution in 10 ml of anhydrous CH ₂ Cl ₂ and treated 1, the yellow mixture for 15 minutes under Argon.bei 15 ⁰ C stirred. The mixture is partitioned between saturated NaHCO 3 solution and CH ₂ Cl ₂ , the organic phase washed with saturated Na 2 SO 4, brine and brine, over anhydrous Na ₂ SO 4. dried and evaporated to 9.44 g of brown oil. The crude product is purified by flash chromatography on silica gel and eluted with hexane-CH-Cl- (95: 5). The product

IQ fractions are evaporated. Yield: 2.87 g (100%) of desired vinyl dibromide title compound as a yellow oil which crystallized on standing. Recrystallization from diethyl ether gives 2.46 g (86 %) of purified product as pale yellow granular crystals, mp 135-137 ° C.

₁₅ TLC (7: 3) HeX-CH ₂ Cl ₂ , R f = 0.45, UV and PMA.

Microanalysis for C ₁₉ H ₁₆ NR Br ₂ : CHN Br

Calc .: 52.20 3.69 3.20 36.56 Found: 52.25 3.68 3.20 36.58

H NMR _(CDCl3): £ i, 15 (6H, d), 4.67 (1H, m), 7.10 to 7.70

(9H, m) ppm.

¹³ C NMR (CDCl ₃ ): $ 21.9, 48.6, 98.6, 111.6, 115.3, 115.6, 115.9, 119.9 [J _Q ^ = 7.6 Hz], 112.4, 127.5, 129.3, 130.5, 130.7, 130.9, 135.2, 161.5 (J _C _ _F = 246 Hz) ppm.

G. 3- (4-Fluorophenyl) -1- (1-methylethyl) -2-ethyl-1H-indole

OQ A solution of 2.395 g (5.48 mmol) vinyl dibromide of Part F in dry water / acetone to -78 ° C in 10 mL anhydrous THF is added dropwise under argon with 6.9 mL (10.96 mmol, 2 eq.). Treated 1.6M solution of n-BuLi in hexanes. The resulting mixture is stirred for 1 hour at -78 ° C.

Og stirred and then quenched with dropwise addition of 5 ml of NH.Cl solution.

iS 28 1 60S -

-93-

-1 The mixture is warmed to room temperature and extracted twice with Et ₂ O. The ether layers are washed with brine, over anhydrous MgSO. dried and evaporated under reduced pressure to 1.893 dark brown oil. The crude product is purified by flash chromatography on silica gel (80: 1) and eluted with hexane-Et-O (200: 1). Yield: 1.12 g of refined product as a mixture (3.3: 1) of acetylene to terminal olefins. This mixture is separated by chromatography on alumina (neutral, Activity - II) in a column and eluted with hexane-Et-O (200: 1). Evaporation of the product fractions gives 900 mg of whitish crystals. Recrystallization from hot hexane gives 700 mg (46%) C. gerinigte acetylene title compound in the form of white needles melting at 105 to 106 ^a

TLC (95: 5) HeX-Et ₃ O, Rf acetylene = 0.44, R f olefin = 0.49 .. UV and PMA.

Microanalysis for C ₁ -H ₁₆ NF: CHNF - * -: "calc .: 82.28 5.81 5.05 6.85 Found: 82.70 5.85 5.10 6.62

¹ H NMR (CDCl ₃ ): 61.70 (6H, d), 3.5 (1H, s), 5.06 (1H, m), 7.10-7.75 (8H, m) ppm.

H. (S) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -äth inyl] -methoxyphosphinyl] -3- (t- butyldiphenylsilyloxy) -butyric acid methylester

A solution of 678 mg (244 mmol, 1.0 equiv.) Of Part G acetylene in 6 ml of anhydrous THF, cooled to -78 ° C. in the dry ice / acetone bath, is added dropwise under argon with 1.53 ml (2.44 mmol , 1.0 eq.) 1.6M solution of n-BuLi treated in hexanes. After 30 minutes at -78 ° C, the mixture is transferred by cannula to a solution of the phosphonochloridate of Example 1, part F (about 4.3 mmol, 1.75 eq.) Cooled to -78 ° C in 5 ml of anhydrous THF , The dark brown mixture

-94-

is stirred for 30 minutes at -78 ⁰ C and then quenched by dropwise addition of 5 ml of saturated NH.Cl solution and warmed to room temperature. The mixture is extracted twice with Et, O, washed with saturated NH.Cl solution and brine, over anhydrous MgSO. dried and evaporated under reduced pressure 2.567 g of brown-red oil. The crude oil is purified by flash chromatography on silica gel eluted with hexane-EtOAc (3: 2). Yield: 756 mg (44 %) of acetylenic phosphinate title compound as a dark yellow oil.

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

¹ H NMR _(CDCl3): £ i, 0 (9H, s), 1.64 (6H, d), 2.10 to 2.90 (4H, m), 3.56 (3H, s), 3 / 58 (3H, dd), 4.6 (1H, bro), 4.90 lc (1H, m), 7.05-7.55 (18H, m) ppm.

¹³ C NMR _(CDCl3): £ 14.2, 19.1, 21.0, 26.7, 27.8, 37.5, 39.2, 42.2, 45.1; .49, -2; 51, 4, 51, 9, 60, -3. 65.5 (J _ _{c p} = 15.1 Hz), 88.1, 91.2; '98, 3, 111.3, "115.3, 115.6, 120.8 (J = 5.7 Hz), 122.3, 124.9, 125.9, 126.4, 127.6, 129.2, 130.7, 133.0, 135.7, 136.1, 170.9 ppm.

j. (S) -A- [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1 H-

indol-2-yl] -äthyl3-methoxyphosphinylj-3- (t-butyldiphenylsilyloxy) -butyric acid methylester

An Argon yespülte solution of 422 mg of acetylenic phosphinate of Part H in 9 ml of CH ₃ OH "is treated with 420 mg of 10 % Pt / C and the resulting mixture on a Parr apparatus for 2 hours under hydrogen at a pressure of about 2, 8 bar, then the catalyst is filtered through kieselguhr and the titrate is evaporated Yield: 380 mg (90 %) of indole-phosphinate title compound as a yellow foam.

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

•. -95-

.1 ¹ H NMR _(CDCl3): ^ 1.00 (9H, s), 1.63 (6H, d), 1,5 - 2,0

(2H, m), 2.20 (1H, m), 2.58-3.00 (5H, m), 3.44 (3H, dd, J _u = 10.6 Hz), 3.61 ( 3H, s), 4.52 (2H, m), 7.07-7.66

M - tr

(18H, m) ppm.

¹³ C NMR (CDCl ₂ ): & 12.6, 16.8, 17.2, 19.1, 21.5, 26.7, 36.0, 42.1, 47.2, 50.9, 51, 4, 65.8; 111.8, 115.3, 119.1, 121.1, 127.7, 128.3, 129.9, 131.2, 131.3, 132.8, 133.4, 134.3, 134 , 8, 135.7, 171.3 ppm.

K. (S) -4- \ J2 - [3- (4-fluorophenyl) -1- (1-methylethyl) -1 H-

indole-2-YLJ-ethyl] -methoxyphosphinyl ^ -S-hydroxybutyric acid methylester

A solution of 379 mg (0.531 mmol) of Silyl Ether of Part I

in 5 ml anhydrous THF is nacheinadner 120 μ.Ι (2.12 mmol, 4 Xc.) of glacial acetic acid and 1.6 ml (1.6 mmol, 3 eq.) 1.0 M ^Λ ....... Tetrabutylammonium fluoride solution. The mixture is diluted with 10 ml of ice-cold H2 O, extracted twice with EtOAc, the organic phase washed with saturated NaHCO3 solution and brine and then dried over anhydrous Na 2 SO 4 The product is purified by flash chromatography on silica gel eluted with acetone-hexane (7: 3), the product fractions are evaporated, yield 197 mg (78 %) of the desired alcohol. Title compound as white foam

 TLC (1: 1) hexane-acetone, Rf = 0.09, UV and PMA.

¹ H NMR (CDCl ₃ ): ¹ , 68 (6H, d), 1.80-2.0 (2H, m), 2.10 (2H, m), 2.58 (2H, m), 3 , 08 (2H, m), 3.63 (3H, dd, J _{H p} = 10.1 Hz), 3.70 (3H, d), 3.96 (1H ₁ t), 4.35 + 4 , 49 (1H, 2 wide multiplets), 4.67 (1H, m), 7.0 - 7.6 (8H, m) ppm.

2 8 16 0

'-96-

1 ¹³ C NMR (CDCl ₃ ): Si 7.6, 17.7, 21.4, 29.2, 29.4, 33.2, 33.3,

34.6, 41.6, 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 _{c p} = 244.1 Hz), 172.1 ppm.

Example 8

(S) -4 - [[2- [3- (4-Fluorophenyl) -1- (1-methylphenyl) -1H-indol-2-ylH-ethyl] -hydroxyphosphiny1-hydroxybutyric acid dilithium salt

t A solution of 197 mg (0.414 mmol) of the diester of Example 7 in 5 ml of dioxane is treated, under stirring, with 1.35 ml (3.5 eq.) of 1.0N LiOH solution and the resulting white suspension in an oil bath under argon 40 Minutes heated to 55 ⁰ C. The mixture is cooled, diluted with H 2 O, filtered and evaporated under reduced pressure. The residue is taken up in the minimum amount of H ₂ O and chromatographed on resin HP-20 and eluted with H ₂ O followed by HO-CH-OH (50:50) .The product fractions are combined and evaporated to give the glassy residue taken up in 50 ml H "O, filtered and lyophilised Yield: 178 mg (85 % by weight of the hydrate) of pure dilithium salt title compound as a white solid.

Microanalysis for C ₂₃ H ₂₅ NFP.2Li +

2.52 moles of H ₂ O (MW 504.71): CHNFP

Cons .: 54.73 6.00 2.78 3.76 6, ', 4

F .: 54.62 5.67 2.90 3.61 6.06

¹ H NMR (400 MHz, CDCl ₃ ):

£ i, 69 ppm (6H, dd, J = 5.8 Hz)

1.71 (2H, multiplet)

1.93 (2H, multiplet)

35 2.38 (2H, multiplet)

3.06 (2H, Quartet)

(1H, -97- 4.32 (1H, Multiplet) 4.87 (1H, Multiplet) 6.97 (1H, dt, J = O, 7 Hz) 7.07 (2H, dt, J = 1.1 Hz) 7.16 (3H. t) 7:41 m)

7.57 (1K, 1/2 AE quartet)

IQ example * 9

(S) -4-Q2- [[1,1'-biphenyl] -2-yl] -ethyl] -methoxyphosphinyl] -

3-hydroxybutyric acid methylester

A. Biphenyl-2-carboxaldehyde

27.64 g (65.2 mmol) of Dess-Martin-Perjodinan is stirred under argon with 150 ml of CH ₅ Cl ₉ . 8.0 ml of anhydrous tert.-BuOH are added to the solution while stirring, and the mixture is stirred for 10 min . Stirred for 20 minutes at room temperature. Then, within 1.5 minutes, 20 ml of a solution of 10 g (54.3 mmol) of biphenyl-2-methanol in CH ₂ Cl _{2 are} added dropwise After 1 hour, 600 ml of anhydrous Et ₂ O are added, then 225 ml of 1N NaOH are added, and after 10 minutes the resulting slurry is filtered and the filter cake is washed with Et ₉ O. The filtrate is washed twice with 250 ml of 1N NaOH The organic layer is dried over MgSO 4, filtered to give 10 g of yellow oil after removal of the solvent, purification by flash chromatography on silica gel and elution with Et ₉ O: hexane = 1:10

3Q gives 9.58 g (97 %) aldehyde title compound as a colorless oil.

TLC (1/9 EtOAc / hexane, silica gel) Rf = 0.29 IR (film) 3065, 3025, 2850, 2760, 1685, 1700, 1600, "470, 1450, 1395 cm" ¹

H NMR (270 MHz) _(CDCl3):

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

ΐ . -98-

vl Mass Spectrum M7e 183 (M ⁺ + Hh

B. 2- (2,2-dibromoethenyl) - [j, 1'-biphenyl]

A solution of 2.0 g (11 mmol) of aldehyde from Part A in 60 ml CH-Cl ₂ is cooled under argon to -1O ⁰ C. Then 9.21 g (35 mmol) Triphenylpholsphin be added and this mixture stirred until the solution of the solid. The solution obtained is within 15 minutes at -10 ⁰ C and 40 ml solution of 5.5 g (16.5 mmol) of CBr. in CH ₂ Cl- added. The reaction mixture is stirred for 1 hour and 15 minutes at -10 ⁰ C and then quenched at -10 ⁰ C with 50 ml of saturated aqueous NaHCO 3 solution. The layers are separated and the aqueous layer extracted once with CH-Cl-. The combined CH_C1 "extracts are washed once with saturated aqueous

NaHCO.-solution and washed once with saturated brine. The CH ₂ C1 ₂ extract is dried over Na ₃ SO ₄ and:. evaporated to dryness. The crude product is purified by flash chromatography and eluted with hexane. Yield: 2.45 g (66 %) of dibromide title compound as an off-white solid

 TLC (5:95 / EtOAc: Hexane Kieselgel) Rf = 0.47.

IR (CHCl ₃ ) 3064, 3011, 1596, 1473, 1450, 1435, 889, 860, 702 cm ^-1

¹ H NMR (270 MHz) (CDCl ₃ ): 7.75 (m, 1), 7.35 (m, 8), 7.20 (s, 1)

30 ¹³ C NMR (67.0 MHz) (CDCl ₃ ):

S141, 06 _# 140.08, 137.49, 133.83, 129.81, 129.45, 129.17, 128.61, 128.22, 127.50, 127.08, 90.78

Mass spectrum m / e 337/339/341 (M ⁺ + H) 35

1 '-99-

1 C. 2-ethynyl [1, 1'-biphenyl]

A solution of 2.31 g (6.9 mmol) of vinyldibromide from Part B in 35 ml of THF is cooled to -78 ° C under argon. Within 10 minutes, the vinyldibromide solution at -78 ° C with 5.52 ml of 2.5M solution of n-BuLi in hexane is added with stirring. Upon complete addition of the n-BuLi, the reaction mixture turns deep purple. After 2 hours 45 minutes of stirring at -78 ⁰ C, the reaction is stopped by addition of saturated aqueous NH.Cl solution. After that, the mixture is on

Room temperature warmed, the THF distilled off and the remaining 'material with H ₂ O diluted and extracted 3 times with Et "O / hexane. The organic extract is over MgSO. dried and filtered to give 1.3 g of yellow oil. Purification by flash chromatography and elution with 1 % EtO / hexane gives 1.04 g (88 %) of desired acetylene

Title compound.

TLC (100 % hexane, silica gel) Rf = 0.1G

IR (Film) 3287, 3061, 3026, 1474, 1449, 1432, 1008, 775, 758, 738 cm ^-1

¹ H NMR (270 MHz)

(CDCl ₃ ) $ 7.68 ( _m> 3) _# 7 ₍ 35 ( _{m /} 6), 3.00 (2, 1). 25

¹³ C NMR (67.8 MHz) (CDCl ₃ )

$ 144.40, 140.22, 133.83, 120.56, 129.20, 128.92, 127.95, 127.49, 126.94, 120.44, 83.03, 80.15

30 mass spectra m / e 179 (i-! ⁺ + H).

D. (S) -4 - [[2 - [[i, 1-biphenyl] -2-yl] -äthinylj-methoxy-

phosphinyl] -3- (t-butyldiphenylsilyloxy) butyric acid methyl ester 35

0.332 g (1.8 x *) mmol) of acetylene of C are at -78 ⁰ C under

I. -100-

* 1 argon stirred in 10 ml of THF. After 5 minutes, add 0.75 ml of 2.5M solution of n-BuLi in hexane. given the acetylene solution. The reaction mixture is stirred for 1 hour at -78 ⁰ C, then warmed to 0 ⁰ C, stirred for a further 10 minutes and then cooled to -78 ° C. The acetylenic anion solution is then (2.98 mmol) was added dropwise within 8 minutes 10 ml solution of the Phosphonochloridats of Example 1, Part F in THF which has been cooled under argon to -78 ⁰ C. After complete addition, the reaction mixture is stirred for 1 hour at -78 ° C and then quenched by the addition of saturated aqueous NH.Cl solution. The mixture is warmed to room temperature, diluted with brine and extracted 3 times with Et ₂ O. The combined Et ₃ O extracts are washed with saturated aqueous NaHCO 3 solution and saturated brine. The Et 2 O layer is dried over MgSO 4 and evaporated to give 1.5 g of yellow

, ..._: \ -. Oil to be obtained: - Cleaning durc.i. Flash chromatography

..- ..:. and elution with hexane: toluene:. EtOAc (5: 1: 4) gives .... 0.543 g (48 %) of the acetylenic: phosphinate title compound.

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

IR (CHCl ₃ ) 3070, 3053, 3035, 3000, 2952, 2934, 2896, 2859, 2178, 1735, 1474, 1448, 1436, 1429 cm ^-1

H NMR (270 MHz) _(CDCl3)

57.65 (m, 3), 7.65-7.28 (m, 16), 4.55 (m, 1), 3.55 (d, 3) 3.40 (dd, 3), 2, 80 (ir, 1), 2.55 (m, 1), 2.35 (m, 1), 2.08 (m, 1), 100 (s, 9) 30

¹³ C (67.8 Mz) (CDCl ₃ )

<Si70.83, 145.29, 145, Ί9, 139.22, 135.95, 135.59, 133.86, 133.75. 133.16, 132.86, 130.57, 129.56, 129.34, 128.81, 127.92, 127.75, 127.44, 127.39, 126.94, 117.90, 100, 91, 100, 38, 100, 18, 84, 51, 81, 60, 65, 53, 65, 42, 60, 106, 51, 61, 51, 50, 51, 11, 42, 07, 41, 90 38.86, 37.16, 26.56, 20.75, 18.97, 13.97

-101-1 mass spectrum m / e 611 (M + H)

E. (S) -4- [2 - [[i, 1'-biphenyl] -2-yl] -ethyl] -methoxyphosphate

phinyl] - (t-butyldiphenylsilyloxy) -butyric acid methylester

Through a solution of 0.515 g (0.85 mmol) of acetylenic phosphinate from Part D in 8 ml of methanol is passed through for 10 minutes argon. Then, 0.190 g of 10 % Pd / C are added to the acetylene solution and the mixture is hydrogenated on a Parr apparatus at about 3 bar hydrogen pressure. After shaking at about 3 bar for 25 hours, the methanol solution is filtered through kieselguhr and the filtrate is evaporated. Yield: 0.510 g (98 %) of the phosphinate title compound as a colorless oil.

15 TLC (4: 1 EtOAc: hexane) Rf = 0.21 ... , ... IR. (CHCl ₃ ) 3071, 3054, 2998, 2954, 2934, 2902,

-. . rf2859,41734, vi477, -14627 '1448, 1438, 1428 cm " ¹

20 ¹ H NMR (270 MHz) (CDCl ₃ )

£ 7.65 (m, 3), 7.55 - 7.00 (m, 16), 4.45 (m, 1), 3.58 (s, 3), 3.30 - 3.20 (2 Doublets, 3, J = 11 Hz), 2.88 (m, 1), 2.60 (m, 3), 2.17 - 1.80 (m, 1), 1.80 - 1.30 (m , 1), 1.00 (s, 3).

25 ¹³ C NMR (67.8 MH) (diagnostic peaks) (CDCl ₃ ) I71.33, 65.78, 51.36, 42.24, 26.75

Mass spectrum m / e 615 (M + H)

30 (S) -4- [2 - [[i, 1'-biphenyl] -2-yl] ethyl J-methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

To a solution of 0.500 g (0.82 mmol) of Part E phosphinate in 10 ml of THF is added, under argon and with stirring, 0.19 ml (3.3 mmol) of HOAc. At room temperature, 2.45 ml of 1.0M solution of nBu.NF in THF is then added dropwise.

-102-

The reaction mixture is stirred for 23 hours at room temperature and then quenched with 15 ml of ice-water. The aqueous layer is extracted twice with EtOAc and the combined organic solutions are washed twice with saturated aqueous NaHCO3, brine and once with saturated brine The organic layer is dried over Na2 SO4 and evaporated to yield 0.437 g of colorless oil. Purification by flash chromatography and elution with acetone: hexane (7: 3) gives 0.247 g (51 %) of the alcohol title compound as a colorless oil.

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

IR (CHCl ₃ ) 3600-3171 (br), 3064, 3009, 2954, 1731, 1479, 1439, 1237, 1180, 1042, 999 cm ^-1

15 1

H NMR (270 MHz) _(CDCl3)

, , 5.7,50 - 7.10 (m, 9), 4.50 - 4.15 (m, 1), 3.70 (s, 3), 3.53 &'-.' 3.50 ( 2: doublets, -, 3, ": J. = 11" Hz), "2.88 (m, 2), 2.50 (m, 2), 2.00 - 1.60 (m, 4)

20 ₁₃

'- ³ C NMR (67.8 MHz) (CDCl ₃ )

5,171.55, 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)

30 example

(S) -4- [2- [j, 1'-biphenyl-2-yf] -ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium maleate

0.239 g (0.64 mmol) of the diester of Example 9 are stirred under argon in 6.5 ml of dioxane. At room temperature, 1.0 ml of 1.0M LiOH solution is then added. The mixture is at 55 ° C

-103-

Stirred for 2.5 hours, then cooled to room temperature and the dioxane and most of the H_0 removed on a rotary evaporator. Purification by chromatography on HP-20 (18 cm χ 2.5 cm) and elution first with 100 % H ₂ O and then with MeOH: H ₂ O (1: 1) gives 0.180 g (79 %) of the title dilithium salt as a white solid.

TLC (8: 1: 1 CH ₂ Cl ₂ : MeOH: AcOH) R f = 0.16

(7: 2: 1 nPrOH: NH ₃ : H ₂ O) R f = 0.37 10

Example 11

(R) -4- [ε (E) -2- [π-fluoro-3,3 ', 5-trimethyl- [i, 1'-biphenyl] -2-yl] -äthenyi] -hydroxyphosphinyl] -3 hydroxybutyric acid-di-

15 lithium salt

A. (Ej-tributyl - ^ - Qr-fluoro-S ^ ¹ , 5-trimethyl- [i, 1'-bi- ".. ν.-. -. _Phenyl] -2-yl-ethenyl]. -Tin

:. : -.: (M. A. Miftakov ürid Mitarb ^ / "Synthesis (Comm.) (1985), p. 496-499)

A mixture of 1.7 g (7.13 mmol) 2-ethynyl-4'-fluoro-3,3 ', 5-trimethyl-D,!' - biphenyl] and 2.9 ml (10.7 mmol, 1 , 5 eq.) (n-Ch.HgKSnH is (7.0 mg 0.426 mmol) of AIBN and heated under argon in an oil bath, the solution rapidly to 120 ⁰ C.

After 15 minutes at 120 ⁰ C, a further quantity of 0.39 ml (1.43 mmol, 0.2 eq.) (NC.H ") _SnH added and the mixture was heated a total of 3 hours. Then the yellow mixture is cooled and purified by Kugelrohr distillation at 0.1 mm Hg and 240 ⁰ C. yield: 3.073 g (81%) vinyl stannane-Ti

30 telverbindung as a colorless liquid. TLC hexane, R _f product = 0.45, UV and PMA.

The product is unstable on silica gel (strip to baseline).

·

-104-

¹ 13

C NMR (67.5 MHz, CDCl _3): 9.5, 13.6, 14.5, 20.9, *

21.1, 27.2, 27.6, 114.0, 114.3, 123.6, 123.9, 128.8, 130.4, 133.0, 135.6, 136 _f l, 138, 1, 140.0, ₅ 144.4, 160.3 (J _CF = 244 H ₂ ) ppm.

¹ H NMR: 60.8-1.5 ppm (27 H, m, Sn (Bu) ₃ )

2.27, 2.31, 2.36 (9H, 3 singlets, aromatic 10 CH ₃ ¹ S)

6.05 (IH, d, J = 20HZ, PhOi = CHSh) 6.68 (IH, d, J = 20Hz, PhCH = CHSn) 6.90-7.13 (5H, m, aromatic proteins)

For example, (E) -4'-fluoro-2- (2-iodoethyl) -3,3 ', 5-trimethyl- [1,2'-biphenylQ

, -j_ A solution of: 1, 537. g (2.9mmol) vinyl stannane from Part A: ········ in 20. ml anhydrous .Et ₂ O: is treated with "734 mg (2.9 mmol, 1Aq.) iodine and the brownish solution was stirred for 2 hours under argon at room temperature. The mixture is washed with saturated sodium thiosulfate solution, 10% NH.OH solution and brine, over anhydrous MgSO 4. dried and evaporated to 1.649 g of yellow oil. The crude product is purified by flash chromatography on 160 g of silica gel and eluted with hexane. The combined product fractions give 832 mg (65 %) of the desired trans-vinyl iodide title compound as a pale yellow oil, which slowly crystallizes on standing, mp 53-55 ° C.

TLC (hexane) R _f trans-olefin x = 0.31, (R _f cis-olefin = 0.26), UV and PMA

¹ H NMR (2 70 MHz):

S 2.30 + 2.32 ppm (9H, 2 singlets, aromatic methyl groups)

6.05 (1H, d, J = 15 Hz, -CH = CHI)

-105-

1 6.92 - 71.0 (5H, m, aromatic H)

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

¹³ C NMR (67.5 MHz): 14.6, 21.0, 21.1, 81.0 5 (= CH-I), 114.4, 114.7, 124.2, 124.5, 128 , 5, 128.7, 130.5, 132.7, 132.8, 133.2, 135.8, 137.2, 140.1, 143.1 (PhCH = CHI), 161.0 (J _CF = 244 Hz) ppm.

Note: 1 H NMR (CDCl 2 70 MHz) of mixed fractions .Q shows that the impurity close to it is the ice-vinyl iodide.

66.54 ppm (IH, d, J _HaHb = 7.9 Hz (PhCHj ₅ = CH -I)) 15 C. (R) _3 - [[(1,1-

3,3 ', 5-trimethyl- [i, 1'-biphenyl] -2- - "Ϊ: j -s . :: - - _: yi] J-ethyl-phenyl] -methoxyphosphinyl] -butyric acid methyl ester

A solution of 812 mg (2.22 mmol) vinyl iodide of Part B in 6 ml anhydrous THF cooled to -78 ° C in dry ice / acetone is added dropwise via syringe with a solution of 1.4 ml (2.2 mmol, 1 Äq.) Treated 1.6M n-BuLi in hexanes and the pale yellow mixture stirred for 45 minutes under argon at -78 ° C, the anion is then added dropwise by cannula within 10 minutes directly into a cooled to -78 ⁰ C solution of Phosphonochloridats of Example 1, Part F (about 3.5 mmol, 1.58 Aq.) In 6 ml of anhydrous THF transferred. The yellow mixture is stirred for 30 minutes at -78 ° C and then warmed to room temperature. The mixture is quenched at room temperature by adding 5 ml of saturated NH.Cl solution. The mixture is treated with Et _? 0, the ether layer washed with saturated NH.Cl solution and brine, then over anhydrous MgSO 4. dried and evaporated to give 2.083 g of yellow oil. The crude product is purified by flash chromatography on silica gel.

, -106-

gel and elution with hex-acetone (85:15). The product fractions are combined and evaporated. Yield: 249 mg (17 %) of the desired trans-olefinic phosphinate title compound as a pale yellow oil. The NMR spectrum shows an approximately 1: 1 mixture of diastereomers on the phosphorus

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

¹ H NMR: O

10 53.27 ppm (3H, d, J _H _ _p = 11.6 Hz, -POCH ₃₎

3.57 + 3.60 (3H, 2 singlets, diasteroemers, -CO ₂ CH ₃ ) 4.33 + 4.50 (1H, 2 multiplets, diastereomers,

-CH-CH (OSiR-) CH "-) 4.84 + 5.25 (1H, 2 dd's, diastereomers, J _HaHb = 17.9

15 Hz, ^ Ha-P ^{= 25} ' ^{3 Hz} '

PhCH. = CH -P-) b -a

D. (R) -4 - [[(E) -2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -äthenyl] -methoxyphosphinyl] 3-hydroxybutyric acid methyl ester

A solution of 249 mg (0.37 mmol) of silyl ether of Part C in 5.0 ml of THF is added sequentially with 85 μΐ (1.48 mMpl, 4; 0 eq.).

² ^ glacial acetic acid and 1.1 ml (1.1 mmol, 3.0 Xq.) 1.0M solution of (nC.H ₉ ) .NF in THF and the yellow mixture stirred under argon for about 15 hours at room temperature. The mixture is diluted with 10 ml of cold H 2 O and extracted with EtOAc. The organic phase is washed with saturated NaHCO 3 solution and brine, then over anhydrous Na 2 SO 4. dried and evaporated to give 243 mg of yellow oil. The crude product is purified by flash chromatography on silica gel and elution with hex-acetone (55:45). The product fractions are combined and evaporated. Yield: 121 mg (75 %) of the desired hydroxy diester title

8U05

-1 ΟΤΙ compound as a colorless, viscous oil.

TLC (6: 4) acetone-Hex, R _f = 0.26, UV & PMA.

¹ H NMR:

O

Il

61.8 to 2.06 ppm (2H, m, CH ₃ O-PCH ₂ -)

I '

2.30, 2.35,. 2.40 (9H, 3 singlets, aromatic

^CH 3> -

2.40-2.60 (2H, m, -CH (OH) CH ₂ CO ₂ CH ₃ )

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

-POCH., J "= 12 Hz),

3.64 (3H, s, -CO ₂ CH ₃ )

• 3.77 + 3.84 (IH, 2 doublets,

Diastereomers, -CH (OH) -)

4.28 + 4.38 (IH, 2 wide multiplets, -CH (OH) -)

5.52 (IH, 2 dd's, diastereomers

^J HH ^Ko PP ^lun 9 & Jjjp ^ Coupling,

5 PhCH = CJ-P (OCH ₃ ) -)

6.90-7.10 (5H, 'aromatic proteins) 7.50 (IH, multiplet,

Diastereomers +

Jtjtj coupling yyjp coupling,

0 PhCH = CH-P (OCH ₃ ) -) I

2 8

-108-

1E (R) -4- [ε (E) -2- [4'-fluoro-3,3 ·, 5-trimethyl- [1, 1'-bis)

pl'enyl] -2-yl] -äthenylj-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

A solution of 121 mg (0.279 mmol) of hydroxy diester of Part D in 2 ml of dioxane is treated with 0.98 mg (0.98 mmol, 3.5 equiv) of 1.0N LiOH solution in excess and the clear, pale yellow solution Stirred for 1.5 hours under Argen in an oil bath at 50 ⁰ C. The mixture is cooled, diluted with H ₂ O, filtered and evaporated under reduced pressure. The residue is taken up in the lowest possible amount of H ₉ O and chromatographed on resin HP-20 (8 cm bed, 25 mm column diameter) and successively with 200 ml of H ₉ O, H ₉ O-CH ₉ OH (8 =: 20) and finally eluted H ₂ O-CH ₃ OH (60:40). The product fractions are evaporated under reduced pressure, taken up in 50 ml H ₉ O and lyophiliriert. Yield: 91 mg of pure dilithium salt title compound as a hygroscopic white lyophilate

TLC (8: 1: 1) CH ₂ CH ₂ -CH ₃ OH-HOAc, R f = 0.19, UV and PMA.

Examples 12 to 24

After the seduction described above, the following further compounds are prepared.

0 H

Il I χ

X OH

Belsp

-109-

12. OH

Cl

-CH-CH- CH.

CH.

Cl

Cl

^C 2 ^H 5-C = C-

15, OLi

[Ο V.CH.-0

Li

16. OH

-CH »CH- H

17. OU

-C = C-

Li

-110-

Ex. No. R

18. OCH,

Γ · ^CH 3

19. OK

* 2

-CH I

O0 I 0

CH.

-CH-CH- OK

20. ONa

door

-C = C-Na

21. OH

-CH ₀ CH- H

-111-

Ex

 No. R

22. OH

C.H.-C C-O

CH ₃ CH ₃

OH

23. CH ₃ O

-CH-CH- CH.

24. OH

-C = C- H

• -112-1 Example 25

(S) -4- (Hydroxymethoxyphosphinyl) -3- [Q (1,1-dimethyl-ethyl-1-yl-diphenylsilyl-oxy] -butyric acid methyl ester dicyclohexylamine (1: 1) salt

A. (S) -4-Diisopropyloxyphosphinyl) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -butyric acid methyl ester

21.70 g (45.1 mmol) of iodide from Example 1, Part F (2) are stirred for 30 minutes in a high vacuum and then treated in an amount with 93.92 g (113.37 ml, 0.451 mol) of freshly distilled triisopropyl phosphite , The reaction mixture is stirred under argon and then heated to 155 ^° C. in an oil bath for 16.5 hours. The mixture is then cooled to room temperature. Excess triisopropyl phosphite and volatile reaction products are obtained by short path distillation (10 mm Hg) followed by Kugelrohr least ⁴ llation (0.50 mm Hg, 100 ⁰ C, 8 hours) * removed. The product is further purified by flash chromatography (95 mm column diameter, Merck 6 "silica gel, eluent hexane / acetone / toluene = 6/3/1, flow rate 2" / minute, 50 ml fractions). Yield: 17.68 g (33.96 mmol, 75 %) of isopropyl phosphonate title compound as a clear, viscous oil

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

^{25 1} HNMR: (270 MH ₂ , CDCl ₃ ) δ 7.70-7.65 (m, 4H)

7.45-7.35 (m, 6H)

4.57-4.44 (m, 3H)

3.59 (s, 3H) ³⁰ 2.94 and 2.88 (2xdi IH J = 3.7 Hz)

2.65 and 2 60 (2xd, IH J = 7 4 Hz) 2.24-1.87 (series of m, 2H) 1.19 and 1.12 (2xd, 12H J = 6.3 Hz) 35 '101 ( s, 9H)

-113-

B. (S) -4- (Hydroxymethoxyphosphinyl) -3- £ Q (1,1-dimethylethyldiphenylsilyl) -oxybut -butylic acid methyl ester dicyclohexylamine (1: 1) salt

10.66 g (30.5 mmol) of isopropyl phosphonate from Part A are stirred under argon at room temperature in 80 ml of anhydrous CH ₂ CL ₂ . The solution is treated dropwise with 8.44 g (8.71 mL, 32.8 mmol) of Bistrimethylsilyltrifluoroacetamide (BSTFA) over 5 minutes and then added dropwise over 10 minutes to 7.84 g (6.75 mL, 51.3 mmol) trimethylsilyl bromide (TMSBr). After stirring for 20 hours at room temperature, the reaction mixture is mixed with 200 ml of 5 % aqueous KHSO.-solution and stirred vigorously for 15 minutes, The aqueous layer is extracted 3 times with ethyl acetate. The organic extracts are combined, washed once with brine, over Na 2 SO 4. dried and evaporated under reduced pressure. The residue is distilled twice azeotropically with 50 ml of toluene. The precipitated precipitate is suspended in toluene and filtered. The hydrate is evaporated and the process of azeotropic distillation and filtration is repeated. The resulting filtrate is evaporated under reduced pressure and then treated under high vacuum for 5 hours. The resulting viscous, clear oil is stirred under argon at room temperature in 50 ml of anhydrous pyridine. This solution is treated in an amount with 4.65 g (22.6 mmol) of dicyclohexylcarbodiimide (DCC) followed by 1.31 g (1.67 mL, 41.0 mmol) of methanol. After stirring for 20 hours at room temperature, the reaction mixture is filtered through kieselguhr in a sintered glass funnel.

The Gieselgur is washed with ethyl acetate and the combined filtrates evaporated under reduced pressure. The residue is redissolved in ethyl acetate and washed twice with 5 % aqueous KHSO.-solution and once with brine. The organic extract is over Na ₂ SO. filtered, the filtrate was evaporated and azeotroped twice with toluene, suspended in toluene.

-114-

diert and filtered. The resulting filtrate is re-evaporated, azeotroped, filtered and the filtrate evaporated under reduced pressure and left under high vacuum for 6 hours. It is the phosphonate monoester as kla-

5 res viscous oil (10.2 g,> 100 % yield). TLC: Kiesegel R- = 0.50 (7: 2: 1 nPrOH / NH.0H / H ₉ 0).

The phosphonate monoester (1.21 g is kept under high vacuum for 4 hours, giving a yield of 1.16 g (2.57 mmol)) is dissolved in 10 ml of anhydrous diethyl ether and added dropwise with 0.48 g (0.528 ml , 2.65 mmol) of dicyclohexylamine. The resulting homogeneous solution is kept at room temperature for 7 hours, forming a significant amount of crystals. The mixture is stored for 16 hours at 2O ⁰ C and then warmed to room temperature and filtered. The crystals are washed with cold, anhydrous diethyl ether and then kept for 18 hours over P ₂ ⁰ C in ^a high vacuum. -Anschließend the crystals are maintained for 4 hours at 45 ° C under high vacuum to 'give 1.25 g (1.98 mmol, 77% yield) of the dicyclohexylamine salt-title compound as a white powdery solid, melting at 155-156 ⁰ C.

TLC: silica gel R _f = 0.57 (20% MeOH / CH ₂ Cl ₂ ) ¹ H NMR: 25. (270 MH ₂ , CDCl ₃ )

δ 7.71-7.65 (m, 4H) 7; 40-7.32 (m, 6H) 4.02 (m, IH) 3.52. (s, 3H)

30, 3.28 and 3.22 (m, IH)

3.11 (d, 3H J = ½ Hz) 2.77-2.64 (m, 2H) 2; 62-2.56 (m, IH) 1.92-1. 08 (series of m, 22H) 35 1.00 (S, 9H)

Mass spectrum :-( FAB) 632 (M & H) ⁺

-115-

IR: (KBr) 3466-3457 (wide)

3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721,

2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426,

1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051, 820 CM-I

Analysis "for

ber .: gef. :

C 8th H 2 N 64 , 63 8th , 61 2 , 22 64 , 51 , 49 , 18

Example 26

(E) -4 - [[2- [4 ¹ -fluoro-3,3 ', 5-trimethyl-1-yl-1-biphenyl] -2-yl] -äthyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

A. [2- [4'-fluoro-S ₁ S ^1, 5-trimethyl- [1, 1 '-biphenyl] -2-yl] -2-hydroxyethyl] phosphonic acid, dimethyl ester

A solution of 1.8 ml cooled to -78 ° C. in C0 ₂ / acetone

(16.5 mmol, 1.6 eq.) Dimethyl methylphosphonate in 20 mL of anhydrous THF is treated dropwise over 20 minutes with 9.7 mL (15.5 mmol, 1.5 eq) of 1.6N n-butyllithium solution in hexanes and the resulting white suspension was stirred at -78 ° C. for 60 minutes under argon, then 2.5 g (10.3 mmol, 1 eq) of biphenyl-aldehyde from Part C in 10 ml of anhydrous THF were added dropwise over 15 minutes. After stirring at -78 ° C. for 30 minutes, the mixture is quenched by dropwise addition of 10 ml of saturated NaCl solution and the mixture is warmed to room temperature between ethyl acetate and H.sub.2 ₉ O, the organic phase washed with brine, dried over anhydrous Na_SO.sub.4 and evaporated under reduced pressure to give 4.127 g of yellow oil, which slowly crystallizes on standing.The crystals are digested with hexanes, which, after filtration and drying under ver -

-116-

reduced pressure 3.38 g (89.4 %) of pure hydroxyphosphonate title compound as white needles of F. 98 to 100 ⁰ C are obtained. An additional 233 mg (3.613 g total yield = 95.6 %) of pure title compound are obtained by flash chromatography of the mother liquor (603 mg) on silica gel LPS-1 (40: 1) and elution with hexane-acetone (7: 3).

R _f = O, 33, UV + ι PMA. PF: 62 C 6 H 5 F 8th P analysis for C. * 24 ° 4 About: 62 , 29 6 60 5 19 8th 45 gef. : , 66 , 56 , 03 , 68

B. [2- [4'-fluoro-3,3 ', 5-trimethyl- [1, 1'-biphenyl] -2-yl] -äthenyl ^ -phosphonic acid dimethyl ester

A solution of 3.513 g (0.6 mmol) of hydroxyphosphonate from Part A in 15 ml of anhydrous toluene (4 A sieve) is treated with .-- 91 mg (0.48 mmol, - 0.05 eq.) PTsOH: 1: H ₂ O treated and 16 hours. ·. the untr argon through a Soxhlet apparatus under reflux

heated, containing 4 A sieve. In the course of the reaction, additional pTsOH.H-0 is added at the following time intervals: 91 mg after 3.5 hours, 91 mg after 5 hours and 91 mg after 6.5 hours. The mixture is cooled, diluted with ethyl acetate and washed with saturated NaHCO 3, - solution, whereby an aqueous phase, an organic phase and an oil layer between the phases is obtained. The aqueous phase and the oil layer are collected and washed with ethyl acetate. The ethyl acetate layer is washed with saturated NaHCO 3 solution and set aside. The two bicarbonate washes are mixed with cone. HCl and extracted with ethyl acetate. The organic phase is washed with brine, over anhydrous Na_SO. dried and evaporated, whereby 520 mg of recovered phosphonic acid monomethyl ester are obtained. The diester is dissolved by dissolving the oil in 5 ml of trimethyl orthoformate and heating the mixture for 4 hours under argon

-117-

1 regenerated. Excess format is distilled off under reduced pressure to give a yellow oil, which is taken up in ethyl acetate and combined with the original neutral organic phase. The vinegar

5 acid ethyl ester layer is washed with brine, dried over anhydrous Wi.SO., and evaporated to give 3.396 g of yellow oil. The crude oil is purified by flash chromatography on silica gel LPS-1 (40: 1) and elution with hexane-acetone (75:25). The product 10 fractions are evaporated. Yield: 2.987 g (89.4 %) of trans-vinyl dimethylphosphonate title compound as a golden yellow oil. , TLC (1: 1) hex-acetone, R _r = 0.44, UV & PMA.

¹ H NMR (CDCl ₃ ):

δ 2.27 (3H, d, J _H _ _p = 1.6 Hz)

2.33 (3H, s)

2.39 (3H, s)

3.61 (6H, d, J _Hp = 11 Hz)

5.51 (IH, dd, J _{H, H} = 18 Hz, J _H _ _p = 20.6 Hz)

6.95-7.09 (5H, m)

7.48 (IH, dd, J _H _ _H = 17.9 Hz, J _H _ _p = 23.7 Hz)

ppm.

¹³ C NMR _(CDCl3):

δ 14.4, 20.9, 52.0 (J _{c p} = 5.7 Hz) 114.4, 114.7, 119.2 (J _{c p} = 185.5 Hz) 124.3, 124 , 5, 128.4, 128.5, 129.0, 130.6, 130.9, 132.6, 132.7, 134.6, 137.1, 141.0,

148.2, 148.2 (J _ _{c p} = 5.7 Hz), 160.5 (J _C _ _F = 244.1 Hz)

-110-

^c · C2- [4'-fluoro-3,3 ', 5-trimethyl-Ql, 1'-biphenyl] -2-yl] -äthenyl] -phosphonic acid monomethyleste ·;

A solution of 2.895 g (8.31 mmol) of vinyldimethylphosphonate from Part E in 20 ml of dioxane is treated with 12.5 ml (12.5 mmol, 1.5 Kq.) Of 1N LiOH solution and the resulting mixture is refluxed under argon for 70 minutes in an oil bath at 75 ⁰ C stirred. After 15 minutes of heating, the mixture becomes homogeneous. The mixture is cooled to room temperature, with about 15 ml of 1.0N HCl

Acidified pH 1, extracted 2 times with ethyl acetate, the organic phase washed with brine, over anhydrous Na ₂ SO ₄ . dried and evaporated under reduced pressure. Yield: 2.663 g (95.8 %) of the desired monoethyl ester title compound as a clear, colorless oil.

₁₅ TLC: (8: 1: 1) CH ₂ Cl ₂ -CH ₃ OH-HOAc, R ₄ = 0.57, UV & PMA.

Mass spectrum (M + H = 335 observed).

¹ H NMR (CDCl ₃ ):

₂₀ δ 2.25 (3H, d, J _H _ _F = 1.6 Hz)

2.33 (3H, s)

2.39 (3H, s)

3.53 (3H, c>, J _H _ _p = 11 Hz)

5.61 (IH, dd, J _H _ _H = 18 Hz, J _H _ _p = 20.6 Hz)

₂₅ 6.90-7.12 (5H, m)

7.38 (IH, dd, J _HH = 18 Hz, J _N _ _p = 24 Hz) ppm.

D. 4- [n2-Q4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -äthenyl] -tiethoxyphosphinyl] -3-oxobutyric acid methyl ester

420 μL (3.9 mmol, 1.3 eq.) Of distilled methyl acetoacetate is added dropwise within 15 minutes, with stirring, to a suspension of 168 mg (4.2 mmol, 1.4 equiv) of 60 % NaH dispersion in mineral oil, in Add 10 ml of anhydrous tetrahydrofuran under argon at 0 ^° C. in an ice bath. The obtained

-119-

clear solution is stirred for 15 minutes at ⁰ ° C and then treated within 10 minutes with 2.25 ml (3.6 mmol, 1.2 ^ q.) 1.6M n-butyllithium solution in hexanes. The yellow Dianionlöaung is stirred for 15 minutes at 0 ⁰ C, and then cooled to prepare for the treatment of Phosphonochloridat to -78 ° C.

A phosphonochloridate is prepared from the monomethyl ester of Part C "" of the following procedure. A solution of 960 mg (2.87 mmol) of monomethyl phthalate from Part C in 8 mL of anhydrous CH ₉ Cl ₉ is treated with 750 μΐ (5.98 mmol, 2 eq.) Of distilled trimethylsilyldiathylamine and the clear mixture under argon Stirred for 1 hour at room temperature. The mixture is evaporated under reduced pressure, azeotroped twice with 15 ml of benzene and the remaining viscous oil is kept in vacuo for 15 minutes. Das'Öl is then Λη .8 ml of dry CH ₉ Cl ₂ and one drop of - ·· added anhydrous DMF, cooled in an 'ice bath to 0 ⁰ C - (. 3.3 mmol, 1.1 eq) and dropwise μΐ 290 treated under Arbon within 5 minutes. After 15 minutes at 0 ^° C., the mixture is stirred at room temperature for 45 minutes and then evaporated under reduced pressure. The crude oil is azeotroped twice in 15 ml of benzene, and after evaporation and drying in vacuo for 15 minutes, the crude phos- phate is distilled off.

25 phonochioridate is obtained as a pale yellow oil.

The phosphonochloridate (about 2.9 mmol, 1 eq.) Is added dropwise in 8 μl of anhydrous THF at -78 ° C through a cannula within 30 minutes to a solution of the methylacetoacetate dianion cooled to -78 ° C. After 30 minutes at -78 ° C, the orange-brown reaction mixture is quenched by dropwise addition of 8 ml of saturated NH ₄ C ¹ solution and warmed to room temperature. The mixture is diluted with ethyl acetate, washed with saturated NaHCO, solution and brine, then v / asserfreiem Na ₉ SO, dried under reduced pressure: 1.481 g of u

-120-

1 orange oil evaporated. The crude oil is purified by flash chromatography on silica gel (Merck) and elution with hexane-acetone (9: 1) followed by hexane-acetone (1: 1). The product fractions are combined and evaporated.

5 Yield: 813 mg (62.9 %) of the desired vinyl phosphite diester title compound as a tough, pale yellow oil. TLC (1: 1) Hex-acetone, R _f = 0.42, UV & PMA.

¹ H NMR (CDCl ₃ ):

δ 2.28 (3H, s)

2.34 (3H, s)

2.40 (3H, s)

, 3.15 (2H, dd, J _H _ _H = 4.7 Hz, J = 18.2 Hz _Hp)

3.54 (3H, d, .J _H _ _p = .11.6 Hz)

3.63 (2H, s)

3.72 (3H, s)

, ; 5.57 (IH, dd, .J _H _ _H = 17.9 Hz, J _H _ _p 25.3 Hz)

:. - -6.95-7.09 (5H, m)

:: - '7.52 (IH, dd,, 7 ^ = 17.9 Hz, J _Hp = 22.7 Hz) ppm.

¹³ NMR _(CDCl3):

.14,0 _(C J _ _F = 3.9 Hz), 20.6, 45.3 (J _ _{c p} = 85j9 Hz), 49.6, 50.9 (J _ _{c p} = 5.8 Hz),

5.18, 113.6, 115.0, 121.4 (J _c _ _p = 128.9 Hz),

123.6, 124.7, 128, 187.7, 129.5, 130, 130, 130.8, 132.1, 132.4, 136.4, 136.8, 138.2, 140.7, 149, 2 _(c _ J _p = 4.9 Hz), 160.3 (J _C _ _F = 245.1 Hz),

166.7, 194.4 (J _ _{c p} = 4.9 Hz) ppm.

E. (E) -4 - [[2- [4 ^l -fluoro-3,3 ^l , 5-trimethyl- [i, 1'-biphenyl]

2-yl] -äthenyl] -methoxyphospinylj -3-hydroxybutyric acid methylester ³⁵

-121-

A solution of 585 mg (1.35 mmol) of Part D ketone in 4 ml of anhydrous THF cooled to ⁰ ° C. in an ice bath is treated with 51 mg (1.35 mmol, 1 ×q) of solid NaBH. treated and then added dropwise with 1 ml of dry CH ₂ OH (3 A sieve). The yellow mixture is stirred for 30 minutes at 0 ^° C. under argon. The mixture is quenched at 0 ^° C. by addition of 6.5 ml of acetone and then 500 mg of silica gel CC-4. The suspension is warmed to room temperature, filtered through sintered glass, rinsed with ethyl acetate and evaporated under reduced pressure to yield 607 mg of yellow oil. The crude oil is purified by flash chromatography on silica gel Merck (30: 1) and elution with pure ethyl acetate. The product fractions are evaporated. Yield: 340 mg (57.6 %) of the desired alcohol title compound as a pale yellow oil. TLC (pure EtOAc), R _f = 0.19, UV + PMA.

i - "moderate spectrum (M + K ^f = 435 observed)

¹ H NMR (CDCl ₃ ):

δ 1.90 (2H, m)

2.27 + 2, 28 (3H, 2 singlets)

2 _; 34 (3H, s)

2.39 + 2 _; 40 (3H, singlets)

2.56 (2R, d), Jb

3.52 MH, d, J _H _ _p = II, 1 Hz)

3.60 + 3.70 (3H, 2 singlets)

3.79 + 3.90 (IH, 2 doublets)

5.52 + 5.54 (IH, 2dd, J _H _ _H = 18 Hz, J _H _ _p = 2.48

Hz)

30.

6.95 - 7.02 (5H, m)

7.52 - 7.54 (IH - 2dd, J _n - _H = 18 Hz, J _H _. _P = 21.6

Hz) ppm

¹³ C IiKR (CDCl ₃ 1 (R, S mixture)

-122-

· Δ '14.3 (J _cF = 3.9 Hz)

20.8, 35.4 + 35.8 (J _ _{c p} = 100.6 Hz) 42.0 (J _ _{c p} = _12, 7Hz), 50.7 (J _c _p = 6.8 Hz) 56 , 5, 63,2 (J _c _ _p ^ 3 _y 9 Hz)

113.8, 115.3, 122.9 + 123.2 (J _c _ _p = 122, 1 Hz) 123.8, 128.2, 128.7, 129.0, 130.4, 131.4, 132.3, 132.7, 136.6, 137.0, 138.2, 140.8, 148.2 + 148.8 _(c _ J _p = 4.9 Hz), 160.5 (J = 245 _cF , 1 Hz)

171.8 ppm.

F. (Ε) -4 ·. [[2- [4'-Ρ1υοΓ-3,3 ', 5-trimethyl- [1,1'-biphenyl] -

2-yl] -äthenyl] -hydroxyphosphinylj-3-hydroxybutyric acid-15 dilithium salt

A solution of 339 mg - (0.781 mmol) diester of part E in -. .1.8 ml of dioxane is treated with excess 2.3 ml (2.3 mmol, 3 eq.) Of 1.0N LiOH and the mixture is stirred for 1.5 h, under argon

20 heated to 50 ⁰ C in an oil bath. After 15 minutes, a white precipitate appears. While still warm, the mixture is diluted with H 2 O until all solids are dissolved and then filtered. The filtrate is evaporated under reduced pressure, taken up in the minimum amount of H ₂ O and at

Chromatograph HP-20 resin and elute with a linear gradient of pure H ₂ → pure CH ₂ O. The product fractions are evaporated, the white residue taken up in 50 ml H ₂ O, filtered and lyophilized. Yield; 270 mg (82.7 %) of the desired dilithium salt title compound as

hygroscopic, white lyophilate.

TLC (8: 1: 1) CH ₂ Cl ₂ -CH ₃ OH-HOAc, R _f = 0.33, UV + PMA.

Analysis for ^C 21 ^H 22 ° 5 ^FP " ^{2Li +}

0.63 mol H ₂ O (MW 429.57): CHFP

reported: 58,71 5.46 4.42 7.21

F: 58.71 5.70 4.18 6.96

-1 23-

¹ H NMR (CDCl ₃ )

δ 1.59 (2H, multiplet't)

2.24-2.37 (2H, 3ultiplets, J _HH = 8> 5 Hz +

4.4HZ)

⁵ 2.28 (3H, doublet, J _RF = 1.8 Hz)

2.30 + 2:39 (6H, 2 singlets) 4.14 (IH, multiplet), 5.78 (IH, J _H _ _H = 17.9 Hz, J = 20.5 Hz _Hp)

6.88-7.21 (6H, multiplet) 10

Example 27

4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl]] -3-hydroxybutyric acid dilithium salt

A. Methyl 4- [[2- [4'-fluoro-3,3'-trimethyl- [1, i'-biphenyl] -2-yl] -ethyl-methpxyphosphinyl) -J-3-hydroxybutyric acid "'

An argon-purged solution of 297 mg of trans-vinylphosphinate from Example 6, Part E, in 6 ml of 3H-OH is treated with 74 mg (25% by weight of 6) 10 % Pd / c and the black suspension is analyzed on a Parr Apparatus shaken for 3 hours under hydrogen at a pressure of about 2.8 bar. The catalyst is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to an oil. The oil crystallizes from hexanes to give, after filtration and drying under reduced pressure, 227 mg (89.5 %) of the saturated phosphinate title compound as a white crystalline solid.

30 TLC (EtOAc) ₁ R _f = 0.20,. UV + PMA.

¹ H NMR (CDCl ₃ , 270 MHz), IF (KBr pellet) mass spectrum (M + H ⁺ - 437 ⁺ observed).

28 ί 60 5

-1 24-

¹ H NMR (CDCl ₃ ):

δ 1.55-1.87 (4Η, πι)

2.29 + 2.30 + 2.31 (6Η, 3 singlets)

2.35 (3Η, d, J _H _ _F = 2.1 Hz)

2.52 (2.H, m)

2.78 (2H, ra)

3.50 + 3.55 (3H, 2 doublets J _H _ _p = 4.3 Hz)

3.71 (3H, s)

3.86 + 3.91 (IH, 2 singlets)

4.25 + 4.39 (IH, 2-wide multiplets) ppm,

10

B. 4 - [[2- [4'-fluoro-S ₁ B ¹ , 5-trimethyl- [i, 1'-biphenyl] -2-yl] -ethyl-] -hydroxyphosphinyl-3-hydroxybutyric acid dilithium salt

A solution of 250 mg (0.573 mmol) of Part A diester in .6 ml of dioxan is added. T,: 72: mi: C3 eq .->. 1.0N LiOH in excess': 1 and the mixture heated for 5 hours under argon in an oil bath at 5O ⁰ C. After 15 minutes, a white precipitate appears. The mixture is diluted while still warm with H ₉ O until all solids are dissolved and then filtered. The filtrate is evaporated under reduced pressure and the white residue dissolved in the least amount of H ₂ O and chromatographed on resin HP-20 and eluted with pure H ₉ O (until neutral) and then with pure CH 2 OH. The product fractions are evaporated under reduced pressure to a white solid which is azeotroped twice with CH 2 CN and then dried under reduced pressure. Yield; 131 mg (55 %) of the desired dilithium salt title compound as a white solid

TLC (8: 1: 1) CH ₂ Cl ₂ -CH ₃ OH acetic acid, R _f = 0.34, UV ₊ PMA.

35

28

-125-

1 analysis for ^C 21 ^H 24 ° 5 ^FPLi 2 ⁺

0.95 mol H ₂ O (MW 437.30): _{c H pp}

Calculated: 57.67 5.97 4.34 7.08

F .: 57.67 5.90 3.92 7.39 5

¹ H NMR (CD ₃ OD + D ₂ O):

δ 1.39-1.57 (4H, multiplet) -. ppm

2.22-2.37 (2H, multiplet).

2.26 + 2.38 (6H, 2 singlets) ¹⁰ 2 _; 31 (3H, doublet, J _HF = 1.8 Hz)

2.71-2.77 (2H, multiplet)

4,13-4,20 (IH, multiplet) '

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

Example 28

.:: / (E) -4 - [- [2- [3- (4-fluorophenyl) -1 - (. 1r-m "ethylethyl) -1H-indol-2-yl] -äthenyl3-hydroxyphosphinyl [ ] ~ 3-hydroxybutyric acid dilithium salt

A. [2- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] 2-hydroxyethyl] -phosphonic acid dimethyl ester

A solution of 1.35 ml (12.42 mmol, 1.6 eq) of methyl dimethylphosphonate in 20 ml of anhydrous THF, cooled to -78 ° C. in acetone / CO 2, is added dropwise over a period of 15 minutes to 7.3 ml (11, 11). 6 mmol, 1.5 Aq.) Treated 1.6M n-BuLi solution in hexanes and the resulting white suspension for 1 hour under argon at -78 ° C stirred. 2.183 g (7.76 mmol) of indole-aldehyde from example 7, part E, in 8 ml of anhydrous THF at -78 ° C. is added dropwise within 10 minutes to the anion and the light orange suspension obtained is left for 30 minutes at - 78 ⁹ C stirred. The mixture is quenched by the dropwise addition of 10 ml of saturated NH.Cl solution, warmed to room temperature, partitioned between H 2 O and ethyl acetate, and the organic phase is washed with saline.

N 4 F 7, P 3 , 46 4 , 69 7, 64 3 30 , 61 32

28 ί 60 5

-126-

1, dried over anhydrous Na ₂ SO ₄ and evaporated to give 3.19 g of white solid. The crude solid is digested with warm hexane. Yield: 2.967 g (94.3 %) of pure hydroxyphosphonate title compound as

white solid from mp 161 to 162 ° C.

TLC (1: 1) hex-acetone, R _f = 0.29, UV + PMA. ' Analysis for. C ₂₁ H ₃₅ O ₄ NPF: CH

Calculated: 62.21 6.22 found: 62.34 6.32 1

¹ H NMR (CDCl ₃ ):

δ 1.69 + 1.74 (6H, 2 doublets)

2.18 + 2.56 (2H, 2 multiplets) 3.61 (IH)

3.67 + 3.71 (6H, 2 doublets, _JH _ _p = ll Hz)

5.32 (IH, m) 5.50 (IH, m)

π 7.04-7 ^ 25 (4H, m) ·. * ·: ·:, :: 7.33-7.39 (2H quartet Γ 7.52 (2H, AB quartet) ppm.

¹³ C NMR _(CDCl3):

δ 21.1, 21.3, 33.1 (J _{c p} = 136.3 Hz) 48.3, 52.6 + 5.2.7 (J _{c p} = 5.7 Hz) 62.1 (J. _c _ _p = _3; 8 HZ)

112.5, 114.3, 115.1, 115.4, 119.5, 120,

122, 128.1, 130.6, 131.9, 132.0, 134.8, 134.9, 135.2, 161.8 (J _C _ _F = 246.1 Hz) ppm.

B. (trans) - [2- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-30-indol-2-yl3-ethenyl] -phosphonic acid dimethyl ester

2.60 g (6.43 mmol) of hydroxyphosphonate from Part A are dissolved in 20 ml of warm benzene and treated with 122 mg (0.1 eq) of pTsOH .H ₉ O and the mixture is stirred for 1 hour under argon 35 through a Soxhlet. Apparatus containing 4 A sieve, heated to reflux. The yellow solution is filtered, washed with acetic acid.

H 3, N 4 F 7, P 5, 98 3, 62 5 90 7, 99 6 03 48 J1 98

-127-

1 acid ethyl ester, the organic phase washed twice with saturated NaHCO ₃ solution and brine, then dried over anhydrous Na ₃ SO ₄ and evaporated to give 2.47 g of crude olefin as a yellow solid. Recrystallization from ethyl acetate-hexanes gives 2.238 g (89.9 %) of pure trans-vinylphosphonate title compound in the form of pale yellow leaves of mp 153 to 155 ^° C.

TLC (1: 1) hex acetone, R _f = 0.33, UV + PMA 10 mass spectrum (M + H + 388 observed)

Analysis for C ₂₁ H ₂₃ O ₃ PNF: C

Calculated: 65.11 Found: 65.27 15

¹ H NMR (CDCl ₃ ):

, .. .. .. .., - .. 1.67 (6H, doublet)!. "." ... J ... .. I3,68 (6H, d, J _H _ _p = ll, 6 1 τ): ..>. '· ....': -. :,: · 4,90 (IH, Septet)

2NC "" 5.73 (IH, dd, J _H _ _H (trans) = 18 Hz, J _H _ _p = 18.2 Hz) 7.05 to 7.56 (8H, m)

7.64 (IH, dd, J _H _ _H = 17.9 Hz, J _H _ _p = 23.7 Hz) ppm.

25 ¹³ C NMR (CDCl ₃ ):

6 21.7, 47.8, 52.2 (J _c _ _p = 5.7 Hz)

111.8, 115.4, 115.7, 118.5 (J _ _{c p} = 43.5 H) 120.1, 120.2, 123.4, 128.2, 130.5, 130.7, 131.1, 131.7, 135.9, 137.9 (J _ _{c p} = 7.6 Hz)

30 161.9 (J _C _ _F = 246 Hz) ppm.

C. (Trans) - [2- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -äthenyl] -phosphonic acid monomethyl ester

35.7787 g (4.61 mmol) of vinyldimethylphosphonate from Part B are dissolved in 12 ml of warm dioxane, with 6.9 ml (6.9 mmol,

28

-128-

1.5 Aq.) 1, ON LiOH and heated to 75 ⁰ C under argon in an oil bath for 30 minutes. The mixture is cooled, acidified with 8 ml of 1.0 N HCl, extracted twice with ethyl acetate, washed twice with H 2 O and brine, dried over anhydrous Na ₃ SO ₄ and evaporated to give 1.859 g of yellow oil. The oil is dissolved in warm hexane, cooled and crystallized. Yield: 1.657 g (96.1 %) of monoacid as a pale yellow solid, mp 181-183 ° C.

Analysis for C _0n H ₀₁ O

• C 02 5 H 3 N 5 F 8th P About: 64 02 5 70 3 , 73 5 , 06 7 25 gef. : 64 , 87 , 64 , 26 90

TLC (20: 1: 1) CH 2 Cl 2 CH 2 OH acetic acid, R _f = 0.26, UV + PMA

¹ H NMR _(CDCl3); 6 1.66 (6H, doublet) 3.64 (3H, doublet 4.89 (1H, septet)

5.81 (1H, dd, J _H _ _H 7.06 to 7.64 (9H, multiplet) ppm.

3.64 (3H, doublet, J _un = 11.6 Hz)

ti c

5.81 (1H, dd, J _H _ _H = 17.9 Hz, J _H _ _p = 18.5 Hz)

¹³ C NMR _(CDCl3): δ 21.8, 47.9, 52.1 (J _ _{c p} = 5.7 Hz)

112.0, 115.5, 115.8, 116.1 / 119.0 (J _ _{c p} = 9.5

Hz)

120.2, 120.4, 123.5, 128.3, 130.4, 130.8, 131.2, 131.8, 131.9, 136.2, 136.8 < ^J CP = ⁷ > ⁶ **>

161.9 (J _cF = 246 Hz) ppm.

D. 4- [2- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-ylQ-ethenyl] -methoxyphosphinyl] -3-oxobutyric acid, methyl ester

2 8 UO

-129-

A phosphonochloridate is prepared by the following procedure. A solution of 1.564 g (4.19 mmol, 1 eq.) Of Part C phosphonic acid in 10 mL of anhydrous CH ₂ Cl is treated with 1.05 mL (8.38 mmol, 2 eq.) Of distilled diethylaminotrimethylsilane and the mixture is stirred for 1 h Room temperature stirred under argon. The mixture is then evaporated under reduced pressure, taken up in 20 ml of benzene, evaporated under reduced pressure and the viscous oil left in vacuo for 15 minutes. A solution of the crude silylated acid in 10 ml of anhydrous CH ₂ Cl ₂ and 1 drop of anhydrous DMF is cooled to 0 ⁰ C, treated dropwise with 400 ml (4.61 mmol, 1.1 eq.) Of distilled (COCl) for ₂ and 15 Stirred for minutes at 0 ⁰ C and then at room temperature for 45 minutes under argon. The yellow mixture is evaporated under reduced pressure, taken up in 20 ml of benzene, evaporated under reduced pressure and stirred for 15 minutes under reduced pressure.

, , ·. leaving the crude phosphonochloridate as a tough yellow ...:.:. Oil .. received -will. A solution of the phosphonochloridate in 8 ml of anhydrous THF is transferred dropwise at> 78.degree. C. through a cannula within 20 minutes into a solution of the methylacetoacetate dianion cooled to -78.degree. C., which according to Example 26 consists of 590 .mu.M (FIG. 45 mmol, 1.3 eq.) Methyl acetoacetate, 235 mg (5.87 mmol, 1.4 eq.) 60 % NaH oil dispersion, 3.1 mL (5.03 mmol, 1.2 eq.) 1.6M n-Butyllithium and 10 ml of THF was prepared. The orange-colored reaction mixture is stirred for 30 minutes at -78 ° C and then quenched by dropwise addition of saturated NH 4 Cl solution and warmed to room temperature. The mixture is partitioned between ethyl acetate and H ₂ O, the organic phase washed with saturated NaHCO 3 solution and brine and then dried over anhydrous Na ₂ SO 4. dried and evaporated to give 2.080 g of yellow oil. The crude oil is purified by flash chromatography on silica gel (Merck) and elution with CH 2 Cl-EtOAc (7: 3). The product fractions are combined and evaporated. Yield: 5 mg J ι '(26.3%) of the desired trans-phosphinate title compound as a light-

-1J0-

ge. \ bes oil.

TLC (1: 1) hex acetone, R _f = 0.48, UV + PMA. Mass spectrum (M + H ⁺ = 472 ⁺ observed)

¹ H NMR (CDCl ₃ ):

δ 1; 66 + 1.71 (6H, 2 doublets) 1.68 (2H, m) 3.23 (2H doublet) 3.54 (3H, d) 3.72 (3H, s)

4.90 (IH, Septett) 5.76 (IH, dd, J " _u = 18 Hz) 7 _T 10-7.58 (8H, m) 7 (66 (IH, dd, J _H _ _H = 18 Hz ) ppm ¹³ C NMR (CDCl ₃ ):

δ 21.8, 45.7 (J _c _p = 87, l Hz).

47 _f 9, 50.0, 51.5 (J _c _ _p = 5.7 Hz)

".Ζ - 52.3, 111.9, 115.5, 118.8 (J _ _{c p} = 104, l Hz)." -. "'119.8,-120.2,' 12OjS. , 123.6, 128.2, 130.4,. ^: .:. ^: Ϊ́130.8, -31.3, 131.9, 136.1, 139.2

(J _{0 -P} = S ₁ O HZ) 161.9 (J _cF = 246 Hz) 167.0, 194 ₇ 6 (J _c _ _p =. "3.8 Hz) ppm.

Ethyl (E) -4 - [[2- [3- (4-fluorophenyl) -1- (1-methylethyl) -iH-indol-2-yl-3-yl-phenyl] -methoxyphosphinyl]] -3-hydroxybutyrate

A solution of 519 mg cooled to -15 ° C in a salt / ice bath

30 (1.1 mmol) of Part D D in 8 mL of anhydrous EtoH (3 A sieve) is combined with 42 mg (1.1 mmol) of solid NaBH. and the yellow mixture is stirred under argon at -15 ° C for 20 minutes, the mixture is quenched by additions of 0.5 ml of acetone and then 500 mg of silica gel CC-4. The mixture

35 is warmed to room temperature, filtered, rinsed with Ess: "gsäureäthylester and evaporated under reduced pressure,

-131-

1 wherein 512 mg of yellow foam are obtained. The crude foam is purified by flash chromatography on silica gel (Merck) and elution with acetic acid ethylester-acetone (4: 1) and then pure acetone. The product fractions will be

5 evaporated. Yield: 317 mg (60.9 %) of the desired alcohol title compound as a yellow oil

TLC (4: 1) EtOAc acetone, R _f = 0.21, UV + PMA. Mass spectrum (M + H ⁺ = 4.74 observed)

¹ H NMR (CDCl ₃ ): δ 1.68 (6H, doublet)

1.97 (2H, m)

2.58 (2H, d) 3.61 (3H, d, _JH _p = ll Hz) 3.68 (3H, s)

3.95 + 4.04 (IH, 2 doublets)

4,40 (IH, bm)

.1Γ 4,95 (lH, Sepfett)

----- .. - 1 - 5.78 (IH, dd, J _Ha = 17, 4 Hz, J _H _ _p = 23, 2 Fs) ..-:. : .- .. ι - ;: -. ", η 05-7 -77 (9H, m) ppm. iq ii

^{± J} C NMR (CDCl ₃ ):

δ 21.7, 34 9 + 36.3 (J _c _ _p = 20, 9 Hz) 42.0 (J _cp = 13.2 Hz) 47.9, 50.8 (J _cp = _5.6 Hz) 51.6, 63.1 (J _ _{c p} = 15, 1 Hz)

111.8, 115.4, 115.7, 118.6, 119.9 + 121.8

(J _ _{c p} = 18, 9 Hz) 120.1, 123.4, 128.2, 130.6, 130, -7, 131.1, 131.7, 131.9, 135.8, 138, 0 + 138.5 (J _c _ _p = 5.7 Hz)

161.8 (J _{r F} = 246, 1 Hz)

^c

171, 7, 171.8 ppm. ·

F. (E) -4- [Q2- [3- (4-fluorophenyl H- (1-methylethyl) -1H-indole]

2-yl] -äthenyl] -hydroxyphosphinylj -3-hydroxybutyric acid-35 dilithium salt

-1 32-

A solution of 264 mg (0.558 mmol) Hydroxydiester of Part E in 6 ml of dioxane with 1.95 ml (3.5 eq.) 1, ON LiOH and heated for 20 minutes under argon in an oil bath at 70 ⁰ C. The mixture is cooled, diluted with H ₂ O, filtered, evaporated under reduced pressure, taken up in a small amount of H ₂ O (1 to 2 ml) and chromatographed on HP-20 and washed with H ₉ O (until neutral, 3-4 Column volumes) and then eluted with CH ₃ OH-H ₂ O (75:25). The product fractions are evaporated, taken up in 50 ml H ₂ O, filtered and lycphilized. Yield: 217 mg (85.1 %) of the desired dilithium salt title compound as a white lyophilate

TLC (8: 1: 1) CH ₂ Cl ₂ ~CH ₃ OH acetic acid, R _f = 0.08, UV + PMA.

Analysis for C ₂₃ H ₂₃ O ₅ NPF · 2 Li +

1.62 moles of H ₂ O (MW 486.46): CH

Calculated: 56.78 5.44

Γ. :. - Found: '.'-'-. 56 ^ 76 5.64

¹ H-NMR ^ OOMHz, _CDCl3): δ 1.67 (6H, doublet)

1.73 (2H, multiplet)

2.38 (2H, doublet of AB quartet, J ^ = IS Hz, J ^ e Hz, J _BX = 4.8 Hz) 4.24 (IH, multiplet)

5.06 (IH, Septet)

6.09 (IH, ^ = 17.6 Hz, 1 ^ = 1 ^, 4 Hz) 7.02-7.61 (9H, multiplet)

Example 29 (S) -4 - [[2-Q- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl-Q-ethyl] -hydroxyphosphinyl-J-S-hydroxybutyric acid dilithium s al ζ

A. 4-Methyl-2-oxopentanoic acid ethyl ester

N 3 F P . ' 2 , 88 '3 91 6 77, 2 , 58 60 6

-133-

25 g of sodium salt of 4-methyl-2-oxopentanoic acid are dissolved in the lowest possible amount of HpO, acidified to pH 1 with concentrated HCl and then extracted several times with CH 2 Cl 2. The aqueous phase is saturated with NaCl and back extracted twice with CH ₂ Cl ₂ . The combined organic phases are washed with brine, over anhydrous Na ₂ SO ₄ . dried and evaporated to give 17.7 g of free acid as a viscous oil.

A mixture of 17.7 g (136 mmol) of the acid in 200 mL of anhydrous benzene is treated with 20.4 mL (136.2 mmol, 1 eq.) Of diazabicycloundecane (DBU) to give an exothermic reaction and a gel-like crystalline salt arises. The mixture is treated with 10.9 ml (1 eq.) Of ethyl iodide and mechanically stirred under argon for 3 hours. The precipitated salts are filtered off, the filtrate once with a. - Washed a small amount of 50 ml H_0 and saline

- · - ·· and then dried over anhydrous Na ₂ SO ₄ . The benzene. is distilled off at atmospheric pressure and the yellow liquid residue is distilled under reduced pressure. Yield: 6.46 g (35.1 %) of the desired ester title compound as a clear pale yellow liquid of bp 65 to 66 ^° C. (5 mm Hg),

TLC (9: 1), hexane-acetone, R _f = 0.55, PMA (pale blue) 25 mass spectrum (M + H ⁺ = 159 ⁺ , observed).

B. 4-methyl-2- (2-pnenylhydrazono) pentanoic acid ethyl ester

A solution of 5 g (31.6 mmol) of ethyl ester of Part A in 30 ml of anhydrous CH ₂ Cl ₃ is mixed with 3.3 ml (33.2 mmol, 1.05

Eq.) Phenylhydrazine treated dropwise within 5 minutes and the resulting yellow mixture under argon 3 hours.

stirred at room temperature over 4 A sieve. The mixture is dried over anhydrous Na ₂ SO. dried, filtered and evaporated under reduced pressure to give 8.105 g of orange oil. The oil is purified by flash chromatography

-1 34-

on silica gel LPS-1 and elution with hexane-ethyl acetate. The product fractions are evaporated. Yield: 6.8 g (86.7 %) of the pure hydrazone title compound and 848 mg (10.8 %) of the geometric isomer of the hydrazone title compound.

5 bond. Overall yield; 9 7.5 %.

TLC (9: 1) hexane-acetone, R geometric isomers = 0.42 + 0.64, UV + PMA.

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

10 C. 3- (1-Methylethyl) -1H-indole-2-carboxylic acid ethyl ester

Gaseous HCl is bubbled through a gas dispersion tube for 30 minutes at room temperature into a solution of 6.8 g (27.4 mmol)

Drazon from Part B in 50 ml of anhydrous ethanol (over 3 A sieve) initiated. The exothermic reaction is indicated by color changes from yellow to red to deep green and subsequent precipitation of NH.Cl. The suspension is stirred for a further '20 minutes' with drierite and then ice-cold in 50 ml. , , _; H_O passed. The. Ethanol is distilled off under reduced pressure and the residue is partitioned between ethyl acetate and H 2 O. The aqueous layer is extracted twice with ethyl acetate, the combined organic phases are washed with H _? O and brine, then anhydrous MgSO4. dried and evaporated to give 4.969 g of green solid. The crude solid is dissolved in hot hexane, treated with Darco, filtered through diatomaceous earth, concentrated to a volume of 30 to 50 ml, and the yellow solution allowed to crystallize. The precipitated crystals are filtered off, rinsed with cold hexane and dried. Yield: 4.34 g (68.5 %) pure indole title compound in the form of white nadine, mp 80-81 "C, with the correct H NMR spectrum (CDCl ₃ , 270 MHz) TLC (9: 1) Hexane-acetone, R _f = 0.42, UV + PMA.

Note: The R _f value of hydrazone and indole are identical, but the indole has a brilliant violet fluorescence. (Mass spectrum: M + H ⁺ = 232 ⁺ , observed.)

-135- 7 H 6 N C 7 , 41 6 , 06 72.70 , 57 00 72.67

1 analysis for C ₁₄ H ₁₇ NO ₂ :

ber .: F .:

D. 1- (4-Fluorophenyl-3- (1-methylethyl) -iH-indole-2-carboxylic acid ethyl ester

A solution of 3.937 g (17 mmol) of indole from part C and 9.34 ml (85 mmol, 5 eq.) Of 1-bromo-4-fluorobenzene in 15 ml of anhydrous DMF is treated with 245 mg (1.7 mmol, 0). 1 eq.) Of copper (I) oxide and heated under argon for 17 hours under reflux. Then, 9.34 ml (5 Xq.) Of additional bromide and 245 mg (0.1 equiv.) Of Cu ₇ O are added, the mixture refluxed for a further 6 hours, and then a further 730 mg (5.1 mmol) of ^Cu 2 ° added and the refluxing continued for a further 60 hours. Thereafter, DMF and excess bromide are distilled off under reduced pressure and the orange-colored oil obtained as the residue is taken up in ethyl acetate, filtered through diatomaceous earth, washed with saturated NaHCO 3 solution and brine, and then dried over anhydrous Na 2 SO 4 and evaporated Yield: 5.385 g (97.2 %) of the desired crude indole title compound as an orange oil

TLC (9: 1) hexane-acetone, R _f = 0.29, UV + PMA.

E. 1- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indole-2-methanol

24 ml in an ice bath to 0 ⁰ C chilled anhydrous diethyl ether is solid under argon with 9.7 mg (23.9 mmol, 1.5 eq.) LiAlH. and then added dropwise within 10 minutes with 5.185 g (15.9 mmol) IndolesLer of Part D in 10 ml of anhydrous Et ₂ C added. The mixture is stirred for 1 hour at 0 ⁰ C and then by successive dropwise addition of 910 μΐ H ₃ O, 910 μΐ 15 % NaOH and 2.373 ml of H _?. O quenched. The suspension is washed by anhydrous MgSO 4. filtered through kieselguhr and the filtrate

-136-

evaporated colorless oil. The oil gradually crystallizes from hexane to yield two batches of 3.771 g and 0.333 g. Yield: 4.10 g (90.9 %) pure indole alcohol title compound in the form of white, granular crystals

5 from F. 81 to 82 ° C.

Mass spectrum (M + H ⁺ = 284 ⁺ , observed).

Analysis for C ₁₀ H ₁₀ NOF: CHNF

la Io

Calculated: 76.30 6.40 4.94 6.71 10 F .: 76.59 6.31 4.93 6.49

F. 1 - (4-Fluorophenyl) -3- (1-methylethyl) -1H-indole-2-carboxaldehyde

A solution of 6.46 g (15.24 mmol) of Dess-Martin-Perjodinan in 30 ml of anhydrous CH-Cl. with 1.44 ml (.. 15.24 mmol, .aq 1) is treated anhydrous tert-butanol and the mixture - was stirred ^U ^ -M 5 minutes at room temperature under argon -. A solution of 3.539 g (.12.7 mmol) of indole alcohol from part E in 13 ml of anhydrous CHCl 2 is added dropwise over 10 minutes and the pale yellow mixture is stirred at room temperature for 30 minutes under argon. The reaction mixture is added to the solution of 14.06 g (89 mmol, 7 eq.) Of sodium thiosulfate in 40 ml of freshly prepared 1N NaHCO 3 solution and stirred for 10 minutes. The aqueous phase is stripped off and the organic phase is washed twice with 1.0N NaHCO 4 solution, H ₂ O and brine, then over anhydrous Na 2 SO 4. dried and evaporated to give 3.877 g of yellow oil. The crude oil is purified by flash chromatography on silica gel LPS-1 and elution with hexane-ether (40: 1). The product fractions are evaporated to give 3.118 g (87.3 % crude yield) of crude product. Recrystallization from hot hexane gives 2.643 g (74 %) of pure title aldehyde compound in the form of fluffy needles, mp 114-116 ° C.

35 mass spectrum: (M + H ⁺ = 282 ⁺ observed). TLC (7: 3) HeX-Et ₂ O, R = 0.51, UV + PMA.

-1 37-

Analysis for C ₁₈ N ₁

76 C 5, H 4, N 6 F calc .: 76 85 5, 73 4, 98 6 75 gef. : , 87 63 89 , 88

G. 2- (2,2-Dibromoethyl) -1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indole

A solution cooled in the salt / ice bath to -15 ⁰ C of 1.615 g (5.74 mmol) of aldehyde of Part F and 4.52 g (17.22 mmol, 3eq.) Triphenylphosphine in 25 ml of anhydrous CH ₂ Cl ₂ Lrd was treated dropwise in 10 minutes with 2.86 g (8.61 mmol, 1.5 eq.) Of CBr ₄ solution in 10 ml of anhydrous CH ₂ Cl ₂ and the resulting dark orange-red solution stirred for 15 min. Stirred 15 ° C under argon. The mixture is then quenched at -15 ⁰ C by the addition of saturated NaHCO ₃ ~ solution with CH ₃ Cl _2, washed the organic phase with saturated NaHCCs solution and brine, "over-anhydrous Na_SO. Ge -._ ^ Dry and evaporate-t, obtaining 8.9 g of red solid The crude solid is chromatographed on flash silica gel LPS-1 and eluted with hexane-ether (100: 1) The product fractions are evaporated Yield: 2.017 g (80.6 %) of pure vinyl dibromide title compound in the form of pale yellow crystals of melting point 123-124 ° C. TLC (9: 1) hexane-ether, R _f = 0.67, UV + PMA.

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

Analysis for C ₁₉ H ₁₆ NFBr ₂ : CHNF Br

Calc .: 52.20 3.69 3.20 4.35 36.56 F .: 52.25 3.69 3.18 4.24 36.59

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

One in CO ₂ / acetone. Cooled to -78 ° C solution of 10 ml of anhydrous THF is treated with 5.5 ml (8.8 mmol, 2.2 eq.) of 1.6M n-butyllithium solution in hexane and then dropwise within 15 minutes under argon with a

-138-

Solution of 1.749 g (4 mmol) of vinyl dibromide from Part G in 10 ml of anhydrous THF. The yellow mixture is stirred for 20 minutes at -78 ° C and then quenched by the addition of 10 ml of saturated Na, Cl solution. After warming to room temperature, the mixture is diluted with ethyl acetate, the organic phase washed with saturated NH, Cl solution and brine, over anhydrous Na 2 SO 4. dried and evaporated to give 1.216 g of dark green-brown oil. The crude oil is purified by flash chromatography on silica gel (Merck) and elution with hexane-ether (300: 1). The product fractions are evaporated. Yield: 1.084 g (97.5 %) of indoleacetylene title compound as a fluorescent green oil. ¹ H NMR (CDCl ₃ , 270, MHZ) shows a mixture (18: 1) of the desired acetylene to unwanted terminal olefin. TLC (50: 1) HeX-Et ₂ O, R _f = 0.55, UV + PMA.

-. - ·. J ^.: .- (S) T4-CC2-D- (4-fluorophenyl) -1- (1-methylethyl) -1H-

- indol-2-yl-3-ethynyl] r -methoxy-phosphinyi] -3- [1, 1-dimethyl-dimethyl-diphenylsilyl] -oxy] -butyric acid methyl ester

The phosphonic acid monomethyl ester dicyclohexamine salt of Example 25 is converted into a phosphono by the following procedure.

25 chloridate produced. The free acid is from 4.32 g

(6.83 mmol, 1.75 eq.) Of the dicyclohexylamine salt. For this purpose, this is partitioned between 1.0N HCl and ethyl acetate, the organic phase washed twice with 1.0N HCl and brine, over anhydrous Na "SO.

dried and evaporated under reduced pressure. There are obtained 6.8 mmol of free acid as a clear, viscous oil. 6.8 mmol of phosphonic acid monomethyl ester in 10 ml of anhydrous CH ₂ Cl ₂ are treated with 1.72 ml (13.7 mmol, 2 eq.) Of distilled trimethylsilyldiäthylamin and the clear solution for 1 hour at room temperature under argon. The mixture is concentrated under reduced pressure, washed twice with

-139-

1 20 ml of anhydrous benzene expelled and 15 minutes in

Leave vacuum. The crude silylated acid in 10 ml CH-Cl- and 1 drop of anhydrous DMF is cooled in an ice bath to 0 ⁰ C and treated dropwise over 5 minutes with distilled 655 μΐ (7.5 it-moles, 1.1 eq.) (COCl ) ₂ treated. The yellow mixture is stirred at ⁰ ° C. for 15 minutes and at room temperature under argon for 45 minutes. The mixture is evaporated under reduced pressure, expelled twice with 20 ml of benzene and left under vacuum for 15 minutes. The crude phosphonochloridate is obtained as a yellow, viscous oil.

A solution of 1.084 g (3.90 mmol, 1 eq.) Of Partial H in 10 ml of anhydrous THF cooled in C0 ₂ / acetone to -78 ° C is added dropwise over 10 minutes with 2.44 ml (3, 9 mmol, 1 eq.) Of 1.6 M n-butyllithium solution in hexanes and the purple suspension stirred for 30 minutes at -78 ° C under argon. The anion is added dropwise via ^cannula% within 30 minutes at -78 ⁰ C to a

'-' - 'cooled to -78 ° C solution of phosphonochloridate in 10 ml of anhydrous THF. The dark brown mixture is stirred for 30 minutes at -78 ° C and then quenched by the dropwise addition of 10 ml of saturated NH.Cl solution. The mixture is warmed to Temper temperature, partitioned between ethyl acetate and saturated NH.Cl solution, washed with brine, over anhydrous Na_SO4. dried and evaporated. Yield: 1.968 g (71.1 %) of acetylenic phosphinate title compound as a light yellow oil. TLC (7: 3) hexane-acetin. R _f = 0.25, UV + PMA. Mass spectrum: (M + H = 710, observed).

K. (S) -3 - [[U, 1-Dimethylethyl) -diphenylsilyf] oxy] -4 - [[2

Methyl [1-fluoro-phenyl) -3- (1-methylethyl) -1H-indol-2-yl] ethyl] -methoxyphosphinyl-butyric acid

An argon-purged solution of 950 mg of Part II acetylene in 10 mL of CH ₃ OH is mixed with 238 mg (25 % w / w 10 % Pt / C) of

1, ϊν.

-140-

and the black suspension is stirred for about 15 hours under hydrogen at a pressure of about 1 bar. The catalyst is filtered through a Millipore polycarbonate filter (0.4 μm) and prefilter and the filtrate evaporated under reduced pressure to a yellow oil. The crude oil is purified by flash chromatography on silica gel (Merck) and elution with hexane-ethyl acetate (8: 2). The product fractions are evaporated. Yield: 915 mg (86.7 %) of pure saturated phosphinate title compound as a white foam.

TLC (4: 1) EtOAc-hexane, R _f = 0.39, UV + PMA. Mass spectrum: (M + H ⁺ = 714 ⁺ , observed).

L. (S) -4 - [[2- [i- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl3-ethyl-1-methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

A solution of ~ 915 .mg (1.22 mmol) of part K silyl ether in 10 ml of THF is added sequentially with 280 μΐ (4.88 mmol, 4 eq.) Of glacial acetic acid and 3.3 ml (3.66 mmol, 3 eq .) Treated 1.1 M nC ^ NF solution in THF and the mixture stirred for about 15 hours at room temperature under argon. 8 ml ice-cold H2 O was added, the mixture extracted with ethyl acetate, the organic phase washed twice with 5 % KHSO.-solution, saturated NaHCO3 solution and brine, over anhydrous Na-SO4. dried and evaporated under reduced pressure to give 955 mg of yellow oil. The crude oil is purified by flash chromatography on silica gel (Merck) and elution with hexane-acetone (1: 1). The product fractions are evaporated. Yield: 521 mg (85.5 %) of the desired alcohol title compound as a pale yellow oil. TLC (3: 2) acetone-hexane, R = 0.21, UV + PMA. Mass spectrum: (M + H ⁺ = 476 ⁺ , observed).

35

-141-

1M (S) -4 - [[2- [j- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] -ethyl] -hydroxyphosphinyl-3-hydroxybutyric acid dilithium salt

A solution of 505 mg (1.06 mmol) of Part L diester in 10 ml of dioxane is treated with 3.7 ml (3.7 mmol, 3.5 eq.) Of 1.0N LiOH in excess and the mixture 1.5 Hours in an oil bath under argon at -65 ⁰ C heated. The mixture is diluted with H ₂ O, filtered and evaporated under reduced pressure to a light yellow solid. The crude solid is suspended in a small amount of H ₂ O and chromatographed on resin HP-20 (15 cm bed, 25 mm column diameter) and eluted with H ₂ O until neutral and then with CH ₃ OH. The product fractions are combined, evaporated, taken up in 50 ml H_O and lyophilized. Yield: 484 mg (95.4 %) of the desired dilithium salt title compound as

· - .. white lyophilisate.

, - · · · · · TLC (8: 1: 1). CH ₂ cr ₂ -CH ₃ OH acetic acid, R _f = 0.39, UV + PMA.

? 0 Analysis for C ₂₃ H ₂₅ NO ₅ TP * 2Li +

1.03 moles of H ₂ O (MW = 477.91): CHNFP

Cons: 57,80 5.72 2.93 3.97 6.48

F .: 57.80 6.01 3.01 3.93 6.41

Example 30

(S) -4 - [[2- [i- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl3-ethyl-5-ylhydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

30% of methyl (S) -4 - [[2- [i- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] -äthinylj-methoxyphosphinyl ^ -3-hydroxybutyrate

A solution of 987 mg (1.39 mmol) of silyl ether of Example 29, Part J, in 12 mL of anhydrous THF is added sequentially with 320 μΐ (5.6 mmol, 4 eq.) Glacial acetic acid and 3.8 mL (4.17 mmol .

-1 42-

3 Xq.) 1.1M nC ₄ H _g NF solution in THF and the mixture stirred under argon at room temperature for about 15 hours. The mixture is diluted with 10 ml of ice-cold H ₉ O and extracted with ethyl acetate. The organic phase is washed 3 times with 5 % KHSO.-solution, saturated NaHCO 3 solution and brine, over anhydrous Na 2 SO 4. dried and evaporated to give 1.0 g of yellow oil. TLC shows the formation of some monoacid, which is converted back to the methyl ester by treatment with ethereal solution of CH ₃ N ₂ . Excess CH ₃ N ₂ is destroyed with glacial acetic acid and the mixture is evaporated under reduced pressure to give 1.012 g of brown oil. The crude oil is purified by flash chromatography on silica gel (Merck) and elution with 600 ml hexane-acetone (8: 2) followed by hexane-acetone (1: 1). The product fractions are evaporated. Yield: 516 mg (78.7 %) free alcohol title compound as a pale brown oil.

TLC (9: 1) CH ₉ Cl ₉ -CH ^ OH, R = 0.41, UV + PMA.

+ + Mass spectrum: (MfH = 472, observed).

β. (S) -4 - [{j2-D- ⁽⁴ - ^fluoro P ^hen y ^l) - ³ - ⁽¹ - ^meth y ^{l läfch} y '- ^{1 H-indol-2-yi3} -äthinyl]] -hydroxyphosphinyl] -3 hydroxybutyric acid dilithium salt

A solution of 516 mg (1.09 mmol) of the diester of Part A in 10 ml of dioxane is treated with 3.8 ml (3.8 mmol, 3.5 eq.) Of 1.0N LiOH solution and the clear mixture 1, 5 hours under argon in an oil bath to 6O ⁰ C and stirred. The mixture is diluted with H ₂ O, filtered, evaporated under reduced pressure, the residual oil taken up in the minimum amount of H ₉ O and chromatographed on resin HP-20 (15 μm bed, 25 mm column diameter) and with pure H ₃ O until neutral and then eluted with H ₂ O-CH ₃ OH (1: 1). The product fractions are evaporated under reduced pressure, taken up in 50 ml H ₉ O, filtered and lyophilized. Yield: 447 mg (82.3 %) of desired di-

-143-

lithium salt title compound as white lyophilate.

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

Analysis for C ₂₃ H ₂₁ O ₅ PNF. 2Li +

2.27 moles of H ₂ O (MW 496.19): CHNFP

: 55.67 5.19 2.82 3.83 6.24

F .: 55.69 5.37 2.82 3.85 6.19

10 example31

(S) -4-XYyI-, 4-Dimethyl-6- [(4-fluoro-phenyl) -methoxy] -phenyl] -äthinyl]] -hydroxyphosphinyl] -3-hydroxybutyric acid-dilithium

salt

A. 1- (methoxymethoxy) -3,5-dimethylbenzene

12 ml of THF solution of 10.42 (85.3 mmol) of 3,6-dimethylphenol r. are added dropwise within 10 minutes to a suspension

- * · sion placed in 150 ml 'of THF and cooled to 0 ⁰ C unter'Argon of 85.3 mmol of NaH with pentane prewashed. After complete addition of the phenol, the reaction mixture is stirred at 0 ^° C. for 10 minutes, warmed to room temperature and stirred for a further 20 minutes. The alkoxide solution is then treated with 42 ml of anhydrous DMF and then slowly with 10 ml of a solution of 11.19 g (89.6 mmol) of bromomethyl methyl ether in THF. The result is a white precipitate. After 2.5 hours of stirring at room temperature, the reaction is stopped by slowly adding 25 ml of 1N NaOH. The THF is distilled off from the reaction mixture on a rotary evaporator and the reading obtained diluted with saturated sodium chloride solution and then extracted 3 times with diethyl ether. The combined ether extracts are over Na_SO. dried and filtered. Removal of the solvent gives an orange-colored oil. Purification by flash chromatography and elution with 5 % ether / hexanes gives 12.0 g (85 %) of methoxy methyl ether title compound (MOI ¹ l), aq. Clear oil.

8 16 0

-144-

1 TLC R _f = 0.45 (15 % Et ₂ O / hexane, silica gel) mass spectrum m / e (M ⁺ ), 165 (M ⁺ -H) "

B. 2- (methoxymethoxy) -4,6-dimethylbenzaldehyde 5

7.70 g (79.45 mmol) of tetramethylethylenediamine are added slowly to 26.5 ml of a 2.5M solution of n-butyllithium in hexane in 30 ml of cyclohexane under argon. The solution is cooled to 0 ⁰ C and added dropwise within 20 minutes with 11.00 g (66.21 mmol) of MOM-ether offset from Part A. After complete addition, the reaction mixture is stirred for 30 minutes at 0 ^Q C, warmed to room temperature and stirred for a further 10 minutes. Then, the anion is added via an addition funnel to a solution of 5.81 g (79.45 mmol) of DMF in 100 ml of anhydrous cyclohexane under argon at room temperature. The reaction mixture is stirred for 2 hours at room temperature and then quenched with methanol. The solvent is distilled off on a rotary evaporator and the resulting orange-colored oil dissolved in a diethyl ether-water mixture (1: 1). The aqueous layer is extracted 3 times with ether and the combined ether extracts over MgSO 4. dried. Filtration and removal of the solvent give an orange oil. Purification of the cis by flash chromatography and elution with 20 % ether / hexane gives 7.7 g (60 %) of the desired aldehyde title compound as a clear oil.

TLC R _f = 0.14 (15 % Et ₂ O / hexane, silica gel)

Mass spectrum m / e 195 (M + H) ^+, 179 (M-CH ₃ J ^+, 163 (M-OCH ₃₎ ^4, "149 (MO ₂ CH ^) ⁺

C. 2-hydroxy-4,6-dimethylbenzaldehyde

35.5 ml of 1M HCl are added to a solution of 6.89 g (35.5 mmol) of Part B MOM ether in 130 ml of dioxane at room temperature. The reaction mixture is heated to a gentle reflux temperature and stirred for 30 minutes. Then the reaction

2 8 UO

-145-

cooled to room temperature and the dioxane removed on a rotary evaporator. The resulting aqueous solution is diluted with H ₂ O and extracted with diethyl ether. The aqueous layer is then saturated with NaCl and back extracted twice with ether. Me ether extracts are combined and then over MgSO. dried. Filtration and removal of the solvent gives a greenish solid, which is purified by recrystallization from hexane. Yield: 4.01 g (75 %).

TLC R _f = 0.48 (25 % Et ₂ O / hexane, silica gel), mp 46-48 ° C. Mass spectrum m / e 151 (M + H) ⁺ , 135 (M-CHg) ⁺

D. 2-Q (4-fluorophenyl) methoxy] -4,6-dimethylbenzaldehyde

15 A solution of 4.0 g (26.7 mmol) of phenol from part C in

30 ml of anhydrous DMF is stirred under argon. At room temperature, 4.43 g are then (32 mmol) of solid K-CO- added to the phenol solution and heated 35 minutes at this 6O ⁰ C. The resulting orange solution is cooled to room temperature and treated with 5.55 g (29.3 mmol) of o-fluorobenzyl bromide. The reaction mixture is warmed to 6O ⁰ C and stirred for 2 hours. Then the reaction mixture is poured into 50 ml of ice-water and the mixture extracted several times with ether. The combined ether extracts are over MgSO.

dried. After removal of the solvent, a yellow solid is obtained. Purification by flash chromatography and elution with 15 % ether / hexane gives 4.48 g (60 %) of the benzyl ether title compound as a white solid. TLC R _f = 0.34 (25 % EtgO / hexane, silica gel)

Mass spectrum m / e 259 (M + H) ⁺ , 231 (M-CHO) ⁺ , 109 (MC ₇ HgF) ⁺

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

A solution of 4.42 g (17.13 mmol) of Part D aldehyde in 170 mL of anhydrous CH-Cl- is added under argon in ice / salt bath

2 8 UO

-146- τ

cooled. The g. Cooled solution is then treated with 14.4 g (55.0 mmol) of triphenylphosphine and the mixture is stirred until all the solid has dissolved. A solution of 8.52 g (25.7 mmol) of CBr ₄ in 50 mL of CH ₂ Cl ₂ is added through an addition funnel over 12 minutes. After complete addition, the orange-colored reaction solution for 1 hour 15 minutes at 0 ⁰ C stirred. Then, the reaction is stopped by adding 60 ml of saturated aqueous NaHCO_ solution and the mixture stirred vigorously. The aqueous layer is removed and extracted twice with CH ₃ Cl ₂ . The combined CH "C1" extracts are washed once with saturated aqueous NaHCCs solution, over MgSO4. dried and filtered to give 13 g of the dibromide title compound as a buff solid. The dibromide is going through

Ib flash chromatography and elution with 2 % diethyl ether / hexane. Yield: 5.49 g (77 %) of dibromide title compound. TLC R _f = 0.28 (2 % Et ₂ O / hexane, silica gel).

Mass spectrum m / e 413 (M + H) ⁺ , 333, 335 (M-Br) ⁺ , 317 (.'C ₆ H ₄ F 109 (MC ₁₀ HgOBr ₂ ) ⁺ .

F. 1-Ethyl-2- [[ 4-fluorophenyl) -methoxy] -4,6-dimethylbenzene

A solution of 5.48 g (13.3 mmol) of the dibromide from part C in 70 mL of THF is cooled under argon to -78 ⁰ C and within 10 minutes with 10.6 ml (26.5 mmol) of 2.5M solution of n-butyllithium in hexane added. The reaction mixture is stirred for 1 hour at -78 ° C and then the reaction stopped by addition of saturated aqueous NH.Cl solution at -78 ° C. After warming the mixture to room temperature it is diluted with 60 ml of H 2 O and the aqueous layer is extracted twice with diethyl ether. The organic layers are combined and dried over MgSO ₄ . Filtration and removal of the solvent give 3.8 g of benzyloxyacetylene title compound as a yellow solid. The benzyl

35 oxyacetylene is purified by flash chromatography and elution

purified with 3 % diethyl ether / hexane. Yield: 2.76 g (85 %)

-147-

1 acetylene title compound as a white solid. TLC R _f = 0.17 (2 % Et _w O / hexane, silica gel). Mass spectrum m / e 255 (M + H) ⁺ , 159 (M-CgH ₄ F) ⁺ , 109

G. (S) -4- [X [2,4-dimethyl-6- (4-fluorophenyl) methoxy] -

phenylj-äthinyl ^ -hydroxyphosphinyl]] -3- (t-butyldiphenylsilyloxy) -butyric acid dilithium salt

- ^ q A solution of 2.76 g (11 mmol) of Part F acetylene in 40 ml of THF is cooled under argon to -78 ⁰ C and within minutes with 4.4 ml of 2.5M solution of n-butyllithium in hexane at -78 ° C added. The reaction mixture is stirred for 40 minutes at -78 ° C.

17.4 mmol Phosphonylchloridat of Example 25 are cooled to -78 ° C in 60 ml of THF under argon. The acetylene anion produced above is then added within 8 minutes. After 1 hour of stirring at -78 ° C, the reaction is quenched with saturated aqueous NH.Cl solution at -78 ⁰ C and the mixture warmed to room temperature. The aqueous layer is diluted with H 2 O and extracted twice with diethyl ether. The THF is removed from the THF reaction layer and the resulting orange oil is taken up in diethyl ether. The ether solutions are combined and washed once with saturated aqueous NaHCO 3 solution and once with brine. The organic layer is over MgSO 4. dried and filtered to give 9.4 g of the title compound acetylenic phosphinic acid in the form of an orange gum after removal of the solvent.

remain by gg. The acetylenic phosphinic acid title compound is purified by flash chromatography and elution with hexane / toluene / ethyl acetate (5: 1: 4). Yield: 4.23 g (56 %) of acetylenic phosphinic acid title compound as a clear gum.

gg TLC R = 0.28 (5/1/4 hexane / toluene / ethyl acetate silica gel).

Mass spectrum m / e 609 (M + HC.H_) ⁺ , 255 (C.H _1n SiO) ⁺

0 5 14 19

2β 1 6 O

-148-

1 H. (S) -4 - [[[2,4-dimethyl-6 - [(4-fluorophenyl) -methoxy] -

phenyij-ethyl-thiocyanate] -3-hydroxybutyric acid methyl ester

0.455 g (0.66 mmol) of Part G acetylenic phosphinate are stirred under argon in 10 ml of THF and treated with 0.16 g (2.66 mmol) of acetic acid and then dropwise over 5 minutes at room temperature with 1.8 ml of a 1 , In THF solution of nC.H _g NF added (2.0 mmol). After stirring for 24 hours

10 room temperature, the reaction by addition of 30 ml

Ice water was broken off. The aqueous layer is removed and extracted twice with ethyl acetate. The THF is removed from the organic reaction layer and the remaining oil is dissolved in ethyl acetate and combined with the extracts of the aqueous layer. The ethyl acetate solution is washed twice with saturated aqueous NaHCO 3 solution and once with saturated brine and then with Na 2 SO 4. dried. Filtration and removal of the solvent give 0.40 g of hydroxyacetylene phosphinate title compound as an oil. The hydroxyacetylene phosphinate is purified by flash chromatography and elution with 100 % ethyl acetate. The hydroxyacetylene phosphinate T + telverbindung is obtained in a yield of 79 % .

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

Mass spectrum m / e 449 (M + H) ⁺ , 431 (M-OH) ⁺ , 417 (M-OCH ₃ ) ⁺

J. (S) -4-Q [2,4-Dimethyl-6 - [(4-fluorophenyl) -methoxy] -phenyl] -äthinyl] -hydroxy-phosphinyl] -3-hydroxybutyric-30-acid-dilithium salt

A solution of 0.191 g (0.43 mmol) of Part H acetylenic phosphinate in 6.0 ml of dioxane is added at room temperature with 1.4 ml of 1N LiOH solution. The reaction mixture is warmed to 55 ^° C. and stirred for 2 hours. Then the mixture is cooled to room temperature and evaporated to dryness,

-149-

whereby the title compound is obtained. The title compound is purified on a 130 x 30 mm diameter column with HP-20 and elution first with 100 ml of H ₂ O and with MeOH / H ₂ O (1: 1). Yield: 0.170 g (91 %) of the title compound as a white lyophilate. TLC R _f = 0.37 (7: 2: 1 nPrOH / NH 2 H / H 2, silica gel). Mass Spectrum (FAB) m / e 421 (M + H) ⁺ , 427 (M + Li) ⁺ , 433 (M + 2 Li) ⁺ ,

Analysis for C ₂₁ H ₂₀ OgFPLi ₂ 1.4 H ₃ O: CHFP! 0 calc .: 55.09 4.98 4.15 6.78

F .: 55.13 5.25 4.08 6.91

Example 32

(S) -4- [[[2,4-Dimethyl-6- (4-fluoro-phenyl) -methoxy-1-phenyl] -ethyl-3-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt A. (S) -3 - [[ (1, 1-Dimethylethyl) -diphenylsilyl] oxy] -4- [1-yl-2-ol (4-fluoro-phenyl) -methoxy] -4,6-dimethylphenyl-ethyl] -methoxy-phosphinyl-i-butyric acid methyl ester

1.34 g (1.95 mmol) of acetylenic phosphinate from Example 31, Part G are stirred in 12 ml of methanol and offset with 0.040 g PtO ". Then, hydrogen gas is passed through the methanol solution for 10 minutes and a hydrogen pressure is maintained by means of a balloon. After 5 hours and 15 minutes at room temperature, the reaction is complete and argon is passed through the reaction solution. The solution is then filtered through diatomaceous earth in a fine,

filtered glass funnel filtered and the catalyst washed with methanol. The solvent is distilled off from the filtrate to give 1.4 g of the saturated phosphinate title compound as a clear gum. The saturated phosphinate is purified by flash chromatography and elution with

g5 60 % ethyl acetate, hexane purified. Then the material from the slightly contaminated fractions with hexane /

-150-

Acetone / toluene (6: 2.5: 1.5) rechromatographed. Yield: 1.17 g (86 %) of saturated phosphinate title compound. TLC R _f = 0.045 (80 % ethyl acetate / hexane, silica gel). Mass spectrum m / e 691 (M + H) ⁺ , 659 (M-OCH ₃ ) ⁺ , 635

5 (MC ₉ H ₁₉ OSi) ⁺

B-. (S) -4- [[[2,4-Dimethyl-6- [(4-fluoro-phenyl) -methoxy]] -phenyl] -ethyl] -methoxy-phosphinyl]] -3-hydroxybutyric acid methyl ester

1.16 g (1.68 mmol) of Part A phosphinate are stirred in 25 ml of THF at room temperature under argon. 0.40 ml of glacial acetic acid are added dropwise to the phosphinate solution and then 4.6 ml of a 1.1M solution of nC.HgNF in THF are added dropwise within 5 minutes. The reaction mixture is stirred for 18 hours at room temperature and then quenched with 50 ml of ice water. After stirring for several minutes, saturated brine is added and the layers are separated. The THF is removed from the organic layer on a rotary evaporator and the residue obtained is dissolved in ethyl acetate. The aqueous layer is extracted twice with ethyl acetate, the ethyl acetate solutions are combined and washed twice with saturated aqueous NaHCO 3 solution and once with brine, then with Na 2 SO 4. dried, filtered and evaporated. Yield: 1.13 g of the hydroxyphosphinate title compound as a clear oil. The hydroxyphosphinate is purified by flash chromatography and elution with 100 % ethyl acetate. Yield: 83 %

30 droxyphosphinat title compound as a clear oil. TLC R _f = 0.27 (6: 4 acetone / hexane, silica gel). Mass spectrum m / e 453 (M + H) ⁺ , 343 (MC ₇ H ₆ F) ⁺

C. (S) -4- [[2,4-Dimethyl-6-Q (4-fluorophenyl) -methoxy] -phenyl] -ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

28 {

-151-

0.594 g (1.3 mmol) of Part B phosphinate are added in 19 ml of dioxane at room temperature while stirring with 4.0 ml of 1N LiOH. The mixture is heated to 55 ° C. After 20 minutes a thick white precipitate separates out. There are added 4.0 ml of dioxane and the suspension obtained at 55 ⁰ C stirred. After 2.5 hours at 55 ° C, 3 ml of H ₂ O are added, the reaction mixture becoming clear. After 3 hours at 55 ⁰ C, the reaction mixture is cooled to room temperature, the dioxane and the water on a rotary evaporator

10 distilled off, the diacid title compound in the form

of a white solid which is kept under high vacuum for 15 minutes. The diacid is chromatographed on HP-20 and eluted first with 100 ml H "O and then with a MeOH-HO solution (1: 1). Yield: 67 % disperse

15 re-title compound as white lyophilate.

TLC R _f = 0.36 (7: 2: 1 n-propanol / NH ₄ OH / H ₂ O, silica gel). Mass spectrum m / e (FAB), 425 (M + H) ⁺ , 437 (M + H + 2 Li) ⁺ .

Analysis for C ^ H ^ OgFP «1.15 H ₂ O: CHFP: 55.19 5.80 4.16 6.78

F .: 55.19 5.80 4.29 6.83

Example 33

(S) -4- [2- [xi, 1'-biphenyl] -2-yl] -äthinyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium maleate

A. (S) -4 - [[2 - [[i, 1'-biphenyl] -2-yl-3-ethynyl] -hydroxyphosphinyl] -3-hydroxybutyric acid methyl ester

0.985 g (1.61 mmol) of phosphinate from Example 9, Part D are stirred under argon at room temperature in 19.6 ml of anhydrous THF and added dropwise with 0.386 g (0.368 ml, 6.44 mmol) of glacial acetic acid and then within 8 minutes added dropwise with 4.40 ml of 1.1M solution of nC ₄ H_NH in THF (4.84 mmol). After stirring for 18 hours at room temperature, the reaction mixture is never quenched with 30 ml of ice-water. The aqueous

-152-

The resulting layer is extracted with ethyl acetate. The organic extracts are combined, washed twice with saturated aqueous NaHCO 3 solution and once with brine, over MgSO 4. dried, filtered and evaporated. The product is obtained by flash chromatography (50 mm column, 6 "Merck silica gel, 40 % acetone / hexane as eluent, 2" / minute flow rate). The product fractions are evaporated, azeotroped with toluene and evaporated under reduced pressure. Yield: 0.369 g (0.991 mmol, 62 %) of the title alcoholic compound as a viscous, yellow oil. Further, 0.098 g (0.263 mmol, 16 %) of slightly contaminated product is obtained.

TLC: silica gel R = 0.35 (50 % acetone / hexane). Mass spectrum CI m / e 373 (M + H) ⁺

B. (S) -4- [2 - [. [I, 1'-biphenyl] -2-yf] -äthinyl] -hydroxyphosphinylj-3-hydroxybutyric acid dilithium salt

0.275 g (0.739 mmol) of Part A diester are dissolved under argon

20 in 7.57 ml of dioxane and with 2.22 ml (2.22 mmol) 1M

LiOH treated. The cloudy reaction mixture is heated to 55 ^° C. in an oil bath for 45 minutes. The mixture is then cooled to room temperature. The solvents are distilled off on a rotary evaporator under high vacuum within 90 minutes. The remaining yellow foam is dissolved in 4 ml of distilled H 2 O and chromatographed through a column of HP-20 (2.5 cm × 19 cm), collecting 10 ml fractions every 1.4 minutes. The column is eluted with H 2 O until 15 fractions are collected and no more basic reaction occurs. It is then eluted with methanol / H 2 O (45:55). After 2 times Lyophilsierunn uvid 16 hours under high vacuum over P ₂ O ₅ , 0.231 g (0.649 mmol, 88 %) of the diacid title compound as a white lyophilate. TLC: silica gel R _f = 0.55 (7: 2: 1 n-propanol / NH 0H / H _o 0).

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

8 16 0

-1 53-

Analysis for C ₁₈ H ₁₅ O ₅ PLi ₂ +

1.42 moles H ₂ O MW = 381.75: CHP

calculated: 56.63 4.71 8.07

Filled: 56.62 4.70 8.07

Example 34

(S) -4- [[2- [3,5-Dimethyl- [1,1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium IQ A. 3, 5-dimethyl - \ j , 1'-biphenyl] -2-carboxaldehyde

Phenylmagnesium bromide is obtained from Aldrich (catalog no. 17, 156-5) as a 3M solution in diethyl ether.

A mixture of 3.35 g (4.48 mmol) of the dipalladium complex of Example 1, Part B, and 9.40 g (3 mmol, 85 mmol) of tri-henylphosphine is stirred for 30 minutes under argon in 67.2 ml of anhydrous toluene at room temperature touched. The reaction mixture is cooled to 0 ⁰ C and batchwise rapidly with 11.95 ml of a 3M solution of phenyl magnesium bromide Grignard reagent (Aldrich) in diethyl ether (35.84 mMo.l) was added. The resulting mixture is stirred for 1.5 hours at room temperature. The mixture is then cooled to 0 ^° C. and treated with 22.4 ml of 6N HCl in an amount and stirred at room temperature for 1 hour. The aqueous layer is separated and extracted with di-ethyl ether. The organic extracts are combined, filtered through diatomaceous earth, washed with ether, the filtrate washed with brine, azeotroped with toluene and evaporated under reduced pressure to a yellow solid.

The product purification procedure by 2-fold flash chromatography (95 mm column diameter, 6 "Merck silica gel, 100 % hexane» ¹ 3 % ether / hexane as eluent, 2 "/ minute flow rate) gives 2.95 g of yellow solid (1, 88 g, 8.96 mmol, 100 % yield of the aldehyde title compound and 1.06 g of triphenylphosphine). The mixture of these compounds is used directly for the preparation of the compound of Part B

28

-154-1 set '.

TLC: silica gel, R _f = 0.30 (5 % ether / hexane), mass spectrum (CI) m / e 211 (M + H) ⁺ , 263 (M ₂ + H) ⁺ , 473 5 (M ₁ + M ₂ + H) ⁺

M ₁ = aldehyde of part A, M ₂ = triphenylphosphine.

B. 2- (2,2-dibromoethyl) -3,5-dimethyl- [i, 1'-biphenyl]

A mixture of "',88g" (8.96 mmol) of aldehyde from Part A and 6.90 g (26.4 mmol) of triphenylphosphine is stirred for 10 minutes at -5 ⁰ C in 88 mL of anhydrous CH ₂ Cl _2. The reaction mixture is then added dropwise at -5 ° C with a solution of 4.38 g (13.2 mmol) of CBr x in 32 ml of anhydrous CH ₉ Cl ₉ within 20 minutes. The resulting reaction mixture is stirred for 1 hour at -5 ⁰ C, and is in the course of Since darker orange-colored. The mixture is then quenched with 85 ml of saturated aqueous NaHCO ₃ solution. The aqueous layer is extracted with CH ₉ Cl ₉ . The organic extracts are combined, washed once with saturated aqueous NaHCO3, once with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The product is prepared by pre-absorption of the crude product in CH ₉ Cl, on 25 g of silica gel (Merck) and placing this product on a column for flash chromatography (50 mm diameter, 6 "Merck silica gel, 4 % CH-Clp / hexane as eluent , 2 "/ minute flow rate). Yield: 2.18 g (5.96 mmol, 68 %) of vinyl dibromide title compound as a viscous, colorless oil.

30 TLC: Kieselgel R _f = 0.37 (4 % CH ₃ Cl ₂ , hexane) mass spectrum (CI) m / e 365/367/369 (M + H) ⁺

C. 3,5-Dimethyl-2- (1-propynyl) - (j, 1'-biphenyl)

A solution of 2.10 g (5.74 mmol) of Vinyidibromide from Part B in 29.11 mL of anhydrous THF is stirred under argon and evaporated

2 8 \ 60

-155-

-78 ⁰ C cooled. The solution is then treated dropwise with 4.59 ml of fine 2.5M solution of n-butyllithium (11.47 mmol) over 20 minutes to give a deep purple solution. After another hour of stirring at -78 ⁰ C, the reaction is stopped at -78 ° C with 25 ml of saturated aqueous NH.Cl solution, the mixture warmed to room temperature, diluted with HC and the aqueous layer with diethyl / hexane (1: 1) extracted. The organic extracts are combined, over MgSO 4. dried, filtered and evaporated under reduced pressure. The product is purified by flash chromatography (50 mm column, 6 "Merck silica gel, 1 % ether / hexane as eluant) Yield: 1.08 g (5.23 mmol, 91 %) of acetylene title compound as a colorless oil, which at 16 hours storage at -20 ⁰ C blue.

15 TLC: silica gel R _f = 0.32 (100 % hexane). Mass spectrum (CI) m / e 207 (MfH) ⁺

D. "(S) -3- [Q (1,1-Dimethylethyl) diphenylsilyl] oxy] -4 - [[2,3,5-dimethyl-qi, 1'-biphenyl] -2-yl] ] -methoxyphosphinyl] butyric acid methylester

A solution of 0.950 g (4.61 mmol) of Part C acetylene in 27.3 mL of anhydrous THF is stirred under argon and cooled to -78 ° C. Thereafter, 1.84 ml of a 2.5M solution of n-butyllithium in hexanes (4.61 mmol) are added dropwise over 20 minutes to give a dark purple / brown solution. The reaction mixture is stirred for 1 hour at --78 ⁰ C where it is heated to ⁰ ° C to a slurry and stirred for 15 minutes. The reaction mixture again becomes a dark purple homogeneous solution. It is again cooled to -40 ⁰ C and remains homogeneous. The acetylene anion solution is then added dropwise at -4O ⁰ C within 25 minutes to a solution of 8.12 mmol Phosphinylchloridat of Example 1, Part F, in 27.3 ml of anhydrous THF, which to -78 ° C under Stirring and cooling under argon. After complete addition

-156-

the solution of the acetylenic anion to the solution of Phosphinalchloridats the dark orange-colored reaction mixture is stirred for 1 hour at -78 ° C and then quenched with 50 ml of saturated NH.Cl solution at -78 ° C, warmed to room temperature and with H ₂ O diluted. The aqueous layer is extracted with diethyl ether. The organic extracts are combined, washed once with saturated aqueous NaHCO3, once with brine, over MgSO4. dried, filtered and evaporated under reduced pressure. The product is purified by flash chromatography (50 ml column diameter, 6 "Merck Kieselgei, 50 % ethyl acetate / hexane as eluent, 2" / minute flow rate). Yield: 0.609 g (0.945 mmol, 21 %) of the phosphinate title compound as a golden orange oil.

TLC: silica gel R _f = 0.32 (50 % ethyl acetate / hexane) mass spectrum (CI) m / e 639 (M + H) ⁺

E. (S) -4 - [[2- [3,5-Dimethyl-1,4-i, 1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl-3- (t-butyldiphenylsilyloxy) -butyric acid dilithium salt

Argon is passed through a solution of 0.876 g (1.37 mmol) of Part D acetylenic phosphinate in 13 mL of methanol for 10 minutes. Then 0.315 g of 10 % Pd / C are added and the reaction mixture is hydrogenated on a Parr apparatus under a pressure of about 2.8 bar. After shaking for 24 hours, the reaction mixture is filtered through silica gel in a sintered glass funnel. The silica gel is washed with methanol and the filtrate is evaporated under reduced pressure to give 0.896 g of yellow oil. This is purified by flash chromatography (50 mm acid diameter, 6 "Merck silica gel, 40 % -> 50 % ethyl acetate / hexane as eluant) Yield: 0.680 g (1.06 mmol, 77 %) of the saturated phosphinate title compound as a pale yellow Foam Stripping off the chromatographic column by elution with methanol gives an additional 0.087 g of slightly contaminated product.

-157- (50 % mass spectrum (CI) m / e 643 / M + H) *.

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

F. (S) -4- [[2- [3,5-Dimethyl-Q, 1'-biphenyl] -2-yl] -ethyl] hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

0.66 g (1.03 mmol) of Part E phosphinate are stirred under argon at room temperature in 12.65 ml of anhydrous THF. This solution is added dropwise with 0.247 g (0.236 ml, 4.12 mmol)

Glacial acetic acid and then 2.81 ml of a dropwise

1.1M solution of n-C ^ NF in THF (3.09 mmol). After stirring at room temperature for 16 hours, the reaction mixture is quenched with 25 ml of ice-water. The aqueous layer is extracted with ethyl acetate. The organic ex

Parts are combined, twice with saturated aqueous

NaHCO3 solution and once with brine, over MgSO4. dried, filtered and evaporated under reduced pressure. The product is purified by flash chromatography (40 mm column, 6 "Merck silica gel, 50 % acetone / hexane as eluent) Yield: 0.363 g (0.898 mmol, 87 %) of the title alcoholic compound as a white solid

TLC: silica gel R _f = 0.30 (50 % acetone / hexane). Mass Spectrum (FAB) m / e 405 (M + H) ⁺ .

G. (S) -4 - [[2- [3,5-Dimethyl-D, J'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl-3-hydroxybutyric acid dilithium salt

0.355 g (0.878 mmol) of the diester from Part F are stirred under argon in 9 ml of dioxane and treated with 2.63 ml (2.63 mmol) of 1M LiOH.

oQ acts. The homogeneous reaction mixture is dissolved in an oil bath

Heated to 55 ° C. After stirring for 10 minutes at 55 ° C, the reaction mixture becomes a white suspension. Another 9 ml of dioxane and 2 ml of H "0 are added and the suspension is heated to 55 ° C. for 45 minutes and then cooled to room temperature.

ok The solvents are distilled off for 1 hour on a rotary evaporator under reduced pressure. The preserved white

-158-

Solid is purified through a column of HP-20 (18 cm χ 2.5 cm). Each 1.4 minutes, 10 ml fractions are collected. The column is eluted with H 2 O until 15 fractions are collected and then eluted with methanol / H ₉ O (1: 1). After 3 times lyophilization and 4 times 8 hours under high vacuum over PpO ₁ . 0.289 g (0.744 mmol, 85 %) of the title acidic acid is obtained as a white lyophilate.

TLC: silica gel, R _f = 0.56 (7: 2: 1, n-propanol / NH ₄ OH / H ₂ =). Mass Spectrum (FAB) m / e) 389 (M + H) ⁺ 10

analysis For ^C 20 »23 ° 5 PLi ₂ + 31 • About: 60 C 6 H 0.34 mol from ^H 2 O M .W . = 394, gef. : 60 , 92 6 , 05 95 , 18

Example 35

(S) -. 4-nL ² - ^[4 '- ^fluoro - ^{3, 5} - ^dimetn y ¹ -D Ί' -biphenyl3-2-yl] ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid-bromo Dilithiumsalζ A. (4-fluorophenyl) -magnesium

1.08 g (44.35 mmol) of magnesium turnings are flame-dried and then stirred under argon in 40 ml of anhydrous diethyl ether. With vigorous stirring, 40.3 mmol of 1-bromo-4-fluorobenzene are added dropwise to the magnesium. The reaction is started in an ultrasonicator and then the halide is added dropwise at a rate sufficient to reflux the mixture. After complete addition of the bromide, the reaction mixture is

Stirred 30 minutes at room temperature for 20 minutes, then under

Refluxed and finally cooled to room temperature. In this method, a gold-orange-colored transparent Grignard solution containing 40.32 mmol Grignard title compound as 0.91M solution in diethyl ether is obtained.

-159-

, 1 B. 4'-fluoro-3,5-dimethyl- [1,1'-biphenyfl-2-carboxaldehyde (Stockker et al., Journal of Med. Chem., 29, (1986), pp. 170-181 )

A mixture of 3.20 g (4.35 mmol) of the palladium complex of Example 26, Part B, and 10.5 g (40.32 mmol) of triphenylphosphine is stirred at room temperature for 30 minutes under argon in 67.2 ml of anhydrous toluene , Then, the reaction mixture is cooled from 0 ⁰ C and batchwise rapidly with 44.43 ml (40.32 mmol) Grignard reaction of Part A was added. The resulting mixture is stirred for 1.5 hours at room temperature. Then the mixture is cooled to 0 ^° C. and treated in an amount with 21.5 ml of 6N HCl and stirred for 1 hour at room temperature. The aqueous layer is separated, extracted with diethyl ether and filtered the combined organic extracts through diatomaceous earth. The diatomaceous earth is washed with diethyl ether and the combined filtrates are washed with brine, azeotroped twice with toluene and stripped to give an orange-yellowish solid. Attempts to isolate the aldehyde title compound by flash chromatography (95 mm column diameter, 6 "Merck silica gel, hexane followed by 3 % EtO / hexanes as eluent, 2" / minute flow rate) yield a reaction product mixture of the desired aldehyde title compound and triphenylphosphine as a pale yellow solid (3.70 g, assumed content of 1.99 g, 8.7 mmol, 100 % aldehyde title compound + 1.70 g triphenylphosphine). This mixture is used directly for the preparation of the compound of Part C.

30 TLC: silica gel R _f = 0.25 (5 % ether / hexane).

¹ H NMR: (270 MHz, CDCl ₃ )

C. 2- (2,2-Dibromoethyl) -4'-fluoro-3,5-dimethyl- [i, 1'-biphenyl]

A mixture of "1.99 g" (8.70 mmol) of Part B and aldehyde

-160-

1. 6.85 g (26.1 mmol) of triphenylphosphine is added for 10 minutes

-5 ° C in 87 ml of anhydrous CH_C1_ stirred. The reaction mixture is maintained at -5 ⁰ C, and a solution of 4.33 g (13.05 mmol) of CBr. in 43 ml of anhydrous CH-Cl dropwise added within 25 minutes. The resulting reaction mixture is stirred for 1 hour at -5 ⁰ C, and a dark orange solution which is then quenched by addition of 80 ml saturated aqueous NaHCO ₃ ~ solution is formed. The aqueous layer is extracted 4 times with CH-Clp. The combined organic extracts are washed once with saturated aqueous NaHCO 3 solution and once with brine. The CH ₂ Cl ₂ extract is washed over MgSO 4. dried, filtered and the filtrate combined with 25 g of silica gel (Merck). The solvent is evaporated and the preabsorbed product is purified by flash chromatography (50 mm column diameter, 6 "Merck silica gel, 4 % CH ₂ Cl ₂ / hexanes eluent, 2" / minute flow rate). Yield: 2.32 g (6.04 mmol, 69 %) of vinyl dibromide title compound as a colorless oil.

20 TLC: silica gel, R _f = 0.43 (5 % CH ₂ Cl ₂ / hexane). Mass spectrum (CI) m / e 383/385/387 (M + H) ⁺

D. 4'-fluoro-3,5-dimethyl-2- (1-propynyl) - [i, 1'-biphenyl]

A solution of 2.30 g (5.99 mmol) of vinyl dibromide from Part C in 33 ml of anhydrous THF is stirred under argon and cooled to -78 ° C. The solution is treated dropwise with 4.79 ml of a 2.5M solution of n-butyllithium in hexanes (11.97 mmol) over 25 minutes to give a deep purple solution. After another hour of stirring at -78 ° C, the reaction is stopped by adding 25 ml of saturated aqueous NH.Co solution at -78 ° C, the mixture is warmed to room temperature and diluted with 25 ml of H ₂ O. The aqueous layer is extracted 4 times with diethyl ether / hexane (1: 1). The organic extracts are combined, over MgSO 4. dried, filtered and evaporated. The product will

-161-

purified by flash chromatography (50 mm column, 6 "Merck silica gel, 0.50 % ether / hexane as eluent, 2" / mm flow rate). Yield: 1.25 g (5.57 mmol, 93 %) of the acetylene title compound as a colorless oil which was used in the

5 blue at 2O ⁰ C becomes blue.

TLC: silica gel, R _f = 0.25 (100 % hexane), mass spectrum (CI) m / e 225 (H + H) ⁺ .

E. (S) -4 - [[2- [4 ¹ -fluoro-3,5-dimethyl- [1,3'-biphenyl] -2-yl] -äthinylj-hydroxyphosphinyl] -3- (t-butyldiphenylsilyloxy) - butyric acid methylester

A solution of 1.18 g (5.24 mmol) of Part D acetylene in 28 mL of anhydrous THF is stirred under argon and cooled at -78 ° C. Then 2.10 ml of a 2.5M solution of n-butyllithium in hexane (5.24 mmol) are added dropwise within 25 minutes, the reaction mixture turning dark purple / brown. The reaction mixture is then stirred for 1 hour at -78 ° C, warmed to 0 ⁰ C, stirred for 10 minutes and cooled again to -78 ° C. This solution of the acetylenic anion is then added dropwise at -78 ° C within 20 minutes to a solution of 8.32 mmol phosphinylchloride of Example 1, Part F in 28 ml of anhydrous THF, which is cooled to -78 ° C under argon and is stirred. After complete addition, the dark orange reaction mixture is stirred for 1 hour at -78 ° C and the reaction is then stopped at -78 ° C by adding saturated aqueous NH ^ Cl solution, the mixture warmed to room temperature and washed with H "O diluted. The aqueous layer is extracted 4 times with diethyl ether. The organic extracts are combined and washed once with saturated aqueous NaHCO 3 solution and once with brine, dried over MgSO 4, filtered and evaporated. The product is purified by flash chromatography (50 mm column diameter, 6 "Merck silica gel, 40 % ethyl acetate / hexane as eluent, 2" / minute flow rate). Yield: 0.730 g (1.11 mmol, 21 %)

-162-

acetylenic phosphinate title compound as green, viscous

Oil. '

TLC: silica gel R = 0.36 (50 % ethyl acetate / hexane).

Mass spectrum (CI) m / e 657 (M + H) ⁺ 5

F. (S) -4 - [[2- [4 ¹ -fluoro-3,5-dimethyl- [i, 1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl]] -3- (t-) butyldiphenylsilyloxy) butyrate methyl ester

Argon is passed through a solution of 0.685 g (1.04 mmol) of part E acetylenic phosphinate in 9.9 ml of methanol for 10 minutes. Then 0.239 g of 10 % Pd / C are added and the reaction mixture is hydrogenated on a Parr apparatus at about 2.8 bar hydrogen pressure. After shaking for 24 hours, the reaction mixture is filtered through kieselguhr in a sintered glass funnel and the diatomaceous earth is washed with methanol. The filtrate is evaporated to give 0.638 g of green oil. The product is purified by flash chromatography (40 mm column diameter, 6 "Merck silica gel, 45 % ethyl acetate / hexane as eluant, 2" / minute flow rate). Yield: 0.530 g (0.802 mmol, 77 %) of saturated phosphinate title compound as a pale yellow foam. In addition, 0.09 g (0.135 mmol, 13 %) of slightly contaminated product is obtained.

TLC: silica gel R = 0.30 (50 % ethyl acetate / hexane). Mass spectrum (CI) m / e 661 (M + H) ⁺

G. (S) -4 - [[2- [4'-fluoro-3,5-dimethyl-qi, 1'-biphenyl] -2-yl] -ethyl-methoxy-phosphinyl-3-hydroxybutyric acid methyl-

30 esters

0.525 g (0.794 mmol) of Part F phosphinate are stirred under argon at room temperature in 9.74 ml of anhydrous THF. This solution is then treated dropwise with 0.91 g (0.182 mL, 3.18 mmol) of glacial acetic acid and then 2.17 mL of a 1.1M solution of n-C.HgNF in THF (2.38 mmol) dropwise. To

-163-

16 hours stirring at room temperature, the reaction mixture is quenched with 15 ml of ice water. The aqueous layer is extracted 3 times with ethyl acetate. The organic extracts are combined, washed twice with saturated aqueous NaHCO3, and once with brine, over MgSO4. dried, filtered and evaporated. The product is purified by flash chromatography (40 mm column diameter, 6 "Merck silica gel, 50 % acetone / hexane as eluent, 2" / minute flow rate). The product fractions are evaporated and azeotroped with toluene to dryness. Yield: 0.281 g (0.665 mmol, 84 %) of the title alcoholic compound as a white solid. H NMR at 270 MHz of visible contamination is not separable in various TLC systems, eg. visible.

15 TLC: silica gel, R _f = 0.31 (50 % acetone / hexane). ¹ H NMR: (270 MHz, CDCl ₃ )

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

H. . (S) -4 - [[2- [V-Fluoro-3,5-dimethyl- [i, 1'-biphenyfj-2-yf] -ethyl] -hydroxyphosphinyl-3-hydroxybutyric acid dilithium salt

0.20 g (0.473 mmol) of Part G diester are stirred in 4.84 ml of dioxane under argon and treated with 1.42 ml (1.42 mmol) of 1M LiOH. The homogeneous reaction mixture is heated to 55 ° C. in an oil bath. After 10 minutes of stirring at 55 ° C, the reaction mixture becomes a white suspension. The mixture is maintained at 55 ° C for an additional 45 minutes and then cooled to room temperature. The solvents are removed on a rotary evaporator in Hechvakuum in 1 hour. The resulting white foam is dissolved in 4 mL of distilled H ₃ O and chromatographed through a column of HP-20 (16 cm χ 2.5 ng). Each 1.4 minutes, 10 ml fractions are collected. The column is eluted with H 2 O until 15 fractions are collected and then further eluted with methanol / H 2 O (1: 1). After 2-fold lyophilization and 11 hours in a high vacuum over Ρ _? 0- become

28 ί

-164-

0.158 g (0.389 mmol, 82 %) of diacid title product as white lyophilate.

TLC: silica gel R _f = 0.59 (7: 2: 1, n-propanol / NH ₄ OH / H ₂ O) mass spectrum (FAB) m / e 395 (M + H) ⁺

Analysis for C ₂₀ H ₂₂ FO ₅ PLi ₂ + 0.39 moles H ₂ O: CH

calc .: 58.12 5.56

F .: 58.14 6.09

Example 36

(S) -4- [[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -J-diethynyl [] -methoxyphosphinyl-3-hydroxybutyric acid methyl ester

15 A. 4-Fluoro-.beta.-oxobenzenepropionic acid ethyl ester

17.4 g (0.43 mmol) of 60 % sodium hydride in mineral oil

Washed twice with dry hexane, dried under reduced pressure and then treated with 44.3 ml (0.36 mmol) of pure diethyl carbonate followed by dropwise addition of 22 ml (0.18 mmol) of p-fluoroacetophenone. After about 10 % of the ketone is added, add 4 drops of ethanol to start the reflux. The remainder of the p-fluoroacetophenone is added over 1 hour at a rate to maintain the reflux conditions.

Then, the resulting yellow solid is suspended in 250 ml of anhydrous diethyl ether and heated under argon for a further 3.0 hours under reflux.

The reaction mixture is cooled in an ice bath, diluted with 200 ml of diethyl ether and slowly treated with 1.3 l of water until all solids are dissolved. The aqueous phase is separated from the organic phase, acidified to pH 1.0 with 32 ml of 12N HCl and extracted with 2 × 500 ml of diethyl ether.

The combined organic extracts are washed with brine (200 ml), anhydrous MgSO4. dried,

-165-

1 filtered and evaporated to dryness. The crude product

(44.0 g) is distilled under reduced pressure (3.5 mm). Yield: 24.88 g (65.8 %) of the title compound as a homogeneous oil. TLC: R _f = 0.46 (silica gel, CH ₂ Cl ₂ : hexane - 4: 1).

3. 4-fluoro- (X- (2-methyl-1-oxopropyl) -β-oxobenzenepropion

acid ethyl ester

10.3 g (0.26 mmol) of 60 % sodium hydride in mineral oil are washed twice with dry hexane, dried under reduced pressure, suspended in 245 ml of anhydrous tetrahydrofuran and cooled to 0 ^° C. in an egg / water bath under argon. The suspension is treated dropwise with 24.5 g (0.12 mol) of Ver bond of Part A within 20 minutes, then warmed to room temperature and stirred for a further 30 minutes. The reaction mixture is cooled in the ice / water bath to 0 ⁰ C, treated dropwise with 18.62 g (0.17 mol) of isobutyryl chloride, to room temperature, .heated and stirred for 3.0 hours. Then the mixture is cooled in the ice / water bath to 0 ⁰ C and quenched with 200 ml of water, creating a homogeneous solution which is evaporated on a rotary evaporator to remove most of the tetrahydrofuran. The aqueous phase is acidified to pH 1.0 with 37 ml of 10% HCl and extracted with 3 times 100 ml of diethyl ether. The combined organic extracts are washed with brine (50 ml), dried over anhydrous MgSO 4, filtered and evaporated to dryness. Yield: 36.85 g of oil which is a mixture of starting material and two further products.

TLC: R _f = 0.46, 0.33, 0.20 (silica gel, CH ₂ Cl ₃ : hexane-4: 1, UV).

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

36.85 g (about 0.12 mol) of the crude compound of Part B are dissolved in 151 ml of glacial acetic acid and treated intermittently with 18.1 ml (0.18 mol)

-106-

97 % phenylhydrazine under nitrogen and 19 hours be '. Room temperature stirred. The reaction mixture is poured into 350 m 3 of water, extracted 3ma.l with 100 ml of diethyl ether and the combined organic extracts are washed with saturated NaHCO 3 solution until the aqueous layer is basic, then washed with 500 ml of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

yes The dark orange oil is evaporated tinctimally from 300 ml of petroleum ether to give a yellow solid. This crude product is digested with 100 ml petroläther to give 15.3 g of crude product, which are in turn saulenchromatographierc on silica gel LPS-1, wherein the jg column with CH ₂ C1 _? : Hexane (2: 1) is eluted. Yield:

11.53 g of pure product. 26.4 g of mother liquor give in the chromatography on a column ivifc silica gel LPS-1 and Di

, ...-.- ing of the compound obtained further 7.12 g desired

•. '. "C - - ..- tes product": (total yield .18.6 g or 44.1 %) . A small amount of the title compound is recrystallized from Et ₂ O: hexane to give a homogeneous solid of mp 92 to 93 ° C

TLC: R _f = 0.35 (silica gel: CH ₂ Cl ₂ : hexane -4: 1)

25 analysis:

71 C 6 H 7, N 5 F About: 71 , 57 5 .01 7th 95 5 .39 gef. : , 62 99 91 .54

D, 5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole-4-methanol

A solution of 11.53 g (32.7 mmol) of compound C in 142 ml of anhydrous diethyl ether is added dropwise over 1.5 hours to a suspension of 3.67 g (cooled to 0 ° C. in ice / salt bath). 96.7 mmol) of lithium aluminum hydride in 70 ml of anhydrous diethyl ether under argon.

-1 67-

ben. The greenish suspension is warmed to room temperature over 1.5 hours, cooled again to 0 ^° C. in the ice / salt bath and quenched by the dropwise addition of 20 ml of water until the evolution of gas ceases. The thick slurry is diluted with 100 ml of diethyl ether and filtered. The precipitates are washed well with 3 times 150 ml of ethyl acetate. The combined organic extracts are washed with 50 mL brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. There are obtained 10.3 g (100 % crude yield) cream-colored solid. 100 mg of crude product are recrystallized from Et "O: hexane to give 58 mg of the title compound as white crystals of mp 138 to 14O ⁰ C. TLC: R _f = 0.01 (silica gel, CH ₂ Cl ₂ )

Analysis for: CHFN

Calc .: 73.52 6.17 6.12 9.03

- .: ...... .. gef.:.73,76 6,15 6,12 8,90

MS (M + H) ⁺ = 311

E. 5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyra-.sol-4-carboxaldehyde

A solution of 10.2 g (about 32.7 mmol) of the crude compound of Part D in 85 mL of anhydrous dichloromethane is added rapidly to a solution of 21.23 g (98.4 mmol) of pyridinium chlorochromate in 125 mL of anhydrous dichloromethane and the resulting dark brown solution stirred for 4.0 hours under nitrogen at room temperature. The mixture is diluted with 750 ml of ether and stirred for 10 minutes. The supernatant solution is decolorized from the tarry residue and the residue digested with 2 times 100 ml of dichloromethane. The dichloromethane extracts are diluted with 750 ml of ether and the combined extracts are filtered through silica gel. The clear filtrate is evaporated to dryness to give 10.0 g of crude product.

-1 68-

H 9 N 6 F 5 .56 9 .09 6 16 5 , 52 12 , 29

The crude product is chromatographed on a column of silica gel (Baker, 60-200 mesh, 400 ml) eluting the column with CH ₂ Cl ₂ : hexane (4: 1). Yield: 9.6 g (95.2 %) of the title compound as a solid. An analytical sample (72 mg, mp 108 to 11O ⁰ C) is obtained by recrystallization of 100 mg of hexane.

TLC: R _f 0.58 (silica, CH ₂ Cl ₂ , UV). Analysis: C

calculated: 74.01

₁₀ f .: 74.10

MS (M + H) ⁺ = 309.

F. 4- (2,2-Dibromoethyl) -5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole

A mixture of 2.0 g (6.48 mmol) of compound E and 5.10 g (19.2 mmol) of diphenylphosphine in 30 mL of anhydrous di- • chloromethane is added in the ice / Sa.l bath under argon Cooled to -10 ⁰ C and then added dropwise within 5 minutes with a solution of 3.22 g (9.61 mmol) of carbon tetrachloride in 10 ml of anhydrous dichloromethane. The Heaxtionsgemisch is stirred for 15 minutes at 15 to 20 ⁰ C and then 10 ml saturated NaHCO ₃ solution and extracted with 3 χ 50 ml dichloromethane. The combined organic extracts are washed with 10 mL of saturated NaHCO 3 solution and 25 mL of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

The crude product mixture (9.33 g) is chromatographed on a column with KieselgO gel LPS-1, wherein the column with CH-Cl-:

Hexane mixtures (1: 9, 1: 1, 4: 1) is eluted. Yield: 2.75 g (91.6 %) of the title compound as a solid. Recrystallization of a sample of the title compound gives white crystals of mp 88 to 90 ⁰ C.

TLC: R _f 0.85 (silica gel, CH ₂ Cl ₂ : hexane-4: 1)

-169-

analysis ι About: 51 C 3, H 6 N 4 P 34 br gef. : 51 75 3, 69 5 , 04 4 , 09 34 , 43 ) ⁺ = 465. 96 51 97 , 22 77 MS (M + H

G. 4-Ethinyl-5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazole

A solution of 2.64 g (5.67 mmol) of Part F compound in 10.5 ml of anhydrous tetrahydrofuran / acetone bath is then cooled to -78 ⁰ C under argon in dry ice and treated dropwise with 7.16 ml (11.37 mmol) 1.6M n-BuLi / hexane. The resulting suspension is stirred for 1 hour and 20 minutes at -78 ⁰ C, quenched by dropwise addition of 10 ml of 25% NH.Cl solution and warmed to room temperature. The reaction mixture is extracted with 3.times.50 ml of diethyl ether and the combined organic extracts are washed with brine (20 ml), dried over anhydrous MgSO4, filtered and evaporated to dryness to give 1.79 g of the title compound as a tan.

The crude product is chromatographed on a column of silica gel and Et _? 0: hexane (5:95) elutes. Yield: 1.08 g (97.4 %) of the title compound as a light gold solid. Recrystallization of a small sample from hexane gives white fluffy crystals, melting at 106 to 108 ⁰ C. TLC: Rf 0.70 (silica gel; Et "O: hexane 1: 9; 2 times developed) MS (M + H) ⁺ = 305 ,

H. (S) -3 - [[(1,1-Dimethylethyl) diphenylsilyl-3-oxy] -4-C [[5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H- pyrazol-4-yl-J-ethylamin-1-methoxyphosphinyl]] -butyric acid methyl ester

A mixture of 277 g (5.55 mmol) of the monomethyl phosphonate of Example 1, Part F (crude), and 2.1 ml (11.05 mmol).

-170-

1 trimethylsilyldiethylamine in 10 ml of anhydrous dichloromethane.

methane is stirred for 1.0 hour at room temperature under argon. Then the mixture is evaporated to dryness, azeotroped with 20 ml of anhydrous benzene and dried for 15 minutes under reduced pressure (pump). The viscous oil is then dissolved in 10 ml of anhydrous dichloromethane again, treated with 1 drop of DMF, cooled in an ice / salt bath to -10 ⁰ C and treated dropwise with 530 μΐ (6.08 mmol) of oxalyl chloride. It occurs vigorous evolution of gas and the dark yellow solution is stirred for 15 minutes at -10 ⁰ C and then for 1 hour at room temperature. The reaction mixture is evaporated to dryness with ^! Distilled 20 ml of benzene azeotropically and dried under reduced pressure.

A solution of 1.12 g (3.67 mmol) compound of Part G in 9.0 ml of tetrahydrofuran is cooled to -78 ° C under argon in dry ice / acetone bath and treated with 2.3 ml (3.67 mmol). Treated with 1.6M n-BuLi / hexane and stirred at -78 ° C for 30 minutes. The phosphonochloridate described above is dissolved in 6.5 ml of tetrahydrofuran, cooled in the dry ice / acetone bath under argon to -78 ⁰ C and treated dropwise by cannula with the solution of the acetylene anion, both solutions during the addition to -78 ° C are kept. The reaction mixture is stirred for 30 minutes at -78 ⁰ C, and the order-setting quenched by dropwise addition of 6.0 ml of 25% NH.Cl solution and the mixture was warmed at room temperature. The mixture is extracted with 3 × 100 ml of diethyl ether and the combined organic extracts are washed with 10 ml of 25 % NH.Cl solution and 25 ml of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

The crude product mixture (about 4.2 g) is chromatographed on a column of silica gel and the column is eluted with hexane: acetone (9: 1). Yield: 1.54 g (57.0 %) of the title compound as a light brown oil.

-171-1 TLC: R _f = 0.33 (silica gel, hexane: acetone - 7: 3).

I. (S) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-

phenyl-1H-pyrazol-4-yl] -äthinyl3-methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

A solution of 593.9 mg (0.81 mmol) of Part H compound in 8.0 mL of anhydrous tetrahydrofuran is added gradually with 190 μΐ (3.24 mmol) of glacial acetic acid and 2.54 mL (2.54 mmol). Treated 1M Bu.NF and stirred under argon at room temperature for about 15 hours. The reaction mixture is cooled in an ice / water bath to 0 ⁰ C, treated with 8.5 ml 5% KHSO ₄ solution and extracted with 3 ~ χ 75 ml of ethyl acetate. The combined organic extracts are washed with 10 ml of 5 % KHSO.-solution and 20 ml of brine, over anhydrous MgSO. dried, filtered and evaporated to dryness.

The crude product is dissolved in a mixture of 14 ml of diethyl ether and 10 ml of dry tetrahydrofuran, cooled in an ice / salt bath to 0 ⁰ C, treated with excess Diazomethandiäthyläther and stirred at 0 ⁰ C for 3.0 hours. The reaction is then stopped by dropwise addition of glacial acetic acid and the mixture is evaporated to dryness and dried under reduced pressure. The crude product is chromatographed on a column of silica gel and the column is eluted with acetone: hexane (1: 2). Yield: 325.6 mg (80.6 %) of the title compound as a semi-solid.

30 Example 37

(S) -4- [Q2- [5- (4-Fluorophenyl) -3- (1-methyl-ethyl) -1-phenyl-1H-pyrazol-4-yl-3-ethynyl-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

A solution of 325 mg (0.65 mmol) of the compound of Example 36 in 7.7 ml of dioxane is charged with 2.25 ml (2.25 mmol) of 1N LiOH.

-1 72-

and stirred for 1.5 hours in an oil bath under nitrogen at 55 ° C and then 16 hours at room temperature. The reaction mixture is evaporated to dryness and dried under reduced pressure. The crude product is chromatographed on a HP-20 (Γ ¹ χ 5 ") column and the column is eluted with 400 ml of steam-distilled water and 500 ml of 50 % aqueous CH 2 OH The desired fractions are combined, evaporated to dryness and concentrated under reduced pressure The solid product is dissolved in steam-distilled water and lyophilized Yield: 317.1 mg (96.4 %) of the title product as a fluffy solid lyophilate TLC: R _p 0.33 (silica gel; i-PrOH: HH ₄ OH : H ₂ O - 8: 1: 1).

(. Mol wt = 505.861 Eff.) Analysis for C ₂₄ H ₂₂ FN ₃ O ₅ P · 2 Li 1.3 H ₂ O: C HNFP

Calculated: 56.99 4.90 5.54 3.75 6.12 Found: 56.98 5.17 5.46 3.90 6.26

H ¹ NMR spectrum (400 MHz, CD ₃ OD):

6 1.40 (d, 6K, J = 7 Hz)

on

™ 1.81-1.98 (m, 2H)

2.35 (dd, IH, J = 9, 15 Hz)

2.48 (dd, IH, J = 4, 15 Hz)

3.35 (septet, IH, J = 7 Hz)

4.42 (m, IH) ·

25

7: 8-7: 41 (m, 9H).

IR (KBr): 2173 cm ^-1 (CnC).

30 Example 38

(E) -4 - [[2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-YLJ-äthenyi] -3-hydroxybutyric -methoxyphosphinylj ¹

acid methylester

A. [2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] ¹ -2-hydroxydithylphosphonic acid e-dime thy 1- ester

J-.

-173-

A solution of 2.81 ml (25.9 mmol) of dimethyl methylphosphonate in C0 ₂ / acetone cooled to -78 ° C in 50 ml of anhydrous THF is charged with 15.2 ml (24.3 mmol) of 1.6M n-BuLi solution treated dropwise in hexanes within 15 minutes and the resulting after about 15 minutes white suspension for 1 hour under argon at -78 ⁰ C stirred. Then treated dropwise within 10 minutes 5.0 g (16.2 mmol) Pyrazolaldehyd of Example 36, Part E, in 15 ml of anhydrous THF and the yellow mixture 30 minutes at -78 ⁰ C is stirred. The mixture is quenched with 20 ml of saturated NaCl solution and warmed to room temperature. The mixture is partitioned between H 2 O and EtOAc, the organic phase washed with brine, over anhydrous Na ₂ SO ₄ . dried and evaporated, giving 7.158 g of crude β-hydroxyphosphonate titled

Ig compound can be obtained as a yellow foam. A small sample is crystallized from hexanes to give pure title compound as white crystals, mp 126-128 ° C.

TLC (1: hexane-acetone, R _f = 0.27.

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

25

analysis for C ₅ ! 2 ^H 26 ^C About: ) 61 C, 10 6 H, 06 6 N, 48 4, F 39 7, P 16 gef. : 60 95 6 , 06 6 .41 4, 22 7, 27 ¹ H NMR 6 (CDCl ₃ 1.42 ί ): 6Η. d

1.94-2.40 (2H ₁ m) 3.29 (IH, Septet)

3.62 + 3.63 (2 doublets ", J _H _ _p = II, 1 Hz) 3.91 (IH, s) 5.11 (IH, bm) 6.90-7.30 (9H, m) ppm.

35

28 I 60S

-1 74-

¹³ C NMR (CDCl ₃ ): 6 22,6, 26,5, 32, 8 (J _{c p} = 136.3 Hz), 52.1 (J _cp = 5.7 HZ), 60.8, 115.0, 115.4, 119.3, 119.5, 124.7, 126.3, 126.6, 128 _; 5, 132.2, 132.3, 139.4, 139.5, 156.7, 164.5 (J _{c p} = 265 Hz) ppm.

B. (E) - [2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl3 -athenylphosphonic acid dimethyl ester

A solution of 7.158 g of crude hydroxyphosphonate from Part A

in 40 ml of anhydrous benzene is treated with 304 mg (1.6 mmol) of pTsOH'H_O and the mixture is refluxed for 2 hours under argon through a Dean-Stark trap with 4 A sieve. The mixture is cooled, diluted with EtOAc, the Io

washed organic phase 2 times with saturated NaHCO.-solution and with brine, then over anhydrous Na ₀ SO. dried and evaporated under reduced pressure to give 6.893 g of yellow oil. The crude oil is treated with hexane to give 5.692 g of nearly pure vinyl phosphonate as off-white crystals. Recrystallization from EtOAc-hexane gave in two crops 5.655 g (84.2% overall yield from the aldehyde) of pure trans-vinyl phosphonate-title compound in the form of white needles melting at 143-144 ^O C.

Mass spectrum (M + H = 415, observed).

TLC (1: 1) hexane-acetone, R _f = 0.40

Analysis for C ₂₂ H ₂₄ O ₃ PN ₂ F: C HNFP

: 63.76 5.84 6.76 4.58 7.47 gefi: 63.99 5.95 6.76 4.54 7.31

28i60S

-175-

¹ H NMR (CDCl ₃ ):

δ 1.42 (6H, d)

3.27 (IH, Septet)

3.70 (6H, d, _JH _ _p = ll, 0 Hz)

5.67 (IH, dd, ^ = 18.4 Hz, ^ = 18.5 Hz)

7.02-7.30 (9H, m)

7.34 (IH, dd, ^ = 18 Hz, ^ = 24.3 Hz) ppm.

¹³ C NMR (CDCl-): 621.8, 27.1, 52.1 (J _{r D} = 5.7 Hz), ^1U 110.4 (J _ _{c p} = 193, l Hz), 114.7 ( J _c _ _p = 24.6 Hz), 115.9, 116.2, 122.2, 124.9, 125.5, 127.3, 128.8, 132.0, 139.2, 140.2 _(c _ J _p = 7.6 Hz), 142.1, 158.0, 163.4 (J _C _ _F = 249.8 Hz) ppm.

C. (E) - [2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl3-ethenyl] -phosphonic acid monomethyl ester

A solution of 2.0 g (4.83 mmol) of Part B dimethylphosphonate in 15 ml of dioxane is treated with 7.3 ml of 1.0 N LiOH and the mixture is refluxed under argon for 1 hour. The mixture is cooled to room temperature acidified to pH 1 with 1.0N HCl, extracted 2 times with EtOAc, extracted the

25 ganic phase with 1.0N HCl and brine, then anhydrous Na ₁₁ SO. dried and evaporated under reduced pressure to give the crude monoacid, which crystallizes slowly from hexane on standing. The crystals are filtered off and concentrated under reduced pressure

30 dried. Yield: 1.918 g (99%) was prepared monoacid title compound as a white crystalline solid, mp 168-170 ⁰ C. An analytical sample is by Umkristallisatxon from EtOAc-hexane.

TLC (8: 1: 1) CH ₂ Cl ₂ -CH ₃ CH-HOAc, R _f = 0.40. Mass spectrum (M + H ⁺ = 401 ⁺ , observed).

Analysis for C

-176-

, PF: C HNFP

Calculated: 62.99 5.54 7.00 4.75 7.74

Filled: 62.95 5.57 6.87 4.58 7.58

¹ H NMR (CDCl ₃ ):

δ 1.40 (6H, d)

3.26 (IH, Septet)

3.65 (3H, d, J _Hp = II _, 6 Hz)

5.74 (IH, dd, J _HH = 17.9 Hz, J _Hp = 19.5 Hz)

7.00-7.36 (10H, m)

8.65 (IH, bs) ppm.

¹³ C NMR (CDCl ₃ ): 6 21.8, 27.0, 51.8 (J _c _ _p = 6 ₇ 3 Hz) 111.7 (J _cp = 198.7 Hz), 114.6 (J _{c p} = 24.6 Hz), 115.8, 116.2, 124.9, 125.4, 127.3, 128.7, 131.9, 132.1, 138.8 (J _c _ _p = 7.6 Hz) _; , 139,2, 142,0, 157 _; 9, 162.9 (J _C _ _F = 249.8 Hz) ppm.

D. (E) -4 - [[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl-3-phenyl] -methoxyphosphinyl] -3-oxobutyric acid methyl ester

The dianion of methyl acetoacetate is prepared by the method of Example 26 using the following amounts: 815 μl (7.53 mmol) of methyl acetoacetate, 324 mg (8.11 mmol) of 60 % NaH dispersion in oil, 4.3 ml (6.95 mmol) of 1.6M N-BuLi in hexanes and 15 ml of THF.

A solution of γ 2,317 g (5.79 mmol) of phosphonic acid and 1.45 ml (10.6 mmol) of trimethylsilyldiathylamine (TMSDEA) in 15 ml of CH ₂ Cl ₂ is stirred for 1 hour at room temperature. The mixture is evaporated to dryness, expelled with 20 ml of benzene and dried under reduced pressure. The residue is taken up in 15 ml of anhydrous CH ₂ Cl-, treated with 555 μl (6.37 mmol) of (COCl) ₂ and 1 drop of DMF

-177-

and stirred for 1 hour at room temperature. The mixture is evaporated to dryness, expelled with 20 ml of benzene and dried under reduced pressure.

A cooled in CO./Aceton to -78 ° C solution of the above phosphonochloridate in 10 ml of anhydrous THF is added dropwise by cannula within 20 minutes in a cooled to -78 ° C solution of the methyl acetoacetate dianion in 5 ml of anhydrous THF. The brown mixture is stirred for 30 minutes at -78 ⁰ C and the reaction then quenched by dropwise addition of 10 ml of saturated NH.Cl solution and the mixture warmed to room temperature. The mixture is partitioned between H 2 O and EtOAc, the aqueous phase back extracted with EtOAc, the combined organic phases washed with saturated NaHCO 4 solution and brine, over anhydrous Na 2 SO 4. dried and evaporated under reduced pressure to give 3.080 g of orange-colored foam. The crude product is purified by flash chromatography on silica gel (Merck) and elution.

20 tion with hexane-Acnton-toluene (5: 3: 2).

The product fractions are combined and evaporated. Yield: 1.247 g (43.2 %) of the desired β-ketophosphonate title compound as a pale yellow oil.

25 TLC (4: 4: 2) acetone-hexane-toluene, R _f = 0.29. Mass spectrum (M + H ⁺ = 40O ⁺ , observed).

¹ H NMFl (CDCl ₃ ):

δ 1.42 & 1.43 (6H, 2 doublets)

30 '3.24 (2H, m)

3.27 (IH ₁ septet)

3.63 (2H, m)

3.66 & 3.67 (3ΙΪ, 2 doublets, J _H _ _p = ll, 6 Hz)

3.72 (3H, s)

35 5.72 (IH, dd, ^ = 18.7 Hz, '^ = 24.3 Hz)

7,08-7, .to (9H, m)

7.37 (IH, dd, ^ = 18.0 Hz, Jgp-22.7 Hz) ppm.

-178-

¹³ C NMR _(CDCl3): - 621.8, 27.1, 46.1 (J = 84 _cp; l Hz), 50.0, 51.2 (J _ _{c p} = 5.9 Hz), 52.3, 112.6 (J _cp = 135 _, 0 Hz), 114.5 (J _cp = 23.5 Hz), 116.0, 116.3, 124.9, ₅ 125.4, 127.4 , 128.8, 132.0, 132.1, 139.1, 141.4 (J _cp = 5.9 Hz), 142.5, 158.2, 163.1 (J _cp = 250.4 Hz), 167.1, 194.9, 195.0 ppm.

E. (E) -4 - [[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl- Iq1H -pyrazol-4-yl]] -ae'thenylj-methoxyphosphinyl ] -3-hydroxybutyric acid methyl ester

A solution of 1.304 g (2.62 mmol) of Part D ketone in 15 ml of anhydrous ethanol, cooled to -15 ° C. in the salt / ice bath

! 5 is mixed with 100 mg (2.62 mmol) NaBH. treated and the mixture for 15 minutes under argon at -15 ⁰ C stirred. Then, the reaction is carried out by adding 0.3 ml of reagent acetone followed by -. 600 mg of silica gel CC-4, broken off, the mixture on Raumi. heated, diluted with EtOAc, filtered and placed under

Evaporated under reduced pressure to give 1.46 g of yellow foam. The crude product is purified by flash chromatography on silica gel (Merck) and elution with EcOAc-acetone (85:15). The product fractions are evaporated, yield: 388 mg pure alcohol title compound as white foam plus 228 mg slightly contaminated product. Total yield: 616 mg (47 %). TLC (7: 3) EtOAc acetone, R _f = 0.31

 Mass spectrum (M + H = 501, observed).

¹ H NMR (CDCl ³ ): 30 ³

θ 1.42 (6H, d)

2.00 (2H, m)

2.60 (2H, d)

3:27 (IH, d)

₃₅ 3.64 (3H, d, J ₁ JP = Il,! Hz)

3.69 (3H ₁ s)

3.93 & 4.02 (IH, 2 doublets)

2 8 ί 6 O

-179-1 4,42 (IH, 2 broad singlets)

5.72 (IH, dd, ^ = 18.0 Hz, J _Hp 23.2 Hz) 7.04-7.47 (1OH, m) ppm.

5 ¹³ C NMR (CDCl ₃ ): δ 21.8, 27.1, 35.7 & 36.5

(J _cp = 100.3 Hz), 42.0, 42.2, 50.8 (J _cp = 5.7 Hz), 51.6, 63.4 (J _cp = 20.8 Hz), 114, 2 & 114.4 (J _cp = 128.7 Hz), 114.6 (J _cp = 20.8 Hz), .115.9, 116.3, 124.9, 125.4, 127.3, 128 , 8, 131.9, 132.1, 139.1, * 10,140, l & 140.6 (J _cp = 5.7 Hz), 142.1, 158.0, 163.0 (J _CF = 251.6 Hz), 171.2, 171.9 ppm.

Example 39

(S) -4- [2- (5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-ylJ-ethenyl-1-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt.

A solution of 487 mg (0.973 mmol) diester of Example 38 in 10 ml of dioxane is treated with 3,4ml (3.4 mmol) of 1.0N LiOH and the resulting mixture heated for 30 minutes to 70 ⁰ C and stirred. The mixture is cooled, diluted with H 2 O, filtered and evaporated under reduced pressure to an off-white solid. The crude product is dissolved in the least amount of H ₂ O and chromatographed on resin HP-20 (15 cm bed, 25 mm column diameter) and eluted with H ₂ O and then CH ₃ OH-H ₂ = (1: 1). The product fractions are evaporated under reduced pressure, the residue dissolved in 75 ml H "O, filtered and lyophilized. Yield: 429 mg (87.3 % pure dilithium salt title compound as flavinous white lyophilate, TLC (8: 1: 1) CH ₂ Cl ₇ -CH ₃ OH-HOAc, P. _f = 0.14

Analysis for C ₂₄ H ₂₄ O ₅ N ₂ PF ^ Li ₂ +

1, ie mole H ₂ O (MW 505.233): CHNFP

: 57.05 5.25 5.55 3.76 6.13

Filled: 57.05 5,18 5, "^ 3,89 6,47

28i60 5

- -180-

¹ H NMR (400 MHz, CD ₃ OD):

δ 1.39 (6H, doublet)

1.71 (2H, m)

2.35 (2H, m)

3.36 (IH, septet) 4.24 (IH, m)

6.00 (IH, dd, ^ = 17.6 Hz, ^ = 19.4 Hz) 7.07-7.35 (1OH, m)

Example 40

(E) -4- [ε- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl3-ethyl-1-methoxyphosphinyl] -3-hydroxybutyrate

acid methyl ester. ,

A. (S) -3- [ε (1,1-dimethylethyl) diphenylsilyf] oxy] -4-

CC ² "C" ^{5 "} - ⁽ 4-f-luorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethyl [-methoxyphosphinyl] -butyric acid methyl ester

A solution of 912 mg (1.24 mmol) compound of Example 36, Part H, in 50 ml of anhydrous methanol is treated with 10 % Pd / C and hydrogenated on a Parr apparatus for approximately 15 hours at approximately 3 bar hydrogen pressure. The suspension

is filtered through diatomaceous earth and the filtrate to dryness 25th

evaporated and dried under reduced pressure. Yield: 908.3 mg (99.1 %) of the title compound as a homogeneous oil. TLC: R _f = 0.23 (silica gel, hexane: acetone - 7: 3).

B. (S) -4- [2- [5- (4-fluorophosyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethyl-methoxyphosphinyl-S-hydroxy- butyric acid methylester

A solution of 908.3 mg (1.23 mmol) of Part A compound in 12 mL of anhydrous tetrahydrofuran is added under argon

Stirred room temperature and treated successively with 0.9 ml (4.94 mmol) of glacial acetic acid and 3.89 ml (3.89 mmol) of 1.0M Bu.NF / hexane.

 28 ° 5

-181-

is. The reaction mixture is stirred for 20 hours at room temperature, diluted with 25 ml of ice-water and extracted with 3 times 100 ml of ethyl acetate. The combined organic extracts are washed with 15 mL of saturated NaHCO 3 solution and 25 mL of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

1.0 g of crude product mixture is chromatographed on a column of silica gel LPS-1 ( ¹ × 9.5 ") and the column is eluted with EtOAc: hexane mixtures (4: 1, 9: 1), EtOAc and acetone TLC: R ₄ s 0.17 (silica gel, EtOAc: hexane -, 4: 1): 529.1 mg (85.6 %) of the title compound as an oil.

Example 41

(S ) -4-1 \ 2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl [] -ethyl3-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium

A solution of 529.0 mg (1.05 mmol) compound of Example 40 in 12.5 ml dioxane is treated with 3.7 ml (3.7 mmol) of 1, ON LiOH solution and added to oil bath for 3.0 hours 55 ⁰ C under nitrogen and then stirred for 20 minutes at room temperature. The reaction mixture is evaporated to dryness and dried under reduced pressure. The crude product is chromatographed on a column of HP-20 (1 "χ 6") and the column chromatographed with 750 ml of steam-distilled water, 500 ml of 10 % aqueous CH ₃ OH, 500 ml of 20 % aqueous CH-OH and 500 ml of 50 % aqueous CH-OH elutes. The desired fractions are grounded

jjQ combined, evaporated to dryness and dried under reduced pressure. The resulting solid is dissolved in 35 ml of steam-distilled water and lyophilized. Yield: 510 mg (92.4 %) of the title compound as a fluffy white solid.

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

-182-

Analysis for C ₂₄ ^H 26 ^{FL i} 2 ^N 2 ° 5 ^P ' 2, O U έ Π λ ⁰ 5 H 5 N 3 F 5 P (Mol. Wt. = 525 .899): C 5 , 83 5 , .33 4 , 61 5 , 88 About: 54 , 81 , 61 , 53 , 06 80 Found .: 54 , 81

IR (KBr) (1596 cm ^-1 , C = O of COO ~).

Spectrum (400 MHz, CD ₃ OD): δ 1.36 (d, 6H, J = 7)

1.60-1.72 (m, 4H)

2.32 (m, 2H).

2.74 (m, 2H) 3.21 (septet.lH, J = 7) 4.23 (m, IH) 7.06-7.32 (m, 9H). 15

Example 42

, · R (S) t4-Q2-L ³ - (4-fluorophenyl 1-.5- (.1-methylethyl) -1-phenyl-1 H-

Methyl pyrazol-4-yl) -äthinyl ^ -methoxyphosphinyl] -3-hydroxybutyrate

A. 4-fluorobenzoic acid 2-phenylhydrazide

A mixture of 25 ml (0.25 mmol) of phenylhydrazine and 35 ml (0.25 mmol) of triethylamine in 500 ml of anhydrous diethyl ether is cooled in ice / salt bath under nitrogen to -5 to -10 ⁰ C and dropwise treated with 30 ml (0.25 mmol) of 4-fluorobenzene carbonyl chloride within 30 minutes. The reaction mixture is warmed to room temperature, stirred for 3.0 hours, then filtered and the solids washed well with 200 ml of diethyl ether. The solids are dissolved in 600 ml of dichloromethane, stripped to near dryness, suspended in 600 ml of hexane and filtered. The clear filtrate is evaporated to dryness, digested with 700 ml of tetrahydrofuran and filtered. The solids are washed well with 100 ml of tetrahydrofuran. The filtrate is evaporated to dryness and dried under reduced pressure, v / o-

-183-

obtained at 34.6 g with two other components contaminated crude product. The crude product is recrystallized from acetone. Yield: 22.36 g (38.8 %) of the title compound as white crystals from P. 182 to 184 ^° C.

The filtrate and the mother liquor are combined and chromatographed on a column of silica gel (Baker, 60-200 mesh, 400 ml). The column is eluted with EtOAc: CH-Cl (1: 9). Yield: 9.78 g (55.8 %) of additional title compound. TLC: R _f = 0.63 (silica gel: EtOAc: CH ₂ Cl ₂ -1: 4).

Analysis for

FN ₂ O: 67 C 4 H 1 2 N 7 8th, F calc .: 67 , 81 4 , 82 1 2 J 4 8th, 25 Gef .: , 86 , 88 J 10

MS (M + H) ⁺ = 231.

 -.... ·. · ..; .B .-: ·. ^ Fluoro-N- ^ phenylbenzolcarbohydrazonoylchlorid

A solution of 6.16 g (26.8 mmol) of compound A in 46 ml of anhydrous diethyl ether is treated with 6.6 g (31.7 mmol) of phosphorus pentachloride and the reaction is refluxed for 16 hours under nitrogen. The reaction mixture is then cooled to room temperature, with

"C of a solution of 11.5 g (122.2 mmol) of phenol in 15 ml" diethyl ether, stirred for 5 minutes and then treated dropwise with 11.4 ml of methanol. The mixture is concentrated at -75 ° C in a rotary evaporator and The resulting oil is cooled to 5 ^° C. The resulting solid is washed with 20 ml 5 %.

_ _N digested aqueous acetone and filtered. The rainfall

you

is washed well with 30 ml of 5 % aqueous acetone. The precipitate is dried under reduced pressure. Yield: 2.2 g of title compound as a solid of mp 118 to 120 ^° C.

The clear filtrate is evaporated to dryness and the pro-

OO

Duktgemisch 2 times on a column with silica gel (Baker, 60 bis

-184-

1200 mesh, 400 ml). The column is with

CH ₂ Cl ₂ and hexane mixtures (1: 3; 1: 1) eluted. There will be more title connection. Total yield: 5.66 g (85 %).

5 TLC: R _f = 0.90 (silica gel, CH ₂ Cl ₂ : hexane -4: 1).

Analysis for C ₁₃ H ₁₀ FN ₂ Cl: CHNF Cl

calculated: 62.78 4.05 11.27 7.64 14.26

Filled: 62.87 3.97 11.34 7.51 13.95 10 MS (M + H) ⁺ => 249.

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

A solution of sodium ethoxide from 0.28 g (12 mmol) of sodium metal and 40 ml of absolute ethanol is treated dropwise under nitrogen with 2.0 ml (12 mmol) of isobutyrylacetic acid ethyl ester, stirred for 15 minutes at room temperature and then admixed with 3.0 g ( 12 mmol) of Part B compound.

The mixture is stirred at room temperature for 4 hours, quenched with 10 ml of 10 % HCl, evaporated to dryness and the resulting solid triturated with 3 times 100 ml of diethyl ether. The combined organic extracts are washed with brine (25 ml), dried over anhydrous MgSO 4,

25 filtered and evaporated to dryness. The crude product

(4.3 g) is chromatographed on a column of silica gel and the column with CH ₂ Cl-: hexane (1: 1) eluted. Yield: 3.27 g (77.3 %) of the title compound as a reddish brown syrup. TLC: R _f = 0.42 (silica gel, CH ₂ Cl ₂ : hexane -4: 1).

D. 3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole-4-methanol

A solution of 3.26 g (9.25 mmol) of Part C compound in 22 ml of anhydrous diethyl ether is added to a cooled in an ice / Sal bath to 0 ⁰ C suspension of 0.71 g (18.7 mmol)

28

-185-

Lithium aluminum hydride in 32 ml of anhydrous diethyl ether and the reaction mixture was stirred for 3 hours under nitrogen at 0 ⁰ C. The reaction is then stopped at 0 ^° C. by dropwise addition of 5.0 ml of ethyl acetate and then 11 ml of 10 % HCl, the mixture is decanted and the residue is digested twice with 100 ml of diethyl ether. Wash the combined organic extracts with 20 mL brine, dry over anhydrous MgSO ₄ , filter, and evaporate to dryness. Yield: 2.87 g (94.4 %) of the title compound.

100 mg of the title compound are recrystallized from diethyl ether to give 57 mg of analytical sample of mp 145 to 147 ⁰ C et.

TLC: R _f = 0.17 (silica gel; CH ₂ Cl ₂ : hexane - 4: 1, 2 χ developed).

, :. .. "Analysis for C ₁₉ H ₁

MS (M + H) ⁺ = 311.

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

A solution of 2.59 g (8.34 mmol) of compound D in 22.0 mL of anhydrous dichloromethane is added rapidly with stirring to a suspension of 5.41 g (25.1 mmol) of pyridinium chlorochromate in 32 mL of anhydrous dichloromethane and the mixture was stirred for 4 hours at room temperature under nitrogen. Then, the reaction mixture is diluted with 190 ml of diethyl ether, boasted for 20 minutes and then decanted. The resinous residue is digested with 100 ml of diethyl ether and 30 ml of dichloromethane and the combined organic extracts are filtered through silica gel. The clear filtrate is evaporated to dryness and the crude product on a

₂ 0 :: 73 C 6 H 7 9 N 6 F About: 73 , 52 6 ,1 1 8th , 03 6 12 gef. : , 26 ,1 96 , 09

28U05

-186-

Column with silica gel (Baker, 60 to 200 mesh, 300 ml) chromatographed. The column is filled with CH ₂ C1 _? : Hexane (4: 1) elutes. Yield: 2.40 g (93.4 %) of the title compound as a solid.

100 mg of the title compound were recrystallized from hexane to 50 ml of analytical sample of melting point 103-105 ⁰ C. TLC: R _f = 0.67 (silica gel, CH ₂ Cl ₂ ).

10 Analysis for C ₁₉ H ₁₇ FN ₂ O: CHNF

: 74.01 5.56 9.09 6.16

found: 74.18 5.35 9.11 6.12 MS (M + H) ⁺ = 309.

F. 4- (2,2-Dibromoethyl) -3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazole

A mixture of 2.296 g (7.45 mmol) of the compound of Part E... And 5.86 g (22.1 mmol) of triphenylphosphine in 35.0 ml of water.

20 free dichloromethane is added in the ice / sal bath under argon

Cooled to -10 to -10 ° C and added dropwise within 5 minutes with a solution of 3.70 g (11.0 mmol) of carbon tetrabromide in 12 ml of anhydrous dichloromethane and stirred at -10 ⁰ C for 20 minutes. Then the reaction mixture is warmed to room temperature, poured into 12 ml of saturated NaHCO ₃ solution and extracted with 3 times 60 ml of dichloromethane. Wash the combined organic extracts with 12 mL of saturated NaHCO3 solution and 10 mL of brine, over anhydrous MgSO4. dried, filtered and dried.

30 ne evaporated.

The solid crude product (11.0 g) is chromatographed on a column of silica gel. The column is eluted with mixtures of CH ₂ Cl ₂ : hexane (1: 1, 4: 1). Yield: 2.96 g (96 % corrected yield) of the title compound and 250.6 mg of unreacted starting material.

28

-187-

100 mg of the title compound are recrystallized from Et "O: hexane to give 36.5 mg of analytical sample of mp 93.5 ° C. TLC: R _f = 0.57 (silica gel, CH ₂ Cl ₂ : hexane - 4: 1).

Analysis for

MS (M + H) ⁺ = 465

N ₂ : CHN calculated: 51.75 3.69 6.04 found: 51.78 3.54 6.07

Br F 34.43 4.09 34.40 3.92

4-ethynyl-3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol

A solution of 2.87 g (6.18 mmol) of Part F compound in 11.44 ml of anhydrous tetrahydrofuran is added to the dry ice /

Cooled acetone bath to -78 ° C and treated dropwise with 11.7 ml (18.6 mmol) of 1.6M n-BuLi / hexane under argon and then stirred at -78 ⁰ C for 2 hours and 20 minutes. The reaction mixture is quenched with 16.5 ml of 25 % NH ₄ Cl at -78 ° C. warmed to room temperature and extracted with 3 times 60 ml of diethyl ether. The combined organic extracts are washed with 22 ml brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. The crude product (1.9 g) is chromatographed on a column of silica gel. The column is eluted with Et "O: hexane (5:95).

The desired fractions are combined and evaporated to dryness. Yield: 1.88 g (100 %) of the title compound as a solid product.

100 mg of the title compound are recrystallized from hexane to give 63.5 mg of analytical sample of melting point 117.degree.-188.degree. TLC: R _f = 0.37 (silica gel: Et ₂ O: hexane -1: 9).

35

Analysis for

MS (M + H) ⁺ = 305.

N ₂ : CHFN

Calculated: 78.92 5.63 6.24 9.21 found: 79.12 5.60 6.02 9.12

28 UO

-188-

H. (S) -3 - [[(1,1-Dimethylethyl) diphenylsilyl] oxy] -4-C [[3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H pyrazol-4-yl] -äthinyl] -methoxyphosphinyl] -butyric acid methyl ester 5

A solution of (S) -3- [ε (1,1-dimethylethyl) -diphenylsilyl] oxy] -4- (hydroxymethoxyphos [) -butyl prepared in Example 1, part F, 2.77 g (5.55 mmol) ) -butyric acid methyl ester in 10 ml of anhydrous dichloromethane is treated with 2.1 ml trimethylsilyldiäthylamin and stirred for 1 hour at room temperature under argon. The reaction mixture is evaporated to dryness, azeotroped with 20 ml of anhydrous benzene and dried under reduced pressure. The syrup is cooled to -10 ⁰ C, with 1 drop of DMF and then treated dropwise with 530 μΐ oxalyl chloride and then 15 minutes at -10 ⁰ C and 1 hour at dissolved in 10 ml of anhydrous dichloromethane again, 'in the ice / salt bath , Room temperature stirred. The mixture is evaporated to dryness, dt 20 ml. Benzene azeotropically distilled and dried under reduced pressure.

1.12 g (3.67 mmol) of the compound of Part G are dissolved in 9.0 ml of anhydrous tetrahydrofuran, cooled to -78 ° C. in the dry ice / acetone bath, with 2.3 ml (3.68 mmol) of 1, 6M nBuLi / hexane under argon and stirred at -78 ⁰ C for 45 minutes. The above phosphonochloridate is dissolved in 6.5 ml of anhydrous tetrahydrofuran, cooled to -78 ° C and treated dropwise via cannula with the solution of the acetylene anion, both solutions being kept at -78 ° C during the addition. The Reäktionsgemisch is stirred at -78 ⁰ C for 30 minutes. Then, the reaction is stopped by dropwise addition of 6.0 ml of 25 % NH ₄ CL and the mixture warmed to room temperature. The mixture is extracted 3 times with 100 ml of diethyl ether and the combined organic extracts are washed with 10 ml of 25 % NH ₄ Cl solution and 25 ml of brine, dried over water.

-189-

free MgSO. dried, filtered and evaporated to dryness.

The crude product mixture (4, C g) is chromatographed on a column of silica gel. The column is eluted with acetone: hexane mixtures (1: 9; 3: 7). Yield: 1.76 g (65.2 %) of the title compound as an oil

TLC: R _f = 0.40. (Silica gel, hexane: acetone -7: 3).

I. (S) -4- [[2- [3- (4-fluoro-phenyl) -5- (1-methyl-ethyl) -1-phenyl-1H-pyrazol-4-yl-1-ethyl-1-yl-methoxy-phosphinyl] -3-hydroxybutyric acid methylester

A solution of 700 mg (0.95 mmol) compound of Part H in 9 mL of anhydrous tetrahydrofuran is added sequentially with 224 μΐ (3.82 mmol) glacial acetic acid and 3.0 mL (3.0 mmol) 1.0M (C ₄ Hg ) ₄ NF treated and about 15 hours under argon at room. t. temperature stirred. The solution is in the ice / salt bath at 0 ⁰ C :. cooled, treated dropwise with 10 ml of 5% KHSCK solution and extracted with 3 times 75 ml of ethyl acetate. The combined organic extracts are washed with 10 ml of 5 % KHSO ₄ solution and 25 ml of brine, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness.

The crude product (890 mg) is dissolved in a mixture of 16 ml DiäthyJdther and 12 ml of tetrahydrofuran, cooled in an ice / salt bath to 0 ⁰ C and treated with an excess of diazomethane in Di'ithyläther. The reaction mixture is stirred for about 3 hours at room temperature. Pann the reaction is stopped by dropwise addition of glacial acetic acid and the mixture is evaporated to dryness. The crude product mixture (764 mg) is chromatographed on a column of silica gel. The column is eluted with mixtures of EtOAj: hexane (1: 1; 4: 1; 9: 1). Yield: 347 mg (73.2 %) Title

35 compound as a semi-greasy substance.

TLC: R _f = 0.28 (silica gel, EtOAc: hexane - 4: 1).

-190-

1 example 43

(S) -4- [Q2- [3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl-3-yn-adenyl]] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt 5

A solution of 347 mg (0.7 mmol) of the compound of Example in 8.3 ml of dioxane is treated with 2.4 ml (2.4 mmol) of 1.0N LiOH and stirred for 45 minutes in an oil bath at 55 ° C under nitrogen. Then the reaction mixture is evaporated to dryness and dried under reduced pressure. The resulting semi-solid is chromatographed on a HP-20 ί 1 "χ 3" column. The column is eJ.uiert with 350 ml of steam distilled water and 250 ml of 50 % aqueous methanol. The desired fractions are combined, evaporated to dryness and the residue is dried under reduced pressure. The product is dissolved in steam-dried water and lyophilized. Yield: 338 mg (97.5%) of the title compound as a white fes + .es lyophilate.

- · - ,. TLC: R _f = 0.50. (Kiesolgel; i-PrOH 1HN ₄ OH. H ₂ O: - 7: 2: 1)

analysis for C 24 ^H 22 ^FLi 2 ^f * 2 ° 5 ' ¹ "5 ^H 2 O: 5 N 3 F 5 P C H 5 , 42 3 , 67 5 99 About: 55 , 71 5 , 04 30 95 96 gef. : 55 90 5 , 46

H ³ NMR spectrum (400 MHz, CD ₃ OD):

6 1.45 (d, 6H, J = 7)

1.89-2.05 (in, 2H)

2.38 (dd, IH, J = 9, 15)

30 2.52 (dd, IH, J = 4, 15)

3.06 (septet, IH, J = 7)

4.48 (m, IH)

7.16-8.11 (m, 9H)

-191-

1 example 44

(S) -4- [2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl) -1H-pyrazol-4-yl]] -ethyl] -methoxyphosphinylj -3- hydroxybutyric acid methyl ester A. (S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-Q2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1 phenyl-1H-pyrazol-4-YL2-ethyl] -methoxyphosphinyl3-methyl butyrate

A solution of 1.0 g (1.36 mmol) of the compound of Example 42, Part I ₁ in 72 mL of anhydrous methanol is treated with 250 mg of 10% Pd / C and in a Parr apparatus for approximately 15 hours at a pressure of approximately Hydrogenated 2.8 bar. The reaction mixture is filtered through diatomaceous earth and the clear filtrate is evaporated to dryness. Yield: 1.0 g (100 %) of crude title compound as a homogeneous oil

TLC: R _f = 0.27 (silica gel, hexane: acetone - 7: 3).

B. - (S) -4 - [[2- [3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethyl 3-methoxyphosphinyl-Q-3-hydroxybutyric acid methyl ester

A solution of 1.05 g (1.41 mmol) of compound of Part A in 14.0 ml of anhydrous tetrahydrofuran is gradually with

25 334 μl (5.83 mmol) glacial acetic acid and 4.46 ml (4.46 mmol) 1.0M

(C ₄ Hg) ₄ NFZTHF and stirred at room temperature for about 19 hours under A.gon. The reaction mixture is diluted with 28 ml of ice water, extracted with 3 times 100 ml of ethyl acetate. The combined organic extracts are washed with 15 mL of saturated NaHCO 3 solution and 25 mL of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. The crude product mixture (1.14 g) is chromatographed on a column of silica gel (Baker, 60-200 mesh, 150 ml). The column is eluted with EtOAc: hexane mixtures (2: 1, 4: 1, 9: 1) ethyl acetate and acetone. Yield: 623.5 mg (88 %) of the title compound

-192-

as a semi-solid material.

TLC: R _f = 0.18 (silica gel, EtOAc: hexane -4: 1)

5 Example 45

(S) -4- [2-Q3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

A solution of 623.5 mg (1.24 mmol) of the compound of Example 44 in 14.7 ml of dioxane is treated under nitrogen with 4.28 ml (4.27 mmol) of 1, ON LiOH and heated to 55 "for 2 hours in an oil bath. C. The reaction mixture is evaporated to dryness, the residue is dried under reduced pressure and chromatographed on a column of HP-20 (1 "× 6"). The column is washed with .750 ml of steam-distilled water , 10 % aqueous CH-OH, 500 ml - .20 % aqueous CH ₃ OH and 500 _: ml _. 50 % aqueous CH ₃ OH. The desired fractions are combined and dried to dryness.

20 steamed. Yield: 560 mg (92.8 %) of the title compound.

TLC: R _f = 0.42 (silica gel; i-PrOH. NH ₄ OH: H ₂ O -8: 1: 1)

Analysis for C ₂₄ H ₂₆ FLi ₂ N ₂ O ₅ P .1.16 H ₃ O:

(Eff. M.W. = 507.197): C H NFP calc .: 56.83 5.62 5.52 3.74 6.11

found: 56.83 5.80 5.76 3.46 6.19 N ¹ NMR spectrum (400 MHz, CD ₃ OD):

6 1.30 (d, 6H, J = 7)

1.60-1.78 (d, 4H) 30

2.36 (m, 2H)

2.96-2.99 (m, 2H)

3.14 (m, IH)

4.26 (m, IH)

7.14-7.68 (m, 9H)

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1 example 46

(S) -4- [CC4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl]] -äthinyl] methyl-methoxyphosphinylJ-3-hydroxybutyrate

5 A. 2- (4-fluorophenyl) -1-phenyl-ethane

A suspension of 928 mg (38 mmol) of magnesium turnings in 38 ml of anhydrous diethyl ether is added dropwise under argon within 45 minutes with 5.3 ml (42 mmol) of 4-fluorobenzyl bromide at a rate which keeps the mixture under gentle reflux. After complete addition, the mixture is further refluxed for 30 _minutes: heated, cooled to room temperature and a solution of 2.96 ml (29 mmol) of benzonitrile treated in 5 ml anhydrous diethyl ether. The mixture is stirred at room temperature for 4.5 hours, poured slowly into 40 ml of cold 10 % HCl and the Er. extracted suspension with 5 times 50 ml of diethyl ether and 2 times 100 ml of ethyl acetate.'The combined or-

, -λ; ganic extracts are washed with 50 ml of saturated NaHCO 3 solution and 50 ml of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. 9.8 g of crude product are chromatographed on a column of silica gel (Baker 60 to 200 mesh, 400 ml). The column is eluted with CH ₂ Cl ₂ : hexane mixtures (1: 4, 1: 2). The desired fractions are combined and evaporated to dryness. Yield: 3.29 g of the title compound as a white solid, melting at 106 to 108 ⁰ C. Additional 2.60 g are obtained from other fractions containing a trace of starting material. Total yield: 94.8 %.

30 TLC: R = 0.60 (silica gel, CH-Cl ₉ : hexane - 1: 1).

Analysis for C ₁₄ H ₁₁ FO: CHF

Calc .: 78.49 5.18 8.87

F .: 78.22 5.22 9.21 35 MS (M + H) ⁺ = 215.

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1 B. 2- (4-fluorophenyl) -1-phenylethano- (1-methylethyl) hydrazone

A solution of 4.45 g (21 mmol) of Part A compound in a mixture of 34 ml of 95 % ethanol and 0.74 ml of glacial acetic acid is treated with 3.63 ml (about 42 mmol) of isopropylhydrazine and left under nitrogen for 1.4 hours heated to 8O ⁰ C in an oil bath. , Thin layer chromatography shows that some starting material is still present. The reaction mixture is therefore treated with 2.0 ml (about 23 mmol) of further isopropylhydrazine and heated to 80 ⁰ C for a further hour in an oil bath. The reaction mixture is then cooled to room temperature and evaporated on a rotary evaporator to remove most of the solvent. The residue is diluted with 200 ml of dichloromethane. The organic solution is mixed with 25 ml

Brine, washed over anhydrous MgSO4. getrock-. net, .- filtered and evaporated to dryness. The obtained

yellow oil is evaporated once from 1.50 ml of toluene. Yield: 5.63 g of the title compound as a crude product contaminated with some starting material and traces of two other components

TLC: R _f = 0.28 (silica gel, CH ₂ Cl ₂ : hexane - 1: 1).

Isopropylhydrazine is prepared as follows:

10.3 ml (0.10 mol) of iodopropane are added to 48.4 ml (1.0 mol) of hydrazine hydrate in the course of 2 hours under nitrogen. The mixture is then stirred for 3 hours under nitrogen in an oil bath at 60 ⁰ C, cooled and extracted with 250 ml of diethyl ether in the liquid-liquid extractor for 20 hours. The ether extract is evaporated to yield 5.63 ml or 5.3 g of isopropylhydrazine.

C. Acetic acid 2- [ 1- { 4-fluorophenyl) -1-phenylethylidene J-1

(1-methylethyl) hydrazide 35

A mixture of 5.63 g (et a 21 mmol) of crude compound from

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Part B and 5.85 ml (42 mmol) of triethylamine in 210 ml of anhydrous toluene is cooled in the ice / salt bath under nitrogen to 0 ° C and treated with 1.86 ml (26.3 mmol) of acetyl chloride. The reaction mixture is gradually warmed to room temperature with stirring within 1.5 hours, diluted with 700 ml of diethyl ether and filtered. The clear filtrate is dried over anhydrous Na ₃ SO ₄ , filtered, evaporated to dryness and evaporated once from 300 ml of toluene. The obtained semi-solid (7.1 g) is chromatographed on a column of silica gel (Baker, 60-200 mesh, 400 ml). The column is labeled CH "C1 _? Hexane mixtures (1: 1; 2: 1), CH ₂ Cl ₂ and CH ₂ Cl ₃ : CH ₃ OH (9: 1) eluted. Yield: 4.11 g crude title compound. The crude product is rechromatographed on another column with silica gel and eluted with EtOAc: hexane (4: 1). The desired fractions are combined and evaporated to dryness. Yield: 3.89 g of the title compound as a thick yellow oil.

TLC: R _f = 0.47 (silica gel, EtOAc: hexane - 1: 1).

D. 4- (4-Fluorophenyl) -5-methyl-1- (1-methylethyl) -3-phenyl-1H-pyrazole

A solution of 1.50 g (4.80 mmol) of compound C in 48 mL of bis (2-methoxyethyl) ether is treated with 615 mg (10.96 mmol) of solid potassium hydroxide and stirred for 2.0 hours under nitrogen Oil bath heated to 8O ⁰ C. The reaction mixture with a second amount of 700 mg stirred (12.5 mmol) of potassium hydroxide and then heated at 8O ⁰ C for 2 hours and 16 hours at room temperature. The mixture is poured into 300 ml of water and extracted successively with 3 times 150 ml of diethyl ether and 200 ml of diacetate of diacetic acid. The organic solutions are combined, washed with 500 ml of cold 3 % HCl and 2 times 100 ml of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

35 The crude product (3.5 g) is chromatographed on a column of silica gel (Baker, 60-200 mesh, 500 ml). slide

2 8 ί

-196-

1 column is eluted with EtOAc: hexane (1: 4). Yield: 1.33 g (94.3 %) of the title compound as a cream solid, mp 135-137 ° C

TLC: R _f = 0.63 (silica gel, EtOAc: hexane - 1: 4).

E. 4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-iH-pyrazole-5-carboxaldehyde

A mixture of 2.21 g (8.85 mmol) of CuSO 4. 5H-O and 9.53 g (35.3 mmol) of potassium persulfate in 65 mL of acetonitrile and 39 mL of water are heated to 65 ° C under nitrogen in an oil bath and treated with 2.6 g (8.83 mmol) of Part D compound , The bath temperature is slowly increased to 75 ° C, left at 75 ° C for 40 minutes and then lowered to room temperature with a water bath. The reaction mixture is diluted with 45 ml of dichloromethane, stirred for 10 minutes and decanted. The aqueous

rige suspension with another 3 times 45 ml of dichloromethane

, ··: .- extracted? .. The combined organic extracts are washed with. , Washed twice with 30 ml of brine, dried over anhydrous MgSO ₄ ', filtered and evaporated to dryness. The crude product (2.75 vj) is chromatographed on a column of silica gel LPS-1. The column is eluted with EtOAc: hexane (1: 9). Yield: 1.57 g (57.7 %) of the title compound as a solid.

25 TLC: R _f = 0.72 (silica gel, EtOAc: hexane -1: 4).

F. 5 - (2,2-Dibromoethyl) -4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-iH-pyrazole

A mixture of 1.75 g (5.68 mmol) of compound from Part E and 4.6 g (16.8 mmol) Triphenylphocphin in 27.0 ml of anhydrous dichloromethane in an ice / salt bath at -5 to -10 ⁰ C was cooled under argon and added dropwise within 5 minutes with a solution of 2.82 g (8.42 mmol) of carbon tetrabromide in 9 ml of anhydrous dichloromethane and stirred at -10 ⁰ C for 20 minutes. The reaction mixture is on

J-fii

-197-

Warmed room temperature, poured into 9.0 ml of saturated 'NaHCO-j solution and extracted with 3 times 50 ml of dichloroethane. The combined organic extracts are washed with 10 mL of saturated NaHCO 3 solution and 10 mL of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

The crude product is chromatographed on silica gel and eluted with CH-Clp: hexane mixtures (1: 4). The desired fractions are pooled. Yield: 2.35 g (91.4 %) of title precursor as an oil

TLC: R j = 0.32 (silica gel, CH ₂ Cl ₂ : hexane - 1: 1).

G. 5-Ethinyl-4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazole

A solution of 1.89 g (4.08 mmol) of compound of Part F in. .-. 7.6 ml: anhydrous tetrahydrofuran-cooled in-dry-ice / acetone • bath at -78 ° C., dropwise with 5.2 ml (8.18: mmol, 2 eq.) Of 1.6M BuLi / hexane treated under argon and stirred for 1 hour, 20 minutes at -78 ° C. The reaction is stopped at -78 ⁰ C by addition of 11.0 ml of 25 % NH ₄ Cl and the mixture warmed to room temperature and extracted with 3 times 50 ml of dichloromethane. The combined organic extracts are washed with 15 mL brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. The crude product (1.77 g) is chromatographed on a column of silica gel. The column is eluted with CH-Cl-: hexane mixtures (1: 4, 1: 1). There are obtained 648 mg of the title compound along with mixed fractions containing the title compound and compound of Part F. The mixed fractions are combined with the product from another batch (490 mg from 1.1 mmol of compound from Part F) and chromatographed in a second column. The column is eluted with CH-Cl-: hexane (1: 9). The desired fractions are combined and evaporated to dryness. Yield:

28) 60

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1.02 g (71.5 % corrected yield for recovered starting material) title compound as an oil.

H. (S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] -ox] ε [4- [4-fluorophenyl) -1- {1-methylethyl) -3-phenyl- 1H-pyrazol-5-yl] -äthinyl] -methoxyphosphinyl] -butyric acid methylester

A solution of 2.341 g (5.01 mmol) of monomethyl phosphonate of Example 1, Part F, and 1.90 ml (10 mmol) of trimethylsilylethylamine in 9.5 ml of anhydrous dichloromethane is stirred for 1 hour at room temperature under argon. The mixture is evaporated to dryness, azeotroped with 15 ml of anhydrous benzene and the residue is dried under reduced pressure. The viscous oil is redissolved in 9.5 ml of anhydrous dichloromethane, treated with 1 drop of DMF,

Cooled 'in an ice / salt bath to --10 to 0 ⁰ C and treated dropwise with 480 ul (5.47 mmol) of oxalyl chloride It is found vigorous gas evolution and the dark yellow solution for 15 minutes at -10: .-... to 0 ⁰ C and then stirred for 1 hour at room temperature. the reaction mixture is evaporated to dryness, azeotroped with 18ml of benzene and the residue dried under reduced pressure.

A solution of 1.016 g (3.34 mmol) compound of Part G in 8 mL of anhydrous tetrahydrofuran is cooled in the dry ice / acetone bath to -78 ° C under argon and with 2.1 mL (3.36 mmol) 1.6M treated n-BuLi / hexane and stirred at -78 ° C for 1 hour. The above Phosphonochloridat is dissolved in 8 ml of anhydrous tetrahydrofuran, cooled in dry ice / acetone bath under argon to -78 ^g C and treated dropwise by cannula with the solution of the acetylene anion, both solutions during the addition to -78 ° C. being held. The Reaktjonsgemisch is stirred for 1 hour at -7 ^ ° C, the reaction then by dropwise addition of

ϊ ' 28

-1 99-

Quenched 9 ml of 25 % NH.Cl solution and the mixture warmed to room temperature. The mixture is extracted 3 times with 100 ml of diethyl ether and the combined organic extracts are washed with 10 ml of 25 % NH.Cl solution and 25 ml of brine, over anhydrous MgS '. dried, filtered and evaporated to dryness.

The crude product is chromatographed on a column of silica gel. The column is eluted with acetone: hexane mixtures (1: 9; 1: 4). Yield: 1.595 g (64.8 %) of the title compound as an oil

TLC: R _f = 0.43 (silica gel, acetone: hexane - 3: 7).

I. (S) -4 - [[[4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -äthinylj-methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

A solution of .1.0 g M, 36 mmol), compound of part H in... 13 ml of anhydrous tetrahydrofuran is successively with

20 320 μl (5.46 mmol) glacial acetic acid and 4.26 ml (4.26 mmol) 1M

(C.Hg) .NF and then stirred for about 15 hours under argon at room temperature. The reaction mixture is cooled in an ice / salt bath to 0 ⁰ C, treated with 15 ml 5% KHSO ₄ solution and extracted with 3 times 125 ml of ethyl acetate. The combined organic extracts are extracted twice with 25 ml of 5 % KHSO.-solution and 25 ml of brine, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness.

The crude product (1.06 g) is dissolved in a mixture of 23 ml of diethyl ether and 18 ml of tetrahydrofuran, cooled in ice / salt bath to 0 ° C, treated with a Überscnuß of diazomethane in diethyl ether and stirred at 0 ° C for 4 hours , The reaction is stopped by dropwise addition of glacial acetic acid, the mixture is evaporated to dryness and the residue is dried under reduced pressure. The crude product

-200-

is chromatographed on a column with silica gel. The column is eluted with acetone: hexane (1: 2). The desired fractions are combined and evaporated to dryness. Yield: 330 mg (48.7 %) of the title compound as an oil. TLC: R _f = 0.23 (silica gel, EtOAc: hexane - 4: 1).

Example 47

(S) -4- C [[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -äthinyl] -hydroxyphosphinyl ^ -S-hydroxybutyric acid dilithium

A solution of 330 mg (0.66 mmol) of Compound of Example 46 in 7.8 ml of dioxane is charged with 2.29 ml (2.29 mmol) of 1N LiOH

15 and 1.5 hours under argon in an oil bath at 55 ° C

and then stirred for 16 hours at room temperature. The reaction

tion mixture is evaporated to dryness and the residue

::. "Under reduced pressure dried. The crude product is on a column with HP-20 .. (1". "JO".) Chromatographed. The

20 column is filled with 750 ml of steam-distilled water, 500 ml

10 % aqueous CH ₃ OH, 500 ml of 20 % aqueous CH ₃ OH and 500 ml of 50 % aqueous CH-OH eluted. The. desired fractions are combined, evaporated to dryness and the residue dried under reduced pressure. The solid product is dissolved in steam-distilled water and lyophilized. Yield: 275 mg (99.5 %) of the title compound as a fluffy solid lyophilate

TLC: R _f 0.57 (silica gel; i-PrOH: HN ₄ OH: H ₃ O - (8: 1: 1).

30 Analysis for C ₂₄ H ₂₂ FLi ₂ N ₂ O ₅ P 2.28

(Eff., Mol. Wt. = 523.310): CHNF P

: 55.08 5.11 5.35 3.63 5.92

F: 55.08 4.98 5.47 3.66 5.99

28i6QS

-201-

.ι ¹ IR (KBr): 2172 cm "¹

H ³ NMR spectrum (400 MHz, CD ₃ OD):

δ 1.57 (d, 6H, J = 7 Hz)

1.86-2.01 (ro, 2H)

2.37 (dd, IH, J = 8)

2.50 (dd, IH, J = 4)

4.40 (m, IH)

5.01 (septet, lH, J = 7)

7.04-7.39 (m, 9H)

Example 48

(S) -4 - [] [2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -ethyl] -methoxyphosphinyl] -3- hydroxybutyric acid methyl ester A. (S) -3- £ Q (1,1-dimethylethyl) diphenylsilyl] -oxy] -4-

- "i-pyrazol-5-yl] -ethyl] -methoxyphosphinyl] -butyric acid

r methyl ester 20

A solution of 608 mg (0.85 mmol) of Compound of Example 40, Part H, in 63 ml of anhydrous methanol is treated with 155 mg of 10 % Pd / C and stirred at room temperature in a Parr apparatus for approximately 15 hours under a pressure of approximately Hydrogenated 2.8 bar. The suspension is diluted with 50 ml of methanol and filtered through kieselguhr in a Millipore unit. The filter bed is washed well with methanol. The clear solution is evaporated to dryness and the residue is dried under reduced pressure. Yield: 559 mg (90.9 %) ^OVJ title ^compound as a homogeneous oil with the correct H-NMR and C ¹³ NMR spectral data

RC: R _fs 0.20 (silica gel; acetone: hexane -3: 7; UV).

B. (s) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-]

phenyl-1H-pyrazol-5-yl] ethyl] -methoxyphosphinyl] -3-hydroxy-butyric acid methylester

-202-

1 A solution of 559 mg (0.75 mmol) of compound A

in 7.5 ml of anhydrous tetrahydrofuran is added successively with 176 μΐ (3.0 mmol, 4 eq.) of glacial acetic acid and 2.34 ml (2.34 mmol, 3.1 Xq.) of 1.0M (C ₄ H ₉ ) ₄ FN / hexane under nitrogen and stirred at room temperature for about 20 hours. The reaction mixture is diluted with 20 ml of ice-water, extracted with 3 times 70 ml of ethyl acetate and the combined organic extracts are washed with 10 ml of saturated NaHCO 3 solution and 20 ml of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. The crude product (580 mg) is chromatographed on a column of silica gel. The column is eluted with EtOAc: hexane (1: 4), EtOAc and acetone / hexane (4: 1). The desired fractions are combined, evaporated to dryness and the residue is dried under reduced pressure. Yield: 33.7 mg (89.4 %) of the title compound as a homogeneous oil. TLC: R _f = 0.18 (silica gel, acetone: hexane -1: 1, UV).

20 Example 49

(S) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-iH-

pyrazol-S-y ^ -äthylJ-hydroxyphosphinylJ-S-hydroxybutyric acid dilithium salt

A solution of 337.0 mg (0.67 mmol) of the compound of Example 4 "? in 8.0 ml of dioxane is added under argon with 2.32 ml (3.-5 eq). 1.0N LiOH and stirred for 3 hours in an oil bath at 55 ⁰ C and then stirred for 20 hours at room temperature. The reaction mixture is evaporated to dryness and dried for 1 hour under reduced pressure (pump). The crude product is chromatographed on a column of HP-20 (1 "χ 8"). The column is eluted with 500 ml of steam-distilled water, 500 ml of 10 % aqueous CH-OH, 500 ml of 20 % aqueous CH ₃ OH and 50 % aqueous CH, OH. The desired fractions are combined, evaporated to dryness and the residue is dried under reduced pressure. The resulting solid is dissolved in steam

28 1 60 p

-203-

dissolved in distilled water, frozen and lyophilized overnight. Yield: 280.4 mg (82.4 %) of titer compound as a fluffy white lyophilate with the correct analytical, mass spectrum, IR and H-NMR spectral data. TLC: R _f = 0.45 (silica gel; i-PrOH: NH ₄ : H ₂ O-8: 1: 1; UV).

Another 24 mg slightly contaminated product is obtained from other fractions.

Analysis for C ₇₄ H ₇ -FLi ₇ NOP 1.19 H ₇ O (Effective MW) = 507.733:

CHN: 56.77 5.63 5.51

, Found: 52.77 5.69 5.49 IR (KBr) # 69377 (1589 CM " ¹ , C = C from

F 6 P 3, 74 6 10 3, 91 50

H ¹ -NMR spectrum (400 MHz, CD ₃ OD): δ 1.55 (d, 6H, J = 7, H.) 1.64-1.84 (m, 4H ₁ -, H _c + H _d ) 2.34 (m, 2H, -, H ₃ ) 2.91 (pseudo-quartet, 2H, -, H _e ) 4.25 (m, IH, -, H ₆ ) 4.77 (septet, lH, to Part obscured by

HOD signal, -, H.) 7.05-7.32 (m, 9H, aromatic proteins)

Example 50 Methyl (S) -4- [[(4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl-3-ethynyl] methoxyphosphinyl] -3-hydroxybutyrate

A. N-enzoylvaline

A solution of 20 g (0.17 mol) of valine in 20 ml of tetrahydrofuran and 111 ml of 2N NaOH is added with ice / water bath under nitrogen.

2 8 UO

-204-

cooled to 10 ⁰ C and treated dropwise with 23.8 ml (0.21 mol) of benzoyl chloride. The reaction mixture is warmed to room temperature, stirred for 3 hours and then cooled in the ice / salt bath to 0 ° C and treated with 8.0 ml of concentrated sulfuric acid. The mixture is extracted 3 times with 2 ml of ethyl acetate. The combined organic extracts are washed with 100 ml of water and 50 ml of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. Yield: 41.97 g (100 %) of crude title compound as a solid.

260 mg of the product are recrystallised from ethyl acetate and petroleum ether to give 205 mg of the title compound as analytical sample, mp 132-133 ° C., TLC: R _f = 0.10 (silica gel, acetone: hexane - 1: 1).

Analysis: About: 65 C 6 N 6 N gef. : 64 , 14 6 , 83 6 , 33 , 81 , 79 , 29

MS (M + H) ⁺ = 222.

N- (1-acetyl-2-methylpropyl) benzamide

A mixture of 41.7 g (about 0.17 mol) compound of part A and 47.3 mL (0.34 mol) triethylamine in 48 mL acetic anhydride is added in two lots with 2.07 g (0.017 mol) 4-dimethylaminopyridine treated and stirred for 16 hours under nitrogen at room temperature. The reaction mixture is cooled to 0 ^° C. in the ice / salt bath, the reaction is stopped with methanol and the mixture is stirred for 30 minutes. The light brown precipitate is filtered off, washed well with 1.1 1 of water and redissolved in 750 ml of dichloromethane. The resulting solution is dried over anhydrous MgSO 4. dried, filtered and evaporated to dryness to give 35.9 g of crude product.

28

70 C 7, H 6 N calc .: 70 20 7, 81 6 39 gef. : , 79 68 31

-205-

The crude product is dissolved in 1.3 l of diethyl ether, filtered to remove insoluble matter and the clear filtrate was concentrated to a volume of about 300 ml and then cooled in an ice bath. There are obtained 21.35 g of the title compound as a cream-colored precipitate of mp 88 to 90 ⁰ C, which is filtered off. Purification of the solid obtained by evaporation of the filtrate on a column of silica gel (Baker, 60 to 200 mesh, 600 ml) and elution of the column with EtOAc: hexane mixtures (1: 7, 1: 4) gives an additional 4.77 g title compound. A small amount of the title compound is recrystallized from diethyl ether, mp 88-89 ° C. TLC: R _f = 0.75 (silica gel, acetone: hexane - 1: 1).

Analysis: 15

MS (M + H) ⁺ = 220.

C. N- \ j - \ j - {J 4-fluorophenyl) -imincTJ-ethyl] -2-methylpropyl3-benzamide

25.0 g (0.114 mol) of the compound of Part B in 250 ml of anhydrous toluene is treated with 12 ml (0.127 mol, 1.11 eq.) Of 4-fluoroaniline and 125 mg of p-toluenesulfonic acid hydrate and the reaction mixture under nitrogen Refluxed for 20 hours with a Dean-Stark distillation trap. The reddish-brown solution is salt bath cooled in an ice / ⁰ to -10 C and used for the next stage.

D. 1 - (4-Fluorophenyl) -5-methyl-4- (1-methylethyl) -2-phenyl-1H-imidazole

The cooled solution of the compound from Part C (about 0.114 mol) is diluted at -10 ⁰ C in an ice / salt bath with 200 ml of anhydrous dichloromethane and batchwise with 47.5 g

-206-

(0.228 mol) of phosphorus pentachloride. The cream-colored slurry is heated, refluxed under nitrogen for 2.5 hours, cooled to room temperature, and poured slowly into a mixture of 400 g of ice and 105 ml of 50 % NaOH. The organic phase is separated off and the aqueous phase is extracted twice with 200 ml of dichloromethane. The combined organic extracts are washed twice with 100 ml brine, over anhydrous MgSO4. dried, filtered and evaporated to dryness.

The crude product mixture (35.0 g) is chromatographed on a column of silica gel (Baker, 60-200 mesh, 600 ml) and eluted with EtOAc: hexane mixtures (1: 9; 1: 4). Yield: 29.24 g (87 %) of the title compound as white needles from the F.

₁₅ . 156 to 148 ⁰ C.

TLC: R _f = 0.40 (silica gel, EtOAc: hexane - 1: 4).

Analysis: About: C 52 6 H 9 N 6 F gef. : 77, 48 6 , 51 9 , 52 6 45 = 295. 77, , 69 40 45 MS (M + H) ⁺

E. 1- (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl-iH-imidazole-5-carboxaldehyde

A mixture of 8.50 g (34.0 mmol) of copper (II) sulfate hydrate and 36.8 g (0.136 mmol) of potassium persulfate in a mixed solvent of 250 ml of acetonitrile and 150 ml of water under nitrogen in an oil bath to 65 ° C and heated with 10 g (34.0

OQ mmol) of Part D compound. The reaction mixture is slowly heated to 75 ° C, held at this temperature for 40 minutes and then cooled to room temperature. The solvent is decatenated from the solids and both aqueous phase and solid are mixed with 3 times 200 ml of

extracted with chloromethane. The combined organic extracts are washed twice with 100 ml of brine, dried over water.

28 160

-207-

MgSO4, dried, filtered and evaporated to dryness. The crude product (17.0 g) is chromatographed on a column of silica gel (Baker, 60-200 mesh, 600 ml). The column is eluted with EtOAc: hexane mixtures (5:95, 1: 7). Yield: 6.27 g (59.8%) of the title compound as a solid.

200 mg of the title compound from Et "O: hexane to 76 mg of analytical sample, melting at 160-161 ⁰ C. TLC: R _f = 0.34 (silica gel, EtOAc: hexane - 1: 4).

Analysis:

MS (M + N ⁺ ) = 309.

F. 5- (2,2-Dibromoethyl) -1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazole

C 01 5 H 9 N 6 F About: 74 98 5 , 56 9 09 6 16 gef. : 73 , 68 04 , 09

A solution of 1.75 g (5.68 mmol) compound of Part E and 4.46 g (16.8 mmol) of triphenylphosphine in 27.0 mL of anhydrous dichloromethane is added under argon in ice / salt bath to -5 to - 10 ⁰ C cooled and treated dropwise within 5 minutes with a solution of 2.82 g (8.42 mmol) of carbon tetrabromide in 9 ml of anhydrous dichloromethane. The mixture is stirred for 20 minutes at -10 ⁰ C, then poured into 9.0 mL saturated sodium bicarbonate solution and extracted with 3 times 50 ml of dichloromethane. The combined organic extracts are washed with 10 mL of saturated NaHCO 3 solution and 10 mL of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. The crude product (8.07 g) is chromatographed on a column of silica gel. The column is eluted with CH-Cl: hexane mixtures (1: 7; 1: 4). Yield: 2.35 g (91.4 %) of the title compound as a solid.

2 8 UO S.

-208-

100 g of the title compound are recrystallized from EtO: hexane to give 49 mg of analytical sample of melting point 164.degree. To 165.degree. TLC: R _f s 0.32 (silica gel, CH ₂ Cl ₂ : hexane-1: 1).

Analysis: CHN F Br

Cons .: 51.75 3.69 6.04 4.09 34.43

F .: 51.80 3.71 6.02 4.08 34.25 MS (M + H) ⁺ = 465..

G. 5-Ethinyl-1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidiazole

A solution of 3.065 g (6.60 mmol) of Part F compound in 12.5 ml of anhydrous tetrahydrofuran is cooled in the dry ice-acetone bath to -78 ⁰ C and treated with 8.4 ml (13.4 mmol) of 1.6M n-BuLi / hexane treated under argon. The reaction mixture is stirred for 1 hour and 20 minutes at -78 ⁰ C, then the reaction is stopped by dropwise addition of 18 ml of 25 % NH.Cl, the mixture warmed to room temperature and extracted with 3 times 100 ml of diethyl ether. The combined organic extracts are washed with 25 ml brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness. The crude product (2.08 g) is chromatographed on a column of silica gel (Baker, 60-200 mesh, 400 ml). The column is eluted with EtOAc: hexane mixtures (1: 9; 1: 4). The desired fractions are combined and evaporated to dryness. Yield: 1.97 g (97.8 %) of the title compound as a solid.

92 mg of the compound of Part G are recrystallized from hexane to 59 mg of analytical sample of mp 148 to 150 ⁰ C. TLC: R _f = 0.60 (silica gel, EtOAc: hexane - 1: 4).

Analysis: = 303. About: 78 C 5 H 9 N 6 F gef. : 78 , 92 5 , 63 9 , 21 6 24 95 , 83 , 07 , 63 MS (M-H) "

2 8 ί

-209-

H. (S) -3 - [[U, 1-Dimethylethyl) -diphenyl] -1-yl-oxy] -4-CCD- (4-fluorophenyl) -4- (1-methylethyl) -S-phenyl-1H-imidazole 5-yl] -äthinylj-methoxyphosphinylbutyric acid methyl ester 5

A mixture of 3.54 g (7.86 mmol) of the crude phosphonic acid monomethyl ester of Example 1, Part F, and 2.70 ml (14.21 mmol) of trimethylsilyldiathylamine in anhydrous dichloromethane is stirred for 1 hour at room temperature under argon. The mixture is then evaporated to dryness, azeotroped with 26 ml of anhydrous benzene and the residue is dried under reduced pressure. The viscous oil is dissolved in 14 ml of anhydrous dichloromethane again, treated with 2 drops of DMF, cooled in an ice / salt bath to -10 ⁰ C and treated dropwise with 0.68 ml (7.79 mmol) of oxalyl chloride. Vigorous evolution of gas is detected and the yellowish-brown solution stirred for 15 minutes at -10 ⁰ C and then for 1 hour at room temperature. The reaction mixture is evaporated to dryness, azeotroped with 26 ml of anhydrous benzene ^and the residue dried under reduced pressure.

A solution of 1.43 g (4.7 mmol) compound of Part G in 11.5 ml of anhydrous tetrahydrofuran is cooled in the dry ice / acetone bath to -78 ° C under argon and washed with 2.94 ml (4.7 mmol ) 1.6M nBuLi / hexane and stirred at -78 ° C for 30 minutes. The above phosphonochloridate is dissolved in 11.5 ml of anhydrous tetrahydrofuran, cooled to -78 ° C in the dry ice / acetone bath under argon and treated dropwise via cannula with a solution of the acetylenic ion, both solutions during addition to -78 ° C were held. The reaction mixture is stirred for 30 minutes at -78 ° C, the reaction was stopped by dropwise addition of 13 ml of 25 % NH.Cl, the mixture warmed to room temperature and then extracted with 3 times 130 ml of diethyl ether. The combined organic extracts are washed with 15 mL of 25 % NH ₄ Cl and 30 mL of brine, over anhydrous MgSO ₄

28

-210-1, filtered and evaporated to dryness.

The crude product mixture (4.3 g) is chromatographed on a column of silica gel. The column is eluted with acetone: hexane mixtures (5:95, 1: 1). The desired fractions are combined and evaporated to dryness. Yield: 2.18 g (62.9 %) of the title compound as a light brown syrup. TLC: R _f = 0.13 (silica gel, hexane: acetone-7: 3).

I · (S) -4- [Qj- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl} -äthynyl [] -methoxyphosphinyl] -3- hydroxybutyrate methyl ester,

A solution of 974 mg (1.32 mmol) of Part H compound in 13.0 mL of anhydrous tetrahydrofuran is added sequentially with 310 μΐ (5.29 mmol) of glacial acetic acid and 4.14 mL (4.14 mmol) of 1M (C ₄ Hg ₄ NF and stirred under argon for about 15 hours at room temperature. The reaction mixture is then cooled in an ice / water bath to 0 ⁰ C, treated 5% KHSCK solution with 14 ml and extracted with 3 times 125 ml of ethyl acetate. The combined organic extracts are washed with 16 ml of 5 % KHSO.-solution and 35 ml of brine, over anhydrous MgSO4. dried, filtered and evaporated to dryness. The crude product (1.48 g) is dissolved in a mixture of 22 ml of diethyl ether and 17 ml of anhydrous tetrahydrofuran, cooled to 0 ^° C. in the ice / water bath, treated with excess diazomethane in diethyl ether and stirred at 0 ^° C. for 4 hours. The reaction is stopped by dropwise addition of glacial acetic acid and the mixture is evaporated to dryness and the residue is dried under reduced pressure. The crude product is chromatographed on a column of silica gel. The column is eluted with EtOAc: hexane mixtures (1: 1; 4: 1). The desired fractions are pooled. Yield: 304 mg (46.2 %) of the title compound

35 as a solid.

TLC: R = 0.33 (silica gel, EtOAc: hexane -4: 1)

-211 -

1 example 51

(S) -4 - [[[p - (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl]] -äthinyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt 5

A solution of 304 mg (0.6 mmol) of the compound of Example in 7.1 ml of dioxane is treated with 2.03 ml (2.08 mmol) of 1N LiOH and stirred for 1.5 hours under argon in an oil bath at 55 ° C and then Stirred for 24 hours at room temperature. The reaction mixture is evaporated to dryness and dried under reduced pressure. The crude product is chromatographed on a column HP-20 (1 "χ 7"). The column is eluted with 750 ml of steam-distilled water, 500 ml of 10 % aqueous CH ₃ OH, 500 ml of 20 % aqueous CH ₂ OH and 500 ml of 50 % aqueous CH ₃ OH. The desired fractions are combined, evaporated to dryness and the residue is dried under reduced pressure. The solid product is dissolved in steam-distilled water.

dissolves and lyophilizes. Yield: 257 mg (84.1 %) of the title compound as a fluffy solid lyophilate.

20 other factions:

TLC: R _f = 0.38 (silica gel; i-PrOH: NH ₄ OH: H ₃ O - 8: 1: 1)

Analysis for C ₂₄ H ₂₂ FLi ₂ N ₂ O ₅ P -1.52 H ₃ O:

CHNFP

25 calculated: 56.56 4.95 5 _r 49 3.73 6.08

Found: 56.56 4.94 5.32 3.89 5.99 H ^ NMR spectrum (400 MHz, CD ₃ OD):

δ 1.37 (d, 6H, J = 7 Hz)

1.79 (m, 2H)

³⁰ 2.31 (dd, IH, J = 9.15 Hz)

2.43 (dd, IH, J = 4.15 Hz)

3.24 (septet, IH, .J = 7 Hz)

4.26 (ra, IH)

7.17-7.35 (m, 9H). ³⁵ IR (KBr) 2163 (C = C), 1590 (C = O) cm ^-1 .

-21 2-

I Example 52

(S) -4- £ (2- [i - (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl-3-ethyl-1-methoxyphosphinyl]] -3 - hydroxybutyric acid methyl ester A. (S) -3- [ε (1,1-dimethylethyl) diphenylsilyl] oxy] -4-LL ² -D - <4-fluorophenyl) -4- (1-methylethyl) - 2-phenyl-1H-imidazol-5-yl] -mentyl] -methoxyphosphinylbutyric acid methyl ester

IQ A solution of 839 mg (1.14 mmol) of Compound of Example 50, Part H, in 86 ml of anhydrous methanol is treated with 213 mg of 10 % Pd / C and stirred at room temperature on a Parr apparatus for approximately 15 hours at a pressure of hydrogenated about 2.8 bar. The suspension is filtered through diatomaceous earth, the

The clear filtrate was evaporated to dryness and the residue was dried under reduced pressure. Yield: 853 mg (100 %) of the title compound as a thick syrup

TLC: R _f = 0.17 (silica gel, hexane: acetone-7: 3).

B- (S) -4- [2- (i-4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl] -ethyl-methoxyphosphinylj] -3 hydroxybutyric acid-methylester

A solution of 853 mg (about 1.14 mmol) compound of Part A in 11.0 ml of anhydrous tetrahydrofuran is added sequentially with 270 μΐ (4.60 mmol) of glacial acetic acid and 3.62 ml (3.62 mmol) of 1.0M ( C.Hg), NF / hexane and stirred for about 15 hours under argon at room temperature. The reaction mixture is diluted with 25 ml of ice water and extracted with 3 times 100 ml EssigsäureäthylgO ester. The combined organic extracts are washed with 15 ml of saturated NaHCO 3 solution and 25 ml of brine, over anhydrous MgSO 4. dried, filtered and evaporated to dryness.

gc The crude product (958 mg) is chromatographed on a silica gel column. The column is treated with acetone: hexane-lemi-

-213-

(1: 1, 4: 1) eluted. The desired fractions weroeri combined, evaporated to dryness and the residue dried under reduced pressure. Yield: 443 mg (77.0 %) of the title compound as a solid

 TLC: R = 0.13 (silica gel, acetone: hexane - 1: 1).

Example 53

(S) -4-Q2- [1- (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl-iH-imidazol-5-yl] -ethyl-hydroxyphosphinyl-3-hydroxybutyric acid dilithium salt

A solution of 443 mg (0.88 mmol) of the compound of Example 52 in 10.5 ml of dioxane is treated with 3.05 ml (3.09 mmol) of 1.0N LiOH and heated in an oil bath under argon at 55 ° C for 3 hours then stirred for about 20 hours at room temperature. Then the reaction mixture is evaporated to dryness and the reaction mixture

-.: ... - dried under reduced pressure. The crude product is chromatographed on an HP-20 ^v . (1 "χ 8") column.

The column is eluted with 750 ml of steam-distilled water, 500 ml of 10 % aqueous CH ₃ OH, 500 ml of 20 % aqueous CH ₃ OH and 50 % aqueous CH ₂ OH. The desired fractions are combined and evaporated to dryness. The resulting solid is dissolved in 30 ml of steam-distilled water and lyophilized. Yield: 376.4 mg (83.9 %) of the title compound as a fluffy white solid

TLC: K _f = 0.40 (silica gel; i-PrOH *. HN ₄ OH: H ₃ O -8: 1: 1)

Analysis for C ₂₄ H ₂₆ FLiH ₂ N ₂ O ₅ P. 0.84 H ₂ O

(Eff. Moles weight = 501.46): C HN FP

: 57.43 5.76 5.69 3.99 6.08 Found: 57.48 5.56 5.59 3.79 6.18 IR (KiIr) (1587 cm " ¹ , C = O COO") H ¹ NMR spectrum (400 MHz, CD ₃ OD): 35

-214-

δ 1.33 (d, 6Η, J = 7 Hz)

1.46-1 _} 61 (m, 4H)

2.30 (m, 2H)

2.76 (m, 2H)

3 ^ J3 (septet, IH, J7 Hz)

4.14 (m, IH)

7.17-7.30 (m, 9H).

example

(S) -4- CCC ² - (cyclohexylmethyl) ~ 4,6-dimethylphenylj ¹ -äthinylj ¹ hydroxyphosphinyIj -3-hydroxybutyric acid Dilithiumsalζ A. N- (2, 4-dimethylbenzylidene) benzenamine (US-A-4,375,475, S 39)

The title compound is prepared according to Example 1, Part A.

B.

(US-A-3,375,475, p. 39)

The Pd complex title compound is prepared according to Example 1, part

B, manufactured.

C. 2-C <cyclohexylmethyl) -4,6-dimethylbenzaldehyde]

144 mg (59.45 mmol) of magnesium turnings are under argon with

-215-

15 ml of anhydrous Et_O overlaid and sonicated for 5 minutes. Then 1.5 ml of cyclohexylmethyl bromide are added to the Mg chips and the sonication is continued. Within minutes, the solution begins to boil under reflux. At the same time, 60 ml of anhydrous Et-O and a solution of residual cyclohexylmethyl bromide in 5 ml Et-O with continuous sonication are added through an addition funnel (total 9.12 ml, 65.3 mmol cyclohexylmethylbromide are added).

After complete addition, the sonication is continued for 15 minutes and the reaction is refluxed for 40 minutes. This Grignard reagent is cooled to room temperature and then cannulated to a solution of 5.55 g (7.43 mmol) of Part B Pd complex and 15.59 g (59.45 mmol) of triphenylphosphine, which lasts 30 minutes under argon at room temperature. t been.

After addition of the Grignard reagent, the reaction mixture

, .. green and it creates a precipitate. The reaction solution is stirred for 2 hours at room temperature and treated with 37 ml of 6N HCl. The mixture is stirred for 1 hour and then filtered through diatomaceous earth in a sintered glass funnel to remove solids. The solid is washed with EtO and the filtrate is heated on a rotary evaporator to remove volatiles. The resulting residue is stirred in Et-O and filtered as above. The filtrate is washed once with brine and the organic layer is washed over MgSO 4. dried. There are obtained 14.5 g of brown oil. Purification by flash chromatography and elution with 4 % EtO / hexane.

30 ben 1.70 g (99 %) of clear oil.

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

IR (CHCl ₃ ) 3030, 3008, 2926, 2853, 1679, 1606, 1448, 1147 rxT ¹

¹ H NMR (270 MHZ-CDCl-) 35 ³

28 t

-216-

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)

2.30 (s, 3)

1.80-1.55 (m, 5)

, 1.55-1.30 (m, 1)

1.30-0.80 (m, 5) 10

Maosene spectrum (Cl) m / e 231 (M + H) ⁺

D. 1- (cyclohexylmethyl) -2- (2,2-dibromoethyl) -3,5-di-

methylbenzene 15

1.68 g (7.30 mmol) of aldehyde from Part C in 65 mL of anhydrous CH-Cl- cooled under argon to 0 ⁰ C. The solution ^is: treated with "6.13 g (23.4 mmol) of triphenylphosphine and ^stirred. Is dissolved until all of the solid at 0 ⁰ C then 3.63 g (11.0 mmol) as a solution in CBr. 20 ml CH ₂ Cl was added. the reaction mixture is orange-colored. the mixture is stirred 1.5 hours at 0 ⁰ C, and the reaction then stopped by addition of saturated NaHCO ₃ solution and the mixture stirred vigorously, the aqueous layer is removed. and extracted twice with CH ₇ Cl _7. The organic solutions were combined, washed once with saturated NaHCO 3 solution, and dried over MgSO 4. Filtration and removal of the solvent yielded 9.6 g of brown solid by purification by flash chromatography and elution with 100% hexane, 2.52 g (90 %) of clear oil is obtained TLC: R = 0.62 (5 % Et ₂ O / hexane, silica gel) PMA.

-1

IR (CHCl ₃₎ 2925, 2852, 1608, 1472, 869

cm

^U H NMR (270 MHz, _CDCl3)

-21 7-

θ 7.39 (s, 1)

6.87 (s, I)

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) in / e 387 (M + H) ⁺

E. 1- (Cyclohexylmethyl) -2-ethyl-1,3,5-dimethylbenzene

2.51 g (6.5 mmol) of Part D Vinyldibromid are stirred under argon with 30 ml THF and cooled to -78 ⁰ C. The dibromide solution is then added at -78 ° C. with 5.20 ml of 2.5M solution of n-butyllithium in hexane within 3 minutes. The resulting red reaction mixture is stirred at -78 ° C. After 1.5 hours at -78 ° C, the reaction is stopped by the addition of saturated aqueous NH.Cl solution and the mixture warmed to room temperature. The aqueous layer is removed and extracted twice with EtO and once with hexane. The organic layers are combined and dried over MgSO 4. dried. After filtration and removal of the solvent, 1.65 g of brown oil are obtained. Purification by flash chromatography and elution with hexane gives 1.39 g (95 %) of acetylene title compound. TLC: R _f = 0.50 (3 % toluene / hexane, silica gel), PMA.

IR (CHCl ₃₎ 3305, 3007, 2924, 2852, 2096, 1607,

1470, 1448 cm "" ¹ ·.

¹ H NMR (270 MHz, CDCl ₃ )

28

-218-

1 6 6.86 (s, 1)

6.79 (s, 1)

3.39 (s, 1)

2.63 (d, 2, J = 6.9 Hz)

5 2.63 (m, 6) ·

1.20 (m, 3) '. ·

1.00 (m, 2)

Mass spectrum (CI) m / e 227 (M + H) ⁺ 10

F. (S) -4- [[[2- (Cyclohexylmethyl) -4,6-dimethylphenyl] -

ethylenyl]] methoxyphosphinyl J-3- [Q 1, 1-dimethylethyl) diphenylsilyl-oxy] -butyric acid methyl ester

136 g (6.0 mmol) of acetylene from Part E in 30 mL of anhydrous THF cooled under argon to -78 ⁰ C. This solution is treated with 2.4 ml of 2.5M solution of n-BuLi in hexane. The reaction solution turns to burgundy. It is stirred for 1 hour at -78 ° C.

4.68 g (9.6 mmol) of phosphonochloridate from Example 1, Part F, are stirred with 30 ml of anhydrous THF and cooled to -78 ° C. The acetylene anion is then added to the phosphonochloridate solution via cannula within 15 minutes. After complete addition, the reaction mixture is stirred for 1 hour at -78 ° C, then the reaction stopped by the addition of saturated aqueous NH.Cl solution and the mixture warmed to room temperature. The THF is removed from the reaction mixture and the remaining material with

30 ^^ O and H-O dissolved. The aqueous layer is washed 3 times

Extracted Et-O. All Et-O extracts are combined and washed once with saturated NaHCO 3 solution and once with brine and then over MgSO 4. dried. Filtration and removal of the solvent gives an orange

35 g of oil by flash chromatography and elution with

EtOAc: hexane: toluene (3.5: 5.5: 1). Out-

2 3 \ 6 O 5;

-21 9-

1 well: 2.80 g (70 %) acetylenic phosphinate title compound as a clear oil.

TLC: R _f = 0.37 (5: 1: 4 / hexane: toluene: EtOAc, silica gel) PMA.

IR (CHCl ₃₎ 3025, 3001, 2929, 2856, 2164, 1736,

1607, 1240, 1112, 1039, 823 cm ^-1 . ¹ H NMR (270 MHz, CDCl ₃ ) δ 7.66 (m, 4) 7.30 (m, 6),

6.87 (s, 1), 6.81 (s, 1) 4.66 (m, 1)

3.70 & 3.66 (d's, 3, J = 14 _, 3 Hz) 3.56 (s, 3)

2.95 (m, 1).

2j69 (ra ,, 1) 2.50 (m, 3) 2.32 (ra, 2) ² ' ³ ° ^(S ' ³⁾

2.27 (s, 3)

1.60 (m, 6) 1.03 (ra, 3) 1.02 (s, 9) ° 1 ^{95 (m} ' ²⁾ Mass spectrum (CI) m / e (M + H)

G. (S) -4- [[[2- (Cyclohexylmethyl) -4,6-dimethyl-plenyl] -äthinyl] -methoxyphosphinyl-3-hydroxybutyric acid ·

methyl ester 3U

0.633 g (0.96 mmol) of Part F acetylenic phosphinate are stirred at room temperature under argon with 14.0 ml of anhydrous THF. The mixture is washed with 0.22 ml (3.84 mmol)

□ add glacial acetic acid and then add dropwise within 5 min.

with 2.62 ml of 1.1M solution of n-BU.NF in THF. After 19

28 i 60 5

-220-

Stirring for 1 hour at room temperature, the reaction is stopped by the addition of ice water and the aqueous layer extracted 3 times with EtOAc. The combined organic solvents are washed twice with saturated aqueous NaHCO 3.

5 solution and washed once with saturated saline. The organic layer is over Na-SO. dried and filtered to give 0.658 g of yellow gum after removal of the solvent. Purification by flash chromatography and elution with EtOAc gives 0.23 g (65 %) of Al-10-alcohol title compound as a clear oil.

TLC: R _f = 0.51 (6: 4 acetone / hexane, silica gel) PMA

IR (CHCl ₃ ) 3450 (br), 3005, 2926, 2852, 2164, 1733, 1607, 1448, 1439, 1039 cm ^-1 . ¹ H NMR (270 MHZ, CDCl ₃ )

5 6 1 89 (S, 1 ) 6 1 82 (S, 1 ) 4 1 63 (Ra, 1 ) 3, 88 « sc 17. ( 2d 's, 3, J = 12 Hz) 3 69 (S, 3 ) 2 \ 70 (S, 2 ) 2 1 62 (D, 2 , J = 6.3 Hz) 2 1 43 (S, 3 ) 2 32 (S, 3 ) 2 1 27 (M, 2 ) 1 1 65 (M, 6 ) 1 19 (M, 3 ) 1 ι 00 (M, 2 ) mass spectrum (CI) m / e 421 (M + H) ⁺

H. (S) -4 - [[[2- (Cyciohexylmethyl) -4,6-dimethylphenyl]

äthinylQ-hydroxyphosphinyl] -3-hydroxybutyric acid Diiithiumsalz

35.212 g (0.51 mmol) of the diester from Part G are stirred in 7 ml of dioxane and at room temperature with 1.5 ml (1.5 mmol) of 1N LiOH

28 t 60

-221-

added. The reaction mixture is heated to 55 ⁰ C and after 20 minutes, the precipitate occurring by addition of 5 ml of dioxane and 4 ml of H _? O brought into solution. After 2 hours and 30 minutes at 55 ° C, the reaction mixture is cooled to room temperature, the solvent is distilled off under reduced pressure and the resulting white solid is kept under vacuum for 15 minutes. The product is purified on a 3.0 χ 19 cm column with resin HP-20 and eluted first with 100 ml H ₂ O and then with MeOH / H ₂ O (1: 1). Lyophilization of the product fractions gives 0.145 g (71 %) of white lyophilate

TLC: R _f = 0.39 (7: 2: 1. N PrOH / NH 4 OH / H 2, silica gel) PMA.

IR (KBr) 3700-3100 (br), 2922, 2850, 2167, 1590, 1447, 1179, 1076 cm " ¹

¹ H NMR (400 MHz, D ₂ O) V 6.99 (s, 1)

6.94 (s, 1),

4.53 (m, 1),

2.64 (m, 1), 20

6.22 (d, 2, J = 6.2 Hz)

2.39 (s, 3). 2.37 (m, 1) 2 _f 26 (s, 3)

2.02 (m, 2)

1.60 (m, 6)

1.14 (m, 3)

1.00 (m, 2)

Mass spectrum (FAB) m / e 409 (M + H) ⁺ , 397 (M-2 Li + H) ⁺

Analysis for C ₂₁ H ₂₇ O ₅ P Li ₂

1, 72 H ₂ ( 57 96 7 H 7, P About: 57 96 7 , 05 6 12 gef. : , 18 96

-222-

Example 55 4- [* {J 2 - [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] -äthenyl] hydroxyphosphinyl Q-3-hydroxybutyric Acid Dilithium Salt A. (E) - [2- [2- (Cyclohexylmethyl) - 4,6-dimethylphenyl3-ethenyl] -phosphonic acid dimethyl ester

1.64 g (13.2 mmol) of dimethyl methylphosphonate in 20 ml of anhydrous THF are cooled to -78 ° C. under argon. This solution is treated at -78 ° C with 5.0 ml (12.4 mmol) of 2.5M solution of n-butyllithium in hexane. After complete addition, the milky-white reaction mixture is stirred for 1 hour. Then the anion solution is added at -78 ° C with a solution of 1.9 g (8.26 mmol) of aldehyde from Example 54, Part A, in 10 ml of THF over 10 minutes through an addition funnel. After 35 minutes of stirring at -78 ° C, the reaction

by the addition of 8 ml of saturated aqueous NH.Cl solution abge-. quenched and the mixture warmed to room temperature. The .--:.: Organic layer is removed and the aqueous layer extracted 3 times with EtOAc. The organic layers are combined and washed once with brine and over Na 2 SO 4. dried. Filtration and removal of the solvent give 3.25 g of yellow oil.

The above yellow oil (3.25 g) is dissolved in anhydrous toluene and refluxed through a Soxhlet extractor containing 4Å molecular sieves. 0.080 g (0.42 mmol) of p-toluenesulfonic acid χ H _? O is added at the beginning, after 3.5 and 18 hours. After 22 hours of reflux, the reaction mixture is cooled to room temperature and the toluene removed under reduced pressure. The resulting yellow residue in EtOAc is washed twice with saturated NaHCO ₂ solution, over Na ₂ SO ₄ . dried and filtered, after removal of the solvent, a yellow oil (A) is obtained

 35

The aqueous solution is acidified with concentrated HCl,

28 i 60 p

-223-

Extract 3 times with EtOAc, over MgSO 4. dried, filtered and the solvent removed to give 0.535 g of yellow oil. The yellow oil is refluxed for 24 hours in 6.0 ml of HC (OCH ₃ ). Excess HC (OCH ₃ J ₃

5 is then removed under reduced pressure. This material is combined with the yellow oil (A) and purified by flash chromatography and eluted with 80 % EtOAc / hexane. Yield: 2.07 g (73 %) of vinyl phosphonate title compound as a white solid

10 TLC: R _f = 0.45 (1: 1 acetone / hexane, silica gel) PMA.

IR (KBr) 2921, 2851, 1623, 1447, 1243, 1186, 1060, 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 = 21.0 Hz, 18.1 Hz):. ./-.!. ^ ^. 3.79 (d, 6, J = Il, 5 H "*)

2.49 (d, 2, J = 7.2 Hz)

2.29 (s, 3)

2.28 (s, 3)

1.65 (m, 5)

1.45 (ro, I)

1.25-0.80 (m, 5)

Mass spectrum (CI) m / e 337 (Μ + ΗΓ

B. (E ι - [2- Q2- (cyclohexylmethyl) -4, 6-dimethylphenylJ äthenylj} -phos phonsäure -me thy he reads

2.07 g (6.16 mmol) of vinyl phosphonate from Part A are stirred with 14 ml of dioxane at room temperature. This solution is then treated with 9.24 ml (9.24 mmol) of 1N LiOH and the mixture warmed to 75 ° C. After 3.5 hours at 75 ⁰ C is the

Reaction mixture cooled to room temperature and the dioxane 35

removed under reduced pressure. The resulting residue

2 8 ί 6 0s

-224-

is stirred with H ₂ O and acidified to about 2 with 1N HCl The aqueous solution is extracted 3 times with EtOAc, dried over Na ₂ SO ₄ , filtered and the solvent removed Yield: 1.95 g whitish solid.

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

¹ H NMR (270 MHz, CDCl ₃ ) 6 12.11 (s, l) ₁₀ 7.61 (dd, I ₁ J = 24.17 Hz, - 17.58 Hz)

6.87 (s, 1). 6.81 (s, 1)

5.88 (dd, 1, J = 21.43 Hz, 17 _T 58 Hz) 3.78 (d, 3, J = Il, 54 Hz)

₁₅ 2.47 (d, 2, J = 6.6 Hz)

2.29 (s, 3) 2.28 (s, 3) 1.65 (m, 5) 1.45 (m, 1)

20 ¹ I ^{15 (m} ' ³⁾

0.95 (m, 2)

C. (E) -4 - [[2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] -äthenyl] -methoxyphosphinyl] -3-oxobutyric acid methyl ester

1.95 g (6.06 mmol) of monomethylphosphonate from Part B in 50 ml of anhydrous CH.Cl- at room temperature under argon 1 Stui-.de 25 minutes with 1.76 g (12.1 mmol) (C ₃ H ₅ ) ₂ NSi (CH ₃ ) stirred. The CH ₉ Cl _{9 is} removed under reduced pressure and the resulting yellow oil is azeotroped once with benzene and then kept under vacuum for 20 minutes. This oil is then dissolved under argon in 50 ml CH_C1_ and cooled to 0 ⁰ C. Subsequently, 2 drops of anhydrous DMF and then slowly added dropwise 0.92 g (7.27 mmol) of oxalyl chloride. Gas evolution is detected. The

2 8 16

-225-

Reaction mixture is stirred for 15 minutes at 0 ⁰ C, then warmed to room temperature and stirred for 1 hour. The CH _? C1 "is distilled off under reduced pressure from the reaction mixture and the resulting orange-colored oil azeotropically distilled twice with anhydrous benzene and then kept under high vacuum for 1 hour (pump). The phosphonochloridate is obtained.

The dianion of methylacetonate is prepared as follows.

0.25 g (8.7 mmol) of oil dispersion washed with pentane NaH in 10 ml of anhydrous THF is cooled under argon to 0 ⁰ C. Then, the NaH suspension is added as a solution in 10 ml of THF with 0.92 g (7.9 mmol) of methyl acetoacetate and stirred for 20 minutes. Then 2.90 ml (7.3 mmol) of 2.5M n-butyllithium ir. Hexane are added and the mixture is stirred for 45 minutes. The dianion solution is cooled to -78 ° C and cooled with a cooled to -78 ° C solution of the above

: ·· _ .. manufactured. Phos- phonochloridate In: 10 ml THF within

··· .--- 15 minutes offset; After stirring for 30 minutes at -78 ° C

the reaction is quenched by addition of saturated aqueous NH.Cl solution and warmed to room temperature. The THF is removed from the reaction mixture and the resulting orange oil is taken up in EtOAc / H 2 O (1: 1). The aqueous layer is extracted 2 times with EtOAc, pie combined EtOAc extracts are combined and washed twice with saturated NaHCO ₃ solution and once with brine and then over Na 2 SO 4. dried. Purification of the 2.75 g crude product! ^q by flash chromatography and elution with EtOAc gives 0.97 g (42 %) of ketoester Ti.

30 telverbindung as yellow oil.

TLC: R _f = 0.24 (EtOAc, silica gel) PMA.

¹ H NMR (270 MHz, CDCl ₃ )

δ 7.71 (dd, 1, J = 22.52 Hs, 18.13 Hz)

6.39 (s, 1) ³⁵ 6.83 (s, 1)

5.89 (dd, 1, J = 26.37 Hz, 17.58 Hz)

28i605

-226-

3.79 (s, 2)

3.73 (s (br), 6)

3.36 (dd, 2, J = 18.68 Hz, 5.5 Hz)

2.50 (m, 2)

2.30 (s, 3)

2.29 (s, 3)

1.70 (m, 5)

1.45 (m; 1)

1,10-0,80 (m, 5)

D. 4-C (j 2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] -äthenyll methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

! 5 0.97 g (2.31 mmol) of beta-ketophosphonate of Part C were stirred under argon in 10 ml THF and cooled to 0 ⁰ C. Then the THP solution (0.087 g, 2.31 mmol), solid NaBH. and then added dropwise with 2 ml of CH 2 OH, with gas evolution occurring. After'50 minutes stirring at 0 ⁰ C is

20 the reaction by the addition of 2 ml of acetone and then terminated by silica gel CC-4. The reaction mixture is warmed to room temperature and filtered through sintered glass. The solvent is removed from the filtrate leaving a yellow oil which is flash chromatographed.

² ^ graphy and elution with EtOAc is purified. Yield: 0.65 g (66 %) of the title alcoholic compound as a clear oil. TLC: R _f = 0.29 (50 % acetone / hexane, silica gel), PMA.

MP 80-83 ⁰ C.

IR (KEr) 3282 (br), 2923, 2918, 2848, 1743, 1614, _i

1450, 1442, 1080, 1045 cm ' ^x .

¹ H NIIR (270 MHz, _CDCl3) 7.68 (m, 1)

6.88 (s, 1) 6.82 (s, 1)

5.89 (m, 1)

$ 28,160

-227-

4.50 (m, Ί) .4.00 (m, 1)

3.77 & 3.74 (2 d's, 3, J = Il, 0 Hz) 3.69 & 3.68 (2 s's, 3) 2.65 (d, 2, J = 6.0 Hz) 2.50 (m, 2) 2 , 30 (S (br), 3) 2.28 (s, 3) 2.15 (m, 2) 1.68 (m, 5) ·

1.45 (m, 1) 1.30 to 0.80 (m, '5) mass spectrum (CI) m / e 423 (~M + H) ⁺

E. 4 - [[2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] -äthenyl3-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

0.565 g (1.33 mmol) of Part D diester are dissolved in 14 ml of Di-20

Oxan stirred until all the solid is in solution. The

Solution is then mixed with 4.0 ml of 1.0N LiOH and heated to 55 ⁰ C. After 30 minutes, the reaction mixture becomes turbid, After 2 hours at 55 ° C, the mixture is cooled to room temperature and the solvent at Rotationsver-25

distilled off distiller leaving a white solid.

The crude product is purified on a 3.0 χ 15 cm column with HP-20 and eluted first with 100 ml H_O and then with 75 % MeOH / H2. Lyophilization of the product fractions gives 0.524 g (98 %) of the title compound as a white 30

Lyophilsates.

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

IR (KBr) 3700-3100 (br), 2921, 2851, 1591, 1446, 1222, 1195, 1161, 1051 cm ^-1 .

¹ H NMR (400 MHz,

[ΐΙ Ί 28

-228-

1 6 7.25 (dd, 1, J = 18.68 Hz)

6.98 (s, 1)

6.94 (s, 1)

6.00 (dd, 1, J = 17.95 Hz)

5 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)

10 2.25 (s, 3)

1.89 (dd, 2, J = 14j3 Hz, 6.6 Hz)

1.60 (m, 5)

1.45 (m, 1)

1.13 (m, 3)

15 0.95 (m, 2)

Mass Spectrum (FAB) m / e 407 (14 + H) ⁺ , 347 (M ⁺ -2 Li ⁺ + 2H).

; ;. Analysis for C ₂₁ H ₂₉ O ₅ PLi ₂ -0, 38 H ^ O:

C 7, H 7, P 61 , 03 7, 45 7, 49 61 , 03 63 66

Example 56

(S) -4- [J2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl]] ethyl ^ hydroxyphosphinyl-1-5-hydroxybutyric acid dilithium salt

^A · 4-Q [[2- (Cyclohexylmethyl) -4,6-dimethylphenyl-3-ethyl] methoxyphosphinyl] -3 - [[(1,1-dimethylethyl) diphenylsilyl-3-oxy] -butyric acid methyl ester

gQ A solution of 1.33 g (2.02 mmol) of acetylenic phosphinate from Example 54, Part F, in 45 mL of methanol is bubbled with argon for 10 minutes. Then, this methanol solution in a Parr bottle is added with 0.34 g of 10 % Pd / C. Hydrogenation on the Parr apparatus for 20 hours at a pressure of about 2.8 bar yields 1.39 g of oil after filtration through diatomaceous earth in a sintered glass funnel. Cleaning by flash

-229-

Chromatography and elution with EtOAc / hexane (1: 1) gives 1.25 g (94 %) of the phosphinate title compound as a clear oil. TLC: R _f = 0.21 (5/4/1 hexane / EtOAc / toluene, silica gel), PMA.

IR (CHCl ₃ ) 3600-3200 (br), 3003, 2925, 2853, 1731, ⁵ 1448, 1440, 1247, 1233, 1179, 1044 cm ^-1 . ¹ H NMR (270 MHz, CDgI ₃ ) δ 6.83 (s, 1) 6.78 (s, 1) 4.50 (m, 1)

¹⁰ 3.80 & 3.77 (2 d's, 3, J = 6.3 Hz) 3.72 & 3.71 (2 s's, 3)

3.38 (m, 1)

2.87 (m, 1)

2.60 (m, 2)

¹⁵ 2.45 (d, 2, J = 6.9 Hz)

2.29 & 2.28 (2 s's, 3) 2.25 (s, 3) 2.00 (m, 4) 1.70 (m / 6) 20 i _j4 5 (m, 1)

1.30-0.90 (m, 6) mass spectrum (EI) m / e 424 (M) ⁺

For example, methyl (S) -4 - [[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl] -ethyl] methoxyphosphinyl] -3-hydroxybutyrate

A solution of 1.2 g (1.8 mmol) of Silyl Ether of Part A in 20 ml of THF is stirred at room temperature under argon. These

Solution is then added successively with 0.41 ml of glacial acetic acid and 5.0 ml (5.44 mmol) of 1.1M solution in THF dropwise over 5 minutes. After stirring for 23 hours at room temperature, the reaction is stopped by adding 50 ml of ice water and the mixture is stirred vigorously. The THF is distilled off under reduced pressure and the resulting residue is diluted with water and extracted 3 times with EtOAc. The

2.6 1 6 0 5

-230-

1 EtOAc extract is washed twice with saturated NaHCO 3 solution and once with brine and then over Na 2 SO 4. dried. Filtration and removal of the solvent yield 1.3 g of clear oil. The product is characterized by flash chroma-

5 tographie with 100 % EtOAc cleaned. Yield: 0.55 g (72 %) of the title alcoholic compound as a clear oil. TLC: R _f = 0.22 (EtOAc, silica gel), PMA.

IR (CHCl ₃ ) 2999, 2950, 2929, 2856, 1734, 1244, 1195, 1183, 1112, 1105, 1065, 1043 cm ^-1 . ¹ H NMR (270 Mez, CDCl ₃ ) δ 7.65 (m, 4 ) 7.28 (in, 6) 6.81 (s, 1) 6.76 (s, 1) 4.51 (m, 1)

3.62 & 3.60 (2 d's, 3, J = 5.3 Hz) 3.49 & 3.46 (2 s's, 3) 2.97 (m, 1) 2.65 (in, 2) 2.35 & 2.33 (2 d's, 2, J = 6.9 Hz) 2.25 (2 s's, 3) 2.16 (2 s's, 3) 1.84 (m, 1) 1.68 (m, 6) 1.55 (m, 1)

1.18 (in, 2) 1.15 (m, 3) l, 00 & 0.99 (2 S ¹ S, 9) 0.91 (m, 2) Mass spectrum (CI) m / e 663 (M + H) ⁺

C. (S) -4 - [[2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyl] ethyl Q-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt 35

0.552 g (1.3 mmol) of Part B diester are added at room temperature.

-231 -

stirred in 14 ml of dioxane. This solution is then with

3.9 ml (3.9 mmol) of 1, ON LiOH and then heated to 55 ° C. After stirring for 30 minutes, a cake-like precipitate is formed, which is dissolved by adding 5 ml of H 2. After 2 hours 15 minutes at 55 ⁰ C, the reaction mixture is cooled to room temperature and the volatiles are removed under reduced pressure. The remaining solid white residue is purified on a 3.0 x 30 cm column with HP-20 and elution first with 100 ml H ₂ O, followed by 10% CH-OH / H ₂ O (1: 1). The product fractions are lyophilized. Yield: 0.482 g (92 %) of white lyophilate. TLC: R _f = 0.36 (7: 2: 1 n-PrOH / NH ₄ OH / H ₂ O, silica gel), PMA.

IR (KBr) 3700-3100 (br), 2923, 2852, 1588, 1446, 1410, 1159, 1132, 1048 cm ^-1 . ¹ H NMR (400 MHz, D ₂ O) δ 6.93 (s, 1)

6.91 (s, 1)

4.34 (m, 1)

2.80 (m, 2) 20

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 ¹ "), 409 (M + H)

Analysis for C ₂₁ H ₃₁ O ₅ PLi ₂ · 0.76 H ₃ O: CHP

: 59.76 7.77 7.34 found: 59.76 7.91 7.53

-232-

1 example 57

4 - [[[Qp-fluoro-3,3 ', 5-trimethyl- [i, 1'-biphenyl] -2-yl] -oxy] methyl] -hydroxyphosphinyl] -3-hydroxybutyric acid-dilithium

salt

5 A. 4'-fluoro-3,3 ', 5-trimethyl-1, 1'-biphenyl] -2-carboxaldehyde

(US-A-4,37.5,475, p. 37/38)

The title compound is prepared according to Example 1, parts A to C, 10.

For example, 4 "fluoro-3,3 ¹ /5-trimethyl-Jj, 1'-biphenyl] -2-methanol

1.03 g (4.26 mmol) of Part A aldehyde are stirred under argon in 30 ml of anhydrous CH 2 Cl 2. Within 15 minutes, the aldehyde solution is added dropwise at room temperature with .1.06 g (5.11 mmol) of m-Cl-perbenzoic acid in 20 ml of CH ₂ Cl _2. After 58 Stirring at room temperature for hours

The reaction mixture is evaporated to dryness on a rotary evaporator, the resulting yellow solid is dissolved in THF and treated with 6.4 ml of 2N KOH. This mixture is stirred at room temperature for 5.5 hours. Then the THF is distilled off. The resulting precipitate is diluted with H ₂ O and the aqueous solution extracted ₃ times with Et ₃ O. The extracts

then over MgSO. dried. The yellow oil obtained after filtration and removal of the solvent is purified by flash chromatography and elution with 5 % Et ₂ O / hexane. Yield: 0.843 g (100 %) of phenol title compound as a white Fissstoff.

30 TLC: R _f = 0.37 (10 % Et ₂ O / hexane, silica gel), PMA.

MP 83-86 ⁰ C.

IR (KBr) 3512, 3500 (br), 2950, 1504, 1482, 1238,

1231, 1215 cm " ¹ .

¹ H NMR (270 MHz, CDCl-) 35 ^J

-233-

¹ δ 7.20 (m, 2)

7.07 (t, 1, J = 9.0 Hz)

6.92 (s, 1).

6.82 (s, 1)

5 4.95 (s, 1)

2.31 (s, 3)

2.25 (s, 6) mass spectrum (Cl) m / e 231 (M + H) ⁺

^c · [[[4'-fluoro-S ₁ S ', 5-trimethyl- [i, 1'-biphenyl] -2-yl] -oxy] -

methyl] -phosphonic acid diethyl ester

*

A suspension of 0.30 g (10.3 mmol) of 80 % oil dispersion of pentane-washed NaH in 15 ml of anhydrous DMF is cooled under argon in an ice bath. Then the NaH suspension is added in 15 minutes with 10 ml of a solution of 2.36 g (10.3 mmol) of Part B phenol in DMF. . Gas evolution is observed ------. -After more complete. Addition, the reaction mixture is warmed to room temperature and stirred for 35 minutes. At room temperature, a solution of 3.31 g (10.26 mmol) of diethyl tosyloxy-methylphosphinate in 11 ml of DMF is added dropwise within 10 minutes (for preparation, see A. Holy and I. Rosenberg, Collection Czechoslovak Cehm , Vol. 47, 1982). After 22 hours at room temperature

^ ° the reaction by addition of saturated aqueous

Quenched NH.Cl solution and the DMF removed under reduced pressure. The resulting solid is dissolved in EtOAc and H ₂ O and the aqueous layer is washed twice with EtOAc. The combined EtOAc extracts are washed with saturated aqueous

³ ^ NaHCO_ solution and brine and then washed over

MgSO. dried. Filtration and removal of the solvent yield 4.3 g of crude ether title compound, which is purified by flash chromatography and elution with 70 % EtOAc / hexane. Yield: 3.2 g (82 %) of ether-title compound

³⁵ as a clear oil.

-234 TLC: R _f = 0.52 (50 % acetone / hexane, silica gel), PMA.

IR (Film) 2983, 2925, 2910, 1504, 1474, 1213, 1032, 971 cm ^-1 .

¹ H NMR (270 MHz, CDCl ₃ )

δ 7.33 (m, 2)

7.01 (t, 1, J = 10.0 Hz)

6.96 (s, 1)

6.91 (s, 1)

4.07 (ro, 4)

3.69 (d, 2, J = 9.3 Hz)

2.34 (s, 3)

2.31 (d, 3, J = I, 7 Hz)

2.29 (s, 3)

1.31 '(t, 6, J = 7.0 Hz)

Mass spectrum (CT.) M / e 381 (M + H) ⁺ , 242 (M ⁺ -C ₄ H ₁₀ PO ₃ ) " ¹ "

- D. [(^ [4'-fluoro-3, 3,5'-t-dimethyl-Q, 1'-biphenyl-3-yl] -oxy] 20

methylQ-phosphonic monoäthy! ester

3.21 g (8.45 mmol) of Part C diester are stirred at 70 ⁰ C in 40 ml of dioxane with 12.7 ml (12.67 mmol) of 1N LiOH. Mach 3 hours at 7O ⁰ C, the reaction mixture at room temperature-

25 cooled and the dioxane removed under reduced pressure. The aqueous solution is diluted with H 2 O and cooled in an ice bath and then acidified to pH about 1 with 6N HCl to give a milky white solution. This solution is extracted 3 times with EtOAc, the EtOAc extracts are transferred over

₃₀ mg of SO. dried and filtered. Yield: 3.1. ' g title compound as a clear gum

TLC: R = 0.20 (9 / 0.5 / 0.5 CH ₂ Cl ₂ / AcOH / MeOH, silica gel), PMA.

¹ H NMR (270 MHz, _CDCl3) δ 10.26 (s, 1) 7.35 (2)

6.96 (m, 3)

-235-

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 = 7jl4 Hz).

E. 4- [ethoxy - [[Q4 ^l -fluoro-3,3 ^l, 5-lrimethyl- [j, 1 '-biphenyl] -2-methyl-3-YLJ-oxyQ phosphinyl] -3-oxo-butyric acid methylester

2.96 g (8.42 mmol) of phosphonic acid from part D. In 75 ml of anhydrous CH_C1_ under argon at room temperature with

2.44 g (16.84 mmol) (C ₉ H _{9 9} Si (CH 2) - stirred) After 1 hour 15

Stirring for 10 minutes, the CH-Cl- under reduced pressure

distilled off and the resulting oil azeotroped once with benzene-de .: and then 15 minutes - kept in a high vacuum. This oil is dissolved in 75 ml of anhydrous CH-Cl- and under argon

cooled to 0 ⁰ C. The cooled solution is mixed with 3 drops 20

anhydrous TMF and then added dropwise with 1.18 g (9.26 mmol) of oxalyl chloride. The reaction mixture is stirred at 0 ^° C. for 20 minutes, then warmed to room temperature and stirred for a further hour. The solvent is removed under reduced pressure and the brown phosphonochloridate oil

Azeotropically distilled twice with benzene and then for 1 hour

Held high vacuum.

The dinanion of methyl acetoacetate is prepared according to Example 55,

Part C, from 1.27 g (10.95 mmol) of methyl acetoacetate, 0.350 g of 30

(12.05 mmol) of oil dispersion "from NaH, 4.0 mL O.07 mmol) 2.5M solution of n-butyllithium in hexane and 35 mL THF.

The Phosphonochloridat prepared above is cooled in 10 ml of THF to -78 ⁰ C and added drop by drop within 20 minutes

added to the cooled to -78 ° C dianion solution.

-236-

1 After stirring for 40 minutes at -78 ⁰ C the reaction at -78 ° C is quenched with saturated aqueous NH.Cl solution and the mixture warmed to room temperature. The THF is distilled off under reduced pressure and the resulting

5 residue in EtOAc and H "O dissolved. The aqueous layer is extracted 2rral with EtOAc. All EtOAc solutions are combined and washed once with saturated NaHCO ₃ solution and once with brine and then over Na ₂ SO ₄ . dried. There are obtained 4.0 g of crude phosphinate title compound as a 10 % oil, which is purified by flash chromatography and elution with 75 % EtOAc / hexane. Yield: 1.4 g (41 %) of the phosphinate title compound as a yellow oil. TLO: R _f = 0.25 (75 % EtOAc / hexane, silica gel), PMA.

IR (CHCl ₃ ) 3004, 2954, 2925, 1744, 1718, 1643, ¹⁶ 1541, 1503, 1472, 1449, 1438, 1425, 1236, 1037 cra.

¹ H NMR (270 MHz, _CDCl3); θ 7.30 (ro, 2)

6 _} 95 * (m, 3) ²⁰ 4.05 & 3.90 (2 m's, 2).

3.75 (ra, 2)

3.736 (3 ^ 6 (2S ¹ S, 3) '3.55 (m, 1) 3.25 (m, 1) ²⁵ 2.33 & 2.29 (2 s' s (br), 9) 1.28 & 1.12 (2 fs, 3, J = 7, 1 Hz)

Mass spectrum (CI) m / e 451 (M + H) ⁺

30 f. 4 - [[[[4 · -Ρ1υοΓ-3,3 ', 5-trimethyl-Q, 1'-biphenyl] -2-yl] -oxyJ-methyQ-äthoxyphosphinyl ^ -J-hydroxybuttersäuromethylester

A solution of 1.39 g (3.09 mmol) of ketone from Part E in 15 mL 35 THF is cooled under argon to 0 ⁰ C. The cooled solution is then treated with 0.12 g (3.09 mmol) NaBH ₄ and then long

-237-

added dropwise with 2.8 ml of CH ₃ OH. After 1 hour at ⁰ ° C., the reaction is stopped by adding acetone and then 1.4 g of silica gel CC-4 and the mixture is warmed to room temperature. The reaction mixture is filtered and the filtrate is rotary evaporated to a yellow oil. The oil is purified by flash chromatography and elution with 90 % EtOAc / hexane. The product-containing fractions are combined and the solvent is distilled off under reduced pressure. The resulting yellow oil is crystallized from Et ₂ O / hexane and the resulting crystal is digested with Et ₂ O / hexane. As a batch: 0.320 g of the alcohol title compound as white crystals

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

MP 116-119 ⁰ C

¹⁵ IR (KBr) 3288 (br), 3000, 2950, 2920, 1735, 1503,

1473, 1440, 1311, 1232, 1195 cm " ^1. " · - - ¹ H NMR (270 MHZ, CDCl ₃ ) 6 7.28 (m, 2) - 7.05 (t, 1, J = 6 ₇ O Hz) ²⁰ "6.98 (s, 1) 6.90 (s _: 1) 4.42 (m, l)

4.05 & 3.85 (m, 2)

3.75 (d, 2, J = 6.0 Hz)

²⁵ 3.70 (s, 3)

2.55 (m, 2)

2.32 (s, Ö)

2.30 (s, 3)

2.00 (m, 2)

^£ ° 1, 30 (t, 3, J = 7,0.Hz)

Mass spectrum (CI) m / e 453 (M + H) ⁺ , 435 (MH ₂ O) ⁺

^G · 4 - [[[[ '!' - fluoro-S ^ ^1, 5-trimechyl-Π, 1 x diphenyl] -2-yl} -oxyT-methyl] -3-hydroxybutyric -hydroxyphosphinyfj

dilithium

-238-

A solution of 0.293 g (0.65 mmol) of Part F diester in 13 ml of dioxane is added at room temperature with 2.0 ml of 1N LiOH. The reaction mixture is warmed to 55 ° C and stirred for 1 hour 45 minutes and then cooled to room temperature.

Then the reaction mixture is evaporated to dryness on a rotary evaporator. The resulting white solid is kept under high vacuum for 10 minutes. The crude product is purified by chromatography on a 15 cm χ 3.0 cm column with HP-20 and elution first with 100 ml H_O and then 50 % CH.OH / H 2 O. Yield: C, 295 g (88 %) pure dilithium salt title compound as a white lyophilate. TLC: R _f - 0.38 (7: 2: 1 n-PrOH / NH ₄ OH / H ₂ O, silica gel), PMA.

IR (KBr) 3400 (br), 3021, 3011, 2981, 2958, 2924, 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175,

15 -1

1087 cm.

¹ H NMR (270 Hz, D ₃ O)

δ 7,20 (ra, 2)

• 7.07 (d, 1, J = 9.9 Hz)

20 7.03 (s, 1)

6.86 (s, 1)

4.03 (m, 1)

3.40 (d, 2, J = 8.3 Hz)

2.24 (s, 3)

25 2.21 (s, 3)

2.20 (m, 2)

2,17 (s, J)

1 ^ 45 (in, 2).

Mass Spectrum (FAB) m / e 423 (M + H) ⁺ 30

Analysis for C ₂₀ H ₂₂ OgFPLi ₂ 0.95 H ₃ O: CH FP

Calc .: 54.67 5.48 4.32 7.05 Found: 54.37 5.03 4.31 7.55

2 8 1 h O

-239-

1 Be itpiel 58

4- [ε-4'-fluoro-3,3 ', 5-trimethyl- (1, 1'-biphenyl-2-yl] -methyl] -hydroxyphosphinyi] -3-hydroxybutyric acid dilithium salt A. 4'-fluoro-3 , 3 ', 5-trimethyl- [i, 1'-biphenyl] -2-methanol 5

A solution of 0.12 g (3.18 mmol) of NaBH. in 9 ml of anhydrous ethanol is added 0.70 g (2.89 mmol) of aldehyde from Example 57, Trjil A, as a solution in 4.5 ml of Et ₂ O and 3.0 ml of EtOH. The reaction mixture is stirred for 2 hours at room temperature. Then the reaction is stopped by addition of saturated NH.Cl solution. The resulting solid precipitate is filtered off. The filtrate is evaporated to dryness on a rotary evaporator and the solid obtained is dissolved in Et 2 O and H 2 O. The white layer is washed twice with EtO and the combined Et ₂ O solutions are poured over MgSO 4. dried.

After filtration and removal of the "solvent", 0.70 g of white solid are obtained. This solid is purified by flash chromatography and elution with 33 % Et ₂ O / hexane. Yield: 0.675 g (100 %) of the title alcohol

TLC: R _f = 0.11 (15 % Et ₂ O / hexane, silica gel), PMA.

₂₅ MP 101-102 ⁰ C.

IR (KBr) 3351, ~ 293, 3267, 3260, 3024, 3016, 2980, 2939, 2921, 1605, 1601, 1502, 1451, 1355, 1243, 1236, 1228, 1189, 1118, 999 cm ^{-1, 1} H NMR (270 MHz, _CDCl3)

30 ^{ό 7} I ¹⁵ (* '2)

7.03 (in, 2)

6> 90 (s, 1)

4.55 (d, 2, J = 6 _} 0 Hz)

2.48 (s, 3)

2.33 (s, 6) if ...

Mass spectrum (CI) m / e 244 (M ⁺ ), 227 (M-OH)

28i 60

-240-

B. H [4'-fluoro-3,3 ', 5-trimethyl- [i, 1'-biphenyl] -2-yl] -methyl] phosphonic acid diethyl ester

A solution of 1.94 g (7.95 mmol) of alcohol of Part A in 50 ml of ^CH 2 ^C ' ¹ "2 ^ ¹ * ³ was cooled under argon to ⁰ ° C. The cooled solution was then treated with 0.965 g (9, 9). 54 mmol) of Et ^ N and then added dropwise (1.00 g 8.75 mmol) of MsCl was added. The reaction mixture is stirred for 30 minutes at 0 ⁰ C and then warmed to room temperature and stirred overnight. The reaction is saturated by the addition of NaHCO_ solution was quenched and the mixture stirred vigorously The organic layer was washed with saturated NaHCO 3 solution and dried over MgSO 4 Filtration and removal of the solvent gave 2.1 g of 2- (chloromethyl) -4'-fluoro-3,3 ', 5-tri-

15 methyl-1,1'-biphenyl | as a clear oil.

TLC: R _f = 0.68 (50 % Et ₂ O / hexane, silica gel), PMA.

: ¹ H NMR (270 MHZ, CDCl ₃ )

δ 7.22 (m, 2)

7.03 (m, 2)

²⁰ 6,90 (s, 1)

4.50 (s, 2)

2.48 (s, 3)

2.33 (s, 6)

Without further purification, 2.1 g of the above chloride are stirred for 3 hours at 150 ^° C. under argon with 30 ml of P (OC ₂ Hc) ₃ . The reaction mixture is then cooled to room temperature and the excess P (OC ₂ H ₅ J ₃ removed by distillation The crude product is purified by flash chromatography and elution

30 with 70 % EtOAc / hexane. Yield: 2.40 g (83 %) of the phosphonate title compound as a clear oil. TLC: R _f = 0.37 (70 % EtOAc / hexane, silica gel), PMA.

IR (CHCl ₃ ) 2992, 2928, 2909, 1501, 1474, 1455, 1343, 1392, 1245, 1239, 1119, 1053, 1029, 970, 963

35 -1 cm

28

-241-

^{1 1} H NMR (270 MHz, _CDCl3)

δ 7.15 (m, 2)

7.00 (m, 2) ...

6.83 (s, 1)

5 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) 10

Mass spectrum (CI) m / e (M + H) ⁺

C. [[4'-fluoro-S ₁ S ', 5-trimethyl- (1, 1'-biphenyl) -2-yl] -methyl] -phosphonic acid monoethyl ester

2.40 g (6.59 mmol) of Part B phosphonate diester are stirred at room temperature in 30 ml of dioxane. This dioxane solution

-. . Is then: with 9.9 ml of iN: LiOH..is offset and the reaction

V: f. mixed-under-return-heat. After-18 and 44 hours each additional 9.9 ml of 1N LiOH are added. After 55 hours under reflux, the reaction mixture is cooled to room temperature and the dioxane distilled off on a rotary evaporator. The resulting aqueous solution is diluted with H ₂ O and extracted twice with Et ₂ O to remove residual diester.

The aqueous layer is then cooled in an ice bath and acidified to pH about 1 with 6N HCl. The milky white solution is extracted 3 times with EtOAc, the EtOAc extracts are washed over MgSO 4. dried, filtered and the solvent removed. Yield: 1.89 g (85 %) of clear oil.

TLC: R _f = 0.26 (9 / 0.5 / 0.5, CB ₂ Cl ₂ / MeOH / AcOH, silica gel), PMA.

IR (CHCl ₃ ) 3029, 3023, 3005, 2983, 2925, 1710, 1605, 1500, 1234, 1042, 988 cm ^-1 . ¹ H NMR (270 MHZ, CDCl ₃ )

-242-

1 δ 11.07 (S ₁ 1)

7.05 (m, 2)

6.95 (m, 2)

6.80 (s, 1) 5.31 (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). ¹⁰ mass spectrum (CI) m / e 337 (M + H) ⁺

D. 4- [ethoxy - ^[[4-fluoro-l 3,3 ^l, 5-trimethyl-Q, 1'-biphenyl] -2-YLJ-methyl} phosphinyl ^ -S-oxo-butyric acid methylester

"A solution of 1.85 g (5.50 mmol) of partial acid half-acid in 50 ml of CH ₂ Cl ₂ is stirred at room temperature for 1 hour 15 minutes with 1.60 g (11.0 mmol) of (C ₃ H ₅ J ₃ NSi (CH ₃ ) ₃ stirred.: "Then the CH ₉ Cl ^ distilled off from the reaction mixture

.and the resulting yellow oil once with benzene azeotropically de- * ^w distilled and then held for 20 minutes under high vacuum. This oil is then dissolved under argon in 50 ml of anhydrous CH ₃ Cl ₂ and cooled to 0 ^° C. The cooled solution is mixed with 2 drops of anhydrous DMF and then trofpenweise with 0.768 g (6.06 mmol) Oxaly.lchlorid. It occurs gas evolution. The reaction mixture is stirred for 20 minutes at 0 ⁰ C, warmed to room temperature and stirred for a further 40 minutes. The color of the reaction mixture changes to Tiefburgunderrot. The CH ₃ Cl ₂ is distilled off from the reaction mixture and the resulting oil 2 times with water

distilled free azeotrope, then kept under high vacuum for 1 hour.

The dianion of methyl acetoacetate is prepared according to Example 57, Part E from 0.830 g (7.16 mmol) of methyl acetoacetate, 0.230 g (7.88 mmol) of oil dispersion of NaH, 2.64 ml (6.59 mmol) of 2.5M solution of n-BuLi in hexane and 20 ml of THF.

-243-

The prepared above Phosphonochloridat in 10 ml of anhydrous THF is cooled to -78 ⁰ C and added by cannula over 20 minutes in the cooled to -78 ° C dianion solution. After 40 minutes of stirring at -78 "C, the reaction at -78 ⁰ C under addition of saturated NH.Cl solution is stopped and the mixture warmed to room temperature. To the solution of solids, the reaction mixture is diluted with H ₃ O and the THF at The resulting mixture is extracted 3 times with EtOAc, the EtOAc extracts are washed once with saturated NaHCO-j solution and once with brine, dried over MgSO 4, and filtered to give 2.6 g of crude orange after removal of the solvent. The crude product is purified by flash chromatography and elution with 75 % EtOAc / hexane Yield: 0.43 g (23 %) of Part D ketone as an orange foam

TLC: R _f . =. .0.32 (50 % acetone / hexane, silica gel), PMA.

IR (KBr) 2952, 2925, 1739, 1718, 1654, 1529, 1503, 1472, 1234, 1206, 1166, 1119, 1035 cm ^{-1, 20 1} H NMR (270 MHz, CDCl ₃ )

6 7.20-6.70 (aromatic H, 5) 4.00-3.70 (m, 2) 3.70 & 3.55 (2 S ¹ S, 3)

3.35 (m, 2) ²⁵ 3.35 (d, 2, J = 15 Hz)

2.92 (m, 1) 2.45 & 2.35 (2 s's, 3)

2.25 (s, 6)

1, 15 & 0.95 (2 fs, 3, J = 7.0 Hz) 30 mass spectrum (CI) m / e 435 (M + H) ⁺

E. 4- {Athoxy - [[4'-fluoro-3,3- ^l , 5-trimethyl- (1, 1'-biphenyl] -2-yl [] - methyl-2-phosphinyl-3-hydroxybutyric acid-methyl)

ester 35

A solution of 0.40 g (0.92 mmol) of Part D ketone in 5 ml

2β 1 6 0-5

-244-

THF is added under argon with 0.035 g (0.92 mmol) of solid NaBH. added. Then, the THF solution is added at room temperature with 0.80 ml of methanol. After 1 hour at room temperature, the reaction is stopped by adding acetone and then 0.4 g of silica gel CC-4. The reaction mixture is filtered and the solvent removed. The reaction product still contains some ketone starting material. Therefore, the above reaction product is subjected to the same reaction conditions as described above; however, it does so before adding the NaBH. gaseous CO "passed through the solution. Work-up as above gives 0.250 g of yellow oil, which is purified by flash chromatography and elution with EtOAc. The pure alcohol title compound is obtained as a clear oil.

15 TLC; R _f = 0.26 (50 % acetone / hexane, silica gel), PMA.

¹ H NMR (270 MHz, CDCl ₃ )

6 7,10 (m, 2) "

:; 7, oo (m, 2)

20 ^{6 '85 (S} ' ^X)

4 _} 28 & 4.03 (2 m ^! S, 1)

4.10-3.70 (in, 2) 3.67 (s, 3) 3.33 (m, 2)

25 ^{2 '47 (S} ' ³⁾

2.40 (ra, 2)

2.30 (s, 6) 1.63 (m, 2) 1.17 (t, 3, J = 6.6 Hz)

^F 4 - [. [. [[4'-fluoro-S ₁ B ¹ , 5-trimethyl- [ ¹ , 1'-biphenyl] -2-yl] methyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

0.110 g (0.252 mmol) of diester from part E in 5.5 ml of anhydrous CH-Cl- are cooled under argon to 0 ⁰ C and 0.046 g

2Bi 60S.

-245-

1 (0.38 mmol) collidine and then 0.182 g dropwise

(0.88 mmol) trimethylsilyl iodide (TMSI). The reaction mixture is stirred at ⁰ ° C. for 2 hours, then warmed to room temperature. After 24 hours, an additional amount of 0.023 g collidine and 0.091 g TMSI is added. After stirring at room temperature for 48 hours, the CH ₂ Cl- is removed and the oil is treated with 6 ml of dioxane and then with 1.7 ml of 1N LiOH. The mixture is refluxed for 16 hours, cooled to room temperature, and the dioxane removed to leave an orange gum. The gum is dissolved in H_0 and filtered through sintered glass to remove solids.

. Fe to remove. The filtrate is lyophilized to give a whitish lyophilate which is purified on a 1.5 cm χ 15 cm HP-20 column. The column is eluted first with 150 ml H ₂ O and then with 50 % MeOH / H ₂ O. The product fractions are lyophilized. Yield: 88 mg (80 %) of title compound as white lyophilate.

.: ^ _ zJ-.TLC: - R _f _ = -0.38. (7: 2 ^ l_nr-: PrOH / NH ₄ OH / H ₂ O, silica gel), PAm.

·.-.-: · ν IR (KBr) 3700-3100 (bfh ^: -2923, 1591, 1501, 1234, 20

1147 cm " ¹ .

¹ H NMR (270 MHz, D ₂ O) δ 7.20-7.00 (m, 4)

6.82 (s, 1) ²⁵ 3.76 (m, 1).

3.11 (m, 2)

2.35 (s, 3)

2.22 (s, 3)

2.21 (s, 3) 30 2.05 (in, 2)

1.16 (dd, 2, J = 12.32 Hz, 6.45 Hz) Mass Spectrum (FAB) m / e 407 (M + H) ⁺

Analysis for C ₂₀ H ₂₂ FO ₅ PLi ₂ 0.30 H ₃ O: CHFP: 57.11 5.65 4.52 7.36

F .: 57.11 6.63 4.44 7.70

2 8i6

-246-

¹ example 5 9

(s) -4- [[[i - (4-fluorophenyl) -B-methyl-naphthalenyl] -äthinyl] -

fiydroxyphosphinylJ-S-hydroxybutyric acid dilithium salt

A. 1-methoxy-2-naphthalenecarboxylic acid

⁵ (J. Organomet. Chem., Vol. 20 (1969), pp. 251-252)

83.44 ml (208.60 mmol) of 2.5M solution of n-BuLi in hexane (Aidrich) are stirred under argon in 42 ml of anhydrous cyclohexane. The solution is cooled to 0 ⁰ C and added dropwise within 10 minutes with 24.24 g (31.48 ml, 208.6 mmol) destillieertes Tetramethylathylendiamin (TMEDA) treated. The resulting slurry is stirred for 30 minutes at 0 ^° C., then added dropwise over 20 minutes to a solution of 33 g (30.28 ml, 208.60 mmol) of 1-methoxynaphthalene (Ald.

5, Chem. Co .; used without further purification) in 84 ml

treated anhydrous cyclohexane. The resulting bright red homogeneous reaction mixture is warmed to room temperature and:. Stirred for 2 hours. Then, the reaction mixture is cooled to 0 ⁰ C off: cooled and are batchwise within 30 minutes by cannula to a cooled to -78 ° C solution of 250 ml of anhydrous optionally with gaseous CO ₂ saturated Et ₂ O (CO ₂ ~ pieces sublimed through a drying tube containing SiO ₂ and introduced at -78 ° C in anhydrous Et_O). The resulting white slurry is heated at 45 Minuten.auf about 0 ⁰ C and treated with 450 ml of 5% aqueous HCl.

The Et_O layer is separated and the aqueous layer extracted 3 times with Et ₂ O. The organic extracts are combined and extracted with 3 times 150 ml of saturated aqueous NaHCO.-solution. The aqueous layer is filtered through a sintered glass funnel to remove insoluble matter and the filtrate is cooled to 0 ^° C. and acidified slowly with concentrated HCl to pH = 1. The resulting precipitate is filtered off, azeotropically distilled twice with 150 ml of toluene and dried at 50 ^° C. under high vacuum for 5 hours. Yield:

32.52 g (0.161 mol, 77 %) of 1-methoxy-2-naphthalencarboxylic acid as an off-white powder, mp. 118 to 121.5 ° C.

28

-247-

1 TLC: silica gel, R _f 0.35 94: 5: 1 / CH ₂ Cl ₂ : MeOH: CH ₃ CO ₂ H

¹ H NMR: (270 MHz, CDCl ₃ ) consistent

¹³ C NMR: (67.8 Mhz, CDCl ₃ ) consistent

Mass spectrum: CI m / e 203 ⁺ (M + H) ⁺ 5 IR: KBr coincident

N- (2-hydroxy-1,1-dimethyl-ethyl) -1-methoxy-2-naphthalenecarboxamide

31.4 g (155.22 mmol) of 1-methoxy-2-naphthalencarbotisäure are stirred under argon in 155 ml of anhydrous CH ₉ Cl ₀ . The solution is then treated with 36.94 g (22.65 ml, 310.44 mmol) of SOCl ₂ . The reaction mixture is stirred at room temperature for 45 minutes and then heated for 45 minutes in a 55 ⁰ C hot oil bath under reflux. The reaction mixture is cooled to room temperature and washed with further

Treated 18.47 g (11.32 ml) of thionyl chloride and heated again for 45 minutes under reflux. The reaction mixture is cooled to room temperature, the excess SOCl ₂ and CH ₉ Cl _{9 are} removed on a rotary evaporator at 35 ° C (purging with argon) and the resulting mustard yellow solid under argon dissolved in 155 ml of anhydrous CH ₉ Cl ₉ . The solution is placed through a cannula into an addition funnel and added dropwise within 14 minutes to a solution of 27.67 g (310.44 mmol) of 2-amino-2-methylpropanol in 155 ml of anhydrous HC ₃ Cl ₂ , which is dissolved under argon at 0 ⁰ C has been stirred. The resulting reaction mixture is warmed to room temperature and stirred for 18 hours. The reaction mixture is then filtered, the precipitate washed with CH ₉ Cl ₉ and the filtrate evaporated under reduced pressure. The residue is redissolved in 350 ml EtOAc and washed once with 250 ml H ₂ O, once with 250 ml 5 % HCl ₁ once 250 ml 5 % NaOH and once 250 ml brine. The aqueous extracts are each back-extracted once with EtOAc. The organic extracts are combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure

-248-

1 orange-colored oil, which is azeotroped with 250 ml of toluene and then kept at 55 ⁰ C under high vacuum for 8 hours. Yield: 38.2 g (139.76 mmol, 90 %) of naphthalamide title compound as a pale yellow solid.

TLC: silica gel, R _f = 0.65 100 % EtOAc

¹ H NMR (270 MHz, _CDCl3) δ 8.19 (s, br, IH) 8.14 (m, IH).

8.03 (d, IH, J = 8.7 Hz) 10

7.83 (m, IH) 7.66 (d, IH, J = 8 _, 7 Hz) 7.55 (ra, 2H) 4.00 (s, 3H) 3.74 (s, 2H) · 1, 47 (s, 6H) mass spectrum · CI m / e (M + H) ⁺ IR: (CHCl ₃ solution)

'3365; = 3063, 3024, 3005Γ 2971, 2938, 2873, 1641, · · =: 1597, 1040) 1456, 1446, 1387, 1371, 1344, 1291, 1256, 1238, 1223, 1210, 1199, 1183, 1168, 1145, 1079, 981, 833 cm " ¹ .

C. 4, 5-Cihydro-2- (1 -ironethoxy-2-naphthalenyl) -4,4-dimethyloxazole

38.2 g (139 mmol) of naphthalamide from Part B are stirred under argon and cooled to 0 ⁰ C. The solution is added dropwise within 15 minutes with 66.15 g (40.56 ml, 0.556 mol) of thionyl chloride. The resulting dark brown oil becomes

Stirred for 45 minutes at room temperature. Then 500 ml of anhydrous Et'O are added and the mixture is stirred mechanically for 2.5 hours. The yellow crystalline precipitate is filtered off, washed with Et_O and suspended in 250 ml Et ₀ O. The suspension is cooled to 0 ^° C. and

^l

made basic with about 200 ml of 10% NaOH. The watery

: 2 8 ί 6

"."

; 1 layer is extracted 3 times with Et ₂ O and once with EtOAc. The organic extracts are combined, washed once with brine, evaporated, the residue over MgSO 4. dried and filtered. The filtrate is azeotroped under reduced pressure with toluene and the residue left for 8 hours at 55 ⁰ C in high vacuum (pump). Yield: 32.10 g (0.126 mol, 90 %) of the oxazoline title compound as a gold powder

TLC: silica gel R _f = 0.37 50 % EtOAc ¹ H NMR: (270 MHz, CDCl ₃ ) 6 8.25 (m, IH)

7j84 (d, IH, J = 8.7 Hz) 7.84 (m, 1H) 7.60 (d, IH, J = 8.7 Hz) 7.54 (m, 2H)

4.19 (s, 2H)

:> 4.04 (s, 3H)

• - 1.46 (s, 6H). '

-. Mass spectrum: CI m / e 256 (M + H)

IR: 2969, 2935, 2896, 1642, 1465, 1447, 1386, 1372, 1349, 1255, 1109, 1074, 991 cm ^-1 .

D. 2- [i- (4-fluorophenyl) -2-naphthalenyl) H-4,5-dihydro-4,4-

dimethyloxazole 25

30.0 g (117.52 mmol) of oxazoline from Part C are stirred under argon in 352.5 ml of anhydrous THF. The solution is heated to 45 ° C in an oil bath. Then the heat source is removed and the solution is added dropwise within 30 minutes with 79.33 ml (158.6 mmol) .2M solution of 4-fluorophenyl magnesium bromide in Et _. 0 (Aldrich) at a rate sufficient to maintain the reaction temperature at about 45 ° C. After complete addition, the temperature of the mixture is kept at 45 ° C and the mixture for 18 hours geruh t. Then, the reaction mixture is cooled to 0 ⁰ C, the reaction by addition of 200 ml of saturated aqueous NH.Cl-

28 1 60 p

-250-

Solution was stopped and the mixture with 200 ml of H ₃ O and 200 ml of EtOAc added. The aqueous layer is extracted 4 times with EtOAc. The organic extracts are combined, concentrated, over MgSO 4. dried and filtered. The filtrate is evaporated under reduced pressure to give 39 g of dark gold solid. The product is purified by flash chromatography (95 mm column diameter, 7 "Merck silica gel, 25 % EtOAc / hexane as eluent, 2" / minute flow rate). Yield: 30.42 g (95.25 mmol, 81 %) of 4-fluorophenyl-substituted naphthalene title compound as a pale yellow solid, mp 94-96 ° C. Further, 3.38 g (10.58 mmol, 9 %) of slightly contaminated product is obtained. TLC: silica gel R _f = 0.45 50 % EtOAc / hexane

¹ H NMR: (270 MHz, CDCl ₃ ) ¹⁵ δ 7.93-7.13 (aromatic, 10H) 3.77 (s, 2H) 1.27 (s, 6H)

Mass Spectrum: CI m / e 320 (M + H) ⁺ IR ₅ (KBr) 3060, 2966, 2927, 2884, 1667, 1603, 1508, ²⁰ 1462, 1383, 1354, 1335, 1293, 1219, 1185, 1160, U19 , 1083, 978, 842, 830 cm " ¹ .

E. 2- [i - (4-fluorophenyl) -S-methyl-Z-naphthalenyl0-4,5-di-

hydro-4,4-dimethyloxazole 25

28 g (87.67 mmol) of 1-fluorophenyl-4-oxazoliraphthyl compound of Part D are stirred under argon in 585 g of anhydrous Et ₂ O. The solution is cooled to -25 ° C and treated dropwise within 1 hour with 56.1 ml (140.27 mmol) of 2.5M solution of n-BuLi in hexane. The reaction mixture converts from a yellow homogeneous solution to a dark red / orange solution and then to an orange / green solution with a precipitate during this one-hour addition. The reaction mixture is stirred for a further 2.5 hours at -25 ° C and then dropwise over 15 minutes with 37.33 g (16.4 ml, 263.01 mmol) of iodomethane

28160

-251-offset. The resulting dark burgundy red solution becomes

Stirred for 4.5 hours at -25 ° C, warmed to 0 ⁰ C and stirred for 16 hours and finally warmed to room temperature and stirred for 7 hours. The resulting yellow, transparent solution is quenched with 500 ml of ice-cold saline. The aqueous layer is extracted 4 times with EtOAc. The organic extracts are combined, evaporated, over MgSO 4. and filtered through Florisil (300 ml sintered glass funnels 2/3 full). The Florisil is washed with DH-Cl »

10 see. The filtrate is evaporated, the residue is azeotroped under reduced pressure with toluene and left under high vacuum (pump) for 3 hours at 55 ° C. Yield: 30.32 g ("90.94 mmol", 100 %) of methylated naphthalene title compound as yellow solid.

TLC: Kieselgel R _f = 0.50 50 % EtOAc / hexane

^ H NMR: (270 MHz, "CDCl" ₃ ) δ 7.79-7.07 (aromatic, 9H) 3.80 (s, 2H)

2.54 (s, 3H) on

1.13 (s, 6H)

Mass spectrum: CI m / e 334 (M + H) ⁺ IR: (CHCl ₃ solution) 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513, 1497, 1461, 1299, 1280, 1235, 1190, 1158 , 1041, 965, 841 cm " ¹ .

F. 2- [1- (4-Fluorophenyl) -3-methyl-2-naphthalenylfl-4,5-dihydro-3,4,4-trimethyloxazolium iodide

29.23 g (87.67 mmol) of oxazoline from Part E are stirred under argon in 140.28 ml of nitromethane. This solution is then treated in an amount with 112 g (49.2 ml, 0.789 mol) of iodomethane. The resulting brown reaction mixture is left for 1 hour

Warmed for 20 minutes in the dark in a 6O ⁰ C hot oil bath.

Then the iodomethane is removed by simple distillation.

2 θ f 6 O

-252-

The nitromethane is removed on a rotary evaporator and then for 45 minutes in a high vacuum (pump). The resulting burgundy red solution is mechanically stirred for 1 hour in 250 ml of anhydrous Et ₂ O. The red filtrate is decanted off and the solid is digested again from Et_O as above. The resulting yellow solid is filtered and left for 4 hours in the dark in a high vacuum (pump). Yield: 44 g ("92.63 mmol", 100 %) of the oxazolinium iodide title compound as a mustard yellow solid. The title compound is kept for 18 hours in the dark at -30 ⁰ C and then used directly for the preparation of the compound of part G. TLC: silica gel R _f = 0.30 10 % MeOH / CH ₂ Cl ₂ .

G. 1 - (4-Fluorophenyl) -3-methyl-2-naphthalenecarboxaldehyde 15

41.67 g (87.67 mmol) of oxazolinium iodide of Part F are dissolved under argon in 526 ml of anhydrous THF and 210 ml of anhydrous

EtOH (dried over molecular sieves 4A). This solution / suspension is cooled to -15 ° C and batchwise within 1 hour with NaBH. treated. After complete addition, the reaction solution is stirred for 2.5 hours at -10 to -15 ° C. Then, the solution is diluted with 210 ml of anhydrous EtOH and the reaction mixture stirred at -15 ° C and treated dropwise over 45 minutes with 438 ml (876 mmol.) Of 2N HCl, the addition is very slow at the beginning. After complete addition, the reaction mixture is warmed to room temperature and stirred for 4 hours. It is then diluted with 500 ml HpO and the aqueous layer extracted with EtO. The organic extracts are combined, evaporated, over MgSO 4. dried, filtered, evaporated, azeotropically distilled twice with 120 ml of toluene and stripped off under reduced pressure. Yield: 12.9 g (48.81 mmol, 36 %) of the aldehyde title compound as a pale yellow solid. TLC: Kieselgel R _f = 0.66 50 % EtOAc / hexane

., A - ²⁵³ ~

1 ¹ H NMR: (270 MHz, CDCl ₃ ) 6 10.0 (s, IH)

7.83-7.18 (aromatic, 9H)

, 2.81 (s, 3H)

5 mass spectrum: CI m / e 265 (M + H) ⁺ IR: (CHCl ₃ solution). 1685, 1512, 1422, 1237, 862 cm " ¹ ,

H. 2- (2,2-Dibromoethyl) -1- (4-fluorophenyl) -3-methyl-10-naphthalene

3.0 g (11.35 mmol) of aldehyde from Part G are stirred under argon in 113.5 ml of anhydrous CH ₃ Cl ₂ . The solution is cooled at 0 ⁰ C and then in an amount of 9.53 g (36.32 mmol) of

Treated triphenylphosphine. The reaction mixture is stirred at ⁰ C for 20 minutes and then treated dropwise with a solution of 6.02 g (18.16 mmol) of carbon tetrabromide in 41 mL of anhydrous CH ₂ Cl- over 20 minutes. The resulting dark orange solution turns dark-burgundy,

while it is stirred for 1 1/4 hours at 0 ⁰ C. Then the reaction mixture is quenched with 150 ml of saturated aqueous NaHCO 3 solution. The aqueous layer is extracted 4 times with CH "C1". The organic extracts are combined, evaporated under reduced pressure, washed once with brine, over MgSO 4. dried and filtered. The filtrate

is pre-absorbed on about 28 g Merck silica gel and then applied to a 50 mm diameter flash chromatography column containing 6 "Merck silica gel and eluted with 7 % EtOAc / hexane as eluent, flow rate 2" / min is. There are obtained 4.23 g of dibromolefin title compound as a slightly contaminated pale yellow solid. Subsequent recrystallization from hexane yields 3.68 g (8.77 mmol, 77 %) of dibromolefin title compound as a white powdery solid, m.p. 134.5-135.5 ^e c.

35 TLC: silica gel R- = 0.60 20% EtOAc / hexane

2 8i6

-254-

^{1 1} H NMR: (270 MHz, CDCl ₃ ) δ 7.79-7.11 (aromatic olefinic, 10H)

2.48 (s, 3H)

Mass spectrum: CI m / e 419/521/423 (M + H) ⁺ IR: (CHCl ₃ solution).

3016, 1604, 1512, 1496, 1234, 1220, 1208, 1158, 886, 858 cm ".

I. 2-Ethynyl-1- (4-fluorophenyl) -3-methylnaphthalene

3.69 g (8.7 mmol) of Part H dibromolefin are stirred under argon in 47.9 ml of anhydrous THF. The solution is cooled to -78 ⁰ C and then treated dropwise within 15 minutes with 6.96 ml (17.4 mmol) of 2.5M solution of n-BuLi in He-15

xan (Aldrich) treated. The reaction mixture is 1 hour

stirred at -78 ° C and the reaction was then stopped by the addition of 40 ml of saturated aqueous NH.Cl solution. After warming to 0 ^° C., the reaction mixture is diluted with 40 ml H ₀ O and 40 ml Et ₀ O. The aqueous phase is washed twice with Et ₀ O and 2 2

extracted once with EtOAc. The organic extracts are combined, over MgSO 4. dried, filtered and the solvent removed under reduced pressure. Initial purification by flash chromatography (50 mm column diameter, 6 "

Merck silica gel, 7 % EtOAc / hexane as eluent, 2 "/ minute 25

Flow rate) gives 2.32 g of yellow oil / solid. The

H NMR at 270 NH ₂ shows a contaminated product. Re-purification by flash chromatography (75 mm column diameter, 6 "Merck-Diefjelgel, 1 % EtOAc / hexane as eluent, 2" /

Minute flow rate) gives 2.11 g (8.11 mmol, 93 %) of 30

Acetylene title compound as a pale blue solid (8 hours

in high vacuum at the pump) from the F. 91.5 to 94.5 ° C. TLC: silica gel, PMA R _f = 0.56 20% EtOAc / hexane

¹ H NMR: (270 MHz, CDCl ₃ ) ₃₅ δ 7.77-7.13 (aromatic, 9H)

I. "

28 ί <50

¹ .3.18 (s, IH)

2.62 (s, 3H)

Mass spectrum: CI m / e 260 M

IR: (CH ₂ Cl ₂ film) ⁵ 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150,

1092, 884, 871, 853, 825 cm " ¹ .

Methyl (S) -3 - [[(1,1-dimethyl-ethyl-diphenylsilyl-oxy) - (CQ-di- (4-fluoro-phenyl) -S-methyl-naphthalenyl] -ethynyl] -methoxy-phosphinyl] -butyric acid

5.57 g (8.82 mmol) of the dicyclohexylamine salt of Example 25 are dissolved in a mixture of 150 ml each of EtOAc / 5 % KHSO. (1: 1) and shaken vigorously. The layers are separated and the EtOAc layer washed twice with 100 ml of fresh 5 % KHSO.-solution. Finally, the organic phase over MgSO. dried, filtered and the solvent removed under reduced pressure. The residue obtained is azeotroped with 2 × 120 ml of benzene, evaporated and kept under high vacuum for 2 hours (pump). "4.33 g"("109%") phosphonate monoester is obtained as a tough, pale yellow oil. This oil is stirred under argon in 24.8 ml of anhydrous CH ₂ Cl ₂ and treated dropwise with 2.56 g (3.34 ml, 17.64 mmol) of distilled diethyltrimethylsilylamine over 8 minutes The solution is stirred at room temperature for 2 hours The volatiles are then removed on a rotary evaporator, aerated with argon and the resulting residue is azeotroped once with 60 ml of anhydrous benzene, then evaporated under reduced pressure and left under high vacuum for 45 minutes (pump) The residue is then dissolved under argon in 24 , 8 ml of anhydrous CH ₂ Cl _2. 2 drops of DMF are added and the solution is cooled to 0 ° C., then 1.34 g (0.923 ml, 10.58 mmol) of oxa-butyl chloride are added dropwise over 10 minutes amber-colored solution is stirred for 30 minutes at 0 ⁰ C and then to room temperature ER-

28

-256-

warms and stirs for 2 hours. The volatiles are removed and the residue azeotropically distilled as described above and kept under high vacuum (pump). Finally, the residue is stirred under argon in 27.7 ml of anhydrous THF. This solution is cooled to -78 ⁰ C and treated dropwise within 15 minutes with a cooled to -78 ° C solution of the resulting acetylenic anion in THF and added to the Phosphonochloridat as follows.

1.35 g (5.19 mmol) of Part I acetylene are stirred under argon in 27.7 ml of anhydrous THF and cooled to -78 ° C. This solution is treated dropwise with 2.08 ml (5.19 mmol) of 2.5M solution of n-BuLi in hexane over 10 minutes. The resulting green solution is stirred for 1.5 hours at -78 ° C, heated to 0 ⁰ C for 15 minutes and cooled again to -78 ⁰ C. This solution is kept at -78 ° C while being batched into an addition funnel and added dropwise to the solution of the phosphonochloridate prepared in THF cooled to -78 ° C. After complete addition, the reaction mixture is stirred for 1 hour at -78 ° C, the reaction is stopped by the addition of 50 ml of saturated aqueous NH.Cl solution and the mixture is warmed to 0 ⁰ C. The reaction mixture is then diluted with 40 ml H ₂ O and 40 ml. The aqueous layer is extracted with 4 times 50 ml Et ₃ O. The organic extracts are combined, concentrated, over MgSO 4. dried, filtered and the solvent removed under reduced pressure. The product is separated by flash chromatography (75 mm column diameter, 6 "Merck silica gel, 5: 4: 1 hexane: EtOHAc: toluene as eluent, 2" / minute flow rate). Yield: 1.53 g (2.21 mmol, 43 %) of the acetylenic phosphinate title compound as a yellow foam. There is also recovered 0.589 grams of impure starting material.

35 TLC: silica gel, PMA R _f = 0.26 5: 4: 1 hexane: EtOAc: toluene

28i60 5

-257-

¹ H NMR: (270 MHz, CDCl ₃ )

δ 7.82-7.09 (aromatic, 19H)

4 _} 52 (m, IH)

3.60 & 3.59 (2X s, 3H)

3.36 & 3.31 (2 χ d, 3Η, J = ll, 5 Hz)

2.54 & 2.49 (2 χ S, 3H)

2.87-2.73 (m, IH)

2.61-2.56 (m, IH)

2.39-2.22 (m, IH) IO

2,12-2,00 (m, IH)

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, 1.197, 1182 , 1158, 1151, 1138, 1110, 1105, 1093, 1038, 1017, 951, 885, 834 cm ^-1 .

K. (S) -4- E [[1- (4-fluorophenyl) -3-methyl-2-naphthalenyl [] -

äthinyl] -methoxyphosphinyl]] -3-hydroxybutyric acid methyl ester

0.60 g (0.866 mmol) of Part J acetylenic phosphinate are stirred under argon in 10.5 mL of anhydrous THF and added with 0.208 g (0.198 mL, 3.46 mmol) of glacial acetic acid and then 2.36 mL (2.60 mL) dropwise mmol) 1.1M solution of tetrabutylammonium fluoride in THF. The reaction mixture is stirred at room temperature for 24 hours, then the reaction is stopped by adding 25 ml of ice water and the mixture

diluted with EtOAc. The aqueous layer is extracted 3 times with EtOAc. The organic extracts are combined, washed once with saturated aqueous NaHCO ₃ solution and once with brine, over MgSO 4. dried, filtered and

evaporated under reduced pressure. The product is replaced by 35

Flash Chromatograph (30 mm column diameter; 35:

28 ί

-258-

Merck silica gel; 100 % EtOAc as Laufmictel; Yield: 0.267 g (0.588 mmol, 68 %) of the title β-hydroxyphosphinate compound as a pale yellow foam.

5 TLC: silica gel, PMA R _f = 0.28 10 % EtOAc

¹ HNMR: (270MHz, CDCl ₃₎ δ 7.81 to 7.18 (aromatic, 9H) 4.38 (m, IH) 3.71 (.. 3H,

3.59 & 3 ₇ 58 (2X d, 3H, J = 12Hz) 2.6662.65 (2XS, 3H) 2.62-2.52 (m, 2H) 2.19-1.92 (m, 2H) Mass spectrum: CI m / e 455 (M + H) ¹⁵ 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 20

L. (S) -4-LC [i- (4-fluorophenyl) -3-methyl-2-naphthalenyl] -äthinyl] -hydroxyphosphinyl]] -3-hydroxybutyric acid dilithium salt

0.265 g (0.583 mmol) of Part K diester are stirred under argon in 6 ml of dioxane and treated with 1.75 ml (1.75 mmol) of 1N LiOH. The reaction mixture is heated for 45 minutes in an oil bath at 70 ⁰ C and then cooled to room temperature. The solvents are removed on a rotary evaporator and then for 1 hour in a high vacuum (pump). The resulting white solid is dissolved in 4 mL of distilled H "0 and applied to a column of HP-20 for chromatography (2.5 χ 17.0 cm, equilibrated with M ₂ O). The column is eluted with 250 ml of H ₃ O and then with 45:55 MeOH: H ₃ O. Fractions of 1.3 minutes each are collected (approximately 10 ml). The product fractions are concentrated under reduced pressure at 35 ° C.

28 I 60 5

-259-

1, lyophilized and kept under high vacuum over P ₂ O ₅ (pump). Yield: 0.237 g (0.541 mmol, 93 %) of the phosphinic acid dilithium salt title compound as a white lyophilate.

5 TLC: silica gel, PMA R _f = 0.40 7 _: 2: 1 11-C ₃ H ₇ OHZNH ₄ OH / ¹ H NMR: "(400 MHz, D ₂ O) δ 7.88 (d, IH, J = 8.43 Hz)

7.80 (s _f IH)

7.58-7.29 (aromatic, 7H) 10 4 ^ 14-4.05 (m, IH) 2.61 (s, 3H)

2.43 (dd, IH, J = S ₁ O, J = 15.39) 2.21 (dd, IH, J = 9 ₁ 16, J = 15.39) • 1.84-1.67 ( m, 2H) '15 Mass spectrum: FAB m / e 439 (M + 2 Li) ⁺

IR: (KBr) 3443-3260 (broad), 3Ο66, 2164, 1594, 1512, 1495, 1434, 1222, 1183, 1160, 1071, 834 cm " ¹ .

Analysis for C ₀ -H _1o F0 _c PLi _o +

20 0.66 moles of H ₂ O; Mol Wt. = 450.14: CHFP

Calc .: 61.38 4.33 4.22 6.88

F .: 61.38 4.07 4.42 6.80

25 example

(E) -4-QJ 2 -Q- (4-fluorophenyl) -3-methyl-2-naphthalenyl] -äthyl] | -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt A. D, - D- (4-fluorophenyl) -3-methyl-2-napthylinyl-2-hydroxyethylphosphonic acid dimethyl ester

3.0 g (2.62 ml, 24.21 mmol) of dimethylmethylphosphonate are stirred under argon in 4 7 ml of anhydrous THF. The solution is cooled to -78 ° C and then trofpenweise with 9.08 ml (22.70 mmol) of 2.5M solution of n-BuLi in hexane within

35 treated 15 minutes. The reaction mixture is stirred for 1.5 hours at -78 ° C and then the resulting milky Lö-

26 ί 60

-260-

was added dropwise within 15 minutes with a solution of 4.0 g (15.13 mmol) of aldehyde from Example 59, Part G, in 14 ml of anhydrous THF. This reaction mixture is stirred for 45 minutes at -78 ° C. Finally, the reaction is stopped by addition of 50 ml of saturated aqueous NH.Cl solution, the mixture is warmed to room temperature and diluted with 50 ml of H-O and 50 ml of EtOAc. The aqueous layer is extracted 4 times with EtOAc. The organic extracts are combined, dried over MgSO 4, filtered, evaporated,

10 azeotropically distilled twice with toluene, under reduced

Pressure evaporated and kept in a high vacuum (pump). Yield: 5.90 g (15.13 mmol, 100 %) of the phosphonate title compound as a yellow solid which is used directly to prepare the compound of Part B.

15 TLC: silica gel, PMA R _f = 0.37 % acetone / hexane

B. (E) - [2- [ lambda] - (4-fluorophenyl) -S-methyl -naphthalenyl] -äthenyl ^ -phosphonic acid dimethyl ester

5.5 g (14.1 C mmol) of β-hydroxyphosphonate from Part A are stirred under argon in 66.5 ml of anhydrous toluene. This solution is treated with 0.673 g (3.54 mmol) of p-toluenesulfonic acid monohydrate (TsOH.H_O). The reaction mixture is heated under reflux in an oil bath of 135 ° C. The condensate is passed through a Soxhlet extractor containing molecular

sieve contains 4 A. After 16 hours at reflux, another 0.404 g (2.12 mmol) of TsOH · H ₃ O is added and the reaction is heated for a further 8.5 hours as above. The reaction mixture is then cooled to room temperature and diluted with 100 ml EtOAc. The mixture is then washed with 100 ml of saturated (aqueous) NaHCO.sub.2 solution. The aqueous layer is extracted 4 times with EtOAc. The organic extracts are combined, over MgSO 4. dried, filtered and evaporated under reduced pressure to give 4.22 g of crude vinyl phosphonate as a brown solid. The aqueous layer is acidified with 5 % HCl and then 3 times with

28 i 60 p

-261 -

Extracted EtOAc. The organic extracts are combined, over MgSO 4. dried, filtered and evaporated to give 1.4 g ("3.92 mmol") of vinyl phosphonate monoester as a light brown solid. This solid is stirred under argon in 15 ml of trimethyl orthoformate and heated for 16 hours in an oil bath of 120 ⁰ C under reflux. The reaction mixture is cooled to room temperature. Excess trimethyl iodoform is removed under reduced pressure and the residue obtained with the 4.22 g of the above

10 crude vinylphosphonate combined. The product is going through

Flash chromatography (75 mm column diameter, 2 "Merck silica gel, 100 % EtOAc as eluent, 2" / minute flow rate). Yield: 3.70 g (9.99 mmol, 71 %) of vinyl phosphonate title compound as a peach-colored solid.

15 fabric.

TLC: silica gel, PMA R _f = 0, <8 100 % EtOAc

¹ H NMR: (270 MHz, CDCl ₃ ) 6 7.79 (d, IH, J = 8.4 Hz)

7.72 (s, IH) 20

7.56-7.13 (m, 8H)

5.54 (dd, IH, J = 17.93 Hz, J = 20.6 Hz)

3.57 (d, 6H, J = Il Hz)

2.54 (s, 3H)

Mass spectrum: CI m / e 371 (M + H) ^{+ 26} IR: (CHCl ₃ solution) 3016, 2956, 2857, 1617, 1521, 1500, 1245, 1188, 1162, 1071, 1047, 834 cm ^-1 .

C. (E) - [2- [1- (4-Fluorophenyl) -3-methyl-2-naphthalenyl] -äthenylU-phosphonic acid monomethyl ester

3.60 g (9.72 mmol) of Part B vinylphosphonate are stirred under argon in 23.5 ml of dioxane and treated with 23.32 ml (23.32 mmol) of 1N LiOH. The reaction mixture is heated for 1 hour in an oil bath of 75 ⁰ C. Then the reaction mixture

28 1 * 05

-262-

cooled to room temperature and the solvents removed under reduced pressure. The residue obtained is diluted with 15 ml H ₂ O, cooled to 0 ^c C and acidified with 5% aqueous HCl to pH =. 1 The aqueous layer is extracted 4 times with EtOAc. The organic extracts are combined, over MgSO 4. dried, filtered, evaporated, azeotropically distilled twice with benzene and evaporated under reduced pressure. Yield: 3.38 g (9.48 mmol, 98 %) of the phosphonate monoester title compound as a peach solid.

TLC: silica gel, PMA R _f = 0.41 10: 1: 1

CH ₂ Cl ₂ / MeOH / CH ₃ CO ₂ H ¹ H NMR: (270 MHZ, CDCl ₃ ) 6 7.76 (d, IH, J = 8.4 Hz) 15 7.68 (s, IH)

7.47-7.09 (m, 8H)

5.61 (dd, IH, J = 18.47 Hz, J = 20.58 Hz) 3.48 (d, 3H, J = IO, 96 Hz) 2} 52 (s, 3H)

20 Mass spectrum: FAB m / e 357 (M + H) ⁺ IR: (CHCl ₃ solution)

3025, 3008, 29.51, 1614, 1605, 1511, 1494, 1235, 1210, 1188, 1158, 1050, 987, 833 cm ^-1 .

D. (E) -4- [2- [i- (4-Fluorophenyl) -3-methyl-2-napthalenyl] -äthenyl] -methoxyphosphiny ^ -S-oxobutyric acid methyl ester

3.29 g (9.12 mmol) of Part C phosphonate monoester are stirred under argon in 60 ml of anhydrous CH ₃ Cl ₇ and added dropwise over 10 minutes to 2.65 g (3.45 ml, 18.24 mmol). distilled trimethylsilyldiäthylamin (TMSDEA) added. The reaction mixture is stirred for 1.5 hours at room temperature. Then the volatiles are removed on a rotary evaporator, this aerated with argon and the residue 40 minutes in a high vacuum (pump).

-263-

Then the residue is stirred under argon in 25 ml of anhydrous CH ₂ Cl ₀ . This solution is cooled to 0 ⁰ C, treated with 2 drops of anhydrous DMF and then treated dropwise within 15 minutes with 1.39 g (0.955 ml, 10.94 mmol) of oxalyl chloride. The reaction mixture is stirred for 20 minutes at 0 ⁰ C and then warmed to room temperature and stirred for 1 hour. The volatiles are removed and the residue is kept as above in high vacuum. Finally, the residue is stirred under argon in 25 ml of anhydrous THF, cooled to -78 ° C and at this temperature, the solution is placed via a cannula in an addition funnel and dropwise within minutes to a cooled to -78 ° C solution of the dianion of Methyl acetoacetate in THF. This Dianion will

15 produced in the following way:

0.317 g (13.22 mmol, 0.397 g 80 % mineral oil dispersion) of NaH are washed once with pentane, dried under a stream of argon and then stirred under argon in 20 ml of anhydrous THF. This suspension is cooled to 0 ^° C. and treated dropwise over 10 minutes with a solution of 1.43 g (1.33 ml, 12.31 mmol) of methyl acetoacetate in 10 ml of anhydrous THF. The resulting clear solution is stirred for 20 minutes at 0 ⁰ C and then treated dropwise within 10 minutes with 4.56 ml (11.40 mmol) 2.5M solution .of n-BuLi in hexane. The resulting yellow solution is stirred for 45 minutes at 0 ⁰ C and then cooled to -78 ⁰ C and treated dropwise with the above-obtained, cooled to -78 ° C solution of the phosphonochloridate in THF. After complete addition, the reaction mixture is stirred for 45 minutes at -78 ° C. Then, the reaction is stopped by adding 50 ml of saturated aqueous NH.Cl solution, the mixture warmed to room temperature and diluted with 50 ml H_O and 50 ml EtOAc. The aqueous layer is extracted 3 times with aqueous NaHCO.-solution and once with CH ₇ Cl ₉ . The organic extracts are combined, 3 times

2 8 ί 6

-264-1 with saturated aqueous NaHCO 3 solution and once with

Saline, washed over MgSO 4. dried, filtered and evaporated under reduced pressure to give 4.0 g of rust-colored foam. First cleaning through

.5 Flash chromatography (40 mm column diameter, 20: 1 Merck silica gel, 100 % EtOAc as eluent, 2 "/ minute flow rate) gives 2.0 g of slightly contaminated keto-phosphinate title compound as an orange oil, further purification by Chromatography (30 mm column diameter, 25: 1 Merck silica, 95 % EtOAc / hexane as eluent, 2 "/ minute flow rate) gives 1.95 g (4.29 mmol, 47 %) of the title keto-phosphinate as orange-f Aromatic foam

TLC: silica gel, PMA R _f = 0.29 100 % EtOAc

^{15 1} H NMR: (270 MHz, CDCl ₃ ) δ 7.78-7.13 (aromatic, olefinic, 10H)

5.62 (dd, "1H, J = 17.93 'Hz, J = 25.84 Hz) 3.71 (s, 3H)

3.63 (s, 2H)

²⁰ 3 ^ 43 (d, 3H, J = ll _f 6 Hz)

3.14 & 3.13 (2 χ d, 2H, J = 18.46 Hz)

2.44 (s, 3H)

Mass spectrum: CI m / e 455 (M + H) IR: (film)

²⁵ 1749, 1717, 1623, 1614, 1604, 1511, 1328, 1223,

1159, 1031, 834 cm " ¹

E. (e) -4-CC ² - D - (4-fluoro-phenyl) -3-methyl-2-naphthalenyl] -äthenylj-methoxyphosphinylj -3-hydroxy-butyric acid methyl ester

1.28 g (2.82 mmol) of Part D ketophosphonate are stirred under argon in 12 ml of anhydrous THF. This solution is cooled to 0 ⁰ C and treated with 0.107 g (2.82 mmol) of NaBH ₄ and then treated dropwise with 2.45 ml over 4 A molecular sieve dried methanol. The reaction mixture is

-265-

Stirred for 1 hour at ^{0 0} C and then quenched with 2.5 ml of acetone. 1.3 g of silica gel CC-4 (Mallinckrodt) are added and the reaction mixture is warmed to room temperature with stirring. Finally, the suspension is filtered through a glass frit, washed twice with EtOAc and twice with CH ₂ Cl ₂ . The filtrate is evaporated under reduced pressure to give 1.3 g of orange-colored foam, which crystallizes on addition of EtOAc. The product is purified by flash chromatography (30 mm column diameter, 30: 1 Merck silica gel, 3 % MeOH / CH-Cl, eluent, 2 "/ Kinute flow rate) The product fractions are combined, evaporated and azeotroped once with benzene : 0.653 g (1.43 mmol, 51 %) of the title hydroxyphosphinate as a pale yellow solid, this pure product is digested from EtOAc / hexane = 7: 3 to give 0.516 g of hydroxyphosphinate as a white solid, mp 132-134.5 ° C TLC: silica gel, PMA R _f = 0.38 4 % MeOH / CH ₂ Cl ₂

, ¹ H NMR: (270 MHz, CDCl-) 20

δ 7.79-7 ^ 16 (aromatic, olefinic, 10H)

5.59 (2 χ dd, IK, J = 17.94 Hz, J = 24.27 Hz)

4.35 & 4.24 (2Xm, IH)

3.70 (s, 3H)

3.49 & 3.47 (2X d, 3H, J = Il Hz)

2.58-2.53 (m, 2H)

2.54 & 2.53 (2X s, 3H)

2.01-1.74 (m, 2H) mass spectrum .: CI m / e 457 (M + H)

30 IR: (KBr)

3422-3382, 3062, 3051, 2951, 2926, 2913, 1738, 1613, 1604, 1511, 1494, 1457, 1438, 1399, 1373, 1330, 1311, 1307, 1286, 1220, 1194, 1177, 1160, 1092, 1077, 1035, 883, 833 cm " ¹ .

-266-

F.. (E) -4 - [[2- [i- (4-Fluorophenyl) -3-methyl-2-naphthalenyl] -äthenylQ-hydroxyphosphinyl]] -3-hydroxybutyric acid dilithium salt

0.50 g (1.1 mmol) of Part E diester are stirred under argon in 10.45 ml of dioxane and treated with 3.3 ml (3.3 mmol) of 1N LiOH. The reaction mixture is heated in an oil bath of 70 ^° C. for 45 minutes. The resulting white slurry is dissolved in about 100 ml H ₂ O / KeOH (9: 1) and dissolved

The white solid is kept under high vacuum (pump) for 1 hour, then redissolved in 100 ml of H 2 O / MeOH (9: 1) and concentrated on a rotary evaporator to a volume of about 8 ml The solution is applied directly to a column of HP-20 (17.5 x 2.5 cm, equilibrated with H ₂ O) and eluted with 250 ml of H ₂ O and then with MeOH / H ₂ O (45:55) Fractions of about 10 ml are collected at intervals of 1.3 minutes, the product fractions are combined, evaporated at 35 ^° C. on a rotary evaporator, redissolved in H ₃ O, lyophilized for 16 hours and kept under high vacuum for 16 hours over PoO 2 (pump). Yield: 0.449 g (1.02 mmol, 93 %) of titanium salt title compound as white lyophilate.

TLC: silica gel, PMA R _f = 0.49 7: 2: 1 (nC ₃ H ₇ OH / NH ₄ OH / H ₂ O)

1 _T

H NMR: (400 MHz, D ₃ O) δ 7.73 (d, IH, J = 8.06 Hz)

7.64 (s, IH)

30 7.43-7.39 (m, IH) 7.25-7.13 (m, 4H) 7.05-6.95 (m, 3H)

5.62 (dd, IH, J = 17.96 Hz, J = 21.2 Hz) 2.43 (s, 3H)

35 2.38 (dd, IH, J = 4.03 Hz, J = 15.39 Hz)

2.22 (dd, IH, J = 9.16 Hz, J = 15.39 Hz) 1.59-1.51 (m, 2H)

-267-

1 mass specF m / e 429 (M + H) ⁺ , 435 (M + Li) ⁺ ,

441 (M + 2Li) ⁺ ·

IR: (KBr)

3431 (br), 1603, 1593, 1511, 1494, 1423, 1221, 51158, 1050 cm " ¹

Analysis for C ₂₃ H ₂₀ FO ₅ PLi ₂ 0.87 mol H ₂ O

Mol Wt. = 455.94: CHF P

Calculated: 60.60 4.80 4.17 6.79

10 found: 60.60 4.73 4.24 6.82

Example 61

(S) -4-Qj2- (j - (4-fluorophenyl) -3-methyl-2-naphthalenyl] -ethyl]] -hydroxyphosphinyl]] -3-hydroxybutyric acid dilithium salt

A. (S) -3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -4-CC ^2- D ~ (4-fluorophenyl) -S-methyl -naphthalenyl] -äthinylQ-methoxyphosphinylj-butyric acid methyl ester

0.675 g (0.974 mmol) of acetylenic phosphinate from Example 59, Part J are dissolved in 14.3 ml of methanol. Argon is then passed through this solution for 10 minutes and 0.270 g of 10 % Pd / C are added. The reaction mixture is shaken on a Parr apparatus for 24 hours under a hydrogen pressure of about 2.8 bar. Then, the reaction mixture is filtered through kieselguhr, washed with methanol, and the filtrate is evaporated under reduced pressure to give a white foam. The product is purified by flash chromatography (50 mm column diameter, 4.52 "Merck silica, 70 % EtOAc / Hoxan as eluent, 2" / minute flow rate). Yield: 0.556 g (0.798 mmol, 82 %) of saturated phosphinate title compound as a white foam. Elution of the column with methanol gives further

35 0.101 g (0.145 mmol, 15 %) of product.

TLC: silica gel, PMA R _f = 0.24 60 % EtOAc / hexane

 281 * 05

-268-

¹ H NMR: (270 MHz, CDCl ₃ ) δ 7.78-7.14 (aromatic, 19H) 4.44 (m, IH) 3.61 (S ₁ 3H)

3.35 & 3.23 (2, td, 3H, J = 10 _, 6Hz) 2.92-2.83 (m, IH) 2.63-2.54 (m, 3H) 2.21-1.27 (m, 4H) 2.45 & 2.42 (2X s, 3H)

1.00 (s, 9H)

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, 1065, 1043, 823 cm ^-1 .

1091, 1073,

B. (S) -4 - [[2- [i- (4-Fluorophenyl) -3-methyl-2-naphthalenyl] ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

A solution of 0.540 g (0.775 mmol) of Silyl Ether of Part A is stirred under argon in 9.45 mL of anhydrous THF and added with 0.186 g (0.177 mL, 3.10 mmol) of glacial acetic acid and then 2.1 mL (2.33 mL) dropwise mmol) 1.1M solution of tetrabutylammonium fluoride in THF. The reaction mixture is stirred for 16 hours at room temperature. Then, the reaction is stopped by adding 30 ml of ice water and the mixture is diluted with EtOAc. The aqueous layer is extracted 3 times with EtOAc. The organic extracts are combined, washed once with saturated aqueous NaHCO 3 solution and once with brine, over MgSO 4. dried, filtered and evaporated under reduced pressure. First purification by flash chromatography (40 mm column diameter, 6 "Merck silica gel, 4 % MeOH / CH-Cl as eluent, 2" / minute flow rate) gives 0.40 g

28i60 5

-269-

1 white solid. This solid is made from 100 % hexane

digested, filtered and kept under high vacuum for 8 hours (pump). Yield; 0.317 g (0.691 mmol, 89 %) of the hydroxyphosphinate title compound as a white solid, mp. 120 5 to I22 ° C.

TLC: Kieselgel R _f = 0.12 2 % MeOH / CH ₂ Cl ₂ ¹ H NMR: (270 MHz, CDCl ₃ ) δ 7.76 (d, IH, J = 7.9 Hz)

7.69 (s, IH) -7.42-7.16 (m, 7H). · 4.42 & 4.26 (2Xm, IH) 3.92 & 3.84 (2Xd, IH, J = 3.16Hz) 3.72 (s, 3H)

3.58 & 3.54 (2X d, 3H, J-3.69 Hz)

2J89-2.76 (ra, 2H)

2.56 (s, 3H)

2.63-2.41 (m, 2H) "

1.92-1.61 (m, 4H)

Mass spectrum: CI m / e 459 (M + H) ⁺ 20

IR: (KBr)

3428 (br), 3287 (br), 3064, 3050, 3017, 2989, 2952, 2921, 1737, 1603, 1510, 1497, 1458, 1438, 1234, 1221, 1191, 1175, 1159, 1042, 826 cm ^-1 ,

C. (S) -4- [2] [1- (4-Fluorophenyl) -3-methyl-2-naphthalenyl] ethyl J-hydroxyphosphinyl J-3-hydroxybutyric acid dilithium salt

30.315 g (0.687 mmol) of Part B diester are stirred under argon in 6.9 ml of dioxane. The solution is treated with 2.06 ml (2.06 mmol) of 1N LiOH. The reaction mixture is heated for 45 minutes in an oil bath of 70 ⁰ C, and then cooled to room temperature. The solvents are

35 tion evaporator distilled off at 35 ° C and the resulting white solid 1 hour under high vacuum (pump),

28 \ 60 p

ν -270-

1 The solid is then dissolved in about 8 ml of distilled H ₂ O and applied to a column of HP-20 (16 χ 2.5 cm, equilibrated with H ₂ O). The column is eluted with 250 ml H ₂ O and then with MeOH / H, O (45:55). Every 1.4 milliliters, fractions of about 10 ml are collected. The pro 'duktfraktionen (37 to 47) are combined, evaporated at 35 ° C on a rotary evaporator, lyophilized 16 hours, and 8 hours in a high vacuum over _P? 0_ held (pump). , Yield: 0.286 g (0.647 mmol, 94 %) of di-lithium salt title compound as white lyophilate,

TLC: silica gel, PMA R _f = 0.42 7: '?. :

₃₇₄₂₁ ¹ H NMR: (400 MHz, D ₂ O)

δ 7.82 (d, IH, J = 8.06 Hz)

7.76 (s, IH)

7 ^ 46-7.42 (m, IH)

7.30-7.25 (m, 3H)

7.18-7.13 (m, 3H)

4.06 (m, IH)

2.72-2.66 (m, 2H)

• 2.54 (s, 3H)

2.34 (dd, IH, J = 4.4 Hz, J = 15.22 Hz)

2.22 (dd, IH, J = 8.43 Hz, J = 15.02 Hz)

1.59-1.51 (m, 2H)

1.44-1.39 (m, 2H) -

Mass Spectrum: FAB m / e 433 (M + H) ⁺ IR: (KBr) 3451-3426 (br), 3151, 3124, 1620, 1593, 1509,

1439, 1422, 1403, 1218, 1159, 1050 cm ^-1, 30

analysis for C 5 ^fI 22 FO ₅ PLi. C 60 Mole H ₂ 4, F 9 6 P Mol Wt. = 453 , 09: 60 H 4, 1 2 6 , 83 About: 60 96 5.16 1 , 82 gef. : 96 5.29

35

* '' * '' - ...- '>' - '

- 28 ί 60

-271-

1 example 62

4 - [[3- [4'-fluoro-3 _# 3 ', 5-trimethyl - [1, 1'-biphenylH-2-yl] -

propylj-hydroxyphosphinylJ-3-hydroxybutyric acid dilithium

salt

A. 3- [4'-fluoro-S ₁ S ¹ _; 5-trimethyl-Ql, 1'-biphenyl] -2-yl] 2-propenecarboxylic acid ethyl ester

0.199 g (4.96 mmol, 0.149 g of an 80 % mineral oil dispersion) of sodium hydride are washed once with hexane under argon and then dried under argon. Then the NaH is stirred under argon in 9.1 ml of anhydrous THF. This suspension is cooled to 0 ⁰ C and dripping mweise within 5 minutes with a solution of 1.1 g (0.983 ml, 4.96 mmol) as a solution in 2.2 ml Triäthylphosphonoacetat wassorfreies THF. The resulting clear solution is stirred for 15 minutes at 0 ⁰ C, then warmed to room temperature and stirred for 30 minutes. Finally, a solution of 1.0 g (4.13 mmol) of aldehyde from Example 1, Part C, in 2.5 ml of anhydrous THF is added dropwise within 8 minutes. The reaction mixture is dissolved for 1 hour at room temperature. The reaction is then stopped by the addition of H 2 O and the aqueous layer extracted twice with EtOAc and twice with Et 2 O. The organic extracts are combined, washed once with brine, over MgSO 4.

dried, filtered and evaporated under reduced pressure. The product is purified by flash chromatography (50 mm column diameter, 6 "Merck silica gel, 6 % EtOAc / hexane as eluent, 2" / minute flow rate). Yield: 1.19 g (3.79 mmol, 92 %) of vinyl ester title compound

30 as a pale yellow foam.

TLC: silica gel, PMA, R _f = 0.22 4 % EtOAc / Hoxan

35

, -272-

, ¹ H NMR (270 MHz, CDCl ₃ )

δ 7.64 (d, IH, J = 16.35 Hz)

7 ^ 09-6.93 (m, 5H)

5.81 (d, IH, J = 16.35 Hz)

4.17 (q, 2H, J = 7 _f 12 Hz)

2.42 (S ₁ 3H)

2 ^ 33 (s, 3H)

2.28 (s, 3H)

T, 25 (t, 3H, J = 7.12 Hz) '·

Mass spectrum: CI m / e 313 (M + H) ⁺

4'-fluoro-3,3 ', 5-trimethyl-Q1, 1'-biphenyl] -2-butter

acid ethyl ester 15

1.15 g (3.68 mmol) of vinyl ester of Part A are dissolved in 36 ml of anhydrous EtOH. Then argon is passed through the solution for 10 minutes. Subsequently, 230 mg of 10 % Pd / C are added and Wasserstorf (g) for 10 minutes through the

* Q solution directed. The reaction mixture is stirred under hydrogen for 2 hours. The reaction mixture is then diluted with EtOfI and filtered through diatomaceous earth 1/2 "in a 60 ml glass frit, the diatomaceous earth is washed with EtOH and the filtrate is concentrated under reduced pressure.

²⁵ quarts: 1.12 g (3.56 mmol, 97 %) of saturated ester-title compound as a white solid

TLC: silica gel, PMA R _f = 0.29 5 % EtOAc / hexane

¹ H NMR (270 MHz, CDCl ")

δ 7.09-6.97 (m, 4H)

6.84 (s, IH)

4.06 (q, 2H, J = 7 ₎ 12 Hz)

2.90-2.84 (m, 2H)

2.37 (s, 3H)

2.30 (2 χ s, 6H)

2.32-2.27 (m, 2H)

1.20 (t, 3H, J = 7.12 Hz)

2 8 U O 5:

-273-1 Mass Spectrum: CI m / e 315 (M + H) ⁺

C. 4'-fluoro-3,3 ', 5-trimethyl-Q, 1'-biphenyl] -2-propanol

0.133 g (3.5 mmol) of lithium aluminum hydride are dissolved in 3.5 ml of anhydrous Et under argon _. O stirred. This suspension is cooled to 0 ⁰ C and treated dropwise within 8 minutes with a solution of 1.1 g (3.5 mmol) of ester from Part B in anhydrous Et ₂ O 3.5 ml. The reaction mixture is yerührt 15 minutes at 0 ⁰ C, then warmed to room temperature and stirred for 45 minutes. The mixture is cooled again to 0 ⁰ C and treated dropwise with 0.133 ml of H ₂ O and then with 0,133 ml of 15% NaOH and finally with 0.399 ml of H "O. The suspension is warmed to room temperature within 30 minutes. The resulting white powdery solid is filtered off and washed with Et ₂ O. The filtrate is evaporated, azeotroped once with benzene and stripped under reduced pressure to give 0.950 g of alcohol, which is purified by flash chromatography (50 mm column diameter, 6 "Merck silica gel, 35 % EtOAc / hexane as eluent, 2" / Minute flow rate) is cleaned. Yield: 0.906 g (3.33 mmol, 95 %) of the title alcohol as a colorless oil.

25 TLC: silica gel, PMA R _f = 0.18 20 % EtOAc / hexane

¹ H NMR (270 MHz, CDCl ₃₎ δ 7.08 to 6.93 (m, 4H) 6.82 (s, 3.H)

₃₀ 3.45-3.40 (m 2H) 2.60-2.54 (m, 2H)

2.34 (s, 3H)

2.28 (2 χ 'J, 6H)

l, 63-x, 52 (m, 2H)

Mass spectrum: CI m / e 273 (M + H) ⁺

28 \

-274-

1D 2- (3-bromopropyl) -4'-fluoro-3,3 ', 5-trimethyl- (j, 1'-biphenyl)

A solution of 2.65 g (10.1 mmol) of triphenylphosphine in 27.5 ml of anhydrous THF is cooled to 0 ° C and added dropwise with a solution of 3.55 g (10.71 mmol) of carbon tetrabromide in 5.5 ml anhydrous THF treated. The resulting yellow / white slurry is stirred at 0 ^° C. for 2 hours. Then, the complex is treated dropwise with a solution of 1.1 g (4.04 mmol) of alcohol of Part C in 8.2 ml of anhydrous THF. The reaction mixture is stirred for 1 hour at 0 ⁰ C, then warmed to room temperature and stirred for 16 hours. The reaction mixture is treated with Et _? O, filtered through a glass frit and the precipitate washed with Et ₂ O. The filtrate is washed once with brine, over MgSO 4. dried, filtered and evaporated under reduced pressure. The product is purified by flash chromatography (50 mm diameter, 6 "Merck silica gel, 2 % EtOAc / hexane as eluant, 2" / minute flow rate). Yield: 1.35 g (4.05 mmol, 100 %) of bromide title compound as a pale yellow oil. TLC: silica gel, PMA R _f = 0.22 100 % hexane

¹ H NMR (270 MHz, CDCl ₃ )

₂₅ 6 7.07-6.99 (m, 4H)

6.82 (s, IH)

3.22 (m, 2H)

2.69-2.63 (m, 2H)

2.36 (s, 3H)

₃₀ 2.30 (s, 3H)

2.28 (s, 3H)

1.90-1 ^ 80 (m, 2H)

Mass spectrum: CI m / e 235 (M + H) ⁺

E. [3- [4'-fluoro-S, ¹ , 5-trimethyl- [ ¹ , 1'-bipheny- 2- yl } -propyl- 1- phosphonic acid dimethacrylate

28 I 60 p.

-275-

1.3 g (3.88 mmol) of Part D bromide are stirred under argon in 38.8 ml of trimethyl phosphite. The reaction mixture is heated in an oil bath of 135 ⁰ C for 36 hours under reflux. Excess (CH ₃ O) ₃ P is removed by distillation

removed over a short distance and the residue 1 hour, in the

High vacuum kept at-100 ⁰ C (pump). The resulting yellow oil is purified by flash chromatography (50 mm column diameter, 6 "Merck silica gel, 85 % EtOAc / hexane as eluent, 2" / minute flow rate). Yield: 1.13 g (3.10 mmol, 80 %) of the dimethyl phosphonate title compound as a colorless oil

TLC: silica gel, PMA, R _f = 0.28 100 % EtOAc

¹ H NMR (270 MHz, CDCl ₃₎ δ 7.08 to 6.97 (m, 4H)

15 '

6.81 (s, IH)

3.65 (d, 6H, J = Il Hz) 2.63-2.56 (m, 2H) 2.34 (s, 3H)

2.30 (2 χ s, 3H)

on '

2.28 (s, 3H) 1.68-1.50 (m, 4H)

Mass spectrum: CI m / e 365 (M + H) ⁺

F. [3- [4'-fluoro-S ₁ S ^1, 5-trimethyl- [i, 1'-biphenyl3-2-yl] -propyl ^ phosphonic acid monomethylester

1.25 g (3.43 mmol) of Part E phosphonate are stirred in 8.23 ml of dioxane under argon. The solution is diluted with 5.15 ml

"Q (5.15 mmol) 1N LiOH and heated in an oil bath of 95 ⁰ C. After 1 hour another 3.43 mmol of LiOH was added and the reaction mixture heated again 3.5 hours at 95 ⁰ C. The reaction mixture is then cooled to room temperature. The solvents are concentrated under reduced pressure

_oc pressure distilled off. The white solid residue is with

25 ml H "O diluted, the slurry is cooled to 0 ° C and

-276-

acidified to pH = 1 with 5 % aqueous HCl. The aqueous layer is extracted 4 times with EtOAc. The combined organic extracts are over MgSO 4. dried, filtered and the filtrate evaporated. The residue is azeotroped twice with benzene and the resulting viscous oily residue is kept under high vacuum for 4 hours (pump). Yield: 1.18 g (3.37 mmol, 98 %) of phosphonate monomethyl ester title compound as a yellow oil.

TLC: silica gel, PMA, R = 0.46 10: 1: 1

CH ₂ Cl ₂ / MeOH / CH ₃ CO ₂ H

¹ H NMR (270 MHz, CDCl ₃ )

δ 7.06-6 ^ 95 (m, 4H)

6.81 ( _{S /} IH)

3.56 (d, 3H, J = Il Hz)

2.62-2.53 (m, 2H)

2.32 (s, 3H)

2.27 (2 x s, 6H)

1.69-1.48 (m, 4H)

20 Mass spectrum: FAB m / e 351 (M + H) ⁺

G. 4- [Q3 ^[4-fluoro-l 3,3 ^l, 5-trimethyl- [j, 1 '-biphenyf] -2-yl] -propyl] - methoxyphosphinyl3-3-oxo-butyric acid methylester

1.13 g (3.22 mmol) of Part F phosphonate monoester are stirred under argon in 12, 9 mL of CH 2 Cl 2. This solution is then treated dropwise over 8 minutes with 0.918 g (1.20 mL, 6.44 mmol) of freshly distilled TMSDEA.

This solution is stirred at room temperature for 1.5 hours.

The volatiles are removed under reduced pressure while venting in argon. The residue is azeotroped once with 70 ml of anhydrous benzene and then evaporated under reduced pressure while venting in argon. Finally, the residue is left for 5 minutes in a high vacuum (pump). Then the return

2 8 U05

-277-

Stir under argon in 12.9 ml of anhydrous CH 2 Cl 2. 2 drops of anhydrous DMF are added, the solution cooled to 0 ⁰ C and added dropwise within 8 minutes in 0.470 g (0.323 ml, 3.70 mmol) of oxalyl chloride. The reaction mixture is stirred for 20 minutes at 0 ^° C., warmed to room temperature and stirred at room temperature for 1-3 hours The volatiles are removed, the residue is azeotroped and kept under high vacuum as above.

* -Q ter argon in 9.0 ml of anhydrous THF. This solution is cooled to -78 ⁰ C and added dropwise at this temperature within 20 minutes to a solution, cooled to -78 ° C solution of the dianion of methyl acetoacetate in THF, which is prepared in the following manner:

0.116 g (4.85 mmol, 0.145 g of an 80 % mineral oil dispersion) of sodium hydride are washed once with hexane and dried under a stream of argon. The solid is then stirred under argon in 7.1 ml of anhydrous THF and this suspension is cooled to 0 ^° C. A solution of 0.506 g (0.471 ml,

^ O 4.36 mmol) of methyl acetoacetate in 3.6 ml of anhydrous THF is added dropwise within 8 minutes and the resulting clear solution for 25 minutes at 0 ⁰ C stirred. Then, the reaction mixture is added dropwise over 10 minutes with 1.62 ml (4.04 mmol) of 2.5M solution of n-BuLi in

^ ° hexane (Aldrich) treated. The resulting yellow solution is stirred for 35 minutes at 0 ⁰ C, then cooled to -78 ° C and treated dropwise over 20 minutes with the cooled to -78 ° C solution of the phosphonochloridate prepared above in THF. The reaction mixture is stirred for 1 hour at -78 ° C, then the reaction is stopped by the addition of 45 ml of saturated aqueous NH.Cl solution and the mixture warmed to room temperature. The mixture is diluted with 45 ml H 2 O and EtOAc. The aqueous layer is extracted 4 times with EtOAc. The organic extracts are combined, washed once with saturated aqueous NaHCO 3 solution and once with brine,

28 1 * 0-5

-278-

* over MgSO. dried, filtered and concentrated :: reduced pressure to give 2.0 g of rust-colored oil. The product is purified by flash chromatography (40 mm column diameter, 35: 1 Merck silica gel, 100 % EtOAc and 5 % MeOHZCH ₂ Cl ₂ as eluent, 2 "/ minute flow rate) Yield: 0.220 g (0.491 mmol, 15 %). ) β-ketophosphinate title compound as a rust-colored oil TLC: silica gel, PMA R _f = 0.19 100% EtOAc

10 ¹ H NMR (270 MHz, CDCl ₃ )

δ 7.08-6.98 (m, 4H)

6.81 (s, IH)

3.73 (s, 3H)

3.65 (d, 3H, J = Il Hz)

15 3.64 (s, 2H)

3.10 (dd, 2H, J = 5.27 Hz, J = 17.41 Hz)

2.67-2.57 (m, 2H) *.

2.35 (s, 3H)

2.30 & 2.28 (2X s, 3H)

20 2.29 (s, 3H)

1.72-1.56 (m, 4H) Mass spectrum: CI m / e 449 (Mt-H) ⁺

H. 4- [3- £ [4 '-fluoro-3, 3', 5-trimethyl- [j, 1 '-biphenyl] -2-yl] l ~ P ^ro Pyl3 -methoxyphosphinyl] -3-hydroxybutyric acid

methylester

0.10 g (0.223 mmol) of β-ketophosphinate from Part G are stirred under argon in 1.9 ml of anhydrous THF. This solution is cooled to 0 ⁰ C and then treated with 0.008 g (0.223 mmol) of NaBH. treated. Subsequently, 0.194 ml of molecular sieve 4 A dried MeOH are added dropwise. The reaction mixture is stirred for 1 hour at 0 ⁰ C, then the reaction is stopped by the addition of 0.194 ml of acetone and then 0.10 g of silica gel CC-4 (Mallinckrodt). The suspension is warmed to room temperature with stirring

-279-

and then filtered through a filter frit. The silica gel is washed with EtOAc. The filtrate is evaporated under reduced pressure to give 0.108 g of a golden oil. Two reaction products are isolated by flash chromatography (10 mm column diameter, 35: 1 Merck silica gel, 4 % MeOH / CH ₂ Cl ₂ as eluant, 2 "/ minute flow rate.) The desired β-hydroxyphosphinate title compound is added in an amount of 0.058 g (0.129 mmol, 58 %) as a pale yellow oil, and 0.019 g (0.043 mmol, 20 %) of 1,3-butanediol phosphinate are also obtained TLC: silica gel, PMA R _f = 0, 1 9 3.5 % MeOH / CH ₂ Cl ₂

¹ H NMR (270 MHz, CDCl 3) δ 7.08-6.98 (m, 4H) "6.82 (S ₁ IH) ¹⁵ 4.44 & 4.32 (2 X m, IH)

3.63 & 3 62 (2 X d, 3H, J = 10 _, 55 Hz)

3.70 (s, 3H)

2.65-2.50 (m, 4H) ·

₂₀ 2 _? 35 (s, 3H)

2.30 (2 X s, 3H)

2.29 (s, 3H)

1.89-1.76 (πι, 2H)

1.71-1.59 (m, 4H) 2g mass spectrum: CI m / e * 451, (M + H)

I. 4 - [[3-C4'-fluoro-3,3 ', 5-trimethyl- [i, 1'-biphenyl-3-2-yl3-propyl-3-hydroxyphosphinyl]] - 3-hydroxybutyric acid dilithium salt

30 '.

0.055 g (0.122 mmol) of Part H diester are taken under argon

stirred in 2 ml of dioxane and treated with 0.366 ml (0.366 mmol) of 1N LiOH. The reaction mixture is heated in an oil bath of 8O ⁰ C for 45 minutes. The reaction mixture is then cooled nc to room temperature and the solvents are distilled off on a rotary evaporator. The resulting yellow solid

28 1 60s

-280-

Fabric is kept under high vacuum for 2 hours (pump).

The di-dilithium salt title compound is obtained as a yellow solid.

TLC: silica gel, PMA R _f = 0.29 8: 1: 1 5

CH ₂ Cl ₂ / MeOH / CH ₃ CO ₂ H

¹ H NMR (270 MHz, D ₂ O)

δ 7.08-7.05 (m, 4H)

6.80 (s _; IH)

₁₀ 4.13 (m, IH)

2.54-2.47 (m, 2H)

2.38-2.28 (m, * 2H) ·

2.30 (s, 3H)

2.22 (s, 3H)

₁₅ 2.20 (s, 3H)

1.59-1.50 (m, 2H)

1.42-1.29 (m, 4H). ,

Example 63

0 S-Qi <a (R *), 2 <a, 4a <b, 8 <b, 8a <a]] -4- [[2- [β- (2,2-dimethyl-1-oxobutoxy) - decahydro-2-methyl-1 -naphthalenyl]] -ethyl-hydroxyphosphinyi-3-hydroxybutyric acid dilithium salt A. TlS- (Ka, 2 <a, 4a <b, 8 <b, 8a <a)] - 8 - [[( 1, 1-dimethylethyl-dimethylsilyl-O-oxy-J-1,2,3,15,6,7,8,8a-octahydro-2-methyl-1-naphthalenemethanol

5 ml of anhydrous Et-O are added at 0 ^° C. in an ice bath with 132 mg (1 molar Aq.) Of lithium aluminum hydride and then dropwise with 1.175 g (3.47 mmol) of [1S- (Ka, 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-naphthalenecarboxylic acid methyl ester (RL Funk et al., Tetrahedron Lett., Vol. 25 (1984), p. 1655) in 5 ml of anhydrous Et 2 O. The resulting gray suspension is stirred for about 15 hours under argon at room temperature.

'0th ^: K

2 8 U O 5

-281-

temperature stirred. The reaction is then carried out by successive dropwise addition of 130 μΐ H_O, 130 μΐ 15/6 NciOH and 390 μΐ H _? ü canceled. The precipitated salts are replaced by anhydrous MgSO 4. filtered through diatomaceous earth. Evaporation under reduced pressure gives 1.112 g of clear oil, which is purified by flash chromatography on silica gel and elution with hexane-EtOAc = 95: 5. Yield: 902 mg (35.7%) desired alcohol title compound as a clear oil which crystallized on standing, mp 79 to 81 ⁰ C.

TLC (9: 1) hexane-EtOAc, R _f = 0.21

15

20

₂₅

analysis For 00 ^c ia ι 34?. ^1# About: 6H) C 1 H , 82 gef. : 9H) 69.61 1 1, 04 , 05 on ) 2H) 69.64 1, 04 ¹ H NMR (CDCJ. , 18 3> IH) δ 0 , 42 (S, 2H) O , 67 (S, 3H) 0.94 to 1 , 89 (M, IH) " 1 , 37 (S, 2 multiplets) 1.2-1 > 42 (M, IH) 1 80 (M, IH) 1 , 93 (M, IH) 2.25 2 , 29 (2H, IH) 3 48 (Bt, IH) ppm. " 3 (Dd, 3 (Bs, 5 (D, 5 (Dq,

B. [iS- (1 <a, 2 <a, 4a <b, 8 <b, 8a <a)] - 8-Q [(1,1-dimethylethyl) dimethylsilyljoxy] -1, 2, 4a 5,6,7,8,8a-octahydro-2-methyl-1-naphthalincarboxaldehyd

281 * 0

-282-

A solution of 895 mg (2.11 mmol) of Dess-Martin-Perjodinan in 6 ml of anhydrous CH-Cl., Is treated with 200 μΐ anhydrous tert. -HgOH and the white suspension stirred under argon for 15 minutes at room temperature. A solution of 596 mg (1.92 mmol) of the alcohol in 6 mL of anhydrous CH ₃ Cl ₂ is added dropwise over 5 minutes and the mixture stirred under Argo.i at room temperature for 20 minutes. The mixture is then added to a solution of 2.12 g of sodium thiosulfate in 12 ml of 1.0N NaHCO 3, and the resulting mixture is stirred until all solids are dissolved. The organic phase is washed with saturated NaHCO ₃ solution, H ₂ O and brine and then dried over anhydrous Na ₇ SO ₄ and evaporated under reduced pressure to give 1.005 g of colorless oil.

The crude product is combined with a smaller batch (total 1.306 g) and then by flash chromatography on silica gel and elution with. Hexane-EtCAc (98: 2). The product fractions are evaporated under reduced pressure. Yield: 66.7 mg (75.7 %) of desired aldehyde-titanium.

20 telverbindung as a colorless oil.

TLC (7: 3) hexane-Et ₂ O, R _f = 0.70, PMA

¹ H NMR (CDCl ₃ ):

δ 0.07 (p. 3H)

₂₅ 0.00 (s, 3H) · ·

0.85 (s, 9H)

0.89 (d, 3H)

0.93-1.10 (m, 2H)

1.38-1.52 (ro, 2H)

₃₀ 1.58-1.78 (ro, 4H)

2.31 (m, IH)

2.66 (m, IH)

2.78 (m, IH)

4.30 (s, IH)

_g5 5.40 (d, IH)

5.50 (m, IH)

9.74 (d, IH)

-283-

C. [1S- (Ka, 2 <a, 4a <b, 8 <b, 8a <af] -1- (2,2-dibroniethyl) -8 - [[(1,1-dimethylethyl) -dimethylsilyl] - oxy] -1,2,4a, 5,6,7,8,8a-octahydro-2-methylnaphthalene

° A in a salt / ice bath to -15 ⁰ C cooled solution of 667 mg (2.16 mmol) of aldehyde from Part B and 1.7 g (6.48 mmol) of triphenylphosphine in 10 ml of anhydrous CH ₇ Cl ₇ is added dropwise treated with 5 ml of a solution of 1.7 g (6.48 mmol) of carbon tetrabromide in CH ₃ Cl ₂ within 5 minutes.

and the deep reddish-brown mixture under argon for 30 minutes at -15 ⁰ C, 2 hours at 0 ⁰ C and finally for about "hours at room temperature.The mixture is cooled again to ^{0 0} C, with another 567 mg (216 mmol ) Triphenylphosphine and then 358 mg (1.08 mmol) CBr, treated and

¹ ^ 4 hours »! stirred at room temperature. Then, the reaction is stopped by adding 10 ml of saturated NaHCO.-solution, the mixture is diluted with CH ₇ Cl, the organic phase is filtered through sintered glass, washed with saturated NaHCO 3 solution and brine, dried over anhydrous Na ₇ SO ₄ and evaporated under reduced pressure to give 3.578 g of brown solid. The crude product is purified by flash chromatography on silica gel and elution with pure hexanes. The product fractions are evaporated. Yield: 677 mg (67.3 / 6) of pure vinyl dibromide title compound as a colorless oil

TLC (9:11 hexane-acetone, R _f = 0.73 UV + PMA)

¹ H NMR (CDCl ₃ )

_g0 δ 0.08 & 0.10 (2 singlets, 6H)

0.85 (d, 3H)

0.90 (s, 9H)

0.98 (m, 2H)

1.25-2.52 (m, 5H)

₃₅ 1.74 (m, IH)

1.82 (m, IH)

2 8 U O

-284-

2.39 (m, IH)

2.56 (m, IH)

2.66 (m, IH)

3.95 (s, IH)

5.48 (d, IH)

5.52 (ra, IH)

6j37 (d, IH) ppm

¹ ^ D. QiS- (Ka, 2 <a, 4a <b, 8 <b, 8a <af] -8- [£ (1,1-dimethylethyl) -dimethylsilyl] oxy] -1-ethynyl-1, 2,43,5,6,7,8,8a-octahydr o-2-me-thymine .naphthalene

A cooled in dry ice / Aceto'.i bath to -78 ° C solution of ¹ ^ 495 mg (1.07 mmol) of Part C Vinyldibromid in 6 ml of anhydrous THF (dropwise over 5 minutes with 1.34 ml of 2 , 14 mmol) 1.6M solution of n-BuLi in hexanes and since »clear, colorless mixture stirred for 30 minutes under argon at -78 ° C. The reaction is stopped at -78 ° C by addition of 5 ml of saturated NH.Cl solution, the mixture warmed to room temperature, diluted with EtOAc, the organic phase washed with brine, dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure , Yield: 291 mg (89.6 %) of crude acetylene title compound as a colorless oil

TLC hexane R _f = 0.43, UV + PMA ¹ H NMR (CDCl ₃ )

0.08 & 0.12 (2 singlets, 6H)

0.90 (s, 9H)

³⁰ 0.99 (m, IH)

1.09 (d, 3H) 1.19 (m, IH) 1.46 x (ra, 2H) 1.74 (m, 3H) 35 2.12 (d, IH)

28 1 60 S:

-235-

¹ 2.30 (m, IH)

, 2.41 (m _; IH)

2.71 (m, IH)

4.37 (m, IH)

⁶ 5.38 (d, IH)

5.55 (m, IH) ppm.

E. (S) -4- (Chloromethoxyphosphinyl) -3- [£ (1,1-dimethylethyl) diphenylsilyl-O-oxy] -butyric acid methyl ester

From the dicyclohexylamine salt of Example 25, Part B, a phosphonochloridate is prepared by the following procedure. The free acid is prepared by partitioning 1.3 g (2.05 mmol) dicyclohexylamine salt between EtOAc and 5 % KHSO. The organic layer is washed 4 times with 5 % KHSO.-solution and brine and then over anhydrous Na 2 SO 4. dried and evaporated under reduced pressure, the free acid being obtained as a clear, viscous oil.

20 will hold.

2.05 mmol of monomethyl phosphonate are taken up in 5 ml of anhydrous CH ₂ Cl, treated with 515 μΐ (4.1 mmol) of distilled Ν, Ν-Diäthyltrimethylsilylamin and stirred the clear, colorless solution at room temperature for 1 hour under argon. Excess reaction participants and solvents are distilled off under reduced pressure and the resulting oil expelled with 2 times 10 ml of benzene.

The crude silyl ester (about 2.05 mmol) is dissolved in 5 ml of anhydrous CH-Cl- and 1 drop of anhydrous DMF cooled in an ice bath to 0 ⁰ C and treated dropwise with distilled μΐ 195 (2.26 mmol) and the yellow mixture Oxaly hlorid stirred under argon at 0 ^° C. for 15 minutes and at room temperature for 45 minutes. The mixture is evaporated under reduced pressure and the residue with 2 times 10 ml of anhydrous

2 8 I

-286-

Benzene driven off, the crude phosphonochloridate title compound is obtained as a viscous yellow oil.

F. QS [i <a (R *), 2 <a _l 4a <b _/ 8 <b, 8a <a] 3-4 - [[[8- [Qi, 1-dimethylethyl) dimethylsilyl] -oxyj -1,2, ta, 5,6,7,8,8a-octahydro-2-methyl-1-naphthalenyl] -äthinyl] -methoxyphosphinyl J-3- [ε (1, 1-dimethyl) -diphenylsilyl] -oxy- butyric acid methylester

A cooled to -78 ° C solution of 356 mg (1.17 mmol) of acetylene from Part D in 5 ml of anhydrous THF is treated dropwise with 730 μΐ (1.17 mmol) 1.6M solution of n-BuLi in hexanes and the The resulting clear mixture was stirred under argon at -78 ° C for 30 minutes. The acetylenic anion

5 is added dropwise via cannula within 15 minutes to a solution of the phosphonochloridate of Part E in 6 ml of anhydrous THF cooled to -78 ° C. The yellow mixture is stirred for 30 minutes at -78 ° C, then the reaction is stopped by dropwise addition of 5 ml of saturated NH.Cl solution and the mixture warmed to room temperature. The mixture is partitioned between EtOAc and H 2 O, the organic phase washed with brine, dried over anhydrous Na ₃ SO ₄ and evaporated under reduced pressure to give 1.282 g of a pale yellow oil. The crude product is purified by flash chromatography on silica gel and elution with hexane-EtOAc (7: 3). The product fractions were evaporated. Yield: 624 mg (72.4 %) of the ecetylenic phosphinate title compound as a colorless glass.

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

G. (J S- [i <a (R *), 2 <a, 4a <b, 8 <b, 8a <a] 3-4- [[2- [8- [[(1,1-dimethylethyl ) -dimethylsilyl] oxy] -decahydro-2-methyl-1-naphthalenyl J-ethyl] -methoxyphosphinyl] -3- [X (1,1-di-methyl)

g - methylathyl (1) -diphenylsilyl-3-oxy) -butyric acid methyl ester

-287-

A solution of 498 mg of acetylenic phosphinate of Part F in 6 ml of CH ₃ OH is treated with 200 mg of 10 % Pt / C and the black suspension is shaken on a Parr apparatus for 48 hours under a hydrogen pressure of approximately 2.8 bar. The catalyst is then filtered off through silica gel, the reaction mixture is charged with 150 mg of new catalyst and shaken on the Parr apparatus for a further 24 hours under a hydrogen pressure of about 2.8 bar. Then the catalyst is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to give 448 mg of clear glass. The crude product is purified by flash chromatography on silica gel and elution with hexane-EtOAc (8: 2). The product fractions are evaporated under reduced pressure. Yield: 334 mg (66.5 %) of the title compound

15 as a colorless glass.

TLC (7: 3) EtOAc-hexane, R _f : 3 diastereomers as one spot

= 0.42; R _f 4. Diasterepmer as a Flech = 0.49, UV +

PMA.

H. [IS- [Ka (R *), 2 <a, 4a <b, 8 <b, 8a <a]] -4- [[2- (decahydro-8-hydroxy-2-methyl-1-naphthalenyl ethyl ethylmethoxyphosphinyl] -3- [ 1,1-dimethylethyldiphenylsilyl] oxy] butyrate

A solution of 248 mg (0.334 mmol) compound of Part G in 4 mL of CH ₃ CN is treated with 36 μΐ (1 mmol, 48 % HF in H ₃ O and the mixture is stirred at room temperature for 6.5 hours under argon partition between EtOAc and saturated NaHCO 3 solution, wash the organic phase with brine, dry over anhydrous Na 2 SO 4, and evaporate under reduced pressure to give 227 mg of colorless glass The crude product is purified by flash chromatography on silica gel and elution in hexane-EtOAc (4: 1) followed by pure EtOAc, The product fractions are evaporated under reduced pressure Yield: 159 mg (75.8 %) pure monoalcohol title compound as a colorless oil.

28 1 60s

 288-

TLC (7: 3) acetone-hexane, R _f = 0.5 (UV (weak) + PMA.

I. [1S- [Ka (R *), 2 <a, 4a <b, 8 <b, 8a <a]] - 3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy-4-yl [ Methyl 2- [8- (2,2-dimethyl-1-oxobutoxy) -decahydro-2-methyl-1-naphthalenyl-ethyl-methoxyphosphinyl-butyric acid

A solution of 147 mg (0.234 mmol) of H portion alcohol in 1.5 mL of anhydrous pyridine is charged with 160 μΐ (1.17 mmol, 5 eq.) Of 2,2-dimethylbutyryl chloride and then with 3 mg (0.1 eq. ) 4-dimethylaminopyridine and the pale yellow mixture is heated under argon at 100 ⁰ C for 4 hours. Then the mixture is cooled, partitioned between 1.0N HCl and EtOAc, the organic phase washed twice with 1N HCl and brine in anhydrous NaSO 4. dried and evaporated to give 255 mg pale yellow-brown oil. The crude product is purified by flash chromatography on silica gel and elution with hexane-EtOAc (55:45). The product fractions are evaporated under reduced pressure. Yield: 112 mg (65.9 %) of the desired dimethyl butyryl ester title compound as a colorless oil. TLC: hexane-acetone, R _f = 0.62, UV + PMA.

J. [1S- [Ka (R *), 2 <a, 4a <b, 8 <b, 8a <a]] - 4 - [[2- [8- (2,2-dimethyl-1-oxobutoxy) decahydro-2-methyl-1-naphthalenylj-ethyl-3-methoxyphosphinyl-3-hydroxy-butyric acid methyl ester

A solution of 130 mg (0.179 mmol) of silyl ester of Part I in 2 ml of THF is successively with 41 μΐ (ι, 716 mmol) of glacial acetic acid (HOAc) and 490 μΐ (0.537 mmol) 1.1M solution of In-C ₄ Hg) ₄ NF in THF and the mixture stirred for about 15 hours under argon. Then the mixture is partitioned between EtOAc and 5 % KHSO ₄ solution, the organic phase washed with H 2 O and brine, dried over anhydrous NaSO ₄ and evaporated under reduced pressure,

-289-

^ to obtain 115 mg of colorless oil. The crude product is purified by flash chromatography on silica gel and elution with hexane-acetone (1: 1). The product fractions are evaporated under reduced pressure. Yield: 72 mg (82.4 %) of the desired alcohol title compound as a colorless oil

TLC (1: 1) hexane-acetone, R _f = 0.20, UV + PMA.

K. Qs [Ka (R *), 2 <a, 4a <b, 8 <b, 8a <a]] - 4 - [[2- (j 3 - (2,2-di-methyl-1-oxobutoxy) -decahydro-2-methyl-1-naphthalenyl [] - ethyl], - hydroxy phosphinyl] -3-hydroxy-butt he acid dilithium salt

A solution of 72 mg (0.147 mmol) of Part J alcohol in 100 ml of dioxane is treated with 0.52 ml of 1.0N LiOH and the mixture heated under argon at 55 ⁰ C for 1.5 hours in oil bath. The mixture is then cooled, diluted with H 2 O, filtered, and evaporated under reduced pressure to an oil. The crude product is chromatographed on resin HP-20 (3 cm bed, 15 mm column 2Q diameter) and treated with H 2 O and then H_O-CH-. OH (70:30) eluted. The product fractions are evaporated under reduced pressure, the residue dissolved in 20 ml H_O and lyophilized. Yield: 55 mg (74 %) of the desired dilithium salt title compound as a white solid.

TLC (8: 1: 1) CH ₂ Cl ₂ -CH ₂ OH-Ch ₃ COOH ₁ R _f = 0.05, PMA.

Analysis for C ₂₃ H ₃₉ O ₇ PLi ₂ + !, 78 mol H ₃ O

Mol Wt. 504.53): CHP

₃₀ at: 54.75 8,50 6,14

F .: 54.75 8.64 5.93

Example 64

(S) -4 - [[[3 '- (4-Fluorophenyl) spiro [cyclopentane-1, 1' - [1 w] in the D-2-ylJ-diethynyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt

^ 2 8 UO

-290- ¹ A. 3- (4-fluorophenyl) -1H-indene

A solution of 4-fluorophenyl magnesium bromide prepared from 6.43 ml of 4-fluorobromobenzene and 1.71 g of Mg in 50 ml of diethyl ether is added dropwise at room temperature under argon within 40 minutes with a solution of 6.61 g (50 mmol ) 1-indanone in 20 ml of anhydrous diethyl ether. After stirring for 1 hour at room temperature, the reaction is stopped by dropwise addition of 15 ml of saturated NH.Cl solution. The mixture is diluted with Et-O, washed with brine, over MgSO 4. • - dried and evaporated. The residue is taken up in 15 ml of glacial acetic acid and heated under argon for 30 minutes under reflux. The acetic acid is distilled off and expelled twice with toluene. The residue (9.45 g) is purified by flash chromatography on silica gel and elution with hexane. Yield: 8.174 g (78%) of title compound as a colorless oil, which crystallized on standing, mp 38 to 40 ⁰ C.

20 TLC (hexane): R _f = 0.21.

B. 3 '- (4-fluorophenyl) spiro [cyclopentane-1, 1' - [Ί h] indene]

A solution of 10.676 g (50.8 mmol) of compound of Part A in 90 ml of anhydrous THF is added dropwise at 0 ⁰ C under argon with 12.2 g (109 mmol) of solid potassium tert-butoxyid. After 30 minutes of stirring at 0 ⁰ C 6.50 ml (101 mmol) of 1,4-dibromobutane are added dropwise. The resulting mixture is warmed to room temperature, stirred for 2 hours and then partitioned between 150 ml each of EtOAc and 5 % KHSO ₄ solution. The organic phase is washed with saturated brine, dried over Na_SO4 and evaporated to dryness. The crude product is purified by flash chromatography on silica gel and elution with hexane. Yield: 9.43 g (70 %) of the title compound as a dyed

2 8 ί 6

-291-

1 loose oil.

TLC (Et ₂ O-hexane, 1: 9): R _f - 0.69 (R _f of compound of part A s 0.6?).

c. 3'-M-fluorophenyl-spiro-j-cyclopentane-i, 1'-1 H] -inden] -2'-carboxaldehyde

A solution of 9.30 g (35.2 mmol) of Part B compound in 50 mL of anhydrous CH ₂ Cl ₂ at 0 ⁰ C under argon with 70 ml (70 mmol) of 1.0 M solution of TiCl ₄ in CH ₂ Cl ₂ offset. The resulting dark green solution is treated dropwise with 3.50 ml (38.7 mmol) of 1,1-dichloromethyl methyl ether. After 1 hour of stirring at 0 ⁰ C and 1 hour at room temperature, the mixture is poured into cold saturated NaHCO_ solution. The organic phase is separated, over Na ₂ SO. dried and evaporated to dryness. The crude product is purified by flash chromatography on silica gel and elution with Et ₂ O-hexane (5:95). Yield: 8.233 g (80 %) of the title compound as a yellow oil. Crystallization of the oil from hexane gives 6.778 g (66 %) of pure title compound as pale yellow crystals, mp 116-117 ° C, TLC (Et ₂ O-hexane; 15:85) R _f = 0.56.

Analysis for C ₂₀ H ₁₇ OF: CH F-

25: 82.17 5.86 6.50

F .: 83.13 5.82 6.29

D. 2'-Ethinyl-3 '- (4-fluorophenyl) spiro-cyclopentane-1,1' - [iHj-indene]

A solution of 0.672 g (6.00 mmol) of potassium tert-butoxide in 8 ml of anhydrous THF is added dropwise at -78 ° C under argon with a solution of 0.960 g (6.40 mmol) of dimethyl diazomethylphosphonate prepared according to J. Org Chem., Vol.

36 (1971), p. 1379, in 4 ml of THF. After 5 minutes of stirring at -78 ° C, the mixture is dropwise within

2 8 UO

-292-

of 10 minutes with a solution of 1.168 g (4.00 mmol) of compound of Part C in 8 ml of THF. After 3 hours stirring at -78 ⁰ C, 1.5 hours at -45 ⁰ C and 1 hour at room temperature the mixture is diluted with 50 ml of hexane and washed with 5% KHSO. solution. The organic phase is washed with brine, over Na 2 SO 4. dried and concentrated to a small volume (not to dryness). The yellow solution is flash chromatographed on silica gel and eluted with hexane. The product-containing fractions are combined, treated with 0.080 g (0.36 mmol) of butylated hydroxytoluene (BHT) and concentrated to a small volume (5 to 10 ml), since it is used immediately as solution for the next step. TLC (Et ₂ O-hexane, 1: 9): R _f = 0.57.

15 ¹ H NMR (270 MHx, CDCl ₃ ) with BHT as internal standard

(1.45 ppm, 18H, s) shows the presence of 3.10 mmol (77.5 %) of the desired acetylenes (3.32 'ppm, 1H, s).

E. (S) -4- (Chloromethoxyphosphinyl) -3- [Q (1,1-dimethylethyl) diphenylsilyl] oxy] -butyric acid methyl ester

The phosphonochloridate title compound is prepared from 3.44 g (54.4 mmol) dicyclohexylamine salt of Example 25, part B, as described in Example 29, part J, using the following amounts: 1.36 ml (10.85 mmol) • trimethylsilyid diethylamine, 15 ml CH ₂ Cl ₂ , 0.50 ml (5.73 (I.Mol) oxalyl chloride, 1 drop DMF and 15 ml CH ₂ Cl ₂ -

F. (S) -3- [Q (1,1-dimethylethyl) diphenylsilyl] oxy] -4- [CL ³ '- (4-fluorophenyl-spiro-cyclopentanean-1, 1' - [j H] indeno] -2-yl] -äthinyl] -methoxyphosphinyl] -butyric acid, methyl ester

A solution of 3.10 mmol acetylene from Part D and 0.36 mmol BHT in hexane is diluted with 15 mL anhydrous THF and cooled to -78 ° C under argon. The solution then becomes

-293-

1 drop by syringe with 2.16 ml (3.46 mmol)

1.6m solution of n-BuLi in hexane. After 45 minutes of stirring at -? '8 ° C, the resulting anion rLösung is transferred through one cannula to a cooled to -78 ⁰ C solution of 54.4 mmol Phosphonochloridat from Part E in 15 ml of anhydrous THP. After 1 hour of stirring at -78 ⁰ C, the reaction is stopped by dropwise addition of 15 ml of saturated NH.Cl solution and the mixture warmed to room temperature. The mixture is extracted with EtOAc, the extracts washed with 5% KHSO. solution, saturated NaHCO ₃ ~ solution and saturated brine gawaschen, Ge over Na ₃ SO _4: dried and evaporated to dryness. The crude product is purified by flash chromatography on silica gel eluting with EtOAc-hexane (25:75). Yield: 1.731 g (80%, based on compound of Part D) of the title compound as a pale yellow glass

TLC (acetone-hexane, 1: 1) R _f = 0.46.

G. (S) -4 - [[[3 '- (4-Fluorophenyl-spiro-1-cyclopentane-1, 1' - [1H-1-yl] -2-ylQ-ethinyl-methoxyphosphinyl] -3-hydroxybutyric acid methyl ester

A solution of 1.00 g (1.39 mmol) of Part F compound in 5 mL of anhydrous THF is added at room temperature under argon with 0.32 mL (5.59 mmol) glacial acetic acid and 3.80 mL (4.18 mmol). 1.1M solution of (nC.Hg) ₄ NF in THF. After 18 hours of stirring at room temperature the mixture is diluted with 50 ml EtOAc and washed successively with 3mnl 30 ml 1N HCl and saturated saline solution, but Na-SO ₄ dried and evaporated to dryness. The residue is taken up in 20 ml tft_O, cooled in an ice bath and treated with excess diazomethane in ether. The residue obtained by distilling off the ether is purified by flash chromatography on silica gel and elution with acetone-hexane (3: 7). Yield: 0 595 g (89 %) of title compound as a colorless glass.

-294- ¹ TLC (acetone-hexane; 1: 1) R _f = 0.29.

H. (S) -4 - [[[3 '- (4-fluorophenyl) spiro [cyclopentane-1, 1' -]

QiHj-inden-J-2-yl] -äthinyl J-hydroxyphosphinyl J-3-5-hydroxybutyric acid dilithium salt

To a solution of 0.580 g (1.20 mmol) of Part G compound in 6 ml of dioxane is added 4.2 ml (4.2 mmol) of 1N LiOH solution at room temperature under argon. After stirring for 3 hours at room temperature, the mixture is diluted with 20 ml of acetonitrile, the white precipitate filtered off, washed with acetonitrile and dried under reduced pressure to give 0.670 g of crude title compound as a white solid. The crude product is suspended in 10 ml of water and applied to a short bed of HP-20 (15 ml bed volume, 2.54 cm diameter) and eluted with 300 ml of water and then 300 ml of MeOH. The product-containing fractions are combined and evaporated to dryness. The solid residue is digested with acetonitrile. Yield: 0.550 g (98 %) of pure title compound as a white solid of mp 301 to 303 ⁰ C (dec.). TLC (iC ₃ H ₇ OH conc. NH ₄ OH-H ₂ O; 7: 2: 1) R _f = 0.48.

25 examples 65 to 122

According to the methods illustrated in the preceding examples, the following additional compounds can be obtained.

30 Cj .H

X OH Z.

35

f ^ * ^ iV ". * Y ^J 1 \" ^ * ίΐίί '^ ί IVR "i V''ijt ^" t ~ Ί' i *, j * ^^ * ·.

-295-

Ex. No. _R

.65. OCH.

Cl

Cl

66. OK

-C = C- H

67. OLi

^CH 3W ^CH 3

[οϊο

CH,

68. CH

-CH ₂ O- H

-296-

2 8 UO 5

Ex. · "No.

69. · OLi

CH ₃ CH ₃ Li

70th OCH,

CH-CH, NCH ₃

71. OK

CH.-CH 2 5 ι

C = OI 0'-CH ₂ -

OK

CH,

72. ONa

-CH ₂ -

N / A

-297-

Ex

 No.

• Z

73. OH

HO.

74. OH ^C 2 ^H ""

.CH ₃ CH ₃ "

HO

C ₂ H ₅

75. CH ₃ OCH ₃

76. OH

-CH ₃ O- H

77. OH

CH ₃ CH ₂ H

28 1 * 05

-298-

Ex

 No.

78. OH

H ₃ C CH ₃ -CH = CH- H

79. OH

80. NaO

-CH = CH-

81. θ "

CH.-C = C-

-299-

28 1 6 0s.

Ex

 No.

82. HO

-CEC-

83. NaO

CH ₃ CH ₃ -c = c-

84. CH ₃ O

CH,

-CH = CH- H

85. CH O

NH ₄

-300-

86. CO

-CH ₂ -

89. K

-CH ₂ -

2 8 UO 5

Example no.

87. O

Ca

88. CH ₃ O

-CH = CH- Na

-301-

1605

Ex

 No.

90. CH ₃ O

C-CH, H

-CH = CH- H

91. HO

-CH = CH- H

92. CH ₃ O

. »/ C-CH, M-S H 3

CH.

CH.

93. LiO

Cl ^Li

-302-

28 i 60 p

Ex

 No.

94. CO

95. HO

CH,

S "

-CH = CH- H

96. HO

-CsC- H

97. HO

-cac- ^H

Ex

 No.

-303-

28 160

98. LiO

CH.

CH

CH ₃ N

-C = C-Li

99. LiO

-CH, - Li

CH

CH ₃ CH ₃

100. HO

-CH "- H

101. HO

Cl

.cl

CH

/ CH

CH ₃

-304-

281 60s

Ex

 No.

102. NaO

103rd

N / A

CH "

104. HO

-CH ₂ -

105. CH O

CH ₃ O ₃ CCH ₃

Γ,

i.

-305-

8 16 0

Ex

 No.

106. HO

CH-CH ₁ / CH,

107. HO

108. CO

Cl Cl

CH - CH.

CH.

Cl Cl

CH-

109. HO

br

bf

N-

CH

-306-

Ex

 No.

UO. LiO

-CH = CH-Li

C = C

111. CO

C = C

XC ₃ H ₇

112. LiC

CH.

C ₂ H ₅

CH.

-CH = CH-- Li

113. CH ₃ O

CH ₃ O

CH.

C = C

CH.

-CK-CH-CH.

Ex

 No. '

-307-

8 16 0

114. OH

115. LiO

CH,

CH-C = C-

116. LiO

CH

> CH CH

117. LiO

CH,

Ol, _CH -3-C = C-

Li

118. LiO

CH.

CH.

Li

120. LiO

, CH,

CH

Ex. ¹ No. R F> -308- X R ^X · Li 119th LiO -C = C- Z • * ®

Li

121. LiO

Li

122. LiO

CH

CH ₃ -CEC

"CH.

CH ₃ O

Li

Claims (6)

10 patent claims 1 . Process for the preparation of compounds of general formula I. OH
¹⁵ RP-CH ₉ -C-CH - CO _or R ^X (i) X OH
I
Z in aer. e _:; X represents a group -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CHeCH-, -C = C- or -CH ₂ O- (where 0 is bound to the rest Z) means Z represents a hydrophobic anchor, and R is a hydrogen atom or a lower alkyl radical, in the form of the free acid or in the form of a physiologically hydrolyzable and compatible ester or salt, characterized in that (A) when X denotes the group -CH = CH-, an acetylenic phosphinate of the formula ³⁰ . 0 Il.,. alkoxy-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl ChC 0 Z SiC (CH ₃ ) ₃ C ^ H ₅ C ₆ H ₅
35 a silyl ether cleavage to produce a diester 2 8 16 0 340  1 of the formula O is alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl, C = C Z subjects and, if desired, the diester to the monoester of the formula Il alky10-P-CH ₂ -CH-CH, -CO ₂ H, II "" ^iU C = C OH the basic salt of the formula Il y a _1C - alkyl O - P - CH - CH - CH _o C0 "R C = COH the dibasic salt of formula 0 R ^Xa O-P-CH9-CH-CHo-CO ₂ R ^Xa I "Z-CsC OH or in the diacid of the formula 0 Il HO-P-CHo-CH-CHo-CO ₂ H ^2S ei 'On' converting; (B) when X is the group -CH = CH- (cis), an acetylenic phosphinate of the formula. 0 is alkylO-P-CHO-CH-CH ₂ -CO ₂ alkyl C = CIZ SiC (CH ₃ ) 3 c '^ > P 511 to the silyl ether of the formula O is alkylO-P-CH ₂ -CH-CH ₂ CO ₂ alkyl, CH j S \ ^Z ~ ^CE (cis) SiC (CHs) ₃ C ₆ H ₅ C ₆ H ₅ reduced, the silyl ether of a silyl ether cleavage to prepare the diester of the formula 0 Il alky 10-P-CH ₂ -CH-CH-, -COO-alkyl, I i (ice) CH OH Il CH I Z and, if desired, the diester in the mono- ester of the formula 0 Il alky10-P-CH ₂ -CH-CH ₂ -CO ₂ H, , CH OH Z-CH (ice) the basic salt of the formula Il xa · alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ R, CH OH Il
(ice) CH on the acid of the formula Il
HO-P-CH ₂ -CH-CHo-COo H I CH OH,. Il
(ice) CH έ 28i60S 311 or the dibasic salt of the formula R OP-CHo-CH-CHo-COo R ^Xd ; I "I" κ CH OK ° 'Il {ice cream) CH IZ converting; (C) when X is the group -CH "-CH ₂ -, the silyl ether of the formula alkylO-P-CH, -CH-CHO COO alkyl "I - - - , CH I Z-CH {ice) SiC (CH ₃ J ₃ CeiiT ^X C ₆ H ₅ to the silyl ether of the formula O
Il
alkylO-P-CHo-CH-CH ₂ CO ₂ alkyl CH ₂ ' I CHo SlC (CH ₃ ) 3 Z V \ ^ 6 ^ 5 C ₀ H ₅ and the silyl ether of a silyl ether cleavage 25 to produce a diester of the formula alkylO-P-CHO-CH-CH ₂ -CO ₂ -alkyl, "I CH ₂ OH I
CH ₂ l, and, if desired, subjecting the diester to the basic salt of the formula alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ R ^Xa , CH ₂ OH CHo I "Z 28 ί 60 5 3 the acid of the formula II alky10-P-CH ₂ -CH-CH ₂ -CO ₂ H, CH ₂ OH CH ₂ Z is the dibasic salt of the formula 'R ^{Xa is} OP-CH ₂ -CH-CH, -CO ₂ R ^Xa II CH ₂ OH CH, I "Z or the diacid of formula 15 HO-P-CHo-CH-CH ₂ -COOH "I CHo OH CH ^Z converting; (D) when X is the group -CH = CH-- (trans), a silyl ether of the formula , ι alkylO-P-CHO. -CH-CH ₂ -CO ₂ alkyl (trans) .CH OSi-C (CH _{3) 3} CH C15H5 CgH5 ^{30 of} a silyl ether cleavage to produce the hydroxy diester of the formula alky10-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl, (trans) CH OH CH I
Z and, if desired, subjecting the hydroxy diester to the basic salt of the formula Il alky10-P-CH ₂ -CH-CH ₂ CO ₂ R (trans) CH OH CH the acid of the formula ίο. O alkylO-P-CH, -CH-CH ₂ -CO ₂ HI "I CH CH CH 25 the basic salt of the formula γ- "Il" a R ^{A <} * O-P "CHo-CH-CH ₂ -CO ₂ R, I "I (trans) CH 0: CH 20 Z or the corresponding diacid of the formula Il HO-P-CH ₂ -CH-CH ₂ -CO ₂ H 25 (trans) CH OH HC (E) when X is the group of the formula -CH = CH- (trans), a phosphonochloridate of the formula 0 alkylO-P-Cl CH (trans) I 35 Z 2 8 ί 60 5 with an alkyl acetoacetate dianion to a ketophosphonate of the formula OO alky10-P-CH ₂ -C-CH ₂ -CO ₂ alkyl, (trans) CH CH condenses, the ketophosphonate to Diesterphosphinat 10 of the formula 0 | l alky10-P-CH ₂ -CH-CH ₂ -CO ₂ alkyl, {trans) CH OH CH I 15 ^z reduced, and if desired, the diester in the dibasic salt of the formula I! _xa alky10-P-CH ₂ -CH-CH ₂ CO ₂ R, 20 {trans) CH OH CH the acid of the formula 25 alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ H, ( trans ) CH OH CH 30 the basic salt of the formula R 0-P-CH, -CH-CH ₂ -COO RI "l CH OH Z-CH {tr.ms) 35 28 or the diacid of the formula 0 HO-P-CH ₂ -CH-CH ₂ -CO ₂ H; CH OH Z-CH (trans) converting; (F) when X represents one of the groups -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH,
a phosphonochloridate of the formula 0 0 alkylO-P-Cl (CH ₂ ) _a where a is 1, 2 or 3 with an alkyl acetoacetate dianion to the ketophosphonate of the formula O ¹ -Il alkylO-P-CH ₂ -C-CH ₂ -CO ₂ alkyl, (CH ₂ ) _a i) Z 20 condenses, the ketophosphonate to the diester of the formula 0 is alkylO-P-CHO-CH-CH ₂ -CO ₂ alkyl, (CH ₂ ) OH I "a Z reduced, and if desired, the diester in the basic salt of the formula 0 Il _xa alky10-P-CH ₂ -CH-CH ₂ CO ₂ R ^d (CHO) OH I " ^a Z the acid of formula 35 i? i
alkylO-P-CH ₂ -CH-CH ₂ -CO ₂ H, (CH ₂ ) _a OH 2 8 ί the dibasic salt of the formula R ^{Xa is} OP-CH ₂ -CH-CH ₂ -CO ₂ R ^Xa (CH ₂ ) _a OH Z or the diacid of the formula HO-P-CH ₂ -CH-CH ₂ -CO ₂ H (CH ₂ ) _a OH 2 converting; and (G) when X is the group - (CH ^ O) -, a phosphonochloridate of the formula 0 II alkylO-P-Cl CH ₂ ZO with an alkyl acetoacetate dianion to the ketophosphonate of the formula 0 Il Il ^ ₁₁ alkylO-P-CH ₂ -C-CH ₂ -CO ₂ alkyl 0 25 I condensed, the ketophosphonate to the diester phosphinate of the formula a ^ kylO-P-CH ₂ -CH-CHo-CO ₂ alkyl ι ι CHo OH 30? reduced, and if desired, the diester in the basic salt of the formula 2 8 ί 60 5 3 48 I! alkyiO-P-CH-, -CH-CHo COo R I "I" " CH ₂ OH the acid of the formula O-alky10-P-CH ₂ -CH-CH ₂ -CO ₂ H, CHο CH ₂ Oh O I Z the dibasic salt of the formula O] 5 R ^Xa OP-CH ₂ -CH-CH ₂ -CO ₂ R ^Xa CH ₂ OH I O I Z or the diacid of the formula J HO-P-CH ₂ -CH-CH ₂ -CO ₂ HZO-CH ₂ OH transforms. 2. The method according to claim 1, characterized
that the hydrophobic anchor represents a lipophilic radical,
which, when bound to the HMG-like upper side chain of the molecule via a suitable inguinal member, is involved 30 connects a hydrophobic site of the enzyme, which is not used for binding the substrate HMG CoA. 319 3. The method according to claim 1, characterized in that Z represents a hydrophobic Ankar, namely one of the rest of the formulas: .2a ^ N ΓΙΟ _τ .8 .-R R ^a R ^b 15 I i 16 R ¹ C = C 2 6 I 6 O S or · 310 , 6 alkyl * 1 0 9 a 9V * in which R ₁ R ₁ R and R are identical or different and independently of one another are hydrogen or halogenatonia, lower alkyl, haloalkyl, phenyl or substituted phenyl radicals or radicals of the formula OR 1 where R 1 is a hydrogen atom, an alkanoyl, Benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl, lower alkyl, adamantyl, lower alkyl or substituted phenyl-lower alkyl;
if Z is the rest of the formula alkyl 5 5 '
is the radicals R and R are the same or different and hydrogen atoms, lower alkyl radicals or hydroxyl groups mean, 0? i 6 "rcC" R Niederalkyi-C, for example CH-, ~ ^c "2 / \ ₇ ' or arylCH, - is, ^cH 3 ^R R ^{a is} a lower alkyl radical, a hydroxy or oxo group or a halogen atom, 2 6 ί 60S 324 q is 0, 1, 2 or 3 and R represents a hydrogen atom or a lower alkyl group;
if Z is one of the radicals N -N OAER 3 4
represents one of the radicals R and R is the radical of the formula means 13 14 and the other is a lower alkyl, cycloalkyl or phenyl (CH) radical, ρ is 0, 1, 2, 3 or 4, wherein R represents a hydrogen atom, a lower alkyl, lower alkoxy (except tert-eutoxy), halogen, phenoxy or benzyloxy rest means   4 R is a hydrogen atom, a lower alkyl, lower alkoxy, 321 1 represents halogen, phenoxy or benzyloxy, R ^{14a is} a hydrogen atom, a lower alkyl or lower alkane. - oxyrest or a halogen atom, with the provisos that R and R ^{a must be} hydrogen atoms sen. when R is a hydrogen atom, R ^a must be a hydrogen atom when R is a hydrogen atom at most one of the radicals R and R denotes a trifluoromethyl group. 13 - | 4 tet at most one of the radicals R and R is a phenoxy group 13 14. pe, and at most one of the radicals R and R is a 10 benzyloxy group means R ^^ a hydrogen atom, a C - alkyl, C ₃ _ ₆ cycloalkyl, - (except t-butoxy), Trif luormethyl-, Means fluoro, chloro, phenoxy or benzyloxy, 9
R is a hydrogen atom, a C., -alkyl, C.- .. alkoxy-, Trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy means G
with the provisos that R must be a hydrogen atom when 8 fl R is a hydrogen atom, at most one of R and 9
R is a trifluoromethyl group, at most one of the 8 9
Radicals R and R represents a phenoxy group and at most 8 9
one of the radicals R and κ represents a benzyloxy group, R and R independently of one another are hydrogen atoms, alkyl, cycloalkyl or adamantyl-1 radicals or radicals of the formula
"13 wherein R, R and R are as defined above and q 0, 1, 2, 3 or 4, Y is an oxygen or sulfur atom or the group -N-R is; if Z is a remainder of the formula
35 2 8 ί 6 O 5 12 R is a hydrogen atom or a primary or secondary C.sub.1-8 alkyl radical, R is a primary or secondary C ₁ , -alkyl radical, or R and R together are one of the groups - (CH-) - or (CiS) -CH ₂ -CH = CH-CH ₂ -, r 2, 3, 4 , 5 or 6 is and 1 2
R is a lower alkyl, or cycloalkyl or a radical the formula means 13 4a wherein R and R, R, R and R ^{a are} as defined above are; if Z is a remainder of the formula R and R are hydrogen, chloro or bromo, cyano, trifluoromethyl, phenyl. C, .- alkyl or ^C ₂ _8 ~ alkoxycarbonyl radicals or radicals of the formulas -CH-OR - or -CH-OCONHR ¹⁸ are, 1 7
R represents a hydrogen atom or a C ₁ -C alkanoyl radical. 1-0 did, 1 8
R is an alkyl or an optionally substituted by a fluorine, chlorine or bromine atom or a C. alkyl radical 111 1 phenyl group means or R ^J and R together form one of the groups - (CH ₉ ) -, -CH ₉ OCH--, -CON (R) CO- or -CON (R) N (R) CO-, s is 3 or 4,
° R is a hydrogen atom, a C ₁ , .- alkyl, phenyl or benzene cylrest is, 20 21
R and R are hydrogen atoms, C. _. -Alkyl or benzyl radicals, and X represents only one of the groups -CH ₉ -, -CH ₂ CH ₉ - or -CH ₂ CH ₂ CH ₂ -;
if Z is a remainder of the formula _23 15 * R ^23a 20 C = C 22
R is a lower alkyl, cycloalkyl or adamantyl-1 radical or means 22
R is a Cv radical of the formula is t is 1, 2, 3 or 4, R and R are the same or different and independently of one another are hydrogen atoms, lower alkyl, lower alkoxy (except tert-butoxy), halogen, phenoxy or benzyloxy radicals, with the provisos that R must be a hydrogen atom, 23
when R is a hydrogen atom, at most one of R and R ^{a represents} a trifluoromethyl group, at most one of R and R ^{a represents} a phenoxy group, and at most one of R and R ^{a represents} a benzyloxy group; 2 8 i 60 if X (the carbon atom of P unc. ^1, the oxygen atom bound to Z) represents the group -CH ^ O-, the hydrophobic anchor Z is a radical of the formula , 2a or , 2a wherein the compounds are in the form of the free acid or as physiologically hydrolyzable and compatible esters or salts. 4. The method according to claim 3, characterized in that χ one of the groups -CH = CH- or -C ^ C-, R is a hydroxyl group or an alkoxy radical, and Z is one of the radicals or 15 · I i , 2a V ⁶ represents. 5. The method according to claim 1, characterized in that the following compounds of formula I are prepared: (S) -4 - [[(E) -2- [4'-fluoro-3,3 ', 5-trimethyl-Ql, 1'-biphenyl] -2-yl] -äthenylj "-hydroxyphosphinyll-3-hydroxybutyric acid and their dilithium salt; (S) -4- [2- [4'-fluoro-3, 3 ', 5-trimethyl- [1,3'-biphenyf] -2-yl] ethyl] -hydroxyphosphinyl- ¹ -methyl-3-hydroxybutyrate and Mono or di-alkali metal salts thereof; (S) -4 - [_ qjl '-fluoro-3, 3 ^1, 5-trimethyl- [}, 1' -biphenylJ-2-YLJ-äthir.yl3-methoxyphosphinylJ-3-hydroxybutyric acid and the Methylester thereof; 28 160 (5Z) -4- [5- ^[4-fluoro-1 3 _I 3 ^1, 5-trimethyl- [j, 1 '-biphenyl] -2-yl] ethenyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and the thereof Methylester ; (S) -4- {X 2- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid methyl ester; (S) -4- [£ * 2 - [[i, 1 ^r -biphenylj-2-yl] -i ^; thylJ-methoxyphosphinyl] -3-hydroxybutyric acid methylester;
(S) -4 - [[2- [V-fluor-S, 3 '. 5-trimethyl- [i, 1'-biphenyl] -2-yl] ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt; (S) -4- [[2- [4'-fluoro-S, 3 ^1, 5-trimethyl- [j, 1 '-biphenyl] -2-yl] ethynyl] -hydroxyphosphinyl] -3-hydroxybutyric acid, dilithium salt; (§Z) -4 - [[2- [4'-Fluoro-S ₁ S ¹ , 5-trimethyl- ( ¹ , 1'-biphenyl] -2-yl] -äthenyl] -hydroxyphosphinyl] -3-hydroxybutyric Acid dilithium salt; (S) -4 - [[2- [3- (4-Fluorophenyl) -1-methylethyl) -1H-indol-2-yl] ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid dilithium 20 salt; (S) -4-Q [2 - [(1,1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl] -3-butyric acid dilithium salt; (S) -4- (Hydroxymethoxyphosphinyl) -3- [Q (1,1-dimethylethyl) diphenylsilyl] oxy] -butyric acid methyl ester and its dicyclo- 25 hexylamine (1: 1) salt; (S) -4 - [[2-Q- (4-fluorophenyl) -3- (1-methylethyl) -1-indoxyl] -äthinyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester;
(S) -4 - [[2- [i- (4-Fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl] -ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester ; (E) -4 - [[2- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -äthenyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its Dilithium salt and methyl ester; 4- [2-Ql'-fluoro-3,3 ', 5-trimethyl- [}, 1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; 1605 (S) -4 - [[2- [4'-fluoro-3,3 ', 5-trimethyl- [i, 1'-biphenyl] -2-yl] -äthenyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4- [yyy. 4-Dimethyl-6- [4- (4-fluorophenyl) methoxy] phenyl] ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4 - [[X 2, 4-Dimethyl thy 1-6- (4-fluoro-phenyl) -methoxy-phenyl] -äthinyl] -hydroxy-phosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4- [2- [3,5-dimethyl- [i, 1'-biphenyl] -2-ylJ-ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4 - [[2- (jr-Fluoro-3,5-dimethyl- (1, 1'-biphenyl] -2-yl] -ethyl] -hydroxyphosphinyl] _-3-hydroxybutyric acid and its dilithium 15 salt and methyl ester; (S) -4- [X 2 - [1, 1'-biphenyl]] -2-ylj-ethylhynyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4- [j 2 -p- (4-fluoro-phenyl) -3- (1-methyl-ethyl) -1-ph-n-1-H-pyrazol-4-yr-äthinyl] -methoxyphosphinyl] -3-hydroxybutyrate 20 acid methyl ester; (S) -4-Q [2- [5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -äthinyl] -hydroxyphosphinyl] -3-hydroxybutyrate acid, dilithium salt; (E) -4 - [[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -äthenyl] -methoxyphosphinyl] -3-hydroxybutyrate acid methyl ester; (E) -4 - [[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -äthenyl] -hydroxyphosphinyl] -3-hydroxybutyric acid Dilithium salt; (S) -4 - [[2- [5- (4-Fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid methyl ester; (S) -4-Q [2-Q5- (4-fluorophenyl) -3- (1-methyl-1-ethyl) -1-phenyl-1H-pyrazol-4-yl] -ethyl] -hydroxyphosphinyl] -3- hydroxybu ^u . 35 acid dilithium salt; 3 * (S) -4 - [[2- [3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl [] -ethyl] -methoxyphosphinyl] -3- hydroxybutyric acid methylester; (S) -4- [£ 2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-YLQ-äthylJ-hydroxyphosphinylJ-3-hydroxybutyric acid, dilithium salt; (S) -4 - [[2- [3- (4-Fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -äthinyl] -methoxyphosphinylf] -3-hydroxybutyric acid methyl ester;
(S) -4- [£ 2- [3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl] -äthinyl] -hydroxyphosphinyl] -3-hydroxybut- tersäure dilithium salt; (S) -4- [[[4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yf] -äthinyl] -methoxyphosphinyl]] -3-hydroxybutyric Acid methylester; (S) -4- · [[[4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -äthinyl] -hydroxyphosphinyl-S-hydroxybutyrate acid, dilithium salt; (S) -4 - [[2- [4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -Q-ethyl] -methoxyphosphinyl-3-hydroxybutyric acid methylester; (S) -4 - [[2- [4- (4-Fluorophenyl) -1- (1-methylethyl) -3-phenyl-1H-pyrazol-5-yl] -äthyj-hydroxyphosphinyl] -3-hydroxybutyric acid dilithium salt ;
(S) -4 - [[[i- (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl] -1H-imidazol-5-yl3-ethylenyl [] -methoxyphosphinyl J-S-hydroxybutyrate acid methylester; (S) -4 - [[[1- (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-imidazol-5-yl-Q-ethynyl] -methoxyphosphinyl]] -3-hydroxybutyric acid methyl ester ; (S) -4 - [[2- [i- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-iH-imidazol-5-YLJ-ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid methylester; (S) -4 - [[2- [i- (4-Fluorophenyl) -4- (1-methylethyl) -2-phenyl-1-1H-imidazol-5-yl3-ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid - acid dilithium salt; 1605 (S) -4 - [, ^ [[2- (Cyclohexylmethyl) -4 ₍ 6-dimethylphenyf) -äthinyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; 4- [[2- [2- (cyclohexylmethyl) -4,6-dimethylphenyl]] -äthenyl] -hydroxyphosphinylQ-3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4- [_ [^ 2- [2- (Cyclohexylmethyl) -4,6-dimethylphenyf] ethyl] hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; 4- [_ [[[4'-fluoro-3, 3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] oxy] methyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and Methylester; 4- [[[4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl] methyl] hydroxyphosphinyl [3-hydroxybutyric acid and its dilithium 15 salt and methyl ester; (S) -4- [[[i- (4-fluorophenyl) -3-methyl-2-naphtha-linyr] -äthinyl] -. Hydroxyphosphinyl-3-hydroxybutyric acid and its dilithium salt and methyl ester;
(E) -4 - [^ [2- [i- (4-Fluorophenyl-3-methyl-2-naphthalenyl) -äthenyl] hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; (S) -4 - [[2- [i- (4-Fluorophenyl) -3-methyl-2-naphthalenyl-3-ethyl] -hydroxyphosphinyl] -3-hydroxybutyric acid and its dilithium salt and methyl ester; Methyl 4-fluoro-4'-fluoro-3,3 ', 5-trimethyl- [1,2,4'-biphenyl] -2-yl] propyl] methoxyphosphinyl] -3-hydroxybutyric acid; ⁴ ~ Q [3- C ⁴ '-fluoro-3, 3', 5-trimethyl- [1, 1 '-biphenyl] -2-yl] propyl] -hydroxyphosphinyl] -3-hydroxybutyric acid, dilithium salt; QiS- [Ka (R *) _< 2 <a, 4a <b, 8 <b, 8a <a1] -4 - [[2- [8- (2 _l 2-dimethyl-1-oxobutoxy) decahydro-2 -methyl-1-naphthalenyl] ethyl] -methoxyphosphinyl] -3-hydroxybutyric acid methyl ester; [1S- [Ka (R *), 2 <a, 4a <b, 8 <b, 8a <a] 3-4 - [[2- [8- (2,2-dimethyl-1-oxobutoxy) decahydro -2-methyl-1-naphthalenyl] -äthylj-hydroxy- 35-phosphinyl-1,3-hydroxybutyric acid dilithium salt; 21.12.1988 70 576 11 330 (S) -4- / "Z ^ / ^1" 3 ^l ~ (4-i ^I luorphenyl) -apiro- ^ cyclopentane-1,1 '- hydroxybutyric acid methyleater; and (S) -4- ^ ¹ /4-i- (4 ~ ¹ luprphenyl) ~ 3piro- / cyclopentane ~ 1,1 '- ^ TH7-inden7-2-ylJ7-ethinyl7-hydroxypho3phinyl7-3- hydroxy-butterjäure dilithium salt.