DD297818A5 - NEW TETRAZOL INTERMEDIATES, THEIR PREPARATION AND THEIR USE OF THE PREPARATION OF ANTIHYPERCHOLESTERINA MIXTURES - Google Patents

Abstract

The invention relates to novel tetrazole intermediates of the formula wherein R1 and R4 are each independently hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or trifluoromethyl; R2, R3, R5 and R6 are each independently hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy; B is hydrogen, C 1-6 alkoxycarbonyl, CH 2 Y or CH 2 Z; Y is hydrogen, hydroxy or X; Z is O.

Description

to prepare a compound of formula VII wherein R ^{8 is} hydrogen, C 1-4 alkoxycarbonyl or methyl,

(b) dehydrating the product of step (a) to produce a compound of formula IV, and either

(c) treating the anion of compounds of formula IV wherein R ^{8 is} hydrogen prepared in situ in an inert organic solvent with a strong base, or (c ') treating the compounds of formulas IV wherein R ⁸ Methyl, with an N-halosuccinimide in the presence of a catalyst and subsequent reaction of the product with 2-nitropropane to produce a compound of formula III.

Field of the invention

The present invention relates to the preparation of novel intermediate tetrazole products which are useful for the preparation of novel inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HGM-CoA) reductase. These in turn are useful for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

State of the art

The natural fermentation products compactin (R = H) described by A. Endo et al. has been disclosed in Journal of Antibiotics, 29.1346 to 1348 (1976) and mevinolin (R = CH ₃₎ of AWAlberts et al. in J. Proc. Natl. Acad. Be. USA, 77, 3957 (1980), are very potent antihypercholesterolemic agents that inhibit cholesterol biosynthesis by inhibiting the HMG-CoA reductase enzyme found in mammals, including humans, the rate-limiting enzyme and the natural point of regulation of cholesterol formation represents, limit. Compactin (R = H) and mevinolin (R = CH ₃ , also known as lovastatin) have the structural formulas shown below:

Compactin, R = H; Mevinolin, R = CH ₃

A number of structurally related synthetic compounds useful in the treatment of hypercholesterolemia have also been disclosed in patents or other publications. The closest related art of synthesis is the following: U.S. Patent 4,184,825, issued April 15, 1980 to S. Mistui et al. released

describes novel mevalonolactone derivatives which are useful for the treatment of hyperlipidemia and which have the following general formula:

srr

wherein A represents a direct link, a methylene, an ethylene, a trimethylene or a vinylene group and R ³ , R ⁴ and R ^{5 represent} different substituents.

European patent application EP-24348 published on Mar. 4, 1981 discloses novel hypocholesterolemic and hypolipemic compounds having the structure:

HO

wherein A, H or methyl; E is a direct bond, -CH ₂ -, - (CH ₂ I ₂ -, - (CH ₂ Ir- or -CH = CH-; R ¹ , R ² and R ^{3 are} each different substituent and the corresponding dihydroxy acids arising from the hydrolytic opening of Lactonringes.

On March 1, 1983, for A.K. Willard et al. published U.S. Patent Application No. 4,375,575 discloses substantially the same structural formulas and is in accordance with the above-mentioned European Patent Application 24348.

European Patent Application EP-68038 published January 5, 1983 discloses and claims the dissolved trans enantiomer. a process for its preparation and a pharmaceutical composition thereof having the structure:

and the corresponding dihydroxy acid or a pharmaceutically acceptable salt thereof.

International Patent Application WO84 / 02131, published June 7, 1984, describes analogs of mevalonolactone having the structure

5a <f π 4

where: R6 is RrR ° R -j- H-R

and the other is a primary or secondary Ci-p-alkyl, C ^ e-cycloalkyl or ¹ phenyl (CH ₂ ) _n -; X is - (CH ₂ ) _n -or-CH = CH-; η is 0,1,2 or 3;

R 'Z is -CH-CH ₂ -C-CH ₂ -COOH and

-CH-CH ₂ -C -OH OH

R ⁴ , R ⁵ , R ⁵ * and R ^{e represent} different substituents. International Patent Application WO 84/02903, published August 2, 1984, describes mevalonolactone analogs with U.S. Pat

structure

where X- (CHj) _n -,

(CH ₂ ) _q -

C = C

X-Z

IB

is;

-CH ₂ ) _q η = 0, 1, ₂ or 3 hours each of both q = 0 or one q = 0 and the other q = 1 and

Z = -CH-CH ₂ -C-CH ₂ -COOH

-CH-CH ₂ -CC OH OH

European patent application EP-142146, published May 22, 1985, describes oxo analogues of mevinolin-like hypocholesterolanic drugs having the structure

wherein E is -CH ₂ -CH, -, - CH = CH- or- (CH ₂ I ₃ -, and Z 0

wherein the dotted lines represent possible chained bonds, namely 0.1 or 2 double bonds.

In J. Med. Chem., 28, 347-356 (1985), G. E. Stokker et al. on the preparation and testing of a series of 5-substituted-3,5-dihydroxypentanoic acids and their derivatives.

In J. Med. Chem., 29, 159-169 (1986) W.F. Hoffmann et al., The preparation and testing of a series of 7- (substituted aryl) -3,5-dihydroxy-6-heptene or - (heptan) säurf.n and their lactone derivatives. One of the preferred compounds in the illustrated series has the structure

"° ° rx

In J. Mod. Chem., 29, 170-181 (1986) G.E. Stokker et al. the synthesis of a series of 7- [3,5-disubstituted (1, V-biphenyl) -2-yl] -3,5-dihydroxy-6-heptenoic acids and their lactones. Two of the preferred compounds described in this article have the structures

"O'

and

approximately

I = 3

U.S. Patent No. 4,613,610, issued September 23, 1986 to J. R. Wareing, describes pyrazole analogues of mevalonolactone and its derivatives useful for the treatment of hyperlipoproteinemia and atherosclerosis, having the general formula

X Z

wherein X is - (CHj) _n -, - CH = CH -, - CH = CH-CH ₂ or -CH ₂ -CH = CH-; η is 0,1,2 or 3 and R ', R ² , R ³ , R ⁴ , R ⁶ , R ^e , R ⁷ and Z are different substituents.

Coins of the cited patents or articles disclose or suggest the scope of the compounds of the present invention. The unique structural feature incorporating a tatrazole moiety in the instant compounds differs significantly from the prior art described.

Summary of the invention

The present invention relates to the preparation of novel tetrazole intermediates having the formula:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^e and B are defined as described below. The tetrazole intermediates are useful for the preparation of inhibitors of the enzyme 3-hydroxy-3-methylglutaryl Cooiuym A (HMG-CoA) reductase. These inhibitors are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

Description of the invention

The present invention provides a process for the preparation of novel tetrazole intermediates which are useful for the preparation of antihypocholesterolemic agents and which have the formula:

wherein R ¹ and R ⁴ R ² , R ³ , R ⁶ and R ⁶ BY

-N

are each independently hydrogen, halogen, C, _4-alkyl, C ₁ ^ -alkoxy or trifluoromethyl;

each independently are hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; Is hydrogen, C 1-6 alkoxycarbonyl, CH ₂ Y or CH ₂ Z; Is hydrogen, hydroxyl or X;

Il

Bromine, chlorine or iodine; C, _4-is alkyl; and Phenyl is which is unsubstituted or substituted by one or two C ^ alkyl or chlorine substituents.

The invention provides processes for the preparation of the compounds of the formula I and processes for the preparation of antihypocholesterolemic active compounds of the formulas

OH

Ha

hb

are available, wherein R ¹ and R ⁴ independently of one another are hydrogen, halogen, C ₁ -C 4 -alkyl, C ₁ -C 4 -alkoxy or trifluoromethyl; R ² , R ³ , R ⁵ and R ⁹ independently of one another are hydrogen, halogen, C 1 -C 4 -alkyl or C ₁ -C 4 -alkoxy; η = 0.1 or 2; and R 'is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt.

The terms "C ₁ _, - alkyl,""C ^ alkoxycarbonyl" and ,, _C1 ^ -alkoxy "as they (except where the context otherwise indicates) Here and in the claims, mean unbranched or branched chain-like alkyl or alkoxy groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. These groups preferably contain 1 to 4 C atoms and, in particular, they contain 1 or 2 C atoms. Unless otherwise specified in the specific example, the term "halogen" as used herein and in the claims is intended to include chlorine, fluorine, bromine and iodine, while the term "halide" as used herein and in the claims is intended to include the chloride anion, The term "a cation to form a non-toxic pharmaceutically-acceptable salt" as used herein and in the claims is intended to include non-toxic alkali metal and alkaline earth metal salts, such as sodium and potassium salts. Salt, potassium salt, calcium salt and M agnesium salt, the ammonium salt and salts with non-toxic amines, the trialkylamines, dibenzylamine, pyridine, N-methyl-morpholine, N-methylpiperidine and other amines used to form salts of carboxylic acids. Unless otherwise specified, the term "a hydrolyzable ester group" as used herein and in the

Claims include an ester group that is physiologically acceptable and physiological

Conditions is hydrolyzable as C ^ alkyl, phenylmethyl and pivaloyloxymethyl.

In the compounds of formulas IIa and IIb, all double bonds should be present in the trans configuration, e.g. B., (E), as indicated in the structural formulas used herein.

In the compounds of the formula I, the radicals R ¹ , R ¹ , R ³ , R ⁴ , R ⁶ and R ^e, independently of one another, are preferably hydrogen,

Halogen, Ct ^ alkyl or C ₁ ^ -Akoxy. Preferably, R ¹ and R ^{4 are} hydrogen and R ¹ , R ³ , R ^s and R ^e , independently of one another, are hydrogen, fluorine, chlorine, methyl or methoxy, and in particular R 'and R ^{4 are} hydrogen and R ² , R ³ , R ⁵ and R ^e are

independently of one another hydrogen, fluorine, methyl or methoxy. It is preferred that B is hydrogen, ethoxycarbonyl, CH ₂ Y in which Y is preferably hydrogen, hydroxyl, chloro or bromo, or CH ₂ Z in which Z is preferably

Triphenylphosphonium bromide or Ct-rAlkylphosphonat is.

The hypocholesterolemic compounds of the formulas Il a un -'al'b can be prepared by various methods, preferably by using the intermediates of the fimel

CHO

N-QL

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{e are} as previously defined. Thus, the present invention provides novel intermediates of formula I and improved processes for the preparation of compounds of formula III

 The compounds of the formula III can be prepared by various processes, preferably starting from a compound of the formula IV

IV,

CH.

wherein R ', R ² , R ³ , R ⁴ , R ⁶ and R ^{e are} as previously defined; and R ^{e is} hydrogen, C 1-4 alkoxycarbonyl or methyl

 The compounds of formula IV can be prepared from the optionally substituted benzophenones of formula V by alkylation with the 5-position suitably substituted 1-methyl-tetrazole of formula Vl followed by dehydration of the resulting tertiary alcohol of formula VII, as shown in the reaction scheme 1 is shown.

Reaction Scheme 1

NN-CH.

R ⁸

N _'N-CH3 N-Ν

VI

VII

IV

CH,

In Reaction Scheme 1, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ° and R ^{8 are} as previously defined. The optionally substituted benzophenones of formula V may be prepared by the general and well known Friedel-Crafts reaction of a substituted phenyl catalyzed by Lewis acids, for example, with aluminum chloride in carbon tetrachloride at about ⁰ ° C. A large number of substituted benzophenones are known and their preparation is described in the prior art, while many others are commercially available. For example, many starting materials of Formula V are described by G. Olah in Friedel-Crafts and Related Reactions, Vol. 3, Part 1 and 2, lnterscience Publishers, New York, 1964, and the references cited therein. The Friedel-Crafts reaction can turn into a mixture of benzophenones and the mixture, if prepared, can be separated by conventional techniques known in the art.

The starting materials of formula VI, wherein R ^{8 is} hydrogen, are commercially available, while the starting materials in which R ^{B is} C 1-4 alkoxycarbonyl or methyl, by reaction of 1,5-dimethyltetrazole with a strong base such as butyllithium at a temperature of about -70 ° C to about O ⁰ C and addition of the anion thus obtained or treatment of the resulting anion with preferably ethyl chloroformate or methyl iodide, as described herein.

The suitable 5-substituted 1-methyltetrazol of the formula Vl can with a strong base such as n-butyllithium at low temperatures from about -2O ⁰ C to about -78 ⁰ C and, preferably, from about ⁰ C to -4o -78 ⁰ C in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and the like. The resulting anion of formula VI can then be treated with the desired benzophenone of formula V to produce the corresponding tertiary alcohols of formula VII.

The compounds of formula IV may be prepared from the compounds of formula VII by conventional dehydration procedures. The dehydration may be carried out by heating the alcohol of formula VII in a suitable inert organic solvent such as toluene, benzene or xylene with a small amount of an organic or mineral acid such as p-toluenesulfonic acid or sulfuric acid in the presence of a desiccant such as e.g. Na ₂ SO ₄ , MgSO ₄ , molecular sieve, etc., or the resulting water is preferably removed azeotropically with a Dean-Stark trap or similar device. Optionally, the alcohol of formula VII may simply be heated with potassium hydrogen sulfate at temperatures of about 19O < ⁰ > C.

In the specific example in which R ^{8 is} ethoxycarbonyl, the reaction of ethyl 1-methyl-5-tetrazolyl acetate with a benzophenone of formula V in the presence of titanium tetrachloride and carbon tetrachloride can be carried out to directly in one step the corresponding olefin of the Formula IV produce.

The preferred aldehydes of formula III can be prepared by various methods from the compounds of formula IV, depending on which substituent R ^{3 is used} in the process. Consequently, it should be apparent to those skilled in the art that the compounds of formula IV wherein R ^{8 is} ethoxycarbonyl (I a). Is hydrogen (I c) or methyl (Id) into which aldehydes of formula III can be converted, as shown in Scheme 2.

Reaction scheme 2

ib

III

Ie

In Reaction Scheme 2, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as previously defined. The alcohols of formula I b may preferably be prepared by reduction of the tetrazoloster of formula Ia with the reducing reagents such as diisobutylaluminum hydride in a nonreducible inert solvent such as methylene chloride and tetrahydrofuran at low temperatures, in particular at about -78 ° C, in one step. The resulting allylic alcohol of the formula I b can then be easily oxidized by conventional oxidizing agents such as pyridinium chlorochromate in a non-reactive solvent, preferably in methyl chloride, at room temperature to produce the desired aldehyde of formula III.

The compounds of formula Ic can be converted directly to the aldehydes of formula III by treating the anion of formula Ic which is in situ in an inert organic solvent, e.g. Tetrahydrofuran or 1,2-dimethoxyethane is prepared with a strong base such as n-butyllithium, with ethyl formate.

The compounds of formula III can also be prepared from the compounds of formula I d by treating the compounds of formula Id with N-bromosuccinimide in the presence of a catalyst such as azobisisobutyronitrile or

Benzoyl peroxide in carbon tetrachloride and subsequent reaction of the resulting allyl bromide of the formula Ie with 2-nitropropane by the general method as described here and in Org. Syn, Coll. Vol. IV, 932 is described. Alternatively, the allyl bromide of the formula He can be prepared from the alcohol of the formula I b by treatment with carbon tetrabromide and triphenylphosphine.

The preferred compounds of formula III can be converted to the preferred compounds of formula Ma and IIb by the general procedures disclosed herein and in U.S. Patent Application Serial No. 018,542, filed February 25, 1987, and in U.S. Pat corresponding divisional application US Serial No. (CT-1888 A) filed on the same day filed by John J. Wright and Sing-Yuen Sit. The use of the aldehydes of the formula III is shown in Reaction Scheme 3.

Reaction scheme 3

¹¹ LJ

CHO

VIII

? ^H PQ

9 IX

Compounds of the formulas Ha and Hb

In Reaction Scheme ³ , the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined and R ⁹ is a hydrolyzable ester group. In general, the aldehydes of formula III can be converted to the dienaldehydes of formula VIII wherein η = 1 by reaction with about one equivalent of triphenylphosphoranylidene acetaldehyde in an inert organic solvent such as benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane and similar. For convenience, we prefer to carry out the reaction at reflux temperature. If necessary, the diene aldehyde of the formula Viii in which η = 1 may be reacted with another equivalent of triphenylphosphoranylidene acetaldehyde to produce the triene aldehyde of the formula VW in which η = 2.

The penultimate intermediate of formula IX in which R ^{9 is} a hydrolyzable ester group can be prepared from the corresponding aldehyde of formula VIII by reaction with the dianion of the acetoacetate ester formed in situ as described herein. The reaction can be carried out boi in an inert organic solvent such as tetrahydrofuran a low temperature of -78 ° C to ungßiähr ⁰ ° C. and, preferably, from about -78 ⁰ C to -40 ⁰ C until the reaction is substantially complete.

The ketone ester of formula IX can be reduced to the dihydroxy ester of formula IIa by reduction of the keto group with reducing agents well known in the art such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, disiamylborane, diborane, ammonium borane, t-butylamine borane , Pyridine-borane, lithium tri-s-butylborohydride or other similar reducing agents that neither reduce nor hydrolyze the carboxylester group. Preferably, the reduction is carried out stereospecifically by a two step stereospecific reduction to maximize the preparation of the preferred erythro isomer of the compound of formula IIa. The stereospecific reduction of a compound of formula IX is carried out with trisubstituted alkylboranes, preferably triethylborane, or alkoxydialkylboranes, preferably methoxydiethylborane or ethoxydiethylborane (Tetrahedron Letters, 28, 155 [1987]) at a temperature of about -7O ⁰ C to about room temperature. The complex thus formed is then reduced with sodium borohydride at a temperature from about -5O ⁰ C to about -78 ⁰ C in an inert organic solvent such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, preferably tetrahydrofuran. The reduction is then completed by the addition of methanol. The resulting compound of formula X can then be converted to the compounds of general formulas IIa and IIb in a conventional manner known to those skilled in the art.

In an optional process for the preparation of the compounds of the formulas IIa and IIb, intermediate compounds of the formulas If and Ig are also provided, as shown in Reaction Scheme 4.

Reaction scheme 4

CH ₂ -P- (OR ¹⁰ )

In Reaction Scheme 4, the radicals R ', R ² , R ³ , R ⁴ , R ⁶ and R ^{9 are} as defined above. The Allylbromld of formula I e can be reacted in the usual way with phosphines such as triphenylphosphine in an inert organic solvent such as cyclohexane to produce the phosphonium salt of formula I f, wherein R ¹¹ is phenyl which is unsubstituted or substituted by one or two C | _4-A Is substituted kyl or chlorine substituents, and wherein X is bromine, chlorine or iodine. Alternatively, the allyl bromide of the formula I e can be reacted neat or undiluted in an inert organic solvent, preferably in a conventional manner with phosphites such as trimethyl phosphite and triethyl phosphite either to produce a phosphonate of the formula I g, in de η R ¹⁰ Ci 4-alkyl.

The intermediates of formulas I f or I g can then be converted to the antihypercholemic compounds of formulas IIa and IIb by a series of reactions shown in Scheme 5.

Reaction scheme 5

If or Ig

OR

XII

In Reaction Scheme 5, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ^{6 are} as defined above, R ⁹ is a hydrolyzable ester group,

R ' ² is t-butyldiphenylsilyl and Z is -P- (OR ¹⁰ )} or .11

Χ ^Θ in which R ^{10 is} C 1 -C 4 -alkyl, R "is phenyl,

which is unsubstituted or substituted by one or two C 1 -j-alkyl or chloro substituents, and X is bromine, chlorine or iodine. The phosphonium salt of formula If or the phosphonate of formula Ig ann can be prepared with the silyl-protected aldehyde of formula XI, which itself can be prepared by the methods described in Tetrahedron Letters, 25, 2435 (1984) and also in US Pat. No. 4,571,428 , are reacted to produce the silyl-deficient compound of formula XII. The reaction may in an inert organic solvent such as tetrahydrofuran or N ₁ N-dimethylformamide in the presence of a strong base such. As lithium diisopropylamide, potassium t-butoxide and n-butyllithium at a temperature of about - 78 ⁰ C to about O ⁰ C are performed. The compound of formula XII can then be desilylated by well-known procedures such as 48% hydrofluoric acid and, preferably, with tetrabutylammonium fluoride in an inert organic solvent such as tetrahydrofuran and acetonitrile in the presence of a small amount of organic acid to produce the erythro compounds of formula X. , The resulting compound of formula X can then be converted to the compounds of general formula Ha and Hb in a manner conventional to those skilled in the art. In a preferred embodiment of the invention, the compounds of the formula I have the structure

wherein R ¹ , R ^J , R ³ , R ⁴ , R ⁵ and R ^{6 are} independently hydrogen, fluoro, methyl or methoxy; and B is hydrogen or C, e -alkoxycarbonyl.

In another preferred embodiment of the invention, the compounds of formula I have the structure

wherein R ¹ , R ', R ³ , R ⁴ , R ⁵ and R ^{6 are} independently hydrogen, fluoro, methyl or methoxy; Y is hydrogen, hydroxyl or X; and X is bromine, chlorine or iodine.

In a further preferred embodiment of the invention, the compounds of the formula I have the structure

wherein R ¹ , R ² , R ³ , H ⁴ , R ⁵ and R ^{6 are} independently hydrogen, fluoro, methyl or methoxy, and Z

.10

-P- (OR ^) ₂ or -P ^ -R--

\ _R JL, wherein R ^{10 is} methyl or ethyl; R ^{n is} phenyl; and X is bromine.

The compounds of the formula IIa and IIb are competing inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HGM-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis and are therefore selective inhibitors of cholesterol. Biosynthesis in animals, including humans. Consequently, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The biological A '' vity of the compounds of the formulas II a and II b can be demonstrated by the inhibition of cholesterol biosynthesis in rats.

In vivo acute cholesterol-blosynthesis inhibition in rats Male Wistar rats (16O-200g, housed 2 pieces per cage) were reconstituted for at least 7 days Lighting schedule (7:00 am to 5:00 pm in the afternoon) on normal diet (Purina rat diet and Water, ad libitum). The feed was removed 15 hours before dosing. The connections were at 8:00

administered in the morning by intragastric intubation, with 0.5-1, OmI water or propylene glycol solutions of the

Sodium salts, lactones or esters of the test compounds were used. Control animals received equal volumes of Carrier.

Thirty minutes after receiving the test substances, rats were given intraperitoneally 0.9 ml of 0.9% NaCl, which was about 120 pCi / kg

Body weight sodium [I- ^ CI acetate (1-3mCi / mmol) was injected. After a 10-minute incorporation period, the Rats were killed and the liver and blood samples taken. Aliquots of plasma (1.0 ml) obtained by centrifugation of heparin + EDTA-treated blood, and aliquots of liver homogenates (equivalent to 0.5g liver wet weight).

were taken for the determination of radioactively labeled 3-hydroxy sterols. For the liver samples was the

Sterisol isolation according to the method of Kates in Techniques in Lipidology, (M.Kates, ed.) Pp. 349,360-363, North Holland Publ. Co., Amsterdam, 1972, while the plasma samples were directly saponified, followed by isolation of the digitonin

precipitable sterols.

^H C-labeled sterols were detected by liquid scintillation counter! (Efficiency corrected) quantified. The middle

percent inhibition of ¹⁴ C incorporated in liver and in Plas.na cholesterol was treated for groups of

Animals and compared with the averages for the controls carried out simultaneously. Thus, the above test provides information about the performance of test compounds, the de novo biosynthesis of To suppress rat cholesterol in vivo by oral dosing. For example, the compound of Example 9 provides Using the above test, a 50% inhibition dose (ED _S0 ) for both plasma and liver cholesterol, resulting in values

were obtained for mevinolin (lovastatin) using a similar procedure. (Alberts et al., Proc. Natl.

Acad. ScI., 77, 3957-3961 [1980]).

Description of specific embodiments

In the following examples, all temperatures are in degrees Celsius. Melting points were recorded with a Thomas Hoover capillary melting point apparatus, and the boiling points were measured at specific pressures (mm Hg). Both temperatures are uncorrected. Proton magnetic resonance spectra ( ¹ H NMR) were recorded on a Bruker AM 300, Bruker WM 360 or Varian T-60 CW spectrometer. All spectra were determined in CDCl ₃ , DMSO-d _s, or D ₂ O unless otherwise indicated, and the chemical shifts are recorded in δ units at smaller field strengths based on the internal standard tetramethylsilane (TMS) the coupling constants between the protons are recorded in hertz (Hz). Splitting patterns are denoted as follows: s, singlet; d, Dubiett; t, triplet; q, quartet; m, multiples; br, broad peak; and dd, doublet of doublet. Carbon-13 nuclear magnetic resonance (' ³ C NMR) spectra were recorded on a Bruker AM 300 or Bruker WM 360 spectrometer and were decoupled to broadband proton. All spectra were reported in CDCl ₃ , DMSOd ₆ or D ₂ O, unless otherwise noted, with internal deuterium exclusion, and chemical shifts are reported in delta units towards smaller field strengths of tetramethylsilane. Infrared (IR) spectra were determined on a Nicolet MX-1 FT spectrometer of 4000cm " ¹ to 400cm" ¹ calibrated to 1601cm " ¹ absorption of a polystyrene film and are reported in reciprocal centimeters (cm" ¹ ). The relative intensities are given as follows: s (strong), m (medium) and w (weak).

Gas chromatography mass spectra (GC-MS) were determined on a Finnigan 4500 gas chromatography quadrupole mass spectrometer at an ionization potential of 7OeV. Mass spectra were also recorded on a Kratos MS-50 instrument using the fast atom bombardment (FAB) technique. The mass data is expressed in the format: parent ion (M ⁺ ) or protonated ion (M + H) ⁺ .

Analytical thin layer chromatography (TLC) was performed on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors and / or staining with one of the following reagents: (a) methanolic phosphomolybdic acid (2%) and heating ; (b) Reagent (a) followed by 2% cobalt sulfate in 5M H ₂ SO ₄ and heating. Column chromatography, also referred to as flash column chromatography, was performed in a glass column using finely divided silica gel (32-63 μm on silica gel-H) and pressures slightly above atmospheric pressure with the indicated solvents. The evaporation of all solvents was carried out under reduced pressure. The term "hexanes" as used herein represents a mixture of isomeric hydrocarbons as determined by the American Chemical Society and the term "inert" atmosphere is an argon or nitrogen atmosphere as far as it is not otherwise specified.

example 1 Ethyl 2-cyano-3,3-bls (4-fluorophenyl) -2-propenoate

A mixture of 20.0 g (92 mmol) of 4,4'-difluorobenzophenone, 11.0 g (97 mmol) of ethyl cyanoacetate in a mixed solvent of 100 mL of dry benzene and 20 mL of glacial acetic acid containing a catalytic amount of β-alanine (0, 9g) is heated to reflux with removal of water using a Dean-Stark trap. Water separation occurs rapidly during the first 2 hours (0.4 ml of aqueous layer is collected) but later slower. The azeotropic distillation was continued for a period of 14 days. Analytical TLC performed with 10% EtOAc in hexane (v / v) (Merck plate, 0.25mm silica gel-F) revealed two spots at R ₁ = 0.2 (desired product) and at R ₁ = 0.45 (4,4'-difluorobenzophenone starting material). The crude reaction mixture was washed with water (40 mL χ 2) and the combined aqueous washes were extracted with EtOAc (150 mL χ 2). The organic phases were combined, dried over MgSO ₄ and concentrated under reduced pressure to give the product a lighter color

cubic crystals crystallized. The crude product was collected, washed with EtuAc in hexane 1: 1 (v / v) and then recrystallized from 8: 1 hexane: ethyl acetate (v / v) to give 16.2 g (56.3%) of the title compound were; Mp. = 114-116 ⁰ C.

IR (KBr) v _mlx : 3000 (s), 2225 (s), 1931 (vs), 1605 (s), 1513 (s), 1250 (s), 844 (s) cm ^-1 ;

¹ HNMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.1 Hz), 4.18 (2H, q, J = 7.1 Hz), 7.08-7.15 (6H, m), 7.40-7.42 (2H, m); ¹³ C NMR (CDCl ₃ ) δ: 13.75, 62.27, 10.04, 0.05, 116, 69, 115.53 (d, ² J _{C, F} = 22.7 Hz), 115.88 (d, ² J ₀ -F = 22, 7Hz), 131.64 (d, ³ J _C -f = 9.1Hz), 132.66 (d, ³ Jc-F = 9.1Hz), 134.25.134, 31.134, 36.164, 0.01 (d, ¹ J ₀ -F = 252.9Hz), 164.52 (d, ¹ J ₀ -F = 254.0Hz), 166.65ppm.

Analysis for C ₁₈ H ₁₃ NO ₂ F _2: Calculated: C 69.01; H 4,15; N 4,47. Found: C68.91; H4.15; N4.62. Example 2 Ethyl-3,3-bls (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate Into a dry 50 ml round bottom flask was added 5.0 g (16.0 mmol) of ethyl 2-cyano-3,3-bis (4-fluorophenyl) -2-propenate followed by

8.0 g (24.1 mmol) of azidotributyl stannate (prepared by the method described in Rev. Trav. Chem. 1981,202-205 [1962]) and 2.0 ml of toluene for synthesis. The heterogeneous mixture was stirred and refluxed

(11O ⁰ C) heated in an oil bath behind a security shield. The solid starting material gradually dissolved to form a salubrious thick syrup and the homogeneous mixture was stirred for 20 hours and heated to reflux. The analytical TLC taken with 20% MeOH in CHCl ₃ (v / v) showed the product at R ₁ = 0.26 (strip). The raw one

Reaction mixture was diluted with an equal volume of diethyl ether and poured into a vigorously stirred saturated

aqueous solution of KF (200 ml containing 2 ml of 48% HBF "). Immediately after mixing became a voluminous

Precipitate (Bu ₃ SnF) was observed and the hydrolysis was allowed to continue for 16 hours. The suspension was

filtered and the filtrate was extracted with EtOAc (100 mL x 2). The organic phases were combined, dried over MgSO ₄ and concentrated under reduced pressure. The above compound crystallized from the concentrate yielding 4.54 g (77%) of analytically pure white material; Mp. = 159-161 ⁰ C.

IR (KBr) v _max : 3438 (br), 1713 (vs), 1600 (s), 1510 (s), 1238 (s), 841 (s) cm "¹;

¹ H NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.6Hz), 3.98 (2H, q, J = 7.6Hz), 7.3-6.7 ( 8H, m), 10 (1H, v. Br.); ¹³ C NMR (CDCl ₃ ) δ: 166.52, 163.54 (d, ¹ J _C - _F = 250.7Hz), 163.46 (d, ¹ J ₀ -F = 262.7Hz), 157.14, 136.40, 134 , 74.131.71 (d, ² J _C _F = 67.2Hz), 131.59 (d, ² J ₀ -F = 66.4Hz), 115.75 (d, ³ J ₀ -F = 18.9Hz) , 115.45 (d, ³ J ₀ -F = 18.1 Hz), 62.11, 13.47 ppm.

Analysis for C) ₈ Hi ₄ F ₂ N ₄ O ₂ : Calculated: C 60.27; H 4.06; N 15.50. Found: C60.67; H3,96; N 15,72.

Belspiel3

Ethyl-3,3-bls (4-Jluorphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenoate To a solution of 0.5 g (1.40 mmol) of ethyl 3,3-bis (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenate in 100 mL of dry Benzene was added at 45 ° C. under argon to 100 mg of sodium hydride (60% in mineral oil 2.5 μmol) in a single portion

grayish suspension was stirred at 45 ⁰ C for 30 minutes, then 1 ml (16.1 mmol) of methyl iodide was added, and the flask was sealed with a rubber stopper. The alkylation was allowed to continue for 40 days to 40-45 ° C for a total of ⁴ days. Analytical TLC, performed twice with 20% EtOAc in hexane, showed only two isomers

Products at R ₁ = 0.16 (major isomer) and ^r 0.22 (minor isomer). The crude reaction mixture was equal to one Volume of water, and the aqueous phase was back-extracted with 50 ml of diethyl ether. The organic layers

were combined, dried over MgSO ₄ and concentrated under reduced pressure to obtain the crude product.

The crude product mixture (5.0 g) prepared as described above was taken up in 20 ml of hot ethyl acetate,

to which 40ml of hot hexane were added. The clear solution was allowed to cool slowly to room temperature to give 2.16 g (52%) of the above compound as colorless large needles; M.p. = 144-145 "C.

IR (KBr) V _n ,,,,: 1713 (vs), 1600 (s), 1513 (s), 1325 (s), 1163 (s), 838 (s) cm ^"1;

¹ H NMR (CDCl ₃ ) δ: 7.4-6.8 (8H, m), 4.06 (2H, q, J = 7.1 Hz), 3.68 (3H, s), 1, 00 (3H, t, J = 7.1 Hz); ¹³ C NMR (CDCl ₃ ) δ: 165.44.163.6 (d, ¹ J ₀ -F = 250.7Hz), 163.4 (d, ¹ Jc-F = 252.9Hz), 156.85, 152.37, 135, 88.131.32 (d, ³ J ₀ -F = 8.3Hz), 115.94 (d, ⁹ J ₀ -F = 21.9Hz), 115.64, (d, ² J ₀ -F = 22, 7 Hz), 61.84, 33.76, 13.59 ppm;

Analysis for C ₁₉ H ₁₆ F ₂ N ₄ O ₂ : Calculated: C61.62; H4.35; N 15,13. Found: C61.63; H4,45; N 15,21. Example 4

3,3-Bls (4-fluorophenyl) -2- (1-methyMH-tetrozol-5-yl) -2-propenoic acid

To a solution of 4.0 g (10.8 mmol) of ethyl 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenate in a mixture,

containing 20ml of methanol and 20ml of tetrahydrofuran, at ⁰ ° C (ice-water bath), a solution of 3molarem

Lithium hydroxide in water (9ml). The saponification reaction continued overnight (about 16 hours), forming

a clear homogeneous solution. The analytical TLC, which was run twice with 30% ethyl acetate in hexane (v / v), showed the desired product at the starting point. The crude reaction mixture was acidified by the addition of 10 ml of 3 molar HCl solution and the organic material was extracted twice in ethyl acetate (20mIx 2). The organic layers were combined, dried over MgSO ₄ and concentrated under reduced pressure to give the product as a pale yellow solid.

Recrystallization from an EtOAc-hexane mixture (1: 9, v / v) resulted in a yield of 3.8 g (100%) of the above Connection; Mp. = 205-206 ⁰ C. IR (KBr) v _m , _x : 3438 (br), 2 900 (br), 1725 (s), 1713 (s), 1600 (s), 1501 (s), 1231 (vs), 1156 (s), 850 (s) cm " ¹

¹ H NMR (CDCl ₃ ) δ: 7.9-6.4 (8H, m), 3.68 (3H, s);

¹³ C NMR (CDCl ₃ ) δ: 166.57.163.3 (d, ¹ J ₀ -F = 249.9Hz), 163.03 (d, ¹ J ₀ -F = 250Hz), 155.68, 152.61, 125.58, 134 , 74.131.75 (d, ³ J ₀ -F = 8.3Hz), 131.28 (d, ³ J _C -F = 9.1Hz), 117.115.7 (d, ² J ₀ -F = 22, 6Hz), 115.4 (d, ² J ₀ -F = 22.6Hz), 33, ppm;

Analysis for C) ₇ H ₁₂ F ₂ N ₄ O _2: Calculated: C 59.05; H 3.53; N 16.37. Found: C59,84; H3.58; N 16,27.

Example 3,3-Bls (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl-2-propenal

A. S, -BlsH-fluorophenyl, -ti-methyl-IH-tetrazol-S-yl-propenylchloride

To a solution of 3.8 g (11,0mmol) dry (0.1 mm Hg at 80 ⁰ C) of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 2-propenoic acid in 20 mL of dry methylene chloride was added 4 mL (46.0 mmol) of purified oxalyl chloride (redistilled over CaH ₂ ) in a single portion. The reaction mixture was gradually heated at reflux temperature for two hours. The mixture was evaporated under reduced pressure to remove volatile solvent, then excess oxalyl chloride for 2 hours and then under high vacuum (0.1 mm Hg) first under vacuum (20 mmHg) at room temperature at 5O ⁰ C for 16 hours to to obtain the above-mentioned compound.

For example, 3,3-bis (4-fluorophenyl) -2 (1-methyl-1H-tetrazol-5-yl) -2-propenol

Dos acyl chloride prepared in step A was dissolved in 150ml of tetrahydrofuran and cooled to -78 ⁰ C under argon. At this blaßbreunen solution in THF solutions (1, Omolar) was added at -78 ⁰ C 8.0 ml of lithium aluminum hydride. Analytical TLC showed only one moving spot after 15 minutes at R ₁ = 0.23 (50% CtOAc in hexane v / v). The crude reaction mixture was diluted with 2M H ₂ SO ₄ (20 mL). The aqueous layer was extracted with ethyl acetate (40 ml χ 2). The organic layers were combined, dried over MgSO ₄ and concentrated under reduced pressure to give 3.64 g (100%) of the title compound. The crude allyl alcohol was used immediately in the next step without further purification.

MS (Cl): m / e = 328 for (M + H) ⁺ ;

IR (KBr) v _max : 3388 (v.br), 1600 (s), 1501 (s), 1225 (s), 1156 (s), 838 (s), 750 (s), cm " ¹ , ¹ H NMR (CDCl ₃ ) δ: 7.5-6.9 (8H, m), 4.52 (2H, br), 3.42 (3H, s), 3.75 (1H, br, D ₂ O ¹ H NMR (DMSO-d,) δ: 7.5-6.9 (8H, m), 5.23 (1H, t, J = 5.5Hz), 4.27 (2H, d , J = 5.5Hz), 354 (3H, s) ppm;

C. 3,3-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal

To a vigorously stirred solution of 3.64 g of the crude allyl alcohol (prepared in Step B) in 40 mL of methylene chloride was added at room temperature 2.6 g (12.0 mmol) of pyridinium chlorochromate in a single portion. An immediate post-analytical TLC showed about 50% of the product at Rf = 0.34 along with the starting material at R ₁ = 0.14 (eluted with 50% EtOAc: hexane v / v). The oxidation was allowed to proceed at room temperature for a total of 16 hours, with all starting material consumed and TLC showing only one product. The crude reaction suspension was filtered through a bed of silica gel, washed with one liter of 10% (v / v) ethyl acetate in hexane and one liter of 20% (v / v) ethyl acetate in hexane. The desired product crystallized at the concentration under reduced pressure to give 2.7 g (74%) of the title compound; Mp = 141-142 ° C.

MS (Cl): m / e = 326 for (M + H) ⁺ ;

IR (KBr) v _mlx : 3075 (m), 2875 (m), 1675 (s), 1600 (s), 1501 (s), 1238 (s), 1156 (s), 850 (s), 750 (s ), cm ^-1 , ¹ H NMR (CDCl ₃ ) δ: 9.63 (1H, s), 9.5-6.9 (8H, rn), 3.74 (3H, s);

¹³ C NMR (CDCl ₃ ) δ: 188.92, 165.44, 164.68 (d, 'J' = 254.4Hz), 164.10 (d, 'J _C -f = 255.9Hz), 151.34, 134.31, 133 , 77 (d, ³ J _C -f = 8.3Hz), 132.69.132,23 (d, ³ J _C -f = 7.5Hz), 123,70,116,26 (d, ² J _C - _F = 21) , 9Hz), 116.18 (d, ² J _C -f = 22.7Hz), 34.10ppm; Analysis for C ₁₇ H ₁₂ F ₂ N ₄ O:

Calculated: C62.58; H3,71; N 17,17.

Found: C, 62.41; H 3.85; N 16.98.

Example 6

5,5-bis (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazole-5-propenal (1.0 g, 3.07 mmol) and triphenylphosphoranylidene acetaldehyde (0.93 g, 3.07 mmol The benzene was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 15% (v / v) ethyl acetate in hexane to give 0.7 g of the title compound were obtained; mp = 156 to 157.5 ^0C.

Analysis for C ₁₉ Ht ₄ F ₂ N ₄ O:

Calculated: C 64.77; H 4.01; N 15.91.

Found: C 65.13; H 4.05; N 15.71.

Example 7

Ethyl 9,9-bl (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadlenate To a cooled suspension (O ⁰ C, ice water bath) of NaH (0.64 g, 16.0 mmol) (60% in mineral oil) in 20 mL of dry tetrahydrofuran was added 2.04 mL (16.0 mmol) of ethyl acetate in four equal portions. The homogeneous clear solution was stirred at ⁰ ° C. for 30 minutes, followed by dropwise addition of 6.4 ml of 2.5 molar n-BuLi (16.0 mmol) over a period of 15 minutes. The orange solution of the dianion was stirred at ⁰ ° C. for an additional ¹ hour. The Eiawasserbad was replaced by a Aoeton-dry ice bath at -78 ⁰ C, and the dianion was cannulated into a tetrahydrofuran solution (20ml), the 5,5-bis (4-fluorophenyl) -4-1-methyl-1H tetrozol-5-yl) -2,4-pentadiene al (2.82 g, 8.01 mmol). Analytical TLC showed the desired major product at Rf = 0.15 (50% EtOAc in hexane) and a byproduct at Rf = 0.2. The crude reaction mixture was diluted with 40 mL of 1N HCl and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over MgSO ₄ and concentrated under reduced pressure. The desired product was eluted by silica gel rapid column chromatography with 20% EtOAc in hexane (v / v) to give 2.26 g (58.5%) of the title compound. MS (Cl): m / e = 483 for (M + H) ⁺ .

IR (KBr) v _max : 3450 (v.br), 1738 (s), 1725 (s), 1606 (s), 1513 (vs), 1225 (s), 1163 (s), 844 (s) cm "¹; ¹ H NMR (CDCl ₃ ) δ: 7.4-6.8 (8H, m), 6.72 (1H, d, J = 15.6Hz), 4.63 (1H, m), 4, 17 (2H, q, J = 7.1Hz), 4.13 (1H, m), 3.60 (3H, s), 3.52 (1H, d, J = 3.9Hz), (D ₂ O exchangeable), 3.47 (2H, s), 2.74 (2H, d, J = 6.0Hz), 1.26 (3H, t, J = 7.1 Hz) ppm; ¹³ C NMR ( CDCl ₃ ) δ: 164.21, 135.98, 132.34 (d, ³ J _C -f = 8.3 Hz), 131.45 (d, ³ Jc _f = 9.1 Hz), 115.74 (d, ² J (M = 21.9Hz), 115.74 (d, ² J _C -r = 21.1Hz), 100.86, 67.61, 61.58, 49.85, 49.07, 33.56, 14, 10 ppm ,

Examples Ethyl (40-erythro-9,9-bl (4-fluorophenyl) -3,5-dlhydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadlanate To a solution of ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienate (2, 19 g,

4,53mmol) (dried under high vacuum at 3O was ⁰ C for 48 hours) in 40 ml of anhydrous tetrahydrofuran at ⁰ ° C (ice water bath) under argon triethylborane solution in tetrahydrofuran (4.8 ml, 4.8 mmol) in a single portion added.

The mixture was stirred under argon for a total of one hour. The ice-water cooling bath was replaced by an acetone Dry ice bath was replaced and to the reaction mixture was added NaBhU (0.20 g, 5.3 mmol) in one portion. The Reaction mixture was stirred at -78 ⁰ C for two hours stirred to form a clear, homogeneous pale yellow solution. The

crude reaction mixture was diluted with 40 mL 1N HCl, followed by extractions with EtOAc (40 mL χ 2). The organic ones

Layers were combined, dried over MgSO ₄ and concentrated under reduced pressure to give the product as a

It was further diluted with 3COmI methanol and the solution was allowed to stand at room temperature for 16 hours before evaporation under reduced pressure. The crude product was purified by silica gel.

Fast column chromatography using 2 liters of 30% EtOAc in hexanes as the eluting solvent. The

suitable fractions were collected and evaporated to give 1.48 g (68%) of the title compound. MS (Cl): m / e = 485 for (M + H) ⁺ ;

IR (KBr) v _mix : 3438 (s), 1734 (s), 1600 (s), 1513 (s), 1225 (s), 1163 (s), 844 (s), cm "¹;

¹ H NMR (DMSO-d,) δ: 7.4-7.3 (4H, m), 7.04 (2H, t, J = 8.9Hz), 6.9-6.7 (2H, m ), 6.52 (1H, dd, J = 1.16.2Hz), 5.16 (1H, dd, J = 5.6.15.7Hz), 4.89 (1H, d, J = 4 , 8 Hz), 4.72 (1H, d, J = 5.5Hz), 4.13 (1H, m), 4.04 (2H, q, J = 7.2Hz), 3.85 (1H, m), 3.75 (3H, s), 2.42 (1H, dd, J = 4.6, 16Hz), 2.28 (1H, dd, J = 8.3, 15Hz), 5.5 (1H, m), 4.2 (1H, m), 1.17 (3H, t, J = 7.2Hz); ¹³ C NMR (DMSO-d _e ) δ: 171.02,163.51,163.05,153,03,145,34,139,46,136,34,132,2 (d, ³ J _{C, F} = 8.3 Hz), 131.0 (d, ³ J _{c, f} = 9.1 Hz), 125.14, 121.64, 115.41 (d, ² J _C -f = 20.4Hz), 115.13 (d, ² J _{C, F} = 21.2Hz), 67, 79,64,76,59,50,44,10,42,34,33,44,14,01 ppm;

Calculated: C 61.98; H 5.4 '; N 11.56

 Found: C 61.51; H5.67; N 11,12.

Example 9 Sodium (+) - Efythro-9,9-bl (4-fluorophenyl) -3,5-dlhydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadlenate To a solution of ethyl 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienate (1.231 g.

2.54 mmol) in 35 ml of tetrahydrofuran are added dropwise at ⁰ ° C 2.54 ml of 1N NaOH solution (1.0 equivalent). The

Addition rate should be slow enough to prevent the reaction mixture from becoming dark yellow in color

or reddish changes. The reaction mixture was stirred at ⁰ ° C for 30 minutes to give a clear homogeneous

Solution. The reaction mixture was allowed to warm to room temperature and saponification continued for an additional 1 hour. Analytical TLC eluting with 20% MeOH in CHCl ₃ (v / v) indicated the desired product at R ₍ = 0.2 Part of the organic solvent (20mmHg) was evaporated at about 1O ⁰ C under reduced pressure. The resulting

thick syrup was diluted with 4 ml of water and then the solution was freeze-dried at 0.01 mmHg to obtain 1.126 g (100%) of the above-mentioned compound in the form of the sodium salt, which apparently contains about 1 mol of water; Mp.

> 100 ° C decomposition.

IR (KBr) v _m ": 3400 (v. Br), 1600 (s), 1576 (s), 1513 (s), 1438 (s), 1404 (s), 1222 (s), 1156 (s), 838 (s) cm "¹;

¹ H-NMR (DMSO-d _e ) δ: 7.3-7.4 (4H, m), 7.06 (1H, br, D ₂ O interchangeable), 7.00-7.06 (2H , m), 6.87-6.91 (2H, m), 6.49 (1H, d,

J = 15.7 Hz), 5.13 (1H, dd, J = 5.4, 15.7 Hz), 5.05 (1H, br, D ₂ O interchangeable), 4.14 (1H, m) , 3.74 (3H, s), 3.62 (1H, m), 1.99 (1H, dd, J = 3.7, 13.5Hz), 1.80 (1H, dd, J = 8.5, 13.5Hz), 1.43 (1H, m), 1.30 (1H, m);

¹³ C NMR (DMSO-d ₆ ) δ: 175.87.161.85 (d, ¹ J _C - _f = 246.1 Hz), 161.37 (d, ¹ Jc-F = 246.9Hz), 153.098, 144.97, 139 , 88.136, 40.135, 51.132, 22 (d, ³ J _C -f = 8.3 Hz), 130.97 (d, ³ J _C -f = 8.3 Hz), 124.86, 121.74, 15.42 (i.e. , ² J _C -f = 21.9 Hz), 115.12 (d, ² J _C -f = 23.4 Hz), 68.23, 65.71, 44.50, 43.55, 33.45 ppm ;

Analysis: for C ₂₃ H ₂₎ F ₂ N ₄ O ₄ Na H ₂ O: Calculated: C 55.64; H 4.67; N 11,28. Found: C55.24; H4,65; N 10.85.

Example 10 Trens-6- [4,4-bl (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadyl enyl] tetrahydro-4-hydroxy-2H -pyran-2-one

A. (+) - Erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadlenic acid

A solution of ethyl (±) -ethro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5yl) -6,8-nonadienate (0 , 64 g, 1.32 mmol) in 25 ml of tetrahydrofuran was treated at ⁰ ° C with 1.32 ml of 1.0 molar NaOH solution. The pale yellow suspension was stirred at 0 ° C for two hours to give a clear light yellow solution. The crude reaction mixture was diluted with 5 mL aqueous HCl solution (2N) and the organic material was extracted into ethyl acetate (40 mL χ 2). The organic extracts were combined, dried over MgSO ₄ and concentrated under reduced pressure to give a pale yellow gum. The crude dihydroxyacid was extensively dried under high vacuum (0.01 mmHg at room temperature for 24 hours) before being subjected to the next reaction step.

Trans-6- [4,4-bls (4-fluorophogyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran -2-one

The dry acid of Step A above was dissolved in 100 mL of dry methylene chloride under argon at room temperature, followed by the addition of 1.7 g (4.0 mmol) of 1-cyclohexy! -3- (2-morpholinoethyl) carbodiimide-metho-p-toluenesulfonate , The lactonizer was complete in less than 15 minutes, as indicated by analytical TLC (Rf = 0.12), eluting three times with 50% ethylene acetate in hexane. Most of the solvent was evaporated under reduced pressure and the residue was washed with water (40 ml), followed by extractions with ethyl acetate (40 ml x 2). The organic layers were combined, dried over MgSO ₄ and concentrated under reduced pressure to give 0.54 g (89.7%) of the product. A pure sample of the product was obtained by passing through a short bed of silica gel eluted with 40% ethyl acetate in hexane (v / v) to give the title compound, which appears to contain about 2 moles of water. MS (Cl): m / e = 438 for (M + H) ⁺ .

IR (KBr) v _max : 3425 (br), 1738 (vs), 1600 (s), 1513 (s), 1225 (vs), 1156 (s), 1033 (s), 838 (s) cm "¹;

¹ H NMR (CDCl ₃ ) δ: 7.26-7.21 (2H, m), 7.14 (2H, d, J = 8.7Hz), 6.86 (4H, d, J = 6.8Hz ), 6.72 (1H, dd, J = 0.8, 15.6Hz), 5.34 (1H, dd,

J = 7.1,15.6Hz), 5.18 (1H, m), 4.37 (1H, m), 3.57 (3H, s), 2.68 (1H, dd, J = 4, 5,18Hz), 2.60 (1H, ddd, J = 3.63, i, 5,18Hz), 2.44 (1H,

d, J = 2.6H "D ₂ O interchangeable), 2.00 (1H, dt, J = 18.1.7Hz), 1.79 (1H, td, J = 2.7.18Hz) ppm.

¹³ C NMR (CDCl ₃ ) δ: 169.20, 166.162, 5.53, 1.48, 81.135, 61.134, 95, 132.45 (d, ³ J _C -f = 8Hz), 132.52, 131.51 (d, ³ Jc- = 8Hz , 130.04, 204.15, 15.95 (d, ² J _C -f = 21.9Hz), 115.83 (d, ² J _{C, F} = 21.9Hz), 75, 67, 62, 54, 38, 58.35, 58.33, 64 ppm;

Analysis for C ₂₃ H ₂₀ F ₂ N ₄ O ₃ 2H ₂ O: Calculated: C58.22; H5.10; N11.81. Found: C59.06; H4.45; N 11,25. A sample of the above lactone was crystallized from cyclohexane-benzene to give the title compound as a crystalline solid,

containing about 1 mole of benzene was obtained; Mp = 105-106 ° C.

Analysis for C ₂₃ H ₂₀ F ₂ N ₄ O ₃ C ₆ H _8: Calculated: C67.48; H 5.07; N 10.85. Found: C, 67.44; H 5,23; N 10.59. Example 11

4,4'-Dilluor-3,3'-dlmethylbenzophenon

2-Fluorotoluene (8 mL, 73 mmol) was added to a vigorously stirred mixture of aluminum chloride (61.43 g, 460 mmol) and

Carbon tetrachloride (135ml) added at ⁰ ° C. After 10 minutes, 2-fluorotoluene (92 mL, 837 mmol) in Carbon tetrachloride (75m ¹⁾ was added dropwise over 4 hours and the mixture was for 2 hours at ⁰ ° C.

touched. WARNING: A s | Iontane violent reaction proceeded after the addition of 2-fluorotoluene. The mixture was cooled to -2O ⁰ C and quenched with 2N HCl (250 ml). The organic layer was separated, washed with brine and dried (MgSO ₄ ). The solvent was removed by evaporation and the residue was dissolved in benzene (200 ml) and treated with water (200 ml) and acetic acid (50 ml). After being stirred for 15 hours, the organic

Layer separated, dried (MgSO ₄ ) and evaporated. Crystallization from ethanol provided 50 g (49%) of the title compound;

Mp. = 128-130 ⁰ C.

IR (KBr) v _m, "165OCnT. ¹

¹ H NMR (CDCl ₃ ) δ: 7.66 (d, J = 7.3Hz, 2H), 7.58 (m, 2H), 7.09 (t, J = 8.8Hz, 2H), 2, 32 (s, 6H).

Analysis for C ₁₆ H ₁₂ F ₂ O: Calculated: C73.16; H4.91. Found: C, 72.96; H 4.80. Example 12

1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyMH-tetrazol-5-yl) ethanol

A solution of 1,5-dimethyltetrazole (2.55 g, 26 mmol) in dry tetrahydrofuran (15 mL) at -7P ⁰ C with n- Butyllithium (12.5ml of a 2.5M solution in hexane, 31.2mmol) was treated and the mixture was stirred for 15 minutes.

4,4'-Diifluoro-3,3'-dimethylbenzophenone (5g, 20.3mmol) in dry tetrahydrofuran (20ml) was added, the mixture was stirred for 1 hour and then quenched with 2N HCl (250ml). The aqueous phase was extracted with ethyl acetate (3x50ml) and the combined organic layers were dried (MgSO ₄ ) and evaporated. The residue was through

Silica gel column chromatography purified using 20% (v / v) EtOAc-hexane as eluent, giving 3.7 g (52%).

of the product. Recrystallization from EtOAc-Hexrn gave the title compound; Mp 41-42 ° C.

IR (KBr) v _{m x,:} 3400 (br) cm ^"1;

¹ HNMR (CDCl ₃ ) δ: 7.20 (d, J = 7.1Hz, 2M), 7.10 (m, 2H), 6.88 (t, J = 8.6Hz, 2H), 4.84 (s, 1H), 3.77 (s, 3H), 3.71 (s, 2H), 2.20 (s, 6H);

Analysis for C ₁₈ H ₁₈ F ₂ N ₄ O: Calculated: C 62.79; H 5,27; N 16,27. Found: C, 62.73; H 5.32; N 16,16. Example 13

1,1-bis (4-fluoro-3-melhylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) Uthen

A mixture of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (3.58 g, 10.9 mmol) and Potassium hydrogen sulfate (530 mg) was heated ⁰ C for 1.5 hours at 195th The mixture was cooled to 70 ⁰ C and Chloroform (50 ml) was added. The insoluble material was separated by filtration and the filtrate became

evaporated. The residue was crystallized from EtOAc-hexane to give 3.38g (100%) of the title compound; = 138-139 ⁰ C.

¹ H NMR (CDCl ₃ ) δ: 7.20-6.80 (m, 6H), 6.65 (s, 1H), 3.56 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H).

Analysis for C ₁₈ Hi ₈ F ₂ N ₄ : Calculated: C66.25; H4.95; N 17,17. Found: C66.15; H5.05; ΝΠ.24. Example 14

3,3-Bls (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal

A solution of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyltetrazol-5-yl) ethene (3.58 g, 11.0 mmol) in dry tetrahydrofuran (20 mL) was at -78 Treated ⁰ C with n-butyllithium (5.3 ml of a 2.5 M solution in hexane, 13.25 mmol) and the mixture w de stirred at -78 ⁰ C for 0.5 hours. Ethyl formate (1.33 mL, 1.22 g, 16.5 mmol) was added and the mixture was allowed to warm to 23 ⁰ C over 1 h, then quenched with 2 N HCl (250 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 ml) and the combined organic layers were dried (MgSO ₄ ) and evaporated. The residue was purified by chromatography using 20% EtOAc-hexane as eluent,

which gave 2.2 g (57%) of the title compound in the form of a foam. MS (CI): m / e = 355 for (M + H) *;

IR (KBr) _vmtx : 1660cm "¹;

¹ H NMR (CDCl ₃ ) δ: 9.62 (s, 1H), 7.25-7.05 (m, 3H), 6.85-6.65 (m, 3H), 3.73 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H).

Analysis for C) ₉ HItF ₂ N ₄ O: Calculated: C 64.41; H 4.56; N 15,82. Found: C64.60; H4.70; N 15.62. Example 15

1.1 Bls {2,4-dlmethylphenyl) -2- (1-methyMH-tetrazol-5-yl) ethanol.

A solution of 1,5-Dimethyltetrazol (8.9 g, 91.0 mmol) in dry tetrahydrofuran was added n-10OmI at -6O ⁰ C with Butyllithium (48ml of a 1.89M solution, 91.0mmol). After stirring for 20 minutes, 2.2 ', 4.4' Tetramethylbenzophenone (18 g, 76 mmol) (prepared by the method described in J. Am. Chem. Soc., 81, 48858 (1959);

is described] was added in 50 ml of dry tetrahydrofuran and the solution was stirred for 1 hour, it was allowed during this time, the solution to warm to -20 ⁰ C. The reaction was quenched with 1N HCl and then extracted with chloroform. The combined organic extracts were dried (MgSO ₄ ) and evaporated, with 22 g of the

Titol compound were obtained; Mp = 175-177 ° C. IR (KBr) v _mix : 3390 (br), 1620 (s), 1460 (s), 1200 (s), 820 (s) cm "¹;

¹ H NMR (CDCl ₃ ) δ: 7.26 (2H, d), 6.95-6.83 (4H, m), 4.00 (1H, s), 3.82 (2H, s), 3 , 41 (3H, s), 2.23 (6H, s), 1.83 (6H, s) ppm; ¹³ C NMR (CDCl ₃ ) δ: 152.34, 139.28, 137.32, 125.79, 133, 216, 126, 25, 92, 77, 47, 35, 64, 32, 22, 21, 28, 28, 28 ppm;

Analysis for C ₂₀ H ₂₄ N ₄ O: Calculated: C 71.41; H 7,20; N 16.67. Found: C70.82; H7.26; J 16:45. Example 18

I.I-Bisia ^ ^ -dlmethylphenyD -d-methyl-IH-tetrazcl S yüethen.

A mixture of 1,1-bis (2,4-dimethylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (1.8 g, 5.4 mmol) and Potassium bisulfate (100 mg), contained in a 50 ml flask, was placed in an oil bath, which was heated to 190 ° C

was preheated. After 15 minutes, the melt was cooled and methylene chloride added to the residue. The insoluble

Ingredients were removed and the solution evaporated. The residue was crystallized from isopropylevher to give 1.2 g

of the title compound: mp = 143 to 143.5 ^0C.

IR (KBr) v _{m, x} 2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 820 (s), 740 (s) cm ^"1;

¹ H NMR (CDCl ₃ ) δ: 7.15-6.80 (6H, m), 6.60 (1H, s), 3.40 (3H, s), 2.36 (3H, s), 2 , 30 (3H, s), 2.18 (3H, s), 1.85 (3H, s) ppm; ¹³ C NMR (CDCl ₃ ) δ: 154, 18, 152, 21, 138, 54, 138, 38, 138, OG, 135, 67, 135, 170, 129, 129, 129, 129, 129, 125, 131, 16, 16, 21, 12, 12, 12, 12, 12 , 20.69, 19.95 ppm;

Analysis for C ₂ OH ₂₂ N ₄ : Calculated: C 76.45; H 6,97; N 17.60. Found: C75.04; H7.03; N 17.63. Example 17

3,3-bis (2,4-dimethylphenyl) -2- (1-methyMH-tetrazol-5-yl) -2-propenal.

A solution of 1,1-bis (2,4-dimethylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (1.0 g, 3.1 mmol) in 10 mL of dry Tetrahydrofuran was treated with n-butyllithium (1,64ml of a 1.89 M solution, 3.1 mmol) at -78 ⁰ C. After 30 minutes Stirring under cooling, ethyl formate (0.3 g, 4.0 mmol) was added, and the mixture was stirred under cooling for 2 hours. The reaction was quenched with 1N HCl and then extracted with chloroform. The combined organic Fractions were dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography on silica gel

Purified, eluting with 10% (v / v) ethyl acetate in hexane to give 0.9 g of the product as an oil. Trituration of the oil with isopropyl ether gave the title compound as a solid; M.p. = 117-12O ⁰ C. MS (Cl): m / e = 347 for

¹ H NMR (CDCl ₃ ) δ: 9.58 (1H, s), 7.25-6.78 (7H, m), 3.70 (3H, s), 2.40 (3H, s), 2.25 (3H, s), 2.20 (3H, s), 1.90 (3H, s) ppm; "C NMR (CDCl ₃ ) δ: 189.49, 168.80, 151, 05, 150, 87, 140, 26, 137, 16, 135 , 86,134,87,133,28,132,04,129,60,129,62,125,28,34,17,21,21,21,06,20,37,20,07ppm;

Analysis: for C ₂₁ H ₂₂ N ₄ O: Calculated: C72.81; H6.41; N 16,18. Found: C72.99; H6.43; N 16.09. Example 18

3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal.

A. 1,1-B! S (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol To a solution of 1,5-Dimethyltetrazol (0.98 g, 10.0 mmol) in tetrahydrofuran (20ml) was added ⁽⁰ C n-butyl lithium at -3O 4.7 ml

a 2.14 M solution, 10.0 mmol). After stirring for 0,25 hours, the solution was cooled to -5o C and ⁰ eswurde 4,4'-difluorobenzophenone (1.74 g, 3.0 mmol) was added. After stirring for one hour at -50 ° C and after one hour

Stirring at -10 ° C, the reaction was quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride,

dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 40% (v / v) ethyl acetate in hexane to give 2.0 g of the title compound; Mp. = 116-118 ⁰ C.

Analysis: for Ci ₈ H ₁₄ F ₂ N ₄ O: Calculated: C60.7C; H4.47; N 17,72. Found: C60.62; H4.52; N 17.63. B. 1,1-Bls (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene A mixture of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (4.2g, 12.7mmol) [prepared in step A] and Potassium bisulfate was heated at 195 ^° C. for 0.5 hours. After cooling, the mixture was dissolved in chloroform

and washed with water. The organic layer was dried and evaporated in vacuo. The residue was with

Triturated diethyl ether to give 3.9g of the title compound; Mp. = 169-171 ⁰ C. Analysis for C ₁₆ H ₁₂ F ₂ N ₄ : Calculated: C 64.43; H 4.06; N 18,88. Found: C 63.93; H 4,00; N 19,25. C. 3,3-Bls (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal

To a finely divided suspension of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (1.0 g, 3.3 mmol) (prepared in Step B) in tetrahydrofuran (10ml) at -80 ° C n-butyllithium (1.54ml of a 2.14M solution, 3.3mmol) was added to afford a dark violet color. After stirring for 40 minutes at -80 ⁰ C, ethyl formate (0.32 g, 4.3 mmol) was added and the mixture stirred at -8O ⁰ C for 2.5 hours. The mixture was hydrolyzed with 1N hydrochloric acid and extracted with methylene chloride. The extracts were dried (MgSO 4) and evaporated in vacuo. The residue was triturated with diethyl ether to give 0.77 g of a yellow solid, mp. 128-131 ⁰ C, resulted. The solid was crystallized from isopropyl acetate-hexane to give 0.55 g of the title compound; Mp = 130-132 ⁰ C. Analysis for C _n H ₁₂ F ₂ N ₄ O: Calculated: C, 62.58;. H 3.71; N 17,18

 Found: C 62.15; H, 3.82; N 16.75.

Example 19 3,3-Bis (4-fluorophenyl) -2- (1-methyl-1H-totazol-5-yl) -2-propanol

A. 5-ethyl-1-methyl-tetrazole

To a slurry of 1,5-dimethyltetrazole (4.9g, 0.05mol) in dry tetrahydrofuran (50ml) was added 2.5M n-butyllithium in hexane (20ml, 0.05mol) over a period of 15 minutes. 78 ⁰ C added under an inert atmosphere. This mixture was stirred for 30 minutes during which time a yellowish precipitate formed. Thereafter, methyl iodide (3.7 ml, 0.06 mol) was added over a period of 15 minutes. After stirring for a further 30 minutes, the clear reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 ml). The aqueous layer was washed with chloroform (2 x 25 ml) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil was purified by distillation to give 5.2 g (92%) of the title compound; Bp. = 89-9O ⁰ C at 0,05mmHg

¹ HNMR (CDCl ₃ ) δ: 4.05 (s, 3H), 2.86 (q, 2H), 1.41 (t, 3H), ¹³ C NMR (CDCl ₃ ) δ: 156.0 , 33,24,16,75,11,20.

For example, 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propanol To a solution of 5-ethyl-1-methyl-1H-terazole (5.6 g, 0.05 mol) [prepared in step A) in 60 mL of dry tetrahydrofuran

was 2.5 M n-butyllithium (20 ml, 0.05 mol) in hexane for 5 minutes at -78 ⁰ C (bath temperature) under a

Inertatmosphäre added. The mixture was stirred for 30 minutes and a solution of 4,4'-difluorobenzophenone

(10.8 g, 0.5 mol) in 25 mL of dry tetrahydrofuran was added over 5 minutes. This mixture was stirred for a further ² hours while the bath temperature was slowly warmed to -20 ° C. The reaction was quenched with 1N HCl and then extracted with ethyl acetate (3 × 50 ml) and chloroform (3 × 50 ml). The combined organic layers were over

Dried sodium sulfate and concentrated under reduced pressure to give a wise solid. The solid

was purified by crystallization from ethanol-hexane to give 10.8 g (65%) of the title compound. m.p. = 160-161 ⁰ C.

IR (KBr) v _{m, x:} 3400cm ^"1;

¹ H NMR (CDCl ₃ ) δ: 7.8-7.02 (m, 8H), 5.95 (s, 1H), 4.65 (q, 1H), 3.98 (s, 3H) , 1,29 (d, 2H).

¹³ C NMR (CDCl ₃ ) δ: 162.57,162.37,159,14,156.71,142,48,140,54,128,25,128,13,127,52,127,42,114,67,114,41,114,38,78,56,36,99,33,43,14 , 52nd

Analysis for C ₁₇ Ht ₆ F ₂ N ₄ O: Calculated: C61.81; H4.88; N 16.96. Found: D61.79; H4.90; N 17,09. C. 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-propene A slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -propanol (8.25g, 0.025 mol) [prepared in Step B] and 100 mg of p-toluenesulfonic acid monohydrate in xylene (60 ml) was treated with a Dean & Stark Wasserabscheidungsapparat heated for a period of 12 hours to reflux. The reaction mixture was while they were

was warm, washed with 1N NaOH (10 ml) and with water (100 ml). Concentration of the organic layer gave off-white crystals of the product. This was purified by recrystallization from ethanol-hexane to give 7.1 g (91%) of the title compound as white crystals; Mp. = 146-147 ⁰ C.

IR (KBr) v _mlx : 1575; 1500cm " ¹

¹ H NMR (CDCl ₃ ) δ: 742-6.85 (m, 8H), 3.53 (s, 3H), 2.14 (s, 3H, 2.14 (s, 3H);

¹³ C NMR (CDCl ₃ ) 6: 163.36, 163.08, 160.13, 15.5, 61.144, 60.145, 34.136, 47, 136, 42, 136, 14, 136, 19, 31, 65, 131, 54, 311, 311, 31, 11, 15, 16, 13, 31, 151, 15, 21, 13 , 50,21,20.

AnBIySOfUrCi ₇ Hi ₄ F ₂ N ₄ : Calculated: C 65.37; H 4.51; N 17,94. Found: C65.64; H4,61; N 18.09. D. 3,3-Bls (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene

A slurry of 1,1-bis (4-fluorophenyl-2- (1-methyl-1H-tetrazol-5-yl) -1-propene (61.46 g, 0.197 mol) (prepared in step C), N-bromosuccinimide (35.06g, 0.197 mol) and a catalytic amount of azobisisobutyronitrile or benzoyl peroxide in carbon tetrachloride (1.21) was heated to reflux in an inert atmosphere for 2 hours The reaction mixture was cooled to room temperature and the solid from the reaction The filtrate was concentrated under reduced pressure and the resulting solid was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals, mp = 159-160 ° C

¹

Ή NMR (CDCl ₃ ) δ: 7.5-7.1 (m, 8H) ₁ 4.44 (s, 2H), 3.53 (s, 3H).

¹ H NMR (CDCl ₃ ) δ: 163, 94.163, 74, 160, 60, 165, 43, 42, 149, 129, 313, 31, 31, 130, 130, 130, 15, 131, 17, 115, 94, 157, 171, 15, 15, 15, 15.50

Analysis for C ₁₇ H _n F ₂ BrN ₄ : Calculated: C 52.19; H 3.34; N 14.32

 Found: C52.58; H3.46; N 14,49.

E. 3,3-Bls (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal

To a solution of sodium etherate (3.93 g of sodium metal, 0.17 mol) in 500 mL of absolute ethanol was added 2-nitropropane (16.66 g, 0.187 mol) slowly over 5 minutes. The bromine compound (67.1 g, 0.17 mol) prepared in the above reaction step D was added portionwise over a period of 10 minutes. The reaction mixture was stirred for 2 hours and the ethanol was removed in vacuo. The residue was dissolved in CH ₂ Cl ₂ (500 ml), washed with water (250 ml) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give an oil. The oil was dissolved in hot toluene (350 ml) and trituration with hexane (350 ml) gave 50.6 g (91%) of the title compound as white crystals; Mp = 135-137 ° C.

Example 20

[1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-propen-3-yl) trlphenylphosphonlum-Bromld

A slurry of 3,3-bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene (1.95 g, 0.005 mol) (prepared

in Example 19, step D] and triphenylphosphine (1.3g, 0.005 mol) in cyclohexane (25ml) was heated to reflux. The

Reaction mixture became a clear solution after 30 minutes and after 1 hour a white precipitate appeared. The Mixture was heated for an additional 8 hours, cooled to room temperature and the solid was filtered off

collected and washed with diethyl ether. This white powder was dried in vacuo at 50 ° C to give 3.0 g (92%) of the title compound; Mp. = 254-255 ⁰ C.

IR (KBr) v _{m, x:} 3450,1600,1500,1425cm ^'1.

¹ H NMR (DMSO-de) δ: 7.92-6.80 (m, 23H), 4.94 (6d, 2H), 3.83 (s, 3H);

¹³ C NMR (DMSO-de) δ: 163.53,163.36,160,23,160,87,154,04,153,19,152,76,135,11,134,79,134,16,133,68,133,54,130,53,130,45,130,35,130,21,130,07,118,02,116,89,116, 18,115,89,115,62,115,62,111,43,111,39,34,22,28,88,28,22.

Analysis for C ₃₅ H ₂₈ BrF ₂ N ₄ P: Calculated: C 64.31; H 4,32; N 8,57. Found: C64.02; H4,37; N8.89. Example 21 Methyl (±) -Erythro-9,9 · bis (4 · fluorophthyl) · 3,5-dihydroxy-8- (1-methyl · 1H-tθtrazol · 5-yl) 6,8-nonadioinate To a slurry of phosphonium bromide (0.326 g, 0.5 mmol) (prepared in Example 20] and Msthyl-erythro-3.5-

bis (diphenygl-t-butylsilyloxy) -6-oxohexanate (prepared by the general method as described by P. Kapa et al

Tetrahedron Letters, 2435-2438 (198) and U.S. Patent No. 4,571,428, issued February 18, 1986 to P.K. Kapa

[0.26 g, 0.4 mmol] in dry dimethylformamide (1 mL) was added potassium t-butoxide (0.067 g, 0.6 mmol) at -20X (bath temperature) in an inert atmosphere. The slurry was stirred a red solution and wurde18 hours at 10 ⁰ C. The reaction was followed by addition of aluminum chloride solution (10ml) and extraction

Methylene chloride (2 χ 30ml) continued. The organic layer was dried over sodium sulfate and concentrated,

whereby an oil resulted. The oil was purified through a pad of silica gel and the major fraction was isolated as an oil (160mg). The oil (160mg) was stirred with 1M tetra-n-butyl-ammonium fluoride solution in tetrahydrofuran (2ml) and a few drops of glacial acetic acid over a period of 18 hours. The reaction mixture was poured into water (10 ml) and washed with

Extracted ethyl acetate (3 χ 20ml). The organic layer was dried over sodium sulfate and concentrated to add an oil

result. The oil was purified by silica gel rapid column chromatography eluting with ethyl acetate: hexane (2: 1) to give 0.08 g (75%) of the title compound as an oil.

¹ H NMR (CDCl ₃ ) δ: 7.26-6.6 (m, 9H), 5.37 (dd, 1H), 4.44 (m, 1H), 4.24 (m, 1H ), 3.71 (s, 3H), 3.56 (s, 3H), 2.47 (d, 2H), 1.58 (m, 2H).

A more polar fraction was also isolated (20 mg) and identified as the corresponding trans-lactone. Example 22

4,4'-Dlfluor-2,2'-dlmethylbanzophenon

To a well-stirred mixture of aluminum chloride (6.1 g, 46.0 mmol) in carbon tetrachloride (14 mL) at ⁰ ° C was added 3-fluorotoluene (1 g from a total of 10 g, 90.0 mmol) and the mixture became Stirred for 10 minutes. The remainder of the 3-fluorotoluene was added in 9 ml of carbon tetrachloride and the mixture was stirred at ⁰ ° C. for 4 hours. The mixture was cooled to -20 ° C and hydrolyzed by the addition of 25 ml of 1N hydrochloric acid. The organic layer was separated and concentrated in vacuo. The residue was stirred for 16 hours with a mixture of benzene (20 ml), water (20 ml) and acetic acid (5 ml). The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were dried (MgSO ₄ ) and concentrated in vacuo. Analytical TLC of the residue showed 3 spots; R | = 0.67, 0.05 and 0.56 [6% (v / v) ethyl acetate in hexane on silica gel]. Column chromatography on silica gel with 0.5% (v / v) ethyl acetate in hexane and collection of the appropriate fractions, the material with the R ₁ -WeH of 0.67

[5% (v / v) ethyl acetate in hexane]; _{1 liter} 3g of the title compound: mp. = 50-52 ^<> C.MS (C): m / e = 247for (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ: 7.26 (2H, dd), 6.96 (2H, dd), 6.87 (2H, dt), 2.42 (6H, s)

Analysis for C ₁₆ Hi ₂ FiO: Calculated: C 73.17; H 4.92

 Found: C73.34; H 5,02.

Example 23

1,1-Bls (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanc

To a suspension of 1,5-dimethyltetrazole (3.8 g, 39.0 mmol) in tetrahydrofuran (40 mL) was butyl lithium at -40 ° C

(17.7 ml of a 2.2M solution, 39.0 mmol). After stirring for 10 minutes, 4,4'-difluoro-2,2'-dimethylbenzophenone (8 g, 32.5 mmol) was added and the solution was stirred for 3 hours. The reaction was quenched with 1N hydrochloric acid. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases dried (MgSO ₄ ) and im

Concentrated to give 7.5 g of the title compound; Mp = 186-188 ° C. Analysis for Ci ₈ Hi ₈ F ₂ N ₄ O: Calculated: C62.99; H 5,27; N 16,27 Found: C63.01; H5.34; N 16,18. Example 24

1,1-bis (4-fluoro-2-methylphBnyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene

A mixture of 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (0.5 g, 1.5 mmol) and

p-Toluenesulfonic acid (0.2 g) was heated in toluene (30 ml) under reflux for 16 hours. The mixture was cooled, with

Diethyl ether (50ml) and extracted with saturated sodium bicarbonate solution and water. The organic layer

was dried (MgSO ₄ ) and concentrated in vacuo. The residue was triturated with diethyl ether, whereby 0.3 g of the

Title compound gave; Mp = 12O-125 ° C. Analysis for Ci ₈ HIeF ₂ N ₄ : Calculated: C66.25; H4,95; N 17,17 Found: C66.55; H4,92; N 16.84. Example 25

3,3-Bls (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal

To a solution of 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (1.6 g, 5.0 mmol) in tetrahydrofuran

Butyllithium (2.3ml of a 2.2M solution, 5.0mmol) was added at -70 ° C. After stirring for 0.25 hours

Ethyl formate (0.44 g, 6.0 mmol) was added and the mixture was stirred for 2 hours. The reaction was with 1N Hydrochloric acid was extinguished and the mixture was extracted with methylene chloride. The extracts were dried and in vacuo

concentrated to give 1.0 g of the title compound; Mp. = 135-136 ⁰ C.

Analysis for Ci ₉ Hi ₆ F ₂ N ₄ O: Calculated: C 64.41; H 4.56; N 15,82 Found: C64.22; H4.59; N 15.50. Example 26 A solution of 3,3-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (0.88 g, 2.5 mmol) and Triphenylphosphoranylidene acetaldehyde (0.75g, 2.5mmol) in benzene (50ml) was heated at reflux for 3 hours. The Solvent was evaporated and the crude residue was purified after column chromatography on silica gel, at 1%.

(v / v) methanol was eluted in methylene chloride, purified. The fractions containing the material with an Rf value of 0.9 [1:20 (v / v)

Methanol-methylene chloride] were combined and concentrated to give 0.8 g of the title compound;

Mp = 75-95 ⁰ C. MS: M = 380 ·;

¹ H-NMR (CDCl ₃ ) δ: 9.25 (1H, d), 7.30-6.67 (7H, m), 5.82 (1H, dd), 3.62 (3H, s), 2.23 (3H, s) 2.00 (3H, s).

Analysis for C ₂₎ Hi ₈ F ₂ N ₄ O: Calculated: C66.31; H4.78; N 14.73 Found: C 65.76; H, 4.85; N 14.52. Example 27

tert-Butyl9,9-bls (4-fluoro-2-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadlenat

To a solution of 5,5-bis (4-fluoro-2-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal (1.0g, 2.5mmol) in Tetrahydrofuran was added at -50 ⁰ C, the dianion of t-butyl acetoacetate (2.5 ml of a 1M solution, 2.5 mmol), which

by addition of t-butyl acetoacetate (4.0g, 25,0mmol) in tetrahydrofuran (4 ml) in a suspension of sodium hydride (60% dispersion 1,0geiner, 25.0 mmol) in tetrahydrofuran at -5 ⁰ C, followed by cooling to -3O ⁰ C and the addition of

Butyllithium (11.4ml of a 2.2 M solution, 25mmol) was prepared. After stirring for 1.5 hours, the analytical showed TLC to the starting point, and aldehyde and further O ₁ SvM of the dianion solution were added. The solution became more

Stirred for 0.5 hours and quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol in methylene chloride to give the title compound (0.6g); Mp = 65-72 ⁰ C.

Analysis for C ₂₉ H ₃₂ F ₂ N ₄ O ₄ : Calculated: C 64.68; H 5.99; N 10.41 Found: C64.50; H5.98; N 10,16. Example 28

tert-buty (±) -γγ1ΙΐΓθ-9,9-ω3 (4 × ρυοΓ · 2 × ΓηΘΐΗνΙ · ρΚΘηγΙ) × 3.5 ×:) ΙΗ, γαΓθχν × 8- (1-ΓηβΙΙιγΙ-1Η-ΙθΐΓ8ζοΙ · 5 · νΙ ) · 6.8 · ηοηβϋΙΰη8ΐ

To a solution of t-butyl 9,9-bis (4-fluoro-2-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8 -nonadienat

(2.6g, 4.6mmol) in tetrahydrofuran (30ml) was added at -5 ° C triethylborane (6.0ml of a 1M solution, 6.0mmol) and the

Solution was stirred for 1 hour. After cooling to -78 ° C, sodium borohydride (0.36 g, 9.0 mmol) and methanol (2 mL) were added.

added. The mixture was stirred at -78 ⁰ C for 2 hours and extracted with hexane (15ml) and washed. The mixture was treated with 1N

Hydrochloric acid hydrolyzed. The aqueous layer was separated and extracted with methylene chloride. The combined organic Solutions were dried and concentrated in vacuo. The residue was dissolved in methanol and the solution

Stirred for 18 hours. The solution was concentrated in vacuo and the residue was purified by column chromatography

Silica gel, eluting with 1% (v / v) methanol in methylene chloride, to give 1.7 g of the title compound in the form

a white powder; Mp = 75-80 ° C.

¹ H-NMR (CDCl ₃ ) δ: 7.15-6.60 (7H, m), 6.43 (1H, d), 5.26 (1H, dd), 4.42 (1H, m) , 4.18 (1H, m), 3.92 (1H, s), 3.64 (3H, s), 2.39 (2H, d), 2.26 (3H, bs), 2.04 (3H, s), 1.57 (2H, m), 1.43 (9H, s);

AnBlySOfuRC ₂₉ H ₃₄ F ₂ N ₄ O ₄ : Calculated: C 64.44; H 6,34; N 10.37 Found (corr. For O, 28% H ₂ O): C64.14; H6,41; N 10,16. Example 29 Sodium (±) -erythro-9,9-bls (4-fluoro-2-methylphenyl) -3,5-dlhydroxy-8- (1-methyl-1H-tetrazol-5-yl)-e, 8-nonadlenate To a solution of t-butyl 9,9-bis (4-fluoro-2-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienate (1.65 g,

3.05mmol) in ethanol (50ml) was added sodium hydroxide (3.05ml of a 1N solution, 3.05mmol) and the solution was stirred at room temperature for 3 hours and at 50 ° C for 1 hour. The solution was concentrated in vacuo to yield 1.3 g of the title compound, which apparently contains about 1 mole of water; Mp = 215-225 ° C Hers.).

Analysis for C ₂₆ H ₂₅ F ₂ N ₄ O ₄ Na H ₂ O: Calculated: C 57.26; H 5:19; N 10.69 Found: C 57.30; H 5.20; N 10.00. Example 30

2,2'-4,4'-dimethylbenzophenone Dlfluor-

Concentration of suitable fractions of the silica gel column chromatography of Example 22 containing the material with the Rp value of 0.56, and trituration of the residue with hexane gave 1.2 g of the title compound; Mp = 84-85.5 ° C.

¹ H NMR (CDCl ₃ ) δ: 7.57 (2H, t, J ₁₄ -H = 8Hz, J m = 8Hz), 7.02 (2H, d, J _H "= 8Hz), 6.89 (2H, d, J _fH = 8Hz), 2.39 (6H, s).

Analysis for C ₁₆ H ₁₂ F ₂ O: Calculated: C73.17; H4.92 Found: C73.19; H 4,88. Example 31

1,1-Bls (2-fluoro-4-mothylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol

To a solution of 1,5-dimethyltetrazole (4,6g, 4,7mmol) in tetrahydrofuran (40ml) at -5O ⁰ C a butyllithium Solution (21.4ml of a 2.2M solution, 4.7mmol) was added. After stirring for 10 minutes, a solution of 2,2'-difluoro-4,4'-

Dimethylbenzophenone in tetrahydrofuran (15ml) was added. The solution was stirred for 2.5 hours, during which time the solution was allowed to warm to -10 ° C. The reaction was terminated by addition of 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried (MgSO ₄ ) and evaporated. The residue was triturated with diethyl ether and extracted

Isopropyl acetate crystallized to give 8.0 g of the title compound; Mp = 150-151 ⁰ C. MS:. M ⁺ = 344 Analysis for C ₁₈ H ₁₈ F ₂ N ₄ O: Calculated: C 62.79; H 5,27; N 16,27 Found: C62.84; H 5,23; N 16,28. Example 32

1,1-Bls (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) Othen

A suspension of 1,1-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (7.3 g, 21.0 mmol) in toluene (200 ml)

With p-toluenesulfonic acid (3g) was heated at reflux for 14 hours. After cooling, the mixture was washed with

Diluted diethyl ether and extracted with saturated sodium carbonate solution and water. The organic layer was

dried (MgSO ₄ ) and evaporated. The residue was triturated with isopropyl ether to give the title compound; Mp = 58-60 ° C.

Analysis for C ₁₈ H ₁₆ F ₂ N _4: Calculated: C 66.25; H 4.95; N 17,17 Found: D66.27; H4.94; N 16.93. Example 33

3,3-bis (2-fluoro-4-methylphenyl) -2- (1-methyMH-tetrazol-5-yl) -2-propenal

To a solution of 1,1-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (1.6 g, 5.0 mmol) in tetrahydrofuran

(20ml) at -78 ⁰ C butyllithium (2,3ml of a 2.2 M solution, 5 mmol) was added. After stirring for 15 minutes

Ethyl formate (0.44 g, 6.0 mmol) was added and the solution was stirred with cooling for 2 hours. The reaction was with

1N hydrochloric acid and the mixture was extracted with diethyl ether. The extracts were dried (MgSO ₄ ) and evaporated. The residue was crystallized from isopropyl acetate to give 0.66 g of the title compound. M.p. = 154-155 ⁰ C.

Analysis for C ₁₉ Hi ₆ F ₂ N ₄ O: Calculated: C 64.41; H 4.56; N 15,82 Found: D64.44; H4.63; N 15.58. Example 34 Ethyl i-methyl-5-tetrazolyl acetate To a solution of 1,5-dimethyltetrazole (10g) in 10% dry tetrahydrofuran and 20ml of hexamethylphosphoramide

was added dropwise at -78 ° C (dry ice-acetone) under an argon atmosphere 50 ml (1.2 equivalents) of n-butyllithium (2.5M in

Hexane). Allowing the deprotonation of 1,5-Dimethyltetrazol at -78 ^C C for forty minutes and then at -20 ° C

for thirty minutes. The solution of the anion was cooled again to -78 ° C and transferred via cannula During a time of 45 minutes to a cold (-78 ⁰ C) solution containing 12 ml of ethyl chloroformate in 50ml of tetrahydrofuran. The reaction mixture was diluted with aqueous 2N HCl and saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The residue of the organic extract was purified by silica gel flash chromatography. The appropriate fractions were combined and evaporated to give 4 g of product. The product was further purified by crystallization from ethyl acetate-hexane to give 3,52g (21%) of the title compound. M.p. = 64-66 ⁰ C.

AnBIySOfUrC ₆ H ₁₀ N ₄ O _2: Calculated: C 42.35; H 5.92; N 32.92 Found: C42.40; H5.98; N33,15. Example 35 Ethyl 3,3-bis (4-fluorophenyl) -2- (1-methylm-tetrazol-5-yl) -2-propenate

A mixture of titanium tetrachloride (2 mL) and carbon tetrachloride (2 ml) was added to 15ml of tetrahydrofuran at -78 ⁰ C under an argon atmosphere. The suspension was stirred for 30 minutes at -78 ⁰ C before 0.2 g of 4,4'-difluorobenzophenone was added. After stirring for a further 30 minutes, a solution of 0.15 g of ethyl 1-methyl-5-tetrazolylacetate in 1 ml of dry pyridine was added dropwise. The dark brownish suspension was stirred at -78 ° C for 15 minutes and then allowed to warm to ⁰ ° C to form a thick paste. The mixture was allowed to stand at room temperature for 24 hours before being poured into water. The aqueous mixture was extracted with ethyl acetate to obtain the crude product. Analytical TLC, eluting five times with 20% (v / v) ethyl acetate in hexane, showed the desired product at Ri = 0.3. Purification by preparative chromatography on two 20χ20cm ² x 0.26mm TLC plates, which were eluted twice with 20% (v / v) ethyl acetate in hexane afforded the title compound which was identical to the compound of Example 3.

Example 36 Dimethyl [3,3-bl (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propen-1-yl] phosphonate A slurry of 3,3-bis (4-fluoro-phenyl) -1-bromo-2- (1-methyl-1H-tetrazole-5-yl) -2-propoene (1.17g, 3.0mmol) and Trimethyl phosphite (0.41 g, 3.3 mmol) was heated at 100 ° C for 5 minutes. After cooling to room temperature was

Excess trimethyl phosphite removed in vacuo to give a slightly yellow solid. This solid was recrystallized ofa ethyl acetate / hexane mixture to give the title compound as a pure white solid, mp = 140-141 ⁰ C..

IR (KBr) v _{m, x:} 1604,1511cm ^"1;

¹ H-NMR (CDCl ₃ ) δ: 7.7-6.8 (8H, m), 3.6 (3H, s), 3.5 (3H, s), 3.42 (3H, s), 3.2 (2H, d);

Analysis for C ₁₉ H ₁₉ F ₂ O ₃ N ₄ P: Calculated: C 54.29; H 4.56; N 13,33 Found: C53.83; Η4.Ί8; N 13.50. Example 37 Methyl (±) -Erythro-9,9-bl (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadlenate To a solution of the phosplionate (0.84 g, 2.0 mmol) (prepared in Example 36) was added one equivalent of n-BuLi (2.0 mmol)

-78 ⁰ C (dry ice / acetone) was added and the resulting deep red colored solution was stirred at -78 ⁰ C 15 minutes.

Methyl erythro-3,5-bis (diphenyl-t-butylsilyloxy) -6-oxo-hexanate (prepared by the general methods described by P.Kapa

et al., Tetrahedron Letters, 2435-2438 (1984) and U.S. Patent No. 4,571,428, issued February 18, 1986 to P. Kapab), (1.30g, 2.0mmol) in THF (2ml). was added and the mixture was stirred for 24 hours. It is necessary to heat the reaction mixture to room temperature during this time. The reaction was quenched by addition of 5 mL NH ₄ Cl and then extracted with ethyl acetate (2 x 20 mL). The organic layer was dried (NA ₂ SO ₄ ) and evaporated under reduced pressure to a yellow oil. The oil was mixed with 1M tetra-n-butyl-ammonium fluoride solution in

Tetrahydrofuran (4 ml) containing a few drops of glacial acetic acid was stirred for a period of 24 hours. The reaction mixture

was poured into water (20ml) and extracted with methylene chloride (3x 20ml). The organic layer was dried

(NA ₂ SO ₄ ), and the oil was purified by silica gel column chromatography eluting with ethyl acetate: hexane (2: 1) to give 0.244 g (41%) of the title compound as an oil. MS (CI): m / e = 471 for

¹ H-NMR (CDCl ₃ ) δ: 7.26-6.6 (9H, m), 5.29 (1H, dd), 4.42 (1H, m), 4.28 (1H, m), 3.69 (3H, s), 3.54 (3H, s), 2.42 (2H, d), 1.5 (2H, m).

Example 38

1- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-phanylothanol

A solution of 1,5-Dimethyltetrazol (29,25g, 0,298mol) in dry THF (400ml) was cooled to -78 ⁰ C and treated with

n-Butyllithium (133 ml of a 2.5 M solution in hexane, 0.3325 mol) treated for 30 minutes. The mixture was stirred at -78 C for 30 minutes and ⁰ with 4-fluorobenzophenone (50 g, 0.25 mol) treated. The mixture was stirred for 30 minutes at -78 ° C and then allowed to warm for 2 hours at 23 ⁰ C. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl ₃ (2 × 100 ml) and the combined organic layers were dried (Na ₂ SO ₄ ) and evaporated to give a brown oil. Purification by chromatography using 20% EtOAc-hexane as the eluent resulted in

Title compound as a white solid (46.3g, 62%). Mp. = 133-114 ⁰ C (crystallized from EtOAc-hexane). MS (Cl):

m / e = 299 for (M + H) ⁺ ;

IR (KBr) v _max : 3300 (br), 1605,1510cm "¹;

¹ H-NMR δ: 7.34-7.15 (m, 7H), 6.93 (m, 2H), 4.93 (s, 1H), 3.73 (s, 2H), 3.67 ( s, 3H) ppm;

¹³ C-NMRo: 163.57.160, 29.152, 28.144, 94.141, 12.141, 08, 1243, 432, 127, 27, 27, 125, 127, 67, 125, 76, 15, 25, 14, 14, 96, 77, 33, 35, 82

Analysis for C ₁₆ H ₁₆ FN ₄ O: Calculated: C64.42; H 5.07; N 18.79 Found: C'A32; H, 5.05; N 18,84 Example 39

phenylethene

A mixture of tetrazolylethanol (3.2g, 10.74mmol) (prepared in Example 38) and potassium hydrogen sulfate (800ml) was added

heated at 195 ° C for 30 minutes. After cooling to 100 ° C, chloroform (30 ml) was added and the mixture was triturated until most of the solid was dissolved The insoluble inorganic material was removed by filtration to remove the insoluble material

Solvent removed by evaporation to give a mixture of the title compounds in the form of a slightly brownish Solid state received (2.8g, 93%). It was crystallized from EtOAc-hexane. MS (Cl): m / e = 281 for (M + H) ⁺ ; IR (KBr) v _{m, x:} 1640,1600,1510,1445,1220crrr ';

¹ H-NMR δ: 7.50-6.90 (m, 9H), 6.75 is .. 1 H), 3.60 (s, 1.7H), 3.43 (s, 1.3H) ppm;

¹³ C-NMR δ: 165.19.164.58.161.26.153,14,152.97,152,22,152,13,140.53,137,81,136.71,133.99,133.94,131.74,131.62,130,38,129,67,129,29,128,85,128,65,128,38,115,97,115, 74,115,66,115,45,108,29,108,15,33,70ppm;

Analysis for CieHnFN ₄ : Calculated: C 68.56; H, 4.68; N 19.99 Found: C 68.63; H 4.77; N 20.37. Example 40

(E) -3- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -3-phenYlpropenalund (Z) -3- (4-fluorphenvl) -2- (1-methyl- 1H-tetrazol-5-yl) -3-phenylpropenol

A suspension of the olefin (20g, 71.43 mmol) (prepared in Example 39) in dry THF (200 ml) was cooled to -78 ⁰ C.

and treated with n-butyllithium (31.5 ml of a 2.5M solution in hexane, 78.75 mmol) and the resulting mixture was stirred at -78 ° C for 30 minutes. Ethyl formate (6.9g, 93mmol) was added and the mixture was stirred at -78 ⁰ C for 2 hours stirring it was allowed to warm to 23 ⁰ C for one hour. The reaction was quenched with 2N HCl (100 mL), the organic solvent was removed by evaporation and the residue extracted with EtOAc (3x 75 mL). The combined organic layers were dried (MgSO ₄ ), evaporated and the residue was purified by chromatography using 35% EtOAc-hexane as eluent to give the title compound as a mixture of aldehydes (7.75 g, 35%). MS (Cl): m / e = 309 for (M + H) ⁺ ;

¹ H-NMR δ: 9.67 (s, 0.66H), 9.64 (s, 0.33H), 7.70-6.90 (m, 9H), 3.74 (s, 1H) , 3.68 (s, 2H) ppm;

Example 41

(E), (D-5- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -5-phenyl-2,4-pentadlenal

A mixture of the mixed aldehydes (5.1 g, 16.56 mmol) (prepared in Example 40) and Formylmethyltriphenylphosphorane (5.05 g, 16.56 mmol) and benzene (200 mL) were refluxed together Nitrogen atmosphere heated for 2 hours. The solvent was removed by evaporation and the residue was passed through Chromatography, in which 30% EtOAc-hexane was used as eluent, purified to give the product in the form of a

to obtain orange foam (4.56 g). Fractional crystallization from EtOAc-hexane gave the title compound as orange crystals (0.93 g, 17%); Mp. = 137-138 ⁰ C (crystallized from EtOAc-hexane). MS (Cl): m / e = 335 for (M + H) ⁺ ;

¹ H-NMR δ: 9.54 (d, J = 7.5Hz, 1H), 7.47 (d, J = 15.6Hz, 1H), 7.35-6.80 (m, 9H), 5.84 (dd, J = 7.4Hz, J '= 15.7Hz, 1H), 3.50 (s, 3H)

¹³ C-NMRo: 192.54,147.86,132.09,19.97, 130.64, 130.41, 128.96, 116.17, 115, 13.83, 63.62 ppm.

Example 42 Ethyl (E), (E) -9- (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -9-phenyl-3-oxonona-6,8-dienate A suspension of sodium hydride (175mg, 80% dispersion, 5.83mmol) in dry THF (10mL) was cooled to ⁰ ° C and

treated with ethyl acetate acetate (725μΙ, 740mg, 5.69mmol) and stirred at ⁰ ° C for 10 minutes. Butyllithium (2.3ml of a 2.5M

Solution, 5.75 mmol) was added and the mixture was stirred at ⁰ ° C for 15 minutes. A solution of the aldehyde

(860mg, 2.57mmol) (prepared in Example 41) in dry THF (10ml) was added and the mixture stirred at ⁰ ° C for 15 minutes. The reaction was stopped by the addition of 2N HCl (30 ml) and the organic solvent was passed through

Evaporate away. The residue was extracted with EtOAc and the combined organic extracts were dried

(MgSO ₄ ) and evaporated. The residue was purified by chromatography using 40% EtOAc-hexane as the eluent to give the title compound as a yellow gum (954 mg, 80%). MS (Cl): m / e = 465 for (M + H) ⁺ ;

IR (film) v _mlx : 3400 (br), 1730, 1600, 1510 cm "¹;

¹ HNMRo: 7.20-6.60 (m, 9H), 6.54 (d, J = 15.6Hz, 1H), 5.16 (dd, 1H), 4.40 (br, 1H ), 4.00 (q and br, 3H), 3.31 (s, 3H), 3.25 (s, 2H), 2.52 (m, 2H), 1.08 (t, 3H) ppm ,

Example 43 Ethyl (±) - (E), (E) -erythro-9- (4-fluorophenyl) -3,5-dlhydroxy-8- (1-methyl-1H-tetrazol-5-yl) -9-phenylnona-6,8 -dienat A solution of the β-ketoester (950 mg, 2.045 mmol) (prepared in Example 42) in dry THF (20 mL) was mixed with a solution

of triethylborane (2.25 ml of a 1 M solution in THF, 2.25 mmol) and stirred at 23 ⁰ C for one hour. Methanol (400μΙ) was added and the mixture cooled to -78 ⁰ C cooled and treated with NaBH ₄ (200mg, 5,26mmol) treated. After 1 hour, the reaction was stopped by the addition of 2N HCl and the organic solvent was removed by evaporation. The

Residue was extracted with EtOAc and the combined organic extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by chromatography using 60% EtOAc-hexane as the eluent, yielding the Title compound in the form of a yellow gum provided (330mg, 35%). MS (Cl): m / e = 467 for (M + H) ⁺ IR (KBr) v _m , ": 3400 (br), 1725, 1600, 1500cm"¹;

¹ HNMRo: 7.30-6.80 (m, 7H), 6.70 (dd, J = 1.0Hz, J '= 15.6Hz, 1H), 5.35 (dd, J = 5.9Hz , J '= 15.7 Hz, 1H), 4.41 (m, 1H), 4.25 (br s, 1H), 4.15 (q, J = 7.1Hz, 2H), 3.83 ( brm, M2H), 3.52 (s, 3H), 2.45 (d, J = 6.1Hz, 2H), 1.60 (m, 2H), 1.26 (t, J = 6.1Hz, 3H) ppm; ¹³ C NMR δ: 172.40, 166.147, 161.17, 153.66, 147, 17.139, 94.138, 21.137, 75, 135, 55, 132, 140, 132, 30, 16, 129, 129, 129, 129, 168, 67, 128, 171, 127, 211, 121, 105, 151, 154, 151, 75, 71, 89 , 69,35,68,34,60,83,60,34,42,34,41,53,41,22,33,56,14,13 ppm.

Example 44 Sodium (±) - (Ε), (Ρ) -ΕΓγΐΗΓθ-9 · (4 · ίΙυοΓρΗθηνΙ) · 3.5 · αΙΗναΓθχν · 8 · (1-Γηθ ^ νΙ-1Η · ΙοΐΓβζοΙ · 5 · νΙ) -9 · ρΗβηνΙηοη8 -β, 8 · · αΙθη8ΐ ΗναΓβΐ A solution of the dihydroxy ester (160mg, 0.343mmol) (prepared in Example 43), ir. EtOH (5ml) was treated with 1N NaOH (343μΙ,

0.343 mmol) and the resulting solution was stirred at 23 ° C for ¹ hour. The solvent was passed through

Evaporation was removed and the residue was dissolved in water (2 ml) and lyophilized to give the title compound in Afforded the form of a light tan solid (155mg). M.p. = 130-137 ⁰ C. IR (KBr) V _011x : 3400 (br), 1560,1510cm " ¹

¹ HNMR (DMSO ^ ₃ ) O: 7.50-6.80 (m, 9H), 6.51 (d, J = 15.7Hz, 1H), 5.15 (dd, J = 5.4Hz, J '= 15.7Hz, 1H), 4.15 (m, 1H), 3.70 (s, 3H), 365 (br, 1H), 3.35 (br, 2H), 1.95 (m , 2H), 1.40 (m, 2H) ppm;

¹³ C NMR (DMSO-dg) δ: 176.42,163.42,153,17,146,07,140.03,139.73,135.70,135,64,132,20,132,09,128,72,128,42,128,07,127,98,124,83,121,51,115,51,115,22, 66, 22,65,69,44,46,43,59,33,42 ppm

Analysis for C ₂₃ H ₂₂ FN ₄ O ₄ Na.H ₂ O: Calculated: C 57,74; H 5.06; N 11,72 Found: C58.70; H5,10; N11.16. Example 45

2 (1-methyltetrazol-5-yl) -1,1-d! Phenylethanol

A solution of 1,5-Dimethyltetrazol (20g, 0.204 mol) in dry THF (200ml) was cooled to -78 ⁰ C and treated with

n-Butyllithium (91 ml of a 2.5 molar solution in hexane, 0.227 mol) and the mixture stirred at -78 ° C for 30 minutes. Benzophenone (31.1 g, 0.171 mol) was added and the mixture was stirred at -78 ° C for 30 minutes. Thereafter, the solution was allowed to warm to 23 ⁰ C and stirred for 15 hours. The mixture was quenched with 2N HCl (100ml) and extracted with EtOAc (3x150ml). The combined organic layers were dried (MgSO ₄ ) and evaporated. The

Residue was crystallized from EtOAc-hexane to give the title compound as a white solid (10.5 g, 22%).

arisen; Mp. = 175-176 ⁰ C (crystallized from EtOAc-hexane). MS (Cl): m / e = 281 for (M + H) ⁺ ;

IR (KBr) v _m ": 3300 (br), 1530, 1500cm"¹;

¹ H NMR δ: 7.50-7.20 (m, 10H), 5.45 (s, 1H), 3.82 (s, 2H), 3.80 (s, 3H) ppm;

¹³ C NMR δ: 152.36.145.63, 128.16, 127.28, 126.05, 125.94, 77.70, 35.90, 33.76 ppm;

Analysis for C ₁₆ H ₁₆ N ₄ O: Calculated: C 68.56; H 5.76; N 20,00 Found: C68.62; H5.81; N20.10. Example 46

2,2-diphenyl-1- (1-methyl-1H-tetrazol-5-yl) ethene

A mixture of 2 (1-methyltetrazol-5-yl) -1,1-diphenylethanol (2.15 g, 7,68mmol) and KHSO ₄ (300 mg) was added at 200 ⁰ C

Heated for 20 minutes. The cooled mixture (5O ⁰ C) was triturated with CHCI ₃ (50ml) and the organic solvent was decanted from the inorganic residue. Evaporation gave the title compound as a creamy

Solid (1.7 g, 85%); Mp. = 147-148 ⁰ C (crystallized from EtOAc-hexane). MS (Cl): m / e = 263 for (M + H) ⁺ ; IR (KBr) V _n ,,,: 1640,1500,1445CnT ^1;

¹ HNMRo: 7.50-7.00 (m, 10H), 6.78 (s, 1H), 3.43 (s, 3H) ppm;

¹³ C NMR δ: 153.94.152,18,140, 40,137, 83,129, 54, 129, 137, 128, 94, 128, 129, 128, 28, 128, 108, 22, 23, 56 ppm.

Analysis for Ci ₆ Hi ₄ N ₄ : Calculated: C73.27; H5.38; N21,36 Found: C73.25; H 5.43; N 21.43. Example 47

3,3-diphenyl-2- (1-methyl-1H-tetrazol-5-yl) propenal

A solution of 2,2-diphenyl-1- (1-methyl-1H-tetrazol-5-yl) -ethene (3.75 g, 14.29 mmol) in dry THF (40 mL) was added

-78 ⁰ C cooled n-butyllithium (6,3ml of a 2.5M solution in hexane, 15,75mmol) and stirred the resulting mixture was stirred at -78 ⁰ C for 30 minutes. Ethyl formate (1.5 mL, 18.58 mmol) was added and the mixture was stirred at -78 ⁰ C for 2 h. The reaction was quenched with 2N HCl and the solvent removed by evaporation. The

Residue was extracted with EtOAc (3x 30ml) and the combined organic layers were dried (MgSO ₄ ) and

evaporated. The residue was purified by chromatography using 25-35% EtOAc-hexane as eluent to give starting material (1.35 g, 36%) and the desired title compound (1.65 g, 39%);

Mp. = 185-186 ⁰ C (crystallized EtOAc-hexane). MS (El): m / e = 290 for M ⁺ ; IR (KBr) v _max : 1675,1600,1445cm "¹;

¹ H NMR δ: 9.66 (s, 1H), 7.70-6.90 (m, 10H), 3.66 (s, 3H) ppm;

¹³ C NMR δ: 189.45, 167.79, 151, 44, 138, 35, 136, 65, 131, 54, 131, 34, 130, 96, 129, 129, 128, 71, 123, 55, 33, 91 ppm.

Analysis for Ci ₇ H) ₄ N ₄ O: Calculated: C 70.34; H, 4.87; N 19,30 Found: C70.63; H4.99; N 19.33. Example 48

(E) -4- (1-methyl-1H-tetrazol-5-yl) -5,5-oil (phenyl) -2,4-pentadlenal

A solution of the aldehyde (1.33g, 4.57mmol) [prepared in Example 47] and triphenylphosphoranylidene acetaldehyde (1.5g,

4.87 mmol) was refluxed in benzene (50 ml) for 24 hours. The solvent was evaporated and the

Residue was purified by chromatography using 30% EtOAc-hexane as the eluant, yielding the Title compound in the form of a yellow foam (1 g, 71%) provided. MS (Cl): m / e = 317 (M + H) ⁺ ;

¹ = 7.5Hz, 1H), 7.55-7.10 (m, 10H), 6.69 (d, J = 16Hz, 1H), 5.84 (dd, J = 16Hz.J '= 7, 5Hz, 1H), 3.50 (s, 3H) ppm.

Example 49 Metnyr (E) -9,9-dlphenyl-3,5-dlhydroxy-8- (1-methyl-1H-totrozol-5-yl) -nona-6,8-dienoate

Methyl acetate acetate (0.525 mL, 4.87 mmol) was added to a suspension of sodium hydride (0.160 g, 80% dispersion in mineral oil) in THF at ⁰ ° C and stirred for 10 minutes. n-Butyllithium (2.14 mL, 2.5 M solution in hexane) was added and the reaction stirred for 15 minutes. This solution was added to a solution of the aldehyde (1, Og, 3.2 mmol) [prepared in Example 48] in THF at ⁰ ° C and stirred for 30 minutes. The reaction was treated with 2N HCl (30ml) and extracted with EtOAc (3x 15ml). The organic layer was dried with MgSO ₄ and evaporated. The crude residue was triturated with hexane (3x 25ml) and then dissolved in THF / CH 3 OH (4: 1, 20ml) and treated with triethylborane (3.2ml, 1M solution in THF). Air was bubbled through the solution for 10 minutes and the reaction stirred for a further 50 minutes. The solution was then cooled to -78 ⁰ C and treated with sodium borohydride (120mg, 3.2 mmol) and stirred for 1 hour. The reaction was quenched with 2MHCl (100mL) and extracted with EiOAc (3x 20ml). The organic layers were dried with MgSO ₄ and evaporated. The residue was dissolved in CH ₃ OH (30 ml) and stirred for 15 hours. The solution was evaporated and the residue was purified by chromatography using 50% EtOAc-hexane as the eluent to give the title compound as a yellow oil (470mg, 33%). MS (Cl): m / e = 435 (M + H) ⁺ ; ¹ H NMR δ: 7.80-6.80 (m, 10H), 6.71 (d, J = 16Hz, 1H), 5.34 (dd, J = 16Hi, J '= 6Hz, 1H), 4 , 60-4.10 (m, 2H), 3.70 (s, 3H), 3.52 (3.3H), 2.45 (d, J = 6Hz, 2H), 1.70- 1.50 (m, 2H) ppm.

Example 50 Sodium (±) - (E) -erythro-9,9-diphenyl-3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -nona-6,8-dienoate hydrate The methyl ester (470 mg, 1.08 mmol) [prepared in Example 49] was dissolved in ethanol (10 mL) and washed with 1N NaOI I (,, 08 mL).

treated. The reaction was stirred for 1 hour. The solvent was evaporated and the residue was freeze dried, resulting in a slightly yellowish powder (500 mg, 100%); M.p. = 145-15O ⁰ C.

IR v _mM : 3400 (br), 1610, 1425, 1360 cm "¹;

¹ HNMR (DMSO-d ₆ ) δ: 7.60-6.60 (m, 10 H), 6.52 (d, J = 16 H /, 1 H), 5.12 (dd, J = 16 Hz J '= 5.5 Hz, 1H), 4.20-4.05 (m, 1H), 3.80-3.55 (m, 1H), 3.70 (s, 3H) , 3.10 (br s, 2H), 2.10-1.10 (m, 5H) ppm.

Analysis for C ₂₃ H ₂₃ N ₄ O ₄ Na H ₂ O: Calculated: C59.99; H5.47; N12.17 Found: C 59.18; H 5.46; N 10.96.

Example 51

2,2-bis (4-methoxyphenyl) ethene -1- (1-methyl-1H-tetrazol-5-yl)

A solution of 1,5-Dimethyltetrazol (20g, 0.204 mol) in dry THF (200ml) was cooled to -78 ⁰ C and treated with

n-butyl lithium (91 ml of a 2.5M solution in hexane, 0,227mol) and the mixture stirred at -78 ⁰ C for 30 minutes.

4,4'-Dimetheoxybenzophenone (41.3 g, 0.171 mol) was added and the mixture was stirred at -78 ° C for 30 minutes and then allowed to warm to 23 ⁰ C over 2 hours. The mixture was acidified with 2N HCl (100 mL) and the organic solvent removed by evaporation. The residue was extracted with EtOAc (3x 300ml) and the combined organic layers were dried (MgSO ₄ ) and evaporated. The residue was crystallized from EtOAc-hexane resulting in a slightly brownish solid (48 g) which was found to be a mixture of the desired

Product and the original aldol adduct (1,1-bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol). This mixture was dissolved in xylene ("SOmI) and p-toluenesulfonic acid in a Dean-Stark apparatus for one hour

heated to reflux. The cooled mixture was diluted with ether (100 ml) and the resulting solid was passed through

Filtration removed to give the title compound as a creamy solid (40g); Mp. = 146-147 ⁰ C (crystallized

from EtOAc-hexane.) MS (Cl): m / e = 323 for (M + H) ⁺ ;

IR (KBr) V _n, ,,: 1605,1520,1250cm ^"1;.

¹ HNMRO: 7.31 (d, J = 7.8Hz, 1H), 6.98 (d, J = 7.8Hz, 1H), 6.90 (d, J = 7.8Hz, 1H) , 6.81 (dJ = 8.6 Hz, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.79 (s, s3H), 3.42 (5.3H), ppm;

¹³ C NMR δ: 160,79,160,16,153,29,133,33,131,25,130,32,129,95,127,36,114,14,113,69,105,57,55,40,55,28, 33,71 ppm.

Analysis for CiBH ₁₈ N ₄ O ₂ : Calculated: C 67.07; H 5.63; N 17.38 Found: C66.93; H5,63; N 17.05. Example 52

propenal 3,3-B! s (4-inethoxyphenyl) -2- (1-mothyl'1H-tetrazol-5-vl)

A solution of the olefin (4.6 g, 14.29 mmol) [prepared in Example 51] in dry THF (50 ml) was cooled to -78 ⁰ C and

It was treated with n-butyllithium (6.3 ml of a 2.5M solution in hexane, 15.75 mmol) and the resulting solution was stirred at -7 ° C for 30 minutes. Ethyl formate (1.5 ml) was added and the mixture stirred at -78 ⁰ C for 2 hours. The

Mixture was quenched with 2N HCl and the organic solvent removed by evaporation. The residue was with EtOAc (3x 30ml) and the combined organic layers were dried (MgSO ₄ ) and evaporated. The Residue was purified by column chromatography using 25-35% EtOAc-hexane as the eluent.

which provided starting material (0.84g, 18%). Further elution afforded the desired title compound (1.78 g, 36%);

Mp. = 130-131 C ⁰ {crystallized from EtOAc-hexane). MS (Cl): m / e 351 (M + H) ⁺ ; IR (KBr) v _m : 1675, 1605, 1515, 1260cm "¹;

¹ H NMR δ: 9.59 (8.1 H), 7.30 (d, J = 8.6 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 1 H), 6, 90 (d, J = 8.9Hz, 1H), 6.74 (d, J = 8.7Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H) , 3.67 (s, 3H) ppm;

¹⁵ C NMR δ: 189.51,167.47,162.59,161.98,152.30,133.91,13299,130.79,129.35,121,05,114,20,114,15,55,80,55,40,33,94 ppm.

Anisysoforc ₁₉ H ₁₈ N ₄ O ₃ : Calculated: C 65.14; H 5:18; N 15.99 Found: C 64.96; H 5.22; N 15,75. Example 53 A solution of 3-bis (4-metl.:xyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal (1.7g, 4.86 mmol) in benzene (100ml) was added Triphenylphosphoranylidenacetaldehyd (1.55g, 5.1 mmol) and heated under reflux for 3 hours. The Solvent was removed by evaporation and the residue was purified by chromatography using 30% EtOAc. Purify hexane as eluent to give the title compound as a yellow foam (1.35 g, 74%). MS (Cl):

m / e = 377 for (M + H) ⁺ ;

IR (KBr) v _m . _x : 1675.1590.1515cm "¹;

¹ H NMR δ: 9.52 (d, J = 7.6Hz, 1H), 7.53 (d, J = 14.2Hz, 1H), 7.23 (d, HJ = 8.5Hz, 1 H), 7.00 (d, J = 9.3Hz, 1H), 6.86 (d, J = 9.2Hz, 1H), 6.70 (d, J = 8.9Hz, 1H) , 5.83 {dd, J = 7.6Hz, J '= 15.7Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.50 (s, 3H) ppm; ' ³ C NMR δ: 192.89, 116.40, 160.97, 157.91, 153, 29, 149, 141, 133, 13, 12, 13, 14, 13, 14, 13, 13, 13, 13, 13, 13, 13, 13, 13, 16, 13, 16, 13, 16, 13, 16, 13, 16, 13, 16, 13, 16, 13, 16, 13, 16, 13, 16, 13, 13, 13 , 61 ppm.

Example 54 Ethyl (E) -9,9-bls (4-methoxyphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxonona-e, 8-dienoate Ethyl acetoacetate (825 μΙ, 842 mg, 6.48 mmol) was added to a suspension of NaH (206 mg, 80% dispersion, 6.86 mmol) in

dry THF (20 ml) at ⁰ ° C. and the resulting mixture was stirred at ⁰ ° C. for 10 minutes. A solution of n-butyllithium (2.7 ml of a 2.5M solution in hexane, 6.75 mmol) was added and the mixture was stirred at ⁰ ° C for 10 minutes. A solution of the aldehyde (1.3 g, 3.46 mmol) (prepared in Example 53) in dry THF (20 mL) was added and the mixture was stirred at 0 ° C for 15 minutes. After 2N HCl was added to quench the reaction, the solvent was removed by evaporation. The residue was diluted with water (30 ml), extracted with EtOMc (2 x 20 ml) and the combined organic phases were dried (MgSO ₄ ) and evaporated. The residue was through

Chromatography using 49% EtOAc-hexane as the eluent to give the title compound as a

yellow Schaurms (1.165g, 66%) provided.

IR (KBr) v _{m, x:-450.} (Br), 1750; 1710,1610,1510cm "';

¹ H NMR δ: 7.31-6.60 (m, 9H), 5.27 (dd, J = 6.1 Hz, J'15.9Hz, 1H), 4.68 (brs, 1H) , 4.14 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 3.47 (s, 3H), 3.43 (s , 2H), 3.17 (brs, 1H), 2.70 (d, J = 6.0Hz, 2H), 1.23 (t, J = 6.0Hz, 3H), ppm ; ¹³ C NMR δ: 202, 48, 160, 09, 15, 17, 15, 15, 16, 14, 14, 14, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 16, 19, 16, 16, 16, 16, 17, 19, 16, 16, 17, 19, 16, 17, 19, 16, 16, 17, 19, 16, 17, 19, 16, 16, 16, 17, 19 , 94.49, 33, 33, 56, 14, 19, ppm.

Example 55 Ethyl (±) - (E) -erythro-9,9-bis (4-methoxyphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dlenate A solution of the β-ketoester (1g, 1.97 mmol) [prepared in Example 54] in dry THF (50 mL) and methanol (300 μΙ)

treated with a solution of triethylborane (2.15 ml of a 1N solution in THF) and the mixture stirred at 23 ⁰ C for one hour.

The solution was cooled to -78 ° C and treated with NaBH ₄ (110mg, 2.92mmol). After 1 hour at -78 ⁰ C, the Reaction with 2 N HCl terminated and the solvent was removed by evaporation. The residue was washed with water

diluted and extracted with EtOAc (3x 30ml). The combined organic extracts were dried (MgSO ₄ ) and

evaporated. The residue was purified by chromatography to afford the title compound as a pale oil (136mg).

IR (KBr) v _m ": 3450 (br), 1750,1710,1610,1510cm" ¹ .

¹ HNMRo:?, 70-6.50 (m, 9H), 5.80 (dd, 1H), 4.45 (br, 1H), 4.15 (q, 2H), 3.85 (s , 3H), 3.72 (s, 3H), 3.50 (s, 3H), 2.45 (m, 2H), 1.55 (m, 2H), 1.26 (i, 3H) ppm;

¹³ C NMR δ: 172.38.160, 18.159, 29.154, 32.148, 92.138, 54.136, 19.132, 81, 132, 29, 132, 20, 12, 12, 131, ^13, 12, 11, 12, 12, 12, 16, 18, ^13, 12, ^13, 12, 12, 18, 18, 18, ^{13, 13, 13, 13,} 14, 17, 15, 15 , 66,31, 60,75,55,35,55,20,42,74,42,14,41,73,41,48,33,50,14,18.

Example 56 Sodium (±) - (E) erythro-9,9-bis (4-methoxyphenyl) 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienate dehydrate A solution of the ester (95mg, 0.196mmol) [prepared in Example 55] in ethanol (15ml) was treated with 1N NaOH solution (196μΙ).

and the compound stirred at 23 ⁰ C for one hour. The solvent was removed by evaporation and the

Residue was dissolved in water (2 mL) and lyophilized to give the title compound as a brown powder

(95mg, 100%) provided; M.p. = 175-18O ⁰ C.

IR (KBr) v _mn : 3400 (br), 1600, 1575, 1510 cm "¹;

¹ HNMR (DMSO-d _e ) δ: 7.70-6.6 & (m, 9H), 6.55 (d, J = 15.5Hz, 1H), 5.08 (dd, J = 5 , 6 Hz, J '= 15.7 Hz, 1H), 4.14 (br, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.66 (s , 3H), 2.10-1.80 (br, 2H), 1.50-1.20 (br, 2H) ppm;

¹³ C NMR (DMSO-d _e ) δ: 159.25.158, 80.153, 78.138, 13.132, 75.131, 88, 31, 16.30, 131, 42, 131, 30, 130, 121, 128, 28, 128, 53, 125, 161, 137, 164, 138, 68, 16, 65, 89 , 55,14,54,99,44,68,43,68,33,34.

Analysis for C ₂₆ H ₂₇ NaN ₂ H ₂ O: Calculated: C 55.76; H 5.81; N 10.41 Found: C54.43; H5.04; N 8,15.

Claims (39)

claims: R ¹ and R ^{4 are} each independently hydrogen, halogen, C ₁ ^ -Al kyl, C ₁ ^ -Akoxy or Trifluoromethyl; R ² , R ³ , R ^{6 are} each independently hydrogen, halogen, C 1-4 alkyl or C ₁ and R ⁶ are; B is hydrogen, C ₁ ^ alkoxycarbonyl, CH ₂ Y or CH ₂ Z; Y is hydrogen, hydroxyl or X; O
Il , 10th is -p- (0R ^iU ) ₂ or - r-] ß ; X is bromine, chlorine or iodine; R ^{10 is} C 1-4 alkyl R ^{11 is} phenyl, which is unsubstituted or by one or two C ^ alkyl or Substituted chlorine substituents. 2. A compound according to claim 1, wherein B is hydrogen. A compound according to claim 2, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each selected from a group of hydrogen, fluoro, methyl and methoxy. A compound according to claim 1, wherein B is C 1-4 alkoxycarbonyl. A compound according to claim 4, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each selected from a group of hydrogen, fluoro, methyl and methoxy. 6. A compound according to claim 1 having the formula '-CH. R ¹ and R ⁴ are each independently hydrogen, halogen, C ^ alkyl, _C1 ^ -alkoxy or Trifluoromethyl; R ² , R ³ , R ^{6 are} each independently hydrogen, halogen, C 1-4 alkyl or C ₁ and R ⁶ ; and Y is hydrogen, hydroxyl or X; and X is bromine, chlorine or iodine. A compound according to claim 6, wherein Y is hydrogen. 8. A compound according to claim 7, characterized in that R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ^{6 are} each selected from a group of hydrogen, fluorine, methyl and methoxy. A compound according to claim 6, wherein Y is hydroxyl. 10. The compound of claim 9, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{8 are} each selected from a group of hydrogen, fluoro, methyl and methoxy. The compound of claim 6 wherein Y is X, wherein X is bromo. The compound of claim 11, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each selected from a group of hydrogen, fluoro, methyl and methoxy. 13. A compound according to claim 1 having the formula R ³ -N in which R ¹ and R ⁴ are each independently hydrogen, halogen, C _1-4 -alkyl, C ^ -alkoxy or ₁ Trifluormethylsind; R ² , R ³ , R ^{5 are} each independently hydrogen, halo, C 1-4 alkyl or C 1-4 alkoxy and R ⁶ ; Z is Jp (OR ¹⁰ ) - or -p - R \ _R 11 R ^{10 is} C 1-4 alkyl; and R ^{11 is} phenyl which is unsubstituted or substituted by one or two C 1-4 alkyl or Chloro substituent is substituted. A compound according to claim 13, wherein Z is triphenylphosphonium bromide. 15. A compound according to saying f 14, in which R ^1, R ^2, R ^3, R ^4, R ⁵ and R ⁶ are each selected from a group consisting of hydrogen, fluoro, methyl and methoxy. 16. A compound according to claim 13, wherein Z is dimethyl phosphonate. The compound of claim 16 wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each selected from a group of hydrogen, fluoro, methyl and methoxy. Compound according to Claim 1, characterized in that it is di-bis-t-fluorophenyl D ^ -O-methyl-1H-tetrazol-5-yl) -1-propene. 19. A compound according to claim 1, characterized in that it is 3,3-bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene. 20. A compound according to claim 1, characterized in that it is 3,3-bis (4-fluorophenyl) -2- (1-methyl-1 H-tetrazol-5-yl) -2-pi openol. A compound according to claim 1, characterized in that it comprises [1,1-bis- (4-fluorophenyl) -2- {1-methyl-1H-tetrazol-5-yl) -1-propen-3-yl] -triphenylphosphonium -bromidist. 22. A compound according to claim 1, characterized in that it is 1,1-bis (4-fluorophenyl) -2- (1-methyl-1 H-tetrazol-5-yl) ethene. 23. A compound according to claim 1, characterized in that it is 1,1-bis (2,4-dimethylphenyl) -2- (1-methyl-1 H-tetrazol-5-yl) ethene. 24. A compound according to claim 1, characterized in that it is 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -ethene. 25. A compound according to claim 1, characterized in that it is 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene. 26. A compound according to claim 1, characterized in that it ethenist 1,1-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl). 27. A compound according to claim 1, characterized in that it is ethyl 3,3-bis (4-fluorophenyl) -2- (1-methyl-1 H-tetrazol-5-yl) -2-propenoate. 28. A compound according to claim 1, characterized in that it is 1- (4-fluorophenyl) -2- (1-methyl-1 H-tetrazol-5-yl) -1-phenylethene. 29. A compound according to claim 1, characterized in that it is 2,2-diphenyl-1- (1-methyiyl-1H-tetrazol-5-yl) ethene. 30. A compound according to claim 1, characterized in that it is 2,2-bis (4-methoxyphenyl) -1- (1-methyl-1H-tetrazol-5-yl) ethene. A compound according to claim 1, characterized in that it is dimethyl [3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propen-1-ylphosphonate. 32. A process for the preparation of the compounds .Lach according to one of the preceding claims by known methods. 33. A process for the preparation of a compound of the formula R ³ wherein R ¹ and R ^{4 are} each independently hydrogen, halogen, C 1-4 -alkyl, C 1-4 -alkoxy or trifluoromethyl; R ^2, R ^3, R ^B and R ⁶ are each independently hydrogen, halogen, C ^ alkyl or C ₁ ^ ₄ -alkoxy and Z _{2 or} _ _p ^ i \ _R 11 in which R ^{10 is} C ₁ ^ alkyl; R ^{11 is} phenyl which is unsubstituted or substituted by one or two C 1-4 -alkyl or chlorine substituents, and X is bromine, chlorine or iodine, characterized in that
(a) a benzophenone of the formula wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above, are reacted with 5-ethyl-1-methyl-1 H-tetrazole to form a compound of the formula Vila wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above;
(b) dehydrating an alcohol of formula VIIa to produce a compound of formula R ⁵ id wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above;
(c) halogenating an olefin of the formula Id to produce a compound of the formula Ie wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are as defined above; and (d) reacting a compound of formula I e with P (OR ¹⁰ J ₃ or P (R ¹¹ J ₃ , wherein R ^{10 is} C ₁ ^ -alkyl and R ¹¹ is phenyl which is unsubstituted or substituted with one or two Ci-4-alkyl or chloro substituent, for preparing a compound of the formula wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above. 34. The method according to claim 33, characterized in that compounds are used in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each selected from a group of hydrogen, fluorine, methyl and methoxy. 35. The method according to claim 34, characterized in that Z is triphenylphosphonium bromide. 36. The method according to claim 34, characterized in that Z is dimethylphosphonate. 37. Use of the compounds according to claims 1 to 31 for the preparation of antihypercholesterolemic agents. 38. A process for the preparation of a compound of the formula l '(la, b, c, dunde) wherein R ¹ and R ^{4 are} each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently hydrogen, halogen, C 1-4 alkyl or C ₁ - ^ - are alkoxy; B is hydrogen, Ci - ^ - alkoxycarbonyl or CH ₂ Y; Y is hydrogen, hydroxyl or X; X is bromine, chlorine or iodine; which includes: (a) reacting a substituted or unsubstituted benzophenone of the formula: O
wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as mentioned above, with a compound of formula "8th VI N "N-CH ₃ Ν-Ν wherein R ^{8 is} hydrogen, C 1-4 alkoxycarbonyl or methyl to produce a compound of formula VII, (b) dehydrating the product of step (a) to produce a compound of formula, wherein R ^{8 is} hydrogen, C 1-4 alkoxycarbonyl or methyl, (c) reacting the product of (b) wherein R ^{8 is} methyl with an N-halosuccinimide in the presence of a catalyst to produce a compound of formula I 'wherein R ^{8 is} methyl halide and (d) reacting the product of (b) wherein R ^{8 is} C 1-4 alkoxycarbonyl with a Reducing agent in a nonreducible inert solvent to produce a compound of formula I 'wherein R ^{8 is} CH ₂ OH.
39. Process for the preparation of compounds of the formulas R ^{5 X} ^ OH hb wherein R ¹ and R ^{4 are} each independently hydrogen, halogen, C 1-4 alkyl, or trifluoromethyl; R ^2, R ³ and R ⁵ and R ⁶ are each independently hydrogen, halogen, C ^ alkyl or _C1 ^ -alkoxy; η = 1; and R ^{7 is} hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt, which comprises: (a) reacting a compound with the formula Ie wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ^{6 are} as defined above, with either a triphenylphosphine, a phosphonium salt of the formula If wherein R ^{11 is} substituted or unsubstituted phenyl or with a phosphite to form a phosphonate of the formula <0R ¹⁰ ) ig where R ^{10 is} C 1-4 alkyl,
(b) reacting one of the products of step (a) with an aldehyde of the formula OR ¹² OB ¹² O xl wherein R ^{9 is} a hydrolyzable ester group and R ^{12 is} t-butyldiphenylsilyl in an inert organic solvent in the presence of a strong base, (c) desilylating the product of (b) by reaction with a desilylating agent in an inert organic solvent and in the presence of a small amount of an organic acid to produce a compound of the formula wherein R ^{7 is} a readily hydrolyzable ester group, (d) cleaving ester function R ⁷ by basic hydrolysis in an organic solvent to produce a compound of formula Ha wherein R ^{7 is} O ⁺ M ⁺ (M ⁺ is a cation), (e) acidifying the product of (d) to produce a compound of the formula II a wherein R ⁷ is hydrogen, and (f) cyclization of the product of (e) to produce a compound of formula IIb by activation of the carboxyl radical with a carbodiimide in an inert organic solvent. 40. A process for the preparation of a compound of the formula III wherein R ¹ and R ⁴ are each independently hydrogen, halogen, C ^ alkyl, _C1 ^ -alkoxy or trifluoromethyl; R ^2, R ^3, R ⁵ and R ⁶ are each independently hydrogen, halogen, C ^ alkyl, _C1 ^ -alkoxy; which includes
(a) reacting a compound of the formula wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ^{6 are} as mentioned above, with an anion of a compound of formula ^ \ Vl N N-CH- V ' N-N