DD279880A5 - METHOD FOR PRODUCING NEW TETRAZOLE COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of novel tetrazole compounds of the general formula I in which R 1 and R 4 are each independently hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 are each, independently of one another, hydrogen, halogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy; n is an integer from 0 to 2; R 7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy Alkoxy (lower) alkyl or 2-methoxyethoxymethyl; X is OH or O and R8 is hydrogen, a hydrolyzable ester group or a cation which forms a non-toxic pharmaceutically-acceptable salt. The compounds of the present invention are potent inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-COA) reductase and are used as drugs for the treatment of hypercholesterolaemia, hyperlipoproteinemia and arteriosclerosis. Formula I

Description

Application of the invention

The present invention relates to a process for the preparation of novel tetrazole compounds having the following general formula I

, 5

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , tet, η and A are as defined below, the effective inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA ) reductase and are used as drugs for the treatment of hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis.

Characteristic of the known state of the art

This application is a partial continuation of our earlier co-pending application No. 018,542, filed on February 25, 1987.

The natural fermentation products compactin (R = H), discovered by A. Endo et. al. in Journal of Antibiotics, 29.1346 to 1348 (19,761 and mevinolin (R = CH _3), discovered by AWAlberts et al., J. Proc. Natl. Acad. Sci. USA, V7,3957 (1980) are very active antihypercholesterolemic agents which limit the biosynthesis of cholesterol by inhibiting the enzyme HMG-CoA reductase which is the rate-inflammatory enzyme and natural point of Cholesterogeneseregulieruiig in mammals, including humans. compactin (R = H) and mevinolin (R = CH _3, Synonym lovastatin) have the following structure:

Compactin, R = H mevinolin, R = CH ₃

In addition, a number of structurally related synthetic compounds useful for the treatment of hypercholesterolemia have been described in patents and other publications. The following is the literature describing the most related syntheses.

U.S. Patent No. 4,198,425, issued April 15, 1980 to S.Mistui et al., Describes novel mevalonolactone derivatives useful in the treatment of hyperlipidaemia and having the general formula:

CH

R-

R-

wherein A is a single bond, methylene, ethylene, trimethylene or vinylene and R ³ , R ⁴ and R ^{5 are} different substituents.

European Patent Application EP-24,348, published 4 May 1981, describes novel hypocholesterolemic and hypolipidemic compounds having the following structure:

ior

wherein A is A or methyl, E is a single bond, -CH ₂ -, - (CH ₂ ) 2 -, - (CH ₂ I ₃ -or-CH = CH-, R ', R ² and R ³ each represent different substituents and the corresponding dihydroxy acids formed upon hydrolytic opening of the lactone ring.

U.S. Patent No. 4,375,475 issued March 1, 1983 to A.K. Willard et al. describes geneu same structures and is the above. EP-24,348 analog.

European Patent Application EP-68,038, published January 5, 1983, describes and claims the isolated trans isomer. Process for its preparation and pharmaceutical preparations thereof having the structure

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

International Patent Application WO 84/02131, published June 7, 1984, describes mevalonolactone analogs having the structure:

wherein one of the substituents is R or R °

and the other is irimäres secondary result or C ₁ -C ₆ -alkyl, C rC ₆ cycloalkyl or phenyl- (CH _{2) n} Nisto, 1,2 or 3;

Z is -QH-CH-CH ₀ -C ₀ -COOH and

I f

OH OH

R ⁴ , R ¹ 'and R ^{6 are} different substituents.

International Patent Application VVC 84/02903, published August 2, 1984, describes mevalonolactone analogs having the structure

X-Z

where X is - (CTL) -

j: c = c.

- (CH ₂ );

η = 0,1,2 or 3 and both q are 0 or one is 0 and the other is 1, and

R ⁶

Z · -CH-CH - C-CH.-COOH 1 ' ²

OH

- (CH ₂ ), -

European Patent Application EP-142,146, published May 22, 1985, describes oxo analogs of mevinolin-type antihyperchol <3sterolemic agents having the structure

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

CH.

wherein the dashed lines represent 0.1 or 2 possible double bonds.

In J. Mod. Chem. 28, 347-358 (1985) G. E. Stokker et al. the preparation and testing of a series of 5-substituted, 3,5-dihydroxy-pentanoic acids and their derivatives.

In J. Med. Chem. 29, 159-169 (1986) W.F. Hoffmann et al. the presentation and testing of a series:

7- (substituted aryl) -3,5-dihydroxy-hept-6-enoic (heptanoic) acids and their lac'o-ie. One of the preferred compounds in the cited series has the structure

" ⁰ XY"

In J. Med. Chem. 29, 170-181 (1986), G.E. Stokker et al. On the synthesis of a series of 7- (3,5-disubstituted 1,1'-biphenyl-2-yl) -3,5-dihydroxy-hept-6-eic acids and their lactones. Two of the preferred compounds mentioned in this article have the structure

and

CH

xf

CH ₃

In US Pat. U.S. 4,613,610, issued September 23, 1386 to J.R. Wareing, discloses useful pyrazole analogs of mevalonolactone and its derivatives, having the following general formula, for the treatment of hyperlipoproteinemia and arteriosclerosis.

wherein X is - (CH ₂ J _n -, -CH = CH-, -CH-CH-CH ₂ -OdBr-CH ₂ -CH = CH-; η is 0,1, 2, or 3, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Z denote various substituents.

None of the cited patents and articles describes or suggests the possibility of representing the compounds of the present invention. The unique structural feature in the present compounds, a tetrazole ring, differs significantly from the cited literature and shows significant HMG-CoA activity.

Object of the invention

With the present invention is a Verfahiti. for the preparation of nut tetrazole compounds. The compounds of the present invention are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are used as drugs for the treatment and prevention of hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis.

Explanation of the essence of the invention

It is an object of the present invention to provide a process for the preparation of novel tetrazole compounds which are inhibitors of the enzyme HMG-CoA reductase and which can be used for the treatment of hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis

 According to the invention, the compounds of the formula I are prepared,

, 5

tet

R 'and R ⁴ each u-: ibhängig represent hydrogen, halogen, C, -C ₄ alkyl, C ₁ -C ₄ -alkoxy or trifluoromethyl are; R ² , R ³ , R ⁵ and R ^{6 are} each independently hydrogen. Halogen, C, -C ₄ alkyl or C) -C ₄ alkoxy;

is;

I or O II N = N is an integer from 0 to 2; X OH I I

^0H

R ⁷ is hydrogen, C ₁ -C ₄ -alkyl, C, -C ₄ alkoxy (lower) alkyl or 2-methoxy-ethoxymethyl;

X is -OH or = 0 and

R ^{8 is} hydrogen, a hydrolyzable ester group or a cation which is eir. non-toxic pharmaceutically acceptable

Salt forms is.

The terms "C ₁ -C ₄ -alkyl", "C ₁ -C ₆ -alkyl" and "C ₁ -C ₄ -alkoxy" used herein and in the claims (unless stated otherwise) mean alkyl or alkoxy groups having straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexy !, etc. Preferably, these groups contain 1 to 4 carbon atoms, most preferably 1 or 2 carbon atoms The term "(lower) alkyl" in the substituent "C ₁ -C 4 alkoxy (lower) alkyl" as used herein and in the claims means straight or branched chain alkyl groups containing from 1 to 4 carbon atoms, preferably with Unless otherwise specified, the term " .alpha" as used herein and in the claims means chlorine, fluorine, bromine or iodine, and the term "halide" means chlorine: J, bromide or iodide anion The term "a cation which is a non-toxic pharmaceutically acceptable The term "salt" used herein and in the claims is intended to include non-toxic alkali metal salts such as sodium, potassium, calcium and magnesium, the ammonium salt and salts with non-toxic amines such as trialkylamines, dibenzylamine, pyridine, N-methylmorpholine, N- Methyl-piperidine and others, which have been used to form salts of carboxylic acids. Unless otherwise indicated, the term "a hydrolyzable ester group" as used herein and in the claims shall include. Ester group which is physiologically compatible and hydrolyzable under physiological conditions, such as C ₁ -C ₆ -AlkVl, benzyl and Pivaloyloxymeihyl.

In the compounds of the formula I, all double bonds in the trans configuration d. H. (E) as indicated in the structural formulas used herein and in the claims.

Since the compounds of the present invention may contain one or two asymmetric carbon atoms, the invention includes all possible manti and diastereomeric forms of the compound of formula I as described herein and in the claims. The compounds of formula I which contain two asymmetric centers "can produce four possible stereoisomers, referred to as (R, R), (R, S), (S, R) and (S, S) enantiomers All four stereoisomers are contemplated for this compound. Specifically, the compounds of Formula I bearing hydroxy groups at the 3- and 5-position can form four possible stereoisomers which are known as (2R, 5S) -, (3S Here, and in the claims, the term "(±) -erythro" is intended to mean the mixture of the (3R, 5S) - and (3S, 5S), (3R, 5R) and (3S, 5S) stereoisomers 5R) enantiomers and the term "(±) -threo" denotes the mixture of the (3R, 5R) and (3S, 5S) enantiomers The use of a single designation such as (3R, 5S) - is intended primarily to be a stereoisomer The lacon forms of the compounds of the formula I also have two asymmetric carbon atoms, in the 4- and 6-position, and the resulting four stereoisomers can be termed (4R, 6S) -, (4S, 6R), (4R, 6R) and (4S, 6S) stereoisomer. Here and in c ".ar \ claims, the term" trans "lactone is intended to mean a mixture of the (4R, 6S) and (4S, 6R) enantiomers and the term" cis "lactone a mixture of (4R, 6R) The isomer mixtures can be separated into the individual isomers by known methods, for example by fractional crystallization, adsorption chromatography or other suitable separation methods. [Geb Geb] Formed racemates can be prepared in a conventional manner after introduction of suitable salt-hindering groups in separating the antipodes, for example by forming a diastereomeric salt mixture with optically active salt-forming reagents, separating the mixture into diastereomeric salts and converting the separated salts into the free compounds The possible enantiomeric forms can also be separated by fractionation on chiral high pressure liquid chromatography columns become.

When it is desired to produce the (+) isomer of the compounds of formula I, the synthetic (±) isomer of the present compound can be resolved by known separation techniques. As an example of a separation process in this general class of compounds, United States Patent No. 4,375,475, issued March 1, 1983 to AK Willard et al., Describes the resolution of a racemischon (±) trans-lactone with excess (+) - 1-phenyl ethylamine (or the corresponding (-) - 1-phenylethylamine), separation of the resulting .iwei-stereomeric amines and hydrolysis z. B. to the corresponding sodium salt. The resulting salt can then be conventionally converted to the corresponding acid, ester and lactone. Preferably, the optically active enantiomers of the compounds of formula I can be prepared by stereoselective synthetic methods, some of which are described herein. The use of optically active reagents in conjunction with the appropriate precursor described herein leads to the desired enantiomer of the compound of formula I.

Since the compounds of formula I appear to contain varying amounts of solvent, as indicated mostly by elemental analysis, the present invention is intended to include the solvates of the compounds of formula I. In some cases, the dots appear to be true solvates, in other cases, the products may contain only adherent solvents or be a mixture of the solvate with some adhering solvent. Preferably, the solvate is water, especially 1-3 moles of water. The following examples indicate the amount of solvent in the analysis, if possible. Melting points are those of the solvated products unless otherwise stated.

In the compounds of the formula I, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^6, independently of one another, are preferably hydrogen, halogen, C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy. More preferred as R ¹ and R ^{4 are} hydrogen and as R ² , R ³ , R ⁶ and R ^{6 are} independently hydrogen, fluoro, chloro, methyl or methoxy, and most preferred are R 'and R ^{4 are} hydrogen and R is ² , R ³ , R _b and R ^{6 are} independently hydrogen, fluoro, methyl or methoxy. Preferably, η is 0.1 or 2, more preferably η is 1. Preferably, tet is 1 H-tetrazol-5-yl or 1-substituted 1H-Totrazol-5-yl. More preferred as tet is 1-methyl-1H-tetrazol-5-yl, 1-ethyl-1H-tetrazol-5-yl, 1-isopropyl-iH-tetrazol-5-yl or 1- (2-methoxy -ethoxymethyl) -1H-tetrazol-5-yl, and most preferably tet is 1-methyl-1H-tetrazol-5-yl. Preferably, X is -OH or = O, most preferably X is -OH. Preferably, R ^{8 is} hydrogen, C 1 -C ₆ alkyl or a pharmaceutically acceptable cation. Most preferred as R ⁸ is a pharmaceutically acceptable cation, especially sodium or potassium.

In the compounds of formula I wherein A contains two asymmetric carbon atoms bearing hydroxy groups, the erythro isomer is preferred; most preferred is the (3R, 5S) isomer. For the compounds of formula I wherein A contains two asymmetric carbon atoms in the lactone form, the trans isomer is preferred; most preferred is the (4R, 6S) isomer.

The compounds of the formula I can be prepared by various methods, preferably starting from a compound of the formula Ha or Hb,

CHO

Ha

wherein R 'and R ^{4 are} independently hydrogen, halogen, C) -C ₄ -AlkVl ₁ Ci-C ₄ -Akoxy or trifluoromethyl; R ^2, R ^3, R ⁵ and R ⁶ are independently hydrogen, halogen, Ci-C ₄ alkyl or Ci-C ₄ alkoxy and R ⁷ Ci-C ₄ alkyl, C ₁ -C ₄ -AIkOXy- ( lower alkyl), 2-methoxyethoxymethyl or R ^7a , wherein R ^{7a is} triphenylmethyl.

The compounds of the formulas Ma and Mb can be prepared from optionally substituted benzophenones III by aldol condensation to the tetrasubstituted olefin IV and conversion into dun tetrazole ester V, subsequent alkylation of the tetrazole unit and reduction of the ester group in the compounds VI and VII with subsequent oxidation of the resulting alcohols VIII and IX are obtained as indicated in Reaction Scheme 1.

Reaction Scheme 1 Reaction Scheme 1

III

CO ₂ C ₂ K ₅

IV

CO ₂ C ₂ H ₅

N-H

VI

CO ₂ C ₂ H ₅

Reaction Scheme 1 (continued)

Reaction Scheme 1 (Continued)

VIII

CH ₂ OH

CH ₂ OH

IX

Ha

lib

In Reaction Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁵ and H ^{7 are} as defined above. The optionally substituted benzophanones of the formula III can be prepared by the general and known Friedel-Crafts reaction einos catalyzed by Lewis acids phenyl, z. 3. with aluminum chloride in carbon tetrachloride at about ⁰ ° C. A large number of substituted benzophenones are known and their preparation is described while many others are commercially available. For example, many of the starting materials of Formula III are described in G. O'Iah, Friedel-Crafts and Related Reactions, Vol. 3, Part 1 and 2, lnterscience Publishers, New York, 1964, and references cited therein. The Friedel-Crafts reaction can result in a mixture of bentophenones and, if formed, can be separated by conventional methods.

The corresponding benzophenone of formula III can be treated with cyanoacetic ester in a solvent mixture containing glacial acetic acid and an organic solvent such as benzene or toluene in the presence of a catalyst, preferably β-alanine. The reaction is carried out at the reflux temperature of the solvent and the water formed is removed azeotropically with a Dean-Stark or similar device until the formation of tetrasubstituted olefin IV is substantially complete. The nitrile group in compound IV is then converted to the heterocyclic tetrazole unit of compound V by reaction with azidotributylstannane in pure form or in an inert organic solvent such as benzene, toluene or xylene at the reflux temperature of this solvent.

The 1 H-tetrazole compound of formula V can then be alkylated with various alkylating agents by known methods. So the 1 H-tetrazole of the forms! V with a strong base such as sodium hydride in a non-reacting solvent, e.g. Benzen, toluene, diethyl ether and Ν, Ν-dimethyl-formamide or a mixture thereof at a temperature between -3O ⁰ C and about 50 ° C and then with an alkylating Mit'ol, z. As melhyl iodide, ethyl iodide, bromotriphenylmethane, etc. are added or reacted with isobutylene in the presence of a starting acid such as sulfuric acid. The temperature is

not critical and usually depends on the alkylating agent used. This nonspecific alkylation results in an isomeric mixture of alkylation products which can be separated by conventional methods such as crystallization or chromatography into the desired 1-substituted tetrazole compounds VI and the 2-substituted tetrazole compounds VII.

As is known, predominantly an isomer can be obtained by combining reaction conditions with a specific alkylating agent. For example, in the alkylation of compound V wherein R ¹ and R ^{4 are} p-fluorine and R ² , R ³ I, R ⁵ and R ^{6 are} hydrogen, with isobutylene it is preferred to obtain the 2-substituted tetrazole as shown in Example 32 , On the other hand, the alkylation conditions can be varied so that the quantitative ratio of tetrazoles Vl and VII formed varies between 1: 1 and 5: 1. When compounds of formula I are to be prepared in which R ^{7 is} hydrogen, alkylation of compound V with a protecting group such as triphenylmethyl is preferred. In this case, predominantly the 2-isomer of Compound VII is formed as shown in Example 106. Subsequent deprotection then results in a compound of formula I wherein R ^{7 is} hydrogen. Thus, the relative amounts of alkylation products VI and VII can be affected by the reaction conditions and the reagents used. The tetrazole esters of the formulas VI and VII can then be converted as a mixture or preferably after separation according to standard methods individually into the alcohols VIII and IX by the series of known reactions. After a reaction route, the compound of formula VI is first hydrolyzed by conventional methods, e.g. By basic hydrolysis with lithium hydroxide, potassium hydroxide or sodium hydroxide. The resulting acid (Example 5) is then converted by reaction with a reagent such as oxalyl chloride in methylene chloride at reflux temperature in an acyl chloride (Example 6A), and this is with a reducing agent, preferably lithium aluminum hydride in tetrahydrofuran at -73 ⁰ C to the alcohols of formula VIII reduced. The alcohols of formula IX can be prepared from the ester of formula VII by a similar series of reactions. Alternatively and more preferably the alcohols VIII and IX can be prepared from the corresponding esters VI and VII by reduction with reducing agents such as diisobutylaluminum hydride in a non-reducible inert solvents such as methylene chloride at low temperatures, preferably be prepared at about -78 ⁰ C in one stage.

The mixture of the allyl alcohol of the formulas VIII and IX can be easily oxidized with conventional oxidizing agents such as pyridinium chlorochromate in an inert solvent, preferably methylene chloride at room temperature. It is more preferred, however, to separately oxidize the separated allyl alcohol of formulas VIII and IX to the corresponding allyl aldehydes of formulas IIa and IIb.

The compounds of the formula I can be prepared from a compound of the formula IIa or IIb according to various alternative reaction schemes via various classes of novel intermediates. The preparation of compounds of formula I wherein η is 0.1 or 2, must necessarily result in three new aldehyde intermediates. Thus, when compounds of formula I are to be represented as η = 0, the compound of formula IIa or IIb is subjected to the corresponding anionic alkylation as described below. However, if compounds of formula I are to be prepared with η = 1 or 2, the corresponding Wittig reactions are carried out to prepare the necessary new homologous aldehydes X and XI for the 1-isomer and the aldehydes XII and XIII for the 2-lscmer as shown in Reaction Schemes 2 and 3.

Reaction scheme 2 Reaction Scheme 2

lie

CHO

CHO

XI

Reaction scheme 3 Reaction Scheme 3

lib

CHO

· 'U

XII

XIII

In Schemes 2 and 3, R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} as defined above; R ⁷ may also be R ^7a , which is triphenylmethyl. For example, in Reaction Scheme 2, an allyl aldehyde of the formula Ha may be treated with triphenylphosphoranylidene acetaldehyde in an inert solvent such as benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane or the like. The reaction temperature is not critical. Nr can be maintained between room temperature and the reflux temperature of the solvent. For convenience, we prefer to conduct the reaction at reflux temperature. The reaction conditions and the number of equivalents of triphenylphosphoranylidene acetaldehyde per equivalent of a compound of the formula Ma is, of course, of crucial importance. If only oin or just over one equivalent of Wittig reagent is used, however, the reaction conditions are not carefully controlled, e.g. Time, temperature, mode of addition, etc., a mixture of the diene aldehyde X and the trienaldehyde XI may be formed. The ratio of aldehydes X and Xl depends, of course, on the reaction conditions. In a specific example, Example 8, a ratio of etv / a 9: 1 of the aldehydes of general formulas X and Xl is formed from the corresponding aldehyde of general formula Ha. The Wittig reaction can also be used to aid in the selective reaction and separation of compounds by employing less than one equivalent of the Wittig reagent, predominantly forming the diene aldehyde X. The use of 1/2 equivalent Wittig reagent as described in Example 69 provides the desired diene aldehyde X and unreacted aldehyde Ma which can be readily separated. Preferably, the reaction is carried out with about one equivalent of Wittig reagent under controlled reaction conditions, e.g. B. as described in Example 77, wherein the desired aldehyde X is obtained without

NMR spectroscopy of the homologous trienaldehyde was detectable. However, if the triene aldehydes of formula XI are to be prepared, the reaction of the aldehyde of formula IIa is carried out with at least two equivalents of Wittig reagent, or the diene aldehyde X is reacted with another equivalent of Wittig reagent to the trienaldehyde XI. Accordingly, the formation of the desired homologous aldehydes X and XI, where η is 1 or 2, may be controlled as desired by employing the appropriate amount of Wittig reagent and reaction conditions. The conversion of an aldehyde of the formula IIb into the corresponding homologous diene aldehydes of the formula XII and triene aldehydes of the formula XIII, as shown in Reaction Scheme 3, can be carried out by methods similar to those described above for the preparation of the aldehydes of the formulas X and / '. Some of the vinylogous aldehydes in Reaction Schemes 2 and 3 are easily and conveniently isolated, while others are more difficult. In special cases, where the aldehydes are difficult to separate with the help of the chromatographic systems used here, the aldehyde mixture, z. For example, aldehydes X and XI are used for the next reaction step, after which separation and isolation of diene and triene compounds by chromatography or other conventional methods may be easier.

The compounds of the formula I in which X is -OH can be prepared from a compound of the formula IIa, IIb, X, XI, XII or XIII according to the general reaction route shown in Reaction Scheme 4. For purposes of discussion, all of the aldehydes of Schemes 2 and 3 are grouped into a formula XIV wherein η is 0.1 or 2 and R ', R ² , R ³ , R ⁴ , R ⁵ and R ^{e are} as defined above.

Reaction scheme 4

CHO

ti

tea

XIV

In Reaction Scheme 4, the penultimate intermediate of Formula XV, wherein R ^{9 is} a hydrolyzable ester group such as methyl, ethyl or tertiary butyl ester, can be prepared from the corresponding aldehyde of Formula XIV by reaction with the in situ generated dianion of the corresponding acetoacetic ester. such as B. in Examples 10 and 90 described. The reaction may be carried out in an inert solvent such as tetrahydrofuran organisachen at low temperatures between -78 ⁰ C and O ⁰ C, distortion, between about -78 ⁰ C and -4o ⁰ C until the reaction is almost complete. When a compound of formula XV has been prepared from an aldehyde mixture of formula XIV, the various compounds of formula XV wherein η is 1 or 2 can be advantageously separated and isolated at this stage by conventional methods.

The ketone ester of the formula XV can be prepared by reduction of the ketone radical with known reducing agents, for. For example, sodium borohydride, sodium cyanoborohydride, zinc borohydride, disiamylborane, diborane, Ammoiiak-borane, tert-butylamine-borane, pyridine-borane, lithium tri-sec-butylborohydride or similar reducing agents that neither reduce nor hydrolyze the carboxylic acid ester group to the dihydroxy ester of the formula I a can be reduced. Preferably, the reduction is stereospecifically carried out as a stereospecific two-step reaction to maximize the formation of the preferred erythro isomer of the compound of formula I. The stereospecific reduction of a compound of formula XV de ~ arfolgt with trisubstituted boranes, preferably triethylborane or Alkoxydialkylboranen, preferably methoxydiethylborane or Ethoxydiethylboran (Tetrahedron Letters, 28.15511987]) at a temperature between about -7O ⁰ C and room temperature. The complex formed is then reduced with sodium borohydride at a temperature between about 5O ⁰ C and about -7B ⁰ C in an inert solvent such as tetrahydrofuran, diethyl ether or 1,2-dimethoxy-ethane, preferably tetrahydrofuran. The reduction is then completed by adding methanol. The compound of the formula I a formed by the stereospecific reaction contains two asymmetric carbon atoms which carry the hydroxy groups in erythro configuration. The reduction of the ketone radical under the reaction conditions used here thus leads predominantly to the erythro-isomers of the compounds of the formula Ia, while only small amounts of the less preferred threo-isomers are formed. The ratio of erythro / threo of the compounds formed varies according to the particular compound used and the reaction conditions used. Normally this ratio is around 9: 1 to 98: 2. In contrast, nonspecific reduction usually results in a 1: 1 isomer mixture. Nevertheless, the isomer mixture can still be separated and purified by conventional methods and converted by known methods into the compounds of general formula I.

The compounds of formula I wherein A is defined by a substituent in which X and R ^{8 are} present, and X-OH and R ^{8 is} hydrogen (1 c), or R ^{e is} a hydrolyzable ester group (I a) or Kat'on, which forms a nichitoxic pharmaceutically acceptable salt (I b), or in dene.ι A is present in lactone form (Id) can be prepared according to Reaction Scheme 5 and converted into each other as desired.

Reaction scheme 5 Reaction Scheme 5 Compounds of Formula %

R ⁵ Ψ

Ia

ib

ic

id

In Reaction Scheme 5, R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , tet and η are as defined above, R ⁹ is a hydrolyzable F. Group and M ⁰ is a cation. The preparation of a compound of the formula I b ε; a compound of formula I a is preferably carried out by basic hydrolysis with bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide in an organic solvent such as tetrahydrofuran, ethanol and methanol bui a temperature between ^{0 0} C and about 50 ° C. The cation is usually determined by the hydroxide used. However, if desired, the cation can also be exchanged for another cation with the aid of ion exchange resins.

The compound of the formula Ic can be cyclized by conventional lactonization methods to give the corresponding lactone of the formula Id, eg. Example by heating the acid in an inert organic solvent such as benzene, toluene and xylene and azeotropic separation of the yebilceten water or by treatment of the compound of formula Iein an inert organic solvent, for. As toluene, benzene, diethyl ether or methylene chloride with an acid such as p-toluenesulfonic acid in the equivalent of a drying agent, for. As Na ₂ SO ₄ , MgSO ₄ or molecular sieves. Preferably, the lactonization takes place. by activating the carboxyl group with a carbodiimide as described in the examples in binary inert organic solvents such as tetrahydrofuran and preferably in methylene chloride or ethyl acetate at room temperature to form the lactone of formula I d. If the relative stereochemical configuration of the two carbon atoms carrying the hydroxy groups is found to be erythro in formula Ic, lacnation results in the preferred trans-lactone of formula I d, otherwise lactonization results in a mixture of the trans and cis lactones ,

The formed lactone of formula Id can, if desired, with bases or acids to the compounds of the forms! I b or Ic are hydrolyzed, or the lactone can be hydrolyzed in the presence of an alcohol to the compounds of formula I a. The compounds of formula I wherein X in substituent A is O can be prepared by reaction of a corresponding aldehyde of formula XIV with the phosphonate compound of formula XVI as shown in Reaction Scheme 6.

Reaction scheme 6

Reaction Scheme 6

0 0 OH

CH ₃ O '

CHO

OCK.

XVI

tet

XIV

In Reaction Scheme 6, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , tet and η are as defined above and R ⁹ is a hydrolyzable ester group. The preparation of a compound of formula Ie may be carried out as illustrated in Reaction Scheme 6 in an inert organic solvent such as acetonitrile, methylene chloride, chloroform, tetrahydrofuran, etc. at a temperature between ⁰ ° C and the reflux temperature of the solvent, preferably at room temperature in the presence of a solvent suitable organic base. Suitable organic bases are tertiary amines such as tiethylamine, N-methylmorpholine, N-methyl-piperidine, 1 / - diazabicyclo [2.2.2] octane (DABCO), ie-diazabicycloSAO lundecene (DBU), 1,5- Diazabicyclo [4.3.0] non-5-ene (DBN), etc. The resulting compound of formula I e wherein R ^{9 is} a hydrolyzable ester group may, if desired, be hydrolyzed by conventional methods to give compounds of formula I wherein R is hydrogen ⁹ through the sub; tituonten R ^{8 is} replaced, as described here in reaction scheme δ.

In an alternative reaction route, a preferred embodiment of the compounds of formula I wherein η = 1 is X-OH and tet is 1-methyl-1H-tetrazol-5-yl may be prepared according to the procedure described in Reaction Scheme 7.

Reaction scheme 7

Reaction Scheme 7 XVII or XVIIa

OR ¹⁰ OR ¹⁰ 0

XIX

9 If

In Scheme 7, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above, R ⁹ is a hydrolyzable ester group, R ¹⁰ is

0 R ¹³

Il ay

tert-butyldiphenylsilyl and Z is -P- (OR ¹² ) ₂ or -P-R ³ X ⁰ ,

R ^1J

wherein R ^{12 is} C 1 -C ₄ alkyl, R ' ^{3 is} phenyl which is unsubstituted or substituted by one or two C 1 -C ₄ alkyl or chloro substituents, and X is bromine, chlorine or iodine. The phosphonium salt of the formula XVII or phosphonate of the formula XVII a, which is described in US Pat. 018,580, registered on February 25, 1987, and in the partial continuation

U'SA patent application Serial No (CT-1890A), registered on (simultaneously) by us and our colleagues

freelakantan Baiasubramanian and Peter J. Brown, can be prepared with the silyl-protected aldehyde of Formula XVIII, which in turn can be prepared by the method described in Tetrahedron Letters 25,2435 (1984) and U.S. Patent 4,571,428, to the silyl-protected compound of U.S. Pat Forme! XIX be implemented. The reaction may be carried out in an inert organic solvent such as tetrahydrofuran or Ν, Ν-dimethylformamide in the presence of a strong base, e.g. As lithium diisopropylamide, butyl lithium or potassium di-tert-butoxide at a temperature between -78 ° C and about ^{0 0} C are performed.

The compound of formula XIX can then be readily desilylated by known methods, e.g. Example, by 48% hydrofluoric acid and preferably with Teir?, Butylammonium fluoride in an inert organic solvent such as tetrahydrofuran or acetonitrile, wherein the Erytr ro compounds of the formula I f are formed, a more preferred embodiment of the compounds of formula I a. The substituent R ⁹ can then be converted to the substituent R ⁸ as described in Reaction Scheme 5 herein and illustrated.

When predominantly a stereoisomer of a compound of formula i is to be prepared, optically pure starting materials are preferably used. The various processes for preparing an isomer of a compound of formula I wherein X is -OH are illustrated in Schemes 8, 9 and 10. The most preferred isomer of a compound of formula I wherein A is defined as

is the (3R, 5S) isomer. and the most preferred isomer of a compound of formula I wherein A is defined as

is the (4R, 6S) isomer. Actually requires only one of the two above definitions of A for compounds of the formula I, di them, wi 8 shown in Reaction Scheme 5, ineinande ^r can be converted. To illustrate the use of optically pure starting materials, the preparation of a preferred embodiment of a compound of formula I such as the (3R, 5S) -isomer of a compound of formula I f is shown in three synthetic routes in Schemes 8, 9 and 10.

Reaction scheme 8

Reaction Scheme 8

Compound of Formula XVII +

Compound of Formula XVII +

XXIII

(3R, 5S) Compound of Formula If

(4R, 6S) Compound of Formula Ig

In Reaction Scheme 8, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^{6 are} as defined above and R ¹⁰ is tert-butyldiphenylsilyl. The starting materials XX and XXII are known and their preparation is described in Tetrahedron Letters 23,4305 (1982) and U.S. Patent 4,613,610. The compound of formula XVII or XVIIa can be reacted with the compound of formula XX in an inert solvent to give the compounds of formula XXI, which can then be hydrolyzed with acid in a solvent mixture containing acetic acid, tetrahydrofuran and water, followed by a mild oxidation with pyridinium chlorochromate in methylene chloride to give the desired trans-lactone of formula XXIII. Alternatively, the trans-lactone of formula XXIII can also be prepared directly by condensation of a compound of formula XVII and a compound of formula XXII. Desilylation with 48% hydrofluoric acid in acetonitrile, but preferably with tetrabutylammonium fluoride affords the (4R, 6S) -isomer compound of formula Ig which, if desired, is then converted to the (3R, 5S) -somoror of a compound of formula If can.

Reaction scheme 9

Reaction Scheme 9

CHO

OTHP

Xa

XXIV

10

OR ⁹ R ²

(3R.5S) compound of Formula If

XXVII

The second stereospecific approach is given in Scheme 9, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above, R ^{9 is} a hydrolyzable ester group and R ^{10 is} tert-butyldiinethylsilyl. The diene-aldehyde of formula Xa can be treated with sodium cyanide and the resulting cyanohydrin is converted to the tetrahydropyranyl (THP) derivative of formula XXIV. The compound of formula XXVI can be prepared by reacting the compound of formula XXIV previously treated with a strong base such as butyllithium with the iodo ester of formula XXV. The preparation of the optically pure protected iodohydrin XXV, wherein R ' ^{0 is} tert-butyldimethylsilyl and R ^{9 is} methyl, is described in Tetrahedron Letters 25,2951 (1985). The removal of the protecting groups may be by acid hydrolysis to the ketoalcohol of formula XXVII The stereospacial reduction of a compound of formula XXVII with sodium borohydride / triethylborane or sodium borohydride / alkoxydialkylborane as described herein may be used to prepare the 5-oxo group to the desired (5S) To reduce the stereochemistry so that the (3S, 5R!) Enantiomer of the compound of formula If is obtained Thus, Scheme 9 provides a method for preparing the (3R, 5S) -isomer of a compound of formula I by using the optically pure starting material XXV, which has the appropriately substituted carbon atom in the 3-position, which directs the stereospecific reduction of the 5-oxo function.

Reaction scheme 10

Reaction Scheme 10

CHOÄX "

^H 3 ^C | Nh

Oh

, / ^! Γ 'N-CH

XXVIII

OH

XXIX

OCH,

XXX

Reaction Scheme 10 (continued)

Reaction Scheme 10 (Continued)

OH ο 0

Ν = ·

XXXI

(3R.5S) Compound of Formula If

The third stereospecific approach is illustrated in Scheme 10 wherein R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{9 are} as defined above. The starting material of formula XXVIII is known. Its preparation is described in Tetrahedron Letters 25, 5031 (1984). The compound of formula XXVIII is first treated with a non-nuclophilic base, preferably lithium diisopropylamide, in an inert solvent such as tetrahydrofuran and the enolate formed is then reacted with an allyl aldehyde of formula Xa to form the triphenyl ester of formula XXIX.

When the compound of formula XXIX is treated with Nairium methylate in methanol, the methyl ester of formula XXX can be isolated. When the methyl ester of formula XXX is reacted with the anion of tert-butyl acetate which is generated in situ with a non-nucleophilic base such as lithium diisopropylamide, the ketooster of formula XXXI is formed. Alternatively, the preparation of a compound of formula XXXI can also be accomplished by direct treatment of the triphenyl ester of formula XXIX with the aryl portion of tert-butyl ester. By selective stereospecific reduction of the formed ketofunction of formula XXXI with sodium borohydride triethylborane or sodium borohydride alkoxydialkylborane as described herein, the (3R.5S) enantiomer of a compound of formula If can be obtained. Thus, Reaction Scheme 10 provides a method of preparing the (3R, 5S) -isomers of a compound of Formula I by using the optically pure starting material XXVIII, which provides an appropriately substituted carbon atom at the 5-position, which provides the stereospecific reduction of the 3-oxo Function directs. In a specific example described herein wherein R ¹ and R ^{4 are} fluorine and R ² , R ³ , R ⁵ and R ^{e are} hydrogen, a method for preparing a compound of the formula If is presented which predominantly contains (3R.5S) Enantiomer is.

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

R ¹ and R ⁴ are each independently of the other hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or trifluoromethyl, R ² , R ³ , R ⁵ and R ⁶ are each independently hydrogen, halogen, C ₁ - C ₄ -AlkVl or C) -C ₄ -alkoxy, η is an integer from 0 to 3,

OW γ

L Jl

is

R ⁷ is hydrogen, C ₁ -C ₄ -alkyl, C, -C ₄ alkoxy (lower) A! Is alkyl or 2-methoxy-ethoxymethyl, X is -OH or = 0 and

R ^{8 is} hydrogen or a hydrolyzable ester group j or a cation containing a non-toxic pharmaceutically acceptable salt

forms is

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

6>

wherein R ', R ² . R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently hydrogen, fluoro, chloro, methyl or methoxy; R ^{7 is} C ₁ -C ₄ alkyl and R ^{8 is} hydrogen, C ₁ -C ₄ alkyl or a cation which forms a non-toxic pharmaceutically acceptable salt. In a particularly preferred embodiment, R ^{7 is} methyl

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

OH

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{e are} each independently hydrogen, fluoro, chloro, methyl or methoxy and R ^{7 is} C 1 -C 4 alkyl. In a particularly preferred embodiment, R ^{7 is} methyl. Especially preferred compounds of the invention are

(a) 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-fr (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoic acid, di-ethyl ester;

(b) ^ S-Bis-t-fluorophenyl-S-B-dihydroxy-e-d-methyl-IH-tetrazol-B-yD-nona-S-dienoic acid or a non-toxic pharmaceutically acceptable salt;

(c) Natriurri-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoate,

(d) OR.SSl-g.g-bis-1-fluoro-phenyl-S.S-dihydroxy-O-d-m-butyl-IH-tetrazol-S-yDnona-e.B-dienoic acid or a non-toxic pharmaceutically acceptable salt;

(e) OR.BSI sodium g.g-bis-t-fluorophyl-S-di-S-dihydroxy-e-d-methyl-IH-tetrazol-B-yn-nona-e.e-dienoate,

(f) trans-6- [4,4-bis (4-fluoro-phenyl) -3- {1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl-4-hydroxy-tetrahydropyran -2-one,

(g) (4R, 6S) -trans-6- [4,4-bis (4-fluoro-phenyl) -3- {1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl ] -4-hydroxy-tetrahydro-2-one, (h) 11, i1-bis (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl-1H-tetrazol-5-yl) undeca-6,8,10-trienoic acid or a non-toxic pharmaceutically acceptable salt,

i) sodium 11,11-bis (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl-tH-tetrazol-5-yl) undeca-6,8,10-trienoate, ( j) trans-6- [4,4-bis- (4-fluoro-phenyl) -3- {2-methyl-2H-tetrazol-5-yl) -buta-1,3-dienyl-4-hydroxy-tetrahydropyran -2-one, (k) 9,9-bis (4-fluoro-phenyl) -3,5-ciihydroxy-8- {2-methyl-2H-tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt,

(I) Sodium 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8 - (? - methyl-2H-tetrazol-5-yl) nona-6,8-dienoate, ( m) 9,9-bis (4-fluoro-phenyl) -3-hydroxy-8- {1-methyl-1H-tetrazol-5-yl) -5-oxo-nona-6,8-dienoic acid or a non-toxic pharmaceutical acceptable salt,

(n) Sodium 9,9-bis (4-fluoro-phenyl) -3-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -5-oxo-nona-6,8-dienoate , (o) 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) -6,8-nonadienoic acid or a non-toxic pharmaceutically acceptable salt .

(p) sodium 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8 (1-isopropyl-1H-tetrazol-5-yl) nona-6,8-dienoate, (q) 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-isopropylco-1H-tetrazol-5-yl) nona-6,8-dienoic acid ethyl ester, (r) 8,9- Bis- (4-fluoro-3-methylphenyl) -3,5-dihydroxy-8'-1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt;

(s) Sodium 9,9-bis (4-fluoro-3-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetra-7-ol-5-yl) -6,8-nonadienoate , (t) 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- {1-ethyl-1H-litr-i-ol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt,

(u) sodium 9,9-bis (4-fluoro-plienyl) -3,5-dihydroxy-8- {1-ethyl-1H-tetrazol-5-yl) nona-6,8-dienoate, (v 9 ₍ 9-bis- (2,4-dimethyl-phoryl) -5,5-dihydroxy-8- (1-methyl-1H-tβ-trazol-5-yl) nona 6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt,

(w) sodium 9,9-bis (2,4-diniethylphenyl) -3,5-dihydroxy-8- [1-methyl-1H-tetrazol-5-yl] nona-6,8-dienoate, (x) 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- [1- {2-methoxyethoxymethyl) -1H-tetrazol-5-yl-nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt,

(y) Sodium 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- [1- (2-methoxyethoxymethyl) -1H-teirazol-5-yl] nona-6,8 dienoate, (z) 9,9-bis (4-fluoro-2-methylphenyl) -3,5-dihydroxy-8- {1-methyl-1H-tetrazol-5-yl) nona-6,8 dienic acid or a non-toxic pharmaceutically acceptable salt, (aa) sodium 9,9-bis (4-fluoro-2-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl ) nona-6,8-dienoai,

(bb) 9,9-bis (2-fluoro-4-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid, a non-toxic pharmaceutically acceptable salt,

(co) Sodium 9,9-bis (2-fluoro-4-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate ,

In another aspect, the present invention provides novel intermediates having the formula:

CHO

XIV

tet

wherein R ¹ and R ^{4 are} each independently of one another hydrogen, halogen, C ₁ -O ₄ -alkyl, C ₁ -C ₄ -alkoxy or trifluoromethyl; R ² , R ³ , R ⁵ and R ^{e are} each independently of one another hydrogen, halogen, C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy;

or

ifit!

η is an integer of 0 to 2 and R ^{7 is} C ₁ -C ₄ -alkyl, Ci-C ₄ -alkoxy (lower) alkyl, 2-methoxy-ethoxymethyl or R ^7a where R ^7a is triphenylmethyl.

In a preferred embodiment, the compounds of formula XIV have the structure

CHO

wherein R ¹ and R ^{4 are} each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl; R ^2, R ^3, R ⁵ and R ⁶ JeWViIs unabhänyig one another are hydrogen, halogen, Ci-C ₄ alkyl or C | are -C ₄ alkoxy; η is an integer from 0 to 2 and R ^{7 is} C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, lower alkyl or 2-methoxyethoxymethyl

 In a more preferred embodiment, the compounds of formula XIV have the structure

wherein R ', R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently hydrogen, fluoro, chloro, methyl or methoxy and R ⁷

C) -C ₄ alkyl. In a particularly preferred embodiment, R ^{7 is} methyl.

In a further more preferred embodiment, the compounds of formula XIV have the structure

-35- / 9,880

CHO

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{e are} each independently hydrogen, fluoro, chloro, methyl or methoxy and R ^{7 is} C 1 -C ₄ alkyl. In a particularly preferred embodiment, R ^{7 is} methyl.

In a further aspect, the present invention provides novel intermediates of the following formula

wherein R ¹ and R ⁴ are each independently hydrogen, halogen, C | are -C ₄ alkyl, C ₁ -C ₄ -alkoxy or TrifluormethyI; R ^2, R ^3, R ⁵ and R ^e are each independently hydrogen, halogen, Ci-C ₄ alkyl or C | are -C ₄ alkoxy; η is an integer from 0 to 2;

or

is;

R ^{7 is} Ci-C-alkyl, C ₍ -C 4 -alkoxy (lower) alkyl, 2-methoxy-ethoxy-methyl or R ⁷ *, wherein R ⁷ * is triphenylmethyl and R ^{9 is} a hydrolyzable ester group.

In a preferred embodiment, the compounds of the formula XV have the structure ₍

wherein R ¹ and R ⁴ are each hydrogen, halogen, Ci-C are independently ₄ alkyl, C) -C ₄ -alkoxy or trifluoromethyl; R ² , R ³ , R ⁵ and R ⁶ are each independently hydrogen, halogen, C 1 -C ₄ alkyl or C 1 -C ₄ alkoxy; η is an integer from 0 to 2; R ⁷ C -C ₄ -alkyl, Ci-Ci-alkoxy (nioderes) alkyl or 2-methoxy-ethoxymethyl is around ¹ R ⁹ a hydrolysiarbare ester group.

In a more preferred embodiment, the compounds of formula XV have the structure

, 5

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^e are each independently hydrogen, fluoro, chloro, methyl or methoxy and R ^{7 is} C 1 -C ₄ alkyl. In a particularly preferred embodiment, R ^{7 is} methyl.

The compounds of formula I are competing inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, and are therefore selective suppressors of cholesterol biosynthesis in animals including humans. Thus, they are useful for the treatment of hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis.

In another embodiment, the present invention includes pharmaceutical compositions containing at least one compound of formula I in combination with a pharmaceutical carrier or diluent. In a further embodiment, the present invention relates to a method for inhibiting cholesteiole biosynthesis in needy animals, consisting in administering to said animal an effective cholesterol-inhibiting dose of at least one of the compounds of formula I.

For therapeutic purposes, the pharmacologically active compounds of the formula I are normally administered as a pharmaceutical preparation which is described as de. '- the one) essential ingredient at least one such compound together with a solid or liquid pharmaceutically acceptable carrier and optionally with pharmaceutically acceptable excipients and binders and are prepared according to standardized and conventional methods. The pharmaceutical preparations can be administered orally, parenterally or rectally as suppositories. A wide variety of pharmaceutical forms can be used. Thus, when using a solid carrier, the preparation can be pressed into Tobleiten, packaged as a powder or pellet in hard gelatin capsules or shaped as a lozenge. The solid carrier may contain conventional 'ά <isaizstoffe such as binders, fillers, tabletting lubricants, release agents, wetting agents, etc.. The tablet may be film coated as desired by conventional methods. When a liquid carrier is used, the paste may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, aqueous or non-aqueous. liquid preparations or a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, nonaqueous vehicles (including edible oils), preservatives, as well as flavoring and / or coloring agents. For parenteral administration, the vehicle will normally contain sterile water, at least in the main, but saline solutions, glucose solutions, etc. may also be used, and injectable suspensions may be used, conventional suspending agents may be used. Conventional preservatives, buffers, etc. may be used The pharmaceutical preparations can also be prepared by conventional methods, depending on the desired preparation, with the appropriate amount of the active ingredient, ie the compound of the formula I which is the object of the invention of such factors as the weight of the patient and the mode of administration, but also the desired degree of inhibition of cholesterol biosynthesis and the efficacy of the compound used. The decision on the single dose and the number of daily Ga ben is the physician and may be varied by adjusting the dose to the specific circumstances of this invention for the satisfactory inhibition or reduction of cholesterol bicycles synthesis, each oral dose containing the active ingredient in an amount of about 0.01 mg / kg to about 10 mg / kg body weight, on r afford may preferably from about 0.05mg / kg to about 2mg / ky kroner weight. The active ingredient should preferably ir. Fine four equal daily doses. be submitted. It wii 'i, however, normally be administered to a small dose and otieso gradually increased until the optimal dosage for the treated patients is observed.

A particularly preferred method of making the most preferred embodiment of the present invention having the formula

CHO nc

CH.

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above, are described in U.S. Patent Application Serial No. 018,558, registered on

February 25, 1987, and in the partial continuation of United States Patent Application Serial No. (CT-1890A), registered on

(simultaneously) described by us and our colleagues Neelakantan Balasubramanian and Peter J. Brown. The compounds of the formula IIIc can be prepared by various processes, preferably from a compound of the formula

XXXII,

N-N

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^{6 are} as defined above and R "is hydrogen, Ci-Ce-Aikoxycarbonyl or methyl.

The use of the compounds of formula XXXII is an effective and selective process which avoids the alkylation mixtures as described in Scheme 1.

The compounds of formula XXXII can be prepared from the optionally substituted benzophenones of formula III by alkylation with the corresponding 5-substituted 1-methyl-tetrazole of formula XXXIII and subsequent dehydration of the resulting tertiary alcohol of formula XXXIV as shown in scheme 11.

Reaction scheme 11

Reaction Scheme 11

Ν-Ν

XXXIII

XXXIVXXXII

In Reaction Scheme 11, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{11 are} as defined above. The optionally substituted benzophenones of the formula III can be prepared by the general and known Friedel-Crafts reaction. The starting material of formula XXXIII, wherein R "is hydrogen, is commercially available while the starting materials wherein R" is C, -C ₆ alkoxycarbonyl or methyl can be prepared by reacting 1,5-dimethyl-tetrazole with a strong base such as butyllithium at a temperature between about - 70 ⁰ C and about ^{0 0} C and reaction of the resulting anion with preferably chloroformate or methyl iodide, as described herein.

The corresponding 5-substituted-1-methyl-tetrazole of formula XXXIII can with a strong base such as butyllithium at temperatures between about -20 rivet rigon ⁰ C and about 78T, preferably between about -40 ° C and -78 ° C in an organic solvent For example, tetrahydrofuran, diethyl ether, 1,2-dimethoxy-ethane, etc. are treated. The resulting anion of formula XXXIII can then be reacted with the desired benzenophenone of formula III to give the corresponding tertiary alcohols of formula XXXIV.

The compounds of formula XXXII can be prepared from the compounds of formula XXXIV according to conventional dehydration procedures. The dehydration may be carried out by heating the alcohol of formula XXXIV in a suitable inert organic solvent, e.g. 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, e.g. B. Na ₂ SO ₄ ,

MgSO ₄ , molecular sieves, etc., or the water formed is preferably separated azeotropically with a Dean-Stark trap or similar apparatus.

Alternatively, the alcohol of the formula XXXIV can be easily with potassium hydrogen sulfate are heated at temperatures of 19O ⁰ C OTWA.

In the specific example wherein R ^{11 is} ethoxycarbonyl, the reaction of 1-methyl-tetrazol-5-yl-ethylacetate with a benzophenone of formula III in the presence of titanium tetrachloride and carbon tetrachloride can be used to directly formate the corresponding olefin of formula XXXII in one step.

The preferred aldehydes of formula Nc can be prepared by various methods from the compounds of formula XXXII, depending on which substituent R "is present in the process Thus compounds of formula XXXII wherein R ^{11 is} ethoxycarbonyl (XXXIIa), hydrogen (XXXIIc ) or methyl (XXXIId) is converted into the aldehydes of methylene chloride according to Scheme 12.

Reaction scheme 12

Reaction Scheme 12

XXXIIB

XXXIIe

XXXIId

In Reaction Scheme 12, R ', R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above. The alcohols of formula XXXII b can be prepared by reduction of the tetrazole ester of formula XXXII with reducing agents such a diisobutyl aluminum hydride in a non-reducible inert solvents such as methylene chloride and tetrahydrofuran at low temperatures, preferably at about -78 ⁰ C, preferably in one stage. The resulting allyl alcohol of formula XXXIIb can be easily oxidized with conventional oxidants such as pyridinium chlorochromate in an inert solvent, preferably methylene chloride, at room temperature to the desired aldehyde of formula Hc. The compounds of formula XXXIIc can be converted directly into the aldehydes of formula IIc by reacting the anion of formula XXXIIc which is in situ in an inert organic solvent, e.g. B. tetrahydrofuran or 1,2-dimethoxy-ethane, is reacted with a strong base such as butyllithium is reacted with formic acid.

The compounds of the formula IIIa may also be prepared from the compounds of the formula XXXIId by treatment thereof with N-bromo-succinimide in the presence of a catalyst such as azoisobutyronitrile or olibenzoyl peroxide in carbon tetrachloride and subsequent reaction of the resulting allyl bromide of the formula XXXIIe with 2-nitropropane according to the general formula Procedure here and in Org.Syn.Coll. Vol. IV, 932. Alternatively, the allyl bromide of formula XXXIIe may be prepared from the alcohol of formula XXXIIb by treatment with carbon tetrabromide and triphenylphosphine.

In an alternative and preferred process for the preparation of compounds of the formula I, intermediates of the formulas XVII and XVIIa according to Reaction Scheme 13 are presented.

Reaction Scheme 13

13

XVII

R-

XXXIIe

- (OR ¹² )

CIL

XVIIa

In Reaction Scheme 13, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹² , R ¹³ and X are as defined above. Dus AIIyIk romid of the formula XXXII e can be prepared in a conventional manner with phosphines such as triphenylphosphine in an inert organic solvent! how cyclohexane are converted to the phosphonium salt of formula XVII. Alternatively, the allyl bromide of formula XXIIe may be reacted in a conventional manner with phosphites, such as trimethyl phosphite and triethyiphosphite, either in pure form or in an inert organic solvent, preferably in pure form, to the phosphonates of formula XVIIa.

The intermediates of formulas XVII and XVIIa can then be converted to the compounds of formula If by a series of reactions set forth in Reaction Scheme 7.

Another particularly preferred method for preparing the compounds of formulas I f and I g of the present invention

consists in the use of intermediates of the formulas

XXXVa

XXXVb

substantially in the cis form, wherein R ¹⁶ and R ^{17 are} each C 1 -C ₄ alkyl or together with the carbon atom to which they are attached, cyclopentyl, cyclohexyl or cycloheptyl and R ^{19 is} hydrogen, C, -C ₄ Alkyl or a metal cation. The preparation and use of the compounds of the formulas XXXVa and XXXVb is described in US Pat. Appl., Lfd. No.

(CT-1928), registered at (concurrently) by William T. Han and John J. Wright.

The substituted 1,3-dioxane compounds of formula XXXVa, XXXVb and other similar compounds described herein also contain two asymmetric carbon atoms in the 4- and 6-positions, as indicated below.

and the possible stereoisomers may be referred to as (4R, 6S), (4S, 6R), (4R, 6R) and (4S, 6S). In the following, the term trans-1,3-dioxane means a mixture of the (4R, 6R) - and (4S, 6S) -enantiomers, while the term cis-1,3-cioxane a mixture of (4R, 6S) - and (4S, 6R) enantiomers. Since the most preferred enantiomer of the lactone compounds of the formula Ig happens to have the same (4 R, 6 S) configuration as the most preferred enantiomer of the 1,3-dioxane intermediates, the additional designation trans and cis was introduced to confuse vermeidon.

The compounds of formulas XXXVa and XXXVb can be prepared by reacting an aldehyde of formula XXXVI with an acetoacetic acid ester and then reacting a ketone or ketal with a compound of formula XXXVIII, followed by hydrolysis of the resulting 1,3-dioxane of formula XXXIX and optionally dissolving the Acid of formula XXXX as given in Reaction Scheme 14.

Reaction scheme 14 Reaction Scheme 14

XXXVT

¹⁸

OH 0

XXXVII

XXXIX

III

XXXVIII

ι « air

R ¹ · '

xxxx

η "j? ¹⁷

XXXVaXXXXI

XXXVb

In Reaction Scheme 14, R ¹⁴ and R ¹⁵ are each independently hydrogen, C 1 -C ₆ -alkyl or phenyl which is substituted by one or two C 1 -C ₄ -alkyl, halogen, C 1 -C ₄ -alkoxy or trifluoro methyl groups may be substituted; R ' ³ is a hydrolyzable ester group, m is 0 or 1 and R ¹⁶ and R ¹⁷ are as defined above. The keto ester of the formula XXXVII by reacting an acetoacetic ester with an aldehyde of formula XXXVI according to known methods in an inert organic solvent such as tetrahydrofuran at temperatures of about ⁰ ° C to about -78 ⁰ C in the presence of a base such as sodium hydride. Lithium diisopropylamide of butyllithium be prepared.

The starting materials of formula XXXVI wherein m = 0 or 1 are known and can be readily prepared by known methods. The starting materials of formula XXXVI wherein m = 1 can also be prepared by reaction of compounds of formula XXXVI wherein m = 0 with Wittig reagents such as triphenylphosphoranylidene acetaldehyde or other known methods. The relative configuration of the double bond (m = 0) or double bonds (m = Dkanntrans, ice or a mixture thereof.) The relative amounts of geometric isomers (E) and (Z) depend on the availability of the commercial products or the presentation conditions used. In a specific example described herein, a mixture containing mainly the trans isomer (E) is used Even if a small amount of the other isomer is present in the entire reaction sequence shown in Reaction Scheme 14, it is clear that the relative amount The ketoester of formula XXXVII can be reduced with known reducing agents to give the dihydroxy ester of formula XXXVIII Preferably, the reduction is stereospecific in a two-step reaction to avoid formation of the isomers of the preferred erythro-isomer of the dihydroxy ester of formula XXXVIII to m aximieren. The stereospecific reduction is carried out with tri-substituted alkylene Iboranen, preferably triethylborane or tributylborane, or Alkoxydialkylboranen, preferably methoxydiethylborane or Ethoxydiethylboran (Tetrahedron Letters, 28.155 [1987]) at a temperature between about -7O ⁰ C and room temperature. The complex formed is then dissolved in an inert organic solvent such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, preferably tetrahydrofuran, reduced with sodium borohydride at a temperature between about -50 ⁰ C and about -78 ° C. The reaction is then completed by adding methanol with or without the addition of aqueous hydrogen peroxide and a buffer. Some of the compounds of formula XXXVIiI are known and described in U.S. Patent Nos. 4,248,889 (issued February 3, 1381) and No. 4,650,890 (issued March 17, 1987).

The compounds of formula XXXIX can be prepared from the compounds of formula XXXVIII by reaction with a ketone such as acetone, pentan-3-one, cyclopentanone or cyclohexanone in a suitable inert organic solvent, e.g. As toluene, benzene or xylene at temperatures of about 20 ° C to the reflux temperature of the solvent in the presence of a small amount of an organic. Mineral or resin acid, eg. For example, p-toluenesulfonic acid or sulfuric acid and optionally with removal of the water formed with a desiccant, eg Na ₂ SO ₄ , MgSO ₄ and molecular sieves or by azeotropic removal with a Dean-Stark trap or similar apparatus manufactured v / ground. The reaction of a compound of the formula XXXVIII with a ketone can also be carried out without a solvent. Alternatively, the above reaction of the compounds of formula XXXIX can be carried out with a ketal such as 2,2-dimethoxypropane, 1,1-dimethoxycyclohexane, etc.

The compounds of formula XXXVa wherein R ^{19 is} a hydrolyzable ester group, preferably Ci-Q-alkyl, can be prepared from the corresponding compounds of formula XXXIX by oxidation of the olefinic group to an aldehyde group by conventional methods. Alternatively, a compound of formula XXXiX is first converted by basic hydrolysis to a compound of formula XXXX, which is then oxidized to a compound of formula XXXVa wherein R ' ^{9 is} hydrogen. A particularly convenient method of oxidation is the reaction of a compound of the forms! XXXIX or XXXX in an inert organic solvent such as methanol, Essigester or Mothylenchlorid with ozone at temperatures between about -50 ° C and about -78 ⁰ C. When the reaction with ozone is complete, as can be seen from the color of the reaction mixture is the intermediate ozonide by addition of a mild reducing agent, e.g. For example, dimethyl sulfide or triphenyl phosphine is decomposed to the desired aldehyde of formula XXXVa.

The preferred cis- (4R, 6S) -aldehydes of formula XXXVb can be obtained from the corresponding racemic acid of formula XXXX by conventional separation techniques such as fractionated crystallization after addition of a suitable salt-forming group. The di-isomeric salt mixture resulting from the addition of an optically active salt-forming reagent such as (1R, 2S) -ephedrine or 1-phenylethylamine is separated and the separated salts are converted to compounds of formula XXXVb. Preferably, the salt-forming reagent is (1S, 2R) -ephedrine and the separation method is fractional crystallization. The dissolution can be carried out in an inert organic solvent, preferably in a hydrocarbon-alcohol mixture, for. For example, hexane-methanol, wherein the separated salts can crystallize from the solution. If desired, the acid of formula XXXVb can be converted to a salt wherein R ^{19 is} a metal cation or to a hydrolyzable ester group wherein R ^{19 is} C) -C ₄ alkyl

 The most preferred antihypercholesterolemic compounds of formulas XXXXIVa, XXXXIVb and Ig may be

a compound of the formula XXXVa or XXXVb according to the here and in the United States patent application Lfd. No. (CT-1928),

registered on (simultaneously) produced by William T. Han and John J. Wright, described general ancestors

become. The use of the aldehydes of formula XXXVa is shown in Scheme 15 and the use of the chiral aldehydes of formula XXXVb is shown in Scheme 16.

Reaction scheme 15 Reaction Scheme 15

R "

6 "16 _D 17

0 Q

XXXXII

OR ⁸ XXXXIVa

• ^l W

Compound of Formula Iq

Reaction scheme 16 Reaction Scheme 16

XVI I or XVIIa

XXXVb

6 "16" 17

XLIII

OR ⁸ XXXXIVb

(4R, 6S) Compound of Formula Ig

In Reaction Schomes 15 and 16, R ¹ , H ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁶ , R "and R ^{19 are} as defined above and Z is

odor -P ^ R ¹³ Χ ^θ , wherein R ^{12 is} C ₁ -C ₄ -alkyl and

R ^{13 is} phenyl which is unsubstituted or substituted by one or two C ₁ -C ₄ -A ¹ ICyI or chlorine substituents and X is Bror / i, chlorine or iodine. The preparation of the phosphonium salt of the formula XV ¹ I and the phosphonate of the formula XVIIa is described here and in Scheme 13. The reaction of a compound of formula XVII or XVIIa with a compound of formula XXXVa or XXXVb to give a compound of formula XXXXII or XXXXIII wherein R ' ^{9 is} C 1 -C ₄ alkyl can be carried out in an inert organic solvent such as tetrahydrofuran or dimethylformamide in Presence of a strong base such as butyllithium at a temperature between about -5O ⁰ C and about -78 ⁰ C. When the reaction of a compound of formula XVII or XVIIa is carried out with a compound of formula XXXVa or XXXVb wherein R ' ^{9 is} hydrogen, preferably two equivalents of a strong base such as butyllithium are used. Alternatively, the salt of a compound of formula XXXVa or XXXVb can be prepared, which is then treated with a compound of formula XVII or XVIIa and a strong base. The methods of addition, salt formation and ylide production are known. The tetrazole compounds of the formula XXXXII or XXXXIII can be easily deprotected by known methods, such as. B. with a mild acid, eg. B. 0.2 η HCl and 0.5 η HCl in an inert organic solvent such as tetrahydrofuran, wherein the erythro compounds of the formula XXXXIVa or the (3 R, 5S) compounds of the formula XXXXIVb are formed, which are then in the trans Compounds of formula I g or in the (4R, 6S) compounds of formula I g can be converted in a conventional manner.

In a further aspect, the present invention provides drug preforming of the preferred embodiments of the compounds of formula I having the structure

CO ₉ R ²⁰

XXXXV.

wherein R ', R ² , R ³ , R ⁴ , R ^b and R ^{0 are} as defined above, R ^{20 is} hydrogen, C, -C ₆ alkyl or a metal cation and R ^{21 is} C, -C ₆ alkyl, hydroxy -C, -C ₆ -alkyl, phenylC, -C _e -alkyl, hydroxy-phenyl-Ci-LValkyl, amido-C 1 -C ₆ -alkyl, C, -C ₆ -alkoxycarbonyl-C | -C ₆ alkyl, imidazol-4-yl - ^ - Co-alkyl, Ci-Ce-alkylthio-d-Ce-alkyl or lndoi-3-yi-C, -Ce-alkyl, wherein the Amidoestertei! the L configuration has.

In the compounds of the formula XXXXV, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are,} independently of one another, preferably hydrogen, halogen, C 1 -C ₄ -alkyl or C 1 -C ₄ -alkoxy. More preferably R 'and R ^{4 are} hydrogen and R ² , R ³ , R ⁵ and R ^{6 are} independently hydrogen, fluoro, chloro, methyl or methoxy, and most preferably R' and R ^{4 are} hydrogen and R ² , R ³ , R ⁵ and R ^{6 are} independently hydrogen, fluoro, methyl or methoxy. Preferably, R ^{20 is} hydrogen, C) -C ₂ -AlkVl ° of a metal cation. Preferably R ^{21 is} C 1 -C ₄ -alkyl, hydroxy-C 1 -C -alkyl, phenyl-C ₁ -C -alkoxycarbonyl-C ₁ -C 4 -alkyl, imidazol-4-yl-C ₁ -C ₂ -alkyl, C ₁ -C ₂ - Alkylthio-Ci-C ₂ -alkyl or indol-3-yl-Ci-C ₂ -alkyl, wherein the Amidoesterteil has the L-configuration. The stereoisomer of the formula XXXXV, which has two asymmetric confluent atoms where the hydroxy groups are in the 3 and 5 positions, is preferably erythro, and the most preferred stereoisomer is the (3R, 5S) isomer of the formula XXXXV.

The compounds of formula XXXXV are prodrugs of the compounds of the present invention which, when systemically administered, are bioconverted to useful antihypocholesterolemic agents. The most preferred amido acid and amido ester derivatives of Formula XXXXV can be prepared from the (4R, 6S) compounds of Formula If following the general procedures described in U.S. Patent 4,678,806 (July 7, 1987 to Baldwin et al.) and is illustrated in Reaction Scheme 17 for the most preferred isomer.

Reaction scheme 17

Reaction S. ..erne 17

NH ₂ CH R ²¹

XLVI

(3R.5S) compound of Formula XXXXV

In Reaction Scheme 17, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^e, and R ^{21 are} as defined above, and R ⁹ is a hydrolyzable ester group. The compounds of formula I f described herein can be reacted with an ester of the corresponding L-amino acid in an inert organic solvent such as tetrahydrofuran, preferably at refluxing temperature of the solvent, to give a compound of formula XXXXVI. If desired. Compounds of formula XXXXV wherein R ^{20 is} hydrogen or a metal cation, the compound of formula XXXXV may be hydrolyzed under controlled conditions with dilute alkali hydroxide such as sodium hydroxide or potassium hydroxide in a conventional manner to give a compound of formula XXXXV.

The prodrugs of the present invention may be administered parenterally or preferably orally in the form of capsules, tablets, injectables or in a form described herein for the compounds of the present invention. The oral dose contains the active ingredient in an amount between 0.01 and about 10 mg / kg of body weight, which can be administered daily in one to four equal doses.

The compounds of formula XXXXV may also be used together with pharmaceutically acceptable non-toxic cationic polymers which can bind bile acids in non-reabsorbable form in the mammalian tract, e.g. Cholestyramine, colestipol, and polylmethyl-IS-trimethylamino-propy-diminotrimethylene-dihalc-genide). The relative amount of the polymer and compound of the present invention is between about Ί0: 1 and about 10,000: 1.

embodiments

In the following examples, melting points are determined with a Thomas Hoover capillary melting point apparatus, and boiling points measured at certain 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. Al.'e spectra were determined in CDCl ₃ , DMSO-d _e or D ₂ O unless otherwise specified. The chemical shifts are reported as δ values at lower field strengths compared to the internal standard tetramethylsilane (TMS). The coupling constants are given in Hertz (Hz). The splitting patterns are denoted as follows: s singlet; d doublet; t triplet; q quartet; m multiple «; br broad peak; dd Duplett of Dupletts. Carbon-13 nuclear magnetic resonance ( ^1J C-NMR) spectra were recorded on a Bruker AM 300 or Bruker WM 360 spectrometer and were used to connect the broadband protoner. All spectra were in CDCI ₃ , ÜMSOd _c or D ₂ O with internal

Deuterium lock recorded unless otherwise stated. The chemical shifts are given in low-field δ units versus tetramethylsilane. Infrared (IR) spectra were recorded on a Nicolet MX-1 FT spectrometer between 4000cm " ¹ and 400cm" ¹ , calibrated for the 1601cm "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. The optical rotations (α) "were determined on a Perkin-Elmer 241 polarimeter in CHCl ₃ at the indicated concentrations.

Gas chromatography mass spectra (GC-MS) were determined on a Finnigan 4500 gas chromatography quadruple mass spectrometer at 7OeV ionization potential. Mass spectra were also recorded on a Kratos MS-50 fast atom bombardment (FAB) instrument. The mass data are given in the format molecular ion (M ⁺ ) or protonated ion (M + H) ⁺ .

Analytical thin layer chromatography (TLC) was performed on previously coated silica gel plates (60 F-254) and visualized with UV light, iodine wells and / or stained with one of the following reagents: (a) methanolic phosphomolybdic acid (2%) and heating ; (b) reagent (a), then 2% cobalt sulfate in 5m H ₂ SO ₄ and heat. Column chromatography, also referred to as flash column chromatography, was carried out in glass columns with finely divided silica gel (32-63 m on silica gel-H) and slightly above atmospheric pressure with the indicated solvents. Ozonolyses were carried out with a Welsbach type T-23 ozonizer. All evaporations of solvents were carried out under reduced pressure. By hexane is meant a mixture of isomeric hydrocarbons as given by the American Chemical Society, and the term inert atmosphere means an argon or nitrogen atmosphere unless otherwise specified.

example 1

2-Cyar. 3,3-b) s- (4-fluoro-phenyl) acrylic acid ethyl ester

A mixture of 20.0 g (92 mmol) of 4,4'-difluorobenzophenone, 11.0 g (97 mmol) of ethyl cyanoacetate in a solvent mixture of 100 ml of dry benzene and 20 ml of glacial acetic acid containing a catalytic amount of β-alanine (0.9 g ), is refluxed, with water being deposited with a Dean-Stark trap. In the first 2 hours, the water separation was strong (0.4 ml aqueous layer separated), but then slowed down. The azeotropic distillation was continued for 14 days. Analytical TLC eluted with 10% ethyl acetate in hexane (vol.%) (Merck plate, 0.25 mm silica gel showed two spots at Rf-0.2 (desired product) and Rf = 0.45 (Starting material 4,4'-difluoro-benzophenone) The crude reaction mixture is washed with 2 × 40 ml of water and the combined washings are extracted with 2 × 150 ml of ethyl acetate The organic layers are combined, dried over MgSO ₄ and concentrated in vacuo, The crude product is separated, washed with ethyl acetate / hexane (1: 1 by volume) and recrystallized from hexane / ethyl acotate (8/1 vol.) to give 16.2 g (56.3%). the analytically pure title compound, F. 114-116 ⁰ C, are obtained.

IR (KBriV ™, *: 3000 (s), 2225 (s), 1931 (vs), 1 605 (s), 1 513 (s), 1 250 (s), 844 (S) Cm "¹;

¹ HNMR (CDCl ₃ ) O: 1.19 (3H, I, J x = 7.1 Hz), 4.18 (2H, q, J = 7 1 Hz), 7.08-7.15 (6H , m), 7.40-7.42 (2H, m);

¹³ CNMR (CDCl ₃ ) O: 13,75,62,27, 104,05,116,69,115,53 (d, ² J _C -f = 22,7Hz), 115,88 (d, ² J ₀ -F = 22 , 7Hz), 131.64 (d, ³ H _C - _F = 9.1Hz), 132.66 (d, ³ Jc-F = 9.1Hz), 134.25, 134.31, 134.36, 161.01 (d, ¹ Jc-F = 252.9Hz), 164.52 (d, ¹ J ₀ -F = 254.0Hz), 166.65ppm.

Anal. Calcd. for C ₁₈ H | ₃ NO;> ^C ₂ :

C, 69.01; H, 4.15; N, 4:47

 Found: C, 68.91; H, 4.15; N, 4.62.

Example 2

3,3-bis- (4-fluoro-phenyl) -2- (1H-tetrazol-5-yl) acrylsäureethylest8r

Into a dry 50 ml round bottom flask are added 5.0 g of (16, OmMoI) 2-cyano-3,3-bis (4-fluorophenyl) ethyl acrylate followed by 8.0 g (24.1 mmol) of azidotributylstannari (prepared according to US Pat optionally Rev. Trav. Chim. 81.202-5 (19621) and 2.0 ml of reagent grade toluene. The heterogeneous mixture is refluxed with stirring behind a protective shield in an oil bath to reflux (11O ⁰ C). The solid starting material gradually dissolves and forms a This homogeneous mixture is refluxed with stirring for 20 hours .. Analytical TLC eluted with 20% by volume of MeOH in CHCl ₃ shows the product at R f = 0.26 (patrol n). The crude reaction mixture is diluted with an equal volume of diethyl ether and added to a vigorously stirred aqueous saturated solution of KF (200 ml with 2 ml of 48% HBF ₄ ). Soon after mixing, a voluminous precipitate (Bu ₃ SnF) appears and the Hydrolysis is continued for 16 hours, the suspension is filtered and the filtrate extracted with EtOAc (2 x 100ml). The organic phases are combined, dried over MgSO ₄ and concentrated in vacuo. The title compound crystallized from the concentrate and provides 4,54g (77%) of white analytically pure material, mp 159-161 ⁰ C.

IR (KBr) V _mex : 3438 (br), 1713 (vs), 1600 (s), 1 510 (s), 1 238 (s), 841 (s) cm " ¹

¹ HNMR (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. );

^1J C NMR (CDCl ₃ ) δ: 106.52,163.54 (d, ¹ Jc-F = 25C.7Hz), 163.46, (d, ¹ J ₀ -F = 262.7Hz), 157.14,136.40,134.74,131.71, (i.e. , ² J ₀ -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) 62.11,13.47ppm.

Arial. Calcd. fo / C ₁₈ H ₁₄ F ₂ N ₄ O ₂ :

C, 60.27; H, 4.06; N, 15.50

 Found: C, 60.67; H, 3.06; N, 15.72.

Example 3

3,3-bis- (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) afrvlsäureethylesterund3,3-bis- (4-fluoro-phenyl) -2- (2-methyl- 2H-tetrazol-5-yDacrylsäureethylester

A. 3,3-Bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-y-acrylic acid ethyl ester

To a solution of 0.5 g (1.4OmMoI) of 3,3-bis (4-fluoro-phenyl) -2- (1H-tetrazol-S-yllacrylsäureethylestor in 100ml of dry benzene at 45 ° C under argon 100 mg (2.5 mmol) of sodium hydride (60% in mineral oil) was added in one portion. the gray-colored suspension is 30 minutes at 45 ⁰ C overnight, then 1 ml (16.1 mmol) of methyl iodide is added and the flask sealed with a rubber stopper. the alkylation is carried out at 40-45 ⁰ C over a period of 4 days. The analytical TLC indicated at twice eluting with 20% EtOAc in H / xan only two isomeric products at Ri = 0.16 (predominant isomer 4) and Rf = 0, 22 (lower isomer 5) The crude reaction mixture is washed with an equal volume of water and the aqueous phase is back-extracted once with 50 ml of diethyl ether The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to give a crude product : Isomor 2 is about 5.6: 1 by gas chromatography and NMR spectroscopy.

The crude product mixture (5.0 g) is taken up in 20 ml of hot ethyl acetate, to which 40 ml of hot hexane are added. The clear solution is allowed to cool slowly to room temperature to give 2.16 g (52%) of the title compound as coarse colorless needles; F. 144-145 ° C.

IR (KBr) j _m ": 1713 (vs), 1600 (s), 1513 (s), 1325 (s), 1163 (s), 838 (s) cm"';

¹ HNMR (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 (CDCI ₃₎ O: 165.44,163.6 (d, ¹ Jc-F = 250.7Hz), 16 £ .4 (d, ¹ Jc-F = 252.9Hz), 156.85,152.37,135.88,131.32 (d, ³ J _C - _F = 8.3Hz), 115.94 (d, ⁹ Jc-F = 21.9Hz), 115.64 (d, ² Jc-F = 22.7Hz), 61.84.33.76.15.59 ppm;

Anal. CaICdJOrC ₁₉ H ₁₆ F ₂ N ₄ O ₂ :

C, 61.62; H, 4.35; N, 15.13 Found: C, 61.63; H, 4.45; N, 15:21.

B. 3,3-bis (4-fluoro-phenyl) -2- (2-methyl-2H-tetrazol-5-yl) ethyl acrylate

The residue (2.0 g) from the recrystallization filtrate in step A (which contains approximately equal amounts of the 1- and 2-methyl isomer) is purified by silica gel chromatography (35 g). The fractions are collected and evaporated to crystalline products. Recrystallization from hexane-ethyl acetate mixture (9: 1 by volume) gives the title compound; F. 117-118 ⁰ C.

IR (KBr) \ / _max : 1713 (vs), 1,600 (s), 1,506 (s), 1250 (sh), 1 225 (vs), 850 (m) cm "¹;

¹ H NMR (CDCl ₃ ) δ: 7.4-6.8 (8H, m), 4.20 (3H, s), 406 (2H, q, J = 7.1 Hz), 0.99 (3H, t, J = 7.1 Hz);

¹³ CNMR (CDCl ₃ ) O: 167.12.163.02 (d, ¹ J ₀ -F = 272.6Hz), 163.03 (d, ¹ J ₀ -F = 225.7Hz), 162.80, 152.59, 137.03 (d, ⁴ J ₀ - F = 4Hz), 135.96 (d, ⁴ Jc-f = 3Hz), 131.94 (d, ³ J _C -f = 8.3Hz), 131.08 (d, ³ J ₀ -F = 8.3Hz), 120.48,115.37 (i.e. , ² J _{C, F} = 21.9 Hz), 115.26 (d, ² J _C - _F = 22.7 Hz) 61.41, 39.40, 13.61 ppm;

Anal. Calcd. for C ₁₉ H ₁₆ F ₂ N ₄ O ₂ :

C, 61.62; H, 4.35; N, 15.13

 Found: C, 61.77; H, 4.44; N, 3:38.

Example 4

3,3-bis- (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) acrylic acid

To a solution of 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) acrylic acid ethyl ester (4g, 10.8 mmol) in a mixture of 20 mL methanol and 20 mL Tetrahydrofuran at ^{0 0} C (ice bath) are added 9ml of a solution of 3m lithium hydroxide. The saponification takes place overnight (about 16 hours), giving a clear homogeneous solution. Analytical TLC, eluted twice with 30% by volume of ethyl acetate in hexane, shows the desired product at the start. The crude reaction mixture is acidified with 10 ml 3m HCl and the organic material extracted with 2 χ 20ml ethyl acetate. The organic phases are pre-purified, dried with MgSO ₄ and concentrated in vacuo to give the product as a pale yellow solid. Reactivation from EtOAc / hexane (1: 9 v / v) provides 3.8 g (100%) of the title compound; F. 205-206 ⁰ C.

IR (KBr) ^ L _x : 3438 (br), 2900 (br), 1725 (s), 1 713 (s), 1 600 (s), 1 501 (s), 1231 (vs), 1156 (s) , 1 231 (vs), 1156 (s), 850 (s) cm ^-1 , ¹ H NMR (CDCl ₃ ) δ: 7.9-6.4 (8H, m), 3.68 (3H, s);

¹³ CNMR (CDCl ₃ ) O: 166.57.163.3 d, ¹ J ₀ -F = 249.9Hz), 163.03 (d, ¹ J ₀ -F = 250Hz), 155 68,152.61,135.58,134.74,131.75 (d, ³ J ₀ -F = 8.3Hz), 131.28Id ₁ ³ J ₀ -F = 9.1Hz) 117.115.7 (d, ² J _C -r = 22.6Hz), 115.4 (d, ^J J _C - _F = 22.6Hz), 33.6ppm;

Anal. Calcd. for C ₁₇ H ₁₂ F ₂ N ₁₁ O ₂ :

C, 59.05; H, 3.53; N, 16:37

 Found: C, 59.54; H, 3.58; N, 16:27.

Example 5

3,3-bis (4fluor-phenyl) -2- (2-methyl-2H-tetrazol-5-yl) acrvlsäure

The general procedure of Example 4 is repeated, using 3,3-bis- (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-y-acrylic acid ethyl ester replaced by 3,3-bis (4-fluoro) fluorophenyl) -2- (2-methyl-2H-tetrazol-5-yl) -acrylsäureethyl ester, whereby after recrystallization from ethyl acetate / hexane, the title compound is obtained in almost quantitative yield, mp 154-155 ° C. ,

IR (KBr) V _mix : 3438 (br), 3000 (br), 1675 (s), 1 600 (s), 1 503 (s), 1 231 (s), 1 225 (s), 1150 (s) , 838 (s) cm "', ¹ H NMR (CDClI-DMSO-de) δ: 7.33-7.28 (2H, m), 7.05-6.96 (4H, m), 6.87 (2H, t, J - 8.64Hz) , 4.23 (3 H, s);

"C NMR (CDClI-DMSO-de) δ: 168.70.163.05 (d, 'J _C -f = 248.4Hz), 163.07, 162.66 (d,' J ₀ -F = 249.9Hz), 151.81, 136.81, 136.22, 131.83 (d, ³ Jc ₁ -F = 8.3Hz), 131.20 (d, ³ J ₀ -F = 8.3Hz), 121.04,115.24 (d, ² J _C -f = 21.9Hz), 115.14Id ₁ ² J ₀ -F = 21.1 Hz) ppm;

Anal. CaICd-IOrCi ₇ H ₁₂ F ₂ N ₄ O ₂ :

C, 59.65; H, 3.53; N, 16:37

 Found: C, 50.56; H, 3.59; N, 16:36.

Example 6 3,3-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde

A. 3,3-Bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-6-yl-acryloyl chloride

(To a solution of dry (0.1 mm Hg at 8O ⁰ C) 3,3-bis- (4-fluoro-phenyl) -2-1-methyl-1 H-tetrazol-5-yOacrylsäure (3.8 g, 11, OmMoI) in 20 mL of dry methylene chloride, 4 mL (46, OmMoI) of purified oxalyl chloride (redistilled over CaH ₂ ) are added in one portion The reaction mixture is gradually heated to reflux for 2 hours The mixture is evaporated in vacuo to remove the volatile solvent , the excess oxalyl chloride in vacuo (20 mm Hg) within 2 hours at room temperature and under high vacuum (0.1 mm Hg) within 16 hours at 50 ^C C so that the title compound is obtained.

B. 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-H-tetrazol-B-yl) allyl alcohol

The acyl chloride as shown in Step A is dissolved in 150 ml of tetrahydrofuran and cooled under argon to -78 ⁰ C. 8.0 ml of lithium aluminum hydride in THF (0.1 m) are added to this light brown solution at -78 ° C. After 15 minutes, analytical TLC showed only one moving spot at R ₁ = 0.23 (50% by volume EtOAc in hexane). The crude reaction mixture is diluted with 20 ml of 2 M H ₂ SO ₄ . The aqueous phase is extracted with 2 χ 40ml ethyl acetate. The organics are combined, dried over MgSO ₄ and concentrated in vacuo to give 3.64 g (100%) of the title compound. The crude allyl alcohol is used immediately without further purification in the next step. MS (CI): m / e = 328 for (M + H) *;

IR (KBr) *? N ": 3388 (v.br), 1600 (s), 1501 (s), 1225 (s). 1156 (s), 838 (s), 750 (s), cm "';

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-exchangeable);

'HNMR (DMSOd ₆ ): 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-fluoro-phenyl) -1- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde

To a vigorously stirred solution of 3.64 g of the crude allyl alcohol shown in Step B in 40 ml of methylene chloride is added at room temperature 2.6 g (12.0 mmol) of pyridinium chlorochromate in a single portion. Analytical TLC immediately after the addition shows about 50% product at Ri = 0.34 next to the starting material at Rf = 0.14 (eluted with 50% by volume EtOAc / hexane). The oxidation is carried out at room temperature for 16 hours, during which time all starting material is consumed and the TLC identifies only product. The crude reaction suspension is filtered through a silica gel bed, washed with 11% ethyl acetate in hexane (10% by volume) and 11% ethyl acetate in hexane (20% by volume). The desired product crystallizes on evaporation under reduced pressure to 2.7 g (74%) of the title Vorbindung; F. 141-142X. MS (Cl) m / e-326 for (M + H) ⁺ ;

IR (KBr)% L _X : 3075 (m), 2875 (m), 1675 (s), 1600 (s), 1501 (s), 1238 (s), 1156 (s), 850 (s), 750 ( s), cm '; ¹ H NMR (CDCl ₃ ) δ: 9.63 (1H, s), 9.5-6.9 (8H, m), 3.74 (3H, s),

' ³ C NMR (CDCl ₃ ) δ: 188.92.165.44.164.68 (d,' J _{C, F} = 254.4Hz), 164.10 (d, ¹ J ₀ -F = 255.9Hz), 151.34, 134.31, 133.77 (d, ³ J ₀ -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;

Anal. Calcd. for C ₁₇ H ₁₂ F ₂ N ₄ O:

C, 62.58; H, 3.71; N, 17.17

 Found: C, 62.41; H, 3.85; N, 16.98.

Example 7

3,3Bis (4-fluoi-phenyl) -2- (2-methyl-2H-tetrazol-5-yl) acrylaldehyde

The general procedure of steps A, B and C of Example 6 is repeated, whereby 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) acrylic acid by 3 3-bis- (4-fluoro-phenyl) -2- (2-methyl-2H-tetrazol-5-yl) acrylic acid, shown in Example 5), to give the titled compound as a gummy solid in an overall yield of 76% becomes. MS (Cl): m / e = 326 for (M HH) ⁺ .

IR (KBr) ^ _x : 2863 (m), 2750 (w), 1681 (s), 1600 (s), 1503 (s), 1225 (s), 1156 (s), 838 (s), 752 (s ),cm"';

¹ H NMR (CDCl ₃ ) δ: 9.65, 7.34-7.30 (2H, m), 7.15 (2H, t, J = 8.5Hz), 7.01-6.96! 2H, m), 6.88 (2H, t, J = 8.4 Hz), 4.29 (3H, s);

' ³ C NMR (CDCl ₃ ) δ: 190.08.164.30 (d,' J ₀ -F = 254.4Hz), 163.5 (d, 'J _C - _F = 252.17Hz), 163.20, 161.37, 135.55, 133.49, 133.66 ( d, ³ J = 7.6Hz ₀ -F), 132.38 (d, ³ J ₀ = -F 9.1Hx), 131.40,127.54,115.86 (d, ² J _C-F = 26.4Hz), 115.57 (d, ² J ₀ -F - · 28.7Hz), 39.55ppm;

Anal. CaICdJOrC ₁₇ H ₁₂ F ₁ N ₄ O:

C, 62.58; H, 3.71; N, 17.17

 Found: C, 62.27; H, 4.22; N, 15.83.

Example 8

5,5-bis- (4-fluoro-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dienal

To a dry mixture of 0.70 g (2.1 mmol) of 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde and 0.72 g ( 2.5 mmol) of triphenylphosphoranylideneacetaldehyde are added under argon at room temperature to 20 ml of dry benzene. The suspension is heated to reflux temperature under argon atmosphere and the reaction is carried out at reflux temperature for 30 minutes. Analytical TLC (eluted four times with 20% ethyl acetate in hexanes) shows only one spot for the product at Rf = 0.15. The crude reaction mixture is poured onto a hexane-saturated silica gel column. The desired product is distilled with 1.5120 v.% EtOAc in hexanes to yield 0.67 g (89%) of the title compound, which appears homogeneous in the TLC.

¹ H NMR (CDCl ₃ ) δ: 9.53 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 15.7Hz), 7.4-8.8, m), 5.80 (1H, dd, J ₁ = 7.4 Hz, J ₂ = 15.7Hz), 4.11 (2H, q, J = 7.1Hz), 3.58 (3H, s), 1.26 (3H, t, J = 7.1Hz) ppm.

The 300 MHz 'H NMR spectrum of the above product shows that it contains about 10% of 7,7-bis (4-fluoro-phenyl) -6- (1-methyl-1H-tetrazol-5-yl). contains hepta-2,4,6-trienal as a by-product, which can not be easily removed. This material is used without further purification for the next presentation.

Example 9

5,5-B! S (4-fluoro-phenyl) -4- (2-methyl-2H-tetrazol-5-yl) penta-2,4-dienal

The procedure of Example 8 is repeated to give 3,3-8is (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl-acrylaldehyde by 0.67g (21, OmMoI) 3 3-bis- (4-fluoro-phenyl) -2- (2-methyl-2H-tetrazol-5-yl) -acrylaldehyde (prepared in Example 7) is replaced with 0.64 g (21, OmMoI). Triphenylphosphoranylidenacetaldehyd carried out to give 0.66 g (90.5%) of the title compound.

HNMR (CDCl ₃ ) δ: 9.b7 (1H, d, J = 6.8Hz), 7.50 (1H, d, J = 16.5Hz), 7.3-6.8 (8H, m), 5.94 (1H, dd , j = 6.8.16.5Hz), 4.30 (3H, s) ppm.

Example 10

Ethyl 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoate and 11.1 -bis- (4-fluorphenyD-S-hydroxy-IO-d-methyMH-tetrazol-S-yD-S-oxo-eeiO-undecatriensäureethylester

A. 9,9-Bis (4-fluoro-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester

To a cooled suspension (0 ⁰ C, ice bath) of 0.64 g (16 OmMoI) NaH (60% in mineral oil) in 20ml dry tetrahydrofuran under argon is 2,04ml (16, OmMoI) Acet9ssigsäureethylester in 4 equal portions was added. The clear, homogeneous solution is stirred for 30 minutes at 0 ° C, then added dropwise 6.4 ml of a 2.5M solution of butyllithium (16, OmMoI) within 15 minutes. The orange solution of the dianion is stirred for a further hour at OX. The ice bath is replaced with an acetone-dry ice bath of -78 ⁰ C, and the dianion via cannula to a solution of 2.82 g (8.01 mmol) of 5,5-bis- (4-fluoro-phenyl) - 4- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dienal transferred in 20 ml of tetrahydrofuran. The analytical TLC shows the desired major product at Ri - 0..15 (50% EtOAc in hexane) and a byproduct at Rf = 0.2. The crude reaction mixture is diluted with 40 ml of 1 η HCl and the aqueous phase extracted with 2 χ 50ml of ethyl acetate. The organic phases are combined, dried over MgSO 4 and concentrated in vacuo. The desired product is purified by flash silica gel column chromatography eluting with 20% by volume EtOAc in hexane to yield 2.26 g (58.5%) of the title compound. MS (Cl): m / e 483 for (M + H) ⁺ .

IR (KBrJlL _1x : 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 = 7.1Hz) ppm;

¹³ C NMR (CDCl ₃ ) δ: 164.21, 135.98, 132.34 (d, ³ J ₀ -F = 8.3Hz), 131.45 (d, ³ J _C - _F = 9.1 Hz), 115.74 (d, ² J _C - _F = 21.9Hz), 115.74 (d, ² J _C -f = 21.1Hz), 100.86, 67.61, 61.58, 49.85, 49.07, 33.56, 14.10ppm.

B. 11,11-bis- (4-fluoro-phenyl) -5-hydroxy-10- (1-methyl-1H-tetrazol-5-yl) -3-oxo-undeca-6,8,10-trienoic acid ethyl ester

The silica gel column from Step A above is further distilled to give the by-product (Rf = 0.2). Repeated flash silica gel chromatography with 20% EtOAc in hexane as eluent yields the title compound.

ΉΝΜΒ (ΰθα3) δ: 7.4-7.1 (4Η ^), 6.9-6.8 (Η4 ^), 6.58 (1Η, α ^ = 15.5Hz), 6.31 (1H, dd, J = 10.7,15.0 Hz), 5.80,1H , dd, J = 10.7, 15.4Hz), 5.66 (1H, dd, J = 5.5.15.1Hz), 4.64 (1H, m), 4.18 (2H, q, J = 6.9Hz), 3.58 (3H, s) 3.46 (2H, s), 3.02 (1H, m), 2.75-2.72 (2H, m), 1.27 (3H, t, J = 6.9Hz) ppm.

Example 11

Ethyl (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid To a solution of 2 , 19g (4.53 mmol) 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8 -diensäureethylester (48 h at 30 ° C in a high vacuum) in 40 ml of anhydrous tetrahydrofuran are added at ^{0 0} C (ice bath) under argon 4.8 ml (4.8 mmol) of triethylborane solution in tetrahydrofuran in one portion The mixture is stirred under argon for a total of 1 hour, the bath of ice is replaced by an acetone-dry ice bath and 0.20 g (5.3 mmol) of Na ¹ SH _{4 are added} in one portion to the reaction mixture Stirred for hours, taking

forming a clear homogeneous light yellow solution. The crude reaction mixture is diluted with 40 ml of 1 N HCl and then extracted with 2 × 40 mL EtOAc. The organic phases are combined, dried over MgSO ₄ and concentrated in vacuo to give the product as a thick syrup: wire ¹ . This is diluted with 300 ml of methanol, the solution allowed to stand for 16 hours at room temperature and then evaporated in vacuo. The crude product is purified by flash silica gel column chromatography with 2130% EtOAc in hexane as eluent. The appropriate fractions are collected and evaporated, yielding 1.48y (68%) of the title compound. MS (CI): m / e - 485 for (M + H) *;

IR (KBr) i / _miix : 3Λ38 (s), 1734 (s), 1600 (s), 151X (s), 1225 (s), 11 !63 (s), 844 (s), cm "¹;

¹ H NMR (DMSO-de) δ: 7.4-7.3 WH, m), 7.04 (2H ₁ 1, J = 8.8), 6.9-6.7 (2H, m), 6.52 (1H, dd, J = 1.15.2 Hz), 5.16 (1H, dd, J = 5.6, 15.7Hz), 4.89 (1H, d, J - = 4.8Hz), 4 72 (1H, d, J = 5.5Hz) 4.13 (1 H, m ), 4.04 (2H, q, J-7.2Hz), 3.85 (1H, m), 3.75 (3H, s), 2.42, (1H, dd, J = 4.6.15Hz), 2.28 (1H, dd , J = · 8.3, 15Hz), 5.S (1H, m), 4.2 (1H, m), 1.17 (3H, t, J = 7.2Hz);

"C NMR (DMSO-d ₆ ) δ: 171.02,163.51,163.05,153.03,145.34,139.46,136.34,132.2 (d, ³ J _C - _F = 8.3Hz), 131.0 (d, ' ³ J _C - _F = 9.1 Hz), 125.1Λ, 121.64.115.41 (d, ² J _C -f = 20.4H ·), 115.13, (d, '' Jc-f = 21.1 Hz), 67.79, 64.76, 59.50, 44.10, 42.34, 33.44 , 14.01 ppm;

Anal. CaICd-WrC ₂₅ H ₂₆ F ₂ N ₄ C ₄ :

C, 61.98; H, 5.41, N, 11.56. ^; Found: C, 61.51; H, 5.67; N, 11.12.

Example 12

Sodium - (+) - ervethro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-tiethyl-1H-tetrazol-5-vl) nona-6,8-dienoate Solution of 1.23 g (2.54 mmol) of 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-totazol-5-yl) nona-6,8 -dienäureethylester in 35 ml of tetrahydrofuran are added dropwise at ^{0 0} C 2.54mi (1 equivalent) of 1 η NaOH solution. The rate of addition must be so slow that the color of the reaction mixture does not change to dark amber or reddish. The reaction mixture is stirred for 30 minutes at ⁰ ° C. and forms a clear homogeneous solution. Then the reaction mixture is allowed to warm to room temperature and allowed to stand for a further hour, wherein the saponification proceeds. Analytical TLC eluting with 20% by volume MeOH in CHCl ₃ shows the desired product at Ri = 0.2. The largest amount of organic solvent is evaporated at about 10 ° C in vacuo (20mm Hg). The resulting thick syrup is diluted with 4 ml of water and then the solution is freeze-dried at 0.01 mm Hg to give 1.126 (100%) of the title compound as a sodium salt containing about 1 mole of water; F.> 100 ⁰ C with decomposition.

! R (KBr) 1? _m ": 3400 (v.br), 1 600 (s), 1 575 (s), 1513 (s), 1438 (s), 1404 (s), 1225 (s), 1156 (s), 838 (s ) cm "';

¹ H NMR (DMSO-d ₆ ) δ: 7.3-7.4 (4H, m), 7.06 (1H, br, D ₂ O exchangeable), 7.00-7.06 (2H, m), 6.87-6.91 (2H, m) , 6.49 (1H, d, J = 15.7Hz), 5.13 (1H, dd, J = 5.4.15.7Hz), 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);

' ³ C NMR (DMSO-d ₆ ) δ: 175.87.161.85 (d,' J _{C, F} = 246.1 Hz), 161.37 (d, 'J _C - _F = 246.9Hz), 153.08, 149.97, 139.88, 135.40, 135.51, 132.22 (d, ³ Jc-F = 8.3Hz), 130.97 (d, ³ Jc-I = = 8.3Hz). 124.66, 121.74, 115.42 (d, ² J _C - _F = 21.9Hz), 115.12 (d, ² J _c _ _F - 23.4Hz), 68.23, 65.71, 44.50, 43.55, 33.45 ppm;

Anal. Calcd. for C ₂₃ H ₂₁ F ₂ N ₄ O ₄ NaH ₂ O:

C, 55.64; H, 4.67: N, 11.28

 Found: C, 55.24; H, 4.65: N, 10.85.

Example 13 Trans-6- [4,4-bis (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl] -4-hydroxytetrahydropyran -2-one

A. (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8 (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid

To a solution of 0.64 g (1.32 mmol) (±) -erythro-9,9-B; s- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1 H) Tetrazol-5-yl) -nona-6,8-diensäureethylester in 25 ml of tetrahydrofuran are added at ^{0 0} C 1.32 ml of 1.0M NaOH solution. The pale yellow suspension is stirred for two hours at ^{0 0} C, forming a clear pale yellow solution. The crude reaction mixture is diluted with 5 ml of 2N aqueous HCl solution, and the organic material is extracted with 2 x 40 ml of ethyl acetate. The organic extracts are combined, dried over MgSO ₄ and concentrated in vacuo to a light yellow gum. The crude dihydroxy acid is dried under high vacuum (0.01 mm Hg at room temperature for 24 hours) and then used in the next step.

Trans-6- [4,4-bis- (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl-butan-1,3-dienyl] -4-hydroxy-tetrahydropyran-2 -one

The dry acid from step A above is dissolved in 100 ml of dry methylene chloride under argon at room temperature and then 1.7 g of (4, OmMoI) 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimide-metho-p-toluenesulfonate are added , Upon detection of the analytical TLC (Rf-0.12, eluted three times with 50% ethyl acetate in hexane), lactonization is complete after 15 minutes. The majority of the solvent is evaporated in vacuo and the residue washed with 40 ml of water and then extracted with 2 χ 40ml of ethyl acetate. The organic phases are separated, dried over MgSO ₄ and evaporated in vacuo to give 0.54 g (89.7% of product). A pure sample of the product is obtained by passing through a short bed of silica gel twice with 40 vol.% Ethyl acetate in hexane to give the title compound, which apparently contains 2 moles of water. MS (Ci): m / e = 438 for (M + H) ^f ;

IR (KBr) ^ _n ,,,: 3425 (br), 1738 (vs). 1600 (s), 1513 (s), 1225 (vs), 1156 (s), 1038 (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 (OH, s), 2 68 (1H, dd, J = 4.5.18Hz), 2.60 (1H, ddd, J = 3.63,2.5,18Hz), 2.44 (1H, d, J = 2.6H ₂ , D ₂ O-exchangeable), 2.00 (1H, dt, J = 18 , 1.7Hz), 1.79 (1H, td, J - 2.7,18Hz) ppm;

' ³ C NMR (CDCl ₃ ) δ: 169.20,163,162.5,153.20,148.81,135.61,134.95,132.45 (d, ³ J _C -f = 8Hz), 132.52,131.51, (el, ³ J _C - _F = 8Hz) .. 130.04,120.44,115.95, (d, ² J _H = 21.9Hz), 115.83 (d, ² J ^ = 21.9Hz), 75.67.62, 54.38, 58.35, 58.33.64ppm;

Anal. CaICdJOrC ₂₃ H ₂₀ F ₂ N ₄ O ₃ 2 H ₂ O:

C, 58.22; H, 5.10; N, 11.81

 Found: C, 59.06; H, 4.45; N, 11.25.

A sample of the above lactone is recrystallized from cyclohexane-benzene to yield the title compound as crystals containing about 1 mole of benzene; F. 105-106 ⁰ C.

Anal. BBrJOrC ₂₃ H ₂₀ F ₂ N ₄ O ₃ C ₆ H ₃ :

C, 67.48; H, 5.07; N, 10.85

 Found: C, 67.44; H, 5.23; N, 10:59.

Example 14 (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-methy-2H-tetrazol-5-yl) nona-6,8-dienoic acid, ethyl ester

A. 9,9-Blis (4-fluoro-phenyl) -5-hydroxy-8- (2-methyl-2H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester

The general procedure of Example 10, Step A, is repeated except that 5,5-bis- (4-fluoro-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -penta-2, 4-dienal replaced by 0.66 g (1.87 mmol) of 5,5-bis (4-fluorophenyl) -4- (2-methyl-2H-tetrazol-5-yl) penta-2,4-dienal, whereby 0.53 g (59%) of the title compound are obtained after silica gel chromatography.

B. (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-methyl-1H-tetrazol-5-yl) non 3, 6,8-dienyl-ethylester

The product of Step A above is treated with triethylborane and sodium borohydride according to the general procedure described in Example 11 to give, after purification by silica gel chromatography, 0.37 g (69.5%) of the title compound.

¹ H NMR (CDCl ₃ ) δ: 7.30-7.22 (2H, m), 7.07 (2H, t, J = 6.7Hz), 6.89-6.86 (2H, m), 6.78 (2H, t, J = 8.7Hz) , 6.66 (1H, d, J = 15.5Hz), 5.39 (1H, dd, J = 6.3.15.5Hz), 4.41 (1H, m) 4.2 (1H, m), 4.27 (3H, s) 4.18 (2H, q, J = 7.1Hz), 3.92 (1H, br, DjO-exchangeable), 3.69 (1H, br, D ₂ O-exchangeable) 2.47-2.42 (2H, m), 1.66-1.58 (2 H, m), 1.26 (3 H, t, J = 7.1 Hz);

¹³ C NMR (CDCl ₃ ) δ: 172.29,162.52 (d, ¹ J ₀ -F = 249.9Hz), 161.94 (d, ¹ J ₀ -F = 248.4Hz), 145.74,137.59,137.33.136.87,132.37 (i.e. , ³ J ₀ -F = 8.3 Hü), 131.69 (d, ³ J _C - _F = 8.3 Hz), 128.53,124.90,115.50 (d, ² J ₀ -F = 21.1 Hz), 115.2 (d, ² J _C - _f = 20 Hz), 72.11, 68.07, 60.74, 42.52,41.73,39.42,14.17ppm.

Example 15

(+) - erythro-11,11 -bis (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl-1-1H-tetrazol-5-yl) undeca-6,8, 10-triensäureethy lester and

Sodium-! ±) erythro-11,11-bis (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl-1H-tetrazol-5-yl) undeca-6,8,10-trienoate

A. (±) -erythro-11,11-bis- (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl) -1H-tetrazol-5-yl) undeca-6,8, 10-trienoic acid ester The general procedure of Example 11 is repeated substituting the 9,9-8- (4-fluoro-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3 -oxo-nona-6,8-dienoic acid ethyl ester by 0.12 g of 11,11-bis (4-fluoro-phenyl) -5-hydroxy-10- (1-rpethyl-1H-tetrazol-5-yl) -3- oxo-undeca-6,8,10-trienoic acid ethyl ester (prepared in Example 10, step B) is replaced to give, after silica gel chromatography, 50 mg (42%) of the title compound.

¹ H NMR (CDCl,.) Δ: 7.4-6.8 (8H, π.), 6.57 (1H, d, J = 15.4Hz), 6.29 (1H, dd, J = 10.8.15.1Hz), 5.80 ( 1 H, dd, J = 10.7.15.4Hz), 5.07 (1H, dd, J = 5.7.15.1Hz), 4.44 (1H, qJ = 5.8Hz), 4.24 (1H, m), 4.16 (2H , q, J = 7.1 Hz), 3.83 (1 H, br, D ₂ O-exchangeable), 3.65 (1 H, br. D ₂ O-exchangeable), 3.58 (3H, s), 2.47 (2 H, d , J = 6.3Hz), 1.62 (2H, m), 1.28 (3H, t, J = 7.1Hz);

' ³ C NMR (CDCl ₃ ) δ: 172.43, 162.87 (d, ¹ J ₀ - _F = 257.46 Hz), 162.47 (d, ¹ J ₀ -F = 249.91 Hz), 153.45.146.20, 138.62, 135.98, 135.50, 133.98,132.39 (d, ³ J _C - _F = 8.3Hz), 131.48 (d, ³ J ₀ -F = 8.3Hz), 131.18.129.80.129.16,121.95,115.75 (d, ² J _C - _F = 22.0Hz ), 115.67 (d, ² J _c ..f - 22.0H?), 71.72.68.34,60.82,42.45,41.57,33.54,14.16ppm

B. Nat ± ium ± erythro-11.11-bis (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl-1H-tetrzol-5-yl) undeca-6,8,10-trienoate The product of Step A above is saponified according to the general method described in Example 12 to give the title compound in quantitative yield.

¹ H NMR (OMSO-d ₆ ) δ: 7.5-6.8 (8H, m), 6.44 (1 H, d J = 18.5Hz), 6.17 (1 H, dd, J = 11.4.14.8Hz), 5.7 (2H, m) 4.14 (1H, q, J = 5.5Hz), 3.7 (2H, br, D ₂ O-exchangeable) 3.67 (3H, s), 3.9U (lH.m), 2.02 (1H , d, J = 11.7Hz), 1.84 (1H, dd, J = 8.6, 14.4Hz), 1.46 (1H, m), 1.29 (1H, m) ppm.

¹³ C NMR (DMSOd ₆ ) δ: 176.12,152.81,141.50,136.25,135.62, 134.02,132.35,132.24,127.72,128.04,122.17,115.48 (d, ² J ₀ -F = 21.9Hz), 11B.19 (i.e. , ² J ₀ -F = 21.1 Hz), 68.31, 65.73, 44.59, 43.57, 33.40 ppm.

Example 16

trans-6- [4,4-bis- (4-fluoro-phenyl) -3- (2-methyl-2H-tetra7ol-5-yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran-2 The general procedure of Example 13, Steps A and B, is repeated, using the (± -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl 1-H-tetrazol-5-yl) nona-6,8-dienoic acid ethyl ester by 370 mg of 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-methyl-2H- tetrazol-5-yl) nona-6,8-dienoic acid ethyl ester and 143 mg (44%) of the title compound are obtained by silica gel chromatography MS (CI): rn / e = 439 for (M + H) ^f ;

IR (KBr) \ J _max : 3438 (v.br), 1731 (s), 1600 (s), 1503 (vs), 1219 (vs), 1153 (s), 1056 (m), 1031 (m), 838 (s) cm "¹;

¹ H NMR (CDCl ₃ ) δ: 7.29-6.82 (8H, m) 6.69 (1H, d, J = 15.6Hz), 5.44 (1H dd, J = 9.0, 15.6H 2), 5.24 (1H, m), 4.27 (3H, s), 4.30 (1H, m), 4.21 (1H, s, D ₂ O-exchangeable) 3.69 (1H, br.s DjO-exchangeable), 2.6-2.4 (2H, m), 2.1-1.7 (2H, m);

¹³ C NMR (CDCl ₃ ) δ: 169.94.162.70 (d, ¹ J ₀ -F = 249.2Hz), 162.12 (d, ¹ J ₀ -F = 249.9Hz), 147.68,147.47,137.27,136.11,132.36 (i.e. , ³ Jc-F = 8.3Hz), 131.71 (d, ³ J ₀ -F ·· = 8.3Hz), 131.17,131.10,130.88,128.62,124.28), 115.52 (d, ² J _C - _F - 20.4Hz) , 114.95 (d, ² J _C -F = 21.9Hz), 76.16, 62.33, 39.49, 38.66, 35.99 ppm;

Anal. Ber. for C ₂₃ H ₂₀ F ₂ N ₄ O ₃ 2H ₂ O:

C, 58.22; H, 5.10; N, 11.81

 Found: C, 58.92; H, 4.62; N, 11.21.

Example 17

Sodium (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-2H-tetrazol-5yl) nona-6,8-dienoate D3S general procedure of Example 12 is repeated, wherein the (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl ) nona-6,8-dienoic acid ethyl ester by 9,9-8is (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-methyl-2H-tetrazol-5-yl) nona-6, 8 diensäureethylester is replaced and after freeze-drying, the title compound is obtained as the sodium salt, which appears to contain about 1 mole of water.

IR (KBr) iL _x : 3413 (v.br), 1600 (sj, 1575 (s), 1500 (s), 1400 (s), 1219 (s), 1088 (s) cm ', ¹ H NMR (DMSOd ₆ ) δ: 7.36-6.82 (8H, m), 6.50 (1H, d, J = 15.5Hz), 5.28 (1H, dd, J = 5.8, 15.5Hz), 5.0 (1H, br, D ₂ O) exchangeable), 4.9 (1H, br. D ₂ O-exchangeable), 4.28 (3H, s), 4.13 (1H, d, J = 5.94Hz), 3.64 (1H, m), 2.03 (1H, dd, J = 3.6,14.9Hz), 1.85 (1H, dd, J = 8.7,14.9Hz), 1.5-1.2 (2H, m);

' ³ C NMR (DMSOd ₆ ) δ: 176.25, 103.18, 167.47, (d, ¹ J ₀ -F - 240Hz), 143.15, 137.60, 136.40, 125.48, 115.12, 14.46, 68.52, 65.84, 44.61, 43.55 ppm.

Anal. Oer. for C ₂₃ H ₂₁ F ₂ ^ ₄ O ₄ NaH ₂ O:

C, 55.64; H, 4.67; N, 11.29

 Found: C, 55.22; H, 4.79; N, 11.21 ..

Example 18

9,9-Bis, - (4-fluoro-phenyl) -3-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -5-oxo-nona-6,8-dienylbenzyl ester 2.5g (7.7 mmol) 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde, 3.93 g (11 mmol) of e-dimethoxyphosphoryl-S; Hydroxy-5-oxo-hexanoic acid benzyl ester and 1.40 g of anhydrous lithium bromide are mixed in acetonitrile with 1.2 ml of (8, OmMoI) 1,8-diazabicyclo [5.4.0lundec-7-ene. The mixture is heated under argon for 44 hours at 23 ⁰ C and then concentrated in vacuo. The residue is partitioned between 50 ml of CH ₂ Cl ₂ and 100 ml of ice-cold H ₃ POa. The organic phase is washed with 2 × 50 ml of water, dried over anhydrous Na ₂ SO ₄ and evaporated to give 4.2 g of an orange foam. The crude product is pre-absorbed on kieselgol and chromatographed on a silica gel column (10-40) three times, using 40% ethyl acetate / hexane as the eluent and yielding 0.36 g of the title compound. MS (Cl): m / e = 545 for (M + H) ⁺ ;

IR (KBr / vL ,: 3440 (OH), 1735cm ^-1 (C (= O) OCH ₂ );

¹ HNMP (CDCl ₃ ) δ: 2.50 (d, 2H, C-2 or C-4 CH ₂ , J 6.2), 2.63 (d, 2H, C-2 or C-4 CH ₂ , J = 5.9), 3:33 (s, 1 H, OH) 3:50 (s, 3H, NCH _3), 4:42 (m, 1H, CHOH), 5:09 (s, 2 H, OCH _2), 5.80 (d, 'H, C-5 olefinic H, J = 16), 6.85-7.34 (m, 13H, ArH), 7.52 (d, 1H, C-7 olefinic H, J = 16).

Example 19

Sodium - (+) - 9,9-bis (4-fluoro-phenyl) -3-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -5-oxo-nona-6,8 dienoate 0.34 g (0.62 mmol) of 9,9-bis (4-fluoro-phenyl) -3-hydroxy-8- (1-methyl-1H-tetrzol-5-yl) -5-oxo-nona 6,8-dienylbenzene ester dissolved in 4 ml of tetrahydrofuran and 1 ml of water. 0.62 ml (0.62 mmol) of 1 N sodium hydroxide solution is added and the solution is stirred for 6 hours at 24 ° C. The mixture is diluted with 10 ml of water and washed with 3 × 50 ml of diethyl ether: The aqueous phase is freeze-dried and yields 0.17 g ( 52%) of the title compound, mp 166-180 ° C (Zerd.j.

IR (KBr) i / n ,, ": 1585cm" ¹ (COO);

¹ HNMR (DMSOd ₆ ) δ: 1.76 (dd, 1 H, C-4 CH, J = 8.4.16), 1.97 (dd, 1 H, C-4 CH, J = 3.5, 16), 2.42 (m, 1 H, C-2 CH ₂ ), 3.71 (s, 3 H, NCH ₃ ), 3.93 (m, 1 H, CHOH), 5.80 (d, 1 H, C-6 olefinic H, J = 16), 6.89 -3.94 (m, 2H, AiH), 7.06-7.12 (m, 2H, ArH), 7.30 (d, 1H, C-7 olefinic H, J = 16), 7.38-7.41 (m, 4H ₁ ArH ).

Anal. Calcd. for C ₂₃ Hi ₉ F ₂ N ₄ O ₄ Na 3.5 H ₂ O:

C, 51.21; H, 4.86; N, 10.39

 Found: C, 51.44; H, 3.97; N, 9.46.

Example 20

3,3-bis- (4-fluoro-phenyl) -2- (1-isopropyl-1H-tetrazol-5-yl) 8crylsäureethylesteruRd3,3-bis- (4-fluoro-phenyl) -2- (2-isopropyl- 2H-tetrazol-5-yl) acrylate

A. 3,3-bis- (4-fluoro-phenyl-2- (2-isopropyl-2H-tetrazol-5-yl) -acrylsäuroethy! Ester (To a cooled solution ⁰ -78 C, dry ice-acetone) of 2 , 6g (7.3 mmol) of 3,3-bis (4-fluoro-phenyl) -2- (1H-tetrazol-5-yl-ethylacrylate shown in Example 2) in 20 ml of dry dimethylformamide are added under argon 0.44g (11, OmMoI)

Add NaH (60% in mineral oil) followed by 2, UmI (20, OmMoI) reagent grade 2-iodopropane in a single portion. The viscous reaction mixture is stirred for 30 minutes at -78 ° C under argon. The mixture is then allowed to warm slowly to room temperature over a period of 16 hours. The analytical TLC, which is eluted once with 50% ethyl acetate in hexane, shows only one spot at Rj = 0.86. The white suspension is diluted with 40 ml semi-saturated pumice and then with 20 ml of ethyl acetate. The aqueous phase is washed with 2 χ 20 ml of ethyl acetate. The organic phases are combined, dried over MgSO ₄ and concentrated in vacuo. The analytical TLC, eluted four times with 8% by volume of ethyl acetate in hexane, shows two spots with Rf = 0.38 (21) and R ₍ = 0.49 (21a).) The desired products are eluted by silica gel column chromatography 8% EtOAc in hexane, the fast-forming product gives 1.64 g (56.5%) of the title compound, MS (Cl): m / e = 399 for (M + H) ⁺ ;

¹ H NMR (CDCl ₃ ) δ: 7.29-6.85 (8H, m), 4.94 (1H, heptet, J = 6.7Hz), 4.09 (2H, q, J = 6.9Hz), 1.50 (6H, d, J = 6.8Hz), 1.01 (3H, »., J = 6.9Hz);

' ³ CN MR (CDCl ₃ ) δ: 167.04.163.20 (d, ¹ J ₀ -F = 248.4 Hz), 162.82 (d,' J _C - _F = 240 Hz), 152.65.136.85, 136.19, 1.31.83 (d, ³ J _C - _F = 8.3 Hz), 131.04 (d, ³ Jc-F = 8.3Hz), 115.97,115.85,115.34 (d, ² J _C - _F = 21.9Hz), 115.11 (d, ² J _C - _F = 21.9Hz), 61.38, 56.48, 22.04.13.68ppm.

B. 3,3-Bis (4-fluoro-phenyl) -2- (1-isopropyl-1H-t-triazole-5-yl) -acrylic acid ethyl ester The silica gel column from step A above is further eluted with 8% EtOAc in hexane and provides the slower running product (R (= 0.38).) The corresponding fractions are collected to give 0.95 g (32.7%) of the title compound MS (Cl): m / e = 399 for (M + H) * ;

¹ H NMR (CDCl ₃ ) δ: 7.25-6.85 (8H, m), 4.30 (1H, heptet, J = 6.8Hz), 4.04 (2H, q, J = 7.1Hz), 1.26 (6H, d, J = 6.8Hz), 1.01 (3H, t, J = 7.1Hz);

¹³ C NMR (CDCl ₃ ) δ: 165.6, 162.7 (d, 'J _C - _F = 200 Hz), 155.7, 135.8, 134.2, 132.2 (d, ³ J _C - _F = 8.3 Hz), 131.0 (d, ³ J _C - _F = 6.8Hz), 115.8 (d, ² Jc-F = 21.9Hz), 115.7 (d, ² J _C - _F = 21.9Hz), 61.81, 51.07, 22.18.13.61 ppm.

Example 21 3,3-Bis- (4-fluoro-phenyl) -2- (1-isopropyl-1H-totazol-5-yl) -acrylic-aldehyde

A. 3,3-Bi "- (4-fluoro-phenyl) -2- (1-isopropyl-1H-tetrazol-5-yl) -acrylic acid

To a cooled to ⁰ ° C solution of 3,3-bis- (4-fluoro-phenyl) -2- (1-isopropyl-1 H-tetrazol-5-yl) acrylate (0.95 g, 2,39mMcl) in 20 ml of a 1: 1 (v / v) mixture of tetrahydrofuran and methanol are added in a single portion to 4 ml of a 3 M aqueous solution of LiOH The reaction mixture is stirred for 15 minutes at ⁰ ° C. and then allowed to warm to room temperature The reaction is carried out for 4 hours at room temperature, forming a very bright clear solution, the crude reaction mixture is diluted with 12 ml of 2 MH ₂ SO ₄ and the product is extracted with 2 × 40 ml of diethyl ether. The organic phases are combined, dried over MgSO ₄ , im Vacuum and then dried under high vacuum (0.01 mm Hg) at room temperature for 24 hours to give the title compound, the acrylic acid is then used in the next step without further purification.

3,3-Bls- (4-fluoro-phenyl) -2- (1-isopropyl-1H-tetrazol-5-yl) -acryloyl chloride

A solution of the dried acid shown in step A in 20 ml of dry methylene chloride is added at room temperature with 4 ml of oxalyl chloride (redistilled over CaH ₂ ). The mixture is refluxed under argon atmosphere for 2 hours to form a light tan solution. The majority of the volatile solvents are evaporated in vacuo and the last traces of oxalyl chloride are removed in a high vacuum over 12 hours at room temperature to give the title compound.

C. 3,3-Bis (4-fluoro-phenyl) -2- (1-isopropyl-1H-tetrazol-5-yl) allyl alcohol

The acid chloride shown in step ü is dissolved in 20 ml of dry tetrahydrofuran and then slowly added 1.5 ml of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran under an argon atmosphere at -78 ° C. Analytical TLC, eluting with 30V'ol .-% EtOAc in hexane, the alcohol product at R ₍₌ 0.46 showed. The crude reaction mixture is poured into dilute H ₂ SO ₄ (2N in H ₂ O) and the desired product with Extract 3 × 40 ml of diethyl ether, combine the organic phases, dry over MgSO ₄ and evaporate in vacuo to give 1.07 g of the title compound, which is used without further purification in the next step.

D. 3,3-Bis (4-fluoro-phenyl) -2- (1-isopropyl-1H-tetrazol-5-y-o-acrylaldehyde

The allyl alcohol (0.96 g) prepared in stage C is dissolved at room temperature in 45 ml of dry methylene chloride. To this vigorously stirred solution is added 0.64 g (2.96 mmol) of pyridinium chlorochromate in a single portion. After stirring the reaction mixture for four hours, the analytical TLC after single development with 10% by volume of EtCAc in hexane and twice with 20% by volume of EtOAc in hexanes shows a major product in RI = 0.22. The crude mixture is added to an approximately 1 "thick silica gel and eluted with 20% EtOAc in hexane to give 0.51 g (53%) of the title compound MS (Cl): m, e = 355 for (M + H) \

Example 22

3,3-B! S (4-fluoro-phenyl) -2- (2-isopropyl-2H-tetrazol-5-yl) acrylaldehyde

The general procedure of Example 21, Step A, B, C and D is repeated using the 3,3-bis (4-fluoro-phenyl) -2- (1-isopropyl-1H-tetrazol-5-yl). acrylic acid ethyl ester is replaced by 3,3-bis (4-fluoro-phenyl) -2- (2-isopropyl-2H-tetrazol-5-yl) acrylic acid ethyl ester and the title compound is obtained in 88% yield.

Example 23

9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester and 11,11-bis - (4-fluorphenyll-ö-hydroxy-IO-li-isopropyl-IH-tetrazol-B-yll-S-oxo-undeca-Seio-triensäureethylester

A. 5,0-Bis- (4-fluoro-phenyl) -4- (1-isopropyl-1H-tetrazol-5-yl) -penta-2,4-dienal and 7,7-bis (4-fluoro-phenyl) - 6- (1-isopropyl-1H-tetrazol-5-yl) hepta-2,4,6-trienal

To a dry mixture of 0.51 g (1.4 mmol) of 3,3-bis (4-fluoro-phenyl) -? - (1-isopropyl-1H-tetrazol-5-yl-acrylaldehyde and 0.48 g (i. The light brownish solution is heated with vigorous stirring in an oil bath to about 120 ° C. The mixture is heated rapidly and refluxed overnight (about 18 hours) Solution, eluted five times with 20% by volume EtOAc in hexane, shows only one spot at Rf - 0.26, the starting aldehyde is undetectable, the crude reaction mixture is chromatographed on a silica gel column and treated with about 11% by volume EtOAc in The appropriate fractions provide 0.54 g (99%) of a mixture of the title compound, which was homogeneous by TLC, and this material is used in the next step without further purification.

B. 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester and 11,11-bis {4-fluoro-phenyll-S-hydroxy-IO-li-isopropyl-IH-tetrazol-S-yll-S-oxo-undeca-eeiO-triensäureethylester

0.36 ml (2.8 mmol) of ethyl acetoacetate dianion in 2.5 ml of tetrahydrofuran are mixed with 0.11 g (2.8 mmol) of NaH (60% in mineral oil) and 1.2 ml (3, OmMoI) 2 as in Example 10, 5M BuLi generated in hexane at O ³ C under argon. The solution of the dianion, after cooling to -78 ° C by means of a cannula in a cooled to -78 ° C solution of 0.52g (1.4 mmol) of the dienal and trienal compounds shown in step A in 5 ml of tetrahydrofuran transferred. The reaction mixture is stirred at -78 ⁰ C for 15 minutes under argon. The analytical TLC, eluted twice with 50% EtOAc in hexane, shows a major spot at Ri = 0.41 and a lower component at R | = 0.47. The light brownish reaction mixture is diluted with 5 ml 2M H ₂ SO ₄ and extracted with 2 × 40 ml EtOAc. The organic phases are combined, dried over MgSO ₄ and concentrated in vacuo. The products are purified by silica gel chromatography with 20% by volume EtOAc in hexane as eluent. The fractions of Rt = 0.41 are combined and evaporated to give 0.29 g (41%) of the title compound 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-isopropyl-1H- tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester.

¹ H NMR (CDCl ₃ ) δ: 7.29-7.25 (2H, m), 7.12 (2H, t, J = 8.64Hz), 6.93-6.81 (4H, m), 6.75 (1H, d, J = 15.5Hz ), 5.27 (1H, dd, J = 5.64, 15.5Hz), 4.62 (1H br.q, J = 5.7Hz), 4.29 (1H, heptet, J = 6.6Hz), 4.17 (2H, q, J = 9.1 Hz), 3.46 (2H, br.s), 2.72 (2H, d, J = 6.0 Hz), 1.26 (3H, t, J = 9.1 Hz), 1.3-1.2 (6H, br ) ppm.

The fractions with Rf = 0.47 are combined and evaporated to give 0.13 g (17.3%) of the title compound 11,11-bis (4-fluorophenyl J-ö-hydroxy-IO-d-isopropyl-IH-tetrazole- B-y-S-oxo-undeca-eeiO-triensäureethylester.

¹ H NMR (CDCl ₃ ) O: 7.29-7.22 (2H, m), 7.2O-7.10 (2H, m), 6.91-6.80 (4H, m), 6.59 (1H, d, J = 15.4Hz), 6.29 (1H, dd, J = 10.7, 15.2Hz), 5.70 (1H, dd, J = 10.7, 15.4Hz), 5.48 (1H, dd, J = 9.9, 15.5Hz), 4.62 (2H, br), 4.27 (1H, heptet, J = 6.6Hz), 4.17 (2H, q, J = 7.0Hz), 3.46 (2H, s), 3.1 (1H, br, D ₂ O-exchangeable), 2.75-2.69 (2H , m), 1.26 (3H, t, J = 7.0Hz), 1.38-1.05 (6H, br. maxima, hindered rotation on the isopropyl group) ppm.

Example 24

9,9-bis- (4-fluoro-phenyl) -5-hydroxy-8- (2-isopropyl-2H-tetrazol-5-yl) -3-oxo-nona-6,8-bis-diensäureethylesterund7,7 (4-Fluoro-phenyl) -5-hydroxy-6- (2-isopropyl-2H-tetrazol-5-yl) -3-oxo-hept-6-enoic acid ethyl ester. The general procedure of Example 23, Step A, is repeated, using 3,3-bis (4-fluoro-phenyl) -2-n-isopropyl-1H-tetrazol-5-yl) acrolein by 3,3-bis- (4-fluoro-phenyl) -2- (2-yl) isopropyl-2H-tetrazol-5-yl) acrolein, replacing mainly 5,5-bis- (4-fluoro-phenyl) -4- (2-isopropyl-2H-tetrazol-5-yl) -penta-2,4- dienal is formed in 82% yield; Ms (CI): m / e = 381 for (M + H) *. This product is then subjected to the general procedure of Example 23, Step B, yielding 69.9% yield 9,9-bis- (4-fluoro-phenyl) -5-hydroxy-8- (2-isopropyl-2 Ethyl 7-bis (4-fluoro-phenyl) -5-hydroxy-6- (2-isopropyl- 2H-tetrazol-5-yl) -3-oxo-hept-6-enoic acid ethyl ester.

¹ H NMR (CDCl ₃ ) δ: 7.31-7.11 (2H, m), 7.10-7.04 (2H, m), 6.91-6.78 (4H, m), 6.72 (1H, d, J = 15.5Hz), 5.46 (1H, dd, J = 5.91,15.7 Hz), 4.95 (1H, heptetJ = 6.8Hz), 4.64 (1H, br.S), 4.17 (2H, q, J = 7.2Hz), 3.46 (2H, s) , 2.75-2.72 (2H, m), 1.49 (6H, d, J = 6.8Hz), 1.28 (3H, t, J = 7.2Hz) ppm.

Example 25

(±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid ethyl ester A solution of 0.9 g (0.57 mmol) of 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) -3-oxo; Nona-6,8-dienoic acid ethyl ester in 6 ml of tetrahydrofuran (ice bath at ⁰ ° C. under argon) is treated with 0.65 ml of a 1.0 M solution of triethylborane in tetrahydrofuran. The reaction mixture is stirred for 1 hour at -5 to ⁰ ° C and then cooled in an acetone-dry ice bath to -78 ⁰ C under argon. This light yellow solution is treated with 25 mg (0.66 mmol) of solid NaBH ₄ and the reduction continued for 2 hours at -78 ° C. The reduction is accelerated by addition of 25 μΙ absolute CH ₃ O. After another hour, the analytical TLC, once eluted with 1: 1 (v / v) EtOAc in hexane, indicates complete disappearance of the starting material. Dilute the cold reaction mixture with 20 mL 1M H ₂ SO ₄ and extract the organic material with 2 χ 40 mL EtOAc. The organic phases are combined, dried over MgSO ₄ and concentrated in vacuo to a light yellow syrup. The syrup is redissolved in 200 mL MeOH and the solution allowed to stand overnight at room temperature. The analytical TLC, eluted twice with 50% EtOAc in hexane, shows a major spot at R ₁ = 0.32. Purification by silica gel chromatography with 30% by volume EtOAc in hexane gives 0.23 g (79%) of the title compound.

IR (KBr) V _max : 3438 (v.br), 1731 (s), 1600 (s), 1 503 (s), 1 225 (s), 1156 (s), 838 (s), 750 (s) cm ¹ ;

¹ H NMR (CDCl ₃ ) δ: 7.29-7.25 (2H, m), 7.12 (2H t, J = 8.6Hz), 6.61-6.93 (4H, m), 6.73 (1H, d, J = 15.8Hz) , 5.15 (1H, dd, J = 15.8, 6.5 Hz), 4.42 (1H, q, J = 5Hz), 4.30 (1H, heptet, J = 6.7Hz), 4.22 (1H, m), 4.22 (2 H, v.br. D ₂ O exchangeable), 4.16 (2 H. q, J = 7.2 Hz), 2.47-2.45 (2H, m), 1.59-1.57 (2H, m), 1.26 (3H, t, J = 7.2Hz), 1.4-1.0 (6H, br, hindered rotation on the isopropyl group);

' ³ CNMR (CDCl ₃ ) O: 172.26, 162.8 (d, Vc-f = 250.7Hz), 162.41 (d,' J _C - _F = 250.7Hz), 152.10, 146.19, 138.44, 137.88, 135.98, 135.40, 132.32 (d, ³ Jc-F = 8.3Hz), 131.72 (d, ³ J _C -f = 8.3Hz), 127.61,121.81,115.71 Id ₁ ² Jc-F = 21.1Hz), 115.48 (d, ² Jc-F = 21.1Hz), 71.63.68.20, 60.77,50.78,42.29,41.68,24-20 (v.br for isopropyl signal due to limited rotation), 14.14ppm;

Anal. Calcd. TOrC ₂₇ H ₃₀ F ₂ N ₄ O ₄ :

C, 59.11; H, 6.25; N, 10.21

 Found: C, 60.40; H, 5.66; N, 9.91.

Example 26

(±) erythro-11,11-bis- (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-isopropyl-1H-tetrazol-5-yl) undeca-6,8,10-triensäureethylester The general procedure of Example 25 is repeated using 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) -3-oxo. nona-6,8-dienoic acid ethyl ester by 11,11-bis (4-fluoro-phenyl) -5-hydroxy-10- (1-isopropyl-1H-tetrazol-5-yl) -3-oxo-undeca-6, 8,10-ienoic acid ethyl ester (0.13 g, 0.24 mmol) is replaced and 140 mg of the title compound are obtained.

¹ H NMR (CDCl ₃ ) δ: 7.29-7.22 (2H, m), 7.13 (2H, t, J = 8.6Hz, 6.92-6.80 (4H, m), 6.58 (1H, d, J = 15.4Hz) , 6.27 (1H, dd, J = 10.7, 15.1 Hz), 5.7'J (1H, dd, J = 10.6, 15.5Hz), 5.66 (1H, dd, J = 5.8, 15.4Hz), 4.43 ( 1 H, q, J = 6.0Hz), 4.27 (1H, heptet, J = 6.5Hz), 4.24 (1H, m), 4.15 (2H, q, J = 7.2Hz), 3.91 (1H, br , D ₂ O on exchange), 3.78 (1 H, br, D ₂ O-exchangeable), 2.48-2.43 (2H, m), 1.65-1.58 (2H, m), 1.42-1.32 ana 0.97-0.67 ( v.br. maxima for isopropyl signals), 1.26 (3H, t, J = 7.2 Hz) ppm.

Example 27

(±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-isopropyl-2H-tetrazol-5-yl) nono-6,8-diensäureethylesterund (± ) -erythro-7,7-bis- (4-fluoro-phenyl) -3,5-dihydroxy-6- (2-isopropyl-2H-tetrazol-5-yl) -hept-6-enoic Acid Ethyl Ester The general procedure of Example 25 is repeated, the ethyl 9,9-bis (4-fluoro-phenyl) -5-hydroxy 8- (1-isopropyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-diensäure by 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (2-isopropyl-2H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester, the little 7 , 7-Bis- (4-fluoro-phenyl) -5-hydroxy-6- (2-isopropyl-tetrazol-5-yl) -3-oxo-hept-6-enoic acid ethyl ester 'shown in Example 24) is replaced , wherein after silica gel column chromatography, the title compounds are obtained in 53% and 38% yield.

¹ H NMR (CDCl ₃ ) δ: 7.28-7.23 (2H, m), 7.07 (2H, t, J = 8.6Hz), 6.86-6.71 (4H, m), 6.66 (1H, d, J = 15.7Hz ), 5.45 (1H, dd, J = 6.4, 15.8 Hz), 4.95 (1H, heptet, J = 6.7 Hz), 4.43 (1H, br), 4.22 (1H, br), 4.16 (2H , q, J = 7.2 Hz), 3.90 (1H, br, D ₂ O-exchangeable), 3.64 (1H, br. D ₂ O interchangeable), 2.47-2.43 (2H, m), 1.67-1.60 (2H , m), 1.48 (6H, d, J = 6.7 Hz), 1.25 (3H, t, J = 7.2Hz);

¹³ C NMR (CDCl ₃ ) δ: 172.32,163.77, 162.53 (d, 'J _C _ _F = 248.4Hz), 161.86 (d, ¹ Jc-F = 247.6Hz), 145.61, 137.88, 137.05, 136.28, 132.88 ( d, ³ Jc-F = 8.3Hz), 131.64 (d, ³ Jc-F = 8.3Hz), 131.19,131.08,128 36,125.42,115.58 (d, ² J _C - _F = 21.9Hz), 114.67 (d, ² J _{C, F} = 21.9Hz), 72.15, 68.08, 60.74, 56.41, 42.54, 41.73, 22.04, 14.17ppm and

¹ HNMR (CDCl ₃ ) δ: 7.30-7.26 (2H, m), 7.07 (2H, t, J = 8.6 Hz), 6.94-6.70 (2H, m), 6.83-6.77 (2H, m), 4.92 (1 H, heptet, J = 6.7 Hz), 4.24 (1H, m), 4.92 (1 H, m, methine proton next to a hydroxy group), 4.14 (2H, q, J = 7.1 Hz), 4.00 (1H, d, J = 6.5Hz, D ₂ O exchangeable), 3.54 (1H, d, J = 2.5Hz), 2.45-2.42 (2H, m), 1.85 (2H, t, J = 6.1Hz), 1.48 (3H , d, J = 6.8Hz), 1.47 (3H, d, J = 65.8Hz), 1.25 (3H, t, J = 7. '. Hz),

¹³ CNMR (CDCI) δ: 172.1t ·. 162.91,162.51, (d, ¹ Jc-F = 248.4Hz), 162.00 (d, ¹ J ₀ -F = 246.9Hz), 146.44,137.33,135.98,131.26 (d, ³ Jc-F = 8.3Hz), 131.19 (d, ¹ J ₀ -F = 8.3 Hz), 128.33,115.52 (d, ² J _C _ _F = 21.1 Hz), 114.73 (d, ² J ₀ -F = 21.9 Hz), 71.31, 67.77, 60.65, 56.50 , 41.85,41.45, 21.98,14,18ppm, respectively.

Example 28

Sodium (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-isopropyl-1H-tetrazol-5-yl) nona-6,8-dienoate To a solution of 230mg (0.45 mmol) of (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-isopropyl-1H-tetrazole-5- yl) -nona-6,8-dienoic acid ethyl ester in 10 ml of tetrahydrofuran at ⁰ ° C. (ice bath) are added 450 μΙ (1.0 equivalent of a 1 N NaOH solution.) The emulsion is stirred at ⁰ ° C. for 1 hour and forms a clear homogeneous solution The analytical TLC, eluted twice with 50% EtOAc in hexane, shows only a stationary spot at the start The main bulk of the volatile solvent is evaporated at 10-15 ^° C. in vacuo and the aqueous solution is freeze-dried under high vacuum at 0 ^° C. and provides the title compound in quantitative yield; F> 120 ^° C (with decomposition).

IR (KBr) I? ™ »: 3438 (ν. Br.), 1 600 (s), 1 581 (s), 1 513 (s), 1400 (s), 1 225 (s), 1160 (s) , 838 (s) cm "¹;

¹ H NMR (DMSOd ₆ ) δ: 7.41-7.29 (4H, m), 7.07-6.91 (4H, m), 6.53 (1H, d, J = 15.6 Hz), 5.06 (1H, dd, J = 5.4 , 15.7 Hz), 4.48 (1H, heptet, J = 6.6 Hz), 4.14 (1H, q, J = 5.9 Hz), 3.64 (1H, m), 3.83.2 (2H br. Maxima), 2.02 ( 1H, dd, J = 3.6,15.0 Hz), 1.84 (1H, dd, J = 8.4,14.9Hz), 1.5-1.3 (1H, m), 1 3-1.1 (1H, m), 1.15 (6H, br, s, isopropyl signals with limited rotation);

¹³ C NMR (DMSOd ₆ ) δ: 176.30.161.82 (d, ¹ J ₀ -F = 246.1 Hz), 161.41 (d, ¹ J ₀ -F = 246.9 Hz), 151.53, 144.45, 139.87, Vi6.11, 135.45, 132.14 (d, ³ J ₀ -F = 8.3 Hz), 131.28 (d, ³ J _{0, F} = 8.3 Hz), 125.39,122.23,115.44 (d, ² J _{C, F} = 21.9 Hz), 115.05 (d, ² J ₀ -F = 21.9 Hz), 68.14, 65.68, 50.05, 44.48, 43.48, 22.06 ppm;

Anal. BBrJUrC ₂₅ H ₂₅ F ₂ N ₄ O ₄ Na ₂ H ₂ O:

C. 55.35; H, 5.39; N, 10:32

 Found C, 54.63; H, 4.79; N, 9.35.

Example 29

Sodium (±) -erythro-11,11-bis- (4-fluoro-phQnyl) -3,5-dihydroxy-10- (1-isopropyl-1H-tetrazol-5-vl) undeca-6,8,10 -trionoate The product of Example 26 is subjected to the general procedure of Example 28 to give the title compound in quantitative yield; F.> 100 ° C. with decomposition.

IR (KBr) v _max : 3425 (v. Br), 1600 (s), 1 575 (sh, s), 1 513 (s), 1400 (s), 1 225 (s), 1163 (s), 838 (s) cm ';

¹ H NMR (DMSOd ₆ ) δ: 7.42-7.30 (4H, m), 7.14-7.03 (2H, m), 6.92-6.87 (2H, rn), 6.46 (1 H, i.e. J = 15.4 Hz), 6.17 (1H, dd, J = 14.8, 15.4Hz), 5.72 (1H, dd, J = 5.2.14.9Hz), 5.61 (1H, dd, J = 10.9,15.3Hz), 5.0 (1H, Dr ) ₁ 4.48 (1 H.heptet, J - 6.6Hz), 4.12 (1H, m), 3.64 (1H, br), 2.01 (1H, d, J = 12.6Hz), 1.84 (1H, dd , J = 8.0, 14.3Hz), 1.6-0.3 (6H, v. Br., Maximum, isopropyl signals with limited rotation);

¹³ CNMR (DMSOd ₆ ) 0: 175.93.162 (d, 'J _C - _F = 250 Hz), 1Cl (d, ¹ Jc-F = 250 Hz), 1.51.35, 144.71, 141.56, 136.09, 135.57, 133.82 , 132.31 (d, ³ Jc-F = 8.3Hz), 131.41 (d, ³ J _C - _F = 8.3Hz), 128.65,127.61,122.58,115.46Id ₁ ² J ₀ -F = 21.1Hz), 115.14 (i.e. , ² J _C - _F = 21.9Hz), 68.41,65.83,50.11,44.65,43.51,22.07 (from br., Signals for! Sopropylhydrocarbons) ppm.

Example 30 Sodium·! ±) -erythro-9,9, bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-isopropyl-2H-tetrazol-5-yl) nona-6,8-dienoate

The ethyl 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-isopropyl-2H-tetrazol-5-yl) nona-6,8-dienoate from Example 27 is subjected to the general procedure of Example 28 to give the title compound in quantitative yield;

F.> 120 ° C with decomposition.

IR (KBr) V _max : 3438 (v. Br.), 1600 (s), 1513 (s), 14C3 (m), 1400 (m), 1321 (s), 1225 (s), 1188 (m), 1156 (s), 838 (S) cm "¹;

'HNMR (DMSOd ₆ ) δ: 7.29-7.22 (4H, m), 6.95 (2H, t, J = 8.8Hz), 6.84-6.78 (2H, m), 6.53 (1H, d, J = 15.6 Hz), 5.34 (1H, dd, J = 5.6, 15.6 Hz), 5.02 (1H, heptet, J = 6.7 Hz), 4.15 (1H, q, J = 5.9 Hz), 3.65 (1 H, q, J = 4.0 Hz), 3.37 (2 H, br. S, D ₂ O interchangeable) 2 04 (1 H, dd, J = 15.0, 3.5 Hz), 1.85 (1 H, dd, J = 8.6.15.1 Hz), 1.40 (6H, d, J = 6.7 Hz), 1.47-1.23 (2H, br. Maxima);

¹³ C NMR (DMSOd ₆ ) δ: 176.28, 162.88, 61.59 (d, 'J _C - _F = 246.13 Hz), 160.94 (d, ¹ J ₀ -F = 245.4 Hz), 143.20, 139.949, 137.81, 136.26, 132.06 (d, ³ Jc-F = 8.3Hz), 131.30 (d, ³ J _C - _f = 3.3Hz), 130.93,126.00,125.85,115.32 (d, ² J _C _ _F = 21.9Hz), 114.46 (d, ² J _C _ _F 21.9 Hz), 79.09,68.53,65.83, 55.72,44.64,43.53, 30.36, 21.69ppm.

Anal. CaICDJORC ₂₅ H ₂₅ N ₄ O ₄ Na ₂ H ₂ O:

C ₁ 55.35; H, 5.39; N, 10:32; found; C, 55.96; H, 4.86; N, 10.27.

Example 31 Sodium - (+) - erythro-7,7-bis (4-fluoro-phenyl) -3,5-dihydroxy-6- (2-isopropyl-2H-tetrazol-5-yl) -hept-6-enoate

The 7,7-bis (4-fluoro-phenyl) -3,5-dihydroxy-6- (2-isopropyl-2H-tetrazol-5-yl) -hept-6-enoic acid ethyl ester shown in Example 27 is subjected to the general procedure of Example 28 to give the title compound in quantitative yield; F.> 120 ⁰ C with decomposition.

IR (KBr) vL «: 3438 (s, v. Br), 1 600 (s), 1 575 (s), 1 512 (s), 1406 (s), 1 225 (s), 1156 (s), 838 (s) cm "¹;

¹ H NMR (DMSOd ₆ ) δ: 7.41-7.36 (2H, m), 7.23 (2H, t, J = 8.7Hz), 6.93 12H, t, J = 8.8Hz), 6.86-6.82 (2K , rrj, 4.98 (1H, heptet, J = 6.7 Hz), 4.67 (1H, t, J = 6.7 Hz), 3.76 (1H, m), 3.35 (br, S, D ₂ O-exchangeable) 1.99 (1 H, dd, J = 3.15.0 Hz), 1.80-1.63 (3H, m), 1.41 (3H, d, J = 6.4 Hz), 1.38 (3H, d, J = 6.5Hz);

' ³ C NMR (DMSOd ₆ ) O: 176.42.161.34 (d,' J ₀ -F = 244.6Hz), 160.7 (d, ¹ J ₀ -F = 237.1 Hz), 162.25,143.93,137.8S, 136.44,131.11 (d, ³ Jc-F = 8.0Hz), 130.85 (d, ³ Jc-F = 8.0Hz), 114.97 (d, ² J _C - _F = 21.1 Hz), 114.33 (d, ² J _{C F} = 21.1. Hz), 67.76, 65.80, 55.40, 43.12, 42.89, 30.33, 21.78, 21.58 ppm (non-equivalent isopropyl signal);

Anal. Calcd. for C ₂₃ H ₂₃ F ₂ N ₄ O ₄ Na H ₂ O:

C, 55.42; H, 5:05; N, 11.24; Found: C, 56.1; H, 4.94; N, 10.79.

Example 32

3,3-bis (4-fluo <- phenyl) -2- (2-tert-butyl-2H-tetrozol-5-yl) acrylsäureethyloster to einsr cooled to -5o ⁰ C stirred solution of 10 g of 3,3- Bis (4-fluoro-phenyl) -2- (1H-tetrazol-6-yl-acrylate in 250 ml of dry diethyl ether is slowly added 60 ml of liquid isobutylene, d3S was condensed from gaseous material in a dry ice-alcohol bath with constant stirring and cool slowly and slowly add 50 mL concentrated H ₂ SO _4. The mixture is then sealed in a stainless steel Parr container and stirred for 40 hours at -30 ^° C. After pressure equalization, the mixture is slowly and carefully poured into excess saturated NaHCO ₃ . The aqueous mixture is extracted with diethyl ether, dried over Na ₂ SO ₄ and concentrated in vacuo to give 7.8 g (67.8%) of the title compound, mp 143-144 ° C.

IR (KBr) vL _x : 3438 (ν br), 1738 (s), 1625 (s), 1600 (s), 1240 (s), 1225 (s), 842 (s) cm ^-1 ;

¹ H NMR (CDCl ₃ ) δ: 7.29-7.24 (2H, m), 7.07-6.84 (6H, m), 4.10 (2H, q), 1.59 (9H, s), 1.03 (3H, t) ppm.

Anal. Calcd. for C ₂₁ H ₂₂ F ₄ N ₄ O ₂ :

C, 64.07; H, 5.38; N, 13.58

 Found: C, 64.15; H, 5.25; N, 13.58.

Example 33

3,3-bis- (4-fluoro-phenyl) -2- (2-tert-butyl-2H-tetrazol-5-yl) acrylaldehyde

A.3,3-8is- (4-fluo ^ phenyl) -2M2-tert-butyl-2H-tetrazol-5-yl) allyl alcohol

To a stirred solution of 2.0 g (4.8 mmol) of ethyl 3,3-bis (4-fluoro-phenyl) -2- (2-tert-butyl-2H-tetrazol-5-yl) -acrylate in 10 ml of dry methylene chloride at -78 ° C under argon 10ml Diisobutylaluminiumhydridlösung (1.0M solution in methylene chloride) within 3 minutes. The reduction is continued for 2 hours at -78 ⁰ C under argon. The analytical TLC eluted twice with 20% v / v ethyl acetate in hexane shows no starting material at R = 0.42, but one major spot at Rf = 0.14 corresponding to the desired product. The crude reaction mixture is diluted at -78 ° C with 10 ml 2 η HCl and then extracted with 2 χ 40ml ethyl acetate. The organic phases are combined, dried over MgSO 4, evaporated in vacuo and dried under high vacuum overnight at room temperature to give the title compound, which is used without further purification in the next step.

¹ H NMR (60MHz) (CDCl ₃ ) δ; 7.4-6.9 (SK, m), 9.7 (-1 / 4H, s, small amount of aldehyde), 4.6 (2H, d, J = 6 Hz), 1.58 (9H, s) ppm.

B.3,3-bis- (4-fluoro-phenyl) -2- (2-tert-butyl-2H-tetrazol-5-yl) -ACR / laldehyd

The crude allyl alcohol shown in step A is dissolved in 60 m! dissolved in dry methylene chloride and added under argon at room temperature to the vigorously stirred solution 1.2 g (5.5 mmol) of pyridinium chlorochromate in a single portion. The slightly exothermic oxidation is carried out for 2 hours at room temperature. The analytical TLC, eluted twice with 20% by volume of ethyl acetate in hexane, shows the aldehyde at R ₁ = 0.35. The crude reaction mixture is chromatographed on a silica gel column and eluted with 115% by volume of ethyl acetate in hexane to yield 1.59 g (89%) of a TLC-uniform product. Recrystallization from EtOAc-hexane gives the pure title compound; F. 131-133 ⁰ C.

IR (KBr) t / _max : 3488 (m), 1 669 (s), 1 600 (s), 1 508 (s), 1475 (m), 1 231 (s), 1 219 (s), 1156 ( s), 850 (s) cm ^-1 , ¹ H NMR (CDCl ₃ ) δ: 9.72 (1H, s), 7.38-7.33 (2H, m), 7.17 (2H, t, J = 8.6Hz), 7.00- 6.84 (4H, m), 1.63

C NMR (CDCl ₃ ) δ: 190.14,164.27 (d, 'J _C - _F = 246.1 Hz), 163.35 (d,' J _C - _F = 240 Hz), 162.5, 160.9, 133.58, (d, ³ J _C - _f = 8.3 Hz), 132.26 (d, ³ Jc-F = 8.3 Hz), 128.4,115.85 (d, ² J _C - _F = 21.9 Hz), 115.22 (d, ² J _C - _F = 21.9 Hz) , 63.95, 29.24 ppm;

Anal. Calcd. for C ₂₀ H ₁₈ F ₂ N ₄ O:

C, 65.21; H, 4.92; N, 15:21

 Found. C, 65.33; H, 4.93; N, 15.44.

Example 34 ö, 5-Bis- (4-fluoro-phenyl) -4- (2-tert-butyl-2H-tetrazol-5-yl) -penta-2,4-dienal

To a warm stirred solution of 1.59 g (4.3 mmol) of 3,3-bis (4-fluoro-ph9nyi) -2- (2-tert-butyl-2H-tetrozol-5-yl) -acrylaldehyde in 60 ml of dry Benzene is added under argon to 1.45 g (4.7 mmol) of triphenylphosphoranylidene acetaldehyde in a single portion. The reagents dissolve rapidly in the 55 ° C solution, and the homogeneous mixture is slowly further heated and refluxed for 16 hours. The analytical TLC, eluted five times with 20% by volume of ethyl acetate in hexane, shows the desired product at Rt = 0.52. The crude reaction mixture is chromatographed on a silica gel column and eluted with 10% by volume of ethyl acetate in hexane to give 1.7 g of product. Recrystallization from EtOAc-hexane gives the pure title compound; F. 171-174 ⁰ C.

IR (KBr) J _mix : 3000 (s), 1675 (s), 1669 (s), 1 600 (s), 1 508 (s), 1225 (s), 1159 (s), 1119 (s), 843 (s) cm ';

¹ H NMR (CDCl ₃ ) δ: 9.55 (1H, d, J = 7.4Hz), 7.50 (1H, d, J = 15.6Hz), 7.33-7.26 (2H, m) 7.18-7.13 (2H, m ), 6.92-6.79 (4H, m), 5.96 (1H, dd, J = 7.5, 15.6Hz), 1.63 (9H, s);

' ³ C NMR (CDCl ₃ ) δ: 193.38, 163.5 (d,' J _C -f = 240Hz), 162.5 (d, 'J _{C, F} = 240Hz), 154.5, 151.5, 149.49, 137, 119.5, 135.5, 132.81 ( d, ³ Jc-f = 8.3Hz), 132.05 (d, ³ J _c _f = 8Hz), 115.80 (d, ² J _C -F = 21.9Hz), 114.98 (d, ² J _C - _F = 21.9Hz) , 64.3,29.23ppm;

Anal. Calcd. for C ₂₂ H ₂₀ F ₂ N ₄ O:

C, 66.99; H, 5.10; N, 14.18

 Found: C, 67.14; H, 5.17; N, 14.55.

Example 35 (±) -eryro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-tert-butyl-2H-tetrazol-5-yl) nona-6,8 -diensäureethylester

A. 9,9-Bis (4-fluoro-phenyl) -5-hydroxy-8- (2-tert-butyl-2H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ester

A solution of 400μΙ (3.1mmol) ethyl acetoacetate in 8ml dry tetrahydrofuran is prepared as described in Example 10 from 130mg (3.2moles) NaH (60% in mineral oil) and 1.27ml (3.2moles) 2.5MBuLi in hexane at 0 ° C under / -, gon

shown. The orange dianion solution is cannulated at -7 ° C into an equally cooled solution of 0.96 g (2.4 mmol) of 5,5-bis (4-fluoro-phenyl) -4- (2-tert-butyl-2H tetrazol-5-yl) penta-2,4-dienaline converted 12ml tetrahydrofuran. The Reaktionsgemisoch is stirred for 5 minutes at -78 ⁰ C. Analytical TLC, eluted once with 50% by volume EtOAc in hexane, shows the spot for Jas major product at Rf = 0.35. The reaction mixture is diluted with 2OmMn HCL and the organiche material with 2 χ 20ml EtOAc extahiert. The organics were combined, dried over MgSO ₄ , evaporated in vacuo and dried under high vacuum (0.001 mmHg) overnight at room temperature (16 hours) to give the title compound, which was used without further purification in the next step.

B. (±) -erythro-9,9-bis (4-fluoro-phenyl) -3 _/ S-dihydroxy-a- (2-tert-butyl-2H-totazol-5-yl) nona-6,8-dienoic acid ethyl ester The crude ketone from step A is dissolved at ⁰ ° C. under argon in 10 ml of dry tetrahydrofuran. To this light brown solution, 3.0 ml of 0.1 M triethylborane in tetrahydrofuran are added. The mixture is stirred for 1.5 hours at 0 ° C and then cooled to -78 ° C (dry ice-acetone bath). 120 mg (3.2 mmol) of NaBH is added <To this stirred solution, and the reduction is carried out for 3 hours at -78 ⁰ C. The cold reaction mixture is diluted with 10 ml of 1 ηHCl and the product is extracted with 2 χ 40 ml of ethyl acetate. The organic phases are combined, dried over MgSO ₄ and evaporated to dryness. The Rnhpr product is redissolved in 200 ml of absolute methanol and the solution is stirred for 16 hours. The analytical TLC, once eluted with 50% by volume of ethyl acetate in hexane, shows only one major spot at R ₁ = 0.31. Silica gel column chromatography with 10-20% EtOAc in Riexan as eluent provides 1.07 g (83.5%) of the title compound.

IR (KBr) Vn _18x : 3438 (s), 2938 (s), 1731 (s), 1 600 (s), 1 503 (vs), 1 225 (s), 1156 (s), 838 (s), 750 (s) cm '; Ή NMR (CDCl ₃ ) δ: 7.28-7.24 (2H, m), 7.07 (2H, t, J = 8.6Hz), 6.86-6.73 (4H, m), 6.69 (1H, d, J = 15.7Hz) , 5.48 (1H, dd, J = 6.3, 15.8Hz), 4.44 (1H, m), 4.23 (1H, M), 4.15 (2H, q, J = 7.0Hz), 3.85 (1H, br, D _z O-exchangeable) 3.50 (1H, br. D ₂ O-exchangeable) 2.48-2.45 (2H, m), 1.69-1.54 (2H, m), 1.59 (9H, s), 1.26 (3 H, t, J = 7.0 Hz);

' ³ C NMR (CDCl ₃ ) δ: 172.38, 1 G2.5 (d,' J _C - _F = 249.2Hz), 161.82 (d, 'J _C - _F = 248.4Hz), 145.53, 137.96, 136.96, 136.29, 132.35 (d, ³ Jc-F = 8.3Hz), 131.61 (d, ³ J _C -r = 7.6Hz), 123.39,125.58,115.31 (d, ² J _C - _F = 21.9Hz), 114.59 (d, ² J _CF = 21.9Hz), 72.24, 68.10, 63.75, 60.75, 42.52, H .62, 29.16, 14.15 ppm.

Anal. Calcd. for C ₂₈ H ₃₂ F ₂ N ₄ O ₄ H ₂ O:

C, 61.75; H, 6.29; N, 10.28

 Found: C, 61.22; H, 6.03; N, 10.02.

Bet game 36

Sodium (±) -örythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-tert-butyl-2H-tetrazol-5-yl) nona-6,8 dienoate To a solution of (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-tert-butyl-2H-tetrazol-5-yl) nona -ö, 8-dienäureethylester (330 mg, 0.63 mmol) in 6 ml of tetrahydrofuran at ^{0 0} C 630μΙ are added to a 1M NaOH solution. The turbid suspension is stirred at ⁰ ° C. for 30 minutes and then at room temperature for a further 2.5 hours, giving a clear, homogeneous solution. The analytical TLC, once eluted with 50% by volume of ethyl acetate in hexane, shows no starting material, only a stationary spot at the start. The bulk of the volatile solvents is evaporated at about 10-15 ⁰ C in vacuo. The solution of the sodium salt is freeze-dried under high vacuum to yield 320 mg (quantitative yield) of the title compound; F.> 12O ⁰ C with decomposition.

IR (KBr) ö _max : 3413 (v. Br), 1600 (s), 1575 (s), 1503 (s), 1338 (s), 1225 (s), 1156 (s), 838 (s) cm "';

Ή NMR (DMSOd ₆ ) =: 7.29 (4H, d, J = 7.2Hz), 6.95 '2H, t, J = 8.9Hz), 6.83-6.78 (2H, m), 6.53 (1H, d, J = 15.5Hz), 5.37 (1H, dd, J = 5.6,15.6Hzi, 5.0 (1H, br. D ₂ O interchangeable) 4.16 (1H, q, J = 6.1Hz), 3.67 (1H, m), 3.37 (1H, br. D ₂ O-exchangeable), 2.05 (1H, dd, J = 15.1.3.5Hz), 1.86 (1H, dd, J = 8.6.15.1 Hz), 1.53-1.29 (2H, m), 1.54 (9H, s);

' ³ C NMR (DMi 0-DE) =: 176.40, 162.50, 16.54 (d,' J _C - _F = 246.1 'z), 160.98 (d,' Jc-f = 259.7Hz), 143.15, 139.54, 137.87, 136.23, 132.0 (d, ³ Jc- _F - 8.3Hz), 131.25 (d, ³ Jc-F = 7.6Hz), 125.01, 15.31 (d, ² J _{c, F} = 21.9Hz), 114.43 (d, ² J _C - _F = 21.9Hz), 68.45, 65.75, 63.35, 44.64, 43.52, 28.53ppm.

Anal. Calcd. for C ₂₆ H ₂₇ F ₂ N ₄ O ₄ NaH ₂ O:

C, 56.11; H, 5.61; N, 10.07

 Found: C, 56.96; H, 5.06; N, 9.99.

Example 37

4,4'-difluoro-3,3'-dimethyl-benzophenone

8 ml (73 mmol of 2-fluorotoluene are added to a vigorously stirred mixture of 61.43 g (46 μmol) and 135 ml carbon tetrachloride at ⁰ ° C. After 10 minutes, 92 ml (837 mmol) 2-fluorotoluene are dissolved in 75 ml carbon tetrachloride at ⁰ C added dropwise within 4 hours and the solution stirred for a further 2 hours.

Attention: After the addition of 2-fluoro-toluene a spontaneous violent reaction takes place. The mixture is cooled to -2O ⁰ C and the reaction with 250 ml 2 η HCl stopped. The organic phase is separated, washed with pumice and dried over MgSO ₄ . The solvent is evaporated and the residue is dissolved in 200 ml of benzene and treated with 200 ml of water and 50 ml of acetic acid. After stirring for 15 hours, the organic phase is separated, dried over MgSO ₄ and evaporated. Crystallization from ethanol provides 50 g (49%) of the title compound; F 128-13O ⁰ C.

IR (KBr) V ^ _3x : 1650cm- '.

¹ H NMR (CDCl ₃ ) =: 7.66 (d, J = 7.3Hz, 2H), 7.58 (m, 2H), 7.09 (t, J = 8.8Hz, 2H), 2.32 (s, 6H).

Anal. CaICdJOrC ₁₆ H ₁₂ F ₂ O:

C, 73.16; H, 4.91

 Found: C, 72.96; H, 4.80.

Example 38

1,1-bis- (4-fluoro-3-methyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethano!

A solution of 2.55 g (26 mmol) of 1,5-dimethyl-tetrazole in 15 ml of dry tetrahydrofuran is treated at -78 ° C. with 12.5 ml of a 2M solution of butyl urithium in hexane (3M, 2 mmol) and stirred for 15 minutes Sg (20.3 mmol of 4,4'-oiduoro-3,3'-dimethy) benzophenone is added in 20 ml of dry hexa-tetrahydro-uran, the mixture is stirred for 1 hour, then the reaction is quenched with 250 ml of 2 N HCl Phase is extracted with 3 × 50 ml of ethyl acetate and the combined organic phases are dried with MgSO ₄ and evaporated The residue is purified by silica gel column chromatography with 20% by volume of EtOAc-hexane as eluent to give 3.7 g (52%) of product Recrystallization from EtOAc-hexane affords the title compound, F.41-42 ° C.

IR (KBr) Vm ": 3400 (br) cm ';

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

Anal. CaICdJOrC ₁₈ H ₁₈ F ₂ N ₄ O:

C, 62.79; H, 5.27; N, 16:27

 Found: C, 62.73; H, 5.32; N, 16:16.

Example 39

1,1-bis- (4-fluoro-3-methyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene

A mixture of 3.58 g (10.9 mmol) of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-letrazol-5-yl) ethanol and 530 mg of potassium hydrogen sulfate becomes 1 , Heated to 195 ° C for 5 hours. The mixture is cooled to 7O ⁰ C and 50 mL of chloroform was added.

The insoluble material is filtered off and the filter evaporated 3t. The residue is recrystallized from EtOAc-hexane to give 3.38 g (100%) of the title compound; F. 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!

Anal. Ber. KJrC ₁₈ H ₁₆ FN ₄ :

C 66.25; H, 4.95; N, 17.17

 Found C, 66.15; H, 6.05; N, 5:24.

Example 40

3,3-bis- (4-fluoro-3-methyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) acrylaldehyde

A solution of 3.58 g (11, OmMoI) of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-y-ethene in 20 ml of dry tetrahydrofuran is added 5.3 ml of a 2.5 M solution of ButyUithium in hexane (13,25mMol) at -78 ⁰ C was added and the mixture was stirred at -78 ⁰ C 0,0'oiunden. Then 1,33ml (1.22 g, 16,5mMol) of ethyl formate was added and the mixture over 1 hour at 23 ⁰ C., and then heat the reaction was stopped with 250 ml of 2N HCl. the aqueous phase is extracted with 3 x 50 ml Essigester and dried the combined organic phases over MgSO ₄ and evaporated The residue is purified by chromatography with 20% EtOAc-hexane as eluent to give 2.2 g (57%) of the title compound as a foam MS (Cl): m / e = 355 for (M + H) ⁺ ;

IR (KBr) V _ma »: 1660cm ^M ;

¹ H NMR (CDCl ₃ ) =: 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).

Anal. Calcd. for Ci ₉ H ₁₆ F ₂ N ₄ O:

C, 64.41; H, 4.56; N, 15.82

 Foui.d: C, 64.60; H, 4.70, N, 15.62.

Example 41

5,5-Bis (4-fluoro-3-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dienal To a mixture of 2.12 g (5, 98 mmol) 3,3-Bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yd-acrylaldehyde and 1.89 g (6.22 mmol) triphenylphosphoranylidene acetaldehyde are added under an argon Atmosphere 26 ml of dry benzene added.

The suspension is heated rapidly to the reflux temperature in an oil bath under argon. The solids dissolve very rapidly at the reflux temperature and the color turns dark brown. The reaction is carried out for a total of 60 minutes at the reflux temperature. The analytical TLC, eluted ten times with 20% by volume of ethyl acetate in hexane, shows: the desired product at Rf = 0.35. The crude reaction mixture is added to a short bed of silicic acid and eluted with 21-20% by volume of ethyl acetate in hexane to give 2.12 g (93.3%) of the title compound (homogeneous by TLC). MS (Cl):

m / e = 381 for (M + H) ⁺ ;

IR (KBrItL _x : 1679 (s), 1 606 (s), 1 591 (s), 1 500 (s), 1438 (m), 1 250 (s), 1 231 (s), 1138 (s), 1125 (s) cm ^-1 ;

¹ H NMR (CDCl ₃ ) δ: 9.53 (1H, d, J = 7.47Hz), 7.44 (1H, d, J = 16.0Hz), 7.15-7.09 (3H, m), 6.9-6.7 (3H, m), 5.80 (1H, dd, J = 15.6, 7.44Hz), 3.55 (3H, s) .2.33 (3H, d, J = 1.9Hz), 2.11 (3H, d, J = 1.8Hz);

¹³ C NMR (CDCl ₃ ) δ: 192.51, 162.4 (d, ¹ J ₀ -F = 260.7H ₁ ) ΐ62.οιο. ¹ Jc-F = 250Hz), 156.23,152.57,147.82,134.88,134.83,134.37,133.77 (d, ^J J ₀ -F = 6.04Hz), 133.19, (d, ³ J ₀ -F = 6.04Hz), 131.94 , 130.04 (d, ³ J ₀ -F = 8.31 Hz), 129.32 (d, ³ J _{c, F} = 8.31 Hz), 126.22,126.00,119.57, 115.66 (d, ² Jc-F =? "· -1Hz) , 115.59 (d, ² J _C - _F = 23.41 Hz) 33.64,14.59,14.36ppm;

Anal. Boron for C ₂ (H ₁₈ F ₂ N ₄ O:

C, 66.31; H, 4.77; N, 14.73

 Found C, 66.36; H, 4.71; N, 14.15.

Example 42

9,9-Bis (4-fluoro-3-methyl-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazul-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester Solution of 1.42 mL (11.1 mmol) of ethyl acetoacetate dianion in 15 mL dry tetrahydrofuran is prepared as described in Example 10 from 450 mg (11.3 mmol) NaH (60% in mineral oil) and 4.5 mL (11.1 mmol) 2, 5M BuLi generated in hexane at ⁰ ° C under argon. The orange solution of the dianion, after cooling to -78 ° C with a cannula in a cooled to -78 ° C solution of 5,5-bis (4-fluoro-3-methyl-phenyl) -4- (1-methyl -1 H -tetrazol-5-yl) penta-2,4-dienal 2.12g, 5, CmMoI) in 1EmI tetrahydrofuran. The reaction mixture is stirred for 15 minutes at -78 ⁰ C. The analytical TLC, once eluted with 50% by volume of ethyl acetate in hexane, shows a major product at Ri = 0.16. The reaction mixture is diluted with 20 ml of 1 η HCl and the organic residues are extracted with 2 χ 30 ml of ethyl acetate. The organic phases are combined, dried over MgSO ₄ and concentrated in vacuo to a light syrup. The crude product is chromatographed on a column of silica gel and extracted with 35% by volume of ethyl acetate to give 1.39 g (48.7%) of the title compound. MS (Cl):

IR (KBr) t? _max : 3219 (vs, br). 3000 (s), 1744 (s), 1719 (s), 1500 (s), 1325 (m), 1250 (s), 1 231 (s), 1119 (s), 1035 (s), 735 (s) cm "¹;

¹ H NMR (COCl ₃ ) δ: 7.1-7.013H, m), 6.8-6.6 (3H, m), 6.68 (1H, d, J = 15.63Hz), 5.30 (1H, dd, J = 5.76, 15.63Hz), 4.63 (1 H, br), 4.18 (2H, q, J = 6.96 Hz), 3:54 (3H, s), 3:44 (2H, s), 2.93 (1 H, br, D ₂ O exchangeable) 2.65-2.75 (2H, m), 2.29 (3H, d, J = 1.65Hz), 2.08 (3H, d, J = 1.41Hz), 1.27 (3H, t, J = 6.96Hz );

' ³ C NMR (CDCl ₃ ) 0: 166.66, 16.52 (d, ¹ J _C _ _F = 248.0 Hz), 161.13 (d, ¹ J ₀ -F = 250.66 Hz), 153.53, 148.08, 135.64.64, 125.26, 135.03, 133.44 (d, ³ J ₀ -F = 4.53Hz), 132.71 (d, ³ J ₀ - _F = 4.53Hz) 129.58 Id ₁ ³ J ₀ -F = 8.31 Hz), 128.73 (d, ³ J ₀ _ _F = 7.55HzI, 128.36,125.33,125.44,120.47 115.21 (d, ² J ₀ F = 21.90 Hz), 67.93,61.59,49.86,49.07,33.56,14.46 (d, ³ J ₀ - _F = 11:33 Hz)., 14:33 , 14.09 ppm;

Anal. Calcd. for C ₂₇ H ₂₈ F ₂ N ₄ O ₄ H ₂ O:

C, 61.36; H, 5.72; N, 10.60

 Found: C, 62.47; H, 5.59; N, 8.23.

Example 43

(±) -t ^% rythro-9,9-bis (4-fluoro-3-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6 Ethyl 8-dienoate The 9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo shown in Example 42 Nona-6,8-dienoic acid ethyl ester (1.39 g, 2.7 mmol) is dissolved at 0 ° C. (ice bath) under argon in 30 ml of tetrahydrofuran. To this yellow solution is added 3 ml (3.0 mmol) of a 1 M solution of triethylborane in tetrahydrofuran in a single portion. The solution is stirred for 1 hour at ⁰ ° C and then cooled in an acetone-dry ice bath to -78 ⁰ C. To this light yellow solution is added with stirring 0.12g (3.2mMoi) of dry NaBH ₄ and the reaction continued at ~ 78 ° C for one hour. The crude reaction mixture is diluted at -78 ⁰ C and 20 ml of 1 η HCI and the cold suspension was allowed to warm to room temperature. The organic residues are extracted with 2 × 30 ml of ethyl acetate and the organic phases combined, dried over MgSO ₄ and concentrated in vacuo to a thick syrup. The crude material is redissolved in 250 ml of methanol and the solution allowed to stand at room temperature for 16 hours. The analytical TLC of the methanolic solution (eluted twice with 50% by volume of ethyl acetate in hexane) shows the product at R = 0.10. The product is purified by silica gel column chromatography eluted with 20% by volume of ethyl acetate in hexane. The respective fractions are pooled to yield 0.95 g (68%) of the title compound

MS (CI): rr / e = 513 for (M + H) ⁺ ;

IR (KBr) V _max : 3438 (s), 3000 (s), 1735 (s), 1500 (s), 1441 (s), 1 250 (s), 1 230 (s), 1119 (s) cm "¹;

¹ H NMR (CDCl ₃ ) δ: 7.08-7.02 (3H, m), 6.77 (1H, t, J = 8.91 Hz), 6.69-6.63 (2H, m), 6.66 (1H, d, J = 15.7Hz), 5.31 (1H, dd, J = 6.12, 15.7Hz), 4.42 (1H, br) 4.22 (1H, br), 4.16 (2H, q, J = 7.2Hz), 3.80 (1H, br, D ₂ O-exchangeable), 3.72 (1 H, br, DjO-exchangeable), 3.56 (3H, s), 2.45 (2H, d, J = 6.12Hz), 2.28 (3H, d, J = 1.65Hz ), 2.08 (3H, d, J = 1 5Hz), 1.8-1.57 (2H, m), 1.26 (3H, t, J = 7.2Hz);

' ³ C NMR (CDCl ₃ ) δ: 172.47.161.1 (d, ¹ J ₀ -F = 248.4Hz), 153.66.147.5,137.66,137.31,135.78,133.36,132.68 (d, ³ J ₀ - _f = 6.04Hz ), 129.58 (d, ³ Jc-F = 8.31 Hz), 128.68 (d, ³ H ₀ -F = 8.31 Hz), 127.43,125.50,115.16 (d, ² J ₀ -F = 22.65 Hz), 71.98.68.40 , 60.88, 42.37, 41.45, 33.56, 14.53, 14.33, 14.15 ppm;

Anal. Calcd. for C ₂₇ H ₃₀ F ₂ N ₄ O ₄ :

C, 63.27; H, 5.00; N, 10:93

 Found: C, 62.80; H, 6.17; N, 10:34.

Example 44 Sodium (±) -erythro-9,9-bis- (4-fluoro-3-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6 , 8-dienoate

To a solution of 0.80 g (1.56 mmol) of (±) -erythro-9,9-bis (4-fluoro-3-methylphenyl) -3,5-dihydroxy-3- (1-methyl-1H tetrazole · 5-yl) nona-6,8-dienoic acid ethyl ester in 20 ml tetrahydrofuran at 0 ⁰ C under argon 1,56ml of a 1.0 η NaOH solution are added a single portion. The light yellow emulsion is stirred for two hours at ⁰ ° C (ice bath), with a bright

279

you form a solution of isichtigigo. The analytical TLC ₁ eluted with 20% by volume methanol in CHCl ₃ shows the product at Ri - 0.16. The H.I.sub.pt amount of the volatile organic solvents is evaporated in vacuo and the desired product is freeze dried under high vacuum to give 0.8 g (quantitative yield) of the title compound, which is likely to contain about 1 mole of water.

IR (KBr) IiL ₁ ,: 3425 (v. Br), 1575 (s), 1500 (s), 1438 (s), 1400 (s), 1225 (s), 1116 (s) cm ';

¹ H NMR (DMSOd ₈ ) δ: 7.26-7.19 (3H, m), 6.95 (1H, t, J = 8.91 Hz), 6.78-6.70 (2H, m), 6.49 (1H, d, J = 15.5 Hz), 5.13 (1H, dd, J = 5.43.15.5Hz), 4.15 (1H, br q, J = 6.03 Hz), 3.68 (3H, s), 3.67 (1H, br), 3.45 (2 H, ν br, D ₂ O exchangeable), 2.26 (3 H, br s), 2.05 (3H, br s), 2.06 (1H, br), 1 85 (1H, J = 8.37,14Hz) , 1.55-1.25 (2H, m);

' ³ C NMR (DMSOd ₆ ) δ: 175.09.159.03 (d,' J _C -f = 242.36Hz), 160.08 (d, 'J _C - _F = 242.36Hz), 151.84.144.17, 13.35.135 01 (i.e. , ³ Jc-F = 3.78Hz), 134.12 (d, ³ Jc-F = 3.02Hz), 131.83 (d, ³ J _C - _f = 4.53Hz), 130.83 (d, ³ J ₀ -F = 3.78Hz) , 128.34 (d, ³ J ₀ -F = 8.31 Hz), 127.11 (d, ³ J ₀ -F = fi.31 Hz), 123.84,123.52,123.30,123.10,112.87,120.49,113.9S (d, ² J _C - _F = 22.65Hz), 113.69 (d, ² J _C - _F = 23.41 Hz), 67.66, 65.12, 44.1:>, 43.24,33,18,14,0,14,15ppm;

Anal. Reference ₂₅ H ₂₅ F ₂ N ₄ O ₄ Na ₂ H ₂ O:

C, 55.35; H, 5.39; N, 10:33

 Found C, 55.01; H, 5.01; N, 9.82.

Example 45

3,3-bis- (4-fluoro-plienyl) -2- (1-ethyl-1H-tetrazol-5-yl) acrylic acid cthylesterund3,3-bis- (4-fluoro-phenvl) -2- (2- ethyl-2H-tetrazol-5-yOacrylsäureethylester

A. 3,3-Bis (4-fluoro-phenyl) -2- (2-ethyl-2H-tetrazol-5-yl) ethyl acrylate

To a solution of 10.0 g (0.028 mol) of 3,3-bis (4-fluoro-phenyl) -2- (1H-tetrazol-S-y-ethylacrylate (prepared in Example 2) in 75 ml of dimethylformamide is added 1.2 g After stirring for 0.5 hours, the sodium hydride has dissolved and 8.5 g (0.056 mol) of iodomethane are added. The solution is stirred at room temperature for 16 hours with Water is diluted to 400 ml and extracted with CH ₂ CS _2. The extracts are dried and concentrated in vacuo To remove the mineral oil, the residue is triturated with hexane Dissolving in CH ₂ Cl ₂ and adding dry silica gel, the residue on silica gel absorbed and then concentrated in vacuo to a dry powder. This material is placed on a silica gel column and eluted with 10VoI .-% Essigester in hexane to give 4.9g (45.5%) of the title compound, mp 113 to 114.5 ⁰ C, get warden.

IR (KBr) \ L _x : 1710 (s), 1 601 (s), 1 505 (s), 1160 (s), 596 (s), 550 (s) cm '¹;

¹ H NMR (CDCl ₃ ) δ: 7.31-7.28 (m, 2H), 7.11-6.85 (m, 6H), 4.56 (q, 2H), 4.10 (q, 2H), 1.51 (t, 3H), 1.02 ( t, 3H) ppm;

¹³ C NMR (CDCl ₃ ) δ: 167.03.165.62 (d), 165.28 (d), 162. ', 160.64 (d), 160.34 (d), 152.76, 136.86 (d), 136.00 (d), 131.92 (d), 131.75 (d), 131.10 (d), 130.92 (d), 115.53 (d), 115.35 (d), 115.13 (d), 114.96 (d), 61.41, 48.31, 14.51, 13.70ppm;

Anal. Calcd. for C ₂₀ Hi ₈ F ₂ N ₄ O ₂ :

C, 62.50; H, 4.73; N, 14.58

 Found: C, 62.28; H, 4.72; N, 14:51.

Ä. 3,3-Bis (4-fluoro-phenyl) -2- (1-ethyl-1H-tetrazol-5-yl) ethyl acrylate

The appropriate fractions from the continued elution of the silica gel column of Step A with 10% by volume of ethyl acetate in hexane are evaporated to yield 5.1 g (47.4%) of the title compound; F. 97-99 ° C.

IR (KBr) \ L,.: 1720 (s), 1605 (s), 1507 (s), 1160 (s), 845 (s), 540 (s) cm "¹;

¹ H-NMR (CDCI ₃₎ δ: 7.40-6.90 (m, 8H), 4.00 (q, 2H); 3.88 (q, 2H), 1.16 (t, 3H), 1.00 (t, 3H) ppm;

Anal. Calcd. TOrC ₂₀ H ₁₈ F ₂ N ₄ O ₂ :

C, 62.50; H, 4.73; N, 14.58

 Found: C.62.27; H.4.73; N, 14:51.

Example 46

3,3-bis- (4-fluoro-phenyl) -2- (1-ethyl-1H-tetrazol-5-yl) allyl alcohol

To a solution of 1.0 g (2.6 mmol) of 3,3-bis (4-fluoro-pher-1-yl) -2- (1-ethyl-1H-tetrazol-G-yl) acrylic acid ethyl ester in CH ₂ Cl ₂ at -78 C ^U rapidly 7,8ml (7,8mMol) of a 1.0M solution of diisobutylaluminum hydride in methylene chloride. After stirring for 45 minutes, the mixture is added to terminate the reaction with 1 η HCl solution. The organic phase is separated, dried with MgSO ₄ and concentrated in vacuo. The residual oil is triturated with hexane and yields 0.9 g (100%) of the title compound, mp 103-111 ⁰ C.

¹ H NMR (CDCl ₃ ) δ: 7.41-7.34 (m, 2H), 7.18-7.09 (m, 2H), 6.91-6.87 (m, 4H), 4.7 (s, 2H), 3.80 (q, 2H), 1.21 (t, 3H) ppm;

' ³ C NMR (CDCl ₃ ) δ: 166.04, 165.91 (d), 165.47 (d), 161. 08, 160.84, 156.12, 135.78 (d), 134.22 (d), 131.73 (d), 131.69 (d), 131.55 ( d), 131.51 (d), 116.01 (d), 115.94 (d), 115.57 (d), 115.50 (d), 61.91, 42.85, 14.13ppm;

Anal. CaCl3 / orC ₁₈ H ₁₆ F ₂ N ₄ O:

C, 63.16; H, 4.72; N, 16.37. Found: C, 62.99; H, 4.73; N, 16.40.

Example 47 3,3-bis- (4-fluoro-phenyl) -2- (2-ethyl-2H-tetra-ol-5-yl) -al-yl-alcohol The general procedure of Example 46 is repeated using 3.3 Bis (4-fluoro-phenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -acrylate by 1.0 g of 3,3-bis- (4-fluoro-phenyl) -2- ( 2-ethyl-2H-tetrazol-5-yl) acrylic acid ethyl ester to give 0.9 g of the title compound, mp 82-84 ⁰ C, are obtained

'HNMR (CDCl ₃ ) δ: 7.30-7.33 (m, 2H). 7.08-6.87 (m, 6H), 4.57 (d, 2H), 4.48 (d, 2H), 2.88 (t , 1H), ', .43 (t, 1H);

^'3 C NMR (CDCI ₃₎ δ: 165.04,164.82 (d), 164.67 (d), 160.12,159.78,147.08,137.56 (d), 136.45 id), 131.47 (d), 131.43 (d), 131.34 (d ), 131.25 (d), 115.53 (t), 115.13 (t), 114.72 (d), 62.89, 48.24, 14.40ppm;

Anal. Calcd. forC ₁₈ H ₁₆ F ₂ N ₄ O:

C, 63.16; H, 4.72; Ν, 16:37. Found: C, 63.22; H, 4.74; N, 16:41.

Example 48

3,3-B [s- (4-fluoro-phenyl) -2- (1-ethyl-1 H -tetrazycir-1-yl) -acrylaldehyde To a solution of 0.8 g (2.3 mmol) 3,3-bis ( 4-fluoro-phenyl) -2- (1-ethyl-1H-tetrazol-5-yl) allyl alcohol in methylene chloride, 0.9 g of pytidinium chlorochromate is added. The solution turns bright yellow and then darker, forming a dark, rubbery precipitate. After 16 hours of stirring at room temperature the mixture is placed directly on a silica gel column and eluted with methylene chloride, 0.65 g (83%) of the title compound, mp 144-145 ⁰ C, are obtained v / obei.

IR (KBr) 0 _max : 1680 (s), 1600 (s), 1515 (s), 1135 (s), 855 (s), 840 (s);

¹ H NMR (CDCl ₃ ) δ: 9.65 (1H, s), 7.36-7.20 (4H, m), 7.05-6.88 (4H, m), 4.01 (2H, q), 1.33 (3H, t);

' ³ C NMR (CDCl ₃ ) δ: 189.02.167.07 (d), 166.51 (d), 164.68, 162.04, 150.41, 133.65 (d), Ί33.49 (d), 132.34 (d), 132.18 (d), 124.11, 116.46 (d), 116.34 (d), 116.02 (d) .. 115.90 (d), 43.00, 14.34 ppm;

Anal. Calcd. for C ₁₈ Ht ₄ F ₂ N ₄ O:

C, 63.53; H, 4.15; N, 16.47. Found: C, 62.90, H, 4.13; N, 16:37.

Example 49 3,3-Bis- (4-fluoro-phenyl) -2- (2-ethyl-2H-tetrdzol-5-yl) -acrylaldehyde According to the procedure described in Example 48 in Example 48, 4.0 g (12, OmMoI) 3,3-Bis (4-fluoro-phenyl) -2- (2-ethyl-2H-tetrazol-5-yallyl alcohol reacted with 4.5 g of pyridinium chlorochromate to give 3.25 g (79.7%) of the title compound, m.p. 139 ⁰ C, to be obtained.

¹ H NMR (CDCl ₃ ) δ: 9.70 (1H, s), 739-7.32 (2H, m), 7.23-7.14 (2H, m), 7.04-6.86 (4H, m), 4.62 (2H, q) , 1.56 (3H>t);

¹³ C NMR (CDCl ₃ ) δ: 190.04166.71 (ο), 165.156 (d), 163.01, 161.68, 166.16 (d), 160 86 (d), 135.62 (d), 135.55 (d), 133.69 ( d), 133.53 (d), 132.37 (d), 137.19 (d), 127.74.116.06 (t), 115.59 (t), 115.17 (t), 48.45,14.59ppm;

Anal. CaICDJORC ₁₈ H ₁₄ F ₂ N ₄ O:

C, 63.53; H, 4.15; N, 16.47. Foond: C, Ö3.53, H, 4.11; N, 1674.

Example 50

5,5-Bis- (4-fluoro-phenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -penta-2,4-dienal A solution of 0.65 g (1.9 mmol) of 3,3-bis - (4-fluoro-pienyl) -2- (1-ethyl-1H-tetrazol-5-yD-acrylaldehyde and 0.64 g (2.1 mmol) of triphenylphosphoranylidene acetaldehyde in benzene is heated at reflux for 2 hours evaporated and the residue purified by silica gel Sä'ii ^ r.-riromatographie eluted with CH ₂ CI _2, to give 0.55 g (79.7%) of the title compound, mp 163-165 ⁰ C, are recovered.

¹ H NMR (CDCl ₃ ) δ: 9.54 (1H, d), 7.49 (1H, d), 7.42-6.96 (8H, m), 5.76 (1H, dd), 8.89 (2H, q), 1.27 (3H, t);

' ³ C NMR (CDCl ₃ ) δ: 192.41.166.21 (d), 165.77 (d), 161.18.160.71, 1555.04, 51.58, 1555.58, 150.10, 148.34, 147.27, 147.91, 138.90, 134.97, 134.53, 132.77, 132.60, 132.20,132.03,120.35,116.43,116.26,116.03,115.78,42.66,14.30ppm;

Anal. Calcd. for Cj ₀ Hi ₆ F ₂ N ₄ O:

C, 65.57; H, 4.41; N, 15.30. Found: C, 65.32; H, 4.77; N, 14.76.

Example 51

5, S-B! S- (4-fluoro-phenyl) -4- (2-ethyl-2H-tetrazol-5-yl) -penta-2,4-dienal

The procedure of Example 50 is repeated with 3.25 g (9.5 mmol) of 3,3-bis (4-fluoro-phenyl) -2- (2-ethyl-2M-tetrazol-5-yl) -acrylaldehyde and 3.05 g (m.p. 10, OmMoI) triphenylphosphoranylidene acetaldehyde to give 3.3 g (95%) of the title compound, mp 117-120 ° C.

¹ H NMR (CDCl ₃ ) δ: 9.54 (1H, d), 7.49 (1H, d), 7.34-7.11 (4H, m), 7.00-6.78 (4H, m), 5.94 (1H, dd) , 4.60 (2H, q), 1.52 (3H, t);

¹³ C NMR (C ¹ DCI ₃ ) δ: 193.23,165.83,165.08,162.91,160.83,160.10,154.47,151.28,149.46,140.21,132.89,132.72,132.13,132.00, 130.56,116.00,115.56,115.28,114.89,48.46 , 14.63 ppm;

Anal. CaICdJOrC ₂₀ H ₁₀ F ₂ N ₄ O:

C, 65.57; H, 4.41; N, 15.30

 Found: C, 65.36; H, 4.40; N. 15.64.

Example 52

Ethyl 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (ethyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoate. To a solution of 0.5 g (l , 4 mmol) 5,5-bis (4-fluoro-phenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -penta-2,4-dienal in tetrahydrofuran at -5O ⁰ C become 1.75 ml (1.4 mmol) of a freshly prepared 0.8 M solution of ethyl acetoacetate dianion (described in Example 10). The solution is stirred 30 minutes at -50 ° C and then heated in the next 30 minutes at -10 ⁰ C.

The reaction is stopped with 1 η HCl and the solution extracted with methylene chloride. The organic extracts are dried and concentrated in vacuo. The residue is purified by silica gel column chromatography (eluted with chloroform) to give 0.4 g of the title compound as an oil. Ms (Cl): m / e = 497 for (M + H) ⁺ ;

¹ H NMR (CDCl ₃ ) O: 7.29-7.11 (4H, m), 6.87-6.83 (4H, m), 6.72 (1H, d), 5.24 (1H, dd). 4.62 (1H, m), 4.16 (2H, q), 3.88 (2H, q), 3.44 (2H, s), 3.44 (2H, s), 3.30 (1H, d), 2.71 (2H, d), 1.25 (3H, t) ppm;

¹³ C NMR (CDCl ₃ ) δ: 166.69.165.31.164.92,160.32,159.95,152.64,146.82,136.7,135.98, 135.34,135.26,135.18,132.38,132.20, '31 .62,131.45,128,26,121.25,115.92,115.78, 115.48,115.34, 91.48, 67.75, 61.51, 49.87, 49.14, 42.55, 14.27, 14.09ppm.

Example 53

Ethyl 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (2-ethyl-2H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoate To a solution of 2 , 0g 5,5-bis- (4-fluoro-phenyl) -4- (2-ethyl-2H-tetrazol-5-yl) penta-2,4-dienal in 20 ml of tetrahydrofuran at -40 ⁰ C 6,9ml (5.5 mmol) of a freshly prepared 0.8M solution of acetylacetic acid-dianion (described in Example 10). The solution is stirred 30 minutes at ⁰ -4o C and then to - 10 ° C heated. After a total of 1 hour, the reaction is stopped with 1 η HCl. The mixture is extracted with chloroform, dried over MgSO ₄ and concentrated in vacuo. The residue is purified by silica gel column chromatography to yield 0.4 g of pure title compound. MS (El): m / e = 496 for M ⁺ ;

¹ H NMR (CDCl ₃ ) δ: 7.29-7.22 (2H, m), 7.13-7.04 (2H, m), 6.90-6.78 (4H, m), 6.71 (1H, d), 4.68-4.48 (3H, m ), 4.15 (2H, q), 3.45 (2H, s), 2.73 (3H, d with broad shoulder), 1.49 (3H, t) 1.27 (3H, t) ppm;

¹³ C NMR (CDCl ₃ ) O: 164.95,164.28,163.91,159.99,159.39,145.98,137.64,137.56,136.20,136.06,135.21,132.42,132.25,131.71, 131.53,128.90,116.54,115.10,114.93,114.48,91.31 , 68.11,61.44,49.93,49.36,48.28,14.62,14.10ppm;

In addition, 1.55 g of crude title compound are obtained, which are used without further purification.

Example 54

(±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-ethyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid ethyl ester Solution of 0.5 g (1, OmMoI) 9,9-bis- (4-fluorophenyl) -5-hydroxy-8- (1-ethyl-1H-tetrazol-5-yl) -3-oxona-6, 1.1 ml (1, ImMoI) of a 1.0M triethylborane solution in tetrahydrofuran are added at 0 ° C. to ethyl 8-dienoate in tetrahydrofuran. The solution is stirred for 2.5 hours and then cooled to -78 ° C. Then 0.08 g (2, OmMoI) of sodium borohydride and then 0.5 ml of methanol are added. After stirring for 2.5 hours at -78 ° ^C. , the mixture is diluted with an equal volume of hexane, the reaction is quenched with 1N HCl and then extracted several times with ethyl acetate. The organic extracts are dried over MgSO ₄ , concentrated in vacuo, dissolved in methanol and then stirred at room temperature for 16 hours. The solution is concentrated in vacuo and the product is purified by column gel column chromatography eluted with 2% methanol in chloroform to give 0.3 g of the title compound as an oil. MS (El): m / e = 498 for M ^;

¹ H NMR (CDCl ₃ ) δ: 7.27-7.13 (4H, m), 6.88-6.84 (4H, m), 6.71 (1H, d), 5.28 (1H, dd), 4.18 (1H, (m), 4.17 (3H, q over broad m) 3.88 (2H, q), 3.71 (2H,, dd), 2.45 (2H, d), 1.59 (3H, t), 1.28 (3H, t), ppm.

' ³ C' \ / 1R (CDCl ₃ ) δ: 172.37,165.26,164.87,160.31,159.90,146.38,137.77,135.89,135.82,135.28,132.29,132,17,131.61,131.43, 127.39,121 48,115.89,115.75,115.49, 115.30,71.80,60.86,42.48,42.25,41.47,14.26,14.18ppm.

Example 55

(I} erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-ethyl-2H-tetrazol-5-yl) nona-6,8-diensäureethylesterund (± ) -erythro-7,7-bis- (4-fluoro-phenyl) -3,5-dihydroxy-6- (2-othyl-2H-tetrazol-5-yl) hept-6-enoate

A. (±) -erytriro-3,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-ethyl-2H-t3-trazol-5-yl) nona-6,8-dienoic acid ethyl ester To a solution of 1.55 g (3, OmMoI) of crude 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (2-ethyl-2H-tetrazol-5-yl) -3-oxo -nona-6,8-dienoic acid ethyl ester (prepared in Example 53) in tetrahydrofuran at ⁰ ° C., 3.3 ml (3.3 mmol) of a 1M solution of

Triethylborane added in tetrahydrofuran. After stirring for 2.5 hours, the solution is cooled to -78 ° C and 0.25 g (6.3 mmol) of sodium borohydride and then 1.2 ml of methanol are added. After stirring for a further 2.5 hours, the reaction mixture is diluted with the same volume of hexane and the reaction is interrupted with 1 η HCl. The mixture was extracted wild with ethyl acetate and the combined organic phases dried with MgSO ₄ and concentrated in vacuo. The residue is dissolved in methanol and stirred at room temperature for 16 hours. The methanolic solution is concentrated in vacuo and the residue is purified by silica gel column chromatography eluaort with 1% CH ₃ OH in CHCl ₃ and evaporated in vacuo to give 0.65 g of the title compound as an oil. MS (El): m / o = 498 for M ⁺ ;

¹ H NMR (CDCl ₃ ) δ: 7.30-7.02 (4H, m), 6.80-6.72 (4H, m), 6.68 (1H, d), 5.45 (4H, dd), 4.52 (2H, q), 4.48 (1H, m), 4.15 (3K, q over m), 3.72CH, m), 2.45 (2H, dd), 1.67 (2H, m), 1.45 (3H, t), 1.25 (3H, t) ppm ;

' ³ C NMR (CDCl ₃ ! Δ: 164.92,164.29,164.11,163.99,159.98,159.34,145.65,141.24,137.69,134.64,136.83,136.29,136.21,132.39, 132.23,131.69,131.51,128.40,125.09,115.53, 115.10,114.93,114.51,72.17, 68.09,60.78,48.26,42.50,41.66,14.68,14.19ppm.

B. (±) -erythro-7,7-3ls (4-Huor-phenyl) -3,5-dihydroxy-6- {2-ethyl-2H-tetrazol-5-yl) -hept-6-enoic Acid Ethyl Ester The appropriate fractions from the elution of the silica gel column of Step A are combined and evaporated, yielding 0.2 g of the title compound; 124-128 ° C. MS (EI) m / e = 473 for M ⁺ ;

Ή NMR (CDCl ₃ ) δ: 7.32-6.78 (8H, m) 4.93 (1H, m), 4.55 (2H, q), 4.17 (3H, q over m), 3.88 (1H, d), 3.64 ( 1 H, d), 2.45 (2H, dd), 1.83 (2H, m), 1.46 (3H, t), 1.27 (3H, tppm;

¹³ C NMR (CDCl ₃ ) δ: 117.18.164.94.164.44.163.16.160.01,159.51, 146.58,137.11,137.05,135.92,135.86,131.31,131.15,130.98, 127.98,115.73,115.31,115.01,114.58, 71.44, 68.56 , 67.86, 65.28, 60.72, 48.33, 42.44, 41.74, 41.44, 41.36, 14.53, M.21 ppm;

Anal. Calcd. for C ₂₄ H ₂₆ F ₂ N ₄ O ₄ 0.5 H ₂ O:

C, 59.87; H, 5.66; N, 11.64

 Found: C, 59.62; H, 5.62; N, 11.21.

Example 56 Sodium (±) arythro-9,9-bis (4-fluoro-phenyl) -3,5-tiihydroxy-8- (1-ethyl-1H-tetrazol-5-yl) nona 6,8-dienoate

A reading of 1.0 g (2, OmMoI) 9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-ethyl-1H-tetrazol-5-yl) nona-6, 8-dienoic acid ethyl ester and 2 ml (2, OmMoI) 1 η sodium hydroxide in 25 ml of ethanol is stirred for 45 minutes. Concentrate the reaction mixture in vacuo and dissolve the residue in water. The aqueous solution is freeze-dried in vacuo to yield the title compound, which is likely to contain 1 mole of water; F. 193 to 203 ^° C. MS (FAB): m / e = 493 for (M + H) ⁺ ;

IR (KBr) V _n ,,,,: 3200 (v.br), 1650 (br), 1 600 (s), 1 5 ^, 0 (s), 1 510 (s), 1410 (br), 1 230 (s), 850cm- ';

¹ HNMR (CDCl ₃ δ: 7.37-7.29 (4H, m), 7.05-6.88.4 H, m) 6.50 (1H, d), 5.08 (1H, dd), 4.12 (1H, m), 4.04 (2H , q), 3.62 (1K, m), 3.35 (2H), 2.03-1.78 (2H, m), 1.46-1.23 (2H, m), 1.18 (3Ί, t) ppm;

Anal. Calcd. for C ₂₄ H ₂₃ F ₂ N ₄ O ₁ Na H ₂ O:

C, 56.48; H, 4.94; N, 10.98

 Found: C, 56.28; H, 4.96; N, 10.56.

Example b7

Sodium (+) - erythro-9,9-bis- (4-fli: or-phenyl) -3,5-dihydroxy-8- (2-ethyl-2H-tetrazol-5-yl) nona-6,8- dienoate A solution of 0.65 g (1.3 mmol) of (±) erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (2-ethyl-2H-tetrazole-5 yl) nona-6,8-dienoic acid ethyl ester and 1.3 ml (1.3 mmol) of 1N sodium hydroxide solution in 25 ml of ethanol are stirred for 1 hour. Concentrate the reaction mixture in vacuo and dissolve the residue in water. The aqueous solution is freeze-dried in vacuo to yield the title compound; F. 170-190 ⁰ C. MS (FAB): m / e = 493 for (M + H) ⁺ ;

IR (KBr) t? _max : 3200 (v.br), 1 650 (br), 1 60s (s), 1 580 (s), 1 512 (s), 1410 (br), 1 230 (s), 850 (s) cm "¹;

¹ HNMR (DMSO-d ₆ ) δ: 7.34-6.79 (8K, m ;, 6.50 (1H, m), 3.63 (1H, m), 3.35 (1H, br.m), 2.03-1.78 (2H, m ), 1.46-1.21 (2H, m), 1.34 (3H, t) ppm.

Anal. Calcd. for C ₂₄ H ₂₃ F ₂ N ₄ O ₄ Na 1.3 H ₂ O:

C, 55.88; H, 5.00; N, 10.86

 Found: C, 55.41; H, 4.67; η, 10.54.

Example 58

A solution of 0.2 g (0.45 mmol) of (±) -erythro-7,7-bis (4-fluoro-phenyl) -3,5-dihydroxy-6 (2-ethyl-2H-tetrazol-5-y !) hept-6-enoic acid ethyl ester (prepared in Example 55, Step B) and 0.45 ml (0.45 mmol) of 1N sodium hydroxide solution in 10 ml of ethanol are stirred for 1 hour. Concentrate the reaction mixture in vacuo and dissolve the residue in methanol. The aqueous solution is freeze-dried in vacuo to yield the title compound.

¹ H NMR (CDCl ₃ ) δ: 7.3-6.7 (8H, m), 5.7 (2H, br. M), 2.7 (2H, m), 1.9 (2H, m), 1.2 (3H, t) ppm;

¹³ C NMR _(CDCl3) O: 179.64,164.S4,164.26,163.27,163.59,159.71,1G9.35,145.67,137 52,137.46,136.06,135.98,131.34,131.20, 129.12.115.65,115.22,114.86,114.44,70.30,58.26 , 48.18,18.41,14.48ppm;

Ana !. Calcd for C ₂₂ H ₂₁ F ₂ N ₄ O ₄ Na 2H ₂ O:

C, 52.59; H, 5.02; N, 11.16

 Found: C, 52.81; H, 5.32; N, 9.64.

Example 59!, I-Bis - ^ -dimethyl-phenyU ^ -n-methyl-IH-tetreiol-S-yU-ethanol

A solution of 8.9 g (91, OmMoI) of 1,5-dimethyl-tetrazole in 100 ml of dry Te'rahydrofuran is added at -60 ° C with 48 ml (91, OmMoI) of a 1.89 M solution of butyllithium. After stirring for 20 minutes, 18 g (76 mmol) of 2,2 ', 4,4' * T6tramethylbenzophenone (prepared by the method described in J. Amer. Chem. Soc. 81, 485 I3 [1959]) in 50 ml of tetrahydrofuran are added and the solution The reaction is quenched with 1 N HCl and the solution extracted with chloroform, the combined organic extracts are dried over MgSO ₄ and evaporated to give 22 g of the title compound. 177 ⁰ C

IR (KBr) ^ L _x : 3390 (br), 1620 (s), 1460 (s), 1200 is), 820 (s) cm ^-1 ;

Ή 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, 135, 79, 133, 24, 126, 26, 125, 92, 77, 47, 35, 43, 32, 99, 21, 28, 20.76 ppm;

Anal. CaICdTOrC ₂₀ H ₂₄ N ₄ O:

C, 71.41; H, 7.20; N, 16.67

 Found: C, 70.82; H, 7.26; N, 16.45.

Example 60

1,1-bis (1-methyl-1H-Tetra2: ol-5-yl) (2,4-dimethyl-phenyl) -2- -ethene

A mixture of 1,1-bis- (2,4-dimethyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -ethanol (1.8 g, 5.4 mmol) and 100 mg of potassium bisulfate is placed in a to 190 ⁰ C preheated oil bath. After 15 minutes, the melt is cooled, and the residue methylene chloride zug ', sets. The undissolved constituents are separated and the solution is evaporated. The residue is recrystallized from diisopropyl ether to yield 1.2 g of the title compound; 143 to 143.5 F. ⁰ C.

IR (KBr) V _n ,,,: 2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 740 (s) cm "';

¹ H NMF. (CDCI 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 CNMR (CDCl ₃ ) O: 154.18.152.21,138.54,138.38,138.06,135.67,135.40,135.18,131.78,131.72,129.90,129.66,126.77,126.55, 111.99,33.65,21.02,20.69,19.95 ppm;

Anal. CaICdJOrC ₂₀ H ₂₂ N ₄ :

C, 75.45; H, 6.97; N, 17.60

 Found: C, 75.04; H, 7.03; N, 17.63.

Example 61 S ^ Up ^^ - dimethyl-phenyD ^ d-methyl-IH-tetrazol-S-y D-acrylaldehyde

A solution of 1.0 g (3.1 mmol) of 1,1-bis (2,3-dimethylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene in 10 ml of dry tetrahydrofuran is added 1.64 ml (3.1 mmol) of a 1.89 M solution of butyllithium at -78 ° C added. After stirring for 30 minutes with cooling, 0.3 g (4.0 mmol) of ethyl formate are added and the mixture is stirred with cooling for 2 hours. The reaction is stopped with 1 η HCl and the solution extracted with chloroform. The combined organic phases are dried over MgSO ₄ and evaporated. The residue is purified by column chromatography on silica gel eluted with 10% by volume of ethyl acetate in hexane to yield 0.9 g of product as an oil. Trituration of the oil with diisopropyl ether provides the title compound as a solid; F. 117-12O ⁰ C. MS (CI): m / e = 347 for (M + H) ^f ;

'HNMR (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;

' ³ CNMR (CDCl ₃ ) O: 189.49.168.80, 151.05, 140.87, 140.26, 137.06, 1335, 86, 134, 87, 133, 163, 1222, 125, 164, 129, 60, 126, 62, 125, 28, 14, 17, 21, 21, 21, 20, 20, 20, 20, 07 ppm;

Anal. Calcd. for C ₂ ) H ₂₂ N ₄ O:

C, 72.81; H, 6.41; N, 16.18; Found: C, 72.99; H, 6.43; N, 16.09.

Example 62

5.5 Bis- (2,4-dimethyl-phenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -penta-2,4-dienal A solution of 4.5 g (13, OmMoI) 3,3 Bis- (2,4-dimethyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde and 4.1 g (13, OmMoI) triphenylphosphorporidene-acetaldehyde in benzene are refluxed for 6 hours. The reaction mixture is evaporated in vacuo and the residue is purified by column chromatography on silica gel eluted with 10% by volume of ethyl acetate in hexane to give 5.9 g of the title compound as an oil.

MS (Cl): m / e = 373 for (M + H) ⁺ ;

IR! KBr) i7 _mex : 1742 (s), 1 680.1650, 1450 (s), 1130 (s), 830 (s), 810 (s) cm ^-1 ;

¹ H NMR (CDCl ₃ ) 0: 9.42 (1H, d), 7.3 (1H, d), 7.14-6.85 (6H, m), 5.80 (1H, dd), 3.52 (3H, s) , 2.35 (3H, s), 2.20 (6H, s), 1.85 (3H, s) ppm;

' ³ CNMR (CDCl ₃ ) O: 192.53,158.44,152,18,150.60,148.18,139.4E, 139.25,136,14,135.98, 135.18, 134.63,131.78,131.70,131.28, 130.10,126.45,126.25,121.26,33.61, 20.90, 20.71,20.18, 20.11 ppm;

Anal: Calcd. for C ₂₃ H ₂₄ N ₄ O:

C, 74.17; H, 6.50; N, 15.05

 Found: C, 72.82; H, 6.85; N, 13:33.

Example 63

The general procedure of Example 42 is repeated using the 5,5-bis (4-fluoro-3-methyl-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -penta-2,4 dienai by 5.9 g (16, OmMoI) of 5,5-bis (2,4-dimethyl-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -penta-2,4-dienal and the resulting crude material is purified by silica gel column chromatography eluted with 1% by volume of methanol in methylene chloride to give 4 g of the title compound.

¹ H NMR (CDCl ₃ ) δ: 7.10-6.95 (3H, m), 6.83-6.75 (3H, m), 6.50 (1H, d), 5.30 (1H, dd), 4.60 (1H, m) , 4.14 (2H, q), 3.60 (3H, s), 3.43 (2H, s), 3.0 (1H, bs), 2.70 (2H, d), 2.35 (3H, s), 2.20 (3H, s) , 1.90 (3H, s), 1.28 (3H, t) ppm;

¹³ C NMR (CDCl ₃ ) δ: 202.15.166.59, 153.39, 149.71, 138.17, 136.15, 135, 98, 135, 81, 135, 32, 134, 96, 131, 63, 131, 42, 130, 34, 130, 124, 128, 22, 126, 36, 126, 21, 122, 07, 91, 61, 34, 49, 79. 49.24,33.76,21.06,20.89,20.49,20.28,14.02ppm;

Anal. CaICdJOrC ₂₉ H ₃₄ N ₄ O ₄ :

C, 69.31; H, 6.82; N, 11.15

 Found: C, 68.29; H, 6.91; N, 10.88.

Example 64 Ethyl (±) -erythro-9,9-bis (2,4-dimethylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-ynomono-6,8-dienoate The general procedure of Example 43 is repeated using the 9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3 4-oxo-nona-C, 8-dienoic acid (8, OmMoI) 9,9-bis (2,4-dimethyl-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazole-5 -yl) nona-6,8-dienoic acid ethyl ester and the resulting crude material is purified by silica gel column chromatography eluting with 1% by volume of methanol in methylene chloride to give the title compound (2.5 g): MS (Cl): m / e = 505 for (M + H) ⁺ ;

¹ H NMR (CDCl ₃ ) δ: 7.10-6.90 (3H, m), 6.85-6.68 (3H, m), 6.43 (1H, d), 5.30 (1H, dd), 4.40 (1H, m) , 3.35 (1H, s), 3.78 (1H, s), 3.58 (3H, s), 2.47 (2H, d), 2.30 (3H, s), 2.15 (6H , s), 1.88 (3H, s), 1.60 (2H, m), 1.25 (3H, t) ppm;

¹³ C NMR (CDCl ₃ ) δ: 172.23,153.67,149.39,149.31,138.18,136.87,136.14,135.95,135.52,131.75,131.54,130.17,127.62,126.47, 126.32,122.37,72.05, 68.26,60.76,42.48, 41.70 , 33.86, 21.18, 21.00, 20.64, 20.40,14.21 ppm;

Anal. CaICd ^ OrC ₂₉ H ₃₆ N ₄ O ₄ :

C, 69.03 H, 7.20; N, 11.11

Found: C, 68.1 "*, H, 7.25, N, 10.84.

Example 65

Sodium (±) -erythro-9,9-bis (2,4-dimethyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,3-dienoate Solution of 2.5 g (4.95 mmol) of (±) -erythro-9,8-bis (2,4-dimethylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole) 4.95 ml (4.95 mmol) of 1.0N sodium hydroxide solution are added to 5-yl-nona-6,8-dienoic acid halide in ethanol After stirring for 1.5 hours, no analytical grade TLC eluted with 25% by volume of ethyl acetate in hexane The solution is concentrated in vacuo and the desired product is freeze dried under high vacuum to give the title compound as a beige powder MS (FAB): m / e = 498 for M ⁺ ;

IR (KBrIiL _x : 3300 (v.br), 1620 (shoulder), 1580 (br), 1450, 1410, 705 (s) cm '¹;

¹ HNMR (D ₂ O) O: 6.93-6.41 (6H, m), 6.31 (1H, d), 5.21 (1H, dd), 4.23-4.17 (1H, m), 3.93 (1H, m ), 3.6C (3H, s), 3.59 (2H, q), 2.31-2.10 (2H, m), 2.01 (3H, s), 1.73 (3H, s), 1.67 (3H, s) 1.65-1.48 ( 1.5H, m), 1.12 (= 2H, t) ppm;

Anal. Calcd.forC ₂₇ H ₃₁ N ₄ O ₄ Na 0.7 moles EtOH:

C, 64.27; H, 6.69; N, 10.56 Found: C, 64.48; H, 6.84; N, 10.56.

Example 66

Ethyl 3,3-bis (4-fluoro-phenyl) -2- [1- (2-methoxy-ethoxymethyl) -1H-tetrazol-5-yl] -acrylate and3,3-bis (4-fluoro-phenyl) - 2- [2- (2-rnethoxyethoxymethyl) -2H-tetrazol-5-yl) acrylate

0.67 g of sodium hydride (60% in mineral oil, 14.OmMoI) are added to a solution of 5.0 g (14, OmMoI) 3,3-bis (4-fluoro-phenyl) -2- (1H-tetrazole-5 -yl) ethyl acrylate (shown in Example 2) in 50 ml of dimethylformamide and the mixture is stirred until a clear solution is formed. Then 3.5 g (28, OmMoI) of 2-methoxy-ethoxymethyl chloride are added and the mixture is stirred for 64 hours. The mixture is diluted with 200 ml of water and extracted with methylene chloride. The organic extracts

The mixture is dried over MgSO ₄ and the solution is concentrated in vacuo to give 6 g of the title compound as an oil in the approximate ratio of 1: 1, as indicated by ¹ H-NMR. MS (CI): m / e = 445 for (M -i H) ⁺ ;

¹ H NMR (CuCl ₃ ) δ: 7.29-6.84 (8H, πι), 5.04 (2H, s), 5.43 (2H, s), 4.06 (2H, m), 3.53-3.40 (4H, m), 3.37 ( 3H, s), 0.99 (3H, m) ppm;

' ³ CNMR (CDCl ₃ ) 0: 166.23.165.90.165.78.165.5S, 165.12,163.15,162.34,160.93,160.77,160.62,160.20,157.36,153.61,152 20, 136.66,136.61,135.94,135.88,134.53,134.45 , 132.20,132.03,131.88,13173,131.1 ¹ J, 131.03,130.87,120.04,115.85,115.66. 70.95,69.53,69.09,67.73,66.73,61.70,61.38,58.89, 36,35,31.30,27.80,26.76,17.65,13.60 ,1; .52 ppm;

Boispiel67

3,3-bis- (4-fluoro-phenyl) -2- [1- (2-ir> ethoxyethoxymethyl) -1H-tetrazol-5-yl] allylalkoliolund3,3-bis- (4-fluoro-phenvi) -2 - [2-i2-methyoxyethoxymethyl) -2H-tetrazol-5-yl] allyl alcohol

A solution of 65 ml (65, OmMoI) of a 1M solution of diisobutylaluminum hydride in methylene chloride is added to a solution of 6.0 g (13, OmMoI) 3,3-bis- (4-fluoro-phenyl) -2- [1- (2-methoxyethoxymethyl) -1-H-tetrazol-5-yl-ethyl acrylate and 3,3-bis (4-fluoro-phenyl) -2-i2- (2-niethoxy-ethoxymethyl) -2H-tetrazole-5- yl) -acrylsäureethylester in 50ml Methylenchloriri at -78 ° C was added. After 3 hours stirring at -78 ⁰ C the reaction mixture is hydrolyzed by adding 1 Überschüssigor η HCI. The aqueous layer is separated and extracted with methylene chloride. Dio combined organic extracts are dried and concentrated in vacuo to yield 5.2 g of the title compound as an oil in the ratio of about 1: 1, as indicated by ¹ H-NMR. MS (El): m / e = 402 for M ⁺ ;

Anal. CaICdJOrC ₂₀ H ₂₀ F ₂ N ₄ O ₃ :

C, 59.70; H, 5.02; N, 13.93

 bound: C, 59.89; H, 5.0S; N, 13.99.

Example 68

a, 3-bis- (4-fluoro-phenyl) -2- [1- (2-methoxy-ethoxymathyl) -1H-tetrazol-5-yl] arylaldehydur d3,3-bis! (af | fluoro-phenyl) -2- [2- (2-methoxy-ethoxymeiir »yl) -2H-tetrazol-5-yl] acrylaldehyde

To a solution of 5.2 g (13, OmMoI) of 3,3-bis (4-fluoro-phenyl) -2- [1- (2-methoxy-ethoxy-ethyl) -1-H-tetrazol-5-yt ] Al! ylcohol and 3,3-bis- (4-fluoro-phenyl) -2-i2- (2-methoxyethoxymethyl) -2H-tetra-ol-5-yl! allyl ¹ OhOI (prepared in Beispiol 67) in methylene chloride, 6.6 g of pyridinium chlorochromate are added. After stirring at room temperature for 18 hours, the reaction mixture darkens to give a gummy precipitate. The \, eaktionsgemisch is decanted and the methylene chloride -. 'Dissolution is concentrated in a vacuum. The residue is purified by silica gel column chromatography eluted with methylene chloride to give 3 g of the title compounds in the ratio of about 1: 1, which is detected by ¹ H-NMR. MS (El): m / e = 400 for M ⁺ ;

¹ H NMR (CDCl ₃ ) δ: 9.73 (1H, s), 9.60 (1H, s), 7.44-6.91 (9H, m), 5.92 (2H, s) 5.b / (2H, s), 3.68- 3.38 (7H, m) ppm;

¹³ CNMR (CDCI ₃ ) 0: 189.62.188.78.166.87,166.57,166.34,165.68,165.60,163.17,161.85,161.65,161.55,161.29,160.66,151.11, 134.39,134.33,133.43,133.55,133.37,133.08,132.42, 132.25,132.06,129.3 ', 129.19,128.96,127.22,123.65,116.12,115.S4, 115.69,115.50,115.26,11 E.07,80.92,77.01,70.87, 59.40,69.26,68.83, 62.03, 58.78, 50.23 , 46.41 ppm;

Anal. CaICdJOrC ₂₀ H ₁₈ F ₂ N ₄ O ₃ :

C, 60.00; H, 4.54; N, 13.99

 Found: C, 58.11, H, 4.65; N, 13.19.

Example 69

3,3-bis- (4-fluoro-phenyl) -2-t2- (2-methoxy-ethoxymethyl) -2H-tetrazol-5-yl] acrylaldehyfJund5,5Bis- (4-fluoro-phenyl) -4- [1 -l2-methoxyethoxymeflyl) -1H-tetrazol-5-yl] penta-2,4-dional

A.3,3-Bis- (4-fluoro-phenyl) -2- [2- (2-methoxyethoxymethyl) -2H-tetrazol-5-yl] -acrylaldehyde A solution of 3.5 g (8.75 mmol) of 3,3- Bis- (4-fluoro-phenyl) -2- [1- (2-methoxy-ethoxymethyl) -1H-tetrazol-5-yl] -acrylaldehyde and 3,3-bis (4 _: fluoro-phenyl) -2- [2- (2-methoxy-ethoxymethyl-2H-tetrazol-5-yl] -acrylaldehyde and 1,33g (4,4 mmol) of triphenylphosphoranylideneacetaldehyde in 50 ml of benzene are refluxed for 6 hours The reaction mixture is concentrated in vacuo and the residue is purified by column chromatography on silica gel, eluted with 15% by volume of ethyl acetate in hexane, concentration of the appropriate fractions leads to an aqueous separation and isolation of the unreacted title compound: MS (Cl): m / e = 401 for (M + H) ⁺ ;

¹ H NMR (CDCl ₃ ) δ: 9.70 (1H, s), 7.40-6.80 (9H, m), 5.85 (2H, s), 3.60-3.40 (4H, m), 3.35 (3H, s) ppm;

¹³ C NMR (CDCl ₃ ) O: 189.66.166.66.165.76.163.2 '. Λ Gi./ ?, 103.21,161.72,1S1.64,160.75,149.10,135.46,135.38,133.61,133.44, 133.27,133.16,132.79,132.64,132.31,132.14,131.94,131.8b. 127.32,116.01.115.91,115.56,115.14,80.99,70.91,69,46, 58.89ppm;

Continued elution of the silica gel column from step A above provides the desired product. The appropriate fractions are pooled and vacuumed. Initial evaporation and yield 1.1 g of the title compound. Mo (CI): m / e = 427 for (M + H) ^f ;

¹ H NMR (CDCl ₃ ) δ: 9.60 (1H, d), 7.45 (1H, d), 7.38-6.80 (8H, m), 5.70 (.1H, dd), 5.30 (2H, s), 3.68-3.40 (4H, m) 3.30 (3H, s) ppm;

' ³ C NMR (CDCl ₃ ) δ: 192.42,166.17,165.72,161.16,160.70,16 * 23,162.49,147.96,135 04,134.96,134.55,134.48,132.90,132.73, 132.21,132.04,131.85,119.94,116.31,116.08,115.87 , 115.64.76.67.71.01.69 53.58.96PPm.

Example 70

A solution of 1.4 g (3.5 mmol) 3,3-bis (4-fluorophenyl) -2-12- (2-methoxy-ethoxymethyl) -2H-tetrazol-5-yl] -acrylaldehyde (isolated in Example 69, step A) and 1.3 g (4.3 mmol) Triphenylphosphoranyiidenacetaldehyd in 25ml benzene is refluxed for 12 hours. Evaporate the reaction mixture in vacuo and purify the residue by column chromatography on silica gel eluted with 20% by volume of ethyl acetate in hexane to give 0.9 g of the title compound as an oil: MS (Cl) m / e = 427 for (M τ H) \

Ή NMR (CDCl ₃ ) δ: 9.5? (1H, d), 7.48 (1H, d), 7.32-7.10 (4H, m), 6.92-6.75 (4H, m), 5.85 (3H, s over dd), 3 6-3.5 (4H, m ), 3.35 (3H, 2) ppm;

' ³ C NMR (CDCl ₃ ) δ: 193.07.165.85.165.04, 1β3.50,160.85,160.07,154.72,14-1.12,136.61,136.59,135.29,135.24,133.64,133.47, 13 ".C4,132.6 ?, 132.35, 132.13,131.96,131.91,123.79,115.99,115.55,115.35,114.93,81.12,70.96, 69.55, 58.98ppm.

Example 71 9,9-bis (4-fluoro-phenyl) -S-hydroxy-3- [1- (2-methoxy-ethoxy-methyl) -1H-tetrazol-5-yl] -3-oxo-nona-6, 3-diencureethyl ester 2.6mi of a freshly prepared 1 fvi solution of ethyl acetoacetate dianion, prepared as in Example 10, are added to a solution of 1.1 g (2.6 mmol) of 5,5-bis- (4-fluoro-phenyl) Add 4- [1- (2-methoxy-ethoxymethyl) -1H-tetrazol-5-yl] -penta-2,4-dienal in 15 mL of tetrahydrofuran at -40 ° C. After stirring for 2 hours, the analytical TLC, eluted with 25% by volume of ethyl acetate in Hoxan, shows only the starting alkdehyde. Therefore, add 1.2 ml of additional dianion solution. The reaction mixture is warmed to 0 ° C and the reaction is interrupted with 1 η HCl. The mixture is extracted with methylene chloride, dried over MgSO ₄ and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluted with 1% by volume of methanol in methylene chloride to give 0.9 g of the title precursor as an oil. MS (CI): m / e = 557 for (M + H) *;

Ή NMR (CDCl ₃ ) δ: 7.5-6.6 (9H, m), 5.43 (2H, s), 5.00 (1H, dd !, 4.6 {IH, m), 3.7- 3.4 (6H, s over m), 3.30 (3H, s), 2.72 (2H, d), 1.25 (3H, t) ppm.

Example 72

d, α-ei <- {4-fluoro-phenyl) -5-hydroxy-8- [2- (2-methoxyethoxymethyl) -2H-tetrazol-5-yr3-oxo-nona-6,8- dienoic acid ethyl ester /, ImI of a freshly prepared 1M solution of ethyl acetoacetate dianion (prepared as in Example 10) is added to a solution of 0.9 g (2, OmMoI) 5,5-bis- (4-fluoro-phenyl) -4- [2- (2-methoxy-ethoxymethyl) -2H-tetrazcl-5-yl | pentg-2,4-dienal was added in 15 ml tetrahydrofuran at -50 ⁰ C. After stirring for a further 1 ml dianion solution is added and the mixture was further stirred Thus min. The reaction is stopped with 1 η HCl and the reaction mixture extracted with methylene chloride. The organic extracts are dried over MgSO ₄ , and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluted with 1% by volume of methanol in methylene chloride to yield 0.55 g of the title precursor. MS (Cl): m / e = 557 for (M + H) *;

Ή NMR (CDCl ₃ ) δ: 7.30-7.05 (4H, m), 6.90-6.70 (5H, m), 5.85 (2H, s), 5.35 (1H, dd), 4.70-4.53 (1H, m), 4.17 (2H, q), 3.48 (4H, m), 3.38 (3H, s), 2.72 (2H, d), 1.26 (3H, t) ppm;

¹³ CNMR (CDCl ₃ ) O: 202.03.190.30,166.60,164.88,164.36,164.15,159.92,146.22,137.49,137.41,135.13,132.29,132.13,131.63, 131.47,131.18,131.05,131.02,130.9Ξ, 1? 8 C7.124.46,115.45,115.03,114.92,114.51,91.16,80.80,70.84,69.28,67.96,61.37,58.90, 49.82,49.18,14.01 ppm.

Example 73

(±) 9-hydroxy-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- [1- (2-methoxyethoxymethyl-H-tetrazol-5-yl] nona-6,8- diensäureethyle3ter

To a solution of 0.9 g (1.6 mmol) of 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- [1- (2-methoxy-ethoxy; "'methyl) -1H tetra-ol-5-yl] -3-oxonona-6,8-dienoic acid ethyl ester in 20 ml of tetrahydrofuran at -10 ° C, add 2.1 ml of a 1 M solution of triethylborane and stir the mixture for 45 minutes, whereby the initially yellow solution becomes colorless. the solution is cooled to -78 ⁰ C and 0.13 g (3.2 mmol) of sodium borohydride and 0.75 ml of methanol are added. After 2 h at -78 ° C the solution is diluted with 50 ml of hexane and hydrolyzed with 1 η HCI. the aqueous Phase is separated and extracted with ethyl acetate The combined organic solutions are dried over MgSO ₄ and concentrated in vacuo The residue is dissolved in 30 ml of methanol and the solution is stirred for 40 h The solution is concentrated in vacuo and the residue is eluted by column chromatography on silica gel with 1% by volume of methanol in methylene chloride to give 0.4 g of the title compound, MS (CI): m / e = 559f r (M + H) ^+;

¹ H NMR (CDCl ₃ ) δ: 7.4-6.8 (8H, m), 6.65 (1H, d), 5.40 (2H, s), 4.95 (1H, dd), 4.4-3.5 (8 H, mi, 3.30 (3H, s), 2.40 (2H, d), 1.80-1.35 (2H, m), 2.20 (3H, t) ppm.

Example 74

(±) -erythro-9 _> 9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- [2- (2-methoxyethoxymethyl) -2H-tetrazol-5-yl] nona-6 , 8-diensäureethyloster

To a solution of 0.9 g (1.6 mmol) of 9,9-bis-4-fluoro-phenyl) -5-hydroxy-8- [2- (2-methoxyethoxymethyl) -2H-tetrazol-5-yl] 2.1 ml (2.1 mmol) of a 1M solution of triethylborane are added at ⁰ ° C. to 3-oxonona-6,8-dienoic acid ethyl ester in 15 ml of tetrahydrofuran, and the solution is stirred for 1.5 hours, during which the yellow color disappears. The mixture is cooled to -75 ° C and 0.13 g (3.2 mmol) of sodium borohydride and 0.9 ml of methanol are added. After stirring for 2 h, the solution is diluted with F.Oml hexane and

hydrolyzed by adding ν Jn 1 η HCl. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic P.iases are dried over MgSO ₄ and concentrated in vacuo. The residue is dissolved in methanol and the solution is stirred for 16 h. The methanolic solution is concentrated in vacuo and the residue is purified by column chromatography on silica gel eluted with 1.5% methanol by volume in methylene chloride to give the title compound (0.6 g). MS (Cl): m / e = 559 for (M ·; · H) *;

¹ H NMR _(CDCl3) δ: 7:38 to 7:04 (4H, m) 6.92-6.65 (5H, m), 6.92 (2H, s), 5:40 (1 H, dd), 4.45 (1 H, m), 4.15 (3H, q over m), 3.43 (4H, s), 3.32 (3H, s), 2.45 (2H, d), 1.72-1.65 (2H, m), 1.25 (3H, t) ppm;

^U C NMR (CDCl ₃ ) δ: 172.45.165.05,164.69,164.32,160.12,159.40,146.06,137.75,137.70,136.96,136.13,132.44,132.28,131.82, 131.66,131.40,131.25,131.05,128.32,124.91,115.65 , 115.40,115.23,114.92,114.69,80.97,72.25,71.05,69.48,68.22,60.90,59.15, 42.53,41.06,14.27 ppm.

Example 75

Sodium (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- [1- (2-methoxy-ethoxymethyl) -1H-tetrazol-5-yl] nona -6,8-dienoate A solution 0.3 g (0.54 mmol) of (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8-1- (2-methoxyethoxymethyl ) .1H-Tetrazol-5-yl nona-6,8-d-ethylenic acid ethyl ester and 0.54 ml (0.54 mmol) of a 1N sodium hydroxide solution in 15 ml of ethanol are stirred for 3 hours. The solution is concentrated in vacuo and the desired product is freeze-dried in high vacuum, where at 250 mg of the title compound, which apparently contains 2 moles of water, are obtained; F. 110-135 ⁰ C. MS (FAB): m / e = 553 for (M + H) ^+;

¹ HNMR (D ₂ O) δ: 7.38-7.33 (2H, m), 7.22-7.18 (2H, t), 6.98-6.89 (4H, m), 6.67 (1H, d), 5.50 (2 H ₁ s), 5.23 (1H, dd), 4.27 (1H, m), 3.93 (1H, m), 3.61-3.46 (4H, m), 3.28 (3H, s), 2.30-2.28 (2H, m), 1.68-1.50 (2H, m) ppm;

' ³ C NMR (D ₂ O) δ: 181.37,165.49,165.02,162.75, Ϊ62.27,149.52,138.74,137.38, 136.57,133.84,133.75,132.97,132.88,129.29, 121.34,116.98,116.73,116.49,78.19,72.00 , 71.02,70.74,68.31, 59.58,46.05,44.Ί1 ppm;

Anal. Calcd. for C ₂₆ H ₂₇ F ₂ N ₄ O ₆ Na ₂ H ₂ O:

C, 53.06; H, 5.31; N, 9.53

Found: C. 53.36; H, 5.04; N, 9.02.

Example 76

Sodium (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- [2- (2-methoxy-ethoxymethyl) -2H-tetrazol-5-yl] nona -G, 8-dienoate A solution of 0.45 g (0.81 mmol) of (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8-2- (2-methoxy -ethoxymethyl) -2H-tetrazol-5-yl nona-6,8-dienoic acid ethyl ester and 0.81 ml (0.81 mmol) of a 1 η sodium hydroxide solution in 10 ml of ethanol is stirred for 30 min. The solution is concentrated in vacuo and the desired product is freeze dried under high vacuum to give 350 mg of the title compound as an orange-colored powder; F. 175-19O ⁰ C. MS (FAB): m / e = 551 for ( ¹ VI-H) ";

IR (KBr) VL ,: 3400 (v.br), 1603, 1585, 1515 (s), 1410 (br), 1230 842 (s) cm ';

¹ H NMR (D ₂ O) δ: 7.17-7.11 (2H, m), 7.02-6.97 (2H, t), 6.81-6.58 (5H, m), 5.86 (2H, s), 5.35 (1H, dd ), 4.26 (1H, m), 3.97-3.93 (1H, m), 3.41-3.24 (4H, m), 3.22, 3H, s), 2.33-2.21 (2H, m), 1.67-1.48 (2H , m) ppm.

Anal. Bsrechnetfür C ₂₆ H ₂₇ F ₂ N ₄ O ₆ Na 0.5H ₂ O:

C, 55.62, H, 5.03; N, 9:98; H ₂ 0,1.60

Found: C, 55.46; H, 5.03; N, 9.79; H ₂ 0,1.89.

Example 77

5,5-bis- (4-fluoro-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dienal)

To a mixture of 71.6 g (0.22 mol) of 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1 H -tetrazol-5-yl-acrylaldehyde and 66.8 g (0.22 mol) The reaction is refluxed for 2 h at reflux temperature The analytical TLC, five times eluisrt with 30 vol% ethyl acetate in hexane, shows only one major spot at Rf = 0.37 The crude product is diluted with the same volume of hexane, and the warm mixture is quickly filtered through an activated carbon bed The filtrate is allowed to stand at room temperature to yield 58.12 g (75.2%) of the desired product Secondary crystallization from the filtrate yields mainly triphenylphosphine oxide Concentration of the filtrate gives an additional amount of the desired product, a total of 71 g (91.8%) of the title compound The combined material is recrystallized from ethyl acetate / hexane rt, whereby the pure title compound is obtained; F. 164-165 ° C. An 'H NMR study of the uncrystallized material shows no detectable double homologated product.

Anal. Calculated for C ₁₉ H ₁₄ F ₂ N ₄ O:

C, 64.77; H, 4.01; N, 15.90

 Found: C, 65.20; H, 4.09; N, 16.03.

Example 78

3,3-Bis (4-fluoro-phenyl) -2- (1-methyl-1,2-H-tetrazole-5-y-D-aldehyde

A. 1,1-8is (4-fluoro-phenyl) -2- (1-methyl-1H-tetra-7-ol-5-yl) -ethanol

To a solution of 0.98 g (10, OmMoI) of 1,5-diinotriyl-tetrazole in 20 ml of tetrahydrofuran at -3O ⁰ C, 4.7 ml (10, OmMoI) of a 2.14M solution of c'ifyllithium are added. Mach 0.25 h stirring the solution at 5O ⁰ C-cooled, and 174g (8, OmMoI)

Added 4,4'-difluoro-benzophenone. After one hour of stirring at -5O ⁰ C and stirring for 1 hour at - 1O ⁰ C, the reaction with 1 η hydrochloric acid is interrupted. The mixture is extracted with methylene chloride, dried and evaporated in vacuo. The residue is purified by column chromatography on silica gel eluted with 40VoI .-% ethyl acetate in hexane to deliver 2.0 g dor title compound, mp 116-118 ⁰ C.

Anal. Calculated for C ₁₆ H ₁₄ F ₂ N ₄ O:

C, 60.76; H, 4. <T7; N, 17.72

 Found: U, 60.62; H, 4.52; N, 17.63.

1,1-8is (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene

A mixture of 4.2g (12.7 mmol) of 1,1-bis-4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -ethanol (prepared in Step A) and potassium hydrogensulfonate Heated to 115 ° C for 0.5 h. After cooling, the mixture is dissolved in chloroform and washed with water. The organic phase is dried and evaporated in vacuo. The residue is triturated with diethyl ether to give 3.9 g of the triethyl compound, F.169-171 ° C.

Anal. Calculated for Ci ₆ H ₁₂ F ₂ N ₄ :

C, 64.43; H, 4.06; N, 18.88

 Found: C, 63.93; H, 4.00; N, 19.25.

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

To a finely divided suspension of 1, 0g (3.3 mmol) of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (prepared in Step B) in 10ml of tetrahydrofuran at -8O ⁰ C 1,54ml (3.3 mmol) are a 2,14M solution of butyllithium was added to obtain a dark violet color occurs. After 40min stirring at -8O ⁰ C 0.32 g (4,3mMol) of ethyl formate are added and the mixture stirred for 2.5 h at -80 ° C. The mixture is hydrolyzed with 1N hydrochloric acid and extracted with methylene chloride. The extracts are dried over MgSO ₄ and evaporated in vacuo. The residue is triturated with diethyl ether and gives 0.77 g of a yellow solid, mp 128-131 ⁰ C. The solid is recrystallized from isopropyl acetate-hexane and provides 0.55 g of the title compound, mp 130-132 ° C.

Anal. Calculated for C ₁₇ H) ₂ F ₂ N ₄ O:

C, 62.58; H, 3.71; N. 17.18 "Found: C, 62.15, H, 3.82, N, 16.75

Example 79

5,5-bis- (4-fluoro-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dienal

A solution of 1.0 g (3.07 mmol) of 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde and 0.93 g (3, 07mMo!) Triphenylphosphoranylidenacetaldehyde in benzene is refluxed for 1 h. The benzene is evaporated in vacuo and the residue purified by column chromatography on silica gel eluted with 15Vol .-% Essigester in hexane, to give 0.7 g of the title compound, mp 156 to 157.5 ⁰ C, are obtained.

Anal. Calculated for C ₁₉ H ₁₄ F ₂ N ₄ O:

C, 64.77; H, 4.01; N, 15.91 Found: C, 65.13; H, 4.05; N, 15.71

Example 80 3,3-Bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde

A. 5-Et hy 1-1-methyl-1H-tetrazole

To a slurry of 4.9 g (0,05MoI) 1,5-dimethyl-tetrazole in 50 ml dry tetrahydrofuran 20 ml (0,05MoI) of 2.5M butyllithium in hexane was added under inert atmosphere at -78 einsr ⁰ C within 15 minutes , This mixture is stirred for 30 minutes, forming a yellowish precipitate. Then, within 15 minutes, 3.7 ml of methyl iodide (0.06 mol) are added. After stirring for a further 30 minutes, the clear reaction mixture is diluted with water and extracted with 3 × 50 ml of ethyl acetate. The aqueous phase is washed with 2 × 25 ml of chloroform, the combined organic phases dried over sodium sulfate and concentrated in vacuo to an oil. The oil is purified by distillation, and yields 5.2 g (92%) of the Titelverbinüung, Kp. 89-9O ⁰ C at 0.05 mm Hg.

¹ H NMR (CDCl ₃ ) δ: 4.05 (s, 3H), 2.8 ί (q, 2H), 1.41 (t, 3H); ¹³ C NM.T (CDCI ₃ ) δ: 156.0,33.24,16.75,11.20.

For example, 1,1-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -propan-1-ol

To a solution of 5.6 g (0.05 mmol) of 5-ethyl-1-methyl-1H-tetrazole (prepared in Stufo A) in 60 ml of dry tetrahydrofuran is added 20 ml (0.05 mol) of 2.5M butyllithium in hexane over 5 min at -78 ° C (bath temperature) added under an inert atmosphere. The mixture is stirred for 30 min and a solution of 10.8 g (0.5 mol) of 4,4'-difluoro-benzophenone in 25 ml of dry tetrahydrofuran is added over 5 min. This mixture is stirred for a further 2 h while the bath temperature is slowly warmed to -20 ⁰ C. The reaction is stopped with 1 η HCl and the reaction mixture extracted with 3 x 50ml ethyl acetate and with 3 x 50ml chloroform. The combined organic phases are dried over sodium sulfate and concentrated in vacuo to give a white solid. The solid is purified by recrystallization from ethanol-hexane to yield 10.8 g (65%) of the title compound; F. 160-161 ⁰ C.

IR (KBr) ^ L _x : 3400cm "';

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: 162.57,162.37,159.14,156.71,142.48,140.64,128.25,128.13,127.52,127.42,114.67,1V. 41,114.38, 78.56, 36.99, 33.43, 14.52.

Anal. Calcd. for C ₁₇ Ht ₆ F ₂ N ₄ O:

C, 61.81; H, 4.88; N, 16.96. Found: C ₁ 61.79; H, 4.90; N, 17.09.

C. 1,1-Bis (4-fluoro-phenyl; -2- (1-methyl) -1H-tetrazol-5-yl) propene. A slurry of 8.25 g (0.025 mol) of 1,1-bis ( 4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -propan-1-ol (prepared in step B) and 100 mg of p-toluenesulfonic acid monohydrate in 60 ml of xylene is stirred for 12 h on a Dean & Stark Water separator boiled under reflux. The reaction mixture is washed with 10 ml of 1 N NaOH warm and then washed with 100 ml of water. Evaporation of the organic phase gives off greyish white crystals. These are purified by recrystallization from ethanol-hexane to give 7.1 g (91%) of the title compound as white crystals; F. 146-147T.

_x : 1575; 1500cnrT \ ¹ H NMR (CDCI ₃₎ δ: 7.42-6.85 (m, 8H), 3:53 (s, 3H), 2.14 (s, 3H); ' ³ C NMR (CDCl ₃ ) δ: 163.37,163.08,160.13,155.61,144.60,145.34,136.47,136.42,136.24,136.19,131.65,131.54,131.11,131.01, 119.53,115.51,115.27,115.22,33.50,21.20.

Anal. Calcd. for C ₁₇ H ₁₄ F ₂ N ₄ :

C, 65.37; H, 4.51; N, 17.94. Found: C, 65.64; H, 4.61; N, 18.09.

D. 1,1-Bis (4-fluoro-phenyl) -3-bromo-2- (1-methyl-1H-tetrazol-5-yl) propene

A slurry of 61.46 g (0.197 mol) of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propene (prepared in Step C), 35.06 g of N -Brom-succinimide (0.197 mol) and a catalytic amount of azoisobutyronitrile or benzoyl peroxide in 1,21 carbon tetrachloride withe 2h in an inert atmosphere under reflux. The reaction mixture is cooled to room temperature and the solid reaction product is filtered off. The filtrate is evaporated in vacuo and the resulting solid recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals; F. 159-16O ⁰ C.

IR (KBr) iL «: 1600cm" ¹ .

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

CNMR (CDCl ₃ ) O: 163.94.163.74.160.60.160.45.143.42.149.68.135.20.135.15.134.69.131.43, 131.31.130.90,130.80,119 57,115.94,115.77,115.65,115.50.

Anal. Calcd. for C ₁₇ Hi ₃ F ₂ BrN ₄ :

C, 52.19; H, 3.34; N, 14:32. Found: C, 52.58; H, 3.47; N, 14.49.

E. 3,3-Bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde

To a solution of sodium ethoxide from 3.93 g of metallic sodium (0.17 mol) in 500 ml of absolute ethanol is added 16.66 g (0.187 mol) of 2-nitro-propane slowly over 5 min. 67.1 g (0.17 mol) of the Brotnverbindung shown in step D are added in portions within 10 min. The reaction mixture is stirred for 2 h and the ethanol evaporated in vacuo. The residue is dissolved in 500 ml of CH ₂ Cl ₂ , washed with water (250 ml) and dried over sodium sulfate. The organic phase is evaporated in vacuo to yield an oil. The oil is dissolved in 350 ml of hot toluene, and after addition of 350 ml of hexane, 50.6 g (91%) of the title compound are obtained as white crystals;

F. 135-137 ⁰ C.

Example 81

[3,3-Bis- (4-fluoro-phenyl) -2- (V-methyl-N-tetrazol-5-yl) allyl] -triphenyl-phosphonium bromide A slurry of 1.95 g (0.005 mol) of 1,1-bis (4 fluorophenyl) -3-bromo-2- (1-methyl-1H-tetrazol-5-yl) propene (prepared in Example 80, Step D) and 1.3 g (0.005 mol) of triphenylphosphinine in 25 ml of cyclchexane are refluxed cooked. After 30 minutes a clear solution forms and after 1 h a white precipitate appears. The mixture is heated for a further 8 h, cooled to room temperature and the solid is filtered off and washed with diethyl ether. This white powder is dried at 5O ⁰ C under vacuum and provides 3.0 g (92%) of the title compound; F. 254-255 ⁰ C.

IR (KBr) lLx: 3450,1600,1 500,1452cm ¹ .

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

' ³ CNMR (DMSO-d ₆ ) δ: 163.53,163.36,160.28,160.87,154.04,153.89,152.76,135.11,134.79,134,16,133.68,133.54,130.53, 130.45,130.35,130.21,130.07,118.02,116.89,115.89 , 116.18,115.62,115.32,111.43,111.39,34,22, 28.88, 28.22.

Anal. Calcd. for C ₃₅ H ₂₈ BrF ₂ N ₄ P:

C, 64.31; H, 4.32; N, 8.57. Found: C, 64.02; H, 4.37; N, 8.89.

Belspiei 82

(+ l-oryihro-gS-Bls-f ^ fluoro-phenyD-aS-dihydroxy-e-l-methyl-IH-tetrazol-S-ylnona-sec-dienoic acid methacrylate) To a slurry of 0.326g (0.5 mmol) of the in Example 81 phosphonium bromide and 0.26 g (0.4 mmol) erythro-3,5-bis (diphenyl) -tert-butylsiloxy) -6-oxo-hexanoic acid methyl ester (prepared according to the in P. Kapa et>!., Tetrahedron Letters , 2435-2438 [1984] and U.S. Patent No. 4,571,428, issued February 18, 1986 to PK Kapa, General Methods) in 1 ml of dry dimethylformamide, 0.067 g (0.6 mmol) of potassium tert-butoxide at -20 ⁰ C (bath temperature) added in an inert atmosphere. The slurry turns into a red solution, which is stirred at -10 ⁰ C 18h. The reaction mixture is worked up by adding 10 ml of ammonium chloride solution and extraction with 2 × 30 ml of methylene chloride. The organic phase is dried over sodium sulfate and concentrated to an oil. The oil is purified by passing over a layer of silica gel and the main fraction is isolated as oil (160 mg). This oil is stirred with 2 ml of a 1Μ solution of tetrabutylammonium fluoride in tetrahydrofuran and a few drops of glacial acetic acid for 18 hours. The reaction mixture is poured into 10 ml of water and extracted with 3 χ 20 ml of ethyl acetate. The organic phase is dried over sodium sulfate and concentrated to an oil. The oil is purified by flash column chromatography on silica gel, eluted with ethyl acetate / hexane (2/1 (, to give 0.08 g (75%) of the title compound as an oil.) MS (CI): m / e = 471 for (M. + H) *;

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) ₁ 3.56 (s, 3H), 2.47 (d, 2H), 1.58 (m, 2H). A more polar fraction (20 mg) is also isolated and identified as the corresponding trans-lactone.

Example 83

4,4'-difluoro-2,2'-dimethyl-benzophenone

To a well-stirred mixture of 6.1 g (46, OmMoI) aluminum chloride in 14 mL carbon tetrachloride at ⁰ ° C is added 1 g of a total of 10 g (90, OmMoI) 3-fluoro-toluene and the mixture stirred for 10 min. Then the remainder of the 3-fluorotoluene in 9 ml carbon tetrachloride is added and the mixture is stirred at ⁰ ° C. for 14 h. The mixture is cooled to -2O ⁰ C and hydrolyzed by the addition of 15 ml of 1 η hydrochloric acid. The organic phase is separated and concentrated in vacuo. The residue is stirred for 15 hours with a mixture of 20 ml benzene, 20 ml water and 5 ml acetic acid. The aqueous phase is separated and extracted with diethyl ether. The combined organic phases are dried over MgSO ₄ and concentrated in vacuo. The analytical TLC of the residue shows 3 spots: R ₍ = 0.67, 0.05 and 0.56 (5% by volume of ethyl acetate in hexane on silica gel) The column chromatography on silica gel with 0.5% by volume of ethyl acetate in hexane and Combination of fractions containing material with R ₍ = 0.67 (5 v / v% ethyl acetate in hexane) provides 1.3 g of the title compound, mp 50-52 ° C, MS (Cl): m / e = 247 for (M + H) ¹ ;

¹ HNMR (CDCl ₃ ) δ: 7.26 (2H, dd), 6.96 (2H, dd), 6.87 (2H, dt), 2.42 (6H, s).

Anal. Calcd. for C ₁₅ H ₁₂ F ₂ O:

C, 73.17; H, 4.92

 Found: C, 73.34; H, 5.02.

Example 84 2,4'-Difluoro-2 ', 4-dimethyl-benzophenone

Evaporation of the appropriate fractions from the silica gel column chromatography of Example 83 containing material of R, = 0.59 gives 2.4 g of the title compound; F.29 to 31 ⁰ C. MS (Cl): m / e = 347 for (M + H) ^+;

¹ H NMR (CDCl ₃ ) δ: 7.53 (1H, t), 7.39 (1H, dd), 7.19-6.85 (4H, m), 2.42 (3H, s), 2.39 (3H, s).

Anal. Calcd. for C ₁₆ H ₁₂ F ₂ O:

C, 73.17; H, 4.92 Found: C, 73.34; H, 4.86.

Example 85

2,2'-difluoro-4,4'-dimethyl-benzophenone

Evaporating the appropriate fractions from the silica gel column chromatography of Example 83 containing material with Ri = 0.56 and triturating the residue with hexane to provide 1.2 g of the title compound; F. 84-85.5 ° C.

¹ H NMR _(CDCl3) δ: 7.57 (2H, t, J _H-H = 8 Hz, J _FH = 8Hz), 7:02 (2H, d, J _H - _H = 8Hz), 6.89 (2H, d, J _FH = 8Hz), 2.39 (6H, s).

Anal. Calcd. for C ₁₆ H ₁₂ F ₂ O:

C, 73.17; H, 4.92

 Found: C, 73.19; H, 4.88.

Example 86

1,1-bis- (4-fluoro-2-mathyl-phenylj-2- (1-methyl-1H-tetrazol-5-yl) ethanol

To a solution of 3.8g (39, OmMoI) 1,5Dimethyl-tetrazole in 40 ml of tetrahydrofuran at -40 ⁰ C 17.7 ml (39 OmMoI) of a 2.2M solution of butyllithium were added. After stirring for 10 minutes, 8 g (32.5 mmol) of 4,4'-difluoro-2,2'-dimethylbenzophenone are added and the solution is stirred for 3 hours. The reaction is stopped with 1 N hydrochloric acid. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to give the title compound (7.5 g); F.186-188 ° C.

Anal. Calculated for Ci ₈ H ₁₈ F ₂ N ₄ O:

C: 62.99; H, 5.27; N ₁ 16.27 Found: C, 63.01; H, 5.34; N, 16.18

Example 87

1,1-bis (4-fluoro-2-methyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene) A mixture of 0.5 g (1.5 mmol) of 1,1-bis Bis (4-fluoro-2-methyl-phenvl) -2- (1-methyl-1H-tetrazol-5-yl) -ethanol and 0.2 g of p-toluenesulfonic acid in 30 ml of toluene ^r . is refluxed for 16h. The mixture is cooled, diluted with 50 ml of diethyl ether and extracted with saturated sodium bicarbonate solution and water. The organic phase is dried over MgSO ₄ and concentrated in vacuo. The residue is triturated with diethyl ether to yield 0.3 g of the title compound;

F. 12O-125 ° C.

Anal. Calculated for C ₁₈ Hi ₆ F ₂ N ₄ :

C, 66.25; H, 4.95; N, 17.17 Found: C, 66.55; H, 4.92; N, 16.84

Example 88 S ^ -bis-H-fluoro ^ -methyl-Phenyo ^ d-methyl-IH-tetrazol-B-yOacrylaldehyd

To a solution of 1,6g (5, OmMoI) 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene in tetrahydrofuran are added - 7O ⁰ C 2.3 ml (5, OmMoI) of a 2.2M solution of butyllithium was added. After stirring for 0.25 h, 0.44 g (6, OmMoI) of ethyl formate are added and the mixture is stirred for 2 hours. The reaction is stopped with 1 η hydrochloric acid and the mixture extracted with methylene chloride. The extracts are dried and concentrated in vacuo to give 1.0 g of the title compound; F. 135-136 ⁰ C.

Anal. Calculated for C ₁₉ H ₁₆ F ₂ N ₄ O:

C, 64.41; H, 4.56; N, 15.82 Found: C; 64.22, H, 4.59; N, 15.50

Example 89

5,5-Bis (4-fluoro-2-methyl-phenyl) -4- (1-methyl-1H-tetrazol-5-yl (penta-2,4-dienal A solution of 0.88 g (2.5 mmol) ) 3,3-Bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) acryladehyde and 0.75 g (2.5 mmol) of triphenylphosphoranylideneacetaldehyde in 50 ml of benzene become 3 h The solvent is evaporated and the crude residue is purified by column chromatography on silica gel eluted with 1% by volume of methanol in methylene chloride The fractions with Rf 0.9 (methanol / methylene chloride 1/20 v / v) are combined and concentrated and yielded 0.8 g of the title compound, mp 75-95 ° C MS: M ⁺ = 380;

¹ H NMR (CDCl ₃ ) δ: 9.52 (1H, d), 7.30-6.67 (7H, m), 5.82 (1H, dd), 3.62 (3H, s), 2.23 (3H, s), 2.00 (3H, s).

Anal. Calcd. for C ₂₁ H ₁₈ F ₂ N ₄ O:

C, 66.31; H, 4.78; N, 14.73. Found: C, 65.76; H, 4.85; N, 14:52.

Example 90

9,9-bis- (4-fluoro-2-methyl-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-diensäuretert- butylestor To a solution of 1.0g (2.5 mmol) of 5,5-bis- (4-fluoro-2-methyl-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -penta-2 , 4-dienal in tetrahydrofuran at -5O ⁰ C, 2.5 ml (2.5 mmol) of a 1M solution of the dianion of tert-butyl acetoacetate, prepared by adding 4.0 g (25, OmMoI) in 4 ml of tetrahydrofuran to a suspension of 1.0g (25, OmMoI) of a 60% dispersion of sodium hydride in tetrahydrofuran at -5 ⁰ C, then cooling to -3O ⁰ C and addition of 11,4ml (25 mmol) of a 2.2 M solution of Butyllithium, added. After stirring for 1.5 h, the analytical TLC shows only the starting aldehyde. Then another 0.5 ml of the dianion solution is added. The solution is stirred for a further 0.5 h and the reaction is interrupted with 1N hydrochloric acid. The mixture is extracted with methylene chloride. The extracts are dried and extracted in vacuo. The residue is purified by column chromatography on silica gel eluted with methanol in methylene chloride to give 0.6 g of the title compound; F. 65-72 ° C.

Anal. Calculated for C ₂₉ H ₃₂ F ₂ N ₄ O _4:

C, 64.68; H, 5.99; N, 10.41 Found: C, 64.50; H, 5.98; N, 10:16

Example 91

(±) -erythro-9,9-bis- (4-fluoro-2-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8 tert-butyl dienoate To a solution of 2.5 g (4.6 mmol) of 9,9-bis (4-fluoro-2-methylphenyl-5-hydroxy-8- (1-methyl-1H-tetrazole -5-yl) -3-oxo-nona-6,8-dienoic acid tert-butyl ester in 30 ml of tetrahydrofuran are added at -5 ° C 6.0 ml (6, OmMoI) of a 1M solution of triethylborane and the solution was stirred for 1 h . After cooling to -78 ⁰ C to 0.36 g (9, OmMoI) of sodium borohydride and 2 ml of methanol was added. The mixture is stirred for 2 h at -78 ⁰ C and diluted with 15 ml of hexane. The mixture is hydrolyzed with hydrochloric acid 1 η. The aqueous phase is separated and extracted with methylene chloride, the combined organic phases are dried and concentrated in vacuo, the residue is dissolved in methanol and the solution is stirred for 18 hours The solution is evaporated in vacuo and the residue is purified by column chromatography eluted with 1 vol .-% methanol in methylene chloride, eng and provides 1.7 g of the title compound as a white powder; F.75-80 ° C.

Ή 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);

Anal. Calcd. for C ₂₉ H ₃₄ F ₂ N ₄ O _4:

C, 64.44; H, 6.34; N, 10.37. Found (corr. For 0.28% H ₂ O):

C, 64.14; H, 6.41; N, 10.16.

Example 92 Sodium (± erythro-9,9-bis- (4-fluoro-2-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6, 8-dienoate

To a solution of 1.65 g (3.05 mmol) of 9,9-bis (4-fluoro-2-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole-5 yl) Nona-6,8-dienoic acid tert-butyl ester in 50 ml of ethanol, 3.05 ml (3.05 mmol) of a 1N sodium hydroxide solution are added, and the solution is stirred at room temperature for 1 h and at 50 ° C. for 1 h. The solution is concentrated in vacuo to yield 1.3 g of the title compound, which probably contains 1 mol of water; F. 215-225 ° C (dec.).

Anal. Calculated for C ₂₆ Hj ₆ F ₂ N ₄ O ₄ NaH ₂ O:

C, 57.26; H, 5.19; N, 10.69 Found: C, 57.30, H, 5.20; N, 10.00

Example 93

1,1-Bis (2-fluoro-4-methyl-phenyl) -2- (1-diethyl-H-tetr-t-zol-5-yl) -ethanol To a solution of 4,6 g (4,7 mmol) 1 , 5-Dimethyltetrazole in 40 ml of tetrahydrofuran are added at -5O ⁰ C 21.4 ml (4.7 mmol) of a 2.2 M solution of butyllithium. After stirring for 10 minutes, a solution of 2,2'-difluoro-4,4'-dimethylbenzophenone in 15 ml of tetrahydrofuran is added. The solution is stirred for 2.5 h and while warmed to - 1O ⁰ C. The reaction is interrupted by the addition of 1N hydrochloric acid. The phases are separated and the aqueous phase extracted with methylene chloride. The combined organic phases were dried over MgSO ₄ and evaporated. The residue is triturated with diethyl ether and recrystallised from ethyl acetate to give 8.0 g of the title compound; F. 150-151 ⁰ C. MS: M * = 344th

Anal. Calculated for C ₁₈ H ₁₈ F ₂ N ₄ O:

C, 62.79; H, 5.27; N, 16.27 Gefundon: C, 62.84; H, 5.23; N, 16:28

Example 94 1,1-Bis- (2-fluoro-4-methyl-phonyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene A suspension of 7.3 g (21, OmMoI) 1.1 -Bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol in 200 ml toluene is treated with 3 g of p-toluenesulfonic acid and the mixture is refluxed for 14 h. After cooling, the mixture is diluted with diethyl ether and extracted with saturated sodium bicarbonate solution and water. The organic phase is dried over MgSO ₄ and evaporated. The residue is triturated with isopropyl ether to yield the title compound; F. 58-6O ⁰ C.

Ana). Calculated for C ₁₈ Hi ₆ F ₂ N ₄ -.

C, 66.25; H, 4.95; N, 17.17 Found: C, 66.27; H, 4.94; N, 16.93

Example 95

3,3-Bis (2-fluoro-4-methyl-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde To a solution of 1.6 g (5, OmMoI) 1,1- Bis- (2-fluoro-4-methylphenyl) 2- (1-methyl-1H-tetrazol-5-yl) ethene in 20 ml of tetrahydrofuran at -78 ⁰ C 2.3 ml (5 mmol) of a 2.2 M solution of Butyllithium added. After stirring for 15 minutes, 0.44 g (6, OmMoI) of ethyl formate are added and the mixture is stirred with cooling for 2 h. The reaction is stopped with 1 N hydrochloric acid and the mixture extracted with diethyl ether. The extracts are dried over MgSO ₄ and evaporated. The residue is recrystallized from ethyl acetate to give 0.66 g of the title compound; F. 154-155 "C.

Anal. Calculated for Ct ₉ H] ₆ F ₂ N ₄ O:

C, 64.41; H, 4.56; N, 15.82 Found: C, 64.44; H, 4.63; N, 15.58

Example 96

5,5-Bis (2-fluoro-4-methyl-phenyl-methyl-IH-tetrazol-S-y-pentadiene) Adienal A solution of 1.35 g (3.8 mlv) of 3,3-bis (2-fluoro 4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-ydacrylaldehyde and 1.16 g (3, SmMoI) triphenylphosphoranylidene acetaldehyde in benzene is refluxed for 3 hours The solvent is removed and the residue is purified by column chromatography on silica gel, eluting with 1% (v / v) methanol in methylene chloride The fractions are combined and concentrated with Rf 0.9 (methanol / methylene chloride 1/20 v / v) to yield 1.3g of the title compound (m.88-108) ° C.

Anal. Calculated for C ₂ ) H ₁₈ F ₂ N ₄ O:

C, 66.31; H, 4.78; N, 14.73 Found: C, 66.34; H, 4.96; N, 14:37

Example 97

9,9-bis- (2-fluoro-4-methyl-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-diensäure- Tert-butyl ester To a solution of 1.3 g (3.4 mmol) of 5,5-bis (2-fluoro-4-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) - penta-2,4-dienalin 15ml of tetrahydrofuran, 3.41; il i3,4mMol) of a 1M solution of the dianion of acetoacetic acid-tert-butylesrter at -5o ⁰ C was added. After stirring for 2 hours, a further 0.7 ml of the dianion solution are added and the solution is stirred for a further hour. The reaction is stopped with 1 η hydrochloric acid and the mixture extracted with methylene chloride. The extracts are dried over MgSO ₄ and concentrated. The residue is purified by column chromatography on silica gel, eluici t with 1 vol .-% methanol in methylene chloride, purified and provides 1.3 g of the title compound, mp 55-63 ⁰ C.

¹ H NMR (CDCl ₃ ) δ: 7.05-6.53 (7H, m); 5.28 (1H, dd), 4.60 (1H, m), 3.75 (3H, s), 3.35 (2H, s), 3.05 (1H, bs), 2.69 (2H, d), 2.39 (3H , s), 2.33 (3H, s), 1.45 (9H, s).

Anal. Calcd. for C ₂₉ H ₃₂ F ₂ N ₄ O _4:

C, 64.68; H, 5.99; N, 10:41

Found (corr. For 0.21% H ₂ O):

C, 64.33, H, 6.07; N, 10.21.

Example 98

(±) -etythro-9,9-bis- (2-fluoro-4-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl) -1H-tetrazol-5-yl) nona-6, 8-Tartaric acid tert-butyl ester To a solution of 1.3 g (2.4 mmol) of 9,9-bis (2-fluoro-4-methylphenyl) -5-hydroxy-8- (1-methyl-1H -tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid tert-butyl ester in tetrahydrofuran are added at -5 "C 3.1 ml (3.1 mmol) of a 1 M solution of triethylborane. after 1 hour of stirring at -5 ° C the solution is cooled to -75 ⁰ C and 0.2 g (4,8mMol) of sodium borohydride and 1 ml of methanol was added. after 2 h stirring at -75 ° C the mixture is diluted with 10 ml hexane, and The aqueous phase is separated off and extracted with methylene chloride The combined organic phases are dried over MgSO ₄ and concentrated in vacuo The residue is dissolved in methanol and the solution is stirred for 19 h at room temperature concentrated and yields 0.6 g of the title compound as a white powder, mp 73-77 ⁰ C.

Anal. Calculated for C ₂ SH ₃₄ F ₂ N ₄ O ₄ :

C, 64.44; H, 6.34; N, 10.37 Found: C, 64.07; H, 6.45; N, 9.87

Example 99 Sodium-l + l-erythro-S.G-bis-lZ-fluoM-rnethyl-phenyD-S, S-dihydroxy-Sli-methyl-IH-tetrazol-S-yDnona-e.e-dienoate

To a solution of 0.6 g (1.1 mmol) of 9,9-bis (2-fluoro-4-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole-5 -yl) nona-6,8-dien-tert-butyl ester in 20 ml of ethanol, 1.1 ml (1.1 mmol) of a 1N sodium hydroxide solution are added and the solution is stirred at room temperature for 1 hour and at 50 ° C. for 1 hour. The solution is concentrated in vacuo to yield 0.44 g of the title compound, which probably contains about 1 mole of water; F. 200-205 ° C (dec.).

Anal. Calculated for C ₂₅ H ₂₅ F ₂ N ₄ O ₂ NaH ₂ O:

C, 57.26; H, 5.19; N, 10.69 Gefu-den: C, 57.00; H, 5.27; N, 10.05

Example 100 Sodium (3R, 5S) -9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6 , 8-dienoate

A. (3S) -7,7-Bis- (4-fluoro-phenyl) -3-hydroxy-6- (1-methyl-1H-tetrazol-5-yl) -hepta-4,6-dienoic acid (1S) -2-hydroxy-1,2,2-triphenylethylester

A solution of 5.33 mL (3.85 g, 38.1 mmol) of diisopropylamine in 40 mL of dry tetrahydrofuran is cooled to ⁰ ° C. and treated with 15.2 mL (3SmMoI) of a 2.5M solution of butyllithium in hexane and the mixture is stirred Heated to 23 ⁰ C for 15 minutes. The solution is cooled to -78 ° C and added to a suspension of 5.07 g (19.2 mmol) of (-) - (S) -1,2,2-triphenyl-2-hydroxyethyl acetate (prepared according to the method described in Tetrahedron Letters , 5031-5034 [1984]) in 40 ml of dry tetrahydrofuran at 78 ° C. The resulting orange solution is cooled to -78 ⁰ C and treated with a solution of 8g (22,73mMol) of 5,5-bis- (4-fluoro-phenyl) -4- (1-methyl-1 H-tetrazol-5- yl) penta-2,4-dienal in 30 ml of dry tetrahydrofuran. After 20 minutes stirring at -78 ⁰ C the reaction is stopped with 80 ml of 2N HCl and the solvent evaporated. The residue is extracted with 3x 50 ml of ethyl acetate and the combined organic phases dried over MgSO ₄ and evaporated in vacuo. The residue is purified by column chromatography on silica gel eluted with 30% by volume of ethyl acetate in hexane to give 9.4 g (90%, based on the chiral acetate) of the title compound. Ia] ₀ = 41.1 ° (c-1.16, CH ₂ Cl ₂ ).

¹ H NMR (DMSOd ₆ ) δ: 7.45-6.80 (m, 2r H), 6.54 <s, 1 H), 6.50 (d, J = 16.0Hz1 H), 6.05 (s, 1 H), 5.15 (dd, J = 15.6Hz, J '= 5.2Hz, 1H), 5.02 (d, J = 5.3Hz, 1H), 4.33 (m, 1H), 3.70 (s, 0.3H lower diastereomer), 3.65 (s, 2 , 7 H predominant diastereoisomer), 2.29 (m, 2H).

' ³ C NMR (DMSO-de) δ: 194.01,170.16,169.32,163.64,163.16,160.36,159.90,153.00,147.77,145.95,145.09,144.50,138.00, 136.88,136.42,135.40,133.04,, 32.28,131.76, 131.00,128.54,127.38,127.05,126.61,126.44,125.74,121.40,115.94,115.60, 115.40,115.06,78.74,70.36,67.50 (lower diasteroemer), 66.75 (predominant diastereomer), 59.67,41.97,33.47,20.68, 14.01.

B. (3S) -7,7-bis (4-fluoro-phenyl) -3-hydroxy-6- (1-methyl-1H-tetrazol-5-yl) hepta-4,6-dienoic acid methyl ester

A solution of 9.4 g (13.74 mmol) of the triphenyl ester shown in Step A in 40 mL of dry methanol is added to a solution of 2.1 g (91 mmol) of metallic sodium in 300 mL of dry methanol and the resulting mixture is stirred at 23 ° for 30 minutes C stirred. The reaction is stopped with 100 ml of 2N HCl and the solvent evaporated. The residue is diluted with 100 ml of water and extracted with 3x 70 ml of ethyl acetate. The combined organic phases are dried over MgSO ₄ and evaporated. The residue is purified by silica gel column chromatography eluted with 40% by volume of ethyl acetate in hexane to give 4.08 g (70%) of the titled compound. Ia] ₀ = + 28.94 "(c = 0.85, CH ₂ Cl ₂ ).

IR (Film) tL> _x : 3400 (br), 1735,1500,1220cm ¹ .

¹ H NMR (CDCl ₃ ) 0: 7.30-6.60 (m, 8H), 6.725 (dd, J = 15.8Hz, J '= 1.4Hz, 1H), 6.34 (dd, J = 15.9Hz ₁ J' = 5.6Hz , 1 H), 4.56 (br s, 1 H), 3.69 (s, 3H), 3.60 (s, 3H), 3.14 (br s, 1 H), 2.50 (m 2H).

¹³ C NMR (CDCl ₃ 0: 172.27,164.61.164.20,161.29,160.88,153.43,147.46,136.04,135.26,132.38,132.26,131.48,131.37,128.01, 120.96,115.91,115.56,68.17, 51.85,40.84,33.57.

C. (5S) -9.9-Bis- (4-fluoro-phenyl) -5-hydroKy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8- dienoic acid tert-butyl ester

A solution of 2.77 ml (2g; 19,8mMol) of diisopropylamine in 15ml dry tetrahydrofuran is cooled to 0 ⁰ C, and 8.1 ml (20.25 mmol) of a 2.5 M solution of butyllithium in hexane and the resulting mixture is heated to 23 ⁰ C within 15 minutes. The solution is cooled to ^{0 °} C and 2.55 ml (2.2 g; 18.9 mmol) tert-butyl acetate were added and the solution stirred for 15 minutes at 0 ° C and then cooled to -78 ⁰ C, then the solution of in step B shown Methylesters (2g; 4,69mMol) was added in 20 ml of dry tetrahydrofuran at -78 ⁰ C. The resulting solution is heated to 23 ⁰ C within 30 minutes and the reaction is interrupted with 20ml 2 η HCl. The solvent is evaporated in vacuo and the residue is diluted with 30 ml of water and extracted with 3x 30 ml of ethyl acetate. Dry the combined organic layers over MgSO ₄ and evaporate in vacuo and purify the residue by silica gel column chromatography eluted with 35% by volume of ethyl acetate in hexane to give 1.858 g (78%) of the title compound. (α | ό ⁵ = + 19.44 ° (c = 1.08, CH ₂ Cl ₂ ).

IR (Film) »/ ™ ,,: 3400 (br), 1735,1710,1 595,1510,1220,1155cm" '.

¹ HNMR (CDCl ₃ ) δ: 7.30-6.80 (m, 8H), 6.72 (dd, J = 16.5Hz, J '= 0.9Hz, 1H), 5.30 (dd, J = 15.6Hz, J' = 5.5Hz , 1H), 4.61 (br, 1H), 3.56 (s, 3H), 3.35 (s, 2H), 2.70 (m, 2H), 1.45 (s, 9H).

¹³ C NMR (CDCl ₃ ) δ: 202.88.168.05,164.61,164.16,161.29,160.85,153.50,147.30,136.01,132.40,132.29,131.51,131.39,127.88, 121.00,115.88,115.83,115.60,115.54,82.35,67.85 , 51.10,49.10,33.59, 27.99.

D. (3R, 5S) -9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-5, 8-dienoic acid tert-butyloster

To a solution of 1.85 g (3.62 mmol) of the β-ketoester shown in Step C in 30 ml of dry tetrahydrofuran is added 3.9 ml (3.9 mmol) of a 1 M solution of triethylborane in THF and the mixture is blown dry Air for 1 hour to 23 ⁰ C stirred. Then 600 .mu.l of methanol are added, the mixture cooled to -78 ⁰ C and treated with 320 mg (8.42 mmol) of sodium borohydride and the mixture stirred at -78 ⁰ C for 20 minutes. The reaction is stopped with 20 ml 2 η HCl and the solvent evaporated. The residue is diluted with 30 ml of water and extracted with 3χ 20 ml of ethyl acetate. The combined organic extracts are dried over MgSO ₄ and evaporated and the residue dissolved in 30 ml of methanol and allowed to stand for 3 hours at 23 ° C. The solvent is evaporated in vacuo and the residue is purified by silica gel column chromatography eluted with 40% by volume of ethyl acetate in hexane to give 962 mg (53%) of the title compound.

Ή NMR (CDCl ₃ ) δ: 7.30-6.80 (8H, m), 6.71 (d, J = 15.6Hz, 1H), 5.34 (dd, J = 15.6Hz, J '= 7Hz, 1H), 4.43 ( br s, 1 H), 4.15 (br s, 1 H), 3.95 (m, 2H), 3.58 (s, 3H), 2.36 (d, J = 6.1 Hz, 2H), 1.6 (m, 2H), 1.45 (s, 9H).

' ³ C NMR (CDCl ₃ ) δ: 172.00,164.52,164.12,153.57,146.79,137.98,132.38,132.26,131.46,131.35,127.00,121.25,115.85,115.80, 115.57,115.51, 81.66,71.88,68.54,42.34, 42.36,33.59, 28.10.

E. Sodium (3R, 5S) -9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-metriyl-1H-tetrazol-5-yl) nona-6,8-dienoate Fine solution of 3bmg (0.068 mmol) of the dihydroxy ester shown in Step D in 2 ml of ethanol is treated with 68μΙ (0.068 mmol) of a 1 η sodium hydroxide solution and the mixture is stirred at 23 ⁰ C for 30 minutes. The solvent is evaporated in vacuo and the residue is dissolved in 2 ml of water and lyophilized to give 36 mg (100%) of the title compound; F.> 11O ⁰ C (Zers.); [α] "= -22.2 ° (c = 0.32, H ₂ O) The 'H-NMR spectrum and the ¹³ C-NMR spectrum are compared with the (±) -erythro- Product identical.

Example 101

1-methyl-tetrazol-5-ylessigesäureethylester

To a solution of 10 g of 1,5-dimethyl-tetrazole in 100 ml of dry tetrahydrofuran and 20 ml of hexamethylphosphoric triarr.id are added dropwise 50 ml (1.2 equivalents) of butyl lithium under argon atmosphere at -78 ° C (dry ice-acetone) (2, 5 M in hexane). The deprotonation of 1,5-dimethyl-tetrazole is 40 minutes at -78 ° C, then 30 minutes at -20 ⁰ C. The anion solution is cooled again to -78 ⁰ C and cannulated within 45 minutes in a on - 78 ⁰ C cooled solution of 12ml ethyl chloroformate in 50ml tetrahydrofuran converted. The reaction mixture is diluted with 2 N aqueous hydrochloric acid and saturated aqueous sodium chloride solution and extracted with ethyl acetate. The residue from the organic extract is purified by silica gel flash chromatography. The appropriate fractions are combined and evaporated, yielding 4 g of product. The product is further purified by recrystallization from ethyl acetate-hexane to yield 3.52f (21%) of the title compound; F. 64-66 ⁰ C.

Anal. Calculated for C ₆ Hi ₀ N ₄ O ₂ :

C, 42.35; H, 5.92; N, 32.92 Found: C, 42.40; H, 5.98; N, 33.15

Example 102

3,3-bis- (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) acrylsäumetliylester

A mixture of 2 ml of titanium tetrachloride and 2 ml of carbon tetrachloride is added at -78 ° C under an argon atmosphere to 15 ml of tetrahydrofuran. The suspension is stirred for 30 minutes at -78 ° C. and then 0.2 g of 4,4'-difluoro-benzoplonenone are added and, after stirring for a further 30 minutes, a solution of 0.15 g of ethyl i-methyl-tetrazol-5-yl-acidate, The mixture is stirred for 24 hours at -78 ° C and then warmed to 0 ° C to form a viscous paste The mixture is allowed to stand for 24 hours at room temperature and then poured into water. The aqueous mixture is extracted with ethyl acetate to give a crude product The analytical TLC, eluted five times with 20% by volume of ethyl acetate in hexane, shows the desired product at R ₍ = 0.3) purification by preparative chromatography to two 20 cm × 20 cm 0, 25mm TLC plates eluted twice with 20% by volume ethyl acetate in hexane afforded the title compound, which is identical to the compound of Example 3, Step A.

Example 103 Erythro-9,9-bis (4-fluoro-pheiiyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid hydrate

A. 5,5-Bi 3 - (4-fluoro-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -penta-2,4-dienal

A mixture of 448 g (1.37 mol) of 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -acrylaldehyde and 445 g (1.46 mol) of triphenylphosphoranylidene-acetaldehyde in 5.51 toluene is heated to 55 ° C with stirring. After removing the heat source, the temperature rises to ö2 ° C. After 20 minutes, continue to heat and maintain the temperature at 60 ° C for 30 minutes. After analysis of the analytical TLC {50% ethyl acetate in hexane), the reaction is complete. 128g (1.47 mol) Lithii mbromid are added and the mixture stirred for 1 hour at 60 ⁰ C. The reaction mixture is filtered and the filtrate evaporated in vacuo. The residue is dissolved in 900 ml boiling absolute ethanol. After 16 hours at room temperature and 2 hours in the refrigerator, the mixture is filtered, yielding 418 g (86%) of the title compound; F. 161-165 ⁰ C.

Anal. Calculated for C ₁₉ H ₁₄ N ₄ F ₂ O:

C64.77; H4.00; N15.90 Found: C, 64.94; H 3.97; N 15,82

B. 9,9-bis (4-fluoro-phenyl) -5-hydroxy-3- (1-methyl-1H-tetra-ol-5-yl) -3-oxo-non8-6,8-dienoic acid tert-butyl ester

A solution of 144 g (0.91 mol) of tert-butyl acetoacetate in 400 mL of tetrahydrofuran is added dropwise over 1.5 hours to a mixture of 44.0 g (1.10 mol) of sodium hydride (60% in mineral oil) in 100 mL of hexane and 500ml tetrahydrofuran added under nitrogen at 0 ° C. After the addition, the mixture is stirred for 2.3 hours. Then a solution of 360 ml (0.91 mol) of 2.5 M butyllithium in hexane is added dropwise within 1 hour. After stirring at ⁰ ° C. 200g (0.57 mol) of the aldehyde are shown added in stage A at once, whereby the temperature rises to 2O ⁰ C. After stirring for 1 hour in an ice bath, 1200 ml of 10% strength aqueous hydrochloric acid are added within 1 hour. The organic phase is washed with 2x 300 ml of water and then with 300 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to yield the title compound, which is used without further purification.

C. erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid tert-butyl ester

The product of Step B is dissolved in 11% tetrahydrofuran and 908 ml (0.908 mol) of 1.0M triethylborane in tetrahydrofuran added over 45 minutes. The solution is bubbled with air for 5 minutes, giving it a lighter color. The resulting solution is stirred for 2 hours at room temperature. The mixture is cooled to -74 ° C and 4.0 g sodium borohydride is added. After 15 minutes an additional 32.0g (total 36.0g, 0.951 moles) of sodium borohydride are added. After stirring for 1 hour, 540 ml of methanol are added carefully within 1.5 hours. The reaction mixture is diluted with 540 ml of 10% aqueous hydrochloric acid and stirred for 16 hours at room temperature. Then 200 ml of water are added and the organic solvent is removed in vacuo. The aqueous mixture is extracted with 2x 500 ml of methylene chloride, the extracts combined and washed with 2x 400 ml of water. The organic phase is evaporated in vacuo to yield the title compound, which is used without much purification.

D. (Irylthio-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid hydrate

The product of step C is dissolved in 1195% ethanol, treated with 111 η aqueous sodium hydroxide solution and stirred for 60 hours at room temperature. The solution is diluted with 21% water and washed with 2 × 800 ml of hexane and 5 × 800 ml of diethyl ether. To the stirred aqueous phase is added dropwise within 4 hours 1.0411 η hydrochloric acid. The mixture is filtered, washed with water and dried, yielding 45 g (91%) of the title compound as a monohydrate; F.111-120 ° C (dec.).

Anal. Calculated for C ₂₃ H ₂₂ F ₂ N ₄ O ₄ .H ₂ O

C58.22; H5.10; N 11.81; H ₂ O 3.80 Found: C59.28; H5.12; N 11:53; H ₂ O3.02.

A sample is recrystallized from 50% aqueous methanol. The solution is slowly cooled from 74 ⁰ C and seeded.

After stirring at room temperature for 16 hours, the solid is filtered off, washed with 50% aqueous methanol and air dried to yield the title compound; F. 107-115 ⁰ C. This product from 90% aqueous Essigester is recrystallized.

The boiling solution is slowly cooled and seeded at 50 ⁰ C.

After stirring for 16 hours at room temperature, the solid is separated, washed with cold aqueous ethyl acetate and air dried to give the title compound; F. 122 to 128 ⁰ C (dec.).

Example 104

Potassium (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5 ^ hydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8- dienoate To a hot solution on 20.0 g (42 mmol) of erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-totazol-1-yl) -nona-6,8-dienoic acid hydrate in 200 ml of propan-2-ol are added 3.0 g of potassium hydroxide in 50 ml of propan-2-ol. The mixture is evaporated in vacuo and the residue is dissolved in 100 ml of propan-2-ol, cooled and the solvent is decanted off. The residue is then dissolved in 100 ml of propan-2-ol, heated to boiling and allowed to cool gradually to room temperature with stirring. After 3 hours, the solid is filtered, washed with propan-2-ol and dried in vacuo at 5O ⁰ C. The product is pulverized and dried for 16 hours under high vacuum at 82 ⁰ C, wherein 10,5ei of the title compound are obtained; F. 131-145 ⁰ C (with softening at 127 ⁰ C).

Anal. Calculated for C ₂₃ H ₂ ) F ₂ KN ₄ O ₄ .0.3H ₂ O:

C55,26; H4.36; N 11,21; H ₂ 01,08 'Found 55,44; H4,47; N 11.05; H ₂ 01:38.

Example 105

Trans-6- [4 _> 4 * bis (4-fluoro-phenyl) 3- {1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl] -4-hydroxy-t-thrahydropyran-2 Method A. A mixture of 308 g (0.649 mol) of the acid shown in Example 103 and 149 g (0.724 mol) of dicyclohexylcarbodiimide in 6.21 ethyl acetate are stirred at room temperature.

After 6 hours, the mixture is filtered and the solvent evaporated in vacuo. The residue, dissolved in 500 ml of toluene, is combined with the residue of a second batch of 310 g of the acid shown in Example 103 and 148 g of dicyclohexylcarbodiimide, also in 500 ml of toluene. The voreinigte solution is diluted with 11 toluene and heated to 60 ⁰ C. After stirring the inoculated mixture for 5.5 hours, the solid is filtered off, washed with 300 ml toluene and air dried to give 446 g (78.2%) of the title compound; F. 146-148 ⁰ C.

Anal. Calculated for C ₂₃ H ₂₀ F ₂ N ₄ O ₃

C63.01; H4.60; N12. '' 8 Found: C62.93; H4.81; N12.78.

Method B. A mixture of 4.3 g of the acid shown in Beis Diel 103 in 40 ml toluene is refluxed and the water formed is removed with a Deai-Stark trap. After 5 hours the product is filtered off, washed with toluene and air dried to yield 3.5 g of the title compound; F. 151-154 ° C.

Anal. Calculated for C ₂₃ H ₂₀ F ₂ N ₄ O ₃ :

C63.01; H4.60; N12.78 Found: C62.78; H4.64; N 12.72.

Example 106

3,3-Bis (4-fluoro-phenyl) -2- (2-triphenylmethyl-2-H-tetrazo! -5-yl) ethyl acrylate To a suspension of 0.64 g (16 mmol) of 50% sodium hydride in 7, 5 ml of dry dimethylformamide are added with 5.7 g (16 mmol of 3,3-bis (4-fluorophenyl) -2- (1H-tetrazol-6-y-ethylacrylate) and the resulting mixture is stirred for 30 minutes , 7 g (18 mmol) of bromotriphenylmethane are added and the mixture is stirred for 24 h The mixture is diluted with 20C ml of water and the insoluble matter is filtered off The product is recrystallised from ethyl acetate to give 6.1 g of the title compound: mp 161.degree.-162.degree (dec.).

Anal. Calculated for C ₃₇ H ₂₈ F ₂ N ₄ O ₂ :

C74.24; H 4.72; N9.36 Found: C74.31; H4.74; N9.63.

Example 107

3,3-bis- (4-fluoro-phenyl) -2- (2-tripheny! Methyl-2H-tetrazol-5-yl) allyl alcohol

To a stirred solution of 3 g (5 mmol) of ethyl 3,3-bis (4-fluoro-phenyl) -2- (2-triphenylmethyl-2H-tetrazol-5-yl) -acrylate in 50 ml of methylene chloride at -7O ⁰ C 10ml ( 15 mmol) of a 1.5 M solution of diisobutylaluminum hydride solution in methylene chloride, and the solution was stirred for 3 hours. The reaction is quenched with water and the mixture extracted with methylene chloride. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo to yield 2.1 g of the title compound; F. 176-178 ° C.

Anal. Calculated for C ₂₅ H ₂₆ F ₂ N ₄ O:

C75.53; H4.71; N10.07 Found: C75.75; H4.57; N 10.22.

Example 10b

S ^ bis-U-fluoro-phenyll ^^ - triphenylmethyl-ZH-tetrazol-S-yllacrylaldehyd

To a solution of 2.2 g (4, OmMoI) of 3,3-bis (4-fluoro-phenyl) -2- (2-triphenylmethyl-2H-tetrazol-5-yl! Allylalkoliol in 100 ml of methylene chloride are added 7 g of activated manganese dioxide After stirring the resultant mixture for 20 hours, the insoluble matter is filtered off and the filtrate concentrated in vacuo to give the title compound in quantitative yield, mp 208 ° C (dec.).

Anal. Calculated for C ₃₅ H ₂₄ F ₂ N ₄ O:

C75.81; H4.37; N10.11 Found: C73.56; H4.44; N9.54.

Example 109

5,5-bis- (4-fluoro-phenyl) -4- (2-1-pyrrolidinyl-2H-tetrazol-5-yl) -penta-2,4-dienal To a solution of 1.75 g (3.15 mmol) 3, 3-Bis- (4-fluoro-phenyl) -2- (2-triphenylmethyl-2H-tetrazol-5-yDacrylalder ·, d in 50ml of dry benzene 0.96g (3.15mMol) Triphenylphosphoranylidenacotaldehyd be added and the solution for 96 hours under . Ve refluxed solution was concentrated in vacuo and de residue was purified by chromatography on alumina (Alcoa Chemicals, grade F-20) eluted with 10% hexane in Essigester purified by evaporation of the appropriate fractions 0.95 g of the title compound are obtained;. F .122-124 ° C.

Anal. Calculated for C ₃₇ H ₂ 6F ₂ N ₄ O:

C76.54; H4.52; N9.65 Found: C75.84; H4.86; N9.46.

Example 110

9,9-bis- (4-fluoro-phenyl) -5-hydroiiy-3-oxo-8- (2-triphenylmet _J yl-2H-tetrazol-5-y!) Nona-6,8-diGnsäuretert-butyl ester 1.2 ml of a 0.5 M solution (0.6 mmol) of the dianion of acetoacetic acid tert-butyl ester, prepared as in Example 90, becomes a solution of 5,5-bis (4-fluorophenyl) -4 - (2-triphenylmethyl-2H-tGtrazol-5-yl) penta-2,4-dienal in tetrahydrofuran at -7O ⁰ C zugegeber .. After 2.5 hours stirring at -7O ⁰ C, the reaction is interrupted with a saturated ammonium chloride solution , The mixture is extracted with diethyl ether, the ethereal solution is dried over MgSO 4 and concentrated in vacuo to give the title compound as an oil, which is used without purification. MS: m / e = 738 for M *.

Example 111

Disodium (±) -erythro-9,9-bis (4-fluoro) -hexyl) -3,5-dihydroxy-8-; iH-tetrazol-b-yl) nona-6,87-dienoate

A. (±) -eryiliro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-O- (2-trir / henylmethyl-2H-tetrazol-5-yl) nona-6,8-dienoic acid -tertbutylester

To a solution of 2.8 g (3.8 mmol) of 9,9-bis (4-fluoro-pheriyl) -5-hydroxy-3-oxo-8- (2-triphenylmethyl-2H-tetrazol-3-yl) nona 3,8mL of a 1M solution of tri-butylborane in tetrahydrofuran are added at 0 ° C to tert-butyl 6,3-dienoic acid in tetrahydrofuran. After stirring for 0.5 hours, the solution is cooled to -70 ° C and 0.4 g (1OmMoI) of sodium borohydride and 2 ml of methanol are added. After 3 hours of stirring at -70 ° C, the reaction is stopped with water and the mixture extracted with diethyl ether. The extract 3 is dried over MgSO ₄ and concentrated in vacuo. The remaining gum is dissolved in 100 ml of methanol and the suspension is stirred overnight at room temperature. The methanolic solution is concentrated in vacuo to give 3.0 g of the title compound as a gum, which is used without further purification in the next step.

B. (±) -erythro-9,9-bis- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1H-tetrazol-5-yl) nono-6,8-diethac t-butyl ester

A solution of 0.8 g (1.08 mmol) of the compound shown in Step A in 50 ml of methanol is acidified with 3 ml of 1 N hydrochloric acid. After stirring for 2 hours at room temperature, the solution is concentrated in vacuo. The residue is washed several times with hexane and the residue is dried in vacuo to give 0.5 g of the title compound as a gummy solid, which is used in the next step without further purification.

C. Disodium (±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5-ilhydroKy-8- (1H-tetrazol-5-yl) nona-6,8-dienoate

The product of Step B is dissolved in 50 ml of ethanol and 2 ml (2 mmol) of 1 N sodium hydroxide solution added. After stirring at room temperature for 16 hours, the solution is concentrated in vacuo. The residue is dissolved in water and extracted with diethyl ether. The aqueous solution is concentrated in vacuo to yield 0.45 g of the title compound as a dry powder; F. 100-105 ^° C.

Example 112

3,3-Bis (4-fluoro-phenyl) -2- (1-methyl-tetrazol-5-yl) -aliphatic-phosphonic acid dimethylester A slurry of 1.17 g (3, OmMoI) 1,1-bis (4-fluoro) fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) propyl and 0.41 g (3.3 mmol) of trimethylphosphite is flashed for 5 minutes at 10 ° C. After cooling to room temperature, excess trimethyl phosphite is evaporated in vacuo, and e ¹ : hl is a light yellow solid. This solid is recrystallized from ethyl acetate / hexane to yield the title compound as a pure. ^! footwear; F. 140 to 141 ^° C.

IR (KBr) X ^ _13x : 1 604.1 511 cm "';

¹ N 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);

Anal. Calcd. for C ₁₉ H ₁₉ F ₂ O ₃ N ₄ P:

C, 54.29; H, 4.56; N, 13.33 Found: C, 53.83; H, 4.48; N, 13.50.

Example 113

(±) -erythro-9,9-bis (4-fluoro-phenyl) -3,5 · dihydroxy · 8 · (1-methyl · 1H · tetrazol-5-yl) nona-6,8 · -dienoic acid to a solution of 0.84 g (2, OmMoI) of the phosphonate prepared in example 112 is added at -78 ⁰ C (dry ice / Ace.cn) 1 equivalent of (2, OmMoI) butyllithium. The resulting deep red solution is stirred for 15 minutes at -78 ° C. 1,30g (2, OmMo!) Erythro-3,5-bis (diphenyl-tert-butylsiloxy) -6-oxohexanoic acid, ethyl ester (prepared according to the general procedure of P.Kapa et al., In Tetrahedron Letters, 2435-2438 (19841 et in U.S. Patent No. 4,571,428 issued to

18 February 1986 to P. Kapa) in 2 ml of THF are added and the mixture is stirred for 24 hours. Meanwhile, the reaction mixture is warmed to room temperature. The reaction is stopped by adding 5 ml of NH ₄ Cl and the mixture is extracted with 2 x 20 ml of ethyl acetate. The organic phase is dried over Na ₂ SO ₄ and evaporated in vacuo to a yellow oil. The oil is stirred with 4 ml of 1 M tetrabutylammonium fluoride solution in tetrahydrofuran containing a few drops of glacial acetic acid for 24 hours. The reaction mixture is poured into 20 ml of water and extracted with 3 χ 20 ml of methylene chloride. The organic phase is dried over Na ₂ SO ₄ , concentrated, and the resulting oil purified by flash silica column chromatography eluting with ethyl acetate / hexane Vi to give 0.284 (41%) of the title compound as an oil. MS (Cl): m / e = 471 for (M + H) *;

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 114

1- (4-iluor-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-phenylethanol

A solution of 29,25g (0,298Mol) 1.5-Dimethyl-teirazol in 400ml of dry THF is cooled to -78 ⁰ C and treated for 30 minutes by 133ml (0.3325 mol) of a 2.5M solution of butyllithium in hexane. The mixture is stirred at -78 ° C for 30 minutes and treated with 50 g (0.25 mole) of 4-fluoro-benzophenone. The mixture is stirred at -78 ° C for 30 minutes and warmed to room temperature over 2 hours. The reaction is stopped with 100 ml 2 η HCl and the organic solvent evaporated. The residue is extracted with 2 x 100 ml CHCl ₃ and the precursors are dried over Na ₂ SO ₄ and evaporated to a brown oil. Purification by chromatography with 20% EtOAc in hexane as eluent yields the title compound as a white solid (46.3g, 62%). F. 113-114 ⁰ C (recrystallized from EtOAc-hexane). MS (Cl): m / e = 299 for (M + H) ⁺ ;

IR (KBr) £, ": 3300 (br), 1605,1510cm" ';

¹ HNMRo: 7.34-7.15 (m, 7H), 6.5) 3 (m, 2H), 4.93 (s, 1H), 3.73 (s, 2H), 3.67 (s, 3H) ppm;

¹³ C NMR δ: 163.57,160.29,152.28,144.94,141.12,141.08,128.43,127.87,127.75,127.67,125.76,115.25,114.96, 77.03,35.82, 33.45 ppm;

Anal. CaICdJOrCi ₆ H ₁₅ FN ₄ O:

C, 64.42; H, 5.0 /, <V, 18.79 Found: C, 64.32; H, 5:05; N, 18.84

Example 115

(E) -1- (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-phenylelene and (Z) -1- (4-fluoro-phenyl) -2- (1-methyl-1H-t3-trazol-5-yl) -1-phenylethene

A mixture of 3.2 g (10,74mMol) of Example Tetrazolylethanols and 114 shown 800ml potassium hydrogen sulfate is heated to 195 ⁰ C for 30 minutes. After cooling to 100 ° C, 30 ml of chloroform are added and the mixture triturated until most of the solid has dissolved. The insoluble inorganic material is filtered off and the solvent evaporated to give a mixture of the title compounds as a tan solid (2.8 g, 93%). The mixture is recrystallized from FItOAc hexane. MS (Cl): m / e = 281 for (M + H) ⁺ ;

IR (KBr) ^ _9x : 1640,1600,1510,1445,1220cm "¹;

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

' ³ C NMR δ: 165.19,164.58,161.26,153,14,152.97,152.22,152,13,140.53,137.81,136.71,133.99,133.94,131.74,131.62,130.30, 129.67,129.29,128.85,128.65,128.38,115.97,115.74, 115.66.115.45,108.29,108.15,33.70 ppm;

Anal. Calcd. for C ₁₆ H ₁₃ FN ₄ :

C, 68.56; H, 4.68; N, 19.99 Found: C, 68.63; H, 4.77; N, 20:37

Example 116

(E) -3- (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) -3-phenylpropenalund (Z) -3- (4-fluoro-phenyl) -2- ( 1-methyl-1H-tetrazol-5-yl) -3-phenyl-propenal

A suspension of 20 g (71.4 SmMoI) of the olefin described in Example 155 in 200 mL of dry THF is cooled to -78 ° C and treated with 31.5 mL (78.75 mmol) of a 2.5M solution of butyllithium in hexane and the resulting mixture is stirred for 30 minutes at -78 ⁰ C stirred. Then 6.9 g (93 mmol) of ethyl formate are added and the mixture stirred for 2 hours at -78 ⁰ C and then heated to 23 ° C within 1 hour, the reaction is stopped with 100ml 2 η HCl, the organic solvent evaporated and the residue with 3x 75ml EtOAc extracted. Dry the combined organic layers over MgSO ₄ , evaporate, and purify the residue by chromatography with 35% EtOAc in hexane as the eluent to give the title compound as the gum of the aldehydes (7.75 g, 35%). MS (Cl): m / e = 309 for

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 117

(E, E) -5- (4-Fluoro-phenyl-4- (1-methyl-1H-tetrazol-5-yl) -5-phenyl-penta-2,4-dienal A mixture of 5.1 g ( 16.56 mmol) of the aldehyde gum shown in Example 116 and 5.05 g (16.56 mmol) of formylmethylenetriphenylphosphorane in 200 ml of benzene is refluxed for 2 hours in a nitrogen atmosphere

Solvent! is evaporated and the residue purified by chromatography with 30% EtOAc in hexane as eluent to give the product as an orange foam (4.56 g). Fractional crystallization from EtOAc-hexane gives the title compound as orange crystals (0.93 g, 17%); F. 137-138 ⁰ C (recrystallized 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 CNMR δ: 192.54,147.86,132.09,131.97,130.64,130.41,128.96,116,17,115.87,33.62ppm.

Example 118

(E, E) -9- (4-fluoro-phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -9-phenyl-3-oxo-nona, 68-dienoic acid ethyl ester Suspension of 175mg &, 83mMol) of an 80% dispersion of sodium hydride in 10ml dry THF is cooled to 0 ° C and treated with 725μΙ (740mg, 5.69 mmol) acetoacetic ester and stirred at 0 ⁰ C for 10 minutes. 2.3m! (5.7 BmMoI) of a 2.5M solution of butyllithium are added and the solution stirred at ⁰ C for 15 minutes. Then a solution of 860mg (2,57mMol) is added to the Adehyds illustrated in Example 117 in 10 ml of dry THF and the mixture stirred 15 minutes at 0 ⁰ C. The reaction is stopped by addition of 30 ml 2 η HCl and the organic solvent evaporated. The residue is extracted with EtOAc and the combined organic extracts are dried over MgSO ₄ and evaporated. The residue is purified by chromatography with 40% EtOAc in hexane as eluent to give the title compound as a yellow gum (954 mg, 80%). MS (Cl): m / e = 465 for (M + H) ⁺ ;

IR (film) i7 _max : 3400 (br), 1730,1600, 1510cm "¹;

1 ^H NMR δ: 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 119

(±) - (E, E) Erythro-9- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -9-phenyl-nona- 6,8-dienoic acid ethyl ester a solution of 950mg (2,045mMol) of example 118 shown ß-keto ester in 20 ml of dry THF is treated with 2,25ml (2.25 mmol) of a 1M solution of triethylborane in THF and 1 hour at 23 ⁰ C. touched. Then 400μΙ methanol are added and the solution au. 78 ⁰ C cooled and treated with 200mg (5.26 mmol) NaBH ₄ . After 1 hour, the reaction is stopped by adding 2N HCl and the organic solvent is evaporated. The residue is extracted with EtOAc and the combined organic extracts are dried over MgSO ₄ and evaporated. The residue is purified by chromatography with 60% EtOAc / 40% hexane as eluent to give the title compound ice-yellow gum (330 mg, 35%). MS (Cl): m / e = 467 for (M + H) ⁺ ;

IR (KBr) V ₁₇₁₈₁₁ : 3400 (br), 1725, 1600, 1500cm "';

Ή NMR δ: 7.30-6.80 (m, 9H), 6.70 (dd, J = 1.0Hz, J '= 15.6Hz, 1H), 5.35 (dd, J = 5.9Hz, J' = 15.7Hz, 1H) , 4.41 (m, 1 H), 4.25 (br s, 1 H), 4.15 (q, J = 7.1 Hz, 2H), 3.83 (br m, 2H), 3.52 (s, 3H), 2.45 (d, J = 6.1 Hz, 2H), 1.60 (m, 2H), 1.26 (t, J = 6.1 Hz, 3H) ppm;

¹³ C NMR δ: 172.40,164.47,161.17,153.66,148.07,139.94,138.21,137.75,135.55,132.40,132.30,130.36,129.82,129.46,128.67, 128.47,127.29,121.05,115,74,115.45,71.89,69.35, 68.34 , 60.83,60.34,42.34,41.53,4 i.22,33.56,14.13ppm.

Example 120

Sodium (±) - (E, E) -6rythro-9- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -9-phenyl- Nona-6,8-dienoate hydrate To a solution of 160 mg (0.343 mmol) of the dihydroxy ester shown in Example 119 in 5 mL EtOH is added 343 μΙ (0.343 mmol) 1 N NaOH and the resulting solution is incubated at 23 ° C for 1 h touched. The solvent is evaporated and the residue is dissolved in 2 ml of water and lyophilized to give the title compound as a tan solid (155 mg); F. 130-137 ⁰ C.

IR (KBr) _mu 3: 3400 (br), 1560,1510cn. ";

'HNMR (DMSO-d _e ) δ: 7.50-6.80 (m, 9H), 6.51 (d, J = 15.7Hz, 1H), 5.15 (dd, J = 5.4Hz, J' = 15.7H *, 1 H ), 4.15 (m, 1H), 3.70 (s, 3H), 3.65 (br, 1H), 3.35 (2H), 1.95 (m, 2H), 1.40 (m, 2H) ppm;

' ³ C NMR (DMSOd ₆ ) 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, 44.46,43.59,33.42ppm.

Anal. Calcd. for C ₂₃ H ₂₂ FN ₄ Na H ₂ O:

C, 57.74; H, 5.06; N, 11.72 Found: C, 58.70; H, 5.10; N, 11.16.

Example 121

2- (1-methyltetrazol-5-yl) -1,1-diphenylethanol

A solution of 20 g (0.204 mol) of 1,5-dimethyl-tetrazole in 200 ml of dry THF is cooled to -78 ° C and treated with 91 ml (0.227 mol) of a 2.5M solution of butyllithium in J-ipxan and the mixture 30 Stirred Boi -78 ° C minutes. Then 31.1g (0,171MoI) of benzophenone are added and the mixture stirred 30 minutes at -78 ⁰ C, warmed to 23 ⁰ C and gorührt 15 hours.

The reaction is stopped with 100 ml 2 η HCl and the mixture is extracted with 3 × 150 ml EtOAc. The combined organic phases are dried over MgSO ₄ and evaporated. The residue is recrystallized from EtOAc-hexane to yield the

Title compound as a white solid (10.5 g, T 2%); F. 175-176 ⁰ C (recrystallized from EtOAc-hexane). MS (CI): m / e = 281 for (M + H) ⁺ ;

IR (KBr) 0 _m ": 3300 (br), 1530.1 δΟΟατΓ 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;

Anal. CaICdJOrC ₁₆ H ₁₆ N ₄ O:

C, 68.56; H, 5.76; N, 20.00 Found: C, 68.62; H, 5.81; N, 20.10.

Example 122

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

A mixture of 2.15 g (7.68 mmol) of 2- (1-methyltetrazol-5-yl) -1,1-diphenylethanol and 300 mg of KHSO ₄ is heated to 200 ° C for 20 minutes. The cooled to 5O ⁰ C mixture is triturated with 50ml CHCl ₃ and the organic solvent abdekantiart of the inorganic residue. Evaporation gives the title compound as a cream solid (1.7 g, 85%); F. 147-148T (recrystallized from EtOAc-hexane). MS (Cl): m / e = 263 for (M + H) *;

IR (KBr) vLx: 1640, 1500, 1445cm- ¹ ;

¹ H NMR δ: 7.50-7.00 (m, 10H), 6.78 (s, 1H), 3.43 (s, 3H) opm;

¹³ C NMR δ: 153.94, 152.18, 140, 40, 137, 83, 129, 64, 129.3. ¹ .128.94,128.59,128.38,128.28,108.22,33.56ppm.

Anal. Calcd. for C ₁₆ H ₁₄ N ₄ :

C, 73.27; H, 5.38; N, 21.36 Found: C, 73.25; H, 5.43; N, 21.43.

Example 123

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

A solution of 3.75 g (14,29mMol). '.', 2-diphenyl-1- (1-methyl-1 H-tetrazol-5-yl) ethene in 40 mL of dry THF is cooled to -78 ⁰ C and treated with 63 ml (15.75 mmol) of a 2.5M solution of butyllithium in hexane. The resulting mixture is stirred for 30 minutes at -78 ° C. Then 1.5 ml (18.58 mmol) of ethyl formate are added and the mixture is stirred at -78 ° C. for a further 2 hours. The reaction is stopped with 2 η HCl and the solvent evaporated. The residue is extracted with 3 x 30 ml EtOAc and evaporated. The residue is purified by chromatography with 25-35% EtOAc in hexane as eluent to yield 1.35 g (36%) of starting material and 1.65 g (39%) of the desired title compound; F. 185-186 ⁰ C (recrystallized from EtOAc-hexane). MS (El): m / e = 290 for M *;

IR (KBr) I? _m ": 1675, 800, 1445 cm"¹;

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

' ³ C NMR δ: 189.45,167.79,151.44,138.35,136.65, 131.54,131.34,130.96,129.63,128.71,123.55,33.91 ppm /

Anal. Calcd. for C ₁₇ H. ₄ N ₄ O:

C 70.34; H, 4.87; N, 19.30 Found: C, 70.63; H, 4.99; N, 19.33.

Example 124

(E) -4- (1-methyl-1H-tetrazol-5-yl) -5,5-diphenyl-2,4-dienal-Peita

A solution of 1.33 g (4.57 mmol) of the aldehyde prepared in Example 123 and 1.5 g (4.87 mmol) of triphenylphosphoranylidene acetaldehyde is refluxed in 50 ml of benzene for 24 hours. The solvent is evaporated and the residue purified by chromatography with 30% EtOAc in hexane as eluent to give the title compound as a yellow foam (1 o, 71%). MS (CI): m / e = 317 (M + H) *;

'HNMRÖ: 9.53 (d, J = 7.5Hz, 1H), 7.65-7.10 (m, 10H), 6.69 (d, J = 16Hz, 1H), 5.84 (dd, J = 16Hz, J' = 7.5Hz, 1H ), 3:50 (s, 3H) ppm

Example 125

(E) -9,9-Diphenyl-3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -nona-6,8-dienoic acid methyl ester 0.525 ml (4.87 mmol) of methyl acetoacetate become a Suspension of 0.160 g of an 80% dispersion of sodium hydride in mineral oil in VHF at ^{0 0} C was added and stirred for 10 minutes. Then 2.14 ml of a 2.5M solution of butyllithium in hexane are added and the reaction is stirred for 15 minutes. This solution is added to a solution of 1.0 g (3.2 mmol) of the aldehyde prepared in Example 124 in THF at ⁰ ° C. and stirred for 30 minutes. The reaction mixture is treated with 30 mL of 2N HCl and extracted with 3x 15 mL EtOAc. The organic phase is dried over MgSO ₄ and evaporated. The crude residue is triturated with 3x 25 ml of hexane, then dissolved in 20 ml of THF / CH 3 OH (4: 1) and treated with 3.2 ml of a 1 M solution of triethylborane in THF. Then, air is bubbled through the solution for 10 minutes and the reaction mixture is stirred for a further 50 minutes. Then, the solution is cooled to -78 ° C and treated with 120mg (3.2mMol) of sodium borohydride and stirred for 1 hour. The reaction is stopped with 100 ml 2M HCI and the mixture with

3x 20ml eggOAc extracted. The organic phases are dried over MgSO ₄ and evaporated. The residue is dissolved in ¹ l of 30 ml of CH ₃ OH and stirred for 15 hours. The solvent is evaporated and the residue is purified by chromatography with 50% EtOAc-hexane as eluent to give the title compound as a yellow oil (470 mg, 33%). MS (Cl): m / e = «5 (M + H) ⁺ ;

¹ H NMR δ: 7.80-6.80 (m, 10H), 6.71 (d, J = 16Hz, 1H), 5.34 (dd, J = 16Hz, J '= 6Hz, 1H), 4.60-4.10 (m, 2H), 3.70 (s, 3H), 3.52 (s, 3H), 2.45 (d, J = 6Hz, 2H), Ί.70-1.50 (m, 2H) ppm.

Example 126 Sodium ltl-IEI-erythro-d.s-üiphenyl-d.s-dihydroxy-e-li-methyl-IH-tetrazol-S-yllnona-e.e-dienoate hydrate

470 mg (1.08 mmol) of the methyl ester prepared in Example 125 are dissolved in 10 ml of ethanol and treated with 1.08 ml of 1N NaOH. The reaction mixture is stirred for 1 hour. The solvent is evaporated and the residue is freeze dried to give a light yellow powder (500 mg, 100%); F. 145-15O ⁰ C.

IR V _max : 3400 (br), 1610.1425.1 360cm "';

'HNMR (DMSO-d ₆ ) δ: 7.60-6.60 (m, 10H), 6.52 (d, J = 16Hz, 1H), 5.12 (dd, J = 16Hz, J' = 5.5Hz, 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.

Anal. CaICD JOrC ₂₃ H ₂₃ N ₄ O ₄ Na H ₂ O:

C, 59.99; H, 5:47; N, 12.17 Found: C, 59.18; H, 5.46; N, 10.96.

Example 127

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

A solution of 20 g (0.204 mol) of 1,5-dimethyl-tetrazole in 200 ml of dry THF is cooled to -78 ° C and treated with 91 ml (0.227 mol) of a 2.5M solution of butyllithium in hexane and the mixture at 30 minutes -78 ° C stirred. Then 41.3 g (0.171 mol) of 4,4'-dimethoxy-benzophenone are added and the mixture stirred for 30 minutes at -78 ⁰ C and then heated to 23 ° C within 2 hours. The mixture is acidified with 100 ml of 2 N HCl and the organic solvent is evaporated. The residue is extracted with 3x 300 ml EtOAc and the combined organic phases are dried over MgSO ₄ and evaporated. The residue is recrystallized from EtOAc-hexane to yield 48 g of a tan solid which is obtained as a mixture of the desired product and the starting aldol adduct 1,1-bis- (4-methoxyphenyl) -2- (1-methyl-1 H-). tetrazol-5-yl) ethanol. This mixture is dissolved in 180 ml of xylene and refluxed with p-toluenesulfonic acid in a Dean-Stark apparatus for 1 hour. The cooled mixture is diluted with 100 mL of ether and the resulting solid is filtered off to give 40 g of the title compound as a cream solid; F. 146-147 ⁰ C (recrystallized from EtOAc-hexane). MS (Cl): m / e = 323 for (M + H) ⁺ ;

IR (KBr) V _n ,,,: 1605,1520,1250cm "';

¹ HNMRo: 7.31 (d, J = 7.8Hz, 1H), 6.S8 (d, J = 7.8Hz, 1H), 6.90 (d, J = 7.8Hz, 1H), 6.81 (d, J = 8.6Hz, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.42 (s, 3H) ppm;

' ³ C NMR δ: 160.79,160.16,153.29,133.33,131.25,130.32,129.95,127.36,114.14,113.60,105.57,55.40, 55.28,? 3: 1 ppm.

Anal. Calcd. for C ₁₈ H ₁₈ N ₄ O ₂ :

C, 67.07; H, 5.63; N, 17.38 Found: C, 66.93; H, 5.63; N, 17.05.

Example 128

propenal 3,3-bis- (4-methoxy-phenyl) -2- (1-methyl-1H-tetrazol-5-yl)

A solution of 4.6 g (14.29 mmol) of the olefin prepared in Example 127 in 50 mL of dry THF is cooled to -78 ° C and treated with 6.3 mL (15.75 mmol) of a 2.5 L solution of butyllithium in hexane and the resulting solution was stirred for 30 minutes at -78 ⁰ C. Then, 1.5 ml Ameisensäureethylesterzugesetzt and the mixture a further 2 hours at -78 ⁰ C is stirred. The reaction is stopped with 2 η HCl and the organic solvent evaporated. The residue is extracted with 3x 30 mL EtOAc and the combined organic phases are dried over MgSO ₄ and evaporated. The residue is purified by column chromatography with 25-35% EtOAc in hexane as eluent to give 0.84 g (18%) of starting material. Further elution provides the desired title compound (1.78 g, 36%); F. 130-131 ⁰ C (recrystallized from EtOAc-hexane). MS (Cl): m / e = 351 for (M + H) ⁺ .

IR (KBr) ^ a *: 1675,1605,1515,1260cm "';

¹ HNMRo: 9.59 (s, 1H), 7.30 (d, J = 8.6Hz, 1H), 7.00 (d, J = 8.7Hz, 1H), 6.90 (d, J = 8.9Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H) ppm;

' ³ C NMR δ: 189.51,167.47,162.59,161.98,152.30,133.91,132.29,130.79,129.35,121.05,114.20,114.15, 55.80, 55.40,33.94ppm.

Anal. CaICdJOrCx) H ₁₉ N ₄ O ₃ :

C, 65.14; H, 5.18; N, 15.99 Found: C, 64.96; H, 5.22; N, 15.75.

Example 129

A solution of 1.7 g (4.86 mmol) of 3,3-bis- (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal in 100 ml of benzene is charged with 1.55 g (5.1 mmol) Triphenylphosphoranylidenacetaldehyd treated and boiled under reflux for 3 hours. The solvent is evaporated and the residue is purified by chromatography with 30% EtOAc in hexane as eluant to give the title compound as a yellowish extract. is obtained (1.35g, 74%). MS (Cl): m / e: 377 for (M + H) *;

IR (KBr) V _max: 1675,1590,1 510cm ^"1;

'HNMR6: 9.52 (d, J = 7.6Hz, 1H), 7.53 (d, J = 14.2Hz, 1H), 7.23 (d, J = 8.5Hz, 1H), 7.00 (d, J = 9.3Hz, 1 H), 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;

¹³ CNMRo: 192.89,161.40,160.97,157.91,153.29,149.41,133.90,132.77,132.29,132.00,131.71, 131.65, 131.25,130.81,117.21, 114.18,114.12, 55.49,55.32,33.61 ppm.

Example 130

(E) -9,9-Bis (4-methoxyphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6,8-dienoic acid ethyl ester a suspension of 206mg of a 80% dispersion of NaH (6,86mMol) in 20 ml of dry THF at 0 ° C 825μΙ; acetoacetic ester was added and stirred the resultant mixture for 10 minutes at O ⁰ C (842mg 6,48mMol). Then 2.7 ml (6.75 mmol) of a 2.5M solution of butyllithium in hexane are added and the mixture is stirred at ⁰ ° C. for a further 10 minutes. Thereafter, a solution of 1.3 g (3.46 mmol) of the aldehyde prepared in Example 129 in 20 ml of dry THF is added and this mixture is stirred for a further 15 minutes at 0 ^° C. After addition of 2N HCl to stop the reaction, the solvent is evaporated. The residue is diluted with 30 ml of water, extracted with 2x 20 ml EtOAc and the combined organic phases dried over MgSO ₄ and evaporated. The residue is purified by chromatography with 40% EtOAc in hexane as eluent to afford the title compound as a yellow foam (1.165 g, 66%).

IR (KBr) ^ _x : 3450 (br), 1 750, 1710, 1610, 1 510 cm "';

¹ H NMR δ: 7.30-6.60 (m, 9H), 5.27 (dd, J = 6.1 Hz, J '= 15.9Hz, 1H), 4.68 (brs, 1H), 4.14 (q, J = 7.1Hz, 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)

¹³ CNMRo: 202.48.160.C9.159.70,154.16,149.40,134,16,132.57,132.14,131.99,131.22,129.08,118.34,113.79, 68.17,61.47, 55.17,49.94,49.33,33.56,14.09 ppm.

Example 131

(±) - (E) -erythro-9,9-bis- (4-methoxy-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,3 A solution of 1 g (1.97 mmol) of the β-ketoester shown in Example 130 in 50 ml of dry THF and 300 μM of methanol is treated with 2.15 ml of a 1M solution of triethylborane in THF and the mixture is stirred for 1 hour stirred at 23 ⁰ C. The solution is then cooled to -78 ° C and treated with 110 mg (2.92 mmol) NaBH ₄ . After 'hour at -78 ⁰ C, the reaction is stopped with 2 η HCl and the solvent was evaporated. The residue is diluted with Ws.jer and extracted with 3x 30 mL EtOAc.

The combined organic extracts are dried over MgSO ₄ and evaporated. The residue is purified by chromatography to give the title compound as a pale oil (136mg).

IR (KBr) 1? _max : 3,450 (br), 1 750,1710,1610,1 510cm " ¹ .

¹ H NMR δ: 7.70-6.50 (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 (t, 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, 132.11,131.90,131.51, .31.22,128.59, 128.41,128.36,118.97,113.90,113.34, 72.15, 66.31, 60.75, 55.35, 55.20.42.74,42.14,41.73,41.48,33.50,14.18.

Example 132

Natrirιm - (+) - (E) -erythro-9,9 · bis (4 · methoxyphenyl) -3,5-dihydroxy-8- (1-methyl · 1H-tetrazol-5-yl) nona-6, 8-dienoate dihydrate a solution of 95mg (0,196mMol) of example 131 in the illustrated ester in 15 ml ethanol is treated with a 1 196μΙ η NaOH solution and the mixture stirred for 1 hour at 23 ⁰ C. Then the solvent is evaporated and the residue is dissolved in 2 ml of water and lyophilized to give the title compound as a brown powder (95 ml, 100%); F. 175-180 ⁰ C.

IR (KBr) 1? _max : 3400 ibr), 1600, 1575, 1510 cm "¹;

Ή NMR (DMSO-d ₆ ) δ: 7.70-6.65 (m, 9H), 6.55 (d, J = 15.5Hz, 1H), 5.08 (dd, J = 5.6Hz, J '= 15.7Hz, 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 ₆ ) δ: 1.59.25, 158.80, 153.7, 138.13.132, 75.131, 88.131, 60.131, 42.131, 30, 130, 41, 128, 68, 128, 53, 125, 72, 113, 74, 113, 48, 68, 56, 65, 89, 55, 14, 54.99, 44.68,43.68,33.34.

Anal. Calcd.forC ₂₆ H ₂₇ NaN ₄ Oe 2H ₂ O:

C, 55.76; H, 5.81; N, 10:41 Found: C, 54.43; H, 5.04; N, 8.15.

Example 133

methyl 2,2-dimethyl-6- (2-phenyl-ethenyl) -1,3-dioxan-4-yl-acid methyl ester 2.37 g (9.48 mmol) of S. ö -dihydroxy-phenyl-hept-C-enoic acid methyl ester ( 98% diastereomeric purity) are stirred with 2,2-dimethoxypropane (20 ml) and a catalytic amount of p-toluenesulfonic acid for 16 hours. The solution is partitioned between diethyl ether and dilute aqueous sodium bicarbonate solution.

The organic phase is dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow solid. After recrystallization from diisopropyl ether, 1.70 g (62%) of the title compound are obtained as a white solid; F. 84-86.5 ° C.

It is also possible to add 0.2 g of solid sodium carbonate to the 2,2-dimethoxypropane solution and to vigorously stir the solution. The solution is filtered through a moistened filter paper. The excess 2,2-dimethoxypropane is evaporated in vacuo to give a yellow solid which is recrystallized from diisopropyl ether.

¹ H NMR (CDCl ₃ ) δ: 7.37-7.19 (5H, m), 6.59 (1H, m), 4.42-4.35 (1H, m), 3.68 (3H, s), 2.58 (1H, d, J = 15.6 , 6.9Hz), 2.14 (1H, dd, J = 15.6, 6.3Hz), 1.74-1.61 (1H, m), 1.52 (3H, s), 1.43 (3H, s), 1.45-1.35 (1H, m) ,

Anal. CaICdJOrC ₁₇ H ₂₂ O ₄ :

C, 70.32; H, 7.63 Found: C, 70.24; H, 7.69.

Example 134

cis-2,2-dimethyl-6- (2-phenyl-ethyl) -1,3-dioxane-4-yl acetic acid

A solution of 8.5 g (29.3 mmol) of 2,2-dimethyl-6- (2-phenylethyl) -1,3-dioxan-4-ylacetic acid methyl ester in 32 ml of 1N NaOH and 64 ml of methanol is refluxed for 45 minutes , After evaporation in vacuo, the aqueous solution is washed once with diethyl ether and acidified with 33 ml of 1 η HCl. The precipitate is separated and recrystallised from ethyl acetate-diisopropyl ether to give 7.2 g (90%) of the title compound as a colorless solid; F. 153-155 ° C.

¹ H NMR (CDCl ₃ ) 0: 7.37-7.20 (5H, m), 6.60 (1H, d, J = 16.0Hz), 6.14 (1H, dd, J = 16.0.6.3Hz), 4.59-4.54 (1H, m), 4.43-4.35 (1H, m), 2.62 (1H, dd, J = 16.0.7.2Hz), 2.51 (1H, dd, J = 16.0, 5.3Hz), 1.77-1.72 (1H, m), 1.54 (3H, s), 1.46 (3H, s), 1.50-1.36 (1H, m).

Anal. Calcd. for C ₁₆ H ₂₀ O ₄ :

C, 69.54; H, 7.30 Found: C, 69.20; H, 7.33.

Example 135

Separation of cis-2,2-dimothyl-6- (2-plienyl-ethyl) -1,3-dioxan-4-ylacetic acid 0.31 g (1.1 mmol) of the racemic cis-2,2 shown in Example 134 Dimethyl 6- (2-phenyl-ethyl) -1,3-dioxan-4-ylacetic acid are dissolved in a boiling solution of (1S, 2R) -ephedrine (0.2 g, 1.1 mmol) in hexane-ethanol , The resulting solution is slowly cooled to room temperature and provides 0.21 g (41.4%) of colorless chiral salt (In the resolution is recommended the use of a diastereomerically pure seed crystal): mp 170-171 ⁰ C.

The chiral acid is by acid work-up (see below) released and the enantiomeric purity determined by 'H-NMR with L-Phenyltrifluormethylcarbinol as a chiral solvent to 1C0%, [al "+ 5.45 ° (c = 1, CHCI _3).

Example 136

cis- (4R, 6S) -2,2-dimethyl-6-formyl-1,3-dioxane-4-yl acetic acid

6.6g (14.9 mmol) of the dissolved salt of (1S, 2R) -ephedrine shown in Example 135 and cis-2,2-dimethyl-6- (2-phenylethyl) -1,3-dioxan-4-ylacetic acid is partitioned between 30 ml of 0.5 N HCl and diethyl ether. The ethereal phase is washed with pumice, dried over MgSO ₄ / Na ₂ SO ₄ and concentrated in vacuo to yield 4.1 g (99.6%) of the free acid. This acid is dissolved in 100 ml of dry methylene chloride and passed through this solution at -78 ° C ozone until a dark blue color appears. Excess ozone is removed by rinsing with nitrogen, and the ozonide formed is decomposed by adding 5 ml of dimethyl sulfide and heating the solution to room temperature, and allowing the mixture to stand for 16 hours. The solution is concentrated in vacuo and the residue is dissolved in diisopentyl ether (about 100 ml). The benzaldehyde formed in the ozonolysis is distilled off azeotropically together with the diisopentyl ether in vacuo, so that the title compound remains.

¹ H NMR (CDCl ₃ ) δ: 9.57 (1H, s), 4.40-4.30 (2H, m), 2.60 (IH, dd, J = 16.0.7.0Hz), 2.49 (1H, dd, J = 16.0, 6.0 Hz), 1.88-1.83 (1H, m) 1.49 (3H, s), 1.46 (3H, s), 1.42-1.31 (1H, m).

Example 137

cis- (4R, 6S) -6- [4,4-bis- (4-fluoro-phenyl) -3- (1-mothyl-1H-tetrazol-5-yl) buta-1,3dienyl] -2,2 -dimethyl-1,3-dioxan-4-ylacetic acid The crude chiral acid of Example 136 is dissolved in 50 ml of dry THF and the solution placed in a nitrogen-purged 250 ml three-necked flask with stirrer. After cooling to -78 ° C 5.96 ml of a 2.5 M solution of butyllithium in hexane is added dropwise with vigorous stirring. Towards the end of the addition, the solution turns into a white gelatinous suspension.

To a second flask containing 6.2 g (14.7 mmol) of the 3,3-bis (4-fluoro-phenyl) -2- (1-methyl-1H-tetrazole-5-one shown in Example 112). yl) allylphosphonic acid dimethyl ester in 50 ml of THF under a nitrogen atmosphere, are slowly added at -78 ⁰ C 5.96 ml of a 2.5 M solution of butyllithium in hexane. The resulting red-brown solution is stirred for 15 minutes at -78 ⁰ C. This solution of Phosphonatanionb is transferred via a cannula at -78 ⁰ C in the vigorously stirred suspension of the lithium salt of the chiral acid. After addition, the resulting brown solution for 30 minutes at -78 ⁰ C and 16 hours at room temperature is stirred. The solution in THF is distributed between 0.5 η HCl and ethyl acetate. The organic phase is washed twice with pumice, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is chromatographed on silica gel (diethyl ether / hexane / acetic acid 66/33/1) and gives 3.8 g (51.6% overall yield, based on the

Output ephedrine salt; the acetic acid residue is distilled off azeotropically with toluene) of the title compound as a yellow foam.

(dg ⁵ = + 106.1 ° (c = 2.23, CHCl ₃ ).

¹ HNMR (CDCl ₃ ) δ: 7.24-6.82 (8H, m), 6.62 (1H, d, J = 15.0 Hz), 5.32 (1H, dd, J = 15.0.5.7 Hz), 4.42-4.37 (1H, m ), 4.30-4.23 (1H, m), 3.51 (3H, s), 2.53 (1H, dd, J = 15.9.7.0 Hz), 2.42 (1H, dd, J = 15.9.5.6 Hz), 1.62-1.57 ( 1H, m), 1.46 '3H, s); 1.33 (3H, s), 1.30-1.20 (1H, m).

Example 138

trans- (4R, 6S) -6- [4,4-bis- (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyl] -4 -hydroxy-tetrahydropyran-2-one 3.7 g (7.45 mmol) cis- (4R, 6S) -C- [4,4-bis (4-fluoro-phenyl) -3- (1-methyl-1H tetrazol-5-yl) buta-1,3-dienyl) -2,2-dimethyl-1,3-dioxan-4-ylacetic acid are dissolved in a mixture of 90 ml of THF and 60 ml of 0.2 N HCl and allowed to stand for 16 hours. The solution is partitioned between ethyl acetate and water. The organic phase is washed 2 χ with pumice, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is dissolved in 60 ml of dry methylene chloride and stirred for 4 hours in the presence of 6.6 g (15.6 mmol) of 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide-methac-p-toluenesulfonate. The solution is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is dried over Na ₁ SO ₄ and concentrated in vacuo. The residue is purified by chromatography on silica gel (ethyl acetate / diethyl ether 1/1). After recrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the title compound are obtained as a solid solid; F. 172-173X. a = + 237.8 ° (c = 2.17, CHCl ₃ ).

Example 139

3-hydroxy-5-oxo-deca-6,8-diensäuremethylester

To a cold solution (-3O ⁰ C) of 41.5 g (357 mmol) of ethyl acetoacetate in 500 ml of THf is added 476 ml of a 1.5M solution of lithium diisopropylamide in cyclohexane (714 mmol). The resulting solution is stirred for 15 minutes at -30 ° C. After cooling to -78 ⁰ C 34,3g (357 mmol) are hexa-2,4-dienal was added and the solution stirred for 10 minutes at -78X and 16 hours at room temperature. The solution is concentrated in vacuo and the remaining syrup is distributed between 1 η HCl and ethyl acetate. The organic phase is washed twice with pumice, dried over Na ₂ SO ₄ and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate / hexane 2/1) to yield 18.5 g (24.4%) of the title compound as an oil.

¹ H NMR for (E), (E) -Icomer (200 MHz, CDCl ₃ ) δ: 6.3 (1 H, dd, J = 14.7, 11.9 Hz), 6.02 (1 H, dd, J = 14.7, 11.9 Hz) , 5.75 (1H, dq, J = 14.7.6.4Hz), 5.5 (1H, dd, J = 18.7.6.4Hz), 4.74-4.5 (1H, m) 3.73 (3H, s), 3.51 (2H , s), 2.6 (2H, d, J = 5.8Hz), 1.77 (3H, d, J = 6.4Hz).

Example 140

S, S-dihydroxy deca-e.e. diensäut'emethylester

To a cold solution (-15 ⁰ C) of 18.5 g (86,9mMol) 3-hydroxy-5-oxo-deca-6,8-diensäuremethylester in 300ml THF 113ml (11SmMoI) of a 1M solution of triethylborane in THF and the solution stirred for 20 minutes. After cooling the mixture 6g (159 TiMoI ¹⁾ NaBH ₄ and 37,5ml methanol to -78 ⁰ C zugegpben. The solution is stirred vigorously at -78 ° C for 30 minutes and at room temperature for 3 hours. The solvent is evaporated in vacuo and the residue is partitioned between 1 N HCl and ethyl acetate. The organic phase is dried over Na ₂ SO ₄ and concentrated. The residue is purified by chromatography on silica gel (diethyl ether / hexane 3/1) to give 7.95 g (42.7%) of the title compound as a yellow

¹ H NMR for (E), (E) isomer (360MHz, CDCl ₃ ) 6: 6.18 (1H, dd, J = 15.1, 10.4Hz), 6.00 (1H, dd, J = 15.1, 10.4Hz), 5.69 (1H, dq, J = 15.1.7.0Hz), 5.52 (1H, dd, J = 15.1, 6.7Hz), 4.46-4.37 (1H, m), 4.29-4.22 (1H, m), 3.69 (3H, s), 2.60-2.42 (2H, m), 1.72 (3H, d, J = 7.0Hz), 1.74-1.57 (2H, m)

Example 141

7.6 g (35.5 mmol) of 3,5-dihydroxy-deca-6,8-dienoic acid methyl ester and 0.1 g of p-toluenesulfonic acid are added to 10 g of cis 1 -15 -penta-is-dienyl-1-iso-dioxa-spiro-methyl. 10 μmol) of cyclohexanol and stirred at room temperature for 16 hours. The yellow solution is applied directly to a silica gel column and the product is eluted with diethyl ether / hexane 1/4. The appropriate fractions are combined to afford 3.52 g (33.6%) of the title compound as a colorless oil.

¹ H NMR for (E), (E) -isomer (360MHz, CDCl ₃ ) δ: 6.16 (1H, dd, J = 15.1.10.6Hz), 6.00 (1H, dd, J = 15.1.10.6Hz), 5.71-5.65 (1H, dd, J = 15.1.6.5Hz), 5.47 (1H, dd, J = 15.1, 6.4Hz), 4.44-4.39 (1H, m), 4.35-4.30 (1H, m) , 3.66 (3H, s), 2.52 (1H, dd, J = 1.54.7.9Hz), 2.30 (1H, dd, J = 15.4.6.5Hz), 2.1-1.18 (12H, m), 1.72 (3H, d, J = 6.5Hz).

Anal. Calcd. for C ₁₇ H ₂₈ O ₄ :

C, 69.36; H, 8.90 Found: C, 69.59; H, 9.16.

Example 142

cis ^ -IPenta-I.S-dienyD-I.S-dioxaspiroß.Blundecan ^ -ylacetic acid

3.5 g (12.4 mmol) of 4- (penta-1,3-dienyl) -1,5-dixoaspiro [5.5] undecan-2-ylacetic acid are refluxed in a solution of 13 ml of 1N NaOH and 26 ml of methanol. The methanol is evaporated in vacuo and the remaining aqueous solution acidified with 1 η HCl and extracted with diethyl ether. The organic phase is dried over Na ₂ SO ₄ and concentrated. The remaining solid is recrystallized from ethyl acetate / hexane to yield 2.0 g (55.9%) of the title compound as a colorless solid; 144 to 146.5 F. ⁰ C.

¹ H NMR (360 MHz, CDCI ₃₎ δ: 6.18 (1 H, dd, J = 18.0,12.0Hz), 5.72 (1 H, dq, J = 18.0, 7.7Hz), 5.99 (1 H, dd, J = 18.0,12.5Hz), 5.48 (1H, dd, J = 18.0.7.6Hz), 4.45-4.37 (1H, m), 4.37-4.25 (1H, m), 2.56 (1H, dd, J = 18.9,8.8Hz), 2.48 (1H, dd, J = 18.9, 6.1Hz), 2.60-1.30 (12H, m), 1.73 (3H, d, J = 7.7Hz).

Anal. CaICdJOrC ₁₆ H ₂₄ O ₄ :

C, 68.54; H, 8.62 Found: C, 68.36; H, 8.55.

Example 143 Cis-4- [4,4-bis (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl] -1,5- dioxaspiro [5.5] undecRn-2-ylacetic acid

A. 4-Formyl-1,5-dioxaspiro [5,5] undecan-2-ylacetic acid

Through a solution of 570mg (2, OmMoI) 4- (penta-1,3-dienyl) -1,5-dioxaspiro 5.5 undecane-2-ylacetic acid in 25 ml of methylene chloride is passed at -78 ⁰ C ozone. When the solution turns blue, nitrogen is passed through the solution to remove excess ozone. Then, 0.5 ml of dimethyl sulfide is added and the solution is concentrated in vacuo to give the title compound as a viscous oil, which is used without further purification in the next step

Ή NMR (60MHz, CUCI ₃ ) δ: 9.57 (1H, s), 4.52-4.14 (2H, m), 2.60-2.31 (2H, m), 2.10-1.10 (12H, m).

B. cis-4- [4,4-bis- (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl-1,5-dioxaspiro [ 5.5] undecane-2-ylacetic acid

To a solution of 1.7 g (4 mmol) of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) allylphosphonic acid dimethyl ester in 2OmITHF at -78 ⁰ C 1 , 6ml (4 mmol) of a 2.5M solution of butyllithium in hexane. The resulting brownish red solution is stirred for 30 minutes hot -78 ⁰ C. With a cannula, this solution is converted into a solution of the 4-formyl-1,5-dioxaspirol5.5] undecan-2-ylacetic acid shown in step A in 10 ml of THF and stirred for 1 hour at -78 ⁰ C and a further 4 hours at room temperature , The solution is then partitioned between 0.5 N HCI and ethyl acetate. The organic phase is washed twice with pumice, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is purified by chromatography on silica gel (diethyl ether / hexane / acetic acid 50/20/1) to yield 342 mg (31.9% overall yield) of the title compound as a yellow foam.

¹ H NMR (360MHz, CDCl ₃ ) δ: 7.25-6.84 (8H, m), 6.66 (1H, d, J = 16.0Hz), 5.32 (1H, dd, J = 16.0, 5.10Hz), 4.45- 4.25 (2H, m), 3.52 (3H, s), 2.56 (1H, dd, J - 16.0.7.6Hz), 2.44 (1H, dd, J = 16.0, 5.1Hz), 1.89-1.17 (12H, m ).

Example 144

trans-6- [4,4-bis- (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyl] -4hydroxy-tetrahydropyran-2-one A mixture of 4-I4,4-bis (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienylJ-1,5-dioxaspiro5.5 undecane 2-ylacetic acid (280mg, 0.52mmol) in 20mL THF / 0.5N HCl (1: 1) is allowed to stand at room temperature for 26 hours. The solution is distributed between salt water and ethyl acetate. The organic phase is washed 2 χ with salt water, dried over Na ₂ SO ₄ and concentrated. The resulting foam (126 mg) is dissolved in 10 ml of dry methylene chloride and treated with 0.24 g of 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimide-metho-p-toluenesulfonate. After 16 hours at room temperature, the solution is evaporated in vacuo and the residue purified by chromatography on silica gel with ethyl acetate as eluent. The appropriate fractions provide 38 mg (16.6%) of the title compound as a colorless oil, which is a racemic mixture of the compound of Example 7.

Example 145

2,2-Dime; hyl-6-formyl-1,3-dioxane-4-acetic acid methyl ester

The illustrated in Example 33 cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid methyl ester dissolved in 10 ml of methanol and at -78 ⁰ C ozone passed through the solution until the blue becomes. The reaction mixture is purged with nitrogen to remove excess ozone. Then, dimethyl sulfide is added and the solution warmed to room temperature. Evaporate the reaction mixture in vacuo and purify the remaining oil by chromatography on silica gel with diethyl ether / hexane (3/1) as eluent to give the title compound.

Ή NMR (360MHz, CDCl ₃ ) δ: 9.53 (1H, s), 4.40-4.23 (2H, m), 3.69 63H, s), 2.53 (1H, dd, J = 15.8, 7.02Hz), 2.37 ( 1 H, dd, J = 15.8, 5.98Hz), 1.85-1.76 (1H, m), 1.44 (3H, s), 1.40 (3H, s), 1.35-1.23 (1H, m).

Example 146

The general procedures of Example 80, Step B, C and D, and Examples 112, 137 and 138 are each repeated sequentially, replacing the 4,4'-difluoro-benzophenone of Example 80, Step B, with an equimolecular amount of

(a) 2,2 ', 4,4'-tetramethoxybenzophenone,

(b) 3,3 ', 4,4'-tetramethoxybenzophenone,

(c) 2,2 ', 4,4'-tetramethylbenzophenone,

(d) 3,3 ', 4,4'-tetramethylbenzophenone,

(e) 3,3 ', 5,5'-tetramethylbenzophenone,

(f) 4'-fluoro-2,4,6-trimethylbenzophenone,

(g) 2,2 ', 3,3', 4,4'-hexamethoxybenzophenone, (h) 2,2 ', 4,4', 6,6'-hexamethylbenzophenone, (i) 4'- Methoxy-2,5-dimethylbenzophenone, (j) 4'-methoxy-2,4,6-trimethylbenzophenone, (k) 2,2 ', 4,4'-tetrachloro-bonophenone,

(I) 2,2 ', 5,5'-tetrachloro-benzophenone, (m) 2,2', 6,6'-tetrachloro-benzophenone,

(η) S.S'-dichlorobenzophenone,

(o) 4,4'-dichloro-benzophenone,

(ρ) 2,2'-dichloro-4,4'-dimethoxybenzophenone,

l) 2,4-dichloro-4'-trifluoromethylbenzophenone,

(r) 2,2'-difluoro-benzophenone,

(s) 3,3'-difluoro-benzophenone,

(t) 2,2'-dimethoxybenzophenone,

(u) 2,2'-dimethoxy-3,3'-dimethyl-b8nzophenone,

(ν ¹ 2,2'-dimethoxy-5,5'-dimethylbenzophenone,

(\ *) 2,4-dimethoxy-2'-trifluoromethylbenzophenone,

(x) 2,4-dimethoxy-4'-trifluoromethylbenzophenone,

(y) 2 ', 4'-dimethoxy-2,4, & -trimethylbenzophenone,

(z) 2,2'-dimethylbenzophenone,

(aa) 3,3'-dimethylbenzophenone,

(bb) 4,4'-dimethylbenzophenone,

(cc) 4'-fluoro-2,4-dimethoxybenzophenone,

(dd) 4,4'-bis (trifluoromethyl) benzophenone,

(ei 4'-chloro-2,4,6-trimethylbenzophenone,

(ff) 4,4'-dibromo-benzophenone,

(gg) 2,2'-dibromo-4,4'-dimethoxybenzophenone,

(hh) 2-chloro-4,4'-dimethoxy-benzophenone or

(ii) 2,2'-dichlorobenzophenone,

being obtained

(a) trans- (4R, 6S) -6- [4,4-bis- (2,4-dimethoxyphenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyl -4-hyroxy-tetrahydropyran-2-one,

(b) trans {4R, 6S ^t -6,14,4-bis (3,4-dimethoxy-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3- dienyl] -4-hydroxy-tetrahydropyran-2-one,

(c) trans- (4R, 6S) -6- [4,4-bis- (2,4-dimethyl-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3 dienyl | -4-hydroxy-tetrahydropyran-2-one,

(d) trans- (4R, 6S) -6- [4,4-bis (3,4-dimethylphenyl) -3- (1-methyl-1H-tetra / ol _: 5-yl) buta-1 , 3-dienyl] -4-hydroxy-tetrahydropyran-2-one,

(e) trans- (4R, 6S) -6- [4,4-bis- (3,5-dimethyl-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3 dienyl) -4-'nydroxy-tetrahydropyran-2-one,

(f) trans- (4R, 6S) - [4-fluoro-phenyl) -4- (2,4,6-trimethyl-phenvl) -3- (1-methyl-1H-tetrazol-5-yl) -buta- 1,3-dienyll-4-hydiOxy-tetrahyropyran-2-one,

(g) trans- (4R, 6S) -6- (4,4-bis- (2,4,6-trimethoxyphenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1 , 3-dienyl) -4-hydroxy-tetrahydropyran-2-one,

(h) trans- (4R, 6S) -6- [4,4-bis- (2,4,6-trimethyl-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1 , 3-dienyll-4-hydroxy-tetrahydro-

pyran-2-one, (i) trans- (4R, 6S) -6- [4- (4-methoxyphenyl) -4- (2,5-dimethylphenyl) -3- (1-methyl-1H -tetrazol-5-yl) buta-1,3-dienyl] -4-hydroxy-

tetrahydropyran-2-one, (j) trans- (4R, 6S) -6- (4- (4-methoxyphenyl) -4- (2,4,6-trimethylphenyl) -3- (1-methyl-1H -tetrazol-5-yl) buta-1,3-dienyl] -4-hydroxy-

tetrahydropyran-2-one, (k) trans- (4R, 6S) -6- (4,4-bis- (2,4-dichloro-phenyl) -3- (1-methyl-1H-tetrazoi-5 yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran

2-one, (I) trans- (4R, 6S) -6- | 44-bis- (2,5-dichloro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1 , 3-dienyl] -4-hydroxy-tetrahydropyran

-2-one, (m) trans- (4R, 6S) -6- [4,4-bis- (2,6-dichloro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyll-4-hydroxy-tetrahydropyran

(n) trans- (4R, 6S) -6- [4,4-bis- (3-chloro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl ] -4-hydroxytetrahydropyran-2-one, (o) trans- (4R, 6S) -6- [4,4-bis (4-chloro-phenyl) -3- (1-methyl-1H-tetrazole 5-yl) buta-1,3-dienyl-4-hydroxy-tetrahydropyran-2-one, (p) trans- (4R, 6S) -6- | 4,4-bis (2-chloro-4-methoxy -phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyl) -4-hydroxytetrahydro-

pyran-2-one, (q) trans- (4R, 6S) -6- [4- (2,4-dichlorophenyl) -4- (4-trifluoromethyl-phenyl) -3- (i-methyl-1H-tetrazole -5-yl) buta-1,3-dienyll-4-hydroxy-tetrahydropyran-2-one,

(r) trans- (4R, 6S) -6- [4,4-bis (2-fluoro-phenyl) -3- (1-methyl-1H-tetrazol-5-y) buta-1,3-dienyl 4-hydroxy-tetrah / dropyran-2-one, (s) trans- (4R, 6S) -6-t4,4-bis (3-fluoro-phenyl) -3- (1-methyl-1H-tetrazole -5-yl) buta-1,3-dienyl-4-hydroxy-tetrahydropyran-2-one, (t) trans- (4R, 6S) -6- [4,4-bis (2-methoxy-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran

2-one, (u) trans- (4R, 6S) -6- (4,4-Bis- (2-methoxy-3-methylphenyl) -3- (1-methyl-1H-tetrazol-5-yl ) buta-1,3-Dieny) - 4-hydroxy-tetra

hydropyran-2-one, (v) trans- (4R, 6S) -6- (4,4-bis (2-methoxy-5-methylphenyl) -3- (1-methyl-1H-tetrazole-5 -yl) buta-1,3-dienyil-4-hydroxy-tetra-

hydropyran-2-one, (w) trans- (4R, 6S) -6- | 4- (2,4-dimethoxyphenyl) -4- (2-trifluoromethylphenyl) -3- (1-methyl-1H- tetrazol-5-yl) buta-1,3-dienyl) -4-

hydroxy-tetrahydropyran-2-one, (x) trans- (4R, 6S) -6- [4- (2,4-dimethoxyphenyl) -4- (4-trifluoromethyl-phenyl) -3- (1-methyl 1H-tetrazol-5-yl) buta-1,3-dienyl | -4-

hydroxy-tetrahydropyran-2-one, (y) trans- (4R, 6S) -6- [4- (2,4-dimethoxyphenyl) -4- (2,4, e-trimethyl-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyll-4-

hydroxytetrahydropyran-2-one, (z) trans- (4R, 6S) -6,14,4-bis (2-methylphenyl) -3 (1-methyl-1H-tetrazol-5-yl) buta -1,3-dienyl] -4-hydroxy-tetrahydropyran-2-one,

-91- 279 830

(aa) trans-tAR.eSl-e-IM-bis-O-methyl-phenyl-ad-methyl-IH-tetrazol-B-y-d-buta-ia-dionyl-hydroxy-i-tetrahydropyran ^ -one, (bo) trans- IR.eSl-e-KM-bis-IA-methyl-phenyD ^ -d-methyl-IH-tetrazol-B-y-d-buta-ia-dienyl-hydroxy-tetrahydropyran-Z-one, (cc) trans- (4R, 6S) -6-I4- (4-fluoro-phenyl) -4- (2,4-dimethoxy-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta-1,3-dienyl) -4-hydroxy

ietrahydropyran-2-one, (dd) trans- (4R, 6S) -6- [4,4-bis (4-trifluoromethylphenyl) -3- (1-methyl-1H-tetrazol-5-yl) buta -1,3-dienyl] -4-hydroxy-tetrahydro-

pyran-2-cn, (ee) trans- (4R, 6S) -6- [4- (4-chloro-phenyl) -4- (2,4,6-trimethyl-phenyl) -3- (1-methyl-1H -tetrazol-5-yl) -buta-1,3-dienyl] -4-hydroxytetrahydropyran-2-one,

(ff) trans- (4R ₍ 6S) -6,14,4-bis (4-bromo-phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -buta-1,3-dienyl ] -4-hydroxy-tetrahydropyraii-2-or., (Gg) trans- (4R ₍ 6S) -C- (4,4-bis (2-bromo-4-methoxy-phonyl) -3-) nnethyl-1 H-tetrazol-5-yl) buta-1,3-dienyl] -4-hydroxy-tetrahydro-

pyran-2-one, (hh) trans- (4R, 6S) -6-I4- (2-a-> lor-4-methoxyphenyl) -4- (4-me '(hoxyphenyl) -3 - (1-methyl-1H-tetrazol-5-yl) biJta-1,3-dienyl | -4-

hydroxy-tetrahydropyran-2-one and (M) trans- (4R, 6S) -6- [4,4-bis (2-chloro-phenyl) -3- (1-methyl-1H-tetrazol-5-yl ) buta-1,3-dienylj-4-hydroxy-tetrahydropyran-2-one.

Example 147

N- [9,9-bis (4-fluoro-phenyl) -3 {R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-nona -6,8-dienyl] -L-leucine methyl ester By refluxing a solution of trans- (4R, 6S) -6- [4,4-bis (4-fluoro-phenyl) -3- (1-methyl- 1 H-tetrazol-5-yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran-2-one in tetrahydrofuran with at least one equivalent of L-leucine methyl ester (prepared in situ from the hydrochloride) to give the title compound ,

Example 148

The general procedure of Example 147 or Example 1 in U.S. Patent 4,678,806 is repeated, substituting the L-leucine methyl ester with an equimolecular amount of

(a) L-serine methyl ester,

(b) L-phenylalanine methyl ester or

(c) L-tyrosine methyl ester to be obtained

(a) N- [9,9-bis (4-fluoro-phenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1- oxo-nona-6,8-dienyl | -L-serine methylester,

(b) N- [9,9-bis (4-fluoro-phenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazo! 3-yl) -1- oxo-nona-6,8-dienyl] -L-phenyl0laninmethylesterund

(c) N-O.sub.g-bis-fluorophenyl-SIRi.SfSJ-dihydroxy-e-d-methyl-IH-tetrazol-B-yD-i-oxo-nona-e.S-dienyl-L-tyrosine methyl ester.

Example 149

N- [9,9-bis (4-fluoro-phenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-nona -6,8-dienyl] -L-leucine. By treating a solution of the compound of Example 14 / in dioxane-water with 1 N NaOH at ⁰ ° C and acidifying after work-up, the title compound is obtained.

Example 150

The general procedure of Example 149 or Example 2 in U.S. Patent 4,678,806 is repeated, replacing the compound of Example 147 with the compounds of Example 148, where obtained

(a) N- [9,9-bis- (4-fluoro-phenyl) -3 (R), 5 (S) -dihydroxy-9-i1-methyl-1H-tetrazol-5-yl) -1-o> o-nona-6,8-dienyl] -L-serine,

(b) N-I9,9-Bis- (4-fluoro-phenyl) -3 (R), 5 (S) -dihydroxy-t. (1-methyl-1H-tetrazol-5-yl) -1-jxo nona-6,8-dienyl) -L-phenylalapinund

(c) N- [9,9-bis- (4-fluoro-phenyl) -3 (R), 5 (S) -dihydroxy-8'1-me'hyl-1H-t9-trazol-C-yi / -1 oxo-nona-6,8-dienyll-L-tyrosine.

The biological activity of the compounds of formula I vir shown in the following three different biological tests.

Test A. In Vitro Inhibition of Microsomal HMG CoA Reductase

The intact, fully activated microsomal form of rat liver HMG CoA reductase (MW subunit about 100,000 daltons) is described by Parker et al., Biochem. Biophys. Commun. 125, 629-635 (1984) and used as an enzyme source for studies. The HMG-CoA reductase activity is mainly determined by the method of Shapiro et al., Biochem. Biophys. Acta 370, 369-377 (1974) with Ingsbritsen and Gibson modifications, Meth. Enzymol. 71, 486-497 (1981), with the exception that the internal standard 'H-mevalonolactone is added after completion of the sample. In this method, the enzyme is evaluated by measuring the formation of the product ¹⁴ C-mevalonate from the substrate [3- ' ⁴ C] HMG-CoA in the presence of NADPH. The ¹⁴ C-mevalonate is converted to its lactone and isolated by thin layer chromatography on silica gel (Whatman LK5D, developed with benzene: acetone 50:50) in the presence of ³ H-mevalonolactcn as internal standard. The evaluations were performed under conditions where product formation was linear with respect to time and enzyme concentration.

To measure the Reduktaseinhibierung the test compounds were dissolved in water or dimethyl sulfoxide and diluted in buffer A (5OmMoI imidazole-HCl, 25OmMoI NaCl, 1 mM EDTA, 1 mM EGTA, 5 mmol DTT, 20μΜοΙ leupeptin, p _H = 7.2) and with aliquots Were incubated with microsomal (80-160 μg protein in buffer A) and then dl- [3- ' ⁴ ClHMG-CoA (0.33 mmol, 2.0 dpm / picomol) and NADPH (3, OmMoI) were added. The 50% inhibition concentration (IC ₆₀ ) for the compounds in Table 1 was calculated from the linear regression line of percent decay (versus control) of enzyme activity versus logarithm of inhibitor concentration determined from at least 4 dilutions of each test compound, each run twice ,

Table 1 Inhibition of microsomal HMG-CoA reductase

Connection of JC ₅₀

Beispiet No. pmolar

11 > 330 12 0.037 ± 0.01 13 1.09 ± 0.29 15 5.7 44 0.16 65 1.6 92 0,029 99 0.58 120 0,044 126 0.019 132 1.4

Test B. Evaluation of the Oolesterol Biosynthesis of Isolated Hepatocytes

Intact parenchymal testocytes are isolated from male Wistar rats (180-280g) fed cholestyramine-containing or normal nourishment using the collagenase perfusion method essentially as described by Seigen in Methods in Cell Biology (Ed. D. Prescott). 13, p.29-83, Academic Press, New York (1976) Cell preparations were only used when viability (trypan blue exclusion) exceeded 90% Cho.esterol biosynthesis was determined to be the incorporation of ³ H from ( ³ H) water in the whole (cellular and from the medium) 3 / J-hydroxysterols by hepatocytes according to Ingebritsen 3 et al., J. Biol. ^R f-m 254.1186-9989 (1979). Sterols and lipids were isolated by modification of the methods of Kates, Tthnique: in Lipidology (ed. M. Kates), pp. 349,360-363, North Holland Publ.Co., Amsterdam, 1972. To isolate the sterols the cells are extracted with methanol: chloroform: water (2: 1: 0.8), the chloroform asese separated and extracted with benzene to remove traces of water and then dried under nitrogen. The residue is saponified at 75 ° C. with 0.30 N NaOH in methanol: water (9: 1). The alkaline mixture is then extracted three times with petroleum ether to yield the unsaponifiable lipids containing the free and initially esterified cholesterol. The extract is dried under nitrogen in the presence of cholesterol (0.1 mg) as a carrier and 10% benzene and the residue is dissolved in acetone: ethanol (1.1). Finally, the 3jS-hydroxy-sterols are precipitated with an excess of digitonin, the precipitate washed in acetone, dried under nitrogen and dissolved in toluene: methanol (1: 1). The ³ H-labeled sterols are determined by liquid scintillation and corrected for counting efficiency. In some experiments, C-cholesterol was added to the original extracts as a recovery index, which averaged 80 ± 3%.

Λιγ measurement of inhibition of cholesterol synthesis were double or triple aliquots of freshly isolated cells (100mg cells net weight in 2.0ml) in EagKs minima! R.sential medium containing bicarbonate and HEPES buffer, p _H 7.35, and 2% bovine serum albumin, under an atmosphere of 95% O ₇ + 5% CO 2 ; suspended. Cells were preincubated with or without aliquots of the test compounds added as aqueous solutions of the sodium salts or as solutions of the la- irons in dimethylsulfoxide. The control experiments contained only the vehicle. Then became | ³ H] water (1, OmCi per ml of ink jbationsvolumen) or [2- ¹⁴ C] acetate (0.5 \ iC \ per ml incubation volume) each added and the cells with constant shaking for 60 minutes at 37 ⁰ C incubated. These conditions led to the linear incorporation of tritium or ' ⁴ C into the sterols. The ICso-Wen of inhibition of sterol synthesis by the test compounds set forth in Table 2 was calculated from the linear regression curve of percent inhibition (vs control) against the logarithm of concentration, using at least 4 concentrations of the inhibitor. Test B is used to measure the ability of the test substances to inhibit intracellular cholesterol doses.

(Table 2)

Inhibition of cholesterol biosynthesis by isolated hematocytes

Connection of IC ₅₀

Example No. nmolar

12 23.0 ± 11

13 24.0 138 7.4 mevinolin (lovastatin) 46.0 ± 26

Test C. In vivo inhibition of acute cholosterol biosynthesis in rats

Male Wistar rats (160-2UOg, 2 each in a cage) were maintained at a normal diet (Purina Rat Chow and water ad libitum) for at least 7 days at a reverse exposure ratio (7:00 to 5:00 pm dark). The food was withdrawn 15 hours before dosing. The compounds were administered at 8:00 am by intragastric intubation of 0.5 to 1.0 ml of a solution of the sodium salts, lactones or esters of the test compounds in water or propylene glycol. The control animals received equal volumes of the vehicle. Thirty minutes after the administration of the test substances, the rats were intraperitoneally injected with 0.9 ml of 0.9% NaCl solution containing approximately 1200mC of sodium M-1-acetate (1-3mCi / mmol) per kg of body weight. After 60 minutes, the rats were sacrificed and liver and blood samples taken. Aliquots of plasma (1.0 ml) obtained by centrifugation of heparinized and EDTA-treated blood and aliquots of serum homogenates (equivalent to 0.50 g liver wet weight) were obtained for the determination of radiolabelled 3/3-hydroxy-sterols. The isolation of the sterols for the liver samples was carried out according to the method of Kates, as described above for the hepatocyte method (Test B), while the plasma samples were directly saponified and then the digitonin precipitable sterols were isolated. The ^H C-labeled sterols were determined by scintillation counting! (Effectiveness corrected). The middle

% inhibition of the ^M C incorporated in liver and plasma cholesterol was calculated for treated animal flu and compared to the mean values for controls performed concurrently.

Test C thus informutiones about the ability of the test substances to suppress the new biosynthesis of cholesterol in vivo in rats when given orally. I.η Test C gave z. For example, the compound of Example 12 had a 50% inhibitory dose (ED ₆₀ ) of 0.08 mg / kg for both plasma and liver holesterol, and for the comparator mevinolin, an ED 50 value of 0.04 mg / kg comparable to levels using mevinolin in a similar assay (Alberts et al., Proc. Acad. Sci. 77: 3957-3961 [1980]).

The results of the above in vitro and in vitro tests A, B and C show that the compounds of formula I inhibit cholesterol biosynthesis and are therefore useful for the treatment of hypercholesterolemia.

Claims (35)

claims: 1. A process for the preparation of novel Tetrüzolverbindungen the general formula I. tet wherein R ¹ and R ⁴ are each independently hydrogen, halogen, C ₁ -C ₄ -AlkYl, C ₁ -C ₄ -alkoxy or trifluoromethyl; R ² , R ³ , R ⁵ and R ^{6 are} each independently of one another hydrogen, halogen, C ₁ -C ₄ -alkyl or C ₁ -C ₄ - Alkoxysind; tet ^{or is;} η is an integer from 0 to 2; or is OR R ^{7 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy (lower) alkyl or 2-methoxy-ethoxymethyl; X-OH or = 0 is and R ^{8 is} hydrogen, a hydrolyzable ester group or a cation which forms a non-toxic pharmaceutically acceptable salt; characterized in that either (1) (a) is a compound of formula Ha or IIb or Ha CHO hb, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^{6 are} as defined above and R ^{7 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy (lower) alkyl, Methoxyethoxymethyl or R ^7a , where R ^{7a is} triphenylmethyl, with triphenylphosphoranylidene acetaldehyde to form a compound of the formula or IX 'X N N V ₁ ZI? CHO wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} as defined above and η = 1 or 2, then (b) the starting or end product of step (a) with the dianion of an acetoacetate ester to a compound of the formula or XV wherein R'-R ^{7 are} as defined above and R ^{9 is} a hydrolyzable ester group and η is 0 to 2, and then (c) the ketone ester of step (b) is reduced to a dihydroxy ester of formula I by reducing agents which neither reduce nor hydrolyze the carboxylic acid ester group, and (d) the dihydroxy ester of step (c) is converted by basic hydrolysis in an organic solvent to a salt of formula I, wherein R ^{8 is} a cation forming a non-toxic pharmaceutically acceptable salt, and optionally (e) acidifying the product of step (d) to give a compound of formula I wherein R ^{8 is} hydrogen, and optionally (f) reacting the product of step (e) by lactonization in an inert organic solvent to give a compound of formula I wherein A is a lactone; or that (2) (a) the starting or final product of step (1) (a) with a phosphonate compound of the formula OH 0 CH ₀ Oj XVI, OCH. wherein R ^{9 is} a hydrolyzable ester group, in an inert organic solvent in the presence of an organic base to give a compound of formula I. , 5 Ie wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , tet and η are as defined above and R ^{9 is} a hydrolyzable ester group, and then (b) optionally the compound of step (2) (a) substituting the substituent R ⁹ by the substituent R ⁸ , wherein R ^{8 is} as defined above, by carrying out steps (1) (c) to (1) ( f) is hydrolyzed to further compounds of formula I; or that (3) (a) a compound of the formula XVIl, XVIIa wherein fl \ R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined above 0
-P- (OR ¹² ) 13 or -P - R - R ¹³ Χ ^θ is, where R ^{12 is} C ₁ -C ₄ -alkyl, R ^{13 is} phenyl which is unsubstituted or substituted by one or two C 1 -C ₄ -alkyl or chlorine substituents, and X is bromine, chlorine or iodine, with an o-nyl-protected aldehyde of the formula OR ¹⁰ OR ¹⁰ 0 XVIII wherein R ^{9 is} a hydrolyzable ester group and R ^{10 is} tert-butyldiphenylsilyl, in an inert organic solvent in the presence of a strong base to a silyl protected compound of the formula OR ¹⁰ OR ¹⁰ 0 XIX is implemented, and then (b) the compound resulting from step (3) (a) to give a compound of formula is desilylated, and then (c) optionally the compound of step (3) (b) substituting the substituent R ⁹ by the substituent R ⁸ , wherein R ^{8 is} as defined above, by carrying out steps (1) (c) to (1) ( f * is hydrolyzed to further compounds of formula I. -5- 279 88C 2. The method according to claim!, Characterized in that a compound of formula wherein R ¹ and R ^{4 are} each independently hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or trifluoromethyl; R ² , R ³ , R ⁵ and R ^{6 are} each independently hydrogen, halogen, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy; η is an integer from 0 to 2; or OH O i st OR ⁸ R ^{7 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy (lower) alkyl or 2-methoxyethoxymethyl; X-OH or = 0 is and R ^{8 is} hydrogen, a hydrolyzable ester group or a cation which forms a non-toxic pharmaceutically acceptable salt. 3. The method according to claim 2, characterized in that a compound, wherein η = 1, he: is made. 4. The method according to claim 3, characterized in that a compound of formula ₍ , 5 wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} each independently hydrogen, fluoro, chloro, methyl or methoxy; A or "" is; X OH O AAA OR R ^{7 is} hydrogen or C ₁ -C ₄ alkyl and R ^{8 is} hydrogen, C ₁ -C ₆ alkyl or a cation which forms a non-toxic pharmaceutically acceptable salt. 5. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazo! -5-yl) nona-6,8-dienoic acid ethyl ester is produced. 6. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tretrazol-5-yl) nona 6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt or hydrate thereof. 7. The method according to claim 6, characterized in that the (3 R, 5 S) enantiomer of 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl 1 H tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt or hydrate thereof. 8. The method according to claim 6, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazol-5-yl) nona 6,8-dienanoic acid monohydrate. Process according to Claim 8, characterized in that the (3 R, 5 S) -enantiomer of 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1 H tetrazol-5-yl) nona-6,8-dienoic acid monohydrate. 10. The method according to claim 6, characterized in that the compound sodium erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole-5- yl) nona-6,8-dienoate is produced. 11. The method according to claim 10, characterized in that the (3 R, 5S) enantiomer of sodium 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl- 1H-tetrazol-5-yl) nona-6,8-dienoate. 12. The method according to claim 6, characterized in that the compound potassium erythro-9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazo! - 5 yl) nona-6,8-dienoate is produced. 13. The method according to claim 12, characterized in that the (3R, 5S; -enantiomer of potassium 9,9-bis (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H tetrazol-5-yl) nona-6,8-dienoate. 14. The method according to claim 1, characterized in that the compound which trans-6- [4,4-bis (4-fluoro-phenyl) -3- (1-methyl-1 H-tetroZol-5-yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran-2-one. 15. The method according to claim 14, characterized in that the (4R, 6S) -enantiomer of 6- [4,4-bis (4-fluoro-phenyl) -3- (1-methyl-1H-tetrazole-5- yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran-2-one. 16. The method according to claim 1, characterized in that the compound erythro-11,11 -bis (4-fluoro-phenyl) -3,5-dihydroxy-10- (1-methyl-1 H-tetrazol-5-yl ) - and eca-6,8,10-trienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 17. The method according to claim 1, characterized in that the compound trans-6- [4,4-bis (4-fluoro-phenyl) -3- (2-methyl-2H-tetrazol-5-yl) buta-1 , 3-dienyl] -4-hydroxy-tetrahydropyran-2-one. 18. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-2 H-tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 19. The method according to claim 1, characterized in that the compound 9,9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl-1 H-tetrazoi-5-yl) -5-oxo nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 20. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-isopropyl-1 H-tetrazol-5-yl) nona 6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 21. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluoro phenyi) -3,5-dihydroxy-3- (1-isopropyl-1 H-tetrazol'5-yl) nona-6,8-dienoic acid ethyl ester is produced. 22. The method according to claim 1, characterized in that the compound erythro-9,9-8is- (4-fluoro-3-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl '! H tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 23. The method according to claim 1, characterized in that the compound trans-6- [4,4-bis (4-fluoro-3-methyl-phenyi) -3- (1-methyl-1 H-tetrazole-5- yl) buta-1,3-dienyl] -4-hydroxy-tetrahydropyran-2-one. 24. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-ethyl-1 H-tetrazol-5-yl) nona -6,8-dienoic acid or a non-toxic ^pharmacist: sch acceptable salt thereof is prepared. 25. The method according to claim 1, characterized in that the compound erythro-9,9-bis (2,4-dimethyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazole-5 -yl) nona-6,8-dionic acid or a non-toxic pharmaceutically acceptable salt thereof. 26. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (2-methoxy-ethoxymethyl) -1H-tetrazole 5-yl] -nona-6,8-dienoic acid, a non-toxic pharmaceutically acceptable salt thereof is prepared. 27. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-fluoro-2-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazole 5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 28. The method according to claim 27, characterized in that the (3 R, 5 S) enantiomer of 9,9-bis (4-fluoro-2-methyl-phenyl) -3,5-dihydroxy-8- (1 -methyl-1H-tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 29. The method according to claim 1, characterized in that the compound trans-6- [4,4-bis (4-fluoro-methyl-phenyD-Sd-methyl-IH-tetrazol-B-yDbutai ^ -dienylJ ^ - Hydroxy-tetrahydropyran-2-one is produced. 30. The method according to claim 29 .. characterized in that the (4R, 6S) enantiomer of 6- [4,4-bis (4-fluoro-2-methyl-phenyl) -3- (1-methyl-1H tetrazol-5-yl) buta-1,3-dienyl] -4-hydroxytetrahydropyran-2-one. 31. The method according to claim 1, characterized in that the compound erythro-9,9-bis (2-fluoro-4-methyl-phenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazo '-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 32. The method according to claim 1, characterized in that the compound erythro-9- (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazol-5-yl) -9-phenyl nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 33. The method according to claim 32, characterized in that the (3R, 5S) -enantiomer of 9- (4-fluoro-phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl ) -9-phenyl-nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 34. The method according to claim 1, characterized in that the compound trans-6- [4- (4-fluorophenyl) -4-phenyl-3- (1-methyl-1 H-tetrazol-5-yl) -buta-1 , 3-di-enyl] -4-hydroxy-tetrahydropyran-2-one. 35. The method according to claim 34, characterized in that the (4R, 6S) -enantiomer of 6- [4- (4-fluoro-phenyl) -4-phenyl-3- (1-methyl-1H-tetrazole-5 -yl) buta-1,3-dienyl-4-hydroxy-tetrahydropyran-2-one. 36. The method according to claim 1, characterized in that the compound erythro-9,9-diphenyl · 3,5-dihydroxy-8- (1-methyl-1 H-tetrazol-5-yl) nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof. 37. The method according to claim 1, characterized in that the compound erythro-9,9-bis (4-methoxyphenyl) -3,5-dihydroxy-8- (1-methyl-1 H-tetrazol-5-yl ) -nona-6,8-dienoic acid or a non-toxic pharmaceutically acceptable salt thereof.