NO178767B - Tetrazole intermediate and process for its preparation - Google Patents

Description

The present invention relates to a tetrazole intermediate, which is useful in the production of hitherto unknown inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The invention also relates to a method for producing a tetrazole intermediate.

The natural fermentation products compactin (R=H) described by A. Endo et al., in Journal of Antibiotics, Vol 29, 1976, p. 1346-1348, and mevinolin (R=CH3) described by A.W. Alberts et al., in J. Proe. Nati. Acad. Sei., U.S.A., Vol 77, 1980, p. 3957, are highly active antihypercholesterolemic agents, which limit cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme and natural point of cholesterologenesis regulation in mammals, including humans . Compactin (R=H) and mevinolin (F^CH^, also known as lovastatin) have the following structure

A number of structurally related synthetic compounds useful in the treatment of hypercholesterolemia have also been described in various patents and other publications. The previously known, closely related synthetically produced compounds are the following: In US patent 4,198,425 hitherto unknown mevalonolactone derivatives are described, which are useful in the treatment of hyperlipidemia and which have the following general formula

where A is a direct bond, a methylene, ethylene, trimethylene or vinylene group, and

3 ' A 5 R , R" and R are different substituents.

In EP patent application 24,348, hitherto unknown hypocholesterolemic and hypolipemic compounds with the formula are described

where A is H or methyl,

E is a direct bond -CH,,-, -(CH2)2-, -(CH2)3- or -CK=CH-,

R , R and RJ are each different substituents,

as well as the corresponding dihydroxy acids which originate from the hydrolytic opening of the lactone ring.

In US patent 4,375,475, largely the same structures are described and agree with the above-mentioned EP patent application 24,348.

EP patent application 68,038 describes the split trans-enantiomer, a method for its preparation, as well as pharma-

and the corresponding dihydroxy acid, or a pharmaceutically acceptable salt thereof. In PCT application WO 84/02131 analogues of mevalonolactone are described with the structure where either R or R^ is

while the other is primary or secondary C1-6-alkyl, C1-6-cycloalkyl or phenyl -(CK2)n~'

X is -(CH_) - or -CH=CH-, 2. n

n is 0, 1, 2 or 3,

4 5 5a 6 R , R , R and R are different substituents.

PCT application WO 84/02903 describes mevalonolacetone analogues with the structures

where X is -(CH-) - z n

n is 0, 1, 2 or 3, and

both q are 0, or one is 0 and the other is 1, and

In EP patent application 14 2.14 6, oxo analogues of mevinolin-like antihypercholesterolernic agents are described with the structure where E is -CH2~CH2, -CH=CH- or -(CH2)3-r and

Z is

where the dashed lines represent possible double bonds, as there can be 0, 1 or 2 double bonds.

G. E. Stokker et al. describes in J. Med. Chem., Vol 28, 1985, p. 347-358 preparation and testing of a number of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives.

W. F. Hoffman et al. describes in J. Med. Chem, Vol 29, 1986, p. 159-169 preparation and testing of a variety of 7-(substituted aryl)-3,5-dihydroxy-6-heptene-(heptane) acids and their lactone derivatives. One of the preferred compounds among those described above has the structure

G. E. Stokker et al. describes in J. Med. Chem., Vol 29, 1986, p. 170-181 synthesis of a variety of 7-[3,5-disubstituted-(1,1'-diphenyl)-2-yl]-3,5-dihydroxy-6-heptenoic acids and their lactones. Two of the preferred compounds described in the above-mentioned article have the structures US patent 4,613,601 describes pyrazole analogues of mevalonolactone and derivatives thereof, which are useful in the treatment of hyperlipoproteinemia and atherosclerosis. These pyrazole analogues have the general formula

where X is -(CH„) -, -CH=CH-, -CH=CH-CH0- or -CH0-CH=CH-, 2 n 2 2

n is 0, 1, 2 or 3, and

R1, R2, R<3>, R4, R5, R6, R<7> and Z are different substituents.

The possibility of producing the compounds according to the present invention is not described or suggested in any of the above-mentioned patent documents or articles. The unique structural feature, which consists in the incorporation of a tetrazole part in the compounds, deviates to a significant extent from the state of the art.

The tetrazole intermediate according to the invention is characterized by having the formula

where R 1 and R 4 are each independently hydrogen, halogen, C 1 -alkyl, C 1 -alkyl or trifluoromethyl,

2 3 5 6 R , R , R and R each independently of one another are hydrogen, halogen, C1_4~alkyl or C^_4~alkoxy,

B is CH2Z,

X is bromine, chlorine or iodine,

R is C 1 -alkyl, and

11 R is phenyl which is unsubstituted or substituted with one or two C^_^-alkyl or chloro substituents.

The intermediate product according to the invention with the formula I can be used for the preparation of antihypercholesterolemic agents with the formulas where R 1 and R 4 are each independently hydrogen, halogen, C 1-6 -alkyl, C 1-6-alkyl or trifluoromethyl,

R , RJ^ , R and R each independently of one another are hydrogen, halogen, C 1-4 -alkyl or C 1-4 - alkoxy,

n is 0, 1 or 2, and

R 7 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic, pharmaceutically acceptable salt.

. The terms "C1-4-alkyl" and "C-1-4-alkoxy" denote, if nothing else is stated, unbranched or branched alkyl-alkoxy groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl or the like . These groups preferably contain 1 or 2 carbon atoms. Unless otherwise stated, the term "halogen" includes chlorine, fluorine, bromine or iodine. The term "a cation to form a non-toxic, pharmaceutically acceptable salt" here includes non-toxic metal salts, such as sodium, potassium, calcium or magnesium salts, and ammonium salts or salts with non-toxic amines, such as trialkylamines, dibenzylamines , pyridine, N-methylmorpholine, N-methylpiperidine or other amines which have been used to form salts with carboxylic acids. Unless otherwise stated, the term "a hydrolysable ester group" includes

an ester group which is physiologically acceptable and hydrolyzable under physiological conditions, such as C 1-6 alkyl, phenylmethyl or pivaloyloxymethyl.

The method according to the invention for producing the intermediate product with the formula (I) is characterized in that

(a) that a benzophenone compound of formula (V)

where

R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the above meaning, are reacted with 5-ethyl-1-methyl-1H-tetrazole, to preparation of a compound with the formula (Vila)

where

R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the above meaning, (b) that an alcohol with the formula (Vila) is dehydrated to produce a compound with the formula (Id)

where

R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the meaning stated above, (c) that an olefin with the formula (Id) is halogenated to produce a compound with the formula (le)

where

R<1>, R<2>, R<3>, R<4>, R<5> and R<6> and X have the meaning given above, and

(d) that a compound of the formula (le) is reacted with

where

R"*"0 is C^_4~alkyl, and R^ is phenyl which is unsubstituted or substituted with one or two C^_4~alkyl or chloro substituents, to produce a compound of the formula (I)

where

R1, R<2>, R3, R4, R^ and R^ and Z have the meaning given above.

1 4

In the compounds of formula (I), R and R are preferably 2 3 5 6 hydrogen while R , R , R and R are independently hydrogen, fluorine, methyl or methoxy, and more preferably R and R 4 are hydrogen while R 2 , R 3 , R^ and R^ are independently hydrogen, fluorine, methyl or methoxy.

The antihypercholesterolemic compounds of the formulas (Ila) and (Ilb) can be prepared by various methods, preferably using intermediates of the formula (III) where R^, R2, R<3>, R4, R^ and R^ have the above indicated importance. The compounds with the formula (III) can be prepared by various methods, preferably from a compound with the formula (IV)

where R^", R<2>, R<3>, R^, R5 and R^ have the meaning indicated above.

The compounds of the formula (IV) can be prepared from optionally substituted benzophenones of the formula (V) by alkylation with 5-ethyl-1-methyl-1H-tetrazole of the formula (VII), followed by dehydrogenation of the resulting tertiary alcohol of the formula (VII), as shown in reaction scheme 1.

In the reaction core 1, R , R , R , , R and R have the meaning indicated above. The optionally substituted benzophenones of the formula (V) can be prepared by means of the general and well-known Friedel-Crafts reaction using a substituted phenyl catalyzed by a Lewis acid, e.g. aluminum chloride in carbon tetrachloride at approx. 0°C. A large number of substituted benzophenones are known and their preparation has been previously described, while many others are commercially available. Many have the starting materials with the formula (V) e.g. described by G. Olah in "Friedel Crafts and Related Reactions", Volume 3, Parts 1 and 2, Interscience Publishers, New York, 1964, and in references cited therein. The Friedel-Crafts reaction can produce a mixture of benzophenones, in which case the mixture can be separated in a conventional manner.

The starting materials of formula (VI) can be prepared by reacting 1,5-dimethyltetrazole with a strong base, such as butyllithium, at a temperature of from -70°C to 0°C, and the resulting anion thereof is added to or preferably treated with respectively ethyl chloroformate or methyl iodide, as described herein.

The 1-methyltetrazole of the formula (VI) can be treated with a strong base, such as n-butyllithium, at a low temperature of from -20°C to -78°C, preferably at from -40°C to -78°C, in an inert organic solvent, e.g. tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or the like. The resulting anion of the formula (VI) can then be treated with the desired benzophenone of the formula (V) to produce the corresponding tertiary alcohols with the formula (Vila).

The compounds of the formula (IV) can be prepared from the compounds of the formula (Vila) using conventional dehydration methods. The dehydration can be carried out by heating the alcohol with the formula (Vila) in a suitable inert organic solvent, e.g. toluene, benzene or xylene, with a small amount of an organic acid or a mineral acid, such as p-toluenesulfonic acid or sulfuric acid, in the presence of a drying agent, e.g. Na 2 SO 4 , MgSO 4 , molecular sieves or the like, and the water that forms is preferably removed azeotropically with a Dean-Stark trap or a similar device. Alternatively, the alcohol with the formula (Vila) can simply be heated with potassium hydrogen sulphate at a temperature of approx. 190°C.

The preferred compounds of the formula (III) can be converted into the preferred compounds of the formula (Ila) and (Ilb) by general methods which are described here and in American patent application 18,542 as well as in Danish patent application 972/88. The use of the aldehydes with the formula (III) is shown in reaction core 2.

In the reaction core 2, R 1 , R 2 , R 3 , Rq., R 5 and R 6 have the meaning given above, and R is a hydrolysable ester group. The aldehydes with the formula (III) can generally be converted to dienaldehydes with the formula (VIII), where n is 1, by reaction with approx. 1 equivalent of triphenylphosphoranylidene acetaldehyde in an inert organic solvent, such as benzene, toluene, tetrahydrofuran, 1,2-dimethoxyoxyethane or the like. It is appropriate to carry out the conversion at reflux temperature. If desired, the dienealdehyde with the formula (VIII), where n is 1, can be reacted with a further equivalent of triphenylphosphoranylidene acetaldehyde to produce the trienaldehyde with the formula (VIII), where n is 2.

The penultimate intermediate, with the formula (IX), where R 9 is a hydrolyzable ester group, can be prepared from the corresponding aldehyde with the formula (VIII) by reaction with the acetoacetate ester dianion described above, produced in situ. The reaction can be carried out in an inert organic solvent, such as tetrahydrofuran, at low temperatures of from -78°C to 0°C, preferably from -78°C to -40°C, until the reaction is practically complete.

The ketone ester of the formula (IX) can be reduced to the dihydroxy ester of the formula (Ila) with reducing agents known in the art, e.g. sodium borohydride, sodium cyanoborohydride, zinc borohydride, disiamyl borane, diborane, ammonia borane, tert-butylamine borane, pyridine borane, lithium tri-s-butyl borohydride or other similar reducing agents, which neither reduce nor hydrolyze the carboxyl ester group. The reduction is preferably carried out in a stereospecific manner by a two-step stereospecific reduction in order to achieve maximum formation of the preferred erythro-isomer of the compound of formula (Ila). The stereospecific reduction of a compound of the formula (IX) is carried out with trisubstituted alkylboranes, preferably triethylborane, or alkoxydialkylboranes, preferably methoxydiethylborane or ethoxydiethylborane (Tetrahedron Letters, Vol 28, 1987, p. 155) at a temperature of from -70°C to ambient temperature. The complex formed is then reduced with sodium borohydride at a temperature of from -50°C to at least -78°C in an inert organic solvent, such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, preferably tetrahydrofuran. The reduction is terminated by the addition of methanol. The resulting compound of formula (X) can then be converted into the compounds of general formulas (Ila) and (IIb) in a conventional manner known to those skilled in the art.

In an alternative method for producing the compounds with the formulas (Ila) and (Ilb), intermediate products with the formulas (If) and (Ig) which are shown in reaction core 3 are also produced.

In reaction scheme 3, R 1 , R 2 , R 3 , , R 5 and R 6 have the meaning stated above. The allyl bromide of formula (le) can be reacted in a conventional manner with phosphines, such as triphenylphosphine, in an inert organic solvent, such as cyclohexane, to produce the phosphonium salt of formula (If), where R is phenyl, which is unsubstituted or substituted with one or two substituents selected from C1-4-alkyl and chlorine, and X is bromine, chlorine or iodine. The allyl bromide of formula (le) can alternatively be reacted in a conventional manner with phosphites, such as trimethylphosphite and triethylphosphite, without solvent or in an inert organic solvent, preferably without solvent to produce a phosphonate of formula (lg), where R is 3-alkyl.

The intermediate products with the formulas (If) or (Ig) can then be converted into the antihypercholesterolemic compounds with the formulas (Ila) and (Ilb) by a series of reactions as shown in reaction scheme 4. In reaction core 4, R , R R , R R and R have the above indicated meaning, R 9 is a hydrolyzable ester group, R 12 is tert-butyldiphenylsilyl, and Z is where R^"° is C^_4~alkyl, R^ is phenyl which is unsubstituted or substituted by 1 or 2 C-^-alkyl- or chlorine substituents, and X is bromine, chlorine or iodine. The phosphonium salt of the formula (If) or the phosphonate of the formula (Ig) can be reacted with a silyl-protected aldehyde of the formula (IX), which itself is prepared by methods described in Tetrahedron Letters, Vol 25, 1984, p. 2435 and in US Patent 4,571,428 for the preparation of the silyl-protected compound of formula (XII). The reaction can be carried out in an inert organic solvent, such as tetrahydrofuran or N,N-dimethylformamide , in the presence of a strong base, eg lithium di isopropylamide, potassium tert-butoxide or n-butyllithium, at a temperature of from -78°C to 0°C. The compound of formula (XII) can then be desilylated in a well-known manner, such as with 48 percent hydrofluoric acid or preferably with tetrabutylammonium fluoride in an inert organic solvent, such as tetrahydrofuran or acetonitrile, in the presence of a small amount of organic acid, to produce the erythro compounds of the formula (X). The resulting compound of formula (X) can then be converted into the compounds of general formulas (Ila) and (IIb) in a conventional manner well known to those skilled in the art.

In the following examples, melting point was recorded in a Thomas-Hoover capillary melting point apparatus, and boiling point was measured at specific pressure (mm Hg), and both temperature readings are uncorrected. Proton magnetic resonance spectra ("<*>"H NMR) were recorded with a Bruker "AM 300", Bruker "WM 360" or Varian "T-60 CW" spectrometer. All spectra were determined in CDCl3, DMS0-dg or D2O, unless otherwise stated, and chemical shifts noted in α units are plotted for the internal standard tetramethylsilane (TMS), and internal proton coupling constants are recorded in Hertz ( Hz). Cleavage patterns are named as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multi-spot, br. = broad peak and dd = doublet of doublet. Carbon-13 nuclear magnetic resonance spectra ( 13 C NMR) were recorded in a Bruker "AM 300" or Bruker "WM 3 60" spectrometer and were broadband proton decoupled. All spectra were determined in CDCl3, DMSO-dg, or D_0 unless otherwise noted, with internal deuterium lock, and chemical shifts were recorded in 6 units downstream from tetramethylsilane. IR spectra were determined with a Nicolet "MX-1 FT" spectrometer from 4000 cm to 400 cm^, calibrated to 1601 cm absorption using a polystyrene film and recorded in reciprocal centimeters (cm^). Relative intensities indicated as follows: s (strong), m (medium) and w (weak).

Gas chromatographic mass spectra (GC-MS) were determined in a Finnigan "4500" gas chromatographic quadruple mass spectrometer at an ionization potential of 70 eV. Mass spectra were then recorded with a Kratos "Ms-50" instrument using a fast atom bombardment (FAB) technique. Mass data are expressed in the format: parent ion (M<+>) or protonated ion (M+H)<+>.

Analytical thin-layer chromatography was performed on pre-coated silica gel plates (60F-254), which were made visible using UV light, iodine vapors and/or staining with one of the following reagents: (a) methanolic phosphormolidic acid (2%) and heating , (b) reagent (a) followed by 2% cobalt sulfate in 5 M H2SO4 and heating. Column chromatography, also called flash column chromatography, was carried out in a glass column using finely divided silica gel (32-63 µm on silica gel-H) and pressure slightly above atmospheric pressure with the listed solvents. All solvent evaporations were carried out under reduced pressure. By the term "hexanes" is meant herein a mixture of isomeric C 8 hydrocarbons as specified by the American Chemical Society, and the term "inert" atmosphere means an argon or nitrogen atmosphere unless otherwise indicated.

Example 1

Ethyl- 2- cyano- 3, 3- bis( 4- fluorophenyl)- 2- propenoate

A mixture of 20.0 g (92 mmol) of 4,4'-difluorobenzophenone and 11.0 g (97 mmol) of ethyl cyanoacetate in a solvent mixture consisting of 100 ml of dry benzene and 20 ml of glacial acetic acid containing a catalytic amount of iso-alanine ( 0.9 g) was refluxed while separating water using a Dean-Stark water trap. The water separation took place rapidly in the first 2 hours (0.4 ml aqueous layer was collected), but then slowly. Azeotropic distillation continued for 14 days. By analytical thin layer chromatography, elution with 10 vol% EtOAc in hexanes (Merck plate, 0.25 mm silica gel-F) showed two spots at Rf = 0.2 (desired product) and R f = 0.45 (4.4<1 ->difluorobenzophenone starting material). The crude reaction mixture was washed with water (2 x 40 mL) and the combined organic washings were extracted with EtOAc (2 x 150 mL). The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure, whereby the product crystallized as light cubic crystals. The crude product was collected, washed with 1:1 EtOAc in hexanes (v/v) and then crystallized from 8:1 hexanes:ethyl acetate (v/v) to give 16.2 g (56.3%) of an analytical pure compound, m.p. 114-116°C.

IR (KBr) vmax: 3000 (s), 2225 (s), 1931 (vs), 1605 (s), 1513 (s), 1250 (s), 844 (s) cm<-1>.

<X>H NMR (CDCl 3 ) δ: 1.19 (3H, t, J=7.1 Hz), 4.18 (2H, q, J=7.1 Hz), 7.08-7.15 ( 6H, m) , 7.40-7.42 (2H, m).

<13>C NMR (CDCl3) δ: 13.75, 62.27, 104.05, 116.69, 115.53 (d, 2JC_F=22.7 Hz), 115.88 (d, 2Jc_p=22, 7 Hz), 131.64 (d, 3Jc_p=9.1 Hz), 132.66 (d, 3J„ „=9.1 Hz), 134.25, 134.31, 134.36, 164.01 ( d, 1 C 1 JC_F=252.9 Hz), 164.52 (d, <X>JC_F=254.0 Hz), 166.5 ppm.

Analysis for C^gH^3N02F2:

Calculated: C: 69.01%; H: 4.15%; N: 4.47%.

Found: C: 68.91%; H: 4.15%; N: 4.62%.

Example 2

Ethyl-3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate

A dry 50 mL round bottom flask was charged with 5.0 g (16.0 mmol) of ethyl 2-cyano-3,3-bis-(4-fluorophenyl)-2-propenoate, followed by 8.0 g (24.1 mmol ) azidotributylstannane (prepared as described in Rev. Trav. Chim., Vol 81, 1962, p. 202-205) and 2.0 ml of reagent grade toluene. The heterogeneous mixture was stirred and heated to reflux temperature (110°C) in an oil bath behind a safety screen. The solid starting material was dissolved gradually using a pale yellow thick syrup, and the homogeneous mixture was stirred and refluxed for 20 hours. By analytical thin-layer chromatography, elution with 20 vol% MeOH in CHCl 3 showed the product at R^ = 0.26 (stripe). The crude reaction mixture was diluted with an equal volume of diethyl ether and poured into a vigorously stirred, saturated aqueous solution of KF (200 mL containing 2 mL of 48 percent HBF^). A voluminous precipitate (Bu3SnF) was observed soon after mixing, and the hydrolysis continued for 16 hours. The suspension was filtered and the filtrate extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure. The title compound was crystallized from the concentrate, yielding 4.54 g (77%) of a white, analytically pure material, m.p. 159-161°C.

IR (KBr) vmax: 3438 (br), 1713 (vs), 1600 (s), 1510 (s), 1238 (s), 841 (s) cm<-1>.

<1>H NMR (CDC13)6 : 0.92 (3H, t, J=7.6 Hz), 3.98 (2H, q, J=7.6Hz), 7.3-6.7 (8H , m), 10 (1H, v.br.).

<13>C NMR (CDCl3 ) 6: 166.52, 163.54 (d, <1>JC_F=250.7 Hz), 163.46 (d, <1>JC_F=262.7 Hz), 157, 14, 136.40, 134.74, 131.71 (d, <2>JC_F=62.7 Hz), 131.59 (d, <2>JC_F=66.4 Hz), 115.75 (d, <3>JC_F<=1>8.9 Hz), 115.45 (d, <3>JC_F=18.1 Hz), 62.11, 13.47 ppm.

Analysis for ci8<H1>4<F>2<N>4°2:

Calculated: C: 60.27%; H: 4.06%; N: 15.50%.

Found: C: 60.67%; H: 3.96%; N: 15.72%.

Example 3

Ethyl-3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate

To a solution of 0.5 g (1.40 mmol) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate in 100 ml of dry benzene, 45°C under argon added 100 mg (60% in mineral oil, 2.5 mmol) sodium hydride in one portion. The greyish suspension was stirred at 45°C for 30 minutes, and then 1 ml (16.1 mmol) of methyl iodide was added, after which the flask was closed with a rubber stopper. The alkylation mixture was allowed to stand at 40-45°C for a total of 4 days. By analytical thin layer chromatography, elution 2 times with 20% EtOAc in hexanes showed only two isomeric products at Rf = 0.16 (major isomer) and Rf = 0.22 (biisomer). The crude reaction mixture was washed with an equal volume of water, and the aqueous phase was extracted once with 50 ml of diethyl ether. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give a crude product.

The crude product mixture (5.0 g), which was prepared as described above, was taken up in 20 ml of hot ethyl acetate, to which was added 40 ml of hot hexane mixture. The clear solution was slowly cooled to room temperature to give 2.16 g (52%) of the title compound as colorless large needles, m.p. 144-145°C.

IR (KBr) v v : 1713 (vs), 1600 (s), 1513 (s), 1325 (s), 1163 (s), 838 (s) cm".

<13>C NMR (CDC13) e : 165.44, 163.6 (d, <1>JC_F=250.7 Hz), 163.4 (d, <1>JC_F=252.9 Hz), 156, 85, 152.37, 135.88, 131.32 (d, <3>JC_F=8.3 Hz), 115.94 (d, <9>JC_F=21.9 Hz), 115.64 (d, <2>JC_F=22.7 Hz), 61.84, 33.76 13.59 ppm.

Analysis for cigHi6F2<N>4°2:

Calculated: C: 61.62; H: 4.35%; N: 15.13%.

Found: C: 61.63; H: 4.45%; N: 15.21%.

Example 4

3, 3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2- propenoic acid

To a solution of 4.0 g (10.8 mmol) of ethyl 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate in a mixture which contained 20 ml of methanol and 20 ml of tetrahydrofuran, a 3 molar solution of lithium hydroxide in water (9 ml) was added at 0°C (ice-water bath). The saponification reaction was carried out overnight (approx. 16 hours) whereby a clear, homogeneous solution was formed. By analytical thin-layer chromatography, elution 2 times with 30 vol% in hexanes showed the desired compound at the starting point. The crude reaction mixture was acidified by the addition of 10 ml of a 3 molar HCl solution, and the organic material was extracted twice with 2 x 20 ml of ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give the product as a pale yellow solid. Recrystallization from an EtOAc-hexane mixture (1:9, v/v) gave 3.8 g (100%) of the title compound, m.p. 205-206°C.

IR (KBr) vmax: 3438 (br), 2900 (br), 1725 (s), 1713 (s), 1600 (s), 1501 (s), 1231 (vs), 1156 (s), 850 (s) cm<-1>.

1 H NMR (CDCl 3 ) 6 : 7.9-6.4 (8H, m), 3.68 (3H, s).

<13>C NMR (CDCl3) p: 166.57, 163.3 (d, <1>JC_F=249.9 Hz), 163.03 (d, iJc_F=250 Hz), 155.68, 152.61 , 135.58, 134.74, 131.75 (d, <3>JC_F=8.3 Hz), 131.28 (d, <3>JC_F=9.1 Hz), 117, 115.7 (d , <2>JC_F=22.6 Hz), 115.4 (d, <2>JC_F=22.6 Hz), 33.6 ppm.

Analysis for ci7<H>i2<F>2<N>4°2<:>

Calculated: C: 59.05%; H: 3.53%; N: 16.37%.

Found: C: 59.54%; H: 3.58%; N: 16.27%.

Example 5

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

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

To a solution of 3.8 g (11.0 mmol) of dry (0.1 mm Hg at 80°C) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5- yl)-2-propenoic acid in 20 ml of dry methylene chloride, 4 ml (46.0 mmol) of purified oxalyl chloride (redistilled over CaH2) was added in one portion. The reaction mixture was gradually heated to reflux temperature for 2 hours. The mixture was evaporated under reduced pressure to remove volatile solvent. Then, excess oxalyl chloride was removed under vacuum (20 mm Hg) at ambient temperature for 2 hours and under high vacuum (0.1 mm Hg) at 50°C for 16 hours to obtain the title compound.

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

The acyl chloride prepared in step A was dissolved in 150 ml of tetrahydrofuran and cooled to -78°C under argon. To this light brownish solution, 8.0 ml of lithium aluminum hydride in tetrahydrofuran solution (1.0 molar) was added at -78°C. Analytical thin layer chromatography showed after 15 minutes only one mobile spot with Rf = 0.23 (50 vol% EtOAc in hexanes). The crude reaction mixture was diluted with 2 M H-^SO^. The aqueous layer was extracted with 2 x 40 ml of ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give 3.64 g (100%) of the title compound. The crude allyl alcohol compound was immediately used in the next step without further purification.

MS (Cl): m/e = 328 for (M+H)<+>.

IR (KBr) vmax: 3388 (v.br.), 1600 (s), 1501 (s), 1225 (s), 1156 (s), 838 (s), 750 (s) cm<-1>.

^■H NMR (CDCl 3 ) 6 : 7.5-6.9 (8H, m), 4.52 (2H, br), 3.42 (3H, s), 3.75 (1H, br, D 2 O switchable ).

<1>H NMR (DMSO-dg) s- 7.5-6.9 (8H, m), 5.23 (1H, t, J=5.5 Hz), 4.27 (2H, d, J =5.5 Hz), 3.54 (3H, s) ppm.

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

To 3.64 g of a vigorously stirred solution of the crude allyl alcohol compound prepared in step B in 40 ml of methylene chloride, 2.6 g (12.0 mmol) of pyridine chlorochromate was added in one portion at room temperature. Analytical thin layer chromatography immediately afterwards showed R^ = 0.34 for about 50% of the product together with R^ = 0.14 for the starting material (elution with 50 vol% EtOAc in hexanes). The oxidation took place at room temperature for a total of 16 hours. During this time, all starting material was consumed and only the compound was detected by thin layer chromatography. The crude reaction suspension was filtered through a layer of silica gel, washed with 1 1 10 vol% ethyl acetate in hexanes and 1 1 20 vol% ethyl acetate in hexanes. The desired compound was crystallized by concentration under reduced pressure, whereby 2.7 g (74%) of the title compound was obtained, m.p. 141-142°C.

MS (Cl): m/e = 326 for (M+H)<+>.

IR (KBr) v ntciK . s : 3075 (m), 2875 (m), 1675 (s)-, i 1600 (s), 1501 (s), 1238 (s), 1156 (s), 850 (s), 750 (s) cm < 1>.

^ NMR (CDCl 3 ) δ : 9.63 (1H, s), 9.5-6.9 (8H, m), 3.74 (3H, s).

<13>C NMR (CDC1-) 6 : 188.92, 165.44, 164.68 (d, ^-J. =254.4 1 o L—r Hz), 164.10 (d, Jn =255 .9 Hz), 151.34, 134.31, 133.77 (d, 3 C 3 JJ =8.3 Hz), 132.69, 132.33 (d, <J>JC_F=7.5 Hz) , 123.70, 116.26 (d, <2>JC_F=21.9 Hz), 116.18 (d, <2>Jc_p=22.7 Hz), 34.10 ppm.

Analysis for ci7H]_2F2N4 :

Calculated: C: 62.58%; H: 3.71%; N: 17.17%.

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

Example 6

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

A solution of 1.0 g (3.07 mmol) of 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal and 0.93 g (3.07 mmol ) triphenylphosphoranylidene acetaldehyde in benzene was refluxed for 1 hour. The benzene was removed under vacuum and the residue purified by column chromatography on silica gel eluting with 15 vol% ethyl acetate in hexane, whereby 0.7 g of the title compound was obtained, m.p. 156-157.5°C).

Analysis for ci9<H>i4<F>2<N>40:

Calculated: C: 64.77%; H: 4.01%; N: 15.91%.

Found: C: 65.13%; H: 4.05%; N: 15.71%.

Example 7

Ethyl- 9, 9- bis( 4- fluorophenyl)- 5- hydroxy- 8-( 1- methyl- 1H- tetrazol- 5-yl)- 3- oxo- 6, 8- nonadienoate

To a cooled (0°C, ice-water bath) suspension of 0.64 g (16.0 mmol) of NaH (60% in mineral oil) in 20 ml of dry tetrahydrofuran, 2.04 ml (16.0 mmol) were added under nitrogen ethyl acetoacetate in 4 equal portions. The homogeneous, clear solution was stirred at 0°C for 30 min, followed by the dropwise addition of 6.4 mL (16.0 mmol) of 2.5 molar n-BuLi over 15 min. The orange colored dianion solution was stirred at 0°C for a further 1 hour. The ice-water bath was replaced with an acetone-dry ice bath at

-78°C, and the dianion was transferred by means of a needle to a 20 ml tetrahydrofuran solution containing 2.82 g (8.01 mmol) 5,5-bis-(4-fluorophenyl)-4-(1-methyl-1H -tetrazol-5-yl)-2,4-pentadienal. Analytical thin layer chromatography showed at Rf = 0.15 (50% EtOAc in hexanes) the desired major product and a minor amount of another product at Rf = 0.2. The crude reaction mixture was diluted with 40 mL of 1 N HCl, and the aqueous layer was extracted with 2 x 50 mL of ethyl acetate. The organic layers were combined, dried over

MgSO^ and concentrated under reduced pressure. The desired compound was purified on silica gel by flash column chromatography eluting with 20 vol% EtOAc in hexanes to give 2.26 g (58.5%) of the title compound.

MS (Cl): m/e: 483 for (M+H)<+>.

IR (KBr) vmax: 3450 (v.br), 1738 (s), 1725 (s), 1606 (s), 1513 (vs), 1225 (s), 1163 (s), 844 (s) cm<- 1>.

<1>H NMR (CDCl 3 ) 6 : 7.4-6.8 (8H, m), 6.72 (1H, d, J=15.6 Hz), 4.63 (1H, m), 4, 17 (2H, q, J=71, Hz), 4.13 (1H, m), 3.60 (3H, s), 3.52 (1H, d, J=3.9 Hz, D20 switchable), 3.47 (2H, s), 2.74 (2H, d, J=6.0 Hz), 1.26 (3H, t, J=7.1 Hz) ppm.

<13>H NMR (CDCl3 ) δ : 164.21, 135.98, 132.34 (d, <3>JC_F=8.3 HZ), 131.45 (d, <3>JC_F=9.1 Hz ), 115.74 (d, <2>JC_F=21.9 Hz), 115.74 (d, 2JO _ —r„=21.1 Hz), 100.86, 67.61, 61.58, 49 .85, 49.07, 33.56, 14.10 ppm.

Example 8

Ethyl-(-)- erythro- 9, 9- bis( 4- fluorophenyl)- 3, 5- dihydroxy- 8-( 1- methyl-1H- tetrazol- 5- yl)- 6, 8- nonadienoate

To a solution of 2.19 g (4.53 mmol) ethyl-9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo -6,8-nonadienoate (dried under high vacuum at 30°C for 48 hours) in 40 ml of anhydrous tetrahydrofuran, 4.8 ml (4.8 mmol) of triethylborane solution in tetrahydrofuran was added at 0°C (ice-water bath) under argon in one portion. The mixture was stirred under argon for 1 hour. The cooling ice-water bath was replaced by an acetone-dry ice bath, and 0.20 g (5.3 mmol) of NaBH 2 was added to the reaction mixture in one portion. The reaction suspension was stirred at -78°C for 2 hours, whereby a clear, homogeneous, pale yellow solution was formed. The crude reaction mixture was diluted with 40 mL of 1 N HCl, followed by extraction with 2 x 40 mL of EtOAc. The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure, whereby the product was obtained as a thick syrup which was further thinned with 300 ml of methanol, after which the solution was left at room temperature for 16 hours before evaporation under reduced pressure. The crude product was purified on silica gel by flash column chromatography using 2 L of 30% EtOAc in hexanes as eluent. The relevant fractions were collected and evaporated, whereby 1.48 g (68% of the title compound) was obtained.

MS (Cl): m/e: 485 for (M+H)<+>.

IR (KBr) vmax: 3438 (s), 1734 (s), 1600 (s), 1513 (s), 1225 (s), 1163 (s), 844 (s) cm<-1>.

"""H NMR (DMSO-d6) 6: 7.4-7.3 (4H, m) , 7.04 (2H, t, J=8.9 Hz), 6.9-6.7 (2H , m), 6.52.(1H, dd, J=l, 15.2 Hz), 5.16 (1H, dd, J=5.6, 15.7 Hz), 4.89 (1H, d , J=4.8 Hz), 4.72 (1H, d, J=5.5 Hz), 4.13 (1H, m), 4.04 (2H, q, J=7.2), 3 .85 (1H, m), 3.75 (3H, s), 2.42 (1H, dd, J=4.6, 15 Hz), 2.28 (1H, dd, J=8.3, 15 Hz), 5.5

(1H, m), 4.2 (1H, m), 1.17 (3H, t, J=7.2 Hz).

<13>C NMR (DMSO-d,.) 6 : 171.02, 163.51, 163.05, 153.03, 145.34, 139.46, 136.34, 132.2 (d, 3JJ„ „=8.3 Hz), 131.0 (d, 13 JC_F=9.1 Hz), 125.14, 121.64, 115.41 (d, <2>^Jc_p=20.4 Hz), 115 .13 (d, <2>JC_F=21.1 Hz), 69.79, 64.76, 59.50, 44.10, 42.34, 33.44, 14.01 ppm.

Analysis for <C>25<H>26<F>2<N>4°4<:>

Calculated C: 61.98%; H: 5.41%; N: 11.56%.

Found C: 61.51%; H: 5.67%; N: 11.12%.

Example 9

Sodium-(—)- erythro- 9, 9- bis( 4- fluorophenyl- 3, 5- dihydroxy- 8-( 1-methyl- 1H- tetrazol- 5- yl)- 6, 8- nonadienoate

To a solution of 1.231 g (2.54 mmol) ethyl-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8 -nonadienoate in 35 ml of tetrahydrofuran, 2.54 ml (1.0 equivalent) of 1 N NaOH solution were added dropwise at 0°C. The rate of addition was sufficiently low to prevent the reaction mixture from changing color to deep amber or reddish. The reaction mixture was stirred for 30 minutes at 0°C, whereby a clear homogeneous solution was obtained. The reaction mixture was heated to ambient temperature, and the saponification proceeded for a further 1 hour. By analytical thin layer chromatography, elution with 20 vol% MeOH in CHCl 3 showed the desired product at Rf = 0.2. Most of the organic solvent was evaporated at approx. 10°C at a pressure of 20 mm Hg. The resulting thick syrup was diluted with 4 mL of water, and the solution was then lyophilized at 0.01 mm Hg, yielding 1.126 g (100%) of the title compound as a sodium salt, which was found to contain ca. . 1 mole of water, m.p. above 100°C during decomposition.

IR (KBr)vmax: 3400 (v.br), 1600 (s), 1575 (s), 1513 (s),

1438 (s), 1404 (s), 1225 (s), 1156 (s), 838 (s) cm"1.

<1>H NMR (DMSO-dg) 6:7.3-7.4 (4H, m), 7.06 (1H, br, D2O switchable), 7.00-7.06 (2H, m), 6.87-6.91 (2H, m), 6.49 (1H, d, J=15.7 Hz), 5.13 (1H, dd, J=5.4, 15.7 Hz), 5 .05 (1H, br, D20 switchable), 4.14 (1H, m), 3.74 (3H, s), 3.62 (1H, m), 1.99 (1H, dd, J=3, 7, 13.5 Hz), 1.80 (1H, dd, J=8.5, 13.5 Hz), 1.43 (1H, m), 1.30 (1H, m).

<13>C NMR (DMSO-dg) 6: 175.87, 161.85, (d, <1>JC_F=246.1 Hz), 161.37 (d, 1Jn =246.9 Hz), 153, 08, 144.97, 139.88, 136.40, C 3 3 135.51, 132.22 (d, °Jn -.=8.3 Hz), 130.97 (d, JJ_ -.=8, 3 Hz), <-—r _ U—r _ 124.66, 121.74, 115.42 (d, =21.9 Hz), 115.2 (d, JC_F=23.4 Hz), 68, 23, 65.71, 44.50, 43.55, 33.45 ppm.

Analysis for C23<H>21F2N404Na H20:

Calculated: C: 55.64%; H: 4.67%; N: 11.28%.

Found: C: 55.24%, H: 4.65%; N: 10.85%.

Example 10

Trans- 6-[ 4, 4- bis( 4- fluorophenyl)- 3-( 1- methyl- 1H- tetrazol- 5- yl)- 1, 3- butadienyl]- tetrahydro- 4- hydroxy- 2H- pyran- 2 - wed

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

A solution of 0.64 g (1.32 mmol) ethyl-(+)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazole-5 -yl)-6,8-nonadienoate in 25 ml of tetrahydrofuran was treated at 0°C with 1.32 ml of a 1.0 molar NaOH solution. The pale yellow suspension was stirred at 0°C for 2 hours, whereby a clear, pale yellow solution was formed. The crude reaction mixture was diluted with 5 mL of 2 N aqueous HCl solution, and organic material was extracted with 2 x 40 mL of ethyl acetate. The organic extracts were combined, dried over MgSO 4 and concentrated under reduced pressure to give a pale yellow gum. The crude dihydroxy acid was dried vigorously under high vacuum (0.01 mm Hg) at room temperature for 24 hours before being subjected to the next step.

B. Trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran - 2- Wed

The dry acid from step A above was dissolved in 100 mL of dry methylene chloride under argon at room temperature, followed by the addition of 1.7 g (4.0 mmol) of 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide-metho-p -toluenesulfonate. The lactone formation was complete in less than 15 minutes, which was evident by analytical thin layer chromatography (Rf = 0.12) after elution 3 times with 50% ethyl acetate in hexanes. Most of the solvent was evaporated under reduced pressure and the residue was washed with 40 ml of water, followed by extraction with 2 x 40 ml of ethyl acetate. The organic layers were combined, dried over MgSO 4 and concentrated under reduced pressure to give 0.54 g (89.7%) of the compound. A pure sample of the compound was obtained by passing it through a short layer of silica gel eluting with 40 vol% ethyl acetate in hexanes, whereby the title compound, which was found to contain 2 moles of water, was obtained.

MS (Cl): m/e = 438 for (M+H)<+>.

IR (KBr) vmax: 3425 (br), 1738 (v.s.), 1600 (s), 1513 (s), 1225 (vs), 1156 (s), 1038 (s), 838. (s) cm"1.

<X>H NMR (CDCl 3 ) 6 : 7.26-7.21 (2H, m), 7.14 (2H, d, J=8.7 Hz), 6.86 (4H, d, J=6 .8 Hz), 6.72 (1H, dd, J=0.8, 15.6 Hz), 5.34 (1H, dd, J=7.1, 15.6 Hz), 5.18 (1H , m), 4.37 (1H, m), 3.57 (3H, s), 2.68 (1H, dd, J=4.5, 18 Hz), 2.60 (1H, ddd, J= 3.63, 2.5, 18 Hz), 2.44 (1H, d, J=2.6 H2, D20 switchable), 2.00 (1H, dt, J=18, 1.7 Hz), 1 .79 (1H, td, 3=2, 1, 18 Hz) ppm.

<13>C NMR (CDCl3) s : 169.20, 163, 162.5, 153.20, 148.81, 135.61, 134.95, 132.45 (d, 3JC_F=8 Hz), 132, 52, 131.51 (d, <3>JC_F= 8 Hz), 130.04, 120.44, 115.95 (d, 2Jr -,=21.9 Hz), 115.83 (d, 2 C~ F JC_F=21.9 Hz), 75.67, 62.54, 38.58, 35.58, 33.64 ppm.

Analysis for C23H20F2N4°3 2H20:

Calculated: 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 was crystallized from cyclohexanebenzene, whereby the title compound was obtained as a crystalline solid containing approx. 1 mole of benzene, m.p. 105-106°C.

Analysis, for C23H2QF2N403 CgHg:

Calculated: C: 67.48%; H: 5.07%; N: 10.85%.

Found: C: 67.44%; H: 5.23%; N: 10.59%.

Example 11

4,4'-difluoro-3,3'-dimethylbenzophenone

8 ml (73 mmol) of 2-fluorotoluene was added to a vigorously stirred mixture of 61.43 g (460 mmol) of aluminum chloride and 135 ml of carbon tetrachloride at 0°C. After 10 minutes, 92 ml (837 mmol) of 2-fluorotoluene in 75 ml of carbon tetrachloride was added dropwise over 4 hours, and the mixture was stirred for 2 hours at 0°C. It should be noted as a warning that a spontaneous, vigorous reaction occurred after the addition of 2-fluorotoluene. The mixture was cooled to

-20°C, and the reaction was quenched with 250 ml of 2 N HCl. The organic layer was separated, washed with brine and dried with M 2 SO 4

4. The solvent was removed by evaporation, and the residue was 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 layer was separated, dried with MgSO 4 and evaporated. Crystallization from ethanol gave 50 g (49%) of the title compound, m.p. 128-130°C.

IR (KBr) vmax: 1650cm"1.

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

Analysis for C]_5<Hi>2F20:

Calculated: C: 73.16%; H: 4.91%.

.Found: C: 72.96%; H: 4.80%.

Example 12

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

A solution of 2.55 g (26 mmol) of 1,5-dimethyltetrazole in 15 ml of dry tetrahydrofuran was treated at -78 °C with 12.5 ml of a 2.5 M solution of n-butyllithium in hexane (31, 2 mmol), and the mixture was stirred for 15 minutes. 5 g (20.3 mmol) of 4,4'-difluoro-3,3'-dimethylbenzophenone in 20 ml of dry tetrahydrofuran was added, the mixture was stirred for 1 hour, and the reaction was then quenched with 250 ml (2N HCl). The aqueous phase was extracted with 3 x 50 mL ethyl acetate, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by silica gel column chromatography using 20 vol% EtOAc:hexane as eluent to give 3.7 g (52%) of the compound. Recrystallization from EtOAc-hexanes gave the title compound, m.p. 41-42°C.

Ir (KBr) v . : 3400 (br) cm<-1>. , max

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

Analysis for C2.gH18F2N4°:

Calculated: C: 62.79%; H: 5.27%; N: 16.27%.

Found: C: 62.73%; N: 5.32%; N: 16.16%.

Example 13

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

A mixture of 3.58 g (10.9 mmol) of 1,1-bis(4-fluoro-3-methyl-phenyl)2-(1-methyl-1H-tetrazol-5-yl)ethanol and 530 mg of kaliurahydro- gen sulfate was heated at 195°C for 1.5 hours. The mixture was then cooled to 70°C and 50 ml of chloroform was added. Insoluble material was removed by filtration, and the filtrate was evaporated. The residue was crystallized from EtOAc-hexane to give 3.38 g (100%) of the title compound, m.p. 138-139°C.

<1>H NMR (CDCl 3 ) 7.20-6.80 (m, 6H), 6.65 (s, 1H), 3.56 (s, 3H), 2.28 (s, 3H), 2, 18 (p, 3H),

Analysis for cj8<H>l8<F>2<N>4<0:>

Calculated: C: 66.25%; H: 4.95%; N: 17.17%.

Found: C: 66.15%; H: 5.05%; N: 17.24%.

Example 14

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

A solution of 3.78 g (11.0 mmol) of 1,1-bis(4-fluoro-3-methyl-phenyl)-2-(1-methyltetrazol-5-yl)ethene in 20 ml of dry tetrahydrofuran was at - 78°C treated with 5.3 ml of a 2.5 M solution of n-butyllithium in hexane (13.25 mmol) and the mixture was stirred at -78°C for one hour. 1.33 mL (1.22 g, 16.5 mmol) of ethyl formate was added and the mixture was warmed to 23°C over 1 h, after which the reaction was quenched with 250 mL of 2 N HCl. The aqueous phase was extracted with 3 x 50 mL ethyl acetate, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 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) \> : 2660 cm"<1>. , max

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

Analysis for C19<H>l<gF>2<N>4<0:>

Calculated: C: 64.41%; H: 4.56%; N: 15.82%.

Found: C: 64.60%; H: 4.70%; N: 15.62%.

Example 15

1, 1- bis-(2, 4- dimethylphenyl)- 2-( 1- methyl- 1H- tetrazol- 5- yl) ethanol

A solution of 8.9 g (91.0 mmol) of 1,5-dimethyltetrazbl in 100 ml of dry tetrahydrofuran was treated at -60°C with 48 ml of a 1.89 M solution of n-butyllithium (91 mmol). After stirring for 20 minutes, 18 g (76 mmol) of 2,2<*>,4,4<*->tetramethyl-benzophenone (prepared by the method described in J. Am. Chem. Soc, Vol 81, 1959, p. 4858) in 50 ml of dry tetrahydrofuran, and the solution was stirred for 1 hour while warming to -20°C. The reaction was quenched with 1N HCl, and then the solution was extracted with chloroform. The combined organic extracts were dried with MgSO 4 and evaporated to give 22 g of the title compound, m.p. 175-177°C.

IR (KBr) ^max: 3390 (br), 1620 (s), 1460 (s), 1200 (s), 820 (s) cm"1.

<1>H NMR (CDCl3 ) 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 (CDCl3) «: 152.34, 139.28, 137.32, 135.79, 133.24, 126.26, 125.92, 77.47, 35.04, 32.99, 21.28, 20.76 ppm.

Analysis for C^I^N^O:

Calculated: C: 71.41%; H: 7.20%, N: 16.67%.

Found: C: 70.82%; H: 7.26%; N: 16.45%.

Example 16

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

A mixture of 1.8 g (5.4 mmol) of 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol and 100 mg of potassium hydrogen sulfate was placed in a oil bath which was preheated to 190°C. After 15 minutes the melt was cooled and methylene chloride was added to the residue. The insoluble materials were removed and the solution was evaporated. The residue was crystallized from isopropyl ether, whereby 1.2 g of the title compound was obtained, m.p. 143-143.5°C.

IR (KBr) vmax: 2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 820 (s), 740 (s) cm"<1>.

^■H NMR (CDCl 3 ) «: 7.15-6.80 (6H, m), 6.60 (1H, s), 3.40 (3H, s), 2.36 (3H, s), 2 .30 (3H, s), 2.18 (3H, s), 1.85 (3H, s) ppm.

<13>C NMR (CDCl3) δ: 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.

Analysis for C2o<H2>2N4:

Calculated: C: 75.45%; H: 6.97%; N: 17.60%.

Found: C: 75.04%; H: 7.03%; N: 17.63%.

Example 17

3, 3- bis( 2, 4- dimethylphenyl)- 2-( 1- methyl- 1B>tetrazol- 5- yl)- 2- propenal

A solution of 1.0 g (3.1 mmol) of 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ene in 10 ml of dry tetrahydrofuran was treated with 1, 64 ml of a 1.89 M solution (3.1 mmol) of n-butyllithium at -78° C. After stirring with cooling for 30 minutes, 0.3 g (4.0 mmol) of ethyl formate was added and the mixture was -stirred with cooling for 2 h. The reaction was quenched with 1 N HCl, and the solution was extracted with chloroform. The combined organic extracts were dried with MgSO 4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 10 vol% ethyl acetate in hexane to give 0.9 g of product as an oil.Treatment of the oil with isopropyl ether gave the title compound as a solid, mp 117-120°C.

MS (Cl): m/e = 347 for (M+H)<+>.

<X>H NMR (CDCl 3 ) «: 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.

<13>C NMR (CDC13) «: 189.49, 168.80, 151.05, 140.87, 140.26, 137.06, 135.86, 134.87, 133.28, 132.04, 129.60, 126.62, 125.28, 34.17, 21.21, 21.06, 20.37, 20.07 ppm.

Analysis for C^<H>^<J>^<O:>

Calculated: C: 72.81%; H: 6.41%; N: 16.18%.

Found: C: 72.99%; H: 6.43%; N: 16.09%.

Example 18

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

A. 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl) ethanol

To a solution of 0.98 g (10.0 mmol) 1,5-dimethyltetrazole in 20 ml tetrahydrofuran at -30°C was added 4.7 ml of a 2.14 M solution (10.0 mmol) n- butyllithium. After stirring for 1/4 hour, the solution was cooled to -50°C, and 1.74 g (8.0 mmol) of 4,4'-difluorobenzophenone was added. After stirring for 1 hour at -50°C and 1 hour at -10°C, the reaction was stopped with 1 N HCl. The mixture was extracted with methylene chloride, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 40 vol% ethyl acetate in hexane, whereby 2.0 g of the title compound was obtained, m.p. 116-118°C.

Analysis for ClgH14<F>2<N>40:

Calculated: C: 60.75%; H: 4.47%; N: 17.72%.

Found: C: 60.62%; H: 4.52%; H: 17.63%.

B. 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 4.2 g (12.7 mmol) of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (prepared in step A) and potassium hydrogen sulfate was heated at 195°C for h hour. After cooling, the mixture was dissolved in chloroform and washed with water. The organic layer was dried and evaporated in vacuo. The residue was treated with diethyl ether, whereby 3.9 g of the title compound was obtained, m.p. 169-171°C.

Analysis for C^7H^2<F>2<N>4<0:>

Calculated: C: 62.58%; H: 3.71%; N: 17.18%.

Found: C: 62.15%; H: 3.82%; N: 16.75%.

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

To a finely divided suspension of 1.0 g (3.3 mmol) 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl Jetene (prepared in step B) in To 10 ml of tetrahydrofuran was added at -80°C 1.54 ml of a 2.14 M solution (3.3 mmol) of n-butyllithium, which resulted in the formation of a dark purple color.After stirring for 40 minutes at -80 °C, 0.32 g (4.3 mmol) of ethyl formate was added, and the mixture was stirred for 2.5 h at -80 °C. The mixture was hydrolyzed with 1 N HCl and extracted with methylene chloride. The extracts were dried with MgSO 4 and evaporated in vacuo. The residue was treated with diethyl ether to give 0.77 g of a yellow solid, mp 128-131° C. The solid was crystallized from isopropyl acetate:hexane to give 0.55 g of the title compound , mp 130-132°C.

Analysis for C-^H^F^^jO:

Calculated: C: 62.58%; H: 3.71%; N: 17.18%.

Found: C: 62.15%; H: 3.82%; N: 16.75%.

Example 19

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

A. 5-ethyl-1-methyl-1H-tetrazole

To a slurry of 4.9 g (0.05 mol) of 1,5-dimethyltetrazole in 50 ml of dry tetrahydrofuran, during 15 minutes at

-78°C under an inert atmosphere added 20 ml of 2.5 M n-butyllithium (0.05 mmol) in hexanes. The mixture was stirred for 30 minutes, during which time a yellowish precipitate formed. 3.7 mL (0.06 mmol) of methyl iodide was then added over 15 minutes. After stirring for an additional 30 minutes, the clear reaction

mixture diluted with water and extracted with 3 x 50 ml ethyl acetate. The aqueous layer was washed with 2 x 25 mL chloroform, and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil was purified by distillation to give 5.2 g (92%) of the title compound, bp: 89-90°C at 0.05 mm Hg.

<X>H NMR (CDCl 3 ) 4.05 (s, 3H), 2.86 (q, 2H), 1.41 (t, 3H). <13>C NMR (CDCl3 ) δ: 156.0, 33.24, 16.75, 11.20.

B. 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol

To a solution of 5.6 g (0.05 mmol) of 5-ethyl-1-methyl-1H-tetrazole (prepared in step A) in 60 ml of dry tetrahydrofuran, during 5 minutes at -78°C (bath temperature ) under an inert atmosphere added 20 ml of 2.5 M n-butyllithium (0.05 mmol) in hexane. The mixture was stirred for 30 minutes, and a solution of 10.8 g (0.5 mol) of 4,4•-difluorobenzophenone in 25 ml of dry tetrahydrofuran was added over 5 minutes. The mixture was stirred for a further 2 hours, while the bath temperature slowly rose to -20°C. The reaction was quenched with 1 N HCl and extracted with 3 x 50 mL ethyl acetate and 3 x 50 mL chloroform. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The solid was purified by crystallization from ethanol-hexane, whereby 10.8 g (65%) of the title compound was obtained, m.p. 160-161°C.

IR (KBr) v . : 3400 cm"<1>. , max

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

<13>C NMR (CDC13) «: 162.57, 162.37, 159.14, 156.71, 142.48, 140.54, 128.25, 128.13, 127.52, 127.42, 114.67, 114.41, 144.38, 78.56, 36.99, 33.43, 14.52.

Analysis for C17<H>l<g?7N>40:

Calculated: C: 61.81%; H: 4.38%; N: 16.96%.

Found: C: 61.79%; H: 4.90%; N: 17.09%.

C. 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propene

A slurry of 8.25 g (0.025 mmol) of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol (prepared in step B) and 100 mg of p-toluenesulfonic acid monohydrate in 60 ml of xylene was refluxed for 12 hours using a Dean-Stark overhead collector. The reaction mixture was washed with 10 mL of 1 N NaOH while hot and with 100 mL of water. Concentration of the organic layer gave off-white crystals of the product. This was purified by recrystallization from ethanol-hexane, whereby 7.1 g (91%) of the title compound was obtained as white crystals, m.p. 146-147°C.

I, R (KBr) v max: 1575, 1500 cm"1.

H NMR (CDCl 3 ): 7.42-6.85 (m, 8H 9 , 3.53 (s, 3H), 2.14 (s, 3H).

<13>C NMR (CDCl3) 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.

Analysis for C^ jE^ F2N^ :

Calculated: C: 65.37%; H: 4.51%; N: 17.94%.

Found: C: 65.64%; H: 4.61%; N: 18.09%.

D. 3 / 3-bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene

A slurry of 61.46 g (0.198 mol) 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (prepared in step C), 35, 06 g (0.197 mol) of N-bromosuccinimide and a catalytic amount of azobis-isobutyronitrile or benzoyl peroxide in 1.2 liters of carbon tetrachloride were refluxed in an inert atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature, and the solid from the reaction mixture was filtered off. The filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals, m.p. 159-160°C.

IR (KBr) v , : 1600 cm"1. , max

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

<13>C NMR (CDCl3) δ: 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.

Analysis for C17H^3F2BrN4:

Calculated: C: 52.19%; H: 3.34%; N: 14.32%.

Found: C: 52.58%; H: 3.47%; N: 14.49%.

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

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

Example 20

[1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propen-3-yl]-triphenylphosphonium bromide

A slurry of 1.95 g (0.005 mol) of 3,3-bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene (prepared in Example 19 , step D) and 1.3 g (0.005 mol) of triphenylphosphine in 25 ml of cyclohexane were refluxed. The reaction mixture became a clear solution after 30 minutes, and a white precipitate formed after 1 hour. The mixture was heated for an additional 8 hours and cooled to ambient temperature, and the solid was collected by filtration and washed with diethyl ether. This white powder was dried in vacuo at 50°C to give 3.0 g (92%) of the title compound, m.p. 254-255°C.

IR (KBr) vmax: 3450, 1600, 1500, 1425 cm"<1>.

<X>H NMR (DMSO-dg) δ: 7.92-6.80 (m, 23H), 4.94 (6d, 2H), 3.83 (s, 3H).

<13>C NMR (DMSO-dg) 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, 116.18, 115.89, 115.62, 115.32, 111.43, 111.39, 34.22, 28.88, 28.22.

Analysis' for C35H2gBrF2N4P:

Calculated: C: 64.31%; H: 4.32%; N: 8.57%.

Found: C: 64.02%; H: 4.37%; N: 8.89%.

Example 21

Methyl-(±)- erythro- 9, 9- bis( 4- fluorophenyl)- 3, 5- dihydroxy- 8-( 1- methyl-1H- tetrazol- 5- yl)- 6, 8- nonadienoate

To a slurry of 0.326 g, (0.5 mmol) phosphonium bromide (prepared in Example 20) and 0.26 g (0.4 mmol) methyl-erythro-3,5-bis-(diphenyl-tert-butylsilyloxy)-6 -oxo-hexanoate (prepared by the general methods described by P. Kapa et al., Tetrahedron Letters, 1984, p. 2435-2438, and in US patent 4,571,428) in 1 ml of dry dimethylformamide was left under a inert atmosphere added 0.067 g (0.6 mmol) potassium tert-butoxide at

-20°C (bath temperature). The slurry turned into a red solution and

was stirred for 18 hours at -10°C. The reaction mixture was worked up by adding 10 ml of ammonium chloride solution and extraction with 2 x 30 ml of methylene chloride. The organic layer was dried over sodium sulfate and concentrated to give an oil. The oil was purified through a layer of silica gel and the main fraction was isolated as an oil (160 mg). The oil (160 mg) was stirred with 2 mL of 1 M tetra-n-butylammonium fluoride solution in tetrahydrofuran and a few drops of glacial acetic acid for 18 hours. The reaction mixture was poured into 10 ml of water and extracted with 3 x 20 ml of ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give an oil. The oil was purified by silica gel flash column chromatography eluting with ethyl acetate-hexane = 2:1 to give 0.08 g (75%) of the title compound as an oil.

MS (Cl): m/e = 471 for (M+H)<+>.

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

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

Example 22

4,4'-difluoro-2,2'-dimethylbenzophenone

To a thoroughly stirred mixture of 6.1 g (46.0 mmol) of aluminum chloride in 14 ml of carbon tetrachloride was added at 0°C 3-fluorotoluene (1 g of a total of 10 g, 90.0 mmol), the remaining amount of 3- fluorotoluene in 9 ml of carbon tetrachloride was added and the mixture was stirred at 0°C for 4 hours. The mixture was cooled to -20°C and hydrolyzed by the addition of 25 ml of 1 N HCl. The organic layer was separated and concentrated in vacuo. The residue was stirred for 16 hours with a mixture of 20 ml of benzene, 20 ml of water and 5 ml of acetic acid. The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were dried with MgSO 4 and concentrated in vacuo. Analytical thin layer chromatography of the residue showed 3 spots, Rf = 0.67, 0.59 and 0.56 (5 vol% ethyl acetate in hexane on silica gel). Column chromatography on silica gel with 0.5 vol% ethyl acetate in hexane and collection of the fractions containing material with R_ = 0.67 (5 vol% ethyl acetate in hexane) gave 1.3 g of the title compound, m.p.' 50-52°C.

MS (Cl): m/e = 247 for (M+H)<+>.

<X>H NMR (CDCl 3 ) s 7'26 <2H' dd)' 6'96 (2H, dd), 6.87 (2H, dt), 2.42 (6H, s).

Analysis for ci5<Hi>2<F>2<0:>

Calculated: C: 73.17%; H: 4.92%.

Found: C: 73.34%; H: 5.02%.

Example 23

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

To a suspension of 3.8 g (39.0 mmol) of 1,5-dimethyltetrazole in 40 ml of tetrahydrofuran, 17.7 ml of a 2.2 M solution (39.0 mmol) of butyllithium was added at -40°C. After stirring for 10 minutes, 8 g (32.5 mmol) of 4,4'-difluoro-2,2*-dimethylbenzophenone were added, and the solution was stirred for 3 hours. The reaction was quenched with 1 N HCl. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phases were dried with MgSO 4 and concentrated in vacuo to give 7.5 g of the title compound, m.p. 186-188°C.

Analysis for C2.8H18F2N4°:

Calculated: C: 62.99%; H: 5.27%; N: 16.27%.

Found: C: 63.01%; H: 5.34%; N: 16.18%.

Example 2 4

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

A mixture of 0.5 g (1.5 mmol) 1,1-bis(4-fluoro-2-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol and 0.2 g of p-toluenesulfonic acid was refluxed in 30 ml of toluene for 16 hours. The mixture was cooled, diluted with 50 ml of diethyl ether and extracted with a saturated sodium bicarbonate solution and water. The organic layer was dried with MgSO 4 and concentrated in vacuo. The residue was treated with diethyl ether, whereby 0.3 g of the title compound was obtained, m.p. 120-125°C.

Analysis for cx8H16<F>2N4:

Calculated: C: 66.25%; H: 4.95%; N: 17.17%.

Found: C: 66.55%; H: 4.92%; N: 16.84%.

Example 25

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

To a solution of 1.6 g (5.0 mmol) of 1,1-bis(4-fluoro-2-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene in tetrahydrofuran was to it at -70°C added 2.3 ml of a 2.2 M solution (5.0 mmol) of butyllithium. After stirring for 0.25 hours, 0.44 g (6.0 mmol) of ethyl formate was added and the mixture was stirred for 2 hours. The reaction was quenched with 1N HCl and the mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give 1.0 g of the title compound, m.p. 135-136°C.

Analysis for ci9H]_5<F>2<N>4°<:>

Calculated: C: 64.41%; H: 4.56%; N: 15.82%.

Found: C: 64.22%; H: 4.59%; N: 15.50%.

Example 2 6

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

A solution of 0.88 g (2.5 mmol) of 3,3-bis(4-fluoro-2-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal and 0.75 g (2.5 mmol) of triphenylphosphoranylidene acetaldehyde in 50 ml of benzene was refluxed for 3 hours. The solvent was removed by evaporation, and the crude residue was purified by column chromatography on silica gel eluting with 1 vol% methanol in methylene chloride. The fractions containing material with R^ = 0.9 (1:20 (v/v) methanol:methylene chloride) were combined and concentrated to give 0.8 g of the title compound, m.p. 75-95°C.

MS: M<+> = 380.

<1>H NMR (CDCl3 ) 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).

Analysis for C2i<H>i8<F>2<N>4<0:>

Calculated: C: 66.31%; H: 4.78%; N: 14.73%.

Found: C: 65.76%; H: 4.85%; N: 14.52%.

Example 27

Tert- butyl- 9, 9- bis( 4- fluoro- 2- methylphenyl)- 5- hydroxy- 8-( 1- methyl-1H- tetrazol- 5- yl)- 3- oxo- 6, 8- nonadienoate

To a solution of 1.0 g (2.5 mmol) 5,5-bis(4-fluoro-2-methyl-phenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4 -pentadienal in tetrahydrofuran was added at -50°C to 2.5 ml of a 1 M solution (2.5 mmol) of the dianion of tert-butyl acetoacetate, which had been prepared by adding 4.0 g (25.0 mmol) tert-butyl acetoacetate in 4 mL of tetrahydrofuran to a suspension of sodium hydride (1.0 g of a 60 percent dispersion, 25.0 mmol) in tetrahydrofuran at -5°C, followed by cooling to -30°C and addition of 11 .4 ml of a 2.2 M solution (25 mmol) of butyllithium. After stirring for 1.5 hours, analytical thin layer chromatography showed the starting aldehyde, and an additional 0.5 mL of dianion solution was added. The solution was stirred for an additional 0.5 h, and the reaction was quenched with 1 N HCl. The mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol in methylene chloride, whereby 0.6 g of the title compound was obtained, m.p. 65-72°C.

Analysis for C2gH32<F>2<N>4<0>4<:>

Calculated: C: 64.68%; H: 5.99%; N: 10.41%.

Found: C: 64.50%; H: 5.98%; N: 10.16%.

Example 2 8

Tert-butyl-(±)- erythro- 9, 9- bis( 4- fluoro- 2- methylphenyl)- 3, 5- dihydroxy- 8-( 1- methyl- 1H- tetrazol- 5- yl)- 6, 8 - nonadienoate

To a solution of 2.5 g (4.6 mmol) of 9,9-bis(4-fluoro-2-methyl-phenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate in 30 ml of tetrahydrofuran, 6.0 ml of a 1 M solution (6.0 mmol) of triethylborane was added at -5°C, and the solution was stirred for 1 hour. After cooling to -78°C, 0.36 g (9.0 mmol) of sodium borohydride and 2 ml of methanol were added. The mixture was stirred at -78°C for 2 hours and diluted with 15 ml of hexane. The mixture was hydrolyzed with 1N HCl. The aqueous layer was separated and extracted with methylene chloride. The combined organic solutions were dried and concentrated in vacuo. The residue was dissolved in methanol, and the solution was stirred for 18 hours. The solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 1 vol% methanol in methylene chloride, whereby 1.7 g of the title compound was obtained as a white powder, m.p. 75-80°C.

NMR (CDCl 3 ) -6 : 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).

Analysis for C29<H3>4<F>2<N>4<0>4<:>

Calculated: C: 64.44%; H: 6.34%; N: 10.37%. Found (corrected for 0.28% H 2 O): C: 64.14%; H: 6.41%; N: 10.16%.

Example 29

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

To a solution of 1.65 g (3.05 mmol) tert-butyl-9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazole- 5-yl)-6,8-nonadienoate in 50 ml of ethanol, 3.05 ml of 1 N solution (3.05 mmol) of sodium hydroxide was added, and the solution was stirred at room temperature for 3 hours and at 50°C for 1 hour. The solution was concentrated in vacuo, whereby 1.3 g of the title compound was obtained, which contained approx. 1 mole of water, m.p. 215-225°C during decomposition.

Analysis for C25H25<F>2<N>4<0>4<N>a H20:

Calculated: C: 57.26%; H: 5.19%; N: 10.69%.

Found: C: 57.30%; H: 5.20%; N: 10.00%.

Example 30

2,2'-difluoro-4,4'-dimethylbenzophenone

Concentration of the fractions with the material with Rf = 0.56 from silica gel column chromatography Example 22 and treatment of the residue with hexane gave 1.2 g of the title compound, m.p. 84-85.5°C.

<1>H NMR (CDCl 3 ) «x : <7.>57 (2H, t, JH_H=8 Hz, JpH=8 Hz), 7.02 (2H, d, JH_H=8 Hz), 6.89 ( 2H, d, JpH=8 Hz), 2.39 (6H, s).

Analysis for C]_5H]_2F20:

Calculated: C: 73.17%; H: 4.92%.

Found: C: 73.19%; H: 4.88%.

Example 31

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

To a solution of 4.6 g (4.7 mmol) of 1,5-dimethyltetrazole in 40 ml of tetrahydrofuran, 21.4 ml of a 2.2 M solution (4.7 mmol) of butyllithium was added at -50°C. After stirring for 10 minutes, a solution of 2,2'-difluoro-4,4'-dimethylbenzophenone in tetrahydrofuran (15 ml) was added. The solution was stirred for 2.5 hours while warming to -10°C. The reaction was stopped by the addition of 1 N HCl. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried with MgSO 4 and evaporated. The residue was treated with diethyl ether and crystallized from isopropyl acetate, whereby 8.0 g of the title compound was obtained, m.p. 150-151°C.

MS: M+ = 344.

Analysis for ci8<H>i<gF>2<N>4<0:>

Calculated: C: 62.79%; H: 5.27%; N: 16.27%.

Found: C: 62.84%; H: 5.23%; N: 16.28%.

Example 32

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

A suspension of 7.3 g (21.0 mmol) of 1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol in 200 ml of toluene was mixed with 3 g of p-toluenesulfonic acid, and the mixture was refluxed for 14 hours. After cooling, the mixture was diluted with diethyl ether and extracted with a saturated sodium bicarbonate solution and water. The organic layer was dried with MgSO 4 and evaporated. The residue was treated with isopropyl ether to give the title compound, m.p. 58-60°C.

Analysis for cigH16<F>2<N>4<:>

Calculated: C: 66.25%; H: 4.95%; N: 17.17%.

Found: C: 66.27%; H: 4.945; N: 16.93%.

Example 33

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

To a solution of 1.6 g (5.0 mmol) of 1,1-bis(2-fluoro-4-methyl-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene in 20 ml tetrahydrofuran, 2.3 ml of a 2.2 M solution (5 mmol) of butyllithium was added at -78°C. After stirring for 15 minutes, 0.44 g (6.0 mmol) of ethyl formate was added, and the solution was stirred with cooling for 2 hours. The reaction was quenched with 1 N hydrochloric acid, and the mixture was extracted with diethyl ether. The extracts were dried with MgSO 4 and evaporated. The residue was crystallized from isopropyl acetate, whereby 0.66 g of the title compound was obtained, m.p. 154-155°C.

Analysis for ci9<H]_>6<F>2<N>4<0:>

Calculated: C: 64.41%; H: 4.56%; N: 15.82%.

Found: C: 64.44%; H: 4.63%; N: 15.58%.

Example 3 4

Ethyl-1-methyl-5-tetrazolyl acetate

To a solution of 10 g of 1,5-dimethyltetrazole in 100 ml of dry tetrahydrofuran and 20 ml of hexamethylphosphoramide, 50 ml (1.2 equivalents) of n-butyllithium (2, 5 M in hexane). The deprotonation of 1,5-dimethyltetrazole was allowed to take place for 40 minutes at -78°C, and then for 30 minutes at -20°C. The anion solution was cooled again to -78°C and transferred via a cannula within 45 minutes to a cold (-78°C) solution containing 12 ml of ethyl chloroformate in 50 ml of tetrahydrofuran. The reaction mixture was diluted with 2N aqueous HCl and a saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The residue from the organic extract was purified by flash chromatography on silica gel. The appropriate fractions were combined and evaporated to give 4

g of the product. The product was further purified by crystallization from ethyl acetate in hexanes, whereby 3.52 g (21%) of the title compound was obtained, m.p. 64-66°C.

Analysis for C5Hiø<N4>°2:

Calculated: C: 42.35%; H: 5.92%; N: 32.92%.

Found: C: 42.40%; H: 5.98%; N: 33.15%.

Example 3 5

Ethyl-3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate

A mixture of 2 ml of titanium tetrachloride and 2 ml of carbon tetrachloride was added to 15 ml of tetrahydrofuran at -78°C under an argon atmosphere. The suspension was stirred at -78°C for 30 minutes before adding 0.2 g of 4,4<1->difluorobenzophenone. After stirring for a further 30 minutes, a solution of 0.15 g of ethyl-1-methyl-5-tetrazolylacetate in 1 ml of dry pyridine was added dropwise. The dark brown solution was stirred at -78°C for 15 minutes and then warmed to 0°C, forming a thick paste. The mixture was left for 24 hours at ambient temperature before being poured into water. The aqueous mixture was extracted with ethyl acetate to give the crude product. By analytical thin-layer chromatography, elution 5 times with 20 vol% ethyl acetate in hexanes showed the desired product at R.f = 0.3. Purification by preparative chromatography on 20 x 20 cm<2> 0.25 mm TLC plates gave the title compound, which was identical to the compound of Example 3.

Example 3 6

Dimethyl-[3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl]phosphonate

A slurry of 1.17 g (3.0 mmol) of 3,3-bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene and 0. 41 g (3.3 mmol) of trimethylphosphite was heated at 100°C for 5 minutes. After cooling to ambient temperature, excess trimethylphosphite was removed in vacuo, whereby a pale yellow solid was obtained. This solid was recrystallized from a mixture of ethyl acetate and hexane to give the title compound as a pure white solid, m.p. 140-141°C.

IR (KBr) vmax: 1604, 1511 cm"<1>.

^■H NMR (CDCl 3 ) 6 : 7.76-6.8 (8H, m), 3.6 (3H, s), 3.5 (3H, s), 3.42 (3H, s), 3 .2 (2H, d).

Analysis for C]_9H]_gF2°3N4P:

Calculated: C: 54.29%; H: 4.56%; N: 13.33%.

Found: C: 53.83%; H: 4.48%; N: 13.50%.

Example 3 7

Methyl-(±)- erythro- 9, 9- bis( 4- fluorophenyl)- 3, 5- dihydroxy- 8-( 1- methyl-1H- tetrazol- 5- yl)- 6, 8- nonadienoate

To a solution of 0.84 g (2.0 mmol) of the phosphonate prepared in Example 3 6 was added 1 equivalent (2.0 mmol) of n-BuLi at -78°C (dry ice bath), and the resulting dark red solution was stirred at -78°C for 15 minutes. 1.30 g (2.0 mmol) methyl erythro-3,5-bis(diphenyl-tert-butylsilyloxy)-6-oxo-hexanoate

(prepared according to the general methods described by P, Kapa et al., in Tetrahedron Letters, 1984, pp. 2435-2438 and in US Patent 4,571,428) in 2 mL of tetrahydrofuran was added, and the mixture was stirred for 24 hours. During this time, the reaction mixture was heated to room temperature. The reaction was stopped by the addition of 5 ral of NH 4 Cl, and the mixture was then extracted with 2 x 20 ml of ethyl acetate. The organic layer was dried with Na 2 SO 4 and evaporated under reduced pressure to a yellow oil. The oil was stirred for 24 h with a 1 M tetra-n-butylammonium fluoride solution 1 tetrahydrofuran (4 mL), containing a few drops of glacial acetic acid. The reaction mixture was poured into 20 ml of water and extracted with 3 x 20 ml of methylene chloride. The organic layer was dried with Na 2 SO 4 and concentrated, and the oil was purified by silica gel column flash chromatography eluting with ethyl acetate:hexane = 2:1 to give 0.284 g (41%) of the title compound as an oil.

MS (Cl): m/e = 471 for (M+H)<+>.

<1>H NMR (CDCl3 ) δ: 7.26-6.6 (9H, m), 5.29 (1H, dd), 4.42 (1H, m), 4.28 (1H, m), 3.69 (3H, s), 3.54 (3H, s), 2.42 (2H, d), 1.5 (2H, m).

Example 38

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

A solution of 29.25 g (0.298 mmol) of 1,5-dimethyltetrazole in 400 ml of tetrahydrofuran was cooled to -78°C and treated for 30 minutes with 133 ml of a 2.5 M solution in hexane (0.3325 mol) n-butyllithium. The mixture was stirred at -78°C for 30 minutes and treated with 50 g (0.25 mol) of 4-fluorobenzophenone. The mixture was stirred at -78°C for 30 minutes and warmed to 23°C for 2 hours. The reaction was quenched with 100 ml of 2N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 2 x 100 mL CHCl 4 , and the combined organic layers were dried with Na 2 SO 4 and evaporated to give a brown oil. Purification by chromatography eluting with 20% EtOAc in hexane gave 46.3 g (62%) of the title compound as a white solid, m.p. 113-114°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 299 for (M+H)<+>.

IR (KBr) vmax: 3300 (br), 1605, 1510 cm"<1>.

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

<13>C NMR5: 163.57, 160.29, 152.28, 144.94, 141.12, 141.08, 128.043, 127.87, 127.75, 127.67, 125.76, 115, 25, 114.96, 77.03, 35.38, 33.45 ppm.

Analysis for C^gH^^FN^O:

Calculated: C: 64.42%; H: 5.07%; N: 18.79%.

Found: C: 64.32%; H: 5.05%; N: 18.84%.

Example 39

( E )- l - j 4- fluorophenyl)- 2-( l- methyl- lH- tetrazol-5- yl)- 1- phenylethene and ( 2)- 1-( 4- fluorophenyl)- 2-( l- methyl - 1H-tetrazol-5-yl)-1-phenylethene

A mixture of 3.2 g (10.74 mmol) of tetrazolyl ethanol (prepared in Example 38) and 800 mg of potassium hydrogen sulfate was heated at 195°C for 30 minutes. After cooling to 100°C, 30 ml of chloroform was added and the mixture was treated until almost all of the solid had dissolved. The insoluble and inorganic material was removed by filtration and the solvent was evaporated to give 2.8 g (93%) of a mixture of the title compounds as a light brown solid. The product was crystallized from EtOAc-hexane.

MS (Cl): m/e = 281 for (M+H)<+>.

IR (KBr) v v : 1640, 1600, 1510, 1445, 1220 cm"1. -j msK s

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

<13>C NMR δ : 165.19, 164.58, 161.26, 153.14, 152.97, 152.22, 152.13, 140.53, 137.81, 136.71, 133.99 , 133.94, 131.74, 131.62, 130.38, 129.67, 127.29, 128.85, 128.65, 128.38, 115.97, 115.74, 115.66, 155 .45, 108.29, 108.15, 33.70 ppm.

Analysis for Clg<H>13FN4:

Calculated C: 68.56%; H: 4.68%; N: 19.99%.

Found: C: 68.63%; H: 4.77%; N: 20.37%.

Example 40

( E )- 3-( 4- fluorophenyl)- 2-( 1- methyl- 1H- tetrazol- 5- yl)- 3- phenylpropenal and ( Z )- 3-( 4- fluorophenyl)- 2-( 1- methyl - 1H-tetrazol-5-yl)-3-phenylpropenal

A suspension of 20 g (71.43 mmol) of the olefin prepared in Example 39 in 200 ml of tetrahydrofuran was cooled to -78°C and treated with 31.5 ml of a 2.5 M solution in hexane (78.75 mmol ) butyllithium, and the resulting mixture was stirred at -78°C for 30 minutes. 6.9 g (93 mmol) of ethyl formate was added and the mixture was stirred at -78°C for 2 hours and warmed to 23°C for 1 hour. The reaction was quenched with 100 mL of 2 N HCl, the organic solvent was removed by evaporation, and the residue was extracted with 3 x 75 mL of EtOAc. The combined organic layers were dried with MgSO 4 and evaporated, and the residue was purified by chromatography using 35% EtOAc in hexane as eluent to afford 7.75 g (35%) of the title compound as a mixture of aldehydes.

MS (Cl): m/e = 309 for (M+H)<+>.

<1>H NMR δ: 9.67 (s, 0.66H), 9.64 (s, 0.33H), 7.70-6.90 (m,

9H), 3.74 (s, 1H), 3.68 (s, 2H) ppm.

Example 41

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

A mixture of 5.1 g (16.56 mmol) of the aldehydes mixed in Example 40 and 5.0 g (16.56 mmol) of formylmethylenetriphenylphosphorane and 200 ml of benzene was boiled together under reflux in a nitrogen atmosphere for 2 hours. The solvent was removed by evaporation, and the residue was purified by chromatography using 30% EtOAc in hexane as eluent to give 4.56 g of the product as an orange foam. Fractional crystallization from EtOAc-hexane gave 0.93 g (17%) of the title compound as orange crystals, m.p. 137-138°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 335 for (M+H)<+>.

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

<13>C NMR δ: 192.54, 147.86, 132.09, 131.97, 130.64, 130.41, 128.96, 116.17, 115.87, 33.62 ppm.

Example 42

Ethyl-( E ), ( E )- 9-( 4- fluorophenyl)- 5- hydroxy- 8-( 1- methyl- 1H- tetrazol-5- yl) --. 9- phenyl- 3- oxonona- 6, 8- dienoate

A suspension of 175 mg of 80 percent dispersion (5.83 mmol) of sodium hydride in 10 mL of dry tetrahydrofuran was cooled to 0°C and treated with 725 µl (740 mg, 5.69 mmol) of ethyl acetoacetate and stirred at 0°C. for 10 minutes. 2.3 mL of a 2.5 M solution (5.75 mmol) of butyllithium was added and the mixture was stirred at 0°C for 15 minutes. A solution of 860 mg (2.57 mmol) of the aldehyde prepared in Example 41 in 10 ml of dry tetrahydrofuran was added, and the mixture was stirred at 0°C for 15 minutes. The reaction was stopped by the addition of 30 ml of 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with EtOAc, and the combined organic extracts were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 40% EtOAc in hexane as eluent to give 954 mg (80%) of the title compound as a yellow gum.

MS (Cl): m/e = 465 for (M+H)<+>.

I, R (film) v mak. s: 3400 (br), 1730, 1600, 1510 cm"<1>.

H NMR 6: 7.20-6.60 (m, 9H), 6.54 (d, J=15.6 Hz, 1H), 5.16 (dd, 1H), 4.40 (br, 1H) , 4.00 (q and br, 3H), 3.31 (s, 3H), 3.25 (s, 2H), 1.08 (t, 3H) ppm.

Example 43

Ethyl-( ±)-( E),( E)- erythro- 9-( 4- fluorophenyl)- 3, 5- dihydroxy- 8-( 1-methyl- 1H- tetrazol- 5- yl)- 9- phenylnona- 6, 8-dienoate

A solution of 950 mg (2.045 mmol) of the γ-ketoester prepared in Example 42 in 20 ml of dry tetrahydrofuran was treated with 2.25 ml of a 1 M solution (2.25 mmol) of triethylborane in tetrahydrofuran and stirred at 23°C for 1 hour. 400 µl of methanol was added and the mixture was cooled to -78°C and treated with 200 mg (5.26 mmol) of NaBH 2 . After 1 hour, the reaction was stopped by the addition of 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with EtOAc, and the combined organic extracts were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 60% EtOAc in hexane as eluent to give 330 mg (35%) of the title compound as a yellow gum.

MS (Cl): m/e = 467 for (M+H)<+>

IR (KBr) vmax: 3400 (br), 1725, 1600, 1500 cm'1.

1H NMR δ: 7.30-6.80 (m, 9H), 6.70 (dd, J=1.0 Hz, J'=15.6 Hz, 1H), 5.35 (dd, J=5 .9 Hz, J'=15.7 Hz, 1H), 4.41 (m, 1H), 4.25 (br s, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.83 (br m, 2H), 3.52 (s, 3H), 2.45 (d, J=6.l 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, 1-15.45, 71.89, 69.35, 68.34, 60, 83, 60.34, 42.34, 41.53, 41.22, 33.56, 14.13 ppm.

Example 44

Sodium-(±)-(E),(E)-erythro-9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-9- f enyl nona- 6, 8- dienoate hydrate

A solution of 160 mg (0.343 mmol) of the dihydroxy ester prepared in Example 43 in 5 mL EtOH was treated with 343 µl (0.343 mmol) 1 N NaOH, and the resulting solution was stirred at 23°C for 1 hour. The solvent was removed by evaporation, and the residue was dissolved in 2 ml of water and lyophilized to give 155 mg of the title compound as a light brown solid, m.p. 130-137°C.

IR (KBr) vmax: 3400 (br), 1560, 1510 cm"1.

1 H NMR (DMSO-dg) δ : 7.50-6.80 (m, 9H), 6.51 (d, J=15.7 Hz, 1H), 5.15 (dd, J=5.4 Hz , J'=15.7 Hz, 1H), 4.15 (m, 1H), 3.70 (s, 3H), 3.65 (br, 1H), 3.35 (br, 2H), 1, 95 (m, 2H), 1.40 (m, 2H) ppm.

<13>C NMR (DMSO-dg) 6 : 176.42, 163.42, 153.17, 146.07, 140.03, 139.73, 135.70, 135.64, 132.20, 132, 09, 128.72, 128.42, 128.07, 127.98, 124.83, 121.51, 115.51, 115.22, .66.22, 65.69, 44.46, 43.59 , 33.42 ppm.

Analysis for C23H22F<N>4<0>4Na.H20:

Calculated: C: 57.74%; H: 5.06%; N: 11.72%.

Found: C: 58.70%; H: 5.10%; N: 11.16%.

Example 45

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

A solution of 20 g (0.204 mol) of 1,5-dimethyltetrazole in 200 mL of dry tetrahydrofuran was cooled to -78°C and treated with 91 mL of a 2.5 M solution in hexane (0.227 mol) of n-butyllithium, and the mixture was stirred at -78°C for 30 minutes. 31.1 g (0.171 mol) of benzophenone was added and the mixture was stirred at -78°C for 30 minutes and warmed to 23°C and stirred for 15 hours. The reaction was quenched with 100 mL of 2 N HCl, and the mixture was extracted with 3 x 150 mL of EtOAc. The combined layers were dried with MgSO 4 and evaporated. The residue was crystallized from EtOAc-hexane to give just over 5 g (22%) of the title compound as a white solid, m.p. 175-176°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 281 for (M+H)<+>.

IR (KBr) v . : 3300 (br), 1530, 1500 cm"<1>. , ms KS

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 { : 152.36, 145.63, 128.16, 127.28, 126.05, 125.94, 77.70, 35.90, 33.76 ppm.

Analysis for C]_5<H]_>gN40:

Calculated: C: 68.56%; H: 5.76%; N: 20.00%.

Found: C: 68.62%; H: 5.81%; N: 20.10%.

Example 46

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 was heated at 200°C for 20 minutes. After cooling to 50°C, the mixture was treated with 50 mL of CHCl 3 , and the organic solvent was decanted from the inorganic residue. Evaporation gave 1.7 g (85%) of the title compound as a cream solid, m.p. 147-148°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 263 for (M+H)<+>.

I. R (KBr) v mak, s: <1>640, 1500, 1445 cm"<1>.

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

<13>C NMR 6: 153.94, 152.18, 140.40, 137.83, 129.54, 129.37, 128.94, 128.59, 128.38, 128.28, 108.22 , 33.56 ppm.

Analysis for cigH]_4N4:

Calculated: C: 73.27%; H: 5.38%; N: 21.36%.

Found: C: 73.25%; H: 5.43%; N: 21.43%.

Example 47

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

A solution of 3.75 g (14.29 mmol) of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene in 40 ml of dry tetrahydrofuran was cooled to -78°C and treated with 6.3 ml of a 2.5 M solution in hexane (15.75 mmol) of n-butyllithium, and the resulting mixture was stirred at -78°C for 30 minutes. 1.5 mL (18.58 mmol) of ethyl formate was added and the mixture was stirred at -78°C for 2 hours. The reaction was quenched with 2N HCl, and the solvent was removed by evaporation. The residue was extracted with 3 x 30 mL EtOAc, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 25-35% EtOAz-hexane as eluent to give 1.35 g (36%) of the starting material and 1.65 g (39%) of the desired title compound, m.p. 185-186°C (crystallized from EtOAc-hexane).

MS (EI): m/e = 290 for M<+>.

IR (KBr) vm. : 1675, 1600, 1445 cm"<1>. , max s

1 H NMR si 9.66 (s, 1H), 7.70-6.90 (m, 10H), 3.66 (s, 3H) ppm.

<13>C NMR 6: 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.

Analysis for C^<H>^<N>^<O:>

Calculated: C: 70.34%; H: 4.87%; N: 19.30%.

Found: C: 70.63%; H: 4.99%; N: 19.33%.

Example 48

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

A solution of 1.33 g (4.57 mmol) of the aldehyde prepared in Example 47 and 1.5 g (4.87 mmol) of triphenylphosphoranylidene acetaldehyde in 50 ml of benzene was refluxed for 24 hours. The solvent was evaporated and the residue was purified by chromatography using 30% EtOAc-hexane as eluent to give 1 g (71%) of the title compound as a yellow foam.

MS (Cl): m/e = 317 (M+H)<+>.

<X>H NMR 6: 9.53 (d, J=7.5 Hz, 1H), 7.55-7.10 (m, 10H), 6.69 (d, J=16 Hz, 1H), 5.84 (dd, J=16 Hz, J'=7.5 Hz, 1H), 3.50 (s, 3H) ppm.

Example 49

Methyl-( E )-9, 9- diphenyl- 3, 5- dihydroxy- 8-( 1- methyl- 1H- tetrazol- 5- yl)- nona- 6, 8- dienoate

0.525 mL (4.87 mmol) of methyl acetoacetate was added to a suspension of 0.160 g (as 80 percent dispersion in mineral oil) of sodium hydride in tetrahydrofuran at 0°C and stirred for 10 minutes. 2.14 mL of a 2.5 M solution in hexanes of N-butyllithium was added and the reaction mixture was stirred for 15 minutes. This solution was added to a solution of 1.0 g (3.2 mmol) of the aldehyde prepared in example 48 in tetrahydrofuran at 0°C, and the solution was stirred for 30 minutes. The solution was treated with 30 mL of 2 N HCl and extracted with 3 x 15 mL of EtOAc. The organic layer was dried with MgSO 4 and evaporated. The crude residue was treated with 3 x 25 ml of hexane, then dissolved in 20 ml of THF/CH^OH = 4:1 and treated with 3.2 ml of triethylborane in the form of a 1 M solution in tetrahydrofuran. Air was bubbled through the solution for 10 minutes and it was stirred for another 50 minutes. The solution was then cooled to -78°C and treated with 120 mg (3.2 mmol) of sodium borohydride and stirred for 1 hour. The reaction was quenched with 100 mL 2 M HCl and extracted with 3 x 20 mL EtOAc. The organic layers were dried with MgSO 4 and evaporated. The residue was dissolved in 30 ml of CH 2 OH and stirred for 15 minutes. The solvent was evaporated and the residue was purified by chromatography using 50% EtOAc in hexane as eluent to give 470 mg (33%) of the title compound as a yellow oil.

MS (Cl): m/e = 435 (M+H)<+>.

<X>H NMR δ: 7.80-6.80 (m, 10H), 6.71 (d, J=16 Hz, 1H), 5.34 (dd, J=16 Hz, J'=6Hz, 1H), 4.60-4.10 (m, 2H), 3.70 (s, 3H), 3.52 (s, 3H), 2.45 (d, J=6 Hz, 2H), 1, 70-1.50 (m, 2H) ppm.

Example 50

Sodium-(±)-(E)-erythro-9,9-dipheny"1-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-nona-6,8-dienoate hydrate

470 mg (1.08 mmol) of the methyl ester prepared in Example 49 was dissolved in 10 ml of ethanol and treated with 1.08 ml of 1 N NaOH. The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue freeze-dried, whereby 500 mg (100%) of a pale yellow powder was obtained, m.p. 145-150°C.

IR vmax: 3400 (br), 1610, 1425, 1360 cm"<1>.

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

Analysis for C23H23N404Na.H20:

Calculated: C: 59.99%; H: 5.47%; N: 12.17%.

Found: C: 59.18%; H: 5.46%; N: 10.96%.

Example 51

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

A solution of 20 g (0.204 mol) of 1,5-dimethyltetrazole in 200 mL of dry tetrahydrofuran was cooled to -78°C and treated with 91 mL of a 2.5 M solution in hexane (0.227 mol) of n-butyllithium, and the mixture was stirred at -78°C for 30 minutes. 41.3 g (0.171 mol) of 4,4'-dimethoxybenzophenone was added and the mixture was stirred at -78°C for 30 minutes and then warmed to 23°C over 2 hours. The mixture was acidified with 100 ml of 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 3 x 300 mL EtOAc, and the combined organic layers were dried with Na 2 SO 4 . oa indamIt. The residue was recrystallized from EtOAc-hexane to give 48 g of a light brown solid, which turned out to be a mixture of the desired compound and the starting aldol adduct (1,1-bis(4-methoxyphenyl)-2-(l -methyl-1H-tetrazol-5-yl)ethanol). The mixture was dissolved in 180 ml of xylene and refluxed for 1 hour with p-toluenesulfonic acid in a Dean-Stark apparatus. The cooled mixture was diluted with 100 ml of ether and the resulting solid was removed by filtration to give 40 g of the title compound as a cream colored solid, m.p. 146-147°C (recrystallized from EtOAc-hexane).

MS (Cl): m/e = 323 for (M+H)<+>.

I, R (KBr) v mak, s: 1605, 1520, 1250 cm"<1>.

H NMR6 : 7.31 (d, J=7.8 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H) , 6.81 (d, J=8.6 Hz, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H) , 3.42 (s, 3H) ppm.

<13>C NMR δ: 160.79, 160.16, 153.29, 133.33, 131.25, 130.32, 129.95, 127.36, 114.14, 113.69, 105.57 , 55.40, 55.28, 33.71 ppm.

A. analysis for cigH]_8N4°2 :

Calculated: C: 67.07%; H: 5.63%; N: 17.38%.

Found: C: 66.93%; H: 5.63%; N: 17.05%.

Example 52

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

A solution of 4.6 g (14.29 mmol) of the olefin prepared in Example 51 in 50 ml of dry tetrahydrofuran was cooled to -78°C and treated with 6.3 ml of a 2 M solution in hexane (15.75 mmol) of n-butyllithium, and the resulting solution was stirred at -78°C for 30 minutes. 1.5 ml of ethyl formate was added and the mixture was stirred at -78°C for 2 hours. The reaction was quenched with 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 3 x 30 mL EtOAc, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by column chromatography using 25-35% EtOAc-hexane as eluent to give 0.84 g (18%) of the starting material. Further elution gave 1.78 g (36%) of the desired title compound, m.p. 130-131°C (crystallized from EtOAc-hexane).

MS (Cl): m/e = 351 for (M+H)<+>.

I, R (KBr) v max: 1675, 1605, 1515, 1260 cm"<1>.

H NMR 6: 9.59 (s, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.90 (d , J=8.9 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.67 (s , 3H) ppm.

<13>C NMR 6 : 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, 33.94 ppm.

Analysis for cigHi9N4°3:

Calculated: C: 65.14%; H: 5.18%; N: 15.99%.

Found: C: 64.96%; H: 5.22%; N: 15.75%.

Example 53

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

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 was treated with 1.55 g (5.1 mmol) of triphenylphosphoranylidene acetaldehyde and refluxed for 3 hours. The solvent was removed by evaporation and the residue purified by chromatography using 30%

EtOAc-Hgxane as eluent, affording 1.35 (74%) of the title compound as a yellow foam.

MS (Cl): m/e = 377 for (M+H)<+>.

IR (KBr) vmax: 1675, 1590, 1510 cm"<1>.

1H NMR 6 : 9.52 (d, J=7.6 Hz, 1H), 7.53 (d, J=14.2 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H ), 7.00 (d, J=9.3 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 6.70 (d, J=8.9, Hz, 1H) , 5.83 (dd, J=7.6 Hz, J'=15.7 Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.50 (s, 3H ) ppm.

<13>C NMR 6: 192.39, 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, 114.81, 114.12, 55.49, 55.32, 33.61 ppm.

Example 54

Ethyl-( E )- 9, 9- bis( 4- methoxyphenyl)- 5- hydroxy- 8( 1- methyl- 1H- tetrazol-5- yl)- oxonona- 6, 8- dienoate

825 µl (842 mg, 6.48 mmol) of ethyl acetoacetate was added to a suspension of NaH (206 mg, 80% dispersion, 6.86 mmol) in 20 mL of dry tetrahydrofuran at 0°C, and the resulting mixture was stirred at 0°C for 10 min. A solution of 2.7 mL of a 2.5 M solution in hexane (6.75 mmol) of n-butyllithium was added, and the mixture was stirred at 0° C. for 10 min. A solution of 1, 3 g (3.46 mmol) of the aldehyde prepared in Example 53 in 20 ml of dry tetrahydrofuran was added, and the mixture was stirred at 0° C. for 15 minutes. After addition of 2 N HCl to stop the reaction, the solvent was removed by evaporation. The residue was diluted with 30 mL of water and extracted with 2 x 20 mL of EtOAc, and the combined organic layers were dried with MgSO 4 and evaporated. The residue was purified by chromatography using 40% EtOAc in hexane as eluent to give 1.165 g (66%) of the title compound was obtained as a yellow foam.

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

H NMR δ: 7.30-6.60 (m, 9H), 5.27 (dd, J=6.1 Hz, J'=15.9 Hz, 1H)y 4.68 (brs, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 3.47 (s, 3H), 3.43 (s, 2H ), 3.17 (brs, 1H), 2.70 (d, J=6.0 Hz, 2H), 1.23 (t, J=6.0 Hz, 3H) ppm.

<13>C NMR s: 202.48, 160.09, 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, 55.34, 55.17, 49.94, 49.33, 33.56, 14.09 ppm.

Example 55

Ethyl-(±)-(E)-erythro-9,9-bis(4-methoxyphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)nona-6,8 - dienoate

A solution of 1 g (1.97 mmol) of the 8-ketoester prepared in Example 54 in 50 ml dry tetrahydrofuran and 300 µl methanol was treated with 2.15 ml 1M triethylborane in tetrahydrofuran, and the mixture was stirred at 23 °C for 1 hour. The solution was cooled to -78°C and treated with 110 mg (2.92 mmol) of NaBH 2 . After 1 hour at -78°C, the reaction was quenched with 2 NHCl, and the solvent was removed by evaporation. The residue was diluted with water and extracted with 3 x 30 mL EtOAc. be combined organic extracts were dried with MgSO^ and evaporated. The residue was purified by chromatography to give 136 mg of the title compound as a light oil.

IR (KBr) ^max: 3450 (br), 1750, 1710, 1610, 1510 cm"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 { : 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, 131.22, 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 56

Sodium-(±)-(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 95 mg (0.196 mmol) of the ester prepared in Example 55 in 15 ml of ethanol was treated with 196 µl of 1 N NaOH solution, and the mixture was stirred at 23°C for 1 hour. The solvent was removed by evaporation, and the residue was dissolved in 2 ml of water and freeze-dried, whereby 95 g (100%) of the title compound was obtained, m.p. 175-180°C.

IR (KBr) ^max: 3400 (br), 1600, 1575, 1510 cm"<1>.

<1>H NMR (DMSO-dg) δ : 7.70-6.65 (m, 9H), 6.55 (d, J=15.5 Hz, 1H), 5.08 (dd, J=5 .6 Hz, J'=15.7 Hz, 1H), 4.14 (br, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.66 (s, 3H) , 2.10-1.80 (br, 2H) , 1.50-1.20 (br, 2H) ppm.

<13>C NMR (DMSO-dg) δ : 159.25, 158.80, 153.78, 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, 43.67, 33.34.

Anaivse for C_,-H__,NaN,0^ . 2H_ 0 .

Calculated: C: 55.76%; H: 5.81%; N: 10.41%.

Found: C: 54.43%; H: 5.04%; N: 8.15%.

Claims (10)

1. Tetrazole intermediate, "characterized by that it has the formula (I) 1 4 where R and R are each independently hydrogen, halogen, C1-4-alkyl, C1-4 alkoxy or trifluoromethyl, R 2 , R 3 , R 5 and R 6 are each independently hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy, B is CH2Z, X is bromine, chlorine or iodine, R<10> is C1-6-alkyl, and 11 - R is phenyl which is unsubstituted or substituted with one or two C1-4-alkyl or chloro substituents. 2. Compound according to claim 1, characterized by atZer triphenylphosphonium bromide. 3. Compound according to claim 2, characterized in that R1, R2, R3, R4, R5 and R6 are each selected from hydrogen, fluorine, methyl and methoxy. 4. Compound according to claim 1, characterized by atZer dimethylphosphonate. 5. Compound according to claim 4, characterized in that R , R , R , R , R and R are each selected from hydrogen, fluorine, methyl and methoxy. 6. Compound according to claim 1, characterized in that it is [1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propen-3-yl] triphenylphosphonium bromide, or dimethyl-[3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl]phosphonate. 7. Process for the preparation of a tetrazole intermediate with the formula (I) where R<1> and R<4> are each independently hydrogen, halogen, C1-4-alkyl, C-1-4-alkyl or trifluoromethyl, 2 3 5 6 R , R , R and R are each independently hydrogen, halogen, C^_4~alkyl or C^_4~alkoxy, B is CH2Z, where R<10> is C, -alkyl, 11 R is phenyl, which is unsubstituted or substituted with one or two C 1-4 alkyl or chloro substituents, and X is bromine, chlorine or iodine, characterized by (a) that a benzophenone compound of the formula (V) where R1, R2, R<3>, R<4>, R<5> and R<6> have the meaning given above, are reacted with 5-ethyl-1-methyl-1H-tetrazole, to produce a compound of the formula (rest) where R1, R<2>, R<3>, R4, R5 and R^ have the above meaning, (b) that an alcohol of the formula (Vila) is dehydrated to produce a compound of the formula (Id) where R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the meaning stated above, (c) that an olefin with the formula (Id) is halogenated to produce a compound with the formula (le) where 1 o T 4 h: c R , R , R , R , R and R and X have the meaning stated above, and (d) that a compound of the formula (le) reacts with where R10 is C1_4~alkyl, and R<11> is phenyl which is unsubstituted or substituted with one or two C1_4~alkyl or chloro substituents, to produce a compound of the formula (I) where R<1>, R<2>, R<3>, R<4>, R^ and R^ and Z have the meaning given above. 8. Method in accordance with claim 7, characterized in that R1, R2, R<3>, R<4>, R<5> and R<6> are each selected from hydrogen, fluorine, methyl and methoxy. 9. Process in accordance with claim 8, characterized in that Z is triphenylphosphonium bromide. 10. Method in accordance with claim 8, characterized in that Z is dimethylphosphonate.