NO179207B - Analogous method of preparing a therapeutically active compound - Google Patents

Abstract

Process for the preparation of compounds of the formula. e r. by reacting a compound having the formula reacting one of the products of the reaction with triphenylphosphine with an aldehyde of the formula. or desilylation of the product from the reaction with phosphite by reaction with a desilylating agent in an inert organic solvent in the presence of a small amount of oiganic acid. cleavage of the residual function by base hydrolysis in an organic solvent to give a compound of formula (IIa), wherein R 1 is O-M +, wherein M + is a cation, and subsequent preparation of a compound of formula (IIa), wherein R and cyclization to produce a compound of formula (IIb) by activating the carboxyl group with carbodiimide in an inert organic solvent].

Description

The present invention relates to an analogue method for the preparation of a therapeutically active compound with the formula

R<1> and R^ each independently of one another are hydrogen, halogen, C 1-1-4 alkoxy or trifluoromethyl,

R^, r<3>, r<5> and r<6> each independently of each other are

hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy,

n is 1, and

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

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=CH 3 ) 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 mevir.olin (R=CH3, also known as lovastatin) have the following structure

compactin, R=H

mevinolin, R=CH-3

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

345

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 -CH2~, -(CK2)2-, -{CH2)3~ or

-CH=CH-,

R R and RJ are each different substituents, as well as the corresponding dihydroxy acids originating 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.

In EP patent application 68.03 8, the resolved trans-enantiomer, a method for its preparation, as well as pharmaceutical preparations thereof are described under the formula $

and the corresponding dihydroxysyrc, or a pharmaceutically acceptable salt thereof. PCT application WO 84/02131 describes analogues of mevalonolactone with the structure n where either R or Rw is

while the other is primary or secondary C1_g-al>:yl, C1_g-cycloalkyl or phenyl -(CH2)n~,

X is -(CH-) - or -CH=CH-,

n is 0, 1, 2 or 3,

R4, R<5>, R<5a> and R<6> are different substituents.

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

where X is - (CH_) - or

2. 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 142,146, oxo analogues of mevinolin-like aritihypercholesterolemic agents are described with the structure where E is -C<H>2~C<H>2,<->CH=CH- or -(CH2)3-, 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 number 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 series 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 -(CH2)n~, -CH=CH-, -CH=CH-CH2~ or -CH2-CH=CH-,

n is 0, 1, 2 or 3, and

1 2 3 4 5 6 7

R , R , R , R , R , R , R and Z are different substituents.

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

The analogy method according to the invention is characterized by

(a) that a compound of the formula (le)

where

R1, R2, R<3>, R<4>, R<5> and R<6> have the above meaning, are reacted with either triphenylphosphine to produce a phosphonium salt with the formula

where

R 11 is substituted or unsubstituted phenyl,

or with phosphite, to produce a phosphonate of the formula

where

R<10> is C1-4-alkyl,

(b) after which the compound of the formula (If) or (Ig) is reacted with an aldehyde of the formula

where

R^ q is a hydrolyzable ester group, and

R<x>^ is tert-butyldiphenylsilyl,

in an inert organic solvent in the presence of a strong base to prepare a compound of formula (XII),

after which the compound of formula (XII) is reacted with a desilylation agent in an inert organic solvent in the presence of a small amount of organic acid, to produce a compound of formula (II), where R<7> is an easily hydrolyzable ester group, after which (in ) the R'-ester function is optionally cleaved by base hydrolysis in an organic solvent to produce a compound with the formula (II), where R<7> is a pharmaceutically acceptable cation, (ii) the product from step (i) is, if desired, acidified to produce a compound of the formula (II), where R<7> is hydrogen, and (iii) the product from step (ii) is optionally cyclized to produce a compound of the formula (II), where A is the lactone, by activating the carboxyl group with a carbodiimide in an inert organic solvent.

"Alkoxy" denotes, if nothing else is mentioned, 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. If nothing else is stated, the term "halogen" includes chlorine, fluorine, bromine or iodine, while the term "halide" means chloride, bromide or iodide anions. 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 hydrolyzable ester group" includes an ester group that is physiologically acceptable and hydrolyzable under physiological conditions, such as C 1-6 alkyl, phenylmethyl or pivaloyloxymethyl.

In connection with formula (II), it is intended that all double bonds should have a trans configuration, i.e. (E), as shown in the structural formulas used.

In the compounds of formula (I), R<1>, R<2>, R<3>, R<4>, R5 and R^ are preferably independently hydrogen, halogen, <C>1-4-alkyl or C^ .3-Alkoxy. R<1> and R<4> are preferably hydrogen while R2, R<3>, R^ and R^ independently of each other are hydrogen, ethoxycarbonyl, CH2Y where Y is preferably hydrogen, hydroxyl, chlorine or bromine, or CH2Z where Z is preferably tri-phenylphosphonium bromide or C1-2-alkylphosphonate.

The compound with formula (II) is prepared as shown in reaction schemes 1 and 2.

12 3 ' I 6

In reaction core 1, R, R, R, R^, R' and R have the above meaning. The allyl bromide of formula (Ie) 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"<*>"<1> is phenyl, which is unsubstituted or substituted with one or two substituents selected from C 1-4 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 C^_^-alkyl. The intermediates 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 diagram 2. In the reaction core 2, R<1>, R^, R3, R<4>, R^ and R^ have the above-9 12 for indicated meanings, R is a hydrolyzable ester group, R is tert-butyldiphenylsilyl, and Z is where R10 is C^_^-alkyl, R1"*" is phenyl which is unsubstituted or substituted with 1 or 2 C^_^-alkyl or chlorine substituents, and X is bromine, chlorine or iodine. The phosphonium salt with ::ormelene ( If) or the phosphonate of the formula (Ig), can be reacted with a silyl-protected aldehyde of the formula (XI), which itself is prepared by methods described in Tetrahedron Listers, 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, e.g. lithium diisopropylamide, potassium tert-buto]< sid or n-butyllithium, at a temperature of from -78°C to 0°C. The compound of formula (XII) can then be desilylated in a convenient 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 (Ilb) in a conventional manner well known to those skilled in the art.

In vivo acute cholesterol biosynthesis inhibitor in rats

Male Wistar rats (160-200 g, 2 rats per cage) were maintained on a normal diet (Purina rat chow and water ad libitum) for at least 7 days in a reverse lighting condition (dark from 7 am to 5 pm). F6r was removed 15 hours before dosing. The compounds were administered at 8 o'clock in the morning by intragastric incubation using 0.5-1.0 ml water or propylene glycol solutions of sodium salts, lactones or esters of the test compounds. Control groups received the same volumes of vehicle. 30 minutes after administration of the test compounds, 0.9 ml of 0.9 per cent NaCl containing approx. 120 (ici per kg body weight sodium [1-<14>C]acetate (1-3 mCi/mmol). After an incubation period of 60 minutes, the rats were euthanized, and livers were removed and blood samples taken. 1.0 ml samples of plasma obtained by centrifugation of heparin + EDTA-treated blood and samples of liver homogenates (equivalent to 0.50 g of liver in wet weight) were taken for the determination of radiolabeled 3-hydroxysterols Sterolization for the liver samples followed the method of Kates, described above for the hepatocyte method (Experiment B), while the plasma samples were saponified directly, followed by isolation of the digitonium-precipitable sterols. The amount of <14->C-labeled sterols was determined by liquid scintillation counting (corrected for efficiency). The mean percent inhibition of ^ 4C incorporated into liver - and plasma cholesterol were calculated for groups of treated animals and compared with average values in control experiments that were carried out at the same time.

The above experiments therefore provide information on the ability of the test compounds to suppress de novo biosynthesis of cholesterol in vivo in rats by oral dosing. During the execution of the above-mentioned experiments, e.g. the connections according to e.g. 2 a 50% inhibitory dose (ED^q) for both plasma and liver cholesterol, which was comparable to values obtained for mevinolin (lovastatin) using a similar method (Alberts et al., Proe. Nati. Acad. Sei. , Col 77, 1980 pp. 3957-3961).

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 indications are uncorrected. Proton magnetic resonance spectra (H NMR) were recorded with a Bruker "AM 300", Bruker "WM 3 60" or Varian "T-60 CW" spectrometer. All spectra were enhanced in CDClJ -, DMSO-db, or D2O, unless otherwise stated, and chemical shifts noted in 6 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 ("^C NMR) were recorded in a Bruker "AM 300" or Bruker "WM 3 60" spectrometer and were broad-band proton decoupled. All spectra were determined in CDCl■. in ,, DMSO-d ^b or D20 unless otherwise noted, with internal deuterium lock, and chemical shifts were recorded in 6 units down 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 H2SO^ 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 evaporations of the solvent 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-(—)-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 MgSO 4 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-dg) 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-dg) f : 171.02, 163.51, 163.C5, 153.03, 145.34, 139.46, 136.34, 132.2 (d, <3>JC_F =8.3Hz), 131.0 (d, <13>JC_F=9.1 Hz), 125.14, 121.64, 115.41 (d, <2J>C_F=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 2

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 was 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. Analytical thin-layer chromatography showed elution with 20 vol% MeOH

in CHCl^ the desired product at R^ = 0.2. Most of the organic solvent was evaporated at approx. 10°C ^ed 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)vmaRs: 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-dc) 6 : 175, 87, 161.85, (d, 1Jr, „=246.1 Hz),

, D C—r

161.37 (d, J^, =246.9 Hz), 153.08, 144.97, 139.88, 136.40,

113245,,5616, , 113221,,2742 , (d11, 5 J3 , J4 n l2 ~—r „(=d8, ,3 _ Jn CH—zr -).=, 2113,9 0,H97 z), ( d1, 1 J35 J, n C2 —r ,(.=d8, ,3 _ Jc H„ —zr„)=,23.4 Hz), 68.23, 65.71, 44.50, 43.55, 33.45 ppm.

Analysis for C23H21<F>2<N40>4<N>a H20:

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

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

Example 3

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 1.3 2 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 MgSO4 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- LH- 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 (8%, 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> .

<1>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 (]H, rn), 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, J=2.7, 18 Hz) ppm.

<13>C NMR (CDCl3) δ: 169.20, 163, 162.5, 1S3.20, 148.81, 135.61, 134.95, 132.45 (d, 3Jc_p=8 Hz), 132, 52, 131.51 (d, <3>JC_F= 8 Hz), 130, 04, 120.44, 115.95 (d, 2Jn =21.9 HO, 115.83 (d, 2J0 (_— -r =21.9 Hz), 75.67, 62.54, 38.58, 35.58, 33.64 ppm.

Analysis for C23<H>20F2N4O3 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 C^H-^N^ <C>g<H>g:

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

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

Example 4

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 a further 30 minutes, the clear reaction mixture was diluted with water and extracted with 3 x 50 ml of 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. <1>H NMR (CDCl3 ) δ : 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) 5-ethyl-1- methyl-1H-tetrazole (prepared in step A) in 60 ml of dry tetrahydrofuran, 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-hexene, 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 (m, 8H), 5.95 (s, 1H), 4.65 (q, 1H), 3.98 (s, 3H), 1.29 (d, 2H).

<13>C NMR (CDCl3) δ : 162.57, 162.37, 159.14, 156.71, 142.48, 140.54, 128.25, 128.13, 127.52, 127.42, 114.67, 114.41, 144.38, 78.56, 36.99, 33.43, 14.52.

Analysis for ci7<H>i6<F>2<N>4<0:>

Calculated: C: 61.81%; H: 4.88%; 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 an Eean-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.

IR (KBr) vmax: 1575, 1500 cm"1.

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

<13>C NMR (CDCl3) δ: 163.37, 163.08, 160.13, 155.61, 144.60, 145.34, 136.47, 136.42, 136.24, 136.19, 131.65, 131.54, 131.11, 131.01, 119.53, 115.51, 115.27, 115.22, 33.50, 21.20.

Analysis for ci7<Hi>4F2<N>4<:>

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 . : 1600cm"1.

, max

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

<13>C NMR (CDC13) : 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 C^7<H>13<F>2<B>rN4:

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

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

E. [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-Dis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene (prepared in 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) <v>max: 3450, 1600, 1500, 1425 en<-1>.

<1>H NMR (DMSO-dg) 6 : 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 5H2<gB>rF2N4P:

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

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

F. 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 of phosphonium bromide (prepared in step E) and 0.26 g (0.4 mmol) of methyl-erythro-3,5-bis-(diphenyl-tert-butylsilyloxy)-6 -oxo-hexa:ioate (prepared by the general methods described by P. Kapa et al., Tetrahedron Letters, 1984, p. 2435-2438, and in JS patent document 4,571,428) in 1 ml of dry dimethylformamide was under an inert atmosphere added 0.067 g (0.6 mmol) of potassium tert-butoxide at

-20°C (bath temperature). The slurry became 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)<+>.

^ 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 5

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 6

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

- 2-propen-l-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 were heated at 100°C for 5 minutes. After cooling to ambient temperature, the excess trimethyl phosphite 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<:><1>604, 1511 cm<-1>.

<1>H NMR (CDCl 3 ) δ = 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>i9<H>i9<F>2°3<N>4<P:>

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

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

B. 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 step A was added 1 equivalent (<:.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 ml of NH 2 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 in 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>E NMR (CDCl 3 ) 6 = 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 7

A. 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 2 N HCl, and the organic solvent was removed by evaporation. The residue was extracted with 2 x 100 mL CHCl 3 , 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 6 : 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 NMR δ: 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 C16<H>15FN40:

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

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

B. (E)-1-(4-fluorophenyl)-2-(1-methyl-1H-tetra;:ol-5-yl)-1-phenyl-1-ethene and (Z)-1-(4- fluorophenyl)-2-(1-methyl-..H-tetrazol-5-yl)-1-phenylethene

A mixture of 3.2 g (10.74 mmol) of tetrazolyl ethanol (prepared in step A) 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 worked up until almost all 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) vmax: 1640, 1600, 1510, 1445, 1220 cm"<1>.

<1>H NMR s • 7.50-6.90 (m, 9H), 6.75 (s, 1H), 3.60 (s, 1.7H), 3.43 (s, 1.3H) .

<13>C NMR 6: 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 C]_gH]_3FN4:

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

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

C. (E)-3-(4-fluorophenyl)-2-(l-methyl-lH-tetra.zol-5-yl)-3-phenyl-propenal and

( Z )- 3-( 4- fluorophenyl)- 2-( 1- methyl- 1H- tetrazol- 5- yl)- 3- phenyl1-propenal

A suspension of 20 g (71.43 mmol) of the olefin prepared in step C in 200 ml tetrahydrofuran was cooled to -78°C and treated with 31.5 ml of a 2.5 M solution in huxane (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 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.

D. ( 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 step C and 5.0 g (16.56 mmol) of formylmethylenetriphenylphosphorane and 200 ml of benzene were refluxed together 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)<+>.

<1>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 p: 192.54, 147.86, 132.09, 131.97, 130.64, 130.41, 128.96, 116.17, 115.87, 33.62 ppm.

E. 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 step D 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. Residues were 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)<+>.

IR (film) vmax: 3400 (br), 1730, 1600, 1510 cm-1.

1H NMR s: 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) , .5.31 (s, 3H) , 3.25 (s, 2H), 1.08 (t, 3H) ppm.

F. Ethyl-(+)-( E),( E)- erythro- 9-( 4- fluorophenylI- 3, 5- dihydroxy- 8-( 1- methyl- 1H- tetrazol- 5- yl)- 9- phenylnona - S, 8-dienoate

A solution of 950 mg (2.045 mmol) of the p-ketoester prepared in step E in 20 ml of dry tetrahydrofuran was treated with 2.25 ml of a 1 M solution (2.25 mmol) of triethylfuran 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 afford 330 mg (35%) of the title compound as a yellow gum.

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

IR (KBr) vmakg: 3400 (br), 1725, 1600, 1500 cm"1.

X H NMR 6: 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, 115.45, 71.89, 69.35, 68.34, 60 .83, 60.34, 42.34, 41.53, 41.22, 33.56, 14.13 ppm.

Example 8

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

A solution of 160 mg (0.343 mmol) of the dihydroxy ester prepared in Example 7 in 5 ml of EtOH was treated with 343

(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.>

<X>H NMR (DMSO-d6) 6: 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) δ: 176.42, 163.42, 153.17, 146.07,

140.03, 139.73, 135.70, 135.64, 132.20, 132.09, 128.72, 128.42, 128.07, 127.98, 124.83, 121.51, 115, 51, 115.22, 66.22, 65.69, 44.46, 43.59, 33.42 ppm.

Analysis for C23H22FN404Na.H20:

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

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

Example 9

A. 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

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/CH3OH = 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 (.1.2 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)<+>.

<1>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.

B. Sodium-(+)-( E )- erythro- 9, 9- diphenyl- 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 step A 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 - 3400 (br), 1610, 1425, 1360 cm -1 .

"4 NMR (DMSO-dg) 6 : 7.60-6.60 (m, 10K), 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 C23H23<N>404Na.H20:

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

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

Example 10

A. 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-hexane as eluent to give 1.35 (74%) of the title compound as a yellow foam.

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

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

at rest.ci.K. pp

_H 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 {:192.89, 161.40, 160.97, 157.91, 153.29, 149.41, 133.90, 132.77, 132.29, 132.00, 131.71 , 131.65, 131.25, 130.81, 117.21, 114.81, 114.12, 55.49, 55.32, 33.61 ppm.

B. 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 minutes. 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 minutes. A solution of 1.3 g (3.46 mmol) of the aldehyde prepared in step A 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 water and extracted with 2 x 20 mL EtOAc, and the combined organic

layer was dried with MgSO 4 and evaporated. Residues were purified by chromatography using 40% EtOAc in hexane as eluent to give 1.165 g (6%) of the title compound as a yellow foam.

IR (KBr) vmax= 3450 (br), 1750, 1710, 1(110, 1510 cm"1.

1H NMR δ: 7.30-6.60 (m, 9H), 5.27 (dd, J==6.1 Hz, J'=15.9 Hz, 1H), 4.68 (brs, 1H) , 4.14 (q, J=7.1Hz, 2E , 3.83 (s, 3H), 3.69 (s, 3H), 3.47 (s, 3H) , 3.43 (s, 2H) , 3.1'' (brs, 1H) , 2.70 (d, J=6.0 Hz, 2H), 1.23 (t, J=6.0 Hz, 3H) ppm.

<13>C NMR δ: 202.48, 160.09, 159.70, 154.10, 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, 14.0) ppm.

C. 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 γ-ketoester prepared in step B 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 stopped with 2 NHCl, since the solvent was removed by evaporation. The residue was diluted with water and extracted with 3 x 30 mL EtOAc. The combined organic extracts were dried with MgSO 4 and evaporated. The residue was purified by chromatography to give 136 mg of the title compound as a light oil.

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

<1>H NMR 6 : 7.70-6.50 (m, 9H), 5.80 (dd, ".H), 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 6: 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, 113.31, 72.15, 66.31, 60.75, 55 .35, 55.20, 42.74, 42.14, 41.73, 41.18, 33.50, 14.18.

Example 11

Sodium-(+)-( E)- erythro- 9, 9- bis( 4- methoxyphenyl)- 3, 5- dihydroxy- 8-( l- methyl- lH- tetrazol- 5- y1) nona- 6, 8- dienoate dihydrate

A solution of 95 mg (0.196 mmol) of the ester prepared in Example 10 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) vmax: 3400 (br), 1600, 1575, 1510 cm"1.

1 H NMR (DMSO-dg) &: 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 (DMSC~dcD) 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.

Analysis for C25H27<N>aN4Og.2H20.

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

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

Claims (8)

1. Analogous method for the preparation of a therapeutically active compound of the formula r<1> and R<4> are each independently hydrogen, halogen, C1-4-alkoxy or trifluoromethyl, R<2>, R<3>, R^ and R^ are each independently hydrogen, halogen, C-1-4 alkyl or C1-4-alkoxy, n is 1, and R 1 is hydrogen, a hydrolyzable ester group or a cation, to form a non-toxic pharmaceutically acceptable salt, characterized vec. (a) that a compound of the formula (le) where R1, R<2>, R<3>, R<4>, R<5> and R<6> have the above meaning, are reacted with either triphenylphosphine to produce a phosphonium salt with the formula where R<11> is substituted or unsubstituted phenyl, or with phosphite, to produce a phosphonate with the formula where R<10> is C1-4-alkyl, (b) after which the compound of the formula (If) or (Ig) is reacted with an aldehyde of the formula where R<r> is a hydrolysable ester group, and R<12> is tert-butyldiphenylsilyl, in an inert organic solvent in the presence of a strong base for the preparation of a compound of formula (XII), after which the compound of the formula (XII) is reacted with a desilylation agent in an inert organic solvent in the presence of a small amount of organic acid, to produce a compound of the formula (II), where R 7 is an easily hydrolyzable ester group, after which (in ) the R'-ester function is optionally cleaved by base hydrolysis in an organic solvent to produce a compound with the formula (II), where R' is a pharmaceutically acceptable cation, (ii) the product from step (i) is, if desired, made to prepare of a compound of the formula (II), where R' is hydrogen, and (iii) the product from step (ii) is optionally added to produce a compound of the formula (II), where A is the lactone, by activating the carboxyl group with a carbodiimide in an inert organic solvent. 2. Analogous process in accordance with claim 1 for the preparation of ethyl-(+.)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl) )-6,8-nonadienoate, characterized by the fact that the corresponding output connections are exchanged. 3. Analogous process in accordance with claim 1 for the production of sodium-(+.)-erythro-9, 9-bis (4-fluorophenyl)-3, 5-dihydroxy-8-(1-methyl-1H-tetrazole-5 -yl)-6,8-nonadienoate, characterized in that the corresponding starting compounds are reacted. 4. Analogous process in accordance with claim 1 for the preparation of trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]tetrahydro-4 -hydroxy-2H-pyran-2-one, characterized in that the corresponding starting compounds are reacted. 5. Analogous process in accordance with claim 1 for the production of sodium-(+.)-erythro-9, 9-bis (4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H -tetrazol-5-yl)-6,8-nonadienoate, characterized in that the corresponding starting compounds are reacted. 6. Analogous process in accordance with claim 1 for the preparation of sodium-(+.)-(E), (E)-erythro-9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl- 1H-tetrazol-5-yl)-9-phenylnona-6,8-dienoate hydrate, characterized in that the corresponding starting compounds are reacted. 7 . Analogous process in accordance with claim 1 for the production of sodium (i)-(E)-erythro-9,9-diphenyl-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-nona -6,8-dienoate hydrate, characterized in that the corresponding starting compounds are reacted. 8. Analogous process in accordance with claim 1 for the preparation of sodium-(+,)-(E)-erythro-9, 9-bis (4-methoxyphenyl)-3, 5-dihydroxy-8-(1-methyl-1H- tetrazol-5-yl)-non<i-6, 8-dienoate hydrate, characterized in that the corresponding starting compounds are reacted.