FI96953C - Tetrazole derivatives and process for their preparation - Google Patents

Description

96953

This invention relates to novel tetrazole derivatives useful as intermediates in the preparation of novel inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme in the treatment of blood enzymes which are 10 lipid levels, high blood lipoprotein levels and atherosclerosis. This invention also relates to a process for the preparation of said tetrazole derivatives.

Natural fermentation products compactin (R = H) presented by A. Endo et al. in Journal 15 of Antibiotics, 29, 1346-1348 (1976), and mevinoline (R = CH3) by A.W. Alberts, et al. in J. Proc. Natl. Acad. Sci. U.S.A., 77, 3957 (1980) are highly active agents that lower blood cholesterol, restrict cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase, a rate-limiting enzyme, and a natural target for the regulation of cholesterogenesis in mammals. Compactin (R = H) and mevinolin (R = CH3), also known as lovastatin) are below. 25 structures shown:

o V

30 <ΓΥΥ * 3 compactin, R = H mevinoline, R = CH3 35 Numerous structurally similar synthetic compounds have been disclosed in patents and other publications that are useful in the treatment of hypercholesterolemia. The most closely related synthetic technique is disclosed in the following publications: 5 U.S. Patent 4,198,425, issued April 15, 1980 to S. Mistui et al., Discloses novel mevalonolactone derivatives useful in the treatment of hyperlipidemia and having a general

A

R * 3 wherein A is a direct bond, methylene, ethylene, trimethylene or a vinylene group and R3, R4 and R5 are different substituents.

EP Patent Application 24,348, published March 4, 1981, discloses novel blood cholesterol and fat lowering compounds having the structure X3 wherein A is H or methyl; E is a direct bond, -CH 2 -, 35 - (CH 2) 2 -, - (CH 2) 3 - or -CH = CH-; R 1, R 2 and R 3 are each a different substituent, and the corresponding dihydroxy acids, 96953 3 obtained by hydrolytic opening of the lactone ring.

U.S. Patent 4,375,475, issued March 1, 1983 (A.K. Willard et al.), Discloses substantially the same structures and is consistent with the aforementioned EP Patent Application 24,348.

EP Patent Application 68,038, published January 5, 1983, discloses and claims a resolved transenantiomer having the structure 10 H.

_ U

, X1 *

15 I

20 * 3 a process for its preparation and its pharmaceutical compositions and the corresponding dihydroxy acid or a pharmaceutically acceptable salt thereof.

International Patent Application WO 84/02131, published June 7, 1984, discloses mevalono- «· * lactone analogs having the structure 2 i

X

30 X-XVrO

R2 * 3 35

wherein one of R and R 0 is R 1 -C: R

4,995953 and the other is primary or secondary C 1-6 alkyl, C 3-6 cycloalkyl or phenyl- (CH 2) n -; X is - (CH 2) n - or -CH = CH-; n is 0, 1, 2 or 3; 5 R6

Z is -CH-CH, -C-CH, -COOH and I 2 I 2 OH OH

R4, R5, R5a and R6 are various substituents.

International Patent Application WO 84/02903, published August 2, 1984, discloses mevalono-lactone analogs having the structures r3 x.z R5a X-2 R5a

IA IB

(CH 2) q - wherein X is - (CH 2) n -, -O = O; - (cH2) r ^ ^ "^ h n is 0, 1, 2 or 3 and each q is 0 or one is 0 and the other is 1 and 25 R6

. I

Z is -CH-CH, -C-CH, -COOH I 2 I 2 OH OH

EP Patent Application 142,146, published May 22, 1985, discloses oxo analogs of 30 blood cholesterol lowering agents such as mevinoline having the structure HO 0 O '

E

z

il: ... Ul <e MH lii -i-em ·. I

96953 5 where E is -CH 2 -CH--, -CH = CH- or - (CH 2), -, and O Z is AAr "53 * io- / Y ^ sv r3 0 r12 ^ 1 = · “Ccrai« “>» where the dotted line indicates possible double bonds, which are 0, 1 or 2.

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

20 In J. Med. Chem., 29, 159-169 (1986) W.F. Hoffman et al. show the preparation and testing of a series of 7- (substituted aryl) -3,5-dihydroxy-6-heptenoic acid and their lactone derivatives. One of the preferred compounds in the reported series has the structure HV ^ ° xy r ~ Cy c’2 ° '] ^ yc'

Cl 96953 6

In J. Med. Chem., 29, 170-181 (1986) G.E. Stokker et al. reported the synthesis of the 7- / 5,5-disubstituted- (1,1'-diphenyl) -2-yl] -3,5-dihydroxy-6-heptenoic acid series and their lactones. Two of the preferred compounds reported in this article 5 have the structures V ”tx F) T j 10 \ and Yj f L JL 1 ci JL 1 CH- cn3 ^ YY 3 ci ra3 15 in U.S. Patent 4,613,610, issued September 23. 1986 (JR Wareing), discloses pyrazole analogs of mevalono-lactone and its derivatives useful in the treatment of high lipoprotein and atherosclerosis of the general formula and having the general formula 20 R6.

RsH- * 7; "- R 2 R 1 wherein X is - (CH 2) n -, -CH = CH-, -CH = CH-CH 2 - or -CH 2 -CH = CH-; N is 0, 1, 2 or 3 and r 1, R 2, R 3, R 2, R 3, r 1, R 2 and Z are various substituents.

None of the aforementioned patents or articles disclose or suggest the possibility of preparing the compounds of this invention. The unique structural feature that these compounds contain a tetrazole moiety differs substantially from the prior art.

This invention relates to novel tetrazole intermediates useful as intermediates in the preparation of novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors useful in the treatment of hypercholesterolemia, high blood lipoprotein breakdown and atherosclerosis. preparation.

The novel tetrazole intermediates according to the invention have the formula (I ") R3 R \ L? J] - R6 15 r3 ΊΓ

r2-K IJ jT CH

R 1-1 / 20 wherein R 1 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 are each independently hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; and

25 Z is _ | _ (0R10) or -? ^ RU P

V1 wherein X is bromine, chlorine or iodine; R 10 is C 1-6 alkyl; and R 11 is phenyl unsubstituted or substituted with one or two C 1-4 alkyl or chloro substituents.

The compounds of formula I "can be used as intermediates in the preparation of blood cholesterol lowering agents of formula • 96953 8 R»

5 CHa Rl W Rl W

wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above; n is 0, 1 or 2; R 7 is hydrogen, a hydrolyzable ester group, or a cation that forms a non-toxic pharmaceutically acceptable salt. The therapeutic activity of the compounds of formulas IIa and Hb is described in patent application 931,580.

The terms "C 1-4 alkyl," C 1-4 alkoxycarbonyl "and" C 1-4 alkoxy "as used herein and in the claims (unless otherwise indicated in the context) mean straight-chain or branched alkyl or alkoxy groups such as methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, t-butyl, amyl, hexyl-20, etc. Preferably, these groups contain 1 to 4 carbon atoms, and most preferably contain 1 or 2 carbon atoms. Unless otherwise specified in individual cases, the term "halogen" as used hereinafter and in the claims is intended to include chlorine, fluorine, bromine and iodine, while the term "halide" when used hereinafter and in the claims is intended to include chloride, bromide and iodide anions. The term "cation forming a non-toxic pharmaceutically acceptable salt" as used hereinafter and in the claims is intended to include non-toxic alkali metal salts such as sodium, potassium, calcium and magnesium, ammonium salt and salts of non-toxic amines such as trialkylamines, pyridylamine, dibenzylamine With N-methylmorpholine, N-methylpiper-35 peridine, and other amines used to form 969593 salt with carboxylic acids. Unless otherwise specified, the term "hydrolyzable ester group" as used herein and in the claims means an ester group which is physiologically acceptable and hydrolyzable under physiological conditions such as C 1-6 alkyl, phenylmethyl and pivaloyloxymethyl ester groups.

In the compounds of formulas IIa and Hb, it is intended that all double bonds be in the trans configuration, i.e. (E), as indicated in the structural formulas used herein.

In the compounds of formula I ", R 1, R 2, R 3, R 4, R 5 and R 6 each independently are preferably hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy. More preferably R 1 and R 4 are hydrogen and R 2, R 3, R 5 and R 6 each is hydrogen, fluorine, chloro-15, methyl or methoxy, and most preferably R 1 and R 4 are hydrogen and R 2, R 3, R 5 and R 6 are each independently hydrogen, fluorine, methyl or methoxy, Z is preferably triphenylphosphonium bromide or C ^ -alkyylifosfonaatti.

Compounds of formula I "are prepared according to the invention according to the invention in that a) a benzophenone compound of formula ** (R 1 -R 5 where R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above) , is reacted with 5-ethyl-1-methyl-1H-tetrazole to give a compound of formula (Vila) 30 R3 □ 3 TJO H Vila 35

: Rl W

96953 wherein R1, R2, R3, R4, R5 and R6 are as defined above; b) dehydrating an alcohol of formula VIIa to give a compound of formula (Id) R 5 R 2 -X X, CH 3 Id 10 r wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above; c) halogenating an olefin of formula Id to give a compound of formula (Ie) R 3

Ie p2 XX Π 'l 20 JJ A. ^ ch3 R1 \ _ /

N-N

wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above; and d) reacting a compound of formula Ie with a compound P (OR 10) 3 or P (R 11) 3, wherein R 10 is C 1-4 alkyl and R 11 is phenyl which is unsubstituted or substituted by one or two C 1-4 alkyl groups. with an alkyl or chloro substituent, to give a compound of formula (1H) V R 5 r 4 -P "+ -r 6 R 3 | T"

r2 -k Π T

R1 \ _ /

N-N

: i m i luu l i i κι 96953 11 wherein R1, R2, R3, R4, R5 and R6 are as defined above.

The initial part of the process according to the invention is illustrated by the following reaction scheme 1.

12 96953

Reaction Scheme 1 XCH-, 3 + N \ »-« s

r1 0 R

VI

10 V

R5 15 7 ^, OH CH3 r2_Γ j | Vila 20? -Ch3 R W 3 25 R5 1 RA- | ^ j} -R6 30 R3 \ ^ X CH3 2 Id and VcH, W 3 96953 13

In Reaction Scheme 1, R 1, R 2, R 3, R 4, R 5 and R 6 are as previously defined. The optionally substituted benzophenones of formula V can be prepared by the general and well-known Frie-5 del-Crafts reaction of a substituted phenol using Lewis acids as a catalyst, e.g. aluminum chloride in carbon tetrachloride at about 0 ° C. Numerous substituted benzophenones are known and their preparation is explained in the literature, while many others are commercially available. For example, G. Olah has disclosed many starting materials of formula V in Friedel-Crafts and Related Reactions, Vol. 3, Parts 1 and 2, Interscience Publishers, New York, 1964 and references therein. The Friedel-Crafts reaction can produce a mixture of benzophenones, and if this occurs, the mixture can be separated by conventional techniques known in the art.

The starting materials of formula VI can be prepared by reacting 1,5-dimethyltetrazole with a strong base such as butyllithium at a temperature from about -70 ° C to about 0 ° C, and the anion obtained therefrom is added, preferably to ethyl chloroformate or methyl iodide, or treated with either. , as explained in this application.

The 5-substituted 1-methyltetrazole of formula VI can be treated with a strong base such as n-butyllithium at low temperatures from about -20 ° C to about -78 ° C, and preferably from about -40 ° C to -78 ° C. ° C in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or the like. The resulting anion of the compound of formula VI can then be treated with the desired benzophenone of formula V to prepare the corresponding tertiary alcohols of formula VIIa.

Compounds of formula Id can be prepared from compounds of formula VIIa by conventional dehydration procedures. The dehydration can be carried out by heating the alcohol of formula VIIa in a suitable inert organic solvent, e.g. toluene, benzene or xylene, in the presence of a small amount of an organic acid or mineral acid such as p-toluenesulfonic acid or sulfuric acid in a desiccant e.g. Na 2 SO 4, MgSO 4, MgSO 4. , in the presence of molecular sieves, etc., or preferably the water formed is azeotropically removed by a Dean-Stark trap or similar device). Alternatively, the alcohol of formula VIIa can be simply heated with potassium hydrogen sulfate at a temperature of about 190 ° C.

Compounds of formula Ie are prepared from compounds of formula Id by halogenation. For example, compounds of formula Id wherein Z is bromine are obtained by treating compounds of formula Id with N-bromosuccinimide in the presence of a catalyst such as azobisisobutyronitrile or benzoyl peroxide in carbon tetrachloride.

The conversion of compounds of formula Ie to compounds of formula 20 I "is illustrated by the following Reaction Scheme 2 in the case where Formula Ie Z is bromine. In Reaction Scheme 2, compounds of formula I" are represented by formulas If and Ig.

t * 96953 15

Reaction Scheme 2 R5 "r'-PX- * 6

. ·> P

R2-hy | J 1 ^ CH3 io R ^ 3 ^ "" R1 V = -n If R ^ Jk / CH * Br *! ET X, ch3 R5 r4- £ 0H '

Ie, ΊΓ 0 p3 II 10 p— <or10)

R 2j? II

V J ^ s »* 20 Rl IXn 19

In Reaction Scheme 2, R 1, R 2, R 3, R 4, R 5 and R 6 are as previously defined. The allyl libromide of formula Ie may be reacted in a conventional manner with phosphines such as triphenylphosphine in an inert: organic solvent such as cyclohexane to form a phosphonium salt of formula If wherein R 1 is phenyl unsubstituted or substituted with one or two alkyl groups. - or with a chlorine substituent, and X is bromine, chlorine or iodine. Alternatively, the allyl bromide of formula Ie may be reacted with phosphites such as trimethyl phosphite or triethyl phosphite in a conventional manner, either undiluted or in an inert organic solvent, and preferably undiluted, to form a phosphonate of formula 1-35.

1-4 16 96953

The intermediates of formulas If or Ig can then be converted to the blood cholesterol lowering compounds of formulas Ha and Hb according to the reaction sequence shown in Reaction Scheme 3.

5

Reaction Scheme 3 R3 ^ 10 r4-PJ} -r6

R W A -CHZ

ί- Jj 1 lf 19 15 ^ en OR12 OR12 0- 20 ^ 0 5 3: 1 3 OR12 of2 0 25 OR9! · s2-tJ Α ΠΙ Τ »S-ch, \ / 3, ι *, R5 ^ 3 0Η '0Η 0 OR9 χ N ^ N-CH,

R W

96953 17

In Reaction Scheme 3, R 1, R 2, R 3, R 4, R 5, R 6 and Z are as previously defined, R 9 is a hydrolyzable ester group and R 12 is t-butyldiphenylsilyl. The phosphonium salt of formula If or the phosphonate of formula Ig can be reacted with a silyl-protected aldehyde of formula XI prepared by the methods disclosed in Tetrahydron Letters, 25, 2435 (1984) and also in U.S. Patent 4,571,428. to form a silyl-protected compound of formula XII. The reaction can be carried out in an inert organic solvent such as tetrahydrofuran or Ν, Ν-dimethylformamide in the presence of a strong base such as lithium diisopropylamide, potassium t-butoxide and n-butyllithium at a temperature of about -78 ° C to about 0 ° C: a. The compound of formula XII can then be desilylated by well known methods such as 48% hydrofluoric acid and preferably tetrabutylammonium fluoride in an inert organic solvent such as tetrahydrofuran and acetonitrile in the presence of a small amount of the organic acid to form the erythro compound of formula X. The resulting compound of formula X can then be converted to compounds of general formulas IIa and Hb in a conventional manner well known to those skilled in the art.

: In the following examples, which illustrate the invention in more detail, all temperatures are given in degrees Celsius. Melting points were recorded on a Thomas-Hoover capillary melting point apparatus and boiling points were determined at a given pressure (mmHg) and both temperatures are uncorrected. Proton resonance spectra (‘1 H-NMR) were recorded on Bruker AM 300, Bruker WM 360 or Varian T-60 CW spectrometers. All spectra were determined in CDCl 3, DMSO-d 6, or D 2 O unless otherwise noted, and chemical shifts are reported as 5 values in the lower field 96953 18 from internal standard tetramethylsilane (TMS), and proton coupling constants are reported in Hertz (Hz). The distribution methods are denoted as follows: s is a singlet, d is a doublet, t is a triplet, 5 q is a quartet, m is a multiplet, a broad is a broad peak, and dd is a doublet of a doublet. Carbon-13 nuclear magnetic resonance spectra (13 C-NMR) were recorded on a Bruker AM 300 or Bruker WM 360 spectrometer, and the spectra were broad-banded, with all protons decoupled. All-10 ki spectra were determined in CDCl 3, DMSO-d 6, or D 2 O unless otherwise indicated using an internal deuterium lock, and chemical shifts are reported as 5 values in the lower field from tetramethylsilane. Infrared spectra (IR) were determined on a Nicolet MX-1 FT spectrometer1-15 from 4000 cm * 1 to 400 cm * 1 with the instrument calibrated at 1601 cm * 1 for polystyrene film and are expressed in inverted centimeters. (cm-1). Relative intensities are reported as follows: s (strong), m (medium), and w (weak).

Gas chromatographic mass spectra (GC-MS) were determined on a Finnigan 4500 gas chromatograph-quadrupole mass spectrometer with an ionization potential of 70 eV. Mass spectra were also recorded on a Kratos MS-50 using fast atom bombardment (FAB) technology. 25 Mass spectral data are reported in the format: original! ion (M +) or protonated ion (M + H) +.

Analytical thin layer chromatography (TLC) was performed on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapor and / or staining with one of the following reagents: a) a solution of phosphomolybdic acid in 2% methanol; b) with reagent a) followed by 2% cobalt sulphate in 5-M H 2 SO 4 with heating. Column chromatography, also referred to as flash column chromatography, was performed on a glass column using fine silica gel 96953 19 (32-63 μιη silica gel-H) and pressures slightly above atmospheric pressure and the indicated solvents. All evaporations of the solvents were performed under reduced pressure. As used herein, the term hexanes means a mixture of isomeric C6 hydrocarbons as specified by the American Chemical Society, and the term "inert" atmosphere means an argon or nitrogen atmosphere unless otherwise indicated.

Example 1 3,3-Bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene A. 5-Ethyl-1-methyl-ΙΗ-tetrazole To a slurry of 1,5-dimethyltetrazole (4.9 g, 0.05 mmol) in dry tetrahydrofuran (50 mL) was added a hexane solution of 2,5-M n-butyllithium (20 mL, 0.05 mol) over 15 minutes. At -78 ° C in an inert atmosphere. This mixture was stirred for 30 minutes during which time a yellow precipitate formed. Methyl iodide (3.7 mL, 0.06 mol) was then added over 15 minutes. After stirring for an additional 30 minutes, the clear reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The aqueous layer was washed with chloroform (2 x 25 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give an oily substance, the oil was purified by distillation to give 5.2 g (92%) of the title compound; tr. = 89-90 ° C at 6.67 Pa (0.05 mmHg).

1 H-NMR (CDCl 3) δ: 4.05 (s, 3H), 2.86 (q, 2H), δ 1.41 (t, 3H) 13 C-NMR (CDCl 3) 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-ethyl-1-methyl-1H-tetrazole (5.6 g, 0.05 mol) / prepared in A / 60 ml of dry tetrahydrofuran was added 2,5-M n-butyllithium. (20 mL, 0.05 mol) in hexane over 5 minutes at -78 ° C (bath temperature) under an inert atmosphere. The mixture was stirred for 30 minutes, and a solution of 4,4'-difluorobenzophenone (10.8 g, 0.5 mol) in 25 ml of dry tetrahydrofuran was added over 5 minutes. This mixture was stirred for another two hours while the bath temperature slowly rose to -20 ° C. The reaction was quenched with 1 M HCl, and the mixture was extracted with ethyl acetate (3 x 50 mL) and chloroform (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a white solid. The solid was purified by crystallization from ethanol / hexane to give 10.8 g (65%) of the title compound; mp. = 160-161 ° C.

IR (KBr) ν: 3400 cm-1; max 1 H NMR (CDCl 3) δ: 7.8-7.02 (m, 8H), δ ^ 5 (s, 1H), 4.65 (q, 1H), 3.98 (s, 3H), 1 .29 (d. 2H).

13 C NMR (CDCl 3) δ: 162.57, 162.37, 159.14, 156.71, 142.48, 140, 54, 128.25, 128.13, 127.52, 127.42, 114.67 , 114.41, 114.38, 78.56, 36.99, 33.43, 14.52.

96953 21

Analysis for C 18 F 2 N 4 O.

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) -1-propene

Slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propanol (8.25 g, 0.025 mol) Prepared in B7 and 100 mg of p-toluene. nisulfonic acid monohydrate in xylene (60 mL) was heated to reflux for 12 hours using

Dean & Stark water collection device. The reaction mixture was washed with 1 M NaOH (10 mL) while still warm and water (100 mL). Concentration of the organic layer gave the product as off-white crystals. They were purified by recrystallization from ethanol / hexane to give 7.1 g (91%) of the title compound as white crystals; mp = 146-147 ° C.

IR (KBr) υ · 1575; 1500 cm'1.

luaX

1 H NMR (CDCl 3) δ: 7.42-6.85 (m, 8H), 3.53 - (s, 3H), 2.14 (s, 3H); 13 C NMR (CDCl 3) δ: 163.37, 163.08, 160.13, 155.61, 144.60, 145.34, 136.47, 136.42, 136.24, 136.19, 25 131, 65, 131.54, 131.11, 131.01, 119.53, 115.51, 115.27,: 115.22, 33.50, 21.20.

Analysis for C 18 H 14 F 2 N 4 Calculated: C, 65.37; H, 4.51; N, 17.94 Found: C, 65.64; H, 4.61; N, 18.09 30 D. 3,3-Bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene

Slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-propene (61.46 g, 0.197 mol) Prepared in CJ, N-bromosuccinimide 35 (35.06 g, 0.197 mol) and a catalytic amount of azobisisol 96953 22 butyronitrile or benzoyl peroxide in carbon tetrachloride (1/2 liter) were heated to reflux under an inert atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature, and the solid from the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from toluene / hexane to give 72 g (93%) of the title compound as white crystals; mp. = 159-160 ° C.

IR (KBr) vm: 1600 cm-1.

Δ max 1 H NMR (CDCl 3) δ: 7.5-7.1 (m, 5H), 4.44 (s, 2H) 3.53 (s, 3H).

13 C NMR (CDCl 3) δ: 163, -94, 16-3.74, 160, -60, 160.45, 143r42, 149.68, 135.20, 135.15, 134; 69, 131.43, 15 131,3i; 130.90, 130.80, 119.57, 115f94, 115.77, 115.65, 115.50.

Analysis for 7H, 3F2BrN4 Calculated; C, 52.19; H, 3.34; N, 14.32 Found; C, 52.58; H, 3.47; N, 14.49 Example 2 E, 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-propen-3-yl] triphenylphosphonium bromide Slurry with 3 1,3-bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene 25 (1.95 g, 0.005 mol) prepared in Example 1 under DJ triphenylphosphine (1.3 g, 0.005 mol) in cyclohexane (25 mL) was heated to reflux. The reaction mixture became clear after 30 minutes and a white precipitate appeared after 1 hour. The mixture was heated for an additional eight hours, cooled to ambient temperature, and the solid 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; mp. = 254-255 ° C.

96953 23 IR (ΚΒτ) v: 3450, 1600, 1500, 1425 cm-1.

ΔαΧ 1 H NMR (DMSO-d 6) δ: 7.92-6.80 (m, 23H), 4.94 (6d, 2H), 3.83 (s, 3H); Δ 13 C NMR (DMSO-d 6) δ: 163.53, 163.36, 160.28, 160.87, 154.04, 153.89, 152.76, 135.11, 134.79, 134.16, 133.68, 133.54, 130? 53, 130.45, 130.35, 130 ^ .21, 130.07, 118.02, 116.89, 116.18, 115.89, 115.62, 115 , 32, 111.43, 10 111.39, 34.22, 28.88, 28.22.

Analysis for C35H2BrF2N4P

Calculated: C, 64.3 L; H, 4.3 2; N, 8.57 Found: C, 64.02; H, 4.37; N, 8.89 Example 3 Methyl - (+) - erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6 , 8-nonadienoate

To a slurry of phosphonium bromide (0.326 g, 0.5 mmol) / illustrated in Example Z7 and methyl erythro-20,5-bis (diphenyl-t-butylsilyloxy) -6-oxohexanoate / prepared according to the general procedures set forth in P Kapa, et al. in Tetrahedron Letters, 2435-2438 (1984) and U.S. Patent 4,571,428, issued February 18, 1986 to P.K. KapaJ (0.26 g, 0.4 mmol) in dry dimethylformamide (1 mL) was added potassium t-butoxide (0.067 g, 0.6 mmol) at -20 ° C (bath temperature) under an inert atmosphere. The slurry turned to a red solution · and was stirred for 18 hours at -10 ° C. The reaction was completed by the addition of ammonium chloride solution (10 mL) and extraction with methylene chloride (2 x 30 mL). The organic layer was dried over sodium sulfate and concentrated to give an oily substance. the oil was purified by passing it through a pad of silica gel and the main fraction was isolated as an oil (160 mg), the oil (160 mg) was mixed with a solution of 1 M tetra-n-butylammonium fluoride tetra-96953 24 in hydrofuran (2 ml) and a few drops of glacial acetic acid for 18 hours . The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 20 mL). 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 (CI): m / e = 471 (M + H) &lt; + &gt;; 1 H-NMR (CDCl 3) δ: 7.26-6.6 (m, 9H), 5.37 (dd, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 3.71 (s, 3H), 3.56 (s, 3H), 2.47 (d, 2H), 1.58 (m, 2H).

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

15 Example 4

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

Slurry of 3,3-bis- (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene (1.17 g, 3.0 mmol) ) and trimethyl phosphite (0.41 g, 3.3 mmol) were heated at 100 ° C for 5 minutes. After cooling to ambient temperature, the excess trimethyl phosphite was removed in vacuo to give a pale yellow solid. This solid was recrystallized from ethyl acetate / hexane to give the title compound as a pure white solid; mp. = 140-141 ° C.

IR (KBr) δ 1604, 1511 cm -1 1 H-NMR (CDCl 3) δ: 7.7-6.8 (8H, m), 3.6 (3H, s), δ 3.5 (3H, S) , 3.42 (3H, s), 3.2 (2H, d)

Analysis for C19H1903NAP

Calculated: C, 54.29; H, 4.56; N, 13.33

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

25 96953

Example 5

Methyl (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl) -lH-tetrazol-5-yl) -6,8-nona-dienoate To a solution of the phosphonate (0.84 g, 2.0 mmol) [prepared in Example 5] was added one equivalent of n-BuLi (2.0 mmol) at -78 ° C (carbonic acid / acetone), and the resulting deep red solution was stirred at -78 ° C for 15 minutes. Methyl erythro-3,5-10 bis (diphenyl-t-butylsilyloxy) -6-oxohexanoate [prepared according to the general methods of P. Kapa et al., Tetrahedron Letters, 2435-2438 (1984) and U.S. Pat. 4,571,428, issued February 18, 1986 to P. Kapa] (1.30 g, 2.0 mmol) in THF (2 mL), and the mixture was stirred for 24 h. The reaction mixture was allowed to warm to room temperature during this time. The reaction was quenched with 5 mL of NH 4 Cl and then extracted with ethyl acetate (2 x 20 mL). The organic layer was dried (Na 2 SO 4) and evaporated under reduced pressure to a yellow oil. The oil was stirred with a tetrahydrofuran solution of 1-M tetra-n-butylammonium fluoride (4 ml) containing a few drops of glacial acetic acid for 24 hours. The reaction mixture was poured into water (20 ml) and extracted with methylene chloride (3 x 25 ml). The organic layer was dried (Na 2 SO 4) and concentrated, and the oil was purified by silica gel flash column chromatography eluting with ethyl acetate-hexane (2: 1) to give 0.284 g (41%) of the title compound as an oil. MS (CI): m / e = 471 (M + H) + for 1 H-NMR (CDCl 3) δ: 7.26-6.6 (9H, m), 5.29 (1H, dd), 4.42 (1H, m), 4.28 (1H, m), 3.69 (3H, s), 3.54 (3H, s), 2.42 (2H, d), 1.5 (2H, m).

Claims (12)

A compound, characterized in that it has the formula (I ") 5 R3 R4-L? Jj-R6 r. R2 -j- | T T 10. JL 2 -CH, 7 3 R w are R 1 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 are each independently hydrogen, halogen, C 1-6 alkyl or C 1-4 alkoxy; and O is R (OR 10) or -f-R 11, O 20, R 11 where X is bromine, chlorine or iodine; R 10 is C 1-4 alkyl; and R 11 is phenyl unsubstituted or substituted with one or two C 1-6 alkyl or chloro substituents. A compound according to claim 1, characterized in that Z is triphenylphosphonium bromide. Compound according to claim 2, characterized in that R1, R2, R3, R4, R5 and R6 are each from the group hydrogen, fluorine, methyl and methoxy. A compound according to claim 1, characterized in that Z is dimethyl phosphonate. Compound according to claim 4, characterized in that R1, R2, R3, R4, R5 and R6 are each from the group hydrogen, fluorine, methyl and methoxy. 96953 31 6. A process for the preparation of a compound of formula (I ") R 3 R 4 - R 10 R 6 R 1 R 2 - R 2 - R 1 - R 1 = N / N - where R 1 and R 4 are each independently hydrogen, halogen, alkyl, C 1-4 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, and Z is 0, 11 - P - (OR 10), or X® N 11 Wherein R 10 is C 1-4 alkyl, R 11 is phenyl unsubstituted or substituted with one or two C 1-6 alkyl or chloro substituents, and X is bromine, chlorine or iodine, characterized in that a) a benzophenone compound of the formula Wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above, reacted with 5-ethyl-1-methyl-1H-tetrazole to give a compound of formula (Vila) R 5 R 4 -C wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above; B) the alcohol of the formula Vila is dehydrated to a compound but the formula (Id) r4 ^ j-r6 p3 In r24? wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above; c) the olefin of formula Id is halogenated to a compound of formula (Ie) R9 25 R4 * ^^ "R6 Ie rS-P || R1 \ _ / 30 N-N. wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above; and d) the compound of formula Ie is reacted with a compound P (OR10) 3 or P (R11) 3, in which R10 is C1-4 alkyl and R11 is phenyl unsubstituted or substituted with one or two C1-4 alkyl - or chloro substituents, to give a compound of formula (I ") R, ipP n 3 τιι / k 2 CHp-Z '· -fxx". R1 \ _ / N-N where R1, R2, R3 , R4, R5, R6 and Z are as defined above 7. The process according to claim 6, characterized in that R1, R2, R3, R4, R5 and R6 are each from the group hydrogen, fluorine, methyl and methoxy. 8. A process according to claim 7, characterized in that Z is triphenylphosphonium bromide. Method according to claim 7, characterized in that Z is dimethyl phosphonate. ♦ I