FI103793B - tetrazole - Google Patents

Description

! 103793

tetrazole derivatives

Separated from patent application 880869 (FI patent 96,601).

5

The present invention relates to novel tetrazole derivatives of the formula R5 io ra-y '-jJ-R6 r3 I ° H j) Pi K i II |' / n 15 tet 1 R 1 wherein Λ R 1 and R 4 are each independently hydrogen, halo, C 1-6 alkyl, C 1-4 alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 are each independently hydrogen, halo-20 gene, C 1-4 alkyl or C 1-4 alkoxy; n is 0, 1 or 2;

7 N

tet is N NB / or ^ f: M 25 Wn N-N \ r 7 • R 7 is C 1-4 alkyl, C 1-4 alkoxy (lower) alkyl or (2- • · · («Methoxyethoxy) methyl; and R 9 is a C 1-8 alkyl group.

... 30 These new compounds can be used as intermediates • ««;] .1 mm. for the preparation of tetrazole derivatives, which are 3-hydroxy-3-methyl-ligutaryl coenzyme A (HMG-CoA) -reductase inhibitors and thus useful in the treatment or prevention of hypertension in the blood; high lipoprotein content and arteriosclerosis 2 2 · 2 103793, and for which known compounds of structure are described in the above-mentioned U.S. Patent Application No. 880869.

FI Patent Application No. 880869 discloses compounds having a unique structural feature, according to the present invention. the compounds have a tetrazole moiety which provides effective HMG-CoA activity. These compounds have the formula (I) wherein R 1 and R 4 each independently represent hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 each independently represent hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; : tet is or: · \ / V / W N-N Ί: ·: 25 ^ R '»· n is 0, 1 or 2,

: V: 9H

X OH 0

A is> ^ X 0 R 8 or X X; R 7 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy (lower) alkyl: or (2-methoxyethoxy) methyl; X is -OH or = O; and R5 is hydrogen, C1-6 alkyl or pharmaceutically acceptable. * 'Flaming metal cation.

3, 103793

The terms "C 1 -C 4 alkyl", "C 1 -C 4 alkyl" and "C 1 -C 4 alkoxy" as used herein and in the claims (unless otherwise stated) mean side-chain or side-chain alkyl or alkoxy groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. Preferably, these groups have 1 to 4 carbon atoms and most preferably have 1 or 2 carbon atoms. The term "(lower) alkyl" in the substituent "C 1-4 alkoxy (lower) alkyl" as used herein and in the claims means side-chain or side-chain alkyl groups having 1 to 4 carbon atoms, and preferably 2 carbon atoms. Unless otherwise specifically stated in a particular case, the term "halogen" as used herein and in the claims is intended to include chlorine, fluorine, bromine and iodine.

The compounds of formula I are prepared according to FI patent application 880869 such that (a) a compound of formula

n 3 I or R? _. ^ CHO

: · 25 rfYT R2-f> il J

Γ * ^ Hb

iia R

Wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined above, is reacted with one or two equivalents of triphenylphosphoranylidene-acetaldehyde to give a compound of the formula: v. 35 103793 4

R4j ^ LR6 is, R ^ S

Wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined above and n is 1 or 2; (b) reacting the starting material or end product of step (a) with a dianion of the acetoacetate ester to provide a compound of the formula R 5 -R 4 -T 1 -J 6 -R 6 R 3 OH 0 0 20 1/1 H 1 R 3 -? x 'n 7 ^ <A 7

/ N N-R

R "\ J

25 • · i! * / It • · «* ·» • # · · V * R3 R6 • · · 30 r3 oh o o

S

35ν 35 r1 \ n_ / r7 * · · 5 103793 wherein R * -R7 have the same meaning as above, R9 is a C1-6 alkyl group and n is 0, 1 or 2; (c) reducing the ketone ester obtained in step (b) by reaction with trisubstituted alkyl borane 5, followed by sodium borohydride and then methanol to give a compound of formula I wherein R 8 is C 1-6 alkyl; and then, if desired, (i) cleaving the Re-ester group by base hydrolysis in an organic solvent to produce a compound of formula I wherein R8 is a pharmaceutically acceptable metal ion, and optionally replacing the cation obtained in the process with another pharmaceutically acceptable metal cation; (ii) acidifying the product of step (i) to prepare a compound of formula I wherein R 8 is hydrogen; and (iii) cyclizing the compound of step (ii) to produce a compound of formula I wherein A is lactone by activating a carboxyl radical imide 20 in an inert organic solvent.

The present invention thus relates to the above. . compounds of said step (b) wherein R 7 is'; C 1-4 alkyl, C 1-4 lower alkoxy) alkyl, or (2-methoxyethoxy) methyl.

* · 25 Compounds of formulas Ha and Hb may be

*. *: of any substituted benzophenones III

By aldol condensation to the tetra-substituted olefinic acid, IV, and conversion to the tetrazole ester V, then alkylation of the tetrazole moiety and reduction of the ester group in compounds VI and VII and subsequent oxidation. alcohols VII and IX as shown in Reaction Scheme 1.

«« 6 103793

Reaction Scheme 1 R5 5 r3 R4 ra_ ^ Cj | _r6 * -Öj ^ r * 5 -> 2vX ^ C * r ^ ö; 6 * -ζΧx,

10 111 r1 'IV

R5 15 rA "^^" r6

-> r3W jf .CO C H V

2 ^ * -5

R1 N ~ N

20 '! · \ 5 I 5 W £ Ϋ Λ

:. '* I 25 R 3 j CO 2 C 2 H 5 _ 1_ R "V

•: | j r2 ^ YY ^ * 3; ^ Τ / 0ΛΗ5

:.: R7 R3 - r. Ij X

R1 N = N, 7:.:: Vt r1 N_Nv 7 30 VI SR '

«I I

VII

V

... V

7 103793

Reaction Scheme 1 (continued) 5 R5

R

RA-rr - $ - 16 ^

3 R3 T CH OH

* <ch2oh · 7-- j1YT

R3 · w'R? r1

VIII IX

15 Ψ

V

20 15 ts R1 ^ -16 3RA- & r6

R3 T CT ° R

: "1.: r ^ · N" Nn η

:: R

• · 1 • «· • · ·:: 1: Ila Hb • • • • • • • • • • 1 t 4 4« «103793 8

In Reaction Scheme 1, R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as previously defined. Optionally substituted benzophenones of formula III can be prepared from the substituent-5-phenyl by a common and well known Friedel-Crafts reaction using Lewis acid as catalysts, e.g., aluminum chloride in carbon tetrachloride at about OeC. A large number of substituted benzophenols are known and their preparation has been described in the art, with many others being commercially available. For example, many of the starting materials of Formula 10 III are described by G. Olah in Friedel-Crafts and Related Reactions, Vol. 3, Part 1 and 2, Interscience Publishers, New York, 1964 and references therein. In the Friedel Cradts reaction, a mixture of benzophenones can be formed and, when prepared, the mixture can be separated by conventional methods known in the art.

A suitable benzophenone of formula III can be treated with ethyl cyanoacetate in a solvent mixture containing glacial acetic acid and an organic solvent such as benzene or toluene in the presence of a catalyst, preferably β-alanyl-20. The reaction is allowed to continue at the boiling point of the solvent and the resulting water is removed by azeotroping. . • using a Dean-Stark trap or similar device until formation of the tetrasubstituted olefin IV • · «

• has essentially happened completely. In compound IV

The 4 'nitrile group (25) is then converted to the heterocyclic tetrazole group of formula V by reaction with • · · azidotributylstannate as such or in an inert organic solvent such as benzene, toluene or xylene at the reflux temperature of the solvent.

The 1H-tetrazole compound of formula V may then be alkylated with various alkylating agents by methods well known to those skilled in the art. Thus, the H-tetrazole of formula V can be treated with a strong base such as nat.

»<I

35 mg of benzene, toluene, diethyl ether and Ν, Ν-dimethyl, ·, -yl formamide or a mixture thereof at a temperature of «9 103793 between -30 ° C and about 50 ° C, and then an alkylating agent, e.g. methyl iodide, ethyl iodide, bromotriphenylmethane and the like, or with isobutylene in the presence of a strong acid such as sulfuric acid. The heat-5 state is not critical and depends on the alkylating agent commonly used. This non-specific alkylation produces an isomeric mixture of alkylated products which can be separated by conventional methods such as crystallization or chromatography to give the desired 1-substituted tetrazole compounds VI and 2-substituted tetrazole compounds VII.

One skilled in the art may conclude that the combination of reaction conditions with the specific alkylating agent employed may yield substantially one isomer.

For example, in the case of a compound of formula V wherein R 1 and R 4 are para-fluoro and R 2, R 3, R 5 and R 6 are hydrogen, alkylation of V with isobutylene yields essentially the 2-isomer tetrazole as shown in Example 32.

Alternatively, the alkylation reaction conditions may be varied to produce the desired tetrazoles VI and VII in ratios ranging from about 1: 1 to about 5: 1.

The tetrazole esters of formulas VI and VII may then be converted together as a mixture, or preferably in batches, after separation by conventional methods to the alcohols VIII and IX, respectively, by known reactions.

series. According to one reaction pathway, formula VI

The compound of formula I is first hydrolyzed by conventional procedures, such as hydrolysis with a base, i.e., lithium hydroxide, potassium hydroxide and sodium hydroxide. Moo- *. the resulting acid (i.e., Example 5) is then converted to the acyl · · · ·, chloride (Example 6A) by reacting with: **: a reagent such as oxalyl chloride in methylene chloride at reflux and the resulting acyl chloride 35 is reduced with a reducing agent, preferably lithium aluminum. sodium hydride in tetrahydrofuran at -78 ° C to prepare the alcohols of formula VIII. The 103793 alcohols of formula IX can be prepared from the ester of formula VII by the same reaction sequence used to convert esters VI to alcohols VIII. Alternatively, and more preferably, alcohols VIII and IX can be prepared in one step from the corresponding esters VI and VII by reduction with reducing agents, cuticle isobutylaluminum hydride in a non-reducing inert solvent such as methylene chloride at low temperatures, preferably about -78 ° C.

The mixture of allyl alcohols of formulas VIII and IX can be readily oxidized with conventional oxidizing agents such as pyridine chlorochromate in an inert solvent, preferably methylene chloride, at ambient temperature. More preferably, the separated allyl alcohols of formulas VIII and IX can be separately oxidized in the same manner to form the corresponding allyl aldehydes of formula Ha and Hb.

Compounds of formula I may be prepared from compounds of formula Ha or Hb by various alternative reaction schemes using a variety of novel, inter alia, m.p. of the present. . via the intermediates of the invention.

It will be appreciated by those skilled in the art that the preparation of compounds of formula I wherein n is 0, 1 or 2 will necessarily involve the use of three new aldehyde intermediates. Thus, if desired, to prepare compounds of formula I wherein: n = 0, the compound of formula Ha or Hb is subjected to suitable anion alkylation as described herein. However, if desired, compounds of formula I are prepared. Where n = 1 or 2, suitable Wittig reactions are performed to provide the necessary new homologous aldehydes

X and XI to obtain the 1-isomers and the aldehydes XII and XIII

To obtain the 2-isomer as shown in Reaction Schemes 2 and 3, respectively.

I a 11 103793

Reaction Scheme 2 R5 -T6 -R6

Rl ^ 1Ia 10 r2-k ”II ΊΓ r1 \ n / 'r7'

N-N

15 20 /: r5 r5 | V: r3 ^ S ^ _, cho +

/ ^ = - ^ A-S7 »1 \ /« R

'·; ·; 30 r1 xj ^

XI

::> X

12 103793

Reaction Scheme 3

rV

W "R w / H -v 15 20 ^ R5 V R5 25 RA-j ^ jJ-R6 + RA-j ^^} - R6:; jj ra ° ^ 30 R1 \\ J R1 y

:. :: N-V ** - V

:.:!: XI1 XIII

103793 13

In Reaction Schemes 2 and 3, R 1, R 2, R 3, R 4, R 5, R 6, R 7 are as previously defined and R 7 can also be R 7a where R is triphenylmethyl. For example, in Reaction Scheme 2, the allyl aldehyde of formula Ha may be treated with tri-phenylphosphoranylidene acetaldehyde in an inert solvent such as benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane and the like. The reaction temperature is not critical and the reaction can be carried out at a temperature between ambient temperature and the reflux temperature of the solvent. For convenience, we find it preferable to carry out the reaction at reflux. It should be clear to one skilled in the art that the reaction conditions and the number of equivalents of triphenylphosphoranylidene-15 acetaldehyde used per equivalent of the compound of formula Ha are crucial. If only one equivalent or slightly more of the Wittig reagent is used but the reaction conditions are not carefully controlled, e.g., in time, temperature, addition method, etc., then a mixture of diene aldehyde X and triene aldehyde XI may be formed. The ratio of aldehydes X to XI depends on the reaction conditions that are naturally employed. In a specific example of this specification, Example 8, the aldehydes of the general formulas X and XI are formed in about 25 to 9: 1 of the corresponding aldehyde of the general formula Ha.

The Wittig reaction can also be used to aid in the selective reaction and isolation of the compounds using less than one equivalent of Wittig reagent to produce predominantly diene aldehyde X. For example, using half a * 30 L of Wittig reagent in Example 69, • i «« · · *. the desired diene aldehyde X and unreacted aldehyde Ha were obtained which was now more easily separated. Preferably, the reaction is carried out using about one equivalent of Wittig reagent under controlled reaction conditions, for example as described in Example 77, to form the desired diene aldehyde X in the absence of (detectable by NMR) 103793 of 14 native triene aldehydes. However, if desired, the triene aldehyde of formula XI is reacted with at least two equivalents of the Wittig reagent, or alternatively the diene aldehyde X is reacted with an additional equivalent of Wittig to form the triene aldehyde of formula XI. Thus, one skilled in the art will readily conclude that the preparation of the desired homologous aldehydes X and XI, wherein n is 1 or 2, respectively, can be controlled as desired using an appropriate amount of Wittig reagent and suitable reaction conditions.

Conversion of the aldehyde of formula Hb to the corresponding homologous diene aldehyde of formula XII and the triene aldehyde of formula XIII, as shown in Reaction Scheme 3, may be carried out by similar procedures as described above for the preparation of aldehydes of formula X and XI. It can be concluded that some of the aldehydes containing the vinyl groups in Reaction Schemes 2 and 3 are easily and conveniently isolated, while others are more difficult to isolate. In special cases where the aldehydes were difficult to isolate using the chromatographic systems used herein, a mixture of aldehydes, for example, aldehydes X and XI, is used in the following step whereby the separation of the diene and the triene compounds can be more easily accomplished. by chromatography or other conventional methods.

• · · ·

Compounds of formula I wherein x is -OH may be prepared from compounds of formula Ha, Hb, X, XI, XII, or XIII by the general reaction route set forth in • in Scheme 4. For the sake of simplification, all of the aldehydes in Reaction Schemes 2 and 3 are combined into one formula and named as compounds of Formula XIV wherein n is 0, 1 or 2 and R1, R2, R3, R4, R5 and R6 are previously defined.

is 103793

Reaction Scheme 4 5 R 5 R 5 »o * - 3 OH 0 0 R 3, v CH0 1 YlA ^ k q

2 r2 p j JA Jn 0R

R1 r1

XIV XV

15 R5 2 0 r3 ° H 0H 0 \ τ, 2 Γ ^ ΐΓ ^ ΊΛ ^ ν OR9 7 R - jl I '' n la tet:; V R1: /.! 25 • ·

! ::.; I

Rs ^: 7: 30 ^. ; ·. RL ^ Cji-OKA 1 tet =: ··: 35 r1 lfi 103793 lb

In Reaction Scheme 4, the last preceding compound of formula XV wherein R 9 is a hydrolyzable ester group, and in the compounds of this invention, especially a C 1-4 alkyl group such as methyl, ethyl and t-butyl ester, can be prepared from the corresponding aldehyde in situ with the dianion of the acetic acetate ester formed, for example as described in Examples 10 and 61. The reaction may be carried out in an inert organic solvent such as tetrahydrofuran at low temperatures between -78 ° C and about 0 ° C and preferably between -78 ° C and -40 ° C until the reaction is substantially complete. If the compound of formula XV was prepared from a mixture of aldehydes of formula XIV, then the isolation and isolation of the compounds of formula XV, especially those wherein n is 1 and 2, can preferably be carried out at this stage by conventional methods.

The ketone ester of formula XV may be reduced to the dihydroxyester of formula Ia by reduction of a ketone radical with reducing agents well known in the art, e.g.

sodium borohydride, sodium cyanoborohydride, zinc: · 'coborohydride, disiamylborane, diborane, ammonium borane, t-butylamine borane, pyridine borane, lithium tri-s-butylborohydride or the like, hydrolyzes the carboxylic ester radical. Preferably, the reduction is effected stereospecifically using biphasic stereospecific reduction to maximize the formation of the preferred erythro isomer of the compound of formula I. • · · * • · «* of a compound of formula XV. stereospecific reduction is carried out with trisubstituted: i.i .: alkyl boranes, preferably methoxydiethyl borane or ethoxydiethyl borane (Tetrahedron Letters, 28, 155 (1987)) at a temperature of about -70 ° C to about 35 ° C. The resulting complex is then reduced with 103793 17 sodium borohydride at a temperature between about -50 ° C and about -78 ° C in an inert organic solvent such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, preferably tetrahydrofuran. The reduction is then completed by the addition of methanol. The resulting compound of formula Ia formed in stereo-specific reduction has two asymmetric carbon atoms with the hydroxy group in the erythro configuration. Thus, the reduction of the ketone radical in the presence of the 10-ratios used herein is predominantly made up of the erythro isomers of the compounds of formula Ia and only a small amount of the less preferred threo isomers. The ratio of the erythrotreo isomers formed will vary depending upon the specific compound used and the reaction conditions used. Normally, this ratio is in the range of about 9: 1 to about 9.8: 0.2. However, when nonspecific reduction is used, a 1: 1 mixture of isomers is usually formed. Nevertheless, the mixture of isomers may be separated and purified by conventional methods and then converted to the compounds of general formula I in a conventional manner well known to those skilled in the art.

If it is desired to prepare most of the stereoisomer of the compound of formula: I, optically pure starting materials are preferably employed. A process employing intermediates of this invention according to formula I

For the preparation of one isomer of a compound of the formula wherein X

: is -OH, is depicted in Reaction Scheme 5. The most preferred formula I

Isomer of the compound of formula · · · · where A is a group OH OH 0 · 7 ··, n OR 8

M1 oU

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

OH

Δ 103793 18 is the (4R, 65) isomer. To illustrate the use of optically pure starting materials, Scheme 5 illustrates the preparation of a preferred subject compound of formula I, such as the (3R, 5S) -isomer of compounds of formula If.

• I

••••••••••••••••••••••

• I I

• • • • • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Li

Reaction Scheme 5 Rv5 5/6 0 Ph <> + ΑΛ / * R3 T CHO + W> Ph

OH

10 j ^ VcH- XXVIII

-1 W

Xa V

κ4 · -Λ-κ6 OH O Ph r3wI / vAA vh R2— y T I Ph

20 Av OH

IK N-CH,

rv Rl W

XXIX I

· Υ ·: 25 * • · • · · e

• · · S

• · · · n · ^ • · · ** ··· · <

*; *! R3 I f ”U

; ·: P2_YYY ^ och3

• * * I II I

. · '* N ^ K-CH,

Rl w,.

35 J,

XXX V

20 103793

Reaction Scheme 5 (O) 5 R 5 R 4 -M-R 6 OH 0 O

R3 T ί II II

N-CH

Rl W 3

15 XXXI

20 R5 3 0H SH jj 25 R2 «s •;:; ·; R1 ^ I rCH3

N = N

'· 1' of formula If; 1j '; (3R, 5S) Compound · · • · · · · 103793 21

In Reaction Scheme 5 depicting a stereospecific pathway, R1, R2, R3, R4, R5, R6 and R9 are as previously defined. The starting material of formula XXVIII is known and its preparation is described in Tetrahedron 5 Letters, 25, 5031 (1984). The compound of formula XXVIII is first treated with a nucleophilic base, preferably lithium diisopropylamide in an inert solvent such as tetrahydrofuran, and then the enolate formed is reacted with an allyl aldehyde of formula Xa to form the triphenyl ester of formula XXIX. When treating a compound of formula XXIX with sodium methylate in methanol, the methyl ester of formula XXX can be isolated. When the methyl ester of formula XXX is reacted with an anion of tert-butyl acetate formed in situ with a nucleophilic base such as lithium diisopropylamide, the keto ester of formula XXXI is formed. Alternatively, the preparation of the compound of formula XXXI may be carried out directly by treating the triphenyl ester of formula XXIX with the anion of the t-butyl ester. The selective stereospecific reduction of the keto function of the resulting compound of formula XXXI with sodium borohydride triethylborane or sodium borohydride alkoxide alkyl borane, as described herein, can be used to form the compound of formula 5S) enantiomer. Accordingly, Reaction Scheme 5 provides a process for the preparation of (3R, 5S) -isomers of a compound of formula I using an optically pure starting material XXVIII, which provides the appropriately substituted. position of the carbon atom leading to stereospecific reduction of the 3 keto • · · · 30 function. Here's a leaflet. in the specific example wherein R 1 and R 4 are fluorine. and R, R, R and R ° are hydrogen, a process is provided for preparing the compound of formula If • t '· * which is predominantly in the (3R, 5S) -enantiomer.

:; The following examples further illustrate the preparation of the intermediates of the invention. The preparation of compounds of Formula I 103793 22 from these intermediates is illustrated in Example FI Patent Application 880869. All temperatures in the examples are in degrees Celsius. Melting points were determined on a Thomas-Hoover capillary melting point apparatus and boiling points were measured at specific pressures (mm Hg) and both temperatures are uncorrected. Proton magnetic resonance (1 H NMR) spectra were recorded on a Bruker AM 300, Bruker WM 360 or Color T-60 CW spectrometer. All spectra were determined in 10 CDCl3, DMSO-d6 or D2O, unless otherwise noted and chemical shifts are reported in δ units downward from the internal standard tetramethylsilane (TMS) and proton coupling constants are expressed in Hertz (Hz). The fragmentation patterns are shown as follows: s, 15 singlet; d, doublet; t, triplet; q, quartet; m, mullet; br, broad peak; and dd, doublet of doublet. The carbon-13-nuclear magnetic resonance (13C NMR) spectra were recorded on a Brukar AM 300 or Bruker WM 360 spectrometer and were broad-band proton decoplases. All spectra were determined in CDCl3, DMSO-d6 or D2O, unless otherwise noted, internal deuterium lock and chemical shifts are reported in δ units downwards from tetramethylsilane. Infrared (IR) spectra were determined on a Nicolet MX-1 FT spectrometer between 4000 cm -1: 25 400 cm -1, calibrated polystyrene membrane 1601 cm -1, Absorbent · · · · · · -. and expressed in in centimeters (cm). Relative intensities are expressed as s (strong), ... m (medium) and w (weak). The optical rotation [a] 'was determined with an' · '/ Perkin-Elmer 241 polarimeter in CHCl 3 at the mentioned concentrations of V' 30.

Gas chromatographic mass spectra (GC-MS) were determined on a Finnigan 4500 Gas chromatography - Quadruple mass Spectrometer with an ionization potential of 70 eV. Mass spectra were also recorded on a Kratos MS-50 · 35 using a fast atom bombardment (FAB) technique 103793 23. Mass values are given in the form; parent ion (M *) or protonated ion (M + H) +.

Analytical thin layer chromatography (TLC) analyzes were performed on pre-coated silica gel plates (60F-254) and visualized using UV light, iodine vapor, and / or staining with one of the following reagents: (a) methanol-containing phosphomolybd; with heating; (b) Reagent (a) followed by 2% cobalt distillate 5 mol. H2SO4 and heating. Chromatography on 10 columns, also called flash column chromatography, was performed on a glass column using fine silica gel (32-63 m silica gel H) and some atmospheric pressure at high pressures in said solvents. Ozonolysis reactions were performed using a 15 Walsbach ozonator style T-23 instrument. All evaporations of the solvents were performed in vacuo. As used herein, the term hexanes means a mixture of isomeric C 6 hydrocarbons, as specified by the American Chemical Society, and the term "inert" atmosphere refers to an argon or nitrogen atmosphere unless otherwise noted.

Example 1: Ethyl 2-cyano-3,3-bis (4-fluorophenyl) -2-propenoic acid: A mixture of 20.0 g (92 mmol) of 4,4'-difluoro -; Benzophenone, 11.0 g (97 mmol) of ethyl cyanoacetate in a mixed solvent of 100 mL of dry benzene and 20 mL of glacial acetic acid containing a catalytic amount of B-alanine (0.9 g) ), was boiled by separating the water using a Dean-Stark- • f * · * 'water trap. Water separation was rapid over the first two hours (0.4 ml of water was collected), but slower thereafter. Azeotropic distillation • · ·. · **. chain for 14 days. TLC analysis eluting with 10% ethyl acetate in hexanes (v / v (Merck plate, 0.25mm Silica gel-F) showed two spots at Rf = 0.25 (desired product) and Rf = 0.45 (4) The crude reaction mixture was washed with water (40 mL, 2 times), and the combined aqueous washings were extracted with ethyl acetate (150 mL, 2 times). The organic layers were combined, dried over MgSO 4, and concentrated in vacuo. The crude product was collected, washed with a 1: 1 mixture of ethyl acetate and hexanes (v / v), then recrystallized from a mixture of 8: 1 hexanes and ethyl acetate (v / v). yielding 10 16.2 g (56.3%) of the analytically pure title compound, mp = 114-116 ° C.

IR (KBr) i> max: 3000 (s), 2225 (s), 1931 (vs), 1605 (s), 1513 (s), 1250 (s), 844 (s) cnT1; 3 H NMR (CDCl 3) δ: 1.19 (3H, t, J = 7.1 Hz), 4.18 (2H, 15 q, J = 7.1 Hz), 7.08-7.5 (6H, m), 7.40-7.42 (2 H, m); 13 C NMR (CDCl 3) δ: 13.75, 62.27, 104.05, 116.69, 115.53 (d, 2 J C F = 22.7 Hz), 115.88 (d 2 J C F = 22.7 Hz) Hz), 131.64 (d, 3JC_F = 9.1 Hz), 132.66 (d, 3JC_F = 9.1 Hz), 134.25, 134.31, 134.36, 164.01 (d, 1Jc) ? r = 252.9 Hz), 164.52 (d,?, - 254.0 at 20 Hz), 166.65 ppm.

Anal Calcd for C 18 H 13 NO 2 F 2: 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- * 1-yl) -2-propenoate * A dry 50 mL round bottom flask was charged with 5.0 g (16.0 mmol). ) ethyl 2-cyano-3,3-bis (4-fluorophenyl) -? -? - 2-propenoate, followed by 8.0 g (24.1 mmol) of azido-tri-? butylstannane [made by Rev. Trav.,. . ·. Chim., 81, 202-5 (1962)], and 2.0 ml of reagent grade toluene. The heterogeneous mixture was stirred and heated to reflux (110 ° C) in an oil bath behind the cover. The solid starting material was gradually dissolved to form a pale yellowish thick syrup 103793 and the homogeneous mixture was stirred and refluxed for 20 hours. 20% eluted by TLC. MeOH in CHCl3 (v / v) showed product at Rf = 0.26 (bar). The crude reaction mixture was diluted with the same volume of die-5 ethyl ether and poured into vigorously stirred saturated aqueous KF (200 mL with 2 mL of 48% HBF4). Shortly after mixing, a voluminous precipitate (Bu3SnF) was observed and the hydrolysis was allowed to continue for 16 hours. The suspension was filtered and the filtrate extracted with ethyl acetate (10 x 2 mL). The organic layers were combined, dried over MgSO 4 and concentrated in vacuo. The title compound crystallized from the concentrate to give 4.54 g (77%) of a white, analytically pure material; mp. 159-161 ° C.

15 IR (KBr) δ: 3438 (br), 1713 (vs), 1600 (s), 1510 (s), 1238 (s), 841 (s) cm -1; 1 HNMR (CDCl 3) δ: 0.92 (3H, t, J = 7.6 Hz), 3.98 (2H, q, J = 7.6 Hz), 7.3-6.7 (8H, m) , 10 (1H, v.br.); 13 C NMR (CDCl 3) δ: 166.52, 163.54 (d, J J F = 250.7 Hz), 20 163.46, (d, J J F = 262.7 Hz), 157.14, 136.40 , 134.74, 131.71 (d, 2JC_F = 67.2Hz), 131.59 (d, 2JC_F = 66.4Hz), 115.75 (d, 3JC_F = 18.9Hz), 115 , 45 (d, 3JC.F = 18.1 Hz) 62.11, 13.47 ppm. Anal Calcd for C18H14F2N4O2: /. C, 60.27; H, 4.06; N, 15.50:, 25 Found: C, 60.67; H, 3.96; N, 15.72.

* i t

EXAMPLE 3 Ethyl-3.3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenoate and ethyl-3.3-bis (4-fluoro) - * · * * phenyl) -2- (2-methyl-2H-tetrazol-5-yl) -2-propenoate • · · V * 30 A. Ethyl-3.3-bis (4-fluorophenyl) -2- (1 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 at 45 ° C under argon protection. 35 mg, 100 mg (60% mineral oil 103793 in 26 mmol, 2.5 mmol) of sodium hydride was added in a single portion. The grayish suspension was stirred at 45 ° C for 30 minutes, then 1 ml (16.1 mmol) of methyl iodide was added and the flask was sealed with a rubber stopper. Alkylation was allowed to occur at 40-45 ° C for a total of 5 days. When starting twice in TLC analysis, hexanes containing 20% ethyl acetate showed only two isomeric products at Rf = 0.16 (major isomer 4) and Rf = 0.22 (less isomer 5). The crude reaction mixture was washed with the same volume of water and the aqueous phase re-extracted once with 50 mL of diethyl ether. The organic layers were combined, dried over MgSO 4 and concentrated in vacuo to give crude product. The ratio of 1-isomer to 2-isomer of the product was determined by gas chromatography and 1 H-NMR spectroscopy. The crude product mixture prepared as described above (5.0 g) was taken up in 20 ml of hot ethyl acetate to which 40 ml of hot hexane was added. The clear solution was allowed to cool slowly to room temperature to give 2.16 g (52%) of the title compound as colorless large needles; mp. = 144-145 ° C.

IR (KBr) uroax: 1713 (vs), 1600 (s), 1513 (s), 1325 ·: · (s), 1163 (s), 838 (s) cm -1; 1 H NMR (CDCl 3) δ: 7.4-6.8 (8H, m), 4.06 (2H, q, J = 7.1 Hz) 3.68 (3H, s), 1.00 (3H, t, J = 7.1 Hz); ¹³C NMR (CDCl3) δ: 165.44, 163.6 (d, λmax = 250.7 Hz), δ · 163.4 (d, 1 JC-P = 252.9 Hz) , 37, 135.88, 131.32 (d, 3JCF = 8.3Hz), 115.94 (d, 9JC_F = 21.9Hz), 115.64 (d, 2J-C_F = 22.7) Hz), 61.84, 33.76, 13.59 ppm; Anal Calcd for C 19 H 16 F 2 N 4 O 2: · 30 ° C, 61.62; H, 4.35; N, 15.13. Found: C, 61.63; H, 4.45; N, 15.21.

. ···. B. Ethyl 3,3-bis (4-fluorophenyl) -2- (2-methyl-2 H -? - tetrazol-5-yl-2-propenoate: Residue (2.0 g) obtained from Step A repeat 35 filtrate (containing equal proportions of 1 and 2-methyl isomers) was purified by chromatography on 27 103793 silica gels (35 g) The appropriate fractions were collected and evaporated to dryness to give a crystalline product by recrystallization from a mixture of hexanes and ethyl acetate ( 9: 1; v / v) gave the title compound, mp = 117-5118 ° C.

IR (KBr) i) Mai (: 1713 (vs), 1600 (s), 1506 (s), 1250 (sh), 1225 (vs), 850 (m) cm -1; 1 H NMR (CDCl 3) 6: 7 , 4-6.8 (8H, m), 4.20 (3H, s), 406 (2H, q, J = 7.1 Hz), 0.99 (3H, t, J = 7.1 Hz) : 10 13 C NMR (CDCl 3) δ: 167.12, 163.02 (d, J 2 = 272.6 Hz), 163.03 (d, 1 J c.f = 225.7 Hz), 162.80, 152, 59, 137.03 (d, 4JCF = 4Hz), 135.96 (d, 4JC_F = 3Hz), 131.94 (d, 3JC_F = 8.3Hz), 131.08 (d, 3JC_F) = 8.3 Hz), 120.48, 115.37 (d, 2JC_F = 21.9Hz), 115.26 (d, 2JC_F * 22.7Hz) 61.41, 39.40, 13.61 ppm Anal. Calcd for C, 61.62; H, 4.35; N, 15.13 Found: C, 61.77; H, 4.44; N, 15.38.

Example 4 3.3-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-20,5-yl) -2-propenoic acid • To a solution of ethyl 3,3-bis (4-fluorophenyl-2-) (1-Methyl-1H-tetrazol-5-yl) -2-propenoate 4.0 g (10.8 mmol) in a mixture of 20 ml of methanol and 20 ml of tetrahydrofuran at 0 ° C (ice-water bath) were added. 25 M solution of 3 molar lithium hydroxide in H2O • · · · m · m (etc.) (9 mL) The saponification reaction was allowed to continue overnight · · · (about 16 hours) to form a clear homogeneous solution .. TLC analysis eluting twice with a mixture of 30% ethyl acetate in hexanes (v / v) showed that the product was present after 30 days along with the starting material Crude: the reaction mixture was acidified by adding 10 ml of 3 molar HCl solution and the organic material was extracted twice with ethyl acetate (20 mL, 2 times). The organic layers were combined, dried over MgSO 4 and evaporated to dryness for 35 h. under vacuum to give the product as a light yellow solid. Recrystallization from ethyl acetate-103793 from 28 hexane (1: 9, v / v) gave 3.8 g (100%) of the title compound: m.p. = 205-206 ° C.

IR (KBr) Dmax: 3438 (br), 2900 (br), 1725 (s), 1713 (s), 1600 (s), 1501 (s), 1231 (vs), 1156 (s), 850 (s) cm-1; 3 H NMR (CDCl 3) δ: 7.9-6.4 (8H, m), 3.68 (3H, s); 13 C NMR (CDCl 3) δ: 166.57, 163.3 d, J = 249.9 Hz), 163.03 (d, 1 J c.f = 250 Hz), 155.68, 152.61, 135, 58, 134.74, 131.75 (d, 3JC.f = 8.3 Hz), 131.28 (d, 3JCF = 9.1 Hz) 117, 115.7 (d, 2Jc.f = 22.6) Hz), 115.4 (d, 2JC.F = 22.6 Hz), 33.6 ppm.

Anal. Calcd for C 17 H 12 F 2 N 4 O 2: C, 59.05; H, 3.53; N, 16.37 Found: C, 59.54; H, 3.58; N, 16.27.

Example 5 3,3-Bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazol-15,5-yl) -2-propenoic acid

The general procedure of Example 4 was repeated except that the ethyl 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenoate used therein was replaced by ethyl 3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-20-tetrazol-5-yl) -2-propenoate, after recrystallization from ethyl acetate-hexane ·; obtaining the title compound in substantially candidate yields; mp. = 154-155 ° C.

IR (KBr) λmax: 3438 (br), 3000 (br), 1675 (s), 1600 (s), 1503 (s), 1231 (s), 1225 (s), 1150 (s), 838 (s) ) cm -1; 1 H NMR (CDCl 3 -DMSO-d 6) δ: 7.33-7.28 (2H, m), 7.05- 6.96 (4H, m), 6.87 (2H, t) , J = 8.64 Hz), 4.23 (3H, s); 13 C NMR (CDCl 3 -DMSO-d 6) δ: 168.70, 163.05 (d, δ) / 1 H [delta] = 248.4 Hz), 163.07, 162.66 (d, δ,). = 249.9 Hz), 151.81, V: 30 136.81, 136.22, 131.83 (d, 3 J C F = 8.3 Hz), 131.20 (d, 3 J C F = 8.3; Hz), 121.04, 115.24 (d, 2JC_F = 21.9 Hz), 115.14 (d, 2JC_F = · 21.1 Hz) ppm.

Anal Calcd for C 17 H 12 F 2 N 4 O 2: C, 59.65; H, 3.53; N, 16.37 Found: C, 59.56; H, 3.59; N, 16.36.

29 103793

Example 6 3.3-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal A. 33-bis (4-fluorophenyl) -2- (1-methyl-1H) -tetrazol-5-yl) -2-propenyl chloride

To a solution of dry (0.1 mm Hg / 80 ° C) 3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenoic acid 38 , g (11.0 nunol) in 20 mL of dry methylene chloride, 4 mL (46.0 mmol) of purified ossalyl chloride (re-distilled over CaH) was added in one portion. The reaction mixture was gradually warmed to reflux over two hours. The mixture was evaporated to dryness in vacuo to remove the volatile solvent, then excess oxalyl chloride was removed in vacuo (20 mmHg) at ambient temperature for 2 hours and under high vacuum (0.1 mmHg) at 50 ° C for 16 hours to give 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 To ° C under argon. To this light brownish solution at -78 ° C was added 8.0 ml of lithium aluminum hydride in THF solutions (1.0 molar). TLC analysis after 15 minutes showed only one moving spot for Rf = 0.23 (50% ethyl acetate in hexanes, v / v).

* · ·

The crude reaction mixture was diluted with 2 mol. H 2 SO 4 (20 mL). The aqueous layer was extracted with ethyl acetate (40 mL, 2 times).

• * f • · ·

The organic layers were combined, dried over MgSO 4 and evaporated to dryness in vacuo to give 3.64 g (100%) of the title compound. · Use of crude allyl alcohol · ***; was immediately carried on to the next step without further purification.

MS (CI): m / e = 328 (M + H) +.

1R (KBr) υΒβχ: 3388 (v.br), 1600 (s), 1501 (s), 1225 (s), 1156 (s), 838 (s), 750 (s), cm -1; 103793 30 H NMR (CDCl 3) δ: 7.5-6.9 (8H, m), 4.52 (2H, br), 3.42 (3H, s), 3.75 (1H, br, D convertible); 1 H NMR (DMSO-d 6) δ: 7.5-6.9 (8H, m), 5.23 (1H, t, J = 5.5 Hz), 4.27, (2H, d, J = 5.5 Hz), 354 (3H, s) ppm; 5 C. 3.3-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal

To a vigorously stirred solution of 3.64 g of crude allyl alcohol [prepared in Step B] in 40 ml of methylene chloride at room temperature was added 2.6 g (12.0 mmol) of pyridinium chlorochromate in one portion. Immediately after, TLC analysis showed about 50% product at Rf = 0.34 with starting material at Rf = 0.14 (eluted with 50% ethyl acetate in hexanes v / v). The oxidation was allowed to continue at room temperature for 15 minutes and TLC indicated that only the product was present. The crude reaction suspension was filtered through a silica gel pad, washed with one liter of 10% (v / v) ethyl acetate / hexane and one liter of 20% (v / v) ethyl acetate in hexane. The desired product crystallized-20 was concentrated under vacuum to give 2.7 g

t I

(74%) of the title compound; mp. = 141-142 ° C. MS (CI): m / e = 326 (+ H) +.

IR (KBr) λmax: 3075 (m), 2875 (m), 1675 (s), 1600 t (s), 1501 (s), 1238 (s), 1156 (s), 850 (s), 750 (s), cm -1; ; , 25: 1 H NMR (CDCl 3) δ: 9.63 (1H, s), 9.5-6.9 (8H, m), 3.74:? (3H, s); 13 C NMR (CDCl 3) δ: 188.92, 165.44, 164.68 (d, ... 1 J c.f = 254.4 Hz), 164.10 (d, 1 H, J = 255.9 Hz). , 151.34, 134.31, • «c *; * / 133.77 (d, 3JCF = 8.3Hz), 132.69, 132.23 (d, 3JCF = 7.5Hz)" 30 123.70, 116.26 (d, 2 J C F = 21.9 Hz), 116.18 (d, 2 J C F = 22.7 Hz), Ϊ 34.10 ppm.

1 «· · ***; Anal Calcd for C 17 H 12 F 2 N 4 O: C, 62.58; H, 3.71; N, 17.17 Found: C, 62.41; H, 3.85; N, 16.98.

31 103793

Example 7 3.3-Bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazol-5-yl) -2-propenal

The general procedure of steps A, B, and C of Example 6 was repeated except that the 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenoic acid used in Step A -po was replaced by 3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazol-5-yl) -2-propenoic acid [prepared in Example 5] to give the title compound as a gummy solid-10. in 76% overall yield. MS (CI): m / e = 626 (M + H) +.

IR (KBr) vax: 2863 (m), 2750 (w), 1681 (s), 1600 (s), 1503 (s), 1225 (s), 1156 (s), 838 (s), 752 (s) , cm -1; 3 H NMR (CDCl 3) δ: 9.65, 7.34-7.30 (2H, m), 7.15 δ (2H, t, J = 8.5 Hz), 7.01-6.96 (2H , m), 6.88 (2H, t, J = 8.4 Hz), 4.29 (3H, s); 13 C NMR (CDCl 3) δ: 190.08, 164.30 (d, δ, δ = 254.4 Hz), 163.5 (d, λ, = 252.17 Hz), 163.20, 161 , 37, 135.55, 133.49, 133.66 (d, 3JCF = 7.6Hz), 132.38 (d, 3JCF = 9.1Hz), 20 131.40, 127.54, 115.86 (d, 2JC_F = 26.4 Hz), 115.57 (d, 2JC_F = 28.7 Hz), 39.55 ppm;

Anal Calcd for C 17 H 12 F 2 N 4 O: C, 62.58; H, 3.71; N, 17.17 ·! Found: C, 62.27; H, 4.22; N, 15.83.

(i; 25 Example 8 • · ·. *. * 5.5-bis (4-fluorophenyl) -4- (1-methyl-1H-tetrazole • · · * ”. * 5-yl) -2,4- pentadienal • · · * · * To a dry mixture of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal 0.70 g * · "V '30 (2.1 mmol) and triphenylphosphoranylidene-acetaldehyde •" V: 0.72 g (2.5 mmol) protected by argon at ambient temperature, 20 ml of dry benzene were added. The suspension was warmed to reflux. under argon and the reaction was allowed to continue at reflux for 30 minutes • 103793 32 TLC analysis eluting four times with 20% ethyl acetate in hexanes (v / v) showed only one spot of product at Rf = 0.15. the reaction mixture was poured onto a hexane saturated silica gel column with hexanes, and the desired product was eluted with 1.5 L of 20% ethyl acetate in hexanes (v / v) to give 0.6 7 g (89%) of the title compound, which appears homogeneous by TLC.

1 H NMR (CDCl 3) δ: 9.53 (1H, d, J = 7.5 Hz), 7.47 (1H, 10 d, J = 15.7 Hz), 7.4-8.8, m ), 5.80 (1H, dd, J = 7.4 Hz, J2 = 15.7 Hz), 4.11 (2H, q, J = 7.1 Hz), 3.58 (3H, s), 1.26 (3H, t, J = 7.1 Hz) ppm.

The proton NMR (300 MHz) of the above product showed about 10% 7,7-bis (4-fluorophenyl) -6- (1-15 methyl-1H-tetrazol-5-yl-2,4,6) heptatrienal as a by-product which was not readily removed and was used in the next preparation without further purification.

Example 9 5,5-Bis (4-fluorophenyl) -4- (2-methyl-2H-tetrazol-5-yl) -2,4-pentadienal

The general procedure of Example 8 was repeated except that the 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal used therein was replaced with 0.67 grams of 21.0 mmol) 3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-4 · -1,1-tetrazol-5-yl) -2-propenal [prepared in Example · · · 7 ]. The reaction was carried out with 0.64 g (21.0 mmol) of tri-N-phenylphosphoranylidene-acetaldehyde to give 0.66 g (90.5%) of the title compound.

1 H NMR (CDCl 3) δ: 9.57 (1H, d, J = 6.8 Hz), 7.50 (1H, d, J = 16.5 Hz), 7.3-6.8 (8H, m), 5.94 (1H, dd, J-6.8, 16.5 Hz), 4.30 (3H, s) ppm.

«1« «i« «33 103793

Example 10

Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienate and ethanol-11 -11. 11-bis (4-fluorophenyl) -5-hydroxy-10- (1-methyl-1H-5-tetrazol-5-yl) -3-oxo-6,8,10-undecatrienoate A. Ethyl 9,9-bis (4- fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6.8-nonadienoate Cooled to a suspension (0 ° C, ice-water bath) containing NaH ( 0.64 g, 16.0 mmol) (60% in mineral oil) in 20 ml dry tetrahydrofuran, protected by argon, was added in four equal portions to 2.04 ml ethyl acetoacetate (16.0 mmol). The homogeneous clear solution was stirred at 0 ° C for 30 minutes, followed by the dropwise addition of 6.4 ml of 2.5 molar n-15 BuLi (16.0 mmol) over 15 minutes. The orange dianion solution was stirred at 0 ° C for an additional hour. The ice-water bath was replaced by an acetone-dry ice bath at -78 ° C and the di-anion was transferred to a tetrahydrofuran solution (20 mL) containing 5,5-bis (4-fluorophenyl) -4- (1- methyl 20H-tetratrol-5-yl) -2,4-pentadienal (2.82 g, 8.01 mmol). TLC analysis showed most of the product to be Rf = 0.15 (50% ethyl acetate in hexanes) and to a lesser extent Rf = 0.2. Raw Reaction, ·. : thiode mixture was diluted with 40 mL of 1N. HCl and aq. Aqueous solution were extracted with ethyl acetate (50 mL, 2 times). The organic layers were combined, dried in vacuo. The desired product was purified by flash column chromatography on silica gel eluting with 20% ethyl acetate (v / v) hexanes to give 2.26 g (58.5% of the title *). · 30 compounds MS (Cl): m / e for 483 (M + H) +.

• · V: IR (KBr) vBax; 3450 (v.br), 1738 (s), 1725 (s), 1606 (s), 1513 (vs), 1225 (s), 1163 (s), 844 (s) cm * 1; 1 H NMR (CDCl 3) δ: 7.4-6.8 (8H, m), 6.72 (1H, d, J = 15.6 Hz), 4.63 (1H, m), 4.17 (2H , q, J = 7.1 Hz), 4.13 (1H, · 35m), 3.60 (3H, s), 3.52 (1H, d, J = 3.9 Hz, D2O) Δ · 103793 δ 3.47 (2H, s), 2.74 (2H, d, J = 6.0 Hz), 1.26 (3H, t, J = 7.1 Hz) ppm; 13 C NMR (CDCl 3) δ: 164.21, 135.98, 132.34 (d, 3 J Cf = 8.3 Hz), 131.45 (d, 3 J C F = 9.1 Hz), 115.74 (d , Δ 2JC.F = 21.9 Hz), 115.74 (d, 2JC.F = 21.1 Hz), 100.86, 67.61, 61.58, 49.85, 49.07, 33, 56, 14.10 ppm.

B. Ethyl 11,11-bis (4-fluorophenyl) -5-hydroxy-10- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8.10-undecatrienolate 10 The A silica gel column was further eluted to give a smaller amount of product (Rf = 0.2). Flash chromatography on silica gel using 20% ethyl acetate in hexanes as eluent gave the title compound.

* 1 H NMR (CDCl 3) δ: 7.4-7.1 (4H, m), 6.9-6.8 (4H, m), 6.58 (1H, d, J = 15.5 Hz), 6.31 (1H, dd, J = 10.7, 15.0 Hz), 5.80, 1H, dd, J = 10.7, 15.4 Hz), 5.66 (1H, dd, J = 5.5, 15.1 Hz), 4.64 (1H, m), 4.18 (2H, q, J = 6.9 Hz), 3.58 (3H, 20 s) 3.46 (2H, s), 3.02 (1H, m), 2.75-2.72 (2H, m), 1.27 (3H, t, J = 6.9 Hz) ppm.

Example 11:. Ethyl 9,9-bis (4-fluoro-phenyl) -5-hydroxy-8- (2-methyl-2H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. The general procedure for 10-wax A, except that it uses 5,5-bis (4-fluorophenyl) -4- • · · * · * 1-methyl-1H -tetrazol-5-yl) -2,4-pentadienal was replaced by · · · * · * 0.66 g (1.87 mmol) of 5,5-bis (4-fluorophenyl) -4- (2- methyl-2H-tetrazol-5-yl) -2,4-pentadienal, and then 0.43 g (59%) of the title compound was prepared after chromatography on SiO 2 gel.

. . ·. Example 12

Phenylmethyl-9.9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -5-oxo-6,8-nonadienoate 3,3-bis (4- fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) prop-2-enal (2.50 g, 7.7 mmol), phenylmethyl-6-103793 35 (dimethylphosphono) -3-hydroxy-5 oxohexanoate (3.93 g, 11 mmol) and dry lithium bromide (1.40 g) were combined in acetonitrile and treated with 1,8-diazobicyclo [5.4.0] un-dec-7-ene (1, 2 mL, 8.0 mmol). The mixture was stirred under argon at 23 ° C for 44 hours before being concentrated in vacuo. The residue was partitioned between CH 2 Cl 2 (50 mL) and ice cold H 3 PO 4 (100 mL). The organic layer was washed with water (2 x 50 mL), dried over anhydrous Na 2 SO 4, and evaporated to dryness to give 4.2 g of an orange foam. The crude product was first absorbed on silica and flash chromatographed three times on silica gel (10-40) column using 40% ethyl acetate in hexane as eluent to afford 0.36 g of the title compound.

MS (Cl): m / e = 545 for (M + H) +; IR (KBr) νmax: 3440 (OH), 1735 cm @ -1 (C (= O) OCH2); NMR (CDCl 3) δ: 2.50 (d, 2H, C-2 or C-4 CH 2, J = 6.2), 2.63 (d, 2H, C-2 or C-4 CH 2, J = 5 , 9), 3.33 (s, 1H, OH), 3.50 (s, 3H, NCH3), 4.42 (m, 1H, CHOH), 5.09 (s, 2H, 20 -OCH2), 5.80 (d, 1H, C-5 olefinic H, J = 16), 6.85-7.34 (m, 13H, ArH), 7.52 (d, 1H, C-7 olefinic H, J = 16).

; '; Example 13

Sodium (±) -9.9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -5-oxo-6,8-nonadienoate Phenylmethyl-9,9- bis (4-fluorophenyl) -3-hydroxy-4 * - *. * 8- (1-methyl-1H-tetrazol-5-yl) -5-oxo-6,8-nonadienoate • · · · * ;. * (0.34 g, 0.62 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL). 1-Norway was added. sodium hydroxide (0.62 mL, 0.62 mmol), and the solution was stirred for 6 hours at 24 ° C. The mixture was diluted with water (10 mL) and washed with diethyl ether (3 x 50 mL). The aqueous portion was lyophilized,. * ·. yielding 0.17 g (52%) of the title compound; mp. = 166-180 ° C (dec.).

IR (KBr) uBax: 1585 cm -1 (C00 *): 35 1 H NMR (DMSO-d 6) δ: 1.76 (dd, 1H, C-4 CH, J = 8.4.16), 1.97 (dd, 1H, C-4 CH, J = 3.5.16), 2.42 (m, 1H, C-2 CH2),, β 103793 ob 3.71 (s, 3H, NCH3), 3, 93 (m, 1H, CHOH), 5.80 (d, 1H, C-6 olefinic H, J = 16), 6.89-6.94 (m, 2H, ArH), 7.06-7.12 (m, 2H, ArH), 7.30 (d, 1H, C-7 olefinic H, J = 16), 7.38-7.41 (m, 4H, ArH).

Anal. Calcd for C 23 H 19 F 2 N 4 O 4 Na 3.5 H 2 O: C, 51.21: H, 4.86; N, 10.39 Found: C, 51.44; H, 3.97; N, 9.46.

Example 14

Ethyl 3.3-bis (4-fluorophenyl) -2- [1- (1-methylphenyl) -1H-tetrazol-5-yl] -2-pronenoate la ethyl 3,3-bis- (4-fluorophenyl) - 2- [2- (1-methylethyl) -2H-tetrazol-5-yl] -2-pronenoate A. Ethyl 3,3-bis (4-fluorophenyl) -2- [2- (1-methylethyl) -2H- tetrazol-5-yl-1-2-propenoate To a cooled (-78 ° C, dry ice-acetone) solution of ethyl 3,3-bis (4-fluorophenyl) -2- (1H-tetrazol-5-yl) - 2-Propenoate (2.6 g, 7.3 mmol) [prepared in Example 2] In 20 mL of dry N, N-dimethylformamide, protected by argon, NaH (0.44 g, 11.0 mmol; 60%) was added. mineral oil) followed by the addition of reagent grade 2-iodopropane (2.0 mL, 20.0 mmol) in one portion The thick reaction mixture was stirred under argon at -78 ° C for 30 minutes and allowed to slowly warm to room temperature over 16 hours. TLC analysis, eluting once with 50% ethyl acetate in hexane, gave one spot in the Rf = 0.86 The light suspension was diluted with 40 mL of semi-saturated saline followed by 20 mL of ethyl acetate. The aqueous layer was washed with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over MgSO 4 and evaporated.

• · I

ί, ϊ '· dry in vacuo. TLC analysis eluted four times. 8% ethyl acetate in hexane (v / v) gave two spots at Rf = 0.38 (21) and Rf = 0.49 (21a). The desired products were purified by chromatography on a silica-35 gel column eluting with 8% ethyl acetate-103793 in hexane. The high-speed product was collected to give 1.64 g (56.5%) of the title compound.

MS (C1): m / e = 399 for (M + H) +; 3 H NMR (CDCl 3) δ; 7.29-6.85 (8H, m), 4.94 (1H, 5 heptet J = 6.7 Hz), 4.09 (2H, q, J = 6.9 Hz), 1.50 (6H , d, J = 6.8 Hz), 1.01 (3H, t, J = 6.9 Hz); 13 C NMR (CDCl 3) δ: 167.04, 163.20 (d, 1H, - 248.4 Hz), 162.82 (d, 1 J c.r = 240 Hz), 152.65, 136.85, 136 , 19, 131.83 (d, 3JC_F = 8.3 Hz), 131.04 (d, 3JC_F = 8.3 Hz), 115.97, 115.85, 10 115.34 (d, 2Jc_f = 21, 9.11), 115.11 (d, 2JCF = 21.9 Hz), 61.38, 56.48, 22.04, 13.68 ppm.

B. Ethyl 3.3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2-propenoate

The silica gel column from Step A above was further eluted with 8% ethyl acetate in hexane to give a slower product (R f = 0.38). Appropriate fractions were collected to give 0.95 g (32.7%) of the title compound. MS (CI): m / e = 399 (M + H) +.

20 1 H NMR (CDCl 3) δ: 7.25-6.85 (8H, m), 4.30 (1H, heptet = 6.8 Hz), 4.04 (2H, q, J = 7.1 Hz) ), 1.26 (6H, d, J = 6.8 Hz), 1.01 (3H, t, J = 7.1 Hz); 13 C NMR (CDCl 3) δ: 165.6, 162.7 (d, J 2 = 200 Hz), δ 155.7, 135.8, 134.2, 132.1 (d, 3 3 Hz), 131.0 (d, 25 3 Jc_f = 6.8 Hz), 115.8 (d, 2 Jc_f = 21.9 Hz), 115.7 (d, 1 * / 2 Jc.f = 21.9 Hz) ), 51.81, 51.07, 22.18, 13.61 ppm.

Example 15 * · * * 3,3-bis (4-fluorophenyl) -2-Γ2-Γ1- (1-methylphenyl) -1H-tetrazol-5-yl] -2-propenal ·. 30 A. 3.3-bis (4-fluorophenyl) -2- [1- (1-methylphenyl) -1H-tetrazol-5-yl] -2-propenoic acid, * ·. To a cooled solution (0 ° C) of ethyl 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H- [tetrazol-5-yl] -2-propenoate ( 0.95 g, 2.39 mmol) in 20 mL of a 1: 1 (v / v) mixture of tet-35 tetrahydrofuran and methanol was added 38 103793 in one portion of aqueous LiOH (4.0 mL, 3 molar). The reaction mixture was stirred at 0 ° C for 15 minutes, then warmed to ambient temperature. The saponification was allowed to continue at room temperature for 4 hours, whereupon a very light clear solution was formed. The crude reaction mixture was diluted with 12 mL of 2 mol. H 2 SO 4 and the product was extracted into diethyl ether (40 mL, 2 times). The organic layers were combined, dried over MgSO 4, evaporated to dryness in vacuo and then dried under high vacuum (0.01 mm Hg) at room temperature for 24 hours to give the title compound. The propylene acid was then used in the next step without further purification.

B. 3.3-Bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2-propenol chloride A solution of the dried acid prepared in Step A in 20 mL of dry methylene chloride at room temperature, treated with 4 ml of oxalyl chloride (redistilled on CaH 2). The mixture was refluxed for 2 hours under argon to form a light tan solution. Most of the volatile solvents were evaporated in vacuo and the last oxalyl chloride residues were removed under high vacuum (0.01 mm Hg) at room temperature for 12 hours to give the title compound.

25 C. 3,3-Bis (4-fluorophenyl) -2- [1- (1-methylphenyl) -1H-tetrazol-5-yl] -2-propenol · · * “, * The acid chloride prepared in Step B was dissolved in 20 mL of dry tetrahydrofuran, followed by the slow addition of 1.8 mL of lithium aluminum hydride (1.0 molar tet · · · V; 30 in hydrofuran) under argon. protected at -78 ° C.

TLC analysis eluting once with 30% ethyl acetate. containing hexane (v / v) gave the alcohol product at Rf = 0.46. The crude reaction mixture was poured into dilute H 2 SO 4 (2N H 2 O) and the desired product was extracted with three portions of diethyl ether (3 x 40 mL). The organic extracts were combined, dried over MgSO 4 and evaporated to dryness in vacuo to give 1.07 g of the title compound which was used without further purification in the next step.

5 D. 3.3-Bis (4-fluorophenyl) -2- [1- (1-methylphenyl) -1H-tetrazol-5-yl] -2-propenal

The allyl alcohol (0.96 g) prepared in Step C was dissolved in 45 mL of dry methylene chloride at room temperature and to this vigorously stirred solution 10 was added 0.64 g (2.96 mmol) of pyridinium chlorochromate in one portion. After stirring the reaction mixture for four hours, TLC analysis eluting once with 10% ethyl acetate in hexane (v / v) and twice with 20% ethyl acetate in hexane (v / v) gave one major product at a spot of Rf = 0.22. The crude reaction mixture was poured onto a silica gel layer about 1-1 / 2 inches and eluted with 20% ethyl acetate in hexane to give 0.51 g (53%) of the title compound. MS (CI): m / e = 355 (M + H) +.

Example 16 3,3-Bis (4-fluorophenyl) -2- [2- (1-methylphenyl) -2H-: tetrazol-5-yl] -2-propenal

The general procedure of Steps A, B, C and D of Example 15 was repeated except that the ethyl, 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole 5-yl] -2-propenoate was replaced by ethyl 3,3-bis (4- * 11 * fluorophenyl) -2- [2- (1-methylethyl) -2H-tetrazol-5-yl] -? * '' 2-propenoate and the title compound was prepared in 88% yield.

EXAMPLE 17 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (1-. Methylethyl) -1H-tetrazole]. 5-yl-3-oxo-6,8-nonadioenoate and ethyl-11'-bis (4-fluorophenyl) -5-hydroxy-10-n- (1-methylethyl) -1H-tetrazol-5-yl -3-oxo-6,8,10-35 undecatrienoate 103793 40 A. 5.5-bis (4-fluorophenyl) -4- [1- (1-methylphenyl) -1H-tetrazol-5-yl] -4,4-pentadienal ia 7,7-bis (4-Fluorophenyl) -6-η 1 - (1-methylphenyl) -1H-tetrazol-5-η 2 -2,4,6-heptatrienal 5 To a dry mixture of 3,3-bis (4-fluorophenyl) li) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2-propenal (0.51 g, 1.4 mmol) and triphenylphosphoranylidene acetaldehyde (0.48 g) , 1.6 mmol) protected by argon at room temperature, 24 ml of dry benzene was added. The light-brownish suspension was stirred vigorously and heated in an oil bath at about 120 ° C. The mixture was heated rapidly and reflux was continued overnight (about 16 hours). TLC analysis of the brownish solution eluting five times with 20% ethyl acetate in hexane 15 (v / v) gave only one spot at Rf = 0.26; no trace of the aldehyde starting material was observed. The crude reaction mixture was chromatographed on a silica gel column and eluted with about 1 L of 25% ethyl acetate in hexane (v / v). From the appropriate fractions 0.54 g (99%) of a mixture of the title compounds was obtained which was homogeneous by TLC. This material was used in the next step without further purification.

B. Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] -3-oxo-6,8-nona [25] dienate and ethyl II. . 11-bis (4-fluorophenyl) -5-hydroxy. * 10 -1- (1-methylethyl) -1H-tetrazol-5-yl] -3-oxo-6.8.10- • · · undecatrienoate • · · "· Ethyl acetoacetate dianion (0.36 mL, 2.8 mmol) was prepared in tetrahydrofuran (2.5 mL) as described in Example 10 · · · V · 30 using NaH (0.11 g, 2.8 mmol). · Ί.ϊ (60% in mineral oil) and 2.5 molar n-butyllithium in hexane (1.2 ml, 3.0 mmol) at 0 ° C under argon ° -78 ° C After cooling, the dianion solution was transferred

was cannulated into a solution of tetrahydrofuran 35 (5 mL) at -78 ° C in 0.52 g (1.4 mmol) in Step A

41 103793 41 napal and trienal compounds. The reaction mixture was stirred at -78 ° C under argon for 15 minutes.

TLC analysis eluting twice with 50% ethyl acetate-5 hexane gave most of the spot at Rf 0.41 and less of the component at Rf 0.47. The light brownish reaction mixture was diluted with 5 mL of 2 mol. H2SO4 and extracted with ethyl acetate (2 x 40 mL). The organic layers were combined, dried over MgSO 4 and evaporated to dryness in vacuo. The products were purified and isolated by chromatography on a silica gel column using 20% ethyl acetate in hexane (v / v) as the elution solvent. The appropriate fractions with Rf = 0.41 were combined and evaporated to dryness to give 0.29 g (41%) of the title compound ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [L- (1-methylethyl) -lH-tetrazol-5-yl] -3-oxo-6,8-nonadienaattia.

1 H NMR (CDCl 3) δ: 7.29-7.25 (2H, m), 7.12 (2H, t, 20 J = 8.64 Hz), 6.93-6.81 (4H, m) , 6.75 (1H, d, J = 15.5 Hz), 5.27 (1H, dd, J = 5.64, 15.5 Hz), 4.62 (1H br.q, J = 5, 7Hz), 4.29 (1H, heptet, J * 6.6Hz), 4.17 (2H, q, J = 9.1Hz), 3.46 (2H, br.s), 2.72 (2H, d, J = 6.0 Hz), 1.26 (3H, t, J = 9.1 Hz), 1.3-1.2 (6H, br. Cup) ppm.

The appropriate fractions with Rf = 0.47 were combined and evaporated to give 0.13 g (17.3%) of the title compound ethyl 11,11-bis (4-fluorophenyl) -5. -hydroxy-10- [1- (1-methylethyl) -1H-tetrazol-5-yl] -3-oxo-6,8,10-undecatrienonate.

···: .delta. 30H NMR (CDCl3) δ: 7.29-7.22 (2H, m), 7.20-7.10 (2H,}; m), 6.91-6.80 (4H, m), 6.59 (1H, d, J = 15.4 Hz), 6.29 (1H, .delta., J = 10.7, 152 Hz), 5.70 (1H, dd, J = 10.7, 15.4 Hz), 5.84 (1H, dd, J = 9.9, 15.5 Hz), 4.62 (2H, br), 4.27 (1H, heptet) , J = 6.6 Hz), 4.17 (2H, q, J = 70 Hz), 3.46 (2H, s) 3.1 (1H, 35 br, D2O alternating), 2.75-2, 69 (2H, m), 1.26 (3H, t, J = 42 42 103793 7.0 Hz), 1.38-1.05 (6H, br domes, blocked rotation for the isopropyl group).

Example 18

Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8β- (1-5 methylethyl) -2H-tetrazol-5-yl-3-oxo-6,8-nonadienoate and ethyl 7.7- bis (4-fluorophenyl) -5-hydroxy-6-Γ2- (1-methylethyl) -2H-tetrazol-5-wli1-3-oxo-6-t-heptenoaat

The general procedure of Example 19, Step A was repeated except that the 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2-propenal used therein was replaced With 3,3-bis (4-fluorophenyl) -2- [2- (1-methylethyl) -2H-tetrazol-5-yl] -2-propenal, and thus most of the 5,5-bis (4-fluorophenyl) was prepared -4- [2- (1-15 methylethyl) -2H-tetrazol-5-yl] -2,4-pentadienal in 82% yield; MS (CI): m / e = 381 (M + H) +. This product was then treated according to the general procedure of Example 19, Step B to give ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (1-methyl-20-ethyl) -2H-tetrazole]. 5-yl] -3-oxo-6,8-nonadienate with some insoluble ethyl 7,7-bis (4-; 'fluorophenyl) -5-hydroxy-6- [2- (1-methylethyl) -2H-Tetrazol-5-yl] -3-oxo-6-heptenoate in 69.7% yield.

1 H NMR (CDCl 3) δ: 7.31-7.11 (2H, m), 7.10-7.04 (2H, 25m), 6.91-6.78 (4H, m), 6.72 (1H, d, J = 15.5 Hz), 5.46 (1H, / / dd, J = 5.91, 15.7 Hz), 4.95 (1H, heptet, J = 6.8 Hz) , 4.64 · · · (1H, br.s), 4.17 (2H, q, J = 7.2 Hz), 3.46 (2H, s), 2.75-2.72 Σ ·: : (2H, m), 1.49 (6H, d, J = 6.8 Hz), 1.28 (3H, t, J = 7.2 Hz) PPm.

··· V * 30 Example 19 • Ethyl 3β-3-bis (4-fluorophenyl) -2- [2- (1,1-dimethylaminomethyl) -2H-tetrazol-5-yl] -1- 2-propenoate (

To a stirred suspension of 10 g of ethyl 3,3-bis (4-fluorophenyl) -2- (ΙΗ-tetrazol-5-yl) -2-propenoate-35 in 250 ml of dry diethyl ether cooled 1 <43 103793 To -50 ° C, 60 ml of liquid isobutylene (previously condensed from gaseous material in a dry ice-alcohol bath) was added slowly. With continuous stirring and cooling, 50 ml of concentrated H2SO4 was slowly and carefully added. The mixture was then sealed in a stainless steel Parr container and stirred at -30 ° C for 40 hours. After releasing the pressure, the mixture was slowly and carefully added to the excess saturated NaHCO 3 solution. The aqueous mixture was extracted with diethyl ether, dried over Na 2 SO 4 and evaporated to dryness in vacuo to give 7.8 g (67.8%) of the title compound, m.p. 143-144 ° C.

IR (KBr) ν 3: 3.38 (v.br.), 1738 (s), 1625 (s) 1600 (s), 1240 (s), 1225 (s), 842 (s) cm -1; 1 H NMR (CDCl 3) δ: 7.2-7.24 (2H, m) 7.07-6.84 (6H, m), 4.10 (2H, q), 1.59 (9H, s) ), 1.03 (3H, t) ppm.

Anal. calcd for C, 64.07; H, 5.38; N, 13.58 Found: C, 64.15; H, 5.25; N, 13.58.

Example 20 3.3-bis (4-fluorophenyl) -2- [2- (1,1-dimethylmethyl) -1H-tetrazol-5-win-2-propenal] · 3-bis (4-fluorophenyl) ) -2-2- (1,1-dimethylethyl) -2H-tetrazol-5-yl-2-propenol; ; To a stirred solution of ethyl 3,3-bis (4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · = · · · · · · · · Yl] -2-propenoate (2 µg, 4.8 mmol) in dry methylene chloride (10 ml) under argon at -78 ° C was added 10 ml of diisobotylaluminum hydride solution (1). , 0 mol / l methylene chloride solution) over three minutes. The reduction was allowed to continue at -78 ° C under argon protection. two hours. TLC analysis, eluting twice with 20% ethyl acetate in hexane, gave no starting material at Rf = 0.42 and gave an end point at Rf = 35.14 for the desired product. The crude reaction mixture (at -78 ° C) 103793 44 was diluted with 10 mL of 2N. HCl followed by extraction with ethyl acetate (2 x 40 mL). The organic layers were combined, dried over MgSO 4, evaporated to dryness in vacuo and dried under high vacuum at room temperature overnight to give the title compound which was used without further purification in the next step.

3 H NMR (60 MHz) (CDCl 3) δ: 7.4-6.9 (8H, m), 9.7 (-1 / 4H, s, small amount of aldehyde), 4.6 (2H, d, J = 6 Hz), 1.56 δ (9H, s) ppm.

B. 3,3-Bis- (4-fluorophenyl) -2- [2- (1,1-dimethylphenyl) -2H-tetrazol-5-yl] -2-propenal

The crude allyl alcohol prepared in Step A was dissolved in 60 mL of dry methylene chloride and to this vigorously stirred solution was added pyridinium chlorochromate (1.2 g, 5.5 mmol) in one portion at room temperature. Slightly exothermic oxidation was allowed to continue for two hours at room temperature. TLC analysis, eluting twice with 20% (c / v) hexane containing ethyl acetate, gave the aldehyde at Rf = 0.35. The crude reaction mixture was chromatographed on a silica gel column and eluted with a liter of 5% (v / v) ethyl acetate. acetate containing hexane to give 1.59 g (89%) of product homogeneous by TLC. Recrystallization from ethyl acetate-hexane gave the pure title compound, mp 131-133 ° C.

• IR (KBr) Dmax: 3488 (m), 1669 (s), 1600 (s), 1508 0: (s), 1475 (m), 1231 (s), 1219 (s), 1156 (s). , 850 (s) cm -1.

3 H NMR (CDCl 3) δ: 9.72 (1H, s), 7.38-7.33 (2H, m), t: 30.17 (2H, t, J = 8.6 Hz), 7, 00-6.84 (4H, m), 1.63 (9H, s); 13 C NMR (CDCl 3) δ: 190.14, 164.27 (d, 246.1 Hz), 163.35 (d, 1H J = 240 Hz), 162.5, 160.9, 135.82, 133.58, 3Jc.f = 8.3Hz), 132.26 (d, 3JC_F = 8.3Hz), 128.4, 115.85 (d, 2JC_F = 21.9Hz), 115.22 ( d, 2JC.F = 21.9 Hz), 63.95, 29.24 ppm. 35 Anal, Calcd for C20H18F2N4O:

1 «I

«14 • · 103793 45 C, 65.21; H, 4.92; N, 15.21 Found: C, 65.33; H, 4.93; N, 15.44.

Example 21 5.5-Bis (4-Fluorophenyl) -4- [2- (1,1-dimethylbutyl) -5 2H-tetrazol-5-yl] -2,4-pentadienal A warm, stirred solution of 3,3-bis (4- fluorophenyl) -2- [2- (1,1-dimethylethyl) -2H-tetrazol-5-yl] -2-propenal (1.59 g, 4.3 mmol) in 60 mL of dry benzene protected by argon , 10 triphenylphosphoroanylidene-acetaldehyde (1.45 g, 4.7 mmol) was added in one portion. The reagents were rapidly dissolved in a warm (55 ° C) solution and the homogeneous mixture was gradually heated to reflux and refluxed for 16 hours. TLC analysis, eluting five times with hexane containing 20% (v / v) ethyl acetate, gave the desired product at Rf = 0.52. The crude reaction mixture was chromatographed on a silica gel column and eluted with 10% (v / v) ethyl acetate in hexane to give 1.7 g of product. Recrystallization from ethyl acetate-hexane gave the pure title compound; mp. = 171-174 ° C.

1R (KBr) umax: 3000 (s), 1675 (s), 1669 (s), 1600 (s), 1508 (s), 1225 (s), 1159 (s), 1119 (s), 843 (s) cm-1.

1 H NMR (CDCl 3) δ: 9.55 (1H, d, J = 7.4 Hz), 7.50 (1H, d, J = 15.6 Hz), 7.33-7.26 (2H, m), 7.18-7.13 (2H, m), 6.92-25 6.79 (4H, m), 5.96 (1H, dd, J = 7.5, 15.6 Hz), 1.63 (9H, s); 13 C NMR (CDCl 3) δ: 193.38, 163.5 (d, λmax = 240 Hz), 162.5 (d, λmax = 240 Hz), 154.5, 151.5, 149.49, 137.0, 135.5, 132.81 (d, 3JCF = 8.3Hz), 132.05 (d, 3JCF = 8Hz), 115.80 (d , 2JC_f = 21.9 Hz), 114.98 (d, 2JC_F = 21.9 Hz), 64.3, 29.23 ppm; 30 Anal, Calcd for C 22 H 20 F 2 N 4 O: C, 66.99; H, 5.10; N, 14.18. Found: C, 67.14; H, 5.17; N, 14.55.

<· 1 <«« «

I I

• «103793 46

Example 22

Ethyl 9.9-bis (4-fluorophenyl) -5-hydroxy-8α-1,1,1-dimethylethyl) -2H-tetrazol-5-yl-3-oxo-6,8-nonadienoate 5 A solution of ethyl diaciono μΐ, 3.1 mmol) in 8 mL dry tetrahydrofuran was prepared as described in Example 10 using 130 mg (3.2 mmol) NaJ (60% in mineral oil) and 2.5 mol. n-butyllithium in hexanes (1.27 mL, 3.2 mmol) at 10 ° C under argon. The orange dianion solution, after cooling to -78 ° C, was transferred via cannula to a tetrahydrofuran (12 mL) solution of 5,5-bis (4-fluorophenyl) -4 at -78 ° C. - [2- (1,1-dimethylethyl) -2H-tetrazol-5-yl] -2,4-pentadienal 15 (0.96 g, 2.4 mmol). The reaction mixture was stirred at -78 ° C for five minutes. TLC analysis, once eluted with 50% (v / v) hexane in ethyl acetate, gave Rf = 0.35 at the major product spot. The reaction mixture was diluted with 20 mL of 1N. HCl and the organic material was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over MgSO 4, evaporated to dryness in vacuo, and dried under high vacuum (0.001 mmHg) at ca. at room temperature overnight (16 hours) to give ';' the title compound used for the compound of formula I; 25 * without further purification as described in Example 35 of FI application.

• ·: Example 23 • f · N * 4,4'-Difluoro-3,3'-dimethyl-benzophenone 2-fluoro-toluene (8 mL, 73 mmol) was added vigorously to a stirred mixture of aluminum chloride (61.43 g, 460 mmol) and carbon tetrachloride (135 mL) at 0 ° C. ·. After 10 minutes, 2-fluoro-toluene (92 mL, 837 mmol) in carbon tetrachloride (75 mL) was added dropwise over 4 hours and the mixture was stirred for 2 hours at 0 ° C.

35 Warning: After addition of 2-fluorotoluene, a violent 4 * 103793 47 spontaneous reaction occurred. The mixture was cooled to -20 ° C and diluted with 2N. HCl (250 mL). The organic layer was separated, washed with brine and dried (MgSO 4). The solvent was removed by evaporation to dryness and the residue was dissolved in benzene (200 mL) and treated with water (200 mL) and acetic acid (50 mL). After stirring for 15 hours, the organic layer was separated, dried (MgSO 4) and evaporated to dryness. Crystallization from ethanol gave 50 g (49%) of the title compound; mp. = 128-10 130 ° C.

IR (KBr) νΒ3Χ: 1650 cm'¹; 1 H NMR (CDCl 3) δ: 7.66 (d, J = 7.3 Hz, 2H), 758 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 2.32 ( s, 6H).

Anal Calcd for C 15 H 12 F 2 O: 15 C, 73.16: H, 4.91 Found: C, 72.96; H, 4.80.

Example 24 1,1-Bis-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol A solution of 1,5-dimethyl tetrazole (2.55 g, 26 mmol) dry tetrahydrofuran (15 mL) at -78 ° C, treated with n-butyllithium (12.5 mL of 2.5 molar hexane solution, 31.2 mmol) and stirred for 15 min. 4'-Difluoro-3,3'-dimethylbenzophenone 25 (5 g, 20.3 mmol) in dry tetrahydrofuran (20 mL) was added, and the mixture was stirred for 1 hour, then diluted. L! · Standard 2 HCl (250 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the combined organic layer was dried (MgSO 4) and evaporated to dryness. The residue was purified by chromatography on a silica gel column using hexane containing 20% (v / v) ethyl acetate as eluent. to give 3.7 g (52%) of product. Recrystallization from ethyl acetate-hexane gave the title compound; mp. 41-42 ° C.

35 IR (KBr) υββχ: 3400 (br) cm -1; 103793 48 H NMR (CDCl3) δ: 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).

Anal Calcd for C 18 H 18 F 2 N 4 O: δ C, 62.79; H, 5.27; N, 16.27 Found; C, 62.73; H, 5.32; N, 16.16.

Example 25 1,1-Bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene A mixture of 1,1-bis (4-fluoro-3) -methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (3.58 g, 10.9 mmol) and potassium hydrogen sulfate (530 mg) were heated at 195 ° C for 1.5 hours. . The mixture was cooled to 70 ° C and chloroform (50 ml) was added. Insoluble material was removed by filtration and the filtrate was evaporated to dryness. The residue was crystallized from ethyl acetate-hexane to give 3.38 g (100%) of the title compound: m.p. 138-139 ° C.

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

20 Anal, Calcd for C18H16F2N4; C, 66.25; H, 4.95; N, 17.17. Found: C, 66.15; H, 5.05; N, 17.24.

, Example 26 *! "3,3-Bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-; 25-tetrazol-5-yl) -2-propenal solution of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyltetrazol-5-yl) ethylene (3.58 g, * 11.0 mmol) in dry tetrahydrofuran (20 mL) at -78 ° C, treated with n-butyllithium (5.3 mL of 2.5 molar hexane · · ·:: 30 slurry solution: 13.25 mmol) and stirred at -78 ° C. at room temperature for 0.5 hour Ethyl formate (1.33 mL, 1.22 g, 16.5 mmol) was added and the mixture allowed to warm to 23 ° C over 1 hour then diluted with 2N HCl (250 mL) The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the organic layers were dried (MgSO 4) and evaporated to dryness, The residue was purified by chromatography on 20% ethyl acetate in hexane to give 2.2 g. (57%) of the title compound as a foam MS (Cl): m / e 355 (M + H) +.

IR (KBr) δ: 1660 cm @ -1; 1 H NMR (CDCl 3) δ: 9.62 (s, 1H), 7.25-7.05 (m, 3H), 6.85-6.65 (m, 3H), 3.73 (s, 3H). , 2.34 (s, 3H), 2.13 (s, 3H).

Anal Calcd for C 19 H 16 F 2 N 4 O: 10 C, 64.41; H, 4.56; N, 15.82 Found: C, 64.60; H, 4.70, N, 15.62.

Example 27 5,5-Bis (4-Fluoro-3-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal A mixture of 3,3-bis (4-fluoro) -3-Methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (2.12 g, 5.98 mmol) and triphenylphosphoranyl were added dry benzene (26 mL). The suspension was quickly heated to reflux under argon in an oil bath. The solids dissolved very rapidly at boiling point and the color turned dark tan. The reaction was allowed to continue at reflux for a total of 60 minutes. TLC analysis, eluting ten times with 20% (v / v) hexane in ethyl acetate, gave the desired product at Rf = 0.35. The crude reaction mixture was poured onto a pad of silica gel and eluted with 2 liters of 20% (v / v) ethyl acetate in hexanes,

• M

Yielding 2.12 g (93.3%) of the title compound (homogeneous by TLC). MS (CI): m / e = 381 (M-H) -.

IR (KBr) δ: 1679 (s), 1606 (s), 1591 (s), 1500 *. (s), 1438 (m), 1250 (s), 1231 (s), 1138 (s), 1125 (s) cm -1; 1 H NMR (CDCl 3) δ: 9.53 (1H, d, J = 7.47 Hz), 7.44 (1H, d, J = 16.0 Hz), 7.15-7.09 (3H, m ), 6.9-6.7 (3H, m), 5.80: 35 (1H, dd, J = 15.6, 7.44 Hz), 3.55 (3H, s), 2.33 ( 3H, d, J = 1.9 Hz), 2.11 (3H, d, J = 1.8 Hz); 1 103793 50 13 C NMR (CDCl 3) δ: 192.51, 162.4 (d, 1 J C F = 250.7 Hz) 162.0 (d 1 J J F = 250 Hz), 156.23, 152 , 57, 147.82, 134.88, 134.83, 134.37, 133.77 (d, 3JC.F = 6.04 Hz), 133.19, (d, 3JC.f = 6.04 Hz), 131.94, 130.04 (d, 3JC_F = 8.31Hz), 129.32 (d, 5JC_F = 8.31Hz), 126.22, 126.00, 119.57, 115.66 (d , 2JC_F = 23.4 Hz), 115.59 (d, 2JC_F = 23.41 Hz), 33.64, 14.59, 14.36 ppm.

Anal Calcd for C 21 H 16 F 2 N 4 O: C, 66.31; H, 4.77; N, 14.73. Found: C, 66.36; H, 4.71; N, 14.15.

Example 28

Ethyl 9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate A solution of ethyl acetoacetate dianion (1.42 mL, 11.1 mmol) in dry tetrahydrofuran (15 mL) was prepared as described in Example 10 using 450 mg (11.3 mmol) of NaH (60% in mineral oil) and 4, 5 mL (11.1 mmol) of 2.5 mol. n-butyllithium in hexane at 20 ° C under argon. The orange dianion solution, after cooling to -78 ° C, was transferred via cannula to a tetrahydrofuran (15 mL) solution of 5,5-bis (4-fluoro-3-methylphenyl) -4- (1-methyl) -1H-tet-, racol-5-yl) -2,4-pentadienal (2.12 g, 5.6 mmol) at 25 -78 ° C. The reaction mixture was stirred at -78 ° C for 15 minutes at 99 ° C. TLC analysis, once eluted with a mixture of · · · · ”/ 50% (v / v) ethyl acetate in hexanes, gave the main product at Rf = 0.16 at • · · * · * *. The reaction mixture was diluted with 20 mL of 1N. HCl and organic residues were extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, dried over MgSO4, and evaporated to dryness in vacuo. to give a light syrup. The crude product was chromatographed on a silica gel column eluting with 35% (v / v) ethyl acetate in hexanes to give 1.39 g (48.7%) of the title compound. MS (CI): m / e = 511 (M + H) +.

103793 51 IR (KBr) υηβχ: 3219 (vs, br), 3000 (s), 1744 (s), 1719 (s), 1500 (s), 1325 (m), 1250 (s), 1231 (s), 1119 (s), 1035 (s), 735 (s) cm -1; 1 H NMR (CDCl 3) δ; 7.1-7.0 (3H, m), 6.8-6.6 (3H, m), δ 6.68 (1H, d, J = 15.63 Hz), 5.30 (1H, dd) , J = 5.76, 15.63 Hz), 4.63 (1H, br), 4.18 (2H, q, J = 6.96 Hz), 3.54 (3H, s), 3.44 (2H, s), 2.93 (1H, br, D2O alternating), 2.65-2.75 (2H, m), 2.29 (3H, d, J = 1.65 Hz), 2.08 (3H, d, J = 1.41 Hz), 1.27 (3H, t, J = 6.96 Hz); 13 C NMR (CDCl 3) δ; 166.66, 161.52 (d, Jc_p = 248.40 Hz), 161.13 (d, 1 Jc.F-250.66 Hz), 153.53, 148.08, 135.64, 135.26, 135.03, 133.44 (d, 3JC_F = 4.53Hz), 132.71 (d, 3JC_F = 4.53Hz) 129.58 (d, 3JC_F = 8.31Hz), 128.73 (d , 3 JC_F = 7.55 Hz), 128.36, 125.33, 125.44, 120.47, 115.21 (d, 2 JC_F = 21.90 Hz), 67.93, 15 61.59, 49.86, 49.07, 33.56, 14.46 (d, 3JCF = 11.33 Hz), 14.33, 14.09 ppm.

Anal Calcd for C 27 H 28 F 2 N 4 O 4 H 2 O: C, 61.36; H, 5.72; N, 10.60 found; C, 62.47; H, 5.59; N, 8.23.

Example 29

Ethyl-3.3-bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2-propenoate and ethyl-3.3-bis (4-fluorophenyl) -2- (2 -ethyl-2H-tetrazol-5-yl) -2-propenoate A. Ethyl-3.3-bis (4-fluorophenyl) -2- (2-ethyl-2H-25-tetrazol-5-yl) -2-propenoate · : To a solution of 10.0 g (0.028 mol) of ethyl 3,3- • · · · bis (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-pronenoate · · · [prepared in Example 2] In 75 ml of N, N-dimethylformamide, 1.2 g of 60% sodium hydride (0.03 mol · · · 30 in mineral oil) was added. The hydride was dissolved and 8.5 g (0.056 mol) of iodine in ethane were added and the solution was stirred at room temperature for 16 hours, diluted to 400 ml with water and extracted with CH2Cl2. The extracts were dried and evaporated to dryness. The residue was triturated with hexane in

I I I

to remove the oil. The residue was absorbed onto silica gel 52 103793 by dissolving in CH 2 Cl 2 and adding dry silica gel, then evaporated to dryness in vacuo to a dry powder. This material was applied to the top of the silica gel column and eluted with 10% (v / v) hexane-5 in ethyl acetate to give 4.9 g (45.5%) of the title compound; mp. = 113 - 114.5 ° C.

IR (KBr) λmax: 1710 (s), 1601 (s), 1505 (s), 1160 (s), 596 (s), 550 (s) cm -1; 1 H NMR (CDCl 3) δ: 7.31-7.28 (m, 2H), 7.11-6.85 (m, 106H), 4.56 (q, 2H), 4.10 (q, 2H) ), 1.51 (t, 3H), 1.02 (t, H) ppm; 13 C NMR (CDCl 3) δ: 167.03, 165.62 (d), 165.28 (d), 162.64, 160.64 (d), 160.34 (d), 152.76, 136.86 (d), 136.00 (d), 131.92 (d), 131.75 (d), 131.10 (d), 130.92 (d), 115.53 15 (d), 115.35 (d), 115.13 (d), 114.96 (d), 61.41, 48.31, 14.51, 13.70 ppm.

Anal Calcd for C 20 H 18 F 2 N 4 O 2: C, 62.50; H, 4.73; N, 14.58 Found: C, 62.28; H, 4.72; N, 14.51.

B. Ethyl 3.3-bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2-propenoate

The appropriate fractions obtained by continuing the elution of the f 'step A silica gel column with 10% (v / v) ethyl acetate in hexane were evaporated to dryness to give 5.1 g (47.4%). the title compound; mp. 97-99 ° C.

IR (KBr) λmax: 1720 (s), 1605 (s), 1507 (s), 1160 (s), 845 (s), 540 (s) cm -1; ... ΧΗ NMR (CDCl3) δ: 7.40-6.90 (m, 8H), 4.00 (q, 2H), λ · 30 / 3.88 (q, 2H), 1, 16 (t, 3H), 1.00 (t, 3H) ppm.

* · * * Anal. Calcd for C 20 H 18 N 2 O 4 4 2: C, 62.50; H, 4.73; N, 14.58 Found: C, 62.27; H, 4.73; N, 14.51.

"103793

Example 30 3.3-Bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2-propenol

To a solution of ethyl 3,3-bis (4-fluorophenyl-5-yl) -2- (1-ethyl-1H-tetrazol-5-yl) -2-propenoate (1.0 g, 2.6 mmol) At -78 ° C in CH 2 Cl 2, 7.8 mL (7.8 mmol) of diisobutylaluminum hydride solution (1.0 mol in methylene chloride) was added rapidly. After stirring for 45 minutes, the mixture was diluted with 1N. HCl. The organic layer was separated, dried (MgSO 4) and evaporated to dryness in vacuo. The residual oil was triturated with hexane to give 0.9 g (100%) of the title compound; mp. = 103-111 ° C.

1 H NMR (CDCl 3) δ: 7.41-7.34 (m, 2H), 7.18-7.09 (m, 2H), 6.91-6.87 (m, 4H), 4.7 (s, 2H), 3.80 (q, 2H), 1.21 (t, 3H) ppm; 13 C NMR (CDCl 3) δ: 166.04, 165.91 (d), 165.47 (d), 161.08, 160.84, 156.02, 135.78 (d), 134.22 (d). , 131.73 (d), 131.69 (d), 131.55 (d), 131.51 (d), 116.01 (d), 115.94 (d), 20 115.57 (d) , 115.50 (d), 61.91, 42.85, 14.13 ppm.

Anal Calcd for C 18 H 16 F 2 N 4 O: C, 63.16; H, 4.72; N, 16.37 Found; C, 62.99: H, 4.73; N, 16.40.

: Example 31 3.3-Bis (4-fluorophenyl) -2- (2-ethyl-2H-tetrazol-5-yl) -2-propenol · · · • · · ·

The general procedure of Example 30 was repeated except that the ethyl 3,3-bis (4-fluorophenyl) -2- (1 -...ethyl-1H-tetrazol-5-yl) -2-propenoate used therein was replaced

• «I

* ·] # * 30 with 1.0 g of ethyl 3,3-bis (4-fluorophenyl) -2- (2-ethyl-2H-4H-tetrazol-5-yl) -2-propenoate and then 0.9 g of the title compound was prepared; mp. 82-84 ° C.

1 H NMR (CDCl 3) 6; 7.30-7.33 (m, 2H), 7.08-6.87 (m, 6H), 4.57 (d, 2H), 4.48 (d, 2H), 2.88 (t, 1H), 1.43 (t, t: 35H); 103793 54 13 C NMR (CDCl 3) δ: 165.04, 164.82 (d), 164.67 (d), 160.12, 159.78, 147.08, 137.56 (d), 136.45 ( d), 131.47 (d), 131.43 (d), 131.34 (d), 131.25 (d), 115.53 (t), 115.13 (t), 114.72 (d) ), 62.89, 48.24, 14.40 ppm.

Anal. Calcd for C18H16F2N4O: C, 63.16; H, 4.72; N, 16.37 Found: C, 63.22; H, 4.74; N, 16.41.

Example 32 3,3-Bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-10-yl) -2-propenal

Pyridinium chlorochromate (0.9 g was added to a solution of 0.8 g (2.3 mmol) of 3,3-bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2- Propenol in methylene chloride The solution turned a clear yellow and then darkened and formed a dark resinous precipitate After stirring at room temperature for 16 hours, the mixture was poured directly onto a silica gel column and eluted with methylene chloride to give 0.65 g (83%) of the title compound; mp = 144-145 ° C.

IR (KBr) λmax: 1680 (s), 1600 (s), 1515 (s), 1135 (s), 855 (s), 840 (s); : 1 H NMR (CDCl 3) δ: 9.65 (1H, s), 7.36-7.20 (4H, m), 7.05-6.88 (4H, m), 4.01 (2H, q) ), 1.38 (3H, t); 13 C NMR (CDCl 3) δ: 189.02, 167.07 (d), 166.51 (d), 25 164.68, 162.04, 150.41, 133.65 (d), 133.49 (d) ), 132.34 (d),: 132.18 (d), 124.11, 116.46 (d), 116.34 (d), 116.02 (d),! ·! ·! 115.90 (d), 43.00, 14.34 ppm.

Anal Calcd for C 18 H 14 F 2 N 4 O: C, 63.53; H, 4.15; N, 16.47. Found: C, 62.90; H, 4.13; N, 16.37.

* · * Example 33:: 3,3-bis (4-fluorophenyl) -2- (2-ethyl-2H-tetrazol-5-yl) -2-propenal

A reaction in the presence of 4.0 g (12.0 mmol) of 3.3-35 bis (4-fluorophenyl) -2- (2-ethyl-2H-tetrazol-5-yl) -2-103793 55 propenol and pyridinium chlorochromate (4.5 g) was carried out according to the procedure described in Example 32, whereby 3.25 g (79.7%) of the otric compound were prepared; mp. = 138-139 ° C.

@ 1 H NMR (CDCl3) .delta .: 9.70 (1H, s), 7.39-7.32 (2H, m), 7.23-7.14 (2H, m), 7.04-6.86 (4H, m), 4.62 (2H, q), 1.56 (3H, t); 13 C NMR (CDCl 3) δ; 190.04, 166.71 (d), 165.86 (d), 163.01, 161.68, 161.16 (d), 160.86 (d), 135.62 (d), 135.55 10 (d), 133.69 (d), 133.53 (d), 132.37 (d), 137.19 (d), 127.74, 116.06 (t), 115.59 (t) , 115.17 (t), 48.45, 14.59 ppm.

Anal Calcd for C 18 H 14 N 2 O 2 O: C, 63.53; H, 4.15; N, 16.47 Found: C, 63.53, H, 4.11; N, 16.74.

Example 34 5.5-Bis (4-Fluorophenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2-20 (1-ethyl-1H-tetrazol-5-yl) -2-propenal (0.65 g, 1.9 mmol) and 0.64 g (2.1 mmol) triphenylphosphoranylidene: acetaldehyde in benzene, heated at reflux for 2 hours. The solution was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel eluting with 25 clubs on CH2Cl2 to give 0.55 (79.7%) of the title compound. m.p. 163-165 ° C.

! · · ·! 1 H NMR (CDCl 3) δ: 9.54 (1H, d), 7.49 (1H, d), 7.42-6.96 (8H, m), 5.76 (1H, dd), 8.89 (2H, q), 1.27 (3H, t); 13 C NMR (CDCl 3) δ: 192.41, 166.21 (d), 165.77 (d), etc. 4 30 161.18, 160.71, 155.04, 151.58, 150.10, 148, 34, 148.27, 117.91, 138.90, 134.97, 134.53, 132.77, 132.60, 132.20, 132.03, 120.35, 116.43, 116, 26, 116.03, 115.78, 42.66, 14.30 ppm.

, Anal, Calcd for C 20 H 16 F 2 N ≤ 0: 35 C, 65.57; H, 4.41; N, 15.30 'Found: C, 65.32: H, 4.77; N, 14.76.

56 103793

Example 35 5,5-Bis (4-fluorophenyl) -4- (2-ethyl-2H-tetrazol-5-yl) -2,4-pentadienal

The procedure of Example 34 was repeated using δ 3.25 g (9.5 mmol) of 3,3-bis (4-fluorophenyl) -2- (2-ethyl-2H-tetrazol-5-yl) -2-propenal and 3.05 g. g (10.0 mmol) of triphenylphosphoranylidene-acetaldehyde to give 3.3 g (95%) of the title compound; mp. = 117-120 ° C.

10 * Η NMR (CDCl 3) δ; 9.54 (1H, d), 7.49 (1H, d), 7.34-7.11 (4H, m), 7.00-6.78 (4H, m), 5.94 (1H, dd), 4.60 (2H, q), 1.52 (3H, t); 13 C NMR (CDCl 3) δ; 193.23, 165.83, 165.08, 162.91, 160.83, 160.10, 154.47, 151.28, 149.46, 140.21, 132.89, 15 132.72, 132 , 13, 132.00, 130.56, 116.00, 115.56, 115.28, 114.89, 48.46, 14.63 ppm.

Anal, Calcd for C 20 H 10 Cl 2 2 O 2: C, 65.57: H, 4.41; N, 15.30 Found: C, 65.36; H, 4.40; N, 15.64.

Example 36

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

To a solution of 0.5 g (1.4 mmol) of 5,5-bis (4-fluorophenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -2,4-penta- naphthalene in tetrahydrofuran At -50 ° C, 1.75 ml was added; 0.8 mol (1.4 mmol) of freshly prepared ethyl aceto · · · ·. ·; acetate-dianion solution [described in Example 10].

• · ·

The solution was stirred for 30 minutes at -50 ° C and then ... allowed to warm to -10 ° C over the next 30 minutes.

The solution was then diluted to 1N. HCl and extracted with methylene chloride. The organic extracts were dried and shark; was dried in vacuo. The residue was purified by chromatography on a silica gel column eluting with chloroform to give 0.4 g of the title compound as an oil. MS • 35 (Cl): m / e = 497 (M + H) +.

57 103793 1 H NMR (CDCl 3) δ: 7.29-7.11 (4H, m), 6.87-6.83 (4H, m), 6.72 (1H, d), 5.24 (1H, dd), 4.62 (1H, m), 4.16 (2H, q), 3.88 (2H, q), 3.44 (2H, s), 3.30 (1H, d), 2, 71 (2H, d), 1.25 (3H, t) ppm; 13 C NMR (CDCl 3) δ: 166.69, 165.31, 164.92, 160.32, 159.95, 152.64, 146.82, 136.7, 135.98, 135.34, 135, 26, 135.18, 132.38, 132.20, 131.62, 131.45, 128.26, 121.25, 115.92, 115.78, 115.48, 115.34, 91.48, 67, 75, 61.51, 49.87, 49.14, 42.55, 14.27, 14.09 ppm.

Example 37

Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (2-ethyl-2H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate

To a solution of 5,5-bis (4-fluorophenyl) -4- (2-ethyl-2H-tetrazol-5-yl) -2,4-pentadienal (2.0 g) in 20 ml of tetrahydrofuran -40 At 0 ° C, 6.9 ml of 0.8 mol was added. (5.5 mol) of freshly prepared ethylacetoacetate dianion solution [described in Example 10]. The solution was stirred at -40 ° C for 30 minutes and then allowed to warm to -10 ° C. After a total of one hour, the reaction mixture was diluted to 1N. HCl. The mixture was extracted with chloroform, dried over MgSO 4 and evaporated to dryness in vacuo. The residue was purified by chromatography on a silica gel column to give 0.4 g of the pure title compound. MS (EI): m / e = 496 for M +; 25 * 1 H NMR (CDCl 3) δ: 7.29-7.22 (2H, m), 7.13-7.04 (2H, m), 6.90-6.78 (4H, m), δ, 71 (1H, d), 4.68-4.48 (3H, m), 41.5 (2H, q), 3.45 (2H, s), 2.73 (3H, d, broad shoulder) , 1.49 • · Γ (3H, t), 1.27 (3H, t) ppm; 13 C NMR (CDCl 3) δ: 164.95, 164.28, 163.91, 159.99, 30 159.39, 145.98, 137.64, 137.56, 136.20, 136, 06, 135.21, · * ·; : 132.42, 132.25, 131.71, 131.53, 128.90, 115.54, 115.10, 114.93, 114.48, 91.31, 68.11, 61.44, 49.93 , 49.36, 48.28, 14.62, 14.10 ppm.

I also obtained 1.55 g of an additional batch of crude title compound, which was used without further purification.

103793 58

Example 38 1,1-Bis (2,4-dimethylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -ethanol

A solution of 1,5-dimethyl-tetrazole (8.9 g 5 91.0 mmol) in 100 ml dry tetrahydrofuran at -60 ° C was treated with n-butyllithium (48 ml, 1.89 mol solution, 91.0 mmol). After stirring for 20 minutes, 2,2 ', 4,4'-tetramethylbenzophenone (18 g, 76 mmol) [prepared by the method described in 10 J. Amer. Chem. Soc., 81, 4858 (1959)] in 50 ml of dry tetrahydrofuran and the solution was stirred for one hour during which it was allowed to warm to -20 ° C. The reaction mixture was diluted with 1N. HCl, then extracted with chloroform. The combined organic extracts were dried (MgSO 4) and evaporated to dryness to give 22 g of the title compound: m.p. = 175-177 ° C.

IR (KBr) νmax: 3390 (br), 1620 (s), 1460 (s), 1200 (s), 820 (s) cm -1; : 1 H NMR (CDCl 3) δ: 7.26 (2H, d), 6.95-6.83 (4H, m), δ 4.00 (1H, s), 3.82 (2H, s), δ , 41 (3H, s), 2.23 (6H, s), 1.83 (6H, s) ppm; 13 C NMR (CDCl 3) δ: 152.34, 139.28, 137.32, 135.79, 133.24, 126.26, 125.92, 77.47, 35.04, 32.99, 21.28 , 20.76 ppm.

25 Anal, Calcd for C20H24N4O; · C: 71.41; H, 7.20; N, 16.67 Found: C, 70.82; H, 7.26; N, 16.45.

• · «

Example 39 ... 1. 1-Bis (2,4-Dimethylphenyl) -2- (1-methyl-1H-tet- • 1,30 racol-5-yl) -ethene • ♦ · * · [* containing 2,2-bis (2,4-dimethylphenyl) -2- (1-: methyl-1H-tetrazol-5-yl) ethanol (1.8 g, 5.4 mmol) and potassium hydrogen sulfate (100 mg), was placed in an oil bath preheated to 190 ° C. After 15 minutes, the melt was cooled and methylene chloride 59 103793 nichloride was added to the residue. Insolubles were removed and the solution was evaporated to dryness. The residue was crystallized from isopropyl ether to give 1.2 g of the title compound: m.p. 143 to 143.5 ° C.

IR (KBr) δ: 2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 820 (s), 740 (s) cm -1; : 1 H NMR (CDCl 3) δ: 7.15-6.80 (6H, m), 6.60 (1H, s), 3.40 (3H, s), 2.36 (3H, s), 2, 30 (3H, s), 2.18 (3H, s), 1.85 (3H, s) ppm; 13 C NMR (CDCl 3) δ: 154.18, 152.21, 138.54, 138.38, 138.06, 135.67, 135.40, 135.18, 131.78, 131.72, 129, 90, 129.66, 126.77, 126.55, 111.99, 33.65, 21.02, 20.69, 19.95 ppm.

Anal Calcd for C 20 H 22 N 4: 15 C, 75.45; H, 6.97; N, 17.60 Found: C, 75.04; H, 7.03; N, 17.63.

Example 40 3,3-Bis (2,4-dimethylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal A solution of 1,1-bis (2,4-dimethylphenyl) ) -2- (1-methyl-1H-tetrazol-5-yl) ethylene (1.0 g, 3.1 mmol)

• I

: In 10 mL of dry tetrahydrofuran, treated with n-butyllithium (1.54 mL of a 1.89 molar solution, 3.1 mmol) at -78 ° C. After stirring under cooling for 30 min-25, ethyl formate (0.3 g, 4.0 mmol) was added and the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with 1N. HCl and extracted with chloroform. The combined organic fractions were dried (MgSO 4) and evaporated to dryness. The residue was purified by chromatography on a silica gel column eluting with a 10% mixture.

'·' (V / v) ethyl acetate in hexane to give 0.9 g of product as an oil. Trituration of the oil with isopropyl ether gave the title compound as a solid; mp. = 117-120 ° C. MS (CI): m / e = 347 (M + H) +.

35H NMR (CDCl3) δ: 9.58 (1H, s), 7.25-6.78 (7H, m), 3.70 (3H, s), 2.40 (3H, s), 2, 25 (3H, s), 2.20 (3H, s), 1.90 (3H, s) ppm; 60 103793 @ 13 C NMR (CDCl3) .delta .: 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. Anal Calcd for C 21 H 22 N 4 O: δ C, 72.81; H, 6.41; N, 16.18 Found: C, 72.99; H, 6.43; N, 16.09.

Example 41 5.5-Bis (2,4-Dimethylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal A solution of 3,3-bis (2,4-dimethylphenyl) ) 2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (4.5 g, 13.0 mmol) and triphenylphosphoranylidene-acetaldehyde (4.1 g, 13.0 mmol) in benzene were heated at reflux for 6 hours. The reaction mixture was evaporated to dryness under vacuum and the residue was purified by chromatography on a silica gel column eluting with 10% (v / v) ethyl acetate in hexane to give 5.9 g of the title compound as an oil. MS (CI): m / e = 373 (M + H) +.

IR (KBr) λ max: 1742 (s), 1680, 1615, 1450 (s), 1130 (s), 830 (s), 810 (s) cm -1; 3 H NMR (CDCl 3) δ: 9.42 (1H, d), 7.3 (1H, d), 7.14-6.85 (6H, m), 5.80 (1H, dd), 3.52 (3H, s), 2.35 (3H, s), 2.20 (6H, s), 1.85 (3H, s) ppm; 13 C NMR (CDCl 3) δ: 192.53, 158.44, 152.18, 150.60, δ. 148.18, 139.45, 139.25, 136.14, 135.98, 135.18, 134.63,! ·: ·! 131.78, 131.70, 131.28, 130.10, 126.45, 126.25, 121.26, • ♦ «33.61, 20.90, 20.71, 20.18, 20.11 ppm.

... Anal, Calcd. For C23H24N4O:? · *; * / 30 C, 74.17; H, 6.50; N, 15.05 '· [; Found: C, 72.82; H, 6.85; N, 13.33.

: Example 42 tr ''

Ethyl 9,9-bis (2,4-dimethylphenyl) -5-hydroxy-8-, 1,1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate The general procedure of Example 28 was repeated. except that the 5,5-bis (4-fluoro-3-methylphenyl) -4-103793 61 (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal used therein was replaced by 5 , 9 g (16.0 mmol) of 5,5-bis (2,4-dimethylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal, and the crude product thus prepared the material was purified by chromatography on silica gel eluting with 1% (v / v) methanol in methylene chloride to give 4 g of the title compound.

1 H NMR (CDCl 3) δ: 7.10-6.95 (3H, m), 6.83-6.75 (3H, m), 6.50 (1H, d), 5.30 (1H, dd) ), 4.60 (1H, m), 4.14 (2H, 10q), 3.60 (3H, s), 3.43 (2H, s), 3.0 (1H, bs), 2, 70 (2H, d), 2.35 (3H, s), 2.20 (3H, s), 1.90 (3H, s), 1.28 (3H, t) ppm.

13 C NMR (CDCl 3) δ: 202.15, 166.59, 153.39, 149.71, 138.17, 136.15, 135.98, 135.81, 135.32, 134.96, 131.63 , 131.42, 130.34, 130.04, 128.22, 126.36, 126.21, 122.03, 15 67.91, 61.34, 49.79, 49.24, 33.76, 21.06, 20.89, 20.49, 20.28, 14.02 ppm.

Anal. calcd for C 29 H 34 N 4 O 4: C, 69.31; H, 6.82; N, 11.15 Found: C, 68.29; H, 6.91; N, 10.88.

Example 43

Ethyl 3,3-bis (4-fluorophenyl) -2-n- (2-methoxyethoxy) methyl 1 H -tetrazol-5-yl 1,2-propenoate la ethyl 3, 3,3-bis ( 4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl] methyl; 2H-tetrazol-5-yl-2-propenoate; Sodium hydride (0.67 g in 60% mineral oil, • 14.0 mmol) was added to a solution of ethyl 3,3-bis (4 → 4 · fluorophenyl) -2- (1H-tetrazole). -5-yl) -2-propenoate • 40 (5.0 g, 14.0 mmol) [prepared in Example 2] in dimethylformamide (50 mL) and the mixture was stirred to give solution. MEM chloride (2- [*] *] methoxyethoxymethyl chloride) (3.5 g, 28.0 mmol) was then added and the mixture was stirred for 64 hours. The mixture was diluted with water (200 mL) and extracted with methylene chloride. The organic extracts were dried (MgSO 4) and the solution evaporated to dryness in vacuo to give 6 g of the title compounds as an oil of approximately 1: 103793 62, 1: 1, confirmed by NMR. MS (CI): m / e = 445 (M + H) +.

1 H NMR (CDCl 3) δ: 7.29-6.84 (8H, m), 5.84 (2H, s), 5.43 (2H, s), 4.06 (2H, m), 3.53 -3.40 (4H, m), 3.37 (3H, 5 s), 0.99 (3H, m) ppm; 13 C NMR (CDCl 3) δ: 166.23, 165.90, 165.78, 165.59, 165.12, 163.15, 162.34, 160.93, 160.77, 160.62, 160.20 , 157.36, 153.61, 152.20, 136.66, 136.61, 135.94, 135.88, 134.53, 134.45, 132.20, 132.03, 131.88, 131 , 73, 131.19, 10 131.03, 130.87, 120.04, 115.85, 115.66, 115.49, 115.42, 115.22, 115.05, 114.96, 95, 54, 92.21, 80.97, 76.79, 71.69, 71.10, 70.95, 69.53, 69.09, 67.37, 66.73, 61.70, 61.38, 58.89, 36.35, 31.30, 27.80, 26.76, 17.65, 13.60, 13.52 ppm; Example 44 3,3-Bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-propenol Ia 3.3-bis (4-fluorophenyl) -2- 2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenol

A solution of diisobutylaluminum hydride 20 (65 mL of a 1 molar solution, 65.0 mmol) in methylene chloride was added to a solution of ethyl 3,3-bis (4-fluorophenyl) -2- [1 - (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-propenoate and ethyl 3,3-bis (4-fluorophenyl) -2- [2- (2-; methoxyethoxy) methyl-2H- tetrazol-5-yl] -2-propenoate, 25 (6.0 g, 13.0 mmol) [prepared in Example 43] in methylene chloride * (50 mL) at -78 ° C. After stirring for 3 hours at -78 ° C, the reaction mixture was hydrolyzed by adding an excess of 1N. HCl. The aqueous layer was separated and extracted with methylene chloride. The combined organic extracts were dried and evaporated to dryness in vacuo to give 5.2 g of the title compound as an oil in a ratio of about 1: 1, confirmed by 1 H NMR. MS (EI): m / e = 402 for M @ +.

f I I

Anal Calcd for C 20 H 20 F 2 N 4 O 3: 1 1 \ 35 C, 59.70; H, 5.02; N, 13.93. Found: C, 59.89; H, 5.09; N, 13.99.

63 103793

Example 45 3.3-Bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl] -1H-tetrazol-5-yl] -2-propenal 1a 3.3-Bis (4-fluorophenyl) -2-r2- ( 2-methoxyethoxy) methyl-2H-tetrazol-5-yl-2-propenal

Pyridinium chlorochromate (6.6 g) was added to a solution of 3,3-bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-propenol and For your 4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tet-10-racol-5-yl] -2-propenol (5.2 g, 13.0 mmol) prepared in Example 44] in methylene chloride . After stirring at room temperature for 18 hours, the reaction mixture had darkened and a resinous precipitate had formed. The reaction mixture was decanted and the methylene chloride solution was evaporated to dryness under vacuum. The residue was purified by chromatography on a silica gel column eluting with methylene chloride to give 3 g of the title compound as an oil in a ratio of approximately 1: 1, as confirmed by 1 H NMR. MS (EI): m / e = 400 for M1.

20 NMR (CDCl 3) δ: 9.73 (1H, s), 9.60 (1H, s), 7.44-6.91 (9H, m), 5.92 (2H, s), 5.57 (2H, s), 3.68-3.38 (7H, m) ppm; 13 C NMR (CDCl 3) δ: 189.62, 188.78, 166.87, 166.57, 166.34, 165.68, 165.60, 163.17, 161.85, 161.65, 161, 55, 25,161.29, 160.66, 151.11, 134.39, 134.33, 133.43, 133.55, 133.37, 133.08, 132.42, 132.25, 132.06 , 129.34, 129.19, 128.96, 127.22, 123.65, 116.12, 115.94, 115.69, 115.50, •: 1: 115.26, 115.07, 80 , 92, 77.01, 70.87, 69.40, 69.26, 68.83, · · · · 62.06, 58.78, 50.23, 46.41 ppm.

30 Anal, Calcd for C 20 H 18 F 2 N 4 O 3: C, 60.00; H, 4.54; N, 13.99 &lt; -1 &gt; C, 58.11; H, 4.65; N, 13.19.

• · • · · · 64 103793

Example 46 3.3-Bis (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl] -2H-tetrazol-5-yl] -2-propenal and 5.5-bis (4-fluorophenyl) -4- C 2 -methoxyethoxy) methyl-1 H -tetrazol-5 5 -yl-2,4-pentadienal A. 3.3-Bis-4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl] -2H-tetrazol-5-yl] -2 -propenaali

A solution of 3,3-bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-pro-10-pencal and 3,3-bis ( 4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tetrazol] -5-yl] -2-propenal (3.5 g, 8.75 raraol) [prepared in Example 45] and triphenylphosphoranylidene acetaldehyde (1.33 g, 4.4 mmol) in benzene (50 mL) was heated at reflux for 6 hours. The reaction mixture was evaporated to dryness in vacuo and the residue purified by chromatography on a silica gel column eluting with 15% (v / v) ethyl acetate in hexane. Concentration of the appropriate fractions afforded efficient separation and isolation of the unreacted title compound. MS 20 (CI): m / e = 401. (M + H) +.

1 H NMR (CDCl 3) δ: 9.70 (1H, s), 7.40-6.80 (9H, m), 5.85 (2H, s), 3.60-3.40 (4H, m) , 3.35 (3H, s) ppm; 13 C NMR (CDCl 3) δ: 189.66, 166.66, 165.76, 163.21, 161.72, 163.21, 161.72, 161.64, 160.75, 149.10, 135, 46, 25 135.38, 133.61, 133.44, 133.27, 133.16, 132.79, 132.64,: ·; 132.31, 132.14, 131.94, 131.86, 127.32, 116.01, 115.91, 115.56, 115.14, 80.99, 70.91, 69.46, 58, 89 ppm.

: B. 5,5-bis (4-Fluorophenyl) -4- [1- (2-methoxyethoxy) -5-methyl] -1H-tetrazol-5-yl] -2,4-pentadienal. Elution of the A silica gel column gave the desired product. The appropriate fractions were combined and evaporated to dryness in vacuo to give 1.1 g of the title compound. MS (CI): m / e = 427 (M + H) +.

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

«I

m) 3.30 (3H, s) ppm; ? 103793 65 13 C NMR (CDCl 3) δ: 192.42, 166.17, 165.72, 161.16, 160.70, 155.23, 152.49, 147.96, 135.04, 134, 96, 134.55, 134.48, 132.90, 132.73, 132.21, 132.04, 131.85, 119.94, 116.31, 116.08, 115.87, 115.64, 76.67, 71.01, 69.53, δ 58.96 ppm.

Example 47 5,5-Bis (4-Fluorophenyl) -4- [2- (2-methoxyethoxy) methyl] -2H-tetrazol-5-yl] -2,4-pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2- [2- (2-10 methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenal (1.4 g, 3.5 g) mmol) and triphenylphosphoranylidene acetaldehyde (1.3 g, 4.3 mmol) [isolated in Example 46, Step A] in 25 mL of benzene were heated at reflux for 12 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by chromatography on a silica gel column eluting with 20% (v / v) ethyl acetate in hexane to give 0.9 g of the title compound as an oil. MS (CI): m / e = 427 (M + H) @ +.

NMR (CDCl 3) δ: 9.52 (1H, d), 7.48 (1H, d), 7.32-20 7.10 (4H, m), 6.92-6.75 (4H, m) , 5.85 (3H, s dd on dd), 3.6-3.5 (4H, m), 3.35 (3H, s) ppm; 13 C NMR (CDCl 3) δ: 193.07, 165.85, 165.04, 163.50, 160.85, 160.07, 154.72, 149.12, 136.61, 136.59, 135.29 ,: V 135.24, 133.64, 133.47, 132.84, 132.67, 132.35, 132.13, 25 131.96, 131.91, 123.79, 115.99, 115, 55, 115.35, 114.93, [delta] 81.12, 70.96, 69.55, 58.98 ppm.

Example 48; Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (2H, 4-methoxyethoxy) methyl-1H-tetrazol-5-yl] -3-oxo-6,8-no-nadienoate

Ethylacetoacetate dianion (2.6 mL of a freshly prepared 1 molar solution as described in Example 10 ·) was added to a solution of 5,5-bis (4-fluorophenyl) -4- [1- (2-methoxyethoxy) ) methyl 1 H -tetrazol-5-yl] -2,4-Penta-35 naphthalene (1.1 g, 2.6 mmol) in 15 mL of tetrahydrofuran · 66 103793 at -40 ° C. After stirring for 2 hours, TLC analysis eluting with 25% (v / v) ethyl acetate in hexane gave the starting aldehyde and therefore another 1.2 ml of dianion solution was added. The reaction mixture was allowed to warm to 50 ° C and then diluted with 1N. HCI. The mixture was extracted with methylene chloride, dried (MgSO 4) and evaporated to dryness in vacuo. The residue was purified by chromatography on a silica gel column eluting with 1% (v / v) methanol in methylene chloride to give 0.9 g of the title compound as an oil. MS (CI): m / e = 557 (M + H) +.

1 H NMR (CDCl 3) δ: 7.5-6.6 (9H, m), 5.43 (2H, s), 5.00 (1H, dd), 4.6 (1H, m), 3.7 -3.4 (6H, over s), 3.30 (3H, s), 2.72 (2H, d), 1.22 (3H, t) ppm.

15 Example 49

Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (2-methoxyethoxy) methyl] -2H-tetrazol-5-yl -3-oxo-6,8-nona dienoate

Ethylacetoacetate dianion (2.1 mL of a freshly prepared 1 molar solution as described in Example 20) was added to a solution of 5,5-bis (4-fluorophenyl) -4- [2- (2-methoxyethoxy) methyl-2H- tetrazol-5-yl] -2,4-pentazal (0.9 g, 2.0 mmol) in 15 mL of tetrahydrofuran: -50 ° C. After stirring for an hour, others were added. 1 ml of dianionic solution and the mixture were stirred for an additional 30 minutes. The reaction mixture was diluted with 1N. HCl and then -: / - were extracted with methylene chloride. The organic extracts were dried (MgSO 4) and evaporated to dryness in vacuo. Ice: 'j ·; The residue was purified by chromatography on a silica gel column eluting with 1% (v / v) methanol in methylene chloride to give 0.55 g of the title compound. MS (CI): m / e = 557 (M + H) +.

1 H NMR (CDCl 3) δ: 7.30-7.05 (4H, m), 6.90-6.70 (5H, m), 5.85 (2H, s), 5.35 (1H, dd) , 4.70-4.53 (1H, m), 4.17 Γ 35 (2H, q), 3.48 (4H, m), 3.38 (3H, s), 2.72 (2H, d) ), 1.26: 1 (3H, t) ppm; ≤ 67 103793 13 C NMR (CDCl 3) δ: 202.03, 190.30, 166.60, 164.88, 164.36, 164.15, 159.92, 146.22, 137.49, 137.41 , 135.13, 132.29, 132.13, 131.63, 131.47, 131.18, 131.05, 131.02, 130.93, 128.67, 124.46, 115.45, 115 , 03, 114.92, 114.51, 5 91.16, 80.80, 70.84, 69.28, 67.96, 61.37, 58.90, 49.82, 49.18, 14, 01 ppm.

Example 50 5,5-Bis (4-Fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadlenal A mixture of 3,3-bis (4-fluorophenyl) -2- (1-Methyl-1H-tetrazol-5-yl) -2-propenal (71.6 g, 0.22 mol) and triphenylphosphoranylidene-acetaldehyde (66.8 g, 0.22 mol) were added 1.1 liters of dry benzene and the suspension was warmed to reflux for 30 minutes. The reaction was allowed to continue at reflux for 2 hours. TLC analysis, eluting five times with 30% (v / v) ethyl acetate in hexane, gave only one end spot at Rf = 0.37 for the desired product. The crude hot reaction mixture was diluted with 20 volumes of hexane and the warm mixture was quickly filtered through a pad of activated charcoal. The filtrate was allowed to stand at room temperature, whereupon. , 58.12 g (75.2%) of the desired product was collected.

Crystallization from the filtrate a second time gave a maximum of triphenylphosphine oxide. Concentrate the filtrate »» ·. ·: An additional amount of the desired product was obtained, yielding a total of 71 g (91.8%) of the title compound. The combined material was recrystallized from ethyl acetate-hexane to give the pure title compound; mp. 30 = 164-165 ° C. The 1 H NMR of the recrystallized material gave no detectable double-homologated product.

Anal Calcd for C 19 H 14 F 2 N 4 O: C, 64.77; H, 4.01; N, 15.90 found; C, 65.20; H, 4.09; N, 16.03.

t <68 103793

Example 51 3.3-Bis (4-Fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal A. 1,1-Bis (4-Fluorophenyl) -2- (1-methyl-1H-tetrachloride) - 5 azol-5-wli) ethanol

To a solution of 1,5-dimethyl-tetrazole (0.98 g, 10.0 mmol) in tetrahydrofuran (20 mL) at -30 ° C was added n-butyllithium (4.7 mL of a 2.14 molar solution, , 0 mmol). After stirring for 0.25 hours, the solution was cooled to -50 ° C and 4,4-difluorobenzophenone (1.74 g, 8.0 mmol) was added. After stirring for 1 hour at -50 ° C and for 1 hour at -10 ° C, 1N was added to the reaction mixture. hydrochloric acid. The mixture was extracted with methylene chloride, dried and evaporated to dryness in vacuo. The residue was purified by chromatography on a silica gel column eluting with 40% (v / v) ethyl acetate in hexane to give 2.0 g of the title compound, m.p. = 116-118 ° C.

Anal, Calculated for 20 C, 60.76; H, 4.47; N, 17.72 Found: C, 60.62; H, 4.52; N, 17.63.

B. 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene; A mixture of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (4.2 g, 12.7 mmol [val-: *) ··· Stirred in Step A] and potassium hydrogen sulfate, heated at 195 ° C for 0.5 h. After cooling, the mixture was dissolved in chloroform and washed with water. The organic layer was dried and evaporated in vacuo. The residue 30 was triturated with diethyl ether to give 3.9 g of the title compound, mp = 169-171 ° C.

Anal Calcd for C16H12F2N4: C, 64.43; H, 4.06; N, 18.88 Found: C, 63.93; H, 4.00; N, 19.25.

103793 69 C.3.3-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal

To a fine suspension of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene 5 (1.0 g, 3.3 mmol) [prepared in Step B] tetrahydrofur n-butyllithium (1.54 mL of a 2.14 molar solution, 3.3 mmol) was added to the slurry (10 mL) at -80 ° C, whereupon the mixture became dark purple. After stirring for 40 minutes at -80 ° C, ethyl formate (0.32 g, 4.3 mmol) was added and the mixture was stirred for 2.5 hours at -80 ° C. The mixture was hydrolyzed to 1N. hydrochloric acid and extracted with methylene chloride. The extracts were dried (MgSO 4) and evaporated to dryness in vacuo. The residue was triturated with diethyl ether to give 0.77 g of a yellow solid, 15 m.p. 128-131 ° C. The solid was crystallized from isopropyl acetate-hexane to give 0.55 g of the title compound; mp. Mp 130-132 ° C.

Anal Calcd for C 17 H 12 F 2 N 4 O: C, 62.58; H, 3.71; N, 17.18 Found: C, 62.15; H, 3.82; N, 16.75.

Example 52 5,5-Bis (4-Fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal (1.0 g, 3.07 mmol) and? triphenylphosphoranylidene-acetaldehyde (0.93 g, * · ·. **: 3.07 mmol) in benzene was heated at reflux for 1 hour. The benzene was removed in vacuo and the residue was purified by chromatography on a silica gel column. A mixture of 15% (v / v) ethyl acetate in hexane gave 0.7 g of the title compound, mp = 156-157.5 ° C.

Anal Calcd for C 19 H 14 F 2n 4 O: C, 64.77; H, 4.01; N, 15.91. Found: C, 65.13; H, 4.05; N, 15.71.

• 1 70 103793

Example 53 3.3-Bis (4-Fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal A. 5-Ethyl-1-methyl-1H-tetrazole. 5-Dimethyl-tetrazole (4.9 g, 0.05 mol) in dry tetrahydrofuran (50 ml) was added with 2.5 mol. n-butyllithium hexane solution (20 mL, 0.05 mol) at -78 ° C for 15 minutes under inert atmosphere. This mixture was stirred for 30 minutes 10 during which time a yellowish precipitate formed. Methyl iodide (3.7 m, 0.06 mol) was then added over 15 minutes. After stirring for a further 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 15 (2 x 25 mL) and the combined organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give an oil. The oil was purified by distillation to give 5.2 g (92%) of the title compound; tr. 89-90 ° C / 0.05 mmHg.

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

B. 1,1-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propanol To a solution of 5-ethyl-1-methyl-1H-tetra · * · “Sol (5.6 g, 0.05 mol) [prepared in Step A] in 60 ml •« *. *; dry tetrahydrofuran, 2.5 mol. n-butyl lithium hexane solution (20 mL, 0.05 mol) 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 dry tetrahydrofuran was added over 5 minutes. This mixture was stirred for a further 2 hours while slowly warming the bath to -20 ° C. To the reaction mixture was added, 35 L of 1N. HCl and extracted with ethyl acetate (3 x 50 mL) and? 103793 71 chloroform (3 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give a white solid. The solid was purified by crystallization from ethanol-hexane-5 to give 10.8 g (65%) of the title compound; mp. = 160-161 ° C.

IR (KBr) δ δ: 3400 cm @ -1; 1 H NMR (CDCl 3) δ: 7.8-7.02 (m, 8H), 5.95 (s, 1H), 4.65 (q, 1H), 3.98 (s, 3H), 1.29 (d, 2H); 13 C NMR (CDCl 3) δ: 162.57, 162.37, 159.14, 156.71, 142.48, 140.54, 128.25, 128.13, 127.52, 127.42, 114, 67, 114.41, 114.38, 78.56, 36.99, 33.43, 14.52.

Anal Calcd for C 17 H 16 F 2 N 4 O: 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

A slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) propanol (8.25 g, 0.025 mol) [prepared in Step B] and 100 mg of p toluenesulfonic acid monohydrate in xylene (60 mL) was heated at reflux for 12 hours using a Dean & Stark water harvester. The reaction mixture was washed warm with 1N. NaOH (10 mL) and water (100 mL).

Evaporation of the organic layer to dryness gave almost white crystals of product. These were purified by crystallization. *: re-blending with ethanol-hexane to give · · f. ·; 7.1 g (91%) of the title compound were obtained as white crystals; : T? mp. = 146-147 ° C.

30 IR (KBr) νmax: 1575; 1500 cm -1; 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, 131.65 , 35 131.54, 131.11, 131.01, 119.53, 115.51, 115.27, 115.22, 33.50, 21.20.

«I

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Anal, Calcd for C17H14F2O2F4 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-5-tetrazol-5-yl) -2-propene

A slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-propene (61.46 g, 0.197 mol) [prepared in Step C], N -bromo-succinamide (35.06 g, 0.197 mol) and a catalytic amount of azobis-isobu-10-thyronitrile or benzoyl peroxide in carbon tetrachloride (1.2 liters) were heated under reflux for 2 hours. The reaction mixture was cooled to ambient temperature and the solid formed in the reaction was filtered off. The filtrate was evaporated to dryness in vacuo 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.

1R (KBr) Dmax: 1600 cm -1.

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

13 C NMR (CDCl 3) 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. Anal Calcd for C 17 H 13 F 2 BrN <: 25 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-1-tetrazol-5-yl) -2-propenal: In a solution, of sodium ethyl (3.93 g of sodium metal, 0.17 mol) in 500 ml of absolute ethanol was added 2-nitropropane (16.66 g, 0.187 mol) slowly over 5 minutes. The bromine compound prepared in the previous step D (67.1 g, 0.17 mol) was added portionwise over 10 minutes. The reaction mixture was stirred for 35 hours and the ethanol removed in vacuo. The residue was dissolved in CH 2 Cl 2 (500 mL), washed with water (259 mL), and dried over sodium sulfate. The organic layer was evaporated to dryness in vacuo to give an oil. The oil was dissolved in hot toluene (350 mL) and trituration with hexane (350 mL) afforded 50.6 g (91%) of the title compound 5 as white crystals; mp. = 135-137 ° C.

Example 54 4,4'-Difluoro-2,2 * -dimethylbenzophenone To a well-stirred mixture of aluminum chloride (6.1 g, 46.0 mmol) in carbon tetrachloride (14 mL) at 10 ° C was added 3-fluoro-toluene ( 1 g from a total of 10 grams, 90.0 mmol) and the mixture was stirred for 10 minutes. The remainder of 3-fluoro-toluene in 9 mL of carbon tetrachloride was added and the mixture was stirred at 0 for 4 hours. The mixture was cooled to -20 ° C and hydrolyzed by the addition of 25 mL of 15 L. hydrochloric acid. The organic layer was separated and evaporated to dryness in vacuo. The residue was stirred for 16 hours with a mixture of benzene (20 ml), water (20 ml) and acetic acid (5 ml). The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were dried (MgSO 4) and evaporated to dryness in vacuo. TLC analysis of the residue gave 3 spots; R f = 0.67, 0.59 and 0.56 [5% (v / v) ethyl acetate in hexane on silica gel]. Chromatography on a column of silica gel with 0.5% (v / v) ethyl acetate in hexane and recovery by evaporation of the appropriate product-containing fractions having an Rf = * * * * 0.67 [5% (v / v) ethyl acetate in hexane] gave * · * J 1.3 g of the title compound; mp. = 50-52 ° C. MS (CI): m / e = 247; For (M + H) +; 0: 1 H NMR (CDCl 3) δ: 7.26 (2H, dd), 6.96 (2H, dd), 6.87 (2H, dt), 2.42 (6H, s).

Anal Calcd for C 15 H 12 F 2 O: C, 73.17; H, 4.92 Found: C, 73.34; H, 5.02.

«74 103793

Example 55 2,4'-Difluoro-4,2'-dimethyl-dibenzophenone

Evaporation to dryness of the appropriate fractions obtained by chromatography on Example 54 silica gel column containing an Rf 0.59 gave 2.4 g of the title compound; mp = 29-31 ° C.

MS (CI); m / e = 347 (M + H) +; NMR (CDCl 3) δ: 7.53 (1H, t), 7.39 (1H, dd), 7.19-6.85 (4H, m), 2.42 (3H, s), 2.39 ( 3H, s).

Anal. Calcd for C 15 H 12 F 2 O: C, 73.17; H, 4.92 Found: C, 73.34; H, 4.86.

Example 56 2.2'-Difluoro-4,441-dimethyl-benzophenone Evaporation of the appropriate fractions obtained by chromatography on silica gel column in Example 54 containing 0.56 Rf and trituration of the residue with hexane gave 1.2 g of the title compound. ; mp. = 84-85.5 ° C.

@ 20 H NMR (CDCl3) .delta .: 7.57 (2H, t, J '= 8 Hz, JFH = 8 Hz), 7.02 (2H, d, J' = 8 Hz), 6.89 (2H, d, JFH = 8Hz), 2.39 (6H, s).

Anal, Calcd for C, 73.17; H, 4.92 Found: C, 73.19; H, 4.88.

* · *: Example 57 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-4 · 4 · tetrazol-5-yl) ethanol: :; To a suspension of 1,5-dimethyl-tetrazole 30 (3.8 g, 39.0 mmol) in tetrahydrofuran (40 mL) at -40 ° C was added butyllithium (17.7 mL of a 2.2 molar solution, 0 mmol). After stirring for 10 minutes, 4,4'-difluoro-2,2'-dimethylbenzophenone (8 g, 32.5 mmol) was added and the solution was stirred for 3 hours. To the reaction mixture was added ·, 35 1M. hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phases were dried (MgSO 4) and evaporated to dryness in vacuo to give 7.5 g of the title compound; mp. = 186-188 ° C. Anal. calcd for C 18 H 18 F 2 N 4 O: 5 C, 62.99; H, 5.27; N, 16.27 Found: C, 63.01: H, 5.34; N, 16.18.

Example 58 1. 1-Bis (4-Fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene A mixture of 1,1-bis (4-fluoro-2) -methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (0.5 g, 1.5 mmol) and p-toluenesulfonic acid (0.2 g) were heated to reflux in toluene (30 mL) ) For 16 hours. The mixture was cooled, diluted with diethyl ether (50 mL) and extracted with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO 4) and evaporated to dryness in vacuo. The residue was triturated with diethyl ether to give 0.3 g of the title compound; mp. = 120-125 ° C.

20 Anal, Calcd for C, 66.25; H, 4.95; N, 17.17 Found: C, 66.55; H, 4.92; N, 16.84.

Example 59 3,3-Bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-25-tetrazol-5-yl) -2-propenal% · · * · 1 | To a solution of 1,1-bis (4-fluoro-2-methyl-1,1-phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene (1.6 g, · 5.0) mmol) in tetrahydrofuran at -70 ° C, butyl-lithium (2.3 mL of a 2.2 molar solution, 5.0 mmol) was added after stirring for 0.25 h, and ethyl formate (0.44 g, 6.0) was added. mmol) and the mixture was stirred for 2 hours. To the reaction mixture was added 1N. hydrochloric acid and the mixture was extracted with methylene chloride. The extracts were dried and evaporated to dryness in vacuo to give 1.0 g of the title compound; 35 mp. = 135-136 ° C.

* I {«« «4 103793 76

Anal Calcd for C 19 H 16 F 2 N 4 O: C, 64.41; H, 4.56; N, 15.82 Found: C, 64.22; H, 4.59; N, 15.50.

Example 60 5,5-Bis (4-fluoro-2-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (0.88 g, 2.5 mmol) ) and triphenylphosphoranylideneacetaldehyde-10 dide (0.75 g, 2.5 mmol) in benzene (50 mL) was heated to reflux for 3 hours. The solvent was removed by evaporation to dryness and the crude residue was purified by chromatography on a silica gel column eluting with 1% (v / v) methanol in methylene chloride. Fractions containing Rf 0.9 [1:20 (v / v) methanol-methylene chloride] were combined and evaporated to dryness to afford 0.8 g of the title compound; mp. = 75-95 ° C. MS: M + = 380; 1 H NMR (CDCl 3) δ: 9.52 (1H, d), 7.30-6.67 (7H, m), δ 5.82 (1H, dd), 3.62 (3H, s), δ , 23 (3H, s), 2.00 (3H, s).

Anal Calcd for C 21 H 10 F 2 N 4 O: C, 66.31; H, 4.78; N, 14.73 Found: C, 65.76; H, 4.85; N, 14.52.

Example 61 25 tert-Butyl-9,9-bis (4-fluoro-2-methyl-phenyl) -5-mmm -1'-1'-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo -6,8-nona- »· *, * * dienoate« · * To a solution of 5,5-bis (4-fluoro-2-methyl-1-phenyl) -4- (1-methyl-1H-tetrazole) -5-yl) -2,4-pentadienal (1.0 g, 2.5 mmol) in tetrahydrofuran at -50 ° C. dianion of t-butyl acetoacetate (2.5 mL of 1 mol.

solution, 2.5 mmol) prepared by adding t-butyl t -acetoacetate (4.0 g, 25.0 mmol) in tetrahydrofuran (4 mL) to a suspension of sodium hydride (1.0 g, 35 mL). % dispersion, 25.0 mmol) in tetrahydrofuran at -5 ° C, 1 · 4 · 103793 77 then cooled to -30 ° C and butyl lithium (11.4 ml) was added 2.2 molar solution, 25 mmol). After stirring for 1.5 hours, TLC analysis indicated the presence of the starting aldehyde, and another 0.5 ml of dianion solution-5 was added. The solution was stirred for an additional 0.5 h and 1N was added. hydrochloric acid. The mixture was extracted with methylene chloride. The extracts were dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of methanol and methylene chloride to give 0.6 g of the title compound; mp. = 65-72 ° C.

Anal Calcd for C 29 H 32 F 2 N 4 O 4: C, 64.68; H, 5.99; N, 10.41 Found: C, 64.50; H, 5.98; N, 10.16.

Example 62 1. 1-Bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol

To a solution of 1,5-dimethyl-tetrazole (4.6 g, 4.7 mmol) in tetrahydrofuran (40 mL) at -50 ° C was added a butyl lithium solution (21.4 mL of a 2.2 molar solution, 4.7 mmol). 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 at which time it was allowed to warm to -10 ° C. To the reaction mixture was added 1N. hydrochloric acid. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried (MgSO 4) and evaporated to dryness. The residue was triturated with diethyl ether.

"B

V and crystallized from isopropyl acetate to give 30.0 g of the title compound; mp. = 150-151 ° C. MS: M1 = 344.

Anal Calcd for C 18 H 18 F 2 N 4 O: C, 62.79; H, 5.27; N, 16.27 Found: C, 62.84; H, 5.23; N, 16.28.

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Example 63 1. 1-Bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene

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

Anal Calcd for C 18 H 16 F 2 N 4 O: 15 C, 66.25; H, 4.95; N, 17.17 Found: C, 66.27; H, 4.94; N, 16.93.

Example 64 3,3-Bis (2-Fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal To a solution of 1,1-bis (2- fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethylene (1.6 g, 5.0 mmol) in tetrahydrofuran (20 mL) at -78 ° C, butyl lithium ( 2.3 mL of a 2.2 molar solution, 5 mmol). After stirring for 15 minutes, ethyl formate 25 (0.44 g, 6.0 mmol) was added and the solution was stirred under cooling to 2 · · · * · * | hours. To the reaction mixture was added 1N. hydrochloric acid • · · * · * ϊ and the mixture was extracted with diethyl ether. The extracts were dried. : (MgSO 4) and evaporated to dryness. The residue was crystallized from

«K

V * from propyl acetate to give 0.66 g of the title compound, m.p. = 154-155 ° C.

Anal Calcd for C 19 H 15 F 2 N 4 O: C, 64.41; H, 4.56; N, 15.82. Found: C, 64.44; H, 4.63; N, 15.58.

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• 4 «4« «• 44 • 4 4« 4 103793 79

Example 65 5.5-Bis-2-Fluoro-4-methyl-phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (2-fluoro-4-methylphenyl-5i) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (1.35 g, 3.8 mmol) and triphenylphosphoranylidene-acetaldehyde (1.16 g, 3.8 mmol) benzene, heated at reflux for 3 hours. The solvent was removed and the residue was purified by chromatography on a silica gel column eluting with a mixture of 1% (v / v) methanol in methylene chloride. Fractions containing Rf 0.9 [methanol-methylene chloride; 1:20 (v / v)], combined and evaporated to dryness to give 1.3 g of the title compound; mp. = 88-108 ° C.

Anal. Calcd for C21H18F2N4O: C, 66.31; H, 4.78; N, 14.73. Found: C, 66.34; H, 4.96; N, 14.37.

Example 66

Tert-Butyl 9-bis (2-fluoro-4-methylphenyl) -5-20 hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonanedioate: of 5,5-bis (2-fluoro-4-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal (1.3 g, 3.4 mmol) in tetrahydrofuran (15 mL) at -50 ° C, dianion of t-butyl acetoacetate (3.4 mL of 1 mol) was added.

• ·· Solution, 3.4 mmol). After stirring for 2 hours, another 0.7 ml of anion solution was added and the solution was stirred for an additional hour. To the reaction mixture was added 1N. hydrochloric acid and the mixture was extracted with methylene chloride. The extracts were dried (MgSO 4) and evaporated to dryness. The residue was purified by chromatography on a silica gel column eluting with silica gel. a stick in a mixture of 1% (v / v) methanol in methylene chloride to give 1.3 g of the title compound; mp. = 55-63 ° C.

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103793 80 1 H NMR (CDCl 3) δ: 7.05-6.53 (7H, m); 5.28 (1H, dd), 4.60 (1H, m), 3.75 (3H, s), 3.35 (2H, s), 3.05 (1H, bs), 2.69 (2H) , d), 2.39 (3H, s), 2.33 (3H, s), 1.45 (9H, s). Anal Calcd for C 29 H 32 F 2 N 4 O 4: 5 C, 64.68; H, 5.99; N, 10.41 Found (corrected for 0/21% H 2 O): C, 64.33 H, 6.07; N, 10.21.

Example 67 tert-Butyl- (5S) -9.9-bis (4-fluorophenyl) -5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6, 8-dienoate A. (1S) -2-Hydroxy-1,2,2-triphenyl-ethyl (3S) -7,7-bis (4-fluorophenyl) -3-hydroxy-6- (1-methyl-1 H- tetrazol-5-yl) hepta-4,6-dionate A solution of diisopropylamine (5.33 mL; 3.85 g; 38.1 mmol) in dry tetrahydrofuran (40 mL) was cooled to 0 ° C. and treated with butyllithium (15.2 mL of a 2.5 molar solution in hexane; 38 mmol) and allowed to warm to 23 ° C over 15 minutes. This solution was cooled to -78 ° C and added to a suspension of (S) - (-) - 1,2,2-triphenyl-2-hydroxyethyl acetate: *: (5.07 g, 19.2 mmol) [ prepared according to the procedure described in Tetrahedron Letters, 5031-5034 (1984)] in dry tetrahydrofuran (40 ml); 25 -78 ° C. The mixture was allowed to warm to 0 ° C over a period of 15 minutes. The resulting orange solution was cooled to ♦ · C * !! kanssa-78 ° C and treated with a solution of 5.5- • • · • t * bis (4-fluorophenyl) -4- (1- methyl 1 H -tetrazol-5-yl) -2,4-pentadienal (8 g, 22.73 mmol) in dry tetrahydrofuran (30 mL). After stirring for 20 minutes, · · · · · · · -78 ° C, 2N was added to the reaction mixture. HCl (80 mL). . ·. and the solvent was removed by evaporation to dryness. The residue, ··· was extracted with ethyl acetate (3 x 50 mL and the combined organic layers were dried (MgSO 4) and evaporated to dryness in vacuo. The residue was purified by chromatography on a · 103793 silica gel column using 30% v / v v) ethyl acetate in hexane to give 9.4 g (90% by weight of co-acetate) of the title compound: [α] D = -41.1 ° (c = 1.16; CH 2 Cl 2).

@ 1 H NMR (DMSO-d6) .delta .: 7.45-6.80 (m, 23H), 6.54 (s, 1H), 650 (d, J = 16.0 Hz, 1H), 6.05 ( s, 1H), 5.15 (dd, J = 15.6 Hz, J '= 5.2 Hz, 1H), 5.02 (d, J = 5.3 Hz, 1H), 4.33 (m , 1H), 3.70 (s, 0.3H minor diastereoisomer), 3.65 (s, 2.7H main diastereoisomer), 2.29 (m, 2H); 13 C NMR (DMSO-d 6) δ: 194.01, 170.16, 169.32, 163.64, 163.16, 160.36, 159.90, 153.00, 147.77, 145.95, 145.09, 144.50, 138.00, 136.88, 136.42, 135.40, 133.04, 132.28, 131.76, 131.00, 128.54, 127.38, 127, 05, 126.61, 126.44, 125.74, 121.40, 115.94, 115.60, 115.40, 115.06, 78.74, 15 78.36, 67.50 (smaller diastereomer) , 66.75 (main diastereomer), 59.67, 41.97, 33.47, 20.68, 14.01.

B. Methyl (3S) -7.7-bis (4-fluorophenyl) -3-hydroxy-6- (1-methyl-1H-tetrazol-5-yl) hepta-4,6-dienoate

A solution of triphenyl ester prepared in Step A (9.4 g, 13.74 mmol) in dry methanol (40 mL) was added to a solution of sodium metal (2.1 g,: 1: 91 mmol) in dry methanol ( 300 ml) and the resulting mixture was stirred at 23 ° C for 30 minutes. 2N was added to the reaction mixture. HCl (100 mL) and the solvent was removed by evaporation to dryness. The residue was diluted with water (100 mL). was extracted with ethyl acetate (3 x 70 mL). The combined layers were dried (MgSO 4) and evaporated to dryness. The residue was purified by chromatography on a silica gel column using 40% (v / v) ethyl V '30 acetate in hexane as the eluent to give 4.08 g (70%) of the title compound.

IR (Film) ν max: 3400 (br), 1735, 1500, 1220 cm -1.

1 H NMR (CDCl 3) δ: 7.30-6.60 (m, 8H), 6.725 (dd, J = 15.8 Hz, J 1 = 1.4 Hz, 1H), 6.34 (dd, J = 15.9 Hz, J '= 5.6 Hz, * · / ·; 35 1H), 4.56 (br ε, 1H), 3.69 (s, 3H), 3.60 (s, 3H), 3.14 (br s, 1H), 2.50 (m, 2H); 82 103753 13 C NMR (CDCl 3) δ: 172.27, 164.61, 164.20, 161.29, 160.88, 153.43, 147.46, 136.04, 135.26, 132.38, 132 , 26, 131.48, 131.37, 128.01, 120.96, 115.91, 115.56, 68.17, 51.85, 40.84, 33.57.

5 C. tert -butyl (5S) -9.9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-nona-6.8-dienoate

A solution of diisopropylamine (2.77 mL; 2 g; 19.8 mmol) in dry tetrahydrofuran (15 mL) was cooled to 0 ° C and treated with butyllithium (8.1 mL of 2.5 mol. solution in hexane; 20.25 mmol) and the resulting mixture was allowed to warm to 23 ° C over 15 minutes. The solution was cooled to 0 ° C and t-butyl acetate (2.55 ml; 2.2 g; 18.9 mmol) was added and the solution was stirred at 0 ° C for 15 minutes, cooled to -78 ° C: was then added to a solution of the methyl ester prepared in Step B (2 g; 4.69 mmol) in dry tetrahydrofuran (20 mL) at -78 ° C. The resulting solution was allowed to warm to 23 ° C over 30 minutes and 2N was added. HCl (20 mL). The solvent was removed by evaporation to dryness and the residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (MgSO 4) and evaporated to dryness in vacuo, and the residue was purified by chromatography on a silica gel column using 35% ethyl acetate as eluent; # · # (V / v) ethyl acetate in hexane to give 1.858 g (78%) of the title compound.

IR (Film) νmax: 3400 (br), 1735, 1710, 1595, 1510, 1220, 1155 cm -1.

V: 30 1 H NMR (CDCl 3) δ: 7.30-6.80 (m, 8H), 6.72 (dd, J = 15.6 «, Hz, J ′ = 0.9 Hz, 1H ), 5.30 (dd, J = 15.6 Hz, J '= 5.5 Hz, 1H),. . *. 4.61 (br, 1H), 3.56 (s, 3H), 3.35 (s, 2H), 2.70 (m, 2H), 1.45 (s, 9H); 13 C NMR (CDCl 3) δ: 202.88, 168.05, 164.61, 164.16, δ 35 161.29, 160.85, 153.50, 147.30, 136.01, 132.40, 132 , 29, 83 103793 131.51, 131.39, 127.88, 121.00, 115.88, 115.83, 115.60, 115.54, 82.35, 67.85, 51.10, 49 , 10, 33.59, 27.99.

Example 68

Ethyl 1-Methyl-5-tetrazolyl acetate Acetate 5 To a solution of 1,5-dimethyl tetrazole (10 g) in 100 ml dry tetrahydrofuran and 20 ml hexamethylphosphoramide at -78 ° C (dry ice acetone) was added under argon. by dropping 50 ml (1.2 equivalents) of n-butyllithium (2.5 mol.

10 in hexane). The diprotonation of 1,5-dimethyltetrazole was allowed to continue at -78 ° C for 40 minutes, then at -20 ° C for 30 minutes. The anion solution was re-cooled to -78 ° C and transferred via cannula to a cold solution (-78 ° C) with 12 ml of ethyl chloroformate in 50 ml of tetrahydrofuran for 45 minutes. The reaction mixture was diluted with 2N. Aqueous HCl and saturated aqueous sodium chloride, and then extracted with ethyl acetate. The organic extract residue was purified by flash chromatography on silica gel. The appropriate fractions were combined and evaporated to dryness to give 4 g of product. The product was further purified by crystallization from ethyl acetate / hexane to give 3.52 g (21%) of the title compound; mp. = 64-66 ° C.

Anal calcd for C 6 H 10 N 4 O 2:. 25 C, 42.35; H, 5.92; N, 32.92: Found: C, 42.40; H, 5.98; N, 33.15.

• · · ... Example 69 • · · 1

Ethyl 3.3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenoate • · · * · * '30 A mixture of titanium tetrachloride (2 mL) and • · · *. * * Carbon tetrachloride (2 mL) was added to 15 mL of tetra-; hydrofuran at -78 ° C under argon atmosphere.

The suspension was stirred at -78 ° C for 30 minutes before 0.2 g of 4,4'-difluorobenzophenone was added. After stirring for a further 30 minutes, a solution of 0.15 g of ethyl 1-methyl-5-tetrazolyl acetate in 1 ml of dry pyridine was added dropwise. The dark brown suspension was stirred at -78 ° C for 15 minutes then allowed to warm to 0 ° C to form a thick pas-5. The mixture was allowed to stand for 24 hours at ambient temperature before being poured into water. The aqueous mixture was extracted with ethyl acetate to give the crude product. TLC analysis, eluting five times with a mixture of 20% (v / v) ethyl acetate in hexanes, showed the product after Rf = 0.3. Purification was by preparative chromatography on two 20 x 20 cm 2 0.25 mm TLC plates, eluting twice with 20% (v / v) ethyl acetate in hexanes to give the title compound identical to that of Example 3. with the compound of Step A.

Example 70 tert-Butyl 9.9-bis (fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate A. 5.5-bis (4- fluorophenyl) -4- (1-methyl-1H-tetr-20-azol-5-yl) -2,4-pentadienal

A mixture of 448 g (1.37 mol) of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal and 445 g (1, 46 mol) triphenylphosphoranylidene acetaldehyde in 5.5 liters of toluene was heated to 25 ° C with stirring. After disconnecting the heat source, the temperature increased to 62 ° C. After 20 minutes, heating was applied and the mixture was kept at 60 ° C for 30 minutes. TLC analysis showed that the reaction was complete (50% ethyl acetate in hexane). Lithium bromide (128 g, ·> 1.47 mol) was added and the mixture was stirred at 60 ° C for 1 hour.

The reaction mixture was filtered and the filtrate was evaporated to dryness; in vacuo. The residue was dissolved in 900 ml of boiling absoiled ethanol. To this solution, 900 ml of hexane was slowly added. After 16 hours at ambient temperature and 2 hours at refrigeration temperature, 10379385 the mixture was filtered to give 418 g (86.6%) of the title compound; mp. 161-165 ° C.

Anal Calcd for C19HmN4F2O: C, 64.77; H, 4.00; N, 15.90. Found: C, 64.94; H, 3.97; N, 15.82.

B. tert-Butyl-9.9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6.8-nonadienoate A solution of 144 g (0 , 91 mol) t-butylacetoacetate in 400 ml tetrahydrofuran was added dropwise over 1.5 hours to a mixture of 44.0 g (1.10 mol) sodium hydride (60% in mineral oil) in 100 ml hexane and 500 ml of tetrahydrofuran protected by nitrogen at 0 ° C. After the addition was complete, the mixture was stirred for 2.3 hours. 2.5 M was added dropwise over an hour. n-butyllithium hexane solution (360 mL, 0.91 mol). After stirring for 1 hour at 0 ° C, 200 g (0.57 mol) of the aldehyde prepared in Step A were added all at once and the temperature rose to 20 ° C. After stirring for 1 hour in an ice-water bath, 20 1200 ml of 10% aqueous hydrochloric acid solution were added over an hour. The organic layer was washed twice with 300 mL of water, 300 mL of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to dryness in vacuo to give the title compound, which was used without further purification. for the preparation of the compound as described in FI application 880869 * · · ··· *.

• · · • · ·

Example 71 ... Ethyl-3.3-bis (4-fluorophenyl) -2- [2- (triphenyl] methyl] -2H-tetrazol-5-yl] -2-propenoate. * * To a suspension of 0.64 g (16 mmol) of 50% sodium hydride in 7.5 mL of dry dimethylformamide was added 5.7 g (16 mmol) of ethyl 3,3-bis (4-Fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate and the resulting mixture was stirred for 30 minutes. To the resulting solution was added 103793 86 5.7 g (18 mmol) of bromotriphenylmethane and the mixture was stirred for 24 hours. The mixture was diluted with 200 mL of water and insoluble material was collected by filtration. The product was recrystallized from ethyl acetate to give 6.1 g of the title compound; mp. = 161-162 ° C (dec.).

Anal Calcd for C 37 H 28 F 2 N 4 O 2: C, 74.24; H, 4.72; N, 9.36 Found: C, 74.31; H, 4.74; N, 9.63 Example 72 10 3,3-Bis (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -2-propenol

To a stirred solution of 3 g (5 mmol) of ethyl 3,3-bis (4-fluorophenyl) -2- [2-triphenylmethyl-2H-tetrazol-5-yl] -2-propenoate in 50 mL: of methylene chloride at 15 -70 ° C, 10 ml (15 mmol) of diisobutylaluminum hydride solution (1.5 mol in methylene chloride) was added and the solution was stirred for 3 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic fractions were dried over magnesium sulfate and evaporated to dryness in vacuo to give 2.1 g of the title compound; mp. = 176-178 ° C.

Anal Calcd for C 35 H 26 F 2 N 4 O: C, 75.53; H, 4.71; N, 10.07 Found: C, 75.75; H, 4.57; N, 10.22.

. 25 Example 73 «::. 3,3-bis (4-fluorophenyl) -2- (2-triphenylmethyl) -2H- • · t # ·. · # Tetrazol-5-yl-2-propenal • · i

To a solution of 2.2 g (4.0 mmol) of 3,3-bis (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H-tetrazol-5-yl · * · * 30 '] -2-propenol in 100 ml of methylene chloride, 7 x activated manganese dioxide was added. After stirring for 20 hours, the insoluble material was removed by filtration and the filtrate evaporated to dryness in vacuo to give the title compound in quantitative yield; mp. = 208 ° C (dec.).

87 103793

Anal Calcd for C 35 H 24 F 2 N 4 O: C, 75.81; H, 4.37; N, 10.11 Found: C, 73.56; H, 4.44; N, 9.54.

Example 74 5,5-Bis (4-fluorophenyl) -4- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -2,4-pentadienal

To a solution of 1.75 g (3.15 mmol) of 3,3-bis (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -2-propenal in 50 mL dry benzene, 0.96 g (3.15 mmol) of triphenylphosphoranylidene-acetaldehyde was added and the solution heated to reflux for 96 hours. The solution was evaporated to dryness in vacuo and the residue was purified by chromatography on alumina (Alcoa Chemicals, grade F-20) eluting with 10% ethyl acetate in hexane-15 to give 0.95 g of the title compound by evaporation to dryness; mp. = 122-124 ° C.

Anal Calcd for C 37 H 26 N 2 O 2 H 2 O 76.54; H, 4.52; N, 9.65 Found: C, 75.84; H, 4.86; N, 9.46 Example 75 tert-Butyl-9,9-bis (4-fluorophenyl) -5-hydroxy-3-oxo-8- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -6. 8-no-na-dienoate

A solution of dia-25-ion solution of tert-butyl acetoacetate (1.2 ml of a 0.5 molar solution, 0.6 mol) in a solution. was prepared as described in Example 61, add- # # «| * j« | was added to a solution of 5, 5-bis (4-fluorophenyl) -4- [2- (4-trifluoromethyl-2H-tetrazol-5-yl) -2,4-pentadienal in tetrahydrofuran at -70 ° C. After stirring for 2.5 hours at -70 ° C, the reaction mixture was diluted with saturated ammonium chloride solution. The mixture was extracted with diethyl ether, the ether solution was dried (MgSO 4) and evaporated to dryness in vacuo to give the title compound as an oil which was used without further purification. MS: m / e = 738 for 35 (M +).

iti • tl «· 103793 88

Example 76 1- (4-Fluorophenyl) -2- (1-methyl-1 H -tetrazol-5-yl) -1-phenylethanol

A solution of 1,5-dimethyl-tetrazole (29.25 g; 5 0.298 mol) in dry THF (400 mL) was cooled to -78 ° C and treated with n-butyllithium (133 mL of 2.5 mol. solution in hexane, 0.3325 mol) for 30 minutes. The mixture was stirred at -78 ° C for 30 minutes and treated with 4-fluorobenzophenone (50 g, 0.25 mol). The mixture was stirred at -78 ° C for 30 minutes and allowed to warm to 23 ° C over 2 hours. 2N was added to the reaction mixture. HCl (100 mL) and the organic solvent were removed by evaporation to dryness. The residue was extracted with CHCl 3 (2 x 100 mL) and the combined organic layers were dried (Na 2 SO 4) and evaporated to dryness to give a brown oil. Purification by chromatography using 20% ethyl acetate in hexane as the eluent gave the title compound as a white solid (46.3 g, 62%); mp. = 113-114 ° C (crystallized from a mixture of 20 ethyl acetate-hexane. MS (CI): m / e = 299 (M + H) +).

j 'IR (KBr) νmax: 3300 (br), 1605, 1510 cm -1; 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 NMR δ: 163.57, 160.29, 152.28, 144.94, 141.12, 141.08, 128.43, 127.87, 127.75, 127.67, 125.76, 115 , 25, • · · 114.96, 77.03, 35.82, 33.45 ppm.

• · r

Anal Calcd for C 16 H 15 FN 4 O: C, 64.42; H, 5.07; N, 18.79: 30 Found: C, 64.32; H, 5.05; N, 18.84.

V * Example 77: (E) -1- (4-Fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-phenylethylene (Z) -1- (4-fluorophenyl) -2 - (1-Methyl-1H-tetrazol-5-yl) -1-phenethylene 35 Mixture of tetrazolyl ethanol (3.2 g: 10.74 mmol) (prepared in Example 76) and potassium hydrogen sulfate 103793 89 ( 800 mg), heated at 195 ° C for 30 minutes. After cooling to 100 ° C, chloroform (30 ml) was added and the mixture was triturated until most of the solid was dissolved. Insoluble inorganic material 5 was removed by filtration and the solvent removed by evaporation to dryness to give a mixture of the title compounds as a light brown solid (2.8 g, 93%). Crystallized from ethyl acetate-hexane. MS (CI): m / e = 281 (M + H) +.

IR (KBr) uroax: 1640, 1600, 1510, 1445, 1220 cm -1; 1 H NMR δ: 7.50-6.90 (m, 9H), 6.75 (s, 1H), 3.60 (s, 1.7H), 3.43 (s, 1.3H) ppm; 13 C NMR δ: 165.19, 164.58, 161.26, 153.14, 152.97, 152.22, 152.13, 140.53, 137.81, 136.71, 133.99, 133, 94, 15 131.74, 131.62, 130.38, 129.67, 129.29, 128.85, 128.65, 128.38, 115.97, 115.74, 115.66, 115.45 , 108.29, 108.15, 33.70 ppm.

Anal Calcd for C 16 H 13 FN 4: C, 68.56; H, 4.68; N, 19.99. Found: C, 68.63; H, 4.77; N, 20.37.

Example 78: (E) -3- (4-Fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -3-phenylpropenal 1a (Z) -3- (4-Fluorophenyl) -2-: (1-Methyl-1H-tetrazol-5-yl) -3-phenyl-propenal A suspension of olefin (20 g; 71.43 mmol) • · (prepared in Example 77) in dry THF (200 mL). The mixture was cooled to -78 ° C and treated with n-butyllithium (31.7 mL of 2.5 molar hexane solution; 78.75 mmol) and the resulting mixture was stirred at -78 ° C. At C for 30 minutes. Ethyl formate (6.9 g, 93 mmol) was added and the mixture was stirred at -78 ° C for 2 hours and allowed to warm up over an hour: 23 ° C: a. 2N was added to the reaction mixture. HCl (100 mL), the organic solvent was evaporated to dryness and the residue was extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried (MgSO 4), evaporated to dryness and the residue purified by chromatography on 103793 90 using 35% ethyl acetate in hexane as eluant to give the title compound as a mixture of aldehyde (7.75 g; 35%). MS (CI): m / e = 309 (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 79 (E). (E) -5- (4-Fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -5-phenyl-2,4-pentadienal A mixture of the aldehyde mixture (5.1 g; 16). , 56 mmol) (prepared in Example 78) and formylmethylene triphenylphosphorane (5.05 g, 16.56 mmol) and benzene (200 mL) were heated together under reflux for 2 hours. The solvent was removed by evaporation to dryness and the residue was purified by chromatography using 30% ethyl acetate in hexane as the eluent to give the product as an orange foam (4.56 g). Fractional crystallization from ethyl acetate-hexane gave the title compound as orange chromium (0.93 g, 17%); mp. = 137-138 ° C (crystallized from ethyl acetate-hexane). MS (CI): 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, 25 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.

• i ·

Example 80 ... Ethyl (E). (E) -9- (4-Fluorophenyl) -5-hydroxy-8- (1-4H) -methyl-1H-tetratrol-5-yl) -9-phenyl-3-oxonone-6,8- • '' *** 'dienoate m: A suspension of sodium hydride (175 mg; 80% dispersion; 5.83 mmol) in dry THF (10 mL) was cooled to 0 ° C and treated with ethyl acetate acetate *. > 103793 91 (725 μΐ; 740 mg; 4.69 mmol) and stirred at 0 ° C for 10 minutes. Butyllithium (2.3 mL of a 2.5 molar solution; 5.75 mmol) was added and the mixture was stirred at 0 ° C for 15 minutes. An aldehyde solution (860 mg; 2.57 mmol) 5 (prepared in Example 79) in dry THF (10 mL) was added and the mixture was stirred at 0 for 15 min. The reaction solution was diluted by the addition of 2N. HCl (30 mL) and the organic solvent were removed by evaporation to dryness. The residue was extracted with ethyl acetate and the combined organic extracts were dried (MgSO 4) and evaporated to dryness. The residue was purified by chromatography using 40% ethyl acetate in hexane as eluant to give the title compound as a yellow resin (954 mg; 80%). MS (CI): m / e = 465 (M + H) +.

15 IR (Film) λmax: 3400 (br), 1730, 1600, 1510 cm -1; ΧΗ NMR δ: 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), 2.52 (m, 2H), 1.08 (t, 3H) ppm. Example 81 20-Bis (4-methoxyphenyl) -1- (1-methyl-1H-tetrazol-5-yl) ethylene

A solution of 1,5-dimethyl-tetrazole (20 g, 0.204 mol) in dry THF (200 mL) was cooled to -78 ° C and treated with n-butyllithium (91 mL of a 2.5 molar solution in hexane; 0.227). mol) and the mixture was stirred at -78 ° C for 30 minutes. 4,4'-Dimethoxy- · · · n · · · · · · benzophenone (41.3 g; 9.171 mol) and the mixture was stirred at? · -78 ° C for 30 minutes and then allowed to warm to -23 ° C over 2 hours. The mixture was acidified with 2 x 30 N HCl (100 mL) and the organic solvent was removed by evaporation to dryness. The residue was extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were dried (MgSO 4) and evaporated to dryness. The residue was crystallized i. 1 ethyl acetate-hexane to give a pale brown solid (48 g) which was found to be

i I I 4 I

103793 A mixture of the desired product and the original aldol adduct (1,1-bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol) was dissolved in xylene (180 ml) and heated to reflux. for 1 hour with p-toluenesulfonic acid-5 in a Dean-Stark apparatus The cooled mixture was diluted with ether (100 mL) and the resulting solid removed by filtration to give the title compound as a cream solid (40 g): mp = 146-147. ° C (crystallized from ethyl acetate-hexane) MS (CI): m / e = 323 for 10 (M + H) +; IR (KBr) ν max: 1605, 1520, 1250 cm -1; 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.

Anal Calcd for C 18 H 18 N 4 O 2: 20 C, 67.07; H, 5.63; N, 17.38 Found: C, 66.93; H, 5.63; N, 17.05.

Example 82! 3,3-bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal; ; A solution of the olefin (4.6 g; 14.29 mmol) (prepared in Example 81) in dry THF (50 mL) was cooled to -78 ° C. C and treated with n-butyllithium (6.3 mL of a 2.5 molar solution in hexane; 15.75 mmol) and the resulting solution was stirred at -78 ° C for 30 minutes. 30 ethyl formate (1.5 ml) was added and the mixture was stirred at -78 ° C for 2 hours. 2N was added to the mixture. HCl and organic «*. the solvent was removed by evaporation to dryness. The residue was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were dried (MgSO 4) and evaporated to dryness.

The residue was purified by column chromatography over 10% -93,793 using 25-35% ethyl acetate in hexane as eluent to give the starting material (0.84 g, 18%). Further elution gave the desired title compound (1.78 g, 36%); mp. = 130-131 ° C (crystallized from ethyl acetate-5'-hexane). MS (CI): m / e = 351 for (M + H) +.

IR (KBr) λmax: 1675, 1605, 1515, 1260 cm -1; 1 H NMR δ: 9.59 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 87 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) ) 10 ppm; 13 C NMR δ: 189.51, 167.47, 162.59, 161.98, 152.30, 133.91, 132.29, 130.79, 129.35, 121.05, 114.20, 114, 15, 55.80, 55.40, 33.94 ppm.

Anal. calcd for C 19 H 19 N 4 O 3: 15 C, 65.14; H, 5.18; N, 15.99 Found: C, 64.96; H, 5.22; N, 15.75.

Example 83 5.5-Bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dipolar A solution of 3,3-bis (4-methoxyphenyl) -2- ( 1-Methyl-1H-tetrazol-5-yl) propenal (1.7 g; 4.86 mmol) in benzene (100 mL) was treated with triphenylphosphoranylidene-acetaldehyde (1.55 g, 5.1 mmol) and warmed. boiling for 3 hours. The solvent was removed by evaporation! 25 clubs were dried and the residue was purified by chromatography on # # # * 30% ethyl acetate / hexane to give the title compound as a yellow; as a foam (1.35 g, 74%). MS (CI): m / e = 377 (M + H) +.

0.30 IR (KBr) νβ3Χ: 1675, 1590, 1510 cm cm¹; : T: J H NMR δ: 9.52 (d, J = 7.6 Hz, 1H), 7.53 (d, J J 14.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 9.3 Hz, in), 6.86 (d, J = 9.2 Hz, IM), 6.70 (d, J = 8, 9Hz, 1H), 5.83 (dd, J = 7.6Hz, J '= 15.7Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 35 3.50 (s, 3H) ppm:? 103793 94 13 C NMR δ: 192.89, 161.40, 160.97, 157.91, 153.29, 149.41, 133.90, 132.77, 132.29, 132.00, 131.71, 131.65, 131.25, 130.81, 117.21, 114.18, 114.12, 55.49, 55.32, 33.61 ppm.

5 Example 84

Ethyl (E) -9.9-bis (4-methoxyphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxonone-6.8-dienoate Ethylacetoacetate (825 μΐ; 842 mg; 6.48 mmol) was added to a suspension of NaH (206 mg; 80% dispersion; 6.86 mmol) in dry THF (20 mL) at 0 ° C and the resulting mixture was stirred at 0 ° C for 10 minutes. A solution of n-butyl lithium (2.7 mL of a 2.5 molar solution in hexane; 6.75 mmol) was added and the mixture was stirred at 0 ° C for 10 minutes. A solution of aldehyde (1.3 g, 3.46 mmol) (prepared in Example 83) in dry THF (20 mL) was added and the mixture was stirred at 0 for 15 min. After addition of 2 N to treat the reaction mixture. HCl, the solvent was removed by evaporation to dryness. The residue was diluted with water (30 mL), extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were dried (MgSO 4) and evaporated to dryness. The residue was purified by chromatography on 40% ethyl acetate-hexane to give the title compound as a yellow solid. as a full foam (1.165 g, 66%).

25 IR (KBr) νmax: 3450 (br), 1750, 1710, 1610, · · · · · 1510 cm-1; 1 H NMR δ: 7.30-6.60 (m, 9H), 5.27 (dd, J = 6.1 Hz, J · 159 Hz, 1H), 4.68 (brs) , 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 3.47 (s, 3H), 3.43 (s, 2H), 3.17 (brs, 1H), 2.70 (d, J = 6.0 Hz, 2H), 1.23 (t, J = 6.0 Hz, 3H) ppm; ;. 13 C NMR δ; 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, δ: 35 14.09 ppm.

Claims (5)

95 103793 Use of an intermediate tetrazole derivative of the formula 5 R 3 OH 0 0 9 9 or 9 R 1 I I v / n tet R 1 R 1 and R 4 each independently represent 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; n is 0, 1 or 2; 20 1 tet is ^ or ^ J; Wn n-n ^ r7; R 7 is C 1-4 alkyl, C 1-4 alkoxy (lower) alkyl or] ** (2-methoxyethoxy) methyl; and * ··· R 9 is a C 1-8 alkyl group. The tetrazole derivative according to claim 1 which is ethyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3 -oxo-6,8-non-dienoate. *. The tetrazole derivative according to claim 2; a derivative of ethyl (5S) -9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-: 35 nonadienoate. 103793 96 A tetrazole derivative according to claim 1 which is tert-butyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6, 8-nonadienoate. The tetrazole derivative according to claim 4 which is tert-butyl (5S) -9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oK-iso-6,8-nonadienoate. ♦ · • • «*« <<• 4 <<• 4 4 4 4 4 4 4 4 4 4 4 4 4 ♦ 4 4 4 4 4 4 4 4 4 4 «97 103793