FI103886B - A process for the preparation of an aldehyde intermediate - Google Patents

Description

103886

A process for the preparation of an aldehyde intermediate

Divided by FI application 890725.

This invention relates to a process for the preparation of compounds of Formula V1-C10-1010b in an almost cis form wherein R9, R10 and R12 are as defined below, useful in the preparation of 3-hydroxy-3-methylgluc-15aryl coenzyme A (HMG-CoA). ) -reductase enzyme inhibitors and are therefore useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

Intermediates useful in the preparation of antihypercholesterolemic agents have the formulas 20

-¾ «10 oi elO

R v ιΛο o cr ^ o o 25

Ula Illb 2,103,886 in almost cis form wherein R 9 and R 10 are each alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl; and R12 is hydrogen, alkyl or a metal cation.

Intermediates of formulas IIIa and IIIb can be used in the formulas R3 R5 R * i? ^ 3-R6?

II

for the preparation of antihypercholesterolemic agents of the formula wherein R 1 and R 4 are independently hydrogen, halogen, alkyl, alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 are independently hydrogen, halogen, C 1-4 alkyl or alkoxy; and R is hydrogen, a hydrolyzable ester group, or a cation to form a non-toxic pharmaceutically acceptable salt.

The terms "C 1-4 alkyl", "C 1-4 alkyl" and "C 1-4 alkoxy" as used herein and in the claims (unless the context otherwise requires) mean straight or branched alkyl or alkoxy groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , t-30 butyl, amyl, hexyl, etc. Preferably, these groups contain from 1 to 4 carbon atoms and most preferably contain 1 or 2 carbon atoms. Unless specifically mentioned, the term "halogen" herein and in the claims is intended to include chlorine, fluorine, bromine and iodine, while the term "halide" as used herein and in claims 3,103,886 is intended to include chloride, bromide, and iodide anion. The term "cation for forming a non-toxic pharmaceutically acceptable salt" as used herein and in the claims is intended to include non-toxic alkali metal salts such as sodium, potassium, calcium and magnesium, ammonium salts and salts of non-toxic amines such as trialkylamines, dibenzylamine, pyridine N-methylmorpholine, N-methylpiperidine and other amines used to form salts of carboxylic acids Unless otherwise stated, the term "hydrolyzable ester group" herein and in the claims is intended to include an ester group which is physiologically acceptable and is physiologically alkyl, phenylmethyl and pivaloyloxymethyl 15.

In the compounds of formulas 1, II, XI and XII, it is meant that the double bonds are in the trans configuration, i.e. (E) as mentioned in the structural formulas used herein and in the claims. On the other hand, in the compounds of formulas IV, 20V, VI, VII, VIII and IX, it is meant that the configuration of the double bonds is trans, cis or a mixture thereof, i.e. (E), (Z) when n 0 0 and (E) (E), (Z ) (Z), (E) (Z) and (Z) (E) when n = 1 as mentioned herein and in the claims.

Because the final compound compounds have two asymmetric carbon atoms, the intermediates contain the enantiomeric and diastereomeric forms used in the processes for preparing the compounds of Formulas I and II as described below. The compounds of Formulas I and II containing two centers of asymmetry may have four possible stereoisomers, designated as RR, RS, SR and SS enantiomers. In particular, compounds of formula I having two asymmetric carbon atoms having hydroxy groups at the 3- and 5-positions may have four possible stereoisomers called? 103886 (3R, 5S), (3S, 5R), (3R, 5R) and? (3S, 5S) stereoisomers.

As used herein and in the claims, the term "erythro" is intended to include a mixture of (3R, 5S) and (3S, 5R) enantiomers and the term "threo" is intended to include a mixture of (3R, 5R) and (3S, 5S) enantiomers. The use of a single label such as (3R, 5S) is intended to include almost only one stereoisomer. The lactone compounds of formula II also have two asymmetric carbon atoms at the 4- and 6-positions and the resulting four stereoisomers can be called (4R, 6S), (4S, 6R), (4R, 6R) and (4S, 6S) stereoisomers . As used herein and in the claims, the term "trans" lactone is intended to include a mixture of (4R, 6S) and (4S, 6R) enantiomers, while the term "cis" lactone is intended to include a mixture of (4R, 6R) and (4S, 6S) enantiomers. The use of a single label such as (4R, 6S) is intended to include almost exclusively one enantiomeric lactone.

Substituted 1,3-dioxane compounds of formula IIIa, IIIb and the like also have two asymmetric carbon atoms at the 4- and 6-positions as described below,

X 0 25 and the resulting four stereoisomers may be referred to as (4R, 6S), (4S, 6R), (4R, 6R) and (4S, 6S) stereoisomers. As used herein, the term "trans" -1,3-dioxane is intended to include a mixture of the (4R, 6R) and (4S, 6S) enantiomers, while the term "cis" -1,3-dioxane is intended to include a mixture of: (4R, 6S) and (4S, 6R) enantiomers. Fortunately, since the stereoisomer of the most preferred enantiomer of a lactone compound of formula II is the same (4R, 6S) as the most preferred enantiomer of the 1,3-dioxane intermediate of this invention, an additional "trans" or "cis" is used to avoid any confusion.

5, 103886

In the compounds of formulas IIIa and IIIb, R 9 and R 10 are each 1-4 alkyl, or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl. Preferably R 9 and R 10 are each methyl 5 or R 9 and R 10 together with the carbon atom to which they are attached are cyclohexyl. It is preferred that R12 is hydrogen, methyl or a metal cation, especially lithium. The cis isomer of the compounds of formula IIIa is preferred and the cls (4R, 6S) isomer of the compounds of formula IIIb is most preferred.

The antihypercholesterolemic compounds of formulas I and II can be prepared by various methods and preferably using the intermediates of formulas r 'r10 rV X ° X 0 X 0 ma mb 20 in almost complete cis form, wherein R9, R10 and R12 are as defined above. The present invention provides a process for the preparation of intermediates of formula IIIb. This disclosure also provides a process for the preparation of compounds of formulas IIIa and I and II.

The compounds of formulas IIIa and IIIb may be prepared by reaction between an aldehyde of formula IV and an ester of acetic acid, and then reacting a ketone or ketal with a compound of formula VI, followed by hydrolysis of the resulting 1,3-dioxane of formula VII and optionally acid purification as shown in Scheme 1.

Reaction Formula 1 6 T03886 r0 0 0 0 5

IV

R8 OH 0 0 io r ^ A ^^ AA ^ or11 __

V

Ra OH OH 0 15 -

VI

r8- * 10 r8 (T ^ o 0 20 n U - *

VII

R9 ^? 10 R9 ^ R10 r8 Λ o _ rs cr ^ o o

25 VIII IX

'r 30 R'j! 10 Rl · ^ 10 irS 0 f ^ j .0.

«^ Y ^ Xs ORLI

Ilia Illb 103886 7 7 8

In Reaction Scheme 1, R and R are each independently hydrogen, C 1-8 alkyl or phenyl optionally substituted with one or two C 1. alkyl, halogen, C.. alkoxy or trifluoromethyl; R is 1 to 4 9 10

5 hydrolyzable ester group, n is zero or 1 and R and R

are as defined above. The keto ester of Formula V may be prepared by reaction between an acetoacetic acid ester and an aldehyde of Formula VI, in well known in the art, in an inert organic solvent such as tetrahydrofuran at temperatures of about 0 ° C to -78 ° C base such as sodium hydroxide, lithium diisopropyl.

Starting materials of formula IV wherein n = 0 and n = 11 are known or can be readily prepared by known methods. The starting materials of formula IV wherein n = 1 may also be prepared by reaction between compounds of formula IV wherein n = 0 and Wittig reagents such as triphenylphosphoranylidene acetaldehyde and other methods known in the art. Those skilled in the art will recognize that the relative configuration of double bonds (n = 0) or double bonds (n = 1) in the starting materials of formula IV may be trans, cis, or a mixture thereof. The relative amount of each geometric isomer (E) or (Z) can; Depending on the commercial availability or the reaction conditions used in the preparation. In the specific example described herein, a mixture containing mainly the trans (E) isomer was used. Although a small proportion of the other isomer may be present throughout the reactions shown in Scheme 1, it is clear to those skilled in the art that the isomers. the relative amount is not critical since the double bond is oxidized and thus removed in the ozonolysis reaction.

The keto ester of Formula V may be reduced to the dihydroxyester of Formula VI by reducing agents known in the art. Preferably, the reaction should be carried out stereospecifically by a two-step stereospecific β 103886 reduction in order to maximize the production of the preferred erythro isomer of the dihydroxy ester of formula VI. Stereospecific reduction is carried out with trisubstituted alkyl boranes, preferably triethyl borane 5 or tri-n-butyl borane, or alkoxide alkyl boranes, preferably methoxydiethyl borane or ethoxy-diethyl borane [Tetrahedron Letters, 28, 1987], ca. The resulting complex is then reduced with sodium borohydride at a temperature in the range of from about 10 ° C to 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 addition of methanol with or without addition of aqueous hydrogen peroxide and buffer. Some compounds of formula VI are known and described in U.S. Pat. patent no. No. 4248889 (issued February 3, 1981), and U.S. Pat. U.S. Patent No. 4,650,890, issued March 17, 1987.

Compounds of Formula VII may be prepared from compounds of Formula VI by reacting a ketone such as 2-propanone, 3-pentatonone, cyclopentatonone or cyclohexanone in a suitable inert organic solvent, e.g. toluene, benzene or xylene at a temperature of about 20 ° C. reflux temperature, with an appropriate amount of organic, mineral, or resinic acid, e.g. or 30 similar devices. The reaction of a compound of formula VI with a ketone can also be carried out without solvent. Alternatively, the above reaction of compounds of formula VII may be carried out with a ketal such as 2,2-dimethoxypropane, 1,1-dimethoxycyclohexane and the like.

9 103886

Compounds of formula IIIa wherein R12 is a hydrolyzable ester group and preferably alkyl can be prepared from the corresponding compounds of formula VII by oxidation of the olefinic group to the aldehyde group using conventional methods. Alternatively, the compound of formula VII is first hydrolyzed by basic hydrolysis to a compound of formula VIII, which is then oxidized to give a compound of formula IIIa wherein R 12 is hydrogen. A particularly useful oxidation process is the reaction of a compound of formula VII or VIII in an inert solvent such as methanol, ethyl acetate or methylene chloride with ozone at a temperature of about -50 ° C to -78 ° C. When the reaction with ozone is complete, as determined by the color of the reaction mixture, the intermediate ozonide is decomposed by the addition of a dilute reducing agent, e.g. dimethylsulfide and triphenylphosphine, to give the desired aldehyde of formula IIIa.

Preferred cis- (4R, 6S) aldehydes of formula IIIb are prepared from the corresponding racemic acid of formula VIII by conventional separation techniques such as fractional crystallization after addition of a suitable salt-forming group. The resulting mixture of diastereoisomeric salts formed with an optically active salt-forming agent such as (1S, 2R) -ephedrine and α-methylbenzylamine 11a is separated and the isolated isolated salt is converted to the compound of formula IIIb. Preferably, the salt-forming agent is (IS, 2R) -ephedrine and the separation process is fractional crystallization. The separation can be carried out in an inert organic solution, and preferably in a mixture of carbon-30 hydrogen alcohol solvents, e.g., hexane-methane. in a zero mixture, where the separated salt can crystallize out of solution. If desired, the acid of formula IIIb can be converted to a salt wherein R12 is a metal cation or to a hydrolyzable ester group wherein R12 is C1-4 alkyl.

10 103886

Preferred antihypercholesterolemic compounds of Formulas I and II may be prepared from a compound of Formula IIIa or IIIb by the general methods described in U.S. Patent No. 4,897,490 to John J.

5 Wright and Sing-Yuen Sit, and U.S. Patent No. 4,898,949 to John J. Wright and Sing-Yuen Sit, Neelakantan Balasubramanian and Peter J. Brown. The use of aldehydes of formula IIIa is illustrated in Reaction Scheme 2 and the use of chiral aldehydes of formula IIIb is depicted in Reaction Scheme 3.

103886 11

Reaction Scheme 2 5 * «'-V * 10 V iiAAs»

-φι J

R V-N ma

10 X

R9

_, r ^ 7l 06 r9 rIO

is R4tir x NT / (T ^ o 0 s3 I I Jl] L u xi

R24-. I I CH

Rl W

20 ρβ: 25 r4-K ^ "r4 3 0H 0H 0 Ia R J ^" 3 30 Ri * 1 /

> * = - N

35

Compound of Formula II.

Reaction Scheme 3 12 103886 R5 5 r4-h -h-r6 ^ 10 or ^ o o ^ \ _ /

10 »~ N

10 Illb

X

R9 15 r ^ -L fl-R4 r 'j? 10 3 cr ^^ o o

^ X A A jl 1 »XII

r2 R / * \ / CH3 R1 \ _ /

20 1.1 — N

R9; 25 r4I? - ^ - r6 OH OH 0 lb 30 S '\ = f 35 (4R, 6S) Compound of Formula II 103886 13

In Reaction Schemes 2 and 3, R 1, R 2, R 3, R 4, R 5, R 6, R 9, R 10 and R 12 are as defined below and Z is O 1 R 14 5 -P- (OR 13)? or -P-R 14 X 2 R 2 R 14 wherein R 13 is alkyl, R 14 is phenyl unsubstituted or substituted with one or two C 1-6 alkyl 10 or chloro substituents and X is bromo, chloro or iodo. The phosphonium salt of formula x and the phosphonate of formula X are described in U.S. Patent 4,898,949. The reaction of a compound of formula X with a compound of formula IIIa or IIIb to give a compound of formula XI or XII wherein R12 is alkyl in an inert organic solvent such as tetrahydrofuran and Ν, Ν-dimethylformamide in the presence of a strong base such as n-butyllithium at a temperature of about -50 ° C to -78 ° C. When the reaction of a compound of formula X with a compound of formula IIIa or IIIb wherein R12 is hydrogen, it is preferable to use two equivalents of a strong base such as n-butyllithium. Alternatively, a salt of a compound of formula IIIa or IIIb can be prepared which is then treated with a compound of formula X | 25 and strong base. Addition, salt-forming and over-training methods are known to those skilled in the art. The tetrazole compounds of formula XI or XII can be readily deprotected by methods known per se, such as dilute acid, e.g., 0.2N HCl and 0.5N 30 HCl in an inert organic solvent such as tetrahydrofuran, for the erythro compounds of formula Ia or (3R, 5S) compounds of formula Ib which can then be converted to the Formula II trans-compounds or Formula II (4R, 6S) compounds in a conventional manner known to those skilled in the art.

103886 14

Preferably, the compounds of formula IIIa have the structure b 'r105, 10 in almost complete cis form wherein R9 and R10 are each C1x2 alkyl or R9 and R10 together with the carbon atom to which they are attached are cyclohexyl; and R 12 is hydrogen, C 1-2 alkyl or a metal cation.

The compounds of the formula IIIb prepared by the process of the invention have the structure of the formula "R 10," almost completely in the cis- (4R, 6S) form wherein R 9 and R 10 are each C 1-2 alkyl or R 9 and R 10 together with the carbon atom: coupled are cyclohexyl; and R 12 is hydrogen, C 1-2 alkyl or a metal cation.

The compounds of formula VIII preferably have a structure of 30 ° C / 10 °

V

R 0 C 1 -C 6 σ 35 103886 15 is almost entirely in the cis form wherein R 7 and R 8 are each independently C 1-6 alkyl or phenyl; R 9 and R 10 are each alkyl or hydrogen, or R 9 and R 10 together with the carbon atom to which they are attached are cyclohec-5-yl; and n is zero or 1.

Preferably, the compounds of formula IX have the structure of R ** l r ° r8 cr crNN) almost entirely in the cis- (4R, 6S) form wherein R7 and R® are each independently hydrogen, alkyl or phenyl; R 9 and R 10 are both C x 2 alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclohexyl; and n is zero or 1.

The intermediates of formula XI are 20 R5

r4! - 'R

< 25 &gt; O: 25 "R w is almost entirely in the cis form wherein R1 and R4 are each independently hydrogen, halogen, C1-4 alkyl, C4-4 alkoxy, or trifluoromethyl; R2, R3, R5 and R6 are independently 01- R 4 and R 10 are each 0-4 alkyl, or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, and R 12 is hydrogen, C 1-4 alkyl or metal cation.

103886 16

The intermediates of Formula XI are preferably in almost complete cis form wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently hydrogen, fluorine, chlorine, methyl or methoxy; R 9 and R 10 are both alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclohexyl and R 12 is hydrogen, C 1-4 alkyl or a metal cation.

XII

10 R4-L? | r-R6 R3, R10 o

R * 1 I I 0 XII

^ - ^^ or12

15 J ^ CHJ

Rl W

the intermediates of Formula I are preferably nearly completely in the cis-20 (4R, 6S) form wherein R 1 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; R 2, R 3, R 5 and R 6 are independently hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; R 9 and R 10 are each C 1-4 alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl; and R 12 is hydrogen, alkyl or a metal cation.

In a more preferred embodiment, the intermediates of formula XII are almost entirely in the cis- (4R, 6S) form wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently hydrogen, fluorine, chlorine, methyl or methoxy; R 9 and R 10 are each C 1-2 alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclohexyl and R 12 is hydrogen, C 1-4 alkyl or a metal cation.

«17 103886

A process for the preparation of an aldehyde of formula Ilia s' * 10 Λ o o γχΑΑ, almost completely in C5-form 10, wherein R9 and R10 are both C1-4 alkyl or R9 and R10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl; and R 12 is hydrogen, C 0-4 alkyl or a metal cation comprising the steps of: (a)

Ra OH OH 0

R VI

The dihydroxy compound of claim 20, which is in almost complete erythromatic form and wherein R 7 and R 8 are independently hydrogen, C 1-6 alkyl or phenyl optionally substituted with one or two C 1-4 alkyl, halogen, C 1-4 alkoxy or trifluoromethyl; R11 is a hydrolyzable ester group and n is zero or 1, in the presence of a small amount of an acid, reacting with at least one equivalent of a compound of the formula R3-R10-R9x.r10 n or ch3P <gc h3 5 0 3 3 9 10 R is as previously defined to give a compound of the formula R 10, R 10, R 8, C 1-10 o 15 wherein R 1, R 8, R 9, R 1, R 11 and n are as defined above;

(b) if desired, hydrolyzing the ester of Formula VII to a Formula VIII

20 r \ j? 10 r® {r ^ o o; „, ΛαΜ1.

8 9 10 for the preparation of a compound of the formula wherein R, R, R and R 30 are as defined above; and (c) oxidizing a compound of Formula VII or a compound of Formula VIII to produce a compound of Formula IIIa 103886 19 cm -1 in almost complete cis form wherein R 9, R 10 and R 12 are as defined above.

The present invention encompasses a process formula

For the production of the aldehyde of Illb 10 R 10 * 10 C 10 - 15 in almost complete cis- (4R, 6S) form wherein R 9 and R 10 are both alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl; and R 12 20 is hydrogen, alkyl or a metal cation comprising the steps of: (a) administering R 8 OH OH 0; The dihydroxy compound of claim 25, which is in almost complete erythromatic form and wherein R 7 and R 6 are each independently hydrogen, alkyl, or phenyl optionally substituted with one or two alkyl, halogen, alkoxy or trifluoromethyl; Ru is a hydrolyzable ester group and n is zero or 1, react in the presence of a small amount of acid with at least one equivalent of formula 103886 20 B? olO R * r10 Y t i c c = 3 ^ 10, 3 9 10 5 wherein R and R are as previously defined to give the formula

10 I JL JL J-L VII

wherein R 1, R 4, R 4, R 4, R 1 and n are as defined above; (b) hydrolyzing the ester of formula VII of formula R 'J? 10

20 o JxT

Re tr o to produce a compound of Formula 25 7 8 9 10 wherein R, R, R, R and n are as defined above; (c) isolating the acid of Formula VIII to give a compound of Formula 30 r8 (r10 0 103886 21) in almost complete cis- (4R, 6S) - form wherein R7, R8, R9, R10 and n are as defined above; (d) oxidizing the acid of Formula IX and, if desired, preparing an ester thereof to produce a compound of Formula "'a1" (T10-O10) in almost complete form in the form of cis- (4R, 6S) -15 wherein R9, R10 and R12 are as defined above.

The compound of formula lila may be used in the preparation of formula 20. oh r4P jj-R4 Ϊ

: 25 R

R V - H

For the preparation of a compound of Formula 30 in an almost complete trans form wherein R 1 and R 4 are independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; and R 2, R 3, R 5 and R 6 are each independently hydrogen, 103886 22 halogen, C 1-4 alkyl or C 1-4 alkoxy, the process comprising the steps of: (a) providing a formula C 5 5 V;

i-R 6

JL / CH2 “Z X

1n ^^ CHi 10 Rl \ _ /

H-N

1 2 3 4 5 6 wherein R, R, R, R, R and R are as defined above and Z is

O ® R

-p- (or13) 7 -P-r14 X® XR14 13 14 where R is alkyl; R is phenyl substituted or unsubstituted with one of two 4 alkyl or chloro substituents; and X is bromine, chlorine or iodine, to react with the formula:

Or ^ 0 0 IIIa 30. with a compound which is almost completely cis form

wherein R and R are both C alkyl or R

10 14 and R together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl; 12 35 and R is hydrogen, alkyl or a metal cation of formula R5 103886 23

r3 j ^ O O XI

5 s to produce a compound of formula X ^ CH '81 w in almost complete cis form wherein R 1, R 2, R 3, R 4, R 5, R 6, R 9, R 10 and R 12 are as defined above; (b) reacting a compound of Formula XI with an acid to give a compound of Formula 15 R5 R'-j ^ jj-R * OH OH2a - ^ - ^ VR12 R2 k * JJ ^ CH3 20 R @ 1 /

N-N

25 wherein R1, R2, R3, R4, R3, R1 and R13 are as defined above; and (c) cyclizing a compound of formula Ia wherein 12 R is hydrogen to give R 30 of formula

j? H

35 fX kX * '' ™ 3 8 w 103886 24 is a compound of almost complete trans where R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above.

The compound of formula IIIb can be used in the formula 5 R 3 R 4 + tr 6 f h T h

r? 4- I

ίο S1 \ _ /

N-N

which is almost completely in the trans (4R, 6S) form and wherein R 1 and R 4 are independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl; and R 2, R 3, R 5 and R 6 are each independently hydrogen, halogen, C 1-4 alkyl or alkoxy, the process comprising the steps of: (a) providing a compound of formula 20 R 8 R 4 .LM] -R 6 '; 25 R2-K l | Tue 7 ^ 3

* W

wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above and Z is n-14

0 e R

-P- (O R 13), -P -R 14 Χθ 35 2 X "1" wherein R is alkyl; R is phenyl, substituted or unsubstituted by one of two alkyl or chloro substituents; and X is bromine, chlorine or iodine, to react with formula 5> V 'γίΛΛ ...

which is almost completely in the cis-9 10 (4R, 6S) form, wherein R and R are each C 1. al-9-10 1-4 alkyl or R and R together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or 12-cycloheptyl; and R is hydrogen, alkyl or a metal cation of the formula R 1 -R * R k / R 10 ° 20

XII

fil w: for the almost complete preparation of the compound of Formula 25 in the cis- (4R, 6S) form, wherein R 1, R 1, R 3, R 4, R 6, R 6, R 6, R 1 4 and R 13 are as defined above; (b) reacting a compound of Formula XII with 30 acids to give R 9

Ib OH OH o

> ^ SkCH3 Rl W

35 103886 26 2 2 3 4 5 6 12

wherein R, R, R, R, R, R and R

are as defined above; and (c) cyclizing a compound of formula Ib wherein 12 R is hydrogen to give formula 5

Rs. * is R -P + tr6 1

- Y rS

The compound of formula B 'w is almost completely in the trans (4R, 6S) form if -15 R, R, R, R, R 5 and R are as defined above.

Male Wistar mice (160-200 g, 2 cages) were maintained on a normal diet (Purina Rat Chow and water, ad libitum) for at least 7 days with 20 turns of light (7:00 to 5:00 pm). Food was removed 15 hours prior to dosing. Compounds were administered at 8.00 am by intragastric intubation using 0.5-1.0 ml of an aqueous or propylene glycol solution of sodium salts, lactones or esters of test compounds. Controls received an equivalent amount of vehicle.

30 minutes after the test compounds were administered, the rats were injected intraperitoneally with 0.9 mL of 0.9% NaCl containing approximately 120 pCi / kg of sodium [1-C] acetate (1-3 mCi / mmol). After a 60 minute incorporation period, rats were sacrificed and. liver and blood samples were taken. Doses of plasma (1.0 ml) obtained by centrifugation of heparin + EDTA-treated blood, and doses of liver homogenates (corresponding to 0.50 g of fresh liver weight) were taken for determination of radiolabeled 3-hydroxysterols. Sterol isolation of liver samples followed Kates's method in 103886 27

Techniques in Lipidology (M. Kates, ed.) Ss. 349, 360- 363, North Holland Pubi. Co., Amsterdam, 1972, while blood samples were saponified directly, followed by isolation of digeston-precipitated sterols. C-labeled steroids were quantitated on a liquid scintillation counter (efficiency corrected). Mean inhibition of hepatic and plasma C-14 C administration was calculated for treated groups and compared to mean controls at the same time.

Therefore, the above assay provides information on the ability of test substances to inhibit de Novo synthesis of cholesterol in rats by oral administration. Using the above assay, for example, the compound of Example 13 produced a 50% inhibitory effect (ED? Q) on both plasma and liver-15 cholesterol, comparable to the values obtained with mevinoline (Lovastatin) using a similar method [Alberts, et al. Proc. Natl. Acad. Sci., 77, 3957-3961 (1980)].

The following examples give all temperatures at 20 degrees Celsius. Melting points were measured on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Proton Magnetic Resonance Spectra (½ NMR) were measured on a Bruker AM, Bruker WM or Varian T-60 CW spectrometer. All spectra were determined as CDCl ^ DMSO-dg or D2O unless; 25 to the contrary, chemical changes are given δ units downward from the internal tetramethylsilane standard (TMS) and the proton coupling constants are given in Hertz (Hz). The division groups are denoted as follows: s, Singlet-ti; d, doublet; t, triplet; q quartet; m, multiplet-30 th; br, broad peak; dd, doublet of doublets; and dq, kvar-. tettidubletti. Carbon-13 nuclear magnetic resonance (13C NMR) spectra were determined on a Bruker AM 300 or Bruker WM 360 spectrometer and were broadband proton detached. All spectra were determined on CDCl ^, DMSO-dg or D2O unless otherwise stated with an internal deuterium lock and chemical shifts are given in 6 units down from tetramethyl-103886 28 silane. Infrared spectra were determined on a Nicolet MX-1 FT spectrometer 4000 cm -1 to 400 cm -1 calibrated for 1601 cm -1 absorption on polystyrene membrane and are reported as Resi-prime centimeters (cm -1). ) and w (weak).

25

Optical rotations [α] D were determined on a Perkin-Elmer 241 polarimeter at concentrations given in CHCl 3.

Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel plates (60F = 254) 10 and visualized using UV light, iodine vapors and / or staining with one of the following reagents: (a) methanol or ethanol-containing phosphomolybdic acid (2%); (b) Reagent (a) followed by 2% cobalt sulfate in 5 M i.sub.2SO.sub.2 and heating. Column chromatography, also called flash chromatography, was performed on a glass column using fine silica gel (32-63 µm silica gel H) and slightly higher atmospheric pressure with said solvents. Ozone lysis reactions were performed using a Welsbach ozonator 20 model T-23. All evaporations of the solvents were performed under reduced pressure. As used herein, the term hexanes is a mixture of isomeric C 1 -C 6 hydrocarbons as defined by the American Chemical Society and the term "inert" atmosphere is argon or nitrogen unless otherwise stated.

Example 1

Cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid methyl ester

Methyl 3,5-dihydroxy-7-phenyl-6-enoate (98% diastereomeric purity) (2.37 g, 9.48 mmol) was stirred in 2,2-dimethoxypropane (20 mL) and catalytic amount; with p-toluenesulfonic acid for 16 hours. The solution was partitioned between diethyl ether and dilute aqueous sodium bicarbonate solution. The organic layer was dried (Na 2 SO 4) and concentrated under reduced pressure to give 35 as a yellow solid. After recrystallization from isopropyl 103886 29 ether, 1.70 g (62%) of the title compound was obtained as a white solid; mp 84-86.5 eC.

Alternatively, 0.2 g of solid sodium carbonate may be added to the 2,2-dimethoxypropane solution and vigorously agitated. The solid is filtered through folded filter paper. The excess 2,2-dimethoxypropane is removed under reduced pressure to give a yellow solid which is recrystallized from isopropyl ether.

1 H NMR (CDCl 3) δ: 7.73-7.19 (5H, m), 6.59 (1H, d, J = 15.9 Hz), 6.14 (1H, dd, J = 15.9 , 6.4 Hz), 4.57-4.35 (1H, m), 4.42-4.35 (1H, m), 3.68 (3H, s), 2.58 (1H, d, J = 15.6, 6.9 Hz), 2.14 (1H, dd, J = 15.6, 6.3 Hz), 1.74-1.61 (1H, m), 1.52 (3H) , S), 1.43 (3H, s), 1.45-1.35 (1H, 15m).

Calcd. For C17H323; H, 7/63 Found: C, 70.24; H, 7.69.

Example 2

Cis-2,2-Dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-20 acetic acid

A solution of 2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid methyl ester (8.5 g, 29.3 mmol) in 1N NaOH (32 mL) and methanol (64 mL) was heated at reflux for 45 minutes.

After evaporation under reduced pressure, the aqueous solution was washed twice with diethyl ether and acidified with 1N HCl (33 mL). The precipitate was collected and recrystallized from ethyl acetate / isopropyl ether to give 7.2 g (90%) of the title compound as a colorless solid; Melting point 153-155 ° C.

. 1 H NMR (CDCl 3) δ: 7.37-7.20 (5H, m), 6.60 (1H, d, J = 16.0 Hz), 6.14 (1H, dd, J = 16.0, 6.4 Hz), 4.59-4.54 (1H, m), 4.43-4.35 (1H, m), 2.62 (1H, dd, J = 16.0, 7.2 Hz) ), 2.51 (1H, dd, J = 16.0, 5.3 Hz), 1.77-1.72 (1H, m), 35 1.54 (3H, s), 1.46 (3H) , s), 1.50-1.36 (1H, m).

Calcd. For ^ΐΐΗ20 ° 4: Cf 69/54; H, 7.30 Found: C, 69.20; H, 7.33.

i.e. 103886

Example 3

Isolation of Cis-2,2-Dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid

Racemic cis-2,2-dimethyl-6- (2-phenylethenyl) -5,3-dioxane-4-acetic acid (0.31 g, 1.1 mmol) (prepared in Example 2) was dissolved in boiling solution of hexane. / ethanol solution of (1S, 2R) -ephedrine (0.2 g, 1.1 mmol). The resulting solution was very slowly brought to room temperature to give 0.21 g (41.4%) of a colorless chiral salt (diastereomerically pure seed crystal is recommended for separation): mp 170-171 ° C.

The chiral acid was liberated by acid working (as described in Example 4) and its enantiomeric purity was determined to be 100% by NMR using L-phenyltrifluoromethylcarbinol as the chiral solvent. [A] D 25 = + 5.45 ° (c * l, CHCl 3).

Example 4

Cis- (4R, 6S) -2,2-Dimethyl-6-formyl-1,3-dioxane-4-acetic acid

Separated salt of cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid and (1S, 2R) -ephedrine (6.6 g, 14.9 mmol) (prepared in Example 3) was partitioned between 0.5N HCl (30 mL) and diethyl ether. The ether layer was washed with brine, dried (MgSO 4 / Na 2 SO 4) and concentrated under reduced pressure to give 4.1 g (99.6%) of the free acid. This acid was dissolved in dry methylene chloride (100 mL) and ozone was passed through this solution at -78 ° C until it was deep blue. More than 30 ozone was removed by purging with nitrogen and form. the resulting ozonide was decomposed by addition of CH 2 Cl 2 (5 mL) and warming to room temperature and allowed to stand for 16 hours. The solution was concentrated under reduced pressure and the residue was dissolved in isoamyl ether (ca. 100 mL). The benzaldehyde formed in ozone-35 lysis was azeotroped with iso- 103886 31 amyl ether under reduced pressure to give the title compound.

1 H NMR (CDCl 3) δ: 9.57 (1H, s), 4.40-4.30 (2H, m), 2.60 (1H, dd, J = 16.0, 7.0 Hz), 2 , 49 (1H, dd, J = 16.0, δ 6.0 Hz), 1.88-1.83 (1H, m), 1.49 (3H, s), 1.46 (3H, s) , 1.42-1.31 (1H, m).

Example 5

Dimethyl [3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propen-1-yl] phosphonate 10 Slurry with 3,3-bis- (4-Fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propane (1.17 g, 3.0 mmol) and trimethyl phosphite (0.41 g, 3.3 mmol) was heated at 100 ° C for 5 minutes. After cooling to ambient temperature, the excess trimethyl phosphate was removed in vacuo to give a pale yellow solid. This solid was recrystallized from ethyl acetate / hexane to give the title compound as a pure white solid; m.p. 140-141 ° C.

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

Calcd. For &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; H, 4.56; N, 13.33 Found: C, 53.83; H, 4.48; N, 13.50.

Example 6

C 1-8 (4R, 6S) -6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1 H -tetrazol-5-yl) -1,3-butadienyl] -2,2- dimethyl-1,3-dioxane-4-acetic acid The crude chiral acid prepared in Example 4 was dissolved in dry THF (50 mL) and the resulting solution transferred to a 250 mL three neck flask which was purged with nitrogen and fitted with a mechanical stirrer. After vigorous stirring and cooling to -78 ° C, n-BuLi (2.5 mL in hexane, 5.96 mL) was added dropwise. At the final stage of Li-103886 32, the solution turned into a suspension of a white solid-like gel.

Separate flask containing dimethyl [3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propen-511-yl] phosphonate (6.2 g) , 14.7 mmol) (prepared in Example 5) in THF (50 mL) under nitrogen atmosphere was cooled to -78 ° C and n-BuLi (2.5 mL in hexane, 5.96 mL) was added slowly. The resulting red-brown solution was stirred for 15 minutes at -78 ° C. This solution of the phosphonate anion 10 was passed through a double-ended needle at -78 ° C to a vigorously stirred suspension above containing the lithium salt of the chiral acid. After the addition, the resulting brown solution was stirred for 30 minutes at -78 ° C and for 16 hours at ambient temperature. The THF solution was partitioned between 0.5N HCl and ethyl acetate. The organic phase was washed with brine (2x), dried (Na 2 SO 4) and concentrated in vacuo. The residue was chromatographed on silica gel (66: 33: 1 / diethyl ether: hexane: acetic acid) to give 3.80 g (51.6% overall yield of the original ephedrine salt; toluene was used to azeotropize acetic acid residue) as a yellow foam. [α] 25 D = + 106.1 ° (c = 2.23, CHCl 3).

1 H NMR (CDCl 3) δ: 7.24-6.82 (8H, m), 6.62 (1H, d, J = 15.0 Hz), 5.32 (1H, dd, J = 15.0, 5.7 Hz), 4.42-4.37 δ (1H, m), 4.30-4.23 (1H, m), 3.51 (3H, s), 2.53 (1H, dd, J

= 15.9, 7.0 Hz), 2.42 (1H, dd, J = 15.9, 5.6 Hz), 1.62-1.57 (1H, m), 1.46 (3H, s), 1.33 (3H, s), 1.30-1.20 (1H, m).

Example 7 Trans- (4R, 6S) -6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] -tetrahydro -4-hydroxy-2H-pyran-2-one

Cis- (4R, 6S) -6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] -2,2-dimethyl -35 1,3-dioxane-4-acetic acid (3.7 g, 7.45 mmol) was dissolved in a solution of THF (90 mL) and 0.2N HCl (60 mL) 33 103886 and allowed to stand for 16 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine (2x), dried (Na 2 SO 4) and concentrated in vacuo. The residue was dissolved in dry methylene chloride 5 (60 mL) and stirred for 4 hours in the presence of 1-cyclohexyl-3- (2-morpholinomethyl) -carbodiimide-p-toluenesulfonate (6.6 g, 15.6 mmol). The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na 2 SO 4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1: 1 ethyl acetate: diethyl ether). Recrystallization from ethyl acetate-hexane gave 1.33 g (40.1%) of the title compound as a white solid; mp 172-173 ° C. [α] D = + 237.8 ° (c = 2.17, CHCl 3).

Example 8

Methyl 3-hydroxy-5-oxo-6,8-dekadienoaatti

To a cold (-30 ° C) methyl acetate (41.5 g, 357 mmol) solution in THF (500 mL) was added lithium di-iso-propylamide (476 mL, 1.5M solution in cyclohexane, 714 mmol). The resulting solution was stirred for 15 minutes at -30 ° C. After cooling to -78 ° C, 2,4-hexadienal (34.3 g, 357 mmol) was added and the solution was stirred for 10 minutes at -78 ° C and 16 hours at ambient temperature. The solution was concentrated under reduced pressure and the remaining syrup was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with brine (2x), dried (Na 2 SO 4) and concentrated. The residue was purified by silica gel chromatography (diethyl ether hexane-30 n / 2: 1) to give 18.5 g (24.4%) of the title compound: as an oil.

1 H NMR (E) (E) Isomer (200 MHz, CDCl 3) δ: 6.3, (1H, dd, J = 14.7, 11.9 Hz), 6.02 (1H, dd, J = 14, 7, 11.9 Hz), 5.75 (1H, dq, J = 14.7, 6.4 Hz), 5.5 (1H, dd, J 35 = 18.7, 6.4 Hz), 4 , 74-4.5 (1H, m), 3.73 (3H, s), 3.53 (2H, s), 2.6 (2H, d, J = 5.8 Hz), 1.77 ( 3H, d, J = 6.4 Hz).

103886 34

Example 9

Methyl-3,5-dihydroxy-6,8-dekadienoaatti

To a cold (-15 ° C) solution of methyl 3-hydroxy-5-oxy-6,8-decadienoate (18.5 g, 86.9 mmol) in THF (300 mL) was added triethylborane (1M in THF: 113 mL, 113 mmol and the solution was stirred for 20 min. After cooling to -78 ° C, NaBH 4 (6 g, 159 mmol) and methanol (37.5 mL) were added. The solution was stirred vigorously for 30 minutes at -78 ° C and for 3 hours at ambient temperature.

The solvent was removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was dried (Na 2 SO 4) and concentrated. The residue was purified by silica gel chromatography (diethyl ether: hexane / 3: 1) to give 7.95 g (42.7%) of the title compound as a yellow oil.

1 H NMR (E) (E) Isomer (360 MHz, CDCl 3) δ 6.18, (1H, dd, J = 15.1, 10.4 Hz), 6.00 (1H, dd, J = 15, 1, 10.4 Hz), 5.69 (1H, dq, J = 15.1, 7.0 Hz), 5.52 (1H, dd, J = 15.1, 6.7 Hz), 4.46- 4.37 (1H, m), 4.29-4.22 (1H, m), δ 3.69 (3H, s), 2.60-2.42 (2H, m), 1.72 (3H). , d, J * 7.0Hz), 1.74-1.57 (2H, m).

Example 10

Methyl cis -4- (1,3-pentadienyl) -1,5-dioxaspiro [5,5] un-decane-2-acetate; Methyl 3,5-dihydroxy-6,8-decadienoate (7.6 g, 35.5 mmol) and p-toluenesulfonic acid (0.1 g) were added to cyclohexanone (10 g, 100 mmol) and stirred for 16 hours at ambient temperature. The yellow solution was loaded directly onto a silica gel column and the product was eluted with diethyl ether: hexane (1: 4). The appropriate fractions were combined to give 3.52 g (33.6%) of the title compound as a colorless oil.

1 H NMR for (E) (E) isomer (360 MHz, CDCl 3) δ: 6.16, (1H, dd, J = * 15.1, 10.6 Hz), 6.00 (1H, dd, J = 15.1, 35 10.6 Hz), 5.71-5.65 (1H, dd, J = 15.1, 6.5 Hz), 5.47 (1H, dd, J = 15.1, 6 , 4Hz), 4.44-4.39 (1H, m), 4.35-4.30 (1H, 103886 35m), 3.66 (3H, s), 2.52 (1H, dd, J = 1.54, 7.9 Hz), 2.30 (1H, dd, J = 15.4, 6.5 Hz), 2.1-1.18 (12H, m), 1.72 (3H) , d, J = 6.5 Hz).

Calcd. For C 17 H 26 ° 4: 5 C, 69.36; H, 8.90 Found: C, 69.59? H, 9.16.

Example 11

Cis-4- (1,3-pentadienyl) -1,5-dioxaspiro [5.5] undecane-2-acetic acid 10-Methyl-cis-4- (1,3-pentadienyl) -1,5-diosaspiro [5 , 5] undecane-2-acetate (3.5 g, 12.4 mmol) was heated to reflux in a solution of 1N NaOH (13 mL) and methanol (26 mL). The methanol was removed under reduced pressure and the remaining aqueous solution was acidified with 1N HCl and extracted with diethyl ether. The organic layer was dried (Na 2 SO 4) and concentrated. The solid residue was recrystallized from ethyl acetate / hexane to give 2.0 g (55.9%) of the title compound as a colorless solid; mp 144-146.5 ° C.

20 * Η NMR (360 MHz, CDCl3) δ: 6.18, (1H, dd, J = 18.0, 12.5 Hz), 5.72 (1H, dq, J = 18.0, 7.7 Hz), 5.99 (1H, dd, J = 18.0, 12.5 Hz), 5.48 (1H, dd, J = 18.0, 7.6 Hz), 4.45-4.37 (1H, m), 4.37-4.25 (1H, m), 2.56 (1H, dd, J = 18.9, 8.8 Hz), 2.48 (1H, dd, J = 18 , 9, 6.1 Hz), 2.60-1.30: 25 (12H, m), 1.73 (3H, d, J = 7.7 Hz).

Calculated Analysis ^ ΐ6Η24 ^ 4; C, 68.54; H, 8.62 Found: C, 68.36; H, 8.55.

Example 12. 30 Cis -4- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) - (1,3-butadienyl]) - 1,5-dioxaspiro [5, 5] undecane-2-acetic acid A. 4-formyl-1,5-dioxaspiro [5.5] undecane-2-acetic acid «35 103886 36

Ozone was passed through a solution of 4- (1,3-pentadienyl) -1,5-dioxaspiro [5.5] undecane-2-acetic acid (570 mg, 2.0 mmol) in methylene chloride (25 mL) -78 ° C. After the solution turned blue, nitrogen was bubbled through solution 5 to remove excess ozone. Dimethylsulfide (0.5 mL) was added and the solution was concentrated under reduced pressure to give the title compound as a thick oil which was used without further purification in the next step.

1 H NMR (60 MHz, CDCl 3) δ: 9.57, (1H, s), 4.52-4.14 (2H, m), 2.60-2.31 (2H, m), 2.10 -1.10 (12 H, m).

B. Cis-4- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) - (1,3-butadienyl]) - 1,5-dioxaspiro [ 5.5] undecane-2-acetic acid 15 To a solution of [3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenyl] phosphonate (1.7 g, 4 mmol) in THF (20 mL) at -78 ° C was added n-BuLi (1.6 mL, 4 mmol, 2.5M in hexane). The resulting brown-red solution was stirred for 30 minutes at -78 ° C. Using a double-pointed needle, this solution was transferred to a solution of 4-formyl-1,5-dioxaspiro [5.5] undecane-2-acetic acid (prepared in Step A) in THF (10 mL) and maintained at -78 ° C. C. After the transfer was complete, the combined reaction mixture was stirred at -78 ° C for 1 hour and then at ambient temperature for 4 hours. The solution was partitioned between 0.5 N HCl and ethyl acetate. The organic layer was washed with brine (2x), dried (Na 2 SO 4) and concentrated in vacuo. The residue was purified by silica gel chromatography (diethyl ether: hexane: acetic acid / 50: 20: 1) to give 342 mg (31.9% overall yield) of the title compound as a yellow foam.

1 H NMR (360 MHz, CDCl 3) δ: 7.25-6.84, (8H, m), 6.66 (1H, d, J = 16.0 Hz), 5.32 (1H, dd, J = 16.0, 5.10 Hz), 4.45-4.25 (2H, m), 3.52 (3H, s), 2.56 (1H, dd, J = 35 16.0, 7.6 Hz), 2.44 (1H, dd, J = 16.0, 5.1 Hz), 1.89-1.17 (12H, m).

103886 37

Example 13

Trans-6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) - (1,3-butadienyl] -tetrahydro-4-hydroxy-2H- pyran-2-one 5 A mixture of 4- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) - (1,3-butadienyl]) - 1, 5-Dioxaspiro [5.5] undecane-2-acetic acid (280 mg, 0.52 mmol) in 20 mL of THF / 0.5N HCl (1: 1) was allowed to stand at ambient temperature for 26 hours. The organic layer was washed with brine (2x), dried (Na 2 SO 4) and concentrated The resulting foam (126 mg) was dissolved in dry methylene chloride (10 mL) and treated with 1-cyclohexyl-3- (2-morpholinomethyl) carbodi After 16 hours at ambient temperature, the solution was evaporated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate to give 38 mg (16.6%) of the title compound as a colorless oil, m.p. is an example in a racemic mixture of 7 yh-20 concentrate.

Example 14

Methane 2,2-dimethyl-6-formyl-1,3-dioxane-4-acetate

Cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid methyl ester (prepared in Example 25) was dissolved in methanol (10 mL) and ozone was passed through the solution at -78 ° C. until the solution turned blue. The reaction mixture was purged with nitrogen to remove excess ozone, then dimethyl sulfide was added and the temperature was allowed to rise to room temperature. Reaction shark. The residue was purified in vacuo and the residual oil purified by chromatography on silica gel using diethyl ether-hexane (3: 1) to elute the title compound.

1 H NMR (360 MHz, CDCl 3) δ: 9.53, (1H, s), 4.40-35 4.23 (2H, m), 3.69 (3H, s), 2.53 (1H, dd) , J = 15.8, 7.02 103886 38

Hz), 2.37 (1H, dd, J = 15.8, 5.98 Hz), 1.85-1.76 (1H, m), 1.44 (3H, s), 1.40 (3H) , s), 1.35-1.23 (1H, m).

Example 15 3,3-Bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5,5-yl) -2-propene A. 5-Ethyl-1-methyl-1H-tetrazole

To a slurry of 1,5-dimethyltetrazole (4.9 g, 0.05 mol) in dry tetrahydrofuran (50 ml) was added 2.5M n-butyllithium in hexanes (20 ml, 0.05 mol) over 10 minutes at -78 ° C. in an inert atmosphere. This mixture was stirred for 30 minutes, during which time a yellowish precipitate formed. Methyl iodide (3.7 mL, 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 (2 x 25 mL) and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil was purified by distillation to give 5.2 g (92%) of the title compound-20; boiling point 89-90 ° C 0.05 mm Hg.

1 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-5-25-yl) -2-propanol

To a solution of 5-ethyl-1-methyl-1H-tetrazole (5.6 g, 0.05 mol) [prepared in Step A] in 60 ml of dry tetrahydrofuran was added 2.5M n-butyllithium (20 ml, 0 , 05 mol) in hexane for 5 minutes at 30 -78 ° C (bath temperature) under an inert atmosphere. The mixture was stirred for 30 minutes and a solution of 4,4'-difluorobenzophenone (10.8 g, 0.5 mol) in 25 ml of dry tetrahydrofuran was added over 5 minutes. This mixture was stirred for an additional 2 hours and the bath temperature-35 was slowly raised to -20 ° C. The reaction was quenched with 1N HCl and extracted with ethyl acetate (3 x 50 mL) and 103886 39 chloroform (3 x 50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The solid was purified by crystallization from ethanol-hexane to give 10.8 g (65%) of the title compound; mp 160-161 ° C.

IR (KBr) -o. : 3400 cm -1; max 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.

Calcd. For ^7Ηΐ6Ρ2Ν40: 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) -2-propene

A slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propanol (8.25 g, 0.025 g of 20 mol) [prepared in Step B] and 100 mg of p-toluenesulfonic acid monohydrate in xylene (60 mL) was heated at reflux in a Dean & Stark water harvester for 12 hours. The reaction mixture was washed with 1N NaOH (10 mL) while warm and water (100 mL). Concentration of its organic layer to 25 yielded the product as heavy crystals. This was purified by recrystallization from ethanol-hexane to give 7.1 g (91%) of the title compound as white crystals; mp 146-147 ° C.

IR (KBr): 1575 cm -1; 1 H max 30 H NMR (CDCl 3) δ: 7.42-6.85 (m, 8H), 3.53 (s, 2H), 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, 131.54, 131.11, 131.01, 119.53, 115.51, 115.27, 115.22, 35 33.50, 21.20.

103886 40

Calcd. For C17H14F2N4: 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-tet-5-rasol-5-yl) -2-propene

A slurry of 1,1-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propene (61.46 g, 0.197 mol) [prepared in Step C], N- bromosuccinimide (35.06 g, 0.197 mol) and a catalytic amount of azobisisobutyrinitrile or benzoyl peroxide in carbon tetrachloride (1.2 liters) were heated to reflux in an inert atmosphere for 2 hours. The reaction mixture was cooled to ambient temperature and the solid from the reaction was filtered. The filtrate was concentrated under reduced pressure 15 and the resulting solid was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals; mp 159-160 ° C.

IR (KBr): 1600 cm @ -1; 1 H NMR (CDCl 3) δ: 7.5-7.1 (m, 8H), 4.44 (s, 2H), δ 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.

Calcd for C ^ ^H H ^FFF BrNN: ’25 C, 52.19; H, 3.34; N, 14.32 Found: C, 52.58; H, 3.47; N, 14.49.

Example 16 [1,1-Bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-propen-3-yl] triphenylphosphonium bromide. A slurry of 3,3-bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene (1.95 g, 0.005 mol) [ was prepared in Example 15, Step D], and triphenylphosphine (1.3 g, 0.005 mol) in cyclohexane (25 mL) was heated to reflux. After 30 minutes, the reaction mixture of the Reak-35 became a clear solution and a white precipitate appeared after 1 hour. The mixture 103886 41 was heated for a further 8 hours, cooled to ambient temperature and the solid collected by filtration and washed with diethyl ether. This white powder was dried in vacuo at 50 ° C to give 3.0 g (92%) of the title compound; mp 254-255 ° C.

IR (KBr): 3450, 1600, 1500, 1425 cm -1.

1 H NMR (DMSO-d 6) δ: 7.92-6.80 (m, 23H), 4.94 (6d, 2H), 3.83 (s, 3H); 13 C NMR (DMSO-d 6) δ: 163.53, 163.36, 160.28, 10 160.87, 154.04, 153.89, 152.76, 135.11, 134.79, 134.16, 133.68, 133.54, 130.53, 130.45, 130.35, 130.35, 130.21, 130.07, 118.02, 116.89, 116.18, 115.89, 115, 62, 115.32, 111.43, 111.39, 34.22, 28.88, 28.22.

Calcd. For Η35Η28ΒγΙΓ2Ν4Ρ: 15 C, 64.31; H, 4.32; N, 8.57 Found: C, 64.02; H, 4.37; N, 8.89.

Claims (5)

103886 A process for the preparation of an aldehyde of the formula: R 'R * ° night. In a substantially cis- (4R, 6S) form wherein R 9 and R 10 are both C 1-6 alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl; and R12 is hydrogen, C1-4 alkyl or a metal cation, characterized in that the ester of formula VII s * cr ^ G o λ ^ μλ is hydrolyzed (15) (a) wherein R7 and Re are independently hydrogen, C 1-6 alkyl or phenyl optionally substituted with one or two C 1-6 alkyl, halogen, C 1-4 alkoxy or trifluoromethyl; R 9 and R 10 are each C 1-6 alkyl or R 9 and R 10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, n is zero or 1; and R 11 is a hydrolyzable ester group to provide a compound of formula VIII wherein R 7, R 8, R 9, R 10 and n are as defined above; 43 103886 (b) divides its enantiomers with an acid of formula VIII to give a compound of formula IX -10 0 0 in substantially cis- (4R, 6S) form wherein R 7, R 8, R 9, R 10 and n are as defined above ; and 10 (c) oxidizing the acid of formula IX to form a compound of formula IIIb e 'R10 (TOO ykAA * »in a substantially cis- (4R, 6S) form wherein R9, R10 and R12 are as defined above and, if desired, converting the aldehyde of formula II Ib to the corresponding salt 20 or alkyl ester. Process according to Claim 1, characterized in that R 9 and R 10 are both methyl. A process according to claim 1, characterized in that R 9 and R 10 together with the carbon atom to which they are attached are cyclohexyl. Process according to claim 1, characterized in that R 7 is phenyl, R 8 is hydrogen and n is zero. .30 Process according to claim 1, characterized in that R 7 is phenyl, R 7 is hydrogen and n is 1. 103886