NO175636B - - Google Patents

Description

The present invention relates to hitherto unknown 6-formyl-1,3-dioxane-4-acetic acid compounds which are useful for the production of inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, and which therefore are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The present invention also relates to a previously unknown method for producing the compounds and intermediate products used in the method.

The hitherto unknown compounds according to the invention

has the formula

predominantly

cis-(4R,6S) form, where

R<9> and R10 are each <C>1-4alkyl, or R<9> and R1<0> together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, and

R<12> is hydrogen, C1-4 alkyl or a metal cation.

The compounds according to the invention are used for the production of antihypercholesterolemic agents with the formulas

where R<1> and R<4> are each independently hydrogen, halogen, C±_ 4alkyl, C1_4 alkoxy or trifluoromethyl, R<2>, R<3>, R<5> and R6 are each independently hydrogen, halogen . The present invention also relates to a method for producing a 6-formyl-1,3-dioxane-4-acetic acid compound with the formula

predominantly

cis (4R,6S) form,

where R<9> and R1<0> are each <C>1_4alkyl, or R<9> and R10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, and R<12> is hydrogen, C1_4alkyl or a metal cation, characterized in that one

a) hydrolyzes an ester with the formula

where R 7 and jj8 are each independently hydrogen, C 1-4 alkyl or phenyl, which is optionally substituted with one or two of the substituents C 1-4 alkyl, halogen, C 1-4 alkoxy or trifluoromethyl, R<9> and each is C<-j >^alkyl, or R<9> and R<10> together with the carbon atom to which they are attached is cyclopentyl, cyclohexyl or cycloheptyl, n is 0 or 1 and R<11> is a hydrolyzable ester group, to produce a compound with the formula where R', R<8>, r9 rIO and n have the above meaning, b) cleaves an acid of formula (VIII) to produce a compound of the formula

predominantly

cis (4R,6S) form,

where R 7, R<8>, R<9>, R<*0> and n have the above meaning, and

c) oxidizes an acid of formula (IX) to produce a compound of the formula

predominantly

cis (4R,6S) form.

where R<9>, R<10> and R<12> have the meaning stated above.

The invention also relates to a 6-substituted 1,3-dioxane-4-acetic acid compound for use in the purification of one of the compounds of formula (IIIb) indicated above, characterized in that it has the formula

in predominantly cis-(4R,6S) form, where

R<7> and R<8> are each independently hydrogen, C^_^, alkyl or phenyl which is optionally substituted with one or two of the substituents C^_4alkyl, halogen, C^_4 alkoxy or trifluoromethyl,

R<9> and R10 are each C1-4alkyl, or R9 and R1<0> together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, and

n is 0 or 1.

The terms "<C>1-4 alkyl", "C 1-4 alkyl" and "<C>1-4 alkoxy" herein denote (unless otherwise indicated) unbranched or branched alkyl or alkoxy groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl or the like. These groups preferably contain 1-4 carbon atoms, especially 1 or 2 carbon atoms. The term "a cation for the preparation of a non-toxic pharmaceutically acceptable salt" herein includes non-toxic alkali metal salts, such as sodium, potassium, calcium or magnesium salts. The ammonium salt and salts with non-toxic amines, such as trialkylamines, dibenzylamine, pyridine, N-methylmorpholine, N-methylpiperidine and other amines which are used for the preparation of salts of carboxylic acids. Unless otherwise indicated, the term "a hydrolyzable ester group" as used herein includes an ester group that is physiologically acceptable and hydrolyzable under physiological conditions, such as C 1-4 alkyl» phenylmethyl or pivaloyloxymethyl.

In the compounds of formula (IIIb), R<9> and R<1>^ are each preferably methyl, or R<9> and R<1>^ together with the carbon atom to which they are attached, are cyclohexyl. R<12> is preferably hydrogen, methyl or a metal cation, especially lithium. The cis-(4R,6S) isomer of the compounds of formula (IIIb) is the most preferred.

The antihypercholesterolemic compounds of formula (I) can be prepared by various methods and preferably by using the intermediates of formula

essentially in the cis(4R, 6S) form,

where R<9>, RIO Cg R-^2 have the meaning given above. According to the present invention is thus provided

a method for producing the intermediate products of formula (Illb).

The compounds of formula (IIIb) can be prepared by reacting an aldehyde of formula (IV) with an ester of acetoacetic acid and then reacting a ketone or ketal with a compound of formula (VI) followed by hydrolysis of the resulting 1,3-dioxane with formula (VII) and optionally dissolve the acid of formula (VIII), as shown in reaction scheme 1. In reaction scheme 1, R<7> and R<8> are each independently hydrogen, C 1-4 alkyl or phenyl, which are optionally substituted with one or two of the substituents C 1-4 alkyl, halogen, C 1-4 alkoxy or trifluoromethyl, rH is a hydrolysable ester group, n is 0 or 1, and R<9> and R<9> have the meaning given above. The keto ester of formula (V) can be prepared by reacting an ester of acetoacetic acid with an aldehyde of formula (IV) by a method known in the art in an inert organic solvent, such as tetrahydrofuran, at temperatures from approx. 0°C to approx. -78° C in the presence of a base such as sodium hydride, lithium diisopropylamide or n-butyllithium.

The starting materials of formula (IV), where n is 0 or 1, are known, or can be easily prepared by known methods. The starting materials of formula (IV), where n is 1, can also be prepared by reacting the compounds of formula (IV), where n is 0, with Wittig reagents, such as triphenylphosphoranylidene acetaldehyde, and by other methods known in the art. It is obvious to the person skilled in the art that the relative configuration of the double bond (n=0) or double bonds (n=1) in the starting materials of formula (IV) can be trans, cis or mixtures thereof. The relative amounts of each geometric isomer (E) or (Z) are determined by the commercial availability or by the reaction conditions used in the preparation. In a specific example described herein, a mixture containing mostly the trans (E) isomer is used. Although a small percentage of the other isomer may be present in the reactions shown in reaction scheme 1, it is obvious to the person skilled in the art that the relative amount of isomers is not critical, as the double bond is oxidized and thereby removed in the ozonolysis reaction.

The keto ester of formula (V) can be reduced to the dihydroxy ester of formula (VI) by reduction of the ketone group with reducing agents known in the art. The reduction is preferably carried out in a stereospecific manner by a two-stage stereospecific reduction in order to maximize the production of the preferred erythroisomer of the dihydroxyester of formula (VI). The stereospecific reduction is carried out with trisubstituted alkylboranes, preferably triethylborane or tri-n-butylborane or alkoxydialkylboranes, preferably methoxydiethylborane or ethoxydiethylborane [Tetrahedron Letters, 28, 155 (1987)] at a temperature from approx. -70°C to ambient temperature. The complex that is produced is then reduced with sodium borohydride at a temperature from approx. -50°C to approx. -78°C in an inert organic solvent, such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, preferably tetrahydrofuran. The reduction is then terminated by the addition of methanol with or without the addition of aqueous hydrogen peroxide and a buffer agent. Some of the compounds of formula (VI) are known, and are described in US Patent Nos. 4,248,889 and 4,650,890.

The compounds of formula (VII) can be prepared from the compounds of formula (VI) by reacting a ketone, such as 2-propanone, 3-pentanone, cyclopentanone or cyclohexanone in a suitable inert organic solvent, e.g. toluene, benzene or xylene at temperatures from approx. 20° C to the cooling temperature of the solvent used, in the presence of a small amount of organic acid, mineral acid or resin acid, e.g. p-toluenesulfonic acid or sulfuric acid and possibly remove the water that forms with a desiccant, e.g., Na2SO4, MgSO4 and molecular sieves or by azeotropic removal with a Dean-Stark trap or a similar device. The reaction of a compound of formula (VI) with a ketone can also be carried out without a solvent. Alternatively, the reaction of compounds of formula (VII) described above can be carried out with a ketal, such as 2,2-dimethoxypropane, 1,1-dimethoxycyclohexane and the like.

Cis-(4R,6S) aldehydes of formula (IIIb) can be prepared from the corresponding racemic acid of formula (VIII) by conventional cleavage methods, 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 (IS,2R)-ephedrine or α-methylbenzylamine, is separated and the separated, dissolved salt is converted into a compound of formula (Illb).

The salt-forming agent is preferably (IS,2R)-ephedrine and the separation method is fractional crystallization. The cleavage can be carried out in an inert organic solvent, and preferably in a mixture of hydrocarbon-alcohol solvent, e.g. hexanemethanol mixture, where the dissolved salt can be crystallized from the solution. If desired, the acid of formula (IIIb) can be converted into a salt, where R<12> is a metal cation, or into a hydrolysable ester group where R12 is C^_4<a>lkyl.

The preferred antihypercholesterolemic compounds of formula (I) can be prepared from a compound of formula (Illb) by those in US Patent Application No. 018,542, DK Patent Application No. 972/88, US Patent Application No. 018,558 and DK Patent Application No. 973/88 described methods. Use of chiral aldehydes of formula (Illb) is shown in reaction core 2. In reaction core 2, R<1>, R<2>, R3f R<4>, R5, R6, R9, R10 and R<12> have the above indicated meaning, and Z is where R<13> is C 1-4 alkyl, R 4> is phenyl, which is unsubstituted or substituted with one or two C 1-4 alkyl or chloro substituents, and X is bromine, chlorine or iodo. The phosphonium salt of formula (X) and the phosphonate of formula (X) are described herein in US Patent Application No. 018,558 and DK Patent Application No. 973/88. The reaction of a compound of formula (X) with a compound of formula (IIIb) to produce a compound of formula (XII), respectively, where R<*2> is C 14 alkyl, can be carried out in an inert organic solvent, such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a strong base, such as n-butyllithium at a temperature from about -50°C to approx. -78°C. When the reaction of a compound of formula (X) is carried out with a compound of formula (Illb), where R<12> is hydrogen, it is preferred to use two equivalents of a strong base, such as n-butyllithium. Alternatively, the salt of a compound of formula (IIIb) can be prepared, which is then treated with a compound of formula (X) and a strong base. The addition methods, salt formation methods and ylide production are known to the person skilled in the art. The tetrazole compounds of formula (XII) can be easily deprotected by known methods, such as a mild acid, e.g. 0.2 N HCl and 0.5 N HCl in an inert organic solvent, such as tetrahydrofuran, to prepare the (3R, 5S) compounds of formula (Ib).

According to the present invention, the compounds of formula (IIlb) have the structure

substantially in the cis (4R,6S) form,

where R<9> and R<1>^ are each C-1-4 alkyl, or R<9> and R10 together with the carbon atom to which they are attached is cyclohexyl, and R<12> is hydrogen, C-1-2 alkyl or a metal cation.

According to the present invention, the compounds of formula (IX) have the structure

substantially in the cis (4R,6S) form,

wherein R<7> and R<8> are each independently hydrogen, C1-6 alkyl or phenyl, R<9> and R<*0> are each C1-6 alkyl or R9 and R1^ together with the carbon atom which they is attached to is cyclohexyl, and n is 0 or 1.

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 with 2,2-dimethoxypropane (20 mL) and a catalytic amount of p -toluenesulfonic acid for 16 hours. The solution was partitioned between diethyl ether and a dilute aqueous sodium bicarbonate solution. The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give a yellow solid. After recrystallization from isopropyl ether, 1.70 g (62$) of the title compound was obtained as a white solid, m.p. 84-86, 5°C.

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

3 H-NMR (CDCl 3 ) S : 7.37-7.19 (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, m).

Analysis for C17<H>22<O>4:

Calculated: C: 70.32$, H: 7.63$.

Found: C: 70.24$, H: 7.69$.

EXAMPLE 2

Cis- 2. 2- dimethyl- 6-( 2- phenylethenyl)- 1. 3- dioxane- 4- 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 to reflux for 45 min. After evaporation under reduced pressure, the aqueous solution was washed once 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, m.p. 153-155°C.

1-H-NME (CDCl3) S: 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), 1.54 (3H, s), 1.46 (3H, s), 1.50-1.36 (1H, m).

Analysis for Cifc<H>go<*>^<1>

Calculated: C: 69.54$, H: 7.30$

Found: C: 69.20$, H: 7.33$.

EXAMPLE 3

Cleavage of cis- 2. 2- dimethyl- 6-( 2- phenylethenyl)- 1. 3- dioxane-4- acetic acid

The racemic cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid (0.31 g, 1.1 mmol) (prepared in Example 2), was dissolved in a boiling hexane/ethanol solution containing (1,2R)-ephedrine (0.2 g, 1.1 mmol). The resulting solution was very slowly brought to room temperature to obtain 0.21 g (41.4%) of a colorless chiral salt (use of diastereomerically pure seed crystal is recommended during the resolution) m.p. 170-171°C.

The chiral acid was liberated by acidic workup (as described in Example 4) and its enantiomeric purity was determined to be 100% by 1 H-NMR using L-phenyltrifluoromethylcarbinol as a chiral solvent.

[a]g<5> = +5.45° (c = CHCl 3 ).

EXAMPLE 4

Cis-(4R.6S)-2.2-dimethyl-6-formyl-1.3-dioxane-4-acetic acid

The cleaved 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 0.5 N HCl (30 mL) and diethyl ether. The ether phase 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 the solution at -78°C, until deep blue coloration. Excess ozone was removed by purging with nitrogen and the ozonide formed was decomposed by adding CH 3 SCH 3 (5 ml) and heating the solution to room temperature and standing for 16 hours. The solution was concentrated under reduced pressure and the residue was dissolved in isoamyl ether (ca. 100 mL). Benzaldehyde formed during the ozonolysis was removed azeotropically with isoamyl ether under reduced pressure to afford the title compound.

<i>H-NMR (CDCl 3 ) δ : 9.57 (1H, s), 4.40-4.30 (2E, m), 2.60 (1H, dd, J = 16.0, 7.0 Hz), 2.49 (1H, dd, J = 16.0, 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

Cis-(4R.6S)-6-f4. 4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1.3-butadiene-2.2-dimethyl-1.3-dioxan-4-acetic acid

The crude chiral acid prepared in Example 4 was dissolved in dry THF (50 mL) and the resulting solution was transferred to a 250 mL three-necked flask purged with nitrogen and fitted with a mechanical stirrer. After vigorous stirring of the solution and cooling to -78°C, n-BuLi (2.5 M in hexane, 5.96 mL) was added dropwise. At the end of the addition, the solution became a suspension of a white solid-like gel.

A separate flask containing dimethyl-[3,3-bis-(4-fluoro-phenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl]phosphonate (6.2 g, 14.7 mmol) (prepared in Example 5) in THF (50 mL) was cooled under a nitrogen atmosphere to -78°C and n-BuLi (2.5 M in hexane, 5.96 mL) was slowly added. The resulting red-brown solution was stirred for 15 minutes at -78° C. The phosphonate anion solution was transferred through a double-ended needle to the above vigorously stirred suspension at -78° C. containing the lithium salt of the chiral acid. After addition, the resulting brown solution stirred for 30 min at -78°C and 16 h at room temperature. The THF solution was partitioned between 0.5 N HCl and ethyl acetate. The organic phase was washed with brine (2x), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was chromatographed on silica gel (66:33:1/diethyl ether:hexane:acetic acid) to provide 3.80 g (51.6% overall yield from the original ephedrine salt, toluene was used for a zeotropic removal of the residual acetic acid) of the title compound as a yellow foam. [a]<B5> = +106.1° c=2.23, CHC13).

<1->H-NMR (CDCl3) S: 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 (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), 1.62-157 (1H, m), 1.46 ( 3H, s), 1.33, (3H, s), 1.30-1.20 (1H, m).

EXAMPLE 6 (Intermediate)

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

To a cold (-30°C) solution of methyl acetoacetate (41.5 g, 357 mmol) in THF (500 mL) was added lithium diisopropylamide (476 mL, 1.5 M 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 room temperature. The solution was concentrated under reduced pressure and the remaining syrup was partitioned between 1N HCl and ethyl acetate. The organic phase was washed with brine (2x), dried (Na 2 SO 4 ) and concentrated. The residue was purified by chromatography on silica gel (diethyl ether:hexane/2:1) to provide 18.5 g (24.4%) of the title compound as an oil.

<i>H-NMR for (E) (E) isomer (200 MHz, CDCl 3 ) S; 6.3 (1H, dd, J = 14.7, 11.9 Hz), 6.02 (1H, dd, J = 14.7, 11.9 Hz), 5.75 (1H,

EXAMPLE 7 (intermediate)

Methyl- 3. 5- dihydroxy- 6. 8- decadienoate

To a cold (-15°C) solution of methyl 3-hydroxy-5-oxo-6,8-decadienoate (18.5 g, 86.9 mmol) in THF (300 mL) was added triethylborane (1 M in THF , 113 mL, 113 mmol) was added, and the solution was stirred for 20 minutes. After cooling the mixture to -78°C, NaBH 4 (6 g, 159 mmol) and methanol (37.5 mL) were added. The solution was vigorously stirred for 30 minutes at -78°C and at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate. The organic phase was dried (Na 2 SO 4 ) and concentrated. The residue was purified by silica gel chromatography (diethyl ether hexane, 3:1) to provide 7.95 g (42.7 g) of the title compound as a yellow oil.

1-H-NMR for (E) (E) isomer (360 MHz, CDCl3) S: 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), 3.69 (3H, s) 2.60-2.42 (2H, m), 1, 72 (3H, d, J = 7.0 Hz), 1.74-1.57 (2H, m).

EXAMPLE 8

Methyl cis-4-(1.3- pentadienvl )-1.5- dioxasplrof 5 . 5~ lundecan-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 h at room temperature. The yellow solution was directly applied to a silica gel column and the product was eluted with diethyl ether:hexane (1:4). The appropriate fractions were combined to provide 3.52 g (33.6$) of the title compound as a colorless oil.

<3->H-NMR for (E) (E) isomer (360 MHz, CDCl 3 ) S: 6.16 (1H, dd, J = 15.1, 10.6 Hz), 6.00 (1H, dd , J = 15.1, 10.6 Hz), 5.71-5.65 (1H, dd, J = 15.1, 6.5 Hz), 5.47 (1H, dd, J = 15.1 , 6.4 Hz), 4.44-4.39 (1H, m), 4.35-4.30 (1H, m), 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 (12 H, m), 1.72 ( 3H, d, J = 6.5 Hz).

Analysis for C17<H>26<O>4:

Calculated: C: 69.36$, H: 8.90$

Found: C: 69.59$, H: 9.16$.

EXAMPLE 9

Cis- 4-( l . 3- pentadienyl 1- 1 . 5- dioxaspiror5. 51 undecane- 2-acetic acid

Methyl 4-(1,3-pentadienyl)-1,5-dioxaspiro[5,5]undecane-2-acetate (3.5 g, 12.4 mmol) was heated to reflux in a solution of 1 N NaOH ( 13 ml) and methanol (26 ml). Methanol was removed under reduced pressure and the remaining aqueous solution was acidified with 1N HCl and extracted with diethyl ether. The organic phase was dried (Na 2 SO 4 ) and concentrated. The remaining solid was recrystallized from ethyl acetate/hexane to provide 2.0 g (55.9 g) of the title compound as a colorless solid, m.p. 144-146.5°C.

<1->H-NMR (360 MHz, CDCl 3 ) S: 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 (12 H, m), 1.73 (3H, d, J = 7.7 Hz).

Analysis for C15H24<O>4<:>

Calculated: C: 68.54$, H: 8.62$.

Found: C: 68.36$, H: 8.55$.

EXAMPLE 10

Methyl- 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 1) 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 and then dimethyl sulphide was added and the temperature rose to room temperature. The reaction was evaporated in vacuo and the residual oil was purified by chromatography on silica gel eluting with diethyletherhexane (3:1) to provide the title compound.

^H-NMR (360 MHz, CDCl3) S: 9.53 (1H, s), 4.40-4.23 (2H, m), 3.69 (3H, s), 2.53 (1H, dd , J = 15.8, 7.02 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).

Claims (13)

1. 6-formyl-1,3-dioxane-4-acetic acid compound, characterized in that it has the formula predominantly cis-(4R,6S) form, where R<9> and R1<0> are each C1-4alkyl, or R9 and R10 together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, and R<12> is hydrogen, C1-4 alkyl or a metal cation. 2. Compound according to claim 1, characterized in that R9 and R1<0> are each methyl, and R<1>2 is hydrogen, C1_4~alkyl or a metal cation. 3. Compound according to claim 2, characterized in that R<12> is hydrogen or a metal cation, the cation being lithium. 4. Compound according to claim 1, characterized in that R<9> and R<10>, together with the carbon atom to which they are attached, is cyclohexyl, and R<12> is hydrogen, C1-6 alkyl or a metal cation. 5. Compound according to claim 4, characterized in that R<12> is hydrogen or a metal cation, the cation being lithium. 6. Process for the preparation of a 6-formyl-1,3-dioxane-4-acetic acid compound of the formula predominantly cis (4R,6S) form, where R<9> and R1<0> are each C-L_4<a>lkyl, or R9 and together with the carbon atom to which they are attached, is cyclopentyl, cyclohexyl or cycloheptyl, and R<*2> is hydrogen, Ci_4 alkyl or a metal cation, characterized in that one a) hydrolyzes an ester with the formula where R<7> and R<8> are each independently hydrogen, C 1-4 alkyl or phenyl, which is optionally substituted with one or two of the substituents C 1-4 alkyl, halogen, C 1-4 alkoxy or trifluoromethyl, R 9 and R 10 is each C 1-4 alkyl, or R<9> and r<!>° together with the carbon atom to which they are attached is cyclopentyl, cyclohexyl or cycloheptyl, n is 0 or 1 and r<11> is a hydrolyzable ester group , for the preparation of a compound of the formula where R<7>, R<8>, R<9>, R<*0> and n have the above meaning, b) cleaves an acid of formula (VIII) for production of a compound with the formula predominantly cis (4R,6S) form, where R<7>, R<8>, R<9>, R<10> and n have the above meaning, and c) oxidise an acid of formula (IX) to produce a connection with the formula predominantly cis (4R,6S) form. where R<9>, RIO and R-^-2 have the above-mentioned meaning. 7. Process according to claim 6, characterized in that it comprises that R<9> and R<10> are each methyl, or R<9> and R<10> together with the carbon atom to which they are attached are cyclohexyl. 8. Method according to claim 6, characterized in that it comprises R<7> is phenyl, R<8> is hydrogen and n is 0, or R<7> is methyl, R<8> is hydrogen and n is 1. 9. 6-substituted 1,3-dioxane-4-acetic acid compound for use in the preparation of the compound of formula (Illb) according to claim 1, characterized in that it has the formula in predominantly cis-(4R,6S) form, where R<7> and R<8> are each independently hydrogen, C1-6 alkyl or phenyl which is optionally substituted with one or two of the substituents C1-6 alkyl, halogen, C1-6 alkoxy or trifluoromethyl, R<9> and R1<0> are each <C>1_4alkyl, or R<9> and R1<0> together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl, and n is 0 or 1. 10. Compound according to claim 9, characterized in that R<7> and R<8> are each independently C-1-4 alkyl or phenyl, n is 0, and R<9> and R<1>0 are each C-1-4 alkyl , or R<9 >and r<!0> together with the carbon atom to which they are attached is cyclopentyl, cyclohexyl or cycloheptyl. 11. Compound according to claim 10, characterized in that R<7> is phenyl, R<8> is hydrogen, n is 0, and R<9> and R10 are each methyl. 12. Compound according to claim 9, characterized in that R<7> and R<8> are each independently C^_4alkyl or phenyl, n is 1, and R<9> and R10 are each C^_4alkyl, or R<9 > and R<10> together with the carbon atom to which they are attached is cyclopentyl, cyclohexyl or cycloheptyl. 13. Compound according to claim 12, characterized in that R<7> is methyl, n is 1 and R<9> and R^<O> together with the carbon atom to which they are attached is cyclohexyl.