DD259864A5 - PROCESS FOR PREPARING A 1,3-DIOXANETHER - Google Patents

Abstract

According to the invention, novel 1,3-dioxane ethers of formula I are prepared in which R1 comprises alkyl, cycloalkyl, phenyl and phenylalkyl, R2 and R3 represent hydrogen and alkyl, n is 1 or 2, m is 2, 3 or 4, p is the same Z is zero, 1 or 2 and Z is carboxy or 1 (H) -tetrazol-5-yl, and pharmaceutically acceptable salts thereof, for use in conjunction with their pharmaceutical compositions for the treatment of certain lung and / or vascular diseases.

Description

For this 2 pages formulas

Field of application of the invention

The invention relates to a process for the preparation of novel 1,3-dioxane ethers, and more particularly to novel (2-alkoxyalkyl and 2-aryloxyalkyl-4-phenyl-1,3-dioxan-5-yl) -alkenoic acids and related compounds containing one or more counteract several effects of thromboxane A2 (hereinafter referred to as "TXA ₂ ") and which are valuable as therapeutic agents.

Characteristics of the known prior art

It is known that TXA _{2 is} a potent platelet aggregation agent and a potent vasoconstrictor. TXA ₂ is also a strong constrictor for the smooth bronchial and tracheal muscle. TXA ₂ can therefore be used for a wide variety of disease states, for example, in ischemic heart diseases such as myocardial infarction, angina, cerebral vascular diseases such as transient blood vacuity in the brain, migraine and stroke, peripheral vascular diseases such as arteriosclerosis, microangiopathy, hypertension and blood coagulation errors due to impaired lipid balance, and lung diseases such as pulmonary embolism, bronchial asthma, bronchitis, pneumonia, respiratory distress and emphysema. Therefore, compounds which counteract the effects of TXA _{2 are} expected to have therapeutic value in preventing or treating one or more of the above-mentioned diseases or other pathological conditions in which the effects of TXA ₃ are to be suppressed. It is known from EU-PA No.94239 that certain 4-phenyl-1,3-dioxan-5-ylalkanoic acids have TXA ₂ antagonist properties.

Object of the invention

The aim of the invention is to provide novel compounds which have strong TXA ₂ antagonist properties.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, a 1,3-dioxane ether of the formula I shown below is prepared in which R ^{1 is} (1-6C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkyl- (1-4C) alkyl, phenyl or phenyl (1-4C) alkyl, the latter two optionally bearing one or two substituents which may be selected from halogen, Ϊ-Ί-4C) alkyl, (1-4C) alkoxy, hydroxy, trifluoromethyl, nitro and cyano; R ² and R ^{3 are} independently hydrogen or (1-4C) alkyl or together form (3-6C) polymethylene optionally bearing one or two (1-4C) alkyl substituents; η is 1 or 2; m is 2, 3 or 4; ρ is zero, 1 or 2; and Z is carboxy or 1 (H) -tetrazol-5-yl; and the groups at positions 2,4 and 5 of the dioxane ring have cis-relative stereochemistry, or a pharmaceutically-acceptable salt thereof. Although a certain relative configuration is shown in the chemical formula shown later, it should be emphasized that this may not necessarily be the absolute configuration.

The compounds of formula I contain at least three asymmetric carbon atoms, and they may exist and be isolated in racemic and optically active forms. It is emphasized that the invention encompasses any racemic or optically active form or mixtures thereof which may counteract one or more effects of TXA ₂ , it being well known in the art how to prepare individual optical isomers (for example by synthesis from optically active precursors or resolution of a racemic form), or how the TXA ₂ antagonist properties are determined using standard tests described later.

A preferred value for η is 1 and for m is 2 or 3.

A particular group for R ¹ when it is (1-6C) alkyl is, for example, methyl, ethyl, propyl or butyl; when it is (3-8C) cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; when it is (3-8C) cycloalkyl- (1-4C) alkyl, for example cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl; and when it is phenyl (1-4C) alkyl, for example, benzyl or 2-phenylethyl.

A particular group for R ² or R ³ when it is (1-4C) alkyl is, for example, methyl or ethyl.

In general, it is preferred that R ² and R ^{3 are} both alkyl and together they have up to 6 carbon atoms.

A particular group for an optical (1-4C) alkyl substituent when R ² and R ³ (3-6C) form polymethylene (for example, trimethylene or tetramethylene) is, for example, methyl.

Certain groups for optical substituents that may be present as part of R ¹ when it is phenyl or

Phenyl (1-4C) alkyl, are, for example:.

for halogen: fluorine, chlorine and bromine;

for (1-4C) alkyl: methyl or ethyl; and

for (1-4C) alkoxy: methoxy or ethoxy.

A preferred group of compounds of the invention of particular interest include those [2,4,5-cis] dioxane derivatives of formula II wherein R ^{5 is} (1-4C) alkyl (such as methyl, ethyl or propyl), (3 -8C) cycloalkyl (such as cyclopentyl or cyclohexyl) or phenyl, the latter optionally being a substituent selected from halo, (1-4C) alkyl (such as methyl), (1-4C) alkoxy (such as methoxy), nitro and cyano; q is 2 or 3; R ⁶ and R ^{7 are} independently hydrogen or methyl; and 2 is carboxy or 1 (H (-Tetrazol-5-yl; and the pharmaceutically acceptable salts thereof.

A preferred group for Z is, for example, carboxy.

A particularly preferred value for q is 2.

Specific compounds of the invention are described in the accompanying examples. Of particular interest, however, are two compounds, namely the carboxylic acids described in Examples 6 and 7 or a

pharmaceutically acceptable salt thereof. :

For example, certain pharmaceutically acceptable salts of compounds of formula I are lithium, sodium, potassium, magnesium and calcium salts, aluminum and ammonium salts, and salts with organic amines and quaternary bases which form physiologically acceptable cations, such as alkali metal and alkaline earth metal salts Salts with methylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, N-methylglucamine, tetramethylammonium hydroxide and benzyltrimethylammonium hydroxide.

The compounds of formula I may be prepared by conventional methods of organic chemistry known in the art for the preparation of structurally analogous compounds. Such processes are regarded as a further aspect of the invention and are illustrated by the following processes, in which R ¹ , R ² , R ³ , R ⁴ , Z, n, m and ρ have one of the meanings explained above:

(a) An aldehyde of formula III is reacted with a Wittig reagent of formula IVa or IVb wherein R 'is (1-6C) alkyl or aryl (especially phenyl) and M ^{+ is} a cation, for example an alkali metal cation as is the lithium, sodium or potassium cation. The process generally produces predominantly the desired compounds of formula I in which the substituents adjacent to the double bond have cis-relative stereochemistry, ie, the "Z" isomer All analogous compounds having trans-relative stereochemistry around the vinyl group can be used a conventional separation method, for example by chromatography or crystallization, are removed.

The process is best carried out in a suitable solvent or diluent, for example, an aromatic solvent of benzene, toluene or chlorobenzene, an ether such as 1,2-dimethoxyethane, t-butylmethyl ether, dibutyl ether or tetrahydrofuran, in dimethyl sulfoxide or tetramethylene sulfone or in a mixture of one or more such solvents or diluents. The process generally proceeds in a zone in the range, for example -80 ⁰ C to 40 ⁰ C temperature, but is best performed at or near room temperature, for example in the range of 0 to 35 ° C.

(b) For a compound of formula I wherein Z 1 is (H) -tetrazol-5-yl, a nitrile of formula V is reacted with an azide.

A particularly suitable azide is, for example, an alkali metal azide such as sodium or calcium azide, preferably together with an ammonium halide, for example ammonium chloride, ammonium bromide or triethylammonium chloride. The process is preferably carried out in a suitable polar solvent, for example Ν, Ν-dimethylformamide or N-methylpyrrolidone, and most preferably at a temperature in the range of for example 50 to 160 ^° C.

(c) From a phenol derivative of the formula IV wherein R "is (1-6C) alkyl (such as methyl or ethyl), acyl (such as acetyl, benzoyl, methanesulfonyl or p-toluenesulfonyl) allyl, tetrahydropyran-2-yl or trimethylsilyl, the The exact conditions for the protection distance depend on the nature of the protective group R ". For example, when it is methyl or ethyl, the deprotection may be by heating with sodium thioethoxide in a suitable solvent (such as Ν, Ν-dimethylformamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidinone ) at a temperature in the range of for example 60 to 160 ⁰ C temperature. Alternatively, an ethyl or methyl protecting group may (such as tetrahydrofuran or t-butyl methyl ether) may be removed at a, for example, in the range from 0 to 6O ⁰ C lying temperature by reaction with lithium diphenylphosphide in a suitable solvent. When the protecting group is acyl, it may (such as sodium or potassium hydroxide) in a suitable aqueous solvent such as an aqueous ([1-4C] alkanol), for example by hydrolysis in the presence of a base located at a in the range, for example 0 to 6O ⁰ C Temperature are removed. For example, when the protecting group is allyl or tetrahydropyran-2-yl, it may be removed by treatment with strong acid (such as trifluoroacetic acid), and if it is trimethylsilyl, it may be removed by reaction with aqueous tetrabutylammonium fluoride or sodium fluoride using a conventional procedure become.

(d) An erythro-diol derivative of formula VII wherein one of Q ¹ and Q ^{2 is} hydrogen and the other is hydrogen or a group of the formula -CRaRb.OH (wherein Ra and Rb are the same or different [1-4C] alkyl ), is reacted with an aldehyde of Fornael VIII, wherein R ¹ , R ² , R ³ and ρ have the meanings explained above, or with an acetal, hemiacetal or hydrate thereof.

The aldehyde of formula VIII (or its hydrate or its acetal or hemiacetal with a [1-4C] alkanol (such as methanol or ethanol) is generally used in excess.

The reaction is generally carried out in the presence of an acid catalyst ₍ such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid or an acidic resin, preferably in the presence of a suitable solvent or diluent, such as toluene, xylene or an ether, for example tetrahydrofuran, Dibutyl ether, methyl t-butyl ether or 1,2-dimethoxyethane, and carried out at a lying in the range, for example, 0 to 80 ⁰ C temperature.

Those starting materials of formula VII wherein Q ¹ and Q ^{2 are} both hydrogen can be obtained, for example, by mild acid-catalyzed hydrolysis or alcoholysis of the dioxane ring of a compound of formula IX wherein Ra and Rb are both alkyl, such as methyl or ethyl. The hydrolysis or alcoholysis is normally carried out at a temperature in the range of 10 to 8O ⁰ C using an aqueous mineral acid such as hydrochloric acid in an alkanol (such as ethanol or 2-propanol) or an ether (such as tetrahydrofuran) as a solvent.

-4- 2S9 864

In the starting materials of the formula VII wherein one of Q ¹ of Q ^{2 is} hydrogen and the other is a group of the formula CRaRb.OH are intermediates in the above-mentioned formation of the starting materials of formula VII, wherein Q ¹ and Q ² both are hydrogen. However, these intermediates are usually neither isolated nor characterized. Therefore, the invention also relates to a modification of process (d) which is in the reaction of a compound of formula IX wherein one of Ra and Rb is hydrogen, methyl or ethyl (preferably methyl or ethyl) and the other is methyl or ethyl an excess of a compound of formula VIII, or an acetal, hemiacetal or hydrate thereof, in the presence of an acid catalyst (such as one of the above), preferably in a range from for example 10 to 8O ⁰ C lying temperature and optionally in the presence of a suitable solvent or diluent (such as one of those listed above).

The starting materials contemplated for use in the above-discussed processes can be prepared by general organic chemistry procedures used to prepare structurally related compounds, such as described in, for example, EU-PA No. 94239.

The nitriles of the formula V can be obtained, for example, by substitution of the relevant YHd of the formula R ' ₃ P =CH · (CH ₂ ) _m ·CN for the ylide of formula IV in the Wittig reaction described in process (a) above. The protected phenol derivatives of Formula VI can be prepared, for example, by employing a process analogous to Process (a) above using a Formula III analogous aldehyde in which the phenolic group has been protected by the group R " of formula IX can be obtained by the use of methods analogous to those described in EU-PA No. 94239.

The required Wittig reagents of formulas IVa and IVb can be obtained by conventional methods, for example by treating the corresponding phosphonium halides with a strong base such as sodium hydride, lithium diisopropylamide, potassium t-butoxide or butyl lithium. They are generally formed in situ immediately prior to the condensation process (a) above.

It should be noted that the compounds of formula I wherein Z is carboxy may also be obtained by other conventional procedures well known in the art for the production of carboxylic acids, for example by base-catalyzed hydrolysis of the corresponding esters, for example the lower alkyl ester; using, for example, lithium or sodium hydroxide as the base. Such procedures are included in the invention.

When a salt of a compound of formula I is required, it is recovered by reaction with the appropriate base having a physiologically acceptable cation, or by any other conventional procedure.

When an optically active form of a compound of the formula I is required, one of the processes explained above is carried out using an optically active starting material. Alternatively, the racemic form of a compound of formula I may be reacted with an optically active form of an appropriate organic base, for example, ephedrine, Ν, Ν, Ν-trimethyl (i-phenylethyl) ammonium hydroxide or 1-phenylethylamine, followed by conventional resolution of the diastereomer Mixture of salts thus obtained is followed, for example, by fractional crystallization from an appropriate solvent, for example a (1-4C) alkanol, after which the optically active form of the compound of formula I is treated by treatment with acid using a conventional procedure , for example, by use of an aqueous mineral acid such as dilute hydrochloric acid, can be released.

Many of the intermediates herein are novel and are provided as further separate inventive subject matter. Certain intermediates of formula IV, especially those in which R "is methyl and m is 2, possess valuable TXA ₂ antagonist properties, and such compounds, along with their pharmaceutically acceptable salts, are provided as a further aspect of the invention.

As already mentioned above, the compounds of the formula I are antagonists for one or more effects of TXA ₂ , for example various of its effects on the platelets, the vascular system and / or the lung. The antagonism can be demonstrated in one or the other of the following standard tests:

(a) The striped model of the rabbit aorta proposed by Piper and Vane (Nature, 1969, 23, 29, 29-35) or the rat aorta strip model developed by Kennedy, et al. (Prostaglandins, 1982, 24, 676-689) using as agonist the U46619 known mimetic TXA ₂ -MiHeI is used (described by RLJones, et al., in "Chemistry, Biochemistry and Pharmacological Activity of Prostanoids", Edited by SM Roberts and F. Scheinmann, on page 211, Pergamon Press, 1979);

(b) a platelet aggregation assay based on that described by Born (Nature, 1962, 1994, 927-929) and comprising:

(i) aggregation of citrated platelet-rich human plasma by the addition of the mimetic TXA ₂ agent U46619 to produce a dose-response curve;

(ii) generating a dose-Reakti.ons curve for stimulated U46619 platelet aggregation in the presence of increasing amounts of test compound (generally in the range of 10 ^"5 M to 10"^"10 M), and (iii) calculating a K _B Value indicating the potency of TXA ₂ antagonism for the test compound, averaged over various concentrations from the calculated 50% reaction value for U46619 agglutination with and without test compound;

(c) a bronchoconstriction test in which the inhibition of bronchoconstriction by the test compound used in the Konzett-Rossler model with anesthetized guinea pigs (after the modification of Collier and James, Brit. J. Pharmacol., 1967, 30, 283-307) intravenous administration of the mimetic TXA ₂ agent U 46619, measured and comprising:

(i) obtaining a cumulative dose-response curve by U46619-induced bronchoconstriction by intravenous administration of constant volumes of increasing concentrations of U46619 (0.2 to 4pg / kg) in physiological saline solutions, and showing bronchoconstriction as the maximum of those which is theoretically achievable without supplying air to the test animal;

(ii) preparing a cumulative dose-response curve of U46619-induced bronchoconstriction at 30 minute intervals for a period of 3 hours after oral administration of the test compound; and (iii) calculating a dose ratio for the test compound (ie, the ratio of the concentration of U46619 required to cause a 50% bronchoconstriction with and without the test compound ₎ demonstrating the potency of TXA ₂ antagonism.

(d) The antagonism of the effects of TXA ₂ on the vasculature can be demonstrated, for example, in rats in the following manner:

Male rats (Alderley Park strain) are anesthetized with sodium pentobarbital and blood pressure is monitored at the carotid artery. The mimetic TXA ₂ agent U 46619 is administered intravenously via the jugular vein at 5 pg / kg to induce an increase in systolic blood pressure of 20 to 30 mm Hg (2640 to 3970 Pascal). The process is repeated twice to achieve the reproducibility of the reaction. A test compound is then administered either intravenously via the jugular vein or orally via cannula directly into the stomach, and the animal is challenged with U 46619 five minutes after administration of the test compound and then successively every 10 minutes until the hypertensive effect of U 46619 is no longer blocked. , ,

Further, the antagonism of the effects of TXA ₂ in vivo can be demonstrated, for example, by the effects of a test compound on platelet aggregation following administration of test compound to an experimental animal such as a rabbit, rat, guinea pig or dog is carried out using standard procedures similar to those described above under (a). However, when the aggregation of platelets is studied in dogs, it is necessary, a predetermined threshold concentration of the platelet aggregation agent adenosine diphosphate use (about 0.4 to 1.2 χ 10 ^"6 M) together with the mimetic TXA ₂ -MiHeI U46619zu.

By way of illustration, the compound described in Example 6 later on has a pA ₂ of 9.71 in rat aorta strands using procedure (a) and shows a K ₈ of 1.75 x 10 ^-8 M in procedure (b) above ,

In general, the compounds of formula I show significant TXA ₂ antagonist properties in one or more of the assays described above, ie, test (a) pA ₂ >6.0;

Test (b) K ₈ <5 χ 10 ~ ⁶ ; Test (c) Dose ratio> 5 at 200 pg / kg po In addition, compounds of Formula I may show significant activity in the rat blood pressure test and / or in one or more of the ex vivo platelet assays discussed above. Significant adverse effects could not be observed at the active dose levels in vivo.

As mentioned above, the compounds of formula I may be used in the therapy or prevention of diseases or adverse conditions in warm-blooded animals for which counteracting one or more effects of TXA _{2 is to be} achieved. In general, a compound of formula I for this purpose will be administered orally, rectally, intravenously, subcutaneously, intramuscularly or by inhalation so that a dose ranging, for example, from 0.01 to 5 mg / kg of body weight will be administered up to four times daily which will vary with the mode of administration, the severity of the condition, and the size and age of the patient to be treated.

The compounds of formula I will generally be administered in the form of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as defined above together with a pharmaceutically acceptable diluent or carrier! having. Such a composition constitutes a further feature of the invention and may be in a variety of dosage forms. It may be in the form of, for example, tablets, capsules, solutions or suspensions for oral administration; in the form of a suppository for rectal administration; in the form of a sterile solution or suspension for administration by intravenous or intramuscular injection; in the form of an aerosol or a spray solution or suspension for administration by inhalation; and in the form of a powder together with pharmaceutically acceptable inert solid diluents such as lactose for administration by insufflation.

The pharmaceutical compositions can be obtained by conventional methods using pharmaceutically acceptable diluents and carriers well known in the art. Tablets and capsules for oral administration may conveniently be made with an enteric coating containing, for example, cellulose acetate phthalate to minimize contact of the active ingredient of formula I with gastric acids.

The pharmaceutical compositions of the invention may also contain one or more agents already known to be of value in the diseases and conditions to be treated; For example, a known platelet aggregation inhibitor, hypolipidemic agent, hypotensive agent, beta adrenergic blocking agent, or vasodilator may also be advantageously present in a pharmaceutical composition of the invention used to treat a heart condition or a vascular disease. Similarly, for example, the presence of an anti-histamine, steroid (such as beclomethasone dipropionate), sodium cromoglycate, phosphodiesterase inhibitor, or a beta-adrenergic stimulant may be beneficial in a pharmaceutical composition of the invention intended for the treatment of a lung disease or condition.

Apart from their application in therapeutic medicine, the compounds of formula 1 are also useful as pharmacological tools in the development and standardization of test systems for evaluating the effects of TXA ₂ in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice as part of the research useful after new therapeutic means. The compounds of formula I, because of their TXArAntagonist properties, may also be used to help maintain the viability of blood and blood vessels (or parts thereof) in warm-blooded animals in which artificial extracorporeal circulation is required, for example, during limb or organ transplantation become. When used for such a purpose, a compound of formula I, or a physiologically acceptable salt thereof, will generally be administered to achieve, for example, a steady state concentration in the blood of 0.1 to 10 mg per liter ,

embodiment

The invention will now be illustrated by the following non-limiting examples, in which, unless otherwise stated:

(i) evaporating by rotary evaporation under vacuum; (ii) operations are carried out at room temperature, that is in the range of 18 ° C to 26 ° C;

(iii) flash column chromatography and medium pressure liquid chromatography (MPLC) on Merck Kieselgel 60 (Article 9385), following the procedure by UV absorption or thin layer chromatography on 0.25 mm silica gel plates 60F254 from Merck (Article 5715) ; these materials were purchased from E. Merck, Darmstadt, Federal Republic of Germany;

(iv) yields are given for illustration only and are not necessarily the maximum achievable;

(v) NMR spectra are normally determined at 200 MHz in CDCl ₃ , using tetramethylsilane (TMS) as the internal standard and plotting the data as chemical shifts (delta values) in parts per million relative to TMS, with the following Abbreviations used to denote major peaks: s, singlet; m, multiple «; t. triplet; b, wide; d, doublet; if a single value of the chemical shift is given for a multiplet (m), then this corresponds to the midpoint of the signals representing the multiple; and (vi) final products are isolated as racemates and characterized by NMR, microanalysis, mass spectroscopy and / or other standard methods.

example 1

A solution of 5 (Z) -7 - ([2,4,5-cis] -2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl) n-heptenoic acid (1.80 g) in dry 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (DMPU) (4ml) was added to a stirred solution of sodium thioethoxide (2.47g) in dry DMPU (50ml). at 85 ⁰ C under argon. The mixture was stirred for 2 hours, cooled to ambient temperature and poured into ice-water (150 ml). The aqueous mixture was washed with dichloromethane (2 × 75 ml), acidified to pH 4 with 2M hydrochloric acid and extracted with ether (3 × 100 ml). These extracts were washed successively with water (3 x 50 ml) and saturated brine (50 ml), then dried (MgSO ₄ ) and evaporated. By. Flash chromatography of the residue, eluting with toluene / ethyl acetate / acetic acid (75: 25: 2V / V), gave SlZJ ^ -issAS-cisJA-o-hydroxyphenyW-methoxyethyl-IS-dioxane-S-yljheptenoic acid as a light yellow oil ( 1.01 g); NMR: 1.63 (3H, m), 1.87 (1H, m), 2.00 (2H, qJ = 7Hz), 2.28 (2H, tJ = 7Hz), 2.62 (1 H, m), 3.45 (3H, s), 3.60 (2H, m), 3.93 (1H, dmJ = 12Hz), 4.14 (1H, ddJ = 12.1 Hz), 4.94 (1H, tJ = 5Hz), 5.25 (1H, dJ = 2Hz), 5.34 (2H, m), 6.90 (3H, m), 7, 17 (1H, m); m / e 350 (M ⁺ ).

The required starting material was obtained as follows:

(i) A 5 (Z) -7- (2,2-dimethyl-4-o-methoxyphenyl-1,3-dioxan-cis-5-yl) heptenoic acid (10.0g), water (33ml) and 2M hydrochloric acid (0.5 ml) in tetrahydrofuran (THF) (267 ml) containing solution was heated for 2 hours with stirring at 60 ⁰ C to 7O ⁰ C. The solvent was then evaporated. The obtained residue was diluted with ether (350 ml). The mixture was washed with water (4 × 75 ml) followed by saturated brine (2 × 75 ml), dried (MgSO ₄ ) and evaporated. The recovered oil was purified by flash chromatography eluting with toluene / ethyl acetate / acetic acid (60: 40: 2 v / v) to give 5 (Z) -erythro-9-hydroxy-8-hydroxymethyl-9-o-methoxyphenyl 5-nonenoesäure as a colorless oil which slowly crystallized and solid (A) (8,40g), m.p., 79 ° C to 8O ⁰ C, NMR (400MHz): 1.66 (2H, m), 1, 90 (1H, m), 2.08 (3H, m), 2.32 (3H, m), 3.69 (2H, m), 3.82 (3H, s), 5.22 (1H , dJ = 4Hz), 5.37 (2H, m), 6.88 (1H, dJ = 8Hz), 6.98 (1H, tJ = 7Hz), 7.25 (1H, m ), 7.43 (1H, dd) J = 7.2Hz).

(ii) A solution containing A (7.70 g) and ethyl acetate (10 ml) in ether (25 ml) was stirred at 4 ° C with ice cold ethereal. Solution of diazomethane treated until yellowing remained. The solution was then treated with acetic acid (0.2 ml) and the solvent was removed in vacuo. The residual oil was purified by flash chromatography eluting with 45% v / v ethyl acetate / hexane to give methyl 5 (Z) -erythro-9-hydroxy-8-hydroxymethyl-9-omethoxyphenyl-5-nonenoate as a colorless oil (B ) (7.83g); NMR (400 MHz); 1.74 (2H, m), 1.89 (1H, m), 2.05 (3H, m), 2.30 (3H, m), 2.47 (1H, brs), 3.13 (1H, dJ = 4Hz), 3.66 (3H, s), 3.68 (2H, m), 3.84 (3H, s), 5.21 (1H, tJ = 4Hz), 5.37 (2H, m), 6.88 (1H, dJ = 7Hz), 6.99 (1H, tJ = 7Hz), 7.2 (1H, m), 7, 43 (1 H, dd J = 7.2Hz).

(iii) A stirred solution of C (3.0 g), p-toluenesulfonic acid (20mg) and 1,2,2-trimethoxyethane (10ml) was heated at 90 ^c C for 3 hours. The cooled reaction mixture was diluted with ether (50 mL) and washed sequentially with 5% M / V sodium bicarbonate solution (3 x 20 mL), water (10 mL) and saturated brine (10 mL), then dried (MgSO ₄ ) and evaporated. Flash chromatography of the residue eluting with 15% v / v ethyl acetate / hexane gave methyl SfZ ^ -i ^ AS-cisj-methoxymethyl-o-methoxyphenyl-i-dioxane-S-y-deaptenoate as a light yellow oil (D) (2 , 50g): NMR: 1.60 (3H, m), 1.83 (1H, m), 1.93 (2H, qJ = 7Hz), 2.22 (2H, tJ = 7Hz), 2 , 38 (1H, m), 3.46 (3H, s), 3.58 (2H, dJ = 4Hz), 3.65 (3H, s), 3.80 (3H, s), 3, 96 (1H, dmJ = 12Hz), 4.09 (1H, ddJ = 12.1Hz), 4.98 (1H, tJ = 4Hz), 5.22 (1H, dJ = 2Hz), 5.25 (2H, m), 6.83 (1H, brdJ = 7Hz), 6.96 (1H, brt J = 7Hz), 7.24 (1H, tdJ = 7.1 , 5Hz), 7.41 (1H, ddJ = 7.1.5Hz).

(iv) 2M potassium hydroxide solution (20ml) was added to a stirred solution of D (2.50g) in methanol (250ml). After 20 hours, water (400 ml) was added. The mixture was washed with ether (100 ml), then acidified to pH 4 with 2 M hydrochloric acid and extracted with more ether (3 × 150 ml). The extracts were washed with saturated brine (2 × 50 ml), dried (MgSO ₄ ) and evaporated. Flash chromatography of the residue eluting with toluene / ethyl acetate / acetic acid (75: 25: 0.2 v / v) gave 5 (Z) -7 - ([2,4,5-cis] -2-methoxymethyl-4-). omethoxyphenyl-1,3-dioxan-5-yl) heptenoic acid as a light yellow oil (2.05g); NMR: 1.60 (3H, m), 1.83 (1H, m), 1.97 (2H, m), 2.26 (2H, tJ = 7Hz), 2.43 (1H, m ), 3.46 (3H, s), 3.60 (2H, m), 3.80 (3H, s), 3.96 (1H, dmJ = 12Hz), 4.09 (1H, dd J = 12.1 Hz), 4.98 (1H, tJ = 5Hz), 5.23 (1H, dJ = 2Hz), 5.27 (2H, m), 6.84 (1H , dd J = 7.1 Hz), 6.97 (1 H, td J = 7.1 Hz), 7.23 (1 H, td J = 7.1.5 Hz), 7.40 (1 H, ddJ = 7.1.5Hz).

Example 2

A solution of 4 (Z) -6 - ([2,4,5-cis] -2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl) hexanoic acid (740 mg) in dry DMPU (5 mL) was added (in dry DMPU 25 ml) was added 1.008 g) at 85 ⁰ C under argon (to a stirred solution of sodium thioethoxide. After 3 hours at 85 ° C, the reaction mixture was cooled to ambient temperature and poured into ice-water (150 ml). The aqueous mixture was washed with dichloromethane (3 x 100 ml), acidified to pH 5 with 2 M hydrochloric acid and extracted with ether (3 x 40 ml). These extracts were washed successively with water (15 ml) and saturated brine (15 ml), then dried (MgSO ₄ ) and the solvent was evaporated. Flash chromatography of the residue eluting with toluene / ethyl acetate / acetic acid (70: 30: 0.2% v / v) gave 4 (Z) -6- [2,4,5-cis] -4-o-hydroxyphenyl-2 -methoxymethyl-1,3-dioxan-5-yl) -hexenoic acid as a yellow oil (329 mg) which slowly crystallized to give a solid with a melting point of 103-104 ° C; NMR: 1.72 (1H, m), 1.90 (1H, m), 2.33 (4H, m), 2.67 (1H, m), 3.44 (3H, s) .

3.59 (2H, dJ = 4Hz), 3.94 (1H, dmJ = 12Hz), 4.16 (1H, ddJ = 12.1Hz), 4.93 (1H, tJ = 4Hz), 5.26 (1H, dJ = 2Hz), 5.27 (1H, m), 5.43 (1H, m), 6.89 (3H, m), 7.16 (1 H, m); m / e 336 (M ⁺ )

 The required starting material was obtained as follows:

(i) A solution of (4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) acetaldehyde (15.8g) in dry THF (75ml) was added under argon to a stirred, the cooled solution of (3-carboxypropyl) triphenylphosphonium bromide (51.48 g) and potassium t-butoxide (26.88 g) in dry THF (400 ml). The mixture was stirred at 4 ° C for 15 minutes, then at ambient temperature for 1.5 hours and then poured into ice-water (1 liter). The recovered mixture was washed with 50% v / v ether / hexane (2 × 250 ml) to remove the bulk of neutral material. The aqueous phase was acidified to pH 5 with acetic acid and extracted with ether (4 × 300 ml). These extracts were washed successively with water (3 x 150 ml) and saturated brine (2 x 100 ml), then dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography eluting with toluene / ethyl acetate / acetic acid (80: 20: 2 v / v). The recovered solid was crystallized from 10% v / v ethyl acetate / hexane (250 ml) to give 4iZ) -6- (4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenoic acid (A) (13.0 g) melting point of 99-101 ⁰ C; NMR: 1.52 (3H, s), 1.54 (1H, m), 1.56 (3H, s), 1.80 (1H, m), 2.28 (4H, m), 2 , 49 (1 H, rn), 3.77 (1 H, dd J = 11.1 Hz), 3.82 (3H, s), 4.16 (1 H, dm J = 11 Hz), 5, 28 (2H, m), 5.45 (1H, dJ = 2Hz), 6.83 (1H, ddJ = 7.1Hz), 6.97 (1H, tdJ = 7.1Hz ), 7.22 (1 H, td J = 8.1 Hz), 7.48 {1 H, dm J = 8Hz).

(ii) A solution of A (4,20g) in a mixture of water (12 ml), 2M hydrochloric acid (0.5 ml) and THF (40 ml) was stirred and heated to 60 to 7O ⁰ C. After 2 hours, the mixture was cooled to ambient temperature and poured into water (100 ml). The aqueous mixture was extracted with ether (3 × 50 ml). The combined extracts were washed successively with water (2 × 40 ml) and saturated brine (40 ml), then dried (MgSO ₄ ) and evaporated to give 4 (Z) -erythro-8-hydroxy-7-hydroxymethyl-8-o -methoxyphenyl-4-octenoic acid as a colorless oil (B) to win (3.80g); NMR: 1.95 (1H, m) "2.11 (1H, m), 2.37 (5H, m), 3.67 (2H, m), 3.83 (3H, s), 4 , 84 (3H, br), 5.22 (1H, dJ = 4Hz), 5.38 (2H, m), 6.88 (1H, brdJ = 7Hz), 6.98 (1H, btJ) = 7Hz), 7.25 (1H, td J = -7.1.5Hz), 7.42 (1H, ddJ = 7.1.5Hz).

(iii) A solution of B (3.70g) in ether (65ml) was treated at ⁰ ° C to 4 ° C with an ice-cold ethereal solution of diazomethane until yellowing persisted. Then, acetic acid (0.2 ml) was added and the solvent was evaporated. Flash chromatography of the residue eluting with ethyl acetate / hexane (45:55 v / v) gave methyl 4 (Z) -erythro-8-hydroxy-hydroxymethyl-so-methoxyphenyl -octenoate as a colorless oil (C) (3.00g ); NMR: 1.90 (1H, m), 2.10 (1H, m), 2.36 (6H, m), 3.20 (1H, br), 3.66 (3H, s), 3 , 67 (2H, m), 3.83 (3H, s), 5.23 (1H, brtJ = 7Hz), 5.35 (2H, m), 6.87 (1H, brdJ = 8Hz), 6, 98 (1H, brt J = 7Hz), 7.24 (1H, tdJ = 8.2Hz), 7.45 (1H, ddJ = 7.2Hz).

(iv) A C (1.5 g), p-toluenesulfonic acid (10 mg) and 1,1,2-Trirnethoxyethan (5 ml) containing stirred solution was kept at 90 ^c C for 3 hours. The cooled reaction mixture was diluted with ether (50 ml) and washed successively with 5% M / V sodium bicarbonate solution (3 x 20 ml), water (10 ml) and saturated brine (10 ml), then dried (MgSO ₄ ) and evaporated. Flash chromatography of the residual oil eluting with ethyl acetate / hexane (15:85 v / v) gave methyl 4 (Z) -6 - ([2,4,5-cis] -2-methoxymethyl-4-o-methoxyphenyl-1 , 3-dioxan-5-yl) hexenoate as a light yellow oil (D) (865 mg); NMR: 1.60 (1H, m), 1.87 (1H, m), 2.24 (4H, m), 2.45 (1H, m), 3.44 (3H, s), 3.58 (2H, dJ = 4Hz), 3.64 (3H, s), 3.80 (3H, s), 3.96 (1H, dmJ = 12Hz), 4.08 (1H, ddJ = 12.1 Hz), 4.98 (1H, tJ = 4Hz), 5.23 (1H, dJ = 2Hz), 5.27 (2H, m), 6.83 (1H, brdJ = 7Hz), 6.96 (1H, tdJ = 7.1Hz), 7.23 (IH, tdJ = 7.1.5Hz), 7.42 (1H, ddJ = 7.1.5Hz) ,

(v) A stirred solution of D (865 mg) in methanol (70 ml) was hydrolyzed at ambient temperature by reaction with 2 M potassium hydroxide (7.0 ml) over a period of 4 hours. Using a similar further processing method as described in part (iv) of Example 1, 4iZ) - [2,4,5-cis] -2-methoxymethyl-4-omethoxyphenyl-1,3-dioxan-5-yl) hexane acid as a colorless oil (740 mg): NMR: 1.60 (1H, m), 1.88 (1H, m), 2.27 (4H, m), 2.48 (1H, m) ' , 3.44 (3H, s), 3.59 (2H, dJ = 4Hz), 3.80 (3H, s), 3.96 (1H, dmJ = 12Hz), 4.09 ( 1 H, dd J = 12.1 Hz), 4.93 (1 H, t J = 4 Hz), 5.23 (1 H, d J = 2 Hz), 5.29 (2H, m), 6, 83 (1H, brdJ = 7Hz), 6.96 (1H, tdJ = 7.1Hz), 7.23 (1H, tdJ = 7.1.5Hz), 7.42 (1 H, dd J = 7, 1.5Hz).

Example 3

A stirred solution of 4 (Z) -6 - ([2,4,5-cis] -2- [2-ethoxyethyl] -4-o-methoxyphenyl-1,3-dioxan-5-yl) hexanoic acid (A) (900mg) in dry THF (3ml) was treated at 4 ° C under argon with a solution of lithium diphenylphosphide (prepared from chlorodiphenylphosphine [1.59g] and lithium metal [202g] in dry THF [10m]). The mixture was stirred for 5 minutes at 4 ⁰ C, for 3 hours at 50 ⁰ C, then cooled to 10 ⁰ C and poured into ice water (50 ml). The aqueous mixture was washed with ether (2 × 20 ml), acidified to pH 5 with acetic acid and extracted with ether (3 × 30 ml). These extracts were washed successively with water (20 ml) and saturated brine (20 ml), then dried (MgSO ₄ ) and evaporated. Flash chromatography of the residue eluting with toluene / ethyl acetate / acetic acid (75: 25: 0.2V / V) gave 4 (Z) -6 - ([2,4,5-cis] -2- [2-ethoxyethyl] 4-o-hydroxyphenyl-1,3-dioxan-5-yl) -hexenoic acid as a light yellow oil (426 mg); NMR: 1.21 (3H, t J = 7Hz), 1.64 (1H, m), 1.88 (1H, m), 2.03 (2H, m), 2.33 (4H, m ), 2.66 (1H, m), 3.51 (2H, qJ = 7Hz), 3.60 (2H, m), 3.90 (1H, dmJ = 12Hz), 4.09 ( 1 H, dd J = 12.1.5 Hz), 4.92 (1 H, t J = 4.5 Hz), 5.20 (1 H, d J = 2 Hz), 5.28 (1 H, m), 5.43 (1H, m), 6.87 (3H, m), 7.17 (1H, tdJ = 7.1.5Hz), m / e (M ⁺ + NH ₄ ), 365 (M ⁺ + H).

The required starting material (A) was obtained by using an analogous method to that described in Example 2 in parts (iv) and (v). Thus, using the procedure of Example 2 (iv) of 1,1,3-triethoxypropane instead of 1,1,2-trimethoxyethane, methyl 4 (Z) -6 - ([2,4,5-cis] -2 - [2-ethoxyethyl] -4-omethoxyphenyl-1,3-dioxan-5-yl) hexenoate in 62% yield as a light yellow oil; NMR: 1.20 (3H, tJ = 7Hz), 1.59 (1H, m), 1.84 (1H, m), 2.04 (2H, m), 2.26 (4H, m) _/ 2.43 (1H, m), 3.49 (2H, qJ = 7Hz), 3.61 (2H, tJ = 7Hz), 3.64 (3H, s), 3.80 (3H , s), 3.92 (1H, dmJ = 12Hz), 4.02 (1H, ddJ = 12.1Hz), 4.92 (1H, tJ = 5Hz), 5.18 ( 1 H, d J = 2Hz), 5.25 (2H, m), 6.83 (1H, brd J = 7Hz), 6.97 (1H, ddJ = 7.1Hz), 7 , 23 (1 H, td J = 7.1.5Hz), 7.43 (1 H, td J = 7.1.5Hz).

This ester was then hydrolyzed using the procedure of Example 2 (v) to give the desired acid (A) aiso-soluble oil in 95% yield; NMR: 1.18 (3H, tJ = 7Hz), 1.57 (1H, m), 1.85 (1H, m), 2.02 (2H, m), 2.27 (4H, m ), 2.47 (1H, m), 3.48 (2H, qJ = 7Hz), 3.61 (2H, tJ = 7Hz), 3.80 (3H, s), 3.91 (1 H, dm J = 12Hz), 4.03 (1H, brd J = 12Hz), 4.92 (1H, tJ = 5Hz), 5.18 (1H, dJ = 2Hz), 5.29 (2H, m), 6.83 (1 H, brd J = 7Hz), 6.97 (1 H, brt J = 7Hz), 7.23 (1 H, td J = 7.1.5Hz), 7.43 (1 H, ddJ = 7.1.5Hz).

Example 4

A stirred solution of 4 (Z) -6 - ([2,4,5-cis] -2-cyclohexyloxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl) hexanoic acid (0.50 g) in dry THF (3 ml) was treated at 4 ^° C. under argon with a solution of lithium diphenylphosphide (prepared from chlorophenylphosphine [0.99 g] and lithium metal [0.13 g] in dry THF [5 ml]). The mixture was then stirred for 5 minutes at 4 ⁰ C for 3 hours at 5O ⁰ C, cooled to 10 ° C and added to ice water (50 ml). The aqueous mixture was washed with ether (3 × 20 ml), acidified to pH 5 with acetic acid and extracted with ether (3 × 25 ml). These extracts were washed successively with water (3 × 20 ml) and saturated brine (20 ml), then dried (MgSO ₄ ) and evaporated. The residue was purified by MPLC eluted with hexane / ethyl acetate / acetic acid (80: 20: 1 v / v) to give 4 (Z) -6 - ([2,4,5-cis] -2-cyclohexyloxymethyl-4-). o-hydroxyphenyl-1,3-dioxan-5-yl) hexenoic acid as a clear oil which slowly crystallized and a solid (0.44 g) having a melting point of 91 ° C to 93 ⁰ C: NMR: 1.28 (5 H, m), 1.52 (1H, m), 1.73 (3H, m), 1.92 {3H, m), 2.32 (4H, m), 2.66 (1H, m ), 3.33 (1H, m), 3.65 (2H, dJ = 4Hz), 3.92 (1H, dmJ = 11Hz), 4.14 (1H, ddJ = 11, 1Hz), 4.92 (1H, tJ = 4Hz), 5.26 (1H, dJ = 2Hz), 5.27 (1H, m), 5.44 (1H, m), 6.88 (3H, m), 7.16 (1H, td J = 7.1.5Hz), 8.50 (2H, br); m / e 422 (M ⁺ + NH ₄ ), 405 (M ⁺ + H). <. ---

The required starting material was prepared as follows:

(a) Cyclohexanol (11.00g) was added slowly over 2 hours to a stirred suspension of sodium hydride (4.80g, 50% M / M dispersion in oil) in dry DMPU (100ml) at 50 ° C under argon , The mixture was stirred for an additional 30 minutes, then cooled to 5 ° C and treated with 2-bromo-1,1-dimethoxyethane (16.9 g). Stirring was continued for 18 hours at ambient temperature. The mixture was then poured into ice-water (250 ml). The aqueous mixture was extracted with ether (4 × 100 ml). The combined extracts were washed successively with water (3 x 100 ml) and saturated brine (100 ml), then dried (MgSO ₄ ) and evaporated. Flash chromatography of the residue, eluting sequentially with hexane, 5% v / v ethyl acetate / hexane and 10% v / ethyl acetate / hexane gave 2-cyclohexyloxy-1,1-dimethoxyethane as an oil (A) (7.32 g ). This was used without further purification. (A sample was distilled under vacuum [piston-piston transfer]; NMR: 1.29 [5H, m], 1.55 [1H, m], 1.76 [2H, m], 1.92 [2H, m], 3.27 [1H, m], 3 , 40 [6 H, s], 3.50 [2 H, dJ = 5 Hz], 4.48 [1 H, t J = 5Hz]).

(ii) A stirred mixture of 4 (Z) -erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acid (1.40g), p-toluenesulfonic acid (5mg) and A (5.40g). wurde4 hours maintained at 100 ⁰ C. The solution was cooled, methanol (10 ml) added and the mixture stirred at ambient temperature for 18 hours. Triethylamine (1.40 g) was added and the solvent was evaporated. The residue was purified by MPLC eluting with 15% v / v ethyl acetate / hexane to give methyl 4 (Z) -6 - ([2,4,5-cis] -2-cyclohexyloxymethyl-4-o-methoxyphenyl-1, 3-dioxan-5-yl) hexenoate as oil (B) (0.97g). (iii) A solution of ester B (0.97 g) in methanol (50 ml) was hydrolyzed for 18 hours using 2 M potassium hydroxide (7 ml) in accordance with the general procedure described in Example 2 (v). After MPLC eluting with hexane / ethyl acetate / acetic acid (75: 25: 1 v / v), 4 (Z) -6 - ([2,4,5-cis] -2-cyclohexyloxymethyl-4-o-methoxyphenyl-1) was obtained , 3-dioxan-5-yl) hexanoic acid as a clear oil (7.2g): NMR: 1.26 (5H, m), 1.63 (4H, m), 1.94 (3H, m), 2 , 27 (4H, m), 2.47 (1H, m), 3.34 (1H, m), 3.66 (2H, dJ = 4Hz), 3.80 (3H, s), 3.9b (1H, dmJ = 11Hz), 4.08 (1H, brdJ = 12Hz), 4.94 (1H, tJ = 4Hz), 5.21 (1H, dJ = 2Hz), 5 , 27 (2H, m), 6.83 (1H, brdJ = 7), 6.96 (1H, brT J = 7Hz), 7.23 (1H, tdJ = 1.5Hz) , 7.40 (1H, ddJ = 7.1Hz).

Example 5

Using a procedure similar to that described in Example 4 but substituting 4 (Z) -6 - ([2,4,5-cis] -4-o-methoxyphenyl-2-phenoxymethyl-1,3-dioxan-5 -yl) hexenoic acid, 4 (Zj-6- (2,4,5-cis-4-o-hydroxyphenyl-2-phenoxymethyl-1,3-dioxan-5-yl) -hexenoic acid as a sticky solid in a yield NMR: 1.77 (1H, m), 1.92 (1H, m), 2.31 (4H, m), 2.68 (1H, m) _/ 4.00 (1H, dm J = 11 Hz), 4.16 (2H, d J = 4Hz), 4.19 (1H, brd J = 11Hz), 5.16 (1H, tJ = 4Hz), 5.31 (1H, dJ = 2Hz), 5.36 (2H, m), 6.50 (1H, 6), 6.92 (6H, m), 7.16 (1H, tdJ = 7.1.5 Hz), 7.29 (2H, m); m / e398 (M ⁺ ).

The starting material was obtained as follows:

A mixture of 4 (Z) -erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acid (792 mg), p-toluene sulfonic acid (5 mg) and 2-phenoxy-1,2-dimethoxyethane (2, 72g) was stirred at 80 ⁰ C for 3 hours. The mixture was cooled and diluted with ether (25 ml) and then extracted with 0.2 M sodium hydroxide (3 × 15 ml). The aqueous extracts were with. Acetic acid acidified to pH 5 and extracted with ether (3 x 20 ml). These extracts were washed successively with water (2 × 15 ml) and saturated brine (15 ml), then dried (MgSO ₄ ) and evaporated. The residue was purified by MPLC eluted with hexane / ethyl acetate / acetic acid (75: 25: 1 v / v) to give 4 (Z) -6 - ([2,4,5-cis] -4-o-methoxyphenyl). 2-phenoxymethyl-1,3-dioxan-5-yl) -hexenoic acid as a clear oil (229 mg); NMR: 1.63 (1H, m), 1.90 (1H, m), 2.29 (4H, m), 2.50 (1H, m), 3.81 (3H, s), 4 , 00 (1H, dmJ = 11Hz), 4.22 (1H, brdJ = 11Hz), 4.17 (2H, dJ = 4Hz), 5.18 (1H, tJ = 4Hz), 5.28 (1H, dJ = 2Hz), 5.31 (2H, m), 6.91 (5H, m), 7.25 (3H, m), 7.41 (1H, dd J = 7,1.5Hz).

Example 6

A stirred solution of 4 (Z) -6 - ([2,4,5-cis] -2- [1-methyl-1-phenoxyethyl] -4-o-methoxyphenyl-1,3-dioxan-5-yl) Hexenoic acid (584 mg) in dry THF (5 ml) was treated at 4 ° C under argon with a solution of lithium diphenylphosphide (prepared from chlorodiphenylphosphine [1.44 ml] and lithium metal [224 mg] in dry THF [8 ml]). The mixture was placed at 4 ° C, then cooled for 3.5 hours at 55 ° C.gerührt at 1O ⁰ C and ice water (100 ml) for 5 minutes. The aqueous solution was washed with ether (2 × 50 ml), acidified to pH 5 with acetic acid and extracted with ether (3 × 50 ml). These extracts were washed successively with water (2 x 50 ml) and saturated brine (50 ml), then dried (MgSO ₄ ) and evaporated. The residue was purified by MPLC eluting with hexane / ethyl acetate / acetic acid (85: 15: 1 v / v) to give 4 (Z) -6 - ([2,4,5-cis] -2- [1-methyl 1-phenoxyethyl] -4-o-hydroxyphenyl-1,3-dioxan-5-y-hexenoic acid as a clear oil (426mg); NMR (90MHZ): 1.36 (6H, bs), 1.88 (2H, m) , 2.36 (4H, m), 2.68 (1H, m), 3.96 (1H, dmJ = 11Hz), 4.23 (1H, bdJ = 11Hz), 4.80 (1H, s), 5.33 (1H, dJ = 2Hz), 5.38 (2H, m),) 7.06 (9H, m), 8.50 (2H, b); m / E444 (M ⁺ + NH _4), 427 (M ⁺ + H).

The starting material was obtained as follows:

A suspension of 4 (Z) -6- (4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenoic acid (1.5 g) in 2-methyl-2-phenoxypropionaldehyde ( 3.0 g) with the addition of p-toluenesulfonic acid (10 mg) was stirred at ambient temperature for 18 hours and then kept at 60 ^° C. for 6 hours. The cooled solution was diluted with ether (30 ml) and 0.5 M

Sodium hydroxide solution (3 × 10 ml) extracted. The aqueous extracts were washed with ether (20 ml), then acidified to pH 5 with acetic acid and extracted with ether (3 × 15 ml). These extracts were washed successively with water (2 × 10 ml) and saturated brine (10 ml), then dried (MgSO ₄ ) and evaporated. The residue was purified by MPLC eluting with hexane / ethyl acetate / acetic acid (85: 15: 1 v / v) to give 4 (Z) -6 - ([2,4,5-cis] -2- [1-methyl 1-phenoxyethyl] -4-o-methoxyphenyl-1,3-dioxan-5-yl) -hexenoic acid as a clear oil (655 mg); NMR: 1.34 (3H, s), 1.42 (3H, s), 1.57 (1H, m), 1.89 (1H, m), 2.30 (4H, m), 2 , 49 (1H, m), 3.81 (3H, s), 3.98 (1H, dmJ = 11Hz), 4.15 (1H, ddJ = 11.1Hz), 4, 80 (1H, s), 5.24 (1H, dJ = 2Hz), 5.32 (2H, m), 6.85 (1H, ddJ = 7.1Hz), 7.03 ( 4H, m), 7.24 (3H, m), 7.43 (1H, ddJ = 7.1.5Hz); m / e 458 (M ⁺ + NH ₄ ), 441 (M ⁺ + H).

The required 2-methyl-2-phenoxypropionaldehyde was recovered in turn as follows: A stirred solution of methyl 2-methyl-2-phenoxypropionate (3.88g) in dichloromethane (100ml) was added dropwise at -70 ° C under argon with a 1 M solution of diisobutylaluminum hydride (Dibal) in dichloromethane (21 ml). The solution was stirred for one hour at -7O ⁰ C, then allowed to warm to -30 ° C allowed to stand, whereupon it in a vigorously stirred aqueous solution of potassium sodium tartrate tetrahydrate (50g) dissolved in water (100 ml), cooled to 4 ° C, was poured. After a stirring time of 30 minutes, the mixture was separated by filtration through diatomaceous earth. The filtrate was extracted with ether (4 × 100 ml) and the extracts were washed with saturated brine (2 × 100 ml), dried (MgSO ₄ ) and evaporated. The residual oil (3.18 g) containing 2-methyl-2-phenoxypropionic aldehyde was used without further purification.

Example 7

A stirred solution of 4 {Z) -6 - ([2,4,5-cis] -2- [1-methyl-1-propoxyethyl] -4-o-methoxyphenyl-1,3-dioxan-5-yl) hexenoic acid (803 mg) in dry THF (2 mL) at 4 ⁰ C under argon with a solution of lithium diphenylphosphide treated (manufactured / off Chlordiphenyiphosphin [1,80ml] and lithium metal [280 mg] in dry THF [1OmI]). The mixture was then stirred for 5 minutes at 4 ⁰ C for 3 hours at 50 ⁰ C, cooled to 1O ⁰ C and added to ice water (50ml). The aqueous solution was washed with ether / hexane (1: 1 v / v) (3 x 25 ml), acidified to pH 5 with acetic acid and extracted with ether (3 x 25 ml). These extracts were washed successively with water (2 × 25 ml) and saturated brine (25 ml), dried (MgSO 4) and evaporated The residue was purified by MPLC eluting with hexane / ethyl acetate / acetic acid (85: 15: 1 v / v to give 4 (Z) -6 - ([2,4,5-cis] -2- [1-methyl-1-propoxyethyl] -4-o-hydroxyphenyl-1,3-dioxan-5-yl). hexenoic acid as colorless oil ⁺ (650 mg); NMR: 0.90 (3H, tJ = 7Hz), 1.25 (3H, s), 1.26 (3H, s) / 1.57 (2H, qJ = 7Hz), 1 , 72 (1H, m), 1.92 (1H, m), 2.33 (4H, m), 2.63 (1H, m), 3.41 (2H, tdJ = 7.1 Hz), 3.88 (1H, dmJ = 11Hz), 4.15 (1H, ddJ = 11.1Hz), 4.59 (1H, s), 5.25 (1H, dJ = 2Hz), 5.38 (2H, m), 6.87 (3H, m), 7.16 (1H, tdJ = 7.1.5Hz), m / e 392 (M ⁺ ).

⁽⁺ The oil slowly crystallized and gave a solid, melting point 62 ° C to 63 ⁰ C [recrystallised from ethyl acetate / hexane]). The required starting material was obtained as follows:

A suspension of 4 (Z) -6- (4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl) -hexenoic acid (1.5 g) in 2-methyl-2-propoxypropionaldehyde ( 4g) with an addition of p-toluenesulfonic acid (10 mg) was stirred for 18 hours. The recovered solution was diluted with ether (25 ml) and extracted with 0.2 M sodium hydroxide solution (3 × 25 ml). The aqueous extracts were acidified to pH 5 with acetic acid and extracted with ether (3 × 25 ml). These extracts were washed successively with water (2 × 25 ml) and saturated brine (25 ml), then dried (MgSO ₄ ) and evaporated. The residue was purified by MPLC eluted with hexane / ethyl acetate / acetic acid (80: 20: 1 v / v) to give 4 (Z) -6 - [(2,4,5-cis] -2- [1-methyl 1-propoxyethyl] -4-o-methoxyphenyl-1,3-dioxan-5-yl) -hexenoic acid as a clear oil (1.01 g); NMR: 0.88 (3H, tJ = 7Hz), 1.27 (3H, s), 1.30 (3H, s), 1.54 (2H, qJ = 7Hz), 1.55 (1H, m), 1.84 (1H, m), 2.28 (4H, m), 2.43 (1H, m), 3.46 (2H, tJ = 7Hz), 3.80 (3H, s ), 3.90 (1 H, dm J = 11 Hz), 4.09 (1 H, dd J = 11 Hz), 4.64 (1 H, s), 5.19 (1 H, d J = 2Hz), 5.28 (2H, m), 6.84 (1H, ddJ = 7.1Hz), 6.97 (1H, tdJ = 7.1Hz), 7.24 (1H , td J = 7.1.5Hz), 7.42 (Ί H, dd J = 7.1.5Hz); m / e (-VE FAB) 405 (MH) ". The 2-methyl-2-propoxypropionaldehyde required as the starting material was added as a clear oil (4.0 g) in a manner similar to Example 2 (a) for 2-methyl 2-pherioxypropionaldehyd procedure described analogous was obtained, but starting from the known compound methyl 2-methyl-2-propoxypropionate (3.8 g) was.

Example 8

Using a similar procedure to that described in Example 4 but substituting 4 (Z) -6 - ([2,4,5-cis] -4-o-methoxyphenyl-2- [1-butoxyethyl] -1,3- dioxan-5-yl) -hexenoic acid, 4 (Z) -6 - ([2,4,5-cis] -4-o-hydroxyphenyl-2- [1-butoxyethyl] -1,3-dioxan-5- yl) hexenoic acid was obtained as a clear oil in a yield of 92%; NMR: 0.91 (3H, tJ = 7Hz), 1.24 (4H, m), 1.38 (1H, m), 1.56 (2H, m), 1.69 (1H, m), 1.90 (1H, m), 2.33 (4H, m), 2.66 (1H, m), 3.55 (3H, m), 3.90 (1H dmJ = 12Hz), 4.15 (1H, dJ = 11Hz), 4.73 (1H, 2dJ = 3Hz), 5.24 (1H, dJ = 2Hz), 5.35 (2H, m ), 6.88 (3H, m), 7.17 (1H, m), 8.10 (1H, bs); m / e 393 (M ⁺ + H).

The required starting material was obtained as follows:

(i) Sodium borohydride (2.84g) was added portionwise to a stirred solution of 3-ketobutyl aldehyde dimethyl acetal (18.0ml) in absolute ethanol (75ml) over 30 minutes, the temperature being reduced to 20 ^° C to 25 ° C by water cooling ⁰ C was held. The mixture was stirred for a further 2 hours at ambient temperature and then poured into saturated ammonium chloride. The resulting mixture was extracted with ether (3 × 100 ml). The extracts were washed with saturated brine (50ml), dried (MgSO ₄ ), and the solvent was evaporated to give 1,1-dimethoxy-2-proponal (A) as a yellow oil; NMR (90MHz): 1.20 (3H, dJ = 6Hz), 2.30 (1H, bs), 3.42 (3H, s), 3.47 (3H, s), 3.75 (1 H, m), 4.08 (1H, dJ = 6Hz).

(ti) A solution of A (3.75g) in DMPU (2ml) was added dropwise under argon to a stirred suspension of sodium hydride (0.75g) in DMPU (25ml). The mixture was heated to 5O ⁰ C for 30 minutes, then cooled to 10 ⁰ C and butyl bromide (3.7 ml) was added. Stirring was continued overnight and then water (100 ml) was added. The mixture was extracted with ether (3 x 50 ml). The extracts were washed with water (50 ml), brine (50 ml), dried (MgSO ₄ ) and the solvent was evaporated. The residue was purified by flash chromatography eluting with 10% v / v ethyl acetate / hexane to give 1,1-dimethoxy-2-butoxypropane (B) as a clear oil (1.8 g); NMR (90MHz): 0.8-1.8 (10H, m), 3.50 (9H, m), 4.15 (1H, dJ = 5Hz). (iii) Using a procedure similar to that described in Example 4 (ii) and (iii), but with 1.1-

Dimethoxy-2-butoxypropane (B), 4 (Z) -6 - ([2,4,5-cis] -4-o-methoxyphenyl-2- [1-butoxyethyl] -1,3-dioxane 5-yl) hexanoic acid as a clear oil in 49% yield;

NMR: 0.91 (3H, m), 1.28 (3H, tJ = 6Hz), 1.35 (2H, m), 1.57 (3H, m), 1.85 (1H, m), 2.36 (5H, m), 3.58 (3H, m), 3.80 (3H, s), 3.93 (1H, dmJ = 11Hz), 4.09 (1H, bd J = 11 Hz), 4.73 (0.5H, dJ = 3Hz), 4.83 (0.5H, dJ = 3Hz), 5.29 (3H, m), 6.84 (1H, d J = 7Hz), 6.97 (1H, tJ = 7Hz), 7.24 (1H, bt J = 7Hz), 7.42 (1H, m); m / e 406 (M ⁺ ).

Example 9

Using a similar procedure to that described in Example 6 but substituting (-) - 4 (Z) -6 - ([2,4,5-cis] -2- [1-methyl-1-phenoxyethyl] -4- o-methoxyphenyl-1,3-dioxan-5-yl) -hexenoic acid (A), became (-) - 4 (Z) -6 - ([2,4,5-cis] -4-o-hydroxyphenyl-2 - [1-methyl-1-phenoxyethyl] -1,3-dioxan-5-yl) hexanoic acid in 64% yield as a colorless oil; NMR substantially the same as in the racemate (Example 6); m / e 427 (M ⁺ + H); ²⁰ [a] _D -129.9 ° (c, 0.85, methanol).

The starting material A was obtained as follows:

(i) Solid potassium t-butoxide (4.48g) was added under argon to a stirred, ice-cooled oeffish of (3-carboxypropyl-triphenylphosphonium bromide (6.44g) and (-) - [2,3-trans] -tetrahydro-5- -hydroxy-3-hydroxymethyl-2-omethoxyphenylfuran (B) (2,24g) in dry THF (75 ml). The mixture was stirred for 15 minutes at 4 ⁰ C, then for 1 hour at ambient temperature and was thereafter (in ice water The resulting mixture was washed with ether (2 × 50 ml) to remove the bulk of the neutral material The aqueous phase was acidified to pH 4 with 1M hydrochloric acid and extracted with ether (1 × 100 ml, 2 × 50 ml) Extracts were washed successively with water (2 × 50 ml) and saturated hydrochloric acid (2 × 50 ml), then dried (MgSO ₄ ) and evaporated The residue was purified by flash chromatography eluting with ether / hexane / acetic acid (80 : 20: 1, v / v) to give (-) - ery thro-4 (Z) -8-hydroxy-7-hydroxymethyl-8-O-methoxyphenyl-4-octenoic acid (C) as a colorless oil (2.76 g); ²² [a] _D -68.3 ° (c 1.1 methanol); NMR: 1.92 (1H, m), 2.0-2.6 (6H, m), 3.67 (2H, m), 3.82 (3H, s), 5.21 (1H, dJ = 5Hz), 5.37 (2H 6.87 (1H, dd J = 8.1Hz), 6.98 (1H, tdJ = 7.1Hz), 7.25 (1H, m ), 7.42 (1 H, dd J = 7.1 Hz), m / e 294 (M ⁺ ).

(ii) A solution of C (2.57g) in 2,2-dimethoxypropane (8.5ml) was mixed with "Amberlyst" -15 (trademark of Rohm and Haas Company), strongly acidic, macroreticular ion exchange resin (0.5g). The mixture was stirred at ambient temperature for 2 1/2 hours The solid was removed by filtration and washed with ether (10 ml) The filtrate and washings were concentrated in vacuo and the residue was purified by MPLC eluting with hexane. Ethyl acetate / acetic acid (80: 20: 1 v / v) to give a clear oil which slowly crystallized and gave (-) - 4 (Z) -6- (4-o-methoxy-phenyl-2,2- dimethyl-1,3-dioxane-cis "5-yl) hexeric acid (D) (2.48g). Recrystallization from hexane gave a solid having a melting point of 71 ⁰ C to 73 ° C, ^J3 [a] _{D /} -145.5 ° (c 1.1, methanol) and an NMR spectrum which is substantially that of the corresponding racemate was the same (Compound A in Example 2).

(iii) Hexenoic acid D was reacted with 2-methyl-2-phenoxypropionaldehyde using the same procedure described in Example 6 for the corresponding racemate. In this way, (-MIZl-e-β-cis-1-ti-methyl-1-phenoxyethyl] -4-o-methoxyphenyl-1,3-dioxan-4-yl) hexenoic acid as a colorless oil in a yield of 21% which had an NMR spectrum substantially the same as that of the racemic starting material described in Example 6.

The furan derivative B was in turn obtained as follows:

(iv) Succinic anhydride (22g), o-methoxybenzaldehyde (20g) and anhydrous zinc chloride (44g) were added to dichloromethane (dried over alumina, 200ml) and the mixture was stirred under argon. Triethylamine (41 ml) was added to the ice-cold mixture over 20 minutes. The reaction mixture was then stirred for 18 hours at 20 ⁰ C to 25 ° C, after which hydrochloric acid (2 M, 130 ml) and ethyl acetate (200 ml) was added. The resulting mixture was stirred for 5 minutes. The aqueous phase was separated and extracted with ethyl acetate (150 ml). The combined extracts were washed with saturated brine (50 ml) and then extracted with saturated sodium bicarbonate solution (3 × 200 ml). The combined aqueous extracts were washed with ethyl acetate and then acidified to pH 2 with concentrated hydrochloric acid. The separating oil was extracted into ethyl acetate (2 × 150 ml). The combined extracts were washed with saturated brine (4 × 50 ml) until acid free, then dried (MgSO ₄ ) and evaporated. Toluene (300 mL) was added to the residue and the mixture was distilled at atmospheric pressure until the residual material reached 110 ° C. After cooling to 20 ° C, tetrahydro-o-methoxyphenyl-o-oxo-S-furancarboxylic acid was separated as a crystalline white solid (27.2 g, 78%) (melting point 106 ° C), which was shown by NMR to be it was a mixture of [2,3-cis] and [2,3-trans] isomers: 2.8-3.0 (2H, m), 3.1-3.6 (1H, m ), 3.8 (3H, s), 5.82 (3 / 4H, d) [trans], 5.95 PAH, d) [ice], 6.8-7.5 (4H, m).

(v) A mixture of [2,3-cis] - and [2,3-trans] -tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylic acid (188.6 g) became an iced solution of concentrated sulfuric acid (320 ml) (480 ml) in water and stirred for 18 hours at 20 ⁰ C to 25 ⁰ C. Thereafter, water (800 ml) was added and the mixture was extracted with ethyl acetate (2 × 750 ml). The combined extracts were washed with brine (4 × 500 ml) until acid free, dried (MgSO ₄ ) and evaporated to a small volume. Toluene (I.Liter) was added and the distillation continued at atmospheric pressure until the remaining material had reached a temperature of 110 ⁰ C. After cooling, pure isolated [2,3-trans] -tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarbonsäureals white crystalline solid from (169,5g, 90%), melting point 133X to 134 ⁰ C; NMR: 2.8-3.0 (2H, d), 3.3-3.6 (1H, m), 3.8 (3H, s), 5.82 (1H, d), 6 , 8-7,4 (4H, m). (vi) A solution of d-ephedrine (61.2g) in hot ethyl acetate (150ml) was added to a solution of [2,3-trans] -tetrahydro-2-omethoxyphenyl-5-oxo-3-furancarboxylic acid (87.6g ) in hot ethyl acetate (350 ml). The mixture was allowed to stand for 2 hours to cool to room temperature and the crystalline salt formed was separated by filtration to give 62 g of solid material with ²⁵ [a] _D + 40.2 ° (methanol). This material was recrystallized twice from ethyl acetate to give 48 g of optically pure solid ²⁵ [a] _D + 50.3 ° (methanol). This solid was added to ethyl acetate (1 liter) and 2M hydrochloric acid (150 ml). The ethyl acetate layer was washed with brine (2 × 100 ml) until the pH of the washings was 2-3, then dried (MgSO ₄ ) and evaporated. The residue was dissolved in boiling toluene (200 ml). Insoluble material was removed by hot filtration. The filtrate was left to cool and

gave (+ H2,3-trans] -tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylic acid (E) (27.4 g) ²⁵ [a] _D + 33.0 ° (methanol) Toluene was recovered as material with ²⁵ [a] _D + 33.8 ° (methanol), mp 125 ° C to 127 ³ C (decomposition), which was found to be> 98% optically pure by adding a small sample their (-) - Amylester converted and the ¹³ C NMR spectrum was examined.

(vii) A solution of E (97,5g) in dry tetrahydrofuran (150ml) was cooled to 15 ° C and treated with a solution of borane in tetrahydrofuran (500 ml of a 1 M solution), wherein dieTemperaturauf 2O ⁰ C to 25 ° C was held. After 30 minutes, the reaction was complete (as evidenced by TLC analysis) and water (200 mL) was added slowly to decompose excess borohydride. The mixture was concentrated in vacuo and the residue was mixed with ethyl acetate (500 ml). The organic layer was washed successively with saturated potassium carbonate solution (2 x 100 ml) and saturated brine, dried (MgSO ₄ ) and evaporated to give [4,5-trans] -tetrahydro-4-hydroxymethyl-5-o-methoxyphenyl-furan-2-one (F) as a viscous oil (81.8g) having ²⁵ [a] _D -14.2 ° (methanol) and a satisfactory NMR spectrum (d ₆ -acetone): 2.6 (3H, m ), 3.7 (2H, m), 3.3 (3H, s), 4.1 (1H, br), 5.55 (1H, m), 6.8-7.5 (4H, rn). , - ·

(viii) A solution of F (as obtained above) in 1,2-dimethoxyethane (150 ml) and dry toluene (500 ml) was cooled to -60 ° C under a nitrogen atmosphere. A toluene solution of diisobutylaluminum hydride (672 ml of 1.23M solution) was then slowly added. After 30 minutes, the reaction was quenched by the addition of methanol (50 ml) and the mixture allowed to warm to room temperature. Then, 2M hydrochloric acid (1 liter) and ethyl acetate (500 ml) were added, and the mixture was stirred. The aqueous phase was separated and extracted with ethyl acetate (2 × 500 ml). The ethyl acetate phase and the extracts were taken together, dried (MgSO ₄ ) and evaporated. The residual oil was dissolved in hot toluene (500 ml). The recovered solution afforded after cooling (-) - [2,3-trans] -tetrahydro-5-hydroxy-3-hydroxymethyl-2-o-methoxyphenylfuran (B) as a white solid (63.3 g), ²⁵ [a] _D -24.2 ° (methanol), melting point 110 ⁰ C to 111 ° C; NMR: 1.5-2.4 (3H, m), 3.4-4.0 (2H, m), 3.8 (3H, s), 4.2-4.8 (2H, br), 5.25 (1H, m), 5.6 (1H; m), 6.9-7.9 (4H, m).

'UL

Formulas

5 I

KO.C

ir

JSL

»CH. (<LH, £ | _m . COf

NT

II. N

IVk

, C .CHO

VLJ

Claims (9)

A process for preparing a 1,3-dioxane ether of the formula I wherein R ^{1 is} (1-6C) alkyl, (3-8C) CyClOalkVl, (3-8C) cycloalkyl-1 (1-4c) alkyl, phenyl or phenyl - (1-4C) alkyl, the latter two optionally bearing one or two substituents selected from halogen, (1-4C) alkyl, (1-4C) alkyl, (1-4C) alkoxy, hydroxy, trifluoromethyl, nitro and cyano are selected; R ² and R ^{3 are} independently hydrogen or (1-4C) alkyl or together form (3-6C) polymethylene optionally bearing one or two (1-4C) alkyl substituents; η is 1 or 2; m is equal to 2, 3 or 4, ρ is zero, 1 or 2; and Z is carboxy or 1 (H) -tetrazol-5-yl; and the groups at positions 2, 4 and 5 of the dioxane ring have cis-relative stereochemistry; or a pharmaceutically acceptable salt thereof and optionally the pharmaceutical administration form thereof, characterized in that (a) reacting an aldehyde of formula III with a Wittig reagent of formula IVa or IVb wherein R 'is (1-6C) alkyl or aryl and M ^{+ is} a cation; (b) for a compound ¹ of formula I wherein Z ^{1 is} {H) -tetrazol-5-yl, reacting a nitrile of formula V with an azide; (c) removing from a phenol derivative of formula IV wherein "R" is a suitable protecting group; (d) an erythro-diol of the formula VII in which one of Q ¹ and Q ^{2 is} hydrogen and the other is hydrogen or a group of the formula -CRaRb.OH in which Ra and Rb are the same or different (1-4C ) Alkyl, with an aldehyde of formula VIII or with an acetal, hemiacetal or hydrate thereof; or (e) a compound of formula IX wherein one of Ra and Rb is hydrogen, methyl or ethyl and the other is methyl or ethyl with an excess of an aldehyde of formula VIII or with an acetal, hemiacetal or hydrate thereof in the presence of an acid catalyst is implemented; where, when an optically active form of a compound of formula I is required, either one of the procedures (a) to (e) above is applied using an optically active form of the starting material concerned, or the racemic form using an appropriate optically active base is dissolved; and when a pharmaceutically acceptable salt is required, reacting the free acidic form of the compound of formula I with an appropriate base yielding a physiologically acceptable cation; and wherein R ¹ , R ² , R ³ , n, m, ρ and Z have the meaning given; and Formulas III, IVa, IVb, V, VII, VII, VIII and IX are shown hereinafter and, optionally, the compounds prepared by this process are processed into a pharmaceutical dosage form with a pharmaceutically acceptable diluent or carrier. 2. The method according to claim 1, characterized in that 1,3-dioxane ethers of the formula I are prepared, wherein R ² and R ^{3 are} independently (1-4C) alkyl. 3. The method according to claim 1, characterized in that 1,3-dioxane ethers of formula I are prepared wherein R ^{1 is} methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl or 2-phenylethyl, the last three optionally bearing one or two substituents selected from fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, hydroxy, trifluoromethyl, nitro and cyano; and R ² and R ^{3 are} independently hydrogen, methyl or ethyl or together form trimethylene or tetramethylene optionally bearing one or two substituents. 4. The method according to claim!, Characterized in that 1,3 ^: Dioxanether of formula II are prepared, wherein R ^{5 is} (1-4C) alkyl, (3-8C) cycloalkyl or phenyl, the latter optionally a halogen, ( 1-4C) alkyl, (1-4C) alkoxy, nitro and cyano bear selected substituents; q is 2 or 3; R ⁶ and R ^{7 are} independently hydrogen or methyl; and Z is carboxy or 1 (H) tetrazo! -5-y! is; and the pharmaceutically acceptable salts thereof. 5. The method according to claim 3, characterized in that in the compounds of formula II R ^{5 is} methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl or phenyl, the latter optionally bearing a substituent selected from fluoro, chloro, bromo, methyl, methoxy, nitro and cyano. Process according to claim 1 or 2, characterized in that it is equal to 1, m is 2 or 3 and Z is carboxy. 7. A method according to claim 3 or 4, characterized in that q is 2 and Z is carboxy. 8. Process according to claims 1 to 7, characterized in that 4 (Z) -6-Z [2,4,5-cis] -2- [1-methyl-1-phenoxyethyl)] - 4-o-hydroxyphenyl- 1,3-dioxan-5-yl) hexanoic acid, 4 (Z) -6 - ([2,4,5-cis] -2- [1-methyl-1-propoxyethyl] -4-o-hydroxyphenyl-1, 3-dioxan-5-yl) -hexenoic acid and the pharmaceutically-acceptable salts thereof. Process according to any one of claims 1 to 7, characterized in that alkali metal, alkaline earth metal, aluminum and ammonium salts and salts with organic amines and quaternary bases are prepared which form physiologically acceptable cations.