Oxetanone

0001From Patent Abstracts of Japan <u style="single">4</u> (C25) (617) (1980) FR-A-2 426 671, FR-A-2

0002379 531 and EP-A-0 129 748, esterase inhibitors are known which are structurally closely related in part to the oxetanones of the formulas I and III described below. The present invention relates to new oxetanones, processes for their preparation, new intermediates which can be used in this process, and also medicaments based on said oxetanones or on the basis of precursors thereof.

0003These oxetanones are compounds of the formula<chemistry id="chem0001" num="0001"><img file="EP0185359B1_D0001.tif" /></chemistry> wherein<dl id="dl0001"><dt>R1 and R2</dt><dd>optionally interrupted by up to 8 double or triple bonds and optionally by an O or S atom which is present in a position other than the α position to an unsaturated carbon atom_₁₋₁₇-Alkyl; or by 0 to 3 C._₁₋₆-Alkyl- (O or S)_{1 or O} ring-substituted phenyl, benzyl or -C₆H₄-X-C₆H₅,</dd><dt>X</dt><dd>Oxygen, sulfur or (CH₂) ₀₋₃</dd><dt>R³</dt><dd>Hydrogen, C₁₋₃ alkyl or C₁₋₃ alkanoyl,</dd><dt>R⁴</dt><dd>Hydrogen or C₁₋₃ alkyl, and</dd><dt>R⁵</dt><dd>Are hydrogen, a group Ar or Ar-C₁₋₃-alkyl or optionally interrupted by Y and optionally substituted by Z C₁₋₇-alkyl, or</dd><dt>R⁴ with R⁵</dt><dd>forms a 4- to 6-membered saturated ring,</dd><dt>Y</dt><dd>Oxygen, sulfur or a group N (R⁶), C (O) N (R⁶) or N (R⁶) C (O),</dd><dt>Z.</dt><dd>a group - (O or S) -R⁷, -N (R⁷, R⁸), -C (O) N (R⁷, R⁸) or -N (R⁷) C (O) R⁸,</dd><dt>n</dt><dd>is 1 or 0, where n is 1, R⁵ is hydrogen,</dd><dt>Ar</dt><dd>phenyl substituted by 0 to 3 groups R⁹ or OR⁹, and</dd></dl> R⁶ to R⁹ are hydrogen or C₁₋₃-alkyl, where if R³ is formyl and R⁵ isobutyl or R³ is acetyl and R⁵ is carbamoylmethyl, and at the same time R² is undecyl or 2,5-undecadienyl and R¹ is n-hexyl, R⁴ has a different meaning than Has hydrogen, and salts of these oxetanones with weak acids.

0004The oxetanones of formula I form salts with weak acids, which are also the subject of the invention. Examples of such acids are p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, ascorbic acid, fumaric acid, maleic acid, malic acid, citric acid and phosphoric acid.

0005The oxetanones of the formula I can be prepared by<ul id="ul0001" list-style="none"><li>a) an acid of the formula<chemistry id="chem0002" num="0002"><img file="EP0185359B1_D0002.tif" /></chemistry> or a functional derivative thereof with an alcohol of the formula<chemistry id="chem0003" num="0003"><img file="EP0185359B1_D0003.tif" /></chemistry> in which R¹-R⁵ and n have the above meaning, esterified,</li><li>b) the amino protecting group W in an oxetanone of the formula<chemistry id="chem0004" num="0004"><img file="EP0185359B1_D0004.tif" /></chemistry> in which R¹, R², R⁴, R⁵ and n have the meaning given above,</li><li>c) unsaturated radicals R¹ and R², if desired, catalytically hydrogenated,</li><li>d) obtained oxetanones of the formula I, in which at least one of R³ and R⁴ is hydrogen and any amino group Y or Z contained in R⁵ is tertiary, if desired C₁₋₃-alkanoylated, and</li><li>e) oxetanones of the formula I obtained, if desired, isolated in the form of their salts with weak acids.</li></ul>

0006The oxetanones of the formula I contain at least 3 asymmetric C atoms and the oxetanones of the formula III can contain one or more asymmetric C atoms. They can therefore be present as optically active enantiomers, as diastereomers or as mixtures, for example as racemic mixtures.

0007The esterification a) can be carried out in a solvent, for example an ether such as tetrahydrofuran (THF), in the presence of triphenylphosphine and diethyl azodicarboxylate, preferably at about room temperature. The corresponding anhydride can be used as the functional derivative of an acid of the formula II.

0008Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl can be mentioned as an example of an amino protecting group W in a starting oxetanone I '. The cleavage reaction b) can be carried out by hydrogenation in a solvent, for example an ether, such as THF, in the presence of a hydrogenation catalyst, such as palladium on carbon (Pd / C), preferably at room temperature.

0009The optional hydrogenation c) can be carried out under conditions similar to the cleavage reaction b) described above.

0010The optional C₁₋₃ alkanoylation d) can be accomplished in the presence of an acid anhydride, for example a mixed acid anhydride, such as formic acid anhydride, in a solvent, for example an ether such as THF, preferably at room temperature.

0011The alcohols III can be prepared by the ether protecting group L in an ether of the formula<chemistry id="chem0005" num="0005"><img file="EP0185359B1_D0005.tif" /></chemistry>    wherein R¹ and R² have the above meaning, split off.

0012Examples of ether protecting groups L are tetrahydro-2H-pyran-2-yl, 1-ethoxyethyl, benzyl and t-butyldimethylsilyl.

0013The ether protecting group L can be removed in a solvent, for example an alcohol, such as ethanol, in the presence of pyridinium 4-toluenesulfonate with heating, for example to 50-65 ° C.

0014The ether IV can be obtained by cyclization of the acids of the formula<chemistry id="chem0006" num="0006"><img file="EP0185359B1_D0006.tif" /></chemistry> produce. This reaction can be carried out in a solvent, such as pyridine, with cooling, for example to 0 ° C., in the presence of benzenesulfochloride.

0015The acids V can either be<ul id="ul0002" list-style="none"><li>a) by saponification of corresponding esters of the formula<chemistry id="chem0007" num="0007"><img file="EP0185359B1_D0007.tif" /></chemistry>    wherein R is C₁₋₄ alkyl and L, R¹ and R² have the above meaning, or</li><li>b) by condensation of an acid of the formula         R¹-CH₂-COOH VII with an aldehyde of the formula<chemistry id="chem0008" num="0008"><img file="EP0185359B1_D0008.tif" /></chemistry> produce.</li></ul>

0016Examples of alkyl radicals R are methyl, ethyl and t-butyl. The saponification a) of an ester VI can be carried out with an alcoholic alkali or alkaline earth metal hydroxide solution, such as a methanolic potassium hydroxide solution, by heating at a temperature up to the reflux temperature of the reaction mixture.

0017The condensation b) of the acid VII with the aldehyde VIII can be carried out in a solvent, such as THF, in the presence of diisopropylamine and butyllithium, with cooling, for example to -50 ° C.

0018The acids V, which are in (5R) or (5S) form, can be converted into the (2S, 3S, 5R) or (2R, 3R, 5S) stereoisomers in the following manner:    A (5R) - or (5S) -acid of the formula V is cyclized, for example while heating to 50-60 ° C. in ethanol using toluene-4-sulfonic acid monohydrate, to give the corresponding (6R) - or (6S) -pyranolone of the formula<chemistry id="chem0009" num="0009"><img file="EP0185359B1_D0009.tif" /></chemistry>    where L 'represents hydrogen and R¹ and R² have the above meaning. This (6R) - or (6S) -pyranolone is then oxidized, for example in acetone using Jones reagent at a temperature below 25 ° C., to the corresponding pyran-2,4-dione and the latter, for example in ethyl acetate in the presence of platinum oxide , stereospecific to (3S, 4S, 6R) - or (3R, 4R, 6S) -pyranolone of the formula VA, in which L 'is hydrogen, hydrogenated. This pyranolone is converted into a compound of the formula VA, in which L 'represents an ether protecting group, such as t-butyldimethylsilyl, for example in dimethylformamide using t-butyldimethylchlorosilane. The cyclic (3S, 4S, 6R) or (3R, 4R, 6S) ether obtained is split, for example by reaction with an aqueous potassium hydroxide solution in dioxane, and the resulting compound in situ in a (2S, 3S, 5R) or (2R, 3R, 5S) ether of the formula<chemistry id="chem0010" num="0010"><img file="EP0185359B1_D0010.tif" /></chemistry> transferred, where L "is hydrogen, L 'is the same ether protecting group as in ether VA, R¹⁰ benzyl or p-nitrobenzyl and R¹ and R² have the above meaning. The ether VB obtained is then converted into a diether of the same formula, in which L ″ stands for an ether protecting group, such as tetrahydro-2H-pyran-2-yl. After splitting off the ether protective group L ', for example with tetrabutylammonium fluoride trihydrate in THF, and then the group R¹⁰, for example by hydrogenation in THF in the presence of Pd / C, the desired (2S, 3S, 5R) or (2R, 3R, 5S) acid of the formula V is obtained.

0019The ester VI can either<ul id="ul0003" list-style="none"><li>a) by alkylation of the corresponding esters of the formula<chemistry id="chem0011" num="0011"><img file="EP0185359B1_D0011.tif" /></chemistry> or</li><li>b) by reducing the β-keto esters of the formula<chemistry id="chem0012" num="0012"><img file="EP0185359B1_D0012.tif" /></chemistry> produce.</li></ul>

0020The alkylation a) can be carried out by reacting the ester IX in a solvent, such as THF, with a solution of n-butyllithium in a solvent, such as n-hexane, in the presence of diisopropylamine, at about -50 ° C., and then reacting with perform a solution of an alkyl halide (R¹-Hal), for example a bromide, in hexamethylphosphoric triamide at a temperature of about 0 to 10 ° C.

0021The reduction b) of the β-keto esters X can be carried out in an inert gas, such as argon, in a solvent, such as THF, with a complex metal hydride, such as sodium borohydride (NaBH₄), at a temperature below 0 ° C.

0022The esters IX can be obtained by reductive removal of the sulfoxide group in a sulfoxide of the formula<chemistry id="chem0013" num="0013"><img file="EP0185359B1_D0013.tif" /></chemistry>    where T is p-tolyl and L, R and R² have the above meaning, produce. This reaction can be carried out, for example, in a solvent such as THF using aluminum amalgam.

0023The β-ketoester X can be obtained by reacting an aldehyde of the formula R²-CHO with a β-ketoester of the formula<chemistry id="chem0014" num="0014"><img file="EP0185359B1_D0014.tif" /></chemistry> and etherification of the alcohol of the formula obtained<chemistry id="chem0015" num="0015"><img file="EP0185359B1_D0015.tif" /></chemistry> produce.

0024The alcohol XIII or its etherification can be prepared as described, for example, in Examples H) and J) e) below.

0025If desired, unsaturated radicals R¹ and R² contained in the intermediates of the formulas I ', III-VI, VB, X and XIII can be hydrogenated, for example under the conditions of the hydrogenolytic removal of a group W or R¹⁰ mentioned above.

0026The sulfoxides XI can be obtained by condensing an aldehyde of the above formula VIII with an ester of the formula<chemistry id="chem0016" num="0016"><img file="EP0185359B1_D0016.tif" /></chemistry> eg as described in example G).

0027The aldehydes VIII can be obtained by reducing the esters of the formula<chemistry id="chem0017" num="0017"><img file="EP0185359B1_D0017.tif" /></chemistry> produce, for example with a di (C₁₋₄-alkyl) aluminum hydride, such as diisobutylaluminium hydride, in a solvent, such as toluene, at a temperature of about -60 to -80 ° C.

0028The esters of the formula XV can be started from the aldehydes of the formula R²-CHO via the sulfoxides of the formula<chemistry id="chem0018" num="0018"><img file="EP0185359B1_D0018.tif" /></chemistry> and the esters of the formula<chemistry id="chem0019" num="0019"><img file="EP0185359B1_D0019.tif" /></chemistry> produce, for example as described in the following paragraphs F) a), d) and f); G) b), d) and f) and J) b), d) and f).

0029Furthermore, an ester of formula XV, wherein R² is 3-alkenyl, can be obtained by ozonolysis of an ester of the formula<chemistry id="chem0020" num="0020"><img file="EP0185359B1_D0020.tif" /></chemistry> and Wittig reaction with the aldehyde of the formula obtained<chemistry id="chem0021" num="0021"><img file="EP0185359B1_D0021.tif" /></chemistry> for example as described in Examples K) and L).

0030To convert the aldehydes of the formula VIII or the formula R²-CHO into the corresponding esters of the formulas IX or XVII, the (R) -α- (hydroxydiphenylmethyl) benzyl acetate can be used instead of a sulfinyl ester XIV. In this case, instead of the sulfoxides of the formulas XI and XVI, the (R) -2-hydroxy-1,2,2-triphenylethyl ester corresponding to the alkyl esters of the formulas IX and XVII is obtained.

0031The oxetanones of the formula I 'can be prepared in the same way as the oxetanones of the formula I, for example as described in Example 1.10 below, by esterifying an acid of the formula II in which W is R³ with an alcohol of the formula III. In this esterification, instead of the acid mentioned, the acid anhydride obtained by reaction with N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride or preferably with dicyclohexylcarbodiimide can be used, which can be accomplished as described in Example 9 B.1) .

0032The preparation of intermediates of the formulas IV to XIX is described in more detail in the following paragraphs A) to M).

A)

Preparation of the ethers of the formula IV

0033<ul id="ul0004" list-style="none"><li>A) a) 0.57 g of a mixture of diastereomers which, inter alia, from (2S, 3S, 5R, 13Z, 16Z) -2-hexyl -3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy ] -13,16-docosadienoic acid are dissolved in 10 ml of pyridine and cooled to 0 ° C. After the dropwise addition of 0.28 ml of benzenesulfochloride, the mixture is stirred at 0 ° C. for a long time. The reaction mixture is made up to 120 ml 10 percent. poured aqueous saline solution and extracted three times with 30 ml of diethyl ether. The combined extracts are dried, filtered and evaporated. After chromatography on silica gel, a mixture of diastereomers of 3-hexyl-4 - [(10Z, 13Z) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanones is obtained as colorless oil, IR: 1815 cm⁻¹. The following are obtained in an analogous manner:</li><li>A) b) 3-ethyl-4 - [(10Z, 13Z) -2 - [(tetrahydro-2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanone, IR: 1820 cm⁻ ¹    from (13Z, 16Z) -2-ethyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid</li><li>A) c) (3S, 4S) -3-ethyl-4 - [(R, Z) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] -10-nonadecenyl-2-oxetanone    from (2S, 3S, 5R, Z) -2-ethyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13-docosenoic acid</li><li>A) d) (3-benzyl-4 - [(10Z, 13Z) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanone, IR: 1818 cm ⁻¹    from (13Z, 16Z) -2-benzyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid</li><li>A) e) (3S, 4S) -3-ethyl-4 - [(S) -p-phenoxy-β - [(tetrahydro -2H-pyran-2-yl) oxy] phenethyl] -2-oxetanone    from (2S, 3S, 5S) -2-ethyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid</li><li>A) f) (3S, 4S) -3-hexyl-4 [(S) -p-phenoxy-β - [(tetrahydro -2H-pyran-2-yl) oxy] phenethyl-2-oxetanone, IR: 1815 cm ⁻¹    from (2S, 3S, 5S) -2-hexyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid</li><li>A) g) 3-Hexyl-4- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] tridecyl] -2-oxetanone    from 2-hexyl-3-hydroxy-5 [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid</li><li>A) h) 3-Hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] tridecyl] -2-oxetanone    from 2-hexyl-3-hydroxy- (R) -5 [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid</li><li>A) i) 3-ethyl-4- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] tridecyl] -2-oxetanone    from 2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid</li><li>A) j) 3-methyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] tridecyl] -2-oxetanone    from 2-methyl-3-hydroxy (R) -5 - [(tetrahydro -2H-pyran-2-yl) oxy] hexadecanoic acid</li><li>A) k) 3-Allyl-4- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] tridecyl] -2-oxetanone    from 2-allyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid</li><li>A) l) 3-Hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] propyl] -2-oxetanone    from 2-hexyl-3-hydroxy (R) -5 [(tetrahydro -2H-pyran-2-yl) oxy] hexanoic acid</li><li>A) m) 3-Hexadecyl-4- [2 - [(tetrahydro-2H-pyran -2-yl) oxy] propyl] -2-oxetanone    from 2-hexadecyl-3-hydroxy (R) -5 - [(tetrahydro -2H-pyran-2-yl) oxy] hexanoic acid</li><li>A) n) 3-Hexyl-4 - [(2 - [(tetrahydro-2H-pyran -2-yl) oxy] -5-hexenyl] -2-oxetanone    from 2-hexyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] nonenoic acid</li><li>A) o) 3-decyl-4 - [(R) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] -5-hexenyl] -2-oxetanone    from 2-decyl-3-hydroxy (R) -5 - [(tetrahydro -2H-pyran-2-yl) oxy] nonenoic acid</li><li>A) p) 3-Hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] -5-tri-decenyl-2-oxetanone    from 2-hexyl-3-hydroxy (R) -5- [tetrahydro -2H-pyran-2-yl) oxy] hexadecenoic acid</li><li>A) q) 3-Hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] -5-hexenyl] -2-oxetanone    from 2-hexyl-3-hydroxy- (R) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] nonenoic acid.</li></ul>

B)

Preparation of the acids of formula V

0034<ul id="ul0005" list-style="none"><li>B) a) 1.0 g of the crude diastereomer mixture (13Z, 16Z) -2-hexyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester in 17 ml of a 2N methanolic potassium hydroxide solution until the starting material has disappeared to reflux. The reaction mixture is cooled and poured onto 60 ml of ice water. The pH is adjusted to 1 by dropwise addition of 1M aqueous hydrochloric acid and then extracted exhaustively with ether. The combined ether phases are dried, filtered and evaporated. The oil is chromatographed on silica gel, a mixture of diastereomers of    (13Z, 16Z) -2-hexyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] -13,16-docosadienoic acid is obtained as an oil, IR: 3350, 1709, 1132, 1078 , 1023 cm⁻¹. The following are obtained in an analogous manner:</li><li>B) b) (13Z, 16Z) -2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] -13,16-docosadienoic acid    from (13Z, 16Z) -2-ethyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester</li><li>B) c) (2S, 3S, 5R, Z) -2-ethyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13-docosenoic acid    from (2S, 3S, 5R, Z) -2-ethyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-8-yl) oxy] -13-docosenoic acid t-butyl ester</li><li>B) d) (13Z, 16Z) -2-benzyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid, MS: 458 (M⁺-dihydropyran ); IR: 3008, 1709, 1160, 1134, 1115 cm -1    from (13Z, 16Z) -2-benzyl-3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester</li><li>B) e) (2S, 3S, 5S) -2-ethyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid    from (2S, 3S, 5S) -2-ethyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester</li><li>B) f) (2S, 3S, 5R) -2-hexyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid    from (2S, 3S, 5R) -2-hexyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester</li><li>B) g) 2-Hexyl-3-hydroxy- (R) -5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid    from 2-hexyl-3-hydroxy- (R) -5 - [(tetrahydro -2H-pyran-2-yl) oxy] hexadecanoic acid t-butyl ester</li><li>B) h) 2-Hexyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid    from 2-hexyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] methyl hexadecanoate.</li></ul>

C)

Production of acids V (variant)

0035<ul id="ul0006" list-style="none"><li>C) a) 2 ml of diisopropylamine in 30 ml of dry THF are cooled to -20 ° C and 9.68 ml of butyllithium (1.6M / hexane) are added dropwise so that the temperature does not exceed -20 ° C. The mixture is then stirred for 15 minutes and then cooled to -50 ° C. Then 0.720 ml of 4-pentenoic acid in 10 ml of THF are added dropwise and stirring is continued at -50 ° C. for 10 minutes. The mixture is stirred for 1 hour at room temperature and then cooled again to -50 ° C. Now 2 g of rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanol in 10 ml of THF are added dropwise and the mixture is stirred for a further 30 minutes at -50 ° C., then for 72 hours at room temperature. After hydrolysis with 2N hydrochloric acid, the reaction mixture is evaporated. The residue is extracted with ether. The organic phase is dried over sodium sulfate, filtered and evaporated. The material obtained is filtered through a column of silica gel. Crude 2-allyl-3-hydroxy-5 [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid is obtained. In an analogous way you get:</li><li>C) b) 2-Ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid    from rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanal and butanoic acid</li><li>C) c) 2-Methyl-3-hydroxy (R) -5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid    from (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanal and propionic acid</li><li>C) d) 2-Hexyl-3-hydroxy (R) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexanoic acid    from (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] butanal and octanoic acid</li><li>C) e) 2-Hexadecyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexanoic acid    from 3- [tetrahydro-2H-pyran-2-yl) oxy] butanal and octadecanoic acid</li><li>C) f) 2-Hexyl-3-hydroxy- (R) -5 [(tetrahydro-2H-pyran-2-yl) oxy] -8-nonenoic acid    from (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -6-heptenal and octanoic acid</li><li>C) g) 2-Decyl-3-hydroxy- (R) -5 [(tetrahydro-2H-pyran-2-yl) oxy] -8-nonenoic acid    from (R) -3 - [(tetrahydro-2H-pyran -2-yl) oxy] -6-heptenal and dodecanoic acid</li><li>C) h) 2-Hexyl-3-hydroxy- (R) -5 [(tetrahydro-2H-pyran-2-yl) oxy] -8-pentadecenoic acid    from (R) -3 - [(tetrahydro-2H-pyran -2-yl) oxy] -6-tetradecenal and octanoic acid</li><li>C) i) 2-Hexyl-3-hydroxy-5 [(tetrahydro-2H-pyran -2-yl) oxy] -8-nonenoic acid    from 3 - [(tetrahydro-2H-pyran-2-yl) oxy] -6-heptenal and octanoic acid.</li></ul>

D)

Preparation of the esters of formula VI

0036<ul id="ul0007" list-style="none"><li>D) a) 3.1 ml of diisopropylamine are cooled to -5 ° C. under argon and 14 ml of approximately 1.6M n-butyllithium solution in n-hexane are added dropwise. Then it is stirred for 10 minutes. After cooling to -50 ° C., the cooling bath is removed and a solution of 5.08 g of a mixture of diastereomers of (13Z, 16Z) -3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13 , 16-docosadienoic acid butyl ester, added dropwise in 5 ml of THF. The temperature rises to -20 ° C. Allow to warm to 0 ° C and stir for 10 minutes. A solution of 2.1 ml of 1-bromohexane in 2.5 ml of hexamethylphosphoric triamide is then added, the temperature rising to 9 ° C. Then allowed to warm up to room temperature and stirred for 2 1/2 hours. The solution is poured onto 200 ml of ice water and saturated with sodium chloride. It is extracted with ether. The combined extracts are dried, filtered and evaporated. The remaining oil is chromatographed on silica gel. A mixture of diastereomers of (13Z, 16Z) -2-hexyl -3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] -13,16-docosadienoic acid t-butyl ester, MS: 519 ( M⁺- (CH₃) ₃CO.): IR: 3503, 1728, 1709, 1153. The following are obtained in an analogous manner:</li><li>D) b) (13Z, 16Z) -2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester, MS: 396 (M. ⁺-dihydropyran isobutylene); IR: 3510, 1728, 1153, 1137 cm -1    from (13Z, 16Z) -3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester and ethyl iodide</li><li>D) c) (13Z, 16Z) -2-benzyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester, MS: 525 (M. ⁺- (H₃C) ₃ CO.); IR: 3498, 1725, 1604, 1585, 1496, 1150 cm -1    from (13Z, 16Z) -3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester and benzyl bromide</li><li>D) d) (2S, 3S, 5R, Z) -2-ethyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] t-butyl docosenoate, MS: 465 (M⁺ - (H₃C) ₃CO.); IR: 3499, 1729, 1155, 1137, 1116 cm -1    from (3S, 5R, Z) -3-hydroxy-5 - [(tetrahydro -2H-pyran-2-yl) oxy] -13-docosenoic acid t-butyl ester and ethyl iodide</li><li>D) e) (2S, 3S, 5R) -2-ethyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester    from (3S, 5R) -3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester and ethyl iodide</li><li>D) f) (2S, 3S, 5R) -2-hexyl-3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester,    from (3S, 5R) -3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester and 1-bromohexane</li><li>D) g) 2-Hexyl-3-hydroxy (R) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid t-butyl ester, TLC silica gel, hexane-diethyl ether 1: 1, Rf = 0 , 65    from 3-hydroxy (R) -5 - [(tetrahydro-2H-pyran -2-yl) oxy] t-butyl hexadecanoate and 1-bromohexane</li></ul>

E)

Preparation of the Esters of Formula VI (Variant)

0037While gassing with argon, 7.76 g of methyl 2-hexyl-3-oxo-5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoate (0.017 mol) dissolved in 500 ml of THF are mixed with 20 ml of MeOH and brought to -5 ° C cooled. 5.3 g of sodium borohydride (0.14 mol) are added in portions, with stirring, so that the temperature does not exceed 0.degree. After stirring for 3 hours, the excess sodium borohydride is filtered off, the reaction mixture is hydrolyzed with 2N hydrochloric acid in the cold (to pH 6) and the solvent is evaporated off. The residue is extracted with ether and the ethereal phase is dried and evaporated. 7.71 g of 2-hexyl-3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid methyl ester are obtained.

F)

Preparation of the esters of formulas XVII and IX

0038<ul id="ul0008" list-style="none"><li>F) a) 147.6 g of a mixture of diastereomers of (11Z, 14Z) -3-hydroxy-2 - [(R) -o-tolylsulfinyl] -11,14-eicosadienoic acid t-butyl ester are dissolved in 5500 ml of THF and then 190 g of amalgamated aluminum foil were added within 6 hours. The temperature is kept between 15 and 20 ° C. After the addition has ended, the mixture is stirred until the reaction has ended. The insoluble material is suctioned off and washed first with 1 l, then with 2 l THF. The filter cake is taken up in 2 l of diethyl ether, stirred and suctioned off again. This procedure is repeated once. The combined organic phases are evaporated and the oily residue is purified by chromatography on silica gel, giving an enantiomer mixture which consists of 80%    (R, 11Z, 14Z) -3-hydroxy-11,14-eicosadienoic acid t-butyl ester, MS: 324 (M⁺-isobutylene); IR: 3452, 1715, 1154 cm -1. The following are obtained in an analogous manner:</li><li>F) b) (13Z, 16Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13,16-docosadienoic acid t-butyl ester, IR: 3481, 1730, 1153, 1075 , 1014 cm⁻¹    from (13Z, 16Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl] -13,14-docosadienoic acid t-butyl ester.</li><li>F) c) (3S, 5R, Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid t-butyl ester, MS: 437 (M⁺- (H₃C ) ₃CO); IR: 3484, 1730, 1655, 1153, 1075, 1024 cm -1    from (3S, 5R, Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl] -13-docosenoic acid t-butyl ester.</li><li>F) d) (R, Z) -3-hydroxy-11-eicosenoic acid t-butyl ester, IR: 3445, 1716, 1154 cm⁻¹    from (R, Z) -3-hydroxy-2 - [(R) -p-tolylsulfinyl] -11-eicosenoic acid t-butyl ester.</li><li>F) e) (3S, 5S) -3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] valeric acid t-butyl ester, MS: 357 (M⁺ -tetrahydropyranyl); IR: 3446, 1727, 1590, 1505, 1489, 1152, 1133, 1118, 1074, 1022 cm -1    from (3S, 5S) -3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -o-tolylsulfinyl] valeric acid t -butyl ester.</li><li>F) f) [(S) -α-hydroxy-p-phenoxybenzyl] acetic acid t-butyl ester, mp. 64-65 ° C (from n-hexane), MS: 314 (M⁺); IR: 3440, 1713, 1590, 1506, 1491, 1158    from (βS) -β-hydroxy-p-phenoxy-α - [(R) -p-tolylsulfinyl-hydrocinnamic acid t-butyl ester.</li><li>F) g) 3-Hydroxy- (R) -5 - [(tetrahydro-2H-pyran -2-yl) oxy] hexadecanoic acid t-butyl ester    from 3-hydroxy- (R) -5-tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl] t-butyl ester of hexadecanoate.</li></ul>

G)

Preparation of the sulfoxides of the formulas XI and XVI

0039<ul id="ul0009" list-style="none"><li>G) a) 16.5 g of [(S) -p-tolylsulfinyl] acetic acid t-butyl ester are dissolved in a mixture of 600 ml of ether and 60 ml of THF and cooled to -78 ° C. Then 43 ml of t-butyl magnesium bromide are added dropwise so that the temperature remains below -70 ° C. After stirring for 1 hour at -78 ° C., 13.4 g of (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanal in 100 ml of THF are added dropwise. After 2 hours at -78 ° C, the reaction mixture is hydrolyzed with 2N hydrochloric acid and the solvent is evaporated off. The remaining reaction mixture is extracted with ether and the ethereal phase is dried and evaporated. Chromatography on silica gel gives 14.9 g of 3-hydroxy- (R) -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl] hexadecanoic acid-t -butyl ester (67% yield), mp. 97-98 ° C. The following are obtained in an analogous manner:</li><li>G) b) (3R, 11Z, 14Z) -3-hydroxy-2 - [(R) -p-tolylsulfinyl] -11,14-eicosadienoic acid t-butyl ester, IR: 3400, 1727, 1653, 1596, 1494, 1279, 1258, 1145, 1085, 1045 cm -1    from 9,12-octadienal and (R) -p-tolylsulfinyl-acetic acid t-butyl ester.</li><li>G) c) (13Z, 16Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl] -13,16-docosadienylic acid t -butyl ester    from (11Z, 14Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11,14-eicosadienal and (S) -p-tolylsulfinyl-acetic acid t-butyl ester.</li><li>G) d) (R, Z) -3-hydroxy-2 - [(R) -p-tolylsulfinyl] -11-eicosenoic acid t-butyl ester, MS: 464 (M⁺-isobutylene), IR: 3403, 1727, 1596, 1494, 1145, 1043 cm -1    from 9-octenal and (R) -p-tolylsulfinyl-acetic acid t-butyl ester.</li><li>G) e) (3S, 5R, Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl-13-docosenoic acid-t- butyl ester    from (R, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosenal and (S) -p-tolylsulfinyl-acetic acid t-butyl ester.</li><li>G) f) (βS) -β-hydroxy-p-phenoxy-α - [(R) -p-tolylsulfinyl] -hydrocinnamic acid t-butyl ester, mp. 126-128 ° C (from n-hexane)    from p-phenoxy-benzaldehyde and (R) -p-tolylsulfinyl-acetic acid t-butyl ester.</li><li>G) g) (3S, 5S) -3-hydroxy-5- (p-phenoxyphenyl) -5 - [(tetrahydro -2H-pyran-2-yl) oxy] -2 - [(S) -p-tolylsulfinyl] valeric acid t-butyl ester, m.p. 140-145 ° C    from (βS) -p-phenoxy-β - [(tetrahydro-2H-pyranyl) oxy] hydrocinnamaldehyde and (S) -p-tolylsulfinyl-acetic acid t-butyl ester.</li></ul>

H)

Preparation of the alcohols of the formula XIII

00405 g of a 55% sodium hydride dispersion are washed with hexane and mixed with 600 ml of THF. 18.9 g of methyl 2-acetyloctanoate dissolved in 80 ml of THF are added dropwise with cooling. After stirring for 2 hours, the mixture is cooled to -10 ° C. and 65 ml of butyllithium (1.6M hexane) are added with cooling. After 1 hour at -10 ° C., a solution of 19.7 g of dodecanal in 80 ml of THF is added dropwise. The mixture is allowed to warm to room temperature and stirred for a further 2 hours. The reaction mixture is hydrolyzed with 100 ml of 2N hydrochloric acid and evaporated. The residue is extracted with ether and the ethereal phase is dried and evaporated. Chromatography on silica gel gives methyl 2-hexyl-5-hydroxy-3-oxohexadecanoate, mp. 38-39 ° C.

I)

Preparation of the aldehydes of the formula VIII

0041<ul id="ul0010" list-style="none"><li>I) a) 9.2 g of (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanoic acid t-butyl ester are dissolved in 115 ml of toluene and cooled to -75 ° C. while gassing with argon and excluding moisture . 26.5 ml of a 1.2M solution of diisobutylaluminum hydride in toluene are then added dropwise so that the temperature does not exceed -70.degree. After stirring for 1 hour at -75 ° C, 7.4 ml of saturated aqueous ammonium chloride solution and then 15.5 ml of 1N hydrochloric acid are added dropwise at -70 ° C. Then let it warm up to room temperature. After stirring for 1 hour, the organic phase is dried, filtered and evaporated. The material obtained is chromatographed on silica gel. (R) -3 - [(Tetrahydro-2H-pyran-2-yl) oxy] tetradecanal is obtained as a colorless oil.</li><li>I) b) rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanal    from rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] methyl tetradecanoate</li><li>I) c) (11Z, 14Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11,14-eicosadienal, MS: 291 (M⁺-2-tetrahydropyranyloxy), 290 (M⁺- Tetrahydro-2-pyranol), IR: 2729, 1726, 1132, 1118, 1077 cm -1    from (11Z, 14Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11,14-eicosadienoic acid t-butyl ester</li><li>I) d) (R, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosanal, MS: 292 (M⁺-tetrahydro-2-pyranol); IR: 2722, 1726, 1132, 1118, 1077 cm -1    from (R, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosanoic acid t-butyl ester</li><li>I) e) (βS) -p-phenoxy-β - [(tetrahydro-2H-pyran-2-yl) oxy] hydrocinnamaldehyde    from [(S) -p-phenoxy-α - [(tetrahydro-2H-pyran-2-yl) oxy] benzyl] acetic acid t-butyl ester</li><li>I) f) (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -6Z-tetradecenal    from (R) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -6H-tetradecenoic acid ethyl ester.</li></ul>

J)

Preparation of the esters of formula XV

0042<ul id="ul0011" list-style="none"><li>J) a) 66.5 g of (R, 11Z, 14Z) -3-hydroxy-11,14-eicosadienoic acid t-butyl ester, which contains about 20% of the (S) -isomer, and 32 ml of freshly distilled 3,4 -Dihydro-2H-pyran are dissolved in 650 ml of methylene chloride and cooled to 3 ° C. Then 640 mg of p-toluenesulfonic acid monohydrate are added, the temperature rising to 8 ° C. The mixture is stirred until the reaction has ended. The solution is then washed with a mixture of 250 ml of saturated aqueous sodium chloride solution, 250 ml of saturated aqueous sodium hydrogen carbonate solution and 500 ml of water. After drying, the mixture is filtered and the solvent is removed. The oily residue is purified by chromatography on silica gel. A mixture of diastereomers of (11Z, 14Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11,14-eicosadienoic acid t-butyl ester, MS: 324 (M⁺-dihydropyran-isobutylene) is obtained; IR: 1731, 1158, 1024 cm -1. The following are obtained in an analogous manner:</li><li>J) b) (R, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosenoic acid t-butyl ester, MS: 326 (M⁺-dihydropyran-isobutylene), IR: 1731 , 1158, 1134, 1118 cm -1    from (R, Z) -3-hydroxy-11-eicosenoic acid t-butyl ester and dihydropyran</li><li>J) c) [(S) -p-phenoxy-α - [(tetrahydro-2H-pyran-2-yl) oxy] benzyl] acetic acid t-butyl ester, MS: 313 (M⁺-tetrahydropyranyl); IR: 1730, 1590, 1506, 1489, 1391, 1367, 1201, 1149, 1118 cm -1</li><li>J) d) rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] methyl tetradecanoate, TLC silica gel, hexane ether 3: 1, Rf = 0.67    from methyl rac-3-hydroxytetradecanoate and dihydropyran</li><li>J) e) 2-Hexyl-3-oxo-5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid methyl ester, mp 37-38 ° C    from 2-hexyl-5-hydroxy-3-oxo-hexadecanoic acid methyl ester and dihydropyran.</li></ul>

K)

Preparation of an ester of the formula XV (variant)

0043<ul id="ul0012" list-style="none"><li>K) a) A solution of 0.51 g of diisopropylamine in 20 ml of THF is mixed with 3.13 ml of a 1.6 molar solution of butyllithium in hexane at 0 ° C. Then it is cooled to -78 ° C. and 2.3 g of heptyltriphenylphosphonium bromide are added and the mixture is left at this temperature for 5 minutes. A solution of 5-formyl- (R) -3 - [(tetrahydro -2H-pyran-2-yl) oxy] pentanecarboxylic acid ethyl ester in 10 ml of THF is then added dropwise. Allow to stir at room temperature overnight. The reaction mixture is mixed with water, extracted with ether, dried and evaporated in vacuo. The residue is chromatographed with toluene-ethyl acetate (9: 1) over silica gel and 0.5 g of (R) -3 - [(tetrahydro-2H-pyran -2-yl) oxy] -6Z-tetradecenecarboxylic acid ethyl ester is obtained.</li><li>K) b) In a similar way one obtains:    (R) -3 - [(Tetrahydro-2H-pyran-2-yl) oxy] -6Z-eicosenecarboxylic acid ethyl ester.</li></ul>

L)

Preparation of an aldehyde of the formula XIX

0044A solution of 2.56 g of (R) -3 - [(tetrahydro-2H-pyran -2-yl) oxy] -6-heptenoic acid methyl ester in 40 ml of ethyl acetate is treated with ozone at -75 ° C. When the reaction has ended, 0.1 g of Pd on carbon is added and the mixture is hydrogenated at room temperature. When the uptake of hydrogen has ended, the catalyst is filtered off, washed with ethyl acetate and evaporated in vacuo. The crude 5-formyl- (R) -3 - [(tetrahydro-2H-pyran -2-yl) oxy] pentanecarboxylic acid methyl ester is obtained.

M)

Separation of the acids of formula V into their stereoisomers

0045<ul id="ul0013" list-style="none"><li>M) a) 15.4 g of a mixture of diastereomers of 2-hexyl-3-hydroxy- (R) -5 - [(tetrahydro-2H) -pyran-2-yl) oxy] hexadecanoic acid are dissolved in 160 ml of ethanol and 800 mg Toluene-4-sulfonic acid monohydrate is added. The reaction mixture is heated to 55-60 ° C until the reaction is complete. The solvent is removed in vacuo and the residue is dissolved in 160 ml of dichloromethane. The mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated. The material obtained is chromatographed on silica gel. The tetrahydro-3-hexyl-4-hydroxy R-6-undecyl-2H-pyran-2-one is obtained, mp. 95-96 ° C.</li><li>M) b) 3 g of a mixture of diastereomers of tetrahydro-3-hexyl-4-hydroxy- (R) -6-undecyl-2H-pyran-2-one are dissolved in 300 ml of acetone. 3 ml of Jones reagent are added dropwise with stirring so that the temperature does not exceed 25 ° C. After 3 hours the reaction mixture is poured onto 700 ml of H₂O. The lactone precipitates and is filtered off. After recrystallization in ether / n-hexane, 1.7 g of tetrahydro-3-hexyl-4-oxo (R) -6-undecyl-2H-pyran-2-one, mp. 112.5-113.5 ° C.</li><li>M) c) 8 g of a mixture of isomers of tetrahydro-3-hexyl-4-oxo (R) -6-undecyl-2H-pyran-2-one are dissolved in 2 l of ethyl acetate and 3 g of PtO₂ are added. Then hydrogenated (50 bar) for 12 hours. The catalyst is filtered off and the solution is evaporated. After recrystallization, m on 7 g of (3S, 4S, 6R) tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one, mp. 108-109 ° C.</li><li>M) d) 1.5 g (3S, 4S, 6R) -tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one are dissolved in 8 ml DMF. Then 0.85 g of t-butyldimethylchlorosilane in 4 ml of DMF is added dropwise. Stir for 48 hours. The reaction mixture is poured into 100 ml of ether and washed with 1N hydrochloric acid. The organic phase is dried, filtered and evaporated. The material obtained is chromatographed on silica gel. 1.26 g of (3S, 4S, 6R) -tetrahydro-3-hexyl-4 - [(t-butyldimethylsilyl) oxy] -6-undecyl-2H-pyran-2-one, MS: 411 (M⁺- t-butyl).</li><li>M) e) 0.3 g (3S, 4S, 6R) -tetrahydro-3-hexyl -4 - [(t-butyldimethylsilyl) oxy] -6-undecyl-2H-pyran-2-one are mixed in a mixture of 12 ml of dioxane and 0.64 ml of 1N aqueous potassium hydroxide dissolved. You stir overnight. Then the reaction mixture is evaporated and dissolved in 10 ml of hexamethylphosphoric triamide. 0.35 ml of benzyl bromide are added. Stir for 2 days. The reaction mixture is poured onto water and extracted with ether. The ether phase is dried, filtered and evaporated. The oil is chromatographed on silica gel. 330 mg (2S, 3S, 5R) -2-hexyl-3 - [(t-butyldimethylsilyl) oxy] -5-hydroxyhexadecanoic acid benzyl ester, MS: 519 (M⁺-t-butyl.</li><li>M) f) 350 mg (2S, 3S, 5R) -2-hexyl-3 - [(t-butyldimethylsilyl) oxy] -5-hydroxyhexadecanoic acid benzyl ester and 0.5 ml of freshly distilled 3,4-dihydro-2H-pyran are in 10 ml of methylene chloride dissolved and cooled to -15 ° C. A crystal of p-toluenesulfonic acid monohydrate is added. The mixture is stirred until the reaction has ended. The solution is then evaporated and the residue is chromatographed on silica gel. 330 mg (2S, 3S, 5R) -2-hexyl-3 - [(t-butyldimethylsilyl) oxy] -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid benzyl ester, MS: 603 (M. ⁺-t-butyl).</li><li>M) g) 480 mg (2S, 3S, 5R) -2-hexyl-3 - [(t-butyldimethylsilyl) oxy] -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid benzyl ester and 350 mg tetrabutylammonium fluoride trihydrate are dissolved in 8 ml of THF and stirred for 12 hours. After evaporation, the residue is dissolved in 50 ml of ether and washed with water. The ethereal phase is dried and evaporated. The crude product is chromatographed on silica gel. 240 mg of (2S, 3S, 5R) -2-hexyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid benzyl ester, MS: 463 [(M + H) ⁺- Dihydro-2H-pyran-2-yl].</li><li>M) h) 430 mg (2S, 3S, 5R) -2-hexyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] benzyl hexadecanoate in 10 ml THF are mixed with Pd / C 10% added and hydrogenated for 3 hours. The catalyst is filtered off and, after evaporation, the crude product is chromatographed on silica gel. This gives (2S, 3S, 5R) -2-hexyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid.</li></ul>

0046Novel are the alcohols of formula III, wherein R¹ and R² have the above meaning, where if R¹ is n-hexyl, R² has a meaning other than undecyl or 2,5-undecadienyl.

0047Preferred oxetanones of the formula I and III are those in which R 1 is methyl, propyl, hexyl, decyl, hexadecyl, allyl, benzyl or in particular ethyl; R² is methyl, undecyl, 3-butenyl, 3-undecenyl, 8,11-heptadecadienyl, phenoxyphenyl or especially heptadecyl; R³ is acetyl or especially formyl: R⁴ is methyl or in particular hydrogen, and R⁵ is hydrogen, methyl, 2-butyl, benzyl, methylthioethyl or in particular i-butyl, or R⁴ together with R⁵ forms a pyrrolidinyl radical.

0048Examples of such connections are:    N-Formyl-L-leucine-1 - [(trans-3-ethyl-4-oxo -2-oxetanyl) methyl] dodecyl ester    N-Formyl-L-leucine-1 - [(trans-3-allyl-4-oxo -2-oxetanyl) methyl] dodecyl ester    N-Formyl- (S) -leucine (S, 9Z, 12Z) -1 - [(2S, 3S) -3-ethyl -4-oxo-2-oxetanyl] methyl] -9.12-octadecadienyl ester    N-Formyl- (S) -leucine (S, Z) -1 - [[(2S, 3S) -3-ethyl-4-oxo -2-oxetanyl] methyl] -9-octadecenyl ester    N-Formyl- (S) -leucine (R) -α - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -p-phenoxybenzyl ester.

0049Is particularly preferred    N-Formyl- (S) -leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester.

0050The oxetanones of the formula I have valuable pharmacological properties. They inhibit pancreatic lipase in particular and can accordingly be used to combat or prevent obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

0051The inhibition of pancreatic lipase by the oxetanones of the formula I can be demonstrated experimentally by titrimetrically recording the oleic acid released when triolein is cleaved by porcine pancreatic lipase. To an emulsion containing 1 mM taurodeoxycholate, 9 mM taurocholate, 0.1 mM cholesterol, 1 mM eilezithin, 15 mg / ml BSA, 2 mM Tris-HCl, 100 mM sodium chloride, 1 mM calcium chloride and the substrate triolein are added the compound of formula I dissolved in ethanol or dimethyl sulfoxide (10% of the emulsion volume) and starts the reaction by adding 100 µg (175 U) of pork pancreatic lipase. The pH is kept at 8 during the reaction by adding sodium hydroxide solution. The IC₅₀ is calculated from the consumption of sodium hydroxide solution determined over 10 minutes. The IC₅₀ is the concentration at which the lipase activity is half maximally inhibited. The following table contains the IC₅₀ values ​​determined for the compounds of the formula I and details of the acute toxicity (toxicity after single oral administration to mice).<tables id="tabl0001" num="0001"><img file="EP0185359B1_D0022.tif" /></tables>

0052The oxetanones of the formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.

0053For the production of pharmaceutical preparations, the products according to the invention can be administered with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such a carrier for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; Depending on the nature of the active ingredient, no carriers are required at all in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

0054The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts, to change the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.

0055As mentioned at the outset, medicaments containing an oxetanone of the formula I are also the subject of the present invention, and also a process for the preparation of such medicaments, which is characterized in that an oxetanone of the formula I and, if appropriate, one or more other therapeutically valuable substances brings a pharmaceutical formulation. As mentioned, the compounds of the formula I can be used in combating or preventing diseases, in particular in combating or preventing obesity, hyperlipaemia, atherosclerosis and arteriosclerosis. The dosage can vary within wide limits and must of course be adapted to the individual circumstances in each individual case. In general, a daily dose of about 0.1 mg to 100 mg / kg of body weight should be appropriate, especially with oral administration.

0056The oxetanones of the formula I can also be added to industrially manufactured foods, fats, oils, butter, margarine, chocolate and other confectionery products being particularly suitable. Such industrially manufactured foods, which can contain about 0.1 to 5% by weight of an oxetanone of the formula I, and their production are also the subject of the present invention.

0057The following examples are intended to explain the present invention in greater detail, but in no way limit its scope. All temperatures are given in degrees Celsius.

example 1

0058<ul id="ul0014" list-style="none"><li>1.1) To a solution of 100 mg (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, 74 mg triphenylphosphine and 45 mg N-formylglycine in 2 ml THF are added dropwise with stirring 44.3 ml of diethyl azodicarboxylate. After stirring overnight, the organic phase is evaporated in vacuo and the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9: 1). You get    the N-formylglycine- (S) -1- (2S, 3S) - [(3-hexyl-4-oxo -2-oxetanyl) methyl] dodecyl ester, [α]<maths id="math0001" num=""><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>25</mtext></mrow><mrow><mtext>D </mtext></mrow></mfrac></mrow></math><img file="EP0185359B1_D0023.tif" /></maths> = -22 ° (CHCl₃, c = 0.88),</li><li>1.2) by esterification of trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone with N-formylglycine    the N-formylglycine-1 - [(trans-3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel, diethyl ether-hexane 9: 1, Rf = 0.34</li><li>1.3) by esterification of rac-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2R, 3S, 4S: 2S, 3R, 4R) with N-acetyl-L-leucine    the N-acetyl-L-leucine-1 - [(trans-3-hexyl-4-oxo -2-oxetanyl) methyl] dodecyl ester, TLC silica gel; CHCl₃: hexane: dioxane 1: 3: 0.25, Rf = 0.36</li><li>1.4) by esterification of (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone with N-formyl-β-alanine    the N-formyl-β-alanine (S) -1- (2S, 3S) - [(3-hexyl-4-oxo -2-oxetanyl) methyl] dodecyl ester, TLC silica gel; Toluene-ethyl acetate 2: 1, Rf = 0.39</li><li>1.5) by esterification of trans-3-hexyl - [(S) -2-hydroxypropyl] -2-oxetanone (3S, 4S: 3R, 4R) with N-formyl-L-leucine    the N-formyl-L-leucine (S) -1 - [(3-hexyl-4-oxo-2-oxetanyl) methyl] ester, TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.27</li><li>1.6) by esterification of 3-methyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone (3R, 4R: 3S, 4S) with N-formyl-L-leucine    the N-formyl-L-leucine (S) -1 - [(3-methyl-4-oxo -2-oxetanyl) methyl] dodecyl ester, TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.34</li><li>1.7) by esterification of rac-trans-3-hexadecyl-4- (2-hydroxypropyl) -2-oxetanone with N-formyl-L-leucine    the N-formyl-L-leucine-1 - [(trans-3-hexadecyl-4-oxo -2-oxetanyl) methyl] ethyl ester, MS: 496 (M⁺); TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.44</li><li>1.8) by esterification of rac-trans-3-ethyl-4- (2-hydroxytridecyl) -2-oxetanone with N-formyl-L-leucine</li><li>1.8) a) the N-formyl-L-leucine-1 - [(trans-3-ethyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.62</li><li>1.8) b) the N-formyl-L-leucine-1 - [(trans-3-ethyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.55</li><li>1.9) by esterification of rac-trans-3-allyl-4- (2-hydroxytridecyl) -2-oxetanone with N-formyl-leucine    the N-formyl-L-leucine-1 - [(trans-3-allyl-4-oxo -2-oxetanyl) methyl] dodecyl ester, IR: 1825, 1739, 1688; TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.58</li><li>1.10) by esterification of rac-trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone with N-benzylcarbamoyl-leucine    the N-benzylcarbamoyl-leucine-1 - [(trans-3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel, hexane-diethyl ether 1: 1, Rf = 0.64</li><li>1.11) by esterification of (3S, 4S) -3-hexyl-4 - [(R, 10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone with N-formyl- (S) -leucine    the N-formyl (S) leucine (S, 9Z, 12Z) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -9,12-octadecadienyl ester, MS : 575 (M⁺); IR: 1824, 1739, 1675 cm -1</li><li>1.12) by esterification of rac-trans-3-hexyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (2R, 3R, 4R: 2S, 3S, 4S) with N-formyl (S) leucine    the N-formyl- (S) -leucine (9Z, 12Z) -1- (trans-3-hexyl) -4-oxo -2-oxetanyl) methyl] -9,12-octadecadienyl ester (2 diastereomers), MS: 575 (M⁺); IR: 1824, 1740, 1687 cm -1</li><li>1.13) by esterification of cis-3-hexyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (mixture of diastereomers) with N-formyl- (S) -leucine</li><li>1.13) a) the N-formyl- (S) -leucine (9Z, 12Z) -1 - [(cis-3-hexyl-4-oxo -2-oxetanyl) methyl] -9,12-octadienyl ester (mixture of diastereomers I) , MS: 575 (M⁺); IR: 1823, 1739, 1674 cm -1 and</li><li>1.13) b) the N-formyl- (S) -leucine (9Z, 12Z) -1 - [(cis-3-hexyl-4-oxo -2-oxetanyl) methyl] -9,12-octadienyl ester (mixture of diastereomers II) , MS: 372 (M⁺-N-formyl-leucine-CO₂); IR: 1822, 1739, 1684 cm -1</li><li>1.14 by esterification of (3S, 4S) -3-benzyl-4 - [(R, 10Z, 13Z) -2-hydroxy -10,13-nonadecadienyl)] - 2-oxetanone with N-formyl- (S) -leucine    the N-formyl- (S) -leucine (S, 9Z, 12Z) -1 - [[(2S, 3S) -3-benzyl-4-oxo -2-oxetanyl] methyl] -9,12-octadecadienyl ester, MS : 581 (M⁺); IR: 1825, 1739, 1683 cm -1</li><li>1.15) by esterification of rac-trans-3-benzyl-4 - [(10Z, 13Z) -2-hydroxy -10,13-nonadecadienyl] -2-oxetanone (2R, 3R, 4S: 2S, 3S, 4S) with N-formyl (S) leucine</li><li>1.15) a) the N-formyl- (S) -leucine (9Z, 12Z) -1 - [(trans-3-benzyl-4-oxo -2-oxetanyl) methyl] -9,12-octadecadienyl ester (diastereomer I) , MS: 581 (M⁺); IR: 1825, 1739, 1676 cm -1 and</li><li>1.15) b) the N-formyl- (S) -leucine (9Z, 12Z) -1 - [(trans-3-benzyl-4-oxo -2-oxetanyl) methyl] -9,12-octadecadienyl ester (diastereomer II) , MS: 581 (M⁺); IR: 1824, 1740, 1687 cm -1</li><li>1.16) by esterification of trans-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (mixture of diastereomers) with N-formyl- (S) -leucine    the N-formyl- (S) -leucine (S, 9Z, 12Z) -1 - [(2S, 3S) -3-ethyl-4-oxo -2-oxetanyl] methyl] -9,12-octadecadienyl ester, MS : 519 (M⁺); IR: 1825, 1739, 1684 cm -1</li><li>1.17) by esterification of cis-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone with N-formyl- (S) -leucine (mixture of enantiomers B)    the N-formyl- (S) -leucine (9Z, 12Z) -1 - [[cis-3-ethyl-4-oxo -2-oxetanyl] methyl] -9,12-octadecadienyl ester (mixture of diastereomers), MS: 316 ( M⁺-N-formyl-leucine-CO₂); IR: 1825, 1739, 1677 cm -1</li><li>1.18) by esterification of (3S, 4S) -3-ethyl-4 - [(R, Z) -2-hydroxy-10-nonadecenyl] -2-oxetanone with N-formyl-S-leucine</li><li>1.18) a) the N-formyl- (S) -leucine (S, Z) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -9-octadecenyl ester (diastereomer I), MS: 521 (M⁺); IR: 1825, 1739, 1673 cm -1 and</li><li>1.18) b) the N-formyl- (S) -leucine (Z) -1 - [(trans-3-ethyl-4-oxo -2-oxetanyl) methyl] -9-octadecenyl ester</li><li>1.19) by esterification of (3S, 4S) -3-hexyl-4 - [(S) -β-hydroxy-p-phenoxyphenethyl] -2-oxetanone with N-formyl- (S) -leucine    the N-formyl- (S) -leucine α - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] -p-phenoxybenzyl ester (mixture of diastereomers), MS: 509 (M⁺); IR: 1821, 1742, 1686 cm -1</li><li>1.20) by esterification of (3S, 4S) -3-ethyl-4 - [(S) -β-hydroxy-p-phenoxyphenethyl] -2-oxetanone with N-formyl- (S) -leucine</li><li>1.20) a) the N-formyl- (S) -leucine (R) -α - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -p-phenoxybenzyl ester, MS: 453 (M⁺); IR: 1824, 1742, 1686 cm -1 and</li><li>1.20) b) the N-formyl- (S) -leucine (S) -α - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] -p-phenoxybenzyl ester, MS: 453 (M⁺); IR: 1823, 1743, 1686 cm -1</li><li>1.21) by esterification of rac-trans-3-hexyl-4- (2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-leucine    the N-formyl-L-leucine-1 - [(trans-3-hexyl-4-oxo-2-oxetanyl) methyl] -4-pentenyl ester (mixture of 2 diastereomers)</li><li>1.22) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-leucine    the N-formyl-L-leucine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester</li><li>1.23) by esterification of (S) -3-hexyl- (S) -4 - [(B) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl- (S) -valine    the N-formyl- (S) -valine-1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester</li><li>1.24) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-isoleucine    the N-formyl-L-isoleucine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester</li><li>1.25) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-phenylalanine    the N-formyl-L-phenylalanine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) methyl] -4-pentenyl ester</li><li>1.26) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-alanine    the N-formyl-L-alanine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) -4-pentenyl ester</li><li>1.27) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-proline    the N-formyl-L-proline (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) methyl] -4-pentenyl ester</li><li>1.28) by esterification of (S) -3-hexyl- (S) -4 - [(R, Z) -2-hydroxy-5-tridecenyl) -2-oxetanone with N-formyl-L-leucine    the N-formyl-L-leucine (S, Z) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-dodecenyl ester</li><li>1.29) by esterification of (S) -3-decyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-leucine    the N-formyl-L-leucine (S) -1 - [[(2S, 3S) -3-decyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester</li><li>1.30) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2-hydroxy-5-hexenyl] -2-oxetanone with N-formyl-L-methionine    the N-formyl-L-methionine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) methyl] -4-pentenyl ester.</li><li>1.31) by esterification of 3-ethyl-4 - [(10Z, 13Z) -2-hydroxy -10,13-nonadecadienyl) -2-oxetanone with N-formyl-N-methyl-L-leucine    the N-formyl-N-methyl-L-leucine (9Z, 12Z) -1 - [(3-ethyl-4-oxo-2-oxetanyl) methyl] -9,12-octadienyl ester.</li></ul>

Example 2

0059A solution of 27 mg of N-formyl- (S) -leucine (S, 9Z, 12Z) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -9.12 octadienyl ester in 1 ml THF, 4.4 mg 10% Pd / C are added. It is hydrogenated at room temperature until the reaction has ended. The catalyst is filtered off and the solvent is removed in vacuo. After drying in vacuo, N-formyl- (S) -leucine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] octadecyl ester as white crystals, mp 64-65 ° C.

Example 3

0060Analogously to Example 2, one obtains:<ul id="ul0015" list-style="none"><li>3.1) from N-formyl- (S) -leucine (S, 9Z, 12Z) -1 - [(2S, 3S) -3-ethyl-4-oxo -2-oxetanyl] methyl] -9,12-octadecadienyl ester    the N-formyl- (S) -leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo -2-oxetanyl] methyl] octadecyl ester as white crystals, mp. 48-53 ° C.</li><li>3.2) from N-formyl-L-leucine-1 - [(trans-3-allyl-4-oxo-2-oxetanyl] methyl] dodecyl ester    the N-formyl-L-leucine-1 - [(trans-3-propyl-4-oxo -2-oxetanyl] methyl] dodecyl ester.</li></ul>

Example 4

0061A solution of 10 mg of N-formyl-L-leucine-1 - [(trans-3-hexyl-4-oxo-2-oxetanyl) methyl] -4-pentenyl ester in 0.5 ml of THF is mixed with 2.5 mg of 5 % Pd / C added and hydrogenated. When the uptake of hydrogen has ended, the catalyst is filtered off and evaporated in vacuo. The residue is chromatographed on silica gel using toluene-ethyl acetate (8: 2) and amorphous N-formyl-L-leucine-1 - [(trans-3-hexyl-4-oxo-2-oxetanyl] methyl] pentyl ester is obtained as a mixture of 2 diastereomers.

Example 5

0062Analogously to example 4, one obtains:<ul id="ul0016" list-style="none"><li>5.1) from N-formyl-L-alanine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester    the N-formyl-L-alanine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] pentyl ester</li><li>5.2) from N-formyl-L-phenylalanine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] -4-pentenyl ester    the N-formyl-L-phenylalanine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] -4-pentyl ester</li><li>5.3) from N-formyl-L-leucine (S) -1 - [[(2S, 3S) -3-decyl-4-oxo-2-oxetanyl] methyl] -4-pentenyl ester    the N-formyl-L-leucine (S) -1 - [[(2S, 3S) -3-decyl-4-oxo-2-oxetanyl] methyl] pentyl ester.</li></ul>

Example 6

0063A solution of 67 mg of N-benzylcarbamoyl-leucine-1 - [(trans -3-hexyl-4-oxo-2-oxetanyl) methyldodecyl ester in 15 ml of THF is in the presence of 10% Pd / C at room temperature under an H₂ atmosphere (Normal pressure) hydrogenated until complete conversion. The product obtained after filtration and evaporation is chromatographed on silica gel. Pure leucine-1 - [(trans-3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, mp 27-30 ° C., is obtained.

Example 7

0064265 mg of a diastereomer mixture of 3-hexyl-4 - [(10Z, 13Z) -2- [tetrahydro -2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanone are dissolved in 2.5 ml of ethanol dissolved and 13 mg of pyridinium 4-toluenesulfonate added. The reaction mixture is heated to 55-60 ° C until the reaction is complete. The solvent is removed in vacuo and the residue is taken up in ether, whereupon crystals precipitate which are removed by filtration. The solvent is evaporated off in vacuo and the residue is chromatographed on silica gel, the products listed below being eluted in the order given. The partially still contaminated products can be cleaned by repeating the chromatography. In this way, the following are obtained:<ul id="ul0017" list-style="none"><li>8.1) ((3S, 4S) -4-hexyl-4 - [(R, 10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (diastereomer I) as a colorless oil, MS: M⁺ (434); IR: 3420, 1820, 1120 cm -1</li><li>8.2) rac-trans-3-hexyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (diastereomer II) as a colorless oil, MS: M⁺ (434); IR: 3448, 1820, 1122 cm -1</li><li>8.3) cis-3-Hexyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (diastereomer III) as a colorless oil, MS: M⁺ (434): IR: 3374 , 1822, 1117 cm -1.</li></ul>

Example 8

0065The following were obtained as in Example 7:<ul id="ul0018" list-style="none"><li>8.A.1) trans-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone, MS: 360 (M⁺-H₂O), 334 (M⁺ -CO₂), 316 (M⁺-H₂O-W₂), IR: 3446, 1823, 1122 cm⁻¹</li><li>8.A. 2) cis-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (mixture of enantiomers A), MS: 378 / M⁺); IR: 3445, 1822, 1116 cm -1 and</li><li>8.A.3) cis-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (enantiomer mixture B), MS: (chemical induction with NH₃): 396 (M + NH<maths id="math0002" num=""><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>+</mtext></mrow><mrow><mtext>4</mtext></mrow></mfrac></mrow></math><img file="EP0185359B1_D0024.tif" /></maths>), 374 (M + H⁺); IR: 3415, 1823, 1115 cm -1    from a cis, trans mixture of 3-ethyl-4 - [(R, 10Z, 13Z) -2- [tetrahydro-2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanone.</li><li>8.B. 3-ethyl-4 - [(Z) -2-hydroxy -10-nonadecenyl] -2-oxetanone, MS: 362 (M⁺-H₂O), 318 (M⁺-H₂O-10₂); IR: 3435, 1823, 1119 cm -1    from 3-ethyl-4 - [(Z) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] -10-nonadecenyl-2-oxetanone</li><li>8.C.1) (3S, 4S) -3-benzyl-4 [(R, 10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone, MS: 440 (M⁺); IR: 3430, 1822, 1120 cm -1</li><li>8.C.2) rac-trans-3-benzyl-4 [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone, MS: 440 (M⁺); IR: 3512, 1822, 1123 cm -1 and</li><li>8.C.3) cis-3-benzyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (2 diastereomers), MS: 378 (M⁺-CO₂-H₂O ), 287 (M⁺-H₂O-CO₂-benzyl); IR: 3420, 1822, 1134 cm -1    from a mixture of diastereomers of 3-benzyl-4 - [(R, 10Z, 13Z) -2- [tetrahydro-2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanone.</li><li>8.D. (3S, 4S) -3-hexyl-4 - [(S) -β-hydroxy-p-phenoxyphenethyl] -2-oxetanone, mp. 51-54 °, MS: 368 (M⁺); IR: 3486, 1793, 1245, 1141    from (3S, 4S) -3-hexyl-4 - [(S) -p-phenoxy-β - [(tetrahydro-2H-pyran-2-yl) oxy] phenethyl] -2-oxetanone.</li><li>8.E. (3S, 4S) -3-ethyl-4 - [(S) -β-hydroxy-p-phenoxyphenethyl] -2-oxetanone, mp. 67-70 ° C, MS: 312 (M⁺); IR: 3416, 1835, 1250, 1108    from (3S, 4S) -3-ethyl-4 - [(S) -p-phenoxy-β - [(tetrahydro-2H-pyran -2-yl) oxy] phenethyl] -2-oxetanone.</li><li>8.F.1. rac-trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2R, 3S, 4S: 2S, 3R, 4R), mp. 44.5-46 °,</li><li>8.F.2. rac-trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2S, 3S, 4S: 2R, 3R, 4R), mp. 45.5-47 ° C,</li><li>8.F.3. rac-cis-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (pair of enantiomers A) TLC silica gel, hexane-ethyl acetate 9: 1, Rf = 0.49 and</li><li>8.F.4. rac-cis-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (pair of enantiomers B), TLC silica gel, hexane-ethyl acetate 9: 1, Rf = 0.46    from 3-hexyl-4- [2 - [(tetrahydro -2H-pyran-2-yl) oxy] tridecyl] -2-oxetanone.</li><li>8.G.1. (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, mp. 46-46.5 ° C and</li><li>8.G.2. (3R, 4R) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, mp 46-47 °; [α]<maths id="math0003" num=""><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>20</mtext></mrow><mrow><mtext>D </mtext></mrow></mfrac></mrow></math><img file="EP0185359B1_D0025.tif" /></maths> = + 12 ° C (CHCl₃, c = 1.5)    from 3-hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] tridecyl] -2-oxetanone.</li><li>8.H. rac-trans-3-ethyl-4- (2-hydroxytridecyl) -2-oxetanone, mp. 35.5-36 ° C    from 3-ethyl-4- [2 - [(tetrahydro-2H-pyran -2-yl] oxy] tridecyl] -2-oxetanone,</li><li>8.I. trans-3-methyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, TLC silica gel, hexane ether 1: 3, Rf = 0.49    from 3-methyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl] oxy] tridecyl] -2-oxetanone.</li><li>8.J. rac-trans-3-allyl-4- [2-hydroxytridecyl] -2-oxetanone, TLC silica gel, hexane ether 1: 1, Rf = 0.39    from 3-allyl-4- [2 - [(tetrahydro-2H-pyran -2-yl] oxy] tridecyl] -2-oxetanone.</li><li>8.K. trans-3-hexyl-4 - [(R) -2-hydroxypropyl] -2-oxetanone, TLC silica gel, hexane ether 1: 3, Rf = 0.36    from 3-hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl] oxy] propyl] -2-oxetanone.</li><li>8.L. rac-trans-3-hexadecyl-4- (2-hydroxypropyl) -2-oxetanone, mp 37-38 ° C    from 3-hexadecyl-4- [2 - [(tetrahydro-2H-pyran -2-yl] oxy] propyl] -2-oxetanone.</li><li>8.M. rac-trans-3-hexyl-4 - [- 2-hydroxy-5-hexenyl] -2-oxetanone (2R, 3S, 4S: 2S, 3R, 4R)    from trans-3-hexyl-4 - [- 2 - [(tetrahydro-2H-pyran -2-yl) oxy] -5-hexenyl] -2-oxetanone.</li><li>8.N. trans-3-decyl-4 - [(R) -2-hydroxy-5-hexenyl -2-oxetanone    from trans-3-decyl-4 - [(R) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] hexenyl] -2-oxetanone.</li><li>8.O. trans-3-hexyl-4 - ((R) -2-hydroxy-5-tridecenyl) -2-oxetanone    from trans-3-hexyl-4 - [(R) -2 - [(tetrahydro -2H-pyran-2-yl] oxy] tridecenyl-2-oxetanone.</li><li>8.P. (S) -3-Hexyl- (S) -4 [(R) -2-hydroxy-5-hexenyl] -2-oxetanone    from 3-hexyl-4 - [[(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] hexenyl] -2-oxetanone.</li><li>8.Q. trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (mixture of diastereomers)    from 3-hexyl-4- [2- [tetrahydro-2H-pyran -2-yl) oxy] tridecyl] -2-oxetanone.</li></ul>

Example 9

9.A.

Manufacture of the product

0066565 mg N - [(benzyloxy) carbonyl] -L-leucine (S) -1 - [[(2S, 3S) -3-ethyl -4-oxo-2-oxetanyl] methyl] octadecyl ester are dissolved in 12 ml THF. It is hydrogenated in the presence of 40 mg of 10% Pd / C at room temperature. After the reaction has ended, the catalyst is filtered off and evaporated. The residue is taken up in 9 ml of THF and 71 μl of formic acid anhydride are added dropwise. It is diluted with 5 ml of diethyl ether and washed twice with 2% sodium hydrogen carbonate solution and then with water. After drying over sodium sulfate, the mixture is filtered and evaporated. Chromatography on silica gel and recrystallization from n-pentane gives the N-formyl- (S) -leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl ] octadecyl ester of mp 60-61 ° C.

9.B.

Production of the starting material

0067<ul id="ul0019" list-style="none"><li>9.Ba) As described in paragraph 9.Be) below, a mixture of diastereomers is obtained which is 85-90% of (S, Z) -3-hydroxy-11-eicosensäure- (R) -2-hydroxy-1,2 , 2-triphenyl ethyl ester, mp. 112-114 ° C.    from oleyl aldehyde and (R) -α- (hydroxydiphenylmethyl) benzyl acetate.</li><li>9.Bb) As described in paragraph 9.Bf) below, (S, Z) -3-hydroxy-11-eicosenoic acid methyl ester is obtained as a colorless oil    from (S, Z) -3-hydroxy-11-eicosenoic acid- (R) -2-hydroxy-1,2,2-triphenylethyl ester.</li><li>9.Bc) As described in paragraph J) a) above for the preparation of the esters of the formula XV, (S, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosenoic acid methyl ester, which contains 10-15% of the (R) -isomer    from (S, Z) -3-hydroxy-11-eicosenoic acid methyl ester.</li><li>9.Bd) As described in paragraph I) a) above for the preparation of the aldehydes of the formula VIII, (S, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosenal, which contains 10-15% of the corresponding (R) -isomer    from (S, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosenoic acid methyl ester.</li><li>9.Be) 7.7 g of (R) -α- (hydroxydiphenylmethyl) benzyl acetate are suspended in 75 ml of THF under argon and cooled to about -75 ° C. This suspension is mixed dropwise with twice the amount of a lithium diisopropylamide solution. The mixture is allowed to warm to 0 ° C. and stirred at this temperature for 10 minutes. The solution is then cooled to -113 to -117 ° C. and 230 ml of diethyl ether are added during the cooling. A solution of (S, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosenal in 20 ml of diethyl ether is added dropwise to the solution and the mixture is stirred for a further 30 minutes. 20 ml of saturated ammonium chloride solution are added dropwise. Allow to warm up to room temperature. The aqueous phase is separated off and the organic phase is washed three times with 80 ml of water and once with saturated sodium chloride solution. After washing twice with 100 ml of saturated ammonium chloride solution, it is dried over sodium sulfate, filtered and evaporated. By recrystallization from methanol several times, a mixture of diastereomers is obtained which consists primarily of (3S, 5S, 13Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid- (R) - 2-hydroxy-1,2,2-triphenyl ethyl ester, mp. 91-93 ° C.</li><li>9.Bf) 12.75 g (3S, 5S, 13Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid- (R) -2-hydroxy-1 , 2,2-triphenylethyl ester are suspended in 130 ml of methanol and mixed with 17.5 ml of 1N methanolic sodium methylate solution. After the reaction has ended, the mixture is poured onto 650 ml of saturated ammonium chloride solution and extracted several times with diethyl ether. After drying over sodium sulfate, the mixture is filtered, evaporated, the residue is taken up in 70 ml of n-hexane and stirred for 1 hour while cooling with an ice bath. The white crystals are filtered off and washed with n-hexane. The filtrate is evaporated and chromatographed on silica gel. A diastereomer mixture is obtained which consists mainly of (3S, 5S, 13Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid methyl ester, IR: 3473, 1739, 1076, 1024 cm⁻¹.</li><li>9.Bg) As described in paragraph D) a) above for the preparation of the esters of the formula VI, a mixture of diastereomers is obtained which is mainly (2S, 3S, 5S, 13Z) -2-ethyl-3-hydroxy-5 - [( contains tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid methyl ester, as a colorless oil    from (3S, 5S, 13Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid methyl ester and ethyl iodide.</li><li>9.Bh) Analogously to Example 2 above, a mixture of diastereomers is obtained, which is mainly (2S, 3S, 5S) -2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] docosanoic acid -methyl ester contains, IR: 1738, 1199, 1167, 1132, 1115, 1176, 1023 cm⁻¹    from a mixture of diastereomers, which mainly consists of (2S, 3S, 5S, Z) -2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenoic acid methyl ester.</li><li>9.Bi) 0.12 g of a mixture of diastereomers, which mainly consists of (2S, 3S, 5S) -2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] docosanoic acid methyl ester , are stirred in 2.5 ml of 2N methanolic potassium hydroxide solution until conversion is complete at room temperature. The cloudy solution is poured onto 10 ml of water and adjusted to pH 2 with 2N hydrochloric acid. After extraction with diethyl ether, it is dried over sodium sulfate, filtered and evaporated. Chromatography on silica gel gives a mixture of diastereomers, which consists mainly of (2S, 3S, 5S) -2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] docosanoic acid, as a colorless oil, IR : 1709 cm⁻¹.</li><li>9.Bj) As described in paragraph Aa) above for the preparation of the ethers of the formula IV, (3S, 4S) -3-ethyl-4 - [(S) -2 - [(tetrahydro-2H-pyran-2- yl) oxy] nonadecyl] -2-oxetanone as the main component of a diastereomer mixture as a colorless oil, IR: 1826 cm⁻¹    from a mixture of diastereomers, which mainly consists of (2S, 3S, 5S) -2-ethyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] docosanoic acid.</li><li>9.Bk) Analogously to Example 7, (3S, 4S) -3-ethyl-4 - [(S) -2-hydroxynonadecyl] -2-oxetanone, mp. 82-84 ° C. (MeOH)    from (3S, 4S) -3-ethyl-4 - [(S) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] nonadecyl] -2-oxetanone.</li><li>9.Bl) 796 mg of N - [(benzyloxy) carbonyl] -L-leucine are dissolved in 10 ml of methylene chloride, cooled to 2-3 ° C. and 309 mg of dicyclohexylcarbodiimide are added. After 15 minutes, the white crystals are filtered off and washed with methylene chloride. The filtrate is evaporated at RT in vacuo and the residue is dissolved in 7 ml of N, N-dimethylformamide (DMF). This solution is added to 574 mg (3S, 4S) -3-ethyl-4 - [(S) -2-hydroxynonadecyl] -2-oxetanone and 22 mg 4-dimethylamino-pyridine in 6 ml DMF. It is stirred for 30 minutes. The solution is poured onto 100 ml of ice water and extracted three times with 20 ml of diethyl ether. The combined organic phases are dried over sodium sulfate, filtered and evaporated. Chromatography on silica gel gives N - [(benzyloxy) carbonyl] -L-leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester as white Crystals of mp 44-47 ° C.</li></ul>

Example A

0068Production of soft gelatin capsules with the following composition: <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" /><entry namest="col2" nameend="col2" align="center">Amount per capsule</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">An oxetanone of formula I or III</entry><entry namest="col2" nameend="col2" align="right">50 mg</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">NEOBEE M-5</entry><entry namest="col2" nameend="col2" align="right">450 µl</entry></row></tbody></tgroup></table></tables>

0069The solution of the active ingredient in NEOBEE M-5 is filled into soft gelatin capsules of a suitable size.