Oxetanone.

0001The 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.

0002These oxetanones are compounds of the formula<chemistry id="chem0001" num="0001"><img file="EP0185359A2_D0001.tif" /></chemistry>wherein<ul id="ul0001" list-style="none"><li>R¹ and R²optionally by up to 8 double or triple bonds and optionally by an O or S atom. which is in a position other than a to an unsaturated C atom, interrupted C_1-17-Alkyl; or by 0 to 3 C._1-6-Alkyl- (O or S) or O ring-substituted phenyl. Benzyl or -C₆H₄-XC₆H₅,</li><li>_X Oxygen. Sulfur or (CH₂)_0-3,</li><li>R³ Hydrogen, C_1-3-Alkl or C_1-3-Alkanoyl,</li><li>R⁴ Hydrogen or C_1-3-Alkyl, and</li><li>R is hydrogen, an Ar or Ar-C group_1-3-Alkyl or optionally interrupted by Y and optionally substituted by Z._1-7-Alkyl, or</li><li>R⁴ with R⁵forms a 4- to 6-membered saturated ring,</li><li>Y oxygen, sulfur or a group N (R⁶), C (O) N (R⁶) or N (R⁶) C (O),</li><li>Z is a group - (O or S) -R⁷, -NO⁷, R⁸), -C (O) N (R⁷, R⁸) or -N (R⁷) C (O) R⁸,</li><li>n is the number 1 or 0, where if n is the number 1, R⁵ Is hydrogen</li><li>Ar through 0 to 3 groups R⁹ or OR⁹ substituted phenyl, and</li><li>R⁶ to R⁹ Hydrogen or C_1-3-Alkyl are</li></ul>where if R³ Formyl and R isobutyl or R³ Acetyl and R⁵ Is carbamoylmethyl, and at the same time R² Undecyl or 2,5-Undecadienyl and R¹ is n-hexyl, R⁴ has a meaning other than hydrogen, and salts of these oxetanones with weak acids.

0003The 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.

0004The oxetanones of the formula I can be prepared by<ul id="ul0002" list-style="none"><li>a) an acid of the formula<chemistry id="chem0002" num="0002"><img file="EP0185359A2_D0002.tif" /></chemistry>or a functional derivative thereof with an alcohol of the formula<chemistry id="chem0003" num="0003"><img file="EP0185359A2_D0003.tif" /></chemistry>where 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="EP0185359A2_D0004.tif" /></chemistry>where R¹, R², R⁴, R⁵ and n have the above meaning, split off,</li><li>c) unsaturated radicals R¹ and R² if desired, catalytically hydrogenated,</li><li>d) obtained oxetanones of formula I, wherein at least one of _R³ and R⁴ Is hydrogen and one at most in R⁵ contained amino group Y or Z is tertiary, if desired C_1-3-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>

0005The 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.

0006The 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.

0007Benzyloxycarbonyl 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 a_Aperform ether, such as THF, in the presence of a hydrogenation catalyst, such as palladium on carbon (Pd / C), preferably at room temperature.

0008The optional hydrogenation c) can be carried out under conditions similar to the cleavage reaction b) described above.

0009The optional C_1-3Alkanoylation d) can 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.

0010The alcohols III can be prepared by the ether protecting group L in an ether of the formula<chemistry id="chem0005" num="0005"><img file="EP0185359A2_D0005.tif" /></chemistry> wherein _R¹ and _R² have the above meaning.

0011Examples of ether protecting groups L are tetrahydro-2H-pyran-2-yl, 1-ethoxyethyl, benzyl and t-butyldimethylsilyl.

0012The 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.

0013The ether IV can be obtained by cyclization of the acids of the formula<chemistry id="chem0006" num="0006"><img file="EP0185359A2_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.

0014The acids V can either be<ul id="ul0003" list-style="none"><li>a) by saponification of corresponding esters of the formula<chemistry id="chem0007" num="0007"><img file="EP0185359A2_D0007.tif" /></chemistry>where RC_1-4-Alkyl and L, R and R have the above meaning, or</li><li>b) by condensation of an acid of the formula<chemistry id="chem0008" num="0008"><img file="EP0185359A2_D0008.tif" /></chemistry>with an aldehyde of the formula<chemistry id="chem0009" num="0009"><img file="EP0185359A2_D0009.tif" /></chemistry>produce.</li></ul>

0015Examples 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.

0016The 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.

0017The acids V, which are in (5R) or (SS) form, can be converted into the (2S, 3S, 5R) or (2R, 3R, 5S) stereoisomers in the following manner:<ul id="ul0004" list-style="none"><li>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 formula<chemistry id="chem0010" num="0010"><img file="EP0185359A2_D0010.tif" /></chemistry>where L 'is hydrogen and R¹ and R² have the above meaning.</li></ul>

0018This (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 ,

0019Stereospecific 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_' for an ether protection group. such as t-butyldimethylsilyl, is converted, for example in dimethylformamide using t-butyldimethylchlorosilane. The cyclic (3S, 4S, -6R) or (3R, 4R, 6S) ether obtained is split up, 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="chem0011" num="0011"><img file="EP0185359A2_D0011.tif" /></chemistry>transferred, in which L "stands for hydrogen, L 'the same ether protecting group as in the ether VA. R¹⁰ Is 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 protecting 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.

0020The ester VI can either be<ul id="ul0005" list-style="none"><li>a) by alkylation of the corresponding esters of the formula<chemistry id="chem0012" num="0012"><img file="EP0185359A2_D0012.tif" /></chemistry>or</li><li>b) by reducing the β-keto esters of the formula<chemistry id="chem0013" num="0013"><img file="EP0185359A2_D0013.tif" /></chemistry>produce.</li></ul>

0021The 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 a solution of an alkyl halide (R¹-Hal), for example a bromide, in hexamethylphosphoric triamide at a temperature of about 0 to 10 ° C.

0022The reduction b) of the B-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.

0023The esters IX can be obtained by reductive removal of the sulfoxide group in a sulfoxide of the formula<chemistry id="chem0014" num="0014"><img file="EP0185359A2_D0014.tif" /></chemistry>where T is p-tolyl and L, R and R have the same meaning as above. This reaction can be carried out, for example, in a solvent such as THF using aluminum amalgam.

0024The β-keto esters X can be obtained by reacting an aldehyde of the formula R^2-CHO with a B-ketoester of the formula<chemistry id="chem0015" num="0015"><img file="EP0185359A2_D0015.tif" /></chemistry>and etherification of the alcohol of the formula obtained<chemistry id="chem0016" num="0016"><img file="EP0185359A2_D0016.tif" /></chemistry>produce.

0025The preparation of alcohol XIII or its etherification can be carried out as described, for example, in Examples H) and J) e) below.

0026In the intermediates of formulas I ', III-VI, VB, X and _XIII contained unsaturated residues R¹ and R² can, if desired, be hydrogenated, for example under the conditions of the hydrogenolytic removal of a group mentioned above _W or R¹⁰.

0027The sulfoxides XI can be obtained by condensing an aldehyde of the above formula VIII with an ester of the formula<chemistry id="chem0017" num="0017"><img file="EP0185359A2_D0017.tif" /></chemistry>eg as described in example G).

0028The aldehydes VIII can be obtained by reducing the esters of the formula<chemistry id="chem0018" num="0018"><img file="EP0185359A2_D0018.tif" /></chemistry> produce, for example with a di (Cl-4-alkyl) aluminum hydride, such as diisobutylaluminium hydride. in a solvent such as toluene at a temperature of about -60 to -80 ° C.

0029The esters of the formula XV can be started from the aldehydes of the formula R.²-CHO on the sulfoxides of the formula<chemistry id="chem0019" num="0019"><img file="EP0185359A2_D0019.tif" /></chemistry>and the esters of the formula<chemistry id="chem0020" num="0020"><img file="EP0185359A2_D0020.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).

0030Furthermore, an ester of the formula XV, in which _R² 3-Alkenyl, by ozonolysis of an ester of the formula<chemistry id="chem0021" num="0021"><img file="EP0185359A2_D0021.tif" /></chemistry>and Wittig reaction with the aldehyde of the formula obtained<chemistry id="chem0022" num="0022"><img file="EP0185359A2_D0022.tif" /></chemistry>for example as described in Examples K) and L).

0031For the conversion of the aldehydes of the formula VIII or the formula R.²-CHO in the corresponding esters of the formulas IX and XVII can be used instead of a sulfinyl ester XIV (R) -α- (hydroxydiphenylmethyl) benzyl acetate. In this case, one obtains the sulfoxides of the formulas X as intermediates_I. or XVI the (R) -2-hydroxy-1,2,2-triphenylethyl ester corresponding to the alkyl esters of the formulas IX and XVII.

0032The oxetanones of formula I 'can *) in the same way as that _Oxetanones of the formula I, for example as described in Example 2.15 below, by esterifying an acid of the formula II, in which W is instead of R, 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 10 B1).

0033The 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

0034A) a) 0.57 g of a diastereomer mixture which, inter alia, from (2S, 3S, 5R, 13Z, 16Z) -2-hexyl -3-hydroxy-5 - [(tetra-hydro-2H-pyran-2-yl ) oxy] -13,16-docosadienoic acid are dissolved in 10 ml of pyridine and cooled to 0 ° C. After 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

0035^*) getting produced

0036colorless oil, IR: 1815 cm^-1.

0037The following are obtained in an analogous manner:<ul id="ul0006" list-style="none"><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-ß - [(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.

0038B) 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- The t-butyl ester is heated to reflux in 17 ml of a 2N methanolic potassium hydroxide solution until the starting material has disappeared. 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

0039(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.

0040The following are obtained in an analogous manner:<ul id="ul0007" list-style="none"><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] hexadecanoic acid methyl ester.</li></ul>

C) Preparation of the acids V (variant)

0041C) 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.

0042In an analogous way you get:<ul id="ul0008" list-style="none"><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-tetra-decenal 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

0043D) 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-Doeosa-dienoic 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-docosa-dienoic acid t-butyl ester is obtained. MS: 519 (M^+-(CH₃)₃CO.); IR: 3503, 1728, 1709, 1153.

0044The following are obtained in an analogous manner:<ul id="ul0009" list-style="none"><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 (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 - [(tetra-hydro-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-butanoate and 1-bromohexane</li></ul>

E) Preparation of the Esters of Formula VI (Variant)

0045While 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 added to - Cooled to 5 ° C. 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

0046F) 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 filtered off and washed first with 1 1, then with 2 1 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%

0047(R, 11Z, 14Z) -3-hydroxy-11,14-eicosadienoic acid t-butyl ester, MS: 324 (M⁺-Isobutylene); IR: 3452, 1715, 11₅₄ -1 cm

0048The following are obtained in an analogous manner:<ul id="ul0010" list-style="none"><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, 10₂4th 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-eicosen 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) -a-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] hexadecanoic acid t-butyl ester.</li></ul>

G) Preparation of the sulfoxides of the formulas XI and XVI

0049G) 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.

0050The following are obtained in an analogous manner:<ul id="ul0011" list-style="none"><li>_G) b) (3R, 11Z, 14Z) -3-hydroxy-2 - [(R) -p-tolylsulfinyl] -11.14 - t-butyl eicosadienate, 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 c_m¹ 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 (RZ) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -ll-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. M.p. 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, mp. 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

00515 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

0052I) 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 brought to -75 ° C. while gassing with argon and excluding moisture cooled down. 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.<ul id="ul0012" list-style="none"><li>I) b) rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanal from rac-3 - [(tetrahydro-2H-pyran-2-yl) oxy] tetradecanoic acid methyl ester</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 - t-butyl eicosadienate</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) (BS) -p-phenoxy-B - [(tetrahydro-2H-pyran-2-yl) oxy] hydrocinnamaldehyde from [(S) -p-phenoxy-a - [(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-tetra-decenoic acid ethyl ester.</li></ul>

J) Preparation of the esters of formula XV

0053J) 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 31 ml of Irish distilled 3,4 -Dihydro-2H-pyran are in <img file="EP0185359A2_D0023.tif" />Dissolve ml of Mathylanahlsrid 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-eicosadic acid t-butyl ester, MS: 324 (M.^+-Dihydropyran isobutylene); IR: 1731, 1158. 1024 cm^-1.

0054The following are obtained in an analogous manner:<ul id="ul0013" list-style="none"><li>J) b) (R, Z) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] -11-eicosonic 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-a - [(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, 3: 1 hexane ether, 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 Formula XV (Variant)

0055K) 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.

0056K) b) In a similar way one obtains:<ul id="ul0014" list-style="none"><li>(R) -3 - [(Tetrahydro-2H-pyran-2-yl) oxy] -6Z-eicosencarbonate, ethyl ester.</li></ul>

L) Preparation of an aldehyde of the formula XIX

0057A 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

0058M) 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.

0059M) 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 to 700 ml H₂0 poured. The lactone precipitates and is filtered off. After recrystallization from 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.

0060M) 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 Pt0₂ are added. Then hydrogenated (50 bar) for 12 hours. The catalyst is filtered off and the solution is evaporated. After recrystallization, 7 g of (3S, 4S, 6R) tetrahydro-3-hexyl-4-hydroxy-6-undecyl -2H-pyran-2-one are obtained. M.p. 108-109 ° C.

0061M) 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).

0062_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 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.

0063M) 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 dissolved in 10 ml methylene chloride 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 of (2S.3S.5R) -2-hexyl-3 - [(t-butyldimethylsilyl) -oxy] -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid benzyl ester, MS are obtained: 603 (M^+-t-butyl).

0064M) 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 of 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 (2S, 3S, 5R) -2-hexyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2-yl) oxy] hexadecanoic acid benzyl ester are obtained. MS: 463 [(M + H)^+-Dihydro-2H-pyran-2-yl].

0065M) 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. (2S.3S, 5R) -2-hexyl-3-hydroxy -5 - [(tetrahydro-2H-pyran-2 - yl) oxy] hexadecanoic acid is obtained.

0066The alcohols of the formula III are new, in which R¹ and R² have the above meaning, where if R¹ n-hexyl and _R² Undecyl or 2nd_Z., 5Z-undecadienyl, at least one of the asymmetric C atoms present in the oxetanone ring and in the B position to the latter has the R configuration.

0067Preferred oxetanones of the formula 1 and III are those in which R¹ Methyl, propyl, hexyl. Decyl, hexadecyl, allyl, benzyl or in particular ethyl: R² Methyl, undecyl, 3-butenyl, 3-undecenyl, 8,11-heptadecadienyl, phenoxyphenyl or especially heptadecyl: R³ Acetyl or especially formyl; R⁴ Methyl or especially hydrogen, and R⁵ Is hydrogen, methyl, 2-butyl, benzyl, methylthioethyl or in particular i-butyl, or R⁴ together with R⁵ forms a pyrrolidinyl residue.

0068Examples of such connections are:<ul id="ul0015" list-style="none"><li>N-Formyl-L-leucine-1 - [(trans-3-ethyl-4-oxo -2-oxetanyl) methyl] dodecyl ester</li><li>N-Formyl-L-leucine-1 - [(trans-3-allyl-4-oxo -2-oxetanyl) methyl] dodecyl ester</li><li>N-Formyl- (S) -leucine (S, 9Z, 12Z) -1 - [(2S, 3S) -3-ethyl -4-oxo-2-oxetanyl] methyl] -9.12-octadecadienyl ester</li><li>N-Formyl- (S) -leucine (S, Z) -1 - [[(2S, 3S) -3-ethyl-4-oxo -2-oxetanyl] methyl] -9-octadecenyl ester</li><li>N-Formyl- (S) -leucine (R) -a - [[(2S.3S) -3-ethyl-4-oxo-2_- -oxetanyl] methyl] -p-phenoxybenzyl ester.</li></ul>

Is particularly preferred

0069N-Formyl- (S) -leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester.

0070The oxetanones of the formulas I and III have valuable pharmacological properties. They inhibit pancreatic lipase in particular and can accordingly be used to combat or prevent obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

0071The inhibition of the pancreatic lipase by the oxetanones of the formulas I and III can be shown experimentally by titrimetric detection of 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. 2mM Tris-HCl, 100mM sodium chloride. 1 mM calcium chloride and the substrate contains triolein, the compound of formula I dissolved in ethanol or dimethyl sulfoxide (10% of the emulsion volume) is added and the reaction is started by adding 100 μg (175 U) of pork pancreatic lipase. The pH is kept at 8 during the reaction by adding sodium hydroxide solution. From the consumption of caustic soda determined over 10 minutes, the IC₅₀ calculated. The IC₅₀ is the concentration at which lipase activity is half maximally inhibited. The following table contains the IC determined for the compounds of the formula I.₅₀- Values ​​and information on acute toxicity (toxicity after single oral administration to mice).<tables id="tabl0001" num="0001"><img file="EP0185359A2_D0024.tif" /></tables>

0072The oxetanones of the formulas 1 and III can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be taken orally, for example in the form of tablets, coated tablets. Dragées, hard and soft gelatin capsules. Solutions, emulsions or suspensions can be administered.

0073To produce pharmaceutical preparations, the products according to the invention can be processed with pharmaceutically inert, inorganic or organic carriers. As such a carrier can be used for tablets. Coated tablets. Dragees and hard gelatin capsules, for example lactose, corn starch or derivatives thereof. Use talc, stearic acid or its salts and the like. Vegetable oils, for example, are suitable carriers for soft gelatin capsules. Waxes. Fat, 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.

0074The pharmaceutical preparations can also contain preservatives. Solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners. Colorants. Flavoring agents. Salts, to change the osmotic pressure, contain buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.

0075As mentioned at the outset are medicaments containing an oxetanone of the formula I or III. the present invention also relates to a process for the preparation of such medicaments, which is characterized in that an oxetanone of the formula I or III and, if appropriate, one or more other therapeutically valuable substances are brought into a pharmaceutical dosage form. As mentioned, the compounds of formula I can be used in the control or prevention of diseases, in particular in the control or prevention of obesity, hyperlipemia. 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.

0076The oxetanones of the formula I or III 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 receive about 0.1 to 5% by weight of an oxetanone of the formula I or III, and their production are also the subject of the present invention.

0077The 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

0078To a solution of 100 mg rac-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2R.3S, 4S: 2S, 3R.4R), 74 mg triphenylphosphine and 45 mg N-formyl-D -leucine in 2 ml of THF is 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<ul id="ul0016" list-style="none"><li>la) the N-formyl-D-leucine (R) -1 - [[(2R, 3R) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester and</li><li>lb) the N-formyl-D-leucine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester.</li></ul>

Example 2

0079Analogously to example 1, one obtains:<ul id="ul0017" list-style="none"><li>2.1) By esterification of rac-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2R, 3R, 4R: 2S, 3S, 4S) with N-formyl-D-leucine<ul id="ul0018" list-style="none"><li>2.1) a) the N-formyl-D-leucine (S) -1 - [[(2R.3R) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester and</li><li>2.1) b) the N-formyl-D-leucine (R) -1 - [[(2S, 35) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester,</li></ul></li><li>2.2) by esterification of rac-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2S, 3R, 4R: 2R, 3S, 4S) with N-formyl-L-leucine the N-formyl-L- leucine (R) -1 - [[(2R, 3R) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester, [α]²⁵_D = -2.2 ° (methanol, c = 0.9%),</li><li>₂.₃) by esterification of rac-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2S, 3S, 4S: 2R, 3R, 4R) or of (3R, 4R) -3-hexyl -4 - [( R) -2-hydroxytridecyl] -2-oxetanone with N-formyl-L-leucine<ul id="ul0019" list-style="none"><li>2.3) a) the N-formyl-L-leucine (R) -1 - [[(2S.3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester, [α]²⁵_D = -19.4 ° (methanol, c = 0.35%) and</li><li>2.3) b) the N-formyl-L-leucine (S) -1 - [[(2R, 3R) -3-hexyl-4-oxo -2-oxetanyl] methyl] dodecyl ester, [α]²⁵_D = -2.87 ° (methanol, c = 0.8%),</li></ul></li><li>2.4) by esterification of rac-cis-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (pair of enantiomers A) with N-formyl-L-leucine<ul id="ul0020" list-style="none"><li>2.4) a) the N-formyl-L-leucine-1 - [(cis-3-hexyl-4-oxo -2-oxetanyl) methyl] dodecyl ester. DC silica gel; Toluene-ethyl acetate 2: 1, Rf = 0.55 and</li><li>2.4) b) the N-formyl-L-leucine-1 - [(cis-3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel; Toluene-ethyl acetate 2: 1, Rf = 0.47,</li></ul></li><li>2.5) by esterification of rac-cis-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (pair of enantiomers B) with N-formyl-L-leucine<ul id="ul0021" list-style="none"><li>2.5) a) the N-formyl-L-leucine-1 - [(cis-3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel; Toluene-ethyl acetate 2: 1, Rf = 0.53 and</li><li>₂.5) b) the N-formyl-L-leucine-1 - [(cis-3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel: toluene-ethyl acetate 2: 1, Rf = 0, 50,</li></ul></li><li>2.6) by esterification of (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone with N-formylglycine the N-formylglycine- (S) -1- (2S, 3S) - [(3-hexyl-4-oxo -2-oxetanyl) methyl] dodecyl ester, [α]²⁵_D = -22 ° (CHCl₃, c = 0.88),</li><li>2.7) 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>2.8) 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-oxe_- tanyl) methyl] dodecyl ester, TLC silica gel; CHCl₃: Hexane: -Dioxane 1: 3: 0.25. Rf = 0.36</li><li>2.9) by esterification of (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone with N-formyl-β-alanine in 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>2.10) 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>₂.₁1) 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>₂.₁2) 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>2.13) by esterification of rac-trans-3-ethyl-4- (2-hydroxytridecyl) -2-oxetanone with N-formyl-L-leucine<ul id="ul0022" list-style="none"><li>2.13) a) the N-formyl-L-leucine-1 - [(t rans-3-ethyl-4-oxo-2-oxetanyl) methyl] dodecyl ester, TLC silica gel, toluene-ethyl acetate 2: 1, Rf = 0.62</li><li>2.13) 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></ul></li><li>2.14) 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>2.15) 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, hexanes - diethyl ether 1: 1, Rf = 0,₆₄</li><li>2.16) 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- octadienyl ester, MS: 575 (M⁺); IR: 1824, 1739, 167₅ cm 1</li><li>2.17) 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] octadecadienyl ester (2 diastereomers). MS: 575 (M⁺); IR: 1824, 1740, 1687 cm^-1</li><li>2.18) by esterification of cis-3-hexyl-4 - [(10Z, 13Z) -2 - hydroxy-10,13-nonadecadienyl] -2-oxetanone (mixture of diastereomers) with N-formyl- (S) -leucine<ul id="ul0023" list-style="none"><li>2.18) 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>2.18) b) the N-formyl- (S) -leucine (9Z, 12Z) -1 - [(cis-3-hexyl - 4-o xo -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></ul></li><li>2.19) 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 (5.9Z, 12Z) -1 - [[(2S, 3S) -3-benzyl - 4-oxo -2-oxetanyl] methyl] -9.12 octadienyl ester, MS: 581 (M⁺); IR: 1825, 1739. 1683 cm^-1</li><li>₂.20) 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<ul id="ul0024" list-style="none"><li>2.20) 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>2.20) b) the N-formyl- (S) -leucine (9Z, 12Z) -1 - [(trans-3-benzyl - 4-oxo -2-oxetanyl) meth yl] -9.12-octadecadienyl ester (diastereomer II), MS: 581 (M⁺); IR: 1824, 1740, 1687 -1 cm</li></ul></li><li>2.21) by esterification of trans-3-ethyl-4 - [(10Z, 13Z) -2 - hydroxy-10,13-nonadecadienyl] -2-oxetanone (mixture of diastereomers) with N-formyl- (S) -leucine den 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>2.22) 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>2.23) by esterification of (3S, 4S) -3-ethyl-4 - [(R, Z) -2 - hydroxy-10-nonadecenyl] -2-oxetanone with N-formyl-S-leucine<ul id="ul0025" list-style="none"><li>2.₂₃) 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>2.23) b) the N-formyl- (S) -leucine (Z) -1 - [(trans-3-ethyl-4-oxo-2-oxetanyl) methyl] -9-octadecenyl ester</li></ul></li><li>2.24) by esterification of (3S, 4S) -3-hexyl-4 - [(S) -β - hydroxy-p-phenoxyphenethyl] -2-oxetanone with N-formyl- (S) - leucine in 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>2.25) by esterification of (3S, 4S) -3-ethyl-4 - [(S) -β - hydroxy-p-phenoxyphenethyl] -2-oxetanone with N-formyl- (S) - leucine<ul id="ul0026" list-style="none"><li>2.25) 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>2.25) b) the N-formyl- (S) -leucine (S) -a - [[(2S, 3S) -3-ethyl-4-oxo -2-oxetanyl] methyl] -p-phenoxybenzyl ester, MS: 453 (M⁺); IR: 1823, 1743, 1686 cm^-1</li></ul></li><li>2.26) 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>2.27) by esterification of (S) -3_-Hexyl- (S) -4 - [(R) -2 - hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-leucine and N-formyl-L-leucine (S) -1 - [[ (2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester</li><li>2.₂₈) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2 - hydroxy-5-hexenyl) -2-oxetanone with N-formyl- (S) -valine in the N-formyl - (S) -valine-1 - [[(2S, 3S) -3- hexyl-4-oxo -2-oxetanyl] methyl] -4-pentenyl ester</li><li>2.29) 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>2.30) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2 - hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-phenylalanine in the N-formyl L -phenylalanine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) methyl] -4-pentenyl ester</li><li>2.31) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2 - hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-alanine in the N-formyl L -alanine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) -4-pentenyl ester</li><li>2.32) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2 - hydroxy-5-hexenyl) -2-oxetanone with N-formyl-L-proline in the N-formyl L -Proline (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) methyl] -4-pentenyl ester</li><li>2.33) by esterification of (S) -3-hexyl- (S) -4 - [(R, Z) -2 - hydroxy-5-tridecenyl) -2-oxetanone with N-formyl-L-leucine den N-formyl -L-leucine (S, Z) -1 - [[(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl] methyl] -4-dodecenyl ester</li><li>2.₃₄) 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>2.35) by esterification of (S) -3-hexyl- (S) -4 - [(R) -2 - hydroxy-5-hexenyl] -2-oxetanone with N-formyl-L-methionine in the N-formyl L-methionine (S) -1 - [(2S, 3S) -3-hexyl-4-oxo -2-oxetanyl) methyl] -4-pentenyl ester.</li><li>2.36) 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

3

0080A 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 4

0081Analogously to example 3, one obtains:<ul id="ul0027" list-style="none"><li>₄.₁) 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>₄.₂) 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 5

0082A 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 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 6

0083Analogously to Example 5, one obtains:<ul id="ul0028" list-style="none"><li>6.1) 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] pentenyl ester</li><li>6.2) from N-formyl-L-phenylalanine (S) -1 - [(2S, 3S) -3-hexyl-4 - oxo-2-oxetanyl] methyl] -4-pentyl ester the N-formyl-L-phenylalanine (S) -1 - [[(2S.3S) -3-hexyl-4 - oxo-2-oxetanyl] methyl] -4-pentyl ester</li><li>6.3) 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 7

0084A 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-Hydrogenated atmosphere (normal pressure) 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 8

0085265 mg of a diastereomer mixture of 3-hexyl-4 - [(10Z, 13Z) -2- [tetrahydro-2H-pyran-2-yl) oxy] -10,13-nonadecadienyl] -2-oxetanone are added in 2.5 ml Dissolved ethanol and added 13 mg of pyridinium 4-toluenesulfonate. 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="ul0029" list-style="none"><li>8.1) ((3S, 4S) -4-hexyl-4 - [(R, 10Z, 13Z) -2-hydroxy-10,13-nona- _decadienyl] -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 9

0086The following were obtained analogously to Example 8:<ul id="ul0030" list-style="none"><li>9.Al) trans-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone, MS: 360 (M⁺-H₂O), 334 (M⁺-CO₂), 316 (M⁺-H₂OW₂), IR: 3446, 1823, 1122 cm^-1</li><li>9.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>9.A.3) cis-3-ethyl-4 - [(10Z, 13Z) -2-hydroxy-10,13-nonadecadienyl] -2-oxetanone (mixture of enantiomers B), MS: (chemical induction with NH₃): 396 (M + NH⁺₄), 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>9.B. 3-ethyl-4 - [(Z) -2-hydroxy -10-nonadecenyl] -2-oxetanone, MS: 362 (M⁺-H₂O), 318 (M⁺-H₂O-10₂); IR: 3435, 1823, 1119 cm₃-Aethyl-4 - [(Z) -2 - [(tetrahydro -2H-pyran-2-yl) oxy] - 10-nonadecenyl-2-oxetanone</li><li>9.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>₉.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>9.C.3) cis-3-Benzyi-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>9.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>9.E. (3S, 4S) -3-ethyl-4 - [(S) -ß-hydroxy-p-phenoxyphen-ethyl] -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>₉._F.₁. rac-trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2R, 3S, 4S: 2S, 3R, 4R), mp. 44.5-46 °,</li><li>9.F.2. rac-trans-3-hexyl-4- (2-hydroxytridecyl) -2-oxetanone (2S, 3S, 4S: 2R, 3R, 4R), mp. 45.5-47 ° C,</li><li>9.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>₉._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>9.G.1. (3S, 4S) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, mp. 46-46.5 ° C and</li><li>9.G.2. (3R, 4R) -3-hexyl-4 - [(R) -2-hydroxytridecyl] -2-oxetanone, mp 46-47 °; [α]²⁰_D = + 12 ° C (CHCl₃, c = 1.5) from 3-hexyl-4 - [(R) -2 - [(tetrahydro-2H-pyran -2-yl) oxy] -tridecyl] -2-oxetanone.</li><li>9.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>9.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>9.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>9.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>9.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>9.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>9.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>9.0. 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>₉._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>9.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 10

10.A. Manufacture of the product

0087565 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^OC.

10.B. Production of the starting material

0088<ul id="ul0031" list-style="none"><li>10.Ba) As described in paragraph 10.Be) below, a mixture of diastereomers is obtained which consists of 85-90% from (S, Z) -3-hydroxy-11-eicosenoic acid- (R) -2-hydroxy-1,2 , 2-triphenyl ethyl ester, mp. 112-114 ° C from _Oleylaldehyde and (R) -a- (hydroxydiphenylmethyl) benzyl acetate.</li><li>10.Bb) As described in paragraph 10.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 - triphenyl ethyl ester.</li><li>10.Bc) As described in paragraph J) a) above for the preparation of the esters of the formula XV, (S, Z) -3 - [(tetra-hydro-2H-pyran-2-yl) oxy] -11- Eicosensäure-methyl ester, which contains 10-15% of the (R) -isomer from (S, Z) -3-hydroxy-11-eicosensäure-methyl ester.</li><li>10.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>10.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 repeated recrystallization from methanol, 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-triphenylethyl ester, mp. 91-93 ° C.</li><li>10.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 mixture of diastereomers is obtained, which mainly consists of (3S, 5S.13Z) -3 - hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] -13-docosenic acid methyl ester, IR: 3473 , 1739, 1076, 1024 cm^-1.</li><li>10.Bg) As described in paragraph D) a) above for the preparation of the esters of formula VI, a mixture of diastereomers is obtained. which mainly contains (2S, 3S, 5S, 13Z) - 2-ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) oxy] - 13-docosenoic acid methyl ester as a colorless oil (3S, 5S, 13Z) -3-hydroxy-5 - [(tetrahydro-2H-pyran-2-yl) -oxy] -13-docosenoic acid methyl ester and ethyl iodide.</li><li>10.Bh) In analogy to Example 3 above, a mixture of diastereomers is obtained which mainly consists of (2S.3S.5S) -2 - ethyl-3-hydroxy-5 - [(tetrahydro-2H-pyran -2-yl) oxy] contains methyl docosanoate. IR: 1738, 1199, 1167, 1132, 1115, 1176, 10_{23 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>10.Bi) 0.12 g of a diastereomer mixture which consists mainly of (2S.3S, 5S) -2-ethyl-3-hydroxy-5 - [(tetrahydro - 2H-pyran-2-yl) oxy] docosanoic acid methyl ester consists, are stirred in 2.5 ml of 2N methanolic potassium hydroxide solution until complete conversion 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>10.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>10.Bk) Analogously to Example 8, (3S, 4S) -3 - ethyl-4 - [(S) -2-hydroxynonadecyl] -2-oxetanone is obtained. Mp 82-84 ° C (MeOH) from (3S, 4S) -3-ethyl-4 - [(S) -2 - [(tetrahydro -2H-pyran-2 - yl) oxy] nonadecyl] -2- oxetanon.</li><li>₁₀._B.l) 796 mg of N - [(benzyloxy) carbonyl] -L-leucine are in ₁₀ Dissolved ml of methylene chloride, cooled to 2-3 ° C and added 309 mg of dicyclohexylcarbodiimide. 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 NN-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. After chromatography on silica gel, N - [(benzyloxy) carbonyl] -L-leucine (S) -1 - [[(2S, 3S) -3-ethyl-4-oxo-2-oxetanyl] methyl] octadecyl ester is obtained as white Crystals of mp 44-47 ° C.</li></ul>

Example A

0089Production of soft gelatin capsules with the following composition:<tables id="tabl0002" num="0002"><img file="EP0185359A2_D0025.tif" /></tables>

0090The solution of the active ingredient in NEOBEE M-5 is filled into soft gelatin capsules of a suitable size.