Oxetanones a process for their manufacture and pharmaceutical compositions containing them

The present invention is concerned with novel oxetanones, a process for their manufacture, pharmaceutical preparations which contain such oxetanones as well as the use of these oxetanones in the manufacture of pharmaceutical preparations.

These oxetanones have the formula

Q-OCHCH2

Q is a group of the formula (R3,R4)NCO(X)_n-CO(R3,r4)NCO-X’Q¹

Q² and

R1 and R^ are alkyl with up to 18 C atoms substituted by 1 to 3 halogen atoms or alkyl, alkenyl, alkynyl or alkadienyl groups with up to 20 C atoms optionally interrupted by a 1,4-arylene group, optionally substituted by an aryl group in the ω-position and optionally substituted by an aryl־C1-4־alkyl group, whereby R1 can be interrupted by an O or S atom

Μέ/16.1.91 or by a sulphinyl or sulphonyl group in a position other than the a-position to an unsaturated C atom, or R1 is an aryl-NH- or aryl-Ci-4־ alkyl-OCONH- group, r3 and R׳* are hydrogen or C!-4־alkyl or together with the N atom to which they are attached form a saturated 3- to 6-membered ring optionally containing an O or S atom in a position other than the aposition to the N atom, n is the number 1 or 0,

X is an alkylene group which contains up to 6 C atoms, which is optionally interrupted by an O or S atom or by a sulphinyl or sulphonyl group and which is optionally substituted by a hydroxy, mercapto, aryl, aryloxy, arylthio, aryl־Ci-4־alkyl, aryl-C1-4-alkoxy, aryl-C!-4־alkylthio, aryl-C1-4-alkylidene, C3-7־cycloalkylidene or C!-6־alkylidene group or by one or two C!-6־alkyl, C1-6־alkoxy or C1-6־alkylthio groups, whereby two C!-6^-alkyl, C1-6-alkoxy or C1-6־alkylthio groups on the same C atom or on two adjacent C atoms can form an optionally mono-unsaturated 3- to

7-membered ring and an optionally present hydroxy or mercapto group or an optionally present unsaturated C atom must be in a position other than the a-position to an optionally present O or S atom or to an optionally present sulphinyl or sulphonyl group, or X is a group of the formula =CHN(R,R°) or -CHN(R,R0)CH2־

R and R° are hydrogen Ci-4־alkyl, C!-4־alkyl(CO or OCO)-, aryl, aryl(CO or OCO)-, aryl-C1-4-alkyl or aryl-Cl-4־alkyl(CO or OCO)- and

X' is an alkylene group containing up to 6 C atoms which can be substituted by a C!-4־alkoxy, aryl, aryloxy, arylthio, aryl-C1-4־alkyl, aryl-Ci-4־ alkoxy or aryl-Cl-4־alkylthio group or by one or two Ci-6־alkyl groups, whereby two Ci-6-alkyl groups attached to adjacent C atoms can form a

3- to 7-membered ring.

The alkyl, alkenyl and alkadienyl groups can be straight-chain or branched. Methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, undecyl and heptadecyl are examples of alkyl groups.

־3־

Aryl and arylene denote phenyl and, respectively, phenylene or phenyl and, respectively, phenylene substituted by up to 5 halogen atoms or up to 3 C!-4־alkyl, Ci-4־alkoxy or nitro groups.

Preferred oxetanones of formula I are those in which Q is a group Ql, R1 and are alkyl, alkenyl or alkadienyl groups with up to 20 C atoms optionally interrupted by a 1,4-phenylene group, optionally substituted by a phenyl group in the (!)־position and optionally substituted by a phenyl־C!-4־alkyl group, whereby R1 can be interrupted by an O or S atom in a position other than the «־position to an unsaturated C atom, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S atom and which is optionally substituted by a hydroxy, mercapto, phenyl, phenoxy, phenylthio, phenyl־Ci-4־alkyl, phenyl־Cl-4־alkoxy, phenyl־Ci-4־alkylthio, phenyl־Ci-4־ alkylidene, C3-7־cycloalkylidene or Ci-6־alkylidene group or by one or two Cl6-alkyl, C!-6־alkoxy or Cl-6־alkylthio groups, whereby two Ci-6־alkyl, C!-6־ alkoxy or Cl-6-alkylthio groups attached to the same C atom can form a 3- to 7־ membered ring and an optionally present hydroxy or mercapto group must be in a position other than the a-position to an optionally present O or S atom, or X is a group =CHN(R,R°), R and R° are hydrogen, C!-4־alkyl, C1-4־alkyI־(CO or OCO)-, phenyl or phenyl-(CO or CXZO)- and n, R³ and R⁴ have the significance given above.

Further preferred oxetanones of formula I, wherein Q is a group Ql, are those in which and are alkyl, alkenyl, alkynyl or alkadienyl groups with up to 20 C atoms optionally substituted by an aryl group in the ω-position, whereby R1 can be interrupted by a S atom in a position other than the aposition to an unsaturated C atom, or R¹ is anilino, alkyl with up to 18 C atoms substituted by a halogen atom or a phenyl־Ci-4־alkyl־OCONH- group, R³ and R⁴ are hydrogen or C!-4־alkyl or together with the N atom to which they are attached form a saturated 6־membered ring containing an 0 or S atom in a position other than the a-position to the N atom, n is the number 1 or O, X is an alkylene group, which contains up to 6 C atoms, which is optionally interrupted by an O or S atom or by a sulphinyl group and which is optionally substituted by one or two C!-6־alkyl or C!-6־alkoxy groups, whereby two C1-6־ alkyl or C1-6־alkoxy groups attached to the same C atom or to two adjacent C atoms can form an optionally mono-unsaturated 3- to 7-membered ring, or X is a group =CHN(R,R°) or -CHN(R,R°)CH2־ and R and R° are hydrogen, C2-5־ alkanoyl or benzyloxycarbonyl.

There are further preferred the oxetanones of formula I in which Q is a group Q², R1 and R² are C1-20־alkyl, R^ and are hydrogen and X' is an alkylene group containing up to 6 C atoms which can be substituted by a C!-4alkoxy group or by one or two C1-6־alkyl groups, whereby two C1-6־alkyl groups attached to adjacent C atoms can form a 3־ to 7-membered ring.

The oxetanones or formula I in which Q is a group Cp, is hydrogen and R1 and R² are C1-20־alkyl, especially hexyl or undecyl, are also preferred.

Especially preferred among the oxetanones of formula I in which Q is a group Ql are those in which R1 is methyl, ethyl, propyl, hexyl, 2-butenyl, 3-methyl2־-butenyl, 2-propynyl, methylthio, pentylthio, 5-chloropentyl, benzyl, phenylthio, benzylthio, pentafluorobenzyl, anilino or benzyloxycarbonylamino, R² is undecyl, heptadecyl or 8,11-heptadecadienyl, and R^ are hydrogen, methyl or isopropyl or together with the N atom form a morpholino or thiomorpholino group, n is the number 1 or 0 and X is the group (CH2)i-8־, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopentylidene, t־butylmethylene, dimethylvinylidene, cyclopentylidene, cydohexylidene, phenethylidene, phenylpropylidene, 1,2-cyclohexylene, cyclohex-3-en־l,6-ylene, acetamidomethylene, benzyloxycarbonylaminomethylene, l-benzyloxycarbonylamino-l,2-ethylene, methyleneoxymethylene, methylenethiomethylene, methylenesulphinylmethylene, ethylenethioethylene, ethylenesulphinylethylene, methoxymethylene or ethylene- or propylenedioxymethylene.

Especially preferred among the oxetanones of formula I in which Q is a group Q² are those in which R¹ is hexyl, R² is undecyl and X is ethylene, 1methoxy-l,2־ethylene or 1,2-cyclohexylene.

The following are examples of such compounds:

(S)-l2)]]־S,3S)־3־Hexyl-4-oxo2־-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, (S)־l2)]]־S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2carbamoylvalerate, (all Z,S)-l2)]]־S,3S)3־-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S)-2-isopropylmalonamate, (S)2)]]־1־S,3S or 2R,3R)-4־oxo-3-pentylthio־2־oxetanyl]methyl]dodecyl (S)-2isopropylmalonamate, (S)-1-[[(2S,3S) or 2R,3R)-4-oxo-3-pentylthio-2־oxetanyl]methyl]dodecyl [S:R(2:l)]-2־isopropylmalonamate, (S)־l-[[(2S,3S)־3־ethyl4־-oxo-2-oxetanyl]methyl]octadecyl (S or R)-2־tbutylmalonamate, (S)-l-[[(2S,3S)-3-ethyl-4־oxo-2-oxetanyl]methyl]octadecyl 1-carbamoylcyclopentanecarboxylate, (S)-l-[[(2S,3S)־3־hexyl4־-oxo-2-oxetanyl]methyl]dodecyl (RS)-2-benzylmalonamate, (S)־l2)]]־S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl3-[(2־carbamoylethyl)thio]propionate,

5-oxo-D-proline (S)־l-[[(2S,3S)-3-ethyl4־-oxo-2-oxetanyl]methyl]octadecyl ester,

5-oxo־L-proline (S)-l-[[(2S,3S)-3־ethyl־4־oxo2־-oxetanyl]methyl]octadecyl ester and especially (S)־l-[[(2S,3S)3־-hexyl-4-oxo-2־oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, (S)־l-[[(2S,3S)־3־hexyl־4־oxo-2-oxetanyl]methyl]dodecyl (RS)-2־carbamoylvalerate (epimers 1:1), (all Z,S)-l-[[(2S_/3S)-3-ethyl4־-oxo־2־oxetanyl]methyl]־9,12־octadecadienyl (S or R)-2־isopropylmalonamate, (S)-l-[[(2S3S)-3-hexyl-4-oxo2־-oxetanyl]methyl]dodecyl (RS)-2-carbamoyl-

4-methylvalerate (epimers 1:1), (S)-l2)]]־S,3S)-3־hexyl0‘4־x00־2־xetanyl]methyl]d0decyl l-carbamoylcydohexanecarboxylate, (S)-l-[[(2S,3S)-3־hexyl-4־oxo2־-oxetanyl]methyl]dodecyl (RS)-2־methylmalonamate (epimers 1:1), (S)-l-[[(2S,3S)3־-hexyl־4־oxo-2־oxetanyl]methyl]dodecyl (RS)-2-ethylmalonamate (epimers 1:1), (S)-l2)]]־S,3S)-3-hexyl-4־oxo-2־oxetanyl]methyl]dodecyl (RS)-2-butylmalonamate (epimers 1:1), (S)-l2)]]־S,3S)-3־ethyl־4־oxo-2-oxetanyl]methyl]octadecyl 1-carbamoylcyclohexanecarboxylate, (S)-12)]־S,3S or 2R_/3R)-4־oxo-3-pentylthio־2־oxetanylimethyl]dodecyl [S:R or R:S(2:l)]-2-isopropylmalonamate and (S)-l2)]]־R,3R)-3-benzyl-4־oxo-2-oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate.

The oxetanones of formula I contain at least three asymmetric C atoms and can accordingly be present as optically active enantiomers, as mixtures thereof, e.g. as racemates, or a diastereomers.

The oxetanones of formula I can be manufactured in a manner known per se by

a) esterifying an alcohol of the formula hochch₂—ς \=0 with an acid of the formula Q^a־OH, wherein Q^a is a group of the formula Ql or q3, or

b) cyclizing an add of the formula (Q-O,r2)CHCH2CH(OH)CH(R1)-COOH

c) converting the carboxy group in the group T in an acid of the formula

-Ί R²

T-OCHCHj

<img file="IL97148A_D0001.tif" />

C=O wherein T is a group of the formula

H0C0(X)_n-CO־

HOCO-X'_T1

T², . 5 into an amide group (R^, r4)nCO־, and

d) if desired, separating a mixture of epimers of formula I into the individual epimers.

The esterification a) can be carried out in the presence of triphenylphosphine and an azodicarbOxylic add diester such as the di-t-butyl ester of diiso10 propyl ester in a solvent, e.g. an ether such as tetrahydrofuran (THF), at room temperature or while cooling, e.g. to 0 to -5°C.

The cyclization b) can be carried out in a solvent such as methylene chloride, dimethylformamide (DMF) or acetonitrile using a molecular sieve, e.g. in the presence of 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium 15 hexafluorophosphate (HBTU) and of a base such as triethylamine at room . temperature or at a temperature up to 50°C:

The amidation c) can be carried out using a solution of ammonia or of an amine of the formula (R3,R⁴)NH, e.g. in acetonitrile, in the presence of HBTU at room temperature or at a temperature up to 40°C.

The optional separation of a mixture of epimers of formula I can be carried out e.g. by chromatography over silica gel with ethyl acetate/hexane/methylene chloride as the eluting agent.

The alcohols of formula Ila are known, e.g. from European Patent Application No. 0 185 359 A2, corresponding to IL 77338, or can be pre25 pared in analogy to the known alcohols of formula Ila or as described in Examples A to I, M and 0 to T.

The acid starting materials of formulae Db and De can be prepared in a manner known per se, e.g. starting from corresponding alcohols of formula Ha as described hereinafter in Examples J and K (for the acids Db) and K, L, and N (for the adds lie).

Example A

a) 465 g of methyl acetoacetate and then 458 g of ethyl bromide are added under nitrogen to 720 g of 30% sodium methylate solution. The reaction mixture is subsequently boiled at reflux. After distilling off the methanol the residue is poured on to ice-water. Then, the mixture is extracted with n-hexane and water. The organic phases are combined and dried. After evaporation of the solvent and distillation there are obtained 328 g of methyl 2-acetylbutyrate, b.p. 7779°/15־T0rr.

b) 144.17 g of the methyl ester from a) are added under argon at 0-5°C to a suspension of 26.4 g of sodium hydride in 1250 ml of THF. After stirring at 05°C for 1.5 hours the mixture is cooled to -10°C. At this temperature there are added 675 ml of 1.56M butyllithium in hexane. After stirring at -10°C for 30 minutes a solution of 149.3 g of methyl stearate in 250 ml of THF is added dropwise. After stirring at -10°C for 1.5 hours the reaction solution is added under argon to 250 ml of 37% hydrochloric acid and 300 g of ice. The mixture is extracted with hexane and water. The combined organic phases are dried, filtered and evaporated.

The residue is dissolved in 2500 ml of THF, treated with 76.1 g of 1,8diazabicyclo[5.4.0]undec-7-ene(1.55־) (DBU) and boiled at reflux under argon. The cooled reaction solution is extracted with 37% hydrochloric acid and then with saturated sodium chloride solution. The combined organic phases are dried and evaporated. The product is dissoved in ethyl acetate. The solution is cooled to room temperature and stirred at 25°C overnight. The crystallizate is filtered off under suction, washed with ethyl acetate and dried. There are obtained 122.5 g of 3-ethyl-6-heptadecyl־4־hydroxy2־H־pyran-2-one, m.p. 101־ 102°C.

c) 100 g of Raney-nickel and 2000 ml of THF are added to 100 g of the pyrone from b). After hydrogenation at 25° for 3 days the catalyst is filtered off under suction and washed with THF. The filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and stirred at 10° for 17 hours. The crystallizate is filtered off under suction, washed with cold (-10°) ethyl acetate •9 and dried at 40° for 17 hours. There are obtained 90.54 g of rac-(2RS,2RS^SR)-2ethyl-5-heptadecyl-3-hydroxy-5-valerolactone, m.p. 101102°־C.

d) 138.5 g of benzoic anhydride and subsequently 2.5 ml of 70% perchloric add are added to a suspension of 191.3 g of the d-lactone from c) in 1250 ml of toluene. After stirring for 2.5 hours the reaction mixture is extracted in toluene with IN sodium hydroxide solution in 20% sodium chloride solution and then with saturated sodium chloride solution. The organic phases are combined, dried and evaporated. There are obtained 243.4 g of rac(2RS,3RS,5SR)-3-benzoyloxy-2-ethyl-5-heptadecyl*6־valerolactone, m.p. 64.5660C.

e) 243 g of the benzoate from d) are dissolved in 450 ml of toluene at 40°C under argon. 1000 ml of methanol and thereafter 2.5 ml of cone, sulphuric acid are added and the reaction mixture is stirred at 25°C for 20 hours. After neutralization of the sulphuric acid with triethylamine the solvent is evaporated. The residue is dissolved in t-butyl methyl ether and washed with water. The aqueous phase is extracted with t-butyl methyl ether and the organic phases are combined and dried over sodium sulphate, the drying agent is filtered off under suction and washed with t-butyl methyl ether and subsequently evaporated. There are obtained 257 g of methyl rac(2RS,3RS,5SR)-3-benzoyloxy2־-ethyl-5-hydroxydocosanoate.

f) 257 g of the hydroxyester from e) in 1250 ml of n־hexane are treated under argon with 152 g of benzyl 2,2,2-trichloroacetimidate. Then, 3.2 ml of trifluoromethanesulphonic add are added. After stirring for 18 hours the predpitate is filtered off under suction and washed with n־hexane. The filtrate is extracted with 5% sodium bicarbonate solution and water. The combined hexane phases are dried, filtered and concentrated. After stirring at -20°C for 20 hours the crystallizate is filtered off under suction, washed with n-hexane and discarded. The filtrate is evaporated. There are obtained 239.6 g of methyl rac(2RS,3RS,5SR)-3-benzoyloxy-5־benzyloxy-2-ethyldocosan oate.

g) 239.6 g of the benzyl ether from f) are treated under argon with a solution of 140 g of potassium hydroxide in 1250 ml of 95% (v/v) methanol/water and stirred at 40°C for 17 hours. Subsequently, the mixture is concentrated at 40°C, the suspension is taken up in t-butyl methyl ether and washed in sequence with 10% sodium chloride solution, IN hydrochloric acid and again with 10% sodium chloride solution. ^,The organic phase is dried with sodium sulphate, the drying agent is filtered off under suction and washed with t-butyl methyl ether. The filtrate is evaporated. There are obtained 182.1 g of rac(2RS,3RS,5SR)-5־benzyloxy2־-ethyl-3-hydroxydocosanoic acid.

h) 33.3 g of (S)־(*)-a-methylbenzylamine are added to a solution of 182.1 g of the β-hydroxyacid from g) in 1250 ml of methyl acetate. The solution is seeded with 50 mg of the phenethylamine salt of (2S,3S,5R)-5־benzyloxy2־-ethyl-3hydroxydocosanoic acid and left to stand for 20 hours. The crystallizate is filtered off under suction, washed with cold (-20°C) methyl acetate and then dried. This 1st crystallizate is dissolved in hot methyl acetate, cooled to 45°C and seeded with 50 mg of the phenethylamine salt of (2S,3S,5R)-5-benzyloxy-2ethyl-3-hydroxydocosanoic acid. The solution is left to stand at room temperature for 20 hours. The crystallizate is filtered off under suction, washed with cold (-20°C) methyl acetate and dried. The same procedure as with the 1st crystallizate is repeated with the 2nd crystallizate. There are obtained 39.4 g of the phenethylamine salt of (2S,3S,5R)-5-benzyloxy-2־ethyl־3־hydroxydocosanoic add, m.p. 92-95°C.

i) 39.4 g of the phenethylamine salt from h) are treated with 400 ml of tbutyl methyl ether and 80 ml of IN hydrochloric acid and dissolved while stirring. The organic phase is washed with water, dried, filtered and concentrated. There are obtained 31.4 g of (2S,3S,5R)־5־benzyloxy-2־ethyl-3־hydroxydocosanoic add, m.p. 62-63.5°C.

j) 17.6 g of benzenesulphonyl chloride are added dropwise at 0°C under argon to a solution of 24.5 g of the β-hydroxyadd from i) in 250 ml of pyridine. After stirring at 0°C for 20 hours 5 ml of water are added dropwise to the solution. The mixture is stirred at room temperature for 1 hour. The pyridine is evaporated. The crystal slurry is taken up in t-butyl methyl ether and washed in sequence with 2N hydrochloric add, 5% sodium bicarbonate solution and 10% sodium chloride solution. The organic phase is dried over sodium sulphate and thereafter triturated with active charcoal. The drying agent and active charcoal are filtered off under suction and the filtrate is evaporated. There are obtained 23.4 g of (3S,4S)-4־[(R)־2־benzyloxynonadecyl]3־-ethyl-2oxetanone.

k) A solution of 23.4 g of the oxetanone from j) in 250 ml of THF is treated with 2.3 g of 10% Pd/C. After hydrogenation for 5 hours the hydrogenation solution is suction filtered. After washing with THF the filtrate is evaporated, the residue is dissolved in n־hexane and seeded with (3S,4S)-3-ethyl-4-[(R)-2hydroxynonadecyl]-2-oxetanone. After 18 hours the CTystallizate is filtered off under suction, washed with hexane and dried. There are obtained 16.1 g of (3S,4S)-3-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone, m.p. 66.5-68°C, the alcohol starting material of Example 1.

Example B

a) 50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine are dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of tbutyldimethylchlorosilane are added. After a further 24 hours under reflux the precipitated triethylamine hydrochloride salt is filtered off, washed with ether and the filtrate is concentrated. The residue is dissolved in ether and washed in sequence with water, 0.5M citric add, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5°C in a high vacuum for 5 hours. There are obtained 71.8 g of (R)-3-[(l,l-dimethylethyl)dimethylsilyloxy]tetradecanoic add, IR (cm־

1):1745,1254,895,776.

b) 18.63 g of the product from a) dissolved in 100 ml of ether are treated with 65 ml of IM diisobutylaluminium hydride solution in hexane at a temperature of -70°C to -75°C and then stirred at this temperature for 1 hour. Thereupon,

2.5 ml of isopropanol, 10 ml of water and 50 ml of 0.5M citric acid solution are added dropwise at a max. of 10°C. The ether phase is separated, the aqueous phase is extracted with ether, the combined ether phases are washed with brine, dried and concentrated. The residue is chromatographed on silica gel with pentane/ether (5:1) and there are obtained 14.47 g of (R)-3-[(l,ldimethylethyl)dimethylsilyloxy]tetradecanal, IR (cm'l): 1728,1254,836,775.

c) A solution of 2.55 ml of diisopropylamine in 45 ml of THF is treated at 0°C with 22.5 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring for 15 minutes, cooled to -75°C. Then, a solution of 2.9 g of pentylthioacetic add in 9 ml of THF is added dropwise. After stirring for 10 minutes the reaction mixture is left to warm to room temperature, stirred for 5 minutes and again cooled to -75°C. At this temperature there is added dropwise a solution of 2.4 g of the aldehyde from b) in 9 ml of THF. After stirring for minutes the reaction mixture is poured into saturated ammonium chloride solution and extracted with hexane. The hexane phase is dried and concentrated. There are obtained 3.89 g of (2R/S,3R/S,5R)-51,1)]־ ־12dimethylethyl)dimethylsilyloxy]-3-hydroxy-2-pentylthiohexadecanoic add as a mixture of 4 diastereomers.

d) A solution of 3.89 g of the product from c), 3.18 g of 2-(lH-benzotriazol-lyl)-l,l,3,3-tetramethylu1Oniu1n hexafluorophosphate (HBTU), 2 g of 4A molecular sieve and 3 ml of triethylamine is stirred for 2 hours in a mixture of 130 ml of methylene chloride and 6 ml of DMF. Thereupon, the mixture is filtered, the filtrate is concentrated, the residue is dissolved in water/methanol (3:7) and extracted with hexane. The hexane phase is dried and concentrated. There are obtained 3.57 g of (3R/S,4R/S)-4־[(R)-2-[(l,ldimethylethyl)dimethylsilyloxy]tridecyl]־3־pentylthio-2-oxetanone as a mixture of 4 diastereomers.

e) A solution of 4.5 g of the product from d) in 200 ml of acetonitrile is treated with 15 ml of 40% hydrofluoric acid and stirred for 18 hours.

Thereupon, sodium bicarbonate solution is added, the mixture is then extracted with hexane and the hexane phase is dried and concentrated. The residue is chromatographed on silica gel with 1-5% ether in methylene chloride. There are obtained 699.9 mg of 3R,4R (or 3S,4S)-4-[(R)2־-hydroxytridecyl]-3-pentylthio־2־oxetanone, m.p. 43°C, and 691.2 mg of 3S,4S (or 3R,4R)-4[(R)2־-hydroxytridecyl]-3-pentylthio-2־oxetanone, m.p. 71°C, the alcohol starting materials of Examples 5 and 6.

Example C

a) 18 ml of a IM solution of lithium bis(trimethylsilyl)amide in THF are treated with 1.8 ml of ethyl acetate under argon at -75°C, stirred at this temperature for 30 minutes and subseuently treated with 4.8 g of (R)-3-benzyloxytetradecanal in 15 ml of THF and stirred at -78°C for half an hour. A solution of 3.8 ml of cone, hydrochloric add in 6 ml of water is added dropwise to the reaction mixture. The solution obtained is extracted with ethyl acetate, the combined organic phases are washed with 10% sodium bicarbonate and water, dried, filtered and concentrated. There is obtained ethyl (3R,5R and 3S,5R)-5-benzyloxy-3-hydroxyhexadecanoate (1:1).

b) A solution of 4 ml of diisopropylamine in 12.5 ml of THF is treated with 17 ml of a 1.6M solution of n־BuLi in n-hexane under argon at 0°C. After stirring for 15 minutes 5 g of the product from a) in 2.5 ml of THF are added dropwise at -50°C. After 10 minutes at -10°C the temperature is lowered to 50°C and, after the dropwise addition of a solution of 3.18 g of benzyl bromide in 3.1 ml of hexamethylphosphoric acid triamide, the mixture is stirred at 50°C for 15 minutes. Thereafter, the cooling bath is removed and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is cooled to 0°C and 50 ml of saturated sodium chloride solution are added thereto, the mixture is extracted with t־butyl methyl ether, the extracts are dried, filtered and the solvent is evaporated. The residue is chromatographed on silica gel with n-hexane/ethyl acetate (4:1). The residue is dried. There is obtained ethyl (2R,3R,5R and 2S,3S,5R)-5־benzyloxy-2-benzyl3־-hydroxyhexadecanoate as 1:1 threo diastereomers.

c) A solution of 3.1 g of the product from b) and 26 ml of 2.5N sodium hydroxide solution in 37.2 ml of ethanol is heated at reflux for 50 minutes and subsequently neutralized at room temperature with 26 ml of 2.5N hydrochloric add. The ethanol is distilled off, whereupon the residue is extracted with tbutyl methyl ether and water. The combined organic phases are dried and concentrated. A solution of 3 g of the residue in 109 ml of methylene chloride is stirred under argon and treated with 2.59 g of HBTO and 2.74 g of molecular sieve. Subsequently, 5.5 ml of DMF and 2.8 ml of triethylamine are added and the reaction mixture is stirred for 1 hour, filtered and concentrated. The residue is taken up in n-hexane, the solution is thereupon extracted with water, dried and concentrated in a vacuum. Chromatography on silica gel with methylene chloride gives a 1st trans diastereomer (3S,4S or 3R,4R)-3-benzyl-4[(R)-2-benzyloxytridecyl]2־-oxetanone, Rf value: 0.45 (thin-layer chromatography over silica gel 5-40 m with methylene chloride) and a 2nd trans diastereomer, (3R,4R or 3S,4S)-3־benzyl-4-[(R)-2-benzyloxytridecyl]-2oxetanone, Rf value: 0.50 (thin-layer chromatography over silica gel 5-40 μ with methylene chloride).

d) A solution of 646 mg of the 2nd trans diastereomer from c) in 65 ml of THF is hydrogenated for 1 hour in the presence of 646 mg of 10% Pd/C. The reaction mixture is filtered and concentrated. There is obtained a trans diastereomer: (3R,4R or 3S,4S)-3-benzyl-4־[(R)-2-hydroxytridecyl]-2-oxetanone, the alcohol starting material in Example 7.

e) As described under d), from the 1st trans diastereomer from c) there is obtained the trans diastereomer: (3S,4S or 3R,4R)־3־benzyl-4־[(R)-2-hydroxytridecyl]-2-oxetanone, the alcohol starting mateial in Example 8.

Example D

A solution of 3.0 ml of diisopropylamine in 50 ml of THF is treated at 0°C with 12.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75°C. A solution of 1.26 g of Z-glycine in 10 ml of THF is then added dropwise. Then, the reaction mixture is left to warm to room temperature and again cooled to -75°C. 0.7 g of (R)-3-(t-butyldimethylsiloxy)tetradecanal in 5 ml of THF is now added dropwise at -75°C. The reaction mixture is stirred at -75°C for 1 hour and at -40° to -50°C for 1/2 hour, then warmed to 5°C, again cooled to -75°C, poured into dilute potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried, concentrated and chromatographed on silica gel with methylene chloride/methanol. There are obtained 540 mg of (2R/S,3R/S,5R)-2-[l-(benzyloxy)formamido]-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic add as a mixture of 4 diastereomers.

In analogy to B)d), from the above product there is obtained benzyl 4-[(R)-

2-(t-butyldimethylsiloxy)tridecyl]2־-oxo־3־oxetanecarbamate as a 1:1 mixture of the two trans-diastereomeric β-lactones, MS: 476 (M⁺*-C4H9.).

In analogy to B)e), from the above mixture there are obtained (3S,4S or 3R,4R)-benzyl 4-[(R)-2-hydroxytridecyl]-2-oxo-3-oxetanecarbamate, the alcohol starting material in Example 15, m.p. 122-124°C, and (3R,4R or 3S,4S)-benzyl-4[(R)-2-hydroxytridecyl]-2-oxo-3-oxetanecarbamate, m.p. 98-99°C.

Example E

In analogy to Example B, from thiophenoxyacetic acid and (R)-3[(l,l-dimethylethyl)dimethylsilyloxy]tetradecanal there is obtained, via

a) (2R/S,3R/S,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2(phenylthio)hexadecanoic add (mixture of 4 diastereomers) and

b) (3R/S,4R/S)4־-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-3-(phenylthio)-2oxetanone (mixture of 4 diastereomers),

IR (cm^): 2927,2855,1833,1254, (3S,4S)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone m.p. 79°C (ether), and (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone, m.p. 47°C (ether), the alcohol starting material of Example 16.

Example F

־15-

a) 270 ml of stearoyl chloride are added dropwise at a maximum of 150°C to a solution of 117 g of Meldrum add and 131 ml of pyridine in 1.51 of methylene chloride. After stirring the reaction mixture is washed with 4N hydrochloric add, the aqueous phase is back-extracted with methylene chloride and the methylene chloride phase is dried and concentrated. The residue is taken up in methanol and stirred unde reflux. After cooling the separated crystals are filtered off, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. There are obtained 175 g of methyl 3־ oxoeicosanoate, m.p. 5254°־C.

b) 1.84 mg of acetyl chloride in 1.84 ml of methanol are added to a solution of 9.1 mg of [(R)-2,2'־bis(diphenylphosphino)-6,6'-dimethylbiphenyl]ruthenium diacetate in 20 ml of methylene chloride. The solution obtained is hydrogenated at 35 bar of hydrogen and 60°C together with 39.8 g of the ketoester from a) and 170 ml of methanol. After the addition of methylene chloride the mixture is evaporated to dryness. Chromatography on silica gel with ether and recrystallization from n־hexane yields 35.6 g of methyl (R)-3hydroxyeicosanoate, m.p. 6464.5°־C.

c) Analogously to Example B, from the product of b) there are obtained, via methyl (R)-3־(t־butyldimethylsiloxy)eicosanoate, IR (cm1255,836 ,1745 :(¹־, (R)-3־(t-butyldimethylsiloxy)eicosanal, IR (cm1728,1463,1255,1104 :(¹־,

836,775, (2R/S,3R/S,5R)5־-(t-butyldimethylsiloxy)-3-hydroxy-2(methylthio)docosanoic acid (mixture of 4 diastereomers), MS: 533 (M+H)⁺,

4-[(R)-2-(t־butyldimethylsiloxy)nonadecyl]־3־(methylthio)-2-oxetanone, (1:1 mixture of two trans diastereomers),

IR (cm1834,1463,1256,1106,836 :(¹־, and

4-[(R)-2-(t-butyldimethylsiloxy)nonadecyl]3־-(methylthio)־2־oxetanone (1:1 mixture of two cis diastereomers), IR (cm836 ,1834,1463,1256,1106,1066 :(¹־, the following alcohol starting materials of Example 17:

(3S,4R or 3R,4S)-4- [(R)-2-Hydroxynonadecyl]-3־(methylthio)-2-oxetanone, m.p. 65°C (from methylene chloride)

־16־ (3R,4S or 3S,4R)־4־[(R)-2-hydroxynonadecyl]־3־(methylthio)־2־oxetanone, m.p. 67°C (from methylene chloride) (3R,4R or 3S,4S)4־-[(R)־2־hydroxynonadecyl]-3־(methylthio)־2־oxetanone, m.p. 71 °C (from ether) and (3S,4S or 3R4_׳R)-4- [(R)־2־hydroxynonadecyl]-3־(methylthio)-2-oxetanone_/m.p. 80°C (from ether).

Example G

Analogously to Example B, from (benzylthio)-acetic acid and (R)־

3-[(l,l-dimethylethyl)dimethylsilyloxy]tetradecanal there is obtained, via (2R/S,3R/S,5R)-2-(benzylthio)5־-[(l,l־dimethylethyl)dimethylsilyloxy]-3hydroxyhexadecanoic acid (mixture of 4 diastereomers) and (3R/S,4R/S)-3-(benzylthio)־4־[(R)־2־(t־butyldimethylsiloxy)tridecyl]-2oxetanone (mixture of 4 diastereomers), MS: 506 (M⁺), the following alcohol starting materials of Examples 19 and 20:

(3S,4S or 3R,4R)-3-(Benzylthio)־4־[(R)-2-hydroxytridecyl]-2־oxetanone, m.p. 65°C (ether), (3R,4R or 3S,4S)3־-(benzylthio)-4-[(R)-2־hydroxytridecyl]2־-oxetanone, MS: 374 (Μ+.-Η20), and (3R,4S and 3S,4R)3־-(benzylthio)4־-[(R)־2־hydroxytridecyl]2־-oxetanone (1:1 diast), MS: 374 (M⁺ .-H2O).

Example H

a) 104 g of the mother liquor from the 1st crystallization in Example Ah) are dissolved in water and methylene chloride. The mixture is acidified to pH 1 by the addition of cone. HC1 while cooling with ice, the methylene chloride phase is separated, the aqueous phase is extracted with methylene chloride and the methylene chloride phase is washed with water, dried and concentrated. There are obtained 86.7 g of enriched (2R,3R,5S)-5־benzyloxy-2-ethyl-3-hydroxydocosanoic acid which are dissolved in 500 ml of ethyl acetate and treated with

20.6 g of (R)-(+)־a-methylbenzylamine while cooling. After the addition of ethyl acetate the mixture is heated to reflux, filtered and crystallized-out. The crystals obtained are recrystallized from ethyl acetate and methyl acetate. There are obtained 70.0 g of the phenethylamine salt of (2R,3R,5S)-5־benzyloxy-2ethyl-3-hydroxydocosanoic acid, m.p. 88-91 °C.

b) Analogously to Example Ai),j),k), from the above salt there is obtained, via (2R,3R,5S)-5-benyzloxy-2-ethyl-3-hydroxydocosanoic add m.p. 61.5-63°C, and (3R,4R)-4-[(S)-2-benzyloxynonadecyl]־3־ethyl-2־oxetanone, m.p. 38-40°C, (3R,4R)-3-ethyl-4־[(S)-2-hydroxynonadecyl]־2־oxetanone, m.p. 66-68°C.

c) A solution of 14.2 g of the product obtained and 8.65 g of triphenylphospine in 250 ml of THF is treated at +5°C with 1.19 ml of formic add and then with a solution of 5.12 g of diethyl azodicarboxylate in 20 ml of THF. The mixture is then again treated with 0.4 ml of formic acid, 2.9 g of triphenylphosphine and 1.7 ml of diethyl azodicarboxylate. The reaction mixture is concentrated and the residue is chromatographed on silica gel with hexane/ethyl acetate; there are thus obtained 13.1 g of (R)-l-[[(2R,3R)-3-ethyl-4oxo-2-oxetanyl]methyl]octadecyl formate.

The product obtained is dissolved in 150 ml of methanol and treated at 15°C with 0.114 g of p-toluenesulphonic acid monohydrate. After stirring the reaction mixture is concentrated, the residue is partitioned between methylene chloride and aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride phase is dried and concentrated and the residue is recrystallized from ethyl acetate. There are obtained 9.5 g of (3R,4R)־ 3-ethyl־4־[(R)־2־hydroxynonadecyl]2־-oxetanone, m.p. 80-82°C, the alcohol starting material in Example 21.

Example I

a) 187.5 ml of n-butyllithium solution (1.6M in hexane) are added dropwise at -20°C to a solution of 42.5 ml of diisopropylamine in 500 ml of THF. After stirring the solution is added dropwise at a maximum of -65°C to a suspension of 39.9 g of (S)-(-)-2-hydroxy־l,2,2-triphenylethyl-acetate in 600 ml of THF. Then, the reaction mixture is warmed to 0°C, stirred, cooled to -70°C and treated with a solution of 51.2 g of (R)-3-[(t-butyl)dimethylsilyloxy]eicosanal in ml of THF. After stirring 500 ml of saturated ammonium chloride solution are added dropwise, the mixture is then warmed to room temperature and stirred. The reaction mixture is concentrated, partitioned between water and ether and extracted with ether, the ether phase is washed with water, concentrated, taken up in 11 of methylene chloride, dried and concentrated. There are obtained 91.9 g of (S)-2-hydroxy־l,2,2-triphenylethyl [3R:3S(4:l),5R]-5(t-butyldimethylsiloxy)-3-hydroxydocosanoate, IR (cm־l): 3525,1719,1448,1250, 1159,838,697.

b) A solution of 90.8 g of the product obtained above in 11 of methanol is treated with 22.15 ml of 5.4M sodium methylate in methanol. After stirring the solution is concentrated, the residue is partitioned between ether and saturated ammonium chloride solution and extracted with ether. The ether phase is dried, concentrated and chromatographed on silica gel with hexane/ ethyl acetate. There are thus obtained 42.7 g of methyl (3R,5R)-5-(t-butyldimethylsiloxy)-3־hydroxydocosanoate, IR (cm3521,3468,1738,1254,1168,1137,1105 :(¹־.

c) Analogously to Example Be) and Cb), c), the latter compound is converted, via methyl (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-2methyldocosanoate, IR (cm־l): 3522,1739,1464,1254,1066, and (3R,4R)-4-[(R)-2(t-butyldimethylsiloxy)nonodecyl]-3-methyl-2-oxetanone, IR (cm־l): 1830,1464, 1254,1129,1071, into (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-methyl-2oxetanone, m.p. 82.584°־C (from EtOAc/hexane), the alcohol starting material in Example 22.

Example I

a) 1.1 g of (3S,4S)־3־hexyl־4־[(R)2־-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4A) are treated with 20 ml of THF and cooled to 0°C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate are added. After warming to room temperature and stirring the reaction mixture is concentrated and the residue is partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase is dried and concentrated and the residue is chromatographed on silica gel with hexane/ethyl acetate (4:1). There are thus obtained 0.727 g of o-[[(S)-l[[(2S,3S)-3־hexyl4־-oxo-2־oxetanyl]methyl]dodecyl]oxy]benzamide, MS: 474 (M+H)+.

b) 972 mg of the product obtained above are dissolved in 12 ml of methanol and treated with 0.2 g of potassium carbonate. After stirring the reaction mixture is concentrated and the residue is partitioned between methanol/water (7:3) and hexane and extracted with hexane. The hexane phase is dried and concentrated. There are thus obtained 854 mg of methyl (25.35.55) -5-(o־carbamoylphenoxy)-2־hexyl־3־hydroxyhexadecanoate, MS: 369 (M⁺.-(o-carbamoylphenoxy)).

c) 850 mg of the product obtained above are dissolved in 12 ml of methanol/water (98:2) treated,with 800 mg of 5 percent rhodium on aluminium oxide and hydrogenated at 100°C and 100 bar of hydrogen. The reaction mixture is filtered, concentrated and chromatographed on silica gel with hexane/ ethyl acetate (1:1). There are thus obtained 213 mg of methyl (25.35.55) -5-[[(cis)-2-carbamoylcyclohexyl]oxy]-2-hexyl-3-hydroxyhexadecanoate (1st. diast.), MS: 367 [M⁺*־(H2NCOC6H10*+H2O)]204 _׳ mg of a mixed fraction and 142 mg of methyl (2S,3S_/5S)-5־[[(cis)-2־carbamoylcyclohexyl]oxy]-2-hexyl-3hydroxyhexadecanoate (2nd.diast.), MS: 367 [M⁺»-(H2NCOC6H10*+H2O)].

d) 210 mg of the 1st diastereomer obtained above are dissolved in 10 ml of acetone and treated with 3 ml of IN potassium hydroxide. After stirring the reaction mixture is poured into potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried and evaporated. There are obtained 277 mg of (2S,3S,5S)5־-[[(ds)-2-carbamoylcyclohexyl]oxy]2־-hexyl-3־ hydroxyhexadecanoic acid (1st. diast.), the add starting material in Example 23a).

e) As described in d), from the 2nd diastereomer from c) there is obtained (25.35.55) -5-[[(ds)־2־carbamoylcydohexyl]oxy]2־-hexyl-3־hydroxyhexadecanoic add (2nd. diast.), the add starting material in Example 23b).

Example K

a) Analogously to Example He), from (3S,4S)-3-hexyl-4־[(R)-2-hydroxytridecyl]-2-oxetanone and formic acid there is obtained, via (S)-l-[ [(25,35)-3hexyl-4־oxo־2־oxetanyl]methyl]dodecyl formate, IR (cm־l): 1826,1725,1177, 1122, (3S,4S)-3-hexyl-4-[(S)-2-hydroxytridecyl]-2-oxetanone m.p. 63-64°C (from hexane).

b) 1.8 g of the hydroxy-b-lactone prepared above, 1.3 g of pyridinium ptoluenesulphonate and 2 g of molecular sieve (4A) in 10 ml of methyl 3,3dimethoxypropionate are stirred at 100°C under argon, the reaction mixture is then filtered, the residue is concentrated and chromatographed on silica gel with ether/ methylene chloride. There are thus obtained

1. 213 mg of methyl (E)-3-[[(S)-l-[[(2S,3S)3־-hexyl4־-oxo-2oxetanyl]methyl]dodecyl]oxy]acrylate, IR (cm1827,1714,1643,1622,1192 :(¹־, and

2. 826 mg of methyl (R/S)-3-[[(S)-l-[[(2S,3S)-3-hexyl־4־oxo-2oxetanyl]methyl]dodecyl]oxy]-3־methoxypropionate (1:1 epimer mixture), IR (cm1824,1743,1438,1117 :(¹־.

c) 235 mg of the product of b)2. are suspended in 25 ml of 0.02N NaOH and the reaction mixture is diluted with acetone. After stirring for 24 hours the mixture is acidified with 5 percent potassium hydrogen sulphate solution and extracted with ether. The ether phase is dried and concentrated and the residue is chromatographed on silica gel with methylene chloride/ methanol. There are thus obtained 60 mg of (2S,3S,5S)-2־hexyl-3-hydroxy5־-[(R/S)-l־methoxy-2(methoxycarbonyl)ethoxy]hexadecanoic acid, MS: 337 (M⁺«-(H2O+-O-(CH3O)CH2-COOCH3)).

d) A solution of 58 mg of the above compound in 4 ml of condensed ammonia is heated at 50°C in an autoclave. Subsequently, the ammonia gas is allowed to escape and the mixture is then treated with potassium hydrogen sulphate solution and extracted with methylene chloride. The methylene chloride phase is dried and concentrated. There are obtained 42.5 mg of (2S,3S^S)-5-[(R/S)-2-carbamoyl-l-methoxyethoxy]־2־hexyl3־-hydroxyhexadecanoic acid, the acid starting material of Example 24.

Example L

A solution of 200 mg of the product of Example Kb)l. in 10 ml of THF is hydrogenated using 200 mg of Pd/C (10%). Then, the mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with 1% ether in methylene chloride. There are obtained 99 mg of methyl 3-[[(S)-l[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]propionate, MS: 285 (M+״-(CllH23.)).

A suspension of 544 mg of this compound in 49 ml of 0.02N sodium hydroxide is treated with acetonitrile. The resulting solution is acidified with aqueous potassium hydrogen sulphate, the reaction mixture is extracted with ether and the ether phase is dried and concentrated. Chromatography on silica gel with 2% ether in methylene chloride and then 5% methanol in methylene ־21chloride yields 43.7 mg of 3־[[(S)־l2)]]־S,3S)־3־hexyl-4-oxo-2oxetanyl]methyl]dodecyl]oxy]propionic add, IR (cm־l): 1823,1715,1466,1105, the add starting material in Example 25.

Example M

Analogously to Example Cb) and c), methyl (3R,5R)-5-(t־butyldimethylsiloxy)-3-hydroxydocosanoate (Example lb) is reacted with propargyl bromide to give methyl (2R,3R,5R)-5-(t-butyldimethylsiloxy)-3-hydroxy-22)־propynyDdocosanoate, IR (cm־l): 3310,2120,1740,1255, the latter is saponified to give (2R,3R,5R)-5־(t-butyldimethylsiloxy)3־-hydroxy2)-2־propinyl)docosanoic add, IR (cm־l): 3315,2120,1715,1255, and this acid is cyclized to give (3R,4R)-4-[(R)-2-(t-butyldimethylsiloxy)nonadecyl]-3-(2propynyl)2־-oxetanone, IR (cm־l): 3315,2130,1830,1255 .

After cleavage of the protecting group analogously to Example Be) there is obtained (3R,4R)-4-[(R)2־-hydroxynonadecyl]-3-(2-propynyl)-2-oxetanone, m.p. 62-63°C (from ethyl acetate), the alcohol starting material in Example 60.

Example N

Analogously to Example 1, from (3S,4S)־3־hexyl־4־[(R)-2-hydroxytridecyl]־

2- oxetanone and monobenzyl malonate there is obtained benzyl (S)-1-[[(2S,3S)-

3- hexyl-4-oxo2־-oxetanyl]methyl]dodecylmalonate, IR (cm־l): 1824,1734,1149, 1125.

A solution of 430 mg of this product in 15 ml of THF is treated with 100 mg of Pd/C and then hydrogenated. The reaction mixture is filtered and the filtrate is concentrated. There are obtained 361 mg of (S)-l-[[(2S,3S)-3-hexyl-

4- oxo-2־oxetanyl]methyl]dodecyl hydrogen malonate, IR (cm1824,1745 :(1 ־, the add starting material of Example 26.

Example O

A solution of 1.96 g of the alcohol product of Example M in 50 ml of ethyl acetate is hydrogenated using 0.25 g of 10 percent Pd/C, the reaction mixture is then filtered and the residue is chromatographed on silica gel with ethyl acetate/ hexane. There are thus obtained 1.44 g of (3R,4R)-4־[(R)־2־hydroxynonadecyl]-3־propyl-2-oxetanone, m.p. 8485°־C (from ethyl acetate/hexane), the alcohol starting material in Example 61.

Example P

a) From (R)-3-(t־butyldimethylsiloxy)tetradecanal (Example Bb) there is obtained analogously to Example Ca),b),c), via ethyl (3R and 3S,5R)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate (epimer mixture) and ethyl (R and S)-2-[(lR and lS,3R)3־-(t־butyldimethylsiloxy)-l-hydroxytetradecyl]-5־methyl-4-hexenoate (1:1 threo diastereomers), (3R,4R and 3S,4S)-4- [(R)-2-(t-butyldimethylsiloxy)tridecyl]-3-(3-methyl-2butenyl)־2־oxetanone (1:1 trans diastereomers).

b) A solution of 1.87 g of the product of a) in 50 ml of acetonitrile is treated with 6.2 ml of 40% hydrofluoric acid. After stirring sodium bicarbonate solution is added, the mixture is then extracted with methylene chloride and the methylene chloride phase is dried and concentrated. The residue is chromatographed on silica gel with ethyl acetate/methylene chloride/nhexane (1:4.5:4.5). The chromatography gives the alcohol starting materials for Examples 62-65:

A 1st trans diastereomer, (3S,4S)-4־[(R)-2־hydroxytridecyl]-3-(3־methyl2־butenyl)-2-oxetanone, Rf-value: 0.31, and a 2nd trans diastereomer, (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(3־methyl2־butenyl)-2-oxetanone Rf value: 0.26 (thin-layer chromatography over silica gel

5-40 μ with ethyl acetate/ methylene chloride/hexane (1:4.5:4.5).

Example O

From ethyl (3R,5R and 3S,5R)-5-benzyloxy-3-hydroxy hexadecanoate (1:1) (Example Ca) there are obtained analogously to Example Cb) to e) via ethyl(2R,3R,5R and 2S,3S,5R)-5-benzyl-2-(5-chloropentyl)3־-hydroxyhexadecanoate (threo diastereomers), a 1st trans diastereomer, (3S,4S or 3R,4R)-4-[(R)-2-(benzyloxy)tridecyl]-3-(5chloropentyl)-2-oxetanone, Rf value: 0.47, and a 2nd trans diastereomer, (3R,4R or 3S,4S)-4־[(R)-2־(benzyloxy)tridecyl]-3-(5chloropentyl)-2-oxetanone, Rf value: 0.28 (thin-layer chromatography over silica gel 5-40 μ with methylene chloride), the alcohol starting materials for Examples 6669־:

(3R,4R or 3S,4S)-3־5)־chloropentyl)-4־[(R)2־-hydroxytridecyl]-2-oxetanone and (3S,4S or 3R,4R)־5)־3־chloropentyl)־4־[(R)־2־hydroxytridecyl]־2־oxetanone.

Example R

From (R)־3־(t־butyldimethylsiloxy)tetradecanal (Example Bb) there are obtained analogously to Example Cb) and c) via ethyl (R and S,E)-2-[(lR and lS,3R)-3-(t-butyldimethylsiloxy)tetradecyl]4־-hexenoate (1:1 threo diastereomers) and (3R,4R and 3S,4S)־3־[(E)־2־butenyl]־4־[(R)־2־(t־butyldimethyl־ siloxy)tridecyl]־2־oxetanone (1:1 trans diastereomers), the alcohol starting materials for Examples 70-73:

A 1st trans diastereomer, (3S,4S or 3R,4R)־3־[(E)־2־butenyl]-4־[(R)-2hydroxytridecyl]־2־oxetanone, Rf value: 0.475 and a 2nd trans diastereomer, (3R,4R or 3S,4S)-3־[(E)2־-butenyl]-4-[(R)-2hydroxytridecyl]־2־oxetanone, Rf value: 0.44 (chromatography and thin-layer chromatography over silica gel with ethyl acetate/methylene chloride/nhexane (1:2:2).

Example S

From ethyl (3R,5R and 3S,5R)-5־benzyloxy-3-hydroxyhexadecanoate (1:1) (Example Ca) there are obtained analogously to Example Cb) and c) via ethyl (2R,3R and 2S,3S,5R)-5-(benzyloxy)-3-hydroxy-2-(2,3,4,5,6-pentafluorobenzyDhexadecanoate (threo diastereomers) and (3R,4R and 3S,4S)4־-[(R)-2-(benzyloxy)tridecyl]-32,3,4,5,6)־pentafluorobenzyl)־2־oxetanone (trans diastereomers), the alcohol starting materials of Examples 74-77:

A 1st trans diastereomer, (3S,4S or 3R,4R)-4־[(R)־2־hydroxytridecyl]3־(2,3,4,5,6־pentafluorobenzyl)־2־oxetanone, Rf value: 0.43, and a 2nd trans diastereomer, (3R,4R or 3S,4S)־4־[(R)־2־hydroxytridecyl]־3־ (2,3,4,5,6־pentafluorobenzyl)-2-oxetanone, Rf value: 0.39 (chromatography and thin-layer chromatography on silica gel with ethyl acetate/methylene chloride/n־hexane (1:4.5:4.5)).

Example T

a) A solution of 0.5 ml of diisopropylamine in 15 ml of THF is treated at 0°C with 2.0 ml of a solution of 1.6M n-buty !lithium in hexane and, after stirring, cooled to 75°C. Then, a solution of 765 mg of N-benzyl-N־phenylglycine methyl ester in 3 ml of THF is added. After stirring a solution of 700 mg of (R)3־(t־butyldimethylsiloxy)tetradecanal (Example Bb) in 5 ml of THF is added dropwise. After stirring at -75°C the reaction mixture is poured into aqueous potassium hydrogen sulphate and extracted with ether. ^,The ether phase is dried, concentrated, partitioned between hexane and methanol/water (7:3), the hexane phase is dried and concentrated and the residue is chromatographed on silica gel with pentane/ether (5:1). There are obtained 96.3 mg of methyl (5R)-2(N-benzylanilino)5־-(t־butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M⁺*-C4H9״), and 142.8 mg of methyl (5R)-2־(Nbenzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer B, MS: 540 (M⁺*־C4H9*), and 313.4 g of a mixture of the above two diastereomers.

b) 134 mg of diastereomer B are suspended in 3 ml of 0.1N NaOH and treated with sufficient acetonitrile to form a clear solution. After stirring the mixture is poured into aqueous potassium hydrogen sulphate and extracted with ether and the ether phase is dried and concentrated. After chromatography on silica gel with methylene chloride/methanol (9:1) there are obtained 108 mg of (5R)־2־(N-benzylanilino)-5־(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid, diastereomer B, MS: 526 (M⁺*-C4H9.).

c) Analogously, from diastereomer A from a) there is obtained (5R)-2-(Nbenzylanilino)-5־(t-butyldimethylsiloxy)־3־hydroxyhexadecanoic acid, diastereomer A, MS: 526 (M⁺«־C4H9.).

d) 1.1 g of diastereomer B from b), 1.1 g of HBTU, 0.5 g of triethylamine and 2 g of molecular sieve 4A are stirred in 50 ml of acetonitrile. After filtration and concentration the product is chromatographed on silica gel with methylene chloride. There are thus obtained 1.04 g of 3R,4R (or 3S,4S)-3-(Nbenzylanilino)-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxetanone, diastereomer B, MS: 566 (M+H)⁺.

e) Analogously, from diastereomer A from c) there is obtained 3S,4S (or 3R,4R)-3-(N־benzylanilino)-4־[(R)-2־(t-butyldimethylsiloxy)tridecyl]-2oxetanone, diastereomer A, MS: 566 (M+H)+.

1.0 g of diastereomer B from d) and 0.8 g of Pd/C (10%) are hydrogenated in 30 ml of THF. Thereupon, the mixture is filtered and concentrated. There are thus obtained 834 mg of 3R,4R (or 3S,4S)-3-anilino-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxetanone, diasteromer B, MS: 475 (M⁺.).

g) Analogously, from diastereomer A from e) there is obtained 3S,4S (or 3R,4R)-3-anilino-4-[(R)-2-(t-butyldimethylsiloxy)tridecyl]-2-oxetanone, diastereomer A, MS: 475 (M⁺.).

h) The products of 0 and g) are converted individually analogously to Example Be) into 3R,4R (or 3S,4S)-3-anilino-4-[(R)-2-hydroxytridecyl]-2oxetanone, diastereomer B, m.p. 104°C, and, respectively

3S,4S (or 3R,4R)-3-anilino-4-[(R)2־-hydroxytridecyl]-2־oxetanone, diastereomer A, m.p. 60-62°C, the alcohol starting materials for Example 79.

The acids of the formula Q^a-OH are known or can be prepared in analogy to the known acids, e.g. by saponifying a corresponding lower alkyl ester in a solvent such as acetone or methanol with an alkali metal hydroxide such as potassium hydroxide in an alcohol such as ethanol or methanol. Thus, the add starting materials of Examples 2d) and 2e) hereinafter can be prepared as follows:

A solution of 3.8 g of ethyl 2-propylmalonamidate in 30 ml of acetone is treated with 22 ml of IN KOH in ethanol and stirred for 4 hours, then concentrated, taken up in sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase is addified to pH 2 at 0°C with hydrochloric add and extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, concentrated and the residue is recrystallized from ethyl acetate/ether. There are obtained 1.96 g of 2-propylmalonic add monoamide, m.p. 137θΟ.

The 2-phenethylmalonamic acid, m.p. 141.5°C, the acid starting material for Examples 58-59, is prepared analogously from ethyl 2-phenethylmalonamate.

The (+) and (-)-2-isopropylmalonic acid monoamide (the amide starting material of Example 11) can be prepared as described hereinafter:

5.5 g of rac-2-isopropylmalonic add monoamide and 12.0 g of quinidine are dissolved in 100 ml of boiling water, seeded with a few crystals of the quinidine salt of (S)-(+)2־-isopropylmalonic acid monoamide and then crystallized out. The crystallizate is filtered off under suction, washed with water and ether and dried; there are thus obtained 8.3 g of the quinidine salt of (S)-(+)-2־isopopylmalonic acid monoamide. This salt is dissolved in 10 percent hydrochloric add and left at 5°C, the separated crystals are filtered off under suction, washed with water, dried and recrystallized again from water with the addition of a few drops of IN hydrochloric acid. There are thus obtained 720 mg of (S)-(+)-2־isopropylmalonic add monoamide, m.p. 174°C, [a]₅^₉= +45.6° (ethanol, c = 1).

The mother liquor resulting in the crystallization of the quinidine salt is made add with 10% hydrochloric add and left at 5°C, the separated crystals are filtered off under suction, washed with water, dried and again recrystallized from water with the addition of a few drops of IN hydrochloric add. There are thus obtained 850 mg of (R)2־(־)־-isopropylmalonic add monoamide, m.p. 176°C, [a]“ = -45.6° (ethanol, c = 1).

The acid starting material for Example 42 can be prepared as follows:

a) 20.6 g of thiomorpholine are added dropwise to a solution of 13.6 g of methyl malonate monochloride in 100 ml of methylene chloride. After stirring the mixture is diluted with 200 ml of methylene chloride, washed with water in a separating funnel, then dried, filtered and evaporated. The residue is purified by chromatography on silica gel with methylene chloride and then methylene chloride/acetone (1:1). There are obtained 17.6 g of methyl tetrahydro- β-οχο-4Η-1,4-thiazine-4-propionate.

b) 85 ml of IN potassium hydroxide solution are added dropwise to a solution of 17.3 g of the ester from a) in 170 ml of acetone. After stirring and filtering the mixture is evaporated and the residue is triturated in 200 ml of acetone and then filtered. The filter cake is washed with acetone and dried. An aqueous solution of the resulting potassium salt is chromatographed with water on a cation exchanger column. The eluate is concentrated to dryness and the residue is triturated with ether and filtered off. There are obtained 13 g of tetrahydro-3־oxo-4H-l,4-thiazine-4-propionic acid, m.p. 119-120°C.

The acid starting material for Example 44 is prepared as follows:

a) 33 ml of IN potassium hydroxide solution are added dropwise to a solution of 5.6 g of methyl 1-carbamoylcyclopentanecarboxylate in 66 ml of acetone. After stirring the mixture is treated with 250 ml of acetone and the separated potassium salt is filtered off and then washed with acetone and dried.

b) A solution of the 5.79 g of potassium salt obtained in 35 ml of water is acidified to pH 1 with 4 ml of cone, hydrochloric acid at 0°C. The precipitate is filtered off and washed with water and then with diethyl ether. 3.5 g of 1carbamoylcyclopentanecarboxylic add are obtained after drying.

The acid starting material for Example 46 can be prepared as follows:

A solution of 10.4 g of monomethyl methoxymalonate in 70 ml of methylene chloride is added dropwise at -10°C to 26 ml of 25 percent aqueous ammonia. After stirring the mixture is evaporated and the residue is dissolved in water and chromatographed on a cation exchanger with water. The eluate is concentrated and the residue is triturated with diethyl ether and filtered off. The predpitate is washed with water and dried. There are obtained 8.9 g of methoxymalonamic acid, m.p. 128-130°C.

The acid starting material for Example 49 can be prepared as follows:

A solution of 1.79 g of carbamoylmethyl thioacetic acid in 42 ml of water is treated with 3.71 g of monoperoxyphthalic acid magnesium salt hexahydrate. After stirring the mixture is filtered and the filtrate is concentrated and addified with 2 ml of cone, hydrochloric add. After filtration the filtrate is percolated over a cation exchanger, eluted with water and the eluate is evaporated to dryness. The residue is suspended in acetone and filtered off. It is washed with acetone and dried. There are obtained 1.65 g of rac[(carbamoylmethyl)sulphinyl]acetic add, m.p. 137-138°C.

The lower alkyl esters corresponding to the adds of formula Q^a-OH are known or can be prepared in analogy to the known esters, e.g. as described hereinafter starting from the monoester of the formula H-(X)n־COOR, wherein R is lower-alkyl, via the dicarboxylic acid monoester of the formula HOCO-(X)n־COOR. Thus, the starting add of Example 2f) can be prepared as follows:

a) 48 ml of a 1.6M n-butyllithium solution in hexane are added dropwise at 15°C to 11 ml of diisopropylamine and 5 g of 4A molecular sieve in 75 ml of THF. After 15 minutes the reaction mixture is cooled to -78°C and a solution of

9.5 g of ethyl l,3-dioxolane-2-carboxylate in 50 ml of THF is added dropwise.

־28־

After stirring for 20 minutes CO2 is introduced at a temperature below -70°C. After saturation the mixture is stirred at -75°C for 20 minutes and then warmed to room temperature. After volatization of the CO2 gas the reaction mixture is concentrated, the residue is treated with saturated bicarbonate solution and ethyl acetate, the ethyl acetate phase is discarded, the aqueous phase is acidified to pH 2 with potassium hydrogen sulphate and extracted with ethyl acetate. The ethyl acetate phase is dried and concentrated.

b) 0.93 ml of isobutyl chloroformate in 5 ml of THF is added dropwise at 0°C to a solution of 1.08 g of the product from a), 1.1 ml of triethylamine and 3 g of molecular sieve 4A in 30 ml of THF. After stirring for 40 minutes ammonia gas is introduced for 10 minutes and the reaction mixture is subsequently stirred overnight. Thereupon, it is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol (95:5). There are thus obtained 420 mg of ethyl 2-carbamoyl-l,3-dioxolane2־carboxylate, m.p. 99100°־C.

c) A solution of 190 mg of the product from b) in 10 ml of methanol is treated with 1 ml of 2N KOH in methanol and stirred at room temperature for 90 minutes. Thereupon, a solution of 280 mg of potassium hydrogen sulphate in 1 ml of water is added, the reaction mixture is suction filtered and the filtrate is evaporated. There is thus obtained 2-carbamoyl-l,3־dioxolane־2־ carboxylic add.

2־Carbamoyl־m־dioxane־2־carboxylic add (the acid starting material for Example 3m) is obtained analogously from ethyl m-dioxane־2־carboxylate.

The adds of the formula (R^,R^)NCO(X)n־COOH in which X is a group =CHN(R,R°) can be prepared starting from the corresponding dicarboxylic add monoester of the formula HOCO-X-COOR via a corresponding sucdnimide and the corresponding amide ester of the formula H2NCO-X-COOR, e.g. as described hereinafter for the acid starting material of Example 9.

a) 4.54 g of dicydohexylcarbodiimide, 4.16 g of monoethyl acetamino־ malonate and 2.53 g of N־hydroxysuccinimide are added to 54 ml of THF at 0°C. After stirring for 1 hour the mixture is left to warm to room temperature and is stirred overnight. Then, it is cooled to 0°C and filtered. The filtrate is treated with 20 ml of 25% aqueous ammonia solution, left to stand at room temperature over the day and at 4°C overnight. Then, the solution is evaporated and the residual aqueous solution is treated with sodium bicar־ bonate. The aqueous phase is separated, the organic phase is washed with saturated sodium chloride solution, then dried and concentrated. The residue is filtered in hexane containing ethyl acetate. The crystals obtained are washed with ether and then dried. There are obtained 1.2 g of [D,L]-N-acetyl-2־carbamoylglydne ether ester, m.p. 126-128°C.

b) A solution of 5.8 ml of IN potassium hydroxide is added dropwise to a suspension of 1.09 g of the amide ester from a) in 7 ml of acetone. After stirring for 3 hours the mixture is concentrated and the residue is dissolved in aqueous sodium bicarbonate solution. The solution is extracted with ethyl acetate, the aqueous phase is acidified to pH 3 with hydrochloric acid while cooling and then percolated over an ion exchanger. The eluate is concentrated to dryness and the residue is triturated wih acetone. There are obtained 500 mg of [D,L]-Nacetyl-2-carbamoylglycine, m.p. 120°C (decomposition).

Acid starting materials of the formula (R3,R⁴)NC0(X)n־COOH in which at least one of R3 and R⁴ is different from H can be prepared by reacting the corresponding acid ester of the formula HOC(O)־(X)n־C(O)O־R with an amine HN(R3,R⁴).

Thus, the acid starting material of Example lOd) can be prepared as follows:

A solution of 3 g of monomethyl malonate in 15 ml of 40% aqueous dimethylamine is concentrated after stirring for 18 hours, filtered through a strongly acidic cation exchanger, concentrated to dryness and crystallized from chloroform. Concentration of the mother liquor and crystallization from ether yield 1.3 g of dimethylcarbamoylacetic add, m.p. 72-76°C.

The oxetanones of formula I have valuable pharmacological properties. In particular, they inhibit pancreas lipase and can accordingly be used in the control or prevention of obesity, hyperlipemia, atherosderosis and arterioscle־ rosis.

The inhibition of pancreas lipase by the oxetanones of formula I can be demonstrated experimentally by measuring titrimetrically the oleic acid liberated in the deavage of triolein by hog pancreas lipase. To an emulsion which contains 1 mM of taurodeoxycholate, 9 mM of taurocholate, 0.1 mM of cholesterol, 1 mM of egg lecithin, 15 mg/ml of BSA, 2 mM of Tris HC1, 100 mM of sodium chloride, 1 mM of calcium chloride and triolein as the substrate is added the compound of formula I dissolved in ethanol or dimethyl sulphoxide (10% of the emulsion volume) and the reaction is started by the addition of 1-3 gg of hog pancreas lipase. The pH is held at 8 during the reaction by the addition of sodium hydroxide solution. The IC50 is calculated from the consumption of sodium hydroxide solution determined during minutes. The IC50 is that concentration at which the lipase activity is inhibited to half of the maximum. The following Table contains the IC50 values determined for the compounds of formula I.

<td> Example</td><td> la,lla</td><td> lb,llb</td><td> 2b,12b</td><td> 2d</td><td> 2e</td><td> 2f</td><td> 2gl.l3a</td><td> 2g2</td>

<td> IC50</td><td> 0.032</td><td> 0.025</td><td> 0.063</td><td> 0.12</td><td> 0.051</td><td> 0.47</td><td> 0.052</td><td> 0.013</td>

<td> Example</td><td> 3c</td><td> 3d</td><td> 3e</td><td> 3f</td><td> 3g</td><td> 3h</td><td> 3i</td><td> 3j</td>

<td> IC50</td><td> 0.39</td><td> 0.90</td><td> 1.41</td><td> 0.083</td><td> 0.294</td><td> 2.1</td><td> 0.42</td><td> 0.16</td>

<td> Example</td><td> 3k</td><td> 31</td><td> 4a</td><td> 6b,14c</td><td> 7b</td><td> 10a</td><td> 10b</td><td> 10c</td>

<td> IC50</td><td> 0.12</td><td> 0.78</td><td> 0.16</td><td> 0.056</td><td> 0.079</td><td> 0.083</td><td> 0.042</td><td> 0.1</td>

<td> Example</td><td> lOd</td><td> lOe</td><td> lOf</td><td> 37</td><td> 43</td><td> 45</td><td> 51</td><td> 78c</td><td> 78d</td>

<td> IC50</td><td> 0.47</td><td> 0.027</td><td> 0.32</td><td> 0.034</td><td> 0.12</td><td> 0.047</td><td> 0.36</td><td> 0.28</td><td> 0.051</td>

The acute toxicity (after single oral administration to mice) amounts to more than 5000 mg/kg for the products of Examples 3d, 3h, 3i, 31,4a and 10a, b, 15 e and f.

The oxetanones of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.

־31־

For the manufacture of pharmaceutical preparations the products in accordance with the invention can be processed with pharmaceutically inert, inorganic or organic carriers. Lactose, maize starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; depending on the nature of the active ingredient no carriers are, however, generally required in the case of soft gelatine capsules. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose.

Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.

As mentioned earlier, medicaments containing an oxetanone of formula I are likewise an object of the present invention, as is a process for the manufacture of such medicaments which comprises bringing an oxetanone of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form. As mentioned, the compounds of formula I can be used in the control or prevention of illnesses, especially in the control or prevention of obesity, hyperlipemia, atherosclerosis and arteriosclerosis. The dosage can vary within wide limits and will, or course, be filled to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 100 mg/kg body weight should be appropriate.

The oxetanones of formula I can also be added to industrially-produced foodstuffs, whereby fats, dils, butter, margarine, chocolate and other confectionery goods especially come into consideration. Such industriallyproduced foodstuffs, which can contain about 0.1 to 5 wt.% of an oxetanone or formula I, and their manufacture are likewise objects of the present invention.

The following Examples illustrate the present invention in more detail, but they are not intended to limit its scope in any manner. All temperatures are given in degrees Celsius.

Example 1

A solution of 574 mg of (3S,4S)-3-ethyl־4־[(R)-2-hydroxynonadecyl]-2oxetanone, 525 mg of triphenylphosphine, 290 mg of 2-isopropylmalonic acid monoamide and 2 g of molecular sieve (4A) in 10 ml of THF are treated which stirring at 0° with 0.4 ml of diisopropyl azodicarboxylate. After stirring at 0° for 30 minutes and at room temperature for 1 hour the reaction mixture is filtered, the molecular sieve is washed with ether and the solvent is evaporated. The residue is dissolved in hexane and extracted with methanol/water (7:3). The hexane phase is diluted with ether, dried and evaported. The residue is chromatographed on silica gel with methylene chloride/ether (9:1). There are obtained

a) 239 mg of (S)-[[(2S,3S)3־-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (R or 5)-2isopropylmalonamate, m.p. 115°, and

b) 266 mg of (S)-[[(2S,3S)-3-ethyl-4־oxo-2-oxetanyl]methyl]octadecyl (S or R)-2isopropylmalonamate, m.p. 118°.

Example 2

Analogously to Example 1, from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]2־oxetanone and 2-isopropylmalonic acid monoamide there are obtained

a) (S)-l2)]]־S,3S)־3־hexyl־4־oxo־2־oxetanyl]methyl]dodecyl (R or S)-2isopropylmalonamate, m.p. 136°, and

b) (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or R)-2isopropylmalonamate, m.p. 82°;

c) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and isopropylidenemalonic acid monoamide there is obtained (S)-l-[[(2S,3S)-3hexyl-4-oxo-2־oxetanyl]methyl]dodecyl 2-carbamoyl-3־methylcrotonate, m.p. 108111°־;

d) from (3S,4S)-3־hexyl־4־[(R)־2־hydroxytridecyl]-2-oxetanone and 2־ propylmalonic acid monoamide there is obtained (S)-l2)]]־S,3S)־3־hexyl־4־oxo־

2-oxetanyl]methyl]dodecyl (RS)-2־carbamoylvalerate (epimers 1:1), m.p. 92-94°;

e) from (3S,4S)-3־ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and 2propylmalonic acid monoamide there is obtained (S)-l-[[(2S,3S)־3־ethyl-4־oxo2־oxetanyl]methyl]octadecyl (RS)-2־carbamoylvalerate (epimers 1:1), m.p. 7880°;

f) from (3S,4S)-ethyl-4-[(R)-2-hydroxynonadecyl]-2-oxetanone and 2־ carbamoyl־l,3-dioxolan-2-carboxylic acid there is obtained (S)-l-[[(2S3_׳S)-3-ethyl4-oxo-2-oxetanyl]methyl]octadecyl 2-carbamoyl-l,3-dioxolane-2-carboxylate, m.p. 95°;

g) from (3S,4S)-3-ethyl-4- [(R,l 0Z,13Z)-2-hydroxy-l 0,13-nonadecadienyl]2־oxetanone and 2-isopropylmalonic acid monoamide there are obtained

1. (all Z,S)-l-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (R or S)־2־isopropylmalonamate, m.p. 87-88° (from ether) and

2. (all Z,S)-l-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S or R)-2-isopropylmalonamate, IR: 3393,1840,1716,1647, 1185 cm^.

Example 3

The following ester amides are obtained analogously to Example 1 by reacting (3S,4S)-3־hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone with the following amides:

a) with 4-carbamoylbutyric acid the 4-carbamoylbutyric acid (S)-1-[[(2S,3S)3־hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 67-68°,

b) with 3-carbamoylpropionic add the 3-carbamoylpropionic acid (S)-l[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 50.5-51°,

c) with 2-carbamoylacetic acid the 2-carbamoylacetic acid (S)-l-[[(2S,3S)-3hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, m.p. 86.5-87°,

d) with oxalic acid monoamide the (S)-l-[[(2S,3S)3־-hexyl-4-oxo-2oxetanyl]methyl]dodecyl oxamate, m.p. 77-78°,

e) with methylcarbamoylacetic acid the (S)-l2)]]־S,3S)3-hexyl-4-oxo-2oxetanyl]methyl]dodecyl N-methylmalonamate, m.p. 63-67°,

f) with rac-2-carbamoyl-4-methylvaleric add the (S)-l-[[(2S,3S)-3-hexyl-4oxo-2-oxetanyl]methyl]dodecyl (RS)-2-carbamoyl-4-methylvalerate (epimere 1:1), m.p. 102-104°,

g) with 1-carbamoylcyclohexanecarboxylic add the (S)-l-[[(2S,3S)-3-hexyl-4oxo-2-oxetanyl]methyl]dodecyl 1-carbamoylcyclohexanecarboxylate, m.p. 50-52°,

־34־

h) with 2,2-dimethylmalonamidic acid the (S)-l2)]]־S,3S)3-hexyl-4-oxo2־oxetanyl]methyl]dodecyl 2,2-dimethylmalonamate, [a]” = 23.8°־ (CHCI3, c = 0.9%),

i) with rac-2-methylmalonamidic acid the (S)-l-[[(2S,3S)3־hexyl-4-oxo-2oxetanyl]methyl]dodecyl (RS)־2־methylmalonamate (epimers 1:1), m.p. 107108°־,

j) with rac-2-ethylmalonamidic acid the (S)-l-[[(2S,3S)3-hexyl-4-oxo-2oxetanyl]methyl]dodecyl (RS)-2-ethylmalonamate (epimers 1:1), m.p. 8790°־,

k) with rac-2-butylmalonamidic acid the (S)-l2)]]־S,3S)־3־hexyl־4־oxo2־oxetanyl]methyl]dodecyl (RS)-2-butylmalonamate (epimers 1:1), m.p. 96-98°,

l) with 2,2-diethylmalonamidic acid the (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2oxetanyl]methyl]dodecyl 2,2-diethylmalonamate, [a]²_D° = -21.1° (CHCI3, c = 1%),

m) with 2-carbamoyl-m-dioxane2־-carboxylic add the (S)-l-[[(2S,3S)-3-hexyl-4oxo-2-oxetanyl]methyl]dodecyl 2-carbamoyl-m-dioxane2־-carboxylate, m.p. 51°.

Example 4

Analogously to Example 1, from (3S,4S)-3-ethyl4־[(R)-2hydroxynonadecyl]-2-oxetanone and

a) 1-carbamoylcydohexanecarboxylic add there is obtained (S)-l-[[(2S,3S)-3ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 1-carbamoylcydohexanecarboxylate, m.p. 7879°־, and

b) 2-carbamoyl-m-dioxane-2-carboxylic acid there is obtained (S)-1-[[(2S,3S)־

3-ethyl־4־oxo-2-oxetanyl]methyl]octadecyl 2-carbamoyl-m־dioxane-2carboxylate, m.p. 79°.

Example 5

Analogously to Example 1, from (3R,4R or 3S,4S)-4[(R)-2-hydroxytridecyl]־ 3-pentylthio-2-oxetanone and 2-isopropylmalonic add amide there are obtained

a) (S)-1-[[(2R,3R or 2S,3S)-4-oxo-3-pentylthio2-oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, MS: 354 [M+.-(2-isopropylmalonic add amide)]; IR (cm3397,2924,1829,1731,1657,1120 :(¹־, and

־35־

b) (S)-1-[[(2R,3R or 2S,3S)-4־oxo-3-pentylthio2-oxetanyl]methyl]dodecyl (S or

R) -2־isopropylmalonamate, m.p. 7778°־ (diethyl ether).

Example 6

Analogously to Example 1, from (3S,4S or 3R,4R)-4[(R)-2-hydroxytridecyl]3-pentylthio-2־oxetanone and 2-isopropylmalonic acid amide there are obtained

a) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio־2־oxetanyl]methyl]dodecyl (R or

S) -2-isopropylmalonamate, m.p. 133° (ethyl acetate), and

b) (S)־I2)]]־S,3S or 2R,3R)-4־oxo־3־pentylthio-2-oxetanyl]methyl]dodecyl [S:R or R:S(2:l)]-2-isopropylmalonamate, m.p. 102-104° (ethyl acetate).

Example 7

Analogously to Example 1, from 3-benzyl-4-[(R)-2-hydroxytridecyl]-2oxetanone and 2־isopropylmalonic add monoamide there is obtained an epimer mixure which is separated by chromatography on silica gel with ethyl acetate/hexane/ methylene chloride (1:2:2) into

a) (S)-l-[[(2R,3R)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2isopropylmalonamate, m.p. 8587°־ (methylene chloride), and

b) (S)־l2)]]־R,3R)־3־benzyl־4־oxo־2־oxetanyl]methyl]dodecyl (S or R)-2isopropylmalonamate, m.p. 108-110° (methylene chloride).

Example 8

Analogously to Example 1, from 3־benzyl4־-[(R)־2־hydroxytridecyl]2־oxetanone and 2-isopropylmalonic add monoamide there is obtained an epimer mixture which is separated by chromatography on silica gel with ethyl acetate/ hexane/methylene chloride (1:2:2) into

a) (S)-l-[[(2S,3S)-3-benzyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)-2isopropylmalonamate, m.p. 107108°־ (methylene chloride), and

b) (S)־l2)]]־S,3S)־3־benzyl־4־oxo־2־oxetanyl]methyl]dodecyl (S or R)-2isopropylmalonamate, m.p. 148149°־ (methylene chloride).

Example 9 .03 g of di-t-butyl azodicarboxylate are added to a suspension, cooled to 10°C, of 1.06 g of (3S,4S)־3־hexyl־4־[(R)-2־hydroxytridecyl]2־-oxetanone, 480 mg of [D,L]-N-acetyl-2-carbamoylglycine, 1.1 g of triphenylphospine and 1.2 g of molecular sieve 4A in 12 ml of THF. After stirring at 0°C for 1 hour and at room temperature overnight the reaction mixture is worked־up analogously to that described in Example 1. There are obtained

a) 190 mg of (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (R or S)2־acetamidomalonamate, m.p. 125126°־, and

b) 100 mg of (S)-l-[[(2S_r3S)3־-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)-2acetamidomalonamate (epimers 1:1), m.p. 110-116°, [a]□ = -8° (c = 0.5, CHCI3)

Example 10

The following ester amides are obtained analogously to Example 1, but using the following amides:

a) from oxalic add monoamide the (S)-l2)]]־S,3S)3־-ethyl-4-oxo-2oxetanyl]methyl]octadecyl oxamate, m.p. 99-100°,

b) from 2-carbamoylacetic acid the (S)-l2)]]־S,3S)-3-ethyl-4-oxo-2oxetanyl]methyl]octadecyl malonamate, m.p. 90.591.5°־,

c) from methylcarbamoylacetic add the (S)-l-[[(2S,3S)-3-ethyl-4-oxo-2־ oxetanyl]methyl]octadecyl N-methylmalonamate, m.p. 84-85°,

d) from dimethylcarbamoylacetic add the (S)-l2)]]־S,3S)-3־ethyl-4-oxo-2oxetanyl]methyl]octadecyl Ν,Ν-dimethylmalonamate, m.p. 66-67°,

e) from rac-2-ethylmalonamidic acid (S)-l-[[(2S,3S-3-ethyl-4-oxo-2oxetanyl]methyl]octadecyl (RS)־2־methylmalonamate (epimers 1:1), m.p. 91.592°,

f) from 3-carbamoylpropionic add the (S)-l-[[(2S,3S)3-ethyl-4-oxo2־oxetanyl]methyl]octadecyl sucdnamate, m.p. 74.5-75.7°.

Example 11

Analogously to Example 1, but using (S)-(+)- or (+)-2-isopropylmalonic acid monoamide, there are obtained

a) (S)-[[(2S,3S)3־-ethyl-4־oxo2־-oxetanyl]methyl]octadecyl (R)-2isopropylmalonamate, m.p. 115°, and

b) (S)-[[(2S,3S)-3־ethyl־4־oxo־2־oxetanyl]methyl]octadecyl (S)-2isopropylmalonamate, m.p. 118°.

Example 12

Analogously to Examples l,2a),b) and 11, from (3S,4S)-3-hexyl-4-[(R)-2hydroxytridecyl]־2־oxetanone and (±)־ and (S)-(+)-2־isopropylmalonic add monoamide there are obtained

a) (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2isopropylmalonamate, m.p. 136°, and respectively,

b) (S)-l2)]]־S,3S)־3־hexyl-4־oxo-2־oxetanyl]methyl]dodecyl (S)-2isopropylmalonamate, m.p. 82°,

c) from (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone and 2propylmalonic acid monoamide, after separation by chromatography on silica gel with methylene chloride/ acetonitrile (85:15),

1. (S)-l-[[(2S,3S)-3-hexyl-4־oxo-2-oxetanyl]methyl]dodecyl (R or 5)-2carbamoylvalerate, m.p. 113° (from methanol/water), and

2. (S)-l-[[(2S,3S)3־-hexyl4־-oxo-2־oxetanyl]methyl]dodecyl (S or R)-2carbamoylvalerate, m.p. 85°.

Example 13

Analogously to Examples 1,2g) and 11, from (3S,4S)-3־ethyl-4[(R,10Z,13Z)-2־hydroxy10,13־-nonadecadienyl]-2-oxetanone and (±)- and (5)-(+)2־isopropylmalonic add monoamide there are obtained

a) (all Z,S)-l2)]]־S,3S)-3־ethyl-4-oxo-2־oxetanyl]methyl]9,12־-octadecadienyl (R) -2-isopropylmalonamate, m.p. 8788°־ (from ether), and

b) (all Z,S)-l-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl (S) ־2־isopropylmalonamate, m.p. 109° (from aqueous methanol).

Example 14 ־38Analogously to Examples 1, 6 and 11, from (3S,4S or 3R,4R)-4-[(R)-2hydroxytridecyl]-3-pentylthio-2-oxetanone and (±)- and (S)-(+)-2isopropylmalonamide there are obtained

a) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl (R)2-isopropylmalonamate, m.p. 133° (ethyl acetate),

b) (S)-1-[[(2S,3S or 2R (S)-2-isopropylmalonamate, m.p. 93° (diethyl ether/hexane) and

c) (S)-1-[[(2S,3S or 2R,3R)-4-oxo-3-pentylthio-2-oxetanyl]methyl]dodecyl [S:R (2:l)]-2-isopropylmalonamate, m.p. 102-104° (ethyl acetate).

Example 15

Analogously to Examples 1 and 11, from (3S,4S or 3R,4R)-benzyl 4-[(R)-2hydroxytridecyl]-2-oxo3־-oxetanecarbamate and (S)-(+)-2-isopropylmalonic acid monoamide there is obtained (S)-1-[[(2S,3S or 2R,3R)-3-[l(benzyloxy)formamido]-4-oxo-2-oxetanyl]methyl]dodecyl (S)-2isopropylmalonamate, m.p. 133° (from ether/hexane).

Example 16

Analogously to Examples 1 and 11,

a) from (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)-2-oxetanone and (S)-(+)-2-Isopropylmalonic acid monoamide there is obtained (S)-l-[[(2R,3R)-4oxo-3-(phenylthio)-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 88° (ether),

b) from (3S,4S)4־-[(R)-2-hydroxytridecyl]-3־(phenylthio)-2־oxetanone and 2isopropylmalonic add monoamide there is obtained (S)-l-[[(2S_/3S)-4-oxo-3(phenylthio)-2-oxetanyl]methyl]dodecyl (RS)-2-isopropylmalonamate (1:1 epimers), m.p. 109° (ether), and

c) from (3R,4R)-4-[(R)-2-hydroxytridecyl]-3-(phenylthio)2־-oxetanone and 2-isopropylmalonic acid monoamide there are obtained the same products as in a) and (S)-l-[((2R,3R)-4-oxo3־-(phenylthio)-2־oxetanyl]methyl]dodecyl 2isopropylmalonamate (R:S = 7:1), m.p. 85° (ether).

Example 17

Analogously to Examples 1 and 11, from (S)-(+)-2-isopropylmalonic add monoamide and the following alcohols there are obtained the following esters:

a) From (3S,4S or 3R,4R)-4-[(R)-2-hydroxynonadecyl]-3־(methylthio)-2oxetanone the (S)-1-[[(2S,3S or 2R,3R)-3-(methylthio)-4-oxo-2oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 133° (from ether),

b) from (3R,4R or 3S,4S)4־-[(R)-2-hydroxynonadecyl]-3-(methylthio)2־oxetanone the (S)-1-[[(2R,3R or 2S,3S)-3-(methylthio)-4־oxo2־- oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 103° (from ether),

c) from (3S,4R or 3R,4S)-4־[(R)2־-hydroxynonadecyl]-3-(methylthio)-2oxetanone the (S)-1-[[(2R,3S or 2S,3R)-3-(methylthio)-4-oxo-2oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, mp. 96° (from ether/hexane), and

d) from (3R,4S or 3S,4R)-4-[(R)-2-hydroxynonadecyl]-3-(methylthio]2־oxetanone the (S)-1-[[(2S,3R or 2R,3S)-3-(methylthio)-4־oxo2־oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 120° (from ether/hexane).

Example 18

Analogusly to Examples 1 and 11, from (R)-(-)-2-isopropylmalonic acid monoamide and

a) (3S,4S or 3R,4R)4־-[(R)-2-hydroxynonadecyl]-3-(methylthio)-2-oxetanone there is obtained (S)-1-[[(2S,3S or 2R,3R)-3-(methylthio)-4-oxo-2- oxetanyl]methyl]octadecyl (R)-2-isopropylmalonamate, m.p. 96° (from ether),

b) (3R,4R or 3S,4S)-4-[(R)־2־hydroxynonadecyl]-3־(methylthio)-2־oxetanone there is obtained (S)-12)]]־R,3R or 2S,3S)-3-(methylthio)-4-oxo-2oxetanyl]methyl]octadecyl (R)-2-isopropylmalonamate, m.p. 87° (from ether/hexane).

Example 19

In analogy to Examples 1 and 11, from (S)-(+)-2-isopropylmalonic add monoamide and the following alcohols there are obtained the following esters:

־40־

a) From (3S,4S or 3R,4R)־3־(benzylthio)-4־[(R)-2־hydroxytridecyl]-2oxetanone the (S)-12)]]־S,3S or 2R,3R)-3־(benzylthio)-4-oxo-2- oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate, m.p. 84° (from pentane),

b) from (3R,4R or 3S,4S)־3־(benzylthio)-4־[(R)2־-hydroxytridecyl]־2־oxetanone the (S)-12)]]־R,3R or 2S,3S)-3-(benzylthio)-4-oxo-2־oxetanyl]methyl]dodecyl-(S)2-isopropylmalonamate, m.p. 65° (from ether/pentane) and

c) from (3S,4R and 3R,4S)-3־(benzylthio)-4-[(R)-2-hydroxytridecyl]-2oxetanone

1. the (S)2)]]־1־S,3R or 2R,3S)-3-(benzylthio)־4־oxo2־-oxetanyl] methyl] dodecyl (S)־2־isopropylmalonamate, m.p. 69° (from pentane), and

2. the (S)-12)]]־R,3S or 2S,3R)3־-(ber1zylthio)-4-oxo-2-oxetanyl] methyl] dodecyl (S)-2-isopropylmalonamate, m.p. 106° (from hexane).

Example 20

In analogy to Examples 1 and 11, from (R)-(-)-2-isopropylmalonic acid monoamide and the following alcohols there are obtained the following esters:

a) From (3S,4S or 3R,4R)-3-(benzylthio)-4-[(R)-2־hydroxytridecyl]2־oxetanone the (S)-1-[[(2S,3S or 2R,3R)-3־(benzylthio)4־-oxo־2־ oxetanyl]methyl]dodecyl (R)־2־isopropylmalonamate, m.p. 130° (from ether/pentane),

b) from (3R,4R or 3S,4S)־3־(Benzylthio)־4־[(R)2־-hydroxytridecyl]2־oxetanone the (S)2)]]־1־R,3R or 2S,3S)-3־(benzylthio)4־-oxo2־- oxetanyl]methyl]dodecyl (R)־2־isopropylmalonamate, m.p. 119° (from hexan/pentane), and

c) from (3S,4R and 3R,4S)-3־(benzylthio)־4־[(R)־2־hydroxytridecyl]-2oxetanone

1. the (S)2)]]־1־S,3R or 2R,3S)-3-(benzylthio)-4-oxo-2-oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 132° (from ether/pentane), and

2. the (S)2)]]־1־R,3S or 2S,3R)־3־(benzylthio)־4־oxo־2־oxetanyl] methyl] dodecyl (R)-2-isopropylmalonamate, m.p. 102° (from ether/pentane).

Example 21

־41־

Analogously to Examples 1 and 11, by reacting (3R,4R)-3-ethyl-4-[(R)-2hydroxynonadecyl]־2־oxetanone

a) with (S)-(+)-2־Isopropylmalonic add monoamide there is obtained (S)-l[[(2R,3R)־3־ethyl־4־oxo־2־oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 116118°־ (methylene chloride), and

b) with l-carbamoylcyclohexanecarboxylic acid there is obtained (S)־l־ [[(2R,3R)-3-ethyl4־-oxo-2-oxetanyl]methyl]octadecyl 1־ carbamoylcydohexanecarboxylate, m.p. 7174°־.

Example 22

In analogy to Examples 1 and 11,

a) from (S)-(+)2־-isopropylmalonic add monoamide and (3R,4R)-4־[(R)2־hydroxynonadecyl]3־-methyl־2־oxetanone there is obtained (S)-l2)]]־R,3R)-3methyl־4־oxo־2־oxetanyl]methyl]octadecyl (S)־2־isopropylmalonamate, m.p. 124126°־ (from ethyl acetate/hexane), and

b) from rac-2-t-butylmalonic acid monoamide and (3R,4R)־4־[(R)־2־ hydroxynonadecyl]־3־methyl־2־oxetanone there is obtained (S)-12)]]־R,3R)3־methyl־4־oxo־2־oxetanyl]methyl]octadecyl (RS)־2־t־butylmalonamate (epimers 1:1), m.p. 5154°־ (ethyl acetate/hexane).

Example 23

A solution of 277 mg of (2S,3S,5S)5־-[[(cis)-2־carbamoylcyclohexyl]oxy]-2hexyl־3־hydroxyhexadecanoic add (Example Jd) in 24 ml of methylene chloride and 3 ml of DMF is treated with 2 g of molecular sieve (4A), 240 mg of HBTU and 240 mg of triethylamine. After stirring 300 mg of HBTU and 300 mg of triethylamine are added thereto. The mixture is then filtered and the filtrate is concentrated. The residue is partitioned between methanol/water (7:3) and hexane and extracted with hexane. The hexane phase is diluted with methylene chloride, then dried and concentrated and the residue is recrystallized from ether/hexane. There are thus obtained

a) 96 mg of (IR or S,2S or R)־2־[[(S)־l2)]]־S,3S)־3־hexyl־4־oxo-2oxetanyl]methyl]dodecyl]oxy]cyclohexanecarboxamide (1st cis diastereomer), m.p. 102° (from ether/hexane), and

־42־

b) analogously from (2S,3S,5S)־5־[[(cis)-2-carbamoylcyclohexyl]oxy]2־-hexyl-3hydroxyhexadecanoic add (2nd diast. add) in Example Je) there is obtained (IS or R,2R or S)-2־[[(S)־l2)]]־S,3S)־3־hexyl-4-oxo־2־ oxetanyl]methyl]dodecyl]oxy]cydohexanecarboxamide (2nd cis diastereomer), m.p. 94° (from ether/hexane).

Example 24

A solution of 42.5 mg of (2S3S,5S)-5־[(R/S)-2-carbamoyl-lmethoxyethoxy]-2־hexyl־3־hydroxydecanoic add (Example Kd) in 10 ml of methylene chloride/acetonitrile (1:1) is treated with 1 g of molecular sieve (4A), 0.1 ml of triethylamine and 50 mg of HBTU. After stirring the reaction mixture is filtered and concentrated and the residue is partitioned between hexane and methanol/water (1:1); the aqueous methanolic phase is extracted with hexane, the hexane phase is dried and concentrated; the residue is subsequently chromatographed on silica gel with 5 percent methanol in methylene chloride. There are thus obtained 21 mg of (R/S)-3־[[(S)2)]]־1־S,3S)3־hexyl־4־oxo־2־oxetanyl]methyl]dodecyl]oxy]־3־methoxypropionamide (epimers 3:1), m.p. 54°.

Example 25

Ammonia gas is blown into a solution of 40 mg of 3-[[(S)־l2)]]־S,3S)3־hexyl־4־oxo־2־oxetanyl]methyl]dodecyl]oxy]propionic acid (Example L) in 2.5 ml of acetonitrile until the solution is saturated and subsequently 50 mg of HBTU are added. Then, the mixture is filtered and evaporated and the residue is chromatographed on silica gel with 5 percent methanol in methylene chloride. There are obtained 32.5 mg of (3S,4S)-4-[(S)-2-(2-carbamoylethoxy)tridecyl]3־hexyl־2־oxetanone, m.p. 35°.

Example 26

A solution of 33 5 mg of (S)־l2)]]־S,3S)־3־hexyl־4־oxo־2־ oxetanyl]methyl]dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile is treated with 60 mg of HBTU and 75 mg of isopropylamine. After stirring the reaction mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel with hexane/methylene chloride/ethyl acetate (2:2:1). There are obtained 31.1 mg of (S)-l-[[(2S,3S)-3hexyl־4־oxo-2־oxetanyl]methyl]dodecyl N-isopropylmalonamate, m.p. 59°.

The following compounds are manufactured in an analogous manner to Example 1:

Example 27: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 5carbamoylvalerate, m.p. 50-51°.

Example 28: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo2־-oxetanyl]methyl]dodecyl 6carbamoylhexanoate, m.p. 52-53°,

Example 29: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 7carbamoylheptanoate, m.p. 40-43°,

Example 30: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 9carbamoylnonanoate, m.p. 29-30°,

Example 31: (S)-l-[[(2S,3S)-3-Ethyl-4־oxo-2-oxetanyl]methyl]octadecyl 4carbamoylbutyrate, m.p. 74-75°,

Example 32: (S)-l-[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl adipamate, m.p. 63.5-64.5°,

Example 33: (S)-l-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 6carbamoylhexanoate, m.p. 71.5-72.5°,

Example 34: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-oxetanyl]methyl]dodecyl (R or S)2-t־butylmalonamate, m.p. 53-54°,

Example 35: (S)-l-[[(2S,3S)3־-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (S or

R) -2-t-butylmalonamate, [a]“ = -16.4° (c 0.8 ־־, CHCI3),

Example 36: (S)-l-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (R or

S) -2-t-butylmalonamate, m.p. 48-49°,

Example 37: (S)-l-[[(2S,3S)-3-Ethyl-4־oxo2־-oxetanyl]methyl]octadecyl (S or R)-2-t-butylmalonamate, m.p. 81-82°,

Example 38: (S)-l-[[(2S,3S)-3-Hexyl-4־oxo-2-oxetanyl]methyl]dodecyl-(S)-3[l-(benzyloxy)formamido]succinamate, m.p. 72-73°,

Example 39: (S)-l-[[(2S,3S)3־-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl cis-6carbamoyl-3-cyclohexene-l-carboxylate, m.p. 55-59°,

Example 40: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl cis-2carbamoylcyclohexanecarboxylate, m.p. l&amp;TF,

Example 41: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl β-οχο-

4-morpholinopropionate, m.p. 49-51°,

Example 42: (S)-l-rr(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl־lmethyl1dodecyl tetrahydro^-oxo-4H-l,4-thiazine-4-propionate, m.p. 59-61°,

Example 43: (S)-l-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl 1carbamoylcyclopentanecarboxylate, m.p. 62-63°,

Example 44: (S)-l-[[(2S,2S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 1carbamoylcyclopentanecarboxylate, m.p. 40-41°,

Example 45: (S)-l-[[(2S,3S)-3-Hexyl-4־oxo-2-oxetanyl]methyl]dodecyl (RS)2-benzylmalonomate (epimers 1:1), m.p. 86-92°,

Example 46: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)2-methoxymalonamate (epimers 1:1), m.p. 65-67°,

Example 47: (S)־l-i[(2S,3S)-3-Hexyl-4-oxo-2-oxetanvl1methvlldodecvl [(carbamoyl)thio]acetate, m.p. 58-60°,

Example 48: (S)-l-[[(2S,3S)-3-Aethyl-4-oxo2־-oxetanyl]methyl]octadecyl [(carbamoylmethyl)thio]acetate, m.p. 83-84°C,

Example 49: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl [(RS)(carbamoylmethyl)sulphinyl]acetate (epimers 1:1), m.p. 55-59°,

Example 50: (S)-l-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl [(RS)(carbamoylmethyl)thio]acetate S-oxide, m.p. 80-82°,

Example 51: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 3-[(2carbamoylethyl)thio]propionate, m.p. 73-74°,

Example 52: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl 3[(RS)-(2-carbamoylethyl)sulphinyl]propionate (epimers 1:1), m.p. 48-51°,

Example 53: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (carbamoylmethoxy)acetate, m.p. 52-53°,

Example 54: (S)-l-[[(2S,3S)-3-Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (carbamoylmethoxy)acetate, m.p. 75-76°,

Example 55: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)2-[l-(benzyloxy)formamido]malonamate (epimers 1:1), m.p. 94-95°,

Example 56: (S)-l-[[(2S,3S)-3-Ethyl-4-oxo2־-oxetanyl]methyl]octadecyl (RS)2-isobutylmalonamate (epimers 1:1), m.p. 96-99°,

Example 57a): (S)-l-[[(2S,3S)־3־Ethyl-4-oxo-2-oxetanyl]methyl]octadecyl (RS)-2-benzylmalonamate (epimers 1:1), m.p. 96103°־,

Example 57b): (S)-l-[[(2S,3S)3־-Ethyl-4-oxo2־-oxetanyl]methyl]octadecyl (R or S)-2-benzylmalonamate, m.p. 118-120°,

Example 58: (S)-l-[[(2S,3S)-3-Hexyl-4-oxo-2-oxetanyl]methyl]dodecyl (RS)2-phenethylmalonamate (epimers 1:1), m.p. 92-93°,

Example 59: (S)-l2)]]־S,3S)-3-Ethyl-4-oxo2־-oxetanyl]methyl]octadecyl (RS)2-phenethylmalonamate (epimers 1:1), m.p. 97-98°.

Example 60

Analogously to Examples 1 and 11, from (S)-(+)-2-isopropylmalonic acid monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-(2־propynyl)-2oxetanone (Example M) there is obtained (S)-l-[[(2R,3R)-4-oxo-3-(2-propynyl)-2oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 92-95°C (from ethyl acetate/ hexane).

Example 61

Analogously to Examples 1 and 11, from (S)-(+)-2-isopropylmalonic add monoamide and (3R,4R)-4-[(R)-2-hydroxynonadecyl]-3-propyl-2-oxetanone (Example O) ther is obtained (S)-l2)]]־R,3R)-4-oxo3־-propyl-2oxetanyl]methyl]octadecyl (S)-2-isopropylmalonamate, m.p. 90-93° (from ethyl acetate/hexane).

The following compounds are manufactured in an analogous manner to Example 1 and 11:

Example 62: (S)-l-[[(2S,3S)3)-3־-Methyl-2-butenyl)-4־oxo-2oxetanyl]methyl]dodecyl (R or S)-2-isopropylmalonamate, m.p. 100-102°,

־46־

Example 63: (S)-l2)]]־S,3S)־3)־3־Methyl־2־butenyl)4־-oxo2־oxetanyl]methyl]dodecyl (S or R)-2-isopropylmalonamate, m.p. 120121°־,

Example 64: (S)־l-[[(2R,3R)־3)-3־Methyl-2־butenyl)4־-oxo-2oxetanyl]methyl]dodecyl (R or S)־2־isopropylmalonamate, m.p. 60-62°,

Example 65: (S)־l2)]]־R,3R)־3)־3־Methyl־2־butenyl)־4־oxo־2־ oxetanyllmethyl]dodecyl (S or R)־2־isopropylmalonamate, m.p. 7678°־,

Example 66: (S)2)]]־1־S,3S or 2R,3R)-3-(5-Chloropentyl)-4-oxo-2oxetanyl]methyl]dodecyl (S)־2־isopropylmalonamate, m.p. 6672°־,

Example 67: (S)2)]]־1־S,3S or 2R,3R)־5)־3־Chloropentyl)4־-oxo-2oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 130°,

Example 68: (S)-1-[[(2R,3R or 2S,3S)-3-(5־Chloropentyl)-4־oxo-2oxetanyl]methyl]dodecyl (S)2־-isopropylmalonamate, m.p. 4450°־,

Example 69: (S)2)]]־1־R,3R or 2S,3S)־5)־3־Chloropentyl)־4־oxo־2־ oxetanyl]methyl]dodecyl (R)־2־isopropylmalonamate, m.p. 8587°־,

Example 70: (S)-12)־S,3S or 2R,3R)3]]־-[(E)-2-Butenyl]-4-oxo-2oxetanyl]methyl]dodecyl (R or S)־2־isopropylmalonamate, m.p. 105-107°,

Example 71: (S)2)־1־S,3S or 2R,3R)-[[3־[(E)־2־Butenyl]־4־oxo2־oxetanyl]methyl]dodecyl (S or R)־2־isopropylmalonamate, m.p. 9698°־,

Example 72: (S)-1-(2R,3R or 2S,3S)-[[3-[(E)-2-Butenyl]-4-oxo-2oxetanyl]methyl]dodecyl (S)־2־isopropylmalonamate, m.p. 8990°־,

Example 73: (S)2)־1־R,3R or 2S,3S)־3]]־[(E)־2־Butenyl]־4־oxo־2־ oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 60-63°,

Example 74: (S)2)]]־1־R,3R or 2S,3S)־2,3,4,5,6)־3־Pentafluorobenzyl)־2־ oxetanyl]methyl]dodecyl (R)־2־isopropylmalonamate, m.p. 107109°־,

Example 75: (S)2)]]־1־R,3R or 2S,3S)-3־2,3,4,5,6)־Pentafluorobenzyl)-2oxetanyl]methyl]dodecyl (S)־2־isopropylmalonamate, m.p. 115118°־,

Example 76: (S)2)]]־1־S,3S or 2R,3R)-32,3,4,5,6)־-Pentafluorobenzyl)-2oxetanyl]methyl]dodecyl (R)-2-isopropylmalonamate, m.p. 88-90°, and

Example 77: (S)-1-[[(2S,3S or 2R,3R)-3-(2,3,4,5,6-Pentafluorobenzyl)-2oxetanyl]methyl] dodecyl (S)-2-isopropylmalonamate, m.p. 52-55°.

Example 78

Analogously to Examples 1 and 2, but using (R)- or (S)-2־pyrrolidone-5carboxylic acid in place of 2-isopropylmalonic acid monoamide there are obtained

a) 5-oxo־D-proline (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, ¹H-NMR (CDC13): 0.88 (m,6H); 1.26 (m,26H); 1.55-1.9 (m,4H); 1.95-2.55 (m,6H); 3.21 (m,lH); 4.25 (m,lH); 4.31 (m,lH); 5.14 (m,lH); 5.80 (s,lH) ppm,

b) 5-oxo-L-proline (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetany 1]methyl]dodecyl ester, m.p. 51-52°,

c) 5-oxo-D-proline (S)-l-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester, m.p. 55° (diethyl ether), and

d) 5-oxo-L-proline (S)-l-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester, m.p. 57-58°.

Example 79

Analogously to Examples 1 and 11, from (S)-(+)-2־isopropylmalonic acid monoamide and

a) 3R,4R (or 3S,4S)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-oxetanone, diastereomer B (Example T) there is obtained (S)-1-[[(2R,3R or 2S,3S)-3־anilino-

4-oxo-2-oxetanyl]methyl]dodecyl (S)-2-isopropylmalonamate (diastereomer B), m.p. 92°, and

b) from 3S,4S (or 3R,4R)-3-anilino-4-[(R)-2-hydroxytridecyl]-2-oxetanone, diastereomer A (Example T) there is obtained (S)-1-[[(2S,3S or 2R,3R)-3anilino-4-oxo-2-oxetanyl)methyl] dodecyl (S)-2-isopropylmalonamate (diastereomer A), m.p. 77°.

Pharmaceutical preparations of the following composition are manufactured in a manner known per se:

Example A

Soft gelatine capsules:

־48Amount per capsule

An oxetanone of formula I 50 mg

<td> Medium-chain triglyceride</td><td> 450 μΐ</td>

<td> Example B</td><td></td>

<td> Hard geltaine capsules:</td><td></td>

<td> An oxetanone of formula I</td><td> 20.0 mg</td>

<td> Lactose cryst.</td><td> 37.0 mg</td>

<td> Microcrystalline cellulose</td><td> 20.0 mg</td>

<td> Polyvinylpolypyrrolidone</td><td> 8.5 mg</td>

<td> Sodium salt of the carboxymentyl ether of starch</td><td> 8.5 mg</td>

<td> Talc</td><td> 4.5 mg</td>

<td> Magnesium stearate</td><td> 1.5 mg</td>

<td> Capsule fill weight</td><td> 100.0 mg</td>

<td> Example C</td><td></td>

<td> Tablets</td><td></td>

<td> An oxetanone of formula I</td><td> 30.0 g</td>

<td> Lactose anhydrous</td><td> 118.8</td>

<td> Microcrystalline cellulose</td><td> 30.0</td>

<td> Polyvinylpyrrolidone</td><td> 10.0</td>

<td> Polymer of carboxymethylcellulose</td><td> 10.0</td>

<td> Magnesium stearate</td><td> 1.2</td>

Tablet weight

200.0 mg

*49־

Example D

Tablets with controlled release of the active ingredient and increased

<td colspan="3"> residence time in the stomach:</td>

<td> An oxetanone of formula I</td><td></td><td> 60.0 mg</td>

<td> Lactose powd.</td><td></td><td> 70.0 mg</td>

<td> Hydroxypropylmethylcellulose</td><td></td><td> 52.5 mg</td>

<td> Polyvinylpyrrolidone</td><td></td><td> 7.5 mg</td>

<td> Talc</td><td></td><td> 8.0 mg</td>

<td> Magnesium stearate</td><td></td><td> 1.0 mg</td>

<td> Colloidal silicic acid</td><td></td><td> 1.0 mg</td>

<td> Nucleus weight</td><td></td><td> 200.0 mg</td>

<td> Hydroxypropylmethylcellulose</td><td></td><td> 2.5 mg</td>

<td> Talc</td><td></td><td> 1.25 mg</td>

<td> Titanium dioxide</td><td></td><td> 1.25 mg</td>

<td> Weight of the film coating</td><td> Example E</td><td> 5.0 mg</td>

<td> Reconstitutable powder:</td><td></td><td></td>

<td> An oxetanone of formula I</td><td></td><td> 200.0 mg</td>

<td> Ethylvanillin</td><td></td><td> 10.0 mg</td>

<td> Aspartame</td><td></td><td> 30.0 mg</td>

<td> Sprayed skinned milk powder</td><td></td><td> 4,760.0 mg</td>

<td></td><td> Total</td><td> 5,000.0 mg</td>

־50־