JPH0564953B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula where X is undecyl or 2Z,5Z-undecadienyl, _C6 is n-hexyl,
Y is isobutyl and Z is formyl, or Y is carbamoylmethyl and Z
is acetyl, and relates to a novel method for producing oxetanones.

Compounds of the formula where Y is isobutyl and Z is formyl are new. These new compounds are distinguished by valuable pharmacological properties. In particular, the compounds inhibit pancreatic lipase and therefore inhibit or prevent diseases, especially obesity, hyperlipaemia, atherosclerosis and arteriosclerosis. It can be used for

The method in the present invention comprises a formula The acid of formula where X, C ₆ , Y and Z have the above meanings, or b is esterified with an alcohol of formula where X' is 3-undecenyl, and
C ₆ , Y and Z have the above meanings, or hydrogenate oxetanone of c formula where C ₁₁ is undecyl, and Y and
_C6 has the above meaning, consisting of treating the oxetanone of with an alkanoylating agent which introduces the group Z.

Esterification a can be carried out in a solvent, for example an ether such as tetrahydrofuran (THF), in the presence of triphenylphosphine and diethyl azodicarboxylate. The reaction temperature is not critical; this esterification is preferably carried out at room temperature.

Hydrogenation b can be carried out in a solvent, for example an ether such as THF, in the presence of a hydrogenation catalyst, for example palladium on carbon, preferably at about room temperature.

Alkanoylated c in the presence of an acid anhydride, for example a mixed acid anhydride such as formic acid/acetic anhydride,
It can be carried out in a solvent such as an ether such as THF, preferably at room temperature.

Alcohol is a formula where C ₆ has the abovementioned meaning and L is a readily cleavable ether group, such as tetrahydro-2H-pyran-2-yl, 1-ethoxyethyl or t-butyldimethylsilyl. It can be produced by cleaving the ether group L in .

This cleavage is carried out in a solvent, e.g. an alcohol such as ethanol, with an acid catalyst, e.g. pyridinium-4-
In the presence of toluenesulfonate, e.g.
This can be carried out while heating to 50-65°C.

ether is the formula It can be produced by forming a ring with the compound.
This reaction is carried out in the presence of benzenesulfonyl chloride in a solvent such as pyridine, e.g.
It can be carried out while cooling to ℃.

The acid has the corresponding formula wherein R is straight-chain or branched _C1-4 -alkyl, such as methyl, ethyl or tert-butyl, and L and X have the meanings given above, Or X is 2Z, 5Z
- undecadienyl or octanoic acid with the formula It can be produced by condensation with an aldehyde.

Saponification of the ester can be carried out using an alcoholic alkali metal hydroxide solution, for example a methanolic potassium hydroxide solution, by heating the reaction mixture to a temperature up to the reflux temperature.

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

Acids of the formula present in the (5R)- or (5S)- form can be converted into the (2S,3S,5R)- or (2R,3R,5S)-stereoisomers in the following manner: (5R)- or (5S)-acids are prepared by toluene-4-sulfonic acid-hydrate while heating to 50-60 °C in ethanol to the corresponding formula (6R)- or (6S)-pyranolone is ring-formed, where L' represents hydrogen and X and _C6 have the meanings given above. This (6R)- or (6S)-pyranolone is then oxidized to the corresponding pyrandione by Jones' reagent, e.g. in acetone at a temperature below 25°C, and this is oxidized in the presence of e.g. platinum oxide. (3S, 4S, 6R) of formula-A where L′ is hydrogen by stereospecific hydrogenation in ethyl acetate as shown below.
- or (3R,4R,6S)-pyranolone is produced. The pyranolone is converted, for example, with t-butyldimethylchlorosilane in dimethylformamide, to a compound of formula -A in which L' represents an ether protecting group such as t-butyldimethylsilyl.
The resulting cyclic (3S, 4S, 6R) - or (3R,
4R,6S)-ether is cleaved, for example by reaction with aqueous potassium hydroxide in dioxane, and the resulting compound is converted in situ to the formula In the formula, L″ represents hydrogen, and L′ represents ether-
the same ether protecting group as in A,
R′ is benzyl or p-nitrobenzyl;
and X and C ₆ are converted into (2S, 3S, 5R)- or (2R, 3R, 5S)-ethers having the above meanings. Ether-B obtained next
is converted into diethyl of the same formula in which L'' represents an ether protecting group, e.g.
After cleavage with tetrabutylammonium fluoride trihydrate in THF and subsequent hydrogenation of the group R′ in THF in the presence of Pd/C, the desired formula (2S,3S,5R )- or (2R,3R,5S)-acids are obtained.

Ester is the corresponding formula or by n-hexylating the ester of formula It can be produced by reducing the β-keto ester of

N-hexylation of esters
react with a solution of n-butyllithium in hexane in the presence of diisopropylamine in a solvent such as THF at about -50°C, then 1-butyllithium in hexamethylphosphoric triamide at a temperature of about 0-10°C. This can be done by reacting with a solution of hexyl halide such as bromohexane.

Reduction of the β-keto ester is performed using a complex metal hydride, such as sodium borohydride (NaBH), in a solvent such as an ether, such as THF, at a temperature below about 0°C, optionally in an inert gas such as argon. ₄ ).

ester is the formula can be prepared by reductive cleavage of the sulfoxide, where T is p-tolyl and L, R and X have the meanings given above. This reduction can be carried out using aluminum amalgam in a solvent such as THF and water.

β-Ketoesters are prepared by reacting an aldehyde of formula X-CHO with C _1-4 -alkyl 2-acetyloctanoate and resulting It can be obtained by etherifying alcohol.

Conversion of aldehyde X-CHO to alcohol can be performed as described in Example 1L.

Sulfoxide X is an aldehyde of formula It can be produced by condensation with an ester of

The aldehyde in the formula is the corresponding formula can be prepared by reduction with diisobutylaluminum hydride in a solvent such as toluene at a temperature of about -60 to -80°C.

Esters of formula
and 1K.a, starting from an aldehyde of formula X-CHO, sulfoxide and formula can be produced through alcohol.

The oxetanone starting material of formula ' can be prepared via the corresponding compound of formula ~ in a similar manner to the preparation of oxetanone of formula starting from an ester of formula in which a 3-undecenyl residue X' is present in place of the group X. It can be manufactured using

The oxetanone starting material of the formula ″ is the formula In the formula, X, Y and C ₆ have the above meanings, and can be produced by cleaving the amino protecting group W in oxetanone. As examples of amino protecting groups W, mention may be made of benzyloxycarbonyl and p-nitrobenzyloxycarbonyl. Cleavage of the group W can be carried out by hydrogenation in a solvent, for example an ether such as THF, in the presence of a hydrogenation catalyst, for example palladium on carbon, preferably at room temperature. The undecadienyl group X present in the formula is hydrogenated to an undecyl group during the hydrogenolytic cleavage of the group W.

The formula oxetanone is the formula Alcohol, formula acid and dicyclohexylcarbodiimide or N
-ethyl-N'-(3-dimethylaminopropyl)
- It can be produced by esterification with an acid anhydride obtained by reacting with carbodiimide hydrochloride.
The preparation of the acid anhydride can be carried out in a solvent such as methylene chloride with cooling, for example to 2-3°C, and the subsequent esterification can be carried out in a solvent such as dimethylformamide.

The alcohol of the formula ' is the (S) of the alcohol of the formula
- epimers which, analogously to the process starting from aldehydes of the formula can be produced via the (S)-epimer of

For the conversion of an aldehyde of the formula α-(hydroxydiphenyl)benzyl can be used. In this case, instead of the sulfoxide of the formula or, the corresponding (R)-2-hydroxy-1,2,2-
Triphenylethyl ester is obtained.

formula Esters of the formula formula via the aldehyde of It can be produced starting from a heptenoic acid ester.

Example 1 Preparation of oxetanone of formula 1A 1A a Racemic-3-hexyl-4 in 2 ml THF
-(2-Hydroxy-tridecyl)-2-oxetanone (2R,3S,4S: 2S,3R,4R) 100 mg or (3S,4S)-3-hexyl-4-[(R)-
2-Hydroxytridecyl]-2-oxetanone 100 mg, triphenylphosphine 74 mg and N
44.3μ of diethyl azodicarboxylate was added dropwise to a solution of 45mg of -formyl-L-leucine with stirring. After stirring overnight, the organic phase was evaporated under vacuum and the residue was purified on silica gel with toluene.
Purified by chromatography using ethyl acetate (9:1). N-formyl-L-
Leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]
20 or 37 mg of dodecyl ester was obtained,
[α] ²⁰ _D = −33° (c = 0.36, CHCl ₃ ).

1A b N-formyl-L-leucine (S,4Z)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl] in 0.1 ml of THF
A solution of 2.5 mg of -4-dodecenyl ester was treated with 1 mg of palladium on carbon, then 3
Hydrogenated for hours. Separate the catalyst and pour the liquid onto silica gel toluene/ethyl acetate (9:1).
It was subjected to chromatography using. N-
Formyl-L-leucine (S)-1-[[(2S,
1.5 mg of 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester was obtained, ⁺ H-NMR spectrum ( _270MHz ,
_CDCl3 ): 0.89 (6H); 0.97 (6H); 1.15−2.25
(34H); 3.22 (2H); 4.29 (1H); 4.70 (1H);
5.04 (1H); 5.91 (1H); 8.23 (1H) ppm.

Analogously to 1A ca, the following was obtained: 1 N-acetyl-3-carbamoyl-L-alanine (S)-1-[[(2S,3S)-3-hexyl-4-oxo- 2-oxetanyl]methyl]dodecyl ester, NS:M ⁺ (510); (M
+1) ⁺ (511); 2 N-formyl-L-leucine (S)-1-
[[(2S,3S)-3-hexyl-4-oxo-
2-oxetanyl]methyl]3Z,6Z-dotecadienyl ester, [α] ²⁰ _D = -19.4℃
(c0.28, CHCl3); MS: (M+1) ⁺ (492); 3 N-formyl-L-leucine (S, 4Z))
-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-dodecenyl ester.

Preparation of alcohol starting material of formula 1B a 265 mg of isomeric mixture of 3-hexyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanone
Dissolve pyridinium in 2.5 ml of ethanol.
13 mg of 4-toluenesulfonate was added. The reaction mixture was heated to 55-60°C until the reaction was completed. The solvent was removed in vacuo and the residue was taken up in ether and crystals were thus separated which were removed by filtration. The solvent was evaporated under vacuum and the residue was chromatographed on silica gel. Racemic-3-hexyl-4-
(2-hydroxytridecyl-2-oxetanone (2R, 3S, 4S: 2S, 3R, 4R) was obtained,
MS: M ⁺ (354), melting point 44.5-46 °C.

In a similar manner, the following was obtained: 1B b (3S,4S)-3-hexyl-4-[(R)-
2-Hydroxytridecyl]-2-oxetanone, melting point 46-46.5°C; 1B c (3S,4S)-3-hexyl-4-[(R)-
2-Hydroxy-4Z,7Z-tridecadienyl]
-2-oxetanone; 1B d trans-3-hexyl-4-[(R)-
2-Hydroxy-5Z-tridecenyl]-2-oxetanone.

Preparation of ether of formula 1C a 2-hexyl-3-hydroxy-5-
0.7 g of the isomer mixture of [(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid was dissolved in 15 ml of pyridine and cooled to 0°C. After dropwise addition of 0.4 ml of benzenesulfonyl chloride, the mixture was stirred at 0°C. reaction mixture
It was poured into 120 ml of 10% sodium chloride solution and extracted three times with 30 ml of diethyl ether. The combined extracts were dried, filtered and evaporated. After chromatography on silica gel,
3-hexyl-4-[2-[(tetrahydro-2H
-pyran-2-yl)oxy]tridecyl-2
- an isomer mixture of oxetanone was obtained,
MS: (M+1) ⁺ (440).

In a similar manner, the following was obtained: 1C b 3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]
tridecyl]-2-oxetanone; 1C c 3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-
4Z,7Z-tridecadienyl]-2-oxetanone; 1C d 3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-
5Z-tridecenyl-2-oxetanone; 1D Preparation of acid of formula 1D a 2-hexyl-3-hydroxy(R)-
5-[(tetrahydro-2H-pyran-2-yl)
A diastereomeric mixture of t-butyl oxy]hexadecanoate was heated under reflux in 17 ml of 2N methanolic potassium hydroxide solution. The reaction mixture was cooled and poured into 60 ml of ice-water. The mixture was adjusted to a pH value of 1 by dropwise addition of 1N hydrochloric acid and then extracted with ether. The combined ethereal phases were dried, filtered and evaporated. This oil was chromatographed on silica gel.
2-hexyl-3-hydroxy(R)-5-
A diastereomeric mixture of [(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid was obtained.

In a similar manner, the following was obtained: 1D b 2-hexyl-3-hydroxy-5-
[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid; 1D c 2-hexyl-3-hydroxy(R)-
5-[(tetrahydro-2H-pyran-2-yl)
Oxy]-7Z,10Z-hexadecadenoic acid.

Preparation of acid of formula 1E (modified method) 1E a. Cool 2 ml of diisopropylamine in 30 ml of dry THF to -20°C, then add butyllithium (1.6M/hexane) 9.68 without allowing the temperature to exceed -20°C. ml was added dropwise. The mixture was then stirred for 15 minutes and cooled to -50°C. Then 1.11ml of octanoic acid in 10ml of THF
was added dropwise and the mixture was stirred for an additional 10 minutes at -50°. The mixture was stirred at room temperature for 1 hour, then cooled again to -50°C. Here, (R)-3-[(tetrahydro-2H-pyran-2
2 g of -yl)oxy]-5Z,8Z-tetradecadienal was added dropwise. The mixture was stirred at −50° C. for 30 minutes and then at room temperature for 72 hours. After hydrolysis with 2N hydrochloric acid, the reaction mixture was evaporated. The residue was extracted with ether. The organic phase was dried, filtered and evaporated. The resulting material was passed through silica gel. 2-hexyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-7Z, 10Z
-hexadecadienoic acid was obtained.

1E b In a similar manner, the following was obtained: 2-hexyl-3-hydroxy(R)-5-
[(tetrahydro-2H-pyran-2-yl)oxy]-8Z-hexadecenylcarboxylic acid.

1F Preparation of an ester of formula 1F a 1.8 ml of diisopropylamine was cooled to -5°C under argon and 1.6Nn in n-hexane was added.
- 8.7 ml of butyllithium solution was added dropwise. The mixture was then stirred for 10 minutes. After cooling to −50° C., the cooling bath was removed. This was added to 3-hydroxy(R)-5-[(tetrahydro-
Diastereomeric mixture of t-butyl 2H-pyran-2-yl)oxy]hexadecanoate 2.67
g solution was added dropwise. Thus, the temperature is -20℃
rose to The mixture was allowed to warm to 0°C and stirred for 10 minutes. Then 0.93 1-bromohexane in 4.4 ml hexamethylphosphoric triamide
ml of solution was added. The temperature rose to 9°C. The mixture was then allowed to reach room temperature and stirred for 21/2 hours. This solution was poured into 200 ml of ice-water and saturated with sodium chloride. The mixture was extracted with ether. The combined extracts were dried, filtered and evaporated. The remaining oil was chromatographed on silica gel. t-Butyl 2-hexyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate was obtained, MS: (M-
O-t-butyl) ⁺ (439).

1F b In a similar manner, the following was obtained: 2-hexyl-3-hydroxy(R)-5-
[(tetrahydro-2H-pyran-2-yl)oxy]-7Z,10Z-t-butyl hexadecadienoate.

Preparation of ester of formula 1G (modified method) 7.76 g of methyl 2-hexyl-3-oxo-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate was added while bubbling with argon.
Dissolved in 500ml of THF, treated with 20ml of ethanol,
Cooled to -5°C. 5.3 g of NaBH ₄ was added in portions with stirring, making sure the temperature did not exceed 0°C. After stirring for 3 hours, excess sodium borohydride was removed, the reaction mixture was hydrolyzed with 2N hydrochloric acid in the cold (PH value 6), and the solvent was evaporated. The residue was extracted with ether, the ether phase was dried and evaporated. 2-hexyl-3-hydroxy-
5-[(tetrahydro-2H-pyran-2-yl)
7.71 g of methyl oxy]hexadecanoate was obtained.

Preparation of esters of formula 1H and 3-hydroxy(R)-5-tetrahydro-2H
-pyran-2-yl)oxy]-2-[(S)-p-
13.6 g of a diastereomeric mixture of t-butyl tolylsulfinyl]hexadecanoate was dissolved in a mixture of THF6 and water 0.1. Then 150 g of amalgamated aluminum foil was added in portions within 6 hours. At that time, the temperature was maintained between 15°C and 20°C. After the addition was complete, the mixture was stirred until the reaction was complete. Aspirate the insoluble material and first
Washed with THF1 and then THF2. The filter cake was taken up in diethyl ether 2, thoroughly stirred and vacuumed off again. Repeat this operation one more time
I went back and forth. Evaporate the combined organic phase,
The oily residue was purified by chromatography on silica gel. 3-hydroxy(R)-5-
t-Butyl [(tetrahydro-2H-pyran-2-yl)oxy]hexadecaate was obtained, MS:
(M-O-t-butyl) ⁺ (355).

In a similar manner, the following was obtained: 1H a 3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-7Z,
10Z-tert-butyl hexadecadienoate; 1H b (R)-3-hydroxy-5Z,8Z-tert-butyl tetradecadienoate, [α] ²⁰ _D = -12.67°
(c=15, _CHCl3 ).

Preparation of sulfoxide of formula 1I 16.5 g of t-butyl [(S)-p-tolylsulfinyl]acetate was dissolved in a mixture of 60 ml of ether and 600 ml of THF and cooled to -78°C. Then add t-butylmagnesium bromide (2N solution in ether) 43
ml was added dropwise within 30 minutes. After stirring for 1 hour at -78°C, 13.4 g of (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal in 100 ml of THF was added dropwise and the mixture was stirred for an additional 2 hours at -78°C. Stir for hours. The reaction mixture was hydrolyzed with 2N hydrochloric acid and the solvent was evaporated. The remaining reaction mixture was extracted with ether, the ether phase was dried and evaporated. The crude product was eluted through a silica gel column. 3-hydroxy(R)-5-
14.9 g of t-butyl [(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]hexadecanoate was obtained, melting point 97.
~98℃.

In a similar manner, the following was obtained: 1I a 3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-
[(S)-p-tolylsulfinyl]-7Z, 10Z-
t-Butyl hexadecanoate; 1I b (R)-3-hydroxy-2-[(R)-p
-Tolylsulfinyl]-5Z,7Z-t-butyl tetradecadienoate.

1J Production of aldehyde of formula 1J a 9.2 g of t-butyl (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanoate was added to 115 ml of toluene while bubbling with argon and excluding moisture. Dissolved in −75
Cooled to ℃. Then 1.2MDIBAH in toluene
26.5 ml of the solution was added dropwise within 1/2 hour, ensuring that the temperature did not exceed -70°C. -75 mixture
The mixture was further stirred at ℃ for 1 hour. Then add 7.4 ml of saturated ammonium chloride solution, followed by 15.5 ml of 1N hydrochloric acid at -70
It was added dropwise at ℃. The cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring for 1 hour at room temperature, the organic phase was separated and washed with water. The organic phase was dried, filtered and evaporated. The resulting material was chromatographed on silica gel. (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal was obtained as a colorless oil.

In a similar manner, the following was obtained: 1J b (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-5Z,8Z-tetradecadienal; 1J c (R) -3-[(tetrahydro-2H-pyran-2-yl)oxy]-6Z-tetradecenal.

1K Preparation of ester of formula and 1K a 3.02 g of tert-butyl (R)-3-hydroxy-5Z,8Z-tetradecadienoate and 2.5 ml of freshly distilled 3,4-dihydro-2H-pyran are dissolved in 300 ml of methylene chloride. Dissolved and cooled to 3°C.
Then, 40 mg of p-toluenesulfonic acid hydrate
was added, which caused the temperature to rise to 8°C.
The mixture was stirred until the reaction was complete. Next, the solution was mixed with 125 ml of saturated aqueous sodium chloride solution, 125 ml of saturated aqueous sodium bicarbonate solution and 250 ml of water.
Washed with a mixture of After drying, filter the solution,
Solvent was removed. (R)-3-[(tetrahydro-
2H-pyran-2-yl)oxy]-5Z, 8Z-
t-Butyl tetradecadienoate was obtained.

1K b In a similar manner, the following was obtained: Methyl 2-hexyl-3-oxo-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate, mp 37-38°C.

Preparation of 1L alcohol 5g of 55% sodium hydride dispersion was washed with hexane and treated with 600ml of THF. A solution of 18.9 g of methyl 2-acetyloctanoate in 80 ml of THF was added dropwise with cooling. After stirring for 2 hours, the mixture was cooled to −10° C. and treated with 65 ml of butyllithium (1.6 M/hexane) while cooling. The reaction mixture was then left at this temperature for 1 hour. A solution of 19.7 g of dodecanal in 80 ml of THF was added dropwise at -10°C. The mixture was allowed to reach room temperature and stirred for a further 2 hours. The reaction mixture was hydrolyzed with 100 ml of 2N hydrochloric acid,
Then it was evaporated. The residue was extracted with ether, the ether phase was dried and evaporated. After chromatography on silica gel, melting point 38-39
10.3 g of methyl 2-hexyl-5-hydroxy-3-oxo-hexadecanoate were obtained.

Preparation of 1M ester of formula-A A solution of 0.51 g of diisopropylamine in 20 ml of THF was prepared at 0°C using butyllithium in hexane.
Treated with 3.13ml of 1.6M solution. Then mix −78
After cooling to 0.degree. C., 2.3 g of heptyltriphenylphosphonium bromide was added and the mixture was kept at this temperature for 5 minutes. This was then treated with 5-formyl-(R)-[(tetrahydro-2H-
A solution of ethyl pyran-2-yl)oxy]pentanecarboxylate was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was treated with water, extracted with ether, dried and evaporated under vacuum.
The residue was chromatographed on silica gel using toluene-ethyl acetate (9:1);
(R)-3-[(tetrahydro-2H-pyran-2-
0.5 g of ethyl)6Z-tetradecenecarboxylate was obtained.

Preparation of aldehyde of formula 1N A solution of 2.56 g of methyl (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6-heptenoate in 40 ml of ethyl acetate was treated with ozone at -75°C. did. After the reaction was completed, 0.1 g of Pd supported on carbon was added, and the mixture was hydrogenated at room temperature. After the hydrogen uptake had ended, the catalyst was separated, washed with ethyl acetate and evaporated under vacuum.
Crude methyl 5-formyl-(R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-pentanecarboxylate was obtained.

1 O Resolution of an acid of the formula into its stereoisomers 1 O a 2-hexyl-3-hydroxy-
(R)-5-[(tetrahydro-2H-pyran-2
Dissolve 15.4 g of the diastereomeric mixture of hexadecanoic acid in 160 ml of ethanol, and dissolve 800 mg of toluene-4-sulfonic acid hydrate.
added. The reaction mixture is heated until the reaction is complete.
Heated to 55-60°C. the solvent is removed under vacuum;
The residue was dissolved in 160 ml of dichloromethane. This solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated. The resulting material was chromatographed on silica gel. Tetrahydro-3-hexyl-4-hydroxy-, melting point 95-96°C
(R)-6-undecyl-2H-pyran-2-one was obtained.

1 O b Tetrahydro-3-hexyl-4-
3 g of diastereomeric mixture of hydroxy-(R)-6-undecyl-2H-pyran-2-one
was dissolved in 300 ml of acetone. John's reagent was added dropwise with stirring, making sure the temperature did not exceed 25°C. After 3 hours, the reaction mixture was purged with _H2
Pour into 700ml of O. The lactone precipitated and was separated. Tetrahydro-3-hexyl-4-oxo-(R)-6- after recrystallization from ether/n-hexane, melting point 112.5-113.5°C.
1.7 g of undecyl-2H-pyran-2-one was obtained.

1.Oc Tetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2H-pyran-
1.7 g of 2-one was obtained.

1 O c Tetrahydro-3-hexyl-4-
8 g of the isomer mixture of oxo(R)-6-undecyl-2H-pyran-2-one was added to 2 ml of ethyl acetate.
3 g of PtO ₂ was added. The mixture was then hydrogenated (50 bar) for 12 hours. The catalyst was separated and the solution was evaporated. After recrystallization, (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-(R)-6- with a melting point of 108-109°C
7 g of undecyl-2H-pyran-2-one were obtained.

1 O d (3S,4S,6R)-tetrahydro-3
1.5 g of -hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one was dissolved in 8 ml of DMF. Next, 0.85 g of t-butyldimethylchlorosilane in 4 ml of DMF was added dropwise. this mixture
Stirred for 48 hours. Add 100ml of ether to the reaction mixture
and washed with 1N hydrochloric acid. The organic phase was dried, filtered and evaporated. The resulting material was chromatographed on silica gel. (3S,4S,6R)-tetrahydro-3-hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-2-one
Obtained 1.26 g, MS: 411 (M ⁺ -t-butyl).

1 O e (3S,4S,6R)-tetrahydro-3
-Hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-
0.3 g of 2-one was dissolved in a mixture of 12 ml of dioxane and 0.64 ml of 1N aqueous potassium hydroxide solution. This mixture was stirred overnight. The reaction mixture was then evaporated and the residue was dissolved in 10 ml hexamethylphosphortriamide. 0.35 ml of benzyl bromide was added. The mixture was stirred for 2 days. The reaction mixture was poured into water and extracted with ether. The ether phase was dried, filtered and evaporated. This oil was chromatographed on silica gel.
330 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-hydroxyhexadecanoate was obtained.
MS: 519 (M ⁺ -t-butyl).

1 Of (2S, 3S, 5R)-2-hexyl-3
-[(t-butyldimethylsilyl)oxy]-5
-Benzyl hydroxyhexadecanonate 350mg
and freshly distilled 3,4-dihydro-2H-
Dissolve 0.5 ml of pyran in 10 ml of methylene chloride, -15
Cooled to ℃. To this was added crystals of p-toluenesulfonic acid hydrate. The mixture was stirred until the reaction was complete. The solution is then evaporated,
The residue was chromatographed on silica gel. (2S,3S,5R)-2-hexyl-3-[(t
-butyldimethylsilyl)oxy]-5-[(t
330 mg of benzyl -tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate were obtained, MS: 603 (M ⁺ -t-butyl).

1 O g (2S, 3S, 5R)-2-hexyl-3
-[(t-butyldimethylsilyl)oxy]-5
-480 mg of benzyl [(t-tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate and 350 ml of tetrabutylammonium fluoride trihydrate were dissolved in 8 ml of THF and stirred for 12 hours. After evaporation, the residue was dissolved in 50 ml of ether and washed with water. The ethanol phase was dried and evaporated. The crude product was chromatographed on silica gel. (2S, 3S, 5R) −2
240 mg of benzyl-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate was obtained, MS:
463 [(M+H) ⁺ -dihydro-2H-pyran-2-
].

1 Oh (2S, 3S, 5R)-2 in 10ml THF
430 mg of benzyl -hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate was treated with 10% Pd/C and hydrogenated for 3 hours. After separating off the catalyst and evaporating the liquid, the crude product was chromatographed on silica gel. (2S, 3S,
5R)-2-hexyl-3-hydroxy-5-
[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid was obtained.

Example 2 Production of oxetanone of formula 2A 9 mg of (S)-leucine 1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester was dissolved in 0.3 ml of THF, and 1.6μ of formic acid/acetic anhydride was added. The reaction was completed in a short time. To this was added 3 ml of diethyl ether and the mixture was washed with 2% sodium bicarbonate solution. The organic phase was then dried over sodium sulfate and
filtered and evaporated. The residue was chromatographed on silica gel. N-formyl-
(S)-Leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl was obtained, [α] ²⁵ _D = -31.9° (c =
0.345, _CHCl3 ).

2B Production of oxetanone of formula ″ N-[(benzyloxy)carbonyl]-L-leucine(S)-1-[[(2S,3S)-3-hexyl-
Dissolve 12 mg of 4-oxo-2-oxetanyl [methyl] dodecyl ester in 0.5 ml of THF and add 10% Pd/
Hydrogenation was carried out at room temperature in the presence of 5 mg of C. After the reaction was completed, the catalyst was separated and the liquid was evaporated. This product, (S)-leucine 1-[[(2S,3S)-3
-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester was used directly in formylation reaction 2A.

2C formula

Claims (1)

[Claims] 1 a Formula The acid of formula In the formula, X ² is synonymous with 3-undecenyl or X ¹ , where X ¹ is undecyl or 2Z,5Z-
undecadienyl, C ₆ is n-hexyl, Y is isobutyl and Z is formyl, or Y is carbamoylmethyl and Z is acetyl, and b is obtained. formula wherein X ¹⁰ is 3-undecenyl and C ₆ , Y and Z have the meanings given above, characterized in that the oxetanone of is hydrogenated A method for producing oxetanones, wherein X ¹ , C ₆ , Y and Z have the above meanings. 2 N-formyl-L-leucine (S)-1-
[[(2S,3S)-3-hexyl-4-oxo-2-
A method according to claim 1 for producing oxetanyl]methyl]dodecyl ester. 3 formulas In the formula, C ₁₁ is undecyl, C ₆ is n-hexyl, and Y is isobutyl or carbamoylmethyl. Oxetanones of the formula in which X ¹¹ is undecyl, Y is isobutyl and Z is formyl, or Y is carbamoylmethyl and Z is acetyl, and C ₆ has the above meaning. Production method. 4 N-formyl-L-leucine (S)-1-
[[(2S,3S)-3-hexyl-4-oxo-2-
A method according to claim 3 for producing oxetanyl]methyl]dodecyl ester.