DK169130B1 - Process for preparing oxetanones - Google Patents

Description

in DK 169130 B1

The present invention relates to a particular process for the preparation of oxetanones of general formula I

Y 0 Cu / Ο Ι H I \

Z-NH-GH-C-O-CH-CH2-fS) (SN C = 0 I)

(C) is undecyl, Cg is n-hexyl, Y is isobutyl and Z is formyl or Y is carbamoylmethyl and Z is acetyl.

The compounds of formula I wherein Y is isobutyl and Z are formyl are characterized by valuable pharmacological properties. In particular, they inhibit pancreatic lipase and, accordingly, can be used to control or prevent disease, especially obesity, hyper-lipemia, atherosclerosis and arteriosclerosis.

The process of the invention is characterized in that an oxetanone of the general formula I ", nh₂O CU / O ^ Y-CH-C-O-CH-CH₂ - <(S) (S) O = 0 I"

(S) (S) xX

Wherein Y and Cg have the above meaning are treated with an alkanoylating agent introducing the group Z.

The peculiarity of the above process is that it is surprising that the amino group contained in compounds of formula I above can be alkanoylated in the presence of the highly reactive portion of these compounds. The reason for this is that oxelactones (or β-lactones), as compounds of formula I, are very unstable in basic and neutral environments. However, oxetanones, especially those having a basic group (cf. the amino group in the oxetanones), are unstable even in acidic environments and would therefore be expected to form complex cyclic compounds upon intramolecular amination of the aminolactones I. Thus, undesirable reactions would be expected even under acidic reaction conditions.

The alkanoylation may be carried out in the presence of an acid anhydride, for example a mixed acid anhydride such as formic acetic anhydride, in a solvent, eg an ether such as THF, preferably at room temperature.

The starting oxetanones of general formula I "can be prepared by leaving the amino protecting group 0 in an oxetanone of general formula I" Y 0 cu / 0v I II \ LL / \ 10 W-NH-CH-C-O-CH-CH 2 (S) (S) C = O in

(S) (S) Y

C6 where Cj_j_, Y and Cg have the above meaning.

As an example of an amino protecting group W may be mentioned benzyloxycarbonyl and p-nitrobenzyloxycarbonyl. The decomposition of W can be carried out by hydrogenation in a solvent, for example an ether such as THF, in the presence of a hydrogenation catalyst such as palladium on coal, preferably at room temperature. An undecadienyl group C] Cj in Iereseres is hydrogenated by the hydrogenolytic cleavage 20 of λ to the undecyl group.

The oxetanones of general formula I '' can be prepared by esterification of an alcohol of general formula III 'OH / 0v 1 X \ C11-CH-CH2-i (S) (S) C = 0 III' 25 ( S) \ 7 c6 wherein the substituents have the above meaning, with an acid anhydride, which is obtained by reaction of an acid of the general formula I "DK-169130 B1 3 NH 2 020-C-C-O-CH -CH2 - <(S) (g) c = 0 I "

(S) (S) Y

C6 wherein the substituents have the above meaning, with dicyclohexyl carboiimide or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride. The preparation of this acid anhydride can be carried out under cooling, for example to 2-3 ° C, in a solvent such as methylene chloride 10 and the subsequent esterification in a solvent such as dimethylformamide.

The alcohols of general formula 111 'can be prepared from the aldehydes of formula C C -CHO via the esters of formula XV, via the ethers of formulas XIII and VII and via the compounds of formulas VIII, VI, V and IV.

For the conversion of an aldehyde of formula C C -CHO or of formula VII into the corresponding esters of formula XV and formula VIII respectively, R (-) - (hydroxydiphenylmethyl) benzyl acetate may be substituted for a sulfinyl ester of formula XII. In this case, instead of the sulfoxides of formula XIV or X, the (R) -2-hydroxy-1,2,2-triphenylethyl esters corresponding to the alkyl esters of formula XV or VIII are obtained.

ο-l y '° \

Cl ~ Ah-CH2 - <^ S) (s) £ = 0 IV

25 (S)

0-L OH C00H

I I I

c11-ch-ch2-ch-ch-c6 V

30-L OH C00R

I I I

c11-ch-gh2-ch-ch-c6 vi DK 169130 B1 4

0-L

cu-ch-ch2-cho VI1 (S)

0-L OH

C11-CH-CH2-CH-CH2-C00R VIII

(S)

0-L OH COOR JO

111 /

Cl1 "CH-CH2" CH-CH-S ^ x

(s) N

10 CV

S-CHo-COOR XI1 /

T

0-L

Cu-CH-CH2-C00R XI11 15

OH COOR O

I 1 / Y7V

C] _j_-CH-CH-S ^ XIV

(S) T

OH

20 ci; l-ch-ch 2 -coor XV

(S)

Where Cg and Cn have the above meaning and L is an easily cleavable ether group such as tetrahydro-2H-pyran-2-yl, 1-ethoxyethyl or tert.-butyldimethylsilyl, T is p-tolyl, and R is straight or branched C alkyl, such as methyl, ethyl or tert-butyl.

DK 169130 Pg 5

EXAMPLES

A. Preparation of an Oxetanone of General Formula I

Dissolve 9 mg of (S) -Leucine-1 - [(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl) methyl] dodecyl ester in 0.3 ml of THF and add 1.6 /: 1 formic acid acetic anhydride. The reaction ends after a short time. Diethyl ether (3 ml) is added and washed with a 2% sodium bicarbonate solution. Then, sodium sulfate is dried, filtered and evaporated. The residue is chromatographed on silica gel. N-for-methyl (S) -leucine- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester is obtained, = -31 9 ° (c = 0.345; CHCl 3).

B. Preparation of an Oxetanone of General Formula I 12 mg of N - [(benzyloxy) carbanoyl] -L-leucine- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2 -oxetanyl] methyl] dodecyl ester is dissolved in 0.5 ml of THF and hydrogenated in the presence of 5 mg 100% Pd / C at room temperature. After the reaction is complete, the catalyst is filtered off and evaporated. The product (S) -leucine-1 - [[ (2S, 3S) -3-Hexyl-4-oxo-2-oxtanyl] methyl] dodecyl ester is added directly into the formylation reaction A.

C. Preparation of an Oxetanone of General Formula I 45 mg of N - [(benzyloxy) carbonyl] -L-leucine is dissolved under moisture exclusion in 0.5 ml of methylene chloride and cooled to 2-3 ° C. 17 mg of dicyclohexylcarboiimide are added and stirred for 15 minutes, the white crystals are filtered off and the filtrate is evaporated, the residue is dissolved in 0.5 ml of Ν, Ν-dimethylformanide and the solution is added to 27 mg (3S, 4S) -3-hexyl 4 - [(S) -2-Hydroxytridecyl] -2-oxetanone and 1 mg of 4-dimethylamino-pyridine in 0.5 ml of DMF, then diluted with water and extracted with diethyl ether. The combined organic phases are dried over sodium sulfate, filtered and evaporated. After chromatography on silica gel, N - [(benzyloxy) carbanyl] -L-leucine- (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxo-tanyl] is obtained. thyl] dodecylester as colorless crystals having a melting point 30 of 43-46 ° C.

D. Preparation of an Alcohol of Formula III 1.23 g (3S, 4S) -4- [(S) -2- (tert.butyldimethylsiloxy) tridecyl] -3-hexyl-3-oxetanone is dissolved in 6 ml of methanol and with the addition of 1.05 g of DOWEX 50W-X8 (acidic cation exchanger based on the polymeric divinylbenzene obtained from sulfonic acid residues) are heated to ten lb. The ion exchanger is filtered off and the filtrate is evaporated. The residue is chromatographed on silica gel. After recrystallization from hexane, (3S, 4S) - 3-hexyl-4 - [(S) -2-hydroxytridecyl] -2-oxetanone is obtained, mp 63-64 ° C.

E. Preparation of an Ether of Formula IV (in (S) Form) (3S, 4S) -4- [(S) - 2- (tert-Butyldime thylsiloxy) tridecyl] -3-hexyl-2-oxeta -non, containing approx. 20% (cis) -4- [2-tert.butyldimethylsiloxy) tri-decyl] -3-hexyl-2-oxetanone is obtained from a diastereomer mixture which contains mainly (2S, 3S, 5S) -5- (tert. butyldime thylsiloxoxy-2-hexyl-3-hydroxyhexadecanoic acid.

F. Preparation of the Acid of Formula V (in (S) Form) 430 mg of Diastereomeric Blade, Preferably Consisting of (2S, 3S, 5S) -5- (tert.Butyldime thylsiloxy) -2-hexyl-3-hydroxyhexadecanoic acid methyl ester, is taken up in 8.6 ml of 2N methanolic potassium hydroxide solution and stirred until the reaction is complete. The reaction mixture is poured onto water and acidified by the addition of 2N hydrochloric acid. After several extractions with diethyl ether, the combined extracts are dried, filtered and evaporated. The residue is chromatographed on silica gel. The carbonic acid thus obtained is directly processed.

G. Preparation of an Ester of Formula VI (in (S) Form)

A diastereomer mixture, preferably containing (2S, 3S, 5S) -5- (tert.butyldime thyls iloxy) -2-hexyl-3-hydroxyhexadecanoic acid methyl ter, is obtained as a colorless oil, IR spectrum (Nujol): i / max = 1719, 1361, 1254, 1076, 836, 774 cm 2, from a diastereomer mixture consisting preferably of (3S, 5S) -5-tert-butyldimethylsiloxy) -3-hydroxyhexa-decanoic acid methyl ester.

DK 169130 B1 7 H. Preparation of esters of formulas VIII and XV (in (S) form) H. a) 14.5 g of diastereomer mixture, the main components of which are (3S, 5S) -5- (tert.butyldimethylsiloxy) -3 -hydroxyhexadecanoic acid (R) -2-hydroxy-1,2,3-triphenylethyl ester is suspended in 145 ml of methanol. Add 5 21.5 ml of 1N methanolic sodium methylate solution and stir for 1 hour at room temperature. The solution is poured onto 700 ml of saturated ammonium chloride solution. It is extracted once with 200 ml and then twice with 100 ml of diethyl ether. The combined extracts are dried, filtered and evaporated. The residue is taken up in 100 ml of n-hexane and stirred in an ice bath. The white crystals are sucked off and the filtrate is evaporated. The residue is chromatographed on silica gel. A diastereomeric mixture is obtained as an oil, preferably consisting of (3S, 5S) - 5- (tert -butyldimethylsilxy) -3-hydroxyhexadecanoic acid methyl ester, IR spectrum (Nujol): i / max = 3464, 1739, 1255, 1171, 1087, 836, 15.775 cm -1.

H. b) Analogously hereby obtained: (S) -3-hydroxytetradecanoic acid methyl ester which contains ca. 15% of the (R) -enantiomer, mp 36-38 ° C, from (S) -3-hydroxytetradecanoic acid (R) -2-hydroxy-1,2,2-triphenyl-ethyl ester containing about 15% of the (R) enantiomer.

I. Preparation of Ester Pre-Products for Esters VIII and XV

I.a) 9.75 g of (R) -α (hydroxide diphenylmethyl) benzyl acetate is cooled to -76 ° C in 100 ml of THF under argon. Then a solution of 2 molar equivalents of lithium diisopropylamide is added dropwise. Heat to 0 ° C and stir for 10 minutes. Then cool again to -76 ° C, drop 0.05 g of (S) -3- (tert -butyldimethylsiloxy) tetradecanal in 20 ml of THF and stir for one hour. For hydrolysis, mix at -76 ° C to -70 ° C with 25 ml of saturated ammonium chloride solution and heat to room temperature. The aqueous phase is separated. After washing with water 30, the organic phase is dried, filtered and evaporated. The residue is taken up in diethyl ether and stirred. Insoluble material is removed by filtration. The solvent is removed in vacuo and the residue is recrystallized several times by acetonitrile. A diastereiner is available.

Claims (2)

A process for the preparation of oxetanones of the general formula I Y 0 Cu / 0 \ i ii in X \ Z-NH-CH-C-O-CH-CH 2 <(S) (S) l: = o · i (S) (S) DK 169130 B1 where is undecyl, Cg is n-hexyl, Y is isobutyl and Z is formyl or Y is carbamoylmethyl and Z is acetyl, characterized in that an oxetanone of the general formula I "NHoO Ci in I 2II I11 / X Y-CH-C-O-CH-CH 2 ^ (S) (s) c = 0 I "(S) (S) X 2 X where C 2 -J 2, Y and Cg have the meaning given above, are treated with an alkanoylating agent which introduces the group Z. Process according to claim 1, characterized in that N-formyl-L-leucine (S) -1 - [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester is prepared. .