FI92061C - 1,3-substituted- (14- [7-methyl-4,6-dioxo-hexahydro-naphth-8-yl / ethyl) -16-protected hydroxy-14,15,17-tetrahydro-18H-pyran- 18-ones and their manufacture - Google Patents

Description

92061 1 1,3-Substituted- (14- [7-methyl-4,6-dioxo-hexahydro-naphth-8-yl] -ethyl) -16-protected hydroxy-14,15,17-tetrahydro-18H -pyran-18-ones and their preparation 1,3-substituents- (14- [7-methyl-4,6-dioxo-hexahydro-naphth-8-yl [ethyl] -16-

hydroxy hydroxy-14,15,17-tetrahydro-18H-pyran-18-one and other frams-D

storage of 1,3-substituted- (14- [7-methyl-4,6-dioxo-hexahydro-naphth-8-yl] -ethyl) -16-protected hydroxy-14,15,17-tetrahydro-18H-pyran- 18-ones of the formula 15 k / 0 J (Ϊ) k 0R 5 20 0 wherein R 3 represents a hydroxide protecting group such as t-butyldimethyl-2Q silyl group f or 2-methylbutyryl group 4a; R 4 is a hydroxy protecting group such as a t-butyldimethylsilyl group; Y represents a hydrogen atom or a netyl group; and the corresponding free hydroxycarboxylic acid or a salt or ester of this acid.

The invention relates to a process for the preparation of 1,3-substituted * (14- [7-methyl-4,6-dioxo-hexahydro-naphth-8-yl] -ethyl) -16-protected hydroxy of the formula V For the preparation of -14,15,17-tetrahydro-18H-pyran-18-ones Y 111 N 0 F 15 H 3 C. , Α.

15 y 0 20 where:

R 5 represents a hydroxide protecting group such as a t-butyldimethylsilyl group or a 2-methylbutyryl group; R4 is a hydroxy protecting group such as t-butyldimethylsilyl; Y represents a hydrogen atom or a methyl group; and to prepare the corresponding free hydroxycarboxylic acid or this acid, salt or ester.

»

The compounds of this invention are a series of novel octahydronaphthalene derivatives which are derivatives of known compounds A, named ML-236A, ML-236B, HB-530A and MB-530B.

35 92061 3 ^ In recent years, numerous compounds have been ignited in which the essential basic structure is 3,5-dihydroxy-5- 2- (1-polyhydronaphthyl) ethyl pentanoic acid. Of which the first, named ML-236A and ML-236B, have formulas (i) and (ii), respectively: 5 10 f (i) 20 V "· k (ii) 35 4 92061 1 and are described in U.S. Pat. 3,983,140. by silencing the cholesterol biosynthesis of cultured cells isolated from the test enzymes by competing with the active, rate-limiting enzyme, i.e. 3-hydroxy-3-methylglutaryl-coenzyme A-enzyme, 10 ml of cholesterol biosynthesis. serum cholesterol levels in Journal of Antibiotics, 29 (1976), 1346.

Subsequently, a similar compound of the genus Monascus mold, in particular Monascus ruber * In, of the genus 15 was invented, and a compound of t3m8, described in e.g. In GB Patent Publication No. 2,046,737, eslttMS is given by formula (111): «HO. .0 20 • s · ν

Hac ^ Jn.

^ 1 (iii) 30 L · u. .

35 In this GB patent publication, the name "Monacolin R" is used interchangeably, but also in this and the same name "MB-530B".

5,92061 1 Since then, GB 2,073,193 discloses a similar compound having a similar anti-hypercholesterolemic effect, designated "MB-530A"; tMma equation shows 5 k “van * <lv): ΗΟγ ^ γΟ 10 OH (iv)

For all of these, the uniform structure is shown below as formula (v), which also shows the point of attachment and / or substitution *; Numerical system used in the identification: 20 17 15 \ 7V 0 25 ^ 12 ur 11 (v 1 r T33 35 Compounds of formulas (I) to (lv) having a hydrogen atom in the 3-position are called ML-236 combinations, while those in which the methyl group in the 3-position is called MB-530, in which case the group 1 in the 1-position is a hydroxy group, in the name M being the appendix "A" (i.e. ML-236A and MB-530A), while those having 2 -methylbutyryloxy group in the 1-position, the appendix is "B" (i.e. ML-236B and MB-530B).

The free hydroxycarboxylic acids corresponding to the compounds of formulas (i) to (iv) are designated HL-236A carboxylic acid, ML-236B carboxylic acid, MB-530B carboxylic acid and MB-530A carboxylic acid, respectively.

All of the aforementioned compounds S have double bonds between the 4- and ΙΟΙ 0 positions and the 5- and 6-positions. The putative compounds have the same structure, except that the double bonds are 3- and 4-position and the 10- and 5-position vSllllS, nlmetl & n suSmSllM prefix "Nso" to the parent compound. The compounds of formulas (1) to (iv) can be represented by the following formulas (vl) - (ix): 15 • a 20 Η 0 X 0 v ° 25 IsoML-236A \ (vi)

OH

30. ^ 35 7 92061 i s.0 Ο 10 IsoML— 23ΒΒ \ (νϋ).

• · 20 k ^ ° 25 „ΙεαΜΒ-5308 30 ίνίίί) 35 8 92061 ΗΟ, / χη ίο IsoM8-53QA χ. j

I OH

H3Cv \ A

CHj 20

As will be explained in more detail below, the naming of the compounds according to the invention is based on the names given to the compounds of the above formulas (I) to (iv) and (vi) to (ix).

:: 25 FI application 823282 (Sankyo Company Limited) discloses compounds which are derivatives of HL-236 and MB-530 together; these co-dlstells have valuable anti-hypercholesterolemic whitening, of which some have an order of magnitude greater than the known whitening of known cholera.

This invention relates to compounds which are valuable in the synthesis of the compound according to FI application 623282.

The invention also provides a method according to the formula (V) for compounding 9 92061 • γ ·.

> 0R5 10 0 20 (wherein X and Y are as defined above) by reacting a compound of formula (IV): :: 25 (E) ^ OR5 (where Y is as defined above and R4 and RJ are the same and each is means hydroxy protecting group) with an oxidant, a compound of formula (V): 10 92061 γ Ν I «! 10 ^ ο 15 (where Υ, R4 and R5 are as defined above) Sámi.

The compounds according to the invention are known in that they have the formula 20 \> 0: v 25 y (I) S. OR * * * 4 w · 35 0 11 92061 1 wherein R3 represents a hydroxide protecting group such as a t-butyldimethyl group, a 1-silyl group or a 2-methylbutyryl group; R4 is a hydroxy protecting group such as t-butyldimethylsilyl; Y represents a hydrogen atom or a methyl group; and the corresponding free hydroxycarboxylic acid or a salt or ester of this acid.

The above reactions give the compounds of the invention in the form of a lactone; if desired, a ring-opening reaction may be carried out to give the free acid or a salt or ester of the free acid, depending on the reagents selected. If desired, the acid may be formed into a salt or ester, the salt may be converted to the free acid or ester by conventional reactions, and the ester may be de-esterified to give the free acid or lactone.

20

The free acids of the compounds of formula (V) may form salts (hereinafter referred to as "carboxylate salts") with their carboxylic acid group, and such salts may be metal salts, ammonium salts or salts with organic amines or amino acids.

The metal carboxylate salts of this invention can be represented by the formula (VII '): 30 t «a t 35 12 92061 5 Ί COO ---! - Μ \ / ΡΗ

10 I

· OR? (ΣΓ) 15 '. ; . '0.

2o L Jn (where R \ R5 and Y are as defined above, M denotes meCalllatomy 25 and n denotes the valence of a metal atom). Examples of metals referred to in the salt of M nAlssA include: alkali metals such as lithium, sodium and potassium; alkaline earth metals such as calcium; and other we stables such as magnesium, aluminum, iron, zinc, nickel i tal cobalt · ti. Of the metals, alkali metals, alkaline earth metals and alumina are preferred; sodium, potassium, calcium and aluminum are more preferred and sodium and potassium are more preferred.

The ammonium, organic amine and amino acid carboxylate salts of the compounds according to the invention can be represented by the formula (VIII '): 35 g 135061 5 [g coir I MH®lm 10 \ | .OR *

(MI

(Wherein R4, R3 and Y are as defined above, A represents ammonia, amino acid contains an organic amine and m is an integer). The total number of <25 m is preferably 1, i.e. the amine amino acid referred to by A is preferably monovalent.

Examples of the amino acids represented by A vol in the above formula (VIII) are such basic amino acids as arginyl, lysil 30, histidine, 2,4-diaminobutyric acid.

When A represents an organic amine, it is preferably a monoamine and may be an aliphatic, aromatic, alicyclic, heterocyclic tal carbohydrate monoamine. Examples are primary alkylamines such as octylamine, t-octylamine or 2-ethylhexylamine; primary, secondary and tertiary C7 or C, aralkylamines such as 92061 14-benzylamine, α-methylbenzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, Ν, Ν-dimethylbenzylamine, N, N-diethylibin, N, N-diethyl -methylbenzylamine or tribenzylamine; primary, secondary and tertiary C5-C7 saturated alicyclic amines such as cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N-ethylcyclohexylamine, N-ethylcyclohexylamine, N-ethyl N-dimethylcyclohexylamine or N, N-diethylcycloheptylamine; 5- or 6-membered heterocyclic amines in which the heteroatom has one type atom, such as pyrrolidine, N-methylpyrrolidine, piperidine or N-methylpiperidine; morpholine-ni; C1-C3 alkyl esters of aliphatic or aromatic amino acids, such as leucine methyl esters, diethylglutamate, phenylglycine ethyl ester, N-phenylalanine propyl ester or β-phenylalanine methyl ester; and carbohydrate amine derivatives such as glucosamine.

When the aforementioned amino acids and amines can exist as stereoisomers or optical isomers, it is possible to use any 20 isomers or mixtures thereof.

Preferred amines are t-octylamine, benzylamine, dibenzylamine, Ν, Ν-dimethylbenzylamine, cyclohexylamine, dicyclohexylamine, Ν, Ν-dimethylcyclohexylamine, N-methylpyrrolidine, L-leucusyl, L-morpholine, glutamates, alkyl esters of D-phenylglycine and D-glucosamine; The most preferred amines are t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, alkyl esters of D-phenylglycine and D-glucosamine.

Esters of the compounds of the invention may be represented by formula (IX *): 35 92061 15 - R8 Ο i \ (Ε}) 10 ^ 0R? · 'H3Cn ^ v ^> 15 -' 0 Jp 20 (where R4, R5 and Y are as defined above, R * denotes the alcohol part of the ester and p * denotes the valence of R *).

• when p is 1, R represents (preferably an alkyl group; an unsubstituted benzyl group; a substituted benzyl group having one substituent on the alkyl group, which is selected from the group consisting of alkyl groups, an alkoxy group substituted with a substituent and a halogenated substituent; is dominated by 30 alkyl groups, alkoxy groups and halogen latomate.

When R * represents an alkyl group, the tamd may be a straight-chain or branched group and preferably contains 1 to 6 carbon atoms. Examples of such a group are methyl, ethyl, propyl, isopropyl, butyl-35 11 -. pentyl and hexyl groups.

16 92061 1 When R * represents a benzyl group, it may be unsubstituted or substituted, the substituent being preferably C, or C2 alkyl or alkoxy groups containing halogen atoms. One or more substituents, preferably one, is possible and if there are more than 5 substituents, these may be the same. Examples of such benzyl groups are benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxy benzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl and 4-bromobenzyl groups.

R 1 vol represents an unsubstituted tal substituted phenacyl group in which the substituents are preferably C 1 or C 2 alkyl or alkoxy groups or halogen atoms. One or more, preferably one, substituent is possible, and when there are more than one substituent, these may be the same or different. Examples of such phenacyl groups are phenacyl, 2-methylphenacyl, 3-methylphenacyl, 4-methylphenyl, 2-ethylphenacyl, 3-ethylphenacyl, 4-20 ethylphenacyl, 2-methoxyphenacyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenacyl, 4-ethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl and 4- bromifenasyyliryhmat.

• · '\ 25 When p is 2, R means a dihydric alcohol moiety, preferably Cj-

Ce alkylene or alkylidene group, for example ethylene-ethylidene, propylene, propylidene, trimethylene, tetramethylene, butylidene, pentamethylene or pentylidene, as well as groups having one or more substituents. hydroxy groups, 30 halogen atoms or trifluoromethyl groups.

When p is 3, R * represents a trivalent alcohol moiety and is preferably a saturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and optionally one or more substituents, e.g. hydroxy groups, halogen atoms or trifluoromethyl groups.

«17 92061

We prefer that p be 1 and that R * denote an alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl or hexyl), an optionally substituted benzyl group (most preferably benzyl, 4-methylbenzyl, 4-methyl -methoxybenzyl or 4-chlorobenzyl) or an optionally substituted phenacyl group (most preferably phenacyl, 4-methylphenacyl, 4-methoxyphenacyl or 4-bromophenyl), most preferably an alkyl group, e.g. methyl, ethyl, propyl, propyl. -, butyl, sec-butyl or t-butyl, especially methyl or ethyl.

The compounds of the invention may exist in a variety of optical isomers due to the presence of asymmetric carbon atoms. Although all of these isomers are shown in a single plane formula herein, it is to be understood that the present invention encompasses both the individual isomers and mixtures thereof.

The compounds of the invention can be prepared by the methods summarized in the following reaction scheme: RL ° y ^ Y ° • | ? r5 '*' η 'OR5 y °' ^ v ^ irSy (E) (I) 0 (b <) 1 '

In the above formulas, R 4, R 2, and Y are as defined above.

18 92061

V ^ y ° OIflK

s Y «OR5 · - H3Cv ^ Y ^ 1

10 0 ^ V ^ Y

inr o cal auola tal éateri J5 In the above formula, R4, R5, and Y are as defined above.

The first step, formula (a), involves the oxidation of a compound of formula (IV) with a suitable oxidizing agent to give a compound of formula (V). This reaction is preferably effected in such a way that the lasna is lluotln, the nature of which is not critical, provided that it has no adverse effect on the reaction. Examples of suitable solvents include: halogenated hydrocarbons such as methylene chloride, ethylene chloride and chloroform; and N, N-dialkyl fatty acid amides such as dimethylformamide and dimethylacetamide; nalsta we prefer .25 methylene chloride to dimethylformamide. The oxidizing Alne used in this reaction is preferably a chromium (III) compound, for example a chromic acid anhydride complex! with an organic base such as chromic acid anhydride / pyridine (Collins reagent), pyridinium dichromate and pyridinium chlorochromate, most preferably chromic acid anhydride / pyridine.

The reaction lamp may be between -10 ° C and + 50 ° C, preferably a room temperature of 0 ° C. The reaction time is usually 1 to 30 hours, preferably 10 to 15 hours.

Once step (a) is complete, the resulting one from each step 35 can be recovered from the reaction mixture by conventional means. For example, the reaction mixture can be diluted with a water-immiscible solvent and washed with water, after which the solvent is removed by distillation to give the desired compound. This compound can be further purified, if necessary, by purifying the clay of conventional clay, for example by recrystallization, reprecipitation by various chromatographic methods, in particular by column chromatography.

The halides of the protecting groups R4 and R5 are removed, but to give the final product of the final product. The nature of the reaction used to remove the protecting group or groups will, of course, depend on the nature of such groups, and any hydroxy-protecting groups known in the art may be used provided that the reactions required to remove them do not adversely affect other parts of the molecule.

For example, the protecting group may be a tri (lower alkyl) silyl group, for example a trimethylsilyl or t-butyldimethylsilyl group.

Suitable protecting groups for halogen include halogenated alkyl groups such as 2,2-dibromoethyl or 2,2,2-trichloroethyl groups.

20

Of the protecting groups described above, the most preferred is a t-butyldimethylsilyl group.

The compounds of the formulas (V) can, if necessary, be converted into the metal carboxylate salt or carboxylate ester of the carboxylic acid of the formula (II ') in which the lactone ring has been opened, by hydrolysis or solvolysis, respectively.

The hetallic carboxylate salt can be obtained by subjecting a compound of formula (V) to a conventional hydrolysis reaction, for example, simply by contacting the compound with an alkali metal hydroxide (such as sodium hydroxide or potassium hydroxide) in water or an aqueous organic solvent such as aqueous alcohol. The alkali metal hydroxide is preferably used in an amount of 1 to 1.5 moles per mole of the compound of formula (V). The reaction is preferably carried out at about room temperature, and the reaction time is preferably 1 to 5 hours.

The carboxylate ester can be obtained by subjecting the lactone of formula (V) to a conventional solvolysis reaction, for example by contacting the compound with an alcohol (such as methanol, ethanol, propanol or isopropanol) in the presence of an acid catalyst, for example a mineral acid (e.g. hydrochloric acid) or sulfuric acid or (e.g. boron trifluoride) or an acidic ion exchange resin. If desired, the reaction may be carried out in the presence of an inert organic solvent (for example, benzene, diethyl ether or chloroform), but it is preferable to use an alcohol as the reaction solvent itself. The reaction is preferably carried out under heating, for example in an elevated temperature, which may range from 50 ° C to the reflux temperature of the solvent used. Normally, several hours should be allowed for the reaction.

Upon completion of the reaction, the desired compound can be taken from the reaction mixture of art by conventional means. For example, when an ion exchange resin is used in the catalyst, it is removed by filtration and the solvent is distilled off from the filtrate to obtain the desired compound. When a mineral acid or Lewis acid is used, the reaction mixture is first neutralized, then the solvent is removed by distillation, the solvent is extracted with a suitable solvent, and then the solvent is distilled from the extract to obtain the desired compound. The compound thus obtained can then, if necessary, be further purified by conventional means, for example by various chromatographic methods, in particular by column chromatography.

If necessary, the prepared salt or ester can be further reacted as in step (b ') described above to obtain salts or esters corresponding to the lactones shown in Reaction Scheme 30. In theory, it is possible to start the reaction scheme using the corresponding salt or ester of the compound of formula (IV), but this is not preferred because it is necessary to protect the free hydroxy group from the opened lactone ring and, of course, add to the above 35 ° C reaction step.

21 92061 In addition to the preparation of the carboxylate ester described above by solvolysis, these esters can also be prepared by reacting a carboxylic acid of formula (II ') with a diazo compound, preferably diazomethane or C-substituted diazomethane, in a reaction condition. 555 831.

Amino acid carboxylate salts of the compounds of formula (II '), i. Compounds of formula (VIII ') wherein A represents an amino acid may be prepared from any of the compounds of formulas (V) and (II'), preferably compounds of formulas (IIf), by the methods described in GB 1 555 831.

Amine salts of the compounds of formula (II '), i. Compounds of formula (VIII ') wherein A represents an organic amine or ammonium battery may be prepared from compounds of formula (V) by first preparing the corresponding alkali metal carboxylate salt, for example sodium carboxylate, by the hydrolysis reaction described above, and then reacting it or with a mineral acid salt of an organic amine (e.g. hydrochloride) in a suitable solvent.

The nature of the solvent is not critical, provided that it has no adverse effect on the reaction; aqueous solvents are preferred. Examples are water itself and mixtures of water with one or more organic solvents such as alcohols (e.g. methanol or ethanol) or ketones (e.g. acetone). The amount of amine salt is preferably equimolar to or slightly above the metal carboxylate, e.g. the molar ratio of amine salt: metal carboxylate is 1: 1 to 1.2: 1. The reaction is preferably carried out at a pH of 7.0 to 8.5 and at or below room temperature, e.g. 0 ° C to 10 ° C, most preferably 5 ° C to 10 ° C. After the reaction, the resulting salt can be separated from the reaction mixture by extraction with a suitable solvent such as ethyl acetate.

• i

The reaction is preferably effected by contacting the appropriate starting material with a metal hydroxide in a suitable solvent. Examples of metal hydroxides that can be used in this reaction include alkali metal hydroxide (e.g., sodium hydroxide or 22,92061 l of potassium hydroxide) and alkaline earth metal hydroxides (e.g., calcium hydroxide or barium hydroxide), preferably alkali metal hydroxide.

The reaction is preferably carried out at about room temperature, and the time required for the reaction is preferably 1 to 3 hours.

Upon completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. For example, the solvent can be removed from the reaction mixture by distillation under reduced pressure, after which the resulting residue is lyophilized to obtain the desired compound. if necessary, the depressed compound can be further purified by conventional means, for example, by recrystallization or various chromatographic methods, especially column chromatography.

The compounds of FI application 823282, wherein one or both of the groups at the 4- and 6-positions marked R1 or R2 are a group of the formula -N-OR3, have been found to inhibit cholesterol biosynthesis in a manner similar to the known compounds ML-236A, ML-236B, MB-530A and MB-530B, but with a significantly more effective effect. The compounds of invention 20, wherein R 1 and R 2 are both oxygen atoms, are valuable selected products in the synthesis of active compounds, as already described.

The preparation of the compounds of the invention is further illustrated by the following examples.

Example 1 3,4-Dihydro-6-oxo-4-hydroxyiminoissoML-236B lactone 30 ·. (i) 16-t-Butyldimethylsilyloxy-3,4-dihydro-4,6-dioxo-iso-236B-lactone 2.0 g of ML-236B-lactone was dissolved in 20 ml of dimethylformamide. To the resulting solution was added 418 mg of imidazole and 850 mg of t-butyldimethylsilyl chloride, followed by stirring at 40-45 ° 0: 888 23 92061 1 for 3.5 hours. At the end of this time, the reaction mixture was diluted with 100 mL of ethyl acetate, washed twice with water and seeded with Glau bersalt. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate in a volume ratio ranging from 8: 2 to 1: 1, to give fractions containing 2.1 g of butyl-2-butylimid-2.1 g of 16-acetyl. -actone, mass spectrum (m / e): 504 (M +).

10.1 g of this compound were then added to Collins' reagent prepared from 22.3 g of pyridine, 14.3 g of chromic anhydride and 300 ml of methylene chloride under fractional cooling. The mixture was then quenched at room temperature over y6n, after which it was diluted with about 200 mL of ethyl acetate and the mixture was filtered using 15 Celite (trademark) filter aid. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate in a volume ratio of 8: 2 to 1: 1, to give fractions containing 4.3 g of the desired compound.

IR absorption spectrum (liquid film) u e cm1: 1735, 1700, 1680.

Nuclear Magnetic Resonance Spectrum (90 MHz: 11a, CDCl 3) δ ppm:. · · 0.88 (9H, singlet, t-butyl); 1.03 (3H, doublet, J = 7.0 Hz, 11-CH 2); 1.10 (3H, doublet, J = 7.0 Hz, 2-CH 2 of 2-methylbutyryl); 2.57 (2H, doublet, J = 4.0 Hz, CH 2 at position 17); 4.28 (1H, multiplet, CH at position 16); 4.40-4.76 (1H, multiplet, CH at position 14); .. 5.51 (1H, broad singlet, CH at position 1); 6.57 (1H, doublet, J = 2.0 Hz, CH at position 5).

mass spectrum (m / e): 35,534 (M +), 432 (M-102).

24 92061 1 (ii) 16-t-Butyldimethylsilyloxy-3,4-dihydro-6-oxo-4-hydroxyimino-IsoML-236B-lactone and 16-t-butyldimethylsilyloxy-3,4-dihydro-4 -oxo-6-hydroxyimino-IsoML-236B-lactone 5 To a solution of 500 mg (0.935 mmol) of the compound obtained in the above false (1) in 10 ml of doxane and 0.5 ml of water was added. 84.7 mg (1.03 mmol) of sodium acetate and 71.5 mg (1.03 mmol) of hydroxylamine hydrochloride under cooling. The mixture was then stirred at room temperature for 1.5 hours, after which it was diluted with about 20 ml of ethyl acetate, washed with water and dried over Glauber's salt. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel chromatography on a Lobar column eluting with a 3: 2 (v / v) mixture of chloroform and ethyl acetate to give 245 mg of the desired 6-oxo-4-hydroxyl mg of 4-oxo-6-hydroxyimino compoundA.

(ill) 3,4-Dihydro-6-oxo-4-hydroxyimino-IsoML-236B-lactone 245 mg of 16-t-butyldimethylsilyloxy-3,4-dihydro-6-oxo-4-hydroxy-20-imino-IsoML -236B-lactone, prepared as described in False (11) above, was dissolved in 5 ml of tetrahydrofuran. To the resulting solution was added 0.2 ml of acetic acid and 600 mg of tetrabutylammonium fluoride, after which the mixture was stirred at room temperature for 48 hours. The mixture was then diluted with 10 mL of ethyl acetate, washed with water and dried over Glauber's salt. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography over silica gel, eluting with a 95: 5 (v / v) mixture of chloroform and methanol to give 151 mg of the title compound.

IR absorption spectrum (Nujol mixture) ν cm -1: 3300, 1730, 1650.

Nuclear Magnetic Resonance Spectrum (90 MHz: 11A, deuteroacetone) δ ppm: 0.87 (3H, triplet, J = 7.0 Hz, 4-CH 2 of 2-methylbutyryl); 35 25 92061 1 1.00 (3H, doublet, J = 7.0 Hz, 11-CH 3); 1.08 (3H, doublet, J = 7.0 Hz, 2-CH 2 of 2-methylbutyryl); 2.75 (1H, singlet, 16-OH); 4.18-4.44 (1H, multiplet, CH at position 16); Δ 4.44-4.80 (1H, multiplet, CH at position 14); 5.51 (1H, broad A singlet, CH at position 1); 6.44 (1H, doublet, J = 3.0 Hz, CH at position 5); 10.82 (1H, singlet, -N-OHJ).

Mass spectrum (m / e): 435 (M +), 417 (M-18).

Example 2 15 (i) 1,16-Bis (t-butyldimethylsilyloxy) -3,4-dihydro-4,6-dioxo-

IsoML-236A lactone 2.0 g of ML-236A lactone was dissolved in 20 ml of dimethylformamide, and to the resulting solution were added 830 mg of imidazole and 1.7 g of t-butyldimethylsilyl chloride, after which the mixture was stirred at 40-45 ° C. For 3.5 hours. The reaction mixture was then diluted with 100 ml of ethyl acetate, washed twice with water and dried over Glauber's salt. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate: to give 2.3 g of 1,16-bis (t-butyldimethylsilyloxy) -ML-236A-lactone.

IR absorption spectrum (liquid film) γ B cm1: 1705.

30. ·· mass spectrum (m / e): 534 (M +).

5 g of 1,16-bis (t-butyldimethylsilyloxy) -ML-236A-lactone, prepared as described above, were added while cooling with Collins-35 reagent prepared from 11.2 g of pyridine. 7.2 g of 26,92061 l of chromic anhydride and 150 ml of methylene chloride, after which the mixture was stirred at room temperature. The mixture was then diluted with about 100 mL of ethyl acetate and filtered using Celite filter aid. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate ranging from 8: 2 to 1: 1 to give 3.2 g of the title compound and the title compound.

Ί0 IR absorption spectrum (liquid film) u e cm1: 1735, 1700, 1680.

mass spectrum (m / e): 564 (M +).

(Ii) 3,4-Dihydro-6-oxo-4-hydroxyiminoisol-236A-lactone 42 mg (0.52 mmol) of sodium acetate and 36 mg (0.52 mmol) of hydroxylamine hydrochloride were added under ice-cooling to the solution, containing 267 mg (0.5 mmol) of the compounds prepared in step (i) above in 5 ml of dioxane and 0.3 ml of water. The mixture was then stirred at room temperature for 1.5 hours, after which it was diluted with about 10 ml of ethyl acetate, washed with water and dried over Glauber's salt. The solvent was then removed by distillation under reduced pressure, and the residue was purified by chromatography on a Lobar column containing silica gel, eluting with a 3: 2 (v / v) mixture of chloroform and ethyl acetate, to give 180 mg of 1,16-bis (t * butyldimethyloxy) methyl , 4-dihydro-6-oxo-4-hydroxyimino-IsoML-236A-lactone.

The whole of this compound was dissolved in 3 ml of tetrahydrofuran, and 0.15 ml of acetic acid and 400 mg of tet- were added to the resulting solution. ·· rabutylammonium fluoride, after which the mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with 5 mL of ethyl acetate, washed with water and dried over Glauber's salt. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluting with a 95: 5 (v / v) mixture of chloroform and methanol to give 103 mg of the title compound.

IR absorption spectrum (Nujol mixture) i / β cm 1: δ 3200, 1710, 1640.

Nuclear Magnetic Resonance Spectrum (90 MHz: IIId, deuteroacetone) δ ppm: 1.13 (3H, doublet, J = 7.0 Hz, 11-CH 2); 4.02-4.43 (1H, multiplet, CH at position 16); 4.43-4.80 (1H, multiplet, CH at position 14); 6.23 (1H, broad singlet, CH at position 1); 6.93 (1H, singlet, CH at position 5); II, 07 (1H, broad singlet, -N-OH).

Mass spectrum (M / e): 317 (M +), 299.

Example 3 (i) 16-t-Butyldimethylsilyloxy-3,4-dihydro-4,6-dioxo-isoMB-530B-lactone 8.0 g of MB-530B-lactone was dissolved in 50 ml of dimethylformamide and ·. 1.63 g of imidazole and 3.62 g of t-butyldimethylsilyl chloride were added to the resulting solution, which was then stirred at 40-45 ° C for 3 hours. The mixture was diluted with 300 mL of ethyl acetate, washed three times with water and dried over Glauber's salt. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography on pligeel, eluting with a mixture of hexane and ethyl acetate. .. with ratios ranging from 8: 2 to 1: 1 to give 7.7 g of 16-t-butyldimethylsilyloxy-MB-530B.

mass spectrum (m / e): 518 (M +).

A solution of 7t5 g of this compound in 50 ml of methylene chloride was added dropwise, with cooling, to Collins' reagent prepared from 16.1 g of pyridine, 10.3 g of chromic anhydride. and 200 ml of methylene chloride, after which the mixture was stirred over nucleus 5 at room temperature. The mixture was then diluted with about 300 mL of ethyl acetate, diluted and filtered using a Celite filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluting with a mixture of hexane and ethyl acetate in ratios ranging from 80 8: 2 to 1: 1 (v / v), to give 3.1 g of the title compound.

IR absorption spectrum (liquid film) v max cm 1: 1735, 1700, 1680.

15 HMR spectrum (CDCl 3) δ ppm: 0.88 (9H, singlet, t-butyl); 1.03 (3H, doublet, J = 7.0 Hz, 11-CH 2); 1.10 (3H, doublet, J = 7.0 Hz, 2-CH 2 of 2-methylbutyryl); 1.15 (3H, doublet, J = 7.0 Hz, CH 2 substituent at position 3); 4.28 (1H, multiplet, CH at position 16); 4.40 * 4.80 (1H, multiplet, CH at position 14); 5.51 (1H, levefi singlet, CH at position 1); 6.60 (1H, doublet, J = 3.0 Hz, CH at position 5).

Mass spectrum (m / e): 548 (M +), 446 (M-102).

(ii) Oximation of 16-t-butyldimethylsilyloxy-3,4-dihydro-4,6-dioxo-IsoMB-530B-lactone 30. A solution of hydroxylamine prepared from 890 mg of sodium acetate, 760 mg of hydroxylamine hydrochloride, 12.5 ml of dioxane and 12.5 ml of water was added dropwise, with cooling, to a solution of 3 .0 g of 16-t-butyldimethylsilyloxy-3,4-dlhy-35 dro-4,6-dioxo-10-MB-530B-lactone, prepared as described in step (i) above, in 25 ml of dioxane; the mixture was stirred for 29 hours. At the end of this time, the mixture was diluted with 300 mL of ethyl acetate, washed with water and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue was purified on a Lobar column (Merck & Co., Inc., Si-60, size B x 2), eluting with mixtures of hexane and ethyl acetate in varying ratios. 3: 7 · 6: 4 to give four fractions containing the desired compound: 155 mg of fraction 1; 168 mg of fraction 2; 183 mg of fraction 3 and 375 mg of fraction 4.

10 (iii) 3,4-Dihydro-4-oxo-6-hydroxyimino-IsoMB-530B-lactone

The procedure described in Example 1 (ii) was repeated, but 127 mg of fraction 1, obtained as described in step (ii) above, 0.1 ml of acetic acid and 300 mg of tetrabutylammonium fluoride were obtained to give 64 mg of the title compound.

IR absorption spectrum (Nujol mixture) v max cm-1: 3350, 1730, 1700.

NMR Spectrum (deuteroacetone) δ ppm: 0.88 (3H, triplet, J = 7.0 Hz, 4-CH 2 of 2-methylbutyryl); 0.95 (3H, doublet, J = 7.0 Hz, 11-CH 2); 1.09 (3H, doublet, J = 7.0 Hz, 2-CH 2 of 2-methylbutyryl); . 1.16 (3H, doublet, J = 7.0 Hz, methyl substituent in position 3); 4.18-4.43 (1H, multiplet, CH at position 16); 4.43-4.78 (1H, multiplet, CH at position 14); 5.48 (1H, broad singlet, CH at position 1); 6.90 (1H, doublet, J = 3.0 Hz, CH at position 5); Δ 10.52 (1H, singlet, -N-OH).

• · mass spectrum (m / e): 449 (M +).

35 (iv) 3,4-Dihydro-6-oxo-4-hydroxyimino-isoMB-530B-lactone »93061 1 The procedure described in Example 1 (iii) was repeated, but using 127 mg of fraction 2, prepared as in the lie (11) as described above, 0.1 ml of acetic acid and 300 mg of tetrabutylammonium fluoride to give 46 mg of the title compound.

Δ IR absorption spectrum (Nujol mixture) v max cm-1: 3300, 1730, 1650.

Nuclear Magnetic Resonance Spectrum (deuteroaceton) δ ppm: δ 0.87 (3H, triplet, J = 7.0 Hz, 4-CH 2 of 2-methylbutyryl); 1.03 (3H, doublet, J = 7.0 Hz, 11-CH 2); 1.10 (3H, doublet, J = 7.0 Hz, 2-CH 2 of 2-methylbutyryl); 1.11 (3H, doublet, J = 7.0 Hz, methyl substituent in position 3); 4.20-4.40 (1H, multiplet, CH at position 16); 4.40-4.80 (1H, multiplet, CH at position 14); 5.50 (1H, levefi singlet, CH at position 1); 6.43 (1H, doublet, J = 3.0 Hz, CH at position 5); 10.70 (1H, singlet, -N-OH).

Mass spectrum (m / e): 449 (M +).

(v) 3,4-dihydro-4,6-bis (hydroxyimino) -isoMB-530B-lactone, isomer a

The procedure described in Example 1 (iii) was repeated, but with 118 mg of fraction 3, prepared as described in formula (ii) above, 1.15 ml of acetic acid and 252 mg of tetrabutylammonium fluoride, yielding 57 mg of the desired isomer a.

30. · IR absorption spectrum (Nujol mixture) v max cm-1: 3300, 1725.

Nuclear Magnetic Resonance Spectrum (deuteroacetonyl) δ ppm: * 35 31 92061 1 0.87 (3H, doublet, J = 7.0 Hz, 4-CH 3 of 2-methylbutyryl); 0.96 (3H, doublet, J = 7.0 Hz, 11-CH 2); 1.09 (3H, doublet, J = 7.0 Hz, 2-CH3 of 2-methylbutyryl); 1.13 (3H, doublet, J = 7.0 Hz, methyl substituent in position 3); Δ 4.17-4.44 (1H, multiplet, CH at position 16); 4.44-4.80 (1H, multiplet, CH at position 14); 5.40 (1H, broad singlet, CH at position 1); 6.70 (1H, doublet, J = 3.0 Hz, CH at position 5); 10.10 (1H, broad singlet, -N-OH); 10.28 (1H, levefi singlet, -N-OH).

mass spectrum (m / e): 464 (M +).

(Vi) 3,4-dihydro-4,6-bis (hydroxyimino) -isoMB-530B-lactone, isomer b

The procedure described in Example 1 (iii) was repeated except that 118 mg of fraction 4, bleached as described in step (ii) above, 1.15 ml of acetic acid and 252 mg of tetrabutylammonium fluorine-20 <M- & · were obtained to give 38 mg of the desired fraction. isomerism b.

IR absorption spectrum (Nujol mixture) v max cm-1: 3325, 1720.

NMR Spectrum (deuteroacetone) δ ppm: 0.87 (3H, triplet, J = 7.0 Hz, 4-CH 2 of 2-methylbutyryl); 0.96 (3H, doublet, J = 7.0 Hz, 11-CH 2); .... 1.10 (3H, doublet, J = 7.0 Hz, 2-CH 2 of 2-methylbutyryl); 1.11 (3H, doublet, J = 7.0 Hz, methyl substituent in position 3); 4.11-4.46 (1H, multiplet, CH at position 16); 4.46-4.80 (1H, multiplet, CH at position 14); 35 5.43 (1H, broad singlet, CH at position 1); 7.30 (1H, doublet, J = 3.0 Hz, CH at position 5); 32 92061 1 10.00 (1H, broad singlet, -N-OH); 10.37 (1H, broad singlet, -N-OH).

mass spectrum (m / e): 5,464 (M +).

10 15 20/25 30 • «35

Claims (4)

1 patent claim 1. 1,3-substituted- (14- [7-methyl-4,6-dioxo-hexa-hydro-naphth-8-yl] ethyl) -16-protected hydroxy-14,15,17-tetrahydro-4 18H-pyran-18-ones of formula 5 ίο Γ * di S ors In 20 minutes: 25 RJ refers to a hydroxy protecting group such as a t-butyldimecylsilyl group or 2-methylbutyryl group; R 4 represents a hydroxy protecting group such as a t-butyldimethylslyl group; Y is a hydrogen atom or a methyl group; and the free hydroxycarboxylic acid corresponding to these acids or a salt or ester thereof. 35 38 92061 2. Process for Preparation of 1,3-Substituted- (14- [7-methyl-4,6-dioxo-hexa-hydro-naphth-8-yl [ethyl) -16-protected hydroxy-14,15,17- tetrahydro-18H-pyran-18-ones of formula (V) 5 10. In OflS 1520: RJ refers to a hydroxy protecting group such as a t-butyldimethylsilyl group or 2-methylbutyryl group; R 4 represents a hydroxy protecting group such as a t-butyldimethylsilyl group; Y represents a hydrogen atom or a methyl group; and the free hydroxycarboxylic acid which corresponds to its or a salt or ester of this acid, may be characterized in that it includes bringing about a purification of formula (IV): (ff) (V y 15 as defined above and R 4 and R 5 are the same or different and each refer to a hydroxy protecting group) to react with etc oxidant: liquid, to obtain a purification of formula (V): (τ 1 > OR 5, optionally, if the compound of formula (V) or (III) is exposed to salt formation or sheep string, it is allowed to obtain its salt or ester or the corresponding free acid. 3. A process according to claim 2, characterized in that the oxidation medium is a complex between an anhydride of a chromic acid and an organic base. 4. Process according to claim 3, characterized in that the oxidation medium is a complex between chromic acid · anhydride and pyridine. 15 e 20 25 30 e <·· 35