DE2646855A1 - NEW PROSTAGLANDINANALOG CYCLOBUTANE DERIVATIVES AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

HOECHST AKTIENGESELLSCHAFT 264685

File number: HOE 76 / P 2 * 16

Date: April 14th, 1976 Dr.LA/Me

New prostaplandin analogs Cyclobutande riyate and process for their preparation

The natural prostaglandins have a carbon structure of generally 20 carbon atoms. Since they do a multitude at the same time Their use is to develop physiological effects and have only a short half-life in the organism as therapeutics set limits.

The search for prostaglandin analogs with longer half-lives and specific effects is therefore becoming increasingly important.

Are known pi ostaglandin analogs of cyclobutane derivatives structure

R - -CO ₂ H, -CH ₂ OH

( A. Guzman , JM Muchowski , MA Vera , Chem. Ind. (London) 1975, 884-885).

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40 - -a--

The invention relates to new prostaglandin-analogous cyclobutane derivatives of formula I.

CO ₂ R ₁

OH
where mean:

R is hydrogen, a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-12 carbon atoms or a cycloaliphatic hydrocarbon radical with 4-7 carbon atoms or an araliphatic Hydrocarbon radical with 7-9 carbon atoms

R _{2 is} a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-10 C atoms, which in turn can be substituted by a cycloalkyl radical with 3-7 C atoms or by a straight-chain or branched alkoxy or alkenyloxy radical with 1-5 C Atoms,

a cycloalkyl radical with 3-7 carbon atoms, which in turn is replaced by one or more alkyl groups with 1-3 carbon atoms can be substituted,

with the exception of the compound of the formula I in which R _{1 is} hydrogen and R 'is the n-pentyl group and in which the OH group in the 15-position has the QL configuration, as well as the physiologically acceptable metal and amine salts of the free acids of the formula I. .

The invention also relates to a process for the preparation of cyclobutane derivatives of the formula I _1, characterized in that

a) the connection of the formal II

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HO ,.

II

in the presence of an aliphatic alcohol of the formula

R ₃ -OH

III

where R- is an alkyl radical with 1-5 C atoms, treated in a reaction stage first with ozone and then with an acid, an ester of the formula

9R3

IV

--CO ₂ R ₃

wherein R _{3 has} the meaning given for formula III, is formed,

b) the ester of the formula IV in the presence of a base to give the ester of the formula

where Rj has the meaning given for formula III, besieged,

c) the ester of the formula V to form an aldehyde of the formula

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\ I

\ I.

\ I.

VI

CHO

wherein R _{3 has} the meaning given for formula III, reduced, or

b ') the ester of the formula IV to form an aldehyde of the formula

"'""" - OR ₃

ι /

VII

⁴ CHO

wherein R _{3 has} the meaning given for formula III, reduced or

b ' ¹ ) the ester of the formula IV to an alcohol of the formula

OR

VIII

wherein R_ has the meaning given for formula III, reduced and

b · '·) the alcohol of the formula VIII to an aldehyde of the formula VII oxidized, and

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c. ¹ ) rearranges the aldehyde of the formula VII in the presence of a base into the aldehyde of the formula VI,

d) the aldehyde of the formula VI obtained with a phosphonate of the formula

0
(R ₄ 0) ₂ P ^ Y ^R 2 ix

wherein R _{2 has} the meaning given for formula I and R _{4 is} an undisplayed (C ₁ -C ₄ ) -AlkyIrest,
to a compound of the formula

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st *

y-

wherein R _{2 has} the meaning given for formula I and R _{3 has} the meaning given for formula III,

e) the substituent R _{3 is} split off in a compound of the formula ..X under acidic conditions, a lactol of the formula

OH

XI

wherein R _{2 has} the meaning given for formula I, arises,

f) the lactol of formula XC to a compound of Formula ""

XIl

wherein R _{2 has} the meaning given for formula I, reduced or
e ') the ketone of the formula .X to an alcohol of the formula

OR,

XIII

wherein R _{2 has} the meaning given for formula I and R _{3 has} the meaning given for formula III, reduced, and

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/ 6

f'J splits off the substituent R ₃ in a compound of the formula XIIE under acidic conditions, a compound of the formula XU being formed,

g) the lactol of the formula XII obtained in the presence of a base with an ylid of the formula

(R ₅ J ₃ P = CH- (CH ₂ J ₃ -CO ₂ Me XIV

wherein the substituents R _{5 can be the} same or different and represent straight-chain (C ₁ -C ₄ ) -alkyl radicals or phenyl radicals and Me is an alkali metal atom, converts to a compound of the formula I and optionally the esters or the physiologically acceptable metal or is amine salts of the free acid.

The following substituents are preferred; Of the _{meanings mentioned for R 1} : hydrogen, (C ^ -C ^ ₂ ) -alkyl radicals, preferably straight-chain (C ₁ -C ₁₂ ) -alkyl radicals, also cycloalkyl radicals with 5-7 C atoms and aralkyl radicals with 7-9 C- Atoms, preferably the benzyl radical; Particularly preferred substituents are straight-chain (C ₁ -Cg) -alkyl radicals and the isopropyl and isobutyl radicals. *

Of the _{meanings given for R 2} : straight-chain and branched, saturated and unsaturated aliphatic hydrocarbon radicals, in particular alkyl radicals with 4-8 carbon atoms and cycloalkyl radicals with 5-7 carbon atoms. More preferred for R _{2 are} radicals of the formula -C (R ¹ O ₂ -CH ₂ -CR ¹ ", in which R" represents a (C ₁ -C ₃ ) -alkyl radical, with the proviso that the two R "'are different and in which R ^{11f denotes} a (C. | -C ₅ ) -alkyl radical. In particular, the radicals listed below are preferred _{for R 2 : - (CH 3} J ₃ -CH ₃ , -C (CH ₃ ) ₂ ~ (CH ₂ J ₂ -C -CF ₂ - (CH ₂ J ₂ -CH ₃ , -CHF- (CH ₂ J ₃ -CH ₃ , -CF ₂ - (CH ₂ J ₃ -CH ₃ , -CH (CH ₃ J- (CH ₂ J ₃ -CH ₃ , -C (C ₂ H ₅ J ₂ - (CH ₂ J ₃ -CH ₃ , -C (CH ₃ J ₂ -CH ₂ -O-CH ₃ , -C (CH ₃ J ₂ -CH ₂ -O- (CH ₂ J ₂ -CH ₃ , -C (CH ₃ J ₂ -CH ₂ -O-CH ₂ -CH = CH ₂ , -C (CH ₃ J ₂ - (CH ₂ J ₄ -CH ₃ , -CF ₂ - (CH ₂ J ₄ -CH ₃ , -C (CH ₃ J ₂ - (CH ₂ J ₅ -CH ₃ , -CF ₂ - (CH ₂ J ₅ -CH ₃ ,

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The endo-bicyclo / 5,2,07hepten- (2) -ol- (6) of the formula II used as starting compound in the process according to the invention is known and can be obtained by reducing bicyclo / 3 ", 2, o7hepten- (2) - Soc be obtained one (6) / "" HL Drvden, Jr., J. Amer Chem 2i ^"28 4-l (1954);... HL Dryden, Jr., and bE Burgert, J. Amer Chem. Soc., 72, 5633 (1955); MV Evans and RC Lord , J. Amer. Chem. Soc. 83, 3409 (1961); B. Adler , Ch. Showerk , R. Ehrig , G. Esser , H. Kasper and W Pritzkow , Prakt. Chem. 315 , 657 (1973); J. Alberti, R. Siegfried and W. Klrmse , Liebigs Ann. Chem. 1974. 1605-7 In addition to the reduction with aluminum triisopropoxide, which primarily provides the exo product , the reduction with lithium aluminum hydride is preferred. The values given in the literature for the endo / exo ratio vary between 4: 1 and 7: 1. The reduction with sodium borohydride in ethanol at temperatures between -70 ° and +40 ⁰ C, preferably at -10 ° to 0 ⁰ C Lead * ·. günsti still a Geren endo / exo ratio of 8: 1 to 9: 1. (The exo component does not interfere with the subsequent reaction, since it gives rise to products that can easily be separated off by distillation in the next reaction stage).

The bicyclo / 3,2, o7nepten- (2) -ol- (6) (endo / exo approx. 9: 1) is in the absence of moisture in an alcohol of the formula R - OH, such as ethanol, propanol, butanol, but preferably methanol, to which a halogenated hydrocarbon such as, for example, methylene chloride is added, if appropriate, dissolved. In this solution is preferably introduced at -80 ° to -60 ⁰ C, the equivalent amount of ozone at temperatures between -100 ° and -30 ⁰ C,. A small excess of ozone has no effect on the yield. Subsequently, any excess ozone is displaced by an inert gas. To convert the intermediate alkoxy hydroperoxide of the formula

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1-R ₆ (R ₆ = R ₃ or H)

\ 0-R ₃ 'CH
DOH

into an ester of formula IV, the reaction mixture is treated with an alcoholic solution of an acid such as hydrogen chloride or hydrogen bromide, and then slowly to 0 to 100 ⁰ C, preferably ° 50 ° to 70 ⁰ C, warmed (K. Griesbaum and H. Keul, Angew. Chem. 87, 748 (1975)). At the same time, the ketalization of the lactol takes place under these conditions. For purification, the reaction product of the formula IV is distilled.

The epimerization of the all-cis product IV into the ester V can be carried out with alkali _{metal alcoholates of the formula R 3} -O ⁰ Me® (where Me® can be, for example, Na® or K®) in the associated alcohol of the form

R ₃ -OH carry out / DT-OS 25 17 586; N. Finch, LD Vecchia, JJ Fitt, R. Stephani and J. Vlattes, J. Org. Chem. 38, 4412 (1973J7 · ^The base is normally added in concentrations between 0.2 and 1.2 equivalents. The rearrangement occurs at temperatures between 20 ° and 100 ⁰ C, preferably between 50 ° and 70 ⁰ C within 2 to 2u hours.

The compound of the formula V is reduced to an aldehyde of the formula VI with a complex aluminum hydride in an aprotic solvent. Is preferably carried out with Diisobuty! Aluminum hydride in toluene at -60 ° to -70 ⁰ C. If necessary, the aldehyde of the formula VI is purified by column chromatography or distillation.

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/ 9

4t

On the other hand, the ester of the formula IV can also be reduced with a complex aluminum hydride in an aprotic solvent to an aldehyde of the formula VII. Here, too, is preferably carried out with diisobutylaluminium hydride in toluene at -60 ° to -70 ⁰ C. The aldehyde is purified by column chromatography or distillation.

The esters of the formula IV can also be reduced to the alcohols of the formula VIII. Suitable reducing agents include diisobutylaluminum hydride, are suitable in toluene at -60 ⁰ C and -70 ⁰ C, and complex metal hydrides; Of the complex metal hydrides, lithium aluminum hydride is particularly preferred (see VM Micovic and M.LJ. Mihailovic , J. Org. Chem. J_8, 1190 (1953).)

The compounds of the formula VIII are oxidized to give the compounds of the formula VII using oxidizing agents which are customary for the oxidation of aliphatic alcohols to aldehydes. Some of these common methods are described in Houben-Weyl, Vol. 7/1, p. 159. Further suitable oxidizing agents are the complexes formed from thioethers such as dimethyl sulfide or thioanisole with chlorine or N-chlorosuccinimide / EJ Corey, CU. Kim, J. Amer. Chem. Soc. 9 ±, 7586 (1972); EJ Corey, CU. Kim, J. Org. Chem. _38>, 1233 (1973-7- Furthermore, the oxidation with dimethyl sulfoxide can be used under the most varied of conditions / WW Epstein, FW Sweat, Chem. Rev. j57, 247 (1967) _7.

A particularly preferred method is the oxidation with chromium trioxide-pyridine complex (JC Collins, Tetrah. Letters 1968, 3363). In first is prepared deri complex in an inert solvent, preferably methylene chloride, and then added at -10 ° C to +10 ⁰ a solution of alcohol VIII is added. The oxidation is rapid and is usually complete in 5 to 30 minutes.

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The rearrangement of the aldehyde VII to the more stable epimeric aldehyde of the formula VI takes place "at room temperature in the presence of a base which is added in catalytic to equivalent amounts. 5) / EJ Corey and RH Wollenberg . J. Org. Chem. 4 £, 2265 (197527 or 1,5-diazabicyclo / 4,3,07nonen- (5) in concentrations between 0.2 and 1 equivalent (based on the Aldehyde) in a halogenated hydrocarbon such as methylene chloride; or catalytic amounts of an alkali metal alcoholate are used in the associated alcohol. Sodium methoxide in methanol has proven particularly advantageous. The rearrangement time is between 1 and 24 hours. In the case of isomerization with nitrogenous bases, one closes to the

Purification advantageously uses column chromatography; in the case of alkali alcoholate catalysis, after the reaction has ended the alcohol is distilled off in vacuo, the residue in an organic solvent that is not miscible with water, added and the catalyst washed out with water. After the solvent has been distilled off, the aldehyde precipitates Formula VI is usually so pure that cleaning is not necessary.

The implementation of the phosphonates of the formula χχ with the aldehyde VI can be carried out under the usual conditions for the Wittig-Horner-Emmons reaction, for example in ethers at room temperature. The preferred ethers are in Consider diethyl ether, tetrahydrofuran and dirnethoxyethane. A preferred embodiment of the reaction is that an alkali salt of phosphonate with sodium hydride in Dimethoxyethane at room temperature or with n-butyllithium in

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to

Dimethoxyethane prepared at -50 ° to -70 ⁰ C, then added are an aldehyde of formula VI and allowed to react at room temperature for 2 to 6 hours. The reaction product of the formula X is then isolated from the reaction mixture by customary methods and purified by column chromatography.

The phosphonates of the formula ix are either known or can be prepared analogously to known processes / DH Wadworth, O. E. Schupp ,, III, EJ Seus and JA Fo r d, Jr. , J. Org. Chem. 3C >> ⁶⁸ ° (1965); EJ, Corey and GT Kwiatkowski , J. Am. Chem. Soc. 88, 5654 (1966J7 ·

The radical R _{3 is} split off from the compounds of the formula X by gentle acidic hydrolysis using aqueous organic or, better, inorganic acids (for example E. J « _t Corey and R. No yorl, Tetrah. Lett. 1970 , 311). The reaction is promoted by adding a solubilizer such as acetonitrile or dimethoxyethane. A preferred embodiment of the hydrolysis consists in using 0.1N hydrochloric acid in acetonitrile (acetonitrile / water = 2: 1). The reaction temperatures are usually from 0 ° to 50 ⁰ C, preferably at room temperature, and the reaction times are 1-24 hours. The products are often so pure that they can be used directly for the next reaction step. If cleaning is to be carried out, this is advantageously done by column chromatography.

The reduction of the ketone xc to the alcohol xri can be carried out with all reducing agents that allow a selective reduction of a keto group to a hydroxyl group. Preferred reducing agents are complex metal hydrides; particularly advantageous is the use of 2 equivalents to 1 equivalent of diisopropyl ketone of formula XI in toluene at -60 ° to -70 ⁰ C.

The conversion of the compounds of the formula .X into the compounds of the formula xii can also be carried out in the reverse order: ⁶ I ¹ St the reduction of the carbonyl group with

/ 19th

Aluminum triisopropoxide or

complex metal hydrides or 1 equivalent of diisobutylaluminum hydride to 1 equivalent of ketone of the formula X to give compounds of the formula XIII and then the cleavage of the radical R ₃ under acidic conditions to give compounds of the formula xri.

The lactol of the formula xil obtained can, according to Wittig, be reacted with an ylid of the formula Xrv to give a carboxylic acid of the formula I. The preferred embodiment is by R. Greenwald, M. Chavkovsky and EJ Corey, J. Org. Chem. 2_8, have been described in 1128 (I963). The compounds of the formula I can, if appropriate, be converted into physiologically compatible metal and amine salts and esters by customary methods.

The diastereomeric mixtures obtained in the synthesis can, for example, by crystallization of well-crystallizing Derivatives, but in particular with the aid of chromatographic methods, both absorption chromatographic as well as Distribution chromatographic methods come into question, are separated.

The racemates can by known methods, as sje in the Literature given are to be separated into their optical antipodes. The chemical separation method is preferred. So an optically active base can be reacted with the carboxyl group of a compound of formula 1. For example, one can have diastereomers Salts with optically active amines, such as quinine, cinchonidine, brucine, cinchonine, morphine,

1-phenylethylamine, l-kaphthylethylamine, phenyloxynaphthylmethylamine, quinidine, strychnine, basic amino acids such as lysine, arginine, amino acid esters. In a similar way, ester diastereomers can be prepared by esterifying carboxylic acids of the formula I (R ₁ = H) with optically active alcohols such as borneol, menthol, octanol-2. The resulting diastereomeric salts are separated by crystallization and the diastereomeric esters, preferably by chromatographic methods.

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IZ

The compounds according to the invention can be used as medicaments with Antihypertensive and diuretic effects, prophylactic and therapeutic effects in thrombosis, induction of labor Effect, as abortives, contraceptives, as means to inhibit gastric juice secretion and as an agent against gastric ulcers and against asthma. In particular the compounds according to the invention are suitable as contraceptives for use in humans and also for synchronization the heat in various animal species. They can be used as free acids, in the form of their physiologically harmless ones inorganic or organic salts or as esters of aliphatic, cycloaliphatic or araliphatic Alcohols are used. Suitable salts are, for example, benzylammonium, triethylammonium or Tris-hydroxymethyl-aminomethane and morpholine salts as well Alkali salts, preferably the esters of saturated branched or unbranched lower aliphatic alcohols as esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl ester and the benzyl ester.

Acids such as salts or esters can be used in the form of their aqueous solutions or suspensions or as solutions in pharmacological harmless organic solvents such as monohydric or polyhydric alcohols, dimethyl sulfoxide or dimethylformamide, can also be used in the presence of pharmacologically harmless ■ polymer carriers such as polyethylene glycol 400 reach.

The usual galenic infusion or injection solutions and tablets, as well as locally applicable, are used as preparations Preparations such as creams, emulsions, suppositories or aerosols in question. ·

The compounds can be used on their own or together with other pharmacological agents such as diuretics or antidiabetic agents are used.

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The compounds of the formulas IV, V, VI, VII, VIII, X, XI, XII and XIII are new valuable intermediates for the preparation of the compounds of the formula I.

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Example 1:

3-Methoxv-6 ~ methoxycarbonvl-2-oxabicvclo / 5 ' _t 2, (^ heptane; (Ia; 3a, ß; 5a: 6a and Iß: 3a, ß; 5ß; 6ß)

150 mmol bicyclo / 3 ", 2.07heptene -. (2) -ol- (6); (la, 5a, 6a and Iß, 5ß, 6ß) (90%), dissolved in 160 ml of absolute methylene chloride and 75 ml abs. methanol are treated at -65 ° to -70 ⁰ C with ozone until a blue color indicating the end of the reaction. the excess ozone is blown with nitrogen at -70 ⁰ C then removed. the cooled to -70 ⁰ C solution 30 ml of 10N methanolic hydrogen chloride solution are added, then the mixture is warmed carefully to the boiling point of the solvent and this temperature is maintained until the methoxy hydroperoxide has decomposed /, approx. 15-90 minutes; TLC control: silica gel / CHCLj: EtOAc = 75: _{25_7 · After cooling, the mixture is adjusted to Ρ Η} = 5-6 with solid sodium hydrogen carbonate and then with saturated sodium hydrogen carbonate solution, the organic solvent is distilled off in vacuo and the remaining aqueous phase is extracted several times with methylene chloride. The solvent is then distilled off in vacuo and the residue a fractionated Va subjected to vacuum distillation.

Bp. _{0> 1} : 62 ° - 64 ° C

% i = 0.07 (CHCl ₃ : EtOAc = 75:25), R _p2 - 0.4-2, R _p3 = 0.49

(Diisopropyl ether) IR (CH ₂ Cl ₂ ): V = 1730 (C = O) cm " ¹
NMR (CDCl ₃ ): <£ = -CO ₂ CH ₃ 3.66, -O-CH-O- 5.12-5.20,

-0- (Jh 4.40-4.70, 0-CO-CH ₃ 3.28 and 3.33 ppm MS: M ⁺ 186, MI 185

^N CO ₂ CH ₈

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GC: (5m VA steel tube with 4 mm ID; 5 f ° Silicon OV-255 on
Chromosorb G-AW-DMCS; Grain size 80-100 mesh; Isoth.
16O ⁰ C, 60 ml He / min.)
KI: 1774 and 1789

Example 2:

3-methoxv-6-methoxycarbony1-2-OXaDiCVClO ^ T, 2.07heptane; (la; 3a, ß; 5a; 63 and Iß; 3a, ß; 5ß; 6a)

37.3 g (0.2 mol) S-methoxy-ö-methoxycarbonyl ^ -oxabicyclo- / J, 2.07heptane (la; 3a, β; 5a; 6a and Iß; 3a, β; 5ß; 6ß) from example (l) are refluxed for 4 hours in 190 ml of 1.16N methanolic sodium methylate solution (0.22 mol). Then about half of the solvent is distilled off and
the residue is neutralized at 0 ° to -10 ⁰ C with 2 N sulfuric acid (p _H = 7). The methanol still present is completely distilled off in vacuo. The residue is extracted with
Methylene chloride. After evaporation of the solvent, the abovementioned epimeric ester is obtained from the organic phase and is purified by distillation.

GC: (5 m VA steel pipe with 4 mm ID; 5 $ Silicon OV-255 on
Chromosorb G-AVi-DMCS; Grain size 80-100 mesh; Isoth.
160 ⁰ C, 60 ml He / min.)
KI: 1684 and 1722

OCH ₃

¹ ^ CO ₂ CH ₃

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Example 3:

g-methoxy-6-formyl-2-oxabicyclo ^ 3 \ 2, o theptane; (la; 3α, β; 5α; 6a and Iß; 3a, ß; 53; 6ß )

5.58 g (30 mmol) of S-heptane from example (l) are dissolved in 75 ml of abs. Dissolved toluene and ^{treated dropwise at -70 0} C within 2 hours with 73.2 ml (30 mmol) of a 0.458 molar solution of diisobutylaluminum hydride in toluene. After stirring for 10 minutes at -70 ⁰ C., 18 ml of isopropanol and warmed to -20 ⁰ C. Then one adds 7.5 ml of water and allowing the temperature to about 0 ⁰ C to rise. For working up, 15 g of Clarcel DIC filter aid and 35 g of sodium sulfate are stirred in; After stirring for 5 minutes, the mixture is filtered off with suction, the precipitate is washed with methylene chloride and the entire filtrate is concentrated in vacuo. The residue is purified by column chromatography (silica gel; ethyl acetate or diisopropyl ether).

Rp ₁ = 0.81 (ethyl acetate); R _p2 = 0.36 (diisopropyl ether)

IR (CH ₂ Cl ₂ ): V = 2715 (CHO), 1720 (C = O) cm " ¹ N] VIR (CDCl ₃ ): S = -CHO 9.72, -O-OH 4.50-4, 80, -0-CH-O- 5.06-

5.20, -0-CH ₃ 3.26 and 3.33 ppm MS: MI = 155

^N CHO

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Example 4:

3-methoxv-6-fo rmyl L-2-C ) xab icyc Io 5β? , 0 / heptane; (Ια: 3α, β; 5α; 6β and eat? 3α, ß; 6α)

3.9 g (25 mmol) 3-methoxy-6-formyl-2 ~ oxabicyclo / 3 ~, 2, (^ heptane (la; 3a, ß; 5a; 6a and Iß; 3a, P; 5ß; 6ß) from example (3) are dissolved in 50 ml abs. methanol, 0.7 ml added in methanolic sodium methoxide and stirred for 7 hours at room temperature. Then, it is placed at 0 ⁰ C with a little dilute sulfuric acid to p _H = 6-7, the methanol distilled off in vacuo, the residue taken up in ether and dried with sodium sulfate After evaporation of the solvent, the rearranged aldehyde is obtained so pure that it can be used directly for the next reaction step.

Rpi = 0.31, Rp ₂ = 0.43 (isopropyl ether) IR (CH ₂ Cl ₂ ): V '= ² 7! 5 (CHO), 1720 (C = O) cm " ¹ NMR (CDCl ₃ ): ^ = -CHO 9.79, -0-ΟΗ 4.50-4.75, -0-CH-0-5.20-5.30

OCH ₃ 3.29 and 3.40 ppm MS: MI = 155

Λ ⁴

Example 5 ;

3-methoxy-6-hydroxymethyl-2-oxabicyclo / 3,2.07heptane; (la; 3ä., ß; 5d; 6oL; and Iß; 3 <iL, ß; 5ß; 6ß)

1 g (26.4 mmol) of lithium aluminum hydride is dissolved in 50 ml of abs. Di-

o ³

submitted ethyl ether. 9i, 3 α (50 mMqli 3-methoxy-6-carbomethoxy-2

oxabicyclo /3.2.0? heptane (U; 3x, ß; 5 *; 6οί- and 1ß; 3 «t, ß; 5ß; 6ß), dissolved in 20 ml abs. Diethyl ether is now added dropwise with stirring so that the solvent boils under reflux. The mixture is then stirred under reflux for 75 minutes. For work-up, 1 ml of water, then 1 ml of 15% strength sodium hydroxide solution and then 3 ml of water are carefully added at room temperature, the mixture is stirred for 30 minutes and the precipitate is then filtered off with suction through a glass frit. The filtrate is dried over sodium sulfate; after evaporation of the solvent, the desired alcohol is obtained as the residue. Sdp. 79 - 81 ^ο / 0.1 mm
R _p 1 = 0.50, R _F 2 = 0.41 (ethyl acetate)
NMR (CDCl ₃ ): S = OCH_ 3.28 and 3.38, O-CH-0 5.10-5.25,

O-CH * , 6oi- _and d 1ß; 3oc, ß ppm Ο? heptane; MS: M-1 = 157 1.45-4.80 6ß) OCH ₃ DH /3.2. Example 6: ; 5ß; ί χ 3-methoxy-6-formyl-2-oxabicyclo 1*; 3oC, ß; 5 ^

16.6 g (166 mmol) of chromium trioxide are added in portions at room temperature to a stirred solution of 26.8 ml (333 mmol) of pyridine in 275 ml of methylene chloride. The mixture is stirred 20 min. At room temperature, cooled to 0 ⁰ C and a solution of 3.16 g (20 mmol) of 3-methoxy-6-hydroxymethyl-2-oxabicyclo /3.2.0? heptane (1oC; 3et, ß; 5 <x; 6 <x and 1ß; 3 «., ß; 5ß; 6ß) in 40 ml

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Add methylene chloride within 10 minutes. After a further 30 minutes, 150 ml of 2N sulfuric acid are added dropwise with cooling; the The organic phase is separated off and the aqueous phase is extracted 2 with methylene chloride. After drying and evaporation the solvent gives the aldehyde, which is purified by filtration through silica gel (diethyl ether).

The physical data are identical to the product from example 3:

OCH ₃

CHO

, Example 7;

3-Methoxy-6-formyl-2-oxabicyclo- ^ g ', 2, oTheptane? (la; 3a, ß; 5a; 6ß and Iß; 3a, ß; 5ß; 6a)

3.9 g (25 mmol) of 3-methoxy-6-formyl-2-oxabicyclo / 3.2.07-heptane (la; 3a, β; 5a; 6a and Iß; 3a, β; 5ß; 6ß) from example (3) in 50 ml abs. Dissolved methylene chloride, with 3.8 g (25 mmol)

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SO

S-en offset and 15 hours at Room temperature stirred. A further 50 are used for work-up. ml of methylene chloride are added and the methylene chloride phase is washed several times with ice cold water. The organic phase is dried over sodium sulfate and concentrated in vacuo. As a residue the rearranged aldehyde is obtained, which is purified by column chromatography (silica gel, isopropyl ether) *

OCH ₃

\ I

f CHO

Example 8;

3-Methoxv-6 - ^ - oxo- (E) -l-octene-vl (lJ7-2-oxabicyclo / 3 \ 2 _< o7heptane; (la; 5a, ß; 5a; 6ß and Iß; 5a, ß; 5ß ; 6a)

2.22 g (10 mmol) of dimethyl (2-oxoheptyl) phosphonate are dissolved in 25 ml of abs. Dissolved dimethoxyethane and treated with 10 mmol of butyllithium (in hexane) ^{at -70 0 C.} After 15 minutes of stirring, are added thereto at -70 ⁰ C over 10 minutes 1.56 g (10 mmol) of 3-methoxy-6-formyl-2-oxabicyclo / J, 2,07heptan (la; 3a, β; Figure 5a; 6ß and Iß; 3a, ß; 5ß; 6a), dissolved in 20 ml abs. Dimethoxyethane. Further 15 minutes at -70 ⁰ C and 60 minutes at room temperature, stirring is continued. Then, it is found at 0 ⁰ C with 2N acetic acid to p _H. 7 100 ml of diethyl ether are then added and the mixture is dried with sodium sulfate. After evaporation of the solvent, the abovementioned compound is obtained, which is purified by column chromatography / silica gel, isopropyl ether / ethyl acetate (9 * 1.27).

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Rpi ⁼ Ο »69, Rp ₂ ⁼ O» 63 (isopropyl ether: ethyl acetate = 9: 1) IR (CH ₂ Cl ₂ ): V = 1665 (C = O); 1620 (C = C) cm " ¹

TMR (CDCl ₃ ): cf = OCH ₃ 3.28 and 3.38, -O-OH-O-5.15-5.30

0 - (} h 4.40-4.80, -C-CH ₃ 0.87, = CH-CO- 6.00,

C-CH = 6.89 ppm

H-

_{= c} Ji = 16 Hz; J _CH _ _{CH =} = 7 Hz

X = C

Example 9:

3-methoxy-6- / J-OXO- (E) -l-nonen-yl (lj72 (la; 3a, 3; 5a; 6ß and Iß; 3a, 3; 53; 6a)

_f 2, OTheptan

obtained analogously to example (8) by using dimethyl- (2 oxooctyl) phosphonate.

₂ = 0.77 (isopropyl ether: ethyl acetate = 9: 1)

V = 0 »70,
IR (CH ₂ Cl ₂ ): V =

1650 (C = O); 1615 (C = C) cm '

NMR (CDCl ₃ ): cf = OCH ₃ 3.24 and 3.36, -O-CH-0 5.15-5.30,

0- (c 5.45 to 5.70, = CH-C0 5.93, C-CH ₃ 0.86, C-CH = 7.01 ppm

J η-πΉ = 16 Hz ;. J _{nu nu} = 7 Hz

809817/0050

Example 10;

g-Methoxy-6 - ^ - oxo- (E) "l-decen-yl (l27--2-Qxa" bicyclo ^ _> 2, O / heptane; (la; 3a, ß ; 5a; 6ß and Iß; 3a , ß; 5ß; 6a)

is obtained analogously to example (s) by using dimethyl (2-oxononyl) phosphonate.

% i = Ο »76, Rp ₂ = Oj81 (isopropyl ether i ethyl acetate = 9: 1)

IR (CH ₂ Cl ₂ )! V "=

¹⁶⁶ 5 (C = O); 1625 (C = C) cm

I ¹ JMR (CDCl ₈ >: I = OCH ₃ 3.25 and 3.37, -Q-CH-O- 5.15-5.30,

0- (Jh 4 * 45-4.75, C-CH ₃ 0.86, = CH «-CO- 5.94, C-CH = 7 j 02 ppm

^J CH-CH = = ^{7 Hz}

Example "11s

) -l «-oct3n

(ία; 3a _v ß; 5ag 6g and Ißg 3 _u a * ß

is obtained analogously to example (β) by using. oxo-3 s 3 = dimethyl (heptyl) phosphonate β

Rp ₁ - 0.71p R _p2 - 0.67 IR (CH ₂ CIg) S 17 = 1675 (C * ( _l3 ) s I- OCI ^ 3 _ΰ 31

1620 (C = C) om *

Al ™ 16 Hs ₉ " J _n? V

S0Si17 / i0Si

1 l

JZ

OCH,

Example 12;

3-methoxy-6 ~ / 3'-oxo-4-methvl-4-ethvl- '(E) -l-octene-vl ( l_) 7-2-oxa- · Mcyclo / T, 2, oilheptane; (la; 3a, ß; 5a; 6ß and Iß; 3a, ß; 5ß; 6a)

is obtained analogously to Example (8) by using dimethyl (2-oxo-3-methyl-3-ethyl-heptyl) phosphonate.

Rpi = 0.70, Rp ₂ = 0.75 (isopropyl ether)

IR (CfI ₂ Cl ₂ ): V = ¹⁶ ? 0 (C = O); 1625 (C = C) cm "

NI-IR (CDCl ₃ ): ί = OCH ₃ 3.31 and 3.42, -0-CH-O- 5.20-5.35,

-O-OH 4.50-4.80, -CO- (J-CH ₃ 1.11, C-CH ₃ 0.87, = CH-CO- 6.02-6.46, C-CH = 6 , 80-7.13 ppm

-1

-C = C

= 16 Hz

CH,

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Example 13.i

3 -Methoxy-6- ^ 3'-oxo-3-cyclohexyl- (E) -l-propen-yl (l27-2-oxabicyclo _J / 3 '_>2.07heptane;(la; 3a, ß; 5a; 6ß and Iß; 3a.ß; 5ß; 6a)

is obtained analogously to Example (8) by using dimethyl (2-oxo-2-cyclohexyl-ethyl) phosphonate.

% i ⁼ 0.53, Rp ₂ = 0.61 (isopropyl ether)

IR (CH ₂ Cl ₂ ): Y = 1665 (C = O); 1625 (C = C) cm "" ¹

NMR (CDCl ₃ ): <£ = OCH ₃ 3.22 and 3.41, -O-CH-O- 5.20-5.32,

-0- (Jh 4.50-4.80, = CH-CO- 6.09, C-CH = 6.95 ppm

_{= (r} H = 16 Hz, J "= 7 Hz

, C = CT

Example 14:

3-methoxy-6- ^ 3'-oxo-4,4-dimethvl ~ 5-ethoxy- (E) ~ l-penten-yl (1 ^ 7 "

2-oxabicyclo ^ 5 « ₎ 2 _< , o7heptane;

3a ₉ β j 5a ', 6ß and Iß

5ß; 6a)

is obtained analogously to Example (q) through the use of Dimethyloxo-3, 3 ~ dimethyl-4-ethoxy-butyl) ~ phosphonate.

^R p ± ⁼ Os56, Rp ₂ = Oj, 62 (isopropyl ether s ethyl acetate = 9 s IR (CH ₂ Cl ₂ ) SV = 1680 (C = O) 5 1620 (C = C) ¹

i # IR (CDClg) s 6 = -OCH _S 3 _δ 43, -O = CH- ^ O- = 5 ₉ 20 = '5 _g 30 ₉ -

4.80, CH ₃ - ^ - CH ₈ 1.14, "(J-CH ₃ I ₉ H ₀ CO-GHg 3s4O ₉ = CH-CO- 6 ₃ 44 _C C-CH = 7 ₉ 02 ppm

CH-CB =

OCH ₃

Example 15: 3-Hydroxv-6- ^ 3-oxo- (E) -l ~ octen-

, 2.07heptane

(la; 3a, ß; 5a; 6ß and 13; 5 «.3; 53; 6a)

2.52 g (10 mmol) of 3-methoxy-6- / I-oxo- (E) -l-octen ~ yl (17-2-oxa-Mcyclo ^ 3 ~, 2.07heptane (la; 3a, β j 5a; 6ß and Iß; 3a, β; 5ß; 6a) from Example (6) in 20 ml of acetonitrile are mixed with 10 ml of 0.1N hydrochloric acid and stirred for 4 hours at room temperature. It is then neutralized with aqueous sodium bicarbonate solution and extracted several times with methylene chloride. After this Drying with sodium sulfate and evaporation gives the lactol, which is determined by column chromatography (silica gel, chloroform : Ethyl acetate = 75 ϊ 25) is purified.

Rp = 0.25 (chloroform: ethyl acetate = 75 s 25)

IR (CH ₂ Cl ₂ ): Vf = 3300-3500 (OH), 1670 (C = O), 1620 (C = C) cm KMR (CDCl ₈ ): S = O-CH-0 5.70-5, 85, O-9H 4.40-4.75,

C-CH ₃ 0.87, = CH-CO 6.02, C-CH = 6.88 ppm

" ¹

809817/0050

Example 16 .:

5-Hydroxy-6- / 5'-oxo-4-methvl-4-ethereal- (E) "l-octene-vl (l27-2-oxabicyclo _j / 3.2 _t o7heptane; (la; 3a, β ; 5a; 6ß and Iß; 3 «iß; 5ß; 6a)

is obtained analogously to example (15) from the acetal of example (12). Response time: 4 hours

Rpi = 0.50, R _F 2 = 0.44 (isopropyl ether: ethyl acetate = 90:10) IR (CH ₂ Cl ₂ ): \ T = 3550-3550 (OH), 1670 (C = O), 1620 (C = C) cm " ¹ NIiR (CDCl ₃ ): & = O-CH-0 5.65-5.90, O-9H 4.50-4.80,

Olefin 6.00-7.10 ppm

= 16 Hz

Example 17:

3-Hydroxy-6- ^ 3 ~ -oxo-3-cyclohexyl- (E) -l-pr openbicyclo ^ 3 ", 2 _t o7heptane; (lg; 3", ß; 5a; 6ß and Iß; 5a, ß ; 5ß; 6a)

is obtained analogously to example (15) from the acetal of example (12). Response time: 4.5 hours.

Rp = 0.39 (isopropyl ether: ethyl acetate = 90:10) IR (CH ₂ Cl ₂ ): V = 3350-3550 (OH); 1665 (C = O),

1620 (C = C) cm " ¹
NIlR (CDCl ₅ ): <$ = Q-CH-O 5.72-5.88, O-OH 4.50-4.80,

= CH-CO 6.12, C-CH = 6.98 ppm

Vc-C- ^{H β 16 Hz} ' ^J CH-CH = ^{s 7 Hz}

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Example 18:

3-Hydroxv-6- / 5 * -oxo-4.4-dimethyl-5 ~ ethoxy- (E) -l-pentene-2-OXaDiCyClo ^ B ". 2. oTheptane: (la; 3a.ß; 5a; 6ß and Iß; 5a.ß: 5ß; 6a)

is obtained analogously to Example Cl 5) from the acetal of the example (14). Response time: 5 hours

Rp = 0.70 (diethyl ether)

IR (CH ₂ Cl ₂ ): V = 3300-3500 (OH), 1680 (C = O), 1620 (C = C) cm " ¹ KMR (CDCl ₃ ): j = OH 3.90-4.15, O-CH-0 5.70-5.90, 0-ΟΗ 4.60-4.80,

CH ₃ -O-CH ₃ 1.14, CO- (J-CH ₂ 3.41, 0-CH ₈ -C 3.44, 0-C-CH ₃ 1.14, = CH-CO 6.42, C-CH = 7.00 ppm

= 16 Hz, J _CH _ _{CH =} = 8 Hz, J) H

= 7 Hz

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• 3 *

Example 19 t

5-methoxy-6 - ^ - (RS) -hydroxy- (E) -l-octen-yl (l27--2-oxabicyclo- / 5 ~, 2.07heptane; (la; 5a, ß; 5a; 6g and Iß; 5a, ß; 5ß; 6 <x)

2.5 g (10 mmol) 3-methoxy-6- / 3 -oxo- (E) -l-octen-yl (l) 7-2-oxabicyclo / J, 2.07heptane (la; 3a, β ; 5a; 6ß and Iß; 3a, β; 5ß; 6a) are in 20 ml abs. Submitted toluene. At -70 ⁰ C are added dropwise over 10 minutes 10 mmol of diisobutylaluminum hydride (in toluene) and stirred for 15 minutes at -70 ⁰ C to. For working up, sets at -7O ⁰ C 4 ml of isopropanol and then stored at -20 ⁰ C 1.5 ml of water and stirred for 10 minutes at 0 ⁰ C. Then, 50 ml of methylene chloride, 5 g of filter aid Clarcel DIC and drying sodium sulfate after stirring for about 10 minutes, the mixture is filtered off with suction and the filtrate is evaporated in vacuo. The remaining oil is purified by means of column chromatography (silica gel; isopropyl ether: ethyl acetate = 9: 1).

Rp ₁ = 0.47, Rp ₂ = 0.39 (chloroform: ethyl acetate = 75:25)

IR (CH ₂ Cl ₂ ): V = 3350-3550 (OH) cm "" ¹

NMR (CDCl ₃ ): ^ = OCH ₃ 3.30 and 3.40, -0-CH-O- 5.24, O-cJh 4.50-

4.80, 0-CH-C = 3.90 to 4.20, C-CH ₃ 0.88, = CH-C-0

5.28-5.55, C-CH = 5.75 ppm

• V ^C = C- ^H = ^{16 Hz} ' ^J CH-CH = = ^{7 Hz}

809817/0050

Example 20:

3-methoxy-6- ^ Τ- (RS) -hydroxy- (E) -1-nonen-yl (l27-2-oxabicyclo- / 3 ~, 2.07heptane; (Ik; 3α, β; 5a; 6ß and Iß ; 3a, ß; 5ß; 6a)

is obtained analogously to example (19) from the ketone of example (9).

Rp ₁ = 0.44, Rp ₂ = 0.36 (isopropyl ether)

IR (CH ₂ Cl ₂ ): V = 3300-3550 (OH) cm " ¹

NMR (CDCl ₃ ): S = OCH ₃ 3.28 and 3.40, -0-OH-O-5.22-5.30, O- (Jh

4.46-4.75, 0-CH-C = 3.92-4.18, C-CH ₃ 0.90, = CH-C-0 5.30-5.50, C-CH = 5, 72 ppm

Example 21 _?

3-Me ^ QXv-O-ZT- (RS) -hydroxv- (E) -l-decen-vl (127-2-oxaTDicvclo- / 3 ".2.07heptane; (la; 3a, ß: 5a; 6ß and Iß; 3a, ß: 5ß; 6a)

obtained analogously to example (19) from the ketone of example (10)

R _F i = 0.41, Rp ₂ = 0.33 (isopropyl ether)

IR (CH ₂ Cl ₂ ): Y = 3350-3550 (OH) cm " ¹

NIyIR (CDCl ₃ ): <§ = OCH ₃ 3.30 and 3.39, -0-CH-0 5.20-5.28, 0- {h

4.40-4.75, 0-CH-C = 3.92-4.17, C-CH ₃ 0.90,

Olefin 5.30-5.70 ppm

J _r _ _r ^ H = 16 Hz

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OCB

Example .22 ι

3-Meth03cy -6- / J- (R S) -hydroxy-4,4-dimethyl- ( E) -l-octene ~ j 2-oxaMcyclo ^ 3 ~ .2, o7heptane ; (la; 3a_ _y ß? 5a; 6ß and Iß; 3a, ß?

obtained analogously to example (19) from the ketone of example (11)

R _F i = O »55, Rp ₂ = 0.61 (isopropyl ether)

IR (CH ₂ Cl ₂ ): y = 3400-3550 (OH) cm "" ¹

NMR (CDCl ₃ ): j = OCH ₃ 3.32 and 3.43, O-CH-0 5.15-5.35, O- (Jh

4.50-4.80, CH ₃ - (J-CH ₃ 1.24, C-CH ₃ 0.88,
= C-CH-0 3.78, = CH-0-0 5.49 _? C-CH = 5.77 ppm

^{β 15}

CH-CH =

CIL

^Hz '

= CH-CH-0

)H

Example ²³ ;

3 - Hydrοχν-β-ΖΤ- C RS) -hydr oxy ^ -methyl ^ -äthyl- (E) -l-octen-yl (1) 7-

, oTheptane; (1 «; 3a, ß; 5a; 6ß and Iß; 3a , ß; 5ß; 6a)

is obtained analogously to Example (19) from the ketone of Example (.16) by using 2 equivalents of diisobutylaluminum hydride.

" ¹

R _p = 0.75 (ethyl acetate) IR (CH ₂ Cl ₂ ): V = 3300-3500 (OH) cm "NMR (CDCl ₃ ): <£ = Ο-ΟΗ-0 5.70-5.92.0 -ΟΗ 4.50-4.80,

Olefin 5.25-5.80 ppm

J " ^ H = 16 Hz

Example 24;

^ -Hydroxy-6- / 5- (R5) -hydroxy-3-cyclohe3: yl- (E) -l-propen-yl (l) 7-2-OXaIDiCVcIoZT, 2 _t 07heptane; (la; 3 «, ßi 5a; 6ß and Iß; 3a« ß; 5ß; 6a)

is obtained analogously to Example (19) from the ketone of Example (17) by using 2 equivalents of diisobutylaluminum hydride.

Rp ₁ = 0.63, R _F 2 = 0.71 (ethyl acetate) IR (CH ₂ Cl ₂ ): V = 3300-3550 (OH) cm "" ¹ NMR (CDCl ₃ ): S = O-CH-0 5.70-5.90, O- (Jh 4.60-4.80

Olefin 5.28-5.80 ppm

C =

^H = ¹⁶

CH-CH =

Hz

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- izrte

Example 25;

-O-ZT- (RS) -hydro xy ~ 4,4-dim ethyl-5- ethoxy ~ l-penten-yl (1 Tf- ^ , 07he ptan; (la; 3 a.ß; 5a; 6ß and Iß; 3a, ß; 5ß; 6a)

obtained analogously to example (19) from the ketone of example (18)
by using 2 equivalents of diisobutyl aluminum hydride. .

Rp = 0.72 (ethyl acetate)
IR (CH ₂ Cl ₂ ): V ~ = 3300-3550 (OH) cm " ¹

): (J = O-CH-0 5.70-5.90, 0 - (} h 4.50-4.80,

Olefin 5.30-5.90, CH ₃ - (J-CH ₃ 1.14, 0-C-CH ₃ 1.14 ppm

= ¹⁶

^j ch-ch = = ^{7 Hz}

OH

OH

809817 / OOSO

COPV

Example 26;

3-Hydroxv-6 ~ / 3- ( RS) -hydroxy- ( E) -l-octene-vl ( l 27 ~ 2-oxabicyclo-- / 3 \ 2.07he ptane; (la; 3a, β ; 5a; 6ß and Iß; 3a, β; 5ß; 6a)

is obtained analogously to example (15) from the acetal of example (1?).

r _f = 0.67 (ethyl acetate)
IR (CH ₂ Cl ₂ ): Y = 3300-3500 (OH) cm " ¹

Iv [MR (CE) Cl ₃ ): ^ = -0-CH-0 5.70-5.85, Ο-9Η 4.50-4.80, -0-CH-C =

From 3.85 to 4.20, C-CH ₃ 0.87, olefin from 5.28 to 5.90 ppm

ir '

ΓΗ-ΓΗ =

Example 27:

3- Hydroxy - 6 - ^ / 3 "- (RS) -hydroxy- (E) -l-nonen-yl (l27-2-oxa"blcvclon;(la; 3a, ß; 5a; 6S and Iß ; 3a, ß; 5ß; 6a)

obtained analogously to example (15) from the acetal of the example (20 Rp = 0.53 (diethyl ether)

MiR (CDCl ₃ ): £ = -o-CH-O- 5.70, -O- (Jh 4.50-4.80, C-CH ₃ 0.88,

Olefin 5.30-5.90 ppm

= 16 Hz

809817/0050

Copy

Example 28;

5-Hydroxy-6 - [S- (RS) -hydroxy- (E) -1-d ec en-ylζ1 JJ-2-oxab icycIo- / 5 ", 2.o7heptane; (la; 5a, ß; 5a; 6ß and Iß; 3a; ß: 5ß; 6a)

is obtained analogously to example (.15) from the acetal of example (20).

% i = 0 »50; Rp ₂ = 0.39 (diethyl ether) IR (CH ₂ Cl ₂ ): V = 3300-3550 (OH) cm "" ¹

MR (CDCl ₅ ): S = -O-CH-O- 5.70 -5.82, O- (Jh 4.50-4.80,

C-CH ₃ 0 _? 88, olefin 5.30-5.85

J ~ , τ / Ή. = 16 Hz

Example 29, 3-Hydroxy-6- / 5 '- (RS) -hydroxy-4 _< 4-dimethyl- (E) -l-octen-yl (I) 7-2

; (read 5 «» β?. 5a? 6ß _n and Iß? 5 «» 3; 5ß

is obtained analogously to Example (15) from the Aestal of Example (22J

= 0.69,

= 0.78 (ethyl acetate)

IR (CH ₂ Cl ₂ ): V = 3300-3500 (OH) cm '

-1

Example 30 ';

l ~ PIy droxy-2 - / (3-car bohvd roxv- (Z) - 2 ~ hexen-yl (127-3- / 3- (RS) -Hy droxy - (E) -l-octen-yl (l ] 7-cyclobutane: (la; 2a: 3ß and Iß; 2ß; 3a)

0.72 g (30 mmol) of NaH are dissolved in 40 ml of abs. Dimethylsulfoxide presented land 45 minutes for 75 ° to 80 ⁰ C heated. A solution of 4.4 g (10 mmol) of 5-triphenylphosphonium pentanoic acid bromide in 15 ml of abs is then added at room temperature. Add dimethyl sulfoxide, stir for 15 minutes at room temperature and then add dropwise a solution of 2.4 g (10 mmol) 3-hydroxy-6- / 3- (RS) ~ hydroxy- (E) -l-octen-yl (l27- 2-oxabicyclo / 3,2,0 / heptane (Ια; 3α, β; 5α; 6β and Iß; 3α, β; 5β; 6α) in 10 ml of absolute dimethyl sulfoxide at room temperature. After stirring for one hour at room temperature, the Reaction solution on ice, acidified with 2N sulfuric acid and extracted several times with methylene chloride. The organic phases are dried over sodium sulfate and evaporated in vacuo. The oily residue is taken up in diethyl ether for preliminary purification and shaken vigorously with 25-30 ml of 2N sodium carbonate solution ; the ether

809817/0050

264685

Phase is discarded and the aqueous phase, after acidification with 2N sulfuric acid to Ρττ 2, extracted several times with diethyl ether. After drying and evaporation of the solvent, the above-mentioned cyclobutanearboxylic acid is obtained as the residue, which is purified by column chromatography (silica gel, ethyl acetate).

Rp = 0.27 (ethyl acetate)

IR (CH ₂ Cl ₂ ): ^ T = 3100-3500 (OH), 1720 (C = O) cm "N ^ iR (CDCl ₃ ): (S = 0- (Jh 4.20-4.50, 0 -CH-C = 3.88-4.25,

C-CH ₃ 0.90, olefin 5.20-5.85 ppm

-1

example

1-Hydr oxy-2 - ^ '5'-carbohydr oxy- (Z) -2- hexen-yl ( I) JJ-ZJ- ( RS) -hydr oxy-

(· * · ^Α ? ^ ^Α ? 3ß and Iß; 2ß;

is obtained analogously to example (.30). from the lactol of example (27),

Rp = 0.30 (ethyl acetate)

IR (CH ₂ CIg) SV = 3100-3500 (OH) ₉ 1725 (C = O) cm " ¹

HCk

Example 32.

l-Hydroxy-2-ffi-carbohvdroxy- (ζ) -2-hexen-yl ( 1) 7-3- / 3- (RS) -hydroxy - (E) -l-decen-yl (lJ7-cyclobutane; (la; 2a; 3 ß and lfij gß; 3a)

is obtained analogously to example (30) from the lactol of example (28).

Rp = 0.39 (ethyl acetate)

-1

IR (CH ₂ Cl ₂ ): V = 3100-3500 (OH), 1720 (C = O) cm NMR (CDCl ₈ ): I = -O-CH 4.24-4.50, -0-CH-C = 3.90-4.21

C-CH ₃ 0.89, olefin 5.20-5.85 ppm

Example 33 .;

1-Hydroxy- 2- / F-carbohydroxy- (Z) -2-hexen-yl (127-3- / 3 '- (RS ) -hydroxy-4 < 4-dimethyl- (E) -l-octen-yl ( 127-c yclobutane; (la; 2a; 3ß and Iß; 2ß; 3a)

is obtained analogously to example (30) from the lactol of example (29).

R _F = 0.31 (ethyl acetate)

IR (CH ₂ Cl ₂ ) JV = 3100-3550 (OH), 1720 (C = O) cm " ¹

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1-Hydroxy-2 _r / g-carbohydroxy (_Z) »2-hexen-yl (127-3- / 3-jRS) -hydroxy-4,4-dimethyl-5-ethoxy- (E) -l-pentene -yl (l27-c yclo "butane; (1«; 2a; 3ß and Iß .; 2ß; 3a)

is obtained analogously to example (30) from the lactol of example (25).

Rp = 0.25 (ethyl acetate)
IR (CH ₂ Cl ₂ ) SY = 3100-3500 (OH) cm "* ¹

Example 35 g

hydroxy - ^ - cyclohexyl- (gj-l-propen-yl (127-cyclobutane (la; 2ag 3ß and Iß; 2ß; 3a)

is obtained analogously to example (30) from the lactol of example (24).

R _p = Og28 (ethyl acetate)

IR (CHgCl ₂ )? IT = 3100-3500 (OH) cm " ¹ .

HO _n

Example 36;

1-Hydr oxy-2- _J / F-carbohydr oxy- (Z) -2-hexen-yl ( 1J7-3- / 3- (RS) - hydroxy-4-n j.ethyl-4-ethy l- (E) -l-octen-yl (l27 - cyclo "butane;(la;2a; 53 and Iß; 23; 5a)

is obtained analogously to example (30) from the lactol of example (23).

r _f = 0.51 (ethyl acetate)
IR (CH ₂ Cl ₂ ): V "= 5100-5550 (OH) cm"" ¹

HO _n

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Example 37;

l-Hydroxy-2- / 5'-ca rbomethoxy- (Z) -2-hexen-yl (127-5- / 5- (RS) - hydrox y ~ (E) -l- o cten- yl (l27- ^c y ^c l ^o t ^{) U} ^. ^an r. (ΐ ^α ? 2α; Iß and Iß; 2ß; 3 «)

To 3.25 g (10 mmol) of l-hydroxy-2- / S'-carbohydroxy- (Z) -2-hexenyl (lJ7-3- / 3- (RS) -hydroxy- (E) -l-octen- yl (l27-cyclobutane (la; 2a; 3.beta. and Iss; 2SS; 3a) in 50 ml of methylene chloride are added at 0 ⁰ C 40 ml of a 0.5 molar ethereal diazomethane solution and the mixture reaction kept for 30 minutes at 0 ⁰ C, and then The reaction solution is then evaporated in vacuo and the residue is purified by column chromatography (silica gel; chloroform: Ae thy lace tat = 1: 1).

Rp ₁ = 0.60, Rp ₂ = 0.52 (ethyl acetate; chloroform = 1 % 1) IR (CH ₂ Cl ₂ ): Y = 3400-3500 (OH), 1725 (C = O) cm " ¹ MIR ( CDCl ₃ ): S = OCH ₃ 3.63, 0- <Jh 4.25-4.50, -0-CH-C = 3.85-4.15,

C-CH ₃ 0.90, olefin 5.30-5.85 ppm

CO ₂ CH ₃

Example 38 p

1-Hydroxy-2- / F-carbomethoxy- ° (Z) -2-hexen-yl (1 j7 ~ 3 - / 5- (RS) hydroxy- (. E) -l-nonen-yl (l) 7 -cyclobutane; (la; 2a · _? 3ß and

is obtained analogously to example (37-) from the carboxylic acid of example (31).

809817 / OOSO

= 0.57, Rp ₂ = 0.48 (ethyl acetate: chloroform = 1: 1)

" ¹

IR (CH ₂ Cl ₂ ): V = 3350-3550 (OH), 1720 (C = O) cm NMR (CDCl ₃ ): S = OCH ₃ 3.64, - (J-CH ₃ 0, .90, 0 - <Jh 4.25 - 4.45,

0-CH-C = 3.90-4.15, olefin 5.20-5.85 ppm

CO ₂ CH ₃

Example 39.:

.l- Hydr oxv-2 - / ^ - car "bometho xy- (Z) -2-hexen-y l (lj7-3- / 3 '- (RS) - hydroxy - (B) -l-de cen- yl (l2 7-cy clobutane ; (la; 2a ; 3ß and Iß; 2ß; 3a)

is obtained analogously to example (37) from the carboxylic acid of example (32).

Rpi = 0.59, Rp ₂ = 0.52 (chloroform: ethyl acetate = 1: 1) IR (CH ₂ Cl ₂ ): V = 3400-3550 (OH), 1725 (C = O) cm "* ¹ IMR ( CDCl ₃ ): <£ = OCH ₃ 3.64, -0- (Jh 4.20 - 4.50,

-0-CH-C = 3.85-4.20, C-CH ₃ 0.89,

Olefin 5.20-5.85 ppm

CO ₂ CH ₃

809817/0050

Example 40. ι

- (Z) -2-hexen-yl ( 1) 7-3- / 3- (RS) -

hydroxy-4t4-dimethyl- (E) -l-octen-yl (l) 7-eyclobutane; (la; 2a; 3ß and Iß; 2ß; 3a)

is obtained analogously to example (37) from the carboxylic acid of the example (33).

Rpi - °> 55, Rp ₂ = 0.63 (chloroform: ethyl acetate = 1: 1) IR (CH ₂ Cl ₂ ) SV = 3350-3500 (OH), 1725 (C = O) cm " ¹ ):« f = OCH ₃ 3.64, D-OK 4.25-4.50, = C-CH-0 3.75,

CH ₃ - (J-CH ₃ 1.24, C-CH ₃ 0.88, olefin 5.20-5.85 ppm

H0 _K

Example 41-:

l-Hvdrox y-2- _J / 6 * -carbomethoxv- (Z) -2-hexen-yl (lj i 7-3- / 3 '- (RS) - hydr oxy-4 <4-dimethyl-5- eth oxy- (B) -l-penten-yl (l_27 ~ cyclobutane; (Ig ^ 2g; 3ß and Iß; 2ß; 3 «)

is obtained analogously to example (37) from the carboxylic acid of the example (34).

Rpi = O »55, Rp ₂ = 0.61 (chloroform: ethyl acetate = 1: 1) IR (CHgCl ₂ ): V = 3350-3500 (OH), 1725 (C = O) cm" ¹ KMR (CDCl ₃ : ) ^ = OCH ₃ 3 ₉ 65 _S O-OH 4.25 "4 ₉ 5O, = C-CH-0 3.80-3.95"

C '

CC-CHg-O 3.25 and 3g34, CH ₃ -C-CH ₃ 0.89, C

-C 3ρ 4-S ₉ 0-C-CH ₃ 1.20, olefin 5.30-5.90 ppm

J _n = 9 Hz, J _{PH PR} = 7 Hz

CO ₂ CH ₃

Example 4 2:

l-Hydroxy-2- / g-ca rbomethoxy- (Z) -2-hexen-yl (1) 7-3- _j / 3- (RS) -hydroxy-3-cyclohexyl- (E) -1-propene - yl (l_ ) 7-cyclobutane; (la; 2a; 3ß and Iß; 2 ß; 3 «)

is obtained analogously to example (.37) from the carboxylic acid of the example (35).

Rp ₁ = 0.49, Rp ₂ = 0.55 (chloroform: ethyl acetate = 1: 1) IR (CH ₂ Cl ₂ ): V = 3350-3500 (OH), 1720 (C = O) cm " ¹ Nm ( CDCl ₃ ): S = OCH ₃ 3.64, O-iJh 4.20-4.50,

Olefin 5.20-5.80 ppm

HO,

809817/0050

In particular, compounds of the formula I which have the radicals listed below _{for R 1} and R _{2 can also be prepared by the same process.} (Of course, in this way, not only the esters, but also the acids and their physiologically compatible amine and metal salts are accessible):

^R 1 Methyl- ^R 2 809817/0010 n-hexyl - _(CH2) 3-CH3 Ethyl- Il Benzyl -C (CH ₃ ) ₂ - (CH ₂ ) ₂ -CH ₃ Methyl ' Il Methyl- -CF ₂ - (CH ₂ ) 2 "CH ₃ n-hexyl -CF ₂ - (CH ₂ ) 3-CH ₃ n-dodecyl I) Benzyl- Il Methyl- Il Benzyl -C (CH ₃ J ₂ - (CH ₂ ) ₄ -CH ₃ Cyclohexyl Il Methyl- Il n-hexyl -C (CH ₃ ) 2-CH ₂ -O-CH ₂ -CH ₂ -CH ₃ Il

^R 1 Methyl- R ₂ Cyclohexyl -C (CH ₃ ) 2-CH ₂ -O-CH ₂ -CH = CH ₂ Methyl- Il Cyclohexyl C (C ₂ H ₅ ) ₂ - (CH ₂ J ₃ -CH ₃ Benzyl 11 Methyl - Il n-hexyl -CF ₂ - (CH ₂ ) ₄ -CH ₃ Cyclohexyl Il n-dodecyl Il Methyl- Il Cyclohexyl -CH (CH ₃ ) - (CH ₂ ) 3-CH ₃ Benzyl- ■ I Il

809817/0050

Claims (6)

HOE 76 / P 246 Patent to s ρ r ü c h e J compounds of formula I. CO ₂ Ri where mean: R _{1 is} hydrogen, a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-12 carbon atoms or a cycloaliphatic hydrocarbon radical with 4-7 carbon atoms or an araliphatic hydrocarbon radical with 7-9 carbon atoms R _{2 is} a straight-chain or branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-10 carbon atoms, which in turn can be substituted by a cycloalkyl radical with 3-7 carbon atoms or by a straight-chain or branched alkoxy or alkenyloxy radical with 1-5 Carbon atoms, a cycloalkyl radical with 3-7 carbon atoms, which in turn is replaced by one or more alkyl groups with 1-3 carbon atoms can be substituted, with the exception of the compound of the formula I in which R _{1 is} hydrogen and R _{2 is} the n-pentyl group and in which the OH group in the 15-position has the QL configuration, as well as the physiologically acceptable metal and amine salts of the free acids of the formula I. . 809817/0050 -W- HOE 76 / P 246 2. Process for the preparation of a compound of the formula I, characterized in that a compound of the formula XII in the presence of a base with an ylide of the formula (R ₅ ) ₃ P = CH- (CH ₂ ) , Me XEV, in which the substituents R_ can be identical or different and straight-chain (C ₁ -C.) - alkyl radicals or phenyl radicals and Me is an alkali metal, converts and optionally represents the ester or a physiologically acceptable metal or amine salt of the free acid. 3. The method according to claim 2, characterized in that for the preparation of a compound of formula XI a) the compound of formula II HO, II in the presence of an aliphatic alcohol of the formula 009817/0050 HOE 76 / F 246 R ₃ -OIl III where R ^ is an alkyl tri-st with 1 - 5 carbon atoms, in a reaction study first with ozone and then treated with an acid, taking a kster of the formula IV --- CO ₂ R ₃ wherein R _{3 has} the meaning given for formula III, is formed, b) the ester of formula IV in the presence of a base to the Ester of the formula wherein R _{3 has} the meaning given for formula III, rearranged, c) the ester of the formula V to an aldehyde of the formula in which R _{2 has} the meaning given for formula I and R _{3 has} the meaning given for formula III, b ') the ester of the formula LV to form an aldehyde of the formula VII HOE 76 / F 246 wherein R _{3 has} the meaning given for formula III, reduced or b ¹ ') the ester of the formula IV to an alcohol of the formula OR 1 I. viii CH ₂ -OH
wherein R-. has the meaning given for formula III, reduced and b ¹¹¹ ) oxidizes the alcohol of the formula VIII to an aldehyde of the formula VII, and c ') the aldehyde of the formula VlI in the presence of a base in the Aldehyde of formula VI rearranged, d) the aldehyde of the formula VI obtained with a phosphonate of the formula 0
^ ^R 2 "IX in which R _{2 has} the meaning given for the formula I and R _{4 is} an undisplayed (C ₁ -C ₄ ) -Alky! radical, to a compound of the formula e) splitting off the substituent R ₃ in a compound of the formula IX under acidic conditions, a lactol of the formula 609817/0060 OH HOE 76 / Ρ XI is formed f) the lactol of the formula X is reduced, or e ¹ ) the ketone of the formula XI to an alcohol · of the formula XIII wherein 1 * 2 those for formula I and R, those for formula III mentioned -Have meaning reduced and f) the substituent R-> in a compound of the formula XIIt under acidic conditions. 4. Compounds of the formula IV wherein R- is an alkyl radical with 1-5 carbon atoms. 009817/0050 5. Compounds of the formula V ' HOE 76 / P wherein R _{3 has} the meaning given for formula IV. 6. Compounds of the formula 9R ₃ VI ^r CHO wherein R_ has the meaning given for formula IV. 7. Compounds of the formula OR, VII ¹ CHO wherein R_ has the meaning given for formula IV. 309817 / Ö050 HOE 76 / P 8. Compounds of the formula OR VIII GH ₂ -OH wherein R _{3 has} ^the meaning given for formula III. 9. Compounds of the formula . ι wherein R- those for formula I and R .. those for formula IV mentioned Has meaning. 10. Compounds of the formula OH Xl wherein R has the meaning given for formula I. 809817/0050 HOE 76 / F 246 11. Compounds of the formula XIl in which R "has the meaning given for formula I. . Compounds of the formula XIIl wherein R _{2 has} the meaning given for formula I and R_ has the meaning given for formula IV. 13. Process for the production of pharmaceuticals, characterized in that that a compound of the formula I mentioned in claim 1, optionally with conventional pharmaceutical Carriers and / or stabilizers, brings into a therapeutically suitable application form. 14 · Medicines, characterized by a content of a compound of the claim ·! mentioned formula I or consisting from such a connection. 15. Use of a compound of the formula mentioned in claim 1 I in pharmaceuticals or as pharmaceuticals. 809817/0050