DD216932A5 - PROCESS FOR PREPARING NEW 7-OXABICYCLOHEPTAN-SUBSTITUTED PROSTAGLANDIN ANALOGS - Google Patents

Abstract

The invention provides a process for the preparation of novel 7-oxabicycloheptane-substituted prostaglandin analogues of the formula I in which B is an oxygen atom (-O-) or a group of the formula - (O) n -formula -S-, where n is a value from 0 to 2, R represents a hydrogen atom, a lower alkyl group, an alkali metal atom or a trihydroxymethylaminomethane group, R 1 represents an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkinyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkynyl group A represents a group of the formula -CHCH- or - (CH 2) 2 -, n has a value of 1 to 4 and m has a value of 1 to 8, and all stereoisomers thereof. The compounds are cardiovascular agents, which are z. B. suitable for the treatment of thrombolytic diseases. Formula I

Description

Process for the preparation of novel 7-oxabicycloheptane-substituted prostaglandin analogs.

Field of application of the invention:

The application of the present invention is in the field of drugs, in particular for the treatment of cardiovascular diseases.

Object of the invention:

The aim of the invention is to provide new medicaments which are suitable for the treatment of cardiac and circulatory diseases, for example of thrombolytic disease states.

²⁵ Explanation of the essence of the invention:

The invention has for its object to provide drugs that are effective in the treatment of cardiovascular diseases.

The invention thus provides a process for the preparation of 7-Qxabicycloheptan-substituted prostaglandin analogues of general formula I.

ι and all stereoisomers thereof, wherein A is one of the groups -CH = CH- or - (CH ^) o ~, B is an oxygen atom (-O) or a group of the formula -S-, n ^{1 is} a value of O to 2 has,

¹ ti

(O) _n ,

m is 1 to 8 and η is 1 to M- , R is hydrogen, alkyl, alkali metal or tris (hydroxymethyl) aminomethane group

Λ · "'

and R indicates an alkyl -r, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, Aralkinyl-, cycloalkyl, cycloalkyl, alkyl, or Cycloalkylalkenyl- Cycloalkylalkinylrest represents, characterized in that a compound of general formula II

^ -CH ₀ -A- (CHJ -CO.alkyl

'. 'Ii'''

in a manner known per se by reaction with a

1 bond of the formula R -OH od <

²⁰ thioethers is converted.

Λ Ί bond of the formula R -OH or R-SH in an ether or

The invention also relates to said process with the particularity that the radical B represents an oxygen atom (-O-). , , , ...

The invention further relates to said process with the particularity that the radical B is a sulfur atom (-S-) ... '.'

The invention further relates to the aforementioned method with the particularity that the radical A indicates the group -CH = CH- loading ^l. ...-. ''

The invention further relates to said method with. the special feature that the radical R is a hydrogen atom.

The invention further relates to said method with the special feature that η has the value 1.

The invention further relates to the said method with the special feature that the remainder η has the value * 2.

The invention further relates to said method with the particularity that the remainder η has the value 3 or 4 ·.

The invention further relates to said method with the particularity that the radical A is the group -CH = CH-, m is a value of 2 to 4 and η is 1 or 2, the radical R is a hydrogen atom and the radical R is

a lower alkyl or cycloalkyl radical.

, '' '. , ''

The invention further relates to said method with the particularity that the radical A is the group -CH = CH-, m is 3 and η is 1, the radical R is a hydrogen atom, a methyl group or a CgH ^. Group represents and the radical R is a lower alkyl radical. "

The invention further relates to said process with the particularity that one of the following compounds is prepared:

/2.2ii7 ⁿ ept-2-yl7-5-heptenoic acid and its hexyl ester, / Tβ, 2ok (5Z), 3 ^, 4β7-7-Z3- / 2- (pentyloxy) -ethyl7-7cyclo ^ / 2.2. i7hept-2-yl7-5-heptenoic acid, / Tβ, 2 Λ (5Z), 3 * *, ßβ7-7- r3-hienylpropoxy) -methyl7-7-oxabicyclo .2.i / hept-2 yl / -5-heptenoic acid,

A & , 2 ot (5Z), 3 ot, ^ - ß7-7-Z5- ^ octyloxy) -methyl7-7-oxabicyclo /2.2.i7hept-2-yl7-5-heptenoic acid,

, 5 O, 4β / -7-yf 3 - (cyclohexylmethoxy) -methyl 7-7-

_Γ ·. - _ - 4 -. Π

^/ 1 The invention further relates to said method with _v the peculiarity that the radical A is the group -CH = CH-, m is 3 and η is 1, n ^{1 is} the value

1 and the radical R is a lower alkyl radical.

, , · '-' -

The invention further relates to said method with the particularity that the radical A is the group -CH = CH-, m is 3 and η is 1, h ^{1 is} the value

2 and the radical R represents a lower alkyl radical. 10

Finally, the invention relates to said process with the particularity that one of the following compounds is prepared: / ⁵ Ta, 2 oc (5Z), 3 ot ', 4β7-7 - ^ - rHexylthio) -methy ^ -y-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid or its methyl ester, / Tβ, 2 ot- (5Z), 3 <*., 4β7-7rZ3-ZrHexylsulf inyl) -methylJ-7-oxabicyclo / 2.2.'i / hept -2-yl / -5-heptenoic acid or its methyl ester,. · ','. / Tβ, 2 oc (5Z), 3 <K , 4β7-7- / 3-ZrHexylsulfonyl) -methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-7-heptenoic acid or its methyl ester,

/ iβ, 2λ (5ζ), 3 ^, W-7- / 5-ZZ ^ ^c y ^clohex y ^lmeth y ¹ ) ^ ^thi 27-methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid or their methyl ester,

_i / ISS ^3, 2 <A- (5Z), 3o _<k, A-SS7-7-Z3-ZZr2-phenylethyl) -thio7-methyl7-7-oxabicycl9 ^ 5-heptenoic acid 2.2.i7hept-2-yl7- " or your methyl ester,

/ Tβ, 2 <x. (5Z), 3 Λ, ^^ - ^ - ZZ ^ -phenylpropyl) -thio7-methylZ ^ -oxabicycloZ? .2.i7hept-2-yl7-5-heptenoic acid or

30 you. Methylester.

 L '. , , , '·. J

The invention relates to a process for the preparation of 7-oxabicycloheptane-substituted prostaglandin analogs, which are valuable drugs with effect on the cardiovascular system and are suitable, for example, for the treatment of thrombolytic disorders. The compounds have the general formula I.

CH, -A- (CH,) -COOR 2 2 Ul

(CH,) -B-R ζ η

CD 1.

and; include all stereoisomers thereof in which A represents a group of the formula -CH = GH- or - (CH ₂ ) ₂ -, B represents an oxygen atom (-O-) or a group of the formula -S-, wherein

η ^{1 has} a value of 0 to 2, m has a value of 1 to 8, η has a value of 1 to 4, R is a hydrogen atom, an alkyl radical, an alkali metal atom or a tris (hydroxymethyl) aminomethane group, and ί? represents an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkinyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl radical.

The terms "lower alkyl" or "alkyl" mean both unbranched and branched radicals having up to 12, preferably 1 to 8 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, Isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,

2,2,4 ~ trimethylpentyl, nonyl, decyl, undecyl and dodecyl, as well as their various branched chain isomers. These also include radicals with halogen substituents, such as fluorine, bromine, chlorine, iodine or trifluoromethyl

L '; , .J

substituents, alkoxy, haloaryl, cycloalkyl (i.e., cycloalkylylalkyl) or alkylcycloalkyl substituents.

The terms "alkenyl" and "alkynyl" refer to similar hydrocarbon radicals having a carbon-carbon double or triple bond, such as the 2-propenyl, 2-hexenyl, 3-hexenyl or 3-hexynyl group ^ or EaIl in an aryl substituent or cycloalkyl substituents as described below, a J-phenyl ^ -propenyl-, ^3-I> henyi-2-proplnyl-, J-cyclohexyl ^ -propenyl- and 3-cyclohexyl-2-propynyl group.. .

The term "cycloalkyl" includes saturated cyclic hydrocarbon radicals having 3 to 12, preferably 3 to 8 carbon atoms. These include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl groups, where each of these radicals may be substituted by 1 or 2 halogen atoms, Λ or 2 lower alkyl radicals and / or lower alkoxy radicals.

2 NC

The term "aryl" or "Ar" refers to monocyclic or bicyclic aromatic radicals having 6 to 10 carbon atoms in the ring moiety, such as the phenyl, capthyl, substituted Phe -.-. nyl or substituted naphthyl group, wherein the substituent on the phenyl or naphthyl group is a lower alkyl group, a halogen atom (Cl, Br or P) or a lower alkoxy group

The terms "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" refer to the above-mentioned lower alkyl radicals having an aryl substituent such as a benzyl group. '.

The terms "(CH ₂ ) _m " and "(CH ₂ ) _n " include straight or branched radicals having from 1 to 8 carbon atoms in; of the normal chain in the case of "(CH ₂ ) _m " or 1 to 4 carbon atoms

r '' '·' -? - '· ""

atoms in the normal chain in the case of. "(C ^)". These radicals can also carry one or more lower alkyl radicals as substituents. Examples of the radicals (C ^) and

^Sin . -CH 1 --CH ₂ CH-, - (CH ₂ ) -, - (CH ₂ ) J, - (CH ₂ ) 1 -, - (CH ₂ ) g ·, - (

- (CH -) - CH-, -CH ₉ -CH-, -CH ₉ -CH CH-CH ₉ - and

~ _r ". CH ₁ CH CH

₁₀ -CH ₂ -CH-CH ₂ -CH-.

The compounds of formula I (wherein R is an alkyl radical) are prepared by reacting a compound of formula II ", -A- (CH ₂ ) _B -CO ₂ alkyl

., "OH. (ID

1 Ί with the desired compound R -OH or R SH or an equivalent thereof in a conventional manner to ethers or thioethers produced.

The preparation of ethers and thioethers is based on the Williamson synthesis (J. Chem. Soc., Vol. 4 (1852), p. 229),

also

where ether (later / thioether) was prepared by alkylation of alkoxides with alkyl halides:

R ¹ (O or S) Na + R ¹¹ X -> R '(O or S) R "+ NaX

The modern version of this synthesis uses other leaving groups in addition to the halides. In view of the above formula II, therefore, the etherification or thioether formation comprises the implementation of a compound of

Formula Ila 35

Ha

X in addition to the hydroxyl group may also be a group -SH or a sodium or potassium salt thereof and a chlorine, bromine or iodine atom or an alkyl, aryl or Aralkylsulfonylöxyrest. The implementation is done with a

si

Complementary compound R X, the following types of compounds of formula I are obtained:

_{m is} -CO ₂ alkyl

_a l _kyl

III

IV

The thioethers of the formula IV can then be oxidized to the sulfinyl and sulfonyl derivatives (in formula I, n ^{1 has} the value 1 or 2) with the following formulas:

_m co ₂ alkyi

CH-A- (CH.) -CO-alkyl .2 2 m ^

Il

VI

The compounds of the formula I in which R is an alkali metal or a hydrogen atom (free acid) can then be prepared from the above compounds in which R represents an alkyl radical by conventional basic hydrolysis with sodium or potassium hydroxide to give the sodium or potassium salt and subsequent Acidification to the free acid can be produced.

The etherification is usually carried out by reaction of a compound of formula II with a compound of formula RX in which X represents a chlorine, bromine or iodine atom or a methylsulfonyloxy or toluenesulfonyloxy group. The reaction is carried out in the presence of a strong base such as sodium or potassium hydroxide in a suitable solvent. When carrying out the reaction, a molar excess of the compound RX of from 0.25 mol excess to 5 mol excess is used. Suitable solvents are xylene, tetrahydrofuran, diraethylsulfoxide or dimethylformamide. If X is a bromine or chlorine atom, a phase transfer etherification can be applied, with tetrahydrofuran used as the solvent and a phase transfer agent such BU4NHSO4 or (C ₆ HCCH ₂₎ (CH _5), NHSO ^

becomes. If R ' ^{1 is} an aryl radical, it is advantageous first to react the alcohol group of the compound of the formula II with triphenylphosphine and diethyl azodicarboxylate in solution with an inert solvent such as tetrahydrofuran and then with an R (aryl) -alcohol such as phenol. It is known that the reaction sequence of the alcohol of formula II can be reversed with the compound RX to the etherification by the alcohol of formula II is converted into a compound of formula II, in which the alcoholic group is replaced by another group from group X. Then, this compound is reacted with an R-alcohol or alkoxide to form a product of formula I.

The thioether formation is usually accomplished by first converting an alcohol of formula II to another X derivative of formula II (as indicated above) and then to the thioether with a mercaptan R SH in the presence of a base, or with an alkali metal salt thereof is implemented. -

Oxidation of a sulfide in which n 'is 0 to the sulfinyl or sulfonyl analog in which n ^{1 is} the value

L. , , ''. ''"· · .. ^; · · J

1 or 2, is easily achieved by reaction with sodium periodate in the presence of methanol and tetrahydrofuran. The resulting sulfinyl and sulfonyl derivatives can then be separated by chromatography or other conventional means

5 will be.

The starting compounds of the formula II in which η has the value 'Λ (hydroxymethyl group) are known from US Pat. No. 4,134,3054 and can be obtained by the process described therein. These compounds can be used for the preparation of starting compounds of the formula II, in which η has a value of 2 to 4. For this purpose, the hydroxymethyl group is oxidized via a Collins oxidation to the aldehyde, for example by reacting a compound of formula II with chromium trioxide in pyridine. This produces an intermediate of the formula VII

_m C0 ₂ alkyl.

The aldehyde of formula VII is then reacted via a Wittig reaction using (CgH ₁ O) P = CHOCH, and subsequent

Hydrolysis (n-1) times a homologation sequence followed by reduction of the aldehyde to the alcohol. For this purpose, a reducing agent such as sodium bohydride or sodium cyanoborohydride is used in a solvent such as methanol. The implementation is explained below.

30

ω cn

ω ο

ro

in

funny -Reactib:

-A- (CH ₂ > _ra -CO ₂ alkyl

₂ > _ra CO ₂

OCH.

H ₃ O

) _m C0 ₂ alkyl

repeat

reduction

NaBH.

H -A- (CH) -Cb "alkyl <£ 2 m 2

(CH) -CH ₀ OH 2 η-1 2

Γ. '. - 12 -

The tris (hydroxymethyl) aminomethane salts of the acids of formula I are obtained by reacting a solution of such an acid in an inert solvent such as methanol with tris (hydroxymethyl) aminomethane and then distilling off the solvent.

The compounds of the invention have four centers of asymmetry, as indicated by the asterisks in formula I. Also, all the formulas given above, in which the asterisks are not listed, include all possible stereoisomers of the compounds. All stereoisomers are part of the invention. ·

The various stereoisomeric forms of the compounds of the invention, for example, cis-exo, cis-endo, and all trans-forms and stereoisomeric pairs can be prepared as described in the following embodiments using the starting materials and employing the methods of U.S. Patent 4,143 (54-). Examples of stereoisomers are listed below.

V f ^H 2 ^A - ^(CH 2 V ^CO 2 ^{R r} *

(CH ₂ ) J ₁ -B-

30

(Cis-endo)

35

If

--CH, -A- (CH,) -CO-R

O (CH,) -B-R

(Cis-exo)

--CH ₂ -A- (CH ₂ ) _ra -CO ₂ R (CH ₂ ) _n -BR ^J

O H (trans)

ih

CH ₂ -A- (CH ₂ VCO ₂ R - H

Ό (CH ₂ ) _n -BR ^J

(Trans)

The core of all these connections is drawn as follows for convenience:

However, it should be understood that the core could also be drawn as follows;

, 0

The compounds of the invention are valuable drugs having an effect on the cardiovascular system. They are useful, for example, as inhibitors of platelet aggregation, i. for the treatment of thrombolytic disorders, such as coronary or cerebral thrombosis. They are also selective thromboxane A2 receptor antagonists and synthetase inhibitors and have a vasodilator effect in the treatment of ischemic states of the heart muscle, such as in angina pectoris.

25 find arachidonic acid cyclooxygenase inhibitors.

The invention therefore also relates to the compounds of the formula I for use in the treatment of cardiovascular diseases and medicaments .A content of a compound of the formula I.

The compounds of the invention may be administered orally or parenterally to various mammals suffering from such diseases, for example, cats or dogs. The amount of active substance should be within a dosage range of about Λ to 100, preferably about 1 to 50 and in particular

L ^: ''. ... '- J

from about 2 to 25 mg / kg in a single or in two to four daily divided doses. The active ingredient can be made into formulations such as tablets, capsules, solutions or suspensions containing about 5 to 500 mg per dosage unit of a compound or mixture of compounds of formula I. The active compounds can in the usual way with physiologically acceptable carriers, Hilfssstcffen. Binders, preservatives, stabilizers, flavorings and the like. In addition, various compounds of the invention simultaneously serve as intermediates for the preparation of other compounds.

The examples illustrate the invention. 15 embodiments

Example 1 ,

/ ⁵ TB, 2 oil (5Z), 3% Ot, 4ß7-7- / 3- / rHexyloxy) -methyl / ^ -oxabicyclo / 2.2.i7hept-2-yl / -5-heptenoic acid hexyl ester

A. / ^ ß, 2oC (5Z), 3c3t, ^ ß7--7 - ^ - ( ^H y ^drox y ^metn y ¹ ) -7-oxabicyclo

(a) A mixture of N-acetylpyridinium chloride is prepared by the dropwise addition of 9.6 ml (136 mmol) of acetyl chloride to 5SmI of pyridine. This is mixed with 5.0 g (27 mmol) of (exo) -3- (2-methoxyethyl) -7-oxabicyclo / 2.2.i7heptan-2-methanol dissolved in 5 ml of pyridine. The resulting mixture is stirred at room temperature for 1.5 hours and then poured into brine. The product is extracted with 3 x 200 ml of diethyl ether. The ether extracts are washed with 2 × 400 ml × 5% hydrochloric acid and 1 × 200 ml brine and dried over sodium sulfate. Evaporation gives a yellow oil, which is purified by a short column of silica gel (150 ml) with dichloromethane. Yield: 4.42 g of oil.

(b) A solution of 4.42 g (19.6 mmol) of the oil in 500 ml

 Γ. '' - - - 16 -. '' / .. .. Π

Tetrahydrofuran containing 50 ml of water is mixed with 31.1 g (97.8 iaMo.l) of mercury (II) acetate. The resulting yellow solution is stirred for 10 minutes and then the whole mixture is poured into a solution containing 200 g of potassium iodide in 2 liters of water. Upon shaking, the yellow color disappears and the mixture is extracted with 3 x 500 ml of benzene. The combined benzene extracts are washed with potassium iodide solution and brine and dried over sodium sulfate. Evaporation gives 3.7 S of product which crystallizes on standing in the refrigerator.

'(C) In DimethylsuIfoxid (about CaIciumhydrid dried)' is prepared by dropwise addition of a solution of Natriummethylsulf inylmethid (prepared by heating 300 mg

 15 g of sodium hydride in 60 mL of dimethylsulfoxy at 75 ° C until the evolution of hydrogen ceased) to a solution of 5.32 g (12 mmol) of 4-carboxybutyltriphenylphosphonium bromide in 100 mL of dimethylsulfoxide, a Wittig reagent. After reaching an orange color for more than 10 seconds for the first time, an equivalent amount of base is added to make the ylide. This deep orange solution is then treated with a solution of the product of part (b) in 20 ml of dimethyl sulfoxide and the resulting mixture is stirred at room temperature for 4-5 minutes. Sodabn the reaction is quenched by the addition of 24 mmol of acetic acid and the mixture poured into 300 ml of brine and extracted with 3 x 200 ml of diethyl ether. Evaporation of these extracts yields an oil which is stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide forms in the mixture. This mixture is washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer is saturated with sodium chloride and extracted with diethyl ether. After drying over sodium sulfate and evaporation, 2.43 g of crude product are obtained. The . Mixture is stirred for 24 hours with 10 $ aqueous sodium hydroxide solution and re-isolated by acidification and ether extraction.

L ·. · ^S -. , J

r. , , - 17 -. '"" π

Then wild, the product purified on 500 g of silica gel with a mixture of ethyl acetate and hexane in a ratio of 50:50 as the eluent. 600 mg of acid are obtained, which crystallizes on standing. The product is washed twice

Ethyl acetate and cyclohexane recrystallized. Yield: 320 mg "^ fB, 2 <x (5Z), 3%, W-7 ^ 3-hydroxymethyl) -7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid of melting point 59-63 ° C.

Analysis for ^^^ 22 ° ^ '' ^over * ^: ° ⁶⁶ I ^{11 H 8} »72

found: C 66.06 H 3.79

    ι '

By treatment with diazomethane, the acid is then reverted to the corresponding methyl ester.

B. / ^: Tβ, 2cx (5Z), 3a, β7,7-Z3-ZrHexyloxy) -methyl7-7-oxabic

- cycloZ2 \ 2, i7hept-2-yl7-5-heptenoic acid hexyl ester

A suspension of! 0.56 g of powdered KOH in 15 ml of anhydrous xylene * is heated under reflux and 7 ml of xylene are distilled off. This mixture is then added to a solution of 300 mg (1.12 mmol) of Part A alcohol ester in 10 ml of anhydrous xylene. The resulting mixture is heated to reflux and 9 ml of xylene are distilled off. 1.0 g (5 »6 mmol) of n-hexyl methanesulfonate are added to the resulting mixture, and the resulting mixture is refluxed for 1½ hours. The reaction mixture is then cooled to room temperature and diluted with 60 ml of methylene chloride. The resulting solution is poured into 50 ml of saturated sodium bicarbonate solution. i) The layers are separated and the aqueous phase extracted with 2 χ 60 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and then evaporated under reduced pressure to give 0.9 g of crude product. The crude product is chromatographed on 33.4 g of silica gel 60 with hexane: diethyl ether in a ratio of 5: 1 as the eluent. Yield: 390 mg ($ 83) of hexyl ester title compound.

dung. , , *

Γ. , , -. - 18 - · ν, -

1 B e i s ρ 1 e I 2

/ Iβ, 2 oe (5Z), 3 ot, W-V - ^ - ^ THexyloxy) -methyl7-7-oxabicyclo- [2.2.i7hept-2-yl7-5-heptenoic acid

A solution of 115 mg (0.27 mmol) of the hexyl ester of Example 1 in 12.0 mL of distilled THP and 1.60 mL of H ₂ O is added

under argon as inert gas and with stirring with 2.4-0 ml of 1N aqueous Lithiumhydroxidlosung added. Then the

, Rinsed 40 minutes with argon and stirred at room temperature for 24 hours. At this time, thin-layer chromatographic analysis shows that the reaction is not complete. Another ml of methanol and 1 ml of 1N aqueous lithium hydroxide solution are added. The reaction mixture is stirred for a further 4 hours and then acidified to pH 4 by the addition of 1N hydrochloric acid, and the resulting solution is poured into 25 ml of saturated brine and saturated with solid NaCl The aqueous layer is treated with 4 × 40 ml _/ ethyl acetate The combined ethyl acetate extracts are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give 124 mg crude oil, which is chromatographed on 20.6 g silica gel 60 using 2: 3 hexane: diethyl ether as eluent The mixture is maintained at high vacuum for about 15 hours at room temperature to give 77 nig (84 $) crude title compound acid TLC: silica gel, 8 $ CH , OH / CH ₂ Cl ₂ ; R _f - / 0.74, iodine. \.

Analysis for Ο _2Ο Η ₅ ^ Ο ^: calc .: C 70.97 H 10,12

30. found: C 70.60 Ή 9.89

13

C NMR _(CDCl3 / 15.OmHz) tau 33.4, 22.6, 24.6, 129.4, 130.1, 26.7, 46.4, 79.4, 29.5, 80.1, 46.8, 71.3, 69.8, 31. 7, 23.7, 29.7,

³⁵ 22,6, 14.0.

1 example 5

/2".2.i7hept-2-yl7-5 -heptenoic acid hexyl ester 503 mg (1.88 mmol) → Tβ, 2 oc (5Z), 3 cx, 4β7-7-Z5- (hydroxynethyl> 7-) ox & bicyclO / 2 \ 2.i7hept-2-yl7-5-heptenoic acid methyl ester, prepared according to Example 1, are dissolved in 2.17 ml of tetrahydrofuran and then the solution is washed with 2.17 ml (15.46 mmol) of n-hexylbromide, 173 4 mg (0.51 mmol) of tetrabutylammonium bisulfate (Bu 2 NHSO 2) and 2.17 ml of 50% sodium hydroxide solution are stirred vigorously at room temperature to give a slightly yellowish-brown solution which stirs after about 15 hours a white precipitate forms.

, , '& ,

The reaction mixture is poured into 25 ml of saturated sodium bicarbonate solution. The mixture is extracted with Λ χ 25 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yield: 1272 mg of </ 1>, 2oc (5Z), 3 oc, ^/ », 7-7-Z5-ZrHexyloxy) -methyl7-7-oxabicyclo-Z2.2-i7hept-2-yl7-5-heptenoic acid hexyl ester, The product is chromatographed on 4-0 g of silica gel using hexane: diethyl ether in the ratio 4: 1 as the eluent to the final product.

For s ρ i e 1 4

(1β, 2 (X, 3 c3L, 4β) -7-Z5-ZrHexyloxy) -methyl7-7-oxabicyclo-Z ^ .2 * l7hept-2-yl7-heptanoic acid hexyl ester

A. (1β, 2 oc, 3o

Z ^ * 2 * i7hept-2-yl7-heptanoic methylester

3G 800 mg (3.0 mmol) of r, 2ot (5Z), 3 ", 4ß7-7 ^ 3- (hydroxymethyl) -7-oxabicycloZ2.2i7hept-2-yl7-5-heptenoic acid methyl ester , prepared according to Example 1 and dissolved in'120 ml of ethyl acetate are added under argon as a protective gas with 160 mg 5 $ Pd on carbon. The argon atmosphere is then replaced with a slight excess of hydrogen pressure and the reaction mixture is stirred for 8 hours at 25 ° C. Then

L,. j

 -,

'. ι.

is filtered through a celite disc and evaporated. Yield: 730 mg (90%) of the title compound A.

B. (1ß, 2 5 / ^^.

The procedure of Example 1 is repeated except that the alcohol ester of Part A is used in place of the alcohol ester of Example 1A. It will get the title connection

 .

B e i s ρ i e 1 5

(1β, 2%, 3 %, 4β) -7- £ 3 - / [hexyloxy) -methyl7-7-oxabicyclo- / 2.2. i7: hept-2-yl7-heptanoic acid Example 2 is repeated with the modification that the hexyl ester of Example 4 is used in place of the hexyl ester of Example 1. The title compound is obtained as an oil; / otJiP ⁼ "* ⁵ ' ¹ ^ ⁰ '" ¹ »57» ^CHC1 3) i ^TLC (silica gel, 8% CH ^ OH) CH ₂ Cl ₂ : R _f = 0.74

- ^: Analysis for C ₂ QH ₅₆ O ^: calc .: C 70.55 H 10.66

20 "F .: C 70.30 H 10.70

¹³ CNMR (CDCIg, 1 $ -QMflz) tau 179.1, 33.9, 24.6 / *

27.6, 29.2, 29.3, 29.0, 47.0, 79.1, 29.7,; 29.6, 80.1, 46.4, 71.2, 69.8, 29.3, 25.3,

25 31.6, 22.6, 14.0 -

'Example6.

/ Iβ, 2 oC (5Z), 3β, 4β7-7-Z3-Zr ^Hex ylo ^{:! C} y) -methyl7-7-oxabicyclo- / 2,2,17hept-2-yl7-5-heptenoic acid

The procedure of Examples 3 and 2 is repeated, except, however, that TTβ, 2 oc (5Z), 3β, 4β7-7 £ 3- (hydroxymethyl) -7-oxabicyclo-2,2'i7hept-2-ryl7-5 -propanoic acid methyl ester instead of / Tβ, 2 .gL ( 5Z),> ot, ^/ ^ -β7-7 - ^ - (hydroxymethyl) -7-oxabicyclo- / 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester , The title compound is obtained as an oil. ₍ Analysis for C ₂₀ H ₃ ^ O ₄ : calc .: C 70.97 H 10.12 '

Found: C 70.93 H 10.33

L ''''^; . ^'':: - j

Γ '- 21 - I

¹³ C NMR (CDCl ₃ , 15.OMHz) tau 178.7, 33.4, 24.6,

26.6, 128.7, 129.9, 32.6, 47.9, 79.1, 29.5, 23.8, 80.5, 49.1, 71.7, 7.1.2, 31.6, 25.8, 29.9, 22.6, 13.9

B e i s ρ i e 1 7

/ ⁵ TB 2-ol (5Z)> 3oC, 4ß7-7- / 3 / faetiiylaxy) -methyiy - ^ - oxabicyclo / 5.2.i7hept-2-yl7-5-heptenoic acid;

The procedure of Example 1 and 2 is repeated but using methyl methanesulfonate in place of n-hexyl methanesulfonate. The title compound is obtained as an oil; / H / p ⁵ = +10.4 (C = 2.21, CHCl ₃ ). Analysis for C ₁₅ H ₂₄ O 2: calc .: C 67.14 H 9.01

Found: C 67.03 H 9.14

¹³ C NMR (CDCl ₃ , 15-OMH ₂ ) tau 178.3, 33'.2, 24.4,

25.5, 129.5, 129.8, 26.5, 46.5, 79.1, 29.3, 29.3, 79.9, 46.2, 71.7, 58.6.

20 examples

Λβ, 2 oc (5Z), 3ß, 4ß7-7- / 3- ^ propyl oxy) -methyl7-7-oxabicyclo-

£ 2 . <|. i7hept-2-yl7-5-heptene acid

The procedure of Example 6 is repeated but using n-propyl bromide in place of n-hexyl bromide. It will get the title connection.

Example 9

(1β, 2α, β, 3α, 4β) -7- / 3-butyl oxy) -methylthio-oxabicyclo- / 2, 2,17hept-2-yl7-heptanoic acid

The procedure of Examples 4 and 5 is repeated except that n-butyl methanesulfonate is used instead of n-hexyl methanesulfonate. It will get the title connection.

Pi. '... - 22 - '. , -

1 B e i s ρ i e 1 10.

, / Tβ, 2oc (5Z), 3 oc, β7-7- / 3- / octyloxy) -methyl7-7-oxabicyclo-

/2.2.17hept-2-yl7-5-heptensäure

The procedure of Examples 1 and 2 is repeated except that n-octyl methanesulfonate is used in place of n-hexyl methanesulfonate. It will get the title connection

hold. ^N

Example 11

/ Tβ, 2 oc (5Z), 3 oc, 4β7-7- / 3- / phenylmoxy) -methylj, - ^ -oxabicyclo / 2 \ 2i7hept-2-yl-5-heptenoic acid

(A) A solution of 1 mmol of triphenylphosphine, 1 mmol Diäthylazodicarboxylat and 1 mmol of alcohol title compound A of Example 1 in 25 ml of THF is added 1 mmol of phenol and stirred under argon as a protective gas at 23 ° C for 48 hours. The reaction mixture is then evaporated under reduced pressure. The residue is digested with diethyl ether and the solids are removed. The filtrate ^l is) evaporated under reduced pressure and chromatographed on silica gel. There is the / fiss, 2 <x (5Z), 3oc, ^ ß7- / 3- / rPhenyloxy) -methyl7-7-oxabicyelo / 2.2.i7hept-2-yl7-5-behenoic acid methyl ester. ⁾

(b) The procedure of Example 2 is repeated »using the ester of part (a). It will

²⁵ telverbindung received. '

B e i s ρ i e 1 12

, / ^; TSS, 2oc (5Z), 3.beta. _t W-7- / 3- / rPhenyloxy) -methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid

(A) A solution of 1 mmol of triphenylphosphine, 1 mmol Diisopropylazodicarboxylat and 1 mmol of alcohol title compound A of Example 1 in 25 ml of THF is added 1 mmol of phenol and stirred under argon as a protective gas at 23 ° C for 48 hours. Then the reaction mixture is evaporated under reduced pressure. The residue is digested with diethyl ether and the solids are removed. The filtrate

Γ. ·; -25 - -, Π

is evaporated under reduced pressure and chromatographed on silica gel. There is obtained the ^ Tβ, 2ct (5Z), 3β, W-7- / 5- / r-phenyioxy) -methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester.

(b) The procedure of Example 2 is repeated but using the ester of part (a). It will get the title connection. ₄

B e i s ρ i e 1 13 / Tβ, 2 ot (5Z), 3 (^, ^^^ - / ^ - / ^ thyloxy ^ methyjT ^ -oxabicyclo-

^ S.2.i7hept-2-heptenoic yl7-5

The procedure of Examples 3 and 2 is repeated except that ethyl bromide is used instead of n-hexyl bromide. It will get the title connection. -.

B e i s ρ i e 1 14

/ Tβ, 2 oc, 3 x, 4β7-7- / 5-pyrhenyloxy) -methyl-1-yl-oxabicyclo- / 2,2,17-hept-2-yl-7heptanoic acid

The procedure of Example 11 is repeated except that (1β, 2α,,, 3 xx, 4β) -7- / 5-hydroxy) methyl-7-oxabicyclo- / 2,2-i-hept-2-yl-7heptanoic acid methyl ester is used of the alcohol of part (a) of example 11 is used. It will get the title connection.

B e i s ρ i: e 1 15

/ Ά & , 2 ol (5Z), 3β, A-β7-7- ^ 3- ^ benzyloxy) -methyl_7-7-oxabicyclo / 2.2.17 "nept-2-yl7-5-heptoic acid

Example 6 is repeated except that benzyl bromide is used in place of h-hexyl bromide. It will

³⁰ telverbindung received.

B e i s ρ i e 1 16

(1β, 2OC, 3 <x, 4β) -7- / 3- (benzyloxy) -melyl) 7-7-oxabicyclo- / 2.2.i7hept-2-yl-7heptanoic acid

The procedure of Examples 4 and 5 is repeated except that benzyl methanesulfonate is used instead of n-hexylmethane.

Γ. ' ,> · ....,. - 24 -. ·. ,

sulfonate is used. It will get the title connection. , ,,

B ei ρ i e 1 1? , 3 (X, W-7- / 3- / t-cyclohexyloxy) -methyl7-7-oxabi-

The procedure of Examples 1 and 2 is repeated, but using cyclphexylmethanesulfonate instead of n-hexylmethanesulfonate. It will get the title connection. , _N '. _

Example 18 ex. (5Z), 3β, W-7/3

The procedure of Examples Λ and 2 is repeated except that cyclopentylmethanesulfonate instead of n-hexylmethanesulfonate and / ßββc-. (5Z) ßβ, W-7-55- (hydroxymethyl) -7-oxabicyclo. i / hept ^ -ylJ ^ - ^ - methyl horsäure, prepared according to US-PS % A * $ 05 ^z l-, instead of / fTß, 2 oc (5Z), Yes, -4ß7-7- / 3- ( Hydroxymethyl) -7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester can be used. It will get the title connection.

, , . ' ; , 'l'. '.

Example '19 ^: >

(iβ, 2 cx. _T 3 <x., 4β) -7- / 5- (cyclohexyloxy) -methyl7-7-oxabicyclo- / 2.2.i7hept-2-yl-7heptanoic acid.

The procedure of Examples 4 and 5 is repeated except that cyclohexylmethanesulfonate is used instead of n-hexylmethanesulfonate. It will get the title connection.

'' .., '. 'B e i s ρ i e 1 20

^ Tβ, 2 * (5Z), 3 OL, 4β7-7- / 3- / 2- (hexyloxy) ethyl 7-7-oxabicyclo- / 2.2.i7hept-2-yl7-5-heptenoic acid

Γ - 25 - ''. Π

A. / ^; TSS, 2o <. (5Z), 3cx, W-7-Z3- (2-oxo) -äthyl7-7-oxabicyclo

/2.2.17hept-2-yl7-5-heptensäure-methylester In a dry 100 ml three-necked round bottom flask, 'which is equipped with a stirring bar, 12.9 g (37.7 mmol) of dried methoxymethyltriphenylphosphonium be ((C ₆ Hc) ₃ P ⁺ -CH ₂ OCH ₃ Cl ") and 235 ml of distilled toluene (stored over molecular sieve) The resulting suspension is stirred in an ice bath under argon as a protective gas until it is cold and then dropwise with a 1, A solution of 18.3 ml (28.3 mmol) of potassium tert-amylate in toluene is added to give a bright red solution, which is stirred at ⁰ ° C. for a further 35 minutes, after which it is passed through a dropping funnel over the course of 35 minutes a solution of 4.97 g (18.8 mmol) / Λ & , 2oc (5Z), 3 <x, W-7- / 5-formyl ^ -oxabicyclo ^^. ^ hept ^ -y ^^ - heptenoic acid methyl ester The reaction mixture is then quenched by the addition of 2.3 g (39 mmol) of acetic acid in 5 ml of diethyl ether Reaction mixture immediately turns pale yellow and is immediately poured into 200 ml of saturated ammonium chloride solution and extracted with 4- χ 200 ml of diethyl ether. The combined ether phases are washed with brine, dried over magnesium sulfate and evaporated to a yellow oil in a white crystalline solid (phosphine oxide). The white solid is digested with ethyl acetate and the mother liquor is purified by chromatography on LPS-1 silica gel column. The fractions obtained are:

(A) /Tβ,2oc(5Z),3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,)

(B) / 1ß, 2oc (5Z), 30L, 4ß7-7- / 3- (2-methoxy) -äthendiyl7-7-oxabicyclo _l /2.2.i7hept-2-yl7-5-heptensäure- methyl ester and

(C) / ^: Tβ, 2oc (5Z), 3oc, 4β7-7- / 3- (2,2-dimethoxy) -ethyl-7-oxa

bicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid, methylester.

The compounds (B) and (C) are each treated with trifluoroacetic acid and thereby converted into the compound (A).

r '· .... "- 26 - ,, ·. π

| B. / TSS, 2OL (5Z), 3öL, 4ß7-7- ^ 3 -, (2-hydroxyethyl) -7-oxabicyclo

/2.2.i7hept-2-yl 7-5 -heptenoic acid methyl ester 1.4 g (5 mM) of aldehyde from part A in 50 ml of methanol are treated with 0.19 g (5 mmol) of NaBH 2 in argon as a protective gas at ⁰ ° C. , After stirring for 1 hour at ⁰ ° C, the reaction

quenched to pH 2 by the addition of 2N hydrochloric acid. The methanol is distilled off under reduced pressure and the reaction mixture is taken up in diethyl ether. The ether solution is washed with saturated potassium bicarbonate solution and saturated brine and dried over magnesium sulfate. The ether is evaporated. The title compound B is obtained.

C. flB, 2 <X (.5Z), 3 <X, 4β7-7-Z3-Z2- (hexyloxy) ethyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Example 1 and 2 is repeated except that 'the above alcohol is obtained in part B are used instead of used in example * \ alcohol. It will

obtained the title compound. <

20 · ..- - '' : -

', . '''B ic ρ i el 21

/2.2.i7hept-2-yl7-5-heptensäure

The procedure of Example 20 is repeated except that the / Tβ, 2oc (5Z), 3β _i ^z <-β 7-7 Z ³ -I ¹ ormyl-7-oxabicyclo / 2.2. ^ 7hept-, 2-yl 7-5- methyl ester of heptenoic acid in place of the ^ Tß, 2ö (_ (5Z), - 3 oC, 4ß7-7-Z3-B ¹ ormyl-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenic acid methyl ester It will change the title

received binding.

Be i s ρ i e 1 22

(1β, 2 oc, 3 *, ßβ) -7- / 3α / 2r (hexyloxy) ethyl 7-7-oxabicyclo- / 2,2,17hept-2-yl7-5-heptanoic acid

The procedure of Example 21 is repeated except that the (1ß, 2OL, 3a, ^ ß) -7- / 5-IOrmyl-7-oxabicyclo _{</2.2.i7hept-2-yl7-heptansäure-methylester} instead of / TSS, 2 oc (5Z), 3β _> ^z '-β7

Γ - 27 - Π,

, Second

methyl ester is used. It will get the title connection.

B e i s ρ i e 1 23.

/ Λ & , 2 «, (5Z), 3β, W-7- ^ 3- ^ 2- (phenyloxy) ethyl7-7-oxabicyclo- / 2,2,17hept-2-yl7-5-heptenoic acid

The procedure of Example 11 is repeated, except that the / Τβ, 2 ^ (5Ζ), 3 ot _i 4β7-7 - ^ - 2- (hydroxy) ethyl7-7-oxabicyclOy / 2.2.i7hept-2-yl7- 5-heptenoic acid methyl ester instead . of ^ 1ß, 2oc (5Z), 3 oc, 4ß7-7 - ^ - (hydroxymethyl) -7-oxabicyclo ^ S.2.i7hept-2-yl7-5-heptensäure-methyl ester is used. It will get the title connection.

15 Example 24

/ Tβ, 2 ex (5Z), 3β, 4β7-7-Z3-Z ² - ( ^Phen y ^lox y) ^-äth yi7-7-oxabicyclo-

/2.2.i7hept-2-yl-5-heptenoic acid

The procedure of Example 12 is repeated, but with the ß ^ 2 * c (5Z) 3.beta. ^ SS7-7-Z5 -. ^ - ^(fi y ^{dl> ox} y) - ^eth yi7-7 - oxabicyclo _</ 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester instead of / ^; Tβ, 2oc (5Z) _i 3β _i ^z -β7-7-3- (hydroxymethyl) -7-oxabicyclo- IP- . 2.i7hept-2-yl7-5-heptensäure-methyl ester used

becomes. It will get the title connection.

²⁵ B ile ie 1 25

(1β, 2 ot, 3 a

The procedure of Example 11 is repeated except that the (1β, 2cx, 3α, 4β) -7- / 5α-5-hydroxy) -ethyl7-7-oxabicyclo- ^ S ^. ^ Hept ^ -y ^ - heptanoic acid methyl ester instead of the ^ Tβ, 2cx. (5Z), 3 OL, ^/ <-7,7- ^ - (hydroxy-ethyl) -7-oxabicyclo- ^ 2.2.i7hept-2-yl / -5-heptensäure-methyl ester used becomes. It will get the title connection. ^

Example 26. .

, 3 ^ ^»4 ß7-7- / 5 - / ^ - (benzyloxy) -äthyl7-7-oxabicyclo / 2.2.i7hept-2-heptenoic yl7-5.

The procedure of Example 20 is repeated except that benzyl methanesulfonate is used instead of n-hexyl methanesulfonate. It will get the title connection.

  7 'example. 2?

10 / 2\2.i7hept-2-yl-7-phthalic acid,

The procedure of Example 21 is repeated except that benzyl rethanesulfonate is used in place of n-hexyl methanesulfonate. It will get the title connection. :

* t

15 · B e i s ρ i e 1 28

/ ⁵ TB 2 <x (5Z), 3 OS A-ß7-7- / 5- / 2- (cyclopentyloxy) -äthyl7-7-oxabicycio / 2.2.i7hept-2-yl7-5-heptenoic acid -

The procedure of Example 20 is repeated except that cyclopentylmethanesulfonate is used instead of n-hexylmethanesulfonate.

nat is used. It will get the title connection.

B e i s ρ i e 1 29

/ / fTβ, 20L (5Z), 3cx, 4β7-7- ^ 3- / 2- (cyclohexyloxy) -ethyl7-7-

oxabicycloZ2.2.1_7hept-2-yl7-5-heptensäu3 e?

The procedure of Example 20 is repeated except that cyclohexyl methanesulfonate is used instead of n-hexyl methanesulfonate. It will get the title connection.

, '-. B e i s ρ i e 1 30

/ ^, 2OC (SZ), 3 <x, ^ ß7-7- _< / 3-5- (hexyloxy) -butyl7-7-oxabicyclo- / 2 · i7hept-2-yl-5-hept-acid

A. /Tβ,20L(5Z) .3ot.40β7-7-^3- (5-oxo) -propyl-7-oxabicyclo-

/2.2.i7hept-2^yl7-5-heptensäure_methylester

³ ^ The procedure of Example 20, Part A is repeated except that the TSS ^, 2 "x. (5Z), 3 o ^, 4ß7-7- / 3- (2-oxo) ethyl-7-

Γ - 29 -. Π

r instead of _{</1ß,2<x.(5Z),3oc)} 4: ß7-7- / 5-I ^l ormyl-7-oxabicyclo / 2 \ 2.i7hept-2-yl7-5-heptenoic acid methylesters The title compound A is obtained.

", '...'

B. fTß, 2oc (5Z) _i 5oc _i 4ß7-7- _< / 3- ( ^z l-0xo) -butyl-7-oxabicyclo-

The procedure of Example 20, part A is repeated, except that the aldehyde of the above Part A is replaced by the / Tβ, 2 ol ( 5Z), 3 oC ₁ 4ß7-7- ^ 3-formyl-7-oxabicyclo ^ 2.2.i7hept-2-yl7-5 ~ heptensäure-methyl ester is used.The aldehyde title compound B is obtained.

C./Τβ,2ο<.(5Ζ), 3 cX, 4-β7-7-Z5- (4-hydroxybutyl) -7-oxabicyclo-. The procedure of Example 20, part B is repeated except that the aldehyde-title compound B is substituted for / Tβ, 2 <X (5Z), 3 £ X, ^ ß7-7 - ^ - (2-oxo) -ethyl-7-pxabicyclo / 2.2.47 hept-2-yl7-5-heptensäure-methyl ester is used. The alcohol title compound C is obtained.

D. /Tβ, 2c (5Z), 3, 4, 7, 7, 7, _< / 5- / ^I i ^: - (hexyloxy) -butyl 7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid

The procedure of Examples 1 and 2 is repeated except that the alcohol C obtained above is used instead of the alcohol used in Example 1. It will get the title connection.

Example 31 ³⁰

bicyclo / 2.2. ^

The procedure of Example 3 ° is repeated except that cyclohexylmethanesulfonate is used instead of n-hexylmethane. sulfonate is used. It will hold the title link.

γ,,; '·. - 30 -. , · ·. π

ι. Example 32 '^

£ te, 2 <* (5Z), 3 oc ^ SS7-7-'Z3 "-Z ²ⁱ -. ^(Phen y ^lox .y) - ^but yi7-7 - oxabicyclo

/ 2ί2 .i7hept-2-yl7-5-heptenoic acid

The procedure of Example 11 is repeated except that the / Tβ, 2oc (5Z), 3x, 4β7-7- / 5- (4-hydroxybutyl) -7-oxabicyclo- / 2.2.i7hept-2-yl7~5 methylheptenate instead of Ziss, 2 oc (5Z), 3 0C, 4ß7-7-Z3- (hydroxymethyl) -7-oxabicycloZ2.2i7-hept-2-yl7-5-heptensäure-methyl ester is used. It

the title compound is obtained. .10. '·. '.. ..'

Example 33

/Tβ..2 oil (5Z), 3 <x, 4β7-7-Z5- / ^z f- (benzyloxy) -butyl 7-7-oxabicyclo-

/2.2»i7hept-2-yl7-5-he _N Pentenoic acid.

The procedure of Example 30 is repeated but using benzyl racethanesulfonate in place of n-hexyl methanesulfonate. It will get the title connection.

Example 34

Tris (hydromethyl) aminomethane salt of 20 7- ^ 3- ^ hexyloxy) -methyl7-7-oxabicyclophenic acid ^! ,

A solution of the compound prepared in Example 2 in

Methanol is treated with an equivalent amount of tris (hydromethyl) aminomethane. The solvent is distilled off. The title compound is obtained as a solid of mp 68.5-70 ⁰ C. TLG '(K.eselgel, 8 ^, CH ₃ OHZCH ₂ Cl ₂ ): R _f = 0,? 4.

Ai.alyse for, G ₂₄ H ^ O ₇ N: calc .: C 62.72 H 9.87 N 3.0A-

Found .: C 62.71 H 9.80 N 3.10

· _X B ice ρ ie 1 35

/ ^; 3,2 "5 (5Z), "",<X, B7-7- / 3-Z ² - (pentyloxy) ~ ethyl7-7-oxabi- / 2: 2" i7hept-2-yl7-5-heptenoic acid

α. z ^: Tß, 2o- (53), 3 (x. ', ^ ß7 ~ 7 ~ Z5-Z ² -

A mixture of 0.36 g of powdered KOH in 15 ml of anhydrous:

Xylene is refluxed under argon as protective gas. 8 ml of xylene are distilled off. The mixture is then added to a solution of 200 mg (0.71 mmol) of the alcohol methyl ester of Part B of Example 20 in 17 ml of anhydrous xylene. The volume of the reaction mixture is

* reduced by distilling off xylene by 15 ml. Then the reaction mixture is treated with a solution of 0.5 g (3 * 55 mmol) of pentyl mesylate in 10 ml of anhydrous xylene. This mixture is refluxed for 2 hours and 5 minutes. After cooling, the reaction mixture is diluted with 50 ml of saturated sodium bicarbonate solution and extracted with 3 x 60 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure.

The purification is carried out by flash chromatography on 33 g of silica gel 60 using hexane: diethyl ether in the ratio of 5: 1 as eluent. There are 238 mg ($ 83) pentyl ester title compound of azure-colored oil

receive. TLC: silica gel, hexane: diethyl ether = 1: 1. 20

cyclo ^ 2.2.i7hept-2-heptenoic yl7-5

A solution of 238 mg (0.58 mmol) of Part A pentyl ester, 26 ml of distilled THP, 2.1 ml of CH ₅ OH, and 3.4 ml of H ₂ O is added

under argon as inert gas and while stirring with 6.4 ml of 1N aqueous lithium hydroxide solution. This mixture is rinsed vigorously with argon for 30 minutes and stirred at room temperature for 7 hours. The reaction mixture is then acidified to pH 3 by the addition of 1N hydrochloric acid. The resulting solution is poured into 50 ml of saturated brine and saturated with solid NaCl. The aqueous layer is extracted with 4- χ 60 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is chromatographed on 24 g silica gel 60 using 3 $ methanol in methylene

L ·. , '. , , , J

Γ. , - 32 -. 'πι-, chloride as the eluent chromatographed. Yield: 181 mg (92%) of the pure acid title compound. TLC: silica gel, 4 $ CH ₅ OH / CH ₂ Cl ₂ : R _f = 0.30, vanillin. Analysis for C ₂₀ H ^ 0 ^: calc .: C 70.97 H 10.12 C ₂₀ H ₅₄ O ^ .0.22 H ₂ O: C 70.16 H 10.14

Found .: C 70.16 H 9.87

¹ ImHR , (CDCl ₃ , 15.OMHz) tau 173.5, 33.8, 24.7, 26; 7, 129.5, 130.1, 28.0, 43. 8, 79. 8, 29.5, 29.5, -30.3, Γ 47.3, 29.7, 71.0, 70 .'3, 28.7, 22.4 ', 28.3, 13.9,

^x 64.3, 28.3, 22.2 ,, 28.3, 13.9

B e i s ρ i e 1 .36

, 3 <x, W-7-Zr3-I ⁾ henylpropoxy) -methyl7- ¹ 7-oxabicyclop. 2. i7hept-2-yl7-5-heptenoic acid ^y

A. /Tβ,2<x.(5Z ),3 cx

bicyclo ^ 2 \ 2.i7hept 2 ~ yl7-5-heptenoic phenylpropyl '

ester

A mixture of 0.59 S powdered KOH in 16 mL anhydrous xylene is refluxed under argon as a blanketing gas. 9 ml of xylene are distilled off. To the mixture is added a solution of 4-10 mg (1.53 mmol) of the alcohol methyl ester of Example 1, part A in 10 ml of anhydrous xylene. The volume of the reaction mixture is reduced by distilling off xylene by 6 ml. The reaction mixture is then treated with a solution of 1.66 g (7.58 mmol) of 3-phenylpropyl mesylate in 36 ml of anhydrous xylene. This mixture is refluxed for 1 hour

30 '

On cooling, the reaction mixture is saturated with 50 ml

'• I ¹ ....

Sodium bicarbonate solution and extracted with 3 x 50 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Purify by flash chromatography on 4-0 g silica gel 60 using hexane: diethyl ether in the ratio ~ b ^m A

r. - 33 - ".:." - "I

carried out as eluent. Yield: 0.61 g (81%) of phenylpropyl ester title compound as a colorless oil. TLC: silica gel, 2% CH ₃ OH / CH ₂ Cl ₂ : R _f = 0.60 iodine.

5 B. ^

A solution of 610 mg (1.24 mmol) of phenylpropyl ester title compound A, 55 mL of distilled THF, 4.40 mL of CH ₅ OH, and 7 x 30 mL of H ₂ O is added under argon as a blanketing gas and 13 * 7 mL 1K with stirring added aqueous lithium hydroxide solution. The mixture is strongly purged with argon for 30 minutes and stirred at room temperature for 14 hours. The reaction mixture is then diluted with 100 ml of 0.1 N aqueous lithium hydroxide solution and washed once with 100 ml of hexane. The reaction mixture is acidified to pH 3 by the addition of 1N hydrochloric acid and then poured into 100 ml of saturated brine. The resulting mixture is saturated with solid NaCl and extracted with 4 χ 150 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The product is chromatographed on 44 g silica gel 60 using 4 $ CH ₃ OH in CH ₂ Cl ₂ as eluent. Yield: 380 mg ($ 82) pure acid title. TLC: silica gel, 4 # CH ₅ OHZCH ₂ Cl ₂ : R _f =

²⁵ 0.30, iodine.

Analysis for C ₂₅ H ₅₂ O ₄ : calc .: C 74.16 H 8.66 C ₂₃ H ₃₂ O ₄ -0.35 H ₂ O: calc .: C 72.94 H 8.70

found: C 72.94 H 8.49

30 ¹³ C NMR (CDCl ₃ , 15.0 MHz) tau 173.7, 33.4, 24.5;

25.7, 129.5., 130.1, 26.6, 46.3, 79.3, 29.5, 30.1, 46.8, 70.2, 69.3, 31.2, 32.3, 141.9, 128.4, 128.4.

r. '. \ - 34 - '

ι -

1 example 37

2ol (5Z), 3 <Χ, W-7-Z? .2-, 17hept-2-heptenoic yl7-5

Α., / ^ Ss, 2c3e (5Z), 3 0L3ß7-7- / 3 / rOctylox, y) -methyl7-7-oxabi- cyclo y / 2.2 'i7hept-2-yl7-5-heptenoic acid A-octyl ester Solution of 508 mg (1.89 mmol) of ester alcohol from Example 1, part A in 2.69 ml of THP is added with 2.69 ml (15.6 mmol) of n-octyl bromide, 64-2 mg (1.89 mmol) of tetrabutylammonium hydrogen sulfate and 2.69 ml of 50% sodium hydroxide solution in this order. The mixture is stirred at room temperature for 19 hours in the dark. The reaction mixture is then poured into 25 ml of saturated sodium bicarbonate solution and extracted with 4-25 ml of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The purification is carried out by flash chromatography on 39.6 g of silica gel 60 using hexane: diethyl ether in the ratio 3: 1 as the eluent. Yield: 333 mg (37 $ octyl ester and 250 mg mixed octyl ester and corresponding methyl ester TLC: silica gel, CH, OH / CH _P C1 ~: R- = (octyl ester) 0.85, methyl ester 0.80

B. / ^, 2 0. (5Z), 3OL, W-7- / 3- / r0ctyloxy) -methyl7-7-oxabicyelo / 2.2. A solution of 333 mg (0.70 mmol) of octyl ester of Part A in 31 mL of distilled THF, 2.50 mL of CH ₂ OH, and 4.1 mL of H ₂ O is added Argon as inert gas and with stirring with 7.70 ml

3 ° 1N aqueous lithium hydroxide solution. The mixture

is vigorously purged with argon for 20 minutes and stirred at room temperature for 16 hours and 30 minutes. The mixture of octyl ester and corresponding methyl ester is in exactly

, "% Hydrolyzed the same way. A solution of this mixture

³⁵ (250 mg) in 29 ml of distilled THF, 2.40 ml of CH ₅ OH and

3.9 ml of HoO is added, with stirring, to 7.30 ml of 1N lithium hydroxide.

L '- \ ^v J

Γ '.. · - 35 -,

solution. This mixture is vigorously purged with argon for 20 minutes and stirred at room temperature for 16 hours and 30 minutes.

The two reaction mixtures are combined and diluted with a solution of 120 ml of 0.1 N aqueous lithium hydroxide solution and 50 ml of HoO. The resulting mixture is extracted once with 220 ml of hexane. The aqueous layer is acidified to pH 3 by addition of 1N hydrochloric acid, saturated with solid NaCl and extracted with 4 × 150 / ml ethyl acetate. The hexane extract and the ethyl acetate extracts are combined (the hexane extract contains the desired acid), dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yield: 0.53 g of crude product, which was added to 4-8 g of silica gel 60 using

CH ₂ -OH in CHpCIp is chromatographed. Exploiter 222 mg $) Acid-title compound. TLC: silica gel, 4 $ CH ₅ OHZCH ₂ Cl ₂ R _f = 0.40, vanillin. '-

Analysis for C ₂₂ H ₅₃ O _4: Calcd .: C 72.09 H 10.4 to 5

²⁰ C ₂₂ H ₅₈ O ₄ .0.24 H ₂ O: calc .: C 71.25 H 10.45

Found: C 71.25 H 10.20

¹³ C NMR (CDCl 3), 15. OmHz) tau. 178.7, 33.8, 2-4.9, ν ~~ ^ ~ 26 _% 2, 129.6, 130.0, 26.8, 46.5, 79.3, 29.5, 29.5, 80.1, 46.9, 71.2 , 69. 9, 31.7,

29.7, 29.2, 28.7, 25.9, 22.6, 14.0, 64.4, 31.7, 29.7, 29.2, 28.2, 25.8, 22.6, 14.0.

By S. ρ i e, 1 38

/ T, 2 OC (5Z), 3 o ^, ^ 7 "7- / 3- (cyclohexylmethoxy) -methyl7-7-oxabicyclo / 2". 2. i7hept-2-yl7-5-heptenoic acid

A. /fTβ.2cx.(5Z) .3 oc, 4β7-7- / 3- (cyclohexylmethoxy) -methyl7-7-oxabicyclo / 2 \ 2.i7hept-2-yl7-5-heptenoic acid cyclohexylmethyl ester

A mixture of 0.56 g of powdered KOH in 15 ml of anhydrous xylene is heated under argon as a protective gas under reflux.

L '. , , '. J

-.36

7 ml of xylene are distilled off. To the mixture is added a solution of 300 mg (1.12 mmol) of the alcohol methyl ester of Example 1, Part A in 10 ml of anhydrous xylene. The volume of the reaction mixture by distilling _off: 5 von'Xylol reduced to 11 ml. The reaction mixture is then treated with a solution of 2.4-7 g (12.9 mmol) of cyclohexyl

β

methylmesylate in 10 ml of anhydrous xylene. This mixture is refluxed for 5 hours. After milling off, the reaction mixture is diluted with 50 ml of saturated sodium bicarbonate solution and extracted with 3 × 50 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Purify by flash chromatography on 35.6 silica gel 60 using

¹ S Λ% CEUOH carried out in CH ₂ Cl ₂ as the eluent. Yield: 0.4-6 g ($ 93) hexyl ester title compound as a colorless oil. TLC: silica gel, 2% CH ₂ OH ₂ OH ₂ Cl ₂ : R _f = 0.80, iodine. :

B. / ^j rß, 2öc (5Z), 3 <x, W-7- / 3-cyclohexylmethoxy) -methyl7-7-

²⁰ , oxabicyclo ^ 2 \ 2.i7hept-2-yl7-5-heptenoic acid

A solution of 460 mg (1.03 mmol) of cyclohexylmethyl ester of Part A, 4-5 ml of distilled THF, 3.80 ml of CH ₅ OH, and 6.10 ml of H 2 PO 4 is added under argon as a blanketing gas and with stirring at 11.4 ml. ml of 1N aqueous lithium hydroxide solution. The mixture is rinsed vigorously with argon for 20 minutes and stirred at room temperature for 16 hours. The reaction mixture is diluted with 83 ml of 0.1 N aqueous lithium hydroxide solution and washed once with 83 ml of hexane. The aqueous layer is acidified to pH 3 by addition of 1N hydrochloric acid and saturated with solid NaCl. The resulting aqueous layer is washed with 4- χ 120 ml of ethyl acetate. extracted. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yield: 0.32 g of crude product which is chromatographed on 34-, 6 g of silica gel 60 using 3% CH ₂ OH in CH ₂ Cl ₂ as eluent. Yield: 278 mg

r .-. 37 -

($ 77) pure acid-titanium compound. (TLC: silica gel, 4 CH ₃ OH / CH ₂ Cl ₂ : E _f = 0.28, iodine

Analysis for C ₂₁ H ₅ ^ O ₄ : calc .: C 71.96 H 9.78

^C 21 ^H 3A * ⁰ ' ⁵ ^ ^H 2 ^{0: over #: c} 7 °, 8A- H 9,80 5 Found: C 70,84 H 9,68

¹³ C NMR (CDCl ₃ , 15.0 MHz) tau 173.5, 33.-7, 24.9, 25. "~~ 129.5, 129.9, 26.0, 46.4, 79.2, 29.6, 29.G, 79.2, 46.8, 70.0, 77.0, 37.9 , 30.0, 26.7, 25.8, 26.7, 30.0, 69.3, 37.1, 29.1, 26.3, 25.6, 26.3, 29.1

Example 59

T <x, 2β (Z), 3β, 4-öc7-7- / 3- (7ri-methylhexyl) -o-15 7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid

The procedure of Example 1 and 2 is repeated except that 1-methylhexyl methanesulfonate is used in place of h-hexyl methanesulfonate. It will get the title connection. TLC (silica gel, 4 $ CH ₅ OHZCH ₂ Cl ₂ ): R _f = 0.4-7.

20 Analysis for C ₀ ^ ₁ -O ₁ , calc .: C 71.55 H 10.29

^ ¹ ^ * Found: C 71.73 H 10.21

¹³ C NMR (CDCl 3, 15.OMHz) tau 178.8, 33.4, 24.6, 25.7, 129.4, 130.2, 26.7, 46.4, 79.5, 29.5, 80.1, 47.1, 67.5, 75.9, 36.7, 25.3, 31.9, 22.6, 14.0, 19.7

B e i s ρ i e 1 40

/ ¹ T oC, 2β (Z), 3β, ^/ l-oc7-7- ^ 3- / 7; 3-hexynyloxy) -methyl-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 1 and 2 are repeated, but using 3-hexynylmethanesulfonate. The title compound is obtained as an oil. TLC (silica gel, 4 # CH ₂ OH / CH ₂ Cl ₂ ), R _f = 0.32. ,: Analysis for ^ 20 ^Η 30 ° 4- ^{: over} : ^c 71.82 H 9.04

Found .: C 71.66 H 9.21

· ''. ^] · · '.'"* ' \ '. ' ¹³ C NMR (CDCl ₃ / 15.OMHz) tau 178.9, 33.4, 22.0,

24.5, 129.5, 130.0, 26.7, 46.4 ·, 79.4, .29.4, 29.5 ", 80.0, 46.7, 69.0, 58.8, 76.1, 86.8, 22.0 / 25.8, 13. ^ 4

B e i s ρ i e 1 41

, 3 C ^ (Z), 4ß7-7-Z3-Z3-hexenyloxy) -methyl7-7-oxabicycloZ2 \ 2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 1 and 2 is repeated, however, cis-3-hexene-i-mesylate is used instead of n-hexylmethanesulfonate. The title compound is obtained as an oil. TLC (silica gel, 4 ^ ¹ CH ₃ OHZGH ₂ Cl ₂ ): R _f = 0.3. Analysis for C ₂₀ H ₅₂ O ^: calc .: C 71.39 H 9.59 ··········: C 71.10 H 9.59

¹³ C NMR CDCl ₃ / 15.OMHz) tau'l78.9, 33.4, 24.5, 25.5, 129.5, 130.1, 27.7, 46: 3, 79.3, 29.4, 80.1, 46.7,, 70.7, 69.8, 26.6, _o 133.6, 124.8, 20.6, 14.2

· ,; ν> B e i. s ρ i e 1 42.

/ Tβ, 2 cc (Z) , 3 x Z), 4β7-7-Z3-Zr2-hexenyloxy) -methyl7-7-oxabicycloZ2.2.1 / hept-2-yl7-5-heptenoic acid The procedure of Examples 1 and 2 is repeated but with 2-1-hex-2-enyl-mesylate instead of n-hexylmethane.

, .-. · *. ' *

^: sulfonate is used. The title compound is obtained as an oil. TLC (silica gel, 2% CH ₅ OHZCH ₂ Cl ₂ ): R _f = 0.22, vanillin.

Analysis for C ₂₀ H ^ ₂ O _4- : C: 71.39! H 9,59

Found .: C 70.97 H 9.64

¹³ C NMR (CDCl, 15.0 MHz) tau 178.8, 33.4, 24.5,

2.5.8, 129.5, 130.1, 26.7, 46 * 4, 79.5, 29.5, 29.5, 80.1, 46 :. 9, 126.2, 29.5, 22.6, 13.6

29.5, 29.5, 80.1, 4Q. 9, 69.3, 66. 6, 133.5,

L ..

γ. _: , - 39 -. ; ..- τ

1 example 43

, 3 o

cyclo ^ 2 \ 2.i7hept-2-yl7-5-heptenoic acid methyl ester 5 * A solution of 310 mg (1.1.6 mmol)

(Hydroxymethyl) -7-oxabicyclo ^ .2.i7hept-2-yl7-5-heptensäuremethylester in 1.34 ml of tetrahydrofuran is under stirring with 1, 3 ^ ml allyl bromide, 107 HJg tetrabutylammonium hydrogen sulfate and 1.34 ml of 50% sodium hydroxide solution in this Order offset.

The mixture is stirred at room temperature in the dark for 23 hours and then poured into 30 ml of saturated sodium bicarbonate solution and extracted 2 χ with 30 ml of methylene chloride. The combined extracts are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The purification is carried out by flash chromatography on 35 g of silica gel 60 using hexane and diethyl ether in a ratio of 2: 1 as eluent. Yield: 220 mg of methyl ester product. TLC (silica gel, hexane / diethyl ether = 1: 1: .R- = 0.4, iodine.

The ester is dissolved in 36 ml of tetrahydrofuran together with a small amount of hydroquinone, 6 ml of water and 7 ml of 1N aqueous lithium hydroxide solution and 5-1 / 2 at room temperature. Hours stirred. Then, the reaction mixture is poured into 80 ml of saturated saline, which is saturated with more solid sodium chloride. The aqueous layer is extracted with '4 χ 125 ml of ethyl acetate, the extracts dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is chromatographed on 30 g of silica gel using 4 $ CH ₅ OHZCH ₂ Cl ₂ as eluent. Yield: 190 mg of acid title compound. TLC (silica gel, hexane / diethyl ether = 1: 1: R _f = 0.15 analysis for C ₁₇ H ₂₆ O ₄ : calc .: C 69.36 H 8.96

Found: C 69.72 H 9.05

¹³ C NMR (GDCl ₃ , 15.OiMHz) tau 178.9, 33.4, 24.5,

25.7, 129.5, 130.0, 26.6, 46'.J, 79.3,, · 29.4, 80.1, 46.7, 69.3, 72.0, 134., 7,

117.0

L - '- ·. , ·,

ί '

Example 44

/ ϊβ , 2 <x (5Z), 3 ο «-, 4β7-7- / 3-AHexylthio) -methyl7-7-oxsCbicyclo- / 2.2. ^ Hept ^ yl ^ - ^ - heptenoic acid methylester

Λ. ^ F, 2OL (5Z), 3 cx., 4ß7-7 - ^ - (hydroxymethyl) -7-oxnbicyclo- ^!

/2 \2.i7hept2-yl7-5 -heptenoic acid -

(A). A mixture of N-acetylpyridinium chloride is prepared by dropwise addition of 9.6 ml (136 mmol) of acetyl chloride to 56 ml of pyridine. This is mixed with 5.0 ß (27 mmol) (exo) -3- (2-methoxyäthenyl) -7-oxabicyclo / 2.2.i7heptan-2-rnethanol, dissolved in 5 ml'Pyridin added. The resulting mixture is stirred at room temperature for 1 1/2 hours and then poured into brine. The product is extracted with 3 × 200 ml of diethyl ether, the ether extracts are washed with 2 × 400 ml of 5% hydrochloric acid and 1 × 200 ml of saline,. and dried over sodium sulfate. Upon evaporation, a yellow oil is obtained, which is passed through a small column of silica gel (1 ^r 50 ml) and eluted with dichloromethane. Yield: 4.42 g of oil. , ',

20:. ^:

(b) To a solution of 4.42 g (19.6 mmol) of the resulting oil in 500 ml of tetrahydrofuran containing 50 ml of water is added 31.1 g (97.8 mmol / l of mercuric acetate) The resulting yellow suspension is left to stand for 10 minutes and then the whole mixture is poured into a solution containing 200 g of potassium iodide in 2 liters, the yellow color disappears on shaking and the mixture is extracted with 3 × 500 ml of benzene are washed with potassium iodide solution and brine and dried over sodium sulphate. Evaporation gives 3 g of product, which crystallizes on standing in the freezer compartment.

(c) In dimethyl sulfoxide (dried over calcium hydride)

is by dropwise addition of a solution ^χ 'νοη sodium. Methylsulfinylmethid (prepared by heating 300 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 75 ° G until

u .:. '. , , , -. , '/ j

Γ - 4-1 -, -. Π

Completion of hydrogen evolution) to a solution of 5.32 g (12 mmol) of 4-carboxybutyltriphenylphosphonium bromide in 100 ml of dimethylsulfoxide. After the first orange coloration for more than 10 seconds, an equivalent amount of base is added to form the ylide. In a solution of the product of part (B) in 20 ml of dimethyl sulfoxide is added to the solution obtained with a deep orange color and the resulting mixture is stirred at room temperature for 4-5 minutes. The reaction is quenched after addition of 24 mmol of acetic acid and the mixture is poured into 300 ml of brine and extracted with 3 x 200 ml of diethyl ether. Evaporation of these extracts gives an oil which is stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide forms in the mixture. This mixture is washed with benzene and acidified with 10 $ hydrochloric acid. The aqueous layer is saturated with salt and extracted with diethyl ether. After drying over sodium sulfate and evaporation, 2.4-3 g of crude product are obtained. The mixture is stirred for 24 hours with 10 $ sodium hydroxide solution and re-isolated by acidification and extraction with diethyl ether. The product is purified on 500 g of silica gel with ethyl acetate and hexane = '50: 50 as eluent. Yield: 600 mg of acid which crystallizes on standing. The product is made twice from ethyl acetate

2 ⁵ and cyclohexane recrystallized. Yield: 320 mg

/ ^; TSS, 2o <. (5Z), 3 <X, 4-ß7-7- ^ 3- (hydroxymethyl) -7-oxabicyclo / 2.2.17hept-2-yl / -5-heptenoic acid.

B. / Τβ, 2 (λ (5Ζ), 3 Ov, 4-ß7-7- / 3- (p-toluenesulfonyloxymethyl) -7-oxabicyclo ^ 2 \ 2.i7hept-2-yl7 -! - - heptenoic acid methyl ester To a solution of 300 mg (1.12 mmol of alcohol-ester of Part A in 4 ml of anhydrous pyridine is added 4-27 mg (2.24 mmol) of tosyl chloride.) The mixture is stirred at room temperature under argon as inert gas for 10 hours the reaction mixture is diluted with 300 ml of diethyl ether, with 3 × 100 ml of 1N hydrochloric acid and 3 × 100 ml of 0.5N sodium hydroxide solution.

washed. The ether layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Purification is carried out by flash chromatography on 30 g silica gel 60 using 50 $ hexane in diethyl ether as eluent. Yield: 450 mg of the title compound. TLC: (silica gel, 4 # "CIUOH in CR _f = 0.80, iodine.

C./1, 2 (X (5Z), 3α, 4β7-7- / 3- / r-hexylthio) -methyl7-7-oxabi-

10 _v cyclop.2.i7hept-2 ~ yl7-5-heptenoic acid methyl ester

A solution of 132 mg (1.17 mmol) potassium tert-butoxide

In 10 ml of anhydrous THP, under argon as a protective gas, it is mixed with 378 mg (3.21 mmol) of 1-hexanethiol, which is then treated with a solution of 450 mg (1.07 mmol) of tosylate of Part II. The reaction mixture is stirred at room temperature under argon for 2 1/2 hours and then heated under reflux for 5 1/2 hours After cooling, the reaction product is diluted with 300 ml of diethyl ether and dissolved in 100 ml of saturated NaHCO 3 -. The aqueous layer is extracted with 2 × 100 ml of diethyl ether and the combined ether extracts (500 ml) are washed with 2 × 100 ml of 6.5N sodium hydroxide solution and 100 ml of brine, then dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting 0.55 g of crude oil are purified by chromatography on 25.2 g of silica gel 60 using petroleum ether: diethyl ether = 5: 1 as eluent Yield: 328 mg ($ 84) of the title compound as an oil, TLC (silica gel, petroleum ether). fcroäthe r: diethyl ether = 3: 2): R _f =

, 0.55, iodine. , 30

Example 45

/ ϊ'β, 2α, (5Z), 3 cX, 4β7-7-Z3-ZtHexylthio) -methyl7-7-oxabicyclo- / 2. 2.i7hept-2-heptenoic yl7-5

A solution of 328 mg (0.89 mmol) of methyl ester of Example 1 in 43.8 ml of THF and 6.67 ml · H ₂ O is added with stirring 8.40 ml of 1N aqueous lithium hydroxide solution. The

Mixture is rinsed vigorously with argon for 20 minutes and stirred at room temperature for 12 1/2 hours. The reaction mixture is then acidified to pH 4- by addition of 1N hydrochloric acid and poured into 50 ml of saturated brine. The resulting solution is saturated with solid NaGl and extracted with 4 χ 50 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting 295 mg of crude acid are purified by flash chromatography on 25 g of silica gel GC-7 using petroleum ether: diethyl ether = 2: 3 as eluent. Yield: 250 mg ($ 79) of the title compound as an oil. TLC (silica gel, petroleum ether, diethyl ether = 2: 3): B _f = 0.25, iodine. Analysis for C ₂₀ H ₃ O ₅ S: calc .: C, 67.80, H, 9.61, S, 9.04

ν found: C 67.80 H 9.85 S 9.14

¹³ C NMR (CDCl ₃ , 15.0 MHz) tau 173.5, 33.1, 24.5, 25.6, 129.9, 128.8, 26.5, 45.9, 79.9,

29.2, 28.8, 78.3, 45.9, 69.5, 144 *. 5, ₂₀ '129.7, 127.6, 132.1, 127.6, 129.7,

21.3, 51.1

Examples,

(1ß, 2 oc, 3 tx, 4ß) -7- / 3- ^ hexylthio) -methyl7-7-oxabicyclo - / ^^

A. (iβ, 2 <x, 3 cs4β) -7- / 3- (hydroxymethyl) -7-oxabicyclo / 2.2.i7-

hept-2-yl-7-heptanoic acid methyl ester /

800 mg (3.0 ffiMol) / ^? Tβ, 2 ^ (5Z), 3 _, 4β-/-3- (hydroxymethyl) -7-cxabicyclo 2.2 2.2.17hept-2-yl7-5-heptenoic acid methyl ester prepared according to Example 1 and dissolved in 120 ml of ethyl acetate, is added under argon as inert gas with 160 mg 5 $ Pd on carbon. The argon atmosphere is exchanged for a slight positive pressure of hydrogen and the reaction mixture stirred for 8 hours at 25 ⁰ C, then filtered through a Celite filter, and evaporated. Yield:

Γ - / μι. - - "Ί

1,730 mg ($ 90) of title compound A.B.

/2".2.i7hept-2~yl7-heptansäure-methylester

The procedure of Example 1 is repeated except that the alcohol ester of. Part A is used instead of the alcohol ester used in Example 1 Α. It will get the title connection.

'' .. '' 'Example '47,.

(1ß, 2 oc, 3 OL, 4ß) -7 - ^ - ^ hexylthio) -methyl7-7-oxabicyclo-

/ 2. , 2. i7hept-2-yl-7-heptanoic acid

The procedure of Example 4-5 is repeated except that the methyl ester of Example 46 is used instead of the methyl ester of Example 45. It will be the title link

receive.

Be i s ρ i e 1 48

/ It, 2 oe (5Z), 3β, 4β7-7 - ^ "- / Pent -pentylthio) -methyl7-9-oxabicyclo- / 2.2.i7hept-2-yl7.5-heptenoic acid methyl ester

Methyl 2,2'-i7hept-2-yl7-5-heptenoic acid A solution of 2.68 g of ^: Tβ, 2 x (5Z), 3σ <., 4β7-7 - / 3-methyl) -7-oxabicyclo 13.26 g of pyridinium dichromate is added to 175.2 g of b2-yl7-5-heptenoic acid in 175 ml of dimethylformamide, and this mixture is stirred at room temperature for 19 hours, after which an additional 8 g of pyridinium dichromate are added, and the mixture is stirred for a further 24 hours The reaction mixture is then mixed with 500 ml of

^ ⁰ ethyl ether diluted and filtered the resulting black gummiarti ge precipitate through a Celite filter. The filtrate is evaporated under reduced pressure. The resulting dark brown oil is passed through 60 g of silica gel 60 and eluted with 5% β0Η / 0Η ₂ 01 ₂ . Yield: 1.86

³⁵ brown oil. <

The oil is purified by chromatography on 150 g of silica gel 60 using pentane / diethyl ether / acetic acid in the ratio 1: 1: 0.01 as the eluent. . Yield: 0.63 g / FSS, 2 PC (5Z), 3 <A, ^ ß) -7- / (3-Carboxy) -7-oxabicyclo / 2.2.1 _i 7hept-2-yl7-5- methyl heptenoate and 0.31 g / T, 2 o (., (5Z) 3β, 4β7-7- / 3- (carboxy) -7-oxabicyclo / 2.2.i7hept ⁱ -2-yl7-5, -heptenic acid-

methYlester. ii

, C NMR (CDCl ₃ , 15.OMHz) tau 177.0, 174.0, 130.6,

127.7, 81.5, 77.9, 54.7, 5l.3, 46.2, 33.4,

32.3, 29.2, 26.6, 25.8, 24.7.

A solution of 350 mg / ^; Tss _i 2 "X. (5Z), 3ss, 4ß7-7- / J (carboxy) -7-; Oxabicyclo /^^^^ Hept-Sy ^ - ^ - heptenoic acid methyl ester and 0.35 ml of triethylamine in 3 »0 ml of anhydrous tetrahydrofuran is cooled to ⁰ ° C. under argon as inert gas. The solution is then added dropwise while stirring with 0.24 ml of ethyl chloroformate. The resulting mixture is stirred at ⁰ ° C. for 50 minutes and then treated with 20 ml of anhydrous diethyl ether. The mixture is filtered through a bed of magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in 2 ml of absolute ethanol and 3ϊ3 ml of anhydrous THP. The resulting solution is placed in an ice bath

  , ''

cooled and then with 80 mg NaBH ^. added. The mixture is stirred for 30 minutes at ⁰ ° and then the ice bath is removed. After 15 minutes, the reaction mixture is poured into 25 ml of ice-cold 1N hydrochloric acid. The aqueous layer is extracted with 3 x 25 ml of diethyl ether. The ether layers are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude product. Purification is carried out by flash chromatography on 22 g of silica gel using 2 # MeOH / CH ₂ Cl ₂ as eluent. Yield: 250 mg of Tβ, 2 x (5Z), 3β, W-7- / 3- (hydroxymethyl) -7-oxabicyclo ^ 2 \ 2.i7hept-2-yl7-5-heptenoic acid methyl ester.

¹³ C NMR (CDCl ₃ , 15.0 MHz) tau 174.1, 130.0, 128.5, 80.6, 78.7, 63.4, 51. 1 \ 51-4, 47.8, 33 .4,

• 32.7, 29.8, 26.6, 24.7, 23.7 "

Γ, ·. ·:. '·. - 46 -. , Ί

B. / ^; Tβ _> 2oe ( ^[ > Z), 3β, ^/ l -β7-7 - ^ - Cp-toluenesulfonyloxyniethyl) -7-

oxabicyclo / 5.2 * 17hept-2-yl7-5 ^ heptenoic acid methyl ester A solution of 300 mg (1.12 mmol) / ^; TSS, 2oC (5Z), 3ss, W-7 £ 3- (Hydroxyme thyl) -7-oxabicyclo / is 2.2.17hept-2-yl7-5-hept-enoic acid methylester of Part A of anhydrous pyridine in 4 ml with 427 mg (2.24 mmol) of tosyl chloride. The mixture is stirred at room temperature under argon as inert gas for 10 hours. Then, the reaction mixture is diluted with 300 ml of diethyl ether, washed with 3 x 100 ml of 1N hydrochloric acid and 3 x 100 ml of 0.5N sodium hydroxide solution. The diethyl ether layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Purification is carried out by flash chromatography on 30 g of silica gel 60 using 50% hexane in diethyl ether as the eluent. Yield: 450 mg of title compound B.

C. / ^; TSS, 2OL (5Z), 3ss, 4ß7 ~ 7- / 3- / rPentylthio) -methyl7-7-oxapi-

cycl o / S. A solution of 132 mg (1.17 mmol) of potassium tert-butoxide in 10 ml of anhydrous tetrahydrofuran is added under argon as inert gas to 378 mg (3 »21) of ethyl acetate mmol) of 1-pentanethiol. This mixture is then added to a solution of 450 mg (1.07 mmol) of part B tosylate in 5 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature under argon for 2 1/2 hours and then heated under reflux for 5 1/2 hours. After cooling, the reaction mixture is diluted with 300 ml of diethyl ether and then poured into 100 ml of saturated sodium bicarbonate solution. The aqueous layer becomes,. extracted with 2 χ 100 ml of diethyl ether. The combined ether extracts (500 ml) are washed with 2 × 100 ml of 0.5N aqueous solution of brine and 100 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.5.5% crude oil. The purification is carried out by chromatography on 25.2 g of silica gel 60 using petroleum ether / diethyl ether = 5: 1 as the eluent. Yield: 328 mg of the title compound.

1 examples

/S.2.i7hept-2-yl7-5-heptensäure

A solution of 328 mg (0.89 mmol) of methyl ester of Example 48 in 43.8 ml of THF and 6.67 ml of H ₂ O is added under argon as a protective gas and with stirring with 8.40 ml of Lithium aqueous lithium hydroxide solution. The mixture is rinsed vigorously with argon for 20 minutes and then stirred at room temperature for 12 1/2 hours. The resulting reaction mixture is acidified to pH 4 by addition of 1N hydrochloric acid and then poured into 50 ml of saturated brine. The resulting solution is saturated with solid NaCl and extracted with 4 χ 50 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting 295 mg of crude acid are purified by flash chromatography on 25 g of J3ilicar CC-7 using petroleum ether and diethyl ether in a ratio of 2: 3 as eluent. It will get the title connection.

B e i s ρ i e 1 50

/ ⁷ Ia, 2 0 (. (5Z), 3 oC _> 4ß7-7 - ^ - / {"methylthio) -methyl7-7-oxabicyclo- / 2 .2.i7hept-2-yl7-5-heptenoic acid

The procedure of Examples 44 and 45 is repeated, with. However, methylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

Example 1 5 ^ / ϊβ, 2 oc (5Z), 3 ³⁰ ^ .2ii7.1aept-2

The procedure of Examples 48 and 49 is repeated except that propyl mercaptan is substituted for 1-pentanethiol. It will get the 'title connection.

Γ '' .- 4-8 -

- Example 52

(1β, 2 x, 3 ol, 4β) -7- / 3- (ethylthio) -methyl7-7-oxabicyclo

The procedure of Examples 4-6 and 4-7 is repeated but using butylmercaptan instead of 1-hexanethiol. It, the title compound is obtained.

, ·, .... s: ' Example 53

/ 1ß, ^ 2NC (5Z), 3 <λ, ^ ß7-7- / 3 - /;.. ROctylthio) .- methyl7-7-oxabicyclοίο /2.2.27nept-2-ryl7~5-heptensäur"e · _A ·.

The procedure of Examples 4-4 and 4-5 is repeated except that 1-octanethiol is substituted for 1-hexanethiol. It will get the title connection. Analysis for G ₂₂ H ₈ O ₇ S: calc .: C, 69.06, H, 10.01, S, 8.38, &quot;,&quot;, Found: C, 69.08, H, 9.75, S, 8.20

^{1 3} C NMR (CDCl ₃ , 15.0 MHz) tau 178.7, 32.6, 29.1, 29.4 ', 129.8, 129.8, 29.4, 46.9, 80.6, 29.7., 31.7, 80.4, 47.5, 33.4, 32.1, 29.1, 28.8, 26.7,

_; 26.2, 24.5, 22.5, 13.9

20 ^% - ', ·':.

'. B e i s ρ i e 1 54 ·

/ Tβ, 2 <X (5Z), 3 o '., 4-β7-7- / 5- / r-phenylthio) -methyl7-7-oxabicyclo ^ 3.2.i7hept-2-yl7-5-heptenoic acid. The procedure of Examples 4-4- and 4-5 is repeated except that phenylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

B e i s ρ i e 1 55

(1β, 2 o, 3α, 4-β) -7- / 3 - / P-phenylthio) -methyl7-7-oxabicyclo- / 2 · 2,17hept-2-yl7-heptanoic acid

The procedure of Examples 4-6 and 4-7 is repeated except that phenylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

35 ·.

Γ, - 49 -

1 example .56

/ oil, 2 oil (-5.Z), 3 öC., 4ß7-7- / 3- / ethylthio) -methyl7-7-oxabicyclo-

^ ι- /2.2.i7hept-2-yl7-5-heptanoic acid

The procedure of Examples 44 and 45 is repeated but employing ethylmercaptan instead of 1-hexanethiol. It will get the title connection.

B e i s ρ i e 1 57

/ Iβ, 2α ( 5Z), 3β, 4β7-7- / 3- / phenyl-thio) -methyl7-7-öxabicyclo- / 2.2.i7hept-2-yl7-5-heptenoic acid

The procedure of Examples 48 and 49 is repeated except that phenylmercaptan is used instead of 1-pentanethiol. It will get the connection!

15 Example 58

/ ¹ TB, 2 (X (5Z), 3β, W-7- / 3-benzylt hi ο) -me-thyl7-7-oxabicyclo- / 2 '' 2. i7hept-2-yl7-5-heptenoic acid

The procedure of Examples 48 and 49 is repeated except that benzylmercaptan is used instead of 1-pentanethiol. It will get the title connection. '. ·

Example 59

/2.2.17hept-2-yl7heptansäure

The procedure of Examples 46 and 47 is repeated except that benzylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

Example 60

/ Iβ, 2 C * X5Z), 3 oC, 4β7-7- / 3- (cyclohexylthio) -methyl7-7-oxabicyclo ^ S.2.i7hept-2-yl7-5-heptenoic acid. The procedure of Examples 44 and 45 becomes repeated, but cyclohexylmercaptan instead of 1-hexanethiol

is used. It will get the title connection. 35

B e i s ρ i e 1 61

bicyclo [2] -2i7hept-2-yl7-5-heptenoic acid The procedure of Examples 48 and 49 is repeated except that cyclopentylmercaptan is substituted for 1-pentanethiol. It will get the title connection.

Example .52. · \

(1β, 2cx., 3oc, 4β) -7- / 5- (cyclohexylthio) methyl-7,7-oxabicyclo / 2.2.i7hept-2-yl-7-heptanoic acid.

The procedure of Examples 46 and 4-7 is repeated except that cyclohexyl mercaptan is used in place of 1-hexane oil. It will get the title connection.

B ice ρ ie 1 63 _(/ TSS, 2 oL (5Z), 3 ° C 4ß7-7 _r-Z3-Z ² "CHE / 2 .2.17hept-2-yl7-5 ^ heptenoic acid

A. ^ Τβ, 3 <Χ0Ζ), 3 ^ <A

In a dry three-neck round bottom flask with stirrer bar 12.9 S (37 »7 in mol) of dry methoxymethyltriphenylphosphonium chloride ((Ο ^ Η ^), P ⁺ -GH ₂ OCH ₅ Cl") and 235 ml of distilled toluene (stored on molecular sieve) is fed ,

The suspension obtained is stirred in an ice bath under argon until it is cold and then added dropwise with 18.3 ml (28.3 mmol) of 1.55M solution of potassium tert-amylate in toluene.

- sets. The result is a bright red solution, which is stirred at 0 C for a further 35 minutes. Then, through a dropping funnel within 35 minutes, a solution of 4.97 g (18.8 mmol) ^ ß is, 2 ° C (5Z), 30C, 4ß7-7- _</ 3-i? Ormyi-7-oxabicyclo Add /2.2.i7hept-2-yl7-5-liepttensäure- methyiester in 60 ml of toluene, with the ice still in place. Then, the reaction is quenched by the addition of 2.3 g (39 mmol) of acetic acid in 5 ml of diethyl ether. The reaction mixture immediately turns pale yellow and immediately afterwards in 200 ml

F - 51 - π

poured saturated ammonium chloride solution and extracted with 4 χ 200 ml of diethyl ether. The combined ether phases are washed with brine, dried over magnesium sulfate and evaporated to a yellow oil in a white crystalline solid (phosphine oxide). The white solid is digested with ethyl acetate and the mother liquor is purified by chromatography on a silica gel column LPS-1 / . The following fractions are obtained:

(A) _< / ^; TSS 2ot (5Z), 3 <x, 4ß7-7 - ^ - (2-0xo) ethyl-7

10 ^ 2 \ 2.i7hept-2-yl7-5-heptenoic acid methyl ester,

(B) ^ Tβ, 2öC (5Z), 3oc, 4ß7-7- ^ 5- (2-methoxy) -äthendi cyclo ^ 2.2.1 / hept ~ 2-yl / -5-heptensäure-methyl ester, and

(C) / ^; Tfi, 2 0L (5Z) _i 3oL, 7-7 ^ - ^ - (2 _i 2-dimethoxy) -athyl-7-oxabicyclo / 2.2.l7hept-2-yl / -5-heptenoic acid, methylester.

The compounds (B) and (C) are each treated with trifluoroacetic acid and converted into the compound (A).

As / Tβ, 20L (5Z), 3oC, 4β7-7- / 3- (2-hydroxyethyl) -7-oxabicyclo-. 1.4 g (5 mmol) of aldehyde from part A in 50 ml of methanol are added with 0.19 g (5 mmol) of NaBH ₇ , under argon as inert gas O ⁰ C treated. Wake for 1 hour stirring at 0 ⁰ C, the reaction is quenched by addition of 2N hydrochloric acid to pH 2 The methanol is distilled off under reduced pressure and the reaction mixture was taken up in diethyl ether. The ether solution is washed with saturated potassium bicarbonate solution and saturated brine and dried over magnesium sulfate. Diethyl ether is evaporated. The title compound B is obtained.

C.

bicyclo ^ .2.i7hept-2-heptenoic yl7-5

The procedure of Examples 44 and 4-5 is repeated except that the alcohol from Part B above is used in place of the alcohol used in Example 44. It will get the title connection.

• γ -.... -. , , - 52 -

1 - Example

, 2oV (5Z), 3ß, 4ß7-7 - ^ - Z2- (hexylthio) -ethyl7-7-oxabicyclo- [2.i7fcept-2-yl7-5-beptenzoic acid. The procedure of Example 63 is repeated except that ^ Tß-, 2cc (5Z) _i 3ß _i 4ß7-7 - ^ - l ^1- ormyl-7-oxa 5-heptenoic acid ethyl ester instead of ^ Tß, 2o (. (5Z), 3 <X, 4ß7-7- / 5-Iormyl-7-oxabicyclo ^ 5.2.i7hept-2-yl7-5-heptenoic acid methyl ester is used to give the title compound.

10; :.

Example 65

(1ß, 2oC, 3oL _v 4-ß) -7- _</ 3- ^ 2- (hexylthio) -äthyl7-7-oxabicyclo

/2.2.17hept-2-yl7heptansäure

The procedure of Example 64 is repeated, except that (1ß, 2oir, 3 _i o ^ 4-ß) -7- _</ 5-i ^{<ormyl-7-oxabicyclo} / 2.2.i7hept ~ 2-yl7-heptanoic acid methylester instead of of _< ^/ ββ,2 _< χ.(5Ζ),3Λ. » ^/ '-β7-7- / 3-Pormyl-7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester is used. It will be the title link

receive" ·

Example 66, 2 oil (5Z), 3 0C, 4ß7-7- ^ 5- ^ 2- (phenylthio) ethyl 7-7-oxabi-

, 2. i7b.ept-2-yl7-5-b.eptoacetic acid The procedure of Example 63 is repeated except that phenylmercaptan is used in place of 1-hexanethiol. The title compound is obtained.

; Example 1 67

/ ß ", 2 <x (5Z), 3ss, 4ß7-7-Z3-Z ² - ^(phen y ^lthi °) - ^ät byl7-7-oxsLbicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid The procedure from Example 64 is repeated except that phenylmercaptan is used instead of 1-hexanethiol to give the title compound.

L. .-. , , , J

_f B ice ρ ie 1 68

(1β, 2cc, 3 oC, 4β) -7 - ^ - ^ 2- (phenylthio) ethyl 7-7-oxabicyclo-γ2.2.27kept-2-yl-7heptanoic acid

The procedure of Example 65 is repeated except that phenylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

Example 69

cy ^ lo ^ 2 \ 2.i7hept-2-yl7-5-hept-enoic acid The procedure of Example 63 is repeated, with each

v © ^v -

but benzylmercaptan is used instead of 1-hexanethiol. iIt will get the title connection.

Example 70

ß & , 2 c ^ (5Z), 3ß, ^ - ß7-7- ^ ^L ^ 2- (Benzylthio) ethyl7-7-oxabicyclo / 2.2.17hept-2-yl7-5-heptenoic acid The procedure of Example 64- but benzylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

Example 71, 2 oL (5Z), 3 Λ, ^ - ß7-7 - ^ - ^ 2- (cyclopentyl) -thio) -äthyl7-7-

T _he procedure of Example 63 but Cyclopentylmercaptan is used instead of 1-hexanethiol is repeated. It will get the title connection.

- Be ί s ρ ie 1 72 / ^; Tβ, 2cC (5Z), 3o (k., 4β7-7- ^ 3- ^ 2- (Cyclohexylthio) -ethyl) 7-7-oxabicyclo [2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Example 63 is repeated but using cyclohexylmercaptan instead of 1-hexanethiol to give the title compound j.

Example 73

A. / 1β, 2oc (5Z), 3α, ^z l -β7 ^; -7 / 5- (3-Ox: o) -propyl ~ 7-oxabicyclo

/ 2 ".) 2. i7hept-2-yl7-5-h-epenoic acid methyl ester The procedure of Example 63, part A is repeated, but with ^, 2o ^ (5Z), 3 <^, ^z i -β7 -7- / 3- (2-Qxo) -ethyl-7-oxabicyclo / 2.2.1 / hΘpt-2-yl7-5-heptenoic-methyle Instead of / ^; Tβ, 2 <X- (5Z), 3 < 4 _t 7 -7-Z3-Formyl-7-oxabicyclo ^ 2.2: .i7-hept-2-yl / -5-heptenoic acid methyl ester is used. The title compound is obtained.

B. / Tß, 2oC (5Z), 3 ö

15 / 2,2.i7hept-2-yl-7-s-5-heptenoic acid methyl ester

The procedure of Example 63, part A is repeated except that the aldehyde of the preceding part A instead of / ⁷ IB , 2 <*. (5Z), 3 OL , 4ß7 ~ 7- / 3-formyl-7-oxabicyclo _{</2.2.^hept^-} yl7-5- used "heptenoic acid methylester. It is the

²⁰ aldehyde title compound B obtained.

C-.

/ 2 .2.i7hept-2-yl7-5-heptenoic acid, methylester Don procedure of Example 63, Part B is repeated, ^WO-25 ..., however, the at Äldehyd-title compound B instead of

^ is used. It

the alcohol title compound C is obtained.

³⁰ DV ^ 1ß, 2o ^ (5Z), 3dL, ^/ l-ß7-7 - ^ - ^ ^z i ^: - (Hexylthio)

cyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples A-4 and 4-5 is repeated, but using the alcohol from Part C _s is used instead of the alcohol used in Example 4-4 * It is the Title-

³⁵ connection received.

Γ. , ^ι - - 55 -. ., '' /. Example 7

The procedure of Example 73 is repeated except that cyclohexane mercaptan is used instead of 1-hexanethiol. It will get the title connection.

Be is ρ i e 1 75.

The procedure of Example 73 is repeated, but using phenylmercaptan instead of 1-hexanethiol. It will get the title connection.

15 'For s ρ i e 1 76

2.1 / hept-2-yl-17-heptenoic acid The procedure of Example 73 is repeated except that benzylmercaptan is used instead of 1-hexanethiol. It will get the title connection. "

, Examples 77, 78 and 79

/ ^ B, 2oC (5Z), 3 <^, W-7- / 3-r-hexylsulfinyl) -niethyl7-7 ^ oxabicyclo _< /2.2.i7hept-2-yl7-5 -heptenoic acid methyl ester (rapidly

25 Wandering Isomer)

/ ⁵ TB, i ! (CAjC 5Z), 3 <K , 4ß7-7- / 3 - / ^ rHexylsulf inyl) -methyl 7-7-öxabi cyclo / 2.2.i7hept-2-yl7-5-heptenoic acid diethyl ester ( slowly migrating isomer) and / ϊβ, 2 <M 5Z), 3 OL, 4β7-7- / 5- / i "hexylsulfonyl) -methyl7-7-oxabi

³⁰ cyclo / 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester

A solution of 634 mg (1.72 mmol) / 1β, 2öL (5Z), 3 ot, ßβJ-7- / 3- (hexylthio) -methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5- heptenoic acid methyl ester, prepared according to Example

in 6.78 ml of methanol is added dropwise at OC within 4 minutes with 8.37 ml of 0.5M aqueous Natriumperjodatlösung. Then 2 ml of tetrahydrofuran are added

Γ - 56 - _. 1-

and the resulting reaction mixture was stirred for 15 hours at room temperature. A white precipitate forms, which is filtered off and washed with 3 × 50 ml of diethyl ether. The filtrate is washed with 60 ml of saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Evaporation under reduced pressure gives 648 mg of oily crude product, which is chromatographed on 54.16 g of silica gel 60 using 0.5-1, 0% ΟΗ, ΟΗ in methylene chloride as the eluent. You will receive: 211 mg (32 $)

¹⁰ IMI (rapidly migrating isomer) sulfoxide (Example 77) »

142 mg (21 $) SMI (slow migration isomer) sulfoxide (Example 78) and 165 mg (24 #) sulfonone (Example 79). The products are oils that solidify when stored in the freezer. TLC (silica gel, 2 # CH ₃ OHZCH ₂ Cl ₂ ): R _f (in

game 77, sulfoxide) = 0.28; (Example 78, sulfoxide) = 0.21; (Example 79, sulfone) = 0.74; Iodine -

B e i s ρ i e 1 80 / 1ß, 2oc (5Z), 3 <3L, 4ß7-7- / 3- / rHexylsulfonyl) -methyl7-7-oxabi-

²⁰ c; yclo ^ .2.i7hept-2-yl7-5-heptenoic acid

A solution of 165 mg (0.41 mmol) / T, 20 L (5Z), 3oc, 4β7-7-. ^ 5-> FrHexylsulfonyl) -methyl7-7-oxabicyclo ^ 2.2.17hept-2-yl7- ⁱ -5-heptenoic acid methyl ester (Example 79) in 20.3 ml of THF and 3.09 ml of HgO is added under argon as inert gas and stirring

with 3 »90 inl added in aqueous lithium hydroxide solution. The mixture is rinsed vigorously with argon for 10 minutes and then stirred for 6 hours at room temperature. Then, the reaction mixture is acidified to pH with addition of 1N hydrochloric acid and poured into 30 ml of saturated sodium chloride solution. The resulting solution is saturated with solid NaCl and extracted with 4 χ 50 ml of ethyl acetate. The combined acetic acid ethyl ester extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yield: 165 mg crude acid. The cleaning

35 '»' '

is flash chromatographed on 20 g silica gel 60 using 3% CH ₅ OH in CH ₂ Cl ₂ as eluant.

L., '' '.' 'J

^Γ '''''"57 -, -''' -.

guided. Yield: 145 mg ($ 91) of acid title compound which solidifies upon freezer storage. TLC (silica gel, 4 # CH, OH / CHgClg): R _f = 0.32, iodine. Analysis for C ₂₀ H ₃₄ O ₅ S: calc .: C, 62.18, H, 8.81, S, 8.29

found: C'61.99 H 9.01 S 8.33

¹³ C NMR (CDCl ₃ , 15.0 MHz) tau 178.4, 33.1, 24.3,

26.7, 123.9, 130.3, '28 .0, 39.9., 79.8,. 31.1, 28.8, 80.9, 47.0, 54.1, 51.7, 29.4, 27.1, 22.2, 21.9, 13.7

: B e i s ρ i e 1 81

/ Tβ, 2 <K. (5Z), 3 <* -, 4ß7-7- / 3 - / ^ hexylsulf inyl) -methyl7-7-oxabicyclo / 2 \ 2.i7hept-2-yl7-5-heptenoic acid A solution of 211 mg (0.55 _v mmol) / T, 2 <* (5Z), 3 <*, 4β7-7- '^ - / ^ hexylsulfonyl) -methyl ^ -yxabicyclo / ^. 2.17hept-2-yl7-5-heptenoic acid methyl ester (fast migratory isomer), prepared according to Example 77, in 27.0 ml of THF and 4.11 ml of H ₂ O under argon as a protective gas and with stirring with 5.19 ml 1N aqueous lithium hydroxide solution. The mixture is rinsed vigorously with argon for 10 minutes and then stirred for 6 hours at room temperature. Then, the reaction mixture is acidified to pH 4 by addition of 1N hydrochloric acid and poured into 50 ml of saturated sodium chloride solution. The resulting solution is saturated with solid NaCl and extracted with 4 χ 100 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yield: 216 mg of crude acid. Purification is performed by flash chromatography on 20.2 g silica gel 60 using 3 # H ^ OH in CH ₂ Cl ₂ as eluent. Yield: 172 mg (85 $) of acid title compound as a white solid. TLC (silica gel, 4 # CH ₃ OHZCH ₂ CL ₂ ): R _f = 0.10, iodine. Analysis for C ₂₀ H ₅₄ O ^ S: calc .: C 64.83 H 9.25 S 8.65

F .: Ό 64.71 H 9,17 S 8,55

¹³ C NMR ^N (CDCl ₃ , 15.OMHz) tau 176.8, 33.3, 24.5, 26.9, 129.0, 130.2, 28.4, · 41.1, 80.1, 31.2, 28.3, 80U, 47.1, 52.7, 52.7, 29.6, 26.7, 22.6, 22.3, 13.8

Example 82

/ Tβ, 2 oL (5Z), 3 oc, 4β7-7- / 3- / t -hexylsulf inyl) -methyl7-7-oxabicyclo ^ 2.2..i7hept-2-yl7-5-heptenoic Acid A solution of 142 mg (0, 37 mmol) / Ά &, 2 <X_ (5Z), 3 O

methyl heptenate (slow-moving isomer) prepared according to Example 78, in 18.2 ml of TIIP and 2.77 ml of H ₂ O is added under argon as a protective gas and with stirring with 3.50 ml of 1N aqueous lithium hydroxide solution. The mixture is rinsed vigorously with argon for 15 minutes and then stirred for 4 hours and 40 minutes at room temperature. The reaction mixture. is acidified to pH 4 by addition of 1N hydrochloric acid and poured into 30 ml of saturated brine.

The resulting solution is saturated with solid NaCl and extracted with 3 χ 70 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yield: 152 mg of crude acid. Purification is carried out by flash chromatography on 20.8 g silica gel 60 using 4 $ CIUOH in CHpClO as eluent. Yield: 116 mg (85 $) acid title compound. TLC (silica gel, 4 # CH ₅ OHZCH ₂ Cl ₂ ): R _f = 0.6, iodine. Analysis for C ₂₀ H ₇₄ O ^ S: calc .: C 64.83 H 9.25 S 8.65

, ^{J found} : C 64.44 H 9.15 S 8.58

¹³ C NMR (CDCl ₃ , 15.OMH2) tau 33.4, 24.6, 26.7,

12'9.0, 130.3 / 27.1, 41.8, 80.Ö, 31.3,

• 23.4, 81.7, 47.3, 52.8, 52.3, 29.4, 35 27.1, 22.4, 22.4, 13.8

r - 59 -

1 example 83

/Tβ, 2, 5, 5, 5, 3, 3, 3, 3, 3, 3, 7, 7, 7, 7, 7, 9, 7, 7, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5, 5) heptenoic acid (rapidly migrating isomer)

The procedure of Examples 44, 77 and 81 is repeated but using methyl mercaptan instead of 1-hexane oil. It will get the title connection.

B ei s ρ ie 1 84 / f, 2 oC (5Z), 3 "-, 4β7-7- ^ 3- (0ctylsulfinyl) -methyl ^ - oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid ( slowly wandering

Isomer)

The procedure of Examples 44, 77 and 82 is repeated except that 1-octanethiol is substituted for 1-hexanethiol. It will get the title connection.

Example 85

/ ⁷ TB, 2 ck ( 5Z), 3β, 4β7-7- / 3-i / r-phenylsulfinyl) -methylj ^ -oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid (rapidly migrating isomer)

The procedure of Examples 48, 77 and 81 is repeated but substituting phenylmercaptan for 1-pentanethiol. The title compound is obtained.

25 B e i s ρ i e 1 86

/ Tβ, 2oc (5Z), 3 OL, 4ß7-7- ^ 3- ^ ethylsulf inyl) -methyl ^^ - oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid (slow-moving

Isomer)

The procedure of Examples 48, 77 and 82 is repeated but using ethylmercaptan instead of 1-pentanethiol. It will receive the Titelverbindurig.

Example 8?

(1β, 2 O, 3β, 4β) -7- (3- (3-heptylsulfinyl) -methyl) 7- quxabi-0.7010 / 2.2.i7hept-2-yl7-5-heptanoic acid (rapidly migrating isomer)

^L · -J

Γ - 60 -

, The procedure of Examples 46, 77 and 81 is repeated except that 1-heptanethiol is substituted for 1-hexanethiol. It will get the title connection.

Example 88 / ff., 2 0L (5Z), 3 oe, 4-ß7-7- / 3- / CBenzylsulfinyl) -methyl7-7-oxabicyclo ^ 2 \ 2.i7hept-2-yl7-5-heptenoic Acid The process of Examples 4-4, 77 and 81 are repeated except that benzylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

B e i s ρ i e ί 89

, / Tβ, 2α (5Z), 3β, 4β7-7 - ^ - ZrBenzylsulf inyl) -methyl7-7-oxabi-

cyclo / 2.2.i7hept-2-yl7-5-heptenoic acid (slowly migrating ¹ ^ isomer)

The procedure of Examples 4-8, 77 and 82 is repeated except that benzylmercaptan is substituted for 1-pentanethiol. It will get the title connection.

, Be is ρ ie 1 ^90/3 Ti., 2-ol (5Z), 3 ov, W-7- / 3- ^ rCyclohexylsulfinyl) -methyl7-7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid (fast moving Isomer), The procedure of Examples 44, 77 and 81 is repeated except that cyclohexylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

Example 91 / Tβ, 2oc (5Z), 3 OC, 4β7-7-3-ZrCyclopentylsulf inyl) -methyl7-7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid (rapidly migrating isomer)

The procedure of Examples 44, 77 and 81 is repeated except that cyclopentylmercaptan is substituted for 1-hexanethiol. The title connection will be maintained

Γ '- 61 - "Π

χ Be itpiel 92

/ Tβ, 2 oC (5Z), 3 ot, 4β7 ~ 7 - ^ - ^ octylsulfonyl) -methyl7-7-oxa

bicyclo ^ 2.2.i7hept-2-heptenoic yl7-5

The procedure of Examples 44, 77 and 80 is repeated except that octylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

Example 193

/ 1ß, 2 oc (5Z), 3 oC, 4ß7-7-y / 5- ^ propylsulfonyl) -methyl7-7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 44, 77 and 80 is repeated except that propylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

   /. ·. ., .-

15 Example 9V

/ Iβ, 2 oc (5-z), 3 oC, 4β7-7- / 3- ^ t-Phenylsulfonyl) -methyl7-7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 4-4 , 77 and 80 are repeated except that phenylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

, B e i s ρ i e 1 95

<Λβ, 2 <Χ (5Ζ), 3 oL, 4ß7-7 - ^ - / 0Benzylsulf onyl) -methyl7-7-oxabicyclo ^. 2 .i7hept-2-yl7-5-heptenoic acid The procedure of Examples 4Λ, 77 and 80 is repeated except that benzylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

For s ρ i e 1 96

/ Tβ, 2α (5Z), 3 c *, 4β7-7 - ^ - / t -cyclohexylsulfonyl) -methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 44, 77 and 80 is repeated, but cyclohexylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

^L. J

Γ:. ·: -62 -. Π

1 example 97

i, 2 OL (5Z), 5β, 4β7-7-Z3-ZrHeptylsulfonyl) -methyl- - -oxabicyclo / S., /I / hept ^ -ylT ^ -hepenoic acid The procedure of Examples 48, 77 and 80 repeated, but using 1-heptanethiol instead of 1-pentanethiol. It will get the title connection.

: B e i s ρ i e 1 98

/ TSS, 2oc (5Z), 3ss, 4ß7-7-Z3 / rBenzylsulfonyl) -methyl7-7-

The procedure of Examples 48, 77 and 80 is repeated except that benzylmercaptan is substituted for 1-pentanethiol. It will get the title connection.

¹⁵ B ice ρ ie 1 99

7-oxabicyclo / 2 *. 2. i7hept-2-yl7-5-heptenoic acid The procedure of Examples 48, 77 and 80 is repeated but using cyclopentylmercaptan instead of 1-pentanethiol. It will get the title connection.

Example 100

£ \ B>, 2 ol (5Z), 3R ^ & 7 "7" - / i3 / X ^ -Q ^ 7 ^ -svLlfoTiyl) -methjl7-7 · ^"25 oxabicycl0 ^ 2.2.i7hept-2-yl7-5 heptenoic acid

The procedure of Examples 48, 77 and 80 is repeated but using phenyl mercaptaii instead of 1-pentanethiol. It will get the title connection.

³⁰ Example 101

(iß, 2c <- _i 3 ^ _i ^ ß) -7-Z3 ~ Z ^ y ^c ^ ^o P ^ro py ^ ^su ^^^ ⁿ y- ' ^L ) "" ^me * ⁿ yl7--7-oxabicycloZ ^ .2.i7hept-2-yl7-5-heptanoic acid The procedure of Examples 46, 77 and 80 is repeated except that cyclic propyl mercaptan is substituted for 1-hexanethiol. It will get the title connection.

L,. J

Example 102 '

(Iβ, 2 oc, 3 ^, 4β) -7- ^ - / l -benzylsulfinyl) -methyl7-7-oxabicyclic / Ζ2,17hept-2-yl7-5-heptanoic acid. The procedure of Examples 47, 77 and 81 becomes but benzylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

Example 103

flB, 2 oc (5Z), 3 <*, 4-ß7r? -45 ^ 2 _T (Pentyl8uIf inyl) -ethyl7-7-oxabicyclp ^ 2.2 .i7hep1? -2-yl7T5 ^ heptene The procedure of Examples 63 j 44 77% 81 is repeated except that 1-pentanethiol is used instead of 1-hexanethiol. It will get the title connection.

- .. ν B ice ρ ie 1 104- / Tβ, 2 oc (5Z), 3 oc, 4-ß7-7 - ^ - ^ 2- (phenylsulfonyl) ethyl7-7-oxabicyclo ^ S.2.i7hept -2-yl7-5-heptenoic acid The procedure of Examples 63, 44, 77 and 80 is repeated except that phenylmercaptan is substituted for 1-hexanethiol. It will get the title connection. '

Example 105

/ 'i, 2 (* * (5Z), 3 OC, 4ß7-7- / 3- ^ 2- (cyclohexylsulfonyl) ethyl7-7-oxabicyclo ^ 5.2.i7hept-2-yl7-heptenoic acid The procedure Examples 63, 44, 77 and 80 are repeated except that cyclohexylmercaptan is used instead of 1-hexanethiol to give the title compound.

Example 106

oxabicyclo ^ .2.17hept-2-yl7-5-heptenoic acid The procedure of Examples 63, 44, 77 and 81 is repeated except that benzylmercaptan is used instead of 1-hexanethiol to give the title compound.

, -. Example 107

/ Τβ, 2α (5Ζ) ', 5B, W-7-Z3-Z ² - ( ^But 7 ^- isulfonyl) -ethyl 7-7-oxabicyclo ^ 2/2-i7hept-2-yl7-5-heptenoic acid The process of Examples 63, ^z l-8.77 and 80 are repeated but with butylmercaptan instead of 1-pentane.

thiol is used. It will receive the title connection. ·., '.....

Example 108

/ ^? Tβ, 2a. (5Z), 3β, ωβ: -7- _i f3 - "- (phenylsulfinyl) ethyl 7,7-oxabicyclo [2.2.27hept-2-yl7-5-heptenoic acid The procedure of Examples 63, 8, 77 and 81 are repeated except that phenylmercaptan is used instead of 1-pentanethiol to give the title compound.

B ic ρ i "el 109.β3β7-7- / 5- ^ 2- (Benzylsulfinyl) -ethyl 7-7-.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 63, 48, 77 and 81 is repeated but benzylmercaptan is used instead of 1'-pentanethiol to give the title compound. ". ^! · '·. '

Example 110

7- ~ 3xabicyclo / 2.2.i7hept-2-yl7-5-nectic Acid The procedure of Examples 63, 48, 77 and 80 is repeated * but using cycloheptylmercaptan instead of 1-pentanethiol. It will get the title connection.

, B e i s ρ i e 1 111 (1β, 2cC, 3o <., 4β) -7- / 3-y / 2- (pentylsulfonyl) -ethyl 7-7-oxabi-

The process of Examples 63, 46, 77 and 80 is repeated.

L '' ', J

but using 1-pentanethiol instead of 1-hexanethiol. It will get the title connection.

Example 112 (1ß, 2oC, 3ot, 4SS) -7 - ^ - Z ~ ^{2 (phen} y ^lsulfin y ^l) - ^eth-yi7-7 oxabi--

cyclo / 5.2.17hept-2-yl7-5-heptanoic acid

The procedure of Examples 63, 46, 77 and 81 is repeated except that phenylmercaptan is substituted for 1-hexanethiol. It will get the title connection.

At s ρ i e 1 113 ι

(1β, 2 Λ, 3 * *, 4β) -7-5-5 / 2- (benzylsulfinyl) -ethyl 7-7-oxabicyclo 2.2 2.2.i7hept-2-yl7-5-heptanoic acid ° The procedure of Examples 63, 46 , 77 and 81 are repeated except that benzylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

20 B β i s ρ i'.e 1 114

oxabicyclo / 5.2.i7hept-2-yl7-5-heptanoic acid

WI mm ot. .,

The process of Examples 63, 48, 77 and BO is repeated, but using cyclohexylmercaptan instead of 1-hexanethiol. It will get the title connection.

example

/ iβ, 2Λ (5Ζ), 3α, 4β7-7 - ^ - / ZF- (pentylsulfonyl) -butyl7-7-oxabicyclo / 5.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 73, 63, 44, 77 and 80 are repeated, except that Eentylmercaptan is used instead of 1-hexanethiol. It will be the title link

receive.

L. '' '-' '· J.

Γ - '. .. - 66 -

Bels pi el 116 / ϊβ, 2 0L (5Z), 3 cL , W-7-Z5-Z ^Z5: - ( ^c y ^clohex y ^lsulf i ^ ¹ ) -butyl-7-V-oxabicyclo ^ S.2.17hept-2 -yl7-5 ~ heptenoic acid The procedure of Examples 73, 63, '44, 77 and 81 is repeated except that cyclohexylmercaptan is substituted for 1-hexanethiol. The title connection is received ·

Example 117

/ ΐβ, 2 <λ (5Ζ), 3 a., 4 | 7-7- ^ 3- ^ ² i- (Hienylsulfinyl) -butyl 7-7-oxabicyclo> /2.2. i7hept-2-yl7-5-hept-ene acid The procedure of Examples 73, 63, 44, 77 and 81 is repeated except that phenylmercaptan is used in place of 1-hexahydric oil. It will get the title connection.

Example 118

/Tβ,2(X.(5Z), 3 c ^, 4β7-7- / 5-A- (benzylsulfonyl) -butyl7-7-oxabicyclo ^ S.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 73, 63, 44, 77 and 80 are repeated except that benzylmercaptan is used instead of 1-hexanethiol to give the title compound. "

Example 119 / Tβ, 2 LL (5Z), 3β, 4 ^7-7- ^ 3- ^ 5- (cyclopentylsulfinyl) -butyl 7-7-oxabicyclo / 2.2.i7hept-2-yl 7-5 -propanoic acid The procedure of Examples 73, 63, 48, 77 and 81 is repeated except that Cyclopentylmercaptan is used portions of 1-pentanethiol. It will get the title connection.

Γ -. _ - - 67 - '·' Π

Example 120

/ iβ, 2α (5Ζ), 3β, W-7-Z3-Z ⁵ - C benzylsulfinyl) -butya.7-7-

oxabicyclo ^ 2 \ 2.i7hept-2-heptenoic yl7-5

The procedure of Examples 73, 63, 48 ', 77 and 80 is repeated except that benzylmercaptan is substituted for 1-pentanethiol. The title connection is obtained.

  B ei s- ρ ie I 121

/Tβ,2OC(5Z), β,4,47,7-7-/3-/5- (propylsulfinyl) -butyl, 7-7-oxabicyclo / 2,2.i7hept-2-yl-7,5-pentahydrene The procedure of Examples 73 »63, 48 , '77 and 81 is repeated, but propylmercaptan is used instead of 1-pentanethiol. It will get the title connection.

15 "B e i s pie I 122

/ TSS, 2 cx (5Z), 3ss, 4ß7-7 - ^ - Z ^2f - ^ y ^{Plien lsulf 0} ^ ¹⁾ -butyl7-7-oxabicyclo / 2.2.17hept-2-yl7-5-heptenoic acid The procedure of Examples 73, 63, 48, 78 and 80 are repeated except that phenylmercaptan is used instead of 1-pentanethiol. It will get the title connection.

Example 123 (1 beta, 2 OL, 3 oL, 4SS) -7- / 5 - ^ - (Nonylsulf ynyl) -butyl7-7-oxabicyclo

The procedure of Examples 73, 63, 46, 77 and 81 is repeated but using .1-nonanthi oil instead of 1-hexanethiol. The compound of the invention is obtained.

Example 124

(1ß, 2oc, 3 <Ä 4SS..) -7 - ^ - Z5 (pentylsulfonyl) -butyl7-7-oxabicyclo / 2.2.i7hept-2-heptanoic yl7-5

The procedure of Examples 73 »63» 46, 77 and 80 is repeated except that 1-pentanthi oil is used instead of 1-hexanethiol. It will get the title connection.

L ..-. , -. _ ', j

1 example 125 ·. ' '

(I, 2 oil, 3 c *, 4β) -7- / 3- / 5- (phenylsulfinyl) -butyl 7-7- '

oxabicyclo / 2.2.i7hep't-2-yl7-5-heptenoic acid. '·

The procedure of Examples 77, 63, 46, 77 and 81 is repeated except that phenylmercaptan is used instead of 1-hexanethiol. It will get the title connection.

, , - '' 'j'

Example 126,

(1β, 2 xx, 3 CC, 4β) -7---- (cyclohexylsulfonyl) -butyl 7-7-

10 oxabicyclo ^ 2 \ 2.i7hept-2-yl7-5-heptanoic acid

The procedure of Examples 73, 63, 46, 77 and 80 is repeated but using cyclohexylmercaptan instead of 1-hexanethiol. It will get the title connection.

B e i s ρ i e 1 127

/ Tβ, 2 oi (5Z), 3 <*, ^ - ß7-7TZ5- / Z ^ yclohexylmethyl) -thio7-methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid

20 A.

methyl7-7rOxabicj ^r clo / 2.2.i7hept-2-yl7-5-heptenoic acid methyl ester

A solution of 88 mg (0.78 mmol) potassium tert-butoxide in 5 ml of anhydrous THP is added under argon as inert gas with 277 mg (2.13 mmol) of cyclohexylmethanethiol (prepared from cyclohexylmethanol according to the method of Volante: Tetrahedron Letters Vol. 22 (1981), page 3119). This mixture is then washed with a solution of 300 mg (0.71 mmol) / 1β, 2oL (5Z), 3 * *, 4-ß7-7 - / ^ - (p-toluenesulfonyl oxymethyl) -7-oxabicyclo ^ ^ hept ^ -y ^^ - heptenoic acid methyl ester, prepared according to Example 44 B, mixed in 5 ml of anhydrous THF. The reaction mixture is refluxed for 7 hours. After cooling, the reaction mixture with 250 ml of diethyl ether, diluted and poured into ^ 00 ml of saturated sodium bicarbonate solution. The aqueous layer is extracted with 2 × 100 ml of diethyl ether. The United

'.L-' '' \ '..' 'J

Γ ./ ·. · - 69 -

Ether extracts (4-50 ml) are washed with 2 × 100 ml of 0.5N aqueous sodium hydroxide solution and 100 ml of saline. The ether extracts are then dried over anhydrous magnesium sulfate and evaporated under reduced pressure to an oily product. The purification is carried out by chromatography on 20.2 g of silica gel 60 using hexane: diethyl ether in a ratio of 3: 1 as the eluent. Yield: 253 mg of methyl ester title compound A as an oil (94 #). TLC (silica gel, petroleum ether: diethyl ether = 3: 2): R _f = 0.70, iodine. .

β.

raethyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid A solution of 24-3 mg (0.64 mmol) of methyl ester of Part A in 31.4 ml of TKP and 4-8 ml of H ₂ O. is added under argon as protective gas -ηηά while stirring with 6.00 ml of 1N aqueous lithium hydroxide solution. The mixture is vigorously purged with argon for 25 hours and then stirred at room temperature for 16 hours. Then the reaction mixture is acidified to pH 5 by addition of 1N hydrochloric acid and poured into 4-0 ml of saturated saline. The resulting solution is saturated with solid NaCl and extracted with 4; extrahiert Extract 50 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate, filtered and evaporated under reduced pressure to 253 rag crude acid. The purification is carried out by flash chromatography on 20.6 g of silica gel 60 using petroleum ether: diethyl ether in a ratio of 2: 3 as the eluent. Yield: 117 mg (50%) of pure title compound together with 108 mg (4-6%) of mixed fractions of which the title product is the major component. TLC (silica gel, petroleum ether: diethyl ether = 2: 3): R _f = 0.32, iodine.

Analysis for C ₂₁ H ₅₄ O ₃ S: calc .: C 68.85 H 9.29 S 8.74

Found: C, 68.90, H, 9.4, S, 8.66, ¹³ C NMR (CDCl ₃ , 15.0 MHz), tau 178.7, 32.9, 24.6, 26.1,

129.7, 129.9, 29.5, 47.1, 80.4, 25.7, 26.3, 80.7, 47.6, "33.4, 40.4, 38.0, 32.9, 29.5,

26.1, 29.5, 32.9

r - '; - 70. "J

! Example · 128

, 3 o 7-oxabicyclo / 2.2.17hept-2-yl7-5-heptenoic acid

, 3 oC

Methyl 7-oxabicyclo ^ 2 \ 2.27hept-2-yl7-5-heptenoic acid A solution of 55> 7 mg (G, 50 mmol) of potassium t-butoxide in 5 ml of anhydrous THP is added under argon to 185 mg (1 , 35 mmol) phenyläthanthiöl added. This mixture is then washed with a solution of 189 mg (0.4-5 mmol) / T, 2 × (5Z) -3 oCi ^Z * -β7-7- ^ 3- {p-toluenesulfonyloxymethyl) -7-oxabicyclo- The reaction mixture is heated under reflux for 4 hours and 30 minutes, after cooling, the mixture is dissolved in 6 ml of anhydrous TEF diluted with 160 ml of diethyl ether and poured into 60 ml of saturated sodium bicarbonate solution The aqueous layer is extracted with 2 × 60 ml of diethyl ether The combined ether extracts (280 ml) are treated with 2 × 60 ml of 0.5N aqueous sodium hydroxide solution and 75 ml . washed ml saline The ether extracts are ¹ then dried over magnesium sulfate and evaporated under reduced pressure to an oily product purification is by chromatography on 21.6 g silica gel using petroleum ether.:. conducted diethyl ether in the ratio 5Ά as the eluent yield: 157 mg ($ 90) Title Link A as TLC (silica gel, petroleum ether: diethyl ether = 2: 1): R _f = 0.60, iodine.

  B. / Iß, 2 <*. (5Z), 3 Ä

30 7-oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid

A solution of 150 mg {0.39 mmol) of methyl ester of Part A in 19 ml of freshly distilled THF and 2.91 ml of H ₂ O is added under argon as a protective gas and while stirring with 3 * 64 ml of 1N aqueous lithium hydroxide solution. This mixture is rinsed vigorously with argon for 25 minutes and then stirred at room temperature for 6 hours. The reaction mixture is through

L '. , - J

Ί addition of 1N aqueous hydrochloric acid acidified to pH 5 and then poured into 40 ml of saturated saline. The resulting solution is saturated with solid NaCl and washed with

4 χ extracted 60 ml of ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting 147 mg of crude acid are purified by IPlash chromatography on 20 g silica gel 60 using 2% CHxOH in GH ₂ Cl ₂ as eluent. Yield: 122 mg ($ 84) of the title compound as an oil. TLC (silica gel, 6 $ CH ^ OH in CH ₂ Cl ₂ ): R _f = 0.32, iodine.

Analysis for C ₂₂ H ₂ O ₂ O: Calcd .: 0 70.55 H 8.07 S 8.56

Found: C 70.54 H 8.08 S. 8.48

¹³ C NMR (CDCl ^ ₁ 15.0 MHz) tau 179.0, 33.4, 24.5, 26.2, 129.9, 129.7, 26.7, 46.9, 80.4, 29.5, 80.6, 47.5, 32.3, -34.1, 36.4, 140.5, 128.4, 126.3, 128.4, 123.4

20 '^ Example 129

, A, 2 oc (5z) ,? λ, 4β7-7- / 5-ZZr3-phenylpropyl) thio7-methyl7-7-xabicyclo / ^ 5.2.i7hept-2-yl7-5-heptenoic acid

* / A. ^ ß, Eoc (5Z), 3a., 4ß7-7-Z5-ZZr3-phenylpropyl) -thio7- _a πleth} ί l7-7-oxabicyclo ^ 2.2.1 ^ lept-2-yl7-5- heptensäure-

methyl ester A solution of 88 mm (0.78 in mol) potassium tert-butoxide in

5 ml of anhydrous THF are added under argon with 324 mg (2.13 mmol) of 3-phenylpropyl mercaptan. This mixture is then treated with a solution of 300 mg (0.71 mmol) ^ ⁱ TSs 2ot (5Z), 3 <x ", 4ß7- '^ 7- 3- (p-toluenesulfonyloxymethyl) -7-oxäbicyclo ^ 2 / 2.i7hept-2-yl7-5-heptenoic acid methyl ester in 7 ml of anhydrous THF was added. The reaction mixture is refluxed for 6 hours and 30 minutes. After cooling, the mixture is diluted with 250 ml of diethyl ether and poured into 100 ml of saturated sodium bicarbonate solution. The aqueous layer is

_{Γ (} - 72 - - π

extracted with 2 χ 100 ml of diethyl ether. The combined ether extracts (450 ml) are washed with 2 × 100 ml of 0.5N sodium hydroxide solution and 100 ml of brine. The ether extracts are dried over magnesium sulfate and evaporated under reduced pressure. The oily product obtained is purified by chromatography on 25 g of silica gel 60 using hexane: diethyl ether in the ratio 3: 1 as eluent. Yield: 280 mg ($ 98) Title Compound A as an oil. TLC (silica gel, petroleum ether: diethyl ether = 2: 1): R _f = 0.60, -, iodine.

B. / Tβ, 2 <x. (5Z), 3 Λ, 4β7-7 - ^ - / Zr3-phenylpropyl) -thio7-

- methyl 7-7 ~ oxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid A solution of 280 mg (0.70 mmol) of methyl ester of Part A in 34.4 ml of freshly distilled THP and 5.30 ml of H ₂ O. is added under argon as a protective gas and with stirring with 6.60, ml of 1N aqueous lithium hydroxide solution. This mixture is purged with argon for 1 hour and then stirred for 3 hours at room temperature. The reaction mixture is acidified to pH 5 by addition of 1N hydrochloric acid and then poured into 50 ml of saturated brine. The resulting solution is saturated with solid NaCl and extracted with 4 χ 60 ml of ethyl acetate. The combined Essigsäureäthylesterextrakte are dried over magnesium sulfate and evaporated under reduced pressure. The resulting 280 mg of crude acid are purified by flash chromatography on 29 g silica gel 60 using 2% CH ₅ OH in CH ₂ Cl ₂ as a mobile mill. Yield: 205 mg ($ 76) of the title compound. TLC (silica gel, 6 # CH ₅ OHZCH ₂ Cl ₂ ): R _f = 0.34-, iodine.

Analysis for C ₅₅ H ₅₂ O ₃ S: calc .: C 71.09 H 8.30 S 8.25

found: C 70.81 H 8,36 S 8,14

¹³ C NMR (CDCl ₃ , 15 OMHz) tau 179.0, 33.4, 24.7, 26.7, 129.7, 129.8, 29.5, 46.9, 80.4,

, 29.5, 80.6, 47.5, 32.1, 31.9, 26.2, 34.7,

141.4, 128.4, 128.4, 125.8, 128.4, 128.4

L,. , · J

r - 73 - '. , ~ ι

1 example Ι30

/ Tβ, 2 Λ (5Ζ), 3β, 4β7-7-Z3-ZZrCyclohexylmethyl) -thio7-methyl7-7-oxabicycloZ2.2. i7liept-2-yl7-5 "· heptenoic acid The procedure of Examples 4-8 and 49 is repeated but using cyclohexylmethanethiol instead of 1-pentanethiol to give the title compound.

B e i s ρ i e 1

methyi7-7-oxabicycloZ2.2i7hept-2-yl7-5-heptanoic acid The procedure of Examples 48 and 4-9 is repeated except that 3-cyclohexylpropanethiol is substituted for 1-pentanethiol. It will get the title connection.

15 Example 132

(1ß, 2 <*, 3 ot, 4SS) -7'-Z3 / Z'C ² - y ^{c clohex läth} y y ¹⁾ - ^{thi-27-niethyi7-7} oxabicycloZ2.2.i7hept-2-yl7- 5-heptanoic acid The procedure of Examples 4-6 and 47 is repeated except that 2-cyclohexylethanethiol is substituted for 1-hexanethiol to give the title compound.

Example 133

Z ^ ß, 2ot (5Z), 3ss, 4ß7-7- / 5-ZZ ^ ² -P ^hen 7 ^läth y ¹⁾ -thio7-methyl7-7-oxabicycloZ2.2.i7hept-2-yl7-5-heptenoic acid The The procedure of Examples 48 and 49 is repeated except that 2-phenylethanol is substituted for 1-pentanethiol. It will get the title connection.

Example 134

/ TSS, 2oc (5Z), 3ss, _4ßZ-7-Z3-P ZZr3-Phenylpro yl) -thio7-methyl7-7-oxabicyclo / 2.2.17hept-2-yl7-5-heptenoic acid The procedure of Examples 48 and 49 is but using 3-phenylpropanethiol instead of 1-pentanethiol. The title connection will be maintained

³⁵ th.,

L. · · 'J

r '-, - 74.-,. '. ~ ι

1 . Example 135

(1β, 2 *, 3 öt, 4β) -7- ^ 5- ^ ZT2-phenylethyl) rthio7-methyl7-7-

The procedure of Examples 46 and 47 is repeated but using 2-phenylethanol instead of 1-hexanethiol. It will get the title connection.

, B e i s pi e 1 136

10 oxabicyclo / 5.2.17hept-2-yl7-5-heptenoic acid

The procedure of Examples 46 and 48 is repeated except that 3-H-butyl propanethiol is substituted for 1-hexanethiol. It will get the title connection.

15 ~ Example 137

methyl7-7-oxabicyclo / 2.2.i7hept-2-yl7-5-heptenoic acid (slowly migrating isomer)

The procedure of Examples 44, 77 and 81 is repeated except that cyclohexylmethanethiol is substituted for 1-hexanediole. It will get the title connection. .,>.

B e i s ρ i e 1 138

/1β,2ot(5Z) ss4β7-7-/5- ^ ZTCyciohexylmethyl) -sulfinyl-7-methyl-7-7-oxabicyclo) -2,2.i7hept-2-yl-7-5-heptenoic acid (rapidly migrating isomer)

The procedure of Examples 48, 77 and 81 is repeated except that cyclohexylmethanethiol is substituted for 1-pentanethiol. It will get the title connection. , · '

Example 139

/ Tß, 2 «. (5Z), 3ß, 4ß7-7- ^ 5-ZZr2-phenylethyl) -sulf inyl7-methyl7-7-oxabicyclo _< /5.2.i7hept-2-yl7-5-heptenoic acid (rapidly migrating isomer) The procedure of Examples 44, 77 and 81 is repeated,

L '-'. J

however, 2-phenylethanethiol is used instead of 1-pentanethiol. It will get the title connection. V

Example 140 *.,

methyl7-7-oxabicyclo / 2.2. ^ 7hept-2-yl7-5-heptenoic acid (slow moving isomer)

The procedure of Examples 48, 77 and 82 is repeated except that 3-PKenylpropanethiol is substituted for 1-pentanethiol. It will get the title connection.

Example 141

C1ß, 2ot, 3 ^, 4-ß) -7-Z5-ZZr2-phenylethyl) -sulfinyl-7-methyl-7-7-oxabicycloZ2.2.17hept-2-yl7-5-heptanoic acid ₍ (rapidly migrating isomer)

The procedure of Examples 46, 77 and 81 is repeated except that 2-phenylethanol is substituted for 1-hexanethiol. It will get the title connection.

20 Example 142

methyl7-7-oxabicyclo / 2 \ 2.17hept-2-yl7-5-heptenoic acid. The procedure of Examples 44, 77 and 80 is repeated using cyclohexylmethanethiol instead of 1-hexanethiol. It will get the Titelyerbindung.

Example 143

/ Tβ, 2 <x (5Z), 3λ, 437-7- / 3-ZZt2-phenylethyl) -sulfonyl7-methyl7-7-oxabicycloZ2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 44, 77 and 80 are repeated, but using 2-phenylethanol instead of 1-hexanethiol. It will get the title connection.

L J

r, - 76 -. "π

1 Be i spie 1 144

/ 1ß, 2OL (5Ζ), 3 _A, 4ß7-7-Z3-ZZr3-phenylpropyl) -sulfonyl7-methyl7-7-oxabicyclo / 2.2.i7hept-2 ~ yl7-5-heptenoic acid

The procedure of Examples 44, 77 and 80 is repeated but using 3-phenylpropanethiol instead of 1-hexanethiol. The title compound is obtained.

For s ρ i e 1 145

/ ⁵ Tb, λ 2 (5Z), 3 oil, 4ß7-7- / 5 "42- ^ y ^{c clohex lmeth} y y ¹⁾ -thio7-

10 ethyl 7-7-oxabicyclo / 2.2.17hept-2-yl7-5-heptenoic acid

The procedure of Examples 63 and 44 is repeated except that cyclohexylmethanethiol is substituted for 1-hexanethiol. It will get the title connection «

15 Be i s p'i e 1 146

/ iβ, 2 öc (5z), 3 <x. _t 4ß7-7 - ^ - Z ² - / ^ y ^{c clohex lmetn} y y ¹⁾ - ^{sul;. f in} yl7-äthyl7-7 "Oxabicy ⁱ cloZ2.2 i7hept-2-yl7-5-heptenoic acid The procedure of Examples 63, 44, 77 and 81 are repeated except that cyclohexylmethanethiol is used instead of 1-hexanethiol to give the title compound.

Example 147

/Tβ,2<X.(5Z) 3 Ä, 4ß7-7 - ^ - Z2- / cyclohexylmethyl) -sulfonyl-7-ethyl-7-7-oxabicycloZ2.2.17hept-2-yl7-5-heptenoic acid The procedure of Examples 63, 44, 77 and 80 are repeated except that cyclohexylmethanethiol is used instead of ν 1-hexanethiol. It will get the title connection.

Example 148

/ TSS, 2ct (5Z), 3 <X, 4ß7-7- / 5-22-Zr2-phenylethyl) -thio7-oxabicyclo äthyl7-7 ~ _{</2\2.i7hept-2-yl7~5-heptensäure} The method of Examples 63 and 44 is repeated, but using 2-phenylethanol instead of 1-hexanethiol. »The title compound is obtained.

, Example 149 .. ^χ ''

/ Τβ, 2 OC (5Ζ), 3R, 4ß7-7-Z3-Z ^ Z ^ ² ~ "y ^{Pnen lä} thyl) -sulf i'nyl7-äthyl7-7-oxabicycloZ2.2.i7hept-2-yl7-5 -heptenic acid The procedure of Examples 63, 44, 77 and 81 is repeated except that 2-phenylethanethiol instead of 1-hexanethiol

ν

is used. It will get the title connection.

Example 150 / Tβ, 2 <* (5Z), 3 <X, 4β7-7-Z ⁵ - / ^ 5-phenylpropyl) -thio7-ethyl-7-7-oxabicycloZ2 \ 2.i7hept-2-yl7-5-heptenoic acid ⁷ The procedure of Examples 63 and 44 is repeated but using 3-phenylpropanthi oil instead of 1-hexanethiol. It will get the title connection.

Example '151 ziss, 2t * (5Z), 3 ot, 4ß7-7-Z3-Z ² -Zr3-phenylpropyl) -sulfinyl7-äthyl7-7-oxabicycloZ2.2.i7hept-2-yl7-5-heptenoic acid The method of the Examples 63> 44, 77 and 81 are repeated except that 3-phenylpropanethiol is used instead of 1-hexanethiol. It will get the title connection.

Example 152

Z ¹ TB, 2 <x (5Z), 3 Λ, 4B7-7-Z3-Z ² "-Zt ² -phenyl-ethyl) -sulfonyl-7-ethyl-7-7-oxabicycloZ 3,2.i7hept-2-yl 7-5-heptenoic acid The procedure of Examples 63, 44, 77 and 80 is repeated except that 2-phenylethanethiol is used in place of 1-hexanethiol to give the title compound.

Example 153

Ethyl 7-7-oxabicycloZ2.2.i7hept-2-yl7-5-heptenoic acid The procedure of Examples 63, 44, 77 and 80 is repeated but using 3-phenylpropanethiol instead of 1-hexanthipl. It will get the title connection. ,

L-

r. "·. - 78 - 1, B e i s ρ i el 154

/ TSS, 2ot (5Z), 3 ö butyl7-7 ^b -Oxabicyclo ^_<i /2.2.i7bept-2-yl7- 5-heptenoic acid. The procedure of Examples 73 * 63 and 44 is repeated except that cyclohexylmethanethiol is substituted for 1-hexanethiol. It will get the title connection.

Be as' 1 155 / Tß-, 2 Λ (5Ζ), 3 Λ _i 4ß7-7 - ^ - ^ ^z i ^: - / rCyclohexylmethyl) -sulf inyl7-

10 butyl 7 ~ 7 ~ oxabicyclo / 2.2.i7hept-2 ~ yl7--5-heptenoic acid

The procedure of Examples 73, 63, 44, 77 and 81 is repeated except that cyclohexylmethanethiol is substituted for 1-hexanethiol. It will get the title connection.

 '' ·. '·. , '.

Example 156

/ fiss, 2oc (5Z), 3 oC, 4 7 ~ 7 »/ 3- ₍ / (cyclohexylmethyl) -sulfonyl-7-butyl-7-7-oxabicyclo) -2.2.i7hept-2-yl-17-pentanoic acid The procedure of Examples 73, 63, 44, 77 and 80 are repeated except that cyclohexylmethanethiol is substituted for 1-hexanethiol. It will get the title connection.

Example 157

^ r, 2oc (5z), 3 «, 4ß7-7-Z ^ - ^ ~ / ^ ² - ^phen 7 ^läth y ¹ ) - ^thio l7-butyi7--7-oxabicyclo _i /2.2.i7hept-2-yl7 -5-heptenoic acid The procedure of Examples 73, 63 and 44 is repeated except that 2-phenylethanethiol is substituted for 1-hexanethiol. It will get the title connection.

B e is ρ ie I 158

/ ⁵ TB, 2 Λ (5Ζ), 3 ot, 4ß7-7 - ^ - / IF ^ 2-phenylethyl) ~ sülf inyl7-butyl7-7-pxabicyclo ^ 2.2.i7hept-2-yl7-5-heptenoic acid The procedure Examples 73, 63, 44, 77 and 81 are repeated except that 2-phenylethanol is substituted for 1-hexanethiol. It will get the title connection.

r - - 79 -. π

1 B e i s ρ i e I 159

{Λ% , 2oc (5Ζ), 3 Λ _i 4β7-7-Z3-Z ^Z i ^: -Zr 2 -phenylethyl) -sulfonyl7-

butyl 7 ~ 7-oxabicyclo / 2 \ 2.i7hept-2-yl7-5-heptenoic acid

The procedure of Examples 73, 63, 44, 77 and 80 is repeated but using 2-phenylethanol instead of 1-hexanethiol. It will get the title connection.

'Example 160

10, /Tβ,2i<(5Z) 3β,4β7-7-Z3-/2- (heptylthio) ethyl-7,7-oxabicycloZ2.2.i7hept-2-yl-7α5 -heptenoic acid and methyl ester By reacting Z ^ ß ^»2ot i5z) 3 <*, W-7- / 3- (2-HydΓOxyäthyl) -7-oxabicycloZ2 \ 2.17hept-2-yl7-5-heptenoic acid methyl ^ ester (see Example 20 B) with tosyl chloride according to Example A4 B and with heptanethiol according to Example 44 C, the title compound is obtained as a methyl ester as a colorless oil. TLC (silica gel, hexane / diethyl ether = 2: 1): R _f = 0.45. Hydrolysis by the method of Example 45 gives the free acid as an oil. TLC (silica gel, 3 # CH ^ OH / CHgCLg): R _f = 0.23. 2C analysis for ^C 22 ^H 38 ° 3 ^{S: over : c} 69.06 H 10.01 S 8.38

Found: C 68.80 H. 9.99 S 8.24

¹³ C NMR (CDCl ₃ , 15.0 MHz) tau 178.8, 33.4, 22.5, 24.5,

129.5, 130.1, 26.6, 46.1, 80.1, 29.7, 29.7, 80.1, 47.3, 32.3, 31.7, 31.7, 29.5, 28.8, 32.3, ^2E 28.8, '26.6, 13.9

B ic pi e 1 161 / 13.2 ä (5Z), 3ά (Ε), 4β7-7-Z3-ZZ ^ 3-phenyl-2-prppenyl) -thio7-methyl7-oxabicycloZ2.2.i7hept-3yl7-5 -liepensäure and -methylester

The procedure of Example 44 is repeated but using 3-phenyl-2-propenylthiol instead of 1-hexanethiol in Example 44C. It will get the title connection. TLC (silica gel, hexane: diethyl ether = 2: 1):

L "· J

 1

R = 0.35. The free acid is obtained by hydrolysis according to Example 45. TLC (silica gel, 3 # CH ₃ OHZCH ₂ Gl ₂ ): R _f = 0.25. Analysis for C ₂₃ H ₃₀ O ₃ S: Calcd .: C 71.46 H 7.82 S 8.30

found: 0 71.3 ^ H 7.87 S 8.26. ' ^: . . ' · '.... -. ...

10

20

30 35

Claims (20)

invention claim 1. A process for the preparation of 7-oxs-bicycloheptan-substituted prostaglandin analogues of the general Formula I CH-A- (CHO-CO ₉ R 10 / \ ^ Τ ' and all stereoisomers thereof, wherein A is one of the groups -CH = CH- or - (CHg ^ ^-, B represents an oxygen atom (-0-) or a group of the formula -S-, m is 1 to 8 and η is 1 to 4, R is hydrogen, alkyl, alkali metal or tris (hydroxymethyl) amino A I and R represents an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkinyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl radical, characterized in that a compound of the general formula II ^ FCH -A- (CH.) -CO ₂ alkyl II is converted in a conventional manner by reaction with a compound of Kormel R -OH or or thioether. Ί Ί ·· Connecting the Kormel R -OH or R-SH in an ether L j 2. The method according to item 1, characterized in that the radical B is an oxygen atom (-O-). 3- Method according to item Ί, characterized in that the radical B is a sulfur atom (-S-). 4. Method according to item 1 to 3 »characterized in that the radical A is a group of the formula -CH = CH-. 5. Method according to items 1 to 3 »characterized by that the radical R is a hydrogen atom *, / 6. Method according to items 1 to 3> characterized in that η has the value Λ . 7. Method according to item 1 to 3 », characterized in that η has the value 2. 8. The method according to item 1 to 3, characterized in that η has the value 3 or 4. 9- method according to item Λ to 3, characterized in that the radical A is a group of formula, -CH = CH-, m is a value of 2 to 4 and η is 1 or 2, the radical R is a hydrogen atom is and the rest R • represents a lower alkyl or cycloalkyl radical. 10. The method according to 'items 1 to 3, characterized in that the radical A is a group of the formula -CH = CH-, m is 3 and η is 1, R is a hydrogen atom, a methyl group or a CgH ^ - Group represents and R represents a lower alkyl radical. 11. The method according to item 1, characterized in that ' / Tβ, 2 <(5Z), 3pC, 4β7-7- / 3'-ZTHexyloxy) -methyl7-7-pxabicycio / 2.2.27 ^he P ^t " ² ~ Yl7-5-heptenoic acid and its hexyl ester. 12. The method according to item 1, characterized in that / Tβ, 2 * C (5Z), 3 <46 ^ 7-7- / 1- / 2- (Pentyloxy) * ethyl7-7-oxabicyclo- / 2.2.jyhept- 2-y3L7-5-heptenoic acid. 13. The method according to item 1, characterized in that / Tβ, 2 * (5Z), 3cC, 4_ß7-7- / T3-phenylpropoxy) -methyl will be produced 14. The method according to item 1, characterized in that / Tβ , 2Λ (5Ζ), 3c (, 4 _, ß_7-7 ^ / 3 "- / TOctyloxy) -methylT ^ -oxabicyclo is produced. 15. The method according to item 1, characterized in that / Tβ, 2oC (5Z), 3/4 ^ 7-7- / 1- (cyclohexylmethoxy) -methyl / ^ -oxa / ¹⁵ bicyclo / J.2. ^ 7hept-2-yl7-5-heptenoic acid. 16. The method according to item 1, characterized in that the radical A is a group of the formula -CHrCH-, m \ has the value 3 and η has the value T, n ¹ , the value 1 and R represents a lower alkyl radical. - f 17. The method according to item 1, characterized in that the radical A is a group of the formula -CHrCH-, m has the value 3 and η has the value 1, n ^{1 has} the value 2 and R represents a lower alkyl radical. - V., 18. Method according to item I, characterized in that / Tβ, 2 * (5Z), 3tf ₍ 4β7-7- / 1-THexylthio) -methyl7-7-oxabicyclo- / 2.2.27hept-2-y3-7- 5-heptenoic acid or its methyl ester. V ³⁰ is made. 19. Method according to item I, characterized in that / Tβ, 2 <* (5Z), 3 <, 4β7-7- / 1- (3-hexylsulfinyl) -methyl3.7-7-oxabicyclo / 2.2. ^ 7hept-2 y3 _: 7-5-heptenoic acid or its methyl ester is produced. L. J ¹ - 34 - 20. The method according to item 1, characterized in that / Tβ, 2 <* (5Z), 3rf, 4 £ 7-7- / 3- / 7Hexylsulfonyl) -methylT'-T-oxabicyclo / ^ 2.2.1 [7hept 2-y] .7 ~ 7-heptenoic acid or its methyl ester. 21. The method according to item 1, characterized in that / Tβ, 2 "* {5Ζ), 3 / _> 4_β7-7- / 1-7Tcyclohexylmethyl) -thio7-methyl, 7-oxabicyclo / 2.2.1_7hept-2-yl7-5-heptenoic acid or its methyl ester. , , . 22. The method according to item 1, characterized in that / Tβ, 2e <(5Z), 3 <K, 4_β_7-7- / 3 - // T2-phenylethyl 1) -thio-methyl-17-7-oxabicyclo / 2.2.1_ / hept-2-yl7.7 -heptenic acid or its methyl ester is produced. 23. The method according to item 1, characterized in that / Tβ, 2 * (5Z), 3 ^, 4 ^ 7-7- / 1- / 713-phenylpropyl) -thio ^ -methyl-? -Oxabicyclo / 22~2.2 _> 7hept-2-yl7- 5-heptenoic acid or its methyl ester is produced.