CS215150B2 - Method of making the 9-deoxy-9a-methylenisosters of the prostacycline pgi2 - Google Patents

Abstract

A wide range of 9-methylene carbaprostacyclin analogs and homologs, and intermediates for them (~250), were prepd. from appropriate bicyclic precursors; racemic and optically active compds. were prepd. Thus, 1.1g Na- borohydride was treated with 11.6g bicyclo [3,3,0 octane-3,7-dione in 100mL ethanol and 100mL CH2CL2 to give 9.1g 7-hydroxy-bicyclo[3.3.0 octane-3-one, 0.065 mol. of which were treated with 12.8g dimethyl-tertiary-butylcyllyl chloride and 8.85g imidazole to give 2.85g 7-oxo-hydroxy-bicyclo[3.3.0 -octane-3-one-dimethyl tertiary-butylcyllyl ether and 11.8g 7-endo-hydroxy-bicyclo-[3.3.0 -octane-3-one-7-dimethyl-tertiary-butylcyllyl ether. The latter compd. in Me2CO3 was treated with Na-hydride to give I.

Description

The present invention relates to a process for the preparation of the 9-deoxy-9α-methyleneisosteres of prostacyclin PGI 2 of formula I,

in which

R is a substituent selected from the group consisting of

a) a free carboxyl group or an esterified carboxyl group of the formula --COOR 8, wherein R 8 represents C 1-12 alkyl or C 1-2 alkenyl;

(b) a group of formula (C (OR ') 3, in which each R' independently represents an alkyl group having 1 to 6 carbon atoms; or. phenyl group,

c) a group of the formula “CH2-R” in which R ”represents a hydroxyl or alkoxy group having 2 to 7 carbon atoms,

d) a group of the general formula

Ra

From —CON, \

R b in which R a, R b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl and phenyl,

(e) a cyano group;

f) the rest of the formula

-C

N-N

II ⁴ NH-N

(g) a group of the formula —CHO;

h) the remainder of the formula

X'-R _and 'Z

-CH

X’-Rb in which everyone. the individual X 'is independently O or S and Ra'. R b ', which may be the same or different, represent an alkyl group having 1 to 6 carbon atoms. . nepp, together form a straight or branched alkylene chain having 2 to 6 carbon atoms,

D is a substituent selected from the group consisting of radicals. of formulas

Y represents the formula groups —CH2 — CH2 —, ´C = C,

Z \ Z

G = C (trans)

Z \ - CH2—, \

CH — OH, z

с — c (cis),

O = C (cis)

Z \ in which

Z represents a hydrogen atom. or a halogen atom, and further a group of formulas —NH — CO— and. —NH — CH2—,

(trans], - Ce = C—, \

C = O, —0—, —S — a

OF \

N — R _c ,

Z wherein R _c represents a hydrogen atom, an alkyl group of 1 to 6. C 2 -C 6 alkanoyl, one of R 1 and R 2, and independently of one another, R 3 and R 4 represent hydrogen, C 1 -C 6 alkyl, C 2 alkenyl; up to 10 carbon atoms, alkynyl having 2 to 2 carbon atoms; 10 atoms, carbon, phenyl. or phenyl ... (or naphthyl) (C 1 -C 6) alkyl, and the second one denotes a hydrogen atom, a hydroxyl group, an alkoxy group. Up to 6 'carbon atoms or phenyl (or'',naphthyl)' - (C 1 -C 6) alkoxy, or R 1, R 2, and independently of them R 3 and R 4, together form oxo,

R 5 and R 6, which may be the same or different, each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom, or R 5 and R 6 together with the carbon atom to which they are attached form a radical of the formula

C · —CH2 or

OF

X denotes a group of formulas - (CH 2) m 3 - in which ms is zero or 1,

H H \ OF 0 = = c (cis) OF X H \ OF (trance) c = = C OF \ H -O-, -WITH- and N — R _c ,

where R c is as defined above, mi, mz, ni, n2, which may be the same or different, denote zero or an integer from 1 to 12 so that the sum of mi j- mz or ni '+ Π2 is less than or equal to 15, p , q denotes zero or an integer 1 to 3, so that the sum of p + q is an integer from 1 to 6, .....

R 7 is a substituent. from the group consisting of a ') a hydrogen atom, b') a (C1-C4) alkyl group, c ') a monocyclic C8-cycloalkyl or cycloalkenyl group. norbornyl _; . or. .amphamanyl, optionally ... mentioned. a group substituted with at least one alkyl group; to .6 ... carbon atoms. or C 1 -C 6 -alkoxy groups, ... _}

ï). fenylovou ..-. or a naphthyl group / group, optionally. substituted. . at least one halogen atom,. . haloalkyloypu '. groups containing from 1 to 6 atoms. A 1-to 6-carbon monocyclylpyridine. carbon atoms having from 1 to 6 carbon atoms. 'Or phenyl, E') saturated or unsaturated 5 or 6-membered heteromonocyclic ring containing at least one heteroatom which is oxygen, sulfur or nitrogen, and optionally substituted with at least one halogen atom, halogenoalkyl having 1 to 6 carbon ^atoms at the alkoxy ^ý s ^K u ^pi Nou 1 to β J8W coal ^{to f} enyl s ^to u ^pi Nou or a ^lkyl cord for ^the UPIN having 1 to 6 carbon atoms, and also lactones derived from compounds of formula I and their pharmaceutically or veterinarily suitable salts.

The invention further includes lactones derived from compounds of Formula I as well as pharmaceutically or veterinarily acceptable. salts, optical antipodes, geometric isomers and diastereomers of the compounds of formula I and mixtures thereof.

In the formulas in the description of the present invention, dashed lines (-------) indicate that the substituents attached thereto are in the α-configuration, i.e. below the plane of the ring, in the case of bicyclo [[p-q-1]. -l), 3,0] of the alkane system (composed of condensed rings A and BJ in the endo configuration and, in the case of the carbon side chain, in the S-configuration.) The solid lines in the form of a wedge (1) indicate that the substituents attached are in the case of the ring in the β-configuration, ie above the plane of the ring, in the case of the bicyclo [[p + q +) 33.0] alkane system in the exo-configuration and in the case of the carbon chain in the R-configuration. refers to a substituent with undefined stoichiometry, such attached substituents may be in the α- or in the -configuration, in the case of the bicycloalkane system in the endo- or exo-configuration and in the case of the carbon side chain in the R or S-configuration.

The compounds of formula I and derivatives thereof described in this invention have a cis linkage between the fused rings A and B; the hydrogen atoms bonded to the bicyclic system at the point of attachment of the rings are both attached from the outside of the two-plane angle. formed by planes of circles in a natural configuration.

The carbon side chain on the cyclopentane ring A (ω-chain) is in the trans position relative to the Bav ring exo position relative to the bicyclic system.

For each compound of the invention. two geometric isomers are possible, which is due to the arrangement of the substituents on the double bond exocyclically bonded to ring B: the carbon chain bound to this double bond (the chain aj may either be on the same side or on the opposite side to the cyclopentane ring A 'chain ω).

In the first case, the exocyclic double bond is defined as cis and in the second case trans. In general. formula I 'and other general formulas,. that follow, the symbol ~ indicates that both geometric isomers are covered by the formula, both individually and in mixtures.

The above substituent arrangements refer to natural compounds. Their enantiomers, which are also within the scope of this invention, exhibit opposite stereochemistry at all asymmetric centers than natural compounds. They are therefore zrcadlevými obpasy will send foregoing and n ^a ppck invite from a ^{Ju J p} u r ^of sor O5 ^RAŽŽR I use the prefix "ENT" key. The designation d, 1 is used for mixtures containing equimolar amounts of natural compounds and corresponding enantiomers.

The alkyl, alkenyl, alkynyl, alkoxy and alkanoyl groups may have a branched or straight carbon chain and may optionally be substituted by one or more halogen atoms, alkoxy groups having 1 to 6 carbon atoms and aryl groups, especially phenyl groups.

The substituent R is preferably a free or esterified or in the form of a salt present carboxyl group. ·

C 1 -C 6 alkyl is preferably methyl, ethyl or propyl.

C 2 -C 7 alkoxy is, for example, acetoxy, propionyloxy or benzoyloxy.

(C 2 -C 6) -alkanoyl ^; preferably an acetyl or propionyl group.

The C 2 -C 6 alkylene radical is preferably an ethylene or propylene group.

C 1 -C 6 -alkoxy is preferably methoxy, ethoxy or propoxy.

The aryl- (C 1-6) alkyl group is preferably a benzyl group.

Aryl- (C 1 -C 6) alkoxy is preferably benzyloxy.

The C 2 -C 10 alkenyl group is preferably a group of the formula -CH = CHR 8, wherein R 5 is hydrogen or a branched or straight-chain C 1 -C 8 alkyl group, preferably a vinyl group.

The C 2 -C 10 alkynyl group is preferably a group of the formula --C 5 C - R 5, in which R 5 is as defined above, preferably an ethynyl group.

C 1 -C 6 haloalkyl is preferably C 1 -C 6 trihaloalkyl, especially trifluoromethyl.

When Z is halogen, it is preferably chlorine or bromine.

Preferably, R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and fluorine.

When R @ 7 is C1 -C4 alkyl, it is preferably methyl.

When R 2 denotes an aryl group, it is preferably a phenyl, (Ύ-naphthyl or β-naphthyl group).

When R7 is a cycloaliphatic, it may be a mono-, bi- or tricyclic residue. In the case of a monocyclic radical, it is preferably a C 3 -C 9 cycloalkyl or cycloalkenyl group, for example cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. Preferably, the bicyclic radical is norbornyl. In the case of a tricyclic residue, this is preferably an adamantyl group.

R 7 represents a cycloaliphatic moiety, it is preferred that the aforementioned monocycloaliphatic group.

If R denotes? heterocyclic ring, it may be a mono- or bicyclic radical containing as heteroatom at least one of nitrogen, sulfur and oxygen atoms. However, it is preferred that the heterocycle is a monocyclic radical as defined above, in particular a tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl radical.

When R is an esterified carboxyl group of the formula -COOR 9, R Ro preferably represents an alkyl group having 1 to 12 carbon atoms, especially a methyl, ethyl, propyl or heptyl group, or an alkenyl group having 2 to 12 carbon atoms, especially an allyl group.

The indices mi, Ш2, ni, пг preferably independently of one another are zero, 1, 2 or 3.

Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) may be formed with both inorganic and organic acids and bases.

Hydrochloric, hydrobromic or sulfuric acids can be used as pharmaceutically or veterinarily suitable inorganic acids, and citric, fumaric, tartaric, malic, maleic, methanesulfonic or ethanesulfonic acids can be used as organic acids. Suitable inorganic bases include alkali metal hydroxides, alkaline earth metal hydroxides, zinc hydroxide or aluminum hydroxide. As suitable organic bases, various amines can be used, such as methylamine, diethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, phenylethylamine, dibenzylamine, ethylenediamine, diethylenetriamine and other similar aliphatic, aromatic and heterocyclic amines such as piperidine, morpholine, pyrrolidine or piperazine, as well as substituted derivatives thereof such as

1-methylpiperidine, 4-ethylmorpholine, i-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine or 2-methylpiperidine, and hydrophilic amine derivatives such as mono-, di- and triethanolamine, 2-amino-2-butanol, 2- amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris- (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-butyl) amylphenyl) diethanolamine, ephedrine or procaine, and α- and β-amino acids such as lysine and arginine.

Preferred salts of the present invention include those compounds of formula I wherein R is a group of formula - COOR _d , wherein R _d is a pharmaceutically or veterinarily acceptable cation derived from any of the above bases.

In the description of the invention, compounds of formula I are referred to as bicyclo [(p + q + 1), 3,0] alkanes or, more preferably, as prostacyclic acid derivatives, compounds of 20 carbon atoms of the formula

wherein the position of the oxygen atom is referred to as the 9a-position.

According to this nomenclature, the compound of formula (I) in which p = q = 1 is a bicyclo [3.3.0] octane derivative or, more preferably, a 9α-deoxo-9α-methyleneprostacyclic acid derivative since the heteroatom at the 9a position of prostacyclic acid is replaced methylene group. A compound of formula I wherein p = 2 and q = 1 is a bicyclo [4.3.0] nonane derivative or, more preferably, a 9a-deoxy-9a, 9b-dimethyleneprostacyclic acid derivative, as the heteroatom at the 9a position of the prostacyclic acid is replaced two methylene groups. Analogously, a compound of formula I wherein p = 2 and q = 1 is a bicyclo [5.3.0] decane derivative or, more preferably, a 9a-deoxy-9a, 9b, 9c-trimethyleneprostacyclic acid.

Analogous prostacyclic acid derivatives of formula I wherein q = 2 or q = 3 are referred to as 7a-homo- or 7a, 7b-dihomo-prostacyclic acid derivatives, and compounds of formula I wherein p or q is zero are called derivatives of 9α-nor-methylene- or 7-nor-methyleneprostacyclic acid.

The same nomenclature (homo, dihomo, nor, dinor, etc.) is used to denote extensions (the former prefixes) or digestion (the latter prefixes) of α- and ω-chains by one, two or more carbon atoms, based on the original number of carbon atoms atoms of prostacyclic acid.

As an example of this nomenclature, the full name of the two compounds Ia and 1b is given.

In the following and other compound names, t = trans and c-cis.

Compound Ia: 7-endo-hydroxy-6-exo- (3,5'-hydroxy-oct-1'-trans-1'-enyl) bicyclic 3,3,0] octyl-3 (5 ') -pent-5 or 5t, 13t-11a, 15S-dihydroxy-9a-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid, compound 1b: 8-endo-hydroxy-7-exo-3 '; R-hydroxy-4'S-methyl-non-1'-yl] bicyclo 4,3,0] nonyl-3 (6 ') -hex-6'-cis-enoic acid, or 5c-11a, 15R-dihydroxy-16S 20-dimethyl-9α-deoxy-9α-methylene-7α, 2a, dihomo-prostacycl-5-ene.

Preferred compounds of the invention are those compounds of formula (I) wherein R is a free or salt-containing carboxyl group, R7 is a straight or branched C1-C4 alkyl group, a phenyl group optionally substituted as above saturated with a monoheterocyclic a radical (preferably a tetrahydrofuryl or tetrahydrothienyl radical) or a C 5 -C 7 monocycloalkyl group in which the other substituents have the meaning given above.

Particularly preferred compounds of formula I are:

5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid, 5c, 13t-11a, 15R-dihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid , 5c-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycl-5-enoic acid and its 15R epimer, 5c-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycl-5-ene-13-ynoic acid and its 15R epimer,

16S-methyl derivatives of the above acids and 20-methyl derivatives of the above acids, 5c, 13t-4-oxo-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycl-5,13-dienoic acid,

5c, 13t-4s, 11a, 15S-trihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid 1,4-y-lactone and its 4R epimer, sodium salt of 5c, 13t-4s, 11a, 15S -trihydroxy-9α-deoxy-9α-methyleneprostacycla-5,13-dienoic acid and its 4R epimer, 5c, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-17-cyclohexyl-18,19, 20-trinor-prostacycl-5,13-dienoic acid, 5c, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-17-phenyl-18,19,20-trinor Prostacyclla-5,13-dienoic acid , 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-17 '(2'] -tetrahydrofuryl-18,19,20-trinor-prostacyclla-5,13-dienoic acid, 5c, 13t -11a, 15S-dihydroxy-9.alpha.-deoxy-9.alpha.-methylene-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prostacyclla-5,13-dienoic acid, 5c, 13t-11a, 15 (S) -dihydroxy-9α-deoxy-9α-methylene-16-methyl-16-butoxy-18,19,20-trinor-prostacycl-5,13-dienoic acid, 5c-11a, 15S-dihydroxy-9α-deoxy-9a- methylene-16R-fluorprostacycl-5-ene-13-ynoic acid, 5t-11a, 15S-dihydroxy-9α-deoxy-deoxy-9α-methyleneprostacycl-5,13-dienoic acid , 5t, 13t-11a, 15R-dihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid, 5t-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycl-5-enoic acid and its 15R epimer , 5t, 13t-llar, 15S-dihydroxy-9a-clooxy-9a-methylenepiocycl-5-ene-13-ynoic acid and its 15R epimei,

16- (4-oxo-11a), (15-dihydroxy-9a), (16'-mtetyl) derivatives of the above acids; -deo.xy-9a-methyleneprostacycl-5,13-diene,

5t, 13t-4S, 11 ', 15S-thihydioxy-9a-deoxy-9a-methyleneprostacyclla-5,13-dienoic acid and its 4R epimer, sodium 5t, 13t-4S, 11a, 1,4-y-lactone, 15S-Trihyldioxy-9a-deoxy-4α, 4β-epoxy-5α, 3β-epoxy, and its 4R epimer, 5t, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-17 -cyclohexyl-18,19,20-trmor-prostacycl-5,13-ditnic acid, 5t, 13tHa, 15S-dihydroxy-9a-deoxy-9a-methylene-17-phenyl-18,19,20-trinor-prostacyclic5, 13-dienoic acid, St / α-11a, 15-dihydroxy-.alpha.-deoxy-9.alpha.-methylene-17.beta.-17 (2-tetrahydro-furyl-4-oxo) -thiocarbonyl-5-dienoic acid, 5t, 13t-11a, 15S-dihydroxy- 9α-Deoxy-9α-methylene-16-m-tifluoromethylphenoxy-7,18,19,20-ethanone-proposacyclate -5,13-dienoic acid, 5t, 13t-11z *, 15S-dihydroxy-9α-deoxy-9atmethylene-16-methyl -16-butoxy-18,19,22-tungmo-prosylcycla-5,13-dienoic acid, 5t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-16R-fluoropropylstacycl-5-en-13-ynoic acid , 5c ₅ 13t-11α, 15Stdihydroxyt9a-deoxy-9a-deoxy-9a-noo meiylenprostacyclla-5,13-dienes 5c-11a, 15S-dihydroxy-9α-deoxy-9α-nor-methylene-20-methyl-13,14-didehydropiostacycl-5-ene-13-ynoic acid, 5 (p1: β-β-β-β-β-γ) acid; 1α, 1S, 5S-dihydroxy-9α-deoxy-7-nomethylylpropacyacyl-5,13t-dioic acid, 5c, 13t-11α, α, 15S-dihydroxy-9α-deoxy-7-no-methylene-17-phenyl-18,19, 20 t-ttrinor prostacykla-5,13-dienoic acid 5ctll.α _J) 15S-dihydroxyt9a-deoxy-7-noΓtmethylen-16S-fluoro-13,14-didehydropгostacyk - 5-en-13-inгvá and its 16R-fluorisomer, 5c, 13t-11α, 15S-dihydroxy-9at-deoxy-9a, 9b-dimethylenepostacycl-5,13-dienoic acid, 5α-α-5S-dihydroxy-9a-xyt9a, 9b-dimethylenepostacycl-5-ene-13-metaic acid , 50,131-11,4,15S-dihydroxy-4-a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18,19,22-thieno-postostycycla-5,13-dienoic acid, 5c, 13t-11a, 15S-dihydroxy- 9α-deoxy-9α, 7α-homo-dimethylenepostostycyclate -5,13-dienoic acid, -clBt-11α-S-dihydroxy-4-dehydroxy-9α, 7α-heterocyclimethyl-15,11-methylprostacycl-5,13-dienoic acid, 5c, 13t-11a, 15S -dihydroxy-9-aldehyde-9a, 7 .alpha.-homo-dimethylene-16S-methylprostacycl-4'-dienoic acid and its 16R-methyl isomer, 5c, 13t-11α ', 15Stdiyldoxoxyt9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,18,19,20 -trans-pro-stacy-5,13-genoic acid, 5c-11a, 15S-dihydroxy-9a-dimoxy-9a, 7a-homo-dimethyleneprostacyct-5-ene-13-enoic acid, 5c, 13t-11α. 15S-dihydioxy-9a-deoxy-9a, 9b, 7a-halo-trimethylene-2-nor-prostacyclla-5,13-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-nor-methylenpiostacycla- 5,13-dienoic acid, 5t-11a, 15S-dihydroxy-9a-deoxy-9a-norlehylene-20-methyl-13,14-dihydroxy-9a-deoxy, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy -7-nor-methyleneprostacycla-5,13-dienoic acid-N-11,4,15-dihydroxy-4-deoxy-7-naphthylene-17-phenyl-18,19,20-trino-postostycycla-5,13-dienoic acid 5'-11 ', 15S-dhlydrol) xy-9a-deoxy-7'-non-methylene-16S-fluoro-13,14-didehydroprostacycl-5-ene-13-ynoic acid and its 16R-fluoroisomer, 5t, 13t-11a, 15S- dihydroxy-9a-deaxy-9a, 9b-dimethylenpiostacycla-5,13-dienes ?, 5t-11a, 158? 11? 1: (? - 93? (? - 9a, 9b-dimethyleneprostacycl-5-ene-13-ynoic acid), StJSt-11lai-5-dihydroxy-4? -deoxyd9a? b-dinl) (1-Ethyl-17-cyclohexyl-18,19,22-thieno-prostacycl-5,13-diaminic acid, 5t, 13t-11 ', 15S-dihydroxy-9α-cleoxy-9α, 7α-hoino-di] diethyleneprostacycl-5 , 13-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homodimethylene-15-methylprostacyclla-5,13-dienoic acid, 5t, 13t-11a, 15S-dihydroxy-9a -deoxy-9α, 7α-homo-dimethylene-16S-methylprostacycla-5,13-dienoic acid and its 16R-methyl isomer, 5t, 13t-11a, 15S-dihydroxy-9α-deoxy-4α-homodimethylene-N-phenoxy-17 , 18,19,20-tetranor-pr ostacycla-5,13-dienoic acid, 5t-11 ', 15S-dihydrcixy-9a-deoxy-9a, 7a-homo-dimethyleneprostacycl-5-en-13-ynoic acid, 5t , 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylthin-2-nor-prstacycla-5,13-diene, as well as 11-deoxy derivatives, 11-epimers, 15R-hydroxyisomers and all enantiomers of the above compounds as well as their pharmaceutically or veterinary suitable salts.

The compounds of formula (I) according to the invention are prepared by the process of:

O

H / ^c \

H ''

^я <tcHy-cx-icnyy л / f fy R ₁ (II) wherein p, q, Y, n _L , n 2, X, R-, R ₆ and R 7 are as defined above, one of the substituents R 1 R 2 * and independently therein one of R ₃ ', R ₄ ' represents hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or phenyl (or naphthyl HQ); —C 1-6 alkyl, and the other represents a hydrogen atom, a hydroxyl group, a (C 1 -C 6) alkoxy group, a phenyl (or naphthyl) - (C 1 -C ₁₀ ) alkoxy or a protecting group bonded to a bicyclic system or side carbon chain by an ether bond, or R 1, R 2 'and independently of them R ₃ ' and R ₄ 'together form a protecting group of the ketone function, alkylated with a compound of formula III,

E — CH— (CH3) m ₁ —D— (CH2jm2 —R '' (III) (-) in which

D, mi and m2 are as defined above, E represents a group of the formula (СЩЩЩR— or (ReOhP- (O) -), wherein each individual R e independently represents a C 1 -C 6 alkyl group or a phenyl group and R "'is selected from the group zahrující a') carboxy, either free or esterified group of the formula -COORg wherein R9 is C ₁ _ 2 alkyl or ₁ C2_i2alkenyl or carboxy in the form of corresponding salts, b ') a group of the formula -C (oR ₁₃ wherein R 'is as defined above, c') a group of the formula —CH2 —R ^IV , wherein R ^IV represents an acyloxy group having 2 to 7 carbon atoms or a protecting group attached to a —CH2 — ether bond, d “) a group of the general formula

Ra /

—CON, \

Rb in which

R a and R b are as defined above, e ") cyano, f") a radical of formula

-CH //

N-N (NH-N and g ') is a radical of formula

X-Ra‘ /

—CH, \

X‘-Rb kterém in which

X ', Ra' and Rb 'are as defined above, and then optionally removing each of the protecting groups present and / or optionally preparing a lactone or an appropriate salt of a compound of Formula I, and / or optionally forming a free compound of Formula I from salts thereof, and / or optionally a mixture of isomeric compounds of formula I is separated into the corresponding individual isomers.

When only one or more substituents are specified in the compounds of formula (I) as described above, all other substituents are as previously defined for formula (I).

As protecting groups for hydroxyl groups, ether or ester radicals which can be easily removed under mild conditions, for example by acid hydrolysis, can be used. Preferred protecting groups include silyl ethers, for example trialkylsilyl ethers, such as trimethyl, dimethyl tert-butyl, dimethylisopropyl or dimethylethylsilyl ethers, as well as acetal and enol ether residues, for example tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether or oxathianyl ether radicals,

in which Alk represents an alkyl group having 1 to 6 carbon atoms.

The ketones are preferably protected in the form of ketals or thioketals of the general formula

X‘R?

\ / c, / \

X‘Rb kterém in which

X ‘, R 1, R b‘ are as defined above.

Alkylation of a compound of formula II with a compound of formula III is carried out using an excess of at least 1.1 mol equivalents of the compound of formula III per mole of the compound of formula

II. The reaction is preferably carried out in an inert solvent, for example a linear or cyclic ether, such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, an aliphatic or aromatic hydrocarbon, such as n-hexane, n-heptane, benzene or toluene, or halogenated. % of a hydrocarbon such as dichloromethane or carbon tetrachloride, as well as mixtures of the solvents mentioned.

In the case that in compounds of formula III, the radical E is a group (C ₆ H _{3 R} J P, the alkylation can be used as a particularly suitable solvents, dimethylsulfoxide, hexamethylphosphoric triamide and other aprotic solvents. Dimethylsulfoxide reaction with an alkali metal hydride dimethylsulfinylkarbaniont, which can then form the carbanions of the formula III from the corresponding phosphates and phosphonates, and this solvent is therefore particularly advantageous since the carbanions of the formula III can be prepared in silo.

The alkylations described above can be carried out at a reaction temperature ranging from m.p. 16 to the boiling point of water, but particularly preferably at room temperature.

In the reaction of the compound of formula II with the compound of formula III, a mixture of geometric isomers is obtained, since the newly formed exocyclic double bond may be cis or trans. If desired, the individual geometric isomers may be separated by fractional crystallization from a suitable solvent or by chromatography, either by thin layer or column, or liquid at low, medium or high pressure. Silica gel or magnesium silicate may be used as the carrier, and a suitable solvent may be used as the mobile phase, for example cyclohexane, n-hexane, benzene, methylene chloride, ethyl ether, isopropyl ether, ethyl acetate or methyl acetate.

If desired, ether protecting groups can be removed from hydroxyl groups by mild acid hydrolysis, for example by treatment with mono- or polycarboxylic acids such as acetic, formic, citric, oxalic or tartaric acid in a suitable solvent such as water, acetone, tetrahydrofuran, dimethoxyethane or in a low molecular weight alcohol, or by treatment with a sulfonic acid such as p-toluenesulfonic acid, in a low molecular weight alcohol such as anhydrous ethanol or methanol, or using a polystyrene-sulfonic type ion exchanger. For example, 0.1-0.25 N polycarboxylic acids (such as oxalic or citric acid) may be used in a suitable low-miscible, water-miscible solvent, which can be easily removed under reduced pressure after completion of the reaction.

The silyl ether protecting groups may be selectively removed in the presence of other protecting groups by treatment with an F-ion in a suitable solvent such as tetrahydrofuran or dimethylformamide.

The ester protecting groups can be removed by the typical saponification methods described below.

Ketal and thioketal protecting groups for ketones are usually removed as well as acetal or thioacetal groups by mild acid hydrolysis under the conditions described above.

Thioketal and thioacetal protecting groups may be selectively removed in the presence of other protecting groups in the molecule, for example by treatment with mercuric chloride in aqueous acetone or acetonitrile, or in a mixture of these solvents, in the presence of alkaline earth carbonates such as calcium or magnesium carbonate.

The following reactions are all carried out using standard procedures: optionally converting a compound of formula I to another compound of formula I, optionally preparing a lactone or salts, preparing a free compound of formula I from a salt thereof, and optionally separating the mixture of isomers into individual isomers.

For example, a compound of formula I wherein R ₃ and R ₄ are hydrogen may be prepared from a compound of formula I wherein one of R ₃ and R 1 is hydrogen and the other is hydroxyl by said alcohol is prepared by a tosylate, for example by treatment with tosyl chloride in the presence of a base, and the tosylate obtained is reduced with either sodium borohydride or sodium cyanoborohydride in water, aqueous alcohol or dimethylformamide or lithium aluminum hybrid in an anhydrous solvent such as ethyl ether or tetrahydrofuran. from room temperature to the boiling point of the solvent used.

Analogously, a compound of formula (I) wherein R 1 and R 2 are hydrogen may be prepared from a compound of formula (I) wherein one of R 1 and R 2 is hydrogen and the other hydroxyl group, and a compound of formula (I) wherein D may be prepared from a compound of formula I wherein D is \

CH-OH.

/

A compound of formula I wherein R3 and R4 together form an oxo group can be prepared from a compound of formula I wherein one of R3 and R1 is hydrogen and the other is hydroxyl by selective oxidation with an excess of activated manganese dioxide in an inert environment, preferably a chlorinated solvent such as methylene chloride or chloroform at room temperature, or alternatively by treatment with 1.1 to 1.2 mol equivalents of dichlorodicyanebenzoquinone in an inert solvent such as dioxane, benzene, or mixtures thereof, at a temperature in the range of from 0 ° C to · up to the boiling point of the solvent used.

In an analogous manner, a compound of formula I in which R 1 and R 2 together form an oxo group can be prepared from a compound of formula I in which one of R ₁ and R 2 is hydrogen and the other hydroxyl group and a compound of formula I, in which D denotes the group \

C = O, /

can be prepared from a compound of formula I wherein D is \

GH — OH.

/ /

If only one of several secondary alcohol functions is to be oxidized, the others must be protected as described above; upon completion of the reaction, the protecting groups are removed again.

A compound of formula I wherein one of R 1 and R 2 is C 1 -C 6 alkoxy or aryl (C 1 -C ₆ ) alkoxy can be prepared from a compound of formula I wherein one of R 1 is C 1 -C ₆ alkoxy; and R 2 is a hydroxyl group, by etherification, in an analogous manner to that described for the preparation of compounds of formula I in which one of R 3 and R 1 is a hydroxyl group. Again, if only one of the several secondary alcohol functions present is to be etherified, the others must be protected and the protecting groups removed again after the reaction is complete.

A compound of formula I wherein R is an esterified carboxyl group (e.g., C 1 -C 12 alkoxycarbonyl) can be prepared from a compound of formula I wherein R is a free carboxyl group by known standard procedures, for example by reaction with an appropriate alcohol, as an aliphatic alcohol having 1 to 12 carbon atoms, in the presence of an acid catalyst, such as p-toluenesulfonic acid, or alternatively by the action of diazoalkane.

Optionally, a compound of formula I wherein R is an esterified carboxyl group (e.g., C 1 -C 12 alkoxycarbonyl) can be converted to a compound of formula I wherein R is a free carboxyl group using standard saponification methods, e.g., with hydroxide an alkali metal or alkaline earth metal in water or aqueous alcohol followed by acidification of the reaction mixture.

A compound of formula I wherein R is —CH2 —R “and · R“ is a hydroxyl group can be prepared from a compound of formula I wherein R is a free or esterified carboxyl group by reduction of the ester group with lithium aluminum hydride in ethyl ether or tetrahydrofuran at the boiling point of the reaction mixture.

A compound of formula I wherein R is a free carboxyl group can optionally be converted to a compound of formula I wherein R is a group of formula 'Ra .........'.

/ —CON \

R b and R a _and R _b are as hereinbefore defined by treatment with an amine of the formula HNR a R _b in the presence of a condensing agent, for example a carboxylic acid such as dicyclohexylcarbodiimide.

A compound of formula I wherein R is an ester of a carboxyl group can be converted to a compound of formula I wherein R is a group of formula

Ra /

—CON, \

Rb by heating with an amine of formula HNR _a R _b in a suitable organic solvent at reflux for 2-3 hours.

A compound of formula I wherein R is a residue

⁴ NH-N can be prepared from a compound of formula I in which R is a free carboxyl group by first converting the starting carboxylic acid to the corresponding acid halide (preferably chloride, for example by heating with thionyl chloride or oxalyl chloride in dichloroethane or dioxane) to refluxing) from which an amide is prepared (e.g. by treatment with ammonia), which is dehydrated to a nitrile (e.g. in the presence of p-toluenesulfochloride in pyridine at 90-100 ° C), and then the nitrile obtained is reacted with sodium azide. in the presence of ammonium chloride in dimethylformamide at a temperature ranging from room temperature to 100 ° C. This procedure converts a carboxyl group into a nitrile and a group

The SNW-N is preferably carried out on the starting material.

Alternatively, a compound of formula I in which R is a free or esterified carboxyl group can be converted to a compound of formula I in which R is —CHO using standard procedures, for example by first preparing the corresponding acid or ester from the corresponding compound chloride, which is then subjected to the Rosenmund reaction as described in Org. Reactions 4, 362 (1948).

A compound of formula I wherein R is —C (OR ') 3 and R' is as defined above can be prepared from a compound of formula I wherein R is a free or esterified carboxyl group by subsequently the compound is converted to the carboximidoester hydrochloride in a known manner and reacted with a suitable alcohol, as described, for example, in J. Amer. Chem. Soc. 64, 1827 (1942).

Acetalization, for example, optionally preparing a compound of formula I wherein R is a group of formula

X'-R _a '/

—CH, \

X'-R _b 'in which X' represents an oxygen atom and R _a 'and R _b ' are as defined above, is carried out by reacting the starting aldehyde with an alcohol or a glycol in the presence of a catalyst such as p acid toluenesulphonic or sulphonated resins, in a suitable solvent to allow water to be removed by azeotropic distillation, or to be exchanged with acetone dioxolane to remove the acetone formed, or reacted with an orthoester to distill off the alcohol formed. . Acetal can also be prepared from the corresponding thioacetal by reaction with a suitable alcohol or glycol in the presence of a mercuric salt, preferably mercuric chloride, as an exchange catalyst, and an alkaline earth metal carbonate, in an inert solvent medium.

Thioacetalization, for example preparation. a compound of formula I wherein R is a group of formula

X '- RR /

—CH, \

X'-R _b 'wherein X' represents a sulfur atom, and Ra 'and Rb' are as defined above, from a compound of formula I in which R represents -CHO, is preferably carried out in such a way that the starting aldehyde is brought into reaction with a mono- or dimercaptan, such as methyl mercaptan, ethyl mercaptan, dithloethylene glycol (1,2-ethanedithiol) or dithiopropylene glycol (1,3-propanedithiol) in the presence of a catalyst such as boron trifluoride etherate, in an inert solvent, preferably a halogenated or aromatic hydrocarbon, , chloroform, benzene or toluene.

The corresponding ketals or thioketals can be prepared from the starting ketals by the methods described above for preparation. acetals and thioacetals.

The preparation of the lactones and salts from the compounds of the formula I as well as the preparation of the free compounds of the formula I from their salts are carried out by conventional methods.

Also, the separation of the mixture of isomers of general formula I15 into the individual isomers is carried out by conventional methods, for example fractional crystallization or chromatography.

Compounds of formula III in which E is a group of formula (R _e O) ₂ P (O) (R _e is as defined above) are prepared by the preparation of compounds of formula VII, -R '

Re ° ₍ in which R _e , m _b D, m ₂ and R "'are as defined above, reacts with at least one mole equivalent of a strong base, for example an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium, lithium or calcium, or an alkali metal or alkaline earth metal alcoholate, such as sodium or potassium tertiary butylate, or an alkali metal or alkaline earth metal amide such as sodium amide, or an alkali metal or alkaline earth metal carboxamide salt , such as the sodium salt of acetamide or succinimide.

Compounds of formula (III) in which E represents a group of formula (C ₆ Н ₅ ) зР - are prepared by the process of preparing a compound of formula (VIII),

Hal - CH ₂ - (CH ₂ ) m _- D - (CH ₂ ) m ₂ -R "(VIII) in which m _b D, m ₂ and R""are as defined above and Hal denotes a halogen atom, reacts with 1.1 to 1.3 mol equivalents of triphenylphosphine in an organic solvent such as benzene, acetonitrile or diethyl ether, and the obtained phosphonium salt is reacted with an equivalent amount of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.

The compound of formula (VII) can be prepared by conventional methods, for example, as described by Corey and co-workers in J. Amer. Chem. Soc. 90, 3247 (1968) and 88, 5654 (1966). The compound of formula VIII can also be prepared by conventional methods.

The compounds of formula (II) are novel.

Compounds of formula (II) in which Y is -CH ₂ -CH ₂ -, -C = C or -CH ₂ -C (trans) and Z are as defined above may be prepared by the preparation of a ^{, (v} ) a compound of formula XI;

wherein p, g, R 1 'and R 1 are as defined above and G represents a protected carbonyl group or a group of the formula wherein G ‘represents a silyl ether or acetal moiety reacted with a compound of the formula

to obtain a compound of formula (XII),

in which

G, p, q, Rf Z, R 1, ni, R 5, R 6, X, m and R 2 are as defined above, b ^IV ) optionally converting a compound of formula XII to a compound of formula XIII,

in which

G, Р, Q, Rl> Кз, R, R, R, X, П2 and

R 2 is as defined above,

Y 'is --CH2 --CH2 -, --C.dbd.C-- or --CH.dbd.C-- (trans) and Z is as defined above, c ^IV ) the protecting group present in G is removed to give a compound of formula XIV,

wherein q, p, R 1, R 2 ', Y', R 5 ', R 6', R 7, R 6, R 6, X, P 2 and R 7 are as defined above and G "denotes hydroxyl or C = O, ad ^1v ) the compound of formula (XIV) in which G 1 is a hydroxyl group and in which other hydroxyl groups, if present, are protected as described above, optionally oxidizing.

Compounds of formula II in which Y is -NHCH 2 - may be prepared by reacting a compound of formula XV,

(XV) in which

G, p and q are as defined above and

R1 ', R2', as defined above, except that they do not represent a hydroxyl group, react with an aldehyde of formula XVI,

ОНС-C- (CWJ 'C-X-tCHjкI ^R ó (XVI) in which

R 1, R 1, n 1, R 5, R 6, X, P 2 and R 7 are as defined above, in the presence of a reducing agent, and then the protecting group present in G and optionally other protecting groups present are removed.

A compound of formula (II) wherein:

Y stands for —NH — C — O, can be prepared by reacting a compound of formula XV with a compound of formula XVII,

Hal -C-C-ICH) - - - in which

Hal represents a halogen atom, preferably chlorine, and

R 3 ', R 1', R 1, R 5, R 6, X, P 2 and R 7 are as defined above, in the presence of a base, and then deprotecting.

Compounds of formula XII may optionally be converted to compounds of formula XIII by methods similar to those described above for the preparation of analogous compounds of formula I from the corresponding ketoderivatives of formula I: for example by nucleophilic addition to the ω-chain carbonyl, etherification of the alcohols formed, dehydrohalogenation and hydrogenation .

As mentioned above, when G is \

CH WVOG ’, /

the protecting group G 'may be a silyl ether residue (for example a trialkylsilyl ether such as trimethyl, dimethyl t-butyl, dimethylisopropyl or dimethylethylsilyl ether, but preferably a dimethyl t-butylsilyl ether residue) or an acetalether residue (for example tetrahydropyranyl ether, tetrahydrofuryl ether, dioxanyl ether or dioxanyl ether) but preferably a tetrahydropyranyl ether residue).

The protecting group G 'in the compound of formula (XIII) can be removed by the methods described above: the silyl ether group is selectively fluoride anion and acetalether ether by acid hydrolysis. If the G * protecting group is to be removed in the presence of other labile ether groups in the molecule, the latter protecting groups must be of the acetalether type if G je is a silyl ether group, or the silyl ether type if OGOG ’is an acetalether group.

When G represents a protected carbonyl group, it is preferred that the carbonyl group is protected in the form of acetal or thioacetal, for example as dimethoxyacetal, diethoxyacetal, dimethylthioacetal or diethylthioacetal, preferably as dimethoxyacetal, or in the form of ketal or thioketal, e.g.

CH2 — OΙ.

CH2-O-propylenedithioketal

CH2 — S—

I (CH2 --S -) - in which p, q are as defined above and

G '' denotes a protected carboxyl group as described above, converting it to a compound of formula XXII, propylenedioxyketal

CH2—0—

Ι>

(CH 2) 2 -O- or ethylenedithioketal

CH2 — S—

AND

CH 2 S - preferably as ethylenedithioketal

The deprotection of the compounds of formula XIII as well as the optional protection of the free hydroxyl groups in the compound of formula XIV, for example in the form of acetal ethers or silyl ethers, can be carried out as described above.

The compound of formula XIV in which G 1 is a hydroxyl group can be oxidized by conventional methods used to oxidize secondary alcohols: for example, by treating a solution of chromium trioxide in sulfuric acid with a solution of the corresponding alcohol in an organic solvent such as acetone under conventional reaction conditions.

Reductive amination between compound. and the aldehyde XVI is carried out under reaction conditions typical of the reaction, preferably using a mixed hydride such as sodium borohydride or lithium aluminum hydride as the reducing agent.

The reaction of a compound of formula XV with a compound of formula XVII is carried out under conditions usual for the acylation of amines.

Compounds of formula XI may be prepared in such a way that a ^{V L)} compound of formula XXI or XXI B

wherein p, q, G are as defined above, bV) the compound of formula XXII obtained is reacted with a compound of formula O = C (OR 13) 2, wherein R 13 represents an alkyl group having 1 to 6 carbon atoms or aryl- a (C 1 -C 6) alkyl group to give a compound of formula XXIII,

wherein p, q, G and R 13 are as defined above, cV) the compound of formula XXIII obtained is reduced to a compound of formula XXIV,

G

CHJ (CH 2 z 2)

H '‘‘

(XXI V) in which

D, ^w ) the compound of formula XXIV is optionally separated into individual optical antipodes, e ^w ) the compound of formula XXIV is optionally converted to a compound of formula XXV,

G (Сн ^ ^(CH ť Μ ^Η _

CO Ο y COOR ^ (XXV) in which

G, p, q, Ris are as defined above, and

F ^VI ) converting a compound of formula XXIV or XXV to a compound of formula XXVI in which:

G, p, q, R 1 and R 2 'are as defined above.

A compound of formula XXII wherein G is a group of formula \

C λα. OG ’, /

in which

G '. has the above. meaning,. . can be prepared from the compounds of formula 'XXI A' by known methods, for example by reacting in a compound of formula XXI. the presence of a base with a silyl halide, sllazane, or silyltrifluoroacetamide, or, for example, by reacting in a known manner with a vinyl ether of the formula:

X ”denotes —0—, —S—, or (CH2) (r = 0.1).

Compounds of formula XXII in which G is a protected carboxyl group can be prepared from compounds of formula XXI B either by oxidation with excess pyridine chromium complex in pyridine or by Muffat oxidation with dicyclohexylcarbodiimide in benzene / dimethylsulfoxide in the presence of pyridinium trifluoroacetate.

The reaction of a compound of formula XXI with a compound of formula O = C (OR 13) 2 (R 13 is as defined above, but preferably represents a methyl group) is carried out in the presence of 2-4 moles of a strong base such as sodium methoxide, sodium ethoxide, sodium hydride or potassium or tert-butoxide, using an excess of 6-12 moles of diester of carbonic acid per mole of ketone, optionally in an inert solvent environment, and excluding air oxygen and moisture. The reaction is carried out at a temperature in the range of about 0 to 80 ° C, preferably at 60 to 80 ° C, for 10 minutes to 1 hour. The yields vary from 5 to 90%, depending on the temperature, reaction time and concentration of the components.

The compound of formula (XXIII) may be reduced either with an alkali metal or alkaline earth metal borohydride, preferably at a pH in the range of 5.3 to 7.2, or with an ethanolic solution of sodium borohydride in a mixture of methylene chloride and ethanol at -20 ° C. The reduction is usually complete within 30 minutes and then the excess reducing agent is quenched by the addition of an easily reducible substance such as acetone, and a proton donor such as acetic acid.

A compound of formula XXIV wherein G. It can be separated into individual optical antipodes by saponifying the ester in the usual manner. is converted to a salt with an optically active base such as quinine, cinchonine,. ephedrine, 1-phenyl-1-aminoethane, dihydroabiethylamine, amphetamine or arginine, and the obtained mixture of diastereomeric salts. is separated, for example by fractional crystallization. The optically active acid is obtained by:. converting the resulting single salt into the sodium salt and aqueous solution. of this salt. acidifies. to a pH that does not matter protecting. group present. ,. v G.. Optical resolution may optionally be preceded by hydrolysis. . protecting. groups; in this case, after the division. racemic mixtures of protecting groups are reintroduced into the molecule.

Optically active free. the acid prepared by the process can then be converted into the optically active ester of formula XXIV by conventional methods, for example by treatment with diazoalkane.

Alternatively, the same procedure may be used. to separate the optical antipodes into a racemic mixture of compounds of formula XXV.

Alternatively, compounds of formulas XXIV and XXV in which G is a protected carbonyl group can be resolved into the appropriate optical antipodes by removing the protecting groups on the carbonyl group in G, the resulting ketone being reacted with a primary amine, e.g. arginine, lysine, alanine, 1-phenyl-1-ethyl-2151-50 amine, 1-phenyl-1-propylamine and the like, and a mixture of the optically active diastereomeric Schiff bases are separated by known methods, for example, fractional crystallization or high pressure liquid chromatography. Uniform optically active imino compounds are hydrolyzed in known manner

C- = O /

The compounds and the optically active ketoesters obtained are converted by ketalization or acetalization in a conventional manner into the optically active antipodes of formula XXIV or XXV.

Alternatively, the compound of formula XXIV can be converted to the compound of formula XXV using either the racemic mixture or the individual isomers separated as described above as starting materials. This transformation inverts the free hydroxyl group on the cyclopentane ring. The transformation is carried out by esterifying the hydroxyl group, for example by treatment with 2-4 moles of triphenylphosphine together with 2-4 moles of carboxylic acid such as acetic, benzoic or p-phenylbenzoic acid, or with 2-4 moles of ethyl azobiscarboxylate in an inert solvent, as in an aromatic hydrocarbon optionally halogenated, for example in benzene or chlorobenzene, or in a cyclic ether such as tetrahydrofuran, and the ester function thus formed is then selectively saponified, for example by transesterification in an inert alcohol medium. RnOH in the presence of an alkali metal carbonate, preferably anhydrous potassium carbonate.

The compound of formula XXVI may be prepared from compounds of formulas XXIV or XXV by known methods, preferably via a compound of formula XXVII below. For example, the hydroxyl group in the compounds of formulas XXIV and XXV can be converted to a C 1 -C 6 alkoxy group or an aryl (C 1 -C 6) alkoxy group, or a labile ether such as silyl ether or acetalether using the preparation procedures described above for analogous reactions. compounds of formula I.

The free hydroxyl group in the compound of formula XXIV or XXV can be oxidized to the oxo group and the ketone obtained can be converted to a ketal or thioketal as described above for the compounds of formula I.

The free hydroxyl group in the compounds of formulas XXIV and XXV can be replaced by a hydrogen atom, for example by treating said hydroxy compound with a sulfonic acid chloride such as p-toluenesulfonyl, methanesulfonyl or benzene sulfonyl chloride, and then reducing the sulfonate obtained by conventional means. , for example by treatment with lithium aluminum hydride.

In the latter case, the carboxylic ester group —C00R13 — is reduced simultaneously to the primary alcohol group —CH2OH, which can then be oxidized to the desired aldehyde by the Moffat reagent.

The compound of formula XXVII, (Ctyjp (CH _L )) obtained by the above methods

R- RCOOR ,,

IXXII) wherein one of R 1 'and R 2' is hydrogen, C 1 -C 6 alkyl, C 2 -C 10 alkenyl, aryl or aryl- (C 1 -C 6) alkyl and the other is hydroxyl a group, an alkoxy group having 1 to 6 carbon atoms, an aryl- (C 1 -C 6 -alkoxy or labile ether group, or R 1 'and R 2' together form a protecting group of the ketone function, can be converted to the corresponding compound of formula XXVI by reduction by conventional means, diisobutylaluminum hydride or lithium diisobutylaluminum hydride.

The compound of formula XXVII can also be reduced in a conventional manner by treatment with lithium aluminum hydride to give the corresponding primary alcohol; the latter alcohol can also be prepared from the free acid by conventional reduction with diborane in tetrahydrofuran. The necessary free acid is prepared by saponification of the ester. The primary alcohol thus obtained can then be oxidized to the desired aldehyde, for example with Moffat's reagent, as mentioned above.

Compounds of formula XV may be prepared by known methods, for example using the starting compounds of formula XXVII, in which all secondary alcohol functions are protected in the form of acetalethers when the group —OG 'is a silyl ether group or in the form of silyl ethers when a group —OGO represents an acetalether group. For example, a compound of formula (XV) may be prepared from a compound of formula (XXVII) by a process comprising: ( ⁷ ) ( ¹ ) optionally selective removal of the protecting group present in G, b ( ^vn );

CH OG ', /

c ^VI1 ) saponification of the ester to an acid, d ^VI1J converting the acid to a mixed anhydride, for example by reaction with an acid chloride, for example an alkyl, benzyl or pivalyl chloroformate, in an inert anhydrous solvent such as acetone, tetrahydrofuran or methylene chloride, mixed anhydride eVUj conversion to an azide, for example with an alkali metal azide in an acetone solution of the amine from preparation fvij azide by Curtius degradation and then g j ^Vil optionally converting the resulting amine of formula X to another compound.

Compounds of formulas (XVI) and (XVI1) are known compounds and can be prepared by known methods.

Compounds of formula (XVIII) may be prepared by the following procedure from compounds of formula (XI) wherein in the case where G represents a group \

CH OG ’, /

preferably G is a silyl ether radical, and when one of Rf and R2 is a hydrogen atom and the other is a hydroxyl group, the latter is protected, preferably in the form of acetalether or ester:

and in ^IH ) the aldehyde group is converted to an acetal or thioacetal group (preferably thioacetal) of the general formula

X'— R _a '

Z —CH

X'-R>'(X', Ra _'and Rb' are as defined above) bVIIj group G optionally are selectively removed by treatment with fluoride ion, cv ^'11) the free hydroxyl groups is optionally oxidized to a keto group with Jones reagent and dv ^{| H} ) protecting groups (Rf and R2 ') on the secondary hydroxyl group are selectively removed.

Compounds of formulas XXI A and XXI B may be prepared by known methods. For example, a compound of formula XXI A wherein p = q = 1 is prepared by selective reduction of bicyclo [3.3.0] octane-3,7-dione [J. - Amer. Chem. Soc. 82, 6347 (1960)) or by reduction of the bicyclo [3.3.0] octane-3,7-dione monoketal [J. Org. Chem. 39, 2377 (1974)) followed by removal of the ketal group from the carboxyl function.

In both cases, a hydroxyketone of formula XXI is obtained in which p = q = 1, endo-hydroxy and exo-hydroxy derivatives in which about 80% of the endo-derivatives are present. The mixture can be readily separated into the individual isomers upon conversion to the corresponding racemic siloxy derivatives, for example, fractional crystallization or chromatography, as described several times above.

A compound of formula XXI in which p = 1 and q = 2 can be prepared from a bicyclo [4.3.0] non-7-en-3-one of formula XXVIII,

H

(XXVIII) in which both rings are linked by cis, by protecting the ketone group as above in the form of ketal or thioketal, the double bond is subjected to hydroboration in the usual manner, and then the keto group protecting groups are removed as described above.

The compound of formula XXVIII can be synthesized, for example, by the method described by JP Videi ["Stereochimia and Selective Reactionelle and Serie Bicyclo [n, 3,0) alcanique", University of Sciences and Languages of Languedoc, Academic University of Montpellier, - serial number CNRSAO 11257 ( 1974)).

A compound of formula XXI A in which p = 1 and q = 2 (prepared, for example, as described above) can be converted to another compound of formula XXI by, for example, ketalization or thioketalization, oxidation and Bayer-Villiger reaction and treatment of the product obtained in analogous ways as described above.

A compound of formula XXI B wherein p is zero and q is 1 or p is 1 and q is zero can be prepared from the corresponding bromohydrin, 5-exo-bromo-6-endo-hydroxy-bicyclo [3.2.0] heptane -2-one [J. Chem. Soc., Perkin, 1, 1767 (1965)), by known methods: for example, said bromohydrin is converted to the corresponding acetal, thioacetal, ketal or - thioketal which - is dehalogenated to a compound of formula XXI B using known organic chemistry methods, for example, by reduction with chromate salts or by catalytic hydrogenation in the presence of palladium to calcium carbonate; or. of palladium on activated carbon in the presence of a hydrohalic acid acceptor, or by reduction with tributyltin hydride.

A compound of formula XXI B wherein p = 2 and q = 1, or q = 2 and p-1 can be prepared, for example, from a compound of formula XXVIII by the following procedure: the carbonyl group is reduced to an alcohol, for example by treatment with lithium aluminum hydride in ethyl ether; the alcoholic group is protected, for example in the form of tetrahydropyranyl ether or silyl ether, the olefinic double bond is hydrogenated in the usual manner, the product obtained is oxidized, then the hydroxy protecting group is removed and the product is acetalized or ketalized.

A compound of formula XXI B wherein p = q = 2 can be prepared by known methods, for example from 2-hydroxyperhydro-azulene

-6-one obtainable by the method of D. K. Banerje and K. Sankara Ram. in Ind. J. of Chem., Volume X, page 1) (1972).

Compounds of formula XXVIII may also be used as starting materials for the preparation of compounds of formula XI in which G is a group of formula \

CH aaa OG ', /

in which

G 'represents the remainder of the silyl ether and in which, when one of the substituents Rf and Rž represents a hydrogen atom and the other a hydroxyl group, the latter is preferably protected in the form of acetalether or ester according to the reaction scheme.

O (xxviii)

(XXXI) (XXXIIa: G '= H) (XXXIIb: G' = silyl ether residue) (XXXIIIa: G '= H) (XXXIIIb: G ^ siether ether residue)

The compound of formula XXVIII is converted to the (-hydroxyester XXX), the hydroxyl group of which is protected in the form of acetalether, by means of known methods, for example those described above, to the para-ketoester of formula XXIX, the olefinic double bond in the obtained acetalether of formula XXXI is subjected to hydroboration in the usual manner to give a mixture of alcohols of formulas XXXIIa and XXXIIIa which is separated by chromatography or fractional crystallization, and the uniform alcohols are converted to the corresponding silyl ethers of formulas XXXIIb and XXXIIIb, which are reduced to compounds of formula

XI, for example by treatment with diisobutylaluminum hydride in toluene.

The compounds of formula I exhibit the same pharmacological activity as natural prostacyclin PGI 2, but compared to PGH, the compounds of the invention are preferable for their greater stability at a pH in the range of 0 to 11, especially at physiological pH; this causes the compounds of formula I to have a longer lasting and more constant biological activity. The reason for this greater stability is that the chemical structure of the compounds of formula I is different from that of natural prostacyclin.

Since the atom is incorporated as a heteroatom in the 2-oxa-bicyclo [3.3.0] octane system of natural prostacyclin. of oxygen, prostacyclin is an exocyclic enol ether and is therefore extremely sensitive to acids. The product of the reaction of prostacyclin with acids, 6-keto-PGFia, shows almost none of the activities characteristic of prostacyclin-born. In contrast, the compounds of formula I do not contain oxygen in the bicyclic system and are therefore not enol ethers. Since they are not as highly labile as the natural derivatives, they can be administered orally.

In addition, those compounds of formula I in which a triple bond is present at the 13,14 side ω-chain position, or in which a suitable protecting group, such as a C 1-6 alkyl group or an electron-receptor group such as a fluorine atom, are present near the hydroxyl group at the 15-position (R 3 or R 4 is a hydroxyl group) are more resistant to metabolic degradation caused by enzymes (e.g., 15-PG dehydrogenase) than natural prostacyclin.

The pharmacological activities of natural prostacyclin are known. For example, inhaled prostacyclin prevents asthmatic patients from developing non-specifically induced (e.g., water fog or exertion) bronchial contraction [see S. Bianco et al. J. Res. Medical Science 6,256 (1978)]. When administered by infusion in humans, prostacyclin exhibits hypotensive and vasodilatory activity and also has anti-platelet and desaggregating effects on platelets [see Szekely et al., Pharm. Res. Comm. 10, 545 (1978)].

Prostacyclin also has stimulating effects on the uterus of monkeys and women; In addition, prostacyclin exhibits luteolytic activity in experimental animals and has the ability to protect the gastric mucosa from ulceration induced in experimental animals such as rats with non-steroidal anti-inflammatory agents such as acetylsalicylic acid (ASA) or indomethacin.

In the case of natural prostacyclin, these activities are associated with a significant chemical instability of the substance which makes the substance unsuitable for pharmaceutical use. As mentioned above, the compounds of formula I have pharmacological effects similar to those of natural prostacyclin, but are free of undesirable chemical instabilities of PGI2.

The table below shows both the in vitro inhibitory activity on platelet aggregation induced by the dose of ΙΟμπι ADP in platelet-rich plasma and the hyoptensive activity in anesthetized rats of two compounds of the invention and PGI2:

Substance antiplatelet effect in vitro hypotensive effect (1) ICsong / ml 1 100 ALIGN! (2) 25 1.15 (3) 20 May 0.25

(3) 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylenepostacycla-5,13-dienoic acid.

IC 50 = concentration inhibiting 50% platelet aggregation.

The anti-ulcer activity of dl-5,13t-11a, 15S-dihydroxy-9α-deoxy-7-nor-methyleneprostacyclla-5,13-dienoic acid, when administered at doses producing the same antiplatelet effect, is about 10-fold higher.

Also, the in vitro luteolytic efficacy in hamsters, compared to PGI2 when administered at doses producing the same antiplatelet effect, is about five times higher for dl-5,13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17- cyclohexyl-18,19,20-trinor-prostacyclla-5,13-dienoic acid and 8-fold higher for 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17, 18,19,20-tetranor-prostacycl-5,13-diene.

With regard to prostacyclin and prostaglandin activity, the compounds of formula I can be used in human and veterinary medicine wherever natural prostaglandins and prostacyclin are therapeutically indicated.

For example, the compounds of formula (I) may be used to treat asthma due to their significant bronchodilator effect. In this application, the compounds of the invention can be administered in various ways: orally in the form of tablets, capsules and pills, or in the form of solutions such as drops or syrups, rectally in suppositories, intravenously, intramuscularly or subcutaneously, inhalation in aerosols or solutions using inhalers, or by inhalation in the form of powders. A suitable dose in this indication is about 0.01 to 4 mg per kg, administered 1 to 4 times daily; the exact dose level will depend on the age, weight and condition of the patient as well as the route of administration.

In antiasthmatic applications, the compounds of formula I may be combined with other antiasthmatics, for example sympathomimetics such as isoproterenol, ephedrine and the like, with xanthine derivatives such as theophylline and aminophylline, and with corticosteroids such as prednisolone and ACTH.

Furthermore, the compounds of formula (I) have oxytoxic activity and can therefore be used in place of oxytocin for inducing labor or expulsion of the fetus, both in human and veterinary obstetrics. For such administration, the compounds of the invention are administered intravenously at a dose of about 0.01 µg / kg / min until birth or orally.

The compounds of formula I also have luteolytic activity and can therefore be used to control fertility; their advantage is that they much less stimulate smooth muscle and do not have the side effects of natural prostaglandins such as vomiting and diarrhea.

(1) PGI2, (2) 5t, 13t-11a, 15S-dihydroxy-9a215150 acid

Furthermore, the compounds of formula I have anti-ulcer activity and can be used to reduce and control gastric juice secretion in mammals. In this way they reduce or eliminate the formation of gastrointestinal ulcers and accelerate the recovery of ulcers already present in the gastrointestinal tract. In such cases, the compounds of the invention may be administered by intravenous infusion or by intravenous, subcutaneous or intramuscular injection. Dosages ranging from 0.1 to 500 µg / kg / min are used for intravenous infusion. The total daily dose for both injection and infusion is of the order of 0.1 to 20 mg / kg, depending on the age, weight and condition of the patient or animal and the route of administration.

However, as with natural prostacyclins, the most important property of the compounds of formula I is their platelet anti-aggregation activity, i.e. the ability to inhibit platelet aggregation, reduce their adherence, prevent blood clots and dissolve blood clots that have just formed. This platelet anti-aggregation activity is also associated with coronary artery relaxation. OF . of the foregoing reasons, the compounds of the invention are useful for the prevention and treatment of myocardial infarction and in general for the treatment of a. the prevention of thrombosis and for the treatment of other vascular diseases such as atherosclerosis, arteriosclerosis and especially dihyperlipidemia.

In such applications, the normal routes of administration, for example intravenous, subcutaneous, intramuscular and others, may be employed. In sudden situations, intravenous administration is preferred, at doses ranging from 0.005 to 20 mg / kg / day, again depending on the age, weight and condition of the patient and the mode of administration.

As mentioned above, the compounds of formula (I) may be used in human and veterinary therapy for various routes of administration. They can be administered orally in the form of tablets, capsules, drops or syrups, rectally in the form of suppositories, parenterally in the form of solutions or suspensions, administered subcutaneously or intramuscularly, by injection, preferably in sudden cases, by inhalation by aerosols or by inhalers in the form of sterile protracted implants, or endovaginally, for example in the form of vaginal suppositories.

Pharmaceutical and veterinary preparations containing compounds of formula I may be prepared using conventional carriers and / or diluents. For example, for intravenous injection or infusion, sterile isotonized aqueous solutions are preferably prepared. For subcutaneous or intramuscular injections, sterile aqueous solutions or suspensions in aqueous or non-aqueous media are used. For sterile implants, sterile moldings or capsules of silicone rubber containing or impregnated with the active ingredient are used.

Water, gelatin, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium and magnesium stearate, glycols, starch, gum arabic, tragacanth, alginic acid, alginates, lecithin, polysorbates, vegetable oils and the like.

By inhalation, the compounds of the invention may be administered by inhalers, using aqueous suspensions or solutions of the compounds of formula I, preferably in the form of their salts, for example the sodium salt. Alternatively, the compounds of formula I may be suspended or dissolved in one of the conventional liquefied propellants, such as dichlorodifluoromethane or dichlorotetrafluoroethane, and filled with suitable pressure vessels such as aerosol cartridges. If the active substance is not soluble in the liquefied propellant, a cosolvent, for example ethanol, dipropylene glycol and / or a surfactant, must be added to prepare said type of pharmaceutical preparation.

The following abbreviations are used in the following examples:

THP = tetrahydropyranyl,

DMtB = dimethyl-tert-butyl,

DIOX = 1,4-diox-2-enyl

THF - tetrahydrofuran,

DMSO = dimethylsulfoxide,

DIBA - diisobutylaluminium hydride a

DMF - dimethylformamide.

The process according to the invention is explained in more detail in the following examples, which, however, do not limit the scope of the invention in any way.

Example 1

To a solution of 11.6 g (8.4 x 10 -2 mol) of bicyclo [3.3.0] octane-3,7-dione in a mixture of 100 ml of methylene chloride with 100 ml of ethanol is added 1.1 g ( 0.029 mol) of sodium borohydride. The mixture is stirred at room temperature for 45 minutes, then the excess reducing agent is quenched by the slow addition of 20 ml of acetone and the solution is neutralized with 1.4 ml of acetic acid. The solids were distilled off under reduced pressure, the residue was taken up in a mixture of water and methylene chloride, the organic layer was separated and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent hexane / ethyl ether 70/30) to give 9.1 g of 7H-hydroxy-bicyclo [3.3.0] octan-3-one.

IC (film) 3400, 1740 cm ^first

To a solution of the latter compound (0.065 mol) in 27 ml of anhydrous dimethylformamide was added 12.8 g of dimethyl tert-butylsilyl chloride and 8.85 g of imidazole and the mixture was heated at 60 ° C for 5 hours. After cooling, the reaction mixture was diluted with two volumes of water and the product was taken up in ethyl ether (3 x 40 mL and 2 x 20 mL). The combined ether extracts were washed with 5% sodium bicarbonate solution and then with water until neutral and the solvent was distilled off; is obtained

15.8 g (95% yield) of crude product. After chromatography on silica gel, 2.85 g of 7-exo-hydroxy-bicyclo [3.3.0] octan-3-one (m.p. 40-42 [deg.] C.) and 11.8 g of 7-exo-hydroxy-bicyclo [3.3.0] octan-3-one are obtained. 7-endo-hydroxy-bicyclo [3.3.0] octan-3-one dimethyl-tert-butylsilyl ether, mp 51-52 ° C.

6.95 g of 80% sodium hydride are added cautiously to a solution of the latter compound (11.8 g, 4, C3 x 10 * ² mol) in 295 ml of methylcarbate (Ме ₂ СОз) while stirring under exclusion of water and under an inert atmosphere. After hydrogen evolution had ceased, the reaction mixture was heated to 75-80 ° C for 49 min. After cooling, the solution was diluted with two volumes of ethyl ether, gently added dropwise 13 g of glacial acetic acid, and then an aqueous pH buffer solution was added thereto.

5.2 to 5.5. The organic layer was separated, the aqueous portion was shaken with ethyl ether, the combined organic extracts were dried over anhydrous sodium sulfate, and the solvent was distilled off. 12.82 g of crude d, 1-7-endo-hydroxy-bicyclo [3.3.0] octan-3-one-2-methoxycarbonyl-7-dimathyl-tert-butylsilyl ether (85% 1 of theory 14.49) are obtained. Purification by column chromatography on silica gel (45 g / g, eluting with hexane / ether 97: 3) gave 10.81 g of the pure product, _λ L-254 nm, ε = 7000.

Using the Gxo-isomer as the starting material, 7-dimethyl-tert-butylsilyl ether d, 1-7-exo-hydroxybicyclo [3.3.0] octane 3-on-2-methoxycarbonyl ester, _λmax = 254 nm was _{obtained in the same manner} . , ε = 6,500.

Example 2

To a solution of 7.5 gd, 1-7-endo-hydroxy-bicyclo [3.3.0] octan-3-one-2-methoxycarbonyl-7-dimethyl-tert-butylsilyl ether (DMtB-silyl ether) in 75 ml of dichloromethane and Ethanol (75 ml) was added with sodium borohydride (0.9 g) while cooling to -20 ° C and stirring. The reaction mixture was stirred at room temperature for 15 minutes and then the excess reducing agent was quenched by the addition of 12 mL of acetone.

The mixture is cooled to 0 ° C, 20 ml of 20% potassium dihydrogen phosphate are added, the solvents are distilled off under reduced pressure, and the aqueous solution is extracted several times with ethyl ether. The organic extracts were combined, washed with 5 ml of water and the solvent was distilled off. The residue was recrystallized from n-hexane to give 4.8 gd, l-3,7-endo-dihydro-bicyclo [3.3.0] octane-2-exo-methoxycarbonyl-7-DMtB-silyl ether, mp 68-70 degrees Celsius. The mother liquors are chromatographed on 25 g of silica gel, eluting with n-heptane / ethyl ether (90/10); an additional 2 g of product is obtained which is sufficiently pure and can be used for further work as such.

To a solution of 6 gd, l-3,7-endo-dihydroxy-bicyclo 3,3,0] octane-2-exo-methoxycarbonyl-7-DMtB-silyl ether in 100 ml of 80:20 methanol / water was added 2 grams of potassium hydroxide and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, the concentrated solution was acidified to pH 5.1 and the product was taken up in ethyl acetate. After distilling off the solvent from the combined organic extracts, 5.1 g of 7-DMtB-silyl ether d, l-3,7-endo dihydroxy-2-carboxy-bicyclo [3.3.0] octane is obtained.

To a solution of the latter acid in 150 ml of acetonitrile was added 2.81 g of d- (+) - ephedrine and the mixture was left to crystallize at room temperature for 4 hours. 2.9 g of salt are obtained, which, after recrystallization twice from acetonitrile, yield 1.85 g of d- (+) - ephedrine salt of 7-DMtB-silyl ether (4 -) - 3,7-endo-dihydroxy-2-exo- carboxy-bicyclo [3.3.0] octane, [α] _D = + 52 °. Combine all mother liquors, evaporate the solvent to dryness, dissolve the residue in water and add a solution of 0.68 g of sodium hydroxide in water; The d- (4 -) - ephedrine is shaken into benzene, the solution of sodium acid in water is acidified to pH 5 and the product is taken up in ethyl acetate. The solvent is distilled off from the combined organic extracts, 1-ephedrine is added to the residue dissolved in acetonitrile and the salt obtained is recrystallized several times; 2.3 g of (-) -3,7-endo-dihydroxy-2-exo-carboxy-bicyclo] 3.3.0] octane-7-DMtB-silyl ether are obtained, [a] o = - 49 °.

Example 3

To a solution of 6.28 g of 7-DMtB-silyl ether d 1,1,1,7-endo-dihydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] octane in 30 ml of anhydrous methylene chloride is added 2.19 g of 2 3-dihydroxypyran and 39 mg of p-toluenesulfonic acid and the mixture was allowed to stand at room temperature for 3 hours. The solution was washed with 5% sodium bicarbonate solution (2 x 5 mL), and 8 g of 7-DMtB-silyl ether of 3-THP-ether 1,1,1,7-endo-dihydroxy-2-exo-methoxycarbonyl was obtained after distilling off the solvent. -bicyclo [3.3.0] octane, which was dried by dissolving in anhydrous benzene (2 x 15 ml) and evaporating the solution to dryness. The product obtained is dissolved in anhydrous ethyl ether and a suspension of 0.6 g of lithium aluminum hydride in 40 ml of anhydrous ethyl ether is added dropwise with stirring over 15 minutes. The reaction mixture is stirred for an additional 30 minutes and then the excess reducing agent is quenched by the careful addition of 5 ml of acetone followed by ethyl ether saturated with water. The mixture is dried over 10 g of anhydrous sodium sulfate, filtered and the solvent is distilled off; 7.2 g of 7-DMtB-silyl ether-3-THP-ether d, l-3,7- are obtained.

endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane, M + 370 m / e.

In the same way, but using optically active starting materials, the following compounds were prepared:

7-DJ-11-thiyl-11-thienyl-1,3-thi-4-thienyl-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.1.0 &lt; 2,7 &gt; 0] octane and

7-DMtB-silyl ether-3-THP-ether-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane.

If 1,4-x-2x-2un is used in place of 2,3-dihydropyran in the above procedure, the corresponding 3-‘2-DIOX] -ethers are obtained.

Example 4

To a solution of 3.8 g of disodium endo-dihydroxy-bicyclo [3.3.0] octane-2-exo-methoxycarbonyl-11-7- (1-carboxylic acid) in 40 ml of benzene is added first 3, 66 g benzoic acid a

7.9 g of triphenylphosphide and then with stirring a solution of 5.30 g of ethyl azobiscarboxylate in 15 ml of benzene.

The reaction mixture was stirred for 40 minutes and then washed successively with 2 N sulfuric acid (2 x 20 mL), sodium carbonate solution (3 x 15 mL) and then neutral to water.After distilling off the solvent, a mixture of 7sDMtB-silyl ether was obtained. 3-benzoate cbP-exo-4-endo-dihydroxyPexo-methoxycarbonyl-bicyclo [3.3.0] octane, NMR:

3-endo (H, 5,8 m),

2-endo (H 3, 32 δ d, d),

CO2CH3 (3H, 3.64 δ, J),

7-endo (H 4, 4µm) and 7-DMtB-Siyl ether d, ls7se2do-hydroxy-2-exo-methoxycarbonyl-bicycl. α [3,3,0] oct-3-ene, M + 296 m / e.

The crude reaction product was dissolved in anhydrous methanol and the solution was stirred with 0.5 g of anhydrous potassium carbonate for 3 hours. The solvent is evaporated to dryness, the residue is taken up in a mixture of ethyl acetate and saturated aqueous potassium dihydrogen phosphate solution, the organic phase is washed neutral and the solvent is distilled off. The residue is chromatographed on a silica gel column, eluting first with hexane and then with hexane / ethyl ether as eluents, to give:

a] 1.01 g of 7-DMtB-silyl ether d, [beta] - [4-hydroxy] -exo-methoxycarbonyl-bicyclo [3.3.0] oct-3-ene, which is dissolved in methanol, added to the solution -0.3 g of 5% palladium on calcium carbonate and the mixture is hydrogenated at room temperature at atmospheric pressure; There was thus obtained 7-1 [11 &apos; -11- [11 &apos;] 11 &apos; -1 &apos; (2 &apos; d, 1- 7-endo-hydroxy-2-exo-methoxycarbonyl-bicyclo [3.3.0] octane, M + 296 m) E.

b] 2.01 g of 7-DMtB-silyl ether d, 1-3S2xos7-endo - dihydroxy-2 - exo-methoxycarbonyl-

-bicyclo] 3.3.0] octane, M + 300 m / e which. by saponification as described in Example 2 by treatment with a 5% solution of potassium carbonate in methanol / water 80:20, and the 7-DMtB-Siyl Ethyl d, l-3-exo-7-endo-dihydroxy-bicyclo [3.3] obtained The .alpha.,. Beta.-2-oxo-carboxylic acids are separated into individual optical antipodes using (+) - and (-. Beta.-amphetamine).

The obtained 7-1ΜΙΒ-ϊ (1) 2112 ((+) - 3-oxo-7-endo-dihydroxy-bicyclo [3.3.0] octane) -exo-carboxylic acid was converted into the corresponding methyl ester by treatment with an ethereal solution of diazomethane. The ester is reacted with 2,3-dihydropyran followed by reduction with lithium aluminum hydride in an ether medium of 3-tert-butylamine. -7-endo-di-hydroxy-2-2-hydroxy-ethyl-bicyclo [2.2.0] octane, M + 370 m / e.

The [- -] enantiomer and the racemic mixture were prepared in an analogous manner.

Example 5

To a solution of 5 g of d-Z-endo-hydroxy-bicyclo [3.3.0] octane-4-carboxylic acid 7-DMtB-methyl ether in 100 ml of aqueous methanol is added 2 g of potassium hydroxide and the mixture is heated to boiling. under reflux. Methanol is distilled off under reduced pressure, neutral residual impurities are extracted from the remaining aqueous potassium acid salt solution with solvent, the solution is acidified and the product is taken up in ethyl ether. The ether extracts were combined and the solvent was distilled off. 4.5 g of dj-acid are obtained, which are separated into optical antipodes by (+) - and (-) -ephedrine.

1.32 g of the obtained (-) -7-endo-hydroxy-bicyclo [3.3.0] octane-2-exo-carboxylic acid DMtB-methyl ether are dissolved in 20 ml of 2-tert-hydroxy-5-carboxylic acid and 10 ml of a 1 M borane solution in THF. The reaction mixture is allowed to stand for 4 hours at room temperature, then the excess reagent is quenched by the careful addition of 20 ml of 1.5 N sodium hydroxide and the solvent is distilled off under reduced pressure. The remaining aqueous solution was extracted with ethyl ether, the organic extracts were combined, washed neutral and the solvent was evaporated to dryness; 1.02 g of 7-chloro-4-chloro-2-yl-4- (4-chloro-2-yl) -2-oxo-bicyclo [3.3.0] are obtained. octane, M + 270 m / e.

The corresponding (+ Risomer and racemic mixture was prepared in an analogous manner.

Example 6

A solution of 0.74 gd, l-2-exo-hydroxymethyl-3-exo-THP-oxyl-7-endo-DMt B-silyloxybicyclo [3.3.0] octane in 15 ml of anhydrous methylene chloride was added. all at once add to a solution 3.1 g of Collins reagent [(¢ 5¾¾ ^. C1O3] in 40 ml of anhydrous methylene chloride with stirring and cooling to 0 to 5 ° C. The mixture is stirred for 15 minutes, then added - filter clay and The solvent was distilled off under reduced pressure, the residue was dissolved in anhydrous benzene and the solution was added to a solution of sodium dimethyl (2-oxooctyl) phosphonate). The latter salt was prepared by dropwise adding a solution of 0.59 g of [2-oxooctyl) dimethylphosphonate in 10 ml of benzene to a suspension of 0.07 g of 80% sodium hydride in 20 ml of benzene, and stirring the mixture for about 1 hour. it stops producing hydrogen. After addition of the aldehyde, the mixture was stirred for an additional 20 minutes, then it was quenched by the addition of an excess of 25% aqueous sodium dihydrogen phosphate solution and the organic layer was separated. After drying, the solvents were distilled off and the residue was purified by chromatography on silica gel using cyclohexane / ethyl ether as eluent. 0.81 gd, l-2-exo- [3'-oxo-non-r-trans-r-enyl] MoO 10 [3,3,0] octane, oil, λ = 228 nm, ε ~ msx = 9940, were obtained. .

Example 7

To a solution of 1.05 gd, L-2-hydroxymethyl-exo-3-exo rHPoxy ^{j-7-endo-DMtB-butyldimethylsilyloxy-bicyclo-3-endo-THP-oxy-7-endo-DMtB-butyldimethylsilyloxy-bicyclo} [3 (3.0) octane in 8 mL of 75:25 benzene / DMSO was added 0.89 g of dicyclohexylcarbodiimide followed by 1.42 mL of pyridinium trifluoroacetate solution with stirring. The mixture is stirred for 3 hours, then 20 ml of benzene is added and the excess carbodiimide is quenched by dropwise addition of a solution of 0.13 g of oxalic acid in 3.8 ml of water. The benzene fraction was separated, washed neutral and concentrated to a small volume under reduced pressure; a solution of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane (non-isolated compound) is obtained.

The d, 1-, nat- and enantioformyl derivatives can be prepared by this process. In the same manner, but using 7-exo-hydroxy-bicyclo [3.3.0] octan-3-one 7-dimethyl-tert-butylsilyl ether prepared as described in Examples 1, 2 and 3, 2-exo-formyl is obtained -3-endoTHP-oxy-7-exo-DMB-silyloxy-bicyclo [3.3.0] octane.

Example 8

A solution of 322 mg of [2-oxoheptyl-dimethylmethylphosphonate in 5 ml of benzene was added to the suspension.

43.5 mg of 80% sodium hydride in 10 ml of benzene and the mixture was stirred until the evolution of hydrogen ceased. 258 mg of finely divided N-bromosuccinimide are then added under light exclusion and the mixture is stirred for an additional 5 minutes.

To the obtained phosphonate carbanion solution is added a solution of 0.37 g of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclophob 3, 3] octane in 5 ml of benzene and the mixture is stirred for an additional 15 minutes. The reaction mixture was shaken with H 2 O 2 benzene and 15% sodium dibasic sodium phosphate solution, the organic portion was dried, concentrated to small volume and chromatographed on silica gel using cyclohexane / ethyl ether (80:20) as eluent. 0.42 g of Z-exo-4-bromo-4-oxo-ocr-enyl] -4-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane is obtained, Amax = 251 nm, ε = 9250.

When (2-oxo-2R-Sluor-leptyl) -dimethylphosphonate is used as starting material, the corresponding 2-exo- [2'-bromo-4-oxo-1R-fluoro-oct-1'-trans- enyl] MOOH

- derivative, λ = 252 nm, ε = 89 400.

max

Example 9

A solution of 0.3 g of [2-oxo-4 (2 R) -tetrahydro-furyl-butyl] -dimethylphosphonate was added dropwise with stirring to a suspension of 36 mg of 80% sodium hydride in 5 ml of benzene. The mixture is stirred until the evolution of hydrogen is complete, then a solution of 0.37 g of 2-exo-form-3-endo-THP-oxy-7-exo-D-thiophen-bicyclo [b] is added. 3,3,0] octane and the reaction mixture was stirred for an additional 20 minutes. The solution was partitioned between benzene and a 20% aqueous sodium dihydrogen phosphate solution, the organics separated, concentrated to a small volume and chromatographed on silica gel using benzene / ethyl ether as eluent. 0.35 g is obtained

2-exo- ^[3'-oxo-! -5 '[2') -tetrahydrofuryl-pent-y-7-exo-DMtB-silyloxy-bicyctol 3,3,0] octane (λ max = 229 nm, ε = 8800).

Example 10

When 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane was used instead of said 2-exo- formyl 7-exo-bicyclo-derivative, and when one of the following phosphonates is used as the second reaction component:

(2-oxo-heptyl) -dimethylphosphonate, (2-oxo-ockyl) -dimethylphosphonate, [2-oxo-2 (6-methylhepkyl) -dimethylphosphonate, [2-oxo-4-syctohexylbutyl) -dimethylphosphonate] onate, (2-oxo-4-phenylbutyl) -dimethylphosphonate, [2-oxo-3-m-trifluoromethylphenoxypropyl) -dimethylphosphonate and (2-oxo-3-methyl-3-butoxybutyl) -dimethylphosphonate, prepare these compounds:

3- tl1do THP-oxy- ^г 7-exo-DMtB-butyldimethylsilyloxy-2-exo- [3'-oxo-oct-Γ-kτans-l'-tnyl) bicyclo [3.3.0] octane A _Raa λ - 228 nm, ε - 8700,

3-endo-THP-oxy-7-exo-DMtB-butyldimethylsilyloxy-2-exo- (3'-oxo-non-14rans-l-enyl) bicyclo [3.3.0] octane and _m = ax УУ8 nm, ε = 8950

3-Indy-0TP-yxy-γ-3xy-0DtB-silylyxy-γ-3xy- (Xoxo-4'S-methyl-oct-1'-trans-1'-3-yl) bicyclo: [3,3,0] yctane Λmax = УУ8 nm, ε = 8400,

3-3ndy-OTP-YXY-y-3xy OM-B-y-'šilylyxy 3xy- [3'-5 ^t-YXY --cyklyh3xyl-pent-R-trans-7nyl Γ) bicyclo [3.3 , 0] octane, λmax = УУ8 nm, ε = 9100,

3-7πdo-OTP-oxy---7xo-OMtB-silyloxy---oxo- [3'-oxo-5'-phenynyl-β-tans-1-en71) bicycles [3,3,0] yktane, λmax = УУУ nm, ε = 14 У50,

3-зndo-OTP-oxy-У-7xo-OMtBoiilyloxy-У-зxo-

- (3‘-oxo-4‘-m-trifluoromethyl-3-ynyl-but) -bicyclo [3.3.0] octane, n3zaznamenyn · a

3-3ndQ-OTP-oxy-y-3xq OMtB-silylQxy-y-3xQ- [3'-QXQ-4 ^{<-mзthyl-4'-butoxy-pent-Γ-trans-Г} 3пу1) bicyclo [3. 3,0] octane, n 2 is recorded.

Example 11

Roztyk 0,3 gd, ly-exo- (γ-bromo-3'-Qxo-4R-f 401-44444 ^ 118-141171) -3-3ndo-OTP-oxy-γ-3ndy-OM ^ 1 ^ - The bicyclo [3.3.0] octane in 10 ml of ethyl acetate over 15 minutes was added to 0.1 M zinc (II) -hyrylate hydrate in 7-ethyl acetate (10 ml). The reaction mixture S3 was stirred for an hour, then the excess reagent was purified with saturated aqueous hydrogen chloride solution and sulfuric acid, the hexane layer was separated and washed with 5% sodium hydrogen carbonate solution and swelling. After the solvent has been distilled off, a mixture of 3'S and 3'R of the hydrosylated derivatives is obtained, which is separated by liquid chromatography using isopropyl ether as the solvent. There is obtained 3 0.11 gd, 1 ^ -3x0- (''-bromo-3'S-hydroxyc-4'R-fluoro-oct-Γ-γγηιιβ-Γ ^ ι ^ Ι) -3-3ndQ-0TP-yxy-y endo-D-tfB- ^ ij ^ ll ^: ^^^ - ^ - ^ · bicyclo [3.3.0] _octane-м'н д о

(СгДТюОу) = 44У, 444 m / 3, and 0.1 g of the corresponding 3‘R- (tp! M7гu.

Example 1У

To a solution of 0.3 g of У-exo- [3'-exQ-5 '(“') - tertiarydrofuryl-1'-trans-4 '- 3'-trans] -3-endo-Ol IP-oxy-7-t-o-OMtB-oyloxy-bicyclo [3.3.0] octane in 3 mixture of 3 · ml of 3-methyl-3-chloride with 3 ml of (tanyl) with cooling at -10 to -15 ° U adds The solution was quenched by the addition of 1.5 ml of acetylene and 3 ml of saturated sodium dihydrogen phosphate solution, the solvent was removed under reduced pressure, and the aqueous solution was extracted with ethyl acetate. The residue was purified by silica gel chromatography using hexane / hexane / hexane as the eluent to give 0.1 g of γ-oxo- [3'S-hydroxy-5 '(U') -t7trabydrofuryl-p7nt- Γ-trans-β-3nyl] -3-endo-THP-oxy-7-exo-OMtB-silyloxy-bicyclo [3.3.0] octane and 0.11 g of the respective 3'R-isomer, both

OH

3У4 m / 3.

Example 1 d

Using the procedure described in Example 2cb 11 and 1У using the α, e-n 3 -saturated ctones of the preparation methods described in Example 7cb 8, 9 and 10 s3, the following compounds were prepared:

3-7ndQ-OTP-oxy-5-oxo-OMtB-silyloxy-3-O- (γ'-bromo-3'S-hydroxy-ock-1'-trans-1'-enyl) bicyclo [3.3.1.0 &lt; 2,7 &gt; 0] octane, [М + —ТуО — 10У] 4У4, 4У6 m / 3,

3-7ndQ-OTP-Qxy-У-з зndo-OMtB-silylQxy-У-3xo- (3'S-hydroxy-oct-Γ-trans-Γ-7nyl) bicyclo [3.3.0] octane, [M + - ТуО — 10У] 346 m / 3,

3-7ndQ-OTP-oxy-У-зndQQ-OMtB-silylQxy-У-3x0- (3'S-hydroxy-4'S-methyl-oct-Γ-β-ε-Γ-ηγγ) bicyclo [3, 3,0] octane, [М + —ТуО — 10У] 360 m / 3,

3-7ndo-OTP-oxy---indigo-OMtB-silyloxy-0-3x0- (3'S-hydroxy-non-Γ-trans-1'-7nyl) bicyclo [3.3.0] octane, [M + - ТуО — 10У] 360 m / 3,

3-3ndo-OTP-oxy-γ-3ndQ-OMtB-silyloxy-γ-3x0- (3 ^ -1 ^^ x7-07 ^ 0116X71 ^ 6 -O-α ^ πε-Ι ^ ηγ!) Bicyclo [ 3,3,0] octane, [M + - ТуО — 10У] 386 m / 3,

3-3ndo-OTP-oxy-γ-3ndo-OMtB-silyloxy-γ-3x0- (3'S-hydroxy-5'-phenyl-pen1---trans-1'-enyl) bicyclo [3.3.0] ] octane, [М + —ТуО — 10У] 380 m / 3,

3-зndQ-OTP-Qxy У-7ndQ-OMtB-silyloxy-У-7xo- ^(3, S-bydro.χy-4'-m-trifluormзtylf 7noxy Γ-but-trans-Γ7nyl) bicyclo [3.3 , 0] octane, [M + —ТуО — 10У] 450 m / 3,

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (3'S-hydroxy-4'-methyl-4'-butoxypent-1'-trans-r-enyl) bicyclo] 3, 3.0] octane, [M + -102] 396 m / e,

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (2'-bromo-3'R-hydroxy-oct-1'-trans-1'-enyl) bicyclo [3.3] 0] octane, [M + -H 2 O-102] 424.46 m / e,

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (3'R-hydroxy-oct-β-trans-r-enylbicyclo] 3,3,0] octane, [M ⁺ -NгО] -102] 346 m / e

3-endo-THP-oxo-7 .'- endoDMtB-butyldimethylsilyloxy-2-exo- (3-hydroxy ^and R 4'S-methyl-oct-l-trans-l-enyl] bicyclo [3,3,0 ] octane, [M + -II20-102] 360m / e,

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (3'R-hydroxy-non-1'-trans-1'-enyl] bicyclo] 3,3,0] octane, [ M + -H 2 O-102] 360 m / e,

3-endo THP-oxy-7-endo-DMT-silyloxy-2-exo- (3'R-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl) bicyclo [3.3.0] ] octane, [M + -H 2 O-102] 386 m / e,

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) bicyclo [3.3.1] O] octane, [M + -H 2-102] 380 m / e,

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-N-trans-r-enyl) bicyclo [3.3.0] ] octane, [M + -H 2 O-102] 450 m / e

3-endo-THP-oxy-7-endo-DMB-silyloxy-2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-T-enyl) bicyclo [3, 3.0] octane, [M + -102] 396 m / e.

Example 14

To a solution of 1.17 g of 2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl] -3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3, O] octane in 12 mL of anhydrous methylene chloride was added 120 mg

Of 2,3-dihydropyran and 5 mg of p-toluenesulfonic acid and the mixture was allowed to stand at room temperature for 4 hours. The solution was washed successively with 5% sodium bicarbonate solution and water and the solvent was distilled off.

The obtained crude 2-exo- (3'S-THP-oxy-oct-1'-trans-1'-enyl] -3-endo-THP-oxy-7-endo-DMtB-silyloxybicklo] 3,3,0] octane ( 1.45 g) was dissolved in 12 ml of THF, 2 g of tetrabutylammonium fluoride was added and the mixture was stirred at room temperature for 12 hours, the solution was concentrated to a small volume and the concentrated mixture was purified by silica gel chromatography eluting with ethyl ether. 920 mg of 2'-exo-3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-bicyclo [3.3.1-bis-THP-ether] is obtained. 0.1 octane, IC (film) 3400 cm -1.

Example 15

The following 3,3´-bis-TH-ethers of bicyclo [3.3.0] octanes were prepared as described in Example 14 using the compounds prepared as described in Examples 11, 12 and 13 as starting materials:

2-exo- (2'-bromo-3'S-hydroxy-4'-fluoro-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, IC (film) 3400 cm- ',

2-exo- (2'-bromo-3'R-hydroxy-4'Rfluoro-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, IR (film) 3400 cm ^-1 ,

2-exo- (3'S-hydroxy-5 '(2') -tetrahydrofuryl-pen.t-1,1'-trans-1'-enyl) -3-endo-7-exo-dihydroxy-,

IR (film) 3400 cm ^-1 ,

2-exo- (3'R-hydroxy-5 '(2') -tetrahydr of uryl-pent-1'-trans-1'-enyl) -3-endo-7-exo-dihydroxy-,

IR (film) 3400, 1250 cm ¹ ,

2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, I6 (film) 3400, 1250 ст ¹ ,

2-exo- (2'-bromo-3'R-hydroxy-oct-1-trans-1-enyl) -3-endo-7-endo-dihydroxy-, IR (film) 3400, 1250 cm ^-1 ,

2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, IC (film) 3400, 1250 cm ^-1 ,

2-exo- (3'R-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-,

IC (film) 3400, 1250 cm ^-1 ,

2-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-T-enyl) -3-endo-7-endo-dihydroxy-, IC (film) 3400, 1250 cm ^-1 ,

2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, IR (film) 3400, 1250 ст ^-1 ,

2-exo- (3'S-hydroxy-non-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, IR (film) 3400, 1250 cm ^-1 ,

2-exo- (3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-, IR (film) 3400, 1250 cm ^-1 ,

2-exo- (3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydL 'oxy-,

IR (film) 3400, 1250 cm ^-1 ,

2-exo- (3 &apos; -R-hydroxy-5 &apos; -yl) -3-endo-7-endo-dihydroxy-,

IC (film) 3400, 1250 cm ^-1 ,

2-exo- (3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl] -3-endo-7-endo-dihydroxy-, IC (film) 3400, 1250 cm -1,

2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl] -3-endo-7-endo-dihydroxy-, IC (film) 3400, 1250 cm'1,

2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1-enyl) -3-endo-7-endo-dihydroxy-, IC (film) 3400, 1250 cm -1,

2-exo- (3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy-,

Example 16

A solution of 0.4 g of chromium trioxide is gradually added to 4 ml of pyridine in several portions with stirring. To the complex thus prepared is added a solution of 0.36 g of 2'-exo- (3'S-hydroxydu-5 '(2') -tetrahydrofuryl-pent-1'-trans-r-enyl) 3,3'-bis-THP-ether -3-endo-7-exo-dihydroxy-bicyclo [3.3.0] octane in 4 ml of pyridine, allowed to stand overnight at room temperature, then diluted with 3 volumes of benzene and filtered. The residue was partitioned between benzene and 2 N sulfuric acid, the aqueous portion was re-extracted with benzene, the organics were combined, washed successively with water, sodium bicarbonate solution and again with water and the solvent was distilled off to give 0.31 g 3.3 2'-bis-THP-eeheru 2-exo-

- (3'S-hydroxy-5 '(2'-liter hydrofuryl-pent-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one; (film) 1740.1220 cm '.

Example 17

To a solution of 0,8 g of 3,3´-bis-THP-eeheru 2-exo-

- (3'S-Hydroxy-okk-r-trans-1'-enyl) -3-endo-

-7-endo-dihydroxy-bicyclo [3.3.0] octane in ml of acetone is added over 15 minutes with stirring and cooling to -10 to -6 ° C

1.6 ml Jones reagent. The reaction mixture is stirred for a further 15 minutes, then 80 ml of benzene is added, the organic layer is separated, washed with a 15% aqueous ammonium sulfate solution until neutral, dried and the solvent is distilled off. 0.71 g of 2'-exo- (3'S-hydroxy-oct-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, 3,3'-bis-tetrahydropyranyl ether, is obtained. IC (fm H) 1741 cm -1.

Example 18

The following 3,3‘-bis-THP-ethers of 3-endo-hydroxy-bicyclo [3.3.0] octan-7-ones are prepared from the trioles described in Example 15 using the oxidation procedures described in Examples 16 and 17:

2-exo- (2‘-bromo-3‘S-hydroxy-4‘R-fluoro-octrothians-1'-enyl) - IR (film) 1740 cm -1,

2-exo- (2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-trans-1-enyl) -,

IC (film) 1740 cm- ¹ ,

2-exo- (3S-hydroxy-5 '(2') -tetrahydrofuryl-pent-1'-trans-1'-enyl) -, iC (film) 1740 cm ',

2-exo- (3'R-hydroxy-5 '(2') -tetrahydrofuryl-pent-1'-trans-1'-enyl) -,

IC (µm) 1740 cm 1,

2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-enyl] -,

IR (film) 1740 cm ',

2-exo- [2'-bromo-3'R-hydroxy-ock-1'-trans-Γ-enyl] -,

IR (film) 1740 cm -1,

2-exo- (3S-hydroxy-non-1'-trans-r-enyl) -, iC (film) 1740 cm -1,

2-exo- (3'R-hydroxy-non-R-R-trans-enyl) - IR (film) 1740 ^cm-1

2-exo- (3'S-hydroyy-5'-cyclohexyllpenS-1'-traos-4-enyl) -, iC (film) 1740 cm ^-1 ,

2-exo- (3'R-hydroxy-5'-cyclohexyllpenS-Γ-trans-1'-enyl) -,

IC (film) 1740 cm ^-1 ,

2-exo- (5S-hydroxy-4-phenyl-pent-1-trans-1 H-1) -,

IR (film) 1740 cm ^-1 ,

2-exo-4R-hydroxy-4-phenyl-pent-1H-trans-14-on-1] -,

IC (film) 1740 cm-1,

2-exo- (3S-hydroyyl-4'-m-trifluoromethylphenyl-but-4-trans-1-enyl) -,

IC (film) 1740 cm ^-1 ,

2-exo- (3'-R-hydroxymethyl) -4- (11-trifluoromethyl-phenoxy-ω-β-traos-Γ-enyl) -1C (film) 1740 cm -1,

2-exo- [3'S-hydroyy-4'-methyl-4'-butoxy-pentene-trans-1-enyl)

IC (film) 1740 cm -1 a

2-eyo- (3‘R-hydroxy-4‘-methyl-4‘-butyxyt)

-pent-1-trans-1'-enyl -,

IC (film) 1740 cm -1.

Example 19

A solution of 2.1 gd, 1- 2-exo- (3'-oxo-non-1'-trans-1'-enyl) -3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3] 3.0] octane (prepared as described in Example 17) in methylene chloride / ethanol was reduced as in Example 12 with 0.17 g of sodium borohydride at -15 ° C; 2.01 gd, 1- 2-exo- [3 '- (S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-THP-oxy-7-endo- DMtB-silyloxy-bicyclo [3.3.0] octane.

The product obtained, without being separated into individual 3'S and 3'R alcohols, is dissolved in 30 ml of methylene chloride and reacted with 0.4 g of 2,3-dihydropyran in the presence of 25 mg of p-toluenesulfonic acid. The obtained 3,3'-bis-THP-ether d, l-2-exo- [3 '- (S, R 1 -hydroxy-non-1'-trans- ¹⁴ -phenyl) -3-exo-hydroxy-7 -endo-DMtB-silyloxy-bicyclo [3.3.0] octane was reacted without further purification with 2,5-mol equivalents of tetrabutylammonium fluoride in THF to remove the silyl ether protecting group.

The obtained 3,3'-bis-THP-ether d, l-2-exo- [3 '(S, R) -hydroxy-non-β-trans-1'-enyl] -3-exo-7-endo- dihydroxy-bicyclo [3.3.0] octane (1.660 g) is then oxidized with pyridine-chromium complex to give

1,25 g of 3,3'-bis-THP-ether d, 1,2-exo- [3 '(S, R) -hydroxy-non-1'-trans-r-enyl] -3-exo- hydroxy-bicyclo [3.3.0] octan-7-one, IC (film) 1740 cm ^-1 .

Example 20

A solution of (2-oxo-5,5,5-trimethoxy-pentyl) -dimethylphosphonate in 10 mL of THF was added dropwise with stirring to a suspension of 68 mg of 80% sodium hydride in 10 mL of anhydrous THF. The mixture is stirred until the evolution of hydrogen is complete, then a solution of 0.67 g of 3,3'-bis-THP-ether d, l-2-exo- [3 '(S, R) -hydroxy-non-1') is added. -trans-1'-enyl] -3-exo-hydroxy-bicyclo [3.3.0] octan-7-one in 5 mL THF and the solution was heated to 40-45 ° C with stirring for 6 hours. To the reaction mixture was added a 20% sodium dihydrogen phosphate solution, THF was distilled off under reduced pressure, the aqueous solution was extracted with ethyl ether, the combined organic extracts were dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is purified by chromatography on silica gel, eluting with cyclohexane / ethyl ether (0.76 g).

11,15 (S, R) -dihydroxy-20-methyl-9α-deoxy-9α-methylene-prostacyclla-5, 15-bis-THP ether of trimethyl orthosterone d, 1-5t, 13t-4-oxo-11 / 3,15 , 13-diene.

To a solution of the latter compound in 15 ml of anhydrous methanol, 6 mg of p-toluenesulfonic acid was added and the mixture was allowed to stand for 5 hours at room temperature. Then, 0.1 ml of pyridine is added, the solution is evaporated to dryness and the residue is purified on silica gel, using an isopropyl ether / ethyl ether mixture as eluent. 0.20 g of trimethyl orthoester d, l-5t, 131-4 is obtained

-oxo-11 / 3,15S-dihydroxy-20-methyl-9α-deoxy-9α-methylene-prostacycl-5,13-diene,

IC (film) 1700, 1690 cm ^-1 , M ^{+ -} H ₂ O 420 m / e, and 0.21 g of the respective 15R-epimer.

Example 21

Using the procedure described in Example 20 using the bicyclo [3.3.0] octan-7-ones prepared as described in Examples 16, 17 and 18, trimethyl orthoesters of the following acids were prepared:

5,13t-4-oxo-11a-15S-dihydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid, M ⁺ -H ₂ O 406, 5,13t-4-oxo-11a, 15S- dihydroxy-9α-deoxy-9α-methylene-20-methyl-prostacyclla-5,13-dienoic acid, M + -H ₂ O 420 m / e, 5,13t-4-oxo-11a, 15S-dihydroxy-9a -deoxy-9α-methylene-17 (2 ') -tetrahydrofuran-18,19,20-trinor-prostacycl-5,13-dienoic acid, M ⁺ -H ₂ O 434 m / e, 5,13t-4 -oxo-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prostacycl-5,13-diene, M ⁺ -H ₂ O 510 m / and also their 15R-epimers.

Each individual orthoester described in Examples 20 and 21 is then converted to the methyl ester by refluxing in methanol (13 mL / g) with 2 mL of 0.2 N oxalic acid; the desired product is isolated by evaporation of methanol and removal of the residue in ethyl ether. Subsequent saponification of the obtained methyl esters with 2% potassium hydrogen carbonate solution in 80% aqueous methanol provides the free acids.

Example 22

To a solution of 0.45 g of 5,13t-4-oxo-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-prostacyclla-5,13-dienoic acid trimethyl orthoester (λ _max = 244 nm, ε = 9850) in 6 1.2 ml of 0.2 N aqueous oxalic acid was added in ml of methanol, and the mixture was heated under reflux for 2 hours. The methanol was distilled off under reduced pressure and the aqueous solution was shaken with ethyl ether; after evaporation of the solvent 0.42 of the corresponding methyl ester is obtained.

A solution of the latter ester in 6 mL of anhydrous ethyl ether was added dropwise over 10 minutes to a 0.1 M zinc borohydride solution (10 mL) with stirring. The mixture was stirred at room temperature for 1 hour, then the excess reducing agent was quenched with 2 N sulfuric acid, the organic layer was separated and washed until neutral. After distilling off the solvent, 0.4 g of 5,13t-4 (S, R), 11a, 15S-trihydroxy-9α-deoxy-9α-methyleneprostacyclla-5,13-clienoic acid methyl ester is obtained. The mixture of isomers is separated by chromatography on silica gel using ethyl ether / ethyl acetate as the eluent. 0.11 g of methyl 5,13-methyl-11,11,1- [1,1,1-d] -hydroxy-9a-deoxy-9a-methyleneprostacycla-5,13-dienoic acid, IR (film), was obtained. one 1 3400 (broad) m + -2H ₂ O - 344 m / e and 0.14 g of methyl ester 4R-epimeric.

To a solution of the latter compound in 5 ml of methanol was added 0.05 g of lithium hydroxide and 0.3 ml of water, and the mixture was stirred at room temperature for 6 hours. After distilling off the methanol under reduced pressure, acidifying the remaining aqueous solution to pH 5.6 and rapidly extracting with ethyl acetate, 5.13t-4R, 11a, 15S-trihydroxy-9α-deoxy-9α-methyleneprostacycl-5,13-dienoic acid is obtained.

Treatment of 0.5 parts of polystyrenesulfonic resin (in H + form) with an ethyl acetate solution of the latter compound under stirring provided quantitatively the 1,4-γ-acton of 5,13t-4R, 11a, 15S-trihydroxy-9a-deoxy- 9a-methyleneprostacycl-5,13-diene, mp 51-52 ° C, M + - H 2 O 330 - m / e.

The 4S-epimeric γ-lactone was prepared in an analogous manner.

Example 23

Under an inert gas atmosphere, a suspension of 0.4 g sodium hydride (75% dispersion in mineral oil) in 13.5 ml DMSO was heated to 60-65 ° C with stirring for 4 hours. The mixture was cooled to room temperature and a solution of 2.6 g was added dropwise at -20 to 22 ° C

Of 4-carboxybutyl-triphenylphosphonium bromide in 6 ml of DMSO and then 0.85 g of 2-exo- (3'S-hydroxy-non-1'-trans-1'-enyl) -3'-bis-THP-ether -endo-hydroxy-bicyclo [3.3.0] octan-7-one.

The reaction mixture is stirred for 3 hours, then diluted with 35 ml of water and the aqueous phase is extracted with ethyl ether (5 x 12 ml) and then with a mixture of ethyl ether and benzene (7 x 12 ml). The combined organic extracts were then shaken with 0.5 N sodium hydroxide (3 x 15 mL) and water until neutral and then discarded. The combined aqueous alkaline extracts were acidified to pH 5.3 and the product was taken up in a 1: 1 mixture of ethyl ether and pentane. The combined organic extracts were washed neutral, dried over anhydrous sodium sulfate, and the solvents were distilled off; 0.86 g of 11,15-bis-TIP-ether-5,13t-11r, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methylprostacyclla-5,13-dienoic acid is obtained. The acid is then esterified with diazomethane and the pyranyl protecting group is removed as follows:

To a solution of - anhydrous methanol was added a solution of 10- ² mole equivalents of p-toluenesulfonic acid, and the mixture was allowed to stand for 4 hours. The p-toluenesulfonic acid is neutralized with pyridine and the solvent is distilled off. The residue is purified by chromatography on silica gel with 5,13t-11a, 15S-dihydroxy-9a-deoxy-9a-trans-methylprostacycl-5,13-dienoic acid methyl ester, M ⁺ H ₂ O 360 m / e M + - - H 2 O - C 2 H 4 O 360 m / e, which was then separated by liquid chromatography into the individual 5c, 13t- and 5t, 13t-isomers.

The acid is obtained in an analogous manner

5t-11α, 15S-dl oxy-9α-deoxy-9α-methylene-20-methylprostacycl-5-ene-13-yne [NMR (CDCl 3) δ ppm: 0.90 (3H, t); 4.00 (1H, m); 4.40 (1 H, t); 5.30 (1H, t)) and its 5c-isomer [NMR (CDCl3) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.27 (1H, t) is also 5t-11α-, 15R-dihydroxy-9α-deoxy-9α-methylene-20-methylp3rostacycl-5-ene-13-ynoic acid [NMR (CDCl 3) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.39 (1 H, t); 5.30 (1H, t)) and its 5c-isomer [NMR (CDCl3) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.28 (1 H, t).

Example 24

With stirring and external cooling at a reaction temperature of 20 to 22 ° C, to a solution of freshly sublimed potassium tertiary butylate in 12 ml of anhydrous DMSO is added first a solution of 1.8 g of 4-carboxybutyl-triphenyl phosphonium bromide in 10 ml dMso and then 0.65 g. 2'-exo- (2'-bromo-3'S-hydroxy-occtl'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.1] bis-THP-e] O) octan-7-one in 5 mL DMSO.

The reaction mixture was stirred at room temperature for 8 hours, then diluted with an equal volume of water, acidified to pH 5 and extracted with a 1: 1 mixture of ethyl ether and pentane. Discard the acidic aqueous portion and shake the combined organic extracts first with 0.8 N sodium hydroxide ( 5 x 20 ml) and then water until neutral. The organic portion is set aside and the aqueous alkaline extract is acidified to pH 5 and the product is taken up in a 1: 1 mixture of ethyl ether and pentane. The combined organic extracts are dried over anhydrous sodium sulfate, the desiccant is filtered and ethereal diazomethane is added. yellow coloring.

After distilling off the volatile components, the crude 11,15-bis-THP-ether of 11a, 15S-dihydroxy-9α-deoxy-9α-methylenepiocycl-5-ene-13-ynoic acid methyl ester is obtained. The pyranyl protecting groups are removed from the product and the mixture of isomers is separated by high pressure liquid chromatography. There was obtained methyl 5c-11a, 15S-dihydroxy-9α-deoxy-9α-methyleneprostacycl-5-ene-13-ynoic acid, M + -H 2 O 344 m / e, M + -H 2 O-C 2 H 4 O 300 m / e, M + -H ₂₀ ° C 5 H 1 273 m / e, and the corresponding 5t geometric isomer.

The compounds prepared in Example 24 were obtained in an analogous manner.

Example 25

Using the procedure described in Examples 33 and 24 using the 3,3'-bis-THP-ethers of bicyclo [3.3.0] octan-7-ones prepared as described in Examples 16, 17, 18 and 19 as starting materials, methyl esters were obtained of these acids:

5c, 13t-11S, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacyclla-5,13 · dienoic acid,

M + - H2O 346 m / e, 5c-11a, 15S-dihydroxy-9a-deoxye acid

-9a-methylene-16R-fluoroprostacycl-5-en-13-yne,

M ⁺ -H ₂ O 362 m / e, 5c-11a, 15S-dihydroxy-9α-deoxy-9α-methyl-16'-fluoroprostacycl-5-en-13-ynoic acid,

M ^{+ -} H ₂ O 362 m / e, 5c-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-17 (2 ') -tetrahydrofuryl-18,19,20-trinor Prostacycl-5-ene- 13-in,

M ⁺ -H ₂ O 386 m / e acid 5c-lla, 15S-dihydroxy-9 and _{C-deoxo-9a-methylenprostacykl-5-en-13-ynoic,}

M + -H ₂ 344 m / e, 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methyleneprostacycaa-5,13-dienoic acid, M ⁺ -H 2 O 346 m / e, M + -H 2 O ^-C 2 H 4 O 288 m / e, M ⁺ -H 2 O-C ₅ H _U 261 m / e, 5c, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-16S-methylprostacycl-5,13-dienoic acid,

M ^{+ -} H ₂ 0 360 m / e, 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-20-methylprostacyclla-5,13-dienoic acid,

M ^{+ -} H ₂ 0 360 m / e, 5c, 13t-Ha, 15S-dihydroxy-9α-deoxy-9, α, β-thylene-17-cycloliexyl-18,19,20-tr. -5,13-diene,

M ^{+ -} H ₂ 0 372 m / e, 5c, 13t-11a, 15S-Dlyl-dioxy-9a-deoxy-9a-methylene-7-phenyl-18,19,20-trinor Prostacyclia-5 , 13-diene,

M ^{+ -} H ₂ 0 380 m / e, 5c, 13t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-16-m-trifluoromethyl-phenoxy-η 7,18,19,2'-Aranoroprostacycl-5, 13-diene,

M + - H ₂ O 450 m / e, 5c, 13t-11a, 15S-dihydroxy-9-aldehyde-9α-methylene-16-methyl-16-butoxy-18,19,20-trinor-β-Stacycla-5,13- dienoic acid, M + 552 m / e as bis-trimethylsilyl ether, as well as their 5-trans geometric isomers, in particular 5t-11a, 15S-c] ilidroxy-9a-deoxy-9a-methyleneprostacycl-5-en-13-ynoic acid methyl ester, and 15R-epimers of both geometric isomers, especially 5'-11a, 15R-dihydroxy-9a-deoxy-9a-methyleneprostacycl-5-ene-13-ynoic acid methyl ester.

All methyl esters are then saponified to give free acids, in particular 5t-11a, 15S-dihydroxy-9α-deoxy-9α-methyleneprostacycl-5-ene-13-ynoic acid [NMR [CDCl 3] δ ppm: 0.90 (3H, ie; 4.00 (1H, m); 4.40 (1H, broad t); 5.28 [1H, broad i.e] and 5t-11a, 15R-dihydroxy-9α-deoxy-9α-methyleneprostacycl-5 -en-13-yne [NMR (CDCl 3) δ ppm: 0.90 [3H, t]; 4.00 [1 H, m); 4.39 (1H, broad ie; 5.29 (1H, broad t)].

Example 26

A solution of 0.45 g of 2-exo- [3'S-hydroxy-oc-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octane S -bis-TRP-ether The 7-one in ethyl acetate is hydrogenated at room temperature and at atmospheric pressure in the presence of 0.1 g of 5%. palladium on calcium carbonate. After filtering off the catalyst and distilling off the solvent, 0.42 g of 2-exo- [3'S-hydroxy-octan-Γ-yl] -3-endo-hydroxy-bicyclo [3.3] 3,3'-bis-THP-ether is obtained. , 3,0] octan-7-one.

Reaction of this compound with the Wittig reagent prepared after 4-carboxybutylphosphonium bromide as described in Examples 23, 24 and 25 affords a product which, after esterification with diazomeethane and deprotection of the pyranyl groups, affords 0.12 g of methyl 11 ', 15S-dihydroxy-. 9α-deoxy-9α-nethyleneprostacycl-5-ene, M + 366 m / e. The methyl ester is separated into the individual 5-cis and 5-trans geometric isomers by liquid chromatography.

Example 27

Using the methods described in Examples 25 and 26, but using [3-carboxypropyl) phosphonium bromide instead of [4-carboxybutyl) phosphonium bromide, the following acids were obtained:

5c, 13t-11a, 15S-diliydroxy-9α-deoxy-9α-methylene-2-nor-prostacycl-5,13-dienoic acid,

M + - H ₂ 0 318 m / e, 5c-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostacycl-4-enoic acid, M ⁺ 338 m / e and 5c-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-2-nor-prostacycl-5-ene-13-yne,

M ^{+ -} H ₂ 0 316 m / e.

Example 28

In the manner described in. Examples 25 and 26, but using (5-carboxypentyl) phosphonium bromide as the starting material, 5c, 13t-11α, 15Stdibydroxy-9a-deoxy-9a-methylene-2a-homo-postostacycl-5,13-dienoic acid was prepared,

M + 580, M + - CH 3 565 m / e as tris-trimethylsilyl ether and 5c, 13t-11-a, 11S-dihydroxy-9α-deoxy-9α-meehylene-20-methyl-2a-homo-prostacyclla5,13-dienoic acid ,

M + 594, M + - CH 3 579 m / e as trimethylsilyl ethers.

Example 29

To a solution of 2.2 g of 3-endo-hydroxy-bicyclo [3.3.0] octan-7-one in 100 ml of anhydrous benzene was added 4 ml of ethylene glycol and 0.2 g of p-toluenesulfonic acid (monohydrate and heated). The solution was treated with 0.25 ml of pyridine, cooled and washed with water, sodium bicarbonate solution and water to give 2.32 g of solvent. ethylendioxidu 7,7-3-endo-hydroxy-bicyclo [3.3.0] octan-7-one; ICffilm) 3450 cm ^_ 1 and no absorption at 1745 cm ^'first

To a solution of the latter product in 40 mL of acetone was added 4.1 mL of Jones reagent while cooling to -5 ° C. The mixture is stirred for 20 minutes at - 5 ° C, then the excess oxidant is quenched by addition of 4 ml of isopropanol, 150 ml of benzene is added and the benzene solution is washed successively with 20% ammonium sulfate solution, water, 5% sodium bicarbonate solution and water. After distilling off the solvent, 2.1 g of 7,7-ethylenedioxide d, 1-bicyclo [3.3.0] octane-3,7-dione-2-carboxymethyl ester is obtained, m.p. 40-42 ° C.

This compound is reacted with methyl carbonate by the procedure of Example 1 to give 7,7-ethylene oxide d, β-bicyclo [3.3.0] octane-3,7-dione-2-carboxymethyl ester, A _m and _X = 254 nm, ε = 7000.

A solution of the latter in a mixture of 20 ml of methylene chloride with 20 ml of ethanol was reduced as described in Example 2 by treatment with sodium borohydride at -20 degrees Celsius to give 1.72 g of 7,7-ethylenedioxide d, l-2-exo- methoxycarbonyl-3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, IC (film) 3400 cm -1 1720 cm ^-1 .

To a solution of the latter compound (157 g) in 3 ml of dimethylformamide was added 1.3 g of dimethyl tert-butylsilyl chloride and 0.885 g of imidazole, and the mixture was allowed to stand at 0 ° C for 5 hours. Under cooling, water is added to the reaction mixture and the solution is worked up in the usual manner; 2.3 g of 7,7-ethylenedioxide d, l-2-exo-methoxycarbonyl-3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, 3-dimethyl-tert-butylsilyl ether, is obtained. IC (film) 1710 cm -1.

Subsequent reduction of this. The product lithium aluminum hydride in anhydrous ethyl ether as described in Example 3 sc quantitatively obtains 3-dimethyl-tert-butylsilylether. d -1,3-endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo 3.0] octan-7-one, IR (µm) 3400 cm -1.

Example 30

By the method described in Example 29, but using dithioethylene glycol instead of ethylene glycol, the corresponding 7,7-ethylenedithio analog was prepared.

Example 31

1.8 g of 3-dimethyl-tert-butylsilyl ether d, l-3-endo-hydroxy-2-exo-hydroxymethy-7,7-ethylenedioxy-bicyclo [3.3.0] octan-7-one is oxidized as described above. in Example 18 to give the corresponding 2-formyl derivative. This product shall be placed in. treatment with (2-oxo-heptyl) -dimethylphosphonate as described in Example 9 to give 1.23 g of d-l-3-endo-hydroxy-2-exo- (3'-oxo) 3-dimethyl-tert-butylsilyl ether oct-1'-trans-1'-enyl) -7,7-ethylenedioxy-bicyclo [3.3.0] octan-7-one (λ max = 228 nm, ε = 8980).

The latter compound was reduced in the manner described in Example 11 by treatment with zinc borohydride in ether to give 1.22 g of d-l-endo-hydroxy-2-exo- [3-dim (ethyl-tert-butyl-silyl ether). 1- (S, N-hydroxy-oc-r-rans-r-enyl) - N -ethylenedioxy-bicyclo [3.3.0] octan-7-one.

To a solution of the latter product in 25 ml of methanol was added 10 ml of 1N sulfuric acid and the mixture was heated under reflux for 50 minutes. The methanol was distilled off under reduced pressure, the aqueous solution was extracted with ethyl ether, the organic extracts were combined and the solvent was evaporated to dryness.

0.72 g of crude d, 1-endo-hydroxy-2-exo- [3 '(S, R) -hydroxy-ok-1'-trans-phenyl] -bicyclo [3.3.0] octane- 7-onu. Chromatography on silica gel using hexane / ethyl ether as eluent gave the individual isomers which were converted to the corresponding tetrahydropyranyl ethers by treatment with 2,3-dihydropyran in methylene chloride as described in Example 14. In this way, a compound identical in all respects to 3,3 tetrahydr-bis-tetrahydropyranyl ether is prepared from the 3‘-S-hydroxyisomer.

2-exo- (3 S -hydroxy-okur-trans-1-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, prepared as described in Example 17.

Similarly, all of the compounds described in Examples 16, 17 and 18 can be prepared as described in Examples 29 and 31.

Example 32

4.8 gd, 1-3-endo-hydroxy-2-exo-methoxycarbonyl-7,7-ethylenedioxy-bicyclo [3.3.0] octan-7-one was saponified for 40 minutes with 100 ml of a 2.5% carbonate solution. After treatment of the reaction mixture as described in Example 2, 4.02 g of 7,7-e215150 thylenedioxide d, l-3-endo-hydroxy-2-exo-carboxy-bicyclo-3 are obtained. - [3,3,0] octan-7-one.

The compound is dissolved in 80 ml of anhydrous tetrahydrofuran, the solution is cooled to -10 ° C and, while cooling to -10 ° C, a solution of 2.1 g of triethylamine in 12 ml of anhydrous tetrahydrofuran and then a solution of 2.2 g of ethyl chloroformate is added dropwise. in 12 mL of anhydrous tetrahydrofuran. The reaction mixture was stirred at -10 ° C for 1 hour, then a solution of 1.4 g of sodium azide in 12 ml of water was slowly added and the mixture was stirred for an additional 25 minutes. The solvents were distilled off under reduced pressure, and the concentrated solution was diluted with water. and excluded

The 2-exo-carboxyazide is rapidly filtered off and dried under reduced pressure.

To a solution of 4.01 g of the latter compound in 8 ml of pyridine was added 4 ml of acetic anhydride and the mixture was allowed to stand at 4-8 ° C for 24 hours. Ice water was added to the reaction mixture, the solution was acidified with 2 N sulfuric acid and washed neutral, dried and the solvent was distilled off under reduced pressure. 3-Endo-hydroxy-bicyclo [3.3.0] octan-7-one-2-exo-carboxylic acid azide 7,7-ethylenedioxide 3-acetate (4.1 g) was obtained, IC

2215 cm ^1st

The latter product is suspended in a mixture of acetic acid (50 ml) with water (8 ml) and the mixture is heated to 40 DEG C. When nitrogen evolves, the temperature is raised to 60-70 DEG C. and the mixture is maintained at this temperature. Excess acetic acid was removed by steam distillation, the remaining aqueous solution was extracted with ethyl ether-ethyl acetate and the aqueous portion was basified with sodium hydroxide to pH 9.

The alkaline solution was shaken with ethyl ether, the organic portion was washed with a saturated aqueous salt solution and the solvent was evaporated; 1.92 g of 3-endo-hydroxy-2-exo-amino-bicyclo [3.3.0] octan-7-one (-HCl, m.p. 111-113 ° C) are obtained.

Reaction of the latter compound with a mixed anhydride prepared from ethyl chloroformate and 2S-hydroxyheptanoic acid 2-acetate affords 3-acetate

3-endo-hydroxy-2-exo- (2 &apos; -S-acetoxyheptanoylamino) -bicyclo [3.3.0] octan-7-one, M + 367 m / e.

A solution of this compound in anhydrous dimethylsulfoxide is then reacted with ylld prepared from 4-carboxybutyl-triphenylphosphonium bromide to saponify the product to give 5t-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-12-aza-13- oxoprostacycl-5-ene, M + 583 m / e as tris-trimethylsilyl ether.

In an analogous manner, the 2 &apos; R-hydroxypentanoic acid is. prepare the corresponding 15R-epanalog.

Example 33

To a solution of 2-cis-bromo-3-cind (β-hydroxybicyclo (3.2.0) heptan-6-one in benzene) was added ethylene glycol (15 mL) and p-toluenesulfonic acid (0.9 g). The mixture was heated to boiling for 12 hours while distilling off the water formed in the reaction, pyridine (0.6 ml) was added to the reaction mixture, the solution was cooled to room temperature, washed with water, 2.5% aqueous sodium bicarbonate solution and water and dried. Some benzene (100 mL) was distilled off under reduced pressure, tributyltin hydride (41 g) was added to the concentrated solution under nitrogen and the mixture was heated at 55 ° C for 8 hours. The residue is purified by column chromatography on silica gel (240 g), eluting with a mixture of benzene and ethyl ether, to give 14.9 g of 3-endo-hydroxy-bicyclo [3.2]. Hepaan-6-one-6,6-ethylenedioxide IR (film) 3460 cm ^{@ 4} , M @ + 242 m / e as trimethylsilyl ether.

Example 34

To a solution of 3-endo-hydroxy-bicyclo [3.2.0] heptane-6-one-1,6,6-ethylenedioxide (12.75 g) in a mixture of benzene (340 mL) with DMSO (112 mL) was added dicyclohexylcarbodiimide (46, 35 g), pyridine (5.9 g) and trifluoroacetic acid (5.4 g) The reaction mixture was stirred for 6 hours, then diluted with benzene (600 ml) and water (50 ml), the precipitated dicyclohexylurea was filtered off, the organic fraction The mixture was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off to give bicyclo [3.2.0] heptane-3,6-dione-6,6-diethylenedioxide, Ic (film) 1742 cm ⁴ , M + 168 m / e .

A solution of the crude product thus obtained in dimethyl carbonate (70 ml) was added to a suspension of sodium hydride (80% dispersion in mineral oil, 4 g), stirred at room temperature until evolution of hydrogen ceased, and then heated to 75-80 for 40 minutes. After cooling, the reaction mixture was diluted with benzene (350 mL), acidified with acetic acid (8.4 g), the solution was washed with water, dried and the solvent was evaporated to dryness to give a mixture (1: 1) of d.1. -bicyclo [3.2.0] heptane-3,6-dione-2-methoxycarbonyl-6,6-ethylenedioxide, M + 226 m / e (p = 0, q = 1) a. 2,0] heptane-3,6-dione-4-methoxycarbonyl-6,6-ethylenedioxide, M + 226 m / e (p = 1, q = 0), which is separated into the individual isomers by ion-free sillkagel chromatography Fe 2+ and Fe 2 O, eluting with hexane / ethyl ether.

Example 35

Using the procedure described in the example, oxidation of 14.85 g of 3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide gives

13.9 g of bicyclo [4.3.0] nonane-3,7-dione-7,7-ethylenedioxide, IC (film) 1740 cm &lt; ⁴ &gt;, M + 196 m / e, from which 4.2 is obtained by carbomethoxylation gd, 1-bicyclo [4.3.0] nonane-3,7-dione-2-methoxycarbonyl-7,7-ethylenedioxide, M ⁺ 254 m / e (p = 1, q-2) and 4.8 gd 1,1-bicyclo [4,3,0] nonane-3,7-dione-4-methoxycarbonyl-7,7-ethylenedioxide, also named d, 1-bicyclo [4,3,0] nonane- 3,8-dione-2-methoxycarbonyl-8,8-ethylenedioxide (p-2, q = 1), M + 254 m / e.

Example 36

A solution of (2-oxo-ethyl) -dimethylphosphonate (0.33 g) in dry benzene (5 mL) was added with stirring to a suspension of sodium hydride (80% dispersion in mineral oil, 43.5 mg) in dry benzene (10 mL). After 1 hour, N-bromosuccinimide (260 mg) was added and then, after 5 minutes, a solution of bicyclo [4.3.0] nonane-3-endo, 8'-dihydroxy-2-exo-formyl-3-THP was added dropwise. ether-8-DMtB-Siyl ether (0.4 g) in toluene (5 mL).

The reaction mixture was stirred for 15 minutes, then washed with aqueous sodium dihydrogen phosphate (15%), dried, and the solvent was distilled off under reduced pressure. There was obtained 2-exo- (2'-bromo-3'-oxo-occtl'-trans-enyl) -3-endlo-THP-oxy-8f-DMtB-silyloxybicyclo [4.3.0] nonane, A _{m and} x 251 nm, ε = 8900.

Example 3 7

A solution of (3-phenoxy-2-oxo-propyl) -dimethylphosphonate (2.85 g) in benzene (10 mL) was added to a suspension of sodium hydride (80% dispersion in mineral oil, 0.33 g) in benzene (50 mL). ml). The mixture was stirred for 45 minutes, then a solution of 2-exo-formyl-3-endo-THP-oxy-4-DMtB-4-yloxy-bicyclo-4,3,0] nonane (3.82 g) in toluene was added and the solution was stirring for another 20 minutes. The organic portion was washed with 20% aqueous sodium dihydrogen phosphate solution and water, dried, and the solvent was distilled off. ^; The crude product was chromatographed on silica gel (38 g), eluting with benzene / ethyl ether 2-exo-4'-oxo-4-phenoxy-buttr-trans-enyl-4-endo-THP-oxy-7-DMtB -silyyloxy-bicyclo [4.3.0] nonane X 3.97 g), [M + -102] 412 m / e.

Using the same procedure but using (5-cyclohexyl-2-oxo-butyl) -dimethylphosphonate and the aldehydes described in Example 49, they were prepared.

2-exo- ^(3-oxo-s 5'-cy] bicyclo] ^ (^^ ^ l - ^ (^ NTT: l-trans-enyl) s3-endOsTHP-oxys7šsDMtB-silyloxys -bicyklof 4.3, 0 nonane and _m x 228 nm, ε = 9300, and

2-exo- (3‘-oxo-5‘-cyclohexylpent-Γ-trans-enyl) -3-endo-THP-oxy-8βDMtBssilyloxy-bicyclo [4.3.0] nonane, λ max 228 nm, ε - 9450.

Example 3 8

The DM β-γ-yeasts of α, β-unsaturated ketones obtained as described in the Examples, obtained as described in Examples 36 and 37, are a) reduced to allyl alcohols, b) the newly formed hydroxyl group is protected in the form of THP- ether, then c) the DMB-silyl ether protecting group is selectively removed and the secondary alcohol obtained is d) oxidized to a ketone; then all remaining protecting groups are removed and f) the mixture of epimeric silyl alcohols is separated by high pressure liquid chromatography on silica gel. Using 2.10 ~ ² molar weights, proceed as follows:

a) Reduction: To a solution of α, β-unsaturated ketone DMTB-sulfonyl ether (2.10 ~ ² mol) in methylene chloride / ethanol (1: 1, 180 ml) was added 1. 10 with cooling at -10 to -15 ° C. -2 mol (0.32 g) of sodium borohydride and the mixture was stirred for 30 minutes. Excess hydride was quenched by addition of acetone (10 mL) followed by saturated aqueous sodium dihydrogen phosphate (25 mL).

The solvents were distilled off under reduced pressure and the residue was partitioned between water and methylene chloride. The organic layer was separated, dried and the solvent was distilled off. To give a mixture of 3'S and 3'R allylic alcohol DMtB-silyl ether (2.10 ~ ² mol). ,

b) a protected allylic alcohol as a THP ether: crude mixture DMIH ^^^^^ 3'R and 3'S allylic alcohol (2.10 ^"2) was dissolved in methylene chloride (30 mL) and to the solution was added with stirring 2,3-dihydropyran (2 g) and p-toluenesulfonic acid (0.038 g) After two hours, the reaction was quenched by addition of pyridine (0.5 mL) and the solvents were distilled off under reduced pressure to give a crude mixture of 3'S, 3'R THR-tert-butyl ethers. of alcohols.

c) Desilylation: To a solution of the latter product in anhydrous THF (80 mL) was added dry tetrabutylammonium fluoride (14 g) and the mixture was allowed to stand at room temperature for 12 hours. The solution was concentrated under reduced pressure to a small volume and the concentrated mixture was chromatographed on silica gel (40 grams), using ethyl ether as eluent; give a mixture of 3'S, 3'R-THP ethers of the appropriate secondary alcohols (about 2.1Ο ² mol).

d) Oxidation: To a solution of the latter 3'S, 34017? - 7? 11 free secondary alcohol in a mixture of benzene and DMSO (75: 25, 60 ml) is gradually added dicyclohexylcarbodiimide (6.5 g), pyridine (1 mL) and trifluoroacetic acid (0.5 mL). After

After 4.5 h, the reaction mixture was diluted with benzene (100 mL) and an aqueous solution of oxalic acid (3 g) was added. The precipitated dicyclohexylurea is filtered off, the organic filtrate is washed neutral, the solution is dried and the solvent is distilled off.

e, f) D-pyranylization and chromatographic separation of the mixture: The solution of the 3'S, 3'R-THP-ethyl (triethyl ketone in methanol (30 ml)) was stirred for 3 hours at room temperature with toluenesulfonic acid. (0.18 g) The mixture was basified with pyridine (0.5 mL) and the solvent was distilled off, and the residue was dissolved in cyclohexane / ethyl acetate (80:20) and injected into the high pressure liquid chromatography inlet to give the following keto alcohols:

2-exo- (2'-bromo-3'S-hydroxy-octtr-trans-enyl) -3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one,

M + - H ₂ O 340, 342 m / e,

2-exo- (2'-bromo-3'R-hydroxy-ok-4'-trans-enyl] -3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one,

M ^{+ -} H ₂ O 340, 342 m / e,

2-exo- [3S-hydroxy-4'-phenoxy-but-1'-trans-enyl] -3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one,

M + 460 m / e as bis-trimethylliilyl ether,

2-exo- (3'R-hydroxy-4'-f (enoxo) -11'-trans-enyl) -3-endo-hydroxy-bicyclo [4.3.0] nonane-7- he,

M + 460 m / e as bis-trimethylsilyl ether,

2-Exo- (3'S-hydroxy-5-cyclohexyl-pent-1'-trans-enyl) -3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one, M + - H2O 302 me,

2-exo- (3R-hydroxy-5-cyclohexyl-pent-6-trans-enyl) -3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one,

M + -H 2 O 302 m / e,

2-exo- (3S-hydroxy-5-cyclohexyl-pent-6-trans-enyl) -3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one,

M + - H 2 O 302 m / e a

2-exo- (3R-hydroxy-5-cyclohexyl-pent-6-trans-enyl) -3- (4-hydroxy-bicyclo [4.3.0] nonan-8-one),

M + - H 2 O 302 m / e.

Example 3 9

A suspension of sodium hydride (80% dispersion in mineral oil, 2.1 g) in anhydrous DMSO (70 mL) was stirred under a nitrogen atmosphere at 65 ° C for 4 hours. After cooling to 25 to 30. ° C, dry 4- is added to the reaction mixture. -carboxybutyl triphenylphosphonium bromide (13 grams) and a dark red colored ylide solution is obtained.

To this solution is added. a solution of 2-exo [2'-bromo-3'S-hydroxy-octa-trans-enyl] -3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one (1.79 g) in anhydrous DMSO ( 6 ml) a. the reaction mixture was stirred at 28 ° C for 1 hour and then at 40 ° C for 4 hours. The mixture was cooled to room temperature, diluted with water. (80 ml, acidified to pH 4.5 by addition of 4 N sulfuric acid solution and the product was taken up in ethyl ether (4 x 50 ml, 2 x 25 ml). The aqueous solution was discarded, the combined organic extracts were washed with water (aqueous washes were washed with water). The mixture was then acidified to pH 5 and extracted with ethyl ether. After distilling off the solvent, 5 [Z, E) -11c acid was obtained. 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-prostacycl-5-ene-13-yne (mixture of 5c- and 5t-isomers); M + 362, M + - H ₂ O 344, M + - 2 H 2 O 328, M + - H ₂ O - C ₅ H 11 273 m / e.

The mixture was separated into individual geometric isomers by acidic silica gel chromatography (40 g for each g of acid), using a mixture of cyclohexane and ethyl ether as eluent.

Example 40

To a solution of freshly sublimed potassium tertiary butylate (3.36 g) in anhydrous dMsO (36 mL) was added 6.5 g of 4-carboxybutyl-triphenylphosphonium bromide under stirring under nitrogen to give a dark red colored ylide solution.

To this solution was added a solution of 2-oxo-3‘R-hydroxy-4‘-phenoxybutyl-1‘-trans-enyl) in anhydrous DMSO [3 mL], and the reaction mixture was stirred at 42 ° C for 5 hours. After cooling, the solution was diluted with water (50 mL), acidified to pH 5 and extracted with ethyl ether (4 x 10 mL), discarded and the combined ether extracts washed with water (10 mL, wash was discarded) and then 0.5 N sodium hydroxide solution (4 x 6 mL) and water until neutral The acidified aqueous alkaline extracts were acidified to pH 5 and the product was taken up in ethyl ether.

The organic extracts were combined, dried and the solvent was distilled off; yielding acid 5 (Z, E), 13t: -1a, 5a, 5a, 5'-dihidyl, 9'-deoxy-9a, 7a-homo-dimethylene-16-phenoxy-17,1.8, 19,20-tetranor-prostacycl-5,13-diene (mixture of (5c- and 5t-geometric isomers), M + 400, MW ^{h 2} O 382 m / e).

The mixture was separated into the individual geometric isomers by acidic silica gel chromatography (40 g SiO ₂ for each gram of acid) using a mixture of cyclohexane and ethyl acetate as eluent.

Example 41

The following prostacyclic acids are prepared as described in Examples 39 and 40 using the keto alcohols obtained as described in Example 37:

5c-11f, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethyleneprostacycl-5-en-13-ynoic acid, M ⁺ 362, M + - Ы2О — С5Н11 273 m / e, 5c, 13t-lloric acid, 15S -dihydroxy-9α-deoxy-9α, 7α-homo-dimethylene-16-phenoxy-17,19,19,20-tetranor-prostacycl-5,13-diene,

M ⁺ 400 m / e, 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene-17-cyclohexyl-18,19,20-trinor-prostacyclla-5,13-dienoic acid, M ⁺ 404 m / e and 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-17-cyclohexyl-18,19,20-trinor-prostacyclla-5,13-dienoic acid, M ⁺ 404 m / e E.

Example 42

In the manner described in Example 1, 30 g

2-acetoxyperhydroazulen-6-one, also referred to as 3-endo-hydroxy-bicyclo [5.3.0] decan-8-one-3-acetate (obtainable by the method described by DK Banerje et al. J. Chem., 10, 1972), converted to the corresponding ethylene dioxide (29.1 g). The compound is saponified by treatment with a 2% solution of potassium carbonate in aqueous methanol and obtained

The 3-endo-hydroxy-bicyclo [5.3.0] decan-8-one-8,8-ethylenedioxide was oxidized as described in Example 2. The ketone obtained was reacted with dimethyl carbonate (see Example 2); and converted to d, 1-bicyclo [5.3.0] decane-3,8-dione-2-methoxycarbonyl-8,8-ethylenedioxide (21.2 g) λ _max 254 nm, ε = 7000.

Example 43

The ethylenedioxides of bicyclo-β ketoesters obtained as described in Examples 34, 35 and 42 are reduced as follows:

Sodium borohydride (0.9 g) was added portionwise to a solution of bicyclo-ketoester ethylenedioxide (2.5 x 10 ^-2 mol) in methylene chloride / ethanol (1: 1, 150 ml) with stirring and cooling to -20 ° C. The mixture was stirred at -20 ° C for an additional 30 minutes. Excess hydride was quenched by the addition of acetone (12 mL), then the reaction mixture was allowed to warm to room temperature and a 20% aqueous potassium dihydrogen phosphate solution was added. The solvents were distilled off, the residue was diluted with water (20 ml) and the product was taken up in methylene chloride. The organic extracts were combined, washed with water until neutral, dried and the solvent was distilled off. The residue was dissolved in absolute methanol (20 mL), sodium methoxide (0.54 g) was added and the mixture was allowed to stand at room temperature for 12 hours. After acidification with acetic acid (0.59 g), the solvents were distilled off and the residue was taken up in methylene chloride. About 0.22.10 ^-2 mol of the following ethylene oxides of bicyclo-4-hydroxy esters are obtained:

d, l-3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one-exo-methoxycarbonyl-6,6-ethylenedioxide,

M ⁺ 300 m / e as trimethylsilyl ether, d, l-3-endo-hydroxy-bicyclo [3.2.0] heptan-6-one-4-exo-methoxycarbonyl-6,6, -ethylenedioxide, also named as d, l-3-endo-hydroxybicyclo [3.2.0] heptan-7-one-2-exo-methoxycarbonyl-7,7-ethylenedioxide, M ⁺ 300 m / e as trimethylsilyl ether, d, l -3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one-2-exo-methoxycarbonyl-7,7-ethylenedioxide,

M ⁺ 328 m / as trimethylsilyl ether, d, l-3-endo-hydroxybicyclo [4.3.0] nonan-8-one-2-exo-methoxycarbonyl-8,8-ethylenedioxide,

M ⁺ 328 m / e as trimethylsilyl ether and 1,1,3-endo-hydroxy-bicyclo [5.3.0] decan-8-one-2-exo-methoxycarbonyl-8,8-ethylenedioxide,

M ⁺ 342 m / e as trimethylsilyl ether.

Next, 2.10 ^-2 mol of each of the above compounds was dissolved in anhydrous methylene chloride (25 mL), 2,3-dihydropyran (2 g) and p-toluenesulfonic acid (38 mg, 2.10 ^-4 mol) were added. and allowed to react at room temperature for 2 hours. The reaction was quenched by addition of pyridine (0.1 mL) and the solvents were distilled off under reduced pressure. The corresponding ones are obtained

3-THP-ethers, which can be used for further work without any purification.

Example 44

The 3-endo-hydroxy-2-exo-carboxymethyl testers and their 3-THP-ethers obtained as described in Example 43 are reduced to the corresponding 2-exo-hydroxymethyl methyl derivatives as follows:

A solution of 2.10 ~ 2 mol of the appropriate J-ketoester (either alcohol or 3-THP-ether) in anhydrous ethyl ether (25 ml) was added dropwise to a suspension of lithium aluminum hydride (0.4 g) in anhydrous ethyl ether (50 ml). After stirring for 30 minutes, excess hydride was quenched by addition of acetone (5 mL) and water-saturated ethyl ether, anhydrous magnesium sulfate (12 g) was added, the mixture was filtered and the solvent was evaporated to dryness.

The following 3-endo-hydroxy-2-exo-hydroxymethyl compounds are prepared as follows:

bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide,

M + 342 m / e as bis-trimethylsilyl ether, bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide,

M + 342 m / e as bis-trimethylsilyl ether, bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide,

M + 370 m / e as bis-trimethylsilyl ether, bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide,

M + 370 m / e as bis-trimethylsilyl ether, bicyclo [5.3.0] decan-8-one-8,8-ethylenedioxide, M + 384 m / e as bis-trimethylsilyl ether and their 3-endo-hydroxy-THP-ethers , in both racemic and optically active form (nat, ent), when the optically active material obtained by resolution of the starting racemic compounds is used in the process.

Example 45

From 2-exo-hydroxymethyl-THP ether prepared as described in Example 44 to 12 _J '^ hydroxymethyllll acetate were prepared by oxidizing the corresponding aldehydes steps:

To a solution of the hydroxymethyl compound (2.10-3 mol) in a mixture of benzene and DMSO (75:25, 6 ml) was added dicyclohexylcarbodilide (0.64 g), pyridine (0.1 ml) and trifluoroacetic acid, with stirring. The reaction mixture was stirred for 4.5 hours, then diluted with benzene (20 mL) and water (10 mL) and stirred for an additional 30 minutes, the precipitated dicyclohexylurea was filtered off, the organic filtrate was washed with water until neutral and concentrated to 10 mL. a solution of the following aldehydes in anhydrous benzene:

3-endo-THP-oxy-2-exo-formyl-bicyclo [3.2.0] -6-one-6,6-ethylenedioxide, [M + -102] 180 m / e,

3-endo-THP-oxy-2-exo-formyl-bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, [M + -102] 180 m / e,

3-endo-THP-oxy-2-oxo-tolyl-bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, [M + -102] 208 m / e,

3-endo-THP-oxy-2-exo-methyl-bicyclo [4.3.0] nonane-8-fluoro-8,8-ethylenedioxide, [M + -102] 208 m / e,

3-endo-THP-oxy-2-exo-tert-butyl-bicyclo [5.3.0] octan-8-one [8,8] -thylenedioxide, [M + -102] 222 m / e,

5- (Z, E] and 5c, 5t-w (2 S) -> 12) octanor-12J-formyl-11c-hydroxy-9a-deoxy-9a, 9b, 7-homo methyl ester 11-acetate, respectively -trimethyl-2-nor-prostacycl-4-ene, M + 322 m / e

11-acetate of methyl 5 - (Z, E), respectively. 5c, 5t-w (20) -? - octano-1? -Formylflaα-hydroxy-9? -Deoxyf9?, 7? -Honomimethyleneprostacycl-5-ene,

M @ + 322 m / e.

These compounds were used in the next Wittig-Horner reaction without further purification.

Example 46

A solution of (2-oxo-heptyl) dimethylphosphonate (0.49 g) in benzene (6 mL) was added dropwise with stirring to a suspension of sodium hydride (80% dispersion in mineral oil, 66 mg, 2.2.10-3 mol) in benzene ( 15 ml). The mixture was stirred for an additional 45 minutes and then a solution was added

2.10 ': 1 mole of 5ΐ-ω (20) -> 12) octanol-12H-formyl-rlafhydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylphen-2-nor-prostacyclic acid 11-acetate 5-ene in benzene (10 ml). The reaction mixture was stirred for an additional hour, then quenched by the addition of a solution of acetic acid (132 mg) in benzene (5 mL), the organic portion was washed with water until neutral, dried and the solvent was distilled off. The residue (1.2 g) is chromatographed on silica gel (10 g), eluting with a mixture of cyclohexane and ethyl acetate; 5t-13t-11a-hydroxy-15-oxo-9a-deoxy-9a, 9b, 7a-homo-trifluoromethylene-2-nor-prostacyclla-5,13-phenylenic acid 11-acetate (0.76 g) was obtained, λmax 228 nm , ε = 9800, M + 418, M ⁺ fCH ² CO ² H 358 m / e.

Using the above procedure but using the other aldehydes described in Example 45, the following N-unsaturated ketones were prepared:

213150

11 methyl ester of methyl ester. 5t, 13t-11a-hydroxy-15-oxc-9a-decxy-9a, 9b, 7a-hcmc-trimethylene-2-nor-pr'ostacyclla-5,13-diene, λ max 228 nm, ε = 9900 and a mixture of the corresponding 5 (z, E) -isomers,

M + 418, M + -CH 3 CO 2 H 358 m / e,

Methyl 11-acetate of the 5t, 13t-11a-hydroxy-15-oxo-9a-deoxy-9a, 7a-dimethyleneprostacyclla-5,13-dienoic acid, λ max 229 nm, ε = 10,000 and the corresponding 5c and 5 (ZjEJ-isomers, M + 418, M + -CH 3 CO 2 H 358 m / e and the following 2-exc- (3'-oxo-oct-Γ-tansanesyl) -3-endohydroxy-THP-ethers:

bicyclo [3.2.0] heptan-6-one-6,6-ethylenedloxide, [M + - 102J276, m / e, bicyclo] 3,2,0] heptan-7-one-7,7-ethylenedioxide, [ M + - 102J276, m / e, bicyclo] 4.3.0] nonan-7-one-7,7-ethylenedioxide, [M + - 102] 304 m / e, bicyclo [4.3.0] nonan-8- on-8,8-ethylenedioxide, [M + -102] 304 m / e and bicyclo [5.3.0] ecane-B-one AB-ethylenedioxide, [M + -102] 318 m / e.

Example 47

The following α, β-unsaturated ketones were prepared as described in Example 46 but using various dimethylphosphonates:

a] by the reaction of 3-end-HHP-oxy-formyl-bicyclo [3.2.0] heptan-7-one-7,7-ethylenedic oxide (2.10 ³ mol) with [2-oxo-3 [S, R 1 - fluoro-heptyl-dimethyl-phosphonate (0.54 g) gave 3-endo-THP-oxy-4-oxo-oxo-4 '(R, S) -fluoro-okk-1'-trans-enyl-bicyclo] 3, 2.0] heptan-7-one-7,7-ethylendioxid (0.72 g), and _m and _X 229 nm, ε = 9900, [a] _D = + 98 DEG (chloroform]

b] reaction of heptanal-6-cis-6,6-ethylenedioxide [2.10-3 mol] with (2-oxo-octyl) -dimethylphosphate yields 3-end-THP-cxy-2-exc (3'-oxo) -non-U-trans-enyl] -bicyclo [3.2.0] heptane-6-ene-6,6-ethylenedioxide, λ max 228 nm, ε = 9300, [M + -102] 290 m / e,

c] reaction of the appropriate heptanal-7-one-7,7-ethylenedioxide with (2-oxo-4-enylbutyl] -dimethylphosphonate (0.565 g) to give 3-endo-THP-oxy-2-exo- (3) 1'-cis-5'-phenyl-pent-Γ-trans-enyl] -bicyclo] 3,2,0] heptan-7-one-7,7-ethylenedioxide, [M + -102] 310 m / e a

d] reaction of the corresponding aldehyde nonan-7

-one-7,7-ethylenedioxide with 0.52 g of [2-oxo-3S-methylheptyl] -, optionally with N, N-oxo-3R-methylheptyl] dimethylphosphonate, gives 3-end-THP-cxy-2-exo- ( 3'-cis-4'S-methyl-oct-1'-tris-enyl] -bicyclo [4.1.0] nonan-7-one-7,7-ethylenedioxide, [M ⁺ -102] 318 m / e, optionally 3-endc -THP-Cxy-2-exc-3'-Cxc-4'R (methyl-ock-Γ-trans-enyl) -bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide , [M + -102] 318 m / e.

Example 48

To solution 3 (endc-THP-Cxy-2-exo- [3'-oxc-4 '(R, S) -fluoro-ock-Γ-trans-tnyl] -bicyclo [3.2.0] heptane -7 (On-7,7-ethylenedioxide in anhydrous pyridine (15 mol) was added with stirring 0.8 g of pyridine hydrobromide perbromide [C5H5N.HBr.Br2] and the mixture was stirred for another 4 hours at room temperature. The filtrate was partitioned between ice water, 2 N sulfuric acid and ethyl acetate, and the organic extract was washed with cold 0.5 N sulfuric acid, brine, 1x sodium carbonate solution and water until neutral.

0.71 g of the respective 2'-bromo-4 '(R, S) -fluoro compound is obtained, which is a mixture of two diastereoisomeric 4'S- and 4'R-derivatives.

Separation of the mixture by high pressure liquid chromatography on silica gel using methylene chloride / ethyl ether (85: 15) as the eluent gave the following individual isomers:

0.22 g of 3-endc-THP-cxy-2-exo- (2'-bromo-3'-cxc-4 ^, R - (:( uor-okk-Γ-krs-enyl) -bicyclo [3, 2,0] heptane-7-cn-7,7-ethylenedioxide, λ max 250 nm, ε = 9830 and

0.19 g of 4'S-fluoroisomer, λ max 251 nm, ε - = 9750, [M + -102] 372, 374 m / e.

By the same procedure, but using other α, β - unsaturated. The following compounds are prepared:

3-endc-THP-Cxy-2-exo- [2'-bromo-3 '- (Cxc-ηοη-Γ-trs-enyl) -bicyclo [3,2,0] heptan-6-on-6, 6-ethylenedioxide, [M + - 102] 368, 370 m / e

3-endc-THP-cis-2-exc- (2'-bromo-3'-cis-oct-r-trans-enyl) bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide , [M + -102] 382.384 m / e.

Example 1 4 9

Using the N-unsaturated ketones described in Examples 46, 47 and 48 as starting materials, the corresponding secondary allylic alcohols were obtained as follows:

A solution of N-unsaturated ketone (2.10 ^-3 mol) in anhydrous ethyl ether (20 mol) was added dropwise to the solution with stirring over 30 minutes.

0.25 M zinc borohydride in anhydrous ether (48 mL) was added and the mixture was stirred for an additional 2 hours. The excess hydride was quenched by the addition of saturated sodium chloride solution, the organic layer was separated, washed neutral, dried over anhydrous sodium sulfate and distilled off. The mixture of isomers obtained by high pressure liquid chromatography on silica gel using methylene chloride / ethyl acetate as eluent gives:

5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacyclyl 5,13-dienoic acid, M ^- 420m / e, and its 5-methyl acetate 11-acetate (Z, Ej- and 5t geometric isomers,

5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethyleneprostacycl-5,13-dienoic acid 11-acetate methyl ester, M ⁺ 420 m / e and its 5 (Z, E) and 5c geometric isomers , and the following 2-exo- (3'S-hydroxy-oct-1'-trans-enyl) -3-endo-THP-oxy-derivatives:

bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide,

M ⁺ 380 m / e, bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide,

M ⁺ 380 m / e, bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, M ⁺ 408 m / e, bicyclo [4.3.0] nonan-8-on-8.8 -ethylenedioxide,

M + 408 m / e, and the following 3-endo-THP-oxy derivatives:

2-exo- (2'-bromo-3'S-hydroxy-4'R-fluoro-oct-1'-trans-enyl) -bicyclo [3,2,0] heptan-7-one-7,7-ethylenedioxide,

M ⁺ 476.477 m / e

2-exo- (2'-bromo-3'S-hydroxy-4'S-] fluoro-oct-1: -trans-enyl) -bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, -ethylenedioxide,

M ⁺ 476.477 m / e

2-exo- (2'-bromo-3'S-hydroxy-non-1'-trans-enyl) -bicyclo [3,2,0] heptan-6-one-6,6-ethylenedioxide,

M + 472.474 m / e

2-Exo- (3'S-Hydroxy-non-l'-trans-enes 1} -bicyclo [3,2,0] heptan-6-on-6,6-ethylenedioxide

M ⁺ 394 m / e

2-exo- (3S-hydroxy-5'-phenyl-pent-1-triazenyl) -bicyclo [3,2.0] heptan-7-one-7,7-ethylenedioxide,

M ⁺ 414 m / e

2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-enyl) -bicyclo [4,3,0] -nonan-7-one-7,7-ethylenedioxide,

M ⁺ 486.448 m / e

2-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-enyl) -bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide,

M ⁺ 420 m / e,

2-exo- (3'S-hydroxy-4'R-methyl-oct-1'-trans-enyl) -bicyclo [4,3,0] nonan-7-one-7,7-ethylenedioxide,

M + 420 m / e,

5c, 13t-11a, 15R-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacyclla-5,13-dienoic acid 11-acetate, M ⁺ 420 m / e and its 5 ( Z, E) and 5t geometric isomers,

5t, 13t-11a, 15R-dihydroxy-9a-deoxy-9a, 7a-homo-dimethyleneprostacycla-5,13-dienoic acid 11-acetate methyl ester, M ⁺ 420 m / e and its 5 (Z, E] and 5c geometric isomers , and the following 2-exo- (3'R-hydroxy-oct-1'-trans-enyl] -3-endo-THP-oxyderivatives of compounds:

bicyclo [3.2.0] heptan-6-one-6,6-ethylenedioxide, M + 380 m / e, bicyclo] 3.2.0] heptan-7-one-7,7-ethylenedioxide, M ⁺ 380 m (e) bicyclo [4.3.0] nonan-7-one-7,7-ethylenedioxide, M ⁺ 408 m / e, bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide, M ⁺ 408 m / e, and the following 3-endo-TIP-oxyderivatives of the compounds:

2-exo (2'-bromo-3'R-hydroxy-4'-Rfluoro-oct-1'-trans-enyl) -bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide ,

M ⁺ 476.477 m / e

2-exo (2'-bromo-3'R-hydroxy-4'S-fluoro-oct-1'-trans-enyl) -bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxide, M ⁺ 476.477 m / e,

2-exo (2'-bromo-3'R-hydroxy-ποη-Γ-trans-imy]) bicyclo [3,2,0] hoptan-6-011-6,6-ethylenedioxide,

M + 472.474 m / e

1 5 1 5 O

2-exo- (3 &apos; R-hydroxy-4 &apos; R-methyl-ock-rtrans-enyl) -bicyclo [4,3.0] nonan-7-one-7,7-ethylenedioxide, M + 422 m / e.

Example 50

Each of the bicyclo-THP-oxy-thylenedioxides prepared. as described in Example 49, was converted to the corresponding prostacyclic acid by the following procedure:

To a solution of 1.10 ^-3 mol of bicyclo-THP-oxy-ethylenedioxide in acetone (15 ml) was added 1 N aqueous oxalic acid (10 ml) and the mixture was heated under reflux for 8 hours. The acetone was distilled off under reduced pressure, the aqueous solution was extracted with ethyl ether, and the combined ether extracts were worked up in the usual manner. After distilling off the solvent, about 0.6 to 1.10 ^-3 moles of the corresponding hydroxyketone are obtained.

The solution thereafter. ketone in anhydrous DMSO (2 mL) was added to a solution of the ylide prepared as follows:

Potassium tertiary butoxide (1.35 g) was added under anhydrous nitrogen to anhydrous DMSO (15 mL) and then 4-carboxybutyltriphenylphosphonium bromide (2.6 g) was added; a dark red colored ylide solution is obtained. After addition of the ketone, the reaction mixture was heated at 40-42 ° C for 6 hours, then cooled, diluted with water (20 mL), acidified to pH 5.1 and shaken with ethyl ether (5X 25 mL). The aqueous portion was left aside, the organic extracts were combined, washed with water (5 mL; wash was discarded) and then extracted with 0.5 N sodium hydroxide solution (6X 6 mL) and then with water until neutral. The aqueous alkaline portions were combined, the solution was acidified to pH 5 and the product was taken up in ethyl ether.

The combined organic extracts were washed with water (2 ml), dried over anhydrous sodium sulfate and the solvent was distilled off; a mixture of 5Z and 5e acids is obtained. The individual geometric isomers are obtained by separating the mixture by acidic silica gel chromatography (free of Fe 2+ and · Fe 3+ ions), using a mixture of methylene chloride and ethyl acetate · as eluent (30 g of silica gel for every 0.2 g of acid):

The following acids are prepared as follows:

5t, 13t-11a, 15S-dlhydroxy-9α-deoxy-9α-nor-methyleneprostacycla-5,13-dienoic acid, M + 552, M + - CH 3 537, M + - C 5 H 11 481 m / e as tris-trimethylsilyl ether, 5t 13t-11a, 15S-dihydroxy-9α-deoxy-9α-loo-methylene-20-m ethylprostacyclla-5,13-diene, M + 566, M + -CH 3 551, M + -481 m / e as trimethylsilyl ether , 5α, 11α, 15S-dihydroxy-9α-deoxy-9α-nor-methylene-20-methyl-prostacycl-5-en-13-ynoic acid, M + · 564, M + - CH ₃ 549, M + - C 6 -13 13 479 m / e as trimethylsilyl ether, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-7a-nor-methyleneprostacycl-5,13-dienoic acid, 5t, 13t-11rz, 15S- dihydroxy-9α-deoxy-9α, 7α-homo-dimethyleneprostacycla-5,13-dienoic acid, M + 364, M + -H 2 O 346, M + -H 2 O 328, M + -H 2 O-C 5 H 11 275 m / e, 5t, 13t: -1 : 1,1'-E, 5'-dihydino-o-xy-9a-deoxy-9a, 9b-dimethyleneprostacycla-5,13-dienoic acid, M + - H2O 346, M + - 2H2O 348 m / e, 5t-11a, 15S -dihydroxy-9α-deoxy-9α-methylene-7α-nor-methylene-16'S-fluoropropylpropyl-5-ene-13-ynoic acid, M + 352 m / e, 5t-11 '·, 15S-dihydroxy-9-L-deoxy-D-methylene-4-a-nor-methylene-to-4-fluoropropyl-5-ene-13-ynoic acid, M + 352 m / e, 5t, 13t-11α, 15Scdihydroxy-9-deoxy-9a -methylene-7α-nor-methylene-17-phenyl-18,19,20-rinor-prostacycl-5,13-dienoic acid, M + 370 m / e, 5t, 13t-11a, 15S-dihydroxy-9a-deoxy -9a, 7a-homo-dimethylene-16S-methylprostlcycla-5,13-dienoic acid, M + 378, M + -H ₂ O 360 m / e, 5t, 13t-11α, 15S-dihydroxy-9l-deoxy-9a, 7a -homo-dimethylene-16R-methylprostacyclla-5,13-denoic acid, M + 378, M + -H2O 360 m / e, 5t-11α, 15S-dihydroxy-9α-deoxy-9α, 7α-homo-dimethyleneprostacycl-5 -en-13-dienoic acid, M + 362 m / e, 5c, 13t-11α, 15S-dihydroxy-9l-deoxy-9α-nor-methyleneprostacyclla-5,13-dienoic acid, M + 336, M + -C 5 H 11 -H 2 O 247 m / e , 5c, 13t-11α, 15S-dihydroxyl-9α-nor-methylene-20α-nor-methylene-1,2-methylprostlcycla-5,13-dienoic acid, M + 350 m / e, 5c-11α, 15S-dihydroxy-9α-nor-methylenl20lmethylprostlc -5len-13-ynoic, M + 348 m / e, 5c, 13t-11α, 15S-dihydroxy-9β-deoxy-9 α-meiylen-7 α-nor-m 5,13-dienoic acid, M + -H 2 O 318 m / e, 5c, 13t-11α, 15S-dihydroxyl-9α-deoxy-9α, 7 α-hom o-prostacycl-5,13 -dienoic, m + -H2O 364 m / e acid 5c · 13 t-lCα, 15S-dihydroxy-9 l-deoxy-9, 9b-dimethyl thylenprostac ykaa-5,13-diene, m ⁺ -H ₂ .O 346 m / e, acid. 5c-11α, 15S-dihydroxy-9,1-deoxyl9almethylene-7-nor-methylene-16S-fluoro-prostyl-5-ene-14-ynoic acid, M + 352 m / e, acid. 5c-11z, 15S-dihydroxy-9α-deoxy-9α-methylene-7α-nor-methylene-16R-fluoroprost-1-yl-5-er-13-yne, M + -H 2 O 334 m / e, acid. 5c, 13t-11c, 15S-dihydroxy-9α-deoxy-9α-methylene-7α-nor-methylene-17-phenyl-18,19,20-rinor-prostacycl-5,13-diene, M + -H 2 O 352 m / e, 5c, 13t-11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16S-methylprostacyclla-5,13-dienoic acid, M + 378 m / e, 5c, 13t -11a, 15S-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-16R-methylprostacyclla-5,13-dienoic acid, M + 378 m / e, 5c-11a, 15S-dihydroxy-9a-deoxy-9a, 7α-homo-dimethylene-prostacycl-5-ene-13-ynoic acid, M + 362 m / e, and 15R-isomers of said acids.

Example 51

To a solution of bicyclo [2.2.1] nonanR-enR-one (11.42 g) in ethanol (80 mL) was added portionwise sodium borohydride (2.5 g) with stirring. The mixture was stirred for an additional 2 hours then. acidified with acetic acid (5 mL) and the solvents were distilled off. The residue is partitioned between water and methylene chloride, the organic layer is separated and the solvent is evaporated to dryness. To a solution of the obtained bicyclo [4.3.0] non-7-en-3-ol (11 grams) in anhydrous DMF was added dimethyl tert-butylsilyl chloride (15.6 g) and imidazole - (10.85 g) successively. and the mixture was heated at 60 ° C for 6 hours. The solution was cooled, diluted with water (66 mL), the product was extracted thoroughly with ethyl ether, and the ether extract was worked up in the usual manner.

The obtained - bicyclo [4.3.0] non-7-en-3-ol-3-DMt-8-ethyl ether (19.1 g) was dissolved in anhydrous THF (100 ml) and the solution was cooled and stirred under stirring. 1 N solution of borane in THF (75 mL) was added at 0 ° C. The reaction mixture was stirred at 25 ° C for 2 hours and then 1 N sodium hydroxide solution (25 mL) and 30% hydrogen peroxide (25 mL) were added. The mixture was heated at 60 ° C for 2 hours, then cooled, diluted with benzene (400 mL), the organic portion separated, washed with 1% sodium carbonate solution, saturated sodium sulfite solution, saturated sodium chloride solution, dried and the solvent was distilled off. . The obtained crude bicyclo [4.3.0 Jnonan-7 (8) ξ s3-dihydroxys3sDMtB-Siyl ether (20.3 - g) was dissolved in a mixture of benzene and DMSO 75:25 (150 mL), and the solution was gradually added with stirring. Cyclohexylcarbodiimide (16 g), pyridine (2 ml) and trifluoroacetic acid (1 ml) After 5 hours, the reaction mixture was diluted with benzene (400 ml), water (50 ml) and a solution of oxalic acid (6 grams) in water were added. (75 ml) - and after another 30 minutes - stirring, the urea precipitate is filtered off,

The organic layer was separated from the filtrate, washed with water until neutral and the solvent was distilled off. The obtained bicyclo [4.3.0] nonan-7 (8) son-3-ol DMtB-silyl ether (18.25 g) was dissolved in methanol (60 ml), and 1.8 g of p-toluenesulfonic acid was added to the solution. and allowed to stand for 12 hours. Pyridine (1.95 g) was then added, the solvent was evaporated to dryness and the residue was chromatographed on silica gel using ethyl ether / ethyl acetate as eluent; There was thus obtained bicyclo [4.3.0] nonan-7 (8) -one-3-ol (10 g).

To a solution of the latter compound in benzene (50 mL) was added anhydrous ethylene glycol (5.2 g) and p-toluenesulfonic acid (0.62 g), and the mixture was heated to boiling while distilling the water formed. After 14 hours, pyridine (2 mL) was added, the solution was cooled, washed with water, 2% sodium carbonate solution and saturated sodium chloride solution until neutral. After distilling off the solvents, bicyclo [4.3.0] nonan-7 (8) -one-3-hydroxy-7,7 (8,8) -ethylenedioxide was obtained, oil iC (film) 3400 cm -1, M + 198 m /E.

Example 5 2

Saponification of d, l-3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide-2-exo-carboxylic acid methyl ester (4.5 g) with a 2% solution potassium carbonate in 80% aqueous methanol gave the corresponding free acid (4.2 g). To a solution of said free acid (4.2 g) in acetonitrile (120 mL) was added d- (+) -ephedrine (2.3 g) and the mixture was allowed to stand at room temperature for 4 hours. The precipitated salt (2.8 g) was recrystallized again from acetonitrile; 2.15 g of (+) - bicyclo [4.3.0] nonane-8-or-8,8-ethylenedioxide-3-endOs-hydroxy-2-exo-carboxylic acid d- (+) -ephedrinium salt are obtained .

All mother liquors were combined, the solvent was distilled off, the residue was dissolved in water and the solution basified with 1 N sodium hydroxide to pH 12-13; The d- (4-) - ephedrine is taken up in ether, the alkaline aqueous phase is acidified to pH 5 and shaken into ethyl acetate. The solvent is distilled off from the combined organic extracts, the residue is dissolved in acetonitrile and the above cleavage procedure is repeated using (-) - ephedrine; (-) - (-) - bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid, 1- (-) -, - (-) dissolved in water, basified with sodium hydroxide, the optically active base was regenerated by shaking into ether, the aqueous alkaline portion was acidified to pH 5 to 5.1, and the optically active acid was extracted into ethyl acetate to give (+) -sulfonic acid (4). , 3, 3-endo-hydroxy-2-exo-carboxylic acid and - (-) - bicyclo [4.3.0] noran-8-or- 8,8-ethylenedloxide -3-eido-hydroxy-2-cis-carboxylic acid.

Said optically active acids disputes ^{1 215150} with diazomethane leads to the corresponding methyl esters.

Example 53

A solution of 26 gd, 1-endo-hydroxy-bicyclo [4.3.0] nonane-2-exo-methoxycarbonyl-7-one-7,7-ethylenedioxide in acetone (100 mL) was heated at reflux with 2N sulfuric acid (20 mL) for 4 hours. The acetone was distilled off under reduced pressure and the aqueous portion was extracted with ethyl acetate. The combined organic extracts were washed until neutral, dried and the solvent was distilled off; 21.2 g of d, 1-3-endo-hydroxy-bicyclo [4.3.0] nonan-2-exo-methoxycarbonyl-7-one is obtained.

To a solution of the obtained ketone in anhydrous acetonitrile (250 mL) was added d-1-phenyl-1-ethylamine (12.1 g), and then 50 mL of solvent was distilled slowly over 30 minutes. The mixture was slowly cooled to room temperature and the precipitated Schiff base was filtered off; 12.12 g of (+) -3-endo-hydroxy-7,7- (Γ-phenyl-1'-ethylidenimino) -2-exo-methoxycarbonyl-bicyclo-4,3,0-Jonan are obtained.

The mother liquors were further concentrated to give 6 g of racemic material. Further concentration of the mother liquors up to a volume of 80 ml gave 11.42 g of (-) -endo-hydroxy-7,7- (1'-phenyl-ethyl-ethylidenimino) -2-exo-methoxycarbonyl-bicyclo [4.3.0] nonanu.

The obtained Schiff bases are each resolved separately into an optically active ketone by dissolving in methanolic 2 N sulfuric acid (200 mL) and refluxing the solution for 2 hours. The solvent is distilled off under reduced pressure, the product is taken up in ethyl acetate, the combined organic extracts are washed neutral. The reaction was dried and the solvent was distilled off under reduced pressure to obtain 8.1 g of (+) -3-endo-hydroxy-bicyclo [4.3.0] nonane-2-exo-methoxycarbonyl-7-one and 7 g. 2 g of (-) -3-endo-hydroxy-bicyclo [4.3.0] nonane-4-exo-methoxycarbonyl-y-one.

In this way, all of the bicyclo [beta] -hydroxycarboxylic acid ester ethylenedioxides described in Example 43 are subjected to optical resolution to give the following end-hydroxy-cyclolols:

(+) -bicyclo [3.2.0] heptan-6-one-2-exo-carboromethyl ester, (+] -bicyclo [3.2.0] heptan-7-one-2-exo-carboxymethyl ester, ( +] -bicyclo [4.3.0] nonan-7-one-2-exo-carboxymethyl ester, (+] -bicyclo [4.3.0] nonan-8-on-2-exo-carboxymethyl ester, (+ ) -bicyclo [5.3.0] decane-B-one -exo-carboromethyl ester, (- [-bicyclo [3.2.0] heptane-α-β-2-exo-carboxymethyl ester, (-) - bicyclo) [3,2,0] Heptan-7-one-2-exo-carboxymethyl ester, (-) -bicyclo [4,3,0] nonan-7-on-2-exo-carboromethyl ester, (-) -bicyclo [4] , 3,0] nonan-8-one-2-exo-carboxymethyl-4-ethyl ester and (-) - bicyclo [5.3.0] decan-8-one-2-exo-carboromethyl ester.

In the manner described in Example 42, the above ketones were converted to the corresponding ethylenedioxides.

Example 54

To a solution of freshly sublimed potassium tertiary butylate (3 g) in anhydrous DMSO (30 mL) was added 4-carborebutyl-triphenylphosphonium bromide (5.4 g) and 2-exo- (3'S-hydroxy) solution successively at room temperature under nitrogen. non-r-ynyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one (600 mg) in DMSO (5 mL).

The reaction mixture was kept for 15 hours at room temperature under a nitrogen atmosphere and then poured into a 30% aqueous solution of sodium dihydrogen phosphate. The aqueous mixture was extracted with ethyl ether and the combined ether extracts were extracted with aqueous 1N sodium hydroxide. The aqueous alkaline extract was then acidified to pH 5 and extracted again with ethyl ether. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The residual oil was chromatographed on silica gel with ethyl ether (95.5) -acetic acid (0.5) as the eluent to obtain 90 mg of ^5c-r lla, 15S-dihydroxy-9a-deoxo-9a-methylene-20 -methylprostacycl-5-ene-13-yne [NMR (CDCl3)? ppm: 0.90 [3H, t]; 4.00 (1 H, m);

4.40 (1 H, t); 5.27 (1H, t)] and 130 mg of St-11a, 11S-dihydroxy-4-deoxy-4-methylene-20-methylprostacycl-5-en-13-enoic acid [NMR (CDCl 3) · 8 ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.30 (1 H, t)].

In an analogous manner, but starting from 2-exo- (3'R-hydroxy-non-r-ynyl) -3-endo-O-yloxy-bicyclo [3.3.0] octan-7-one, 5Cl III < 5.15R-dihydroxy-9α-deoxy-9α-methylene-20-methyl-prostacycl-5-ene-13-ynoic acid [NMR (CDCl 3) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.28 (1H, ie) and 5t-11 &lt; 5.15R-dihydrodrory-9a-deoxy-9a-methylene-20-methylprostacycl-5-en-13-ynoic acid [NMR (CDCl3) δ ppm: 0.90 (3H, t): 4.00 (1H, m); 4.39 (1H, t): 5.30 (1H, t)], while using 2-exo- (3'S-hydroxy-oct- (R-ynyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one or, optionally, its 3'R-hydroxyisomer, 5C11a, 15S-dihydrory-9a-deoxy-9a starting material -methyleneprostacycl-5-ene-1,3-yne [NMR (CDCl 3) δ ppm: 0.90 (3H, t); 4.00 (1H, m); 4.39 (1H, broad t); 5.29 (1H, 215150 years) and 5t-11a, 15S-dihydroxy-9a-dtoxy-9a-methylenpiostacycl-5-en-13-ynoic acid [NMR (CDCl3) δ ppm: 0.90 (3H, i) 4.00 (1H, m); 4.40 (1H, broad i); 5.28 (1H, broad t)] or, optionally, 5 [alpha] (1,15R-dihydroxy-9a-deoxy-9a-propylstylcyclohexyl) -acetic acid; 5ten-13tm [NMR (CDCl 3) δ ppm: 0.90 (3H, t); 4.00 (1H, m); 4.40 '(1H, broad t); 5.28 (1H, broad t]] and 5-thiyl-15R-dihydroxyt9atdeoxy-9atmethylenepiylcyclic-5-ene-13tinic acid [NMR (CDCl3) Δ ppm: 0.90 (3H, t) 4.00 (1H, m) 4.39 (1H, broad t); 5.29 (1H, broad t)].

Example 55

Dicyclohexylcarbodiimide (12.7 g), pyridine (1.65 mL), and trifluoroacetic acid (0.83 mL) were added sequentially to solution 3 with stirring and external cooling to maintain the reaction temperature at 20-22 ° C. 2-Exo-hydroxymethyl-5-hydroxy-bicyclo [3.3.0] octane-7-ethoxy-7,7-ethylenediamine -THP-ether in benzene / DMSO 75/25 (80 mL). (50 ml), filtered, washed with water until neutral and dried over sodium sulfate.

The solvents were evaporated to a small volume (30 mL) and this solution was added with stirring to a solution of sodium phosphonate prepared by adding a solution of 2-oxo-octyl-dimethylphosphonate (10.8 g) in benzene (30 mL) to a suspension of 80% hydride. After 15 minutes, the reaction is complete and the reaction mixture is heated with acetic acid (6 ml), washed with water until neutral, dried over sodium sulfate, and the solvent is evaporated to dryness in vacuo. The residue was chromatographed on silica gel, eluting with n-hexane with ethyl acetate (80:20) to give 2-exo- (3'-oxo-non-r-) as a yellow oil of 3THP-ethyl 7,7-ethylenedioxide. trans-r-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-4-one (12.7 g), 16 (pure) in cm -1: 2970, 1690, 1670, 1625, NMR (CDCl 3) δ = 0.88 (3H, t); 3.2 ± 4.2 (7H, m); 4.60-4.75 (1H, m); 6.18-6. 20 (1H, d) 6.79 + 6.89 (1H, dd).

To a solution of this compound in dry pyridine (100 mL) was added pyridine bromide dihydrobromide (24 g) with stirring. After 1.30 h, the mixture was diluted with 30% aqueous sodium dihydrogen phosphate solution (500 mL) and extracted with ethyl acetate, the organic extracts were combined and washed to neutral, dried over sodium sulfate and evaporated to dryness in vacuo. hexane with ethyl ether, 80:20] to give 3-THP-Ethyl 7,7-ethylenedioxide 2-exo- (2'-bromo-3'-exo-non-Γ-trans-Γ-tnyl) -3-endg-hydroxytbicyclo [3,3,0] octanone (13, g), 16 (neat) in cm -1: 2940, 1685, 1610.

A solution of the obtained bromkelone (12.6 g). in methanol (32 ml) was added dropwise to a solution of b (10-sodium hydroxide (4.2 g) in methanol (65 ml) cooled to -20 ° C. The reduction was complete in 1 hour. The reaction mixture was then diluted with an excess of 30% aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate, the organic extracts were combined, washed with brine, dried over sodium sulfate and the solvent was evaporated to dryness in vacuo. (100 ml) and then treated with 1 N aqueous oxalic acid (50 ml) for 12 hours at 40 degrees Celsius.

After removal of acetone at 50 ° C under vacuum, the aqueous suspension was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate and, after evaporation, the solvents were subjected to silica gel chromatography. Using n-hexane with ethyl acetate (50:50), the following alkaloids were obtained:

2-exo- (2'-bromo-3'R'hydroxy-non-Γ-trans-Γ-enyl) -3-endothydioxytbicyclo [3.3.0] octan-7-one (3 g); and

2-Exo- (2'-biom-3'S-Hydroxy-non-1'-trans-1'-hexyl) -3-endo-hydroxybicyclo [3.3.0] octan-4-one (4.2 g) ).

Under an inert gas (N ₂ ) atmosphere, to a solution of potassium tertiary butylate (18 g) in anhydrous DMSO (180 mL) was added 4-carboxybutyl-triphenylphosphonium bromide (32.4 g) to give a red ylide solution. After 5 minutes a solution of the above obtained 3'S alcohol (4.2 g) was added. The reaction mixture is kept under an inert gas atmosphere for 15 hours with stirring at room temperature. The reaction mixture was diluted with an excess of a 30% aqueous solution of sodium dihydrogen phosphate (= 350 mL) and extracted with ethyl acetate (5 x 50 mL). The ether extracts were combined, washed with brine (15 mL) and then extracted with 1 N sodium hydroxide solution (5 x 15 mL) and water until the washings were neutral.

The basic extracts were combined and acidified to pH 5 and then extracted with ethyl ether (3 x 30, 1 x 15, 1 x 10). These organic extracts were combined, washed with brine, dried over sodium sulfate and the solvent was evaporated to dryness in vacuo. The residue was chromatographed on silica gel using acetic acid ether (100: 0.5) as eluent to give 5Z-11α, 15S-dihydroxy-9-methylethyloxy-9α-methyl-len-20-methyl-prostacycl-5- on-13-yne (1.21 g), NMR (CDCl ₃ ) δ ppm: 0.90 (3H, i); 4.00 (1 H, m); 4.40 (1 H, t); 5.27 (1 H, i); and 5E-11α, 15S-dihydroxy-9α-de-) xy-9α-methylene-20-methylpiosyl-cycl-5-ene-13-ynoic acid (1.84 g), 1C (pure), v (cm ^-1 ): 3350 2115, 1705, NMR (.CF 3 CO 2 D) δ = 0.9 (3H, t); 4.00 (1 H, m); 4.40 (1 H, t); 5.30 (1 H, t);

6.38 (3 H, m). . . .

In an analogous manner, but using 3‘R alcohol as the starting material obtained after

Wittig reaction with 4-carboxybutylethyl-triphenylphosphonium bromide and chromatographic chromatography on SiO ₂ using ethyl ether with acetic acid (99.5: 0.5) gave the following compounds in the order:

5Z-11a, 15R-Dihydroxy-9α-deoxy-9α-methylene-20-methylprostacycl-5-en-13-ynoic acid (0.4 g), NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t ); 4.00 (1 H, m); 4.40 (1 H, t); 5.28 (1 H, t); and 5E-11a, 15R-dihydroxy-9α-deoxy-9α-methylene-20-methylprostacycl-5-en-13-ynoic acid (0.8 g), NMR (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.00 (1 H, m); 4.39 (1 H, t); 5.30 (1 H, t).

Example 56

Using the procedure described in Example 55 but substituting 2-oxo-nonyl dimethylphosphonate in place of 2-oxo-octyl dimethylphosphonate, the following compounds were obtained:

5Z-lla, 15S-dihydroxy-9a-deoxo-9a-methylene-20-ethylprostacykl-5-en-13-ynoic acid, m / e 358 (M + -H ₂ 0), 340 (M ⁺ -2H ₂ O ); NMR (CDCl ₃ ): 0.88 (3H, t); 2.37 (2 H, t); 3.98 (1 H, m); 4.40 (1 H, t); 5.30 (1H, broad t); 5.98 (3H, broad);

5E-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-ethylprostacycl-5-ene-13-ynoic acid, m / e 358 (M + - H ₂ O), 340 (M ⁺ - ₂ H ₂ ) O), NMR (CDCl ₃ ): 0.88 (3H, t); 2.36 (2 H, t); 3.98 (1 H, m); 4.39 (1 H, t); 5.30 (1H, broad t); 5.62 (3H, broad) and their 15R epimers:

5Z-lla, 15R-dihydroxy-9-deoxy-9-methylene-20-ethylprostacykl-5-en-13-ynoic acid, m / e 358 (M ⁺ -H2O), 340 (M ⁺ - H2O -2) and 5E-11a, 15R-Dihydroxy-9α-deoxy-9α-methylene-20-ethylprostacycl-5-ene-13-ynoic acid, m / e 358 (M + - H, O), 340 (M ⁺ - 2 H ₂₎ O).

Example 57

Following the procedure of Example 55 using 2-oxo-decyl-dimethylphosphonate, 2-oxo-isodecyl-dimethylphosphonate, 2-oxo-undecyl-dimethylphosphonate and 2-oxo-isoundecyl-dimethylphosphonate, the following compounds were obtained:

5E-11α, 15S-dihydroxy-9α-deoxy-9α-methylene-20-n-propylprostacycl-5-en-13-ynoic acid, MS (mass spectrum): m / e 372 (M ⁺ H ₂ O) NMR spectrum (CDC1 ₃₎ δ ppm: 0.88 (3H, t), 4.37 (1H, t), 5.26 (1H, t), 7.21 (3H, br), acid 5Z- 1.la, 15S-dihydroxy-9α-deoxy-9α-methylene-20-n-propylprostacycl-5-en-13-yne, MS: m / e 372 (M ^{+ -} H ₂ O), NMR (CDCl 3) δ ppm: 0.88 (311, t), 4.36 (1H t),

5.23 (1H, t), 7.34 (3H, broad), 5E-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-isopropylprostacycl-5-ene-13-tartaric acid, MS: m / e 372 (M + - H ₂ O), NMR (CDCl ₃ ) <5 ppm: 0.86 (6H, d), 4.38 (1H, t),

5.24 (1H, t), 7.52 (3H, broad), 5Z-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-isopropylprostacycl-5-en-13-ynoic acid, MS: m / e 372 (M + - H ₂ O), NMR (CDCl 3) δ ppm: 0.85 (6H, d), 4.36 (1H, t),

5.25 (1H, t), 6.24 (3H, broad), 5E-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-n-butylprostacycl-5-ene-13-ynoic acid, MS: m / e 386 (M ^{+ -} H ₂ O), NMR (CDCl 3) δ ppm: 0.89 (3H, t), 4.39 (1H, t), 5.28 (1H, t), 7.88 ( 3H, broad), 5Z-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-20-n-butylprostacycl-5-ene-13-enoic acid, HS m / e 386 (M + -H ₂ O), NMR ( CDC1 ₃₎ δ ppm: 0.89 (3H, t), 4.39 (1H, t), 5.25 (1H, t), 6.70 (3H, br) acid, 5E-lla, 15S-dihydroxy -9α-deoxy-9α-methylene-20-isobutylprostacycl-5-en-13-yne, MS: m / e 386 (M + H ₂ O), NMR (CDCl 3) δ ppm: 0.86 (6H, d) 4.34 (1 H, t),

5.26 (1H, t), 7.32 (3H, broad), 5Z-11a, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isobutylprostacycl-5-ene-13-ynoic acid, MS: m / e 386 (M ^{+ -} H ₂ O) NMR (CDCl 3) δ ppm: 0.86 (6H, d), 4.32 (1H, t),

5.27 (1H, t), 6.54 (3H, broad), 5E-11a, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-propylprostacycl-5-ene-13-ynoic acid, MS: m / e 372 (M + - H ₂ O), NMR (CDCl 3) δ ppm: 0.88 (3H, t), 4.38 (1H, t),

5.26 (1H, t), 6.26 (3H, broad), 5Z-11a, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-propylprostacycl-5-ene-13-ynoic acid, MS: m / e 372 (M + - H ₂ O), NMR (CDCl 3) δ ppm: 0.88 (3H, t), 4.38 (1H, t),

5.24 (1H, t), 6.02 (3H, broad), 5E-11a, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isopropylprostacycl-5-en-13-ynoic acid, MS: m / e 372 (M ^{+ -} H ₂ O), NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d), 4.37 (1H, t),

5.27 (1H, t), 6.58 (3H, broad), 5Z-11a, 15R-dihydroxy-9α-deoxy-9α-methylene-20-isopropylprostacycl-5-en-13-ynoic acid, MS: m / e 372 (M ^{+ -} H ₉₀ ), NMR (CDCl 3) δ ppm: 0.86 (6H, d), 4.36 (1H, t),

5.27 (1H, t), 6.36 (3H, broad), 5E-11a, 15R-dihydroxy-9a-deoxy-9a-methylene-20-n-butylprostacycl-5-en-13-ynoic acid, HS m / e 386 (m ⁺ -H ₂ 0) NMR (CDCl3) δ ppm: 0.89 (3H, t), 4.39 (1H, t),

5.26 (1H, t), 6.40 (3H, broad), 5Z-11a, 15R-dihydroxy-9α-deoxy-9α-methylene-20-n-butylprostacycl-5-en-13-ynoic acid, HS NMR (CDCl 3) δ ppm: 0.89 (3H, t], 4.39 (1H, t), m / e 386 (M + -H 2 O),

5.25 (1H, t), 6.43 (3H, broad), 5E-11a, 15R-dihydroxy-9a-deoxy-4-a-methylene-4-isobutylprostacycl-4-ene-13-enoic acid, MS: m / e 386 (M + - H 2 O), NMR (CDCl ₃ ) δ ppm: 0.86 (6H, d), 4.38 (1H, t),

5.25 (1H, t), 6.58 (3H, broad) and 5Z-11a, 15R-dihydroxy-9a-deoxy-9a-methylene-20-isobutylprostacycl-5-en-13-ynoic acid, MS: m / e 386 [M ^{+ -} H ₂ O], NMR (CDCl 3) δ ppm: 0.87 (6H, d), 4.37 (1H, t),

5.25 (1H, t), 6.04 (3H, broad).

Example 58

By the method of Example 55, using 2-oxo-2R-methylheptylldimethylphosphonate and N, N -exo-hydroxymethyl-4-endo-hydroxy-bicyclo, [3,3,0] octan-7-one-7,7-ethylenedioxide-3- Starting from bromination of the intermediate α-unsaturated ketone with pyridinium hydrotribromide, reduction with sodium borohydride, deprotection and chromatographic separation of the mixture gives d, i-2-exo- (2'-bromo-4'-S-hydroxy-5-hydroxy-10-cyclo-1-trans-1-enyl) -3-endo-hydroxy-bicyclo [3.3.0] octan-7-one, NMR (CDCl 3) δ ppm: 0.76 (3H, d), 1.00 (3H, d), 3.73 (1H, d), 5.83 (1H, 'd), 5.85 (1H, d), and its 3'R-epimer .

These intermediates were also converted according to the procedure of Example 55 to d, l-5 (Z, E) -11a, 15S-dihydroxy-9α-deoxy-9α-methylene-16R-methylprostacycl-5-en-13-ynoic acid and d, i-5 (Z, E) -1a, 15R-dlhydroxy-9a-deoxy-9a-methylene-16R-methylprostacycl-5-en-13-yn, NMR (CDCl3) δ ppm: 0.97 (3H, d), 4.27 (1H, broad d), 5.25 (1H, broad t).

Example 59 d, 1-16 (R, S) -Fluoro-20-methylcarboprostacycline [d, i-5E, 13E-11a, 15S-dihydroxy-9α-deoxy-9α-methylene-16 (R, S) -f Fluoro-20-methylprostacycl-5,13-dieno] d, 1-3a-Hydroxy-2,3,3- [3'-S-hydroxy-4'- (R, S) -fluoro-1'-trans- nonenyl] -7-oxo-bicyclo [3.3.0] octane (320 mg) was reacted as in Example 24 to give 103 mg of the title compound as well as its 5Z-isomer, d, 1-5Z, 13E-11a ', 15S-dihydroxy-9a-deoxy-9a-methylene-16 (R, S) -fluoro-20-methylprostacycl-5,13-diene; of both acids. The title compound having at tlc, the system diethylether with 2% acetic acid, R _F 0.25.

NMR (CDCl 3) δ ppm: 0.89 (3H, t), 3.77 (1H, m), 4.0-4.3 (1.5H, m), 4.67 (0.5H) , m), 5.27 (1H, ie; H at C ₁₆ : J _{H- r} = -50 Hz).

Example 60

Using the methods described in Examples 23 and 24, using the appropriate bicyclo [3.3.0] octane-T-one-N-bis-THP-eheres prepared according to Examples 16, 17, 18 and 19, the following methyl esters were obtained:

5Z-11a, 15S-dihydroxycycl-5-ene-13-ynoic acid methyl ester, M + -H2O 362, 5Z-11a, 15S-dihydroxy-9a-deoxy-9a-methylene-16S-fluoro-propacycl-5-en-13 methyl ester -inine, M + - H2O 362, 5E-11a, 15S-dihydroxy-9a-d6Oxy-9a-methylene-16R-fluorprostacycl-5-en-13-ynoic acid methyl ester, M + - H2O 362, 5E-11a methyl ester 15S-dihydroxy-9a-deoxy-9a-methylene-16S-fluorophosphostacycl-5-en-13-ynoic, M + -H2O 362, 5Z-11a methyl ester, 15R-dihydroxy-9a-d6Oxy-9a-methylene-16R- fluooprostacykl-5-en-13-ynoic, m + -H2O 362 methyl 5Z-lla, 15R-dihydroxy-9-deoxo-9a-m € ^ 6 ^ 1 ^ ¹ ^] ^ <6п-1 <6 S- 11u-prostacycl-5-ene-13-ynoic acid, M + -H2O 362, 5E-11a methyl ester, 15R-dihydroxy-9a-deoxy-9a-methylene-16R-, luooprostacycl-5-en-13-ynoic acid, M + —H2O 362 and 5E-11a, 15R-dihydroxy-9'-deoxoic acid methyl ester (6 '- (5' - 5 '- 5' - 5 ') - irostacycl-5-ene-13-ynoic acid, M + - H2O 362.

All methyl esters are then saponified to give the free acids.

Claims (1)

A process for the preparation of the 9-dtoxy-9α-methyltnisosteres of prostacyclin PGI 2 of formula I, wherein: R is a substituent selected from the group consisting of a) a free carboxyl group or an esterified carboxyl group of formula -COCO 9 wherein R 8 is C 1-6 alkyl or C 2-12 alkenyl, b is a group of formula -C (OR ') 3, wherein each individual substituent R 'is independently C 1 -C 6 alkyl or phenyl; c) a group of the formula "CH 2 -R" in which R "is a hydroxyl group or a C 2 -C 7 alkoxy group, d) a group of the formula Ra / —CON \ R b wherein R a, R b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl and phenyl, e) cyano, f) radical of formula // -C N-N II ⁴ NH-N g) a group of formula —CHO, h) a radical of formula X‘ — Ra‘ / —CH,. X '- R b' wherein each individual X 'is independently O or S and the groups Ra', Rb ', which are the same or different, represent an alkyl group having 1 to 6 carbon atoms or together form a running or branched chain C 2 -C 6 alkylene chain, D is a substituent from the group consisting of the radicals of the formulas --CH2 -; CH — OH, / Η H \ / C = C / \ [cis], H \ / C = C / \ H (trans), —C = C—, \ c = c, / —O—, —S—, and \ NR _c , / wherein R c is hydrogen, C 1 -C 6 alkyl or C 2 -C 6 alkanoyl, one of R 1 and R 2 and independently of one of R 3 and R 4 is hydrogen, C 1 -C 6 alkyl carbon atoms, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or phenyl (or naphthyl) (C 1 -C ₆ ) alkyl, and the other is hydrogen, hydroxyl, C 1 -C ₁₀ alkoxy up to 6 carbon atoms or phenyl (or naphthyl) - [C ₁ -C ₆ ] alkoxy, or R 1 and R 2, and independently of them R 3 and R 4, together form an oxo group, R 5 and R 6, which are the same or different, each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom, or R 5 and R ₆ together with the carbon atom to which they are attached form a radical of the formula C ^ CH2 / or Y represents -CH ₂ -CH ₂ -, -C≡C-, From \ / c = c / \ H (trans) HZ \ / C = C / \ (cis) wherein Z represents a hydrogen or halogen atom, and further -NH-CO- and -NH-CH ₂ -, X represents a group of formula - (СНг) тз- wherein _m;! is zero or 1, H H / c = c /. \ (cis), II \ / c = c / \ H (trans), -O-, -S- and N-R _c , where R _c is as defined above, m _t , m ₂ , n and n and ₂ which are the same or different denote zero or an integer from 1 to 12 wherein the sum of g + m ₂ or n _t + n ₂ is less than or equal to 15, p and q are each zero or an integer from 1 to 3, wherein the sum of p + q is an integer from 1 to 6, and R ₇ is a substituent selected from the group consisting of a ') a hydrogen atom, b') a C 1 -C 4 alkyl group, c ') a monocyclic C 1-8 cycloalkyl or a cycloalkenyl, norbornyl or adamantyl group optionally substituted with at least one C 1 -C 4 alkyl group (D ') phenyl or naphthyl optionally substituted by at least one halogen atom, (C1-C6) haloalkyl, (C1-C6) alkyl, (C1-C6) alkyl carbon atoms or phenyl, e ') to a saturated or unsaturated 5 or 6 membered heteromonocyclic ring containing at least one heteroatom, which is an oxygen, sulfur or nitrogen atom and optionally substituted by at least one halogen atom, a (C 1 -C 6) haloalkyl group, (C 1 -C 6) alkoxy, phenyl or (C 1 -C 6) alkyl, and lactone derived from compounds of the formula I and also the pharmaceutically or veterinarily acceptable salts, optical antipodes, geometrical isomers and diastereomers of compounds of formula I and mixtures thereof, wherein the compound of formula II, IVc wherein p, q, Y, n _b n ₂ , X, R ₅ , R ₆ and R ₇ are as defined above, one of the substituents R 1 and R ₂ 'and independently of them one of the substituents R ₃ ' and R ₄ 'represents a hydrogen atom, an alkyl group having 1 to 2 6 carbon atoms, alkenyl group having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, phenyl or phenyl (or naftylHCi-C _C) alkyl, and the other is hydrogen, hydroxyl, alkoxy having from 1 to 6 carbon atoms, phenyl (or naphthyl) - (C ₃ -C ₆ ) alkoxy or a protecting group bonded to a bicyclic system or to a side carbon chain by an ether bond, or R f and R ₂ 'and independently of them R ₃ ' and R ₃ form together ketone protecting group, alkylated with a compound of formula III, E —CH— (CH2) mi —D— (СН2) тг) —R ’” (III) (-) in which D, πη, m ₂ are as defined above, E represents a group of formula (С ₆ Н ₅ ) зР— or (R _e O) ₂ P - (O) -, in which each R _c is independently an alkyl group having 1 to 6 carbon atoms or phenyl and R '"is selected from the group consisting of a') carboxy, either free or esterified -COORg group of the formula wherein R ₉ represents C ₁ _ ₁₂ alkyl or C ₂ _ ₁₂ alkenyl, or carboxy in form of an appropriate salt thereof, b ') a group of the formula -C (OR') _3, where R * is as defined above, c ') a group of the formula -CH ₂ -R ^IV wherein R ^IV represents acyl89 9θ of an oxycycline having 2 to 7 carbon atoms or a protecting group bonded to an "--CH 2 - ether bond", d ") a group of the general formula Ra / —CON, \ R b wherein R a and R b are as defined above, e ") a cyano group, f") a radical of formula and g ") a radical of general formula X‘-Ra‘ / - CH, \ X'-Rb 'wherein X', Ra 'and Rb' are as defined above, and then optionally removing each of the protecting groups present and / or optionally converting a compound of Formula I to a lactone or a corresponding salt, and / or optionally preparing a free compound of formula I from a salt thereof, and / or optionally mixing a mixture of isomeric compounds of formula I into the corresponding individual isomers.