CH630071A5 - Process for the preparation of intermediates for the synthesis of prostaglandin analogues - Google Patents

Abstract

Prostaglandin compounds of the formulae <IMAGE> and <IMAGE> in which the substituents are defined in Claim 1, are prepared. These compounds are obtained by starting from a compound of the formula <IMAGE> and reducing the 9-oxo group in this to the hydroxyl group and subsequently acylating. The silyl protective group is then eliminated, and the radical -CH2-COOR11 is introduced into the side chain by condensation with an appropriate halide. Protective groups which are present are replaced by hydrogen, and finally the acyl radicals in positions 1 and 9 are eliminated, resulting in compounds of the formula XLII. The compounds of the formula XLI are obtained by starting from the compounds which already contain the side chain -CH2-COOR11. The acyl radicals in positions 1 and 9 in these compounds are then eliminated, the 9-hydroxyl group is oxidised to the 9-keto group, and finally the protective group R2 is replaced by hydrogen. The resulting compounds can be used as intermediates for the preparation of prostaglandins.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 
EMI3. 1
 produces in which R13 is defined above and the radicals R2, R3, R11 and Q1 have the meaning given in claim 1, and then carries out the following process steps:

   e) Replacement of R8 and R11 in the product from stage d by
Hydrogen by basic hydrolysis to form a compound of the formula
EMI3. 2nd
 wherein Q1, R2 and R13 are as defined above; f) oxidation of the product from stage e to form a compound of the formula
EMI3. 3rd
 wherein Q1, R2 and R13 are as defined above and g) replacement of the groups R2 in the product from stage f including the R2 radical of Q1 by hydrogen by mild acid hydrolysis. 



   The invention relates to processes for the preparation of intermediates for the synthesis of prostaglandin analogs. 



   The compounds that can be produced according to the invention have the following formulas
EMI3. 4th
 where Q
EMI3. 5
 means in which R1 represents hydrogen or an alkyl radical of 1 to 4 carbon atoms and in which R13 represents
EMI3. 6
 in which CgH2g is an alkylene radical having 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CR14Rl8- and the terminal methyl group, in which R14 and R15 are hydrogen, an alkyl radical of 1 to 4 carbon atoms or fluorine mean, where these can be the same or different, provided that one of the radicals R14 and R15 is only fluorine if the other is hydrogen or fluorine, and under the further condition that neither R14 nor R15 represent fluorine,

   when Z is oxa (-0-), where Z is an oxa atom (-0-) or CjH2j, where CjH2j is a valence bond or an alkylene radical of 1 to 9 carbon atoms with 1 to 6 carbon atoms between CR14Rls and represents the phenyl ring, and in which the radical L represents an alkyl radical of 1 to 4 carbon atoms, fluorine, chlorine, a trifluoromethyl group or OR16- and in which R16 represents an alkyl radical of 1 to 4 carbon atoms and p represents zero, 1 or 2 , provided that no more than two L radicals are different from alkyl, and when p is 2 or 3, the L radicals can either be the same or different.   



   All known prostaglandins are derivatives of prostane



  acid, which has the following formula and numbering:
EMI4. 1

The systematic name for prostanoic acid is 7 - [(28- octyl) cyclopent-la-yl] heptanoic acid. 



   Prostaglandin E1, PGE1, has the following formula
EMI4. 2nd
 Prostaglandin F1a, PGF1an>, has the following formula
EMI4. 3rd

The prostaglandin formulas mentioned above have several centers of asymmetry.  The formulas shown each reflect the special optically active form of the prostaglandin in question, which can be obtained from certain mammalian tissues, e.g. B.  Vesicular glands of sheep, porcine lung or human seminal plasma or by reduction or dehydration of such prostaglandin; see e.g. B.  Bergstrom et al. , Pharmacol.  Rev. 



  20, 1 (1968) and literature cited there.  The mirror image of all formulas represents the other enantiomer of this prostaglandin.  The racemic form of a prostaglandin contains the same number of two types of molecules, one of which is represented by one of the formulas above and the other by its mirror image.  Both formulas are therefore required to represent a racemic prostaglandin.  For a discussion of the stereochemistry of prostaglandins, see Natur 212, 38 (1966). 



   In the above formulas as in the later ones, dashed lines on the cyclopentane ring denote substituents in the o: configuration, i. H.  below the level of the cyclopentane ring.  Bold lines on the cyclopentane ring represent substituents in the ss configuration, i.e. H.  above the level of the cyclopentane ring.  In the above formulas, the hydroxyl group attached to the side chain at C-15 is in an a configuration, as indicated by the dashed line.  In the formulas below, this convention is also used for intermediates that have hydroxyl substituents at the appropriate position in the side chain.  A wavy line denotes a bond to the side chain in an a or P configuration.    



   The various optically active and racemic prostaglandins and their alkyl esters are suitable for various pharmacological purposes.  Especially for PGF, a, see e.g. B.  Bergstrom et al. , Pharmacol.  Rev.  20, 1 (1968), and literature cited there.  For more prostaglandins, see e.g. B.  Ramwell et al. , Nature 221, 1251, (1969). 



   A group of prostaglandin analogues which has a divalent phenylene unit in the carboxyl-terminal side chain of the prostanoic acid skeleton (I) is described in the pending patent application in the U. S. A.  by Norman A.  Nelson, serial number 604,158, filed on June 13,  August 1975. 



   Examples of these phenylene prostaglandin analogs are the compounds represented by the following formulas:
EMI4. 4th
 where Q
EMI4. 5
 means, and Rl represents hydrogen or an alkyl radical having 1 to 4 carbon atoms. 



   Recently, certain prostaglandin analogues with an oxa oxygen atom (-0-) and a divalent phenylene residue have been developed
EMI4. 6
 published in the side chain terminated by carboxyl group in the prostanoic acid structure (I).  See U. S. - Patent No.  3,933,898. 



   Examples of these phenylene oxa prostaglandin analogs are compounds expressed by the following formulas:
EMI4. 7
  
EMI5. 1
 where Q is as defined above. 



   Each of the phenylene and phenylene oxa prostaglandin analogs can be used in place of the corresponding known prostaglandin for at least one of its known pharmacological purposes.  These can be as follows: reduction of gastric acid secretion, inhibition of platelet aggregation, against nasal diseases and induction of labor. 



   It is the object of this invention to provide a process for the preparation of useful intermediates for the production of phenylene and phenylene oxa prostaglandin analogs. 



   The compounds of the formula
EMI5. 2nd
 in which the substituents R13 and Q are defined above are obtained according to the invention by using a compound of the formula
EMI5. 3rd
 starts, in which A is an alkyl radical of 1 to 4 carbon atoms, the phenyl radical, a phenyl radical substituted with one or 2 fluorine, chlorine or alkyl radicals of 1 to 4 carbon atoms, an aralkyl radical of 7 to 12 carbon atoms, the A groups can be the same or different;

   where Q1
EMI5. 4th
 means in which R1 represents hydrogen or an alkyl radical of 1 to 4 carbon atoms and R2 represents a protective group, preferably tetrahydropyranyl, tetrahydrofuranyl or 1-ethoxyethyl, or a radical of the formula
EMI5. 5
 wherein R4 is an alkyl radical of 1 to 18 carbon atoms, a cycloalkyl radical of 3 to 10 carbon atoms, an aralkyl radical of 7 to 12 carbon atoms, the phenyl radical or one having 1, 2 or 3 alkyl radicals of 1 to 4 carbon atoms substituted phenyl radical, R5 and R6 can be identical or different, these representing hydrogen, an alkyl radical of 1 to 4 carbon atoms, the phenyl radical or a phenyl radical substituted by 1, 2 or 3 alkyl radicals of 1 to 4 carbon atoms,

   or if R5 and R6 are taken together, mean - (CH2) a- or - (CH2) bO- (CH2) e-, where a is 3, 4 or 5, b 1, 2 or 3 and c 1, 2 or 3 provided that b plus c is 2, 3 or 4, and in which RT represents hydrogen or the phenyl radical, and in which R13 is as defined above, and subject them to the following stages:

   a) Reduction of the starting compound of formula XXVII to form a compound of formula
EMI5. 6
 wherein A, Q1, R2 and R13 are as defined above, b) acylation of the product from step a to form a compound of the formula
EMI5. 7
 wherein A, Q1, R2 and R13 are as defined above, and wherein R8 is an acyl group of the formula
EMI5. 8th
 represents, wherein R9 is hydrogen, an alkyl radical of 1 to 19 carbon atoms, an aryl radical or one
Aralkyl radical of 7 to 12 carbon atoms, in which the alkyl or aralkyl radicals can optionally be substituted with up to 3 halogen atoms, c) replacement of the -Si (A) 3 group in the product from stage b by hydrogen to form a compound of
formula
EMI6. 1
 where Q1, R2,

   R8 and R13 are as defined above; d) condensation of the product from stage c with a
Halogen acetate of the formula Hal-CH, -COOR11 where Hal is chlorine, bromine or iodine, and R1l for
Hydrogen, an alkyl radical from 1 to 12 carbon atoms, a cycloalkyl radical from 3 to 10 carbon atoms, an ar alkyl radical from 7 to 12 carbon atoms, the phenyl radical or one with 1, 2 or 3 chlorine or alkyl radicals from 1 to 4
C atoms substituted phenyl radical, forming a compound of the formula
EMI6. 2nd
    wherein1, R2, R8, R1l and R13 are as defined above, e) replacement of the protective group R2 in the product from stage d including the R2 groups of Q1 by hydrogen with mild,

   acidic hydrolysis to form a compound of the formula
EMI6. 3rd
 wherein Q, R6, R11 and R13 are as defined above, and f) replacement of the groups R3 and R1l in the product from stage e by hydrogen by basic hydrolysis. 



   The compounds of the formula XLI are prepared according to the invention by, after steps a) - d) of the process described above, a compound of the formula
EMI6. 4th
 produces, in which the substituents have the meaning given above, and then carries out the following process steps: e) replacement of R3 and R1l in the product from stage d by
Hydrogen by basic hydrolysis to form a
Compound of formula
EMI6. 5
 wherein Q1, R2 and R13 are as defined above; f) oxidation of the product from stage e to form a compound of the formula
EMI6. 6
 wherein Q1, R2 and R13 are as defined above and g) replacement of the groups R2 in the product from stage f including the R2 radical of Q1 by hydrogen by mild acid hydrolysis. 



   In relation to the above formulas, alkyl radicals having 1 to 4 carbon atoms are the methyl, ethyl, propyl, butyl radical and their isomeric forms.  Examples of alkyl radicals having 1 to 18 carbon atoms are the above radicals, furthermore the pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl , Octadecylrest and their isomeric forms. 

  Examples of cycloalkyl radicals having 3 to 10 carbon atoms, including alkyl-substituted cycloalkyl radicals, are the cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl-, 2,3,4-triethylcyclobutyl, cyclopentyl-, 2,2-dimethylcyclopentyl-, 2-pentylcyclopentyl, 3-tert-butylcyclopentyl-, cyclohexyl-, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl-, 2, 2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the cyclodecyl radical. 

  Examples of alkyl radicals of 7 to 12 carbon atoms are benzyl, phenethyl, 1-phenylethyl, 2-pheaylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (1-naphthylethyl) -, and 1- ( 2-naphthyl-methyl) residue.     Examples of a phenyl radical substituted by 3 chlorine or alkyl having 1 to 4 carbon atoms are the (o-, m- or p-) chlorophenyl-2,4-dichlorophenyl, 2,4,6-trichlorophenyl, (o-, m -, or p-) tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and the 2,4-dichloro-3-methylphenyl radical. 



   Examples of alkylene residues of 1 to 9 carbon atoms, with 1 to 5 carbon atoms in the chain within the range of CgH2g as defined above, are methylene, ethylene, trimethylene, tetramethylene and pentamethylene, and those alkylene residues with one or more alkyl substituents on one or more the carbon atoms in question, e.g. B. 

   -CH (CH3) -, -C (CH3) 2-, -CH (CH2CH3) -, -CH2-CH (CH3) -, -CH (CH3) -CH (CH3) -, -CH2-C (CH3) 2-, -CH2-CH (CH2) -CH3 -, - CH2-CH2-CH (CH2CH2CH2) -, -CH (CH3) -CH (CH3) -CH2-CH2-, -CH2-CH2-CH2-C ( CH3) 2-CH2 and -CH2-CH2-CH2-CH2-CH (CH3) -.     Examples of alkylene radicals having 1 to 9 carbon atoms, which are optionally substituted with 1 or 2 fluorine atoms, with 1 to 6 carbon atoms in the chain within the range of C, H2j, as defined above, are those which are above for CgH2g and hexamethylene, inclusive Hexamethylene with one or more alkyl substituents on one or more of the carbon atoms in question and including those alkylene groups with one or 2 fluorine substituents on 1 or 2 carbon atoms, e.g. B. 



     -CHF-CHI-, -CHF-CHF-, -CH2-CH2-CF2-, -CH2-CHF-CH2-, -CH2-CH2-CF (CH3) -, -CH2-CH2-CF-CH2-, - CH (CH3) -CH2-CH2-CHF -, - CH2-CH2-CH2-CH2-CF2-, -CHF-CH2-CH2-CH2-CH2-CHF-, -CF2-CH2-CH2-CH2-CH2-CH2 -, -CH2-CH2-CH2-CF2-CH2-CH2 and -CH2-CH2-CH2-CH2-CH2-CH2-CF2.    



   examples for
EMI7. 1
 are, as defined above: phenyl, (o-, m-, or p) -tolyl, (o-, m-, or p-) ethylphenyl, (o-, m-, or p-) propylphenyl, (o- , m-, or p-) butylphenyl, (o-, m-, or p-) isobutylphenyl, (o-, m-, or p -) - butylphenyl, 2,3-xylyl, 2,4-xylyl, 2 , 5-xylyl, 2,6-xylyl, 3,4-xylyl, 2,6-diethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, 2-propyl - (o-, m-, or p-) tolyl, 4-butyl-m-tolyl, 6-tert-butyl-m-tolyl, 4-isopropyl-2. 6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6- or 2,4,5-) trimethylphenyl, (o-, m- or p-) fluorophenyl, 2-fluoro- (o-, m-, or p-) tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3rd , 4- or 3,5-) ditluorophenyl, (o-, m-, or p-) chlorophenyl, 2-chloro-p-tolyi, (3-, 4-, 5-, or 6-) chloro-o- tolyl,

   4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4 -, or 3,5-) dichlorophenyl, 4-chloro-3-fluorophenyl, (3-, or 4-) chloro-2-fluorophenyl, a, a, x-trifluoro- (o-, m-, or p- ) tolyl, (o-, m-, or p-) methoxyphenyl, (o-, m-, or p-) ethoxyphenyl, (4- or 5-) chloro-2-methoxyphenyl, and 2,4-dichloro- ( 5- or 6-) methoxyphenyl. 



   If the protective group R2 is tetrahydropyranyl or tetrahydrofuranyl, the corresponding reagent, such as. B.  2,3-dihydropropane or 2,3-dihydrofuran, in an inert solvent such as dichloromethane, in the presence of an acidic condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride.  The reagent is usually used in a slight excess, preferably 1.0 to 1.2 times more than is theoretically required.  This reaction is preferably carried out in the range from 20 to 50 ° C. 



   If R2 is a residue of the following formula
EMI7. 2nd
 is, a vinyl ether, e.g. B.  Isobutyl vinyl ether, wherein R4, R5, R6 and RT are as defined above or an unsaturated cyclic or heterocyclic compound e.g. B.    1-cyclohex-1-ylmethyl ether
EMI7. 3rd
 or 5,6-dihydro-4-methoxy-2H-pyran
EMI7. 4th

See C. B.  Reese et al. , J.  At the.  Chem.  Soc.  89, 3366 (1967).  The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for the above dihydropyran. 



   In step (a), silylated compounds of XXVII can be obtained by methods which are known or have been described here.  See e.g. B.  Pierce, Silyation of Organic Compounds, Pierce Chemical Co. , Rockford, Illinois (1968).  The silylating agents required for these conversions are known or can be prepared by known methods.  See e.g. B.  Post Silicones and Other Organic Silican Compounds, Reinhold Publishing Corp. , New York, N. Y.  (1949).  These reagents are usually used in the presence of a tertiary base such as pyridine at temperatures in the range of about 0 to +50 ° C.  

  Examples of trisubstituted monochlorosilanes which are suitable for this purpose are chlorotrimethylsilane, chlorotriisobutylsilane, tert-butyldimethylchlorosilane, chlorotriphenylsilane, chlorotris (p-chlorophenyl) silane, chlorotri-m-tolylsilane and tribenzylchlorosilane.  On the other hand, a chlorosilane with a corresponding disilazane can be used. 

  Examples of other silylating agents are pentamethylsilylamine, pentaethylsilylamine, N-trimethylsilyldiethylamine, 1,1,1-triethyl-N, N-dimethylsilylamine, N, N-diisopropyl-1,1,1-trimethylsilylamine, 1,1,1 -tributyl -N, N-dimethylsilylamine, N, N-dibutyl-1,1, 1-trimethylsilylamine, 1-isobutyl-N, N, 1,1-tetramethylsilylamine, N-benzyl -N-ethyl-1,1,1 -trimethylsilylamine, N, N, 1, 1-tetramethyl-1 - -phenylsilylamine, N, N-diethyl-1,1-dimethyl-1-phenylsilylamine, N, N-diethyl-1,1-dimethyl-1- phenylsilylamine, N, N-diethyl-1-methyl-1,1-diphenylsilylamine, N, N-dibutyl-1,1,1-triphenylsilylamine and 1-methyl-N, N, 1, 1-tetraphenylsilylamine.    



   Although a wide variety of silysing agents are available, it is preferred that the silyl groups on the ring contain at least one inhibitory group: e.g. B. 



  Isopropyl, sec-butyl, tert-butyl, cyclohexyl, or phenyl. 



  The preferred silyl groups with the substituents mentioned, such as. B.  Trimethylsilyl, are characterized in that they are less sensitive to hydrolysis and are therefore resistant to cleavage during the subsequent steps.  The following groups are preferred: isopropyldimethylsilyl, sec-butyldimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, cyclohexyldimethylsilyl, and triphenylsilyl. 



   In addition to the silylation processes listed above, it is advantageous to silylate with a chlorosilane in the presence of imidazole in a solvent such as dimethylformamide.  See Corey et al. , J.  At the.  Chem.  Soc.  94, 6190 (1972).  The temperature range for the reaction is usually around - 100 to + 80 C.    



   In step (c), the compound of formula XXX is obtained from the terminal carboxyl group by hydrolysis of the silyl group.  In general, an alkali metal carbonate in water and a further solvent, such as methanol, tetrahydrofuran or dioxane, are used, preferably in a temperature range from about -100 to +1000C.  If the silyl groups on the ring are sterically hindering, a stronger base such as sodium hydroxide can be used to remove the silyl groups from the carboxyl residues. 



   A base in a liquid medium, such as dioxane or tetrahydrofuran, is preferably used to remove the protective groups. 



   For the preparation of the 9-oxo compound of the formula XXXIII, pyridinium chlorochromate, the Collins reagent, and in particular the Jones reagent, are preferably used at a temperature of about -400C to about 25 "C. 



     Rs is an acyl radical in the compounds described above, such as. B.  Formyl, acetyl, pivaloyl and so on.  R3 is preferably an aromatic acyl radical, such as substituted benzoyl or benzoyl, unesterified phthaloyl, naphthoyl or substituted naphthoyl.  The acyl group has the following formula
EMI8. 1
 wherein R9 represents hydrogen, an alkyl radical of 1 to 19 carbon atoms, an aryl radical or an aralkyl radical of 7 to 12 carbon atoms, wherein the alkyl or aralkyl radicals are optionally substituted with up to 3 halogen atoms.  Aromatic acyl groups are e.g. B. 

  Benzoyl and substituted benzoyl as represented by the formula
EMI8. 2nd
 is expressed in which T represents an alkyl radical of 1 to 4 carbon atoms, a phenylalkyl radical of 7 to 10 carbon atoms or nitro and s represents 0 or a number of 1 to 5, provided that no more than two radicals T are different from alkyl, and that the total number of carbon atoms in the radicals T does not exceed 10 carbon atoms; a mono-esterified phthaloyl residue as represented by the formula
EMI8. 3rd
 in which Rlo represents an alkyl radical of 1 to 4 carbon atoms, or naphthoyl and substituted naphthoyl, as represented by the formula
EMI8. 4th
 where T and s are as defined above. 



   Known methods or those described here can be used when introducing the R3 radical into compounds of the formula XXVI II.  Acylation can be accomplished with an acid anhydride, such as acetic anhydride, or with an acyl halide, such as pivaloyl chloride.  The reaction is preferably carried out in the presence of a tertiary amine such as pyridine, triethylamine and so on; it can be carried out under very different conditions using generally known methods. 



  Mild conditions are usually used, such as B. 



  20 to 60 "C, wherein the reactants in a liquid medium, such as. B.  brings together an excess of pyridine or an inert solvent such as benzene, toluene or chloroform.  The acylating agent can be used either in a stoichiometric ratio or in excess. 



   Various acylating agents which are useful for this conversion are known or can be easily prepared by known methods; these can be acyl halides, preferably chlorides, bromides or fluorides, i.e. H. 



     R9C (O) Cl, RgC (O) Br or RgC (O) F and carboxylic acid anhydrides,
EMI8. 5
 where R9 is as defined above.  Examples of acid anhydrides that are useful for this purpose are acetic anhydride, propionic anhydride, butyran anhydride, pentanoic anhydride, nonanoic anhydride, tridecanoic anhydride, stearic anhydride, (mono, di, or tri) chloroacetic anhydride, 3-chloroethyl- (3-chloro-valeric) anhydride 4,8-Dimethylnonansäureanhydrid, Cyclopropanacetanhydrid, 3-Cycloheptanpropionsäureanhydrid, 13-Cyclopentantridecansäureanhydrid, Phenylacetanhydrid, (2 or 3) -Phenylpropionsäureanhydrid, 13-Phenyl-tridecansäureanhydrid and Phenoxyacetanhydrid. 

  The choice of anhydride depends on the identity of R9 in the acylated product; for example, if R9 is to be methyl, acetic anhydride is used; if Rg is to be 2-chlorobutyl, 3-chloro-valeric anhydride is used. 



   When R9 is hydrogen, the group is of the formula
EMI9. 1
 Formyl.  The formylation can be carried out by known methods, e.g. B.  by reacting the hydroxy compound with the mixed anhydride of acetic acid and formic acid or with formylimidazole.  See e.g. B.  Fieser et al. , Reagents for Organic Synthesis, John Wiley and Sons, Inc. , Pages 4 and 407 (1967) and literature cited therein. 



     Rg can also represent benzoyl, substituted benzoyl, monoesterified phthaloyl, naphthoyl or substituted naphthoyl.  Known methods are commonly used to introduce these protecting groups.  Thus an aromatic acid, e.g. B.  Benzoic acid, with an appropriate compound in the presence of a dehydrating agent, e.g. B.  Sulfuric acid, zinc chloride, or phosphoryl chloride, are reacted; or an aromatic acid anhydride, e.g. B.  Benzoic anhydride used. 



   The following acids, anhydrides or acyl chlorides can serve as examples of reagents which provide Ra for the stated purposes: benzoyl; substituted benzoyl, such as. B. 



  (2-, 3- or 4-) methylbenzoyl, (2-, 3- or 4-) ethylbenzoyl, (2-, 3- or 4-) isopropylbenzyl, (2-, 3- or 4-) butylbenzoyl, 2, 4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2. 4,6-trimethylbenzoyl, pentamethylbenzoyl, Gc-phenyl- (2-, 3- or 4-) toluyl, 2-, 3- or 44-phenethylbenzoyl, 2-, 3- or 4-nitrobenzoyl, (2,4-, 2,5- or 3,5-) dinitrobenzoyl, 4'5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono-esterified phthaloyl, e.g. B. 
EMI9. 2nd


 

  Isophthaloyl, e.g. B. 
EMI9. 3rd

EMI9. 4th




  (1- or 2-) naphthoyl; and substituted naphthoyl, for example (2-, 3-, 4-, 5-, 6- or 7 -) - methyl-1-naphthoyl, (2- or 4- (ethyl-1-naphthoyl, 2-isopropyl-1- naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl, 4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5- or 8 -) - Nitrol-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or 8 -) - methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-) - Nitro-2-naphthoyl. 



   The reaction scheme below shows preferred embodiments for the processes according to the invention, starting with the preparation of the starting compound of the formula XXVII.  The substituents listed in the reaction scheme have been defined above.   



  Scheme
EMI10. 1
 Scheme (continued)
EMI10. 2nd
   Scheme (continued)
EMI11. 1

In step (a), the enone compound XI can be conjugatively added with a lithium diaryl cuprate reagent, which consists of
EMI11. 2nd
 was prepared, to give the compound of formula XXVII.  The radicals -Si (A) 3 have already been defined above.  The reaction conditions are the same as those described above. 



   In step (b), compound XXVIII is obtained by reduction of the ketone, usually using known or disclosed methods. 



   In step (c), the acylated compound of formula XXIX is formed by acylating XXVIII using generally known methods or those described above. 



   In step (d) the terminal silyl groups are removed to give compound XXX by using the methods described above, e.g. B. 



   hydrolysis with tetra-n-butylammonium fluoride.    



   In step (e) a Williamson synthesis is used to obtain the compound of formula XXXI.  The phenol of the formula XXX is condensed with a halogen acetate of the formula Hal-CH2-COOR, where Hal stands for chlorine, bromine or iodine and R1l is defined above. 



  Usually the reaction is carried out in the presence of a base such as n-butyllithium, pheniyllithium, triphenyllithium, sodium hydride, potassium hydride, potassium t-butoxide, sodium hydroxide or potassium hydroxide. 



   In step (f), the free acid of the formula XXXII is obtained by basic hydrolysis in order to replace the radicals R3 and R1l with hydrogen, as is generally known. 



  An aqueous potassium hydroxide solution at about 25 to 100 "C is preferred. 



   In step (g), the ketone XXXIII is obtained by oxidation, for example using the Jones reagent. 



   In step (h) the product of the formula XLI of the PGE type is removed by removing the R2 protective groups by mild, acidic hydrolysis, as is generally known or has been described above. 



   The PGF-type products of formula XLII are obtained from the intermediate of formula XXXI via the route of steps (i) and (g) from the reaction scheme.  In step (i) the R2 protecting groups are removed, e.g. B.  with the process of step (h), so that the compounds of formula XXXIV are formed, which are then converted into compounds of formula XLII in step (j) by mild hydrolysis.  The desired 9a compound is optionally separated from the 9ss epimer by known methods, including silica gel chromatography. 



   The new intermediates obtained according to the invention do not need to be isolated, they can be used directly for the subsequent reaction step. 



  If they are isolated, known methods of purification can be used, for example partial extraction, fractional crystallization and preferably column chromatography with silica gel. 



   The products obtained according to the invention, as shown above, have the same stereo configuration on the C-15 as is also present in the corresponding starting materials. 



   If an optically active intermediate or starting material is used, subsequent steps result in optically active intermediates or optically active products.  When the racemic form of the intermediate or the starting material is used, the subsequent intermediates or products are obtained in their racemic forms. 



   The invention can be better understood from the following examples and methods:
All temperatures are in degrees Celsius. 



   Infrared absorption spectra were recorded on a Perkin Elmer Model 421 or a Perkin-Elmer Infarcord infrared spectrophotometer.  Unthinned samples were used unless otherwise noted. 



   NMR spectra were recorded on a Varian A-60, A-60D, or T-60 spectrophotometer using deuterochloroform solutions with tetramethylsilane as the internal standard (downfield). 



   Mass spectra are recorded on a double-focusing high-resolution mass spectrometer CEC Model 110B or on a gas chromatograph mass spectrometer LKB Model 9000 ionization voltage 70 EV. 



   Circular dichroism curves were recorded on a Carey 60 spectropolarimeter. 



   The specific rotation values were determined for solutions of a compound in the listed solvent with an automatic polarimeter Perkin Elmer model 141. 



   Here saline solution refers to an aqueous, saturated sodium chloride solution. 



    Skellysolve-B refers to a mixture of isomeric hexanes. 



   In this context, silica gel chromatography is understood to mean the elution, collection of the fractions and the pooling of these fractions, and thin-layer chromatography has shown that they contain the desired product, which has been cleaned of the starting material and impurities. 



   The A-IX system for DC was developed by Hamberg and Samuelsson, J.  Biol.  Chem.  241, 257 (1966), and is based on ethyl acetate-acetic acid 2,2,4-trimethylpentane-water (90: 20: 50: 100). 



   Preparation 1 3- [3-t-butyldimethylsilyloxy) propyl] phenyllithium cuprate reagent
I.  L-Bromo-3- [3-t-butyl-dimethylsilyloxy) - -propyl] benzene is first prepared:
EMI12. 1

A solution of 3- (3-bromophenyl) propan-1-ol (4.30 g) in 15 ml of dimethylformamide is treated with t-butyldimethylchlorosilane (3.62 g) and imidazole (3.40 g) at 25 "C. during Treated for 3.5 hours.  The mixture is diluted with saturated NaCl solution and extracted with diethyl ether-Skellysolve B (1: 1).  The extracts are washed with 1N hydrochloric acid, aqueous sodium bicarbonate and brine and dried over magnesium sulfate.  6 g of an oil are obtained on concentration, which resulted in a distillation of 5.68 g of the silyl derivative, boiling point 84-86 "C / 0.15 mm. 



   II.  A solution of the above bromine compound (0.82 g) in 20 ml of diethyl ether is treated at 780C with t-butyllithium (2.25 ml of a 1.20 M solution in pentane) and stirred for 0.5 hours.  The resulting solution of the aryllithium compound becomes Cu].    (n-C4H9) 3P complex, which independently of copper (I) iodide (0.238 g) and tri (n-butyl) phosphine (0.253 g) in 20 ml of diethyl ether at 25 "C for 45 minutes and - 78 "C was cooled.  The resulting lithium cuprate reagent is then used directly in solution without isolation. 



   Preparation 2 5a- (t-butyldimethylsilyloxy) -3 a-hydroxy-2 p- [(3 S) -3-hydroxy-trans-1 -octenylj - 1 a-cyclopentanacetic acid, 3,3'-bistrahydropyranyl ether (Q1 means
EMI12. 2nd
 wherein THP for tetrahydropyran-2-yl, R2 for THP and
Si (A) 3 represents t-butyldimethylsilyl). 



   I.  A solution of the lactone 3a, 5a-dihydroxy-2B - [(3'S) -3- -hydroxy-trans- 1 '-octenyl] - 1 a-cyclopentanacetic acid, bis-tetrahydropyranyl ether (Corey et al. , J.  At the.  Chem.  Soc.  92, 397 (1970), (1.14 g) in 10 ml of methanol is treated with 10 ml of a 1N aqueous sodium hydroxide solution at about 25 ° C. for 2 hours.  The reaction mixture is then concentrated to about half its volume, diluted with 50 ml of water and saturated with sodium chloride. 



  The pH is then adjusted to about 5-6 with 1 M aqueous potassium hydrogen sulfate solution: the mixture is extracted with ethyl acetate.  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to obtain the compound of formula XIV in the form of an oil. 



   II.  The resulting triol acid, bis-tetra-hydropyranyl ether is taken up in 5 ml of dimethylformamide and added to a solution of t-butyldimethylchlorosilane (0.94 g) and imidazole (0.88 g) in 15 ml of dimethylformamide.  The mixture is stirred at 25 "C and after about 17 hours more reagents (0.47 g t-butyldimethylsilyl chloride and 0.44 g imidazole) are added; stirring is carried out first at 25" C for one hour and then at 400C for 3 hours continued, so that the reaction was then complete, as shown by DC.  The reaction mixture is cooled, diluted with saturated NaCl solution and extracted with 400 ml of Skellysolve B-diethyl ether (1: 1). 

  The organic phase is separated off, washed with 1N hydrochloric acid and saturated NaCl solution, dried over sodium sulfate and concentrated to obtain the compound of the formula XV. 



   III.  The residue from II is dissolved in 175 ml of a mixture of methanol-tetrahydrofuran-water (100: 50: 25) and treated with potassium carbonate (3.0 g) at 25 ° C. for one hour.  The reaction mixture is concentrated, diluted with 200 ml of saturated NaCl solution, adjusted to a pH of 4-5 with 1 M aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate.  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to give an oil which contains the title compound of the formula XVI. 

  The product is then chromatographed on silica gel eluting with ethyl acetate (10-20%) - Skellysolve B to give 1.36 g of the title compound which has a Ri of 0.14 [TLC on silica gel in ethyl acetate Skellysolve B (1: 3)], and NMR peaks at 0.3, 0.89, 0.7-2.8, 3.2-4.47, 4.68, 5.27-5.72 and 9, 63 8 and IR absorption bands at 2980, 2890, 1735, 1710, 1460, 1253, 1198, 1183, 1130, 1110, 1074, 1019, 981, 870, 838 and 776 cm-1. 

 

   Preparation 3
1 - (t-Butyldimethylsilyloxy) -2-methylene-4z-hydroxy-3 - - [(3 'S) -3'-hydroxy-trans-1' -octenyl] cyclopentane, 4,3'-bis tetrahydropyranyl ether (Q1 , R2 and Si (A) 3 as defined in preparation 2). 



   A mixture of the silylated acid obtained (preparation 2, 2.20 g) in 35 ml of benzene is stirred with copper (II) acetate monohydrate (0.19 g) and 1.16 ml of pyridine until a homogeneous solution has been prepared, then 5.03 g of lead tetraacetate were added and the mixture was stirred at about 250 ° C. in a dark place for 1.5 hours, a slow stream of nitrogen flowing through the mixture.  While nitrogen continued to flow through the mixture, the mixture was heated to 80 ° C. in the course of 30 minutes and held at 80 ° C. for a further 45 minutes.  The course of the reaction is followed by thin layer chromatography.  The mixture is finally cooled to about 25 ° C., diluted with 300 ml of saturated NaCl solution and extracted with ethyl acetate. 

  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to a residue which contained 2.25 g of the title compound.  The residue is chromatographed on silica gel, eluting with ethyl acetate (5-45%) Skellysolve B to give 0.80 g of the title compound which has an Rg of 0.64 [TLC on silica gel in ethyl acetate-Skellysolve B (1: 3)]; NMR peaks at 0.08, 0.92, 0.75-2.9, 2.9-4.5, 4.72, 4.93, 5.17 and 5.33-5.64 b; and IR absorption bands at 2960, 2895, 1460, 1345, 1251, 1199, 1120, 1075, 1065, 1034, 1020, 1002, 973, 900, 870, 838, 817 and 775 cm-1. 



   Preparation 4 2-methylene-4 a-hydroxy3 ss - [(3'S) -3'-hydroxy-trans-1'-octenyl] cyclopentanol, 4,3'-bis-tetrahydropyranyl ether (Qi and R2 as in Preparation 2 defined). 



   A solution of the resulting silylated compound (preparation 3, 3.40 g) in 40 ml of tetrahydrofuran is treated with 15 ml of a 0.6 M solution of tetra-n-butylammonium fluoride, and the mixture is stirred at about 25 ° C. for one hour.  The resulting mixture is diluted with 300 ml of saturated NaCl solution and extracted with diethyl ether.  The organic phase is washed with saturated NaCl solution, dried over magnesium sulfate and concentrated. 



  The residue (3.77 g) is chromatographed on silica gel, eluting with ethyl acetate (10-50%) - Skellysolve B to give 1.94 g of the title compound, which is now free of silyl groups; a white solid, which showed an Rf value of 0.19 [TLC on silica gel in ethyl acetate-Skellysolve B (1: 3)].  An analytical sample obtained by recrystallization from Skellysolve B had a melting point of 83-84.50C; NMR peaks at 0.88, 0.6-2.8, 3.0-4.5, 4.70, 5.02 and 5.20-5.62 B; and IR absorption bands at 3220, 3140, 1660, 1125, 1080, 1065, 1040, 1020, 1000, 970 and 910 cm-1. 



   Preparation 5
2-methylene-4z-hydroxy-3 ss- [(3 'S) -3'-hydroxy-trans-1' - -octenyl cyclopentanone, 4,3'-bis-tetrahydropyranyl ether (Q4 and R37 as in preparation 2 Are defined). 



   A solution of the allyl alcohol obtained (preparation 4, 0.41 g) in ml of acetone is mixed at -20 ° C. with 0.50 ml of 2.67 m Jones reagent (see Merck Index, eighth edition, page 1182 and cited therein) Literature) treated.  The mixture is stirred at -30 "to - 150C for 30 minutes and then terminated with 0.25 ml of isopropyl alcohol and stirred for a further 10 minutes.  The reaction mixture is then diluted with saturated NaCl solution and extracted with diethyl ether. 

  The organic phase is washed with aqueous sodium bicarbonate solution and saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 0.39 g of the title compound, which have IR absorption bands at 2980, 1735, 1647, 1200, 1129, 1112, 1076 , 1035, 1020 and 978 cm-1; and NMR peaks at 0.91, 0.8-3.1, 3.1-4.4, 468 5,11,5,47,5,983; and showed an Rf of 0.44 [TLC on silica gel in ethyl acetate-Skellysolve B (1: 3) 1. 



   Preparation 6 2x- [7- (t-butyldimethylsilyloxy) -2,3,4-trinor-1,5-inter-m- -phenylene-heptyl] -4x-hydroxy-3 ss- [(3'S) -3'- hydroxy-trans -1-octenyl] cyclopentanone, 4,3'-bistro-tetrahydropyranyl ether (Q1, R2 and Si (A) 3 as defined in preparation 2). 



   A solution of the resulting enone compound from preparation 5 (0.39 g) in 4 ml of diethyl ether at -78 ° C. is added to a solution of the lithium cuprate reagent (preparation 1) at -78 ° C. for 5-10 minutes and then stirred at -78 "C for 30 minutes.  The reaction mixture is added with rapid stirring to a mixture of 50 ml of a 1 M potassium hydrogen sulfate, 50 ml of saturated NaCl solution and ice, diluted with saturated NaCl solution and extracted with diethyl ether.  The organic extracts are washed with aqueous sodium bicarbonate and saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 1.5 g of an oil. 



  The oil is chromatographed on silica gel, eluting with ethyl acetate (10-30%) - Skellysolve B to give 0.49 g of the title compound as an oil which has infrared spectral absorption bands at 2980, 2890, 1749, 1251, 1200 , 1128, 1108, 1077, 1037, 1020, 947, 837, 776 cm-1; NMR peaks at 0.004.0.9, 0.9-3.05, 3.1-4.3, 3.62, 4.63, 5.43 and 6.68-7.37 b; Rf values of 0.30 and 0.35 [TLC on silica gel plates in ethyl acetate-Skellysolve B (1: 3)] showed. 



   Preparation 7
2a- [7- (t-Butyldimethylsilyloxy) -2,3,4-trinor-1,5-inter-m- -phenylene-heptyl] -4x-hydroxy-3 ss - [(3'S) -3'-hydroxy- trans- -l-octenyl] cyclopentanol, 4,3'-bistrahydropyranyl ether (Q1, R2 and Si (A) 3 as defined in preparation 2)
A solution of the resulting ketone from preparation 6 (0.49 g) in 10 ml of methanol is treated at 0 C with sodium borohydride (0.060 g) in 2 ml of water; Tetrahydrofuran (5 ml) is added and the mixture is stirred at 0 C for one hour.  The mixture is concentrated, diluted with saturated NaCl solution and extracted with ethyl acetate. 

  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to give 0.48 g of the title compound and its C-9 epimer in the form of an oil, which have Rf values of 0.29 and 0, 16 [TLC on silica gel plates in ethyl acetate-Skellysolve B (1: 3)]. 



   Preparation 8
2- (7-hydroxy-2,3,4-trinor-1,5-inter-m-phenylene-heptyl) - -4x-hydroxy-3 ss - [(3 'S) -3'-hydroxy-trans- 1-octenyl] cyclopentanol, 4,3'-bistro-tetrahydropyranyl ether (Q1 and R2 as defined in preparation 2). 

 

   A solution of the reduction product obtained (preparation 7, 0.48 g) in 10 ml of tetrahydrofuran is treated with tetra (n-butyl) ammonium fluoride (3 ml) of a 0.5 m solution at 25 ° C. for one hour and then with a treated another 1 ml of a tetra (n-butyl) ammonium fluoride solution for a further hour).  Saturated NaCl solution is added and the mixture extracted with ethyl acetate. 



  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to give 0.57 g of the title compound and of its C-9 epimer, which have Rf values of 0.16 and 0.08 [TLC] Show silica gel plates in ethyl acetate-Skellysolve B (1: 1)].   



   Preparation 9
4,5,6-Trinor-3,7-inter-m-phenylene-PGE1, 11.15-Biste trahydropyranyl ether (Q1 and R2 as defined in preparation 2). 



   A solution of the compound of preparation 8 (0.82 g) in 30 ml acetone is at 20 C with Jones reagent (2.0 ml of a 2.67 m solution, which consists of 2.1 g chromium trioxide, 6 ml water and 1 , 7 ml of concentrated sulfuric acid was treated).  After 1.6 hours the reaction is complete and the reaction is terminated with 1.0 ml of isopropyl alcohol at 0 C for 10 minutes.  The mixture is diluted with saturated NaCl solution and extracted with ethyl acetate.  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 0.86 g of the title compound of formula XXI in the form of an oil, Rf = 0.59 (TLC on silica gel plates in the A-IX system ). 



   Preparation 10 4,5,6-trinor-3, 7-inter-m-phenylene-PGE1 (Q means
EMI14. 1

A solution of the compound obtained from preparation 9 (0.86 g) in 15 ml of a mixture of acetic acid-water tetrahydrofuran (20: 10: 3) is left to stand at about 250 ° C. for 19 hours.  The mixture is then diluted with 20 ml of water and concentrated.  The residue is taken up in 5 ml of dichloromethane and chromatographed on silica gel, eluting with ethyl acetate (50-100%) - Skellysolve B to obtain 0.25 g of the title compound of formula IV, melting point 67-770C, Rf value 0 , 19 (TLC on silica gel in the A-IX system). 

  An analytical sample obtained by recrystallization from diethyl ether-Skellysolve B has a melting point of 65.9-69.5 C; NMR peaks at 0.95, 1.2-1.7, 1.9-3.2, 3.9-4.2, 5.3-5.7, 5.9-6.2 and 6, 9-7.3 B; [z] D 870 (c = 0.8465 in chloroform); and mass spectrum peaks (TMS derivative) at 604. 3408, 589, 533, 514, 499, 443, 417, 389, 313, 279 and 199. 



   If one works according to the instructions of preparations 2-10, but the lactone used is replaced by another corresponding lactone, in which the terminal pentyl group of the octenyl side chain of 3a, 5a-dihydroxy-2ss- - [(3'S) -3'-hydroxy -trans-1 '-octenyl] - 1 a-cyclopentanacetic acid, bis-tetrahydropyranyl ether is replaced by any of the following groups, which are already known or can be prepared by customary methods:

  : 1-methylpentyl 1,1-dimethylpentyl 1-fluoropentyl 1,1-difluorpentyl phenoxymethyl (m-tolyloxy) methyl (p-tolyloxy) methyl (m-chlorophenoxy) methyl (p-chlorophenoxy) methyl (m-fluorophenoxy) methyl (p -Fluorophenoxy) methyl (m-trichloromethylphenoxy) methyl (p-trichloromethylphenoxy) methyl (m-anisyloxy) methyl (p-anisyloxy) methyl l-phenoxyethyl 1-methyl-1-phenoxyethyl benzyl 2-phenethyl 2- (m-tolyl) ethyl 2- (p-tolyl) ethyl 2- (m-chlorophenyl) ethyl 2- (p-chlorophenyl) ethyl 2- (m-fluorophenyl) ethyl 2- (p-fluorophenyl) ethyl 2- (m-trichloromethylphenyl) ethyl 2- (p-Trichloromethylphenyl) ethyl 2- (m-anisyl) ethyl 2- (p-anisyl) ethyl 3-phenylpropyl
1-methyl-1-phenylethyl
1-methyl-2-phenylethyl
1,1-dimethyl-2-phenylethyl
1,1-dimethyl-3-phenylpropyl a, a-difluorobenzyl 1-fluoro-2-phenylethyl 1.1

   -Difluoro-2-phenylethyl and 1,1-difluoro-3-phenylpropyl, each of the corresponding analogs 4,5,6-trinor-3,7-inter-m-phenylene-PGE1 can be obtained, which have one of the following structural features :
1 6-methyl
16.1 6-dimethyl
16-fluorine
16.1 6-difluoro
16-phenoxy-17,18,19,20-tetranor-
16- (m-tolyloxy) - 17,18,1 9,20-tetranor-16- (p-tolyloxy) -17,18,19,20-tetranor-1 6- (m-chlorophenoxy) 17,18,1 9,20-tetranor-16- (p-chlorophenoxy) -17,18,19,20-tetranor
1 6- (m-fluorophenoxy) 17,18,1 9,20-tetranor-1 6- (p-fluorophenoxy) - 17,18,1 9,20-tetranor
16- (m-trichloromethylphenoxy) -17,18,19,20-tetranor-
16- (p-trichloromethylphenoxy) -17,18,19,20-tetranor-1 6- (m-anisyloxy) - 17,18,1 9,20-tetranor-16- (p-anisyloxy) -17,1 8 , 19.20 tetranor

   16-phenoxy-18,19,20-trinor 1 6-methyl-1 6-phenoxy-18.1 9,20-trinor-16-phenyl-17, 18,19,20-tetranor-
17-phenyl-18, 19,20-trinor-
1 7- (m-tolyl) - 18.1 9.20-trinor-17- (p-tolyl) - 18, 19.20-trinor-17- (m-chlorophenyl) - 18.19.20-trinor 17 - (p-Chlorophenyl) - 18,19,20-trinor-1 7- (m-fluorophenyl) - 18.1 9,20-trinor-17- (p-fluorophenyl) -18,19,20-trinor-1 7- (m-trichloromethylphenyl) - 18,19,20-trinor 17- (p-trichloromethylphenyl) - 18,19,20-trinor- 17- (m-anisyl) -18,19,20-trinor17- (p- Anisyl) -18,19,20-trinor 1 8-phenyl- 1 9,20-dinor- 16-methyl- 16-phenyl- 18,19,20-trinor- 16-methyl- 17-phenyl- 18,19, 20-trinor-16, 16-dimethyl-17-phenyl-1 8, 19.20-trinor-16.1 6-dimethyl-1 8-phenyl-1 9.20-dinor-16,

   16-difluoro-1 6-phenyl-17, 18,19,20-tetranor- 16-fluoro-1 7-phenyl-18,1 9,20-trinor-16,16-difluoro-1 7-phenyl-18, 1 9.20-trinor- or 16.1 6-difluoro-1 8-phenyl- 1 9.20-dinor-.    



   If you e.g. B.  starting from 3a, 5a-dihydroxy-2ss - [(3'S) -3'-hydroxy-trans-l '- (5'-phenyl) pentenyl] - 1 a-cyclopentanoacetic acid, bis-tetranhydropyranyl ether, becomes 4.5, 6,18,19, 20-hexanor-3,7-inter-m-phenylene-17-phenyl-PGE1.   



   If one also starts from the corresponding (3'R) -3 '-hydroxylactones, the 15-epimer products are obtained. 



   Preparation 11 2-methylene-4z-hydroxy-3 3- [(3'S) -3 '-hydroxy-trans-1'- -octenyl] -cyclopentanol, 4,3'-bis-tetrahydropyranyl ether (Ql and R2 as in Preparation 2 defined). 



   a) A solution of 4.29 g of the lactone obtained [Corey et al. , J.  At the.  Chem.  Soc.  92, 397 (1970)] in 15 ml of tetrahydrofuran is added dropwise to a stirred mixture of 4.3 g of sodium bis (2-methoxyethoxy) aluminum hydride (70% solution in benzene) and 50 ml of tetrahydrofuran at about 20 ° C. .  The mixture is stirred for a further 2 hours, after which 100 ml of 5 percent aqueous potassium hydroxide solution are carefully added with stirring.  The mixture is diluted with 200 ml of diethyl ether and water (1: 1). 

  The organic phase is washed with 5% aqueous potassium hydroxide and saturated NaCl solution, dried over sodium sulfate and concentrated to give 4.59 g of the compound in the form of an oil, which have infrared absorption bands at 3450, 2980, 2890, 1465, 1450, 1438 , 1346, 1338, 1200, 1130, 1110, 1075, 1034, 1020, 974 and 869 cm- '. 



   b) The diacylated compound obtained is next obtained from the diol product of step (a) (4.59 g) and treated in 40 ml of pyridine and 10 ml of acetic anhydride together with 0.1 g of 4-dimethylaminopyridine as a catalyst.  The reaction mixture is stirred at about 250C for 16 hours, then diluted with saturated NaCl solution and extracted with diethyl ether.  The organic phase is washed with ice-cold 1M potassium hydrogen sulfate solution and saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 5.24 g of the diacetate. 



   c) The product obtained from stage (b) (5.24 g) is treated with potassium carbonate (0.14 g) in 100 ml of methanol at about 40 "C for 1.25 hours and finally at about 25" C for 0.75 Hours treated.  The mixture is diluted with ice-cold, saturated NaCl solution and brought to pH 2-3 with 1 M potassium hydrogen sulfate and extracted with ethyl acetate.  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 4.56 g of an oil which contained the monoacetate. 

  The residue is chromatographed on silica gel, eluting with acetone (5-75%) dichloromethane to give the compound of formula XXIV, an oil; the yield is 0.69 g, an R, value of 0.20 is found [TLC on silica gel in acetone-dichloromethane (15:85)]; Infrared absorption bands at 3530, 2970, 1740, 1242, 1130, 1111.  1073, 1032, 1020.972cm-1; NMR peaks at 0.88, 0.7-3.0, 2.03, 3.15-4.3, 4.65, 5.13, 5.3- 5.82 3.    



   d) The product from step (c) (0.69 g) in 20 ml acetone is treated with 1.5 ml 2.67 M Jones reagent, which was added dropwise.  The mixture is stirred at about 25C for 0.5 hours, diluted with saturated NaCl solution and extracted with diethyl ether.  The ether extract is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to give 0.58 g of an oil.  The residue is chromatographed on silica gel, eluting with ethyl acetate (10-50%) - Skellysolve B to obtain 0.31 g of the acid compound, which have Rf values of 0.56 and 0.51 (TLC on silica gel in A -IX system); Infrared absorption bands at 2970, 1745, 1240, 1032 and 1020 cm-1; NMR peaks at 0.89, 0.7-3.1, 2.05, 3.15-4.4, 4.65, 5.19, 5.46, 9.06 3 shows. 



   e) The product from step (d) (0.31 g) is treated in 10 ml of benzene with 0.12 ml of pyridine and 0.02 g of copper (II) acetate monohydrate.  After stirring at about 25 ° C for 45 minutes in a dark place, the mixture is treated with 0.52 g of lead tetraacetate.  The mixture is stirred, first heated at about 25 ° C. for 45 minutes, then heated to 80 ° C. for 15 minutes and then left to stand at 80 ° C. for 10 minutes.  The mixture is cooled, diluted with saturated NaCl solution and extracted with ethyl acetate.  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 0.37 g of an oil. 



  The residue is chromatographed on silica gel, eluting with ethyl acetate (20-50%) - Skellysolve B to give 0.03 g of the methylene compound which has an Rf value of 0.61 [TLC on silica gel in ethyl acetate-Skellysolve B (1: 1)]; Infrared absorption bands at 2970, 1740, 1235, 1035 and 1020 cm- '; and NMR peaks at 0.90, 0.8-3.0, 2.07, 3.1-4.3, 4.67, 5.00, 5.27 and 5.43 3. 



   f) Finally, the title compound is obtained by saponification of the remaining acyl groups of the product from step (e) (0.03 g) by treatment in 2 ml of methanol with 0.02 g of potassium carbonate at about 25 ° C. for 45 minutes .  The reaction mixture is diluted with saturated NaCl solution and extracted with ethyl acetate.  The extract is washed with saturated NaCl solution, dried over sodium sulfate and concentrated in order to obtain 0.22 g of the title compound in the form of an oil, the Rf value of which is identical to that of the product from preparation 4 above. 



   Preparation 12 2-methylene-4z-hydroxy-3 3- [(3'S) -3 '-hydroxy-trans-l'- -octenyl] -cyclopentanol, 4,3'-bis-tetrahydropyranyl ether (Q, and R2 as defined in preparation 2). 



   a) The compound in which R, in the terminal position of the chain is acetyl and R8 on the ring is pivaloyl, is prepared in 2 stages.  The monoacetate is first prepared from the compound of preparation 1 1a (5.56 g), 50 ml of pyridine and 1.45 ml of acetic anhydride, stirred at 0 ° C. for 2 hours, then allowed to warm to about 20 ° C. in 16 hours.  The mixture is then diluted with saturated NaCl solution and extracted with ethyl acetate. 



  The organic phase is washed with 1N hydrochloric acid to pH 2 in the washing liquids, then with saturated NaCl solution, dried and concentrated to obtain 5.88 g of an oil.  The residue is chromatographed on silica gel, eluting with ethyl acetate (10-100%) - Skellysolve B to give 3.41 g of the monoacetate, which has an R value of 0.29 [TLC on silica gel in ethyl acetate Skellysolve B ( 1: 1)]; Infrared absorption bands at 3530, 2975, 2890, 1745, 1239, 1133, 1077, 1032, 1020 and 981 cm-1; and NMR peaks at 0.89, 0.9-2.8, 2.04, 3.1-4.38, 4.15, 4.72 and 5.53 show 3. 



   b) The product from step (a) above, which has a terminal acetyl group on the chain (3.41 g), is treated with 30 ml of pyridine and 1.74 ml of pivaloyl chloride at about 25 ° C. for 12 hours.  The reaction is continued with another 1.74 ml pivaloyl chloride at 40 "C for 3 hours and at 23" C for 16 hours.  The reaction is terminated with 4 ml of 85 percent lactic acid at 230C for one hour.  The mixture is diluted with saturated NaCl solution and extracted with ethyl acetate.  The extract is washed with 1N hydrochloric acid ice, sodium bicarbonate and saturated NaCl solution, dried over sodium sulfate and concentrated to give a compound which had an acetyl group at the end of the chain and a pivaloyl residue on the ring.  

  3.84 g are obtained, which has an Rf value of 0.59 [TLC on silica gel in ethyl acetate Skellysolve B (1: 1)]; Infrared absorption bands at 2980, 2890, 1745, 1755, 1280, 1160, 1032 and 1020 cm- '; and NMR peaks at 0.87, 1.19, 1.98, 4.03, 4.67, 5.10 and 5.52 3. 



   c) The product from step (b) above (3.84 g) is treated in 100 ml of anhydrous methanol with 0.09 g of potassium carbonate at about 25 ° C. for 0.5 hours and at 40 ° C. for 1.5 hours.  The reaction is continued with a further 0.09 g of potassium carbonate at 40 ° C. for 2 hours and at 24 ° C. for 16 hours.  The mixture is concentrated, and then diluted with saturated NaCl solution and extracted with ethyl acetate.  The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and concentrated to obtain the product in which R3 is pivaloyl and R2 is THP. 

  3.42 g are obtained, with an Rf value of 0.34 [TLC on silica gel in ethyl acetate-Skellylsolve B (1: 1)]. 



   d) The product from step (c) above (3.42 g) is oxidized to the acid in 75 ml of acetone at OOC with 6.54 ml of 2.67 m Jones reagent.  The reaction is terminated in one hour with 2 ml of isopropyl alcohol, with stirring at 0 ° C. for 15 minutes.  The mixture is concentrated, diluted with saturated NaCl solution and extracted with ethyl acetate.  The extract is washed with water and saturated NaCl solution, dried over sodium sulfate and concentrated to give 3.44 g of an oil. 

  The residue is chromatographed on silica gel, eluting with ethyl acetate (20-40Sc) -Skellysolve B to give 1.99 g of the acid in the form of an oil, the Rf values are 0.69 and 0.74 (TLC on Silica gel in the A-IX system); and NMR peaks are found at 0.88, 1.18, 0.8-3.0, 3.1-4.3, 4.67, 5.16, 5.48 and 10.54 3.    



   e) The product from step (d) above is subjected to an oxidative decarboxylation, so that the compound of formula XXVI is formed.  The acid (1.99 g) in 35 ml of benzene is treated with 0.18 g of copper (I) acetate monohydrate and 1.11 ml of pyridine at about 250C for one hour.  Lead tetraacetate (4.80 g) is added and stirring continued in a dark place at about 25 for one hour, then to 80 ° C in 10 minutes and at 80 ° C for 25 minutes.  The mixture is cooled, diluted with saturated NaCl solution and extracted with ethyl acetate.  The extract is washed with saturated NaCl solution, dried with sodium sulfate and concentrated to obtain 2.11 g of an oil. 

  The residue is purified by chromatography on silica gel, eluting with ethyl acetate (5-40%) - Skellysolve B to give the methylene compound of formula XXVI, where R, pivaloyl and R, THP.  0.15 g of an oil are obtained, an Rf value of 0.43 [TLC on silica gel in ethyl acetate-Skellysolve B (1: 3) 1 and NMR peaks at 0.88, 0.8-2.9 , 1.18, 3.0-4.4, 4.72, 5.00, 5.22, 5.45 3 can be found. 



   f) Finally, the title compound is obtained by saponification of the product from step (e) above, using an excess of sodium hydroxide in aqueous methanol at about 25 ° C. until the thin layer chromatogram indicates the conversion.  This is followed by the usual working up with saturated NaCl solution, extraction, washing and concentration, giving the title compound which has the same properties as the product from preparation 4 above. 



   If you follow the procedures of preparations 2-5, 11 and 12, but instead of the starting material 3a5z-dihydroxy-23- - [(3'S) -3'-hydroxy-trans-1 '-octenyl] -l a-cyclopentane acetic acid, bistrahydropyranyl ether If any other lactone is used, which are compiled in the list in preparation 10, the corresponding enone compounds are obtained which have substituted side chains. 



   Preparation 13
31 (t-butyldimethylsilyloxy) phenyl lithium cuprate
reagent
I.  First l-bromo-3- (t-butyl-dimethylsilyloxy) benzene is produced:
EMI16. 1

A solution of m-bromophenol (10.0 g) in 40 ml of dimethylformamide is treated with t-butyldimethylchlorosilane (17.42 g) and imidazole (15.74 g) at 23 ° C. for 16 hours.  The mixture is diluted with saturated NaCl solution and extracted with Skellysolve B-dichloromethane (3: 1).  The extracts are washed with saturated NaCl solution, dried over sodium sulfate and concentrated to give 29.09 g of an oil.  The oil is distilled to give the desired 1-bromo-3- (t-butyldimethylsilyloxy) benzene.  Yield 13.47 g, boiling point 66OC (0.28 mm). 



   II.  A solution of the above bromine compound (4.40 g) in 75 ml of diethyl ether is treated at -78 ° C. with butyllithium (12.14 ml of a 1.26 m solution in pentane) and stirred for 40 minutes.  The resulting solution of the aryllithium compound is added to the Cu (I) tri-n-butylphosphine complex, which independently of copper (I) iodide (1.55 g) and tri (n-butyl) phosphine (1.55 g ) in 50 ml of diethyl ether at 250C for 45 minutes. 



   The resulting lithium cuprate reagent is used directly without isolation. 



   Preparation 14
2a- [m- (t-Butyldimethylsilyloxy) benzyl] -4a-hydroxy-3 3- - [(3'S) -3'-hydroxy-trans-1-octenyl] cyclopentanone, 4,3 '
Bistrahydropyranyl ether (Formula XXVII: Ql, R2 and
Si (A) as defined in preparation 2). 



   Compare scheme, level (a). 



   A solution of the enone compound from preparation 5 (2.49 g) in 30 ml of diethyl ether at -78 "C is added to a solution of the lithium cuprate reagent (preparation 12) at -78" C for 15 minutes with vigorous stirring and then stirred for 30 minutes.  The reaction mixture is added to a mixture of 25 ml of acetic acid in 225 ml of diethyl ether at -780C with vigorous stirring.  The resulting solution is warmed to about 25 "C, washed with saturated NaCl solution and aqueous sodium bicarbonate and concentrated to give 8.9 g of an oil.  

  The oil is purified by chromatography on silica gel, eluting with ethyl acetate (10-40%) - Skellysolve B to give 3.36 g of the title compound of formula XXVII in the form of an oil, the NMR peaks at 0.18, 0.90, 0.98, 0.6-3.1, 3.2-4.4, 4.68, 5.50 and 6.52-7.42 b; Infrared absorption bands at 2970, 2890, 1750, 1612, 1583, 1485, 1470, 1440, 1272, 1258, 1200, 1160, 1132, 1129, 1112, 1080, 1037, 1020, 976 and 784cm-1; and Rf values of 0.29 and 0, 34 showed [TLC on silica gel in ethyl acetate Skellysolve B (1: 3)].   



   Example 1 2a - [3 - (t-Butyldimethylsilyloxy) benzyl] -4a-hydroxy-3 ss- - [(3 'S) -3' -hydroxy-trans-1 -octenyl] cyclopentanol, 4,3 '
Bistrahydropyranyl ether (formula XXVIII: Q ,, R2 and
Sl (A) 3 as defined in preparation 2). 



   Compare scheme, level (b). 



   A solution of the ketone of formula XXVII (preparation 13, 3.2 g) in 30 ml of tetrahydrofuran is added dropwise to a mixture of lithium tri- (sec-butylborohydride) (8.2 ml of a 1 M solution in tetrahydrofuran) in 50 ml of tetrahydrofuran given at -78 "C and the mixture stirred at -78" C for 2 hours.  The reaction mixture is quenched with 5 ml of water and 2 ml of 30 percent hydrogen peroxide and heated to about 25 ° C. for one hour.  The mixture is diluted with 500 ml of saturated NaCl solution and extracted with ethyl acetate. 

  The extracts are washed with saturated NaCl solution, dried over magnesium sulfate and concentrated to provide the title compound of formula XXVIII in the form of an oil of 3.54 g, the RE value being 0.30 [TLC on silica gel in ethyl acetate] Skellysolve B (1: 3)]. 



   Example 2 3a-Hydroxy-5z-acetoxy-2 3- [(3'S) -3'-hydroxy-trans-1 - -octenyl-1 a- [3- (t-butyldimethylsilyloxy) benzyl] -cyclopentane, 3, 3'-bis-tetrahydropyranyl ether (formula XXIX:
R represents acetyl and Ql, R2 and Si (A) 3 are as in
Preparation 2 defined). 



   Compare scheme, level (c). 



   A solution of the hydroxy compound of the formula XXVIII (Example 1, 3.54 g) in 30 ml of pyridine is treated with 7 ml of acetic anhydride and 0.32 g of 4-dimethylaminopyridine at OOC and at 0 ° C. for one hour, finally at about 250 ° C. for 1 , Stirred for 75 hours.  The mixture is diluted with 400 ml saturated NaCl solution and extracted with ethyl acetate.  The extracts are washed with saturated NaCl solution, ice-cold 1N aqueous hydrochloric acid, aqueous sodium bicarbonate and saturated NaCl solution, dried over sodium sulfate and concentrated to give 3.49 g of the title compound of formula XXIX in the form of an oil, which has an Rr Value of 0.44 [TLC on silica gel in ethyl acetate-Skellysolve B (1: 3)]. 



   Example 3 3 a-Hydroxy-5a-acetoxy-2ss- [(3'S) -3 '-hydroxy-trans-1- -octenyl- 1 a- (m-hydroxybenzyl) -cyclopentane, 3, 3'-bis-tetrahydropyranyl- Ether (Formula XXX: Q ,, R2 and R5 as defined in Example 2). 



   Compare scheme, level (d). 



   A solution of the silyl derivative of the formula XXIX (Example 2, 3.49 g) in 15 ml of tetrahydrofuran is treated with 14.4 ml of 0.5 M tetra-n-butylammonium fluoride in tetrahydrofuran at about 25 ° C. for 1.5 hours.  The mixture is diluted with 200 ml saturated NaCl solution and extracted with ethyl acetate.  The extracts are washed with saturated aqueous sodium bicarbonate solution and saturated NaCl solution, dried over sodium sulfate and concentrated.  to get 3.71 g of the oil. 

  The oil is chromatographed on silica gel, eluting with ethyl acetate (25-55go) -Skellysolve B to give 2.25 g of the title compound of formula XXX in the form of an oil which has a RE value of 0.11 [DC Silica gel in ethyl acetate-Skellysolve B (1: 3)]; NMR peaks at 0.88, 2.06, 0.73.0, 3.10-4.37, 4.48-5.04, 5.56, 6.37-7.38 and 7.06 b ; and infrared absorption bands at 3390, 2960, 2885, 1737, 1715, 1590, 1446, 1368, 1237, 1100, 1152, 1128, 1073, 1020 and 972 cm-1. 



   Example 4 3-Oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGF1a, 9-acetate,
11,15-Bistrahydropyranyl ether, methyl ester (formula
XXXI: R1, means a methyl radical, and Q ,, R2 and R3 are as defined in preparation 2). 



   Compare scheme, level (e). 



   A mixture of the phenol of formula XXX (Example 3, 2.48 g) in 30 ml of 1,2-dimethoxyethane-methylbromoacetate (1.39 g) and 0.29 g of a 57 percent sodium hydride dispersion is at about 25 ° C. stirred for 2 hours.  The mixture is then treated with 2 ml of glacial acetic acid, diluted with saturated NaCl solution and extracted with ethyl acetate. 



  The extract is washed with saturated aqueous sodium bicarbonate solution and saturated NaCl solution, dried over magnesium sulfate and concentrated to obtain 3.20 g of the title compound of formula XXI in the form of an oil which has an Rf value of 0.48 in Acetone dichloromethane (15:85) shows. 



   Example 5 3-Oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGF1a, 11,15- -bistrahydropyranyl ether (formula XXXII: Q, and R2 as defined in preparation 2). 



   Compare scheme, level (f). 



   A mixture of the diester of the formula XXXI (Example 4, 2.45 g) in 100 ml of methanol and 30 ml of percent aqueous potassium hydroxide is heated under reflux for 5 hours, cooled, diluted with ice-cold saturated NaCl solution, with 1 m aqueous potassium hydrogen sulfate solution acidified to pH 3 and extracted with ethyl acetate.  The extracts were washed with saturated NaCl solution, dried over sodium sulfate and concentrated to give 2.46 g of the title compound of formula XXXII. 



   Example 6 3-Oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGEl, 11,15- -bistrahydropyranyl ether (formula XXXIII: Q1 and R2 as defined in preparation 2) and 3- Oxa-4,5,6-trinor-3,7- -inter-m-phenylene-PGE1 (Formula VI: Q means
EMI17. 1

Compare scheme, level (g). 



   A solution of the compound of the PGF type, of the formula XXXII (Example 5, 2.46 g) in 100 ml of acetone is cooled to -200C and treated with 1.76 ml of 2.67 m Jones reagent, at -20 to - 150C is stirred for 45 minutes.  The reaction mixture is quenched with 3 ml of isopropyl alcohol; stirring is continued for 10 minutes, diluted with saturated NaCl solution and extracted with ethyl acetate.  The extracts were washed with saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 2.17 g of the title compound of formula XXXIII. 

 

   II.  Level (h). 



   A solution of the above pyranyl ether (2.17 g) in 5 ml of tetrahydrofuran, 30 ml of acetic acid and 15 ml of water is stirred at 40 ° C. for 2.5 hours.  The reaction mixture is then diluted with 300 ml of water and freeze-dried to obtain a semi-solid residue containing the title compound.  The residue is chromatographed on silica gel, eluting with ethyl acetate (50-100%) - hexane to recover 0.77 g of the title compound of Formula VI.  Recrystallization from ethyl acetate-hexane gave colorless crystals, melting point 134.5-136.5 "C.    



   Example 7 3-Oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGFL, z, 9-acetate,
Methyl ester (formula XXXIV: Q means
EMI18. 1
 R stands for acetyl and R ,, for methyl); and 3-oxa -4,5,6-trinor-3, 7-inter-m-phenylene-PGF, n (formula VII: Q means
EMI18. 2nd

I.  Compare scheme, stage (i). 



   A mixture of the compound of formula XXXI (Example 4, 0.75 g) in 2 ml of tetrahydrofuran, 10 ml of acetic acid and 5 ml of water is stirred at 35 ° C. for 1.5 hours and at 250 ° C. for 2 hours.  The mixture is diluted with saturated NaCl solution and extracted with ethyl acetate.  The extract is washed with saturated aqueous sodium bicarbonate solution and saturated NaCl solution, dried over sodium sulfate and concentrated to obtain 0.60 g of the diester of formula XXXIV in the form of an oil. 



   II.  Stage (j). 



   A solution of the above diester (0.60 g) in 10 ml of methanol is treated with 5 ml of percent aqueous potassium hydroxide at 25 ° C. for 12 hours and then refluxed for 2 hours.  The mixture is cooled, washed with ice-cold saturated NaCl solution, acidified to pH 3 with 1 M aqueous potassium hydrogen sulfate and extracted with ethyl acetate.  The extracts are washed with saturated NaCl solution, dried over sodium sulfate and concentrated to a residue of 0.44 g.  The residue is chromatographed on silica gel, eluting with acetone (20-100%) dichloromethane to give 0.23 g of the title compound as a solid. 



  The product is recrystallized from ethyl acetate-hexane in order to obtain colorless crystals, melting point 100.1 108.3 ° C., Rr value 0.06 (TLC on silica gel in the A-IX system); NMR peaks at 0.88, 0.6-3.2, 3.97, 4.58, 4.64, 5.53 and 6.52-7.50 8; Infrared absorption bands at 3460, 3300, 2740, 2610, 2550, 1720, 1605, 1595, 1495, 1275, 1235, 1195, 1080, 1055, 1025, 975, 945 cm- '; [a] D -18 "(C 0.7145 in ethanol); and mass spectral ions at 665. 3512, 680, 609, 590, 575, 549, 519, 500, 443, 404, 353, 314, 237 and 217. 

 

   If one works according to the instructions of preparation 14 and examples 1-7, but the starting material 2-methyl-4a-hydroxy-3 P- [(3'S) -3'-hydroxy-trans-l 1 '-octenyl] cyclo pentanone is replaced by any of the enones according to preparation 12, each of the corresponding 3-oxa-4,5,6-tri nor-3,7-inter-m-phenyl-PGF ,, is obtained, - analogs which reflect the structural properties of the PGE1 analogs obtained according to preparation 10.  


    

Claims (3)

 PATENT CLAIMS 1. Process for the preparation of compounds of the formula EMI1.1  where Q EMI1.2  means in which R1 represents hydrogen or an alkyl radical of 1 to 4 carbon atoms and in which R13 represents EMI1.3  in which CgH2 is an alkylene radical of 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CRl4Rls- and the terminal methyl group, wherein R14 and R15 are hydrogen, an alkyl radical of 1 to 4 carbon atoms or fluorine mean, where these can be the same or different, provided that one of the radicals R14 and R15 is only fluorine if the other is hydrogen or fluorine, and under the further condition that neither R14 nor R15 represent fluorine if Z stands for oxa (-0-),  wherein Z represents an oxa atom (-0-) or CjH2j, wherein CjH2j is a valence bond or an alkylene radical of 1 to 9 carbon atoms with 1 to 6 carbon atoms between CR1zRls and the phenyl ring, and wherein the radical L is for one Alkyl radical of 1 to 4 carbon atoms, fluorine, chlorine, a trifluoromethyl group or OR16- and in which RIG is an alkyl radical of 1 to 4 carbon atoms and p is zero, 1 or 2 represents, provided that no more than two radicals L are different from alkyl, and if p is 2 or 3, the radicals L can either be the same or different, characterized in that one of a compound of the formula EMI1.4  where A is an alkyl radical of 1 to 4 carbon atoms, the phenyl radical, a phenyl radical substituted by one or 2 fluorine, chlorine or alkyl radicals of 1 to 4 carbon atoms,  is an aralkyl radical of 7 to 12 carbon atoms, where the A groups can be the same or different; where Q1 EMI1.5  means in which R1 is hydrogen or an alkyl radical of 1 to 4 carbon atoms and R2 is a protective group, and these are subjected to the following stages in succession:  a) Reduction of the starting compound of formula XXVII to form a compound of formula EMI1.6  wherein A, Q1, R2 and R13 are as defined above, b) acylation of the product from step a to form a compound of the formula EMI1.7  wherein A, Q1, R2 and R13 are as defined above, and wherein R3 is an acyl group of the formula EMI 1.8  represents, wherein R9 is hydrogen, an alkyl radical of 1 to 19 carbon atoms, an aryl radical or an aralkyl radical of 7 to 12 carbon atoms, wherein the Alkyl or aralkyl radicals can optionally be substituted with up to 3 ha halogen atoms,  c) Replacement of the -Si (A) 3 group in the product from stage b by hydrogen to form a compound of formula EMI1.9   wherein Q1, R2, R8 and R13 are as defined above; d) condensation of the product from stage c with a Halogen acetate of the formula Hal-CH2-COORII where Hal is chlorine, bromine or iodine, and R11 for Hydrogen, an alkyl radical from 1 to 12 carbon atoms, a cycloalkyl radical from 3 to 10 carbon atoms, an ar alkyl radical from 7 to 12 carbon atoms, the phenyl radical or one with 1, 2 or 3 chlorine or alkyl radicals from 1 to 4 carbon atoms are substituted phenyl, forming a compound of the formula EMI2.1  e) replacement of the protective group R2 in the product from stage d including the R2 groups of Q1 by hydrogen with mild,  acidic hydrolysis to form a compound of the formula EMI2.2  wherein Q, R8, R11 and R13 are as defined above, and f) replacement of the groups Ra and R11 in the product from stage e by hydrogen by basic hydrolysis.  2. The method according to claim 1, characterized in that the protective groups in the meaning of the substituent R2 are tetrahydropyranyl, tetrahydrofuranyl or 1-ethoxyethyl groups or a radical of the formula EMI2.3  mean in which R4 is an alkyl radical of 1 to 18 carbon atoms, a cycloalkyl radical of 3 to 10 carbon atoms, an aralkyl radical of 7 to 12 carbon atoms, the phenyl radical or one having 1, 2 or 3 alkyl radicals of 1 to 4 carbon atoms -Atoms are substituted phenyl radicals, in which R5 and R6 can be identical or different, these being hydrogen, an alkyl radical of I to 4 C atoms, the phenyl radical or one substituted by 1, 2 or 3 alkyl radicals by 1 to 4 C atoms Phenyl radical,  or if R5 and R6 are taken together, - (CH2) a- or - (CH2) bO- (CH2) C- where a is 3, 4 or 5, b is 1, 2 or 3 and c is 1, 2 or 3, provided that b plus c is 2, 3 or 4, and wherein R7 represents hydrogen or the phenyl radical.  3. Process for the preparation of compounds of the formula EMI2.4  where Q EMI2.5  means in which R1 represents hydrogen or an alkyl radical of 1 to 4 carbon atoms and in which R13 represents EMI2.6  in which CgH2g represents an alkylene radical of 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CRl4Rls- and the terminal methyl group, wherein 814 and R 1, hydrogen, an alkyl radical of 1 to 4 carbon atoms or Are fluorine, which may be the same or different, provided that one of the radicals R14 and R15 is fluorine only if the other is hydrogen or fluorine, and under the further condition that  that neither R14 nor R15 is fluorine if Z is oxa (-0-), where Z is an oxa atom (-0-) or CjH2j, where CjH2j is a valence bond or an alkylene radical of 1 to 9 carbon atoms with 1 to 6 carbon atoms between CR14Rls and the phenyl ring, and in which the radical L is an alkyl radical of 1 to 4 carbon atoms, fluorine, chlorine, a trifluoromethyl group or OR16- and in which R16 is an alkyl radical of 1 to 4 carbon atoms and p represents zero, 1 or 2, provided that no more than two L radicals are different from alkyl, and if p is 2 or 3, the L radicals can either be the same or different, characterized in that  that after steps a) - d) of the process of claim 1, a compound of the formula EMI3.1  produces in which R13 is defined above and the radicals R2, R3, R11 and Q1 have the meaning given in claim 1, and then carries out the following process steps:  e) Replacement of R8 and R11 in the product from stage d by Hydrogen by basic hydrolysis to form a compound of the formula EMI3.2  wherein Q1, R2 and R13 are as defined above; f) oxidation of the product from stage e to form a compound of the formula EMI3.3  wherein Q1, R2 and R13 are as defined above and g) replacement of the groups R2 in the product from step f including the R2 residue of Q1 by hydrogen by mild acid hydrolysis.  The invention relates to processes for the preparation of intermediates for the synthesis of prostaglandin analogs.  The compounds that can be produced according to the invention have the following formulas EMI3.4  where Q EMI3.5  means in which R1 represents hydrogen or an alkyl radical of 1 to 4 carbon atoms and in which R13 represents EMI3.6  in which CgH2g is an alkylene radical having 1 to 9 carbon atoms with 1 to 5 carbon atoms in the chain between -CR14Rl8- and the terminal methyl group, in which R14 and R15 are hydrogen, an alkyl radical of 1 to 4 carbon atoms or fluorine mean, where these can be the same or different, provided that one of the radicals R14 and R15 is only fluorine if the other is hydrogen or fluorine, and under the further condition that neither R14 nor R15 represent fluorine,  when Z is oxa (-0-), where Z is an oxa atom (-0-) or CjH2j, where CjH2j is a valence bond or an alkylene radical of 1 to 9 carbon atoms with 1 to 6 carbon atoms between CR14Rls and represents the phenyl ring, and in which the radical L represents an alkyl radical of 1 to 4 carbon atoms, fluorine, chlorine, a trifluoromethyl group or OR16- and in which R16 represents an alkyl radical of 1 to 4 carbon atoms and p represents zero, 1 or 2 , provided that no more than two L radicals are different from alkyl, and when p is 2 or 3, the L radicals can either be the same or different. ** WARNING ** End of CLMS field could overlap beginning of DESC **.