CA1313670C - Carbacyclin analogs - Google Patents

Abstract

3893-f ABSTRACT

The present specification provides novel analogs of carbacyclin (CBA2), 6a-carba-prostacyclin (6a-carba-PGI2), which have pronounced prostacyclin-like pharmacological activity, e.g., as platelet anti-aggregatory agents. Specifically the novel chemical analogs of CBA2 are those substituted by fluoro (C-5), alkyl (C-9), interphenylene (C-5), methano (C-6a,9), and an additional (olefinic) valence bond (C-6a,9). Further provided are benzindene analogs of CBA2 and sub-stituted forms thereof, i.e., 9-deoxy-2',9-methano (or 2',9-metheno)-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PCFI compounds. Also provided are a variety of novel chemical intermediates, e.g., substi-tuted bicyclo[3.3.0]octane intermediates, and chemical process utilizing such intermediates which are useful in the prepardtion of the novel CBA2 analogs.

Description

-1~ 1 3 I 7 ~' 7 0 3893-~
~ is a division of ~opending Canadian Patent Application Serial No. 368,710, fi].ed ~anuary 16, 1981.

BACKGROUND OF THE INVENTION
The present invention relates to novel compositions of matter and novel processes for preparing these compositions of matter~ Moreover, there are provided novel methods by which certain of these novel compositions of matter are employed for pharmacologically useful purposes. Further there are provided novel chemical intermediates for preparing these compositions of ma~ter.
The present invention is specifically concerned with novel ana-logs of prostacyclin or PGI2. Specifically, the present invention is concerned with analogs of carbacyclin modified at the C-5 or C-9 position, e.g., C-5 inter-phenylene analogs of carbacyclin, 5-fluoro analogs of carbacyclin, 9~-alkyl analogs of carbacyclin, C-6a,9 tri-cyclic ~cyclopropyl) analogs of carbacyclin, and combinations thereof as well as novel benzindene analogs thereof.
Prostacyclin is an endogenously produced compound in mammalian species, being structurally and biosynthetically related to the prostaglandins (PG's). In particular, prostacyclin exhibits the structure and carbon atom numbering of formuta I when the C-5,6 positions are unsaturated. For convenience, prostacyclin is often referred to simply as "PGI2". Carbacyclin, 6a-carba-PGI2, exhibits the structure and carbon atom numbering indicated in formula II when the C-5,6 positions are unsaturated. Likewise, for convenience, car-bacyclin is referred to simply as "CBA2".
A stable partially saturated derivative of PGI2 is PGII or5,6-dihydro-PGI2 when the C-5,6 positions are saturated, depicted with carbon atom numbering in formula II when the C-5,6 positions are saturated. The corresponding 5,6-dihydro-CBA2 is CBA1, depicted in formula II.
As is apparent from inspection of formulas I and II, prostacyclin and carbacyclin may be trivially named as derivatives of PGF-type compounds, e.g., PGF2a of formula III. Accordingly, prostacyclin is trivially named 9-deoxy-6,9~-epoxy-~5Z)-5,6-didehydro-PGF1 and carba-cyclin is named 9-deoxy-6,9~-methano-(5E)-5,6-didehydro-PGF1. For description of prostacyclin and its structural identification, see Johnson, et. al., Prostaglandins 12:915 (1976).
For convenience, the novel prostacyclin or carbacyclin analogs '~

J ~ 7 will be referred to by the trivial, art-recognized system of nomen-clature described by N.A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin deriva-tives herein will be named as 9-deoxy-PGFl-type compoùnds, PGI2 deri-vatives, or preferab1y as C3Al or CBA2 derivatives.
In the formulas herein, broken line attachments to a ring indi-cate substituents in the "alpha" (a) configuration, i.e., below the plane of said ring. Heavy solid line attachments to a ring indicate sùbstituents in the "beta" (~) configuration, i.e.~ above the plane of said ring. The use of wavy lines (~) herein will represent attachment of substituents in the alpha or beta configuration or attached in a mixture of alpha and beta configurations. Alternatively wavy lines will represent either an E or Z geometric isomeric configuration or the mixture thereof.
A side chain hydroxy at C-15 in the formulas herein is in the S
or R configuration as determined by the Cahn-Ingold Prelog sequence rules, J. Chem. Ed. 41:16 (1964). See also Nature 212:38 (1966) for discussion of the stereochemistry of the prostaglandins which dis-cussion applies to the novel prostacyclin or carbacyclin analogs herein. Molecules of prostacyclin and carbacyclin each have several centers of asymmetry and therefore can exist in optically inactive form or in either of two enantiomeric (optically active) forms, i.e.,the dextrorotatory and laveorotatory forms. As drawn, the formula for PGI2 corresponds t~o that endogenously produced in the mammalian species. In particular, refer to the stereochemical configuration at C-8 (~), C-9 (a), C-ll () and C-12 (~) of endogenously produced prostacyclin. The mirror image of the above formula for prostacyclin represents the other enantiomer. The racemic form of prostacyclin contains equal numbers of both enantiomeric molecules.
For convenience, reference to prostacyclin and carbacyclin will refer to the optica~lly active form thereof. Thus, with reference to prostacyclin, reference is made to the form thereof with the same absolute configuration as that obtained from the mammalian species.
The term "prostacyclin-type" product, as used herein, refers to any cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes for which prostacyclin is employed.
A formula as drawn herein which depicts a prostacyclin-type product or an intermediate useful in the preparation thereof, represents that particular stereoisomer of the prostacyclin-type product which is of the sdme relative stereochemical configuration as prostacyclin ob-tained from mammalian tissues or the particular stereoisomer of the intermediate which is useful in preparing the above stereo;somer of S the prostacyclin type product.
The term "prostacyc1in analog" or "carbacyclin analog" represents that stereoisomer of a prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or a mixture comprising stereoisomer and the enan-tiomers thereof. In particular, where a formula is used to depict aprostacyclin type product herein, the term "prostacyclin analog" or "carbacyclin analog" refers to the compound of that ~ormula or a mix-ture comprising that compound and the enantiomer thereof.
PRIOR ART__ Carbacyclin and closely related compounds are known in the art.
See Japanese Kokia 63,059 and 63,060, also abstracted respectively as Derwent Farmdoc CPI Numbers 48154B/26 and 48155B/26. See also British published specifications 2,012,265 and German Offenlungsschrift 2,900,352, abstracted as Derwent Farmdoc CPI Number 54825B/30. See also British published applications 2,0l7,699, 2,014,143 and 2,013,661.
The synthesis of carbacyclin and related compounds is also reported in the chemical literature, as follows: Morton, ~.R., et al., J. Organic Chemistry, 44:2880 (1979); Shibasaki, M., et al.
Tetrahedron Letters, 433-436 (1979); Kojima, K., et al., Tetrahedron Letters, 3743-3746 (1978); Nicolaou, K.C., et al., J. Chem. Soc., Chemical Communications, 1067-1068 (1978); Sugie, A., et al., Tetra-hedron Letters 2607-2610 (1979); Shibasaki, M.l Chemistry Letters, l299-l300 (l979), and Hayashi, M., Chem. Lett. 1437-40 (1979); and Li, Tsung-tee, "A Facile Synthesis of 9(0)-Methano-prostacyclin", Abstract No. 378, (Organic Ghemistry), and P. A. Aristoff, "Synthesis of 6a-Carbaprostacyclin I2", Abstract No. 236 (Organic Chemistry) both at Abstract of Papers (Part II) Second Congress of- the North American Continent, San Francisco, California (Las Vegas, Nevada), USA, 24-29 August 1980.
7-Oxo and 7-hydroxy-CBA2 compounds are apparently disclosed in United States Patent 4,192,891.
l9-Hydroxy-CBA2 compounds are also known. CBA2 7 0 3704/3803/3823/3833/387~/3893 aromatic esters are disclosed in United States Patent 4,180,657.11-Deoxy-~1- or ~l1-CBA2 compounds are described ;n Japanese Kokai 77/24,865, published 24 February 1979.
SUMMARY OF THE INVENTION
The present specification particularly provides:
(a) a carba~yclin intermediate of formula IV, V, VI, VII, YIII, or ~X; and (b) a carbacyclin analog of formula X or XI;
wherein g is 0, 1, 2, or 3;
wherein n is one or 2;
wherein Ll is ~-R3:B-R4, a-R4:~-R3, or a mixture of ~-R3:B-R4 and ~-R4:~-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of 23 and R4 is fluoro only when the other is hydrogen or fluoro;
wherein Ml is ~-OH:B-Rs or a-Rs:!3-OH, wherein Rs is hydrogen or methyl;
wherein M6 is a-ORlo:B-Rs or -Rs:~-OR1o, wherein Rs is hydrogen or methyl and Rlo is an acid hydrolyzable protective group;
wherein R7 is (1) -CmH2m-CH3, wherein m is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (Cl-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (Cl-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH=CH-CH2-CH3, (5) -(CH2)2-CH(OH)-CH3, or (6) -(CH2)3-CH=C(CH3)2;
wherein -C(L1)-R7 taken together is (1) (C4-C7)cycloalkyl optionally substituted by one to 3 (Cl-C5) alkyl, (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl;
wherein R3 is hydroxy, hydroxymethyl, or hydrogen;
wherein Rls is hydrogen or fluoro;
wherein R16 is hydrogen or R16 and Rl7 taken together are -CH2-S or Rl6 and R47 taken together form a second valence bond between C-6a and C-9 or are -CH2-;
wherein Rl7 is as defined above or is (1) hydrogen, or (2) (Cl-C4)alkyl;
wherein Rl8 is hydrogen, hydroxy, hydroxymethyl, -ORlo or -CH20Rlo, wherein Rlo is an acid-hydrolyzable protective group;
. wherein (1) R20, R2l, R22, R23, and R24 are all hydrogen with R22 being either -hydrogen or ~-hydrogen, (2) R20 is hydrogen, R2l and R22 taken together form a second valence bond betwen C-9 and C-6a, and R23 and R24 taken together form a second valence bond between C-8 and C-9 or are both hydrogen, or (3) R22, R23, and R24 are all hydrogen, with R22 being either a-hydrogen or ~-hydrogen, and (a) R20 and R2l taken together are oxo, or (b) R20 is hydrogen and R2l is hydroxy, being a-hydroxy or ~-hydroxy;
wherein R27 is the same as R7 except that -(CH2)2-CH(OH)-Cli3 is Z5 - (CH2) 2-C~ (OR~ H3;
wherein R32 is hydrogen or R3l, wherein R3l is a hydroxyl hydrogen replacing groupi wherein R33 is -CH0 or -CH20R32, wherein R32 is as defined above;
wherein R47 is as defined above or is (1) (Cl-C4)alkyl, or (2) -CH20~;
wherein Xl is (1) -COORl, wherein Rl is (a) hydrogen, (b) (Cl-Cl2)alkyl, (c) (C3-ClO)cycloalkyl (d) (C7-Cl2)aralkyl, - (e) phenyl, optionally substituted with one, 2 or 3 ~ ' 7 3704/3803l3823/3833/3879/3893 chloro or (Cl-C 3 ) alkyl, (f) phenyl substituted in the para position by ( i ) -NH-CO-R2s, ( i i ) -CO-R26 ~
(iii) -0-C0-Rs4, or (iv) -CH=N-NH-C0-NH2 wherein R2s is methyl, phenyl, acetamidophenyl, benzamidophenyl, or -NH2; R26 is methyl, phenyl, -NH2, or methoxy; and R54 is phenyl or acetamidophenyl;
inclusive, or - 10 (9) a pharmacologically acceptable cation;
(2) -CH20H, (3) -COL4, wherein L4 iS
(a) amino of the formula -NRslR52, wherein Rsl and Rs2 are (i) hydrogen, (ii) (Cl-Cl2)alkyl, (iii) (C3-ClO)cycloalkyl, (iv) (C7-CI2)aralkyl, (v~ phenyl, optionally substituted with one, 2 or .
3 chloro, (Cl-C3)alkyl, hydroxy, carboxy, (C2-Cs)alkoxycarbonyl, or nitro, (vi) (C2-Cs)carboxyalkyl, (vii) (C2-Cs)carbamoylalkyl, ( vi i i ) (C2-Cs ) cyanoal kyl, (ix) (C3-C6)acetylalkyl, - .
(x) (C7-Cll)benzoalkyl, optionally substituted by one, 2 or 3 chloro, (Cl C3)alkyl, hydroxy, (Cl-C3)alkoxy, carboxy, (C2-Cs)alkoxycarbonyl, or nitro, .
(xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (Cl-C3)alkyl, or (Cl-C3)alkoxy, (xii) (C6-Cg)pyridylalkyl optionally substituted by one, 2 or 3 chloro, (Cl-C3)alkyl, hydroxy, or (Cl-C3)alkoxy, (xiii) (Cl-C4)hydroxyalkyl, (xi v) (C l-C4)di hydroxyal kyl, (xv) (Cl-C4)trihydroxyalkyl, with the further proviso that not more than one of Rsl and Rs2 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of 3704/3~03/3823/3833/3879/3893 pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (Cl-Cl2)alkyl of one to 12 carbon atoms, inclusive, (c) carbonylamino of the formula -NR53CORsl, wherein R~3 is hydrogen or (Cl-C4)alkyl and Rsl is other than hydrogen, but otherwise as defined above, (d) sulfonylamino of the formula -NRs3S02Rsl, wherein R2l and R23 are as defined in (c), (4) -CH2NL2L3, wherein L2 and L3 are hydrogen or (Cl-C4)-alkyl, being the same or different, or the pharmacologically accept-able acid addition salts thereof when Xl is -CH2NL2L3, wherein Yl is trans-CH=CH-, cis-CH=CW-, -CH2CH2-, or -C-C-;
wherein Zl is (1) -CH2-(CH2)f-C(R2)2, wherein R2 is hydrogen or fluoro and f is zero, one, 2, or 3, (2) trans-CH2-CH=CH-, (3) -(Ph)-(CH2)9-, wherein (Ph) is 1,2-, 1,3-, or 1,4-pheny1ene and 9 is zero, one, 2, or 3;
wherein Z4 iS -CH2- or -(CH2)f-CF2, wherein f is as defined above;
with the overall proviso that (1) Rls, Rl6, and Rl7 are all hydrogen only when Zl is -(Ph)-(CH2)9-, and (2) Zl is -(Ph)-(CH2)9- only when Rls is hydrogen.
With regard to the divalent substitutents described above (e.g., Ll and Ml), these divalent radicals are defined as a-Rj:~-Rj, wherein Rj represents the substituent of the divalent moiety in the alpha configuration with respect to the plane of the C-8 to C-12 cyclo-pentane ring and Rj represents the substituent of the divalent moiety in the beta configuration with respect to the plane of the ring.
Accordingly, when ~l is defined as a-OH:~-Rs, the hydroxy of the Ml moiety is in the alpha configuration, i.e., as in PGI2 above, and the Rs substituent is in the beta configuration.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (Cj-Cj) indi-cates a moiety of the-integer "i" to the integer "j" carbon atoms, inclusive. Thus (Cl-C3)alkyl refers to alkyl of one to 3 carbon , - 1 3, , 3 3704/3~03/3823/3833/3879/3893 ~toms, inclusive, or methyl, ethyl, propyl, and isopropyl.
Certain novel prostacyclin analogs herein, i.e., formula X
compounds, are a11 named as CBAI or CBA2 compounds, respectively, by virtue of the substitution of methylene for oxa in the heterocyclic S ring of prostacyclin. CB~2 compour~ds are those exhibiting the olefinic double bond at C-5,6, while CBAl compounds are those saturated at C-5,6. Formula XI compounds are named dS PGEl or PGFI derivatives as hereinafter described.
Novel compounds wherein Zl is (Ph)~(CH2)g are designated inter-o-, inter-m-, or inter-p-phenylene depending on whether the attachment between C-5 and the ~(CH2)g~ moiety is ortho, meta, or para, respectively.
For those compounds wherein g is zero, one, 2 or 3, the carba-cyclin ana,logs so described are further characterized as ?,3,4-trinor~, 3,4-dinor-, or 4-nor, since in this event the Xl-terminated side chain contains (not including the phenylene) 2, 3, or 4 carbon atoms, respectively, in place of the five carbon atoms contained in PGI2. The missing carbon atom or atoms are considered to be at the C-4 to C-2 positions such that the phenylene is connected to the C-5 and C-l to C-3 positions. Accordingly these compounds are named as 1,5-, 2,5-, 3,5-, and 4,5-inter-phenylene-CBA compounds when g is zero, one, 2, or 3, respectively.
Those C8A analogs wherein Zl is -CH2-(CH2)f-CF2- are character-ized as "2,2-difluoro-" compounds. For those compounds wherein f is zero, 2, or 3, the carbacyclin analogs so described are further char-acterized as 2-nor, 2a-homo, or 2a,2b-dihomo, since in this event the Xl-terminated side chain contains 4, 6, or 7 carbon atoms, respec-tively, in place of the five carbon atoms contained in CBA2. The missing carbon atom is considered to be at the C-2 position such that the C-l carbon atom is connected to the C-3 position. The additional carbon atom or atoms are considered as though they were inserted between the C-2 and C-3 positions. Accordingly these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.
Those CBA analogs wherein Zl is trans-CH2-CH=CH- are described as "trans-2,3-didehydro-CBA" compounds.
Those novel compounds where n is 2 are further characterized as 7a-homo-CBA compounds by virtue of the cyclohexyl ring replacing the 1 3, J ) 7 ~ 37~4/3803/3823/3833/3879/3893 heterocyclic ring of prostacyclin.
Further, the novel compounds are named as 9~-alkyl-CBA compounds when Rl7 is alkyl.
When Rl6 and R17 taken together are -CH2-(methylene), the novel compounds so described are "6a~,9~-methano-CBA" compounds by virtue of the methylene bridge between C-6a and C-9.
When Rls is fluoro, "5-fluoro-CBA" compounds are described.
The formula XI CBA analogs wherein R20, R21, R22, R23, and R24 are all hydrogen with R22 being g-hydrogen are characterized as.
"9-deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl" compounds. Corresponding compounds wherein R22 is -hydrogen are characterized as "9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1" compounds. CBA analogs wherein R20, R23, and R24 are all hydrogen and R21 and R22 taken together form a valence bond between C-9 and C-6a are characterized as "9-deoxo-2',9-metheno-3-oxo-3,4,5-trinor-3,7-(1',3'-inter-phenylene)-PGFl" com-pounds. C3A analogs wherein R20 is hydrogen and R21 and R22 taken together form a second valence bond between C-9 and Ç-6d and R23 and R24 taken together form a $econd valence bond between C-7 and C-8 are characterized as "9-deoxo-2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1',3'-inter-phenylene)-7,8-didehydro-PGEl" compounds. The formula XI CBA
analogs wherein R22, R23, and R24 are all hydrogen and R20 and R2l taken together are oxo are characterized as "6a-oxo-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl" or "6a-oxo-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl" depending on whether R22 is a-hydrogen or ~-hydrogen, respectively. Formula XI CBA analogs wherein R20, R22, R23, and ~24 are all hydrogen and R21 is ~-hydroxy are characterized as "6a~-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl" or "6a~-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl" compounds depending on whether R22 is a-hydrogen or ~-hydrogen, respectively. Finally, formula XI C~A analogs wherein R20, R22, R23, and R24 are all hydrogen and R2l is g-hydroxy are characterized as "6a~-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1" or "6a~-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1" compounds depending on whether R22 is ~-hydrogen or B-hYdrosen~ respectively. When Z~ is -(CH2)f-CF2 and f is zero, the ~ J 1 J J 7 3704/3~03/3823/3833/3879/3893 formula XI CBA analogs are additionally characterized as "2,2-di-fluoro" compounds. When f is one, 2, or 3, such compounds are addi-tionally characterized as "2a-homo", "2a,2b-dihomo" ar "2a,2b,2c-trihomo" compounds.
S When R5 is methyl, the carbacyclin analogs are all named as "15-methyl-C8A" compounds. Further, except ~or compounds wherein YI
is cis-CH=CH-, compounds wherein the Ml moiety contains an hydroxyl in the beta configuration are additionally named as "15-epi-CBA" com-pounds.
For the compounds wherein Yl is cis-CH=CH-, then compounds wherein the Ml moiety contains an hydroxyl in the alpha configuration are named as "15-epi-C8A" compounds. For a description of this convention o~ nomenclature for identifying C-15 epimers, see U.S.
Patent 4,016,184, issued 5 April 1977, particularly columns 24-27 thereof.
The novel carbacyclin analogs herein which contain -(CH2)2-, cis-CH=C~-, or -C_C- as the Yl moiety, are accordingly referred to as "13,14-dihydro", "cis-13", or "13,14-didehydro" compounds, respec-tively.
When R7 is straight chained -CmH2m-CH3, wherein m is as defined above, the compounds so described are named as "19,20-dinor", "20-nor", "20-methyl" or "20-ethyl" compounds when m is one, Z, 4 or 5, respectively. When R7 is branched chain -CmH2m-CH3, then the compounds so described are "17-, 18-, 19-, or 20-alkyl" or "17,17-, 17,18-, -17,19-, 17,20-, 18,18-, 18,19-, 18,20-, 19,19-, or 19,20-dialkyl" compounds when m is 4 or 5 and the unbranched portion of the chain is at least n-butyl, e.g., 17,20-dimethyl" compounds are described when m is 5 (1-methylpentyl).
When R7 is phenyl and neither R3 nor R4 is methyl, the compounds so described are named as "16-phenyl-17,18,19,20-tetranor" compounds.
When R7 is substituted phenyl, the corresponding compounds are named as "16-(substituted phenyl)-17,18,19,20-tetranor" compounds. When one and only one of R3 and R4 is methyl or both R3 and R4 are methyl, thén the corresponding compounds wherein R7 is as de~ined in this paragraph are named as "16-phenyl or 16-(substituted phenyl)-18,19,20-trinor"
compounds or "16-methyl-16-phenyl- or 16-(substituted phenyl)-18,19,20-trinor" compounds respectively.
When R7 is benzyl, the compounds so described are named as "17-! ` 1 3 1 3 6 7 ~J
3704/3803/3~23~3833/3879/3~g3 phenyl-18,19,20 trinor" compounds. When R7 is substituted benzyl, khe corresponding compounds are named as "17-(substitlted phenyl)-18,19,Z0-trinor" compounds.
When R7 is phenylethyl, the compounds so described are named as "18-phenyl-19,20-dinor" compounds. When R7 is substituted phenyl-ethyl, the corresponding compounds are named as "18-(subskituted phenyl)-19,20-dinor" compounds.
When R7 is phenylpropyl, the compounds so descr~bed are named as "19-phenyl-20 nor" compounds~ When R7 is substituted phenylpropyl the corresponding compounds are named as "19-(substituted phenyl)-20-nor"
compounds.
When R7 is phenoxy and neither R3 nor R4 is methyl, the compourds so described are named as "16-phenoxy-17,18,19,20-tetranor" co~pounds.
When R7 is substituted phenoxy, the corresponding compounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R3 and R~ is methyl or both R3 and R4 are methyl, then the corresponding compounds wherein R7 is as defined in this paragraph are named as "16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds or "16-methy -16-phenoxy- or 16-(substl-tuted phenoxy)18,19,20-trinor" compounds, respectively.
When R7 is cis-CHaCH-CH2CH3, the compounds so described are named as "cis-17,18-didehydro" compounds.
When R7 is -(CH~)2-CH(OH)-CH3J the compounds so described are named as "19-hydroxy" compounds.
When R7 is -(CH2)3-CH-C(CH3)2, the compounds sa described are named as "20- sopropyl~dene" compounds.
When -C(Ll)-R7 is optionally substituted cycloalkyl, 2-(2-furyl3-ethyl, 2-(3-thienyl)ethyl~ or 3-thienyloxymethyl, the compounds so described are respectively 15-cycloalkyl-16,17~18,19720-pentanor com-pounds, 17-(2-furyl)-18,1~,20-trinor-CBA compounds, 17-~3-thienyl)-18,19,20-trinor com~ounds, or 16-(3-thienyl)oxy-17,18,1g,20-tetranor - ~ compounds.
When at least one of R3 and R4 is not hydrogen then (except For the 16-phenoxy or 16-phenyl compounds discussed above) there are described the "16-methyl" (one and only one of R3 and R4 is methyl), "16,16-dimethyl" (R3 and R4 are both methyl), "16-fluoro" (R3 or R4 is fluoro), "16,16-difluorb" (R3 and R4 are both fluoro) compounds~ For those compounds wherein R3 and R4 are different, the prostaglandin l 7~ l 7 S 7 i~ 3704/3803/3823/3833/3879/3893 analogs so represented contain an asymmetric carbon atom at C-16.
Accordingly, two epimeric configurations are possible: "(165)" and "(16R)". Further, there is described by this invention the C-16 epimeric mixture: "(16R~)".
S When Xl is -CH20H, the compounds so described are named as "2-decarboxy-2-hydroxymethyl" compounds.
When Xl is -C~NL2L3, the compounds so described are named as "2-decarboxy-2-aminomethyl" or "2-(substituted amino)methyl"
compounds.
When Xl is -COL4, the novel compounds herein are named as CBA-type amides. Further, when Xl is -COORl, the novel compounds herein are named as CBA-type esters and CBA-type salts.
Examples of phenyl esters substituted in the para position (i.e., Xl is -COORI, Rl is p-substituted phenyl) include p-acetamidophenyl ester, p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester, p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl ester, p-acetylphenyl ester, p-benzylphenyl ester, p-amidocarbonyl-phenyl ester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde semicarbazone ester.
Examples of novel amides herein (i.e., Xl is -COL4) include the following:
(1) Amides within the scope of alkylamino groups of the formula-NRslRs2 are methylamide, ethylamide, n-propylamide, n-butylamide, n-pentylamide, n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide, n-undecylamide, and n-dodecylamide, and isomeric forms thereof. Further examples are dimethylamide, diethylamide, di-n-propylamide, di-n-butylamide, methylethylamide, methylpropylamide, methylbutylamide, ethylpropylamide, ethylbutylamide, and propylbutyl-amide. Amides within the scope of cycloalkylamino are cyclopropyl-amide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentyl-amide, 2,2-dimethylcyclopentylamide, 2-methylcyclopentylamide, 3-tert-butylcyclopentyl amide, cyclohexylamide, 4-tert-butylcyclohexylamide, 3-isopropylcyclohexylamide, ?,2-dimethylcyclohexylamide, cycloheptyl-amide, cyclooctylamide, cyclononylamide, cyclodecylamide, N-methyl-N-cyclobutylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexyl-amide, N-ethyl-N-cyclopentylamide, and N-ethyl-Ncyclohexylamide.
Amides within the scope of aralkylamino are benzylamide, 2-phenyl-~ I ~ 7 0 ethylamide, and N-methyl-N benzyl-amide. Amides within the scope of substituted phenylamide are p-chloroanilide, m-chloroanilide, 2,4-dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitro-anilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimethoxy-anilide, p-hydroxymethylanilide, p-methylanilide, m-methyl anilide, - p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonyl anilide, p-carboxyanilide and o-hydroxyanilide. Amides with;n the scope o~ carboxyalkylamino are carboxyethylamide, carboxypropylamide and carboxymethylamide, carboxybutylamide. Amides within the scope of carbamoylalkylamino are carbamoylmethylamide, carbamoylethylamide, carbamoylpropylamide, and carbamoylbutylamide. Amides within the scope of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyano-propylamide, and cyanobutylamide. Amides within the scope of acetyl-alkylamino are acetylmethylamide, acetylethylamide, acetylpropylamide, and acetylbutylamide. Amides within the scope of benzoylalkylamino are benzoylmethylamide, benzoylethylamide, benzoylpropylamide, and benzoylbutylamide. Amides within the scope of substituted benzoyl-alkylamino are p-chlorobenzoylmethylamide, m-chlorobenzoylmethylamide, 2,4-dichlorobenzoylmethylamide, 2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxy-benzoylmethylamide, 2,4-dimethoxy benzoylmethylamide, 3,4,5-tri-methoxybenzoylmethylamide, p-hydroxymethylbenzoylmethylamide, p-methylbenzoylmethylamide, m-methylbenzoylmethylamide, p-eth~vlbenzoyl-methylamide, t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide, m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethylamide, o-hydroxybenzoylmethylamide, p-chlorobenzoylethylamide, m-chloro-benzoylethylamide, 2,4-dichlorobenzoylethylamide, 2,4,6-trichloro-benzoylethylamide, m-nitrobenzoylethylamide, p-nitrobenzoylethylamide, p-methoxybenzoylethylamide, p-methoxybenzoylethylamide, 2,4-dimethoxy-benzoylethylamide, 3,4,5trimethoxybenzoylethylamide, p-hydroxymethyl-benzoylethylamide, p-methylbenzoylethylamide, m-methylbenzoylethyl-amide, p-ethylbenzoylethylamide, t-butylbenzoylethylamide, p-carboxy-benzoylethylamide, m-methoxycarbonylbenzoylethylamide, o-carboxy-benzoylethylamide, o-hydroxybenzoylethylamide, p-chlorobenzoylpropyl-amide, m-chlorobenzoylpropylamide, 2,4-dichlorobenzoylpropylamide, 2,4,6-trichlorobenzoylpropylamide, m-nitrobenzoylpropylamide, p-nitrobenzoylpropylamide, p-methoxybenzoylpropylamide, 2,4-dimeth-oxybenzoylpropylamide, 3,4,5-trimethoxybenzoylpropylamide, p-' )' 3704/3803/3823/3833/3879/3893-14-hydroxymethylbenzoyl propylamide, p-methyl benzoyl propylamide, m-methyl-benzoyl propy1amide, p-ethylbenzoyl propylamide, t-butylbenzoyl propyl-amide, p-carboxybenzoyl propylamide, m-methoxycarbonylbenzoyl propyl-amide, o-carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide, 5 p-chl orobenzoylbutylamide, m-chl orobenzoyl butylamide, 2,4-dichl oro-benzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide, m-nitrobenzoyl-methylamide, p-nitrobenzoyl butylamide, p-methoxybenzoylbutyl amide, 2,4-dimethoxybenzoylbutyl-amide, 3,4,5-trimethoxybenzoylbutylamide, p~hydroxymethylbenzoylbutyl-amide, p-methylbenzoyl butyamide, m-methyl-10 benzoylbutylamide, p-ethyl-benzoylbutyalmide, m-methylbenzoylbutyl-amide, p-ethylbenzoyl butyl-amide, t-butyl benzoylbutylamide, p-carboxy-benzoylbutylamide, m-methoxycarbonylbenzoylbutylamide, o-carboxyben-zoylbutylamide, o-hydroxybenzoylmethylamide. Amides within the scope of pyridylamino are a-pyridylamjde, ~-pyridylamide, and y-pyridyl-15 amide. Amides within the scope of substituted pyridylamino are4-methyl--pyridylamide, 4-methyl-~-pyridylamide, 4-chloro-a-pyridylamide, and 4-chloro-~-pyridylamide. Amides within the scope of pyridylalkylamino are a-pyridylmethylamide, ~-pyridylmethylamide, Y-pyridyl met hyl amide, a-pyridyl ethyl amide, B-pyridyl ethyl amide, 20 y-pyridylethylamide, a-pyridyl propylamide, ~-pyridyl propylamide, y-pyridyl propylamide, a-pyridylbutylamide, ~-pyridyl butylamide, and y-pyridylbutylamide. Amides within the scope of substituted pyridyl-alkylamido are 4-methyl-a-pyridylmethylamide, 4-methyl-~-pyridyl-methylamide, 4-chloro-a-pyridylmethylamide, 4-chloro-~-pyridylmethyl-25 amide, 4-methyl-a-pyridyl propyl amide, 4-methyl-~-pyridyl propyl amide, 4-chloro-a-pyridylpropylamide, 4-chloro-~-pyridylpropylamide, ~-methyl-c~-pyridylbutylamide, 4-methyl-~-pyridylbutyl amide, 4-chl oro-a-pyridylbutylamide, 4-chloro-~-pyridylbutylamide, 4-chloro-y-pyridylbutyl-anlide. Amides within the scope of hydroxyalkylamino are 30 hydroxymethylamide, ~-hydroxyethylamide, ~-hydroxypropylamide, y-hydroxypropyldmide~ l-(hydroxymethyl)ethyl-amide, 1-(hydroxymethyl)-propylamide, (2-hydroxymethyl)propylamide, and ,,-dimethyl-hydroxy-ethylamide. Amides within the scope of dihydroxyalkylamino are dihy-droxymethylamide, ~,y-dihydroxypropylamide, l-~hydroxymethyl)2-35 hydroxymethylamide, ~,y-dihydroxybutyl~mide, ~,~-dihydroxybutyl-amide, Y,~-dihydroxybutylamide, and 1,1-bis(hydroxymethyl)ethylamide. Amides within the scope of trihydroxyalkylamino are tris(hydroxy-methyl)-methylamide and 1,3-dihydroxy-2-hydroxymethyl propylamide.

31 7~,70 (2) Amides within the scope of cycloamino groups described above are pyrrolidylamide, piperidylamide, morpholinylamide, hexamethylene-iminylamide, piperazinylamide, pyrrolinylamide, and 3,4-didehydro-piperidinylamide.
(3) Amides within the scope of carbonylamino of the formula -NRs3CORsl are methylcarbonylamide, ethylcarbonylamide, phenylcar-bonylamide, and benzylcarbonylamide.
(4) Amides within the scope of sulfonylamino of the formula -NRs3SU2Rsl are methyl sul fGnylamide, ethylsufonylamide, phenylsul-10 fonylamide, p-tolylsul fonylamide, benzylsul fonylamide.
Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, actyl, nonyl, decyl, undecyl, dodecyl, isomeric forms thereof.
Examples of (C3-ClO)cycloalkyl which includes alkyl-substituted 15 cycl oalkyl, are cyclopropyl, 2-methylcycl o-propyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclo-propyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-tri-ethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclo-pentyl, 3-tert-butylcyclopentyl, cycl ohexyl, 4-tert-butyl cyclohexyl, 20 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclo-octyl, cyclononyl, and cycl odecyl.
Examples of (C7-Cl2)aralkyl are benzyl, 2-phenylethyl, 1-phenylethyl, 2-phenyl propyl, 4-phenylbutyl, 3-phenylhutyl, 2-(1-naphthylethyl), and 1-(2-naphthylmethyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclsive, are p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethyl phenyl, p-tert-butyl phenyl, 2,5-dimethyl phenyl, 4-chl oro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.
Exampl es of (Cs-C7)cycl oal kyl optionally substituted by (Cl-Clt)-alkyl dre cyclobutyl, 1- propylcyclobutyl, l-butylcyclobutyl, 1- pentyl-cyclobutyl, 2-methylcyclobutyl, 2-propylcycl obutyl, 3-ethyl cycl obutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-di-methyl cycl opentyl, 3-ethylcycl opentyl, 3-propylcyc1opentyl, 3-butyl-35 cyclopentyl, 3-tert-butylcyclopentyl, 1-methyl-3- propylcyclopentyl, 2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclo-hexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyc7 0hexyl, 4-propylcycl ohexyl, 4-butylcyclohexyl, 4-tert-7~ 7~ 3704/3803/3823/3833/3879/38g3 butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, 2,6-dimethyl-4-propylcyclohexyl, and cycloheptyl~
Examples of substituted phenoxy, phenylmethyl, phenylethyl, or phenylpropyl of the R7 moiety are (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, or p-)-propylphenyl, 2-propyl-(m- or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethyl-phenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(m- or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-,m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (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-)dichloro-phenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoromethylphenyl, (o-, m-, or p-)methoxyphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, 2,4-dichloro-(4- or 6-)methylphenyl, (o-, m-, or p-)tolyloxy, (o-, m-, or p-)ethylphenyloxy, 4-ethyl-o-tolyloxy, 5-ethyl-m-tolyloxy, (o-, m-, or p-)propylphenoxy, 2-propyl-(m- or p-)tolyloxy, 4-isopropyl-2,6-xylyl-oxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)-trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 2-fluoro-(m- or p-)-tolyloxy, 4-fluoro-2,5-xylyloxy, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)-difluorophenoxy, (o-, m-, or p-)-chlorophenoxy, 2-chloro-p-tolyloxy, (3, 4, 5, or 6-)chloro-o-tolyloxy, 4-chloro-2-propylphenoxy, 2-iso-propyl-4-chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyloxy, 4-chloro-3-fluorophenoxy, (3-or 4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoromethylphenoxy, (o-, m-, or p-)methoxyphenoxy, (o-, m-, or p-)ethoxyphenoxy, (4- or 5-)chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6-)methylphenoxy, (o-, m-, or p-)tolylmethyl, (o-, m-, or p-)ethylphenyl methyl, 4-ethyl-o-tolylmethyl, 5-ethyl-m-tolylmethyl, (o-, m-, or p-)propylphenylmethyl, 2-propyl-(m- or p-)tolylmethyl, 4-isopropyl-2,6-xylylmethyl, 3-propyl-4-ethylphenylmethyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)tri-methylphenylmethyl, (o-, m-, or p-)fluorophenylmethyl, 2-fluoro-(m- or p-)tolylmethyl, 4-fluoro-2,5-xylylmethyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-, m-, or p-)chlorophenylmethyl, 2-chloro-p-tolylmethyl, (3, 4, 5, or 6-)chloro-o-tolylmethyl, 4-chloro-2-propyl-phenylmethyl, 2-isopr.opyl-4-chlorophenylmethyl, 4-chloro-3,5-xylyl-methyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylmethyl, l l..j,, O

4-chloro-3^fluorophenylmethyl, (3- or 4-)chloro-2-fluorophenylmethyl, (o-, m-, or p-)trifluoromethylphenylmethyl, (o-, m-, or p-)methoxy-phenylmethyl, (o-, m-, or p-)ethoxyphenylmethyl, (4- or 5-)chloro-2-methoxyphenylmethyl, and 2,4-dichloro-(4- or 6-)methoxyphenylmethyl.
The novel CBA analogs disclosed herein produce certain prostacyclin-like pharmacological responses.
Accordingly, the novel formula X and XI CBA analogs are used as agents in the studyg prevention, control, and treatment of diseases, and other undesirable physiological conditions, in mammals, particularly humans, valuable domestic animals, pe~s, zoological specimens, and laboratory animals (e.g., mice, rats, rabbits and monkeys). In particular, these compounds have useful application as antithrombotic agents, anti-ulcer agents, and anti-asthma agents, as indicated below.
(a) Platelet Aggregation Inhibition These novel CBA analogs disclosed herein are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, or to remove or prevent the formation of thrombi in mammals, including man. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, to treat peripheral vascular diseases, and to treat conditions such as atherosclerosis, 3rterio-sclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with 1ipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long term prophylaxis following myocardial infarcts and strokes. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.01 to about 10 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
The preferred dosage form for these compounds is oral, although other non-parenteral routes (e.g., buccal, rectal~ sublingual) are ~ 3, 7 0 3704/38g3/3823/3833/3879/38g3 likewise employed in preference to parenteral routes. Oral dosage forms are conventionally formulated (tablets, capsules, et cetera) and administered 2-4 times daily. Doses in the range of about 0.05 to 100 mg per kg of body weight per day are effective.
S The addition of these compounds to whole blood provides in vitro applications such as storage of whole blood to be used in heart-lung machines. Additionally whole blood containing these compounds can be circulated through organs, e.g., heart and kidneys, which have been removed from a donor prior to transplant. They are also useful in preparing platelet rich concentrates for use in treating thrombo-cytopenia, chemotherapy, and radiation therapy. In vitro applications utilize a dose of OoOOl~l~O ~9 per ml of whole blood. For treatment of peripheral vascular diseases, see U.S. Patent 4,103,026.
(b) Gastric Secretion Reduction These novel CBA analogs disclosed herein are also useful in mam-mals, including man and certain useful animals, e.g., dogs and pigs~
to reduce and control gastric secretion, thereby to reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this pur-pose, these co~pounds are injected or infused intravenously, subcuta-neously, or intramuscularly in an infusion dose range about 0.1 ~9 to about 20 ~9 per kg of body weight per minute, or in a tota~ daily dose by injection or infusion in the range about 0.01 to about 10 mg per kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
Preferably, however, these novel compounds are administered orally or by other non-parenteral routes. As employed ora11y, one to 6 administrations daily in a dosage range of about l.O to 100 mg per kg of body weight per day is employed. Once healing of the ulcers has been accomplished the maintenance dosage required to prevent recur-rence is adjusted downward so long as the patient or animals remains asymptomatic.
(c) NOSAC-Induced Lesion Inhibition These novel CBA analogs disclosed herein are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are useful for that purpose by concomitant adminis-~ l 3 1, 7 ,~ 3704/3803/3823/3833/3879/3893 tration of the prostaglandin derivative and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge, et al., IJ.S.
Patent No~ 3,781,429, for d disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglan-dins~ Accordingly these novel CBA analogs herein are useful, for example, in reducing the undesirable gastrointestinal effects result-ing from systemic administration of indomethacin, phenylbutazone, and aspirin*. These are substances specifically mentioned in Partridge, et al. as non-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhibitor, for example, indome-thacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory conditions, for example, in any dosage regimen and by any of the known routes of systemic administration.
(d) Bronchodilation (Anti-asthma) These novel analogs disclosed herein are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediator-induced bronchocbn-striction, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial bronchitis, bronchiectasis, pneumonia and emphysema. For thes~ pur-poses, these compounds are administered in a variety of dosage forms,e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories, parenterally, subcutaneously, or intra-muscularly, with intravenous administration being preferred in emer-gency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.01 to 5 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condi-tion of the patient and on the frequency and route of administration.
For the above use these C8A analogs can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isopro-terenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theo-phylline and aminophylline); and corticosteroids (ACTH and predniso-lone).

*trade mark 1 31 7~ ~7 ~J

These compounds are effectively administered to human asthmapatients by oral inhalation or by aerosol inhalation. For adminis-tration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant 5 active ingredient in dil ute solution, preferably at concentrations of about one part of medicament to from about 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bisulfite, and 10 the like can be employed. For adminis~ration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) togèther 15 with a co-solvent, such as ethanol, flavoring materials and stabili-zers. Suitable means to employ the aerosol inhalation therapy tech-ni4ue are described fully in United States Patent 3,868,691, for example.
When Xl is -COORl, the novel CBA analogs so described are used 20 for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable salt form. IAlhen the ester form is used, the ester is any of those within the above definition of Rl.
However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are espec-25 ially preferred for optimum absorption of the compound by the body orexperimental animal system; and straight-chain octyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.
Pharmacologically acceptable salts of ~he novel prostaglandin analogs of this invention for the purposes described above are those 30 with pharmacologically acceptable metal cations, ammonia, amine cations, or quaterna~ry ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic 35 forms of other metals, e.g., aluminum, zinc, and iron a~e within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Examples of suitable amines ~ J, ~ iJ 3704/3803/3823/3833/3879/3~93 are methylamine, dimethylamine, trimethylamine, ethylamine, dibutyl-amine, triisopropylamine, N-methylhexylamine, decylamine, dodecyl-amine, allylamine, crotylamine, cyclopentylaminel dicyclohexylamine, benzylamine, dibenzylamine, ~-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, adamantylamine, and the like aliphatic, cycloaliphatic, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereto, e.g., 1-methylpiperidine, 4-ethylmorpholine, 1 isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanol-amine, ethyldiethanolamine, N-butylethanolamine, 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-amyl-phenyl)-diethanolamine, galactamine, N-methylglycamine, N-methyl-glucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like. Further useful amine salts of the basic amino acid salts, e.g., lysine and arginine.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyl-trimethylammonium, phenyltriethylammonium, and the like.
When Xl is -CH2NLzL3, the novel C8A analogs so described are used for the purposes described in either free base or pharmacologically 25 acceptable acid addition salt form. ~
The acid addition salts of the 2-decarboxy-2-aminomethyl- or 2-(substituted aminomethyl)-C8A analogs provided by this invention are the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, - cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzene-sulfonates, toluenesulfonates and the like, prepared by reacting the CBA analog with the stoichiometric amount of the acid corresponding to the pharmacologically acceptable acid addition salt.
To obtain the optimum combination of biological response specifi-city, potency, and duration of activity, certain compounds within the scope of this invention are preferred.
It is preferred that in the Xl-terminated side chain for inter-p-phenylene-CBA compounds, g be zero, for inter-m-phenylene-CBA -com-pounds g be zero or one (especially zero), and for inter-o-phenylene 1 7 ~ 7 ~ 7m J
3704/3803/3823t3833/387gt3893 C8A compounds g be zero, one, or 2 (especially one). Inter-o- and inter-m-phenylene-CBA compounds, especially inter-m-phenylene-C~A
compounds are preferred. Moreover when Zl is -CH2-(CH2)f-C(R2)2, f is preferably one and R2 is preferably hydrogen. ~hen Rl7 is (Cl-C4)-alkyl, Rl7 is preferably methyl. Further, when the C-12 side chain contains -CmH2m-CH3, it is preferred that m be 3, 4, or 5, most preferably 3. When m is 5, more straight chain iso~neric forms are preferred, especially methyl-substituted butyl. Further, it is pre-ferred that, when R7 is aromatic, R7 be phenoxy, phenyl, or benzyl, including substituted forms thereof. For those compounds wherein R7 is substituted phenoxy or phenylalkyl, it is preferred there be only one or 2 substituents selected from the group consisting of chloro, fluoro, or trifluoromethyl. Further, for those compounds wherein R7 is aromatic, it is preferred that R3 and R4 both be hydrogen.
Most expecially pre~erred to biological potency are formula X
CBA2 analogs exhîbiting the same C-5 isomeric con~iguraton as C~A2 itself.
Especially preferred are those compounds which satisfy two or more of the above preferences. Further, the above preferences are expressly 7ntended to describe the preferred compounds within the scope of any generic formula of novel CBA analogs disclosed herein.
Those protective groups within the scope of Rlo are any group which replaces a hydroxy hydrogen and is neither attacked by nnr is reactive to the reagents used in the transformations used herein as a hydroxy is and which is subsequently replaceable by acid hydrolysis with hydrogen in the preparation of the prostaglandin-type compounds.
Several such protective groups are known in the art, e.g., tetra-hydropyranyl and substituted tetrahydropyranyl. See for reFerence E.J. Corey, Proceedings of the Robert A. ~elch Foundation Conferences on Chemical Research, XII Organic Synthesis, pgs. 51-79 (1969). Those blocking groups which have been found useful include:
(a) tetrahydropyranyl;
(b) tetrahydrofuranyl, -(c) a group of the formula -C(ORll)(Rl2)-CH(Rl3)(Rl4), wherein Rll is alkyl o~ one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclu-sive, phenyl or phenyl substituted with one to 3 alkyl of one to 4 carbon atoms, inclusive, wherein Rl2 and Rl3 are alkyl of one to 4 1 3 ~1 7` '~J 7 ~704/3~03/3823/3833/3879/3893 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3alkyl of one to ~ carbon atoms, inclusive, or when R12 and R13 are taken together -(CH2)a- or when R12 are R13 are taken together -(CH2)b-0-(cH2)c, wherein a is 3, 4, or 5 and b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4, with the further proviso that R12 and R13 may be the same or different, and wherein Rl4 is hydrogen or phenyl; and (d) silyl groups according to R28, as qualified hereinafter.
When the protective group R1o is tetrahydropyranyl, the tetra-hydropyranyl ether derivative of any hydroxy moieties of the C8A-type intermediates herein is obtained by reaction of the hydroxy-containing compound with 2,3-dihydropyran in an inert solvent, e.g., dichloro-methane, in the presence of an acid condensing agent such as p-tolu-enesulfonic acid or pyridine hydrochloride. The dihydropyran is used in large stoichiometric excess, preferably 4 to 100 times the stoich-iometric amount. The reaction is normally complete in less than an hour at 20-50C.
When the protective group is tetrahydrofuranyl, 2,3-dihydrofuran is used, as described in the preceding paragraph, in place of the 2,3-dihydropyran.
When the protective group is of the formula -C(ORll)(Rl2)-CH(Rl3)(Rl~), wherein Rll, Rl2, Rl3, and Rl4 are as defined above; a vinyl ether or an unsaturated cyclic or heterocyclic compound, e.g., 1-cyclohexen-1-yl methyl ether, or 5,6-dihydro-4-methoxy-2H-pyran is employed. See C.B. Reese, et al., J. American Chemical Society 89, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for dihydropyran above.
R28 is a silyl protective group of the formula -Si~Gl)3. ~n some cases, such silylations are general, in that they silylate all hydroxyls of a molecule, while in other cases they are selective, in that while one or more hydroxyls are silylated, at least one other hydroxyl remains unaffected. For any of these silylations, silyl groups within the scope of -Si(Gl)3 include trimethylsilyl, dimethyl-phenylsilyl, triphenylsilyl, t-butyldimethylsilyl, or methylphenyl-benzylsilyl. With regard to Gl, examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl, and the like.
Examples of aralkyl are benzyl, phenethyl, -phenylethyl, 3-phenyl-7~ ', 7 a 3704/3803/3823/3833/3879/3893 propyl, a-naphthylmethyl, and 2-(-naphthyl)ethyl. Examples of phenyl substituted with halo or alkyl are p-chlorophenyl, m-fluoro-phenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butyl phenyl, 4-chl oro-2-methyl phenyl, and 2,4-dichloro-3-methyl phenyl.
These silyl groups are known in the art. See for example, Pierce "Silylation of Organic Compounds," Pierce Chemical Company, Rockford, Ill. (1968). When silylated products of the charts below are intended to be subjected to chromatographic purification, then the use of silyl groups known to be unstable to chromatography (e.g. tri-10 methylsilyl) is to be avoided. Further, when silyl groups are to be introduced selectively, silylating agents which are readily available and known to be useful in selective silylations are employed. For example, t-butyldimethylsilyl groups are employed when selective introduction is required. Further, when silyl groups are to be 15 selectively hydrolyzed in the presence of protective groups according to R1o or acyl protective groups, then the use of silyl groups which are readily available and known to be easily hydrolyzable with tetra-n-butylammonium fluoride are- employed. A particularly useful silyl group for this purpose is t-butyldimethylsilyl, while other 20 silyl groups (e.g. trimethylsilyl) are not e~ployed when selective introduction and/or hydrolysis is required.
The protective groups as defined by Rlo are otherwise removed by mild acidic hydrolysis. For example, by reaction with (1) hydro-chloric acid in methanol; (2) a mixture of acetic acid, water, and 25 tetrahydrofuran, or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran, at temperatures below 55~ C., hydrolysis of the blocking group is achieved.
R31 is a hydroxy-hydrogen protective group, as indicated above.
As such, R31 may be an acyl protective group according to Rg, an acid 30 hydrolyzable protective group according to R1o, a silyl protective group according to R28, or an arylmethyl hydroxy hydrogen replacing group according to R34.
Acyl protective groups according to Rg include:
(a) benzoyl;
(b) benzoyl substituted with one to 5 alkyl of one to ~ carbon atoms, inclusive, or phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro, with the proyiso that not more than two substituents are other than alkyl, and that the total number of carbon atoms in the substituents does not exceed 10 carbon atoms, with the further proviso that the substituents are the same or different;
(c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms, incl usivei S (d) naphthoyl;
- (e) naphthoyl substituted with one to 9, inclusive, alkyl of one to 4 carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, with the proviso that not more than two substi-tuents on either of the fused aromatic rings are other than alky. and 10 ~hat the total number of carbon atoms in the substituents on either of the fused aromatic rings does not exceed 10 carbon atoms, with the further proviso that the various substituents are the same or differ-ent; or (f) alkanoyl of 2 to 12 carbon atoms, inclusive.
In preparing these acyl derivatives of a hydroxy-containing compound herein, methods generally known in the art are empl oyed.
Thus, for example, an aromatic acid of the formula RgOH, wherein Rg is as defined above (e.g., benzoic ac-id), is reacted with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. p-20 toluensulfonyl chloride or dicyclohexylcarbodiimide; or alternatively an anhydride of the aromatic acid of the formula (Rg)OH, e.g., benzoic a~hydride, is used.
Preferably, however, the process described in the above paragraph proceeds by use of the appropriate acyl halide, e.g., RgHal, wherein 25 Hal is chloro, bromo, or iodo. For example, benzoyl chloride is reacted with the hydroxyl-containing compound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine, triethylamine or the like. The reaction is carried out under a variety of conditions, using procedures generally known in the art.
30 Generally mild conditions are employed: 0-60C., contacting the reactants in a liquid medium te.g., excess pyridine or an inert solvent such as benzene, toluene, or chloroform). The acylating agent is used either in stoichiometric amount or in substantial stoichîo-metric excess.
As examples of Rg? the following compounds are available as acids (RgOH), (Rg)20, or acyl chlorides (RgCl) benzoyl; substituted ben-zoyl, e.g., (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-, 3-, or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tert-butylbenzoyl, 7 ~ ~7~ 3704/3803/3823/3833/3879/3893 ~26-2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl(2-, 3-, or 4-)toluyl, (2-, 3-, or 4-)phenethylbenzoyl, (2-, 3-, or 4-)nitrobenzoyl, (2,4, 2,5-~ or 2,3-)dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-di-methyl-2-nitrobenzoyl, 2-nitro-6-phenylethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethyl-benzoyl; mono esterified phthaloyl, isophthaloyl, or terephthaloyl;
1- or 2-naphthoyl; substituted naphthoyl, e.g., (2-, 3-, 4-, S-, 6-, or 7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-d;methyl-1-naphthoyl, 6-;sopropyl-4-methyl-1-naphthoyl~ 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or 8-)-methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or ~-)nitro-2-naphthoyl and acetyl.
There may be employed, therefore, benzoyl chloride, 4-nitro-benzoyl chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. RgC1 compounds corresponding to the above Rg groups. If the acyl chloride is not available, it is prepared from the corresponding acid and phosphorus pentachloride as is known in the art. It is preferred that the RgOH, (Rg)20, or RgC1 reactant does not have bulky hindering sub-stituents, e.g. tert-butyl on both of the ring carbon atoms adjacent to the carbonyl attaching site.
The acyl protective groups, according to Rg, are removed by de-acylation. Alkali metal carbonate or hydroxide are employed effec-tively at ambient temperature for this purpose. For example, potas-sium carbonate or hydroxide in aqueous methanol at about 25 C is ad-vantageously employed.
R34 is defined as any arylmethyl group which replaces the hydroxy hydrogen of the intermediates in the preparation of the various CBA
analogs herein which is subsequently replaceable by hydrogen in the processes herein for preparation of these respective prostacyclin analo~s, being stable with respect to the various reactions to which R34-containing compounds are subjected and being introduced and su6-sequently removed by hydrogenolysis under conditions which yield substantially quantitative yields of desired products.
Examples of arylmethyl hydroxy-hydrogen replacing groups are (a) benzyl;
(b) benzyl substituted by one to 5 alkyl of one to 4 carbon ~ 3 ~ 7 /`i 7 0 3704/3803/3823/3833/3879/3893 atoms, inclusive~ chloro, bromo, iodo, fluoro, nitro, pheny1alkyl of 7 to 12 carbon atoms, inclusive, with the further proviso that the various substituents are the same or different;
(c) benzhydryl;
(d) benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms, inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, inclusive, with the further proviso that the var-ious substituents are the same or different on each of the aromatic rings;
(e) trityl;
(f) trityl substituted by one to 15 alkyl of one to 4 carbon atoms, inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, inclusive, with the further proviso that the various substituents are the same or different on each of the aromatic rings.
The introduction of such ether linkages to the hydroxy-containing compounds herein, particularly the benzyl or substituted benzyl ether proceeds by methods known in the art, for example by reaction of the hydroxy-containing compound with the benzyl or substituted benzyl halide (chloride, bromide, or iodide) corresponding to the desired ether. This reaction procePds in the presence of an appropriate condensing agent (e.g., silver oxide). The mixture is stirred and - heated to 50-80C. Reaction times of 4 to 20 hours are ordinarily sufficient.
~he Charts herein describe the methods whereby the novel inter-mediates and end products of the present specification are prepared by the novel processes herein. ~ith respect to these charts, 9, n, Ll, Ml, M6, R7, R,3, R1o, Rl5, Rl6, Rl7, R1a~ R20, ~21~ R22~ R23, and R24, R28, R3l, X1, Y1, Z1, and Z4 are as defined above. R37 is the same as R47, but other than -CH20H. R38 is -OR31, hydrogen, or -CH20R3l, wherein R31 is defined as above. R27 is the same as R7 except that -(CH2)2-CH(OH~-CH3 is -(CH2)2-CH(ORlo)-CH3~ R37 is the same as R17, but other than hydrogen. AC is acetyl. Z2 is the same as Z1 but not -(Ph)-(CH2)9-. Z3 is the same as Z1~ but not trans-CH2-CH-CH-.
With respect to Chart A, a method is provided whereby the known formula XXI bicyclic lactone is transformed to the carbacyclin inter-mediate of formula-XXV useful in the preparation of formula X CBA
compounds wherein R17 is alkyl or R16 and Rl7 taken together are 1 3 ~ ~ ,) 3704/3803/3823/3833/3879/38g3 metha~o or a second valence bond between C-6a and C-9. With respect to Chart A, the formula XXI compound is transformed to the formula XXII compound by treatment with the anion of dimethyl methylphosphonate. Methods for such a reaction are known in the art.
S See Dauben, W.G., et al., JACS, 97:4973 (1975), describing a reaction of this type.
The formula XXII lactol is transformed to the formula XXIII
diketone by oxidation me~hods known in the art. For example, Collins reagent or Jones reagent is employed in this oxidative transformation.
The formula XXIII diketone is cycllzed to the formula XXIY com-pound by an intramolecular Horner-Emmons reaction. The chemical methodology for analogous transformations is known in the art. See Piers, E., et al., Tetrahedron Letters, 3279 (1979) and Clark, R.D., et al., Synthetic Communications 5:1 (1975).
The formula XXIV compound is transformed to the novel formula XXV
compound wherein Rl6 is hydrogen and R37 is alkyl by treatment with lithium dialkyl cuprate. The lithium dialkyl cuprate is prepared by conventional means, e.g., reaction of anhydrous copper iodide in diethyl ether with an alkyllithium in diethyl ether, and thereafter reacted with the formula XXIV compounds, e.g., in diethyl ether.
The formula XXIV compound is transferred to the novel formula XXV
compound wherein Rl6 and R37 taken together are methylene (-CH2-) by one of two methods. By the first method, the formula XXV compound is prepared by treatment of the formula XXIV compound with the anion of trimethyloxosulfonium iodide. See for reference E. J. Corey, et al., JACS 87:1353 (1965). By this method, the anion is conveniently gener-ated by treatment of trimethyloxosulfonium iodide in sodium hydride.
By a second method, the formula XXIV compound is converted to the formula XXV compound wherein Rl6 and R37 taken together are methylene by first converting the formula XXIV compound to the corresponding formula XXVI hydro~ymethyl compound by photochemical addition of methanol (e.g., see G. L. Bundy, Tetr. Lett. 1957, 1975), thereafter treating the resulting hydroxymethyl compound with an excess (e.g., two equivalents) of p-toluenesulfonyl chloride in a tertiary amine base to yield the corresponding formula XXVII tosylate, and finally treating the resulting formula XXVII tosylate with base (e.g., potassium t-butoxide) to yield the formula XXV cyclopropyl compound.
With respect to Chart 8, a method is provided whereby the formula .

1 3 ~ - 3 3704/3803/3823/3833/3879/3893 XXXI compound prepared in accordance l~lith methods of Chart A is trans-formed to the novel CBA2 analogs of formula XXXVI.
The formul a XXXI compound is transformed to the formula XXXVI
compound by methods known in the art for preparing carbacyclin. See 5 for example, British published applications referred to above. Alter-natively, the formula XXXI compound is reacted with formula XXXII com-pound and thereby successively transformed to the formula XXXIII, formula XXXIV and formula XXXV compounds.
The reaction of the formul a XXXI compound employing the formula 10 XXXII compound is accomplished by methods known in the art. See Moersch, G.W., J. Organic Chemistry, 36: 1149 (1971) and Mul zer, J., et al., Tetrahedron Letters, 2949 (1978). The formula XXXII reactants are known in the art or are prepared by methods known in the art. See Example 4 describing one such method of preparation of a formula XXXII
15 compound.
The formul a XXXIII compound is then transformed to the formul a XXXIV compound by decarboxylative dehydration. Procedures for this reaction are known in the art~ See Eschenmoser, A., et al., Helv.
Chim. Acta. 58:1450 (1975), Hara, S., et al., Tetrahedron Letters, 20 1545 (1975) and Mulzer, J., et al., Tetrahedron Letters, 2953 (1978) and 1909 (1979).
Finally, the formula XXXV compound is prepared from formula XXXIY
compound by selective desilylation. Such procedures are known in the art and typically employ the use of tetra-n-butyl ammonium fluoride 25 and tetrahydrofuran. See Corey, E.J., et al., JACS 94:6190 (1972).
The formula XXXV compound is transformed to various acids, esters, amides, and amines of a formula XXXVI by methods known in the art. Particularly useful in this regard are methods described in the aforementioned British published specifications describing the prepa-30 ration of carbacyclin anal ogs.
The preparatioq of formula XXXVI compounds from the formula XXXVcompounds proceeds by, for example, oxidation to the corresponding carboxylic acid, followed by hydrolysis of any protective groups at the C-ll or C-15 position of the molecule. Such carboxylic acids are 35 then esterified by conventional means or amidized by conventional means. Such amides may, for example, then be reduced to corresponding amines (Xl is -CH2NL2L3-by reduction by lithium aluminum hydride. See U.S. Patent 4,073,808. In a preparation of the primary alcohols 1 ~ ~ 7 ~-7rl 3704t3803/3823/3833/3~79/3893 according to formula XXXVI from the formula XXXV compound, hydrolysis of any protective groups at C-ll or C-15 yields such products directly. Hydrolysis is accomplished by procedures described above, e.g., mild acidic conditions at elevated temperatures.
Chart C provides a method whereby the known formula XLI compounds are transformed to the formula XLIV aldehydes employed in Chart D in the preparation of inter-phenylene-CBA2 compounds therein.
With respect to Chart C, the formula XLII compound is prepared from the formula XLI compounds by reduction. Conventional methods known in the art for the transformation of carboxylic acids to corres-ponding primary alcohols are employed. For example, one extremely useful conventional means for this reduction is employing lithium aluminum hydride as a reducing agent.
The formula XLIII compound is then prepared from the formula XLII
compound by monosilylation. Particularly, formula XLIII compounds are prepared wherein R28 represents a relatively stable silyl group, most preferably being t-butyldimethylsilyl or phenyldimethylsilyl. Other silyl groups, particularly trimethyl-silyl (TMS) are not preferred for use in connection with the methods of Chart C.
The formula XLIII monosilyl derivatives are prepared from the formula XLII compound by reacting the formula XLII compounds with about an equal molar amount of the silylating agent. For example, when R28 is t-butyldimethylsilyl, a single equivalent of t-butyl-dimethylsilyl chloride is employed in the transformation. Accord-ingly, there are prepared both monosilyl derivatives of the formula XLII compound as well as the bis-silyl derivatives corresponding to formula XLII. From this mixture of products, the formula XLIII
compound is recovered by conventional means, e.g., column chroma-tography. Otherwise? the silylation proceeds under conditions con-ventionally employed for silylating hydroxyl groups. ~efer to the discussion hereinabove.
The formula XLIV compound is then prepared from the formula XLIII
compound by oxidation of the formula XLIII alcohol to the corresponding aldehyde. Conventional oxidizing agents are employed, e.g., manganese dioxide.
Chart D provides a method whereby the known formula LI ketones are transformed to the formula LX inter-phenylene CBA2 analogs dis-closed herein.

7' 7~7~

,n accordance with Chart D the formula LII compound is preparedfrom the formula LI compound by reduction of the formula LI ketone to the corresponding secondary alcohol. This reduction proceeds by conventional means, employing readily available reducing agents.
S Accordingly, sodium, potassium, or lithium borohydride is conveniently employed in this reduction.
Thereafter, the formula LII alcohol is transformed to the corres-ponding mesylate (methanesul fonate). Conventional methods for the transformation of alcohols to corresponding mesylates are emp10yed.
10 Thus, the formula LII alcohol is reacted with methane-sulfonyl ch10r-ide in the presence of a tertiary amine (e.g., tri-ethylamine) in the preparation of the formula LIII compound.
Other sulfonyl derivatives corresponding to the formula LII
alcohol may be employed in place of the formula LIII compound in the 15 transformations of Chart D. These other sul fonyl derivatives are preferably those derived from readily available sulfonylating reag-ents, i.e., the corresponding sulfonyl chlorides. One especially important alternative to the formula LIII compound is the tosylate (tol uenesul fonate) corresponding to the formula LII compound.
The formula LIII compound, or an alternate sul fonate corres-ponding thereto, is transformed to the formula LIV compound by treat-ment with sodium lithium or potassium thiophenoxide. The thiophenox-ide is conveniently prepared just prior to the transformation by mixing approximately equal molar amounts of thiophenol and base, e.g., 25 potassium t-butoxide.
This formula LIV compound is then oxidized to the corresponding formula LV compound by oxidation with a readily available oxidizing agent such as m-chloroperbenzoic acid.
The formula LV compound is then condensed with the formula XLIV
30 compound prepared according to Chart C by first treatment of the formula LV compound with a strong base, e.g., n-butyllithium, to generate the anion corresponding to the formula LV compound, treatmçnt of the corresponding anion with the aldehyde of formula XLIV and finaliy treating the resulting adduct with acetic anhydride to yield 35 the formula LVI acetyl compound.
The formula LVI compound is then transformed to the formul a LVII
compound by reaction with a sodium amalgam. Methods by which the formula LVII olefin is formed from the formul a LV compound are anal o-1 7 ~ 7 ~ 7 3 ~, I ~ , . 3704/3803/3g23/3833/3879/3893 gous to known methods described by Kocienski, P.J., et a1., "Scope and Stereochemistry of an Olefin Synthesis from B-Hydroxysulphones", JCS
Perkin I, 829-834 (1978).
The formula LVII compound is then transformed to the formula S LYIII compound by selective hydrolysis of the silyl group according to R28. Conventional means for this hydrolysis are employed, e.g., tetra-n-butyl ammonium fluoride. Refer to the discussion above for a discription of this hydrolysis.
The formula LVIII C-S diastereomers thusly prepared are con-veniently purified into (5-E) and (5-Z) isomeric forms. This trans-formation proceeds by conventional means, e.g., column chromatography.
Thereafter either the (SE) or (5Z) isomer of formula LVIII is transformed to the formula LIX carboxylic acid or ester by conven-tional oxidation, followed by optional esterification. One especially convenient means of oxidation is employing the Jones reagent, although other oxidizing agents are employed. Esterification then proceeds by methods hereinafter described.
Finally, the formula LX products are prepared from the formula LIX compound by first hydrolyzing the protective groups under ~acidic conditions, e.g., mixtures of water, tetrahydrofuran, and acetic acid.
Thereafter, the formula LIX acids and esters are transformed to var-ious other C-l derivatives by methods hereinafter described.
One especially convenient means of preparing the formula LX com-pound as a free carboxylic acid (Xl is -COOH), is by purification of ~S the corresponding methyl ester, followed by saponification under basic conditions (e.g., the treatment with potassium carbonate or sodium or potassium hydroxide).

Chart E provides a method whereby the known formula LXI compound is transformed into formula LXIII intermediate useful in the preparation of the novel CBA2 analogs.
The procedures for the transformation of the formula LXI compound to the formula LXIII compound are analogous to those describing the transformation in Charts A, 8, and D of the formula XXI compound to the formula XXXVI and LX compounds (i.e.~ corresponding to the transformation of formula LXI compound to the formula LXII compound is the transformation in Chart A of the formula XXI compound to the formula XXV compound and corresponding to the transformation of the formula LXII compound to the formula LXI~I compound is the 1 3 1 ~, i 3 3704/3803/3823/3833/3879/3893 transformation in Chart D of the formula LI compound to the formula LX
compound.). For convenience, the protective groups R3l and R38 may be the same or different, although preferably such protective groups are different, whereby the hydrolysis of a protective group according to S R31 is accomplished in the presence of a protective group according to Chart F then provides a method whereby the formula LXXI compoundprepared according to Chart E is transformed to the formula LXXII
carbacyclin anatog in accordance with the present invent;on. I~ith respect to Chart F, the formula LXXI compound is transformed to the formula LXXII compound by selective hydrolysis of the protective group according to R31. Thereafter, the formula LXXII compound is transformed to formula LXXIII compound by methods known in the art, e.g., oxidation of the formula LXXII primary alcohol to the corres-ponding aldehyde, Wittig oxylacylating the aldehyde, and reduction of the resulting ketone to the secondary or tertiary alcohol correspond-ing to Ml. For an example of the various transformations employed according to Chart F, see Chart A tpart VI) of U.S. Patent 4,107,427, issued 15 August 1978.
Chart G provides a method whereby the novel formula LXXXI
intermediate, prepared according to Chart A, is transformed to the formula LXXXVIII and LXXXIX isomers of the novel C-6a- and/or C-9-substituted C3A2 analogs.
With respect to Chart G, the ~ormula LXXXIII compound is prepared from the formula LXXXI ketone by a Wittig ~-carboxyalkylation employing a formula LXXXII triphenylphosphonium compound. The Wittig reaction is undertaken under conventional reaction conditions for preparing prostaglandin-type substances. The formula LXXXIII compsund is then optionally hydrolyzed to yield the formula X carboxylic acid products or employed in the further transformations of Chart G in ester form.
The formula LXXIII compound thusly prepared is thereafter preferably separated directly into C-5 isomers of formulas LXXXVIII
and LXXXIX (e.g., by chromatographic means followed by hydrolysis of any protective groups at C-ll or C-15 position of the molecule), or is alternatively transformed to the formula LXXXIV ester by conventional esterification techniques, e.g., ethereal diazomethane treatment or treatment with methyl iodide. The formula LXXXIV ester is then l 7l 7 :' 7 J 3704/3803/3823/3833/3879/3893 = -34-reduced to the corresponding primary alcohol by reduction with a sujtable reducing agent, e.g., lithium aluminum hydride, by methods known in the art for preparing prostaglandin-type primary alcohols from corresponding prostaglandin esters.
The formula LXXXV compound represents an especially convenient intermediate for the facile separation of the C-5 diastereomers.
Accordingly~-the formula LXXXV compound may be separated by conven-tional means of separation of diastereomeric mixtures, e.g., column chromatography, whereby the formula LXXXVI and formula LXXXVII com-pounds are prepared in isomerically pure form. These primary alcohols are then conveniently transformed to the formula LXXXVIII and LXXXIX
products by methods described above. Refer to the transformat;ons of the formula XXXV compound to the formula XXXVI compound in Chart B.
Chart H provides a method whereby the formula XCVII 5-fluoro-CBA2 compounds are prepared from the formula XCIII CBA2 intermediates known in the art~ See, for example, British Published Application 2,014,143, especially the discussion relative to step (b) of Chart A
therein. This formula XCI sulfoximine is transformed to the formula XCII fluorinated sul~foximine by first generating an anion of the formula XCII compound, e.g., by treatment with n-butyllithium in hexane, and treating the resulting anion with a fluorine source.
Particularly preferred as a source of fluorine is perchloryl fluoride (FCl03)-The formùla XCI compound thusly prepared and the known formula ~5 XCIII compound described above are then employed in the preparation ofthe formula XCIV compound by known methods. Refer again to step (b) of Chart A of British Published Application 2,C14,143.
The formula XCIV compound thusly prepared is then transformed to the formula XCV primary alcohol by hydrolysis under mild acidic conditions (e.g., mixtures of acetic acid, water, and tetrahydrofuran) as is known in the art. Thereafter, the formula XCV primary alcohol is oxidized to the corresponding formula XCVI carboxylic acid employ-ing conventional means. For example, treatment with oxygen and an aqueous suspension of platinum oxide hydrogenated at ambient tempera-3~ ture and pressure yields the formula LXXVI carboxylic acid. There-after, the formula XCVI compound is transformed into the various formula XCVII products by derivatization or transformation of- the carboxyl group of the formula XCVI compound~

7 3704/3803/3~23/3833/3879/3893 The C-5 isomers of the formula XCIV to formula XCVII compounds are conveniently separated at any step during the process of Chart H, but are most conveniently and preferably separated from the formu1 a XCIV diastereomeric mixture. Conventional means, e.g., column 5 chromatography, are employed in the separation.
Chart I provides an optional method whereby the known formula CI
compound is transformed to the formula CIII products herein. hlith respect to Chart I, the formula XCII is prepared from the formula XCI
compound by the procedure described in Chart H for the preparation of 10 the formula XCVII compound from the formula XCIII compound. This formula CII CBA2 intermediate is then transformed to the formula CIII
- compound by the procedures described in Chart F for the transformation of the formul a LXXI to the formul a LXXIII compound.
Chart J provides the preferred methods for preparing the formula 15 X CBA analogs wherein Z1 is trans CH2-CH=CH-. With respect to Chart J, R, therein is other than hydrogen or a cation, preferably being lower alkyl. The formula CXIV is prepared from the formula CXI
compound by first preparing the c~phenylselenyl derivative thereof, dehydrophenylselenizing, whereby the formula CXIII ~,~-unsaturated 20 ester is prepared. This ester is then transformed to the formula CXIV
free acid (Xl is -COOH) by saponification and this free acid is trans-formed to the various other formula CXIV compounds as indicated in Chart H (refer to the transformation of the formula XCVI compound to the formula XCVII compound).
Chart K provides the preferred method whereby the formula VI CBA
intermediates wherein Zl is trans-CH2-CH=CH- are prepared. With respect to Chart K, the formul a CXXI compound is transformed to the formula CXXIII compound by methods analogous to those described in Chart J for the preparation of the formul a CXIV compound from the 30 formula CXI compound.
For a detailed~description of the methodology employed in Charts J-K, refer to the discussion in British Patent 2,014,143, and references cited therein.
Charts L-O provide methods whereby CBA2 intermediates and analogs 35 are employed in the synthesis of corresponding CBAl intermediates and anal ogs.
Chart L provides the preferred method for preparing the formul a VII CBA1 intermediates wherein Zl is trans-CH2-CH=CH-. With respect 7 0 3704/3803/3823/3833/3~79/3893 to Chart L the formula CXXXI compound, prepared as the formula CXXIIcompound of Chart K, is reduced to the formula CXXXII compound by conven~ional methods. For a discussion of such methods, and general methodologies for transformlng CBA2 intermediates and analogs to corresponding CBAl intermedlates and analogs, refer to British Published Application 2,017,699. for example, catalytic hydrogenation with conventional catalysts under atmospheric pressure is employed.
Thereafter, this formula CXXXII compound is successively transformed to the ormula CXXXIII a, ~-unsaturated ester and the formula CXXXIV CBA1 intermediate by methods described in Charts J-K
(i.e., the transformation of the formula CXII compound to the corresponding ~ormula CXIV compounds and the transformation of the formula CXXI I compound to the formula CXXI I I compound).
Otherwise, the formula VII CBAl intermediates are prepared according to the method of Chart M, wherein the formula CXLI compound, prepared above, is reduced to the formula CXLII intermediates by techniques described in Chart L and references cited therein.
Chart N describes the preparation of the various C~A1 analogs from the formula CLI compounds prepared in Charts L and M. Procedures employed in Chart N are those described in Chart F above.
- Finally, Chart O provides an alternative method for the prepara-tion of the formula CLXII CBAl analogs directly from formula CLXI CRA2 analogs. This transformation of Chart O proceeds by direct reduction of the formula CLXI compound by methods described in Chart M and references cited therein. Chart O is an especially convenient method for the preparation of CBAl analogs wherein Y1 is -CH2CH2-.
The formula XI CBA analogs are prepared according to the methods described in Charts P-U. With respect to Chart P, the formula CLXXI
compound is known in the art or prepared by methods known in the art.
See United States Patent 4,181,789. This compound is conveniently transformed to the corresponding formula CLXXII methylene and formula CLXXIII hydroxymethyl compounds by methods known in the art. Such procedures are particularly and especially described in United States Patent 4jO12,467 and 4,060,534.
The formula CLXXIII compound thusly prepared is thereafter con-verted to the ~ormula CLXXIV mesylate by methods known in the art, e.g., reaction with methanesulfonyl chloride in a tertiary amine base.
Alternatively, other sulfonated derivatives corresponding to the for-t 7 ~ 7 ~ r, ., ~ , i J

mula CLXXIV compound are prepared such as those described in connec-tion with formula LIII in Chart D.
Thereafter, the formula CLXXIV mesylate (or other sulfonate) is selectively hydrolyzed to yield the formula CLXXV phenol derivatives.
Selective hydrolysis of R28 silyl ether groups in the presence of ` protected R18 or M6 hydroxyl groups is accomplished by methods herein-above described, i.e., the use of tetra-n-butyl ammonium floride by methods known in the art and hereinabove described. The formula CLXXV phenol derivative is then cyclized to yield the formula CLXXVI
compounds. Cyclization proceeds most conveniently by treatment of the formula XVI compound with base at elevated temperatures. For example, n-butyllithium, sodium hydride, or potassium hydride are conveniently employed at reflux temperatures in organic solvent such as tetrahydrofuran or glyme.
- 15 The cyclized formula CLXXVI compound is then transformed to the formula CLXXVII compound by ~-carboxyalkylation. Methods known in the art are employed, e.g., methods for preparing 3,7-inter-phenylene-PGFa cornpounds and corresponding phenolic intermediates. For example, the preparation of the formula CLXXVII compound proceeds by reaction of the formula CLXXVI compound with sodium hydride and the alkyl bromo-alkanoate corresponding to the -Z4-COOR1 group to be introduced into the molecule. Thereafter, the formula CLXXVIII compound is prepared by deprotection, i.e., hydrolysis under mild acidic conditions of the protective groups, followed by transformation to various other C-1 derivatives by methods hereinafter described.
Chart Q provides a method whereby further formula XI C8A analogs in accordance with the present invention are prepared. In particular, formula XI compounds wherein at least one f R20~ R2l, R23, or R24 is not hydrogen are prepared. ~n accordance with Chart Q, the formula CLXXXI compound, referred to above in the discussion pertaining to Chart P, is oxidized to the corresponding formula CLXXXII aldehyde by methods known in the art. For example, Collins reagent is employed in this oxidation. ~hen conversion of one C-9 stereoisomer of formula CLXXXIII to the other is described, refer to the procedure in Chart R.
Thereafter the formula CLXXXII aldehyde is hydrolyzed to the corresponding formula CLXXXIII phenol derivative by methods described above for the preparation of the formula CLXXV compound from the for-mula CLXXIV compound of Chart P.

7 ~ ~

lhereafter, cyclization of the formula CLXXXIII to the corres-ponding formula CLXXXIV compound is accomplished by heating at reflux in an organic solvent the phenoxide anion of the formula CLXXXIII com-pound. See for reference Casiraghi, G., et al., J.C.S. Perkin I, 2027 5 (1979). The C-9 isomers of the formula CLXXXIV compound are conven-iently separated by conventional techniques, e.g., column chramato-graphy. Thereafter, the formul a CLXXXIV compound is transformed to the formula CLXXXV compound by methods described in Chart P for the preparation of the fGrmula CLXXVII compound from the formula CLXXVI
10 compound. This alcohol is then oxidized to the corresponding formula CLXXXVI ketone (e.g., by methods described above for the preparation of the formula CLXXXII compound from the formula CLXXXI compound~ or dehydrated to yield the formula CLXXXVIII compound. Such dehydrations proceed by methods known in the art and include first preparing the 15 mesylate coresponding to the formula CLXXXV compound following by treatment with base.
Thereafter, the formula CLXXXVI or CLXXXVIII compound is trans-formed, respectively, to the formula CLXXXVII or CLXXIX compound by methods hereinafter described.
Finally, the formula CLXXXIX compound thusly prepared is dehydrogenated to yield the formula CXC compound by conventional means, e.g., catalytic dehydrogenation ~palladium-on-carbon catalyst) or treatment with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone~/
Chart R provides a method whereby the C-g epimeric forms of com-25 pounds prepared according to Chart P are prepared. With respect to Chart R, the formula CXCI aldehyde, prepared as the formula CLXXXII
compound of Chart Q is isomerized by treatment under basic conditions (i.e., the use of an organic base such as 1,8-diazobicycloC5.4.0~-undec-7-ene in an organic solvent (e.g., methylene chloride)). There-30 after this 9~-aldehyde is reduced to the corresponding formula CXCIII
alcohol by treatment with a suitable reducing agent, such as a boro-hydride reducing agent. (e.g., sodium, lithium7 or potassium borohy-dride~. Thereafter, the formula CXCIII alcohol thusly prepared is transformed to the corresponding 9~-CBA analogs by methods described 35 in Chart P, e.g., the transformation of the formula CLXXIII to the formula CLXXVIII compound.
Optionally, the various formula XI CBA analogs prepared accord-ing to Charts P, Q, and R are prepared by the procedure of Chart S.

1 3 1 - 70 3704t3803/3823/3833/387g/3~93 The procedure of Chart S employs the formula CCI starting materia1described in chart P which is thereafter converted to the formula CCII
compound prepared in accordance with methods described for the prepa-ration of the formula CLXXYIII compound from the formula CLXXI com-pound of Chart P, the formula CLXXXVII, formula CLXXXIX, formula CXCcompounds from the formula CLXXXI compound of Chart Q and the formula CXCIV compounds from the formula CXCI compound of Chart R. The for-mula CCII compound thusly prepared is then transformed to the formula CCIII compounds by methods hereinabove described, e.g., the transform-ation of the formula LXXI compound to the formula LXXIII compound ofChart F.
Chart T provides a preferred method whereby the 9-deoxo-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-PGEl compounds of formula CCXIII are prepared. In accordance with Chart T the formula CCXI compound, prepared as the formula CLXXXIII compound of Chart Q, is treated with a methyl Grignard reagent, methyl magnesium bromide and heated at reflux in an organic solvent (e.g., glyme).
The formula CCXII thusly prepared is then transformed to the formula CCXIII product by the method described in Chart P for the preparation of the formula CLXXVII~I product from the formula CLXXVI
phenol intermediate.
Chart U provides a convenient method whereby formula XI compounds wherein Yl is trans-CH=CH-, the formula CCXXI compound of Chart U, are transformed to corresponding formula CCXXII aldehyde intermediates.
This transformation is accomplished by ozonolysis by methods otherwise known in the art.
The formula CCXXII intermediate is then conveniently transformed to various formula XI products (the Formula CCXXI~I compound of Chart U) by methods described above, i.e., reaction of the formula CCXXII
compound with the appropriate Wittig reagent followed by reduction and hydrolysis. Accor~ingly by the procedure described in Chart U-the C-12 side chains of the various formula CCXXI compounds is conven-iently modified by the formula CCXXII aldehyde intermediates.
As discussed above, the processes herein described lead variously to carboxylic acids (Xl is -COORl and Rl is hydrogen) or to esters or primary alcohols (Xl is -CH20H).
When the alkyl ester has been obtained and an acid is desired, saponification procedures, as known in the art for PGF-type compounds 1 1 3 i 3704/3803/3823/3833/3879/3893 are employed.
When an acid has been prepared and an alkyl, cycloalkyl, oraralkyl ester is desired, esterification is advantageously accomplished by interaction of the acid ~ith appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl ester is produced. Similar use of diazoethane, dia20butane, and 1-diazo-2-ethylhexane, and diazodecane, for example, gives the ethyl, butyl, and 2-ethylhexyl and decyl esters, respectively. Similarly, diazocyclohexane and phenyldiazomethane yield cyclohexyl and benzyl esters, respectively.
Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about 10 min, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).
An alternative method for alkyl, cycloalkyl or aralkyl esterification of the carboxy moiety of the acid compounds comprises transformation of the free acid to the corresponding substituted ammonium salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide, and the like.
Various methods are available for prepar.ing phenyl or substituted phenyl esters within the scope of the invention from corresponding aromatic alcohols and the free acid, differing as to yield and purity of product.
With regard to the preparation of the phenyl, particularly p-substituted phenyl esters disclosed herein (i.e., Xl is -COORl and R1 is p-substituted phenyl), such compounds are prepared by the method described in U.S. Patent No. 3,890,372. Accordingly, by the preferred ` ~ 3704/3803/3823/3833/3879/3893 method described therein, the p-substituted phenyl ester is prepared first by forming a mixed anhydride, particularly following the procedures described be10~ for preparing such anhydrides as the first step in the preparation of amido and cycloamido derivatives.
This anhydride is then reacted with a solution of the phenol corresponding to the p-substituted phenyl ester to be prepared. This reaction proceeds preferably in the presence of a tertiary amine, such as pyridine. ~hen the conversion is complete, the p-substituted phenyl ester has been recovered by conventional techniques.
A preferred method for substituted phenyl esters is that disclosed in U.S. Patent No. 3,890,372 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. The anhydride is formed from the acid with isobutylchloroformate in the presence of a tertiary amine.
Phenacyl-type esters are prepared from the acid using a phenacyl bromide, for example p-phenyl phenacyl bromide, in the presence of a tertiary amine. See, for example, U.S. Patent No. 3,984,454, German Offenlegungsschrift 2,535,693, and Derwent Farmdoc No. 16828X.
Carboxyamides (Xl is -COL4) are prepared by one of several 20 amidation methods known in the prior art. See, for example, U.S.
Patent No. 3,981,868, issued 21 September 1976 for a description of the preparation of the present amido and cycloamido derivatives of prostaglandin-type free acids and U.S. Patent No. 3,954,741 describing the preparation of carbonylamido and sul fonylamido derivatives of 25 prostaglandin-type free acids.
The preferred method by which the present amido and cycloamido derivatives of the acids are prepared is, first, by transformation of such free acids to corresponding mixed acid anhydrides. ~y this procedure, the prostaglandin-type free acid is first neutralized with 30 an equivalent of an amine base, and thereafter reacted with a slight stoichiometric exces~s of a chloroformate corresponding to the mixed anhydride to be prepared.
The amine base preferred for neutralization is triethylamine, although other amines (e.g., pyridine, methyldiethylamine3 are 35 likewise employed. Further, a convenient, readily available chloroformate for use in the mixed anhydride production is isobutyl chl oroformate.
The mixed anhydride formation proceeds by conventional methods 7 f ~ f ~
3704/3803/3823/3833/3879/38g3 and accordingly the free acid is mixed with both the t~rtiary aminebase and the chloroformate in a suitable solvent (e.g., aqueous tetrahydrofuran~, allowing the reaction to proceed at -1CC to 20C.
Thereafter, the mixed anhydride is converted to the corresponding amido or cycloamido derivatives by reaction with the amine corres-ponding to the amide to be prepared. In the case where the simple amide (-NH2) is to be prepared, the transformation proceeds by the addition of ammonia. Accordingly, the corresponding amine (or ammonia) is mixed with the mixed annydride at or about -10 to +10C, until the reaction is shown to be complete.
Thereafter, the novel amido or cycloamido derivative is recovered from the reaction mixture by conventional techniques.
The carbonylamido and sulfonylamido derivative of the presently disclosed PG-type compounds are likewise prepared by known methods.
See, for example, U.S. Patent No. 3,954,741 for description of the methods by which such derivatives are prepared. ~y this known rnethod the acid is reacted with a carboxyacyl or sulfonyl isocyanate, corres-ponding to the carbonylamido or sulfonylamido derivative to be pre-pared.
By another, more preferred method the sulfonylamido derivatives of the present compounds are prepared by first generating the PG-type mixed anhydride, employing the method described above for the prepar-ation of the amido and cycloamido derivatives. Thereafter, the sodium salt of the corresponding sulfonamide is reacted with the mixed anhy-dride and hexamethylphosphoramide. The pure PG-type sulfonylamido derivative is then obtained from the resulting reaction mixture by conventional techniques.
The sodium salt of the sulfonamide corresponding to the sulfonylamido derivative to be prepared is generated by reacting the sulfonamide with alcoholic sodium methoxide. Thus, by a preferred method methanolic sodium methoxide is reacted with an equal molar amount of the sulfonamide. The sulfonamide salt is then reacted, as described above, with the mixed anhydride, using about four equivalents of the sodium salt per equivalent of anhydride. Reaction temperatures at or about 0C are employed.
The compounds of this invention prepared by the processes of this invention, in free acid form, are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the - I 1 7 0 3704/3803/3823/3833/387g/3893 corresponding inorganic or organic base, examples of which correspond to the cations and amines listed hereinabove. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. in the case of the inorganic salts, i~ is usually suitable to dissolve an acid of this invention in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water~miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired~
To produce an amine salt, an acid of this invention is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation.
It is preferred to use stoichiometric amounts of the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by mixing an acid of this invention with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
_ The present invention is more completely understood by the operation of the following examples:
Example 1 3-oxo-7a-tetrahydropyran-2-yloxy-6~(3ls)-3l-tetra-hydropyran-2-yloxy-trans-l'-octenyl]-bicyclo~3.3.0~-oct-1-ene (Formula XXIV: R18 is tetrahydropyranyloxy;
Yl is trans-CH=CH-, M6 is -tetrahydropyranyloxy:~-H, L1 is a-H:~-H, R27 is n-butyl; and n is the integer one).
Refer to Chart A.

7 ~ 7 ' 7~j 3704/3803/3823/3833/3879/3893 A. To a stirred solution of 19 ml (170 mrnoles) dimethyl methyl-phosphonate and 600 ml of dry tetrahydrofuran at -78C under an argon atmosphere is added dropwise over 5 min 110 ml (172 mmoles) of 1.56 M
n-butyllithium in hexane. The resulting solution is stirred for 30 min at -78C, treated with 25.4 9 of 3a~5~-dihydroxy-2~-(3a-hydroxy-trans-1-octenyl)-1~-cyclopentaneacetic acid, lactonè, bis(tetrahydro-pyranyl)ether, in 100 ml of dry tetrahydrofuran dropwise oYer one hr, and stirred for one hr at -78C and four hr at room temperature. The reaction is then quenched by addition of 10 ml glacial acetic acid, diluted with 700 ml of brine, and extracted with diethyl ether (3 x 700 ml). The combined ethereal layers are washed with 200 ml bicarb and 500 ml brine and dried over anhydrous sodium sulfate and concen-trated under reduced pressure to yield 37 9 of formula XXII compound as oily white solid: 3-dimethylphosphonomethyl-3-hydroxy-2-oxa-7a-tetrahydropyran-2-yloxy-6~(3'5)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo~3.3.0~octane. Crystallization of the crude product from hexane and ether yields 22.1 9 of purified formula XXII product.
Silica gel TLC Rf is 0.22 in ethyl acetate. The melting range is 89-93C. NMR absorptions are observed at 3.72 (doublet, J=llHz) and 3.83 (doublet, J=llHz)~. Characteristic infrared absorptions are 3340, 1250, 1185, 1130, 1075, and 1030 cm B. To a solution of 10.0 9 of the product of Part A in 75 ml acetone stirring under a nitrogen atmosphere at -10C is added over 3n min 9.0 ml of Jones reagent. The resulting suspension is stirred for 30 min at -10C and then quenched with 4 ml 2-propanol. The solvents are decanted away from the green residue and most of the acetone removed at reduced pressure. The acetone concentrate is then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine and dried over anhydrous sodium sulfate. Concen-tration under reduced pressure yields 8.2 g of formula XXIII product:2-decarboxy-6-desbutyl-6-dimethylphosphonomethyl-6-keto-PGE1, 11,15-bis(tetrahydropyranyl ether). Chromatography of formula XXIII product on 600 9 silica gel eluting with 20% acetone in methylene chloride yields 4.95 9 of pure formula XXIII product. Silica gel TLC Rf (in 20% acetone in methylene chloride) is 0.22. Characteristic NMR
absorptions are observed at 3.14 (doublet, J=23 Hz) and 3.80 (doublets Ja11 Hz), 5.4-5.8 (m)~. Characteristic infrared absorptions are observed at 1745, 1715, 1260, 1200, 1185, 1130, 1030, 970, 870 cm~ .

7~ ' .7 7 0 3704/3~n3/3s23/3s33/3s7s/3ss3 C. A suspension of 5.37 9 of the product of Example 1, Part B,1.33 9 anhydrous potassium carbonate, and 5.37 g 18-Crown-6 ether in 200 ml toluene is heated at 75C for six hr under a nitrogen atmos-phere, cooled to 0C, and washed with 200 ml brine, 200 ml of 3:1 water:brine, and 200 ml brine, and dried over anhydrous sodium sulfate. Most of the solvents are removed under reduced pressure and the residue is filtered through 50 g silica gel eluting with 25n ml ethyl acetate to give 3.9 9 of formula XXIV product: 3-oxo-7-tetra-hydropyranyl-2-yloxy-~g~(3'S)-3'-tetrahydropyran-2-yl-trans-1'-octenyl~bicyclo[3.3.0]oct-1-ene. The crude product is chromatographed on 300 9 silica gel eluting with 60:40 hexane:ethyl acetate to give 2.39 g of pure title product. Silica gel TLC Rf is 0.22 in 60:40 hexane:ethyl acetate. NMR absorptions are observed at 5.18-5.86 (m) and 5.94 (broad singlet~. Infrared absorptions are observed at 1710 and 1632 cm~ .
Following the procedure of Example 1, but employing the various 3~,5a-hydroxy-2-substituted-1a-cyclopentaneacetic acid ~-lactones of formula XXI, there are prepared each of the various corresponding formula XXIV products wherein n is one.
Further, following the procedure of Example 1, but employing each of the various 3a,5~-dihydroxy-2-substituted-1-cyclopentanepriopionic acid, ~-lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein n is 2.
Further, following the procedure of Example 1, but employing each of the various 5a-hydroxy-2-substituted-la-cyclopentanealkanoic acid lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein Rl8 is hydrogen. Finally, following the procedure of Example 1, but employing each of the various 3a-hydroxymethyl-5~-hydroxy-2-substituted-la-cyclopentanealkanoic acid lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein R1g is -CH20R1o-Examp1e 2 3-oxo-8a-tetrahydropyran-2-yloxy-7~[(3'S)-3l-tetrahy-dropyran-2-yloxy-trans~ octenyl]bicyclo~4.3.0~non-1-ene (Formula XXIY: R18, Yl, M6, R7 are defined in Example 1 and n is the integer 2).
Refer to Chart A.
A. A solution of 2.05 ml (18.9 mmoles) of dimethyl methylphos-phonate and 100 ml of dry tetrahydrofuran is stirred at -78C under a nitrogen atmosphere and treated dropwise with 11.8 ml (18.9 mmoles) of1.6 molar n-butyllithium in hexane. After stirring for 30 min at -78C, the resulting mixture is treated dropwise over 25 min with 4.25 g of 3a,5-dihydroxy-2~-(3a-hydroxy-trans-1-octenyl) la-cyclopentane propionic acid, ~-lactone, 11,15-bis(tetrahydropyranyl ether), in 30 ml of dry tetrahydrofuran. The resulting mixture is then stirred for one hr at 78C. The solution is then allowed to stir at ambient temperature for 2 hr and is quenched by addition of 1.2 ml of acetic acid. The mixture is then added to 250 ml of brine and 200 ml of diethyl ether. The aqueous and organic layers are then separated and the aqueous layer extracted twice with diethyl ether. The ethereal extracts are then washed with brine, dried over anhydrous sodium sulfate, and concentrated to yie1d 5.6 9 of crude formula XXII com-pound, as an oil: 3-(dimethylphosphonomethyl)-3-hydroxy-2-oxa-8~-tetra-hydropyran-2-yl-oxy-7~C(3'S)-3'-tetrahydropyran-2-yloxy-transl'-octenyl]-bicyclo[4.3.0~nonane. Chromatography on silica gel eluting with 4:1 ethyl acetate:acetone yields 4.1 g o~ purified formula XXII
product. Characteristic NMR absorption is observed at 5.15-5.65 (multiplet)~. Silica gel TLC Rf is 0.34 in 4:1 ethyl acetate:acetone.
Characteristic infrared absorptions are observed at 3350, 1235, and 1030 cm~ .
B. A suspension of 3.42 9 of chromium trioxide and 80 ml of methylene chloride is treated with 5.8 ml of pyridine, stirred at ambient temperature under a nitrogen atmosphere for 30 min, and combined with 3 scoops of dry diatomaceous earth. The resulting mixture is then treated with 3.25 9 of the reaction product of Part A
and 8 ml of dry dichloromethane, stirred ~or 30 min at ambient temperature under nitrogen, filtered through 30 9 of silica gel (eluting with 200 ml of ethylacetate and acetone, 2:1) and concen-trated under reduced pressure. Chromatographing the residue (3.73 9)on 120 9 of silica gel, eluting with ethyl ace~ate and acetone (4:1) yields 2.07 9 of formula XXIII product: 2-decarboxy-5-despropyl-6-dimethylphosphonomethyl-5-keto-PG~l, 11,15-bis(tetrahydropyranyl ether). Characteristic infrared absorptions are observed at 17~0 and 1715 cm Characteristic NMR absorptions are observed at 3.1 (doublet, J=23 Hz) and 3.8 (doublet, J-11 Hz)~.
C. A suspension of 12 mg of 50% sodium hydride in mineral oil - l 7 1 7if~'~J 3704/3~03/3~23/3833/3879/3893 and 3 ml of diglyme is stirred at 0C. under an argon atmosphere~ The suspension is then treated with 150 mg of the product of Part 8 in 3 ml of diglyme. After 1 hr, the cooling bath is removed and the resulting solution is stirred at ambient temperature under argon.
After a total of 20 hr from addition of the formula XXIII reactant, the resulting solution is then added to 30 ml of water and extracted with 90 ml of diethyl ether. The ethereal extract is washed with brine (30 m1), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (110 mg) and chromatographed on 10 9 of silica gel eluting with hexane and ethyl acetate (1:1). There is accordingly prepared 15 mg of formula XXIV compound: 3-oxo-8a-tetra-hydropyran-2-yloxy-7~-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo[4.3.0]non-1-ene. NMR absorptions are observed at 4.7 (broad singlet) and 5.3-6.0 (multiplet)~. IR absorption is observed at 1670 cm~ .
Alternatively, the formula XXIV compound above is prepared as fol1Ows:
A solution of 150 mg of the product of Part B and 5 ml of dry tetrahydrofuran at 0C under an argon atmosphere is treated dropwise with 0.5 ml of 0.52 M potassium hydride and 18-crown-6 ether (Aldrich Chemical Co. Catalog Handbook of Fine Chemicals 1979-1980, Milwaukee, Wisconsin, p. 133; Pedersen, J.C., JACS 92:386 (1970)) in tetra-hydrofuran (prepared from 800 mg potassium hydride and 1.0 9 18-crown-6 ether in 8.7 ml of dry tetrahydrofuran). After stirring for one hr at O~C under argon, the mixture is added to 30 ml of water, extracted with 90 mg of diethyl ether and the ethereal extract is washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 9 9 of slica gel elut-ing with ethyl acetate and hexane. Formula XXIV product (40 mg) is thereby obtained. Silica gel TLC Rf is 0.30 in ethyl acetate and hexane ( 1~
Example 3 1~-Methyl-3-oxo-7a-tetrahydropyran-2-yl-oxy-6~-~(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl~-bicyclo-~3.3.0]octane (Formula XXV: R1~, Yl, ~6, n, L1, R7 are as defined in Example 1, Rl6 is hydrogen and R37 is methyl).
Refer to Chart A.
A suspension of 2.70 9 of anhydrous copper iodide is stirred in 7 ' 3704/3803/3823/3833/3879/3893 lO0 ml of anhydrous diethyl ether at -20C under an argon atmosphere and is treated dropwise with 20.0 ml of 1.4 M ethereal methyllithium.
The resulting solution is then stirred for 15 min at -20C and treated over 2.5 hr at -20C with a solution of 2.00 9 of the title product of Example 1 in 100 ml of anhydrous diethyl ether. Stirring is continued for an additional 1.5 hr at -20C and the resulting mixture added to 200 ml of 1 M aqueous ammonium chloride. The aqueous and organic layers are then separated and the aqueous layer extracted with diethylether (400 ml). The combined organic extracts are then washed with 200 ml ~f brine, dried over anhydrous sodium sulfate, concen-trated under reduced pressure to yield 2.4 9 of title product as a pale green oil. Chromatography on 25 9 of silica gel eluting with hexane in ethyl acetate (3:1) yields 2.0 9 of title product as a colorless oil. Characteristic NMR absorptions (CDCl3) are observed at lS 1.18, 3.20-4.43, 4.70, and 5.2-5.9~. Characteristic infrared absorp-tions are observed at 1745, 1665, 1200, 1130, 1110, 1075, 1035, 1020, 980, and 870 cm~ . Silica gel Rf is 0.26 in ethyl acetate and hexane ~1:3).
By procedures known in the art, each of the various novel formula XXV intermediates is transformed to a 9~-methyl-CBA2 or CBAl compound by methods examplified hereinafter or known from ~ritish Published Specifications 2,013,661, 2,014,143, and 2,017,699.
Example 4 5~Carboxypentanol, t-butyldimethylsilyl ether A solution of 4 9 of sodium hydroxide in 100 ml of methanol and water (4:1~ is treated with 10 ml of caprolactone and stirred at ambient temperature under a nitrogen atmosphere. After 20 hr, solvent is evaporated following addition of toluene, yielding 15 9 of solid, crude 5-carboxypentanol.
The above solid is suspended in 300 ml of dimethylformamide under a nitrogen atmosphere, cooled to 0C, treated with 35 9 of imidazole, stirred for 15 min at 0C and 15 min at ambient temperature, cooled to 0C and treated with 39 9 of t-butyldimethyl silylchloride. The resulting solution is then allowed to warm to ambient temperature under a nitrogen atmosphere. After 26 hr, the resulting solution is treated with 8 9 of sodium hydroxide in 40 ml of water and 40 ml of methanol, with stirring maintained under a nitrogen atmosphere. After 13 hr, the suspension is acidified to pH 4 with 500 ml of 1 N aqueous hydrogen chloride, then saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts are then washed with 1N aqueous sodium hydroxide. The basic extracts are then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine, and extracted with ethyl acetate. The ethyl acetate extracts are then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 22.6 9 of a yellow liquid, 5-carboxy-pentanol, t-butyldimethylsilyl ether. Chromatography on 800 g of silica gel eluting with ethyl acetate and hexane (1:9 to 1:1) yields 14.8 ~ of 5-carboxypentanol, t-butyldimethylsilyl ether. N~R
absorptions are observed at 0.05 (singlet) and 0.90 (singlet)~.
Infrared absorptions are observed at 3000 (broad) and 1700 cm Following the procedure of Example 4, but employing each of the various lactones corresponding to the ~-carboxyalkanol compounds of formula XXXII there are prepared each of the various formula XXXII
products.
Example S 2-Decarboxy-2-tt-butyldimethylsilyloxy)methyl-5-car-boxy-6-hydroxy-9~-methyl-CBAl, 11,15 bis(tetrahydro-pyran)ether (Formula XXXIII: R28 is t-butyldimethyl-silyl, Z2 is -(CH2)3-, n is 1, and Rl6, Rl8, R37, M6, Ll, and R4 are as defined in Example 3).
Refer to Chart B.
A solution of 0.58 ml of dry diisopropylamine and 20 ml of dry tetrahydrofuran at 0C under an argon atmosphere is treated wi~h 2~6 ml of 1.56 M n-butyllithium in hexane, stirred for 5 to 10 min at O~C, treated with O.S0 g of the title product of Example 4 in 5 ml of tetrahydrofuran, stirred for 15 min at 0C and 1 hr at ambient temperature, cooled to O~C, treated with 0.91 9 of the title product of Example 3 in S ml of tetrahydrofuran, and allowed to slowly warm to ambient temperature under an argon atmosphere. Thereafter, 130 ml of water and 20 ml of brine are added and the mixture extracted with diethyl ether. The ethereal extracts are then washed with 4 ml of 1 N
aqueous hydrochloric acid and 150 ml of brine and dried over sodium sulfate, and concentrated under reduced pressure to yield title product.
Following the procedure of Example S, but employing each of the various formula XXXI compounds described following Example 1, there are prepared each of the various formula XXXIII compounds wherein R28 is t-butyldimethylsilyl and Z2 iS

-(CH~)3--Example 6 2-Decarboxy-2-(t-butyldimethylsilyloxy)methyl -9~-methyl-CBA2. 11,15-bis-(tetrahydropyranylether) (Formula XXXIV: 22a, Z2~ n, R18, Y1, M6, L1 and R7 are as defined for Examples 1 and 5).
The reaction product of Example 5 (1.37 g) and 16 ml of methylene chloride is treated with 2.9 ml of dimethyl formamide dineopentyl acetal, stirred for 3 hr at ambient temperature under nitrogen, added to 160 ml of ice water and 40 ml of brine, and extracted with diethyl 10 ether. The ethereal extracts are then washed with 150 ml of sodium bicarbonate and 150 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude title product.
Chromatography on 100 9 of silica gel el uting with 10~ ethyl acetate in hexane yields pure title product.
Following the procedure of Example 6, but employing each of the various formula XXXIII compounds described following Example 5, there are prepared each of the various corresponding formula XXXIV products wherein R28 is t-butyldimethylsilyl and Z2 is -(CH2)3-.
Example 7 2-Decarboxy-2-hydroxymethyl-9~-methyl-CBA2, 11,15-bis(tetrahydropyranyl)ether (Formula XXXV: Z2, n, Rl6, R37, R1g, Yl, M6, Ll, and R7 are as defined in Examples 1 and 5).
Refer to Chart B.
A solution of 0.71 9 of the ~i~le product of Example 6 and 16 ml 25 of dry tetrahydrofuran at 0C under a nitrogen atmosphere is treated with 3.2 ml of 0.75 molar tetra-n-butylammoniumfl uoride and tetrahy-drofuran. After allowing the reaction mixture to slowly warm to ambient temperature overnight w1th stirring, 150 ml of brine is added and the resulting mixture extracted with ethyl acetate. The ethyl 30 acetate extracts are then washed with 0.5 N aqueous potassium bisulfate, 100 ml of sodium bicarbonate, and 100 ml of brine, dried over sodium sulfate; and concentrated under reduced pressure to yield crude title product. Filtering through 25 9 of silica gel with 200 ml of ethyl acetate and hexane yields 0.61 9 of further purified product.
35 Chromatography on silica gel eluting with 35% ethyl acetate in hexane yields pure title product.
Following the procedure of Exampl e 7, but empl oying each of the various formula XXXIV compounds described in and following Example 6, 1 7 ' 71) 3704/3803/3823/3833/3879/3893 there are prepared each of the various formul a XXXV compounds whereinZ2 is -(CH2)3-~
Following the procedure of Examples 5, 6, and 7, and employ;ngthe various starting materials described in and following these 5 exampl es and each of the various formul a XXXII compounds described in and following Example 4, there are prepared each of the various formula XXXY compounds.
Example 8 2-Decarboxy-2-hydroxymethyl-9~-methyl-CBA2 (Formul a XXXYI: Xl is -CH20H, Z2 is -(CH2)3-, ~8 is hydroxy, Yl is trans-CH=CH-, Ml is -OH:~-H, Ll is a-H:~-H and R7 is n-butyl).
Refer to Chart B.
The title product of Example 7 (0.25 g) is combined with 9 ml of acetic acid, water and tetrahydrofuran (6:3:1) and heated to 37-40C
15 for two hr. Thereafter the resulting mixture is cooled and extracted with diethyl ether. The ethereal extracts are then washed with brine, dried over sodium sulfate and concentrated to yield crude title pro-duct. Chromatography on silica gel yields pure title product.
Following the procedure of Example 7, but empl oying each of the 20 various formula XXXV primary alcohols described in and following Example 7 there are prepared each of the various corresponding formula XXXVI products wherein Xl is -CH20H.
Example 9 o-tt-Butyldimethylsilyloxyethyl)benzaldehyde (Formul a XLlV: R28 is t-butyldimethylsilyloxy and 9 is one).
Refer to Chart C.
A. To a mixture of 7.6 9 of lithium aluminum hydride and 400 ml of dry tetrahydrofuran under a nitrogen atmosphere is added dropwise with stirring 18 g of homophthalic acid (Aldrich Chemical Company) in 250 ml of dry tetrahydrofuran. Dropwise addition rate is adjusted 30 such that mild refl ux is maintained during the course of the exothermic reaction. The resulting mixture is then heated at reflux for S hr, cooled to 0C, and 7.6 g of water in 50 ml of tetrahydro-furan is added dropwise with stirring. Thereafter 27 ml of 10 aqueous sodium hydroxide is added and the resulting mixture is stirred 35 at ambient temperature for 20 min, filtered, and the filter solids washed with 150 ml of tetrahydrofuran. The filtrate and tetrahydro-furan wash are then- concentrated under reduced pressure to yield 14.0 g of crude formula XXXII dio1, 2-(o-hydroxymethylphenyl)ethanol.

! 7 ~
~ ' ' 3704/3803/3823/3833/3879/3893 Chromatography on 1.2 kg of silica gel, deactivated by addition of 240ml of ethyl acetate, eluting with ethyl acetate, yields 13.5 g of formula XLII product. Melting range is 41.5-43C.
B. To a solution of 13.5 9 of the reaction product o~ Part A in 50 ml of dry tetrahydrofuran under a nitrogen atmosphere is added with stirring 9.05 9 of imidazole. The resulting solution is then coo1ed to -5C and 13.9 9 of t-butyldimethylsilyl chloride is added. The resulting mixture is then maintained for 20 min and thereafter allowed to warm to ambient temperature. After 1 hr, the resulting mixture is then shaken with 500 ml of hexane and diethylether (2:1) and 250 ml of water and brine (1:1). The organic layer is then washed with water and brine, dried over magnesium sulfate, and concentrated under re-duced pressure to yield a crude mixture of mono- and bis-silyl ethers corresponding to the starting material of Part A. This mixture of products is then chromatographed on 2 kg of silica gel, deactivated with 400 ml of ethyl acetate and eluted with 25X ethyl acetate and Skellysolve* B to yield 6.82 9 of formula XLIII product, o-(t-butyl-dimethylsilyloxyethyl)phenylmethanol. ~MR absorptions are observed at 7.20-7.52, 4.57, 3.91 (t, J G.13, 2.93 (t, J 6.1), 0.82, and -0.08~.
Silica gel ~LC Rf is 0.54 in 25~ ethyl acetate and hexane.
C. A mixture of 5.0 9 of the reaction product of Part R, 100 ml of trichloromethane, and 25 9 of activated manganese dioxide (MnO2) is stirred at ambient temperature for 4 hr. Chloroform (100 ml) is then added and the resulting mixture filtered through diatomaceous earth.
After washing filter solids with 200 ml of trichloromethane, the re-sulting filtrate and wash is then concentrated under reduced pressure to yield a residue containing title product. Chromatography on 400 g of silica gel, deactivated with 80 ml of ethyl acetate and elution with 25Z ethyl acetate and hexane yields 2.93 9 of pure title product.
Silica gel TLC Rf is 0.74 in 25g ethyl acetate and hexane. NMR
absorptions are observed at 10.34, 7.25-8.00, 3.89 (t, J 6.0), 3.27 (t, J 6.0), 0.~3 and -0.09~. The mass spectrum exhibits a peak at 265 (M+1) and other peaks of decreasing intensity at m/e 75, 207, 73, 133, 223, 208, 77, 177, 76 and 105.
Following the procedure described in Chart C, but employing each of the various formula XXXI acids, there is prepared each of the various corresponding formula XXXIV aldehydes wherein R28 is t-butyl-dimethylsilyl.

*trade mark . 7 ~
3704/3803/3823/3833l3879/38g3 Examlole 10 m-(t-butyldimethylsilylox~nethyl)benzaldehyde (Formula XLIV: g is zero and R28 is t-butyldimethylsilyl).
Refer to Chart C.
A. To a solution of 10.0 g of m-(hydroxymethyl~phenylmethanol in 40 ml of dry tetrahydrofuran under a nitrogen atmosphere is added with stirring 7.35 g imidazole. The resulting solution is then cooled to 0C and 11~3 y of t-butyldimethy1silyl is added. The resulting mix-ture is then stirred with cooling for 15 min and thereafter allowed to warm to ambient temperature. After 90 minJ the resulting mixture is then shaken in 400 ml of hexane and diethyl ether (2:1) and 200 ml of water and brine (1:1). The organic layer is then washed successively with water and brine (1:1, 300 ml) and brine (150 ml), dried over mag-nesium sulfate and concentrated under reduced pressure to yield a mix-ture of mono- and bis-t-butyldimethylsilyloxy ether corresponding to the formula XXXII compound. This mixture of products is then chroma-tographed on 1.4 kg of silica gel, deactivated by addition of 280 ml of ethyl acetate and eluted with 25-40qo ethyl acetate in hexane to yield 7.65 g of pure formula XL~II product, m-(t-butyldimethylsilyl-oxymethyl)phenylmethanol. Silica gel TLC Rf is 0.46 in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.25, 4.72, 4.60, 2.23, 0.92, and 0.09~. The mass spectrum exhibits a peak at 251 (M+-1) and other peaks of decreasing intensity at m/e 235, 121, 195, 237, 105, 133, 75, 89, 236, and 119.
B. A mixture of 5.0 g of the reaction product of Part A and 100 ml of trichloromethane and 25 9 of activated manganese dioxide (MnO2) is stirred at ambient temperature for 4 hr. Chloroform (100 ml) is then added and the resulting mixture filtered through diatomaceous earth. The filter solids are washed with 200 ml of trichloromethane and the filtrate and trichloromethane wash are then concentrated under reduced pressure to yield 5.2 g of crude title product. Chromato~
graphy on 400 g of silica gel, deactivated with 80 ml of ethyl acetate and elution with ethyl acetate and hexane (1:3) yields 3.65 g of pure title product. Silica gel TLC Rf is 0.46 in 10% ethyl acetate and hexane. NMR absorptions are observed at 10.00, 7~26-7.86~ 4.81, 0.95, and 0.11~.
Example 11 3-Phenylsulfonyl-7~-tetrahydropyran-2-yloxy-6~-~(3'5)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]-bicyclo-[3.3.0]octane (Formula LV: n is the integer one, Q18 1 3 1 7` " ' 3704/3803/3823/3833/3879/3893 is tetrahydropyranyloxy, Yl is trans-CH=CH-, M6 is a-tetrahydropyranyloxy:~-hydrogen, Ll is c~-hydrogen:-~-hydrogen, Rl6 and R17 are both hydrogen, and R~7 is n-butyl).
Refer to Chart D.
A. Sodium borohydride (0.38 g) is added with stirring to a solution of 2.90 g of 3-oxo-7-tetrahydropyran-2-y1Oxy-6~-~(3'S)-3'-tetrahydropyran-2-yl oxy-trans-1'-octenyl]-bicyclo~3.3.0]octane in 25 ml of 95% aqueous ethanol. The resulting mixture is then stirred at 10 amhient temperature for 20 min. Thereafter th~ resulting mixture is shaken in 100 ml of brine and 200 ml of ethyl acetate. The organic layer is then immediately washed in brine, dried over magnes1um sulfate, and concentrated under reduced pressure to yield 2.94 g of formula LII alcohol: (3RS)-3-hydroxy-7a-tetrahydropyran-2-yloxy-6~-15 C(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl]bicyclo~3.3.0]-octane. Infrared absorptions are observed at 3600 and 3450 cm~ and no carbonyl absorption. Silica gel TLC Rf is 0.63 and 0.~7 in ethyl acetate and hexane (1:1).
B. To d solution of 2.9 g of the reaction product of Part A in 20 25 ml of dry dichloromethane and 1.4 ml (1.02 g) of triethylamine at 0C is added with stirring 0.57 ml (0.848 g) of methanesulfonyl chloride over 5 min. The resulting mixture is then stirred an additional 20 min and shaken with 160 ml of diethyl ether and 80 ml of cold (0C) dil ute aqueous hydrochloric acid. The organic layer is 25 then washed successively in brine, dil ute aqueous potassium bicarbon-ate, and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 3.5 g of crude formula LIIr compound:
(3Rs)-3-hydroxy-7a-tetrahydropyran-2-yloxy-6~-~(3~s)-3'-tetrahydr pyran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]octane, 3-methyl sul fon-30 ate.
C. Thiophenol (1.13 ml, 1.21 g) is added to a mixture of 1.12 9of potassium t-butoxide in 15 ml of dry dimethylsulfoxide (DMS0) under a nitrogen atmosphere. To the solukion of potassium thiophenoxide thus prepared is added 3.5 9 of the reaction produck of Part B in 8 ml 35 of dimethylsulfoxide. The resulting mixture is then stirred at ambient temperature for 16 hr, whereupon additional potassium t-butoxide is added so as to transform the solution to a distinct yellow color. The resulting mixture is then stirred an additional 4 hr at o 3704/3803/3823/3833/3879/3~g3 ambient temperature, diluted with 100 ml of diethyl ether and 100 mlof hexane, washed with 5~0 aqueous potassium hydroxide (200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 5 g of a residue of crude formula EIV
compound: 3-phenylthio-7--tetrahydropyran-2-yloxy-5~-[(3'S)-3'-tetra-hydropyran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]octane. Chroma-tography on 300 9 of silica gel, deactivated with 40 ml of diethyl ether and 40 ml of trichloromethane and eluted with 5% diethyl ether in trichloromethane yields 3.1 9 of pure product. Silica gel TLC Rf is 0.75 in 10% ethyl acetate in dichloromethane.
D. To a solution of 3.1 g of the reaction product of Part C and 50 ml of dichloromethane at 0C is added with stirring over 10 min 2.43 9 of 85% m-chloroperbenzoic acid. The resulting mixture is then stirred at 0C for 30 min, diluted with 150 ml of dry ethyl ether, washed with ice cold dilute aqueous potassium hydroxide and brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield 3.4 9 of crude title product. Chromatography on 350 9 of silica gel, deactivated with 70 ml of ethyl acetate and elution with 500 ml of 30-50% ethyl acetate in hexane yields 2.90 g of pure title product as a mixture of C-6 isomers. Silica gel TLC Rf's are 0.41, 0.45 and 0.48 in 30% ethyl acetate in hexane (stereoisomers). N~R
absorptions are observed at 7.52-8.02, 5.30-5.67, 4.70, and 3.30-4.13~.
Following the procedure of Example 11,. each of the formula LI
compounds is transformed to the corresponding formula LV 3-phenyl-sulfonyl compound.
Example 12 (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 (Formula LX:
X1 is -COOH, g is one, n is one, R16 and R17 are hydrogen, R8 is hydroxy, Y1 is trans-CH=CH-, Ml is -OH:~-H, Ll is -H:b-H, and R7 is n-butyl), its methyl ester~ and the corresponding (5Z) isomers thereof.
Refer to Chart C.
A. To a solution of 1.26 9 of the title product of Example 11 in 15 ml of dry tetrahydrofuran at -78C under a nitrogen atmosphere is added dropwise with stirring 1.48 ml of 1.6 M n-butyllithium in hexane over 1 min. After 10 min 0.66 g of title product of Example 4 in 5 ml of dry tetrahydrofuran is added. After 45 min 0.26 ml of distilled acetic anhydride is added. Stirring is then continued at 7 '~`! 7 0 3704/3803/3823/3833/3879/3893 -78C ,or 3 hr and at ambient temperature for an additional 2 hr. The resulting mixture is then shaken with 120 ml of diethyl ether and 80 ml of saturated aqueous ammonium chloride. The organic 1ayer is then washed with 15 ml of brine, dried over magnesium sulfate, and concen-trated under reduced pressure to yield 2.21 9 of formula LVI productas a mixture of isomers: 3-[a-acetoxy-o-(t-butyldimethylsilyloxy-ethyl)-a-tolyl]-3-phenylsulfonyl-7a-(tetrahydropyran-2-yl)oxy-6~-C(3'S)-3'-(tetrahydropyran-2-yl)oxy-trans-1'-octenyl]bicyclo[3.~.01-octane. R28, g, Rl7, n, Rl8, Yl, M6, L1, and R27 are defined in Examples 9 and 11. Silica gel TLC Rf range is 0.30-0.53 (8 spots3 (stereoisomers) in 25% ethyl acetate and hexane.
3. The mixture of isomeric products of Part A (2.21 9) and 40 ml of methanol and 20 ml of ethyl acetate is stirred at -20C with chips of 5.6% sodium amalgam for 60 min. After decanting liquid, excess amalgam and solids are rinsed by decantation employing 200 ml of diethyl ether. The organic solutions are then combined, washed with brine, dried, and concentrated under reduced pressure to yield 1.8 g of crude 2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-2,5-inter-o-phenylenë 3,4-dinor-CBA2, 11,15-bis(tetrahydropyranyl ether). Chroma-tography on 250 9 of silica gel, deactivated with 5n ml of diethyl ether and eluted with 30% diethyl ether in hexane yields 1.06 g of pure product. Silica gel TLC Rf's are 0.49, 0.56, and 0.62 (stereo-isomers? în 30% di~thyl ether and hexane. NMR absorptions are observed at 7.20, 6.54,~5.22-5.80, 4.72, 3.38-4.16 and 2.74-3.00~.
C. A solution of 1.06 9 of the reaction product of Part B in 10 ml of dry tetrahydrofuran is treated with 3.2 ml of 0.75 N tetra-n-butylammonium fluoride in tetrahydrofuran at ambient temperature for 40 min. The resulting mixture is then diluted with 125 ml of diethyl ether. The resulting solution is then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a resid~e of isomeric formula LYI~ products: (5E)- and (5Z)-2-decar-boxy-2-hydroxymethyl-2,5-inter-o-phenylene-3,4-dinor-CBA2, 11,15-bis-(tetrahydropyranyl ether). Chromatography on 100 g of silica gel, deactivated with 20 ml of ethy! acetate and eluted with 25-50% ethyl acetate in hexane yields 0.40 9 of (SZ) isomer and 0.51 9 of (SE) isomer. For the (SZ) isomer silica gel TLC Rf's are 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.20, 6.51, 5.10-5.72, 4.69, 3.32-4.16, and 2.76-3.00~.

1 3 l 7~5~77 0 3704/3803/3823/3833/3879J3893 For the (5E) isomer silica gel TLC Rf's are 0.20 and 0.24 (stereo-isomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.19, 6.50, 5.10-5.64, 4.70~ 3.32-4.10, and 2.88-3.01~.
D. To a solution of 400 mg of the (5Z) reaction product of Part C in 20 ml of dry acetone at -50C is added with stirring 1.0 ml of Jones reagent ~prepared as follows: 26.72 9 of chromium trioxide in 23 ml of concentrated sulfuric acid diluted with water to a volume of 100 ml). The resulting mixture is then allowed to warm to -20C over a 20 min period and stirred at -20C for 30 min. Excess Jones reagent is then destroyed by addition of 0.5 ml of isopropanol. After 5 min the reaction mixture is then shaken in 100 ml of ethyl acetate and 80 ml of brine containing 0.5 ml of concentrated hydrochloric acid. The organic layer is then washed twice in 50 ml of water containing a trace (10 drops) of concentrated hydrochloric acid, twice in 50 ml of water and in brine. The organic layer is then dried over magnesium sulfate and concentrated under reduced pressure to yield 360 mg of crude (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydro-pyranyl ether), a formula LIX compound. Crude formula LIX compound is then taken up in 30 ml of diethyl ether and extracted in the mixture of 15 ml of water and 5 ml of methanol containing a trace amount (10 drops) of 45% aqueous potassium hydroxide. The extraction is repeated 6 times, until the acid is completely extracted from the ethereal solution. The aqueous extracts are then acidified to pH2 and ex-tracted with ethyl acetate. The organic extract is then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a residue of pure title product. Silica gel TLC is a streak to about Rf 0.50 in ethyl acetate and hexane (1:1). Puri~ied acid is then converted to the corresponding ethyl ester by treatment with excess ethereal diazomethane for 10 min. Following esterifica-tion, the resulting reaction mixture is treated with ethyl acetate andwashed with dilute aqueous potassium hydroxide and brine. After dry-ing and concentrating to a residue, chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and elution with 10% ethyl acetate in trichloromethane yields 210 mg of (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2, methyl ester, 11,15-bis(tetrahydropyranyl ether). Silica gel TLC Rf's are 0.52, 0.56, and 0.60 (stereoisomers~
- in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.20, 6.45, 5.34-5.78, 4.70, 3.68, and 3.30-4.28~.

~ ` 3704/3803/3823/3833/3879/3893 E. A mixture of 200 mg of methyl ester of Part D, 5 ml of aceticacid, 205 ml of water, and 1 ml of tetrahydrofuran is heated to 40C
and stirred for 4 hr. The resulting mixture is then diluted with 100 ml of ethyl acetate and washed with a mixture of 6 g of 85% aqueous potassium hydroxide in 20 ml of water and 30 g of ice, washed with brine (40 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 180 mg of crude (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2, methyl ester. Chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and elution with 100 ml of S~
ethyl acetate in trichloromethane and 100 ml of SO~O acetone in tri-chloromethane yields 105 mg of pure product. Silica gel TLC Rf is 0.57 in 40% acetone and trichloromethane and 0.52 in ethyl acetate.
NMR absorptions are observed at 7.20, 6.43, 5.45-5.59, 3.65, 3.40-4.20, and 3.18~. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 74, 147, 43, 129, 41, 45, 167, 59, and an M+-CsH11 peak at 485.2513.
F. To a solution of 105 mg of the reaction product of Part E in 5 ml of methanol and 2.5 ml of water under a nitrogen atmosphere is added 0.33 g of potassium carbonate. The resulting mixture is stirred Z0 at ambient temperature for 20 hr whereupon a small quantity (5 drops) of 45% aqueous potassium hydroxide is added. The resulting mixture is stirred for an-additional 4 hr at ambient temperature. Thereupon the mixture is shaken with 100 ml of ethyl acetate and excess cold dilute aqueous hydrochloric acid. The organic layer is then washed with brine, dried, and concentrated under reduced pressure to yield 100 mg of pure (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel TLC Rf is 0.56 in the A-IX solvent system (the organic phase of an equil-librated mixture of ethyl acetate, acetic acid, cyclohexane, and water, 9:2:9:10). The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 129, 167, 74, 55, 69, 57, 147, and 45 and an M+-CH3 peak at 599.3418.
&. Following the procedure of Part D, 510 mg of the (5E) reaction product of Part C is transformed to 310 mg of (SE)-2,5-inter-o-phenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydropyranyl ether).
Silica gel TLC Rf is 0.41 in 25% ethyl acetate and hexane con-taining 1% acetic acid, and 220 mg of (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2, 11,15-bis(tetrahydropyranyl ether)methyl ester. Silica gel TLC
Rf's are 0.48, 0.51, and 0.56 (stereoisomers) in 25% ethyl acetate and 1 3 1, 7 37o4/38o3/3823/3~33/3879/3893 hexane. NMR absorptions are observed at 7.20, 6.43, 5.26-5.64, 4.70, 3.65, and 3.30-4.10~.
H. Following the procedure of Part E, the reaction product of Part G (210 mg) is transformed to 110 mg of (5E)-2,5-inter-o-phenyl-ene-3,4-dinor-CBA2, methyl ester. Silica gel TLC Rf is 0.57 in 40 acetone and trichloromethane and 0.46 in ethyl acetate. NMR absorp-tions are observed at 7.22, 6.44, 5.32-5.47, 3.68, 3.50-4.08, and 3.10~. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 129, 227, 167, 55, 57, 173, 74, 466 and an M+-CH3 peak at 541.3198.
I. Following the procedure of Part F, the reaction product of Part H (110 mg) is transformed to 102 mg of (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel TLC Rf is 0.50 in the A-IX
solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 167, 129, 524, 453, 285, 147, 434, 213, and an M -CH3 peak at 599.3424.
Example 13 (5E)-1,5-inter-m-phenylene-2,3,4-trinor-C~A2, its methyl ester, and the corresponding (5Z) isomers.
Refer to Chart D.
A. Following the procedure of Example 12, Part A, a solution of 1.26 g of the title product of Example 6 and 0.62 9 of the title product of Example 5 are transformed to 2.3 9 of formula LVr compound.
Silica gel TLC Rf range is 0.37-0.56 (7 spots)(stereoisomers) in 2570 ethyl acetate in hexane.
B. Following the procedure of Example 12, Part B, the reaction product of Part A (2.3 9) is transformed to 1.0 9 of isomeric formula LVII compounds: (SE)- and (5Z)-2-decarboxy-2-(t-butyldimethylsilyl-oxymethyl)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(tetra-hydropyranyl ether). Silica gel TLC Rf's are 0.47, 0.54 and 0.58 (stereoisomers) in 30% diethyl ether and hexane.
C. Following the procedure of Example 12, Part C, 1.0 9 of the isomerically mixed reaction product of Part B is transformed to 0.51 9 of (5Z)-2-decarboxy-2-hydroxymethyl-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis(tetrahydropyrany1 ether) and 0.40 g of (5E)-2-decarboxy-2-hydroxymethyl-1,5-inter-m-phenylene-2,3,4-trinor-C~A2, 11,15-bis(tetrahydropyranyl ether). For the (5Z)-isomer, silica gel TLC Rf's are 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.18, 6.36, 5.19-5.65, 4.63, 1 3 1 ~ J 7 0 3704/3803/3823/3833/3879/3893 -6~-4.58, 3.31-4.08, and 2.92C. For the (5E)-isomer, silica gel TLC Rf's are 0.23 and 0.27 (stereoisomers) in 25% ethyl acetate and hexane. NMR
absorptions are observed at 7.19, 6.37, 5.29-S.72, 4.67, 4.6n, 3~30-4.17, and 2.78~.
D. Following the procedure of Example 12, Part D, 510 mg of the (5Z) reaction product of Part C is transformed to 310 mg of (SZ)-1,5-inter-m-phenylene-2,3,4-trinor-C8A2, 11,15-bis(tetrahydropyranyl ether) and 240 mg of (5Z)-l,5-inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester, 11,15-bis(tetrahydropyranyl ether). For the acid, sili-ca gel TLC streak to about Rf 0.54 in 50Z ethyl acetate and hexane.
For the methyl ester, silica gel TLC Rf'S are 0.58, 0.63, and 0.68 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are 'observed at 7.28-8.00, 6.40, 5.13-5.73, 4.71, 3.89, and 3.28-4.08~.
E. Following the procedure of Example 12, Part E, 240 mg of the methyl ester product of Part D is transformed to 140 mg of (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester. Silica gel TLC Rf is 0.49 in ethyl acetate. NMR absorptions are observed at 7.28-7.93, 6.40, 5.34-5.48, 3.88, and 3.32~. The mass spectrum of the bis T~S
derivative exhibits peaks of decreasing intensity at m/e ~3, 85, 73, ~7, 213, 75, 129, 48, 87, 77, and an M+-C~3 peak at 527.2996.
F. To a solution of 140 mg of the reaction product of Part E in 6 ml of methanol under a nitrogen atmosphere is added a solution of 0.20 9 of 85% potassium hydroxide in 2 ml of water. The resulting mixture is then stirred at ambient temperature for 7 hr, shaken with 200 ml of ethy1 acetate and excess cold dilute aqueous hydrochloric acid. The organic layer is then washed with brine, dried over magne-sium sulfate, concentrated under reduced pressure to yield 110 9 of pure (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2. Silica gel TLC Rf is 0.60 in the A-IX solvent system. The mass spectrum of the tris T~S
derivative exhibits peaks of decreasing intensity at m/e 73, 271, 394, 129, 420, 510, 75, 147, 32, 74, and an M+-CH3 peak at 585.3234.
G. Following the procedure of Example 12, Part D, 400 mg of the (5E) reaction product of Part C is transformed to 260 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, 11,15-bis~tetrahydropyranyl ether) and 190 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-C~A2, methyl ester, 11,15-bis(tetrahydropyranyl ether). For the acid silica gel TLC streak to about Rf 0.36 in 50% ethyl acetate and hexane. For the methyl ester, silica gel TLC Rf's are 0.50, 0.53, and 0.57 1 3 1 7 j 7 0 3704/3803/3823/3833/3879/3893 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions areobserved at 7.38-7.95, 6.42, 5.13-5.75, 4.68, 3.89, and 3.30-4.09~.
H. Following the procedure of Example 12~ Part E, 190 mg of the reaction product of Part G is transformed to 81 mg of (SE)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester. Silica gel TLC Rf is 0.51 in ethyl acetate. NMR absorptions are observed at 7.30-7.93, 6.43, 5.45-5.59, 3.89, 3.50-4.14, and 3.09~. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing intensity at m/e 73, 213, 129, 75, 83, 452, 173, 85, 262, 362, and an M~-CH3 peak at 527.2996.
I. Following the procedure of Example 13, Part F, 81 mg of the reaction product of Part H is transformed to 65 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2. Silica gel rLC Rf is 0.60 in the A-IX
solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 271, 394, 75, 510, 129, 420, 147, 173, 395, and an M -CH3 peak at 585.3227.
Following the procedure of Examples 12-13, but employing each of the various formula LV compounds described in and following Example 11 in each of the various formula XLIV described in and following Exam-ples 9 and 10, there are prepared each of the various formula L com-pounds in free acid or methyl ester form.
Example 14 9e-methyl-CBA2, methyl ester, 11,15-bis(tetrahydro-pyranyl ether) (Formula LXXXI V: Rl6 is hydrogen, R37 is methyl, Z2 is -(CHz)3- and R1a~ Yl, ~6~ Ll~ and R7 are as defined in Example 3) and the corresponding (SE) and (5Z) free acids (Formula LXXX~II).
Refer to Chart G.
A. A suspension of 57% sodium hydride in mineral oil (1.90 9) is washed with hexane and treated with 130 ml of dry dimethyl sulfoxide (DMS0). The resulting suspension is heated at 65C for 1 hr under a nitrogen atmosphere. and the resulting solution cooled to 15C and treated dropwise over 15 min with 10.0 9 of 4-carboxybutyl~riphenyl-phosphonium bromide. The resultins orange solution is stirred for 15 min at 10C and then treated dropwise over 15 min with a solution of 2.12 9 of the title product of Example 3 in 20 ml of dry DMS0. The resulting solution is then stirred at ambient temperature under a nitrogen atmosphere for 60 hr, treated with 15 ml of water, stirred for 30 min at ambient temperature, added to 200 ml of ice water and t 3 l 7~'' 7 'J 3704/3~03/3~Z3/3833/3879/3893 100 ml of brine, acidified with 1 N aqueous hydrochloric acid, andextracted with 900 ml of diethyl ether. The ethereal extracts are then washed with 1 Q of water and 200 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.8 g of a yellow oil, the formula LXXXIII carboxylic acid.
B. The formula LXXXIII product and 42 ml of diisopropylethylamine in 120 ml of acetonitrile at 10C under a nitrogen atmosphere is treated with 15 ml of methyl iodide and allowed to warm slowly to ambient temperature. The resulting suspension is then stirred for 16 hr, treated with 3.0 ml of methyl iodide, stirred for an additional 2 hr, added to 500 ml of brine, and extracted with 1 ~ of ethyl acetate. The organic extracts are then washed with 250 ml of 0.5 N potassium bisulfate, 250 ml of saturated aqueous sodium bicarbonate, 250 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a solid residue. The residue is then chromatographed on 500 9 silica gel, eluting with 8X
acetone in hexane to yield 2.25 9 of title formula LXXXIV product.
NMR absorptions (CDC13) are observed at 0.9, 1.05, 1.08, 3.66, 3.02-4.35, 4.70, and 4.95~. Infrared absorptions are observed at 1730, 1~70, 1645, 1200, 1165, 1135, 1080, 1035, 102~, 980, and 870 cm . Silica ~el TLC Rf is 0.46 in ethyl acetate and hexane (1:3) and 0.26 in ethyl acetate and hexane (1:6).
C. Alternatively the isomeric formula LXXXIII reaction products of Part A are separated into the (5E) and (5Z) title free acid pro-ducts by chromatograhpy on acid washed silica gel eluting with 10-30%
ethyl acetate in hexane.
Following the procedure of Example 9, but employing each of the various formula LXXXI ketones in place of the Example 3 product, there are prepared each of the various formula LXXXIV methyl esters wherein Z2 is -(CH2)3-' Further following the procedure of Example 14, but employing a formula LXXXII ~-carboxytriphenylphosphonium compound wherein Z2 is other than -(CH2)3-, each of the various formula LXXXI ketones is transformed to corresponding formula LXXXIV ester wherein Z2 is other than -(CH2)3-.
Example 15 (5Z)-2-Decarboxy-2-hydroxymethyl-9e-methyl-C~A2, 11,15-bis(tetrahydropyranyl ether) (Formula LXXXVI:
Rl6, R37, Z2~ Rl8~ M6, Ll, and R7 are as defined in 1 3 7 ~~ 7 0 3704/3803/3823/3~33/3879/3893 Example 14) and its (5E) isomer (formula LXXXVII).
Refer to Chart G.
A suspension of 0.16 g of lithium aluminum hydride in 45 ml ofdry tetrahydrofuran at 0C under a nitrogen atmosphere is treated dropwise with 1.93 g of the title product of Example 14 in 15 ml of dry tetrahydrofuran. The resulting suspension is stirred for 1 hr at 0C and thereafter for 1 hr at ambient temperature. The resulting mixture is then cooled to 0C, quenched by addition of 0.16 ml of water, 0.16 ml of 15% aqueous sodium hydroxide. After stirring for 1 hr at ambient temperature, treatment with magnesium sulfate and filtration with diatomaceous earth, rinsing with diethyl ether, yields a mixture which is concentrated under reduced pressure. The resulting product, 0.25 g, is chromatographed on 180 g of silica gel, eluting with 30% ethyl acetate in hexane to yield 1.03 g of formula LXXXVII
product and 1.06 g of formula LXXXVI product. For the formula LXXXVI
product NMR absorptions (CDCl3) are observed at 0.90, 1.09, 3.2-4.4, 4.72, 5.0-5.9~. Infrared absorptions are observed at 3470, 1760, 1200, 1135, 1120, 1075, 1035, 1020, and 980 cm~ . Silica gel TLC Rf is 0.29 in ethyl acetate and hexane (35:65). For the formula LXXXVII
product ~MR absorptions (CDC13) are observed at 0.90, 1.05, 3.2-4.4, 4.6-4.95, 5.05-5.97~. Infrared absorptions are observed at 3470, 1670, 1200, 1125, 1110, 1080, 1035, 1020, and 985 cm . Silica gel TLC Rf is 0.36 in ethyl acetate and hexane (35:65).
Following the procedure of Example 15, but employing each of the various formula LXXXIV esters described following Example 14, there are prepared each of the respective formula LXXXVI and formula LXXXVII
primary alcohols.
Example 16 (5Z)-9~-methyl-CBA2, methyl ester (Formula LXXXVIII: X
is -COOCH3, R8 is hydroxy, Ml is ~-OH~ , and R16, Rl7, L1, R7, Yl, and Z2 are as defined in Example 15).
Refer to Chart G.
A. A solution of the formula LXXXVI title product of Example 15 in 38 ml of acetone at -20C under a nitrogen atmosphere is treated over 5 min with 1.9 ml of Jones reagent (prepared by dissolving 133.6 9 o~ chromium trioxide in 115 ml concentrated sulfuric acid and diluting with water to a volume of 500 ml), stirred for 2 hr at -20C, quenched by addition of 2.3 ml of isopropanol, stirred for 40 min at -20C, diluted with 200 ml of brine, extracted with 400 ml of ethyl 7 1 7 ',7 ~ 3704/3803/3823/3833!3879/3893 acetate, washed with 600 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 1.n1 g carboxylic acid corresponding to the formula LXXXVI primary alcohol as a pale green oil.
B. A solution of the product of Part A in 11 ml of acetonitrile dt 15~C under a nitrogen atmosphere is treated with 4.1 ml of diiso-propylethylamine and 1.5 ml of methyl iodide. The resulting suspen-sion is then stirred at ambient temperature for 17 hr, treated with 0.3 ml of methyl iodide, stirred for 2 hr at ambient temperature, diluted with 50 ml of brine, extracted with 100 ml of ethyl acetate, washed with 50 ml of 0.5 M potassium bisulfate, 50 ml of aqueous so-dium bicarbonate and 50 ml of brine, dried over anhydrous sodium sul-fate, and concentrated under reduced pressure to yield 1.02 9 of the methyl ester corresponding to the carboxylic acid product of Part A.
C. A solution of the product of Part B in 56 ml of a mixture of tetrahydrofuran, water, and acetic acid (1:2:4) is heated to 45C
under a nitrogen atmosphere for 3 hr, cooled, diluted with 200 ml of brine, and extracted with 400 ml-of diethyl acetate. The organic extracts are then washed with 600 ml of saturated acqueous sodium-bicarbonate and 400 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.9 9 of crude title product as a yellow oil. Chromatographing on 100 9 of silica gel, eluting with hexane and ethyl acetate (3:7) yields 0.39 9 of pure title product as a colorless oil. NMR absorptions (CDC13) are observed at 0.89, 1.08, 3.5-4.35, 3.66, 5.0-5.7~. Infrared absorp-tions are observed at 3360, 1740, 1670, 1455, 1435, 1370, 1240, 1225, 1195, 1170, 1C75, 1020, and 970 cm . Silica gel TLC Rf is 0.22 in ethyl acetate and hexane (7:3).
Following the procedure of Example 16, but employing each of the various for~ula LXXXVI compounds described following Example 15, there are prepared each of the various formula LXXXVIII 9~-methyl-CBA2 compounds wherein X1 is -COORl.
Example 17 (5E)-9~-methyl-CBA2, methyl ester (Formula LXXXIX:
Rl6, Rl7, Xl, Z2, R8, Rl, Ml, L1, and R7 are as defined in Example 16).
Refer to Chart G.
A. Following the procedure of Example 16, Part A, 0.60 9 of the formula LXXXVII product of Example 15 is transformed to the carboxylic 1 3 1 7-~ 7 0 3704/3803/3823/3833/3879/3893 acid corresponding to the formula LXXXVII primary alcohol, yielding0.66 9 of a green oil.
B. Following the procedure of Example 16, Part B, the product of Part A above (0.66 9) is transformed to the methyl ester corresponding to the carboxylic acid product of Part A, yielding 0.58 9 of a yellow oil.
C. Following the procedure of Example 16, Part C, the product of Part B above (0.58 9) is transformed to 0.25 9 of title product as a colorless oil. NMR absorptions (CDCl3) are observed at 0.90, 1.05, 1 3.30, 3.~6, 3.75-4.259 5.0-5.7~. Infrared absorptions are observed at 0 3360, 1740, 1670, 1455, 1435, 1250, 1225, 1195, 1170, 1075, 1020, and 970 cm~ . Silica gel TLC Rf is 0~22 in ethyl acetate and hexane (3:7).
Following the procedure of Example 17, but employing each of the various formula LXXXVII compounds described following Example 15, there are prepared each of the various formula LXXXIX products wherein X1 is -COOCH3.
Example 18 (5Z)-9~-methyl-CBA2.
A solution of 0.28 9 of the title product of Example 16 in 8 ml of methanol is stirred at ambient temperature under a nitrogen atmos-phere and ~reated with 1 ml of 8 M aqueous sodium hydroxide. The resulting yellow solution is then stirred for 5 hr at ambient tempera-ture under a nitrogen atmosphere, diluted with 90 ml of ice and brine, acidified to pH2 with 1 N hydrochloric acid, extracted with 360 ml of ethyl acetate, washed with 120 ml of brine, dried over anhydrous so-dium sulfate, and concentrated under reduced pressure to yield 0.25 9 of crude title product. Chromatography on 30 g of silica gel, eluting with the A-IX solvent system (the organic phase of an equillibrated mixture of ethyl acetate, acetic acid, cyclohexane, and water, 9:2:5:10), yields 0.235 9 of pure title product as a colorless oil.
NMR absorptions (CDCl3) are observed at 0.89, 1.08, 3.5-4.35, 5.0-5.7, 6.05~. Infrared absorptions are observed at 3340, 2660, 1710, 1240, 1205, 1175, 1130, 1075, 1055, 1020, and 970 cm~ . Silica gel TLC Rf is 0.25 in the A-IX solvent system.
Following the procedure of Example 18 each of the various methyl esters prepared following Example 16 is transformed to the corres-ponding carboxylic acid.

1 3 1 7 ~ 7 0 3704/3803/3823/3833/3879/3893 Example 19 (5E)-9~-methyl-CBA2.
Following the procedure of Example 18, 0.25 9 of the title product of Example 17 is transformed to 0.21 9 of title product as a colorless oil. NMR absorptions (CDC13~ are observed at 0.90, 1.06, 3.5-4.3, 5.0-5.7, and 5.93~. Infrared absorptions are observed at 3340, 2660, 1710, 1300, 1240, 1175, 1130, 1075, 105~, 1020, and 970 cm . Silica gel TLC Rf is 0.27 in the A-IX solvent system.
Each of the various carboxylic acids corresponding to LXXXVIII
and LXXXIX wherein X1 is -COOH- can be prepared from the corresponding formula LXXXIII reaction products by acid hydrolysis of the tetra-hydropyranyl ether protecting groups of C-ll and C-15. [The (5Z) LXXXIII re~ction products from Example 14, Part C go to formula LXXXVIII products; and the (5E) LXXXIII reaction products from Example 14, Part C go to formula LXXXIX products.]
Following the procedure of Example 19, but employing each of the various formula LXXXIX methyl esters described following Example 17, there are prepared each of the various corresponding carboxylic acids.
Example 20 2~-(t-butyldimethylsilyloxymethyl)-5~-methyl-7-oxo-3a-tetrahydropyran-2-yl-oxy-bicyclo~3.3.0]octane (Formula LXII: n is the integer one, R31 is t-butyl-dimethylsilyl, and R38 is tetrahydropyranyloxy).
Refer to Chart E.
A. A solution of 40.6 9 of 3a-benzoyloxy-5a-hydroxy-2~-hydroxy-methyl-1-cyclopentaneacetic acid, ~-lactone in 250 ml of dimethyl-formamide, stirring at 0C under a nitrogen atmosphere, is treated with 25 9 of imidazole in 28 9 of t-butyldimethylsilyl chloride. The resulting solution is then stirred for 67 hr at ambient temperature, added to 500 ml of water, extracted with three 500 ml portions of diethyl ether, washed with 500 mi of 10g aqueous potassium bisulfate, 500 ml of aqueous sodium bicarbonate and 500 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 59.9 g of 3-benzoyloxy-5a-hydroxy-2~-(t-butyldimethylsilyloxymethyl)-1a-cyclopentaneacetic acid, ~ lactone as a white solid. NMR absorptions (CDCl3) are observed at 0.06, 0.91, 2.1-3.12, 3.74, 4.94-5.54, 7.24-7.67, and 7.9-8.2~. Infrared absorptions are observed at 1780, 1720, 1600, 1585, 1490, 1270, 1255, 1180, 1115, 1100, 1070, 1050, 830, 790, and 710 cm . Silica gel TLC Rf is 0.20 in ethyl acetate and hexane (1:4).

: 1 3,, - 70 3704/3803/3823/3833/3879/3893 B~ A solution of 59.1 9 of the reaction product of Part A and 500 ml of absolute methanol, stirring at ambient temperature under a nitrogen atmosphere, is treated with 35 ml of a 25% solution of sodium methoxide and methanol. The resulting reaction mixture is then stirred for 90 min at ambient temperature and quenched by addition of 9.5 ml of glacial acetic acid. Methanol is removed under reduced pressure and the resulting residue diluted with 500 ml of saturated aqueous sodium bicarbonate. The resulting mixture is then extracted with two S00 ml portions of ethyl acetate, washed with 300 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 58 9 of an oily solid, crude 3~5a-dihydroxy-2~-(t-butyldimethylsilyloxy-methyl)-la-cyclopentaneacetic acid, ~ lactone. This crude product is then chromatographed in 800 9 of silica gel, eluting with 20-75~ ethyl acetate in hexane to yield pure title product as a white crystal solid. Melting range is 60.5C to 62C. NMR absorptions (CDCl3) are observed at 0.06, 0.90, 1.7-3.0, 3.67, 3.9-4.4, and 4.7-5.13~. Silica gel TLC Rf is 0.3 in 50% ethyl acetate in hexane.
C. A solution of 37.3 9 of reaction product of Part B in 400 ml of methylene chloride, stirring at 0C under a nitrogen atmosphere, is treated with 18 ml of dihydropyran and 0.14 9 of pyridine hydrochlor-ide. The resulting solution is stirred at ambient temperature for 13 hr, treated with an additional 3 ml of dihydropyran and 30 mg of pyrid ne hydrochloride, stirred for an additional 4 hr, washed with two 400 ml portions of saturated aqueous sodium bicarbonate and 400 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced presssure to yield 49 9 of a pale yellow oil, crude 5~-hydroxy-3-tetrahydropyran-2-yloxy-2~-(t-butyldimethylsilyloxymethyl)-1-cyclopentaneacetic acid, ~ lactone. Chromatography on 800 g of silica gel, eluting with 0-75% ethyl acetate in hexane yields 37 9 of pure product as a colorless oil. NMR absorptions (CDC13) are observed at 0.05, 0.90, 1.62, 2.0-3.0, 3.6, 3.2-4.4, 4.67, and 4.8-5.2~.
Infrared absorptions are observed at 1780, 1255, 1175, 1160, 1116, 1080, 1035, 1020, 1005, 975, 835, and 775 cm . Silica gel TLC Rf is 0.25 in hexane and ethyl acetate (2:1).
D. A solution of 28 ml of dimethyl methylphosphonate in 800 ml of dry tetrahydrofuran at -70C under a nitrogen atmosphere is treated with 160 ml of 1.56 M n-butyllithium in hexane, stirred for 30 min at -70C. The resu1ting mixture, maintained at -70C, is then treated dropwise over 30 min with 41.7 g of reaction product of Part C in 200 ml of tetrahydrofuran. The resulting solution is then stirred at -70C for 1 hr, allowed to warm, stirred for an additional 2.5 hr at ambient temperature, quenched by addition of 14 ml of glacial acetic acid, added to 1 Q of brine, extracted with three 700 ml portions of diethyl ether, washed with 500 ml of brineg dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 63 g of a yellow oil, crude 6~-(t-butyldimethylsilyloxymethyl)-3-dimethyl-- 10 phosphonomethyl-3-hydroxy-2-oxa-7a-tetrahydropyranyloxy-bicyclo~3.3.0]
octane. Chromatography on 800 g of silica gel eluting with 50-75~O
ethyl acetate in hexane yields 44.2 g of pure title product as a colorless oil. NMR absorptions (CDC13~ are observed at 0.05, 0.89, 1.23-3.0Z, 2.2-4.37, 4.70, and 4.99~. Infrared absorptions are observed at 3380, 1255, 2235, 1120, 1050, 1035, 835, and 775 cm 1.
Silica gel TLC Rf is 0.25 in ethyl acetate.
E. A suspension of 29.2 9 of chromium trioxide in 700 ml of methylene chloride, stirring at ambient temperature under a nitrogen atmosphere, is treated rapidly with 50 ml of pyridine, treated with 20 dry diatomaceous earth, stirred for 5 min, and then treated with 23.8 g of title product of Part D in 60 ml of methylene chloride. The resulting suspension is then stirred for 45 min at ambient temperature under a nitrogen atmosphere and filtered through 300 g of silica gel, eluting with 2 Q of ethyl acetate in acetone (2:1). Concentration 25 under reduced pressure yields 24 g of a brown yellow oil, crude 3 ~- ( t-butyldimethylsilyloxymethyl)-2a- (2 ' -dimethylphosphonomethyl -2 ' -oxoethyl)^4~-tetrahydropyranyloxy-pentanone. High pressure liquid chromatography of 12 9 of the crude product on silica gel eluting with 20% acetone in methylene chloride yields 4.54 g o~ pure product as a 30 colorless oil. NMR absorptions (CDCl3~ are observed at 0.05, 0.88, 2.8-4.5, 3.77, and 4.86~. Infrared absorptions are observed at 1745, 1715, 1255, 1130, ~115, 1060, 1025, 835, 810, and 775 cm . Silica gel TLC Rf is 0.27 in 20% acetone in methylene chloride and 0.3 in ethyl acetate.
F. A degassed suspension of 0.52 9 reaction product of Part E, 0.15 9 anhydrous potassium carbonate, and 0.59 9 18-crown-6 ether in 20 ml toluene are stirred at 75C for 6 hr under a nitrogen atmosphere and thereafter cooled ~o 0C. The resulting solution is then washed successively with 20 ml brine, a solution of 15 ml water and 5 mlbrine, and 20 ml brine, dried over anhydrous sodium sulfate, and concentrated to yield a brown residue crude 6~-t-butyldimethylsilyl-oxymethyl-7~-tetrahydropyran-2-yl-oxybicyclo[3.3.0]oct-1-en-2-one, filtering thraugh 7 9 of silica gel and eluting with hexane and ethyl acetate (70 ml, 1:,1) yields 0.31 9 of product as an oil. High pressure liquid chromatography (10 ml fractions, 3.8 ml/minute ~low rate) on silica gel, eluting with hexane and ethyl acetate (3:1) yields 0.20 9 o~ pure product as a colorless oil. NMR absorption (CDCl3) of the trimethylsilyl derivative are observed at 0.06, 0.90, 1.20-3.20, 3.20-4.85, and 5.85-6.0~. Infrared absorptions are observed at 1710, 1630, 1250, 1130, 1115, 1075, 1030, 965, 870, 835, 810, 775 cm~ . Silica gel TLC Rf is 0.34 in hexane and ethyl acetate (2:1).
G. A suspension of 0.35 9 of anhydrous copper iodide in 12 ml of anhydrous diethyl ether at -20C under an argon atmosphere is treated dropwise with 2.0 ml of 1.4 M methyllithium. The resulting solution is then stirred at -20C for 15 min, treated at -2n~c dropwise over 1.5 hr with a solution of 0.22 9 of the reaction product of Part F in 12 ml of ~anhydrous diethyl ether. The resulting suspension is then stirred at -20C for 2 hr, added to 50 ml of 1 M
aqueous ammonium chloride, extracted with 150 ml of diethyl ether, washed with 50 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.23 9 of crude title product as a pale yellow oil. Chromatography on 30 g of silica gel, eluting with ethyl acetate and hexane (1:4) yields 0.22 9 of pure title product as a colorless oil. N~R absorptions (CDCl3) are observed at 0.05, 0.90, 1.16, 1.3-2.9, 3.3-4.4, and 4.63~. Infrared absorptions are observed at 1745, 1255, 1135, 1110, 1095, 1075, 1n35, 1020, 835, and 775 cm~ . Silica gel TLC Rf is 0.32 in ethyl acetate and hexane (1:4).
Example 21 N-me~hyl-(1-fluoro-5-tetrahydropyranyloxypentyl)-phenylsulfoximine (Formula XCII: ~2 is -(CH2)32- and R1o is tetrahydropyranyl.
Refer to Chart H.
Diisopropylamine (0.59 9) is dissolved in 21 ml of tetrahydro-furan and the resulting mixture cooled to -78C with stirring under an argon atmosphere. Thereafter triphenylmethane is added, for use as an 7 () 3704/3803/3823/3833/3879/3893 indicator, and a solution of n-butyllithium and hexane is added dropwise until the resulting mixture attains a pink color. After StiPring for an additional 75 min, the resulting mixture is treated with 1.50 g of N-methyl-(5-tetrahydropyranyloxypentyl)-phenylsulfox-imine dissolved in 6 ml of dry tetrahydrofuran. The resulting mixtureis then stirred for an additional 30 min at -78C. Thereafter excess perchloryl fluoride (FCl03) is bubbled through the solution for 4-5 min, during which time a stream of argon is also bubbled through the mixture for safety reasons. The resulting mixture is then stirred at additional 90 min at -78~C and tnen the reaction is quenched by addition of 5% aqueous sodium bicarbonate. After equilibration of the reaction mixture to ambient temperature, the mixture is diluted with additional 5% aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts are then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield 1.64 g of a yellow oil. Chromatography on silica gel columns in a series, eluting with ethyl acetate and hexane (1:1) yields 0.18 g of the formula XCII title product as a mixture of diastereomers. Silica gel TLC Rf in ethyl acetate and hexane (1:1) are 0.54 (less polar isomer) and 0~45 (more polar isomer). NMR absorptions (CDCl3) for the less polar isomer are 1.2-2.15, 3.65, 3.68, 3.1-4.1, 4.4-4.8, 5.5, and 7.4-8.1~. NMR absorptions (CDCl3) for the more polar isomer are 1.15-2.?0, 3.63, 3.1-4.1, 4.45-4.65, 5.27, and 7.4-8.1~.
Following the pracedure of Example 21, but ~mploying each oF the various formula XCI phenylsulfoxamines, there are prepared each of the various corresponding formula XCII fluorinated phenylsulfoxamines.
Example 22 5 Fluoro-2-decarboxy-2-hydroxymethyl-CBA2, 1,11,15-tris(tetrahydropyranyl ether). (Formula XCIV: R16 and R17 are both hydrogen, R1o is tetrahydropyranyl, Z2 iS
-(CH2)3-, n is the integer one, Rl8 is tetrahydropyranyloxy, Yl is trans-CH=CH-, M5 is a-tetrahydropyranyloxy:~-hydrogen, R3 and R4 of the L
moiety are both hydrogen, and R7 is n-butyl).
Refer to Chart H.
Diisopropylamine (164 mg) and triphenylmethane (1.5 mg) are dissolved in 4 ml of dry tetrahydrofuran and the resulting solution is cooled to -78C under a nitrogen atmosphere. A solution of n-butyl-lithium and hexane is added until a faint pink color is attained.

1 3 ; `' 3704/3803/3823/3833/387g/3893 This solution is then stirred an additional 80 min. Thereafter, 0.488 g of the title product of Example 21 in 4 ml of dry tetrahydrofuran is added dropwise. Thereafter 608 mg of 7-oxo-3~-tetrahydropyran-2-yl-oxy-2~-~(3'S3-3'-tetrahydropyran-2-yloxy-trans-1'-octenyl] bicyclo-C3.3.0]octane (Formula XCIII: Rl6, Rl7, n, R18, Y1, M6, L1, and R7 areas defined for the title product) in 4 m1 of tetrahydrofuran is added to the reaction mixture. After 4 min, the resulting mixture is quenched by addition of saturated aqueous ammonium chloride and ethyl acetate is thereafter added to the reaction mixture, which is main-tained at -78QC. The resulting mixture is then allowed to warm until solids separate. Thereupon additional ethyl acetate is added, the reaction extracted with brine. The ethyl acetate layer is then dried over sodium sulfate and concentrated under reduced pressure.
An aluminum amalgam is then prepared by reacting 0.31 9 of 20 mesh aluminum with 2.5 ml of aqueous mercuric chloride followed by washing with ethyl acetate and diethyl ether; The residue from the ethyl acetate layer (described in the preceeding paragraph) is dis-solved in 5 ml of tetrahydrofuran and the solution cooled to 0C.
This cooled solution is then treated with aluminum amalgam, 2 ml of water, and 1 ml of glacial acetic acid. The resulting mixture is then stirred for 2 hr at O~C and 16 hr at 20C. The reaction is then diluted with ethyl acetate and filtered with diatomaceous earth. The ethyl acetate layer is then washed with 5% aqueous sodium bicarbanate and saturated brine, dried over sodium sulfate, and concentra~ed under reduced pressure to yield 0.96 9 as an oily residue. Chromatographing over 100 9 of silica gel and eluting with 500 ml of 15% ethyl acetate in mixed hexanes, 500 ml of 25% ethyl acetate in mixed hexanes, 300 ml of 50% ethyl acetate in mixed hexanes, and 800 ml of 50~O acetone in methylene chloride, taking 20 ml fractions, yields a less polar isomer in fractions 22-26 (~0 mg) and a more polar isomer in fractions 30-36 (74 mg). These isomers represent the C-5 diastereomers o~ the formula XCIV product. For ~he less polar isomer, NMR absorptions (CDCl3) are observed at 0.65-2.65, 3.15-4.15, 4.35-4.75, and 5.25-5.75~. For the more polar isomer, NMR absorptions (CDC13) are observed at 0.6-2.65, 3.10-4.15, 4.40-4.7, and 5.2-5.7~. Silica gel TLC Rf for the less polar isomer is 0.66 and for the more polar isomer is 0.57 in ethyl acetate and mixed hexanes (3:7).
Fol1Owing the proc`edure of Example 22, but employing each of the 1 3 l 7 7~J 3704/3803/3823/3833/3879/3893 various formula XCIII ketones, there are obtained each of the variousformula XCIV intermediates wherein Z2 is -(CH2)3-.
Further following the procedure of Example 22, but substituting each of the various fluorinated phenylsulfoximines described following Example 21, there are prepared from the various formula XCIII ketones each of the various formula XCIV products wherein Z2 is other than -(CH2l3--Example 23 5-Fluoro-2-Decarboxy-2-hydroxymethyl-C8A2 (more polar isomer) (Formula XCV: Rl6, Rl7, Z2~ n, R8, M1, L1, and R7 are as defined in Example 17).
Refer to Chart H.
The title product of Example 22 (74 mg~ is dissolved in 2 ml of a mixture of tetrahydrofuran, water, and glacial acetic acid (2:2:1) and the resulting mixture stirred under a nitrogen atmosphere. The reac-tion mixture is maintained at ambient temperature for 17 hr, there-after at 40C for 7 hr, and finally at 23C for an additional 24 hr.The resulting mixture is then diluted with ethyl acetate, washed with 5~ aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 52 mg of crude title product. Chromatography over silica gel, eluting with acetone and methylene chloride (60:40) yields 19 mg of pure title product. NMR absorptions (CDC13) are observed at 0.6-2.60, 2.6n-3.30, 3.30-4.15, 5.1-5.9~. 13C-NMR absorptions (CDC13) are observed at 135.8, 133,0, 117.5 (d J=18Hz), 77.4, 73.3, 62.6, 57.6, 46.4, 41.1, 38.0, 37.2, 36.2 (d J=S Hz), 31.9, 31.8, 31.2, 29.5 (d J=29Hz), 25.2, 22.5, 14.0~. Silica gel TLC Rf is 0.280 in acetone and methylene chloride (1:1').
Example 24 5-Fluoro-2-decarboxy-2-hydroxymethyl-C3A2 (less polar isomer) Following the procedure of Example 23, 85 mg of less polar title product of Example 22 are transformed to 25 mg of pure title product.
NMR absorptions (CDCl3) are observed at 0.5-2.5, 3.1-4.75, and 5.05-5.8~. C-NMR absorptions (CDC13) are observed at 137.0, 132.6, 77.0, 73.6, 62.3, 57.4, 45.5, 41.6, 36.9, 36.5, 34.4 (d J=3.1Hz), 32.5 (d J=5.4Hz), 31.8, 31.7, 29.2 (d J=28.9Hz), 25.4, 22.6, 22.4, and 14.0~.
Silica gel TLC Rf is 0.33 in acetone and methylene chloride.
Following the procedure of Examples 23 and 24, but employing the various diastereomeric products described following Example 22, there 1 7~ 7~
3704/38~3/3823/3833/3879/3893 are prepdred each of the various diastereomers corresponding toformula XCV.
Example 25 5-fluoro-C8A2 (more polar isomer) (Formula LXXVI: Z2~
n~ R8, Y1, M1, L1, and R7 are as defined in Example 23).
Refer to Chart H.
The platinum oxide catalyst is prepared by suspending 46 mg of 85% platinum oxide in 9 ml of water and hydrogenating the resulting mixture at ambient temperature and pressure for 34 min. To this suspension is added 58 mg of sodium bicarbonate and 18 mg of the title product of Examp1e 23 dissolved in 2 ml of acetone. The resulting mixture is then warmed to 60C and oxygen bubbled therethrough for 80 min. The reaction mixture is then filtered through diatomaceous earth and the filter cake washed in water. The filtrate is then acidified to pH4 with 5% aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The organic extracts are then dried over magnesium sulfate and concentrated under reduced pressure to yield 21 mg of pure title product. NMR absorptions (CDC13) are observed at 0.6-2.8, 3.0-4.2, and 4.65-5.8~. l3C-NMR absorptions (CDCl3) are observed at 176.9, 135.5, 133.2, 118.5 (d J=17.5Hz), 77.7, 73.5, 57.3, 46.5, 41.0, 38.2, 37.0, 36.2 (d J=4.8Hz), 32.3, 31.7, 31.1 (d J=13.5Hz), 28.5 (d J=28.3Hz), 25.2, 22.6, 21.0, and 14.0~. Silica gel TLC Rf is 0.39 in the A-IX solvent system.
Example 26 5-Fluoro-CBA2 (less polar isomer).
Following the procedure of Example 25, 24 mg of the title product of Example 24 yields 23 mg of pure title product. NMR absorptions (CDCl3) are observed at 0.6-2.9, 3.3-4.2, 5.0-6.0~. C-NMR absorp-tions (CDCl3) are observed at 176.8, 135.4, 132.9, 118.3 (d J=18.2Hz), 77.6, 73.4, 57.2, 46.3, 41.2, 37.8, 36.8, 34.6 (d J=2.7Hz), 32.8, 32.4, 31.7, 28~7(d J=28.4Hz), 25.2, 22.6, 21.1, and 14.0~. TLC Rf is 0.50 in the A-IX solvent system.
The reaction products of Example 25-26 are obtained as diastereo-meric mixtures of (5E) and (5Z) geometric isomers. These geometric isomers are characterized herein as "less polar" and "more polar"
isomers based on TLC motilities. The isomers of these 5-fluoro-CBA2 compounds correspond to the (5E) and (5Z~ geometric isomers of CBA2 itself. On the basis of relative biological activities, the more polar 5 fluoro-CBA2 isomer yields more potent pharmacological effects 1 3 1 7 ~ 0 3704/3803/3823/3833/3879/3893 and on this basis could be assigned the (5Z) structure based on phar-macological considerations alone. Ho~ever, the C-NMR data suggests the more polar isomer corresponds to the (SE) structure of the 5-fluoro-C8A2 compound.
Following the procedure of Examples 25-26, there are prepared each of the various formula XCVI S-fluoro-CBA2 diastereomers from the starting materials described following Example 24.
Further following the procedures known in the art, each of the various 5-fluoro-CBA2 compounds described in and following Examples 24-25 is transformed to the corresponding formula XCVII 5-fluoro-CBA2 analogs.
Example 27 (5Z)-9~-methyl-CBA2 adamantylamine salt The title product of Example 18 (54 mg), (5Z)-9~-methyl-CBA2 in 6 ml of diethyl ether is combined with 23 mg of adamantylamine. After 10 min the precipitate forms which is thereafter stirred for 12 hr, decanted, and concentrated under reduced pressure to yield 68 mg of a solid, pure title product. Melting range is 110-114C.
Example 28 (5Z)-9~-methyl-CBA2, calcium salt hydrate.
The title product of Example 18 (0.95 g), 9~-methyl-(5Z)-CBA2, calcium oxide (0.064 g), freshly boiled water (9.2 ml), and distilled tetrahydrofuran (6 ml), are combined by heating to 50C under a nitro-gen atmosphere with stirring for 20 min. The resulting mixture is then filtered, washed with tetrahydrofuran, and concentrated under reducea pressure to yield a residue. The residue is~then dissolved in 2S tetrahydrofuran (10 ml) and concentrated 8 times to yield a cream-colored foam. This foam is then dissolved in 6 ml of tetrahydrofuran which is dripped into anhydrous diethyl ether (95 ml). The resulting suspension is then stirred for 15 min at ambient temperature under a nitrogen atmosphere and filtered. The filter cake is then washed with anhydrous diethyl ether and dried for 20 hr under reduced pressure at ambient temperature to yield 0.686 g of title product. Melting range is 101-108C. Following atmospheric equillibration melting range is 80-117C. Infrared absorptions are observed at 3330, 1670, 1555, 1455, 1345, 1310, 1270, 1075, 1020, 970 cm~1.
Example 29 8a-hydroxy-7~-(3a-hydroxy-trans-l-octenyl)-tr [4.3.1]nonan-4-one, 8,3'-bis(tetrahydropryanyl ether) (Formula XXV: R1ô, Yl, M6, Ll, R27, and n are as defined in Example 1, Rl6 and R37 taken together 1 7 ~ ~ ~7!~
I " J - ' -) 3704/3803/3823/3833/3879/3893 are-CH2- ) Refer to Chart A.
A. The formula XXIV title product of Example 1 (4.0 9) and benzophenone ~2 9) in one liter of methanol is photolyzed (3500 A
lamp) for 3 hr while argon is bubbled through the solution. The methanol is then removed by concentration under reduced pressure and the residue chromatographed on 600 9 of silica gel eluting with a mixture ranging from ethyl acetate in hexane (1:3) to 100~ ethyl acetate. Compound XXVI, 1 ~- hydroxymethyl-7~-hydroxy-6~- (6'~-hydroxy-t rans-1'-octenyl)bicycloC3.3.0]octan-3-one, 7,3'-bis(tetrahydropyranyl ether) is obtained as a white solid (3.45 9). Crystallization from ethyl acetate in hexane yields a white solid with melting range 65-70C. NMR absorptions (CDC13) are observed at 0.89, 1.17-2.90, 2.92-4.40, 4.69, and 5.24-5.77~. Infrared aborptions are observed at 3420, 1730, 1200, 1125, 1110, 1070, 1040, 1020, and 970 cm 1. Silica gel TLC R~ is 0.29 in hexane and ethyl acetate (1:4).
B. A solution of 0.6 g of the reaction product of Part A and 0.49 9 of p-toluenesulfonyl chloride in 30 ml of pyridine is cooled to 0C under argon for 70 hr, added to 100 ml of ice, diluted with 300 ml of water, and extracted with diethyl ether (800 ml). The ethereal extracts are then washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and chromatographed eluting with 50~ to 80% hexane in ethyl acetate to yield 0.49 9 of formula XXVII
compound, 3-oxo-7a-tetrahydropyran-2-yloxy-6~-~(3's)-3'-tetrahydro-pyran-2-yloxy-trans-1'-octenyl]-1~-(p-toluenesolfonyl)-oxymethyl-bicyclo~3.3.0]octane, as a colorless oil. NMR absorptions (COCl3) are observed at 0.88, 1.06-Z.9, 2.45, 3.17-4.35, 4.52-4.83, 5.2-5.8, 7.37, and 7.81 ~. Infrared âbsorptions are observed at 1740, 1600, 1~60, 1200, 1190, 1175, 1130, 1110, 1075, 1035, 1020, 970, and 820 cm 1.
Silica gel TLC Rf is 0.45 or 0.26 in ethyl acetate and hexane (1:1 or 1 2).
C. A degassed solution of 0.49 9 of the reaction product of Part B and 1 ml of t-butanol in 50 ml of dry tetrahydrofuran at 0C under an argon atmosphere is treated with 0.8 ml of 1.7 M potassium t-butoxide in tetrahydrofuran. After 5 min the reaction is allowed to warm and the resulting brown solution stirred for 3 hr at ambient temperature. Thereafter 90 ml of brine is added and the mixture is 1 3 `-' O 37o4/38o3/3823/3833/3879/3893 extracted with 270 ml of ethyl acetate. The ethyl acetate extracts are then washed with 100 ml of saturated agueous sodium bicarbonate, 100 ml of brine, dried over ankydrous magnesium sulfate, concentrated under reduced pressure, yielding 0.37 9 of a brown oil, and chroma- -tographed on 40 g of silica gel eluting with hexane and ethyl acetate (2:1) to yield 0.32 9 of pure formula XXV title product as a colorless oil.
D. Alternatively , a suspension of 207 mg of 57% sodium hydride in mineral oil and 1.08 9 of trimethyloxosulfonium iodide is treated dropwise under a nitrogen atmosphere with 6 ml of dimethylsulfoxide.
The resulting grey slurry is then stirred at ambient temperature for 20 min, treated with 2.03 9 of the title product of Example 1 in 4 ml of dry dimethylsulfoxide and stirred for 2 hr at ambient temperature.
Thereafter stirring is continued for 1 hr at 50C, the reaction mixture is cooled and diluted with 200 ml of water and thereafter extracted with three 100 ml portions of diethyl ether. The combined ethereal extracts are then washed with 200 ml of water, washed with 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, yielding a bro~ln oil, and chromatographed on 250 g of si1ica gel eluting with ethyl acetate and hexane (1:2) to yield 453 mg of pure title product.
E. For title product prepared according to Part C or Part D
above, NMR absorptions (CDC13) are observed at 0.25-2.75, 3.15-4.39, 4.68, and 5.2-5.8~. Infrared abscrptions are observed at 1725, 1665, 1135, 1080, 1040, 1020, 980 cm~1. -The mass spectrum exhibits a molecular ion at 446 and silica gel TLC Rf is 0.30 in ethyl acetate and hexane.
Examele 30 (5Z) and (5E)-6a~,9~-methano-CBA2 (Formula X: Xl is -COOH, Z1 is -~CH2)3-, R15 i-s hydrogen, Rl6 and R17 taken together are methano, n is one, R8 is hydroxy, Y1 is trans-CH=CH-, M1 is a-OH:B-H, Ll is a-H:~-H, R7 is n-butyl, and the C-5, C-6 positions are unsaturated).
Refer to Chart G.
A. A suspension of 452 mg of 57% sodium hydride in mineral oil - 35 and 30 ml of dimethylsulfoxide is heated to 65C for 1 hr under ~
nitrogen atmosphere, coo1ed to 17C and thereafter treated over 15 min with 2.39 9 of 4-carboxybuthyltriphenylphosphonium bromide. The resulting red solution is then stirred for 15 min at 17-20Cl treated 7 1 7 ~ 7 r' J ~I 'j 3704/3803/3823/3833/3879/3893 with a solution of 716 mg of the tit1e product of Example 29~ 6 ml of dry dimethylsulfoxide, stirred for 43 hr at 40CJ cooled to 0C, treated with 3.S ml of water, stirred for 30 min at 05, added tG 75 ml of water and brine (2:1), acidified with one N aqueous hydrochloric 5 acid, and extracted with 225 ml of diethyl ether. The ethereal extracts are then washed with 375 ml of water and 75 ml of brine, dried over magnesium sulfate, concentrated under reduced pressure, and chromatographed on 150 9 of acid-washed silica gel eluting with 10-2570 ethyl acetate in hexane to yield 290 mg of (SZ)-6a~,9~-methano-CBA2, 11,15-bis(tetrahydropyranyl ether), 70 mg of (5E~-6a~,9g-methano-CBA2, 11,15-bis(tetrahydropyranyl ether), and 400 mg of a mixture of (5E) and (5Z) formula LXXXIII isomers. Rechromatographing the isomeric mixture on 150 9 of acid-washed silica gel yields an additional 50 mg of (5E) isomer and 180 mg of (5Z) isomer.
For the (5Z) isomer NMR absorptions (CDC13) are observed at 0.5-2.85, 3.22-4.4, 4.70, 4.9-5.75, and 10.1 ~. Infrared absorptions are observed at 3600-3000 (a broad band), 1740, 1710, 1240, 1210, 1135, 1080, 1035, 1020, 980, and 870 cm~1. Silica gel TLC Rf is 0.27 in hexane, ethyl acetate, and acetic acid (65:34:1). For the (5E) isomer NMR absorptions are observed at 0.40-2.70, 3.2-4.4, 4.70, 5.0-5.8, and 8.82~. Infrared absorptions are observed at 3600-3000, 1740, 1710, 1460, 14~5, 1200, 1135, 1075, 1035, 1020, and 980 cm~1.
Silica gel TLC Rf is 0.32 in hexane, ethyl acetate, and acetic acid (65:3~:1). -B. A solution of 446 mg of the (5Z) reaction product of Part A
in 44 ml of acetic acid, water, and tetrahydrofuran (6:3 2) is heated at 45C under a nitrogen atmosphere for 3 hr, cooled, added to 200 ml of brine, extracted with 160 ml of ethyl acetate in hexane (3:2), washed with 500 ml of ~rine, extracted ~ith 120 ml of ethyl acetate and hexane (3:2) dried over sodium sulfate, concentrated under reduced pressure, yielding 0.38 g of a yellow oil and chromatographed on 60 9 of acid washed silica gel eluting with 70% ethyl acetate in hexane to yield 170 mg of pure (5Z) title product as a colorless oil. NMR
absorptions are observed at 0.5-2.90, 0.89, 4.05, 4.B5-5.8, and 6.13~.
Infrared absorptions are observed at 3360, 2260, 1710, 1245, 1240, 1075, 1025, and 970 cm~1. The mass spectrum for the tris-trimethyl-silyl derivative exhibits a high resolution peak at 578.3653. Silica gel TLC Rf is 0.30 in the A-IX solvent system (the organic phase of an 7 1 7 / 7 r i / J 3704/3803/3823/3833/3879/3893 equilibrated mixture of ethyl dcetate, acetic acid, cyclohexane, andwater; 9:2:5:10).
C. Following the procedure of Part B above 90 mg of the (5E) reaction product of Part A is converted to 46 mg of (SE) title product S as a colorless oil. NMR absorptions are observed at 4.40-2.8, 0.89, 4.06, and 5.0-5.85 ~. Infrared absorptions are observed at 3340, 2630, 1710, 1070, 970 cm~1. The mass spectrum exhibits a high resolution peak at 578.3664. Silica gel TLC Rf is 0.32 in the A-IX
solvent system.
Following the procedure of Examples 27-29, each of the various formula X products is prepared wherein Rl6 and R17 are methano from the corresponding formula LXXXI reactants of Chart G.
Accordingly, the above examples provide methods for preparing each of the various formula X CBA analogs of the present invention.
Example 31 9-deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1~ (Formula XI: Xl is COnH, R20, R2l, R23, and R24 are all hydrogen, Z4 iS -CH2-, R22 is ~-hydrogen, R8, Y1, ~1~ Ll, and R7 are as defined in Example 8) and its corresponding methyl ester (Xl is -COOCH3).
Refer to Chart P.
A. A solution of methyl phenyl-N-methyl sulfoximine (3.39 9) in dry tetrahydrofuran (60 ml), is alternately degassed and flushed with nitroyen, cooled to -78C and treated dropwise ov~r 7 min with 2.8 M
methyl magnesium chloride (7.16 ml). The resulting solution is stirred at -78C for 30 min, then at 0C for 15 min. The reaction is cooled to -78C and treated with a solution o~ 3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGEl, 3-(t-butyldimethylsilyl ether), 11;15-bis(tetrahydropyranyl ether~ (6.05 9), a formula CLXXI compound, in dry tetrahydrofuran (35 ml). The resulting mixture is stirred for 1.75 hr while the temperature permitted to go from -78C to 0C and then stirred for one hr at 0C. The reaction mixture is then diluted with brine (170 ml) and extracted with diethyl ether. The ethereal extracts are then washed successively with brine (170 ml), 0.5 aqueous potassium bisulfate (170 ml), saturated aqueous sodium bicar-bonate (170 ml) and brine (170 ml), dried over magnesium sulfate, filtered and concentrated to a yellow oil (8.0 9), 9-[(N-methyl)-phenylsulfoximinomethyl]-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-1 3 1 ~ ! ~) 3704/3803/3823/3833/3879/38g3 phenylene-PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetra-hydropyranyl ether). A degassed solution of 9-C(N-methyl)phenylsul-foximinomethyl]-3-oxa-1,Z,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), ;1,15-bis(tetrahydropyranyl ether) (8.0 g) in tetrahydrofuran (150 ml) is cooled to 0C, treated with 50%
acetic acid/water (45 ml) then immediately with aluminum amalgam under nitrogen. (The aluminum amalgam is prepared by washing 20 mesh alumi-num, 8.00 9, with diethyl ether, 170 ml, methanol, 340 ml, mercuric chloride, 8.03 g, in water, 275 ml, methanol, 170 ml, and diethyl ether, 170 ml).
The resulting black suspension is stirred for 1.75 hr during which the reaction temperature is permitted to go from 0 to 15C
(slowly) then cooled to 0, treated with ethyl acetate ~210 ml) and stirred for an additional 30 min at 0C. The suspension is filtered through diatomaeous earth and the filter cake washed with ethyl acetate. The combined filtrate is then washed with brine (300 ml), 0.5 M aqueous potassium bisulfate (300 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (300 ml), dried, filtered, and concentrated to a yellow oil, crude formula CLXXII compound (6.03 g), 9-deoxy-9-methylene-3-oxa-1,2,3,4,5,6-pentanor-3,7-inter-m-phenylene-P
GF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether). The crude product is combined with that from a repeat preparation to yield 10.1 g of formula CLXXII product which is chromatographed on silica gel eluting with 5% ethyl acetate in Skellysolve B (SS8, isomeric hexanes) to yield 6.93 g of 9-deoxy-9-methylene-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether).
NMR absorptions are observed at 4.52-5.12 and 6.53-7.30~. Infrared absorptions are observed at 1600 and 1655 cm~l. Silica gel TLC ~f is 0.39 in 10% ethyl acetate in hexane.
B. A degassed solution of 9-deoxy-9-methylene-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether), the reaction product of Part A, (1.33 g) in dry tetrahydrofuran (70 ml) is cooled to 0C and treated under nitrogen with 0.5 M 9-borabicyclo~3.3.1]nonane (14 ml), dropwise over 5 min. The colorless solution is stirred for 4.5 hr at 0 and treated with 30% hydrogen peroxide (6 ml) followed by 3 N potassium hydroxide (6 ml). The resulting suspension is stirred for an addi-~ ' 3704/3803/3823/3833/3879/3893-80-tiona1 30 min at 0C and for 75 min while warming to room temperature.The reaction mixture is transferred to a separatory funnel, diluted with brine (300 ml) and ethyl acetate (300 ml). The layers are separated, and the aqueous layer extracted with ethyl acetate (600 ml). The organic extracts are washed with brine (6 ml), dried, filtered, and contrated to formula CLXXIII product, a colorless oil (3.3 g), 9-deoxy-9~-(hydroxymethyl)-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis-(tetrahydropyranyl ether). The crude formula CLXXIII product is chromatographed on silica gel (300 g) in 35% ethyl acetate in hexane to yield 1.26 y of 9-deoxy-9-(hydroxymethyl)-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether) as a colorless oil. NMR absorp-tions are observed at 4.73, 5.12-5.70, 6.52-7.23~. Infrared absor-ptions are observed at 3480 and 1670 cm~1. Silica gel TLC Rf is 0~21in 35% ethyl acetate in hexane.
C. A degassed solution of 9-deoxy-9a-hydroxyme~hyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether) (2.01 9), reaction product of Part B, in dry methylene chloride (45 ml) is cooled to -5C under nitrogen and treated with triethylamine (0.72 ml), then with methane-sulfonyl chloride (0.76 ml). The resulting solution is stirred at -5C for S min then for 75 min while warminy to ambient temperature.
The reaction solution is poured cver ice, and the resu~ting mixture swirled for a few minutes then transferred to a separatory funnel and partitioned between diethyl ether and brine. The layers are sepa-rated, and the aqueous layer extracted with ether (400 ml). The organic layer is washed with brine (200 ml) and saturated aqueous sodium bicarbonate (400 ml), dried, filtered, and conctrated to a ~ormula CLXXIV product, a colorless oil (2.69 9), 9-deoxy-9~-mesyl-oxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether).
This product (2.69 9) is chromatographed on silica gel (185 g) eluting with 25Z ethyl acetate in Skellysolve B to yield 1.99 g of 9-deoxy-9~
-mesyloxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1), ~ 11,15-bis(tetrahydropyranyl ether). NMR absorptions are observed at2.95, 4.70, 5.20-5.70, and 6.52-7.22~. Silica gel TLC Rf is 0.30 in 35% ethyl acetate in hèxane.

1 3 1 ~ j~3 3704/3803/3823/3833/3879/3893 D. A degassed solution of 9-deoxy-9-mesyloxymethyl-3-oxa-1,2,4~5,6-pentanor-3,7-inter-m-phenylene-PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether) (0.971 9), the reaction product of Part C9 in dry tetrahydrofuran (35 ml) is cooled to 0C and treated under nitrogen with 0.75 M tetrabutylammonium fluoride (2.6 ml). The resulting amber solutoin is stirred for 2.5 hr at 0-5C and is partitioned between ethyl acetate (150 ml) and brine (150 ml). The layers are separated, and the aqueous layer extracted with ethyl acetate (300 ml). The organic layer is then washed with 0.5 M aqueous ammonium chloride (150 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (150 ml), dried, filtered and concentrated to give 0.82 g of formula CLXXV product~ 9-deoxy-9~-mexyloxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF 1, 11,15-bis(tetrahydropyranyl ether. Infrared absorptions are observed at 3330 cm~1. Silica gel TLC Rf is 0.37 in 50% ethyl acetate in hexane.
E. A degassed solution of 9-deoxy-9-mesyloxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFl, 11,15-bis(tetrahydro-pyranyl ether) (0.82 9), reaction product of Part D, is cooled to -40C under argon and treated with 57% sodium hydride (0.67 9). The resulting suspension is then stirred for 40 min at -40C then 15 min at 0C. The suspension is stirred for an additional 20 min while warming to room temperature and then stirred for 2.5 hr at reflux.
The reaction is then cooled to 10C, diluted with ice cold brine (2nO
ml) and extracted with ethyl acetate (450 ml). The ethyl acetate extracts are then washed with brine (300 ml), dried, filtered and concentrated to give 0.72 9 of the formula CLXXVI crude product. The crude product is chromatographed in silica gel (175 g) in 25% ethyl acetate in Skellysolve B to yield 0.49 9 of 9-deoxy-2',9-methano-3-oxa-1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-PGFl, 11,15-bis-(tetrahydropyranyl ether). NMR absorptions are observed at 4.77,5.32-6.03, and 6.52-7.22~. Infrared absorptions are observed at 3340 and 1670 cm~1. Silica gel TLC Rf is 0.56 in 35~ ethyl acetate in hexane.
F. A degassed solution of 9-deoxy-2',9-methano-3-oxa-1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-PGFl, 11,15-bis(tetra-hydropyranyl ether) (0.47 9), reaction product of Part E, in dry glyme (15 ml) is cooled to 0C and treated under nitrogen withmethyl bromo-acetate (0.26 ml) followed by 57% sodium hydride suspension (0.136 9).

7 ~ 7 3 3704/3gO3/3823/3833/3879/3893 Following vigorous effervescence, a white precipitate is formed. Theresulting suspension is stirred for 2.5 hr at 0-5C, diluted with ice cold brine (200 ml) and extracted with ethyl acetate (450 ml). The ethyl acetate extracts are washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated to a pale yellow oil (0.62 g), formula CLXXVII compound, 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGF1, methyl ester, 11,15-bis(tetra-hydropyranyl ether). Infrared absorptions are observed at 1765 and 1740 cm~1.
G. A solution of 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1, methyl ester, 11,15-bis(tetrahydro-pyranyl ether) (0.62 9), reaction product of Part F, in acetic acid (15 ml), water (7.5 ml) and tetrahydrofuran (5 ml) is reacted at 45C
under nitrogen for 2.75 hr, cooled and diluted with ice cold brine (200 ml). The resulting suspension is extracted with ethyl acetate (400 ml), and the organic extracts washed with brine (400 ml), saturated aqueous sodium bicarbonate (600 ml) and brine (200 ml). The ethyl acetate extracts are then dried over magnesium sulfate, filtered and concentrated to give 0.44 9 of pale yellow oil.
This crude product is chromatographed on silica gel (60 9) in 50~O
ethyl acetate in Skellysolve B to yield 0.37 9 of product which was crystallized to yield 0.216 9 of title product, 9-deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF~, methyl ester.
Melting range is 82-84C. NMR absorptions are observed at 3.77, 4.62, 5.42-5.63, and 6.53-7.25~. Infrared absorptions are observed at 3520, 3400, and 1735 cm 1. Silica gel TLC Rf is 0.30 in 35% acetone in methylene chloride.
H. A solution of 9-deoxy-2'-9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1, methyl ester (0.15 9), reaction product of Part G, in 5% potassium hydroxide in 9:1 methanol-water (5.5 ml) is stirred at 0C under nitrogen. The solution is turbid initially and a precipitate forms within 5 min. The reaction is then stirred for one hr at 0C, diluted with ice cold brine (90 ml), acidified with 1 N
hydrochloric acid, and extracted with ethyl acetate (180 ml). The ethyl acetate extract is then washed with brine (270 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield a waxy, semi-solid (0.131 9), which is crystallized to yield 0.105 9 of title product, 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-1 3 I J 7 ~ 3704/3803/3823/3833/3879/3893 inter-phenylene)PGF1. Me1ting range is 131-133C. NMR absorptions are observed at 4.68, 5.48-5.72, 6.68-7.22. Infrared absorptions are observed at 3460, 3280, 1735, 1720, and 1700 cm~1.
I. The dosage at which the title compounds should be adminis-tered to achieve their effect, chiefly anti-platelet aggregation or blood pressure lowering, will vary according to the potency of the particular compound under study. When given orally, the compounds will show a desired èffect in man at a dose from about 0.05 to about SO mg/kg orally, preferably from about 0.1 to about 5 mg/kg. The compounds 9-deoxy-2',~a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1, methyl ester, given to a rat orally at a dose of 1 mg/kg lowered blood pressure 44 mmHg. After 52 min the blood pressure was still lower 14 mm. Intravenous dosages for the desired effect are from about 1 to about SOO ng/kg/min in man, preferably from about 10 to about 100 ng/kg/min.
Example 32 9-Deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'~
inter-phenylene)-16,16-difluoro-PGFl tFormula XI: X1 is -COOH, Ll is -fluoro:B-flUOrO, R20, R20, ~21' R23' and R24 are all hydrogen, Z4 i 5 -CH2-, R22 i S
~-hydrogen, R8, Yl, M1, and R7 are as defined in Example 8) and its corresponding methyl ester (Xl is -COOCH3).
Refer to Chart P.
A. Diethyl ether (55 ml) tri-n-butylphos~hine (2.28 9) and cuprous iodide (2.13 9) are combined with stirring with the resulting mixture being alternately degassed and flushed with nitrogen at 25C
for 1 hr. The resulting solution is then cooled to -78C and is hereafter referred to as solution 32-I. Thereafter 60 ml of anhydrous diethyl ether and 6.47 9 of m-bromo-phenol, t-butyldimethylsilyl ether are combined and the resulting solution alternately degassed and flushed with nitrogen and cooled to -78C. After cooling, the resulting mixture is treated with 44.16 ml of a 1.02 M solution of t-butyllithium in n-pentane. This reaction mixture is then stirred at -78C for 1 hr and hereinafter referred to as solution 32-II.
Solution 32-II is then transferred with stirring over 15 min to solution 32-I under a nitrogen atmosphere. The resulting solution changed in color from clear to yellow to an orange-brown to tan.- The resulting mixture is then stirred at -78C. for 30 min and labelled 1 3 7 '73 3704/3803/3823/3833/3879/38g3 solution 32-III. Thereafter 4a-hydroxy-3~-(4~4l-difluoro-3 hydroxy-trans-1'-octenyl)-2-methylene-cyclopentanone, 4,3'-bis(tetra-hydropyran-2-yl ether), 4 9, Example 25 of United States Patent-4,181,798, and 38 ml of anhydrous dry ethyl ether are combined with stirring and the resulting mixture alternately degassed and flushed with nitrogen and thereafter cooled to -78C. The resulting solution is referred to herein as solution 32-IV. Solution 32-IV is then added to solution 32-III with vigorous stirring over 25 min at -78C under a nitrogen atmosphere. The reaction mixture is then stirred at -78C
for 30 min and thereafter transferred to 100 ml of 8% glacial acetic acid in diethyl ether (-40C) with vigorous stirring under a nitrogen atmosphere. The resulting mixture is then diluted with brine and extracted with diethyl ether. The ethereal extracts are then washed with aqueous sodium bicarbonate in brine, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica ~el eluting with 20% ethyl acetate in Skellysolve B to yield 5.56 g of pure formula CLXXI compound: 16,16-difluoro-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGEl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyran-2-yl ether). NMR absorptions (CDCl3) are observed at 0.18, 3.1-5.0, 5.67, 6.5Z-6.88, and 6.88-7.2 ~. Infrared absorp-tions are observed at 1745, 1600, 1585, 1490, 1275, 1260, 1200, 1155, 1125, 1075, 1035, 1025, 975, 840, and 780 cm~1. Silica gel TLC Rf is 0.36 and 0.41 in 25% ethyl acetate in Skellysolve B. Silica gel TLC
Rf is 0.5 in 5% acetone in methylene chloride.
8. Following the procedure of Example 31, Part ~, 3.47 g of the reaction product of Part A of this example is converted to 2.98 9 of formula CLXXII product as a colorless oil, 9-deoxy-9-methylene-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGF1, 3-(t-butylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMR absorp-tions are observed at 0.17, 0O97~ 1.0-3.2, 3.2-4.4, 4.4-5.0, 5.3-6.0, and 6.4-7.3~. Infrared absorptions are observed at 1655, 1605, 1585, 1485, 1275, 1260, ~200, 1144, 1125, 1080, 1025, 970, 870, and 780 cm 1. Silica gel TLC Rf is 0.31 and at 0.36 in 10~ ethyl aceta~e in hexane.
C. Following the procedure of Example 31, Part B, 2.83 9 of the reaction product of Part B of this example is converted to 2.S g of formula C-XXIII product as a colorless oil 9 9-deoxy-9~-(hydroxy-methyl)-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-7 ~ ~ r ` ~ 3704/3803/3~23/3833/3879/3893 PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMR absorptions (CDC13) are observed at 0.18, 0.98, 1.15-3.0, 3-0-4.5, 4.5-5.0, 5.3-5.~, and 6.4-7.3~. Infrared absorptions are observed at 3460, 1670, 1600, 1585, 1485, 1275, 1Z60, 1160, 1135, 1125, 1075, 1025, 975, 840, and 780 cm~l. Silica gel TLC Rf is 0.28 in 35~ ethyl acetate in hexane.
D. Following the procedure of Example 31, Part C, the reaction product of Par~ C of this example (2.29 g~ is converted to 1.83 g of formula CLXXIV product as a colorless oil, 9-deoxy-9a-mesyloxymethyl-10 3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether).
NMR absorptions are observed at 0.18, 0.98, 1.15-2.85, 2.95, 311-4.5, 4.5-5.0, 5.2-5.9, and 6.5-7.4~. Infrared absorptions are observed at 2930, 2860, 1605, 1590, 1490, 1465, 1440, 1360, 1275, 1200, 1175, 1120, 1025, 975, and 840 cm l. Silica gel TLC Rf is 0.28 in 30% ethyl acetate and hexane.
E. Following the procedure of Example 31, Part D, 1.7 9 of the reaction product of Part D of this example is converted to 1.6 g of formula CLXXV product as a yellow oil, 9-deoxy-9~-mesyloxymethyl-3-oxa-1,2,4J5,6-pentanor-3,7-inter-m-phenylene-16,16-difluoro-PGFl, 11J15-bis~tetrahydropyranyl ether). Silica gel TLC Rf is 0.34 in ethyl acetate and hexane (1:1).
F. Following the procedure of Example 31, Part E, 1.52 9 of the reaction product of Part D of this example is converted to 0.83 9 of formula CLXXVI product as a white foam, 9-deoxy-2',9a-methano-3-oxa-1,2,4,5,6-pentanor-3,7-(1' ,3'-inter-phenylene)-16,16-difluoro-PGFl, 11,15-bis(tetrahydropyranyl ether). NMR absorptions are observed at 0.95, 1.05-2.95, 3.5-5.0, 5.3-6.0, and 6.5-7.2~. Infrared absorptions are observed at 3350, 2930, 1670, 1615, 1590, 1465, 1280, 1200, 112n, 1070, and 975 cm~l. The mass spectrum exhibits peaks at 534, 451, 446~ 402, and 348. Silica gel TLC Rf is 0.26 in ethyl acetate and hexane (1:3) and 0.40 in acetone and methylene chloride (1:19).
G. Following the procedure of Examp1e 31, Part F, 0.80 9 of the reaction product of Part F of this example is converted to 1.06 9 of formula CLXXVII product as a colorless oil, 9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-16,16-difluoro-PGFl, methyl ester, 11,15-bis(tetrahydropyranyl ether). Silica gel TL~ Rf is 0.44 in 5% acetone and methylene chloride.

H. Follow1ng the procedure of Example 31, Part G, 1.0 g o~ the reaction product of Part G of this example is converted to 0.62 9 of crystalline methyl ester title product, a Formula CLXXVIII white solid. Recrystallization from hexane in diethyl ether yields a material with melting range 93-95C. ~MR absorptions are observed at 0.95; ].10-2.90, 2.90-4.8, 5.4-5.8, and 6.4-7.3. Infrared absorptions are observed at 3560, 3400, 1765, 1750, 1735, 1720, 1675, 1605, 1585, 1~70, 1215, 1205, 1120, 1105, 1080, 1010, 970, and 770 cm 1. The mass spectrum for the bis-trimethylsilyl derivative exhibits a high resolu-tion peak at 582.2997. Silica gel TLC Rf is 0.35 in hexane and ethyl acetate (1:4).
Following the procedure of Example 31, Part H, the reaction product of Part H of this example (0.25 g) is converted to the carboxylic acid title product (158 mg) as a crystalline solid.
Melting range is 128-130C. NMR absorptions (COCD3) are observed at 0.9, 1.3-3.0, 3.0-4.6, 4.68, 4.8-5.5, 6.5-6.9, 5.5-5.9, and 6.6-7.3~.
Infrared absorptions are observed at 3570, 3480, 3370, 3220, 2800, 1740, 1720, 1605, 1585, 1235, 1210, 1125, 1105, 1080, 1000, and 970 cm~1. The mass spectrum for the tris-trimethylsilyl derivative exhi-bits a high resolution peak at 640.3232. Silica gel T~C Rf is 0.18 in the A-IX solvent system.
Following the procedure of Examples 31 and 32, there are prepared each of the various formula CLXXVIII products in free acid or ester form from corresponding formula CLXXI reactants.
2S Formula CLXXV~II compounds wherein Yl is unsaturated (trans- or cis-CH=CH-) are transformed to corresponding formula CLXXVIII com-pounds wherein Y is saturated (-CH2CH2-) by hydrogenation, as exemplified below:
Example 33 9-Deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-13,14-dihydro-PGF1 (Formula XI: Xl is COOH~ Yl is -CH2CH2-, R20, R21, R23, and R24 are all hydro~en, Z4 iS -CH2-, R22 iS ~-hydrogen, R8, Ml, L1, and R7 are as defined in Example 8) and its corres-ponding methyl ester (X1 is -COOCH3).
A. A solution of the methyl ester title product of Example 31 (0.341 9) in ethyl acetate (35 ml) is treated at ambient temperature with 5% palladium-on-charcoal and hydrogenated at atmospheric pres-sure. The resulting suspension is then stirred for 70 minutes with a 7~ 7~7r 1 ' I ,1 ~) ` ~ 3704/3803/3823/3833/3879/3893 hydrogen uptake of 20 ml (atmospheric pressure). The resulting sus-pension is then filtered through diatomaceous earth and the filter cake washed with ethyl acetate. The combined filtrate is then con-centrated under reduced pressure to yield a colorless oil which is chromatographed on silica gel eluting with ethyl acetate in Skelly~
solve B to yield 0.306 9 of title product (methyl ester), a colorless oil~ NMR absorptions (CDC13) are observed at 0.9, O. 1.07-1.23, 3.3-4.03, 3.77, 4.62, 6.52, and 7.27~. Infrared absorptions are observed at 3350, 2930, 2855, 1760, 1740, 1605, 1585, 1467, 1435, 1275, 1205, 1120, 1080, 1025, and 775 cm 1. Silica gel TLC Rf is 0.54 in ethyl acetate.
B. Following the procedure of Example 31, Part H, the title product of Part A of this example (0.177 g) is converted to 0.23 g of title product (free acid) as a solid. Recrystallization from ethyl acetate in hexane yields 0.096 9 with melting range 121-123C. The mass spectrum for the tris-trirnethylsilyl derivatives exhibits a high resolution peak at 606.3553 and other peaks at 591-535, 516, 427, 426, 275, 274, 173, and 157. Silica gel TLC Rf is n.27 in A-IX.
Example 34 9-Deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl (Formula XI: Xl is COOH, R20, R21, R22, and R2~ are all hydrogen, Z4 iS -CH2-~ R22 iS
~-hydrogen, R8, Yl, M1, L1, and R7 are as defined in Example 8) and its corresponding methyl ester (Xl is -COOCH3).
Refer to Charts Q and R.
A. A solution of 0.82 9 of the reaction product of Example 31, Part B, in 16 ml of methylene chloride is stirred at ambient tempera-ture under nitrogen atmosphere and treated with diatomaceous earth followed by 26 ml of Collins reagent prepared from 2.5 ml of pyridine and 1.55 9 of chromium trioxide in 50 ml of methylene ch10ride). The resulting suspension is then stirred for 35 min at ambient temperature under a nitrogen atmosphere and filtered through 30 9 of silica gei, eluting with 150 ml of ethyl acetate. Concentration under reduced pressure yields 0.90 9 of a pale yellow oil. Chromatographing on 85 9 of silica gel eluting with 20% ethyl acetate in Skellysolve ~ yields 0.644 9 of pure formula CLXXXII aldehyde as a colorless oil, 9-deoxo-9a-formyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGE1, 3-(t-1 7 1 7 ' -7 !l ''' iJ 3704/3803/3823/3833/3879/3893 butyldimethylsilyl ether), 11,15-bis(tetrahydropyranyl ether). NMR
absorptions are observed at 0.18, 0.88, 0.98, 1.13-3.08, 3.23-4.35, 4.73, 5.25-5.75, 6.57-7.37, and 9.88~. Infrared absorptions are observed at 2730, 1720, 1600, 1585, 1~85, 1275, 126n, 1075, 1035, 1030, 1020, 975, and 840 cm~1. Silica gel TLC Rf is 0.47 in ethyl acetate and hexane (1:3).
B. A degassed solution of 1.5 g of the reaction product of Part A and 0.36 ml of 1,8-diazobicyclo[5.4.0]undec-7-ene in 150 ml of methylene ch1Oride is stirred for 40 hr at ambient temperature under a nitrogen atmosphere, washed with 100 ml of ice cold 0.15 M aqueous potassium bisulfate, 100 ml of saturated aqueous sodium carbonate, and 100 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.5 9 of formula CXCII product as a yellow oil, 9-deoxy-9~-formyl-3-oxa-1,2,4,596-pentanor-3,7-inter-phenylene-PGFl, 3-(t-butyldimethylsilyl ether), 11,15-bis(tetrahydro-pyranyl ether). NMR absorptions (CDC13) are observed at 0.18, 0.89, 0.98, 1.1-3.2, 3.2-4.4, 4.68, 5.2-5.8, 6.58-7.4, and 9.22~. Infrared absorptions are observed at 1725, 1600, 1585, 1485, 1440, 1275, 1260, 1200, 1160, 1130, 1075, 1035, 1020, 975, 870, and 840 cm~1. Silica gel TLC Rf is 0.24 in ethyl acetate and hexane (1:3).
C. A solution of 1.5 g of the reaction product of Part B in 40 ml of methanol is treated with stirring at 20C under a nitrogen atmosphere over several minutes with 400 mg of sodium borohydride, stirred for 20 min at 20C~ The result;ng mixture is then added to a cold solution of 200 ml of brine and 32 ml of 0.1 M aqueous potassium sulfate, extracted with 600 ml of ethyl acetate, washed with 200 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed on 200 g of silica gel eluting with 35% ethyl acetate in hexane to yield 1.37 g of formula CLCIII product as a colorless oil, 9-deoxy-9~-hydroxymethyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF1, 3-(t-butyldimethylsilyl ether), 11,15-(tetra-hydropyranyl ether). NMR absorptions (CDC13) are observed at 0.17, 0.88, 0.99, 1.1-3.0, 3.0-4.35, 4.7, 5.25-5.85, and 6.5-7.4~. Infrared absorptions are observed at 3460, 1665, 1605, 1685, 1490, 1275, 126n, 1200, 1160, 1135, 1115, 1075, 1~l20, 1005, 975, 840, and 780 cm~1.
Silica gel TLC Rf is 0.20 in 35% ethyl acetate in hexane.
D. A degassed solation of 1.32 g of the reaction product of Part 1 3 ~ ` 0 3704/3803/3823/3833/3879/3893 in 0.47 ml of triethyl amine and 30 ml of methylene chloride at 20Cunder a nitrogen atmosphere is treated with 0.5 ml o~ methanesulfonyl chloride, stirred for 5 min at 0C, warmed to 20C over 90 min, added to 50 g of ice, diluted with 150 ml of brine, extracted with 450 ml of S diethyl ether, washed ~ith 150 ml of brine and 300 rnl of saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure ~o yield an oil, and filtered through 70 9 of silica gel eluting with 30% ethyl acetate in hexane to yield 1.47 g of mesylate corresponding to the starting material, i.e., the 9~ analog of formula CLXXIY. Silica gel TLC Rf is 0.23 in 30%
ethyl acetate in hexane.
E. A degassed solution of 1.47 9 of the reaction product of Part D and 50 ml of dry tetrahydrofuran at 0C under a nitrogen atmosphere is treated with 3.9 ml of 0.45 M tetra-n-butylammonium fluoride. The resulting solution is then stirred at 0C for 4 hr, treated with another 0.5 ml of tetra-n-butylammonium fluoride, stirred for 30 min at 0C, diluted with 150 ml of brine, extracted with 450 ml of ethyl acetate, washed successively with 150 ml of 0.5 M aqueous ammonium chloride, 300 ml of saturated aqueous sodium bicarbonate, and 150 ml~
of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1.3 9 of a yellow oil, the phenol corres-ponding to the starting material, i.e., the 9~ isomer of the formula CLXXV compollnd. Silica gel TLC Rf is 0.11 in 35% ethyl acetate in hexane.
F. A degassed solution of 1.3 9 of the reaction product of Part E in 75 ml of dry glyme at -40C under a nitrogen atmosphere is treated with 90 mg of 57% sodium hydride dispersion in mineral oil, stirred at -40 to -30C for 40 min, stirred at 0C for 15 min, stirred at ambient temperature for 15 min, heated and refluxed for 5 hr, cooled to ambient temperature, added to 200 ml of ice cold glyme, extracted with 450 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous on 175 9 of silica gel eluting with 25% ethyl acetate in hexane to yield 0.61 9 of the 9~ isomer corresponding to the formula CLXXVI compound as a viscous oil. NMR absorptions are observed at 0.90, 1.07-3.1, 3.1-4.4, 4.75~ 5.33-6.16, and 6.5-7.2~.
Infrared absorptions are observed at 3340, 1665, 1610, 1585, 1500, 1465, 1135, 1110, 1075, 1020~ and 980 cm 1. Silica gel TLC Rf is 0.26 in 25% ethyl acetate in hexane and 0.23 in 5% acetone in methylene 1 7 1 7 / ' j 3704/3803/3823/3833/3879/3893 chloride.
G. A solution of 0.50 9 of the reaction product of Part F in 28 ml of methyl bromoacetate in 16 ml of dry glyme at 0C under an argon atmosphere is treated with 0.14 9 of a 57% mineral oil dispersion of sodium hydride. The resulting suspension is then stirred for 2.5 hr at 0C, quenched with 200 ml of cold brine, extracted with 460 ml of ethyl acetate, washed with 300 ml of brlne, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.68 g of an oil, the 9~ isomer corresponding to the formula CLXXVII
compound.
H. A solution of the reaction product of Part G (0.68 g) in 5 ml of tetrahydrofuran, 7.5 ml of water, and 15 ml of acetic acid is heated for 2.5 hr at 45C, cooled, diluted with 200 ml of brine, extracted with 400 ml of ethyl acetate, washed with 400 ml of brine, washed with 200 ml of saturated aqueous sodium bicarbonate, and 200 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield an oil, chromatographed on 75 9 of silica gèl eluting with 307~ hexane in ethyl acetate to 100% ethyl acetate to yield 0.32 9 of title methyl ester as a white foam. Crystallization from hot diethyl ether in hexane yields 0.23 9 of pure ester product as a white solid. Melting range is 85-87C. ~MR absorptions (CDCl3) are observed at 0.90, 1.07-2.9, 2.9-4.5, 4.61, 5.4-5.8. and 6.38-7.34C. Infrared absorptions are observed at 3520, 3420, 1735, 1720, 1605, ~580, 1300, 1240, 1210, 1110, 1085, 1050, 1010, 970, 760, 720, and 710 cm~1. The mass spectrum of the bis-trimethylsilyl derivative exhibits a high resolution peak at 546.3182. Silica gel TLC Rf is 0.14 in 30~ ethyl acetate in hexane.
I. Following the procedure of Example 31, Part H, the title product of Part H (158 mg) is transformed to the tit1e free acid (129 mg) as a white solid. Melting range is 150-154C. NMR absorptions are observed at 0.90, 1.07-3.5, 3.85-4.35, 4.70, 5.09-5.9, and 6.5-7.3C. Infrared absorptions are observed at 3380, 2640, 2560, 1730, 1605, 1580, 1260, 1230, 1115, 1050, 1025, 970, and 770 cm~1.
Following the procedure of Example 34, each of the various formula XI compounds are prepared wherein R22 is a-hydrogen. Further following the procedure of Example 33, the various 9~-methano isomers of Example 34 and corresponding formula XI compounds wherein Y1 is cis- or trans-CH=CH- are hydrogenated to corresponding 13,14-dihydro-71 7~7r i J J I ~J 3704/3803/3823/3833/3879/3893 PGFl compounds.
Examp1e 35 9-Deoxo-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGEl (Formula XI: X1 is COOH, R20, R23, and Rz4 are all hydrogen, Z4 iS -CH2-~ ~21 S and R22 taken together form a valence hond, R8, Y1, M1, Ll, and R7 are as defined in Example 8) and its corresponding methyl ester (X1 is -COOCH3).
Refer to Chart T.
A. A degassed solution of the reaction product of Example 34, Part A, (1.68 g~ in dry tetrahydrofuran (50 ml) is cooled to O~C and treated under a nitrogen atmosphere with 0.75 M tetrabutylammonium fluoride (4.37 ml). The resulting solution is then stirred at 0C for 2 hr, diluted with brine (300 ml), extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concen-trated under reduced pressure to yield 2.3 g of an oil. The oil is chromatographed on silica gel (160 g) in 25% ethyl acetate in Skelly-solve 3 yielding 1.21 g of formula CCXI compound, 9-deoxo-9a-formyl-1,2,4.5,6-pentanor-3,7-inter-m-phenylene-PGE1, 11,15-bis(tetra-hydropyranyl ether). NMR dbsorptions (CDCl 3) are observed at 0.88, 1.13-3.15, 3.27-4.47, 4.71, 6.10, 6.53-7.41, 9.27~. Infrared absorp-tions are observed at 3345, 2930, 2860, 2720, 1735, 1715, 1605, 1595, 1585, 1485, 1450, 1370, 1350, 1255, 1235, and 970 cm~l. Silica gel TLC Rf is 0.12 in 25% ethyl acetate and hexane and 0.39 in 50% ethyl acetate in hexane.
B. A degassed solution of 0.28 9 of the reaction product of Part A in 33 ml of glyme is cooled to -40C under argon and treated with 2.95 N methylmagnesium chloride in tetrahydrofuran (0.2 ml). The reaction mixture is stirred at -40C for 15 min, stirred at 0C for 15 min, permitted to warm to ambient temperature, stirred at reflux for 115 hr under an argon atmosphere, cooled, diluted with ice cold brine (150 ml), extracted with ethyl acetate (300 ml), washed with brine (300 ml), dried over magnesium sulfate, filtered, concentrated under reduced pressure to yield 0.31 9 of an oil, and chromatographed on silica gel eluting with 25%-ethyl acetate in Skellysolve B to yield 0.16 9 of the formula CCXII compound, 9-deoxo-2',9-metheno-3-oxa-1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-PGE1, 11,15-bis(tetra-hydropyranyl ether). The mass spectrum of the trimethylsilyl deriva-tive exhibits a molecular peak at 568 and other peaks dt 466, 382, 1 ~ 3704/3803/3823/3833/387g/3893 364, 314, 297, 267, 255, 243, 230, 270, 153, and 85. Silica gel TLCRf is 0.25 in 25% ethyl acetate in hexane and 0.58 in 50% ethyl acetate in hexane.
C. A degassed solution of the reaction product of Part C (0.16 g) in dry glyme (5 ml) is cooled at -5C and treated with methylbromo acetate (0.04 ml) under a nitrogen atmosphere. The resulting solution is then treated with 50% sodium hydride dispersion in mineral oil (0.
16 g). Precipitate forms in 5 min in the resulting suspension is stirred for 1.5 hr at 0C, diluted with brine (100 ml), extracted with ethyl acetate (240 ml), washed with brine (100 ml), dried over magne-sium sulfate, filtered, concentrated to yield a brown residue which solidifies on refrigeration, and chromatographed on 25 g of silica gel eluting with 20% ethyl acetate in Skellysolve B to yield 0.136 9 of the bis(tetrahydropyranyl ether) of a formula CCXIII compound: 9-deoxy-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-PG~l, methyl ester, 11,15-bis(tetrahydropyranyl ether). Melting range is 81-83C. The mass spectrum exhibits peaks at 366, 384, 364, 279, 247,230, 215, 149, and 85. Silica gel TLC Rf is 0.45 in 5~O acetone in methylene chloride.
D. A solution of the reaction product of Part C (0.12 9) in tetrahydrofuran (1 ml), water (2 ml) and acetic acid (4 ml) is heated at 45C under a nitrogen atmosphere for 2.25 hr, cooled, and parti-tioned between brine (100 ml) in ethyl acetate (90 ml). The layers are separated and the aqueous layer extracted with ethyl acetate (160 2S ml). The organic layers are then washed successively with brine (100 ml), water (100 ml), saturated aqueous sodium bicarbonate (3nO ml) and brine (200 ml), dried over magnesium sultate, filtered, concentrated to yield 0.97 g of a solid, and chromatographed on 30 g of silica gel, eluting with 85% ethyl acetate in hexane to yield 0.083 g of white crystalline formula CCXIII title product in methyl ester form.
Recrystallization from diethyl ether in hexane yields 0.056 9 of pure methyl ester tit~e product. Melting range is 96-98C. ~MR
absorptions (CDC13) are observed at 0.94, 3.86, 3.92-4.28, 4.72, 5.58-5.86, and 6.62-7.18~. Infrared absorptions are observed at 3420, 1765, 1665, 1600, 1575. 1465. 1440, 1275, 1215, 1190, 1105, 1085, 970~
and 770 c~-l. The mass spectrum for the trimethylsilyl derivative exhibits a molecular ion at 554 and other peaks at 454, 383, 365, 364, 230, 229, 225. Silica gel TLC Rf is 0.41 in ethyl acetate.

A 7 t ';;1 ~ 7 r~
J ~ J 3704/3803/3823/3833/3879/3g93 E. Following the procedure of Example 31, Part H, the reactionproduct of Part D (0~19 9) is converted to 76 mg of crystalline title product in free acid form. Melting range is 150-152O. NMR
absorptions (CDC13) are observed at 0.91, 1.2-3.4~, 3.88-4.15, 4.70, - 5 5.62-4.66, and 6.63-7.11. The mass spectrum for the trimethylsilyl derivative exhibits a high resolution peak at 602.3251 and other peaks at 512, 422, 287~ 225, 174, and 173. Silica gel TLC Rf is 0.23 in the A-IX solvent system~
Example_36 9-Deoxy-2~9a-methano-3-oxa-4~5~6~l3~l4~lsJl6~l7~l8 19,20-undecanor-3,7-(1',3'-inter-phenylene)-12-formyl-PGFl, methyl ester (formula CCXXII: Xl is -COOCH3, Z4 is -CH2-, R20, R21, and R23 are hydrogen, R22 is ~-hydrogen, and R18 is tetrahydropyran-2-yl-oxy).
Refer to Chart U.
15 Ozone is bubbled through a solution of 0.72 g of the reaction product of Example 31, Part F, in 50 ml of absolute methanol at -78C
for 5 min. Thereafter oxygen is bubbled through the resulting solu-tion for S min and the solution is treated with 16 ml of dimethyl sulfide. After standing at 16 hr for 0C under a nitrogen atmosphere and 2-112 hr at ambient temperature, the so1ution is diluted with 200 ml of ethyl acetate, ~ashed successively with 100 ml of brine, 100 ml of saturated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 175 g of silica gel eluting with 35% ~thyl acetate in hexane to yield 367 mg of title product as a colorless oil.
NMR absorptions ~CDCl3) are observed at 1.0-3.0, 3.1-4.5, 3.63, 6.45-7.34, and 9.77~. The mass spectrum exhibits peaks at 388 and 304. Silica gel TLC Rf is 0.19 and 0.22 in 25% and 30% ethyl acetate in hexane.
30 Example 37 9-Deoxy-2',9-methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl (Formula XI:
Xl~ Z4~ Ra~ R20, R21, R22, R23, R24, Y1, M1, and L1 are as defined in Example 31 and R7 is n-pentyl) its methyl ester (Zl is -COOCH3), its 15-epimer (Ml is a-H:~-OH3, and 15-epimer methyl ester (M1 is a-H:~-OH and Z1 is -COOCH3).
Refer to Chart U.
A. A suspension o~ 56 mg of a 57% sodium hydride dispersion in 1 7 1 7~7r~ -~ ; J i 3704/3803/3823/3833/3879/38g3 mineral oil and 4 ml of tetrahydrofuran at 0C under a nitrogen atmos-phere is treated with a solution of 286 mg of dimethyl-2-octylphos-phonate in 4 ml of tetrahydrofuran, stirred for 5 min at 0C, stirred for 1 hr at ambient temperature, cooled to 0C, treated with a solu-tion of 0.39 9 of title product of Example 36 and 4 ml of tetrahydro-furan, stirred for 2-1/2 hr at ambient temperature, cooled in noc, added to a solution of 40 ml of ethyl acetate containing several drops of acetic acid3, extracted with 120 ml of ethyl acetate, washed with 30 ml of saturated aqueous sodium bicarbonate, washed with 30 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield an oil, and chromatographed on 60 9 of silica gel eluting with 25~ ethyl acetate in hexane to yield 0.42 9 of a color-less oil, 9,15-dideoxy-15-keto-2',9a-methano-20-methyl-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl, methyl ester, 11-tetrahydropyranyl ether. NMR absorptions are observed at 0.89, 1.05-3.0, 3.5-4.37, 4.62, and 5.97-7.30~. The mass spectrum exhibits peaks at 414, 396, 323, 311, and 301. Silica gel TLC Rf is 0.26 in 25% ethyl acetate in hexane.
B. A degassed solution of 42 mg of sodium borohydride and 4 ml of absolute methanol at -30C under a nitrogen atmosphere is treated dropwise with a solution of 391 mg of the title reaction product of Part A in 0~3 ml of methylene chloride and 3 ml of methanol, stirred for 1-lt2 hr at -30C, quenched by careful addition of 0.2 ml of glacial acetic acid, diluted with 70 ml of brlne, extracted with 210 ml of ethyl acetate, washed with 70 ml of saturated aqueous sodium bicarbonate, washed with 70 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield 0.42 9 of a colorless oil, and chromatographed on 60 9 of silica gel eluting with 40% ethyl acetate in hexane to yield 0.36 9 of an epimeric mixture of C 15 alcohols. Silica gel TLC Rf is 0.20 in 40% ethy1 acetate in hexane.
C. A solution of the reaction products of Part B above in 3 ml of tetrahydrofuran, 4.5 ml of water, and 9 ml of acetic acid is heatéd to 45C under a nitrogen atmosphere for 2.5 hrs, cooled, diluted washed with 100 ml of brine, extracted with 200 ml of ethyl acetate, washed with 100 ml of brine, washed with 300 ml of satureated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to a yellow oil, and 7 ~ 3704/3~03/3823/3833/3879/3893 _95_ chromatographed on 60 9 of silica gel eluting with 20% ethyl acetate in methylene chloride to yield 96 mg of 9-deoxy-2',9a-methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-15-epi-PGFl, methyl ester as a colorless oil and 159 mg of 9-deoxy-2',9a-methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1,3~inter-phenylene)-PGFl, methyl ester as a white solid. Recrystallization of the 15~-hydroxy compound from hot hexane in diethyl ether yields 140 mg as a white solid.
Melting range is 79-82C. For the title product methyl ester, NMR
absorptions are observed at 0.92, 1.08-3.0, 3.38-4.5, 4.64, 5.33-5.70, and 6.5-7.4. The mass spectrum of th~ trimethylsilyl derivative exhibits a high resolution peak at 560.3375. Silica gel TLC Rf is 0.19 in 20% ethyl acetate in methylene chloride and 0.31 in 2n~ hexane in ethyl acetate. - For the 15-epi compound, NMR absorptions (CDCl3) are observed at 0.89, 1.07-3.0, 3.7-4.33, 4.63, 5.5-5.8, and 15 6.55-7.37~. Infrared absorptions are observed at 3360, 1765, 1750, 1735, 1605, 1585, 1470, 1440, 1205, 1120, 1080, 970, and 770 cm~1.
The mass spectrum for the trimethylsilyl derivative exhibits a high resolution peak at 560.3385. Silica gel TLC Rf is 0.35 in 20~ acetone and methylene chloride and 0.45 in 207~ hexane and ethyl acetate.
D. Following the procedure of Example 31, Part H, the 15~-hydroxy title product of Part C (94 mg) is transformed to 9-deoxy-2',9-methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-PGFl, title free acid, as a white solid, 81 mg. Melting range is 144-146C. NMR absorptions (CD3COC~3) are observed at 0.8, 1.05-2.9, 25 3.2-4.5, 4.65, 5.38-5.56, and 6.6-7.2~. The mass spectrum of the trimethylsilyl derivative exhibits a high resolution peak at 618.3576.
Silica gel TLC Rf is 0.14 in the A-IX solvent system.
E. Further following the procedure of Example 31, Part H, the 15-epi title product of Part C (93 mg) is converted to 9-deoxy-2',9-30 methano-20-methyl-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-15-epi-PGF1, a white solid, 72 mg. Melting range is 105-108C. MMR
absorptions (CD3COCD3) are observed at 0.90, 1.05-2.9, 3.2-4.3, 4.71, 5.0-5.84, and 6.5-7.34~. Silica gel TLC Rf is 0.19 in the A-IX
solvent system.
Following the procedures of Examples 36 and 37, there are substituted C-12 side chains according to the procedure of Chart U for each of the various formula XI compounds.
Thus, according to procedures described above, there are prepared 7 ~) 3704/3803/3823/3833/3879/3893 (5E)-9~-methyl-CBA2 compounds, (5Z)-9~-methyl-CBA2 compounds, (5E)-5-fluoro-93-methyl-CBA2 compounds, (SZ)-5-fluoro-9~-methyl-CBA2 compounds, (5E)-5-fluoro-CBA2 compounds, (5Z)-5-fluoro-CBA2 compounds, (5E~-9~-~ethyl-2,5-inter-o-phenylene-3,4 dinor-CBA2 compounds, (5Z)-9~-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5E)-9~-methyl-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds, (5E)-9~-methyl-1,5-inter-o-phenylene-3,4,5-trinor-C8A2 compounds, (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, 2,2-difluoro-(5E)-9~-methyl-C8A2 compounds, 2,2-difluoro-(5Z)-9~-methyl-C8A2 compounds, 2,2,5-trifluoro-(5E)-9~-methyl-CBA2 compounds, 2,2,5-trifluoro-(5Z)-9~-methyl-CBA2 compounds, 2,2,5-trifl~o~o-(5E)-CBA2 compounds, 2,2,5-trifluoro-(5Z)-CBA2 compounds, 2.,2-difluoro-(5E)-9~-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5Z)-9,~-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5E)-9~-methyl-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds, 2,2-difluoro-(5E)-9~-methyl-1,5-inter-o-phenylene-3,4,5-trinor-CBA2 compounds, 2J2-difluoro-(5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5E)-195-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, 2,2-difluoro-(5Z)-1,5~inter-m-phenylene-2,3,4-trinor-CB'A2 compounds, - 35 trans-2,3-didehydro-(5E)-9~-methyl-CBA2 compounds, trans-2,3-didehydro-(5Z)-9~-methyl-CBA2 compounds, trans-2~3-didehydro-(5E)-5-fluoro-9B-methyl-cBA2 compounds, trans-2,3-didehydro-(5Z)-5-fluoro-9~-methyl-C8A2 compounds, 7 ) -g7-trans- 293-d i dehydro- ( SE ) -5- fl uoro-C8A2 compounds, trans-Z,3-didehydro-(5Z)-5-fl uoro-C3A2 compounds, trans-2,3-didehydro- (5E)-9g-methyl -2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5Z)-9~-meth~1-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5E)-9~-methy1-1,5-inter-o-phenyl ene-2,3,4-trinor-CBA2 compounds, trans-2,3-didehydro-(5E)-9R-methyl-1,5-inter-o-phenylene-3,4,5-10 trinor-CBA2 compounds, trans-2,3-didehydro-(5E)-2,5-inter-o-phenyl ene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5Z)-2,5-inter-o- phenyl ene-3,4-dinor-O~A2 compounds, trans-2,3-didehydro-(5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, trans-2,3-didehydro-(SZ)-l,S-inter-m-phenylene-2,3,4-trinor-C~A2 compounds, 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7- (1 ' ,3 '-inter-20 phenylene)-PGFl compounds, 9-deoxy-2',9g-methano-3-oxa-4,5,6-trinor-3,7- (1 ',3 ' -i nt er-phenylene)-PGFl compounds, 9-deoxo-2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1 ',3'-inter-phenylene)-7,8-didehydro-PGEl compounds, 9-deoxo-2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1 ',3'-inter-phenylene)-PGEl compounds, 6a-oxo-9-deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFl compounds, 6a-oxo-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-30 phenylene-PGFl compounds, 6a-hydro~xy-9-deoxy-2l~9a-methano-3-oxa-4~s~6-trinor-3~7- (1 ',3'-inter-phenylene)-PGFl compounds, 6aa-hydroxy-9-deoxy-2',9~-methano-3-oxa-4,5,6-trinor-3,7-(1 ',3'-inter-phenylene)PGFI compounds, 6ag-hydroxy-9-deoxy-2l~9a-methano-3-oxa-4~s~6-trinor-3,7- (1 ',3'-inter-phenylene-PGFl, and 6a~-hydroxy-9-deoxy-2',9g-methano-3-oxa-4,5,6-trinor-3,7- (1 ',3'-inter-phenylene)-PGFl compounds, ln free acid or methyl ester form which exhibit the following side chain substituents:
15-cyclohexyl-16,17,18,19,20-pentanor-;
17-t2-furyl)-18,19,Z0-trinor-;
16-(3-thienyl)oxy-17,18,19,20-tetranor-;
17-(3-thienyl)-18,19,20-trinor-;
15-methyl-;
16-methyl-;
15,16-dimethyl-;
16,16-dimethyl-;
17,20-dimethyl;
16-fluoro-;
15-methyl-16-fluoro-;
16,16-difluoro-;
15-methyl-16,16-difluoro-;
17-phenyl-18,19,20-trinor-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-;
17-(m-chlorophenyl)-18,19,20-trinor-;
17-(p-f1uorophenyl3-18,19,20-trinor-;
15-methyl-17-phenyl-18,19,20-trinor-;
16-methyl-17-phenyl-18,19,20-trinor-;
16,16-dimethyl-17-phenyl-18,19,20-trinor-;
16-fluoro-17-phenyl-18,19,20-trinor-;
16,16-difluoro-17-phenyl-18,19,20-trinor-;
16-phenyl-17,18,19,20-tetranor-;
15-methyl-16-phenyl-17,18,19,20-tetranor-;
16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-;
16-phenyl-18,19,20-trinor-;
15-methyl-16-phenyl-18,19,20-trinor-;
16-methyl-16-phenyl-18,19,20-trinor-;
15,16-dimethyl-16-phenyl-18,19,20-trinor-;
16-phenoxy-17,18,19,20-tetranor-;
15-methyl-16-phenoxy-17,18,19,20-tetranor-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-;

1 3 1 ~`) 3 3704/3803/3823/3833/3879/3893 _99_ 16-phenoxy-18,19,20-trinor-;
15~methyl-16-phenoxy-18,19,20-trinor-;
16-methyl-16-phenoxy-18,19,20-trinor-;
15,16-dimethyl-16-phenoxy-18,19,20-trinor-;
13,14-didehydro-;
15-cyclohexyl-16,17,18,19,20-pentanor-13,14-didehydro-;
17-(2-furyl)-18,19,20-trinor-13,14-didehydro-;
16-(3-thienyl)oxy-17,18,19,20-tetranor-13,14-didehydro-;
17-(3-thienyl)-18,19,20-trinor-13,14-didehydro-;
15-methyl-13,14-didehydro-;
16-methyl-13,14-didehydro-;
15,16-dimethyl-13,14-didehydro-;
16,16-dimethyl-13,14-didehydro-;
17,20-dimethyl-13,14-didehydro-;
16-fluoro-13,14-didehydro-;
15-methyl-16-fluoro-13,14-didehydro-;
. 16,16-difluoro-13,14-didehydro-;
15-methyl-16,16-difluoro-13,14-didehydro-;
17-phenyl-18,19,20-trinor-13,14-didehydro-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-didehydro-;
17-~m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-;
17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;
15-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16-fluoro-17-phenyl-13,19,20-trinor-13,14-didehydro-;
16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;
16-phenyl-17,18,19,20-tetranor-13,14-didehydro-;
15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-trifluoromethylphenyl)-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-13,14-didehydro-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-13,14-didehydro-;
16-phenyl-18,19,20-trinor-13,14-didehydro-;
lS-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;
16-methyl-16-phenyl-18,19,20-trinor-13,14-didehydro-;
15,16-dimethyl-l6-phenyl-l8~l9~2o-trinor-l3~l4-didehydro-;
16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-;

~ 3704/3803/3823l3833/3879/3893 15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-trifluoromethy1phenoxy)-17,18,19,20-tetranor-13,14-didehydro-;
16-(m-chlorophenoxy~-17,18,19,20-tetranor-13,14-didehydro-;
S 16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;
16-phenoxy-18,19,20-trinor-13,14-didehydro-;
15-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;
16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;
15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-;
13,14-dihydro-;
15-cyclohexyl-16,17,18,19,20-pentanor-13,14-dihydro-;
17-(2-furyl)-18,19,20-trinor-13,14-dihydro-;
16-(3-thienyl)oxy-17,18,19,20-tetranor-13,14-dihydro-;
17-(3-thienyl)-18,19,20-trinor-13,14-dihydro-;
15-methyl-13,14-dihydro-;
16-methyl-13,14-dihydro-;
15,16-dimethyl-13,14-dihydro-;
16,16-dimethyl-13,14-dihydro-;-17,20-dimethyl-13,14-dihydro-;
16-fluoro-13,14-dihydro-;
15-methyl-16-fluoro-13,14-dihydro-;
16,16-difluoro-13,14-dihydro-;
15-methyl-16,16-difluoro-13,14-dihydro-;
17-phenyl-18,19,20-trinor-13,14-dihydro-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;
17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;
17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;
15-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16,16-dimethyl-17-phenyl-18,i9,20-trinor-13,14-dihydro-;
16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;
16-phenyl-17,18,19,20-tetranor-13,14-dihydro-j 15-methyl-16-phenyl-17,18,19,20-tetranor-13,14-dihydro-;
16-(m~trifluoromethylphenyl)-17,18,19,20-tetranor-13,i4-dihydro-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-13,14-dihydro-;
16-(p-fluorophenyl )-17,18,19,20-tetranor-13,14-dihydro-;
16-phenyl-18,19,20-trinor-13,14-dihydro-;

1 3 . 70 3704/3803/3823/3833/3879/3893 15-methyl-16-phenyl-18,19,2n-trinor-13,14-dihydro-;
16-methyl-16-phenyl-18,19,20-trinor-13,14-dihydro-;
15,16-dimethyl-16-phenyl-18,19,20-trinor-13,14-dihydro-;
16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-;
S 15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-;
16-(m-trifluoromethyl phenoxy)-17,18,19,20-tetranor-13,14-dihydro-;
16-(m-chlorophenoxy~-17J18,19,20-tetranor-13,14-dihydro-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;
1~ 16-phenoxy-18,19,20-trinor-13,14-dihydro-;
15-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
15,16-dimethyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;
13-cis-;
15-cyclohexyl-16,17,18,19,20-pentanor-13-cis-;
17-(2 furyl)-18,19,20-trinor-13-cis-;
16-(3-thienyl)oxy-17,18,19,20-tetranor-13-cis-;
17-(3-thienyl)-18,19,20-trinor-13-cis-;
15-methyl-13-cis-;
16-methyl-13-cis-;
15,16-dimethyl-13-cis-;
16,16-dimethyl-13-cis-;
17,20-dimethyl-13-cis-;
16-fluoro-13-cis-;
lS-methyl-16-fluoro-13-cis-;
16,16-difluoro-13-cis-;
lS-methyl-16,16-difluoro-13-cis-;
17-phenyl-18,19,20-trinor-13-cis-;
17-(m-trifluoromethylphenyl)-18,19,20-trinor-13-cis-;
17-(m-chlorophenyl)-18,19,20-trinor-13-cis-;
17-(p-fluorophenyl)-18,19,20-trinor-13-cis-;
15-methyl-17-phényl-18,19,20-trinor-13-cis-;
16-methyl-17-phenyl-18,19,20-trinor-13-cis-;
16,16-dimethyl-17-phenyl-18,19,20-trinor-13-cis-;
16-fluoro-17-phenyl-18,19,20-trinor-13-cis-;
16,16-difluoro-17-phenyl-18,19,20-trinor-13-cis-;
16-phenyl-17,18,19,20-tetranor-13-cis-;
15-methyl-16-phenyi-17,18,19,20-tetranor-13-cis-;

7~i 3704/3803/3823/3833/3879/3893 16-(m trifluoromethylphenyl)-17,18,19,20-tetranor-13-cis-;
16-(m-chlorophenyl)-17,18,19,20-tetranor-13-cis-;
16-(p-fluorophenyl)-17,18,19,20-tetranor-13-cis-;
16-phenyl-18,19,20-trinor-13-cis-;
15-methyl-16-phenyl-18,19,20-trinor-13-cis-;
16-methyl-16-phenyl-18,19,20-trinor-13-cis-;
15,16-dimethyl-16-phenyl-18,19,20 trinor-13-cis-;
16-phenoxy-17518,19,20-tetranor-13-cis-;
15-methyl-16-phenoxy-17,18,19,20-tetranor-13-cis-;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13-cis-;
16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-cis-;
16-(p-fluorophenoxy)-17,18,19,20-tetranor-13-cis-;
16-phenoxy-18,19,20-trinor-13-cis-;
15-methyl-16-phenoxy-18,19,20-trinor-13-cis-;
16-methyl-16-phenoxy-18,19,20-trinor-13-cis-; and 15,16-dimethyl-16-phenoxy-18,19,20-trinor-13-cis-.

3'i 7'~7 0 _ 103 3704/3803/382~/3833/3879/3893 FORMULAS

COOH
~LI -~ ~
~9~

HO OH

COOH

6a~ ~
, , II
\
/~\
d . OH

HO
~'~ COOH
III

Hd OH

FORMULAS (conti nued) 6a /~\
R16 ~ (CH2)n R~7 ~ -a~ IV
~o 1~
~/ -~Y 1- lC--IC-R z 7 R I M6 L~
1a Rl6~\(CH2)n R47 ~ 9 a~ V
~,0 1,,~
~ ~ CH20R32 R1' R15 ~Z1--X1 2S R16 ~ (CH2)n R17 ~ ~ VI

~ CH20R32 CH(R1s)~Zl~X
R16~CH2~n, R17+

~ CH20R32 VII
R1a 1 ~JI 3 los- 3704t3803/3823/3833/3879/3893 FORMULAS (continued) X1-Z4-O ~

R21 ~ ~ R23 VIII
R22_f ~ Rz4 R3a R1s HO ~

~ Y1-C - C-R27 R1 a M6 L1 IX

R15 ~5~ Zl-X
R16 ~ 6(cH2)n R1~ ~ X
~ Y1-C - C-R7 R20 ~
R21 ~ ~ 7 R23 XI
.\ _ D
R22_1/ g a - ~24 (10 12~
~ ~ Y1-C - C-R7 R Ml L1 . ~

CHART A
o S ~ , n XXI
Y,-C - C-R2-~
R, 8 M6 L

\ / / P(OCH3)2 X~
lS ~ ~ , 2)n XXII
Y,-C - C-R27 Il 11 O O
, (CH2)n-C-CH2-P(OCH3)2 XXIII
\~--Y 1 -C--C-R2 .

H2)n XXIV , '' ~ Y,-C - C-R
/ R~ 8 M6 L1 -~ ~
To XXV . To XXV I

- 107^ 3704 /3803/3823/3833 /3879/3~3 CHART A (continued) From XX I V

R, 6 ~( CH2) n ~37-~ XXV
~Yl -C--C - R
R~ a M6 L-\

15, \~ ( 2)n H2c t~ XXVI
~ Y1-C--C-R
R~ 8 M6 L

Ts 1O ~ CH2 ) n H2C ~ XXVII
~Y1 -C--C-R27 ,~3 l , 7 7~

CHART B
o R16 ~ (~cH2)n S R37 ~ XXXI
/ ~ Y1-C - C-R2 Rl8 1 1l LiOC-CH-Z2-CH20R28 XXXII
\ / Li HO ~ CH-Z2-CH20R28 Rl6 ~ (CH2~n R37 ~ XXXIII
~ Y1-C - ICl-R27 ~ ~ \ /
To . To XXXVI XXXIV

7 1 J~i7~
- l O9- 3704/3803 /3823/3833/3879/3893 CHART B (continued) From From XXX I XXX I I I

R16 ~(,CH2) n R37~ XXXIV
~Y1 -C - ICI -R27 ~Z2-CH20H
~ .
R16_~ (CH2)n D ~ XXXV
~'37~( R, ~ Y 1 -C - C -R27 \~

~Z~2--x1 J~ .
, R16 _~ (CH2)n - 35 R37 7~( XXXV I

Il 11 R Ml L1 ~, J 7 J
-110- 3704/3803/3823/3833/3~79/3893 CHART C

~ (CH2)g-COOH XLI

COOH

~ (CH2)9-CH20H

~ (CH2)9-CH20P`28 XLIII

(CH2)9-CH2-OR28 XLIV

CHO

1 3 1, ) 7 i) ~ 3704/3803/3823/3833/3879/3893 CHART D

R16 ~ (CH2)n R17 ~ LI
Y1-C - C~R27 Il Rl~ M~ L

' OH

R16 ~ ,CH2)n R17~ LII
~ Y1-C - C-R27 1~1 ~1, 0 o R16 4 (lCH2)n R17 ~ LIII
Y1-C - ~-R27 Il 11 .
\ /
To LIV

~ 7 1 ,~70 CHART D (continued) From LIII

S ~ /
S~ SO2 R17 ~ ,CH23n LIV ~R16 ~ tcH2)n LV
~ Y1-C C-R27 ~ Y1-C _ C-R
R, 8 M6 L~ R1s M6 L, ~ /
502 ~OAc (CH2)9-CH20R28 R16 ~ /CH2)n R17 ~ LYI

R1s I M6 L

~ (CH2)9-CH20R29 n' Rl6 ~ (,CH2)n R17 ~ LVII
Y~-C - C-R27 R,9 I M6 L

To LVIII

I .,, ',, ,~
-113- 3704/3803/3823/3~33/3879/3893 CHART D (continued) From LVII

1, ~ ~ 2)9 20 R16 ,CH2)n LVIII
R17 ~
~Y1 -C--C-R27 R M6 L, ~ (CH2Jg-COOR

2~ ~
R16 ~ (,CH2)n R17 ~ . LIX
~ Y1-C - C-R27 ll ll ~ (CH2)9-X1 R16 ~ ~CH2)n LX
R17 ~
~ Y1-C - C-R7 I M~ L1 7~
~ ,, IJ
-114- 3704/3803/3823/3833/3879/3i393 CHART _ (,CH2)n LXI

R3a 1, O
15R16 ~ (,CH2)n R17 ~ LXII

R3s \ /

R16 ~ (,CH2)n R17 ~ LXIII
~ CH20R

R3a .

t 3 1 i i 7 0 -115- 3704/3803/3823t3833/3879/3893 CHART F

Z ~ -Xl Rl6 f ~;CH2)n Rl, ~ LXXI
~ CH20R

~ Z1-Xl R16 ~ (,CH2)n R1, ~ LXXII
~ CH20H
R3s .~
R,6 ~ (,CH2)n R17 ~ LXXIII
Y,-C - C-R7 1 11 u ~ I I, 7 0 -116- 3704/3803/3823/3833/3~79/.~893 C~ART G
o R16 ~(CH2)n S R37~ LXXX I
~Y1 -C - C-R27 R~ ~ M6 Ll ¦ Br() ~ P - CH-Z,-COOH
I LXXXII
1S ~ 3 fZ2-COOH

R16 ~(CH2)n R37 ~ - LXXX I I I
/ ~Yl-C - C-R27 R1 a M6 L

~ Z2-COOCH3 Rl~ ~ (CH2)n R37~ LXXXIV

~ n n j / Rl a I M6 L
To ~1~
and LXXXIV To LXXXV

, , J

CHART G (continued) From LXXXIV
,5 ~ Z2-CH20H

R16 ~ (CH2)n R37 ~ LXXXV

ll ll R M6 L, ~ ~

~( Y
R16 ~ (~CH2)n R16 ~ (CH2)n R37 ~ LXXXVI R3, ~ LXXXVII
~ Yl-C C-Rz7 ~ Y1-C C-R27 Il 11 11 11 .
R M6 Ll R M6 L, ,1, ~1, X1-Z2 H H Zz-X1 R16 ~ CH2)n Rl6 ~ (,CH2)n Rl7 ~ LXXXVIII R~7 ~ LXXXIX

R~ Y1-C ~ C-R7 R~ Y1-C - C-R7 1 . 1 7 ~ 7 -I
,, J
-118- 3704/3803/3823/3~33/3879/3893 CHART H
O
~ S - CH2~CH2-Z2-CH20R10 5~ H3CN XCI

S---CH(F)-CH2-Z2-CH20R10 XCII
~ H3CN

R16 ~ (CH2)n . R17 ~ ~ XCIII
~ / ~ Y1-C - C-R27 20F~ Z2-CH20R1O ~ R1s M6 L
R-6 ~ (CHZ)n R17 ~ XCIV
~ Y1-C - C-R27 R1l M6 Ll R,6 ~ (CH2)n Rl7 ~ XCV
Y,-C - C-R7 To XCV I

171 ~f7!~
_ I ..,',,, -l l9- 3704/3803/3823/3833/3879/3893 CHART H (continued) From XCV

F~ Z2-COOH

R,6 ~ (CH2)n R17~- ~ XCVI
~Y, -C - C-R7 Il ~I
R8 Ml L, ,1, .

.. .. .
~ Z2-X1 R16 ~(,CH2)n R-7 ~ XCVII
~Y,-~C - C-R7 R M1 L, 7 1 7 ~ -7 -1 ,' I J `l; J

CHART I

R16 ~(,CH2) n R17 ~ CI

R
~0 ~ Z2-Xl Rl 6 ( CH2)n R17 ~ CII

~ CH20R

~/

F ~ Z2-x1 Rl6 ~ (CH2)n R17 7 ---- ( CIII
~ Yl-C - C-R~
Il 11 ~ 7 ~ 7 ~
, ~, ~, i ~J
-121- 3704/3803/3~23/3833/3879/3893 CHART J

R16 ~ (,CH2)n R17 ~ CXI

Il tl R Ml L~

/ PhS~
cH2-cH2-cH-cooR1 R16 ~ (,CH2)n CXII
R17 ~

ll ll R8 M1 L, 1 .
~ H ~ C C -~COOR
R1s ~ ~ CH2-~ ~ H

R16 ~ (~CH2)n CXIII
R1i ~

ll ll H ,, ~5 CH C C ~ H

3~ Rl6 (CH2)n R17 ~ CXIV
~ Y1-C - C-R7 Il 11 o CHART K

R1 5 CH2-CH2-CH2-COORl S R16 ~ (,CH2)n CXXI
R17t~
~ CH20R3 ~ PhS~
1 ~ ~ CH2-CH2-CH-COOR1 R16 ~ (lcH2)n CXXII
R17 t~
~ CH20R3 1 H - C-C ,,COORl -R15~ ~ CH2 H

R16 ~ (,CH2)n CXXIII

R

.

1 7~1 7~)7 0 CHART L
PhSe R~5 ~ CH2 CH2 CH COOR1 R16--~ (CHz)n R17 ~ CXXXI
~ CH20R31 R38 ~

PhSe ~CH(R15) -CH2-CH2-CH-COOR

R16 ~ (CH2)n R17 ~ CXXXII

~ H ~ C C - COOR
5 CH(R15)_ CH2 ~ H

R1G ~ (,CH2)n R17 \~ CXXXIII
2~ / \

~/ H - c=c ~
~ CH(R15)_CH2 ~ H

R1G ~ (CH2 jn R17 ~ CXXXIV

1 3 I J ~ 7 ~

CHART M

Rl 5 Z3-Xl R16 ~ (,CH2)n CXLI
R
~ CH20R

CH(R15)-Z3-X1 R16 ~ (CH23n CXLII
R

1 3 1 3 ~70 -125- 3704~3803/38Z3/3833/3879/3~93 CHART N

C(R15)-Z1-X1 Rl6 ~ (~CH2)n CLI
R

R3a CH(R15)-Z1-X

R 16 ~ (,CH2)n R17 ~ ~LII
~ Y1-C - C-R7 1 ll ll Ra - M1 L.

.

7 ~J
-126- 3704/3~03/3823/3833/3879/38g3 Rl ~ ~ Z1-Xl R16 ~ (,CH2)n Rl7 ~ CLXI
~ Y1-C - C-R7 Il 11 CH(R1s)~Zl-Xl R~s ~ (CH2)n CLXII
Rl7 ~

Il 11 -.

1 3 1 ~7~
-127~ 3704/3803/3823/3833/3879/3893 CHART P
. ~ ~

CLXXI

1 a M6 L~
~ ' C~2 ~OR2s CLXXII

t Y 1 -C - C -R27 .

.

CH20H OR~ CLXXIII

Yl-C - C-R27 R 18 l To CLXXIV

l J l J , 7 J
-lZ8- 3704/3803/3823/3833/3879/3893 CHART P ~continued) From CLXXIII

CLXXIV~
,Y,-C - C R27 ~ ~ CLXXV ~ ~ CLXXVI
R1B Y,-C - C Ra7 R1sY1-C - C R27 CLXXVII~ ~
~ ~ ~ CLXXYII

R~B Y1-C - C-R7 , ~ Y1-C - C_R27 M1 ~1 1B ~6 L1 ~129- 3704/3803/3823~/~8~3~3J8~9~3893 CHART Q

CH~OH CLXXXI ~ ~ CLXXXII
R,8Yl-C - C-R27 ~ R18 Y1-C - C-R27 M6 L1 M6 L.

HO

H ~ ~ ~ ~ CLXXXIII

R1a ~l-C - C-R27 R18 M6 L

ZO

R,OOC-Z4-O
H
`W' ,J CLXXXV
~ ' ' .l-C - C-R27 30 R1~ ll ll I \
~ ~
To CLXXXVI To CLXXXVIII

~ 3 1 ~ J

Q (continued) From CLXXXV

~ ~

~ ? CLXXXV~ cLxxxvlll R Y~-C - C-R27 R1s Y -6 - C-R27 ~ ~

0~ 0~

20 ~ CLXXX~II ~ CLXXXIX
R8 Y,-C - C-R7 R8 Y~-C - C-R7 Ml L

~
,~r cxc ~8 Y1-C - C-R7 7 ~

CHART R
CHO

~C - C-R,7 CXCI
R,~

CHO
~ OR28 lS , Y1-C - - C-R27 CXCII
R18 ll ll M6 L.

~ OR2~ ~

,,~1 .
~, CXCIV

,~

Il 11 ~ J l J J/ 0 CHART S

~ ~ OR28 CCI

~ ~

R2 ~
~ ~ R23 CCII

R~ H20R

~

Xl -Z4-O

R22 ~
~ R24 CCIII
R~a Y1-C - C-R7 Il 11 3 ~ J `f~ 7 0 - l 33- 3704/3803/3823/3833/3879/38g3 CHART T

CHO
~ ~OH

Rla n HO

~ CC:(II

'~ 1 ~Z4-0 ~, r ~ CCXIII
R8 '~ Y 1 -C--C-R7 CHART U
~3~ 7a -' ~ R2~
R22~ LR23 rR24 CCXXI
/~ ~H
R1 8 'C=C
H-- ~ C_C-R7 \~

R R2~
R2~ LR23 CCXXII

~ ~
R1 a ~CHO
.

R2~
R2~R24R23 CCXX I I I
~
Ra ~Y 1 -C--C-R7

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a carbacyclin intermediate with a general formula selected from the group consisting of:

IV, V, VI, VII, VIII and IX

?aim 1...cont'd.(2) 136 wherein for the intermediate of general formula IV:
n is one or 2;
L1 represents a group selected from .alpha.-R3:.beta.-R4, .alpha.-R4:.beta.-R3 wherein R3 and R4, independently, represent a group selected from H, F and -CH3, with the proviso that one of R3 and R4 is F only when the other is H or F;
M6 represents a group selected from .alpha.-OR10: .beta.-R5 and .alpha.-R5: .beta.-OR10, wherein R5 represents a group selected from H and -CH3, and R10 represents an acid hydrolyzable protective group;
R16 represents H;
R47 represents a group selected from -CH2OH and (C1-C4)alkyl; or R16 and R47, when taken together, form a second valence bond between C6a and C9 or represent -CH2-;
R18 represents a group selected from H, -OH, -CH2OH, -OR10 and -CH2OR10, wherein R10 is as defined above;
R27 represents a group selected from:
(A) -CmH2m-CH3, wherein m is an integer of one to 5, inclusive, (B) phenoxy, mono-, di- and tri-substitutedphenoxy, wherein the substituent group are selected from F, Cl, -CF3, (C1-C3)alkyl and (C1-C3)alkoxy, with the proviso that not more than two substituents are other than (C1-C3)alkyl, and with the further proviso that R27 is as defined in (B) only when R3 and R4, independently, represent a group selected from H and -CH3, (C) phenyl, benzyl, phenylethyl, phenylpropyl and mono-, di- and tri-aromatic-ring-suhstituted derivatives thereof, wherein the substituent group are selected from F, Cl, -CF3, (C1-C3)alkyl and (C1-C3)alkoxy, with the proviso that not more than two substituents are other than (C1-C3)alkyl, and Claim 1...cont'd.(3) 137 (D) cis-CH=CH-CH2-CH3, -(CH2)2-CH(OR10)-CH3, wherein R10 is as defined above, and -(CH2)3-CH=C(CH3)2; or -C(L1)-R7, when taken together, represent a group selected from:
(E) (C4-C7)cycloalkyl, mono-, di- and tri-(C1-C5)alkyl-substituted (C4-C7)cycloalkyl, and (F) 2-(2-furyl)ethyl, 2-(3-thienyl)ethoxy and 3-thienyloxy-methyl; and Y1 represents a group selected from trans-CH=CH-, cis-CH=CH-, -CH2CH2- and -C?C-;
wherein for the intermediate of general formula V:
n, R16, R47 and R18 are as defined above for the intermediate of general formula IV; and R32 represents a group selected from H and R31, wherein R31 represents a hydroxyl-hydrogen protecting group;
wherein for the intermediate of general formula VI:
n, R16 and R18 are as defined above for the intermediate of general formula IV;
R32 is as defined above for the intermediate of general formula V;
R15 represents a group selected from H and F;
R17 represents a group selected from H and (C1-C4)alkyl; or R16 and R17, when taken together, represent -CH2-;
X1 represents a group selected from:
(G) -COOR1, wherein R1 represents a group selected from:
(a) H, (C1-C12)alkyl, (C3-C10)cycloalkyl and (C7-C12)aralkyl, (b) phenyl, mono-, di- and tri-substituted phenyl, wherein the substituent group are selected from C1 and (C1-C3)alkyl, Claim 1...cont'd.(4) 138 (c) phenyl para-substituted by -NH-CO-R25, wherein R25 represents a group selected from -CH3, NH2, phenyl, acetamidophenyl and benzamidophenyl, (d) phenyl para-substituted by -CO-R26, wherein R26 represents a group selected from -CH3, -OCH3, NH2 and phenyl, (e) phenyl para-substituted by -O-CO-R54, wherein R54 represents a group selected from phenyl and acetamidophenyl, (f) phenyl para-substituted by -CH=N-NH-CO-NH2, and (g) a pharmacologically acceptable cation, (H) -CH2OH, (I) -COL4, wherein L4 represents a group selected from:
(h) -NR51R52, wherein R51 and R52, independently, represent a group selected from:

(i) H, (C1-C12)alkyl, (C3-C10)cycloalkyl, (C7-C12)aralkyl, (C2-C5)carboxyalkyl, (C2-C5)carbamoylalkyl, (C2-C5)cyanoalkyl, (C3-C6)acetylalkyl, (C1-C4)hydroxyalkyl, (C1-C4)dihydroxyalkyl and (C1-C4)trihydroxyalkyl, (ii) phenyl, mono-, di- and tri-substituted phenyl, wherein the substituent group are selected from Cl, -OH, -COOH, -NO2, (C1-C3)alkyl and (C2-C5)alkoxycarbonyl, (iii) (C7-C11)benzoalkyl, mono-, di- and tri-substituted (C7-C11)benzoalkyl, wherein the substituent group are selected from Cl, -OH, -COOH, -NO2, (C1-C3)-alkyl, (C1-C3)alkoxy and (C2-C5)alkoxycarbonyl, Claim 1...cont'd.(5) 139 (iv) pyridyl, mono-, di- and tri-substituted pyridyl, wherein the substituent group are selected from Cl, (C1-C3)alkyl and (C1-C3)alkoxy, and (v) (C6-C9)pyridylalkyl, mono-, di- and tri-substituted (C6-C9)pyridylalkyl, wherein the substituent group are selected from Cl, -OH, (C1-C3)alkyl and (C1-C3)alkoxy, with the proviso that not more than one of R51 and R52 is other than H or (C1-C12)alkyl, (i) pyrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, 3,4-didehydropiperidinyl, mono- and di-(C1-C12)alkyl-substituted 3,4-didehydro-piperidinyl, (j) -NR53COR51, wherein R51 is as defined in (h) other than H and R53 represents a group selected from H
and (C1-C4)alkyl, (k) -NR53SO2R51, wherein R51 and R52 are as defined in (j), and (J) -CH2NL2L3, wherein L2 and L3, independently, represent a group selected from H and (C1-C4)alkyl, and (1) when X1 is as defined in (J) a pharmacologically acceptable acid addition salt thereof; and Z1 represents a group selected from:
(K) trans-CH2-CH=CH-, (L) -CH2-(CH2)f-C(R2)2-, wherein f is zero, one, 2 or 3 and R2 represents a group selected from H and F, and (M) -(Ph)-(CH2)g-, wherein g is zero, one, 2 or 3 and Ph represents a group selected from 1,2-, 1,3- and 1,4-phenylene;

Claim 1...cont'd.(6) 140 with the proviso that:
(N) R15, R16 and R17 all represent H only when 1 is as defined in (M), and (O) Z1 is as defined in (M) only when R15 represents H;
wherein for the intermediate of general formula VII:
n, R16 and R18 are as defined above for the intermediate of general formula IV;
R32 is as defined above for the intermediate of general formula V; and R15, R17, X1 and Z1 are as defined above for the intermediate of general formula VI;
wherein for the intermediate of general formula VIII:
R18 is as defined above for the intermediate of general formula IV;
X1 is as defined above for the intermediate of general formula VI;
R20, R21, R22, R23 and R24 obey the following conditions:
(P) R20, R21, R23 and R24 all represent H and R22 represents .alpha.-H or .beta.-H, (Q) R20 represents H, R21 and R22, when taken together, form a second valence bond between C6a and C9, and R23 and R24, when taken together, form a second valence bond.
between C7 and C8 or both represent H, or (R) R22 represents .alpha.-H or .beta.-H, R23 and R24 represent H, and (m) R20 and R21, when taken together, represent =O, or (n) R20 represents H and-R21 represents .alpha.-OH or .beta.-OH;
R33 represents a group selected from -CHO and -CH2OR32, wherein R32 is as defined above; and Claim 1...cont'd.(7) 141 Z4 represents a group selected from -CH2- and -(CH2)f-CF2-, wherein f is as defined in (L); and wherein for the intermediate of general formula IX:
L1, M6, R18, R27 and Y1 are as defined above for the intermediate of general formula IV;
said process comprising:
for the intermediate of general formula IV:
(aa)(x) treating a lactone of general formula:

XXI

wherein n, L1, M6, R18, R27 and Y1 are as defined above, with the anion of dimethyl methylphosphonate to produce a lactol of general formula:

XXII

wherein n, L1, M6, R18, R27 and Y1 are as defined above;
(xi) oxidizing the lactol of general formula XXII to produce a diketone of general formula:

Claim 1...cont'd.(8) 142 XXIII

wherein n, L1, M6, R18, R27 and Y1 are as defined above; and (xii) by a Horner-Emmons reaction intramolecularly cyclizing the diketone of general formula XXIII
to produce the desired intermediate of general formula IV, wherein R16 and R47, when taken together, form a second valence bond between C6a and C9; or (xiii) treating the intermediate product of step (xii) with lithium dialkyl cuprate to produce the desired, intermediate of general formula IV, wherein R16 represents H and R47 represents (C1-C4)alkyl; or (xiv) treating the intermediate product of step (xii) with the anion of trimethyloxosulfonium iodide to produce the desired intermediate of general formula IV, wherein R16 and R47, when taken together, represent -CH2-; or (xv) by photochemical addition of CH3OH converting the intermediate product of step (xii) to the desired intermediate of general formula IV, wherein R16 represents H and R47 represents -CH2OH; or (xvi) tosylating the intermediate product of step (xv) to produce a compound of general formula:.

Claim 1...cont'd.(9) XXVII

wherein n, L1, M6, R18, R27 and Y1 are as defined above; and (xvii) treating the compound of general formula XXVII
with base to produce the desired intermediate of general formula IV, wherein R16 and R47, when taken together, represent -CH2-;
for the intermediate of general formula V:
(bb)(xviii) repeating steps (x) to (xii), (xiii), (xiv), (xv) or (xvi) and (xvii) and using in step (x) a starting compound of general formula:

LXIa wherein n, R18 and R31 are as defined above, to produce the desired intermediate of general formula V, wherein R16 and R47, when taken together, represent a second valence bond between C6a and C9 or -CH2-, or R16 represents H and R47 represents (C1-C4)alkyl or -CH2OH, and R32 represents R31, wherein R31 is as defined above; or Claim 1...cont'd.(10) (xix) removing the R31 protecting group from the intermediate products of step (xviii) to produce the desired intermediate of general formula V, wherein R32 represents H;
for the intermediate of general formula VI, wherein R15 represents H and Z1 represents -(Ph)-(CH2)g-, wherein g and Ph are as defined above:
(cc)(xx) reducing a ketone of general formula:

LIa wherein n, R16, R17, R18 and R31 are as defined above, to the corresponding secondary alcohol of general formula:

LIIa wherein n, R16, R17, R17 and R31 are as defined above;
(xxi) sulfonylating the secondary alcohol of general formula LIIa to produce a compound of general formula:

laim 1...cont'd.(11) 145 LIIIa wherein n, R16, R17, R18 and R31 are as defined above and W represents a group selected from -CH3 and tolyl;
(xxii) reacting the compound of general formula LIIIa with an alkali metal thiophenoxide to produce a compound of general formula:

LIVa wherein n, R16, R17, R18 and R31 are as defined above;
(xxiii) oxidizing the compound of general formula LIVa to produce a compound of general formula:

LVa Claim 1...cont'd. (12) 146 wherein n, R16, R17, R18 and R31 are as defined above;
(xxiv) by the use of a strong base generating the anion of the compound of general formula LVa, which anion is condensed with an aldehyde of general formula:
XLIV

wherein g is as defined above and R28 represents a group of general formula Si(G1)3, wherein G1 represents a silyl protective group, and the adduct thus produced is reacted with acetic anhydride to produce a compound of general formula:

LVIa wherein n, R16, R17, R18, R31, g and R28 are as defined above;
(xxv) reacting the compound of general formula LVIa with sodium amalgam to produce a compound of general formula:

Claim 1...cont'd.(13) 147 LVIIa wherein n, R16, R17, R18, R31, g and R28 are as defined above; and (xxvi) selectively hydrolyzing the R28 silyl group of the compound of general formula LVIIa to produce the desired intermediate of general formula VI, wherein R15 represents H, R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH and Z1 represents -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxvii) oxidizing the -CH2OH group of the intermediate product of step (xxvi) to produce the desired intermediate of general formula VI, wherein R15 represents H, R32 represents R31, wherein R31 is as defined above, X1 represents -COOH and Z1 represents -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxviii) converting the -COOH group of the intermediate product of step (xxvii) to the salts, esters, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VI, wherein R15 represents H, R32 represents R31, wherein R31 Claim 1...cont'd.(14) 148 is as defined above, X1 is as defined above other than -CH2OH and -COOH and Z1 represents -(Ph)-(CH2)9-, wherein g and Ph are as defined above; or (xxix) removing the R31 protecting group from the intermediate products of steps (xxvi) to (xxviii) to produce the desired intermediates of general formula VI, wherein R32 represents H;
for the intermediate of general formula VI, wherein R15 represents H and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above:
(dd)(xxx) reacting a compound of general formula:

XXXIa wherein n, R16, R18 and R31 are as defined above;
and R37 corresponds to R17 as defined above other than H; with a compound of general formula:

XXXII

wherein R28 is as defined above; and Z2 corresponds to 21 as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above;
to produce a compound of general formula:

Claim 1...cont'd.(15) 149 XXXIIIa wherein n, R16, R18, R31, R37, R28 and Z2 are as defined above;
(xxxi) subjecting the compound of general formula XXXIIIa to decarboxylative dehydration to produce a compound of general formula:

XXXIVa whereln n, X16, R18, R31, R37, R28 and Z2 are as defined above; and (xxxii) desilylating the compound of general formula XXXIVa to produce the desired intermediate of general formula VI, wherein R15 represents H, R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxxiii) reacting the compound of general formula XXXIa in a Wittig reaction with a triphenylphosphonium Claim 1...cont'd.(16) 150 of general formula:

wherein Z2 is as defined above, to produce the desired intermediate of general formula VI, wherein R15 represents H, R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxxiv) when R17 represents H and X1 represents -CH2OH, removing the protective group (C1-C4)alkyl, for R37, from the intermediate product of steps (xxxii) or (xxxiii) to produce the desired intermediate of general formula VI, wherein R15 and R17 represent H, R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxxv) when R17 represents (C1-C4)alkyl and X1 is as defined above other than -CH2OH, converting the -CH2OH group of the intermediate product of steps (xxxii) or (xxxiii) to the free acids, salts, esters, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VI, wherein R15 represents H, R17 represents Claim 1...cont'd.(17) (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, X1 is as defined above other than -CH2OH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxxvi) when R17 represents H and X1 is as defined above other than -CH2OH, effecting step (xxxiv) with the intermediate products of step (xxxv) to produce the desired intermediate of general formula VI, wherein R15 and R17 represent H, R32 represents R31, wherein R31 is as defined above, X1 is as defined above other than -CH2OH
and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxxvii) removing the R31 protecting group from the intermediate products of steps (xxxii) to (xxxvi) to produce the desired intermediates of general formula VI, wherein R32 represents H; or (ee)(xxxviii) Wittig .omega.-carboxyalkylating the compound of general formula XXXIa with a triphenylphosphonium of general formula:

LXXXII

wherein Z2 is as defined above, to produce the desired intermediate of general formula VI, wherein R15 represents H, R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, X1 represents -COOH and Claim 1...cont'd.(18) Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (xxxix) when X1 represents -CH2OH, esterifying the intermediate product of step (xxxviii) to the methyl ester of general formula:

LXXXIVa wherein n, R16, R18, R31, R37 and Z2 are as defined above; and reducing the compound of general formula LXXXIVa to produce the desired intermediate of general formula VI, wherein R15 represents H, R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (x1) when X1 is as defined above other than -COOH or -CH2OH, converting the -COOH group of the intermediate product of step (xxxviii) to the salts; esters, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VI, wherein R15 represents H, R17 represents (C1-C4)alkyl, R32 respresents R31, wherein R31 is as defined above, X1 is as Claim 1...cont'd.(19) 153 defined above other than -COOH and -CH2OH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (x1i) when R17 represents H, removing the protective group (C1-C4)alkyl, for R37, from the intermediate products of steps (xxxviii) to (x1) to produce the desired intermediates of general formula VI, wherein R15 and R17 represent H, R32 represents R31, wherein R31 is as defined above, and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (x1ii) removing the R31 protecting group from the intermediate products of steps (xxxviii) to (x1i) to produce the desired intermediate of general formula VI, wherein R32 represents H;
for the intermediate of general formula VI, wherein R15 represents F and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above:

(ff)(x1iii) generating an anion from a sulfoximine of general formula:

XCI

wherein Z2 and R10 are as defined above, and treating the resulting anion with a fluoro source to produce a fluorinated sulfoximine of general formula:

Claim 1 ...cont'd.(20) XCII

wherein Z2 and R10 are as defined above;
(xliv) reacting the fluorinated sulfoximine of general formula XCII with a compound of general formula:

XCIIIa wherein n, R16, R17, R18 and R31 are as defined above, to produce a compound of general formula:
XCIVa wherein n, R10, R16, R17, R18, R31 and Z2 are as defined above; and mild acid hydrolyzing the compound of general formula XCIVa to produce the desired intermediate of general formula VI, wherein R15 represents F, R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH and Z1 is as defined above Claim 1...cont'd.(21) 155 other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; the -CH2OH group of which is oxidized to produce the desired intermediate of general formula VI, wherein R15 represents F, R32 represents R31, wherein R31 is as defined above, X1 represents -COOH
and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; the -COOH group of which is converted to the salts, esters, amides, amines, cyclo-amines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VI, wherein R15 represents F, R32 represents R31, wherein R31 is as defined above, X1 is as defined above other than -CH2OH and -COOH and Z1 is as defined above other than -(Ph)-(CH2)g-, wherein g and Ph are as defined above; or (x1v) removing the R31 protecting group from the intermediate products of step (x1iv) to produce the desired intermediate of general formula VI, wherein R32 represents H;
for the intermediate of general formula VI, wherein Z1 represents trans-CH2-CH=CH-:
(gg)(x1vi) preparing the .alpha.-phenylselenyl derivative of a compound of general formula:

CXXIa Claim 1...cont'd.(22) 156 wherein n, R15, R16, R17, R18 and R31 are as defined above and R1 is as defined above other than H or a cation, to produce a com-pound of general formula:

CXXIIa wherein n, R15, R16, R17, R18 and R31 are as defined above and R1 is as defined immediately above; and (x1vii) dehydrophenylselenizing the compound of general formula CXXIIa to produce the desired intermediate of general formula VI, wherein R32 represents R31, wherein R31 is as defined ahove, X1 represents -COOR1, wherein R1 is as defined in step (x1vi), and Z1 represents trans-CH2-CH=CH-; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VI, wherein R32 represents R31; wherein R31 is as defined above, X1 represents -CH2OH and Z1 represents trans-CH2-CH=CH-; or (x1viii) transforming the ester group -COOR1 of the intermediate product of step (x1vii) to the free acid to produce the desired intermediate Claim 1...cont'd.(23) 157 of general formula VI, wherein R32 represents R31, wherein R31 is as defined above, X1 represents -COOH and Z1 represents trans-CH-CH=CH-; or (x1ix) converting the -COOH group of the intermediate product of step (x1viii) to the salts, amides, amines, cycloamines, carbonylamines or sulfonyl-amines, as required, to produce the desired intermediate of general formula VI, wherein R32 represents R31, wherein R31 is as defined above, X1 is as defined above other than -COOH, -CH2OH
and -COOR1, wherein R1 is as defined in step (x1vi), and Z1 represents trans-CH-CH=CH-; or (1) removing the R31 protecting group from the inter-mediate products of steps (x1vii) to (x1ix) to produce the desired intermediate of general formula VI, wherein R32 represents H;
for the intermediate of general formula VII, wherein Z1 represents trans-CH2-CH=CH-:
(hh)(li) reducing a compound of general formula:

CXXXIa wherein n, R15, R16, R17, R18 and R31 are as defined above and R1 is as defined in step (x1vi), to produce a compound of general formula:

Claim 1...cont'd.(24) 158 CXXXIIa wherein n, R15, R16, R17, R18 and R31 are as defined above and R1 is as defined immediately above;
(lii) dehydrophenylselenizing the compound of general formula CXXXIIa to produce the desired intermediate of general formula VII, wherein R32 represents R31, wherein R31 is as defined above, X1 represents -COOR1, wherein R1 is as defined in step (x1vi) and Z1 represents trans-CH2-CH=CH-; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VII, wherein R32 represents R31, wherein R31 is as defined above, X1 represents -CH2OH
and Z1 represents trans-CH2-CH=CH-; or (liii) transforming the ester group -COOR1 of the intermediate product of step (lii) to the free acid to produce the desired intermediate of general formula VII, wherein R32 represents R31, wherein R31 is as defined above, X1 represents -COOH and Z1 represents trans-CH2-CH=CH-;
or (liv) converting the -COOH group of the intermediate product of step (liii) to the salts, amides, Claim 1...cont'd.(25) 159 amines, cycloamines, carbonylamines or sulfonyl-amines, as required, to produce the desired intermediate of general formula VII, wherein R32 represents R31, wherein R31 is as defined above, X1 is as defined above other than -COOH, -CH2OH and -COOR1, wherein R1 is as defined in step (xlvi), and Z1 represents trans-CH2-CH=CH-; or (lv) removing the R31 protecting group from the intermediate products of steps (lii) to (liv) to produce the desired intermediate of general formula VII, wherein R32 represents H;
for the intermediate of general formula VII, wherein Z1 is as defined above other than trans-CH2-CH=CH-:
(ii)(lvi) reducing a compound of general formula:

CXLIa wherein n, R15, R16, R17, R18, R31 and X1 are as defined above and Z3 corresponds to Z1 as defined above other than trans-CH2-CH=CH-, to produce the desired intermediate of general formula VII, wherein R32 represents R31, wherein R31 is as defined above, and Z1 is as defined above other than trans-CH2-CH=CH-; or Claim 1...cont'd. (26) 160 (lvii) removing the R31 protecting group from the intermediate product of step (lvi) to produce the desired intermediate of general formula VII, wherein R32 represents H;
for the intermediate of general formula VIII, wherein R20 to R24 represent H:
(jj)(lviii) methyleneating a compound of general formula:

CLXXIa wherein R18, R28 and R31 are as defined above, to produce a compound of general formula:

CLXXIIa wherein R18, R28 and R31 are as defined above;

(lix) converting the compound of general formula CLXXIIa to the corresponding aldehyde of general formula:
CXCIa wherein R18, R28 and R31 are as defined above;

Claim 1....cont'd.(27) (lx) isomerizing the aldehyde of general formula CXCIa under basic conditions to produce the correspondinq .beta.-aldehyde of general formula:

CXCIIa wherein R18, R28 and R31 are as defined above;
(lxi) reducing the .beta.-aldehyde of general formula CXCIIa to the corresponding alcohol of general formula:

CXCIIIa wherein R18, R28 and R31 are as defined above;
(lxii) sulfonylating the compound of general formula CXCIIIa to produce a compound of general formula:

CLXXIVa wherein R18, R28, R31 and W are as defined above;
(lxiii) selectively hydrolyzing the compound of general formula CLXXIVa to produce a phenol of general formula:

CLXXVa Claim 1...cont'd.(28) wherein R18, R31 and W are as defined above;
(lxiv) cyclizing the phenol of general formula CLXXVa to produce a compound of general formula:

CLXXVIa wherein R18 and R31 are as defined above; and (lxv) .omega.-carboxyalkylating the compound of general formula CLXXVIa to produce the desired inter-mediate of general formula VIII, wherein R20 to R24 represent H, R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOR1, wherein R1 is as defined above; or when R1 represents H
converting the -COOH group to the salts, amides, amines, cycloamines, carbonylamines or sulfonyl-amines, as required, to produce the desired intermediate of general formula VIII, wherein R20 to R24 represent H, R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -CH2OH and -COOR1; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VIII, wherein R20 to R24 represent H, R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or Claim 1...cont'd.(29) 163 (lxvi) removing the R31 protecting group from the intermediate products of step (lxv) to produce the desired intermediate of general formula VIII, wherein R33 represents -CH2OR32, wherein R32 represents H; or (lxvii) oxidizing the -CH2OH group of the intermediate products of step (lxvi) to produce the desired intermediate of general formula VIII, wherein R33 represents -CHO;
for the intermediate of general formula VIII, wherein R21 and R22, when taken together, form a second valence bond between C6a and C9 and R20, R23 and R24 represent H:
(kk)(lxviii) reacting with a methyl Grignard reagent a compound of general formula:

CCXI a wherein R18 and R31 are as defined above, to produce a compound of general formula:

CCXII a wherein R18 and R31 are as defined above; and Claim 1...cont'd.(30) 164 (lxix) repeating steps (lxv) to (lxvii) with the compound of general formula CCXIIa to produce the desired intermediate of general formula VIII, wherein R21 and R22, when taken together, form a second valence bond between C6a and C9 and R20, R28 and R24 represent H;
for the intermediate of general formula VIII, wherein R20 and R21, when taken together, represent =O and R22, R23 and R24 represent H:
(11)(lxx) selectively hydrolyzing an aldehyde of general formula:

CLXXXII a wherein R18, R28 and R31 are as defined above to produce a phenol of general formula:

CLXXXIIIa wherein R18 and R31 are as defined above;
(lxxi) preparing the phonoxide anion of the phenol of general formula CLXIIIa, which anion is cyclized by heating to a compound of general formula:

Claim 1...cont'd.(31) 165 CLXXXIVa wherein R18 and R31 are as defined above;
(lxxii) .omega.-carboxyalkylating the compound of general formula CLXXXIVa to produce an alcohol of general formula:

CLXXXV a wherein R18, R31, R1 and Z4 are as defined above; and (lxxiii) oxidizing the alcohol of general formula CLXXXVa to produce the desired intermediate of general formula VIII, wherein R20 and R21, when taken together, represent =O, R22, R23 and R24 represent H, R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOR1, wherein R1 is as defined above; or when R1 represents H converting the -COOH group to the salts, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general Claim 1...cont'd.(32) formula VIII, wherein R20 and R21, when taken together, represent =O, R22, R23 and R24 represent H, R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -CH2OH and -COOR1, wherein R1 is as defined above; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VIII, wherein R20 and R21, when taken together, represent =O, R22, R23 and R24 represent H, R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and Xl represents -CH2OH; or (lxxiv) removing the R31 protecting group from the intermediate products of step (lxxiii) to produce the desired intermediate of general formula VIII, wherein R33 represents -CH2OR32, wherein R32 represents H; or (lxxv) oxidizing the -CH2OH group of the intermediate products of step (lxxiv) to produce the desired intermediate of general formula VIII, wherein R33 represents -CHO;
for the intermediate of general formula VIII, wherein R21 and R22, when taken together, form a second valence bond between C6a and C9, R23 and R24, when taken together, form a second valence bond between C7 and C8, and R20 represents H:
(mm)(lxxvi) dehydrogenating the intermediate products of step (lxix) to produce the desired intermediate of general formula VIII, wherein R21 and R22, Claim 1...cont'd.(33) when taken together, form a second valence bond between C6a and C9, R23 and R24, when taken together, form a second valence bond between C7 and C8, and R20 represents H;
for the intermediate of general formula VIII, wherein R20, R22, R23 and R24 represent H and R21 represents -OH:
(nn)(lxxvii) reducing the intermediate products of steps (lxxii) to (lxxv) to produce the desired intermediate of general formula VIII, wherein R20, R22, R23 and R24 represent H
and R21 represents -OH;
for the intermediate of general formula VIII, wherein at least one of R20 to R24 is other than H:
(oo)(lxxviii) by ozonolvsis converting a compound of general formula:

CCXXIa wherein R18, R20 to R24, X1 and Z4 are as defined above and at least one of R20 to R24 is other than H, to the desired intermediate of general formula VIII, wherein at least one of R20 to R24 is other than H and R33 represents -CHO; or (lxxix) reducing the -CHO group of the intermediate products of step (lxxviii) to produce the Claim 1...cont'd.(34) 168 desired intermediate of general formula VIII, wherein R33 represents -CH2OH; or (lxxx) converting the -CH2OH group of the intermediate products of step (lxxix) to -CH2OR31, wherein R31 is as defined above, to produce the desired intermediate of general formula VIII, wherein R33 represents -CH2OR31, wherein R31 is as defined above; and for the intermediate of general formula IX:
(pp)(lxxxi) methyleneating a compound of general formula:

CLXXI

wherein L1, Y1, M6, R18, R27 and R28 are as defined above, to produce a compound of general formula:

CLXXII

wherein L1, Y1, M5, R18, R27 and R28 are as defined above;
(lxxxii) converting the compound of general formula CLXXII to the corresponding hydroxymethyl of general formula:

Claim 1.. .cont'd. (35) 169 CLXXIII

wherein L1, Y1, M6, R18, R27 and R28 are as defined above;
(lxxxiii) sulfonylating the compound of general formula CLXXIII to produce a compound of general formula:

CLXXIVa wherein L1, Y1, M6, R18, R27, R28 and W are as defined above;
(lxxxiv) selectively hydrolyzing the compound of general formula CLXXIVa to produce a phenol of general formula:

CLXXVa wherein L1, Y1, M6, R18, R27 and W are as defined above; and (lxxxv) cyclizing the phenol of general formula CLXXVa to produce the desired intermediate of general formula IX;
wherein said process is adapted to produce all possible isomers of the intermediates of general formulae IV to IX singly or in combination.

2. The process defined in claim 1, wherein R10 represents a group selected from tetrahyaropyranyl, tetrahydrofuranyl, -C(OR11)(R12)-CH(R13)(R14) and R28, wherein R28 is as defined in claim 1, R11 represents a group selected from (C1-C18)alkyl, (C3-C10)cycloalkyl, (C7-C12)aralkyl, phenyl, mono-, di- and tri-(C1-C4)alkyl substituted phenyl, R12 and R13, independently, represent a group selected from (C1-C4)alkyl, phenyl, mono-, di-and tri-(C1-C4)alkyl-substituted phenyl, or when R12 and R13 are taken together they represent a group selected from and , wherein a represents 3, 4 or 5, b represents one, 2 or 3 and c represents one, 2 or 3, with the proviso that b+c is 2, 3 or 4, and wherein R14 represents a group selected from H and phenyl.
3. The process defined in claim 2, wherein R31 represents a group selected from R9, R10 and R28, wherein R10 and R28 are as defined in claim 2 and R9 represents a group selected from:
benzoyl;
mono-, di-, tri-, tetra- and penta-substituted benzoyl, wherein the substituent are selected from (C1-C4)alkyl, (C7-C12)phenylalkyl and nitro, with the proviso that no more than 2 substituents are other than (C1-C4)alkyl, and the total number of carbon atoms in the substituents does not exceed 10;
(C2-C5)alkoxycarbonyl-substituted benzoyl;
naphthoyl;
mono-, di-, tri-, tetra, penta-, hexa, septa-, octa and nona-substituted naphthoyl, wherein the substituent are selected from (C1-C4)alkyl, (C7-C10)phenylalkyl and nitro, with the proviso that no more than 2 substituents on either fused aromatic ring are other than (C1-C4)alkyl, and the total numker of carbon atoms in the substituents on either fused aromatic ring does not exceed 10; and (C2-C12)alkanoyl.

4. A carbacyclin intermediate with a general formula selected from the group consisting of:

IV, V, VI, VII, VIII and IX

wherein n, L1, M6, R15 to R18, R20 to R24, R27, R32, R33, R47, X1, Y1, Z1 and Z4, for each of said intermediates, are as defined in claim 1.

5. A process for preparing a carbacyclin intermediate of general formula:

IV

wherein n, L1, M6, R16, R18, R27, R47 and Y1 are as defined in claim 1; said process comprising:
(x') treating a lactone of general formula:

XXI

wherein n, L1, M6, R18, R27 and Y1 are as defined above, with the anion of dimethyl methylphosphonate to produce a lactol of general formula:
XXII
wherein n, L1, M6, R18, R27 and Y1 are as defined above;

Claim 5...cont'd.(2) (xi') oxidizing the lactol of general formula XXII
to produce a diketone of general formula:

XXIII

wherein n, L1, M6, R18, R27 and Y1 are as defined above; and xii') by a Horner-Emmons reaction intramolecularly cyclizing the diketone of general formula XXIII
to produce the desired intermediate of general formula IV, wherein R16 and R47, when taken together, form a second valence bond between C6a and C9; or (xiii') treating the intermediate product of step (xii') with lithium dialkyl cuprate to produce the desired intermediate of general formula IV, wherein R16 represents H and R47 represents (C1-C4)alkyl; or (xiv') treating the intermediate product of step (xii') with the anion of trimethyloxosulfonium iodide to produce the desired intermediate of general formula IV, wherein R16 and R47, when taken together, represent -CH2-; or (xv') by photochemical addition of CH3OH converting the intermediate product of step (xii') to the desired intermediate of general formula IV, wherein R16 represents H and R47 represents -CH2OH; or (xvi') tosylating the intermediate product of step (xv') to produce a compound of general formula:

XXVII

wherein n, L1, M6, R18, R27 and Y1 are as defined above; and (xvii') treating the compound of general formula XXVII
with base to produce the desired intermediate of general formula IV, wherein R16 and R47, when taken together, represent -CH2-;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula IV singly or in combination.
6. A carbacyclin intermediate of general formula:

IV

wherein n, L1, M6, R16, R18, R27, R47 and Y1 are as defined in claim 5.

7. A process for preparing a carbacyclin intermediate of general formula:

V

wherein n, R16, R18, R32 and R47 are as defined in claim 1;
said process comprising:
(xviii') effecting steps (x) to (xii), (xiii), (xiv), (xv) or (xvi) and (xvii) of claim 1 and using in step (x) a starting compound of general formula:

LX Ia wherein n and R18 are as defined ahove and R31 is as defined in claim 1, to produce the desired intermediate of general formula V, wherein R16 and R47, when taken together, represent a second valence bond between C6a and C9 or -CH2-, or R16 represents H and R47 represents (C1-C4)alkyl or -CH2OH, and R32 represents R31, wherein R31 is as defined above; or (xix') removing the R31 protecting group from the intermediate products of step (xviii') to produce the desired intermediate of general formula V, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula V singly or in combination.
8. A carbacyclin intermediate of general formula:

V

wherein n, R16, R18, R32 and R47 are as defined in claim 7.

9. A process for preparing a carbacyclin intermediate of general formula:

VIa wherein g, n, R16, R17, R18, R32, X1 and Ph are as defined in claim 1; said process comprising:
(xx') reducing a ketone of general formula:

LIa Claim 9...cont'd.(2) wherein n, R16, R17 and R18 are as defined above and R31 is as defined in claim 1, to the corresponding secondary alcohol of general formula:
LIIa wherein n, R16, R17, R18 and R31 are as defined above;
(xxi') sulfonylating the secondary alcohol of general formula LIIa to produce a compound of general formula:

LIIIa wherein n, R16, R17, R18 and R31 are as defined above and W is as defined in claim 1;
(xxii') reacting the compound of general formula LIIIa with an alkali metal thiophenoxide to produce a compound of general formula:

Claim 9...cont'd.(3) LIVa wherein n, R16, R17, R18 and R31 are as defined above;
(xxiii') oxidizing the compound of general formula LIVa to produce a compound of general formula:

LVa wherein n, R16, R17, R18 and R31 are as defined above;
(xxiv') by the use of a strong base generating the anion of the compound of general formula LVa, which anion is condensed with an aldehyde of general formula:

XLIV
wherein g is as defined above and R28 is as defined in claim 1, and the adduct thus produced is reacted with acetic anhydride to produce a compound of general formula:

Cla:im 9...cont'd.(4) LVI a wherein g, n, R16, R17, R18, R28 and R31 are as defined above;
(xxv') reacting the compound of general formula LVIa with sodium amalgam to produce a compound of general formula:

LVIIa wherein n, g, R16, R17, R18, R28 and R31 are as defined above; and (xxvi') selectively hydrolyzing the R28 silyl group of the compound of general formula LVIIa to produce the desired intermediate of general formula VIa, wherein R32 represents R31, wherein R31 is as defined above and X1 represents -CH2OH; or (xxvii') oxidizing the -CH2OH group of the intermediate product of step (xxvi') to produce the desired intermediate of general formula VIa, wherein R32 represents R31, wherein R31 is as defined above and X1 represents -COOH; or (xxviii') converting the -COOH group of the intermediate product of step (xxvii') to the salts, esters, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIa, wherein R32 represents R31, wherein R31 is as defined above and X1 is as defined above other than -CH2OH and -COOH; or (xxix') removing the R31 protecting group form the intermediate products of steps (xxvi') to (xxviii') to produce the desired intermediates of general formula VIa, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIa singly or in combination.
10. A carbacyclin intermediate of general formula:

VIa wherein g, n, R16, R17, R18, R32, X1 and Ph are as defined in claim 9.

11. A process for preparing a carbacyclin intermediate of general formula:

Claim 11 cont'd.(2) VIb wherein n, R16, R17, R18, R82, X1 and Z2 are as defined in claim 1; said process comprising:
(xxx') reacting a compound of general formula:

XXXIa wherein n, R16 and R18 are as defined above, and R31 and R37 are as defined in claim 1; with a compound of general formuia:

XXXII

wherein Z2 is as defined above; and R28 is as defined in claim 1; to produce a compound of general formula:

XXXIIIa Claim 11...cont'd.(3) wherein n, R16, R18, R28, R31, R37 and Z2 are as defined above;
(xxxi') subjecting the compound of general formula XXXIIIa to decarboxylative dehydration to produce a compound of general formula:

XXXIV a wherein n, R16, R18, R28, R31, R37 and Z2 are as defined above; and (xxxii') desilylating the compound of general formula XXXIVa to produce the desired intermediate of general formula VIb, wherein R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above,and X1 represents -CH2OH; or (xxxiii') reacting the compound of general formula XXXIa in a Wittig reaction with a triphenylphosphonium of general formula:

wherein Z2 is as defined above, to produce the desired intermediate of general formula VIb, wherein R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or Claim 11...cont'd.(4) (xxxiv') when R17 represents H and X1 represents -CH2OH, removing the protective group (C1-C4)alkyl, for R37, from the intermediate product of steps (xxxii') or (xxxiii') to produce the desired intermediate of general formula VIb, wherein R17 represents H, R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or (xxxv') when R17 represents (C1-C4)alkyl and X1 is as defined above other than -CH2OH, converting the -CH2OH group of the intermediate product of steps (xxxii') or (xxxiii') to the free acids, salts, esters, amides, amines, cyclo-amines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIb, wherein R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -CH2OH; or (xxxvi') when R17 represents H and X1 is as defined above other than -CH2OH, effecting step (xxxiv') with the intermediate products of step (xxxv') to produce the desired intermediate of general formula VIb, wherein R17 represents H, R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -CH2OH; or (xxxvii') removing the R31 protecting group from the intermediate products of steps (xxxii') to Claim 11...cont'd.(5) (xxxvi') to produce the desired intermediates of general formula VIb, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIb singly or in combination.
12. A process for preparing a carbacyclin intermediate of general formula:

VIb wherein n, R16, R17, R18, R32, X1 and Z2 are as defined in claim 1; said process comprising:
(xxxviii') Wittig .omega.-carboxyalkylating a compound of general formula:

XXXIa wherein n, R16 and R18 are as defined above, and R31 and R37 are as defined in claim 1, with a triphenylphosphonium of general formula:

LXXXII

wherein Z2 is as defined above, to produce the desired intermediate of general formula VIb, Claim 12...cont'd.(2) wherein R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, and X1 represents -COOH; or (xxxix') when X1 represents -CH2OH, esterifying the intermediate product of step (xxxviii') to the methyl ester of general formula:

LXXXIVa wherein n, R16, R18, R31, R37 and Z2 are as defined above; and reducing the compound of general formula LXXXIVa to produce the desired intermediate of general formula VIb, wherein R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or (x1') when X1 is as defined above other than -COOH
or -CH2OH, converting the -COOH group of the intermediate product of step (xxxviii') to the salts, esters, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIb, wherein R17 represents (C1-C4)alkyl, R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -COOH and -CH2OH; or (xli') when R17 represents H, removing the protective group (C1-C4)alkyl, for R37, from the intermediate products of steps (xxxviii') to (x1') to produce the desired intermediates of general formula VIb, wherein R17 represents H and R32 represents R31, wherein R31 is as defined above; or (xlii') removing the R31 protecting group from the intermediate products of steps (xxxviii') to (xli') to produce the desired intermediate of general formula VIb, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIb singly or in combination.
13. A carbacyclin intermediate of general formula:

VIb wherein n, R16, R17, R18, R32, X1 and Z2 are as defined in claim 11.

14. A process for preparing a carbacyclin intermediate of general formula:

VIc Claim 14...cont'd.(2) wherein n, R16, R17, R18, R32, X1 and Z2 are as defined in claim 1; said process comprising:
(xliii') generating an anion from a sulfoximine of general formula:

XCI

wherein Z2 is as defined above and R10 is as defined in claim 1, and treating the resulting anion with a fluoro source to produce a fluorinated sulfoximine of general formula:

XCII

wherein Z2 and R10 are as defined above;
(xliv') reacting the fluorinated sulfoximine of general formula XCII with a compound of general formula:

XCIIIa wherein n, R16, R17 and Rl8 are as defined above and R31 is as defined in claim 1, to produce a compound of general formula:

Claim 14...cont'd.(3) XCIVa wherein n, R10, R16, R17, R18, R31 and Z2 are as defined above; and mild acid hydrolyzing the compound of general formula XCIVa to produce the desired intermediate of general formula VIc, wherein R32 represents R31, wherein R31 is as defined above,and Xl represents -CH2OH; the -CH2OH group of which is oxidized to produce the desired intermediate of general formula VIc, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOH; the -COOH
group of which is converted to the salts, esters, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIc, wherein R32 represents R31, wherein R31 is as defined above, and Xl is as defined above other than -CH2OH and -COOH; or (xlv') removing the R31 protecting group from the intermediate products of step (xliv') to produce the desired intermediate of general formula VIc;
wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIc singly or in combination.

15. A carbacyclin intermediate of general formula:

VIc wherein n, R16, R17, R18, R32, X1 and Z2 are as defined in claim 14.

16. A process for preparing a carbacyclin intermediate of general formula:

VId wherein n, R15, R16, R17, R18, R32 and X1 are as defined in claim 1; said process comprising:
(xlvi') preparing the .alpha.-phenylselenyl derivative of a compound of general formula:
CXXIa wherein n, R15, R16, R17 and R18 are as Claim 16...cont'd.(2) defined above, R1 is as defined in claim 1 other than H or a cation and R31 is as defined in claim 1,to produce a compound of general formula:
CXXIIa wherein n, R1, R15, R16, R17, R18 and R31 are as defined above; and (xlvii') dehydrophenylselenizing the compound of general formula CXXIIa to produce the desired intermediate of general formula VId, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOR1, wherein R1 is as defined above; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VId, wherein R32 represents R31, wherein R31 is as defined above,and X1 represents -CH2OH; or (xlviii') transforming the ester group -COOR1 of the intermediate product of step (xlvii') to the free acid to produce the desired intermediate of general formula VId, wherein R32 represents R31, wherein R31 is as defined above,and X
represents -COOH; or (xlix') converting the -COOH group of the intermediate product of step (xlviii') to the salts, amides, amines, cycloamines, carbonylamines or sulfonyl-amines, as required, to produce the desired intermediate of general formula VId, wherein R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -COOH, -CH2OH and -COOR1, wherein R1 is as defined above; or (l') removing the R31 protecting group from the intermediate products of steps (xlvii') to (xlix') to produce the desired intermediate of general formula VId, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VId singly or in combination 17. A carbacyclin intermediate of general formula:

VId wherein n, R15, R16, R17, R18, R32 and X1 are as defined in claim 16.

18. A process for producing a carbacyclin intermediate of general formula:

laim 18...cont'd.(2) VIIa wherein n, R15, R16, R17, R18, R32 and X1 are as defined in claim 1, said process comprising:
(li') reducing a compound of general formula:

CXXX Ia wherein n, R15, R16, R17 and R18 are as defined above, R1 is as defined in claim 1 other than H
or a cation and R31 is as defined in claim 1, to produce a compound of general formula:

CXXXIIa wherein n, R1, R15, R16, R17, R18 and R31 are as defined above;

Claim 18...cont'd.(3) (lii') dehydrophenylselenizing the compound of general formula CXXXIIa to produce the desired intermediate of general formula VIIa, wherein R32 represents R31, wherein R31 is as defined above,and X1 represents -COOR1, wherein R1 is as defined above; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VIIa, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or (liii') transforming the ester group -COOR1 of the inter-mediate product of step (lii') to the free acid to produce the desired intermediate of general formula VIIa, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOH; or (liv') converting the -COOH group of the intermediate product of step (liii') to the salts, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIIa, wherein R32 represents R31, wherein R31 is as defined above,and X1 is as defined above other than -COOH, -CH2OH and -COOR1, wherein R1 is as defined above; or (lv') removing the R31 protecting group from the inter-mediate products of steps (lii') to (liv') to produce the desired intermediate of general formula VIIa, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIa singly or in combination.

19. A carbacyclin intermediate of general formula:

VIIa wherein n, R15, R16, R17, R18, R32 and X1 are as defined in claim 18.

20. A process for preparing a carbacyclin intermediate of general formula:
VIIb wherein n, R15, R16, R17, R18, R32, X1 and Z3 are as defined in claim 1; said process comprising:
(lvi') reducing a compound of general formula:
CXLIa wherein n, R15, R16, R17, R18, X1 and Z3 are as defined above and R31 is as defined in claim 1, to produce the desired intermediate of general formula VIIb, wherein R32 represents R31, wherein R31 is as defined above; or (lvii') removing the R31 protecting group from the intermediate product of step (lvi') to produce the desired intermediate of general formula VIIb, wherein R32 represents H;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIb singly or in combination.
21. A carbacyclin intermediate of general formula:

VIIb wherein n, R15, R16, R17, R18, R32, X1 and Z3 are as defined in claim 20, 22. A process for preparing a carbacyclin intermediate of general formula:

VIIIa wherein R18, R33, X1 and Z4 are as defined in claim 1; said process comprising:

Claim 22...cont'd.(2) (lviii') methyleneating a compound of general formula:

CLXXIa wherein R18 is as defined above, and R28 and R31 are as defined in claim 1, to produce a compound of general formula:

CLXXII a wherein R18, R28 and R31 are as defined above;
(lix') converting the compound of general formula CLXXIIa to the corresponding aldehyde of general formula:

CXCIa wherein R18, R28 and R31 are as defined above;
(lx') isomerizing the aldehyde of general formula CXCIa under hasic conditions to produce the corresponding .beta.-aldehyde of general formula:

CXCIIa Claim 22...cont'd.(3) wherein R18, R28 and R31 are as defined above;
(lxi') reducing the .beta.-aldehyde of general formula CXCIIa to the corresponding alcohol of general formula:

CXCIIIa wherein R18, R28 and R31 are as defined above;
(lxii') sulfonylating the compound of general formula CXCIIIa to produce a compound of general formula:

CLXXIVa wherein R18, R28 and R31 are as defined above and W is as defined in claim 1;
(lxiii') selectively hydrolyzing the compound of general formula CLXXIVa to produce a phenol of general formula:

CLXXVa wherein R18, R31 and W are as defined above;
(lxiv') cyclizing the phenol of general formula CLXXVa to produce a compound of general formula:

Claim 22...cont'd.(4) CLXXVIa wherein R18 and R31 are as defined above; and (lxv') .omega.-carboxyalkylating the compound of general formula CLXXVIa to produce the desired inter-mediate of general formula VIIIa, wherein R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOR1, wherein R1 is as defined in claim 1;
or when R1 represents H converting the -COOH
group to the salts, amides, amines, cycloamines, carbonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIIIa, wherein R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -CH2OH and -COOR1; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VIIIa, wherein R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or (lxvi') removing the R31 protecting group from the intermediate products of step (lxv') to produce the desired intermediate of general formula VIIIa, wherein R33 represents -CH2OR32, wherein R32 represents H; or (lxvii') oxidizing the -CH2OH group of the intermediate products of step (lxvi') to produce the desired intermediate of general formula VIIIa, wherein R33 represents -CHO;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIIa singly or in com-bination.
23. A carbacyclin intermediate of general formula:

VIIIa wherein R18, R33, X1 and Z4 are as defined in claim 22.

24. A process for preparing a carbacyclin intermediate of general formula:

VIIIb wherein R18, R33, X1 and Z4 are as defined in claim 1;
said process comprising:
(lxviii') reacting with a methyl Grignard reagent a compound of general formula:

CCXIa wherein R18 is as defined above and R31 is as defined in claim 1, to produce a compound of general formula:

CCXIIa wherein R18 and R31 are as defined above; and (lxix') repeating steps (lxv) to (lxvii) of claim 1 with the compound of general formula CCXIIa to produce the desired intermediate of general formula VIIIb;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIIb singly or in combination.
25. A carbacyclin intermediate of general formula:

VIIIb wherein R18, R33, X1 and Z4 are as defined in claim 24.

26. A process for preparing a carbacyclin intermediate of general formula:

VIIIc wherein R18, R33, X1 and Z4 are as defined in claim 1; said process comprising:
(lxx') selectively hydrolvzing an aldehyde of general formula:

CLXXXIIa wherein R18 is as defined above, and R28 and R31 are as defined in claim 1, to produce a phenol of general formula:

CLXXXIIIa wherein R18 and R31 are as defined above;
(lxxi') preparing the phonoxide anion of the phenol of general formula CLXXXIIIa, which anion is Claim 26.. cont'd.(2) cyclized by heating to a compound of general formula:

CLXXXIVa wherein R18 and R31 are as defined above;
(lxxii') .omega.-carboxyalkylating the compound of general formula CLXXXIVa to produce an alcohol of general formula:

CLXXXVa wherein R18, R31 and Z4 are as defined above and R1 is as defined in claim 1; and (lxxiii') oxidizing the alcohol of general formula CLXXXVa to produce the desired intermediate of general formula VIIIc, wherein R33 rep-resents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -COOR1, wherein R1 is as defined above; or when R1 represents H converting the -COOH group to the salts, amides, amines, Claim 26...cont'd.(3) cycloamines, carhonylamines or sulfonylamines, as required, to produce the desired intermediate of general formula VIIIc, wherein R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 is as defined above other than -CH2OH and -COOR1, wherein R1 is as defined above; or when R1 represents -CH3 reducing the -COOCH3 group to produce the desired intermediate of general formula VIIIc, wherein R33 represents -CH2OR32, wherein R32 represents R31, wherein R31 is as defined above, and X1 represents -CH2OH; or (lxxiv') removing the R31 protecting group from the intermediate products of step (lxxiii') to produce the desired intermediate of general formula VIIIc, wherein R33 represents -CH2OR32, wherein R32 represents H; or (lxxv') oxidizing the -CH2OH group of the intermediate products of step (lxxiv') to produce the desired intermediate of general formula VIIIc, wherein R33 represents -CHO;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIIc singly or in com-bination.
27. A carbacyclin intermediate of general formula:

VIIIc wherein R18, R33, X1 and Z4 are as defined in claim 26, 28. A process for preparing a carbacyclin intermediate of general formula:

VIIId wherein R18, R33, X1 and Z4 are as defined in claim 1; said process comprising:
(lxxvi') dehydrogenating the intermediate products of step (lxix) of claim 1 to produce the desired intermediate of general formula VIIId;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIId singly or in com-bination.
29. A carbacyclin intermediate of general formula:

VIIId wherein R18, R33, X1 and Z4 are as defined in claim 28.

30. A process for preparing a carbacyclin intermediate of general formula:

VIIIe wherein R18, R33, X1 and Z4 are as defined in claim 1, said process comprising:
(lxxvii') reducing the intermediate products of steps (lxxii ) to (lxxv ) of claim 1 to produce the desired intermediate of general formula VIIIe;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIIIe singly or in com-bination.
31. A carbacyclin intermediate of general formula:

VIIIe wherein R18, R33, X1 and Z4 are as defined in claim 30.

32. A process for preparing a carbacyclin intermediate of general formula:

Claim 32...cont'd.(2) 208 VIII

wherein R18, R20 to R24, R33, X1 and Z4 are as defined in claim 1 and at least one of R20 to R24 is other than H; said process comprising:
(lxxiii') by ozonolysis converting a compound of general formula:

CCXXIa wherein R18, R20 to R24, R33, X1 and Z4 are as defined above to the desired intermediate of general formula VIII, wherein at least one of R20 to R24 is other than H and R33 represents -CHO; or (lxxix') reducing the -CHO group of the intermediate products of step (lxxviii') to produce the desired intermediate of general formula VIII, wherein R33 represents -CH2OH; or (lxxx') converting the -CH2OH group of the intermediate products of step (lxxix') to -CH2OR31, wherein R31 is as defined in claim 1, to produce the desired intermediate of general formula VIII, wherein R33 represents -CH2OR31, wherein R31 is as defined above;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula VIII singly or in com-bination.
33. A carbacyclin intermediate of general formula:

VIII

wherein R18, R20 to R24, R33, X1 and Z4 are as defined in claim 32.

34. A process for preparing a carbacyclin intermediate of general formula:

wherein L1, M6, R18, R27 and Y1 are as defined in claim 1 said process comprising:
(lxxxi') methyleneating a compound of general formula:

CLXXI

Claim 34...cont'd.(2) wherein L1, Y1, M6, R18 and R27 are as defined above and R28 is as defined in claim 1, to produce a compound of general formula:

CLXXII

wherein L1, Y1, M6, R18, R27 and R28 are as defined above;
(lxii') converting the compound of general formula CLXXII to the corresponding hydroxymethyl of general formula:

CLXXIII

wherein L1, Y1, M6, R18, R27 and R28 are as defined above;
(lxxxiii') sulfonylating the compound of general formula CLXXIII to produce a compound of general formula:

CLXXIVa wherein L1, Y1, M6, R18, R27 and R28 are as defined above and W is as defined in claim 1;

(lxxxiv') selectively hydrolyzing the compound of general formula CLXXIVa to produce a phenol of general formula:

CLXXVa wherein L1, Y1, M6, R18, R27 and W are as defined above; and (lxxxv') cyclizing the phenol of general formula CLXXVa to produce the desired intermediate of general formula IX;
wherein said process is adapted to produce all possible isomers of the intermediate of general formula IX singly or in combination.
35. A carbacyclin intermediate of general formula:

IX

wherein L1, M6, R18, R27 and Y1 are as defined in claim 34.