CA1209154A - Intermediates for preparing 9-hydroxy substituted carbacyclin derivatives - Google Patents

Abstract

A B S T R A C T

Intermediates for preparing 9-hydroxy substituted carbacyclin derivatives of general formula:

wherein s is one or 2; Y is -CH2CH2, cis-CH=CH-, trans-CH=CH-or -C-C-; Mx is .alpha.-OR:.beta.-R14 or .alpha.-R14:.beta.-OR, wherein R is an -OH-protecting group and R14 is H or -CH3; L1 is a-OR15:.beta.-R16, .alpha.-R16:.beta.-R15 or a mixture thereof, wherein R15 and R16, independently, are H, F or -CH3, with the proviso that one of R15 and R16 is F only when the other is not -CH3; L50 is H:H, .alpha.-OR:.beta.-H, .alpha.-H:.beta.-OR, a-CH2OR:.beta.-H or .alpha.-H:.beta.-CH2OR, wherein R is as defined above; R13 is an -OH-protecting group; and R17 is (i) cis-CH=CHCH2CH3,-(CH2)2CH(OH)CH3, -(CH2)3CH=C(CH3)2, phenyl, benzyl, phenylethyl, phenylpropyl, or , (ii) -CmH2mCH3, wherein m is an integer of from one to 5, or (iii) mono-, di- and tri-F, -C1, -CF3, -C1-3alkyl or -C1-3alkoxy-(phenyl)-substituted-phenyl, -benzyl, -phenylethyl, -phenylpropyl, with the proviso that not more than two substituents are other than C1-3alkyl; or when taken together, is:
(iv)

Description

t . ~Z09154 This is a di-~isional application of copending application serial no. 423,186, filed March 9, 1983.

BACKGROUND OF rHE INVENrION
, I, , The present invention relates to novel compounds which are 9-sub-stituted carbacyclin analogs, to processes for the preparation of said S carbacyclin analogs and the use of said analogs as pharmacological agents or as intermediates for the preparation of compounds useful as pharmacological agents. This invention also relates to chemical intermediates for preparing the novel 9-substituted carbacyclin com-- pounds described and claimed herein.
Prostacyclin is an endogenously produced compound in mammalian - species, being structurally and biosynthetically related to the pros-:~~` taglandins (PG's). In particular, prostacyclin exhibits the structure - and carbon atom numbering of formula I when the C-5,6 positions areunsaturated. For convenience, prostacyclin is often referred to simply as "PGI2". for description of prostacyclin and its structural identi~icat-ion, see Johnson, et al, Prostaglandins 12:915 (1976).
Carbacyclin, 6a-carba-PGI~, exhibits the structure and carbon atom numbering indicated in formula II when the C-5,6 positions art unsaturated. Likewise, for convenienceS carbacyclin is referred to simply as "CBA~".
A stable partially saturated derivative of PGI~ is PGI1 or 5,6-dihydro-PGI~ when the C-5,6 positions are saturated, depicted with carbon atom numbering in formula I when the C-5,6 positions are satu-'7. rated. The corresponding 5,6-dihydro-CBA~ is CBAl, depicted in formula II when the C-5,6 positions are saturated.
A formula as drawn herein which depicts a prostacyclin-type product or an intermediate useful in the preparation thereof, repre-sents that particular stereoisomer of the prostacyclin-type product which is of the same relative stereochemical configuration as prosta-cyclin obtained from mammalian tissues or the particular stereoisomerof the intermediate which is useful in preparing the above stereoiso-mer of the prostacyclin type product. As drawn, formula I corresponds to that of PGI~ endogenously produced in the mammalian species, In particular, refer to the stereochemical confisuration at C-8 (a), C-,9 (a), C-11 (~) and C-12 (~) of endogenously produced prostacyclin. rhe mirror image of the above formula for prostacyclin represents the other enantiomer.

-.

1209~54

-2- 4082 The term "prostacyclin analog" or "carbacyclin analog" represents that stereoisomer of a prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mani,~alian tissues or a mixture comprising stereoisorner and the enanti-omers thereof. In particular, where a ~ormul~ is used to depict aprostacyclin type product herein, the term "prostacyclin analog" or "carbacyclin analog" rerers to the compound of that formula 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 PI Numbers 48154B/26 and 48155Bt26. See also British published specifications 2,012,265 and German O~fenlungsschl~ift 2,900,352, abstracted as Derwent Farmdoc CPI Number 54825a/30. See also British published applications 2,0l7,699 and 2,013,661 and U.S.
patent 4,238,414. The synthesis of carbacyclin and related compounds - is also reported in the chemical literature, as fol10ws: Morton, D.R., et al, J. Org. Chem., 44:2880 (1979); Shibasaki, M., et al, Tetrahedron Lett., 433-436 (1979); Kojima, K., et al, Tetrahedron Lett., 3743-3746 (1978); Nicolaou, K.C., et Al, J. Chem. Soc., Chemical Communications, 1067-1068 (1978); Sugie, A., et al, Tetra hedron Lett., 2607-2610 (1979); Shibasaki, M., Chem. Lett., l2g9-l300 (l979), and Hayashi, M., Chem. Lett., 1437-40 (1979); Aristoff, P.A., J. Org. Chem. 46, 1954-1957(1981); Yamazaki, M., et al, Chem. Lett., 1245-1248(1981); and Barco, A., et al, J. Or. Chem. 45, 4776-~778 -, (1980); and Skuballa, W., et al, Angew. Chem., 93, 1080-1081 (1981).
7-OXo and 7-hydroxy-CBA2 compounds are apparently disclosed in United States Patent 4,192~891. 19-Hydrox~-CBA2 compounds are disclosed in United States patent No. 4,225,508. CBA2 aromatic esters are disclosed in United States Patent 4,180,657. 1l-Deoxy-alD-or ~Il-CBA~ compounds are described in Japanese Koka~i 77/24,865, pub-lished 24 February 1979. Related 9~-substituted compounds are dis-closed in U.S. 4,306,075 and 4,306,076.
SU~lMARY OF THE INVENTION
, The parent application relates to compounds of formula I I I
IV wherein D is cis-C=CH-, trans-C=CH- or -CHCH2-;
wherein R3 is hydrogen, methyl or acetyl;

, ~20gl54 _3_ 40~2 wherein Z i 5 (1) -CH~-(CH2)f-C(R4)~- wherein each R4 is the sarne and is hydro-gen cr ~luoro, and f is zero, one, 2 or 3;
(2) trans-CH~-CH-CH-; or

(3) -(Ph)-(CH2)9- wherein Ph is 1,2-, 1,3-, or 1,4-phenylene and g is zero, one, 2 or 3;
wherein Q is (1) -COOR5, wherein R5 is (a) hydrogen, (b) (Cl-Cl~)alkyl, (c ) (Ca -Cl o )cycl oa 1 kyl, (d) (C7-Cl2)aralkyl, (e) phenyl optionally substituted with one, 2 or 3 chloro or (Cl-C4)alkyl, (f) phenyl substituted in the para-position with -NHCOR6, -COR7,. -OC(O)R~ or -CH=N-NHCONH~, wherein R6 is methyl, phenyl,~acet-amidophenyl, benzamidophenyl or -NH2; R7 is methyl, phenyl, -NH~, or methoxy; and R~ is phenyl or acetamidophenyl;
(g) phthalidyl, (h)3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxxopro-pan-l-yl P-oxide, (i)3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-22-yl)-2-oxopropan-1-yl P-oxide, or (j) a pharmacologically acceptable cation;
(2) -CHzOH;
(3) -COLz, wherein Lz is (a) an amino group ox the formula -NRyRlo wherein Rg is hydrogen or (Cl-Clz)al~yl and Rlo is (i) hydrogen (ii) (Cl-Cl~)alkyl (iii) (C~-C1O)cycloalkyl, .
(iv) (C7,Cl2)aralkyl (v) phenyl optionally substituted with one, 2 or 3 chloro, (Cl-C~)alkyl, hydroxy, carboxy, (C~-C5)alkoxycarbonyl, or nitro, (V i ) (C~-C5 )carboxyalkyl, (vii) (C;~-Cs)carbamoylalkyl, (viii) (C~-Cs)cyanoalkyl, . i . ' i , lZ09154

-4~ 4082 ( i x ) O -C~j )acetyl a l kyl, (x) (C7-Cl2)benzoylalkyl, optionally substituted by one, 2, or 3 chloro, (Cl-C,)alkyl, hydroxy, (Cl-C3)alkoxy, carboxy, (Ci! -C5 ) -a l koxyca rbonyl, or n i t ro , (xi) pyridyl, optionally substituted by one, 2, or 3 - chloro, (Cl-C3 )al kyl, or (Cl-C3 )al koxy~
(xii) (C6-Cg)pyridylalkyl optionally substituted by one, 2, or 3 chloro, (Cl-C3)alkyl, hydroxy, or (Cl-C3)alkyl, (Xiii) (Cl-c4) hydroxyal kyl, (xiv) (Cl-C4)dihydroxyalkyl, (xv) (Cl-C4)trihydroxyalkyl;
(b) cycloamine selected from the group consisting of pyro-lidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrroline, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (Cl-Cl2)alky!;
(c) carbonylamino of the formula -NRllCORln, wherein Rll is hydrogen or (Cl-C4)alkyl and RlU is other than hydrosen, but otherwise `defined as above;
td) sulfonylamino of the formula -NRllS02Rlo, wherein R
and Rl~ are defined in (c);
(4) -CH~NL~L4, wherein L3 and L4 are hydrogen or ~Cl-C4)alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when Q is -CH~NL3L4; or

(5) -CN;
25 wherein s is the integer one or 2;
wherein L is H,H; -ORl2,~-H; a-H,~-ORl2; ~-CH2OXl2,~ H; ~-H,~-. CH20Rl2 wherein Rl2 is hydrogen or a hydroxyl protective group;
wherein Y is trans -CH=CH-, cis-CH-CH-, -CH2CH2-, or -C_C-;
wherein M is -ORl~,~-Rl4; or a-Rl4,~-ORl~. wherein Rl~ is as defined above, and Rl4 is hydrogen or methyl;
wherein Ll is -Rls~-Rl6; -RlO,~-Rls; or a mixture thereof wherein R15 and R16 are hydrogen, methyl, or fluoro being the same or different with the proviso that one of Rls and Rl6 is fluoro only when the other of Rls and Rl6 is hydrogen or fluoro;
wherein Rl 7 iS
(1) -Cm~l2 CH3 wherein m is an integer of from ona to 5,(particularly C~13 C ~CH2)3-CH3) , ,H
~2) phenoxy optionally substituted by one, 2 or 3 chloro, fluoro, trlfluoromethYl~ ~Cl-C3)alkyl, or ~Cl-C3tal~xy, with the 1209~54 proviso that not more than two substituents are other than alkyl and with the proviso that R17 is phenoxy or substituted phenoxy, only when R15 and R16 are hydrogen or methyl, being the same or different;
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, 2, or 3 chloro, fluoro, tri-fluoromethyl,(Cl-C3)alkyl, or (Cl-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl.
(4) cis-CH=CH-CH2CH3, (5) -(CH2)2-CH(OH)-CH3,

(6) -(CH2)3-CH=C(CH3)2, C,H3

(7) -C-CH2CH2CH2 3

(8) -CH2 , or

(9) -CH2 , or wherein -C-R17 taken together is Ll (1) (C4-C7)cycloalkyl optionally substituted by one to 3 (cl-c5)alkyl~
(2) 3-thienyloxymethyl, ~CH3 (3) -cH-cH2c-C-CH3 , (4) ~C~C~CqH2qCH3 wherein q is an integer of from 2 to 6, or (5) -CpH2pCH=CH2 wherein p is an integer of from 3 to 7;
and lndividual optical isomers thereof.
The compounds of Formulas A-2 and C-2 which are useful as intermediates in the preparation of the compounds of Formula IV, are claimed in this application. In the various formulas used herein the substituent groups L, Y, M, Ll, R17 (except for intermediates A-2, wherein R17 is not phenoxy), s,D, Z, and Q have the same meanings as defined in Formula IV. The group L50 is H,H; ~-OR;~-H; ~-H,~-OR;
~-CH2OR ,~-H; ~-H,~-CH2OR wherein R has the same meaning as R12 only R
is not hydrogen. me group Mx is ~-OR,~-R14, R14, the same meaning as R12 only R is not hydrogen; R14 is hydrogen or methyl.
The group R13 is a hydroxyl protecting group as mab/

0 9~l5 4 -6- 40~2 defined hereinafter. The group Q~ is the same as Q only Q~ is other than -CH~OH. The group Z1 is the same as Z only Zl is other than -(Ph)-(CHz)9-. DETAILED DESCPIPTION OF INVENTION
In naming the novel compounds of the present inYention in general the art-recognized system of nomenclature described by N.A. ~lelson, J.
Med. Chem. 17:g11 (1974) for prostaglandins is followed. As a matter of convenience, however, the novel carbacyclin derivatives herein are named as 6a-carba-prostaglandin l2 compounds.
In the formulas herein, broken line attachments to a ring, i.e., (---) indicate substituents in the "alpha" (~) configuration, i.e., below the plane of said ring. Heavy solid line attachments to a ring, i.e., ( _ ) indicate substituents in the "beta" (B) configuration, i.e., above the plane of said ring. rne use or wavy lines (~) herein will represent attachment of substituents in the alpha or beta config-uration or attached in a mixture of alpha and beta configurations.
Alternatively wavy lines will represent either an E or geometric isomeric configuration or the mixture thereof. Also, solid and dotted lines used together, as for example, in formulas I and II at C-5,6 positions indicates the presence of either a double bond or alterna-tively a single bond.
A side chain hydroxy at C-l5 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 discus-,f sion applies to the novel carbacyclin analogs herein.
With regard to the divalent groups described above, i.e., M, Land Ll said divalent groups are defined in terms of an a-substituent and a ~-substituent which means that the -substituent of the divalent group is in the alpha configuration with respect to the plane of the C-8 to C-12 cyclopentane ring and the ~-substituent is in the beta configuration with respect to said cyclopentane ring.
The carbon atom content of various hydrocarbon containing groups is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety. For example, in defining the moiety Lo in the -COLT substituent group the definition (C1-Cl~)alkyl means that L2 can be an alkyl group having from one to 12 carbon atoms. Addition-ally, any moiety so defined includes straight chain or branched chain 7 ~L'~U~ 4 4082 groups. Thus (Cl-Cl~)alkyl as set forth above includes straight or branched chain alkyl groups ha/ing frorn 1 to 12 carbon atoms and as additional illustration, when Lo represents, for example, (C~-Cs)carb-oxyalkyl, the alkyl moiety thereof contains from 1 to 4 carbon atoms and is a straight chain or a branched chain alkyl group.
Novel compounds wherein Z is -(Pn)-(CH2)9- are designated inter-o-, inter-m-, or inter-p-phenylene depending on whether the attachment between C-5 and the -(C~)g_ moiety is ortho, meta, or para, respec-tively. For those compounds wherein g is zero, one or 2, the carba-cyclin analogs so described are further characterized as 2,3,4-tri-nor-, 3,4-dinor-, or 4-nor, since in this event the Q-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-, and 3,5-inter-phenylene compounds when g is zero, one, or 2, respectively and when g is 3 the compounds are named as 4,5-inter-phenylene compounds.
The compounds of Formula IV wherein Z is O CH~)f-C(R4)2-wherein R4 is fluoro are characterized as "2,2-difluoro-" compounds.
For those compounds wherein f is zero, 2, or 3, the compounds so described are further characterized as 2-nor, 2a-homo, or 2a,2b-di-homo, since in this event the Q-terminated side chain contains 4, 6, or 7 carbon atoms, respectively, in place of the five carbon atoms contained in PGI~. The missing carbon atom is considered to be at the C-2 position such that the C-1 carbon atom is connected to the C-3 position. ye additional carbon atom or atoms are considered as though they were inserted between the C-2 and C-3 positions. Accord-ingly these additional carbon atoms dre referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.
The compounds of Formula IV wherein Z is trans-CH2-CH=CH- are described as "trans-2,3 didehydro-CBA" compounds.
Those novel compounds where s is 2 are further characterized as 7a-homo-C~A compounds by virtue of the cyclohexyl ring replacing the heterocyclic ring of prostacyclin.
Further, all of the novel compounds of the present invention are substituted at the 9B-position witn a hydroxy group and are named 12~9154 as 9~-hydroxy compounds, or with a methoxy group and are named 9~-methoxy compounds, or with an ~cetoxy group and are named 9~-acetoxy compounds.
When Rl4 is methyl, the carbacyclin ana1Ogs are all named as "15-methyl-" compounds. Further, except for compounds wherein Y is cis-CH=OH-, compounds wherein the moiety contains an hydroxyl in the beta configuration are additionally named as "15-epi-" compounds.
For the compounds wherein `f is cis-CH=CH-, then compounds wherein thé M moiety contains an hydroxyl in the alpha configuration are named as "15-epi-" compounds. For a description of this convention of nomenclature or 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 -(CH~2->
cis-CH=CH-, or -C_C- as the Y moiety, are accordingly referred to as "13,14-dihydro", "cis-13", or "13,14-didehydro" compounds, respec-tively.
When R17 is straight chained -CmH~m-CH~, wherein m is an integer of from one to 5, the compounds so described are named as "19,20-dinor", "20-nor", "20-methyl" or "20-ethyl" compounds when m is one, 2, 4 or 5, respectively. When Rl7 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 (l-methylpentyl).
When Rl7 is phenyl and neither Rls nor Rl6 is methyl, the com-pounds so described are named as "16-phenyl-17,18,19,20-tetranor" com-pounds. When R17 is substituted phenyl, the corresponding compounds are named as "16-(substituted phenyl)-17,18,19,20-tetranor" compounds.
When one an4 only one of Rls and R16 is methyl or both Rls and R16 are methyl, then the corresponding compounds wherein Rl7 is as defined 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 R17 is benzyl, the compounds so described are named as "17-phenyl-18,19,20-trinor" compounds. When Rl7 is substituted benzyl, the corresponding compounds are named as "17-(substituted phenyl)-18,19,20-trinor" compounds.

9_ 1Z~9~54 When R17 is phenylethyl, the compounds so described are named as "18-phenyl-19,20-dinor" compounds. When R17 is substituted phenyl-ethyl, the corresponding compounds are named as "18-(substituted phenyl)-19,20-dinor" compounds.
S When Rl~ is phenylpropyl, the compounds so described are named as "l9-phenyl-20-nor" compounds. When Rl7 is substituted phenylpropyl the corresponding compounds are named as "l9-(substituted phenyl)-20-nor" compounds.
When Rl7 is phenoxy and neither Rl5 nor Rl6 is methyl, the com-pounds so described are named as "16-phenoxy-17,1~,19,20-tetranor"
compounds. When Rl7 is substituted phenoxy, the corresponding com-pounds are named dS "16-(substituted phen~xy)-17,18,19,20-tetranor"
compounds. when one ard only one of R15 and R16 is methyl or both Rls and R16 are methyl, then the corresponding compounds wherein R17 is as defined in this paragraph are named as "16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds or "16-methyi-16-phenoxy- or 16-(substituted phenoxy)l8,19,20-trinor" compounds, respectively.
When R17 is cis-CH=CH-CH2CH~, the compounds so described are named as "cis-17,18-didehydro" compounds.
When R17 is -(CH2)~-CH(OH)-CH3, the compounds so described are named as "I9-hydroxy" compounds.
When R17 is -(CH~)~-CH=C(CH3)~, the compounds so described are named as "20-isopropylidene" compounds.
When R17 is .. .
-C-CH~CH~CH~CH~
H
the compounds so described are named as 17(S),2~-dimethyl compounds.
When Ri7 is 2-furylmethyl or 3-thienylmethyl, i.e., respectively the compounds so described are named as "17-(2-furyl)-18,19,20-trinor" compounds and "17-(3-thienyl)-18,19,20-trinor" com-ponds respectiYely.

When -C(Ll)-R17 is -CH-CH~C_C-CH~, the compounds are named as

-10- 40~2 "16-(R,S)methyl-l~,l9-tetradeh~dro" cornpounds.
When -C(LI)-Rl7 is optionally substituted cycloalkyl or 3-thien-yloxymethyl, the compounds so described are named respectively 15-cycloalkyl-16,17,18,19,20-pentanor compounds and 16-(3-thienyl)oxy-17,18,19,20-tetranor compounds. The term 3-thienyloxymethyl means the moiety having the structure:
-CH~-0 ' S
When -C(Ll)RI7 is -C C-CqH~qCH~ wherein q is an integer ox from 2 to 6 the compounds so described are named as "16>17-tetradehydro'`, "16,17-tetradehydro-20-methyl", "16,17-tetradehydro-20-ethyl", "16,17-tetrahydro-20-n-propyl" and "16,17-tetrahydro-2~-n-butyl~ compounds as the integer as represented by q varies from 2 to 6 respectively.
~5 When -C(Ll)Rl7 is -CpH2pCH=CH~ wherein p is an integer of from 3 to 7 the compounds so described are named as "19,20-didehydro"~
"19,20-didehydro-18a,18b-dihomo", "19,20-didehydro-18a,18b,18c-tri-homo", "19,20-didehydro-18a,18b,18c,18d-tetrahomo" compounds as the integer represented by p varies from 3 to 7 respectively.
2~ OH
When -C(Ll)Rl7 is -CH(CH~)4-CH~ the compounds so described are named as "16(R,S),20-dimethyl" compounds.
When at least one of Rls and R16 is not hydrogen then (except for the 16-phenoxy or 16-phenyl compounds discussed aboYe) there are described the "16-methyl" (one and only one of R15 and Rl~ is methyl), ; "16,16-dimethyl" (Rl5 and Rl~ are both methyl), "16-fluoro" zone and only one of Rls and Rl6 is fluoro), "16,16-difluoro" (R~s and Rl6 are both fluoro) compounds. For those compounds wherein Rls and R16 are di~erent, the carbacyclin analogs so represented contain an asymmet-ric carbon atom at C-16. Accordingly, two epimeric configurations are possible: "(16S)" and "(16R)". Further, there is described by this invention the C-16 epimeric mixture: "(16RS)".
When Q is -CH20H, the compounds so described are named as "2-de-carboxy-2-hydroxymethyl" compounds.
When Q is -CH~NL~L4, the compounds so described are named as "2-decarboxy-2-aminomethyl" or "2-(substituted amino)methyl~ compounds.
When Q is -COLT, the novel compounds herein are named as amides.
Further, when Q is -cOORs and Rs is other than hydrogen the novel com-lZ09154 40~2 pounds herein are named dS esters dnd salts.
Ihen Q is CN the novel compounds herein are named as 2-decarboxy-2-cyano compounds.
Examples of phenyl esters substituted in the para position (i.e., Q is -COOR5, R5 is p-substituted phenyl) include p-acetamidophenyl ester, p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester, p-(p-benzamido~enzamido)phenyl ester, p-amidocarbonylaminophenyl ester, p-acetylphenyl ester, p-benzoylphenyl ester, p-aminotarbonyl-phenyl ester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehyde semi-carbazone ester.
Examples of novel amides herein (i.e., Q is -COLT) include the following:
(1) Amides within the scope of alkylamino groups of the formula-NRgRlU are methylamide, ethylamide, n-propylamide, isopropylamide, n-butylamide, n-pentylamide, tert-butylamide, neopentylamide, n-hexyl-amide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide, n-undecylamide~ and n-dodecylamide, and isomeric forms thereof. Fur-ther examples are dimethylamide, diethylamide, di-n-propylamide, di-isopropylamide, di-n-butylamide, methylethylamide, di-tert-butylamide, methylpropylamide, methylbutylamide, ethylpropylamide, ethylbutyl-amide, and propylbutylamide. Amides within the scope of cycloalkyl-amino are cyclopropylamide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide, 2-methylcyclo-pentylamide, 3-tertbutylcyclopentylamide, cyclohexylamide, 4-tert-butylcyclohexylamide, 3-isopropylcyclohexylamide, 2,2-dimethylcyclo-i hexylamide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclo-decylamide, N-me~hyl-N-cyclobutylamide, N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexylamide, N-ethyl-N-cyclopentylamide, and N-ethyl-N-cyclohexylamide. Amides within the scope of aralkylamino are benzyl-amide, 2-phenylethylamide, and N-methyl-N benzyl-amide. Amides within the scope of substituted phenylamide are p-chloroanilide, m-chloro-anilide, 2,4-dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimeth-oxyanilide, p-hydroxymethylanilide, p-methylanilide, m-methyl anilide, p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonyl anilide, p-carboxyanilide and o-hydroxyanilide. Amides within the scope of carboxyalkylamino are carboxyethylamide, carboxypropylamide ~209~54 -12- 4~2 and carboxymethylamide, carboxybutylarnide. Amides within the scope of carbamoylalkylarnino are carbamoylmethylamide, carbamoylethylamide, carbamoylpropylamide, and carbamoylbutylamide. Amides within the scope of cyanoal~ylamino are cyanomethylamide, c~anoethylamide, cyano-propylamide, and cyanobutylamide. Amides within the scope ox acetyl-alkylamino are acetylmethylamide, acetylethylamide, acetylpropylamide, and acetylbutylamide. Amides within the SCOp2 of benzoylalkylamino are benzoylmethylamide, benzoylethylamide, benzoylpropylamideJ and - benzoylbutylamide. Amides within the scope o, substituted benzoyl-alkylamino are p-chlorobenzoylmethylamide, m-chlorobenz~ylmethylamide, 2,4-dichlorobenzoylmethylamide, 2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide, p-nitrobenzoylmethylamide, p-methoxybenz-oylmethylamide, 2,4-dimethoxy benzoyîmethylamide, 3,~,5-trimethoxy-benzoylmethylamide, p-hydroxymethylbenzoylmethylamide, p-methylbenz oylmethylamide, m-methylbenzoylmethylamide, p-ethylben20ylmethylamide, t-butylbenzoylmethylamide, p-carboxybenzoylmethylami&e, m-methoxy-carbonylbenzoylmethylamide, o-carboxybenzoylme hylamide, o-hydroxy-benzoylmethylamide, p-chlorobenzoylethylamide, m-chlorobenzoylethyl-amide, 2,4-dichlorobenzoylethylamide, 2,4,6-trichlorobenzoylethyl-amide, m-nitrobenzoylethylamide, p-nitrobenzoylethylamide, p-meth-oxybenzoylethylamide, p-methoxybenzoylethylamide, 2,4-dimethoxybenz-oylethylamide, 3,4,5trimethoxybenzoylethylamide, p-hydroxymethylbenz-oylethylamide, p-methylbenzoylethylamide, m-methylbenzoylethylamide, p-ethylbenzoylethyldmide, t-butylbenzoylethylamide, p-carboxybenzoyl-ethylamide, m-methoxycarbonylbenzoylethylamide, o-carboxybenzoyl-i ethylamide, o-hydroxybenzoylethylamide, p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide, 2,4-dichlorobenzoylpropylamide, 2,4,6-trichlorobenzoylpropylamide, m-nitrobenzoylpropylamide, p-nitrobenz-oylpropylamide, p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpro-pylamide, 3,4,5-trimethoxybenzoylpropylamide, p-hydroxymethylbenzoyl_ propylamide, p-methylbenzoylpropylamide, m-methylbenzoylpropylamide, p-ethylbenzoylpropylamide, t-butylbenzoylpropylamide, p-carboxybenz-oylpropylamide, m-methoxycarbonylbenzoylpropylamide, o-carboxybenzoyl-propylamide, o-hydroxybenzoylpropylamide, p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide, 2,4-dichlorobenzoylbutylamide, 2,4,6-tri-chlorobenzoylbutylamide, m-nitrobenzoylmethylamide, p-nitrobenzoyl-butylamide, p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutyl amide, 3,4,5-tri~ethoxybenzoylbutylamide, p-hydroxymethylbenzoylbutyl-_13_ ~209154 4082 amide, p-meth~lbenzoylbutyamide, m-methylbenzoylbutylamide, p-ethyl-benzoylbutyalmide, m-methylbenzoylbutylamide, p-ethylbenzoylbutyl-amide, t-butylDenzoylbutylamide, p-carboxybenzoylbutylamide, m-meth-oxycarbony1benzoylbutylamide, o-carboxybenzoylbutylamide, o-hydroxy-benzoyl~ethylamide. Amides within the scope of pyridylamino are~-pyridylamide, ~-pyridylamide, and Y-pyridylamide. Amides within the scope of substituted pyridylamino are 4-methyl-~-pyridylamide, 4-methyl-~-pyridylamide, 4-chloro--pyridylamide, and 4-chloro-B-pyridylamide. Amides within the scope of pyridylalkylamino are I-pyridylmethylamide, ~-pyridylmethylamide, ~-pyridylmethylamide, -pyridylethylamide, ~-pyridylethylamide, y-pyridylethylamide~
a-pyridylpropyldnlide~ B-pyridylpropylamide~ y-pyridylpropylamide, a-pyridylbutylamide, B-pyridylbutylamide, and ~-pyridylbutylamide.
Amides within the scope of substituted pyridylalkylamido are 4-methyl-~-pyridylmethylamide, 4-methyl-~-pyridylmethylamide, 4-chloro-~-pyridylmethylamide, 4-chloro-B-pyridylmethyl-amide, 4-methyl-~-pyridylpropylamide, 4-methyl-~-pyridylpropylamide, 4-chloro-~-pyridylpropylamide, 4-chloro-B-pyridylpropylamide, 4-methyl-~-pyridylbutylamide, 4-methyl- ~-pyridylbutylamide, 4-chloro-~-pyridyl-butylamide, 4-chloro-~-pyridylbutylamide, 4-chloro-y-pyridylbutyl-amide. Amides within the scope of hydroxyalxylamino are hydroxy-methylamide, ~-hydroxyethylamide, ~-hydroxypropylamide, y-hydroxy-propylamide, l-~hydroxymethyl)ethyl-amide, l-(hydroxymethyl)propyl-amide, (2-hydroxymethyl)propylamide, and a,~,-dimethyl-hydroxy_ ethylamide. Amides within the scope ox dihydroxyalkylamino are dihy-droxymethylamide, ~,y-dihydroxypropylamide, l-(hydroxymethyl)2-hydroxymethylamide, ~,y-dihydroxybutylamide, ~,~-dihydroxybutyl-amide, y~-dihydroxybutylamide~ and l,l-bis(hydroxymethyl)ethylamide. Amides within the sco?e of trihydroxyalkylamino are tris(hydroxy-methyl)-methylamide and 1,3-dihydroxy-2-hydroxymethylpropylamide.
(2) Amides within the scope of cycloamino groups described aboYe are pyrrolidylamide, piperidylamide, morpholinylamide, hexamethylene-iminylamide, piperazinylamide, pyrrolinylamide, and 3,4-didehydro-piperidinylamide each of which may be optiona11y substituted with one or 2 straight or branched al~yl chains having from 1 to 12 carbon atoms.
(3) Amides within the scope of carbonylamino of the formula -~IRllCORlo are methylcarbonylamide, ethylcarbonylamide, phenylcar-~~4~ 1209~154 408~
bonylamide, and benzylcarbonylamide.
(4) Amides within the scope ox sulfonyldmino of the formula -~RllCORlu are methylsu1fonylamide, ethylsufonylamide, phenylsulfonyl-amide, p-tolylsulfonylamide, benzylsulfonylamide.
S Examples of alkyl ox one to 12 carbon atoms, inclusive, are methyl, ethyt, propyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, isomeric forms thereof.
Examples of (C~-C10)cycloalkyl which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclo-propyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, - - cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropyl-cyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl, and cyclodecyl.
Examples of (C7-Cl~)aralkyl are benzyl, 2-phenylethyl, l-phenyl-ethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthyl-ethyl), and 1-(2-naphthylmethyl).
Examples ox 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-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2methyl-phenyl, and 2,4-dichloro-3-methylphenyl.
Examples of (C4-C7)cyClOal~yl optionally substituted by one to 3 t (Cl-C5)alkyl are cyclobutyl, l-propylcyclobutyl, l-butylcyclobutyl, l-pentylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3-ethyl-cyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 1-methyl-3-propylcyclo-pentyl, 2-methyl-3-propylcyclopentyl, 2-methyl-4-propylcyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclo-hexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-butylcyclohexyl, 4-tert-butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclo-hexyl, 2,6-dimethyl-4-propylcyclohexyl, and cycloheptyl.
Examples of substituted phenoxy, phenyl, phenylmethyl, i.e., benzyl, phenylethyl, or phenylpropyl ox the Rl~ moiety are (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, 4-ethyl-o-tolyl, 5-ethyl-m-1209~54 -15- 4~82 tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(m- or p-)tol~l, 4-iso-propyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(m- or p-)tolyl, 4-~luoro-2,5-xylyl, (2,4-, 2,5-, 2,5-, 3,4-, or 3,5-)di-fluorophenyl, (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-)dichlorophenyl, 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-meth-oxyphenyl, 2,4-dichloro-(4- or 6-)methylphenyl, (o-, m-, or p-)tolyl-oxy, (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-xylyloxy, 3-propyl-4-ethylphenyloxy, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, ~-fluoru-(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-pro-pylphenoxy, 2-isopropyl-4-chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyloxy, 4-chloro-3-~luoro-phenoxy, (3- or 4-)chloro-2-fluorophenoxy, (o-, m-, or p-)trifluoro-methylphenoxy, (o-, m-, or p-)methoxyphenoxy, (o-, m-, or p-)ethoxy-phenoxy, (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, S-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-)trimethylphenylmethyl, (o-, m-, or p-)fluorophenyl-methyl, 2-fluoro-(m- or p-)tolylmethyl, 4-fluoro-2,5-xylylmethyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenylmethyl, (o-, m-, or p-)tolylethyl, (o-, m-, or p-)ethylphenylethyl, 4-ethyl-o-tolylethyl, 5-ethyl-m-tolylethyl, (o-, m-, or p-)propylphenylethyl, 2-propyl-~m-or p-)tolylethyl, 4-isopropyl-2,6-xylylethyl, 3-propyl-4-ethylphenyl-ethyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenylethyl, Jo-, m-, or p-)fluorophenylethyl, 2-~luoro-(m- or p-)tolylethyl, 4-fluoro--2,5-xylylethyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenylethyl, (o-, m-, or p-)chlorophenylmethyl, 2-chloro-p-tolylmethyl, (3, I, 5, or 6-)chloro-o-tolylmethyl, 4-chloro-2-propylphenylmethyl, 2-isopro-!

lZ09154 pyl-4-chlorophenylmethyl, 4-chloro-3,5-xylylmethyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylmethyl, 4-chloro-3-fluorophenyl-methyl, (3- or 4-)chloro-2-fluoroph2nylmethyl, (o-, m-, or p-)tri-fluoromethylphenylmethyl, (o-, m-, or p-)~ethoxyphenylmethyl, (o-, m-, or p-)ethoxyphenylmethyl, (4- or 5-)chloro-2-methoxyphenylmethyl, and 2,4-dichloro-(4- or 6-)methoxyphenylmethyl, (o-, m-, or p-)chloro-phenylpropyl, 2-chloro-p-tolylpropyl, (3, 4, 5, or 6-)chloro-o-tolyl-propyl, 4-chloro-2-propy1phenylpropyl, 2-isopropyl-4-chlorophenyl-propyl, 4-chloro-3,5-xylylpropyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenylpropyl, 4-chloro-3-fluorophenylpropyl, (3- or 4-)-chloro-2-fluorophenylpropyl, (o-, m-, or p-)trifluoromethylphenylpro-pyl, (o-~ m-, or p-)methoxyphenylpropyl, (o-, m-, or p-)ethoxyphenyl-propyl, (4- or 5-)chloro-2-methoxyphenylpropyl, and 2,4-dichloro-(4-or 6-)methoxyphenylpropyl.
The group -C~H~mCH~ wherein m is an integer of from one to 5 which Rl7 may be represents straight or branched alkylCl-Cs groups such as named hereinabove.
The terms phthalidylj 3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2~yl)-2-oxopropan-1-yl P-oxide; and 3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide; which Rs Jay represent in the -COOR5 group Jean the following respective moieties (a), (b) and (c):

; 25 (a) I, . O

O o CH3 -CH~-CCH~-P\ CH3 (b) -CH~-C-CH~-P\ (c) As indicated hereinabove Rl~ is hydrogen or a protecting group.
Those protective groups within the scope of Rl~ are any group which - replaces a hydroxy hydrogen and is neither attacked by nor is reactive _17_ 1209154 40~2 to the reagents used in the transformations used herein as a hydro~
is and which i5 subsequently replaceable by hydrolysis ~lith hydrogen in the preparation of the carbacyclin-type compounds. Several such protective groups are known in the art, e.g., tetrahydropyranyl and substituted tetrahydropyranyl. See for reference E.J. Corey, Pro-ceedings of the Robert A. Welch Foundation Conferences on Ohemical Research, XII Organic Synthesis, pp. 51-79 ~196~). Those blocking groups which have been found useful include:
(a) tetrahydropyranyl;
(b) tetrahydrofuranyl;
(c) a group of the formula -C(OR~4)(Rl~)-CH(Rlg)(R~o), wherein R24 is alkyl of 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 lS carbon atoms, inclusive, wherein Rl~ and Rly are alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, inclusive, or when Rl~ and Rlg are taken together -(CH~)a- or when Rl~ and Rly are taken together to form -(CH~)b-O-(CH~)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 Rl~ and Rlg may be the same or different, and wherein R20 is hydrogen or phenyl; and (d) silyl groups according to R2l, as qualified hereinafter.
When the protective group Rl2 is tetrahydropyranyl, the tetra-hydropyranyl ether derivative of any hydroxy moieties of the CBA-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 3û 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 Rl2 protective group is tetrahydrofuranyl, 2,3-dihydro-furan is used, as described in the preceding paragraph, in place of the 2,3-dihydropyran.
When the R12 protective group is of the formula -C(OR~4)(Rl~)-CH(Rlg)(R~o)~ wherein R~4, Rl~, Rlg, and Rho are as defined above; a vinyl ether or an unsaturated cyclic or heterocyclic compound, e.g., 1209~54 Il 0~2 1-cyclohexen-1-yl methyl ether, or 5,6-dihydro-4-methoxy-2H-pyran is employed. See C.B. Reese, et al., J. Americ2n Chemical Society ~9, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those ror dihydropyran above.
R~l is a silyl protective group of the formula -Si(G1)~. In some cases, such silylations dre general, in that they silylate alp 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)~ 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-b~tyl, pentyl, and the like.
Examples of aralkyl are benzyl, phenethyl, a-phenylethyl~ 3-phenyl-propyl, -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-bu~ylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.
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-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 selec-tively hydrolyzed in the presence of protective groups according to Rl~ 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 silyl groups (e.g. trimethylsilyl) are not employed when selective introduc-tion and/or hydrolysis is required.
The protective groups as defined by Rl~ are otherwise removed bymild acidic hydrolysis. For example, by reaction with (1) hydrG-chloric acid in methanol; (2) a mixture of acetic acid, water, and tetrahydrofuran, or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran, at temperatures below 55 C., hydrolysis of the blocking group is achieved.
Rl~ is d hydroxyl protective group, as indicated above. As such, Rl~ may be an acyl protective group according to R2~ as defined below, an acid hydrolyzable protective group according to ~12 as defined above, or a silyl protective group according to R~l as defined above.
Acyl protective groups according to R~ include:
(a) benzoyl;
(b) benzoyl substituted with one to 5 al~yl of one to 4 carbon atoms, inclusive, or phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro, with the proviso that not more than two substituents are other than alkyl, and that the total number o, carbon atoms in the substituents does not exceed 10 carbon atoms, wi h the further proviso that the substituents are the same or different;
(c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms, inclusive;
(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 alkyl and that 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 some 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 dre employed.
Thus, for example, an aromatic acid of the formula R~20H, wherein R~2 is as defined above (e.g., R~OH is benzoic acid), is reacted with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. p-toluensulfonyl chloride or dicyclohexylcarbodiimide; or alter-natively an anhydride of the aromatic acid of the formula (R~)OH, e.g., benzoic anhydride, is used.
Preferably, however, the process described in the above paragraph proceeds by use of the appropriate acyl ha1ide, e.g., Real, wherein Hal is chloro, bromo, or iodo. For example, benzoyl chloride is -20- lZ(~9~L54 ~0~2 reacted witll the hydroxyl-containing compound in the presence of a hydrogen chloride scavenyer, 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.
Generally mild conditions are employed: 0-60C., contacting the reactants in a liquid medium (e.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 stoichio-metric excess.
- 10 As examples of R~, the fo11Owing compounds are available as acids (R~20H), (R~ 0, or acyl chlorides (R~2Cl): benzoyl; substi-tuted benzoyl, e.g., (2-, 3-, or 4-)methylbenzoyl, (Z-, 3-, or 4-)-ethylbenzoyl, (2-, 3-, or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyl-toluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl(2-, 3-, or 4-)tolu~l, (2-, 3-, or 4-)phenethylbenzoyl, (2-, 3-, or 4-)nitro-benzoyl, (2,4, 2,5-, or 2,3-)dinitrobenzoyl, 2,3-dimethyl-?-nitro-benzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenylethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono esterified phthaloyl, isophthal~yl, or tere-phthaloyl; 1- or 2-naphthoyl; substituted naphthoyl, e.g., ~2-, 3-, 4-, 5-, 6-, or 7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-l-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (, 4-, 6-, 7-, or 8-)-methyl-1-; naphthoyl, 4-ethyl-2-naphthoyl, and (S- or 8-)nitro-Z-naphthoyl and acetyl.
nlere may be employed, therefore, benzoyl chloride, 4-nitro-benzoyl chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R~Cl compounds corresponding to the above groups. It thy acyl chloride is not available, it is prepared from the corresponding acid and phos-phorus pentachloride as is known in the art lt is preFerred that the R2~0H, (R22)~0, or R~2Cl 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 R~2, are removed by deacylation. Alkali metal carbonate or hydroxide are employed effec-tively at ambient temperature for this purpose. For example, potas--21- 1209~5~ 408~
sium carbonate or hydroxide in aqueous rnethanol at about 25 C is advantageously employed.
The novel CBA analogs disclosed herein wherein R12 is hydrogen produce certain prostacyclin-like pharmacological responses.
5Accordingly, the novel formula IV compounds wherein Rl2 is hydro-gen are used as agents in the study, prevention, control, and treat ment ox diseases, and other undesirable physiological conditions, in mammals, particularly humans, valuable domestic animals, pets, zoo-logical specimens, and laboratory animals (e.g., mice> rats, rabbits and monkeys). In particular, these compounds are useful as anti-ulcer agents and anti-asthma agents, and additionally the compounds wherein s is one are useful as antithrombotic agents as indicated below.
(a) Platelet Aggregation Inhibition The compounds of formula MY wherein R12 is hydrogen, and s is one are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, cr to remoYe 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 athero-sclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying et-iology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebra1 ischemic attacks and long term prophylaxis following myocardial infarcts and strokes. For these purposes, these compounds are administered sys-temically, e.g., intravenously, subcutaneously, intramuscularly, and in the Norm of sterile implants for prolonged action. For rapid response, especially in emergency situations, thy intravenous route of administration is preferred.
The preferred dosage route for these compounds is oral, although other non-parenteral routes (e.g., buccal, rectal, sublingual) are likewise employed in preference to parenteral routes. Oral dosage forms are conventionally formulated as, e.g., ta51ets or capsules 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 in treating the afore-described conditions associated with the inhibition of platelet aggre--22- `1;209154 40~2 gation. Doses in the range about 0.01 to about 10 mg per kg of body weight per day are preferred, the exact dose depending Gn the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
5The 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. Th2y are also useful in preparing platelet rich concentrates for use in treating thrombocyto-penia, chemotherapy, and radiation therapy. In vitro applications utilize a dose of 0.001-1.0 ~9 per ml of whole blood. These com-- pounds, i.e., the compounds of formula IV wherein R12 is hydrogen, and s is one are useful in the treatment of peripheral vascular diseases, in the same manner as described in U.S. Patent 4,103,026.
(b) Gast,i~ Secretion Reduction Compounds ox Formula IV wherein R1~ is hydrogen are useful in mammals, 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 purpose, these compounds are injected or infused intravenously, subcu-taneously, or intramuscularly in an infusion dose range of about 0.1 ~9 to about 20 ~9 per kg of body weight per minute, or in a total 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 fre-quency and route of administration.
Preferably, however, these novel compourds are administered orally or by other non-parenteral routes. As employed orally, one to 6 administrations daily in a dosage range of about 1.0 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 asymptolnatic.
(c) NOSAC-lnduced Lesion Inhibition Compounds of Formula` IV wherein Rl~ is hydrogen are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaqlandin synthetase inhibitors, and are useful for that purpose by concomitant adminis-tration of said compounds of Formula l`J and the anti-inflammatory prostaglandin synthetase inhibitor. Sex Partridge, et al., U.S.
Patent No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E series. Accordingly these novel Formula IV conlpounds are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of known prostaglandin synthetase inhibitors, e.g., indomethacin, phenylbutazone, and aspi-rip, in the same manner as described by Partridge, et al, for the PGE
compounds in U.S. 3,781,429.
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) The compounds of Formula IV wherein Rl~ is hydrogen are also use-ful in the treatment of asthma. For exam?le, these compounds are use-ful as bronchodilators or as inhibitors of mediator-induced broncho-.
cohstriction, 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 s bronchitis, bronchiectasis, pneumonia and emphysema. For these pur-poses, these compounds are administered in a variety of dosage forms, I
e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories, parenterally, subcutaneously, or intramus-cularly, with intravenous administration being preferred in emergency 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 Formula IV compounds can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isopro-terenol, phenylephrine, ephedrine, etc.); xanthine derivatives ~theo-I.
trade murk -24- 1209~154 40~2 phylline and arninophylline); and corticosteroids (ACTH and prednisol-one).
The pharmacologically useful Formula It compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation. For administration by the oral inhalation route with con-ventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preferably at concentrations of about one part of medicament to from about 100 to 200 parts by weight of total solution. Entirely conventional addi-tives may be employed to stabilize these solutions or to provide iso-tonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bisulfite, and the like can be employed. For administra-- tion as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the compo-sition can comprise the active ingredient suspended in an inert pro-pellant (such as a mixture of dichlorodifluoromethane and dichloro-tetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Suitable means to employ the aerosol inhalation therapy technique are described sully in United States Patent 3,868,691, for example.
When Q is -COORs, the novel Formula IY compounds so described are used for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R5. However, it is preferred that the ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially preferred for optimum absorption ox the compound by the - body or experimental animal system; and straight-chain octyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.
Pharmacologically acceptable salts of the novel compounds of Formula IV for the purposes described above are those with pharmaco-logically acceptable metal cations, ammonia, amine cations, or quater-nary ammonium cations. Illustrative pharmacological acceptable cat-ions which R5 may represent are the hollowing.
Especially preferred metal cations are those derived from thealkali metals, e.g., !ithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic -2~- 1209~L54 40Z2 forms of other metals, e.g., aluminuM, zinc, and iron are ~lithin thP
scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Examples of suitable amines are methylamine, dirnethylamine, trimethylamine, ethylamine, dibutyl-amine, triisopropylamine, N-methylhexylamine, decylamine, dodeoyl-amine, allylamine, crotylamine, cyclopentylamine, 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 .ower-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 Q is -C~I~NL3L4, the Formula IY compounds so described are used for the purposes described in either free base or pharmacologi-cally acceptable acid addition salt form.
The acid addition salts of the 2-decarboxy-2-aminomethyl- or 2-(substituted aminomethyl)-Formula IV compounds provided by this invention are, for example, the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfamates, methane-sulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and the like, prepared by reacting the appropriate compound of Formula IV
with the stoichiometric amount of the acid corresponding to the pharm-acologically acceptable acid addition salt.
The compounds of Formula IY wherein Rl2 is a hydroxyl protecting ~209154 -26- 40~2 group are useful as intermediates to the compounds of Formula IV
wherein Rl~ is hydrogen.
To obtain the optimum combination of biological response specifi-city, potency, and duration of activity, tertain compounds within the scope of this invention are preferred. Preferred compounds o, the present invention are the CBA2 analogs, i.e., the compounds of Formula IV wherein the C-5,6 position is unsaturated, and of these compounds those wherein Y is -CH~CH2-, -C_C- or trans-CH=CH- andlor Q is -COORs or -COLT are preferred especially when Rs is hydrogen, methyl, ethyl, or a pharmacologically acceptable cation such as sodium, and when each of Rg and R1u of the Lo substituent moiety is hydrogen. To further - -characterize the preferred embodiments of the present invention, compounds ox Formula IV wherein Rl7 is -Cm~t2mCH~, benzyl. phenoxy, 3-thienytmethyl, or phenyl or wherein -C(LI)Rl7 taken together is cyclohexyl, 3-thienyloxymethyl or 3-ethylcyclobutyl, or -CH~~CH~)C~t~/
C_CCH~ are especially preferred. Also compounds wherein Rl7 is C~H~mCH3 and each of R15 and RI6, which make up the L. substituent, - are fluoro are especially preferred.
Preferred for biological potency are formula IV CBA~ analogs exhibiting the same C-5 isomeric configuraton as CBA2 itself. As is apparent from the faregoing as compounds satisfy more of the above preferences, said compounds are more preferred.
The carbacyclin analogs of the present invention as represented by Formula IV are prepared by various procedures thigh are all gener-ally known in the art. The charts provided herein are useful inillustrating the preparation of the compounds.
As indicated hereinabove the hydroxyl groups at positions C-~1 and C-15 of the compounds of the present invention may be protected by various groups generally employed in the art and protection of the hydroxyl functions and is generally desirable or necessary during the preparation of the compounds. Although any of the various protecting groups described herein may be employed those preferred are tetra-hydropyranyl (THP) and tert-butyldime~hylsilyl. Particularly, nip is a preferred protecting group during the various reactions required to add the side chains and t-butyldimethylsilyl is a preferred group to employ during separation of the isomers. Of course it may be useful or desirable to utilize protecting groups which may be selectively hydrolyzed. A1SOJ when R17 is -(CH~)~CH(OH)-CH~ the hydroxyl group at 120!~54 C-19 generally is protected by the same type of groups utilizd to pro-tect the C-ll end C-15 hydroxyl groups during the preparation of said compounds and subsequently deprotected by hydrolysis as described herein.
Also, it will be apparent that in the preparation of the compounds the 5(E) and 5(Z) isomers generalty may be separated when the C-ll and C-15 hydroxyl groups are either protected or are unpro-tected. However, it has been found that protection of these hydroxyl groups with, e.g., tert-butyldimethyl silyl often facilitates clean l separation of the isomers in high yield. Separation of the 5(E) and 5(Z) isomers is achieved by conventional means, typically column chromatography is employed.
The compounds of Formula IV wherein Z is other than -(Ph)-(CH2)9-and D is Cis-C=cH- or trans-C=cH- are prepared as depicted in Chart lS A hereof. An enone of Formula A-1 is epoxidized with alkaline hydrogen peroxide then reduced with aluminum amalgam by procedures known in the art, e.g., see G. L. Bundy, et al., J. Am. Chem. Soc. 94, 2122 (1972) to give the corresponding hydroxy substituted compound of Formula A-2 wherein R1~ is hydrogen. The enones of Formula A-1 are known in the art or readily prepared by procedures known in the art as set forth hereinafter.
In preparing the compounds of Formula A-4 from the compounds of Formula A-2 the 1-position hydroxyl group is first protected by an R12 protecting group as defined hereinabove. The hydroxy protected A-2 compounds are treated with the dianion of Formula A-3 by methods known in the art. See, for example, G.W. Moersch, J. Org. Chem. 36, 1149 (1979) and J. Mulzer, et al., Tetrahedron Lett. 2949 (1978) to give compounds of Formula A-4. The dianion compounds are known in the art or are prepared by procedures known in the art. For example, see the illustrative procedure set forth in Example 2 hereof. The hydroxy acids of Formula A-4 are subjected to decarboxylative dehydration using dimethylformamide dineopentyl acetal by generally known proce-dures, e.g., see A. Eschenmoser, et al., Helv. Ghim. Acta. 58 1450 (1975); S. Hara, et al., Tetrahedron Lett. 1545 (1975) and J. Mulzer, et al., Tetrahedron Lett. 2953 (1978) and 1909 (1979) to give com-pounds of Formula A-5 which are selectively hydrolyzed to remove the R12 protecting group at the C-9 position to give compounds of Formula A-6 wherein R~ is hydrogen. The 9~-hydroxy compounds of Formula A-6 : . . . .

1209~54 -28- ~0~2 can be used to prepare the corresponding 9~-methox~ and 9B-acetoxy compounds. By treating a 9~-hydrox~ compound of Formula A-6 with a base such as a metal hydride and methyl iodide one obtains the corre-sponding 9~-methoxy compound of Formula A-6 wherein 23 is methyl. By treating a 9~-hydroxy compound of Formula A-6 with acetic anhydride using dimethylaminopyridine as a catalyst one obtains the correspond-ing 9~-acetoxy compound of Formula A-6 wherein R3 is acetyl. The chemistry employed to prepare the 9~-methoxy and 9~-acetoxy compounds from the 9~-hydroxy derivatives is well known in the art. The com-pounds of Formula A-6 can be hydrolyzed to remove the Yarious protect-ing groups at position C-i and which may be present at positions C-ll, C-15 and C-l9 to give the compounds of A-7. Or, the ~21 silyl pro-tecting group in compounds of Formula A-6 can be selectively hydro-lyzed, e.g., by fluoride mediated hydrolysis to give compounds corre-sponding to those of A-6 only wherein R2l is replaced by hydrogen.
These C-l deprotected compounds corresponding to Forr,)ula A-6 are use to prepare the compounds of Formu'la A-7 wherein Q~ is the same as Q
except it is other than -CH20H. The Formula A-5 compounds can be oxi-dized, e.g., using Jones reagent or platinum oxideloxygen oxidation (J. Fried and J. C. Sih, Tetrahedron Lett. 1973, 38g9), to the corre-sponding carboxylic acid which in turn can be converted to the esters and amides of Formula A-8 by conventional means. The C-l position alcohols corresponding to A-6 also can be oxidized to the correspond-ing carboxaldehyde which upon treatment with a salt of hydroxylamine gives the oxime which is dehydrated to give he nitrile, i.e., the compounds of'Formula A-8 wherein Q2 js CN. These conversions are all carried out by procedures generally known in the art. See, or example,'the aforementioned British specifications which describe the synthesis of various carbacyclin compounds, and in particular G.B.
2,013,661. The amide also can be reduced to the corresponding amines, i.e., compounds of Formula A-8 wherein Q~ is -CH2L3L~ by using, e.g., lithium aluminum hydride. See U.S. patent 4,073,808. During the con-version of the C-l position alcohols corresponding to !Formula A-6 to the various other C-l position derivatives as represented by Formula A 8, the C-ll and C-15 hydroxyl groups and wnen present the C-l9 hydroxyl groups are protected as described herein which yroups can ultimately be deprotected by hydrolysis as generAlly described herein-before.

-29- 3L20~L54 40~2 The 5(E3 dnd 5(Z) isomers can be separated using either the com-pound of Formulas A-6, A-7 or A-8.
The compounds of Formu1a IV wherein D is cis-CH=CII- or trans-CH=~H- and wherein Z is -(Ph)-(CH2)y~ are prepdred as ~o)lows refer-ence being made to Chart B. The ketones of Formula A-2 are reduced by conventional means using, for example, a borohydride reducing agent such as sodium, potassium or lithium boroh~dride, to the corresponding alcohol. The al'cohol is converted to a sulfonate derivative, typi-cally a methanesulfonate or toluenesulfonate by treatment with meth-anesulfonyl chloride or toluenesulfonyl chloride in the presence of dtertiary amine such as triethylamine. The sulfonate derivative is treated with sodium, lithium or potassium thiophenoxide to give the compounds of Formula B-1. The thiophenoxide is preferably prepared by reacting equal molar amounts of thiophenol and a base such as potas-sium tertiary butoxide just prior to reaction with the sulfonate. Thecompounds of Formula B-l are oxidized to the corresponding pnenyl-sulfonate using, e.g., m-chloroperbenzoic acid then treated with a strong base such as n-butyllithium to generate the corresponding ' anion. The anion is treated with an aldehyde of Formula B-2 and the resulting adduct is treated with acetic anhydride to give compounds of Formula B-3. The compounds of Formula B-3 are treated with sodium amalgam by procedures analogous to those described by P.J. Kocienski, et al., "Scope and Stereochemistry of an Olefin Synthesis from ~-Hydroxysulphones", JCS Perkin I, 829-834 (1978) and are selectively hydrolyzed to remove the hydroxyl protecting group at the C-9 position 7 ' to give the olefins of Formùla B-4 wherein R3 is hydrogen. The 9~-hydroxy derivatives of Formula B-4 can be used to prepare the corre-sponding'9~-methoxy and 9~-acetoxy derivatives to give compounds of Formula B-4 wherein R3 is methyl or acetyl by procedures described hereinabove in connection with the preparation of the compounds of Formula A-6 . The compounds of Formula B-4 are used to prepare the products of Formula B-5. The various hydroxyl groups are protected in such a manner to permit selective hydrolysis to give ultimately the deprotected products of Formula B-5. The R21 silyl protecting group is conveniently removed via fluoride mediated hydrolysis using, e.g., tetrabutyl ammonium fluoride to give the C-l position alcohols of For-mula B-5 which are utilized to prepare the corresponding carboxylic acids, esters, amides, amines and nitriles of Formula B-5 by the same ~.~09~S4 -30- 40~2 general procedures dS described hereinabove in reference to the prep-aration of compounds of Formula A-8. The 5(E) and 5(Z) isomers can be separated convPniently using the alcohol corresponding to Formula B-4 an the ~/arious C-9, C-ll, C-15 and C-l9 hydroxyl protecting groups which may be present are removed by mild acid hydrolysis using, e.g., mixtures of water, tetrahydrofuran and acetic acid.
The compounds of Formula B-2 are prepared using known bis-acids of the formula (CH2)9-COOH

COOH

wherein g is zero, one, 2 or 3, which are reduced to the corresponding diol by conventional procedures, e.g., by using lithium aluminum hydride. About equal molar amounts of the diol and a silylating reagent of R~l are combined thereby preferentially silylating the alkanol hydroxyl although some di-silylated compound is produced. The mono-silylated compounds of the formula (CH2)9-CH~OR2l ., ;i are oxidized to the a1dehydes of Formula B-2 by conventional means, e.g., using manganese dioxide. See U.S. patent 4,306,075.
The compounds of Formula IY may also be prepared d5 depicted in Chart C hereof. When a compound of C-l, which compounds are known in the art or are readily prepared by means known in the art, is substi-tuted for and treated in the same manner as the compounds of Formuta A-1 in Chart A compounds of Formula C-2 are obtained. When compounds of Formula C-2 are substituted for and treated in the same manner as compounds of Formula A-2 in each of Charts A and B compounds of For-mula C-3 are obtained which may be converted to the various C-l posi-tion analogs of Formula C-4 by the general procedures described here-inabove for conversion of compounds of Formula A-6 to A-7. When R3 in Formula C-3 is hydrogen it is preferred that the C-9 hydroxy group is -3l- 1209~54 40~2 protected by a hydroxy pro-tec-ting group as defined by Rl~ hereinabove.
Also, the compounds of Formulas C-3 and C-4 can be reduced to the corresponding 5,6-dihydro deri~Jatives of Formula Y by kno~"n procedures, e.g., as generally described in X application G.B.
2,017;699. For example, the reduction may be achieved by d standard hydrogenation in the presence of a catalyst such as palladium on charcoal or platinum dioxide in a lower alkanol such as methanol or ethanol.
The intermediates of Formulas C-3, C-4 and V are utilized in pre-paring the compounds of Formula IV by procedures which are also usefulin~preparing compounds of Formula A-1 (Chart A). Initially the inter-mediates of Formulas C-3, C-4 and V are hydrolyzed to remove the R13 protecting group thus giving the primary a k ohol derivatives which are oxidized to the corresponding aldehyde by conventional procedures, e.g., under the conditions of a Collins reaction, to give compounds of Formulas C-5, ~-6 and \III. To prepare compounds of Formula A-1 one utilizes aldehydes of Formula VI which are obtained by oxidation of the corresponding "C-12 position" substituted alcohol by conventional procedures. The alcohols are known in the art or are readily prepared by procedures known in the art. The aldehydes of Formulas C-5, O
VI and VII are then treated as described hereinbelow, wherein for purposes of convenience only the chemical trans,ormations which occur at the "C-12 position" of said compounds are depicted. When R3 in Formulas C-5, C-6 and C-7 is hydrogen it is preferred that the C-9 hydroxy group is protected by a hydroxy protecting group as defined by R12 hereinabove.
the "C-12" aldehydes are subjected to a Wittig reaction with the anion of an alkyl phosphonate derivative of the formula O O
', (alkYl-0-)2-P-CH CC-Rl7 which is obtained by addition of the anion of dialkylmethylphosphon-ate, i.e., (alkyl-0-)-P-CH2 with an ester of the formula -32 1~09~154 40~2 o CH;,OCC-R
Ll by procedures known in the art, wherein R1~ and L1 have.the same mean-ings defined in Formula IV, to give the corresponding ketone inter-mediates wherein W is the group trans-CH=CH-C-C-Lo ' ' Thè ketone intermediate is then reduced by dissolving petal hydride reduction to the I- or B-alcohol as defined by M in Formula I to give - compounds corresponding to Formulas C-5, C-6, YI and VII only wherein W is the group trans-CH=CH-C - C-R17 Ml, L, wherein M1 is -OH,~-H or a-H,~-OH and wherein L1 and ~17 have the meanings defined in Formula I. The thus obtained trans-vinyl com-pounds can be hydrogenated to give compounds correspondi.ng to Formulas C-5, C-6, VI and VII only wherein W is the group Il 11 Ml Ll or can be halogenated followed by tetradehydrohalogenation to give the corresponding compounds whereiniW is the group -C_C-C - C-R17

11 11 Ml Ll Hydrogenation of the thus obtained acetylene containing compounds with a Lindlar catalyst gives the corresponding cis-vinyl compounds, i.e., compounds corresponding to Formulas C-5, C-6, YI or VII only wherein W
is the group cis-cH=cHc - C-R17 Il 11 Ml Ll The compounds of Formula A-1 and IV are also prepared by treating a compound of Formula C-5, C-6, VI or YII with a phosphine of the formula (alkyl)3-P=CHCHO under the conditions of a Wittig reaction to give the corresponding compounds wherein is a trans-vinyl aldehyde group of the formula trans-CH=CHCHO which is reduced Jo the corre-.

33 4082sponding trans-vinyl alcohol, i.e., Formula C-5, C-6, VI or VII
wllerein W is trans-CH=CHCH~OH. The trans-vinyl alcohol can be hydro-genated to give the corresponding compounds wnerein W is the group -CH~CH2CII20H, or the trans-vinyl alcohol can be halogenated then tetradehydrohalogenated to give the corresponding acetylene alcohol, i:e., compounds of Formula G-5, C-6, VI or YII "hereir 'I is the group -C--CCH20H. Hydrogenation of the acetylene alcohol with a Lindlar catalyst gives the corresponding cis-vinyl alcohols, i.e., compounds wherein W is the group cis-CH=C~CH~OH.
The thus obtained alcohols, i.e., compounds of Formula C-5, C-6, VI or-YII only wherein N is trans-CH=CHCH20H, -CH2CH2CH20H, -C_CH20H or cis-CH=CHCH20H are oxidized to the corresponding alde-hydes then treated with a Grignard reagent of the formula halo ~gCpH2pCH=CH2, wherein halo is a halogen or an alkyl lithium of the formula LiCpH2pCH-CH2, or an acetylide anion of the formula -C_CCpH2pCH3 or an anion of the formula LiCHCH2C_CCH3 to give the corresponding compounds of Formula wherein is 20_Y-C _C-Rl7 Ml Ll wherein Y, Ll and R17 have the meanings defined in Formula I and Ml is a-OH,~-H or a-H,B-OH. The C-15 hydroxyl group can be protected as required with an R12 group as described hereinbefore.
To prepare compounds of Formula A-1 or IY wherein Rl4 of the M
substituent group is-CH3 the corresponding C-15 alcohol derivatives are oxidized to the corresponding C-15 ketone then treated with methyl lithium or a methyl Grignard by procedures known in the art.
30Removal of protecting groups which may be present at positions C-9 or C-11 is achieved by hydrolysis as generally described herein-above.
Upon completion of the above-described "C-12 position" transform-ations with respect to the compounds of Formula YI the resulting lactone derivatives are converted to the compounds of Formula A-1 via lactol and diketone phosphonate derivatives in a manner analogous to that described in U.S. patent 4,306,075 in reference to Chart A
thereon.

_34_ lZ0915~ 4082 preferred method of prepa~in~ thy CB~l co~p~unds of Formula IV ~'nerein Z is trans-CE12Cil=CEI- (and D is -C~ICE12-) is to utilize the appropriate inter-mediates of Formula C-6 wherein Z is -Cfl2-(CH2)f-C(R4~2- wherein f is one and R4 is hydrogen and wherein Q is a carbox~lic acid ester, prefer-ably the methyl ester which derivatives are referred to herein as the butanoic acid esters. The butanoic acid ester derivatiYes are treated with lithium amide base and phenylselenyl chloride to give the corre-sponding a-phenylselenyl derivatives which are reduced by, e,g., general procedures described in U.K. Application G~2,017,69g to give the 5,6-dihydro intermediates. The 5,6 dihydro intermediates are dehydrophenylselenized by treatment with hydrogen peroxide to give intermediates corresponding to Formula C-6 wherein Z is -CH~CH=CH2, Q2 is a carboxylic acid ester and the carbon atoms at positions 5 and 6 are saturated, which intermediates can be converted to the correspond-ing derivatives wherein the terminal C-1 position corresponds to Q as defined herein by the general procedures described herein3bove it con-nection with the preparation of compounds of Formula B-5 in Chart B.
These 5,6-dihydro intermediates are then converted to the CBAl com-pounds of Formula IV wherein Z is -CHzCH=CH- by treatment in a manner analogous to that described hereinabove in connection with the conver-sion of Formula C-6 to CBA2 compounds of Formula IV.
When the alkyl ester has been obtained and an acid is desired, saponification procedures, as known in the art for PGF-type compounds are employed.
When an acid has been prepared and an alkyl, cycloalkyl, or aralkyl ester is desired, esterification is advantageously accom-plished by interaction of the acid with appropriate diazohydrocarbon.
For example, when diazomethane is used, the methyl ester is produced.
Similar use of diazoethane, diazobutane, and }-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, prefer-ably diethyl ether, with the acd 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 ~2~9~;4 ~35~ 40~2 is preferred that contact of the acid reactdnts with the diazohydro-carbon be no longer than necessary to effect the desired esterifica-tion, preferably about one to about 10 minutes, 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 Reac-tions, John Wiley and Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 ~1954).
An alternative method for al~yl, cycloal~yl or aralkyl esterifi-cation of the carboxy moiety of the acid compounds comprises trans-formation of the free acid to the corresponding substituted ammoniumsalt, 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, cyclo-pentyl iodide, benzyl iodide, phenethyl iodide, and the like.
Var,ous methods are available for preparing phenyl or substituted phenyl esters ~Jithin the scope of the invention from correspondiny aromatic alcohols and the free acid, differing as to yield and purity of product.
With regard to the preparation of the phenyl, particularly p-sub-stituted phenyl esters disclosed herein (i.e., Q is -COOR5 and R5 is p-substituted phenyl), such compounds are prepared by the method described in U.S. Patent No. 3,890,372. Accordingly, by the preferred method described therein, the p-substituted phenyl ester is prepare first by worming a mixed anhydride, particularly following the proce-dures described below for preparing such anhydrides as the first stepin 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. When the conversion is complete, the p-substituted phenyl ester has been recovered by conventional techniques.
A preferred method for substituted phenyl esters is that dis-closed in U.S. Patent No. 3,890,372 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. rne anhydrid~ is formed from the acid with isobutylchloroformat~ in the presence of a tertiary amine.
Phenacyl-type esters are prepared froln the acid using a phenacyl bromide, for example p-phenylphenacyl bromide, in the presence of a tertiary amine. See, for example, U.S. Patent No. 3,984,454, Germ3n Offenlegungsschrift 2,535,693, and Derwent Farmdoc ~Iv. 1682~X.
The phthalidyl esters are obtained by treating the corresponding acid with a phthalidyl halide such as the bromide in, e.g., dimethyl-formamide in the presence of an amine base. The phosphoranyl estersare obtained by treating the corresponding acid with a 1-halo deriva-live e.g., the 1-chloro derivative of 3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide and 3-~5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxid~ in, e.g., acetonitrile in the presence of an organic amine.
Carboxyamides (Q is -COLT) are prepared by one of se~Jeral amida-tin methods known in the prior art. See, for example, U.S. Patent No. 3,981,868, issued September 21, 1976, or a description ox the - preparation of the present amido and cycloamido derivatiYes of prosta-glandin-type free acids and U.S. Patent No. 3,~54,741 Idescribing the preparation of carbonylam~do and sulfonylamido deriv3tives oF prosta-glandin-type free acids.
The pre,erred method by which the present amido end cycloamido derivatives of the acids are prepared is, first, by transformation of such free acids to corresponding mixed acid anhydrides. By this pro-cedure, the carbacyclin-type free acid is first neutralized with an equivalent of an amine base, and thereafter reacted with a slight stoichiometric excess ox a chloro~ormate corresponding to the mixed anhydride to be prepared.
The amine base preferred for neutralization is triethylamine, ,~ although other amines ~e.g., pyridine, methyldiethylamine) are like-- wise employed. Further, a convenient, readily availably chloroformatefor use in the mixed anhydride production is isobutyl chloro~ormate.
The mixed anhydride formation proceeds by conventional methods and accordingly the free acid is mixed with both the tertiary amine base and the ch10roformate in a suitable solvent (e.g., aqueous tetra-hydrofuran), allowing the reaction to proceed at -10 C to 20 C.
Thereafter, the mixed anhydride is converted to the corresponding amido or cycloamido derivatives by reaction with the amine correspond-ing 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 anhydride at or about l to +10 C, until the ~209~54 _37 4082 reaction is shown to be complete.
Thereafter, the novel amido or cycloamido derivative is recovered from the reaction mixture by conventional techniques.
The carbanylamido and sulfonylamid~ derivative of the presently disclosed carbacyclin compounds are likewise prepared by known meth-ods. See, for- example, U.S. Patent No. 3,954,741 for description of the methods by which such derivatives are prepared. By this known method the acid is reacted with a carboxyacyl or sulfonyl isocyanate, corresponding to the carbonylamido or sulfonylamido derivative to be prepared.
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 prepara-tion of the amido and cycloamido derivatives. ~lereafter, the sodium salt of the corresponding sulfonamide is reacted with the mixed anhydride and hexa,nethylphosphoramide. The pùle carbatyclin sulfonyl-amido derivative is then obtained from the resulting reaction mixture by conventional techniques.
The sodium salt of the sulfonamide corresponding to the sulfonyl-amido derivative to be prepared is generated by reacting the sulfon-amide with alcoholic sodium rnethoxide. 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 thesodium salt per equivalent of anhydride. Reaction temperatures at or , about 0 C 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 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 if inorganic, i.e., metal or ammonium salts. The choice of procedure depends in part upon the 3s solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve an acid of this invention in water containing the stoichiometric amount of d hydroxide, carbonate, or bicarbonate corresponding to the inor-3~ lZO9154 ~0~2ganic 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 wator-miscible solvent of moderate polarity, for example, a lower alkanol or a lower a1~anone, 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 former are ethanol, acetone, and ethyl acetate. Examples of the lat-ter are diethyl ether and benzene. At least a stoichiometric amountof 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 pre-ferred to use stoichiometric amounts of the less volatile amines.
Salts wherein the cation is quaternary an~onium are produced bymixing an acid of this invention with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

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09~5~
-39- 40~2 Example 1 (a) 3-Oxo-7a-tetrahydropyran-2-yloxy-oB[(3'S)-tetra-hydropyran-2-yloxy-trans-1'-octenyl]-bicyclo-[3.3..0~-oct-1-ene-1,2-oxide A solution of 11.69 9 (27.0 mmol) of 3-oxo-7~-tetrahydropyran-2-5 yloxy-6~C~3'S)-3'-tetrahydropyran-2-yloxy-trans-1''-octenyl]-bicyclo-~3.3.0]oct-1-ene, 20 ml of 30% hydrogen peroxide, and 200 Al of iso-~ropanol was cooled to -40C. This solution was treated dropwise wi-th 25 ml of 3N lithium hydroxide reagent over 10 minutes and the result-ing solution was allowed to warm between -25~ to 20C and stirred for 2 hours. An additional 2 ml of 3N lithium hydroxide reagent was added followed by 5 ml of 30% hydrogen peroxide. While maintaining the tem-perature between -25 to -20C the reaction was stirred an additional - 2 hours. The reaction mixture was neutralized to pH 7 by the addition of 10% sodium bisulfate. Iso-propanol was removed under reduced pres-sure and the concentrate was diluted with water and ethyl acetate.
Solid sodium bisulfite was added (until bubbling ceased) to remove excess hydrogen peroxide (addition of ice was necessary to Inoderate the exothermic reaction). The mixture was extracted with ethyl acetate (500 ml) and the organic phase was washed with brine, dried over 70 anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow oil. This material was chromato-graphed on 1 kg silica gel-60 (63-200~), eluting with hexane-acetone (8:1) to give the title compound.
NMR (CDCl3, TMS) C: 5.92-5.15 (m, 2H, -CH=CH-), 4.67 (broad s, 25 2H, -O-CH-O-), 3,33-2.12 (m, 6H, -CH2-O-, -CH-O-), and 3.26 (s, lH, ., JO
- -CH - C').
Infrared (film) vmax: 2930, 2860, 1740, 1435, 1200, 1125, 1070, 1020, 970, 865, and 815 cm~1.
TLC (Silica gel GF): Rf 0.44 in hexane-ethyl acetate (2:1j.
(b) 5~-Hydroxy-7-oxo-3~-tetrahydropyran-2-yloxy-2~-C(3'S)-3'-tetrahydropyran-2-yloxy-trans-1'-octenyll]_ bicyclo-C3.3.0]-octane Twenty grams of aluminum turnings (20 mesh) were washed with 100 ml of ether followed by 100 ml of methanol. A saturated solution of mercuric chloride (100 ml) was added to the washed aluminum, swirled, and decanted when vigorous hydrogen evolution was evident. rhis amal-gam was then washed with methanol (2 x 100 ml) followed by ether (100 :~Z09154 -~0- 40Z2 ml). A solution of 3-oxo-7~-tetrahydropyran-2-yloxy-6~C(3'S)-tetra-hydropyran-2-yloxy-tr~ns-1'-octenyl]-bicyclo-~3.3..0]-oct-1-ene-1,2-oxide (9.91 9, 22.1 mmol ) in 200 ml of ether was added in one portion to the amalgam. Methanol (20 ml) and water (2 ml) were added and the resulting mixture WdS stirred for 2 hours at room temperature. The mixture was filtered and the residue was washed with ethyl acetate.
The combined filtrates were concentrated in VdCUO to give 10.04 9 of crude product as d colorless oil. rnis material was chromatographed on 1.2 kg of silica gel-60 (63-200 I) eluting with hexane-acetone and concentrated in vacuo to give the title compound.
NMR (CDCl~, rMS) I: 5.90-5.11 (m, 2H, -CH=CH~ .62 (broad S, 2H~ -0-CH-0-), 4.37-3.25 (m, 6H, -CH-0-, -CH2-0~ .52 (s, 2H, -C-CH~-C0-).
- lnfrared: vmax (film): 3430, 2930, 2860, 1740, 146~, 1450, 1435,15 1385, 1350, 1260, 1195, 1100, 1070, 1015, 970, 905, 865, and 815 cm 1 TLC (Silica gel GF): Rf 0.41 in hexane-aceton2 (2~
(c) 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy) methyl-9~-hydroxy-6a-carba-prostaglandin It, 11,15-bis-(tetrahydropyranyl ether) (1) A round-bottomed flask equipped with a magnetic stirring bar was charged with 11.Q 9 (24.4 mmol) of 1'-octenyl]-bicyclo-[3.3.0~-octane and 43.8 ml of 1,1,1,3,3,3-hexamethyldisi!azane-trimethyl-chlorosilane-pyridine (6:3:10) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 10 minutes and the excess reagent was removed by blowing with nitrogen stream. The concentrate (including a white ppt) was diluted with toluene and the mixture was filtered through a layer of Celite*. The filtrate was concentrated in vacuo to give a lisht yellow oil.
(2) A 3-neck, round-bottomed flask equipped with a magnetic stirring bar, a dropping funnel and a gas inlet tube was dried and flushed with nitrogen. The flask was charged with ~3.2 9 (80.5 rnmol) of diisopropylamine and 183 ml of tetrahydrofuran (THF). The solution was cooled to 0-5C and 47.2 ml (73.2 mmol) n-butyllithium in hexane (1.55 M) WdS added dropwise over 5 minutes via dropping funnel. To this mixture a solution of 9.0 9 (36.6 mmol) 6-(dimethyl-t-butylsilyl-oxy)-hexanoic acid in 61 ml of THF was added over 5 minutes. After stirring an additional 10 minutes, the ice-water bath was removed and the mixture was stirred at roorn temperature. The solution was cooled *trade mark ~209154 -41- 40~2 again to 0-5~C and the yellow oil obtained in step (1) dissolved in 61 ml of rHF was added over 5 minutes. The ice-wat2r bath was again removed and the solution was stirred at room temperature for 2 hours.
The mixture was quenched with saturated âmmoni~m chloride and THF was removed under reduc2d pressure. The concentrate was carefully acidi-fied with cold 10% sodium bisulfate and extracted with ether (2 x 1 liter). The ether layer was washed with water (x4) and brine. After drying over anhydrous magnesium sulfate, the solution was filtered through a layer of Celite~ and the filtrate was concentrated in vacuo to give a crude adduct as an oil, R~ 0.08-0.33 on hexane ethyl acetate (5;1).
(3) The crude oil obtained in step (2) was dissolved in a so1u-tion of 28.2 9 (122.0 mmol) of dimethylformamide-dineopentylacetal (DMF-DNPA) and 183 ml of chloroform. The flask was equipped with a magnetic stirring bar, a reflux condenser and a nitrogen inlet tube.
The solution was stirred a room temperature overnight (16 hours) and at 65C for 8 hours under a nitrogen atmosphere. Chloroform was then removed under reduced pressure and the concentrate was extracted with ether (1 liter). The ether layer was washed with water, cold 10%
sodium bisulfate, lN sodium hydroxide, brine, and dried over anhydrous magnesium sulfate. Activated charcoal was added to decolorize the deep brown color. Filtration and concentration in vacuo gave a brown oil, Rf = 0.78 in hexane-ethyl acetate (2:1).
(4) The oil obtained in step (3) was then dissolved in a mixture containing 6.79 (48.8 mmol) of potassium carbonate and 488 ml of ; methanol-water (9:1). The mixture was stirred at room temperature for 18 hours. TLC analysis showed the reaction to be completed. Methanol was removed under reduced pressure and the concentrate was extracted with ether (1 liter). The ether 1ayer was washed with water, brine, and dried over anhydrous magnesium sulfate. Filtration and concentra-tion gave a brown oil. HPLC, using 2 x 324 9 silica gel-60 (40-63 I, E. Merck), packed in t~lo Michel-Miller columns, eluting with hexane-acetone, afforded the title compound as a pale yellow oil.
NMR (CDCl~, ~lS) I: 5.86-S.13 (m, 3H, -CH=CH-), 4.80-4.60 (m, 2H, -0-CH-0-), 4.32-3.34 (m and t, 8H, -CH-0-, -CH2-0-), 0.88 (s and t, 12H, -Si-t-Bu, and OH
IR (film) v max: 3400, 2930, 2850, 2730, 1660, 1630, 1460, 1440, 1380, 1350, 1255, 1200, 1180, 1025, 980, 905, 870, 840, 810, and 780 I, -42- 1Zo9154 40~2 TLC (Silica gel GF): Rf 0~25 in hexane-acetone (3:1).
(d) 5(E and Z)-2-Decarbox~-2-h~droxymethyl-9~-hydroxy-6a-carba-prostaglandin I2 A round-bottomed flask equipped with a magnetic stirring bar was charged with 1.9 9 (3.0 mmol) of 5(E and Z)-2-decarboxy-2-(t-butyldi-methylsilyloxy)-methyl-9~-hydroxy-6a-carba-prostagglandin I2, 11,15-bis(tetrahydropyranyl ether), 6 ml of 1 N HCl, and 24 ml of iso-pr-~panol. ` The mixture was stirred at room temperature for 24 hours.
The solution was then neutralized with saturated sodium bicarbonate to pH 7 and iso-propanol was removed under reduced pressure. The concen-trate was extracted with ethyl acetate (2 x 1 liter). The organic phase was washed with brine and dried over anhydrous magnesium sulf-ate. Filtration and concentration afforded a yellow oil. HPLC, using 324 9 silica gel-60 (40-63 I, E. Merck), eluting with methylene chlor-ide-acetone-ethanol (10:10:1), and taking 40 ml fractions, gave two major products with very similar polarity. The less polar component contained mostly the E isomer. The more polar component contained mostly the Z isomer. Crystallization of the less polar component from ethyl acetate gave a white solid (m.p. 131-132C, 406.2 mg, pure E
isomer). The mother liquor of this crystallization was combined with - the more polar-component and repurified by HPLC using the same condi-tion as described above. Fractions 64-71 (40.0 mg) gave mostly the E
isomer, fractions 72-80 (95.5 mg) gave the mixture o. E and Z isomers, and fractions 81-112 (311.3 mg) gave pure Z isomer as an oil.
E isomer:
NMR (CD~OD, TMS) I: 5.82-5.18 (m, 3H, -CH=CH-), 4.20-3.70 (m, 2H, -CH-O-), 3.55 (t, 2H, -CH~O), 2.45 (broad s, 2H, -CH2-C=C-).
IR (film) v max: 3350, 2950, 2930, 2860, 1640, 1440, 1290, 1070, 1020, 970, and 640 cm 1.
TLC (Silica gel GF): Rf 0.35 in methylene chloride-acetone-ethanol (10:20:1).
Z isomer:
NMR and lR were very similar to those of E isomer.
TLC (Silica gel GF): Rf 0.31 in methylene chloride-acetone-ethanol (10:20:1).
Example 2 6-(t-Butyldimethylsilyloxy)hexanoic Acid A round-bottomed flask equipped with a magnetic stirring bar was 43 1209~S4 40Z2 charged with 22.~ 9 (0.2 mol) of -caproldctonG, 8 8g (0.22 Sol) of sodium hydroxide and 200 ml of methanol-water (4:1). The yellow solution was stirred at room temperature under a nitrogen atmosphere for Z4 hours. Methanol-water was removed under reduced pressure.
Toluene azeotrope was used to remove water. The resulting solid mass was broken up and ground tc a fine powder. rnis powder was heated with 72.0 g (0.48 mol) of t-butyldimethylchlorosilane, 6i.3 g (0.96 mol) of imidazole, and 200 ml of dimethylformamide. 7he mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours.
Water (20 ml) was added to this mixture, stirred for minutes, and was diluted with 800 ml of water. The mixture was extracted with 1 liter of hexane-ether (1:1). The aqueous layer was extracted once more with 1 liter of ether. The combined organic phase was washed with water (x2), brine, and dried over anhydrous magnesium sulfate.
Filtration and concentration afforded a light yellow oil. This oil was then stirred in a mixture of 27.6 9 (0.2 molt potassium carbonate and 200 mL of methanol-water (4:1). After 3 hours, methanol was removed under reduced pressure. The concentrate was acidified with cold 10~ sodium bisulfate until pH 3-5 and the mixture was extracted ether (2 x 1 liter). The ether layer was washed with water (x3), brine and dried over anhydrous sodium sulfate. Filtration and con-centration afforded the crude product. Cotumn chromatography, using 1 Kg CC-4 silica gel, eluting with Skelly B-EtOAc (10:1), gave a pale yellow oil which solidified in the freezer.
Example 3 (5E)-9B-Hydroxy-6a-carba-prostaglandin It A 3-neck round-bottomed flask equipped with a magnetic stirring bar was charged with 323.4 mg of platinum oxide and 23.8 ml of water.
The brown suspension was stirred under hydrogen atmosphere using hydrogenation apparatus at room temperature for one hour. The catalyst turned black and coagulated. The flask was then purged thoroughly with nitrogen and attached with a reflux condenser and a gas inlet tube. The tip of the tube was placed below the surface of the solution. Nitrogen was bubbled through while the mixture was being stirred. After 10 minutes, nitrogen was replaced by oxygen. To this mixture, 709.2 mg of sodium bicarbonate and 10.6 ml of water was added. This was fol lowed by addition of 300 mg (0.~51 mmol) of 5(E)-2-decarboxy-2-methyloxy-9~-hydroxy-6a-carba-pprostaglandin l in ; 10.6 ml of acetone. The mixture was heated at 60C (bath temperatllre) ` 4a lZ09lS4 4082 while stirring and bubbling of oxygen continued. The mixture was acidified with 10% sodium bisulfate (to pH 5 6), diluted with about 1 liter of acetone and the mixture was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure. The concentrate was saturated with sodium chloride and extracted with ethyl acetate (1 liter). The organic phase was washed with brine ~x4) and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude oil which was purified by HPLC using CC-4 silica gel (52.59 was packed in a Michel-Miller column). Eluting with methylene chloride-acetone (1:1) and concentrating in vacuo gave the title com-pound as an oil.
NMR (CD~OD, TMS) I: 5.72-5.12 (m, 3H -CH=CH-j, 4.24-3.60 (m, 2H, -CH-O_).
Infrared film) vmax : 1710, 1030, and 970 cm 1.
~TLC (Silica gel GF): Rf 0.38 in chloroform-methanol-acetic acid (10:1:1). ' Example 4 (5Z)-9B-Hydroxy-6a-carba-prostaglandin I2 Exactly the same procedure as described in Example 3 was followed. Using 242.5 mg of platinum oxide in 17.8 ml of water, add-ing 531.9 mg of sodium bicarbonate as well as 225 mg ~0.638 mmol) of 5(Z)-2-decarboxy-2-methyloxy-9g-hydroxy-6a-carba-pprostaglandin It and 15.9 ml acetone-water (1:1). The crude product was purified by ~PLC
using 52.5 9 CC-4 silica gel. Eluting with methylene chloride-acetone (2:1), and concentrating in vacuo gave the title compound as an oil.
NMR (CD~OD, TMS): Identical with that of Examp1e 3 except peaks ; around 2.6-1.7.
Infrared: ldentical with that of Example 3.
TLC (Silica gel GF): Rf 0.35 in chloroform-methanol-acetic acid (10:1:1).
Example 5 5(E and Z)-2-Decarboxy-2-hydroxymethyl-9B-hydroxy-6a-carba-prostaglandin It, 11,15-bis(tetrahydropyranyl ether) A round-bottomed flask equipped with a masnetic stirring bar was charged with 381.0 mg (0.6 mmol) of 5(E and Z)-2-decarboxy-2-(t-butyl-dimethylsilyloxy)-methyl-gB-hydroxy-6a-carba-prosttaglandin l 11,15-bis-(tetrahydropyranyl ether), 1.6 ml of tetra-n-butylammonium fluor-ide in THF (0.75 I) and 3.2 ml of T~F. The mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. THF was 120~54 removed under reduced pressure and the concentrate was treated with water and extracted with ether. The organic phase was slashed with water, 10~ sodium bisulfate, saturated sodium bicarbonate, brine, and drièd over anhydrous magnesium suet Filtration and concentration in vacuo gave a light yellow oil. HPLC, using 106 9 silica ge1 ~40-63 I), eluting ~lith hexane-acetone (3:1), and taking 15 ml fractions, afforded the following products: The less polar component, R~ 0.43 in hexane-acetone (3:2), was assigned as E isomer and the more polar component, Rf 0.39 in the same solvent, was as,igned as isomer. In addition there was obtained a mixture of E and Z isomers.
NMR (CDCl3, nMS) for both E and Z isomers) I: 5.86-5.08 (m, 3H, -C.~=CH-, =CH-), 4.82-4.54 (m, 2H, -0-CH-0-?, 4.34-3.;28 (m and t, -CH-0-, -CH~-0).
IR (film) (for both E and Z isomers) vmax: 34~, 2930, 2850, 1440, 1350, 1260, 1200, 1180, 1120, 1020, 980, 910, and B10 cm 1.
Example 6 When in the procedure of Example 1(a) (3'5)-7~-tetr~hydropyran-2-yloxy-6B-[3'-tetrahydro-2-yloxyoctanyl~bicyclo~33.3.0~octen-3-one or (3'S)-7~-tetrahydropyran-2-yloxy-6B-[3'-tetrahydroo-2-yloxy-1'-octynyl~bicyclo~3.3.0]octen-3-one is substituted for 3-oxo-~3'S)-7-tetrahydropyran-2-yloxy-6~-~3'-tetrahydropyran-2-yyloxy-trans-1'-octenyl]-bicyclo[3.3.0]oct-1-ene and the general procedure of Example 1(a) and 1(b) is otherwise followed one obtains respectively 5~-hydroxy-7-oxo-3a-tetrahydropyran-2-yloxy-2B[(3'S)--3'-te~rahydropyran-2-yloxy-trans-1'-octanyl]bicyclo[3.3.0]octane and ~B-hydroxy-7-oxo-- 3~-tetrahydropyran-2-yloxy-2~[¦3'S)-3'-tetrahydroppyran-~-yloxy-trans-1'-octynyl]bicyclo[3.3.0]octane, and when each of these compounds so obtained is substituted for 5~-hydroxy-7-oxo-3~-tetrahydropyran-2-yloxy-2~-[(3'S)-3'-tetrahydropyran-2-yloxy-trans-11'-octenyl]bicyclo-C3.3.0]octane in Example 1(c) and the procedure ox Exam?le 1(c3 and l(d) is followed one obtains respectively the 5E and 5Z isomers of 2-decarboxy-2-hydroxymethyl-9~-hydroxy-13,14-dihyddro-6a-carba-prosta-glandin I2 and2-decarboxy-2-hydroxymethyl-9~-hydroxy-13~14-didehhydro-ta-carba-prosta9landin 1 2 -3S Example 7 When (5Z)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-13,14--dihydro-6a-carba-prostaglandin l or (5Z)-2-decarbOxy-2-hydrOxymethyl-9B-hydroxy-13,14-didehydro-ta-carba-prostaglalldin l. is substituted for lZ09~54 (5E)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-6a-c~rrba-prostaglandin It in the procedure of Example 3 the following are obtained:
(SZ)-9g-hydroxy-13,14-dihydro-6a-carbd-prostagldnddin I2 and (sz)-9~-hydroxy-l3~l~-didehydro-6a-carba-prostaglaandin I2.
Example_8 5~E and Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy) methyl-9~-methoxy-6a-carba-PGI2, 11,15-bis(tetrahydro-pyranyl ether) A two-neck round-bottomed flask equipped ~Yith a magnetic stirring bar, a dropping funnel, and a gas inlet tube under a nitrogen atmos-phere was charged with 576 mg (12 mmol) of sodium hydride ~5C%active). The hydride was washed twice with dry hexane and the powder was- suspended in 20 ml of D~IF. 5(E and Z)-2-Decarboxy-2-(t-butyldi-methylsilyloxy)methyl-9~-hydroxy-6a-carba-prostagllandin l 11,15--bis-(tetrahydropyranyl ether) (1.9 9, 3 mmol) dissolved in 5 ml of dimethylformamide was added. The resulting mixture was stirred at room temperature tor one hour. To this mixture 1.7 9 (12 mmol) of II
methyl iodide dissolved in 5 ml of DMF was added dropwise Yia dropping funnel over 30 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was quenched with saturated ammonium chlor-ide and extracted with ether. The ether layer was washed with water, 1070 sodium bisulfate, saturated sodium bicarbonate, brine, and dried over anhydrous ma,nesium sulfate. Filtration and concentration gave a brown oil. HPLC, using 324 9 of silica gel-60 (40-63 I), eluting with hexane-acetone (2C:1), and taking 40 ml fractions, afforded 1.6 9 (fr.
16-63, 82~) of the title compound as an oil.
. NMR (CUCl3, TMS) I: 5.8-5.1 (m, 3H, -CH=C~-), 4.80-4.58 (m, 2H, -O-CH-O-), 4.24-3.30 (m and 5, 8H, -CH-O-, -CH~-o-j, 3.20, 3.18 (s, 3H, -OCH3).
Infrared (film) vmax: 2930, 2850, 1460, 1440, 1360, 1350, 1260 1200, 1100, 1020, 975, 900, 870, 840, 820, and 730 am TLC (Silica gel GF) Rf 0.40 in hexane-acetone (3:1).
Example 9 5(E and Z)-2-Decarboxy-2-methyloxy-9~-methoxy-6a-carba-prostaglandin l A round-bottomed flask equipped with a magnetic stirring bar was charged with 1.4 9 (2.2 m~nol) of S(E and Z)-2-d~carboxy-2-(t-butyldi-methylsilyloxy)methyl-9~-m2thoxy-6a-carba-prostaglldndin l 11,15-bis-(tetrahydropyr~nyl ether), 6.6 ml of lN HCl, and 26.4 ml of iso-pro- !
panol. The mixture was stirred at room temperature for 24 hours.

1%09~54 Saturated sodium bicarbonate was added until pH 7 and iso-propanol wa, removed under reduced pressure. The concentrate was extracted with ethyl acetate. The organic layer was washed h brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded an oil. HPLC, using t"o HPLC columns attached in a series (324 9 and 166 g silica gel-60, 40-63 I), eluting with rneth~lene chloride-acetone-methanol (20:20:1), and taking 40 ml fractions gave two major products with very similar TLC mobility. Fractions 23-27 (344.0 mg) gave mostly E-isomer and fractions 58-8S (382.5 mg) gave mostly Z-isomer.
Repurifiation of each isomer by the same HPLC condition afforded pure E and Z isomers.
E isomer: -NMR (CDCl3, n~s) I: 5.68-5.05 (m, 3H, -CH=CH-), 4.20-3.60 (m, 7H, -CH-O-, -CH20-), 3.22 (s, 3H, -OC~
Infrared (film) vmax: 3350, 2960, 2g30, 2850, 1640, 1460, 1300, 1260, lC60, and 970 cn~1.
TLC (Silica gel GF) Rf 0.42 in methylene chloride-acetone-methan-ol (10: 10: 1 ) Z isomer:
NMR and IR were similar to those of E isomer.
TLC (Silica gel GF) Rf 0.40 in methylene chloride-acetone-methanol (10:10:1).
Example 10 (5Z)-9~-Mothoxy-6a-carba-prostagl~ndin 12 .

The same procedure as described in Example 3 was followed. Using 363.0 mg of platinum oxide in 26.8 ml of water, adding 795.9 mg ox sodium bicarbonate as well as 350.0 mg (0.955 mmol) of (5Z)-2-decarboxy-2-methyloxy-9~-methoxy-6a-carba-prostagllandin Iz and 23.9 ml of acetone-water (1:1). Ihe crude product obtained was then purified by HPLC using CC-4 silica gel, eluting with methylene chloride-acetone (2:1), and taking 30 ml fractions. The fractions homogeneous by TLC
were combined and concentrated in vacuo to give 302.0 mg (83.2%) of pure (SZ)-9~-methoxy-6a-carba-pros~aglandin l2.
NMR (CDCl3, rMS) 6. 5.75-S.08 (m, 3H, -CH=CH-), 4.2-3.5 (m, 2H, -CH-O-), 3.20 (s, 3H, -OCH~), 2.42 (s, 2H, -CHz-C=C).
Infrared (film) Max: 1710, 1060, and 970 cm 1.
High Resolution Mass Spectrum (as TMS derivative): Calc'd for C~oH5705Si~ (M OH 581.3514. Found: 581.350~.
TLC (Silica gel GF) Rf 0.29 in chloroform-methanol-acetic acid -48- 1 9 40~2 (20:1:1).
Example 11 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsilylox~) methyl-93-acetoxy-6a-carba-prostaglandin It, 11,15-bis-(tetrahydropyran~l ether) A round-bottomed flask equipped with a magnetic stirring bar was charged with 1,9 9 (3.0 mmol) of 5(E and Z)-2-decarboxy-2-(t-butyldi-methylsilyloxy)methyl-9~-hydroxy-6a-carba-prostagllandin It, 11,15-bis-~tetrahydropyranyl ether), 3.0 ml of acetic anhydride and 3.0 ml of pyridine. To this mixture 76 mg of diethylaminopyridine was added.
The solution turned yellow in color. After stirring at room tempera-ture for 2 hours the mixture was cooled to O-SC and -.6 ml of water was added. The mixture was stirred for 10 minutes and then extracted with ether. The etherlayer was washed with 10% sodium bisulfate, water, saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave a yellow oil (2.0 9) .
NMR (CDCl3, TMS) showed a singlet at 2.00 indicating -OCOCH3.
Infrared (tilm) showed vmax 1740 cm _1.
TLC (Silica gel GF) showed R~ 0.5 in hexane-acetone (5:1).
Example 12 5(E and Z)-2-Decarboxy-2-methyloxy-9B-acetoxy-6a-carba-prostaglandin It A round-bottomed flask equipped with a magnetic stirring bar was charged with 2.0 9 (3.0 mmol) of 5(E and Z)-2-decarboxy-2-(t-butyl-dimethylsilyloxy)methyl-9~-acetoxy-6a-carba-prostaaglandin lz, 11,15-bis-(tetrahydropyranyl ether), 9 ml of lN HCL and 36 ml ox iso pro-panol. The mixture was stirred at room temperature for 24 hours.
Saturated sodium bicarbonate was added until the mixture was about pH
7 and iso-propanol was removed under reduced pressure. The concen-trate was saturated with sodium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave a light yellow oil. The crude oil was subjected to HPLC, using two silica gel-60 (40-63 I) columns (324 9 and 321 9) attached in a series, eluting with ethyl acetate-methanol (20:5:1), and taking 30 ml fractions. Fractions 82-96 (540.4 mg) gave E-isomer and fractions 58-84 (577.0 mg) gave Z-isomer.
E isomer:
NMR (CDCl~, TMS) I: 5.68-5.04 (m, 3H, -CH=CH-), 4.20 (broad s, 1209~S4 ^49- 4082 3H, -OH), 4.02-3.60 (m, 2H, -CH-O-), 3.54 (t, 2~, -CH~-O-), 2.00 (s, 3H, -O-CO-CH~).
Infrared (film) Max 3400, 2940, 2870, 1730, 1440, 13~0, 1240, 1070, 1020, 970, and 905 cm~l.
TLC (Silica gel GF) Rf 0.35 in ethyl acetate-hexane-methanol (20:5:1).
Z isomer:
NMR and IR were very similar to those of E isomer, Rf 0.33 in the same solvent systems.
Example 13 (5E)-9~-Acetoxy-6a-carba-prostaglandin I2 The same procedure as described earlier in Exam?le 3 was foilowed. Using 380.0 mg ox platinum oxide in 28 ml of water, adding 833.3 mg of sodium bicarbonate as well dS 394.5 mg (1.0 mmol) of (5E)-2-decarboxy- 2-methyloxy-9~-acetoxy-6a-carba-pprostaglandin I2 and 25 ml of acetone-wdter (1:1). The crude product obtained was then purified by HPLC using 52.5 g CC-4 silica gel, eluting with methylene chloride-acetone ~2:1), and taking 30 ml fractions. The fractions homogeneous by TLC were combined and concentrated in vacuo to give 2~0.2 mg (58.5~ of pure (5E)-9~-acetoxy-6a-carba-prostaglandin I2 (oil).
NMR (CDCl~, TMS) I: 5.68-5.04 (m, 3H, -CH=CH-), 5.10 (broad s, 3H, -C02H, -OH), 4.20-3.70 (m, 2H, -CH-O-), 2.00 (s, 3H, -OCOCH3).
Infrared (film) vmax 3600-2400, 1730, 1710, 1440, 1370, 1240, 1080, 1020, and 970 cm~1.
TLC (Silîca gel GF) Rf 0.32 in chloroform-methanol-acetic acid ; (20:i:1).
Example 14 (a) I-Bromo-2-butyne To a stirred solution of 2-butyne-1-ol (10.0 g, 0.143 mol) in 30 ml of ether at 0 C is added pyridine (4.84 9, 0.06 mol, 0.43 eq) at once followed by careful dropwise addition of phosphorous tribromide (26.3 9, 0.097 mol, 0.68 en) over a 30 minute period. An additional 10 ml of ether was added to facilitate stirring and the contents warmed to reflux for 2 hours. The reaction mixture is cooled in ice bath, treated cautiously with ~0 ml of ice water and extracted with ether (2 x 150 ml). The combined ether extracts are washed with saturated brine (2 x 25 ml), the combined aqueous washings extracted with ether (1 x 50 ml) and the combined organic extracts dried over anhydrous sodium sulfate. The filtrate is concentrated on d rotary `
1209~5~
_50 4082 evaporator while keeping the water bath temperature less than 10 C.
Twice the contents are diluted with 100 ml of pentane and reconcen-trated as before. The heterogPnous looking oil is dissolved in 300 ml of pentane, dried over anhydrous magnesium sulfate and reconcentrated as before to obtain 11.0 9 (58%) of 1-bromo-2-butyne.

(b) 2-Methyl-4-hexynoic acid - Diisopropylamine (26.0 9, 0.257 mmol, 3.1 eq) in 130 ml of tetrahydrofuran initially at -50 C is treated dropwise with n-butyl-lithium (98.8 ml, 1.6 M, 0.158 mol, 1.9 eq) over an 8 minute periodwhile allowing the temperature to rise to -25 C. After S minutes longer at -20 C, the reaction mixture is treated dropwise with a mixture of-hexamethylphosphoramide (17.8 9, -0.099 mol, 1.2 en) and propionic acid (6.14 9, 0.083 mol, 1.0 eq) over a 7 minute period while the temperature rises to 0 C. Following addition the reaction mixture is warmed to room temperature and mainta1ned there for 3 minutes. The contents are then cooled to 0 C in an ice bath, treated dropwise over a 12 minute period with 1-bromo-2-butyne g, 0.083 mol, 1.0 eq) in 8 ml of tetrahydrofuran. The temperature, which rises to 16 C during addition, is allowed to warm to room temperature thereafter where it is maintained for 2 hours. The contents are carefully poured into 300 ml of 10~ HCl with stirring (exothermic) followed by 500 ml of ether-pentane (1:1). The organic layer is separated and the aqueous phase extracted 2 more times with ether-pentane (1:1) giving 1800 ml of totdl extract volume. The combined i 'r extracts are washed with water 2 x 60 ml) and the combined organic extracts are dried over anhydrous sodium sulfate, magnesium sulfate and concentrated at reduced pressure to provide 11.1 9 Dover theory) of 2-methyl-4-hexynoic acid which is converted to the methyl ester by treatment with methyl iodide.

(c) 3-Methyl-2-oxo-hept-5-yne phosphonic acid dimethyl ester A solution of dimethyl methylphosphonate (22.47 go 181.24 mmol) in 260 ml of tetrahydrofuran is cooled to -78 C and treated dropwise with n-butyllithium (113 ml, 181.24 mmol), 1.6 Al in hexane) over a 25-min~lte period. The mixture is stirred an additional 30 minutes at -78 C, then treated dropwise with 2-methyl-4-hexynoic acid methyl lZ09~54 ester (7.25 9, 51.7~ mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes. The contents are stirred for another 3 hours at -78 C
and then 17 hours at ambient temperature. ye reaction mixture is cooled to C, treated with 14 ml of acetic acid, stirred at ambient temperature for 30 minutes, then concentrated in vacuo. The residue is treated with 100 ml of saturated brine and 100 ml of ice water to form a slurry and extracted 3 times with ether- (1400 ml total) and once with 250 ml of ethyl acetate-ether (1:1). The combined organic extracts are washed with saturàted brine (2 x 75 ml), the combined aqueous washings extracted with ethyl acetate-ether (1:1, 1 x 100 ml) and dried over anhydrous sodium sulfate, and concentrated at reduced pressure. Vacuum distillation gives 10.21 9 of the title product, m.p. 121-125 C, 0.15 mmHg.
Example 15 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy-methyl)-9~-hydroxy-13,14,15,16,17,18,19,20-octanorr-

12~-(benzyloxYmethyl)-6a-carba-prostaglandin It 11-tetrahydropyranyl ether When in the procedure of Example 1(a) 6~-[(benzyloxy)methyl~-7a-(tetrahydropyran-2-yloxy)-bicyclo[3.3.0]octen-3-onne is substituted for 20 3-oxo-7-(tetrahydropyran-2-yloxy)-6B-[(3'S)-3'-teetrahydropyran-2-yloxy-trans-1'-octenyl~-bicyclo[3.3.0~oct-1-ene and the general proce-dure of Example 1(a) and 1(b) is followed one obtains 6~-(benzyloxy-methyl)-7~-~tetrahydropyran-2-yloxy)-1~-(hydroxy)--bicyclo[3.3.0toctan-3-one. When this compound is substituted for 5~-hydroxy-7-oxo-3-25 tetrahydropyran-2-yloxy-2~-[(3'S)-3'-tetrahydropyrran-2-yloxy-trans-1'-octenyl]bicyclo[3.3.0]octane in Example 1(c) and the procedure of Example 1(c) is followed one obtains the title compound.
Example 16 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsily)oxy-methyl)-9~-hydroxy-13,14,15,16,17,18,19,20-octanorr-12~-hydroxymethyl-6a-carba-prostaglandin It, 11-tetra-hydropyranyl ether Liquid ammonia (100 ml) is distilled into a solution of 5(E and Z)-2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-99~-hydroxy-13,14,15,-16,17,18,19,20-octanor-1Z~-(benzyloxymethyl)-6a-caarba-prostagldndin It, 11-tetrahydropyranyl ether (5.4 9, 10 mmol) in 100 ml of tetra-hydrofuran and 2.0 ml of t-butyl-alcohol at ^50 C utilizing a dry ice-acetone trap. no temperature is maintained at about -40 C while freshly scraped lithium wire (4 inches) is added in small pieces until ' , -52- 1209~54 40~2 the rnixture is turned blue. After stirring the mixture for 30 minutes solid ammonium chloride is added to quench excess lithium. rne dis-appearance of blue color indicates the stoppage of reaction. A nitro-gen stream is swept through the flask tc expel the excess ammonia.
rhe solid resdue is treated with 100 ml of saturated ammonium chloride and extracted with ethyl acetate. The organic phase is ~Jashed with brine and dried over anhydrous magnesium sulfate. Filtration and con-centration in vacuo afford the title compound.
Example 17 (a) 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy-methyl)-9~-hydroxy-13,14,15,16,17,18,19,20-octanorf 12~-formyl-6a-carba-prostaglandin I2, 11-tetrahydro-pyranyl ether Collins oxidation, known in the art, ox 5(E and Z)-2-decarboxy-2-(t-butyldimethylsilyloxymethyl)-9~-hydroxy-13,14,115,16,17,18,19,20-- 15 octanor-12~-hydroxymethyl-6a-carba-prostaglandin It, 11-tetrahydro-pyranyl ether, the title compound of Example 16, gives the title com-pound.
(b) 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy-methyl)-9B-hydroxy-15-~eto-16(R,S)-16-methy1-18,199-tetradehydro-6a-carba-prostaglandin I2, 11-tetrahydro pyranyl ether Thallium ethoxide (634 mg, 2.55 ~mol) in l ml ox benzene at 0 C
-- in a round-bottomed flask is treated with dimethyl-2-oxo-3-methyl-5-heptynyl phosphonate (613 mg, 2.64 mmol) in 2.5 ml ox benzene. After stirring for 50 minutes at 0 to 10 C, the title compound in Example - 17(a) (889 mg, 1.96 mmol) in 5 mL of benzene i5 added at once to mix-i ture at 0 C. After stirring the mixture at room temperature for one hour, the mixture is again cooled to 0 C, quenched with 0.5 ml of acetic acid followed by addition ox aqueous potassium iodide to pre-cipitate the thallium as a yellow salt. The contents are diluted with ether, stirred at room temperature and filtered through a pad of Cel-ite. The organic phase is washed with ice water, saturated sodium bicarbonate, brine, and dried over anhydrous magnesium sulfate.
Chromatographic purification gives the 17(b) title compound.
(c) 5(E and Z)-2-Decarboxy-2-(t-butyldimethylsilyloxy-methyl)-9~-hydroxy-15(R,S)-~6(R,S)-16-methyl-1g,199-tetradehydro-6a-carba-prostaglandin It tetrahydro-_53 ~209~54 40~2 pyranyl ether A round-bottomed flask equipped with a m~netic stirring bar is charged with 0.55 9 (1.0 mmol) of the title compound in Example 17(b) and 10 ml of methanol. The solution is cooled tO -20~ to -15 and sodium borohydride (76 mg, 2 mmol) is added. The mixture is stirred for one hour and quenched with saturated ammonium chloride. Methanol is removed under reduced pressure and the residue is extracted with ethyl acetate. The organic phase is washed with brine and dried o'er anhydroùs magnesium sulfate. Chromatographic separation resolves the 15(R) and 15(S) isomers.
Example 18 (a) 5(E and Z)-2-Decarboxy-2-hydroxymethyl-~-hydroxy-16(R,5)-16-methyl-18,19-tetradehydro-6a-carba-prossta-glandin I2 When in the procedure of Example 1(d) 5(E and Z)-2-decarboxy-2-15 (t-butyldimethylsilyloxymethyl)-9~-hydroxy-16(R,5))-16-methyl-18,19-tctradehydro-6a-carba-prostaglandin 12, 11-tetrahydropyranyl ether is substituted for 5(E and Z)-2-decarboxy-2-(t-butyldimethylsi~lyloxy-methyl)-9~-hydroxy-6a-carba-prostagtandin I2, 11,15-bis-(tetrahydro-pyranyl ether3, one obtains the title compound. As in the case of Example 1(d), the (5E) and (SZ) isomers are resolved by the chromato-graphic separation.

(b)9~-Hydroxy-16(R,S)-16-methyl-18,19-tetradehydro-6aa-carba-prostaglandin It When in the procedure of Example 3 (5Z)-2-decarboxy-2-hydroxy-methyl-9~-hydroxy-16(R,S)-16-methyl-18,19-t2tradehhydro-6a-carba-prostaglandin It is substituted for (5E)-2-decarboxy-2-methyl-oxy-9~-hydroxy-6a-carba-prostaglandin I2 one obtains the title compound after the chromatographic purification.
Example 19 When in the procedure of Example 17(b) each of the following phosphonates is substituted for dimethyl-2-oxo-3-methyl-5-heptynyl phosphonate and the procedures of Examples 17(b), i7(c) and 18 are followed one ultimately obtains the 9~-hydroxy products listed below:
dimethyl-2-oxo-3-phenylpropyl phosphonate;
dimethyl-2-oxo-4-phenylbutyl phosphonate;
dimethyl-2-oxo-3-phenoxypropyl phosphonate;
dimethyl-2-oxo-4-(3-thienyl)butyl phosphonate;

54 ~20~ 40~2 dimethyl-2-cyclohexyl-2-oxoethyl phosphonate;
dimethyl-2-oxo-3-(3-thienyloxy)propyl phosphonate; or dimethyl-2-oxo-2-(3-ethylcyclobutyl)e~hyl phospho~ate;

5(E anclZ)-2-decarboxy-2-hydroxyme-thyl-9B-h~droxy-16-Phennyl 17,1~,19,20-tetran~r-6a-carba-prostaglandin It;
5(E andZ)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-17-phenyyl-18,19,20-trinor-6a-carba-prostaglandin It;
5~E andZ)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-16-phenooxy-10 17,18,19,20-tetranor-6a-carba-prostaglandin I2;
5~E andZ)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-17-(3-thhienyl)-18,19,20-trinor-6a-carba-prostaglandin It;
5(E andZ)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-15-cycloohexyl-16,17,18,19,20-pentanor-6a-carba-prostaglandin I2;
5(E andZ)-2-decarboxy-2-hydroxymethyl-Y~-hydroxy-16-~3-thhienyl-oxy)-17,18,19,20-tetranor-6a-carba-prostaglandln It;
5(E andZ)-2-decarboxy-2-hydroxymethyl-9~-hydroxy-15-(3-etthyl-cyclobutyl)-16,17,18,19,20-pentanor-oa-carba-prosttaglandin I2;

5(E andZ)-9B-hydroxy-16-phenyl-17,18,1~,20-tetran~r-6a-caarba-prostaglandin I2;
5(E andZ)-9~-hydroxy-17-phenyl-18,19,20-trinor-6a-carba-pprosta-glandin It;
5(E andZ)-9~-hydroxy-16-phenoxy-17,18,19,20-tetranor-6a-ccarba-prostaglandin I2;
-j S(E andZ)-9~-hydroxy-17-(3-thienyl)-18,19,20-trinor-6a-caarba-prostaglandin l S(E andZ)-9~-hydroxy-15-cyclohexyl-16,17,18,19,20-pentanoor-6a-carba-prostaglandin It;
5(E andZ)-9~-hydroxy-16-(3-thienyl-oxy)-17,18,19,20-tetraanor-6a-carba-prostaglandin It;
5(E andZ)-9~-hydroxy-15-(3-ethylcyclobutyl)-16,17,18,19,220-pentanor-6a-carba-prostaglandin It;

;
-55- ~.209~54 40Z2 FOR~1ULAS
COC:i .,~
0~
, ,~ "

HO 0~!
- COO' -I
. .. .
6a ox OH
~0 .. )~-- ~CCOH
I I

HO GH
, ~-Q
CH2) s R30 7~ IV
~Y--C--C--Rl7 -L ,'1 L

-56- 40~2 FORMULAS (continued) CH2~Z-Q
(CH2)s R30 - ~3~

W Fo~mul a W
U -C!~20R1 3 .L50 ( CH 2 ) S

,~ Formul a W

I;

. I

.' . I

57- ~.209154 40~2 CHART A

~(CH2)s - . Y-C--C-R,, Formula A-l ... ..
Lo Mx L

l CH2) 5 ~\Y-C--C-R17 Formula A-2 .. ..
Lso Mx L1 .

,0, LiOC-CH-Z1-CH20R2~Formula A-3 . Li ' 'I
\ /

HO~,~,CH-Z1CHzOR

/~( CH2) 5 ~\Y-C--C-R17 Formula A-4 Lso Mx L

Formula A-5 ~209~l54 -58- 40~2 CHART A (continued) H~_Z1CH20Q2 _ (C~l2Js v -C--C- R, 7 L Mx L1 Formula A-5 so 10 ' \ / , H I_ Z1 -CHzOR
_ ( CH2) s R30 1 1 .

~\Y-C--C-R~7 For7ula A-6 Lso Met L1 I .

. H Z,- CH20H
/'~(CH2?s - . ~\Y-C--C-R~ 7 L M L1 Formula A-?
,. '' H~_Z1-Q2 _ (CH2)s Y -C--C- R l 7 L M L1 Formula :
. . .

59 ~Zo9~54 40~2 CHAR T B

Formula A-2 ______ > ~(CH2)s S R~20 I=
~\Y-C--C-R17 Lso ~lx Ll i Formula B-l R21O-CH2-(CH2)a ~3 Formul a B-2 CH0 (CH2)~-CH20R2~ "
( C:~z~ 5 ' ( CH2)9-ciizOR2.

R30 (CHz)s ~\Y-C--C-R17 R,~O~Y-C--C-R~, Formul a B-4 . . . Formul a B-3 25 \ /
~(CH2)~-Q
!
(C~2) S
30 R30~

" 1, L50 Mx L-Formul a B-5 .... . I

. ~209~54 CHART C

~( CH2) S
5.
CH20R,3 Formul a C-l . L50 10, , O
J~(CH2JS

CH20R13 Formula C-2 .. L50 H~"~?,Z-CH20R

= (CHz)5 . R 0 Formula W
.~ W C-3 -CH20R13 . . L 50 .

( CHZ) s Formula W
' W C-4 -CH20R,3 .

Claims (6)

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

1. A process for preparing an intermediate compound, for preparing 9-hydroxy substituted carbacyclin derivatives, having a general formula selected from:

wherein for the compound of general formula (A-2a):
s is one or 2;
Y represents a group selected from -CH2CH2-, cis-CH=CH-, trans-CH=CH- and -C?C-;
Mx represents a group selected from .alpha.-OR:.beta.-R14 and .alpha.-R14:.beta.OR, wherein R represents an -OH-protecting group and R14 represents a group selected from H and -CH3;
L1 represents a group selected from .alpha.-R15:.beta.-R16, .alpha.-R16:.beta.-R15 and a mixture thereof, wherein R15 and R16 independently, represent a group selected from H, F
and -CH3, with the proviso that one of R15 and R16 represents F only when the other does not represent -CH3;

L50 represents a group selected from H:H,.alpha. -OR:.beta.-H, .alpha.-H:.beta.-OR, .alpha.-CH2OR:.beta.-H and .alpha.-H:.beta.-CH2OR, wherein R is as defined above; and R17 represents a group selected from:
(i) cis-CH=CHCH2CH3, -(CH2)2CH(OH)CH3, -(CH2)3CH=C(CH3)2, phenyl, benzyl, phenylethyl, phenylpropyl, (ii) -CmH2mCH3, wherein m is an integer of from one to 5, and (iii) mono-, di- and tri-F, -C1, -CF3, -C1-3alkyl and -C1-3alkoxy-(phenyl)-substituted-phenyl, -benzyl, -phenylethyl and -phenylpropyl, with the proviso that not more than two substituents are other than C1-3alkyl; or , when taken together, represent a group selected from:
(iv) , 3-thienyloxymethyl, C4-7cycloalkyl and mono-, di- and tri-C1-5alkyl-substituted-C4-7cycloalkyl, (v) -C?CCqH2qCH3, wherein q is an integer of from 2 to 6, and (vi) -CpH2pCH=CH2, wherein p is an integer of from 3 to to 7; and wherein for the compound of general formula (C-2'):
s and L50 are as defined above for the compound of general formula (A-2a); and R13 represents an -OH-protecting group;
said process comprising:
for the compound of general formula (A-2a):
(a) epoxidizing an an enone of general formula:
(A-1') wherein s, L1, L50, Mx and Y are as defined above and R' corresponds to R17 as defined above except that -(CH2)2-CH(OH)-CH3 is -(CH2)2-CH(OR13)-CH3, wherein R13 is as defined above, with an alkaline hydrogen peroxide and reducing the product thereof with an A1-amalgam; and, when required, removing R13 to produce the desired compound of general formula (A-2a); or for the compound of general formula (C-2'):
(b) repeating step (a) with a compound of general formula:

(C-1) wherein s, R13 and L50 are as defined above, to produce the desired compound of general formula (C-2').

2. An intermediate compound, for preparing 9-hydroxy substituted carbacyclin derivatives, having a general formula selected from (A-2a) and (C-2') as defined in claim 1, when prepared by the process defined in claim 1 or an obvious chemical equivalent thereof.

3. The process of claim 1, wherein step (a) is effected.

4. An intermediate compound, for preparing 9-hydroxy substituted carbacyclin derivatives, of general formula (A-2a) as defined in claim 1, when prepared by the process defined in claim 3 or an obvious chemical equivalent thereof.

5. The process of claim 1, wherein step (b) is effected.

6. An intermediate compound, for preparing 9-hydroxy substituted carbacyclin derivatives, of general formula (C-2') as defined in claim 1, when prepared by the process defined in claim 5 or an obvious chemical equivalent thereof.