CA1226280A - 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin i.sub.2 derivative - Google Patents

Abstract

TITLE OF THE INVENTION:

5,6,7-TRINOR-4,8-INTER-m-PHENYLENE

ABSTRACT OF THE DISCLOSURE:

A compound of the formula (I) wherein R1 is a pharmaceutically acceptable cation, hydrogen or n-alkyl of 1 to 12 carbon atoms; R2 is hydrogen, acyl of 2 to 10 carbon atoms or aroyl of 7 to 13 carbon atoms; R3 is hydrogen, acyl of 2 to 10 carbon atoms or aroyl of 7 to 13 carbon atoms;
R4 is hydrogen, methyl or ethyl; R5 is n-alkyl of 1 to 5 carbon atoms; n is an integer of 0 to 4; A is -CH2-CH2- or trans -CH=CH-; and X is -CH2-CH2- or trans -CH=CH-.

Description

Lo I

Background of the invention .__ The present invention relates to novel prostaglandin It derivatives, more particularly, to 5,6,7-trinor-~,8-inter-m-phenylene prostaglandin It derivatives.
Prostaglandin It, hereinafter referred to as PGI2, of the formula 2 1 I

a H

was first found by Jo Vane eta in 1976 and is biosynthe-sized from arachidonic acid via endoperoxide(PGH2 or PGG2) in the vascular wall. PGI2 is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels & EN, Dec. 20, 1976, page 17 and S. Monkeyed et at., Nature, 263,633(1976)).
Because of the unstable exo-enolether structure thereof, PGI2 is extremely unstable even in a neutral aqueous solution and is readily converted to 6-oxo-PGFl~ which is almost physiologically inactive. Such instability of PGI2 is a big obstacle to its use as a drug. Furthermore, PGI2 is unstable in viva as well and shows only short duration ox action.
The compounds of the present invention are novel PGI2 derivatives in which the exo-enolether moiety characteristic of PGI2 is transformed into "inter-m-phenylene" moiety. In this sense the compounds may be regarded as analogs of PGI2.

~22~2~i~

The compounds of the present invention feature much improved stability in vitro as jell as in viva in comparison with PGI2. The compounds are highly stable even in an aqueous solution and show long duration of action in viva. Further, the compounds have advantages over PGI2 for pharmaceutical application because they exhibit more selective physiological actions than PGI2, which has multifarious, insuperable biological activities.
Some prostaglandin It derivatives which have try-nor-4,8-inter-m-phenylene structure have already been described in publication by some of the present authors. (Kiyotaka Ohio, issue Nishiyama and Shunter Nash, US 4,301,164 (1981)).
But, the compounds of the present invention, which feature the presence of alkynyl side chain, have more potent physiological activities as well as decreased side effects than the already disclosed compounds analogous to those of the present invention.
It is an object of this invention to provide novel prostaglandin It derivatives which are stable and possess platelet aggregation-inhibiting, hypotensive, anti-ulcer and other activities.
Another object of this invention is to provide the coy--pounds improved on physiological efficacy as compared with the compounds which have already been disclosed by some of the present authors.
Other objects and advantages of this invention will be apparent from the description hereinbelow.

628C~

Summary of the invention A compound of the formula:

SHAKER

H CHURCH ) -C_C-R5 R20 or wherein R is a pharmaceutically acceptable cation, hydrogen or n-alkyl of 1 to 12 carbon atoms; R2 is hydrogen, azalea of 2 to 10 carbon atoms or aureole of 7 to 13 carbon atoms; R3 is hydrogen, azalea of 2 to 10 carbon atoms or aureole of 7 to 13 carbon atoms;
R4 is hydrogen, methyl or ethyl; R5 is n-alkyl of 1 to 5 carbon atoms; n is an integer of O to 4; A is -CH2-CH2- or trays -CH=CH-; and X is -CH2-CH2- or trays -CH=CH-.

Detailed Description of the Invention In the compound of the formula (I), examples of the pharmaceutically acceptable cation defined in Al include a metal cation, an ammonium ion, an amine cation or a quarter nary ammonium cation.
Preferred metal cations are alkali metal, for instance, lithium, sodium, potassium and alkaline earth metal, for instance, magnesium and calcium. Other metal ions, for instance, aluminum, zinc and iron are also suitable as cation R in the invention.
The pharmacologically acceptable amine cations as are those derived from primary, secondary and tertiary amine.
Suitable amine are, by way of example, methyl amine, dimethylamine, triethylamine, ethyl amine, dibutylamine, tri-isopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotyl-amine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzyl-amine, alpha-phenyl-ethylamine, beta-phenyl-ethylamine, ethylene-Damon, diethylenetriamine. Alternatively, preferably included are the analogous aliphatic-, cycloaliphatic- and heterocyclic amine having carbon atoms up to about 18, for instance, l-methyl-piperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methyl-pyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, etc. and the water-soluble amine or the amine having hydrophilic group, for instance, moo-, dip and triethanolamine, ethyldiethylamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-l~:Z6Z~30 propanediol, tris(hydroxymethyl)aminomethane, N-phenylethanol-amine, N-(p-tert-amylphenyl)-diethanolamine, galactamine, N-methylglutamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, etc. and furthermore, basic amino acids, for instance, Lawson, arginine, etc.
Examples of the normal alkyd group of l to 12 carbon atoms defined in Al include methyl-, ethyl-, propel-, bottle-, ponytail-, Huxley-, hotly-, octal-, dodecyl group, etc.
Examples of the azalea group of 2 to lo carbon atoms lo defined in R2 include acutely-, propionyl-, bitterly-, octanoyl-and decanoyl group. The azalea group R2 is, however, not limited to those mentioned above.
Examples of the aureole group of l to 13 carbon atoms defined in R2 include bouncily-, p-toluoyl-, p-phenylbenzoyl group, etch The aureole group R2 is, however, not limited to those mentioned above.
Though R3 has the same meaning as R2, R2 and R3 may be the same substituent or may be different from each other.
Examples of the normal alkyd group of l to 5 carbon atoms defined in R5 include methyl-, ethyl-, n-propyl-, n-butyl-, n-pentyl group.
The compounds of the general formula (I) produced my the invention are named after the nomenclature for prostaglandins and prostacycline analogs proposed my N. A.
Nelson eta (NOAH. Nelson, Jo Med. Chum., 17, 911 tl974) and ROY. Johnson et at., Prostaglandins, 15, 737 (1978)).

`'`11 Z~6;~0 The most fundamental compound in which the exo-enol ether moiety of PGI2 has been converted to the intraoral-phenylene moiety is represented by the following phyla:

HO

and after numbering each carbon atom as shown above, the compound is named as 5,6,7-trinor-4,8-inter-m-phenylene PGI2.
Following the above-mentioned nomenclature, one of the compounds included in the present invention and represented by the following formula (II):

COO

= C--C-CH3 (II) HO OH

is named as16-methyl-18,19-tetradehydro--5,6,7-trinor-4,8-intton-m-phenylene PGI2 lZZ6;~80 Alternatively, the compound of the formula (II) may be named as a derivative of butyric acid by the more formal nomenclature. In such a case, the condensed ring moiety is named after the bicycle structure of lH-cyclopenta~b~benzofuran of the following formula:

Accordingly, the formal n me of the compound of the formula is given as4-[2-endo-hydroxy-1-exo-(3-hydroxy-4-methyl-6,7-teextra-dehydro-l-octenyl)-3a,8b-cis-2,3,3a,8b-tetradehydrro-lH-5-cyclo-penta[b]benzofuranyl]butyric acid.
In this specification, the structural formula of the compound of this invention is indicated only by one of a pair of optical isomers. It is, however, noticed that the compounds of the aforementioned general formula (I) are intended to include d-isomer, Q-isomer and rhizomic mixture. In addition, the US

representation showing the absolute configuration of the compound is omitted herein.
The compounds represented by the general formula (I) are exemplified as follows, but these illustrations are not to be construed as limiting the invention.

i;~26;~80 16-Methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteerr phenylene PGI2 (I) 16-Methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteerr phenylene PGI2 methyl ester (II) 18,19-Tetradehydro-5,6,7-trinor-4,8-inter-m-phenyltone PGI2 (III) 18,19-Tetradehydro-5,6,7-trinor-4,8-inter-m-phenyltone PGI2 methyl ester (IV) 20-Methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteerr 10 1 phenylene PGI2 (V) 20-Methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteerr phenylene PGI2 methyl ester (VI) 16,20-Dimethyl-18,19-tetradehydro-5,6,7-trinor-4,88-inter-m-phenylene PGI2 (VII) 16,20-Dimethyl-18,19-tetradehydro-5,6,7-trinor-4,88-inter-m-phenylene PGI2 methyl ester (VIII) 20-Ethyl-16-methyl-18,19-tetradehydro-5,6,7-trinorr-4,8-inter-m-phenylene PGI2 (IX) 20-Ethyl-16-methyl-18,19-tetradehydro-5,6,7-trinorr-4,8-inter-m-phenylene PGI2 methyl ester (X) 16-Methyl-2,3-didehydro-18,19-tetradehydro-5,6,7-ttrainer-4,8-inter-m-phenylene PGI2 (XI) 16-Methyl-2,3-didehydro-18,19-tetradehydro-5,6,7-ttrainer-4,8-inter-m-phenylene PGI2 methyl ester (XII)

2,3-Didehydro-18,19-tetradehydro-5,6,7-trinor-4,8--inter-m-phenylene PGI2 (XIII) issues ¦ 16-Methyl-13,14-dihydro-18,19-tetradehydro-5,6,7-ttrainer-4,8-inter-m-phenylene PGI2 (XIV) 16-Methyl-13,14-dihydro-18,19-tetradehydro-5,6,7-ttrainer-4,8-inter-m-phenylene PGI2 methyl ester (XV) 20-Methyl-19,20-tetradehydro-5,6,7-trinor-4,8-inteor-m-phenylene PGI2 (XVI) 17,18-Tetradehydro-5,6,7-trinor-4,8-inter-m-phenyltone PGI2 (XVII) l Among the compounds of the invention, those in which A
1 is the group of -CH2-CH2-, R2 and R3 are hydrogen and X is the group of trays -CH=CH- may be prepared by the following Reaction Scheme A.

11 Z; :6Z80 . Jo ISSUE

H U . ¦
I '/0 I V I

Jo I

lZ26;~80 ' ::~
$ us Jo o I
Jo I
" 'I I , .,~ I

I! I

i ~LZ26Z8(~

I Jo -- , lZ26Z80 The starting material of bromocarboxylic acid, Compound 1, and the process for the preparation thereof are disclosed in Japanese Patent Application No. 29637/81.
The step Aye represents the conversion of Compound 1 to Compound 2 by the so-called Print reaction and is ordinarily proceeded by heating bromocarboxylic acid 1 and formal in or a compound equivalent to the formal in in the solvent of acetic acid under the presence of an acid catalyst. As the compound equivalent to thy formal in, paraformaldehyde and traction may be mentioned.
¦ As the catalyst, sulfuric acid, chlorosulfonic acid, trifler-acetic acid, perchloric acid, phosphoric acid, etc. may be mentioned, and the sulfuric acid is preferably used. The reaction is carried out at a temperature in the range from an ambient temperature to 200C and ordinarily the favorable reaction rate is available at a temperature in the range of 60 to 90C. After the solvent and the solid derived from the formaldehyde were removed from the reaction system, the product 2 is used as a starting material without further purification.
The step A-II is a step for hydrolysis of the ester group of Compound 2, which can be conducted by adding to a solution of the Compound 2 in methanol or ethanol an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate in an amount more than 3 equivalent amount.
The reaction is carried out at a temperature from 0 to 150C, and is preferably from 20 to 100C to give a preferred reaction rate. After the solvent is removed, water is added to the residue ~LZZ6Z80 and the mixture is acidified (pi 2-4) and extracted with organic solvent not miscible with water such as ethyl acetate, ether, chloroform, dichloromethane etc. to give a crude crystal 3.
The organic solvent for the extraction is not restricted to the above-mentioned.
I Compound _ is used in the next step as the starting I material without purification.
¦ The step A-III is a step of conversion or the carboxylic acid obtained in step A-II into the corresponding methyl ester, which can be carried out by addition of an amount of more than ¦ stoichiometrical amount of a solution of diazomethane in ether to a solution of 3 in a solvent at a temperature from -20 to ~0C.
The reaction proceeds instantaneously to afford Compound 4.
As another method for carrying out step A-III, for instance, a method wherein Compound 3 is methylated with methyl iodide in acetone in the presence of potassium carbonate and a method wherein Compound 3 is heated with methanol in the presence of an acid catalyst, preferably p-toluenesulfonic acid, sulfuric acid, alkylsulfate, acidic ion exchanging resin or phosphoric acid, in 20 Bunsen or Tulane followed by removing water formed during the reaction may be mentioned. For more in detail, refer to JAW
McOmie protective Groups in Organic Chemistry", pages 183 to 210 (1973) by Plenum Press, SIR. Sandier' and W. Kayo 'Inorganic Functional Group Preparations', pages 245 to 265 (1968) by Academic Press or KIWI. Buckler and DYE. Pearson "Survey of Organic lZ~6Z80 Syntheses" Chat. 14, pages 802 to 825, Wiley-Interscience Ed.
The usual methods of esterification shown in these references are applicable to step A-III.
The step A-IV is a step for the dehalogenation of Compound 4 and carried out by the so-called hydrogenation.
More in detail, the step is completed by effecting the reaction under a pressure of hydrogen (from an ordinary pressure to 10 elm) in the presence of a catalyst such as palladium-carbon, palladium-barium sulfate, Raney-nickel, etc. It is preferable to effect the reaction in the presence of a neutralizing agent such as sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, etc. for the purpose of neutralizing hydrogen bromide formed in the reaction.
The step A-V is a step for conversion of the dill in Compound 5 into the acutely of acetaldehyde, Compound 6.
For that purpose, Compound 5 is dissolved into a solvent together with acetaldehyde, l,l-dimethoxyethane or l,l-diethoxyethane, and after an acid is added to the solution, the mixture is heated at a temperature from 0 to 150C, preferably at a temperature from 40 to 100C to cause reaction. As the solvent, an aprotic solvent such as tetrahydrofuran, dimethoxyethane, Dixon, Bunsen Tulane, dimethylformamide, ether, ethyl acetate, dichloromethane, chloroform, trichloroethylene and the like may be mentioned, and tetrahydrofuran is preferable. As the acid, p-toluenesulfornic acid, phosphoric acid, sulfuric acid, acidic ion-exchanging resin SUE

or trifuloroacetic acid may be mentioned, and the use of p-toluenesulfonic acid gives a satisfactory result.
The step A-VI is a reduction step for converting the acutely 6 to the corresponding alcohol 7. As the reducing agent, lithium aluminum hydrides and hydrogen in the presence of a Quicker catalyst may be mentioned, and lithium aluminum hydrides is preferable.
The step A-VII is the conversion step of the alcohol 7 to the corresponding chloride, wherein the Compound 7 is reacted with thinly chloride in an organic solvent in the presence of a base. As the base, although pardon is preferably used, a tertiary amine may be used. Instead of thinly chloride, phosphorous trichloride, triphenylphosphine-CC14, phosphorous o~ychloride and the like may be used in the step A-VII.
The step A-VIII is the conversion step of the halide 8 into a carboxylic acid 9 having three elongated carbons.
The step is carried out by converting the chloride in Compound 8 to the corresponding Grignard reagent and adding ~-propiolactone to the Gringnard reagent in the presence of a copper catalyst.
Though cuprous iodide is preferable as the copper catalyst, other monovalent copper compound such as cuprous chloride, cuprous bromide, tetrakis~tributylphosphin)cupro-l-pentylide may be used in this step.
The step A-IX is the conversion step of the carboxylic acid 9 to the corresponding methyl ester 10. The step is carried lZ26Z80 out substantially in a similar manner as in the step A-III.
The step X is a step for the solvolysis of the cyclic acutely in Compound 10 to give a dill, wherein the solvolysis ¦ is effected by the addition of an acid to a solution of Compound The solvent is exemplified by methanol, ethanol, aqueous _`
methanol, aqueous ethanol, isopropyl alcohol, buttonhole.
The acid catalyst is exemplified by hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic l acid, acidic ion-exchanging resin, acetic acid, etc., however, 10 ¦ not being restricted thereto. The hydrochloric acid ordinarily gives a sufficiently desirable result. The reaction temperature is in the range from -20 to 200C, and is preferably from 0 to 70C.
The step A-XI is a step for selective protection of the primary hydroxyl group in dill 11 using dimethyl-t-butylsilyl-chloride. In this step, imidazole is preferably used as a base.
The step A-XII is a step for esterification of the remaining free hydroxyl group of Compound 12, in which Compound 12 is reacted with an azalea- or aureole halide represented by the formula of RAY wherein R2 is the same as has been defined herein before but excepting a hydrogen atom and Y is an atom of chlorine, bromide or iodine, or an acid android represented by the formula WRIER wherein R2 is the same as has been defined before but excepting a hydrogen atom.

~2;;~6~8~

Examples of the azalea- and aureole halide include acutely chloride, propionyl chloride, bitterly chloride, acutely iodide, decanoyl chloride, bouncily chloride, p-toluoyl chloride, p-phenylbenzoyl chloride, etc. The azalea- and aureole halide is, however, not restricted to these illustrations.
Examples of the acid android include acetic android, prop ionic android, butyric android, benzoic android, etc.
The acid android is, however, not restricted to these illustra-lions.
The reaction of step A-XII may be carried out in the coexistence of an acid or a base. Particularly, in the condense-lion of R Y and the alcohol of Compound 12, the base, for instance, pardon or a tertiary amine such as triethylamine is coexisted as a catalyst. The condensation reaction of the alcohol 12 with the acid android may be carried out by heating a mixture in the presence or absence of the acid or the base. As the acid, sulfuric acid, phosphoric acid, acidic ion-exchanging resin or boron trifluoride is preferably used, and as the bases, pardon, an analogous compound such as p-dimethyl-aminopyridine or a tertiary amine such as triethylamine is preferably used. Ordinarily, the pardon is preferably used and it serves as the base and also as the solvent. In the reaction, solvent may be or may not be used. In using a solvent, an aprotic one is used, for instance, tetrahydrofuran, dimethoxy-ethanes Bunsen, Tulane, ether, dimethylformamide, Dixon, etc.
The step A-XIII is A step for removing the dirnethyl-t-6~80 butylsilyl group in Compound 13 to obtain Compound 14. The reaction is effected by leaving a solution of Compound 13 in an aqueous solution of acetic acid to stand for 0.5 to 48 hours at a temperature from 15 to 100C. Alternatively, the compound 13 may be reacted with quarter nary ammonium fluoride in an organic solvent. The examples of the quarter nary ammonium fluoride are I tributylammonium fluoride, trioctylammonium fluoride and the ¦¦ like but not restricted thereto.
If The step A-XIV is a step for oxidation of the alcohol 14 to give an alluded 15. Although various oxidizing agent have been known for the oxidization, chronic android-pardon complex Collins reagent), dimethylsulfoxide dicyclohexyl-carbodiimide, dimethylsulfide-chlorine and a base, dimethylsul-five N-bromosuccinic imide or the like are particularly preferable.
The step A-XV is a step for reaction of the alluded 15 with a sodium salt of dialkylphosphonic acid ester of the formula:

O O R
UP SHEA C-CH-(CH2)n-C _ CRY

wherein R4, US and n are the same as has been defined above and R6 is an alkyd group such as methyl, ethyl, propel, octal, etc., in an organic solvent to afford Compound 16. The examples of the solvent are an ether such as tetrahydrofuran and dimethoxyethane and the solvent used in Wittig's reaction, for instance, 2;~6Z80 dime thy is us f oxide, do alkyd f or aside and the it key .
The dialkylphosphonic acid ester may be easily Cynthia-sized according to the following reaction (EDGY. Corey et at., J. Am. Chum. So , 88, 5654~1966)): R4 60) 2P-CH2 Q H + ~5-c_c-(cH2)n-cH-coocH3 I 6 o R4 (R O)2P-CH2-C-CH-(CH2)n-C-C-R
wherein R4, R5, R6 and n are the same as has been defined above.
The step A-XVI is a reduction step of I, B-unsaturated l kitten to afford ally alcohol. The reducing agent is preferably zinc bordered, Zn(BH4)2. Other non limitative examples of the reducing agent are curium chloride/sodium boronhydride(NaBH4), lithium aluminum hydrides (Lyle, ~'-binaphthol, diisobutyl-aluminum(2,6-dimethylphenoxide), aluminum triisopropoxide and the like.
The reduction product in this step A-XVI contains a mixture of the isomer and the isomer, and the mixture is used in the next step A-XVII without purification. The necessary product, isomer may be isolated by column chromatography after the next step A-XVII. .¦
The step of A-XVII is a step for ester exchange of Compound 17. The step is carried out by dissolving Compound 17 in methanol and adding a base such as an hydrous potassium carbonate and sodium methoxide as a catalyst to the solution.
Among the compounds of the invention, those in which A
.1 l l ~Z26Z80 is -CH2-CH2-, Al, R2 and R3 are respectively a hydrogen atom may be prepared according to the following Reaction Scheme B.
REACT ION S CHIME B

COUCH

Ho CH-(CH2)n-C_C-R5 C H

X CH-(CH2)n-C-C-R5 HO OH

The step B-I is a step for hydrolysis of the methyl ester 18 to afford a free carboxylic acid 19. This hydrolysis is carried out by dissolving Compound 18 in methanol or ethanol and after adding an aqueous solution containing more than the stoichiometric amount of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate to lZ~:6;~80 the alcoholic solution, heating the mixture at a temperature from 0 to 150C, preferably 20 to 60C. The base is not necessarily restricted to the above-mentioned bases, and the solvent of aqueous tetrahydrofuran, aqueous Dixon, aqueous dimethoxyethane, dimethylsulfoxide or the like may be used in stead of methanol or ethanol.
Among the compounds included in the present invention, those in which Al, R2 and R3 are respectively a hydrogen atom and A is trays -CH=CH- may be prepared according to the following Reaction Scheme C.
REACTION SCHEME C

r Coquette C-I

_ CH-(CH2)n-C-C-R5 [I

C Of -- Go ~L2~28~

I >

X ~_,CH-(CH2)n-C-C-R5 HO OH

COO

C-III O

_ ~_~ CH(CH2)n-C-C-R5 HO OH

The step C-I is a reaction step wherein a hydrogen atom attached to the carbon atom at alpha position of the carbonyl .¦
carbon atom of the methoxycarbonyl group of Compound 18 is sub- ..
stituted by a phenylseleno group. The substitution is carried out by bringing 3 to 3.5 equivalent amount of diisopropylamino-lithium into reaction with one equivalent amount of Compound 18 at a low temperature from -80 to -40C and adding diphenyl diselenide to the mixture in an organic solvent, most preferably ~LZ26Z80 in tetrahydrofuran. The solvent is not necessarily limited to tetrahydrofuran. It is preferable to add hexamethylphosphonic trimmed (HMPt) to the reaction system for raising the reactivity of the reactants after the addition of diphenyl diselenide and to heat the mixture to 0 to 60C for completing the reaction.
The step C-II is a step for hydrolysis of the methyl ester 20 to give a free carboxylic acid I. The reaction may be carried out in a similar manner to that in the step B-I.
l The step C-III is a step for removing the phenylseleno group in Compound 21. Ordinarily, for such a purpose, hydrogen pro-wide is used. The hydrogen peroxide oxidizes the phenylseleno group followed by removing the group. An aqueous 30~ by weight solution of hydrogen peroxide is used in excess in this step, and after the reaction is over, the excess was reduced by a reducing agent such as dim ethyl sulfide, Sydney thiosulfate, Sydney hydrogen sulfite and the like.
Among the compounds included in the present invention, those in which Al is the normal alkyd group of 1 to 12 carbon atoms are prepared by the following Reaction Scheme D.
REACTION SCHEME D

H D-I

2- X I" CH-(CH2)n-C--C-R5 R O or lZ26Z80 SHAKER

R
¦ X y OH (Sheehan C-C R

l R20- or The step D-I is a step for the esterification of a carboxylic acid. In general, when a solution of diazoalkane in ether is added to a solution of Compound 23 in an organic solvent, the esterification proceeds instantly with the evolution of gaseous nitrogen. The non-limitative examples of diazoalkane are diazomethane, diazoethane, diazo-n-propane, diazo-n-butane, diazo-n-dodecane and the like. Other methods for the esterifi-cation may be preferably applicable wherein Compound 23 is at first converted to sodium salt or a salt of a tertiary amine and ethyl chlorocarbonate is added to form a mixed acid android in the reaction system, and then an alcohol, RlOH wherein Al is a normal alkyd of 1 to 12 carbon atoms is added to the system and the system is heated.
Among the compounds of the invention, those in which R and R are the same azalea or aureole group may be prepared by the following Reaction Scheme E.

REACTION SCHEME E

CH2-A-COORl X I_" CH-(CH2)n-c--c-R5 HO OH

Charlie X ~_~CH-(cH2)n-C-C-RS

The step E-I may be proceeded as in the step A-XII.
Among the compounds of the invention, those in which X is -CH2-CH2-, R is the methyl group and A is -CH2-CH2- may be prepared by the following Reaction Scheme F.

Lo 81~

REACTION SCHEME F

COUCH

H CUT (CU2)n-C-C-RS F-I
R 20 o 2 I--) OH ITCH ) n-C_C-FS

KIWI

HO OH

1;~26;~80 The step F-I is a simultaneous reduction step of a double bond between the carbon atoms of positions 13 and 14 of Compound 16 and a carbonyl group adjacent to the double bond.
In the step, sodium bordered (Nub) is added as a reducing agent to a solution of Compound 16 in pardon to carry out the reaction.
The step F-II may be carried out as in the Step AVOW.
Among the compounds of the invention, those compounds in which X is -CH2-CH2- may be generally prepared by carrying out lo the suitable reactions shown in each step of Reaction Schemes B, C, D and E while using Compound 27 as the starting compound.
Any one of Reaction Schemes A to F may be applied for producing the d-isomer, the Q-isomer and the rhizomic compound of the compound according to the present invention. The optical isomer of the compound can be obtained from the optically active product resolved, for instance, in Reference Example 20 or 21 hereinafter mentioned.
The compounds within the present invention have potent platelet aggregation inhibiting activity and blood pressure decreasing activity by vasodilating action. Furthermore, the compounds have the potent gastric mucus protecting action and potent gastric juice~ecretion inhibiting action.
According to Born's method (Nature, 19~, 927(1962)), the efficacy of the compound to inhibit platelet aggregation was examined. The blood was collected from human or anesthetized rabbits. The blood was anti-coagulated with a 3.8 % aqueous solution of sodium citrate in an amount of a tenth volume of the blood and was centrifuged for 10 minutes at 200 x g to obtain platelet rich plasma. After pretreatment with the compound of the invention to the platelet rich plasma aggregation was measured by aggregometer with arachidonic acid, adenosine-2-phosphate(ADP) or collagen as aggregation inducer. It was shown that compound (I), (III), (VII) and (XI) had the same or more potent inhibitory activity than prostaglandin El. It should be noted that the compound [EDDY ng/ml] or (III) [EDDY ng/ml] exhibit more potent human platelet aggregation inhibiting activity induced by ASP than the corresponding I C19-Saturated compounds, 16-methyl-5~6~7-trinor-4~8-inter-m-phenylene PGI2 [EDDY ng/ml] or 5,6,7-trinor-4,8-inter-m-phonylene PGI2 [EDDY 19 ng/ml] respectively.
To examine the efficacy of the compound to reduce the blood pressure, the blood pressure of carotid artery of rats under pentobarbital anesthesia was measured. The compounds (I), ~III), (VII) and (XI) were injected into the vein through in-welling catheter. These compounds of the invention exhibited the same activity as prostaglandin El at the same dose of 0.05 to 100 gig but compounds (I), (III~, (VII) and (XI) had the longer duration than prostaglandin El.

According to the method of Robert et al.(Gastroente-urology, 77, 433(1979)), the activity of- compounds (I), (III), (VII) and (XI) to protect the gastric mucosal membrane was examined.
The compounds efficiently suppressed the lesions caused by ethanol on the gastric mucus of rats by oral administration at the dose of 10 to 30 gig which is 0.3 to 1 time of the equipotent dose of prostaglandin En.

l.Z26~80 According to Shays method tGastroenterology, 26, 906 (1954)), the activity of the compounds in the present _ invention to suppress the secretion of gastric juice was examined.
Compound VII significantly suppressed the secretion of gastric juice by subcutaneous injection in a dose of 0.3 to 1 mg/kg which corresponds to 0.1 to 0.3 times of the equipotent dose of prostaglandin E?. The compounds of the invention, particularly¦
Compounds I, III, VII and XI showed no symptoms of diarrhea in rats even up to the dose of 3 mg/kg by subcutaneous administration.
Therefore, the compound of this invention may be used as medicine for an anti-peptic ulcer agent, an anti-thrombotic agent and a blood pressure-reducing agent. In addition, the compounds may also be applied to an anti-asthmatic agent because of their relaxing activity of the tracheal smooth muscle.
The anti-thrombotic agent containing the compounds of the present invention as an active component may be applied to extra corporeal circulation, treatment of the disturbance of peripheral circulation such as Burgers disease and Rounds disease, prevention and treatment of myocardial infarction, angina pocketers and cerebral infarction, prevention of TIP, treatment of diabetic thrombosis and prevention and treatment of arterioscrelosis.
For the treatment of gastric ulcer, the subject compound is administrated in a pharmaceutically effective amount 1~26~3 of 0.01 to 100 mg/person one to three times a day orally, subcutaneously, intramuscularly or intrarectally. For the treatment of Burgers disease, the pharmacologically effective intravenous dose of the subject compound amours 0.001 to 100 ~g/kg/min. In case of using the subject compound as the anti-thrombotic agent, 0.001 to 50 my of the compound is orally administrated per person one to three times a day, and in case of using the subject compound as the blood pressure-reducing agent, 0.01 to 50 my of the compound is orally ad minis-treated per person one to three times a day.
The compound according to the present invention canoe orally administered as a form of solid substance containing an excipient such as starch, lactose, sucrose, a certain kind of clay and a seasoning agent, or can be parenterally ad minis-toned in a form of a sterilized aqueous solution. Such a soul-lion may contain another solute, for instance, glucose or sodium chloride in an amount sufficient for making the solution is-tonic. Since the compound has a considerable stability due to the chemical structure thereof, there is no difficulty in manufacturing the preparation. Therefore, various preparations for oral administration, injections and suppositories can be prepared.
The present invention will be explained more in detail while referring to the following examples and reference examples.

Methyl 2 endo-hydroxy-1-exo-hydroxymethyl-3a,8b -is-lZZ6~8~) 2r3~3a~8b-tetrahydro-lH-5-cyclopenta~b]

benzofurancarboxylate To a suspension of 4 g of traction in 28 ml of acetic acid was added 1.2 ml of concentrated sulfuric aid, and the mix-lure was heated to 80C with stirring. To the solution was added in small portions 2 g of 7-bromo-3a,8b-cis-3a,8b~dihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid. After being stirred at 80C for 14 hours, the reaction mixture was cooled, and the acetic acid was removed under reduced pressure.
The residue was subjected to azeotropic operation with Tulane two times, and ether was added to the residue. the prostrate derived from traction were removed by filtration and washed with ether, and the combined ethereal solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and aqueous saturated solution of sodium chloride, was dried, and was concentrated to give 4 g of an oily material.

_33-lZ;~6280 ¦ The oily material was dissolved in 20 ml of methanol and to the i solution was added 20 ml of aqueous lo solution of sodium hydroxide, and the mixture was stirred for 14 hours at a room , temperature. After removal of methanol under reduced pressure, water was added to the mixture, and this solution was acidified to phi with aqueous ON hydrochloric acid. The mixture was extracted five times with ethyl acetate, and the ethyl acetate extract was dried and concentrated to give 3.5 g of crude crystals. After addition of ethanol to the crude crystals, the ¦ crude crystals were filtered. The filtrate was concentrated, and to the residue was added ethanol and ethyl acetate, and precipitate was collected by filtration. The combined amount of the crude crystals was 1.6 g.
After the combined crude crystals were methylated with diazomethane, the reaction product was dissolved in 20 ml of ethyl acetate. To this solution was added lo g of sodium acetate and 300 my of 10 % palladium-carbon, and the mixture was stirred for 2 hours under hydrogen. Then, the reaction product was filtered, and after addition of aqueous saturated solution of sodium hydrogen carbonate to the filtrate, the mixture was extracted two times with ethyl acetate.
The extract was washed with an aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.3 g of crude crystals. The crud crystals were recrystallized from ethyl acetate to yield 765 my of the captioned compound (melting point;
134 to 135C, yield; 43 %).
IT spectrum (KBr~v: 3400, 1715, 1605 and 760 cm NOR spectrum in CDC13)~ 0 to 2.80(5H), 3.50(1H, t J=7.0 Ho), 3.80(2H, m), 3.90(3H, s), 4.12(1H, q, J=6.0 Ho), 5.30(1H, m), 6.90(1H, t, J=8.0 Ho), 7.14(1H, d, J=8.0 Ho), and 7.74(lH, d, J=8.0Hz) Mass spectrum 2.64(M ) C H
! Elementary analysis: Calculated as KIWI 63.62 6.10 10 I Found 63.36 6.20 Jo REFERENCE EXAMPLE 2 ¦ Methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1, 4a,5,5a,10b,10c-hexahydro 7-dioxino[5,4-a]cyclo-penta~b]benzofurancarboxylate Ho H Al ..
4 ox I

To a stirred suspension of 3 g of methyl 2-endo-hydroxy-1-exo-hydroxymethyl-3a,3b-cis-2,3,3a,8b-tetrahydroowe-cyclopenta~b]benzGfurancarboxylate in 30 ml of an hydrous ~ZZ6Z80 tetrahydrofuran was added lo ml of a solution which is obtained by dissolving 10 ml of l,l-diethoxyethane and 200 my of p-toluenesulfonic acid MindWrite into 10 ml of tetrahydrofuran followed by drying over molecular sieves, and the mixture was stirred for 14 hours at 60C and then cooled.
To the reaction mixture was added 100 my of sodium hydrogen carbonate, and the mixture was stirred for 10 mix at a room temperature. Then, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate.
1, The combined organic layers were washed with water and aqueous ¦ saturated solution of sodium chloride, was dried, and was ¦ concentrated to give 3.5 g of the crude crystals. The crude ¦¦ crystals were recrystallized from benzene-hexane to yield 2 g of Jo the titled compound (mop. 162-163C).
¦ The filtrate was concentrated and the residue was dissolved again in 10 ml of an hydrous tetrahydrofuran. To this session were added I ml of l,l-diethoxyethane and 1 ml of the above-mentioned solution of p-toluenesulfonic acid MindWrite in tetrahydrofuran and the mixture was stirred for I hours at 60 QC and then cooled. To the reaction mixture was added 100 my of sodium hydrogen carbonate, and the mixture was stirred for 10 mix at a room temperature. After addition of water the mixture was extracted three times with ethyl acetate.

~2Z~2~3~

¦ The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.5 g of crude crystals. The crude crystals were recrystallized from benzene-hexane to yield 740 my of the captioned compound was obtained (mop. 154-156~C, yield 83 %).
IT spectrum(K~r) v : 1715, 1607, 1210 and 755 cm ¦ NMR(CDC~3) : 1.36(3H, d, J=5.0Hz), 2.00 (OH, m), .80(1H, m), 3.40~2~, m), 3.72(1H, t, J=10.0 Ho), l 3.90(3H, s), 4.40(1H, dud, J=10.0 Ho), 4.74(1H, q, J=4.0 Ho), 5.30(1H, m), 6.89(1H, t, J=8.0 Ho), 7.26(1H, dud, J=8.0 and 2.0 HO) and 7.80(1H, dud, J=8.0 and 2.0 Ho) Mass spectrum 290(M ) and 259(-31)

3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5, 5a,10b,lOc-hexahydro-7-dioxino~5,4-a]-cyclopenta [b]benzofranylmethanol To a suspension of 1 g of lithium aluminum hydrides in 10 ml of an hydrous tetrahydrofuran cooled in an ice oath was added drops a solution of 1.94 g of methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7--Dixon]-cyclopenta[b]-benzofurancarboxylate in 40 ml of an hydrous tetrahydrofuran. After being stirred for 30 mix at a room temperature, the reaction mixture was cooled in an ice bath.
The excess of lithium aluminum hydrides was decomposed by the addition of ethyl acetate, and aqueous saturated solution of 12Z6Z'30 potassium sodium tart rate was added to the reaction mixture.
¦ After filtration of the mixture, the filtrate was concentrated and the residue was dissolved in 10 ml of methanol. After addition of 2 g of potassium carbonate to the solution, the I¦ mixture was stirred for 3 hours at a room temperature and was ¦¦ concentrated. After water was added to the residue, the aqueous mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous l solution of sodium chloride, dried, and concentrated to give 2 g of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 1.49 g of the pure crystals (mop.;
124 to 125C, yield; 85 I).
IR(KBr) v : 3305, 1595, 1155, 1015 and 745 cm 1 NMR(CDCQ3) : 1.36(3H, d, J=5.0 Ho), 2.00(2H, m), 2.72(1H, m), 3.38(2H, m), 3.70(1H, t, J=10.0 Ho), 4.40 (lo, dud, J=10.0 Ho and 4.0 Ho), 4.70(3H, m), 5.08 (lo, m), 6.82(1H, t, J=7.5 Ho), 7.04(1H, dud, J=7.5 Ho and 1.5Hz), 7.14(lH, dud, J=7.5 Ho and 1.5Hz) Museum) : 262(~ ) and 229(-33) 7-chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydrodioxino[5,4-a]
cyclopenta[b]benzofuran l~Z6Z80 c~3 To a solution of 1.14 g of 3-methyl-trans-4a-cisoid-4a,5a-cis-Sa-1,4a~5,5a,10b,10c-hexahydro-7-dioxinoo[5,4-a]cyclo-penta~b]benzofuranylmethanol in 10 ml of dimethylformamide cooled in an ice bath was added 0.43 ml of an hydrous pardon and 0.38 ml of thinly chloride, and the mixture was stirred for 3 hours at a room temperature. After addition of ether to the reaction mixture, the precipitate was filtered, and water was added to the filtrate and the mixture was extracted three times with ether.
The extract was washed with aqueous saturated solution of copper sulfate, water, aqueous saturated solution of sodium hydrogen carbonate and aqueous saturated solution of sodium chloride, dried, and concentrated to give 1.2 g of crude crystals.
The crude crystals were recrystallized from ethyl acetate-hexane to yield 1 g of the pure chloride (mop.; 94 to 95C, yield;

IR(KBr) : 1600 and 745 cm NMR(CDC13) : 1.36(3H, d, J=S.0 Ho), 2.00(2H, m), lZZ6Z80 2.78(lH, m), 3.38(2H, m), 3.72 (lo, t, J=10.0 Ho),

4.40 (lo, dud, J=10.0 Ho and 4.0 Ho), 4. 60 (OH, s), 4.72(1H, q, J=5.0 I 5.20(1H, m), 6.83(1H, t, J=7.0 Ho) and 7.10 (OH, m) Mass (m/e) : 280 and 282 (M ) and 245 4-[3-methyl-trans-4a-cisoid_~a,5a-cis-5a-1,4a,

5,5a,10b,10c-hexahydro-7-dioxino [5,4-a]cyclopenta [b~benzofuranyl]butyric acid ) A solution of 482 my of 7-chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c--hexahydrreduction]
cyclopenta[b]benzofuran in 5 ml of an hydrous tetrahydrofuran was added drops to 84 my of turnings of metallic magnesium with stirring to prepare a Grignard reagent. To the thus prepared Grignard reagent cooled in an ice bath were added 30 my of cuprous iodide and 0.1 ml of beta-propiolactone, and the mixture was stirred for one hour. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was acidified with ~L2~6; I

lo hydrochloric acid to PI 3~4 to decompose the excess ox magnesium.
The resulting solution was extracted 5 times with ether, and the combined ethereal layers were washed with waxer and aqueous saturated solution of sodium chloride t dried and concentrated to give 500 my of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 279 my of the pure crystals of the carboxylic acid (melting point; 148 to 149C, yield; 54 %).

IR(XBr) Jo : 3600 Jo 2200, 1715; 1600 and 755 cm NMR(CDC13) : 1.36(3H, d, J=5.0 Ho), 1.95(4H, m), 2.38(2H, t, J=6.0 Ho), 2.64(3H, m), 3.00 to 3.90 (OH, m), 4.40(lH, dud, J=10.0 Ho and 4.0 Ho), 4.62 (lo, q, J=5.0 Ho), 5.10(lH, m), 6.80(lH, t, J=7.0 Ho) and 6.95(3H, m) Museum) : 318(M ) O Ho Elementary analysis: Calculated as KIWI 67.91 6.97 Found 67.93 7.14 Methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro-lH-5-cyclopenta [b]benzofuranyl]butyrate ~6Z80 To a solution of 390 my of methyl trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7-dioxinoo-[5,4-alcyclopenta~b]benzofuranyl]butyric acid in 5 ml of ethyl acetate cooled in an ice bath was added an excess of an ethereal solution of diazomethane, and after being stirred for 5 mix the mixture was concentrated. The resulting oily material was dissolved in 3 ml of methanol, and to the solution was added 1 ml of lo hydrochloric acid and the mixture was stirred for 3 hours at a room temperature. After concentration of the reaction mixture and addition of 1 ml of water, the mixture was extracted 3 times with eschew ml of ethyl acetate. The combined layers of ethyl acetate were washed with 3 ml of water and 3 ml of aqueous saturated solution of sodium chloride, dried and concentrated to give 380 my of crude crystals. The crude crystals were recrystallized from ethyl acetate-hexane to yield 200 my of the pure captioned product (mop.; 56 to 57C, yield; 53 %).

~Z26;~8~

IT (KBr) : 3400, 1737, 1595, 1255 and 745 cm 1 NOR (CDC13) :1.70 to 2.90(llH), 3.40(lH, t, J=8.0 Ho), 3.65(3H, s), 3.80(2H, m), 4.10(1H, q, J=7.0 Ho), Slyly, m), 6.80(1H, t, J=7.0 Ho) and 7.00(1H, m) Museum) : 306(M ) REFERENCE EXAl~qPLE 7 Methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-¦ 3a,8b-cis-2,3,3a,8b-tetrahydro-lH-5-cyclopenta l [b]benzofuranyl]butyrate 10 1 To a solution of 350 my of methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro-llH-S-cyclopenta [b]benzofranyl]butyratein 3.5 ml of an hydrous dimethylformamide cooled in an ice bath were added 140 my of imidazole and 360 my of t-butyl-dimethylsilyl chloride, and after the mixture was stirred for 3 hours at a room temperature, dimethylformamide was removed under reduced pressure. The residue was dissolved in a mixture of 10 ml of acetic android and 5 ml of pardon.
After the mixture was stirred for 2 hours at a room -temperature, the reaction mixture was concentrated. Then the residual oil was dissolved in 5 ml of acetic acid, and to the solution were added 5 ml of tetrahydrofuran and 2 ml of water. After the mixture was stirred for 14 hours at 50C and concentrated, the residue was subjected to azeotropic operation two times with Tulane. The residue was purified by column chromatography on silica gel using ethyl acetate-cyclohexane (1:2) to give ~ILZZ6Z80 280 my of the pure compound (yield; 70 %).
IR(liquid film) v : 3450, 1740, 1595, 1240 and 745 cm 1 NMR(CDC13) : 1.82(3H, s), 1.82 to 2.80(10H), 3.66 (OH, s), 3.70(3H, m), 5.00 to 5.35(2H, m), 6.80(3H, t, J=7.0 Ho) and 6.95(2H, m) Museum) : 348(M ) l Methyl ester of 11,15-dideoxy-11-acetoxv-16-methyl-15-oxo-18,19-tetradehydro-5,6,7-trinor-4,8 inter-m-phenylene PGI2 In 1.4 ml of a solution of 0.3 ml of pardon in 10 ml of Bunsen was dissolved 178 my of methyl 4-[2-endo-acetoxy-l-exo-hydroxymethyl-3a,8b-cis-2,3,3a,,8b-tetrahydro-lH-S-cyclopenta[b]benzofranyl]butyrate. To the solution were added 0.42 ml of the solution obtained by dissolving 0.14 ml of trifluoroacetic acid in 10 ml of dimethylsulfoxide and 320 my of dicyclohexylcarbodiimide, and the mixture was stirred for 14 hours at room temperature. The precipitate was filtered and washed well with Bunsen. The filtrate was washed with water (3 x 3 ml), dried and concentrated to give 250 my of crude alluded.
In the next step, 118 my of sodium hydrides (55 dispersion in mineral oil) was suspended in 20 ml of dim ethyl-formamide under argon. To the suspension was added a solution of 689 my of dim ethyl 3-methyl-2-oxo-hept-5-yne-phosphonate in 10 ml of Sue dimethylformamide, and the mixture was stirred for 30 mix at a room temperature.
To the thus prepared mixture was added a solution of 250 my of the above-mentioned crude alluded in 5 ml of dimethylformamide, and the mixture was stirred for 30 mix at a room temperature. After neutralization (phi) with acetic acid the mixture was concentrated. The residue was dissolved in 10 ml of pontoon and ether (1:1), and the precipitate was l filtered, and the filtrate was concentrated to give 800 my of an oily material. The oily material was purified by column-chromatography using ethyl acetate and cyclohexane (1:3) as an fluent to yield 162 my of the pure captioned product (yield; 70 I).
IR(liquid film) v : 17~0, 1700, 1670, 1630 and 1595 cm NMR(CDC13) : 1.20(3H, d, J=6.3 Ho), 1.78(3H, t, J=3.1 Ho), 1.60 to 2.60(12H), 3.67(3H, s), 3.68 (OH, m), 5.00(1H, q, J=6.3 Ho), 5.40(1H, m), 6.25 (lo, d, J=16.0 Ho) and 6.60 to 7.10(4H) Museum) : 452(M

ll-deoxy-ll-acetoxy-16-methyi-18,19-tetrade-hydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 To a stirred solution of 122 my of 11,15-dideoxy-11-acetoxy-I
I16-.Methyl-15-oxo-18~19-tetradehydro-5~6~7-trinor--interim-l¦ phenylene PGI2 in 10 ml of methanol was added 150 my of curium Al chloride heptahydrate, and then the solution was cooled in ¦¦ an ice bath, and lo my of sodium bordered was added to the ¦ solution. After 10 mint to the mixture was added 2 ml of aqueous i saturated solution of sodium hydrogen carbonate, and the mixture was further stirred for 10 min.
After concentration of the reaction mixture, 5 ml of I ethyl acetate was added to the residue, and the precipitate 10 l¦ was filtered and washed with ethyl acetate (2 x 2 ml).
¦ The combined organic layers were washed with water and aqueous ¦ saturated solution of sodium chloride, dried and concentrated give 130 my of an oily material. The oily material was purified by column-chromatography on silica gel using ethyl acetate and cyclohexane (1:2) as fluent to give 54 my of the captioned compound.
IR(liquid film) v : 3475, 1740, 1595 and 970 cm Museum) : 454(M ) Methyl ester of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 To a solution of 54 my of methyl ester of lode oxy-ll-acetoxy-16-methyl-18,19-tetradehydro-5,6,7--trinor-4,8-inter m-phenylene PGI2 in 4.5 ml of an hydrous methanol was added 0.001 ml I!

12Z6;~80 ¦ of 4.8N sodium methoxide under argon, and the reaction mixture was stirred for 1.5 hours at a room temperature.
After addition of acetic acid to the reaction mixture and concentration of the mixture, the residue was dissolved in 20 ml of ethyl acetate, and the solution was washed with aqueous saturated solution of sodium hydrogen carbonate, water and aqueous saturated solution of sodium chloride, dried and concentrated to afford 55 my of an oily material.

I This oily material was purified by column chromatography 10 ¦ using ethyl acetate and cyclohexane (3:1) as fluent to give 48 my of the captioned compound.
IR(liquid film) v : 3370, 1740, 1595, 970 and 745 cm NMR(CDC13) : 1.00(3H, dud, J=6.3 Ho), 1.80(3H, t, Joy Ho), 1.80 to 2.80(14H), 3.45(1H, t, J=7.8 Ho), 3.65 (OH, s), 4.00(2H, m), Slyly, m), 5.65(2H, m) and

6.60 to 7.00(3H) Museum) : 412(M ) 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 To a solution of 41 my of methyl ester of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenyltone PGI2 in 4.3 ml of methanol was added 1 ml of lo sodium hydroxide, and thy mixture was allowed to stand for 17 hours at 30C. Then the reaction mixture was concentrated, and 1 ml of water was added to ~;:Z6Z80 I
I
the residue. After acidification of the solution to pi 4, the mixture was extracted with three 5 ml portions of ethyl acetate.
The extract was washed with 5 ml of water and 5 ml ox aqueous I saturated solution of sodium chloride, dried and concentrated to I give 39 my of the pure carboxylic acid.
IR(liquid film) v : 3700 to 2200, 1710, 1595 and 743 cm 1 NMR(CDC13) : 1.00(3H, m), 1.79(3H, s), 1.50 to 3.00 ill (12 H), 3.35(1H, t, J=9.1 Ho), 4.00(2H, m), 5.20(4H, 10 l¦ m), 5.50(2H, m), 6.80(lH, m) and 6.90(2H, m) Mass (m/e) : 398(M ) After the oily product had been restored in a reforge-¦ rotor, it was found that the oily product crystallized extremely I slowly. The thus obtained crude crystals were fractionally recrystallized to give 15 my of 16-B-methyl isomer (mop.; 123.5 to 124C) and 10 my of methyl isomer (mop.; 92 to 94CJ.
The 16-B-methyl isomer showed the following analytical data.
IR(KBr) v : 3600 to 2400, 1740, 1680, 1595, 965, 775, 765 and 740 cm 1 NMR(CDC13) : 0.97(3H, d, J=7.2 Ho), 1.80(3H, t, J=1.5 Ho), 3.40(3H, t, J=8.3 Ho), 3.95(2H, m), 4.70 (OH, m), 5.05(lH, m), 5.60(2H, m) and 6.83(3H, m) Museum) : 398(M ) HO Museum) : 398.20850 caulked for KIWI; 398-2093 The methyl isomer showed the following analytical I¦ data.
¦ IR(KBr) v : 3600 to 2400, 1710, 1595, 970, 762 and 740 cm 1 NMR(CDC13) : 1.05(3H, d, J-7.2 Ho), 1.80(3H, t, J=1.5 Ho), 3.40(1H, t, J=8.3 Ho), 3.85(1H, m), 4.12 (lo, m), 5.10(3H, m), 5.65(2H, m) and 6.85~3H, my !
Museum) : 398(M ) l HO Mass (m/e) : 398.21347 caulked for C24H305; 398-2093 Methyl ester of 11,15-dideoxy-11-acetoxy-15-oxo-18,19-tetradehydro-5,6,7-trinor-4,8-inter-I
I m-phenylene PGI2 To a solution of 150 my of methyl 4-[2-endo-acetoxy-l-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydroo-lH-5-cyclo-penta[b]benzofuranyl]butyrate in 122 ml of a solution obtained by dissolving 0.3 ml of an hydrous pardon in 10 ml of an hydrous Bunsen were added 0.37 ml of a solution obtained by dissolving 0.14 ml of trifluoroacetic acid in 10 ml of an hydrous dim ethyl-sulfoxide and 340 my of dicyclohexylcarbodiimide. The resulting mixture was stirred for 14 hours at a room temperature, and then the deposited precipitate was removed by filtration and washed well with Bunsen. The filtrate was washed with three 3 ml portions of water, dried and concentrated to give 260 my of lZ~6Z80 ¦ crude alluded.
If In the next step, under argon atmosphere to a stirred l!¦ suspension of 118 my of sodium hydrides (55 % dispersion in mineral oil) in 10 ml of dimethylformamide, was added a solution of 689 my of dim ethyl 2-oxo-hept-5-yne-phosphonate in 10 ml of dim ethyl-formamide, and the mixture was stirred for 30 miss. To the thus ¦ prepared reaction mixture was added a solution of 260 my of the above-mentioned crude alluded in 5 ml of dimethylformamide, and I the mixture was stirred for 30 mix at a room temperature. After It neutralization (pi 7) with acetic acid, the mixture was convent-rated.
! The residue was dissolved in 10 ml of pontoon and ether (1:1), and the precipitate was filtered, and the filtrate was concentrated to give 800 my of an oily material. The oily material was purified by column chromatography using ethyl acetate and cyclohexane (1:3) as fluent to yield 116 my of the captioned compound (yield; 62 %).
IR(Liquid film) v : 1740, 1700, 1675, 1630, 1595 and 750 cm 1 NMR(CDC13) : 1.69(3H, t, J-3.1 Ho), 1.71(3H, s), 1.70 to 3.05(13H), 3.60(3H, s), 3.62(lH, m), 4.90 (lo, q, J=6.2 Ho), Lowe, m), 6.15(lH, dud, J=16.0 Ho and 2.0 Ho) and 6.50 to 7.10(4H, my Museum) : 438(M ) Methyl ester of ll-deoxy-ll-acetoxy-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Example 1, from 116 my of methyl ester of 11,15-dideoxy-11-acetoxy-15-oxo-18,19-te~radehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 56 my of the captioned compound was obtained with the following analytical data.
IT (Liquid film ) v : 3475, 1740, 1595 and 970 cm 1 Museum) : 440(M ) Methyl ester of 18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Example 2, from 56 my of methyl ester of ll-deoxy-ll-acetoxy-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 49 my of the captioned compound was obtained with the following analytical data.
IR(liquid film) v : 3370, 1740, 1595, 970 and 745 cm 1 NMR(CDC13) : 1.70(3H, t, J=3.0 Ho), 1.20 to 2.80 (15 H), 3.40(lH, t, J=7.8 Ho), 3.59(3H, s), 3.80 (lo, q, J=6.1 Ho), 4.50(1H, m), 5.05(lH, m), 5.60 (OH, m) and 6.60 to 7.00(3H) Museum) : 398(M ) 18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-ph~nylene PGI2 In a similar manner as in Example 3, from 43 my of methyl ester of 18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 41 my of the captioned compound was obtained with the following analytical data.
IR(liquid film) : 3700 to 2200, 1710, 1595, 975 and 740 cm 1 10 1 NMR(CDC13) : 1.65(3H, t, J=3.0 Ho), 1.40 to 2.80 ~14H), 3.30(1H, t, J=8.0 Ho), 3.80(1H, m), 4.20(1H, m), 5.00(1H, m), 5.10 to 5.80(4H) and 6.5 to 7.00~3H) Museum) : 384 (M ) Methyl ester of 16~methyl-2-phenylseleno-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 To a stirred solution of 0.15 ml of diisopropylamine in 10 ml of an hydrous tetrahydrofuran was added at -78C 0.7 ml of 1.5 N m-butyl lithium, and the mixture was stirred for 15 min.

To the thus prepared solution was added at -78C a solution of 90 my of16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteerr phenylene PGI2 in 2 ml of an hydrous tetrahydrofuran, and the mixture was stirred at the same temperature for 30 miss. Then, to the mixture was added a solution of 200 my of diphenyl diselenide in 1 ml of an hydrous HMPA and the whole mixture was stirred for 20 miss at -78C. Then to the mixture was added solid ammonium chloride and the resulting mixture was stirred for 20 miss at -78C and for 10 miss at a room temperature. After addition of water, the mixture was extracted three times with ether. The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried and l! concentrated to give 100 my of an oily material. The oily 1¦ material was purified by column chromatography on silica gel using ¦ ethyl acetate and cyclohexane (3:1) as fluent to afford 87 my ¦ of the captioned compound.
IR(liquid film) v : 3370, 1735, 1595 and 970 cm Mass (m/e) : 566 and 568 Methyl ester of 16-methyl-2,3-didehydro-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene To a solution of 40 my of methyl ester of 16-methyl-2-phenylseleno-18,19-tetradehydro-5,6,7-trinor-4,88-inter-m-phenylene PGI2 in 5 ml of ethyl acetate was added 0.16 ml o-f 35 aqueous hydrogen peroxide solution, and the reaction mixture was stirred for one hour at a room temperature. After addition of 1 ml of dim ethyl sulfide and 200 my of potassium acetate to the reaction mixture, the reaction mixture was stirred for 10 mix at ~L~Z6;~80 a room temperature, and concentrated under a reduced pressure.
After addition of water to the residue, the reaction mixture was extracted three limes with ethyl acetate, and the combined extracts were washed with aqueous saturated solution of sodium hydrogen carbonate, water and aqueous saturated solution of sodium chloride, dried and concentrated to give 40 my of an oily material. The oily material was purified by column chromatography on silica gel using ethyl acetate and cyclohexane (3:1) as fluent to yield 25 my of the captioned compound (yield;
890 .
IR(liquid film) v : 3350, 1710, 1650, 1595, 970 and 745 cm 1 NMR(CDC13) : 1.00(3H, dud, J=6.3 Ho), 1.80(3H, t, J= 3.1 Ho), 1.80 to 3.00(12H), 3.45(1H, t, J=7.8 Ho), 3.64(3H, s), 4.00(2H,m), 5.10(1~1, m), 5.62(3H, m) and 6.60 to 7.00(4H) Museum) : 410 (M ) Methyl ester of 2-phenylseleno-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Reference Example 10, from 80 my of methyl ester of 18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 76 my of the captioned compound was obtained.
IR(liquid film) v : 3372, 1736, 1594 and 971 cm 1 Museum) : 552 and 554 ¦ EXAMPLE 8 Methyl ester of 2,3-didehydro-18,19-tetradehydro-I
5,6,7-trinor-4,8-inter-m-plenylene PGI2 I
In a similar manner as in Example 7, from 40 my of I methyl ester of 2-phenylseleno-18,19-tetradehydro-5,6,7-trinor-¦¦ 4,8-inter-m-phenylene PGI2, I my of the captioned compound was obtained.
IT (liquid film ) v : 3350, 1710, 1650, 1595, 970 l and 745 cm 10 1 NMR(CDC13) : 1.70(3H, t, J=3.0 Ho), 1.20 to 2.81 (lush), 3.40(lH, t, J=7.6 Ho), 3.59(3H, s), 3.80(lH, ! q, J= 6.0 Ho), 4.52~lH, m), 5.05(lH, m), 5.63(3H, m) and 6.60 to 7.00(4H) Museum) : 396(M ) 2-phenylseleno=18,19-tetradehydro-5,6,7 trinor-4,8-inter-m-phenylene PGI2 To a solution of 42 my of methyl ester of phenol-seleno-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mm-phenylene PGI2 in 4 ml of methanol was added 0.8 ml of lo sodium 'hydroxide solution , and the reaction mixture was stirred or 14 hours at a room temperature. After concentration of the reaction mixture under a reduced pressure, water was added to the residue.

The reaction mixture was cooled in an ice bath, ~LZ26Z80 acidified to pi 4 with lo hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried, and concentrated to give 41 my of the pure captioned compound.
IT ( liquid film ) v : 3600 to 2200, 1700, 1595 and 965 cm 1 Museum) : 552 and 554 I¦ REFERENCE EXAMPLE 13 ~-phenylseleno-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Reference Example 12, from 40 my of methyl ester of 2-phenylseleno-18,19-tetradehyclro-5,6,7-trinor-4,8-inter-m-phenylene PI 38 my of the captioned compound was obtained.
IT ( liquid film ) v : 3600 to 2200, 1700, 1595 and 965 cm 1 Museum) : 538 and 540 16-methyl-2,3-didehydro-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 To a solution of 41 my of 16-methyl-2-phenylseleno-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenyltone PGI2 in S ml of ethyl acetate was added 0.16 ml of aqueous 35 solution of 3L2~ I

hydrogen peroxide, and the mixture was stirred for 1 hour at a room temperature. To the reaction mixture were added 1 rnl of dim ethyl sulfide and then 100 my of potassium acetate and the mixture was stirred for 10 mix at a room temperature. After concentration of the reaction mixture under a reduced pressure, water was added to the residue, and the pi of the mixture was adjusted to 6 with 0.25N hydrochloric acid under ice cooled condition. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with water and aqueous saturated solution of sodium chloride, dried, and concentrated to give, 34 my of an oily material. The oily material was purified by column chromatography on acidic silica gel using ethyl acetate and cyclone (3:1) as fluent to yield 25 my of the captioned compound.
IR(liquid film) v : 3600 to 2200, 1700, 1640, 1600 and 960 cm NMR(CDC13) : 1.10(3H), 1.82(3H, t, J=3.1 Ho), 1.80 to 3.00(13H), 3.46(1H, t, J=7.8 Ho), 4.05(4H, m), 5.11(1H, m), 5.66(3H, m) and 6.60 to 7.00(4H) Museum : 396 (M ) 2,3-didehydro-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Example 9, from 38 my of issues 2-phenylseleno-18,19-tetradehydro-5,6,7-trinor-4,88-inter-m-phenylene PGI2, 22 my of the captioned compound was obtained.
IRK liquid Him ) v : 3600 to 2200, 1700, 1640, 1600 and 960 cm ¦ NMR(CDC13) : 1.80(3H, t, J=3.1 Ho), 1.80 to 3.00 (13H), 3.45(1H, t, J=7.8 Ho), 4.00(4H, m), 5.11(1H, I
m), 5.65(3H, m) and 6.60 to 7.00(4H) ill Museum) : 382(M ) Jo REFERENCE EXAMPLE 14 10 1 Methyl ester of 11,15-dideoxy-11-acetox~-16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Reference Example 8 except for using dim ethyl 3-methyl-2-oxo-oct-5-yne-phosphonate instead of dim ethyl 3-methyl-2-oxo-hept-5-yne-phosphonate, from 150 my of methyl4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,aye, 8b-tetrahydro-lH-5-cyclopenta[b]benzofranyl]butyraate, 120 my ox the captioned compound was obtained.
IRK liquid film 1 v : 1740, 1700, 1670, 1630, 1595 and 970 cm 1 Museum) : 466(M ) lZZ6Z80 Methyl ester of ll,lS-dideoxy-ll-acetoxy-20-butyl-16-methyl-15-oxo-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Reference example 8 except !
for using dim ethyl 3-methyl-2-oxo-undec-5-yne-phosphonate instead of dim ethyl 3-methyl-2-oxo-hept-5-yne-phosphonate, from 150 my I of methyl4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,aye, i!8b-tetrahydro-lH-5-cyclopenta[b]benzofuranyl]butyrrate, 100 my 1 of the captioned compound was obtained.

I IRK liquid film) v : 1740, 1700, 1670, 1630, 1595 I and 975 cm 1 Museum : 508 Methyl ester of ll-deoxy-ll-acetoxy-16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 In a similar manner as in Example 1, from 130 my of methyl ester of 11,15-dideoxy~ll-acetoxy-1,20-dimethyl-15-oxo-18, 1 19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylenee PGI2, 58 my of the captioned compound was obtained. -1 IRK liquid film) v : 3475, 1740, 1595 and 970 cm Museum) : 468(M ) ~;~Z6Z~30 Methyl ester of 16,20-dimethyl-18,19-, tetradehydro-5,6,7-trinor-4,8-inter-m-PGI2 ¦ In a similar manner as in Example 2, from 58 my of methyl ester of ll-deoxy-ll-acetoxy-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, So my of the captioned compound was obtained.
IR(liquid film) v : 3370, 1740, 1595 and 970 cm 1 I¦ Museum) : 426(M ) 16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 .
In a similar manner as in Example 3, from 50 my of methyl ester of 16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 48 my of the captioned compound was obtained.
IR(liquid film) v : 3700 to 2200, 1710, 1595 and 975 cm 1 Museum) : 412(M ) ~Z6~80 If EXAMPLE 14 ethyl ester of ll-deoxy-ll-acetoxy-20-butyl-If 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-!' l inter-m-phenylene PGI2 I
In a similar manner as in Example 1, from 120 my of I methyl ester of 11~15-dideoxy-11-acetoxy-20-butyl-16-methyl-15-¦oxo-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phHeinlein PGI2, 50 my of the captioned compound was obtained.
I IRK liquid film ) v : 3473, 1740, 1595 and 970 cm 10 if Museum) : 510(M ) ¦ EXAMPLE 15 Methyl ester of 20-butyl-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-!
phenylene PGI2 In a similar manner as in Example 2, from So my of methyl ester of ll-deoxy-ll-acetoxy-20-butyl-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 44 my of the captioned compound was obtained.
IT (liquid film) v : 3372, 1740, 1595, 970 and 745 cm Museum) : 468(M ) 20-butyl-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 lZ;~6Z80 In similar manner as in Example 3, prom 44 my of methyl ester of 20-butyl-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, 42 my of the captioned compound was obtained.

Sodium salt of 16-methyl-18,19-tetradehydro-I
5,6,7-trinor-4,8-inter-m-phenylene PGI2 To a solution of 100 my of 16-methyl-18,19-tetra-l dehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 in methanol was added 0.25 ml of an aqueous lo solution of sodium hydroxide, and the reaction mixture was stirred for 10 mix under ice cooled condition, and concentrated to give 105 my of the captioned compound.
IR(KBr) v : 3400, 1605 and 1595 cm In a similar manner as above, from 16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 instead of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteer-m-phenylene PGI2, sodium salt of 16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 is obtained, and from bottle-20 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteer-m-phenylene PGI2 instead of 16-methyl 18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-pheny~ene PGI2, sodium salt of 20-bu-tyl-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2is obtained.

1~26Z8~) Triethanolamine salt of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 . ._ To a solution of 100 my of 16-methyl-18,19-tetra-dehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 in 5 ml of methanol was added 38 my of triethanolamine. The reaction mixture was stirred for 10 miss at a room temperature and concentrated to give 137 my of the captioned compound.
l IR(liquid film) : 3400, 1604 and 1595 cm 1 10 ¦ In a similar manner as above, from 16,20-dimethyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 instead of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inteer-m-phenylene PGI2, the triethanolamine salt of 16,20-dimethyl-18,19-tetra-dehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 is obtained and fro m 20-butyl-16-methyl-18,19-tetradehydro-5,6,7-trinorr-a,8-inter-m-phenylene PGI2 instead of 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2, the triethanolamine salt of 20-butyl-16-methyl-18,19-tetradehydro-5,6,7-trinorr-4,8-in-ter-m-phenylene PGI2 is obtained.

buttonhole A mixture of 250 g of 1,3-dichloro-2-butene and 1.25 liters of aqueous 10 % by weight solution of sodium carbonate was reflexed for 3 hours and then cooled. The reaction mixture was extracted three times with ether, and the extract was dried.
The ether was distilled off at atmospheric pressure using Wider column, and then the residue was distilled under :

lzæ6Z8 I¦ reduced pressure to give 134 g of 3-chloro-2-buten-1-ol by 58 - 60C/8 mmHg).
Jo In the next step, into a flask provided with a Doria-¦ condenser was introduced 3 liters of liquid ammonia, and 1.5 g Jo of ferris nitrate was added to the liquid ammonia with stirring i and then 65 g of metallic sodium was added in several points.
To the mixture was added over 30 miss 134 g of the above-mentionec 1 3-chloro-2-buten-1-ol, and the mixture was stirred for 14 hours.

i After addition of 148 g of ammonium chloride, the mixture was 10 1 stirred for 30 miss, and the ammonia was removed from the i reaction mixture.
Then, the residue was extracted five times with ether, i and the ether was distilled off using Vigreaux column, and the residue was distilled under reduced pressure to give 66 g of i buttonhole by 55C/8 mmHg).
IR(liquid film) v : 3350, 2230, 1145 and 1050 cm 1 NMR(CDC13) : 1.84(3H, t, J=3.0 Liz), 2.60(1H, s) and 4.24(2H) l REFERENCE EXAMPLE 17 1-bromo-2-butyne To a solution of 63 g of buttonhole in 250 ml of an hydrous ether was added 5 ml of pardon, and the solution was stirred at -30C. To the thus cooled solution was added drops 86 g of phosphorus tribromide, and the mixture was stirred for 2 hours at -30C. Then, the temperature of the 'I

l I

reaction mixture was raised to 20C over 3 hours and stirred for 30 miss at 40C. The mixture was poured into 500 ml of an aqueous saturated solution of sodium chloride, and upper layer was i separated from aqueous layer. The aqueous layer was extracted with a small amount of ether and the combined ethereal solution was dried. The ether was distilled off through a 40 cm-Widmer ¦ column under atmospheric pressure, and then the residue was distilled under reduced pressure to yield 95 g of l-bromo-2-butane (60C/80 mug lo I IR(liquid film) v : 2240, 1220 and 1210 cm ~MR(CDCl3) : 1.85(3H, t, J=3.0 Ho) and 3.90(2H, m) Dim ethyl 3-methyl-2-oxo-hept-5-yne-phosphonate To a solution of 30 g of diisopropylamine in 186 ml of an hydrous tetrahydrofuran was slowly added at -20C 182.3 ml of l.51N n-butyl lithium, and the mixture was stirred at the !
same temperature for 20 miss. Then, to the mixture were slowly added drops at -20 to -10C 12 g of prop ionic acid and 25 ml of HMPA. The temperature of the reaction mixture was raised to a room temperature and the mixture was stirred for 40 miss, and then 16.7 g of l-bromo-2-butene was added drops at 0C to the mixture. After being stirred for 2 hours, the mixture was poured into 130 ml of aqueous lo % solution of hydrochloric acid, and the mixture was extracted three times with mixture of ether and pontoon (1:1). The combined organic layers were washed with water, dried and concentrated to give an oily material. The thus obtained oily material was esterified by the addition of an excess of ethereal solution of diazomethane.
After concentration of the mixture, the residue was distilled under reduced pressure to yield 10.4 g of the ester (60 to clue mmHg).
Next, to a solution of 18 g of dim ethyl methane-phosphonate in 294 ml of an hydrous tetrahydrofuran was added at -78C 86 ml of n-butyl lithium N), and the mixture was stirred for 20 miss. To the thus prepared reaction mixture was added a solution of 10.4 g of the above-mentioned ester in 20 ml of an hydrous tetrahydrofuran. Then, the mixture was stirred for 15 miss at -78C and for 1 hour at a room temperature and 300 ml of ether was added. The solution was washed with 150 ml of aqueous saturated solution of oxalic acid, 15n ml of water and 50 ml of aqueous saturated solution of sodium chloride and condensed. The residue was distilled under a reduced pressure to give 14.7 g of dim ethyl 3-methyl-2-oxo-hept-5-yne-phosphonate (138 to 142C/0.62 mmHg).
IR(liquid film) v : 3450, 1715r 1255 and 1030 cm NMR(CDC13) : 1.15(3H, d, J=6.0 Ho), 1.75(3H, t, J=3.0 Ho), 2.35t2H, m), 2.90(1H, m), 3.20(2H, d, J=18.8 Ho), 3.75 (OH, s) and 3.80(3H, s) Dim ethyl 2-oxo-hept-5-yne-phosphonate 1~6;~80 To a stirred solution of 7.78 g of diisopropylamine in US ml of an hydrous tetrahydrofuran was added at -10C 49 ml of n-butyl lithium (1.59N). The mixture was stirred for 20 miss at 0C. To the thus prepared reaction mixture was added drops at 0C 2.34 g of acetic acid, and the mixture was stirred for 40 miss at 30 to 35C. To the mixture were added drops at 0C 6.1 ml of HMPA and further 4 g of l~bromo-2-butene.
After stirring for 14 hours at a room temperature, the mixture was poured into 25 ml of aqueous 10 % hydrochloric acid solution, and the mixture was extracted three times with mixture of pontoon and ether (1:1). The organic layer was washed with water, dried and concentrated to give an oily material. The oily material was methylated by addition of an excess of a solution of diazomethane in ether. The reaction mixture was concentrated and distilled under reduced pressure to yield 1.6 g of an ester (boiling at 66 to clue mmHg).
To a solution of 3.2 g of dim ethyl methanephosphonate in 52 ml of tetrahydrofuran was added at -78C 155 ml of n-butyl lithium (1.59N) and the mixture was stirred for 25 miss at -78C. To the mixture was added at -78C a solution of 1.6 g of the above-mentioned ester in 3.2 ml of tetrahydrofuran.
The mixture was stirred for 15 miss and for one hour at room temperature. After addition of 100 ml of ether to the reaction mixture, the mixture was washed with 30 ml of aqueous saturated solution of oxalic acid, 50 ml of water and 40 ml of aqueous lX~:6;~8~

saturated solution of sodium chloride. The washed mixture was dried and concentrated to give an oily material. The oily material was distilled under reduced pressure to yield 2.2 g of dim ethyl 2-oxo-hept-5-yne-phosphonate (143 to 146C/0.7 mmHg).
IR(liquid film) v : 3450, 1720, 1250 and 1040 cm 1 NMR(CDC13) : 1.75(3H, t, J=3.0 Ho), 2.45(2H, m), 2.80 (OH, m), 3.15(2H, d, J=18.8 Ho), 3.72(3H, s) and 3.85(3H, s) 10 i (+)-7-bromo-3a,8b-cis-3a,8b-dihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid In 30 ml of a mixture of methanol and water (1:1) were dissolved by heating 1.00 g (3.56 Molly) of -Brigham-3a,8b-cis-3a,8b~dihydro-3H-5-cyclopenta[b]benzofurrancarboxylic acid and 0.78 g (3.56 Molly) of (-)-(cis-2-benzylaminocyclohexyl) methanol. The solution was cooled to a room temperature, seeded with the salt of the captioned compound with (-)-(cis-2-benzyl-aminocyclohexyl)methanol, and allowed to stand for 24 hours.
The thus obtained crystals were filtered and recrystallized from 30 ml of a mixture of methanol and water to give 0.68 g of the salt of the captioned compound with (-)-(cis-benzyl-aminocyclohexyl)methanol (mop.; 184 to 185C, yield; 76 I, Do = + Claus, in methanol)).

Z6~80 After addition of 50 ml of ethyl acetate and 150 ml of lo aqueous hydrochloric acid solution to the crystals, the layer of ethyl acetate was washed with water and concentrated to yield 0.37 g of the captioned compound (mop.; 207 to 209 (sublimation), [x]22 = + 174(C = 0.4, in methanol), yield;
74 %).

(-)-7-bromo-3a,8b-cis-3a,8b-dihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid In 100 ml of a 2:1 by volume mixture of methanol and water were dissolved by heating 2.00 g (7.1 Molly) of (+)-7-bromo-3a,8b-cis-3a,8b-dihydro-3H-5-cyclopenttaEb]benzofuran-carboxylic acid and 2.09 g (7.1 Molly) of cinchonidine. The solution was cooled to a room temperature, seeded with sunken-dine salt of the captioned compound, and allowed to stand for 24 hours. The thus precipitated crystals was collected by filtration and recrystallized from 30 ml of the mixed solvent of methanol and water to give Lyle g of the cinchonidine salt of the captioned compound (yield; 49 %, mop.; 194 to 195C, [ ED = -118(C = 1.0, in methanol)).

The thus obtained crystalline salt was dissolved in 20 ml of ethanol, and after addition of 3.5 ml of aqueous lo hydra-caloric acid solution to the solution, the ethanol was distilled off. To the thus obtained residue were added 20 ml of ethyl acetate and 20 I of loon hydrochloric acid The organic layer 1 ~26280 was collected, washed with water and concentrated to yield 0.48 g of the captioned compound (yield; 48 %, mop.; 207 to 209 C

(sublimation); Do = -174 (C = 0.4, in methanol))-(+)-16-methyl-18,19--tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 By following Reference Examples 1 to 8 and Examples 1 to 3, from S g of (-)-7-bromo-3a,8b-cis-3a,8b-dihydro-3H-5-l cyclopenta[b]benzofurancarboxylic acid as the starting material, 3 my of the captioned compound is obtained.
IR(liquid film) v : 3700 to 2200, 1710, 1595 and 743 cm 1 MNR(CDC13) : 1.00(3H, m), 1.79(3H, s), 1.50 to 3.00(12H), 3.35(1H, t, J=9.lHz), 4.00(2H, m), 6.80(lH, m) and 6.90(2H, m) Museum) : 398 (M ) (-)-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 By following Reference Examples 1 to 8 and Examples 1 to 3, from 5 g of (+)-7-bromo-3a,8b-cis-dihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid, 3.4 my of the captioned compound is obtained.

l;~Z6;~80 IR(liquid film) v : 3700 to 2200, 1710, 1595 and 743 cm NMR(CDC13) o: 1.00(3H, m), 1.79(3H, s), 1.50 to 3.00(12H), 3.35(lH, t, J=9.1 Ho), 4.00(2H, m), 6.80 (lo, m) and 6.90(2H, m) Mass (m/e) : 398 (M ) if EXAMPLE 21 , (+)-18,19-tetradehydro-5,6,7-trinor-4,8~inter-m-phenylene PGI2 , I .
10 I By following Reference Examples 1 to 7 and 9 and Examples 4 to 6, from 5 g of (-)-7-bromo-3a,8b-dihydro-3H-5-cyclopenta[b] benzofurancarbOxylic acid, 3.2 my of the captioned If compound is obtained.
Jo IR(liquid film) v : 3700 to 2200, 1710, 1595, 975 and 740 cm 1 NMR(CDC13) : 1.65 (OH, t, Jo 0 Ho), 1.40 to 2.80 (14H), 3.30(lH, t, J=8.0 Ho), 3.80(iH, m), 4.20(lH, m), 5.00 (lo, m), 5.10 to 5.80 (OH) and 6.50 to 7.00 (OH) Mass (m/e) : 384(M ) (-)-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 By following Reference Examples 1 to 7 and 9 and Examples 4 to 6, from 5 g of (+)-7-bromo-3a,8b-cis-3a,8b-dihydro-3H-S-cyclopenta[ blbenzofurancarboxylic acid, 3.1 my ~2~80 ¦¦ of the captioned compound is obtained.

!1IR(liquid film) v : 3700 to 2200, 1710, 975 and 740 cm 1 NMR(CDC13) : 1.65(3H, t, J=3.0 Ho), 1.40 to 2.80 ¦(14H), 3.30(1H, t, J=8.0 Ho), 3.80(1H, m), 4.20 (lo, m), 5.00 (lo, m), 5.10 to 5.80(4H) and 6.50 to

7.00 (OH) assume) : 384(M ) 10 1(+)-16(S)-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 By following Reference Example 8 and Examples 1 to 3, from 2.2 g of methyl ester of (+)-4-~2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro-lH-5--cyclopenta[b]
benzofuranyl]butyrate and 2.2 g of dim ethyl 3(S)-3-methyl-2-oxo-kept 5-yne-phosphonate having a specific rotation of +29.8 Do (C = 4.5, in ethanol)), ~50 my of the captioned compound was obtained in a crude state. The crude product was recrystallized from ethyl acetate and hexane to yield 112 my of the pure compound (mop.; 64 to 66C).

IR(Kbr) v : 3700 to 2200, 1712, 1595, 1255, 1235, 1195 1155, 1105, 1095, 1075, 1035, 1015, 1000, 962, 865, 835, 765 and 745 cm NMR(CDC13) : 0.97(3H, d, J=7.2 Ho), 1.08(3H, t, J=
1.5 Ho), 3.40(3H, t, J=8.3 Ho), 3.95(2H, m), 5.00(4H, læz6zs m), 5.60(2H, m), 6.75(1~, m) and 6.70(2H, m) C NMR(CDC13) : 3.521 15.737 22.401 24.622 29.118 38.193 41.119 50.246 5i3.806 75.627 77.036 77.198 78.471 84.214 120.565 121.865 123.274 128.962 129.666 133.350 134.054 and 157.268 Museum) : 398(M ) Do (C = 0.7, methanol) : + 120.6 (+)-16(R)-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 By following Reference Example 8 and Examples 1 to 3, from 200 my of methyl (+)-4-~2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2~3~3a,8b-tetrahydro-lH-5-cyclopenta[b]bbenzofuranyl~
bitterroot and 230 my of dim ethyl 3(R)-3-methyl-2-oxo-hept-5-yne-phosphonate having a specific rotation of -28.6([~]22 (C = 4.8, in ethanol)), 47 my of the captioned compound was obtained.

IR(liquid film : 3~00 to 2400, 1710, 1595, 970, 762 and 740 cm 1 H NMR(CDC13) : 1.05(3H, d, J=7.2 Ho), 1.80(3H, t, J=1.5 Ho), 3.40(lH, t, J=8.3 Ho), 3.85(lH, m), 4.12 (lo, m), 5.10(3H, m), 5.65~2H, m) and 6.85(3H, m) Museum) : 398(M ) Do (C = 0.47, methanol) : + 110.3

Claims (2)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing a compound of the formula:

(I) wherein R1 is a pharmaceutically acceptable cation, a hydrogen atom or a n-alkyl group of 1 to 12 carbon atoms;
R2 is a hydrogen atom, an acyl group of 2 to 10 carbon atoms or an aroyl group of 7 to 13 carbon atoms; R3 is a hydrogen atom, an acyl group of 2 to 10 carbon atoms or an aroyl group of 7 to 13 carbon atoms; R4 is a hydrogen atom, a methyl group or an ethyl group; R5 is a n-alkyl group of 1 to 5 carbon atoms; n is an integer of 0 to 4;
A is -CH2-CH2- or trans -CH=CH-; and X is -CH2-CH2- or trans -CH=CH-, which comprises reacting a compound of the formula:

wherein R1, R2 and A have the same meaning as defined above except that R2 is other than hydrogen, with an alkali metal salt of dialkylphosphonic acid ester of the formula:

wherein R4, R5 and n are the same as defined above and R6 is an alkyl group, to form a compound of the formula (IV):

(IV) and i) in case of producing a compound of the formula (I) wherein A represents the group of -CH2-CH2-, R2 and R3 represent the hydrogen atom and X represents the group of trans -CH=CH- the process being further characterized by reducing the above compound (IV) to form a compound of the general formula (V):

wherein R 1, R 2, R 4, R5 and n have the same meaning as de-fined above provided that R2 does not represent a hydrogen atom, and converting the compound (V) into a compound of the formula (VI):

(VI) wherein R1, R4, R5 and n have the same meaning as defined above, respectively, ii) in case of producing a compound of the formula (I) wherein A represents -CH2-CH2- and R1, R2 and R3 represent a hydrogen atom, respectively, the process being further characterized by reducing, when required, the com-pound (IV) wherein A is -CH2-CH2- to form a compound of the formula (VII):

(VII) and hydrolyzing a compound (VI) or (VII) wherein R1 and R2 are other than hydrogen to a compound of the formula (VIII):

(VIII) wherein R4, R5 n and X have the same meaning as defined in the formula (I), respectively, iii) in case of producing a compound of the formula (I) wherein R1, R2 and R3 represent a hydrogen atom, respectively, and A represents trans -CH=CH-, the process being further characterized by converting the compound (VI) or (VII) into a compound of the formula (IX) (IX) wherein R4, R5, n and X have the same meaning as defined in the formula (I), respectively, and removing the phenyl-seleno group of the above compound (IX) to form a compound of the formula (x):

(X) wherein R4, R5, n and X have the same meaning as defined in the formula (I), respectively, iv) in case of producing a compound of the formula (I) wherein R1 represents a normal alkyl group of 1 to 12 carbon atoms, the process being further characterized by converting the compound (IV) into a compound of the formula (XI):

(XI) wherein R2, R3, R4, R5, n, A and X have the same meaning as defined in the formula (I), respectively, and esteri-fying the above compound (XI) to form a compound of the formula (XII):

(XII) wherein R1 represents a normal alkyl group of 1 to 12 carbon atoms and R2, R3, R4, R5, n, A and X have the same meaning as defined in the formula (I), respectively, v) in case of producing a compound of the formula (I) wherein R2 and R3 represent the same acyl group or aroyl group, the process being further characterized by converting a compound (IV) into a compound of the formula (XIII):

(XIII) wherein Rl, R4, R5, n, A and X have the same meaning as defined in the formula (I), respectively, and converting the above compound (XIII) into a compound of the formula (XIV):

(XIV) wherein Rl, R4, R5, n, A and X have the same meaning as defined in the formula (I), respectively, and R2 and R3 represent the same acyl or aroyl groupr and vi) in case of producing a compound of the formula (I) wherein X represents -CH2-CH2-, Rl represents a methyl group and A represents -CH2-CH2-, the process being fur-ther characterized by reducing a compound (IV) wherein R1 represents the methyl group, A represents -CH2CH2- and R2, R4, R5 and n have the same meaning as defined in the formula (I) provided that R does not represent a hydrogen atom, to form a compound of the formula (XV):

(XV) wherein R2, R4, R5 and n have the same meaning as defined in the formula (I) provided that R2 does not represent a hydrogen atom, and, when required, converting the above compound (XV) into a compound of the formula (XVI):

(XVI):

wherein R2, R3, R4, R5 and n have the same meaning as defined in the formula (I), respectively.

2. The compound of formula (I) as defined in claim 1 whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.