CA1072956A - Pharmaceutically useful prostenoic acid derivatives - Google Patents

Abstract

ABSTRACT

Prostenoic acid derivatives of formula (I) wherein:
A represents an ethylene group or a cis-vinylene group;
R1 and R2 may be the same of different and each represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
R3 and R4 may be the same of different and each represents an alkyl group having from 1 to 3 carbon atoms; and R5 represents a hydrogen atom or a hydroxyl group;
and pharmaceutically acceptable salts thereof, useful medically as anti-ulcerogenic and bronchodilating agents, are prepared by oxidizing the corresponding 9? -hydroxy-15?-(protected hydroxy)-20-alkylideneprost-13(trans)-enoic acid derivatives.

Description

This invention relates to prostenoic acid delivatives which are u~eful pharm~ceutic~lly a~ anti-ulcerogenic and bronchodilatin~r agents .

The invention provides prostenoic acid derivatives having the formula O ,.
\ A ~C oOR2 R~l/\~ R~5 ( 1.) wherein:
A represents an ethylene group or a cis-vinylene group;
R and R may be the same or different and each represents a hydrogen atom or an alkyl group having fForn 1 to 3 carbon atoms;
R and R may be the same or different and éach represents an alkyl group having from 1 to 3 carbon atoms; and R represents a hydrogen atom or a hydroxyl group;
and pharmaceutically acceptable salts thereof.

In. formula (I), each of R and R is preferably a hydrogen atom or a methyl, ethyl, n-propyl or isopropyl group; and each of R3 and R is preferably a methyl, ethyl, n-propyl or isopropyl group, (1) ~
, '' '.

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In formula (I), and elsewhere in this Specification, a bond attached to the cyclopentane nucleus which is in the ~-configuration (i, e. extends below the plane of the cyclopentane ring as depicted) is represented by a broken line, and a bond which is in the ~-configuration (i. e. extends above the plane of the cyclopentane ring as depicted) is represented by a solid line. A wavy line indicates that either steric configuration is possible. The individual isomers of the compounds of formula (I) and of the pharmaceutically acceptable salts thereof, as well as their racemic mixtures, are included within the scope of the inventiGn.

The compounds of formula (I) wherein R represents a hydrogen atom can be salified by the conventional techniques, to form pharma-ceutically acceptable salts. These include alkali and alkaline earth metal salts (e. g. the sodium, potassium, magnesium and calcium ~alts), the ammonium salts, quaternary ammonium salts (e. g. the tetramethylammoniurn, tetraethylammonium, benzyltrimethyl-arnmonium and phenyltriethylammonium salts), aliphatic, alicyclic or aromatic amine salts (e. g. the methylamine, ethylamine, dimethylamine, diethylamine, trirnethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine and ethylenecliamine salts), heterocyclic amine salts (e. g. the piperidine, morpholine, pyrrolidine, piperazine, pyridine, l-methylpiperazine and 4-ethylmorpholine salts), and salts s)f amines which contain a hydrophilic group (e. g, the monoethanolamine, ethyldiethanolamine and 2-amino-1-butanol salts).

(2) :

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, The following is a non-limiting listofspecificexamples ofthe compounds provided bytheinvention:-(1) 9-Oxo-11a,15a(or ~)-dihydroxy-20-isopropylideneprost-13(trans~-enoic aci.d, and methyl, ethyl, n-propyl and isopropyl esters o~ the same (2) 9-Oxo-11a,15(or ~)-dihydroxy-20-isopropylideneprost--5(Cis)~13(trans)-dienoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(3) 9-Oxo-11a,15a(or ~)-dihydroxy-17~-methyl-20-isopropyli.deneprost-13(trans)-enoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(4) 9-Oxo-11a,15a(or ~)-dihydroxy-17~-methyl-20-isopro-pylideneprost-5(cis),13(trans)-dienolc acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(5) 9-Oxo-11a,15~(or ~)-dihydroxy-17~-methyl-20~
methyl)-isopropylideneprost-13(trans)-enoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(6) 9 Oxo-11a,15a(or ~)-dihydroxy-17~-methyl-20~
methyl)-isopropylideneprost-5(cis),13(trans)-dienoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(7) 9-Oxo-11~,15~(or ~)-dihydroxy-17~-methyl-20-(1',3'-dimethyl)-isopropylideneprost-13(trans)-enoic acid, and ~ethyl, ethyl, n-propyl and isopropyl esters of the same

(8) 9-Oxo-11a,15a(or ~)-dihydro~y-17~-methyl-20-(1',3'-dimethyl)-isopropylideneprost-5(cis)~13(trans) dienoic acid, and methyl~ ethyl, n-propyl and isopropyl esters o~ the same (3) ' Z~

(9) 9-Oxo-11~15~(or ~)-dihydroxy-20-(1'-methyl)-isopro-pyli.deneprost-13(trans)-enoic acid, and methyl, ethyl, n-propy7 and isopropyl esters of th.e same

(10) 9-Oxo-11~,15~(or ~)-dihydroxy-20 (1'-methyl)-lsopro-pylideneprost-5(cis),13(trans)-dienoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(11) 9-Oxo-11,15a(or ~)-dihydroxy-20-(1',3'-dimethyl)-isopropylideneprost-13(trans)-enoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(12) 9-Oxo-11a,15a(or ~)-dihydroxy-20-(1',3'-dimethyl.)-isopropylideneprost-5(cis),13(trans)-dienoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(13) 9-Oxo-15(or ~)-hydroxy-20-isopropylideneprost-13(trans)-enoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(14) 9-Oxo-15(or ~)-hydroxy-17~-methyl-20-isopropyli-deneprost-13(trans)-enoic acid, and methyl, ethyl, n-propyl and isopropyl .esters of the same

(15) 9-Oxo-15a(or ~)-hydroxy-20-isopropylideneprost-5(cis),13(trans)-dienoic acid, and methyl, ethyl, n-propyl and isopropyl esters of the same

(16) 9-Oxo-15(or ~)-hydroxy-17~-methyl-20-isopropyli-deneprost-5(cis)~13(trans)-dienoic acid, and methyl., ethyl, n-propyl and isopropyl esters of the same (4) l~qZ~5~;

We have discovered that the compounds provi~ed by the present invention are potent inhibitors of gastric secretion and have strong bronchodilating activity, whilst exhibiting little or no hypotensive or intestinal-contracting activity. By virtue of these properties, the compounds are useful medically as anti-ulcerogneic and bronchodilating agents, The pharmacological properties of the compounds of the invention are comparéd with those of known compounds in the following tests.

(1) Inhibition of gastric secretion Two of the compounds of the invention and the known compound prostaglandin El were tested, employing essentially the same method as described by M. N. Ghosh and H, O, Schild in the British Journal of Pharmacology and Chemotherapy, Vol. 13, Pages 54-61 (1958)~
A solution of physiological saline containing a small amount of sodium hydroxide was perfused at the rate of 1 ml/min. through the stomach of a male rat (Donryu strain) anaesthetized with urethane;
and then 10 ~g/kg/hr of the gastric secretion stimulating agent tetragastrin was injected continuously into a vein of the rat until the outflowing perfusate had stabilized at about pH 3, The test compound was then injected into the vein of the rat for 30 minutes, and the pH of the outflowing perfusate was measured. The measure-ment was repeated at different concentrations of the test compound.
Table 1 shows the intravenous dose of each test compound needed to increase the p~I by a value of 1. O, (5) . ' : ' .

- ~IO~Z~5t;
Table 1 Test Compound Dose (mg/kg/hr) Compound A 0. 074 Compound B 0. 070 Prostaglandin El 0. 086 Compound A 9-oxo~ ,15a-dihydroxy-17~-methyl-20-isopropylideneprost -1 3(trans ) -enoic acid.

Compound B: 9-oxo-lla, 15~-dihydroxy-17,B-methyl-20-isopropylideneprost - 5(cis ), 1 3(trans ) -dienoic acid.

From these results, it will be seen that compounds A and B
are at least as potent inhibitors of gastric secretion as prostaglandin El; but, on the other hand, our investigations have shown that the compounds of the invention exhibit an oxytocic acticity only about 0. 5% as strong as that of prostaglandin El. Thus, the compounds of the invention possess medically useful properties not shared by the natural prostaglandins.

(2) Bronchodilating activit;y The activity of five of the compounds of the invention was compared with that of prostaglandins El and E2, and the known bronchodilating - agents isoprenaline and salbutamol. The test compounds were administered by intravenous injection to guinea pigs (body weight:
~00-600 g) anaesthetized with pentobarbitone sodium, and 2-3 ,(Jg/kg (6) : - ..... .. . . :
- , . ~ . . ~ ., of histamine was also administered by intravenous injection. The inhibitory ratio of the increase in air-way resistance was determined by a variant of the Konzett-R'ossler method - Archiv f~r Experimen-telle Pathologie und Pharmakologie, Vol. 195, Page 71 (1940~, The 50% inhibition dose (ID50) was calculated for each test compound, and the results are shown in Table 2. The results shown in parentheses are for 95% confidence limits.

Table 2 Test Compound ` ID50 (~/kg. i. r. ) Compound A 0. 019 (0, 026 - 0, 015) Compound B 0. 014 (0, 019 - 0, 010) Compound C 0, 032 (0, 048 - 0, 022) Compound D 0, 021 (0, 035 - 0, 013) Compound E 0. 039 (0. 056 - 0. 028) Prostaglandin E1 0, 14 (0. 19 - 0, 11) Prostaglandin E2 0, 21 (0, 28 - 0. 16) Isoprenaline 0, 08 (0. 14 - 0. 05) Salbutamol 0. 042 (0, 058 - 0, 031) Compound A: As in Table 1 Compound B: As in Table 1 Compound C: 9-oxo-15a-hydroxy-20-isopro-pylideneprost - 1 S(trans ) -enoic acid Compound D: 9-oxo-15a-hydroxy-20-isopro-pylideneprost - 5( cis ),13 -(_a s)-dienoic acid (~7) lO~Zg~

Compollnd 13: ~3 oxo-llcY, 15~x-dihydroxy-20-isopropylideneprost - 5(cis ), 1 3(trans )-dienoic acid Our investigations show that the bronchodilating activity of the compounds of the invention is not inhibited by ,B-adrenergic blocking agents which inhibit the activity of salbutamol and isoprenaline.

Accordingly, the compounds of the invention are useful medically as gastric secretion inhibitors and bronchodilators; and the invention provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier or diluent. The pharmaceutical compositions of the invention can be formulated in the conventional manner, using known pharmaceutical carriers and diluents, and optionally also pharmaceutical adjuvants, of a type suited to the intended mode of administration. Frequently, compositions in unit dosage form are preferred.

When the compounds of the invention are used as gastric secretion inhibitors, they are generally administe red orally, or parenterally by intravenous, subcutaneous or intramuscular injection, Examples of formulations suitable for this purpose are tablets, granules, capsules and injections. The posology will vary with the body weight, age and condition of the patient, and the method of administration, but the daily dose for adults is generally from 0.1 to 15 mg.

(8) , . .. , . . . ~ ~ .
:

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When the compounds of the invention are used as bronchodilators, they are gencrally administered by inhalation from an aerosol spray.
Such an aerosol spray can be formulated with the conventionally used pharmaceutically acceptable aerosol propellants, Once again, the posology depends on the age, body weight and condition of the patient, but the daily dose for adults is generally from 20 to 150 ~g.

In accordance with the invention, the compounds of formula (I) and their pharmaceutically acceptable salts can be prepared by oxidizing a compound of formula OH

\ ~ C OOR2 ,~)? R5~ R3 (II) oR6 R

(wherein A, R, R, R and R have the meanings previously given;
R represents a hydrogen atom or the group -OR; and R rep,resents a hydroxyl-protecting group) to produce a compound having the formula O ..

\A /~\/\cooR2 (III) R5 \~(/ ~=< R4 oR6 R1 i A Rl R2 R3 R4 R5 and R6 have the meanings previouslY
given), removing any hydroxyl-protecting groups from the resulting product and, if appropriate, salifying the product of formula (I) thus (9) 1~7~9~6, obtained to produce a pharmaceutically acceptable salt thereof.

In formulae (II) and (III), R6 may be any hydroxyl-protecting group which can subsequently be removed so as to leave a free hydroxyl group without affecting other parts of the molecule. For example, it may be a 5- or 6-membered heterocyclic group containing oxygen or sulphur as the hetero-atom and which may optionally be alkoxy-substituted, for example 2-tetrahydrofuranyl, 2-tetrahydro-pyranyl, 2-tetrahydrothienyl, 2-tetrahydrothiopyranyl or 4-methoxy-tetrahydropyran-4-yl; it may be a straight or branched alkyl group containing from 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n pentyl or isopentyl; it may be a straight or branched alkoxyalkyl group containing from 1 to 5 carbon atoms in the alkyl moiety, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, n-pentoxymethyl, isopentoxymethyl, l-ethoxyethyl, l-ethoxypropyl, 2-ethoxybutyl or l-ethoxypentyl; it may be a trialkyl-silyl group containing from 1 to 5 carbon atoms in each alkyl moiety~for example trimethylsilyl, triethylsilyl, tri-n-propylsilyl, tri-i60propylsilyl, tri-n-butylsilyl, tri-isobutylsilyl or tri-n-pentylsilyl;
or it may be a carbonic acid ester residue of formula XOC0- (IV) wherein X represents a straight or branched alkyl group containing from 1 to 5 carbon atoms (e. g, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n pentyl), an ethyl group substituted with from 1 to 3 halogen atoms ~t the ,B-position (e. g. 2, 2, 2-trichloroethyl, 2, 2-dibromoethyl or 2-iodoethyl), a phenyl or substituted phenyl group (10~

.

(e, g. phenyl, 4-nitrophenyl, 2-chlorophenyl or '', 4-dichlorophenyl), or an aralkyl group comprising a substituted or unsaubstituted aromatic ring and an alkylcne moiety having from 1 to 5 carbon atoms (e. g. benzyl, phenethyl, phenylpropyl, phenylbutyl, phenyl-pentyl, 4-nitrobenzyl or 4-chlorophenethyl). Other hydroxyl-protecting groups can also be used.

In the first step of the process of the invention, the compound of formula (III) is produced by treating the compound of formula (II) with an oxidizing agent, optionally in the presence of a solvent.
Preferred examples of oxidizing agents are those of the chromic acid type, such as chromic anhydride, chromic anhydride/pyridine complex (Collins reagent), chromic anhydride/aqueous sulphuric acid (Jones reagent), sodium dichromate or potassium dichromate; organic active halogen compounds, such as N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-chloro-p-toluenesulphonamide and N-chloro-benzenesulphonamide; aluminium aloxides, such as aluminium t-butoxide and aluminium isopropoxide; dimethylsulphoxide/dicyclo-hexylcarbodiimide; and dimethylsulphoxide/acetic anhydride.

If a sol~ent is employed, its choice is not particularly critical, so long as it is inert to the reaction, When using oxidizing (11) il)7'~9~i~

agents of the chromic acid type, the preferred solvents are organic acids and mixtures of organic acids with organic anhydrides (e. g.
acetic acid, or acetic acid/acetic anhydride), or halogenated hydro-carbons (e. g, dichloromethane, chloroform or carbon tetrachloride).
When using organic active halogen compounds as oxidizing agents, aqueous organic solvents are preferred, such as aqueous t~butanol, aqueous acetone or aqueous pyridine, When using aluminium a~oxides as the oxidi~ing agents, the preferred reaction solvents are aromatic hydrocarbons (e. g. benzene, toluene or xylene), and the reaction is also preferably performed in the presence of an excess of a hydrogen aeceptor (e. g. a ketone, such as acetone, methyl ethyl ketone, eyelohexanone or benzoquinone): the reaction system should also be eompletely free from water. If the oxidizing agent is dimethyl-~ulphoxide/dicyclohexylcarbodiimide or dimethylsulphoxide/acetic anhydride, an excess of the dimethylsulphoxide can be used as solvent, no other solvent generally being needed; and, when dimethylsulphoxide/di-eyclohexylcarbodiimide is employed, it is preferred to add a :atalytic amount of an acid (e. g, phosphoric or acetic acid), in the conventional manner.

ao The preferred oxidizing agents are those of the chrornic acid type, especially chromic anhydride/pyridine complex (Collins reagent) and chromic anhydride/aqueous sulphuric acid (Jones reagent).

The reaction temperature is not particularly critical, but it is preferred to perform the oxidation at a relatively low temperature, ( 1 2) i so as to suppress side-reactions Temperatures from -20 C to roorn temperature are generally suitable, and those from 0C lo room temperature are preferred. The reaction time will depend on the reaction temperature and the type of oxidizing agent employed, but it is generally from about 5 minutes to 2 hours.

After completion of the reaction, the product of formula (III) can be recovered from the reaction mixture by conventional techniqwes.
For example, an organic solvent such as ether is added to the reactio mixture, insolubles are removed, the organic phase is washed and dried, and the solvent is evaporated off, leaving the compound of formula (III). If necessary, the product thus obtained can be further purified by conventional techniques, for example by column chromatography or thin-layer chromatography.

The hydroxyl-protecting group R can be removed from the compound of formula (III) by conventional techniques as appropriate to the nature of this protecting group.

Thus, when the hydroxyl-protecting gxoup is a heterocyclic group such as 2-tetrahydropyranyl, an alkoxyalkyl group such as methoxymethyl, or an alkoxycycloaLkyl group such as l-methoxycyclo-hexyl, it can readily be removed by treating the compound of formu,a (III) with an acid, for example an organic acid such as formic, acetic, (13) l~q'~6 propionic, butyric, oxalic or malonic acid, or a mineral acid such as hydrochloric, hydrobromic or sulphuric acid. The reaction can be carried out in the absence of any solvent, but the presence of a solvent is preferred because the reaction then proceeds more smoothly.
The choice of solvent is not critical, provided that it is inert to the reaction; but preferred solvents are water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and mixtures of such organic solvents with water. The reaction temperature is not particularly critical, and may suitably be between room temperature and the reflux temperature of the solvent, if one is employed.

If the hydroxyl-protecting group is an a~kyl group such as ~nethyl, it can readily be removed by treating the compound of formula (III) with a boron halide, such as boron trichloride or boron tribromide.
The reaction can be carried out in the absence of any solvent, but the 3 , 15 presence of a solvent is preferred because the reaction then proceeds more smoothly. The choice of solvent is not critical, provided that it is inert to the reaction, but halogenated hydrocarbons such as dichloromethane and chloroform are preferred. The reaction temperature is also not particularly critical, but i~ is desirable to ..se a relatively low temperature in order to suppress side-reactions, an~
temperatures between -30C and room temperature are preferred, If the hydroxy~-protecting group is a trialkylsilyl group such as trimethylsilyl, ~t can readily be removed by treating the compound (14) .. . . . ~ . . :
.

gS~;

of formula (III) with water, or with an aqueous acid or base. There are no particular limits on the choice of the acid or base. For instance, the acid may be an organic acid, such as formic, acetic, IroPionic, butyric, oxalic or malonic acid, or a mineral acid, such as hydrochloric, hydrobromic or sulphuric acid; and the base may be an alkali or alkaline earth metal hydroxide or carbonate, such as potassium hydroxide, calcium hydroxide, potassium carbonate or calcium carbonate. When water is employed in this step, no other solvent is necessary; but, if an additional solvent is employed, it may suitably be a mixture of water with an organic solvent, for example an ether such as tetrahydrofuran or dioxane, or an alcohol such as methanol or ethanol. The reaction temperature is not particularly critical, but it is generally convenient to perform the reaction at around room temperature, If the hydroxyl-protecting group is a carbonic ester residue such as ethoxycarbonyl, it can readily be removed by treating the compound of formula (III) with an acid or base. Examples of preferred acids and bases are mineral acids, such as hydrochloric, hydrobromic and sulphuric acid, and ao alkali or alkaline earth metal hydroxides and carbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate. It is generally most convenient to perform the reaction under basic conditions. The reaction can be carried out without any solYent, but the presence of a solvent is preferred since the reaction then (~5) , '. . ~ , 9~

proceeds more smoothly. There are no particular limits on the choice of solvent, so long as it is inert to the reaction, but preferred e?~amples are water, alcohc.ls such as methanol and ethanol, et'ners such as tetrahydrofuran and dioxane, or mixtures of such organic ~olvents with water. The reaction temperature is also not particularly critical, but it is preferred to operate at between room temperature and the reflux temperatllre of the solvent (if one is employed), and can vary with the nature of the protecting group to be removed.

After removal of the hydroxyl-protecting group, the desired product can be recovered from the reaction mixture by conventional techniques. For example, the reaction mixture is neutralized and extracted with an organic solvent, and the solvent is evaporated off from the extract to leave the desired product If necessary, the product thus obtained can be further purified by conventional means, such as column chromatography or thin-layer chromatography.

If the compound of formula (I) thus obtained is one wherein R represents a hydrogen atom, this product can, if desired, be salified in the conventional manner. Also, the various geometrical and/or optical isomers of the product can be isolated or resolved at an appropriate stage in the synthesisJ by conventional techniques.

The compounds of formula tII), used as starting materials in the process of the invention, are themselves new and can be prepared by the methods shown in the following reaction schemes 1 - 4.

(1~;) ,: (1) Preparation of ths~ compounds of forrnula (II) whcre_n A
i9 an ~thylene group and R is a protect~d hydroxyl group ( CH2 ) 6 ~ 2 6 ~ ~ 1st step ~

R80~ CoOR9 E~110 CoOR9 (VI) (V) ~¦! 2nd s-tep ~> ,~ 2 6 ~ ~ ( CH2 )6COOR
\ 3rd step ~
R110` CH20H R110 CoOR9 (VIII) (VII) 4th st ep (CH2)6COOR 3 ~ (CH2)6COOR13 ~ 5th step ~( ( IX) (X) 6 th st ep ocoR7 1~ ocoR7 ~(CH2)6cOolt ,) ~ (CH2~)6COOR
<R3 ~7th step ~ /

R11~" ~R~ R4 (Xl)

(17) .

lU~Z9~6 ~th steE¦
9t;h st ep 7 OCO~ ~ OC()~
(C~2)6CR ~ CH2)~,COOR~3 R'l 1,\~ R4~\~/~R4 (XIII) (XIV) 1 0th st ep \l .
OH
~" \A~cooR2 R5 ~ \~4 (II) In the formulae of reaction æcheme (1), A, Rl, R, R, R, R and R have the meanings prevîously given, .

The hydroxyl-protecting group R is one which will not be removed simultaneously with the hydroxyl-protecting group R CO-in the tenth step; and R represents a straight or branched alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or n-pentyl, R and Rl also represent hydroxyl-protecting groups: any protecting groups can be used which can subsequently be removed so as to leave a free hydroxyl group without affecting other parts of the molecule, and those exemplified hereinbefore for R are suitable. R represents a straight or branched alkyl group, for example methyl, ethyl, n-propyl or

(18) .~ - . . :
.

l~q~9c`~;

isopropyl. R and R represent carboxyl-protecting groups:
any protecting groups can be used which can subsequently be removed so as to leave a free carboxyl group without affecting other parts of the molecule, and suitable e~amples are hydro-carbon groups (e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl and benzyl), halogenated alkyl groups (e. g, 2, 2, 2-trichloroethyl), and heterocyclic groups (e. g, 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl and 4-methoxytetra-hydropyran-4-yl). R represents a hydrogen atom or one of the carboxyl-protecting groups previously exemplified. Z represents a carbonyl-protecting group: any protecting group can be used which can subsequently be removed without affecting other parts of the molecule, and suitable examples are a hydroxyimino group forming an oxime, a dialkoxy group (e, g, dimethoxy or diethoxy), an alkylenedioxy group (e. g, methylenedioxy or ethylenedioxy), and an alkylenedithio group (e. g. trimethylenedithio).

The steps of reaction scheme (1) will now be described in greater detail, starting with the known compounds of formula (V), which are disclosed in Japanese Provisional Patent Publication No, 57958/73, In the first step of the reaction scheme, the compound (VI) is prepared by protecting the carbonyl group of the compound (V) and, when necessary, replacing the hydroxyl-protecting group R
by:a more suitable one R . These two operations can be carried out in either order, In order to protect its carbonyl group, the

(19) 9~i6 compound (V) is treated with a carbonyl-protecting agent, optionally in the presence of a solvent. Preferred examples Or carbonyl-protecting agents are hydroxylamines which form oxime groups (e. g. hydroxyl~mine, methylhydroxylamine and sodium hydroxyl-aminesulphonate), orthoformic acid esters which form ketal groups (e, g. methyl orthoformate and ethyl orthoformate), alkylene glycols which form cyclic ketal groups (e, g. methylene glycol and ethylene glycol), and alkylene dithioglycols which form cyclic thioketal groups (e, g. ethylene dithioglycol and trimethylene thioglycol).
The reaction conditions depend on the nature of the carbonyl-protecting agent.used, If the hydroxyl-protecting group R is not suitable for the subse, quent reaction steps, it can be removed and replaced by a suitable protecting group R , by means of conventional techniques; otherwise, when the protecting group R
is suitable, it can be allowed to remain and Rll will be the same group as R .

The second step in the reaction scheme consists in the optional removal of the protecting group R . This is done because a higher yield of the compound (VIII) can then be obtained in the third step if R in compound (VII) represents a hydrogen atom; but it is not essential, and if not performed then R will be the same protecting group as R , The protecting group R can be removed by using the conventional techniques appropriate to the nature of the group, .

In the third step of the reaction scheme, the compound (VII) is .

(20) ~ O';t~95~c;
reduced to the compound (~TIII), normally in the presence of a solvent. If ~ in compound (VII) is a hydrogen atom, then the carboxyl group in the reduction product is re-protected by means of the protecting group R ; otherwise, when R itself is a 5 protecting group, R can be the same protecting group, In the fourth step, the carbonyl-protecting group Z is removed from the compound (VIII), giving the compound (IX), by using conventional techniques appropriate to the nature of the protecting group.

In the fifth step, the compound (X) is obtained by oxidizing the compound ~X). The oxidation is suitably performed by treating the compound (lX) with a peroxide, preferably hydrogen peroxide or an organic peracid such as performic, peracetic, perpropionic, perlauric, percamphoric, trifluoroperacetic, perbenzoic, _-chloro-15 perbenzoic or monoperpthalic acid. The presence of a reaction solvent is optional.

In the sixth step of reaction scheme (1~, the compound (XI) is obtained by oxidizing the compound (X), Suitable oxidizing agents and reaction conditions are those described hereinbefore in connection 20 with the oxidation of the compounds of formula (II) to the compounds of formula (III).

In the seventh step, the compound (XII) IS prepared by reacting

(21) .

10~956 the compound (XI) with a Wittig reagent of formula 40)2 P - CH - C0 /\(~/\~<R4 (XV) R

wherein R, R and R have the meanings previously given; R
represents an alkyl group (e. g. methyl) or an aryl group (e. g. phenyl);
5 and ~ (3represents a metal ion (e. g. sodium, potassium or lithium).
The reaction can be carried our in any of the solvents conventionally employed for Wittig reactions, In the eighth step, the compound (XII) is reduced to the compound (XIII), Any reducing agent can be used which will reduce 10 the carbonyl group to a hydroxyl group without affecting the ethylenic double bonds; and the reducing agent is preferably a metal hydride, for instance sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-t-butoxyaluminium hydride, lithium trimethoxyaluminium 15 hydride, sodium cyanoborohydride or lithium 9_-boraperhydro-phenalene hydride. The use of a reaction solvent is optional.

In the ninth step, when necessary the hydroxyl-protecting group R of compound (XIII) is changed to one which will not be removed when the group R C0- is removed during the tenth 20 step. The hydroxyl-protecting agents and reaction conditions used for the first step of reaction scheme (1) are suitable for this step also,

(22) '. ', ~ :

9~ , In the tenth step, the compound (II) is prepared by removing the protecting groups R CO- and R from the compound (XIV) and, if appropriate, esterifying the carboxyl group. The hydroxyl-protecting group ~7co- can readily be removed by treating the compound (XIV) 5 with either an acid or a base; and the carboxyl-protecting group ~
can be removed by conventional techniques appropriate to the nature of this group, In some instances, no separate action need be taken to remove group R , because it is removed concomitantly with the group R CO-. The optional esterification of the carboxyl group can 10 be effected by means of the reagents conventionally employed to convert a carboxyl group into an alkoxycarbonyl group, in the presence or absence of a solvent.

(2) Preparation of compounds of formula (II) wherein A is a cis-vinylene group and R is a protected hydroxyl group . _.
O O
0~/ 0 'lst step R 50 CHO ~J\~/~<113 (XVI) (XVII)O R

(23) .
, l~qZ9~

¦ ~nd step O ~ ~0~ .
~` \ 3r~ step ~` .

RS ~ ~ R1 ~/~\/ `~~4 (XIX) (XVIII) 4th st ep OH OH
5th step ~` \A COOR R3 RS / ~ \ ~ R

(XX) , (-~I) ti h (2) A ~1 R2 R3 R4 R5' and R6 have the meanings previously given; and R represents any hydroxyl-protecting group which can subsequently be removed to leave a free hydroxyl group without affecting other parts of the molecule, for example one of those e~emplified for R, The starting materials of formula (XVI) in reaction scheme (2) are disclosed in J. Am. Chem. Soc., 91, 5675 (1969).

(24) In the first step of reaction scheme (2), compound (XVII) is prepared by treating compound (XVI) with a Wittig reagent of the aforementioned formula (XV), under the same reaction conditions as used for the seventh step of reaction scheme (1).

In the second step of reaction scheme (2), compound (XVII) is reduced to compound (XVIII), suitably by means of the same reducing agents as used for the eighth step of reaction scheme (1).

The third step of reaction scheme (2) comprises changing the protecting group R and protecting the side-chain hydroxyl group in the compound (XVIII), to obtain the compound (XIX).
These operations correspond to those carried out in the ninth step of reaction scheme (1), and can be performed under the same reaction conditions.

In the fourth step of reaction scheme (2), the compound ~XIX) is reduced to give the compound (XX), Finally, in the fifth step, the compound (XX) is reacted with a Wittig reagent of formula (R j3P~- CH - (CH2)3 - COOM2 (XXI) wherein R represents a hyclrocarbon group such as an aryl group a~ (e. g. phenyl) or an alkyl group (e. g. n-butyl), and M2 represents an alkali metal (e. g. sodium or potassium). The desired compound of

(25) .

lO~Z956 formula (II) is obtained by acidifying the product of the Wittig reaction and, when appropriate, esterifying the carboxyl group of the resulting free acid. The esterification can be performed by conventional techniques, as in the preparation of the esters 5 of formula (II) in reaction scheme (l).

(3) Preparation of compounds of formula (II) wherein A is an ethylene group and R is a hydrogen atom O OH
" ~ :~ ~o~J' /\"` 1 st s tep /~ 2nd step ~1"`
\ < 16 ~H2H CH20R1 6CH20R
(XXII ) (XXI II )( XXIV ) ., ¦ 3rd step oR18 OH

/~17 Q"` ~=/\ COOR

2 ~---- 2 4th step ( XXVI ) ( X~V )

(26) . . ~

-lU''~95 ~,~ 5th step oR18 OR18 17 ~2 --COOR1 7 ~ COOR

CH20H 6th step CH20H
(XXVII ) (XXVIII ) 7th st ep OR C 17 oR18 ~1~ 17 ~~ OOR 8th step o ~ ~COOR

Y\~ R CHO

R1 (XXIX) (XXX) OR18 ¦ 9th step=o~L18 CoOR17 ~ cooR1 7 C1" /V R~

~ R4 > ~\~/C/IRI) (XXXI) l11th step ~~ COOR

(2'l) - . ' In reaction scheme (3), R, ~, R, R and R have the meanings previously given; but the protecting group R6 rnust be selected so that it is not removed when the protecting group R18 is removed during the eleventh step. Each of R and R represents a hydroxyl-5 protecting group, and can be any protecting group which cansubsequently be removed to give a free hydroxyl group without affecting other parts of the molecule: suitable examples are those listed hereinbefore for group R, with the already mentioned proviso that R should be removable without the removal of R6, and 3~1 10 is preferably an acyl group such as acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, benzoylj 4. nitrobenzoyl, 2-chlorobenzoyl, 2,4-dichlorobenzoyl or phenylacetyl. R represents any carboxyl-protecting group which can subsequently be removed to give a free carboxyl group without affecting other parts of the molecule, for 15 instance a hydrocarbon group (e, g, methyl, ethyl, n-propyl, isopropyl, n, butyl, isobutyl, phenyl or benzyl), a halogenated alkyl group (e. g. 2, 2, 2-tr;chloroethyl), or a heterocyclic group (e. g. 2-tetra-hydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 4 -methoxytetrahydropyran -4 -yl).

The starting materials of formula (X~II) used in reaction scheme (3) are disclosed in Tetrahedron Letters, 1972, 115.

In the first stcp of reaction scheme ~3), the hydroxyl group of the compound (~XII) is protected with the group R , by conventional techniques, giving the compound tX~III).

(28 ~ 10~5~
;

In the second step, the compound (X~IV) is obtained by reducing the compound (XXIII), Metal hydride reducing agents are preferred, for example di-isobutyl aluminium hydride, sodium borohydride, potassium borohydride, lithium borohydride, 5 lithium tri-t-butoxyaluminium hydride or lithium trimethoxy-aluminium hydride, In the third step, the compound (XXIV) is reacted with a Wittig reagent of formula (R19)3P6;~- CH - (CH2)3 - COOM3 (XXXIII) 10 wherein R represents a hydrocarbon group such as an aryl group (e, g, phenyl) or an alkyl group (e, g. n-butyl?, and M3 represents an alkali metal (e. g. sodium or potassium). The product of the Wittig reaction is acidified in the conventional manner, to obtain the free carboxylic acid, The carboxyl group of the acid is 15 protected by treatment with a reagent providing the protecting group R , optionally in the presence of a solvent, to give the compound (XXV)~

In the fourth step of reaction scheme (3), the hydroxyl group of compound (XXV) is protected with the group R , by conventional 20 techniques, giving the compound (X~VI).

In the fifth step, the hydroxyl-protecting group R is removed from the compound (XXVI), to prepare the compound (XXVII). This is suitably effected by the same techniques as described hereinbefore (29) l~qZ9~ .

for the removal of the hydroxyl-protecting group from the compounds of formula (III), In the sixth step of reaction scheme (3), the compound (XXVIII) is prepared by reducing the ethylenic double bond in the side-chain 5 of the compound (XXVII), The reduction is suitably carried out in a solvent; and any reducing agent can be used which will reduce the ethylenic double bond without affecting the carbonyl group. It is preferred to employ a catalytic reduction, using hydrogen in the presence of a catalyst such as palladium on carbon or platinum 10 oxide.

-In the seventh step of reaction scheme (3), the compound (XXVIII) -' ! iS oxidized to the compound (XXIX). The oxidizing agents and reaction conditions described hereinbefore for the oxidation of the compounds of formula (II) to those of formula (III) are also suitable 15 for this step.

In the eighth step, the compound (XXX) is prepared by reacting the compound (XXIX) with a Wittig reagent of formula 3 (R200)2p _ CH C/\~\~< (XXXIV) wherein ~, R and 1~ have the meanings previously given; R
20 represents an alkyl group (e. g. methyl) or an aryl group (e. g, phenyl);
and M ~) represents a metal ion (e. g, sodium, potassium or lithium).

( 30) 107Z~S~

The ninth step of reaction scheme (3) comprises the reduction of the compound (XXX) to give th.e compound (X~XI); and this can be effected by means of the same reducing agents and under the æame reaction conditions as described previously for the eighth 5 step of reaction scheme (1).

In the tenth step of reaction scheme (3), the compound (XXXII) i6 prepared by protecting the hydroxyl group of the compound (XXXI) with the protecting group R . This can be done in the same manner as described previously for the protection of hydroxyl groups, with 10 the proviso that group R must be chosen so that it is not removed along with group R in the following step.

Finally, in the eleventh step of reaction scheme (3), the hydroxyl-protecting group R and the carboxyl-protecting group R are removed from the compound (X~:II). Group R can 15 readily be removed by treating the compound (XXXII) with either an acid or a base, and ~roup R can be removed by conventional techniques appropriate to its nature; but, in some instances, no separate reaction is needed to remove the carboxyl-protecting group R , because it is removed concomitantly with the hydroxyl-20. protecting group ~18, If desired, the free carboxyl group in the resulting compound of formula (II) can be esterified by conventional techniques .

(4) Preparation of compounds of formula (II) wherein A is a cis-vinylene group and R is a hydrogen atom (~1) - . . : .

lV7Z9S6 .
oR18 , R18 cooR17 ~ CooR17 CH2oH1 st st ep HO

(XXVII ) (XXXV) l 2nd step 3rd step ~18COOR1 7~ OR19 COOR1 7 \~ \~R1 (XXXVII ) . (XXXVI ) `¦ 4th st ep ; . 1 ~/COOR 7 4~ 2 5th step ORR1 oR6 R1 (XXXVIII ) ( II) In reaction scheme (4), Rl, R2 R3 R4 R6 R17d R18 h 5 the meanings previously given.

The starting materials of formula (XXVII) used in reaction scheme (4~ can be prepared by means of the first five steps of reaction scheme (3).

(32) , l~qZ956 In the first step of reaction scheme (4), the compound (X~V) is preparecl by oxidizing the compound (XXVII). The oxidi~ing agents and reaction conditions used in the seventh step of reaction scheme (3) can also be used for this step.

In the second step of reaction scheme (4), the compound (XXXVI) is prepared by reacting the compound (~V) with a Wittig reagent of formula (XXXIV), as already described with reference to the eighth step of reaction scheme (3).

The third step of reaction scheme (4) comprises the reduction of the compound (X~VI) to the compound (XXXVII), under the same reaction conditions are previously described for the ninth step of reaction scheme (3).

In the fourth step of reaction scheme (~), the compound (XXXVIII) is prepared by protecting the hydroxyl group of the compound (XXXVII) with the protecting group R, under the same reaction conditions as previously described for the tenth step of reaction scheme (3), .
Finally, in the fifth step of reaction scheme ~4), the compound of formula (II) is prepared by removing the protecting groups R

and R17 from the compound (~XVIII) and then, if appropriate, esterifying the carboxyl group of the resulting compound. These operations can be carried out under the same reaction conditions as (33) ,. , ~ . .. .

~Z95~

previously described for the eleventh step of reaction scheme (3).

At the end of any of the steps in reaction schemes (l) to (4), the desired product can be isolated from the reaction mii~ure by conventional techniques and, if necessary, purified for example by 5 column chromatography or thin-layer chromatography. When the product is obtained as a mixture of geometrical and/or optical isomers, these can be isolated or resolved by conventional techniques, at an apprppriate stage in the synthesis.

The invention is illustrated by the following Examples l to 16;
lO and the subsequent "Referential Examples" illustrate the preparation of the startirlg materials of formula (II) used in the process of the invention.

, Example 1 ~ =~xo~ ~rox~1-17~-methyl-2-isopropylideneprost lS 13(trans)-enoic acid _ _.__ _ (1 ) In ? ml of acetone was dissolved 766 mg of 9~-hydroxy-11c~ ,15--di(2-tetrahydropyranyloxy)~17~-methyl-20-isopropylideneprost-13(trans)-enoic acid. To this solution was added at -11~-13C, 1 ml of Jones reagent 20 (prepared by dissolving 26. 72 g of chromic anhydride in 23 ml of sulfuric acid which was then mixed with a certain amount of water until the total amount reached 100 ml), and the resulting mixture was stirred for 20 minutes. After completion of the reaction, an excess of the reagent was decomposed by additi on of i~opropyl alcohol, and the solution was, after addition of water, extrac ted with ethyl acetate . The extract was washed (34) with water and dried over anhydrous sodium sulfate. The solvent was then evaporated from the extract under reduced pressure to leave 652 mg of 9-oxo-11a,15~-di(2-tetra-hydropyranyloxy)-17~-methyl-20-isopropylideneprost-13-(trans)-enoic acid as an oil;
IR spectrum (liquid film) v max cm 1745, 1712 N~R spectrum (CCl4) ~ ppm:
0.90 (3H, doublet, J=6 Hz), 5.0 (1H, triplet, J=6 Hz), 5.55 (2H, multiplet) (2) In a mixture of acetic acid, water and tetra-hydrofuran (15 ml, 15 ml and 5 ml, respectively) was dissolved 652 mg of 9-oxo-11a,15-di(2-tetrahydropyranyl-oxy)-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid, and the resulting solution was stirred at 35C for 4.5 hours. After completion of the reaction, the reaction mixture was, after addition of water, extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. ~he solvent was evaporated from the extract to leave 640 mg of the residue. r~he residue was then purified on a column of silica gel to give 210 mg of 9-oxo-11~,15a-dihydroxy-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid as an oil.
IR spectrl~n (liquid film) v max cm 1:
33~0~ 1735, 1710 N~ spectrum (CDCl3) o pprn:
0.90 (3H, doublet, J=6 Hz), 1.58 (3H, singlet), 1.62 ~3H, singlet), 4.1G (2H, multiplet), 5.57 ~0 (2H, multiplet) (35) ., . ~ - .

1~)7Z9S~

(3) Potassium salt In 10 ml of 30% aqueous alcohol was dissolved 408 mg of the above obtained carboxylic acid. '~o this solution was added 100 m~ of potassium hydrogen carbonate in 10 ml of 30% aqueous methanol, and the resulting mixture was then stirred at room temperature for one hour.
After completion of the reaction, the solvent was evapo-rated at a low temperature to leave 507 mg of potassium 9-oxo-11a,15~-dihydroxy-17~-methyl-20-isopropylideneprost-13(trans)-enoate as an oil.
IR spectrum (liquid film) v max cm 1:

Example 2 9-Oxo-11a,15~-dihydroxy-17~-meth~l-20-isoprop~lidene-prost-13(trans)-enoic acid (1) 764 mg of 9~-hydroxy-11a,15~-di(2-tetrahydro-pyranyloxy)-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid was reacted and treated in the same manner as in Example 1 - (1) to give 750 mg of 9-oxo-11~,15~-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid as an oil.
IR spectrum (liquid film v max cm 1:
1739, 1708 NMX spectrum (CCl~ ppm:
-9 (3~' doublet, J=6 Hz), 5~03 (1H, triplet, J=6 Hz), 5.50 (2II, multiplet) (2) 750 mg of 9-oxo~ ,15~-di(2-tetrahydropyranyl-oxy)-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid was reactèd and treated in the same manner as in (36~

- : , , . : .:

~ . . .. ~ .

~oqz9s~

/
Example 1 - (2) to give 163 mg of 9-oxo-11a,15~-dihydroxy-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid as an oil.
IR spectrum (liquid film) v max cm 1:
3400, 1730, 968 NMR spectrum (CDCl3) ~ ppm:
0.91 (3H, doublet, J=6 Hz), 1.58 (3H, sin~let), 1.64 (3H, singlet), 4.10 (2H, multiplet), 5.66 (2H, multiplet) Example 3 Meth~l 9-oxo-11a,15a-dihydroxy-17~-rneth~1-20-isopropylideneprost-13(trans)-enoate (1) 351 mg of methyl 9~-hydroxy-11~,15a-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylideneprost-13(trans)-enoAte was reacted and treated in the same manner as in Example 1 - (1) to give 298 mg of~ methyl 9-oxo-11a, 15a-di(2-tetrahydropyranyloxy)17~-methyl~20-isopropylidene-prost--13(trans)-enoate as an oil.
IR spectrum (liquid film) ~ max cm 1:
174-~
NMR spectrum (CCl4) ~ ppm 0.91 (3H, doublet, J=6 Hz), 3.68 (3H, single-t), 5.01 (1H, triplet, J=6 Hz), 5.55 (2H, multiplet) (2) 280 mg of methyl 9-oxo-11a,15~-di(2--tetrahydro-25 pylanyloxy~-17~-methyl-20-isopropylideneprost-13(trans~-enoate was reacted and treated in the same manner as in Example 1 - (2) to give 71 mg of` methyl 9-oxo-11~,15-dihydroxy-17~-methyl-20-isopropylideneprost-13(trans)-enoate as an oil.

(37) ~: .

.

~ 5~

lR spectrum (]iquid ~lm) v ~ax cm 1:
33~,0j 1735 NMR spectrum ((,D3COCD3) o ppm:
0.90 (3H, doublet, J=6 ~z), 3.67 (3H, singlet)~
5.57 (2H, multiplet) Example 4 9-OYO-11 a ,15~-dihydrox~-17~-methyl-20 soprop~l dene-prost-5~cls~ ,13( _ a s)-dienoic acid (1~ In 20 ml of acetone was dissolved 750 mg of 9a-hydroxy-11a,15a-di(2-tetrahydropyranyloxy)-17~-me-thyl-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid, and the resulting solution was, after addition of 1 ml of Jones reagent at about -13C, stirred for 20 minutes.
After completion of the react:ion, an excess of the reagent was decomposed by addition of isopropyl alcohol. ~he solution was, after addition of water, extracted with ethyl acetate. ~he extract was washed with water and dried over anhydrous sodium sulfate. ~he solvent was then evaporated from the extract to leave 631 mg of 9-oxo-11~,15a-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid as an oil.
IR spectrum (liquid film) v max Cm 1:
1745, 1710 N~R spectrum (CCl4) ~ ppm:
0.91 (3H, doublet, J=6 Hz) (2~ In a mixture of acetic acid, water and tetra-hydrofuran (15 ml, 15 ml, 5 ml, respectiv~ly) was dissolved 625 mg o~ 9-oxo-11~,15~-di(2--tetrahydropyrarlyloxy)-17~-(3~) ..
. .

~1~)7Z~3~6 me-thyl-20 isopropyl.idene~rost-5(cls), 13(trans)-dienoic acid, and -the solution was stirred at 35C for 4 hOUrS.
After completion of the reaction~ the reacticn mi.xture ulas wJashed with water and dri.ed over anhydrous sodium 5 sulfateO The solvent was evaporated from the extract to leave 610 mg of the residueO '~he residue was then puri~
fied on a column of silica gel to give 203 mg of 9-oxo-11a ,15a-dihydroxy-17~methyl-20-isopropylideneprost-5-(cis) ,13(trans)-dienoic acid as an oil.
IR spectrum (liquid film) v max cm 1:
3380, 1740, 1710 NMR spectrulrl (CD3COCD3) ~ ppm:
0.91 (3H, doublet~ J=6 Hz), 1.59 (3H), 10~5 (3H), 4.11 (2H, mul-tip]~t), 5~38 (2H, multiplet), 5.65 (2H, multiplet) :E:xample 5 9-Oxo-11a,15a~-dihydroxy-17~-methyl-20-isoprop;ylidene-prost-5(ci~ 3~s)-dienoic acid (1) 9a-Hydroxy-11a,15~-di(2-tetrahydropyranyloYy)-17~-methyl-20-isopropyl-.der.eprost-5(_is), 13(trans)-dienoic acid was reacted and treated in the same manner as in Example 4 - (1) to g ~e 9--oxo-11a,15~-di(2-tetra-hydropyranyloxy) -1 7~-met~71--20--isopropy:Lideneprost-5(cis) ,13(trans)-dienoic aci.d as an oil.
I~ spec-trum (1 iquid fil.7n.) ~ max cm 1:
1745, 1710 NMR spectlum ~CC1L, ) ~ PPm:
0091 (3H, doublet, J=6 Hz) (3~) ~ 9~6 (2) 9-Oxo-11,15~-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylideneprost-5(cls) ,13(trans)-dienoic acid was reacted and treated in the same manner as in Example 4 - (2) to give 9-oxo-11,15~-dihydroxy-17~-methyl-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid as an oil.
IR spectrum (liquid film) v max cm 1:
3380, 1730, 1710 NMR spectrum (CD3COCD3) ~ ppm:
0.91 (3H, doublet, J=6 EIz), 1.59 (3H, singlet), 1.63 (3H, singlet), 4.15 (2H, multiplet), 5.43 (2H, multiplet), 5.69 (2H, multiplet) Example 6 ethyl _-oxo-11~15-dihydroxy-17~-methyl-20-isopropylideneprost-5(cis~ ,13(trans)-dienoate (1) 751 mg of methyl 9-hydroxy-11,15-di(2-tetra-i . hydropyranyloxy)-17~-methyl-20-isopropylideneprost-5(cis), J , 13(trans)-dienoate was reacted and treated in the same manner as in Example 4 - (1) to give 630 mg of methyl 20 9-oxo-11,15-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoate as an oil.
IR spectrum (liquid film) v max cm 1:

NMR spectrum (CCl4) ~ ppm:
0.90 (3H, doub]et, J=6 Hz), 3.67 (3FI, singlet) (2) 610 mg of methyl 9-oxo-11,15-di(2-te-trahydro-pyranyloxy)-17~-methyl-20-isopropylideneprost-5(cis), 13( _ ans)-dienoate was reacted and treated in the same manner as in Example 4 - (2) to glve 190 mg of methyl (40 ' . , 9-oxo-11a,15~-dihydroxy-17~-methyl-20-isopropylideneprost-5(cis~, 13(trans)-dienoate as an oil.
IR spectrum (liquid film) v max cm :
340~, 1736 NMR spectrum (CD3COCD3) ~ ppm:
0.90 (3H, doublet, 6 Hz), 1.58 (3H, singlet), 1.60 (3H, singlet), ~.67 (3H, singlet), 5.38 (2H, multiplet), 5.65 (2H, multiplet) Example 7 9-Oxo-11~,15~-dihydroxy-20-isopropyli.deneprost-13(trans)-enoic acid and. 9-oxo-11,15~-dihydroxy-20-isopropylidene-.. .~
prost-13(tran )-enoic acid (1) 1.01 g of 9~-hydroxy-11 a, 15-di(2-tetrahydro-pyranyloxy)-~O-isopropylideneprost-13(trans)-enoic acid was reacted and treated in the same manner as in Example ; 1 - (1) to give 91C mg of 9-oxo-11a,15-di(2-tetrahydro-pyranyloxy)-20-isopropylideneprost-13(trans)-enoic acid i as an oi.l.
IR spectrum (liquid film) ~ m~x cm 1:
1710? 10/~0, 1020 NMR spectrum (CCl4) ~ ppm:
5.54 (2H, mul.tiplet) (2) 910 mg of 9-oxo-11~,15-di(2-tetrahydropyranyl_ oxy)-20-isopropylideneprost-13(trans)-enoic acid was .
reacted and treated in the same manner as in Example 1 -(2) to give a crude product. IThe obtained crude product was purified by means of preparative thin layer chromato-graphy and by using a mix~ure of benzene, dioxane and acetic acid (18 : 12 : 1) as a developing solventq There (41~

~ 9~ ~
were obtained 9-oxo~ ,15~-dihydroxy-20-isopropylidene-prost-13(trans)-enoic acid as an oil frorn the more polar portion and 9-oxo~ ,15~-dihydroxy-20-isopropylidene-prost-13(trans)-enoic acid from the less polar eluates.
~ somer IR spectrum (liquid film) v max cm 1:
3360, 1735, 1710, 970 NMR spectrum (CD3COCD3) o ppm:
1.58 (3H, singlet), 1.66 (3E~, singlet), 5.58 (2H, multiplet) IR spectrum (liquid film) v max cm 3370, 1735, 17~0, 9ao NMR spectrum (CD3COCD3) ~ ppm:
1.59 (3H, singlet), 1.66 (3H, singlet), 5.64 (2H, multiplet) Example 8 9-Oxo-11~,15a-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid (1) In 300 ml of acetone was dissolved 12.9 g of 9~-hydroxy~ ,15-di(2-tetrahydropyranyloxy)-20-iso-propylideneprost-5(cis) , 13(trans)-dienoic acid. q'o the solution was added at -20C., 25 ml of Jones reagent.
The mixture was stirred for one hour at ~20C. After completion of the reaction, the mixture was poured into 2 ~ of ice water. q'he mixture was ex-tracted with ether and the extract was dried over anhydrous sodiurn sulfate.
The solvent was distilled off to give 10.3 g of oil. The oil was purifted by colur,~ chromatography using 100 g of silica gel to give 8.41 g of 9-oxo~ ,15~-di(2-(42) -~729~6 tetrahydropyranyloxy)-20-isopropylideneprost-5(cis), 13(trans)-lienoic acid as an oilO
IR spectrum (liquid film) v max cm 1:
1745, 1710, 1135, 1020, 970 NMR spec-trum (CDCl3) ~ ppm:
4.7 (2H, multiplet) 5.0 - 5.8 (5H, multiplet) (2) In a mix-ture of 100 ml of acetic acid, 100 ml of water and 30 ml of tetrahydrofuran was dissolved 8.41 g of 9-oxo-11a,15a-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-5(cis) ~ 13(trans)-dienoic acid.
~he solution was stirred at 40C. for 1.5 hours. After addition of 100 ml of water, the solution was heated at 40C. for 1.5 hou~s. The solution was diluted with 500 ml of aqueous saturated sodium chloride and extracted with a mixture of ethyl acetate and benzene (1 : 1).
The extract was washed with aqueous saturated sodium chloride and the solvent was distilled off to give 6.9 g of oil. The oil was purified by column chr~matography 20 using 100 g of silica gel to afford 2.8 g of crystals.
The crystals were recrystallized from a mixture of ethyl ace-tate and hexane to give 2.1 g of 9-oxo~ ,15~-dihydroxy-20-isopropylideneprost-5(cis) ,13(trans)-dienoic açid as crystals melting at 64 - 66C.
IR spectrum (liquid paraffin) v max c~
3380,:1730, 1705, 1160, 970 NMR spectrum (CD3COCD3) ~ ppm:
4.08 (2~1, multiplet), 5.17 ~1H, triplet), 5~42 ~2H, multiplet), 5068 (2H, mul-tiplet) Mass spe~trum m/e : 392 ~ 3) .. - - . ~

i~29S6 ~xample 9 9-Oxo-11a,15~-dihydroxy-20-isopropylideneplost-5(cis), 13(trans~-dienoic acid (1) Following the same procedure as in Example 8 -(1), but replacing 9~-hydroxy-11a~15~-di(2-tetrahydro-pyranylo~y)-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid with 6.5 g of 9-hydrox~-11,15~-di(2-tetra-hyd.ropyranyloxy)-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid, there was obtained 4.1 g of 9-oxo-11~,15~-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid as an.oil.
- IR spectrum (liquid film) v max cm 1:
, . 1745, 1710, 1135S 1020, 970 NMR spectrum (CDCl3),, ~ ppm:
,4.7 (2H, multiplet) 5.0 - 5.8 (5H, multiplet) (2) FollowirLg the same procedure as in Example 8 -(2), but replacing 9-oxo-11a,15a-di(2-tetrahydropyranyl-oxg)-20-isopropylideneprost-5(cis) ~13(trans)-dienoic acid with 4.2 g. of 9-oxo-11a,15~-di(2-tetrahydropyranyl-oxy)-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid~ there was obtained 1.2 g of 9-oxo~ ,15~-dihydroxy-20-isopropylideneprost-5(cis)~ 13(tran.s)-d.ienoic acid as an oil.
IR spectrum (liquid film) v max cm 1:
338Q, 1730, 1160, 970 N~ spectrum (CD3COCD3) ~ ppm:
4.07 (2E, multiplet), 5.15 (1H, triplet) 5.4 (2H, multiplet), 5.68 (2H, multiplet) 3o , Mass spec-trum-m/e : 392 ' (~4) : . : . ~ ~' ' ' ' ' ~q'~956 t Example 10 Meth~l 9-oxo-15~(or ~)-h~droxy-20-isoprop~lideneprost-13(trans)-enoate -(1) 5-Oxo-15-(2-tetrahydropyranyloxy)-20-isopropylidene-prost-13(trans)-enoic acid In 80 ml of acetone was dissolved 2.6 g of 9~--hydroxy-15-(2-tetrahydropyranyloxy)-20-isopropylidene-prost-13(tran )-enoic acid, and 5 ml of Jones oxidizing reagent was added thereto with stirring at -20~ -10C.
The stirring was then continued at -20~ -10C for 30 minutes until the reaction terminated. ~he reaction mixture was diluted with 2ao ml of ice-water and ex-tracted with ether. The extract was washed with water and dried over anhydrous sodium sulrate. Upon evapo-i 15 ration of the solvent under reduced pressure, there was obtained 2.6 g of the desired compound as an oil.
IR spectrwn (liquid film) ~ max cm 1:
3200, 2750, 1740, 1710, 1200, 1130, 1110, 1020, 970 NMR spectrum (CDCl3) ~ ppm:
5.55 (2H, multiplet), 5.10 (1H, multiplet), 4.70 (1H, multiplet) (2) Methyl 9-oxo-15a(or ~)-hydrox~-20-isoproP!ylidene-prost-13(trans)-enoate In 50% aqueous acetic acid was dissolved 2.6 g of 9-oxo-15-t2-tetrahydropyranyloxy)-20-isopropylidene-prost-13(trans)-enoic acid, and the solution was stirred at 50C for 1.5 hours until the reaction terminated. The reaction mixture was then diluted wi-th 200 ml of ice-water (4~) : . . .
~ ' ,. ' ~ ' l~Z~56 and extracted with ethyl acetate. ~he extract was washed with water and dried over anhydrous sodium sulfate. Upon evaporation of the solvent under reduced pressure, 2.2 g OI an oily residue was obtained. To the residue was added an ethereal solution of dia~omethane until the yellow color of the added dia~omethane remained in the residue. ~he ether was evaporated to leave 2.23 g of an oily residue. The obtained residue was separated and purified by means of column chromatography and thin layer chromatography to give the desired 15a-nydroxy (730 mg) and 15~-hydroxy (6~30 mg) derivatives, each as an oil.
15a-H;ydrox.y derivative IP~ spectrum (liquid film) ~ max cm 1:
3480, 1740, 1200, 1170, 970 NMR spectrum (CDCl3) o ppm:
3.65 (3H, singlet), 4.10 (1H, multiplet), 5.10 (1H, multiplet), 5.60 (2H, multiplet) Mass spectrum m/e: 392 15~-H;ydrox~deriv~tive IR spectrum (liquid film) v max cm 1:
3480, 1740, 1200, 1170, 970 NMR spectrum (CDCl3) ~ ppm:
3.65 (3H, singlet), 4.10 (1H, multiplet), 5.13 (1H, multiplet), 5.60 (2H, multiplet) ~lass spectrum m/e: 392 Example 11 9-Oxo-15~-hydroxy-20-isopropylideneprost-13(trans)-enoic acid In 1~5 ml of methanol was dissolved 730 mg of methyl 9-oxo-15~-hydroxy-20-isopropylideneprost~13(trans)-(46) lV~Z956 ,;

enoate, and, after addition of 10 ml of 5~0 aqueous sodlum hydroxide solution, the resulting solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with 150 ml of ice-water. The solution was then neutralized with 7% aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. Upon evaporation of the solvent under reduced pressure, 730 mg of an oily residue was obtained. ~he obtained residue was crystalliæed from ether and n-hexane to give 524 mg of the desired compound as crystals, m.p. 40 - 45C.
IR spectrum (liquid film) v max cm 1:
3400, 2670, 1740, 1720, 1460, 1410, 1280, 1220, 1160, 970 NMR spectrum (CD3COCD3) ~ ppm:
4.08 (1H, ~ultiplet), 5.16 (1H, triplet), 5.64 (2H, multiplet), 6.50 (2H, multiplet) Mass spectrum m/e : 378 Example 12 Potassium 9-oxo-15~-hydroxy-20-isopropylideneprost=
13(trans)-enoate In a mixture of 8 ml of methanol and 2 ml of water was dissolved 150 mg of 9-oxo-15~-hydroxy-20-isopro-pylideneprost-13(trans)-enoic acid, andS after addition of 28 mg of potassium carbonate, the resulting solution was stirred at room temperature for one hour. After completion of the reaction, the solvent was evaporated from the reaction solution under reduced pressure to - (~73 11.3t7'~6 give 170 mg of the desired compound as a powder.
IR spectrum (fluid paraffin) ~ ~ax cm 1:
3400, 1735, 1580 - 1560 Example 13 9-Oxo-15~-hydroxy-20-isopropylideneprost-13(trans)-enoic acid 680 mg of methyl 9-oxo-15~-hydroxy-20-isopro-pylideneprost-13(trans)-enoate was reacted and treated in the same manner as in Example 11 to give 650 mg of the desired compound as an oil.
IR spectrum (liquid film) v max cm~1 3400, 2680, 1740, 1720, 1270, 1160, NMR spectrum (CD3COCD3) o ppm:
4.08 (1H, multiplet), 5.12 (1H, triplet), 5.60 (2H, multiplet) Mass spectrum m/e : 378 Example 14 Methyl 9-oxo-15a(or ~)-hydroxy-20-isopropylideneprost-5(cis),13(trans)-dienoate (1) 9-Oxo-15-(2-tetrah;sdropyran;ylox;y)-20-isopropylidene prost-5(cis) ~13(trans)-dienoic acid 2.5 g of 9a-hydroxy-15-(2-tetrahydropyranyloxy)-20~isopropylideneprost-5(cis)~13(trans)-dienoic acid was reacted and treated in the same manner as in Example 10 -(1) to gi~e 2.35 g of the desired compound as an oil.
I~ spectrum (liquid film) v max cm 1:
3200, 2650, 1740, 1710, 1130, 1015 (48) - .
.
.
, (2) Meth~l 9-oxo ~ or ~)-hydrox~-20-isopropylideIle-prost-5~c ) ,13(trans~-dienoate 2.34 g of 9-oxo-15-(2-~etrahydropyranyloxy)-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid was reacted and treated in the same manner as in Example 10 - (2) to give the desired 15~-hydroxy (0.~0 g) and 15~hydroxy (0.77 g) derivatives, each as ~n oil.
15-H~droxy isomer IR spectrum (liquid film) v max cm 1:
3450, 1740, 1435, 1200, 1155, 1010, NMR spectrum (CDCl3) o ppm:
3.65 (3H, singlet), 4.08 (1H, multiplet), 5.08 (1H, triplet), 5.33 (2H, multiplet), 5.56 (2H, multiplet) 15~-H~Qrox~ isomer IR spectrum (liquid film) v max cm~1 3480, 1740, 1430, 1240, 1215, 1155, NMR spectrum (~DCl~) ~ ppm:
3.65 (3H, singlet), 4.08 (1H, multiplet), 5.1~ (1H, multiplet), 5.35 (2H, multiplet), 5.56 (2H, multiplet) Example 15 9-Oxo-15~-hydroxy 20-isopropylideneprost-5(cis), 13(trans)-dienoic acid _ In 15 ml of methanol was dissolved 690 mg of methyl 9-oxo-15~-hydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoate, and, after addition of 15 ml of 5%

(49) 1t)~7~9~G

aqueous sodium hydroxide solution, the resulting solution was stirred at room temperature for one hour. hfter com-pletion of the reaction, the reaction solution was diluted with 100 ml of ice-water. ~he solution wa~ then neutralized with 7% aqueous hydrochloric acid and extracted with ethyl acetate The extract was washed with water and dried over anhydrous sodium sulfate. A~ter evaporation of the solvent under reduced pressureS the oily residue was puri~ied on colu~n to give 511 mg of the desired compound as an oil.
IR spectrum (liquid film) v max cm 1:
3400, 2650, 1740, 1710, 1400, 1230, 1150, 1060, 960 NM~ spectrum (CD3COCD3) o ppm:
4.04 (1H, multiplet), 5.12 (1H, multiplet) ; 15 5.32 (2H, multiplet), 5.57 (2H, multiplet) Mass spectrum m/e : 376 Exa~ple 16 9-Oxo-15~-hydroxy-20-isopropylideneprost-5(cis), ,~ .
13(trans~-dienoic acid __ .
765 mg of methyl 9-oxo-15~-hydroxy-20-isopro-pylideneprost-5(cis) ,13(trans)-dienoate was reacted and treated in the same manner as in Example 15 to give 667 mg of the desired compound as an oil.
IR spectrum (liquid film) ~ max cm 1:
3400, 2650, 1740, 1710, 1400, 1230, 1150, 1000, 960 NMR spectrum (CD3COCD3) ~ ppin:
4~03 (1H, nultiplet), 5.10 (1H, multiplet), 5.36 (2H, multiplet), 5.60 (2H, multiplet) Mass spectrum m/e : 376 ' (~0) :

l~J~

Referential example 1 ~E~roxy-11a,15a(or ~)-di(2-tetra~ydr~ r~-yloxy)-17~-methyl-2()-isopropylideneprost-13(trans)-enoic acid ~II) (1) 1~- oxy-2~-methoxycarbon~ a-~6-ethoxycarbonyl-hexyl~-4~-(1,1'-ethYlenedithioet~yl~cyclopentane (VI) In 50 ml of dichloromethane was dissolved 22r14 g of 1a-acetoxy-2~-methoxycarbon~Tl-3a-(6-ethoxycarbon~rlhexyl)-4a-acetylcyclopentane (V). To this solution were added under ice-cooling 80 ml of ethylene dithioglycol and 16 ml of a boron trifluorideethyl ether complex, and the mixture was stirred for one hour. After completion of the reaction, ice-water was added to the reaction mixture, and the resulting mixture was extracted with ether. ~he extract was washed with water, an aqueous potassium hydrogen carbonatc solution and water, successively~ and dried over anhydrous sodium sulfate. After the d~ying, the solvent ! ~ was evaporated to leave a gum. ~he obtained gum was then purified on a column of silica gel and by developing with benzene and a benzene solution containing 5% of ethyl acetate. ~he eluates were combined and evaporated to remove the solvent, leaving 23.0 g of the desired compound as an oil.
IR spectrum (liquid film) v cm 1:
max NMR spectrum (CDCl3) 8 ppm:
1.23 (3H 5 triplet), 1.78 (3H, singlet), 2 02 (3H, singlet), 3.70 (3H, singlet) (2) 1~ Tdro~y=~-meth~rcarbon-~Jl-3~-(6-m_thoxycarbo~y]-3 ke~Tl~-L~-(1,1'~et~ylenedithioet~T~ rclopentane (VI

(51) ' ' - .

lQ72956 In 250 ml of methanol were dissolved 2~0 g of 1a-acetoxy-2~-methoxycarbonyl-3~-(6-etho~ycarbonylhexyl)~
4a-(1,1'-ethylenedithioethyl)cyclopentane and 10 g of potassium carbonate, and the solution was stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was, after addition of aqueous acetic acid 7 extracted with ether. The extract was washed with water and dried over anhydrous sodium sulfate. After drying, the solvent was evaporated to leave a gum. ~he obtained gum was purified on a column of silica gel and by developing with benzene and a benzene solution containing 30% of ethyl acetate. The eluates were combined and evaporated to remove the solvent, leaving 20~4 g of the desired compound as an oil.
IR spectrum (liquid film) ~1 max 1730, 3450 N~R spectrum (CDCl3) ~ ppm:
3.66 (3H, singlet), 3.70 (3H, singlet) (3) 1 _ drop~ranyIoxy)-2~-m tho~c~ y~
~6-met o~ rbo~-~lhex~ a-(1,1'-ethylenedithioethy cyclopentane (VI) In 120 ml of benzene was dissolved 20.4 g of 1a-hydroxy-2~-methoxycarbony1-3a-(6-methoxycarbonylhexyl)-4a-(1,1'-ethyienedithioethyl)cyclopentane. To this solution were added lmder ice-cooling 7C ml of dihydropyran and a catalytic amount of picric acid, and t~e resulting mixture was stirred for 15 hours. After completion of the reaction, the solvent was evaporated from the reaction ~ixture to leave a gumO The obtained g,um was purified on a column of neutral alumina (Woelm Co~ product Grade II

(52) .. .. ..
, i~7Z9~6 350 g) and by developing a hexane solutlon containing 10%
of benzene and a benzene solution cont~ining 5% of et~yl acetate. The eluates were combined and evaporated to remove the solven-t, leaving 21.44 g of the desired co~.pound as an oil.
IR spectrum (liquid film) v maxcm 1:
1030, 1730 NMR spectrum (CCl4) ~ ppm:
3.60 (3H, singlet), 3.65 (3H, singlet) (4) 1a-(2-Tetrahydropyra~Yloxy)-2~-meth-xycarbon~
(6-carbo~ -4a-(1,1'-eth,ylenedithio_th~l)-9~
In 200 ml of 30% aqueous methanol containing 5%of potassium carbonate was dissolved 3.4 g of 1~-(2-tetrahydropyranyloxy)-2~-methoxycarbonyl-3~-(6-methoxy-carbonylhexyl)--4~-(1,1'-et4ylenedithioet~yl)cyclopentane, and the solution was stirred at room temperature for 4 houIs and 40 minutes. After completion of the reaction, water was added to the reaction mixture and the resulting mixture was then~extracted with hexane. Further, the aqueous portion was acidified,with acetic acid and extracted with ether. The extract was washed with water and dried over anhydrous sodium sulfate. After drying the solvent was evaporated from the extract to leave 2.4 g of the desired compound as an oil.
IR spectrum (liquid film) v maxCm 1710, 1730 NMR spectrum (CCl4) 8 ppm:
3.70 (3~I, singlet) (5) 1a (2-Tetrah~dropyra~ylo~r)-2~ ydloY~ymet~

- (53) ,~ .

107Z9~i~

C_-m~tho c~clo~entane (VIII) A potassium salt of the starting compo~nd prepared from 2.7 g of 1~-(2-tetra~rdropyra~rlox~) 2~-methoxy-carbonyl-3~-(6-carboxyhex~l)-4~-(1~ ethylenedithioethyl)-cyclopentane and 1.3 g of potassium hydrogen carbonate was dissolved in 200 ml of anhydrous tetra~rdrofuran. To this solution was added dropwise at room temperature 3.2 g of lithium boron hydride. After completion of the addition, the reaction mixture was stirred at room temperature for 15 hours and then at the reflux temperature fGr 5~5 hours.
After completion of the reaction, the reaction mixture was poured into ice-wa~er, acidified with dilute hydro-chloxic acid and acetic acid, and extract~d with ether.
The extract was washed with water and dried over anhydrous sodium sulIate. ~hen, the extract was subjected to esterification by the use of diazomethane. After comple-tion of the reaction, the solvent was evaporated to leave the residue. The obtained residue was purified on a column of 41 g of neutral alumina (Woelm CoO product Grade III) a~d using benzene and a benzene solution containing 3% of ethyl acetate. The combined eluates were evaporated to remove the solvent, leaving 1.58 g of the desired compound as an oil.
IR spectrum (liquid film) vmaxcm 1:
1735, 3460 N~ spectrum (CCl4) ~ ppm:
1.75 (3H, singlet), 3.59 (3H, singlet) (6) _ -( ~ t~r~ d opyran~l x~) 2~-h~d~ y~ethyl~3~-(6 methoxYcarbonylhey~Lyl)-l~-acet~yl-c~clo~)eIltane--(Ix) (5~) - , - . .. . . . . - . . .

~L0~29S~i ; In 300 ml of aqueous tetra~ydrofuran (15%) were suspended 14.0 g of mercury (II) oxide and 9.2 g of a boron trifluoride - ethyl ether complex. To this suspension ~as added with stirring under ice-cooling 5.0 ~ of 1a-(2-tetrahydropyranyloxy)-2~-hydrox~7methyl-3a-(6-methoxy-carbonylhexyl)-4~-(1,1' ethylenedithioethyl)cyclopentane, and the mixture was stirred for 25 munutes~ After completion of the reaction, ether was added to the reaction mixture, which was then filtered. The filtrate was washed with an aqueous sodium hydrogen carbonate solution and water, successively, and dried over anhydrous sodium sulfate. The solvent was then evaporated from the extract to leave the residue. The obtained residue was purified on a column of 100 g of alumina and using benzene and a benz~ne solution containing 1 - 40% ethyl acetate. The eluates were combined and evaporated to remove the solvent, ! leaving 3.421 g of the desired compound as an oil.
IR spectrum (liquid film) v maxcm 1:
1705, 1738, 3450 NMR spectrum (CCl4) ~ ppm:
1.12 (3H, singlet), 3.62 (3H, singlet) (7) 1 -~2-~e In 300 ml of 50% aqueous methanol containing 2.5% of potassi~m carbonate was dissolved 3.421 g of 1a~(2-tetrahydropyranyloxy)-2~-hydroxymethyl-3a-(6-methoxycarbonylhexyl)-4x-cicetylcyclopentane prepared in Referential example 1-(6), and the solution was stirred at 50C for 2.5 hours. Afte~ completion of the reaction, methanol was evaporated from the reaction mixturc. The (55) .
.. , ,. , , . , . - ~

:lOq~gS~; ' residual ~olution was, after acidified with acetic acid, extracted with et~yl ~cetate~ The extract was dried over anhydrous sodium sulfate and evaporated to remove the solvent. r~he residue thus obtained was purified on ~
column of 30 g of alumina (Woelm Co. product Grade III) and using benzene and a benzene solution containing 1 -40% of ethyl acetate. The eluates were combined and evaporated to remove the solvent, leaving 3.40 g of the desired compound as an oil.
IR speetrum (liquid film) v maxcm 1:
1705, 1738, 3460 NMR spectrum (CDCl3) ~ ppm:
1.14 (3H, singlet), 3.62 (3H, singlet) (8) 1a-(2-Tetrahydropyra~ylo~l)-2~-h~dro ym~thyl-3~-(6-, methoxycarbonylhexyl)-4~-ac~toxyc~clopentalle (X) In 70 ml of dichloromethane was dissolved 3.2 g of 1~-(2-tetrahydropyranyloxy)-2~-hydro~ymethyl-3~-(6-methoxycarbo~ylhe~yl)-4~-acetylcyclopentane. To the solution were added 5,3 g of solid sodiurn hydrogen earbonate and 5.3 g of m-chloroperbenzoic acid, anA the mixture was stirred ~t room temperature for 15 hours.
Aft~r completion of the reaction, the reRction mixture was then treated in the same manner as in Referential example 1~(1) to give 1.658 g of the desired cornpound as an oil.
IR spectrum (liquid film) ~ maxcm 1740, 3470 NMR spectrum (CCl4) 8 ppm:
1.98 (3H, singlet), 3062 (3H, singlet) (9) 1~-(2-Te~ y~ r,~yr~ oxy)-2~-for~yl-3~-(6 __ . __ !56) .
.

~ 9S6 metho~yc~ he~yl)-4~-acetoxyc~clo~e.~ntane (XI) In ~00 ml of dichloromethane was dissolved 1.753 g of 1~-(2-tetrahydropyranyloxy)-2~-~Tdro~ymethyl-3a_(6-methoxycarbonylhexyl)-4~-acetoxycyclopentane. ~o this solution was added 17 g of a chromic anhydride -p~yridine complex, and the mixture was stirred under ice-cooling for 15 minu'ues. After completion of the reaction, to the reaction mixture were added successively ether and cooled dil.u.te hydrochloric acid. The ethereal portion was washed with an aqueous sodium hydrogen carbonate solution and. dried ov~r anhydrous sodium sulfa-te. After drying, the reaction mixture was evaporated to remove the solvent, leaving ~.63 g of the desired compound as an oil.
IR spectrum (liquid film) v maxCm 1740, 2700 ~R spectrum (CDCl3) ~ ppm:
1.93 (3H, singlet), 3.58 (3H, singlet), 9,69 (1H, broad doublet) (10) ~ 3~l 2 41 ml of a hex&~e solution containing 15.1 %
of n butyllithium ~as added dropwise wi-th stirring at -60C in a ~tream of argon to 80 ml of a tetrahydrofuran solution containing 10.2 g of dimethyl methylphosphonate to prepare dimeth-~l methylphosphonate carbanion. ~o the carbanion thus obtained was added dropwise 30 ml of a tetrahydrofuran solution containing 7.227 g of methyl 3,7-dimethyl-6-octenoate with Xeeping the temperature below -50C. The resulting mixture was then s-tirred at -50 ~ -60C for ~ hours and 10 millutes, ~d, after .removal of the cooling bath, the stirring was further (57) 1S~7Z~5~ .

continued until the inside temperature reached 0C. After completion of the reaction, acetic ~cid and water were added successivel~ to the reaction mixture and the mixture was then extracted with ether. ~he extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to remove the solvent The residual solution was distil]ed at 124 - 127C/0.1 m~Hg to give 4.858 g of the desired compound as an oil.
IR spectrum (liquid film) ~ maxcm ~:

~MR spectrum (CCl4) ~ ppm:
0.90 (3H, doublet, J=6 Hz), 1.57 (3H, singlet), 1 64 (3H, singlet), 2.89 (2H, doublet, J--23 Hz), 3 66 (6H, doublet, J=11 Hz), 4.96 (1H, triplet, J=7 Hz) (11) Met~yl 9~-acetox~-11~-(2-tetrahydrop~ranylo oxo-17~-methyl-20-isoproPylidelleprost-1~(t~ s) , .
enoate (XII) 292 mg of 52.9% oily sodium hydride was washed with dry petroleum ether to remove the oil and suspended in 20 ml of dimethoxyethane. To this suspension was added dropwise with stirring under ice-coo1ing in a stre~m of argon 1.85 g of dimethyl 2-oxo-4,8~dimethyl-7-nonenyl-phosphonate in 20 ml of dimethoxyethane. After stirring for additional 3.5 hours, 10 ml of dimethoxyethane was added. To this solution was added dropwise under ice-cooling 2~35 g of 1~-(2-tetrahydropyran~loxy)-2~-formyl 3a-(6-methoxycarbonylhexyl)-4~-acetoxycvclopentane in 30 ml of dimethoxyethane, and the mixture was stirred for 25 minutes. After completion of the reac-tion, acetic acid (58) l~q'~9~

and. an excess amount of ether were successively added to the reaction mixtureO rrhc: organic solvent portion was . washed with water and dried over anhydrous sodium sulfate.
The solvent was evaporated to leave 4.08 g o~ the residue, r~he obtained residue was puri~ied on a column of alumina to give 2,018 g of the desired compound as an oil, IR spectrum (llquid film) v maxcm 1:
1740, 1695, 1670, 1630, 1035, 1025 NMR spectrum (CCl~ ppm:
100,90 (3~, doublet, J=6 ~Iz), 1.60 (3H, singlet), 1.64 (3H, singlet), 1.98 (3H, singlet), 3.59 (3H, singlet), 4.90 (2H, multiplet), 6.31 (2H, multiplet) (12) _et~yl 9~- _ toxy~ (2-te r~ drop~Jranyloxy)-15-rdroxy-17~-meth,yl-20-isoprop~yliclene~r~ ~ans)-enoate (XIII) 1,5 g of sodium boron hLydride in small portions was added under ice-cooling to 2~025 g of metl~yl 9~-acetox~r-11a-(2-tetrahydropyra~Yloxy)-15-oxo-17~-met~
20-isopropyrid.eneprost-13(trans)-enoate in 50 ml of anhydrous methanol, and the mixture was stirred for 20 minutes. After cor.pletion of the reacti.on, acetic acid was added to decompose an excess of the sodium boron ~ydride. r~he mixture was, after addition. of wa-ter, extracted with eth~yl acetate. r~he extract was washed wi~h water and dried over allhydrous sodiur~ sulfate. rnhe solvent was evaporated from the extract to leave 2.2 g of the residue~ The obtained residue was theIl purified on a column of silica gel to give 1.9~9 g of the d.esired compound as an oil.

(59) . ~ .
.

lOqZ~S6 IR spectrum (liquid film) y maxcm 1:
3L~30, 1 7L~O
NMR spectrum (CCl4) ~ ppm:
0~91 (3I~, doub3et, J=6 Hz~, 1.57 (~H, singlet), 1.64 (3~I, singlet), 1,95 (3H, singlet), 3.60 3H, singlet), 5.~9 (2H, multiplet) (13) Methyl 9~-acetoxy~ ,1 ~ dil~,~roxy-17~-methyl-20_ sopr~ epros_ 13(t _ s~-enoate (XIII) In a mixture of acetic acid, water and tetra-4ydrofuran (40 ml, 17 ml and 8 ml, respectively) was dissolved 1.987 g of methyl 9~-acetoxy-11a-(2-tetra-hydropyranyloxy)~15-hydroxy-17~-methyl-20-isopropylidene-prost-13(trans)-enoate, and the solution was stirred at about 35C for 4,5 hours. After completion of the reaction, water was added to the reaction mixture, and this was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. ~he solvent was evaporated from the extract to leave 2.11 g of the residue. The obtainecl residue was purified on a column of silica gel. Elution with a ben~ene solution containing 15 - 20% of ethyl acetate gave 418 mg of the 15~-hydroxy isomer of the desired compoundO Elution with a benzene solution containing 20 - 30% of ethyl acetate ~ave L~19 mg of a mixture of the isomers with respect to the 15 position. Further, elution with a benzene solution containing 30 - 80,~ of ethyl acetate gave 326 mg of the 15~-hydroxy isomer of the desired compo~d.
15~-H~dro~y isomer -IR spectrum ~liquid film) v maxcm 1:

(60) ' ~ ~

10~956 3380, 1735 NMR spectrum (C~Cl3) ~ ppm:
0 91 (3H, doublet, J=6 Hz~, 1,57 (3H, singlet), 1.64 (3H, singlet), 3~60 (3H, singlet), 4 95 (2H, multiplet), 5.45 (2H, mu]tiplet) 15~-Hydroxy isomer IR spectrum (liquid film) v maxCm 3430, 1735 NMR spectrum (CDCl3) ~ ppm:
1.57 (3H, singlet), 1.68 (3H, singlet), 1.98 (3H, singlet), 3.63 (3H, singlet)~ 4.92 (2H, multiplet), 5.58 (2X, multiplet) (14) Met~yl 9~-acetoxY-11a ~15a-di(2-tetra~ydrop~ranylox~)-17~-methyl-20-isopropylideneprost-13(trans)-enoate (XIV) ; 5 ml of dih~dropyran was added at room tempera~ure to 510 mg of methyl 9~-aceto~y-11a ,15a-dihydroxy-17~-methyl-20-isopropylideneprost-1~(trans)-enoate in 5 ml of benzene. ~he resulting mixture W3S, after addition of a cataly~ic amount of picric acid under ice-coolin~, allowed to stand for 2.5 hours. After completion of the rcaction, the reaction mixture was directly purified on a column of alumina to gi~re 1.491 g of the desired compound as a crude oil.
IR spectrum (liquid film) v maxc~i :
1735, 1030, 1020 NMR spectrum (CCl4) ~ ppm:
0~91 (3H, doublet, J=6 Hz), 1.93 (3E, singlet), 3~57 (3H, singlet), 5.43 (2H, multiplet) ; 30 (15) Met~yl 9~-acetox~-11a ,15~~di(?-tetra~ydropyra~ylo~y)~

(61) .
.
: - - ' - , . . . :

lO~Z9S6 1?,B-meth~l-~ =

555 mg of methyl 9~-acetoxy~ 15~-dihydroxy-17~-methyl-20-isoprop~rlideneprost-13(trans)-enoate was reacted and treated in the same manner as in Referential example 1-(14) to give 1.30 g of a crude product of the desired compound.
IR spectrum (liquid film) v maxcm 1:
1735, 1030, 1015 NMR spectrum (CCl4) ~ ppm:
0.89 (3H, doublet, J=6 Hz), 1.98 (3H, 5inglet), 3.58 (3H, singlet), 5.41 (2H, multiplet) (16) ~¦~-Hydro~y-11~ ~15a-di(2-tetrah~dropyra~yloxy)-1713-meth,yl-20-isoPropylideneprost-13(~,r~ns~-enoic a d (II~
In a solution of 15 ml of water and 35 ml of methanol containing 1.5 g of potassium hydroxide was suspended 1.491 g of crude methyl 9~-acetoxy-110 ,15a-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropyiidene-prost-13(trans)-enoate, and the suspension was vigrously stirred at room temperature but with intermittent heating 17 hours and 45 minutes later, water was added to the reaction mixture. The resulting mixture was then extracted with a hexane solution containing 50% of ether ~5 to remove the neutral materials, and subsequently the aqueous portion was, after acidification with acetic acid, extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate~ ~he solvent was then evaporated from the extract to leave 766 mg of the desired compound as an oil.

(62) . .

IR spectrum (liquid film) v maxcm 1:
3400, 1710 NMR spectrum (CCl4) ~ ppm:
0091 (3H, doublet, J=6 Hz), 5~03 (1E, triplet~
J=6 Hz), 5.47 (2H, multiplet) (17) 9~-Hydrox~ ,15~-di(2-tetrahydro~yra~yloxy)-'17~-meth~yl-20-isopropylideneprost-1.3~trans)~enoic acid (II) 1.3 g of crude methyl 9~-acetoxy-11a ,15~-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylidene-prost-13(trans)-enoate was reacted and treated in the : same manner as in Referential example 1-(16) to give 764 mg of the desired compound as an oil.
IR spectrum (liquid film) v maXcm 1:
3400, 1710 NMR spectrum (CCl4) ~ ppm:
0~84 (3H, doublet, J=6 Hz)~ 4098 (1H, triplet, J=6 Hz)~ 5.38 (2H, multiplet) Refe.rential example 2 Methyl 9@~hydrox~T-11a ,15~-di(2-tetrahydroEyrany _xy)-17~-methyl-20-isopropylideneprost-13(trans)-enoate (II) Diazomethane in ether was added to 125 mg of 9~-hydroxy-11~ ,15~-di(2-tetrahydropyranyloxy)-17~-methyl-20-isopropylideneprost-13(trans)-enoic acid in 5 ml of ether until the reaction mixture turn.ed pale yellow.
After completion of the reaction, the solvent was evaporated under reduced pressure to leave 127 mg of t~le desired compound as an oil.
IR spectrum (liquid film) v maxcm 1:
3400, 1730 - (63) .

i~72956 Referential exampl~ 3 9a-~droxy~ ,15~ ~or ~-di(2-tetrahydro~anyloxy)_ 17~-methyl-20-isopropylidenepros-t-5(cis) ,13(trans)-dienoic acid (II) (1) 3-Oxo-6-s~(3-oxo-5,9-dimethyldeca-1,8-dier~l)-7-antiacetoxy-2--oxabicyclo (3-3-0)-octare (XVII) 321 mg of 52.9% oily sodium hydride was washed with dry petroleum ether to remove the oil and suspended in 20 ml of dimethoxyethane. ~o the resulting solution was added dropwise with stirring under ice-cooling in a stream of argon 20 ml of a dimethoxyethane solution containing 2.035 g of dimethyl 2-o~o-4,8 dimethyl-7-nonenylphosphonate obtained in Referential ex~l1ple 1-(10).
After stirring for 3 hours, 10 ml of dimethoxyethane was further added. ~o this solution was added dropwis~ under ice-cooling 1.35 g of 3-oxo-6-~formyl-7-antiacetoxy-2-cxabicyclo-(3 3 0)-octane (XVI) in 30 ml of dimethoxyethane, and the mixture was stirred for additional 2 hours After completion of the reaction, acetic acid and ether were successively added to the reaction mixtlu~e. ~he organic solvent portion was washed with ~ater, dried over anhydrous sodium sulfate, and evaporated to remove the solvent.
The obtained residue was purified on a column of silica gel to give 1.69 ~ of the desired compound as an oil.
IR spectrum (li~uid film) v maXcm 1:
1770, 1740, 1695, 1670, 1630 NMR spectrum (CDCl3) ~ ppm:
0.90 (3H, doublet, J=6 Hz), 1.61 (3X, singlet), 1.65 (3H, singlet), 2.03 (3H, singlet) 30 (2) 3-Oxo-6~ (3~ (or ~)-1~droxy-5,9~dimethy1deca_ (64) 11)7Z9S~;

dier~Yl)-7-antiaceto~-2-~xabicyclo (3-3-0)-___ 0.8 ml of 0.55 M zinc boron hydride dimethoxy-methane sGlution was added under ice-cooling to 270 ~g of 3-oxo-5-syn(3-oxo-5,9-dimethyldeca-1,8-dienyl)-7-anti-acetoxy-2-oxabicyclo(3 3~0)-octane in 4 ml of dimethoxyethane, and the mi{ture was stirred for one hour.
After completion of the reaction, acetic acid was added to the mixture so as to decompose an excess of the reagent, and the mixture was, after addition of water, extracted with ethyl acetate. ~he extract was washed ~th ~ater, dried over anhydrous sodium sulfate and evaporated to remove the solvent. ~he obtained residue was subjected to preparative thin layer chromatography and purified by developing with ether. There ~;ere obtalned 89 mg of the 3a~iSomer of the desired compound from the less polar portion and 80 mg of the 3~-isomer of the desired compound from the more polar portion.
3a~ droxy isomer IR spectrum (liquid film) v maxcm 1:
3500, 1780 NMR spectrum (CDC13) ~ ppm:
0.91 (3H, doublet, J=6 Hz), 1.58 (3H, singlet), 1.65 (3H, singlet), 5.51 (2H, multiplet) 3~-~ydroxy i~somer IR spectrum (liquid fil~) v maxcm 1:
3500, 1780 NMR spectrum (CDC13) ~ ppm:
0.90 (3H, doublet, J=~jHz),1.57 (3H, singlet)5 1.64 (3H, singlet), 5.51 (2H, multiplet) (65) . - . . . . ..
. . - . . .

9S~

!
(3) 3-Oxo-5~s~Tn(3a ~ydroxy-5,9~di~ethyldeca-1,8-(3 3 O)-octane In 2 ml of anhydrous methanol was dissolved 120 mg of 3-oxo-6-~yn(3a-hy~roxy-5,9-dimethyldeca-1,8-dienyl)-7- ntiacetoxy-2-oxabicyclo (3 3 0)-octane, and the so1ution was, after addition of 65 mg of anhydrous potassium carbonate, stirred for 20 minutes. After completion of the reaction, acetic acid and water were successively added to -the mixture, and this was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated from the extract to leave 93 mg of the desired compound as an oil.
IR spectrum (liquid film) v l~axcm NMR spectrum (CDCl3) ~ ppm:
0.91 (3~-I, doublet, J=6 Hz),1.58 (3H, singlet), 1.68 (3~I, singlet), 5.54 (2H, multiplét) (4) 3-Oxo--6-s~n(3B-hydro~ 5,9-d methyldeca-1,8-___ ___ ___ . . ____ dienyl)-7- _tihydroxJ-2-oxabLcycl (3-3 03-octane (XVIII) 3-Oxo--6~ n(3~-h~droxy-5,9-dilrlethyldeca-1,~-dienyl)-7-atltiacetox~--2-oxabicyclo (3 3-0)-octane was reacted and treated in the sarne ]nanner as in Referential ex~nplc 3--(3) to give the desired compo~n~ as an oil.
IR spectrum (liquid lil~) v maxcm 1:

N~ spectrum (CD~13) ~ ppm:
0~90 ~3H~ doublet, J=6 Hz)~1.57 (3~1, sing]et), - (66) - ' ~-:., ~ ', ' ' 1.68 (3H, singlet), 5.54 (2M, multiplet) (5) 3-Oxo 6~syn(3a-(2-tetrahydropyranyloxy)-5,9-dimethyldeca-1,8-dienyl)-7~anti(2 tetra-.___ _ hydroPyra~yloxy)-2-o~ o (3 3 O)-oct&ne (XIX) 150 mg of 3-oxo-6-syn(3a-hydro~y-5,9-dimeth~yl-deca~ -dienyl)-7-antihydroxy-2-oxabicyclo (3~3 0)-octane was reacted and treated in the same manner as in Referential example 1-(14-) to give 301 mg of a crude product of the desired compound.
IR spectrum (liquid fil~) v maxcm 1:
1770, 1030 ~MX spectrum (C~Cl3) ~ ppm:
0.91 (3H, doublet, J=6 Hz) 15 (6) 3-Oxo-~ (3~-(2-tetrahydropyranyloxy)-5,9-. ~
dimet~yldeca~1,8-dienyl)-7-anti(2-tetra-~y~ pyranylox~r)-2-oxabic;Yclo (3 3 0)^octane (XIX) 3-Oxo-6-syn(3~-hydroxy-5,9-dimethyldeca-1,8-20 dienyl)-7-antihydroxy-2-oxabicyclo (3 3 0)-octane was reacted and treated in the same manner as in Referential example 1-(14) to give a crude product of the desired compound.
IR spectrum (liquid film) v maxcm 1:
1770, 1025 ~MR spectrum (CDCl3) 8 ppm:
0.90 (3H, doublet, J=6 Hz) (7) 3-Hydro~r-6-sYn(3a-(2-tetrahydro~yra~yloxyj-5,9-dimethyldeca-1,8-dienyl)-7-anti(2-,etra_ ~dropyra~lo~ ~ o~ c~ O~-o ~n~

(6 ' . .

~ 956 In 5 ml OI toluene was dissolved 190 mg of 3 oxo~ n(3a-(2~tetrahydropyranyloxy)-5,9-dimethyldeca-1,3-dienyl~-7-anti(2-tetrahydropyranyloxy)~2-o:cabicyclo-(3-3-0)-octane, and the so]ution was cooled to -60C. To this solution was added with stirring 190 mg of diisobutyl-alwninum hydride in 1 ml of toluene, and the mixture was stirred for 30 minutes. After completion of th~ reaction, 1 ml of methanol and water were added to the reaction mixture, and this was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfateO ~he solvent was evaporated from the extract to leave 170 mg of the desired compound as an oil.
IR spectrum (liquid film) v ~axcm 1:
3420, 1030 NMR spectrum (CDCl3) ~ ppm:
0.91 (3H, doublet, J=6 Hz) (8) 3-~ydroxy-6-~~(3~-(2-tetrah~dro~yranyloxy)-5,9-dimethyldeca-1,8-dienyl)-7-anti(2-tetra-~_r ~ 0)-octane (XX) 3-Oxo-6-s~(3~-(2-tetrahydropyrar~loxy)-5,9-dimethyldeca-1,8-dienyl)-7-anti(2-tetrahydropyranyloxy)-2-oxabicyclo(3-3-0)-octane ~as reacted and treated in the same manner as in Referential example 3-(7) to give the desired compound as an oil.
IR spectrum (liquid film) v maxcm 1:
3410, 1030 N~ spectrum (CDCl~) 8 ppm:
0.90 (3H, doublet, J=6 Hz) (9) 9a-Hydroxy-11a ~5a-di(2-tetrahydropyr~loxy)-17~-methyl-20-isopropylideneprost-5(cis) ~13~trans)-.
~ .. . . ~ . , i~Z9s6 dienoic acid (II) .__ 624 mg o~ tripherlylcarboxybutylphosphoni.um bromide in 2 ml of dimeth~lsulfoxide was added dropwise with stirring below -20C in a stream of ar~on to 1 3 ml 5 of 2M sodium methylsulfinyl carbanion in dimethylsulfoxide so that a ylide solution having red color was obtained.
'~o this solution was added 220 mg of 3-hydroxy-6-~t3~-(2-t~trahydropyranyloxy)-5,9-dimethyldeca-1,8-die~yl3-7-anti(2-tetrahydropyranyloxy)-2-oxabicyclo(3 3 0)-octane in 5 ml of dimethylsulfoxide, and the mixture was stirr.ed at room temperature for 20 hours. After completion o~
the reaction, the dimethylsulfoxide was evaporated under reduced pressure to leave the residue~ An aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was then washed with ethyl acetate to remove the neutral materials. 'rhe a~ueous portion was adjusted to about pH 3 with oxalic acid and extracted with a mixture of hexane - ether (1 : 1). 'rhe extract was washed with water and dried over anhydrous sodium sulfate~ '~he solvent was evaporated from the extract to leave 198 mg of the desired compound as an oil.
IX spectrum (liquid film) v maxcm 1:
3L~00 ~ 1 708 N~R spectrum (CCl~ ppm:
0.91(~H,doublet,J=~Hz),5.01 (1H,triplet, J=6 Hz) (10) 9~-.Hydroxy-11~ ~1~B-di~2-tetra4ydrop;l~s~3~
methyl-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid (II~
3-Hydroxy-5 ~(3~-(2-tetrah~dropyr~Tloxy)-5,9-dimethyldeca-1,8-dienyl)-7~aT1ti(2--tetrabydropyranyloxy)-~6~) ~i .
2-oxabicyclo (3 3 0)-octane was reacted and treated in the same manner as in Xeferential example 3-(9) to give the desired. compound as an oil.
IR spectrum (liquid film) v maxcm 1:
3400, 1710 ~MR spectrum (CCl4) ~ ppm:
0.91 (3H, doublet, J=6 Hz),5~02 (1H, triplet, J=6 Hz) Referential example 4 10 Methyl 9a-hydroxy-11a ~15~-di(2-tetra~ydrop~rc~yloxy)-17~-met~yl-20-isopropylideneprost-5( is) ,13(trans)-dienoate (II) An ethereal solution of diazomethane was added to 730 mg of 9~-~ydroxy-11a,15~-di(2-tetra~ydropyranyloxy)-15 17~-met~rl-20-isopropylideneprost-5(cis) ,13(trans)-dienoic acid in 5 ml of ether until the reaction mixture turlled pale yellow. After completion of the reaction, the solvent was evaporated under reduced pressure to give 728 mg of the desired compound as an oil.
IR spectrum (liquia film) ~ maxcm 1:
3400, 1730 MR spectrum (CCl4) ~ ppm:
0.91 (3~I, doublet, J=6 Hz),5.01 (1H, triplet, J=6 Hz) Referential example 5 ydroxy~11~.,15-di(2-tetra~ydropyranylo~y)-20-isopropylideneprost-13(trans)-enoic acid (1) 9~-Aceto~-11c~-(2-tetra~ydropyrc~yloxy)-15-oxo-20-isopropylideneprost-13(tran;)-enoic acid (XII) . .
117~4 mg of 52 ~9//o oily sodiv~ hydride, 1 g of . - 71 (70) ' l~qZ956 dimet~rl 2-oxo-~3~met~yl-7-nonenylphosphonate prepared by the procedurc stated in l~eferential ex~Tlple 1~(10) and 680 mg of 1~-(2-tetra~ydropyranyloxy)-2~-formy1-3~-(6-metho~ycarbonylhexyl)-4~-acetoxycyclopentarle were reacted and treated in the same manner as in Referential example 1-(11) to give 898 mg of the desired compound as an oil~
IR spectrum (liquid film) v maxcm 1:
1735, 1~95, 1570, 1625, 1035 ~MR spectrwn (CCl4) ~ ppm:
1~48 (3H, singlet), 1.58 (3H, singlet)1 1.87 (3H, sin~let) 7 3.48 (3H, singlet), 6.22 (2H, multiplet) (2) ~ __cetoxy~ (?-tetrahydr~ ar~loxy)-15 hydroxy-20-isopropylid.eneprost-13(trans)-enoate (XIII) 898 mg of methyl 9~-acetoxy-110-(2-tetra-hydropyranyloxy)-15-oxo-20-isopropylideneprost-13(_rans)-enoate was reacted and treated in the sme manner as in Referential exa~ple 1-(12) to give 851 m~ of the desired compound as an oil.
IR spectrum (liquid film) v maXcm 3420, 1735 (3) ethyl ~ - 1a~15-di(2-tet h~__opyranylo~Y)-o~ylideneprost-13(tr~ ~ = o te (XIV) 851 m~ of Methyl 9~~acetoxy~ -(2-tetra-hydropyranyloxy)-15-hydroxy-20-isopropylideneprost-13(trans)-e~oate ~as reacted and treated in the same manner as in ~eferential example 1 (14) to ~ive 1.55 ~ of a crude product of the aesired compound.
(4) 9~-Hydr~ d~ t~
isoprop~ r~E~__t-1~(trans)-enoic acid (II) ` (71 29~6 1.j5 g of crude methyl 9~-ac~to~-11~,15-di(2--tetrah~dropyranyloxy)-20~isopropylideneprost-13(trans)-enoate was reacted and treated in the same manner as in Referential example 1-(16) to Oive 1.01 g of the desired compound as an oil.
IR spec~rum (liquid film) v maxcm 1:
3380, 1710, 1035, 1020 ~R spectrum (CCl4) ~ ppm:
5~44 (2H, multiplet) Referential example 6 droxy-11f~ ,15~ (or ~)-di(2-tetrahydropyranyloxy) ? -isopropylideneprost-5(cis) ,13(-trans)-dienoic acid (II) . .
(1) 3-Oxo-6-~s~n(3-oxo-9-methyldeca-1,8-dienyl)-7-. .
~nbi(p-phe~ylbenzoyloxy)-2-oxa-cls bicylco-(~ 3 O)-oct ne (XVII) ~ 346 mg of 52.9% oily sodium hydride was washed with dry petroleum ether to remove the oil and suspended ! . in 20 ml of dimethoxyethane. '~o the suspension was added dropwise under ice-cooling in a stream of ~rgon 20 ml of dimethoxyethc-~.e solution containi.ng 2.075 g of di~ethyl 2-oxo~8-methyl-7-nonenylphosphQnate obtained in Referential example 5-(1), followed by stirring for additional j.5 hours. To the suspension was added 10 ml of dimethoxy-ethane and added ~lropwise under ice-cooling 30 ml of 2~ dimethoxyethane solution containing 1~22 g of 3-oxo-6-~,formyl-7-cmti(p-phenylbenzoyloxy)-2-oxa-cis-bicyclo-~3-3-0)-octane ~XVI). The mixture was stirred for 2 hours.
After completion of the reaction, the mix-ture was treated with the sc~le procedure as in Rel`erential example 3 to give 1.37 g of the desired product as an oil.

(7~) l~q~956 IR spect;rum (liquid ~ilm) v maxcm 1:
1733, 1723, 1680, 1635, 1280, 1185, 1120, 755 NMR spec-trum (CDCl~) ~ ppm:
5~0-5.5 (3H, multiplet), 6.28 (1H, doublet), 6.8 (11I, quartette), 7.3-~.2 (9H, multiplet) (2) 3-Oxo-6~s~n(3~ (or 3~)-hyd~ h~yl-1,8-die~yl)-7- n _ (p-phe~ylbenzolyloxy)-2 oxa- _s-bicyclo (3 2 0)_oc_ane (XVIII) In 5 ml of dimetho~yethane was dissolved 290 mg of 3-oxo-6-~(3-oxo-9-methyldeca-1,8-dienyl)-7-anti(p-phe~ylbenzoyloxy)-2-oxa-cis-bicyclo (3-3-0)-octane.
To the solution was added under ice-coolin~ 1 ml of 0.55 molar concentrati~n zinc boron hydride di~ethoxyethane solution, followed by stirring for one hour. After ; 15 comp]etion of the reaction, the mixture was treated with the same procedure as in Referential example 3-(2). ~he product obtalned was ~ubjected to a preparative thin layer chromatograp~y and developed with ether to give 95 mg of the 3~-isomer of the desired product from the less polar portion and 77 mg of the 3~-isomer of the desired product from the more polar portion.
3~ droxy isomer IR spectrum (liquid film) v maxcm 3500, 1780, 1720, 1615, 1280, 1185, 1120 975, 750 NMR spectrum (CDCl3) 8 ppm:
4.13 (1H, multiplet), 4.9-504 (3II, multiplet), 5.64 (2H, multiplet), 7.3~8.2 (9EI, multiplet) 3~-Hydroxy isomer IR spectrum (liquid Iilm) v maxcm 1:

(73) .
.
. .

3500, 1780, 1720, 1615, 1280, 1185, 1120, 975, 750 NMR spectrum (CDCl3) ~ ppm:
4 13 (1H, multiplet), 4.9-5.4 (3H, multiplet), 5.64 (2H, multiplet), 7.3-8.2 (9H~ multiplet) (3) 3-Oxo-6-~n(3~-hydroYy-9-methyldeca-1,8-dienyl)-7-antihydroxy-2-oxa-cis--bicyclo (3-3 0)-octane (XVIII) In 3 ml of anhydrous methanol were dissolved 140 m~ of 3-oxo-6-~n(3~-hydroxy-9-methyldeca-1,8-dienyl)-7-anti(p-phenylbenzoyloxy)-2-oxa-cls-bicyclot3-3 0)-octane and 75 mg of anhydrous potassium carbonate, followed by stirring for 35 minutes After completion of the reaction, the mixture was treated by the same procedure as in Re~erential example 3-(3) to giv~ 99 mg of the desired , ; produot as an oil.
IR spectrum (liquid film) v maycm 1:
3400, 1760, 1175, 1080, 970 N~IR spectrum (CDCl3) ~ ppm:
1.60 (6H, doublet), 3.8-4.2 (2~, multiplet), 4.8-5.3 (2~i, multiplet), 5.55 (2H, multiplet) (4) 3-Oxo-6-syn(3~-hydrox~-9-methyldeca-1,8-dienyl~-7-a tihydroxy-2-oxa-cis-bicyclo (3-3-0)-octane (XVIII) ~ollowing the same procedure as in Referential example 6-(3), but replacing 3-oxo-6-~(3~-~ydroxy-9-methyldeca-1,8-dienyl)-7-anti(p-phenylbenzoyloxy)-2-oxa-_ -bicyclo (3 3 O)-octane with 91 mg of 3-oxo-6-syn(3~-hydrox~-9 methyldeca-1,8-dienyl)-7-&nti-(p-phenylb~nzoylo~r)-2-oxa-cis-bicyclo t3-3-0)-octane, there was obtained the (74J
.

~ Z~56 ; desired product.
I~ spectrum (liquid film) v maxcm 1 3400, 1760, 1175, 1080, 970 N~IR spectrum (CDCl3) ~- ppm:
1.6 (6H, doublet), 3 8-4.2 (2H, multiplet), 4.8-5.3 (2H, multiplet), 5.55 (2II, multiplet) (5) 3-Oxo-6~ n(3~-(2-te-trahydropyranyloxy)-9-methyldeca-1,8-dienyl)-7-anti(2-tetra-hy~ropyranyloxy)-2-oxa-cis-bicyclo (3 3 0)-_ctane_(XIX~
To 15 ml of benzene solution of containing 3.08 g of 3-oxo-6-syn(3a-hydroxy-9-methyldeca-1,8-dienyl)-7-antihydroxy-2-oxa-cis-bicyclo (3 3 0)-octane was added 1.~5 g dihydropyrane at room temperature ~nd added a cat~lytic amount of picric acid under ice-cooling, followed by allowing for 3 hours. After completion of the rcaction, 200 ml of ether was added to the reaction mixture. 'rhe mixture was neutralized with 10/~ aqueous ~odium bicarbonate, washed with water and dried o-ver anhydrous sodium sulfate.
The solvent was distilled off and the residue was purified by silica gel ool~mn chromato~ral)hy to give 4.3 ~ of the de~ired product as an oil.
IR spectrum (liquid ~ilm) v maxcm 1:
1775, 1130, 1070, 1015, 970 NMR spectru~ (CDCl3) ~ ppm:
4.7 (2H, multiplet), 4.8-5.2 (2H, multiplet), 5 r O (2H, multiplet) (6) 3-Oxo-6-syn(3~-(2-t;etrdllydrop~Jrany1oxy)-9-methyldeca-1,8-di~nyl)-7-anti(2-tetrahydropyran~-lox~-~-2-oxa-ci~-bicyclo (3 ~ 0)-octane (XIX~

(75) .

7Z9s~

~ 'ollowing -the same proccdure as in Referential exampl~ 6-(5), but replacing 3-oxo-6-s~in(3~-hydroxy-9-methyldeca-1,8-dienyl)-7-anti4ydroxy-2-oxa-cis-bicyclo (3-3 0)-octane with 2,7 g of 3-oxo-6-syn(3~-h~Ydroxy-9-methyldeca-1,8-dienyl)-7-antihydroxy-2-oxa-cis-bicyclo-t3-3 0)-octane, there was obtained 3.5 g of the desired product as an oil, IR spectrum (liquid film) v maxcm 1:
1775, 1130, 1070, 1015, 970 NMR spectrurn (CDCl3) ~ ppm:
4O7 ~2H, multiplet), 4.8-5.2 (2H, multiplet), 5.0 (?H, multiplet) (7) 3-Hydro~J-6-syn(3~-(2-tetrahydropyra~yloxy~-9-methyldcca-1,8-dienJl)-7-anti(2-tetrahydropyra~yloxy)-2-oxa-cis-bicyclo (3 3 3)-octane (XX) . , _~
~ ollowing the same procedure as in Re~erential example 3-(7), but replacing 3-oxo-6-~(3~-(2--tetra-hydropyranyloxy)-5,9-dimethyldeca-1,8-dienyl)-7-anti(2-tebrahydropyranyloxy)-2~oxa-cis-bicyclo (3-3 3)-oc-tane with 4.3 ~ of 3~oxo-6-~(3~-(2-tetrahydropyranyloxJ)-9-methyldeca-1,8-dienyl)-7-anti(2-tetrahydropyranyloxy)-2-oxa-cis-bicyclo (3 3 0)-octane, there was obtained 4.1 g of the desired product as an oil.
IR spectrum (liquid film) v maxCm 3400, 1130, 1070, 1015, 970 N~ spectrum (CDCl3) ~ ppm:
4~7 (2H, multiplet), 5.15 (1~, triplet), 5.6 (2H, multiplet) (8) 3-IIydroxy-6-s~n(3~-(2-tetrahydrop~-rc~nyloxy)-9-methyldeca~1,8~dienyl)-7-anti(2-te-trahydropyra~yloxy)-. _ .__ -- _ . ._ .

~ (76 .... . ..

~7~5~

2--oxa-cis-bicyclo (3 3 0)-octane (XX) Following th~ same procedure as in Referential ex~nple 3-(7), but replacing 3-oxo-6~ (3cx-(2-tetra-~ydropyranyloxy)-5,9 di~ethlyldeca-1,8-dienyl)-7-anti-(2--tetrahydropyra~yloxy)-2-oxa-cis-bicyclo (3 3 0)-octane with 3.5 g of 3-oxo-6-syn(3~-(2-tetra~yclropyranyloxy)-9-methyldeca-1~8~dienyl)-7-anti(2-tetrahydropyra~ylo~y)-2-oxa-cis-bicyclo (3 ~ 0)-octane, there was obtained 3.3 g . _ .
of the desired product as an oil.
IR spectrum (liquid filrn) v maxcm 1:
3400, 1130, 1070, 1015, 970 I~MR spectrum (CDCl3) ~ ppm:
4-7 (2H, mul-tipl~t)1 5.1, (1H, triplet), 5.6 (2H, multiplet) (9) 9cx-Ilydrox~-11cx ~15cx di(2-tetrah~ydro~ranylox~)-20-isopropylideneprost~5( _s) ,13(trans)-dienoic acid (II) Following the same procedure as in Referential exarnple 3-(9), but replacing 3-hydro~y-6-~y~(3~-(2-tetr~hydropyranylo-,cy)-5,9-dirnethyldeca-1,8-dienyl)-7-anti(2-tetIahydropyranyloxy)-2-oxa-bicyclo (3 3 0)-octane ~_., with 4.1 g of 3-hydroxy-6-syn(3a-(2-tetra.~-dropyr~ylox~)-9-met~yldeca-1,~-dienyl)-7-anti(2-tetrahyrlropyranyloxy)-2-oxa-cis-bicyclo (3 3 0)-octane, there was obtained 3.6 g of the desired product as an oil.
IR spectrum (lic1uid film) v maxcm 1: -34-509 3200, 2750, 1715, 1160, 1105~ 1020 NMR spectrum (CDCl3) ~ ppm:
4~73 (2H, muitiplet), 5.17 (1H, triplet~, 5.5 (4~, multiplet) ` ~77) .
... . . .

(10) ~ ,15~-di(2 tetrah~ydro~yranyloxy)-20-isopropylideneprost-5(cis) ,13(+v ns~-clienoic acid (II) ~ollowing the same procedure as in Referential example 3-(9), but replacing 3-oxo~6-~y~(3~~(2-tetra-hydropyranyloxy)-5,9-di3nethyldeca-1,8-dienyl)-7-anti(2-tetrahydropyra~yloxy)-2-oxa-eis-bicyclo (3 3 0)-octane with 3 3 g of 3-~ydroxy-6-~(3~-(2-tetra~ydropyra~yloxy)-9-methyldeea-1,8-dienyl)-7-anti(2-tetrahydropyranyloxy)-2-oxa-_is-bicyclo ~3 3 0)-octane, there was obtained 3.0 g of the desired product as an oil.
IR speetrum (liquid film) v maxem 1:
3450, 3200, 2750, 1715, 1160, 1105, 1020 NM~ speetrum (CDCl3) ~ ppm:
4 73 (2H, multiplet), 5~17 (1H, triplet), 5.5 (4~, multiplet) Referential example 7 9~Hydroxy-15-(2-tetrahydropyranyloxy)-20-isopropyl_dene-prost-13(trans)-enoic aeid (II) (1) 3-Oxo-6-syn(2-tetrahydropyranylo~meth~l) -?-oxa-bicyclo ~3 3 0)-octane (XXIII) In 15 ml of anhydrous 2,3-dihydropyran was dissolved 3.35 g of 3-oxo-6-synhydroxymethyl-2-oxa bleyclo-(3-3-0)-oetane, and, after addition oi 15 mg of p-toluenesulfo~ie aeid, the resulting solu-tion~ls stirred at room temperature for 20 minutes. After completion of the reaction, the solution was diluted with 200 ml of et~yl acetate and washed with three portions of 100 ml of a saturated aqueous doiu~ ehlorid solution. After drying it over anh~drous sodium sulfate, the solvent was (78) .
.

lO'~Z95~

evaporated to leave 5~55 g of the desire~ compound as an oil.
IR spectrum (liquid film~ v maxcm 1:
1780, 1165, 1125, 1035 (2) 3-Hydroxy-6-syn(2-tetrahydropyranyloxymetnyl)-2-oxa-bicyclo (3 3 0)-octane (~XIV~
In 100 ml of anhydrous toluene was dissolved 5.9 g of 3-oxo-6-syn(2-tetrahydropyranyloxymethyl)-2-oxa-bicyclo (3-3-0)-octane obtained in Referential example 7-(1), and the solution was then stirred at -70C in the stream of argon. ~o this solution was slowly added 21 ml of a diiso~utylaluminwTn hydride solution (25 g/100 ml of n-hexane), and the solution was stirred at -70C ~or 30 minutes~ ~fter completion of the reaction, to the solution was added slowly 180 ml of a rnixture of t~tra-hydrofuran and water (2:1). After the temperature of the resulting mixture reached room temperature, the precipitated insoluble substance was filtered off over Celite. The filtrate was diluted with a saturated aqueous sodium chlori-le solution ~nd extracted with et-hy] acetate. ~he organic portion was then washed with wat~r and dried over anhydrous sodium sulfate. Upon evaporation of the solvcnt, there was obtained 5.89 g of th~ desired compouncl as an oil.
IR spectrum (liquid film) v maxcm 1:
3450, 1125, 1065, 1025 NMR spectru~l (CDCl3) ~ ppm:
4.6-4.8 (2H, multiplet), 5.58 (1H, m~ltiplet) (3) 1~-Hydroxy 2a-(6-met'lo~carbonyl-2-ci_-hexeIl~l)-3~-~2-tetrahydrop~ranyloxymethyl)-c~rclopentane (XXV) (79) 107~g56 ~o a sodium methy]sulfonylcarbonion solution prepared Erom 7~10 g of sodium hydride containing 50% of an oil and 200 ml of dimethylsulfoxide was added, below a temperature of -20C in a stream of ar~on, 32 g o~
5 triphenylphosphonium bromide, to prepare a red color ylide solution. To this solution was added 20 ml of dimethyl-sulfoxide containing 5.8 g of 3-hydroxy-6-s~n(2-tetra-hydropyranyloxymethyl)-2-oxa-bicyclo(3~3~0)-octane, and the mixture was stirred at room temperature for 30 minutes.
, 10 After completion of the reaction, the reaction mixture was diluted with 500 ml of cold (0C) 15% aqueous ~ hydrochloric acid and extracted with ether. ~he extract 3 was washed with water and dried over anhydrous sodium ~, sulfate. The solvent was evaporated to leave an oily ~ 15 residue of the carbo~ylic acid~
'~ ~he obtained residue was treated with an ethe~eal solution of diazomethane. Upon evaporation of the ether, 14 g of the ester was obtained as a residue.
The residue was treated with column chromato~raphy using 140 g of silica gel to ~ive 6.57 g of the desired compound ' as an oil.
IR spectrum (liquid I'il~) V maxcm 1:
34~0, 1740, 1200, 1140, 1120, 1030 N~ spectrum (CDC13) ~ ppm:
25 ' 3.67 (3H, singlet)~ 4.23 (11I, multiplet~, 4.~0 (1H, multiplet), 5~50 (2H, multiplet) I (4) 1~-hcet ~ 1-2 ci,.s,~hexenyl~-; ~-(2-tet,rah~ r ~ lo~ _ th~ opentane ~X~
In a mixture of 20 ml of pyridine and 10 ml of 0) ~ 56 ;; acetic anhydride was dis~olved 6.49 g of ~-hydroxy-2~-(6-methoxycclrbonyl-2~cis-hexenyl)-~-(2 tetr~h~dropyran~l-oxymethyl~-cyclopentane, and the resulting solution was stirred at 40C for 2 hours. After completion of the reaction, the reaction mixture was diluted with 150 ml of water and extracted with a mixture of benzene and ethyl acetate.
The extract was then washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to leave 7.26 g of the desired compound as an oil.
IR spectrum (liquid film) v maxcm 1:
1740, 1245, 1030 NMR spectrum (CDCl3) ~ ppm:
2.03 (3H, singlet), 3.67 (3H, singlet), 4.62 (1H, multiplet) t 5.23 (1H, multiplet), 5.42 (2H, multiplet) (5) 1~-Acetox~-2a-(6-methox~carbo~yl-2-_~-hexenyl)-3~-~ydroxymet~yl-cyclopentane (~rVII~
In 150 ml of aqueous methanol containing water (10%) was dissolved 7.20 g of 1~-acetoxy-2~-(6-methoxy-carbo~yl-2-cis-hexenyl)-3~-(2-tetrahydro~yranyloxymethyl)-cyclopentane, and, after addition of 1.4 g of p-toluene-sulfonic acid, the mixture was stirred at 40C for one hour. After completion of the reaction, thc mixture was diluted with 400 ml of ether and washed with a saturated aqueous sodiu~ chloride solution to remove the acid.
After drying it ovex anhydrous sodium sul~ate, the solvent was evaporated under reduced pressure to leave 5.79 g of an olly residue. The obtained residue was treated with (81) .

~72956 column chromatography usin~ 80 g of silica gel to give 5.053 g of the desired compound as an oil.
IR spectrum (liquid film) v maxcm 1:
3500, 1740, 1380, 1250, 1170, 1025 NMR spectrum (CDCl3) ~-ppm:
2.03 (3H, sin~let), 3.65 (2~, multiplet), 3.68 (3H, singlet), 5.25 (1H, multiplet), 5.45 (2H, multiplet) (6) 1a-AcetoxY-2o-(6-methoxycarbon~ylhe~yl)-3~ ydr meth~ clopentane (XXVIII) In 50 ml of methanol was dissolved 3.0 g of 1o~acetoxy-2O-(6-methoxycarbonyl-2-cis~hexenyl) 3~-hydroxymethyl-cyclopentane, and the resulting solution was subjected to the usual ~ydrogenation using 2.0 g of 5% palladium - carbon catalyst. After filtering off the catalysG, the solvent was evaporated under reduced pressure to lea~e 2.8 g of the desired compound as an oil IR spectrum (liquid film) v maxcm 1:
3500, 174C, 13~0, 1250, 1175, 1020 ~MR spectrum (CDCl3) ~ ppm:
2.03 (3~I, singlet), 3.63 (2H7 multiplet), 3.70 (3H, singlet), 5.28 (1H, mul-tiplet) (7) 1a-Acet_~-2a ~ -methoxycarbon~1he~
~ nt ~ X) To a mixture of 200 ml of anhydrous dichloro-methane and 11.7 g of pyridine was added with stirring at 15C in a stream of argon, 7.36 g of chro~ic anhydride, to prepare Collins oxidi~ing reagent. ~he obtained solution was cooled to 3 - 5C, c~ld 2.76 g of 1O-acetoxy-2o-(6-methoxycarbonylhexyl)-3~-hydroxymethyl-cyclopentane ~,2) , -~ -lO~Z~35~

was added thereto. ~he mixture was then stirred for 20 minutes~ After completion of the reaction~ the reaction mixture was diluted with 1 liter of ether. ~he mixture was then washed with 3% aqueous sodium hydroxide solution, 3% hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and water, successively, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2.56 g of the desired compound as an oil (8) ~ 9a-aceto~-15-oxo-20-isoprop~ideneprost-13(~x~n_~-enoate (XXX) 0.495 g of 50% oily sodium hydride was washed with dry petroleum ether to remove the oil. The obtained sodium hydride was suspended in 150 ml of anhydrous dimethoxyethane, and under ice-cooling, to this suspension was a~ded dropwise with stirring in a stream of argon, 2.7 g of dimethyl-2-oxo-8-methyl-7-nonerlylphosphonate.
The mixture was then stirred at room temperature for 4 hours. To the resulting solution was added under ice-cooling 2.50 g of 1~-acetoxy-2~-(6-methoxycarbonylhexyl)-3~-formyl-cyclopentane, and the mixture was stirred for 2 hov--s. After completion of the react-ion~ 200 ml of ether was added to the resulting solutionu The organic s~lution was washed with dilute hydrochloric acid and water, successively, and dried over anhydrous sodium suifate. The organic solvent was evaporated under reduced pressure to leave 4.58 g of an oily resldue. The obtained residue was purified o~ alumina column to give 2.45 g of the desired compound as an oil.
IR spectrum (liquid film) v m~cm~1:
~0 1740, 1700, 1670, 1625, 1370, 1240, 1170, 1020 (83) : . . , 9~6 ~MR spectrum (CDCl3) ~ ppm:
2.Q3 (3H, singlet), 3.64 (3H, ~ingl~t), 5.00 - 5.35 (2H, multiplet), 6.10 (1H, doublet), 6.52 (1H, quart~et) 5 (9) Methyl 9a-acetoxy-15-4ydroxy-20-isopro~y~ 3~ ost-__ 13(trans)-enoate (XXXI) In 50 ml of anhydrous methanol was dissolved 2.4 g of methyl 9a-acetoxy-15-oxo-2o-isopropylideneprost 13( ra_s)-enoate, and th~ solution was cooled to 3 - 5C
and stirred. ~o this solution was added 210 mg of sodium boron hydride, and the mixt~lre was stirred at 3 - 5C for OD.O hour. After completion of the reaction, the mixture was diluted with cold 3% aqueous hydrochloric acid and extracted with a mixture of benzen~ and ethyl acetate.
~'he extract was washed with water and dried over anl~drous sodium sulfate. ~he solvent was evaporate to l~ave 2.5 g of an oily re~idue. The obtained residue was purified on silica ~ei column to give 2.36 g of the desired compound as an oil.
~R spectrum (liquid film) v ~axcm 1:
3500, 1740, 1245, 1020 NM~ spectrum (CDCl3) ~ ppm:
2.0 ~3H, singlet), 3 65 (3~I, singlet), 4.07 (1II, multiplet), 5.0 - 5.4 (2~ ultiplet), 5-5 (2H, multipiet) (10) ~ dro~ra~loxy)-20-iso~p~lideneprost 13(trans)-enoate (XX~II) _____ In 5 ml of 2,3-dihydropyran was dissolved 2.3 g o~ ~nethyl 9a acetoxy-15-hydroxy-20-isopro~)y~ideneprost-13(trans)-enoate, and, aftcr addition of 10 mg of (84) . . , ..

1~72gS6 p-toluenesulfonic acid, the mixture was stirred at .room temperature for 30 minutes. After compl.etion of the reaction, 200 ml of ether was added to the mixture. '~he ~ixture was then washed with 3 portions of 100 ml of.water 5 and dried over anhydrous sodium sulfate. ~he solvent was ev~porated to 2.8 g of the desired compound as an oil.
IR spectrum (liquid film) v maXcm 1:
1740, 1375, 1240, 1200, 1020, 965 (11) ~ -H;ydroxy-15-(2-tetrahydropyranylo~ )-20-isopropylideneprost-13(tran.s)-enoic acid (II) In 90 ml of methanol. was dissolved 3.0 g of methyl 9~-acetoxy-15-(2-tetrahydropyranyloxy)-20-isopropylideneprost-13(trans)-enoate, and~ after addition of 30 ml of 5% aqueous sodium hydroxide solution, the 15 mixture was stirred at 40C for 3 hours After completion of the reaction, the mixture was diluted wi.th ice-water, . . . - neutralized with 7% aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate. T~e 20 solvent was evaporated under reduced pressure to leave 2.6 g of the desired compound as an oil.
IR spectrum (liquid fi:Lm) v maxcm 1:
3420, 2750, 1710, 1200, 1110, 1020, 970 NMR spectrum (CDCl3) ,~ ppm:
4.7 (1H, multiplet), 5.0 - 5.5 (3H, multiplet), 6~0 (2H, multiplet) Referential example 8 H~drox~y-15-(2-tetrah;s~drop~ranylox~)-?0-~r~idene-prost-5(cis), 13(trans)-dienc-ic acid (II) 30 (1) 1c~-Aceto}~-20~-(6-me~ ~ex~.~l) (85) ` , .. ' lV7Z9S6 3~-formyl-cyclo~entc~ne (~XXV) 2.0 g of 1~-aceto}~-2~-(6-methoxycarbonyl-2-cis-hexenyl)-3~-hydroxymet4yl-cyclopentane was reacted and treated in the same manner as in Referential example 7-(7) to give 1.95 g of the desired compound as an oil.
(2) Methyl 9~-acetoxy-15-oxo-?0-isopropylideneprost-5( s) ,13(t an ~-dienoate (XXXVI) 1.95 g of 1a-acetoxy-2~-(6-methoxycarbon~yl-2-cis-hexe~yl)-3~-formyl-cyclopentane was reacted and treated in the same manner as in Referential example 7-(8) to give 2.53 g of the desired compound as an oil.
IR spectrum (liquid film) ~ maxG~ 1:
1735, 1695, 1670, 1630, 1370, 1240, 1160, 1030 NMR spectrum (CDCl3) ~ ppm:
2.02 (3H, singlet), 3.65 (31I, singlet), 5.0 - 5.5 (3H, multiplet), 6.10 (1H, doublet), 6~72 (1H, quarttet) (3) Me 4yl 9a-acetoxy-1~ dr x~-20-iso~rop~lidene~rost-5(cis) ,13(_rans)-dienoate (XY~rVII) ! 2-58 g of methyl 9~-acetoxy-15-oxo-20-isopropylideneprost-5(cis), 13(trans)-dienoate was reactcd and treated in the same manner as in ~eferential example 7~(9) to give 2.24 g of the desired compou~ld as an oil.
IR spectrum (liquid film) v maX~m 1:
3500, 1740, 1370, 1240, 1160, 1020, 965 NM~ spectr1lm (CDCl3) ~ ppm 2~01 (3H, singlet), 3.67 (3H, singlet), 4.0~ (1F1, multiplet), 5.0 - 5.6 (5H, multiplet) 30 (4) ~ 9~- etoxy-15-(?-tetral~ydro-pyranyl xy)-20-(86) .
- - ~
- : . - ' : . . .

l~qZ956 isopropylideneprost-5(cis) ,13(trans)-dienoate ~XXXVIII) 2.20 g of methyl 9-acetoxy-15-hydroxy-20-isopropylideneprost-5(cis) ,13(trans)-clienoate was reacted and treated in the same manner as in Referential example 7-(10) to give 2.90 ~ of the desired compound as an oil.
IR spectrum (llquid film) v maxcm 1:
1740, 1370, 1240, 1200, 1015, 970 (5) 9a-Hydro~-15-(2-tetrah dropyranylo~y~-20-isopropylideneprost-5(cis) ,1~(trans)-dienoic acid (II) In 80 ml of methanol was dissolved 2.91 g of methyl 9a-acetoxy-15-(2-tetrahydropyranyloxy-20-isopropylideneprost-5(cis) ,13(trans)-dienoate, aIld after addition of 50 ml of 5% aqueous sodium hydroxide ~solution, the mixture was stirred at 40C for 3 hours. hfter completion of the reaction, the reaction mixture was diluted with 200 ml of ice-water, neutralized with 7%
aqueous l~ydrochloric acid and extracted with ethyl acetate.
The extract was then washed with water and dried over anhydrous sodium sulfate. ~he solvent was evaporated under reduced pressure to leave 2.51 g of the desired compound as a~ oil.
I}2 spectrum (liquid film) v maxcm 1:
3450, 3150, 2650, 1710, 1200, 1130, 1110, 1015, 965 N~ spectrum (CDCl3) ~ ppm:
4.70 (1H, multiplet), 4~95 - 5.60 (5H~ multiplet), 5~90 (2Hg multiplet) - (~7)

Claims (40)

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

1. A process for producing prostenoic acid derivatives having the formula (I) wherein, A represents an ethylene group or a cis-vinylene group;
R1 and R2 may be the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
R3 and R4 may be the same or different and each represents an alkyl group having from 1 to 3 carbon atoms; and R5 represents a hydrogen atom or a hydroxyl group; and pharmaceutically acceptable salts thereof, which comprises oxidizing a compound of formula (II) (wherein A, R1, R2, R3 and R4 have the meanings previously given, R5' represents a hydrogen atom or the group -0R6; and R6 represents a hydroxyl-protecting group) to a compound of formula (III) wherein A, R1, R2, R3, R4, R5' and R6 have the meanings pre-viously given), removing the hydroxyl-protecting group R6 from said compound of formula (III) to obtain a compound of said formula (I) and, when a pharmaceutically acceptable salt is required, salifying the product of formula (I).

2. Prostenoic acid derivatives having the formula (I) wherein, A represents an ethylene group or a cis-vinylene group, R1 and R2 may be the same or different and each represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, R3 and R4 may be the same or different and each represents an alkyl group having from 1 to 3 carbon atoms, and R5 represents a hydrogen atom or a hydroxyl group, and pharmaceutically acceptable salts thereof, when prepared by the process according to Claim 1 or an obivous chemical equivalent thereof.

3. A process as claimed in claim 1 in which in the reactants R5' is a hydrogen atom.

4. A process as claimed in claim 1 in which in the reactants R5' is the group OR6 where R6 is as in claim 1.

5. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 represents a hydrogen atom whenever prepared or produced by the process as claimed in claim 3 or an obvious chemical equivalent thereof.

6. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 represents a hydroxyl group whenever prepared or produced by the process as claimed in claim 4 or an obvious chemical equivalent thereof.

7. A process as claimed in claim 1 which comprises treating9.beta.-hydroxy-ll.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoic acid in acetone with Jones reagent at a sub-zero temperature and treating the 9-oxo-11.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylidene-prost-13(trans)-enoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

8. 9-oxo-11.alpha.,15.alpha.-dihydroxy-17.beta.-methyl-20-isopropyl-ideneprost-13(trans)-enoic acid whenever prepared or produced by the process as claimed in claim 7 or an obvious chemical equiva-lent thereof.

9. A process as claimed in claim 7 in which the 9-oxo-11.alpha.,15.alpha.-dihydroxy-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoic acid so obtained is treated in aqueous alcohol with potas-sium hydrogen carbonate in aqueous methanol.

10. Potassium 9-oxo-11.alpha.,15.alpha.-dihydroxy-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoate whenever prepared or pro-duced by the process as claimed in claim 9 or an obvious chemical equivalent thereof.

11. A process as claimed in claim 1 which comprises treating 9.beta.-hydroxy-11l.alpha.,15.beta.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoic acid in acetone with Jones reagent at a sub-zero temperature and treating the 9-oxo-11.alpha., 15.beta.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

12. 9-oxo-11.alpha.,15.beta.-dihydroxy-17.beta.-methyl-20-isopropyl-ideneprost-13(trans)-enoic acid whenever prepared or produced by the process as claimed in claim 11 or an obvious chemical equiva-lent thereof.

13. A process as claimed in claim 1 which comprises treating methyl-9.beta.-hydroxy-11.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoate in acetone with Jones reagent at a sub-zero temperature and treating the methyl 9-oxo-11.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyyl-20-isopropylidene-prost-13(trans)-enoate so obtained with a mixture of acetic acid, water and tetrahydrofuran.

14. Methyl 9-oxo-ll.alpha.,15.alpha.-dihydroxy-17.beta.-methyl-20-isopropylideneprost-13(trans)-enoate whenever prepared or pro-duced by the process as claimed in claim 13 or an obvious chemical equivalent thereof.

15. A process as claimed in claim 1 which comprises treating 9.alpha.-hydroxy-11.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid in acetone with Jones reagent at a sub-zero temperature and treating the 9-oxo-ll.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

16. 9-oxo-ll.alpha.,15.alpha.-dihydroxy-17.beta.-methyl-20-isopropyl-ideneprost-5(cis), 13(trans)-dienoic acid whenever prepared or produced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.

17. A process as claimed in claim 1 which comprises treating 9.alpha.-hydroxy-ll.alpha.,15.beta.-di(2-tetrahydropyranyloxy)-17.beta.--methyl-20-isopropylideneprost-5(cis),13(trans)-dienoic acid in acetone with Jones reagent at a sub-zero temperature and treat-ing the 9-oxo-ll.alpha.,15.beta.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

18. 9-oxo-ll.alpha.,15.beta.-dihydroxy-17.beta.-methyl-20-isopropyl-ideneprost-5(cis), 13(trans)-dienoic acid whenever prepared or produced by the process as claimed in claim 17 or an obvious chemical equivalent thereof.

19. A process as claimed in claim 1 which comprises treating methyl-9.alpha.-hydroxy-ll.alpha.,15.alpha.-di(2-tetrahydropyranyloxy) 17.beta.-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoate in acetone with Jones reagent at a sub-zero temperature and treat-ing the methyl 9-oxo-ll.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoate so obtained with a mixture of acetic acid, water and tetrahydrofuran.

20. Methyl 9-oxo-ll.alpha.,15.alpha.-dihydroxy-17.beta.-methyl-20-isopropylideneprost-5(cis), 13(trans)-dienoate whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.

21. A process as claimed in claim 1 which comprises treating 9.beta.-hydroxy-ll.alpha.,15-di(2-tetrahydropyranyloxy)-20-iso-propylideneprost-13(trans)-enoic acid in acetone with Jones reagent at a sub-zero temperature and treating the 9-oxo-lla, 15-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-13(trans)-enoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

22. 9-oxo-ll.alpha.,15.alpha.(or .beta.)-dihydroxy-20-isopropylidene-prost-13(trans)-enoic acid whenever prepared or produced by the process as claimed in claim 21 or an obvious chemical equivalent thereof.

23. A process as claimed in claim 1 which comprises treating 9.alpha.-hydroxy-ll.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-20-iso-propylideneprost-5(cis), 13(trans)-dienoic acid in acetone with Jones reagent at a sub-zero temperature and treating the 9-oxo-ll.alpha.,15.alpha.-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

24. 9-oxo-ll.alpha.,15.alpha.-dihydroxy-20-isopropylideneprost-5-(cis), 13(trans)-dienoic acid whenever prepared or produced by the process as claimed in claim 23 or an obvious chemical equiva-lent thereof.

25. A process as claimed in claim 1 which comprises treating 9.alpha.-hydroxy-ll.alpha.,15.beta.-di(2-tetrahydropyranyloxy)-20-iso-propylideneprost-5(cis), 13(trans)-dienoic acid in acetone with Jones reagent at a sub-zero temperature and treating the 9-oxo-ll.alpha.,15.beta.-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-5-(cis), 13(trans)-dienoic acid so obtained with a mixture of acetic acid, water and tetrahydrofuran.

26. 9-oxo-11.alpha.,15.beta.-dihydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid whenever prepared or produced by the process as claimed in claim 25 or an obvious chemical equiva-lent thereof.

27. A process as claimed in claim 1 which comprises treating 9.alpha.-hydroxy-15-(2-tetrahydropyranyloxy)-20-isopropyl-ideneprost-13(trans)-enoic acid in acetone with Jones reagent at sub-zero temperature, treating the 9-oxo-15-(2-tetrahydro pyranyloxy)-20-isopropylideneprost-13(trans)-enoic acid so obtained with aqueous acetic acid, treating the product obtained with an ethereal solution of diazomethane and separating the product by means of column chromatography and thin layer chroma-tography.

28. Methyl 9-oxo-15.alpha.(or.beta.)-hydroxy-20-isopropylidene-prost-13(trans)-enoic acid whenever prepared or produced by the process as claimed in claim 27 or an obvious chemical equivalent thereof.

29. A process as claimed in claim 27 in which the methyl 9-oxo-15.alpha.-hydroxy-20-isopropylideneprost-13(trans)-enoate so obtained is treated with aqueous sodium hydroxide and neutralized.

30. 9-oxo-15.alpha.-hydroxy-20-isopropylideneprost-13(trans)-enoic acid whenever prepared or produced by the process as claimed in claim 29 or an obvious chemical equivalent thereof.

31. A process as claimed in claim 27 in which the methyl 9-oxo-15.beta.-hydroxy-20-isopropylideneprost-13(trans)enoate so obtained is treated with aqueous sodium hydroxide.

32. 9-oxo-15.beta.-hydroxy-20-isopropylideneprost-13(trans)-enoic acid whenever prepared or produced by the process as claimed in claim 31 or an obvious chemical equivalent thereof.

33. A process as claimed in claim 29 in which the 9-oxo-15.alpha.-hydroxy-20-isopropylideneprost-13(trans)-enoic acid so obtained is treated in aqueous methanol with potassium carbonate.

34. Potassium 9-oxo-15.alpha.-hydroxy-20-isopropylidene-prost-13(trans)-enoate whenever prepared or produced by the pro-cess as claimed in claim 33 or an obvious chemical equivalent thereof.

35. A process as claimed in claim 1 which comprises treating 9.alpha.-hydroxy-15-(2-tetrahydropyranyloxy)-20-isopropyli-deneprost-5-(cis), 13(trans)-dienoic acid in acetone with Jones reagent at sub-zero temperature, treating the 9-oxo-15-(2-tetrahydropyranyloxy)-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid so obtained with aqueous acetic acid, treating the product obtained with an ethereal solution of diazomethane and separating the product by means of column chromatography and thin layer chromatography.

36. Methyl 9-oxo-15.alpha.(or .beta.)-hydroxy-20-isopropylidene-prost-5(cis), 13(trans)-dienoate whenever prepared or produced by the process as claimed in claim 35 or an obvious chemical equivalent thereof.

37. A process as claimed in claim 35 in which the methyl 9-oxo-15?-hydroxy-20-isopropylideneprost-5(clis), 13 (trans)-dienoate so obtained is treated in methanol with aqueous sodium hydroxide and neutralized.

38. 9-oxo-15.alpha.-hydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid whenever prepared or produced by the pro-cess as claimed in claim 37 or an obvious chemical equivalent thereof.

39. A process as claimed in claim 35 in which the 9-oxo-15.beta.-hydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoate so obtained in methanol is treated with aqueous sodium hydroxide and neutralized.

40. 9-oxo-15.beta.-hydroxy-20-isopropylideneprost-5(cis), 13(trans)-dienoic acid whenever prepared or produced by the pro-cess as claimed in claim 40 or an obvious chemical equivalent thereof.