Prostaglandin D compounds production
United States Patent 91 Hyashi et al.  
 [451 Apr. 15, 1975 22 Filed:  
 [ PROSTAGLANDIN D COMPOUNDS PRODUCTION [75] Inv nt MasakiHayashi; Tadao Tanouchi,  
 both of Osaka, Japan [73] Assignee: Ono Pharmaceutical Co., Ltd., Osaka, Japan May 1, 1973 211 App]. No.: 356,248  
 [30] Foreign Application Priority Data May 9, 1972 Japan 47-45794 [52] US. Cl...... 260/514 D; 260/240 R; 260/317 B; 260/468 D; 474/305; 474/317 [51] Int. Cl. C07c 01/36 [58] Field of Search 260/468 D, 514 D [56] References Cited OTHER PUBLICATIONS Nygteren et al., Recv. Trav. Pay Bus 85, 405 (1966). Granstrom et al., TBC 243, 4104 (1968).  
 House, Modern Synthetic Reactions, 2nd Ed., pp. 261-262 (1973).  
 Primary Examiner-Robert Gerstl Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow [57] ABSTRACT This invention relates to prostaglandin D compounds of the general formula:  
 &#39; x Mcoon OH R3 4 Claims, No Drawings x News wherein X is CH2CHg or cis-CH=CH1 wherein one or two of R,, R and R are methyl and the remainders are hydrogen. or all of R R and R are hydrogen. and indicates attachment of hydroxyl to C-l5 in alpha and/or beta configuration. These compounds are useful as hypotensive agents and smooth muscle stimulants.  
  The prostaglandin D compounds of this invention include the natural optical isomers, the enantimorphs. and the racemates thereof. These are within the scope of the present invention.  
  This invention also relates to the process for producing the prostaglandin D compounds represented by the aforementioned formula.  
  According to a feature of the present invention. the compounds of general formula I are prepared by the following procedures.  
 Compounds of the general formula:  
 on a x M COOH wherein X. R R and R are as hereinbefore defined. are oxidized to obtain compounds of the general formula:  
 III  
  Some of the known prostaglandins are classified into three groups depending on the chemical structure of the five-membered ring. i.e.. prostaglandin E compounds when it is prostaglandin F compounds when it is and prostaglandin A compounds when it is In the course of biosynthesis of PGE and PGE with the homogenate of a sheep seminal vesicle using 8.1 l.l4-eicosatrienoic acid as the substrate. a very small amount of the compound of formula IV has been formed as a by-product. See. for example. B. Samuelsson et al.. Journal of Biological Chemistry. 243. 4l04 1968).  
 See also Offenlegungsschrift 1927802.  
  Referring now to formula IV and PGE. the oxo and hydroxyl group of PGD are located in an opposite position to those of prostaglandin E compounds (9-hydroxy-l l-oxo-prostanoic acids). The compounds of this invention are generically classified as prostaglandin D compounds.  
  We have found. surprisingly. that when compound ll was oxidized. the hydroxyl group at O] l of compound ll is selectively oxidized to form compound Ill. The present invention stems from this surprising discovery.  
  As the result of oxidation. prostaglandin E of the chemical structure represented by the formula V was formed as a minor product. However. the quantitative ratio of compound [11 and compound V was 2-3 1.  
  It is postulated that the selective oxidation is due to the influence by the configuration of the substituents at C-9 and C-1 1. It was revealed that the compound (dioxo-compound) wherein the hydroxyl both at C-9 and C-1 1 are oxidized, cannot be formed by the oxidation under mild conditions.  
  The starting materials for the present invention (formula [1 compounds) are novel compounds, and are prepared by the following reaction sequence.  
  The starting material for the preparation of compounds 11 are 2-oxa-3-oxo-6 syn-[3a-hydroxy-l &#39;transoctenyl1-7 anti-acetoxy-cis-bicyclo[3, 3, 0]-octane (V1, R,=R. ,=R =H), which is a known substance [See, for example, .1. Am. Chem. Soc., 92,397 (1970), and 91, 5675 (1969)] and 2-oxa-3-oxo-6 syn-[3&#39;-hydroxy- 3&#39;-methyl-l trans-octenyll-7 anti-acetoxy-cisbicyclol3, 3, 0]-octane, 2-oxa-3-oxo-6 syn-[3&#39;ahydroxy-4( R )-methyl-1 &#39;trans-octenyl]-7 antiacetoxy-cis-bicyclo[3, 3, 0]-oetane, 2-oxa-3-oxo -6 syn-[ 3 &#39;a-hydroxy-4&#39;( S)-methyl-l &#39;trans-octenyl1-7 anti acetoxy-cis-bicyclo[3, 3, O]-octane, 2-oxa-3-oxo-6 syn- [3 &#39;a-hydroxy-5&#39;-methyl-l &#39;trans-octenyl1-7 antiacetoxy-cis-bicyclo[3, 3, 0]-octane, and 2-oxa-3-0xo-6 syn-l 3&#39; -hydroxy-3 &#39;,4-dimethyl-l &#39;trans-octenyl1-7 anti-acet0xy-cis-bicyclo[3, 3, O]-octane, which are described in our copending US. application Ser. No. 247,803, filed Apr. 26, 1972.  
  The synthesis of compound 11 from compound V1 is carried out by the sequence of the transformation as shown in Chart A.  
  More particularly compound V11 is prepared by the. reaction of compound V1 with dihydropyran in methylene chloride using p-toluene sulfonic acid as the condensing agent. Next, compound Vll is reduced with di-z isobutyl aluminum hydride in toluene for about 15 minutes at about 60C to obtain compound Vlll. Dimsyl anion, previously prepared with sodium hydride and dimethyl sulfoxide, is made to react with 4-carboxy-nbutyl-triphenyl phosphonium bromide to form 4-carboxy-n-butylidene triphenyl phosphorane (1X). Compound Vlll is added to 1X, and the mixture is made to react to dimethyl sulfoxide for 2 hours at room temperature. Compound 11a is converted into compound &#34;17&#39; by catalytic hydrogenation, e.g., with palladium in methanol. i  
  The oxidation of compound 11 to compound 11] is carried out by the following reaction sequence.  
  As compound 11] is quite unstable to acid, alkali or heat, the oxidation thereof is effected under selective conditions. The preferred oxidizing agent is chromic acid. Especially preferred methods are the two-phase oxidation (See Fieser and Fieser Reagents for Organic Synthesis, page 143 1968) Wiley, New York), or the method for Jones reagent. The reaction should take place at a low temperature, e.g. 10C to 50C. After extraction procedures, the crude product is purified by column chromatography. Although the separation of compounds [11 and V can be achieved by column CHART A O O ,oii  
  /&amp; R  
  2 2 R R1 dihydropyran R1 ilKisoliu) p-toluene I z AC 2 3 sulfonic acid OAC O R OH O 0 3 U U (v1) (VII) (VIiI) shromatography, it is simpler to separate compound 1 and PGE E or similar compounds after the hydrolysis. Therefore, at this stage. it is not necessary to separate compounds 111 and V.  
  The subsequent hydrolysis is carried out with aqueous solution of organic acid. e.g., acetic acid, or with dilute solution of mineral acid, e.g.. hydrochloric acid. Since compound 111 is very sparingly soluble in water, the hydrolysis should preferably take place in the presence of a solvent miscible with water, e.g.. alcohol or tetrahydrofuran. Inasmuch as compounds 1 and 111 are unstable to acid and heat, the reaction is preferably effected at a low temperature, typically less than 45C. The pure compound of formula 1 is readily obtained after extraction and purification by column chromatography of the mixture of reaction products.  
  The Rf value on thin-layer chromatography and the infra-red spectrum of the formula 1 compound (X=CH CH R =R =R =H) prepared by the above methods agree with those of 9oz,l5oz-dihydroxyll-oxo-13 trans-prostenoic acid, as in the Samuelson publication. More particularly, the structure of said compound I is determined and confirmed by:  
 a. greater Rf value than that of PGE on thin-layer chromatography,  
 b. same peaks as PGE, in infra-red spectrum,  
 c. same peaks as PGE in mass spectrum. but slightly different peaks of olefinic proton region in the nuclear magnetic resonance spectrum,  
 (1. maximum absorption at 235 ,u with alkalitreatment, but PGE shows at 278 ,u, and  
 e. PGF is formed by the reduction with sodium borohydride.  
  All the compounds of this invention of generic formula 1 and their derivatives are determined by these physical measurements.  
  The melting point, infra-red spectrum, nuclear magnetic resonance spectrum, Rf value on thin-layer chromatography and biological activities of PGE formed as a by-product in the course of the preparation for the compound 1 (X=CH CH R =R =R;,=H) completely agree with those of natural PGE,.  
  Prostaglandin D compound prepared by the sequence of the aforementioned procedures can be fur ther converted, by known methods, to various analogous compounds each of them having specific properties.  
  When it is treated, for example, with an equivalent of alkali or organic amine, a metallic salt or organic amine salt of prostaglandin D compound, which is easily soluble in water, is formed.  
  It can be stabilized if it is treated with certain molecules, e.g., cyclodextrin, to form the clathrate compound utilizing the procedure described in US. patent application Ser. No. 147,255, filed May 26, 1971.  
  An ester form of prostaglandin D compounds is formed by one of (i) esterification with diazoalkanes, (ii) reaction with alcohol or thiol in the presence of dicyclohexyl carbodiimide a condensing agent, or (iii) reaction with alcohols following the formation of a mixed acid anhydride by adding tertiary amine and pivaloyl halide or alkyl sulfonyl halide (our Belgium Patents, Nos. 775106 and 776294).  
  An alcohol form of prostaglandin D compounds is formed by converting methyl ester to oxime, reducing with lithium aluminum hydride to form oxime alcohol, and hydrolyzing it.  
  Furthermore, if two double bonds of prostaglandin D compounds are reduced with Pd or Pt, a dihydro form of prostaglandin D compounds are formed.  
  The compounds of general formula 1 possess the valuable pharmacological properties typical of prostaglandins including. in particular, the production of hypotension, stimulation of intestinal contraction, inhibition of blood platelet aggregation and bronchodilation, and are useful in the prevention and treatment of hypertension. the treatment of disorders of peripheral circulation, the treatment of intestinal dyskinesia and post-operative intestinal paralysis, the prevention and treatment of constipation, cerbral thrombosis and myocardial infarction, and the treatment of asthma. For example, in laboratory screening tests, the compound of general formula 1 wherein X represents cis-vinylene and R R and R are each hydrogen produces:  
 a. A 26 mm. Hg fall for 6 minutes in the blood pressure of the allobarbital-anaesthetized dog at a dose of plg/kg animal body weight;  
 b. a stimulatory effect on the contraction of the isolated ascending colon of the guinea pig, producing 50 percent contraction at a concentration of l.4 10 g/ml;  
  inhibitions of adenosine diphosphate-indused blood platelet aggregation in platelet-rich plasma of rabbits of 67.4 percent at a dose of 10 ug/ml, 44.4 percent at a dose of l ug/ml and 20.8 percent at a dose of 0.1 ,ug/ml in comparison with controls. and  
 d. in vivo bronchodilator activity by aerosol administration against convulsions in the guinea pig induccd by the inhalation of histamine-containing aerosol, the ratio of the pre-convulsion time after inhalation of an aerosol generated from a solution containing 10 ,ug/ml of the said compound of general formula 1 to the pre-convulsion time in animals not receiving the compound being 1.52:1 [use of the same concentration of isoprenaline (isoproterenol) gave a corresponding ratio of 1.49:1. which indicates that the compound of formula 1 is equipotent to isoprenaline in bronchodilator activity].  
  The LD dose of the aforesaid compound when administered sub-cutaneously to mice was 40 mg/kg animal body weight. In the management of hypertensive states in mammals such as cats and dogs, the recommended dose is 0.1 mg/kg to 10 mg/kg 2 to 3 times daily, orally or by intramuscular injection. This dosage regimen can be varied depending upon the species of mammal being treated and the severity of the condition, by methods well known to the healing arts.  
  In order to further illustrate the practice of this invention, the following examples are included:  
 REFERENCE EXAMPLE 1 2-oxa-3-oxo-6 syn-[ 3 &#39;a-( 2&#34;-tetrahydropyranyloxy-1 &#39;trans-octenyl1-7 anti-acetoxy-cisbicyelo[3, 3, OI-octane anhydrous magnesium sulfate. and freed of solvent in vacuo to yield 31.6 g of 2-oxa-3-oxo-6 syn-[3&#39;a-(2&#34;- tetrahydropyranyloxy-l &#39;trans-octenyl1-7 anti-acetoxycisbicyclo[3. 3. 01-octane (yield 100 percent) as a colorless oil. having the following physical characteristics: Infra-red spectrum (liquid film): 2920. 2850. I775. 1735,1440.I370.1240.l200,ll75.1115.1108. 1080. 1030, 980 cm Nuclear magnetic resonance spectrum (in CDCl;,): 6 5.6-5.3 (m). 5.2-4.8 (m), 4.7-4.3 (m). 4.2-3.2 (111). 2.8-2.5 (m). 2.0 (s). 1.58 (s). 0.82 (t) Thin-layer chromatography (methylene chloride:me-  
 thanol=20:l Rf--0.92  
 REFERENCE EXAMPLE 2 2-oxa-3-oxo-6 syn-[ 3 2 &#39;-tetrahydropyranyloxy )-3 &#39;-methyl-l &#39;transoctenyll-7 anti-acetoxy-cisbicyclo [3. 3. ]-octane 21.25 g of 2-oxa-3-oxo-6 syn-[3&#39;-hydroxy-3&#39;-methylltrans-octenyl1-7 anti-acetoxy-cisbicyclo[3. 3, 0]- octane was dissolved in 200 ml of methylene chloride. Whilst stirring at about -25C. 8.7 g of dihydropyran and a catalytic amount of p-toluene sulfonic acid were added to make them react for 20 minutes. After the reaction. the solution was post-treated with the same manner as in the Reference Example I to yield 26.2 g of 2-oxa-3-oxo-6 syn-[3&#39;-(2&#34;- tetrahydropyranyloxy )-3 &#39;-methyl-l &#39;trans-octenyl]-7 anti-acetoxy-cisbicyclo[3, 3. 0]-octane (yield 98 percent) as a pale yellow oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 2930. 2850. I780. l740.l440.l370. 1240.1200. I175. 1115.1100. I080. I030. 980 cm Nuclear magnetic resonance spectrum (in CDCl 8 5.6-5.25 (m). 5.20-4.75 (M). 4.75-4.30 (m). 4.24-3.20 (m). 2.02 (s) Thin-layer chromatography (methylene chloride:me-  
 thanol=20:l  
 REFERENCE EXAMPLE 3 2-oxa-3-oxo-6 syn-l 3 a-( 2&#39; -tetrahydropyranyloxy )-4 R )-mcthyll&#39;trans-octenyll-7 anti-acetoxy-cisbicyclo[3. 3. 0 l-octane 18.2 g of 2-oxa-3-oxo-6 syn-[3&#39;a-hydroxy-4&#39;(R)- methyl-l &#39;trans-octenyl1-7 anti-acetoxy-cisbicyclo[3. 3. 0]-octane was dissolved in 180 ml of methylene chloride. Whilst stirring at about 20-25C. 7.5 g of dihydropy-ran and a catalytic amount of p-toluene sulfonic acid were added to make them react for 20 minutes. After the reaction. the solution was post-treated with the same manner as in the Reference Example I to yield 22.9 g of 2-oxa-3-oxo-6 syn-[3&#39;a-(2&#34;- tetrahydropyranyloxy )-4 R )-methy1- I &#39;trans-octenyl1- 7 anti-acetoxy-cisbicycl0[3. 3, OJ-octane (yield 100 percent) as a colorless oil. having the following physical characteristics:  
 Infra-red spectrum (liquid film): 2930. 2850. I775. I740. I465,-I440. I375. I240. 1200.1170. I075, I020. 975 cm Nuclear magnetic resonance spectrum (in CDCl 8 5.65-5.27 (m), 5.16-4.73 (m). 4.73-4.30 (m), 4.20-3.20 (m). 1.98 (s) 8 Thin-layer chromatography (methylene chloridezmethanol=20:l  
 REFERENCE EXAMPLE 4 2-oxa-3-oxo-6 syn-[ 3 &#39;a-( 2 -tetrahydropyranyloxy )-4 S )-methyl- 1 trans-octenyl1-7 anti-acetoxy-cisbicyclo[3, 3. 0]-octane 26.4 g of 2-oxa-3-oxo-6 syn-[3&#39;a-hydroxy-4&#39;(S)- methyl-1trans-octenyl]-7 anti-acetoxy-cisbicyclo3, 3. 0]-octane was dissolved in 260 ml of methylene chloride. Whilst stirring at about 2025C, 10.9 g of dihydropyran and a catalytic amount of p-toluene sulfonic acid were added to make them react for 20 minutes. After the reaction, the solution was post-treated with the same manner as in the Reference Example I to yield 31.9 g of 2-oxa-3-oxo-6 syn-[3&#39;a-(2&#34;- tetrahydropyranyloxy)-4(S )-methyl-l &#39;trans-octenyH- 7 anti-acetoxy-cisbicyclo[3. 3, 0]-octane (yield 96 percent) as a colorless oil, having the following physical characteristics:  
 Infra-\ed spectrum (liquid film): 2930. 2850. I775. I735. I440, I370. 1320. 1240. I200. I170, I130. I075. I020. 975 cm Nuclear magnetic resonance spectrum (in CDCl 8 5.63-5.28 (m), 5.23-4.75 (m). 4.70-4.32 (m). 4.26-3.20 (m), 2.02 (s) Thin-layer chromatography (methylene chloride:me-  
 thanol=20:l  
 REFERENCE EXAMPLE 5 2-0xa-3-oxo-6 syn-[3&#39;a-(2&#34;-tetrahydropyranyloxy)-5&#39;-methyll&#39;trans-octenyl1-7 anti-acetoxy-cisbicyclo [3. 3. 0]-octane 33.0 g of 2-oxa-3-oxo-6 syn-l3&#39;a-hydroxy-5&#39;-methylltrans-octenyl1-7 anti-acetoxy-cisbicyclo[3. 3. 0]- octane was dissolved in 330 ml of methylene chloride. Whilst stirring at about 20-25C. 13.5 g of dihydropyran and a catalytic amount of p-toluene sulfonic acid were added to make react them for 20 minutes. After the reaction. the solution was post-treated with the same manner as in the Reference Example I to yield 41.2 g of 2-oxa-3-oxo-6 syn-[3 &#39;a-( 2&#34;- tetrahydropyanyloxy )-5 -methyl-] &#39;trans-octenyl1-7 anti-acetoxy-cisbicyclo[3. 3. 0]-octane (yield 99 percent) as a colorless oil. having the following physicalcharacteristics:  
 Infra-red spectrum (liquid film): 2930. 2850. 1780, I740. I435. I370. I320. I240. I170. I080, I030. 975 cm Nuclear magnetic resonsnce spectrum (in CDCl,,): 8 5.65-5.24 (m). 5.20-4.73 (m), 4.73-4.30 (m). 4.24-3.20 (m), 2.03 (s) Thin-layer chromatography (methylene chloride:me-  
 thanol=20:l  
 REFERENCE EXAMPLE 6 2-oxa-3-hydroxy-6 syn-[ 3 &#39;a-( 2 &#34;-tetrahydropyranyoxy )-l &#39;trans-octenyl1-7 anti-hydroxy-cisbicyclo[3. 3. 0l-octane 31.5 g of 2-oxa-3-oxo-6 syn-[ 3 &#39;a-( 2&#39; 9 tetrahydropyranyloxy )-l trans-octenyl ]-7 antiacetoxy-cisbicyclo[3. 3. Ol-octane was dissolved in 630 ml of toluene. Whilst stirring and cooling to 60C in an atmosphere of nitrogen. 230 ml of toluene solution of diisobutylaluminium hydride (concentration 0.25 g/ml) was added dropwise during about 10 minutes. and stirred for subsequent 15 minutes at the same temperature. Methanol 10 ml was then added. and warmed up to C. Water 30 ml was then added. and was stirred for one hour at room temperature. The precipitate was filtered off. and the filtrate was washed with saturated sodium chloride solution. dried over anhydrous magnesium sulfate. and freed of solvent in vacuo to yield 27.0 g of 2-oxa-3-hydroxy-6 syn-[3&#39;a-(2&#34;- tetrahydropyranyloxy)-l &#39;trans-octenyl]-7 antihydroxy-cisbicyclol 3, 3, O]-octane (yield 94.5 percent) as a colorless oil. having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3600-3100. 2950-2850. 1460, 1450. 1440. 1380, 1355, 1322, 1292. 1260. 1200. 1180. 1105. 1078. 1020.975. 905, 875. cm Thin-layer chromatography (methylene chloridezmethanol=20z1):  
 REFERENCE EXAMPLE 7 2-oxa-3-hydroxy-6 syn-[3&#39;-(2&#34;-tetrahydropyranyloxy)-3&#39;-mcthyl-1&#39;transoctenyll-7 anti-hydroxy-cisbicyclo[3. 3. 0]-octane 26 g of 2-oxa-3-oxo-6 syn-[3-(2&#34;- tetrahydropyranyloxy )-3 &#39;-methyl-1 &#39;trans-octenyl1-7 anti-acetoxy-cisbicyclo[ 3. 3. 0l-octane was dissolved in 520 ml of toluene. Whilst stirring and cooling to 60C in an atmosphere of nitrogen, 190 ml of toluene solution of diisobutylaluminium hydride (concentration 0.25 g/ml) was added dropwise during about 10 minutes. and was stirred for subsequent minutes. After the reaction. the solution was post-treated with the same manner as in the Reference Example 6 to yield 21.5 g of 2-oxa-3-hydroxy-6 syn-[ 3 2&#34;- tctrahydropyranyloxy)-3-methyl-1trans-octenyl]-7 anti-hydroxy-cisbicyclo[3. 3, 0]-octane (yield 92 percent) as a pale yellow oil. having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3380. 2930, 2850. 1460-1440. 1380. 1355.1290.l265,1200.1180. 1110. 1075. 1020, 980. 905 cm Thin-layer chromatography (methylene chloride:me-  
 thanol=:]  
 REFERENCE EXAMPLE 8 2-oxa-3-hydroxy-6 syn-[ 3 &#39;a-( 2&#34;-tetrahydropyranyloxy )-4&#39;( R )-methylltrans-octenyl1-7 anti-hydroxy-cisbicyclo[3. 3, 0]-octane I tetrahydropyranyloxy)-4(R)-methyl-l trans-octenyll- 7 anti-acetoxy-cisbicyclo[3. 3, 0]-octane was dissolved in 440 ml of toluene. Whilst stirring and cooling to 60C in an atmoshpere of nitrogen. 170 ml of toluene solution of diisobutylaluminium hydride (concentra- REFERENCE EXAMPLE 9 2-oxa-3-hydroxy-6 syn-l3&#39;a-(2&#34;-tetrahydropyranyloxy)-4&#39;(S)-methyll&#39;trans-octenyl1-7 anti-hydroxy-cisbicyclo [3. 3. O]-octane tetrahydropyrany1oxy)-4&#39; (S)-methyl-&#39; 1 &#39;trans-octenyfl- LII  tion:0.25 g/ml) was added dropwise during about 10 minutes. and was stirred for subsequent 15 minutes. After the reaction. the solution was post-treated with 7 anti-acetoxy-cisbicyclo[3. 3. O]-octane was dissolved in 620 ml of toluene. Whilst stirring and cooling to 60C in an atmosphere of nitrogen. 230 ml of toluene solution of diisobutylaluminium hydride (concentration:0.25 g/ml) was added dropwise during 10 minutes. and was stirred for subsequent 15 minutes. After the reaction, the solution was post-treated with the same manner as in the Reference Example 6 to yield 25.4 g of 2-oxa-3-hydroxy-6 syn-[3&#39;a-(2- tetrahydropyranyloxy)-4&#39;(S )-methyl-1 &#39;trans-octenyl 7 anti-hydroxy-cisbicyclo[3, 3. 0]-octane (yield 91 percent) as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3360. 2930. 2850. 1460-1440, 1380. 1355. 1290. 1265. 1200. 1175. 1105. 1080. 1020. 905 cm&#34; Thin-layer chromatography (methylene chloridezmethanol=20:1  
 REFERENCE EXAM PLE l0 2-oxa-3-hydroxy-6 syn-[ 3 a-( 2&#34;-tetrahydropyranyloxy )-5 &#39;-methylltrans-octenyl]-7 anti-hydroxy-cisbicyclo [3. 3. Ol-octane 41 g of 2-oxa-3-oxo-6 syn-[3 &#39;a-( 2&#34;- tetrahydropyranyloxy)-5 &#39;-methyl-1 &#39;trans-octenyl1-7 anti-acetoxy-cisbicyclo[ 3. 3. 0]-octane was dissolved in 820 ml of toluene. Whilst stirring and Rf= 0.25 and cooling to 60C in an atmosphere of nitrogen, 300 ml of toluene solution of diisobutylaluminium hydride (concentration:0.25 g/ml) was added dropwise during 10 minutes, and was stirred for subsequent 15 minutes. After the reaction, the solution was post-treated with the same manner as is the Reference Example 6 to yield 35.8 g of 2-oxa- 3-hydroxy-6 syn-[3 &#39;a-(2&#34;-tetrahydropyranyloxy)- 5 -methyl-1 trans-octenyl]-7-anti-hydroxy-cisbicyclo- [3, 3, 0]-octane (yield 97 percent) as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3400. 2940. 2850. 1460-1440. 1380. 1355. 1320. 1290. 1260. 1200. 1180. 1105. 1075. 1020. 975. 910 cm Thin-layer chromatography (methylene chloride:me-  
 thanol=20z1):  
 REFERENCE EXAMPLE 11 904,1 la-dihydroxyl 2 &#39;-tetrahydropyranyloxy )-5 cis, l3 trans-prostadienoic acid To 300 ml of dimethyl sulfoxide solution of 4- carboxy-n-butyl-triphenyl-phosphonium bromide 168 g. demsyl anion, which has been obtained by heating 370 ml of dimethyl sulfoxide containing 32.6 g of sodium hydride at 70C for one hour. was added dropwise at about -25C. Next, 100 ml of dimethyl sulfoxide solution of 2-oxa-3-hydroxy-6 syn-[ 3 &#39;oz-( 2 tetrahydropyranyloxy )-l &#39;trans-octenyl]-7 antihydroxy-cisbicyclo[3, 3, 0]-octane 27 g was added, and was stirred for two hours. The reaction mixture was placed into 4 l of ice water, and was extracted with ethyl acetate to eliminate by-products. The water layer was then acidified with saturated oxalic acid solution. and was extracted with the mixture of ether and pentanc (1:1). After washed with water and saturated sodium chloride solution, the extract was dried over anhydrous magnesium sulfate, and freed of solvent in vacuo. The residue (26 g) was purified by the column chromatography on silica gel using the mixture of ethyl acetate and cyclohexane (3:2) as an eluant to yield 22 g of pure 9a,] la-dihydroxy-l 1a-(2-tetrahydropyranyloxy)-5 cis,] 3 trans-prostadienoic acid (yield 66 percent) a colorless oil, having the following physical characteristics:  
 lnfra-red spectrum (liquid film): 3600-2400, 1710, 1460, 1440,1380,1250, 12001195, 1120,1110, 1080, 1060, 1040, 1020, 995 cm Nuclear magnetic resonance spectrum (in CDClg): 8 6.5-6.1(br.s), 5.6-5.2(m), 4.9-4.5(m), 4.4-3.2 (m), 2.5-1.9 (m). 1.8-1.4 (m), 1.4-1.1 (m), 0.86 (t) Thin-layer chromatography (methylene chloridezmethanol=20:l  
 Rf=0.2l  
 REFERENCE EXAMPLE 12 901,1 la-dihydroxyl 5-( 2 &#39;-tetrahydropyranyloxy l 5- methyl-S cis,l3 trans-prostadienoic acid To 250 ml of dimethyl sulfoxide solution of 4- carboxy-n-butyl-triphenyl-phosphonium bromide 140 g, demsyl anion, which has been obtained by heating 310 ml of dimethyl sulfoxide containing 27.0 g of sodium hydride at 70C for one hour, was added dropwise at about 2025C. Next, 85 ml of dimethyl sulfoxide solution of 2-oxa-3-hydroxy-6 syn-I 3 2 tetrahydropyranyloxy )-3-methyl-l &#39;trans-octenyl]-7 anti-hydroxy-cisbicyclo-[3, 3, O]-octane 23.3 g was added, and was stirred at C for two hours. After the reaction, the solution was post-treated with the same manner as in the Reference Example 11 to yield 16.6 g of pure 9a,] la-dihydroxy-l5-(2&#39;- tetrahydrpyranyloxy 1 5-methyl-5 cis, 1 3 transprostadienoic aicd (yield 58 percent) as a pole yellow oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3400, 2930-285- Nuclear magnetic resonance spectrum in CDCl 8 5.67-5.20 (m), 5.15-4.83 (broad s), 4.83-4.60 (m), 4.30-3.50 (m). 1.03-0.73 (t) Thin-layer chromatography (methylene chloride:me-  
 thanol=20: l  
 Rfdl23 REFERENCE EXAMPLE l3 901,1 la-dihydroxy- 1 5a-( 2 &#39;-tetrahydropyranyloxy l6(R)-methyl-5 cis,l3 trans-prostadienoic acid To 210 ml of dimethyl sulfoxide solution of 4- carboxy-n-butyl-triphenyl-phosphonium bromide 1 19 g, demsyl anion, which has been obtained by heating 260 ml of dimethyl sulfoxide containing 23.0 g of sodium hydride at C for one hour, was added dropwise at about 2025C. Next, ml of dimethyl sulfoxide solution of 2-oxa-3-hydroxy-6 syn-[ 3 a-( 2 tetrahydropyranyloxy)-4(R)-methyl-l trans-octenyl]- 7 anti-hydroxy-cisbicyclo-[3, 3, 0]-octane 20.0 g was added, and was stirred at 25C for two hours. After the reaction, the solution was post-treated with the same manner as in the Reference Example 1 1 to yield 155 g of pure 9a,] la-dihydroxy-l5a-(2&#39;- tetrahydropyranyl0xy)- l 6( R )-methyl-5 cis,] 3 transprostadienoic acid (yield 63 percent) as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3350, 2930-285- Nuclear magnetic resonance spectrum (in CDCl;,): 5 5.70-5.20 (m), 5.20-4.90 (broad s), 4.78-4.55 (m), 4.32-3.20 (m), 1.06-0.70 (m) Thin-layer chromatography (methylene chloride:me-  
 thano1=20:1  
 REFERENCE EXAMPLE l4 901,1 la-dihydroxy- 1 5a-( 2 -tetrahydropyranyloxy 16(S)-methyl-5 cis,l3 trans-prostadienoic acid To 270 ml of dimethyl sulfoxide solution of 4-carboxy-n-butyl-triphenyl phosphonium bromide 15] g, demsyl anion, which has been obtained by heating 330 ml of dimethyl sulfoxide containing 29.2 g of sodium hydride at 70C for one hour, was added dropwise at about 2025C. Next, ml ofdimethyl sulfoxide solution of 2-oxa-3-hydroxy-6 syn-[3&#39;a-(2&#39;- tetrahydropyranyloxy)-4(S)-methyl-l &#39;trans-octenyl]- 7 anti-hydroxy-cisbicyclo-[3, 3, 0]-octane 25.4 g was added, and was stirred at 25C for two hours. After the reaction, the solution was post-treated with the same manner as in the Reference Example 11 to yield 20.6 g of pure 9a, 1 la-dihydroxy-l5a-(2&#39;- tetrahydropyranyloxy l 6( S )-methyl-5 cis, 1 3 transprostadienoic acid (yield 66 percent) as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3350, 2930-285- Nuclear magnetic resonance spectrum (in CDCl,,): 8 5.70-5.20 (m). 5.05-4.72 (broad s), 4.72-4.58 (m), 4.323.20 (m), 1.03-0.72 (m) Thin-layer chromatography (methylene chloridezmethanol=20:l  
 . ide  
  Rf=0.23 REFERENCE EXAMPLE 15 901,1 1 a-dihydroxy- 1501-(2 &#39;-tetrahydropyranyloxy)-17- methyl-S cis,13 pl trans-prostadienoic acid To 1 15 ml of dimethyl sulfoxide solution of 4-carboxy-n-butyl-triphenyl phosphonium bromide 88.2 g, demsyl anion, which has been obtained by heating 200 ml of dimethyl sulfoxide containing 17.0 g of sodium hydride at 70C for one hour, was added dropwise at about 2025C. Next, 55 ml of dimethyl sulfoxsolution of 2-oxa-3-hydroxy-6 syn-[3&#39;0z-(2&#39;- tetrahydropyranyloxy)-5&#39;-methyl-1&#39;trans-octenyl]-7 anti-hydroxy-cisbicyclo-[3, 3, ]-octane 14.7 g was added, and was stirred at 25C for two hours. After the reaction, the solution was post-treated with the same manner as in the Reference Example 1 1 to yield 1 1.2 g of pure 904,1la-dihydroxy-la-(2&#39;- tetrahydropyranyloxy )-l 7-methyl-5 cis, 1 3 transprostadienoic acid (yield 62 percent) as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3380, 2930-285- Nuclear magnetic resonance spectrum (in CDCl 5 5.70-5.05 (m,broad s), 4.82-4.60 (m), 4.27-3.21 (m), 1.04-0.75 (m) Thin-layer chromatography (methylene chloride:me-  
 thanol=20:l  
 REFERENCE EXAMPLE 16 901,1 1 a-dihydroxy- 1 501-(2 &#39;-tetrahydropyranyloxy)-13 trans-prostenoic acid 2.0 g of 9a,] la-dihydroxy-l5a-(2&#39;-tetrahydropyranyloxy)-5 cis,l3 trans-prostadienoic acid was dissolved in 60 m1 of methanol. 250 mg of palladiumcarbon was then added, and stirred for 30 minutes at room temperature in an atmosphere of hydrogen at a pressure of 1 atm. The catalyst was filtered off, and the filtrate was freed of solvent in vacuo to yield 2.0 g of 901,1 la-dihydroxy-l 5a-( 2 &#39;-tetrahydropyranyloxy)-13 trans-prostenoic acid (yield 99.5 percent) as a colorless oil,- having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3600-2400, 1710,  
  1460,1440,1380,1250,1200,1l95,1120,1l10. 1080, 1055, 1040, 1020, 990 cm Nuclear magnetic resonance spectrum (in CDCl;,): 8 6.5-6.1 (s), 5.5-5.3 (m), 4.9-4.5 (s), 4.4-3.2 (m), 2.5-1.9 (m), 1.8-1.4 (m), 1.4-1.1 (m), 0.86 (t) Thin-layer chromatography (chloroformztetrahydrofuransacetic acid=10:2:l  
 REFERENCE EXAMPLE 17 9a,] 1a-dihydroxy-15-(2&#39;-tetrahydropyranyloxy)-15- methyl-l 3 trans-prostenoic acid 8.0 g of 9a,] 1a-dihydroxy-15-(2&#39;- tetrahydropyranyloxy)--methyl-5 cis, l3 transprostadienoic acid was dissolved in 100 ml of methanol, and was added to the solution which has been prepared by adding 1 g of 5 percent-palladium-carbon to 6. 150 m1 of&#39;methanol. The catalytic reduction was taken place. at room temperature in an atmosphere of hydrogen at a pressure of 1 atm, until the absorption of a theoretical amount of hydrogen. The catalyst was filtered off, and the filtrate was concentrated in vacuo to yield 7.94 g of 901,1 1a-dihydroxy-15-(2&#39;- tetrahydropyranyloxy)-15-methyl-13 trans-prostenoic acid (yield 98 percent) as a pale yellow oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3400, 2930-285- Nuclear magnetic resonance spectrum (in CDCl 5.6-5.3 (m),5.3-4.8 (br.s),4.8-4.5 (m), 4.4-3.2 (m),l.0-0.7 (t) Thin-layer chromatography drofuramacetic acid=10:2:1):  
 REFERENCE EXAMPLE 18 9a,] 1 a-dihydroxy- 1 5a-( 2 -tetrahydropyranyloxy l6(R)-methyl-l 3 trans-prostenoic acid 7.5 g of 901,1 la-dihydroxy-l5a-( 2- tetrahydropyranyloxy)- 1 6( R )-methyl-5 cis,13 transprostadienoic acid was dissolved in 100 ml of methanol, and was added to the solution which has been prepared by suspending 920 mg of 5 percent-palladiumcarbon in ml of methanol and by replacing with hydrogen. The catalytic reduction was taken place. at room temperature in an atmosphere of hydrogen at a pressure of 1 atm, until the absorption of a theoretical amount of hydrogen. The catalyst was filtered off. and the filtrate was concentrated in vacuo to yield 7.28 g of 901,1 1a-dihydroxy-15a-(2-tetrahydropyranyloxy)- l6(R)-methyl-13 trans-prostenoic acid (yield 97 percent),as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3350,2950-285- Nuclear magnetic resonance spectrum (in CDCI 8 5.6-5.4 (m), 5.4-5.0 (broad s), 4.9-4.5 (m), 4.3-3.2 (m), 1.03-0.68 (m) Thin-layer chromatography drofuranzacetic acid=10:2: 1  
 REFERENCE EXAMPLE 19 9a,] la-dihydroxy- 1 5a-( 2&#39;-tetrahydropyranyloxy l6(S)-methyl-l 3 trans-prostenoic acid 9.5 g of 901,1 la-dihydroxy-l5a-( 2- tetrahydropyranyloxy)-l6(S)-methyl-5 cis,l3 transprostadienoic acid was dissolved in 90 m1 of methanol, and was added to the solution which has been prepared by suspending 1.19 g of 5 percent-palladium-carbon in 200 ml of methanol and by replacing with hydrogen. The catalytic reduction was taken place, at room temperature in an atmosphere of hydrogen at a pressure of 1 atm, until the absorption of a theoretical amount of hydrogen. The catalyst was filtered off, and the filtrate was concentrated in vacuo to yield 9.4 g of 901,110- dihydroxy-15a-(2&#39;-tetrahydropyranyloxy)-16(5)- methyl-13 trans-prostenoic acid (yield 99 percent) as a colorless oil, having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3350, 2950-285- chloroformztetrahy- (chloroform :tetrahy- Nuclear magnetic resonance spectrum (in CDCla): 5.6-5.4 (m), 5.4-5.0 (b1&#39;.S), 4.9-4.5 (m), 4.3-3.2 (m), 1.05-0.7 (m) Thin-layer chromatography (chloroformItetrahydrofuranzacetic acid=l:2:l  
 9a,] la-dihydroxy- 1 oz-( 2 &#39;-tetrahydropyranyloxy I 7- methyl-13 trans-prostenoic acid 5.2 g of 901,1 la tetrahydropyranyloxy l 7-methyl-5 cis.1 3 transprostadienoic acid was dissolved in 50 ml of methanol. and was added to the solution which has been prepared by suspending 650 mg of 5 percent-palladium-carbon in 150 ml of methanol and by replacing with hydrogen. The catalytic reduction was taken place, at room temperature in an atmosphere of hydrogen at a pressure of 1 atm, until the absorption of a theoretical amount of hydrogen. The catalyst was filtered off, and the filtrate was concentrated in vacuo to yield 5.15 g of 901,110:- dihydroxy- 1 5a-( 2 &#39;-tetrahydropyranyloxy l 7-methyll3 trans-prostenoic acid (yield 99 percent) as a colorless oil. having the following physical characteristics:  
  Infra-red spectrum (liquid film): 3350, 2950-285- 0,-2300, 1710. 1460, 1440, 1380, 1250, 1200, 1180. 1125,1075, 1020, 980 cm- Nuclear magnetic resonance spectrum (in CDCl;,):  
 5.6-5.35(m),5.2-4.85 (br.s),4.85-4.5(m). 4.3-3.2 (m), l.03-0.7 (m) Thin-layer chromatography (chloroform:tetrahydrofuranzacetic acid=:2:1):  
 EXAMPLE l-(Al 9a-hydroxy-1 l-oxo- 1 5a-( 2&#39;-terahydropyranyloxy)-5 cis, 13 trans-prostadienoic acid 7.1 g of 901,1 la-dihydroxy- 1 5a-(2&#39;-tetrahydropyranyloxy)-5 cis,13 trans-prostadienoic acid was dissolved in 350 ml of acetone. After cooling to -25C. 7.5 ml of Jones reagent (26.7 g of chromium trioxide and 23 ml of sulfuric acid was dissolved in water to make total volume of 100 ml) was added dropwisc, and was stirred for 10 minutes at the same temperature. To this solution, 3 ml of isopropyl alcohol was added. and then diluted with 2 l of ether. washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield 6.1 of crude product. The crude product was purified by column chomatography on silica gel using the mixture of ethyl acetate and cyclohexane (3:2) to yield 5.1 g of the mixture of IS-tetrahydropyranyl ether of PGD and -tetrahydropyranyl ether of PGE2 (yield 72 percent).  
  Although the above two compounds can be separated by this column chromatography, the separation between PGD and PGE after the hydrolysis is easier than the above. Therefore, the next reaction was taken place with this mixture.  
  For the purpose of the confirmation of the structure, the said mixture was separated by the said column chromatography under strict conditions to obtain pure 9a-hydroxy-l l-oxo- 1 5a-( 2 -tetrahydropyranyloxy )-5 cis, 13 trans-prostadienoic acid as a pale yellow oil. having the following physical characteristics:  
  infra-red spectrum (liquid film): 3650-3300, 3250-2300, 1740. 1705, 1455, 1450, 1400. 1390.  
 Nuclear magnetic resonance spectrum (in CDCI 8 6.7-6.0 (s). 5.6-5.1 (m), 4.78 (s), 4.23.3 (m), 2.6 (d). 2.18 (d), 1.8-1.5 (m), 1.45-1.05 (m), 0.87 (t) Thin-layer chromatography (chloroformztetrahydrofuranzacetic acid=l0::2:1  
 EXAMPLE l-(B) 9al5a-dihydroxy-11-oxo-5 cis, l3 trans-prostadienoic acid 2.2 g of the mixture, which has been prepared according to the methods described in the Example l-(A), was dissolved in 50 ml of the mixture of acetic acid, water and tetrahydrofuran (65:35:10). After stirring for one hour at 40C, the solution was placed into 150 ml of ice water. extracted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium, and concentrated in vacuo to yield 2 g of crude product. The crude product was purified by column chromatography on silica gel using the mixture of ethyl acetate and cyclohexane (2:1) as an eluant to yield 935 mg of pure PGD (yield 52.6 percent) as white crystals with the melting point 6870C, having the following physical characteristics:  
 Infra-red spectrum (KBr tablet): 3430, 3320, 3000, 2950, 2920, 2850,-2400. 1725, 1700. 1450, 1425, 1405, 1360, 1340, 1320, 1285, 1260, 1200. 1160. 1080, 1035, 1000, 970, 945, 900, 750 cm&#34; Nuclear magnetic resonance spectrum (in CDClg): 8 5.7-5.35 (m), 5.35-4.80 (m), 4.48 (d), 4.25-3.95 (m). 2.93-2.7 (d--d). 2.5 2.37 (m). 2.37-2.20 (m), 2.15 (d), 1.85-1.43 (m), 1.43-1.10 (m), 0.88 (t) Thin layer chromatography (benzenezdioxanezacetic acid=:20:2):  
  Furthermore, when ethyl acetate was used an an eluant in the column chromatography, 368 mg of PGE was obtained (yield 21 percent) as white crystals with the melting point 65-67C. The behaviors of this PGE, on the infra-red spectrum, nuclear magnetic resonance spectrum, thin-layer chromatography, and the biological activities were completely agreed with those of natural PGE Thin-layer chromatography (benzenezdioxanezacetic acid=80:20:2):  
 EXAMPLE 2-(A) 9a-hydroxy-1 1 -oxo- 1 5a-( 2&#39;-tetrahydropyranyloxy l 3 trans-prostenoic acid (PGD 17 yellow oil. having the following physical characteristics:  
 Infra-red spectrum (liquid film): 3650-3300. 3250-2300. 1740. 1705. 1455. 1450. 1400. 1385. 1240. 1200. 1190. 1160.1135. 1105. 1080. 1020. 980 cm&#34; Nuclear magnetic resonance spectrum (in CDCl;,): 5 6.7-6.0 (s). 5.58-5.14 (m). 4.78 (s). 4.2-3.3 (m). 2.6 (d). 2.18 (d). 1.8-1.46 (m). 1.45-1.03 (m). 0.86 (t) Thin-layer chromatography drofuramacetic acid=l:2:1  
 EXAMPLE 2-( B) 9a.l5a-dihydroxy-l l-oxo-l3 trans-prostenoic acid (PGD1) 1.358 g of the mixture which has been prepared according to the methods described in Example 2-(A) was treated with the same manner as Example l-(B) to yield 468 mg of PGD (yield 43 percent) and 207 mg of PGE (yield 19 percent).  
 The physical characteristics of PGD, are as follows:  
 lnfra-red spectrum (KBr tablet): 3600-3200. 3000-2500. 1730. 1700. 1460. 1400. 1360. 1320. 1280.1255.1220.1180.1160.1115.1110.1080. 1020. 980. 975 cm&#34; Nuclear magnetic resonance spectrum (in CDCl;.): 6 5.70-5.45 (m). 5.30-4.80(br.s)4.47 (d). 4.17-3.90 (m). 2.93-2.70 (dd). 2.50-2.37 (m). 2.37-2.23 (m). 2.15 (d). 1.80-1.43 (m). 1.43-1.10 (m). 0.88  
 Thin-layer chromatography (benzenezdioxanemcetic acid=80:20:2):  
 (ch1oroform:tetrahy- The behaviors of PGE. on the infra-red spectrum. nuclear magnetic resonance spectrum. thin-layer chromatography. and the biological activities were completely agreed with those of natural PGE,.  
 Thin-layer chromatography (benzenezdioxanezacetic acid=80:20:2):  
 EXAMPLE 3 9a,l5-dihydroxy-l l-oxo-l-methyl-5 cis. 13 trans-prostadienoic acid 15-mcthyl-PGD- 5.0 g of 901.1 la-dihydroxy-l5-(2- tetrahydropyranyloxy l S-methyl-S cis.l 3 transprostadienoic acid was dissolved in 230 ml of aceton.  
 After cooling to 25C. 5.3 ml of Jones reagent (See Example l-(A)) was added dropwise. and was stirred for minutes at about 20-30C. To this solution.  
 2 m1 of isopropyl alcohol was added. and then diluted with 1.5 l of ether. washed with water. dried over anhydrous magnesium sulfate. and concentrated in vacuo. The residue was purified by column chromatography on silica gel using the mixture of cyclohexane and ethyl acetate (2:3) to yield 3.2 g of the mixture of tetrahydropyranyl ether of 15-methyl-PGD and 15- tetrahydropyranyl ether of l5-methyl-PGE (yield 64 percent).  
  Next. 3.2 g of the above mixture was dissolved in 75 m1 of the mixture of acetic acid. water and tetrahydrofuran (65:35: 1 O). and was stirred for one hour at 40C. Then. the solution was placed into 300 ml of ice water.  
 extracted with ethyl acetate. washed with water. dried over anhydrous magnesium sulfate. and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using the mixture of ethyl acetate and cyclohexane (2:1) as an eluant to yield 1.22 g of pure l5-methyl-PGD (yield 47 percent). having the following physical characteristics:  
 lnfra-red spectrum (liquid film): 3420, 2960-285- 0.-2400. 1735. 1705. 1450. 1405. 1375. 1240. 1180. 1160. 1040. 975 cm Nuclear magnetic resonance spectrum (in CDCl;.): 6 5.75-4.34 (m). 5.16-4.70 (broad s). 4.56-4.38 (m). 4.25-3.92 (m). 2.73 (dd). 1.00-0.70 (t) Thin-layer chromatography (benzenezdioxanezacetic acid=80:20:2):  
  Furthermore. when ethyl acetate was used as an eluant in the column chromatography. 468 mg of 15- methyl-PGE: was obtained (yield 18 percent).  
 Thin-layer chromatography (benzene:dioxane:acetic acid=80:20:2):  
  EXAMPLE 4 9a.15a-dihydroxy-1 1-oxo-16(R)-methyl-5 cis. 13 trans-prostadienoic acid (l6(R)-methyl-PGD 6.65 g of 901.1 1a-dihydroxy-15a-( 2&#39;- tetrahydropyranyloxy)-16( R)-methyl-5 cis. l 3 trans-prostadienoic acid was dissolved in 300 ml of acetone. and then oxidized by 7.0 ml of Jones reagent (See Example 1-(A)) for 15 minutes at 2()- -30C. The solution was post-treated and purified according to the methods described in Example 3 to yield 4.72 g of the mixture of 15- tetrahydropyranyl ether of l6(R)-methyl PGD- and IS-tetrahydropyranyl ether of l6(R)-methyl PGE (yield 71 percent).  
  Next. 4.72 g of the above mixture was hydrolyzed in 100 ml of the mixture of acetic acid. water and tetrahydrofuran (:35:10) for 1 hour at 40C. and then posttreated and purified according to the methods described in Example 3 to yield 1.50 g of 16-(R)-methyl -PGD: and 720 mg of 16(R)-methyl-PGE- (totalyield 58 percent).  
 Infra-red spectrum of 16(R)-methyl-PGD (liquid film): 3400. 2960 2850. 2300. 1740. 1710. 1460. 1405. 1380. 1245. 1175. 1160. 1040. 980  
  cm Nuclear magnetic resonance spectrum of 16(R)- methyl-PGD (in CDCl;.): 6 5.68-5.35 (m).  
 5.05-4.55 (broad s). 4.55-4.39 (m). 4.25-3.90 (m). 2.74 (dd). 1.03-0.72 (m) Thin-layer chromatography (benzene:dioxane:acetie acid=:20:2):  
 l6(R)-methyl-PGD Rf=0.28 16(R )-methyl-PGE Rf=0.13  
 EXAMPLE 5 9a.l5a-dihydroxy-l 1-oxo-l6(S)-methyl-5 cis. 13 trans-prostadienoie acid (16(S)-methyl-PGD- 9.15 g of 901.1la-dihydroxy-l5a-(2&#39;- tetrahydropyranyloxy)-l6(S)-methyl-5 cis. l3 transprostadienoic acid was dissolved in 300 ml of ether. After cooling to 0C. 300 ml of chromic acid solution (CrO 2.75 g. MnSO..H. .O 14.5 g and H 80 3.1 ml  
 were dissolved in 65 ml of water) was added. and was stirred for 40 minutes at about -5C. Then. 3 m1 of isopropyl alcohol was added. The water layer was separated. extracted with ethyl acetate, added to the previous ether layer. well-washed with water. dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using the mixture of cyclohexane and ethyl acetate (2:3) as an eluant to yield 4.85 g of the mixture of l5-tetrahydropyrany1 ether of l6(S)-methyl-PGD- and l5-tetrahydropyranyl ether of 16(S)-methy1-PGE (total yield 53 percent).  
  Next. 4.85 g of the above mixture was hydrolyzed in 100 ml of the mixture of acetic acid. water and tetrahydrofuran (65:35:10) for 1 hour at 40C. and then posttreated and purified according to the methods described in Example 3 to yield 1.75 g of l6(S)-methyl- PGD and 780 mg of l6(S)-methyl-PGE (total yield 64 percent).  
 Infra-red spectrum of l6(S)-methyl-PGD (liquid film): 3400, 2960-2850-2300. 1735. 1710. 1460, l405.1380.1245.1175.1160.1035. 980 cm Nuclear magnetic resonance spectrum of 16(8)- mcthyl-PGD (in CDCl-,;): 6 5.68-5.50 (m). 5.50-5.10 (broad s). 4.55-4.39 (m), 4.25-3.90 (m). 2.74 (dd). 1.03 -0.72 (m) Thin-layer chromatography (benzene:dioxane:acetic acid=80:20:2):  
 16(S)-methyl-PGD R%0.27 16(S)-methyl-PGE Rf=0.l3  
 EXAMPLE 6 9a,l5a-dihydroxy-l l-oxo-l7-mcthyl-5 cis. l3 trans-prostadienoic acid (l7-methyl-PGD 5.5 g of 901,1 la-dihydroxy- 1 Set-(2&#39;- tetrahydropyranyloxy)-l7-methyl-5 cis. 13 transprostadienoic acid was dissolved in 250 ml of acetone. and then oxidized by 6.0 ml of Jones reagent (See Example 1(A)) for 15 minutes at ---30C. The solution was post-treated and purified according to the methods described in Example 3 to yield 3.47 g of the mixture of IS-tetrahydropyranyl ether of l7-methyl- PGD and l5-tetrahydropyranyl ether of l7-methyl- PGE. (yield 63 percent).  
  Next. 3.47 g of the above mixture was hydrolyzed in 80 ml of the mixture of acetic acid. water and tetrahydrofuran (65:35:10) for 1 hour at C. and then posttreated and purified according to the methods described in Example 3 to yield 1.356 g of l7-methyl- PCB: and 520 mg of l7-methyl-PGE (total yield 58 percent).  
 lnfra-red spectrum of l7-methyl-PGD- (liquid film):  
  3400. 29602850,-2300. 1735. 1710. 1460, 1405. 1380. 1240. 1180. 1160. 1040. 980 cm Nuclear magnetic resonance spectrum of 17-methyl- PGD (in CDCl;,): 5 5.70-5.32 (m). 5.32-4.90 (broad S). 4.58-4.35 (m), 4.25-3.88 (m). 2.74 (dd). 1.03-0.68 (m) Thin-layer chromatography (benzene:dioxane:acetic acid=80:20:2 l7-methyl-PGD Rf=0.29 l7-methyl-PGE Rf=0. 15  
  EXAMPLE 7 9a,15-dihydroxy-l 1 -oxol S-methyl-l 3 trans-prostenoic acid (IS-methyI-PGD 7.5 g of 9a,] 1a-dihydroxy-15-( 2&#39;- tetrahydropyranyloxy)- 1 5 -methyl- 1 3 trans-prostenoic acid was dissolved in 350 ml of acetone, and then oxidized by 8.0 ml of Jones reagent (See Example l-(A)) for 15 minutes at 20-30C. The solution was posttrcated and purified according to the methods described in Example 3 to yield 5.02 g of the mixture of IS-tetrahydropyranyl etherof IS-methyI-PGD, and 15- tetrahydropyranyl ether of l5-methyl-PGE (yield 67 percent).  
  Next. 5.0 g of the above mixture was hydrolyzed in l 10 ml of the mixture of acetic acid, water and tetrahydrofuran (65:35: 10) for 1 hour at 40C, and then posttreated and purified according to the methods described in Example 3 to yield 1.70 g of IS-methyI-PGD. and 780 mg of l5-methyl-PGE (total yield 61 percent).  
  lnfra-red spectrum of l5-methyl-PGD (liquid film): 3400, 2960-2850-2300. 1740, 1710, 1460. 1410. 1380. 1245. 1180. 1160, 1045. 985 cm Nuclear magnetic resonance spectrum of 15-methylv PGD (in CDCl 8 5.75-5.50 (m), 5.45-5.00 (broad s), 4.63-4.38 (m), 4.25-3.86 (m), 2.75 (dd) 1.03-0.75 (t) Thin-layer chromatography (benzene:dioxane:acetic acid=:20:2):  
 15-methyl-PGD. Rf=0.27 lS-methyl-PGB Rf=0. l 3  
 EXAMPLE 8 9a, 1 Sa-dihyclroxy-l l-oxol 6( R )-methyl-l 3 trans-prostenoic acid (l6(R)-methyl-PGD,)  
  6.80 g of 901,1 la-dihydroxy-15a-(2&#39;- tetrahydropyranyloxy 1 6( R )-methyl- 1 3 transprostenoic acid was dissolved in 300 ml of acetone. and then oxidized by 7.2 ml ofJones reagent (See Example l-(A)) for 15 minutes at 20-30C. The solution was post-treated and purified according to the methods described in Example 3 to yield 4.0 g of the mixture of 15- tetrahydropyranyl ether of l6(R)-methyl-PGD and l5-tetrahydropyranyl ether of 16(R)-methyl-PGE (yield 59 percent).  
 Next. 4.0 g of the above mixture was hydrolyzed in m1 of the mixture of acetic acid. water and tetrahy-.  
 Rf=0.29 Rf=0.14  
  EXAMPLE 9 901,1 Sa-dihydroxy-l l-oxol 6( S )-methyl-l 3 trans-prostenoic acid 16(S)-methyl-PGD,)  
  8.5 g of 9a,1 1a-dihydroxy-15a-( 2&#39;- tetrahydropyranyloxy )-1 6( S )-methyl-1 3 transprostenoic acid was dissolved in 280 ml of ether. and then oxidized by 280 ml of chromic acid (See Example 5) for 45 minutes at about 5C. The solution was post-treated and purified according to the methods described in Example to yield 4.08 g of the mixture of IS-tetrahydropyranyl ether of 16(S)-methyl-PGD and IS-tetrahydropyranyl ether of l6(S)-methyl-PGE (yield 48 percent).  
  Next. 4.0 g of the above mixture was hydrolyzed in 900 ml of the mixture of acetic acid, water and tetrahydrofuran (65:35:10) for 1 hour at 40C, and then posttreated and purified according to the methods described in Example 3 yield 1.45 g of 16(S)-methyl- PGD and 630 mg of 16(S)-methyl-PGE (total yield 64 percent).  
 Infra-red spectrum of 16(S)-methyl-PGD, (liquid film): 3400, 2960-2850,-2300. 1735. 1705, 1455. 1380. 1240, 1180, 1160. 1040.980 cm Nuclear magnetic resonance spectrum of 16(8)- methyl-PGD. (in CDCl;.): 8 5.72-5.50 (m). 5.25-4.80 (broad s). 4.63-4.42 (m), 4.24-3.94 (m). 2.74 (d-d). 1.00-0.72 (m) Thin-layer chromatography (benzenezdiozanezacetic acid=80:20:2):  
 l6(S)-methyl-PGD, Rf=0.29 l6(S)-methyl-PGE, Rf=0.l4  
 EXAMPLE l0 9a.,15a-dihydroxy-l 1-oxo-17-methyl-13 trans-prostenoic acid (17-methyl-PGD 5.0 g of 90:1 1a-dihydroxy-15a-(2- tetrahydro&#39;pyranyloxy)-17-methyl-13 trans-prostenoic acid was dissolved in 220 ml of acetone. and then oxidized by 5.4 ml of Jones reagent (See Example l-(A)) for minutes at -30C. The solution was posttrcated and purified according to the methods described in Example 3 to yield 3.25 g of the mixture of IS-tetrahydropyranyl ether of l7-methyl-PGD, and 15- tetrahydropyranyl ether of 17-methyl-PGE. (yield 65 percent).  
  Next, 3.2 g of the above mixture was hydrolyzed in 75 ml of the mixture of acetic acid, water and tetrahydrofuran (65:35:10) for 1 hour at 40C, and then posttreated and purified according to the methods described in Example 3 to yield 1.128 g of 17-methyl- PGD, and 433 mg of l7-methyl-PGE (total yield 60 percent).  
 Infra-red spectrum of l7-methyl-PGD (liquid film):  
  2 COOH M OH R wherein X is CH- ,CH. or cis-CH=CH, and R R and R are each hydrogen or one or two of R R and R are methyl and the remainder are hydrogen, which comprises oxidizing with a member selected from the group consisting of chromic acid and Jones reagent at a temperature of about 10 to 50 C. the hydroxy radical in the ll-position of a compound of the formula:  
 wherein X R R and R are as hereinbefore defined, and THP represents a 2-tetrahydropyranyl group. and hydrolyzing in a aqueous acid a temperature of less than 45C the resulting compound of the formula:  
 O THP-O UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3 878 239 DATED April 15, 1975 |NVENTOR( 1 Masaki Hayashi, et al.  
  It is certified that error appears in the ab0veidentified patent and that said Letters Patent are hereby corrected as shown below:  
 Please cancel the structure in the Abstract as well as the structure in Claim 1 on Column 22 between Lines 11-20, and  
 substitute therefor UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,878,239 DATED April 15, 1975 lNvENTORtS) Masaki Hayashi, et al.  
  It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
 Page 2 On Column 16, Line 56, please cancel: (PGD On Column 22, Line 30, after &#34;the formula:&#34; please insert Signed and Scaled this eighteenth Day Of November 1975 [SEAL] AIIESI.  
  C. MARSHALL DANN (mnmr&#39;ssioner (11&#39; Parents and Trademarks RUTH C. MASON Arresting Officer