NO144385B - INTERMEDIATE FOR THE PREPARATION OF NEW PENTANOR PROSTAGLANDINES OF THE E OR F SERIES - Google Patents

Description

This invention relates to bis-tetrahydropyranyl ethers of prostaglandin compounds for use as intermediates in the production of new pentanorprostaglandins of the E and F series.

In our patent 143,663, hereinafter referred to as the parent patent, an analogue method for the production of a physiologically active prostaglandin compound of the E or F series is described with the formula:

or the C^ epimer thereof,

where

A is 1-adamantyl, 2-(1,2,3,4-tetrahydronaphthyl) which is racemic or optically active, 2-indanyl or 2-(5,6-dimethoxy-indanyl);

n is 0-, 1 or 2j

W is a cis double bond»

Z is a trans double bond;

M is Okso or

X is 5-tetrazolyl, a group of the formula -COOR', where R' is hydrogen or alkyl of from 1 to 10 carbon atoms, aralkyl of from 7 to 9 carbon atoms, p-biphenyl or cycloalkyl of from 3 ±i. l 8 carbon atoms, or a group of the formula -CONHR", where R" is alkylsulfonyl with from 1 to 7 carbon atoms,

and the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups in the Cg, C^ and C^^ positions, or a pharmaceutically acceptable salt of a compound of formula (I) where X is -COOH.

The procedure is characterized by

(a) a compound of the formula: wherein A, n, M, R, W, X and Z are as defined above, and THP is 2-tetrahydropyranyl, is reacted with an appropriate acid; (b) a compound of formula (I) above wherein M is oxo is reacted with a suitable reducing agent to form a compound of formula (I) wherein M is and A, n, R, W, X and Z are as indicated above; and optionally the compound of formula (I) where X is -COOH is converted into an ester or a substituted amide, as defined above, by reaction with a suitable esterifying or amidating agent, respectively; '• and optionally the 9a-, 11a- and 15a-lower alkanoyl-, -formyl- or -benzoyl esters of any free hydroxyl groups are prepared by reacting the compound of formula (I) with a suitable acylating agent;

and optionally a pharmaceutically acceptable salt is prepared of a compound of formula (I) where X is -COOH.

The bis-tetrahydropyranyl ether intermediates of formula II above are new compounds and are the subject of the present invention. These new intermediates are derivatives of "two-series" prostaglandins. The term "prostaglandin" here includes both epimers at C 1 , .. The term "lower" alkyl group here means alkyl groups containing from 1 to 4 carbon atoms.

The starting material used in the series of steps leading to the production of the new intermediate products with formula II according to the present invention are available commercially or can be produced according to known methods. For the production of dimethyl-2-oxo-2-(2-indanyl)ethylphosphonate, which is the starting material for the synthesis of bis-tetrahydropyranyl ethers of 15-(2-indanyl)-prostaglandins f>, a solution of dimethylmethylphosphonate in tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere and then slowly adding n-butyllithium dropwise in he-k.sranv.1 acEÆttexs-<pn»3s£rSflQcSyribaæfeteSST ^^^ SéKk& r^^ ud- i 2-karbok3.yl.ait^niE ;f:teji:'?3j. ti% h& d2jqm& æ&& frtø°z- Q$ Z& ft& iJQ&%^^&S3-<S.ns-blanding1e'ro Æ-aiL joingri^e&seÆteSitøafctfala^crf^^efj^lstÆeje©^ røSfili ejdd^fe-i;5 acid ^dgsJr-bitaSijpnsÆOKtfamiøSsLltiab^&rl^æfett\getfxiif;I?féife g^l^i^Asfåi^ 9 hayamaiec^trais^oppjca- v,amf.;/^éM-iV3n<ligs5fc€^Qj>Ic©fe% eteah^iSQC<<%s -sip k lo r o the waterfall; log» ndsi ^kdrabiirne^tex iøiSg a^jlskiejlekj^^r^feeri fefe^ ajfeejyy^toesrå is dried •sage ktomsentjrrejrteTSMrPg^^^ io*?

(Eo^-riikiemsifeOljgiagia^ 15-suhsLtefitn^x;te.-;(fi^ ria.^l&fiøre^ieni-jd^e^ j ;6§'s eg'rie.de^Ls:y:rélé -sx&i ^ ^sterejvetejBeidS-isfÆr IfeM -j^M^be|>te?is^5-yige&,|j methods and then to phosphonates as stated abovefjøjij. cf-.©^ j:dn. o' Y 15-(2-i !ndanYlO":«titgairg;sirøtÆasi^aliejt itsb vb ri3TJns. ilx ja^ s- jj. ' 10I

■-- (JY^EoanBfijBeid$te£l IsMgléiS saswde 1;KSmartee^ gafåitøniP^Gdajl^ ~X) - XI ,18- (2*4*0> (lp2I, 3}:4-téferabydr^iWity:l) j) Trp&^-t^iaM4n^j£afiM^caq

s toJMreso:(-fe);-a2-£ Ut, 2cp3?:43-in!å>phthalen-jsotaKfeoKaylscyjE^. -:efvber ,ine;%©den \~ j £ to Cohen et al. , n&r.IBfrolriuSftem lightning% <& tii. § 2. §4- ? d%6.>9) ^ov^rf ør>e;s mas til este* ertjlog-odemeftest feiijffo^f oafttefe somnbéskÆe,<y>ie..t;ifQr,<g >15-''02^indan> yl))nf(Spbiindelfseri i. v^Terio^fovir/i-i^s.-ji ) {i) -£) ~ ?i

nsSorefsremstillingén^av.dde^^^^ < R v 15*.f2* (ly2 , 3 H^tétfcåftydrojiaf ty,lf)>) T^EQStaglan&rner KogEgnv? j * is set (~^92-;(3>v2?3$idna£fea£etil.l?9>tl»o}£SXi9y]7@.i'ei^£- metpden^tijl Cohen et al., J. Biol. Chem. IO, 2664i3.(lM?.)jKoQverføg^sjtil-5 [ estfeeréniégmderef teerrifcilifdsÆonafeétaso^i^skre^etsforjj -~ bq

15- '('2&ihdanytLj).'»f orblijdelsenil Liriamøtl toa rtbnsvae sieq^I^ox we, manvønskernåvf rems £il<l$Bdefe j desired^ me ^LloHig,Eo<3ijkit Q

for 15- (2-indany-lf>??pf ©Sitag^andi ne<r in forwardsfeiliefmé©d§B~% Vn ob vo carboxylic acid e.g. according to the method of Bergman and Hoffman,

J. Org. Chem., 26, 3555 (1961), transfers it to the ester and then to the phosphonate as described above^

For the preparation of the desired intermediate for 16-(2-indanyl)-prostaglandins, 2-indanyl-acetic acid is prepared as described by Berman and Hoffman, J. Org. Chem. 26, 3555

(1961) , transferring it to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

For the preparation of the desired intermediate for <» >15-(2-(5,6-dimethoxyindanyl)-prostaglandins, the necessary 5,6-dimethoxyindan-2-carboxylic acid must be prepared. Condensation of 4,5-bis-chloromethylveratrol (prepared as described by Wood, Perry and Tung, J. Am. Chem. Soc, 72, 2989 (1950)) with ethyl t-butyl malinate in the presence of sodium hydride gives 2-carboethoxy-2-carbo-t-butoxy-5,6 Treatment of this diester with p-toluenesulfonic acid in refluxing benzene followed by decarboxylating distillation of the product gives ethyl 5,6-dimethoxyindan-2-carboxylate, which is transferred to the phosphonate as described for 15-(2-indanyl) - the connection.

~ i For the production of the desired intermediate for l|r-(1-adamantyl)-prostaglandins, (1-adamantyl)-e'«jjÉacetic acid is prepared from Aldrich Chem. Co. (No. 12, 727-2), is transferred

t•-* jt-1 . the ester and then to the phosphonate as for 15-(2-indanyl)-

<.*■

'■the connection.

For the preparation of the desired intermediate for 17-(1-adamantyl)-prostaglandins, 3-(1-adamantyl)-propionic acid is prepared according to the method of Fieser et al., J. Med. Chem., 10, 517 (1967), is transferred to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

_For the preparation of the desired intermediate for 15-(2-(I)-(1,2,3,4-tetrahydronaphthyl))-prostaglandins, (I)-2-(1,2,3,4-naphthalene)carboxylic acid is prepared according to the method of Cbhen et al-, J. Biol. Chem. 10, 2664 (1969) is transferred to the ester and then to the phosphonate as described for the 15-(2-indanyl) compound.

The following 'reaction core A' illustrates the production of precursors used for the production of subsequent intermediate products1 and starting materials for use in the production of the new "intermediate products of the invention" in the invention, .- •

As shown in Scheme A, the first step (1 + - 2) is the condensation of the appropriate ester with a dialkylmethylphosphonate to give oxophosphonate 2. Typically, the desired methyl ester is condensed with dimethylmethylphosphonate.

12+3, the ketophosphonate 2 is reacted with the known [Corey,

et al., J. Am. Chem. Soc., 93, 1491 (1971)] the aldehyde H and one obtains, after chromatography or crystallization, the enone 3. The compound in which the p-biphenylcarbonyl group is replaced by a p-biphenyl-carbamoyl protecting group is also usable as a substituent for H and has moreover, the advantage is that in the reduction step (3+4) a higher percentage of the desired α-isomer is obtained.

The enone 3 can be reduced with zinc borohydride or with a lithium trialkylborohydride, such as lithium triethylborohydride to a mixture of the alcohols 4^ and 5_, which can be separated by column chromatography. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane can be used as solvents, although it is sometimes preferred to use methanol to ensure a specific reduction. Additional transfers of 4^ are shown in Scheme B.

4_ 6_ is a base-catalyzed hydrolysis where p-biphenylcarbonyl protecting groups are removed. This is conveniently performed with . potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6_ -+ 1_ includes the protection of the two free hydroxyl groups with a protecting tetrahydropyrahyl (THP) group. The tetrahydropyranyl group is introduced into the molecule by treatment with dihydropyran and an acid catalyst in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid.

7 -»• 8 is a reduction of the lactone 7 to the hemiacetal 8

by using diisobutylaluminum hydride in an inert solvent. It is preferred to use low reaction temperatures and -60° to -70°C is common. However, higher temperatures can be used if an over-reduction is not obtained. 8 is purified, if desired, by means of column chromatography. 8 + 9 is a Wittig condensation where the hemiacetal is reacted with e.g. (4-Carbohydroxy-n-butyl)triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinyl methide.

9_ cleaned as above.

9 + 10 is an oxidation of the secondary alcohol 9 to the ketone 10. This can be achieved by using an oxidizing agent that does not attack the double bonds, but Jones's reagent is usually preferred. The product is cleaned as above.

The intermediates 9 and 10 according to the invention can then be hydrolysed by the method according to the parent patent to form new prostaglandin analogues.

The transfer 9 -> 12_ is an acid hydrolysis of tetrahydro-pyranyl groups. Any acid can be used which does not destroy the molecule during the removal of the protecting group; however, this is often carried out using 65% aqueous acetic acid. The product is cleaned as above. 10 +-1_1 is performed in the same way as 9 1_2. The product is cleaned as above. The reduction of the compound 1_1 with sodium borohydride gives the 9α-isomer of the prostaglandin analogues of the F series, i.e. the PGF2g_ compounds. These can also be obtained via sodium borohydride reduction of 10 followed by hydrolysis as described above for 10 ->• 11 .

As shown in Scheme C, compound 5_ can be used in place of compound £ in Scheme B to form prostaglandin analogues 12<1> and 11'.

The new esters of the compounds of formula II can be prepared in a number of different ways. These differ from each other in that the esterifying group is attached to the prostaglandin or its precursor in different stages of the synthesis.

E.g. Scheme D illustrates two routes to the ester "E".

In each case, the esterifying group is introduced by an esterification reaction which can be carried out by bringing the appropriate prostaglandin analogue or its precursor into contact with the alcohol or phenol in the presence of a catalyst. Alternatively, the prostaglandin or its precursor can be treated with a diazoalkane or cycloalkane in reaction-inert solvents to give the desired ester. A prostaglandin analogue can be used as a substrate for the above esterification reactions and further precursors to such prostaglandins or prostaglandin analogues can also be used as illustrated in Scheme D. E.g. can 9_ be transferred to 9E by the esterification reaction as indicated above and 9E can then be transferred to 1OE by the same methods used to transfer 9^ to 10 as previously discussed.

Various modifications are possible on the top side chain of the intermediates according to the present invention.

A 5-tetrazolyl group can be placed in the C^ position.

E.g. can the compound £3 be reacted with the ylide which has been prepared

from (4-(tetrazol-5-yl)-n-butyl)-triphenylphosphonium bromide and sodium methylsulfinyl methide and gives C-^-tetrazole-substituted compound j).

Another modification of the top side chain can

is done in the intermediates according to the present invention by replacing the carboxylate group in the C-^ position with a carboximide or carboxysulfonamide group. E.g. £5 can be reacted with the ylide obtained from (methanesulfonylaminocarbonyl-n-butyl)-triphenylphosphonium bromide and sodium methylsulfinyl methide to give C1-N-methanesulfonylcarboxamide-substituted compound 9_. Alternatively, the new compounds according to the present invention with formula II (where X is COHNR" and where R" is as previously indicated), can be prepared, e.g. from connections 9 and 10

in Scheme B by reaction with appropriate acyl or sulfonyl isocyanates, followed by hydrolysis with dilute acid.

In the foregoing methods, where it is desired to purify by means of chromatography, suitable chromatographic supports are neutral alumina, silica gel and fluoracil. The chromatography is suitably carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane, n-hexane and methanol.

The previously stated formulas produce optically active compounds. It is clear, however, that the corresponding racemates can also* be used for the preparation of the final prostaglandin analogues of formula I which will be in possession of valuable biological action due to the content of the above-mentioned biologically active optical isomer, and such racemates are covered by the preceding formulas. The racemic mixtures are easily prepared according to the same methods used to synthesize the optically active compounds by using the corresponding racemic precursors instead of the optically active starting materials.

In numerous in vivo and in vitro tests, it has been demonstrated that the new prostaglandin analogs of formula I prepared from the new intermediates of formula II have selective physiological effects comparable to those exhibited by the natural prostaglandins. The effect of the compounds of formula I is explained in more detail in patent 14 3.66 3.

The following examples 1-6 illustrate the preparation of the starting materials leading to the new intermediate products of formula II, and examples 7-10 illustrate the preparation of the intermediate products themselves. Their use for the production of the biologically active prostaglandins of formula I is illustrated in patent 143.66 3. In the examples, all temperatures are given in °C, all melting points and boiling points are uncorrected.

Example 1

Dimethyl- 2- oxo- 2-( 2- indanyl) ethyl phosphonate

A solution of 20.4 g (164 mmol) of dimethyl methylphosphonate (Aldrich) in 200 ml of dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added dropwise 82>6 ml of 2.25M-n-butyllithium in hexari solution (Alfa Inorganics, Inc.) during 20 minutes at such a rate that the reaction temperature did not exceed approx. -6 5°. After a further 5 minutes of stirring at -78°, 14.0 g (73.5 mmol) of methylene-2-carboxylate was added dropwise at such a rate that the reaction temperature was kept lower than -70°

(-20 minutes). After 1.0 hour at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml -acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 mL water, the aqueous phase was extracted with 75 mL portions of methylene chloride (4x), the combined organic extracts were backwashed (75 mL H 2 O), dried (MgSO 4 ) and concentrated (water aspirator) to a impure residue and distilled, c.p. 150-160° (0.1 mm), yielding 17.0 g (86.4%) dimethyl-2-oxo-2-(2-indanyl)ethylphosphonate.

Nuclear magnetic resonance spectrum (CDCl 3 ) of the distilled product showed a singlet at 7.15 <S for aromatic protons, a doublet at 3.76 (J = 11 eps) for OCH^, a singlet at 3.25 6 for benzylic protons, a doublet at 3.18 6 (J = 23 eps) for PCH_2 and a deformed triplet at 3.13 <5 (J = 2 eps) for •

CHCO.

Example 2

2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2&-(3-oxo-3-(2-indanyl)-trans-l-propen-l-yl)-cyclopent-la-yl]acetic acid, y- lactone

To a solution, cooled in ice under nitrogen, of 17.2 mL (32.6 mmol) of a 1.90 M solution of n-butyllithium in hexane in

150 ml of dry 1,2-dimethoxyethylene was added dropwise to 9.2 g

(34.5 mmol) dimethyl 2-oxo-2-(2-indanyl)ethylphosphonate. The solution was stirred cold for 10 minutes and then 11.9 g (33.5 mmol) of the known 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-a(3-formyl-cyclopent-la-yl]acetic acid was added , γ-lactone..The ice bath was removed, the mixture was stirred for 1.0 h and then quenched by the addition of glacial acetic acid (pH ^ 5). The mixture was concentrated and the resulting mixture was dissolved in methylene chloride (300 mL). The organic layer was washed with water (100 mL), saturated sodium bicarbonate (50 mL), brine (50 mL), dried (anhydrous magnesium sulfate), and concentrated to a semi-solid.Recrystallization of the crude product from isopropyl alcohol methylene chloride gave the desired 2-[3a-p-phenyl^benzoyloxy-5a-hydroxy-2&-(3-oxo-3-(2-indanyl)-trans-l-propen-l-yl)-cyclopent-la-yl]acetic acid, 6 -lactone as white feathers melting at 170-172°, weight 6.85 g (42.8%).

Infrared spectrum (CHC1,) of the product showed absorptions at 1775 cm for lactone carbonyl, at 1710 cm for ester carbonyl, 16 70 and 16 25 cm for ketone carbonyl and at 975 cm for trans double bond.

Example 3

2-( 3a- p- phenylbenzoyloxy- 5a- hydroxy- 2g-( 3a- hydroxy- 3-( 2- indanyl)- trans- l- propen- l- yl) cyclopent- la- yl) acetic acid, y- lactone and 2-( 3a- p- phenylbenzoyloxy- 5a- hydroxy- 23-( 30- hydroxy- 3-( 2- indanyl)- trans- l- propen- l- yl) cyclopent- la- yl) acetic acid, Y- lactone

To a solution of 6.73 g (14.0 mmol) of 2-(3a-p-phenylbenzoyloxy-5a-hydroxy-2B-(3-oxo-3-(2-indanyl)-trans-l-propen-l- yl) cyclopent-la-yl) acetic acid, γ-lactone in 67 ml of dry tetrahydrofuran in a dry nitrogen atmosphere at ambient temperature was added dropwise to 14.0 ml of a 0.5 M zinc borohydride solution. After stirring at room temperature for 1.5 hours, a saturated sodium bitartrate solution was added dropwise to 14.0 ml of a 0.5M zinc borohydride solution. After stirring at room temperature for 1.5 hours, a saturated sodium bitartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes and 150 ml of dry methylene chloride was added.-After drying (MgSO 4 ) and concentration (water aspirator) the resulting semi-solid material was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) at to use mixtures of ethyl acetate:ether as eluents. After elution of less polar impurities, a fraction containing 2.21 g (32.8% yield) of 2-(3α-phenylbenzoyloxy-5α-hydroxy-2α- (Sα-hydroxy-S-(2-indanyl)-trans) was collected -l-propen-l-yl)cyclopent-la-yl)acetic acid, γ-lactone and a fraction containing 1.79 g (26.6% yield) 2-(3a-p-phenylbenzoyloxy-5a-hydroxy-23 -(33-hydroxy-3-(2-indanyl)-trans-1-propen-yl)-cyclopent-la-yl)acetic acid, γ-lactone.

Infrared spectrum (CHC1-.) of both products had

strong adsorption at 1770 cm (lactone carbonyl) and 1705 cm (ester carbonyl) and a medium adsorption at 970 cm (trans-olefin).

Example 4

2-[ 3a, 5a- dihydroxy- 2B-( 3a- hydroxy- 3-( 2- indanyl)- trans- l- propen-l- yl) cyclopent- la- yl] acetic acid, y- lactone

A heterogeneous mixture of 2.21 g (4.46 mmol) of 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2B-(3a-hydroxy-3-(2-indanyl)-trans-l-propen-l- yl ) cyclopent-la-yl ] acetic acid , γ-lactone, 40 ml of dry tetrahydrofuran, 40 ml of absolute methanol and 0.61 g of finely powdered, anhydrous potassium carbonate were stirred at room temperature for 1 hour and then cooled to 0°. To the cooled solution was added 4.46 ml of a 1.0N aqueous hydrochloric acid.

After stirring at 0° for a further 10 minutes, was added

75 ml of water with simultaneous formation of methyl-p-phenylbenzoate which was collected by filtration. The filtrate was concentrated by rotary evaporation and was then extracted with ethyl acetate (3x), the combined organic extracts were dried (MgSO 4 )

and was concentrated, yielding 924 mg (66%) of viscous, oily 2-{3a,5a-dihydroxy-2B-(3a-hydroxy-3-(2-indanyl)-trans-l-propen-l-yl)cyclopent -la-yl]-acetic acid, γ-lactone.

Infrared spectrum (CHC1,) showed a strong adsorption by

-1 J

1770 cm for lactone carbony1 and a medium adsorption at 970 cm ^ for trans double bond.

Example 5

2-[ 5a- hydroxy- 3a-( tetrahydropyran-2- yloxy)- 26-( 3a- tetrahydropyran- 2- yloxy]- 3-( 2- indanyl)- trans- 1- propen- 1- yl) cyclopent- la - yl]-acetic acid, y- lactone

To a solution of 0.924 g (2.94 mmol) of 2-[3α,5α-dihydroxy-26-(3α-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la- yl]-acetic acid, γ-lactone in 49 ml of anhydrous methylene chloride and 0.86 ml of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere were added a few crystals of p-toluenesulfonic acid, monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 mL of ether, the ether solution was washed with saturated sodium bicarbonate (1 x 15 mL), then brine (1 x 15 mL), dried (MgSO 4 ) and concentrated to give 1.38 g ( 97.8%) crude 2- [5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2-0-(3α-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1- propen-1-yl)cyclopent-la-yl] acetic acid, γ-lactone which was used without purification.

Infrared spectrum (CHC1-) of the product showed a strong

-1

adsorption at 1755 cm for the lactone carbonyl and a medium absorption at 965 cm for the trans double bond.

Example 6

2- [ 5a- hydroxy- 3a- ( tetrahydropyran- 2- yloxy)- 2B-( 3a-[ tetrahydropyran- 2- yloxy]- 3-( 2- indanyl)- trans- l- propen- l- yl) cyclopent- la- yl]- acetaldehyde, y- hemiacetal

A solution of 1.39 g (2.9 mmol) of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2B-(3α-[tetrahydropyran-2-yloxy]-3-(2-indanyl) -trans-1-propen-1-yl)cyclopent-la-yl]acetic acid, γ-lactone in 20 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere. To this cooled solution was added dropwise 4.2 ml of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) at such a rate that the internal temperature did not exceed -65° (15 minutes). After a further 30 minutes of stirring at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature and was concentrated by rotary evaporation. The resulting oil was suspended in methanol and then filtered to remove aluminum salts. The concentration of the filtrate gives the crude product which was purified by means of silica gel (Baker "Analyzed" 60-200 mesh^ column chromatography using mixtures of benzenerethyl acetate as eluents. After the removal of less polar impurities, the desired 2-[5a-hydroxy -3a-(tetrahydropyran-2-yloxy)-23-(3a-[tetrahydropyran-2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl)-cyclopent-la-yl]acetaldehyde , γ-hemiacetal as a viscous oil^ weight 1.17 g (84.3%).

.Infrared spectrum (CHC1-). of the purified product showed

-1 a medium absorption at 975 cm for the trans double bond and no carbonyl absorption.

Example 7

9a- hydroxy- lla, 15a- bis-(tetrahydropyran-2- yloxy)- 15-( 2- indanyl)-cis- 5- trans- 13- co- pentanorprostadic acid

To a solution of 3.21 g (7.24 mmol) of (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 6.0 ml of dry dimethyl sulfoxide was added 6.96 ml (14.0 mmol)

of a 2.01M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1.16 g (2.41 mmol) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-20-(3a-[tetrahydropyran-2-yloxy]- 3-(2-indanyl)-trans-1-propen-1-yl)-cyclopent-la-yl]acetaldehyde, γ-hemiacetal in 2.0 mL of dry dimethylsulfoxide over 20 minutes. After further stirring for 2 hours at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3x) and the combined organic extracts washed with water (2x), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue

was triturated with ether and filtered. The filtrate was concentrated, and gives 1T99 g (>100%) of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-α)- pentanor-prostadienic acid which was used without purification.

Infrared spectrum (CHC1-.) of the purified product showed

a strong absorption at 1710 cm -1 for the acid carbonyl and a medium absorption at 970 cm for the trans double bond.

Example 8

9- oxol-lla, 15a- bis-( tetrahydropyran-2- yloxy)- 15-( 2- indanyl)- cis-5- trans- 13- o)- pentanorprostadic acid

To a solution cooled to -10° under nitrogen

of 1.32 g (2.34 mmol) of 9α-hydroxy-lla, 15α-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-u)-pentanorprostadic acid in 15 ml of analytical grade acetone was added dropwise to 1.17 ml of Jones reagent. After 15 min at -10°, 1.17 mL of 2-propanol was added and the reaction mixture was stirred for an additional 5 min and then combined with ethyl acetate, washed with water (2x), dried (MgSO 4 ) and concentrated to give 1, 11 g (84.2%) of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-o)-pentanorprostadioic acid which was used without purification.

Example 9

N- methanesulfonyl- 9a- hydroxy- lla, 15a- bis-( tetrahydropyran-2- yloxy)- 15-( 2- indanyl)- cis- 5- trans- 13- u- pentanorprostadienamide

To a solution of 2.37 g (4.56 mmol) of (methanesulfonylamino-carbonyl-n-butyl)-triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml of dry dimethyl sulfoxide was added 4.50 ml (8.62 mmol) of a 1 .90M solution of sodium methylsulfinylmethide

in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution of 735 mg (1.52 mmol) 2-[5ct-hydroxy-3a-(tetrahydropyran-2-yloxy)-26-(3a-[tetrahydropyran-2-yloxy]-3- (2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]acetaldehyde, Y-hemiacetal in 6.0 mL of dry dimethylsulfoxide. After a further 1 hour of stirring at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x) and the combined organic extracts were washed once with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. The crude product was purified by column chromatography on silica gel (Baker "Analyzed " reagent 6O-200 mesh) using mixtures of chloroform: ethyl acetate as eluents. After the removal of high Rj impurities, 899 mg (81.5%) of N-methane-sulfonyl-9a-hydroxy-lla,15a-bis were collected -(tetrahydropyran-2-yloxy)-15-(2-indanyl)-cis-5-trans-13-a)-pentanorprostadienamide.

Infrared spectrum (CHC1,) of the product showed medium

-1 -1 absorptions at 1710 cm for carbonyl group and at 970 cm for trans double bond.

The treatment of the above hemiacetal with the ylide from (4-(tetrazol-5-yl)-n-butyl)-triphenylphosphonium bromide gives a product which can be converted to 2-decarboxy-2-(tetrazol-5-yl)-prostaglandins.

Example 10

N-methanes:ulfonyl- 9-oxol- lla, 15a- bis-( tetrahydropyran-2- yloxy)- 15-( 2- indanyl)- cls- 5- trans- 13- a)- pentanorprostadienamide

To a solution, cooled to -10° under nitrogen, av

399 mg (0.62 mmol) N-methanesulfonyl-9a-hydroxy-11a, 15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)-;is-5-trans-13 -(D-pentanorprostadienamide in 15 ml of acetone of arylase quality was added dropwise, 0.31 ml of 2-propanol and the reaction mixture was stirred for a further 5 minutes and then combined with ethyl acetate, washed with water (2 x), dried (MgSO^ ) and concentrated, yielding 371 mg (93%). N-methanesulfonyl-9-oxo-11a , 15a-bis-(tetrahydropyran-2-yloxy)-15-(2-indanyl)- cis-5-£■ trans-13=-w-pentanorprostadienamide which was used without purification,

Claims (1)

Bis-tetrahydropyranyl ether of a prostaglandin compound for use as an intermediate in the preparation of physiologically active prostaglandin compounds of the E or F series with the formula: or -epimer thereof, where A is 1-adamantyl, 2-(1,2,3,4-tetrahydronaphthyl) which is racemic or optically active, 2-indanyl or 2-(5,6-dimethoxyindanyl); n is 0, 1 or 2; M is oxo or X is 5-tetrazolyl, a group of the formula -C00R', where R' is hydrogen or alkyl of from 1 to 10 carbon atoms, aralkyl of from 7 to 9 carbon atoms, p-biphenyl or cycloalkyl of from 3 to 8 carbon atoms, or a group of the formula -C0NHR", where R" is alkylsulfonyl with from 1 to 7 carbon atoms, characterized in that it has the general formula: where A, n, M and X are as defined above, and THP is 2-tetrahydropyranyl.