DE2344839A1 - NEW PHOSPHONATES AND METHODS FOR THEIR PRODUCTION - Google Patents

Description

Our No. 18 848 -

Pfizer Inc.
New York, NY, V.St.A,

New phosphonates and processes for their production.

The invention relates to new phosphonates which are used as starting products for the production of 18-oxa-, 19-oxa-, 20-0xa- and 19-oxa-u ^ homo-prostaglandins and their intermediates are suitable as well as processes for their production.

The compounds of the invention have the general formula

0 0

CH, (CH ₉ ) -0- (CHp) _n (CHo) ₃ -C-CH -PCT

where η is an integer from 0 to 2 and m is an integer A number from 1 to 5, the sum of η and m not exceeding 6.

The prostaglandins are unsaturated fatty acids that have diverse physiological effects. For example, the prostaglandins of the E and Α series are potent vaso-

O 9 8 O 9/1 2 2 O

dilators (Bergström et al., Acta-.Physiol. Scand. 64: 332-33 * 1965 and Bergström et al., Life Sci. 6: 449-455, 1967) and lower the systemic arterial blood pressure (vasodepression) in intravenous Administration (Weeks and King, Federation Proc. 23: 327, 1964; Bergström et al., 1965, op.cit .; Carlson et al., Acta. Med. Scand, I83: 423-43O, 1968s and Carlson et al., Acta. Med. Scand, I83: 423-43O, 1968s and Carlson et al. , Acta Physiol. Scand

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75: 161-169 j 1969). Another well-known physiological effect of PGE ₁ and PGE _? is that as a bronchodilator (Cuthbert, Brit. Med. J. 4: 723-726, 1969).

Another important physiological role of naturally occurring prostaglandins is related to the reproductive cycle. PGE ₂ is known to have the ability to induce labor (Karim et al., J. Obstet Gynaec. Brit. Cwlth. 77: 200-210, 1970) "induce therapeutic abortion (Bygdeman et al., Contraception, 4, 293 (1971)) and to be suitable for controlling fertility (Karim, Contraception, 3 * 173 (1971)). Patents have been issued for various prostaglandins of the E and F series as compounds which cause abortion in mammals ( BE-PS 754 158 and

DT-PS 20 3 ² J 641) and for PGP ₁ , F ₂ , and F for controlling the reproductive cycle (ZA-PS 69/6089).

Further known physiological effects of PGE ₁ are the inhibition of gastric acid secretion (Shaw and Ramwell, In: Worcester Symp. On Prostaglandins, New York, Wiley, 1968, pages 55-64) and also of platelet aggregation (Emmons et al., Brit. Med J ₄ 2: 468-472, 1967).

It is now known that such physiological effects after administration of the prostaglandin in vivo only for one generated for a short time. Substantial evidence indicates that the reason for this rapid decline in Effectiveness consists in the fact that the naturally occurring prostaglandins are metabolically deactivated quickly and effectively v / earth through the ß-Oxidatlon of the carboxylic acid side chain and by oxidation of the! ^ - hydroxyl group (Anggard et al., Acta. Physiol. Scand., 81, -396 (1971) and references cited therein).

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It was therefore considered to be worth seeing, analogous to the To create prostaglandins whose physiological effects are equal to those of the natural compounds in which however, the selectivity of the effect and the duration of the activity are increased. An increased selectivity of the Effect is expected to avoid serious side effects, especially gastrointestinal side effects, to mitigate, which is often observed after systemic administration of the naturally occurring prostaglandins (see Lancet, 536, 1971).

The compounds according to the invention, i.e. the u / -Trisnorprostaglandins, those in the 17-position have two hydrogen atoms and a substituent of the formula

where h is an integer from 0 to 2, m is an integer Number from 1 to 5, the sum of η and m not exceeding 6, mean and those in the 15 ~ position have a hydrogen substituent or have an alkyl substituent with 1 to 3 carbon atoms, satisfy in a unique manner the above requirements. This means that they have activity profiles that are similar to those of the parent prostaglandins are comparable, although they are more tissue-selective in their effect and have a longer duration of action than the parent prostaglandins.

U) -Trisnorprostaglandins of A, B are particularly preferred or Ε series, which have two hydrogen atoms in the 17-position and a substituent of the formula

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<CH ₂ ) _n -O- (CH ₂ ) _m CH

where η is an integer from 0 to 2, m is an integer from 1 to 5, the sum of η and ra not exceeding 6, and those in the 15-position
have a hydrogen substituent or an alkyl substituent with 1 to 3 carbon atoms.

The present invention includes prostaglandins, Intermediates and reagents of the formulas

■ / -τ *

N'll

(CH ₂ ) _n ~ 0- (CH ₂ ) _m CH ₃

HO ' ¹ '

K C-OH

(CH ₂ ) _n -0- (CH ₂ ) _m CH ₃

XVI

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HO ¹ '

XVII XVIII

XIX II

III

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(CH ₂ ) _n -0- (CH ₂ ) _m CH ₃

R OH

(CH ₂ ) _n -O- (CH ₂ ) _ia CH ₃

t) H

THPO

(eH ₂ ) _n -o- (CH ₂ ) _m CH ₃ !

R OTHP

OC

OCH-:

-O- (CH ₂ ) _m CH ₃

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(CH ₂ J _n -O- (CH ₂ ) _m CH ₃

VI

THPO ''

Oh

R- OTHP

(CH ₂ ) _n ~ 0- (CH ₂ ) _m CH ₃

THPO

XII

'OTHP

wherein R is a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms, R _{1 is} a hydrogen atom, a 2-tetrahydropyranyl radical or a radical of the formula W ^

-C-R,

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wherein Rp is an alkyl radical with 1 to 5 carbon atoms, denotes a phenyl radical or a p-biphenyl radical, R, a hydrogen atom or a 2-tetrahydropyranyl radical, η is a number from 0 to 2, m is a number from 1 to 5, the sum of η and m not exceeding 6, W a single bond or a cis double bond, Z a single bond or a trans double bond and M a keto radical or a radical of the formulas

- or

and where, when L is _a hydrogen atom, a N is a -hydroxyl radical, or N and L together form a single bond, and where THP is the 2-tetrahydropyranyl radical.

Particularly preferred new prostaglandins according to the invention are:

9-Oxo-llajl5a.-dihydroxy-i9-oxa-cis-5-trans ~ 13 - prostadic acid,

prostadic acid,

9-oxo-lla, 15α-dihydroxy-l8-oxa-cis-5-trans-l3-prostadiene-

acid,

9σ, 11α, 15a-trihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid,

9 a, llajlSa-Trihydroxy-lQ-oxa-cis ^ -trans - ^ - uHomoprostadienoic acid, 9a, lla, 15a-trihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid.

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Other new and valuable oxaprostaglandin analogs are the C _q -, C -, - ^{un (} - C "esters, in which the ester radical is a formyl radical, an alkanoyl radical with 2 to 5 carbon atoms or a benzoyl radical.

The aim of the present invention is a process for the preparation of a compound of the general formula./

(CH ₂ V0- (CH ₂ ) _m GH ₃

wherein R is a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, W a single bond or a cis double bond, Z a single bond or a trans double bond and M is a keto radical or the remainder of the formulas

'' 0H

or

"OH

and where N and L together form a single bond or, when L is a hydrogen atom, N is one a-hydroxy radical, and where η is a number from 0 to 2 and m is a number from 1 to 5, the sum of. η and m does not exceed 6, and where X, M and N are selected to have the structure of a prostaglandin

,to
the A, E or F series / complete, and the C _q -, C ₁ - and C, .- esters thereof, the ester radical denoting the formyl radical, an alkanoyl radical having 2 to 5 carbon atoms or a benzoyl radical, the characterized by

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draws is that one

a) for the preparation of a compound of the formula in which N is an α-hydroxy radical and L is a hydrogen atom, and n, m, R, M, W and Z are as defined above, the 11- and 15-tetrahyctopyranyl esters Compound of formula I treated with aqueous acetic acid

b) for the preparation of a compound of the formula in which N and L together form a single bond and M is a keto radical means, and n, m, R, W and Z are as defined above, a compound of the formula I, wherein N is an α-hydroxy radical and L is hydrogen and M is a keto radical and n, m, R, W and Z are the have the above meaning reacts with formic acid,

c) for the preparation of a compound of the formula in which N is a -hydroxy radical, L is a hydrogen fatom and M is the radical

< or <

and n, m, R, V / and Z represent those mentioned above Have meaning, a compound of the formula I in which N is an α-hydroxy radical, L is a V / assers t of fatom and M is a Mean keto radical and n, m, R, W and Z have the meaning given above with sodium borohydride, reacts and, optionally separating the 9 ~ cx ~ and 9 ~ ß-hydroxy isomers, and, optionally, by reacting these compounds with the suitable acylating agent, the formyl, alkanoyl or benzoyl esters of the free 9 "» H ~ or 15-hydroxy radicals forms.

Another object of the present invention is a process for the preparation of the compound of the general formula

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C «OH

R "'OH

IA.

Viorin R is a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms, W is a single bond or a cis double bond, Z is a single bond or a trans double bond, η is a number from 0 to 2 and m is a number from 1 to 5, above the sum of η and m does not exceed the number 6, and the Cg, C ^ - and C "-esters thereof, the ester radical denoting the formyl radical, an alkanoyl radical having 2 to 5 carbon atoms or a benzoyl radical which is characterized in that one

a) the 11- and 15-tetrahydropyranyl ethers of a compound of formula I treated with aqueous acetic acid,

b) a compound of the formula

wherein n, m, R, W and Z have the meanings stated above, is reduced with sodium borohydride and then the 9 ~ S ~ CT and SS isomers and j are separated, where appropriate, _y these compounds with suitable acylating agents of the bi-ldung formyl, alkanoyl - or benzoyl esters of the free 9 ~, H ~ and 15 ~ hydroxy radicals.

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Another object of the present invention is a method for the preparation of a compound of the general formula

R OH

{CH _{2) n} -O- (CH _{2) ra} 0H3

IB

wherein R is a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms, W is a single bond or a cis double bond, Z is a single bond or a trans double bond, η is a number from 0 to 2 and m is a number from 1 to 5, where the The sum of η and m does not exceed the number 6, and the C ₁₁ and C ^ esters thereof, the ester radical denoting the formyl radical, an alkanoyl radical with 2 to 5 carbon atoms or a bensoyl radical, which is characterized in that the 11 - Treated and 15 ~ tetrahydropyranyl ether derivatives of the above-mentioned compound with aqueous acetic acid and optionally / by reacting these compounds with the appropriate acylating agent to prepare the formyl, alkanoyl or benzoyl esters of the free 11- and 15-hydroxy radicals.

Another object of the present invention is a process for the preparation of a compound of the general formula

^R '"-OH

-C-OII

CH ₂ ) _n -0- (CH ₂

IC

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where R is a water atom or an alkyl radical having 1 to 3 carbon atoms, W is a single bond or a cis double bond, Z is a single bond or a trans double bond, η is a number from 0 to 2 and m is a number from 1 to 5 , where the sum of η and m does not exceed the number 6, and the C _lt - esters thereof, v / obei the ester radical means a formyl radical, an alkanoyl radical with 2 to 5 carbon atoms or a benzoyl radical, because it is characterized in that one a compound of the formula

(CH ₂ ) _n -O ~ (CH ₂ ) _m CH ₃

IB

in which n, m, R, W and Z have the meanings given above, treated with formic acid and, if appropriate, by reacting this compound with suitable acylating agents, the formyl-i-alkanoyl or benzoyl esters of the C ₁ 5 -hydroxy group are formed.

The present invention also relates to a method for the preparation of a compound of the general formula

THPO

R 'XOTHP

-OH

CH ₂ ) _n -0- (CH ₂ ) _m CH

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v / orin R is a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, V / a single bond or a cis double bond, Z is a single bond or a trans double bond, M is a keto radical or a radical of the formula

H '' 'OH

η is a number from 0 to 2 and m is a number from 1 to 5> ^r where the sum of η and m does not exceed the number 6, and THP is the 2-tetrahydropyranyl radical, which is characterized in that one

for the preparation of a compound of the formula wherein M is a Keto and n, m, R, VJ and Z denote the above Have meaning, a compound of the formula

OH

-OH

in which n, m, R, W and Z have the meanings given above, with chromic acid, aqueous sulfuric acid and Acetone oxidizes,

for the preparation of a compound of the formula in which M is the radical of the formula

•H

> 0H

and V / denotes a cis double bond, and m, n, R and Z are as defined above, a compound

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the formula

(CH ₂ ) _n ~ 0- (CH ₂ ) _ra CH ₃

with an ylid of the formula

(C ₆ H ₅ ), P = CH-CH ₂ Ch ₂ CH ₂ -COOH

converts andj if necessary, subsequently the one obtained in this way Product of the formula for the preparation of a compound in which n, m, R and Z are as defined above and V / denotes a single bond, reduced, -for the preparation of a compound of the formula, vjorin n, jn, R and M are as defined above and W and Z are single bonds, a compound of the formula

C-OH

.1IA

wherein n, m, R and M have the meaning given above, V / one cis double bond and Z one trans double bond mean, reduced,

for the preparation of a compound of the formula in which M is the radical

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2 3 4 A 8 3 9

means, η, m and R the abovementioned meaning have, W a single bond and Z a trans double bond mean a compound of the above. Formula HA selectively reduced.

The invention further relates to a process for the preparation of a compound of the general formula

CH ₃ (CH ₂ ) _m -0- (CH ₂ ) _n (

j> ^0GH 3 \ 0CHo

III

where η is a number from 0 to 2 and m is a number from 1 to, the sum of η and m not exceeding the number 6, which is characterized in that a compound of the formula

with a compound of the formula

lower-alkyl-0-G (GH ₂ ) ₂ (Gfi ₂ ) _n -0-

wherein η and m are as defined above.

The invention also relates to a process for the preparation of a compound of the formula

IV

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where η is a number from 0 to 2 and m is a number from 1 to where the sum of η and m does not exceed the number 6, and R _{1 is} a hydrogen atom, a 2-tetrahydropyranyl radical or a radical of the formula

Il

mean where R _? denotes an alkyl radical having 1 to 5 carbon atoms, the phenyl radical or the p-biphenyl radical, which is characterized in that a compound of the general formula

wherein R ^ has the meaning given above ^ with a Compound of the general formula

wherein m and η are as defined above.

Another object of the present invention is a process for the preparation of a compound of the general formula

0 0 #

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wherein R is a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms, η is a number from 0 to 2 and · in is a number from 1 to 5, the sum of η and m
the number does not exceed 6, and FL represents a hydrogen atom, a 2-tetrahydropyranyl radical or a radical of the formula

ti

—C — Rp

xtfo where Rp is an alkyl radical having 1 to 5 carbon atoms, a phenyl radical or a p-biphenyl radical, and R, a hydrogen atom or the 2-tetrahydropyranyl radical, which is characterized in that one
a) for the preparation of a compound of the general formula in which R ^ is the remainder

If

-CR ₂

means and Rp has the meaning given above, R and R-z represent hydrogen atoms, a compound of general formula

CH ₂ ) _n -0- (GH ₂ ) _Irl GH ₃

. ■ Ό

wherein R _{1 is} the remainder

where Rp has the meaning given above and η and m have the meaning given above,

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reduced with zinc borohydride,

b) for the preparation of a compound of the formula in which H the rest

ti

-CR ₂

where Rp has the meaning given above, R ^ is a hydrogen atom and R is an alkyl radical, a Reacts compound of formula II with lithium alkyl,

c) for the preparation of a compound of the formula, v / orin R ₁ and R ^ are hydrogen atoms and R, η and m are as defined above, treating the compound prepared under b) above with potassium carbonate,

d) for the preparation of a compound of the formula in which R and R are 2-tetrahydropyranyl radicals and R, η and m are the Have the above meaning, the compound prepared above under c) in the presence of _ Reacts p-toluenesulfonic acid with 2,3 ~ ü ± hydropyran.

The present invention further relates to a process for the preparation of a compound of the general formula

(CH ₂ ) _n -0- (CH ₂ ) _m C] l · THPO * \ ^ X ^ "

wherein R is a hydrogen atom or an alkyl radical with 1 to Carbon atoms, η a number from 0 to 2 and m a number from 1 to 5, the sum of η and m not being the number 6

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exceeds _a and THP is the 2-tetrahydropyranyl radical, which is characterized in that a compound of the general formula

^ CH ₂ ) "- (> - (CH ₂ ) _B GH

R * 'OTHP

in which R, η and m have the meaning given above, reduced with diisobuty! aluminum hydride,

Eir, a further aim of the present: Er-f.ir-dung is a process zwv production of a compound of the general formula

O -

THPO ¹ ''

where R is an hydrogen atom or an alkyl radical with 1 up to 3 carbon atoms, η a number from 0 to 2 and m one Number from 1 to 5, where the sum of η and m is 6 does not exceed, and TKP mean the 2-tetrahydropyranyl radical, which is characterized in that one Compound of formula

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(CH ₂ ) _n ~ 0- (CH ₂ ) _m CH ₃

R '/ OH

in which R, η. and m have the meaning given above, in the presence of p-toluenesulfonic acid with 2,3-dihydropyran implements.

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Reaction scheme A

¹ CHO

0

! Γ jf-

+ CH, (CH ₂ ) _m -0- (CH ₂ J _n CH ₂ C-CH ₂ -P- (OCH,) ₂

II

III

<CH ₂ ) _n -O- (CH ₂ > _n CH

0Η ·

(CH ₂ ) _n -O- (CH ₂ ) _m CH ₃

(CH ₂ ) _n -O- (CH ₂ ) _m CH ₃

IV

R 'OH

(CH ₂ ) _n -O-CCH ₂ ) _B CH ₃

(CH ₂ ) _n -O- (CH ₂ ) _m CH ₃

OTHP

VI

OJ

ti

CM

C \!

C • Η

CD

tn ο

CS

σ ι

CM

O = O

AO 9 "8 09/1220

Reaction scheme B

(CH ₂ ) _n -0- (CH ₂ ) _m CH ₃

OTHP

(CH ₂ ) _n -O- (CH ₂ ) _m CH ₃

R ^ '' 'OTHP

VII XII

XIII

(CH ₂ ) _n -O- (CH ₂ ) _m CH ₃

'OTKP R ₁ O

XIV

■ C-OH
<CH ₂ ) _n -O- (CH ₂ ) _m CH ₃

R ^ "'t) THP

13, l * J-Dihydro-oxaprostaglandin F ₀ , E_ and A _n

As can be seen from Reaction Scheme A, the aldehyde of the formula I is with the new reactant of Formula II implemented to form the ketone of the formula III. The reactants are in essentially Equirnolar ratios related and the reaction proceeds preferably within 30 minutes.

The ketone of the formula III is reacted for about 1 hour with 1,2-dimethoxyethane and zinc borohydride to form the alcohols of the formulas IV and V, which are then separated using, for example, column chromatography with ether as the eluent. If the 15-lower-alkyl derivative is desired, lower-alkyllithium, v / ie methyllithium, is added to compound III at this point in time.

The conversion of the compound of formula V into the compound of formula VI comprises treatment with anhydrous potassium carbonate for a period of about 1 hour, treatment with hydrochloric acid and extraction, e.g. with Ethyl acetate and finally consentration.

The conversion of the compound of formula VI into the compound Formula VII requires about 15-minute ^ under Nitrogen: taking place, treatment with 2,3-dihydropyran and p-toluenesulfonic acid and then the union with ether, washing with, for example, sodium bicarbonate and then with saline solution (brine), and then Concentration.

The conversion of the compound of the formula VII into the compound of Formula VIII is carried out by adding the compound of Formula VII under nitrogen in about 1 hour

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with Diisobutylaluruiniumhydrid in cooled to -73 C η-hexane reacted. The mixture was then mixed with ether, washed, dried and concentrated.

The conversion of the compound of formula VIII in the The compound of the formula IX is prepared by reacting the compound of the formula VIII at room temperature for at least 2 hours with (4-carbohydroxy-n-butyl) triphenylphosphonium bromide and Methylsulfxnylmethid achieved in dimethyl sulfoxide. The mixture was then washed with, for example, aqueous Acidified hydrochloric acid and then extracted with ethyl acetate, evaporated and concentrated.

The conversion of the compound of the formula IX into oxaprostaglandin F ₂ comprises hydrolysis with aqueous acetic acid, concentration and purification by column chromatography.

The conversion of the compound of formula IX in Oxaprostaglandln E ₂ requires about 20-minute treatment with Jones reagent at -10 ⁰ C to form a second intermediate product before the acid treatment and purification as described above, was carried out.

Oxaprostaglandin A ~ is obtained by treating oxaprostaglandin E ₂ with formic acid, concentrating and purifying it by column chromatography.

The conversion of the compound of formula IX into oxaprostaglandin F. requires reduction with palladium on carbon and methanol to produce the compound of Formula X which is then hydrolyzed with aqueous acetic acid and then cleaned as described above.

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The conversion of the compound of the formula X into oxaprostaglandin E ₁ and its conversion into oxaprostaglandin A ₁ follows exactly the same procedure as _{indicated above for the PGE 2} -PGA ₂ series.

The conversion of the compound of formula IX in 13.1 ^ -dihydro-oxaprostaglandin F requires the reduction with palladium-on-carbon, and methanol, wherein the compound of formula XI is prepared, which is then hydrolyzed with v / ässriger acetic acid and ₇ above wle described is cleaned.

For the production of the other 13,14-dihydro-derivatives is worked according to the method described above.

According to Reaction Scheme B, the lactone of the formula VII is reduced with palladium-on-carbon, the compound being the formal XII is prepared, which is then formed with the formation of the Hemiacetals.der formula XIII with diisobutylaluminum hydride is treated.

The conversion of the compound of formula XIII in the The compound of the formula XIV proceeds analogously to the conversion of the compound of the formula VIII into the compound of the formula IX according to reaction scheme A.

The conversion of the compound of the formula XIV into 13,14-dihydro-oxaprostaglandin F ₂ comprises hydrolysis with aqueous acetic acid, concentration and purification by column chromatography.

The conversion of the compound of formula XIV in 13,14-dihydro-oxaprostaglandin E ₂ requires about 20-minütge treatment with Jones reagent at -10 ⁰ C, then v / obei formed a second intermediate product before and treated with acid as above is described, cleaned.

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l ^ jl ^ -dihydro-oxaprostaglandin A _{2 is} obtained by treating 13,1 ^ -dihydro-oxaprostaglandin E ₂ with formic acid, concentrating., and purifying by column chromatography.

The new reagent of formula II is prepared by adding a suitable phosphonate such as dimethylraethy1-phosphonate in a reaction-inert solvent, such as tetrahydrofuran, and under nitrogen with an organolithium compound, like n-butyllithium. Then with a suitable alkoxy ester, such as Methyl 4-methoxybutyrate was added. The product is through Purified extraction in methylene chloride and concentrated.

The new alkanoates, formates and benzoates of the E, F and Α series of the oxaprostaglandins are produced by reacting the suitable prostaglandins with an acid chloride. For example, if 19 ~ 0xa-PGEp is reacted with benzoyl chloride in the presence of a tertiary amine in a reaction-inert solvent, 11,15-dibenzoyl-19-oxa-PGEp is obtained. In the same way, if 18-oxa-PGF _{2 is} reacted with pivaloyl chloride, 9,11,15 "

Tripivaloy1-18-oxa-PGF ₀ obtained.

do.

Analogous reaction sequences can be used for the production of 20-oxaprostaglandins can be used. For the production the 20-oxaprostaglandins becomes the aldehyde of formula I. reacted with the new phosphonate of the formula Hb, with the enone, as shown in the following equation of the formula HIb is obtained. The subsequent conversion of the compound of Formula IHb to 20-oxaprostaglandins proceeds according to the sequence shown in Reaction Schemes A and B.

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ο. ο : lib

IIIb

From the literature cited above it is known that natural prostaglandins have a spectrum of physiological activities. In numerous in-vivo and In vitro tests have shown that the oxaprostaglandin analogs have the same physiological activities as shown by the natural prostaglandins became. These tests include, among others

on
Test / the effect on the isolated smooth muscle from the ileum of guinea pigs and the uterus of rats, a test for the effect on histamine-induced bronchial spasm in sea chvs-nchen, a test for the effects on blood pressure in dogs, a test for the induction of diarrhea in mice; and a test for induction of early abortion in pregnant rats.

The results of these various physiological tests are summarized in Table I. It is important to

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indicated that not only these oxaprostaglandin analogs quantitatively with the natural prostaglandin have comparable effect, but that they also have the Advantage of tissue selectivity, especially the 19-oxa-prosta

glandin Ep, own. On the basis of the difference between the values obtained in the rat uterus and guinea pig ileum tests with 19-oxaprostaglandin E, a reduction in the unpleasant gastrointestinal side effects that occur when using natural PGEp as a means of inducing the abortion (Lancet, 536, 1971) should be expected. This important advantage was enhanced by the fact that 19-oxaprostaglandin E _{2 is} only 10 % as effective as natural PGEp in inducing diarrhea in mice in vivo, while it is just as effective in inducing early abortion in pregnant rats, like natural PGEp, confirmed. Furthermore, it can be seen from Table I that the 18-Oxa-PGE _{2 is} particularly selective with regard to the effects on blood pressure, while the 19-Oxa-iu-honio-PGEp is a more selective bronchodilator than natural PGS ₂ .

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Table I.

Blood pressure. Histamine rat uterus ( ^c ) guinea pig

Prostaglandi n dogs. \ ^a ) AerosolO ³ ) ng / ml ileum (") na / ml

19-Oxa PGE ₂ 20

19-Oxa-W-homo-PGE ₂ 4

l8-0xa PGE ₂ 2

19-Ox a PGP _2C i 19 -oxa-uz-homo -PGP ₂ ^ l8-0xa

PGE

15%

50-100 100-500 2.5x10- 100 100 4xl0 "° M 100-300 ■ 100-300 - 100-500 '■ ■ 100-500 βο-300 > αοο 300-600 100-300 - .10-30 10-30 '4x10 " ⁷ M.

(a) Relative dose at which the oxaprostaglandin derivative has the same effectiveness as PGE ₂ on the depressor effectiveness on the blood pressure of anesthetized dogs.

(b) Percentage protection by 100 μg / ml aerosol dose for that induced by histamine Bronchial spasm in guinea pigs.

(c) Threshold dose for the spasmogenic effect on in-vitro estrogenized rat uterus.

(d) Threshold dose for the spasmogenic effect on guinea pig Il'eum, in vitro.

(e) Inhibition constant for norepinophrine-stimulated lipolysis ..

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The physiological responses that result from these tests are observed to determine the usability of Testubstanaen for the treatment of various natural and pathological conditions useful. Such specific uses include: ant! Hypertensive potency, bronchodilator effectiveness, antithrombogenic effectiveness, antiulcerogenic effectiveness, effectiveness on smooth muscles (useful as a contraceptive as a means of inducing labor, and as an abortion) and preventive pregnancy Effectiveness through one that does not affect the smooth muscles Mechanism, e.g. the luteolytic mechanism.

The compounds according to the invention have more selective efficacy profiles than the corresponding naturally occurring prostaglandins and in many cases have a longer duration of action. If, for example, intravaginal treatment to induce the abortion is desired, a ^{tampon impregnated with 19-0xa-a>} -homoprostaglandin F or lactose tablets of the same agent are a suitable vehicle. In such cases, a suitable dosage is about 100 mg, with 1 or 2 cans can be used.

In cases where midterm abortion is necessary, an intravenous infusion is given physiological saline solution of 19-0xa-PGEp an effective means. A suitable dosage is from about 5 to 100 .Mg / min., Which over a period of about 2 to 10 hours is administered.

A09809 / 1220

_v 23U839

Another use for the oxaprostaglandins is as a means of inducing labor. For this purpose, a physiological saline solution of 18 ~ 0xa-PGB 'is given as an intravenous infusion in an amount of about 5 to pg / kg / min. in about one hour to 10 hours or 18-Oxa-PGP ₂ administered orally at doses of 5 to 100 mg every 2 hours.

Other uses for the oxaprostaglandins are to achieve bronchial dilatation or to increase the nasal passage. A suitable form of application for this Use is an ethanol solution of 19-0xa-u> -hoino ~ PGEp, which is available as an aerosol using fluorinated hydrocarbons in an amount of about 50 to 500 pg / day is applied.

-Series oxaprostaglandins are useful as hypotensive agents, as are those of the Ε-series. For the treatment of hypertension, these compounds are administered as intravenous injections at doses of about 0.5 to 10 pg / kg or preferably orally in the form of capsules or tablets. Administered in doses of 0.005 to 0.5 mg / kg / day »

The novel 15-lower alkyl compounds of the present invention have the same potency profile as that Prostaglandin analogs of the present invention wherein R of the formula is hydrogen from which they are derived are. Their special usability is linked to the fact that their duration of action is compared to the of the above-mentioned compounds in which R is a hydrogen atom is, is greatly increased. In those cases where this is essential they are the 15-lower alkyl compounds

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^ H 2344039

usually preferred. The prostaglanclin analogs, which have a β-hydroxyl group in the C ^ position and a C ₁ p-lower alkyl group, have a similar effect to their epimers. In some cases, the selectivity, however, exceed _s show these connections, the epimers of the compounds. Furthermore, the prostaglandins of the PGF _ß series have essentially the same activities as the prostaglandins of the PGF -PL series as well as the Cq , ^c -ti ~~ and C _{1 (} - esters of the new prostaglandins according to the invention. The latter are particularly suitable for preparations for oral dosing.

409809/1220

The new compounds can be used in a variety of pharmaceuticals Preparations are used which contain the compounds or their pharmaceutically acceptable salts, and they can be used in the same way as natural prostaglandins in various ways, such as intravenous, oral and topical, including administered as aerosols, intravaginally and intranasally. Pharmaceutically acceptable salts include salts of pharmaceutically acceptable bases, such as the alkali and alkaline earth metal, ammonium and amine salts.

For the manufacture of any of the foregoing dosage form or any of numerous other forms possible Various inert diluents, extenders, or carriers can be used. Such substances include e.g. water, ethanol, gelatins, lactose, starches, I-tagnesi stearate, Tallow, vegetable oils, benzyl alcohol, gum, Polyalkylene glycols, petrolatum, cholesterol and other known excipients for drugs. These pharmaceutical compositions Optionally, auxiliaries such as preservatives, wetting agents, stabilizers or others can be used contain therapeutic agents such as antibiotics.

The following examples serve to explain the invention in more detail.

example 1

A solution of 12, *? g (100 millimoles) of dimethyl methylphosphonate (Aldrich) in 125 ml of dry tetrahydrofuran was cooled in a dry nitrogen atmosphere to -78 ⁰ C. To the stirred for 30 minutes Phosphonatlösurg was dropwise '45 ml of a solution of 2.37 mol of n-butyllithium in hexane was added at such a rate, daP · did not increase the P.eaktionstemperatur about -65 ⁰ C. After additional stirring at -78 ⁰ C for S minutes were f. g (50.0 filimoles) of i-ethyl-'l-methoxyhutyrate

A09809 / 1220

^. Produced according to the method of P. Huisgen and J. Peinerts-Aafter, Ann., Ed. 575, p. 197 (1952) 7 was added dropwise at such a rate that the reaction temperature was less than -7O ⁰ C (10 minutes). The reaction mixture was allowed to warm to room temperature Mach 3 hours at -78 ⁰ C; It was neutralized with 6 ml of acetic acid and evaporated to a white gel on a rotary evaporator. The gelatinous material was taken up in 25 ml of water, the aqueous phase was extracted three times with portions of 100 ml of methylene chloride each time, the combined organic extracts were dried over magnesium sulfate and concentrated to a crude residue (water pump) and distilled, whereby 7.6 g ( 68 f> yield) dimethyl 2-oxo ~ 6-oxaheptylphosphonate with a boiling point of 1 ^ 1 - lk5 ° C / 1.7-0.6 mm were obtained.

A vapor phase chromatography analysis (using a 152 χ 0.635 cm column, the 10 2 SF. ^ O to Chronosorb P, clear

(80 -J.:00 mesh) _n ! "! Ashes size: 0.175-0.1 ^ 7 mmf, at 105 ° C.) showed a purity of ^ 99.9 %. The NMR spectrum (CDCl ₅ ) showed an at 3 , 78 S centered duplet (J = 11.5 cps, 6.H) for a triplet centered at 3.375 (2H) for CK ₃ -O

a singlet at 3.28 ί (3H) for CH ₃ -O-CH ₂ -, one at ^, \ h £

(J = 23 cps, 2H) centered doublet for -C-CH ₂ -P-, a at

(3 p,) ₂ ,

£ 2.71, (2H) / for -CH ₂ -CH ₂ -C = O and a multiplet at 1.57-2.10

Example 2

I? 68 g (7.5 F'Iillimol) of the dimethyl-2-oxo-6-oxaheptylnhosphonats prepared in Example 1 in 125 ml of anhydrous ether were mixed with 2.5 ml (5.9 Hillinol) 2.37 mol of n-butyllithiurninYfi- Treated hexane in a dry nitrogen atmosphere at Paunt temperature. After stirring for 5 minutes, another 225 ml of anhydrous ether and then all at once 1.75 i "(5-.O hillinol) 2- / 3 _tv Cp-phen; / lbenzoyloxy-5>: C -hydroxy-2ß-forrnylc, vclonentan- l cC-y3J ^7- vinegar-

BATH ORIQINAL

acid - ^ - lactone added. After 30 minutes, the reaction mixture was treated with 2.5 ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed twice with 200 ml of 10% hydrochloric acid, and then once with 200 ml of saturated sodium bicarbonate solution and once with 100 ml of water, dried over magnesium sulfate and evaporated to give 1.972 g (88 % yield) 2 ~ / 3oC-p-phenylbenzoyloxy-5j £ -hydroxy-2ß- (3-oxo-7-oxa-trans-1-octen-1-yl) -cyclopent-liC -ylT-acetic acid - ^ - lactone was obtained as an oil.

The IR spectrum (CHCl,) of the product showed adsorption bands at 1770 cm ¹ (strong), 1717 cm ¹ (strong), 1675 cm ¹ (medium) and 160 cm (medium), which can be attributed to the carbonyl groups. The UV spectrum showed an x ". = 27 *" nu and a £ \ - 21,380 (sthanol solution). The NMR spectrum (CDCI,) showed a multiplet at £ 233-3.18 (9H) for the p-biphenyl group, a doublet of £ 6.71 (IH, J = 71/16 tips) and one at 6.27 S "(IH", J = 16 cps) centered doublet for the olefinic protons, a triplet at 3.30 £ (2H) for -CH ₂ -CH ₂ -O-CH-., A singlet at 3, £ 21 (3H) for -CH ₂ -O-CH ₃ and multiplets at 4.90 5.50 S (2H), 2.21 - 3.07 S (8H) .. and T758 - 2.06 S (2H) for the rest of the protons.

Example 3

To a solution of 1972 mg (k , *} millimoles) 2/3 <£. -p-Pher.ylbenzöyloxo ~ 5cC -hydroxy-2B- (3 ~ oxo-7-oxa-trans-1-octen-1-yl) -cyclopent-1 <C -yiy-acetic acid-Jf-lactone, prepared according to example 2, in 15 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere were added dropwise * t, 0 ml of a 0.5 molar solution of zinc borohydride at ambient temperature. After stirring at room temperature, the Reaktionsgemiscl was cooled to 0 ⁰ C, and a saturated Natriumbitartratlösung was tropfem-ieise added until the hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, after which 25Ο ml of dry ethylene chloride was added. After drying over magnesium sulphate and concentration (water jet pump), the half-

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solid material by column chromatography on silica gel (Baker "Analyzed" reagent, with a mesh size of 0.248 0.074 mm) Purified using ether as an eluant. After elution of less polar impurities, fractions with one; Content of 450 rag 2- / 3oC-p-phenylbenzoyloxy-

hvdroxy _v "_

5cC '~ VPi- (3dL ~ hydroxy-7-oxa-trans-l-octen-l-yl) -cyclopent-l'cC -yl / ~ acetic acid-a ° ~ lactone, of 294 mg 2- £ j, cC -p-phenylbenzoyloxy- ^ oC-hydroxy-2ß- (3ß-hydroxy-7-oxa-trans-1-octen-1-yl) -cyclopent-loC-ylj-acetic acid - $ "- lactone and 486 mg of the two mixed Products eluted.

The IR spectrum (CHCl-,) of the first of these compounds had strong carbonyl adsorption bands at 1770 and 1715 cm ~.

Example H

A heterogeneous mixture of 450 mg (I ₇ O millimoles) of 2- / 3oC p-phenylbenzoyloxy-5; iC-hydroxy-2ß- (? 3t l-hydroxy-7-oxa-trans-l-octenl-yl) -cyclopent -lX-yl7-acetic acid - ^ - lactone, prepared according to Example 3, 4.5 ml of absolute methanol and 140 mg of finely powdered anhydrous potassium carbonate were stirred at room temperature for one hour and then cooled to ^{0 ° C.} 2.0 ml (2.0 millimoles) of 1.0 η \\ ^T aqueous hydrochloric acid were added to the cooled solution. Stir at 0 ^° C. for a further 0 minutes

Ixchy 5 ml of water were added, whereby instant / T ^ ethyl-p-. Phenyl benzoate formed which was filtered off. The piltrate was saturated with solid sodium chloride, extracted four times with 10 ml of ethyl acetate each time, the combined organic extracts were washed with 10 ml of saturated sodium bicarbonate, dried over magnesium sulfate and concentrated, with 204 mg (76 % yield) of viscous, oily 2 ~ C5cC _} 5 _: £ ~ dihydroxy-2ß- (3-r £ -hydroxy ~ 7 ~ oxatrans-1-octene-1-yD-cyclopent-1 c-yl-zZ-acetic acid-V -lactone were obtained.

The IR spectrum (CHCl,) showed a strong adsorption band

-1
at 1770 cm for the lactone carbon! group and a medium one

+ (60-200

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Adsorption band at 9 ^ 0 cm for the trans double bond. Example 5

A solution of 192 mg (0.71 millimoles) 2- / 3dC.5. £ -dihydroxy-2ß- (3 (jC-hydroxy-7-oxa-trans-l-octen-yl) -cyclopent-ldC -yl7- acetic acid -) ^ -lactone, prepared according to Example 4, in 5 ml of anhydrous methylene chloride, and 1 ml of 2,3 ~ dihydropyran were treated with 5 mg of p-toluenesulfonic acid ^{monohydrate at 0 ° C. in a dry nitrogen atmosphere.} After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether. The ether solution is washed once with 15 ml of a saturated sodium bicarbonate solution and then once with 15 ml of saturated salt water, dried over magnesium sulfate and concentrated, giving 310 mg (100 % yield) 2 ~ / 5 £. ~ Hydroxy-3 _c p- (tetrahydropyran-2-yloxy) -2β- (3 ₌ CZ "tetrahydropyran-2-yloxy7 ~ 7-oxa-trans-1-octen-1-yl) -cyclopent-1 -C -yl7-acetic acid-} f -lactone were obtained.

The NHR spectrum (CDCI,) showed a multiplet at 5.30-5.62 G (2H) for the olefinic protons, a singlet at 3 ^ 3 ^ δ (3H) for the methyl ether protons and cultiplets at 4.36-5 , 18 β (^ H), 3.22-4.2'lfi (9H) and 1.18-2.92 S (20H) for the remaining protons.

Example 6

A solution of 310 mg (0.71 millimoles) 2- / 5'jC-hydroxy-3 ^ - (tetrahydropyran-2-yloxy) -2ß-3oC -Z.tetrahydropyran-2-yloxy_7 ~ 7-oxa-transl-octene -l-yD-cyclopent-.LOC -y ^ -acetic acid if-lactone prepared according to example 5 ₅ 5 nl of dry toluene was cooled in a dry Stnckstoffatmosphäre to -78 ⁰ C. This cooled solution vmrde dropwise with 1.5 ¹ ^ of a solution of 20% diisobutylaluminum hydride in η-hexane crosslinked at such a rate that the internal temperature is about -f> 5 ° C did not exceed (15 minutes), iiach v; Eiteren stirring at -73'C for 45 minutes

4098Q9 / 122Ö ^BAD

anhydrous methanol was added until the evolution of gas ceased, and the reaction mixture was allowed to warm to room temperature. The reaction mixture vmrde with 100 ml of ether combines four times ml with 20 of a 50 / ^ strength flatriun potassium tartrate solution, dried then concentrated over magnesium sulfate, and to obtain 290 mg (93 $ yield) of 2- / ~ 5 <£ hydroxy 3. £ .- (tetrahydropyran-2-yloxy) -2ß- (3 _o C - / tetrahydropyran-2-yloxyJ7-7-oxatrans-l-octen ~ l-yl) -cyclopent-l-yl7-ficetaldehyde- ^ " - hemiacetal

were obtained. Example 7

A solution of 870 mg (2.0 millimoles) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 50 ml of dry dimethyl sulfoxide vmrde with 2.0 ml (4.4 millimoles) of a 2.2 molar solution of sodium methylsulfinyl methide added in dimethyl sulfoxide. 7 \ i this red ylide solution was added dropwise a solution of 290 mg (0.66 millimoles) of 2- / 5'K - hydroxy-3χ - (tetrahydropyran-2-yloxy) -2P> - (3rd £ -Ztetrahydropyran -2-yloxy7-7-oxa-trans-l-octen-l-yl) -cyclopent-l, x-yl7-acetaldehyde -) [half-acetal, prepared according to Example 6, in 3.0 ml of dry dimethyl sulfoxide for 20 minutes admitted. After stirring for a further 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution is washed twice with 20 ml of ethyl acetate and acidified to a pH of about 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted three times with 20 ml of ethyl acetate each time, and the combined organic extracts were washed once with 10 ml of water, dried over magnesium sulfate and concentrated to a solid residue weighing 734 mg. This solid residue was triturated with ethyl acetate and filtered. The piltrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0.248-0.074 mm) using ethyl acetate as the eluent. After removal of

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Impurities with high R ~ -values give 225 ^ g (66 % yield) 9ί £ -hydroxy-HC, 15J3 -bis ~ (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadienoic acid .

The NMR spectrum (CDCl _n ,) showed a multiplet (variable) at "5.8 * 1 - 6.38 S (2H) for the OH protons, a multiplet at 5.27 5.68 ^, (4h) for the olefinic protons, a multiplet at 4.52 - 4.84 ξ, (2H) for the acetal protons, a singlet at 3.34 £> (3H) for the methyl ether protons and multiplets at 3.25 - 4.35 £ ( 9H) and 1.20 - 2.72 S (28H) for the remaining protons.

Example 8

A cooled to -10 ⁰ C, standing under nitrogen solution of I90 mg (0.356 mmol) 9 <£ hydroxy-LLOC, 15c £ -bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans 13-p ** ostadienoic acid, prepared according to Example 7, in 5 ml of reagent grade acetone was admixed dropwise with 0.143 ml (0.356 millimoles) of Jones' reagent. After 20 minutes, 0.140 ml of 2-propanol were added at -10 ° C., and the reaction mixture was stirred for a further 5 minutes, after which it was combined with 40 ml of ethyl acetate, washed three times with 5 ml of water each time, dried over magnesium sulfate and then concentrated to obtain 174 mg of 9-oxo-11, 15-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadienoic acid.

Example 9

A solution of 174 mg (0.334 millimoles) 9-oxo-II, £, 15dC -bis-tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadienoic acid, prepared according to Example 8, in 3, 0 ml of a mixture of glacial acetic acid and water in the ratio of 65:35 was stirred under nitrogen for 5 hours at 40 ° C. and then concentrated using a rotary evaporator. The crude oil obtained was purified by column chromatography on silica gel (Mallinckrodt CC-4 with a clear width hash 0.147 to 0.074 mm) under Verwendunp * ^"Λ") ftthylacetat as eluent. After elution of a few γ ·· γ ϊolars

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Impurities v: urderi 33 mg of the semi-solid 9-o-11 ", 15 <ν dihydroxy-19-oxa-cis-5-trans-13-prostadic acid obtained. This product is 1Q-Oxaprostaglandin E ^ ₃ P. = 58 - 59 ° C (ethyl acetate, cyclohexane). Analysis: her. C 64.39; K 8.53;

found C 64.30; H 8.28.

£ c-7J ~ ⁵ = -71.2 ° (C = 1.0; methanol).

The IR spectrum (CHCl-,) of the product showed a strong adsorption band at 1715 cm for the carbonyl groups and a middle band at 9 ^ 5 cn for the trans double bonds. The UV spectrum in methanol with additional potassium hydroxide solution showed a value of 278 mji and a & _max of 28,000.

If the corresponding 19-oxaprostaglandin A _{p is} desired, the above IQ-oxaprostaglandin E can be treated with formic acid and the product can then be purified by column chromatography.

Example 10

A solution of 52 mg (0.10 millimoles) 9 £ -hydroxy-11- / ", 15.C -bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-pi * ostadienoic acid prepared according to example 7 »in 3.0 nl of a mixture of glacial acetic acid and water in a ratio of 65:. was 35 * v under nitrogen / hile 5 hours at 40 ⁰ C stirred and then with a rotary evaporator The crude oil was chromatographed on Silica gel (Maliin ckrodt CC-4 with a mesh size of 0.1 * 17-0.07 * 4 mm) was purified using ethyl acetate and then methanol as the eluent. After elution of less polar impurities, 15 mg of oily 9 <£. , Trihydroxy-cIs-5-trans-13-prostadienoic acid obtained «This product is 19-oxoprostaglandin

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Example 11

A solution of 12 * 4 g (100 millimoles) of dimethyl methylphosphonate (Aldrich) in 125 ml of dry tetrahydrofuran was cooled under nitrogen atmosphere trokkener to -78 ⁰ C. To the stirred phosphonate solution a solution of 2.67 mol of n-butyllithium in hexane was added at such a rate that the reaction temperature did not exceed about -65 ⁰ C for 30 minutes, dropwise 40 ml. After stirring for a further 5 minutes at -78 ° C., 8.0 g (50.0 millimoles) of ethyl - *! - ethoxybutyrate (prepared according to the method of R-Huisgen and J. Reinertshafter, Ann., Vol. 575, p. 197 (1952) dropwise at such a rate added such that the reaction temperature was maintained at less than -7O ⁰ C (10 minutes). After hours at -78 ⁰ C allowed the reaction mixture to ambient temperature, after which it mL with 6 acetic acid neutralized and evaporated to a white gel using a rotary evaporator. The gelatinous material was taken up in 25 ml of water, the aqueous phase was extracted three times with 100 ml of ITethylene chloride, the combined organic extracts were dried over magnesium sulfate and concentrated to a crude residue ( Viasser jet pump) and distilled, where 1, h g (62 % yield) of dimethyl 2-oxo-6-oxa-octylphosphonate, b.p. = 130 132 ^O C (0.1 mm) were obtained.

The NMR spectrum (CDCl _x ) showed a at 3.78 & (J = 11.5 cps, 6H)

-> 0

centered doublet for (CH-.OK-P-, a triplet centered at 3.28 S (2H) for CH ₃ -OCH ₂ -, elrTquartet at 3, ^ 3 * b (2H) for CH ₂ -O-CH ₂ -,

~ Ö ~ 0

η "

a doublet centered at 3> 1 ^ £ (J = 23 cps, 2H) for -C-CH ₂ -P-,

0 "

a triplet centered at 2.71S (2H) for -CH ₂ -CH ₂ -C-, a multiplet at 1.57 - 2.20 & (2H) for -CH ₂ -CK ₂ -CH ₂ and one at 1, 15 S (3H) centered triplet for CH ₃ -CH ₂ ^:: Ö

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Example 12

2.5 S (10.7 Γ-Tillimol) dimethyl - ^ - oxo-P-oxa-octylphosphonat prepared according to Example 11, in 175 nl anhydrous' At ago vjurden at room temperature under a dry nitrogen atmosphere with 5j0 ml (8.0 Millimoles) of 1.6 moles of n-butyllithium treated in η-hexane. After stirring for 5 minutes, 350 ml of anhydrous ether were added, followed by 2.5 g (7.2 millimoles) of 2- / ~ 3oC-p-phenyl-benzoyloxy-ScC-hydroxy-2ß-formylcyclopentan-1cC-yl7 ~ acetic acid - ^ - lactone added. After 30 minutes, the reaction mixture was mixed with 5.0 ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed twice with 200 ml of 10 ^ hydrochloric acid, once with 200 ml of saturated sodium bicarbonate solution and once with 100 ml of water. After drying over magnesium sulfate and evaporation, 3.591 S (10Q % yield) of crude 2- / 3.-C-p-'phenyl-benzoyloxy- ^ --C -hydroxy-2ß- (3-oxo-7-oxa-trans- l-nonen-l-yl) -cyclopent-1 -f: ~ y] J7-essip; acid-) T-lactone obtained as an oil.

The IR spectrum (CHCl-,) of the product showed adsorption bands at 1760 cm " ¹ (strong), 1707 cm" ¹ (strong), 1665 cm " ¹ (medium) and <160 cm (medium), which are attributable to the carbonyl groups The NKR spectrum (CDCl ^) was consistent with the structure of the compound.

Example 13

At room temperature and in a dry nitrogen atmosphere a solution of 3 ^ 91 mg (7.6 l -illimol) of crude 2- / 3cC-p-phenyl-benzoyloxy-5'C -hydroxy-2P> - (3-oxo ~ 7-oxa-trans-l-nonen-lyl) -cyclopent-l £ -yiy-acetic acid- ^ -lactone, prepared according to Example 1 ?, in 30 ml of dry 1,2-thin ethoxyethane with 7.5 ml to a 0.5 molar zinc borohydride solution. Nac The reaction mixture was stirred for one hour at room temperature cooled to 0 ° C, and a saturated matrium bitartrate

09809/1220

BATH ORIGINAL

solution was added dropwise until the evolution of hate substances ceased. The reaction mixture was stirred for 5 minutes, after which 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the semi-solid product obtained was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0.248-0.07 * 1 mm) using ether as the eluent. After elution of less polar impurities, fractions containing 703 mg 2- / 3 oC -p-phenylbenzoyloxy-5oC-hydroxy-2ß- (3cC ~ hydroxy-7-oxa-trans-l-nonene-l-yl) -cyclopent- lt £ -yl7-acetic acid- h -lactone, a fraction containing 2- / 3dC ~ P ~ phenylbenzoyloxy-5 ^ -hydroxy-2ß- (3ß ~ hydroxy-7-oxa-trans-1-nonen-1-yl ) -cyclopent-loC -ylj-acetic acidy-lactone, and a fraction of the two mixed products eluted.

The IR spectrum (CHCl ^) of the above first compound showed strong carbonyl adsorption bands at 1770 and 1705 cm. That NMR spectrum (CDCI.,) Was consistent with the structure of the compound right.

example lH

A heterogeneous mixture of 703 mg (1.5 millimoles) 2- / 3oC-p-phenylbenzoyloxy-5cC-hydroxy-2ß- (3oC ~ hydroxy-7 ~ oxa-trans-l-nonenl-yl) -cyclopent-laC -ylj-acetic acid, Jf-lactone prepared according to example 13, 7 ₅ 0 ml of absolute methanol and 207 mg of finely powdered potassium carbonate Viasserfreiem stirring for one hour at room temperature and then cooled to 0 ⁰ C. 3.5 ml (3.0 millimoles) of 1.0 η aqueous hydrochloric acid were added to the cooled solution. After stirring for a further 10 minutes at 0 ° C., 7 ml of water were added, with simultaneous formation of methyl p-phenylbenzoate, which was filtered off. The filtrate v.'urde saturated with solid sodium chloride and extracted four times with 10 ml of ethyl acetate. The combined organic extracts

409809/1220

350 Rait were 10 ml of a saturated TIatriumbicarbonatlösung washed, dried and concentrated to v over magnesium sulfate / obei mg (85j5% yield) of viscous, oily 2- / J> _c c, 5 ^ C ^- dihydroxy-2ß- (3X-hydroxy- 7-oxa-trans-l-nonen-l-yl) -cyclopent-l _l - ₇ C yl7-acetic acid- \ -lactons were obtained.

The IR spectrum (CHCl,) showed a strong adsorption band at 1770 cm for the lactone carbonyl and a mean adsorption band at 965 cm for the trans double bond.

Example 15

A solution of 350 mg (1.28 millimoles) 2- / 3oC, 5dC-dihydroxy-2ß- (3 ^ -hydroxy-7-oxa-trans-1-nonenyl) -cyclopent-lcc -yiy-acetic acid- X- lactone , prepared according to Example 1Ά, in 3> 5 nl anhydrous methylene chloride and 350 pl 2,3-dihydropyran was ^{mixed under a dry nitrogen atmosphere at 0 0} C with 3> 5 ^ g p-toluene sulfone acid monohydrate. After stirring for a long time, the reaction mixture was combined with 100 ml of ether, the ether solution was washed once with 15 ml of saturated sodium bicarbonate solution and then once with 15 ml of saturated sodium chloride solution, dried over magnesium sulphate and then concentrated, whereby 590 mg (> 100 % -) 2- / 5><=^{<C-hydroxy-3;} - (tetrahydropyran-2-yloxy) -2ß- _(3c; C- / tetrahydropyran-2-yloxy7-7-oxa-trans-l- nonen-l-yl) -cyclopent- -yiy-acetic acid-Jf-lactone were obtained.

The NMR spectrum (CDCl ^) showed a multiplet at 5 * 30-5> 65 (2H) for the olefinic protons, a quartet at 3> 50 (2H) for the ethyl ether protons, multiplets at i}, 35-5.18 δ ( ¹ IH), 3.22 - ^, 2iJS (8K) and at 1.18 - 2.92 S (21H) as well as a triplet at 1.02 ζ (3H).

409809/1220

Example 16

A solution of 575 mg (1.28 millimoles) of crude 2- / 5oC-hydroxy-3;, C tetrahydropyran-2-yloxy) -2ß- (3 <C ~ Ztetrahydropyran-2-yloxy- ^ 7-7 ~ oxa- trans-l-nonen-l-yl) cyclopent-l ~, jC -yiy-acetic acid ^ T-Iac ton, prepared according to example 15 in 5.75 ml dry toluene v / urde under a dry nitrogen atmosphere to -78 ⁰ C cooled. To this cooled solution was added dropwise 1.8 ml of a solution of diisobutylaluminum hydride in 2O5igen ■ η-hexane at a rate such added such that the internal temperature of -65 ⁰ C never exceeded (I5 minutes). After stirring for a further hour, anhydrous methanol was added until the evolution of gas ceased, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 50 ml of ether four times ml with 10 of a 50 ^ strength Hatrium potassium tartrate solution, dried and concentrated dried over magnesium sulfate, where ^J i58 mg (80 ", yield) of 2- / 5jC ~ hydroxy ~ 3 ° C - ( tetrahydropyran-2-yloxy) -2ß- (3, ^ C - /. tetrahydropyran-2-yloxy.7-7-oxa-trans-lr.onen- l-yl) -cyclopc? nt-l-yl7-acetaldehyde- % hemiacetal were obtained.

Example 17

A solution of 1330 mg (3.0 millimoles) of (Ji-carbohydroxy-n-butyl) triphenylphosphonium bromide in 6 ml of dry dimethyl sulfoxide was under a dry nitrogen atmosphere with J> _s k ml (6.8 millimoles) of a 2.0 molar solution of Sodium methyl sulfinyl methide is added to dimethyl sulfoxide. A solution of H ^ H mg (1.0 millimole) of crude 2-Z5 ^ ~ hydroxy-3> C- (tetrahydropyran-2-yloxy) -2β- (3oC- / tetrahydropyran-2-yloxy_7) was added dropwise to this red ylide solution -7-o_xa-trans-l-nonen-l-yl) -cyclopent-l <£ -yrZ-acetaldehyde- ) i hemipcetal, prepared according to Example 16, in 3.0 ml of dry dimethyl sulfo: ·: jd v ;. ^:: added for 20 minutes. After 2 hour at ^r n Pühren Pam.itenporatnr v / urde the Roakt ΐ onsgemisch in Fisv.'asser ncr, pr; r »cn. The bas i -marriage v / äßerige solution was swoimal with 30 ml Ät> iyü. Icoi.at-r.fv.'fischon with 10 ^ ir ^rv? Rv / äßeriger hydrochloric acid ο j non pU-l. ^r iU'i. by f-tv: a 3 acidified. The acidic solution was four-

'.09809 / 1220 ^ OWQWiL

extracted times with 25 ml of ethyl acetate each time, and the combined organic extracts are washed once with 25 ml of water, dried over magnesium sulfate and then concentrated to a solid residue weighing 900 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0.248-0.07 * 1 mm) using ethyl acetate as the eluent. After removing impurities with high Rj. Values, 290 mg (5 ¹ * % yield) 9 £ -hydroxy-11 £, 15dC -bis- (tetrahydropyran-2-yloxy) -ISHoxa-cis-5-trans-13- "W-honio-prostadic acid obtained.

The NMR spectrum (CDCI,) showed a multiplet (variable) at 6.2-6.6S (2H) for the OH protons, a multiplet at 5.3-5.7 k (4H) for the olefinic protons, a multiplet at 4.6-4.9 £ (2H) for the acetal protons, a quartet at 3> 5 £ (2H) for the Ethyl ether protons and multiplets at 3.3 - 4.4 £> (9H) and 1.0 2> 6ξ, (31H) for the remaining protons.

Example 18

A cooled to -10 ⁰ C solution of 290 mg (0.540 millimoles) 9BC-hydroxy-lli: 15 _c C.-bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13 ~ w HOMO-prostadienoic acid, prepared according to example 17, in 5j '* ^m l of acetone from Reagenzreinheitsgrad treated dropwise with 0.226 ml (0.600 mmol) 2,67molarem Jones reagent was added. After 5 minutes at -10 ⁰ C 0.230 ml of 2-propanol vmrden added and the reaction mixture was stirred for an additional 5 minutes, after which it combines with 30 ml of ethyl acetate, washed three times with 5 ml of water, dried over magnesium sulfate, concentrated and chromatographed (Baker Silica gel with a mesh size of 0.243-0.074 mm ', methylene chloride as the eluent) was obtained, whereby 180 mg of Q-Oxo-llcC ₃ 15r.C-bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans -13 ~ w-homo-prostadienoic acid were obtained.

409809/1220 ORIGINAL BATHROOM

Example 19

A solution of 129 mg (0.240 millimoles) 9-Oxo-ll £, 15- £ -bis- (tetrahydropyran-2-yloxy) -19-OXa-CiS-5-trans-13-w-homoprosta ~ dienic acid, prepared according to example 18, in 3 John ml of a mixture of glacial acetic acid and water in a ratio of 65 '35 · was stirred for 2.5 hours under nitrogen at 40 ° C and then concentrated by rotary evaporation. The crude oil obtained was purified by column chromatography on silica gel (Mallinckrodt CC-4 with a mesh size of 0.147-0.074 mm) using ethyl acetate as the eluent. After elution of less polar impurities, 40 mg of 9-oxo-II £, 15 <£ - dihydroxy-19-oxa-cis-5-trans-13-vr-homoprostadienoic acid (11) with a melting point of 56-57 ° C. were obtained . This product is 19-0xa-whomoprostaglandin E ".

The UV spectrum in methanol with the addition of potassium hydroxide showed

^a "K _mov ^{of 2} 78 mu and a £", "" of 25 700. max ι max

If 19 ~ 0xa-w ~ homoprostaglandin Ap is desired, after the Procedure of Example 9 can be used.

If 19-Oxa-w-homoprostaglandin Fpj-is desired, after The procedure of Example 10 was carried out using the product of Example 18 as the starting compound.

Example 20

A solution of 12.4 g (100 millimoles) of dimethyl methyl phosphonate (Aldrich) in 125 ml of dry tetrahydrofuran was under a cooled to -78 ° C in a dry nitrogen atmosphere. The stirred Phosphonate solution was with 40 ml of a 2.67 molar solution of n-Butyllithium in hexane (commercial product from Alfa Inorganics Inc.) dropwise over 30 minutes at such a rate offset that the reaction temperature never over

409809/1220

etv / a -65 ⁰ C rise. After further stirring at -78 ⁰ C 5minütigern 7.6 S (50.0 millimoles) of ethyl-3 ~ äthoxypropionat dropwise at such a rate added such that the reaction temperature was less than -70 ⁰ C (10 minutes). After 3 hours at -78 ⁰ C the reaction was allowed to warm to room temperature, followed by neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase was extracted three times with 100 ml of ether each time, the combined organic extracts were dried over magnesium sulfate and concentrated to a crude residue (vacuum pump) and distilled, with 5.6 g (50 % Yield) Dimethyl 2-oxo ~ 5-oxaheptylphosphonate (2) with a boiling point of 107-11> J ° C at 0.1 mm.

The NMR spectrum (CDCl ₃ ) showed a at 3.79S (J = 11.5 cps, 6H)

centered doublet for (CH ₃ O) ₂ -P-, a triplet centered at 3.28S (2H) for CH ₃ -O-CH ₂ -CHp ¹ T a quartet at 3, 'i3b (2H) for -, a beT "5 _s 14 $ (J = 23 cps, 2H) centered doublet

0 0 ti »I

for -C-CH ₂ -P-, a triplet centered at 2.87S (2H) for

0 ti

CH ₂ -CH ₂ -C- and a triplet centered at 1.19S (3H) for

^ .GH «—0 — CH«. Example 21

3.8 g (17.1 millimoles) of dimethyl 2-oxo-5-oxa-heptylphosphonate, prepared according to Example 20, in 200 ml of anhydrous ether were mixed with 1.8 ml (12 millimoles) of a 2.5 molar solution of n -Butyllithium treated in η-hexane under a dry nitrogen atmosphere at room temperature. After stirring for 5 minutes, another 400 ml of anhydrous ether and then suddenly '! g (11.4 millimoles) 2- / 35 "il-p-Phenylbenzoyloxy-5 <C -hydroxy-2 [beta] -fornylcylopentane-1 _t C-yl7-acetic acid- ^ -lactone was added. After 35 minutes

-M- ,, 40.9809 / 12 20

th, the reaction mixture with 5 ₃ O added ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed twice with 200 ml of lO ^ hydrochloric acid, once with 200 ml of saturated Natriumbiearbonatlösung and washed once with 100 ml of water, dried and concentrated over magnesium sulfate, then, wherein 4.057 (80 % yield) crude 2- / 3dC-p-phenylbenzoyloxy-5dC-hydroxy-2ß- (3-oxo-6-oxa-trans-locten-1-yD-cyclopent-icC-ylJ-acetic acid-Ji-lactone were obtained as an oil.

The IR spectrum (CHCl ^) of the product showed adsorption bands at 1770 cm " ¹ (strong), 1707 cm" ¹ (strong), 1670 cm " ¹ (medium) and 160 cm (medium), which are attributable to the carbonyl groups NMR spectrum (CDCl-,) was consistent with the structure.

Example 22 ""

A solution of 4 100 mg (9.2 millimoles) of crude 2- / 3tC-p-phenylbenzoyloxy-5-C ~ hydroxy-2P> - (3 ~ oxo-6-oxa-trans-l-octen-l-yl) -cyclopent-1 Si -ylj-acetic acid-i -lactons in 30 ml of dry 1,2-dimethoxyethane was treated dropwise under a dry nitrogen atmosphere at 0 ° C. with 4.5 ml of a 1.0 molar zinc borohydride solution. After stirring at 0 ⁰ C a saturated Natriumbitartratlösung was dropwise added until the V / asserstoffentwicklung ceased. The reaction mixture was stirred for 5 minutes after which time 200 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the semi-solid product obtained was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0.248-0.074 mm) using a mixture of ether and ethyl acetate in a ratio of 5: 1 as the eluent cleaned. After elution of less polar impurities, fractions with a content of 778 mg 2- / 3.tC -p-phenylbenzoyloxy-5-vC-hydroxy-2ß- (3 oC-hydroxy-6-oxa-trans-1-octene-1 -y1) -cyclopent-ldC-ylJ-acetic acid-X -lactone (5), 2- / 3 - <lp-phenylbenzoyloxy-5 - C -hydroxy-2ß- (3ß-hydroxy-6-oxa-trans- 1-octen-l-yl) -cyclopent-1C-ylJ-acetic acid- ϊ -lactone and

409809/1220

355 ^ Z of the two mixed products eluted.

The IR spectrum (CHCl,) of the first of the two abovementioned fractions showed strong carbonyl ^{adsorption bands at 1775 and 1715 cm "1.} The IIIR spectrum (CDCl,) agreed with the structure of the product.

Example 23

A heterogeneous mixture of 1006 mg (2.24 millimoles) 2-βcC-p-phenylbenzoyloxy-SdC-hydroxy-2β- (3oC-hydroxy-oair-oxa-trans-locten-1-yD-cyelopent-loC-yljf -essigsaure- ^ "- lactone, prepared according to example 22, 10 ml of absolute methanol and 310 mg of finely powdered anhydrous potassium carbonate was stirred for one hour at room temperature UiKi ₁ then to 0 ⁰ C cooled The cooled solution was treated with 10 ml (10 millimoles. ) a 1.0 η aqueous hydrochloric acid. After stirring at 0 C for a further 10 minutes, 10 ml of water were added, with simultaneous formation of methyl * -p-phenylbenzoate, which was filtered off. The filtrate was saturated with solid sodium chloride, twice with 100 ml of ethyl acetate was extracted each time, and the combined organic extracts were washed twice with 25 ml of saturated sodium bicarbonate solution each time, dried over magnesium sulfate and concentrated, giving 570 mg (9 ^ % yield) of the viscous oily 2-Z3oC, 5-dihydroxy-2ß- (3oC -hydroxy-6-oxa-trans-1-oct en-l-yl) -cyclopent-1 c £. ~ yl7-acetic acid- ίΤ.-lactones were obtained.

The IR spectrum (CHCl,) showed a strong adsorption band at

"Τ ■>

1770 cm for the lactone carbonyl group and a mean adsorption band at 9 ^ 5 cm for the trans double bond.

Example 24

A solution of 570 mg (2.11 millimoles) 2- / 30 £, 5 ^ c-Dihydroxy-2ß- (30 £ -hydroxy-6-oxa-trans-1-octene) -cyclopent-1c £ -yl7 ~ acetic ^ ure-Ji-lactone, prepared according to Example 23, in 5 ₅ 7 ml of anhydrous methylene chloride and 57OuI 2,3-dihydropyran was at 0 ° C in a

^ '40 980 9/12 20

Atmosphere of dry nitrogen with 5> 7 mg of p-toluenesulfonic acid monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 200 ml of ether, the ether solution was mixed once with 25 ml of a saturated sodium carbonate solution and then with | Washed once with 25 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated, giving 925 mg (100 % yield) 2 ~ Z5c £ -hydroxy-30 £ - (tetrahydropyran-2-yloxy) -2ß- (3c £ - ' / tetrahydropyran-2-yloxyJ-6-oxa-trans-1-octen-1-yl) -cyclopent-lo <C -j yl7-acetic acid- ^ T -lactone.

The NMR spectrum (CDCI,) showed a multiplet at 5.30-5.70 6 (2H) for the olefinic protons, a quartet at £ 3.40 (2H) for the ethyl ether protons, multiplets at 4.35 - 5.18S (4H), 3.1? - 4.32S (8II) and 1.18 - 2.92 & (25H) as well as a triplet at 1.10 (3H).

Example 25

A solution of 880 mg (2.01 millimoles) of crude 2- / 5oC-hydroxy-3 = C ~ tetrahydropyran-2-yloxy) -2ß- (3 ^ -Ztetrahydropyran-2-yloxy7-6-oxatrans-1-octen- Dry l-yl) -cyclopent-lo £ -yiy-acetic acid- } f -lactone, prepared according to Example 24, in 8.8 ml! Toluene was cooled under a dry nitrogen atmosphere to -78 ⁰ C. 3 ml of a 20% solution of diisobutylaluminum hydride in η-hexane were added dropwise to this cooled solution at such a rate that the internal temperature did not exceed about -65 ° C. (15 minutes). Mach further stirring for 30 minutes at -78 ⁰ C was added anhydrous methanol was added until gas evolution ceased, and was allowed to sod.ann the reaction mixture to warm to room temperature. The reaction mixture was combined with 100 ml ether, washed four times with 10 ml of a 50 .je ¹ ^ strength Matrium potassium tartrate washed, and concentrated dried over magnesium sulfate to give 654 mg of 2 ~ Z5oC -hydroxy ^. * :-( tetrahydropyran-2-yloxy ) -2β- (3oC - / tetrahydropyran-2-yloxy7-6-oxa-trans-l-octen-l-> yl.) - cyclopent-l-yl7-acetaldehyde- ^ f-hemiacetal.

ORJGlNAL INSPECTED 409809/1220

Example 26

A solution of 2600 mg (6.0 mF'iol) (ty-Carbohydroxy-n-butyl) -trxphenylphosphoniumbromid in a dry nitrogen atmosphere in 6 ml of dry dimethyl sulfoxide was treated with 6 ₃ 0 ml (12.0 mmol) of a 2.0 M solution of Sodium methylsulfinyl methide is added to dimethyl sulfoxide. This red ylide solution was added dropwise over 20 minutes with a solution of 660 mg (1.5 mmol) of crude 2- [5a-hydroxy-3a- (tetrahydropyran-2-ylo; <y) -2β- (3 ^a - [tetrahydropyran-2-yloxy 3-6-oxa-trans-1-octen-1-yl) -eye lopentla-yl] -acetaldehyde-Y-hemiacetal®, prepared according to Example 25, added to 5.0 ml of dry dimethyl sulfoxide. After stirring for a further 2 hours at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with 100 ml of ethyl acetate and then acidified to a pH of about 3 with 10 # aqueous hydrochloric acid Extracted three times with 100 ml of ethyl acetate and the combined organic extracts washed once with 25 ml of water, dried over MgSO 4 and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography over silica gel (Baker Reagent "Analyzed", particle size 0.0 jH - 0.2 43 mm) using ethyl acetate as the eluant. After removing impurities with a high R ~ value, 550 mg (70 %) 9ct-Hydroxy-Ila, 15 ^ -bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadic acid collected.

The NMR spectrum (CDCl) showed a multiplet (variable) at 6.2-6.6 S (2H) of the -OH protons, a multiplet at from 5.3 to 5.7 8 ⁽¹ JH) for the olefinic Protons,

409809/1220

a multiplet at from 4.6 to 4.9 $ (2H) for the acetal proton, a quartet at 3.5 S (2H) for the ethyl ether protons and multiplets at 3.3 to. 4.4 S (9H) and 1.0 - 2.6g (31H) for the remaining protons.

Example 27

A solution of 400 mg (0.765 mmol) of 9cx-hydroxy-II <x, 15a-b.is ~, cooled to -10 ° C and kept under nitrogen (tetrahydropyran-2-yloxy) -18-OXa-CiS-5-trans-13-p ** ostdienoic acid, prepared according to Example 26, in 8 ml of acetone (degree of purity "reagent grade") was added dropwise 0.338 ml (0.900 mmol) of 2.67 M Jones' reagent was added. To 0.350 ml of 2-propanol were added for 5 minutes at -10 ° C and the reaction mixture stirred for a further 5 minutes, after which it combined with 60 ml of ethyl acetate, with 3x5 ml of water washed, dried over MgSO ^ and concentrated, 280 mg of 9-oxo ~ lla, 15a-bis (tetrahydropyran-2-yloxy) -18-oxa-cis-5 ~ trans-13-prostadienoic acid received.

Example 28

A solution of 280 mg (0.240 mmol) of g-Oxo-lloCjlSa-bis (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-pi * ostadienic acid, prepared according to Example 27, in 4.0 ml of a mixture of 65 parts of glacial acetic acid and 35 parts of water was stirred for 2.5 hours at 40 ° C. under nitrogen and then concentrated by rotary evaporation. The crude oil obtained was purified by column chromatography on silica gel (Mallinckrodt CC-4, particle size 0.074 0.147 ^mm ) using ethyl acetate as the eluent. After eluting less polar impurities, 66 mg of 9-oxo-IIIa, 15a-dihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid were collected in the form of an oil. This product was 18-0xaprostaglandin Ep.

A09809 / 1220

<T4 23U839

The UV spectrum in methanol with added potassium hydroxide solution showed an X 278 mu and a £

max 'max

23.800 to 25.6ΟΟ.

When the corresponding 18-oxaprostaglandin A _? if desired, the procedure of Example 9 can be followed.

Example 2g

A solution of 75 mg (0.10 mmol) 9a-hydroxy-IIIa, 15abis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13- prostadic acid, prepared according to Example 26, in 3.0 ml a mixture of 65 parts of glacial acetic acid and 35 parts of water was stirred for 5 hours at 40 ° C. under nitrogen and then concentrated by rotary evaporation. The crude oil obtained was dried over silica gel (Mallinckrodt CC-4, Particle size 0.074 - 0.14? mm) using ethyl acetate and then methanol as eluants cleaned. After eluting the less polar impurities, 20 mg of gcXjllfXjlSot-trihydroxy-IS-axa-cis-5-trans-13-prostadic acid became collected in the form of an oil. This product x * ar 18-Oxaprostaglandin F ".

Example 30

A solution of 49.4 g (398 mmol) of dimethyl methylphosphonate (Aldrich) in 300 ml of dry tetrahydrofuran was cooled in a dry nitrogen atmosphere to -78 ⁰ C. 173 ml of 2.34 M n-butyllithium in hexane (Alfa Inorganics, Inc.) were added dropwise to the stirred phosphonate solution in the course of 50 minutes at a rate such that the reaction temperature never rose to above -65 ° C. After there: <Mixture for 5 minutes

409809/1220

was stirred at -78 C, were in the course of 11 minutes at a rate that the reaction temperature was kept below -7O ⁰ C, was added dropwise 27 g (199.0 mmol) of methyl 5-methoxyvalerat added. After 3 hours at -78 ⁰ C, the reaction mixture was allowed to come to ambient temperature, neutralized with 22 ml of acetic acid and received by rotary evaporation a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase was extracted three times with 300 ml of ether, and the combined organic extracts were dried over MgSOj. dried and then concentrated (steam) to give a crude residue. The residue was distilled, 34.8 g (50/5) of dimethyl 2-oxo-7-oxaoetylphosphonate (2) being obtained at 135-137 ° C. and 0.1 mm Hg.

The NMR spectrum (CDCI,) was compatible. Example 31

2- ^ 3g-p-phenylbenzoyloxy-5a ~ hydroxy-2ß- (3 ~ oxo ~ 8-oxatrans-l-nonen-l-yl) ~ cyclopent-la-yl7-acetic acid-Y-lactone (3)

7.05 g (29.6 mmol) of dimethyl 2-oxo-7-oxaoctylphosphonate (2) in 50 ml of anhydrous DME were mixed with 13 »^ ml (29 mmol) of 2.2 m n-buty at room temperature in a dry nitrogen atmosphere ! lithium treated in η-hexane (Alfa Inorganics, Inc.). After the mixture had been stirred for 40 minutes, 102 g (28.2 mmol) of 2 ~. / 3x-p-phenylbene-soyloxy-5a-hydroxy-2ß-formylcyclopentanla-yiy-acetic acid-γ-lactone in 40 ml of anhydrous DM'C added. After 35 minutes, the reaction mixture was quenched with 2.5 ml of glacial acetic acid and evaporated. After recrystallization from 2-propanol, 7.0 g (54 %) of 2 - / * 3a-p-phenylbenzoyloxy-5a-hydroxy-2ß- (3-oxo-8-oxa-transl-nonen-l-yl) -cyclopent ~ la-yl7 ~ acetic acid-Y-lactone (3)

409809/1220

as a solid with a melting point of 83 - 83> 5 were obtained.

The IR spectrum (CHC1_) of the product showed adsorption bands at 1775 cm " ¹ (strong), 1715 cm" ¹ (strong), 1675 cm (medium) and 1630 cm "(medium), which were attributable to the carbonyl groups, and at 975 cm "for the double bond in the trans position.

Example 32

2-Z30 ^g -p-phenylbenzoyloxy-5Qi "-hydroxy-2ß- (30f-hydroxy-8-oxa-trans-1-nonen-1-yl) -cyclopent-loC-yl7-acetic acid-) ^> -lactone (5 )

A solution of 10.3 g (22 mmol) 2 - /. 3 ^c <- p ~ Phenylbenzoyloxy-5: £ -hydroxy-2ß- (3-oxo-8-oxa-trans-1-nonen-1-yl ) -eyclopentlc. £ -y! / - acetic acid -} ^ - laeton (3) in 100 ml of dry 1,2-dimethoxyethane was added dropwise at ambient temperature in a dry nitrogen atmosphere with 21.6 ml of a 0.5 M zinc borohydride solution . After stirring for 2 hours at 0 ^° C., a saturated sodium bitartrate solution was added dropwise until the evolution of hydrogen ceased. The reaction mixture was stirred for an additional 5 minutes at which time 300 ml of dry methylene chloride was added. After drying over MgSO ₂₁ and concentration (water vapor), the semisolid material obtained was purified by column chromatography over silica gel (Baker reagent "Analyzed", particle size 0.074-0.248 mm) using cyclohexane and ether as eluants. After elution of less polar impurities, 4 _S 4 ε of a fraction from 2 -_ /> Xp-phenylbenzoylcxy-5Ot-hydroxy-2ß- (3oC-hydroxy-8-oxa-transl-nonen-1-yl) -cyelopent-loc -yl / -acetic acid-y-lactone (5),

409809/1220

3.3 g of a mixed fraction from (^) and (5) and finally 3.0 g of a fraction of 2- / 3oc-p-phenylbenzoyloxy-5ot-hydroxy-2ß- (3ß-hydroxy-8-oxa-trans-1-nonenyD-cyclopent-loc-ylV-acetic acid-γ-lactone (if) received.

The IR spectrum (CHCl ^) of (5) had strong carbonyl adsorptions at 1770 and 1715 cm and an adsorption at 970 cm for the trans double bond.

Example 33

2-Qoc. ₉ 5fc ~ Pihydroxy-2ß- (3QC-hydroxy-8-oxa-t rans-1-nqnen- · l-yl) -cyclopent-loc-yl7-acetic acid-7 '^< -lactone (6)

A heterogeneous mixture of H ₉ k g (9 »5 mmol) 2- / 3 & -p-phenylbenzoyloxy-5c ^c -hydroxy-2ß- (3cC-hydroxy-8-oxa-transl-nonen-l-yl) -cyclopent- ia-yl7-acetic acid- ') ^; Lactone (5)> 60 ml of absolute methanol and 1.3 g of finely powdered, anhydrous potassium carbonate were stirred for one hour at room temperature and then cooled ^{to 0 ° C.} The cooled solution was treated with 18 ml (18 mmol) of a 1.0 η aqueous hydrochloric acid. After the solution had been stirred for a further 10 minutes at ⁰ ° C., 70 ml of water were added, with the formation of the methyl p-phenylbenzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride and extracted three times with 50 ml of ethyl acetate, after which the combined organic extracts were washed with hO ml of saturated sodium bicarbonate solution, dried over MgSO ^ and concentrated, 2.3 g (85 %) 2- / 3a, 5 ^ -Dihydroxy-2ß- (3oc-hydroxy-8-oxa-trans-1-nonen-l-yl) -cyclopent-lcc-y 1 / -es sigsäure-Y-lactone (6) in the form of a viscous, oily substance were obtained.

409809/122

The IR spectrum (CHCl) showed strong adsorption

- 1
at 1770 cm for the Laeton carbonyl and a medium

-1

strong adsorption at 970 cm for the trans double bond.

Example 34

2- / 30C15 <X-dihydroxy-2ß- (3ß-hydroxy-8-oxa-trans-l-nonenl-yl) -cyclopent-lcc-yl7-acetic acid-Y-lactone (6a)

A heterogeneous mixture of 3.0 g (6.5 mmol) 2- / 3fl.-p ~ phenylbenzoyloxy-5cc-hydroxy-2ß- (3ß-hydroxy-8-oxa-transl-nonen-l-yl) -cyclopent- loc-yl7-acetic acid-y-lactone (5) »50 ml of absolute methanol and 900 mg of finely powdered, anhydrous potassium carbonate were stirred for one hour at room temperature and then cooled ^{to 0 ° C.} The cooled solution was admixed with 13 wl (13 mmol) of a 1.0 η aqueous hydrochloric acid. After the solution had been stirred for a further 10 minutes at 0 ^° C., 60 ml of water were added, with the formation of the methyl p-pe ^ inylbenzoate, which was collected by filtration. The piltrate was saturated with solid sodium chloride and three times with 100 ml Ethyl acetate extracted, the combined organic extracts were washed with 35 ml of saturated sodium bicarbonate solution, over MgSOj. dried and concentrated, whereby 1.84 g (82 %) 2- / 3 * 15 "-dihydroxy-2ß- (3ß-hydroxy-8-oxa-trans-1-nonen-1-yl) -cyclopent-loc-yl_7 -acetic acid- ^: Y-lactone (6a) were obtained in the form of a viscous oily substance.

The IR spectrum (CHCl3) showed strong adsorption

-1

at 1770 cm for the lactone carbonyl and a medium strength Adsorption at 970 cm for the trans double bond.

Λ09809 / 1220

Example 35

2- / 5a-Hydroxy-3 * - (tetrahydrofuran-2-yloxy) -2ß- (3oir ~ Ztetrahydropyran-2-yloxy / -8-oxa-trans-l-nonen-l-yl) -cyclopentlcC-ylJ ^ - acetic acid-y-lactone (7)

A solution of 2.3 g (8.1 mmol) 2 - / * 3oc, 5sc-dihydroxy-2ß- (3oC-hydroxy-8-oxa-trans-1-nonen-yl) -cyclopent-icc ~ y lyes setic acid y-lact one (6) in 40 ml of anhydrous methylene chloride and 2.3 ml H-dihydropyran was added at 0 ⁰ C in a dry nitrogen atmosphere with 30 mg of p-toluenesulfonic acid monohydrate. After the reaction mixture had been stirred for 15 minutes, it was combined with ether and the ethereal solution was washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, _{dried over MgSO 1} and concentrated to give 3.5 g (95.5 / O crude 2- / 5oc-Hydroxy-3cC- (tetrahydropyran-2-yloxy) -2ß- (3iX- / tetrahydropyran-2-yloxy-7-S-oxa-trans-1-nonen-1-ylJ-cyclopent-1cC-yiy-acetic acid-ylactone (7) were obtained.

The IR spectrum (CHG1_) showed a medium-strong adsorption

- 1

tion at 970 cm for the trans double bond. Example 36

2-Z5 «: - Hydroxy-3sc- (tetrahydropyran-2-yloxy) -2ß- (3ß- /" tetrahydropyran-2-yloxy7-8-oxa-trans-1-nonen-1-yl) -cyclopentlcc-ylJ- acetic acid - ^ - lactone (7a)

A solution of 1.5 g (5.3 mmol) 2- / 3a ', 5cC-dihydroxy-2ß- (3ß-hydroxy-8-oxa-trans-1-nonen-yl) -cyclopent-loc-yl-7-acetic acid -7-lactone (6a) in 30 ml of anhydrous methylene chloride and 1.5 ml of 2,3-dihydropyran were treated with 20 mg of p-toluenesulfonic acid monohydrate ^{at 0 ° C. in a dry nitrogen atmosphere.} After the reaction mixture 15 minutes

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was stirred, it was combined with ether and the ether solution was then washed with saturated Natriumbiearbonatlösung and with saturated brine, dried over MgSO. dried and concentrated, with 2.6 g (> 100 %) crude 2- / ~ 5ct-hydroxy-3 <£ - (tetrahydropy: ran-2-yloxy) -2ß- (3ß- / tetrahydropyran-2-yloxy ^? - 8-oxa-trans ~ lnonen-1-yl) -eyclopent-IGC-yl-7-acetic acid-Y-lactone (7a) were obtained.

The IR spectrum (CHCl-,) showed a moderately strong ad-

-1

sorption at 97O cm for the trans-double bond.

Example 37

2-Z5oc-Hydroxy-3oc- (tetrahydropyran-2-, yloxy) -2ß- (5 & -Ztetrahydropyran-2-yloxy-7-8-oxa-trans-1-nonen-1-yl) -cyclopentlGC-yl7-acetaldehyde ~ ^f y-hemiaceta l (8a)

A solution of 900 mg (2.0 mmol) 2- / 5CC-hydroxy-3cC- (tetrahydropyran-2-yloxy) -2β- (3β- / tetrahydropyran-2-yloxy_ / ~ S-oxa-trans-1-nonene -l-YLJ-cyclopent-loc-YLJ ^ -acetic acid Tflacton (7a) in 15 ml of dry toluene was. cooled in a dry nitrogen atmosphere to -78 ⁰ C. This cooled solution was added over 15 minutes at such a rate. that the internal temperature never rose above -65 ⁰ C, added with 2.7 ml of a 20 catfish # solution of diisobutylaluminum hydride in η-hexane (Alfa Inorganics, Inc.) was added. After the mixture for a further 45 minutes at -78 ⁰ C. After stirring , anhydrous acetic acid was added until the evolution of gas had ceased, whereupon the reaction mixture was allowed to come to room temperature, the reaction mixture was combined with 60 ml of toluene, washed with 25 ml of a 50% sodium potassium tartrate solution, dried over Na SOj and focused, being

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after chromatography 564 mg 2- / 5oc-hydroxy-3 & - (tetrahydropyran-2-yloxy) -2ß- (3ß- / tetrahydropyran-2 ~ yloxyy-8-oxa-trans-1-nonen-1-yl) - cyclopent-1-yl / acetaldehyde-Y hemiacetal (8a) were obtained.

Example 38

2- / 5 ^ -Hydroxy-3oC- (tetrahydropyran-2-yloxy) -2ß- (5y-Ztetrahydropyran-2-yloxyJ7-8-oxa-trans-l-nonen-l-yl) -cyclopentlcC-yl7 ~ acetaldehyde- y-hemiacetal (8)

A solution of 3.5 g (7.75 mmol) 2- / 50C ~ hydroxy-3cC- (tetrahydropyran-2-yloxy) -2ß- (3GC- / te t rahydropyran-2-yloxy7-8-oxa- trans-l-nonen-l-yD-cyclopent-lcC-ylJ-acetic acid-ylactone (7) in 25 ml of dry toluene was cooled in a dry nitrogen atmosphere to -78 C. This cooled solution was in the course of 15 minutes at a such a rate that the internal temperature never rose above -65 ⁰ C, treated dropwise with 10.5 ml of a 20 $ solution of diisobutylaluminum hydride in n-hexane (Alfa Inorganics, Inc.) was added. After the reaction mixture further * i5 minutes at -78 ⁰ C was stirred, acetic acid would be added in toluene, was until gas evolution stopped and the reaction mixture vmrde warmed to room temperature. the reaction mixture was combined with 100 ml of ether, washed with 50 ml of a 50 $ strength sodium potassium tartrate solution over Na -SOj, dried and concentrated, whereby, after chromatography, 2.6 g of 2- / 5oc-hydroxy-3oc- (tetrahydropyran-2-yloxy) -2ß- (3 a * - / tetrahydropyran-2-yloxy7-8-oxa-trans-1-nonen-1-yl) -cyclopent-1-ylJ-acetaldehyde-Y-hemiacetal (8).

Λ09809 / 1220

Example 39

90c-Hydroxy-llcc, 15 ^ -bis- (tetrahydropy ran-2-yloxy) ~ 20-oxa-cis-5-trans-13 "^ hQKiQ-Prostadienäure. (9)

A solution of 7.65 g (17.25 mmol) of (4-carbohydroxy-nbutyl) -trxphenylphosphonium bromide in 20 ml of dry dimethyl sulfoxide in a dry nitrogen atmosphere was mixed with 15.3 ml (32.2 mmol) of a 2.1 M solution added by sodium methylsulfinyl methide in dimethyl sulfoxide. This red ylid solution was added dropwise over 20 minutes with a solution of 2.6 g (5.76 mmol) of 2-Z5oC-hydroxy-3oC- (tetrahydropyran-2-yloxy) -2β- (3cC-Ztetrahydropyran-2 -yloxy7-8-oxa-trans-l-nonen-l-yl) -cyclopentloc-ylj-acetaldehyde-y-hemiacetal (8) in 15.0 ml of dry dimethyl sulfoxide. After the reaction mixture had been stirred for a further 2 hours at room temperature, it was poured onto 60 ml of ice water, rewashed with 250 ml of ethyl acetate and acidified with 35 ml of 1 HCl. The acidic solution was extracted further twice with 120 ml of ethyl acetate and the combined organic extracts were washed once with 60 ml of water, dried over MgSOj and evaporated to a residue. The residue was purified by column chromatography over silica gel (Baker reagent "Analyzed", particle size 0.074-0.248 mm) using ethyl acetate as the eluent. After the impurities with higher R _f values had been removed, 3.1 g of 9a-hydroxy-lloc, 15a-bis (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13-0J-homoprostadienoic acid were obtained collected.

4Q98Q9 / 1220

Example 40

9c ^ -Hydroxy-lloc _J 15ß-bis- (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13 - ^ - homo-prostadic acid (9a)

A solution of 2120 mg (5.0 mmol) (4-Carbohydroxy-nbutyl) -triphenylphosphoniumbromid in 8.0 ml dry dimethyl sulfoxide was in a dry nitrogen atmosphere with 5 »02 ml (9> 3 mmol) of a 1.85 M solution of Sodium methylsulfinyl methide is added to dimethyl sulfoxide. This red ylide solution was added dropwise over 20 minutes with a solution of 564 mg (1.22 mmol) of 2- / 5cx-hydroxy-3cC- (tetrahydropyran-2-yloxy) -2ß- (3.beta.-Ztetrahydropyran-2- yloxy7-8-oxa-trans-l-nonen-lyl) -cyclopent-lcC-yl7-acetaldehyde-7'-hemiacetal (8a) in 5.0 ml of dry dimethyl sulfoxide. After the reaction mixture had been stirred for a further 2 hours at room temperature, it was poured onto ice water. The basic aqueous solution was extracted twice with 100 ml of ethyl acetate and the combined organic extracts were washed once with 40 ml of water, dried over MgSOj and evaporated to a residue. This residue was purified by column chromatography on silica gel (Baker reagent "Analyzed", particle size 0.074-0.248 mm) using chloroform and ethyl acetate as eluents. After removing impurities with a high value, 642 mg of 9CC-hydroxy-llcc, 15β-bis (tetrahydropyran-2-yloxy) ~ 20-oxacis-5 ~ trans-13- ^w "* homoprostadienoic acid were collected .

409809 / 122Q

example St.

9-Oxo-lloC, 15ß-bis- (tetrahydropyran-2-yloxy) -20-oxaci3-5-trahs ~ 15-lJ-homoprostadienoic acid (IQa)

A solution of 642 mg (1.19 mmol) 9 ": - Hydroxy-IICC, 15ßbis- (tetrahydropyran-2-yloxy) -2Q-oxa-cis-5-trans-13- £ iS-homa-prostadienoic acid (9a) in 20 ml of acetone (purity "reagent grade"), which was cooled under nitrogen to -10 ⁰ C, was added dropwise 0.59 ml (1.58 mmol) Jones reagent ^T. After the reaction mixture had been kept at -10 C for 20 minutes, 0.6 ml of 2-propanol was added and the reaction mixture was stirred for an additional 5 minutes, at which time it was combined with 80 ml of ethyl acetate, washed three times with 15 ml of water, over MgSO 4 ₁ , was dried and concentrated to give 578 mg of 9-oxo-IIcC, 15β-bis- (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13 - ^ - homo-prostadic acid (10a) .

example k2

9-Qxo-11CC, 15Qt> -bis- (tetrahydropyran-2-yloxy) -2Q-oxa-ci3 5-trans-13 ^ ~ k ^; -homo-prostadic acid (10)

A solution of 2000 mg (3.72 mmol) of 90C-hydroxy-110c, bis- (tetrahydropyran-2-yloxy) -20-oxa-cis-5 ~ trans-13- ^ ~ homoprostadienoic acid (9) in 50 ml Acetone (reagent grade), cooled to -15 ° C under nitrogen, was added dropwise with 1.85 ml (0.655 mmol) of Jones' reagent. After the reaction mixture was held for 20 minutes at -10 ⁰ C, it was treated with 1.85 ml of 2-propanol was added and stirred for a further 5 minutes, after which it combined with 125 ml of ethyl acetate, washed three times with 25 ml water, dried over MgSOr and was concentrated,

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where 2.1 g of 9-oxo-lla, 15iX-bis- (tetrahydropyran-2-yloxy) 20-oxa-cis- ~ 5-trans-13-k-tetranor-prostadienoic acid (10) were obtained.

Example 43

prostadic acid (11)

A solution of 2100 mg (3.29 JnMol) g- (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13- ⁶ ^ * homoprostadienic acid (10) in 21 ml of a mixture of 65 parts of glacial acetic acid and 35 parts of water was stirred under nitrogen at room temperature for 16.5 hours and then concentrated by rotary evaporation. The obtained crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of more polar impurities, 369 mg of 9-oxo-11ct, 15 <X-dihydroxy-20-oxa-cis-5 ~ ti ^> ans - 13-i ^ -homo-prostadienoic acid (11) were obtained in the form an oily substance collected.

Example 44

'It

9 ~ 0xo-llcC ₎ 15ß-dihydroxy-20-oxa-cis-5-trans-13-f0-hpmoprostadienoic acid (Ha)

A solution of 578 mg (1.08 mmol) g-

(tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13-iJ-homo-

prostadic acid (10a) in 3.0 ml of a mixture

65 parts of glacial acetic acid and 35 parts of water were stirred for 24 hours at 25 ° C. under nitrogen and then through Rotary evaporation concentrated. The obtained raw

Oil was purified by column chromatography over silica gel

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(Mallinekrodt CC-7) using chloroform and ethyl acetate as eluents. After elution of less polar impurities, 131 mg of semi-solid 9-oxo-lloc _a 15β-dihydroxy-20-oxa-cis-5-trans-13-6 -'-hemomoprostadienoic acid (IIIa) were collected.

example H5

- Trihydroxy-20-oxa-cis-5-trans-13 - & - H-iorn o prostadienoic acid (12)

A solution of 800 mg (1.49 mmol) of 9 # -hydroxy-II <x., 15o: ~ - bis- (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13-ft> homo -prostadiensäure (9) was stirred for l6 hours under nitrogen at 25 ⁰ C and then concentrated by rotary evaporation in 3> 0 ml of a mixture of 65 parts of glacial acetic acid and 35 parts of water. The crude oil obtained was purified by column chromatography over silica gel (Mallinckrodt CC-7) using ethyl acetate and ethyl acetate / methanol as eluents. After elution of less polar impurities, 335 mg of 9X, IICC, 15oC-trihydroxy-20-oxa-cis-5-trans-13-u> homoprostadic acid (12) were collected as an oil.

Example 46

A solution of 76 mg of 19-oxa-PGF ₂ in 1.0 rcl. 120 mg (1.0 mmol) of pivaloyl chloride were added to pyridine. The solution was stirred under nitrogen at 45 ° C. for 5 hours and then cooled to room temperature. 36 mg (2.0 mmol) of water were then added to the solution and the mixture was stirred at room temperature for 2.0 hours and then diluted with ethyl acetate. The diluted solution was washed three times with 0.1 η hydrochloric acid, once with water and once with saturated sodium chloride solution

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Dried an anhydrous magnesium sulfate and concentrated. Purification of the crude residue by means of column chromatography over silica gel gave the desired 9a, 11 <x, 15oC-tris-pivaloyloxy-19-oxa-PGP _2oc .

Example 4 7

A solution of 37 mg of 19-0xa-PGA in 0.5 ml of dry tetrahydrofuran was admixed with 29 mg (0.33 mmol) of formic acid-acetic acid anhydride and 35 mg (0.33 mmol) of 2,6-lutidine . The solution was stirred for H hours under nitrogen at room temperature and then 36 mg (2.0 mmol) of water were added. The mixture was stirred for a further 1.0 hour at room temperature and then diluted with ethyl acetate. The diluted solution was washed once with 0.1 η hydrochloric acid, once with water and once with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by column chromatography over silica gel gave

Example * t8

A solution of 75 mg of 19-oxa-iu-homo-PGEp in 1.5 ml of methylene chloride, which was cooled in ice and kept under nitrogen, was admixed with 350 μl of pivaloyl chloride and then 50 μl of triethylamine. After the mixture was stirred at room temperature for 5 hours, it was poured onto a mixture of ethyl acetate and ice. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with 10% hydrochloric acid, with saturated bicarbonate solution and with water, dried over anhydrous magnesium sulfate.

409809/1220

dries and concentrates. Purification of the crude product by means of column chromatography gave the desired lloc, 15 & -bis-pivaloyloxy-19-oxa-a £ -honio-

PGE ₂ . ·

Example 49

A solution of 125 mg of 18-Oxa-PGE ₂ in 2.5 ml of methylene chloride, which was cooled in ice under nitrogen, was admixed with 0.50 ml of benzoyle chloride and then with 0.625 ml of triethylamine. After the mixture was stirred at room temperature for 5 hours, it was poured onto a mixture of ethyl acetate and ice water. The aqueous layer was extracted again with ethyl acetate. The combined organic extracts were washed with 10 # hydrochloric acid and with water, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude product by means of column chromatography gave the desired llcc,

Dibenzoyloxy-18-oxa-PGE ₂ and 15oc-benzoyloxy-18-oxa-PGA ₂ . Example 50

A solution of 35 mg of 19-oxa-PGEp, prepared according to Example 9, in 7 ml of absolute methanol, which was cooled in ice, was treated with an ice-cooled solution of 105 mg of sodium borohydride in 12 ml of absolute methanol. The solution xiurde under nitrogen for 20 minutes at 0 - 5 ⁰ C and then 1.0 hour at room temperature. The reaction mixture was then cooled in ice, 2 ml of water were added and the mixture was concentrated. The concentrated mixture was covered with ethyl acetate and acidified with 10% hydrochloric acid. The acidified

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aqueous layer was extracted four times with 5 ml of ethyl acetate. The combined extracts were washed with water and with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The crude residue was purified by column chromatography (Mallinckrodt CC-7). purified using mixtures of methanol and methylene chloride as eluents to give 19-oxa-PGF ₂ and 19-oxa-PGF _2β .

Example 51

9 <y-Hydroxy-110C, 15 <X-bis- (tetrahydropyran-2-yloxy) -19-oxa-p rost anic acid ...

A heterogeneous solution of 93R-hydroxy-ll <fc, 15cc-bis- (tetrahydropyran-2-yloxy) -cis-5-trans-13-19-oxaprostadiensäure and 5% palladium on carbon in methanol for 2 hours at 0 C ⁰ hydrogenated (1 at). The reaction mixture was filtered and evaporated to give the desired product.

Example 52

9 e & -Hydroxy-Hoc, 1500-bis- (tetrahydropyran-2-yloxy) -13-trans-19-oxa-pros'tenic acid

A heterogeneous solution of 9QC-Hydroxy-110t ', 15 € 6-bis (tetrahydropyran-2-yloxy) -eis-5-trans-13-19-oxa ~ prostadienoic acid ^% and 5 % palladium on charcoal in methanol was made for 4 hours hydrogenated at -22 ° C (1 at). The reaction mixture was filtered and chromatographed to give the desired product.

409809/1220

Claims (2)

23U83 & claims: 1. Compound of the general formula where η is an integer from 0 to 2 and m is an integer Numbers from 1 to 5 mean v / whether ei does not exceed the sum of η and m 6. 2. The method aar preparation of a compound according to claim 1, characterized in that one a compound of the formula with a compound of the formula 409809/1220 - -yt - tr Lower alkyl-OC (CH ₂ ) ₂ (CII ₂ ) _n ~ O- where η and m have the above meaning, converts, For Pfizer / Ine, (Dr. H. J. Wolff) Lawyer 409809/1220