DE2334945A1 - NEW PROSTAGLANDIN ANALOGS AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

^Dr ' ^ J; :: * - ^ j * Juu 1973

Frankfurt s. ·: - ■; .- fcCchit

Ad * lonitr «2e 58 - XeL 301024

Our no. 18 777

Pfizer Inc. New York, N.Y., V.St.A.

New prostaglandin analogs and methods of making them

The invention relates to certain new analogs of the natural prostaglandins. In particular, it relates to new 15-substituted ones lu-pentanorprostaglandins and several new intermediates, useful in their manufacture.

The prostaglandins are unsaturated C-20 fatty acids that have several physiological effects. For example, the prostaglandins of the E and Α series are effective vasodilators (Bergstrom et al., Acta Physiol. Scand., 64, 332-333 (1965) and Bergstrom et al., Life Sci., £, 449-455 (1967 )) and lower the systemic arterial blood pressure (vasodepression) with intravenous administration (Weeks

409810/1150

and King, Federation Proc, j? 3, 327 (196 ¹ I); Bergstrom et al., 1965> op. Cit .; Carlson et al., Acta Med. Scand. , 183, 423- ¹ Oo (1968); and Carlson et al., Acta Phyeiol. Scand., 75y. I6I-I69 0969)). Furthermore, _{the physiological effect of PGE 1} and PGE ₂ as bronchodilators is generally known. (Cuthbert, Brit. Med. J., Jl, 723-726 (1969)).

Another important physiological effect of natural prostaglandins is influencing the menstrual cycle. PGE ₂ is known to induce When (Karim et al., J. Obstet Gynäc. Brit. Cwlth., 77, 2oo-21o (197o)) to induce therapeutic abortions (Bygdeman et al.,) Contraception, J », 293 (197D) and can be used to regulate fertility (Kärim, Contraception, J5, 173 (1971)). Patents have been granted for several prostaglan-ines of the E and F series as labor triggers in mammals (Belgian patent specification 754 158 and West German patent specification 2 03Ί 6 ¹ Il) and _{the South African one for PGF 1} , F ₂ and F as a mentstrual regulator Patent 69/6089. It has been shown that as a result of the administration of PGFon. Luteolysis can take place (Labhsetwar, Nature 230 , 528 (1971)) and that prostaglandins are therefore used for fertility control by a method in which the stimulation of the smooth muscles is not necessary.

Still other known physiological effects dee PGE ₁ inhibition of gastric acid secretion (Shaw and Ramwell, Worcester Symp. Concerning. Prostaglandins, New York, Wiley (1968), pages 55-64) are) and platelet aggregation (Emmons et al., Brit. med. J. 2, ¹ l68- ¹ »72 (1967)) *

409810/1150

It is now known that these physiological effects are only brief after administration of a prostaglandin Time can be achieved in vivo. It can be assumed that this cause the rapid fading of the effects of natural Prostaglandins is that the compound is fast and effective by ß-oxidation of the carboxylic acid side chain and metabolically deactivated by oxidation of the 15a-hydroxyl group (Anggard et al., Acta Physiol. Scand., 81, 396 (1971) and the references cited therein).

It has been shown that placing a 15-alkyl group in the prostaglandins has the effect, the duration of the effect possibly by preventing the oxidation of the C., - hydroxyl group (Yankee and Bundy, JACS 9Ji, 3651 (1972), Kirton and Forbes, Prostaglandins, JL, 319 (1972).

It was of course desirable to produce prostaglandin derivatives, whose physiological effectiveness corresponded to the natural compounds, but which worked more selectively and one showed improved duration of action. The improved selectivity was expected to reduce the various side effects cancels out, especially gastrointestinal effects that are common when the natural prostaglandins were administered systemically (see Lancet, 536 (1971)).

2 3 3 4 9 A 5

INOfPKNBt INNAOHQEREIpHT

0 ".A-WPL-OBLIUAIMIFf - k -

«* · J». HOUSE CKR. Kt

MAXIMUM

The new compounds according to the invention, i.e. the 15-subst. cu-pentanorprostaglandins, in which the in question Substituent the formula

in which Ar has an α- or ß-furyl radical, an α- or ß-thienyl radical, a cc.- or ß-naphthyl radical, a phenyl radical, the 3, ¹ -dimethoxyphenyl radical, the 3, ^ - methylenedioxyphenyl radical, the 3j ¹ ', 5 ~ trimethoxyphenyl radical or a monosubstituted phenyl radical, v; whether the substituent is an halogen atom, a trifluoromethyl radical, a phenyl radical, a lower alkyl radical, or a lower alkoxy radical, and η is a number from 0 to 5, where, if Ar denotes a phenyl radical, a substituted phenyl radical or a maphthyl radical, η denotes 0 or 1, and in which the remaining 15-hydrogen atom can optionally be replaced by a 15-lower alkyl radical, uniquely meet the above requirements.

In addition to the 15-substituted a ^ pentanorprostaglandins, in which the prostaglandin is PGF, PGF _β , PG ^ ₁ , PGA_, 13 ₃ l ¹ i-Dihydro-PGF _1n -PGF ₁ _, -PGE. and -PGA, PGF, PGF ", PGE 1, PGA ₀ , 13 ₅ l ^/ i-dihydro-PGF _2a , -PGF _β , -PGE ₂ and -PGA ₃ , and the 15-lower alkyl derivatives of the above compounds -

around
the present invention encompasses the following valuable intermediates for these prostaglandins:

409810/1150

fccMUMrtin

M. Ji 3.0!, 'L-CHlM. WMK * Kl

«FfiO HOEPPEi-E *

OR. JUR. Da.-CWM. H.-J. WOlFf Tue !. YYY,?. HANS you ,. BItL

423 ίϊΑΚΚΠί. · »: Α ^: ·; KAIfJ-HÖCHST

ADUCNSIUSSf Jl

Oct 12, 1973

- c -

a compound of the formula JNAQ Hc = «

(Cff ₂ ) n-Ar

v; orin Z is a single bond or a trans double bond means,

a compound of the formula

(CH ₂ J _n -Ar

409810/11 SO

wherein R is a hydrogen atom or a lower alkyl radical, Q is a hydrogen atom or a parabiphenylcarbonyl radical,

η a number from 0 to 5 »^ a single bond or a

S H trans double bond and X = O or ^ denote a compound of the formula

(CiU) _n -Ar THPO- '- "~" ° ⁿ

where THP denotes tetrahydropyranyl and X = O or

mean,

a compound of the formula

THPO- '

OTHP

wherein W is a single bond or a cis double bond,

a compound of the formula

409810/11 SO

(CIIg) _n -Ar

OTHP

in which W, Z, THP, R, Ar and η have the meaning given above, and especially lo-phenyl-co-tetranor-PGE ,,, 16-phenyl-u »tetranor-PGF _2a , 16-phenyl-aj-tetranor -PGEj, 16-p-Methoxyphenyl-ou-tetranor-PGE ₂ , 16-p-Biphenyl- tt ^ tetranor-PGE ₂ , 16o ^ naphthyl-0) -tetranor-PGE ₂ , 16ß-naphthyl- «t> tetranor -PGE ₂ , l6-o-methylphenyl-u> -tetranor-PGE ₂ , l6-p-methylpheny 1- tt> -tetranor-PGE ₂ , 13,1 ^ -dihydro-15-phenyl-u ^ pentanor-PGE ₂ , 16-Phenyl-13, a ^ -dihydro-15-methyl-u-tetranor-PGE ₂ , lo-p-Biph ^ r ^ 'l-tt'-tetranor-PGFp ^ 16-o-methylphenyl-tt-tetranor -PGF _2a , l6a-naphthyl- (w-tetranor-PGF _2a> l6u-naphthyl-uitetranor-PGF and l6-phenyl-13, l ¹ <-dihydro-U'-tetranor-PGA ₂ , 13, l ¹ <- Dihydro-16-phenyl-a! -Tetranor-PGE ₂ , 16-phenylw-tetranor-13, 1 ⁱ 4-dihydro-PGE ₁ , 16a-thienyl- (w-tetranor-PGE ₂ , 16ß-thienyl-u> - tetranor-PGE ₂ , lTa-thienyl-ui-tris-nor-PGE ₂ , 17α-Fury lu> -tris-nor-PGE ₂ , 17a-furyl-tw-tris-nor-PGF _2a and 17a-thienyl-tt > -tris-nor-PGE ₂ , 17β-furyl-to-trisnor-PGE ₂ , 17β-furyl -ui-trisnor-PGF _2o ^ 17ß-thienyl - «^ trisnor-PGEp and _{- the C lc} - ~ epimers of these compounds, such as 15 ~ Epi-16-phenyl-l 3,1 ^ -dihydro-u> -tetranor- PGE ₂ .

It will be understood by those skilled in the art that the structural formulas exhibited by the hemiacetals are not stereochemical on the lactol carbon atom.

It is also understandable that the _; The term "prostaglandin in the zero rows" used in the present _{specification, e.g. PGE Q} , refers to prostaglandins in which the 5-6 and 13-1 ^ double bonds are saturated, ie PGE ₀ is 5-6, 13 IM tetrahydro PGE ₂ . Continue to relate

+) 17β-thienyl-u> -trisnor-PGF _2a
409810/1150

-ZJ34945

the terms "zero series", "1 series" or "2 series" as used herein refer to the degree of unsaturation in the side chains, e.g. PGE ₂ , PGA ₂ and prostaglandins are 2 series, while PGE ₁ , PGF _la and _{1 are} prostaglandins of the "1 series". Further, the term "lower alkyl" as used herein refers to alkyl groups having 1 to 4 carbon atoms.

An object of the present invention relates to a process for the preparation of a compound of the general formula

C-OH

CH ₂ J _n -Ar

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, a 3, ^ - dimethoxyphenyl radical, a 3 »^ - methylene-dioxyphenyl radical, a 3, ¹ 1,5-trimethoxyphenyl radical or a monosubstituted phenyl radical, in which the substituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower alkyl radical or a lower alkoxy radical, η a number from 0 to 5 $ where, if Ar is a phenyl radical, a substituted phenyl radical or is a naphthyl radical, η is 0 or 1, R is a hydrogen atom or a lower alkyl radical, W is a single 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 formulas

409810/1150

or

and N and L together form a single bond, or N is an α-hydroxyl radical when L is a hydrogen off is atom, and where L, M and N are selected so that they complete the structure of a prostaglandin of the A, E or F series, the lower alkanoyl, Formyl or benzoyl esters of any free hydroxyl group at the Cq, CL ^ - and C. ^ "Positions and the pharmaceutically acceptable salts thereof, characterized in that one

a) for the preparation of a compound of the formula in which N is a cu-Hydroxy radical and L is a hydrogen atom and Ar, n, M, W and Z are as defined above, and the 11- and 11- and 15-tetrahydropyranyl ethers are one Treated compound of formula I with a suitable acid,

b) for the preparation of a compound of the formula in which N and L together form a single bond, M is a keto radical and Ar, n, R, W and Z are as defined above, a compound of the formula I in which N is α-hydroxy and L is hydrogen and M is keto; and Ar, n, R, W and Z are as above Have the meaning mentioned, with a suitable dehydrating agent implements,

c) for the preparation of a compound of the formula in which N an α-hydroxy group, L is a hydrogen atom and M is a group of the formulas

or ^ CT '• OK E

40981Ö / ι 150

and Ar, η, R, W and Z are as defined above have a compound of the formula I in which M is α-hydroxy, L is hydrogen and M is Keto and Ar, n, R, W and Z are as defined above, with a suitable reducing agent converts and optionally the 9a and 9β isomers separates,

d) for the preparation of a compound of the formula in which N

,and
an α-hydroxy radical 'L denotes a hydrogen atom and

Ar, R, η and M are as defined above, and W and Z are single bonds, a compound of Formula I, in which Ar, R, η and M are as defined above, W is a single bond or a cis double bond, when Z denotes a trans double bond and Z denotes a single bond when W denotes a cis double bond means, catalytically reduced,

e) for the preparation of a compound of the general formula in which N is an α-hydroxy radical and L is a hydrogen atom, and Ar, R, η and M are as defined above, W is a single bond and Z is a trans double bond denotes a compound of the formula I in which Ar, R, η and M are as defined above and W and Z are double bonds, selectively reduced, and optionally the 9a, lla and lSa-lower alkanoyl, formyl or benzoyl esters of any free hydroxyl group by reacting the compounds with the suitable acylating agent and optionally the pharmaceutical produces acceptable salts of these compounds.

In particular, the present invention relates to a process for the preparation of a compound of the general formula

A09310 / 1150

OH

where Ar is an α- or ß-puryl radical, an α- or A-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, the 3,4-dimethoxyphenyl radical, the 3, ^ - methylenedioxyphenyl radical, the 3,4,5- Trimethoxyphenyl radical or a monosubstituted phenyl radical, the substituent being a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower alkyl radical or a lower alkoxy radical, j η a number from 0 to 5, where, if Ar is a phenyl radical, a substituted phenyl radical or a naphthyl radical, η is 0 or, R is a hydrogen atom or a lower alkyl radical, W is a single bond or a cis double bond and Z is a single bond or a trans double bond, the lower alkanoyl, formyl or benzoyl esters of the free hydroxyl group on the Cq, C ₁₁ - and CLc positions and the pharmaceutically acceptable salts thereof, which is characterized in that one

.the

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

b) a compound of the formula

409810/1150

wherein Ar, η, R, W and Z are as defined above, reduced with a suitable reducing agent and then separating the 9a and 9β isomers,

c) a compound of the formula

I!

COOK"

HO *

(CH ₂ J _n -Ar

'OH

wherein W is a single bond and Ar, n, R and Z have the meanings given above and R 'is Means hydrogen atom or a lower alkyl radical, with converts a suitable base,

d) a compound of the formula IA in which Ar, R and η are as defined above, W is a single bond or denotes a cis double bond when Z denotes a trans double bond and Z denotes a single bond, when W is a cis double bond, to form a compound of the formula IA in which Ar, R and N have the meaning given above and W and Z are single bonds, catalytically reduced,

e) the dimethylisopropylsilyl derivative of a compound of the formula IA, in which Ar, R and η are as defined above have, W is a cis double bond and Z is a trans double bond, to form a compound of the formula IA, wherein Ar, R and η have the above

409810/1150

have named meaning, W is a single bond and Z is a trans double bond, selectively catalytically reduced, and optionally the 9a-, Ha- and 15 "-lower-aikanoyl-, formyl or benzoyl esters of the free hydroxyl groups by reacting the compounds with the appropriate acylating agents produces and optionally wins the pharmaceutically acceptable salts of these compounds.

In particular, the present invention relates to a process for the preparation of a compound of the general formula

COOH

IB

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, a c- or ß-naphthyl radical, a pheny radical, the 3,4-dimethoxyphenyl radical, the 3,4-methylenedioxyphenyl radical, the 3,4,5- Trimethoxyphenyl radical or a monosubstituted phenyl radical, where the substituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower alkyl radical or a lower alkoxy radical, η a number from 0 to 5, where, if Ar is a pheny radical, a substituted phenyl radical or a haphthyl radical means, η is 0 or 1, R is a Wassei'stoffatoro or a lower alkyl radical, W is a single bond or a cis double bond and Z is a single bond or a trans double bond meaning the lower illkanoyl, formyl

40981 G / 's 1S-0

or benzoyl esters of the free hydroxyl groups at the C _1. , - and C. ^ - positions and the pharmaceutically acceptable salts thereof, which is characterized in that

a) the 11- or 11- and 15-tetrahydropyranyl ethers one A compound of the formula IB wherein Ar, R, n, W and Z are the have the above meaning, treated with a suitable acid,

b) a compound of the formula IB, in which Ar, R and η are as defined above, W is a single bond or denotes a cis double bond when Z denotes a trans double bond and Z denotes a single bond means when W is a cis double bond, to form a compound of the formula IB in which Ar, η and R have the meaning given above and W and Z are single bonds, catalytically reduced,

c) the dimethylisopropylsilyl derivatives of a compound of the formula IB, in which Ar, R and η are as defined above, W is a cis double bond and Z is a trans double bond, with formation of a compound of the formula IB ₁ in which Ar, R and η are as defined above, W is a single bond and Z is a trans double bond, selectively catalytically reduced, and optionally the lower alkanoyl, formyl or benzoyl esters of the free 11- and 15-hydroxyl groups by treating the compounds with the appropriate acetylating agent and, optionally, the pharmaceutically acceptable salts of these compounds.

409810/1150

In particular, the present invention relates to a process for the preparation of a compound of the formula

IT '"OH

GOOH

IG

wherein Ar is a u- or ß-furyl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, the Sjii dimethoxyphenyl radical, the 3,4-methylenedioxyphenyl radical, the 3, M, 5-trimethoxyphenyl radical or a monosufo-substituted one Phenyl radical, in which the substituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a is a lower alkyl radical or a lower alkoxy radical, η is a number from 0 to 5 »where, if Ar is a phenyl radical, is a substituted phenyl radical or a naphthyl radical, η is 0 or 1, R is a hydrogen atom or a lower alkyl radical, W a single bond or a cis double bond and Z a single bond or a trans double bond mean,

the lower alkanoyl, formyl or benzoyl esters of Hydroxy group and the pharmaceutically acceptable salts thereof, which is characterized in that that a compound of the formula IB

COOH

IB

40981 0/1150

wherein Ar, R, η, W and Z are as defined above, with a suitable dehydrating agent implements and

optionally with the production of the C.j -.- lower-alkanoyl-, Pormyl or benzoyl ester this compound with a suitable one Reacts acylating agent and optionally the pharmaceutically acceptable salts of these compounds manufactures.

Another object of the present invention relates to the preparation of a compound of the general formula

II

wherein Ar is an α- or ß-puryl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, the 3,4-dimethoxyphenyl radical, the 3, ^ - methylenedioxyphenyl radical, the 3,4,5-Trimethcxyphenylrest or a monosubstituted Phenyl radical, in which the substituent is a halogen atom, the trifluoromethyl radical, the phenyl radical, a lower one Denotes alkyl radical or a lower alkoxy radical, and η denotes a number from 0 to 5, where, when Ar is a Denotes a phenyl radical, a substituted phenyl radical or a naphthyl radical, η is 0 or 1, which means that

/, 09810/1150

- vt -

is characterized in that one is a compound of the formula

CHO

with a dialkyl methyl ketophosphonate of the formula

0 0
"t

Ar- (CH ") C-CH _o -P (O-lower alkyl), c. η c ι

wherein Ar and η are as defined above.

The present invention further relates to a method for producing a compound of the general formula

χττ

409 & 10/1150

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, a <x- or ß-naphthyl radical, the phenyl radical, the 3, i | -dimethoxyphenyl radical, the 3 » ⁱ * -methylenedioxyphenyl radical,

,mono-

the 3,4,5-trimethoxyphenyl radical or a substituted one Phenyl radical, in which the substituent is a halogen atom, the trifluoromethyl radical, a phenyl radical, a lower one Alkyl radical or a lower alkoxy radical, η a number from 0 to 5, where, when Ar is a phenyl radical, a substituted one Denotes phenyl radical or a naphthyl radical, η is 0 or 1, R is a hydrogen atom or a lower one Alkyl radical and Q is a hydrogen atom or a p-biphenylcarbonyl radical mean, which is characterized in that one

a) a compound of the formula

IIA

in which Ar, η and Q have the meaning given above, with formation of a compound of the formula III in which Ar, η and Q are as defined above and R denotes a hydrogen atom, reduces and optionally separates the 15 »- and 15β-isomers,

b) a compound of the formula HA with a suitable one

09810/1150

Reacting alkylating agent, a compound of the formula III is obtained, wherein Ar, η and Q are the above and R is a lower alkyl radical means,

and optionally a compound of the formula III in which Ar, η and R are as defined above, and Q is the biphenylcarbonyl radical with K ₂ CO, treated to give a compound of the formula III in which Q is a hydrogen atom, and optionally the Separates 15tt and 15ß isomers.

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

THPO

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, a & - or ß-naphthyl radical, a phenyl radical, the 3,4-dimethoxyphenyl radical, the 3, ¹ * ~ methylenedioxyphenyl radical, the 3, ^ _} 5 -Trimefchoxyphenylrest or a monosubstituted phenyl radical, where the substituent is a halogen atom, the trifluoromethyl radical, the phenyl radical, a lower alkyl radical or a lower alkoxy radical, η a number of

0 to 5, where, when Ar is a phenyl radical, a substituted phenyl radical or a naphthyl radical, η 0 or

1, H is a hydrogen atom or a lower alkyl radical, TKP is the 2-tetrahydropyranyl radical, Z is a single bond

810/1150

or a trans double bond and X. the remainder of the formulas

= 0 or

OH

mean, which is characterized in that a) a compound of the formula

(CH ₂ ) _n -Ar

ΙΙΙΔ

wherein Ar, R, η and Z are as defined above and X is the radical = 0, in the presence of one acidic catalyst reacts with 2,3-dihydropyran, wherein a compound of the formula IV, wherein Ar, R, η and Z are the above have the meaning mentioned and X denotes the remainder = 0, is obtained,

b) a compound of the formula IV in which Ar, R, η and Z are as defined above and X is the radical = 0 means, is reacted with diisobutylaluminum hydride, a compound of the formula IV in which Ar, R, η and Z are the have the meaning given above and X is the radical of the formula

means, is preserved,

U 0 9 8 1 C / ¹ 1 5 0

c) a compound of the formula III, wherein Ar, R and η are the Have the abovementioned meaning, Z is a trans double bond and X is the radical of the formula = 0, with formation of a compound of the formula IV in which Ar, R and N are the have the abovementioned meaning, X is a radical of the formula = 0 and Z is a single bond, catalytically reduced.

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

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, the phenyl radical, the 3,4-Dimethoxyphenylrest, the 3 »^ - Methylendioxyphenylrest, the 3,4,5-trimethoxyphenyl radical or a monosubstituted one Phenyl radical, where the substituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower one Alkyl radical or a lower alkoxy radical, η a number from 0 to 5, where, when Ar is a phenyl radical, a substituted phenyl radical or a napthyl radical, η is 0 or 1, R is a hydrogen atom or a lower one Alkyl radical, THP the 2-tetrahydropyranyl radical, W a single bond or a cis double bond and Z denotes a single bond or a trans double bond, that thereby is marked that one

a) a connection of general ;! formula

1150

THPO

ir "Ότηρ

in which Ar, R, η and Z have the meaning given above, with an ylid of the formula

(CgH ₅ ), P = CH-CH ₂ -CH ₂ -CH ₂ -COO ^ "*

with formation of a compound of the formula V, wherein Ar, R, η and Z have the meaning given above, and W denotes a cis double bond, reacts and optionally the compound so obtained to form a compound of Formula V wherein Ar, R, η and Z are as above have the meaning mentioned and W is a single bond, subsequently reduced,

b) a compound of the formula V, in which Ar, R and η are as defined above, W is a cis double bond and Z is a trans double bond to form a compound of Formula V wherein Ar, R and η have the meaning given above and W and Z mean single bonds, reduced,

c) a compound of the formula V in which Ar, R and η are as defined above, W is a cis double bond and Z is a trans double bond to form a compound of Formula V wherein Ar, R and η

A09810 / 1150

have the abovementioned meaning, W is a single bond and Z is a trans-coupling bond, selectively reduced.

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

where Ar is an α- or ß-puryl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, the 3,1-Dimethoxyphenylrest, the 3,4-Methylendioxyphenylrest, the 3,4,5-trimethoxyphenyl radical or a monosubstituted one PhenylreS, in which the substituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower one Älkylrest or a lower alkoxy radical, η a number from 0 to 5, where, when Ar is a phenyl radical, a substituted phenyl radical or a naphthyl radical, η 0 or. 1, R is a hydrogen atom or a lower alkyl radical, THP a 2-tetrahydropyrgmyl radical, Ii is a symphaah bond or a cis double bond and Z mean a single bond or a trans double bond, which is characterized in that a compound of formula

810/1150

OH

THPO

COOH

wherein Ar, H, η, W and Z have the meaning given above, with chromic acid in aqueous sulfuric acid and Acetone converts.

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

p OGR "

^ CK ₂ J ₆ COOR *

THPO

VII

where Ar is an α- or .ä-furyl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, the phenyl radical, the 3, ^ - dimetnoxyphenyl radical, the 3> ^ - methylenedioxyphenyl radical, the 3> ^) 5 ~ ^r L ^I rimethoxypher.ylrest or a monosubstituted phenyl radical, where the 3ubstituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower alkyl radical or a lower alkoxy radical, η a number from 0 to 5, where, if Ar is a phenyl radical, a substituted phenyl radical or a naphthyl radical, η is 0 or 1, THP len 2-tetrahydropyranyl radical, R 'a lower alkyl radical and R "a lower alkyl radical, an aralkyl radical with" up to 10 carbon atoms, a phenyl radical and

4033 ^ C / ι 150

mean a substituted phenyl radical, where the substituent a lower alkyl radical, a lower alkoxy radical, a halogen atom, the fluoromethyl radical or the phenyl radical mean, which is characterized in that a compound of the formula

GOOR '

THPO ^^ GHO

with a compound 'of the formula

0
t

Ar (CH ₀ ) -C-CH ₀ -P- (0-lower alkyl) _ c. η κ dd

in which Ar, R ', R "and η are as defined above.

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

0
it

THPO *

0 S t'l ι * / ¹ 1 5 0

in which Ar is an α- or β-furyl radical, a sinen u ~ or β-thienyl radical, an α- or β-naphthyl radical, the phenyl radical, the 3,4-dimethoxyphenyl radical, the 3, ⁱ * -methyl] ffidioxyphenyl radical, the 3 » ¹ *> 5-trimethoxyphenyl radical or a monosubstituted phenyl radical, in which the substituent is a halogen atom, a trifluoromethyl radical» a phenyl radical, a lower alkyl radical or a lower alkoxy radical, η a number from 0 to 5, where, if Ar is a phenyl radical, a substituted phenyl radical or a naphthyl radical, η is 0 or 1, THP is the 2-tetrahydropyranyl ^{radical, R 1 is} a lower alkyl radical and R "is a lower alkyl radical, an aralkyl radical of 7 to 10 carbon atoms, a phenyl radical or a substituted phenyl radical, in which the substituent denotes a halogen atom, a trifluoromethyl radical, a lower alkyl radical, a lower alkoxy radical or a phenyl radical, which is characterized in that one

a) a compound of the formula

OCR ¹¹

COOR *

VII

in which Ar, R ¹ , R "and η are as defined above, to form a compound of the formula VIII in which Ar, R ¹ , R" and η are as defined above and R is a hydrogen atom,

409810/1150

- 2t -

b) a compound of formula VII to form a compound of formula VIII wherein Ar, R ', R "and η are those above Have the meaning mentioned and R is a lower alkyl radical means, reacted with a suitable alkylating agent

and optionally separating the 15a and 15β isomers,

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

0 v.

O-C-R "

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, the 3,4-dimefchoxyprienyl radical, the 3 »^ - methyiendioxyphenyl radical, the 3j ^ 5 5- Triniethoxyphenyl radical or a monosubstituted phsnyl radical, in which the substituent is a halogen atom, the trifluoromethyl radical, the phenyl radical, a lower alkyl radical or a lower alkoxy radical, η a number from 0 to 5s where, if Ar is a phenyl radical, a substituted phenyl radical or a naphthyl radical, η or i, THP the 2-tetrahydropyranyl radical, R 'a lower alkyl radical, R "a lower alkyl radical, an aralkyl radical with 7 to 10 carbon atoms, ₅ the phenyl radical or the substituted phenyl radical, where the substituent

-09810/1150

a lower alkyl group, a lower alkoxy group. Halogen atom, the trifluoromethyl radical or the phenyl radical and R represents a hydrogen atom or a lower one Mean alkyl radical, which is characterized in that a compound of the formula

0 »

O-C-R "

COOR *

(GH ₂ J _n -Ar

in which Ar, H, R ¹ , R ″ and η have the meaning given above and R, a hydrogen atom or the THP radical, is reacted with 2,3-dihydropyran in the presence of p-toluenesulfonic acid.

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

OH

L ^ iCH ₂ ) ₆ C00H

THPO

"" OTHP

wherein Ar is a <x or ß-furyl radical, an α- or ß-thienyl · radical, an α- or ß-naphthyl radical, the phenyl radical, the 3, ¹ i-dimethoxyphenyl, the 3,4-Methylendioxyphenylrest,

409810/1 1 50

the 3, ^ 15-trimethoxyphenyl radical or a monosubstituted one Phenyl radical, where the substituent is a halogen atom, a trifluoromethyl radical, the phenyl radical, a lower one Alkyl radical or a lower alkoxy radical, η a number of

0 to 5j where, when Ar is a phenyl radical, a substituted one Denotes a phenyl radical or a naphthyl radical, η 0 or

1, THP is the 2-tetrahydropyranyl radical and R is hydrogen atom or a lower alkyl radical, which is characterized in that one is a compound of Formula IX

0 κ O-C-R "

rr ™

OTHP IX

where Ar, R and η are as defined above, R ^{1 is} a lower alkyl radical and R "is a lower alkyl radical, an aralkyl radical with 7 to 9 carbon atoms, a phenyl radical or a substituted phenyl radical, the substituent being a halogen atom, a lower alkyl radical, a lower alkoxy radical, a trifluoromethyl radical or a phenyl radical is reacted with a suitable base

The present invention relates to an experience for the production of a connection isr- a 11 gladly in θ η formula

4038 1 C / ) 15C

ο ο

¹¹ f ^ __— O-nied. -Alkyl

Ar- (CHp) -C-CH ^ -P Cdi

ⁿ * ^ ~ "^^ O-lower alkyl XI

where Ar is an α- or ß-furyl radical, an α- or ß-thienyl radical, an α- or ß-naphthyl radical, a phenyl radical, a 3,4-Dimethoxyphenylrest, the 3, ^ - Methylendioxyphenylrest, the 3, ^, 5, -trimethoxyphenyl radical or a monosubstituted one Phenyl radical, where the substituent is a halogen atom, a trifluoromethyl radical, a phenyl radical, a lower one Denotes an alkyl radical or a lower alkoxy radical, and η denotes a number from 0 to 5, where, if Ar is a phenyl radical, denotes a substituted phenyl radical or a naphthyl radical, η is 0 or 1, which is thereby marked is that you have a lower alkyl ester of the formula

Il

Ar (CH ₂ ) _n -CO-lower alkyl

with a dialkylmethylphosphonate of the formula

0 t (lower-alkyl-O) ₂ P-CH,.

implements.

As shown in Reaction Scheme A, the first stage i.e. reaction is 1 -> 2, the condensation of the appropriate ester with a «dialkyl methylphosphonate, whereby the Ketophosphonate 2 is obtained. Typically, the desired methyl ester is condensed with dimethyl methyl phosphonate

4098 10/1150

When transferring connection 2 to connection 3 the ketophosphonate 2 with the well-known / ~ Corey et al., J.Org. Chem., 37, 3043 (1972) _7 reacted aldehyde H, whereby after chromatography or crystallization the enone 3 is obtained.

The enone 3 can be converted to a mixture of tertiary alcohols 13 and 14 by reaction with a suitable lithium alkyl or Grignard reagent and the isomers 13 and I ¹ J can be separated by column or high pressure liquid chromatography. The enone 3 can be reduced with zinc borohydride to form a mixture of alcohols 4 and 5, which can be separated as described above. If the 1-2 reduction is desired, lithium triethylborohydride is particularly preferred. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents, although methanol is occasionally preferred to guarantee the specificity of the reduction. Further transformations of compound 4 are shown in Scheme B.

The conversion of the compound of formula 4 into the compound of formula 6 is a base-catalyzed transesterification, with the p-biphenyl-carbonyl protective group Will get removed. Suitably this reaction is carried out with potassium carbonate in methanol or methanol-tetrahydrofuran carried out as a solvent. The conversion of the compound of Formula 6 to the compound of Formula 7 comprises the protection of the two free hydroxyl groups with an acid-labile protecting group. Any suitable acid-labile Group is satisfactory, but the most common is the tetrahydropyrany! Group, which is incorporated into the molecule by loading

/, 09810/1150

treatment with dihydropyran and an acidic catalyst can be incorporated in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid.

409810/1150

Scheme A

ο ο If τ

Ar- (CK ₂ ) -C-CrI ₂ -P (OCIi ₃ ) ₂

CH ₂ I _n -Ar

EAR

409810/1150

Scheme B

THPO '

. (CH ₂ ) _n -Ar • OTHP

-Vi-

23349AS

^ fCH ₂ ) Ar IT '-OH

ΤΗΡσ

CH ₂ ) _n -Ar OTHP

THPO '

COOH

JCHg) _n -Ar H ^ "" OTHP THPO '

OTH?

OH

COOH

, _0H 10 ι

COOH

HO- '

H"*

XCH ₂ J _n -Ar

"•OH

12th

15th

11

409810/1150

23349Α5

The conversion of the compound of the formula 7 into the compound of the formula 8 is a reduction of the lactone 7 to the hemiacetal 8 using diisobutylaluminum hydride in an inert solvent. While low Reaktionetemperaturen are preferred and usually are applied from -60 to -70 ⁰ C .. If there is no reduction takes place, however, higher temperatures may be used.

The compound of formula 8 is optionally purified by column chromatography cleaned.

The conversion of the compound of the formula 8 into the compound of the formula 9 is a Wittig condensation in which the hemiacetal of formula 8 in the presence of sodium methylsulfinyl methide with (M-carbohydroxy-n-butyl) triphenylphosphonium bromide is reacted in dimethyl sulfoxide. The compound of formula 9 is purified as described above.

The conversion of the compound of the formula 9 into the compound of the formula 12 is an acid hydrolysis of the tetrahydropyranyl groups. Any acid that does not destroy the molecule towards the removal of the protecting groups causes can be used. The most common way of doing this is by using a 65? Aqueous acetic acid causes. The product is purified as described above.

The conversion of the compound of formula 9 into the compound of formula 10 is an oxidation of the secondary one Alcohol of formula 9 to the ketone of formula 10. This is effected by using an oxidizing agent which

409810/1150

does not attack the double bonds. Jones reagent is usually preferred. The product is, as described above, cleaned.

The conversion of the compound of the formula 10 into the compound of the formula 11 is carried out in the same manner as that Conversion of the compound of the formula 9 into the compound of the formula 12 carried out. The product will be as above. described, cleaned.

The conversion of the compound of the formula 11 into the compound of the formula 15 is an acid-catalyzed dehydration. Any acid can be used for the process which does not cause extensive decomposition of the product but the most common method is to dissolve the compound of Formula 11 in excess of 97 ϊ-formic acid, and subsequent dilution with ice water and extraction of the product after the starting material was consumed. The product was purified as described above.

409810/1150

Scheme C

- 37 · -

OH

0OH

COOH (CH ₂ J _n -Ar

COOH

OH

HO '

HO '(CH ₂ ) _n -Ar

HO

HO ''

± c

(CH ₂ ) _n -Ar IZ

40981 0/1150

GOuH (CH ₂ J _n -Ar

As illustrated in Reaction Scheme C, the compound of Formula H in Reaction Scheme B can be substituted with the compounds of Formula 5-13 and 14 to provide the prostaglandin derivatives of Formulas 12'-18 '.

Scheme D illustrates the synthesis of the precusors for the 13> l ¹ * -dihydro-15-substit .- »- pentanorprostaglandins.

When converting the compound of the formula 3 into the compounds of the formula 19 and 19 ', the enone of the formula 3 is converted by using one of the complex metal hydrides used as a reducing agent, such as LiAlH ₁ ^, NaBH ₁ J, KBH ₁ ^, LiBH ₁₄ or Zn ( BH ₁ ^) ₂ , reduced to the tetrahydro compound. _{NaBH 1} is particularly preferred. The products of the formulas 19 and 19 'are separated from one another by column chromatography or by liquid chromatography taking place under high pressure.

Furthermore, the compounds of the formulas M and 5 of Scheme A can be catalytically reduced with hydrogen to the compound of formula 19 or 19 '. The level at which the double bond is reduced is not critical. the

VQn Scheme B Hydrogenation of the compounds of the formulas 6 or 7 'also provides valuable intermediates for the 13,14-dihydroprostaglandin analogs of the present invention. This reduction can be achieved either with a homogeneous catalyst such as tristriphenylphosphine rhodium chloride or with a heterogeneous catalyst such as platinum, palladium or rhodium. The precursors for the 15-lower-alkyl-15-substit-tu-pentanorprostaglandins are synthesized in a similar manner by substituting the compounds of the formulas 4 and 5 by the compounds of the formulas 13 and I ¹ * in the system described above. The transfer of the

409810/1150

Compounds of formulas 19, 19 '»20' and 20 into their corresponding prostaglandins proceeds on the route shown in Scheme B when the compound of formula 4 is replaced by the compound of formula 19, 19 ', 20 ¹ and 20, the 13, 14-dihydro-PGE ₂ , -PGA ₂ and -PGF ₂ ~ series of prostaglandin derivatives containing hydrogen or lower alkyl groups on carbon atom 15 can be obtained.

409810/1150

I)

-Ar

CHo) _n -Ar

• Ο

40981O / 1150

Reaction scheme E illustrates the preparation of various reduced 15-substit. -U> -pentanorprostaglandin precursors.

The conversion of the compound of the formula 19 into the compound of the formula 22 is carried out as illustrated in reaction scheme B for the conversion of the compound of the formula 4 into the compound of the formula 9. The compound of the formula 22 can be used both as a precursor for a 13 * 14-dihydro-15-substit. - u> -pentanorprostaglandin the "2 series" or as an intermediate for the compound of formula 23, a precursor for a 13, l ⁱ * -dihydro-15-substit.-uu-pentanorprostaglandin the "1 series" can be used. The conversion of the compound of the formula 22 into the compound of the formula 23 is carried out by catalytic hydrogenation using a catalyst as described for the reduction of the compound of the formula k to the compound of the formula 19 from Scheme D. The intermediates of the type of formula 21 are obtained by selective reduction of the 5-6-cis double bond at low temperature using catalysts such as those used for the conversion of the compound of the formula ¹ I into the compound of the formula # and 17 and their conversion into the compound of formula 23 has been described. Especially preferred for this reduction is the use of palladium-on-carbon as a catalyst and a reaction temperature of -20 ⁰ C. Intermediates of the type of formula 21 are not only Präcusoren for 15 substit. OB Pentanorprostaglandine the "1-series" on the way of converting the compound of the formula 9 into the compound of the formula 15 of Scheme B, but are also precursors for compounds of the type of the formula 23 on the already dis-

409810/1 150

-Mz-

Cutaneous route of conversion of the compound of the formula into the compound of formula 23.

Furthermore, the 15-substit .- (r-pentanorprostaglandins of the E. and F _la ~ series can be obtained directly from the corresponding prostaglandin analogs of the "2 series" by 1) protecting the hydroxyl group by introducing the dimethylisopropylsilyl groups, selective reduction of the cis -Double bond and removal of the protecting group can be obtained directly.

The introduction of the protecting group is usually accomplished by treating the prostaglandin analog with dimethylisopropyl chlorosilane and triethylamine achieved, the reduction is, as for the conversion of the compound of formula 9 in the compound of formula 21 described, carried out and the protective group is removed by reducing the protected compound with acetic acid and water in a ratio of 3: 1 for 10 minutes or until the reaction occurs essential is complete, brings in touch.

The C _1t epimers of the compounds of the formulas 21, 22 and 23 can be used as precursors for the 15-epi series of prostaglandin derivatives which have been described above and the 15-lower-alkyl-15-substit. -w-pentanorprostaglan-dine, which _{are reduced at the 5 f} 6 and / or the 13, I ¹ * position, and their Cc epimers can be prepared from appropriately substituted analogues of the compounds of the formulas 9 and 19, the synthesis of which is according to Reaction schemes A and B are made.

13, 14-dihydro-15-lower-alkyl-15-substit.-tt! -Pentanorprostaglandins are available from the appropriately substituted precusors via reaction scheme E.

409810/1150

Schcm-a F.

Sf

OH

THPO

COH

H '-OTHP

OH

THPO

--OTHP

22nd

21

THPO '

00H

(CH ₂ ) _n -Ar IT "ΌΤΗΡ

23

409810/1150

2 3J / .9 / .5

In the foregoing procedures in which purification by chromatography is desired, suitable chromatographic supports include neutral alumina and silica gel, with silica gel having a particle size of 0.25-0.07 mm (60-200 mesh) being generally preferred. The chromatography is suitably carried out in a reaction inert solvent such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and η-hexane, as illustrated in the examples below.

In numerous in vivo and in vitro tests it has been proven that the new prostaglandin analogs have physiological activities similar to those of the natural ones Prostaglandins (as described above) are comparable. These tests include the investigation, among other things the effect on the isolated smooth muscle from the guinea pig uterus, guinea pig ileum and rat uterus the inhibitory effect on norepinephrine-induced .. lipolysis on isolated rat fat cells, the inhibitory effect on Histamine-induced bronchospasm in guinea pigs, the effect on blood pressure in dogs, the inhibitory effect on stress-induced ulceration in rats, the inhibitory effect on pentagastrin-induced hydrochloric acid secretion in rats and dogs and the inhibitory effect on ADP- or collagen-induced aggregation of platelets.

The physiological effects observed in these tests allow the test compounds to be used in the treatment of numerous natural and pathological conditions. Such certain Uses include antihypertensive effective

0 9 8 1 0/1 1 5 0 0 ~ 'O ^ AL INSPECTED

ability, effectiveness as a bronchodilator, effectiveness as Vasodilator, antithrombogenic effect, antiarrhythmic Efficacy, cardiac stimulating effectiveness, antiulcerogenic effectiveness, effectiveness on the smooth muscles / Valuable as a contraceptive, for inducing labor and as an abortion agent_7 and antifertilitive effectiveness above one, not the smooth one

affect
Musculature flowing mechanism, e.g. the luteolytic mechanism. Compared with the corresponding naturally occurring prostaglandins, the new compounds according to the invention have selective efficacy profiles and in many cases have a longer duration of action. A main example of the therapeutic importance of these prostaglandin analogs is the effectiveness of 13,14-dihydro-16-phenyl-ur-tetranorprostaglandin-E ₂ , which compared to PGEp itself has a greatly improved hypotensive effectiveness and duration of action. At the same time, the smooth muscle stimulating effectiveness is markedly reduced in comparison with PGEp.

The other 13, 14-dihydro-16-Arsubstit.-PGE ₂ "analogues _{show in the same way;} the new 15-substit. -Ω-pentanorprostaglandins of the Α series and the 16-Ar-substit.-PGE _Q PGE ₂ ) and 16-Ar-substit.-PGEg prostaglandins of the present invention, and particularly 16-α-thienyla-tetranor-PGEp and lo-β-naphthyl-u'-tetranor-PGEp, are desirable hypotensive potency. In addition, the 16- Arsubstit.-prostaglandins of the E and Α series are particularly effective in inhibiting gastric acid secretion. When administered orally and as a consequence thereof, they are valuable for the treatment of gastric ulcers or gastric hyperactivity. The 15-substit.-13,14-dihydro-m -pentanor-

4 0 9 8 T 0/1 1 5 0 AA- SMSPECTED

2 YY 4 9 U 5

prostaglandins of the present invention are particularly valuable because of their increased selectivity. For example, there l6-Ar-5ubstit.-U? -Tetranor-13, l ⁱ 4-dihydro-PGEP a highly selective hypotensive activity, while the 17-ArsubstLt. - u ^w Tris-nor-13, l ^ ~ dihydro derivatives have a highly selective activity on the smooth muscles. Furthermore, the 15-Ar-substit according to the invention. -U) -Pentanor-13, l4-dihydro-E2-prostaglandir.e a highly selective activity as a bronchodilator.

17-Furyl-ü ⁱ -trisnorprostaglandin-Fp and -E ~ show excellent smooth muscle stimulating efficacy, which makes them valuable for fertility control, for abortion and induction of labor, while at the same time they have reduced effects on blood pressure. Furthermore, show the other new 17-substit. U · -trisnorprostaglandins of the E and F series of the present invention, ie 17,13, 19 and 20 Ar-substit. Prostaglandins of the E and F series of the present invention Invention of desirable smooth muscle stimulating efficacy. The new 15-Ar-substit.- tu-pentanorprostaglandins of the F-series are also valuable for inducing labor and abortions and for fertility control, while the 16-Ar-substit.-u-tetranorprostaglandins of the P-series are valuable for those Are fertility control via a mechanism that does not affect smooth muscle tissue.

Furthermore, Lö-thienyl-cu-tetranorprostaglandin-E ^ and 16-p-Biph.enyl-tr-tetranorprostaglandin-E2 show high effectiveness as bronchodilators with reduced effectiveness on the non-vascular smooth muscles. The other 16-Ar-substit.-O ^w tetranorprostaglandin-

409810/1150 ORIGINAL INSPECTED

-H ₇ -

E ₁ and EP analogs of the present invention exhibit desirable bronchodilator activity.

The novel 15-lower alkyl compounds of the present invention have the same profile of activity as that Prostaglandin analogs of the present invention in which R represents a hydrogen atom 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 present compounds in which R is a hydrogen atom is greatly increased. Hence are in such Cases where this is essential, the 15-lower-* -alkyl compounds usually preferred.

All prostaglandins according to the invention are also valuable in the form of their salts with pharmaceutically acceptable cations. Furthermore, the esters share at the C ", C. and C ₁ -, in which the acyl radical is a lower alkanoyl radical, a formyl radical or a benzoyl radical, in the same way the usability of the prostaglandins from which they are derived. In some cases, the use of these esters is accompanied by minor undesirable side effects compared to the corresponding non-esterified prostaglandins. Those skilled in the art understand that these compounds include the monoesters in the case of Α-series prostaglandins, diesters in the case of Ε-series prostaglandins and triesters in the case of F-series prostaglandins.

Such esters are readily prepared by methods known to those skilled in the art.

10/1150

- MS -

The prostaglandin analogs, which have a ß-hydroxyl _{residue on C-atom 15 and a C lc} -low.-alkyl group, have an activity that corresponds to that of their epimers. In some cases, however, the selectivity exhibited by these compounds exceeds that of the epimeric compounds.

The new compounds according to the invention can in a Variety of pharmaceutical preparations containing the compound or a pharmaceutically acceptable salt thereof, and they can be used in the same way as the natural prostaglandins on one Variety of routes, such as intravenous, extra- and intra-amniotic, Orally and topically, including aerosol, intravaginally and intranasally.

For the induction of abortions, an aqueous suspension of a 17-substitute-UJ trinorprostaglandirader E or F series or tablets can be administered at oral doses of about 1 to 20 mg, with 1 to 7 doses being used per day. For intravaginal administration, lactose tablets or an impregnated tampon of the same agent are a suitable formulation. Doses suitable for such uses are from about 1 to 20 mg / dose for the 17-α-furyl-PGF4 derivative or from about 10 to 200 mg / Dose for the 17-a-furyl-PGE _? - Derivative, using 1-7 doses.

Alternatively, the 17-substit.-Iu-trisnorprostaglandins can be administered intra-amniotic at doses of 5 to ¹ JO mg, 1 to 5 times per day, or intravenously at doses of 5 to 500 μg / min. for a period of about

4 09810/1150

Infused for 24 hours.

Alternatively, the 17-substit. -tn-trisnorprostaglandins by extra-amniotic infusion at doses from 0.5 to 50 µg / min. for a period of 1 to 24 Hours to be administered.

409810/1150

~ 50- 2 J 3 A 9 4 5

The 17, 18, 19 and 20 Ar substituted prostaglandin analogs of the present invention can also be used as labor inducers. For this purpose a Ethanol salt solution of a 17-substituted ω-Trisnor-PGF or -PGEp derivatives as an intravenous infusion in a Amount from about 0.05 to 50 yug /. '! In. during a period of about 1 to 10 hours or orally in the form of capsules, tablets, solutions or suspensions in doses of 0.005 up to 5 mg can be used, 1 to 7 doses being used.

To achieve a bronchodilator, a suitable dosage form consists of an aqueous ethanolic solution of 16-Ar-substituted Tetranor-PGE .. or -PGE_, the Rl * aerosol using fluorinated hydrocarbons as propellant in an amount of about 3 to 500% Dose with up to 16 doses per day is used. To improve keeping the nose open, a suitable dosage form is an aqueous solution of 16-Ar-substituted Tetranor-PGE ^ or -PGE _? , which is used in the form of nasal drops in an amount of 1 to 100 iig / dose as required.

The 16-Ar-substituted u) -Tetranorprostaglandins der Ep series, which are 13,1 ^ dihydro Ep and Ap series useful anti-ulcer agents. For the treatment of gastric ulcers, these agents are conveniently administered orally in the form of aqueous suspensions, solutions or preferably in the form of capsules or tablets with doses of 0.001 to 0.10 mg / kg per dose with up to 12 doses per Administered day.

the above 15-substituted it> -pentanorprostaglandin

409810/1150

the "!" series can be synthesized in the manner outlined in Scheme F. In the first Stage is the hemiacetal U with the 4-carbohydroxy-n-butyl-triphenylphosphonium bromide implemented, whereby the intermediate product W arises.

In stage W- ^ X there is a treatment with diazomethane, then a treatment with acetic anhydride and pyridine, then a reduction with palladium on charcoal in a mixture of ethanol and acetic acid, and finally an oxidation with dimethyl sulfoxide, Dicyclohexylcarbodiimide and pyridinium trifluoroacetate.

In stage X- > Y , treatment with the sodium or lithium salt of a suitable phosphonate (2) and purification by column chromatography takes place.

In the Y-> Z stage, a reduction with zinc borohydride takes place or lithium triethylborohydride, hydrolysis and separation of the C, epimers by column chromatography .

Treatment with dihydropyran takes place in stage Z-> Zl with an acid catalyst and then mild hydrolysis with an aqueous base.

In the stage Z1- * PGF ₁ ^, PGE ₁ and PGA ₁ as 15-substituted «/ -Pentanorprostaglandins the same process is carried out that has already been described above for the and PGA series.

409810/1150

ORIGINAL INSPECTED

O = O '

ΙΓ \

O OJ

te

(U

O O O = O.

in

VO O OJ

S--

PI

409810/1

S CHEMA F (Ports.) '

-P-CD

THPO- '

OTHP

15-substituted

, PGE ₁ and

T ¹ O OJ U)

All of the new compounds of the present invention are also useful in the form of their CL esters. examples for preferred esters are those in which the esterification group is an alkyl group with 1 to 12 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms, an aralkyl group with 7 to 9 carbon atoms, a phenyl or ß-naphthyl group or a monosubstituted phenyl

is"

or ß-naphthyl group / those as substituents a halogen atom, a lower alkyl group, a lower alkoxy group or contains a phenyl group. The p-biphenyl esters are particularly preferred. These special esters are valuable because they are very easy to crystallize and you can get them in this way in a very pure and excellent form May gain yield while prostaglandins are generally very difficult to crystallize in general. The new p-biphenyl esters have the activities of the corresponding new parent compounds and have moreover the advantage of a flattened effectiveness curve over time, which is often an advantage. she also have decreased gastrointestinal smooth muscle effects, such as by diminishing of side effects such as diarrhea. The new compounds in the form of the p-phenylphenol ester are after Process prepared already in the above reaction schemes for corresponding intermediates with suitable substituents have been described. For example, the compounds 9 and 10 with p-phenylphenol esterified in the presence of dicyclohexylcarbodiimide to give the p-phenylphenol ester of precursors for 15-tü-pentanorprostaglandin-p-phenylphenol ester to obtain. This can be done via levels 9-12, 10-11 and 11-12 in the above called new p-phenylphenol ester.

409810/1150

Furthermore, the compounds 11, 12 and 15 can also be esterified with p-phenylphenol and dicyclohexylcarbodiimide in order to obtain the desired esters. The p-biphenyl ester part can also be introduced at an earlier stage, in which a tri-p-phenylphenol-orthoester-phosphonium bromide of the formula / (C ₆ H), P ^ H ₂ CH ₂ CH ₂ CH ₂ C (OR) ₃ 7Br®, in which R is p-phenylphenol, was used to obtain the corresponding orthoester of 9, which can be converted into the desired p-phenylphenol esters via steps 9-15.

The 15-substituted W-pentanorprostaglandins of the Α series as well as the l6-Ar-substituted W-tetranorprostaglandins of the E ₁ -JE ₂ -JEq- and the 13, l ¹ -dehydro-E ₂ - and -A ₂ series are useful antihypertensive agents (such as the 15-Ar-substituted W-pentanorprostaglandins of the Ε series). For the treatment of high blood pressure, these drugs can conveniently be administered as intravenous injection in doses of about 0.5 to 10 µg / kg or preferably in the form of capsules or tablets with doses of 0.005 to 0.5 mg / kg / day.

To any of the above dosage forms or any Of the numerous other possible forms, many inert diluents, excipients, can be used or carrier substances are used. Such substances include e.g. water, ethanol, gelatin, Lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum resins, polyalkylene glycols, petrolatum, cholesterol and other known carriers for Medication. If desired, these pharmaceutical preparations can use auxiliaries, such as preservatives,

409810/1 150

Contain wetting agents, stabilizers or other therapeutic agents such as antibiotics.

The biological data given below were obtained using the following test methods:

Histamine-induced bronchoconstriction - Guinea pigs

Bronchodilatation efficacies were determined in conscious female Reed-Willet-Guinea pigs (200-250 g) that had not been fed overnight by the method of Van Arman, Miller and O'Malley (SC-10,049: "A catacholamine bronchodilator and hyperglycemic agent ", J. Pharmacol. Exp. Ther., 133: 90-97 (1961). At a preselected interval (pre-excitation interval) after oral or aerosol administration of water or the test drug in water, each animal was excited with histamine aerosol as follows: A 0.4% aqueous solution of histamine was placed in a nebulizer (Vaponephrine Standard Nebulizer from Vaponephrine Company, Edison, New Jersey) and sprayed into an enclosed 20.32 χ 20.32 x 30.48 cm clear plastic container for ^{one minute under an air pressure of 0.42 kg / cm 2.} Immediately thereafter, the guinea pig was placed in the container. The respiratory status (a reflection of the bronchial constriction) of the guinea pig after one minute in the container was determined as follows: 0 = normal breathing, 1 = somewhat increased breathing, 2 = laborious breathing, 3 = very laborious breathing and ataxia, 4 = unconsciousness . The data for a control group and a test group (8 animals per group) were summed and compared, and

A0981C / 1 150

- sr -

the difference was expressed as the percentage protection. · Blood pressure - dog

Hybrid dogs were given 30 mg / kg / i.v. anesthetized on sodium pentobarbitol. Then the femoral artery blood pressure became measured with a mercury manometer and recorded on paper (smoked paper), and the pulse rate was determined from electrocardiograms, the nit subcutaneous Electrodes were recorded. The drugs were administered through a cannula into a femoral vein.

Isolated gastrointestinal and reproductive tissue

All measurements were made in a 2 ml tissue bath using a Phipps-Bird Linear Motion Transducer Model ST-2 made. The fabrics were allowed to respond to a stable maximum, at which point they were washed and let her get back on the baseline condition. All determinations represent an average of Represent at least 3 individual tissues at each dose indicated. Data for analogs were with dose-response obtained for a natural prostaglandin in a given tissue. For purposes of For efficacy comparisons, a standard dose of natural prostaglandin was selected and all responses were calculated as a percentage of their response. Further data were given as the minimum effective dose (MED) and as Consistent Effective Dose (IBD) recorded to record compound detection levels for each tissue. A standard dose equivalent (SED) was determined. This value was called the amount of compound (ng / ml) which gave a response similar to the response of the tissue to a given dose of the standard

03810/11 5 0

Prostaglandins corresponded.

Ileum - Guinea Pig

The ileum sezi ° rc was formed from 200-300 g male Guinea pigs that had been killed by neck dislocation. The tissue was suspended in 2 ml of Tyrode's solution (Haie, Biol. Lab Data, p. 92, 1958) at 37.degree. 30 ng / ml PGE and / or 30 ng / ml PGF ^. were used to demonstrate tissue effectiveness.

Uterus - Guinea Pig

(Clegg, Hopkinson and Pickles, J. Physiol, 167: 1, 1963)

Nulliparous females (300-400 g) that were not in heat were sacrificed by neck dislocation. The dissected uteri were incubated in 2 ml of a modified Krebs solution at 37 ° C. The uterine effectiveness was made using 1.0 ng / ml PGEp and / or 10 ng / ml PGFp-. proven.

The invention is illustrated by the following examples in which all temperatures are expressed in C, all melting and boiling points are uncorrected, and all biological test data are expressed as% potency of PGEp or given at the same level (ie PGEp = 100) unless otherwise stated i't.

409810/1150

example 1 Dimethyl 2-oxo-3-phenylpropylphosphonate (2a)

A solution of 6.2 g (50 mmol) of dimethyl methylphosphonate (Aldrich) in 125 ml of dry tetrahydrofuran was cooled in a dry nitrogen atmosphere to -78 ⁰ C. The stirred phosphonate solution was added dropwise over 18 minutes at such a rate that the reaction temperature never exceeded, offset -65 ⁰ C with 21 ml of 2.37 m n-butyl lithium in hexane (Alfa Inorganics, Inc.). After the mixture for another 5 minutes was stirred at -78 ⁰ C long, were added at such a rate over the course of 20 minutes was added dropwise 7.5 g (50.0 mmol) of methyl phenylacetate that the reaction temperature below-half of - 7O ⁰ C was held. After 3.5 hours at -78 ⁰ C, the reaction mixture was warmed to ambient temperature, neutralized with 6 ml of acetic acid and evaporated by rotary evaporation (water vapor) to a white gel. The gelatinous material was taken up in 75 ml of water, the aqueous phase was extracted 3 times with 100 ml of chloroform each time and the combined organic extracts were washed with 50 ml of water; over MgSO ₁ , dried and concentrated to a crude residue (steam) and distilled, giving ^{3.5 g of the title compound (2a) at a boiling point of 13 1} I-135 ° C. and a pressure <0.1 ram, which corresponded to a yield of 29 %.

The NMR spectrum (CDCI,) showed a doublet centered

at 3.72S (J = 11.5 cps, 6H) for (CH O) -P-, one cublet

- ⁵ OO

centered at $ 3.14 (J = 23 cps, 2H) for -C-CH-P-, a

0 ^ά

Singlet at 3.88 S (2H) for -CH ₃ -C- and a broad one

09810/1150

- to -

Singlet at 7.22, f (5H) for C ₆ H ₅ -.

In the manner described above, dimethyl 2-0x0-3- (p-chlorophenyl) propylphosphonate, dimethyl 2-0x0-3- (m-phenylphenyl) propylphosphonate and dimethyl 2-oxo-3- (o-trifluoromethylphenyl ) propylphosphonate can be prepared from the appropriately substituted methyl phenyl acetates. These products are suitable for conversion into the corresponding 16-substituted U) - tetranorprostaglandins according to the reaction sequence described below.

Example 2

2-Z * 3 <X.-p-Pheny lbenzoyloxy-5a-hydr oxy-2ß- (3-0x0 - ^ - trans-1-buten-1-yl) -cyclopent-10-O-yl / acetic acid- «V lactone (3a)

Method A:

3.4 g of dimethyl 2-oxo-3-phenylpropylphosphonate (2a) (14 j2 mmol) in 200 ml of anhydrous ether were added at room temperature in a dry nitrogen atmosphere with 5.0 ml (12.5 mmol) of 2.5 m n- Butyllithium taped in n-hexane (Alfa Inorganics Inc.). After the mixture had been stirred for 5 minutes, an additional 100 ml of anhydrous ether and then 3.85 g (11 mmol) of 2- / 30t-p-phenylbenzoyloxy-5aC-hydroxy-2ß-formylcyclopentan-10L-yl7-acetic acid were added. </ - lactone added in one serving and 50 ml of anhydrous ether. After 35 minutes the reaction mixture was treated with 5 ml of glacial acetic acid, H χ with 100 ml of saturated sodium carbonate solution, Z χ with 100 ml of water and 1 χ with 100 ml of saturated sodium chloride solution, _{dried over.-IgSG 11} and evaporated, whereby after column

4098 * 0/1150

Chromatography over silica gel (Baker, particle size 0.074-0.248 mm (60-200 mesh)) 2.908 g of the title compound (3a) were obtained in the form of a foam with a melting point of 107-108 ° C. (ether), which corresponds to a yield of 57 % is equivalent to.

Method B:

2.9 g (12 m mol) of dimethyr ^ -oxo ^ -phenylpropylphosphonate (2a) in 20 ml of anhydrous dimethoxyethane were in a dry nitrogen atmosphere with 4.7 ml (11 mmoles) of 2.34 m n-buty! Lithium in n-Hexane (Alfa Inorganics Inc). After the mixture had been stirred for 40 minutes, 3.5 g (10 mmol) of 2- / 30C-p-phenylbenzoyloxy-50C-hydroxy-2β-formylcyclopentanlOL-ylJ-acetic acid-Tf-lactone were added in one portion, followed by 15 ml anhydrous 1,2-dimethoxyethane added. After 30 minutes the reaction mixture with 1 mL of glacial acetic acid was added, filtered, 2 χ with 20 ml of saturated sodium bicarbonate solution and 1 χ with 20 ml of saturated brine, dried over Na ₀ SOW dried and evaporated to give after column chromatography on silica gel (Baker, particle size 0, 07 ¹ S - 0.248 mm) 2 g of the fitness compound (3a) were obtained in the form of a foam, which corresponds to a yield of 43 %

The IR spectrum (CHCl ^) of the product (3a) showed

"" "- 1 ~ 1

Absorption bands at 1775 cm (strong) 1715 _cm-s (strong), I675 cm (moderate), and 1630 cn ~ ^x (moderate), the carbonyl

- 1 groups were attributable, and at 973 cm for the

trans-double bond, the NMR spectrum (CDCl,) showed a multiplet at 7.23-8.18g (9H) for the p-biphenyl group, a doublet of doublets centered at 6.75 4 ( ^1H , J = 16 cps) and a doublet centered at 6.27 6 (IH, J = 16 cps) for the olefinic protons, a broad singlet at

409810/1 150

7.20 (5H) for C ₆ H ₅ -CH ₂ -C-, a singlet at 3.8Ü S (2H)

for C ₆ H ₅ -CH ₂ -C and multiplets at * J, 90 - 5.50 8 (2H)
and 2.21-3.07 S (6H) for the remaining protons.

Example 3

2- / 3gC-P "phenylbenzoyloxy-5oC-hydroxy-2ß- Qd phenyl-trans-l-butene-1-yp-cyclopent-loc-y ^ -acetic acid i? -Lac ton ( ¹ yes) and 2- / 3oC -p-phenylbenzoyloxy-5 (X.-hydroxy-2ß- (3ß-hydroxy- * i-phenyl-tra n s-l-buten-l-yl) -cyclopent-

(5a)

A solution of 2908 mg (6.2 mmol) 2- / 30C-p-phenylbenzoyloxy-5ot-hydroxy-2ii- (3-0x0-4-phenyl-trans-1-buten-1-yl) -cyclopent-lo ^ -ylj-acetic acid-'y-lactone (3a) in 30 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere was added dropwise at ambient temperature with 2.0 ml of a? 1.0 m solution of zinc borohydride in 1,2-Dimethoxj'äthan added. After da3 mixture was stirred at 0 ⁰ C for 2 hours, it was treated dropwise with a saturated Natriumhitartratlösung was until the evolution of hydrogen finished, the reaction mixture was stirred for a further 5 minutes and then treated with 250 ml dry methylene chloride. After drying over 1MgSO ₁ and concentrating (water vapor), the semisolid material obtained was purified by column chromatography over silica gel (Baker "Analyzed", particle size 0.07 ¹ I 0.248 mm) using ether as the eluent. After less polar impurities had been eluted, a fraction of 658 mg of the title compound ( ¹ Ia) and a fraction of ² JBO mg of a mixture were obtained

409810/1150

and (5a) and finally a fraction of 671 mg of the Title compound (5a) obtained.

The IR spectrum (CHCl,) of (4a) and (5a) was strong

-1 carbonyl absorptions at 1770 and 1715 cm and one

mm Λ

Absorption at 970 cm for the trans double bond.

The NMR spectrum (CDCl,) ⁽¹ Ia) and agreed (5a) coincide

with the given structure.

example

2- £ 3oi, 5oi-dihydroxy-2ß- (30C-hydroxy-4-phenyl-trans-lbuten-1-yl) -cyclopent-1QC-yl / -e5sigsäure- ^ - lactone (6a)

A heterogeneous mixture of 658 mg (1.35 mmol) 2- / 3cfC-p-phenylbenz "oyloxy-5oC-hydroxy-2β- (3 (Ä -hydoxy-4-phenyl-transl-buten-1-yl ) -cyclopent-lQL-yl7-esSigsäure- ^ - lactone ( ^l '<&) ₃ 7.1 ml of absolute methanol and 188 mg of finely powdered, anhydrous potassium carbonate were stirred for 1 hour at room temperature and then cooled ^{to 0 ° C.} the cooled solution was treated with 2.8 ml (2.8 mmol) of a 1.0 η aqueous hydrochloric acid. After the mixture for another 10 minutes was stirred at 0 ⁰ C for, t ^ ere 5 ml of water are added, whereby Methyl p-phenyl benzoate formed, which was collected by filtration, the filtrate was saturated with solid sodium chloride, extracted 4 times with 10 ml of methyl acetate, the combined organic extracts were washed with 10 ml of saturated sodium bicarbonate solution, over MgSO ₁₁ dried and concentrated / whereby 38I mg of the title compound (ca) were obtained in the form of a viscous oil,

The IR spectrum (CHCl,) showed a strong absorption at

t, 0 9 3 1 0/1 1 S 0

1770 cm "for the Laeton carbonyl and moderate absorption at 965 cm for the trans double bond.

Example 5

2- / 5oc »5oC-dihydroxy-2ß- (3ß-hydroxy- * 4-phenyl-trans-lbutene-1-yD-cyclopent-loC-ylJ-acetic acid-'V-lactone (6 * a)

A heterogeneous mixture of 761 mg (1.57 mmol) 2- / 3oC-p-phenylbenzoyloxy-5fC-hydroxy-2ß- (3ß-hydroxy-4-phenyl-transl-buten-1-yl) -cyclopent-loC-yl7 Acetic acid / γ-lactone (5a), 7.1 ml of absolute methanol and 216 mg of finely powdered, anhydrous potassium carbonate were stirred for 1 hour at room temperature and then cooled ^{to 0 ° C.} 3.2 ml (3.2 mmol) of 1.0 η aqueous hydrochloric acid was added to the cooled solution. After the mixture had been stirred for a further 10 minutes at ⁰ ° C., 5 ml of water were added, with methyl p-phenylbenzoate being formed, which was collected by filtration. The filtrate was saturated with solid sodium chloride and extracted with 10 ml of ethyl acetate h χ. The combined organic extracts were washed with 10 ml of saturated sodium bicarbonate solution, over MgSO 4. dried and concentrated, with 382 mg of the title compound * (b'a) being obtained in the form of a viscous oil, which corresponded to a yield of 85 % .

The IR spectrum (CHCl3) showed a strong absorption at 1770 cm for the lactone carbonyl and a moderate absorption at 965 cm " ¹ for the trans double bond.

/. Ö 9 8 1 C / 1 1 5 0

Example 6

2- / 5 Qi-Hydroxy-3 <x- (tetrahydropyran-2-yloxy) -2ft- (30C-Ztetrahydropyran-2-yloxyJ? -4-phenyl-tran3-l-butenl-yp-cyclopent-JgC-ylJ -acetic acid-qf-laeton (7a)

A solution of 38 mg (1.33 mmol) 2- / 3of, 5oC-Dihyäroxy-2ß- (3et-hydroxy-4-phenyl-trans-l-buten-yl) -cyelopent-iaC-yl7-es3igsäure-iy- lactone (6a) in 5 ml of anhydrous methylene chloride and 0.4 ml of 2 _S 3-dihydropyran were treated with 5 mg of p-toluenesulfonic acid monohydrate ^{at 0 ° C. in a dry nitrogen atmosphere.} After the mixture was stirred for 15 minutes, it was combined with 100 ml of ether. The ether solution was washed 1 with 15 ml of saturated sodium bicarbonate solution and then 1 χ with 15 ml of saturated sodium chloride solution, over MgSOj. dried and concentrated to give 615 mg of the crude title compound (7a), which corresponded to a yield of> 100 % .

The product (7a) of this example, according to the procedures of Examples 16, IB and 20-24 in the 13 l ⁱ i-dihydro-16-phenyl-tf-tetranorprostaglandine of the A, E or F-series be converted.

Example 7

2- £ 5oC-Hydroxy-3 <* - (tet rahydropy ran-gy .! Oxy) -2fi ^ (J ß - / tetra hydropyran-2 * -; / lcxy7- ⁱ l-phen, yi-trans-l- bute? i ~ l- »yl2-cyclO" pent-3flC-y3j - 3ssi ^ acid- <f-lactone (7'a)

A solution of 382 mg (0.71 mmol) 2- / 35iC, 5gC "dihydroxy-2ß- (3ß-hydroxy-4-phenyl-trans-1-buten-yl) -cyclopenfc-loC-yl7-acetic acid-c ^ -Lactone (6'a} in 5 ml of anhydrous methylene

409810/1150

chloride and 0.4 ml of 2,3-dihydropyran were mixed with 5 mg of p-toluene-3ulfonic acid monohydrate ^{at 0 ° C. in a dry nitrogen atmosphere.} After the mixture was stirred for 15 minutes, it was combined with 100 ml of ether. The ether solution was washed 1 with 15 ml of saturated sodium bicarbonate solution and then 1 with 15 ml of saturated sodium chloride solution, _{dried over MgSO 11} and concentrated to give 621 mg of the crude title compound (7 "a), which corresponded to a yield of> 100 % .

The NMR spectrum (CDCI,) of (7a) and (7'a) showed a multiplet at $ 5.30-5.62 (2H) for the olefinic protons, a singlet at 7.2 S (5H) for the Phenyl protanes and multiplets at £ 4.36-5.18 (4H), £ 3.22 & 4.24 (9H) and $ 1.18-2.92 (16H) for the remaining protons. The IR spectrum (CPlCl-,) showed a moderate absorption at 970 cm for the trahs double bond.

Example 8

2-Z5oC-Hydroxy-3 ^ - (tetrahydropyran -2- y loxy) -2B - (3oC-Ztetrahydropyran-2-yloxy-7-4 -phenyl- trans-1-Duten-1-yl) -cyclo- . pent-ltt-ylj-ac etaldeh yd-tf-ha lb acetal (8a)

A solution of 605 mg (1.33 mmoles) 2 - / "5 <rt, -Hydroxy-3oC- (tetrahydropyran-2-yloxy} -2ß- (3c <r £ tetrahydropyran-2-yloxyJ-4-pheny 1- trans -! - buten-1-y I) -eye lopent-1 «Cy l? -acetic acid y-iactone (7a) in 8 ml of dry toluene was cooled in a dry nitrogen atmosphere to -78 ° C. This cooled solution became in the course of 15 minutes dropwise at such a rate that the internal temperature rose never -65 ⁰ C, with 3.0 ml of a 20% - solution of diisobutylaluminum hydride | offset in η-hexane (Alfa Inorganics, Inc.) After the mixture. had been stirred for a further 45 minutes at -78 ^{0 C, water was}

409810/1150

free methanol was added until the evolution of gas ceased, and the reaction mixture was warmed to room temperature. 100 ml of ether were added to the reaction mixture, and U. χ was washed with 20 ml of a 50% sodium potassium tartrate solution over Na ₂ SO ₁ . dried and concentrated, whereby 615 mg of the title compound (8a) were obtained, which corresponded to a 100% yield.

Example 9

2-Z "5 * -Hydroxy-3 <* .- (tetrahydropyran-2-yloxy) -2ß- (3ß- £ tetrahyropyran-2-yloxy _i 7 - ^ - phenyl-trans-1-buten-1- yl) -cy clopent-ld-yjj-acetaldehyde-qf-hemiacetal (8 * a)

A solution of 621 mg (1.3 ¹ J mmol) 2- / ~ 50l-hydroxy-3cC- (tetrahydropyran-2-yloxy) -2ß- (3ß- / tetrahydropyran-2-yloxyJ ^ -iJ-phenyl-trans- 1-buten-1-yD-cyclopent-loC-yl? -acetic acid- <y-lactone (7'a) in 8 ml of dry toluene was cooled to -780 ° C. in a dry nitrogen atmosphere and this cooled solution was dissolved over the course of 15 minutes dropwise at such a rate that the internal temperature never rose above -65 ⁰ C, treated with 3.0 ml of a 20% solution of diisobutylaluminum hydride in η-hexane (Alfa Inorganics). After the mixture more H for 5 minutes at -78 ⁰ C was stirred, it was added with wassserfreiem methanol until gas evolution ceased and then heated to room temperature. the reaction mixture was treated with 100 ml ether, 4 χ with 20 ml of a 50% sodium potassium tartrate solution, _{dried over Na 3} SO ₁₄ and concentrated, whereby 621 mg of the title ^{compound (8!} a) were obtained, which corresponds to a 100% yield H.

4098 10/1150

Example 10

901-Hydroxy-lKX., 15oC-bis (tetrahydropyran-2-yloxy) -16-phenyl ~ cis-5-trans-13-W-tetranor-prostadienoic acid (9a)

A solution of 1760 mg (4.0 mmol) of (4-carbohydroxy-nbutyl) triphenylphosphonium bromide in 5.0 ml of dry dimethyl sulfoxide in a dry nitrogen atmosphere was mixed with 3.2 ml (70 mmol) of a 2.2 M solution of sodium methylsulfinyl methide in dimethyl sulfoxide was added.-This red ylide solution was added dropwise over the course of 20 minutes with a solution of 615 mg (1.3 ** mmol) 2- / 5c (-Hydroxy-3tf- (tetrahydropyran-2-yloxy) - 2ß- (3ot- / tetra-hydropyran ^ -yloxyy - ^ - phenyl-trans-1-buten-1-yD-cyclopent-lei-yl / -acetaldehyde- <y-half acetal (8a) in 5.0 ml dry dimethyl sulfoxide After the mixture was stirred for an additional 2 hours at room temperature, it was poured onto ice water, the aqueous basic solution was washed 2 with 20 ml of ethyl acetate and acidified to pH about 3 with 10% aqueous hydrochloric acid The acidified solution was extracted 3 with 20 ml of ethyl acetate, and the combined organic extracts were 1 χ with 10 ml of water Washed, _{dried over MgSOj 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 "Analyzed", particle size 0.07 ¹ l - 0.2 ^ 8 mm) using ethyl acetate as the eluent. After removing high R n impurities, 150 mg of the title compound (9a) was collected.

Example 11

9q (-Hydroxy-lloi _> 15ß-bi3- (tetrahydropyran - 2 "yloxy) -l6» phenyl-cis-5-tran3-13 "ft> -tetranor-pro3tadienic acid (9 * a)

A solution of 176O mg (4.0 mmol) of (4-carbohydroxy-nbutyl) -triphenylphosphoniurabromide in 5 »0 ml of dry dimethyl sulfoxide in a dry nitrogen atmosphere was with 3 _S 2 ml (7.0 mmol) of a 2.2 ra solution of Sodium methylsulfinyl methide is added to dimethyl sulfoxide. This red ylide solution was added dropwise over 20 minutes with a solution of 621 mg (1.34 mmol) of 2-Z50i-hydroxy-3oC- (tetrahydropyran-2-yloxy) -2β ~ C5β- / tetrahydropyran-2-yloxy _< 7-4-phenyl-trans-1-buten-1-yi) -cyclopent-lot-yl7-acetaldehyde- «y-hemiacetal (8'a) was added to 5» 0 ml of dry dimethyl sulfoxide. After the reaction mixture was stirred for an additional 2 hours at room temperature, it was poured onto ice water. The aqueous basic solution was washed 2 with 20 ml of ethyl acetate and acidified to a pH of about 3 with 10 strength aqueous hydrochloric acid. The acidified solution was extracted 3 with 20 inl ethyl acetate, and the combined organic extracts were washed 1 : c with 10 ml water, dried over MgSOj and evaporated to a solid residue. The solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography over silica gel (Baker "An &lyzed", particle size 0.074-0.248 rom) using stylacetate as the solvent, Naefc removal of impurities with a high Ep-W'j-rt -wurbe 300 mg öer title compound (9 ^f a) collected.

T 0/116

Example 12

9 —Oxo- HOC, 15 <J-bis- (tetrahydropyran-2-y loxy) - 16-pheny 1-ci3-5-tran8-13 - ^ "tetranoi * -pro3tadienaic acid (IQa)

A cooled under nitrogen to -10 ⁰ C solution of 2300 rag (1.24 mmol) ^ -hydroxy-lloCjlSoC-bis-itetrahydropyran-2-yloxy) -l £> -phenyl-cis ~ 5-trans-13-fc * Tetranorprostadienäure (9a) in 50 ml acetone ("reagent grade") was added dropwise with 11.3 ml (29.6 mmol) Jones ¹ reagent. After the reaction mixture had been kept at -10 ⁰ C for 20 minutes, it was treated with 10 ml of 2-propanol and further stirred for 5 minutes, after which it combined with 300 ml of ethyl acetate, washed twice 3 using 50 mL of water, dried over MgSO ₁ . was dried and concentrated to obtain 1983 mg of the title compound (10a),

Example 13

15fi > - big- (tetrahydropyran-2-y 1 oxy) -l6-phenyl cis-5-trans-13 -m- tetranor-prostadien a acid (lO'a)

A solution of 300 mg (0.551 mmol) of ^ -hydroxy-llPC ^ ß-bis-Ctetrabydropyran-2-yloxy) -l6-phenyl ~ ci3 ~ 5 ~ tran3-13-itf-teti ', cooled under nitrogen to -10 ° C inorganic pro3tadienoic acid (9'a) in Q., 2 ml of acetone ("reagent grade") was added dropwise with 0.262 ml (0.655 mmol) of Jones' reagent. After the reaction mixture had been kept at -10 ⁰ C for 20 minutes, it was treated with 0.260 ml 2-propanol and stirred for an additional 5 minutes, after which it combined with 75 ml Äthylaeetat, washed 3 x with 10 ml Waseer over MgSQj. has been dried and concentrated,

0 9 810/1150

whereby 220 mg of the title compound (iO'a) were obtained. Example IM

9-Oxo-lla- »15flC-dihydroxy-16-phenyl-cis-5-tran3-13-q> · ' tetranor-prostadic acid (Ha)

A solution of 1637 mg (3.02 mmol) of 9-oxo-110t, 15c (.- bis (tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13 - ^ "'- tetranor-prostadienoic acid (10a) in 20 ml of a mixture of 65 parts of glacial acetic acid and 35 parts of water was stirred for 24 hours under nitrogen at room temperature and then concentrated by rotary evaporation The crude oil obtained was purified by column chromatography over silica gel (Mallinckrodt CC-M, particle size 0.07 ¹ l 0.147 (100-200 mesh)) using ethyl acetate-cyclohexane as the eluent, after eluting less polar impurities, 365 mg of the title compound (Ha) was collected as an oily substance.

Biological effectiveness: guinea pig - uterus 3, Guinea pig - ileum 1, Guinea pig - histamine aerosol test 100, dog - blood pressure 3OQ-4OO.

Example 15

9-Oxo-lloC _> 15ß-dihydroxy-l6-phenyl-cis-5 "tran3-13 - ^ - tetranor-prostadienoic acid (ll'a)

A solution of 220 mg (0.334 mmol) of 9-oxo-lloC, 15ol-bis- {tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13- £ «> tetranor-prostadienoic acid (10'a) in 3.0 ml of a mixture of 65 parts of glacial acetic acid and 35 parts of water was 5 hours

40381.0 / 1

the long stirred under nitrogen at 38 ⁰ C and then concentrated by rotary evaporation. The crude oil obtained was purified by column chromatography over silica gel (Mallinckrodt CC-II, particle size 0.07 ¹ l - 0.1 ^ 7 mm) using ethyl acetate as the eluent. After eluting less polar impurities, 8 mg of the title compound (II'a) were collected in the form of a semi-solid.

Example 16

9oC _t ll (^ ₁ 15oC - trihydroxy-l6-phenyl-cis-5-trans-13 - ^ - tetranor-prostadienoic acid (12a)

A mixture of 0.7 g of 9 <jC ^H ydroxy-LIEC, 15o (-bishydropyran ^ yloxy) -L6-phenyl-cis-5-trans-13 & J-tetranor-prostadienoic acid (9a) and 5 ml of a mixture 65 parts of acetic acid and 35 parts of water were stirred overnight at room temperature under nitrogen and then concentrated under reduced pressure to a viscous oil. The crude product was purified by column chromatography over silica gel (Mallinckrodt CC-O using ethyl acetate as the eluent. By removing less polar impurities, 51 g of the desired title compound (12a) were obtained in the form of a viscous, colorless oil.

The IR spectrum (CHCl -.,; Of the product (12a) showed a strong absorption at 1710 cm for the carbonyl group and a moderate absorption at 970 cm " ¹ for the trans double bond.

The product (12a) obtained above can according to the

Procedure of Example 26 can be converted into 16-phenyl-W-tetranorprostaglandin F ^ r . The product (12a) can also be converted into 16-phenyl-id-tetranor-prostaglandin P _QQC according to the procedure of Example 25.

Example 17

methyl-U-phenyl-trans-l-buten-l-yD-cyclopent-l ^ -y Ijacetic acid-t / -lactone (13a) and 2 - / * 3Q (-p- phenylbenzoyloxy-5oC-hydroxy-2B- (3β ~ hydroxy-30C-methyl-M-'phenyl-tran3-lbuten-1-yl) -cyclopent-loC-yl7-es3igs aure- ^ ~ lactone

A solution of 2908 mg (6.2 mmol) 2- / 3eC-p-phenylbenzoyloxy-5oC-hydroxy-2ß- (3-oxo-ii-phenyl-trans-l-buten-l-yl) -cyclopent-loC- ylT-acetic acid-r ^ -laetone (3a) in 26 ml of anhydrous ether and 20 ml of tetrahydrofuran (distilled from LAH) was added dropwise in a dry nitrogen atmosphere at -78 ° C with 6.8 ml of an O _$ 92 m solution of Methy! lithium mixed in ether (Alfa). After the reaction mixture was stirred for 15 minutes at 78 ° C ^ra, it was treated dropwise with glacial acetic acid was ₅ until the pH is about. 7 The mixture was then diluted with Methylenchicria, and άεαιη was the. Dilute organic solution washed 1 χ with water and 1 with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and concentrated, whereby the epiineren alcohols were obtained.

The crude product was purified by Saulan chromatography over 108 g of silica gel (Baker "Analyzed", particle size ο, Ο7 ⁴ ϊ O, 2 ^J ! -8! Kai using an i? the

40SS10 / 1 150

Title compounds (13a) and (l ^ a) obtained in pure form became.

This material (I ¹ Yes) can be converted to the 15β-methyl-16-phenyl-W-tetranor-prostaglandins of the A-, E- and F-series by following the procedures of Examples 4-16 and 18-26.

Other lower alkyl derivatives of the type (I ¹ ^ a) can be prepared by using a corresponding alkyllithium derivative instead of methyllithium in the above procedure. These derivatives can be converted into the IS-lower alkyl-lo-phenyl-tetranorprostaglandins of the A, E and F series according to the procedures of Examples 3-16 and 18-26.

Example 18

9-Oxo-150C-hydroxy-16-phenyl-cis- 5--4 ^{10> 11} -tran8-13 - »- tetranor- prosfcar.rie n acid (15a)

A solution of 50 mg Methylene chloride and 10 ml of formic acid was
Stirred for 5 hours at room temperature. The reaction mixture was diluted with 50 ml of toluene and evaporated to give the title compound (15a) which
was purified by chromatography.

In the same way, 15-substituted iü-pentanorprostaglandins of the A, A _Q and 13, l * i ~ Pihydro ~ A ₂ series from the corresponding 15-substituted fe) -pentanorprostaglandins of the E ₁ -, Eq and 13, 1 ^ dihydro series can be obtained.

409810/1150

Example 19

Compound (19a) can be prepared by following the procedure of Example 3, using zinc borohydride is replaced by sodium hydride. The connection (19a) can then be converted into compound (24a) by following the procedure of Examples M and 6, which in turn, according to the procedures of Examples 21-24, 16 and 18 into the ^, ^ - dihydro-lo-phenyl-W-tetranorprostaglandins the A, E or F series can be converted.

Example 20

2 ° - £ * 5vi-nyuA ⁱ üxy-3 ^(< - (tetrahydropyran-2-yloxy) -2ß- (3ol ~ £ tetrahydropyran-2-yloxy7 - ^ - phenylbut-1-yl) -cyclopent-loC ~ yl7 -acetic acid - </ - lactone (24a)

A stirred heterogeneous solution of 1.555 g (3 _S 4 mmol) 2- / 5 "-hydroxy-3oi- (tetrahydropyran-2-yloxy) -2ß- (3t (- / ^: betraliydropyran-2-yloxyJ- ⁱ l-phenyl- trans-1-buten-1-yl) -cyclopent-1 <X-yl7-acetic acid-y-lactone (7a) and 300 mg of 5 % palladium on carbon in 35 ml of absolute methanol were hydrogenated for 90 minutes. The reaction mixture was filtered through filter aid and concentrated in vacuo to give 1.457 g of the title compound (24a) »

The IR spectrum (CHCl,) of the product (24a) showed a

- 1

Absorption at 1770 cm for the lactone carbonyl.

Example 21

2- / 5cC-Hydroxy-3oC- (tetrahydropyran-2-yloxy) -2ßhydropyran-2-yloxy7- ⁱ <-phenylbut ~ l-yl) -cyclopent-loC-yl7-acetaldehyde-cy-hemiacetal (25a)

A solution of 1 ^ 57 mg (3.2 mmol) 2 - / * 5cC-hydroxy-3cC- (tetrahydropyran-2-yloxy) -2ß- (3oC-Z ~ tetrahydropyran-2-yloxy_7-Jl-phenylbut-1- yl ^ cyclopent-LCC YLJ-acetic acid ey'-lactone (24a) in 15 ml dry toluene was cooled in a dry nitrogen atmosphere to -78 ⁰ C. to this cooled solution was added dropwise over 3 minutes at a rate such that the internal temperature never rose above -65 ⁰ C, treated with 5.0 ml of a 20% solution of diisobutylaluminum hydride in η-hexane (Alfa Inorganics). After the reaction mixture was stirred at -78 ⁰ C for a further 30 minutes Anhydrous methanol was added until the evolution of gas ceased and the reaction mixture was then warmed to room temperature, combined with 150 ml of ether, washed 1 with 50 ml of a 50% sodium potassium tartrate solution, dried over NapSO ^, and concentrated and chromatographed to obtain 1200 mg of the title compound (25a), which is a yield of 81.5 % .

Example 22

9Oi-Hydroxy-110 (, 15 ^ bJs- (tetrahydropyran-2-yloxy) -l6-phenyl-cis-5-ft ^ tetranor-prostenic acid _ (22a)

A solution of 5150 mg (11.6 mmol) (^ -carbohydroxy-n-butyl) -triphenylphosphonium bromide in 10.1 ml of dry dimethyl sulfoxide in a dry nitrogen atmosphere

U 0 9 c 1 C / 1 1 5 0

233494S

10.8 ml (21 * 1 mmol) of a 1 _S 96 M solution of sodium methylsulfinyl methide in dimethyl sulfoxide were added. This red ylio solution was added dropwise over the course of 20 minutes with a solution of 1200 mg (2.6 mmol) 2- / 5cC-hydroxy-3 «^ - (tetrahydropyran-2-yloxy) -2 [beta ]- (30C-Z ^ ^e ^ ^r ahy <i ^I * ^o Py2'an-2-yloxy_7- ⁱ ä-phenylbut-l-yl) -cyclopent-loi-ylJ-acetaldehyde - ^ - half acetal (25a) added in 7.0 ml of dry dimethylsulfoxy »After the reaction mixture had been stirred for a further 2 hours at room temperature, it was poured onto ice water. The aqueous basic solution was acidified to pH before 3 with 10 S aqueous hydrochloric acid. The 'acidified solution was extracted 3 times with 100 ml of ethyl acetate. The combined organic extracts were washed 1 with 50 ml of water, over MgSOj. dried and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The piltrate was purified by column chromatography over silica gel (Baker "Analyzed", particle size 0.074-0.248 mm) using ethyl acetate as the eluent. After removing high R _f impurities, 880 mg of the Tifeel compound (22a) was collected.

The IR spectrum (CHCl,) of the product (22a) showed a

- 1

Absorption at 1715 cm for the carboxyl group.

That protrude *! obtained product (22a) can be converted into I (> - Fh © nyl - &> - tetranor- 13, l ^ -dihydr-c. "Pa-F ₀₀ ^ - r ^ r-dSLi * according to the procedure of Example 16

Example 23

9-Oxo-lloC ₁ 15oC-bis- (tetrahydropyran-2-yloxy) -l6-phenylcis-5 - ^ - tetranor-propenoic acid (26a)

A solution of 880 mg (1.68 mmol) of 9QC-hydroxy-11C, 15 <X-bis- (tetrahydropyran-2-yloxy) -15-phenyl-cis-5-6> tetranor, cooled under nitrogen to -10 ° C -protenic acid (22a) in 15 ml of acetone ("reagent grade") was added dropwise with 0.75 ml (2 mmol) of Jones ¹ reagent. After the reaction mixture had been kept at -10 ° C for 20 minutes, it was treated with 0.75 ml of 2-propanol and then stirred for a further 5 minutes, after which it was mixed with 100 ml of ethyl acetate, washed 3 times with 25 ml of water, about MgSOj. was dried and concentrated to give 775 mg of the title compound (26a).

The IR spectrum (CHCl,) showed absorptions at 1710 and

-1 1735 cm for the carbonyl group.

example 2k

9-Oxo-lloC ₁ 15oC-dihydroxy-16-phenyl-cis-5 "^ tetranorprostenic acid (27a)

A solution of 772 mg of 9-oxo-110f, 15Ä-bis (tetrahydropyran-2-yloxy) -16-phenyl-ci3-5-ÄJ-tetranor-prostenic acid (26a) in 7.0 ml of a mixture of 65 parts of glacial acetic acid and 35 parts of water were ^{stirred for 20 hours under nitrogen at 25 °} C. and then concentrated by rotary evaporation. The crude oil obtained was purified by column chromatography over silica gel (Mallinckrodt CC-iJ, particle size 0.07 * 1-0.1 ^ 7 μm) using ethyl acetate as the eluent. After eluting less polar impurities, 361 mg of the Title compound (27a) collected in the form of an oil.

409810/1150

The IR spectrum (CHCl ₅ ) showed carbonyl bands 1710 and 1735 cm " ¹ .

Biological effectiveness: guinea pig - uterus 1, guinea pig - histamine aerosol test 0, dog - blood pressure 1 * 00 (long duration of effectiveness).

Example 25

g-Oxo-lloC.lSoC-Dihydroxy-lo-phenyl - ^ - tetranor-prostanoic acid (28a)

A heterogeneous solution of 3 ¹ »mg (0.089 mmol) 9-oxo-lloi, 150t-dihydroxy-16-phenyl-cis-5-trans-13 - ^ - tetranorprostadienäure (IIIa) and 13 mg of 5 SS-palladium Charcoal in 3 ml of absolute methanol was ^{hydrogenated for 2 hours at 0 °} C. (1 at). The reaction mixture was filtered and evaporated to give 30 mg of the titre compound (28a).

The IR spectrum (CHCl,) of the product (28a) showed

- 1 - 1

Sorptions at 1715 cm and 1735 cm for the carbonyl group, a broad .OH range and no absorption for a trans double bond.

Example 26

9 ~ öxo-ll () C _> 15 ^ -dihydroxy-l6-phenyl -trans-13 ~ &? - tetranerprostenic acid (29a)

A solution of h € mg g-Oxo-llotslSoi-dihydroxy-Lö-phenylcda-S-trans-iS- ^ tetranor-prosiadienoic acid (Ha) in 5 ml dry ether was treated with ^ 3 mg O36 HiMoI for 48 hours at 25 ° C ) Dimethyl-isopropyl-chlorosilane and ZtO mg (% 6 "'MoI) triethylamine treated. The reaction

J ί ζ. I U / t: 5V

- RO -

mixture was ^{cooled to 0 °} C. and mixed with methanol. The resulting solution was washed 3 times with 2 ml of water, over MgSOj. dried and evaporated to give 67 mg of a residue. The crude residue was then taken up in 6 ml of methanol and treated with 30 mg of 5 palladium on carbon, and the resulting slurry was hydrogenated for 4 hours at -22 ° C. (CCl ^ / dry ice). After filtration through a filter aid (super cell) and evaporation, the hydrogenated product was hydrolyzed for 10 minutes in 2 ml of a mixture of 3 parts of acetic acid and 1 part of water, then diluted with 20 ml of water and extracted 4 with 15 ml of ethyl acetate. The combined organic extracts were washed 2 with 10 ml of water, _{dried over MgSOj 4} and evaporated, whereby 44 mg of the title compound (29a) were obtained.

Example 27

2- <£ 3fl. ~ P-Phenylbenzoyloxy-5 ⁰ l-hydroxy-2ß- (3 ~ hydroxy-4-phenyll-butyD-cyclopent-loi-ylJ-acetic acid-y-lactone (19a)

A solution of 14.5 g (3 »10 mmol) of the product (4a) in 195 ml of absolute methanol containing 0.5 g of 5% palladium on carbon was added for 5.5 hours at atmospheric pressure and room temperature hydrogenated. The reaction mixture was filtered through a filter aid (Celite) and evaporated to give 14.0 g of the desired title compound (19a), which corresponded to a yield of 95.5 % .

The IR spectrum (GHCl,) of the product (19a) showed

-1 carbonyl absorption at 1775 cm (S, lactone) and

h 0 9>: 1 0/1 1 SC

-U-

1715 cm (S, ester) and no absorption for a trans double bond.

Example 28

2- ^ 3ol ~ p-phenylbenzoyloxy-5 <X ~ hydroxy-2ß- (3 ~ oxo " ¹ * -phenyll-butyD-cyelopent-loC-yüJ-acetic acid-'K'-lactone (50a)

A maintained at 0 ⁰ C solution of 1 * 4.0 g (30.0 mmol) of compound (19a) in 150 ml dry acetone was added dropwise in the course of 7 minutes with 11.9 ml (31.0 mmol) of 2, 6 m Jones' reagent added. After a further 10 minutes, 11 ml of 2-propanol and then 1 ml of ethyl acetate were added to the reaction mixture. The ethyl acetate layer was washed successively 3 with 100 ml of water, 1 χ with 100 ml of sodium bicarbonate solution and 1 with 100 ml of brine, dried over MgS (K and evaporated to give 9 »5 g of the desired title compound (50a) with a melting point of 8M 86 ° C.

40S810 / 1150

Example 2Q

2- / 3. <. 5 iZ -dihydroxy-? P- (3-oxo- ' ¹ -phenyl-1-butyl) -cyclnent-IcC-y 17-acetic acid-) f-lactone (51 a).

A heterogeneous mixture of 9.5 g (20, Ί fillinol) 2- / 3 <■ -pphenylbenzoyloxy-5 ^ C-hydroxy-SP- (3-oxo-ii-phenyl-1-butyl) -cyclopent-loC -yl ^ -acetic acid X "-laeton ( ¹ JO a), 100 ml of absolute methanol, 100 ml of dry ^Φ ΗΡ and 3.7 R finely powdered anhydrous potassium carbonate was stirred for 3.5 hours at Paum temperature and then cooled to 0 ⁰ C. 53.2 ml (53.2 ^M illinol) 1.0 η w # peripheral hydrochloric acid were added to the F, ^ ^{-cooled solution, and 50 ml of water were added to the tubes at 0} ° C. for an additional 10 minutes , v / is p-facilitated time obei ^M ethyl-p-phenylbenzoate formed, DAB was filtered off. The filtrate was extracted with solid sodium chloride ros ^ TTIF ^ t and ie MOO ml Kthylacetat twice. Di <° combined organic extracts were washed twice with ie ^P washed 0 ml of saturated Hatriumbicarbonatlösung, ^f Jber "agnesiumsulfat dried and concentrated to give?, 3 g (3 ^n" ^ u ^ yield) of viscous oily 2-Z "3 tC, 5DC dihydroxy? P- (3-oxo -ii-phenyl-1-butyl) -cyclope nt-IC-yU-acetic acid-T-lactons ("51 a).

The IR spectrum (CHCl,) showed a strong absorption band at 1770 cm for the lactone carbonyl group, a strong absorption band at 1Q15 cn "for the ketone carbonyl group and none Absorption at ^ 5 cm ~ (trans double bond).

Example 30

2-pi. <. -Hydroxy-3dC - (tetrahydropyran-2-yloxy) -? P- (3-oxo-'iphenyl-butyl) -cyclopent-l.> Cy \ 7-acetic acid - ^ - lactone (5? A).

A solution of 2.2? ^ 7, ^ 5 ^M illimol) 2- / 3 £, ~. £ -dihydroxy-PP- (3-oxo-i) -phenyl-1-butyD-cyclopent-1cC-ylJ-acetic acid- t lac ton

409810/1150

f ^r la) in 35 ml of anhydrous chloroform and 0.5 ml of?, 3-dihydropyran was ⁰ C In a dry StickstoffatriosphSre with 5 p-ToluolsulfonsSuremonohydrat ng were added at O. After 80 minutes, he. The reaction mixture was combined with 350 ml of ether, the ether solution was washed twice with 100 ml of saturated sodium bicarbonate solution, then saturated with 100 ml of sodium chloride solution, dried over magnesium sulphate and concentrated, with 2.2 g of crude 2- / f5i £ -hydroxy -? .- £ - (tetrahydropyran-2-yloxy) -2ß- (3-oxo-'i-phenyl-1-butyl) -cyclopent-ldCi-y ^ y-acetic acid-ίΤ-lactone (52 a) .

Example 31

? - / ~ 5cC-Hydroxy-30C- (tetrahydropyran-2-yloxy) -2ß- (3-hydroxy-3-methyl- ¹ i-phenyl-1-butyl) -cyclopent-1dC -ylJ-lactone (5 ^ a ).

A solution of 2, ^p > g (7, ^ ^ illimol) of the compound 52a in 100 ml of ether (INSTA-STAFT-TM from Baker) under a nitrogen atmosphere was drop-free for 2.8 ml (8, ¹ J ^T 1allimol) 3 π ^M ethylnagnes: unbromid verpetzt After lst ^r indi; em P / her vmrde a further quantity of 1 ml of methyl magnesium bromide is added after 25 minutes, the Reaktionsgemiseh vmrde with 250 ml Äther.verdünnt with.?. 25 nl of saturated annoniochloride are added, dried over magnesium sulphate, evaporated and, using ether, al "Flutionmitt ?! Ehronatographed (Paker, lichte ^:: - * aschenvjeite 0.248-0.0? ii nl), whereby oiio ng of the desired product 53 a are obtained.

Example 32

2-L5 ^: - Hydroxy - ".-? C- {tetrahydropyran -? - yloxy ^< J-2P <- (3-hydrc"': 7 - "- nethyl-u-phenvl-l-butyD-cyclopent-l .>: -ylj-acetaldehyde- ^% ~~

ü Η ■■■; 1 0/1 "i S 0

- RH -

A solution of 1.113 g (2.87 millimoles) of 2-Z ^ - c (tetrahydropyran-2-yloxy) -2ß- (3-hydroxy-3-methyl- * J-phenylbut-1-yl) -cyclopent-InC -ylZ-acetic acid-i'-lactone (53 a) in 15 ml of dry toluene was cooled to -78 ° C. under a dry nitrogen atmosphere. 5.0 ml of a 20 "solution of diisobutylaluminum hydride in η-hexane (commercial product from Alfa-Inorganics) were added dropwise to this cooled solution at such a rate that the internal temperature never exceeded -fi5 ° C (7 minutes ). After additional stirring at -7R ⁰ C for 30 minutes, anhydrous methanol was added until gas evolution ceased, and was allowed the reaction mixture to room temperature. the peak ion mixture was ml nit 3 50 lather combined, washed with 50 ml of a 50 / ^ sodium potassium tartrate Tlatrium washed über.natriumsulfat dried and concentrated to give S ^ 7 ulenchromätographie after ^oR mg of 2- / 5-hydroxy-3 .TC OC (tetrahydropyran-2-yloxy) -Pft- (3-hydroxy-'i methyl-4-phenyl-but-l-yl) .cyclopent-l-ylj-acetaldehyde-ίΓ-hemiacetal (5'ia) were obtained.

Example 33

2- / 2ß-Benzyloxymethyl-3 oC- (tetrahydropyran-2-yloxy) ~ 5tC hydroxy-cyclopent-loC-ylJ-acetaldehyde- <T-semi-acetal.

A stirred and ^{cooled to -7 Ö} ° C solution of 2- / 2fi-benzyloxymethyl-3:) C - (tetrahydropyran-2-yloxy) -5 χ: -hydroxycyclopentloC-yU-acetic acid- ^ "- lactone in 78, R ml ^m oluol vmrde tropfenvreise with I ?, ¹⁾ ml (10.8 millimoles) of a 0.805 m solution of Diisobutylaluniniunhydrid in hexane crosslinked. the solution vmrde ir. the cold under nitrogen, stirred for one hour and then treated dropwise with "'ethanol, until the gas evolution ceased. The obtained Genisch i-'urde to room temperature ervrärmt with 79 ml '-ther diluted three times a nit 50 "strength sodium Kaliur.tartratlösur ^ and eir ^ P ¹ p-nit esSttigter Kochsalslösung rewascher,.." Ber anhydrous; "" he '-. esium sulphate

4096 1 0/1 1 SO

dried and concentrated, with 3 »15 Z (92.0 * yield) crude, colorless, oily 2- /" 2ß-benzyloxymethyl-3oC- (tetrahydropyran-2-yloxy) -5dC-hydroxycyclopent-loC-y! / - acetaldehyde -) T ~ hemiacetal obtained. The IR, NMR and mass spectra of the agreed with the assumed structure.

Spectra:

I £ (CHCl-): no carbonyl

NMR (CDCl,):

7.31 ς

5.32 - 5.75 p

4.50 <£> 4.45 - 4.Q8 G 3.44 δ

1.20 - 4.40 Example 34

7- / 2β-Benzyloxymethyl-3> X- (tetrahydropyran-2-yloxy) -5cC-hydroxy-cyclopent-loC -

Singlet 5H aromatic broad
Singlet IH OH Singlet 2 II 0CH ₂ -O Multiplet 2H O-CH-0 Quartet
J = 9 cps
J = 4 cps 2 H -CH ₂ O-BZ Multiplets lfiH remaining prot

A solution of 4, Q6 g (11.2 willimol) (4-carboxy-n-butyl) triphenylphosphonium bromide in 8.85 ml of dimethylsulfoxide was treated dropwise with Q, 73 _m i (21.2 Millinol) of a 2.18 m solution of sodium methyl sulfinyl methide in dimethyl sulfo ^ id added. In the red ylide solution obtained, 1.57 g (4.50 millimoles) of a solution of the crude halbacetal according to Example 33 in 13.7 μl of dimethyl sulfoxide were added dropwise over the course of one hour. After stirring for vreitsren 45 minutes, the reaction mixture was poured into ice water. The basic aqueous solution was treated twice with 60 ml each of a mixture of £. * ;. r> yla3er.at and a ratio of 2: 1

40S310 / 1150

extracted, then coated with ethyl acetate and acidified to a pH of about 3 with 1.0 η hydrochloric acid. The aqueous layer was extracted again with ethyl acetate, the combined ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to a viscous yellow oil. The crude ttl was purified by chromatography on 30 g of silica gel using ethyl acetate as the eluent. After elution of the impurities with a crude R ^ value, 1.75 F. (0.0 % yield) of the desired 7- / 2? -Benzyloxymethyl-3.TC- (tetrahydropyran-2-yloxy) -5; C. -hydroxycyclopent-1 . ■ -yl7-cis-5-heptenic acid obtained.

Spectra: (CHCl,) ): Acid Carbonyl aromatic IR. -OH 5.82 (CDCl ₃ & Singlet 5H olefinic NMR. S. wide singlet 2H -O-CH-0 7.30 - 7:00 9 Multiplet 211 0-CH ₂ -O 6.44 - 5.58 wide singlet IH -CH ₂ -O + -CH-O 5.28 - 4.79 & Singlet 2H remaining protoner 4.62 S. 6th Multiplets RH 4.51 - 4.38 ^M ultipletR 1 ^ H 3.23 - 2.53 1.22

Optical rotation:

25th
D.

= + 15.1 ° (e

Example 35

; HCCl ^)

Methyl 7- ^ 2ß-benzyloxymethyl-3K- (tetrahydropyran-2-yloxy) -5 £ ■ hydroxycyclopent-1 jC-yl7-cis-5 ^j -heptenoate,

A solution of 1.75 g (4.06 f'illimol) of the ¹ '"obtained in Example 3

409810/1150

The chronographed acid provided in 17.5 ml of anhydrous jither was titrated with an ethereal diazonethane solution at room temperature until the yellow color persisted for 5 minutes. The reaction mixture was then decolorized by adding glacial acetic acid dropwise. The Ktherlösung was then washed once with a saturated sodium bicarbonate solution and once with a saturated saline solution, 'iber anhydrous magnesium sulfate and concentrated to give 1.80 g (99.0 1 yield) of pale yellow oily methyl 7 ~ Z2ß-benzyloxymethy1 -3oC- (tetrahydropyran-2-yloxy) -5oC-hydroxycyclopent-1 x. yl_7-cis-5-heptenoats were obtained.

Spectra :

IR ^ I [CHCl,) • Ester carbonyl 5H aromatic 5.77 2H olefinic NMR. (CDCl, ): Singlet IH -O-CH-0 7.31 & Multiplet 2 H 0-CH ₂ -O 5. ^ 2 - 5.30 & wide singlet 3H -0-CH ₃ ii.Pl - U.f3 b Singlet Oh -CHp-O + -CH-O Ji. 53 b Singlet 121! remaining protons Multiplets - 3> 7 Multirlets 2, 55 - 1.3 * S Example 3?

"ethyl-7 - /" 2P-bensylox: / methyl-3 -:> C- (tetrahydropyran-2-yloxy) -5tC -acetoxycyclopent-ldC -ylJ-cis - ^ - heptenoate.

A mixture of 1 _? 5 ^P g (3.5 * »Millinol) prepared in Example 3 ^ crude Hydroxyestsrs, 5.0 ml of pyridine and 0.73 ml ^ (7 ₂ 73 millimoles) Acetar hydride urter nitrogen at 50 ° C overnight was gerHhrt . The mixture was then cooled to room temperature and diluted with 75 liters of ether

-09210/115

once with water and three times with saturated copper sulfate solution washed, dried over anhydrous magnesium sulfate and concentrated, l, 6l g (P3, '5 ^ yield) colorless, oily methyl 7- / 2ß-benzyloxymethyl-3dC- (tetrahydropyran-2-yloxy) -5oC-acetoxycyclopent-1 cC-yl7-cis-5-heptanoate.

Spectra:

IR. (CHCl ₃ ): 1750 cm ** ¹

NMR: (CDCl ₃ ):

7.30 fe

5.51 - 5.23 *> 5.22 - H.QlS M.52 S
3.63 Ό
1.67 - 3.20 &

2.06 h

2.55 - 1.22 b

Ester carbonyls

Singlet

Multiplet

Multiplet

Singlet

Singlet

Multiplets

Singlet multiplets

5H aromatic 2H olefinic IH -CH-O-Ac 2H 0-CH ₂ -O- 3H -0-CH ₃ bra -O-CH + -0 0
It 3H
lfiH -CCH ₃
resti. Prot

Example 37

Methyl 7- / l? Ft-hydroxymethyl-3 ^ c- (tetrahydropyran-2-yloxy) -5OC acetoxycyclopent-loC-yl7-heptanoate.

A heterogeneous mixture of 1.53 g (3.1 ¹ l millimoles) of the crude acetoxy ester prepared in Example 36, 305 mg of 5J? Palladium-on-charcoal and 15.3 ml of a mixture of absolute ethanol and glacial acetic acid in a ratio of 20: 1 were stirred under a hydrogen atmosphere at room temperature 1) for 8 hours. The mixture was then filtered through Celite 5 ^ 5 and the piltrate was concentrated to give 1.10 g (87.5 % yield) of the colorless, oily methyl-7- / 2ft-hydroxymethyl-30C- (tetrahydropyran-2-yloxy ) -5o £ -acetoxycyclopent-loC 409810/1150

yl7 ~ heptanoate were obtained.

Spectra;

Ester carbonyls

IR. (CHCl,):

1750 cm " ¹

HMR: (CDCl,):

5.23 - 4.92 & 4.83 - i ».i» 6 <r 3.65 &

4.32 - 3.18 p

3.06 - 2.70 p

2.58 - 1.00 S example 38

Methyl-7-_ ^r 2ß-formyl-3- (tetrahydropyran-2-yloxy) -5oC-acetoxycyclopent-loC -ylj-heptanoate.

Multiplet IH -CH-OAc Multiplet IH -O-CH-0 Singlet 3H -0-CH ₃ Multiplets 7H -0-CH + -0-CH ₂ wide singlet 3H 0
ti -CCH ₃ Multiplets 2OH re stl Pr

A mechanically stirred solution of 3 * 3? ml (& 1.7 millimoles) of pyridine in 50 ml of methylene chloride under nitrogen, which was cooled to 10-15 ° C. was added in portions over 30 minutes with 1.89 g (18.9 millimoles) chromium dioxide offset the dark burgundy solution was to then to room temperature to warm up, after which it is cooled to ⁰ ° C wus-de. Zv- the cold solution has a solution of 0 _$ oü ·? g (2.37 millimoles) of the crude alcohol prepared in Example 37 in 7 »0 ml of methylene chloride were added; v; d - ri itself (Tl ^ i inside a clicker

Z: j ~ S:? & Oension viiroe in de?

black cold ^ cold 15 yar ..

(52.2 millirv given -. Εε,: -

bäitl ?,. 7 _f 21

κ f- _s 25 g '' 3 ":

090; w, 115C

mol) anhydrous magnesium sulfate was added. Go on Stirring for 5 minutes, the dark suspension was filtered through a pad of Celite with methylene chloride washed and by rotary evaporation (bath temperature: <10 ° C) concentrated, whereby the crude, dark brown, oily methyl-7 - ^ * 2ß-formyl-3. £ - (tetrahydropyran-2-yloxy) -5 ^ -acetoxycyclopent-loC-ylJ-heptanoate which was used without further purification.

Example 39

Methyl 9cC -acetoxy-11x- (tetrahydropyran-2-yloxy) -15-oxotrane-13-16-phenyl-Ui-tetranorprostenoate.

A suspension of 110 mg (2, fil millimoles) of a 57, Oxigen Dispersion of sodium hydride in mineral oil in 20 ml of dimethoxyathane was with 63I mg (2.6L millimoles) of dinethyl-2-oxo-3-phenylpropylphosphonate offset. The mixture was stirred for one hour under nitrogen at room temperature. These Suspension was made with a solution of Ο, οίίγ g (2.37 millinoles) of the crude aldehyde prepared in Example 38 in 4 ml of dimethoxyethane offset. The resulting slightly cloudy brown solution was left under nitrogen for two hours at room temperature stirred, and then adjusted to pH 7 with glacial acetic acid and concentrated by rotary evaporation. That Crude product was purified by column chromatography on silica gel, wherein the desired methyl 9oC-acetoxy-lloC- (tetrahydropyran-2-yloxy) -15-oxo-trans-13-16 "phenyl-uj-tetranorprostenoate was received «

Example MO

Methyl-9oC-acetoxy-llcC- (tetrahydropyran-2-yloxy) -15-hydroxy trans ~ 13-16-phenyl ~ and tetranorproatenoate.

A solution of 1.1.5 (2.17 millimoles) of that in Example 39 409810/1 150

The enone prepared in 6.5 ml of dimethoxyethane was admixed dropwise with 2.17 ml (1.08 millimoles) of a 0.5 M solution of Zn (BH ₁ J) ₂ in dimethoxyethane. After stirring for 3 hours under nitrogen at room temperature, a saturated aqueous solution of sodium bitartrate was added dropwise to the reaction mixture until the evolution of gas ceased. The resulting heterogeneous solution was stirred at room temperature for 5 minutes, diluted with methylene chloride, dried over anhydrous magnesium sulfate and concentrated, whereby methyl-9oC-acetoxy-lloC- (tetrahydropyran-2-yloxy) -15-hydroxytrane-13-16- phenyl ω-tetranorprostenoate was obtained.

Example »41

Methyl 9oC-acetoxy-lloC, 15R-dihydroxy-trans-13-16-phenyl-ujtetranorprostenoat and methyl-QoC-acetoxy-lloC, 15 cC-dihydroxy trans-13-lf ^; phenyl ω-tetranorprostenoate.

A solution of 1.1 p; (2.16 millimoles) of the crude THP ether, prepared in Example Ί0, in 10.7 ml of an Oemisohes of acetic acid and water in the ratio of f> 5:35 was under nitrogen for 2.5 hours at HO * 2 ° C touched. The reaction mixture was then concentrated to give the crude diol-epimer mixture. The crude product was purified by SSulenchromatographie on silica gel to give the desired methyl-PoC-acetoxy-LLCC, ^ P-dihydroxy-trans - ^ - phenyl- LFI UJ -tetranorprostenoat and the epimeric ethyl ~ ^M 9jC-acetoxy-11 u, 15 £ dihydroxy-trans-13-lP-phenyl-UJ-tetranorprostenoat were obtained.

example H2

i'ethyl-9 ^ -acetoxy-lloC, 15cC-bis (tetrahydropyran-2-yloxy) -trans-13-16-phenyloz-tetranorprostenoate.

409810/1150

A mixture of 220 mg (0.510 mmol) of the chromatographed diol of Example ill, ^'1 I 0.1 ml (1.53 mmol) of dihydropyran, H _s 2 ml of methylene chloride and a crystal of p-toluenesulfonic acid monohydrate was added at room temperature under nitrogen for 20 minutes touched. The reaction mixture was then diluted with ether, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to give the desired methyl-QoC -acetoxy-11 ^ C, 15 ^ C -bis- (tetrahydropyran-2-yloxy) -trans -13-16-phenyl-W-tetranorprostenoate was obtained.

example H ^

9oC, 11oC, 15 3C-Trihydroxy-trans-13-1 ^ -phenyl-üu-tetranorprostenic acid.

A mixture of 55 mg (0.15 millimoles) of the chromatographed diol prepared in Example hl , 0.5 ml (0.45 millimoles) of 1.0 η aqueous sodium hydroxide solution, 0.5 ml of tetrahydrofuran and 0.15 ml of absolute methanol was stirred at room temperature for 1.5 hours under nitrogen. The solution was then acidified by adding 0.5 ml of a 1.0 η aqueous hydrochloric acid (the pH of the acidified solution was about 5). The acidified solution was extracted four times with ie 2 ml of ithyl acetate. The combined extracts were dried over anhydrous magnesium sulfate and after concentration gave the desired 9oC, 1LtC, 15aC-trihydroxy-trans-13-16-phenyl-oü-tetranorprostenic acid.

example HH

9aC -hydroxy-lloC, 15oC-bis (tetrahydropyran-2-yloxy) -trans-13-16-phenyl- ω- tetranorprostenic acid.

409810/1150

A homogeneous solution of 262 mg (0.436 millimoles) of the in example 42 crude bis-THP ester prepared, 1.3 ml (1.30 x millimoles) of the 1.0 η aqueous sodium hydroxide solution, 1.3 ml Methanol and 1.3 ml of tetrahydrofuran were stirred over power under nitrogen. The reaction mixture was then 1.30 ml (1.30 millimoles) of a 1.0 η w ^ Berigen hydrochloric acid added, and the solution was diluted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the crude product. This was determined by column chromatography on silica gel (Baker "Analyzed" reagent; clear mesh size: 0.248 - 0.07 * 1 mm) cleaned, whereby 9c £ -hydroxy-2oC, 15oC-bis ~ (tetrahydropyran-2-yloxy) -trans-13-16-phenyl-w-tetranorprostenic acid was obtained.

Example 45

π-Oxo-lloC, 15cC-bis- (tetrahydropyran-2-yloxy) -13-trans-lP-phenyl-w-tetranorprostenic acid.

An under nitrogen to -15 - -20 ⁰ C cooled solution of 195 mg (0.371 mmol) of the compound prepared in Example 44, the chromatographed acid in 4.0 ml of acetone was treated dropwise with 0.163 ml (0.408 mmol) Jones reagent. The reaction mixture was stirred in the cold for 15 minutes and then 0.194 ml of isopropanol was added, stirred in the cold for 5 minutes and then diluted with thylacetate. The organic layer was washed twice with water and once with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated to give the desired 9-oxo-lloC, 15 ^) C -bis- (tetrahydropyran-2-yloxy) -13-trans-16 -phenyl-w-tetranorprostenic acid was obtained.

Example 46

9-Oxo-ll ^, ^ oC-dihydroxy - ^ - trans-l ^ -phenyl-w-tetranorprosten acid.

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A homogeneous solution of 178 mg (0.32 ^ millimoles) of the crude T ¹ HP-Kthers of Example ^ 5 in 2 ml of a mixture of acetic acid and water in the ratio of 65:35 was for 5 hours under nitrogen at 40-2 ° C stirred. The reaction mixture was first concentrated by rotary evaporation and then with an oil pump. The crude product was purified by column chromatography on silica gel (Mailinckrodt CC-7), the desired 9-oxo-II Ό. , 15 <£ -dihydroxy - ^ - trans - ^ - phenyl-wtetranorprostenäure was obtained.

example Hj

Dimethyl 2-oxo-3- (p-methylphenyl) propylphosphonate (2 e).

A solution of 7 * 1.5 r (0.6 mol) of dimethyl methylphosphonate (commercial product from Aldrich) in 700 ml of dry ethrahydrofuran was ^{cooled in a dry nitrogen atmosphere to -7 pO} C. To the stirred phosphonate solution, 38 ^ ml of a solution of 1.6 mol of n-butyllithiun in hexane (Alfa Inorganics, Inc.) was added dropwise over 18 minutes at such a rate that the reaction temperature ^{never exceeded -fv5 o} C. After stirring for a further 5 minutes at -7B ⁰ C. 49.1 g (0.3 mole) of methyl p-methylphenyl acetate is added dropwise at such a rate, daP kept P.eaktdonstemperatur to less than -7O ⁰ C (20 minutes). After 3.5 hours at -78 ⁰ C. The reaction mixture was allowed to warm to ambient temperature after which it was neutralized with 30 ml of acetic acid and rotary evaporated to a white gel, the gelatinous material was taken up in 75 ml of water, the aqueous phase was washed three times With 100 ml of chloroform each, the combined organic extracts were backwashed with 50 cm ^ V / water, dried over aprresium sulphate and concentrated (water jet pump), whereby a crude residue was obtained which, on distillation, was 3 ^ '^ F, (^ 7 , 7 * yield) dimethyl 2-oxo-3- (p-methylphenyl) propylphosphonate (2 e) with a boiling point of 1 ^ 5 - 1 ^Ü 7 ° ^ ^r <0.2 mm) were obtained.

409810/1150

-9S-

The NMR spectrum (CDCI,) showed a doublet centered at 3.75 S (J = 11.5 cps, fH) for (CH ₃ O) ₂ -PO-, one at 3, I ¹ * & (J = 23 cps, 2H) centered double ~ "for -CO-CH ₂ -PO-, a singlet at 3.8 & (2H) for CHp-CO-, a broad slnplet at 7.1 δ ( ¹ IH) for PC ^ H ₁₄ and a "1 singlet at 2.3 8 (3H) for P-CH ₅ -CpH ₁ , -. The IP spectrum (CHCl- ^) showed a carbon lab sorptlön band at 5.79 / A.

Example 48

2-Cbdi -p-Phenylbenzoyloxy-5-C -hydroxy-2B- (3-oxo - ^ - (p-methylphenyl) -trans-1-buten-1-yl) -cyclopent-1: £ -ylj-acetic acid- T- lactone (3 e).

Dinethyl 2-oxo-3- (p-ethylpheny ^) propylphosphonate (2 e) ( ¹ S, 7 g, 22.3 millimoles) in Ί0 ml of anhydrous 1,2-dimethoxy thane (DME) was at ice water temperature in a dry The nitrogen atmosphere was treated with 9.2 ml (21.7 millinoles) of a 2.3 mm rutyllithium solution in η-hexane (Alfa Inorganics, Inc.). After stirring for 25 minutes, 7.1 g (20.3 millimoles) of 2-Z3oC-p-phenylhenzoyloxy-5oC-hydroxy-2P> formylcyclopentan-1-TC-yilJ-acetic acid-ίΤ-lactone and then 30 ml of anhydrous DME were added . The reaction mixture warmed to room temperature and after 35 minutes with 15 ml of glacial acetic acid together with 50 ml of CH ₂ Clp and washed successively twice with 100 ml of saturated sodium bicarbonate solution each time, twice with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated, with 7.7 g (79 "■ yield) 2-Z3JC-p-phenylbenzoyloxy-5oC-hydroxy-2P> - (3-oxo-'J- (p-methylphenyl) -trans-1-butene-1- yl) -cyclopent-LCC-YLJ-essigsSure-) f-lactone (3 e) as a solid after SSulenchromatographie (Paker-Sil kagel, light Faschenweite: 0.2 * 8 to 0.07 mm I ¹⁾ in front. Melting point 1 ^ 5 - I ¹ Ii ⁰ C were obtained.

The IR spectrum (CHCl,) of the product showed absorption bands at 1777 cm " ¹ (strong), 1717 cm" ¹ (strong), 1680 cm " ¹ (medium)

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and 1630 era (middle) attributable to the carbonyl groups and a band at Q73 cm for the trans double bond. The NMP spectrum '.' CDCl ₃ ) showed an "ultiplet at 7.23 - B ₅ IB S (9H) for the r-piphenyl group, a duplicate of duplets centered at 6.75 (SYIH, J = 7, 16 cps) and a doublet centered at 6.25 5 (IR, J = 16 cps) for the olefinic protons, a broad singlet at 7, OQk (UH) for C ^ H ₁₅ -CH ₂ -CO-, a singlet at 3.7 ¹ JS (2H) for C ₆ H ₅ -CH ₂ -CO-, eirTSTnRlet at 2.27 S (3H) for P-CH ₅ -C ₆ H ₁ , - and multiplicity at H, 85-5 ^ 7 S (2H) and 2.21 - 3.07 £> (6H) for the plague of the protons.

The product of this example (3e) can be prepared according to the procedures of the 'Examples Ik, 16, lB-IQ and 21-2 * J in 13, l ^a -dihydro-l6-pmethylphenyl-w-tetranorprostaglandins of the series A, E or ^ be transferred.

The product (3e) can also be converted into IS-lower alkyl-lo-p-methylphenyl-w-tetranorprostaglandins of series A, E or F ^{by the process of Examples 1 I-26.}

^, lil-dihydro - ^ - lower alkyl - ^ - p-methylphenyl-vr-tetranorprostaglandins of the series A, E or F can be obtained from the compound 3e by the method of Example 1 * - ίο and 21-2 ¹ I will.

Example ¹ JQ

2- / f3cC-p-phenylbenzoyloxy-5oC-hydroxy-2F> - (3cC-hydroxy - ^ - (pmethylphenyl) -trans-l-buten-l-yl) -cyclopent-l-) C-yl7-acetic acid-) f-lactone (k e) and 2 - / "3X-p-phenylbenzoyloxy-5oC-hydroxy-2P> (3f ^s -hydroxy-i | - (p-methylphenyl) -trans-l-buten-l-yl) - cyclopent ~ l <aC y3j-acetic acid-X "-lac ton (5e).

A solution of 17.7 g (16 millimoles) 2- / 3cC-p-phenylbenzoyloxy-5 cC-hydroxy- ?! ³ »- (3-0x0-4- (p-methylphenyl) -trans-1-but-en-l-yl) -cyclopent-lcC-ylJ-acetic acid- ^ T-lactone (3e) n'n 65 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere v ^r urde

A09810 / 1150

at ⁰ ° C. with U1, ^ nl of a 0.5 M 7inkborhydridlösung added dropwise. After ^ OminHtigen run at room temperature. a saturated sodium hitrate solution was added dropwise at ⁰ ° C. until the evolution of hydrogen ceased. After stirring the reaction mixture for 5 minutes, 200 ml of dry methylene chloride were added. Mach drying over sodium sulphate and evaporation (water aspirator), the semi-solid product obtained by S ^ ulenchromatogranhie on silica gel (Baker "Analyzed" reagent with a mesh aperture of O, 2 ^u 8 0,07'J mm) "Using ether as After elution of less polar impurities, 1.3 g of 2-Γ5-Χ -p-phenylbenzoyloxy-5 ° C-hydroxy-PP- (3c £ -hydroxy-4- (p-methylphenyl) -trans-1- buten-l-yl) -cyclopent-1-C-yl ^ -acetic acid- "ίΤ-lactone (Ί e) containing fraction, a fraction of 0.31 g of the mixed compounds h e and 5 e and finally a fraction (1 , 5 g) of 2- / 3: Jc-p-phenylbenzoyloxy-5 <-hydroxy-2ß- ^{(3.beta.-hydroxy-i} i- (p-methylphenyl) -trans-l-buten-yD-cyclopent-LOC-yiy -acetic acid ^ 'ure-) f-lactone (5e) obtained.

The IR spectrum (CHCl-,) of Ί showed strong carbonyl absorption bands at 1770 and 1710 cm and an absorption band at 965 cm for the trans double bond.

Example 50

, 5oC-Dihydroxy-2ß- (3cC-hydroxy-ü- (p-methylphenyl) -transl-buten-1-yl) -cyclopent-1 X-yl7-acetic acid-ίΤ-lactone (6e).

A heterogeneous mixture of 1.7 g (3.5 ^ illimol) 2- / 3 ^ C ~ P ~ -phenylbenzoyloxy-5-> l-hydroxy-2ß- (3. <-hydroxy- ¹ ! - (p-methylphenyl ) trans-l-buten-l-yl) -eyclopent-lr) C -yl.7-acetic acid ^ -lactone (4e), 25 ml of absolute ^ ethanol, 25 n <l dry tetrahydrofuran and 51 ^ nig finely powdered anhydrous Potassium carbonate was stirred at room temperature for one hour and then cooled to 0 ° C. The cooled solution was treated with 7 _s h ml (7.1 willimol) 1.0 η wp'periger hydrochloric acid. After further

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After stirring for 10 minutes at ⁰ ° C., 5 ml of Hasser were added, vobe ?! methyl p-phenylbenzoate formed at the same time, which was filtered off. The filtrate was saturated with solid sodium chloride and extracted three times with 200 ml of ethyl acetate each time. The combined organic extracts were washed with saturated sodium bicarbonate solution (25 τπΐ), dried over magnesium sulfate and concentrated, whereby 1.0 g ( ^η 5.5 " yield) of the viscous, oily 2- / 3 ^ C, 5 ^ -dihydroxy- 2B (3oC-hydroxy-ii- (pmethylpheny1) -träns-l-buten-l-yD-cyclopent-LOC-yiy-essirr ure- ^H ^ f lactone (Pe) was obtained.

The IR spectrum (CHCl ₇ ,) showed a strong absorption band at 1770 cm for the lactone carbonyl group and a mean absorption band at ° 70 cn for the trans double bond.

Example 51

2- / 5oC-Hydroxy-3.: C- (tetrahydropyran-2-yloxy) -2P '- (3 ^ C-hydropyran-2-yloxy_7-ii- (p-methylphenyl) -trans-1-buten-l-yl) cyclopent-ldC-ylZ-acetic acid-5-lactone (7 e).

A solution of 1.0 g (3.3 millimoles) of 2-Cb - / 0.5JZ -dihydroxy-2P- (37C-hydroxy-4- (p-methylphenyl) -trans-1-buten-yl) -cyclopent -

- i-lactone (fe) in 15 ^ l of dry methylene chloride and 2.0 ml of 2,3-dihydropyran was added at 0 ⁰ C under a dry nitrogen atmosphere ^ re nit 10 mg of p ^{m-oluolsulfons} uremonohydrat. Mach 15 ^ inütigem stirring vmrde the Pesktionsgemisch with 150 ml of ether united, the ^ therlösung vurde once with 15 ml of saturated Natriumbicarbonatlßsunp: and then washed once with 15 ml of saturated brine, dried over magnesium sulfate and concentrated to vrobei 1, ^ g (100 "■ > Yield) crude 2- Ϊ5 < -hydroxy-3 -C- (tetrahydropyran-2-yloxy) -2P- (3dC-ztetrabydropyran-2-yloxy7- ^il - (p-metHyiphenyl) -trans-lbuten-1-yl) -cyclopent-lJC-yl ^ -acetic acid, If-lactone (7e) were obtained.

409810/1150

The IP spectrum (CHCl ₃ ) showed a mean absorption band at ^ 70 cm " ¹ for the trans double bond.

The product of the present example (7e) can be converted into the 13, l ¹ »-dihydrol6- (p-methylpheny]) w-tetranorprostaglandins of series A, E or F by the method of Examples 1 *, 18, 20-2Ii be transferred.

Example 52

2- / 5 .- £ -hydroxy-3-c - (tetrahydropyran -? - yloxy) - ?. P> - (3 £ - / tetrahydropyran-2-yloxy_7-k- (p-methylphenyl) -trans-l- buten-1-yl) -cyclopent-1 -C -y! / - acetaldehyde-λ-hemiacetal (R e).

A solution of 1. P g (3.3 millimoles) 2- / V? C-hydroxy-3oC- (tetrahydropyran-2-yloxy) -21 ^ -3 oC-Ztetrahydropyran-i-yloxyj- ^ l- (pinethylphenyD-trans-l-buten-l-yli-cyclopent-liC -ylJ-essiRsSure-

> -lactone (7 e) in 20 ml of dry toluene was cooled ^{to -7B 0 C in a dry nitrogen atmosphere.} This cooled solution was treated dropwise with B, 0 ml of a solution of 20 £ Diisobutylaluininiumhydrid in η-hexane (Alfa Inorganics) was added at such a rate daf> the internal temperature of -65 ⁰ C never exceeded (15 Hinuten). After further ^ 5 ^ inütigem performing at -78 ⁰ C was added anhydrous methanol was added until the Oasentwicklung ceased _/ and allowed to be d, "heat as peak ion mixture to room temperature. The peak ligation mix was combined with 200 ml ether, washed twice with 50 ml of 50 Washed * 'iger sodium potassium tartrate solution, dried over sodium sulfate and concentrated, with Ι,' ι g (87.5 * yield) 2- / 5 rC-hydroxy-33C- (tetrahydropyran-2-yloxy) -2ß- (3 dC - / tetrahydropyran-2-yloxyJ-'4- (p-methylphenyl) -trans-1-buten-1-yl) -cyclopent-1-ylZ-acetaldehyde-Jf-half acetal (8e).

Example 53

9i £ -hydroxy-llcC, 15 ^ -bis- (tetrahydropyran-2-yloxy) -16- (pmethylphenyl) -cis-5-trans-13-w-tetranor-prostadic acid (9 e).

4 09810/1150

A solution of 5.3 mg (12.0 millimoles) of (^ -Carbohydroxy-nbutyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 10 ml of dry dimethyl sulfoxide vmrde with 9.5 nl (21.0 millimoles) of a 2.2 π solution of Natriumnethylsulfinylnethid added in dimethyl sulfoxide. From this red ylide solution a solution of 1.2% (2.5 "millimoles) 2-Z5 ^ C-hydroxy-3 <- (tetrahydropyran-2-yloxy) -2P- (3 < -Ztetrahydropyrar) was added dropwise over 20 minutes - ^ - yloxy / - ^ - (p-methylphenyD-trans-l-buten-l-yD-cyclopont-l £ -ylJ-acetaldehyde -X-hemiacetal (R e) in 5.0 ml of dry dimethyl sulfoxide was added. After stirring for a further two hours at room temperature, the reaction mixture was poured into ice water and acidified with 10% aqueous hydrochloric acid to a pH of about 3. The acidic solution was extracted three times with 100 ml of ethyl acetate each time, and the combined organic Extracts were washed three times with 50 ml of water each time, dried over magnesium sulfate and concentrated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. 2'l8 - 0.07 ** mm) using first chloroform and then xthylaceta t cleaned as a flushing agent. After removing impurities with a high R value, 1.2 g of OoC-hydroxy-ll jz , 15oC -bis- (tetrahydropyran-2-yloxy) -l6-phenyl-cis-5-trans-13-vj-tetranor- prostadiensSure (9 e) collected.

The IR spectrum (CHCl3) showed a carbonyl absorption band

-1 -i

at 1710 cm and an absorption band at Q ^ 5 cm for the

trans double bond.

The product of the present example (Q e) can be converted into the 1 ^ -p-methylphenylw-tetranorprostaglandins of the series F (P ₀ / -, F _-1 ^, by the methods of Examples I ^, 2k and 25.

i, 09810/1150

Example 5 * 1

° -0xo-llcC, 15 <£ -bis- (tetrahydropyran-2-yloxy) -lf- (p-methylphenyl) -cis-5-trans-13-w-tetranor-prostadienic acid (10 e).

A solution of 1.2 g (2.0 millimoles) °., C-Hydroxy-11 iZ, bis- (tetrahydropyran-2-yloxy) -l ^ - (p-ynethylphenyl) -cis- ⁱ 5-trans ~ 13 -w-tetranor-prostadiensMure (° e) in o, 2 ml of acetone from Reagenzreinheitsgrad, which was cooled to -10 ⁰ C and was under nitrogen was treated dropwise with 1.0 ml (2.67 mmol) Jones reagent . After 20 minutes at -10 ⁰ C 1.0 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, after which it combines with 75 ml of ethyl acetate, three times with .je. Was washed 10 ml of water, dried over magnesium sulfate and concentrated, 1.0 g of Q-Oxo-11cC, 15oC-bis (tetrahydropyran-2-yloxy) -16- (p-methylphenyl) -cis-5-trans-13 -w-tetranor-prostadienoic acid "(10 e). After purification by column chromatography, 575 mg of the pure compound were obtained.

The IR spectrum (CHCl3) showed carbonyl absorption bands

- 1 - 1 - 1

1735 cm and 1710 cn as well as an absorption band at ° ^ 5 cm

for the trans double bond. Example 55

9-Oxo-11cC, 15dC-dihydroxy-16- (p-methylphenyl) -cis-5-trans-13-w-tetranor-prostadic acid (11 e).

A solution of 5.75 mg (1.0μ millimoles) o-oxo-lldC, 15eC-bis- (tetrahydropyran-2-yloxy) -16- (p-methylphenyl) -cis-5-trans-13-w-tetranor Prostadienic acid (10 e) in 5.7 ml of a mixture of glacial acetic acid and water in the ratio of. ^ 5 × 35 was stirred at room temperature under nitrogen for 20 hours and then concentrated by rotary evaporation. The crude obtained was purified by ^ Säulenchromatogranhie on silica gel (* !, Mitllinckrodt CC mesh size: 0, li 7 to 0.07 mm ² J!) L under comparable

A09810 / 1150

use of ethyl acetate-cyclohexane as eluent. Purified. Less after elution of impurities Polarity was 250 mg of the semi-solid o-oxo-lldC, 15-C-di hydroxy-lf- (p-methylphenyl) -cis-5-trans-13-w-tetranorprostadienoic acid (11 e) obtained.

The IR spectrum (CHCl ₇ ,) of this compound showed a broad one

-1 -1

OK band, carbonyl absorption bands at 1735 cm and 1710 cm.

and an absorption band of the trans double bond at 065 cm " ¹ .

Compound (11e) of this example can be converted to the l ^ -p-f'ethylphenylw-tetranorprostaglandins E., EqA ₂ , A ₁ and A ₀ by the procedures of Examples 25, 26 and 18.

Example 56

Dinethyl 2-oxo-2-phenylethylphosphonate (2 f).

A solution of 7Ί, 5 g (600 millimoles) of dimethyl methylphosphonate (commercial product of Aldrich) in 750 nl dry tetrahydrofuran was cooled in dry ¹ Stickstoffat? Nosph £ re to -78 ⁰ C. The stirred Phosphonatlßsung was added dropwise over 30 minutes with 265 ml of a 2.3 ¹ I M solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) was added at such a rate that the Peaktionstenperatur never exceeded -65 ⁰ C. ! laughing further 5 minutes, at -78 ⁰ C were Pühren 'ti g (300 ^M illimol) methyl benzoate is added dropwise at such a rate that the ion peak temperature was maintained at less than -7 ^ ⁰ C (10 minutes). After one hour at -7 ° C., the reaction mixture was allowed to warm to ambient temperature. It was then neutralized with 35 ml of acetic acid, and the reaction mixture was converted into a white oil by evaporation.

Λ 09 8 1 0/1 1 50

tight. The gelatinous material was taken up in 75 ml of water, the aqueous phase was extracted three times with 300 ml of water, the combined organic extracts were extracted with 50 ml. Water backwashed, dried over magnesium sulfate and concentrated to a crude residue (water jet pump), with the distillation 35 g (2 ° " yield) of dimethyl 2-oxo-2-phenyl ethylphosphonate (2 f) with a boiling point of 130 - 135 ° C ( Ο, Ο'-i mm) obtained.

The NMP spectrum (CDCl ₁₅ ) showed a ^{Dunlet centered at 3.7 P} 'k (J = 11.5 cr> s, PH) for (CH ^ O) ₂ -PO-, one at 3, ^ 3 S ( J = 23 ens, 2H) centered doublet for CO-CHp-PO- and an i-'ultiplet at 7.3 - ^, 2t ^ H) for C ^ H ^ -.

Peisriel 57

2-Z "⁷; α -p-Phenylbenzoyloxy - ^, - ^: -hydroxy-2P - (3-oxo-3-phenyltrans-1-propen-1-yl) -cyclopent-1dC-ylZ-acetic acid - ^ -lactone C? D. Method A:.

Dinethyl-2-oxo-2-phenylSthylphoRphonat (2 f) (3.4 g, l ^u, 2 mmol) in 225 ml vrasserfreiem Xther was treated with 5.9 ml (ο, ς millimoles) of a 1.6 M solution of n -Butyllithium in n-hexane (commercial product from Poote Tnc.) Treated in a dry nitrogen atmosphere at room temperature. After stirring for 5 minutes, an additional 100 ml. ³ -formylcyclopentane-1.TC-yU-EssngsSure- ^ -lacton added all at once and then 75 ml of anhydrous ither. After 2 hours, 30 ml of anhydrous 1,2-dimethoxy ^ thane were added and the reaction mixture was stirred overnight. Then 5 ml of Eisessir were added and filtered, with 2.375 g (^ ⁰ * yield) 2- / 3 ^ -p-Phenylbenzoyloxy-5oC-hydroxy-2P> - (3-oxo-3-phenyl-trans-1-prorien-1-yl) -cyclopentl: £ -yl7-acetic acid ^ -lactone (3f) as a solid from A09810 / 1150

Melting point 1 ^ 5 - 1 ^ 9 ° C were obtained.

The IR spectrum (CHCl,) of the product (3 f) showed absorption

"I 1 -1

tied at 1775 cm "(thick), 1715 cm (medium) and 1 * 25 cn (medium) attributable to the carbonyl groups, and at

mm D

975 cm (in middle) for the trans double bond.

From this compound (3 f) can according to the examples

I ^ - ίο and 21 - 2 * »l ^, l ⁱ J-Dihydro-15-lower alkyl-5-phenyl-w-pentanorprostaglandins of the series A, F, or F can be obtained.

Method B;

5.17 g (22.6 millimoles) of dimethyl-2-oxo-2-phenylpropylphosphonat (2 f) in 30 ml of anhydrous 1, ^2-H Pimethoxy than were mixed with P, ü ml (22 millimoles) of a 2.3 * J m solution of n-butyllithium in η-hexane (Alfa Inorganics, Inc.) in a dry nitrogen atmosphere at ^{0 0} C treated. After vigorous stirring at room temperature, 7.6 ε (21 at once, and then 15 ml of anhydrous 1,2-dimethoxyethane added. After 30 minutes, 2 ml of glacial acetic acid were added to the reaction premix, combined with 200 ml of CHpCl ^ and extracted successively with 75 ml of water (twice), 75 ml of saturated sodium bicarbonate solution (twice) and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated, whereby 8 , 2 g (^ 5 " yield) 2- / 3JC-p-phenylbenzoyl-oxy-5 cC-hydroxy-2? - (3-OXO-3-phenyl-trans-1-propen-1-yl) -eyelopent -lcC-ylJ-acetic acid-Γ-lactone (3 f) were obtained as a solid.

The product (3f) of the present example can be converted into 15-phenyl-w-pentanorprostaglandins of the series A, E or F <J according to the procedures of Examples 1, 25 and 2f.

4098 10/1150

The product (3 f) can also be carried out according to the method of the examples

4-26 in 15-lower alkyl-5-phenyl-w-pentanorprostaglandins of series A, E or P can be transferred.

Example 58

2- / 3. <- p-Phenylbenzoyloxy-5 <£ -hydroxy-2i * - (3-hydroxy-3-phenyl-prop-1-yl) -cyclopent-loC -ylj-acetic acid- I -lactone (I " f).

A solution of 7, ^ g (1 ^, 8 millimoles)? -Z ~ 3cC-p-phenylbenzoyloxy-5oC-hydroxy-2B- (3-oxo-3-phenyl-trans-l-propen-l-yl) - Cyclopent-l.- £ -ylj-acetic acid-) f-lactone (3 f) in 100 ml of dry tetrahydrofuran was added dropwise Tl ^, ^p ml of a 0.5 M zinc borohydride solution in a dry nitrogen atmosphere at ambient temperature. After stirring at 25 ° C. for 2 hours, a saturated sodium bitartrate solution was added dropwise until the evolution of hydrogen ceased. After running for 5 minutes, 250 ml of dry methylene chloride were added to the reaction mixture. 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 mm) using chloroform as the eluent. After elution of less polar impurities, a fraction was obtained which contained 2.8 g of 2- / 3dC-p-phenylbenzoyloxy-5-.iC-hydroxy-2f ^> .- (3-hydroxy-3-phenyl-1-prop-l -yl) -cyclopent-loC-yl7-acetic acid- h -lactone (1? f).

The IR spectrum (CHCl,) of Compound 1 showed strong ° f i Carbonylabsorpt onsbanden at 1770 and 1715 cm

If the 2- / 3oC-p-phenylbenzoyloxy-5.- £ -hydroxy-2fc- (3-hydroxy-

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3-phenyl-l-propen-l-yl) -cyclopent-LTC-yl7 esBigsSure- ^ f-lactone is desired, the reaction is carried at -78 ⁰ C, and using instead of Lithiumtriäthylhorhydrid 7inkborhydrid through.

The product example "(ίο f) can be according to the procedure of the examples I3, IR - 1 ° and 21 - 2 '' in ^, lu-dihydro-15-phenyl-w-pentanorprostaglandins of series A, E or P can be transferred.

Example 59
Dimethyl 2-oxo-3-Cp-methoxyphenyl) propylphoRphonate (2h).

A solution of 7 ^, 5 g (FOO millimoles) Dimethvl methylphosphonate (commercial product of Aldrich) in 700 nl of dry tetrahydrofuran was cooled in a dry StickstoffatmosphPre to -78 ⁰ C. The stirred phosphonate solution was added dropwise over 10 minutes with 385 ml of a 1 M solution of ^ η-butyllithium in hexane (Poote Inc.) was added at such a rate daf ⁵ · the Reaktionsternperatur - never exceeded 5 ⁰ ^ C. After stirring for a further 5 minutes at -7B ⁰ C, 5 * 1 g (300 millimoles) of methyl-p-methoxyphenyl acetate were added dropwise at such a rate that the reaction temperature was kept at less than -70 ⁰ C (20 minutes). After 3.5 hours at -78 ⁰ C liep the Reaktionsgenisch to ambient temperatures warm nan. After neutralization with 55 ml of acetic acid, a wide gel was obtained during the evaporation of the potation. The gelatinous "was aterial was added to 75 ml of v / ater, the wäP-ERIGE phase was washed with 300 ml of chloroform three times, the united organic extracts were backwashed with 50 ciTK water, dried over magnesium sulfate and to a crude residue ^(w asserstrahlpunr > e), wherein in distillation 39.6 g ⁽¹ JQ, ^ "■ yield) of dimethyl-2-oxo-3- (p-methoxyphenyl) propylphosphonate (2 h) L67 having a boiling point 195 ° C (0.2 - 0.3 mm).

409810/1150

The NMR spectrum (CDCl ₃ ) showed a ^{doublet centered at 3, R} 3S (J = 11.5 cps, 6H) for (CH ₃ O) ₂ -P- ^ O-, a at 3.11 S ( 2H) centered doublet f ^f lr -CH ₂ -C (P, a singlet -at 3, BLLs (3H) CH ₃ OC ^ Hj ₁ and a MÜTtiplet for C ^ H _1, wherein from 6.82 to 7, ¹¹ IS

Dinethyl-2-oxo-3- (3, ^ij -methylendioxy) -, dimethyl-2-oxo-3-C5, dimethoxy) - and dimethyl-2-oxo-3 - (^, ⁱ i, 5-trimethoxy) - phenylpropylphosphonate can be prepared by the above process and converted into the corresponding l6-substituted w-tetranorprostaglandins of the series A, E or P by the process of Examples 2 - P ^,

Example 60

2- / 3.TC-p-phenylbenzoyloxy-5oC-hydroxy-2B- (3-oxo-i} - / p-methoxypheny17-trans-1-buten-l-yl) -eyelopent-loC-y 17 -acetic acid- y lactone (3 h).

3.2 g (11.7 yillimol) of dimethyl 2-oxo-3-Zp * -methoxyphenyl7-propylphosphonate (2 h) in 200 ml of anhydrous ether were mixed with 5.6 ml (o i-iillinol) of a 2 , ¹ ^ m solution of n-putyllithium in η-hexane (Foote Inc.) treated in a dry nitrogen atmosphere at room temperature. After stirring for 5 minutes, a further 100 ml of anhydrous ether, 2.5 g (7.15 MlIimol) 2- ^ 3 - ^ - p-Phenylbenzoyloxy-5oc -hydroxy-2P'-formylcyclopentane-1 ^ C-ylI-acetic acid-tT -lactone at once and then 75 ml of anhydrous ether added. After 35 minutes, the reaction mixture was treated with 5 ml of glacial acetic acid and extracted four times, ie 100 ml of saturated sodium bicarbonate solution, twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, whereby after column chromatography on silica gel (Baker , clear mesh size: 0 * 2iiP - 0.07 * »mm) 1.611 g (Ί6.5 % yield) 2- £ 3oC-p-phenylbenzoyloxy-5-oC-hydroxy-2i ^J > -

409810/1150

(3-OXO-4- (p-methoxyphenyl) -trans-l-buten-l-yl) -cyclopent-loC-yl7-acetic acid- Ϊ -lactone (3 h) as a ^ l.

The NMR spectrum (CDCI,) was consistent with the structure.

The product of this example (3 h) can be prepared according to the methods of Examples 1 *, IB - IQ and 21 -? H in 13, l ^ü -dihydro-l £ - p-methoxyphenyl-w-tetranorprostaglandins of series A, E or P be transferred.

The product (3 h) can also be converted into ^ -nied.Alkyl-li-p-methoxyphenyl-w-tetranorprostaglandins of series A, E or F ^{by the method of Examples 1 I - 26.} From the product (3 h) by the processes of Examples 16 and 21 - 2H 13, l ^] } -dihydro-15-lower alkyl-l ^ -p-methoxyphenylw-tetranorprostaglandins of the series A, E or F can be obtained.

Example 61

2- / 3oC-p-phenylbenzoyloxy-5oC-hydroxy-2ft- (3oC-hydroxy-ü- (pmethoxyphenyl) -trans-l-buten-l-yl) -cyclopent-loC-yl.7-acetic acid- T -lactone (* J h) and 2- ^ 3oC-p-phenylhenzoyloxy-5oO hydroxy-2ß- (3ß -hydroxy- ¹ * - (p-methoxyphenyl) -trans-1-buten-1-yl) -cyclopent-1 sC -ylJ-essigsimre - # "- lacton (5 h),

A solution of 5.5 g (11.1 millimoles) 2- <f3oC-p-phenylbenzoyloxy-5 <£ -hydroxy-2P> - (3-oxo- ^; 4- (p-methoxyphenyl) -trans-1-butenl -yl) -cyclopent-l ^: - yl7-acetic acid-ίΤ-lactone (3 h) in 50 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was treated dropwise with 10.0 ml of a 0.5 M zinc borohydride solution . Mach stirring for 2 hours at 0 ⁰ C was added dropwise a saturated Natriumbitartratlösung, until hydrogen evolution ceased. After stirring the reaction mixture for 5 minutes, 200 ml of dry methylene chloride was added. After drying over

/ »09810/1 1 50

Magnesium sulfate and concentration (water jet pump), the oil obtained was purified by column chromatography on silica gel (Baker "Analyzed" reagent with a mesh size of 0.248-0.07 mm) using ether as the eluent. After elution of less polar impurities, a fraction containing 1.0 "g of 2- / 3c £ -p-phenylbenzoyloxy-5-tC-hydroxy-2R- (3 oC-hydroxy-4- (p-methoxypheny 1) -trans -1-buten · l-yl) -cyclopent-loC-yl7-acetic acid-ü -lactone (H h), a fraction of 0.75 g of the mixed compounds H h and 5 h and finally a fraction of 2.05 g of 2- / 3oC-p-phenylbenzoyloxy-5-) C'-hydroxy-2ß- (3- ^p '-hydroxy-4- (p-methoxyphenyl) -trans-1-buten-yl) -cyclopent-1: xl-yl7-acetic acid o lactone (5 h) obtained.

The IR spectrum (CHCl,) of the compounds H h and 5 h were congruent and showed strong carbonyl absorption bands at 1775 and 1720 cm and an absorption band at 9 ^ 5 cm for the trans double bond.

Example 62

2- / 3 zC , 5 dC. r Dihydroxy-2ß- (3oC -hydr oxy-'i- (p-methoxypheny 1) trans-1-buten-1-yl) -cyclopent-lo £ -ylj-acetic acid-a-lactone (6 h).

A heterogeneous mixture of 1091 mg (2.2 millimoles) 2- / 3oC-p-PhenyIbenzoyloxy-5 aC -hydroxy-21 ⁵ .- (3 οίΤ-hydroxy-ü- (p-methoxyphenyD-trans-1-butene-l -YD-cyclopent-loi-yU-acetic acid a lactone (H h), 30 ml of absolute methanol and 306 mg of finely powdered, anhydrous potassium carbonate was stirred for one hour at room temperature, and s "odann cooled to 0 ⁰ C. The cooled solution was treated with 1.0 η w ^ ßeriger hydrochloric C ^{1, 1} * millimoles) was added. Hach lOminütigem stirring at ⁰ ° C were added 5 ml of water, whereby simultaneously methyl-pphenylbenzoat formed which was filtered off. the filtrate was saturated with solid sodium chloride and extracted three times with 100 ml of ethyl acetate each time.

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The tracts were washed with 25 ml of saturated sodium carbonate air, dried over magnesium sulfate and concentrated, leaving 700 mg (100 % yield) of viscous, oily 2- / 3 dC, 5cC-, dihydroxy-2ß- (3 oC-hydroxy-u- (p -methoxyphenyl) -trans-1-butenl-yl) -cyclopent-löc-ylj-acetic acid-if-lactone (fi h) were obtained.

The IR spectrum (CHCl,) showed a strong absorption band at 1770 cm for the lactone carbonyl group and a mean absorption band at 970 cm for the trans double bond.

409810/1 150

Example 63

2- / 3Qf, 5x-dihydroxy-2ß- (3ß-hydroxy-4- (p-metho * y ^ pheny J) -trans-l-buten-l-yl) -cyclöpent-lq ^ -yl7Äeeigsäure-j ^A " -lacton (6'h)

A heterogeneous mixture of 2.05 g (4.04 mmol) 2- / 3Λ.-ρ-phenylbenzoyloxy-5C (-hyclroxy-2ß- (3ß'-hydroxy-4- (p-ynethoxyphenyD-trans-1-buten- l-yDcyclopent-lx-yiZessigsäure-y ^ -lactone (5h), 50 ml of absolute methanol and 56Ο 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 mixed with 8.2 ml (8, 2 mmol) 1.0 η aqueous hydrochloric acid was added. After further lOminüfcigem stirring at 0 ⁰ C 5 ml of water was added with concomitant formation of methyl p-phenylbenzoate which was filtered off. the Piltrat was saturated with solid sodium chloride, with Ethyl acetate (4 150 ml) extracted, the combined organic extracts washed with saturated sodium bicarbonate (25 ml), dried over magnesium sulfate and dried to give 990 mg (76 %) viscous oily 2 - / ^, 5 ^ -Bihydroxy-2ß- (3ß-hydroxy-4- (p-methoxyphenyl) -trans-1-butene-1-yDcyclopent-1cC-y ^ acetic acid-j ^ lactone (6'h) concentrated.

The IR spectrum (CHCl,) showed a strong absorption at

-1 *

1,770 cm for the lactone carbonyl and a mean absorption at 970 cm for the trans double bond.

Example 64

2- / 3> o.-Hydroxy-3CiC- (tetrahydropyran-2-yloxy) -2β- (3 £ - (tetrahydropyran-yloxyj; -4- (p-methoxyphenyl) -trans-l-buten-l-yl) cyclopent-la-yl-acetic acid- ^ lactone (7h)

098 10/1 150

- 11? -

A solution of x 700 mg (2.2 mmol) 2 - _ / 3 *, 5 ^ -dihydroxy-2ß- (3X-hydroxy-4- (p-methoxyphenyl) -trans-1-buteni-yDcy clopentlX-y ^ L7essigsäure-y ^s ~ lactone (6h) in 15 ml of aqueous methylene chloride and 1,5-dihydropyran ml'2,3 was added at O ⁰ C in a dry nitrogen atmosphere with 10 mg of p-toluenesulfonic acid. After stirring for 25 minutes the reaction mixture was 100 ml of ether were combined, the ether solution was washed with saturated sodium bicarbonate. (2 × 20 ml) and then with saturated saline solution (1 × 20 ml), dried over magnesium sulfate and yielded 1,200 mg (> 100 % ) of crude 2- / 5 Jii-Hydroxy ^ -t-Ctetrahydropyran ^ -yloxy) -2ß- (3 \ - tetrahydropyran-2-yloxy 4- (p-methoxyphenyl) -trans- 1-buten-l-yl) eye lopent-tt-y l7- acetic acid-p-lactone (7h) concentrated.

The IR spectrum (CHCl _x ) showed a medium absorption at

- 1

970 cm for the trans double bond and a lactone

- i

carbonyl absorption (strong) at 1770 cm

The product of this example (7h) can be converted into the 13,14-dihydro-16-p-methoxyphenyl-M. * - tetranorprostaglandins the A, E or F series according to the procedure of Examples 14, 16, 18 and 20 to 24 are transferred.

Example 65

2- / 5x-Hydroxy-3 ^ (tetrahydropyran-2-yloxy) -2ß- (3ß- {tetrahydropyran-2-yloxy | -4- (p-methoxyphenyl) -trans-1-buten-1-yl ) -cyclopent-lCt-yl / acetic acid-J ^ lactone (7'h)

409810/11 SO

- Ill -

A solution of 990 mg (3.12 mmol) 2 - / _ 3; _tj 5 _l 5 (.- Dihydroxy-2ß-Oß-hydroxy-il-ip-methoxyphenyD-trans-l-butenl-yDcyclopentijC-yl-acetic acid - ^ - lactone (6'h) in 20 ml of anhydrous methylene chloride and 2.0 ml of 2 , 3-Dihydropyran was ^{treated with 10 mg of p-toluenesulfonic acid monohydrate in a dry nitrogen atmosphere at 0} ° C. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ether solution was mixed with saturated sodium bicarbonate (1 × 25 ml) and then with saturated salt solution (1 χ 25 ml), dried over magnesium sulfate and formed 1700 mg (> 100 %) crude 2- / 5jc-hydroxy-3. * - (tetrahydropyran-2-yloxy) -2ß- (3ß- {tetrahydropyran -2-yloxy4-4- (p-methoxyphenyl) -trans-l-buten-l-yl) cyclopent-l-; t-yl7-acetic acid - ^ - lactone (7'h) concentrated.

The IR spectrum (CHCl-,) showed a medium absorption

ng -1

at 970 cm for the trans-double bond and a lactone

carbonyl absorption (strong) at 1770 cm Example 66

-2ß- (3x- / tetra-

hydropyran-2-yloxy} -4- (p-methoxyphenyl) -trans-1-buten-1-yl) -cyclopent-lcv-y27acetaldehyde-j ^ -hemiacetal (8h)

A solution of 2.2 mmol 2- / 5dr-hydroxy-3 ^ - (tetrahydropyran-2-yloxy) -2ß-3x- {tetrahydropyran-2-yloxy j -4- (p-methoxypheny I) -trans -l-buten-l-ylicyclopent-l ^ V ^ -yiyessigsaure-lactone (7h) in 15 ml dry toluene was cooled to -78 ⁰ C in a dry nitrogen atmosphere. This, cooled solution was added 5.0 ml of 20 £ sodium Diisobuty! Aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ⁰ C (15 minutes). After further stirring for 45 minutes at -78 ⁰ C, anhydrous methanol was added until gas evolution ceased, and was allowed the reaction mixture to Raumtempera-

4 0981 0/1150

warm the door. The reaction mixture was combined with 100 ml of ether, washed with 5% sodium potassium tartrate solution (4 × 20 ml), dried over Na ^ SO ^ and concentrated and chromatographed, 900 mg (84% ) of the title compound (8h) being obtained.

Example 67

2- / 5x-Hydroxy-3Cfc- (tetrahydropyran-2-yloxy) -2β- (3β-ft> ethrahydropyran-2-yloxyJ- ¹ J- (p-methoxyphenyl) -trans-1-buten-1-yl) cyclopent-lc (.-yl7acetaldehydy-hemiacetal (8 * h)

A solution of 2.68 mmol 2- / jj <x -hydroxy-3 £ - (tetrahydropyran-2-yloxy) -2ß- (3ß- [tetrahydropyran-2-yloxyj - ^ - (p-methoxyphenyl) -trans-1 -buten-l-yl) eye lopentlactone (7 ^f h) in 15 ml of dry toluene was cooled to -78 ° C. in a dry nitrogen atmosphere. This cooled solution was treated with 8.0 ml 20iigem Diisobuty! Aluminum hydride in η-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ⁰ C (15 minutes). After further ^ minutes of stirring at -78 ⁰ C, anhydrous methanol was added until gas evolution ceased and the reaction was allowed to warm to room temperature. The reaction mixture was combined with 100 ml of ether, ^{washed with 50% sodium potassium tartrate solution (1} l 20 ml), dried over Na 2 SO 4, concentrated and chromatographed. A yield of 1,150 mg (87%) of the title compound (8'h) was obtained.

Example 68

9 c ^ -Hydroxy-Hoc, 15oc ~ l> is- (tetrahydropyran-2-y Ioxy) -16- (pmethoxyphenyl) -cis-5-trans-13-u> -tetranor-prostadienoic acid

(9h)

09810/1 1 50

A solution of 3720 mg (8.55 mmol) of (iJ-carbohydroxy-n-butyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 7.4 ml of dry dimethyl sulfoxide was mixed with 7 »9 ml (15» 3 mmol) of a 1.96 m solution added by sodium methyl sulfinyl methide in dimethyl sulfoxide. This red ylid solution was added dropwise with a solution of 900 mg (1.84 mmol) 2 - / "5QCr hydroxy-3o (r (te trahy dropyran-2-yloxy) -2ß- (3o (-ftetrahydropyran-2-yloxyj - ⁱ <- (p-methoxyphenyl) -trans-lbutene-1-yDcyclopent-1-yl / acetaldehyde-1-hemiacetal (8h) in 5.0 ml of dry dimethyl sulfoxide added over a period of 20 minutes, after stirring for a further 2 hours The reaction mixture was poured into ice water at room temperature. The basic aqueous solution was acidified with 10% aqueous hydrochloric acid to a pH of about 3. The acidified solution was extracted with ethyl acetate C3 x 100 ml) and the combined organic * were extracted once with water ( 50 ml), dried over magnesium sulfate and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" Regent grain size 7H - 250 microns) using chloroform and then Ethyl acetate as Eluent purified. After removing the high R ^ impurities, 762 mg of the title compound (9h) were obtained.

The IR spectrum (CHCl3) showed a carbonyl absorption at

-1 1715 cm and a trans double bond absorption at 970 cm " ¹ .

The product of this example (9h) can be converted into the 16-p-methoxyphenyl-u> tetranorprostaglandins of the F series (P ₂ , P ₁ , P_) by the processes of Examples 16, 2k and 25.

0 98 1 0/1150

Example 69

9UCHyIOXy-IICC, 15β-bis (tetrahydropyran-2-yloxy) -16- (pmethoxyphenyl) -cis-5-transi-ü> tetranor-prostadienoic acid (9 'h)

A solution of 4876 mg (10.95 mmol) of (4-carbohydroxy-nbutyl) triphenylphosphonium bromide in a dry nitrogen atmosphere in 9.7 ml of dry dimethyl sulfoxide was mixed with 10.3 ml (20.0 mmol) of a 1.96 m solution of Sodium methyl sulfinyl methide is added to dimethyl sulfoxide. This red ylid solution was added dropwise with a solution of 1150 mg (2.34 mmol) 2- / 5u £ -hydroxy-30Cr (tetrahydropyran-2-yloxy) -2ß- (3ß- £ tetrahydropyran-2-yloxyJ- ¹ l- (p-methoxyphenyl) -trans-1-buten-1-yDcyclopent-loC-yl / acetaldehyde- ^ A 'hemiacetal (8 ^f h) in 7.0 ml of dry dimethyl sulfoxide were added over a period of 20 minutes, after which the mixture was stirred for a further two hours the reaction mixture was poured onto ice water at room temperature, the basic aqueous solution was acidified with 10% aqueous hydrochloric acid to a pH of about 3. The acidified solution was extracted with ethyl acetate (3 × 100 ml) and the combined organic extracts were mixed 1 × with Washed water (50 ml), dried over magnesium sulfate and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The piltrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent grain size 7 ^ 4-250 mm) using of chloroform and then ethyl acetate purified as an eluent. After removing the * ¹⁰ ] ^ ¹¹ R _f impurities, 898 mg of the title compound were obtained (9'h).

The IR spectrum (CHCl3) showed a carbonyl absorption at

-1 1715 cm and a trans double bond absorption at 970 cm " ¹ .

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Example 70

9-Oxo-llail5Qi-bis (tetrahydropyran-2-yloxy) -16- (pmethoxyphenyl) -cis-5-trans-13-0> -tetranor-prostadienoic acid (10 h)

A solution, cooled to -10 ° C and under nitrogen, of 762 mg (1.3 mmol) of 9ot hydroxy-llo (, 15 <£ -bis- (tetrahydropyran-2-yoxy) -16- (p-methoxypheny l) -cis-5-trans-13-U- ^ t etranorprostadienäure (9h) in 15 ml reagent-pure acetone was added dropwise with 0.6 ml (1.6 mmol) Jones ¹ reagent. After 20 minutes at -10 ⁰ C 0 , 6 ml of 2-propanol was added and the reaction mixture was stirred for an additional 5 minutes and then combined with 100 ml of ethyl acetate, washed with water (3 x 25 ml), dried over magnesium sulfate and concentrated to give 617 mg of the title compound (10h).

The IR spectrum (CHCl ₃ ) had strong carbonyl absorptions at 1710 and 17 * 10 cm "and a trans -Doppe Ib indungsabsorption at 970 cm".

Example 71

9-Oxo-llo ^, 15β-bis (tetrahydropyran-2-yloxy) -16- (p-methoxyphenyl) -cis-5-trans-13-0J-tetranor-prostadic acid (10'h)

A solution, cooled to -10 ° C under nitrogen, of 898 mg (1.57 mmol) of 90C-hydroxy-llct, 15β-bis (tetrahydropyran-2-yloxy) -16- (p-methoxyphenyl) -cis-5- trans-13-U ^ ^r tetranor-prostadienoic acid (9'h) in 15 ml of reagent-grade acetone was added dropwise with 0.64 ml (1.7 mmol) of Jones ¹ reagent. After 20 minutes at -10 ° C., 0.64 ml of 2-propanol were added and the reaction mixture was stirred for a further 5 minutes, then combined with 125 ml of ethyl acetate, washed with water (3 × 25 ml), over MgSOj. dried and concentrated to give

409810/1150

of 823 mg of the title compound (10 η).

The IR spectrum (CHCl,) showed strong Carbonylabsorptionen at 1710 and 17 ¹ IO cm and a trans-double bond absorption at 970 cm ~.

Example 72

9-0x0-11 «., 13-CJ-tetranor-prostadienoic acid (llh)

A solution of 617 mg of 9-oxo-lloc, 15 ^ -bis-tetrahydropyran-2-yloxy) -16- (p-methoxyphenyl) -cis-5-trans-13 - <- »> tetranorprostadienoic acid (10h) in 6.1 ml of a 65:35 mixture of glacial acetic acid / water was under nitrogen at 25 ° C for 20 minutes stirred for a long time and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-I, grain size 74-1Ί9 microns) using ethyl acetate as Eluent purified. After eluting the less polar impurities, there was obtained 230 mg of the oily title compound (llh) won.

The IR spectrum (CHCl-) showed carbonyl absorptions at

- 1
1715 and 17 ^ 5 cm and a x trans double bond absorption

at 970 cm ".

The product of this example (IIh) can be converted into the 16-p-methoxyphenyl-U> tetranorprostaglandins E 1, E _Q A ₂ , A ₁ and A ₀ by the methods of Examples 25, 26 and 18.

40981 0/1150

Example 73

9-Oxo-IIq ,, ISβ-dihydroxy-lo-Cp-methoxyphenyD-cis-S-trans-13-U> -tetranor-prostadienoic acid (ll'h)

A solution of 823 mg of 9-oxo-llO £, 15SS-bis-tetrahydropyran-2-yloxy) -l6- (p-methoxyphenyl) -cis-5-trans-13-ü> ^fc tetranorprostadiensäure (10'H) in 8 , 2 ml of a 65:35 mixture of glacial acetic acid / water was stirred under nitrogen at 25 ° C. for 20 minutes and was then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-Jl, particle size 74-1 ^ 9 microns) using ethyl acetate as the eluent. After the less polar impurities had been eluted, 300 mg of the title compound (II'h) were obtained.

The IR spectrum (CHCl-) of 11'h showed carbonyl absorption at 1740 and 1750 cnT * and a trans double bond absorption at 970 cm

409810/1150

Example 74

2-0x0-3- (.beta.-naphthyl) -propylphosphonsäuredimethylester (2m): A solution of 74.5 g (0.6 mole) of dimethyl methylphosphonate (Aldrich) in 750 cc of dry tetrahydrofuran at -78 ⁰ under an atmosphere of dry nitrogen C chilled. To the stirred solution were added dropwise 265 ecm of a 2.34 M solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) over a period of 40 minutes at such a rate that the temperature did not rise above -65.degree. After stirring at -78 ° C. for a further 5 minutes, 60 g (0.3 mol) of methyl 2- (β-naphthyl) acetic acid were added dropwise at such a rate that the temperature remained below -70 ° C. (10 minutes). After 3 1/2 hours of reaction time at -78 ⁰ C, the reaction mixture was neutralized with 35 cc acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ecm of water, the aqueous phase was extracted 3 times with 200 ecm of methylene chloride each time, the combined organic extracts were washed with 50 ecm of water, dried with magnesium sulfate, concentrated to a crude residue (water jet vacuum) and distilled. Was obtained the 2-0xo-3- (ßnaphthyl) -propylphosphonsäuredimethylester (2 m), bp .: 195-200 ⁰ C 1 mm Hg).

KMR spectrum (CDCl,): doublet at 3.72 «Γ (J = 11.5 cps, 6H) for

(CH, O) _P -P-; Duplicate at 3.09 J (J = 2Z cps, 2H) for -C-CH-P-: 2 c- »ι ti ^ Ii

0 0 0

Singlet at 4.0 / (2H) for -CJ ₂ -C- and multiplet at 7.18 7.92 cT (7H) for C ₁₀ H ₇ . Q

The compound is a suitable starting product for manufacture

409810/1150

of i6- (ß-naphthyl) -tf-tetranorprostaglandins of the A, E or F series following the procedures of Examples 2 to 26.

2-Oxo- (v-naphthyl) -propylphosphonic acid dimethyl ester is as above described, but using the 2 - (<x-naphthyl) · methyl acetate instead of methyl 2- (ß-naphthyl) acetic acid. This compound is a suitable starting product for the production of 16 - (<x-naphthyl) -u) -tetranorprostaglandins of the A, E or F series following the procedures of Examples 2 to 26.

409810/1150

More connections

O it

Ar- (CH ₂ ) _n -C-CH ₂ -P (OCH ₃ )

Ar

Kp./F. ( ⁰ C)

(a)

0-ToIyI 1 β-naphthyl 1 * -Naphthyl 1 2-ethylphenyl 1 p-biphenyl 1 f * -naphthyl 0

155-163 ° (0 .05 mm) 1 .1 195-200 ° (1 mm) 1 22nd (b) 22nd (b) 1 1 F.r 56-58 0 (b) 22nd (b) 77

KMR data (Jcps)
(c) (11.5) 3.10 (d) I. 3.75 (11.5) 3.09 (23) ro 3.72 (11.5) 3.06 (22) I. 3.75 (11) 3.15 (23) 3.83 (11.5) 3.12 (25) 3.79 (11.5) 3.79 (23) 3.80 (23)

(a) Connection has been established according to the example given,

(b) Purified by column chromatography.

(c) methoxyl protons.

(d) -C-CHp-P-

Il <- It

TO CO CO

CO cn

Additional compounds of the formula:

ο to oo

Ar η F. ⁰ C p-biphenyl 1 150-153 tx-naphthyl 1 oil β-naphthyl 1 120-128 o-tolyl 1 120-121

(a)

2 2 2 (CH ₂ J _n -Ar

IR data

1715, 1775, 1630, 1680, 970

1710, 1770, 1625, 1675, 970

1710, 1770, 1625, 1670, 970

1720, 1775, 1625, 1680, 970

(a) Manufactured according to the example given.

Additional compounds of formula (a):

-Ar

Ar

Z (b)

O (D OO

p-biphenyl 1 OH D. p-biphenyl 1 OH D. o-tolyl 1 OH D. o-tolyl 1 OH D. p-naphthyl 1 OH D. p-naphthyl 1 OH D. cx-naphthyl 1 OH D. «-Naphthyl 1 OH D. Phenyl (noun) 1 (e) S.

Pol. (C)

LP MP LP MP LP MP LP MP

(e)

SS (d) IR data

B 1715,1775,970

B 1715,1775,970

A 1710, 1770, 965

C 1710.1770.965

B 1715,1775,970

C 1715,1775,970

A 1715,1775,970

A 1715,1775,970

1710.1775

a) Manufactured according to the procedure of the example

b) D = trans double bond, S = single bond.

c) mobility in thin layer chromatography; LP = less polar, MP = more polar.

d) Solvent system for isomer separation by column chromatography:

A) 9: 1 diethyl ether / cyclohexane.

B) diethyl ether.

C) 1: 1 diethyl ether / ethyl acetate.

e) Mixture not separated at the hydroxyl carbon. ¹ ^

f) Prepared by catalytic reduction of the compound in which Z = trans. ^

CO

cn

Additional compounds of formula (a)

HO -

(CH ₂ ) _n -Ar

Ar

p-biphenyl 1 p-biphenyl 1 o-tolyl 1 0-ToIyI 1 (i-naphthyl 1 f ^ -naphthyl 1 D (-naphthyl 1 «-Naphthyl 1 Phenyl 1 Phenyl 0

D D D D D D S S

ρ, -ΟΗ

«-0H

(!, - 0H

ix -OH

ß-OH

οί-ΟΗ

(i-OH

(c) -0H

(c) -OH

IR data

1770.970 1770.970 1760.960 1760.960 1770.970 1770.970 1770.970 1770,970 1770

1770

a) Manufactured according to the procedure of the example

b) D = trans double bond, S = single bond.

c) Mixing of epimers.

Additional compounds of formula (a):

.THPO ,.

(CH ₂ ) Ar

O
to Ar CO P-biphenyl O p-biphenyl -ν. o-Tülyl -α ο-ToIyI - * ft-naphthyl cn / i-naphthyl a-naphthyl * -Naphthyl Phenyl Phenyl Phenyl

1 1 1 1 1 1 1 1 1 1 O

D D D D D B D D S S S

ex -OTHP fi-OTHP

.k-OTHP Oi-OTHP (V-OTHP ö (-OTHP ft-OTHP K-OTHP P-OTHP (C) -OTHP

ΙΏ data

1770.970 1770.970 1760.960

1770.965 1770.970 1770.970 1775.970

1775,970 1770

1770

1770

a) Manufactured according to the procedure of Example 6.

b) D = trans double bond, S = single bond.

c) Mixing of epimers.

co co

cn

Additional compounds of formula (a):

THPO · - ^{1 1} ^ ^ v - ( ^CH 2) n " ^Ar

tXr

O
CD Ar η OO -> p-biphenyl 1 O p-biphenyl 1 o-tolyl 1 o-tolyl 1 cn P-naphthyl 1 O | * -Naphthyl 1 «-Naphthyl 1 «<-Naphthyl 1 Phenyl 1 Phenyl 0 Phenyl 1 Phenyl 1

Z (b)

D D D D D D D D S S S S

CH-OTHP ρ "-OTHP" -OTHP (V-OTHP a-OTHP & -OTHP α -OTHP (^ -OTHP ό (-ΟΤΗΡ

(c) -OTHP

(c) -OH | i -OTHP

R. IR data H 970 H 970 H 970 H 970 H 970 H 970 H 970 H 970 H H wm CH, M. H * mm

a) Prepared according to the method of Example 7

b) D = trans double bond, S = single bond

c) Mixing of epimers.

TO Ca)

CO

cn

Additional prostaglandins of the formula:

Ar

p-biphenyl

p-biphenyl

o-tolyl

ο-ToIyI

p-naphthyl

fc-naphthyl

Oi-naphthyl

«-Naphthyl

Phenyl

Phenyl

Phenyl

Phenyl

Ca) O

D D D D D D D D S S S S

HO '

p> -OH

-OH

^ -OH
ft-OH
ot-OH
fi-OH
• -OH
-OH

-H

-H

-H

-H

-H

-H

-H

-H

-H

-H

-CH,

-H -

• ^ \ COOH 17 * fO 970 Isomer (d) (CH ₂ ) nAr 174Ο 970 MP 1737 970 LP IR data 1730 965 MP 1710 1740 970 LP 1710 1740 970 MP 1712 17 * fO 965 LP 1712 17 ^ 0 965 MP 1710 1735 mm LP 1710 1735 - MP 1705 1735 - LP 1705 1735 (e) 1710 (e) 1710 I710 1705

a) Manufactured according to the method of Example I4.

b) Prepared according to the method of Example 15.

c) D = trans double bond, S = single bond.

d) Mobility in thin layer chromatography, MP = more polar, LP = less polar. N3

e) Left / right mixture, the CO separated by high pressure liquid / liquid chromatography can be. '^

Additional compounds of the formula:

• THPO.

COOH

Ar

p-biphenyl 1 D. p-biphenyl 1 D. o-tolyl 1 D. o-tolyl 1 D. P-naphthyl 1 D. p-naphthyl 1 D. tf-naphthyl 1 D. H-naphthyl 1 D. Phenyl 1 S. Phenyl 1 S. Phenyl 1 S. Phenyl 0 S.

W-OTHP (! »- OTHP u -OTHP / S-OTHP 0 (-OTHP (^ -OTHP Q (-0THP j * -OTHP ot-OTHP £ -OTHP

(d) -OH

(d) -OTHP

-H (a) -H (b) -H (a) -H (b) -H (a) -H (b) -H (a) -H (b) -H (a) -H (b) -CH, (a) -H ³ (a)

a) Manufactured according to the procedure of Example 12,

b) Manufactured according to the procedure of Example 13 «

c) D = trans double bond, Ss single bond.

d) Mixing of epimers.

ro co co

Additional compounds of the formula:

THPO

COOH (CH ₂ ) Ar

p-biphenyl

p-biphenyl

o-tolyl

o-tolyl

f * -naphthyl

β-naphthyl

<X-naphthyl

tx-naphthyl

Phenyl

Phenyl

Phenyl

Phenyl

Z (c)

1 D. 1 D. 1 D. 1 D. 1 D. 1 D. 1 D. 1 D. 1 S. 1 S. 1 S. 0 S.

O ^ -OTHP (S-OTHP <* - OTHP f> -OTHP W-OTHP (V-OTHP öi-OTHP S-OTHP ίχ-ΟΤΗΡ

(d) -OH (d) -OTHP

-H -H -H -H -H -H -H -H -H -H -C -H

(a) Cb) (a) (b) (a) (b) (a) (b) (a) (b) (a) (a) IR data

1705.970 1705.970 1712.975 1712.970 1710.970 1710.970 1705.970 1705.970 1710 1710 1710 1710 -

a) Manufactured according to the procedure of Example 10.

b) Prepared according to the procedure of Example 11.

c) D = trans double bond, S = single bond.

d) Mixing of epimers.

co co .ο co

cn

Additional prostaglandins of formula (a)

OH

HO.

COOH

Ar

p-biphenyl 1 D. p-biphenyl 1 D. o-tolyl 1 D. o-tolyl 1 D. p-naphthyl . 1 D. (i-naphthyl 1 D. «X-naphthyl 1 D. <tf-naphthyl 1 D. Phenyl 1 S. Phenyl 0 S.

ft-OH

«-0H

(V-OH

λ-OH

(i-OH

«-0H

' joyful

(c) -OH

(c) -OH

H H H H H H H H H H IR data

1710.965

1712.970 1710.975 1705.970

1710.970 1700.970 1710

1705

a) Prepared according to the procedure of Example 16.

b) D = trans double bond, S = single bond.

c) Mixing of epimers.

Example 75

9-0x0-11ος, 1 5oc-dihydroxy-1 öp-biphenyl-iJ-tetranorprostanoic acid: A heterogeneous solution of 9-Oxo-i U, 15 * -dihydroxy-i6-p-biphenyl · cis-5-trans-13- w-tetranorprostadienoic acid and 5 % palladium on charcoal in absolute methanol was hydrogenated for 2 hours at 25 ° C. (1 atm). The reaction mixture was filtered and evaporated. The above compound was obtained, F .: 120 to 123 ^° C.

IR spectrum (KBr _x ): carbonyl absorptions at 1715 cm "and 1735 cm J a broad OH range and no trans double bond absorption.

Example 76

9β, 1 lot, 15 ^ -Trihydroxy-16-phenyl-cis-5-trans-13-v ^ -tetranorprostadienäure:

Oc to a solution of 7k mg (0.2 mmol) 9-0xo-11, 15 «* - dihydroxyi6-phenyl-cis-5-trans-13 - ^> - tetranorprostadiensäure in 10 cc of absolute methanol was added at O ⁰ C a given a cooled solution of 300 mg of sodium borohydride in 35 ecm of absolute methanol. After 20 minutes at ⁰ ° G, the mixture was allowed to warm to room temperature and stirred for a further hour. The reaction mixture was then ^{cooled to 0} ° C., 2 ecm of water were added, the solvent was evaporated in vacuo, the residue was taken up in 10 ecm of ethyl acetate and acidified in an ice bath with 10 percent hydrochloric acid to a pH of about 3. This mixture was extracted with ethyl acetate (if χ 5 ecm), dried (Na-SO,), concentrated and chromatographed on silica gel (00-7). Using 97% methylene chloride / methanol and 95 % methylene chloride / methanol as the eluent, 22 mg of 9er "11" .15x-trihydroxy-16 -] & enyl-

409810/1150

cis-5-trans-13-M> -tetranorprostadienoic acid and then 18 mg of the desired 9β, 11β (, 1 5K-trihydroxy-16-phenyl-cis-5-trans-13-u> -tetranorprostadienoic acid obtain.

EXAMPLE 77

2-0xo-3- (2-thienyl) -propylphosphonsäuredimethylester (2d): Under dry nitrogen, a solution of 37.2 g (0.3 mole) of dimethyl methylphosphonate (Aldrich) in dry tetrahydrofuran ecm ZfOO was cooled to -78 ⁰ C. To this stirred solution was added dropwise innorhalb of 18 minutes 1% cc of a 1.6 m solution of n-butyllithium in η-hexane (Alfa Inorganics, Inc.) at such a rate, where _t that the temperature did not -65 ° C rise. After further stirring for 5 minutes at -78 ⁰ C 23Λ g (0.15 mol) of 2- (2-thienyl) acetate was added dropwise at such a rate that the temperature remained below -70 ⁰ C (20 minutes) . After 3 1/2 hours at -78 ⁰ C the mixture was allowed to warm to room temperature, neutralized with 6 cc of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ecm water, the water phase was extracted 3 times with 100 ecm chloroform each time, the combined organic extracts were washed with 50 com H2O, dried with magnesium sulfate, concentrated in a water jet vacuum to a crude product and this was distilled. Obtained were 4.8 g of 2-oxo-3- (2-thienyl) -propylphosphonsäuredimethylester (2d), bp .: 150-152 ⁰ C "0.5 mm Hg).

KMB spectrum (CiDCl *): Duclette at 5 _r ? / CJ = 11.0 cps _s 6E> for - (GE ₇ -O) PP-? Singled bsi * f _t 12 ^ (2H * for Ar-GHt-CCH doublet at

J ^ 22 cps, 2H) for -G-CH., \ Mta-fciplstts. at 6 _t S-7.3 «T (3H)

1?

for the thionyl i / z-j-lono. ^

40SS10 / 1 ISfI

In the same way, the corresponding β-thienyl compound manufactured.

KMR spectrum: 3.65 c / (J = 11 cps) 3, IcT (J = Zk cps).

Example 78.

2- £ 3 "-p-phenylbenzoyloxy-5" -hydroxy-2 [beta ]- (3-oxo-4- (2-thienyl) -trans-1-buten-1-yl) -cyclopent-1oc-yl3-acetic acid-jf -lactone (3d): 2-0x0-3- (2-thienyl) -propylphosphonic acid dimethyl ester (2d) (6.4 g, 25.7 milimoles) was in 300 ecm anhydrous ether under dry nitrogen at room temperature with 7.7 ecm ( 18 milimoles) of a 2.34 M solution of n-butyl lithium in η-hexane (Alfa Inorganics, Inc.). After stirring for 5 minutes, a further 300 ecm of anhydrous ether were added, followed by 6.0 g (17 milimoles) of 2- £ 3tf-p-phenylbenzoyloxy-5i (-hydroxy-2ß-formylcyclopent-1 Oi-yl ^ J-acetic acid in one portion -jf-lactone and 50 ml of water-free ether were added. After 35 minutes, the reaction mixture was quenched with 5 ml of glacial acetic acid, washed 1 with 100 ml of saturated sodium chloride solution, dried with magnesium sulfate and evaporated. After column chromatography (silica gel "Baker ¹¹ , pocket width 76 to 251 microns), -3.28 g of the above compound (3d) was obtained as an oil.

IR spectrum (CHCl,): bands at 1770 cm, 1675 cm " ¹ (medium strength) and 1625 cm" ¹ (i

~ ¹ (strong), 1705 cm " ¹ (strong), (medium strong), which belong to the carbonyl groups and at 970 cm" for the trans double bond.

ΚΚίϊ spectrum (CDCl,) ί doublet at 6 _f 27c / (1H, Ja ifi cps) for the olefinic Protonj singlet at 4.01 / (2H) for Ar-CH ₂ -C; Multiplets at 4.90-5.50 ^ (2H) and 2.05-3.20 </ (6H) for the remaining Ρίο tones,

Ir: for example , the corresponding β-thienyl compound became in the same way

409Ö10 / HS0

135 IR spectrum: bands at 1715, 1775, 1630, 1670 and 970 cm " ¹ .

The compound (3d) of this example can be according to those described herein Process in the 13, i ^ -Dihydro-iö-te-thienyl ^ -tetraiiQrprastaglandine A, E or F series can be converted.

The compound (3d) can also be carried out according to the methods of the examples 80 to 102 into the 15- (n-mer) alkyl-16- (2-thienyl) -w * -tetranorprostaglandins A, E or F series can be converted.

Follow the procedures of Examples 10-13 and 15-18 the compound (3d) into the 13,14-dihydro-15- (lower) alkyl-16- (2- •; hienyl) - *> - tetranorprostaglandins A, S or F series can be converted.

Example 79

3 * -p-phenylbenzoyloxy-5 * -hydroxy-2ß- (3 <* - hydroxy-4- (2 _r thienyl) trans-i-buten-i-yl ^ -acetic acid - ^ - lactone (4d) and 2- {3 ^e <-p-phenylbenzoyloxy-5 * i-hydroxy-2ß- (3ß-hydroxy-if- (2-thienyl) -t? Ans-1-buten-1-yl) -cyclopent-1 * i-yl I-acetic acid- ^ t-lactone (5d): To a solution of 4.7 g (10 millimoles) 2 "- [3" iP-phenylbenzoyloxy-5 ".- hydroxy-2ß- (3-oxo-4- (2-thie nyl) -trans-1-butene-1-yl} -cyclopenta i ^ -yl ^ -acetic acid-Jf-lactone (3d) in 30 ecm of dry 1,2-diinethoxy-methane were added under dry nitrogen room temperature was added dropwise 10 cc of a 0.5 m-Zinkborhydridlösung optionally After einatündigem stirring at room temperature, a saturated Katriumbitartrat solution was dropwise added until the hydrogen 93twicklung ceased, the reaction mixture was further 5 ^Minii;.:. i: gsrührt and then 200 cc dry methylene chloride added, drying with MgSO, and concentration in a water jet vacuum; the semi-solid product is destroyed by the use of ether as the eluent by chromium matograph on a silica gel column ("Baker-

409810/1 1 50

Analyzed "reagent, mesh size 76 to 251 microns). After eluting less polar impurities, the following fractions were obtained: 710 mg 2- [3 * -p-phenylbenzoyloxy-5o (-hydroxy-2ß- (3ß-hydroxy-if- (S-thienyD-trane-i-buten-i-yli-cyclopent-iiy-yl-acetic acid- ^ -lactone (5d), 50 mg of an if and 5 mixture and 862 mg 2- £ 3K-p-Phenylbenzoyloxy-5 ^ -hydroxy-4- (2-thienyl) -trana-1-buten-yD-cyclopent-iH-ylJ-acetic acid-y-lactone (* fd).

IH spectrum (CHCIj) of ^: strong carbonyl absorptions at 1770 and 1710 cm and an absorption at 965 cm for the * trans double bond,

The corresponding β-thienyl compound was prepared in the same way from the appropriate starting material. "-Hydroxylepimer (in TLC less polar) F .: 101.5-102.5 ⁰ C. ß-Hydroxylepimer (in the more polar TLC) F .: 109-111 ⁰ C. The products were recrystallized from ethyl acetate / pentane .

Example 80

² - [3tt, 5oc-Dihydroxy-2ß- (3K-hydroxy-4- (2-thienyl) -trans-1-butene-1 ylj-cyclopent-itt-ylj-acetic acid- ^ lactone (6d): a heterogeneous mixture from 1.35 g (2.85 millimoles) 2-f3 «-p-phenylbenzoyloxy-5 * -nydroxy-2ß- (3 ^ -hydroxy- / f- (2-thienyl) -trans-1-butene-1- yl) -cyclopent-1 «\ - yl j-acetic acid - ^ - lactone (4d), 13 ecm of absolute methanol and 394 mg of finely powdered, anhydrous potassium carbonate were stirred for one hour at room temperature and then ^{cooled to 0} ° C. To the cooled The solution was given 5.6 ecm of an aqueous 1.0 η hydrochloric acid After stirring for a further 10 minutes at ⁰ ° C., 15 ecm of water were added, methyl p-phenylbenzoate being formed which was filtered off

409810/1150

became. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (if χ 20 ecm), the combined organic Washed extracts with 10 ecm saturated sodium bicarbonate solution, dried (MgSO,) and concentrated. There were 738 mg of the above compound obtained as a viscous oil (6d)

IR spectrum (CHC1 ·,): strong absorption at 1755 cm "" 'for the

- 1

Lactone carbonyl and mean absorption at 965 cm for the

trans double bond. The corresponding β-thienyl compounds were prepared in the same way. 15- «0H, IR: 177 *« ·, 970 cm ""¹;15-f> 0H, -IR: 1775, 970 cm " ¹ .

Example 81

5 "\ - Hydroxy-3o *, - (tetrahydropyran-2-yloxy) -2β- (3 <* - (tetrahydropyran-2-yloxy) -if- (2-thienyl) -trans-1-buten-1-yl ) -cyclopent-1e < _k -

ylj-acetic acid-j-lactone (7d):

To a solution of 738 mg (2.5 millimoles} 2- [3ot, 5 * "- Mhydroxy-2ß- * (3 ° i-hydroxy-4- (2-thienyi) -trans-1-buten-yl) - Cyclopeiat-1ei-yl3-acetic acid - ^ - lactone (6d) in 5 ecm anhydrous methylene chloride and 0.5 ecm 2,3-dihydropyran were added 7 mg p-toluenesulfonic acid ^{monohydrate at 0 ° C. under dry nitrogen} the reaction mixture is combined with 100 cc of ether, the ether solution 1 χ with 15 CCE. saturated Natriumbiearbonatlösung, then 1 χ with 25 cc of saturated brine, dried with MgSO, dried and concentrated. Ais crude product, 1.2 g (MOD%) of the ^ oengsnamitaa connection 'irnulten (7d).

!! »Spectrum (CHCI,): mean absorpticr. at 9? 0 cm "for the trans double bond and at V" 72. ο * Γ "i ^ r the Lactoncarbosjl.

Γι ·! © Compound diss.'e E-siffpiils CTi, ka.n? I according to the In Examples 86, 88 ^T ir.e ^C O V-: ε 9 ^ - 'u-ssclu-i - "- ^ rsa ¥ experience in dia 13 »

Dihydro-16- (2-thienyl) -uJ «tetranorprostaglandins of the A, E or F series are converted. The corresponding β-thylenyl compounds were prepared in the same way. 15 * -0THP, IR: 1770, 970 ca " ¹ IR: 1770, 970 cm" ¹ .

Example82

5ev-Hydroxy-3 "- (tetrahydropyran-2-yloxy) -2ß- (3" - (tetrahydropyran ^ -yloxyj-if-phenyl-trans-1-buten-i-yD-cyclopent-ac-yl] -acetaldehyde- jf-semi-acetal (8d):

A solution of 1.2 g (2.5 millimoles) 2- £ 5 * -hydroxy-3 * - (tetrahydropyran-2-yloxy) -2ß- (3 * - {tetrahydropyran-2-yloxy] -4- (2 thienyl) -trans-1-buten-1-yl) -cyclopent-K-J-yl acetate - ^ - lactone (7d) in 25 cc of dry toluene was C under dry nitrogen cooled to -78 ^0, to this cooled solution 3, A-ecm of a 0.8 m-diisobutylaluminum hydride / n-hexane solution (Alfa Inorganics) were added dropwise at such a rate that the internal temperature did not rise above ~ 65 ° C (15 minutes), after an additional ½ minute stirring at -78 ⁰ C was added anhydrous methanol was added until gas evolution ceased. The reaction mixture was then allowed to warm to room temperature. The reaction mixture was combined with 150 cc of ether, if ic with 20 cc of 50 percent sodium / potassium washed tar stepped solution with NapSO, dried and concentrated. The abovementioned compound was obtained in quantitative yield in oily form (8d).

; 5 spectrum ι broad absorption at 3400 cm for the hydroxyl group »The corresponding β-thienyl compounds were prepared in the same way.

15K-0THP, IRs 970 cm " ¹

15p ~ 0TEP, IR: 970 cm " ¹ .

409810/1150

Example 83

9 "* - Hydroxy-11", 15 "-bis- (tetrahydropyran-2-yloxy) -16- (2-thienyl) -cis-5-trans-13-0-tetranor-proBtadienoic acid (9d): To a solution of 2.6 g (6 millimoles) (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in 5 | 0 ecm dry dimethyl sulfoxide were under dry nitrogen 5.7 ecm (11.4 millimoles) of a 2.2 m solution of sodium methylsulfinyl methide in dimethyl sulfoxide given. To this red ylide solution was added dropwise over 20 minutes a solution of 1.03 g (2 millimoles _t Z) 2- [5e <hydroxy-3 * - (tet tetrahydro pyran-2-yloxy) -2ß- (3 "X - ft e trahy dropyran-2-yloxy3- / f- (2-thienyl) -tran8-1-buten-i-yl) -cyclopent-1ei-yl3-acetaluGiiyd-if-iitil ^ acetal (8d) in 5 | 0 ecm dry dimethyl sulfoxide given. After stirring for an additional 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed 2 with ethyl acetate (20 ecm) and acidified to about pH 3 with 10 percent aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 × 20 ecm), the combined organic extracts 1 × with. Washed with water (10 ecm), with MgSO. dried and evaporated to a solid residue. The solid residue was triturated with ethyl acetate and the filtrate was concentrated. This gave 1 j02 g of the abovementioned product (9d).

IR spectrum: strong band at 1.00 cm " ¹ and absorption between 2800 to 2600 cm" ¹ for the carboxyl group.

The product of this example (9d) can be converted to the 16- (2-thienyl) -0X.tetranorprostaglandins of the F-series (F ^, F ^, F _{Q (<} ) by the methods of Examples 86, 9k and 95. In the corresponding β-thienyl compounds were prepared in the same way.

15U-0THP, IR: 1710, 970 cm " ¹

15P-0THP, IR: 17IO, 970cm " ¹ .

409810/1150

- IZ ₄ -O

Example 84

9-Oxo-i 1c ', L5C _<l -bis- (tetrahydropyran-2-yloxy) -i6- (2-thienyl) -cis-5-trans-13- ^"J -tetranor-prostadienoic (1Od).:

To a solution, cooled to -10 ° C, of 1.02 g (1.86 millimoles) of 9 * -hydroxy-11m, 1 ^ Cx-bis-itetrahydropyran ^ -yloxyJ-i 6- (2-thienyl) -cis-5 -trans-13 - ^ - tetranorprostadienoic acid (9d) in 18 ecm (reagent grade) acetone was added dropwise 0.82 ecm (2.0Zf millimoles) of "Jone's" reagent under nitrogen. After 20 minutes, 2-propanol was added at -10 ⁰ C 0.260 cc and stirred for a further 5 minutes. Then 75 ecm of ethyl acetate were added, washed 3 times with 10 ecm V / water, dried with MgSO ^ and concentrated. This gave 952 mg of the abovementioned compound. This was chromatographed on silica gel using ethyl acetate as the eluant. This gave 760 mg of the pure compound (10d). The two corresponding C ₁ [--epimeric β-thienyl compounds were prepared in the same way.

Example 85

9-Oxo-1 *, 15 ".- dihydroxy-16- (2-thienyl) -cis-5-trans-13-v.> - tetranorprostadienoic acid (11d):

A solution of 760 mg (1.39 millimoles) 9-0xo-11cx, 15 <X-bis-tetrahydropyran-2-yloxy) -i6- (2-thienyl) -cis-5-trans-13-ui) -tetranorprostadienoic acid (1Od) in 3.0 cc of a 65: 35 mixture of glacial acetic acid and water was stirred for 18 hours under nitrogen at 25 ⁰ C and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinekrodt CC-Zf, 76-152 microns mesh) using ethyl acetate as the eluent. After eluting less polar impurities, 369 mg of the above

40981 0/1150

named product in semi-solid form (lld).

IR spectrum: carbonyl absorptions at 1730 and 1705 cm "" and a weak band at 972 cra ~ for the 13,14-trans double bond.

The product of this example can be converted to the i6- (2-thienyl) - *> - tetranorprostap; landine E., E, A-, A ₁ and A by the procedures of Examples 95, 96 and 88 · In the same Way, the corresponding β-thienyl compounds were prepared.

15V-0H, IR: 1715, 1740, 970 cm "" ¹ 15p-0H, IR: 1715, 1740, 970 cm " ¹ .

Example 86

, 15o < _r -Trihydroxy-16- (2-thienyl) -cis-5-trans-13- ^k «^ -tetranorprostadienäure (12 d):

A mixture of 0.76 g of 9x-hydroxy-11tx, 15i * -bis- (tetrahydropyran-2-yloxy) -16- (2-thienyl) -cis-5-trans-13- ^ tetranorprostadienoic acid (9d) and 5 ecm of a 65J35 mixture of acetic acid and Water was stirred at room temperature overnight under nitrogen and then under reduced pressure to a viscous oil concentrated. The crude product was purified by column chromatography (Mallinckrodt CC-4 silica gel). After removing less polar contaminants 51 mg of the above product (12d) were found as viscous, colorless oil was obtained.

The above product (12d) can be converted to the i6- (2-thienyl) -vA-tetranorprostaglandin-F- by following the procedure of Example 96. Furthermore, the product (12d) can be converted into 16- (2-thienyl) -w) -tetranorprosta--FQ by the method of Example 95.

409810/1150

- Λΐ + 2 -

example

3 ^ -p-phenylbenzoyloxy-5cv-hydroxy-2ß- (3 <v-hydrox.y-3ß-methyl-4- (2-thienyl) -trans-1-buten-1-yl) -cyclopent-K-yl J-essi ^ säurej ^ -lacton C13d) and 2- [3 <* - p-phenylbenzoyloxy-5 ^ -hydroxy-2ß- (3ßhydroxy-3 ° ^ -methyl-4- (2-thienyl) -trans-1-buten-1-yl) -cyclopent -K-yl } -acetic acid - / - lactone (1 ^ d):

To a solution of 3190 mg (6.2 millimoles) 2- [3ος-P-Pheny 1-benzoyloxy-5 (* - hydroxy-2ß- (3-oxo-4- (2-thienyl) -trans-1 -butene -! yl) -cyclopent-K-yl j-acetic acid-Z-lactone (3d) in 26 ecm anhydrous ether and 20 ecm tetrahydrofuran (distilled over LAH) were under dry nitrogen at -78 ⁰ C dropwise 6.8 ecm of a ( optionally 0.92 m) of methyl lithium solution in ether (Alfa). After stirring for 15 minutes at -78 ⁰ C the reaction, the pH was 7 by dropwise addition of glacial acetic acid, to about achieved was stopped. the mixture was then diluted with methylene chloride , the diluted organic solution was washed 1 with water and 1 with saturated saline, dried with anhydrous magnesium sulfate and concentrated to obtain epimeric alcohols.

The crude product was column chromatographed using a mixture of benzene and ethyl acetate as an eluent on 108 g silica gel (Baker "Analyzed" reagent, sieve mesh size 76 to 251 microns) cleaned. The two above-mentioned were obtained Compounds (13d) and (14d).

The product (lifd) can be according to the method of Examples 80 to and 88 to 96 into the 15β-methyl-16-2- (thienyl) -v> -tetranorprostaglandins A, E or F series can be converted.

By using the suitable alkyllithium derivatives instead of the methyllithium used above, other (lower) -

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(1 / + d) -type alkyl derivatives are prepared. Serve derivatives suitable for the production of 1 5- (lower) -Alky 1-1 6-2- (thienyl) - * u-tetranor prostaglandins of the A, E or F series according to the procedure of Examples 79 to 86 and 88 to 96.

Example 88

9-.Oxo-15A-hylrox.y-16-2- (thienyl) -cis-5- ^ ^{10 '11} - trans-13-oJ-tetranorprostatrienoic acid (1 5d):

At room temperature a solution of 55 mg 9-Oxo-nu., 15 <\ -
dihydroxy-16-2- (thienyl) -cis-5-trans-13- « ⁾ -tetranorOrostadienoic acid (III) in 10 ecm dry methylene chloride and 10 ecm
Formic acid is stirred for 5 hours. The reaction mixture was then diluted with 50 ecm of toluene and evaporated. The above product (15d) was obtained.

In the same way, _{the 16-substituted-u * -pentanorprostaglandins of the E, E Q} and 13,14-dihydro series can be converted into the 16-substituted-u * -pentanorprostaglanlins of the A .., A _Q and 13,14-dihydro series -A series.

Example 89

Following the procedure of Example 3, using
Sodium borohydride instead of zinc borohydride, the compound (19d) can be prepared. This can then be converted to compound (2 / fd) by the procedure of Example 4. This is then further for the preparation of 13.1! F-Dihydr0-16-2- (thienyl) -O- tetranorprostaglandine of the A, E or F-series according to the methods of Examples 91 to 94 used 86 and 88 thereof.

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- 1 / fZf -

Example 90

5 * -Hydroxy-3 <* - (tetrahydropyran-2-yloxy) -2β- (3 "- £ tetrahydropyran-2-yloxyj-4- (2-thienyl) -but-1-yl) -cyclopent-1x-yl ] acetic acid - / - lactone (2.1 + d):

A stirred heterogeneous solution of 1.7 S (3Λ millimoles) 2- [5 * - hydroxy-3 ^ - (tetrahydropyran-2-yloxy) -2ß- (3 <* - \ tetrahydropyran-2-yloxy} -4-2 - (Thienyl) -trans-1-buten-1-yl) -cyclopent-1'X-ylJ-acetic acid-j'-lactone (7d) and 300 mg of 5% palladium on carbon in 35 ecm of absolute methanol was 90 minutes hydrogenated. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The above-mentioned product (2i + d) was obtained.

Example 91

5 ^ -hydroxy-3 <x, - (tetrahydropyran-2-yloxy) -2β- (3c> <- £ tetrahydropyran-2-yloxy} -if-2- (thienyl) -but-1-yl) -cyclopent-1i <-yl ^ -acetaldehyde - / - hemiacetal (25d):

Under dry nitrogen, a solution of 1,600 mg (3.2 millimoles) of 2- [5 ^! * -Hydroxy-3oi- (tetrahydropyran-2-yloxy) -2ß- (3tx- £ te trahydropyran-2-yloxyj -if-2- (thienyl) -but-1 -yl) -cyclopent-1 * .- yl] -acetic acid-y-lactone (24d) in dry toluene (15 ecm) cooled to -78 C. To this cooled solution was added 5.0 cc of a 20% diisobutylaluminium hydride / n-hexane (Alfa Inorganics) dropwise at such a rate that the internal temperature does not exceed -65 ⁰ C rise (3 minutes). After further stirring for 30 minutes at -78 ⁰ C, anhydrous methanol was added until gas evolution ceased and the reaction mixture allowed to warm to room temperature. The reaction mixture was combined with 150 ecm of ether, washed with 50 percent sodium-potassium tartrate solution (1 × 50 ecm), dried with sodium sulfate, concentrated and chromatographed. The above-mentioned product (25d) was obtained.

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Hf 5 -

Example 92

9 ". -Hydroxy-11 *, 15 <x-bis (tetrahydropyran-2-yloxy) -16- (2-thienyl) -cis-5 -") - tetranorprostenic acid (22d):

To a solution of 5150 mg (11.6 millimoles) (4-carbohydroxy-n-butyD-triphenylphosphonium bromide in 10.1 ecm dry dimethyl sulfoxide were added 10.8 ecm (21.1 millimoles) of a 1.96 m solution of sodium methylsulfinyl methide under dry nitrogen To this red ylide solution was added a solution of 1300 mg (2.6 millimoles) 2- [ ^{5'-hydroxy-3 <} x- (tetrahydropyran-2-yloxy) -2β- (3fc ⁱ -) within 20 minutes. itetrahydropyran-2-yloxyV-4 "- (2-thienyl) -but-1-yl) -cyclopent-1w _> -ylJ-acetaldehyde - / - hemiacetal (25d) in 7.0 ecm of dry dimethyl sulfoxide added dropwise. After stirring for hours at room temperature, the reaction mixture was poured into ice water, and the basic solution was acidified with 10 percent aqueous hydrochloric acid to about pH 3. The acidic solution was extracted 3 times with 100 ecm of ethyl acetate, and the combined organic extracts were washed 1 with 50 ecm of water , dried with magnesium sulfate and evaporated to a solid residue urde triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent, 76-25 micron mesh) using ethyl acetate as the eluent. After removing impurities with high R n values, the above-mentioned product (22d) was obtained.

This product (22d) can be converted to the i6- (2-thienyl) -w-tetranor-13 | 1 ^z f-dihydro-PGF _{2a (} by following the procedure of Example 86 .

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Example 93

9-Oxo-11c <, 15 * -bis- (t e trahydropyran-2-yloxy) -16- (2-thienyl) -c is-5 - ^) _ tetranorprostenic acid (26d):

To a cooled to -10 ⁰ C solution of 950 ng (1.68 mmol) of 9-hydroxy-1K *, 15 <* - bis- (tetrahydropyran-2-yloxy) -16- (2-thienyl) -cis-5 -vj-tetranorprostenaure (22d) in 15 ecm acetone (reagent grade) were added dropwise 0.75 ecm (2 millimoles) Jone's reagent under nitrogen. After stirring for 20 minutes at -10 ⁰ C were added 0.75 cc of 2-propanol and stirred for an additional 5 minutes. The reaction mixture was then combined with 100 ecm of ethyl acetate, washed 3 times with 25 ecm V / water, dried with magnesium sulfate and concentrated to give the abovementioned product (26d).

Example 9k

9-Oxo-1 *, 15 "-dihydroxy-16- (2-thienyl) -cis-5-v *> - tetranorprostenic acid (2? D):

Under nitrogen, a solution of 800 mg was 9-oxo-i1 *, 15 -bis- (tetrahydro pyran-2-yloxy) -16- (2-thienyl) -013-5 - *** - tetranorprost ^s acid (26d) 35 mix us ^a glacial acetic acid and water at 25 ° C for 20 hours and then concentrated by rotary evaporator: 7.0 in a 65 cc. The obtained crude product (oil) was purified by column chromatography on silica gel (Mallinckrodt CC-Zf, mesh size 76 to 152 microns) using ethyl acetate as the eluent. After removing less polar impurities, the above-mentioned product (27d) was obtained as an oil.

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Example 95

9_Oxo-11c (, 15cn-dihydroxy-16- (2-thienyl) -I-tetranorprostanoic acid (28d):

A heterogeneous solution; of 37 mg (0.089 millimoles) 9-0xo-11sx, -1 5tn-dihydroxy-i6- (2-thienyl) -cis-5-trans-13-iO-tetranorprostadienoic acid CiId) and 13 m ~ 5 % palladium on carbon in 3 ecm of absolute methanol was ^{hydrogenated at 0} ° C. for 2 hours (1 atm). The reaction mixture was then filtered off and evaporated. The above-mentioned product (28d) was obtained.

Example 96

9-Oxo-i 1ϊ \, 1 5 <* - dihydroxy-i6- (2-thienyl) -trans-13 - *> - tetranoroprostic acid (29d):

At 25 ° C., a solution of 50 mg of 9-0xo-11 & v, 15 »-dihydroxy-1 6- (2-thionyl) -cis-5-trans-13-w-tetranorprostadienoic acid (1Id) in 5 ecm of dry ether 48 was obtained Hours treated with 1-8 mg (3.6 millimoles) of dimethylisopropylchlorosilane and 360 mg (3.6 millimoles) of triethylamine. The reaction mixture was ^{cooled to 0} ° C., mixed with methanol, and the solution obtained was washed 3 × with 2 ecm of water, dried with magnesium sulfate and evaporated. The crude residue was taken up in 6 cc of methanol, 30 mg 50% Pd / C and the resulting slurry k hours at -22 ⁰ C hydriertζCCl / dry ice). After filtering through a super cell and evaporation, the hydrogenated product was hydrolyzed for 10 minutes in 2 ecm acetic acid / water (3: 1), diluted with 20 ecm water and extracted Zf χ with 15 ecm ethyl acetate. The combined organic extracts were washed 2 with 10 ecm water, dried with magnesium sulfate and evaporated. The above-mentioned product (29d) was obtained.

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Example 97

9-o (-Acetoxy-1 ioc- (tetrahydropyran-2-yloxy) -1 5-oxo-trans-13-16- (3-thienyl) -v? -Tetranorphic acid methyl ester: To a suspension of 110 mg (2.61 646 mg (2.61 millimoles) of 2-oxo-3- (3-thienyl) -propylphosphonic acid dimethyl ester were added at room temperature for 1 hour under nitrogen A solution of 0.947 g (2. ^ 37 millimoles) of the crude aldehyde prepared according to Example 38 in 4 ecm of dimethoxyethane was added to the suspension. The slightly cloudy, brown solution obtained was stirred at room temperature for 2 hours under nitrogen Completed the addition of glacial acetic acid to pH about 7 and concentrated the reaction mixture by rotary evaporation The crude product was purified by column chromatography on silica gel to give the above product.

B e i s ρ i el 98

9 * -Acetoxy-11w- (tetrahydropyran-2-yloxy) -15-hydroxy-trans-13-16- (3-thienyl) -wJ-tetranorprostenic acid methyl ester:

To a solution of 1.60 g (2.17 millimoles) of the enone prepared according to the example in 6.5 ecm of dimethoxyethane were added dropwise 2.17 ecm (1.08 millimoles) of a 0.5 M solution of Zn (BH,) ~ given in dimethoxyethane. After stirring for 3 hours at room temperature the reaction was carried out under nitrogen by the dropwise addition of a saturated aqueous solution of sodium bitartrate, until the evolution of gas ceased, ended. The heterogeneous reaction mixture was stirred for a further 5 minutes at room temperature, then diluted with methylene chloride with anhydrous magnesium sulfate

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- 1 / f9 -

dried and concentrated. The above product was obtained.

B e i s ρ i el 99

9o »-acetoxy-1It *, 15ß-dihydroxy-trans-13-16- (3-thienyl) -w> -tetranorprostenäuremethylester and 9 * -acetoxy-1 te, 15 <v-dihydroxytrans-13-16- (3- thienyl) -'-? - tetranorprostenic acid methyl ester: A solution of 1.60 g (2.16 milliraol) of the crude THP ether prepared according to Example 98 in 10.7 ecm of a 65 * 35 mixture of acetic acid and water was added under nitrogen at ZfO +; 2 ⁰ C stirred for 2 1/2 hours. Then the reaction mixture was concentrated to a crude mixture of the epimeric diols. The crude product was purified by column chromatography on silica gel. The above-mentioned products were obtained.

Example 100

Acetoxy-11 o (, 15 "-bis- (tetrahydropyran-2-yloxy) -trans-13-16- (3-thienyl) -cu-tetranorprostic acid methyl ester: a mixture of 0.223 g (0.510 millimoles ) of the chromatographed diol prepared according to Example 99, 0.1if ecm (1.53 millimoles) dihydropyran, 1 + _f 2 ecm methylene chloride and a crystal of p-toluenesulfonic acid monohydrate were stirred for 20 minutes. The reaction mixture was then diluted with ether and washed with saturated aqueous sodium bicarbonate solution , dried with anhydrous magnesium sulphate and concentrated to the above product,

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Example 101

9 *, 11 <*, 15o <-Trihydroxy-trans-13-i6- (3-thienyl) -M> -tetranorprostenic acid:

A mixture of 65 mg (0.15 millimoles) of the chromatographed diol prepared according to Example 99, 0.45 ecm (0.45 millimoles) of aqueous 1.0 N sodium hydroxide, 0.45 ecm of tetrahydrofuran and 0, was obtained under nitrogen at room temperature. 45 ecm of absolute methanol was stirred for 1 1/2 hours. The solution was then acidified with 0.45 ecm aqueous 1.0 η-hydrochloric acid (to a pH of about 5). The acidified solution was extracted 4 with 2 ecm ethyl acetate. The combined extracts were dried with anhydrous magnesium sulfate and concentrated to the above product.

Example 102

9 * <- Hydroxy-11 *, 15oc-bis (te trahy dropyran-2-yloxy) -trans-13-16- (3-thienyl) -u> -tetranorprostenic acid

A homogeneous solution of 0.263 g (0.436 millimoles) of the crude bis-THP ester prepared according to Example 100, 1.3 ecm (1.30 millimoles) of an aqueous 1.0 N sodium hydroxide solution, 1.3 ecm, was obtained overnight under nitrogen Methanol and 1.3 ecm tetrahydrofuran were stirred. The reaction was terminated by adding 1.30 ecm (1.30 millimoles) of an aqueous 1.0 N hydrochloric acid solution. Then the solution was diluted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated. The crude product thereby obtained was purified by Säulenchromatografieren on silica gel (Baker Analyzed ^{n M} reagent, sieve mesh size 76 to 251 microns). The above product was obtained.

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Example 103

9-Oxo-IV, 1 5 <* - bis (tetrahydropyran-2-yloxy-13-trans-16- (3-thienyl) -vJ-tetranorprostenic acid:

Η was added dropwise to a ⁰ C cooled to -20 to -15 solution of 0.201 g (0.371 mmol) of the acid prepared according to Example 102 in 4 chromatografierten _f 0 cc acetone under nitrogen 0.163 cc (0.2 + 08 millimoles) Jone's reagent given. The mixture was stirred in the cold for 15 minutes and then the reaction was terminated by adding 0.194 ecm of isopropanol. The mixture was stirred for a further 5 minutes in the cold and then diluted with ethyl acetate. The organic solution was washed 2 with water and 1 with saturated saline, dried with anhydrous magnesium sulfate and concentrated. The above-mentioned product was obtained.

Unprecedented

9-Oxo-i 1 *, 15tx-dihydroxy-13-trans-16- (3-thienyl) -u-tetranorpros tenic acid:

A homogeneous solution of 0.179 g (0.328 millimoles) of the crude THP ether prepared according to Example 103 in 2 ecm of a 65:35 mixture of acetic acid and water was stirred for 5 hours under nitrogen at ZfO + 2 ^{0 C.} The reaction mixture was concentrated by rotary evaporation and then in an oil pump vacuum. The crude product was purified by column chromatography on silica gel (Mallinckrodt CC-7). The above product was obtained.

Example 105

2-0x0-4- (2-thienyl) -butylphosphonic acid dimethyl ester (2b):

Under dry nitrogen, a solution of 11.6 g (94 milli-

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mol) of dimethyl methylphosphonate (Aldrich) cooled in 130 cc of dry tetrahydrofuran at -78 ⁰ C. To the cooled solution was added dropwise 43 ecm of a 2.26 M solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) over a period of 18 minutes at such a rate that the reaction temperature did not rise above -65 ° C. After further 5 minutes of stirring at -78 ⁰ C 8.0 g (47 millimoles) of 3- (2-thienyl) -propionic acid methyl ester were added dropwise at such a rate that the reaction temperature below -70 ⁰ C remained (20 min). After 3 1/2 hours at -78 ⁰ C the reaction mixture was allowed to warm to room temperature, neutralized with 5 cc of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ecm water, the aqueous phase extracted 3 times with 100 ecm chloroform each time, the combined organic extracts washed with 50 ecm water, dried with magnesium sulfate and concentrated to a crude residue in a water jet vacuum. By distilling at 156 ⁰ C (0.2 mm Hg), 9.7 g 2-0xo-4- (2-thienyl) -butylphosphonsäuredimethylester obtained.

KMR spectrum (CDCl ₃ ): doublet at 3.75 ^ (J = 11.5 cps, 6H) for (CH ₃ O) -P-; Triplet at 3.11 <T (4H) for -CH ₂ -CH ₂ ; Duplicate

0
at 3.14 </ (J = 23 cps, 2H) for -C-CH ^ -P-; Multiples at 6.7

Il * - Il

0 0 to 7Λ <^ (3Η) for the thienyl ring protons.

In the same way, methyl 3- (3-thienyl) propionate was made the 2-0xo-4- (3-thienyl) -butyl-phosphonic acid dimethyl ester produced. This is also a suitable starting product for the production of 17- (3-thienyl) -i £ -trisnorprostaglandins of the A, E or F series following the procedures of Examples 112 to 125. In the same way, from the suitable esters,

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common products for the conversion to 18,19- or 20o (- or ß-thienyl-substituted Prostaglandins can be prepared according to the procedures of Examples 111-125.

Example 106

3'-p-Phenylbenzoyloxy-5cx-hydroxy-2β- (3-oxo-5- (2-thienyl) -trans-1-penten-1-yl) -cyclopent-10 <; - yl J-acetic acid-y-lactone (3b):

Under dry nitrogen at room temperature, 2.81 g (7.5 millimoles) of 2-0xo- / f- (2-thienyl) -butylphosphoric acid dimethyl ester (2b) in 100 ecm of anhydrous ether with 3.32 ecm (7.5 millimoles) of a 2.26M solution of n-butyllithium in n-hexane (Alfa Inorganics, Inc.). After stirring for 5 minutes, a further 200 ecm of anhydrous ether and then in one portion 2.0 g (5.7 millimoles) of 2- [3fc-P-phenylbenzoyloxy-5x-hydroxy-2ß-formylcyclopentan-1tx-ylJ-acetic acid-y -lactone and 20 ecm of anhydrous ether added. After 35 minutes, the reaction was terminated with 0.5 ecm of glacial acetic acid. The reaction mixture was washed 1+ χ with 100 ecm saturated sodium bicarbonate solution, 2 with 100 ecm water and 1 with 100 ecm saturated sodium chloride solution, dried with magnesium sulfate and evaporated. The oil obtained in this way was recrystallized from CH-Clo / hexane. 2.1 g of the abovementioned product (3b), F .: 121 to 123 ^° C., were obtained

IR spectrum (KBr): absorption bands at 1776 cm "(strong), -1710 cm" ¹ (strong), 1676 cm " ¹ (medium) and 1636 cm" ¹ .

The product of this example (3b) can be converted into the 13,14-dihydro-17- (2-thienyl) -u-trisnorprostaglandins of the A-, E- or F- by the methods of Examples 86, 88 to 89 and 91 to 9k Series to be converted. Furthermore, the product (3b) according to the method

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of Examples 80 to 96 into the 15- (lower) -alkyl-17- (2-thienyl) -kA.trisnorprostaglandins A, E or F series can be converted. Furthermore, from the product (3b) following the procedures of Examples 86-89 and 91-94 15- (lower) -alkyl-13,14-dihydro-17- (2-thienyl) -u> -trisnorprostaglandins the A, E or F series.

Example 107

2- £ 3 * -P-phenylbenzoyloxy-5 * -hydroxy-2ß- (3 «-hydroxy-5- (2-thienyl) -trans-1-penten-1-yl) -cyclopent-1o (-yl] - acetic acidy-lactone (4b) and 2- [3a-p-phenylbenzoyloxy-5c * -hydroxy-2ß- (3ß-hydroxy-5- (2-thienyl) -trans-1-penten-1-yl) -cyclopentloc-yl J-acetic acid-y-lactone (5b) '

Under dry nitrogen at room temperature they became a Solution of 4.53 g (9.3 millimoles) 2- [3tf-p-phenylbenzoyloxy-5i * - hydroxy-2β- (3-oxo-5- (2-thienyl) -trans-1-pen-ten-1-yl) -cyclopentloi-yl J-acetic acid-y-lactone (3b) in 28 ecm of dry 1,2-dimethoxyethane added dropwise 9.3 ecm of a 0.5 m zinc borohydride solution. After stirring for 45 minutes at room temperature a saturated sodium bitartrate solution was added dropwise until the evolution of hydrogen ceased. The reaction mixture stirring was continued for 5 minutes and then 300 ecm of dry methylene chloride were added. After drying with Magnesium sulfate and concentration in a water jet vacuum was the semi-solid product obtained through column chromatography on silica gel using ether as the eluent (Baker "Analyzed" reagent, mesh size 76 to 251 microns) cleaned. After eluting less polar impurities, a fraction of 1.44 g of the above-mentioned compound became (4b), a fraction of 200 mg of a mixture of the compounds (4b) and (5b) and finally a fraction of 1.72 g of the compound (5b) obtained.

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IR spectrum (CHCl,) of (4b) and (5b): strong carbonyl ^{absorption at 1765 and 1709 cm "1} and an absorption at 970 cm" for the "rans double bond."

e ι

üiel 108

'. _Λ , 5 <x-dihydroxy-2ß- (3 «(- hydroxy-5- (2-thienyl) -trans-penten-1 yl) -cyclopent-1o <-yl] ~ acetic acid - &" - lactone (6b) : Roi room temperature was a heterogeneous mixture of 1.4 ^ S (2.95 millimoles) 2- £ 3 * -P-phenylbenzoyloxy ^ a-hydroxy ^ ß-O-hydroxy ^ - ^ - thienyD-trans-i-pentene- i-yli-cyclopent-ioc-yl J-acetic acid-y-lactone (4b), 16 ecm of absolute methanol and 75 mg of finely powdered, anhydrous potassium carbonate, stirred overnight and then ^{cooled to 0} ° C. 1 ecm (1 millimole) of an aqueous 1 η hydrochloric acid. After stirring for a further 10 minutes at 0 ° C., 10 ecm of water were added, ethyl p-phenylbenzoate being formed, which was filtered off. The filtrate was saturated with solid sodium chloride, 4 x each 20 ecm ethyl acetate was extracted, the combined organic extracts washed with saturated sodium bicarbonate solution (10 ecm), redried with magnesium sulfate and concentrated, giving 839 mg (92 %) of the crystalline compound (6b), F .: 98 b is 100 ⁰ C.

IR spectrum (CHCl,): strong absorption at 1765 cm for the Lactone carbonyl and mean absorption at 970 cm for the trans double bond.

Example 109

2- [3 "<, 5c <-I> ihydroxy-2β- (3β-hydroxy-5- (2-thienyl) -trans-1-pentene. 1-yl) -cyclopent-1 <x-yl] -acetic acid-y-lactone (6'b): At room temperature a heterogeneous mixture of 1.72 g

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(3.52 millimoles) 2-f 3 ° (-P-phenylbenzoyloxy-5oi-hydroxy-2β- (3β-hydroxy-5- (2-thienyl) -trans-1-penten-1-yl) -cyclopent-Iw -yl ^ -acetic acid-y-lactone (l + b) , 20 ecm of absolute methanol and 90 mg of finely powdered, anhydrous potassium carbonate, stirred for 18 hours and then ^{cooled to 0} ° C. 1 ecm (1 millimole) of an aqueous solution was added to the cooled solution 1N hydrochloric acid was added. Stirring was continued for 10 minutes at ⁰ ° C. and then 15 ecm of water was added, p-phenylbenzoic acid methyl ester being formed, which was filtered off. The filtrate was saturated with solid sodium chloride, extracted 4 times with 10 ecm of ethyl acetate each time, the combined organic extracts were washed with 10 ml of saturated sodium bicarbonate solution, dried with magnesium sulfate and concentrated, giving 967 mg (90 %) of the abovementioned compound (6'b) as a viscous oil.

IR spectrum (CHCl _7. ): Strong absorption at 1768 cm for the lactone carbonyl and average absorption at 968 cm "" for the trans double bond.

Example 110

2- £ 5 "-Hydroxy-3" - (tetrahydropyran-2-yloxy) -2β- (3or- "| tetrahydropyran-2-yloxy] -5- (2-thienyl) -trans-1-penten-1-yl ) -cyclopent-iK-ylJ-acetic acid - ^ - lactone (7b):

Under dry nitrogen at ⁰ ° C., a solution of 839 mg U _t 72. millimoles) 2- [3 ", 5 ^e <-dihydroxy-2ß- (3o <-hydroxy-5- (2-thienyl) -trans- 1-penten-1-yl) -cyclopent-1'-yl-acetic acid (-lactone (6b) in 15 ecm anhydrous methylene chloride and 0.75 ecm 2,3-dihydropyran added 9 mg p-toluenesulfonic acid monohydrate. It was 15 minutes stirred, then the reaction mixture is mixed with 200 ecm of ether, the ether solution 1 χ with 25 ecm saturated sodium bicarbonate solution and 1 χ with 25 ecm saturated

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Washed brine, dried with magnesium sulfate and concentrated. 1.28 g (> 100 %) of the abovementioned compound (7b) were obtained as a crude product.

IR spectrum (CHCl ^): strong absorption at 965 cm " ¹ for the trans double bond.

The product of this example (7b) can be converted into the 13,14-dihydro-17- (2-thienyl) -wI -trisnorprostaglandins by the procedures of Examples 86, 88 and 90-94 A, E or F series can be converted.

Example 1111

tf-Hydroxy-3 <x- (tetrahydro pyran-2-yloxy) -2ß- (3ß- (te trahydropyran-2-yloxy) -5- (2-thienyl) -trans-1-penten-1-yl) - cyclopent-1 ¹ * - YLJ-acetic acid, Y-lactone (7 ^f b) J

Under dry nitrogen at ⁰ ° C., a solution of 967 mg (3.14 millimoles) of 2- [3 ", 5 <* - I> ihydroxy-2β- (3β-hydroxy-5- (2-thienyl) -trans -1-penten-1-yl) -cyclopent-1 οί -yl ^ -acetic acid - ^ - lactone (6'b) in 10 ecm anhydrous methylene chloride and 0.85 ecm 2,3-dihydropyran added 10 mg p-toluenesulphonic acid monohydrate. The mixture was stirred for a further 15 minutes, then 100 ecm of ether were added to the reaction mixture, the ether solution was washed 1 with 15 ecm of saturated sodium bicarbonate solution, then 1 with 15 ecm of saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Of the above compound, 1.47 g (> 100%) (7'b) whose melting point was by recrystallization from ether / hexane 80 to 82 ⁰ C were retained.

IR spectrum (CHCl ^): strong absorption at 960 cm for the trans double bond.

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Example 112

2- £ 5e <-Hydroxy-3 ° c- (tetrahydropyran-2-yloxy) -2ß- (3ft- {te trahydropyran-2-yloxyj-5- (2-thienyl) -trans-1-penten-yl) - cyclopent-io ^ -yl T-acetaldehyde - ^ - hemiacetal (8b):

Under dry nitrogen, a solution of 1.28 g (2.7 millimoles) of 2- {5cx-hydroxy-3ot- (tetrahydropyran-2-yloxy) -2ß- (3o <- {tetrahydropyran-2-yloxyj-5- ( 2-thienyl) -trans-1-penten-1-yl) -cyclopent-1o (-ylj-acetic acid - / -. cooled lactone (7b) in 13 cc of dry toluene at -78 ⁰ C. to this cooled solution was added dropwise 3 that the internal temperature did not rise above -65 C, 7 cc of a 0.8 m solution of diisobutylaluminum hydride in η-hexane (Alfa Inorganics) at such a rate, where, (15 minutes). It was further Zf5 minutes at -78 ⁰ C. stirred, 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 150 ecm of ether, washed with 20 ecm of 50 percent sodium-potassium tartrate solution, dried with sodium sulfate and concentrated. In quantitative yield the above-mentioned product (8b) was obtained in oily form.

Example 113

2- £ 5 «<- Hydroxy-3tx- (te t rahydropyran-2-yloxy) -2ß- (3ß- (tetrahydropyran-2-yloxy) -5- (2-thienyl) -trans-1-pentene-1- yl) -cyclopent-1 «- ylj-acetaldehyde-y-hemiacetal (8'b):

Under dry nitrogen, a solution of 1.47 g (3.1 millimoles) of 2-f 5 <* -hydroxy-3ot- (tetrahydropyran-2-yloxy) -2β- (3β- (tetrahydropyran-2-yloxy) -5 - (2-thienyl) -trans-1-penten-1-yl) -cyclopent-loi-YLJ-acetic acid-v-lactone (7'b) cooled in 15 cc of dry toluene at -78 ⁰ C. To this cooled solution were

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4.25 ecm of a 0.8 M solution of diisobutylaluminum hydride in η-hexane (Alfa Inorganics) was added dropwise at such a rate that the internal temperature did not rise above -65 ° C. (15 minutes). It was a further 45 minutes at -78 ⁰ C overnight, then added to anhydrous methanol until gas evolution ceased and then the reaction mixture allowed to warm to room temperature. The reaction mixture was combined with 100 ecm of ether, washed h x with 20 ecm of a 50 percent solution of sodium / potassium tartrate, dried with sodium sulfate and concentrated. 1.38 g of the above-mentioned compound (8'b) were obtained.

B e i s ρ i "e 1 11 / f

9 * -Hydroxy-11 ", 15 * -bis (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-5-trans-13-u-trisnorprostadienoic acid (9b): Under dry nitrogen, a solution of 1.8 g (4.01f millimoles) was added (Zf-carbohydroxy-n-butyl) triphenylphosphonium bromide in 8.0 ecm dry dimethyl sulfoxide 3.5 ecm (7.8 millimoles) added to a 2.2 M solution of sodium methylsulfinyl methide in dimethyl sulfoxide. This red ylid solution became within a solution of 717 mg (1.5 millimoles) 2- [5ä-hydroxy-30C- (tetrahydropyran-2-yloxy) -2ß- (3c (- {tetrahydropyran-2-yloxyj-5- (2-thienyl ) -trans-1-penten-1-yl) -cyclopent-1o <-yl acetaldehyde-jf-hemiacetal (8b) dripped into 5 ecm of dry dimethyl sulfoxide. It was another 2 hours at room temperature stirred and then poured the reaction mixture into ice water. The basic aqueous solution was washed 2 with 20 ecm ethyl acetate and acidified to pH 3 with 10 percent aqueous hydrochloric acid. The acidic solution was 3 χ with 20 ecm ethyl acetate extracted, the combined organic extracts 1 χ with 10 ecm Washed water, dried with magnesium sulfate and evaporated to a solid residue. The solid residue was with ethyl

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acetate triturated and filtered. The filtrate was using of ethyl acetate as the eluent by column chromatography on silica gel (Baker "Analyzed" reagent, 76 to 251 micron mesh) - purified. After removing impurities with high R »values, 260 mg of the abovementioned compound (9b) were obtained.

The product of this example (9b) can be converted to the 17- (2-thienyl) -w-trisnorprostaglandins of the F-series (F _2. , ^F i _Ä > ^F ocp ) by following the procedures of Examples 86, 9k and 95.

Example 11 5

9a-Hydroxy-11 <X, 15β-bis (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-5-trans-13- \ »i-trisnorprostadienoic acid (9'b): Under dry Nitrogen were added to a solution of 1.8 g (i +, 05 millimoles) (if-carbohydroxy-n-butyl) triphenylphosphonium bromide in 5.0 ecm of dry dimethyl sulfoxide 3 »2 ecm (7 _} 0 millimoles) of a 2.2 m-Lö 'Solution of sodium methylsulfinyl methide in dimethyl sulfoxide given. A solution of 717 mg Ο> 3 ^ millimoles) 2- [5 "-hydroxy-3o (- (tetrahydropyran-2-yloxy) -2ß- (3" - {tetrahydropyran-2-) was added to this red ylide solution within 20 minutes. yloxyj-5- (2-thienyl) -trans-1-penten-1-yl) -cyclopent-1o <-yl ^ -acetaldehyde-y-hemiacetal (8 * b) in 5.0 ecm dry dimethyl sulfoxide was added dropwise Stirred for a further 2 hours at room temperature and then poured the reaction mixture into ice water.The basic aqueous solution was washed 2 × with 20 ecm ethyl acetate and acidified with 10 percent aqueous hydrochloric acid to about pH 3. The acidic solution was extracted 3 times with 20 ecm ethyl acetate , the combined organic extracts washed 1 χ with 10 ecm V / water, dried with magnesium sulfate and evaporated to a solid residue. The solid residue was triturated with ethyl acetate and filtered,

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The filtrate was eluted using ethyl acetate by column chromatography on silica gel (Baker "Analyzed" reagent, Screen mesh size 76 to 251 microns). After removing impurities with high R "values, 740 mg of the above-mentioned compound (9't>) won.

Example 116

9-0x0-11 * -15 «-bis- (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-5-trans-13-i«> - trisnorprostadienoic acid (10b): Under nitrogen, one to -10 ⁰ C cooled solution of 250 mg (0.445 millimoles) 9 <x-hydroxy-11o <, 15 "-bis- (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-5-trans- 13-i> -trisnorprostadiensäure (9b) in 10 ecm, acetone (reagent grade) 0.18 ecm (0.487 millimol) Jone's reagent added dropwise. After 20 minutes of reaction time at -10 ⁰ C was added 0.2 cc of 2-propanol was added, the reaction mixture stirred for another 5 minutes, then combined with 75 cc of ethyl acetate, washed 3 x with 10 cc of water, dried with magnesium sulfate and concentrated. 240 mg of the abovementioned compound (10b) were obtained.

Example117

9-Oxo-i 1 <x, 1 5β-bis (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-5-trans-13-vo-trisnorprostadienoic acid (10'b): Under nitrogen a gekühltai to -10 ⁰ C solution of 640 mg (1.14 mmol) 9 '-hydroxy-11 <X, 15SS-bis- (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-5 -trans-13- * O-trisnorprostadienoic acid (9'b) in 9.2 ecm acetone (reagent grade) 0.502 ecm (1.25 millimoles) Jone's reagent. After a

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Reaction time of 20 minutes at -10 ⁰ C was added 0.5 cc of 2-propanol was added, the reaction mixture stirred for another 5 minutes, then added with 75 cc of ethyl acetate, 3 χ with 10 cc of water, dried with magnesium sulfate and concentrated. 500 mg of the above-mentioned compound (10'b) were obtained.

Example 118

9-Oxo-i 10 (, 15ii-dihydroxy-17- (2-thienyl) -cis-5-t: rans-13-t risnorpros tadienoic acid (11b):

Under nitrogen was a solution of 2ZfO mg (0.334 millimoles) 9-Oxo-i 1 <*, 15oc-bis- {tetrahydropyran-2-ylcxy) -17- (2-thienyl) · cis-5-trans-13- U> -trisnorproΞtadienεäure (10b) in 3P ecm of a 65:35 mixture of glacial acetic acid and water for 18 hours at 25 ⁰ C and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4, 76-152 microns mesh) using ethyl acetate as the eluent. After removing less polar impurities, 100 mg of the above-mentioned compound (11b) was obtained as an oily product.

The product of this example (11b) can be converted into the 17- (2-thienyl) -i ** -trisnorprostaglandins E ₁ , E , A ₂ , A ₁ and A _Q by the methods of Examples 95, 96 and 88 .

Example 119

9-Oxo-i 1 «, 15ß-dihydroxy-17- (2-thienyl) -cis-5-trans-13-t <> - trisnorprostadienoic acid (11 * b):

Under nitrogen, a solution of 500 mg (0.893 millimoles) 9-Oxo-i Itf, 15ß-bis (tetrahydropyran-2-yloxy) -17- (2-thienyl) -cis-

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5-trans-13 ~ <"J-tetranorprostadienoic acid (10'b) in 7.0 ecm one 65:35 mixture of glacial acetic acid and water was stirred at 25 ° C. for 18 hours and then concentrated by rotary evaporation. The received Crude oil was column chromatographed on silica gel using ethyl acetate as the eluant (Mallinckrodt CC-4, screen mesh size 76 to 152 microns). After removing less polar impurities, 215 mg of the above-mentioned compound (11'b) was obtained as a semi-solid product.

Example 120

2-0xo - ^ - (2-furyl) -butylphosphonsäuredimethylester under dry nitrogen was cooled a solution of 25 g (0.21 mol) of dimethyl methylphosphonate (Aldrich) in 300 cc of dry tetrahydrofuran at -78 ⁰ C. To this stirred solution, 80 ecm of a 2.67 M solution of n-butyllithium in hexane (Alfa Inorganics, Inc.) were added dropwise over the course of 18 minutes at such a rate that the reaction temperature did not rise above -65 ° C. It was then stirred for a further 5 minutes at -78 ^0C. Subsequently, 16.0 g (0,10lf mol) was added dropwise 3- (2-furyl) propionate at such a rate that the reaction temperature below -70 ⁰ C remained (20 min). After a reaction time of 3 1/2 hours at -78 ⁰ C the reaction mixture was allowed to warm to room temperature, neutralized with 6 cc of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ecm of water, the aqueous phase extracted 3 with 100 ecm of chloroform, the combined organic extracts washed with 50 ecm of water, dried with magnesium sulfate and concentrated in a water jet vacuum to a crude residue. By distilling the residue at 1if8 to 150 ⁰ C (0.5 mm Hg) 8, if g of the

/, 09810/1 150

- 16Zf -

obtained above compound (2j). ■

KMR spectrum (CDCl ₃ ): doublet at 3.73J (J = 11.5 cps, 6H) for

₃
(CELOK-P-; singlet at 2.95 cT (2H) for -CHp-CHp; doublet at,

3.12cf (J = 23 cps, 2H) for -C-CH ₀ -P-; Multiplets at 5.96, 6.23

ti ^{l £ L} 11

O O and 7.23 <f (both IH) for the furan ring protons.

In the same way, using methyl 3- (3-furyl) propionate instead of methyl 3- (2-furyl) propionate, dimethyl 2-oxo-4- (3-furyl) -butylphosphonate can be obtained. This compound is suitable as a starting product for the preparation of 17- (3-furyl) ->«> - trisnorprostaglandins of the A, E or F series by the process of Examples 121 to 129. In the same way, the 2- Oxo-2- (ß-furyl) -äthylphosphonsäuredimethylester produced, Kp .: IZfO ⁰ C (0.2 mm Hg). The ester is a suitable starting product for the production of 15- (β-furyl) -it> -pentanorprostaglandins of the A, E or F series by the process of Examples 121 to 129.

The dimethyl 2-0xo-2'-thienylethylphosphonate can be used in the same way getting produced. It is suitable as a starting material for the production of 15e <-thienyl-o-pentanorprostaglandins of the A, E or F series following the procedures of Examples 112 to 125.

In the same way, 2-0x0-3- (ö (-furyl) -propylphosphonic acid dimethyl ester, 2-0xo-5- (ö <furyl) -pentylphosphonic acid dimethyl ester, 2-0xo-6 - (^ - furyl) -hexylphosphonic acid dimethyl ester and 2-0xo-7- (W-furyl) -heptylphosphonic acid dimethyl ester getting produced. These products are suitable as starting materials for the production of the 16-,

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18-, 19- and 20- «- furyl-substituted prostaglandins according to the Process of Examples 121 to 129. The ß-furyl derivatives can using the suitable η starting products in the same Way how the * -Furylderivate are made.

Example 121

3o <-p-phenylbenzoyloxy-5o <^> -hydroxy-2ß- (3-oxo-5- (2-furyl) -trans-1-penten-1-yl) -cyclopent-1w "-yl J-acetic acid- ^ -lactone (3j): To a solution of 230 ecm of anhydrous dimethoxyethane and 860 mg (20 millimoles) of 57 percent NaH were added 5.2 g (21.1 millimoles) of 2-oxo-4- (2-furyl) -butylphosphonic acid dimethyl ester and heated under reflux until no more hydrogen was given off (1 hour). After cooling, 5.2 g (21 millimoles) of 2- ^ 3 <χ-ρ-phenylbenzoyloxy-5tx-hydroxy-2ß-formylcyclopentan-1 &<- yl I-acetic acid - ^ - lactone was added in one portion and then 100 ml of thoxyethane were added.After one hour, the reaction was terminated by adding 2 ml of glacial acetic acid, the reaction mixture was filtered and concentrated to dryness. The residue was dissolved in ethyl acetate, the solution Zj. Χ washed with 100 ecm saturated sodium bicarbonate solution _? 2 χ with 100 ecm water and 1 with 100 ecm saturated sodium chloride solution, dried with magnesium sulfate and evaporated Atography on silica gel (Baker, mesh size 76 to 251 microns), 6.02 g of the above-mentioned compound (3j) was obtained in the form of an oil.

IR spectrum (CHCl,): absorption bands at 1774 cm (strong), 1710 cm " ¹ (strong), 1670 cm" ¹ (medium) and 1625 cm " ¹ (medium) for the carbonyl groups and 973 cm" for the trans Double bond.

The product of this example (3j) can be converted into the 13,14-dihydro-17- (2-luryD-iJ-trisnorprostaglandins of the A- ₁ E or F series by following the procedures of Examples 77, 88 to 89 and 91 to 94 converted

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The product (3j) can also be produced by the methods of the examples 80 and 96 into the 15- (lower) -alkyl-17- (2-furyl) -vJ-trisnorprostaglandins A, E or F series can be converted.

Following the process of Examples 86 to 89 and 91 to 94 can be obtained from the product (3d) 1 5- (lower) -alkyl-17- (2-furyl) -u> -tetranorprostaglandins of the A, E or F series getting produced. In the same way, 2- £ 3 "-p-phenylbenzoyloxy-5 (X-hydroxy-2β- (3-oxo-3-β-furyl-trans-1-propen-1-yl) -cyclopent-1" -ylJ -acetic acid-y-lactone produced, F .: 140 to 141 ⁰ C. IR spectrum: 1715, 1775, 1625, 1675 and 975 cm "" ^1. The compound is a suitable starting material for the 15 * -Furyl- ^ according to the invention pentanorprostaglandins according to the procedures of Examples 79 to 96.

Example 122

2- [3 "-p-pnenylbenzoyloxy-5 (X-hydroxy-2β- (3Ä-hydroxy-5- (2-furyl) -trans-1 -penten-1 -yl) -cyclopent-1o <-ylJ-acetic acid-fl-lactone (4j) and 2-C3 <XP-phenylbenzoyloxy-5ot-hydroxy-2ß- (3ß-hydroxy-5- (2-furyl) -trans-1-penten-1-yl) -cyclopent-10 <-yl ^ -acetic acid- ^ - lactone (5j) i

Under dry nitrogen at room temperature, 12.7 ecm a 0.5 M solution of zinc borohydride to a solution of 5 »97 g (12.7 millimoles) 2- [3 * -P-phenylbenzoyloxy-5oc-hydroxy-2β- (3-oxo-5-2-furyl) -trans-1-penten-1-yl] -cyclopent-1x-ylJ -acetic acid-ylactone (3j) dripped into 3 ecm of dry 1,2-dimethoxylithane. the The mixture was stirred for 45 minutes at room temperature and then saturated sodium bitartrate solution was added dropwise, until the hydrogen evolution ceased. The mixture was stirred for a further 5 minutes and then with 300 ecm of dry methylene chloride offset. The mixture was dried with magnesium sulfate and concentrated in a water-jet vacuum. The semi-solid

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Residue was passed through using ether as the eluant Column chromatography on silica gel (Baker "Analyzed" reagent, Screen mesh size 76 to 251 microns). After eluting less polar impurities, 2.26 g of the compound was obtained O +, i), 270 mg of a mixture of the compounds (ifj) and (5j) and finally 2.2 g of compound (53) are obtained.

IR spectrum (CHCl _x ) of (ifj) and (5o *): strong carbonyl bayoroptions

- ^ 1 1

at 177O and I710 c

trans double bond

(fj) (5o) y

- 1 -1

at 1770 and 1710 cm and an absorption at 970 cm for the

Example 123

2- [3 ", 5" -dihydroxy-2ß- (3oi-hydroxy-5- ( Z- furyl) -trans-1-penten-1-yl) -cyclopent-1oi-ylJ-acetic acid - ^ - lactone ( 6a *): At room temperature a heterogeneous mixture of 2.26g (^, 8 millimoles) 2- £ 3 <XP-phenylbenzoyloxy-5t * -hydroxy-2ß- (3o <-hydroxy-5- (2-furyl) - trans-1-penten-i-yl) -cyclopent-iOi-yl J-acetic acidy-lactone (4j) »26 ecm of absolute methanol and 660 mg of finely powdered, anhydrous potassium carbonate, stirred for one hour and then cooled to ^{0 ° C.} 9 »6 ecm of aqueous 1.0 η hydrochloric acid were added to the cooled solution. The ^{mixture was stirred at 0} ° C. for a further 10 minutes and then 20 ecm of water was added, with methyl p-phenylbenzoate being formed which was filtered off. The piltrate was saturated with solid sodium chloride, extracted 4 with 20 ecm ethyl acetate, the combined extracts washed with 10 ecm saturated sodium bicarbonate solution, dried with magnesium sulfate and concentrated. There was obtained 1.02 f of the above-mentioned compound (6j) in the form of a viscous oil.

IR spectrum (CHCl,): strong absorption at 1765 cm for the Lactone carbonyl and mean absorption at 96Ο cm for the trans Double binding.

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Example 12Zf

2- [5 "-Hydroxy-3x- (tetrahydropyran-2-yloxy) -2ß- (3" - £ tetrahydropyran-2-yloxy} -5- (2-furyl) -trans-1-penten-1-yl) -cyclopent-1o (-yl3-acetic acid - ^ - lactone

Under dry nitrogen at ⁰ ° C., 10 mg of p-toluenesulfonic acid monohydrate were converted into a solution of 1 g (3.42 millimoles) 2- £ 3 "-,: 5 <K-dihydroxy-2 [beta ]- (3o <-hydroxy-5 - (2-furyl) -trans-1-penten-yl) -cyclopent-10 (-yl J-acetic acid-y-lactone (6j) in 5 ecm anhydrous methylene chloride. It was stirred for 15 minutes, then the reaction mixture with 100 1 of ether was added, the ether solution was washed 1 with 15 of saturated sodium bicarbonate and 1 with 20 of saturated sodium chloride solution, dried with magnesium sulfate and concentrated, giving 1.63 g (MOO %) of the above-mentioned compound (7j) as a crude product.

IR spectrum (CHCl ^): strong absorption at 960 cm for the trans double bond.

The product of this example (7j) can be converted to the 13,14-dihydro-17- (2-furyl) -w-trisnorprostaglandins of the A-, E- or F-series by following the procedures of Examples 86, 88 and 90 through 9k will.

Example125

2- [5 «<- hydroxy-3 <x- (tetrahydropyran-2-yloxy) -2ß- (3« - {tetrahydro-

pyran-2-yloxyJ-5- (2-furyl) -trans-1-penten-1-yl) -cyclopent-1oi-

ylJ-acetaldehyde-y-hemiacetal (8j):

Under dry nitrogen, a solution of 1.6 g ( 3.k millimoles) 2- [5 * -hydroxy-3oi- (tetrahydropyran-2-yloxy) -2ß- (J & -

tetrahydropyran-2-yloxy-5- (2-furyl) -trans-1-penten-1-yl) -cyclo-

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pent-1 'C-yl] -acetic acid] j-lactone (7j) in 16 cc of dry toluene cooled to -78 ⁰ C. 4.68 ecm of a 0.8 M solution of diisobutylaluminum hydride in n-hexane (Alfa Inorganics) were added dropwise to this cooled solution at such a rate that the internal temperature did not rise above -65 ° C. (15 minutes). It was> stirred for a further 45 minutes at -78 ⁰ C then anhydrous methyl alcohol was added until gas evolution ceased and the reaction mixture allowed to warm to Bäumtemperatür. The reaction mixture was combined with 150 ecm of ether, washed 4 with 20 ecm of 50 percent sodium potassium tartrate solution, dried with sodium sulfate and concentrated. As a result, the above-mentioned compound (8j) was obtained in a quantitative yield in an oily form.

Example 126

9 * -Hydroxy-11o <, 15 "* - bis (tetrahydropyran-" 2-yloxy) -17- (2-furyl) -cis-5-trans-13 - »*> - trisnor-prostadienoic acid (9 j):

Under dry nitrogen, 7.0 ecm (1i +, 0 millimoles) of a 2.0 m-solution of sodium methylsulfinyl methide in dimethyl sulfoxide to a solution of 3.36 g (7.6 millimoles) of (if-carbohydroxy-n-butyl) -triphenylphosphonium bromide given in 15.0 ecm dry dimethyl sulfoxide. Within 20 minutes it became this red one Ylid solution a solution of 1.3 g (2.81 millimoles) 2- £ 5 * -hydroxy-3k- (tetrahydro pyran-2-yloxy) -2β- (3 * (- f tetrahydropyran-2-yloxyj-5- (2-furyl) -trans-1-penten-1-yl) -cyclopent-1oi-yl J-acetaldehyd-y hemiacetal (8j) dripped into 5.0 ecm of dry dimethyl sulfoxide. It was stirred for a further 2 hours at room temperature and then the reaction mixture was poured into ice water. The BsELSche Aqueous Solution was washed 2 χ with 20 ecm ethyl acetate and with 10 percent aqueous hydrochloric acid acidified to about pH 3. The acidic solution was extracted 3 times with 20 ecm ethyl acetate combined organic extracts washed 1 χ with 10 ecm water,

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redried with magnesium sulfate and evaporated to a solid residue. The solid residue was extracted with ethyl acetate ground and filtered. The filtrate was column chromatographed using ethyl acetate as an eluant Silica gel (Baker "Analyzed" reagent, mesh size 76 to 251 microns) cleaned. After removing impurities with high R »~ values, 1.53 g of the above-mentioned compound were obtained (9j) won.

Example 127

9-Oxo-1 «, 15o (-bis-Ctetrahydropyran-2-yloxy) -17- (2-furyl) -cis-5-trans-13-v> -trisnor-prostadienoic acid (1Oj):

Under nitrogen, a solution of 1.1 g (2.01 millimoles) of 9 <tf-hydroxy-11x, 15 <* - bis (tetrahydropyran-2-yloxy) -17- (2-furyl ) -cis-5-trans-13 - **> - trisnor-prostadienoic acid (9j) in 20 ecm acetone (reagent grade) 0.88 ecm (2. _f 2 millimoles) Jone's reagent dripped. After a reaction time of 20 minutes at -10 ⁰ C were 0.260 cc of 2-propanol was added, stirred for a further 5 minutes, then 75 cc of ethyl acetate added, washed 3 x with 10 cc of water, dried with magnesium sulfate and concentrated. 425 mg of the abovementioned compound (10j) were obtained.

Example 128

9-Oxo-10 (, 15o-dihydroxy-17- (2-furyl) -cis-5-trans-13-0-trisnorprostadienoic acid (11 j):

Under nitrogen, a solution of 425 mg (0.782 millimoles) 9-Oxo-i 1 *, 15o (-bis-tetrahydropyran-2-yloxy) -17- (2-furyl) -cis-5-trans-13-iO-trisnor-prostadienoic acid (10j) in 3.0 ecm of a 65:35 mixture of glacial acetic acid and water and stirred for 18 hours at 25 ° C

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then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-Zf ₁ mesh size 76 to 152 microns) using ethyl acetate as the eluent. After the elution of less polar verunia.ni _f ~ un: en 20Zf mg of the abovementioned compound CiTJ) were obtained in crystalline form, temperature: 98 to 99 ° C.

The product of this Example (11j) may according to the procedures of Examples 95, 96 and 88 into the 17- (2-furyl) -u> -trisnorprosta- -landine E, - E, A ~, A ₁ and A are converted.

I ⁷ O d. ⁷ IO

Example 129

9ei, 11 ", 15o (-Trihydroxy-17- (2-furyl) -cis-5-trans-13-u> .trisnorprostadienäure (12j):

Under nitrogen, a solution of 700 mg (0.33 ^ millimoles) 9ct-Hydroxy-11 ", 15" -bis- (tetrahydropyran-2-yloxy) -17- (2-furyl) -cis-5-trans-13 - ** - trisnorprostadienoic acid (9j) stirred in 5 ecm of a 65:35 mixture of glacial acetic acid and water at 25 ° C. for 20 hours and then concentrated by rotary evaporation. That The crude oil obtained was purified by column chromatography on silica gel using ethyl acetate as the eluent (Mallinckrodt CC-Zf, screen mesh size 76 to 152 microns). After eluting less polar impurities 108 mg of the above-mentioned compound (12j) became oily Maintain shape.

IR spectrum (CHCl,): carbonyl absorption at 1710 cm and a

-> 1

trans double bond absorption at 965 cm.

The product of this example (12j) can be converted to the 17- (2-furyl) -t> .trisnorprostaglandins F ₁ and F ₀₀₁ by the procedures of Examples 9k and 95.

409810/1150

Claims (1)

Patent claims: 1. Oj "-Pentanorprostaglandins with a hatred only off atom or a lower alkyl radical and a substituent of the formula Ar- (CH ₂ ) _n - * in the 15-position, in which Ar is a oi- or ß-furyl, OC or jß-This.nyl-, Ot or ß-naphthyl, phenyl, 3, ¹ I-dimethoxyphenyl, 3, ^ - methylenedioxyphenyl, 3, ^, 5-trimethoxypheny.l- or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical and η is an integer from 0-5, where, when Ar is a phenyl, means substituted phenyl or maphthyl radical, η is 0 or 1. 2. Lvj "-Pentanorprostaglandins of the A, E or F-Relhe, with a hydrogen atom or a Mlederalkylrest and a substituent of the formula In the 15-position, in which Ar is a Ct- or ß-furyl, oil or ß-thlenyl, CC or ß-haphthyl, phenyl, 3,4-dimethoxyphenyl, 3, ¹ J-methylenedioxyphenyl, 3, ¹ I ^ - trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical and η is an integer from 0 to 5, where 'when Ar is. Denotes phenyl, substituted phenyl or kaphthyl radical, η is 0 or 1. 409810/1150 5. Connection of the general formula wherein Ar is a QL or .beta.-furyl, OC- or ß-thienyl, OC- or .beta.-naphthyl, phenyl, 3 »l ^{1-Diinethoxyphenyl-,} 3a · ^ -Methylendioxyphenyl-, 3, J ^1, 5-trimethoxyphenyl or 'mönosubstatuierten phenyl wherein the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or Miederalkoxyrest, η is an integer of 0 mean to 5, wherein when Ar is a phenyl substituted phenyl or _y Maphthylrest means η is 0 or 1, R is a hydrogen atom or lower alkyl ¹ * ⁵⁵ ^ * V / and L is a single or cis double bond, Z is a single or trans double bond, M is keto, ^ - "H ^or ^ N represents a hydrogen atom or a Qj-hydroxyl radical and in which L, 14 and M are selected so that they complete the structure of a prostaglandin of the A ₅ E or F series. H. A compound according to claim 3, wherein V7 is a cis double bond and Z is a trans double bond. 5. A compound according to claim 3, wherein Vi is a cis double bond and Z represent a single bond. 09810/1150 ~ Yo - O ¹ I ί SUBSCRIBED 6. A compound according to claim 3, wherein V / is a single bond and Z is a trans double bond. 7- Compound according to claim 3, v / orin V / and Z both Mean single bonds. 8. Compound of the general formula COOH HO- ' where Ar einend - or ß-furyl- _} cK - or ß-thienyl-, ^ k - or ß-naphthyl-, phenyl-, 3, ¹ i ~ dimethoxyphenyl-, 3, 'I-methylenedioxyphenyl-, 3,' * , 5-trimethoxyphenyl or mono-substituted phenyl radical, viorin the Substitue.it a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or Maphthyl radical means η is 0 or 1,. R is a hydrogen atom or lower alkyl radical, W is a single or cis double bond and Z is a single or trans double bond. 9. Compound of the general formula GOOH R * OH XB 409810/1150 ORIGINAL INSPECTED where Ar is an Oi- or ß-furyl, Ct- or ß ~ thienyl-, OCr or ß-naphthyl-, phenyl-, 3, Ί-dimethoxyphenyl-, 3,1} -hethylenedioxyphenyl-, 3, ^, 5- Trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η denotes an integer from 0 to 5, v / obei when Ar denotes a phenyl, substituted phenyl or naphthyl radical η O or 1, R is a hydrogen atom or a lower alkyl radical, VJ is a single or cis double bond and Z is a single or trans double bond. 10. Compound of the general formula IG vxorin Ar a 3 £ - or ß-furyl, C £ - or ß-thienyl, (Xj or ß-naphthyl-, phenyl-, 3, ^ - dimethoxyphenyl-, 3, ¹ * -methylenedioxyphenyl-, 3 , ^ ₃ 5-trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η denotes an integer from 0 to 5, where when Ar denotes a phenyl, substituted phenyl or naphthyl radical η is 0 or 1, R is a hydrogen atom or lower alkyl radical, W is a single or cis double bond and Z is a single or trans double bond. 409810/1150 \ AFTERWORTHY fit 11. Compound of the general formula , 0 0- ι
ι .C-O- " where Ar is a QC- or ß-furyl-, OC- or ß-thienyl-, C £ - or ß-> Iaphthyl-, phenyl-, 3, ^ - diinethoxyphenyl-, 3, ⁱ t-methylenedioxyphenyl-, 3 , ^ 3 5-trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoroniethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or Naphthyl radical η denotes 0 or 1, and Z denotes a single or trans double bond. 12. Compound of the general formula QO ' XIIiL 409810/1150. [NACHQEREic - τ where Ar is a q £ ~ or ß-furyl, CCr or ß-thienyl, CCr or ß-naphthyl, phenyl, 3> 4-dimethoxyphenyl, 3, H -methylenedioxyphenyl, 3>'ί, 5- Trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or Nie.deralkoxy radical, η is an integer of. 0 to 5, where, when Ar is a phenyl, substituted phenyl or naphthyl radical, 0 or 1, Z is a single or trans double bond, R is a hydrogen atom or lower alkyl radical and. Q. denote a hydrogen atom or p-biphenylcarbonyl radical. . 13. Compound of the general formula THPO '- ^ _x01 HP wherein Ar is OCr or ß-furyl, OC- or ß-thienyl, Oc- or ß-naphthy.l-, phenyl, 3> ⁱ '-dimethoxyphenyl- _> 3,4-methylenedioxyphenyl, 3, A, 5-trimethoxyphenyl or monosubstituted phenyl wherein the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or Nideralkoxyrest, η is an integer of 0 to mean, where \ iav.n Ar is a phenyl, substituted phenyl or naphthyl η denotes 0 or 1, R denotes a hydrogen atom or lower alkyl group, THP denotes the 2-tetrahydropyranyl group,
Z is a single or trans double bond and X = 0 or ^ - H. 409810/1150 I ¹ I. Compound of the general formula THPO '"' C = OH wherein Ar is a Oi- or .beta.-furyl, c ~ £ ¹ or ß-thienyl, 0 £ - or ß-naphthyl-, phenyl-, 3, ^Z * -dimethoxyphenyl-, 3,4-Methylenedioxyphenyl, 3> ⁱ *> 5-Trijnethoxyphenyl- or monosubstituted phenyl, in which the substituent is a halogen atom, trifluoromethyl 1-, phenyl, lower alkyl or Is lower alkoxy, η is an integer from 0 to mean, where when Ar is a phenyl, substituted Phenyl or naphthyl radical means η is O or 1, R is a hydrogen atom or lower alkyl radical, THP is the 2-tetrahydropyranyl radical, V / is a single or cis double bond and Z is a single or trans double bond. 15- compound of the general formula C-OH THrO- " wherein Ar is a (£ - or ß-furyl-, οέ ~ or ß-thienyl-, OC- or ß-maphthyl-, phenyl-, 3, ^f i-dimethoxyphenyl-, 3, * i-methylenedioxyphenyl-, 3, ^I *, 5-trimethoxyphenyl ~ or monosubstituted phenyl radical, in which the substituent 409810/1150 I NAOHQEREIOHT a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy, η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or naphthyl radical, η is 0 or 1, R is hydrogen or lower alkyl, THP the 2-tetrahydropyranyl radical, W is a single or cis double bond and Z is a single or trans double bond. 16. Compound of the general formula 0
OC-II " wherein Ar is a -χ- or ß-furyl, v \ - or ß-thienyl, A .. 'or ß-naphthyl, phenyl, 3, ^ - dimethoxyphenyl, 3, ⁱ t-r4ethylenedioxyphenyl, 3, ¹ U5-trimethoxyphenyl or monosubstituted phenyl radical, in which -the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to, where if Ar is a phenyl, substituted phenyl or Naphthyl radical means η is 0 or 1, THP the 2-tetrahydropyranyl radical,
R ^{1 is} a lower alkyl radical and R "is a lower alkyl, aralkyl with 7 to 10 carbon atoms, Phenyl or substituted phenyl radical, in which the substituent is a halogen atom, a lower alkyl, Means lower alkoxy, trifluoromethyl or phenyl radical. 409810/1150 4 * 0 17- compound of the general formula 0
η O-C-R " THPO- '' XCH ₂ ) ₆ C00R » VIII wherein Ar is a OC or .beta.-furyl, QC or ß-thienyl, oil or .beta.-naphthyl, phenyl, 3, ^ - dimethoxyphenyl, 3, i | -Methylendioxyphenyl-, 3, ^, 5 -Trimethoxyphenyl or Kiono-substituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical ^ η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or raphthyl radical, η 0 or 1, R ^{1 is} a lower alkyl radical, R "is a lower alkyl, aralkyl radical with 7 to 10 carbon atoms Phenyl or substituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, Is lower alkyl, lower alkoxy or phenyl radical and R means a hydrogen atom or a lower alkyl radical. l8. Compound of the general formula 0 ν OCR ¹¹ J [CH ₂ ) ₆ C00R ³ ΪΗΡΟ- ' , .IX 409810/1150 wherein .Ar a > X ~ or ß-furyl-, Q / - or ß-thienyl-, Q £ - or ß-naphthyl-, phenyl-, 3, ^ - dimethoxyphenyl-, 3, * f-methylenedioxyphenyl-, ~ 5 ₃ k , 5-trimethoxyphenyl- or mono-. substituted phenyl radical, v / orin the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to 5 ■, where if Ar is a phenyl, substituted phenyl or naphthyl radical, η 0 or 1 is ^ THP the 2-tetrahydropyranyl ^{radical, R 1 is} a lower alkyl, aralkyl radical with 7-10 C atoms, phenyl or substituted phenyl radical, in which the substituent is a halogen atom, a lower alkyl, lower alkoxy-trifluoromethyl or phenyl radical and. R denotes a hydrogen atom or a lower alkyl radical. 19- compound of the general formula OK (CH ₂ > ₆ G00H (CiIρ) _n where Ar is an oil or ß-puryl, (V- or. ß-thienyl, 0 / - or ß-naphthyl- _a phenyl, 3, ⁱ * -Diniethoxyphenyl-, 3, ^ - methylenedioxyphenyl, 3, ^, 5-triniethoxyphenyl or monosubstituted phenyl radical, vrorin the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or naphthyl radical η denotes 0 or 1, THP denotes the 2-tetrahydropyranyl radical and R denotes a hydrogen atom or a lower alkyl radical. 409810/1150 20. 16-phenyl-0Atetranor 21. 16-Phenyl-L.j-tetranor PGP 22. 16-phenyl-U-tetranor 23. 16-p-methoxyphenyl-ii, '- tetranor PGEp. 2k. 16-p-biphenyl-tc'-tebranor PGE ₂ . 25.16.; V-Naphthyl- u .'-tetranor PGE ₂ - 26. 16β-Naphthyl-U-tctranor PGE ₂ ~ 27. 16-p-methylphenyl-vv-tetranor 28. 15-Phenyl-13, lli-dihydro-Lv / -tetranor PGE ₂ 29. 16-Phenyl-13,1 ^] 1-dihydro-15-methyl- ^ ü-tetranor PGE 30. 16-p-biphenyl-U-'-tetranor 31. 16-o-methylphenyl-tv ^: tetranor 32. 16 OC-naphthyl-W-tetranor PGP ₀ 33. 16β-Naphthyl-W-tetranor A09810 / 1150 ORIGINAL BATHROOM I postponedI 34. 16-Pheny 1-13,1 ¹ »-dihydro-u'-tetranor 35. 16-phenyl-L- _v ; -13, l ^| l-dihydro-tetranor 36. i6rX-thienyl-CU-tetranor PGK ₂ - 37. 16β-thienyl-Lu-tetranor 38.. i7o; -thienyl-W-trisnor 39. 17 Λ; -Fury 1-Lv --- tr is nor PGE ₂ - Ho. 17 X-Furyl-O. -trisnor 41. 17-thienyl-U ¹ -trisnor ^ ² · 17ß-furyl-U'-trisnor 43. '17β-furyl-u, -trisnor 44. 17β-thienyl-L :. -trisnor 45. 17β-thienyl-cv .-- trisnbr 46. 17 -Furyl-W-trisnor 47. 16-phenyl-13,14-dihydro-u, '- tetranar PGEp. 48. 15epi-lo-phenyl-13 _a l4-dihydro-LC / -tetranor PGE ■ · "2 409810/1150 ORIGINAL BATHROOM _4t , Process for the preparation of a compound of the general formula -C-OH I / ητΓ Λ Ä - where Ar is an α- or ß-furyl-, OC- or ß-thienyl-, Cc- or ß-maphthyl- ₃ phenyl-, 3, ⁱ -diniethoxyphenyl- _> 3,4-methylenedioxyphenyl-, 3 ₃ ^^ " Trimethoxyphenyl or monosubstituted phenyl radical, v; orin which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or Mlederalkoxy radical, η is an integer from 0 to 5, viobei if Ar is a phenyl, substituted phenyl or naphthyl radical η 0 or 1 1st, R is a hydrogen atom or a lower alkyl radical, Vi is a single or cis double bond, Z is a single or trans double bond, M is keto, ^ .H or ^ OH G, N and L taken together form a single bond or, when L is a hydrogen atom, N is an OCl hydroxy radical and in which L, M and N are chosen so that they complete the structure of a prostaglandin of the A, E or F series, whose lower alkanoyl, Formyl or benzoyl esters of each of the free hydroxyl groups at the C, ^C ii ~ ^and C ^ positions and their pharmaceutically acceptable salts, characterized in that inan 409810/1150 a) if N is a: ^ - hydroxyrest and L is a V / asserstorfatoni and Ar, n, M, W and Z have the above meanings, the 11-, and 11- and 15-tetrahydropyranyl ethers treating a compound of the above formula I with a suitable acid; . b) when N and L taken together form a single bond and M is keto and Ar, n, R, W and Z are above Have meaning, a compound of the above formula I, wherein N is an o ^ -hydroxy radical, L is a hydrogen atom ■ and M is keto and Ar, n, R, W and Z are as defined above with a suitable dehydrating agent implements; c) if N dencK -hydroxy radical, L denotes a hydrogen atom and H ^ - ^ H or ^ -0H and Ar, N, R, VJ, and Z Have the above meaning, a compound of the above formula I, wherein M denotes the vV-IIydroxyrest _Λ L denotes a hydrogen atom and M denotes keto and Ar, n, R, W and Z have the abovementioned meaning, reacts with a suitable reducing agent and, if necessary, d.ie 9sV ~ and 9 ~ isomers separates; d) if N is the C £ -hydroxy radical and L is a hydrogen atom mean Ar, R, η and M are as defined above and W and Z are single bonds, a compound; the Formula I above, in which Ar, R, η and H have the above meanings, V / a single bond or cia — double bond is when Z is a trans double bond and Z is a single bond when Vi is a cis double bond is, catalytically reduced; 4098 10/1150 I SUBMITTEDI e) if N denotes the X-hydroxy group, L denotes a hydrogen atom, V / • denotes a single bond and Z denotes a trans double bond and Ar, R, η and IA are a compound of the above formula I in which Ar, R , η and M are as defined above and W and Z double bonds are selectively reduced and gegebenenfaUi in the SBC _"s HX" and 15 £ -Niederalkanoyl-, formyl or benzoyl each of the free hydroxyl groups by reaction with the corresponding acylating agents and optionally in the their pharmaceutically acceptable salts transferred. 50. Procedure for the establishment of a connection of the general formula OH IA wherein Ar is a 'Z- or ß-Füryl-, Of- or ß-thienyl-, O (j- or ß-naphthyl-, phenyl-, 3, ⁱ J-dimethoxyphenyl-, 3a ^ -Methylenedioxyphenyl-, 3, ^, 5-trimethoxyphenyl or monosubstituted phenyl radical, v; orin the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to, above when Ar is a phenyl, substituted phenyl or Maphthylr-est means η is 0 or 1, R is a hydrogen atom or lower alkyl radical, W is a single bond or cis double bond and Z is a single bond or trans double bond, the lower alkanoyl, formyl or benzoyl esters of which are each of the free hydroxyl groups on the C "- , C .- and 409810/1150 7331 & 45 Positions and their pharmaceutically acceptable salts, characterized in that one a) the 11-, and 11- and '15-Tetrahydropyranylather der Treated the above compounds of formula I with a suitable acid,. b) a compound of the general formula C-OH -.IB in which Ar, η, R, VI and Z have previous meanings, reduced with a suitable reducing agent * and then the 9x, - and 9ß ~ isomers separated; c) a compound of the general formula 0 COOR ² : in which W is a single bond, Ar, n ₃ R and Z have the above meanings and R ¹ denotes a hydrogen atom or a lower alkyl radical, treated with a suitable base 409810/1150 d) a compound of the above formula IA, wherein Ar, R and η have the above meaning, W a single bond or . ; cis-double bond means when Z is a trans double bond and Z is a single bond when VJ is a cis double bond to one Compound of the formula IA, wherein Ar, R and "* V above" Have meaning and Vi and Z are single bonds, catalytically reduced; ■. . e) the dimethylisopropylsilyl derivative of a compound of the above formula IA, in which Ar, R and η have the previous meaning., W is a cis double bond and Z is a trans double bond, to a compound of the formula IA in which Ar, R and η have the previous meaning have, V / denotes a single bond and Z denotes a trans double bond, catalytically reduced and optionally in their 9X ~> H ^: v- and 15-X-lower alkanoyl, formyl or benzoyl esters of each of the free hydroxyl groups by reaction with the corresponding acylating agents and optionally converted into the pharmaceutically acceptable salts. . 51 · Process for the preparation of a compound of the general formula. 0 where Ar is an Al- or ß-furyl-, Q_- or ß-thienyl-, CC- or ß-naphthyl-, phenyl-, 3, ^/ l-dintethoxyphenyl- _> 3, ^ - ethylenedioxyphenyl-, 3, 'l, 5-trimethoxyphenyl or 409810/1150 SUBSCRIBED monosubstituted phenyl radical, in which the substituent a halogen atom, trifluoromethyl, phenyl, lower alkyl. or lower alkoxy radical, η is an integer from 0 to 5, where Ar is a phenyl, · substituted Phenyl or naphthyl radical means η is 0 or 1, R is a hydrogen atom or a lower alkyl radical, V / denotes a single or cis double bond and Z denotes a single or trans double bond, their lower alkanoyl, pormyl or benzoyl esters each the free hydroxyl groups at the C and C "positions and their 'pharmaceutically acceptable salts, thereby marked that one a) the 11- or 11- and '.'5-Tetrahydropyranylather one Compound of the above formula IB, wherein Ar, R, n, Vi and Z have the preceding meaning with an appropriate Acid converts; b) a compound of the above formula IB ₅ in which Ar, R and η have the above meaning, W is a single bond or a cis double bond, werη Ζ is a trans double bond and Z is a monoclonal when Vi is a cis double bond isfc. , on a compound of the formula. IB, where Αι% η- and R have the above meaning and Vi and Z are single bonds, reduced; c) the dimethylxsopropylsilyl derivative of a compound tererr Formula IB above, in which Ar, R and η have the preceding meaning, Vi is a cis double bond and Z is one denote trans double bond, to a compound of the above formula IB, wherein Ar, R and η above Have meaning, Vi a single bond and Z one "trans- 409810/1150 Double bond, selectively catalytically reduced, and optionally into the lower alkanoyl, formyl or Benzoyl esters of any of the 11- and 15-hydroxy groups by reaction with the appropriate acylating agents and optionally converted into the pharmaceutically acceptable salts. 52. Method of making a compound of general. Formula. 0 -, XG where Ar is an OJ- or ß-furyl-,. \ '~ or ß-thienyl-, r \ - or ß-naphthyl-, phenyl-, 3, ⁱ ' -dimethoxypheriyl-, 3, * J-methylenoiGxyphenyl-, 3> ^J ', 5-trimethoxyphenyl or mono-substituted phenyl radical, viorin the substituent is a halogen atom, trLluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η is an integer from 0 to, where when Ar is a phenyl- _y substituted phenyl - or naphthyl radical η is O or 1, R is a hydrogen atom or lower alkyl radical, W is a single or cis double bond and Z is a single or trans double bond, the lower alkanoyl, formyl or benzoyl esters of which are the C ₁ (-hydroxy group and their pharmaceutically acceptable salts, characterized in that a compound of the formula IB 409810/1150 HO ' maohgerejchtJ R ^X '0H IB wherein Ar, R ₉ ti, W and Z have the above meanings, treated with a suitable dehydrating agent and optionally converted into their C, - lower alkanoyl, formyl or benzoyl esters by reaction with the suitable "acylating agents and optionally into their pharmaceutically acceptable salts. 53. Process for the preparation of a compound of general formula where Ar is an et'- or ß-furyl-, Qc- or ß-thienyl-, f £ ~ or ß-naphthyl-, phenyl-, 3 ^ -dimethoxyphenyl-, 3, ^ - methylenedioxyphenyl-, 3, ¹ J, 5-Trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, lower alkyl or lower alkoxy radical, η denotes an integer from 0 to 5 ", where, when Ar denotes a phenyl, substituted phenyl or naphthyl radical, η 0 or 1, characterized in that a compound of the general formula ■ ■. A09810 / 1150 CHO with dialkyl methyl ketophosphonate of the formula Ar- (CH ") -C-CH ₀ -P (O-Nxederalkyl) ,,
wherein Ar and N are as defined above. 5 * 1. Process for the preparation of a compound of the general formula , XXX wherein Ar is a C £ - or ß-furyl, Of - or ß-thienyl., Qj- or ß-naphthyl, phenyl _s 3, ^ - dimethoxyphenyl, 3 ₃ * t-methylenedioxyphenyl-, 3, ^, 5 ~ trimethoxyphenyl- or monosubstituted phenyl radical ₃ v; or in which the substituea is a halogen atom, trifluoromethyl, phenyl, lower alkyl or N-alkoxy radical, η denotes an integer from 0 to 5, where, when Ar is a phenyl, substituted Phenyl or naphthyl radical means η is 0 or 1, R is a hydrogen atom or lower alkyl radical and Q is a hydrogen or p ~ biphenylcarbonyl radical, characterized in that one. ' 409810/1150 χ 1 IN AXIAL AREA ] a) a compound of the formula JLA '0 in which Ar., η and Q have the preceding meaning, to a compound of the formula III, in which Ar, η and Q have the preceding meaning and R is a hydrogen atom, and optionally separates the 15 o £ ~ and 15 β isomers, b) a compound of the above formula HA to form a compound of the formula III, where Ar, η and Q have the above meaning and R denotes a lower alkyl radical, treated with a suitable alkylating agent and optionally a compound of the formula III in which Ar, η and R above have meaning and Q bipheny! carbonyl means _a hilt IC ^ CO ^, with formation of a compound of the formula III, in which Q means a hydrogen atom, treats unl ge ^ et ^ nenfsP ^ separates the 15 CtT and 15β isomers » 55 «Method of connecting the general -nen formula. A09810 / 1150 I PAYED AFTERWARDS ] wherein Ar is a C £ - or ß-furyl, C £ - or ß-thienyl, Oi, - or ß-naphthyl, phenyl, 3 » ¹ l-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3, ¹ 1 _> 5-trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a halogen atom, trifluoromethyl, phenyl, _a lower alkyl or lower alkoxy radical, η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or Naphthyl radical means_η O or 1, R is a hydrogen atom or lower alkyl radical, THP is the 2-tetrahydropyranyl radical, Z is a single or trans double bond and X = 0 or y \\ , characterized in that one a) a compound oer formula IIIA X
Or — fr vxorin Ar, R, η and Z have the above meaning and X = 0, with 2,3 ~ dihydropyran in the presence of a acidic catalyst to form a compound of the formula IV, in which Ar, R, η and Z have the preceding meaning have and X -0 means, converts, 409810/1150 NAOHQERtIwM I b) a compound of the above formula IV, wherein Ar, R, - η and Z have the above meaning and X = 0, diisobutylaluminum hydride is formed with formation a compound of the formula IV, in which Ar, R, η and Z are as defined above and X / H is, implements, OH c) a compound of the above formula III, wherein Ar, R and ή have the above meaning, Z is a "trans" double bond and X = 0, with the formation of a Compound of the formula IV, in which Ar, R and η have the preceding meanings, X = 0 and Z mean a single bond, catalytically reduced. 56. Process for the preparation of a compound of the general formula THPO where Ar is a Cf- or ß-furyl-, Oi- or ß-thienyl-, Ct- or ß-naphthyl-, phenyl-, 3 _a ^I * -dimethoxyphenyl-, 3, ^ - ethylenedioxyphenyl-, 3 ₃ ^ , 5 -Trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is a kalogenatoin, trifluorraethyl, phenyl, lower alkyl or lower alkoxy, η is an integer from 0 to 5, where if Ar is a phenyl, substituted phenyl or iaphthyl radical, η 0 or 1, R is a hydrogen or lower alkyl radical, THP is the 2-tetrahydropyranyl radical
V / denotes a single or cis double bond and Z denotes a single or trans double bond,. 409810/1150 characterized in that 2334945 a) a compound of the formula IVA Z ^^ jCH ₂ ) _n ^ r in which Ar, R ₃ η and Z have the above meaning, with a ylid of the formula (C ^ H ₁ -) JP = eH-CH "-CH" -CH _o -C00 ⁽ ~ ^ Ό Z> J - d. dd d to form a compound of the formula V, in which Ar, R, η and Z have the preceding meanings and Vi is a cis double bond, and optionally then converts the compound that is formed to a compound of the formula V in which Ar, R _a η and Z protrude · d & have meaning and V / a simple term. means reduced, b) a compound of the above formula V, wherein Ar, R and η have the above meaning, W is a cis double bond and Z is a trans double bond, under Formation of a compound of the above formula V, in which Ar, R and η are as defined above and W. and Z are Exnfachbindungen, reduced, c) a compound of the above formula V, in which Ar ₃ R and η are as defined above, VJ is a cis double bond and Z is a trans double bond, with formation of a compound of the formula V in which Ar, R and U. have the above meaning, VJ an Exnfachbind and 409810/1150 Z denotes a trans double bond, selectively reduced. 57 · Process for the preparation of a "compound of general formula THP (J * itSdthp wherein Ar "is a C £ - or ß-furyl, C £ - or ß-thienyl, Od- or β-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3j ^, 5-trimethoxyphenyl or monosubstituted phenyl, in which the substituent is a halogen atom, trifluoromethyl, phenyl- ^ lower alkyl or lower alkoxy radical, η denotes an integer from 0 to 5 ', where, when Ar denotes a phenyl, substituted phenyl or naphthyl radical, η Q or I Isü_, R is a hydrogen atom or half alkyl radical, THP is the 2-tetrahydropyranyl radical,
W denotes a single or cis double bond and Z denotes a single or trans double bond Ib: ". Rfdung, characterized in that a compound of the formula V OH THPO ^00H Λ 098 1 0/1150 v / orin Ar, R ₃ η, V / and Z have the preceding meaning, reacted with chromic acid in aqueous sulfuric acid and acetone- 58. Process for the preparation of a compound of the formula YXX Wherein Ar is an OC- or ß-furyl-, OC- or ß-thienyl, QC ~ or β-naphthyl, phenyl, 3, ^l '-dimethoxyphenyl- ₃ 3, ⁱ l-kethylenedioxyphenyl, jj, ¹ 1,5-trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent is an Ilaloge na t cm, trifluoromethyl -, phenyl, lower alkyl or Niederaikcyyrest, η is an integer from 0 to, where if Ar is a phenyl, substituted phenyl or Lii ^ ntbylrest η 0 or 1, THP is the 2-tetrabydropyrany! R * a Wieceralkylrest and R "is a Kiedercilkyl-, aralkyl having 7 to 10 carbon atoms, phenyl / substituted phenyl, wherein the sub- stituent is a lower alkyl, lower alkoxy, trifluoromethyl or phenyl radical or a Halogenatoni mean, characterized in that a compound of the general formula 409810/1150 GOOR * with a compound of the general formula 0
Ar (CH ₀ ) -C-CH ₀ -P- (O-lower alkyl) in which Ar, * R ', R "and η have the above meaning. 59. Process for the preparation of a compound of the general formula
0 0-GR ¹¹ '. "·'. VIII. wherein Ar is a JL- or ß-furyl-, CC- or ß-thienyl-, Ct ~ or β-haphthyl, phenyl, 3, ¹ * -Diinethoqcyphenyl-, 3, ¹ -Kethylendioxyphsny1-, 3, ^ ₉ 5-Tr * iniethoxyphenyl- or monosubstituted phenyl, before the substituent a halogen atom, trifluoromethyl, Is phenyl, N-alkyl or lower alkoxy , η is an integer from 0 to 5 , where, when Ar is phenyl, substituted phenyl or TIaphthyl, η is 0 or 1, R is a hydrogen atom or a lower alkyl radical, THP is the 2-tetrahydropyranyl radical ₃
R * is a lower alkyl radical and
R "is a _{lower alkyl a} aralkyl with T to iO carbon atoms, Phenyl or substituted phenyl radical, vrorin der · Sub- 409810/1150 NAOHQb, .. λ 00 substituent is a halogen atom, the trifluoromethyl radical, a Lower alkyl, lower alkoxy or phenyl radical is ,,, characterized in that one a) a compound of the general formula VII THPO ^ COOR * ' VIX in which Ar, R ¹ , R "and η have the preceding meaning, to form a compound of the formula VIII in which Ar, R ^r , R" and η have the preceding meaning and R is a hydrogen atom, b) a compound of formula VII with a suitable alkyl oxidizing agent to form a compound of Formula VIII, in which Ar, R ', R "and η have the preceding meaning and R represents a lower alkyl radical and optionally separating the 153r and 15β isomers. 6o. Process for the preparation of a compound of the general formula '■ • 0 I. TRT (T R ^ "OTiIP 409810/1150. - Tfb - ν; or in Ar a ci ~ or ß-furyl-, (χ- or ß-thienyl-, X.- or ß-naphthyl-, phenyl-, 3 ₃ ² * -dimethoxyphenyl-, 3, ^ -methylenedioxyphony 1-, 3 , ^, 5 ~ Tr: Lmethoxypheny 1- or monosubstituted phenyl radical, v / orin the substituentsfc is a halogen atom, trifluoromethyl, phenyl, _{3 lower alkyl or lower alkoxy radical, 3} η is an integer from 0 to 5 · _3, if Ar is a phenyl -, substituted phenyl or naphthyl radical means η is 0 or 1, · R is a Vfassstoffatoiu or a lower alkyl radical, THP is the 2-tetrahydropyranyl radical, ■ '.- ■ ""R' is a lower alkyl radical and R "is a lower alkyl, aralkyl with 7 to 10 carbon atoms, 'Phenyl- ·· or substituted phenyl radical, in which the substituent a halogenator, the trifluoromethyl radical, a Is lower alkyl, Mjeieralkoxy or phenyl radical characterized; that a connection of the general formula , COOR * viorin Ar, R, R ¹ , R "and η have the above meaning and R denotes a hydrogen atom or THP, is reacted with 2,3-dihydropyran in the presence of p-toluenesulfonic acid. Process for the preparation of a compound of the general formula 409810/1150 χακ OH ΐΚ ^ 'ΌΤΕΡ wherein Ar is "CL- or β-J? uryl-, Ct" - or β-thienyl, <X- or β-naphthyl-, phenyl-, 3 ₃ ^ -dimethoxyphenyl-, 3 ₃ ^ -methylenedxoxyphenyl-, 3 _J ^I ls5 ~ trimethoxyphenyl or monosubstituted phenyl radical, in which the substituent i; is a halogen atom, trifluoromethyl, phenyl, Nlederalkyl- or lower alkoxy radical, η is an integer from 0 to, where if Ar is a phenyl, substituted phenyl or .naphthyl radical η is 0 or 1, THP is the 2-tetrahydropyranyl radical and R denotes a hydrogen atom or lower alkyl radical, characterized in that a compound of the general formula IX 0
« O-C-R " —Ar * where Ar, R and η have the above meaning, R ^{T is} a NiederalkyIrest and R "is a lower alkyl, aralkyl with 7 to 9 carbon atoms, Phenyl or substituted phenyl radical, in front of which the sub- stuent is a halogen atom, the trxfluoromethyl radical Is lower alkyl, lower alkoxy or phenyl reacts with a suitable base. For Pfizer I 409810/1 150 (Dr. H.j. Woiff) Lawyer