DE2619638A1 - PYRROLIDONE AND THE METHOD FOR MANUFACTURING THEIR - Google Patents

Description

HIGHEST y |

Joint stock company 26 19 S3 8

File number: _{Η0Ξ? 6 / p} ^

Date: ^. jyj _a i 1976 Dr.LA/¥

PYRROLIDONE AND THE METHOD OF MANUFACTURING THEREOF

Prostaglandins are a group of natural substances made up of various Animal tissues were isolated. In mammals they are responsible for a variety of physiological effects. the natural prostaglandins have a carbon structure of generally 20 carbon atoms and differ primarily due to the excess or minor content of hydroxyl groups or double bonds in the cyclopentane ring (with regard to the structure and effects of prostaglandins see, inter alia, M.F. Cuthbert, "The Prostaglandins, Pharmacological and Therapeutic Advances," William Heinemann Medical Books, Ltd. London (1973))

The synthesis of non-naturally occurring analogs of prostanoic acids, in which the large number of pharmacological effects of the natural prostanoic acids are differentiated, is becoming increasingly important. In the German patent applications P 25 28 664.0 and P 25 56 326.2 prostaglandins are described for the first time, in which the carbon of the 8-position of the natural prostaglandins is replaced by nitrogen. Independently of this, the synthesis of a single representative of this type is described in Tetrahedron Letters 2931 (1975).

The present invention relates to new compounds of the formula I which are analogous to prostaglandins

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A.
N-CH '

BR ³

in which mean

R is a straight, branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-10 carbon atoms or a cycloaliphatic hydrocarbon radical with 3-7 carbon atoms, each of which is substituted can through

a) a straight, branched alkoxy, alkylthio, alkenyloxy or alkenylthio radical with 1-5 carbon atoms,

b) a phenoxy radical, which in turn is replaced by an optionally halogen-substituted alkyl group with 1-3 carbon atoms, Halogen atoms, an optionally halogen-substituted phenoxy radical or an alkoxy radical with 1-4 carbon atoms can be mono- or disubstituted,

c) a furyloxy, thienyloxy or benzyloxy radical, which in turn in the nucleus by an optionally halogen-substituted alkyl group with 1-3 carbon atoms, halogen atoms or an alkoxy group with 1-4 carbon atoms can be mono- or disubstituted,

d) a trifluoromethyl or pentafluoroethyl group,

e) a cycloalkyl radical with 3-7 carbon atoms,

f) a phenyl, thionyl or puryl radical, which in turn by an optionally halogen-substituted alkyl group

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Al

with 1-3 carbon atoms, calogen atoms or an alkoxy group with 1 - h carbon atoms can be mono- or disubstituted,

R is a straight-chain, branched, saturated or unsaturated one aliphatic or cycloaliphatic hydrocarbon radical with 2-6 carbon atoms, an araliphatic hydrocarbon radical with 7 or 8 carbon atoms or, if

1 3

not at the same time R hydrogen, R n-pentyl, A the -CH_- CH _? -Group, B is the -CH = CH group and η is the number three, a methyl group or a hydrogen atom,

3
R is hydrogen or a straight or branched alkyl radical with 1 to 5 carbon atoms, an alkenyl or alkynyl radical with 2 to 5 carbon atoms or an araliphatic hydrocarbon radical with 7 or 8 carbon atoms,

A and B are a -CH-CH- or a -CH = CH- group, where A and B can be the same or different, but cannot at the same time represent a -CH = CH- group,

η the number two, three or four

and the physiologically acceptable metal or amine salts of these compounds.

The invention also relates to a method for production of compounds of the formula I, which is characterized in that one

a) a compound of the formula II

tr ...

k y \

RO

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-X-

AZ

wherein R and R have the meaning given for formula I.

and R represents a protective group that can be split off under acidic conditions, deprotonated with a base on nitrogen and the anion thus formed with a carboxylic acid derivative of the formula III

Y-CH ₂ - CH ₂ - CII ₂ - (CH ₂ ) _n - COOR ² III

wherein R and η have the meaning given for formula I and Ύ is a replaceable in a nucleophilic substitution Represents radical to a compound of formula IV

riTj OTT f ^ XJ ι ftTX I f ** (~ \ C \ O

CH = CH - CC _{or similar}

implements,

a. ) splitting off the alcohol protective group R in a compound of the formula IV, a compound of the formula I being formed in which A is a -CH-CH- group and B is a -CH = CH- group, and the compound obtained is optionally converted into a physiologically acceptable metal - or amine salt transferred, or

a.,) a compound of the formula V as described under a ₁ ) to 2 * 1

a compound of formula VI

- CH ₂ - CH ₂ - (CH ₂ ) _n -C00R ²

! (VI) CH = CH-C-R

1 °

wherein R, R ~ and η have the meanings given for formula I. have, implemented, _

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copy -

-X-

2619G38

_ _o ) reduced the ketone function in a compound of the formula YJ or produced with an organometallic compound

3 3

represents from R - X ", in which 3Γ denotes a halogen atom, R has the meaning given for formula I, but cannot be hydrogen, converting a compound of the formula I, wherein A is a -CH-CH- group and B is one -CH = CH- group, receives, and optionally

a_) the compound of the formula I in which A is a -CH -CH- group and B is a -CH = CH- group, hydrogenated, where a compound of the formula I in which A and B are each a -CH "-

₂ - group, results, and this compound is optionally converted into a physiologically acceptable metal or Aminesalζ, or

_o ,) a compound of the formula IV is hydrogenated, a compound of the formula VII being formed,

- CH ₂ - CH ₂ - CH ₂ - (CH ₂ ) _n - COOR ²

k ^x 3
RO R ^J

12 3
wherein R ₁ R ₁ R and η are the values given for formula I

4th
have meanings and R represents a protective group which can be split off under acidic conditions, and

a_ _) splits off the alcohol protective group in a compound of the formula VII, a compound of the formula I being formed in which A and B are each a -CH ₂ -CH ₂ - group, and optionally the compound obtained is converted into a physiologically acceptable metal or aain salt convicted, or

b, A in a compound of formula V.

f; 709948/0258

ι COPY

^. CH-

.R

CH ''

ίί

■ hydrogenates the double bond, a compound of the Formula VIII is formed, in which R has the meaning given for formula I,

NH. VIII

ch:

• ch;

b. ) the compound of formula VIII with a base on nitrogen deprotonated and the anion formed with an allyl halide to a compound of formula IX

- CH ₂ - CH = CH ₂

■ H,

CH,

,1

IX

converts, wherein R has the meaning given for formula I,

b, “) the compound of formula IX obtained from ozonolysis • · J

subject, where an aldehyde of the formula X

arises, in which R has the meaning given for formula I,

b _1. ) the obtained aldehyde of the Fermel X with an ylid of the formula XI

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(Ρ?) Ρ = CIl (CH ₂ ) _n C00R ² XI

where η and R have the meaning given for formula I,

2

or R can also represent an alkali metal atom which R identical or different, straight-chain (C - C ^ -alkyl-

w _ _ J- - _ _J _ - TM. - - —— ~ t - -. _ -L · _ "L ^ _ J _. J_ _ β ·" « tr - ^ T-" «· J - · J -»

XUO ^ U UUtJl riiCil ^ XXCO l / C UCUUUUCIl) ZjLI 9XXXtTX VCi. U J. XXt-L ULXX 3 VACTJ.

Formula XII

* ϊ - CH_ - CH = CH - (CH_) - COOR ²
2 2 η

_)
2 η

\ ^ / ^CH 2 x ^XI1

^CH 2 ^ 9 ^r1

1 2
converts, in which R, R and η have the meanings given for formula I,

b,) the keto group of the compound of formula XII

- CH = CH - (CH ₂ ) _n - COOR ²

XII
- CH ₂ - Q - R ¹

with an organometallic compound made from

3 3

R - X ', where X "represents a halogen atom, and R' the

has the meaning given for formula I, but cannot be hydrogen, or the keto group in XII is reduced, a compound of the formula I being formed,
wherein A is a -CH = CH group and B is a -CH -CH group, and the compound obtained is optionally converted into a physiologically acceptable metal or amine salt, or

b) the double bond is hydrogenated in a compound of the formula II wherein a compound of the formula XIII

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XIII

CH ₂ -

1 3

arises, in which R and R are the BeZi given for formula I
have meaning and R an easily under acidic conditions

represents a detachable group,

) the compound of formula XIII obtained with a base on nitrogen deprotonxert and the anion formed with a Allyl halide to a compound of the formula XIV

- CH ₂ - CH =

CH '

h RO

1 3
converts, wherein R and R have the formula I given

k
have interpretations and R an easily under acidic conditions

represents removable protecting group,

b “) the compound of formula XIV obtained from ozonolysis
2.3

subject, where an aldehyde of the formula XV

- CHO

XV

CH ₂ - CH ₂ - JC "

RO

1 3

arises, in which R and R are the attachments given for formula I.

have interpretations and R one under acidic conditions

represents an easily split off residue,

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b ι) the obtained aldehyde of the formula XV with an ylide of Formula XI

(R ⁵ ) P = CH (CH ₂ ) _n C00R ² XI

where η and R ~ have the meaning given for formula I,

2 5

or R also represents an alkali metal atom and R represents identical or different, straight-chain (C ₁ -C) -alkyl radicals or phenyl radicals, to a compound of the formula XVI

-: ϊ - CH - CH = CH - (CH) - COOR

2'n

XVI

RO

12 3
converts, in which R, R, R and η have the meanings given for formula I and R represents a protective group which can be easily split off under acidic conditions,

b _) the protective group R from a compound of the formula XVI splits off, resulting in a compound of the formula I in which A is a -CH = CH group and B is a -CH ^ -CH ^ group, and if necessary

b) a compound of the formula I ₁ in which A is a -CH = CH group and B is a -CH_-CH ₂ group, hydrogenated to a compound of the formula I in which A and B are each a -CH_-CH ₂ group represent, or

bjL ₁ ) the ketone function is reduced in a compound of the formula VIII or with an organometallic compound

3
made up of R - X ', in which X ^{- represents} a halogen atom

3
and R has the meaning given for the formula I, but cannot represent hydrogen, where a compound of the formula XVII

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XVII

1 3
wherein R and R have the meanings given for formula I, arises, and

r ₂ ) the compound of the formula XVII is deprotonated with a base on nitrogen and the anion formed with a carboxylic acid derivative of the formula XVIII

Y - CH ₂ ^ """* -» (CH ₂ J _n - COOR ² XVIII

2
in which R, A and η have the meaning given for formula I and Y is a radical which can be replaced in a nucleophilic substitution, a compound of the formula I being formed in which, A is a -CH ₉ -CH- or a -CH = CH -Group and B is a -CH ₂ -CH ₂ -, or

C ₁ ) deprotonating a compound of the formula VIII with a base on nitrogen and reacting the anion formed with a carboxylic acid derivative of the formula III, a compound of the formula XIX

- CH ₂ - CH ₂ - CH ₂ - (CH ₂ ) _n - COOR ² CH ₂ - CH ₂ - Q - R ^{1 XIX}

1 2

wherein R, R and η have the meanings given for formula I, arises, and

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- yf -

c) the key function of the compound of the formula XIX is reduced or made from with an organometallic compound

Ί 3

R ^ - X- ', where Xy is a halogen atom and R is the Formula I has the meaning mentioned, but cannot represent hydrogen, where a compound of the formula I en to leliL, wuriü A üiid B each one - CH ^ -CK - G stables,

or

d) a compound of the formula XX

N - CH ₀ - CH = CH - (CH ₀ ) - COOR ^{2 1} <ί ^s Z 'τη.

XX

CH = CH-C-R

HO \ _R 3

hydrogenated to form a compound of the formula I in which A and B each represent a -CHp-CH group.

12 τ

Among the meanings mentioned for the substituents R ₁ Ru. R ^J and for n, A and B, the following are preferred:

For R: a straight, branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-7 carbon atoms or a cycloaliphatic hydrocarbon radical with j> ~ 7 carbon atoms, each substituted can be with

a) a straight or branched alkoxy, alkylthio, Alkenyloxy or alkenylthio radical with 1-4 carbon atoms ,

b) a phenoxy radical, which in turn has an alkyl group with 1-3 carbon atoms, the trifluoromethyl group, Halogen atoms, an optionally halogen-substituted phenoxy radical or an alkoxy radical with 1 or 2 carbon atoms mono- or di-

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can be substituted,

c) a thienyloxy or benzyloxy radical, which in turn with an alkyl group with 1-3 carbon atoms, the trifluoromethyl group, halogen atoms or an alkoxy group having 1 or 2 carbon atoms can be mono- or disubstituted,

d) a trifluoromethyl group,

e) a cycloalkyl radical with 5-7 carbon atoms,

f) a phenyl radical or thienyl radical, which in turn with an alkyl group having 1-3 carbon atoms, the trifluoromethyl group, halogen atoms or one Alkoxy group with 1 or 2 carbon atoms mono- or disubstituted,

For R: a straight-chain or branched alkyl radical with 1-6 carbon atoms, a straight-chain or branched one Alkenyl radical with 2-4 carbon atoms, a cycloalkyl radical with 5 or 6 or an aralkyl radical with 7 or 8 Carbon atoms.

3
For R: hydrogen, a straight or branched alkyl radical with one to five carbon atoms, an alkenyl or alkynyl radical with two to five carbon atoms.

In particular, the following meanings are preferred:

For R: a straight or branched alkyl radical with 1-7 carbon atoms, a straight-chain or branched alkenyl radical with 3 - 5 carbon atoms or a cycloalkyl radical with 5-7 carbon atoms, which can be substituted with:

a) a straight or branched alkoxy, alkylthio, Alkenyloxy or alkenylthio radical with 1-3 carbon atoms,

b) a phenoxy radical, which in turn is linked to a methyl,

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Trifluoromethyl or methoxy group, chlorine, fluorine or a phenoxy radical optionally substituted by chlorine or fluorine can be mono- or disubstituted,

c) a thienyloxy or benzyloxy radical, which respectively Mono- or disubstituted in the core with a methyl, tri fluorine thy I or methoxy group, chlorine or fluorine could be,

d) a trifluoromethyl group,

e) a cycloalkyl radical with 5-7 carbon atoms,

f) a phenyl or thienyl radical, which in turn is associated with a methyl, trifluoromethyl or methoxy group, Chlorine or fluorine can be mono- or disubstituted.

For R: a straight-chain alkyl radical with 1 to 6 carbon atoms, a branched alkyl radical with 3 ~ 5 carbon atoms, a straight-chain alkenyl radical with 2 carbon atoms, the cyclopentyl or cyclohexyl as well as the benzyl radical.

For R: hydrogen, the methyl, ethyl or propyl radical or an alkenyl or alkynyl radical with two or three carbon atoms

η preferably means the number 3

Those compounds in which B is the -CH -CH group are particularly preferred.

Among the substituents for R, for example, those listed below are very particularly preferred:

2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 3-ethylpentyl, 1-dimethyl-4-pentenyl, 5-methyl-4-hexenyl, 1-methyl-5-cyclohexylpentyl, 4-cycloheptylidenebutyl, 4-trifluoromethylbutyl, 5-trifluoromethylheptyl, 1,1-dimethyl-6-trifluoro-

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methylhexyl, i-methyl-5-trifluoromethylpentyl, 1, i-difluoro-4, 4-diraethylpentyl, h , ^ - difluorocyclohexyl, 4-trifluoromethylcyclohexyl, 3-trifluoromethylcyclohexyl, 2-trifluoromethylcycloheptyl, 3,3-trifethylcycloheptyl, 3-trifethylcycloheptyl -2-oxapentyl, 3-methyl-2-oxahexyl, h, 4-dimethyl-2-oxapentyl, 1,1, 4-trimethyl-2-oxapentyl, 3 »4-dimethyl-2-oxapentyl, 5-meth.yl -2-oxa-4-hexenyl, 2,2-dimethyl-3-oxaheptyl, 1,1-dimethyl-3-oxahexyl, 1,1-dimeth.yl-3-oxaoctyl, 1,1,5,5-tetramethyl -3-oxahexyl, 1-methyl-3-oxahexyl, 1-methyl-3-oxaoctyl, 1,1,6-trimethyl-3-oxa-5-heptenyl, 1,1,6-trimethyl-3-oxaheptyl, 7 -Methyl-4-oxaoctyl, 1,1-dimethyl-4-oxa-6-heptenyl, k -metlioxycyclohexyl, 3-butoxycyclohexyl, 2-ethoxycyclohexyl, 3-ethoxycyclopentyl, 4-methoxycycloheptyl, 2-thiapentyl, 2 -Thiahexyl, 2-thiaheptyl, h, it-dimethyl-2-thiapentyl, 5-methyl-2-thia-4-hexenyl, 3-thiapentyl, 3-thiahexyl, 5,5-dimethyl-3-thiahexyl, 1,1 -Dimethyl-3-thiapentyl, 1,1-dimethyl-4-thiapentyl, 4-chlorophenoxymethyl, 2-chlorophenoxy methyl, 2,3-di-Cl ¹ I-phenoxymethyl, 2,4-dichlorophenoxymethyl, 2,5-dichlorophenoxymethyl, 2,6-dichlorophenoxymethyl, 3 »^ - dichlorophenoxymeth.yl, 3,5-diclilorphenoxymethyl, 2-chloro-6- methylph.enoxymethyl, 2-Ch.lor-4-methylphenoxymethyl, 3-chloro-2-methylpheπoxymethyl, 4-chloro-2-methylphenoxymethyl, 5-chloro-2-methylph.enoxymeth.yl, 4-trifluoromethylphenoxymethyl, 2-trifluoromethylphenoxymethyl, 2-methyl-5-trifluoromethylphenoxymethyl, 3-methy1-5-trifluoromethylphenoxymethyl, 3-fluorophenoxymethyl, 2-fluorophenoxymethyl, 2-fluoro-4-trifluoromethylphenoxymethyl, 3 »4-difluorophenoxymethyl, 4-fluoro-2-methylphenoxymethyl, 3oxypyl., 4-phenoxymethyl -p-chlorophenoxyphenoxymethyl, 4-methoxyphenoxymethyl, 3-methoxyphenoxymethyl, ^ -Chlor ^ -methoxyphenoxyinethyl, 3-chloro-4-methoxyphenoxymethyl, 4-methoxy-3-methylphenoxymethyl, 4-methoxy-2- methylphenoxymethyl, 3-methoxy-5-diethylphenoxymethyl, 3-chlorophenoxyethyl, 4-chloroplienoxyethyl, 3-trifluoromethylphenoxyethyl, 4-methoxyphenoxyethyl, 3-methylphenyl noxyethyl, 4-fluorophenoxyethyl, 3-chloro-5-methylphenoxyethyl, 1- (3-trifluoromethylphenoxy) propyl-2, 1- (3-chlorophenoxy) propyl-2, 1- (4-fluorophenoxy) propyl-2 , 1- (4-chloro-3-methylphenoxy) -propyl-2, 1- (3-chloro-4-methoxyphenoxy) -propyl-2, 1- (3-trifluoromethyl-phenoxy) -2-methylpropyl-2, 1 - (3-Chlorophenoxy) -2-methylpropyl-2, 1- (4-fluorophenoxy) -2-methylpropyl-2, 1- (3 »4-dichlorophenoxy) -2-methylpropyl-2, ^ -

709S46 / 0258

1- (3-chloro-4-methylphenoxy) -2-methylpropyl, 1- (3-chloro-4-phenoxyphenoxy) -2-methylpropyl, 1, i-dimethyl-4-phenoxybutyl, 1,1-dimethyl-4- (3-ti "if luormethyljahenoxy-) -butyl, benzyloxymethyl, 3-chlorobenzyl-oxymethyl, 3-trifluoromethyl-benzyloxymethyl, 4-methoxybenzyl-oxymethyl, 3-plisnoxybenzyloxymethyl, 2-methyl-

Ήe »-n (7ir1 r» wmn 4-Vi "* r1 h. __ Ph Ί ΛΤ-'ί mn +>» * - * virKotlTtri r \ vtrmn 4- \ itr1 ^ 3_ Μλ + 1- »i- \ vnv R -

methylbenzyloxyraethyl, 1- (3-chlorobenzyloxy) -2-methylpropyl-2, 1- (4-trifluoromethylbenzyloxy) propyl-2, 4-fluorobenzyloxypropyl, 4- (3-chlorophenoxy) cyclohexyl, 4- (3-trifluoromethylphenoxy ) -cyclohexyl, 2-phenoxycyclohexyl, k- (2-chlorobenzyloxy) -cyclohexyl, benzyl, 3-trifluoromethylbenzyl, 4-methylbenzyl, 3-chlorophenylethyl, 4-fluorophenylethyl, 2-methyl-1-phenylpropyl-2, 1,1- Dimethyl-4-phenyl, 2-methyl-3-thienylοxyraethyl, 2-chloro-3-thienyloxyraethyl, 2-chloro-4-thienylοxyraethyl, 3 ~ chloro-4-thienyloxymethyl, 2,5-dimethyl-3-thienylοxymethyl, 2- Chloro-3-methyl-4-thienyloxymethyl, 2-thienylοxymethyl, 4-methyl-2-thienyloxymethyl, 5-chloro-2-thienyloxymethyl, 5-chloro-3-methyl-2-thienyloxymethylj 3> S-dimethyl - ^ - thienyloxyraethyl, 1- (3-thienyl) ~ 2-methylpropyl-2, 3- (3-thienyl) -1-methylpropyl, (2-methoxythienyl-4) -propyl, 3-thenyl, 2- Chloro-4-thenyl, 2-methyl-5-thenyl, thienylbutyl, 1, i-dimethyl-3-thienyl-propyl, (4-methoxy-2-thienyl) -ethyl.

As starting materials for the processes mentioned under a) Compounds of the formulas II (R = Η) and V used are according to the patent application P 25 28 664.0 (HOE 75 / F I69) synthesized conditions mentioned. The compounds of the formula II (R 5 / H) can according to the patent application P 25 56 326.2 (HOE 75 / F 315).

The alkylation of the compounds of the formula II and V with a carboxylic acid derivative of the formula XIII is carried out by customary methods carried out. One proceeds so that one with a suitable base such as sodium or potassium hydroxide, sodium or Potassium amide, sodium hydride, potassium tert-butoxide, lithium diisopropylamide or lithium cyclohexyl isopropylamide the nitrogen deprotonated and then adding the alkylating agent in bulk or dissolved in the solvent in question.

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The main substituents Y in XII are the acid residues methanesulfonic acid, p-bromobenzenesulfonic acid and p-Toluenesulfonic acid, but mainly chlorine, bromine and iodine in Question where bromine and iodine are the most important.

The reaction · dex · base with the compounds of the Foiiuel II and V is carried out with the exclusion of air and moisture because of the air and moisture sensitivity of the bases and the carbanions formed. Particularly suitable solvents are aprotic polar liquids which, even at low temperatures, still have sufficient solvent power and are inert under the reaction conditions. If necessary, mixtures of two or more solvents are used to lower the freezing point. Ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, and also dimethylformamide, dimethyl sulfoxide, or toluene are preferred. The reaction temperatures are between -30 C and +100 C, preferably between -10 C and + 8O ⁰ C.

Working up can be carried out, for example, by adding a certain amount of water to the reaction mixture, the organic phase is separated off, the aqueous phase is extracted several times with an organic solvent and the combined organic phases dries and constricts. In a few cases, the residue must be subjected to a high vacuum distillation most cases, however, can be purified by column chromatography. Often the products are already so pure that they can cleaning is not necessary.

Compounds of the formula I (A: -CH -CH, B: -CH = CH-, B? = H) can be obtained by treating the compounds of the formula VI with a reducing agent. The reduction can be accomplished with any reducing agent that enables a selective reduction of a keto group to a hydroxyl group. Preferred reduction; mediums are complex metal hydrides, in particular the borohydrides such as sodium borohydride, zinc borohydride or lithium perhydro-9b-bora-phenalkylhydride (j. Amer. Chem.

709848/0258

Soc. ° J2, 709 (1970)) or complex aluminum hydrides such as e.g. sodium bis (2-methoxy-ethoxy) aluminum hydride. Usually the reduction is between -10 and +50 C in one opposite the hydrides inert solvents such as ethers such as diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether or hydrocarbons such as benzene or in an alcohol / water mixture such as methanol / water carried out. The isomeric oC- and ß-hydroxy compounds formed in this reduction can with the help of the usual chromatographic Methods can be separated into the two isomers.

The organometallic compounds used for converting the compounds of the formula VI into compounds of the formula I (A = -CH ₂ -CH-, B = -CH = CH-, R ³ H) are derived from metals of main group I and II away. In particular, organolithium or organomagnesium compounds (Grignard compounds) come into consideration, which can be obtained in one of the usual ways, for example from a

3 3

bond R - X, where R has the meaning given for formula I. and X represents a halogen atom such as chlorine, bromine or iodine, and the corresponding metal such as Li or Mg will.

Such solvents are used for the implementation of the pyrrolidones of the formula VI which are inert under the reaction conditions such as hydrocarbons or preferably Xther such as diethyl ether, tetrahydrofuran or 1, 2-dimethoxyä than. It can be used at temperatures between -60 ° C and +30 C, preferably work at -30 C to -0 C. It is irrelevant whether the substrate is the organometallic compound or the organometallic compound Connection to the substrate is given.

However, the organometallic compound is preferably added to the substrate in order to prevent possible side reactions. For working up, water, dilute mineral acid or a solution of ammonium salts are added such as ammonium chloride in water and isolate the reaction product in the usual way.

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709846/0258

For the cleavage of the AlkGholschutsgruppe, the compounds of the formula IV being converted into compounds of the formula I (A: -CH ₃ -CH ₂ B: -CH = CH-), the usual reagents and test conditions are used.

In the compounds of the formula IV, the alcohol function is preferred protected by an acetal group. The cleavage of this protective group, which leads to compounds I, is the simplest by acid hydrolysis with dilute aqueous / alcoholic acid, preferably in dilute aqueous / alcoholic Oxalic acid at 10 - 50 C or by heating with 50 - 70% iger Acetic acid to 50 - 60 ° C.

The hydrogenation of the compounds of the formula I (A: -CH_-CH-, B: -CH = CH-) to compounds of the formula I (A, B: -CH-CH ₂ -) is possible under the conditions required for a hydrogenation of a carbon Carbon double bond usual conditions. Possible catalysts are metal catalysts such as nickel, mainly noble metal catalysts such as palladium in pure form or also applied to supports such as barium carbonate or activated carbon. The solvents used are mainly alcohols such as methanol. The temperature and pressure range can vary within wide limits, with the temperature range from room temperature to 60 C and the pressure range up to 10 atm being of particular importance.

As described above, the compounds of the formula IV can also be hydrogenated to give compounds of the formula VII. The elimination of the alcohol protecting group in compounds of the formula VII according to the procedure given for the _{conversion from IV to I (A: -CH 2} -CH--, B: -CH = CH-) also gives the compounds of the formula I (A, B : -CH ₂ -CH ₂ -).

The compounds of the formula VI and I ₁ in which R is hydrogen can also be synthesized analogously to the instructions given in Tetrahedron Letters 2931 (1975).

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The procedural variants b), c) and. d) necessary hydrogenation, ie. the conversion of V into VIII, I (A: -CH = CH-., Bi -CH ₂ -CH ₂ -) in I (A, B: -CH ₂ -CH ₂ -), II in XIII, VIII in XIX , XX to I, alkylations, ie the conversion of VIII to IX, XVII to I, XIII to XIV, VIII to XIX, introduction of the radical R ³ , ie the conversion of XII to I (a: -Ch = CH-, Hi -UH ₉ -OH ₃ -), XIX in I (A, B: -CH-CH-) and the cleavage of the alcohol protective group R (XVI in l) are carried out under the conditions as already explained for process a) , whereby the use of potassium hydroxide as base in dimethyl sulfoxide at temperatures between +10 C and ko C is preferred for the introduction of the allyl radical in VIII or XIII for conversion to IX or XIV of the conditions mentioned.

The conversion of the olefins of the formula IX into the aldehydes of the formula X by ozonolysis takes place analogously to the literature (jChem. Rev. ^ 8, 990 (1958), Tetrah. Lett. ^ 6, ^ 273 (1966)] in the following way:

The olefins are, if appropriate with the exclusion of moisture, in a certain amount of methanol, which may also contain a halogenated hydrocarbon such as methylene chloride is mixed, dissolved. The equivalent is added to this solution at temperatures between -100 C and -50 C, preferably at -70 C. Amount of ozone introduced. A small excess of ozone has no effect on the yield. Then you displace that in excess existing ozone through an inert gas, adds to the reduction of the Ozonolysis products add dimethyl sulfide and stir at -10 C, 0 C and 20 C for about an hour.

To isolate the aldehydes, the solutions are concentrated in vacuo at the lowest possible temperatures, and the residue is optionally Treated with saturated .Natrxumbicarbonatlösung and then the product is extracted with a suitable solvent, preferably benzene, or the crude product is used directly chromatographed.

The aldehydes are either directly or after prior purification

- 20 -

709846/0258

generation e.g. by column chromatography for the subsequent Wittig-Ri - »! etion.

The compounds of the formula XII are prepared by reacting a phosphonium ylide of the formula XI, in which the radical R is preferred Phenyl denotes and R is preferably hydrogen, which was replaced by a metal atom in the ylide production, with the Aldehydes of the formula X obtained in a suitable solvent. The phosphonium ylides and the phosphonium salts on which they are based are prepared according to analogous procedures described in the literature, Lj. Amer. Chem. Soc. £ 1 »5 ^ 75 (1969) 1

Inorganic bases such as sodium hydride, sodium amide or lithium amide or organic bases, e.g. organic alkali metal compounds such as potassium tert-butoxide, Lithium butyl, lithium diisopropylamide or the sodium salt of dimethyl sulfoxide are used.

Suitable solvents are, for example, ethers such as diethyl ether, Tetrahydrofuran, diethylene glycol dimethyl ether, di-lower alkyl sulfoxides such as dimethyl sulfoxide or amides of carboxylic acids such as dimethylformamide, diinethylacetamide, or also hexamethylpho spheric acid triamide.

The preferred solvent is dimethyl sulfoxide. In particular, the sodium salt of dimethyl sulfoxide is used as the base. Under these conditions, cis double bonds are preferentially formed.

The manufacture of the ylid and the subsequent implementation with the aldehyde happens in a one-pot reaction. In detail, for example, the procedure is as follows:

The solution of the phosphonium salt is added at room temperature with the exclusion of moisture and under inert gas to one equivalent of a base, which is also in an aprotic solvent, mostly dimethyl sulfoxide, is dissolved. After approx. 1 After stirring for hours, a solution of 0.30 to 0.95 is added

709846/0258

Equivalents of the aldehyde added. The reaction is over after Z-Zh hours. It is acidified with a mineral acid at -5 C to +5 C (if R = H), the acid is extracted from the reaction mixture with a suitable solvent such as ether, methylene chloride or benzene, the organic phase is dried and concentrated *

The reaction steps just described for the conversion of IX in XII can be carried over in an analogous manner to the implementation of XIV in XVI.

In addition to the methods described in more detail here, the invention also includes those methods that differ in an analogous manner from the Derive the reaction steps listed here..In particular, count in addition, such process steps that are carried out on connections which differ only in a higher or lower content of one or different protective groups (e.g. Conversion of XIIl (R = H) to XVI (R = H)).

The reduction of the keto group, which is introduced by the Homer reaction, or the reaction of this keto group with an organometallic reagent gives a mixture of α and β isomers with respect to the resulting secondary hydroxyl group. The separation into the two epimers can either take place on these reaction products or after one of the subsequent reaction stages. This means that all subsequent reactions, e.g. hydrogenation, conversion into the free acid or esterification or conversion into metal or amine salts, both on the pure <χτ ^{un {} * ß-isomers, as well as on a mixture of cc- and ß-isomers can be carried out.

If the individual reaction products are not already obtained in pure form, so that they are necessary for the following reaction step can be used, cleaning by means of e.g. column, thin-layer or high-pressure liquid chromatography is recommended.

The compounds of formula I have two asymmetric ones

- 22 -

709846/0258

Centers, namely, the carbon atom, which is the secondary Bears hydroxyl group, and the carbon atom adjacent to the nitrogen in the five-membered ring, which corresponds to the 5-position in the pyrrolidone ring.

Since none of the reaction pathways indicated gives sterically uniform products, the invention relates to all compounds of Formula I regardless of the steric arrangement on the various carbon atoms. In addition to the two above, this already applies mentioned optically isomeric carbon atoms also for the geometrically isomeric compounds with respect to the double bond. In general, however, one can assume that in the Homer reaction, Due to the way the reaction is carried out, mainly a trans linkage is obtained, and only to a small extent the resulting cis product is removed by chromatographic purification steps. The Wittig reaction is similar to introduce the carboxyl side chain mainly the corresponding cis -olefin is formed. Again, this can be a by-product occurring trans-olefin are separated by appropriate purification operations.

The geometry of the double bond given in the carboxylic acid derivatives XVIII (A: -CH = CH-) is determined by the alkylation step transferred to the later end products. This means that when using the corresponding trans derivative of XVIII (A: -CH = CH-) the product has a trans double bond in the carboxyl side chain wearing. The same applies analogously to the use of the cis derivative of XVIII (A: -CH = CH-).

Because of the possibilities for introducing the two double bonds one can assume that the geometry of the double bond is uniform. That is because of the two optically isomers A mixture of two diastereomers present in carbon atoms can be obtained in the case of crystallizable derivatives by fractionated Crystallization or with the help of chromatographic methods, such as column, gas, thin-layer or medium or Separate high pressure liquid chromatography into the two racemic diastereomers. The splitting of the racemates into the op-

709848/0258

table-active compounds are achieved by generally customary processes such as treatment of the compounds of formula I (R = H) with optically active bases such as brucine.

- Zk -

709846/0258

In addition to the compounds mentioned in the examples, in particular, the following compounds can also be produced.

1- (5-methoxycarbony1-pent-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

1- (5-methoxycarbonyl-pent-1-yl) -5- (3-hydroxy-4,4-methyl-5-ethoxy-pent-1-yl) -pyrrolidone-2

1- (5-methoxycarbonyl-pent-1-yl) -5- (3-hydroxy-6-pentafluoroethyl-hex-1-yl) -pyrrolidone-2

1- (5-methoxycarbonyl-pent-1-yl) -5- [3-hydroxy-4- {3-thienyloxy) · but-l-yl] pyrrolidone-2

1- (5-Methoxycarbonyl-pent-1-yl) -5- [3-hydroxy-5-phenyl-pent-1-y1] -pyrrolidone-2

1- (5-methoxycarbonyl-pent-1-yl) -5- (3-hydroxy-4,4-dimethyloct-1-yl) -pyrrolidone-2

1- (5-methoxycarbonyl-pent-1-yl) -5- [3-hydroxy-4- (3-trifluoromethylphenoxy) but-1-yl] pyrrolidone-2

1- (7-n-Propoxycarbonyl-hept-1-yl) -5- (3-hydroxy-3-prop-2-enyl-oct-1-yl) -pyrrolidone-2

- 25 -

709846/0258

1- (7-iso-ayloxycarbonyl-iiept-l ~ yl) -5- (S-oct-l-yl) -pyrrolidone-2

1- (7-Carboxy-hep-1-yl) ~ 5- [3-hydroxy-4- (4-methoxy-phenoxy) -but-1-yl] -pyrrolidone-2

1- (5-n-Butoxycarbonyl-pent-1-yI) -5- [3-hydroxy-4- (3-chloro-4-ynethyl-phenoxy ) -but-1-yl] -pyrrolidone-2

1- (6-Carboxy-hex-1-yl) ~ 5- [3-hydroxy-4- (5-methyl-3-thienyloxy) -but-1-yl] -pyrrolidone-2

1- {6-Phenylethoxycarbonyl-hex-1-yl) -5- [3-hydroxy-4- (4,5-dimethyl-3-thienyloxy) -but-1-yl] -pyrrolidone-2

1- [6-n-Butoxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-oct-lyl] -pyrrolidone-2

1- [6-n-Hexyloxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-3-benzyl-oct-1-yl] pyrrolidone-2

1- [5-Ethoxycarbonyl- (Z) -2-penten-1-yl] -5- [3-hydroxy-oct-1-yl] -pyrrolidone-2

1- [7-Phenylethoxycarbonyl- (Z) -2-hepten-l-yl] -5- [3-hydroxy-oct- -pyrrolidone-2

- 26 -709846/0258

l- [6-Kethoxycarbonyi- (Z) ~ 2-hexen-l ~ yl] ~ 5 ~ [3-hydroxy-3-ethynyJ · oct-1-ylI-pyrrolidcn-2

1- [7 ~ Metlioxycarbonyl- (Z) -2-hepten-l ~ yl] -5- [3-hydroxy-undec-lyl l-pyrrolidone-2

1- [6-Methoxycarbonyl- (Z) -2-hexen-1-ylI-5- [3-hydroxy- (E _/ E) -4 _/ 6-octadien-l-ylI-pyrrolidone-2

1- [6-Methoxycarbonyl- (Z) -2-hexen-1-ylj-5- [3-hydroxy-5-cyclopentyl-pent-1-ylI-pyrrolidone-2

1- L6-Carboxy- (Z) -2-hexen-1-ylI-5- [3-hydroxy-5-phenyl-but-l-ylI-pyrrolidone-2

1- [6-Cart> oxy- (Z) -2-nexen-l-y ± j-b-L3-hydroxy-6-pentafluoroethylhex-1-yl] -pyrrolidone-2

1- [6-Methoxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-5-ethoxypent-1-yl] pyrrolidone-2

1- [6-n-Hexyloxycarbonyl- (E) -2-hexen-1-yl] -5- [3-hydroxy-6-methylmercapto-hex-1-yl] pyrrolidone-2

1- [6-Carboxy- (E) -2-hexen-1-yl] -5- [3-hydroxy-5-isobutyloxy-4,4-diinethyl-pent-1-yl] -pyrrolidone-2

- 27 709846/0258

l_ [5-Carbuxy- (Z) -2-pentGn-l-yll-5- [3-hydroxy-5-allylmercapto-4, 4-dimethylpent ~ i- * yl] pyrrolidone-2

1- [5-Carboxy- (Z) -2-penten-1-yl] -5- [3-hydroxy-4- (4-methylphenoxy) but-l ~ yl] pyrrolidone ~ 2

1- [6-Mefhoxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-4- (3-chlorophenoxy ) -but-1-yl] -pyrrol.idon-2

1- [5-Methoxycarbonyl- (z) -2-penten-l ~ yl] -5- [3-hydroxy-4- (4-methoxyphenoxy) but-1-yl] pyrrolidone-2

1- [6-Methoxycarbonyl- (z) -2-hexen-1-yl] -5- [3-hydroxy-4- (4-phenoxyphenoxy) but-l ~ yl] pyrrolidone-2

1- [6-Ethoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-4- (4-chlorophenoxyphenoxy) -4-methy1-but-1-yl] pyrrolidone- 2

1- [5-Ethoxycarbonyl- (Z) -2-penten-1-yl] -5- [3-hydroxy-4- (3-chlorophenoxy) -but-1-yl] -pyrrolidone-2

1- [5-iso-propoxycarbonyl - (Z) -2-penten-1-yl] -5- [3-hydroxy-4- (2-chloro-4-methy1-phenoxy) -but-1-yl] - pyrrolidone-2

1- [7-Methoxycarbonyl- (Z) -2-hepten-1-yl] -5- [3-hydroxy-4-benzyloxy-but-1-yl] pyrrolidone-2

709846/0258 _ _2g _

1- [7-Athoxycarbonyl- (Z) -2-hep: en-1-yl] -5- [3-hydroxy-4- (5-methyl-3-thienyloxy) -but-1-yl] -pyrrolidone- 2

1- [7-Ethoxycarbonyl- (Z) -2-hepten-1-yl] -5- [3-hydroxy-4- (4,5-dimethyl-3-thienyloxy) -but-1-yll-pyrrolidone-2

1- [5-Athoxycarbonyl- (E) -2-penten-1-yl] -5- [3-hydroxy-4- (4-fluorobenzyloxy) but-1-yl] pyrrolidone-2

1- [6-Carboxy- (E) -2-hexen-1-yl] -5- [3-hydroxy-4- (3-trifluoroethylbenzyloxy) but-1-yl] pyrrolidone-2

1- [6-n-Hexyloxy- (E) -2-hexen-1-yl] -5- [3-hydroxy-4- (4-methoxybenzyloxy) -but-1-yl] -pyrrolidone-2

1- [6-Carboxy- (Ξ) -2-hexen-1-yl] -5- [3-h / droxy-4- (2-chloro-4-methy1-benzyloxy) -but-1-yl] - pyrrolidone-2

1- [6-Carboxy- (E) -2-hexen-1-yl] -5- [3-hydroxy-7-trifluoromethylhept-1-yl] pyrrolidone-2

1- [6-Hethoxycarbonyl- (E) -2-he: <en-l-yl] ~ 5- [3-hydroxy-3-ethyl-5-cyclopentyl-pent-1-yl] pyrrolidene-2

1- [6-Methoxycarbonyl- (Z) -2-liexen-1-yl] -5- [3-hydroxy-4-cycloheptyl-but-1-yl] pyrrolidone-2

709848/0258 - 29 -

COPY

1- [6-Ethoxycarboriyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-4- (4-chlorophenyl) -but-i-yl] -pyrrolidone-2

1- [6-n-Butoxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-5- (3,4-dichlorophenyl) -pcnt-1-yl] -pyrrolidone-2

1- [6-Carboxy- (E) -2-hexen-1-yi] -5- [3-hydroxy-5- (4-toluyl) pent-1-yl] pyrrolidone-2

1- [6-MethoxycarbonyI- (E) -2-hexen-1-yl] -5- [3-hydroxy-4- (5-methyl-3-thienyl) -but-1-yl] -pyrrolidone-2

1- [6-Carboxy- (E) -2-hexen-1-yl] ~ 5- [3-hydroxy-4,4-dimethyl-5- (4-methoxyphenyl) -pent-1-yl] -pyrrolidone -2

1- [6-n-Butoxycarbonyl-hex-1-y1] -5- [3-hydroxy- (E) -I-octen-1-yl] -pyrrolidone-2

1- [6-n-Hexyloxycarbonyl-hex-1-yl] -5- [3-hydroxy- (E) -l-octen-1-yl] -pyrrolidone-2

1 - [5-lithoxycarbony 1-pent-1-yl] -5- [3-hydroxy- (E) -I-octene-1-y 1] -pyrrolidone-2

1- [7-Ethoxycarbonyl-hept-1-yl] -5 ~ [3-hydroxy- (E) -1-octen-1-yl] -pyrrolidone-2

7098A6 / 0258

1 - [6-Phenätlioxycarbony 1-iiex-1-yl] -5- [3-hydro :: y- (S) -1 -octen- "pyrrolidone-2

1- [6-Isoamyloxycarbonyl-hex-1-yl] -5- [3-hydroxy- (E) -l-oc "len-1-yl] pyrrolidone-2

1- [6-Isopropyloxycarbonyl-hex-1-yl] - 5- [3-hydroxy- (E) -1-octene l-yl] pyrrolidone-2

1- [6-MethoxycarbonyI-hex-1-yl] -5- [3-hydroxy-3-isopropyl- (E) -1-octen-1-yl] pyrrolidone-2

yl] pyrrolidone-2

pyrrolidone-2

1- [6-Methoxycarbony1-hex-1-yl] -5- [3-hydroxy-5-ethoxy- (E) -I-penten-1-yl] -pyrrolidone-2

1- [6-n-Hexyloxycarbonyl-hex-1-yl] -5- [3-hydroxy-6-methylmercapto- (E) -l-hexen-1-yl] -pyrrolidone-2

1- [6-Carboxy-hex-1-yl] -5- [3-hydroxy-5-isobutyloxy-4,4-dimethyl- (E) -1-penten-1-yl] -pyrrolidone-2

709846/0258

- 31 -

1- [6-Carboxy-hex-1-yl] -5- [3-hydroxy-5-allylmercapto-4,4-dimethy1- (E) -1-penten-1-y1] -pyrrolidone-2

1- [6-carboxy-hex-l-yl] -5- [3-hydroxy-4- (4-methyl-phenoxy) - (E) -

l- [6-methoxycarbonyl-hex-l-yl] -5- [3-hydro> cy-4- (4-chlorophenoxy) · (E) -l-buten-l-yl] pyrrolidone-2

1 - [5-methoxycarbony-1-pent-1-yl] - 5- [3-hydroxy-4- (4-methoxyphenoxy) - (E) -1-buten-1-yl] pyrrolidone-2

1- [6-Methoxycarbonyl-hex-1-yl] -5- [3-hydroxy-4- (4-phenoxyphenoxy) - (E) -1-buten-1-yl] pyrrolidone-2

1- [6-Ethoxycarbonyl-hex-1-yl] -5- [3-hydroxy-4- (4-chlorophenoxyphenoxy) -4-methyl- (E) -l-buten-1-yl] pyrrolidone-2

1- [6-Ethoxycarbonyl-hex-1-yl] -5- [3-hydroxy-4- (3-chlorophenoxy) - (E) -1-buten-1-yl] -pyrrolidone-2

1- [6-iso-propoxycarbonyl-hex-l-yl] -5 - '[3-hydroxy-4- (2-chloro-4— methyl-phenoxy) - (E) -1-buten-1-yl] -pyrrolidon-2

1- [6-Methoxycarbonyl-hex-1-yl] -5- [3-hydroxy-4-benzyloxy- (E) -1-buten »1-yl] pyrrolidone-2

7098A6 / 0258

- 32 -

1- [6-Ethoxycarbonyl-hex-1-yl] -5- [3-hydroxy-4- (5-methyl-3-thienyloxy) - (E) -l-buten-1-yl] ~ pyrrolidone-2

1- [6-Äthoxycarbonyi-h.ex-l-yl] - 5- [3-hydroxy-4- (4,5-dimethyl-3-thienyloxy) - (E) -l-buten-l ~ yl] - pyrrolidone-2

1- [5-Ethoxycarbonyl-pent-1-yl] -5- [3-hydroxy-4- (4-fluorobenzyloxy- (E) -l-buten-1-yl] -pyrrolidone-2

1- [6-Carboxy-hex-1-yl] -5- [3-hydroxy-3-methyl-4- (3-trifluoromethylbenzyloxy) - (E) -1-buten-1-yl] -pyrrolidone-2

1- [6-n-Hexyloxy-hex-1-yl] -5- [3-hydroxy-4- (4-methoxy-benzy3-oxy) - (E) -1-buten-1-yl] -pyrrolidone- 2

1- [6-Carboxy-hex-l-yl] -5- [3-hydroxy-4- (2-chloro-4-methyl-benzyloxy) - (E) -1-buten-l-yl] -pyrrolidone- 2

1- [7-Carboxy-hept-1-yl] -5- [3-b-hydroxy-7-trifluoro-methyl- (E) -lhepten-1-yll-pyrrolidone-2

1- [7-Methoxycarbonyl-hept-i-yl J-5- [3-hydroxy-5-cyclopentyl- (E) -l-penten-1-yl] -pyrrolidone-2

1- [7-methoxycarbonyl-hept-1-yl] -5- [3-hydroxy-4-cycloheptyl- (E) -l-buten-1-yl] pyrrolidone-2

709846/0258

2619638 7-ÄthoxycarbonyI-liept-1-yl i-5- i3-hydroxy-4- (4-chlorophenyl) - w - ¹ L ..

(E) -1-buten-1-yl! -Pyrrolidon-2

1- ι 5-II-butoxycarbonyl-pent-1-ylJ-5- [3-hydroxy-5 ~ (31 ^ -dichlorophenyl) - (E) -1-penten-1-yll-pyrrolidon-2

1-J5-Carboxy-pent-1-ylJ-5-j 3-hydroxy-5- (4-toluyl) - (E) -1-penten-1-yl-pyrrolidon-2

1- iB-methoxycarbonyl-pent-i-yl "] - ^ -" 1 3-hydroxy - ^ - (5-methyl-3-thienyl) - (E) -1-buten-1-yl , -pyrrolidone-2

1-15-Carboxy-pent-i-yl-5-13-hydroxy-4,4-dimethyl-5 - (^ - ro © thoxyphenyl) - (E) -1-penten-1-ylj-pyrrolidone-2

The compounds according to the invention are characterized on the one hand by spasmogenic, on the other hand by bronchodilator, also · vasoactive, gastric secretion-inhibiting and abortive Properties. They can therefore be used as medicinal products will.

The compounds of the formula I according to the invention can be used as free Acids, in the form of their physiologically harmless inorganic or organic salts or as esters of aliphatic, cycloaliphatic or araliphatic alcohols are used.

Suitable organic salts are, for example, alkali, Alkaline earth or ammonium salts, while for salt formation with organic bases those come into consideration that differ from primary, derive secondary or tertiary amines, whereby other hydrophilic groups can also be present in the amine * There are, for example, salts with methyl, triethyl, benzyl, Phenylethyl, allylarain or with piperidine, pyrrolidine, Morpholine or ethanolamine, triethanolamine, tris (hydroxymethyl) methylatnin in question, the ester is preferred as an ester

709846/0258 - 34 -

of lower aliphatic alcohols such as methyl, ethyl, propyl, Butyl or hexyl esters and benzyl esters.

Acids and salts or esters can be in the form of their aqueous solutions and suspensions or also dissolved or suspended in pharmacologically acceptable organic solvents such as monohydric or polyhydric alcohols, e.g. ethanol, ethylene glycol or glycerine, oils such as sunflower oil or cod liver oil, ethers such as diethylene glycol dimethyl ether or polyethers such as polyethylene glycol odex "also in the presence of others pharmacologically harmless polymer carriers such as polyvinylpyrrolidone are used.

The usual pharmaceutical infusion or injection solutions and tablets, as well as locally applicable Preparations such as creams, emulsions, suppositories, in particular aerosols are also possible.

Another application of the new compounds is in combination with other active ingredients. In addition to other suitable substances, such as compounds that affect fertility and These include hormones such as LH-RH, FSH, estradiol or LH:

Diuretic such as furosemide, antidiabetic agents such as Glycodiazine, tolbutamide, glibenclamide, phenformin, buformin, Metformin or circulatory drugs in the broadest sense, e.g. coronary dilators such as Chromonar or Prenylamine, antihypertensive substances such as reserpine, oC-Methyl-Dopa or Clondine or antiarrhythmics, Lipid-lowering drugs or geriatrics and other metabolically effective preparations, psychotropic drugs, such as chlordiazepoxide, diazepam or Meprobamate and vitamins, or other prostaglandins or prostaglandin-like ones Compounds as well as prostaglandin antagonists.

The compounds of the formula IV, VI, VII, VIII, IX, X, XII, XIII, XIV, XV, XVI, XVII, XIX are new valuable intermediates for the preparation of the compounds of formula I.

709846/0258

- 35 -

Example i;

1. 1- (6-Meth.oxycarbonyl-iiex-1-yl) -5- (3- ^ ydruxy-oct-1-yl) pyrrolidone-2

1 mmole 1- (6 ~ methoxycarbonyl- (Z) -2-hexen-1-yl) -5- (3-hydroxy- (E) -1-octen-1-yl) -pyrrolidone-2 are dissolved in 10 ml of ethanol and with palladium / carbon 5 ^ kei normal pressure and room temperature hydrogenated. The catalyst becomes hydrogen after it has finished filtered off, the solvent was concentrated and the remaining oil is chromatographed.

Chromatography toluene / ethyl acetate / methanol 5 * ^ ί 0> 3 NMR (f = 3.7 ppm (s) COOCH ₃ 3 Prot.

IR 1680 cm " ¹ Vc = 0

1735 cm " ¹ V'C = 0

The following compounds are synthesized from the underlying doubly unsaturated compounds in the same way as indicated in the above procedure. The chromatographic purification of the compounds was carried out, unless otherwise stated, on silica gel using the mobile phase: toluene / ethyl acetate / methanol 5 j k : 0.3.

709846/0258 -36-

2. 1- (6-Methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-d.ee-1-yl

pyrrolidone-2

<f = 3.65

ppm

1680 cm
1735 cm

" ¹

" ¹

(s)

= 0

COOGH

3 prot

3. l- (6 ~ methoxycarbonyl-hex-l-yl) -5- (3-hydroxy-4 ₁ 4-dimethyl-

5-ethoxy-pent-1-yl) pyrrolidone-2

NMR (. 0, 9 ppm (see O L. 3.7 ppm (see O IR 1685 cm " ¹ ^ C = 1735 cm " ¹

C (CH ₃ ) ₂ 6 prot, COOCH ₃ 3 prot.

4. 1- (6-Methoxycarbonyl-hex-1-yl) -5- [3-hydroxy-4- (4-chlorophenoxy) phenoxy-4,4-dimethyl-but-1-yl] pyrrolidone-2

NtJR 0 = 1.05 ppm (s) 0 = 3.7 ppm (s) 0 = 6.9-7.9 ppm (m) Aromatic protons 8 prot

C (CH ₃ ) ₂ 6 prot. COOCH ₃ 6 prot.

1680 cm

" ¹

1730 cm

" ¹

^ C = 0 '^ C = O

709846/0258

- 37 -

5. 1- (6-Methoxycarbonyl-hex-I-yl) -5- [3-hydroxy-4- (3-thxenyloxy) ■ but-l-yl] pyrrolidone-2

NMR ό = 3.7 ppm (s) 3 Prot.

Q = 5-7 ppm (m) thiophene protons 3 prot.

IR 1685 cm " ¹ ^ C = 0

1730 cm " ¹ Vc = 0

6 "1- (6-Methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-6-pentafluoroethyl-hex-1-yl) -pyrrolidone-2

NMR ό = 3.7 ppm (s) COOCH ₃ 3 Prot. IR 1675 cm " ^{1 V} C = 0 1730 cm" ¹ v> c = 0

7. 1- (6-Methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-S-cyclopentyl-4,4-dimethyl-pent-1-yl) -pyrrolidone-2

NMR ί = 0.9 ppm (s) C (CH ₃ ) ₂ 6 prot. Ο = 3.65 ppm (s) COOCH ₃ 3 prot.

8. 1- (6-Methoxycarbonyl-hex-l-yl) -5- (S-hydroxy-o-phenyl-pent-

l-yi) -pyrrolidone-2 (s) COOCH ₃ 3 Prot. NMR Q = 3.7 ppm (s) ^C 6 ^H 5 5 Prot. & = 7.3 ppm v> c = 0 • IR 1682 cm " ¹ V ⁷ C = 0 1730 cm " ¹

709846/0258 - 38 -

9. 1- {6-M3thoxycarbonyl-hex-1-yl) -5- [3-hydroxy-5- (4-meth.yl-2-chlorophenyl-4,4-dimethyl-pent-1-yl] -pyrrolidone-2

Chromatography toluene / ethyl acetate 5: 4

NMR 0 = 1.0 ppm (s) C (CH,)., 6 paws. ί = 2.25 ppm (s) CH ₃ 3 Prot.

0 = 7.1-7.5 ppm (xn) aromatic protons 3 prot. IR 1670 cm " ¹ V> c = 0
1735 cm " ¹ ^ C = 0

10. 1- (6 ~ ethoxycarbonyl-hex-l-yl) -5- (3 ~ hydroxy-7-methyl-oct-l-

yl) pyrrolidone-2 (d) CH (CH ₃ J ₂ 6th Prot. NMR Q = 1.0 ppm (t) COOCH ₂ CH ₃ 3 Prot. ο = 1.25 ppm ^ C - O IR 1685 cm " ¹ V> C = 0 1725 cm " ¹

11. 1- (6-Ethoxycarbonyl-hex-1-yl) -5- (3-hydroxy-4,4-dimethyl-octl-yl) -pyrrolidone-2

NMR <i = 0.9 ppm (s) C (CH ₃ J ₂ 6 Prot.

IR 1680 cm "^ C = 0
1735 cm " ¹ Vc = 0

12. 1- (6-Ethoxycarbonyl-hex-1-yl) -5- [3-hydroxy-4- (3-trifluoromethylphenoxy) -but-1-yl] -pyrrolidone-2

NMR I = 1.1 ppm (t) COOCH CH 3 Prot.

709848/0258 - 39 -

ο = 7.1-7.4 ppm (m) Aromatic protons 4 prot.

IR 1678 cm " ¹

1730 cm " ¹ ^ C =

benzyloxy) - "but-l ~ yl] -pyrrolidon-2

NMR «Γ = 1.1 ppm (t). COOCH ₂ CH ₃ 3 Prot.

<J - 7.0-7.5 ppm (m) Aromatic protons 4 prot.

m " ¹ ^ C = 0 1735 cm" ¹ v> c = 0

IR 1680 cm " ¹ ^ C = 0

14. 1- (6-Ethoxycarbonyl-hex-1-yl) -5- [3-hydroxy-4- {2-thienyl) -but-1-yl] -pyrrolidone-2

NMR Q = 7.1-7.3 ppm (m) thxophene protons 3 prot. Ο = 1.1 ppm (t) COOCH ₂ CH ₃ 3 prot. IR 1680 cm " ¹ V> c = O 1740 cm" ¹ V> c = 0

15. 1- (7-Ethoxycarbonyl-hept-l-yl) -5- (3-hydroxy-5-ethoxy-4,4-

dimethyl-pent-1-yl) pyrrolidone-2 (s) C (CH ₃ ) ₂ 6th Prot. NMR f = (t) COOCH ₂ CH ₃ 3 Prot. ^ C = 0 V> C = 0 ^: 0.9 ppm : 1.2 ppm 1675 cm " ¹ 1730 cm " ¹

709846/0258 -4ο-

16. 1- (6-Methoxycarbonyl-hex-l-yl) -5- (3-hydroxy-3-niethyl-oct-

l-yl) pyrrolidone-2 (s) C (CPI ₃ ) 3 Prot. NMR <f = 1.3 ppm (s) COOCH ₀ 3 Prot. <J = 3.7 ppm V> C = 0 IR 1680 cm " ¹ v> c = o 1735 cm " ¹

17. 1- (6-Methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-3,4,4-trimethyl-

5-ethoxy-pat-1-yl) pyrrolidone-2 ό = 0.9 ppm (S) C (CH ₃ J ₂ 6th Prot. NMR O = 1.4 ppm (S) -CH ₃ 3 Prot. Q = 3.7 ppm (S) COOCH ₃ 3 Prot. 1680 cm " ¹ Vc = O IR 1728 cm " ¹ 1> C = O

18. l- (6-methoxycarbonyl-hex-l-yl) -5- (S-hydroxy-S-benzyl-dec-

1-y1) pyrrolidone-2 (m) ^C 6 ^H 5 5 Prot. NMR <T = 7.1-7.3 ppm (s) COOCH ₃ 3 Prot. Q = 3.7 ppm v> c = 0 IR 1675 cm " ¹ jj ρ - (\
^W \ -r ~~ \ J 1730 cm " ¹

709846/0258

Example 2;

a) (VIII)

5- (3-oxo-oct-1-yl) pyrrolidone-2

As described in Example 1 No. 1, 5- (3-Oxo-E- (1) -octen-1-yl) -pyrrolidon-2 is described hydrogenated to 5- (3-oxo-oct-1-yl) -pyrrolidon-2.

The crude product is used for the further implementation.

IR 1680 cm " ¹ YC = 0

1705 era "Vc = 0 not completely separated

Absorptions

b) (XIX)

1- (6-methoxycarbonyl-hex-i-yl) -5- (3-oxo-oet-1-yl) -pyrrolidone-2

1 mmol of 5- (3-oxo-oct-1-yl) -pyrrolidon-2 are dissolved in 10 ml of dimethylformamide dissolved, treated with 1 mmol of sodium hydride and at 50.degree Stirred for 1 1/2 hours. After the addition of catalytic amounts of sodium iodide, 1.2 mmol of 6-bromohexylcarboxylic acid methyl ester are added dissolved in 5 ml of dimethylformamide and then held for a further 5 hours at this temperature. For work-up if you add water, shake it out several times with ether, cleans the organic phases, dries and concentrates.

Chromatography carbon tetrachloride / acetone 7 ί 3 NMR </ = 3.7 ppm (-s) COOCH "3 Prot.

IR 1675 cm " ¹ YC = 0

1705 cm " ¹ YQ = 0

cm

" ¹ Vc = 0

709846/0258

1- (6-Methoxycarbonyl-hex-1-yl) -5- (S-hydroxy-S-ethinyl-oct-1-yl) -pyrrolidone-2

A solution of 10 mmol of 1- (6-methoxycarbonyl-hex-l-yl) -5- (3-oxo-oct-l-yl) -pyrrolidone-2 in 70 ml of ether is cooled to -10 ° C. under nitrogen. While stirring, 12 ml of a 1 molar solution of lithium acetylide in tetrahydrofuran are added and the mixture is stirred for a further 30 minutes. At OC is added then ^t ^ ^J 1.5 ml of a saturated Ämmoniumchloridlösung to. After about ten minutes, anhydrous magnesium chloride is added, the mixture is filtered off with suction, concentrated and chromatographed. (SiO ₂ ? Toluene / ethyl acetate / methanol 5: 4: 0.1)

NMR 0 = 3.6 ppm (s) COOCH ₃ 3 prot. 0 = 2.7 ppm (s) C == CH 1 prot.

IR 1735 cm " ¹ Vc = O

1685 cm " ¹ i> C = 0

709846/0258

S?

a) (VIII)

1. 5- (3-Oxo-dec-1-yl) -pyrrolidone-2

By hydrogenation of 5- (3-oxo- (E) -l-decen-l-yl) pyrrolidone according to example 2 a.

IR 1705 cm " ¹ ^ C = 1675 cm" ¹ Pp =

2. 5- (3-Oxo-4,4-dimethyl-oct-1-yl) pyrrolidone -2

By hydrogenation of 5- {3-oxo- (E) -l-octen-l-yl) pyrrolidone-2 according to Example 2a. NMR ( -1.05 ppm (s) C (CH ₃ J ₂ 6 Prot.

₃ J ₂

IR 1700 cm " ¹ ^ C = O 1670 cm" ¹ V> c = 0

3. 5- (3-0XO-4,4-dimethyl-5-ethoxy-pent-1-yl) -pyrrolidone-2

By hydrogenation of 5- (3-0xo-4,4-dimethyl-5-ethoxy- (E) -I penten-1-yl) -pyrrolidone-2 analogous to Example 2a.

NMR / = 0.9 ppm (s) C (CH ₃ J ₂ 6 Prot. IR 1680 cm " ¹ ^ C = O 1710 cm" ¹ Vc = O

709846/0258 ' ^kk '

4. 5- [3 ~ 0xo-4- (3-trifluoromethy! Phenoxy) -but ~ i-yl] ~ pyrrolidone ~ 2

By hydrogenation of 5- [3-oxo-4- (3-trifluoromethylphenoxy) - (E) -l-buten-l ~ yl] -pyrrolidone-2 analogous to example 2 a.

NMR 0 = 4.5 ppm (s) CH ₀ 2 Prot. IR 1680 cm " ¹ ^ C = O

«J

1700 cm "Vc = ο

The compounds synthesized under 1 to 4 are used as crude product for the further reactions.

bl (IX)

1. l-Allyl-5- (3-oxo-dec-l-yl) -pyrrolidone-2

2.5 mmol 5- (3-oxo-dec-l-yl) -pyrrolidon-2 v / earth in 15 ml Dissolved dimethyl sulfoxide (dried) and treated with 3 mmol of potassium hydroxide. 3 nimoles of allyl bromide are added dropwise while cooling with ice dissolved in 3 ml of dimethyl sulfoxide. The mixture is then stirred for 2 hours, the reaction solution warming to room temperature. Water is added and the product is extracted with ether, the organic phases are combined, dried and concentrated on and chromatographed.

The chromatographic separation is carried out, as in the following 4 examples, on silica gel with toluene / ethyl acetate 5: 4 as the eluent.

NMR 0 = 5.0-6.2 ppm (m) CH = CH ₂ 3 prot. IR 1700 cm " ¹ ^ C = 0
1685 cm " ¹ * t> C = 0

709848/0258

2. 1-Allyl-5- (3-oxo-4,4-dimethyl-oct-1-yi) -pyrrolidone-2

By alkylating 5- (3-oxo-4,4-dimethyl-oct-1-ylI-pyrrolidon-2 with allyl bromide as in Example 3 b 1

NMRU = 5, o - 6.2 ppm (m) CH = CH ₀ 3 prot. Q = 1.05 ppm (s) C (CH ₃ J ₂ 6 prot.

IR 1705 cm " ¹ ^ C = O

1675 cm " ¹ VC = 0

3. l-Allyl-5- (3-oxo-4,4-dimethyl-5-ethoxy-pent ~ l-yl> -pyrrolidone- 2

By alkylating 5- (3-oxo-4,4-dimethyl-5-ethoxy-pentl-yl) -pyrrolidone-2 with allyl bromide as in Example 3 b 1

NMR ο β 0.9 ppm (s) C (CH ₃ J ₂ 6 Prot.

0 = 5.0 - 6.2 ppm (m) CH = CH ₀ 3 Prot.

IR 1680 cm " ¹

1705 cm " ¹ Vc = 0

4. 1-Allyl-5- [3-OXO-4- (3-trifluoromethylphenoxy J-but-1-yl] pyrrolidone-2

By alkylation of 5- [3-0xo-4- (3-trifluoromethylphenoxyJ-but-1-yl] -pyrrolidone-2 with allyl bromide as in Example 3 b

NMR (T = 4.5 ppm (s) CH ₂ 2 prot. Ο = 5.0 - 6.2 ppm (m) CH = CH ₂ 3 prot. 0 = 7.1 - 7.4 ppm (m) aromatic protons 4 prot. IR 1680 cm " ¹ Vc = O
1700 cm " ¹ V _c _ ₀

709846/0258

5. 1-AlIyI-5- (3-oxo-oct-1-yl) -pyrrolidone ^.

By alkylating 5- (3-oxo ~ oct-l-yl) -pyrrolidone-2 with Allyl broinide analogous to Example 3 b 1

HMR ί = 5.0-6.2 ppm (m) CH = CH ₂ 3 Prot. IR 1700 cm " ¹ ^ C = O
1675 cm " ¹ Uc = 0

1. l-Formylmethyl-5- (3-oxo-dec-l-yl) -pyrrolidone-2

0.02 moles of 1-alkyl-5- (3-oxo-dec-1-yl) -pyrrolidone-2 dissolved in 1 (JO ml of methylene chloride and diluted with 10 ml of methanol offset. It is cooled to -78 ° C and ozone is introduced at this temperature until the blue solution no longer dissolves discolored. The reaction mixture is warmed to -20 ° C. 0.2 mol of dimethyl sulfide is left at this temperature drip. The cooling bath is removed and the reaction flask is left at room temperature for two hours. It is narrowed and chromatographed.

(Silica gel; chloroform, acetone 8: 2)

KMR U = 9.6 ppm CHO 1 prot.

As described above, there are the following 1-formylmethyl compounds by ozonolysis from the 1-allyl compounds manufactured.

- k ₇ -

709846/0258

2. 1-Formylmethyl-5- (3-oxo-4,4-dimethyl-oct-1-yl) -pyrrolidone-2

Chromatography: chloroform / acetone 8: 2 NIiR 0 = 9.6 ppm CHO 1 prot.

3. 1-Formymethyl-5 - (3-oxo-4,4-dimethyi-b-ethoxy-pent-i-yi) -pyrrolidone-2

Chromatography: carbon tetrachloride / acetone 7: 3 NMR ί = 9.5 ppm CHO 1 prot.

£ = 0.9 ppm C (CH ₃ J ₂ 6 Prot.

4. 1-Formylmethyl-5- [3-OXO-4- (3-trifluoromethylphenoxy) but-lyl] pyrrolidone-2

Chromatography: chloroform / acetone 8: 2

NMR A ~ 4.4 ppm (s) CH ₂ 2 Prot.

ο = 7.1-7.4 ppm (m) Aromatic protons 4 prot.

d = 9.3 ppm CHO "1 prot.

5. l-Formylmethyl-5- (3-oxo-oct-l-yl) -pyrrolidone-2

Chromatography: chloroform / ethyl acetate 4: 1 NMR <f = 9.6 ppm CHO 1 prot.

709846/0258

te.

d) (XII)

1. 1- (6-Carboxy- {Z) -2-hexen-1-yl) -5- (3-oxo-dec-1-yl) -pyrrolidone-2

0.01 mol of sodium hydride are stirred in 5 τη] dimethyl sulfoxide at 60 C until the evolution of hydrogen has ended. It is then cooled to room temperature and 5 mmol of 4-carboxy-butyl-triphenylphosphonium bromide dissolved in 5 ml of dimethyl sulfoxide are added. It is stirred for 30 minutes at room temperature. Then 2 mmol of 1-formylmethyl-5- (3-oxo-dec-l-yl) -pyrrolidone-2 dissolved in 3 ml of dimethyl sulfoxide are run in and then heated to 50 ° C. The mixture is stirred for three hours at this temperature. After cooling, 40 ml of water are added and the pH is adjusted to 2 with 5% sodium hydrogen sulfate solution. It is extracted with ether, dried and concentrated.
Chromatography: chloroform / methanol 95: 5 NMR δ = 5.2-5.7 ppm (m) CH = CH 2 Prot

As described above, the following four 1- (6-Carboxy- (Z) -2-hexen-l-yl) compounds from the corresponding 1-formylmethyl compounds by Wittig reaction made with the 4-carboxy-butylidene-triphenylphosphorane.

- 49 -

709846/0258

2.1 ~ (6-Carboxy- (Z) -2-hexeii-1-yl) -5- (3-OXO

-4,4-ÄimetkyB-oct-

1-yl) pyrrolidone-2

Chromatography: toluene / ethyl acetate / glacial acetic acid 5: 4: 0.03 NMR Q = 5.3 - 5.5 ppm (m) CH = CH 2 prot. = 1.05 ppm (s) C (CH ₃ J ₂ 6 prot .

3. 1- (6-Carboxy- (Z) -2-hexen-1-y1) -5- (3-oxo-4,4-dimethyl-5-ethoxy-pent-1-yl) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR f = 5.3 - 5.5 ppm (m) CH = CH 2 prot. 0 = 0.9 ppm (s) C (CH ₃ J ₂ 6 prot.

4. 1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- [3-oxo-4- (3-trifluoromethyl phenoxy) but-1-yl] pyrrolidone-2

Chromatography: chloroform / methanol 95: 5 NMR <T = 5.1-5.2 ppm (m) CH = CH 2 Prot.

0 = 7.1-7.4 ppm (m) Aromatic protons 4 prot. Ei ₈

4.4 pp _m ( _s ) CH ₂ 2 prot.

5. 1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- (3-oxo-oct-1-yl) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR 0 = 5.2-5.5 ppm (m) CH = CH 2 Prot.

- 50 709846/0258

ORIGINAL INSPECTED

6. 1- (5-Carboxy- (Z) -2-penten-1-yl) -5- (3-oxo-oct-1-yl) -pyrrolidone-2

From l-formylinethyl-5- (3-oxo-oct-1-yl) -pyrrolidon-2 and 3-Carboxypropylidenetriphenylphosphoran according to Example 3dl

Chroraatography: ethyl acetate / glacial acetic acid 98: 2 NMR O = 5.1-5.3 ppm (m) CH = CH 2 Prot.

7. 1- (7-Carboxy- (Z) -2-hepten-l ^ yl) -5- (3-oxo-oct-l-yl) -pyrrolidone-2

From l-formylmethyl-5- (3-oxo-oct-l-yl) -pyrrolidon-2 and 5-Carboxypentylidenetriphenylphosphoran according to Example 3dl

Chromatography: ethyl acetate / toluene / glacial acetic acid 4:. 5 ι 0.01 NMR 0 = 5.2-5.4 ppm (m) CH = CH 2 Prot.

1. 1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- (3-hydroxy-dec-1-yl) -pyrrolidone-2

4 mmol of anhydrous zinc chloride are dissolved in 10 ml of dimethoxyethane suspended and 16 mmol sodium borohydride added carefully. The mixture is then stirred for one hour at room temperature. It is filtered off and 0.8 mmol of 1- (6-carboxy- (Z) -2-hexen-1-yl) -5- (3-oxodec-1-yl) -pyrrolidone-2 are added dropwise to the solution thus obtained dissolved in 2 ml of dimethoxyethane

- 51 -

709846/0288

is

within 10 minutes and stirred for 2 1/2 hours at room temperature. Acidify with glacial acetic acid, concentrate and chromatographed (silica gel; ethyl acetate / glacial acetic acid 98: 2)

NMR u = 5.3-5.5 ppm (m) CH = CH 2 prot. IR 1680 cm " ¹ ^ C = 0 1700 cm" ¹ ^ C = 0 r * J 3200 cm "broad absorption V ^ OH

The following compounds listed under 2 to 7, as described under 1), are derived from the underlying Ketones made by reduction. The chromatographic purification takes place exclusively on silica gel Ethyl acetate / glacial acetic acid 98: 2

2. 1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- (3-hydroxy-4,4-dimethyloct-1-yl) -pyrrolidone-2

NMR (T = 5.2-5.4 ppm (m) CH = CH 2 Prot.

I ₃ ) ₂

0 = 0.9b ppm (s) C (CH ,,) - 6 prot.

3. 1- (6-Carboxy- (Z) -2-hexen-1-y1) -5- (3-hydroxy-4,4-dimethy1-5 ~ ethoxy-pent-1-yl) -pyrrolidone-2

NMR (T = 5.1-5.3 ppm (m) 6 = 0.9 ppm (s)

ei = 1.1 ppm (t)

- 52 709846/0258

CH = CH 2 Prot C (CH ₃ ) ₂ 6th Prot OCH ₂ CH ₃ 3 Prot

4. 1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- [3-hydroxy ~ 4- (3-trifluoro

ethylphenoxy) but ~ l ~ yl] pyrrolidone-2

NMR $ = 5.1-5.25 ppm (m) CH = CH 2 Prot.

ti = 4.4 ppm (d) CH ₂ 2 prot.

y = 7.2-7.4 ppm (m) aromatic protons 4 prot.

5. 1- (6 ~ Carboxy- (Z) ~ 2-hexen-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

NMR <T = 5.2-5.4 ppm (m) CH = CH 2 Prot.

IR 1680 cm " ¹ /.,

/ Vc = not completely separated

1700 cm J absorption

6. 1- (5-Carboxy- (Z) -2-penten-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

NMR <T = 5.2-5.4 ppm (m) CH = CH 2 Prot. 1680 cm " ¹ ^ ¹ C = 1700 cm" ¹ ^ C = O

7. 1- (7-Carboxy- (Z) -2-hepten-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

NMR Q = 5.25-5.4 ppm (m) CH = CH 2 Prot.

IR latitude absorption at 1680-1700 cm " ¹ ^ C =

709848 / 02S8

8. l-iö-CaiJC

1-yl) pyrrolidone-2

From the compound of Example 3 b 5 by reaction with Methyl magnesium iodide analogous to Example 2 c.

Chromatography: toluene / ethyl acetate / glacial acetic acid 50: 50: 2 NMR C = 2.3 ppm (s) CH ₃ 3 Prot.

<Γ = 5.2-5.4 ppm (m). CH = CH 2 prot.

9. 1- (6-Carboxy- (Z) -hexen-1-yl) -5- [3-hydroxy-3- (prop-2-en-lyl) -oct-1-yl] -pyrrolidone-2

From the compound of Example 3 b 6 by reaction with Allyl magnesium bromide analogous to Example 2c.

Chromatography: ethyl acetate / glacial acetic acid 98: 2

NMR <Γ = 5.0-6.2 ppm (m) CH = CH and CH = CH ₂ 5 Prot.

IR 1680 cm "and 1700 cm" are two not sharply separated

Absorption maxima ( VC = 0)

10. 1- (6-Methoxycarbonyl- (Z) -2-hexen-1-yl) -5- (3-hydroxy-oct-lyl) -pyrrolidone-2

1 mmole 1- (6-carboxy- (Z) -2-hexen-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2 are dissolved in 10 ml of 0.1 normal aqueous sodium hydroxide solution and then the solvent is concentrated. The remaining traces of water are removed in a high vacuum. 8 ml of acetonitrile and 10 ml of mol of methyl iodide are added

- 5h -

709846/0258

te

reflux for five hours. The reaction solution is distributed between water and ether, the organic phase dried, concentrated and chromatographed.

Eluants: toluene / ethyl acetate / methanol 5: 4: 0.3 NMR cf- 3.7 ppm (ε) CCOCH ₃ 3 Prct.

2-5.35 ppm (m) CH = CH 2 prot.

IR 1680 cm ^! ^ C = 0
1735 cm " ¹ ^ C = 0

11. 1- (6-n-Hexoxycarbonyl- (Z) -2-hexen-l ~ yl) -5- (3-hydrox.y-octl-yl) -pyrrolidone-2

Analogous to the above procedure from 1- (6-carboxy- (Z) -2-hexen-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2 and n-hexyl bromide.

Chromatography: toluene / ethyl acetate / methanol 5 ι 4: 0.1 NMR = 5.2-5.35 ppm (m) CH = CH 2 prot.

= 4.2-4.4 ppm (t) spread COOCH ₂ - 2 prot.

Signals

f) (D

1- (6-methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

By hydrogenation of 1- (6-methoxycarbonyl- (Z) -2-hexen-1-yl) · 5- (3-hydroxy-oct-1-yl) -pyrrolidone-2 analogously to Example 1.

Physical data correspond to those of example 1 no.

- 55 709846/0258

g) (XVII)

5- (3-Hydroxy-oct-1-yl) -pyrrolidone 2

By reducing 5- (3-oxo-oct-l-yl) -pyrrolidon-2 with Zinc borohydride analogous to Example 3 e 1

Chromatography: chloroform / methanol 95: 5 IR 1780 cm " ¹ ^ C = 0 MS M ® = 213

1. 1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

From 5 ~ (3-hydroxy-oct-1-yl) -pyrrolidone-2 by alkylation with 6-bromo- (Z) -4-hexene-1-carboxylic acid analogous to Example 3 b 1

Chromatographic conditions and physicochemical data according to Example 3 e 5.

2. 1- (6-Carboxy- (E) -hexen-1-yl) -5- (3-hydroxy-oct-1-yl) -pyrrolidone-2

From 5- (3-kydroxy-oct-l-yl) -pyrrolidone-2 by alkylation with 6-bromo- (E) -4-hexene-1-carboxylic acid analogous to Example 3 b 1.

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR 0 = 5.1-5.35 ppm CH = CH 2 Prot.

IR 1680 cm "and 1700 cm" ¹ two incomplete

separate absorption

maxima door ^ C = 0

709846/0258

? 0

ό . J - (b-Carboxy-iiex-1 -y 1 j - b ~ l J-nyaroxy-oct-- 1-yχ; -pyrrolidone- 2

From 5- (3-Hydroxy ~ oct-1-yl) -pyrrolidon-2 through. Alkylation with 6-brorahexanecarboxylic acid as in Example 2 b

Chromatography: ethyl acetate / glacial acetic acid 98: 2

R _f value: 0.25

i) (XIII)

5- [3- (Tetralydropyran-2-yl-oxy) -3-methyl-oct-1-yl] -pyrrolidone-2

By hydrogenation of 5- [3- (tetrahydropyran-2-yl-oxy) -3-methyl- (E) -l-octen-1-yl] -pyrrolidone-2 according to the rule given in Example 1 No. 1.

Chromatography: chloroform / ethyl acetate / methanol 5: 4: 0.5

NMR ü = 4.65 ppm broad singlet O-CH-0 1 Prot.

δ = 2.1 ppm (s) 'CH ₃ 3 Prot. IR 1680 cm " ¹ V'c = 0

k) (XIV)

1-Allyl-5- [3- (tetrahydropyran-2-yl-oxy) -3-methyl-oct-1-yl] -pyrrolidone-2

From 5- [3- (tetrahydropyran-2-yl-oxy) -3-methyl-oct-1-yl] -pyrrolidon-2 by alkylation with allyl bromide analogously to Example 3 b 1.

- 57 -

709846/0258

Chromatography: carbon tetrachloride / acetone 7: 3

NMR ^ -5.2-6.0 ppm (in) CH = CH ₂ 3 Prot.

£ = 4.65 ppm broad singlet O-CH-0 1 Prot.

6 = 2.05 ppm (s) CH ₃ 3 Prot. IR 1680 cm " ¹ V * C = 0

1-Formylmethy.1-5- [3- (tetrahydropyran-2-yl-oxy) -3-methyl-oct-1-yl] -pyrrolidone-2

From 1-allyl-5- [3 ~ (tetrahydropyran-2-yl-oxy) -3-methyl-octl-yl] -pyrrolidone-2 by ozonolysis analogous to Example 3 c 1.

Chromatography: toluene / ethyl acetate 5: 4

NMR O = 9.6 ppm (s) CHO 1 prot.

Q = 4.6 ppm broad singlet O-CH-0 1 Prot.

U = 2.05 ppm (s) CH ₃ 3 Prot.

m) (XVI)

1- (6-Carboxy- (Z) -2-hexen-1-yl) -5- [3- (tetrahydropyran-2-yloxy) -3-methyl-oct-1-yl] -pyrrolidone-2

Analogously to example 3 dl from l-formylmethyl- [3- (tetrahydropyran-2-yl-oxy) -3-methyl-oct-l-yl] -pyrrolidone-2 and 4-carboxy-butylidene-triphenylphosphorane.

Chromatography: toluene / ethyl acetate / glacial acetic acid 5: 4: 0.02 NMR ο = 5.2-5.5 ppm (m) CH = CH 2 prot. Ί = 4.65 ppm broad singlet 0-CH-O 1 prot.

- 58 -

709846/0258

1- (6-Carbxy- (Z) -2-hexen-1-yl) -5- (3 ~ hydro:>: y-3-methyl-oct-1-yl) -pyrrolidone-2

0.05 mol of 1- (6-carboxy- (Z) -2-hexen-1-yl) -5- [3-tetrahydropyran-2-yi-oxy) -3-methyi-oct-i-yi] pyrrolidone -2 are in a mixture of 20 ml of ethanol and 10 ml of 6% aqueous Oxalic acid was stirred for 4 hours at room temperature and then for 4 hours at 40-45 ° C. The reaction mixture is then distributed between ether and water and the aqueous phase extracted several times with ether, the organic phase is dried and concentrated, and the residue is chromatographed.

Chromatographic conditions and physico-chemical properties see Example 3 e 8.

Example 4:

a) (IV)

The compounds specified under 1 to 9 are prepared from the starting materials specified in each case according to the example 2 b specified regulation produced. In the case of the alkylation with an acid, it must be neutralized the corresponding additional amount of sodium hydride can be used.

1. 1- (6-Carboxy-hex-1-yl) -5- [3- (tetrahydropyran-2-yl-oxy) - (E) -1-decen-1-yl] -pyrrolidone-2

From 5- [3- (tetrahydropyran-2-yl-oxy) - (E) -l-decen-l-yljpyrrolidon-2 and 6-bromohexanecarboxylic acid.

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709 * 46/0258

2G19G38

Chromatography: ethyl acetate / toluene / methanol 4: 5: 0.2 NMR ii = 4.4 ppm broad singlet 0-CH-G 1 prot. 0 = 5.1-5.4 ppm (m) CH = CH 2 prot.

2. 1- (6-Carboxy-hex-l-yl) -5- [3- (tetrahydropyran-2-yl-oxy) -4,4-dimethyl- (E) -1-octen-1-yl] -pyrrolidone-2

From 5- [3- (tetrahydropyran-2-yl-oxy) -4,4-dimethyl- (E) -I-octen-1-yl] -pyrrolidon-2 and 6-bromohexanecarboxylic acid.

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR vT = 1.0 ppm (s) C (CH ₃ J ₂ 6 prot. 0 = 5.2-5.4 ppm <m) CH = CH 2 prot. = 4.5 ppm broad singlet O-CH-O 1 prot.

3. l- (6-Carboxy-hex-l-yl) -5- [3- (tetrahydropyran-2-yl-oxy) -5-phenyl- (E) -1-penten-1-yl] -pyrrolidone- 2

From 5- [3- (tetrahydropyran-2-yl-oxy) -5-phenyl- (E) -1-pentene l-yl] pyrrolidone-2 and 6-bromohexanecarboxylic acid.

Chromatography: carbon tetrachloride / acetane 7: 3

NMR ά = 4.4 ppm broad signal O-CH-0 1 Prot.

<T = 5.2-5.35 ppm (m) CH = CH 2 Prot.

= 7.3 ppm (s) C ₆ H ₅ 5 prot.

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709846/0288

4. l- (5-carboxy-pent-l-yl) -5- [3- (tetrahydropyran - ^ - yl-oxy) - · (E) -1-octen-1-yl] pyrrolidone-2

From 5- [3- (tetrahydropyran-2-yl-oxy) - (E) -1-octen-1-yl] pyrrolidone-2 and 5-bromopentane carboxylic acid.

Chromatography: ethyl acetate / glacial acetic acid 98: 2 = 4.35 ppm broad signal O-CH-0 1 Prot. = 5.3-5.45 ppm (m) CH = CH 2 prot.

5. 1- (7-Carboxy-hept-] - yl) -5- [3- (tetrahydropyran-2-yl-oxy) - (E) -l-octen-1-yl] -pyrrolidone-2

From 5- [3- (tetrahydropyran-2-yl-oxy) - (E) -1-octen-1-y1] -pyrrolidone-2 and 7-bromo-heptanecarboxylic acid.

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR 0 = 4.40 ppm broad singlet O-CH-0 1 Prot. 6 - 5.25-5.40 ppm (m) CH = CH 2 Prot.

6. 1- (6-Methoxycarbony1-hex-1-yl) -5- [3- (tetrahydropyran-2-yl-oxy) -4,4-dimethyl-5-ethoxy- (E) -1-pentene-1 -yl] -pyrrolidone-2

From 5- [3- (tetrahydropyran-2-yl-oxy) -4,4-dimethyl-5-ethoxy- (E) -l-penten-1-yl] -pyrrolidone-2 and methyl δ-bromohexanecarboxylate.

Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.3 NMR ^ ~ 0.9 ppm (s) C (CH ₃ J ₃ 6 prot. VT = 3, 7 ppm (s) COOCH ₃ 3 prot.

(T = 5.2-5.4 ppm (m) CH = CH 2 prot. IR 1680 cm " ¹ ^ C = O

1730 cm " ¹ VC = 0 - 6i -

709846/0258

7. 1- (6-Methoxycarbonyl-hex-1-yl) -5- [3- (tetrahydropyran-2-y1-oxy) -3.4.4-trimethyl-5-ethoxy- (E) -1-pentene-1 -yl] -pyrro ~ lidon-2

• From 5- [3- (tetrahydropyran-2-y1-oxy) -3.4.4-trimethyl-5-ethoxy- (E) -l-penten-1-yl] -pyrrolidone-2 and 6-bromohexanecarboxylic acid methyl ester.

Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.3

NMR ό = 3.7 ppm (s) COOCH ₃ 3 Prot.

0-0.95 ppm (s) C (CH ₃ ) ₃ 6 prot.

o = 4.45 ppm broad signal -O-CH-0- 1 prot. IR 1680 cm " ¹ VC = 0
1735 cm " ¹ V> C = 0

8. 1- (6-Carboxy-hex-i-yl) -5- [3- (tetrahydropyran-2-y1-oxy) -3-methyl- (E) -l-octen-1-yl] -pyrrolidone- 2

From 5- [3- (tetrahydropyran-2-y1-oxy) -3-methyl- (E) -l-octenl-yl] -pyrrolidone-2 and 6-bromohexanecarboxylic acid.

Chromatography; Ethyl acetate / glacial acetic acid 98: 2 = 1.95 ppm (s) CH ₃ 3 prot. = 5.2-5.45 ppm (m) CH = CH 2 prot.

709846/0258

9. 1- (6-Carboxy-hex-1-yl) -5- [3- (tetrahydropyran-2-yl-oxy) -3- (prop-2-en-yi) ~ (E) -l-octene -l-yl] pyrrolidone-2

From 5- [3- (tetrahydropyrans-2-yl-oxy) -3- (prop-2-en-yl) - (E) -l-octen-1-yl] -pyrrolidone-2 and 6-broinhexane carboxylic acid

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR 0 = 5.2-6.0 ppm (m) CH = CH, CH = CH ₂ 5 prot. Δ = 4.45 ppm (s, broad) O-CH-0 1 Prot.

The connections listed under 1 to 9 are not otherwise indicated by cleavage of the THP protective group from those described in Example 4 a under 1 to 9 Compounds analogous to the prescription given in Example 3 manufactured.

1. 1- (6-Caruoxy-hex-1-yl) -5- (J-hydroxy- (E) -l-decen-1-yl} -pyrrolidone-2

Chromatography: ethyl acetate / toluene / glacial acetic acid 4: 5: 0.02

R _f = 0.3
NMR ί = 5.1 - 5.4 ppm (m) CH = CH 2 Prot.

2. 1- (6-Carboxy-hex-1-yl) -5- (3-hydroxy-4,4-dimethyl- (E) -I-octen-1-yl) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR «f = 1.0 ppm (s) C (CH ₃ J ₂ 6 Prot.

i = 5.2-5.4 ppm (m) CH = CH 2 Prot.

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3 · I- (δ-carboxy-hex-1-yl ) -5- · (3-hyuroxy-5-phenyl- (E) -l-penten-1-y1) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: NMR ei = 5.2-5.35 ppm (rn) CH = CH 2 prot. Q = 7.3 ppm (s) C ₅ H ₅ 5 prot.

4. 1- {5-Carboxy-pent-1-yl) -5- (3-hydroxy- (E) -l-octen-l-yl) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2

R _f = 0.35
NMR (J = 5.3-5.45 ppm (m) CH = CH 2 Prot.

5. 1- (7-Carboxy-hept-1-yl) -5- (3-hydroxy- (E) -l-octen-1-yl) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2 NMR ( = 5.25-5.40 ppm (m) CH = CH 2 Prot.

IR 1680cm-1705cm "non-separated absorption

two ^ C = 0

6. 1- (6-Methoxycarbonyi-hex-1-yl) -5- (3-hydroxy-4,4-dimethyl-5-ethoxy- (E) -l-penten-1-yl) -pyrrolidone-2

In a modification of the procedure given under Example 3, instead of aqueous / ethanolic oxalic acid, 1% strength is used Solution of oxalic acid in methanol used as a solvent.

- 6h 709846/0258

Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.3

NMIl G = 0.9 ppm (s) C (CH ₃ J ₃ 6th Prot. <f = 3.7 ppm (s) COOCIl ₃ 3 Prot. ί- 5.2-5.4 ppm (m) CH = CH 2 Prot. IR 1680 ^"1 cm v> V ^ ^^ ^ * 1735 cm " ¹ ν- \ * - KJ

7. 1- (6-Methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-3.4.4-trimethyl-5-ethoxy- (S) -l-penten-1-yl] -pyrrolidone-2

Splitting off of the ether protection group as stated above.

Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.3 NMR (T = 3.7 ppm (s) COOCH ₃ 3 prot. <I = 0.95 ppm (s) C (CH ₃ J ₃ 6 prot. IR 1685 cm " ¹ ^ C = 0
1735 cm " ¹ UC = O

8. 1- (6-Carboxy-hex-1-yl) -5- (3-hydroxy-S-methyl- (E) -l-octen-1-yl) -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2

R _f = 0.35

NMR 0 = 1.95 ppm (s) CH ₃ 3 Prot.

Γ = 5.25-5.40 ppm (m) CH = CH 2 Prot.

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709846/0258

9. 1- (6-Carboxy-hex-1-yl) -5- (3-hydroxy-3- (propyl 2-on-yl) - (E) -l-oeten-1-yl} -pyrrolidone-2

Chromatography: ethyl acetate / glacial acetic acid 98: 2

NMR & = 5.2-6.0 ppm (m) CH = CH, CH = CH ₂ 5 Prot.

IR 1680-1705cm ^x wide absorption two no

separate J ^ C - 0

1. 1- (6-Methoxycarbonyl-hex-1-yl) -5- (S-hydroxy-S-methyl-oct-1-yl) -pyrrolidone-2

Analogously to Example 1, item 1, by hydrogenating 1- (6-carboxyhex-1-yi) -5- (S-hydroxy-S-methyl- (E) -l-octen-1-yl) -pyrrolidone-2 and subsequent esterification with diazomethane. Physical data and chromatographic conditions see example 1 no.16.

2 . 1- (b-Carboxy-nex-1-ylJ-5- (3-hydroxy-dec-1-yl) -pyrrolidone-2

Analogously to Example 1 No. 1 by hydrogenation of 1- (6-carboxyhex-l-yl) -5- (3-hydroxy- (E) -l-decen-l-yl) -pyrrolidone-2.

Chromatography: ethyl acetate / toluene 5: 5: 0.02

R _f = 0.33

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709846/0258

d) (VI)

1- {6-Methoxycarbonyl-hex-1-yl) -5- (3-oxo-4,4-dimethyl-5-ethoxy- (E) -I-penten-1-y1) -pyrrolidone-2

From 5- (3-oxo- (E) -l-penten-1-yl) -4,4-dimethyl-5-ethoxy- (E) -l-penten-1-yl) -pyrrolidone-2 and 6-bromohexanecarboxylic acid methyl ester analogous to Example 2 b

Chromatography toluene / ethyl acetate / methanol 5: 4: 0.3 NMR

r- ο. 9 ppm (s) C (CH ₃ J ₃ 6th Prot. 3, 7 ppm (s) COOCH ₃ 3 Prot. ί 5, 5-6.2 ppm (m) CH = CH 2 Prot. 1680 cm " ¹ V ¹ C = O

1. 1- (6-Methoxycarbonyl-hex-l-yl) -5- (3-hydroxy-4,4-dimethyl-

-5-ethoxy- (E) -l-penten-1-yl) -pyrrolidone-2

By reducing the compound described under d) with ZinXborhydrid analogously to Example 3 e 1.

Physico-chemical data see example 4 b 6.

2. 1- (6-Methoxycarbonyl-hex-1-yl) -5- (3-hydroxy-3,4,4-trimethyl-5-ethoxy- (E) -1-penten-1-y1) -pyrrolidone- 2

By reacting the compound mentioned under 4 d) with methyl magnesium iodide analogously to Example 2c.

Physico-chemical data see example 4 b 7.

- 67 70984670258

f) (VII)

1- (6-Carboxy-hex-1-yl) - • 5- [3- (tetrahydropyran-2-yl-cxy) -3-methyl-oct-1-yl ] pyrrolidone-2

From 1- (6-carboxy-hex-1-yl) -5- [3- (tetrahydropyran-2-yl-oxy) -3-methyl- (E) -l-octen-1-yl] -pyrrolidone-2 by hydrogenation analogous to Example 1 No. 1.

Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.1 NMR G = 4.4 ppm (s, common) O-CH-0

1- (6-Methoxycarbonyl-hex-1-yl) ~ 5- (S-hydroxy-S-methyl-oct-1-yl) -pyrrolidone-2

From the compound described under 4 f) by cleavage the THP protective group and simultaneous esterification of the carboxy group analogous to Example 4 b 6, but p-toluenesulfonic acid as a catalyst instead of oxalic acid.

Physico-chemical data see Example 1 No. 16.

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709846/0258

ORIGINAL INSPECTED

Claims (1)

HOE 76 / F 095 Patent claims Compounds of Formula I.
O ή. ^ place / -ουι. / JX
R ³ OH in which mean R is a straight, branched, saturated or unsaturated aliphatic hydrocarbon radical with 1-10 carbon atoms or a cycloaliphatic hydrocarbon radical with 3-7 carbon atoms, each of which is substituted can be through a) a straight, branched alkoxy, alkylthio, alkenyloxy or alkenylthio radical with 1-5 carbon atoms, b) a phenoxy radical, which in turn is replaced by an optionally halogen-substituted alkyl group with 1-3 carbon atoms, Halogen atoms, an optionally halogen-substituted phenoxy radical or an alkoxy radical with 1-4 carbon atoms be mono- or disubstituted can, c) a furyloxy, thienyloxy or benzyloxy radical, which for their part in the core by an optionally halogen-substituted alkyl group with 1-3 carbon atoms, Halogen atoms or an alkoxy group with 1-4 carbon atoms can be mono- or disubstituted, d) a trifluoromethyl or pentafluoroethyl group, e) a cycl, oalkyl radical with 3-7 carbon atoms, f) a phenyl, thienyl or furyl radical, which in turn is optionally substituted by halogen Alkyl group with 1-3 carbon atoms, halogen atoms 7703846/0258 - ⁶ ^ - ORIGMAL INSPECTED 2B19638 7. HOE 76 / P 095 or an alkoxy group with 1 - h carbon atoms can be mono- or disubstituted, R is a straight-chain, branched, saturated or unsaturated one aliphatic or cycloaliphatic carbon * _ * Xl-W.LX.t- ΌΧΛΟ 1 / U ^ J. CL (/ VUtCIl, CXtLCIl ClX U..1.X phate hydrocarbon radical with 7 or 8 carbon 1 3 atoms or, if not identical, R is hydrogen, R n-pentyl, A the -CH -CH group, B the -CH = CH group and η the number three mean a methyl group or a hydrogen atom, R is hydrogen or a straight or branched alkyl radical with 1 to 5 carbon atoms, an alkenyl or alkynyl radical with 2 to 5 carbon atoms or an araliphatic Hydrocarbon radical with 7 or 8 carbon atoms, A and B a -CH - CH- or a -CH = CH- group, where A and B can be the same or different, but cannot at the same time represent a -CH = CH- group, η the number two, three or four and the physiologically acceptable metal or amine salts of these compounds. 2. Process for the preparation of compounds of the formula I, thereby marked that one a ₁ ) a compound of the formula II II 1 3
wherein R and R have the meaning given for formula I. 7098A6 / 02B8 -70- Λ HOE 76 / P 095 have, and R represents a protective group which can be split off under acidic conditions, with a base on nitrogen deprotonated and the anion thus formed with a carboxylic acid derivative of the formula III Y - CH - CH ₀ - CH - (CH) - COOR ² III 2
wherein R and η have the meaning given for formula I. and Y represents a radical which can be replaced in a nucleophilic substitution, to a compound of the formula IV
Q 1 IV implements, \ k a} splits off the alcohol protecting group R in a compound of the formula IV, a compound of the formula I being formed in which A is a -CH _O -CH _O group and B is a -CH = CH group, and the compound obtained is optionally in a transferred physiologically compatible metal or amine salt, or a_ _Λ ) a compound of the formula V as described under a,) <£ 1 1 to a compound of the formula VI - CH ₀ - CH ₀ - CH ₀ - (CH ₀ ) - COOR 1 2 wherein R, R and η have the meanings given for formula I, converts, - 71 - 709846/0258 q, hoe 76 / p 095 a) in a compound of the formula VI, the ke tonfunkt j.on is reduced or with an organometallic compound, 3
represents from R - X ^, in which X 'denotes a halogen atom, 3
R has the meaning given for formula I, but cannot be hydrogen, converting a compound j "TTv · _. . 1 ~ r. __ .; λ _ j # -iTT / ITT / ■ *. - * τ »- -ϊ -. % χ * 3ί luiiuex j., wui JLIi λ. a - x-> xi_ - v / .n "- vx-Luppe uiiu x> ei 11 ta -CK = CH group, is obtained, and optionally a_) the compound of the formula I »wherein A is a -CH ^ p and B denotes a -CH = CH group, hydrogenated, whereby a compound of the formula I in which A and B are each a -CH -CH group results, and this compound optionally in a physiologically acceptable metal or Amine salt transferred, or a _{o 1} ) hydrogenated a compound of the formula IV, resulting in a compound of the formula VII, - CH ₂ - CH ₂ - CH ₂ - (CH ₂ ) _n - COOR ^{2 CH} 2 " ^CH 2" Λ " ^R VII I ₁ / \ 3 RO R ^J 12 3
where R, R, R and η have the meaning given for formula I and R represents a protective group which can be split off under acidic conditions, and a "_) splits off the alcohol protecting group in a compound of the formula VII, a compound of the formula I being formed in which A and B each represent a -CH ₂ -CH" group, and optionally convert the compound obtained into a physiologically acceptable metal or Amine salt transferred, or b _i ,) in a compound of formula V.
· 1 - 72 - 709848 / 02S8 HOE CH CH ' hydrogenates the double bond, resulting in a compound of the formula VIII, wherein R is the formula I CH VIII has given meaning b., _o ) the compound of the formula VIII is deprotonated with a base on nitrogen and the anion formed with an allyl halide to form a compound of the formula IX ΌΗ, - CH =
CH, IX Β " -R converts, wherein R has the meaning given for formula I, b _i ") the compound of the formula IX obtained from an ozonolysis • · j subject, where an aldehyde of the formula X - CH - CHO OH arises, in which R has the meaning given for formula I, - 73 - 709846/0258 -76 - 6 HOE "6 / F 095 b.) the obtained aldehyde of the formula X with an ylide of
Formula XI (R ⁵ ) P = CH (CH ₂ ) _n C00R ² XI 2
where η and R have the meaning given for formula I, 2 * or R can also represent an alkali metal atom which R can represent identical or different, straight-chain (C - C.) -alkyl radicals or phenyl radicals to a compound of the formula XII - CH = CH - (CH ₂ ) - COOR 1 2
converts, in which R, R and η have the meanings given for formula I, b) the keto group of the compound of formula XII
ι · j _ CH - CH = CH - (CHg) _n - COOR - CH ₂ - C - with an organometallic compound ^ made from 3 3 R - X "', where X ~ represents a halogen atom, and R the has the meaning given for formula I, but cannot be hydrogen, or the keto group in XII
reduced, wherein a compound of the formula I is disfigured, wherein A is a -CH = CH group and B is a -CH -CH "group
represents, and the compound obtained, if any
converted into a physiologically compatible metal or amine salt, or - 7k - 709846/0258 b _Λ ) in a connection of the form]. II hydrogenates the double bond, a compound of the formula XIII XIII R ⁴ O R ' 1 3
arises, in which R and R have the formula I 4th
have meaning and R represents a group that can easily be split off under acidic conditions, ) the compound of formula XIII obtained is deprotonated with a base on nitrogen *, and the anion formed with an allyl halide to a compound of the formula XIV - CH = CH ₂ XIV 1 3
converts, wherein R and R are those given for formula I. k
Have meanings and R represents a protective group that can be easily split off under acidic conditions, ") The compound of the formula XIV obtained from an ozonolysis subject, where an aldehyde of the formula XV \ —N - CH ₂ - CHO XV CH ₂ - CH ₂ - h 3 RO R ^J 1 3
arises, in which R and R have the meanings given for formula I and R represents a radical which can be easily split off under acidic conditions, - 75 - 709548/0258 ORIGINAL INSPECTED HOE 76 / F 095 b ·) the obtained aldehyde of the formula XV with an ylide of Formula XI (R ⁵ ) P = CH (CH ₀ ) _n C00R ² XI 2
wherein π and R has the meaning given for formula I. 2
or R also represents an alkali metal atom and the R identical or different, straight-chain (C - C ^) alkyl radicals or phenyl radicals to a compound of the formula XVI - CH = CH - ( ⁰¹ ^) _n * ^C00β2 CH ₂ - CH ₂ - C ₁ XVI Λ ^No3 12 3
converts, in which R, R, R and η have the meanings given for formula I and R represents a protective group which can be easily split off under acidic conditions, b _o _) the protective group R from a compound of the formula XVI
splits off, a compound of the formula I being formed,
wherein A is a -CH = CH group and B is a -CH_-CH ₂ group
represent, and if applicable b _o ) a compound of the formula I in which A is a -CH = CH group and B is a -CH ₂ -CH group, hydrogenated to a compound of the formula I in which A and B are each a -CH ₂ -CH ₂ -Group represent, or b. ₁ ) the ketone function is reduced in a compound of the formula VIII or with an organometallic compound, 3
made from RX ^, where X 'represents a halogen atom, 3
R has the meaning given for formula I, but cannot represent hydrogen, where a compound of formula XVII - 76 - 709846/0258 νην, 76 / F 095 XVII 1 CH ₂ CH ₂ . R. HO 1 3
wherein R and R have the meanings given for formula I. own, arise, and b. ) the compound of formula XVII with a base on nitrogen deprotonated and the anion formed with a carboxylic acid derivative xler formula XVIII Y - ^CH 2 ^ ( ^CH 2 ^ n " ^C00R XVIII 2
in which R, A and η have the meaning given for formula I and Y is a radical which can be replaced in a nucleophilic substitution, a compound of the formula I in which A is a -CH ₂ -CH- or a -CH = CH- Group and B is a -CH ₂ -CH group, or a compound of formula VIII is deprotonated with a base on nitrogen and the anion formed with a carboxylic acid derivative of the formula III, where a compound of the formula XIX ⁹ 2 - CH ₂ - CH ₂ - CH ₂ - {CH ₂ J _n - COOR * CH _ - CH_ - C - R VTY 1 2 wherein R, R and η have the meanings given for formula I, arises, and reduced the ketone function of the compound of formula XIX or made with an organometallic compound 3 3 from R - X ^, wherein X ^ is a halogen atom and R is the has the meaning mentioned for formula I, but not water 709846 / 02B8 " ⁷⁷ ~ HOE 76 / F 2610638 can represent substance, converts, whereby a compound of the formula I is formed, wherein A and B are each a -CH_-CH group represent, or d) a compound of the formula XX Λ- CH ₀ - CH = CH - (CH ") - COOR * Ii 2'η CH - CH - -C - R ¹ HO hydrogenated, a compound of the formula I being formed in which A and B are each a -CH _? ~ Represent CH group. 3 Compounds of the formula IV - CH ₀ - CH ₀ - CH ₀ - (CH ₀ ) - COOR ² ti <. ti. ti Xl IV 12 3 in which R, R and R are as defined for formula I. and R is a protective group that can be easily split off under acidic conditions. 4. Compounds of the formula VI J - CH ₂ - CH ₂ - CH ₂ - (CH ₂ ) _n - COOR ² > 1 VI CH = CH-C-R 709846/0258 HOE 76 / P wherein R and R have the meaning given for formula I. 5 Compounds of the formula VII - CH_ - CH ₀ - CH_ - (CH_) - COOR ^ 2'n CH ₂ - CH ₂ - C- C R l / \ 3 RO R ^J VII 12 3 in which R, R and R are as defined for formula I. and R denotes a protective group which can be split off under acidic conditions. 6. Compounds of the formula VIII H, R ¹ ₂ . VIII wherein R has the meaning given for formula I. 7. Compounds of the formula IX - CH ₂ - CH = IX Ν » Ϊ ^R wherein R has the meaning given for formula I. 709846/0258 tk 8. Compounds of Formula X HOE 76 / P 095 N - CH - CHO 1 row O wherein R has the meaning given for formula I. 9 · Compounds of the formula XII - CH - CH = CH - (CH_) - COOR 2'ti XII CH, CH, 1 2 wherein R and R have the meaning given for formula I. 10. Compounds of the formula XIII ΓΎ XIII ^ CH-CH R ^ 4 / \ 1 RO R 1 3 wherein R and R have the meaning given for formula I. and R denotes a protective group which can be split off under acidic conditions. 11. Compounds of the formula XIV - CH- _r CH = CH2 XIV RO - so - 709846/0258 HOE 76 / P 1 3 where R and R have the meaning given for Foi'mel I. and R is a protective group which can be split off under acidic conditions means" 12. Compounds of the formula XV - CH_ - CHO XV - CH ₂ - CR ¹ k ' RO 1 3 wherein R and R have the meaning given for formula I. and Ü denotes a protective group which can be split off under acidic conditions. 13 · Compounds of the formula XVI J - CH ₂ - CH = CH - ^(CH _{2) n} ^"C00r ₂ ) _n CH ₀ - CH- - C-- ~ ^R 13th in which R and R have the meaning given for formula I and R is a protective group which can be split off under acidic conditions means. * \ k. Compounds of the formula XVII I LcH ₂ - CH ₂ R ¹ HOT R ³ Formula I given meaning 1 3 wherein R and R have the meaning given for formula I. 709846/0258 HOE 76 / F 095 2619838 15 · Compounds of the formula XIX ? 2 ^^ ji - CH ₂ - CH ₂ - CH ₂ - (CH ₂ ) _n - COOR χΐχ CH _p - CH - C - R ¹ Ii
0. 1 ? wherein R and R ″ have the meaning given for formula I. to have. 16. Process for the production of pharmaceuticals, characterized in that that a compound of the formula Σ mentioned in claim 1, optionally with conventional pharmaceutical Carriers and / or stabilizers, brings into a therapeutically suitable application form. 17 · Medicines characterized by a content of one A compound of the formula I mentioned in claim 1 or consisting of such a compound. 18. Use of a compound of the formula I mentioned in claim 1 in medicaments or as medicaments. 709846/0258