Note: Descriptions are shown in the official language in which they were submitted.
~ F 169
5~ _
The present invention rela~es to pyrrolidones and to a
- process ~or their manufacture.
Prostaglandins are a group of natural substanc~s which have
been isolated ~rom various animals tissues~ In mammals 9 they
are responsible ~or a variety of physiological ef~ectsO
Natural prostaglandins have a hydrocarbon skeleton generally
containing 20 carbon atoms and di~fer predominantly from one
another in contai~ing more or le s hydroxy groups and double
bonds in the cyclopentane ring ~a~ to the structure and activity
o~ prostaglandins9 see inter alia M.F. Cuthbert "The Prosta-
glandins, Pharmacological and Therapeutic Advances", William
Heinemann Medical Books Ltd.9 Lo~don ~1973)),
Synthesis methods of prostanoic acid analogues which do not
occur naturally and in which the great variety of pharmaco-
logical~ effects of natural prostanoic acids is differentiated
are gai~ing increasing importance~
The present in~ention now provides new pyrrolidones which
are analogues of prostàglandins and correspond to the formula I
~ -CH2-C~=CH-~CH2~-COOR2
GH=CH-~H-R
OH
i~ which R1 represents a straight chained or branched9 satur-
ated or unsa~urated, aliphatic hydrocarbon radical having 1
to 10 carbon atoms, or a cycloaliphatic hydrocarbon radical
having 3 to 7 carbon atoms9 which may both be substituted by
a~ a s-traight-chained or branched alkoxy, alkylthio, alkenyl-
29 oxy or alkenylthio group of 1 to 5 carbon atoms 7 .~
8 ~b
- 2 - ~
, . .
:: , . , ~ . .
. . ~" ~ .
n~L
~85~
b) a phenoxy group which may carry one or two, optionally
- halogenated, alkyl groups of 1 to 3 carbon atoms, halogen
atoms, optionally halogenated phenoxy groups or alkoxy
groups of 1 to 4 carbon atoms,
c~ a furyloxy, thienyloxy or benzyloxy group which may carry,
in its nuoleus, one or two, optionally halogenated, alkyl
groups of 1 to 3 carbon atoms, halogen atoms or alkoxy
groups of 1 to 4 carbon atoms,
d) a trifluoromethyl or pentafluoroethyl group,
e) a cycloal~Yl group of ~ to 7 carbon atoms,
f) a phenyl, thienyl or furyl group which may carry one or
two, optionally halogenated, alkyl groups o~ 1 to 3
carbon atoms, halogen atoms or alkoxy groups of 1 to 4
carbo~ atoms,
R2 represents a ~traight-chained or branched, saturated or un-
saturatedg aliphatic or cycloaliphatic hydrocarbon radical
having 1 to 6 carbon atoms9 or an araliphatic hydrocarbon
radical having 7 or 8 carbon atoms, and n represents the in-
teger two, three or ~our~ as well as the free acids of these
compounds and the physiologically acceptable metal or amine
salts ~hereo~,
The prese~t invention further provides a process ~or the
manufacture o~ these pyrrolidones of ~ormula I, wherein
a1) a pyrrolidone of the formula II
0
~ II
~ 0~
29 is protected at the nitrogen atom by introducing a pro-
~ 3 ~
,
; ,
~ ~ .
, ",. : .
- . ~ . :
- . , ., ,, .
" , . .
HOE 75/F 169
~ 5~
tective group (R3), which can easily be spllt of~9 thus
yielding a pyrrolidone o~ the ~ormula III
O
t ~-R~ III
~ 0~l
a~) a pyrrolidone o~ the ~ormula III
O
R III
~ OH
is oxidlzed to yield an aldehyde o~ the formula IV
~3
CHO
a3) the so-obtained aldehyde of formula IV is reacted with
a pho~phonate o~ the ~ormula V
(R40)2-~-CH21~-R
i~ which R1 is defined as abo~e, and R4 represent~ an un-
branched alkyl group of 1 to 4 carbon atoms~ to yield a
compound o~ the ~ormula VI
~ -R~ ~I
C~=CH-~-R ~
a4) in the so-obtained compound o~ ~ormula VI, the keto-carb-
29 onyl group is reduced to yield a compound o~ the formula VII
-
- : ,, : :
HOE 75~F 169
5~
R~
¦ VII
CH=C~-CH-R
1 OH
in which R is de~ined as above,
a5) in the compou~d of formula VII, the protective group
linked to the nitrogen atom is split of~ to yield a
compound of the formula VIII
. .
VIII
CH=CH-CH-R
i~ which R1 ls defined as above0 or
a5 ) the pyrrolidone of ~ormula II is oxidized to yield an
aldehyde o~ the ~ormula IX
O
.
C~O
a5 ) the ~o-obtained aldehyde of ~ormula IX is reacted with
a pho~phonate of formula V to yield a compound of the
formula X
1,~ ' X'
29 C~=CH C R1
: - 5 -
i~lwhiQh R~ de~ined a~o~e9 or
a5 ) in a compound~~of_formula YI, the pro~ective grou~ l:inked
to the nitrogen is split off to yield a compound o~
formula X,
a5 ) in a compound o~ ~ormula X, the ketocarbonyl group is
reduced to yield a compound o~ ~ormula VIII,
a6) the alcohol function in a compound of formula VIII is
protected with a group, which can easily be split of~
under acid conditions, to yield a compound of the
formula XI
O ' : .
~ NH XI
<_1~ 1
CH-CH-CX-R
. 1~5
- ~ .
in which R1 i~ defined as above, and R5 represents a
protective group~ which can be easily split of~7
a7) the pyrrolidone of ~ormula X]: is deprotonized by mea~s of
a base at the nitroge~ atom~ and the thus-formed anion
is reacted with a carboxylic acid derivative of the
~ormula XII
Y-CH2-CH=C~-(CH2)n-CO~R XII
in which R and n are de~ined as above~ and Y represents
a radical~ which can be substituted by a ~ucleophilic sub~
stitution reaction9 to yield a compound of the formula
XIII
29
: - 6 -
., .
.
: . . ;,. ..
. , ,, . ~ , ~-
:.: . .. .. ~ .
HOE 7 ~ 169
S~
~ CH2-CH=CH-(cH2)n-cooR2 XIII
CH=CH~H~R
oR5
in which R19 R2 a~d n are defined as above, and R5 re-
presents a protective group, which can easily be split off
under acid conditions, the resulting ester is optionally
hydrolyzed to yield the corre~ponding acid o~ formula XIII,
in which R2 represents hydrogen~ -
a~) the alcohol protective group R5 in the compound o~
~ormula XIII is split off to yield a compound of ~ormula
I, a~d optionally this compo~d is converted in-to the
free aoid or a physiologically acceptable metal or amine
salt thereof~ or
a8,) the compound of formula VIII ~s deprotonized by means of
a base, a~d the resulting a~i.o~ is reac~ed with a carb-
ox~lic acid derivative of fo~ula XII to yield a com-
pound o~ formula I directly, or
a7 ) the pyrrolidone of ~ormula XI is deprotonized at the
nitrogen atom by mea~s of a baseg and the resulting anio~
i9 reacted with a carboxylic acid derivative of ~ormula
XII, in ~hich R2 represen.ts hydrogen, to yield a compound
o~ ~ormula XIII, in which R2 represents hydrogen, and
the resulting acid i~ optionally converted into an e~ter
o~ ~ormula XIII~
a8 ~ the alcohol protective group in the compou~d o~ ~ormula
2g XIII, in which R2 represents hydrogen, is split o~f to
7 --
, ~ :', ''' : `, :
. ~ " .~
. ;., . , ;
- ; , ~ .i, .. .
HOE '75!F 169
855~
yield a compound o~ ~ormula I, in which R2 repre~ents
- hydrogen, and this acid is optionally converted into a
physiologically a~ceptable metal or amine salt or an
ester thereo~ or
a8 ) the oompound of ~ormula VIII is deprotonized by means of
a base, and the resulting anion is reacted with a carb-
oxylic acid deri~ative o~ formula XII, in which R2 re-
`.--=-` presents hydrogen, to yield directly a oompound o~
formula I, in which R2 represents hydrogen~ or
b1) into the pyrrolidone o~ ~ormula II
II
. CH~-OH
an alcohoi protective group R6, which can easily be split
o~f under aoid condi-tions, is introduced to yield a
compo~d of the formula XIV
~ ~H XIV
2~ ~ 6
CH2 OR
b2) the pyrrolido~e of formula XIV is deprotonized at the
nitrogen atom by means o~ a base~ and the resulting anion
ls reacted with an allyl halide to yield a pyrrolidone o~
the formula XV
~CH2-CH=CH2
CH2-OR6
29 ..
- . . . . . ..
.
. , .
.,, : . .
.~
,.... . .
~ 8~
b3) the so-obtained pyrrolidone~ of ~ormula XV is ozonolyzed
- to yield an aldehyde of the formula XVI
~-CH2-CHO
CH2-OR6
b4) the so-obtained aldehyde of ~ormula XVI is reacted with
an ylide of the formula XVII
(R7)~p=cH(cH2)ncGoMe XVII
in which n is de~l~ed as abo~e~ R7 represents identical
or di~ferent straight chained alkyl groups of 1 to 4
carbon atoms or phenyl groups, and Me represents an
alkali metal atom, to yield a compound of the formula
XVIII
H2-cH=cH-~cH2)n-cooMe XVIII
CH~-OR
Z and this compound is treated to set free the corre-~
sponding acid of the formula XIX
CH2-c~H=( H-~cH2)n-cooH XIX
CH -OR
in which formulae n is defined as above, or
-
b4,) the protected pyrrolidone of formula XIV is deproto~ized
at the nitrogen atom by means of a base, and the re-
29 sulting anion is reacted with a carboxylic acid deri-
_ g w
.. . .
..
: : ; . . ..
.. ,, ~' , `', .,i' ,
.,. ,~ . : , ,; , ~ :
vative of ~ormula XII, in which R2 represents hydrogen,
to yield a compound of formula XI~,
b5) the so-obtained compound of ~ormula XIX is converted into
the corresponding ester o~ the formula XX
~ N-CH2-CH=C~- (CH2 )n-COOR2
.1,
CH2 oR6
in which R2 and n are de~ined as above, or
b5,3 the protected pyrrolidone o~ formula XIV is deprotonized
at the nitrogen atom by means o~ a base, and the resulting
anion is reacted with a carboxylic acid derivative of
~ormula XII to yield the compound of ~ormula XX directly,
b6) the protecti~e group R6 in the so-obtained compound of
formula XX is split off under acid conditions to yield an
alcohol o~ the ~ormula XXI
0 2
~ H~-CH=GH-(CH2)n-COOR XXI
~
C$12-OH
-
in which R and n are defined as above9 and then the
corresponding acid may optionally be set ~ree 9 or
2~ b61) esterification o~ a compound of formula XIX and splitting-
of~ of the protective group R6 are carried out in a si~gle
step, or
b6") the pyrrolidone of ~ormula II is deprotonized at the
29 nitroge~ atom by means of a base, and the resulting anion
- 10 -
.
. ~, :, ,
s~ ~
is reacted with a carboxylic acid derivative of formula
XII to yield a compound of formula XXI directly, or
b6 ) the pyrrolidone of formula II is deprotonized at the
nitrogen atom by means of a base7 and the resulting anion
is reacted with an allyl halide to yield a compound of
the formula XXII
O
CH2-CH=CH2 XXII
CH20H
b6 ) The so-obtained compound of formula XXII is ozonolyzed to
yield a compound of the formula XXIII or its cyclisized
tautomer of the formula XXIV
C 2-CNO
CH~-OH
XXIII ~xr~
or
b6- 3 the protective group R6 is split off from a compound of
formula XVI also to yi~ld the compound of ~ormula XXIII
or XXIV,
b6 ) the compound of formula XXIII or XXIY is reacted with an
ylide of formula XVII to yield a compound of the formula
XXV o
~-CH2WCH=CH- ( CH2 )n-COOMe
29 . CH2~0
- ;:. ::- - , . ~
, . , , . ..
... . ....
:: ; ,
., . ~ ,,
.~ i
,:
.: ,
:
.
85~5~
and the corresponding acid of the formula XXVI
~ -CH2-CH=CH-(CH2)n-C~OH XXVI
CH20H
is set free therefrom and optionally converted into an
ester of formula XXI, in which formulae XXV and XXVI n
is de~ined as above, or
b6~) the pyrrolidone o~ formula II is deprotonized at the
nitrogen atom by means of a base, and th~ resulting anion
i5 reacted with a carboxylic acld derivative of ~ormula
XII, in which R represents hydrogen, or
b6 ) the protective group R6 is split of~ from a compound of
formula XIX to yield a compound of formula XXVI9
b7) the so-obtained al~ohol of formula XXI is oxidized to
yield an aldehyde of the formula XXVII
~ CH2-CH=CH-(C~2)~-COOR XX~II
CH0
in which R2 and n are de~ined as above, and optionall~
~he corresponding acid of formula XXVII (R2 = H) is set
free therefrom,
b~) the so-obtained aldPhyde of formula XXVII is reacted with
a phosphonate o~ formula V to yield a compound o~ the
~ormula XXVIII
~ -CH~-CH-CH-(CH2)n-COOR2 XX~ITI
29 ll
_12 -
. , - ,~
.. ~ ; .. , ; .. , , :: , ,
: - .. . .
y - ~
~ 5~
in which R1, R2 and n are de~ined as above, or
b8,) a compound o~ ~ormula X is deprotonized at the nitrogen
atom by means of a base, and the resulting anion is
reacted with a carboxylic acid deri~ative of formula XII
to yield a compound of ~ormula XXVIII directly,
bg) in the so-obtained compound o~ formula XXVIII, the keto-
carbonyl grou~ is reduced to yield a compound o~
~ormula I 9 and this compound i~ optionally converted into
the free acid or a physiologically acceptable metal or
amine salt thereof, or
b7 ) a compound of formula XXVI is oxidized to yield an alde-
hyd~ o~ formula X~VII, in which R represent~ hydrogen,
. and thi~ is optionally con~erted into an ester of formula
XXVII,
b8 ) an aldehyde of formula XXVII, in which R2 represents
hydrogen, is reacted with a phosphonate of formula V to
yield a compound of ~ormula XXVIII~ in which R2 represents
hydrogen, and this is optionally ~onverted into an ester
of ~ormula XXVIII, or
b8 ) a compound of ~ormula X is deprotonized at the nitrogen
atom by means of a base~ and the resulting anion is
reacted with a carboxylic acid derivative of formula XII,
in which R represents hydrogen, directly to yield a com-
pound of formula XXVIII, in which R2 represent~ hydrogen9
b9 ) in a compound of ~ormula XXVIII, in which R2 represents
hydrogen, the ketocarbo~yl group is reduced, and the
resulting co~pound of formula I, in which R represents
hydrogen, is optionally converted into a physiologically
acceptable metal or amine salt or an ester thereof.
- 13 -
..
~. ' ''' ~ '
.
..
- , .. , . :
~:"; ' , ,' : ,
HOE 75/F 169
~ ~ 5~ 5~
Among the meanings gi~en for the substituents R17 R2 and n,
the follo~ing are preferred:
For R a straight-chained or branched9 saturated or unsaturated,
aliphatic hydrocarbon radical having 1 to 7 carbon atoms,
or a cycloaliphatic hydrocarbon radical having 5 to 7
carbo~ atoms7 which may both be substituted by : ~
~) a straight-chained or branched aIkoxy, alk~lthio,
alkenyloxy or alkenylthio group of 1 to 4 carbon
atoms,
b) a phenoxy group which may carry one or two alkyl
groups of 1 to 3 carbon atoms 9 tri~luoromethyl groups,
halogen atoms, optionally halogenated phenoxy groups
or alkoxy group~ of 1 or 2 carbon atoms,
c) a thienyloxy or benzyloxy group which may carry one
or two alkyl groups of 1 to 3 carbon atoms, trifluoro-
methyl group~9 halogen atoms or alkoxy groups of 1
or 2 carbon atoms,
d) a trifluoromethyl group~
e) a cycloalkyl group of 5 to 7 carbon atoms,
~) a phenyl or thienyl group which may carry one or two
alkyl groups of 1 to 3 carbon atoms, trifluoromethyl
~roup~g halogen atoms or alkoxy groups of 1 or 2
carbon atoms9
for R2 a straight-chained or branched alkyl group of 1 to 6
~ carbon atoms9 a straight-chained or branched alkenyl
group of 2 to 4 carbon atoms, a cycloalkyl group of 5
or 6 carbon atoms, or an aralkyl group of 7 or 8 carbon
atomsO
- 14 - .;
,. , , ;
,. . .
~z.~
~ 5~
Particularly preferred are the following substituents for
R1 a straight--chained or branched alkyl group o~ 1 to 7 carbon
atoms 9 a straight-chained or branched alkenyl group o~ 3
to 5 carbon atoms 9 or a cycloalkyl group of 5 to 7 carbon
a-toms~ which may be substituted by
a) a straight-chained or branched alkoxy, alkylthio,
alkenyloxy or alkenylthio group of 1 to 3 carbon atsms,
b) a phenoxy group which may c~rry one or two methyl, tri-
fluoromethyl or methoxy groups, chlorine or fluorine
atoms, or optionally chlorinated or fluorinated phenoxy
groups,
c) a thienyloxy or benzyloxy group which may carry in its
nucleus one or two methyl, tri~luorome~hyl or methoxy
groups, chlorine or fluorine atoms,
d) a trifluoromethyl group,
~) a cycloalkyl group o~ 5 to 7 carbon atoms~
f) a phenyl or thienyl group which may carry one or two
methyl~ ~rifluoromethyl or methoxy group or chlorine
or fluorine atoms;
for R2 a straight~chained alkyl group of 1 to 6 carbo~ atoms,
a branched alkyl group of 3 to 5 carbon atoms, a straight-
chained alkenyl group of 2 to 4 carbon atoms, the cyclo-
pentyl and cyclohexyl group, and the benz~l group, and
for n pre~erably the integer 30
Th~ hydroxymethyl-pyrrolidone of formula II 9 used as a
starting material ~rn the process o~ the invention, is prepared
according to methods known in the art (cf~ J.Amer~ Chem. Soc. 74,
p. 851, (1952)).
29 For this purpose~ a glutamic acid is refluxed for some hours
- 15 -
. . , , . -, : . ,.
... . . . .
. .
. , ., ;
.. .
.. .. ~ .
, ,
110~
in -the presence o~ an alcohol ROH and an acid oatalyst to yield
- the 5~alkoxycarbonyl-pyrrolidone-(2) of the formula ~XIX
4~
~
COOR
in which R is defined as above~
This reaction can especially advantageously be carried ou-t
using concentrated sulfuric acid as a catalyst and n-butanol as
the alcoholic compone~t, since the reaction water can be separ-
ated by means of a water separator during thë reaction.
The co~version of a compound o~ formula XXIX into a com-
pound of ~ormula II by catalytic hydrogenation is also dis-
closed in J.Amer. Chem. Soc. _ , p, 851 ~1952)~. As catalysts
suitable for the hydrogenation~ numerous metals and noble
metals 9 such as Raney nickel 9 copper chromium oxide and
ruthenium oxide on carbon, may be used. The hydrogenation
reactions are generally carried out at 100 - 250C~ preferably
at 140 - 180Cg u~der a pressure o~ 150 to 250 atmsg., in a
2Q suitable sol~ent~ preferably alcohols~ such as methanol,
ethanol or isopropanol, or ethers such as tetrahydro~uran and
dioxan.
The process o~ the invention mentioned sub (a) starts by
introducing the protective group R3 at the nitrogen atom,
practically at any stage preceding the proper alkylatiQn
reaction. This protective group may generally be split of~ at
any stage preceding the alkylation reaction, but adva~tageously
at the last step preceding the introduction o~ the carboxy side
29 chain.
_ 16 -
.. . .
~ ' ' : ,'',. : ', , ' '
;. ., , ,, -. ~ . . ....
: ... . : .
: . ." ,
~o~ 75/~ ~69
3C~ .
The protective group may best be introduced already into the
- compound of ~ormula II 9 pre~erably by converting the lactam
into the corresponding carbamic acid ester, for example by
means o~ chloroformic acid ethyl ester under alkylating con-
ditions, for example an alcoholate in ethyl alcohol, sodium
amide i~ be~zene or toluene, potassium hydroxide in dimethyl-
sul~oxide. From the compound of formula II; for example a
compound o~ the ~ormula XXX
~ C ~ 5
OH
.... , _ . .. .
... . _ _ . _ _ . .
is then obtained.
Further protective groups are, ~or example, the benzyl
group, the tert. butyl group, the trimethyl-silyl group or the
~ormyl group.
The oxidizing reaction o~ the compounds of formula III
yielding the compounds of ~ormula IV is carried out using oxi-
dizi~g ~ge~ts as currently used ~or the oxidation o~ aliphatic
alcohols,yielding aldehydes~ Some methods are disclosed in
Houben-Weyl, Vol. 7/1, page 159. Further suitable oxidants
are the complex compounds obtained from thio ethers~ such as
dime~hylsul~ide or thio anisole with chlorine or N-chloro-
succi~imide (cf. J~Am~r~ Chem. Soc. 94, p. 7586 (1972), J. Org.
Chem .~9 p. 1233 (1973)). Furthermore, an oxidation with di-
methylsul~oxide under various conditions is also applicable
(c~ Chem. Rev. 67, pO 247 (1967)).
An especially preferred process is the oxidation with the
29 complex compound of chromium trioxide and p~ridine which is
- - 17 -
: ,. : ; :
. . ,, `. " ,,, ~, ., ',
.~. . . ..
HOE
~ ~ 5~
prepared in an inert solyent~ preferably methylene~chloride,
and then blended with a solut,ion of the alcohol o~ formula III
at -20 to ~20C. The oxidation is speedy and is generally
complete after 5 to 45 minutes, when ~ollowing the indications
given in J.Org. Chem. ~5 ? page 4000 (1970), or JO Org. Chem.
26, page 4814 (1961). The aldehyde oY ~ormula IV may be used
without ~urther puri~ication ~or the next reaction step.
Where required9 the aldehyde is puri~ied by column chromato-
graph~.
The reaction o~ the phosphonates of ~ormula V with com-
pounds of ~ormula IV may be carried out undër the conditions
usual ~or the Horner reactio~, ~or example in ethers at room
tempera~re. As ethers, there are preferably used diethyl
ether 9 . tetrahydrofuran and dimethoxy-ethane. The phosphonate
is used in an excess to e~sure a complete reaction.
The reaction is gener~lly complete after 1 to 5 hours ~
at room temperature. The reaction product is isola~ed and
purified by the usual methods. Details concerning the
handling of this reaction are given in J. Amer. ChemO Soc. 83,
p~ i7~3 (1961)).
Th~ phosphonates of formula V are either known (cf. J.
Org. Chemq ~, p. 680 (1965)) or may be prepared in a man~er
analogous to the known methods (for @xample, J. Amer. Chem.
SocO 88, p. 5654 (1966)). Compounds of ~ormula VII may be
obtained by treating compounds o~ ~ormul~ VI with a reducing
agent. Such a reducing agent may be any substance capable of
selectively reducing a keto group to a hydroxy group 9 pre-
ferably a complex metal hydride, especially a boron hydride,
29 such as sodium bor~on~hydride,~~~zinc boron hydride or lithium
- 18 -
. .
perhydro~9b-boron phenalkyl hydride (J.Amer. Chem. Soc~
p. 709 (1970)), or also complex aluminium hydride~ for ex-
ample sodium-bis-(2 methoxy-ethoxy)-aliminium hydride. The
reduction is generally carried out at a temperature o~ ~rom
-10 to 50C in a solvent which is inert towards the hydrides,
such as ethers~ for example diethyl ether, dimethoxy-ethane9
dioxan9 tetrahydro~ura~ or diethylene glycol dimethyl ether;
or hydrocarbons9 for example benzene, or in a mixture of an
alcohol and water, for example methanol/water~ The isomeric
~ and B-hydroxy compounds resulting from this reduction may
be separated into the two isomers by the usual chrom~to-
graphical methods.
The subsequent reactions can also be carried out using a
mixture of the~e two isomers9 so that a separation into ~- and
B-hydroxy com~ounds can be performed at any stage following the
reduction~
In the case of R3 being COOC2H~ 9 it is possible for pre-
paring the compounds o~ form~la VIII to split of~ the pro-
tectiv~ group by saponification and subsequent decarboxylationg
~or example by a treatment with an acid or a base in wa-ter,
alcohols or aqueous alcohols. The formyl group may also be
eliminated in ~his manner. The benz~l group is eliminated by
a treatment with acids, ~or example boron trifluoride ethera-te
in glacial acetic acid~ or by catalytic hydrogenation, whereas
the tert.-butyl group is split off by means o~ high tempera~ r
tures9 for example of from 90 to 250C. The splitting-o~f
reaction may be carried out in any of the compounds of
formula IV, VI or VII but ad~antageously in the compounds of
29 formula VI or VII~
- 19 _
.,
. ~ . ,
.. , .: " ,
"....
.: ,, :; ' ... . ": ,
HOE 75/F 169
~ 5~
The reaction o~ the compounds o~ ~ormula VI yields the
pyrrolidones o~ ~ormula X, which may, however~ also be obtained
more directly ~rom 5-hydroxymethyl-pyrrolidone of ~ormula II.
The compound o~ formula II can be oxidized as described above
for the reaction o~ compound III into compound IV to yield the
compou~d o~ iormula IX, and this can be reacted under the con-
ditions of a Horner reaction (see conversion o~ IV into VI) in
the presence of a phosphonate of ~ormula V to yield a compound
o~ ~ormula X. The reduotion o~ the ketocarbonyl group in this
compound in ~he manner described above (con~ersion of VI into
VII) pro~ides the oompound o~ formula VIII.
The alcohol function in the compounds of formula VIII can
generally be protected by all the ~rotective groups easy to
split off, especially by those men-tioned in the disclosure for
the con~ersion of compound II into compound XIV. For the con-
version o~ a compo~nd of ~ormula VIII into a compound of
~ormula XI, especially those protective groups are suitable
which are introduced by acid catal~sis, predomînantly by
reaction with an enol ether. As enol ethers, 2,3-dihydropyran9 .
eth~l vinyl ether or methyl-isopropenyl ether, and as acid
catalysts, for example p toluene~sulfonic acid or sul~uric acid
are especially suitable. The reaction is ad~antageously carried
out in a solvent~ for example diethyl etherg dioxan or benzene3
at temperatures of from -10 to +60C.
The pyrrolidones of ~ormula XI are alkylated by means o~ a
carboxylic acid deri~ati~e of formula XII according to the
usual methods, by deprotonizing the nitrogen atom by means o~
a suitable base9 ~or example sodium or potassium hydroxide,
29 sodium or potassium amide, sodium hydride, potassium tert.-
_ 20 -
" .:.
~ 5
butylate~ lithiwm diisopropyl amide or llthium cyclohexyl-iso~
propyl amide, and then adding the alkylating agent in substance
or in solution in the corresponding solventv
As substituents Y in the compounds of formula XII, the
acid radicals of methane-sul~onic acid, p-bromobenzene~sul~onic
acid and p-toluene~sulfonic acid are especially mentioned, in
particular chlorine, bromine and iodine~ bromine and chlorine
being of outstanding importance in this co~nection.
The reaction o~ a base with the compounds of formula XI is
carried out with exclusion of air and moisture since the bases
and resulting anion5 are sensitive to air ana moisture. As
solvents, especially aprotic polar liquids are mentioned which
have a su~ficient dissolving power also at low temperatures and
which are inert under the reaction conditions. Where required,
mixtures of two or more solvents are used to reduce the solidi-
fication point, pre~eraby ethers, such as dimethyl ether9 di-
ethyl ether, diisopropyl ether, tetrahydrofuran, dioxan, glycol
dimethyl e~her~ dimethylformamide~ dimethylsul~oxide or toluene.
The reaction temperatures ra~æ from -~0C to ~80C, pre-
ferably ~rom 10 to +50C, in particular from 0C to room
temperatureO The reaction is generally carried out by adding
a solution of a pyrrolidone of formula XI with agitation to
a ~rozen solution o~ the base in one of the said solvents, so
as to maintain the temperature range desired for the reaction;
the components may also be added to one another vice ~ersa.
The alkenyl derivati~e is then added to the frozen solution
thus obtained so that the temperature range o~ the reaction
mixture is not substantially exceeded as a result of the exo-
29 thermic reaction.
- 21 _
.
. .
....
-
~0 ~ 5~ ~
A~ter the addition, the mixture is stirred ~or half an
hour to 12 hours and then worked up.
The mixture may be worked up, for example by adding a de-
termined amount o~ water to the reaction mi~ture, separating
the organic phase, extracting the aqueous phase several times
with an organic solvent, drying the united organic phases and
concentrating them. In a few cases9 the residue can be puri-
~ied by a high-vacuum distillation, in most cases only by
column chromatograph~. In many cases, the products are ob-
tained already in suoh a pure state as to make purification
unnecessary.
To split of~ the ether protecti~e group for the conversion
o~ the compound of ~ormula XIII into a compound of formula I or
i~to the corresponding acidS the usual reactants and test con-
ditions are applied. In the compounds o~ ~ormula XIII9 the
alcohol ~unction is pre~erably protected by an acetal group
which is split of~, in the simplest case, by an acid hydrolysis
with dilute aqueous/alcoholic acid, preferably dilute aqueous
alcoholic oxalic acid, at 10 - 50C, or by heating it with
60 70 ~ acetic acid at 50 - 60C to yield the compound o~
formula I~
Depending on the reaction co~ditions 9 the compounds o~
~ormula I or the corresponding acid~are obtained9 which may
then, optionally, be converted into further derivatives, such
as esters, metal or amine salts.
The above alkylation reaction ~or the con~ersion o~ the
compoundso~ ~ormula XI into compounds of formula XIII may also
be carried out using the corresponding carboxylic acids oX
29 ~ormula XII (R2 _ H), and the resulting compounds o~ ~ormula
- ~ 22 -
. "
,
. . .
:, ,;, - ~ ; :
HOE 75
~l 358e~9
XIII (R2 = H) may be converted into compounds o~ formula I
(R = H) by splitting off the alcohol protective group. In
the same manner, the compounds o~ formula VIII may be alkyl-
ated as above, optionally using both carbo~ylic acic ester
derivatives of formula XII and carboxylic acid derivatives o~
formula XII (R = H). In this case, the compounds of formula I
are obtained i~ a single step.
The second reaction method (b) of the i~vention also starts
from 5-hydroxymethyl-pyrrolîdone-(2) of formula II. It starts
by introducing the alcohol protective group R6 to yield com-
pounds of formula XIV.
As protective groups R6 suitable ~or the hydroxymethyl-
pyrrolidone9 those groups are primarily mentioned which can be
split o~ agai~ under mild conditions, for example by acid
hydroly~is or hydrogenation, in particular the allyl, benzyl,
tert.-butyl ~nd chloromethyl groups, as well as enol ether
groups (c~. JO Org. Chem. 38, 32~4 (1973); Tetrah.Lett. 107
(1972)).
The alcohol group may also be protected by acyl groups,
advantageously by a reaction with acetic anhydride in pyridine
at -10 to +20C.
Preferred is the formation of acetals which may be pr~-
pared by reacting the alcohol of formula II with an enol ether,
for example 2~3-dihydropyran, ethylvinyl ether or methyl-iso-
propenyl ether, in an aprotic sol~ent in the presence of a
catalytic amount of a strong acid, such as a mineral acid9 for
example hydrochloric acid, sulfuric acid or phosphorus oxy-
chloride a Lewis acid, for example boron trifluoride etherate;
29 or ~n organic acid, such as p-toluene-sulfonic acid or tri-
- 23 -
;~
"
HOE 75~F 169
5~
fluoroacetic acid.
As solvents, alipha-tic or aromatic hydrocarbons7 such as
pentane or benzene, or halohydro arbons9 such as chloroform,
~ methylene chloride; nitriles, ~or example acetonitrile~ or
ethers, for example diethyl ether or dioxan, have proved to be
useful. The reaction is preferably carried out at -10 to
~60C for a period of from 1 hour to about 24 hours. To iso-
late the compou~ds o~ formula XIV9 the reaction mix-ture is
shaken with a sufficient amount of an acid binder, preferably
a saturatedg aqueous sodium bicarbonate solution, or if water
is to be excluded, for example triethylamine is addedg the
organic phase is dried by means of sodium sul~ate, and the ;~
product is purified, after elimination of the solvent, by high-
vacuum distillation or by col~mn chromatography.
The subsequent alkylation reaction is carried out as des-
cribed for the reaction of the compounds of formula XI to yield
the compounds of ~ormula XIII, the alkylating agents being
mai~ly allyl chloride or allyl bromide.
The olefi~s o~ formula XV are oonverted into the aldehydes
of ~ormula XVI by ozo~olysis as disclosed in the art ~cf.-Chem.
Re~. 58, p. 990 (1958), Tetrah. Lett., 36, p. 4~73 (1966 ~ in
the following manner:
The ole~ins are dissol~ed, optionally with the exclusion of
moisture9 in a determined amount of methanol, to which a halo-
hydrocarbon, for example methylene chloride, may optionally be
admixed. Into this solution, the equivalent amount of ozonium
is introduced at a temperature of from -100 to -50C9 pre-
ferabl~ at -70C. A slight excess amount o~ ozonium does not
29 influence the yield. Excess ozonium i~ then expelled by an
_ 24 -
'
~ F_~2
inert g~s t dimethyl sul~ide is added to reduce the products ob-
tained by the ozonolysis, and stirring is oontinued Lor about
1 hour at -10C9 0C and 20C~ respectivelyO
To isolat~ the aldehydes, the solutions are concentrated
in vacuo at the lowest possible temperature, the residue is
treated optionally with ~aturated sodium bicarbo~ate solution,
a~d the product is the~ extracted with an appropriate solvent,
pre~erably benzene, or directly chromatographed.
The aldehydes are used either directly for the subsequent
Wittig reaction or after purification~ ~or e~ample by column
chromatography.
The compounds of formula XIX are obtained by reacting a
; phosphonium ylide of ~ormula XVII, in which R7 represents pre-
~erably phenyl, with the aldehydes of formula XVI in an appro- ~
priate sol~ent. The phosphonium ylides and the phosphonium
~alts~ ~rom which they are deri~ed9 are prepared according to
analogous methods described in the art ~J.Amer. ChemO Soo. 91,
p. 5675 (1969)~.
For the preparation of the ylide, there may be used in
organic bases such as sodium hydride, sodium amide9 lithium
amide or potassium tert.-butylate, or organic ba~es, as ~or
example alkali metal organic compounds, for example lithium
butyl or lithium di-isopropyl amide, or the sodium salt of di-
methyl sulfoxide.
As solvents, there are suitable ethersp for example diethyl
ether~ tetrahydrofuran, diethylene glycol dimethyl ether, di-
lower alkyl sulfoxidesp for example dimethyl sulfoxide, or
amides of carboxylic acidsp for example dimethylformamide, di-
29 methyl acetamide.
- 25 -
:, , .. ~ ;,
, . .
,: .. , .. ~ :
. . . . . ... ..
, . :,
~ ~ 5~5~ D~8__3~
The solvent preferréd is dimethyl sul~oxide. As a ~ase,
the sodium salt of dimethyl sul~oxide is pre~erably used. Under
the~e conditions, cis-double bonds are pre~erably formed.
The preparation o~ the ylide and the sub~equent reaction
with the aldehyde are carried out without îsolation of inter-
mediate products, ~or example in the following manner:
The solution o~ the phosphoniu~ salt is added at room
temperature, with the exclusion of h~midity and under an inert
gas, to one ~ui~alent o~ a base which is also dissolved in an
aprotic solvent, for example d`imethyl sulfoxide. After stirring
for about 9 hour, a solution o~ from 0.30 to 0.95 equiYalent
o~ the aldehyde is added. The reaction is complete after 2 to
24 hours. The solution is acidified with a mineral acid at
-5 to +5C9 the acid is extracted ~rom the reaction mixture
with a suitable solvent, for example an ether, methylene chlor-
ide or benzene~ the organic phase is dried and concentrated.
To separate by-products and the phosphine oxide, the acid is
recon~erted into the alkali metal salt thereof~ and the aqueous
phase is extracted with a suitable solvent. From the aqueous
phase, the carboxylic acids of formula XIX are isolated by
acidifying and extracting them again with an appropriate solvent~
To separate the triphenyl phosphine oxide and the diphenyl-
~ ~hydroxy-ca~Pnylalk~l-phosphine oxide obtained by hydrolysis
o~ excess ylide, the crude material may be dissolved in ether,
pre~erably diethyl ether, and the phosphine oxides are allowed
to crystallize at temperatures below -20C. Under these con-
ditions 9 the desired reaction products remain in a dissolved
state and are separated together with the solvent ~rom the
29 contaminants.
- 26 -
,~
' :
HOE_ 75LF 169
The esters o~ formulae XX ~ncl XXI may be prepared according
to analogous methods described in the art. For example, the
acids can be esterified with the corresponding alcohol in the
presence o~ a strong acid, such as sulfuric acid, hydrochloric
acid, p-toluene-sulfonic acid, trifluoroacetic acid9 optionally
in the presen~e of an entrainer for the resulting water, the
alcohol being used in excess. Under these conditio~s9 the pro-
tective group R6 is simultaneously split o~f~ and the compounds
of ~ormula XXI are directly obtained In contradistinction
thereto, esterification with alcohols in the presence of carbo~
diimides does ~ot attack the protective group R6. Also the
reaction with diazo alk~nes, pre~erably diaz~ methane, in an
inert solven-t, leads to the same result as does the reaction o~
the sodium salt o~ the acid with an alkyl halide in a polar
solvent, for example dimethylformamide.
As it is indicated above, the splitting-off reaction of the
protective group R6 and the esterification can be carried out
in a single step. Alternatively9 the esters of formula XX are
heated to 50 - 80C for about 30 minutes in an alcohol, such
as methanol 9 ethanol or isopropanoly in the presence of an acid
catalyst to split off the protective groupO The co~pound o~
~ormula XXI is then neutralized a~d isolated by extraction with
an appropriate solvent, for example methylene chloride, chloro-
form or diethyl ether.
2~ When the alcohol protecti~e group is split off ~rom the
compound of formula XIX mainly in an aqueous medium in the pre-
sence of the abo~e acid catalysts, the hydroxy-carboxylic acids
of ~ormula XXVI are obtained, which again may either be esteri-
29 fied or used directly ~or further reaction steps.
-- 27
. .. .
..
.;, . ...
, . - ~ -
,. . . .
HOE ~lF 169
The compounds of formula XIX, XX, XXI and XXVI may also be
- obtained by alkylating the compounds of ~ormulae XI~ or II with
a carboxylic acid ester derivative of ~ormula XII or a carb-
oxylic acid derivative of formula XII (R2 = H~, the alkylation
conditions given for the compounds of formula XI being ac-
cordingly applied to these reaction steps.
The aldehydes of ~ormula XVI may be slowly cyclisized to
give the lactols of the formula XXIV while splitting off the
cQrresponding protective group:
CN -C ~ O OH
CH2 0
~XVI XXIV
This cyclization reaction may generally be carried out in
solvents, such as aliphatic or aromatic hydrocarbons, for
example pentane or toluene; in halohydrocarbons, ~or example
chloroform in ethers~ for example diethyl ether~ dioxan, or in
alcohols, for example methanol or ethanol, with or without an
acid catalyst, for example concentrated sulfuric acid, p-tolu-
ene~sulfonic acid or boron trifluoride etherate9 at a temper-
ature of ~rom -10 to the boiling poi~t of the solYe~t used.
The compounds of ~ormulae XXIII and XXIV, respectively~ are
obtained by directly alkylating the 5 hydroxymethyl-pyrro.
li~o~e-2 of formula II, without introduction of an alcohol
protective group R3, with an allyl halide. The conditions
given for the conversion of compounds of formula XI into com-
29 pounds of formula XIII may also be applied to the introduc-tion
- 28 -
: ''
;
.. . .
_E 75/F 169
~ ~ 5~ 5~
o~ the allyl group into compounds o~ ~ormula II, the said
conditions preferably including the use of potassium hydroxlde
as a base in dimethyl sulfoxide at a temperature of from
t10 to ~40C.
The compound of ~ormula XXII resulting from this reaction
can then be subjected to an analogous ozonolysis as described
~or the compounds o~ ~ormula XV to yield the corresponding
aldehyde of formula XXIII which, however, has an only poor
stability in the open form and generally is already cyclisized
during the work-up givi~g the compound of formula XXIV. This
cyclization may optionally be completed by applying :the con-
ditions given ~or the conversion o~ compounds o~ formula XVI
into compounds of formula XXIV. The compounds of formulae
XXIII and XXIV, respectively9 can be subjected to a Wittig
reactlon as described already above for the compounds o~ for-
mula XVI~ This reaction immediately yields the compounds of
formula XXVI~ .
The already-mentioned conditions for the reaction sequence
including oxidation, Horner reaction, reduction of the keto-
carbonyl group for the con~ersion of the compoundSof formula
II or III into compounds o~ formula XIII may acoordingly be
applied to the reaction of the compounds o~ ~ormula XXI or
XXVI yielding the compound o~ ~ormula I. I-t does, therefore,
not matter if the ester of formula XXI or the free acid of
~ormula XXVI is used or if, at one of the three steps, an acid
is esterified or an ester is hydrolyzed to yield the acid.
It has 9 however, pro~ed to be use~ul to carry out a corre-
sponding con~ersion reaction into various derivatives only on
29 the ~inal product, unless it is brought about by the reaction
- 29 -
~, , ., " . .
~, , : ..
~a~_
~ 35
conditions applied.
An esterification reaction is carried out according to the
method known in the art, for example described already for the
conversion of the compounds of formula XIX into compounds of
formula XX or XXI.
The reduction of the keto group introduced by the Horner
reaction yields a mixture of ~- and B-isomers as concerns the
resulting secondary hydro~y groups. The separation into the
two antipodes may b~ brought about either in the product re-
sulting from the reduction or in one of the subsequent reaction
steps. This m~ans that all the reactions ~ollowi~g the re-
duction of this ketocarbonyl group, for example conversion
into the free acid or esterification or conversion into metal
or amine saltsp can be carried out both on the pure d- and
B-isomers and on a mixture of d~ and B-isomers.
Unless the separate reaction ~roducts are obtained already
in a pure ~tate so as to be uced for the following reaction
step9 it is adv~sable to puri~y them~ for example by means of
column, thin-layer or high~pres~ure fluid chromatography.
The oompounds of formula I have two asymmetric centres,
namely the carbon atom carrying the secondary h~dro~y group
and the carbon atom neighboring the nltrogen atom in the five-
membered ring, which corresponds to the 5-position in the
pyrrolidone ring.
Since none of the reaction methods indicated provides
sterically homogeneous products~ the present in~ention re-
lates to all compounds of formula I, irrespective of the
sterical arrangement at the various carbon atom~ Besides
29 the two above mentionèd optically isomeric carbon atoms 9 this
- 30
.
-, ~ . ,; ... ,. .~
HOE 75 ~
also applies to geometrically isomeric compounds with regard
to the two double bonds. Generally, it is true to say that
the Horner reaction, due to the reaction conditions applied,
mainly yields a trans-type compound~ and the corresponding
cis~type product obtained to only a minor extent is eliminated
by chromatographical puri~ication steps. Similarly, the
Wittig reaction for -the introduction o~ the carboxy side chain
mainly yields the corresponding cis-olefin. In this case, too,
the t~rans-ole~in obtained as a byproduct can be separated by
corresponding purification operations.
The geometry of the double bonds predetermined in the
carboxylic acid derivatives o~ formula XII is transferred by
the alkylation reaction to the final products to be obtained.
This means that, when the corresponding trans~type deri~ative
f ~ormula XII is used, the ~inal product carries the trans
double bond in the carboxy side chain. Accordingly, the
same applies to the us~ o~ the cis-type derivat~ve of ~ormula
XII.
Owing to the possibilities of introducing the two double
bonds~ it can be claimed that the geometry of the two double
bonds is homogeneous. The mixture of two diasteromers due to
the two optically isomeric carbon atoms can be separated, in
the case o~ crystallizable deri~ati~es, into the two racemic
diasteromer~ by ~ractionated crystallization or by means of
~5
chromatographical methods, for example column, gaseous-phase
or medium - or high-pressure fluid chromatography. The split-
ting of the racemates into the optically active compounds can
be brought about according to the generally used methods~ for
29 example by treatment of the compounds of formula I (R2 = H)
~ 31 -
:, ~: .. . .. .
, . .
- .,
. , ;. .. . .,;, ~ :, ; , ,.
- ,. .. .
.
HOE ~ ~F 169
S~
with optically active bases, ~or example brucine.
According to the process o~ the invention, the ~ollowing
compounds may preferably be prepared in addition to the com-
pounds mentioned in the Examples:
1- ~-n-butoxycarbonyl-(Z)-2-hexen-1-ylJ-5-L3-hydroxy-(E)-1-
octen1-yl~-pyrrolidone-2,
1-~6-n-hexyloxycarbonyl-(Z)-2-hexen-1-yl~-5-L3-hydroxy-(E)-
100.cten~1-yl~-pyrrolidone-2,
1- ~5-ethoxycarbonyl-(Z)_2-penten-1-yl~-5-~3-hydroxy-(E)-1-
octen-1-y ~ -pyrrolidone-2~
1-r7-etho~ycarbo~yl-(Z)-2-hepten 1-yl~-5-~3-hydroxy-(E)-1-
octen-1 yl~-pyrrolidone~2s
1-~6-methoxycarbonyl-(Z)~2-hexen-1~yl~-5-~3-hydroxy-(E)-1-
hexen-1-ylJ~pyrrolido~e-2,
1-~6-methoxyc~rbonyl-(Z)-2-hexen-1-yl7 5-~3-hydroxy-(E)-1-
undecen-1-ylJ-pyrrolidone-2,
1-~6_methoxycarbonyl-(Z)-2-hexen-1-yl7-5-[3-hydroxy-(EgE,E)-
194,6-octatrien-1-yl3-pyrrolidone-2,
1-L6-methoxycarbonyl-(Z)-2-hexen-1-yl~-5-~3-hydroxy-4~methyl-
(E)-1-penten-1-yl~-pyrrolidone-2,
1-~6-carboxy-(Z)-~-hexen-1-yl~-5-~3-hydrogy-3-cyclopentyl~
(E)_1~buten-1-yl~-pyrrolidone-2,
1_r6_carbox~_(Z)-2_hexen_1_ylJ-5-~2-hydroxy-3-cyclohexyl-
(E)-1-buten-1-yl~-pyrrolidone-2,
1_~6_methoxycarbonyl-(Z)-2-hexen-1-yl~-5-C3-hydroxy-5-etho~y-
(E)-1-penten-1-yl~-pyrrolidon-2~
1-~6-n-hexyloxycarbonyl-(Z)-2-hexe~ yl~ -5 ~3-hydroxy-6-
methylmercapto-(E)-1-hexen 1-ylJ-pyrrolidone-2~
29 1-~6-carboxy-(Z)~2-hexen-1-yl~-5-~3 hydroxy-5-isobutyloxy-
- 32 -
: ,. ...... .
. ... .
.
'
110
~ 3
4,4=dimethyl-(E)~1-penten-1-yl~-pyrrolidone~2 ,
1-[6-carboxy-~Z)-2-hexen-1-yl~-5--~3-hydroxy-5-allylmercapto-
4,4~dimethyl-(E)-1-penten-1-yl~-pyrrolidone-2,
1-~6-carboxy-(Z)-2-hexen-1-yl~-5-~3-hydroxy-4-(4-methyl-
phenoxy)~(E) 1_buten-1_ylJ_pyrrolidone_2~
1-~6-methoxycarbonyl-(Z)-2-hexen-1-yl~5-~3-hydroxy-4-(4-
chlorophenoxy) (E) 1_buten-1_ylJ_pyrrolidone_2,
1-~5 methoxycarbonyl-(Z) 2-penten-1-yl~-5-~3-hydroxy-4-(4.
methoxyphenoxy)-(E~ buten-1-yl~-pyrrolidone-29
1-~6 methoxgcarbonyl-(Z)-2-hexen-1-yl~-5-~3-hydroxy-4-(4-
phenoxyphenoxy)-(E)-1-buten-1-yl~-pyrrolidone2~
1-l6-ethoxycarbonyl-(Z) 2-hexen-1-yl~-5-~3-hydroxg-4-(4-
chloropheno~-phenoxy)-4-meth~l-(E)-1-buten~1 yl7~pyrrolidone-2,
1- ~-ethoxycarbonyl-(Z)~2-hexen-1-yl~-5 ~-hydroxy-4-(3
chlorophenoxy)-(E)-1-buten-1-yl~-pyrrolidone-2,
1 ~6-iso-propoxycarbonyl-(Z)-2 hexen1-yl~-5-~3-hydro~y-4-
(2-chloro-4-methyl-phenoxy3-(E)-1-~buten-1-yl~-pyrrolidone-2,
1-L6~me~hoxycarbonyl-(Z)-2-hexen-1-yl~-5-~3 hydroxy-4-
benzyloxy-(E)-1-buten-1-ylJ-pyrrolidone-2~
1- ~-ethoxycarbonyl-(Z)-2-hexen-1-yl~-5-~3-hydroxy-4-(5-
methyl-3-thienylo~y)-(E)-1-buten-1-yl~-pyrrolidone-29
1-~6_ethoxycarbonyl-(z)-2-hexen-1-ylJ-5-~3-hydroxy-4-(4;5-
dimethyl-3-thienyloxy)-(E)-1-buten-1-yl~ pyrrolidone-2,
~ ethoxycarbonyl-(Z)-2-penten-1-yl~-5-~3-hydroxy-4-(4-
fluorobenzyloxy)-(E)-1-buten-1-ylJ-pyrrolidone-2i
1-~6-carboxy-(Z)-2-hexen-1-yl~-5-~3-hydroxy-4-(3~trifluoro-
methylbenzyloxy)-(E~-1 buten 1-yl~pyrrolidone_2,
1-~6-n hexgloxy-(Z)-Z-hexen-1 yl~-5-~3-hydroxy-4-(4-methoxy
29 benzyloxy) (E)-1-buten-1-ylJ-pyrrolidone-2,
- ~3 -
: `
HOE 75
~ ~ S~5
1-~6-carboxy-(Z)~2-hexen-1-yl~-5-~3-hydro~J 4-(2chloro~
4-methyl~benzyloxy)-(E) 1-bu~en~1~yl~-pyrrolidone-2~
1 ~6-carboxy-(Z)-2-hexen-1-yl~-5- ~ -hydroxy-7-trifluoro-
m~thyl-(E)~1 hepten-1-yl~-pyrrolidone-2,
1-~6-methoxycarbonyl (Z) 2-hexen~ ylJ-5-~3-hydroxy-5-
cyclopentyl-(E)-1-penten-1-yl~-pyrrolidone-2,
1~ methoxycarbonyl-(z)-2-hexen-1-ylJ-5~ hydroxy-4-
cycloheptyl-(E) 1-buten-1-yl3-pyrrolidone-2,
1-[6-ethoxycarbonyl-(z)~2-hexen_1-ylJ-5-~3-hydroxy 4-(4-
chlorophe~yl)~(E)-1-buten-1-yl~-pyrrolidone-2,
1-~6-n-butox~carbonyl-(Z)-2-hexen-1-yl~-5-~3-hydroxy-5
(3,4 dichlorophenyl)-(E)-1-penten-1-yl~pyrrolidone-2,
1-~6_carboxy-(Z)-2_hexen-1 y ~ -5-~3-hydroxy-5-(4-toluyl)-
(E)-1-penten-1-yl~-pyrrolidone-2,
1-~6 methoxycarbonyl-(Z)-2-hexen-1-yl]-5-~3-hydroxy-4-(5-
methyl-~-thienyl) (E)-1-buten-1-y ~-pyrrolidone-2,
1-~6 carboxy-(Z)-2-hexen-1-yl~--5 r3-hydroxy-4, 4-dimethyl-
5-(4-methoxyphenyl)-(E)-1~penten-1-yl~-pyrrolidone-2,
1-~6 n-butoxycarbonyl-(E)-2-hexen-1-yll-5-L3-hydroxy-(E)-1-
octen-1-y ~ -pyrrolidone-2,
1-~6-n-hexyloxycarbonyl~(E)-2 hexen-1-ylJ-5-~3-hydroxy-(E)-
1-scten 1-yl~ pyrrolidone-2,
1 f5-ethoxycarbonyl-~E)-2-penten-1-ylJ-5-f3-hydrox5r-(E)-1-
octen-1-yl~-pyrrolidone-2~
1 ~7-ethoxycarbonyl-(E)-2-hepten-1-yl~-5-L3-hydroxy-(E)-1-
octen-1-yl~-pyrrolidone-2,
1 ~6-methoxycarbonyl-(E)-2-hexen-1-yl~-5-~3-hydroxy-(E)-1-
hexen-1-yl~-pyrrolidone2
29 1-~6-methoxycarbonyl-(E)-2-hexen;1-ylJ-5-~3-hydro~y-(E)-1
- - 34 -
. .
., . ~ ... .. .. . : ,
HOE 75/F 169
~8~ 5i~
undecen-1-y ~ -pyrrolidone-2~
1-L6-methoxycarbonyl-(E)-2-hexen-1-yl~-5- ~ -hydroxy-(E,~,E)-
1,4,6-octatien-1-yl~-pyrrolidone-2,
1-L6-methoxycarbonyl-(E)-2-hexen-1-ylJ-5-L3-hydroxy-4-methyl-
(E) 1-penten-1-ylJ-pyrrolidone-2~
1-L6~carboxy-(E)-2~hexen-1-yl7-5-~3-hydroxy-3-cyclopentyl-
(E~ buten- pyrrolidone-2~ . .
-r6-ÇarboA~y- (E) -2-hëxen-1-yl 7'-5~ hydroxy-3-cyclohexyl-
~E)-l-buten-l-yl 7 pyrrolidor~e-2 ~
1- r 6-methoxycarbonyl-(E)-2-hexen-l-yl7-5-/ 3-hydroxy-5-ethoxy-
(E)-1-penten-1-yl 7-pyrrolidone~-~2,
1-/ 6-n-hexyloxycarbonyl-(E)-2-he~en-1-yl /-5- r3-hydroxy-6-
methylmercapto-(E)-l-hexen-l-yl-7-pyrrolidone-2~
1- C 6-~arboxy-(E)-2-hexen-~-yl 7-5-/~3-hydroxy-5-isobutyloxy-
4,4-dimethyl-~E)-1-penten-1-yl ~-pyrrolidon~2 ,
~- r 6-carbo~y-(E~-2-hexen-1-yl_7-5-/ 3-hydroxy-5-allylmercapto-
4,4-dimethyl-(E)-l-penten-l-yl 7-pyrrolido~e-2~ '
~-/ 6 carboxy-(E)-2-he~e~-1-yl ~--5-/ 3-hydroxy-4-(4-methyl-
phe~oxy)-tE)-1-buten-1-yl 7-pyrrolidone~2~
- 1 ~ 6-~ethoxycarbonyl-tE)-2-hexen-1-yl 7-5-/ 3-hydroxy-4-(4- chlo~henoxy)-(E)-1-buten-1-yl_~ pyrrolidone~2,
1~ 5-methoxycarbonyl-(E)-2-penten-1-yl 7-5 / 3-hydroxy-4-(4-
methoxypheno~y)~ buten-l_yl 7-pyrrolidone-2~
l- r6-~ethoxycarbonyl (E)-2-hexen-1-yl 7-5- r3-hydroxy-4-(4-
phenoxypheno~y)-(E)-l-buten-l-yl-7-pyrroiidone
1-/ 6-ethoxycarbonyl-(E)-2-hexen-l-yl ~-5-~ 3-hydroxy-4
chlo~phenoxy-phenoxy)-4-methyl-(E)-l-b~ten-1-yl 7-pyrrolidone_~
1-/ 6-èthoxycarbonyl-(E)-2-he~en-l-yl-7-5-/ 3-hydroxy-4-(3-
chlo~henoxy)-(E)-1-buten-1-yl 7-pyrrolidonè~2,
1-/ 6-i~o-Propoxycarbonyl-~E)-2-hexen-1-yl 7-5-/ 3-hydroxy-4-
(2-chlo~4-methyl-phenoxy)-(E)-1-buten-1-yl_/-pyrrolidone-2,
29 1-/ 6-~bthoxycarbonyl-(E)-2-hexen-1-yl_7-5--r3-hydroxy-4- -
- 35 -
" ~ ~
.,,, : .~' ~ . .. : . .
., ., . : ~
,, . :,.. ~:: :,:
benzyloxy-(E}~ uten-l-yl-7-pyrrolidone-2~
1-~ 6-ethoxycarbonyl-(E)-2-hexen-1-yl 7-S-/ 3-hydroxy-4-(5-
methyl-3-thi~nyloxy)-(E)-1-buten-1-yl_7-pyrrolidone~2,
- 1-~6-~thoxycarbonyl-(E)-2-hexen-1-yl_7-5-r3-hydroxy-4-(4,~-
~ dimethyl-3-thienyloxy)-(E)-1 buten-1-yl 7-pyrrolidonæ-2,
- .
1-/ s-ethoxycarbonyl-(E)-2-penten-l-yl 7-5-/ 3-hydroxy-4-(4-
f luo~benzyloxy- (E) -1-bu ten-~ -yl 7-pyrrolidone-2-~
1-/ 6-carboxy-(E)-2-hexen-1-yl ~-5- r3-hydroxy 4-(3-trifluoro_
Dlethylbenzyloxy)-(E)-1-buten-1-yl 7-pyrrolidone~ 2,
~.- r~-n-hexyloxy-(E~-2-hexen-1-yl /-5-/ 3-hydroxy-~-( 4-me th o~y-
benæyloxy)-(E)-1-buten-1-yl 7-pyrrolidone-2 ,
1-/ 6-~rboxy-(E)-2-hexen-1-yl 7-5- r3-hydroxy-4-~2-chlor-4-
methyl-benzyloxy)-(E)-1-buten-1-yl 7-pyrrolidone_2s
1- f 6--~rboxy-(~)-2-hexen-1-yl 7-5-/ 3-hydroxy-7 tri~l~o~o-
~ethyl-(~)-1 hepten-l-yl ~-pyrrolidone-2~
1~ 6-:~2thoxycarbonyl-(E)-2-he~en 1-yl 7-5-/ 3-hydroxy-5-
cyclopentyl-(E)-1-penten-1-yl 7-pyrrolidone-2~
1-¢ 6-m:ethoxycarbonyl-(E)-2-hexen-1-yl 7-5-/ 3-hydroxy-4-
cy¢loheptyl-(E)-l~b~ten-~-yl 7-pyrrolidone-2,
1-/ 6-etho~ycarbonyl-(E)-2-hexen-1-yl_~-5-/ 3-hydroxy-4-(4-
chlo~henyl~-(E)-l-buten-l-yl 7-pyrrolidone~2~
1-r6-n-butoxycarbonyl- (~ 2-hexen-1-yl_7-5-/ ~-hydroxy-5-
(3, 4 -d i ch lo~heny l) - (E) -1 -penten-1 -y l_7'-pyrrolidone--2,
1-r6~arboxy-(E)-2-hexen-1-yl_7-5-/ 3-hydroxy-5-(4-toluyl)-
~E~-1-penten-1-yl 7-pyrrolidone-2,
1-/ 6~ethoxycarbonyl-(E)-2-hexen-1-yl_/-5-~ 3-hydroxy-4-(5-
metl~yl-3-thienyl)-(E)-l-buten-l-yl-7-pyrrolidone-2~ and
l~r~6-carboxy-(E)-2-hexen-1-yl_7-5-/ 3-hydroxy-4,4-dimethyl-
5-(~-methoxyphenyl)-(E)-1-penten-1-yl_7-pyrrolidone~2-
2~
,.
- 36 -
,
,, . . -
- , , ,: ~ ,
The compounds o~ the invention are disti~guished by an ac-
tivity which ls both spasmogenic and spasmolytic~ for~ example
they ha~e bronchodilatatory and antihyper~e~sive properties~
they are able to inhibit the secretion of gastric ~uice and
ha~e abor-tive e~ectsO m ey may ~here~ore be used as drugs.
m e compounds of ~ormula I may be employed as ~ree acids,
i~ the ~orm o~ the physiologically acceptable inorganic or
orga~ic salt thereo~ or as est0rs of aliphatic, cyclsaliphatic
or araliphatic alcohols.
As lnorg~n$c salts, there may be used, for example, alkali
metal salts, alkaline earth metal salts or ammonium salts; for
a ~ormation of salt~ with organic bases 9 there are used bases
derived from primary9 secondary or tertiary amines which may
contain ~urt~er~hydrophilic groups~ for example salts with
methyl, tri~thyl~ be~zyl~ phenylethyl, allyl amine or also with
plperid~ne, pyrrolidine, morpholine or with ethanol amine, tri-
ethanol ami~e~ tr~methamine; as esters, there are preferably
u~ed esters o~ lower allphatic alcohols, such as methyl, ethyl,
propyl~ butyl or hexyl ester, and be~zyl ester.
m e acids and salt~ or esters may be admi~istered in the
~orm of the aqueous solutions or ~uspensions thereof or also in
a ~olution or suspension ~n pharmacologica~ly acceptable or-
ganic solvents~ such as mono- or polyhydric alcohols~ ~or ex
ample ethanol, ethylene glycol or glycerol; oils~ for example
sun~lower oil or castor oil; ethers, ~or example diethylene
glycol dimethyl ether9 or polyether~ for example polyethylene
glycol, or even in the pre~ence of other pharmacologically ac-
ceptable polymer carrlers, for example polyvinyl pyrrolidone.
29 ~harmaceutical compos~tions are the usual galenic ln~usion
- 37 -
,.. . . . . .... .
.~ ,. .
,.,. . ;. , .
.. .
., .
HOE 75/F 169
~ 8
or injection solutio~s as well as tablets, and locally ad~
ministerable compositions, such as creams, emulsions, suppo-
sitories and especially ~prays.
The compounds of the invention are dissolved, if intended
for use as sprays, in the usual, physiologically acceptable sol-
vents which do not irritate the taste, for example water or etha-
nol, or they are suspended for instance in lower alkyl esters of
higher fatty acids, such as myristic acid isopropyl ester, op-
tionally with an addition of surfactants as stabilizexs, for
example sorbitan- or pentaerythritol fatty acld esters, and they
are packaged together with the usual inert propellants in spray
containers. The said compositions may, however, als be admini-
stered using a conventional spraying de~ice operated by compres-
sed air.
The new compounds may ~urther be used in combination with
other active l~gredients, amo~g wllich the ~ollowing compounds
may be e~pecially me~tioned:
Dluretic~g ~or example Furosemide~ antihyperglycemics, for
example glycodiazi~, tolbutamide, glibenolamlde, phen~ormin,
bu~orming met~ormin, or circulatory agents i~ the broadest
~ense of the term, ~or example ~ardiovascular-dilatatory agentsg-
such as ¢hromonar or prenylamine, antihypertensive agents, such
as reserpinj ~-methyl-dopa or clonidine~, or a~ti-arrhythmicsJ
antihyperlipidemic agent3 or geriatric~, and other compositions
acting on the metabolism, psychopharmaceutlcals, ~or exam~le
chlorodiazepoxide, diazepam or heprobamate, as well as vitamins,
or other pros~agla~dins or prostaglandin like compounds and
prostaglandin antag.onis~O
29 For the va~ious possible indications, the following dosage
- 38 -
: ','~ ~- ' .
HOE 75/F 169
units and daily dosage units are considered re~pectively:
~ Bronchidilatory effect (as a spray):
Dosage unit: 0.3 to 3,000 ~g~
preferable unit: 3 to 600 ~g~ (per spray shot~
daily dosage unit: 0.3 to 30 mg
Antihypertensive effect:
Dosage unit: 5 to 5,000 ~g
preferable u~it: 5 to 500 ~g parenteral (i.v.)
daily dosage unit: 5 to 50 mg
oral administration:
dosage unit: 1 to 100 mg
preferable unit: 1 to 50 mg oral
daily dosage unit: 10 to 500 mg
The dosage units administerecl against gastro-intestinal
tu~bulances correspond to those mentioned for the use as anti-
hypertensive agen~s.
The compounds of the formulae III, IV, YI, VII, VIII, IX,
X, X , XIII, XIV, XV, XVI, XVIII~ XIX, XX, XXI9 XXII, XXIII,
XXIV~ XXV, XXVI, XXVII and XXVIII are ~aluable intermediates
~or the ma~ufacture o~ the compounds o~ formula I.
The ~ollowing Examples illustrate the invention.
aI) 1-ethoxycarbonyl-5-hydroxymethyl-pyrrolidone-2 (III)
0.25 Mol o~ 5-hydroxymethyl-pyrrolidone-2 were dissolved
in 150 ml of dried dimethyl sul~oxide9 and 0.3 mol of
pota~sium hydroxide powder was added. While cooling with
ice, 0.3 mol of chloroformic acid ethyl ester was added
: _ 38a_
. ::: : .. . :. . .: . ,:,
, -, : '. ' . .
. , : :. : ,. -: : . ,.. . :
~ 8 ~ 5~
dropwise withln 30 minute ~ Stirring was continued for
2 hours D whereupon the reaction solution Is temperature
rose to room temperature. Water was added,and the product
- was extraoted with ether~ dried, conoentrated and dis-
tilled.
Boiling point under a pre~ure of 0.5 mm Hg: 171 - 178C.
b~ ethoxycarbo~yl 5 formyl-pyrrolidone-2 (IV)
00075 mol o~ chromium(~I) oxide was added to 0~15 mol of
. pyrldine in 160 ml of methylene chloride, and the mixture
wa then stirred ~or 15 minutes at room temperature. It
was cooled to 0C, 0.01 mol o~ 1-ethoxycarbonyl-5-hydroxy-
methyl-pyrrolidone-1 a~ a solution in 40 ml of methylene
chloride ~a~q added~a~d stirring was continued for 40
minutes while cooling with ice. 0.3 Mol o~ sodium bi-
~ul~ate mo~ohydrate powder was added, and stirring was
co~inued for 30 mlnute~ whi:le cooli~g with ice. The
product was suction-~iltered, dried with sodium sulfate,
and concen-trated i~ vacuo at 5 - 10C. The crude 1-ethoxy-
carbonyl-5-formyl pyrro1idone-2 could be used without
~urther purification for the next reaction step.
cI~ (VI)
1) 1-Ethoxycarbonyl 5-(3-oxo-(E) 1-octen-1 yl)-pyrrolidone-2
0.0~3 Mol of sodium hydride wa~ added to 0.03 mol of di-
methyl~2-oxoheptyl-phosphonate in 140 ml of absolute di-
methoxy-ethane9 and the suspension was ~tirred for 105
hours at room temperature. Then, 0.03 mol of 1~ethoxy-
carbonyl-5-formyl-pyrrolidone~2 as a solution in 10 ml of
dimethoxy-ethane was added, and stirring was co~-ti~ued
29 for 2.5 hours at room temperature. The product was
~ 39 -
i9
neutralized with glacial acetic acid and concen~rated~ The
residue was chromatographed on silica gel with chloroform/
ethyl aoetate (4 : 1~ as an elue~t.
NMR spectrum at ~= 6~0 - 7.0 ppm (m) CH-CH-CH-II 2 prot~
5 . 0
Accordingly, the-~ollowi~g compounds were ~ynthesized as
above:
2) 1-Ethoxyoarbonyl 5 (3-oxo-4 9 4-dimethyl-(E)-1-octen-1-yl)-
. pyrrolidone-2
~MR spectrum: ~= 6.0 - 7.0 ppm (m) CHAC~-CH-II 2 prot.
~_ oOg ppm (s) C(CH3)2 6 prot.
3) 1-Ethoxycarbonyl-5~ oxo-494-dimethyl-5-ethoxy-(E)-1-
penten-1ryl)-pyrrolidone-2
NMR spectrum: ~a O.95 ppm (~) C(CH3~2 6 prot.
= 3.3 ppm (s) 2 prot. ` ~
~ = 3.5 ppm (q) 2 prot.
4~ 1-Ethoxycarbo~yl-5-L3-oxo-4-(3~tri~luoromethyl-phenoxy)-
(E)-1-buten-1-yl~-pyrrolidone-2
~MR spectrum: ~- 4.7 ppm (s) CH2-0- 2 prot.
~= 6,9 - 7.8 ppm (m) aromatic prot. 4 prot.
dI~ (VII)
1) 1-Ethoxycarbonyl;5-(3-hydroxy-(E)-1-octen-1-yl)-pyrro-.
lidone 2
0.2 Mol o~ anhydrous zinc chloride were suspended in 300 ml
29 of dimethoxy ethane~ ~nd 0.8 mol o~ sodium boron hydride
_ ~0
. .
.. ...,, .
. ~ .
. ~
' ' .. :. ; ~ . ,
. . ~.
HOE__~5 ~
was added cautiously. The mixture was then stirred for 1
hour at room temperature, ~iltered~ and 0008 mol of
1-ethoxy-carbo~yl-5-(3-oxo-(E)-1-oct~n 1-yl) pyrrolidone-2
in 50 ml of dimethoxy-ethane was added dropwise with~n
10 minutes to the so-obtained solution3 and stirring was
continued ~or 2.5 hourx at room temperature. ~he solution
wa~ acidified with glacial acetic acid, concentrated, and
the residue was chromatogr~phed on silioa gel with chloro-
~orm/methanol (95 : 5) a~ the eluent.
N~IB: ~ = 5 9 3 - 5~8 ppm (m) CN=CN 2 prot.
In the same manner, the following compounds were syn- ` _
the~ized ~rom the substances mentioned sub cI 2,3 9 4:
2) 1-Ethoxycarbonyl~.5~(3-hydroxy4,4-dimethyl-(E)-1-octen-1-
yl)-pyrrolidone 2
NMR: S = Og9 ppm (s) CtCE3)2 6 prot.
~ = 5,3 - 5,8 ppm C =~H 2 ~rot.
.. ~
thoxycarbonyl-5-(3-hydroxy-4,4-dimethyl-5 ethoxy-(E)-
1-rpenten-1oyl)-pyrrolidone-2
NMR: = 0,93 ppm (s) C(C ~ )2 6 prot.
= 5,2 - 5.? ppm (m) CH=CH 2 prot.
4) 1-Ethoxycarbonyl5-~3-hydroxy-4;(3-tri~luoromethyl-phen
oxy)-(E)-1 buten-1-yl)¦-pyrrolidone-2
NMR: 5 4,65 ppm (s) CH2-0 2 prot.
= 5,25 - 5,7 ppm (m3 CH--CH 2 prot.
~ 41 -
,
' '' ,'' ~ ' ' ~ -
~L~
eI: (VIII)
- 1) 5-(3-Hydroxy-(E)-1-octen-1-yl)-pyrrolidone-2
0.05 Mol of 1-ethoxycarbonyl-5-(3-hydroxy-(E)-1-octen-1-
yl)rpyrrolidone-2 were sus~ended in 100 ml o~ 0.5 N hydro-
chloric acid9 and the suspension was then heated to 75 -
80C for 3 hoursO A~ter oooling~ the suspension wa~ ex-
tracted with ether, dri~d and concentrated. Chromato-
graphy on ili a gel with chloroform/methynol (9 : 1) was
indicated ior purification purposes.
IR spectrum: l680 cm~l V~=0
NMR spectrum: S = ~j3 - 5~ ppm (m) _ -CH. 2 prot.
In an analogou~ manner, the following compounds were syn-
thesized ~rom the substancees cited sub dI 2,3,4:
2) 5-(3-~ydroxy-4,4-dimethyl-(E)-1 octen-1-yl~-pyrrolidone-2
IR: l680 cm l ~ C-0
= OL9 ppm (s) C(C:~)2 6 prot.
S = 5 3 - 5~8 ppm (m) CH=CH 2 prot.
3) 5-;(3-Hydroxy-474-dimethyl-5-ethoxy-(E)-1-penten-1-yl)-
pyrrolidone-2
IR: 1~80 cm VC=0
NMR: S =~ 0i94 ppm (s) C(~H3)2 ~ prot.
~ = 5.25 5.75 ppm Im) C~=CH 2 prot.
4) 5-~3 Hydroxy-4~ tri~luoromethyl-phenoxy) (E) 1-buten-1-
yl3-pyrrolidone 2
IR: 1680 cm l ~C=0
NMR: ~ = 4c6 ppm (s) CH~-0 2 prot.
S ~ ~,9 - 7,8 ppm (m) aromatic prot~ 4 prot.
. . ..
42 r
;~'' ,.,"" " ' i ,
aII) 5-Formyl-pyrrolidone~2 (IX)
This product was prepared by oxidation of 5-hydroxy-
methyl-pyrrolidone-2 as described sub ~bI). .
The 5~ormyl-pyrrolidone-2 thus prepared was used with-
out ~urther purification ~or the following step.
N~IR: S = 9~ pp~ C~I0 ~ protO
bII) (X~
1) 5-(3~0xo~(E)-1~octen-1 yl)-pyrrolidone 2
This product was obtained by reacting 5-formyl-pyrrow
lidone-2 with dimethyl-2~oxo~h~ptyl-phosphonat~ ac-
cordi~g to (cI).
N~ 6.0 - 7,0 pp~ ~m) _=CH-C 2 prot.
2) Accordi~gly, the same reaction yielded the 5-f3-oxo-4-
(3-trifluoromethyl-phenoxy)-butenw1-yl~-pyrrolidon~-2
~rom 5 ~ormyl~pyrrolidone-2 and dimethyl-~2-oxo-3-(3-tri-
fluoromethyl-pheno~y)-propyl~ phosphonate according to
(I)-
N~: S = 4~65 ppm (s) ~ -~ 2 prot.
S ~ 6..9 - 7,75 ppm (m) aromatic prot. 4 prot.
b~ 5-(3~0xo-;(E)-1-o~ten-1 yl)-pyrrolidone-2 (X)
This product was obtained ~rom 1-ethoxycarbonyl-5-(3-oxo-
(E)-1-octen~1-yl~-pyrrolidone-2 by a reaction according
to (eI)-
The ~pectroscopical data were identical with those of
the derivative prepared sub (bII) 1).
- ~3 ~
:: , , ,
., , :,
. . .
. .: ;
. . .
~s~
c~ (VII~)
- 1) 5-(3-Hydroxy-(E)-1-octen-1-yl)-pyrrolidone-2
T~is product was prepared by reducing 5-(3-oxo-(E)-1-
octen-1-yl)-pyrrolidone-2 according to dI).
In the same manner, there were prepared:
2) 5-~3-Hydroxy-4~(3-trifluoromethyl-phe~oxy)-buten-1-yl~-
pyrrolidone-2 by reducing the 5 ~3-oxo-4-(3-tri~luoro-
methyl-phenoxy ~-buten-1~yl~-pyrrolidone-2.
The spectrometrical data of the two compounds were
identical with the co~pounds prepared according to
eI 1) and e~ 4).
E X A M P L E 2:
Compounds of the general ~ormula I
aI) : (XI)
1) 5-~3-(tetrahydropyran-2=yl oxy)-(E)-1-octen-1 yl)~
pyrrolido~e-2
0.1 Mol of 5-(3-hydroxy-~E)-1-octen-1-yl)-pyrrolidone-2
together with 0.15 mol of dihydropyra~ and 0.25 mol o~
p~tolue~e-sulfonic acid in 1~0 ml of dioxan were re-
flu~ed for 4 hours. The acid was then neutralized by
means o~ triethylamine, and the ~olvent wa3 eliminated by
distillation i~ ~acuoO
~hromatography was carrled out on silica gel with
chloro~orm/ethyl acetate (4 : 1) as the eluent.
N~= 5~3 - 5,7 ppm (m) CH=CH 2 prot.
~ =r~3 ppm ~m~ 0-C~I-0 1 prot.
IR:1680 cm 1 ~CzO
29
-- ~4
H~/~
51~5~
The tetrahydropyranyl ether protective group was intro-
duced into the alcohols underlying the ~ollowing com-
pounds in an analogou~ manner. There were obtained:
2) 5- ~ -(tetrahydropyran-2-yloxy)-4,4-dimethyl-(E)-1-octen-
1-yl)~-pyrrolidone-2
N3~: ~ = 0.9 ppm (s) C~C~ )2 6 prot.
I~: l680 cm ~ ~o
3) 5 t3-(tetrahydropyran-2-yloxy)-4 9 4-dimethyl-5-ethoxy-
(E) 1-penten~1-yl~-pyrrolidone-2
NMR: S = 0~94 ppm (s) C(CH3)2 6 prot.
S 3 3..3 ppm (s~ C~2 0 ~ prot.
~ = 3,46 p~m tq) -CH2 2 prot.
4) 5~3-~tetrahydropyran-2-yloxy)-4-(3-trifluoromet~
phenoxy)-(E)-1~buten-1 yl~-pyrrolidone-2
NMR: ~ Y 4,7 ppm (s) ~ -0 2 prot.
~8 6,9 - 7,8 ppm ~m~ o~atic prot. 4 protO
IR: l680 cm 1 ~C=0
bI: (XIII)
1) 1l(6Methoxycarbonyl-(Z)-2-hexen-1-yl~-5-l3 ~tetrahydro-
pyran-2-yloxy)-(E)-1-octen-1-yl~-pyrrolidone-2
This product was obtained from 5 ~(tetrahydropyran-2-
yloxy)~(E)-1-octen 1-yl~-pyrrolidon~-2 by alkylatio~
with 6-bromo-(Z)-4-hexen-1-yl-carboxylic acid methyl
ester u~der the conditions men~ioned for Example 1 aI.
. - 4~ _
` .
.
.
.. :. .
.. .. . ..
~85~35~ ~ Z~
N.~R S ~ 5~3 ~ 5.~ ppm (m) CH=CH 4 prot.
3.7 ppm (s) COOC~ 3 prot.
-IR: 1680 cm ~ C=O
~35 c~ l V C-O ~.
2~ 1-(6-Ethoxycarbonyl-(Z)-2-hexen-1-yl) 5-~3-(tetrahydro-
pyran 2-yloxy)~4~4-dimethyl-(E3-1-octen~1-ylJ-pyrro- '
lidone 2
Thi~ product was obtained as in Example 1 aI ~rom 5-/3-
(tetrahydropyran~2-yloxy)-4,4~dimethyl (E~ octen-1-yl~-
pyrrolidOne-2 and 6-bromo-(Z)~4-hexen-1-yl~carboxylic acid
ethyl ester.
NMR: ~= 5~3 - S,8 ppm (m) CH=CH 4 prot.
~= o~9 ppm (s) C(CH3)2 6 prot.
IR: l680 cm l ~C=O
1740 cm~~ ~C=O
3) 1-(6-methoxycarbonyl_(Z)_2-hexen-1-yl)-5-~3~(tetrahydro-
pyran-~-yloxy~-4,4 dimethyl-5-ethoxy-(E)-1-penten-1-ylJ-
pyrrolidone 2
m e product was obtained in a man~er analogous to
Example 1 aI from 5-~3 (tetrahydropyran-2-yloxy~-4,4-di-
methyl 5-ethoxy~(E)-1-penten-1-ylJ-pyrrolidone and
6-bromo-(Z)-4-hexen-1-yl-carboxylic acid methyl ester.
NM~: ~ = 0,9 ppm (s) C(C ~)2 6 prot.
~ ~ 3~7 ppm (s) C~O ~ ~ pr~t.
IR: 1680 cm l ~ C=O
1735 cm l V C=O
- 46 -
.. . ; ,, ~,,, ,. . .
. . ..
'. : . .. . . :.. .
.. ..
HOE ?5 /F 169
~ ~ 5~
4) 1-(6-Ethoxycarbonyl-(Z)-2-hexen 1-yl)-5- ~ -(tetrahydro-
pyran-2-yloxy)-4-(3-tri~luoromethylphenoxy)-~E)-1-buten-1
yl~- pyrrolidone-2
The product was obtained in a manner analogous to Example 1
aI ~rom 5-~3-(tetrahydropyran-2-yloxy)-4-(3-tri~luo~omethyl-
ph~noxy)-(E)-1 buten-1-ylJ-pyrrolidone-2 and 6-bromo-(Z)-4-
he~en-1 yl-carboxylic acid ethyl ester.
~NR: ~ = 5~2 5,7 ppm CH-CH 4 prot.
IR: 1680 cm l ~ C=O
1~30 cm~l ~C=O
.... .. ~ _ _ . .. . .
5) 1-(6-M~thoxycarbonyl (E)-2-hexen-1-yl)-5~-~3-(tetrahydro-
pyran-2-yloxy)-(E)~1 -octen-1 -yl3- pyrrolldone-2
m is product was obtained ~rom 5-~3-(ketrahydropyran-2-
yloxy) (E)-1-octen-1-yl)~-p~rrolidoner2 by alkylation with
6 bromo-(E) 4-hexen-1-yl-carboxylic acid methyl ester
according to the conditions :mentioned in Example 1 aI.
~R: ~ = 5.3 - 5~8 ppm (n~ CH=CH 4 prot.
~ = 3.7 ppm ~s) COO ~ 3 prot.
IR: l~æO ~m l ~ ~=0
1735 cm l ~ C=O
6) 1 (6-Ethoxycarbonyl-(E)-2-hexen-1-yl)-5-~3-(tetrahydro-
pyran-2-yloxy~-4,4Ddimethyl-(E)-1-octen-1 yl~-pyrro,
lidone-2
The product was obtained in a manner analogous to Ex-
ample 1 aI ~rom 5-L3-(tetrahydropyran 2 yloxy)-4,4-di-
methyl-(E)-1-octen-1-ylJ-pyrrolidone-2 and 6-bromo-(E)-4-
hexen~1 ylcarboxyllc acid ethyl ester,
- 47 -
.,
. ~ ~
:: -. ~: ...... . .
. ~ :: . :. .
~ 1~,
l~D8a ~1~5~9
N~R~ 5.3 ~ pm ~ CH=CH a prot.
0~9 ppm~s) ~(CH3) 2 ~ protO
IR: 1680 cm ~ ~1) C =0
173 5 cm~l . V CzO
c~
1) 1-(6-Methoxycarbonyl-(Z)-Z~hexen-1 yl)-5-(3-hydroxyl)-
(E)-1-Qcten-1-yl)-pyrrolidone 2
O.05 Mol of 1 (6-m~thoxycarbonyl-(Z)-2-hexen-1-yl)-5-~3-
5tetrahydropyran-Z-yloxy)-(E)-1-octen 1-yl~-pyrrolidone-2
were stirred in 100 ml o~ 1 % methanolic oxalic acid ~or
4 hours at room temperature and then ~or 4 hours at 40C.
The acid was neutralized with triethylamine, and the
reaction mixture was concentrated. Purification wa~
carried out by chromatography on silica gel u~ing toluene/
ethyl a~-etate/meth2nol (5 D 4 : O . ~ ) ~
NMR: S= 5,3 - ~,8 ppm (n~ C~=CH 4 prot
~ = 3, 7 ppm (s) C00~3 3 prot.
IR. .1680 cm 9C~0
1735 cm 1 V C=0
The ~ollowi~g compounds were prepared from the corre-
sponding tetrahydropyran~l ether~ in the ma~ner described
above:
2) 1-(6-Ethoxycarbonyl-(Z)-2~hexen-1-yl)-5-(3 hydroxy-4~4-
dimethyl (E)-1-octen-1~yl) pyrrolido~e-2
N~lR: ~= 5~3 - 5,8 ppm (m) CH--CH 4 prot.
~ = 0 . 9 ppm (s ) C ~ ~3)2 6 prot.
IR: 1680 c~ ~ 1) C =0
1 7 40 cm 1 1) C=t~
-- 48 --
, , ~ , ; , ~ :
3) 1-(6_~ethoxycarbonyl-(Z~-2-hexen-1-yl)-5-(hydroxy-4,4-
- dimethyl-5 ethoxy-(E)-1-penten~1-yl)-pyrrolidone-2
M~R: S= 0,9 ppm (s) C(CH3)2 6 prot.
~ ~ 3 ? 7 ppm (s) C0~ ~ 6 protO
IR: l680 cm l ~C=0
173~ c~ VC=O
4) 1-t6-Ethoxycarbonyl-(Z) 2-hexen-1-yl)-5-~3-hydroxy-4-(3~
tri-fluoromethylphenoxy)-(E) 1-buten-1 ylJ-pyrrolidone-2
NMR: ~ - 5~2 - 5.7 ppm CH=CH 4 prot.
l6B0 cm~l ~ C=0
1730 cm~l ~CzO
. .
5) 1-(6-Methoxycarbonyl-(E) 2_hexen_1-yl)-5-(3_hydroxy (E)-1-
octen-1-yl) pyrrolidone-2
N~R: ~ a 5 ~ 3 ~ 5 ~ 8 ppm (n~ CH--C~ 4 prot.
6 G 3~7 ppm (s) C00 ~ ~ prot.
IR: 1680 cm ~ ~ C=0
l735 cm~~ ~ C=0
6) 1-(6-~thoxycarbo~yl (E)~2-hexen~1-yl)-5-(3-hydroxy-4,4-di
methyl-(E)~1 octen-1-yl)-pyrrolidone-2
N~ = 5,3 - ~,8 ppm (m) C~=CH prot.
~ = 0,9 ppm (x) C(CH3)~ ~ prot.
IR: 1680 cm ~ CzO
1735 cm~l V C=0
aII) 1-(6-Methoxycarbonyl-(Z)-hexen-1-yl)~5-(~-hydroxy-(E)-1-
octen-1-yl~ pyrrol$done-2
Thi product wa~ obtai~ed by alkylating 5-(3-hydroxy (E)
octen-1-yl)-pyrrolidone-Z with 6-bromo-(Z)-4-hexen-1-yl-
- 49 -
.. . ,
; , - .;
. ~ . , ~, ... .
HOÉ 75/F 169
~ ~ 58~
carboxylic acid methyl ester in a manner analogou~ to
Example 1 aI.
The spectroscopical data were identical with those o~ the
compound obtained according to Example 2 CI.
aIII: (XIII9 R = H)
1) 1-(6 Carboxy-(Z)-2-hexen~1-yl) 5~ ~ -(tetr~hydropyran-2-
yloxy)-~E~ ooten-1-yl)~-pyrrolidone 2
This product was obtained from 5-L3-(tetrahydropyran-2-yl-
oxy)~(E)-1 octen-1-yl3-pyrrolidone~2 by alkylation with
6;bromo-(Z)-4-hexen 1-yl-carboxylic acid according to the
conditions me~tioned in Example 1 aI~
~R: ~ = 5.3 - 5,8 ppm (n~ CH=CH 4 prot,
IR: 1680 cm ~ C=O
l705 cm~l ~ C=O
2) 1-(6-carboxy-(E)-2-hexen-1-yl)-5-~3-(tetrahydropyran-2-
yloxy)-(E)-1~octen-1-yl~-pyrro7idone~2
- Thi~ product was prepared from 5 ~3-(tetrahydropyran-2-
yloxy)-~E)-1~octen-1-yl3-pyrrolidone-2 by alkylation with
6-bromo (E)-4~hex~n-1-yl-carboxylic acid according to the
oonditions indicated in Example 1 aI,
N~ = 5.3 - 5~8 ppm (n~ CH=CH 4 prot.
IR: ~680 cm ~ C=O
170~ cm~ ~ C=O
bIII~ R2 = H)
1) 1 (6-Carboxy (Z)-2-hexen~ 5-(3 hydroxy-(E)-1-octen-1-
yl) pyrrolidone-2
This product was prepared from 1~(6 carboxy-(Z)-2-hexenw1-
- 50 -
. . ~ . . ,
;, ,; , ~ . ,;
:...... ~ . .,
.. .
.
~L~
~ 5~
-yl)~5-~3-(tetrahydropyran-2-yloxy)~ (E)-octen-1-yl~-pyrro-
lidon~-2 in a manner analogous to Example 2 cI but using
a mixture o~ 100 ml of ethanol and 50 ml o~ 6 % aqueous
oxalic acid as a reaction medium instead o~ methanolO
NMR: ~= 5,3 - 5,8 ppm (n~ CH=CH 4 prot.
IR: ~680 cm ~ ~ C=0
l705 cm~l ~ C=0
2) 1-(6-Carboxy;(E)-2-hexen-~-yl)-5 ~3-hydroxy-(E)-1-octen-1-
yl~-pyrrolidone-2
Thi~ product wa~ prepared from 1-(6-carboxy-(E)-2-hexen-
1`r~l)~5~3-(I;etrahydropyran-2-yloxy)-(E)~1-octen-1-ylJ
p~rrolidone-2 in a manner analogous to the above con-
ditions.
NMR: ~ = 5, 3 5 2 8 p pm ( n) CH=~ 4 prot.
IR: l680 cm l ~ C-0
1700 c~ =0
a~ (6-Carboxy-(~)-2-hexen-1 yl)-5-(3-h~droxy-4,4-dimethyl- -
5-ethoxy-(E)-1-penten-1-yl)-pyrrolidone-2 (I, R2 = H)
This product was obtained in a manner analogou~ to
Example I aI from 5-(3-hydroxy-4,4-dimethyl-5-ethoxy-(E)
1-penten-1-yl)-pyrrolidone-2 and 6-bromo-(Z)-4 hexen~1-
yl-carboxylic acid~
N~5R: ~ c o,g ppm (s) C(C~3)2 6 prot.
~R: 1680 cm~~ ~C=0
- ~700 cm ~ ~C=0
av) (I)
(6-Methoxycarbonyl (Z~-2 hexen-1-yl)-5 (~-hydroxy~(E)-
- 51 -
.:: . ' : ' !. .
,, :: . .: : ', : '
~ 5
1 oot~n-1 yl)-pyrrolidone-2
0.03 Mol o~ 1-(6-carboxy-(Z)-2~hexen-1_yl)~5-(3_hydroxy-
tE)-1 octen 1-yl)-pyrrolidone-2 was dissolved in 75 ml o~
d.iethyl ether, ~nd an ethereal diazomethane solution was
added until the yellow color remained uncha~ged. Excess
diazomethane was destroyed by mea~q o~ a trace of glacial
acetic acid. The solution was concentrated, and after
elimination o~ all the solvents~ the pure end product
was obtained.
The physiGal data were the same as in Example 2 cI 1).
2) 1-(6 iso-propoxy-(Z)-2-hexen-1-yl)-5-(3-hydroxy-(E)-1-
octen-1-yl ~-pyrrolidone-2
O.02 Mol o~ 1 (6-carboxy (Z)-2 hexen-1-yl)-5 (3-hydroxy-
(E)-1~octen-1-yl)-pyrrolidone-2 were dissolvPd in 40 ml
o~ a 0~5-molar aqueous sodium ~ydroxide solution, and
the ~olution was ~tirred for 14 hours at room temperature.
It was then co~centrated, and the remaining traces o~
water were eliminated under greatly reduced pressure.
The remai~ing residue was dissol~ed in 75 ml o~ dimethyl-
formamide~ and 0.025 mol of isopropyl iodide was added.
Stirring was continu~d for 7 hours at room temperature,
ether and water w~re added, the aqueous phases was ex-
tracted with ether several times~ the organic phases
were united~ dried and conoentrated. Puri~ication was
made by chromatography on silica gel and elution with
toluene/ethyl acetate/iso-propanol ~5 : 4 : 0. 5)-0
NMR: ~ = 5,3 - 5,8 ppm (n~ C~=CH ~ prot.
1,2 ppm (d) C~t ~ )2
~9 IR: 16~0 cm ~ C-0
1730 c~ l ~ C=0
~ 5~ -
, .
- , ~ ',~ ,,"' '
. .
.
~ ~. . ' ' '- .. ' ` ~
~ 5~
aVI 1-(6-Carboxy~(Z)-2-hexen-1-yl)-5-(3-hydroxy-(E)-1 octen-
1;yl)-pyrrolidone-2 (I9 R2 = H)
30 Milliliters o~ a 0~5-molar aqueous sodium hydroxide
solution were added to 0,01 mol of 1-(6-methoxycarbonyl-
(Z)-2-hexe~ yl)-5-(3-hydroxy-(E)~1 octen 1-yl)-pyrro-
lidone-2 9 and the mixture was stirred overnight at room
temperature. It was acidified with dilute hydrochloric
acid~ an~ the aqueous phase was extracted several times
with ether. The residue resulting after drying and con-
centration of the sol~ent could be purified as usual by
chromatography.
The phy~ical data were the same as i~ Example 2 bIII 1).
~b~
Compounds o~ the general formula XIX
aI~ 5-Tetrahydropyran-2-yloxy-methyl-pyrrolidone (XIV~
This product was obtained from 5-hydroxyme~hyl-pyrrolidone
a~d dih~dropyran~ in a manner analogou~ to Example 2 aI~
Puri~ication was made by chromatography on silica gel
with tolue~e/ethyl acetate/methanol (5 : 4 : 1) as an
eluent.
NMR spectrum: ~a 6.5 ppm (broad single peak~ NH 1 prot.
- 4.6 ppm (broadened si~gle peak) 0-CH-0
1 prot.
bI) 1-Allyl-5-(tetrah~dropyran-2-yloxy-methyl)-pyrrolidone-2
(XV)
This product was obtained from 5-(tetrahydropyran-2-
ylo~y-methyl) pyr:rolidone 2 by alkylation with allyl
bromide according to Example 1 aI. Chromatography on
29 silica gel. Eluent: chloroform/aceto~e (8 : 2).
- 53 -
J , ! ' .. . .,
'' , ,',''' . . ' '~ '.i ' .,,;
~ ~ 5~5~ .
NMR ~pectrum: S= 5.0 - 6.2 ppm (several multiple peaks)
CH=CH2 3 pr~t-
~= 4.7 ppm (broadened si~gle peak) 0-CH-0
1 prot.
IR spec~rum: 1680 cm 1 ~ C = O
C~ Formylmethyl-5~(tetrahydropyran~2~yloxymethyl)-pyrro-
lidone-2 (~VI)
0~02 Mol of 1-allyl-5-(tetrahydropyran-2-ylo~ymethyl)-
pyrrolidone-2 was dissol~ed in 100 ml of methylene chloride,
and 10 ml o~ methanol were added. The ~olution was cooled
to -78C, ~nd at this temperature, ozoni~m was passed in
until the blue color of the solution did no longer change.
The reaction mixture was heated to -20C~ At this temper-
ature, 0.2 mol of dim thyl sul~ide was added dropwise.
The cooli~g bath was then remo~ed9 and the reaction mixture -
was ætored for 2 hours at room temperature~ concentrated
and then chromatographed on silioa gel u~ing chloroform/
acetone (8 : 2) as the elu~nt.
NMR: ~ - 9.6 ppm (s) _ O iL protO
~ - 4,6 p~m ~ broade~ed single peak)
dI ) ('XIX)
1) ~w(5-carboxy-(Z)-2~penten-1-yl~ 5-(tetrahydropyran~2-yloxy-
methyl)-pyrrolidone-2
0~1 mol o~ ~odium hydride was stirred in 45 ml of dimethyl
~ulfoxide at 60C until the evolution o~ hydrogen ceasedc
The mixture wa~ then cooled to room temperature and a
~olution of 0.05 mol of 3-carboxy-butyl-triphenyl phos-
pho~ium bromide in 40 ml o~ dimethyl sulfoxlde wa~ added.
- 54 -
.. .
~ ' ,',.''' .: ' ''. ' ' ,' ~
OE 75/F 169
~ 5~
Stirring was continued ~or 30 minutes at room temperature.
Then, a solution o~ 0.02 mol o~ ormylmethyl-5-(te~r~-
hydropyran-2-yloxy~methyl)-pyrrolidone in 25 ml of di-
methyl sul~oxide was added, and the mixture was heated
to 50Co At this temperature~ stirring was continued for
3 hours. A~ter cooling to 10C, 400 ml of water were
added, and the pH was adjusted to 2 by means o~ a 5 %
aqueous sodium bisulfate solution. The ~olution was once
more extracted with ether, dried and concentrated. The
residue was pur~ied by chromatography on silica gel, th~
eluent being chloro~orm/methanol (95 : 5).
NMR: SY 9,Q ppm~~~(br.oad 8'~) COO~ 1 prot.
S - ~, 2 - 5 ~, ppm ~D ) ~ - . ~ prot.
~ ~ 4,62 ppm t broadened ~ingle peak) 0-CH-0 1 prot.
2) 1 (6~Carboxy (Z)-2-h~xen-1 yl) 5-(tetrahydropyran-2-yl-
oxy-methyl)-pyrrolidone-2
The r~action wa~ carried ou~ i~ the above manner ~rom
1-~ormylmethyl--5 (tetrahydropyran-2-yloxymethyl)-pyrro-
lidone 2 and 4-carboxy-butyl_triphenyl phosphonium bromide.
Chromatography on silica gel~ Eluent: chloro~orm/methanol
(95 : 5).
NMR: ~ = 9.~ ppm (broad signal) COOH 1 protO
~D 5~2 _ 5,7 ppm (m) C~5C~ 2 protO
. ~ - 4~6~ ppm ( 4.64 ppm ~broadened single peak)
o-CH-0 1 prot.
3) 1-(7-Carboxy-(Z)-2-hepten 1-yl)-5-(tetrahydropyran-2-yl-
oxy-methyl)~pyrrolidone-2
29 This product was prepared from 1-~ormyl-5-(tetrahydro-
- 55 ~
, . .
~9
~ 35~35~
pyran 2-yloxy-methyl)-pyrrolidone~-2 and 5 carboxy-pentyl-
triphenyl-phosphonium bromide in the a~ove manner.
Chromatography on ~ilica gel, the solYe~t being chloro-
~ ~orm/methanol (95 : 5)0
N~R: ~ - 9.0 ppm ~broad signal~ COOH 1 prot.
= 5Ll ~ ~,8 p~n (m) CH=CH 2 prot.
4960 ppm (s) -0-CH-0 ~ prot.
~R: 1680cm l ~C=0
l700cm~~ ~C=0
aII) 1-(6-Carboxy-(Z)-2-hexen-1-yl)-5-(tetrahydropyran-2-yl-
oxy-methyl) pyrrolidone-2
Thi~ product was obtained from 5-(tetrahydropyran-2-yl-
oxy-methyl)-pyrrolidone-2 by alkylation with 6-bromo-(Z)-
4-hexen-1-yl-carboxylic acid according to the method of
Example 1 aI.
Physioal data see above.
E X A M P L E 4~ -;
Compounds of the general formula XX
a~ (6-Methoxycarbonyl-(Z)-2-hexen-1 yl)-5-(tetrahydro-
pyran~2-yloxy-methyl)-pyrrolido~e 2 (XX~
This product was obtained by esterifying 1-(6-carboxy-(Z)-
2-hexen-~-yl)-5-(tetrahydropyran 2-yloxy-methyl)-pyrro-
lidone 2 with diazomethane according to Example 2 aV 1).
~hromatography on silica gel, the solvent being carbon
tetrachloride/acetone (7 : 3).
NMR: ~ ~ 50lS - 5~0 ppm (m) CH=~H 2 prot.
~ ~ 4,7 ppm (broad single peak) 0-CH-0 1 prot.
IR: l680 cm ~ C=0
l~35 cm l ~C=0
56
.. . ..
. : ' , ; ~ :
.. ~ .
~ 3~
aII) 1-(6-Methoxycarbonyl-(Z)~2-h0xen-1~yl)-5-(tetrahydropyran-
2 yloxy-methyl) prrrolidone-2 (XX)
This product was obtained from 5-(tetrahydropyran-2~yl-
o~y-methyl~-pyrrolidon~-2 by alkylation with 6-bromo-(Z)-
4-hexen-1-yl carboxylic acid methyl ester according to
~xample 1 aI.
The phy~ical data were the same as indicated above.
Compounds of the general ~ormula XXI
aI) 1-(6-Methoxycarbonyl ~Z)-2-hexen-1 yl)-5 hydroxy methyl-
pyrrolidone-2 (XXI)
0.01 Mol of 1(6-methoxycarbonyl-(Z);2-hexen1-yl)-5-
tetrahydropyra~-2-ylo~y-methyl)-pyrrolidone-2 was dis-
solved in 50 ml of methanol, and the solution was re-
~luxed together with a ~ew grains of p-toluene sulfonic
acid for 3 hoursO A drop o~ triethylamine was added to
neutralise the acid9 the solution wa~ conoentrated and
chromatograph~d on silica gel using toluene/ethyl acetate/
methanol (5 : 4 : 1).
~R: ~ - 5.2 - 5,8 ppm (~.) CH~CH 2 ~rot.
4.~ ppm ABX-Sp~rum ~ -OH
. ~ 3.7 ppm (s~ COO
IRo 1680 cm ~ ~C=O
1735 cm~l ~C=O
aII3 (XXI)
1) 1-(6-Methoxycarbonyl (Z)-2-hexen-1-yl3 5-hydroxy-methyl-
pyrrolidone-2
1-(6=Carboxy-(Z-2-hexen-1-yl~-5-(tetrahydropyran-2-yloxy-
meth~ pyrrolidone was treated in methanol with
57 -
.. .
-
:
F 16g
~ ~ 5~ 5~ ~
p-toluene-sul~onic acid as indicated in Example 5 aI.
Chromatography and physical data were the same as in-
dicated above.
2) 1~(6-Ethoxycarbonyl-(Z)-2-hexen~1-yl)~5-hydroxymethyl-
~ pyrrolidone-2
This product was prepar~d a~ above (aII 1)) using ethanol
i~tead of methanol. Chromatography on silica gel using
toluene/ethyl ace~ate/ethanol (5 : 4 : 1.5).
N~: S = 5~2 - ~,8 ppm tm) CH--CH 2 prot,
. IR- 1680 cm l ~ C=0
1730 cm l ~ C=0
3) 1-(7-Ethoxycarbonyl-(Z) 2-hepten 1-yl) 5-hydroxy-methyl-
pyrrol~done-2
~his product was obtained from 1-(7-carboxy-(Z) 2-hepten-
1-yl)-5-(tetrahydropyran-2-yloxy-methyl)-pyrrolidone-2 by
a treatment with ethanol in the pre~ence of p-toluene-
sul~onic acid a~ indic ted above (aII 1)). Chromato-
graphy on silica gel- using toluene/ethyl acetate/etha~ol
(5 : 4 : 1.5) as the elue~t.
8 5~2 - 5,~S ~pm (m) CY=C~ 2 prot.
~ G l.35 ppm (~) 0-C~2 ~ 3 prot,
IR: l680 cm ~C=0
1735 cm 1 ~C=0
aIII) (XXI)
(6 Met~o~ycarbonyl (Z)-2-hexen~ 5~hydroxy-m~thyl-
pyrrolidone-2
This product was obtained from 5-hydroxymethyl-pyrro-
29 lidone-2 by alkylation with 6-bromo (Z)-4-hexen-1-yl-
- 58 -
;
' ' : :`'"" ' ~ .
.
~ 5~ ~
carboxylic acid methyl ester as in Example 1 (aI).
Puri~ication and phy~ical da-ta as abo~e.
2~ 1-(6-Methoxycarbonyl-(E)-2-hexen-1-yl~-hydroxy-methyl
pyrrolidone-2
This product was prepared from 5-hydroxymethyl-pyrro-
lido~e-2 by alkylation with 6-bromo-(E~-4-hexen-1-yl-
carbox~lic acid methyl ester according to Example 1 aI.
Chromatography on silica gel, the solvent being toluene/ -
ethyl acetate/methanol (5 : 4 : 1)O
NM~: ~ = 5~2 ~ 5,9 ppm ~m) CH=CH 2 ~.rot.
S~ 3!65 pp~ (s) C~OCH3
IR: 173~ cm l ~ C=O
l680 cm ~CsO
aIV) 1-Allyl-5-hydroxymethyl-pyrrolidone-2 (XXII)
This product wa~ obtained by alkylation o~ 5-hydroxy-
methyl pyrrolidone 2 with allyl bromide according to
Example 1 a~: Boiling point under a pressure of
0.3 mm Hg : 161 169C.
- NMR spect~um: ~= 5.0 - 6.3 ppm (several multiple peaks)
-CH2 3 prot.
IR spectrum: 1680 cm 1 ~C = O
bIV) 1-Formylmethyl-5hydroxymethyl-pyrrolidone 2- ~-lactol
tXXIV)
This product was obtained by ozonoly~is o~ 1-allyl 5-
hydroxy-methyl pyrrolidone-2 according to Example 3 CI.
A~ter concentration o~ the reaction mixture, the cry~tal-
llzed re~idue was recrystallized ~rom ethanol.
29 M.p. 152 - 154C.
- 59
. ., , .
. ~: . .
.~ ..
~ 169
c~v) (XXVI)
1) 1 (5-Carboxy-(Z) 2-penten-1-yl)-5-hydroxy~methyl-pyrro-
lidone-2
- This product was obtained ~rom 1~formylmethyl-5-hydroxy-
methyl~pyrrolidone-2- ~lactol and 3-carboxy-propyl-tri-
phenyl phosphonium bromid~ as in Example 3 dI.
Chromatography was per~ormed on silica gel u~lng chloro-
~orm/methanol (8 : 2) as the solvent.
_
N~ ,l5 - 5 85 ppm (m) CH=C~ 2 prot.
IR: 1680 cm ~ C=0
1~03 cm~l ~ cso
. ,:
2) 1-(6 Carbox~-(Z)-2-hexen-1-yl) 5-hydroxymethyl-pyrro-
li~one-2.
This product was obtained from 1-~ormylmethyl-5-hydroxy-
methyl-pyrrolidone-2- ~-lactol and 4-carboxy-butyl-tri-
phenyl phosphonium bromide Rccordi~g to Example ~ dI.
Chromatography on silica gel, eluent: chloro~orm/methanol
(85 : 15).
NMR: ~= 5.2 - 5,8 ppm ~m) CH=C~ 2 ~rot.
IR: 1700 cm ~ C~0
1680 cm~l ~ C=0
CIy,) 1w(6-Carboxy-(Z~2-hexen-1 yl)-5-hydroxymethyl-pyrro-
lidone-2.
Thi~ product was obtai~ed ~rom 5-hydroxymethyl-pyrro-
lidone-2 by alkylation with 6-bromo-(Z)-4-h~xen-1-yl-
carboxylic acid according to Example 1 aI.
Physical data as above.
- 60 -
: . .
OE ~5/F 169
cIv") 1-(5-Carboxy-(Z)~2~penten-1-yl)-5-hydroxymethyl-pyrro-
lidone-2-
This product was obtained ~rom 1-(5 carboxy (Z)-2-
penten-1-yl)-5-(tetrahydropyran-2-yloxy-methyl)-pyrro-
lido~e-2 by spli~ting o~ the tetrahydropyranyl pro-
tective group ~ccording to Example 2 bIII.
Physical data as above.
dI~ (6-Methoxycarbonyl-(Z)-2-hexen-1-yl)~5-hydroxymethyl-
p~rrolidone 2
This product was obtained by esterifying 1-(6-carboxy-
(Z)-2-h~xen-1-yl)-5-hydroxyme~hyl-pyrrolidone-2 with
metha~ol. The reaction was a~alogous to Example 5 aII.
Th~ physical data correspo~d~d to those of the compound
obtained in Example 5 aI.
E X A M P L E 6:
Compounds of the general formula I
aI (XX~II)
1) 1-(6-Methoxycarbonyl~ 2-hexen-1-yl)-5~formyl-pyrro-
lidone-2
hi~ product was obtained by oxidation o~ 1-(6-meth-
oxycarbonyl-(Z)-2;hexen 1-yl) 5-hydroxymethyl-pyrro-
lldo~e-2 according to Example 1 bI. ~ -
2) 1-(6 Ethoxycarbo~yl-(Z)-2-hexen-1-yl)-5-formyl-pyrro-
lidone-2
Thi~ product was prepared by oxldation of 1-(ethoxy-
carbonyl-(Z)-2-hexe~ yl)-5~hydroxymethyl-pyrrolidone-2
according to Example 1 bI. ~ ~~ ~ ~ ~`~
3) 1 (6-Methoxycarbonyl-(E~-2-hexen-1-yl)-5-~ormyl-pyrro-
29 lidone-2
- 61 -
.. .
.
.. ~
. . . .
t ' ' - ' ` ` `
~` ' ` ' ,',' ':` ` ` ' ' : '
' :'' " ~ ' ' '~' : .:
': ' '~ ' '''.' '' , ' ' ' ' : .
~L~
This produst was prepared by oxidation o~ 1-(6-methoxy-
carbonyl (E) 2 hexen-1-yl)~5-hydroxymethyl-pyrrolidone-2
aceording to Example 1 bI.
4) 1~(7-Ethoxycarbonyl-(Z)-2 hepten-1-yl)-5-formyl-pyrro-
lidone-Z
Thls product was obtai~ed by oxidation o~ 1~r(7~ethoxy-
carbonyl-~Z)-2 hepten-1-yl)-5-hydroxymethyl-pyrrolidone-2
ac~ording to Example 1 bI.
Owlng to their i~stability, the so-obtained compounds o~
formula XXVII 1 to 4 were u ed without ~urther purifi-
cation as crude product~ ~or the next step.
bI: (XXVIII)
According to the method indicated in Exa~ple 1 c~, the
~ollowing compounds were prepared:
1) 1~(6 Methoxycarbonyl-(Z)-2hexen1-yl)-5-(3-oxo-(E)-1-
octen-1-yl~-pyrrolido~e-2
Thi~ product was prepared ~rom 1-(6-methoxycarbonyl;(Z~-
2-hexe~;-1 yl) 5-formyl-pyrrolidone-2 and dimethyl-2-oxo-
... .
heptyl phosphonate. Chromatography: tolue~e/ethyl
acetateJmethanol ~5 4 : 0.3).
NMR: ~ = 5t2 - 5,8 ppm (m) H=CH (cis) 2 ~rot,
S = ~05 - 7~0 ppm (m) CH--~H (trans3 2 ~rot~
S ~ 3.~ ppm (s) C ~ .
2 7 1-(6-Methoxycarbonyl r (E)2-hexen 1-yl)-5~ oxo-(E)-1-
oct~n-1-yl)-pyrrolidone-2
The product was prepared ~rom 1-(6-methoxycarbonyl (E)- -
2-hexen-1 yl)-5-formyl-pyrrolidone-2 and dimethyl-2-oxo
heptyl-phosphonate. Chromatography: toluene/ethyl acetate/
- methanol (5 : 4 : 0.3).
- 62 -
HOE 75/F 169
~3~ ~8~
N~m~ 5,9 ppm (m) CH=C}~ (trans, unconjugatedj
2 prot.
= 6.0 - 6,9 ppm ~) Cl~=C~ (trans, con~ugated)
.. .. . .
~ ~ 3,75 pp~ (s) COO ~
3) 1-(6.;Methoxycarbonyl-(Z)-2-hex~n-1-yl)-5-(3-oxo-(E)-1
decen-1-yl~-pyrrolidone-2 t
This product wa~ prepared from 1-(6 metho~ycarbonyl-(Z)-2-
hex~n~1-yl)-5-~ormyl pyrrolidone-2 and dimethyl-2-oxo-
nonyl-1~phosphonate. Chromatography: toluene/ethyl
a~etate/methanol (5 : 4 : 0.1).
NMR: ~ = 5,2 - 5,85 ppm (m) CH=CH (ClS~ 2 ~-Fot, '
S~ 6,0 - 6~7 ppm (m) C~=CH (trans) 2 :Rrot,
S- 3~75 ppm (s) COO ~
.
4) 1-~6-Methoxycarbonyl-(Z)-2-hexen-1-yl)-5-(3-oxo-5-ethoxy-
. 4~4-dimethyl-(E)-1-penten-1-y.L~-pyrrolidone-2
This product was prepared ~rom 1-(6-methoxycarbonyl-(Z) 2-
h~xen~1-yl) 5 formyl-pyrrolidone-2 and dimethyl-(2-oxo~-4-
ethoxy-3 t 3-dimethyl-butyl)-phosphonate.
~romatography: toluene/ethyl acetate (5 4)
. . _ ,
NM~ J = lJQ ppm (s) C(C~332 6 ~rot-
~= 3,7 pp~ (s) COO ~
~ - 5,2 - 5~8 ppm (m) CH--CH (cis) ~ ~rot.
53 1-(6-Methoxycarbonyl-~Z)-2hexen-~-yl)-5 (3~oxo-5-allyloxy-
2~ 4,4-dimethyl-(E)-1-penten-1-yl)-pyrrolido~e-2
,,
- 6~ -
. - . . . . .
. . " . . ...
,: ... ..
. : , . .
OE 75/F 169
Thi~ product was prepared from 1-(6-methoxycarbonyl-(Z)-
~ 2-hexen-1-yl3~5-formyl-pyrrolidone-2 and dimethyl-(2-oxo-4-
allyloxy3,3-dimethyl butyl) pho~phonate.
Chromatography: toluene/ethyl acetate (5 0 4)
NM~ ~ _ 5,~ _ ~.o pp~ (m) all the ole~inic protons
~~ 6 prot.
~ ~ 3.~65 ppm (s~ COO ~
6) 1-(6 Methoxycarbonyl-(Z)-2-hexen-1 yl)-5-~3-oxo-4-(4 chloro-
phenoxy)-pheno~y-4,4-dimethyl-(E~-1-bute~ yl~-pyrro-
lido~e-2.
This product was obtained from 1-(6-methoxyoarbonyl~(Z)-2-
hexen-1-yl)-5-formyl-pyrrolidone 2 and dimethyl- ~ -oxo-3-
(4-chlorophenoxy)-phenoxy-3,3-dimethyl-propyl~-phosphonate.
Chromatography: chloro~orm/ethyl acetate (4 o 1)
N~ 005 ppm ~s~ C(C~)~ 6 ~'rot.
~= ~,9 _ 7,9 ppm (m) aromatic protons 8 prot.
, . .
~3 3.? pp~ (s) C~OCH3
. . .
7) 1-(6-Me~hoxycarbo~yl-(Z)-2-h~xen-1 yl)-5-~3-oxo-4-(3-
~hie~yl-oxy) (E)-1-buten-1-y ~ -pyrrolidone~2
This product was obtained ~rom 1-(6-methoxycarbo~l-(Z)-
2-hexen 1-yl)-5-~ormyl pyrrol~done-2 and dimethyl L~-oxo-
3-~3-thienylo~y~-propyl~-phosphonate.
Chromatography: carbon tetrachloride/acetone (7 : ~)
N~R- ~ = 5,2 - 5 g ~pm (m~ CH5CH ci~ 2 pr~,
~- 6,0 - 6~9 ppm (m) CH=CE trans 2 prot.
~= 3,7 ppm ~s) COO~H3
8) . 1 ~6-Methoxycarbonyl-(Z)-2 hex~ yl)~5-(3-oxo-6-penta-
- 64 -
fluoro~ethyl-(E3-1-hexen-1-yl)-pyrrolidone-2
This product was obtained ~'rom 1-(6_methoxycarbonyl-(Z)-
2-hexen-1-yl)-5-~ormyl-pyrrolidone-2 and dimethyl-(2-oxo-
5-penta~luoroethyl-pentyl)phosphonate~
Chromatography: toluene/ethyl acetate/methanol -
(5 : ~ : 0-5)-
~M~: S = 3 7 7 pp~ (s~ ~OOC1~3
S= 5,2 - 5,9 pp~ (m~ CH-C cis 2I prot._ ~
~- 6~0 - 6,7 ppm (ABX-Sp~3~tr,) CH=C~I traIls :2 prot.
.
9) 1-(6-Methoxycarbonyl (Z)-hexen-1-yl)-5 (3-oxo-5-cycio-
pe~tyl-4,4-dimethyl-(E)-1-penten-1-yl)-pyr~olidone-2
This product was obtained ~rom 1-(6~methoxycarbonyl-(Z)-
2-hexen-1-yl)~5-~ormyl-pyrrolidone-2. and dimethyl-(2-oxo-
4 cyclopentyl ~ dimethylbutyl)-phosphonate.
Chromatography: toluene/ethyl acetate (5 : 4)
~R: ~ ~ 1, C) ppm (s) C ~CH3) 2 6 prot .
3 . 7 ppm (s) COOCH3
~= 6~0 - 7,0 ppm ~m~ C}l=(:i~ trans 2 prc~t. .-
10) 1-~6-Methoxycarbonyl-(Z)-2 hexen-1-yl)-5-(3-o~o-5-phenyl-
(E)~1 penten-1-yl) pyrrolidone-2
~his product was obtainsd ~rom 1-(6~methoxycarbonyl-(Z)-
2-hexen-1-yl)-5-~ormyl-pyrrolidone-2 and dim~thyl-(2-oxo-
4-phenyl-butyl)-phosphonate.
C~romatography: carbon tetrachloride/acetone (7 : 3)
NMR. ~- 7.3 ppm (5) aromatlc proton~ 5 pr~
3,7 pp~ (s) C00 ~
5,lS - 5~75 ppm (~) CH=~I (cis) 2 prot.
65
.. . . . .
. . . .
~ , . . .
~ 6~
,"
11. 1-(6-Methoxycarbonyl-(Z)~2-hexen-1 yl)-S- ~ -oxo-5-(4-
methyl 2 chlorophenyl)-4 7 4-dimethyl~(E) 1-penten-1-yl )J-
pyrrolidone~1
This product was obtained from 1-(6-methoxycarbonyl-(Z)-
2-hexen-1-yl)-5-formyl~pyrrolidone and dimethyl-t2-oxo-4
(4-methyl-2-ohlorophenyl)-3 9 3-dimethylbutyl~-phosphonate.
Chromatography: toluene/eth~l acetate (5 : 4)
NMR ~3 l~o ppm (s) C~C ~ ~2 6 prot.
~ 5 2,~ ppm (s) CH3 3 prot,
S ~ 6,~ - 6,5 ppm ~m~ CH--CH (trans) 2 prot.
120 1 (6~;Ethoxycarbonyl~ 2-hexen-1-yl)-5 (3-oxo-7 methyl-
(E)-1-octen-1-yl) pyrro~idone-2
. This product was obtained frQm 1-(6-ethoxycarbonyl-(Z)-2-
hexe~-1-yl~-5~formyl pyrrolidone-2 and dimethyl-(2Doxo-
6-methyl-heptyl)-phosphonate.
Chromatography- chlorofoFm/ethyl ace~ate (4 : 1)
N~IR: ~ = 1,05 ppm (d) CH~CH3)2 6 prot~
~3 1~3 ppm ~t) C00~2CI~3 3 ~rot.
~ - S,2 - 5,9 pp~ (m~ ~H=~ (cis) .2 p~ot.
13. 1-(6-Ethoxycarbonyl-(Z)-2 he~èn ~-yl)-5~ oxo-4,4-di- ~ -
methyl-(E~ octe~-1-yl~-pyrrolidone-2
This product wa~ obtained from 1-(6;ethoxycarbonyl-(Z)-2-
hexen-1-yl)-5-formyl-pyrrolidone-2 and dime~hyl-(2-oxo-
3 9 3-dimethyl heptyl~-phosphonate. _ -
chromatography: toluene/ethyl acetate/ethanol
(5 : 4 : .3)
..
~, , I
`..
N~R: ~ = 0,9S ppm (s) C( ~ )2 ~ ~rot,
~= 1,25 ppm (t) COOCH2CH3 3 p~rot,
~= 5.15 - 5,95 ppm (m) C~=CI~ (cis) 2 prot.
S ~ 6,0 - 7~05 ppm ~m) CH=CH ~trans) 2 pirot.
14) 1-(6-Ethoxycarbonyl-(Z)-2-hexen-1 yl~-5~ oxo-4-(3-tri-
~luoro-methyl-phenoxy)-(E)-1-buten-1-yl~-pyrrolidsne-2
Thl~ product was pr~pared from 1~(6-ethoxycarbonyl-(Z)-2- -
hexen-1-yl) 5-~ormyl-pyrrolido~e-2 and dimethyl-~2-oxo-3-
(3-trifluoromethyl pheno~y) propyl~-pho~phonate~
Chromatography: toluene/e~hyl acetate ~5 o 4)
NMR: 5~ 1~2 ppm (t) COOCH2CH~ 3 protons
~- 4,~ ppm ~s) ~ -0 ~ 2 proton~
S~ 6,0 ~ 6,95 ppm (m) CH=~ 2 l protons
. _ . . . .. . ..
15) 1 (6 Ethoxycarbonyl-(Z)-2hexen-1-yl)-5-[3~oxo-4-(4-chloro-
benzyloxy) (E)-1 buten-1-yl~--pyrrolidone;2
This product was obtained ~rom 1~(6-ethoxycarbonyl-(Z)-2-
hexen-1-yl)5 ~ormyl-pyrrolicLone-2 and dimethyl-~2-oxo-3-
(4-chlorobenzyloxy)-propyl)~phosphonate~
Chromatography: carbo~ tetrachloride/acetone (7 : 3)
NMR: S = ~,4 ppm ~nd 4,6 ppm (2 Sing.) OEI2-0 4 prot.
1,2 ppm ~t) COOC~2 CH3 3 protO
~= 7,0 - 7.5 ppm (m3~~aromatic pro~ons 4 protO
16) 1 (6~Ethoxycarbonyl-(Z~-2-hexen-1-yl)-5-~3-oxo-4-( 20
thienyl)-(E)-1-buten-1-yl~-pyrrolidone-2
This product was obtained ~rom 1-~6-ethoxycarbonyl-(Z)_2_ ~~
hexen-1-yl)-5 ~ormyl pyrrolidone-2 and dimsthyl-~2-oxo-3-
29 (2 thienyl)~propy ~ -pho~phonate.
67 -
~~L
~ 5~
Chromatographie: toluen~/ethyl acetate/etha~ol
(5 : 4 : 001)
, 9 ppm (s j -'CH2 2 prot,.
S -- 7.1 - 7,3 ppm (~ thiophenone protons ~ prot.
G,0 - G~90 ppm (m) CH=~ trans) 2 prot.
17) 1-(7-Ethoxycarbonyl-(Z)-2-hepten-1-yl)-5~ oxo-5-ethoxy-
4,4-dimethyl-(E)-1-penten-1-yl)-pyrrolidone-2
Thi~ product was obtalned from 1-(7 ethoxycarbonyl-(Z)-
~ 2-hepten-1 yl) 5-~ormyl-pyrrolidone-2 and dimethyl-
(2-oxo~4-e~hoxy 3,3;dimethyl-butyl)-phosphona~e.
Chromatography: toluene/ethyl acetate (5 : 4)
S~ l10 ppm (s~ C(C~3)2 6 prot.
~= l,2 ppm (t) COOCH2C ~ 3 . prot.
~= 600 - 6,95 (m) _ -CH (trans) 2 prot~
bI' 1 (6-Methoxycarbonyl-(Z)-2-hexen-1-yl)-5-(3-oxo-(E)_1-
octen 1~yl)-pyrrolido~e-2 ~XXVIII)
Thi~ product was obtained by alkylation o~ g (3-oxo-(E)-1-
octe~ yl)-pyrrolidone-2 and 6-bromo-(Z)-4-hexen-1-yl-
carboxylic acid methyl e~ter according to the method o~
Example 1 aI. Physical data and chromatography as i~
~xa~ple 6 bI 1).
C~
The reduction o~ the abo~e me~tioned ~B~unsaturated
ketone~ o~ formula XXVIII was carried out as in Example 1
dI to yield the compounds o~ ~r~ula I. Speci~ically~ ~ ~~
the ~ollowi~g compounds were prepared:
29 1) 1-(6-Methoxycarbonyl-(z)-2-hexen-1-yl-5-(3-hydroxy-1
- 6~
OE 75/F 169
octen-1-yl)-pyrrolidone-2
- This product was obtain~d from 1~(6-methoxycarbonyl(Z)-2-
hexen-1-yl)-5 (3-oxo-(E)-1-octen-1-yl) pyrrolidone-2
Physical data and chromatography as in Example 2 cI 1),
2) 1-(6-Metho~yearbonyl(E)_2_hexen-1-yl)-5 (3-hydroxy~1-octen-
1-yl)-pyrrolldone-2
This product was obtained Prom 1-(6-methoxycarbonyl-(E)-2-
hexen-1-yl3-5-(3-oxo-(E)-1-octen 1-yl)-pyrrolidone-2
Phy~ical data as in Example 2 cI 5)0
3~ 1 (6 Methoxycarbonyl-(Z)-2-hexen-1-yl)-5-(3-hydroxy-1-
decen-1-yl)-pyrrolidone~2
Thls product was obtained from 1-(6-methoxycarbonyl~(Z)-2-
hexen~1-yl)-5-(3-oxo-(E) 1-decen 1-yl)-pyrrolidone-2
Chromatography: toluene/ethyl acetate/methanol (5:4:0.5)
15
~: ~ 5~2 - 5~ QS pp~ ~m~ CH3CH 4 prot.
~_ 3~7;~ ppm (~;) COOCH3
IR: 1680 cm ~ tJC:=o
173 5 cm 1 ~C=C)
4) 1-(6-~e~hoxycarbonyl-(Z~)-2-hexen-1-yl)~ hydroxy-5-
ethoxy~4~4-dimethrl-(E)-1-pe~ten-1-yl)-pyrrolidone-2
This product was obtained from 1-(6-methoxycarbonyl (Z)-2-
hexen-1 yl)-5-(3-oxo 5-ethoxy-4,4-d~methylw(E)-1-penten-1-
yl)-pyrrolidone-2-.
Physical d~ta and chromatography a~ in Example 2 cI 3).
5) 1-(6-Methoxycarbonyl-(Z)~2-hexen 1-yl)-5-(3-hydroxy-5-
~~ ~ ` aI~yl-oxy-4,4-dimethyl-(E) 1-penten-1-yl)-pyrr-olidone-2~
This product was obtained ~rom 1-(6-metho~ycarbonyl-(Z)-2-
29 hexen-1-yl) 5 (3 oxo-5-allyloxy-4,4-dimethyl~(E)-1-penten-
- 69
: -: . .
,
; . :. .~ : :, .. ..
. ~: :.,., . . .,.
,.. . . .
HOE 75/F 169
1-yl)-pyrrolidone-2 .
Chromatography: toluene/ethyl acetate/methanol (5 : 4 : 1)
NMR~ ,o - ~,5 ppm (~) all the ole~inic protons
6 prot.
=3,~3S PP~(Sj ~ OCH3
6~0 cm~l yC=O
- 1735 c~ l ~C~O
. . .
6) 1-(6-Methoxycarbonyl-(Z)-2-hexe~-1-yl)-5-~3-hydroxy-4-(4-
chlorophenoxy) phenoxy-4 9 4-dimethyl-(E) 1-buten-1 -ylJ-
pyrrolidone-2
This product was obtalned from 1-(6-methoxycarbonyl-(Z)-2-
hexen 1- yl ) -5-L~;-oxo-4- ( 4 chlorophenoxy) -phenoxy-4, 4-di-
methyl- ( E) -1 buten-1-yl~-pyrrolidone-2.
Chromatography: chloroform/ethyl acetate (4 : 1)
NMR: ~= 1,05 ppm (s) C(CH~ 6 prot.
.. . .. . ~ . .
~= 619 - 7~ ppm ~m) aromatic protons 8 pr~.
~= 3,7 ppm (s) COOCH3
I~; l6~0 cm l ~C=O
l733 cm~ ~ c=n
7) 1-(6-Methoxycarbonyl-(Z)-2-hexen 1-yl)-5-~3;hydroxy-4
thienyloxy)-(E)-1-buten-1-yl~-pyrrolidone-2
This product was obtai~ed from 1-~6-methoxycarbonyl-tZ)-2-
hexen-1 yl) 5- ~ -oxo-4-(3-~hienyloxy)-(E)-1-buten-1 -ylJ
pyrrolidone-Z ~ _ -
Chromatography: toluene/ethyl acetate/ethanol (6 : 4 : O.2)
- 70 -
.;
: . . , , . :
,. ~
.; . ~.. . .
s~
NMR ~ D 5,3 5,6 ppm (m) CH=C~ 4 prot,
S_ q ~ pp~ (~) C~OC~3
IR: 1580 ~m 1 ~C=~
1738 cm~~ ~ C50
8) 1-(6-Methoxycarbo~yl_(Z) 2-hexen 1-yl~-5 (~-hydroxy-6-
penta~luoroethyl-~E)-1hexen-1-yl)-pyrrolidone-2
This product wa~ obtained from 1~(6-methoxgcarbonyl-(Z)-2-
hexen-1-yl)-5-(3-oxo-6-penta~luoroethyl (E)-1-hexen-1-yl)-
pyrrolido~e-2.
~hromatography: toluene/~thyl acetate/methano1 (5:4:0.5)
N~R: ~ = 3,7 ppm (s) ~OOCH3
~ 5,2 - Sj6 ppm (m) CH=CI-I 4 prot
IR: 1680 cm ~ C~O .
1~30 c~~ ~ C=~
9) 1-(6-Methoxycarbonyl-(Z)-hexe~-1 yl)-5-(3-hydroxy-5-cyclo-
pentyl-494-dimethyl-(E)-1-penten 1 yl)-pyrrolidone-2
This product was obtain~d ~rom 1-(6-metho~ycarbonyl-(Z)-
hexe~-1-yl)-5-(3-oxo-5cyclopentyl-4,4-dimethyl-(E)-1-
penten 1-yl)-pyrrolidone-2.
Chromatography: toluene/ethyl acetate/me~hanol (5:4:0.3)
NMR: ~ 5 Oo 9 ppm (s) C(CH3)~ 6 prot.
~= 3,7 ppm (s) COOCH3
~= 5,3 - 5,5 ppm (m) CH=CH 4prot.
IR: 1680 cm 1 vc=o
1740 cm 1 ~C=O
103 1-(6-Methoxycarbonyl-(Z~ 2-he~en-1-yl)-5-(3-hydroxy-5
phenyl-(E)-1-penten-1-yl) pyrrolidone-2
- 71 -
; . .:
~, . . .... .
: ' .. .. ';:, ' ! : .
:' " . . ~' :~ ' . :
,,~,5~,
~ 5~
This product was obtai~ed ~rom ~-(6-methoxycarbonyl-(Z)-2-
hexe~-1 yl)-5-(3-oxo-5-phenyl-(E)-1-penten~1-yl)-pyrro-
lidone-2~
Chromatography: toluene/ethyl acetate/methanol (5:4:0.1)
NMR: ~ 7~3 ppm (s) aromatic protons 5 protons
~= 3~7 p~m (s) COO~H3
. S= 5,1~ - 5,50 ppm (m) CH--~H ~ proton~
IR: 1730 cm l ~C=0
~680 cm l ~C=0
11) 1-(6-Methoxycarbonyl-(Z)-2~hexen-1-yl)-5-~3-hydroxy-5 (4-
methyl~2-chlorophe~yl)-494-dimethyl-(E~ penten-1-yl)-
pyrrolidone-2
This product was obtained from 1-(6-methoxyoarbonyl-(Z)
2 hexen-1 yl)-5-l~-oxo-5-(4~methyl-2-chlorophenyl)-4,4-
dimethyl-(E)-1-penten-1-yl~-pyrrolidone-2.
Chromatography: toluene/ethy:L acetate (5 : 4)
NMR: d = l~o ppm (s) C(CH3)~ 6 prot.
D ~ ~3 ppm (s) C~3 3 prot.
S= 5,3 - 507 ppm C~I=CH 4 prot.
IR: l740 cm ~ C~0
1680 c~ ~ V C=0
,.
12) 1-(6-Ethoxycarbonyl-(Z)-2-hexen-1-yl)-5-(3-hydroxy-7-
methyl-(E)-1-octen 1-yl)-pyrrolidone-2
This product was obtained ~rom 1-(6-ethoxycarbonyl-(Z)2-
hexen-1-yl)-5-(3-oxo-7-methyl-(E)-1-octen 1-yl)-pyrro-
lidone-2~
Chromatography: chloro~orm/eth~l acetate/ethanol
~8 : 2 : 0.5)
29
- 72 -
. .. . . .
.
., . ..... ,, , . ,; ~ ,
:
~85~
~MR: ~ = 1,0 ppm (.d) CH(CH3)2 6 protons
= 1,25 ppm (Z) COOCH2CH3 3 protons
~ = 5,2 - 5,5 ppm (m) CH=CH 4 protons
IR~ 1730 cm ~C=~
1675 cm 1 ~C=O
13) 1-(6-~thoxycarbonyl-(Z)-2-hexen-1-yl)-5-(3-hydroxy-4,
4-dimethyl-(E)-l-octen-l-yl)-pyrrolidone-2
This product was obtained from 1-(6-ethoxycarbonyl-
(Z)-2~hexen-1-yl)-5-(3-oxo-4,4-dimethyl-(E)-l-octen-
1-yl)-pyrrolidone-2.
Physical data as in Example 2 cI 2).
14) 1-(6-Ethoxycarbonyl-(Z)-2-hexen-1-yl)-5-~3-hydroxy-4-
t3-trifluoromethyl-phenoxy)-(E)-l-buten-l-yl]
pyrrolidone-2
This product was obtained from 1-(6-ethoxycarbonyl-
(Z)-2-hexen-1-yl)-5-[3-oxo-4-(3-trifluoromethyl-
phenoxy)-(E)-l-buten-l-yl]-pyrrolidone-2.
Physical data as in Example 2 cI 4).
15) 1-(6-Ethoxycarbonyl-(Z)-2-hexen-1-yl)-5-[3-hxdroxy-4-
(4-chlorobenzyloxy)-(E)-l-buten-l-yl]-pyrrolidone-2
This product was obtained from 1-(6-ethoxycarbonyl-
(Z)-2-hexen-1-yl)-5-[3-oxo-4-(4-chlorobenzyloxy)-(E)-
l-buten-l-yl]-pyrrolidone-2.
Chromatography: carbon tetrachloride/acetone (-7 : 3)
NMR: S = 5,1 - 5,4 ppm (m) CH=CH 4 prot.
~ = 1,1 ppm (t) COOCH2-CH3 3 prot.
S = 7,0 - 7,5 ppm (m) aromatic protons 4 prot.
IR 1735 cm YC=O
1680 cm 1 YC=O
. . -. : . , . :: : ,~ :
, . .:: . : .: .
. . . : . . ~
,., ' :' ' ~, ~ ., . :
. . :: :: : :: ,
5~
)~ 7~
16) 1-(6-Ethoxycarbonyl-(Z)-2-hexen-1-yl)-5-l3-hydroxy-
4-(2-thienyl)-(E)-l-buten-l-yl]-pyrrolidone-2
This product was obtained from 1-(6-ethoxycarbonyl-
(Z)-2-hexen-1-yl)-5-[3-oxo-4-(2-thienyl)-(E)-l-
buten-1-yl]-pyrrolidone-2~
Chromatography: toluene/ethyl acetate/ethanol
(5:4:0.5)
NMR: S = 7,1 - 7t3 ppm (m) thiophenone protons
3 prot.
~ = 5,2 - 5,6 ppm (m) CH=CH 2 prot.
IR: 1740 cm 1 ~C=O
1680 cm~l ~C=O
17) 1-(7-Ethoxycarbonyl-(Z)-2-hepten-1-yl)-5-(3-hydroxy-S-
ethoxy-4,4-dimethyl-(E)-l-penten-l-yl)-pyrrolidone-2
This product was obtained from 1-(7-ethoxycarbonyl-
(Z)-2-hepten-1-yl)-5-(3-oxo-5-ethoxy-4,4-dimethyl-
(E)-l-penten-yl)-pyrrolidone-2~
Chromatography: toluene/ethyl acetate/ethanol
(5~4:0.5)
NM~: ~ = 0,9 ppm (s) C(CH3)2 6 prot.
= 1,2 ppm (t) COOCH2CH3 3 prot.
~ = 5,15 - 5,5 ppm (m) CH=CH 4 prot.
IR: 1738 cm 1 ~ ~=O
1680 -1
II (XXVII, R = ~I)
1) 1-(5-Carboxy~(Z)-2-penten-1 yl)-5-formyl-pyrrolidone-
This product was prepared by oxidation of 1-(5-
carboxy-(Z~-2-penten-1-yl)-5-hydroxymethyl-
.. ., :. ~ ,. . :
- :, ,: . .
.~
.. .,. .. . ~ ,~ .
s~
7~a
pyrrolidone-2 according to Example 1 bI.
2) 1-(6-Carboxy-(Z)~2-hexen-1-yl)-5-formyl pyrrolidone
--2
.. . , ., ' ` ~ :' ' .:. . ~ i,
., :. , : ,. . ::: .: . : ., :. :: :::i
:. ... ~ . ,: :, : . -
:: :: . .... : : : :, . : :
169
~ 5~
Thi~ product was prepared by oxidation o~ 1-(6-carboxy-
(Z)-2-hexen-1-yl)-5-hydro~ymethyl-pyrrolidone-2 according
to Example 1 b~.
The two aldehydes thus prepared were used without ~urther
puri~i~ation as crude products for the ~ollowing step.
bII: ~XXVIII 9 R2 = H)
1) 1~(5-Carboxy;(Z)-2-penten-1-yl) 5-(3-oxo-494-dimethyl-5-
ethoxy-(E)-1-penten-1-yl)-pyrrolidone-2
This product was obtained ~rom 1-(5-carboxy-(Z)-2-pe~t2n
1-yl)~5~ormyl-pyrrolidone 2 and dimethyl-(2-oxo-3,3-di-~
methyl~4-ethoxy-butyl)-phosphonate according to Example
1 ~I.
~hromatographyo ethyl acetatetglacial acetic acid (98:2)
NMR~ 0 ppm (s) C(CH3j2 6 prot.
~= 5~ 2 - 5, 5 ppm (m) C~ C~I cis 2 prot.
~ 5 6,,1 - 6~9 ppm (m) CH=C~I tr~ns 2 prot
2) 1 (6~Carboxy-(Z)-2-hexen-1~yl)-5-(3-oxo-(E)-1-octen-
1~yl)-pyrrolidone-2
Thi~ product wa~ obtained from 1-(6-carboxy-(Z)-2-hexen-
1-yl)-5-~ormyl-pyrrolidone-2 and dimethyl-2-oxo heptyl-
phosp~onate according to Example 1 I-
Chromatograph~: ethyl acetate/glacial acetic acid (98:2)
.. ... .. . . . .
NMR: ~= 5,2 _ 5~85 ppm tm) CH=rH (cis) 2 prot
~ ~,0 - 6~9s ppm~(m) H-C~ ttrans) ~. prot
bII ? 1 (6-Carboxy-tZ)-2-hexen 1-yl) 5-(3-oxo-(E) 1 octen-
1-yl)-pyrrolidone~2 (XXVIII, R2 _ H)
Thi8 product was obtained ~rom 5-(3-oxo-(E)-1-o~t~n-1-
29 yl)-pyrrolidone-2 by alkylatlon with 6-bromo-(Z)-4-hexen
~ 75 -
- ,;, ., , ,
,
": ' "
~2~.~L
~ ~ 5~5~
1~ylcarboxylic acid according to Example 1 aI.
~ Physical data and puri~ioation as above.
cII: (I, R2 = H)
1) 1-(5-Carboxy-(Z)~2-penten~1-yl)-5~ hydroxy-4,4-dimethyl-
5-ethoxy-(E)-1-penten-1-yl) pyrrolidone-2
This product was obtained from 1-(5-carboxy-(Z)-2-penten-
~-yl)-5-(3-oxo-4,4-dimethyl-5-ethoxy-(E) 1-penten-1-yl)-
pyrrolidone-Z according to Example 1 dI.
Chromatograph~: ethyl acetate/glacial acetic acid (98:2)
NMR: S= l,0 ppm (s) C(C~I~)2 ~ prot.
~;~ 5,2 - 5,5 ppm (m) rH=CH 4 prot.
IR: l705 cm l ~C=0
~.680 cm~~ ~5=0
2) 1-(6-Carboxy-(Z)_2-hexen-1_yl)-5-(3-hydroxy~(E)-1-octen-
1 yl)-pyrrolidone-2
This produot was obtained from 1-~6-carboxy-(Z)-2-hexen-1-
y~ 5-(3-oxow(E)~1-octen-1-yl)-pyrrolidone-2 according to
Example 1 dI.
Chromatography: ethyl acetate/glacial acetic acid
t97.5 : 2.5)
NMR: ~= 5,3 - 5,7 ppm (m) CH=CH 4 prot.
IR: l700 Cm 1 ~C=O
l682 cm 1 ~C=0
aIII: (I, R - H)
1) 1-(6-Carboxy-(Z)-2~hexen-1-yl)~5 (3-hydroxy-(E)~1-decen
1-yl)-pyrrolido~e-2 .- . _
This product was obtained ~rom 1-(6-methoxyoarbonyl-
(Z) 2-hexen-1-yl)-5 (3-hydroxy-(E)-1-decen-1-yl)-pyrro
- 76 -
.; ., .~ . :
.:. .. ...
- ,"~ ,, , , .,., ; -
~ 1_
lidone-2 according to Example 2 avIO
Chromatography: ethyl acetate/glaclal acetic acid (98:2)
NMR: S= 5, 2 w 5 0 B5 ppm (~ 3 ~-Ci~ 4 prot.
IR: l680 cm l ~C=~
1705 cm ~ ~C~0
2) 1-(6-Carbo~y_(Z)_2_hexen_1 yl)-5-~3-hydroxy-4-(4-chloro-
phenoxy3-phenoxy-4 D 4-dimethyl~ buten 1-yl)~-pyrro-
lidone-2
This product was obtained from 1-(6- methoxycarbonyl-(Z)-2
2-hexe~-1-yl) 5-~3-hydroxy-4-(4-ohlorophenoxy)-phenoxy-
4,4-dimethyl-(E)-1-buten-1-yl~-pyrrolidone-2 according
to Example 2 aVI,
Chromatography: cyclohexane/ethyl acetate/glacial acetic -
. acid (6 : 4 : 0.1).
N3~R: S= 1,05 ppm (s) C(CH3)2 5 prot.
~- 599 - 7~9 ppm (m) aromatic protons 8 prot.
IR: 1680 cm l ~C=0
~` l700 cm~l ~=o
3) 1 (6-Carboxyl-(Z)-Z-hexen 1 yl)5-(3-hydroxy-6-penta-
~luoro-eth~l-(E)-1-hexe~-1-yl)-pyrrolidone-2
The product was obtained ~rom 1-(6-methoxycarbo~yl-(Z~-
2-hexen-1 yl)-5 (3-hydro~y 6-pentafluoroethyl-(E)-1-
hexen-1-yl)-pyrrolidone-2 according to Example 2 a~I.
Chromatography: toluene/~thyl acetate/glacial acetic
acid (5 : 4 0 0~
.
169
~b~: ~- 5~2 - 5,45 ppm (m) CH-CH 4 prot.
IR: 1685 cm l ~C=o
1705 Cffl 1 ~J C=0
4) 1 (6-Carbo~y-(Z)-2-hexen-1-yl)~5-~3-hydroæy-5-(4-methyl-2-
chlorophenyl)-4,4-dimethyl (E)-1-pente~ yl~-pyrro-
lidone-2
Thi~ product was obtai~ed ~rom 1-(6-methoxycarbonyl-(Z)-
2-hexen-1-yl)-5-~3 hydroxy 5~(4-methyl-2-chlorophenyl)-
494-dimethyl-(E)-1-penten-1-yl7-pyrrolidone-2.
Chromatography: cyclohexa~e/ethyl acetate/glacial acetic
acid (6 : 4 : 0.1).
NMR: ~= 009 ppm (s) C(CH3)2 6 prot.
d = 2,3 ppm (s) CH3 3 prot.
~=- 5,3 ~ 5 9 1 ppm ~=CH 4 prot.
IR: l705 ~m ~C=0
1680 cm~l ~ C=0
- 78 -
...
". ', ','
~1 . ' . '~ . .' ' '
S~
SUPPLEMENTARY DISCLOSURE
" . . .
We have further found that pyrrolidones of the formula I'
O 2
N-CH2-CH=C~- (CH2 ~ n-COOR
R3
CH=CH-C \
OH R
in which Rl, R2 and n are defined as in formula I and R3 is
a str~aight-chained or branched alkyl radical having from 1
to 5 carbon atoms, an alkenyl or alkinyl radical having from
2 to 5 carbon atoms or an araliphatic hydrocarbon radical
having 7 or 8 carbon atoms, can be obtained by
- c) reacting the pyrrolidone of the formula XXVIII
O 2
N-CH2-CH=CH-(CH2) -COOR
\ 1 XXVIII
~__ - CH=CH-C-R
o
in which Rl, R2 and n are defined as in formula I, with
a metal-organic compound prepared from R3-X, in which X
is a halogen atom and R3 is defined as in the formula I~
above, to give compounds of the formula I , and convert-
ing the same optionally into the free ~cid or the
physiologically acceptable metal or amine salts thereof,
or
dl)reacting the pyrrolidone of the formula X
~ NH
< 1 CH=CH-C-Rl X
Il ,
-- 79 --
.. . .
- .:.. , . . :
35~
in which ~1 is defined as in the formula I with a rnetal-
organic compound prepared from R3-X, in which X is a
halogen atom and R3 is defined as in the formula I , to
give a compound of the formula XXIX
o
NH 3
R XXIX
CH=CH-C
OH R
d2~protecting in the pyrrolidone of the formula XXIX the
alcohol group by a group R4 which can easily be removed
under acid conditions, thus forming a compound of the
formula XXX
~ NE~
~I Rl XXX
~<
R o R
in which Rl and R3 are defined as in formula I',
d3)deprotonizing the pyrrolidone of the formula XXX with a
base at the nitrog-en atom and reacting the anion thus
formed with a carboxylic acid derivative of the formula
XII
Y CH2 - CH ~ CH - (CH23n - COOR XII
in which R2, Y and n are defined as in formula XII
above to give a compound of the formula XXXI
- 80 -
~ .: ,,, ;. : .
~5~359
~ .N - CH2 - CH - CH - (CH2)n - COOR2
~l ~
CH = CH C \ XXXI
R l
d4)splitting off the alcohol protective group R4 in a
compound of the formula XXXI, thus forming a compound
of formula I' and converting the latter optionally into
the free acid or the physiologically acceptable metal
or amine salt thereof, or
d4'3deprotonizing the pyrrolidone of the formula XXIX
without introducing a protective group at the hydroxyl
function at the nitrogen atom and reacting the anion
formed with a carboxylic acid derivative of the formula
XII to give a compound of the formula I', and converting
the latter op.Lionally into the free acid or the
physiologically acceptable metal or amine salt thereof.
Amo~g the meanings mentioned for R3, preference is given
to the following:
Straight-chained or branched alkyl groups having from 1
to 4 carbon atoms, especially the methyl, ethyl, propyl
and isopxopyl groups, furthermore, alkenyl and alkinyl
groups having from 2 to 4 carbon atoms, especially the
vinyl, propenyl~ allyl and
- 81
.:,. . i , .
ethinyl gro~lps, and finally the benzyl group.
The metal-organic compounds used for the process of the
invention according to c3 as well as d) are derived from
metals of the first and second main group of the Periodic
Table of the Elements. There are mentioned in particular
lithium- or magnesium-organic compounds (Grignard compounds),
which are prepared according to one of the usual methods,
for example, from a compound ~3-X, in which R3 is defined
as in formula I' and X is a halogen atom, for example
chlorine, bromine or iodine, and the corresponding metal,
such as Li or Mg.
- For the reaction of the pyrrolidones of the formulae
XXVIII or X there are mentioned those solvents which are
inert under the reaction conditions, for example, hydro-
carbons or preferably ethers, such as diethylether,
tetrahydrofuran or 1~2~dimethoxyethane. In this process,
temperatures in the range of from -60 C to +30C,
pre~erabl~ from -30C to -OC, may be applied. It is of
no importance whether the substrate is added to the metal-
organic compound or vice versa.
However, the metal-organic compound is preferably
added to the substrate, in order to prevent side reactions
which might occur. For the working-up, the reaction
product is mixed with waterr diluted mineral acid, or a
solution of ammonium salts, such as ammonium chloride in
water, and is then isolated in common manner~ If the
synthesis method d) is chosen, the reaction of X to XXIX
is carried out while using a ~etal-organic compound, in
- 82 -
. ~ : : ,:. .. ; . ~. . ,, ::.
,. -, : . . . .. : : :
.: .
.. , .:
8t~
which process the conditions already mentioned for process
c) are applied,
The steps d2) to d4) and d4'), respectively are carried
through under the same conditions as described relating to
the steps a6) to a8) on pages 20 to 23.
The compounds of the invention are distinguished by an
activity which is spasmogenic on one hand and bronchodilat-
atory~on the other hand, furthermore, they have anti-
hypertensive properties, they are able to inhibit the
secretion of gastric juice and have abortive effects. They
may therefore be used as drugs~
The pharmacological properties were tested on the
following animals and/or organs:
Spasmogenic effect: isolated rat stomach,
isolated guinea-pig uterus
Bronchodilatatory effect: guinea-pig
Antihypertensive effect: dog
~ecretion_of;gastric juice: rat
Abortive ef~ect: hamster~
.
The compounds of formula I~ of the invention may be
employed as free acids, in the form of the physiologically
acceptable inorgànic or organic salts thereof or as esters
of aliphatic, cycloaliphatic or araliphatic alcohols.
As inorganic salts, there may be used, for example,
alkali metal salts, alkaline earth metal salts or ammonium
salts; for a formation of salts with organic bases, there
are used bases derived from primary~ secondary and tertiary
- 83 -
,, ;
:...... : , . . . .
: : : .. . . ,;
-: .... .
~135~5~
amines which may contain further hydrophilic groups; for
example salts with methyl, triethyl, benxyl, phenylethyl,
allyl amine or also with piperidine, pyrrolidine, morpholine
or with ethanol amine, triethanol amine, tris-(hydroxymethyl)
methylamine; as esters, there are preferably used esters
of lower aliphatic alcohols, such as methyl, ethyl, propyl,
butyl or hexyl ester, and benzyl ester.
~ he acids and salts or esters may be administered in
the form of the aqueous solutions and suspensions thereof
or also in a solution or suspension in pharmacologically
acceptable organic solvents, such as mono- or polyhydric
alcohols, for example ethanol, ethylene glycol or glycerol;
oils, for example sunflower oil or castor oil; ethers,
for example diethylene glycol dimethyl ether, or polyethers,
for example polyethylene glycol, or even in the presence
of other pharmacologically acceptable polymer carriers,
for example polyvinyl pyrrolidone
Pharmaceutical compositions are the usual galenic
infusion or injection solutions as well as tablets, and
locally administerable compositions; such as creams,
emulsions, suppositories and especially sprays.
The new compounds may further be used in combination
with other active ingredients. Among other appropriate
substances, for example compounds influencing the
fertility and hormones, such as LH-RH, FSH, estradiol or
LH, the following compounds may be especially mentioned:
- 84 -
, ., : . : ~ ,
.; : ..
:. . ~ .... : , .
:. : .: .
.
135~5~
Diuretics, for example Furosemide, antihyperglycemics, ~or
example glycodiazin, tolbutamide, glibenclamide, phenformin,
buformin, metformin, or circulatory agents in the broadest
sense of the term, for example cardiovascular-dilatatory
agents, such as chromonar or prenylamine, antihypertensive
agents, such as reserpin, a-methyl-dopa or clonidines, or
anti-arrhythmics, antihyperlipidemic agents or geriatrics,
and other compositions acting on the metabolism,
psychopharmaceuticals, for example, chlorodiazepoxide,
diazepam or heprobamate, as well as vitamins, or other
prostaglandins or prostaglandin-like compounds and
prostaglandin antagonists.
The dosage unit is in the range of from about 5 7g
to 5 mg, the daily dosage unit is from about 10 ~g to 20 mg.
The compounds o~ the formulae IV, V, VII are novel
valuable intermediates for the manufacture of the compounds
of formula I.
The following Examples illustrate the invention.
- 85 -
..-
}IOÆ 75/F 169
10~35~
E X A M P L E 7
.
1-~(6-Methoxycarbonyl-(Z)-2-hexene-1-yl)-5~~3-hydroxy-3-methyl-
(E)-1-octene-1-yl)-pyrrolidone-2
A solution of 10 mmoles of 1-(6-methox~carbonyl-(Z)-2-hexene-
1-yl)-5-(3-oxo-(E)-1-octene-1-yl) in 70 ml of ether was cooled
to -15 C under an argon atmosphere. Subsequently, 8 ml oE a
1.5 molar solution (12 millimoles) of methyl-magnesium iodide in
ether was added dropwise, while stirring, the mixture was con-
tinued to be stirred for 30 minutes and was heated to room tem-
perature. Afterwards about 1.5 ml of a saturated ammonium chlo-
xide solution was added at 0 C, in which process a colorless
precipitate-was formed. -After about 10 minutes, anhydrous mag-
nesium sulfate was added, the product was suction-filtered, con-
centrated and chromatographed on silica gel ~eluent: toluene/
acetic ester/methanol 5:4:0.3)~
NMR: S = 3.7 ppm ts) COOCH3
= 5.4 - 5.-7 ppm (m) CH=CH 2 prot.
~ = 1.35 ppm (s) C-CH3
IR: ~680 cm 1 ~ C=O
1730 cm 1 ~ C=O
E X A M P L E 8
1-(6-Methoxycarbon~l-(Z)-2-hexene-?-yl)-5-(3-hydroxy-3-ethi
(E)-1-octene-1-yl)-pyrrolidone-2
was prepared according to the method descri~d in Example 7 ~rom
1-(6-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-(E)-1-octene-1-
yl) and lithium ethinyl.
Chromatography: toluene/acetic ester/methanol 5:4:0.1
I~MR: ~ = 3.6 ppm (s) COOCH3
~ = 2.7 ppm (s) C-CH
~ - 86 -
'~b. ' ,
, ,' ~
~'; "',' '' '' ' ' ',
.: ', ~ ", ' `' :, . . :
~o~ 75/~169
~D8S9
.,
~ = 5.4 _ 5~6 p~m (m~ C~=CH
IR: ~730 cm ~ ~ C=O
168Q cm ~ ~ C=O
A !~ Y ):
1-(6-Methox carbonyl-(Z~ 2-hexene-~- l)-5 (3-hydrox~ op-2
- - -- Y .-~ Y.
en-yi- (E? -1-octene~ pyrrolidone-2
was prepared according to the method described in Example 7 from
~-(6-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-(E)-1-octene-
~-yl~-pyrrolidone-2 and allyl-magnesium bromide.
Chromatoc~raphy: toluene/acetic ester/methanol 5:4:0.1
NMR: S = 3.7 ppm (s) COOCH3
~ = 502 - 5.7 ppm (m) CH=CH and C~=CH2 (5 prot.
IR: 1735 cm 1 ~ C=O -
- ~685 cm~1 ~ C=O -
E X A M P L E 10:
~- (6-Metlloxycarbonyl- (Z? ~2-hexene-1-yl?-5-(3-hydroxy-3-methy~-
5-ethoxy-4,4-dimethyl-(E)-1-pentene-1-yl)-pyrrolidone-2
was prepared according to the meth~d described in Example 7 from
~-(6-methoxycarbonyl-(Z)-2-hexene~1-yl)-5-(3-oxo-5-ethoxy-4,4-
dimethyl-(E)-~-pentene-1-yl)-pyrrolidone-2 and methyl-magnesium
iodide.
Chromatography: toluene/acetic ester/methanol 5:4:0.3
NMR: ~ = O.~S ppm C[CH3)2 6 prot.
~ = ~.4 ppm C-CH3
S = 3.65 ppm COOCH3
IR; ~685 cm ~ 3 c-o
~735 cm ~ ~ C=O
7 -
. . . - ~ ,
~0l~7 s~
35~
E X A M P ~ E 11: -
1-(6-Methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-hydro~y-3-phen~1-
meth~l-(E)-1-decene-1-yl)-pyrrolidone-2
~as prepared according to the method described in Example 7 from
- 1-(6-methoxycarbonyl-(Z)-2-hexene-1-yl)-5-(3-oxo-(E)-1-decene-
.
1-yl)-pyrroli-done-2 and benzyl-magnesium chloride.
Chromatography: toluene/acetic ester/methan~l 5:4:0.1
NMR: . ~ = 3.7 ppm COOCH3
= 5.4 - 5.6 ppm CH=CH -
= 7.1 - 7.3 ppm C6H5
IRo 1730cm 1 ~ C=O .
. ~680 cm 1 ~ C=O
.. .
''~ ,
',
'' '' '
. .
, ' ' ' ' '
~ ' ' - ' .
.,' '' ~", '""" ',,''".
' - . ' ' '
: . ' .
- 88 -
''~ ' , , ' . .
,. . .
