Note: Descriptions are shown in the official language in which they were submitted.
13~:0~53
Our Patent Application Serial No 605,572 relates to
new 3-quinolone- and -naphthyridonecarboxylic acid
derivatives, processes for their preparation and
antibacterial agents and feed additives containing them. This
application is divided out of Application Serial No. 605,572
and is directed to certain diazabicyclo compounds that are
useful as intermediates in the preparation of the new 3-
quinolone- and -naphthyridonecarboxylic acid derivatives.
A number of 3-quinolone- and naphthyridonecarboxylic
acids which are substituted in the 7-position by a
pyrrolidinyl ring have already been disclosed. German Patent
Application 3,318,145 and European Patent Applications 106,489
and 153,826.
It has been found that the 3-quinolone- and
naphthyridonecarboxylic acid derivatives of the formula (I)
O
COOR2
3
2o R
R1
in which
X1 represents halogen,
X2 represents hydrogen, amino, alkylamino having 1 to 4
carbon atoms, dialkylamino having 1 to 3 carbon
atoms per alkyl group, hydroxyl, alkoxy having 1 to
4 carbon atoms, mercapto, alkylthio having 1 to 4
- 1 -
carbon atoms, arylthio or halogen,
R1 represents alkyl having 1 to 4 carbon atoms, alkenyl
having 2 to 4 carbon atoms, cycloalkyl having 3 to
6 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl,
methoxy, amino, methylamino, ethylamino, dimethyl-
amino or phenyl which is optionally substituted by
1 or 2 fluorine atoms,
RZ represents hydrogen, alkyl having 1 to 4 carbon
atoms or (S-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,
R3 represents a radical of the structure
R' Z-R4 R' R'
Z R .. .
N 5 ~ - N ~~--R ~ ~ - N
N N
R" ~ R.. R..
R6 Rb
wherein
R~ can represent H, C1-C~-alkyl, aryl or C1-C~-acyl,
RS can represent H, C1-C~-alkyl, OH or OCH3, it
also being possible for R' and RS together to
denote a C,-C,-alkylene bridge which is option-
ally mono- or disubstituted by methyl,
R~ can represent H, optionally hydroxyl-substi-
tuted C1-C4-aikyi, as well as aryl, heteroaryl, benzyl,
Le A 26 108 - 2 -
,.. I
130553
C1-C,-alkoxycarbonyl, C1-C,-acyl , ( 5 -me t by 1 - 2 -
oxo-1,3-dioxol-4-yl)-methyl, or C3-C6-cyclo-
alkyl,
R' can represent H or C1-C,-alkyl,
R' can represent H, CH3 phenyl,
or
R" can represent H, CH3 phenyl,
or
R"' can represent H
or
CH3,
Y can represent O, CH2,
CH2CHz
or
CH2-O,
it
being
possible for the CH2-0 group to be linked to
the nitrogen either O or via CH2, and
via
Z can represent 0 or S, and
A represents N or C-R8, wherein
RB represents H, halogen, methyl, cyano, vitro,
hydroxyl or methoxy or, together with Rl, can
form a bridge having the structure
-0-CH2-CH-CH3, -S-CH2-CH-CH3 or
1 I
-CH2-CH2-CH-CH3
I
and pharmaceutically usable hydrates and acid
addition salts thereof and the alkali metal, alka-
Le A 26 108 - 3 -
1340553
line earth metal, silver and guanidinium salts of
the underlying carboxylic acids, have a high
antibacterial action, in .particular in the Gram-
positive region.
Preferred compounds are those of the formula (I)
XZ 0
X1 ~ I I COOR2
R3~A NJ ( I )
R1
in which
X' represents fluorine or chlorine,
X2 represents hydrogen, amino, alkylamino having 1 or
2 carbon atoms, dimethylamino, hydroxyl, methoxy,
mercapto, methylthio, phenylthio, fluorine or
chlorine,
R1 represents alkyl having 1 to 3 carbon atoms, alkenyl
having 2 or 3 carbon atoms, cycloalkyl having 3 to
5 carbon atoms, 2-hydroxyethyl, 2-fluoroethyl,
methoxy, amino, methylamino, ethylnmino, dimethyl-
amino or phenyl which is optionally substituted by
1 or 2 fluorine atoms,
Ri represents hydrogen, alkyl having 1 to 3 carbon
atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,
Le A 26 108 - 4 -
f .--.
1~~~~53
R' represents a radical having the structure
R' Z-R4 R' R' ,
Z R"
r
_ N 5 ~ _ N~ ~~"R7 ~ _ N
N
R" \R6 R" R,. R6
wherein
R~ can represent H, C1-C3-alkyl or C1-CZ-acyl,
R3 can represent H, C1-C3-alkyl, OH or OCH3, it
also being possible for R' and Rs together to
denote a C1-Cz-alkylene bridge which is option-
ally mono- or disubstituted by methyl,
R6 can represent H, optionally hydroxyl-substitu-
ted C1-C3-alkyl, a s we 1 1 a s p he ny 1 , benzyl ,
C1_C4-41 koxy-
carbonyl, Cl-C2-acyl, (5-methyl-2-oxo-1,3-
dioxol-4-yl)-methyl, yr C3-CS-cycloalkyl,
R' can represent H or C1-C2-alkyl,
R' can represent H or CH3,
R" can represent H or CH3,
R"' can represent H or CH3,
- Y can represent 0, CHZ, CH2CH2 or CHZ-O, it being
Le A 26 108 - 5 -
i
1.'.3~0~~ ~3
possible for the CH2-O group to be linked to
the nitrogen either via O or via CH2, and
Z can represent 0 or S, and
A represents N or C-R~, wherein
R~ represents H, fluorine, chlorine, bromine,
methyl, vitro, hydroxyl or methoxy or together
with Rl can form a bridge having the structure
-0-CHZ-CH-CH3
I
Particularly preferred compounds are those of the formula
(I)
X2 0
X1 ~ COOR2
R3 ~~j~~ ( I )
R1
in which
X1 represents fluorine,
X2 represents hydrogen, amino, methylamino or fluorine,
RI represents alkyl having 1 or 2 carbon atoms, vinyl,
cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy,
methylamino, 4-fluorophenyl or 2,4-difluorophenyl,
Le A 26 108 - 6 -
n
RZ represents hydrogen or alkyl having 1 or 2 carbon
atoms,
R' represents a radical having the structure
R' Z-R4 R' R'
Z R"'
-N , -N~ ,~-R~ , -N~~
S NN
R" \ R" R"
R6 R6
wherein
R' can represent H, C,-C2-alkyl or acetyl,
R5 can represent H or Cl-CZ-alkyl, it also being
possible for R' and RS together to form .a C1-C2
alkylene bridge which is optionally substituted
by methyl,
R6 can represent H,CH3, CZHS, HOCH2CH2, benzyl,
C1-
C'-alkoxycarbony l or C1-C2-acyl,
R' can represent H or CH3,
R' can represent H or CH3,
R" can represent H or CH3,
R"' can represent H or CH3,
Le A 26 108 - 7 -
t
1340e3
Y can represent O, CH2, CHZCH2 or CH2-O, it being possible
for the CH2-O group to be linked to the nitrogen either
via O or via CH2, and
Z can represent O or S, and
A represents N or C-R8, wherein
R$ represents H, fluorine or chlorine, or together with Rl
also can form a bridge having the structure
-O-CH2-CH-CH3.
I
It has furthermore been found that the compounds of the formula
(I) are obtained by a process in which compounds of the formula
(II) r
XZ O
X1 ~ I ' COORZ (II)
X 3 wA~IJ~
R~
in which
Rl, R2, Xl and X2 have the abovementioned meaning and
X3 represents a leaving group, such as alkyl- or
arylsulphonyloxy or halogen, in particular fluorine or
chlorine, are reacted with compounds of the formula (III)
g .~ '
.~3~~05~
Rj-H ( I I I )
in which
R3 has the abovementioned meaning,
if appropriate in the presence of acid entrainers, and if
appropriate protective groups contained in R3 are removed
(method A).
Compounds of the formula (I) according to the invention
XZ 0
~ ~ cooR2 (I)
R3
R1
in which
X1, R1, RZ, R3 and A have the abovementioned meaning and
X2 represents amino, alkylamino having 1 to 4 carbon
atoms, dialkylamino having 1 to 3 carbon atoms per
alkyl group, hydroxyl, alkoxy having 1 to 4 carbon
atoms, mercapto, alkylthio having 1 to 4 carbon
atoms or arylthio,
can also be obtained by reacting a compound of the
formula (IV)
Le A 26 108 - 9 -
f
13~~0~~3
F 0
X1 i COOR2
R3 ~A~ ~ ~ (IV)
N
R1
in which
X1, R1, R2, R' and A have the abovementioned meaning,
with compounds of the formula (V)
X2-H ( V )
in which
X2 has the abovementioned meaning, if appropriate in
the presence of acid entrainers (method B).
Compounds of the formula (Ia) according to the invention
XZ O
X1 ~ COORZ (Ia)
R ~ ~~~N~
R1
in which
X', g2, R~, R2 and A have the abovementioned meaning and R3
represents a radical having the structure
Le 26 1Q8 - IO -
13~~? Q53
R'
R' Z-Rq R., .
or - N~ ~ ~ ~Y
_ N ~N.
R..
R.. \ R6
R6
wherein
R~, R5, R~, R' , R" , R" ' , y and Z have the abovementioned
meaning,
can also be obtained by a process in which a compound of
the f orniula ( VI )
X2 0
X1 ~ COOR2 (VI) .
R3 a~~,j~N~
R1
in which
X1, X2, Rl, RZ and A have the abovementioned meaning and
R'' represents a radical having the structure
R' Z-R4 ,
R'
-N . R"'
or -N 'Y
R" I R., i.
H H
Le A 26 108 - 11 -
130553
wherein
R'", Rs, R' , R" , R" ' , Y and Z have the abovementioned
meaning,
is reacted with compounds of the formula (VII)
R6-X' ( VI I )
in which
R6 has the abovementioned meaning and
X' represents chlorine, bromine, iodine, hydroxyl or
acyloxy,
if appropriate in the presence of acid entrainers (method
C).
If, for example, 1-cyclopropyl-6,7,8-trifluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid and 1-methyl-
octahydropyrrolo[3,4-b]pyridine are used as starting
substances, the course of the reaction can be represented
by the following equation:
Le A 26 108 - 12 -
130553
0
COOH BasQ
i ~ NH -.
F ~ -HF
F ~ CH3
O
COOH
~N N
F
CH3
If, for example, 7-chloro-6-fluoro-1-(4-fluorophenyl)-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and
cis-3-tert.-butoxycarbonylamino-4-methoxy-pyrrolidine are
used as starting substances, the course of the reaction
can be represented by the following equation:
Le A 26 108 - 13 -
13U553
0
CH30
r v COOH Basa
I ~ NH --
C1 N -HC1
(CH3)3C-0-CO-NH
I
r
I
F
COOH
HC1
CH30
(CH3)3C-0-CO-NH
I
r
F
0
r ( ~COOH
CH3 N ~ N
NHZ I r
F
x HC1
0
N
Le A 26 108 - 14 -
f, ~ .
If, for example, 1-cyclopropyl-5,6,8-trifluoro-1,4-
dihydro-7-(2-methyl-2,7-diazbicyclo[3.3.0]oct-3-yl)-4-
oxo-3-quinolinecarboxylic acid.and ammonia are used as
starting substances, the course of the reaction can be
represented by the following equation:
F O
COOH
NH3
~N
~N
F
H3C-N
NH, O
00H
N
N
H3C'
a
If, for example, 1-cyclopropyl-7-(2,7-diazabicyclo-
[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid and ethanool/hydrogen chloride are used
as starting substances, the course of the reaction can be
represented by the following equation:
Le A 26 108 - 15 -
0
COOH HC1
~ C2H50H .
N
N
HN
0
COOCZHS
~NJ
~N
HN
x HC1
The compounds of the formula (II) used as starting
substances are known or can be prepared by known methods.
Examples which may be mentioned are:
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,142,854),
1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid (European Patent Application 113,091),
6-chloro-1-cyclopropyl-7,8-dfluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,420,743),
Le A 26 108 - 16 -
I~~U 5~3
8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,420,743),
1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid (German Patent Application
3,318,145),
6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,420,743),
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-
quinolinecarboxylic acid,
1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-8-n:itro-4-
oxo-3-quinolinecarboxylic acid,
6,7-difluoro-1-ethyl-1,4-diyydro-4-oxo-3-quinoline-
carboxylic acid,
7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid,
7-chloro-6-fluoro-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-
3-quinolinecarboxylic acid,
6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
Le A 26 108 - 17 -
13~~J~53
8-chloro-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid (European Patent
Application 235,762),
7-chloro-6-fluoro-1,4-dihydro-1-methoxy-4-oxo-3-quino-
linecarboxylic acid,
7-chloro-6-fluoro-1,4-dihydro-1-methyiamino-4-oxo-3-
quinolinecarboxylic acid,
6,7-difluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinoline-
carboxylic acid,
7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid,
6,7-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid,
ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3
quinolinecarboxylate (German Patent Application
3,318,145),
9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-
de][1,4]benzoxazine-6-carboxylic acid (European Patent
Application 47,005),
8,9-dif luoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[i,j]-
quinolizine-2-carboxylic acid,
Le A 26 108 - 18 -
7-chloro-6-fluoro-1-phenyl-1,4-dihydro-4-oxo-1,8-naph-
thyridine-3-carboxylic acid (European Patent Application
153,580),
7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid (European Patent
Application 153,580),
6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quino-
linecarboxylic acid (German Patent Application
3,409,922),
1-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid (German Patent Application 3,409,922),
6,7,8-trifluoro-1,4-dihydro-1-dimethylamino-4-oxo-3-
quinolinecarboxylic acid (German Patent Application
3,409,922),
7-chloro-6-fluoro-1,4-dihydro-8-nitro-4-oxo-1-phenyl-3-
quinolinecarboxylic acid,
7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-8-nitro-
4-oxo-3-quinolinecarboxylic acid,
6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-8-methyl-4-
oxo-3-quinolinecarboxylic acid,
6-chloro-7-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid (European Patent Application
Le A 26 108 - 19 -
- -
.. t.
13~~~ ~~
131,839),
5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid,
5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid,
5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
6-chloro-7-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4
oxo-3-quinolinecarboxylic acid (European Patent Applica
tion 131,839),
6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4Toxo-3-
quinolinecarboxylic acid (European Patent Application
154,780),
6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo
3-quinolinecarboxylic acid (European Patent Application
154,780),
6,7,8-trifluoro-1,4-dihydro-4-oxo-1-phenyl-3-quinoline-
carboxylic acid (European Patent Application 154,780),
7-chloro-1-ethyl-b-fluoro-1,4-dihydro-4-oxo-1,8-naph-
thyridine-3-carboxylic acid,
6,7-difluoro-1,4-dihydro-4-oxo-1-vinyl-3-quinoline-
Le A 2b 108 - 20 -
~3~!~0~53
carboxylic acid,
1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,
1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-hydroxy-4-oxo-3-
quinolinecarboxylic acid, and
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
quinolinecarboxylic acid.
The compounds of the formula (III) used as starting
compounds are new in some cases, and this divisional
application is directed to compounds selected from the group
consisting of 2-oxa-5,8-diazabicyclol4.3.0]nonane
dihydrochloride, traps-2-oxa-5,8-diazabicyclo[4.3.0]nonane, 5-
methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride,
2,8-diazabicyclo-[4.3.0]nonane, 4-methyl-2,8-diazabicyclo-
[4.3.0]nonane, 2-methyl-2,8-diazabicyclo[4.3.0]nonane, 2,7-
diazabicyclo-[3.3.0]octane, 2-methyl-2,7-diazabicyclo-
[3.3.0]octane, 3-oxa-2,7-diazabicyclo[3.3.0]octane, 2-methyl-
3-oxa-2,7-diazabicyclol3.3.0]octane, 2,5-dimethyl-3-oxa-2,7-
diazabicyclo-[3.3.0]octane, 2,8-dimethyl-3-oxa-2,7-diaza-
bicyclo-[3.3.0]octane, 2-methyl-4-oxa-2,8-diazabicyclo-
[4.3.0]nonane, 3-methyl-2,7-diazabicyclo[3.3.0]octane, 2,3-
dimethyl-2,7-diazabicyclo[3.3.0]octane, ethyl-2,7-
diazabicyclo[3.3.0]octane-2-carboxylate, 2-phenyl-2,7-
diazabicyclo[3.3.0]octane and 4-oxa-2,8-diazabicyclo[4.3.0]-
nonane.
Compounds of formula (III) can be prepared by the
- 21 -
13~055~
following processes.
1. Starting from the N-protected 3,4-epoxypyrrolidine (1)
(German Offenlegungsschrift (German Published
Specification) 1,929,237 and U.S. Patent 4,254,135),
which can optionally also carry one or two methyl or
phenyl radicals, the starting compounds of the formula
(IIIa) (IIIe) are prepared.
- 21a -
HQ /RS renrova l of HO, /R
/R5 \Rb protective- groups , \R6
~ HN '_""
6 N
\R N
R9 R9 H
(1) (IIIa)
R4X3 Basa R40 /R5
removal of
R40 /RS \R6
protective groups N
~.~\R6
N H
R9 tIIIb)
R9 - benzyl, acyl, alkoxycarbonyl, benzyloxyca=bonyl,
trialkylsilyl or sulphonyl (examples of protec-
tive groups),
X' - a leaving group, such as halogen, or alkyl- or
arylsulphonyloxy
Le A 26 108 - 22 -
13445e
R4 0 A.."
HOw 3 R4X3
N3 N
(1) N
Ba~a R9
Rq0 h,~~ H R40~~, H-COOC ( CH3 ) 3
2
N
N
R9 H
(IIIc)
_ RqOb~," OH
Rq0
(1l N
0 \ R4 H2
N
R40
O
N
Le A 26 108 - 23 -
13~OW3
R40. H-R6 R40 4
~R6 R ~R6
H IPd N
N
N 2
H
' .
tIiIe)
HZIPd
Rq0 H_R6
N
(IIId)
H
2. Starting compounds of the formula (IIIf) are
obtained from 2-(1,2-dichloroethyl)-oxirane via the
following reaction sequence:
Ho ci _
R40
C I NJ
R40 OH R40 0
NJ N
'~ '
Le A 26 108 - 24 -
r
~~~a~~~
~5 ~5
Rq0 N R40 N
\R 6 \R 6
HZ
Ni --' N
H
(IIIf)
3. By addition of azides onto N-benzylmaleimides which
are optionally substituted by one or two methyl or
phenyl radicals, starting compounds of the formula
(III g) can be prepared:
R9
N~NwN-R9 N
N~~ ~N p 0 ~N~O
I
RqO~ru~f, H-Rg Rq~n.~~f H_R10
seduction
.-.-. N~ N
Le A 26 108 - 25 -
13~~~5~
R40~~".. H_R10
N
H
(IIIg)
R1~ - H, alkyl or benzyl.
4. :prom the 3,4-epoxypyrrolidines (1), the starting
compounds of the formula (III h) are obtained via
cyclization with thionyl chloride:
HOn~~ HZ HO~~~~.- H-CO-R~
(1) 50C12
R 9 R 9 ---.
R~ R~
C~N O~N
N N
R9 H
(III h)
5. Hy reaction of the 3,4-epoxypyrrolidines (1) with
ethanolamines, the starting compounds of the formula
(III i) are~obtained by intramolecular etherifica
tions
Le A 26 108 - 26 -
1~~~~~3
R6 ,
/~/NH-R6 HO N~OH
HO He
(~) ~ _-.
N
R9
0 N-R6 ----~ p N-R6
H
(III i).
6. The starting compounds of the formula (III~~j) are
obtained from aminoacetaldehyde dimethyl acetal via
intramolecular 1,3-dipolar cycloaddition.
R'
OCH3
HZN i~CH3 --' R9'NH /~OCH3 HZC~/X3
Base
/~OCH3 H~ /'CHO R6-NH-OH
R9_N~/CH2 . 3 ~ R9_N~/CH2
R, R.
Le A 26 108 - 27 -
134Q53
~N-R6 ~N-R6
R. R.
N~ i
R9 H
(III j)
7. Starting from pyridine-2,3-dicarbouylic acid N-
benzylimide, starting compounds (III k) or (III 1)
are prepared via the reaction steps shown.
0
I \N CH2-C6H5
alkyl iodide 0 H2~Ru-C 'or
Pd-C
0 O
I \N-CHZ-C6H5 N-CHZ-C6H5
IA
H O
0
J11ky1
LiAlHa of
IHZIPt02 NaBH4~
l BF3~(C2H5)ZO
O
N-CHZ-C6H5 N-CHZ-C6H5
H
0
Alkyl
Le A 26 108 - 28 -
1~~0~~~3
LiAlH4 H2IPd-C
N-CH2-C6H5 NH
H
Alkyl
(III 1)
HZ/Pd-C
NH
Alkyl
(III k)
8. N-Benzyl-maleimide adds onto 2-chloroethylamines to
give 3-{2-chloroethylamino)-succinimides, which are
converted into the starting compounds of the formula
(III m):
0
I \N-CHZ-C6H5 + C1-CHZCHZ-NH-R6
O
Cl 0
I NaH
iHZ N-CH2-C6H5
CHZ-i O
R6
O
N-CHZ-C6H5 LiAlH4 N-CH2-C6H5
0 I
R6 R6
Le A 26 108 - 29 -
13~0~~3
NH
H2lPd-C
R6
(III m)
9. 2-Methyl-2-propenal-dimethylhydrazone reacts with N-
benzylmalei_mide to give a cycloadduct, which can be
converted into the starting compound (IIIn) by the
reaction sequence shown.
0 O
CH3~~CH2 \ CH3 \
N-CH2-Ph --~ ~ N N-CH2-Ph
N 0 N 0
/ \ / \
CH3 CH3 CH3 CH3
O O
-(CH3)2NH CH3 \ H21 CH3 \
N ~ N-CHZ-Ph catalyst ~ N N-CH2-Ph
H / H
0 O
LiJ~lH4 CH3 H2/Pd-C CH3
---~ N~N-CH2 Ph ---~ N~NH
H H
(III n)
Le A 26 108 - 30 -
H
0
134~~~3
10. Starting compounds of the formulae (IIIo), (IIIp) or
(IIIq) can be obtained in the following way, start-
ing from N-protected 2,5-dihydropyrroles (3-pyr-
rolines) by addition of sulphenyl chloridess
Le A 26 108 - 31 -
1340e3
C1 S-R11
~ R11-S-C1 "~"'
N N
1. ~R6-NHZ (R119= CHZCHZ-Hal) Rsw
~ NH
2~ Removal or R R6i
R6
R6-N~S ' S_R11
R6/N \ /
N
N I9
H R
(IIIo)
R5
R6~ SH Remova L o-f R~ 6\ S-R11
R R /N \ /
11 _ Alkox N
N (R Acyl, y-
H carbonyl) H
(IIIp) (IIIq)
R11 - C1-C,-alkyl which is optionally substituted by
halogen or phenyl, which is optionally substituted
by halogen, nitro, alkyl or alkoxy, as well as
5 acyl or alkoxycarbonyl.
The following starting compounds, for example, can be
prepared in accordance with these general equations . They
Le A 26 108 - 32 -
"
13 ~ O~~a
can be prepared and employed as diastereomer mixtures or
in the diastereomerically pure or enantiomerically pure
form.
4-amino-3-hydroxypyrrolidine,
3-hydroxy-4-methylaminopyrrolidine,
4-dimethylamino-3-hydroxypyrrolidine,
4-ethylamino-3-hydroxypyrrolidine,
3-amino-4-methoxypyrrolidine,
4-methoxy-3-methylaminopyrrolidine,
3-dimethylamino-4-methoxypyrrolidine,
3-ethylamino-4-methoxypyrrolidine,
3-amino-4-ethoxypyrrolidine,
4-ethoxy-3-methylaminopyrrolidine,
3-dimethylamino-4-ethoxypyrrolidine,
4-ethoxy-3-ethylaminopyrrolidine,
3-hydroxy-4-hydroxyaminopyrrolidine,
3-hydroxy-4-methoxyaminopyrrolidine,
3-hydroxyamino-4-methoxypyrrolidine,
4-methoxy-3-methoxyaminopyrrolidine,
3-benzylamino-4-methoxypyrrolidine,
4-methoxy-3-(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl-
amino)-pyrrolidine,
3-amino-4-methylmercaptopyrrolidine,
3-acetoxy-4-dimethylaminopyrrolidine,
3-acetamido-4-methoxypyrrolidine,
4-methoxy-3-methoxycarbonylaminopyrrolidine,
3-formamido-4-methoxypyrrolidine,
3-amino-4-methoxy-2-methylpyrrolidine,
3-amino-4-methoxy-5-methylpyrrolidine,
Le A 26 108 - 33 -
4-methoxy-2-methyl-3-methylaminopyrrolidine,
4-methoxy-5-methyl-3-methylaminopyrrolidine,
3-amino.-4-methoxy-2-phenylpyrrolidine,
4-methoxy-3-methylamino-5-phenylpyrrolidine,
3-methyl-2,7-diazabicyclo[3.3.0]octane,
4-methyl-2,7-diazabicyclo[3.3.0]octane,
5-methyl-2,7-diazabicyclo[3.3.0]octane,
3,5-dimethyl-2,7-diazabicyclo[3.3.0]octane,
1,5-dimethyl-2,7-diazabicyclo[3.3.0]octane,
2-oxa-4,7-diazabicyclo[3.3.0]octane,
3,3-dimethyl-2-oxa-4,7-diazabicyclo[3.3.0]octane,
3-oxa-2,7-diazabicyclo[3.3.0]octane,
1,2-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane,
2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane,
2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane,
5-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane,
2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene,
3-methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene,
3-phenyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene,
6-methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene,
8-methyl-2-oxa-4,7-diazabicyclo[3.3.0]oct-3-ene,
3-methyl-2,8-diazabicyclo[4.3.0]nonane,
4-methyl-2,8-diazabicyclo[4.3.0]nonane,
5-methyl-2,8-diazabicyclo[4.3.0]nonane,
6-methyl-2,8-diazabicyclo[4.3.0]nonane,
3-methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane,
4-methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane,
1-methyl-2-oxa-5,E-diazabicyclo[4.3.0]nonane,
3,5-dimethyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane,
2-this-5,8-diazabicyclo[4.3.0]nonane,
Le A ~6 108 - 34 -
13 ~~~53
5-methyl-2-thia-5,8-diazabicyclo[4.3.0]nonane, 3,5-dimethyl-2-
thia-5,8-diazabicyclo(4.3.0]nonane, 3-oxa-2,8-
diazabicyclo(4.3.0]nonane, 2-methyl-9-oxa-2,8-
diazabicyclo[4.3.0]nonane, 4-methyl-3-oxa-2,8-
diazabicyclo[4.3.0)nonane, 2-5-dimethyl-3-oxa-2,8-
diazabicyclo(4.3.0]nonane, 3-oxa-5,8-diazabicyclo[4.3.0]nonane, 5-
methyl-3-oxa-5,8-diazabicyclo[4.3.0]nonane, 1,5-dimethyl-3-oxa-
5,8-diazabicyclo[4.3.0]nonane and 4,4-dimethyl-3-oxa-5,8-
diazabicyclo[4.3.0]nonane.
The reaction of (II) with (III) according to method A,
in which the compounds (III) can also be employed in the form of
their hydrochlorides or other acid addition salts, is preferably
carried out in a diluent, such as dimethyl sulphoxide, N,N-
dimethyl-formamide, N-methylpyrrolidone, hexamethyl-phosphoric
acid triamide, sulpholane, acetonitrile, water, an alcohol, such
as methanol, ethanol, n-propanol or isopropanol, glycol monomethyl
ether or pyridine. Mixtures of these diluents can also be used or
the reaction can be carried out without any solvent.
Acid-binding agents which can be used are a11 the
customary inorganic and organic acid-binding agents. These
include, preferably, the alkali metal hydroxides, alkali metal
carbonates, organic amines and amidines. Particularly suitable
acid-binding agents which may be mentioned specifically are:
triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-
diazabicyclo(5,4,0]undec-7-ene (DBU) or excess amine (III).
~'3 ~p~~3
The reaction temperatures can be varied within a substan-
tial range. The reaction is in general carried out
between about 20 and 200~C, preferably between 80 and
180~C.
The reaction can be carried out under normal pressure,
but also under elevated pressure. It is in general
carried out under pressures between about 1 and l00 bar,
preferably between 1 and IO bar.
In carrying out the process according to the invention,
1 to 15 mol, preferably 1 to 6 mol, of the compound (III)
are employed per mol of the carboxylic acid (II).
Free hydroxyl groups can be protected during the reaction
by a suitable hydroxyl-protective group, for example by
the tetrahydropyranyl radical, and can be liberated again
when the reaction has ended (see J.F.W. McOmie, Protec-
tive Groups in Organic Chemistry (1973), page 104).
Free amino functions can be protected during the reaction
by a suitable amino-protective group, for example by the
ethoxycarbonyl or tert.-butoxycarbonyl radical, and
liberated again when the reaction has ended by treatment
with a suitable acid, such as hydrochloric acid or
trifluoroacetic acid (see Houben-Weyl, Methoden der
organischen Chemie (Methods of Organic Chemistry), Volume
E4, page 144 (1983); and J.F.W. McOmie, Protective Groups
in Organic Chemistry (1973), page 43).
Le A 26 108 - 36 -
-.-.
,:
The reaction of (IV) with (V) according to method B is
preferably carried out in a diluent, such as dimethyl
sulphoxide, dioxane, N,N-dimethylformamide, N-methyl-
pyrrolidone, hexamethyl-phosphoric acid triamide, sulpho-
lane, water, an alcohol, such as methanol, ethanol, n-
propanol or isopropanol, glycol monomethyl ether or
pyridine. Mixtures of these diluents can also be used.
Acid-binding agents which can be used are a11 the cus-
tomary inorganic and organic acid-binding agents. These
include, preferably, the alkali metal hydroxides, alkali
metal carbonates, organic amines and amidines. Particu
larly suitable acid-binding agents which may be mentioned
specifically are: triethylamine, 1,4-diazabicyclo(2.2.2]
octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU).
The reaction temperatures can be varied within a substan-
tial range. The reaction is in general carried out
between about 70 and about 200~C, preferably between 100
and 180~C .
The reaction can be carried out under normal pressure,
but also under increased pressure. It is in general
carried out under pressures of between about 1 bar and
about 100 bar, preferably between 1 and 10 bar.
In carrying out the process according to the invention by
method H, 1 to 50 mol, preferably 1 to 30 mol, of the
compound (V) are employed per mol of the compound (IV).
Le A 26 108 - 37 -
1~3~0~53
To prepare the esters according to the invention, the
carboxylic acid on which they are based is preferably
reacted in excess alcohol in. the presence of strong
acids, such as sulphuric acid, anhydrous hydrochloric
acid, methanesulphonic acid, p-toluenesulphonic acid or
acid ion exchangers, at temperatures from about 20~ to
200~C, preferably about 60~ to 120~C. The water of reac
tion formed can also be removed by azeotropic distilla
tion with chloroform, carbon tetrachloride, benzene or
toluene.
The esters are also advantageously prepared by heating
the acid on which they are based with dimethylfonaamide
dialkyl acetal in a solvent, such as dimethylformamide.
The 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl esters.used as
a prodrug are obtained by reaction of an alkali metal
salt of. the carboxylic acid on which they are based with
4-bromomethyl- or 4-chloromethyl-5-methyl-1,3-dioxol-2-
one in a solvent, such as dimethylformamide, dimethyl-
acetamide, N-methylpyrrolidone, dimethyl sulphoxide or
tetramethylurea at temperatures of about 0~ to 100~C,
preferably 0~ to 50~C.
The acid addition salts of the compounds according to the
invention are prepared in the customary manner, for
example by dissolving the betaine in excess aqueous acid
and precipitating the salt with a water-miscible organic
solvent, such as methanol, ethanol, acetone or aceto-
nitrile. It is also gossible to heat equivalent amounts
Le A 26 108 - 38 -
1~~0~~
of the betaine and acid in water or an alcohol, such as
glycol monomethyl ether, and then to evaporate the
mixture to dryness or filter off the precipitated salt
with suction. Pharmaceutically usable salts are to be
understood as, for example, the salts of hydrochloric
acid, sulphuric acid, acetic acid, glycolic acid, lactic
acid, succinic acid, citric acid, tartaric acid, methane
sulphonic acid, 4-toluenesulphonic acid, galacturonic
acid, gluconic acid, embonic acid, glutamic acid or
aspartic acid.
The alkali metal or alkaline earth metal salts of the
carboxylic acids according to the invention are obtained,
for example, by dissolving the betaine in excess alkali
metal or alkaline earth metal hydroxide solution, filter-
ing from the undissolved betaine and evaporating the
filtrate to dryness. Sodium, potassium or calcium salts
are pharmaceutically suitable. The corresponding silver
salts are obtained by reaction of an alkali metal or
alkaline earth metal salt with a suitable silver salt,
such as silver nitrate.
The compounds listed by way of example in Table 1 can
also be prepared, in addition to the active compounds
mentioned in the examples, it being possible for these
compounds to be present both as diastereomer mixtures or
as the diastereomerically pure or enantiomerically pure
compounds.
Le A 26 108 - 39 -
I340~~3
..'
X
,
z z
z z-~
x
i
x 1z x
0
i ~- z z
r-
v
~a
N
~lr'
O
O
U
O Z a.'
N
X <
.. ~7
x
Le A 26 108 - 40 -
!'
~.3405~<3
<I U U U U U
N I N
XI x
I x Z x x x
-~ I f~. LL LL CL Li.
YC I
I
I
I
I
I
I
I ! i i i i
I Z Z Z Z Z
I
c~7 I
zx zx zx zx zx
I
I
y
n
C
O
r
,..I
N
(p f~ x x x x x
C
i
C
O
N
I / /
.r I w u~ U
S I U U Li. U
Le A 26 108 - 41 -
<I U U
U U U
N
x ti, Iz x x
~~ I ~ L~. Lt LL Iz
X I
I
I
I
I
1
I
I
I
I
I
I
I
I
I
I z z z z z
I
i
~ I
I
I zx x ~ x ~ x ~ x
I
I
I
I x x
U U
I
C ~ O
~O
y
N
x x x N
U r7
C
I N U
C ~ x
O U
I
N
'"' S
I N
x
~~ U
~ I i
O I
Le A 26 108 - 42 -
1~~0~ ~~
I
I
I -.
I
I
< U U U U Z
(
N N
Z Z
i Z O Z
I L~. LL t~. Iz.
X I
I
I
I
I
I
I
I
I
I
I ~ i i i i
I Z Z Z Z Z
I
I
I
r7 I
I
I
I O Z Z O Z O Z Z Z O Z
~/ ~J
0
C
~r I
i, I
C
0 I
a I
v
.~.
I
Le A 26 108 - 43 -
13~~~53
< V ~' ~. ~. x
U U U U
I
I
N
X
x c~ x tz x
cs. ct.
x
I
I
I
I
I
I
I
1
I
I
I
Z Z Z Z Z
I
r7 I
x x
U - U
O Z x O Z Z x x
I Y
I
C
O
co
C
r.
C
O
I
..
I N
I
U
N
Z x
U
Le A 26 1 8 - 44 -
r ..
l~~p Q53
,,
~ i z~ z~ z z z
i I x ~x Zx I x Zx
C
O
.r
C
~r
C
O
a
..
v
m
H
Le A 26 108 - 45 -
J ~~~
1340e3
n _~
U
U
tl U U V U
N I
X = Z = Z
.(,L. ri. (i ni.
X
I
I
I
I
t
I
I
I
I .,
I i
i Z
I
I ,
_--~ Z--' ~ Z 1
_~ _~ I
_ _ 1..~ ~, Z =
I Z '.' I U U O~ ''~Z ~..J
U
Z
Z Z Z t U
I
..
to Z ~ Z Z .' S Z
7
G
G
O
v
-. i
I I
Le A 26 108 - 46 -
1a 40553
< v U U U U v
..
C
O
..
7
C
y
C
O
V
v
.r
.d
A
r
Le A 26 108 - 47 -
table 1 (continuation)
crD ttl t~~ Xl X2 A
____ ________________ __-_
__-
N _ ~
~ CII~D~N'
F II N
H 2 N \1, ~
t
C1130 N-
' F NH2 CF
I,~N ~,,
' cli3a~N_
,p -C F tl CF
i ~ fl2N '~~..,
S
CN30 N-
~~ F 11 C F
11 L N ~""".
CH30 ~N-
F H N E..a.
_~ _J
II~N
~;",; f
F H N
C ~~ -
N
Ii
Table 1 (continuation)
r
R3 _
--____ _
---______'_~_-_
CH30 N-
CF
N
O
ao H2N
CH30 N-
_C2H5
N
H2N
_
Ho
~J CF
H2N~;
~a
HO~..
N -
~ C F
!iL~JI
HZN"
CH30 IN-
CH
H3-NH
v~
..,
134~~~3
_-~
o Z o
_ ~ z ~ x/ ~ z/
U c'~ U ~ U c"~ U c~ c''~ U c"~ c~
I Z Z Z t Z t Z
I U U U U U U U
C
O
+~ ~ Z Z Z Z Z
co
7
C
sr
C
0
V
v
r
J ~ I
H
Le A 26 108 - 50 -
~~~(~003
< I U U U U U
t I
i Z~ Z~ Z Z Z
I I
Z
I O Z O Z O Z u7 Z cn Z
Z tl> N f'1 N t'7 N
S S ~n S S S S S S
U = = U N CN U U
U U U
C
O
r
y'
N
O Z Z S S S
S
7
C
r
(
I
C
I
O
U
v
r
N u7
J
N N
Le
A
26
108
- 51 -
-~ L~, Cr. Lz LL Is.
x
Table 1 (coqtinuation)
s
r
N RI R2 ft3 X1 X2 A
_-_______ __ _ -__-____________ _ _______ ____________ -'_______ _______
N CH3C0-O N-
H CH-~\ r J F H - CH
o N~
ao CH3/
CH3C0-O ~N-
H CH3\ '~ F H CF
N
CH3/
CH3C0-O ~N-
H CH3\ F H CC 1
t - N
v, CH3/
N
w
O O CH3 CH30 N-
H ~ - F H CH
O CH2- -N
w
CH3 CH30 N-
_ H O~O ~ _ F H CF
O~C H -N
2
w
O O CH3 CH30 N-
H ~ =- F H C C 1
O-~CH --N
2
_,
ts. U Is. _
< Z U U U U
~
I
I
t
Z Z Z t
;h I t t ~ U U i
Z I \ % I
~I
I O ~ O Z O Z O Z O Z
I ~ f~ N f'7 N f'1 N f''1 N
I /?-O Z Z Z Z Z Z V Z
U U U
C
O I
Z I t Z Z S Z
C
i
C
O I
I
v I
I
I I
4! I
J I
Z ~ I I
I
Le A 26 108 - 53 -
13~~0~3
x
U
Lt. Iz.
< U U U U
1
I
I
I
I
I I
N
x Z
I Ct Iz ~. s
X
I
I
I
I
I
I
I
I
I Z
I
I
I
I
~ z ~Z1
i iZ \ / = x ~ I
Z I i \ / U =
I U '-,
I ~ N O Z ~ r N
Z x
V = U = ~ U
I U
I
..
C
O
s' N
x x x x
I
C I
I
+, ,
C I
O
U
v
I
4J ~ I I
H
I~e A 26 108 - 54 -
Table 1 tcontinuataon)
N
K-) X 1 X 2 A
CH30 N
H F H CF
CH30-CONH-'
CH30 N-
H F H CF
OCH-NH
1
CH30 ~N-
~ H F
H C C 1
tn
OCH-NH
i
CH30 ~N-
l~ F H C F
HO-NH
CH30 ~N-
H F H CF
CH
0-NH r
3
G~
cr:'t
~1i
-w
,,
1~~0.~~3
< I U U U U U
N I
~ I Z Z Z Z Z
-. t~. Lz. ~. ~ h.
t
X
I
I
I
I
I Z Z
I Z ~ Z Z
I O O Z
c~ I _c'~ Z c'~ Z
~ ! U O U O
i O ~ O ~ O
Z ~ ~ Z
I U U
I
i
C I
o I
N I
Z ~ Z Z Z Z Z
7
C
C I
O
U I
v I
I
I
4J
Z I
H
Le A 26 108 - 56 -
.-..,
t
134053
U
< U U U U U
I
f
N I
Xi Z
Z Z
I
I
7C
I
I
I
I
1
I
I
I i Z Z Z
I Z
i
I
Z ~ Z ~ Z Z Z
I
I U U
I ~
Z Z
C
O
~o
C
C
O
c~
..
J
I
Le A 26 108 - 5~ -
1~4t~~~~
Z U Ls.
t Z U U U U
i i i i i
I Z Z Z Z Z p
N
U
N
Z ~ t ~ Z Z-U
..
C
O
7
C
~r
C
O
a
v
I
t0
H
~,e A 26 108 - 58 -
r. _,
13~~5~3
I
i
i ~ ~ i i
I Z Z Z Z Z
I
I
I
Z
I
i s s zs zs zs
I
..
c
0
s s x
I
' I
c I
'~, I
c I
o I
i
I
I
I ~ i
zI
I
Le A 26 108 - 59 -
s
U U Z U U
I
I
13~~~~3
t U ft U U
U U V
1 I
N N
Z h Z ~r .r
I U U
7C I (z' Cz ts. h.
I
I
I
I
i i i i
I Z Z Z Z Z
i
C7 I
I
Z Z Z ~ T Z Z
I
I
I
I
f
C
O
'~ N
Qi T.
C
I
C
I
(Z
r
i ~ ~ ~ ~
~ ~ ~ I
~ I
Le A 26 108 - 60 -
~3~~~~3
I
I
I
< Z U U :~ U
'
I
N N
I
X x
I
I x Z = ~t Z
I
i
I
I
~ h h Ls. fs Is.
X
I I I I
Z Z Z Z Z
i
Z ;
I
o x o z ~x o ,zx ~x
i
c i
0
N
Z I Z Z x x x
(p I
7 I
C I
~r ,
H I
C
o I
U I
v I (Z, (y (i, (i (i
I
I
J
~Lr ~L ~L. ~L (,i.
Le A 26 108 - 61 -
~3~0~53
I
I
I
I
< U U Z U U
I
I
I
I ,
I
m .
N
I
1C
U U Z x
i
I
I
I
-. I ft (s. Is. Lt h..
aC I
I
I
I
I
i
I
I i i ~ i i
I Z Z Z Z Z
I
I
r7 I
Z I
I
i o zz o x o x o x o zx
a ~ a ~ a
I
I
I
~ I
c
O N
~
z x x x x x
I
I
c
r
C I
_ I
/ / / / /
..) I I I I I i
~I
I
Le A 26 108 - 62
1~~~~~
I
I
I
I
I
I
zl
I
~ x ~ x o~x ~ x ~ x
~/I
0
N
x x x x x
C I
'~' I
O
a I
v I
I LL Ii. Lt. IL ~i
4! / / / / /
I ~ I
I
Le A 26 108 - 63 -
i i
I Z ~ i
Z~ Z~ Z Z--i
xi
i i
I Z Z Z . Z . Z Z
I
I
I
C I
0
N I
v ~ ... r. = Z Z
7 I
C I
~r I
a~ I
C
a
I Cz Ci. (z tz U.
I
I
/ /
v i I I I
I I I I
H
Le A 26 108 - 64 -
m.
Is, Z U ft (z.
< ~ U U U U U
I
I
I
I
I U V Z Z Z
I
f
I
(
I _ ._
i
N
7C .-.
U Z Z t S
... I
~c I ~ t~' c~, ~, ~,
.. f
c
0
N
S Z
C
I
i
C
O
I
lz / / / /
IL ~L ~L (Z, ,/ L~
f-
Le A 26 108 - 65 -
I
U
Z O~ Z
I_
x s ~= z
I U U U
Table 1 (continuation)
N 1 2 R3 X1
X2 A _
R
,.- --
__ _____-___---____-____ _~_.__-____ _____
__
__ _ _
N
O~
s ,r GH 30~N-
o _\ H I1 1! F
H N
cp F ,
H 2 N ~~~,
F
CH30~N-
~ F H F
H CH
H 2N '~,.,
F
CH30~N-
\ F H F
H CC1
H 2 N \~~~,
F
H CH30 N- F F CF r~
C....~
F H2N ~~"'
F H CH3 N- ' F
NHZ CF
F H N~~1
2
Table 1 (con tinuation)
R~ R~
__
R _
y~ ~ ________,__~_ ___
X1____ ____X2 _
_
_ _____
N __~__-__ __- _
r~ CH- O N-
H 3 ~~ F CI CH
H 2 N \',,
9
F
i
F H CH~O N- F C1
CF
HZN'~,
F
C2H50 N- N
i ~F H F H
- H 2N ~~~~'
F
GJ
~ F H C2H50 N- F H
CF
H N ws
F 2
c:.:r
-~ F H C2H5 N- ~ F H
CH
F 1
s H2N
..
I
z-~ z~ Z~ Z~ z,~
I
zi I
I
z ~ Z ~ Z ~7 N
Z N Z N Z N Z N Z Z
i U Z U Z U Z U Z U
C
O
N
" Z Z Z Z Z I
C
C
G
a
.. I ~. Iz !r. Li.
I
/ / / / /
I I I I I
m h ~ f:. ~ Iz Lc LL
Le A 26 108 _ 68 -
13~~~~~3
< U U Z U U
I
N
X ~ .-. ,."
U U t Z t
I
I
I
I
I
I
I
XI
I
I
I
I
i
I
I
I
I ~ i i i
Z ~ Z Z'-'' Z Z -~
I
f'7
Z I
I
I O
I ~"~ Z _~ Z ~ Z Z yn Z to N
I U = U = N Z N
1 U U U
I
C
O
'r
a N
Z =
7 = Z Z
C I
I
C I
O E
a I
I
r- I s LL (~ t~. It
v / /
r I I ~_ ~~.. ' . ~ ~.
Le A 26 108 _ 6g _
i .~..
Example of a tablet according to the invention
Each tablet contains:
Compound of Example 1 583.0 mg
Microcrystalline cellulose 55.0 mg
Maize starch 72.0 mg
Insoluble poly-(1-vinyl-2-pyrrolidone) 30.0 mg
Highly disperse silica 5.0 mg
Magnesium stearate 5.0 mq
750.0 mg
The lacquer shell contains:
Poly-(O-hydroxypropyl-O-methyl)-
cellulose 15 cp 6.0 mg
Macrogol 4000, recommended INN
polyethylene glycols (DAB) 2.0 my
Titanium(IV) oxide _~.0 ma
10.0 mg
The compounds according to the invention, while having a
low toxicity, exhibit a broad antibacterial spectrum
against Gram-positive and Gram-negative germs, in par-
ticular against Enterobacteriaceae; above a11 also
against those which are resistant towards various
antibiotics, such as, for example, penicillins, cephalo-
sporins, aminoglycosides, sulphonamides and tetra-
cyclines.
Le A 26 108 - 70 -
1~:~~5'~3
These useful properties enable them to be used as chemo-
therapeutic active compounds in medicine and as sub-
stances for preserving inorganic and organic materials,
in particular a11 types of organic materials, for example
polymers, lubricants, paints, fibres, leather, paper and
wood, and foodstuffs and water.
The compounds according to the invention are active
against a very broad spectrum of microorganisms. Gram-
negative and Gram-positive bacteria and bacteria-like
microorganisms can be combated and the diseases caused by
these pathogens can be prevented, alleviated and/or cured
with the aid of these compounds.
The compounds according to the invention are particularly
active against bacteria and bacteria-like microorganisms.
They are therefore particularly suitable in human and
veterinary medicine for the prophylaxis and chemotherapy
of local and systemic infections caused by these patho-
gens.
For example, local and/or systemic diseases caused by the
following pathogens or by mixtures of the following
pathogens can be treated and/or prevented:
Gram-positive cocci, for example Staphylococci (Staph.
aureus and Staph. epidermidis) and Streptococci (Street.
agalactiae, Street. faecalis, Street. pneumoniae and
Street. pyogenes); Gram-negative cocci (Neisseria gonor-
rhoeae) and Gram-negative rod-shaped bacilli, such as
Enterobacteriaceae, for example Escherichia coli, Haemo-
Le A 26 108 - 71 -
l~~fl~5
philus influenzae, Citrobacter (Citrob. freundii and
Citrob. divernis), Salmonella and Shigella; and further-
more Rlebsiella (Blebs. pneumoniae and Blebs. oxytoca),
Enterobacter (Ent. serogenes and Ent. agglomerans),
Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mira-
bilis, Pr. rettgeri and Pr. vulgaris), Providencia and
Yersinia, and the genus Acinetobacter. The antibacterial
spectrum moreover includes the genus Pseudomonae (Ps.
aeruginosa and Ps. maltophilia) as well as strictly
anaerobic bacteria, such as, for example, Bacteroides
fragilis, representatives of the genus Peptococcus,
Peptostreptococcus and the genus Clostridium; and fur
thermore Mycoplasma (M. pneumoniae, M. hominis and M.
urealyticum) and Mycobacteria, for example Mycobacterium
tuberculosis.
The above list of pathogens is to be interpreted merely
as examples and in no way as limiting. Examples which may
be mentioned of diseases which are caused by the patho-
gens or mixed infections mentioned and can be prevented,
alleviated or cured by the compounds according to the
invention are:
infectious diseases in humans, such as, for example,
otitis, pharyngitis, pneumonia, peritonitis, pyelo-
nephritis, cystitis, endocarditis, systemic infections,
bronchitis (acute and chronic), septic infections,
diseases of the upper respiratory tract, diffuse panbron-
chiolitis, pulmonary emphysema, dysentery, enteritis,
liver abscesses, urethritis, prostatitis, epididymitis,
gastrointestinal infections, bone and joint infections,
Le A 26 I08 - 72 -
:I3~~J ~~3
cystic fibrosis, skin infections, postoperative wound
infections, abscesses, phlegmons, wound infections,
infected burns, burn wounds, infections in the oral
region, infections following dental operations, osteomye-
litis, septic arthritis, cholecystitis, peritonitis with
appendicitis, cholangitis, intraabdominal abscesses,
pancreatitis, sinusitis, mastoiditis, mastitis, tonsil-
litis, typhoid, meningitis and infections of the nervous
system, salpingitis, endometritis, genital infections,
pelveoperitonitis and eye infections.
As well as in humans, bacterial infections can also be
treated in other species. Examples which may be mentioned
are:
Pigs: colidiarrhoea, enterotoxaemia, sepsis, dysentery,
salmonellosis, mastitis-metritis-agalactia syndrome and
mastitis;
Ruminants (cattle, sheep and goats): diarrhoea, sepsis,
bronchopneumonia, salmonellosis, pasteurellosis, myco-
plasmosis and genital infections;
Horses: bronchopneumonias, joint i11, puerperal and
postpuerperal infections and salmonellosis;
Dogs and cats: bronchopneumonia, diarrhoea, denaatitis,
otitis, urinary tract infections and prostatitis;
Poultry (chickens, turkeys, quails, pigeons, ornamental
birds and others): mycoplasmosis, E. coli infections,
chronic respiratory tract infections, salmonellosis,
pasteurellosis and psittacosis.
Bacterial diseases in the rearing and keeping of stock
Le A 26 108 - 73 -
r'
~~~~~a3
and ornamental fishes can also be treated, the antibac-
terial spectrum extending beyond the abovementioned
pathogens to further pathogens, such as, for. example,
Pasteurella, 8rucella, Campylobacter, Listeria, Erysi-
pelothrix, Corynebacteria, Borrelia, Treponema, Nocardia,
Rickettsia and Yersinia.
The present invention includes pharmaceutical formula-
tions which contain, in addition to non-toxic, inert
pharmaceutically suitable excipients, one or more com-
pounds according to the invention or consist of one or
more active compounds according to the invention, and
processes for the preparation of these formulations.
The present invention also includes phanaaceutical
formulations in dosage units. This means that the for-
mulations are present in the form of individual parts,
for example tablets, coated tablets, capsules, pills,
suppositories and ampoules, the active compound content
of which corresponds to a fraction or a multiple of. an
individual dose. The dosage units can contain, for
example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4
of an individual dose. An individual dose preferably
contains the amount of active compound which is adminis
tered in one application and which usually corresponds to
a whole, one half, one third or a quarter of a daily
dose.
Non-toxic inert pharmaceutically suitable excipients are
to be understood as solid, semi-solid or liquid diluents,
Le A 26 108 - 74 -
13~a~5y
fillers and formulation auxiliaries of a11 types.
Preferred pharmaceutical formulations which may be
mentioned are tablets, coated tablets, capsules, pills,
granules, suppositories, solutions, suspensions and emul-
sions, pastes, ointments, gels, creams, lotions, dusting
powders and sprays.
Tablets, coated tablets, capsules, pills and granules can
contain the active compound or compounds in addition to
the customary excipients, such as (a) fillers and
extenders, for example starches, lactose, sucrose,
glucose, mannitol and silicic acid, (b) binders, for
example carboxymethylcellulose, alginates, gelatine and
polyvinylpyrrolidone, (c) humectants, for example gly-
cerol, (d) disintegrating agents, for example agar-agar,
calcium carbonate and sodium carbonate, (e) solution
retarders, for example paraffin, and (f) absorption
accelerators, for example quaternary ammonium compounds,
( g ) wetting agents , for example cetyl alcohol and gly-
cerol monostearate, (h) adsorbents, for example kaolin
and bentonite, and (i) lubricants, for example talc,
calcium stearate, magnesium stearate and solid polyethyl-
ene glycols, or mixtures of the substances listed under
(a) to (i).
The tablets, coated tablets, capsules, pills and granules
can be provided with the customary coatings and shells,
optionally containing opacifying agents, and can also be
_ of a composition such that they release the active
Le A 26 108 - 75 -
~.~40 a~3
compound or compounds only or preferentially in a certain
part of the intestinal tract, if appropriate in a delayed
manner, examples of embedding compositions which can be
used being polymeric substances and waxes.
If appropriate, the active compound or compounds can also
be present in microencapsulated form with one or more of
the abovementioned excipients.
Suppositories can contain, in addition to the active
compound or compounds, the customary water-soluble or
water-insoluble excipients, for example polyethylene
glycols, fats, for example cacao fat, and higher esters
(for example C1,-alcohol with C16-fatty acid) or mixtures
of these substances.
Ointments, pastes, creams and gels can contain, in
addition to the active compound or compounds, the cus
tomary excipients, for example animal and vegetable fats,
waxes, paraffins, starch, tragacanth, cellulose deriva
tives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures of these
substances.
Dusting powders and sprays can contain, in addition to
the active compound or compounds, the customary excipi-
ents, for example lactose, talc, silicic acid, aluminium
hydroxide, calcium silicate and polyamide powder, or
mixtures of these substances. Sprays can additionally
contain the customary propellants, for example chloro-
Le A 26 108 - 76 -
i~~o~ e~
fluorohydrocarbons.
Solutions and emulsions can contain, in addition to the
active compound or compounds, the customary excipients,
such as solvents, solubilizing agents and emulsifiers,
for example water, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, di-
methylformamide, oils, in particular cottonseed oil,
groundnut oil, maize germ oil, olive oil, castor oil and
sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of
sorbitan, or mixtures of these substances.
For parenteral administration, the solutions and emul
sions can also be in a sterile form which is isotonic
with blood.
Suspensions can contain, in addition to the active
compound or compounds, the customary excipients, such as
liquid diluents, for example water, ethyl alcohol and
propylene glycol, and suspending agents, for example
ethoxylated isostearyl alcohols, polyoxyethylene sorbitol
and sorbitan esters, microcrystalline cellulose, alumin-
ium metahydroxide, bentonite, agar-agar and tragacanth,
or mixtures of these substances.
The formulation forms mentioned can also contain colour-
ing agents, preservatives and additives which improve the
smell and taste, for example peppermint oil and eucalyp-
Le A 26 108 - 77 -
tus oil, and sweeteners, for example saccharin.
The therapeutically active compounds should preferably be
present in the abovementioned pharmaceutical formulations
in a concentration of about 0.1 to 99.5, preferably about
0.5 to 95% by weight of the total mixture.
The abovementioned pharmaceutical formulations can also
contain other pharmaceutical active compounds in addition
to the compounds according to the invention.
The abovementioned pharmaceutical formulations are
prepared in the customary manner by known methods, for
example by mixing the active compound or compounds with
the excipient or excipients.
The formulations mentioned can be used on humans and
animals either orally, rectally, parenterally (intra-
venously, intramuscularly or subcutaneously), intra-
cisternally, intravaginally, intraperitoneally or locally
(dusting powder, ointment, drops) and for the therapy of
infections in hollow spaces and body cavities. Possible
suitable formulations are injection solutions, solutions
and suspensions for oral therapy and gels, infusion
formulations, emulsions, ointments or drops. Ophthal-
mological and dermatological formulations, silver salts
and other salts, eardrops, eye ointments, dusting powders
or solutions can be used for local therapy. In the case
of animals, intake can also be in suitable formulations
via the feed or drinking water. Gels, powders, dusting
Le A 26 108 - 78 -
~~~-~~53
powders, tablets, delayed release tablets, premixes,
concentrates, granules, pellets, boli, capsules, aero-
sols, sprays and inhalants can furthermore be. used on
humans and animals. The compounds according to the
invention can moreover be incorporated into other carrier
materials, such as, for example, plastics (chains of
plastic for local therapy), collagen or bone cement.
In general, it has proved advantageous both in human and
in veterinary medicine to administer the active compound
or compounds according to the invention in total amounts
of about 0.5 to about 500, preferably 5 to 100 mg/kg of
body weight every 24 hours, if appropriate in the form of
several individual doses, to achieve the desired results.
An individual dose preferably contains the active com-
pound or compounds according to the invention in amounts
of about 1 to about 80, in particular 3 to 30 mg/kg of
body weight. However, it may be necessary to deviate from
the dosages mentioned, and in particular to do so as a
function of the nature and body weight of the object to
be treated, the nature and severity of the disease, the
nature of the formulation and of the administration of
the medicament and the period or interval within which
administration takes place.
Thus in some cases it can suffice to manage with less
than the abovementioned amount of active compound, whilst
in other cases the abovementioned amount of active
compound must be exceeded. The particular optimum dosage
and mode of administration required for the active
Le A 26 108 - 79 -
1~4~W3
compounds can easily be determined by any expert on the basis of
his expert knowledge.
The new compounds can be administered in the customary
concentrations and formulations together with the feed or with
feed formulations or with the drinking water. Infection by Gram-
negative or Gram-positive bacteria can in this way be prevented,
alleviated and/or cured and promotion of growth and an improve-
ment in feed ultization can in this way be achieved.
The invention also extends to a commercial package
containing as active pharmaceutical ingredient a compound of the
invention, together with instructions for its use in combating
bacteria.
The minimum inhibitory concentrations (MIC) were
determined by the series dilution method on Iso-Sensitest agar
(Oxoid). For each test substance, a series of agar plates which
contained concentrations of the active compound which decreased
by a dilution factor of two each time was prepared. The agar
plates were inoculated with a multi-point inoculator (Denley).
Overnight cultures of the pathogens which had first been diluted
so that each inoculation point contained about 104 colony-
forming particles were used for the inoculation. The inoculated
agar plates were incubated at 37~C and the germ growth was read
off after about 20 hours. The MIC value (ug/ml) indicates the
lowest active compound concentration at which no germ growth was
to be detected with the naked eye.
The MIC values of some of the compounds according to
the invention are shown in comparison with ciprofloxacin in the
following table.
- 80 -
MIC values (mg/1) agar
determined by dilution
the
test (~enley multipoint inoculator; Iso-sensitest
agar)
Example
r
1 2 3 4 S 8 9 tU
--____ ___ _~_-__- ____________~-____ ~_ _ - ~__
__-
Test strain
Escherichia _<0.01S _<0.015 <0.0t5 <0.0t5 <0.Q15 f0.015
O.25 0.12S
coli Neumann
Proleus mica- 1 4 I 0,5 2 2 8
16
bilis 8223
Proleus vul- _f0,n15 0.12S _<0.01S <0.015 0.03 0.O6 0.5
1
garis 1O17
anella f0 0.03 0.O3 <O.015 f0.015 0,O6 0.5
0.5
Mor 015
g _
,
m morganii 932
N
Providencia- 1 4 2 0,5 4 4 32
64
sLuar~ei 12052
S~aphylococ-
cus aureus
FK 422 O.06 0,125 0.0b <0,01S 0.12S 0.03
O,06 0,12S
I756 0.06 0.12S 0.06 f0.015 0.12S 0.03
O.Ob 0.125
133 0.U6 0.125 U.03 _ 0.12S O.03
O,06 O,125
<0.0t5
Enterocotcus
faecalis 27101 O,125 - O,125 0,06 O,25 0,12S
0,2S. 2
9790 0,125 0,5 0,2S O,ilb O,25 0,125
0,25 2
I
MIC values (mg/I) agar dilution
determined by
the
test (Denley ~nultipoint inoculator; Iso-s ensitest agar)
Example
13 14 IS lb 17 18 Ciprofloxacin
~
T _----_-'~__-_- ~ -~- _-~--_ ~ --.--~-~-__~-__-_- --~-- -
---------
Test strain
Escherichia 0.06 0,06 _<0.0150.06 0.125 0.03
<0.01S
coli Neumann
Prot_eus mira-
bilis 8223 1 4 0.5 4 8 1 1
Proleus vul- 0.03 0.5 0,03 O,06 0.5 0,06
<0.01S
garis 1017
Morganella O,125 0.2S 0.03 0.06 0.5 0.O6
_<U.015
morganii 932
Providencia- 2 4 1 32 8 4 4
stuartei 120S2
Staphylococ-
cus aureus
FK 422 O.06 0.25 O.03 0.125 0;5 0.12S
0,2S
1756 0.06 0.2S 0.03 0,12S 0.5 0.125
0.2S
133 O.Ob O,25 O,03 0.12S 0.5 0.125
0.25
v~J
Enterococcus ~
G.s:7
faecalis 271O1 O,125 0.2S O,03 0.5 1 0.2S
O,OS
9790 0.25 0.5 - 0.5 2 0.5
0.25
1~~~W3
The following examples illustrate the invention:
Preparation of the intermediate products:
Example A
tert.-Butyl N-(cis-4-methoxy-pyrrolidin-3-yl)-carbamate
a) traps-1-Benzyl-3-hydroxv-4-methoxvayrrolidine
34,9 g (0.2 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]-
hexane (U.S. Patent 4,254,135) are heated with 3.6 g
(20 mmol) of sodium methylate solution (30% strength) at
120~C in 200 ml of absolute methanol in an autoclave for
10 hours. After cooling, the mixture is neutralized with
1.2 g (20 mmol) of acetic acid and the solvent is removed
on a rotary evaporator. The residue is taken up in
tetrahydrofuran and the sodium acetate is filtered off.
The filtrate is concentrated and the residue is dis-
tilled.
Yield: 40.9 g (91% of theory)
Boiling point: 112-116~C/0.1 mbar
Content: 92% pure
b) cis-3-Amino-1-benzyl-4-methoxy-pyrrolidine
5.6 g (25 mmol) of traps-1-benzyl-3-hydroxy-4-methoxy-
pyrrolidine and 8 . 6 g ( 33 mmol ) of triphenylphosphine are
initially introduced into 40 ml of absolute tetrahydro-
Le A 26 108 - 83 -
r ~~
134553
furan and a solution of 6 g (34 mmoll of diethyl azodi-
carboxylate in 40 ml of absolute tetrahydrofuran is added
dropwise at 0~C. 3.9 g (27 mmol.) of phthalimide.are then
added in small portions at 0~C in the course of one hour.
The mixture is stirred at room temperature overnight and
concentrated. The residue is dissolved in 80 ml of ethyl
acetate and 80 ml of petroleum ether are added. The
mixture is left to crystallize out overnight and the
crystals (triphenylphosphine oxide and diethyl hydrazine-
dicarboxylate) are filtered off. The filtrate is con-
centrated and the residue is heated under reflux with 60
ml of concentrated hydrochloric acid overnight. The
undissolved residues are decanted and the solution is
concentrated. The residue is taken up in a little water
and the solution is rendered alkaline with solid potas-
sium carbonate and extracted five times with 50. ml of
chloroform. The extract is dried over potassium carbonate
and concentrated and the residue is distilled.
Yield: 3.4 g (65.9% of theory)
Boiling point: 95~C/0.2 mbar
c) tert.-Butyl N-(cis-1-benzyl-4-methoxypyrrolidin-3-
yl)-carbamate
3 g (14.5 mmnol) of cis-3-amino-1-benzyl-4-methoxy-pyr-
rolidine and 11 ml of tert.-butanol are added to a
solution of 0.65 g of NaOH in 8 ml of water. 3.5 g (16
mmol) of di-tert.-butyl dicarbonate are added dropwise.
The mixture is stirred at room temperature overnight, the
Le A 26 108 - 84 -
-,
- f
13~~'ir
inorganic salts are filtered off with suction and the
filtrate is extracted with chloroform. The extract is
dried over potassium carbonate. and concentrated and the
residue is distilled.
Yield: 3.8 g (85.5% of theory)
Boiling point: 130-140~C/0.05 mbar
d) tert.-Butyl N-(cis-4-methoxypyrrolidin-3-yl)-
carbamate
3.5 g (11.4 mmol) of tert.-butyl N-(cis-1-benzyl-4-
methoxypyrrolidin-3-yl)-carbamate are hydrogenated in 100
ml of methanol on 2 g of palladium-on-active charcoal
(10% of Pd) at 100~C under 100 bar. The catalyst is
filtered off, the filtrate is concentrated and the
residue is distilled.
Yield: 1.9 g (81.6% of theory)
Boiling point: 84~C/0.1 mbar
Example B
tert.-Butyl N-(traps-4-methoxy-pyrrolidin-3-yl)-
carbamate
a) traps-3-Amino-1-benzyl-4-methoxy-pyrrolidine
27 g (0.41 mol) of sodium azide are dissolved in 50 ml of
Le A 26 108 - 85 -
water, and 17.5 g (0.1 mol) of 3-benzyl-6-oxa-3-azabi-
cyclo(3.1.0]hexane in 300 ml of dioxane are added. The
mixture is heated under reflux for 72 hours~and con-
centrated, the inorganic salts are dissolved in water and
the mixture is extracted with chloroform. The extract is
dried over potassium carbonate and concentrated. The
residue is dissolved in 50 ml of absolute tetrahydrofuran
and the solution is added dropwise to 4 g of sodium
hydride (80% strength in paraffin oil) in 200 ml of
absolute tetrahydrofuran. The mixture is heated under
reflux for one hour and 15 g (0.1 mol) of methyl iodide
are then added dropwise. The mixture is subsequently
heated under reflux overnight and concentrated, the
residue is taken up in water and the mixture is extracted
with chloroform. The extract is dried over potassium
carbonate and concentrated and the residue is distilled.
13.1 g of a material which is 73% pure according to the
gas chromatogram are obtained. 12.7 g of this material in
40 m1 of absolute tetrahydrofuran are added dropwise to
a suspension of 4 g of lithium aluminium hydride in 150
ml of absolute tetrahydrofuran and the mixture is heated
under reflux for 2 hours. Excess lithium aluminium
hydride is decomposed by careful dropwise addition of 4
ml portions of water and 15% strength potassium hydroxide
solution and again 4 ml of water. The inorganic salts are
filtered off with suction and washed several times with
chloroform. The organic phases are dried over potassium
carbonate and concentrated and the residue is distilled.
Yield: 9 g (32.8% of theory)
Le A 26 108 - 86 -
Boiling points 91~C/0.07 mbar
The product has a content of- 75%, determined by gas
chromatography (area method).
b) tert.-Butyl N-(traps-1-benzyl-4-methoxypyrrolidin-3-
Y1)carbamate
8.2 g (30 mmol) of traps-3-amino-1-benzyl-4-methoxy-
pyrrolidine and 21 ml of tert.-butanol are added to a
solution of 1.3 g of NaOH in 15 ml of water. 7.1 g
(31 mmol) of di-tert.-butyl dicarbonate are added drop
wise and the mixture is then stirred at room temperature
overnight. Inorganic salts are filtered off with suction,
the filtrate is extracted with chloroform, the extract is
dried over potassium carbonate and concentratedwand the
residue is distilled.
Yield: 7.7 g (84.4% of theory)
Boiling point: 14S~C/0.1 mbar
Melting point: 88-90~C
c) tert.-Butyl N-(tram-4-methoxypyrrolidin-3-yl)-
carbamate
6.7 g (22 mmol) of tert.-butyl N-(traps-1-benzyl-4-
methaxypyrrolidin-3-yl)carbamate are hydrogenated in
150 ml of methanol on 2 g of palladium-on-active charcoal
(10% of Pd) under 100 bar at 100~C. The catalyst is
filtered off with suction, the filtrate is concentrated
Le A 26 108 - 87 -
13~~~~3
and the residue is distilled.
Yield: 2.2 g (46% of theory)
Boiling point: 94~C/0.05 mbar
Example C
traps-3-Amino-4-hydroxy-pyrrolidine
a) traps-3-Amino-1-benzyl-4-hydroxy-pvrrolidine
8.9 g (50 mmol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hex-
ape are heated in 75 ml of ammonia solution (25%
strength) at l20~C in an autoclave for 8 hours. The
solution is concentrated and the residue is distilled.
Yield: 6 g (62.4% of theory)
Boiling point: 130-140~C/0.1 mbar
Melting point: 82-84~C
b) traps-3-Amino-4-hydroxv-pyrrolidine
5.2 g (27 mmol) of traps-3-amino-1-benzyl-4-hydroxy-
pyrrolidine are hydrogenated in 40 ml of methanol on 1 g
of palladium-on-active charcoal ( 10% of Pd) at 100~C under
100 bar. The catalyst is filtered off with suction, the
filtrate is concentrated and the residue is distilled.
Yield: 1 g (36.3% of theory)
Le A 26 108 - 88 -
..
~3~~5~3
Boiling point: 110~C/0.3 mbar
Example D
traps-4-Hydroxy-3-(2-hydroxyethylamino)-pyrrolidine
a) traps-1-Benzyl-4-hydroxy-3-(2-hydroxyethylamino)-
pYrrolidine
40 g (0.22 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hex-
ane are heated under reflux with 42 g (0.68 mol) of 2-
aminoethanol in 450 ml of water overnight. The solution
is extracted once with tert.-butyl methyl ether and the
aqueous phase is concentrated. The residue is distilled.
Yield: 34.1 g (65.6% of theory)
Boiling point: 190~C/0.1 mbar
b) traps-4-Hydroxy-3-(2-h~rdroxyethylamino, -pyrrolidine
traps-1-Henzyl-4-hydroxy-3-(2-hydroxyethylamino)-pyr-
rolidine is hydrogenated analogously to Example C b) to
give the reaction product as an oil.
Le A 26 108 - 89 -
13~OJ53
Example E
traps-4-Hydroxy-3-(2-hydroxyethyl-methyl-amino)-
pyrrolidine
a) traps-1-Benzyl-4-hydroxy-3-(2-hydroxyethyl-methyl-
amino]-pyrrolidine
17.5 g (0.1 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]-
hexane are reacted with 17 g ( 0 . 1 mol ) of methylamino-
ethanol in 200 ml of water analogously to Example D a).
Yield: 1B.2 g (73% of theory)
Boiling point: 180-190~Cl0.1 mbar
b) traps-4-Hydroxy-3-(2-hydroxyethyl-methyl-amino)-
pyrrolidine
traps-1-Benzyl-4-hydroxy-3-(2-hydroxyethyl-methyl-amino)-
pyrrolidine is hydrogenated analogously to Example C b)
to give the reaction product as an oily compound.
Example F
2-Oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride
a) 8-Benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane
Le A 26 108 - 90 -
134~~~
15.6 g (66 mmol) of 1-benzyl-4-hydroxy-3-(2-hydroxyethyl-
amino)-pyrrolidine are heated under reflux in a mixture
of 60 ml of concentrated sulphuric acid and 20 ml of
water for 6 hours. The mixture is rendered alkaline with
concentrated sodium hydroxide solution, the sodium
sulphate which has precipitated is filtered off with
suction and the filtrate is extracted with chloroform.
The extract is dried over potassium carbonate and con-
centrated and the residue is distilled.
Yield: 4.1 g (28.5% of theory)
Boiling point: 122-128~C (0.08 mbar)
b) 2-Oxa-5,8-diazabicycloj4.3.0_]nonane dihydrochloride
A solution of 4 g (18.2 mmol) of 8-benzyl-2-oxa-5,8-
diazabicyclo[4.3.O~nonane in 100 ml of methanol and 3.5
ml of concentrated hydrochloric acid is hydrogenated on
2 g of palladium-on-active charcoal (10% of Pd) at 80~C
under 100 bar. The catalyst is filtered off and washed
with water. The filtrates are concentrated and the
product is crystallized by trituration with a little
methanol. The crystals are filtered off with suction,
washed with acetone and dried in air.
Yield: 1.85 g (51% of theory)
Melting point: 280~C with decomposition
Le A 26 108 - 91 -
~~~~ ~~y
c) 2-Oxa-5,8-diazabicyclo[4.3.Olnonane
7.2 g (33 mtnol) of 8-benzyl-2-oxa-5,8-diazabicyclo
[4.3.0]nonane are hydrogenated in 400 ml of methanol with
2.5 g of palladium-on-active charcoal (10% of Pd) under
50 bar at 100~C. The catalyst is filtered off with suc
tion, the filtrate is concentrated and the residue is
distilled.
Yield: 3.1 g (73.4% of theory)
Boiling point: 58~C/9.1 mbar.
d) traps-2-Oxa-5,8-diazabicyclo/~.3.O~nonane
3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane is reacted
with 2-(benzylamino)-ethanol, analogously to Example
D a), to give traps-1-benzyl-3-[N-benzyl-N-(2-hydroxy-
ethyl)-amino]-4-hydroxypyrrolidine which is then reac-
ted analogously to Example F a) to give 5,8-dibenzyl-
2roxa-5,8~diazabicyclo[4.3.0]nonane which is purified
by chromatography (silica gel, cyclohexane/tert.-butyl
methyl ether/ethyl acetate 1:1:1).
The hydrogenolytic debenzylation is carried out analo-
gously to Example F c) to give traps-2-oxa-5,8-diaza-
bicyclo[9.3.0]-nonane, boiling point: 60'C/0.1 mbar.
35
Le A 26 108 - 92 -
f.. _
Example G
5-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane
dihydrochloride
a) 8-Benzyl-5-methyl-2-oxa-5.8-diazabicycloL4.3.0]nonane
18 g (71.9 mmol) of 1-benzyl-4-hydroxy-3-(2-hydroxyethyl-
methyl-amino)-pyrrolidine are reacted in 60 ml of con-
centrated sulphuric acid and 30 ml of water as in Example
F a).
Yield: 10 g (60% of theory)
Boiling point: 122~C/0.08 mbar
b) 5-Methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane
dihydrochloride
A solution of 9.4 g (40 mmol) of 8-benzyl-5-methyl=2-oxa-
5,8-diazabicyclo[4.3.0]nonane in 150 ml of methanol and
7.4 ml of concentrated hydrochloric acid is hydrogenated
on 3 g of palladium-on-active charcoal (10% of Pd) at
80~C under 100 bar. The catalyst is filtered off with
suction and the filtrate is concentrated. The residue is
triturated with butanol/acetone 1:1 and the crystals are
filtered off with suction and dried over P,Olo in a
desiccator. The product is very hygroscopic.
Yield: 8.2 g (95% of theory)
Mass spectrum: m/e 142 (Mf ) , 112 (M'-CH20) , 100 (M'-CH2-
N=CH2 ) , 8 2 ( C,H,NO+ ) , 6 8 ( C,H6N'' )
' Example H
2-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane
a) Ethvl N-(2,2-dimethoxyethyl)-carbamate
214 g (2 mol) of ethyl chloroformate are added dropwise
to 214 g !2 mol) of aminoacetaldehyde dimethyl acetal in
Le A 26 108 - 93 -
~3~~~J3
1 1 of toluene and 90 g of NaOH in 500 ml of water at
10~C. The mixture is stirred at room temperature for a
further 2 hours and the aqueous phase is separated off,
saturated with sodium chloride and extracted with tol-
uene. The toluene solutions are dried over magnesium
sulphate and concentrated and the residue is distilled.
Yield: 338 g (95.4% of theory)
Boiling point: 60~C/0.03 mbar
b) Ethyl N-allyl-N-j2,2-dimethoxyethyl)-carbamate
g of sodium hydride (80% strength in paraffin oil) are
initially introduced into 500 ml of toluene and 89 g (0.5
15 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added
dropwise at 80~C. The mixture is stirred at 80~C for one
hour and 73 g (0.6 mol) of allyl bromide are then added
dropwise in the course of three hours. The mixture is
stirred at 80~C overnight, the salts are dissolved with
water and the organic phase is separated off. The aqueous
phase is extracted with toluene, the organic phases are
dried over potassium carbonate and concentrated and the
residue is distilled.
Yield: 68 g (62.5% of theory)
Boiling point: 65~C/0.09 mbar
c) Ethvl N-allyl-N-l2-oxoethyl~-carbamate
68 g (0.313 mol) of ethyl N-allyl-N-(2,2-dimethoxyethyl)-
carbamate are heated with 150 ml of formic acid at 100~C
for one hour. The mixture is poured onto ice and
extracted several times with methylene chloride, the
organic phases are washed with sodium bicarbonate solu
tion, dried over magnesium sulphate and concentrated and
'5 the residue is distilled.
Yield: 46.7 g (87.2% of theory)
Le A 26 108 - 94 -
_ ,...
1~~W53
Roiling point: 58~C/0.09 mbar
d) Ethyl 2-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-
carboxvlate
g (0.12 mol) of methylhydroxylamine hydrochloride are
5 dissolved in 50 ml of methanol, the solution is cooled in
an ice-bath and 22 g ( 0 . 12 mol ) of 30% strength sodium
methylate solution in methanol are added dropwise. The
sodium chloride is filtered off with suction and the salt
is washed with 80 ml of toluene. The methylhydroxylamine
10 solution is added dropwise in the course of one hour to
g (0.117 mol) of ethyl N-(2-(oxoethyl)-carbamate,
which is heated under reflux in 160 ml of toluene, using
a water separator. The mixture is heated under reflux
overnight and the product is extracted twice with 80 ml
15 of 10% strength hydrochloric acid each time. The hydro-
chloric acid solutions are saturated with potassium
carbonate and extracted six times with 200 ml of chloro-
form each time. The extract is dried over R2C03 and
concentrated and the residue is distilled.
20 Yield: 18.6 g (79.5% of theory)
Melting point: 93~C/0.09 mbar
e) 2-Methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane
13 g (65 mmol) of ethyl 2-methyl-3-oxa-2,7-diazabicyclo-
[3.3.0]octane-7-carboxylate are heated under reflux in
300 ml of water with 41 g of Ba(OH)2.8H20 overnight.
Le A 26 108 -
F.r.
~~4Q~~3
Potassium carbonate is added, the barium carbonate which
has precipitated out is filtered off with suction and the
filtrate is extracted ten times with 100 ml of chloroform
each time. The extract is dried over potassium carbonate
and concentrated and the residue is distilled.
Yield: 5.4 g (65% of theory)
Boiling point: 80~C/10 mbar
Example I
1-Methyl-octahydropyrrolo[3,4-b]pyrrole (2-methyl-2,7-
diazabicyclo[3.3.0]octane)
a) 1-Henzyl-3-(2-chloroethyl-methyl-amino)-pyr=olidine-
2,5-dione
74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308,
489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methyl-
amine hydrochloride are initially introduced into 400 ml
of dioxane and 40.4 g (0.4 mol) of triethylamine are
added dropwise at 20~C. The mixture is then boiled under
reflux for 5 hours . The batch is subsequently poured into
2 1 of ice-water and extracted with 3 portions of 400 ml
of chloroform and the extract is washed with water, dried
over sodium sulphate and concentrated on a rotary
evaporator. Chromatography of the residue (l01.1 g) on
silica gel using ethyl acetate: petroleum ether (1:2)
gives 56.8 g (51% of theory) of an oil.
Le A 26 108 - 96 -
1.
RF value: 0.33 (silica gel, ethyl acetate/petroleum ether
- 1:2)
b) 5-Benzyl-4,6-dioxo-1-methyl-octahydropyrrolo[3,4-b]-
p~rrro le
?.2 g (0.24 mol) of an 80% strength sodium hydride
suspension in mineral oil are suspended in 150 ml of
absolute dimethylformamide (dried over calcium hydride),
and 62 g (0.22 mol) of 1-benzyl-3-(2-chloroethyl-methyl-
amino)-pyrrolidine-2,5-dione are added dropwise as a
solution in 50 ml of absolute dimethylformamide at room
temperature. During this, an exothermic reaction takes
place with foaming. The mixture is diluted with a further
50 ml of absolute dimethylformamide and subsequently
stirred at room temperature for 1 hour and is then poured
into ice-water and extracted with methylene chloride. The
extract is washed with water, dried with sodium sulphate
and concentrated on a rotary evaporator. The residue is
chromatographed on silica gel using ethyl acetate:petro-
leum ether (1:2) and later (1:1). 16.4 g of educt are
initially recovered here, and 17.2 g (44% of theory,
based on the educt reacted) of an oily product are then
isolated.
R= value = 0.26
(silica gel, ethyl acetate: petroleum ether = 1:1).
Le A 26 108 - 97 -
._ 1340e3
c) 5-Benzyl-1-methyl-octahydro yrroloj3,4-blpyrrole
1.52 g (40 mmol) of lithium aluminium hydride are
initially introduced into 30 ml of anhydrous tetrahydro-
furan, and 4.9 g (20 mmol) of 5-benzyl-4,6-dioxo-1-
methyl-octahydropyrrolo[3,4-b]pyrrole are added dropwise
as a solution in 15 ml of anhydrous tetrahydrofuran. The
mixture is then subsequently stirred at the boiling point
for 3 hours. 1.5 ml of water, 1.5 ml of 15% strength
potassium hydroxide solution and 4.5 ml of water are
added dropwise in succession to the batch and the pre-
cipitate is then filtered off with suction and washed
with tetrahydrofuran. The filtrate is concentrated on a
rotary evaporator and the residue is distilled. 3.1 g
(72% of theory) of a colourless distillate of boiling
point 80~C/0.07 mbar are obtained.
d) 1-Methyl-octahydropyrrolof3~4-b7pyrrole
6.49 g (30 mmol) of 5-benzyl-1-methyl-octahydropyrrolo-
[3,4-b]-pyrrole are dissolved in 100 ml of absolute
ether, and 5.2 g of hydrogen chloride dried over phos-
phorus pentoxide are passed in. The hydrochloride suspen-
sion formed is concentrated in vacuo and the residue is
taken up in 100 ml of methanol. It is then hydrogenated
with 2 g of Pd-on-C (5% strength) at 80~C under 50 bar
for 4 hours. The catalyst is subsequently filtered off,
the filtrate is concentrated and 30 ml of 40% strength
sodium hydroxide solution and 50 ml of ether are added to
the residue. The ethereal phase is separated off and the
Le A 26 108 - 98 -
13~0~~
aqueous phase is extracted with 2 x 50 ml of ether. The
combined organic phases are dried over sodium sulphate
and concentrated and the residue is distilled. 1.3 g (34$
of theory) of a colourless oil of boiling point 65-66~C/
12 mbar are obtained.
Purity: >99%
Example J
Octahydropyrrolo[3,4-b]pyrrole (2,7-diazabicyclo[3.3.0]-
octane)
a) 1-Benzyl-3-(2-chloroethylamino)-pyrrolidine-2,5-dione
74.8 g (0.4 mol) of N-benzylmaleimide are reacted with
58 g (0.5 mol) of 2-chloroethylamine hydrochloride and
50.5 g (0.5 mol) of triethylamine in accordance with the
working instructions of Example Ia. After working up by
chromatography, 81.6 g (77% of theory) of an oil with an
RF value of 0.24 (on silica gel using ethyl acetate:
petroleum ether = 1:1) are obtained.
b) 5-Benzyl-4,6-dioxo-octahydro_pyrrolo~3.4-blp,~rrrole
17.4 g (0.58 mmol) of sodium hydride suspension are
reacted with 119 g (0.45 mol) of 1-benzyl-3-(2-chloro-
ethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute
dimethylformamide in accordance with the working instruc-
tions of Example Ib. After the mixture has been left to
Le A 26 108 - 99 -
stand overnight, it is worked up under aqueous condi-
tions. On purification by chromatography, impurities are
first eluted with ethyl acetate and the product is then
eluted with ethyl acetate: methanol (3:1) (Rp value 0.55).
57.7 g of product (56% of theory) are isolated.
c) 5-Henzyl-octahydropyrroloj3,4-blpyrrole
57.7 g (0.25 mol) of crude 5-benzyl-4,6-dioxo-octahydro-
pyrrolo[3,4-b]pyrrole are reduced with 21.4 g (0.56 mol)
of lithium aluminium hydride by boiling in 700 ml of
absolute tetrahydrofuran for 10 hours in accordance with
the working instructions of Example Ic. Working up by
distillation gives 21.0 g (41.1% of theory) of an oil of
boiling point 95~C/0.1 mbar.
d) Octahvdrowrroloj3.4-b Lpyrrole
21.0 g (0.104 mol) of 5-benzyl-octahydropyrrolo-
[3,4-b]pyrrole are initially introduced into 180 ml of
ice-cooled methanol, and 17.3 ml (0.208 mol) of concen-
trated hydrochloric acid are added. The mixture is then
hydrogenated with 2 g of Pd-on-C (5% strength) at 90~C
under 100 bar for 4 hours. The catalyst is filtered off,
37.4 g (0.208 mol) of 30% strength sodium methylate
solution are added to the filtrate, the mixture is
filtered again and the filtrate is concentrated. The
residue is distilled through a small Vigreux column. 5.6
g of a colourless oil (48% of theory) of boiling point
93-95~C/30 mbar, which fumes in air and slowly solidifies
Z,e A 26 108 - 100 -
134~~~3
in the receiver (melting point 40~C) are obtained.
Example R
Octahydropyrrolo[3,4-b]pyridine (2,8-diazabicyclo[4.3.0]-
nonane)
a) 6-Henzyl-5,7-dioxo-octahydropyrrolo[3,4-b]pyridine
47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid N-
benzylimide (British Patent 1,086,637; Chem. Abstr. 68,
95695w) are hydrogenated in 400 ml of glycol monomethyl
ether over 15 g of ruthenium-on-active charcoal (5%
strength) at 90~C under 100 bar until the calculated
amount of hydrogen has been taken up. The catalyst is
then filtered off and the filtrate is concentrated on a
rotary evaporator. 44 g of an oily crude product are
obtained.
The corresponding hydrogenation with palladium-on-active
charcoal (5% strength) gives a quantitative yield of a
pure product of melting point 67-69~C.
b) 6-Benzyl-octahydropyrroloj3.4-blpyridine
44 g (about 0.1B mol) of crude or pure 6-benzyl-5,7-
dioxo-octahydropyrrolo[3,4-b]pyridine are reduced with
15.2 g (0.40 mol) of lithium aluminium hydride in 390 ml
of absolute tetrahydrofuran in the course of 10 hours in
Le A 26 108 - 101 -
~...~
13~05~3
accordance with the working instructions of Example Ic.
24.4 g of a colourless oil having a boiling point of 93-
95~C/0.06 mbar are obtained on distillation.
c) Octahydropyrroloj3,4-blpyridine
69 g (0.32 mol) of 6-benzyl-octahydropyrrolo[3,4-b]pyri-
dine are hydrogenated in 450 ml of methanol over 7 g of
palladium-on-active charcoal ( 5% strength) at 90~C/90 bar
in the course of 3 hours. The catalyst is then filtered
off, the filtrate is concentrated and the residue is
distilled. 33.8 g (84% of theory) of a colourless solid
having a melting point of 65-67~C and a boiling point of
78~C/9 mbar are obtained.
Example L
1-Methyl-octahydropyrrolo[3,4-b]pyridine (2-methyl-2,8-
diazabicyclo[4.3.0]nonane)
a) 1-Methyl-pyridinium-2,3-dicarboxylic acid N-benzyl-
imide iodide
190.5 g (0.8 mol) of pyridine-2,3-dicarboxylic acid N-
benzylimide are dissolved in 800 ml of nitromethane,
while heating, and 136 g (0.96 mol) of methyl iodide are
added dropwise. The mixture is then boiled for 8 hours
while cooling under reflux (cooling water 0~C). After
_ cooling, the solid is filtered off with suction and
Le A 26 108 - 102 -
washed with methylene chloride. 123 g of dark red crys-
tals having a melting point of 162-165~C (decomposition)
are obtained.
b) 6-Benzyl-1-methyl-5,7-dioxo-octahydropyrrolo[3,4-b]-
pyridine
38 g (0.1 mol) of 1-methyl-pyridinium-2,3-dicarboxylic
acid N-benzylimide iodide are hydrogenated over 1 g of
platinum oxide in 450 ml of glycol monomethyl ether at
30~C under 70 bar until the uptake of hydrogen has ended
(51 hours). The catalyst is then filtered off, the
filtrate is concentrated, the residue is taken up in 300
ml of chloroform and the solution is washed 2 x with
300 ml of 10% strength sodium carbonate solution each
time and with 300 ml of water. After drying over.. sodium
sulphate, it is concentrated. 27 g of an oily residue
remain.
c) 6-Henzyl-1-methyl-octahydropvrrolo[3,4-b]pyridine
19.2 g (0.08 mol) of crude 6-benzyl-1-methyl-5,7-dioxo-
octahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g
(0.16 mol) of lithium aluminium hydride in absolute
tetrahydrofuran in accordance with the working instruc-
tions of Example lc.
yield: 9.5 g (52% of theory),
Boiling points 93-96~C/0.1 mbar.
Le A 26 108 - 103 -
.....
130553
d) 1-Methvl-octahydropyrroloj3,4-b]pyridine
11.7 g (54 mmol) of 6-benzyl-1-methyl-octahydropyrrolo-
[3,4-b]pyridine as the dihydrochloride are hydrogenated
in 100 ml of methanol over palladium-on-active charcoal
in accordance with the working instructions of Example
Id. Working up by distillation gives 2.6 g (34% of
theory) of a colourless oil of boiling point 83-85~/12
mbar).
Example M
traps-4-Methoxy-3-methylamino-pyrrolidine dihydrochloride
a) traps-1-Benzyl-3-benzylmethylamino-4-hydroxy.-
pvrrolidine
19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3-
azabicyclo[3.1.0]hexane are heated under reflux with
14.5 g (0.12 mol) of benzylmethylamine in 100 ml of
dioxane and 200 ml of water overnight. The mixture
is extracted with CIiCl3, the extracts are dried with
K2C03 and concentrated and the residue is subjected
to incipient distillation up to 160~C (oil bath
temperature).
Crude yields 18.3 g
Contents 100% (determined by gas chromatography)
Le A 26 108 - 104 -
.....
r
b) traps-1-Benzyl-3-benzylmethylamino-4-methoxy-
pvrrolidine
17.3 g (58 mmol) of crude traps-1-benzyl-3-benzyl-
methylamino-4-hydroxy-pyrrolidine in 80 ml of abso-
lute tetrahydrofuran are added dropwise to 2.8 g
(93.3 mmol) of 80% strength sodium hydride in 40 ml
of absolute tetrahydrofuran and the mixture is
heated under reflux at the same time. When the
evolution of hydrogen has ended, 8.7 g (61 smnol) of
methyl iodide are added dropwise and the mixture is
then heated under reflux overnight. It is poured
into ice-water and extracted with toluene, the
extracts are dried with R2C03 and concentrated and
the residue is distilled.
Yield: 9.7 g (52% of theory)
Boiling point: 140-150~C/0.1 mbar
c) traps-4-Methoxy-3-methylamino-pyrrolidine
dihydrochloride
9.3 g (29 mmol) of traps-1-benzyl-3-benzylmethyl-
amino-4-methoxy-pyrrolidine are dissolved in 100 ml
of methanol, 4.8 ml of concentrated hydrochloric
acid are added and the mixture is hydrogenated on
4 g of 10% strength Pd-on-active charcoal at 90~C
under 100 bar. The catalyst is filtered off with
suction, the filtrate is concentrated and the
residue is recrystallized from isopropanol/methanol.
Yields 3.7 g (62.8% of theory)
Le A 26 108 - 105 -
Melting point: l57-162~C
Example N
2,5-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane
a) N-(2-Methylprop-2-enyl)-N-(2,2-dimethoxyethyl)-
urethane
89 g (0.5 mol) of N-(2,2-dimethoxyethyl)-urethane
are added dropwise to 20 g of sodium hydride (80%
strenqth) in 500 ml of absolute toluene at 90~C. When
no further hydrogen is formed, 54 g (0.6 mol) of
methallyl chloride are added dropwise and the
mixture is stirred overnight at 90~C. The sodium
chloride which has precipitated out is dissolved
with a little water, the organic phase is separated
off, dried over R2C03 and concentrated and the
residue is distilled.
Yield: 7I.3 g (61.7% of theory)
Boiling point: 60~C/0.08 mbar
b) N-(2-Methylprop-2-enyl)-N-(2-oxoethvl)-urethane
11.5 g (50 mmol) of N-(2-methylprop-2-enyl)-N-(2,2-
dimethoxyethyl)-urethane and 1.25 g (5 mmol) of
pyridinium p-toluenesulphate in 100 ml of acetone
and 10 ml of water are heated under reflux for two
days. The mixture is concentrated and the residue is
Le A 26 108 - 106 -
l~~DO ~~
distilled.
Yield: 5.3 g (61.2% of theory)
Boiling point: 73~C/0.1 mbar
c) Ethyl 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.Q]-
octane-7-carboxylate
21.7 g of 30% strength sodium methylate solution are
added dropwise to 10 g (0.12 mol) of N-methyl-
hydroxylamine hydrochloride in 26 ml of methanol.
The sodium chloride is filtered off with suction and
washed with 8 ml of methanol and 80 ml of toluene.
This solution is added dropwise to 19 . 2 g ( 0 . 11 mol )
of N-(2-methyl-prop-2-enyl)-N-(2-oxoethyl)-urethane,
which is heated under reflux in 160 ml of toluene
using a water separator. The mixture is heated under
reflux overnight, the product is extracted ~iith 160
ml of 10% strength hydrochloric acid and the hydro-
chloric acid solution is rendered alkaline with
potassium carbonate and extracted with six portions
of 200 ml of CHC13. The extracts are dried over K2CO3
and concentrated and the residue is distilled.
Yield: 13 g (55% of theory)
Boiling point: 88-95~C/0.08 mbar
d) 2.5-Dimetl~l-3-oxa-2.7-diazabicycloj3.3.0]octane
13 g (60.6 mmol) of ethyl 2,5-dimethyl-3-oxa-2,7-
diazabicyclo[3.3.0]octane-7-carboxylate are heated
under reflux with 33 g of Ha(OH)2.8H20 in 330 ml of
Le A 26 108 - 107 -
. 134055a
water overnight. The HaC03 is filtered off with
suction, RZC03 is added to the filtrate, the solid is
filtered off with suction again and the filtrate is
extracted ten times with 100 ml of CHC13 each time.
The extracts are dried over R2C03 and concentrated
and the residue is distilled.
Yield: 5.9 g (63.7% of theory)
Roiling point: 64~C/5 mbar
Example 0
2,8-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane
a) N-11,1-Dimethoxyprop-2-yl)-urethane
80 g (0.73 mol) of ethyl chlorofonuate are added
dropwise to 86.2 g (0.72 mol) of 2-aminopropion-
aldehyde dimethyl acetal in 350 ml of toluene and
32 g (0.8 mol) of NaOH in 300 ml of water. The
mixture is stirred at room temperature for a further
2 hours, the organic phase is separated off, the
aqueous phase is extracted with toluene and the
toluene solutions are dried aver RZC03. The solution
is concentrated and the residue is distilled.
Yield: 132 g (95% of theory)
Boiling point: 55~C/0.06 mbar
Le A 26 108 - 108 -
_ --~.
f
b) N-Allvl-N-(1,1-dimethox~pro_p-2-vl)-urethane
131 g (0.686 mol) of N-(1,1-dimethoxyprop-2-yl)-
urethane are added dropwise to 25 g of sodium
hydride (80% strength) in 700 ml of absolute toluene
at 90~C. When the evolution of hydrogen has ended,
6l.2 g (0.8 mol) of allyl chloride are added drop-
wise at 90~C and the mixture is stirred overnight at
90~C, The sodium chloride which has precipitated out
is dissolved with water, the organic phase is
separated off, dried over RZC03 and concentrated and
the residue is distilled.
Yield: 78 g (31.7% of theory)
Boiling point: 62-69~C/0.06 mbar.
Content: 64.5% pure (determined by gas chromato-
graphy)
c) N-Allyl-N-(1-oxoprop-2 yl)-urethane
76.5 g (0.213 mol) of 64.5% pure N-allyl-N-(1,1-
dimethoxyprop-2-yl)-urethane are heated in 180 ml of
formic acid at 100~C for one hour. The mixture is
poured into ice-water and extracted with CHZC12, the
extracts are washed neutral with NaHC03 solution,
dried over MgSO, and concentrated and the residue is
distilled.
Yield: 36 g (80.9% of theory)
Roiling point: 97-102~C/8 mbar
Content: 88.8% pure (determined by gas chromato-
graphy)
Le A 26 108 - 109 -
....
a
~'3~~~~~3
d) Ethyl 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]-
octane-7-carboxylate
A methanolic methylhydroxlrlamine solution is pre-
pared from 16.4 g (0.2 mol) of N-methylhydroxylamine
hydrochloride in 33 ml of absolute methanol and
36 g (0.2 mol) of 30% strength sodium methyiate
solution, and the solution formed is diluted with
130 ml of toluene and added dropwise to 354 g
(0.17 mol) of N-allyl-N-(1-oxoprop-2-yl)-urethane in
250 ml of toluene, which is heated under reflux
using a water separator. The mixture is heated under
reflux overnight, the product is extracted with
dilute hydrochloric acid and the hydrochloric acid
solution is rendered alkaline with R2C03 and
extracted with CHC13. The extract is dried over RZC03
and concentrated and the residue is distilled.
Yield: 18.5 g (50.8% of theory)
Boiling point: 95-105~C/0.1 mbar
e) 2.8-Dimethyl-3-oxa-2,7-diazabicyclor3.3.0]octane
9.2 g (42.9 mmol) of ethyl 2,8-dimethyl-3-oxa-2,7-
diazabicyclo[3.3.0]octane-7-carboxylate are heated
under reflux with 23.5 g of Ba(OH)2.8H20 in 235 ml of
water overnight. The BaCO, is filtered off with
suction, RZC03 is added to the filtrate and the solid
is filtered off with suction again. The filtrate is
extracted ten times with 50 ml of CHC13 each time,
the extracts are dried over R2C03 and concentrated
Le A 26 108 - 110 -
~~~o~~
and the residue is distilled.
Yield: 1.7 g
Boiling point: 87-92~CI10 mbar
The product is a mixture of the possible stereo-
s isomers in a ratio of 3:1 (lIi-NMR).
4 g of starting material could to be recovered in
the after-runnings.
Example P
2-Methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane
a) Ethyl 4-hydroxymethyl-3-methylaminopyrrolidine-1-
carboxylate
10 g (50 mmol) of ethyl 2-methyl-3-oxa-2,7-diazabi-
cyclo[3.3.0]octane-7-carboxylate (Example H d)) are
hydrogenated in 200 ml of ethanol on 3 g of Pd-on-
active charcoal ( 10% of Pd) at 50~C under 50 bar.
The catalyst is filtered off, the filtrate is
concentrated and the residue is distilled.
Yield: 8.1 g (80% of theory)
Roiling point: 135-140~C/0.1 mbar
b) Ethyl 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane-
8-carboxYlate
10.l g (50 mmol) of ethyl 4-hydroxymethyl-3-methyl-
amino-pyrrolidine-I-carboxylate and 8 g (0.1 mol) of
Le A 26 108 - 111 -
_ ....,
3?% strength formaldehyde solution are dissolved in
100 ml of butanol and the solution is stirred at
room temperature overnight.. It is then concentrated
and the residue is distilled.
Yield: 9.5 g (88.7% of theory)
Boiling point: 110~C/0.1 mbar
c) 2-Methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane
9 g (42 auaol) of ethyl 2-methyl-4-oxa-2,8-diaza-
bicyclo[4.3.0]nonane-8-carboxylate are heated under
reflux with 28 g of Ha(OH)2.8H20 in 280 ml of water
overnight. The BaC03 is filtered off with suction,
the filtrate is concentrated and the residue is
boiled up with dioxane. The dioxane solution is
concentrated and the residue is distilled. ,
Yield: 1.3 g (21.8% of theory)
Roiling point: 115~C/8 mbar
d) 4-Hydrox_~rmethyl-3-methylaminopyrrolidine
34 g (0.168 mol) of ethyl 4-hydroxymethyl-3-methyl-
aminopyrrolidine-1-carboxylate are heated under
reflux with 100 g of Ba(OH)2.8H20 in 400 ml of water
overnight. The HaCO, is filtered off with suction,
the filtrate is concentrated and the residue is
boiled up ten times with 100 ml of dioxane each
time. The dioxane solutions are filtered, the
filtrate is concentrated and the residue is dis-
tilled.
Le A 26 108 - 1l2 -
-~.
1~3~~~~3
Yield: 13 g (60.3% of theory)
Boiling point: 85-88~C/0.08 mbar
e) 2-Methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane
8.1 g (0.1 mol) of 37% strength formaldehyde solu-
tion in 20 ml of n-butanol are added dropwise to
13 g (0.101 mol) of 4-hydroxymethyl-3-methylamino
pyrrolidine in 100 ml of n-butanol at room tempera
ture. The mixture is stirred at room temperature
overnight and concentrated and the residue is
distilled.
Yield: 8.7 g (61.2% of theory)
Boiling point: 84~C/6 mbar
Example 0
3-Oxa-2,7-diazabicyclo[3.3.0]octane
a) Ethyl 2-(tetrahydropyran-2-yl)-3-oxa-2,7-diazabi-
cyclo[3.3.0]octane-7-carboxylate
18.1 g (0.106 mol) of ethyl N-allyl-N-(2-oxoethyl)-
carbamate (Example M c)) are heated under reflux in
220 ml of toluene, and l4.2 g (0.12 mol) of 5-
hydroxypentanal oxime (Acts Chim. Acad. Sci. Hung.,
14, 333 (1958)), dissolved in 55 ml of hot toluene,
are added dropwise. The mixture is heated under
reflux overnight and concentrated and the residue is
Le A 26 108 - 113 -
J. n (.
1~~~ ) l~3
distilled.
Yield: 15.5 g (54% of theory)
Boiling point: 160~C/0.01 mbar
b) Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7-
carboxvlate
g (55.5 mmol) of ethyl 2-(tetrahydropyran-2-yl)-
3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate
are heated under reflux with 8.25 g (56 mmol) of 70%
strength perchloric acid in 100 ml of ethanol for 30
10 minutes. 10.5 g (58 mmol) of 30 strength sodium
methylate solution are added, the mixture is con-
centrated, the residue is taken up in water and the
solution is saturated with R2C03 and extracted with
CHC13. The extract is dried over R2C03 and concentra-
15 ted and the residue is distilled.
Yield: ?.6 g (73.5% of theory)
Boiling point: 125-130~C/0.1 mbar
c) Ethvl 3-oxa-2.7-diazabicyclo[3.3.0]octane-7-carboxy-
late
8.5 g (50 mmol) of ethyl N-(2-oxoethyl)-N-allyl-
carbamate are heated under reflux with 5.5 g (50
mmol) of o-trimethylsilylhydroxylamine in l00 ml of
xylene overnight. The mixture is concentrated and
the residue is distilled.
Yield: 6.8 g (73% of theory)
Boiling point: 120-122~C/0.05 mbar
Le A 26 108 - 114 -
134053
d) 3-Oxa-2,7-diazabicvcloj3.3.Ojoctane
This substance is obtained analogously to Example
N d) by hydrolysis of ethyl 3-oxa-2,7-diazabicyclo-
[3.3.0]octane-7-carboxylate with Ba(OH)Z.8H20.
Boiling points 75~C/10 mbar.
Example R
3-Methyl-2,7-diazabicyclo[3.3.0]octane
3-Methyl-2,7-diazabicyclo[3.3.0]octane is obtained
analogously to Example I.
Roiling point: 68-70~C/6 mbar.
Example S
2,3-Dimethyl-2,7-diazabicyclo[3.3.0]octane
2,3-Dimethyl-2,7-diazabicyclo[3.3.0]octane is obtained
analogously to Example I.
Boiling point: 72-74~C/10 mbar.
Example T
1,2-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane
Le A 26 108 - 115 -
I
1~~~~.53
a) N-Allyl-N-(2.2-dimethoxypropyl)-acetamide
119 g (74 mol) of 2,2-dimethoxypropylacetamide are
added dropwise to 29.6 g (0.987 mol) of sodium
hydride (80% strength in paraffin oil) in 750 ml of
absolute toluene at 80~C. The mixture is then stirred
for one hour and 100 g (0.83 mol) of allyl bromide
are subsequently added dropwise at 80~C. The mixture
is stirred overnight at 80~C and cooled and the salts
are dissolved with water. The aqueous phase is
separated off and extracted twice with 100 ml of
toluene each time. The toluene solutions are dried
over RZC03 and concentrated and the residue is
distilled.
Yield: 112 g (75.6% of theory)
Boiling point: 70~C/0.08 mbar.
b) N-Allyl-N-~2-oxopropyl)-acetamide
85.5 g (0.425 mol) of N-allyl-N-(2,2-dimethoxy-
propyl)-acetamide are heated under reflux with
212 ml of formic acid for one hour. The mixture is
poured onto 500 g of ice and extracted several times
with methylene chloride, the organic phases are
washed with sodium bicarbonate solution, dried over
magnesium sulphate and concentrated and the residue
is distilled.
Yield: 50 g (75.8% of theory)
Boiling point: 79~C/0.25 mbar.
Le A 26 108 - 116 -
13~(~ ~~a .
c) 7-Acetyl-1,2-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]-
octane
15.5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acet-
amide are dissolved in 100 ml of dioxane, and 9 g of
anhydrous sodium acetate and 9 g (0.108 mol) of N-
methylhydroxylamine hydrochloride in 10 ml of water
are added. The mixture is heated under reflux
overnight and cooled and the salts are filtered off
with suction and washed with dioxane. The filtrate
is concentrated, the residue is taken up in 100 ml
of water and R2C03 is added. The mixture is extracted
with CHC13, the extract is dried over R2C0~ and
concentrated and the residue is distilled.
Yield: 15.9 g (86.3% of theory)
Boiling point: 75~C/0.1 mbar.
d) 1.2-Dimethyl-3-oxa-2.7-diazabicyclo L3.3.0]octane
11.8 g (64 mmol) of 7-acetyl-1,2-dimethyl-3-oxa-2,7-
diazabicyclo[3.3.0]octane are heated under reflux
with 12 g of NaOH in 36 ml of water overnight. The
mixture is saturated with R2C03 and extracted several
times with CHC13, the extract is dried over RZC03 and
concentrated and the residue is distilled.
Yield: 4.7 g (51.6% of theory)
Boiling point: 40~C/0.2 mbar.
Le A 26 108 - 117 -
~34(~0 ~3
Exan~le U
2,4-Dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane
a) Ethyl N-(but-2-enyl)-N-(2,2-dimethoxyethyl)-car-
bamate
89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-
carbamate are added dropwise to 17.5 g (0.58 mol) of
NaH (80% strength in paraffin oiI) in 500 ml of
absolute toluene at 80~C. The mixture is then stirred
for one hour and 80 g ( 0 . 59 mol ) of 1-bromo-2-butene
are subsequently added dropwise at 80~C. The mixture
is stirred at 80~C overnight and cooled, the salts
are dissolved with water and the aqueous phase is
separated off and extracted with toluene. The
toluene solutions are dried over R2C03 and concentra-
ted and the residue is distilled.
Yield: 90 g (77.8% of theory)
Boiling point: 65~C/0.1 mbar.
b) Ethvl N-(but-2-enyl~(2-oxoethylL carbamate
90 g (0.39 mol) of ethyl N-(but-2-enyl)-N-(2,2-
dimethoxyethyl)-carbamate are heated under reflux
with 200 ml of fonaic acid for one hour. The mixture
is poured onto 500 g of ice and extracted with
methylene chloride, the organic phases are washed
with sodium bicarbonate solution, dried over mag-
Le A 26 l08 - 118 -
._ a.-
F
~~~O~~;j
nesium sulphate and concentrated and the residue is
distilled.
Yield: 33.6 g (46.5% of theory)
Boiling point: 65~C/0.1 mbar.
c) Ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]-
octane-7-carboxylate
18.4 g (0.1 mol) of ethyl N-(but-2-enyl)-N-(2-oxo-
ethyl)-carbamate are dissolved in 100 ml of dioxane,
and 9 g of anhydrous sodium acetate and 9 g (0.108
mol) of N-methylhydroxylamine hydrochloride in 10 ml
of water are added. The mixture is heated under
reflux overnight and cooled and the salts are
filtered off with suction and washed with dioxane.
The filtrate is concentrated, the residue is taken
up in 100 ml of water and R2C03 is added. The mixture
is extracted with CHC13, the extract is dried over
R2C03 and concentrated and the residue is distilled.
Yield: 15.0 g (70% of theory)
Boiling point: 74-87~C/0.1 mbar.
d) 2,4-Dimethyl-3-oxa-2,7-diazabicycloj3.3.0~joctane
13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,7-
diazabicyclo[3.3.0]octane-7-carboxylate are heated
under reflux with 39 g of Ha(OH)Z . 8H20 in 200 ml of
water overnight. R2C0j is added, the BaC03 is fil-
tered off with suction and the filtrate is extracted
several times with CHC13. The extract is dried over
Le A 26 108 - 119 -
I340 ~'~3
RZC03 and concentrated and the residue is distilled.
Yield: 4.8 g (54.8% of theory)
Boiling point: 74~C/8 mbar.
~xam~le V
Ethyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate
7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is
reacted with ethyl chloroformate analogously to Example
Oa) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane-
2-carboxylate, and this is then debenzylated hydrogeno-
lytically analogously to Example Jd). A colourless oil of
boiling point 90~C/0.1 mbar is obtained.
Example W
2-Phenyl-2,7-diazabicyclo[3.3.0]octane
The preparation is carried out analogously to Example I);
Boiling point: 103~C/0.08 mbar.
Le A 26 108 - 120 -
1~4~~~~3
Example X
4-Oxa-2,8-diazabicyclo[4.3.0]nonane
a) Ethyl 3-amino-4-hydroxymethyl-pyrrolidine-1-
carboxylate
Ethyl 3-oxa-2,7-diazabicyclo[3.3.0]octane-7-car-
boxylate (Example Qc) is hydrogenated analogously to
Example Pa).
Boiling point: l63-168~C/0.8 mbar
b) 3-Amino-4-hydroxvmethyl-pyrrolidine
Ethyl 3-amino-4-hydroxymethyl-pyrrolidine-1-car-
boxylate is hydrolyzed analogously to Example Pd).
Boiling point: 78~C/0.06 mbar.
c) 4-Oxa-2.8-diazabicyclo~4.3.0]nonane
3-Amino-4-hydroxymethyl-pyrrolidine is reacted with
formaldehyde solution analogously to Example Pe).
Boiling point: 50-60~C/0.07 mbar
Le A 26 108 - 121 -
~340~fi3
Example Y
traps-3-Ethylamino-4-methylthio-pyrrolidine
a) 1-Henzoyl-traps-3-ethylamino-4-methylthio-
pyrro 1 idi ne
8.65 g (50 mmol) of 1-benzoyl-2,5-dihydropyrrole
[Chew. Ber. ~2, 252l (1889)] are initially intro-
duced into 30 ml of methylene chloride, and 4.94 g
(60 mmol) of methanesulphonyl chloride in 20 ml of
methylene chloride are added dropwise at 0~C. The
mixture is subsequently stirred at 20-25~C for 16
hours and concentrated under 8 mbar and the residue
is dissolved in 50 ml of tetrahydrofuran. 18 g
(0.2 mol) of 50% strength aqueous ethylamine solu-
tion are then added. The batch is boiled for 18
hours, while cooling under reflux, poured into water
and extracted with methylene chloride. On concen-
trating, 11.1 g of crude product are obtained, and
the crude product is chromatographed with ethyl
acetate/ethanol 5s1 on silica gel (RF value 0.34).
Yield: 7.4 g (56% of theory).
b) traps-3-Ethylamino-4-methylthio-pvrrolidine
6.0 g (22 nmiol) of 1-benzoyl-traps-3-ethylamino-4-
methylthio-pyrrolidine are stirred vigorously with
22 ml of 5N NaOH at 100~C for 24 hours, until the
Le A 26 l08 - 122 -
1~~0 ~~3
conversion is homogeneous. The mixture is then
extracted with 3 x 80 ml of ether and the extract is
dried over sodium sulphate and concentrated on a
rotary evaporator. The crude product is distilled
through a micro-puncture column.
Yield: 1.56 g (44% of theory) of colourless liquid,
Boiling point: 52~C/0.1 mbar
Example Z
trans-3-amino-4-methylthio-pyrrolidine
1-Benzoyl-2,5-dihydropyrrole is reacted with methylsu]fe-
nyl chloride analogously to Example Y to give 1-benzyl-3-
chloro-4-methylthiopyrrolidine which is reacted as a crude
product with ammonia to give 3-amino-1-benzoyl-4-.methyl-
thio-pyrrolidine and the benzoyl radical is removed with
sodium hydroxide solution.
Yield over 3 stages: 47 ~ of theory
Boiling point: 108-110'C/11 mbar.
Example ZA
4-Methyl-2,8-diazabicyclof9.3.0]nonane
a) 5-Methyl-1,4-dihydropyridine-2,3-dicarboxylic acid
N-benzylimide
33 g (0.29 mol) of 2-methyl-2-propenal-dimethylhydra-
zone and 55 g (0.29 mol) of N-benzylmaleinimide are
stirred in 225 ml of acetonitrile for 3 hours at 60'C.
Le A 26 108 - 123 -
l~~1~~~3
Then the solvent is removed in a rotary evaporator,
the residue is taken up in 600 ml of toluene and,
after adding 150 g of silica gel, the mixture is
boiled for 1 hour under reflux.
Then the mixture is filtered while hot and the silica
gel is boiled out several times with ethanol. The
combined organic phases are concentrated in a rotary
evaporator.
17.5 g (24 ~ of theory) of red crystals of a melting
point of 184-186'C are obtained.
b) 5-Methyl=hexahydropyridine-2,3-dicarboxylic acid
N-benzylimide
17.5 g (70 mmol) of 5-methyl-1,4-dihydropyridine-2,3-
dicarboxylic acid N-benzylimide are hydrogenated in
150 ml of tetrahydrofuran at 70'C and under 100 bar
over palladium on active charcoal. Then the catalyst
is filtered off and the filtrate is concentrated by
evaporation. The solid oily residue (13.0 g) is used
as a crude product in the next stage.,
c) 8-Benzyl-4-methyl-2,8-diazabicyclo[4.3.0]nonane
13.0 g of crude 5-methyl-hexahydropyridine-2,3-dicarb-
oxylic acid N-benzylimide are added in the form of a
solution in 50 ml of absolute tetrahydrofuran to 4.6 g
(0.12 mol) of lithium aluminium hydride in 100 ml of
absolute tetrahydrofuran, already present in the
vessel. Then the mixture is boiled for 17 hours
under reflux. 4.6 g of water in 14 ml of
~5 tetrahydrofuran, 4.6 g of 10 ~ strength sodium hydrox-
ide solution and 13.8 g of water are added dropwise
one after the other. The salts are filtered off, the
filtrate is concentrated by evaporation and the
residue is distilled.
- 124 -
1~~~ j~3 f..-.
Yield: 8.7 g (54 %, based on 5-methyl-1,9-dihydropyri-
dine-2,3-dicarboxylic acid N-benzylimide);
boiling point: 95-98'C/0.1 mbar.
d) 4-Methyl-2,8-diazabicyclo[4.3.0]nonane
8.0 g (35 mmol) of 8-benzyl-9-methyl-2,8-diaza-
bicyclo[4.3.0]nonane are dissolved in 60 ml of
methanol and hydrogenated over palladium on acitive
charcoal at 100'C and under 100 bar. Then the cata-
lyst is filtered off, the filtrate is concentrated by
evaporation and the residue is distilled.
Yield: 3.3 g (67 % of theory)
boiling point: 88-89'C/llmbar.
The 1H-NMR spectrum shows the compound to be a mixture
of two stereoisomers in a ratio of 7:2.
ExamQle AA
5,6,7,8-Tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid
a) Ethyl 2-(2,3,4,5,6-pentafluorobenzoyl)-3-(2,4-
difluoroghenylamino~ -acrylate
44.3 g of 2,4-difluoroaniline are added dropwise to
a solution of 115 g of ethyl 3-ethoxy-2-(2,3,4,5,6
pentafluorobenzoyl)-acrylate in 380 ml of ethanol,
while cooling with ice and stirring. The mixture is
stirred at room temperature for 1 hour, 380 ml of
water are added, while cooling with ice, and the
precipitate is filtered off with suction, washed
with ethanol/HZO (1:1) and dried. 135.4 g of the
title compound of melting point 97-99~C are obtained.
Le A 26 108 - 125 -
~~4~JJ~
b) Ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-
1,4-dihydro-4-oxo-3-quinolinecarboxylate
A mixture of 135.4 g of ethyl. 2-(2,3,4,5,6-
pentafluorobenzoyl)-3-(2,4-difluorophenylamino)-
acrylate, 20.6 g of sodium fluoride and 300 ml of
anhydrous dimethylforznamide is heated at 140-150~C
for 3 hours. The suspension is poured hot onto 2 kg
of ice and the precipitate is filtered off with
suction, washed with water and dried. 122 g of the
title compound of melting point 160-162~C are
obtained.
i5
c) 5,6,7,8-Tetrafluoro-1-(2,4-difluorophenyl)-1,4-
dihydro-4-oxo-3-cLuinolinecarboxylic acid
40.1 g of ethyl 5,6,7,8-tetrafluoro-1-(2,4-difluoro-
phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are
added to a mixture of 28.5 ml of concentrated
sulphuric acid, 250 ml of glacial acetic acid and
200 ml of water and the mixture is heated under
reflux for 2 hours. The hot solution is poured onto
ice and the precipitate is filtered off with suc-
tion, washed with water and dried. 34.5 g of the
title compound of melting point 250-252~C are
obtained.
Ex~Ple AB
5,7-Dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-
- cuinolinecarboxvlic acid
a) Fthvl (2,4-dichloro-3,6-difluorobenz~ll-acetate
Le A 26 108 - 126 -
1340 ~~
2.1 g of magnesium filings are suspended in 5 ml of
anhydrous ethanol. 0.5 ml of carbon tetrachloride is
added and, when the reaction has started, a mixture
of 14 g of ethyl malonate, 10 ml of absolute ethanol
and 41 ml of toluene is added dropwise. The mixture
is then heated at 70C for a further 1.5 hours and
cooled to -5C to -10C with acetone/dry ice, and a
solution of 21.5 g of 2,4-dichloro-3,6-difluoro-
benzoyl chloride in 30 ml of toluene is slowly added
dropwise at this temperature. The mixture is stirred
at 0C for 1 hour and allowed to come to room temper-
ature overnight, and a mixture of 35 ml of ice-water
and 5 ml of concentrated sulphuric acid is allowed
to run in, while cooling with ice. The phases are
separated and subsequent extraction is carried out
twice with toluene. The combined toluene splutions
are washed once with saturated sodium chloride
solution and dried with NaZSO, and the solvent is
stripped off in vacuo. 34.7 g of diethyl (2,4-
dichloro-3,6-difluorobenzoyl)-malonate are obtained
as a crude product.
0.04 g of p-toluenetoluenesulphonic acid is added to
an emulsion of 34.7 g of crude diethyl (2,4-di-
chloro-3,6-difluorobenzoyl)-malonate in 40 ml of
water. The mixture is heated at the boiling point
for 3 hours, while stirring thoroughly, the cooled
emulsion is extracted several times with methylene
chloride, the combined CH2C12 solutions are washed
once with saturated sodium chloride solution and
Le A 26 108 - 127 -
dried with Na2S0, and the solvent is distilled off in
vacuo. Fractionation of the residue (33.9 g) in
vacuo gives 13.9 g of ethyl (2,4-dichloro-3,6-
difluorobenzoyl)-acetate of boiling point 110-115~C/
0.05 mbar, np5. 1,5241.
b) Ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-
acrylate
13.7 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-
acetate are heated under reflux with 10.25 g of
triethyl orthoformate and 11.8 g of acetic anhydride
for 2 hours. The mixture is then concentrated in
vacuo up to a bath temperature of 140~C and 15.7 g
of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-
ethoxy-acrylate are obtained as an oil, np5.. 1,5302.
c) Ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclo-
propvlamino-acrylate
15.6 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-
3-ethoxy-acrylate are dissolved in 50 ml of ethanol,
and 2.75 g of cyclopropylamine are added dropwise,
while cooling. The mixture is stirred at room
temperature for 1 hour, 50 ml of water are added,
while cooling with ice, and the precipitate is
filtered off with suction, rinsed with ethanol/H20
(1:1) and dried. l4.1 g of ethyl 2-(2,4-dichloro-
3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate of
melting point 106-107~C are obtained.
Le A 26 108 - 12g
t
d) Ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylate
6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-
3-cyclopropylamino-acrylate are heated in 100 ml of
dimethylfonaamide at 150~C with 2.75 g of potassium
carbonate for 2.5 hours. The mixture is poured into
600 ml of ice-water and the precipitate is filtered
off with suction, washed with water and dried.
5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro
1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting
point 227-229~C are obtained.
e) 5,7-Dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxo-3-cZuinoinecarboxylic acid
5.2 g of ethyl 5,7-dichloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylate are heated
under reflux in a mixture of 38 ml of acetic acid,
30 ml of water and 4.3 ml of concentrated sulphuric
acid for 2.5 hours. After cooling, the mixture is
poured into 250 ml of ice-water and the precipitate
is filtered off with suction, washed with water and
dried. 4.8 g of 5,7-dichloro-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of
melting point 277-278~C are obtained.
Le A 26 108 - 129 -
~~3~I~ )J~
Example AC
5,7-Dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid
a) Ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4-
difluorophen~laminol-acrylate
35.3 g of ethyl 2-(2,4-dichloro-3,6-difluoro-
benzoyl)-3-ethoxyacrylate are dissolved in 120 ml of
ethanol, and 12.9 g of 2,4-difluoroaniline are added
dropwise, while cooling with ice. The mixture is
stirred at room temperature for 1.5 hours, 120 ml of
water are added, while cooling, and the precipitate
is filtered off with suction, rinsed with ethanol/-
H20 ( 1:1 ) and dried . 4 0 . 5 g of ethyl 2- ( 2 , 4-dichloro-
3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)-
acrylate are obtained, melting point: 84-86~C.
b) Ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-
1.4-dihydro-4-oxo-3-quinolinecarboxylate
43.6 g of ethyl 2-(2,4-dichloro-3,6-difluoro-
benzoyl)-3-(2,4-difluorophenylamino)-acrylate are
heated in 260 ml of dimethylformamide at 150~C with
15.2 g of potassium carbonate for 2.5 hours. The
mixture is poured into 1 litre of ice-water and the
precipitate is filtered off with suction, washed
with water and dried. 38.6 g of ethyl 5,7-dichloro-
Le A 26 108 - 130 -
i~~a~~
6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-
3-quinolinecarboxylate are obtained.
c) 5,7-Dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-
dihYdro-4-oxo-3-guinolinecarboxylic acid
41.6 g of ethyl 5,7-dichloro-6-fluoro-1-(2,4-di-
fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecar-
boxylate are heated under reflux with 250 ml of
acetic acid, 200 ml of water and 28.5 ml of con-
centrated sulphuric acid for 3 hours. After cooling,
the mixture is poured into 2 litres of ice-water and
the precipitate is filtered off with suction, washed
with water and dried. 35.5 g of 5,7-dichloro-6- .
fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid are obtained, melting point:
244-246~C.
Example 1
0
COOH
'J
N
HZ N ~ x HC1
F
CH30r~
A. 855 mg (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated
under reflux in a mixture of 9 ml of acetonitrile and 4.5
ml of dimethylformamide in the presence of 330 mg (3.3
mmol) of 1,4-diazabicyclo[2.2.2]octane and 750 mg of
Le A 26 108 - 13'. -
1~4~~~3
traps-3-tert.-butoxycarbonyl-amino-4-methoxy-pyrrolidine
for 1 hour. The mixture is evaporated, the residue is
stirred with water and the mixture is dried.
Yield: 1.3 g (90.5% of theory) of 7-(traps-3-tert.-
butoxycarbonylamino-4-methoxy-1-pyrrolidinyl)-1-cyclo-
propyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid.
Melting point: 222-224~C (with decomposition) (from
glycol monomethyl ether).
B. 1.2 g (3.5 mmol) of the product from stage A are
introduced into 10 ml of 3N hydrochloric acid, the
mixture is stirred until a solution is obtained and the
solution is concentrated. The residue is triturated with
ethanol, filtered off with suction and dried at 60~ under
a high vacuum.
Yield: 0.73 g (70% of theory) of 7-(traps-3-amino-4-
methoxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-4-oxo-
3-quinolinecarboxylic acid hydrochloride.
Melting point: 279~C (with decomposition).
Le A 26 108 - 13c -
I~~~~~:
Example 2
0
~COOH
N
H 2 N~.~N
xHCl
CH30".~
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid is reacted analogously to Example 1 to
give:
A. 7-(traps-3-tert.-Butoxycarbonylamino-4-methoxy-1-
pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid, melting point: 247-249~C (with
decomposition).
8. 7-(traps-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclo-
propyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid hydro-
chloride, melting point: from 293~C (with decomposition).
Example 3
0
~COOH
N
H2 N ~ x HC1
F
CH3
A reaction is carried out analogously to Example 1 with
Le A 26 l08 - l33 -
1~41~y3
cis-3-tert.-butoxycarbonylamino-4-methoxy-pyrrolidine to
give:
A. 7-(cis-3-tert.-Butoxycarbonylamino-4-methoxy-1-
pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid, melting point: 230-231~C
(with decomposition).
B. 7-(cis-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclo
propyl-6,8-difluoro-4-oxo-3-quinolinecarboxylic acid
hydrochloride, melting point 201-203~C (with decomposi
tion).
Example 4
O
COOH
N
HZ N x CF3COOH
C 1~
CH3
A. 1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are
heated under reflux in a mixture of 10 ml of acetonitrile
and 5 ml of dimethylformamide with 550 mg (5 mmol) of
1,4-diazabicyclo[2.2.2]octane and 1.2 g (5.6 mmol) of
cis-3-tert.-butoxycarbonylamino-4-methoxy-pyrrolidine for
2 hours. The mixture is allowed to cool and the precipit-
ate which has separated out is filtered off with suction,
rinsed thoroughly with water and dried at 100~C in vacuo.
Le A 26 108 - 134 -
..
1~~~~~~
Yield: 2.0 g (80.7%) of 7-(cis-3-tert.-butoxycarbonyl-
amino-4-methoxy-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
melting point: 222-225~C (with decomposition).
B. 1.9 g (3.8 mmol) of the product from stage A are
stirred in 10 ml of trifluoroacetic acid at room tempera-
ture for 20 minutes, the solution is concentrated, the
oil which remains is evaporated twice with methylene
chloride and the residue is stirred with ether. The
precipitate which has separated out is filtered off with
suction, washed with ether and dried at 60~C in vacuo.
Yield: 1.9 g (97% of theory) of 7-(cis-3-amino-4-methoxy- _
1-pyrrolidinyl)-8-chloro-I-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid trifluoro-
acetate, melting point: 235-239~C (with decomposition).
Example 5
0
~COOH
J'[N
H2N1~/~N ~ xHC 1
CH3
cis-3-tert.-Butoxycarbonylamino-4-methoxy-pyrrolidine is
reacted with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-
oxo-3-guinolinecarboxylic acid analogously to Example 1
to gives
Le A 26 108 - 135 -
r
A. 7-(cis-3-tert.-Butoxycarbonylamino-4-methoxy-1-
pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
3-quinolinecarboxylic acid, melting point 232-233~C (with
decomposition).
B. 7-(cis-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclo-
propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid hydrochloride, melting point 252-256~C (with decom-
position) (sintering beforehand).
Example 6
0
~COOH
JN
H2 N ~ xHCl
CH3 ,.
cis-3-tert.-Butoxycarbonylamino-4-methoxypyrrolidine is
reacted with7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid analogously to
Example 1 to give:
A. 7-(cis-tert.-Hutoxycarbonylamino-4-methoxy-1-
pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid, melting point 214-
216~C (with decomposition).
B. 7-(cis-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclopro-
pyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Le A 26 108 - 136 -
., ~ ._
~3~Q~53
carboxylic acid hydrochloride, melting point 205-210~
(with decomposition).
Mass spectrum: m/e 362 (M+) , 330 (M+-32 ) , 318 (M+-COZ) ,
286, 260, 41 (C3Hs), 36 (HC1).
Example 7
0
COON
_~J
N
H2 UN
H0,~~
1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and
0.55 g (5.4 mmol) of traps-3-amino-4-hydroxy-pyrrolidine
are added to 1.33 g (5 mmol) of 1-cyclopropyl'=6,7-di-
fluoro-I,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a
mixture of 30 ml of acetonitrile and 5 ml of dimethyl-
formamide and the mixture is heated under reflux for 1
hour. The suspension is concentrated, water is added to
the residue and the undissolved product is filtered off
with suction and recrystallized from dimethylformamide.
Yield: 1.2 g (73% of theory) of 7-(traps-3-amino-4-
hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid,
Melting points Z74-278~C (with decomposition).
Le A 26 108 - 137 -
---,
13~~~~3
Example 8
OOH
850 mg (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid are heated under
reflux in 9 ml of pyridine with 630 mg (3.1 mmol) of 2-
oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride and
500 mg (4.5 mmol) of 1,4-diazabicyclo[2.2.2]octane for 1
hour. The mixture is concentrated, the residue is stirred
with water and the precipitate is filtered off with
suction, washed with water, dried and recrystallized from
glycol monomethyl ether.
Yield: 840 mg (72% of theory) of 1-cyclopropyl-6,8-
difluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-
8-yl)-4-oxo-3-quinolinecarboxylic acid,
Melting point: 289-291~C (with decomposition);
Mass spectrum: m/e 391 (M+), 347 (M'-COZ), 331, 306, 294,
262, 234, 98, 41 (C3H5) .
Le A 26 108 - :38 -
N
H
..
Example 9
0
COOH
N ~ N~
F
~CH3
The reaction is carried out analogously to Example 8 with
5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane dihydro-
chloride to give: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-
7-(5-methyl-2-oxa-5,8-diaxabicyclo[4.3.0]non-8-yl)-4-oxo-
3-quinolinecarboxylic acid, melting point: from 270~C
(with decomposition);
Mass spectrum: m/e 405 (M+) , 361 (M'-C02) , 331, 112,
(100%). w
Exam_"ple 10
0
COON
'J
N
~N
~H3
795 mg (3 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-di-
hydro-4-oxo-3-quinolinecarboxylic acid are heated under
reflu: in a mixture of 9 ml of acetonitrile and 4.5 ml of
dimethylformamide with 890 mg (4.1 mmol) of 5-methyl-2-
oxa-5,8-diazabicyclo[4.3.0]nonane dihydrochloride and
Le A 26 108 - 139 -
i~~0~~3
860 mg (7.8 mmol) of 1,4-diazabicyclo[2.2.2]octane for 2
hours. The mixture is evaporated, the residue is stirred
with water and the undissolved product is filtered off
with suction, washed with water, dried and recrystallized
from dimethylformamide.
Yields 0.8 g (69% of theory) of 1-cyclopropyl-6-fluoro-
1,4-dihydro-7-(5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]non-
8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point
340~C (with decomposition) (on heating up, the substance
already becomes dark from about 300~).
Mass spectrum: m/e (Mi) , 343 (M+-C02) , 313, 244, 112
(100%).
Example 11
0
~COOH
N
C1~
N
~GH3
The reaction is carried out analogously to Example 10
with 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid to give 8-chloro-1-cyclo-
propyl-6-fluoro-1,4-dihydro-7-(5-methyl-2-oxa-5,8-diaza-
bicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid,
melting point 258-262~C (with decomposition) (recrystal-
lized from dimethylformamide).
Le A 26 108 - 14u -
f
C
Example 12
0
00H
~CH3
The reaction is carried out analogously to Example 10
with 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid to give 1-ethyl-6,8-difluoro-1,4-
dihydro-7-(5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]non-8-
yl)-4-oxo-3-quinolinecarboxylic acid, melting point 279-
281~C (with decomposition).
Example 13 0
00H
NCH 3
0.84 g (3 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid are heated under
reflux in a mixture of 6 ml of acetonitrile and 3 ml of
dimethylformamide with 0.66 g (6 mmol) of 1,4-diazabi-
cyclo[2.2.2]octane and 0.49 g (3.5 aunol) of 2-methyl-2,8-
diazabicyclo[4.3.0]nonane for 2 hours. The suspension is
concentrated, the residue is stirred with 20 ml of water,
Le A 26 108 - 1~1 -
~H\
~.34~:~3
the mixture is brought to pH 7 with 2N hydrochloric acid
and the precipitate is filtered off with suction, washed
with water, dried and recrystallized from glycol mono-
methyl ether.
Yield: 0.7 g (58% of theory) of 1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-7-(2-methyl-2,8-diazabicyclo[4.3.0]-
non-8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point
204-207~C.
Example 14
0
00H
~CH3
Analogously to Example 13, 1-cyclopropyl-6-fluoro-1,4-
dihydro-7-(2-methyl-2,8-diazabicyclo[4.3.0]non-8-yl)-4-
oxo-3-quinolinecarboxylic acid, melting point 234-236~,
is obtained with 1-cyclopropyl-6,7-difluoro-I,4-dihydro-
4-oxo-3-quinolinecarboxylic acid.
~e A 26 108 - 1~~ -
- 1~~~053 i~.
Example 15
OOH
A. 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid is reacted with 2,8-diazabi-
cyclo[4.3.0]nonane analogously to Example 13 to give 1-
cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-
difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
melting point 265-267~ (with decomposition) (recrystal- _
lized from dimethylformamide).
B. If the reaction of Example 15 A) is carried out in
a mixture of acetonitrile/1-methyl-2-pyrrolidinone and
the crude product is recrystallized from dimethyl-
formamide, 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-
8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic of melting point 269-271~C (with decomposition)
is obtained. According to a comparison by chromatography
and spectroscopy, the product is identical to the product
prepared according to process A).
C . 65 g ( 167 mmol ) of the betaine ( stage A) are dis-
solved in 330 ml of half-concentrated hydrochloric acid
by heating, the solution is concentrated and the residue
is stirred with 300 ml of ethanol. The undissolved
Le A 26 108 - 143 -
13~~~~3 t~'i'
precipitate is filtered off with suction, washed with
ethanol and dried at 100~C in vacuo.
Yield: 66.3 g (93% of theory) of 1-cyclopropyl-7-(2,8-
diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid hydrochloride, melting
point: 303-305~C (with decomposition).
Example 16
0
00H
Analogously to Example 13, 1-cyclopropyl-7-(2,7-diazabi-
cyclo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid, melting point: 260-282~ (with
decomposition), is obtained with 1-cyclopropyl-6,7-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and
2,7-diazabicyclo[3.3.0]octane.
Mass spectrum: m/e 357 (M'), 313 (100%, M+-C02), 269, 257,
244, 82, 28.
Le A 26 108 - 144 -
13~0~~3 .. .T.
Exata~le 17
O
COOH
CH\
Analogously to Example 13, 1-cyclopropyl-6-fluoro-1,4-
dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-
oxo-3-quinolinecarboxylic acid, melting point: 206-208~C
(with decomposition), is obtained with 1-cyclopropyl-6,7-
difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and
2-methyl-2,7-diazabicyclo[3.3.0]octane. _
Example 18
0
I I cooH
CH3
N
N
F
Analogously to Example 13, 1-cyclopropyl-6,8-difluoro
1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)
4-oxo-3-quinolinecarboxylic acid, melting point 198
200~C (with decomposition) , is obtained with 2-methyl-2, 7
diazabicyclo[3.3.0]octane.
Le A 26 108 - l~:i -
13~Q5~~~
Example 19
o
00H
H3C~ n~
N
I F
A mixture of 2.83 g (10 mmol) of 1-cyclopropyl-6,7,8-
trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
1.1 g (10 nnnol) of 1,4-diazabicyclo[2.2.2]octane and
1.4 g (11 mmol) of 2-methyl-3-oxa-2,7-diazabicyclo[3.3.-
0]octane in 20 ml of acetonitrile and 10 ml of 1-methyl-
2-pyrrolidinone is heated under reflux for 1 hour. It is
concentrated in vacuo, the residue is stirred with water
(pH 7) and the precipitate is filtered off with suction,
washed with water and dried at 60~ in vacuo. The crude
product (3.7 g) is recrystallized from dimethylformamide.
Yield: 1.9 g (49% of theory) of 1-cyclopropyl-6,8-di-
fluoro-1,4-dihydro-7-(2-methyl-3-oxa-2,7-diazabicyclo-
[3.3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylic acid,
melting point 221-223~C (with decomposition).
Le A 26 108 - 146 -
Example 20
0
H3C 00H
"'3
The reaction is carried out analogously to Example 19
with 2,5-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to
give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,5-
dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-
quinolinecarboxylic acid of melting point 237-238~C (with
decomposition).
Example 21
0
00H
H3C\ CH3 I\
N
F
The reaction is carried out analogously to Example 19
with 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane to
give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,8-
dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-
quinolinecarboxylic acid of melting point 197-199~C.
Le A 26 108 - 147 -
4
~.34~ Q53
Example 22
0
COON
~N
C 1~
A. 3 g (10 mmol) of 8-chloro-1-cyclopropyl-6,7-di-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are
heated under reflux in a mixture of 30 ml of acetonitrile
and 15 ml of 1-methyl-2-pyrrolidinone with 1.4 g (11
mmol) of 2,8-diazabicyclo[4.3.0]nonane and 1.65 g (15
mmol) of 1,4-diazabicyclo[2.2.2]octane for 1 hour. After
cooling, the suspension is stirred with about 150 ml of
water and the undissolved precipitate is filtered off
with suction, washed with water and ethanol and dried at
80~C/12m bar. The crude product is recrystallized from
40 ml of glycol monomethyl ether.
Yield: 2.3 g (57% of theory) of 8-chloro-1-cyclopropyl
7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro
4-oxo-3-quinolinecarboxylic acid, melting point: 224
226~C (with decomposition).
H. The crude betaine is prepared analogously to Example
22 A. and is suspended in 50 ml of water and dissolved by
addition of 17 ml of 1N hydrochloric acid and heating.
After cooling in an ice-bath, the precipitate which has
separated out is filtered off with suction, washed with
ethanol and dried at l00~C in vacuo.
Le A 26 108 - 148 -
....~
s
~340~5~
Yield: 2.7 g (61% of theory) of 8-chloro-1-cyclopropyl-
7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid hydrochloride, melting
point: from 225~C decomposition.
Example 23
O
OOH
The reaction is carried out analogously to Example 22
with 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-
[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and the
reaction product obtained is purified by chromatography
on silica gel using methylene chloride/methanol/17%
strength aqueous ammonia solution (30:8:1) as the mobile
phase. 10-(2,8-Diazabicyclo[4.3.0]non-8-yl)-9-fluoro-2,3-
dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxa-
zine-6-carboxylic acid of melting point 291-Z 92~C (with
decomposition) is obtained.
Le A 26 108 - 149 -
r.~
f
~~44j5~t~
Example 24
00H
6 g (20 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid are heated under
reflux in 30 ml of 1-methyl-2-pyrrolidinone and 60 ml of
acetonitrile with 2.2 g (20 mmol) of 1,4-diazabicyclo-
[2.2.2]octane and 2.7 g (21.4 mmol) of 2,8-diazabicyclo-
[4.3.0]nonane for 1 hour. The mixture is concentrated to
a substantial degree in vacuo, the residue is stirred
with 200 ml of water and the undissolved crystals are
filtered off with suction, washed with water and dried.
Yield: 6.3 g (77.4% of theory) of 1-cyclopropyl-7-(2,8-
diazabicyclo[4.3.0]non-8-yl]-5,6,8-trifluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid
Melting point: 266-269~C (with decomposition); after
recrystallization from dimethylfonuamide: melting point:
272-273~C (with decomposition).
Le A 26 108 - 15u -
13~~p~~y
Example 25
NHZ 0
COOH
~N
F
20 ml of saturated ethanolic ammonia solution are added
to 4.1 g (10 mmol) of the product from Example 24 in 40
ml of pyridine, and the mixture is heated at 120~C in an
autoclave for 12 hours. The suspension is evaporated, the
residue is stirred with water and the pH is brought to 7
with 2N hydrochloric acid. The precipitate which has
separated out is filtered off with suction and recrys-
tallized from glycol monomethyl ether.
Yield: 0.7 g (17% of theory) of 5-amino-1-cyclopropyl-7-
(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid, melting point:
275-277~C (with decomposition).
Mass spectrum: m/e 404 (M+), 384 (M''-HF), 290, 249, 96
(100%).
Le A 26 108 - 151 -
~34~~53
Examflle 26
0
00H
H
A. Analogously to Example 13, 1-cyclopropyl-7-(2,7-
diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid, melting point: 277-280~
(with decomposition), is obtained with 2,7-diazabicyclo-
[3.3.0]octane.
B. 370 mg of the betaine are dissolved in 13 ml of
half-concentrated hydrochloric acid, the solution is
concentrated and the residue is treated with 10 ml of
ethanol. The undissolved product is filtered off with
suction, washed with ethanol and dried.
Yield: 290 mg of 1-cyclopropyl-7-(2,7-diazabicyclo
[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino
linecarboxylic acid hydrochloride, melting point: 269
271~C (with decomposition).
Le A 26 108 - 152 -
1340 ~~'~
Example 27
0
~ I ~COOH
CH3~N ~ N
CH3-NH~;wU F
The reaction is carried out analogously to Example 8 with
trans-4-methoxy-3-methylamino-pyrrolidine dihydro-
chloride. 1-Gyclopropyl-6,8-difluoro-1,4-dihydro-7-
(trans-4-methoxy-3-methylamino-1-pyrrolidinyl)-4-oxo-3-
quinolinecarboxylic acid, melting point: 268-270~C (with
decomposition) is obtained.
Example 28
0
COOCZHS
~' J
C H 3 01./N N
HZN~ F
xCF3C00H
A. 1. 4 g ( 2 . 9 mmol ) of the product from Example 3 A)
and 1.98 ml (1.7 g, 12 mmol) of dimethylformamide di-
ethyl acetal are heated at 120~C in 15 ml of absolute
dimethylformamide for 2 hours. The mixture is then
concentrated in vacuo. The residue which remains is
stirred with acetonitrile. The precipitate is filtered
Le A 26 l08 - 1~3 -
~.34U:~~~
off with suction, washed with a little acetonitrile and
dried.
Yield: 0.8 g (54.4% of theory) of ethyl 7-(cis-3-tert.-
butoxycarbonylamino-4-methoxy-1-pyrrolidinyl)-1-cyclo-
propyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylate,
melting point: 151-152~C.
H. 0.3 g (0.6 mmol) of the product from Example 28 A)
are stirred in 10 ml of trifluoroacetic acid at 20~C for
10 minutes. The trifluoroacetic acid is then removed in
vacuo. The residue solidifies on addition of diethyl
ether. The solid is isolated, washed with diethyl ether
and dried.
Yield: 0.25 g (80.6% of theory) of ethyl 7-(cis-3-amino-
4 -methoxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylate trifluoroacetate
Melting point: 124-126~C.
Example 29
0
00H
H3C~
Analogously to Example 13, 1-cyclopropyl-6,8-difluoro-
1,4-dihydro-7-(2-methyl-4-oxa-2,8-diazabicyclo[4.3.0)non-
8-yl)-4-oxo-3-quinolinecarboxylic acid, melting point
Le A 26 108 - 1S4 -
i
258-260~C (with decomposition) , is obtained with 2-methyl-
4-oxo-2,8-diazabicyclo[4.3.0]nonane.
Exa~np~.e 30
0
~COOH
I
N
HN
F
Analogously to Example 19, 1-cyclopropyl-6,8-difluoro-
1,4-dihydro-7-(3-oxa-2,7-diazabicyclo[3.3.0]octan-7-yl)-
4-oxo-3-quinolinecarboxylic acid is obtained with 3-oxa-
2,7-diazabicyclo[3.3.0]octane.
Example 31
O
00H
xHCl
A. 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and
1.4 g (11 mmol) of 2,8-diazabicyclo[4.3.0]nonane are
added to 2.53 g (10 mmol) of 1-ethyl-6,7-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of
acetonitrile and 15 ml of dimethylfonaamide and the
mixture is heated under reflux for 1 hour. The mixture is
Le A 26 108 - 15~ -
t
concentrated, the residue is stirred with water and the
precipitate is filtered off with suction, washed with
water and dried.
Yield: 3.1 g (86% of theory) of 7-(2,8-diazabicyclo
[4.3.0]non-8-yl)-1-ethyl-6-fluoro-4-oxo-3-quinoline
carboxylic acid, melting point: 259-261~C (with decom
position).
B. 2.9 g (8 mmol) of the betaine from stage A are
dissolved in 20 ml of half-concentrated hydrochloric acid
under the influence of heat, the solution is filtered hot
and the hydrochloride is precipitated from the filtrate
by addition of ethanol. This hydrochloride is filtered
off with suction, washed with ethanol and dried at 120~C/
12 mbar.
Yield: 1.8 g (57% of theory) of 7-(2,8-diazabicyclo-
[4.3.0]non-8-yl)-1-ethyl-6-fluoro-4-oxo-3-quinoline-
carboxylic acid hydrochloride, melting point, with decom-
position: 299~C (dark coloration already starting from
about 215~C ) .
Example 32
OOH
Reaction analogously to Example 31 with 1-cyclopropyl-
Le A 26 10B _ 1~~ _
1
6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
gives:
A. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-
6-fluoro-4-oxo-3-quinolinecarboxylic acid,
melting point: 249-257~C (with decomposition)
B. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-
6-fluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride,
melting point with decomposition: 320~C (dark coloration
already starting from about 288~C).
Example 33
00H
OCH.
1.1 g (3 asnol) of 1-cyclopropyl-7-(2,8-diazabicyclo-
[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid are heated under reflux in 10 ml of
dimethylformamide and 1 ml of formic acid for 4 hours.
The mixture is evaporated, the residue is stirred with
4 ml of water and the precipitate is filtered off with
suction, dried (crude yield: 1 g, content: 99.5%) and
recryatallized from dimethylformamide.
Yield: 0.8 g (64% of theory) of 1-cyclopropyl-6,8-di-
fluoro-7-(2-formyl-2,8-diazabicyclo[4.3.0]non-8-yl)-1,4-
Le A 26 108 - i57 -
.....
~~~0~~3
dihydro-4-oxo-3-quinolinecarboxylic acid, melting point:
276-278~C.
Example 34
0
00H
CH3C0~
1.1 g (3 mmol) of 1-cyclopropyl-7-(2,8-diazabicyclo-
[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid are dissolved in a mixture of 8 ml of
dioxane and a solution of 120 mg of sodium hydroxide in
1 ml of water, and at the same time 3 ml of 1N sodium
hydroxide solution and 260 mg of acetyl chloride are
added, while cooling with ice. The mixture is subse-
quently stirred at room temperature for 2 hours and
diluted with 30 ml of water and the precipitate which has
separated out is filtered off with suction. The crude
product is recrystallized from glycol monomethyl ether.
Yield: 0.6 g (46% of theory) of 7-(2-acetyl-2,8-diaza-
bicyclo[4.3.0]non-8-yl)-1-cyclopropyl-6,8-difluoro-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid, melting point:
261-263~C (with decomposition)
Le A 26 108 - '-5t3 -
134Q~~'S3
0
J
H3C~ N ~ N
N
C 1~
OOH
A. Analogously to Example 13, 8-chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-7-(2-methyl-2,?-diazabicyclo[3.3.0]-
oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, melting
point: 222-227~C (with decomposition), is obtained with
8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid and 2-methyl-2,7-diazabicyclo-
[3.3.0]octane.
B. 2.3 g (5.8 mmol) of the betaine from stage A are
dissolved in 15 ml of 1N hydrochloric acid under the
influence of heat, the solution is evaporated and the
residue is treated with ethanol. The precipitate is
filtered off with suction, washed with water and dried.
Yield: 2.2 g (8?.7% of theory) of 8-chloro-1-cyclopropyl-
6-fluoro-1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]-
oct-7-yl)-4-oxo-3-guinolinecarboxylic acid hydrochloride,
melting point: 303-305~C (with decomposition).
Le A 26 108 _ 15~ _
..
rs
Example ~6
0
OOH
H ~--N~Ni xHC 1
CH3
Analogously to Example 13, 1-cyclopropyl-6,8-difluoro-
1,4-dihydro-7-(3-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-
4-oxo-3-quinolinecarboxylic acid is obtained with 3-
methyl-2,7-diazabicyclo[3.3.0]octane, and is converted
into 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-
2,7-diazabicyclo(3.3.0]oct-7-yl)-4-oxo-3-quinolinecar-
boxylic acid hydrochloride, melting point: ZI6-Z21~C (with
decomposition), analogously to Example 15 C. with half-
concentrated hydrochloric acid.
Example 37
00H
H3C~
CH3
A. A mixture of 1.45 g (5 mmol) of 1-cyclopropyl-6,7,8-
trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
0.S5 g (7.5 mmol) of 1,4-diazabicyclo[Z.2.2]octane and
0.77 g (5.5 msnol) of 2,3-dimethyl-2,7-diazabicyclo-
Le A 26 108 - iS~J -
1340e3
[3.3.0)octane in 15 ml of acetonitrile and ?.5 ml of
dimethylformamide is heated under reflux for 1 hour.
After cooling, the precipitate is filtered off with
suction, washed with water and recrystallized from glycol
monomethyl ether.
Yield: 1 g (47% of theory) of 1-cyclopropyl-7-(2,3-
dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-6,8-difluoro-
1,4-dihydro-4-oxa-3-quinolinecarboxylic acid, melting
point: 208-209~C (with decomposition).
B. 0.7 g (1.7 mmol) of the betaine from stage A are
dissolved in 6 ml of hot half-concentrated hydrochloric
acid and the solution is filtered and concentrated to a
substantial degree in vacuo. About 15 ml of ethanol are
added, the mixture is cooled in an ice-bath and the salt
is filtered off with suction, washed with ethanol and
dried at 100~C/1 mbar.
Yield: 0.64 g (84% of theory) of 1-cyclopropyl-7-(2,3-
dimethyl-2,7-diazabicyclo[2.2.2)oct-7-yl)-6,8-difluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro-
chloride, melting point: 233-236~C (with decomposition).
Le A 26 108 -~Gi
Q340553
Example 38 0
COOH
H3C~ N N xHCl
C 1~
CH3
Analogously to Example 37 A. and B., 8-chloro-1-cyclo-
propyl-7-(2,3-dimethyl-2,7-diazabicyclo[2.2.2]oct-7-yl)-
6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
hydrochloride, melting point: 240-241~C (with decomposi-
tion), is obtained with 8-chloro-1-cyclopropyl-6,7-
difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Example 39
o
00H
N3C~
The reaction is carried out analogously to Example 19
with 1,2-dimethyl-3-oxa-2,?-diazabicyclo[3.3.0]octane to
give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1,2-
dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-
quinolinecarboxylic acid of melting point 269-27l~C
(with decomposition).
Le A 26 108 - 1~2 -
1340e3
Ex~ple 40
0
~COOH
N xHCl
C1
H
1.45 g (13 mmol) of 1,4-diazabicyclo[2.2.2]octane and
1.23 g (9.6 mmol) of 2-oxa-5,8-diazabicyclo[4.3.0]nonane
are added to 2.6 g (8.7 mmol) of 8-chloro-1-cyclopropyl-
6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
in a mixture of 25 ml of acetonitrile and 12.5 ml of
dimethylformamide and the mixture is heated under reflux
for 1 hour. It is concentrated, the residue is stirred
with water and the undissolved precipitate is filtered
off with suction and washed with water. This crude 1-
cyclopropyl-8-chloro-6-fluoro-1,4-dihydro-7-(2-oxa-5,8-
diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic
acid is introduced into 85 ml of 1N hydrochloric acid,
and 6 ml of concentrated hydrochloric acid are added. The
hydrochloride which has precipitated out is filtered off
with suction, washed with ethanol and dried.
Yield: 3.0 g (77.7% of theory) of 8-chloro-1-cyclopropyl
6-fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non
8-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride,
melting point: from 290~C decomposition.
Le A 26 108 - 153 -
9
~34~J'~~3
Example 41
0
'- ~ I ~COOH
H3C~ N ~ ,,jj''N
N
C1/ \
Analogously to Example 13, 8-chloro-1-cyclopropyl-6-
fluoro-7-(2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]non-8-
yl)-4-oxo-3-quinolinecarboxylic acid, melting point: 202-
203~C (with decomposition), is obtained with 8-chloro-1-
cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-
carboxylic acid and 2-methyl-4-oxa-2,8-diazabicyclo- .
[4.3.0]nonane.
FAH mass spectrum: m/e 422 ([M+H]~), 404 (422-H20)..
Example 42
0
00H
A. The reaction is carried out analogously to Example
13 with ethyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate
to give 1-cyclopropyl-7-(2-ethoxycarbonyl-2,7-diazabi-
cyclo[3.3.Ojoct-7-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid of melting point 191-192~C.
Le A 26 108 - 1G4 -
~C02CZH5
ly~~j5~3
H. 1.8 g (4 mmol) of the product from Example 42A are
heated in 30 ml of concentrated hydrochloric acid under
gentle ieflux for 15 hours. The solution is concentrated,
the residue is stirred with ethanol and the precipitate
is filtered off with suction, washed with ethanol and
dried at 120~C/12 mbar.
Yield: 1.1 g (67% of theory) of 1-cyclopropyl-7-(2,7-
diazabicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid hydrochloride, melting
point: 273-275~C (with decomposition). The product is
identical to the compound obtained according to Example
26B.
Example 43 _
A. 7.8 g (20 mmol) of 1-cyclopropyl-7-(2,8-diazabi-
cyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid are introduced into 175 ml of
ethanol, and 2.4 g (25 mmol) of methanesulphonic acid are
added at about 70~C. The betaine dissolves, and on cool-
ing the salt precipitates out, this being filtered off
with suction, washed with ethanol and dried at 120~C/12
mbar. It is readily soluble in water.
Yield: 8.6 g (88.6% of theory) of 1-cyclopropyl-7-(2,8-
diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid mesylate, melting points
262-265~C (with decomposition).
The following compounds are obtained analogously:
Le A 26 108 - lb5 -
-..>.
.1~~~I~~a 3
8. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-
6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
tosylate, melting point: 248-250~C (with decomposition).
C. 1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-
6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
lactate, melting point: 205~C-215~C, after sintering
beforehand.
Example 44
3.9 g (10 mmol) of 1-cyclopropyl-7-(2,8-diazabicyclo-
[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quino-
linecarboxylic acid are suspended in 50 ml of water, and _
10 ml of 1N sodium hydroxide solution are added at room
temperature, whereupon the product largely dissolves. A
slight turbidity is removed by filtration through a
membrane filter, the filtrate is concentrated under a
high vacuum and the residue is stirred with ether,
filtered off with suction and dried.
Yield: 3.4 g (82.7% of theory) of sodium 1-cyclopropyl
7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-di
hydro-4-oxo-3-quinolinecarboxylate; the salt decomposes
slowly above 210~C without melting.
Le A 26 108 - 15~ -
~3~~W3
xample 45
0
'" \ I ~COOH
HO-CH2CH2~ N N
N
A mixture of 3.9 g (10 annol) of 1-cyclopropyl-7-(2,8-
diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydro-4-
oxo-3-quinolinecarboxylic acid in 100 ml of dimethyl-
formamide is heated at 80-100~C with 4.2 g of triethys-
amine and 2.8 g of 2-bromoethanol for 20 hours. The
solution is then concentrated in vacuo and the residue _
obtained is purified by chromatography on 200 g of silica
gel ( mobile phase : CH2C12/CH30H/ 17 % strength NH3 = 3 D : 8 :1 ) .
The eluate is concentrated and the residue is stirred
with ethanol, filtered off with suction and dried.
Yield: 1.8 g (41.6% of theory) of 1-cyclopropyl-6,8-
difluoro-1,4-dihydro-7-j2-(2-hydroxyethyl)-2,8-diazabi-
cyclo[4.3.0]non-8-yl]-4-oxo-3-quinolinecarboxylic acid,
melting point: 200-206~C (with decomposition).
Mass spectrum: m/e 433 (M+), 402 (M+ -CH20H), 140, 110
(100%), 96
Le A 26 108 - 1b7 -
13~~~ )a
Example 46
0
00H
'2H5
CH
The reaction is carried out analogously to Example 13
with trans-3-ethylamino-4-methylthio-pyrrolidine to give
1-cyclopropyl-7-{trans-3-ethylamino-4-methylthio)-6,8-
difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
melting point: 215-216~C (with decomposition).
Example 47
O
00H
The reaction is carried out analogously to Example 13
with 2-phenyl-2,7-diazabicyclo[3.3.0]octane to give 1-
cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2-phenyl-
2,7-diazabicyclo[3.3.0]oct-7-yl)-3-quinolinecarboxylic
acid, melting point: 259-260~C (with decomposition).
Le A 26 Q08 - 15$ -
1~4~~~3 ~'
Example 48 F O
vC 00H
N w I NJ
I I
F ,,
N I
(
CH3 I
F
Analogously to Example 13, 5,6,8-trifluoro-1-(2,4-di-
fluorophenyl)-1,4-dihydro-7-(2-methyl-2,8-diazabicyclo-
[4.3.0]non-8 -yl)-4-oxo-3-quinolinecarboxylic acid is
obtained with5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Example 49
COON
F
H
F
Analogously to Example 24, 7-(2,8-diazabicyclo[4.3.0]non-
8-yl)-5,6,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid is obtained with
5,6,7,8-tetrafluoro-1-(2,4-difluorophenyl)-1,4-dihydro-
4-0:o-3-quinolinecarboxylic acid.
Le A 26 108 - 169 -
F.f.~
t
I~4t~ ~~~~3~
~~:am,~le so
NHZ 0
~COOH
F
r F
N
H
F
Analogously to Example 25, 5-amino-7-(2,8-diazabicyclo-
[4.3.0]non-8-yl)-6,8-difluoro-1-(2,4-difluorophenyl)-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid is obtained with
7-(2,8-diazabicyclo[4.3.0]non-8-yl)-5,6,8-trifluoro-1-
(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecar- _
boxylic acid.
Example 51
C1 0
00H
H
Analogously to Example 15 A, 5-chloro-1-cyclopropyl-7-
(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-
4-oso-3-quinolinecarboxylic acid, melting point: 270~C
(decomposition), is obtained with 5,7-dichloro-1-cyclo-
propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid (reflux for 5 hours).
Le A 26 108 - 17u -
1~~0~~3 .~.:~.
Examol~ 52
C1 o
~cooH
N ~ N
'--N
H
Analogously to Example 8, 5-chloro-1-cyclopropyl-6-
fluoro-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo[4.3.0]non-
8-yl)-4-oxo-3-quinolinecarboxylic acid is obtained with
5,7-dichloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid (reflux for 5 hours).
Examgle 53
C1 O
COON
i
N
H
F
Analogously to Example 15 A, 5-chloro-7-(2,8-diazabi-
cyclo[4.3.0]non-8-yl)-6-fluoro-1-(2,4-difluorophenyl)-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained
with 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-
dihydro-4-oxo-3-quinolinecarboxylic acid (reflux for 5
hours).
~e A 6 108 - :71 -
....
~~4~553 ':
Example 54
C1 0
COOH
I I
i
~.-N \ I
H
I
F
Analogously to Example 8, 5-chloro-6-fluoro-1-(2,4-
difluorophenyl)-1,4-dihydro-7-(2-oxa-5,8-diazabicyclo-
[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid is
obtained with 5,7-dichloro-6-fluoro-1-(2,4-difluoro-
phenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
(reflux for 5 hours).
Example 55
0
~ ~~COOH
~ZHSNH~,, N~N
CH35
The reaction is carried out analogously to Example 13
with traps-3-ethylamino-4-methylthio-pyrrolidine and 8-
chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid to give 8-chloro-1-cyclopropyl-
7-(traps-3-ethylamino-4-methylthio-1-pyrrolidinyl)-6-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,
melting points 217-218~C (with decomposition).
Le A 26 108 - 172 -
1405,3
Example 56
O
F COOH
N N x HC1
H2N ~"".... F
1 o CH3S
7-(trans-3-Amino-4-methylthio-1-pyrrolidinyl)-1-cyclopro-
pyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic,
melting point: 208-211'C (with decomposition) and 7-(trans-
3-amino-9-methylthio-1-pyrrolidinyl)-1-cyclopropyl-6,8-di-
15 fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro-
chloride, melting point: 255-257'C (with decomposition),
are obtained with trans-3-amino-4-methylthio-pyrrolidine
analogously to Examples 13 and 15. .
Example 57
O
F COOH
N N x HC1
HN F
3 0 CH3
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl-2,8-
diazabicyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic
acid, melting point: 213-215'C (with decomposition)
(recrystallised from glycol monomethyl ether), and 1-cyclo-
propyl-6,8-difluoro-1,9-dihydro-7-(4-methyl-2,8-diazabi-
cyclo[4.3.0]non-8-yl)-4-oxo-3-quinolinecarboxylic acid
hydrochloride, melting point: 204-212'C (with decomposi-
Le A 26 108 - 173 -
....
I34~~~~
tion) are obtained with 9-methyl-2,8-diazabicyclo~~.3.0%-
nonane analogously to Examples 13 and 15.
The product consists of a mixture of 2 stereoisomers.
15
25
35
Le A 26 108 - 174 -
