Note: Descriptions are shown in the official language in which they were submitted.
CA 02500558 2005-03-10
TITLE OF INVENTION
A Process for the Preparation of Aza-Containing Bicyclic Compounds and the
Use Thereof in the Preparation of Cilazapril
FIELD OF INVENTION
The present invention relates to a novel process for the manufacture of
bicyclic
compounds of formula I, as defined below, wherein Rl represents a hydrogen,
alkyl or aryl radical and R2 and R3 are independently selected from hydrogen,
alkyl, aryl, aralkyl or amino protective groups, in a more facile, less
expensive
manner and with higher stereoselectivity than has been previously described.
For a comprehensive review of amino protective groups, see Greene, T.W. and
Wuts, P.G. M., Chapter 7. 'Protection for the Amino Group', in "Protective
Groups in Organic Synthesis", Third Edition, John Wiley & Sons, Inc.,1999, pp.
494-653. In this context, the preferred groups include, but are not limited
to, Cr
C12 carbonyl group, benzyl, aralkoxy and alkoxy carbonyl groups. The most
preferred protecting group is a phthalimido group. This invention also relates
to
the use of this process in the preparation of the ACE inhibitor Cilazapril II.
In
the compounds of the present invention, the configuration at each asymmetric
carbon atom is preferably (S).
O
N
v
N
COORS ~ O
R2 N O O E
R3 _
CA 02500558 2005-03-10
2
BACKGROUND OF THE INVENTION
Bicyclic, aza-containing ring systems are present in a variety of important
pharmacological products including inhibitors of angiotensin converting enzyme
(ACE) such as Cilazapril. Current methods for preparing compounds of formula
I are described in US 4,512,924, US 6,201,118, US 6,512,111 and US 6,258,947.
These methods involve coupling an appropriately protected amino acid halide or
amino acid anhydride with one of the nitrogens of a suitably protected
piperazic
acid or ester. The protecting groups are then removed and the amino acid is
activated with a halogenating agent. The resulting acid halide is then coupled
at
the subsequent nitrogen position forming bicyclic system I in approximately a
1:1 diastereomeric mixture of the S,S (Ia) and S,R (Ib) form. The following is
a
more detailed description of the prior art.
p O O
R2R3 ~ R2RaN N R2R3~"...
N IV' Ivl'
O O O
8100 R100C RIOOC~'.
(S, S) (S, R) (R, R)
la Ib Ic
The syntheses of bicyclic compounds of formula I were originally described in
US 4,512,924 and is depicted below in Scheme 1. An N(2)-protected piperazic
acid or ester III is coupled with amino acid halide IV to provide V. In this
instance, the protecting groups of V (i.e. the benzyl group, Bn) are removed
by
hydrogenolysis using reagents such as hydrogen and palladium on carbon to
give VI which can then be cyclized in situ using a halogenating agent such as
thionyl chloride or phosphorus pentachloride, in the presence of a base, to
provide VII as a diastereomeric mixture of the S,S and S,R form.
CA 02500558 2005-03-10
3
SCHEME 1
O
NH Bn0 ~ Bn0~0
O 2
ii
BnOCN + Bn0
HN C-CI N
O O
p COOR
COOR H2N
III IV V
O
HO
90C12
H2 (g), Pd/C HN
t DMF
N
H2N O COOR
VI VII
US 6,258,947 discloses a process for preparing compounds of formula VII in
optically pure form VIIa as demonstrated below in Scheme 2. 'The amine is
preferably in protected form. Compound VII is first prepared according to
Scheme 1 and then dehydrogenated with reagents such as a strong base, an
oxidizing agent or a sulfur or selenium derivative to give alkene VIII. In
this
particular instance, lithium diisopropylamide (LDA) benzeneselenenyl bromide
(PhSeBr), hydrogen peroxide (H~) and acetic acid (AcOH) are used.
Compound VIII is then isolated by column chromatography in low yield (~40%)
and converted to the desired stereoisomer VIIa by hydrogenation in the
presence
of a catalyst such as Raney nickel or palladium on carbon.
CA 02500558 2005-03-10
4
SCHEME 2
O O O
1 ) LDA
~N 2) PhSeBr ~N Ni, H2 (g)
(S) N 3) H202, AcOH N (S) N
(S)
H2N O COOR
H2N O COOR H2N O COOR
VII VIII Vlla
US 6,201,118 discloses a shorter process relative to those previously
described,
whereby the selective protection/ deprotection of the piperazic acid/ ester is
avoided and the desired bicyclic system is formed in two steps. As shown in
Scheme 3, an N(1) and N(2)-protected piperazic acid/ester IX is treated with
an
amino acid anhydride such as X with simultaneous removal of the protecting
groups of IX to furnish XI. In the preferred embodiment, anhydride X contains
a
phthalimido-protecting group such that the acylation of the N(2) nitrogen is
forced to occur at the carbonyl functionality furthest away from the
phthalimide
substituent. The phthalimido group can be removed with hydrazine at a later
stage if desired. An excess of thionyl chloride (SOCl2) is slowly added to XI
in
the presence of dimethylformamide (DMF) and a base, such as 2,6-lutidine, to
provide XII. This product is a 1:1 mixture of the S,S (XIIa) and S,R (XIIb)
diastereomers, hence, isolation of the pure (S,S) isomer is necessary.
CA 02500558 2005-03-10
SCHEME 3
O O
~N O O
JO/ ~ / O O N
BnO~ 0
X _ N HN SOC12/2,6-lutidine
Bn0 N H2,PdlC ~ / ~O OOH OOR Toluene, DMF
COOR
O XI
IX
0
~N
i
O N
N p COOR
~O
I
xn
US 6,512,111 claims a process similar to that described in US 6,201,118 but
includes an additional step for the preparation of compounds of formula XII in
5 optically pure form XIIa. This process is illustrated in Scheme 4. The
cyclization
reaction is carried out in a basic medium as above but using a phosphoric acid
derivative such as phosphorus oxyhalide, such as phosphorus oxychloride
(POCl3) or phosphorus oxybromide (POBr3) instead of thionyl chloride, to
provide XII as a 1.1:1 mixture of the S,S:S,R diastereomers. A deracemization
and/ or epimerization step is then conducted by deprotonating with a strong
base, such as potassium tent-butoxide (KOtBu), in the presence of
dimethylformamide (DMF) at a low temperature (-45°C) followed by
quenching
with tent-butyl alcohol (tBuOH) to obtain XIIa (S,S).
CA 02500558 2005-03-10
6
SCHEME 4
O O
O - ~N O O
Bn0-CAN ~ ~ O O O
I i
N X ~ N HN' J POCI3 or POBr3
Bn0-O~ COOR H2, Pd/C ~ / 2,6-lutidine
COOR
O O OH Dichloroethane
IX XI
O O
1 ) KOtBu, DMF
N -45 °C O~ N ~~ )
N O COOR t O COOR
2) BuOH
O ~ ~O
l
XII Xlla
There are several general drawbacks to the above-mentioned processes. For
instance, in each process the bicyclic compound (VII or XII) is prepared as a
1:1
diastereomeric mixture of the S,S and S,R form. Given that only the S,S
diastereomer can be used in the synthesis of Cilazapril and other similar
bioactive compounds, these processes require additional separation/resolution
steps and are therefore time-consuming, low yielding and costly. Secondly,
they
require the use of toxic reagents such as thionyl chloride or phosphorus
oxychloride to activate the amino acid ligand in order to achieve cyclization.
Thus, a process overcoming the deficiencies of the prior art, especially in
terms of
selectivity and toxicity, was desired.
SUMMARY OF THE INVENTION
It has been surprisingly found that compounds of formula I can be prepared by
a
method that, relative to the processes of the prior art, is simple,
economical, does
CA 02500558 2005-03-10
7
not require the use of toxic reagents to achieve cyclization, provides a
product
with high stereoselectivity and is therefore more amenable to large-scale
production.
Accordingly, in one aspect the invention provides for a process for the
preparation of a compound of the formula Ia described above wherein Rl is
selected from the group consisting of hydrogen, alkyl or aryl and R2 and R3
are
independently selected from the group consisting of hydrogen, alkyl, aryl,
aralkyl or various amino protective groups, comprising cyclizing a compound of
the formula,
O OH
;.
NN
N
R -N3 ~'O COORS
R
wherein R1, R2 and R3 have the above meaning, by refluxing in an organic
solvent.
In yet another aspect, the invention provides for a process for the
preparation of
a compound of formula Id having an enantiomeric excess of at least 60% of the
(S,S) isomer over the (R,R) isomer, wherein Rl is selected from the group
consisting of hydrogen, alkyl and aryl, R2 and R3 are independently selected
from hydrogen, alkyl, aryl or various amino protecting groups
O
N
N
COORS
R2 N O
13
R
Id
CA 02500558 2005-03-10
8
comprising:
(i) reacting a compound of formula XXIII
Ra
O
O
CO2H
R2- N
13
R
XXIII
wherein R4 represents a protecting group such as alkyl, aryl, or
S aralkyl, with a conventional carboxylic acid activation reagent to
obtain a compound of formula XIII
Ra
O_ O
__, :.
2
R -N C-X
R3 O
XIII
wherein X represents a carboxylic acid activating group in optically
pure form;
(ii) reacting said compound of formula XIII with a compound of
formula XIV,
O
R50CN
i
HN
COORS
XIV
CA 02500558 2005-03-10
9
wherein R5 represents a protecting group such as alkyl, aryl or
aralkyl, to obtain a compound of formula XV in the form of a
mixture of S,S and S,R stereoisomers
O
Ra0 R50~0
N
N
2
R R3 p COORS
XV
(iii) deprotection of said compound XV to obtain a compound of
formula XVI in the form of a mixture of S,S and S,R stereoisomers
O OH
H
t
N
i
N
R2-N
R3 p C02R~
XVI
;and
(iv) reacting said compound of formula XVI by refluxing in an organic
solvent whereby a compound of formula Id in the form of (S,S) and
(R,R) isomers having an enantiomeric excess of at least 60% of the
(S,S) isomer is formed.
In another aspect, the invention provides for processes wherein the organic
solvent also contains an organic acid, preferably in a catalytic amount.
In yet another aspect, the invention provides for processes wherein the
organic
acid is preferably selected from p-toluenesulfonic acid, camphorsulfonic acid
and
benzoic acid.
CA 02500558 2005-03-10
In yet another aspect, the invention provides for processes wherein the
organic
solvent can be selected from C6 to C9 aromatic solvent, Ca to C6 ketone, or a
cyclic
or acyclic amide and solvent mixtures thereof.
In yet another aspect, the invention provides for processes wherein the
organic
5 solvent is preferably selected from toluene, methyl isobutyl ketone,
dimethylformamide, N-methylpyrollidinone and solvent mixtures thereof.
In yet another aspect, the invention provides for processes wherein the
cyclization can be performed at a temperature between 50 and 200°C.
In yet another aspect, the invention provides for a process described above
10 wherein the reaction completion of step (iv) is about 60% and the
enantiomeric
excess is greater than 95%.
In yet another aspect, the invention provides for processes wherein product Id
is
further purified by mixing with an organic solvent to obtain the
enantiomerically
pure isomeric (S,S) form.
In yet another aspect the invention provides for processes wherein the mixing
with an organic solvent is performed in the presence of a chiral base,
preferably
(+)-methylbenzylamine.
In yet another aspect the invention provides for processes wherein the organic
solvent to obtain the enantiomerically pure isomeric (S,S) form is a Ci to C6
alcohol, preferably ethanol.
In yet another aspect, the invention provides for a process for the
manufacture of
cilazipril comprising the cyclizing of a compound of the formula XVI discussed
above wherein Rl is selected from the group consisting of hydrogen, alkyl or
aryl
and R2 and R3 are independently selected from the group consisting of
hydrogen,
CA 02500558 2005-03-10
11
alkyl, aryl, aralkyl or various amino protective groups, by refluxing in an
organic
solvent and then converting said compound to cilazipril.
DETAILED DESCRIPTION OF THE INVENTION
The synthesis of I, as disclosed in this invention, is illustrated in Scheme
5.
SCHEME 5
O
R50C -N~'
Ji
O\ ORa hi N\ /
O
COORS R40 R50~ O
XIV l' deprotecbon
N
X I
RZ R3 N
O R2R3N 1 COORS
O
XIII XV
O OH O / O
H
i
N heat RzRsN ~ + 2 s ,.
RZR3N N N R R N ' NJ
O COORS O O
R' OOC R' OOC
XVI la Ic
Thus, a protected and activated amino acid XIII (prepared, for instance, as in
US
4,512,924) is coupled with an N(2)-protected piperazic acid/ ester XIV in the
presence of a inorganic base, such as sodium carbonate, potassium carbonate or
sodium bicarbonate. Preferably the inorganic base is sodium bicarbonate. In
this
invention, Rl represents a hydrogen, alkyl or aryl radical and R2 and R3 are
independently selected from hydrogen, alkyl, aryl, aralkyl or amino protective
groups, in a more facile, less expensive manner and with higher
stereoselectivity
than has been previously described. For a comprehensive review of amino
protective groups, see Greene, T.W. and Wuts, P.G. M., Chapter 7. 'Protection
for
the Amino Group', in "Protective Groups in Organic Synthesis", Third Edition,
CA 02500558 2005-03-10
12
John Wiley & Sons, Inc.,1999, pp.494-653. In this context, the preferred
groups
include, but are not limited to, CZ-Ci2 carbonyl group, benzyl, aralkoxy and
alkoxy carbonyl groups. The most preferred protecting group is a phthalimido
group. R4 and R5 are independently selected protecting groups, for instance
alkyl, aryl and aralkyl groups. The most preferred group is a benzyl group. X
is
a carboxylic acid activating group, most preferably a chloro. The coupling
reaction is conducted in an organic solvent such as a Cs to C6 ketone solvent
or a
cyclic or acyclic C3 to C~ ether solvent. Preferably the coupling reaction is
conducted in methyl isobutyl ketone or tetrahydrofuran. The coupling reaction
gives compound XV as a 1:1 mixture of the S,S and S,R forms. The protecting
groups of XY are removed to give XVI. Unexpectedly, we have discovered that
by simply heating the compound of formula XVI in an organic solvent, with or
without the presence of an organic acid catalyst, causes cyclization,
producing
compounds of formula I with high stereoselectivity. The fact that this
cyclization
can be accomplished in the absence of costly and toxic acid-activating
reagents is
highly desirable. The cyclization is carried out by first dissolving XVI in an
organic solvent such as a C6 to C9 aromatic solvent such as toluene, a C3 to
C6
ketone solvent such as methyl isobutyl ketone, a C3 to C6 cyclic or acyclic
amide
such dimethylformamide or N-methylpyrollidinone, or a solvent mixture
thereof. Preferably the solvent is methyl isobutyl ketone. The cyclization is
conducted optionally in the presence of a catalytic amount of an organic acid,
such as benzoic acid, or a sulfonic acid such as p-toluenesulfonic acid or
camphorsulfonic acid. The solution is then heated between 50°C and
200°C.
Preferably the solution is heated to reflux. Furthermore, the reaction is
facilitated
by the removal of water using a Dean-Stark apparatus or the like. After
heating
the reaction mixture for some time, it is cooled and the solid product
containing
Ia and Ic is isolated by filtration. It was found that when the reaction
mixture is
maintained at reflux until completion, the product contains mainly (about 80%)
the S,S form Ia and its enantiomer (about 20%) R,R form Ic (i.e., an
enantiomeric
CA 02500558 2005-03-10
13
excess of 60°~ of the (S,S) form). Furthermore, to our surprise and
advantage, we
have found that under this simple condition, the S,R isomer of formula Ib is
not
detectable. In another aspect of the invention it was found that if the
reaction
completion is controlled to about 60%, the isolated product has a higher
enantiomeric excess (>95%) of S,S form Ia. The product is then purified
further
by mixing with an organic solvent, preferably a Ci to C6 alcohol, most
preferably
ethanol, in the presence of a chiral base, such as (+)-methylbenzylamine, to
obtain enantiomerically pure Ia. Alternatively, if the product obtained has an
enantiomeric excess of >95%, purifying by mixing with an organic solvent,
preferably a Ci to C6 alcohol, most preferably ethanol, provides Ia having
sufficient enantiomeric purity for further elaboration to Cilazapril.
EXPERIMENTAL PART:
Preparation of Octahydro-6,10-dioxo-9(S)-phthalimido-6H-pyridazo[1,2-
a][1,2]diazepine-1(S)-carboxylic acid (Ia):
Stage 1: Preparation of 1-Benxyloxycarbonyl-2-[4-benzyloxycarbonyl-2-(1,3-
d ioxo-1,3-dihydro-isoindo 1-2-yl) butyryl]hexahydro-pyridazine-3-carboxylic
acid (XX)
0
BnOC -N O
O OBn O OBn H-N BnO B~~O
COOH N
11 socl2 11 xlx o N
N C02H N COCI \
N O COON
\ / ~O \ / ~O ~ ~O
XVII XVIII XX
A mixture of a(S)-(2-benzyloxycarbonylethyl)-1,3-dihydro-1,3-dioxo-2-
isoindoleacetic acid XYII (15.2 g), from US 4,512,924, and thionyl chloride
(15.0
g) in toluene (150 ml) was heated at 60-70°C for 4-6 hours. Solvent and
excess
thionyl chloride were distilled under reduced pressure. The residue was dried
CA 02500558 2005-03-10
14
under vacuum to give acid chloride XVIII (15.6 g) in the form of a pale yellow
oil.
A mixture of XVIII (15.6 g), prepared above, NaHC03 (5.1 g) and 1-
(benzyloxycarbonyl)-hexahydro-3-pyridazinecarboxylic acid XIX (10.7 g) in dry
THF (150 ml) was stirred at room temperature. The solid was removed by
filtration and the filtrate was evaporated to dryness. The residue was
dissolved
in ethyl acetate (150 mL) and the solution was washed with 5 % aqueous HCl
(150
mL) followed by water (150 mL) and then dried over Na2SOQ. After filtration
and washing with ethyl acetate, the filtrate was evaporated to dryness to give
XX
(24.6 g) as foam which was used in the next step without further purification.
HPLC purity: Two diastereomers S,S-form and S,R-form in a ratio of 1:1 with a
total purity of 89%, contains 8% starting material XVII.
Stage IZ Preparation of 2-[4-Carboxy-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-
butyryl]hexahydro-pyridazine 3-carboxylic acid (I1~1II1)
O O OH
Bn0
H
HZ/Pd/C O N
O N N
\\ N ~ N
O COOH
,~O ~O O COzH
Compound XX (24.6 g), obtained from stage I, was dissolved in methanol (150
ml) and hydrogenated at atmospheric pressure over 10% palladium-on-charcoal
(2.5 g) until uptake of hydrogen ceased. The catalyst was removed by
filtration
and the filtrate was evaporated to give XXI (18.0 g) as an off-white solid in
a 1:1
diastereomeric ratio of S,S:S,R with a total purity of 89% by HPLC (contains
8%
phthaloyl-protected glutamic acid XVII).
CA 02500558 2005-03-10
Stage III: Preparation of Octahydro-6,10-dioxo-9(S)-phthalimido-6H
pyridazo[1,2-a][1,2]diazepine-1 (S)-carboxylic acid and Octahydro-6,10-dioxo-
9(R)-phthalimido-6H pyridazo[1,2-a)[1,2]diazepine-1(R)-carboxylic acid (XXIIa
and XXllc)
0 0
0 off % 1l
_, ,
H S . N.. .,__~ I N, w1
O \ N ~ O ~ N
~~ N ~ ~ ~ ~ ~ ' + ~~ N
N O C02H O CO2H
~O ~ ~O
/ ~O O C02H
XXI XXlla XXllc
Example 1
Compound XXI (9.0 g), prepared in a manner as described in stage II, was
dissolved in methyl isobutyl ketone (85 mL). The solution was carefully
distilled
until about 20 ml solvent was removed. The reaction mixture was heated to
10 reflux with a Dean-Stark apparatus and maintained for 48 hours and then
cooled
to 4-5~C. The solid was filtered and washed with methyl isobutyl ketone to
give
6.34 g (74% yield) as a beige-coloured solid as a mixture of XXIIa (SS) and
XXIIc
(RR) in a ratio of 82.7:17.3.
Mass Spectrum: 372.13 (M++1,100)
15 1H- NMR: (300 MHz, DMSO-D6):13.30 (br s,1H); 7.94-7.87 (m, 4H); 5.22
(dd,1H);
5.16 (dd,1H); 4.48 (d,1H); 3.54-3.42 (m,1H); 3.27-3.15 (m,1H); 2.94-2.85
(m,1H);
2.47-2.90 (m, 2H); 2.14-2.09 (m,1H);1.81-1.64 (m, 2H);1.59-1.42 (m,1H).
iaC-NMR (75 MHz, DMSO-D6):171.3;171.0;167.5;167.1;134.9;131.1;123.3; 52.3;
49.6; 40.9; 29.6; 25.3; 24.6;19.9.
Chiral HPLC showed a mixture of Octohydro-6,10-dioxo-9(S)-phthalimido-6H-
pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid and Octohydro-6,10-dioxo-
CA 02500558 2005-03-10
16
9(R)-phthalimido-6H-pyridazo[1,2-a][l,2Jdiazepine-1(R)-carboxylic acid in a
82.7:17.3 ratio
Examyle 2
Compound XXI (9.0 g), prepared in a manner as described in stage II, was
dissolved in methyl isobutyl ketone (85 mL). p-Toluenesulfonic acid (0.15 g)
was
added and the solution was carefully distilled until about 20 ml solvent was
removed. The reaction mixture was heated to reflux with Dean Stark apparatus
and maintained for 48 hours and then cooled to 4-5~C. The solid was filtered,
washed with methyl isobutyl ketone and dried to give I (6.02 g, 70% yield, Rl,
R2,
R3 = H) as a beige-coloured solid in a mixture of XXIIa (SS) and XVIIc (RR) in
a
ratio of 84.2:15.8.
Example 3
Compound XXI (9.0 g), prepared in a manner as described in stage II, was
dissolved in 85 mL methyl isobutyl ketone. p-Toluenesulforuc acid (0.15 g) was
added and the solution was carefully distilled until about 20 ml of solvent
was
removed. The reaction mixture was heated to reflux with Dean-Stark apparatus
and maintained until 60-70% reaction completion was achieved and then cooled
to 4-5~C. The solid was filtered, washed with methyl isobutyl ketone and dried
to give 4.11 g (48% yield, Rl, R2, R3 = H) as an off-white solid as a mixture
of
XXIIa (S, S) and XXIIc (R,R) in a ratio of 97.2:2.8, respectively.
Stage IV Preparation of Enantiomerically Pure Octahydro-6,10-dioxo-9(S)-
amino-6H-pyridaxo(1,2-a)(1,2)diazepine-1(S)-carboxylic acid (XXlla)
Examyle 1
Compound XJQI (6.87 g), obtained from stage III, Example I, was suspended in
ethanol (100 ml) and treated with 0.2 equivalent of (+)-methylbenzylamine. The
mixture was stirred at room temperature overnight under nitrogen. The solid
CA 02500558 2005-03-10
17
was filtered, washed with ethanol and dried under vacuum to give 70CIIa (4.12
g,
60 °~ ) as a white solid.
[a]D2° _ -138° (c = 0.5 in DMF) ([a]D2° _ -139°
from US 4,512,924)
ee: 99% (chiral column HPLC)
S m.p.305~C1(decomposition)
Example 2
Compound XXII (4.02 g), obtained from Stage III, Example 3 was stirred in
ethanol (30 ml) at room temperature for 12 h. The solid was filtered and
washed
with a little ethanol. After drying, XXIIa (3.54 g, 88%) was obtained.
[a]D2~ _ -137 (c = 0.5 in DMF) ( [a]D2° _ -139 from US 4,512,924)
While the foregoing provides a detailed description of a preferred embodiment
of the invention, it is to be understood that this description is illustrative
only of
the principles of the invention and not limitative. Furthermore, as many
changes
can be made to the invention without departing from the scope of the invention
and it is intended that all material contained herein be interpreted as
illustrative
of the invention and not in a limiting sense.
