CA2500558A1 - A process for the preparation of aza-containing bicyclic compounds and the use thereof in the preparation of cilazapril - Google Patents
A process for the preparation of aza-containing bicyclic compounds and the use thereof in the preparation of cilazapril Download PDFInfo
- Publication number
- CA2500558A1 CA2500558A1 CA002500558A CA2500558A CA2500558A1 CA 2500558 A1 CA2500558 A1 CA 2500558A1 CA 002500558 A CA002500558 A CA 002500558A CA 2500558 A CA2500558 A CA 2500558A CA 2500558 A1 CA2500558 A1 CA 2500558A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- group
- acid
- formula
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for the preparation of a compound of the formula (SEE FORMULA I) having an enantiomeric excess of greater than 0% wherein R1 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, (SEE FORMULA II) wherein R1, R2 and R3 have the above meaning, by refluxing in an organic solvent.
Description
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
R3 _ 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.
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
R3 _ 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.
O
NH Bn0 ~ Bn0~0 ii BnOCN + Bn0 HN C-CI N
O O
p COOR
III IV V
O
HO
H2 (g), Pd/C HN
t DMF
N
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.
NH Bn0 ~ Bn0~0 ii BnOCN + Bn0 HN C-CI N
O O
p COOR
III IV V
O
HO
H2 (g), Pd/C HN
t DMF
N
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.
O O O
1 ) LDA
~N 2) PhSeBr ~N Ni, H2 (g) (S) N 3) H202, AcOH N (S) N
(S) 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.
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
~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).
1 ) LDA
~N 2) PhSeBr ~N Ni, H2 (g) (S) N 3) H202, AcOH N (S) N
(S) 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.
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
~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).
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 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
R
Id comprising:
(i) reacting a compound of formula XXIII
Ra O
O
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
__, :.
R -N C-X
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
i HN
COORS
XIV
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 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
R
Id comprising:
(i) reacting a compound of formula XXIII
Ra O
O
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
__, :.
R -N C-X
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
i HN
COORS
XIV
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
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
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.
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, 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.
O
R50C -N~' Ji O\ ORa hi N\ /
O
COORS R40 R50~ O
XIV l' deprotecbon N
X I
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, 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 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 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) 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 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).
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 off % 1l _, , H S . N.. .,__~ I N, w1 O \ N ~ O ~ N
~~ N ~ ~ ~ ~ ~ ' + ~~ N
~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-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 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.
Ra0 R50~0 N
N
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
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.
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, 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.
O
R50C -N~' Ji O\ ORa hi N\ /
O
COORS R40 R50~ O
XIV l' deprotecbon N
X I
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, 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 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 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) 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 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).
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 off % 1l _, , H S . N.. .,__~ I N, w1 O \ N ~ O ~ N
~~ N ~ ~ ~ ~ ~ ' + ~~ N
~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-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 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.
Claims (24)
1. A process for the preparation of a compound of the formula Ia wherein R1 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, wherein R1, R2 and R3 have the above meaning, by refluxing in an organic solvent.
2. The process of claim 1 wherein said organic solvent contains an organic acid.
3. The process of claim 2 wherein said organic acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid and benzoic acid.
4. The process of Claims 2 or 3 wherein the organic acid is present in a catalytic amount.
5. The process of any of claims 1 to 4 wherein said organic solvent is selected from the group consisting of a C6 to C9 aromatic solvent, C3 to C6 ketone, or a cyclic or acyclic amide and solvent mixtures thereof.
6. The process of any of claims 1 to 4 wherein said organic solvent is selected from the group consisting of toluene, methyl isobutyl ketone, dimethylformamide, N-methylpyrollidinone and solvent mixtures thereof.
7. The process of any of claims 1 to 6 wherein said cyclization is performed at a temperature between 50 and 200°C.
8. 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 R1 is selected from the group consisting of hydrogen, alkyl and aryl, and R3 are independently selected from hydrogen, alkyl, aryl or various amino protecting groups comprising:
(a) reacting a compound of formula XXIII
wherein R4 represents a protecting group such as alkyl, aryl, or aralkyl, with a conventional carboxylic acid activation reagent to obtain a compound of formula XIII
wherein X represents a carboxylic acid activating group in optically pure form;
(b) reacting said compound of formula XIII with a compound of formula XIV, 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 (c) 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 (d) 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.
(a) reacting a compound of formula XXIII
wherein R4 represents a protecting group such as alkyl, aryl, or aralkyl, with a conventional carboxylic acid activation reagent to obtain a compound of formula XIII
wherein X represents a carboxylic acid activating group in optically pure form;
(b) reacting said compound of formula XIII with a compound of formula XIV, 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 (c) 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 (d) 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.
9. The process of Claim 8 wherein said organic solvent contains an organic acid.
10. The process of Claim 9 wherein said organic acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid and benzoic acid.
11. The process of Claims 9 or 10 wherein said organic acid is present in a catalytic amount.
12. The process of any of Claims 8 to 11 wherein the reaction completion of step d is about 60% and the enantiomeric excess is greater than 95%.
13. The process according to any of claims 8 to 12 wherein product Id is further purified by mixing with an organic solvent to obtain the enantiomerically pure isomeric (S,S) form.
14. The process according to Claim 13 wherein said mixing with an organic solvent is performed in the presence of a chiral base.
15. The process of Claim 14 wherein said chiral base is (+)-methylbenzylamine.
16. The process of any of claims 13 to 15 wherein said organic solvent to obtain the enantiomerically pure isomeric (S,S) form is a C1 to C6 alcohol.
17. The process of claim 16 wherein said alcohol is ethanol.
18. A process for the manufacture of cilazipril comprising the cyclizing of a compound of the formula:
wherein R1 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, by refluxing in an organic solvent and then converting said compound to cilazipril.
wherein R1 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, by refluxing in an organic solvent and then converting said compound to cilazipril.
19. The process of claim 18 wherein said organic solvent contains an organic acid.
20. The process of claim 19 wherein said organic acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid and benzoic acid.
21. The process of Claims 19 or 20 wherein said organic acid is present in a catalytic amount.
22. The process of any of claims 18 to 21 wherein said organic solvent is selected from the group consisting of a C6 to C9 aromatic solvent, C3 to C6 ketone or a cyclic or acyclic amide and solvent mixtures thereof.
23. The process of any of claims 18 to 21 wherein said organic solvent is selected from the group consisting of toluene, methyl isobutyl ketone, dimethylformamide, N-methylpyrollidinone and solvent mixtures thereof.
24. The process of any of claims 18 to 23 wherein said cyclization is performed at a temperature between 50 and 200°C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002500558A CA2500558A1 (en) | 2005-03-10 | 2005-03-10 | A process for the preparation of aza-containing bicyclic compounds and the use thereof in the preparation of cilazapril |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002500558A CA2500558A1 (en) | 2005-03-10 | 2005-03-10 | A process for the preparation of aza-containing bicyclic compounds and the use thereof in the preparation of cilazapril |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2500558A1 true CA2500558A1 (en) | 2006-09-10 |
Family
ID=36998143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002500558A Abandoned CA2500558A1 (en) | 2005-03-10 | 2005-03-10 | A process for the preparation of aza-containing bicyclic compounds and the use thereof in the preparation of cilazapril |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2500558A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012049646A1 (en) | 2010-10-12 | 2012-04-19 | Ranbaxy Laboratories Limited | Process for the preparation of an intermediate of cilazapril |
-
2005
- 2005-03-10 CA CA002500558A patent/CA2500558A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012049646A1 (en) | 2010-10-12 | 2012-04-19 | Ranbaxy Laboratories Limited | Process for the preparation of an intermediate of cilazapril |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Jouin et al. | Stereospecific synthesis of N-protected statine and its analogues via chiral tetramic acid | |
| JP4994427B2 (en) | Modified Pictet-Spengler reaction and its products | |
| KR20120014219A (en) | Methods for synthesizing 3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine, and intermediates thereof | |
| JP2691442B2 (en) | Novel proline derivative | |
| IL279725B1 (en) | Novel pyridine and pyrazine compounds as inhibitors of cannabinoid receptor 2 | |
| JP2004525944A (en) | Method for producing 4,6-diaminopyrimido [5,4-d] pyrimidine | |
| KR100691735B1 (en) | New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulphonate | |
| ZA200500290B (en) | Process for the preparation of amino-pyrrolidine derivatives. | |
| CA2500558A1 (en) | A process for the preparation of aza-containing bicyclic compounds and the use thereof in the preparation of cilazapril | |
| Salvati et al. | New developments in the synthesis of pyrrolizidinone-based dipeptide isosteres | |
| KR20180118054A (en) | Production Method of Intermediate Compound for Synthesizing Medicament | |
| WO2014145507A1 (en) | A process for making a 4-amino-4-oxobutanoyl peptide cyclic analogue, an inhibitor of viral replication, and intermediates thereof | |
| JPH11349565A (en) | Production of pyridonecarboxylic acid derivative and intermediate thereof | |
| EP1280780A2 (en) | Asymmetric synthesis of piperazic acid and derivatives thereof | |
| AU776300B2 (en) | Synthesis of 3-amino-3-aryl propanoates | |
| JPS5833877B2 (en) | Yuukikagobutsunikansurukairiyou | |
| Chacun-Lefevre et al. | Intramolecular Heck coupling of alkenyl 3-iodoindole-2-carboxamide derivatives | |
| US6197974B1 (en) | Enantioselective synthesis of 3-aminopyrrolidines | |
| SU351369A1 (en) | METHOD OF OBTAINING ALKALOIDS | |
| US5959141A (en) | 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives | |
| JP2003518124A (en) | Peptide β-turn structure mimetic compound and process for producing the same | |
| Jones et al. | A new 3-ethoxycarbonylisoxazolopyridone as a precursor to acylpyridones | |
| Gavrielatos et al. | Synthesis and spectroscopic studies of optically active n‐acetyl butenoates and n‐acetyl‐2‐alkyl‐pyrrolin‐4‐ones | |
| EP1197489A1 (en) | Pyrimidine derivatives and process for the preparation thereof | |
| JPH06336495A (en) | Production of l-alanyl-l-proline derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |