Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-07-27
2003-01-28
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C544S224000
Reexamination Certificate
active
06512111
ABSTRACT:
A subject of the present invention is a novel process for the preparation of bicyclic compounds and the use of this process as an intermediate stage in the preparation of a compound which inhibits the interleukin-1 beta converting enzyme (ICE).
The compound of formula (I) as defined below, in which R represents a terbutyl radical and the amine is protected in the form of phthalimido, is described in the Patent EP 94095. This compound of formula (I) is also used for the preparation of the compound of formula (V) having an inhibitory activity on the interleukin-1 beta converting enzyme described in the International Application WO 97/22619.
One of the objectives of the invention is to find a novel process of obtaining the compounds of formula (I).
Therefore a subject of the invention is a process for the preparation of the compounds of formula (I)
in which R represents a hydrogen atom, an alkyl, aryl or aralkyl radical containing up to 18 carbon atoms and the amine function can be free or protected, starting from a compound of formula (IA)
in which R has the same meaning as previously and the amine function can be free or protected,
characterized in that the cyclization is carried out in a basic medium and in the presence:
of a derivative of phosphonic acid of formula (P1):
P(═Z)(X
1
)(X
2
)(X
3
)
in which Z is a sulphur or oxygen atom, X
1
represents a halogen atom, X
2
and X
3
, identical or different, represent a halogen atom, an alkyloxy radical containing 1 to 6 carbon atoms, an aryloxy radical containing 6 to 12 carbon atoms or an arylalkyloxy radical containing 7 to 15 carbon atoms,
or of a trimer of formula (P2)
R preferably represents a hydrogen atom, a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertbutyl, benzyl, phenyl or naphthyl radical and quite particularly methyl, ethyl and tertbutyl.
When the amine function is protected, the protection can be done according to the standard methods known to a person skilled in the art.
The amine function can be protected in the form of an —NR
1
R
2
radical in which
either R
1
represents a
radical, Ra, Rb, Rc and Rd representing an alkyl or aryl radical containing up to 18 carbon atoms or a mono or polycyclic radical containing one or more heteroatoms, X representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or an aryl radical containing up to 14 carbon atoms, and R
2
represents a hydrogen atom,
or R
1
and R
2
together form a mono or polycyclic radical containing 1 or more heteroatoms. The amine can thus be protected in the form of a phthalimido
or also in the form of the
radical.
Preferably, the amine is protected in the form of a phthalimido.
Among the derivatives of phosphonic acid of formula P(═Z)(X
1
)(X
2
)(X
3
), it is in particular the following derivatives:
(Cl)P(O)(Ph)
2
, (Cl)
2
P(O)(OPh)
2
, (Cl)P(O)(OEt)
2
, (Cl)
2
P(O)(OEt)
2
, POCl
3
, POBr
3
and P(S)Cl
3
.
The cyclization reaction is preferably carried out in the presence of POCl
3
or POBr
3
and the base is in particular an organic base, for example triethylamine, pyridine or 2,6-lutidine.
A more particular subject of the invention is the process as described previously in which the trihalogenophosphonic acid is POCl
3
.
A more particular subject of the invention is the process as described previously in which the trihalogenophosphonic acid is POBr
3
.
A more particular subject of the invention is the process as described previously in which the base is chosen from pyridine or 2,6-lutidine.
A more particular subject of the invention is the process as defined previously characterized in that the cyclization temperature is comprised between 70 and 80° C.
A more particular subject of the invention is the process as defined previously characterized in that the solvent is dichloroethane.
The compound of formula (IA) is in the form of a mixture of SS and SR diastereoisomers or in the form of the SR diastereoisomer.
The compound of formula (I) is in the form of a mixture of SS and SR diastereoisomers or in the form of the SR diastereoisomer.
A subject of the invention is also a process for the preparation of the compound of formula (I) in racemic or optically active (Iopt) form, comprising the cyclization process as described above, and characterized in that it comprises the following successive stages:
a) A compound of formula (II)
in which R is as defined previously and Hal represents a halogen atom, is subjected to the action of a compound of formula (III)
in which Aryl represents an aryl radical containing up to 14 carbon atoms, in order to obtain the compound of formula (IV)
in the form of a mixture of S and R stereoisomers,
b) the compound of formula (IV) is subjected to the action of an anhydride of formula (F)
the amine function being in protected or non-protected form, while carrying out a deprotection by hydrogenolysis, in order to obtain the compound of formula (IA)
as defined above,
c) the compound of formula (IA) is subjected to the action of a derivative of phosphonic acid (P1) or (P2) as defined above, in the presence of a base, in order to obtain the compound of formula (I) as defined above
d) if appropriate, the amine function is deprotected in order to obtain the compound of formula (I) in which the amine function is not protected,
e) if appropriate, the compound of formula (I) in the SS+SR or SR form is subjected to the action of a deracemization and/or epimerization agent in order to obtain the compound of formula (Iopt) corresponding to the SS diastereoisomer,
f) if appropriate, the amine function is deprotected in order to obtain the compound of formula (Iopt) in which the amine function is not protected.
In a preferred embodiment:
Hal represents a chlorine atom;
R represents an alkyl radical containing 1 to 4 carbon atoms;
Aryl represents a phenyl or naphthyl radical,
Compound (F) is N-phthaloyl-L-glutamic anhydride
The amine function of the compounds of formulae (IA), (I) or (Iopt) is in protected form and in particular in phthalimido form;
The reaction between the compounds of formula (II) and the compounds of formula (III) takes place in the presence of a base for example in the presence of an alkaline carbonate such as potassium carbonate;
The deprotection by hydrogenolysis is carried out according to standard conditions known to a person skilled in the art, for example the hydrogenolysis agent is hydrogen in the presence of palladium on carbon;
The deracemization and/or epimerization agent is a base, more especially a strong base, for example an alkaline or alkaline-earth alcoholate such as sodium or potassium methylate, sodium or potassium terbutylate or a lithiated amine such as LDA;
The action of a deprotection agent of the amine can be carried out in particular by the action of a hydrazine.
A quite particular subject of the invention is the process as defined previously in which (F) is the anhydride of phthaloyl glutamic acid.
A quite particular subject of the invention is the process as defined previously in which the amine function of the compounds of formulae (IA), (I) or (Iopt) is protected in the form of a phthalimido group.
A quite particular subject of the invention is the process as defined previously in which, within the compounds of formula (II), (IV), (IA), (I) and (Iopt), R is a methyl, ethyl or tertbutyl radical.
A quite particular subject of the invention is the process as defined previously in which the compound of formula (I) is ethyl 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate:
A quite particular subject of the invention is the process as defined previously in which the compound of formula (Iopt) is ethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate:
The compounds of formula (I) can in general be used for the synthesis of medicaments as indicated in the Patent EP 94095. The compounds of formulae (II) and (III)
Roussel Patrick
Veronique Crocq
Aventis Pharma S.A.
Bierman, Muserlian and Lucas
Kifle Bruck
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