Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-02-14
2004-12-07
Shameem, Golam M M (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S518000
Reexamination Certificate
active
06828442
ABSTRACT:
The invention relates to a new process for the preparation of (1′-tert-butoxycarbonyl-2-oxo-[1,3′]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium halogenide compounds of formula I
wherein * signifies an asymmetric center with an (R) or (S) configuration and X represents chlorine, bromine or iodine.
The compounds of formula I are known from EP-A 0 849 269 and can be obtained through multiple-step synthesis of the corresponding allyloxycarbonyl (ALLOC) protected [1,3′]bipyrrolidinyl-2-oxo derivative by removal of the allylocycarbonyl protecting group and protection reaction with a tert-butoxycarbonyl moiety to yield tert-butoxycarbonyl (t-BOC) protected [1,3′]bipyrrolidinyl-2-oxo compounds of formula I.
It has now been found that the compounds of formula I can be manufactured in an improved and shortened way by the process of the present invention. The new process for the preparation of (1′-tert-butoxycarbonyl-2-oxo-[1,3′]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium halogenide compounds of formula I
wherein * signifies an asymmetric center with an (R) or (S) configuration and X represents chlorine, bromine or iodine; comprises
step 1) coupling N-benzyl-3-pyrrolidinamine of formula II
wherein * is as defined above with a compound of formula X(CH
2
)
2
CH(X)COX
wherein X is independently of each other chlorine, bromine or iodine; and subsequent cyclization in the presence of a base to obtain a compound of formula III
wherein * and X are as defined above;
step 2) reacting the compound of formula III with triphenylphosphine to obtain the phosphonium salt of formula IV
wherein * and X are as defined above; and
step 3) reacting the phosphonium salt of formula IV with di-tert.-butyl-dicarbonate under hydrogenation conditions to obtain the compounds of formula I.
Surprisingly, it has been found that the N-benzyl-3-pyrrolidinamine of formula II undergoes the reaction sequence described above to yield the compounds of formula I, despite the expected instability of intermediate III. The corresponding t-Boc and Alloc protected derivatives of starting material of formula II are not available through the described process.
In the structural formulae of the compounds given throughout this application, a wedged bond (
) indicates a substituent which is above the plane of the paper.
In the structural formulae of the compounds given throughout this application, a dotted bond (
) indicates a substituent which is below the plane of the paper.
The compounds of the present process invention exhibit stereoisomerism and can be any stereoisomer. The compounds of the present process invention having one asymmetric carbon atom may be obtained as racemic mixtures of stereoisomers which can be resolved, at the appropriate steps in the process of this invention by methods well known in the art to obtain a given stereoisomer or pure enantiomer having a desired stereoconfiguration. Alternatively, the desired isomers may be directly synthesized by methods known in the art.
The asymmetric carbon atom in the compound of the present invention is denoted as “*”. The stereoconfiguration of the asymmetric carbon atom denoted as “*” can be designated according to the particular stereoisomer it represents. Compounds of the present invention include those compounds wherein the carbon atom denoted as “*” have the S, R or R,S-configuration, preferably the R-configuration.
The term halogen stands for chlorine, bromine and iodine, more preferred chlorine or bromine, most preferred halogen is bromine.
The compounds of the present invention are prepared as shown in the reaction scheme 1.
Reaction Scheme 1:
wherein * and X are as defined above.
In the 1
st
step of the reaction the compound of formula II is coupled with 1-4 equivalents, preferably 1-2 equivalents of X(CH
2
)
2
CH(X)COX wherein X is independently of each other chlorine or bromine or iodine, preferably bromine (preparation see below) in the presence of bases such as Na
3
PO
4
, K
2
CO
3
, Na
2
CO
3
, KOH or NaOH, preferably Na
3
PO
4
and an appropriate solvent. Appropriate solvents are polar aprotic solvents such as acetonitrile (CH
3
CN), dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably CH
3
CN. The reaction is carried out at a reaction temperature between about −20° C. and about 30° C., preferably at a reaction temperature between about −10° C. and about 10° C. Subsequently, a cyclization reaction is carried out with the intermediate coupling product to obtain compounds of formula III. The cyclization reaction is carried out in the presence of 1-3 equivalents, preferably 2-2.5 equivalents of a base, such as K
2
CO
3
, Na
2
CO
3
, KOH or NaOH, preferably NaOH in aqueous solution, at a reaction temperature between about −10° C. and about 50° C., preferably between about 10° C. and about 30° C.
Compounds of formula X(CH
2
)
2
CH(X)COX wherein X is independently of each other chlorine or bromine or iodine are commercially available or are synthesized according to methods known from textbooks. For example the compound of formula X(CH
2
)
2
CH(X)COX wherein X is chlorine is prepared according to Mathew, K. K. et al. Indian J. Chem., Sect. B (1981), 20B(4), 340-2. The compound of formula X(CH
2
)
2
CH(X)COX wherein X is bromine is prepared according to Marinelli, E. R. et al. Tetrahedron (1996), 52(34), 11177-11214. The compound of formula X(CH
2
)
2
CH(X)COX wherein X is iodine can be obtained by reacting the tribromide (X═Br) with NaI in CH
3
CN.
In a preferred embodiment of the invention the compound of formula IIIa
is formed according to the above described 1
st
step of the reaction. The compound of formula IIIa is new and therefore part of the present invention.
In the 2
nd
step of the process the compound of formula III is reacted with 1-5 equivalents, preferably 2-4 equivalents of triphenylphosphine to obtain the phosphonium salt of formula IV. The reaction is carried out in an aromatic solvent such as toluene, o-xylene, m-xylene, p-xylene or benzene, preferably toluene at a reaction temperature between about 20° C. and about 180° C., preferably between about 80° C. and about 140° C.
In a preferred embodiment of the invention the compound of formula IVa
is formed according to the above described 2
nd
step of the reaction. The compound of formula IVa is new and therefore part of the present invention.
In the 3
rd
step of the process the phosphonium salt of formula IV is reacted with 1-5 equivalents, preferably 2-4 equivalents of di-tert.-butyl-dicarbonate (commercially available from Fluka) under hydrogenation conditions in the presence of a catalyst such as Pd/C (commercially available from Degussa) preferably with 10% Pd on activated carbon, to obtain compounds of formula I. The reaction is carried out in an alcoholic solvent such as methanol, ethanol or isopropanol, preferably in methanol at a reaction temperature between about 10° C. and about 100° C., preferably between about 40° C. and about 80° C.
In a preferred embodiment of the invention steps 1-3 are carried out for compounds wherein * signifies an asymmetric center with (R) configuration and X is chlorine or bromine, preferably bromine.
Compounds of formula II, used as starting material in the present process is prepared according reaction steps a→b→c as shown in reaction scheme 2. The preparation of the compound of formula II is also part of the present invention.
Reaction Scheme 2:
wherein R
1
is alkyl, R
2
is an amino protecting group and * is as defined above.
The terms which have already been mentioned and will be mentioned in the description of the invention are defined as follows:
The term “alkyl” as used herein denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and its isomers.
Alkyl in R
1
is preferably unsubstituted straight or
Basilea Pharmaceutica AG
Shameem Golam M M
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