Coupling process

Details Coupling process Coupling process

2001-03-28

2003-02-11

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S953000

Reexamination Certificate

active

06518434

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a novel process for the production of compounds comprising peptide linkages.
PRIOR ART
It is well known in the art that peptide linkages are typically formed via the coupling of an amine to a carboxylic acid.
Such coupling reactions are often carried out in the presence of so-called “coupling reagents”, such as oxalyl chloride, EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) DCC (dicyclohexylcarbodiimide), isobutyl chlorocarbonate, HBTU ([N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium hexafluorophosphate]), HATU (O-(azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) or TBTU ([N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate]), and an appropriate base.
Such agents, which are typically used to enhance the efficiency of the coupling reaction and/or the yield of the “coupled” product, have the disadvantage that they are expensive. Further, they may promote side-reactions and/or the formation of by-products, leading to a coupled product that has to be purified before it can be used, and/or to unacceptable levels of chemical effluent being released into the environment.
Thus, there is a need for an improved, cost-effective process for the formation of peptide linkages. Such a process should preferably minimise the number of reagents that need to be employed, and thus the number of side-reactions and by-products that are formed and need to be removed prior to further processing of the coupled product.
European patent applications EP 168 769 and EP 336 368. and U.S. Pat. No. 5,359,086 disclose the coupling of N-carboxyanhydrides (NCAs) to cyclic amino acids, such as proline and esters thereof. There is no mention in these documents of the coupling of NCAs to cyclic amino acid amides.
We have found, surprisingly, that peptide linkages may be formed by way of an efficient one-step process, in which NCAs are coupled directly to inter alia cyclic amino acid amide derivatives.
DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided a process for the production of a compound of formula I,
wherein
R
1
represents H or C
1-3
alkyl optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, S(O)
2
NH
2
, C(O)R
4
, C(O)OR
5
, SR
6
, S(O)R
7
, S(O)
2
R
8
, N(R
9
)R
10
or OR
11
;
R
2
represents C
1-8
alkyl, —A
1
-C
4-8
cycloalkyl or —A
1
-C
6-10
aryl, all of which are optionally substituted by one or more substituents selected from C
1-4
alkyl (which latter group is optionally substituted by one or more halo substituents), methylenedioxy, halo, cyano, nitro, S(O)
2
NH
2
, C(O)R
4
, C(O)OR
5
, SR
6
, S(O)R
7
, S(O)
2
R
8
, N(R
9
)R
10
or OR
11
;
R
3
represents N(R
12
)R
13
or CH(R
12
)R
13
;
R
13
represents, at each occurrence, phenyl, C
1-3
alkylphenyl or C(O)phenyl, all of which groups are optionally substituted by one or more substituents selected from cyano, amidino, hydroxyamidino, halo, C
1-4
alkyl (which group is optionally substituted by one or more halo group), SR
6
, N(R
9
)R
10
or OR
11
;
R
9
and R
10
independently represent, at each occurrence, H, C
1-4
alkyl or C(O)R
14
;
A
1
represents, at each occurrence, a single bond or C
1-4
alkylene; n represents 1, 2 or 3;
R
5
represents, at each occurrence, H, C
1-6
alkyl or C
1-3
alkylphenyl, which latter group is optionally substituted by one or more substituents selected from C
1-4
alkyl (which latter group is optionally substituted by one or more halo substituents), methylenedioxy, halo, cyano, nitro, S(O)
2
NH
2
, C(O)R
4
, C(O)OR
5a
, SR
6
, S(O)R
7
, S(O)
2
R
8
, N(R
9
)R
10
or OR
11
; R
4
, R
5a
, R
6
, R
11
, R
12
and R
14
independently represent, at each occurrence, H or C
1-4
alkyl; and
R
7
and R
8
independently represent, at each occurrence, C
1-4
alkyl,
which process comprises reaction of a compound of formula II,
wherein R
1
and R
2
are as defined above, with a compound of formula III,
wherein R
3
and n are as defined above,
and which process is referred to hereinafter as “the process of the invention”.
Alkyl groups that R
1
, R
2
, R
4
, R
5
, R
5a
, R
6
, R
7
, R
8,
R
9
, R
10
, R
11,
R
12
and R
14
may represent, and with which R
2
, R
5
and R
13
may be substituted, may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cyclic. Further, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl groups may also be part cyclic/acyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.
For the avoidance of doubt, the point of attachment of alkylphenyl groups that R
5
and R
13
may represent is at the alkyl part of such groups. The alkyl part of such groups may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched. Such alkyl parts may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.
Alkylene chains that A
1
may represent may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched. Such chains may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen.
As used herein, the term “halo” includes fluoro, chloro, bromo or iodo.
Preferred values of R
1
include C
1-3
alkyl groups (e.g. an ethyl or, particularly a methyl group) substituted and/or terminated by a C(O)OR
5
substituent, and, particularly, when the alkyl group is a C
2-3
alkyl group, those in which the optional C(O)OR
5
substituent is not located at the carbon atom to which the NH group is also attached. Preferred values of R
5
include H, linear or branched C
1-3
alkyl (e.g. iso-propyl or ethyl) or C
1-2
alkylphenyl (e.g. benzyl).
Preferred values of R
2
include —A
1
-C
5-7
cycloalkyl or —Al-phenyl, in which, in both cases, A
1
represents a single bond or C
1-2
alkylene. Particularly preferred R
2
groups include cyclohexyl.
Preferred values of R
3
include N(R
12
)R
13,
in which R
12
represents C
1-2
alkyl or, especially, H, and R
13
represents C
1-2
alkylphenyl (e.g. benzyl), which latter group is substituted with an amidino group, a hydroxyamidino group or, preferably, a cyano group, which substituent is preferably located at the 4-position on the phenyl part of that group (relative to the C
1-2
alkyl part). When R
13
represents an alkylphenyl group substituted at the phenyl part with amidino, hydroxyamidino or cyano, further such groups that may be mentioned include those that are also optionally substituted at the phenyl part with one or more halo (e.g. fluoro) atoms.
Preferred values of n include 2 and, especially, 1.
The process of the invention is preferably carried out in the presence of an appropriate base and a suitable solvent system, which solvent system may comprise aqueous and/or organic solvents. The base and solvent system that are employed should not react chemically with, or give rise to stereochemical changes in, the reactants or product once formed, or give rise to other side reactions.
Suitable bases include inorganic bases, such as hydroxides, alkoxides, hydrogen carbonates or carbonates of alkali metals (such as Na or K), or organic bases, such as common tertiary amine bases (e.g. triethylamine, diisopropylethylamine and N-methyl morpholine). Particularly preferred bases include amine bases.
Suitable aqueous solvents include water. Suitable organic solvents include acetates (e.g. ethyl acetate, iso-propyl acetate, butyl acetate), acetonitrile, toluene, dichloromethane, tetrahydrofuran, dimethylformamide and mixtures of any of these solvents.
It is preferred that water is present in the solvent system that is employed. We have found, advantageously, that, when water is employed as a solvent, the efficiency of the process is insensitive to the solid state properties of the

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