Process for preparing integrin antagonist intermediates

Details Process for preparing integrin antagonist intermediates Process for preparing integrin antagonist intermediates

2002-06-05

2004-03-16

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S334000, C546S335000

Reexamination Certificate

active

06706885

ABSTRACT:

FIELD OF THE INVENTION
The present invention discloses a novel process and novel intermediates toward the preparation of optionally protected 2,5-di-(3′-aminopropyl)pyridines which are useful in the synthesis of &agr;v integrin receptor antagonists.
BACKGROUND OF THE INVENTION
The present invention provides a novel process for the preparation of optionally amino group-protected 2,5-di-(3′-aminopropyl)pyridines of structural formula I,
wherein P
1
is H
2
or a primary amine protecting group. The present invention also provides novel intermediates useful in the disclosed process.
The synthesis of the compound of formula I wherein P
1
is H
2
was previously disclosed in UK Patent Application GB 2,356,630 (May 30, 2001). In that publication, the 2,5-bis-substituted pyridine ring system was constructed by means of a one-pot double Suzuki cross-coupling of a 2,5-dihalopyridine with a protected allylamine in the presence of 9-BBN and subsequent removal of the primary amine protecting groups.
In the present invention, the compound of formula I wherein P
1
is H
2
is produced in a highly efficient manner in a total of three chemical steps featuring a one-pot double Sonogashira reaction of a 2,5-dihalopyridine with an optionally protected propargylamine, followed by hydrogenation, and final cleavage of the primary amine protecting groups P
1
, if required.
The compounds of formula I wherein P
1
is a primary amine protecting group are also prepared in an efficient fashion by two consecutive Sonogashira reactions with orthogonally protected propargylamines, followed by hydrogenation, and removal of protecting group P
2
on the aminopropyl functionality at the C-5 position of the pyridine ring leaving the aminopropyl group at the C-2 position of the pyridine ring protected with P
1
.
SUMMARY OF THE INVENTION
This invention is concerned with a process for preparing optionally amino group-protected 2,5-di-(3′-aminopropyl)pyridines of structural formula I, wherein P
1
is H
2
or a primary amine protecting group, and useful intermediates obtained during that process. The process utilizes a double Sonogashira reaction of a 2,5-dihalopyridine with optionally protected propargylamines, hydrogenation, and final removal of the primary amine protecting group, if required.
The novel process and novel intermediates are illustrated in the following embodiments denoted in Schemes 1 and 2 below. Scheme 1 illustrates the preparation of the compound of formula I wherein P
1
is H
2
.
Scheme 2 illustrates the preparation of compounds of formula I wherein P
1
is a primary amine protecting group.
Another aspect of the present invention is concerned with an improved process for the preparation of N-formylpropargylamine, a substrate for the Sonogashira reaction disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the process of the present invention involves the preparation of the compound of structural formula Ia:
comprising the steps of:
(a) producing a compound of structural formula II:
wherein P
1
is H
2
or a primary amine protecting group, by reacting a 2,5-dihalopyridine with an optionally protected propargylamine of structural formula III:
in the presence of a palladium catalyst and a base;
(b) producing a compound of structural formula IV:
by hydrogenating a compound of structural formula II:
and (c) removing the primary amine protecting groups P
1
in a compound of structural formula IV:
when P
1
represents a primary amine protecting group.
The key steps in this first aspect of the process of the present invention include a double Sonogashira reaction of a 2,5-dihalopyridine with an optionally protected propargylamine, hydrogenation, and removal of the primary amine protecting groups, if necessary.
One substrate for the double Sonogashira reaction is an optionally protected propargylamine. In one embodiment of the process of the present invention, the propargylamine is protected as its N-acetyl derivative. This is accomplished by treatment of propargylamine with acetic anhydride or acetyl chloride in a suitable solvent, such as methylene chloride, tetrahydrofuran, toluene, hexane, ethyl acetate, isopropyl acetate, water, lower alkanol, and aqueous lower alkanol, or mixtures thereof.
In a second embodiment of the process of the present invention, the propargylamine is protected as its N-formyl derivative. This is accomplished by treatment of a propargyl halide, a propargyl C
1-4
alkylsulfonate, such as propargyl methanesulfonate, propargyl trifluoromethanesulfonate, a propargyl arylsulfonate, such as propargyl benzenesulfonate and propargyl p-toluenesulfonate, or a propargyl di(C
1-4
alkyl)phosphate with an alkali metal diformylamide, such as sodium diformylamide, in a suitable organic reaction solvent, such as acetonitrile, tetrahydrofuran, DMF, and the like. One of the two formyl protecting groups in the resulting N,N-diformylpropargylamine is then cleaved by treatment with an inorganic base, such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide, in the presence of methanol or ethanol, preferably one to two molar equivalents thereof, to afford N-formylpropargylamine, the substrate for the Sonogashira reaction of the present invention. In one embodiment, An alternative but less economical synthesis of N-formylpropargylamine was described in
Bull. Soc. Chim. Fr.,
588 (1967). The use of sodium diformylamide as a modified Gabriel reagent for the synthesis of primary amines was described in
Synthesis,
122-124 (1990).
Other amine protecting groups may also be used and include t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (FMOC), allyloxycarbonyl (Alloc), phthaloyl, benzoyl, and pivaloyl. Reference is made to T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis,
2
nd
Edition (1991) for a description of other primary amine protecting groups which may be employed in the present process.
The second Sonogashira coupling partner is a 2,5-dihalopyridine. In one embodiment, the 2,5-dihalopyridine is 2,5-dibromopyridine. However, 2,5-dichloropyridine, 2,5-diiodopyridine, or a mixed 2,5-dihalopyridine, such as 2-chloro-5-bromo-pyridine, may also be employed in the reaction.
The double Sonogashira reaction of a 2,5-dihalopyridine is effected with the optionally protected propargylamine in the presence of a palladium catalyst and a base.
The Sonogashira reaction is optionally carried out in a suitable organic solvent, such as THF, benzene, toluene, dioxane, acetonitrile, aqueous acetonitrile, DME, DMSO, DMF, DMAC, and NMP, or a mixture of these solvents, such as THF/DMF.
Palladium catalysts which may be used in the Sonogashira reaction include a palladium alkanoate, a palladium acetonate, a palladium halide, a palladium halide complex, a palladium-dibenzylidene acetone complex, and a triarylphosphine palladium complex. More specifically, the palladium catalyst is selected from the group consisting of Pd(II) acetate, Pd(II) acetylacetonate, Pd(0)bis-dibenzylidene acetone (“dba”), Pd(II) bromide, Pd(II) chloride, Pd(II) iodide, Pd(II) sulfate, Pd(II) trifluoroacetate, Pd(II)Cl
2
(CH
3
CN)
2
, Pd
2
(dba)
3
, Pd(II)(dppf)Cl
2
, Pd(II)Cl
2
(PPh
3
)
2
, Pd(PPh
3
)
4
, and Pd(II)Cl
2
(PhCN)
2
. In one embodiment the palladium catalyst is Pd(II)Cl
2
(PPh
3
)
2
.
Bases which may be employed in the process of the present invention include organic aliphatic amines, such as triethylamine, diethylamine, diisopropylamine, diisopropylethylamine, n-butylamine, t-butylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and quinuclidine, and organic aromatic amines, such as pyridine and 4-dimethylaminopyridine (DMAP). In one embodiment, the organic amine may serve as the reaction solvent as well as the base. In a class of this embodiment, the organic amine is diisopropylamine. Inorganic bases, such as potassium carbonate, may also be used in place of the organic amine.
The reaction is performed at a temperature range of about 10° C. to about 120° C. In another embodiment, the optionall

Affiliated with

Also associated with

Rating

Process for preparing integrin antagonist intermediates does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing integrin antagonist intermediates, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing integrin antagonist intermediates will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3217708