Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-09
2001-07-17
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S277100, C546S329000
Reexamination Certificate
active
06262268
ABSTRACT:
FIELD OF THE INVENTION
The present invention discloses a novel process and novel intermediates toward the preparation of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propylamine which is useful in the synthesis of &agr;v integrin receptor antagonists.
BACKGROUND OF THE INVENTION
The present invention provides an improved process for the preparation of 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propylamine (I).
The present invention also provides intermediates useful in the disclosed process.
The synthesis of compound (I) has previously been disclosed in U.S. Pat. No. 6,048,861 (Apr. 11, 2000); U.S. Pat. No. 5,952,341 (Sep. 14, 1999); WO 98/18460; and WO 99/31061. In these references, the naphthyridine ring is constructed by way of a Friedländer reaction between 2-amino-3-formyl-pyridine and 2-oxo-5-(benzyloxycarbonylamino)-pentane or 2-oxo-5-(t-butyloxycarbonylamino)-pentane. The described procedures involve a total of seven chemical transformations, several chromatographic purifications, and an overall yield of about 38%.
In the present invention, compound (I) is produced highly efficiently in a total of three chemical steps from a protected allylamine with an improved overall yield of about 76%. The method features a one-pot double Suzuki cross-coupling of a 2,5-dihalopyridine with a protected allylamine, deprotection, and a highly regioselective intramolecular Chichibabin-type cyclization to afford the final product (I).
SUMMARY OF THE INVENTION
This invention is concerned with a process for preparing 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propylamine of structural formula (I) and certain useful intermediates obtained during that process. The process utilizes a double Suzuki reaction of a 2,5-dihalopyridine with a protected allylamine, deprotection, and an intramolecular Chichibabin reaction.
The novel process and novel intermediates are illustrated in the following embodiment denoted in Scheme 1 below.
Scheme 1
As disclosed in U.S. Pat. No. 6,048,861 (Apr. 11, 2000); U.S. Pat. No. 5,952,341 (Sep. 14, 1999); WO 98/18460; and WO 99/31061, compound (I) is a key intermediate in the synthesis of &agr;v integrin receptor antagonists which are useful for inhibiting bone resorption and therefore for treating and/or preventing osteoporosis.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention involves the preparation of the compound of structural formula (I):
comprising the steps of:
(a) producing a compound of structural formula (III):
wherein P is an amine protecting group, by treating a 2,5-dihalopyridine with a protected allylamine of structural formula (IV):
in an organic solvent B, in the presence of a hydroboration reagent, a palladium catalyst, a phosphine ligand, and a proton acceptor;
(b) producing the compound of structural formula (II):
by cleaving the amine protecting groups P in a compound of structural formula (III):
wherein P is amine protecting group;
(c) treating the compound of structural formula (II):
with base in an organic solvent A; and
(d) isolating the resulting product (I).
The key steps of the above process of the present invention include a double Suzuki reaction of a 2,5-dihalopyridine with a protected allylamine, deprotection, and an intramolecular Chichibabin-type cyclization reaction.
One substrate for the double Suzuki reaction is an appropriately protected allylamine. In one embodiment of the process of the present invention, the allylamine is protected as its phthalimide derivative. This is accomplished by treatment of allylamine with phthalic anhydride in a suitable solvent, such as DMF. However, other amine protecting groups may also be used and include t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (FMOC), allyloxycarbonyl (Alloc), acetyl, 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 amine protecting groups which may be employed in the present process.
The second Suzuki 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. A further optional Suzuki coupling partner for the protected allylamine is 2,5-di-(trifluoromethanesulfonyloxy)pyridine.
The double Suzuki reaction of a 2,5-dihalopyridine is effected with the hydroborated product resulting from the reaction of a hydroboration reagent with the protected allylamine in a suitable solvent in the presence of a palladium catalyst, a proton acceptor, and a phosphine ligand. In one embodiment of this step of the process, the hydroboration reagent is 9-BBN. However, other boron reagents may also be used and include disiamylborane, dicyclohexylborane, and borane. In a second embodiment of this step, the phosphine ligand is DPPF. However, other phosphine ligands may also be employed and include triphenylphosphine, tri(o-tolyl)phosphine, DPPE, and DPPP.
Palladium catalysts which may be used in the Suzuki 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(O)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(dppf)Cl
2
, PdCl
2
(PPh
3
)
2
, Pd(PPh
3
)
4
, and Pd(II)Cl
2
(PhCN)
2
. In one embodiment the palladium catalyst is Pd(II) acetate.
The Suzuki reaction is carried out in a suitable organic solvent B, such as THF, benzene, toluene, dioxane, DME, DMSO, DMF, DMAC, and NMP, or a mixture of these solvents, such as THF/DMF. In one embodiment, the organic solvent B is DMF. The reaction is carried out in the presence of a proton acceptor, which includes an organic base, such as alkylamine, in particular triethylamine or diisopropylethylamine, and an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium phosphate (K
3
PO
4
), an alkali metal alkoxide such as sodium methoxide, and aqueous sodium or potassium hydroxide. In one embodiment, the base is powdered potassium carbonate. The reaction is performed at a temperature range of about 25° C. to 80° C. In another embodiment, the protected allylamine is used in an amount of about 2 to 3 molar equivalents of the 2,5-dihalopyridine. In a further embodiment, the “active” Pd-catalyst is generated separately via heating a solution of Pd(II) acetate and DPPF in DMF for 30 to 60 minutes instead of adding Pd(II) acetate, DPPF, and DMF separately to the reaction mixture.
The double Suzuki cross-coupling reaction product is a compound of structural formula (III):
wherein P is an amine protecting group. The next step of the process of the present invention is the removal of the protecting groups P in substrate (III) to generate compound (II). When the amine protecting group is phthaloyl, it may be cleaved by treatment with aqueous hydrazine in an alcoholic solvent, such as refluxing ethanol, or with an alkylamine, such as methylamine in methanol or ethanol, preferably at an elevated temperature. In one embodiment, the phthaloyl group is cleaved with hydrazine in refluxing ethanol. When the amine protecting group is t-butyloxycarbonyl, it may be cleaved by treatment with trifluoroacetic acid, sulfuric acid, HCl in ethyl acetate, HCl in diethyl ether, or HCl in dioxane. Other protecting groups are removed by standard literature conditions, such as those found in T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis
, 2
nd
Edition (1991).
The final step in the process of the present invention is the cyclization of compound (II) to elaborate the final product (I). This intramolecular transformation is
Hughes David L.
Palucki Michael
Yang Chunhua
Yasuda Nobuyoshi
Dentz Bernard
Durette Philippe L.
Merck & Co. , Inc.
Winokur Melvin
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