Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1998-07-01
2001-11-06
Raymond, Richard L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06313292
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,654,307 which is herein incorporated by reference discloses bicyclic compounds which includes a series of 4,6-disubstituted pyrido[3,4-d]pyrimidines.
The compounds disclosed in the above United States Patent are useful in inhibiting the epidermal growth factor receptor and related receptors and, in particular, their tyrosine kinase activity, and thus are useful in the treatment of proliferative diseases including cancer, psoriasis, proliferative glomerulonephritis and diabetes-induced renal disease, pancreatitis, and as contraceptives. The aforementioned compounds have been prepared by a synthetic route which affords the target compounds in extremely low yields, i.e., in less than 0.34% overall yield from the starting material, 2-chloro-5-nitropyridine, requires chromatographic purification at several stages and furthermore, is difficult to conduct on a large scale.
The object of the present invention is an improved process for preparing the compounds described above on a large scale using inexpensive starting materials.
SUMMARY OF THE INVENTION
Accordingly, a first aspect of the present invention is a novel process for the preparation of a compound of Formula I
wherein R is aryl, alkyl, or arylalkyl;
R
1
and R
2
are the same or different and each is selected from the group consisting of:
hydrogen,
alkyl,
hydroxyalkyl,
dihydroxyalkyl,
aminoalkyl,
diaminoalkyl,
carboxyalkyl,
hydroxyalkylaminoalkyl,
dihydroxyalkylaminoalkyl, and
R
1
and R
2
may be combined with N to form a 5- or 6-membered ring optionally containing an N, O, or S atom wherein the N atom may be optionally substituted by an alkyl group; and pharmaceutically acceptable salts thereof which comprises:
Step (A) reaction of the compound of Formula X
with a tertiary butoxycarbonyl (Boc) reagent in the presence of a solvent to afford the compound of Formula IX
Step (B) reaction of the compound of Formula IX with a base and a carboxylate source in the presence of a solvent to afford the compound of Formula VIII
Step (C) reaction of the compound of Formula VIII with a Boc cleaving reagent in a solvent to afford the compound of Formula VII
Step (D) reaction of the compound of Formula VII with a annulating reagent in a solvent to afford the compound of Formula VI
Step (E) reaction of the compound of Formula VI with a chlorinating reagent in a solvent to afford the compound of Formula V
Step (F) reaction of the compound of Formula V with a compound of Formula IV
R—NH
2
IV
wherein R is as defined above in a solvent to afford a compound of Formula II
Step (G) reaction of a compound of Formula II with a compound of Formula III
wherein R
1
and R
2
are as defined above in a solvent to afford a compound of Formula I; and Step (H), if desired, converting a compound of Formula I to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula I by conventional means.
A second aspect of the present invention is an improved process for the preparation of a compound of Formula II
wherein R is aryl, alkyl, or arylalkyl; and
pharmaceutically acceptable salts thereof which comprises: Step (A) reaction of the compound of Formula X
with a Boc reagent in the presence of a solvent to afford the compound of Formula IX
Step (B) reaction of the compound of Formula IX with a base and a carboxylate source in the presence of a solvent to afford the compound of Formula VIII
Step (C) reaction of the compound of Formula VIII with a Boc cleaving reagent in a solvent to afford the compound of Formula VII
Step (D) reaction of the compound of Formula VII with a annulating reagent in a solvent to afford the compound of Formula VI
Step (E) reaction of the compound of Formula VI with a chlorinating reagent in a solvent to afford the compound of Formula V
Step (F) reaction of the compound of Formula V with a compound of Formula IV
R—NH
2
IV
wherein R is as defined above in a solvent to afford a compound of Formula II; and
Step (G), if desired, converting a compound of Formula II to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula II by conventional means.
A third aspect of the present invention is a novel process for the preparation of the compound of
and pharmaceutically acceptable salts thereof which comprises:
Step (A) reaction of the compound of Formula X
with a Boc reagent in the presence of a solvent to afford the compound of Formula IX
Step (B) reaction of the compound of Formula IX with a base and a carboxylate source in the presence of a solvent to afford the compound of Formula VIII
Step (C) reaction of the compound of Formula VIII with a Boc leaving reagent in a solvent to afford the compound of Formula VII
Step (D) reaction of the compound of Formula VII with a annulating reagent in a solvent to afford the compound of Formula VI
Step (E) reaction of the compound of Formula VI with a chlorinating reagent in a solvent to afford the compound of Formula V; and
Step (F), if desired, converting the compound of Formula V to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to the compound of Formula V by conventional means.
A fourth aspect of the present invention is a novel process for the preparation of the compound of
and pharmaceutically acceptable salts thereof which comprises:
Step (A) reaction of the compound of Formula X
with a Boc reagent in the presence of a solvent to afford the compound of Formula IX
Step (B) reaction of the compound of Formula IX with a base and a carboxylate source in the presence of a solvent to afford the compound of Formula VIII
Step (C) reaction of the compound of Formula VIII with a Boc cleaving reagent in a solvent to afford the compound of Formula VII
Step (D) reaction of the compound of Formula VII with a annulating reagent in a solvent to afford the compound of Formula VI; and
Step (E), if desired, converting the compound of Formula VI to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to the compound of Formula VI by conventional means.
A fifth aspect of the present invention is a novel process for the preparation of the compound of
and pharmaceutically acceptable salts thereof which comprises: Step (A) reaction of the compound of Formula X
with a Boc reagent in the presence of a solvent to afford the compound of Formula IX
Step (B) reaction of the compound of Formula IX with a base and a carboxylate source in the presence of a solvent to afford the compound of Formula VIII
Step (C) reaction of the compound of Formula VIII with a Boc cleaving reagent in a solvent to afford the compound of Formula VII; and
Step (D), if desired, converting the compound of Formula VII to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to the compound of Formula VII by conventional means.
A sixth aspect of the present invention is a novel process for the preparation of the compound of
and pharmaceutically acceptable salts thereof which comprises: Step (A) reaction of the compound of Formula X
with a Boc reagent in the presence of a solvent to afford the compound of Formula IX
Step (B) reaction of the compound of Formula IX with a base and a carboxylate source in the presence of a solvent to afford the compound of Formula VIII; and
Step (C), if desired, converting the compound of Formula VIII to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to the compound of Formula VIII by conventional means.
A seventh aspect of the present invention is a novel process for the prepa
Denny William A.
Rewcastle Gordon W.
Showalter H. D. H.
Winters Roy T.
Balasubramanian Venkataraman
Merchant & Gould P.C.
Raymond Richard L.
Warner-Lambert & Company
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