Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1997-07-14
2001-05-01
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C558S418000, C560S035000, C560S107000, C560S138000, C560S250000, C562S440000, C564S015000, C564S221000, C564S272000, C564S273000, C564S274000, C564S443000
Reexamination Certificate
active
06225499
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to preparing aminoarylacetylenes. More specifically, it relates to preparing aminoarylacetylenes from aminoarylhalides and terminal acetylenes and to novel compounds which are useful in their preparation. Aminophenylacetylenes are valuable as precursors to pharmaceutically active compounds and to acetylene terminated polymers. In particular, 3-aminophenylacetylene is used as an end-capping agent for high performance polyimide resins.
BACKGROUND OF THE INVENTION
Sabourin,
Prepr. Div. Pet. Chem., Am. Chem. Soc.,
vol. 24, pp. 233-239 discloses the preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol (an aminophenylacetylene) and 3-aminophenylacetylene in two and three steps, respectively, from 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol. In the first step, 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol were reacted in the presence of a catalyst system of bis(triphenylphosphine)palladium dichloride, additional triphenylphosphine, and cuprous iodide in triethylamine solvent at the reflux temperature to obtain 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol. In the second step, this nitrophenylacetylene was hydrogenated in isopropanol in the presence of a Ru/Al
2
O
3
catalyst to obtain 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol. This reference states that is essential to stop the hydrogenation reaction at the stoichiometric point because reduction of the triple bond ensues. In the third step, this aminophenylacetylene was heated in toluene in the presence of sodium hydroxide pellets, with removal of the acetone co-product by distillation, to obtain 3-aminophenylacetylene.
This reference also discloses an attempt to similarly react 3-bromoaniline, instead of 3-bromonitrobenzene, with 2-methyl-3-butyn-2-ol to obtain 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol directly, and reports that 3-bromoaniline failed to react at any appreciable rate at temperatures up to ca. 100 ° C.
U.S. Pat. Nos. 4,128,588 and 4,204,078 (each also from the same Sabourin as inventor, with Selwitz) also discloses this preparation of 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol from 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol. U.S. Pat. No. 4,139,561 and
J. Org. Chem.,
vol. 44 (1979), pp. 1223-1236 (both Onopchenko as well as the same Sabourin and Selwitz) also discloses the preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol from 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol by hydrogenation with a ruthenium catalyst, and its subsequent conversion to 3-aminophenylacetylene. Both the patent and journal disclosures highlight the difficult challenge of selectively hydrogenating the nitro group in the presence of the acetylene group. Subsequent U.S. Pat. Nos. 4,215,226; 4,216,341; 4,219,679 and a publication
J. Org. Chem.,
vol. 44 (1979), pp.3671-3674 from Onopchenko, Sabourin, and Selwitz disclose hydrogenations of 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol to 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol using other hydrogenation catalysts.
Synlett,
1995, pp.1115-1116 discloses this preparation of 2-methyl-4-(4-nitrophenyl)-3-butyn-2-ol from 4-bromonitrobenzene and 2-methyl-3-butyn-2-ol in high yield using a catalyst system comprising palladium on carbon, triphenylphosphine, and cuprous iodide in the presence of 2.5 equivalents of potassium carbonate in 1:1 1,2-dimethoxyethane:water at 80 ° C. This reference also discloses the preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol in 78% isolated yield from 3-iodoaniline (in place of 4-bromonitrobenzene) using the same system and the same conditions. The reference does not disclose any attempt to similarly react 3-bromoaniline.
OBJECTS OF THE INVENTION
The object of this invention is to provide an economically preferable, effective and efficient process for the preparation aminophenylacetylenes. A further object of this invention is to provide a process for the preparation of aminophenylacetylenes that avoids the inherent challenge of selectively hydrogenating a nitro group in the presence of an acetylene group. Another object of this invention is to provide a process for the preparation of aminophenylacetylenes from aminophenylhalides. The present invention is directed towards one or more of the above objects. Other objects and advantages will become apparent to persons skilled in the art and familiar with the background references from a careful reading of this specification.
SUMMARY OF THE INVENTION
In its most general terms, the present invention provides a process for preparing aminoarylacetylenes comprising reacting an N-arylmethylidene aminoarylhalide with a terminal acetylene in the presence of a base and a catalyst system comprising a palladium catalyst and a cuprous salt to produce a novel N-arylmethylidene aminoarylacetylene. The N-arylmethylidene aminoarylacetylene may be hydrolyzed to remove the N-arylmethylidene group and provide the aminoarylacetylene. The present invention thereby provides a practical process for preparing an aminophenylacetylene comprising reacting a N-benzylidene aminophenylhalide with a terminal acetylene in the presence of a base and a catalyst system comprising a palladium catalyst and a cuprous salt to produce a novel N-benzylidene aminophenylacetylene, and hydrolyzing the N-benzylidene aminophenylacetylene to the aminophenylacetylene. N-benzylidene aminophenylhalides can be readily prepared from the corresponding benzaldehyde and the corresponding aminophenylhalide by methods known in the art, typically in the presence of an acid catalyst. In certain embodiments of the present invention, the N-benzylidene aminophenylhalide is provided in the reaction by the benzaldehyde, the aminophenylhalide, and an acid catalyst. The invention thereby provides a process for the preparation of aminophenylacetylenes from aminophenylhalides that avoids the inherent challenge of selectively hydrogenating a nitrophenylacetylene to an aminophenylacetylene.
From experiments using a substoichiometric amount of benzaldehyde relative to the aminophenylhalide, it was surprisingly discovered that the remaining free aminophenylhalide in the mixture with the resulting N-benzylidene aminophenylhalide also reacts, providing a mixture of the aminophenylacetylene and the N-benzylidene aminophenylacetylene. Apparently, the substoichiometric amount of the benzylidene group catalyzes the conversion of aminophenylhalide to the aminophenylacetylene. While not intending to be bound by theory, this can be explained by the benzylidene group being transferred, during the reaction, from the initial product, the N-benzylidene aminophenylacetylene, to the unreacted free aminophenylhalide, converting it to the more reactive N-benzylidene aminophenylhalide.
In one preferred embodiment, the present invention provides a process for the preparation of 3-aminophenylacetylene carbinols from 3-aminophenylhalides comprising reacting a N-benzylidene derivative of the 3-aminophenylhalide with a alpha-hydroxy terminal acetylene in the presence of an amine base and a catalyst system comprising a palladium catalyst comprising a phosphorus ligand and a cuprous halide, and hydrolyzing the resulting novel N-benzylidene 3-aminophenylacetylene carbinol to the 3-aminophenylacetylene carbinol. Optionally, a mixture of the 3-aminophenylhalide and the N-benzylidene 3-aminophenylhalide is reacted to provide a mixture of the 3-aminophenylacetylene carbinol and the corresponding N-benzylidene aminophenylacetylene carbinol. 3-amino-phenylacetylene carbinols may be converted to 3-aminophenylacetylene by methods known in the art. The invention thereby provides an efficient process for the preparation of 3-aminophenylacetylene from 3-aminophenylhalides.
DETAILED DESCRIPTION OF THE INVENTION
Suitable starting materials and intermediates for the preparation of aminoarylacetylenes by the present invention are aminoarylhalides in general, arylcarboxaldehydes in general, terminal acetylenes in general, N-arylmethylidene aminoarylhalides in general, and N-arylmethylidene aminoarylacetylenes in general. The N-arylmethylidene aminoarylhalide and the N-arylmethylidene
Catalytica Pharmaceuticals, Inc.
Grate John
O'Sullivan Peter
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