Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-04-27
2002-10-08
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S493000
Reexamination Certificate
active
06462238
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to a process for the reduction of nitriles to amines. This invention further relates to a process for the reduction of a nitrile without reducing a sulfone also present in the molecule.
2. Summary of the Related Art
The reduction of nitrites is an extremely important synthetic tool for the production of primary and secondary amines, as well as alcohols. In particular, the hydrogenation of a nitrile group to the corresponding primary amine is very well known in the art. For example, hydride compounds such as lithium aluminum hydride or aluminum hydride have been employed. Another conventional method for the reduction of a nitrile is use of an alkali metal such as lithium, sodium or calcium in aqueous ammonia or an amine solvent. Yet another reducing agent for nitriles, and perhaps the most well known and documented procedure, is catalytic hydrogenation.
The use of borane (BH
3
) and substituted boranes have been used to reduce aldehydes and ketones to the corresponding alcohols. Similarly, oximes can also be reduced by borane to yield the respective hydroxylamine. Substituted boranes have also been used to reduce nitriles to primary amines (Brown et al.,
Synthesis
1981, 605). Reagents such as sodium borohydride, however, do not generally reduce nitrites unless the reaction is carried out in an alcoholic solvent when a CoCl
2
catalyst is added or in the presence of Raney nickel.
As with any organic synthetic reaction, the key of the reduction is to selectively reduce the desired functional group without reducing or in any way altering other functional groups in the molecule. An example of another functional group that is susceptible to reducing agents is the sulfone group.
Common reagents that can reduce a sulfone to its respective sulfide are diisobutyl aluminum hydride (Gardner et al.,
Can. J. Chem.
1973, 51, 1419) and lithium aluminum hydride (Bordwell et al.,
J. Am. Chem. Soc.
1951, 73, 2251). Heating with elemental sulfur can also reduce sulfones. Sulfones with a &bgr;-hydrogen can also undergo elimination reactions and are thus susceptible to cleavage, particularly at higher temperatures.
Due to the large technical and industrial importance of amines, new and improved methods for their production are desired. However, it is often necessary to reduce a nitrile in a molecule without affecting another reducible group. The technology of hydrogenating nitriles has been a convenient route to affording primary amines, but high temperatures involved in catalytic hydrogenation and the ability of alkali metals and many hydride compounds to affect different functionalties increases the need for a more selective nitrile reducing process
For example, the preparation of sulfonethylamines is a necessary intermediate for the preparation of certain tyrosine kinase inibitors (Carter, M. et al., WO 99/35146). However, applying standard nitrile reduction techniques to &agr;-sulfonitriles produces an unwanted isomerization of the metalloimine intermediate to the corresponding vinylogous amide. Thus, to date, an alternate multi-step approach is necessary for synthesizing these compounds.
Finally, the use of nucleophillic reducing agents such as sodium borohydride or lithium aluminum hydride requires the removal of salts by washing with water; many amine products (particularly aminoalkylene substituted sulfones) are soluble in water and therefore a non-aqueous work-up is desired.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process for the selective reduction of nitrites to amines. According to the present invention, there is provided a process for the reduction of a nitrile containing organic compound without reducing a sulfone also present in the molecule.
It is a further object of the present invention to provide a process of reducing a 2-(substitutedsulfonyl)ethanenitrile to the corresponding amine without isomerizing a metalloimine intermediate to a vinylogous amide.
It is still further an object of the present invention to provide a process for the selective reduction of nitrites to amines that employs a non-aqueous workup.
It is still another object of the invention to provide a convenient, efficient and economical one-step process to prepare sulfonoethylamines as intermediates for various biologically active compounds (see Carter, M. et al., WO 99/35146).
The invention process generally involves subjecting a cyanoalkylsulfone to borane-tetrahydrofuran complex, neat or in a suitable inert solvent, and then purifying the resulting crude product to afford the desired aminomethylenealkylsulfone.
In a preferred embodiment of the invention, a 2-(substitutedsulfonyl)ethanenitrile is reduced to aminoethyl methylsulfone with borane-tetrahydrofuran complex.
DETAILED DESCRIPTION OF THE INVENTION
The novel feature of the present process resides in the employment of borane or substituted borane for the hydrogenation of a nitrile containing organic compound that also contains a sulfone moiety. The object of the process is to keep the sulfone intact while selectively reducing the nitrile group to the respective primary amine.
Accordingly, one embodiment of the present invention is a process for the preparation of a compound of the formula I
which comprises reacting a compound of the formula II
with about 1 to 2 equivalents borane or a substituted borane neat or in a substantially inert organic solvent at a temperature of about −10° C. to 60° C. wherein
R and R
1
are independently lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; and
n is 0-6.
The term “borane” or “diborane” in the present invention refers to the chemical reagent with the formula BH
3
. By “substituted borane” is meant a compound that includes but is not limited to the following: borane-methyl sulfide complex, borane-dimethylsulfide complex, borane-morpholine complex, borane-piperdine complex, borane-pyridine complex, borane-tetrahydrofuran complex, borane-triethylamine-complex and borane-trimethylamine complex. A preferred substituted borane for the present invention is borane-tetrahydrofuran complex. Borane can be purchased (e.g. Aldrich Chemical Company) or prepared in situ by reacting sodium borohydride and boron trifluoride diethy letherate.
By “alkyl”, “lower alkyl”, and “C
1
-C
6
alkyl” in the present invention is meant a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like. The alkyl group can be optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, mono- or dialkylamino and hydroxy.
“Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbomyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed “heterocyclyl”, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or N, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
By heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7- membered rings containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, tetrazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl, phthalimidyl, benzimidazolyl, benzoxazolyl. The heteroaryl can be mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, aryl, heteroaryl, amino, mono- or dialkylamino and hydroxy.
By aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biph
Hwang Jack (ChanKou)
Piscopio Anthony D.
Tarlton Eugene
Array BioPharma Inc.
Davis Brian J.
McDonnell & Boehnen Hulbert & Berghoff
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