Synthesis of 4-substituted pyrrole-2-carbaldehyde compounds

Details Synthesis of 4-substituted pyrrole-2-carbaldehyde compounds Synthesis of 4-substituted pyrrole-2-carbaldehyde compounds

2000-10-23

2002-08-27

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06441194

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for selective synthesis of 4-substituted-pyrrole-2-carbaldehyde compounds, via alkylation reactions.
BACKGROUND OF THE INVENTION
Pyrroles are a family of heterocyclic compounds comprising a five-membered ring residue with four carbon atoms, one nitrogen atom, and two carbon-carbon double bonds. A wide variety of substituent groups (designated generally herein as “S
x
”) may be bonded to any of the five atoms of the pyrrole ring. The permissible substituent groups include but are not limited to hydrogen, alkyl groups, aromatic groups, acyl groups, halides, etc . The present invention relates to methods for selectively converting certain pyrrole-2-carbaldehydes (i.e. pyrrole compounds having an aldehyde substituent at the 2-position of the pyrrole ring) to 4-alkylated-pyrrole-2-carbaldehyde compounds having alkyl residues or groups (“R
4
”) at the 4-position of the pyrrole ring, as shown below.
wherein R
4
is an alkyl or substituted alkyl substituent having at least four carbon atoms.
As disclosed by Streitweiser and Heathcock (
Introduction to Organic Chemistry
, Macmillan Publishing Co. Inc., New York, 1976, at pages 1080-1088) pyrrole rings may undergo electrophillic substitution reactions analogous to those typical of benzene-type aromatic compounds. For example, pyrroles undergo “Friedel-Crafts” type “alkylation” reactions, in which an alkylating agent (such as an alkyl halide, an alcohol, or an olefin) is reacted with a pyrrole in the presence of a catalyst, which results the removal of a hydrogen from one of the pyrrole carbons, and substitution of an “alkyl” group or residue therefore.
Friedel-Crafts alkylation reactions have been utilized by prior workers to synthesize 4-substituted-pyrrole-2-carbaldehyde compounds. For example, Anderson et.al. (Can. J. Chem. 56, 654-657 (1978)) reacted pyrrole-2-carbonitrile with t-butyl chloride in the presence of aluminum or gallium chloride catalysts, to obtain either 4-t-butyl-pyrrole-2-carbonitrile, or 5-t-butyl-pyrrole-2-carbonitrile. Each of the two isomers of the t-butyl-pyrrole-2-carbonitriles were then reduced to the corresponding aldehydes.
In another approach, Mueller-Westerhoff and Sweigers (Synthetic Communications, 24(10), 1389-1393 (1994)) protected the nitrogen atom of a pyrrole, alkylated in the 4-position with t-butyl chloride/aluminum chloride, deprotected the nitrogen atom, then formulated the 2-position utilizing a Vulsmeir reagent.
In yet another approach to 4-alkyl-pyrrole-2- carbaldehydes, Anderson et.al.(Can. J. Chem., 44, 1831-1839 (1966)) disclosed selective isopropylation of pyrrole-2-carbaldehyde in the presence of various catalysts to give 4-isopropyl-pyrrole-2-carbaldehyde.
Recently, three United States patent applications, including provisional patent application Serial No. 60/123,058, filed Mar. 5, 1999, provisional patent application Serial No. 60/123,962, filed Mar. 12, 1999, and U.S. utility patent application Ser. No. 09/518,863, filed Mar. 3, 2000 (which are hereby incorporated by reference in their entirety) disclose use for certain classes of 4-alkyl-substituted-pyrrole-2-carbaldehydes, i.e., as intermediates for the synthesis of certain porphyrin compounds.
The 4-alkyl-pyrrole-2-carbaldehydes provided by the current invention can also be used to synthesize various dipyrroles or tripyrroles, which can be intermediates for the synthesis of porphyrins having 4-alkyl substituents, according to the methods described in U.S. patent application Ser. No. 09/524,621, filed Mar. 13, 2000. Additionally, these classes of 4-alkyl-pyrrole-2-carbaldehydes and 4-alkyl-2-hydroxymethyl pyrroles may be valuable intermediates for the synthesis of pharmaceuticals containing heterocyclic residues.
Therefore, there is a need for improved methods and processes for synthesizing 4-alkyl-pyrrole-2- carbaldehydes including, and 4-tertiary-alkyl-pyrrole-2-carbaldehydes.
SUMMARY OF THE INVENTION
The present invention provides improved processes for synthesizing 4-alkyl-pyrrole-2-carbaldehydes, including 4-tertiary-alkyl-pyrrole-2-carbaldehydes. Therefore, this invention, in one aspect, relates to a process for making a 4-alkyl substituted pyrrole-2-carbaldehyde compound comprising reacting:
a. a pyrrole-2-carbaldehyde compound; and
b. an alkylating agent having at least four carbon atoms; in the presence of at least one catalyst; to form a 4-alkyl substituted pyrrole-2-carbaldehyde compound.
The invention further provides a process for making 4-t-butyl-pyrrole-2-carbaldehyde compound comprising:
a. dispersing pyrrole-2-carbaldehyde and from about 1.0 to about 1.5 molar equivalents of AlCl
3
in a solvent:
b. adding from about 0.8 to about 1.3 molar equivalents of a t-butyl-halide compound to the dispersion, and
c. reacting the dispersion to form 4-t-butylpyrrole-2-carbaldehyde.
In yet another aspect, the instant invention provides a process for making a 4-tertiary-alkyl substituted pyrrole-2-carbaldehyde compound comprising:
a. reacting a pyrrole and a Vilsmeir reagent to produce a 2-substituted pyrrole compound; and
b. further reacting the 2-substituted pyrrole compound with an alkylating agent, in the presence of a catalyst; to form the 4-tertiary-alkyl substituted pyrrole-2-carbaldehyde compound.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein and to the Figures and their previous and following description.
Before the present compounds, compositions and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods, specific pharmaceutical carriers, or to particular pharmaceutical formulations or administration regimens, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an aromatic compound” includes mixtures of aromatic compounds, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
References in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article, denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight comp

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