Process for preparing amides

Details Process for preparing amides Process for preparing amides

1998-07-08

2001-11-06

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S286000, C544S291000, C544S337000, C544S374000, C544S379000, C544S386000, C548S132000, C549S366000, C549S487000, C564S134000, C564S135000, C564S136000, C564S137000

Reexamination Certificate

active

06313294

ABSTRACT:

The present invention relates to a process for preparing an amide.
BACKGROUND OF THE INVENTION
Many conventional synthetic pathways exist for preparing amide compounds. For instance, the reaction of an amine and an ester in a solvent, a well-known basic organic reaction, can be used to form an amide. In particular, it is known that the formation of an amide linkage by the reaction of a primary amine with an ester in a solvent under heating is possible. Moreover, the formation of an amide by reacting a secondary amine and an ester, can require not only a solvent, but also a catalyst, such as Lewis acid, strong base, or enzyme.
From conventional methods, the syntheses of amides, such as N-substituted carbonyl alkylenediamines, have several common features outlined below.
(1) Typically, the starting material is the corresponding organic acid. The organic acid is activated to an acid chloride or acid anhydride of higher activity, which is then reacted with a diamine to form the desired N-substituted carbonyl alkylenediamine.
(2) Since acid chlorides or acid anhydrides are highly reactive, the diamine used, typically, is treated with hydrogen chloride, hydrogen bromide, acetic acid, or tert-butoxycarbonyl to protect one of the amine groups. This step helps to reduce the formation of undesired diamides. The desired N-substituted carbonyl alkylenediamine can be obtained by a de-protection step.
(3) The conventional synthesis, typically, requires at least four reaction steps to form the N-substituted carbonyl alkylenediamine product. Furthermore, the synthetic process does not have a desirably high yield of the N-substituted carbonyl alkylenediamine product (only about 40% to 70%), and chemical wastes are generated, thus causing environmental problems.
SUMMARY OF THE INVENTION
The invention features a novel preparation of amide compounds.
The present invention advantageously solves the above-mentioned problems, e.g., multiple step/complex process, low yield, and chemical waste, by providing a process for preparing an amide through one simple step having a high yield of the desire amide product. The starting materials are an amine and an ester, which can be directly reacted in a molten form to produce an amide without the use of solvents and catalysts.
In addition, amide compounds play a very important role in organic chemistry and are used in the synthesis of many compounds. For instance, amide compounds can be used as intermediates or precursors to form a desirable chemical product. For example, an N-substituted carbonyl alkylenediamine can be used as the intermediate for synthesizing compounds used as an antihypertensive drugs, e.g., quinazoline derivatives.
In one aspect, the invention features a process for preparing an amide which includes contacting, in the absence of a solvent, an amine with an acyclic ester, where both the amine and the acyclic ester are in a molten form.
The amine can be a diamine having a secondary amino group. Alternatively, the amine can be an alkylenediamine.
An aspect of the above-described process includes a process for forming an N-substituted carbonyl alkylenediamine, wherein the amine is
in which R
1
is selected from the group consisting of H, C1-8 alkyl, C1-8 alkenyl, C1-8 heteroalkyl, and C1-8 heteroalkenyl; m is 2 or 3; and n is 2 or 3; or
in which each of R
2
and R
3
is independently selected from the group consisting of H, C1-8 alkyl, C1-8 alkenyl, C1-8 heteroalkyl, and C1-8 heteroalkenyl; k is 1 to 8; and the ester is
in which R is selected from the group consisting of C1-8 alkyl, C1-8 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C4-8 aryl, C2-8 heterocycle; and R
4
is C1-8 alkyl or C1-8 alkenyl.
A subset of the process for forming the above-described N-substituted carbonyl alkylenediamine features diamines having R1 selected from the group consisting of H, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, sulfhydryl substituted C1-8 alkyl, and amino substituted C1-8 alkyl.
A subset of the process for forming the above-described N-substituted carbonyl alkylenediamine features diamines having each of R2 and R3 independently selected from the group consisting of H, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, sulfhydryl substituted C1-8 alkyl, and sulfhydryl substituted C1-8 alkyl.
A subset of the process for forming the above-described N-substituted carbonyl alkylenediamine features esters having R selected from the group consisting of C2-8 heterocycle, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, and alkoxy substituted C1-8 alkyl.
Representative examples of R can include, for example,
In yet, another subset of the above-described process, a quinazoline derivative is formed by contacting, in the absence of a solvent, an amine in a molten form with an ester in a molten form to form an N-substituted carbonyl alkylenediamine,
wherein the amine is
in which R
1
is selected from the group consisting of H, C1-8 alkyl, C1-8 alkenyl, C1-8 heteroalkyl, and C1-8 heteroalkenyl; m is 2 or 3; and n is 2 or 3; or
in which each of R2 and R3 is independently selected from the group consisting of H, C1-8 alkyl, C1-8 alkenyl, C1-8 heteroalkyl, and C1-8 heteroalkenyl; k is 1 to 8; and the ester is
in which R is selected from the group consisting of C1-8 alkyl, C1-8 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C4-8 aryl, C2-8 heterocycle; and R4 is C1-8 alkyl or C1-8 alkenyl; and
contacting said N-substituted carbonyl alkylenediamine with a quinazoline to form a quinazoline derivative, wherein said quinazoline derivative is
in which R, m, and n are defined above; and each of R8-R10 is independently selected from the group consisting of halogen, hydrogen, amino, C1-8 alkyl, C1-8 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C4-8 aryl, C1-8 alkoxyl, C1-8 alkylthio, C3-8 heterocycle; X is selected from N, O, or S; and R5 is selected from the group consisting of C1-8 alkyl, C1-8 alkenyl, C1-8 heteroalkyl, and C1-8 heteroalkenyl; or
in which R, R2, R3, R8-R10, X, R5, and k are defined above.
A subset of the above-described process for forming the quinazoline derivatives features diamines having R1 selected from the group consisting of H, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, sulfhydryl substituted C1-8 alkyl, and amino substituted C1-8 alkyl.
A subset of the above-described process for forming the quinazoline derivatives features diamines having R5 selected from the group consisting of C1-8 alkyl, hydroxy substituted C1-8 alkyl, sulfhydryl substituted C1-8 alkyl, and amino substituted C1-8 alkyl.
A subset of the above-described process for forming the quinazoline derivatives features diamines having each of R2 and R3 independently selected from the group consisting of H, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, sulfhydryl substituted C1-8 alkyl, and amino substituted C1-8 alkyl.
In yet, another subset of the above-described process for forming the quinazoline derivatives features esters having R is selected from the group consisting of C2-8 heterocycle, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, and alkoxy substituted C1-8 alkyl. Representative examples of R can include, for example,
In another aspect, the invention features an N-substituted carbonyl alkylenediamine having the formula:
wherein n=2 or 3; m=2 or 3; and R1 is selected from the group consisting of C1-8 alkyl, C1-8 alkenyl, C1-8 heteroalkyl, and C1-8 heteroalkenyl; and R is selected from the group consisting of C1-8 alkyl, C1-8 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C4-8 aryl, and C2-8 heterocycle; or
R1 is hydrogen and R is selected from the group consisting of C1-8 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C4-8 aryl, and thiophenyl.
A subset of the above-described N-substituted carbonyl alkylenediamines features compounds having R1 selected from the group consisting of H, unsubstituted C1-8 alkyl, hydroxy substituted C1-8 alkyl, sulfhydryl substituted C1-8 alkyl, and amino substituted C1-8 alkyl.
The N-substituted carbonyl alkylenediamine can be, for example, 1-(1,4-benzodioxan-2-yl-c

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