One step synthesis of 1,2,3-triazole carboxylic acids

Details One step synthesis of 1,2,3-triazole carboxylic acids One step synthesis of 1,2,3-triazole carboxylic acids

2002-07-11

2003-11-04

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06642390

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a one-step process to prepare triazole carboxylic acids from azides and &bgr;-ketoesters.
2. Description of the Related Art
The 1,2,3-triazole unit is an important element in a number of drugs and development candidates. The triazole is a structural backbone of many antibiotics, antiallergics, antimetastasis agents, anticonvulsants and antidepressants. Their synthesis usually involves the reaction of organic azides with unsaturated compounds. Such unsaturated compounds are usually acetylenic compounds (Hiroto et al.,
Chem Pharm. Bull.
1990, 38(9), 2597-2601; Palacios et al.,
Heterocycles
1994, 38(1), 95-102), as, for example, acetylene dicarboxylic acid derivatives. Because these acetylenic starting materials usually carry the same substituents on both acetylenic carbon atoms, the reaction gives rise to symmetrically substituted 1,2,3-triazoles (i.e. 1,2,3-triazoles carrying identical substituents in positions 4 and 5). If unsymmetrical substituted acetylenes are used, the resulting 1,2,3-triazoles are usually mixtures of regioisomers. Regioselectivity issues can be avoided with &bgr;-ketoesters as starting materials (Bertelli et al.,
Eur. J. Med. Chem.
1998, 33(2), 113-122). However, &bgr;-ketoesters have been used only in rare cases, and the yields have been poor. Additionally, azides are difficult to obtain, and published 1,2,3-triazole syntheses are usually not very efficient with respect to throughput and scale.
An object of the present invention is to develop a large scale, safe and efficient procedure for the syntheses of azides. Another object of the present invention is to provide an efficient one-step synthesis of triazole-carboxylic acids from azides and &bgr;-keto esters.
SUMMARY OF THE INVENTION
This invention provides for a one step process for preparing 1,2,3-triazole carboxylic acids from an azide and a &bgr;-ketoester. Specifically, the method of the present invention calls for the treatment of an azide and a &bgr;-ketoester with a base to form a 3H-[1,2,3]triazole-4-carboxylic acid. These compounds are important precursors for antibiotics, antiallergics, antimetastasis agents, anticonvulsants and antidepressants.
The invention also provides for a method for preparing an aromatic azide intermediate from an aromatic amine. The aromatic amine is treated with a nitrate ion in the presence of an acid to form a diazonium salt. Subsequent treatment with an azide ion affords the desired aromatic azide.
The invention further provides for a method for preparing an aliphatic azide intermediate from the corresponding alkyl halide and an azide ion. The reaction proceeds via S
N
2 nucleophilic aliphatic substitution and the time and temperature of the reaction is dependent on the individual alkyl halide.
The invention further provides for a method for preparing a &bgr;-hydroxy aliphatic azide intermediate by regioselective nucleophilic opening of an epoxide by an azide ion in the presence of ammonium chloride. For azides to be converted to the corresponding 1,2,3-triazole carboxylic acids according to the method of the present invention, the alcohol is subsequently protected.
DETAILED DESCRIPTION OF THE INVENTION
According to Scheme 1, a preferred embodiment of the present invention relates to a method for the formation of a 3H-[1,2,3]triazole-4-carboxylic acid III by reacting an azide I with a &bgr;-ketoester II in the presence of a base.
In Scheme 1:
R
1
and R
2
independently are lower alkyl or cycloalkyl optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, —C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, mercapto, alkylthiol, —C(O)NH-alkyl, C(O)N-dialkyl, —NHC(O)-alkyl, alkenyl or alkynyl, or
R
1
and R
2
independently are aryl, arylalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl wherein the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, —C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, mercapto, alkylthiol, —C(O)NH-alkyl, C(O)N-dialkyl, —NHC(O)-alkyl, alkenyl or alkynyl; and
R
3
is lower alkyl.
In a more preferred embodiment of the invention R
2
is aryl or heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkoxy, —C(O)-alkyl, hydroxy, amino, mono- or dialkylamino, mercapto, alkylthiol, —C(O)NH-alkyl, C(O)N-dialkyl, —NHC(O)-alkyl, alkenyl or alkynyl.
By “alkyl”, “lower alkyl”, and “C
1
-C
6
alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. These groups may be substituted with up to four groups mentioned below for substituted aryl.
By “alkoxy”, “lower alkoxy”, and “C
1
-C
6
alkoxy” in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. These groups may be substituted with up to four groups mentioned below for substituted aryl.
By the term “halogen” in the present invention is meant fluorine, bromine, chlorine, and iodine.
A “carbocyclic group” or “cycloalkyl” is a nonaromatic cyclic ring or fused rings having from 3 to 7 ring members. Examples include cyclopropyl, cyclobutyl, and cycloheptyl. These rings may be substituted with one or more of the substituent groups mentioned below for aryl, for example alkyl, halo, amino, hydroxy, and alkoxy. Typical substituted carbocyclic groups include 2-chlorocyclopropyl, 2,3-diethoxycyclopentyl, and 2,2,4,4-tetrafluorocyclohexyl. The carbocyclic group may contain one or two heteroatoms selected from oxygen, sulfur, and nitrogen, and such ring systems may be referred to as “heterocyclyl” or “heterocyclic”. Examples include pyranyl, tetrahydrofuranyl, and dioxanyl. These heterocyclyl groups may be substituted with up to four of the substituent groups mentioned for aryl.
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, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl, benzimidazolyl, benzoxazolyl. The heteroaryl group is optionally substituted with up to four groups mentioned below for substituted aryl.
By aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, —OH, —SH, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, trifluoromethoxy, lower acyloxy, aryl, heteroaryl, amino, mono- or dialkylamino, and nitro. A preferred aryl is phenyl.
In another more preferred embodiment, the azide I, the &bgr;-ketoester II and the base are reacted together in a suitable solvent. The reaction mixture in such a solvent can be homogenous or heterogenous. Examples of suitable solvents for the present method include, but are not limited to, one or more of the following: a protic solvent such as methanol, ethanol or water; or aprotic solvents such as dimethylsulfoxide, dimethylformamide or hexamethylphosphorotriamide. In an even more preferred embodiment, the solvent is ethanol or water; and the most preferred is a combination of water and ethanol.
Examples of acceptable bases used in the present method are those with alkali metals or alkaline earth metals such as sodium, potassium, calcium and magnesium, and those with organic bases including, but not limited to, amines. Preferred bases are alkali metal

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