Process for the preparation of paraoxadiazolyphenylboronic...

Details Process for the preparation of paraoxadiazolyphenylboronic... Process for the preparation of paraoxadiazolyphenylboronic...

1999-12-13

2001-03-06

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S286000, C558S287000, C558S289000

Reexamination Certificate

active

06197967

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATION
The present invention is described in the German priority application No. 198 57 765.6, filed Dec. 15, 1998, which is hereby incorporated by reference as is fully disclosed herein.
BACKGROUND OF THE INVENTION
para-Oxadiazolylphenylboronic acids are of considerable industrial importance as precursors for active ingredients, in particular as precursors for correspondingly substituted biphenyl derivatives, which are used as AT (II) antagonists, or as precursors for liquid-crystalline compounds, as liquid crystals or as a constituent of liquid-crystalline mixtures. Phenylboronic acids can be coupled to haloaromatic compounds with catalysis by transition metals with the aid of methods described in the literature, to give biphenyl derivatives (N. Miyaura et al., Tetrahedron Lett., 3437 (1979); A. L. Casalnuovo et al., J. Amer. Chem. Soc. 112, 4324 (1990)).
SUMMARY OF THE INVENTION
Owing to the interest in this class of compounds, there is a need for an economical and technically simple synthesis of 4-(2′-oxadiazolyl)-phenylboronic acids.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
This object is achieved by a process for the preparation of a compound of the formula (I)
in which R′ is hydrogen, C
1
-C
12
-alkyl, C
3
-C
12
-cycloalkyl, C
2
-C
12
-alkenyl, C
2
-C
12
-alkynyl, C
1
-C
12
-alkoxy, alkoxy-(C
1
-C
12
-alkyl), alkoxy-(C
2
-C
12
-alkenyl), alkoxy-(C
2
-C
12
-alkynyl), acyloxy-(C
1
-C
12
-alkyl), acyloxy-(C
2
-C
12
-alkenyl), acyloxy-(C
2
-C
12
-alkynyl), aryl, heteroaryl, OH, SH, F, Cl, Br, I or NR′R″, where R′ and R″, independently of one another, are hydrogen, C
1
-C
12
-alkyl, C
3
-C
12
-cycloalkyl or aryl, R
2
to R
5
, independently of one another, are hydrogen, C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl, C
2
-C
12
-alkynyl, C
3
-C
12
-cycloalkyl, (C
1
-C
12
-)-alkoxy, (C
1
-C
12
)-acyloxy, O-phenyl, O-benzyl, aryl, heteroaryl, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, CN, SO
2
R or SOR, where R is hydrogen, C
1
-C
4
-alkyl, aryl, chlorine or fluorine, or are NH
2
, N(alkyl)
2
, N[Si(C
1
-C
4
-alkyl)
3]
2
, CF
3
, CCl
3
, COO-(C
1
-C
12
-alkyl), CO-(C
1
-C
12
-alkyl), CO-phenyl, COO-phenyl, CHCHCOO-(C
1
-C
2
-alkyl), PO-phenyl
2
, PO-(C
1
-C
8
-alkyl)
2
or PO
3
(C
1
-C
8
-alkyl)
2
, or R
2
and R
3
, and/or R
4
and R
5
, together form an aliphatic or aromatic ring,
wherein
a compound of the formula (V)
in which Z
5
is —COOH;
is reacted with a compound of the formula (X)
to give the compound of the formula (I′)
in which Z
1
is
and the compound of the formula (I′) is hydrolyzed to give the compound of the formula (I),
or the compound of the formula (V) is firstly reacted with hydrazine to give a compound of the formula (II)
in which Z
2
is —CONHNH
2
, and
the compound of the formula (II) is cyclized and hydrolyzed; where Q
1
and Q
2
are each a radical of the formula —O-(C
1
-C
12
)-alkyl, —O-(C
2
-C
12
)-alkenyl, —O-(C
2
-C
12
)-alkynyl, —O-aryl, —O-alkylaryl or —O—Si(C
1
-C
4
-alkyl)
3
; or Q
1
, Q
2
and the adjacent boron atom form a cyclic boronic ester with the following alcohols: (C
3
-C
12
)-cycloalkane-1,2-diol, (C
5
-C
12
)-cycloalkene-1,2-diol, (C
5
-C
12
)-cycloalkane-1,3-diol, (C
5
-C
12
)-cycloalkene-1,3-diol or with alcohols of the formulae (Ia) to (If)
in which R
1
a to R
8
a, independently of one another, are hydrogen, C
1
-C
12
-alkyl, C
1
-C
12
-hydroxyalkyl, C
2
-C
12
-alkenyl, C
2
-C
12
-alkynyl, C
3
-C
12
-cycloalkyl, (C
1
-C
12
)-alkoxy, (C
1
-C
12
)-acyloxy, O-phenyl, O-benzyl, aryl, heteroaryl, fluorine, chlorine, bromine, iodine, NO
2
, CN, SO
2
R, SOR, where R is as defined above, or are NH
2
, N(alkyl)
2
, N[Si(C
1
-C
4
-alkyl)
3
]
2
, CF
3
, CCl
3
, CBr
3
, COO-(C
1
-C
12
-alkyl), CO-(C
1
-C
12
-alkyl), CO-phenyl, COO-phenyl, CHCHCOO-(C
1
-C
12
-alkyl), PO-phenyl
2
, PO-(C
1
-C
8
-alkyl)
2
or PO
3
(C
1
-C
8
-alkyl), and/or two adjacent radicals R
1
a to R
8
a together form an aliphatic or aromatic ring, and in which n is an integer from 2 to 12, or in which Q
1
and Q
2
together form a divalent radical of the formula (Ig)
in which all radicals Z, in each case correspondingly, have one of the meanings of Z
1
to Z
5
.
In the above definitions, alkyl is preferably C
1
-C
4
-alkyl, aryl is preferably phenyl, alkylaryl is preferably benzyl, alkoxy is preferably C
1
-C
4
-alkoxy, and aclyoxy is preferably C
2
-C
4
-acyloxy.
Preferred radicals R
1
are hydrogen, C
1
-C
4
-alkyl, C
3
-C
6
-cycloalkyl, C
2
-C
4
-alkenyl, phenyl, NH
2
, OH, SH and C
1
-C
4
-alkoxy, in particular hydrogen, methyl, ethyl, phenyl and NH
2
.
Preferred radicals R
2
to R
5
are hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine and bromine.
Preferred radicals Q
1
and Q
2
are —O-(C
1
-C
6
)-alkyl, —O-(C
2
-C
6
)-alkenyl, —O-(C
3
-C
6
)-alkynyl, —O-phenyl, —O-benzyl, or Q
1
and Q
2
, together with the boron atom, form a cyclic boronic ester with the following alcohols: ethylene glycol, 1,3-propanediol, 1,4-butanediol, 2,2-dimethylpropane-1,3-diol, pyrocatechol, pinacol, 2,3-dihydroxynaphthalene, diethanolamine, triethanolamine, trishydroxy-methylphosphine, 1,2-dihydroxycyclohexane, 1,3-dihydroxycyclopentane or 1,2-dihydroxycyclooctane.
The compound of the formula (V) can be obtained in a known manner, for example by oxidation of 4-tolylboronic acid using potassium permanganate (U.S. Pat. No. 5,631,364) and esterification with alcohols on which the radicals Q
1
and Q
2
are based in an inert organic solvent, for example methanol, ethanol, xylene or toluene. Methanol and ethanol can be used as inert solvents if, for example, the esterification is to be carried out using a diol, since this reacts significantly more quickly than methanol or ethanol.
The compound of the formula (V) is reacted with a compound of the formula (X), preferably formylhydrazine, acetohydrazide, propionohydrazide, benzohydrazide or semicarbazide in the presence or absence of an organic solvent which is inert toward the reaction participants, such as N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl carbonate, sulpholane or dimethyl sulphoxide, and in the presence of an excess of a condensation agent, such as phosphorus oxychloride, phosphorus trichloride, polyphosphoric acid or acetic anhydride, at temperatures of from 50 to 250° C., preferably from 80 to 250° C., particularly preferably from 100 to 240° C.
The molar ratios between the compound of the formula (X) and the compound of the formula (V) are advantageously from 5:1 to 1:1 per carboxyl group in the compound of the formula (V).
The condensation agent is advantageously employed in a 1- to 5-fold molar excess per carboxyl group of the compound of the formula (V).
The resultant compound of the formula (I′) can, for example, be precipitated by pouring the reaction mixture into aqueous bicarbonate solution and isolated by recrystallization from a suitable solvent, such as, for example, tetrahydrofuran, methylene chloride, chloroform or toluene, or hydrolyzed to the compound of the formula (I) without isolation. The hydrolysis of a compound of the formula (I′) to the free boron acid can be carried out in the presence or absence of an organic solvent which is inert toward the reaction participants at temperatures of from 0 to 150° C., preferably from 5 to 100° C., particularly preferably from 20 to 80° C., by means of water or aqueous acids, such as, for example, aqueous ammonium chloride solution, dilute hydrochloric acid, dilute phosphoric acid, dilute sulphuric acid, dilute acetic acid, preferably with water or dilute acetic acid, heterogeneously, i.e. in the form of a suspension, or homogeneously by dissolving compounds of the formula (I′) in suitable organic solvents. Examples of solvents which are suitable for this purpose are methanol, ethanol, propanol, cyclic and acyclic ethers, such as tetrahydrofuran, diethyl ether, methyl isobutyl ether, methyl isobutyl ketone, methyl ethyl ketone, toluene, o-, m-, p-xylene, N,N-dimethylformamide, dimethylacetamide, N-methylpyrroli

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