Preparation of substituted 4-(N′-hydroxycarbamimidoyl)benzoic acids

Patent metadata

Field	Value
Publication number	US-12486221-B2
Application number	US-202117925873-A
Country	US
Kind code	B2
Filing date	May 20, 2021
Priority date	May 29, 2020
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

The present invention relates to a process for the preparation of substituted 4-(N′-hydroxy-carbamimidoyl)benzoic acids, which can be obtained by nitrilase catalyzed hydration of substituted terephthalonitriles of formula (II) in an aqueous medium to afford (ammonium) 4-cyanobenzoic acids (IIa). The hydration is followed by treatment of the aqueous reaction medium with hydroxylamine or a salt thereof to afford amidoximes (I).

First claim

The invention claimed is:

1 . A process for preparing amidoxime compounds of formula I,

wherein
R is halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, or C 1 -C 4 -haloalkoxy;
n is 0, 1 or 2;
the process comprising
i. providing an aqueous medium comprising water, one or more nitrilase, and a terephthalonitrile of formula II, wherein the variables n and R have the meaning as defined for compound of formula I;

ii. incubating the aqueous medium to obtain 4-cyanobenzoic acid of formula IIa or a salt thereof in an aqueous medium, wherein the variables n and R in 4-cyanobenzoic acid IIa have the meaning as defined for compound of formula 1;

iii. removal of biological material from the aqueous medium;
iv. treatment of the aqueous medium obtained in step iii with hydroxylamine or a salt thereof.

2 . The process according to claim 1 , wherein n is 0 in compounds of formulae I, II, and IIa.

3 . The process according to claim 1 , wherein the terephthalonitrile II is added to the aqueous medium before incubation in a concentration between 1% and 30% by weight.

4 . The process according to claim 1 , wherein the aqueous medium in process steps i and ii has a pH value of 4 to 9.

5 . The process according to claim 1 , wherein the aqueous medium in step ii is incubated at a temperature in the range of from 10° C. to 50° C.

6 . The process according to claim 1 , wherein 1 to 3 molar equivalents of hydroxylamine or a salt thereof are used in step iv, based on the amount of terephthalonitrile II.

7 . The process according to claim 1 , wherein the temperature in step iv is in a range of from 0° C. and 100° C.

8 . The process according to claim 1 , wherein the compound of formula I is isolated by filtration or centrifugation after step iv.

9 . The process according to claim 2 , further comprising reacting the compound of formula I to obtain a compound of formula III

10 . The process according to claim 9 , further comprising reacting the compound of formula III to obtain a compound of formula IV

11 . The process according to claim 10 , further comprising reacting the compound of formula III or IV with a compound of formula V,
R 1 —NH—R 2   V
wherein R 1 is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 11 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 2 -C 6 -alk-enyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxyimino-C 1 -C 4 -alkyl, C 2 -C 6 -alkenyloxyimino-C 1 -C 4 -alkyl, C 2 -C 6 -alkynyloxyimino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino, diC 1 -C 6 -alkylamino, —C(═O)—C 1 -C 6 -alkyl, —C(═O)—O—C 1 -C 6 -alkyl, phenyl-C 1 -C 4 -alkyl, phenyl-C 2 -C 4 -alkenyl, phenyl-C 2 -C 4 -alkynyl, heteroaryl-C 1 -C 4 -alkyl, phenyl, naphthyl, or a 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle contain besides carbon atoms further 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heteroaryl group in the group heteroaryl-C 1 -C 4 -alkyl is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocyclic ring contain besides carbon atoms 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different groups R 1a ; or R 1 and R 2 , together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle contains beside one nitrogen atom and one or more carbon atoms no further heteroatoms or 1, 2 or 3 further heteroatoms independently selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or up to the maximum possible number of identical or different groups R 1a ; wherein R 1a is halogen, oxo, cyano, NO 2 , OH, SH, NH 2 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 3 -C 8 -cycloalkyl, —NHSO 2 —C 1 -C 4 -alkyl, —(C═O)—C 1 -C 4 -alkyl, —C(═O)—O—C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonyl, hydroxyC 1 -C 4 -alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1 -C 4 -alkyl), C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl, aminoC 1 -C 4 -alkyl, C 1 -C 4 -alkylamino-C 1 -C 4 -alkyl, diC 1 -C 4 -alkylamino-C 1 -C 4 -alkyl, aminocarbonyl-C 1 -C 4 -alkyl, or C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl; R 2 is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, C 3 -C 11 -cycloalkyl, —C(═O) H, —C(═O)—C 1 -C 6 -alkyl, —C(═O)—C 3 -C 11 -cycloalkyl, or —C(═O)—O—C 1 -C 6 -alkyl; and wherein any of the aliphatic or cyclic groups in R 2 are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and C 3 -C 11 -cycloalkyl; to obtain a compound of formula VI

12 . The process according to claim 11 , further comprising reacting the compound of formula VI to obtain a compound of formula VII

13 . The process according to claim 12 , wherein in compounds of formula V, VI and VII
R 1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, OH, NH 2 , methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl; and R 2 is hydrogen, methyl, or ethyl.

14 . The process according to claim 12 , wherein in compounds of formula V, VI and VII
R 1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2,4-difluorophenyl; and R 2 is hydrogen.

Assignees

• Basf Se

Inventors

• Vogt Florian
• Borate Kailaskumar
• Wolf Bernd
• Gebhardt Joachim
• Garivet Guillaume Michel Jacques
• Shinde Harish
• Goetz Roland

Classifications

• C12P13/002

  Nitriles (-CN) · CPC title

• C07D271/06 Primary

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• C07C255/57

  containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton · CPC title

• C07C255/30

  containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton · CPC title

• C07C259/18 Primary

  having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings · CPC title