Production of N-substituted aromatic hydroxylamine

Abstract

An economic, one-step method for the production of N-substituted aromatic hydroxylamines of formula (I)
R—N(OH)—C(═O)—(O)R.sub.1  (I),
with hydrogen, by catalytic hydration with possibly modified hydration catalysts in an aprotic solvent and in the presence of a halogen formic acid ester and in some cases in the presence of a base.

Claims

1. Method for production of N-substituted aromatic hydroxylamines of formula I:
R—N(OH)—C(═O)—(O)R.sub.1  (I), by a single process step of hydration of aromatic nitrogen compounds of formula II
R—NO.sub.2  (II), with a hydration catalyst and hydrogen in an aprotic solvent, characterised in that the reaction is performed in the presence of at least stoichiometric quantities of a compound of formula III
Y—C(═O)—(O)R.sub.1  (III), wherein R is an aromatic residue, R.sub.1 a hydrocarbon residue and Y is halogen.

2. Method according to claim 1, characterised in that the group R comprises aromatic hydrocarbons or heteroaromatics, or condensed or linked ring systems, and the group R is unsubstituted or substituted.

3. Method according to claim 1, characterised in that R.sub.1 stands for linear or branched C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.8-cycloalkyl, benzyl or phenyl.

4. Method according to claim 1, characterised in that the compounds of formula III are C.sub.1-C.sub.4-alkyl-O—CO—Cl.

5. Method according to claim 1, characterised in that the compounds of formula III are chloroformic acid methylester.

6. Method according to claim 1, characterised in that it is performed in the presence of an inert aprotic and apolar or polar solvent.

7. Method according to claim 1, characterised in that water is added to the reaction mixture.

8. Method according to claim 1, characterised in that the catalyst is a platinum catalyst.

9. Method according to claim 1, characterised in that the noble metal catalysts are used in quantities of 0.1 to 10% by weight relative to the substrate.

10. Method according to claim 1, characterised in that modifiers are added to the catalyst or to the reaction mixture.

11. Method according to claim 10, characterised in that tertiary amines, phosphorus compounds or sulphur compounds or mixtures thereof are added as modifiers.

12. Method according to claim 11, characterised in that the phosphorus compounds are selected from the group of phosphines, phosphine oxides and phosphoric acids.

13. Method according to claim 12, characterised in that the phosphorus compound is hypophosphoric acid H.sub.3PO.sub.2.

14. Method according to claim 11, characterised in that the sulphur compounds are selected from the group sulphides, thiols, thioethers, sulphoxides, thioureas and aromatic sulphur compounds.

15. Method according to claim 12, characterised in that the sulphur compound is dimethyl sulphoxide.

16. Method according to claim 1, characterised in that as a catalyst, platinum on carbon (Pt/C) is used in combination with dimethyl sulphoxide and/or hypophosphoric acid H.sub.3PO.sub.2.

17. Method according to claim 13, characterised in that the hypophosphoric acid or its derivative is used in the ratio of modifier to catalyst of 0.01-20 to 1 part by weight, preferably 0.1-5 to 1 catalyst part by weight.

18. Method according to claim 15, characterised in that dimethyl sulphoxide is used in the ratio of 0.1-20 to 1 part by weight, preferably 1-6 to 1 catalyst part by weight.

19. Method according to claim 1, characterised in that a compound of formula A ##STR00004## is produced by catalytic hydration of the corresponding nitrogen compound of formula B ##STR00005## with hydrogen in the presence of a noble metal or base metal catalyst in an inert solvent and in the presence of an inorganic base, characterised in that it is performed in the presence of at least stoichiometric quantities of chloroformic acid methylester of the formula methyl-O—C(═O)—Cl.

20. Method according to claim 1, characterised in that N-methyl-hydroxy-(phenyl) carbamate is produced by hydration of 2-nitrobenzene nitrobenzene with hydrogen in the presence of a noble metal or base metal catalyst in an inert solvent and in the presence of an inorganic base, characterised in that it is performed in the presence of at least stoichiometric quantities of chloroformic acid methylester.

Description

Example 1: Production of Methyl Hydroxy(Phenyl) Carbamate

(1) 50 mg 5% Pt-carbon catalyst is placed in a glass vessel with 15 mg 50% watery hypophosphoric acid and 1 ml deionised water, and agitated for 10 minutes.

(2) In a Parr® glass flask, 1.04 g nitrobenzene is placed in 30 ml cyclopentyl methylether, and 1.68 g (1.4 equivalent) disodium hydrogen phosphate and 1.04 g (1.3 equivalent) chloroformic acid methylester added. The catalyst suspension is then rinsed with 4 ml deionised water in the Parr® glass flask, and hydrated for 3 hours at a temperature of 22° C. and a hydrogen pressure of 4 bar. After rendering the apparatus inert with nitrogen, 1 ml methanol is added and agitated for 15 minutes to destroy the surplus chloroformic acid methylester. Then the solids are filtered out and washed with 20 ml cyclopentyl methylether. The filtrate is dried over sodium sulphate and evaporated in a vacuum at 60° C. This produces 1.43 g (101% of theoretically possible) methyl hydroxy(phenyl) carbamate with a purity of 91.7% (yield 92.6%), which still contains 8.3% methyl phenyl carbamate (determined by HPLC (220 nm)).

Example 2: Production of Methyl (2-(((1-(4-Chlorophenyl)-1H-Pyrazol-3-Yl)Oxy)Methyl)Phenyl)(Hydroxy) Carbamate

(3) 83 mg 5% Pt-carbon catalyst is placed in a glass vessel with 164 mg 50% watery hypophosphoric acid and 1 ml deionised water and agitated for 10 minutes.

(4) 1.65 g 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyrazol is placed in 30 ml cyclopentylmethylether in a Parr® glass flask, and 0.994 g (1.4 equivalent) disodium hydrogen phosphate and 0.614 g (1.3 equivalent) chloroformic acid methylester are added. The catalyst suspension is then rinsed with 4 ml deionised water in the Parr® glass flask and hydrated for 7 hours at a temperature of 22° C. and a hydrogen pressure of 4 bar. After rendering the apparatus inert with nitrogen, 1 ml methanol is added and agitated for 15 minutes in order to destroy the surplus chloroformic acid methylester. Then the solids are filtered out and washed with 20 ml cyclopentyl methylether. The filtrate is dried over sodium sulphate and evaporated in a vacuum at <1 mbar and 60° C. This gives 1.80 g beige solid consisting of methyl (2-(((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)methyl)phenyl)(hydroxy) carbamate with a purity of 97% according to HPLC (220 nm), which according to HPLC and LC-MS still contains 3% methyl (2-(((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)methyl)phenyl) carbamate. This represents a yield of 93% of the theoretically possible.

Example 3: Production of Methyl (2-(((1-(4-Chlorophenyl)-1H-Pyrazol-3-Yl)Oxy)Methyl)Phenyl)(Hydroxy) Carbamate

(5) 1086 mg 5% Pt-carbon catalyst (water content: 54%) is placed in a glass vessel with 3 ml deionised water and 550 mg 50% watery hypophosphoric acid, and agitated for 10 minutes.

(6) In a 100 ml agitation autoclave, 10.00 g 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyrazol is placed in 50 ml 2-methyl tetrahydrofuran, and 6.03 g (1.4 equivalent) disodium hydrogen phosphate and 3.73 g (1.3 equivalent) chloroformic acid methylester are added. The catalyst suspension is then rinsed with 2 ml deionised water in the autoclave and hydrated at a temperature of 21° C. and a hydrogen pressure of 7 bar. After 1.5 hours, the hydrogen absorption stops. After rendering the apparatus inert with nitrogen, 1 ml methanol is added and agitated for 20 minutes in order to destroy the surplus chloroformic acid methylester. The reaction mixture is then rinsed with 20 ml 2-MeTHF and 5 ml water from the autoclave, and the catalyst filtered out. The watery phase is separated in the separation funnel. The organic phase is washed with 3 ml water and, after separation of the watery phase, dried over sodium sulphate, filtered and evaporated in the rotary evaporator at 60° C. The residue is dried for 1 hour at 80° C./<1 mbar. 11.06 g beige solid is isolated with a purity of 98.4% according to HPLC (254 nm), corresponding to a yield of 96%. The solid is dissolved in 40 ml 2-methyl tetrahydrofuran at 60° C., 30 ml of this is then distilled off and the resulting solution cooled under agitation to 15° C. After 30 minutes' agitation, the resulting crystals are filtered under suction and washed with 10 ml cold 2-MeTHF. This gives 9.46 g re-crystallised methyl (2-(((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)methyl)phenyl)(hydroxy) carbamate with a purity of 100% according to HPLC (220 nm and 254 nm). The parent lye is evaporated and the residue dried for one hour at 80° C./<1 mbar. This gives 1.54 g of a reddish solid which, according to HPLC (220 nm), contains 86.8% methyl (2-(((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)methyl)phenyl)(hydroxy) carbamate and 9.8% methyl (2-(((1-(4-chlorophenyl)-1H-pyrazol-3-yl)oxy)methyl)phenyl) carbamate.

Example 4: Production of Methyl Hydroxy(O-Tolyl) Carbamate

(7) 38 mg 5% Pt-carbon catalyst (water content: 54%) is placed in a 22 ml glass vial with 0.7 ml deionised water and 19 mg 50%, watery hypophosphoric acid and agitated for 10 minutes. Then 3.4 ml tetrahydrofuran, 343 mg 2-nitrotoluene, 497 mg disodium hydrogen phosphate and 307 mg methyl chloroformate were added. After flushing with argon and hydrogen, the mixture is agitated for 7 hours under 6 bar hydrogen at 25° C. The organic phase is then analysed by means of HPLC and LC-MS. this shows 90% methyl hydroxy(o-tolyl) carbamate and 7% methyl (o-tolyl) carbamate, and 3% of an unknown secondary product (area %, UV 220 nm).

Examples 5-11: Production of Methyl Hydroxy(O-Tolyl) Carbamat

(8) In the same way as example 4, various solvents were tested.

(9) The table below shows the results of the HPLC analysis (area % at 220 nm) of the organic phase.

(10) TABLE-US-00001 Ratio of methyl hydroxy(o-tolyl) Methyl carbamate to Exam- Conver- hydroxy(o-tolyl) methyl (o-tolyl) ple Solvent sion carbamate carbamate 4 THF 100% 90 93/7  5 2-MeTHF 100% 85 87/13 6 cyclopentyl 100% 76 79/21 methylether 7 tert-butyl 100% 73 76/24 methylether 8 iso- 100% 66 78/22 propylacetate 9 chlorobenzene  92% 19 63/37 10 2-butanone 100% 48 14/86 11 acetone  80% 38  6/94

Example 6: Production of Methyl (2-(((1-(4-Chlorophenyl)-1H-Pyrazol-3-Yl)Oxy)Methyl)Phenyl)(Hydroxy) Carbamate

(11) 545 mg 5% Pt-carbon catalyst (water content: 58%) are placed in a glass vessel with 3 ml deionised water and 550 mg 50% watery hypophosphoric acid, and agitated for 10 minutes.

(12) In a 100 ml agitation autoclave, 10.00 g 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyrazol is placed in 30 ml dimethyl carbonate, and 6.03 g (1.4 equivalent) disodium hydrogen phosphate and 3.73 g (1.3 equivalent) chloroformic acid methylester added. The catalyst suspension is then rinsed with 2 ml deionised water in the autoclave and hydrated at a temperature of 15-20° C. and a hydrogen pressure of 15 bar. After 5 hours, the hydrogen absorption stops. After rendering the apparatus inert with nitrogen, 1 ml methanol and 30 ml dimethyl carbonate are added and agitated for 20 minutes in order to destroy the surplus chloroformic acid methylester. It is then heated to 80° C. to ensure that all product has dissolved. It is then cooled to 55° C. and the reaction mixture is rinsed with 20 ml dimethyl carbonate and 5 ml water from the autoclave, and the catalyst filtered off. The watery phase is separated in the separation funnel. The organic phase is washed with 3 ml water and, after separation of the watery phase, dried over sodium sulphate, filtered and evaporated in the rotary evaporator at 60° C. The residue is dried for one hour at 80° C./<1 mbar. 11.06 g beige solid is isolated with a purity of 95% according to HPLC (220 nm and 254 nm), corresponding to a yield of 93%.

Example 7: Production of Methyl Hydroxy(3-(2-Methyl-2H-Tetrazol-5-Yl)Phenyl) Carbamate

(13) 83 mg 5% Pt-carbon catalyst (water content: 58%) are placed in a glass vessel with 164 mg 50% watery hypophosphoric acid and 1 ml deionised water, and agitated for 10 minutes.

(14) 1.25 g 2-methyl-5-(3-nitrophenyl)-2H-tetrazole is placed in a Parr® glass flask with 12.5 ml 2-methyl tetrahydrofuran, and 1.15 g (1.4 equivalent) disodium hydrogen phosphate and 0.71 g (1.3 equivalent) chloroformic acid methylester are added. The catalyst suspension is then rinsed with 4 ml deionised water in the Parr® glass flask and hydrated at a temperature of 15° C. and a hydrogen pressure of 4 bar. After 15 minutes, the hydration stops. After rendering the apparatus inert with nitrogen, 0.5 ml methanol is added and agitated for 15 minutes to destroy the surplus chloroformic acid methylester. Then the solids are filtered off and washed with 20 ml 2-methyl tetrahydrofuran. After phase separation, the organic phase is dried over sodium sulphate and evaporated in a vacuum at <1 mbar and 60° C. This gives 1.46 g beige solid consisting of methyl hydroxy(3-(2-methyl-2H-tetrazol-5-yl)phenyl) carbamate (according to LC-MS) with a purity of 98% according to HPLC (220 nm), corresponding to a yield of 98% of the theoretically possible.

Example 8: Production of Benzyl Hydroxy(O-Tolyl) Carbamate

(15) 70 mg 5% Pt-carbon catalyst (water content: 58%) is placed in a 22 ml glass vial with 1 ml deionised water and 35 mg 50% watery hypophosphoric acid, and agitated for 10 minutes. Then 10 ml tetrahydrofuran, 823 mg 2-nitrotoluene, 1.19 g disodium hydrogen phosphate and 1.4 g benzyl chloroformate are added. After flushing with argon and hydrogen, the mixture is shaken for 5 hours at 5 bar hydrogen at 15° C. After rendering the apparatus inert with nitrogen, 0.5 ml methanol is added and agitated for 15 minutes in order to destroy the surplus chloroformic acid benzylester. Then the solids are filtered off and washed with 10 ml 2-tetrahydrofuran. After phase separation, the organic phase is dried over sodium sulphate and evaporated in a vacuum at <1 mbar and 60° C. This gives 1.57 g light beige oil consisting of benzyl hydroxy(o-tolyl) carbamate (according to LC-MS), with a purity of 86% according to HPLC (220 nm), corresponding to a yield of 87% of the theoretically possible.