Granted Patent B2

US 9,309,185 · App. 14/063,560 · Granted Apr 12, 2016

Abstract

Claims (40)

1. A process for the preparation of 2-methoxymethyl-1,4-benzenediamine (IV-a), other compounds of formula (IV), and the salts thereof comprising:

a. performing a carbonyl reduction of a compound of formula (I) to prepare a compound of formula (II);

b. performing an etherification of the compound of formula (II) to prepare a compound of formula (III); and

c. performing a hydrogenation of the compound of formula (III) to prepare a compound of formula (IV);

wherein R 1 , R 2 , and R 3 are substituents selected from the group consisting of:

i. C-linked substituents selected from the group consisting of:

a) alkyl groups;

b) aryl groups; and

c) substituents selected from the group consisting of COOA 1 , CONA 1 , CONA 1 COA 2 , C(=NA 1 )NA 1 A 2 , and CN;

wherein the C-linked substituents comprise from 1 to about 10 carbon atoms and from 0 to about 5 heteroatoms selected from the group consisting of O, F, Cl, N, P, Si, and combinations thereof;

ii. S-linked substituents selected from the group consisting of SA 1 , SO 2 A 1 , SO 3 A 1 , SSA 1 , SOA 1 , SO 2 NA 1 A 2 , SNA 1 A 2 , and SONA 1 A 2 ;

iii. O-linked substituents selected from the group consisting of OA 1 , ONA 1 A 2 ;

iv. N-linked substituents selected from the group consisting of NA 1 A 2 ; (NA 1 A 2 A 3 ) + , NA 1 SA 2 , NO 2 ;

v. halogens selected from the group consisting of F, Cl, Br, and I;

vi. hydrogen; and

vii. combinations thereof;

wherein A 1 , A 2 , and A 3 are alkyl groups comprising from 1 to about 10 carbon atoms and from 0 to about 5 heteroatoms selected from the group consisting of O, F, Cl, N, P, Si, and combinations thereof;

wherein R 5 is an alkyl group; and

wherein R 6 and R 7 are selected from the group consisting of hydrogen, alkyl groups, aminoalkyl groups, hydroxyalkyl groups, and combinations thereof, and further comprising inserting a nitro function into anthranilic acid or compounds thereof in the presence of a nitrating agent and a solvent to prepare the compound of formula (I):

2. The process according to claim 1 , wherein the carbonyl reduction of the compound of formula (I) into the compound of formula (II) is performed in the presence of a carbonyl reducing agent, a carbonyl reduction catalyst, and a solvent.

3. The process according to claim 2 , wherein the carbonyl reducing agent is selected from the group consisting of hydrazine, hydrazine hydrate, H 2 , LiAlH 4 , LiBH 4 , DIBAL-H, NaBH 4 , NaCNBH 3 , B 2 H 6 , BH 3 /THF, sodium hydrosulfite, sodium sulfide, and combinations of thereof.

4. The process according to claim 2 , wherein the carbonyl reduction catalyst is selected from the group consisting of nickel, palladium, Lindlar's catalyst, cobalt, copper chromite, platinium, platinum oxide, rhenium, tin(II) chloride, titanium(III) chloride, zinc, amarium, iron and combinations thereof.

5. The process according to claim 1 , wherein the etherification of the compound of formula (II) into the compound of formula (III) is performed by alkylation in the presence of an alkylating agent, a phase transfer catalyst, a solvent, and a base.

6. The process according to claim 5 , wherein the alkylating agent is selected from the group consisting of methanol, (C 1 -C 4 )—I, (C 1 -C 4 )—Br, (C 1 -C 4 )—Cl, Me 2 SO 4 , and combinations thereof.

7. The process according to claim 5 , wherein the phase transfer catalyst is selected from the group consisting of tetrapentylammonium bromide, tetraoctylammonium chloride, tetraoctylammonium bromide, tetrahexylammonium iodide, tetrahexylammonium chloride, tetrahexylammonium bromide, tetraheptylammonium bromide, tetraethylammonium tetrafluoroborate, tetraethylammonium chloride, tetraethylammonium bromide, tetradodecylammonium tetrafluoroborate, tetradodecylammonium chloride, tetradodecylammonium bromide, tetradecyl-trimethylammonium chloride, benzyltriethyl ammonium chloride, phenyl-trimethylammonium bromide, octyl-trimethylammonium bromide, octadecyl-trimethylammonium chloride, octadecyl-trimethylammonium bromide, methyl-trioctylammonium iodide, and combinations thereof.

8. The process according to claim 5 , wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, aluminum hydroxide, ferrous hydroxide, ferric hydroxide, zinc hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, and combinations thereof.

9. The process according to claim 1 , wherein the etherification of the compound of formula (II) into the compound of formula (III) is performed by a condensation reaction in the presence of a condensation catalyst and a solvent.

10. The process according to claim 9 , wherein the condensation catalyst is selected from the group consisting of mineral acids, Lewis Acids, aluminum chloride, titanium tetra-isopropoxide, and combinations thereof.

11. The process according to claim 1 , wherein the hydrogenation of the compound of formula (III) into the compound of formula (IV) is performed in the presence of hydrogen, a hydrogenation catalyst, and a solvent.

12. The process according to claim 11 , wherein the hydrogenation catalyst is selected from the group consisting of, nickel, palladium, Lindlar's catalyst, cobalt, copper chromite, platinium, platinum oxide, rhenium, tin(II) chloride, titanium(III) chloride, zinc, samarium, iron and combinations thereof.

13. The process according to claim 1 further comprising transforming the compound of formula (IV) into the salt of formula (V) in the presence of mHZ and a solvent:

14. The process according to claim 13 , wherein HZ is selected from the group consisting of D,L-malic acid, L-malic acid, D-malic acid, hydrochloric acid, hydrobromic acid, citric acid, acetic acid, lactic acid, succinic acid, tartaric acid, sulfuric acid, and combinations thereof; and wherein m =1.

15. The process according to claim 1 , wherein the carbonyl reduction, then etherification, and then hydrogenation are performed successively.

16. The process according to claim 1 comprising:

a. reducing a carbonyl group of 5-nitroanthranilic acid (I-a) to prepare 2-amino-5-nitrobenzyl alcohol (II-a):

b. performing the etherification of 2-amino-5-nitrobenzyl alcohol (II-a) to prepare 2-methoxymethyl-4-nitroaniline (III-a):

 and

c. hydrogenating 2-methoxymethyl-4-nitroaniline (III-a) to prepare 2-methoxymethyl -[1,41]-benzenediamine (IV-a):

17. The process according to claim 16 , wherein reducing the carbonyl group is performed at a temperature from about 50 ° C. to about 80 ° C.

18. The process according to claim 17 , wherein the etherification is performed by phase transfer alkylation.

Assignments (8)