Process for manufacturing substituted 5-methoxymethylpyridine-2,3-dicarboxylic acid derivatives

1. A process for manufacturing a compound of formula (I),

wherein

Z is H or halogen;

Z 1 is H, halogen, CN or NO 2 ;

Y is OM, and

M is an alkali metal or an alkaline earth metal, the process comprising

(i) reacting and methoxylating under pressure in a closed vessel at a temperature of from about 90° C. to 105° C. a compound of formula (II)

in a reaction mixture comprising methanol, water, a base, and the compound of formula (II), thereby forming the compound of formula (I);

wherein

Q is a tertiary aliphatic or cyclic, saturated, partially unsaturated or aromatic amine;

Z is H or halogen;

Z 1 is H, halogen, CN or NO 2 ;

Y 1 and Y 2 are each independently OR 1 , NR 1 R 2 , or when taken together Y 1 Y 2 is —O—, —S— or —NR 3 —;

R 1 and R 2 are each independently H, C 1- C 4 alkyl optionally substituted with C 1- C 4 alkoxy, or phenyl optionally substituted with one to three C 1- C 4 alkyl groups, C 1- C 4 alkoxy groups, or halogen atoms, or phenyl optionally substituted with one to three C 1- C 4 alkyl groups, C 1- C 4 alkoxy groups or halogen atoms;

R 3 is H or C 1- C 4 alkyl;

the water is present in the reaction mixture in the range of 30 to 70% by weight, based on the sum of the water and the compound of formula (II) in the reaction mixture;

the base comprises MOH and optionally MOCH 3 , where M is an alkali metal or an alkaline earth metal;

the molar ratio of total amount of the base added to the compound of formula (II) in the reaction mixture is 3-7:1;

the weight ratio of the methanol to the compound of formula (II) in the reaction mixture is in the range of from 1-10:1;

the molar ratio of MOCH 3 , if present, added to the compound of formula (II) in the reaction mixture is in the range of 1.25-7:1;

the molar ratio of MOH added to the compound of formula (II) in the reaction mixture is in the range of 1-5:1; and

the reaction time is in the range of from 6 to 20 h.

2. The process of claim 1 , further comprising:

(i-1) reacting a compound of formula (IV),

with bromine in the presence of a radical initiator in a solvent mixture comprising an aqueous phase and an organic phase, wherein the organic phase comprises a solvent selected from the group consisting of 1,2-dichloroethane, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene and tetrachloromethane, and where the pH-value of the aqueous phase is from 3 to <8,

to obtain a compound of formula (V),

and

(i-2) reacting the compound of formula (V) with a tertiary amine Q in a solvent at a temperature range of 0 to 100° C. to the compound of formula (II).

3. The process of claim 1 , wherein the compound of formula (II) is the compound (IIa)

4. The process of claim 1 , wherein the base comprises MOCH 3 and MOH.

5. The process of claim 4 wherein the molar ratio of MOCH 3 to the compound of formula (II) is in the range of from 1.25-2:1.

6. The process of claim 1 , wherein the reaction temperature is in the range of from about 90 to 100° C.

7. The process of claim 1 , which is carried out at a pressure of 1.01 to 5.00 bar.

8. The process of claim 1 , wherein, prior to reacting and methoxylating under pressure in the closed vessel at the temperature of from about 90° C. to 105° C., the process further comprises:

adding an aqueous MOH base to a mixture comprising the compound of formula (II), water, and methanol, thereby forming the reaction mixture.

9. The process of claim 1 , wherein, prior to reacting and methoxylating under pressure in the closed vessel at the temperature of from about 90° C. to 105° C., the process further comprises:

adding an aqueous MOH base to a mixture comprising the compound of formula (II), water, and methanol; and

adding an MOCH 3 base in methanol to the mixture to which the aqueous MOH base has been added, thereby forming the reaction mixture.

10. The process of claim 9 , comprising:

adding the aqueous MOH base at a temperature in a range from about 25° C. to 40° C.; and

adding the MOCH 3 base in methanol at a temperature in a range from about 40° C. to 50° C.

11. The process of claim 10 , wherein:

the MOH base is NaOH; and

the MOCH 3 base is NaOCH 3 .

12. A process for preparing a compound of formula (III),

wherein

Z is H or halogen;

Z 1 is H, halogen, CN or NO 2 ;

R 4 is C 1- C 4 alkyl;

R 5 is C 1- C 4 alkyl, C 3- C 6 cycloalkyl or R 4 and R 5 , when taken together with the atom to which they are attached, represent a C 3- C 6 cycloalkyl group optionally substituted with methyl, and

R 6 is hydrogen; a group of the formula —N═C (lower alkyl) 2 ; C 1- C 12 alkyl optionally substituted with one of the following groups: C 1- C 3 alkoxy, halogen, hydroxyl, C 3- C 6 -cycloalkyl, benzyloxy, furyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyl, lower alkoxycarbonyl, cyano or tri lower alkylammonium; C 3- C 12 alkenyl optionally substituted with one of the following groups:

C 1- C 3 alkoxy, phenyl, halogen or lower alkoxycarbonyl or with two C 1- C 3 alkoxy groups or two halogen groups; C 3- C 6 cycloalkyl optionally substituted with one or two C 1- C 3 alkyl groups; or

a cation;

comprising:

(i) preparing the compound of formula (I) according to claim 1 ;

(ii) converting the compound of formula (I) into the compound of formula (III).

13. The process of claim 12 , further comprising:

(i) preparing the compound (I), where Y is OH,

(ii-1) converting the compound (I) to the compound of formula (VI),

wherein

Z is H or halogen;

Z 1 is H, halogen, CN or NO 2 ;

(ii-2) reacting the compound of formula (VI) with a compound of formula (VII), H 2 N—CR 4 R 5 —CONH 2 (VII),

wherein

R 4 is C 1- C 4 alkyl;

R 5 is C 1- C 4 alkyl, C 3- C 6 cycloalkyl or R 4 and R 5 , when taken together with the atom to which they are attached, represent a C 3- C 6 cycloalkyl group optionally substituted with methyl,

to yield a compound of formula (VIII),

and

(ii-3) condensing the compound of formula (VIII) to yield the compound of formula (III).

14. The process of claim 12 , further comprising:

(i) preparing the compound (I), where Y is OH,

(ii-1) converting the compound of formula (I) to the compound of formula (VI),

(ii-2) reacting the compound of formula (VI) with a compound of formula (IX),

H 2 N—CR 4 R 5 —CN (IX);

to obtain a compound of formula (X),

(ii-3) hydrolyzing the compound of formula (X) to yield a compound of formula (VIII),

and

(ii-4) condensing the compound of formula (VIII) to yield the compound of formula (III).