Process for Manufacturing Substituted 5-Methoxymethylpyridine-2,3-Dicarboxylic Acid Derivatives

Abstract

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

##STR00001##

Comprising reacting a compound of formula (II)

##STR00002##

in a methanol/H.sub.2O mixture. Compounds of formula (I) are useful intermediates in the synthesis of herbicidal imidazolinones, like imazamox.

Claims

1. (canceled)

2. A process for manufacturing a compound of formula (I), ##STR00021## wherein Z is H or halogen; Z.sup.1 is H, halogen, CN or NO.sub.2; Y is OM, and M is an alkali metal or an alkaline earth metal, comprising (i) reacting a compound of formula (II) ##STR00022## wherein Q is a tertiary aliphatic or cyclic, saturated, partially unsaturated or aromatic amine; Z is H or halogen; Z.sup.1 is H, halogen, CN or NO.sub.2; Y.sup.1 and Y.sup.2 are each independently OR.sup.1, NR.sup.1R.sup.2, or when taken together Y.sup.1Y.sup.2 is —O—, —S— or —NR.sup.3—; R.sup.1 and R.sup.2 are each independently H, C.sub.1-C.sub.4 alkyl optionally substituted with Ch.sub.1-C.sub.4 alkoxy, or phenyl optionally substituted with one to three C.sub.1-C.sub.4 alkyl groups, C.sub.1-C.sub.4 alkoxy groups, or halogen atoms, or phenyl optionally substituted with one to three C.sub.1-C.sub.4 alkyl groups, C.sub.1-C.sub.4 alkoxy groups or halogen atoms; and R.sup.3 is H or C.sub.1-C.sub.4 alkyl, in a methanol/H.sub.2O mixture, comprising at least 20% by weight H.sub.2O, based on the sum of water and the compound of formula (II), with a base comprising MOCH.sub.3 and/or MOH, where M is alkali metal or alkaline earth metal, and wherein the molar ratio of total amount of base added to the compound of formula (II) is 3-7:1, under pressure in a closed vessel at a temperature of from about 80 to 105° C.

3. The process of claim 2, further comprising: (i-1) reacting a compound of formula (IV), ##STR00023## 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), ##STR00024## 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), and (i-3) reacting the compound of formula (II) in a methanol/H.sub.2O mixture, with a base comprising MOCH.sub.3 and MOH, where M is alkali metal, under pressure in a closed vessel at a temperature of from about 80 to 105° C.

4. The process of claim 2, wherein the compound of formula (II) is the compound (IIa) ##STR00025##

5. The process of claim 2, wherein the ratio of methanol to compound of formula (II) is in the range of from 0.5-25:1.

6. The process of claim 2, wherein the base is a mixture of MeOM and MOH.

7. The process of claim 2, wherein the base is MeOM.

8. The process of claim 6 wherein the molar ratio of MeOM to compound of formula (II) is in the range of from 1-2:1.

9. The process of claim 7, wherein the molar ratio of MeOM to compound of formula (II) is in the range of from 3-5:1.

10. The process of claim 2, wherein the base is MOH.

11. The process of claim 6, wherein the molar ratio of MOH to compound of formula (II) is in the range of from 1-5:1.

12. The process of claim 10, wherein the molar ratio of MOH to compound of formula (II) is in the range of from 4-7:1.

13. The process of claim 2, wherein the reaction temperature is in the range of from about 80 to 100° C.

14. The process of claim 2, which is carried out at a pressure of 1.01 to 5.00 bar.

15. A process for preparing a compound of formula (III), ##STR00026## wherein Z is H or halogen; Z.sup.1 is H, halogen, CN or NO.sub.2; R.sup.4 is C.sub.1-C.sub.4 alkyl; R.sup.5 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl or R.sup.4 and R.sup.5, when taken together with the atom to which they are attached, represent a C.sub.3-C.sub.6 cycloalkyl group optionally substituted with methyl, and R.sup.6 is hydrogen; a group of the formula —N═C (lower alkyl).sub.2; C.sub.1-C.sub.12 alkyl optionally substituted with one of the following groups: C.sub.1-C.sub.3 alkoxy, halogen, hydroxyl, C.sub.3-C.sub.6-cycloalkyl, benzyloxy, furyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyl, lower alkoxycarbonyl, cyano or tri lower alkylammonium; C.sub.3-C.sub.12 alkenyl optionally substituted with one of the following groups: C.sub.1-C.sub.3 alkoxy, phenyl, halogen or lower alkoxycarbonyl or with two C.sub.1-C.sub.3 alkoxy groups or two halogen groups; C.sub.3-C.sub.6 cycloalkyl optionally substituted with one or two C.sub.1-C.sub.3 alkyl groups; or a cation; comprising: (i) preparing the compound of formula (I) according to claim 18; (ii) converting the compound of formula (I) into the compound of formula (III).

16. The process of claim 15, further comprising: (i) preparing the compound (I), where Y is OH, (ii-1) converting the compound (I) to the compound of formula (VI), ##STR00027## wherein Z is H or halogen; Z.sup.1 is H, halogen, CN or NO.sub.2; (ii-2) reacting the compound of formula (VI) with a compound of formula (VII),
H.sub.2N—CR.sup.4R.sup.5—CONH.sub.2   (VII), wherein R.sup.4 is C.sub.1-C.sub.4 alkyl; R.sup.5 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl or R.sup.4 and R.sup.5, when taken together with the atom to which they are attached, represent a C.sub.3-C.sub.6 cycloalkyl group optionally substituted with methyl, to yield a compound of formula (VIII), ##STR00028## and (ii-3) condensing the compound of formula (VIII) to yield the compound of formula (III).

17. The process of claim 15, 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), ##STR00029## (ii-2) reacting the compound of formula (VI) with a compound of formula (IX),
H.sub.2N—CR.sup.4R.sup.5—CN   (IX); to obtain a compound of formula (X), ##STR00030## (ii-3) hydrolyzing the compound of formula (X) to yield a compound of formula (VIII), ##STR00031## and (ii-4) condensing the compound of formula (VIII) to yield the compound of formula (III).

Description

EXAMPLES

Comparative Example 1

Preparation of 5-(methoxymethyl)-2,3-pyridinedicarboxylic acid (according to ex. 3 of EP-A 0 548 532)

[0127] ##STR00017##

[0128] A mixture of 25% sodium methoxide in methanol (270 g, 1.25 mol) and [(5,6-dicarboxy-3-pyridyl)-methyl]trimethylammonium bromide, dimethyl ester (Ia) (347 g, 1.00 mol) in methanol (650 ml) is heated at reflux for 1 hour under nitrogen. Water (1 l) and sodium hydroxide (80.0 g, 2.0 mol) are added and the reaction mixture is distilled until the pot is 100-105° C. The reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161-162° C.) which is greater than 99% pure by HPLC analysis.

[0129] No water is present in the first step of the reaction (methoxylation of the 5-methyl group), which requires a laborious drying or solid isolation process for the starting material. Thus the process is less suitable for industrial application.

Comparative Example 2

Preparation of disodium 5-(methoxymethyl)pyridine-2,3-dicarboxylate from disodium [5,6-(dicarboxylate-3-pyridyl)methyl]trimethylammonium bromide (according to ex. 3 of EP-A 0 747 360)

[0130] ##STR00018##

A mixture of disodium [(5,6-dicarboxylate-3-pyridyl)nethyl]trimethylammonium bromide (5.0 g, 13.8 mmol) and a 25% wt/wt solution of sodium methoxide in methanol (4.46 g, 20.7 mmol of NaOCH.sub.3) in 75 g of methanol is heated at 120° C. for 21 hours in a pressure reactor. The reaction is cooled to room temperature, treated with water and con-centrated to a final weight of 55.03 g. A 5.0 g sample is assayed by LC analysis (30% CH.sub.3CN, 0.77 M H.sub.3PO.sub.4). The remainder of the reaction solution is evaporated to dryness to give a solid residue, identified by NMR analysis.

[0131] In spite of the higher temperature the reaction time is considerably longer than in the inventive process.

Example 1

Preparation of 5-(methoxymethyl)-2,3-pyridinedicarboxylic acid

[0132] Bromide (IIa), (0.41 mol) containing about 40% by weight of water, is taken up in methanol. Aqueous NaOH is added over 30 min. at 35° C., and the mixture is stirred for an additional 15 min. NaOCH.sub.3 in methanol is added over 20 min at 45° C.

[0133] The reaction mixture is moved to a Parr pressure reactor and heated to the reaction temperature (80 to 100° C.). At about 60° C. the reactor is closed, whereupon pressure builds up reaching about 40 to 45 Psi at the reaction temperature. No external pressure is applied.

[0134] After 6 to 8 h, the mixture is cooled and work up is conducted according to known procedures.

[0135] E.g. the reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161 to 162° C.) which is greater than 99% pure by HPLC analysis.

[0136] In a similar fashion examples 2 to 17 shown in Table 1 were carried out.

TABLE-US-00001 TABLE 1 % H.sub.20 after molar molar weight temperature pressure addition of ratio ratio ratio reaction- conversion ex. [° C.] [bar] NaOH NaOMe NaOH MeOH time [h] [%] 2 100 2.76-3.45 48 3 0 3 8.75 99.6 3 100 2.76-3.45 42 5 0 3 8 98.4 4 100 2.76-3.45 61 5 0 3 8 95.2 5 90 1.38-2.07 48 5 0 5 8 91.9 6 80 1.03-1.38 48 5 0 3 8 81.8 7 100 2.76-3.45 55 2 3 5 8 87.5 8 100 2.76-3.45 56 1 4 5 8 92.4 9 100 2.76-3.45 43 1.5 4 5 8 99.7 10  100 2.76-3.45 43 2 4 5 8 100 11  100 2.76-3.45 51 1.5 3 5 8 100 12* 100 2.76-3.45 50 2 2.5 5 8 99.5 13* 100 2.76-3.45 51 1.5 1 6 8 80.0 14  100 2.76-3.45 42 1.5 3 3 5.5 85.0 15  100 2.76-3.45 40 1.5 3 3 6.75 94.0 16  100 2.76-3.45 40 1.5 3 3 8 99.8 17  100 2.76-3.45 37 1.5 3 2 8 99.9 *NaOH added to (II) before H.sub.2O removal under vacuum. MeOH added, then stripped (II), split in 2. NaOMe added just before Parr high temp/press run.

[0137] It can be seen that higher temperatures and longer reaction times improve the conversion rate. In addition, conversion is enhanced by a higher amount of base. The process of the invention can be carried out in the presence of large amounts of water as compared to the Comparative Examples.

Example 18

Synthesis of [(5,6-dicarboxy-3-pyridyl)methyl] trimethylammonium bromide, dimethylether (IIa)

a) Synthesis of dimethyl 5-(bromomethyl)-2,3-pyridinedicarboxylate (Va) (50% conversion)

[0138] ##STR00019##

218.4 g (1.0 mol) compound (Va) were dissolved in 1139.0 g 1,2-dichloroethane (EDC) and 160.0 g water were charged and heated to 72° C. (about 1-2° C. below reflux). 14.4 g (0.075 mol) 2,2′-azobis(2-methylbutyronitrile) (Vazo 67) in 160.0 g EDC were added over 2 h at 72° C. After 30 minutes 143.8 g (0.9 mol) bromine were added over 2 h, under pH control (pH 5-7) by dosage of about 375.0 g aqueous NaOH (15%). The mixture was stirred over 1 h for reaction completion (HPLC assay). After cooling to 40° C. the phases were separated.

b) Synthesis of Compound (IIa)

[0139] ##STR00020##

[0140] 288.1 g (1.0 mol) compound (IIIa) in mixture with di- and tribromination byproducts in 3359.0 g EDC (organic phase from step a, including unreacted compound (Ha) and higher brominated byproducts) were charged. The mixture was heated to 30° C. and the vessel evacuated to 200 mbar.

[0141] 70.9 g (1.2 mol) trimethylamine (TMA) was added to the gas phase during 2 h at 40° C. (closed system). The mixture was stirred one additional hour (HPLC con-version check: compound (IIIa) in solution <0.1%).

[0142] Excess TMA was distilled off together with EDC (mass: 40% of the EDC mass) transferred to step 2 (1344 g) at 50-55° C. (370-250 mbar). The pH of the distillate was <9. 630.0 g water was sprayed to the wall so that the solid is dissolved and the mixture was transferred to the next vessel. The mixture was then stirred 0.25 h, and the lower organic phase was separated at 40° C. 320.4 g EDC were added. The mixture was stirred and the lower organic phase was separated at 40° C. The back extraction was repeated (40° C.) with 320.4 g EDC. The two organic back extraction phases were combined with the first organic phase and re-cycled to the next bromination batch (after addition of 50% fresh compound (IIa) for a further cycle.

[0143] Steps a) and b) were repeated six times. In the last cycle no compound (IVa) was added in step a) and 0.8 mol TMA were added in step b).

[0144] The overall conversion rate of compound (IIa) is 96.6%. The yield of compound (IIa) (over 7 cycles) is 77.4% at a purity of >95% (as determined by HPLC).