PROCESS TO PREPARE 3-METHYL-2-NITROBENZOIC ACID BY AIR OXIDATION

Abstract

A method for preparing 3-methyl-2-nitrobenzoic acid is disclosed wherein 1,3-dimethyl-2-nitrobenzene is combined with an oxidation catalayst in the presence of an oxygen source and an initiator, provided that less than 99% of the 1,3-dimethyl-2-nitrobenzene is oxidized.

A method for preparing compounds of Formula 7 and Formula 11 is also disclosed wherein the method is characterized by using 3-methyl-2-nitrobenzoic acid as prepared by the method disclosed above.

##STR00001##

wherein R.sup.1 is C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.4-C.sub.7 alkylcycloalkyl

Claims

1. A method for preparing a compound of Formula 7 ##STR00044## wherein R.sup.1 is C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.4-C.sub.7 alkylcycloalkyl; comprising (A) contacting a compound of Formula 2 ##STR00045## with a reducing agent to form a compound of Formula 3 ##STR00046## (B) contacting the compound of Formula 3 with R.sup.2OC(O)Cl to form a compound of Formula 4 ##STR00047## wherein R.sup.2 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 alkenyl, each optionally substituted with up to 3 halogen and up to 1 phenyl; (C) contacting the compound of Formula 4 with a chlorinating agent to form a compound of Formula 5 ##STR00048## (D) contacting the compound of Formula 5 with a cyclizing agent to form a compound of Formula 6 ##STR00049## (E) contacting the compound of Formula 6 with R.sup.1NH.sub.2 to form the compound of Formula 7; characterized by using the compound of Formula 2 as prepared by a method comprising, contacting a compound of Formula 1 ##STR00050## with an oxidation catalyst in the presence of an oxygen source and an initiator, provided that less than 99% of a compound of Formula 1 is oxidized.

2. The method of claim 1 wherein R.sup.1 is C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl.

3. The method of claim 2 wherein R.sup.1 is methyl, isopropyl, cyclopropyl or t-butyl.

4. The method of claim 3 wherein R.sup.1 is methyl or t-butyl.

5. The method of claim 1 wherein R.sup.2 is C.sub.1-C.sub.4 alkyl.

6. The method of claim 5 wherein R.sup.2 is methyl or ethyl.

7. The method of claim 6 wherein R.sup.2 is ethyl.

8. The method of claim 1 wherein the cyclizing agent is PBr.sub.3.

9. The method of claim 1 wherein the chlorinating agent is HCl and H.sub.2O.sub.2.

10. A method for preparing a compound of Formula 11 ##STR00051## wherein R.sup.1 is C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.6 cycloalkyl or C.sub.4-C.sub.7 alkylcycloalkyl; comprising (A) contacting a compound of Formula 2 ##STR00052## with an activating agent and R.sup.1NH.sub.2 to form a compound of Formula 8; ##STR00053## (B) contacting the compound of Formula 8 with a reducing agent to form a compound of Formula 9 ##STR00054## (C) contacting the compound of Formula 9 with a brominating agent to form a compound of Formula 10 ##STR00055## (D) contacting the compound of Formula 10 with a cyanating agent to form the compound of Formula 11; characterized by using the compound of Formula 2 as prepared by a method comprising, contacting a compound of Formula 1 ##STR00056## with an oxidation catalyst in the presence of an oxygen source and an initiator, provided that less than 99% of a compound of Formula 1 is oxidized.

11. The method of claim 10 wherein R.sup.1 is C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl.

12. The method of claim 11 wherein R.sup.1 is methyl, isopropyl, cyclopropyl or t-butyl.

13. The method of claim 12 wherein R.sup.1 is methyl or t-butyl.

14. The method of claim 13 wherein R.sup.1 is methyl.

15. The method of claim 14 wherein R.sup.1 is t-butyl.

Description

EXAMPLES 1 - 9

Synthesis of 3-methyl-2-nitrobenzoic acid (2) (Runs with 5-50% Loading of 1,3-dimethyl-2-nitrobenzene(1))

[0371] A one liter Hastelloy C-276 pressure reactor was used for oxidation studies using air as the oxygen source. The nitrogen and air supply lines to the reactor were equipped with mass flow meters and valves to control the gas addition rates. The vent line from the reactor was equipped with a valve connected to a pressure transducer for reactor pressure control. The reactor was heated and cooled using an oil system that circulated through the reactor jacket and an internal heat exchange coil. The reactor was also equipped with a mechanical agitator for reaction mixture stirring at 800 rpm. The air was supplied sub-surface into the reaction mixture. The acetaldehyde was supplied sub-surface into the reaction mixture.

[0372] In each example, a mixture of cobalt(II) acetate tetrahydrate, 1,3-dimethyl-2-nitrobenzene (compound of Formula 1) and water in acetic acid was prepared and the mixture was added to the pressure reactor. The reactor was sealed, purged with nitrogen and the contents stirred. The reactor was then pressurized with nitrogen to 500 psig (3450 kPa) and heated. As the internal temperature of the reactor approached 100 C., the nitrogen supply was stopped and air was fed at a rate of 2 SLPM (standard liters per minute). Acetaldehyde was then fed to the reactor from a syringe pump at a rate of 40 mL/h. The reaction was strongly exothermic and the reactor jacket temperature was adjusted to maintain the reaction mixture at 100 C.

[0373] After addition of each 40 mL aliquot of acetaldehyde, the acetaldehyde and air feeds were temporally stopped and the reactor fed with nitrogen. A sample of the reaction mixture, while still under pressure, was then taken via a reactor sub-surface dip-tube. The nitrogen feed was then stopped and the air and acetaldehyde restarted at the target rates.

[0374] After the desired total amount of acetaldehyde was added, acetaldehyde and air feeds were stopped and the reactor purged was with nitrogen. A final sample of the reaction mixture was then collected and the reactor depressurized. The reaction mixture was discharged (while still at about the reaction temperature) from the bottom of the reactor to a product collection vessel.

[0375] After allowing the reaction mixture to cool to room temperature (with optional concentration using a rotary evaporator) the 3-methyl-2-nitrobenzoic acid (compound of Formula 2) and 2-nitro-1,3-benzenedicarboxylic acid (compound of Formula 13) oxidation products were separated as crude solids by filtration. The reaction conditions for Examples 1-9 are shown below in Table 1A, along with the total reaction times. The initial reaction mixture concentrations of the compound of Formula 1 were varied form about 5 to 50 wt % in the examples. The selectivity to the compound of Formula 2 was calculated by [(moles 3-methyl-2-nitrobenzoic acid (2) formed)/(moles 1,3-dimethyl-2-nitrobenzene (1) converted)]. Conversion and selectivities at specific times for Examples 1-9 are shown in Table 1B.

TABLE-US-00002 TABLE 1A Material Loads and Rates of Addition for Examples 1 through 9 Ex. 1 2 3 4 5 6 7 8 9 Material 1,3-dimethyl-2-nitrobenzene (1) (g) 20 20 40 80 120 172 150 200 250 Cobalt(II) acetate tetrahydrate (g) 5 5 5 5 5 5 5 5 5 Water (g) 2 2 2 2 2 2 2 2 2 Acetic acid (g) 400 400 400 400 400 400 348 298 248 Acetaldehyde Rate (mL/h) 40 40 40 40 40 40 40 40 40 Air Flow Rate (SLPM) 2 2 2 2 2 2 2 2 2 Run Time (h) 4 6 4 4 2.7 2.7 4 4 4 Initial wt % 1,3-dimethyl-2- 4.8 4.8 9.1 16.7 23.1 30.1 30.1 40.2 50.2 nitrobenzene (1) in acetic acid

TABLE-US-00003 TABLE 1B Conversions and Selectivities at Specific Times for Examples 1-9 Ex. 1 2 3 Time (h) 1 2 3 4 1 2 3 4 5 6 1 2 3 4 Calc'd Conv. of (1) (%) 80.8 96.4 98.9 99.5 87.3 96.8 98.9 99.6 99.6 99.7 60.2 80.9 92.9 96.3 Calc'd Select. to (2) (%) 74 44 28 22 71 45 31 22 19 15 79 68 59 51 Ex. 4 5 6 Time (h) 1 2 3 4 1 2 2.7 1 2 2.7 Calc'd Conv. of (1) (%) 36.5 58.8 76.1 84.6 19.8 39.1 54.5 17.5 32.0 42.6 Calc'd Select. to (2) (%) 83 82 76 71 86 86 84 85 87 86 Ex. 7 8 9 Time (h) 1 2 3 4 1 2 3 4 1 2 3 4 Calc'd Conv. of (1) (%) 16.9 31.1 40.9 52.7 9.5 18.1 29.1 36.9 7.8 15.3 23.4 31.6 Calc'd Select. to (2) (%) 77 79 81 83 67 81 83 83 71 80 84 86
It was observed that the selectivity for 3-methyl-2-nitrobenzoic acid (the compound of Formula 2) was maximized above 70% between about 10 to 85% conversion of 1,3-dimethyl-2-nitrobenzene (1).

EXAMPLES 10 and 11

Synthesis of 3-methyl-2-nitrobenzoic acid (2)

[0376] Two oxidation experiments with 1,3-dimethyl-2-nitrobenzene (1) were completed in the pressure reactor under reaction conditions similar to those described for Examples 1-9. The specific conditions for each run are provided in Table 2A. In these runs, the reaction times were 5.5 h (Example 10) and 6.5 h (Example 11). Samples of the reaction mixture were collected immediately at the end of the oxidations and analyzed by GC. Table 2B provides the calculated 1,3-dimethyl-2-nitrobenzene (1) conversions and selectivities to 3-methyl-2-nitrobenzoic acid (2) for Examples 10 and 11 based on the GC analysis. In both cases, the 1,3-dimethyl-2-nitrobenzene (1) conversions exceeded 65%. Based on the conversion and selectivity for Example 10, the calculated mass of 3-methyl-2-nitrobenzoic acid (2) in the reaction mixture was about 103 g. Based on the conversion and selectivity for Example 11, the calculated mass of 3-methyl-2-nitrobenzoic acid (2) in the reaction mixture was about 110 g.

TABLE-US-00004 TABLE 2A Material Loads and Rates of Addition for Examples 10 and 11 Ex. 10 Ex. 11 1,3-dimethyl-2-nitrobenzene (1) (g) 150 150 Cobalt(II) acetate tetrahydrate (g) 5 5 Water (g) 2 2 Acetic acid (g) 348 348 Acetaldehyde Rate (mL/h) 40 40 Air Flow Rate (SLPM) 2 2 Run Time (h) 5.5 6.5 Reaction Temperature ( C.) 100 100 Agitator Speed (rpm) 800 800 Reactor pressure (N/m.sup.2) 3.45e+006 3.45e+006

TABLE-US-00005 TABLE 2B 1,3-Dimethyl-2-nitrobenzene (1) Conversions and 3-Methyl-2-nitrobenzoic acid (2) Selectivities for Examples 10 and 11, Based on GC analysis Conv. of 1,3-dimethyl-2- Select. to 3-methyl-2- nitrobenzene (1) (mole %) nitrobenzoic acid (2) (%) Ex. 10 69.4 81.6 Ex. 11 77.2 78.8

[0377] The oxidation product for Example 10 was collected and concentrated using a laboratory rotary evaporator apparatus at 70 C. and 30 mbar (3.0 kPa). After cooling to room temperature, the concentrate was slurried in 130 g of a 65 wt % acetic acid in water solution and then vacuum filtered using a coarse porosity glass Bchner filter funnel. The collected solid was then washed with a 65 wt % acetic acid in water solution (162 g), a 50 wt % acetic acid in water solution (155 g) and water (148 g). After air drying over several days, the mass of the dry solid was found to be 90.4 g. The crude solid had a composition of about 1% 1,3-dimethyl-2-nitrobenzene (1), 89.9% 3-methyl-2-nitrobenzoic acid (2) and 8.4% 2-nitro-1,3-benzenedicarboxylic acid (13) by GC analysis. The crude solid was combined with acetic acid (132.7 g), water (71.5 g) and sodium hydroxide (2.9 g) in a glass kettle. The mixture was heated to a gentle reflux (about 105 C.) for about 15 min during which time much of the solid dissolved. The mixture was then allowed to cool to room temperature. The solid that crystallized was isolated by vacuum filtration using a coarse porosity glass Bchner filter funnel. The solid was then washed with a 25 wt % acetic acid in water solution (80 g) and water (80 g). After air drying the mass of the dry solid was found to be 67.3 g. The recrystallized solid had a composition of about 0.13% 1,3-dimethyl-2-nitrobenzene (1), 99% 3-methyl-2-nitrobenzoic acid (2) and 0.72% 2-nitro-1,3-benzenedicarboxylic acid (13) by GC analysis. The calculated isolated mole yield of recrystallized 3-methyl-2-nitrobenzoic acid (2) was 37% for Example 10 based on the 1,3-dimethyl-2-nitrobenzene (1) loaded to the oxidation reactor.

[0378] The oxidation product for Example 11 was collected and concentrated using a laboratory rotary evaporator apparatus at 70 C. and 30 mbar (3.0 KpA) pressure. After cooling to room temperature, the concentrate was slurried in 124 g of a 25 wt % acetic acid in water solution and then vacuum filtered using a coarse porosity glass Bchner filter funnel. The product solid was then washed with a 25 wt % acetic acid in water solution (125 g) and three times with water (122 g each time). The crude solid was then re-slurried in heptane (205 g) and again filtered and washed with heptane (68 g). After air drying over several days, the mass of the dry solid was found to be 107.6 g. The crude solid had a composition of about 1.2% 1,3-dimethyl-2-nitrobenzene (1), 79.2% 3-methyl-2-nitrobenzoic acid (2) and 17.3% 2-nitro-1,3-benzenedicarboxylic acid (13) by GC analysis. The crude solid was combined with acetic acid (159.4 g), water (85.6 g) and sodium hydroxide (6.69 g) in a glass kettle. The mixture was heated to a gentle reflux (about 105 C.) for about 15 min during which time much of the solid dissolved. The mixture was then allowed to cool to room temperature. The solid that crystallized was isolated by vacuum filtration using a coarse porosity glass Bchner filter funnel. The solid was then washed with a 25 wt % acetic acid in water solution (80 g) and four times with water (480 g). After air drying the mass of the dry solid was found to be 74.8 g. The recrystallized solid had a composition of about 0.1% 1,3-dimethyl-2-nitrobenzene (1), 98.4% 3-methyl-2-nitrobenzoic acid (2) and 1.2% 2-nitro-1,3-benzenedicarboxylic acid (13) by GC analysis. The calculated isolated mole yield of recrystallized 3-methyl-2-nitrobenzoic acid (2) was 41% for Example 11 based on the 1,3-dimethyl-2-nitrobenzene (1) loaded to the oxidation reactor.

EXAMPLE 12

Purification of 3-methyl-2-nitrobenzoic acid (2) by Recrystallization

[0379] Crude 3-methyl-2-nitrobenzoic acid (2) was recovered from several oxidation reactions and blended together. (The oxidations were completed at an average of <50% 1,3-dimethyl-2-nitrobenzene (1) conversion, as exemplified in Examples 5 through 9. The recovery was completed by allowing the reaction mixtures to cool to room temperature and then isolating the resulting solids by vacuum filtration using a 70-100 micron glass filter. The solids were then washed 3-4 times with acetic acid and/or acetic acid in water solutions (35-50 wt %) and with water before air drying and blending.) The blended crude 3-methyl-2-nitrobenzoic acid (2) (75.05 g) was slurried in a 35 wt % water in acetic acid solution (300 g). The mixture was then heated to reflux for about 30 min to dissolve most of the crude material. The mixture was cooled over 3 h to room temperature, after which time a precipitate formed. The precipitate was collected by filtration using a glass 25-50 micron glass filter under a mild vacuum. The solids were then washed with a 50 wt % water-acetic acid solution (100 mL) followed by water (100 mL). The product (64.59 g) was a crystalline, free flowing solid of 3-methyl-2-nitrobenzoic acid (2) with >99% purity by GC analysis. Crude and purified product analytical data for this process is provided below in Table 3.

TABLE-US-00006 TABLE 3 Recrystallization Example Material Composition GC (Area %) NAA (ppm) Recovery Material Identity (1) (2) (13) Cobalt of (2) (%) Crude 2 1.55 93.88 3.74 ND 91 Recrystallized 2 0.00 99.14 0.86 11

EXAMPLE 13

Purification of 3-methyl-2-nitrobenzoic acid (2) by Precipitation From Aqueous Base

[0380] Crude 3-methyl-2-nitrobenzoic acid (2) was recovered from several oxidation reactions and blended together. (The oxidations were completed at an average of <50% 1,3-dimethyl-2-nitrobenzene (1) conversion, as exemplified in Examples 5 through 9. The recovery was completed by allowing the reaction mixtures to cool to room temperature and then isolating the resulting solids by vacuum filtration using a 70-100 micron glass filter. The solids were then washed 3-4 times with acetic acid and/or acetic acid in water solutions (35 to 50 wt %) and with water before air drying and blending.) The blended crude 3-methyl-2-nitrobenzoic acid (2) (20.16 g) was added to an aqueous sodium hydroxide solution (1 M, 144 mL) and stirred for 15 min to dissolve most of the crude material. An aqueous solution of hydrochloric acid was then added (3 M, 39 mL) slowly with stirring to reach a measured solution pH of 4.48. The precipitated solid was isolated by vacuum filtration using a 25-50 micron glass filter under mild vacuum and washed 2 times with water (100 mL). After air drying, the product (14.60 g) was an off-white solid of 3-methyl-2-nitrobenzoic acid (2) with 96.2% purity by GC analysis. Crude and purified product analytical data for this process is provided below in Table 4.

TABLE-US-00007 TABLE 4 Base-Acid Purification Example Material Composition GC (Area %) Recovery Material Identity (1) (2) (13) of (2) (%) Crude (2) 1.83 93.70 3.86 74 Precipitated (2) 1.11 96.23 1.69 at pH 4.48

EXAMPLE 14

Synthesis of 3-methyl-2-nitrobenzoic acid (2) (Run with 60% Loading of 1,3-dimethyl-2-nitrobenzene(1))

[0381] Three experiments on the air oxidations of 1,3-dimethyl-2-nitrobenzene (1) to 3-methyl-2-nitrobenzoic acid (2), Examples 14-1, 14-2 and 14-3, were carried out at a 60wt % initial loading of 1,3-dimethyl-2-nitrobenzene (1). The experiments were carried out in the pressure reactor applying operation procedures similar to those described for Examples 1 - 9. The specific conditions for each experiment are provided in Table 5.

TABLE-US-00008 TABLE 5 Material Loads and Rates of Addition for Examples 14-1, 14-2 and 14-3 14-1 14-2 14-3 Reactor Temperature ( C.) 100 100 100 1,3-dimethyl-2-nitrobenzene (1) (g) 300 300 300 Cobalt(II) acetate tetrahydrate (g) 5 5 5 Water (g) 2 2 2 Acetic acid (g) 198 198 198 Acetaldehyde Rate (mL/h) 40 40 40 Air Flow Rate (slpm) 2 2 2 Agitator Speed (rpm) 800 800 800 Reactor pressure (psig) 500 500 500 Run Time (h) 4 3.5 3.5

[0382] Process samples were collected every hour in Example 14-1. Only final reaction mixture samples were collected in Examples 14-2 and 14-3. These samples were analyzed by GC analysis and the reaction conversions and selectivities calculated. Table 6 provides the calculated 1,3-dimethyl-2-nitrobenzene (1) conversions and selectivities to 3-methyl-2-nitrobenzoic acid (2) for 14-1, 14-2 and 14-3 based on hourly and final samples taken during the oxidation experiments.

TABLE-US-00009 TABLE 6 Conversions and Selectivities at Specific Times for Examples 14-1, 14-2 and 14-3 14-1 14-2 14-3 Time (h) 1 2 3 4 3.5 3.5 Calc'd Conv. of (1) (%) 10.0 18.8 25.3 33.0 27.0 28.1 Calc'd Select. to (2) (%) 75.1 84.5 86.2 86.6 87.0 87.2

[0383] The data in Tables 5 and 6 demonstrates that the oxidation reaction can operate at an initial loading of 60wt % 1,3-dimethyl-2-nitrobenzene (1).

EXAMPLE 15

Synthesis of 3-methyl-2-nitrobenzoic acid (2)Effects of Temperature

[0384] Four experiments on the air oxidations of 1,3-dimethyl-2-nitrobenzene (1) to 3-methyl-2-nitrobenzoic acid (2), Examples 15-1, 15-2, 15-3 and 15-4, were completed at four different reaction temperatures. The experiments were completed in the pressure reactor applying operation procedures similar to those described for Examples 1 - 9. The specific conditions for each experiment are provided in Table 7.

[0385] Process samples were collected every hour in Examples 15-1, 15-2, 15-3 and 15-4. These samples were analyzed by GC analysis and the reaction conversions and selectivities calculated. Table 8 provides the calculated 1,3-dimethyl-2-nitrobenzene (1) conversions and selectivities to 3-methyl-2-nitrobenzoic acid (2) for Examples 15-1, 15-2, 15-3 and 15-4 based on the hourly samples taken during the oxidation experiments.

[0386] The data in Tables 7 and 8 demonstrates that the oxidation reaction can provide high selectivities to 3-methyl-2-nitrobenzoic acid (2) between 90 and 115 C.

TABLE-US-00010 TABLE 7 Material Loads and Rates of Addition for Examples 15-1, 15-2, 15-3 and 15-4 15-1 15-4 15-2 15-3 Reactor Temperature ( C.) 90 100 110 115 1,3-dimethyl-2-nitrobenzene (1) (g) 200 200 200 200 Cobalt(II) acetate tetrahydrate (g) 5 5 5 5 Water (g) 2 2 2 2 Acetic acid (g) 300 300 300 300 Acetaldehyde Rate (mL/h) 40 40 40 40 Air Flow Rate (slpm) 2 2 2 2 Agitator Speed (rpm) 800 800 800 800 Reactor pressure (psig) 500 500 500 500 Run Time (h) 4 4 4 4

TABLE-US-00011 TABLE 8 Conversions and Selectivities at Specific Times for Examples 15-1, 15-2, 15-3 and 15-4 15-1 15-4 15-2 15-3 Time (h) 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 Calc'd 12 20 28 37 15 26 37 45 16 32 44 54 16 32 46 56 Conv. of (1) (%) Calc'd 75 84 86 86 80 87 87 87 82 87 87 85 82 87 87 85 Select. to (2) (%)

EXAMPLE 16

Synthesis of 3-methyl-2-nitrobenzoic acid (2)Recycle Process Demonstration

[0387] Six experiments (examples 16A through 16F) were conducted in series to demonstrate the air oxidation of 1,3-dimethyl-2-nitrobenzene (1) to 3-methyl-2-nitrobenzoic acid (2) with recovery of crude 3-methyl-2-nitrobenzoic acid (2) and recycle of unreacted 1,3-dimethyl-2-nitrobenzene (1) and cobalt catalyst in a subsequent oxidation reaction. The targeted oxidation conditions used in examples 16A through 16F are outlined in Table 9.

TABLE-US-00012 TABLE 9 Targeted Oxidation Conditions for Examples 16A through 16F (1) Load (g) 300 Cobalt(II) Acetate .Math. 4H.sub.2O Load (g) 6.25 Acetic acid Load (g) 300 Acetaldehyde Feed Rate (mL/h) 40 Air Flow Rate (slpm) 2 Run Time (h) 4 Reaction Temperature ( C.) 100 Agitator Speed (rpm) 800 Reactor pressure (psig) 500

[0388] The oxidation products were collected from the pressure reactor and concentrated using a laboratory rotary evaporator apparatus at 70 C., 30 mbar (3.0 kPa). A small amount of acetic acid (30-100 g) was added to the concentrated reaction mixture while it was still warm and then the mixture was allowed to cool to room temperature. After at least two hours at ambient temperature, the mixture was vacuum filtered using a coarse porosity glass Buchner filter. The resulting solid was washed with acetic acid twice (2100 g). The crude 3-methyl-2-nitrobenzoic acid (2) was then washed once with water (1100 g) and set aside to air dry. The crude solid was analyzed by GC to determine material composition.

[0389] The filtrate and acetic acid washes from the previous experiment were combined, weighed and analyzed by LC to quantitate the residual 1,3-dimethyl-2-nitrobenzene (1). Based on this analysis, a quantity of make-up 1,3-dimethyl-2-nitrobenzene (1) was then added to the filtrate and acetic acid washes to bring the total 1,3-dimethyl-2-nitrobenzene (1) to 300 grams. This was now the reformulated 1,3-dimethyl-2-nitrobenzene (1) feed for the next oxidation experiment. The required amount of make-up acetic acid to reformulate the reformulated 1,3-dimethyl-2-nitrobenzene (1) solution to a total target mass of 606.25 grams was then calculated and set aside. The reformulated 1,3-dimethyl-2-nitrobenzene (1) solution, make-up cobalt(II) acetate- 4H.sub.2O catalyst and the make-up acetic acid were added to the oxidation reactor. The oxidation reaction, product recovery, and reformulation in preparation for subsequent experiments were then completed under the same conditions used in the first experiment.

[0390] Table 10 provides the actual raw material inputs and composition for the six oxidation experiments in examples 16A through 16F and Table 11 provides the mass and composition of the product streams during the recovery processes for examples 16A through 16F. The first experiment run is labelled A. Subsequent experiments are labelled B, C, D, E, F in order of experiments completed, respectively.

TABLE-US-00013 TABLE 10 Actual Raw Material Inputs for Oxidation Examples 16A to 16F Feed Materials 16A 16B 16C 16D 16E 16F Amount of (1) charged (g) 299.69 137.28 118.79 119.78 131.76 113.23 Mass of reformulated feed (g) 608.8 517.7 512.1 515.9 504.7 Acetic acid charged (g) 300.00 0.00 87.15 92.44 67.05 89.64 Cobalt(II) acetate tetrahydrate added 6.2515 0.5082 0.4905 0.4933 0.4961 2.6801 (g)

TABLE-US-00014 TABLE 11 Mass and Composition of the Product Streams During Recovery Processes for Examples 16A to 16F Products 16A 16B 16C 16D 16E 16F Reaction mixture mass exiting 779.73 781.57 768.98 771.53 771.08 776.22 reactor (g) Concentrated reaction mixture 319.99 359.90 358.60 356.14 369.98 363.61 mass (g) Filtrate + acetic acid rinses of 472.39 400.18 393.52 408.32 403.67 384.43 solid (g) Crude (2) solids, dry (g) 97.19 118.41 112.95 103.76 105.03 108.06 Purity of crude (2) (GC Area %) 88.69 89.78 87.04 91.04 89.37 88.67 Amount of (2) in crude (g) 86.20 106.31 98.31 94.46 93.87 95.82

[0391] Table 12 provides the cumulative yields of pure product in the crude 3-methyl-2-nitrobenzoic acid (2) based on the 1,3-dimethyl-2-nitrobenzene (1) added to the process. Ignoring the initial 1,3-dimethyl-2-nitrobenzene (1) loading (experiment A), the data for examples 16A through 16F shows that the cumulative yield stays constant at about 64-68% across experiments B to F.

TABLE-US-00015 TABLE 12 Cumulative Yields for Examples 16A to 16F Yield 16A 16B 16C 16D 16E 16F Cumulative yield of (2) in crude based on (1) 24.0 36.8 43.5 47.5 50.6 53.1 added (%) Cumulative yield of (2) in crude based on (1) 64.6 66.4 66.2 66.9 67.6 added, excluding 16A (%)

[0392] The cumulative yield of 3-methyl-2-nitrobenzoic acid (2) in the crude solid for examples 16 were calculated in the following way:

[0393] Cumulative Yield (2) in crude solid from experiment A to experiment X=[(total moles 3-methyl-2-nitrobenzoic acid (2) isolated in experiment A through X)/(moles 1,3-dimethyl-2-nitrobenzene (1) loaded in experiment A through X)]100. Experiment X is either experiment B, C, D, E or F.

[0394] Cumulative Yield (2) in crude solid from experiment B to experiment X =[(total moles 3-methyl-2-nitrobenzoic acid (2) isolated in experiment B through X)/(moles 1,3-dimethyl-2-nitrobenzene (1) loaded in experiment B through X)]100. Experiment X is either experiment C, D, E or F.

EXAMPLE 17

Synthesis of 3-methyl-2-nitrobenzoic acid (2)Recycle Process Demonstration

[0395] A multi-experiment study was completed, involving ten experiments (examples 17A through 17J), to demonstrate the air oxidation of 1,3-dimethyl-2-nitrobenzene (1) to 3-methyl-2-nitrobenzoic acid (2) with recovery of crude 3-methyl-2-nitrobenzoic acid (2) and recycle of unreacted 1,3-dimethyl-2-nitrobenzene (1) and cobalt catalyst in a subsequent oxidation reaction. The targeted oxidation conditions used in examples 17A through 17J are outlined in Table 13.

TABLE-US-00016 TABLE 13 Targeted Oxidation Conditions for Examples 17A through 17J (1) Load (g) 400 Cobalt(II) Acetate .Math. 4H.sub.2O Load (g) 7.5 Acetic acid Load (g) 200 Acetaldehyde Feed Rate (mL/h) 40 Air Flow Rate (slpm) 2.0 Run Time (h) 4.0* Reaction Temperature ( C.) 100 Agitator Speed (rpm) 1600 Reactor pressure (psig) 500 *Experiment 1C and 1F were terminated at 3.7 and 2.9 hours respectively

[0396] The oxidation reactions were completed as described in prior examples. At the end of the oxidation, the reactor pressure and agitator speed were reduced to 50 psig and 400 rpm and the reaction products were cooled from reaction temperature to 35 C. The oxidation products were then discharge and collected from the pressure reactor and the reactor was rinsed with acetic acid (-100 g). The oxidation products were placed in an ice bath to cool for at least one hour and then the cold mixture was vacuum filtered using a coarse porosity glass Buchner filter. The recovered solid was washed with the reactor rinse acetic acid and acetic acid (100 g). The crude 3-methyl-2-nitrobenzoic acid (2) was set aside to air dry. The crude solid was analyzed by LC to determine material composition.

[0397] The filtrate and acetic acid washes were combined and weighed. A calculated mass of acetic acid and water were then removed by distillation at elevated temperature (50-80 C.) and reduced pressure (50-60 torr) to bring the mass of the concentrate to approximately 465 grams. 1,3-dimethyl-2-nitrobenzene (1) (typically 128 g) was added to the concentrate to give the reformulated 1,3-dimethyl-2-nitrobenzene (1) feed for the next oxidation experiment. The required amount of make-up acetic acid to bring the reformulated 1,3-dimethyl-2-nitrobenzene (1) solution to a total target mas s of approximately 606 grams was then calculated. The reformulated 1,3-dimethyl-2-nitrobenzene (1) solution and make-up acetic acid were then added to the oxidation reactor for the next experiment of the multi-experiment process.

[0398] In experiment 17C, an equipment issue led to the termination of the oxidation process at 3.7 hours. In experiment 17F, an equipment issue led to the termination of the oxidation process at 2.9 hours. Consequently, only 100 grams of make-up 1,3-dimethyl-2-nitrobenzene (1) was added in experiment 17G. With the exception of these minor changes to the oxidation reaction time and make-up 1,3-dimethyl-2-nitrobenzene (1) added, the same conditions were applied for the oxidation reaction, product recovery and reformulation processes in all experiments.

[0399] Table 14 provides the actual raw material inputs and composition for the ten oxidation experiments in examples 17A through 17J. Table 15 provides the mass and composition of the product streams during the recovery processes for examples 1A through 1J. The first experiment run is labelled A. Subsequent experiments are labelled B, C, D, E, F, G, H, I and J in order of experiments completed, respectively. No additional cobalt catalyst was added in experiments B through J.

TABLE-US-00017 TABLE 14 Actual Raw Material Inputs for Oxidation Examples 1A to 1J Feed Materials 17A 17B 17C 17D 17E 17F 17G 17H 17I 17J (1) charged 399.94 127.81 127.97 127.98 128.00 128.00 100.0 128.08 128.00 127.98 (g) Mass of 583.36 595.26 594.62 594.47 592.11 592.12 578.95 598.13 596.35 reformulated feed (g) Acetic acid 200.32 23.55 11.15 11.13 10.99 14.02 13.01 26.58 7.56 10.77 charged (g) Fresh 7.51 0 0 0 0 0 0 0 0 0 Cobalt(II) acetate tetrahydrate charged (g)

TABLE-US-00018 TABLE 15 Mass and Composition of the Product Streams During Recovery Processes for Examples 17A to 17J Feed Materials 17A 17B 17C 17D 71E 17F 17G 17H 17I 17J Reaction mixture 775.52 766.41 759.21 757.60 768.00 713.04 770.29 763.19 763.10 767.95 mass exiting reactor (g) Crude (2) solids 95.15 123.14 126.83 120.2 118.47 102.61 122.46 123.88 117.92 118.13 recovered, dry (g) Filtrate and acetic 826.14 770.76 729.45 734.90 754.98 727.75 729.03 701.57 725.67 744.66 acid rinses (g) Concentrated 457.34 469.96 467.05 467.28 462.08 464.14 453.93 471.04 468.37 reaction mixture mass (g) Purity of crude 94.2 92.5 86.6 94.0 89.1 80.8 87.8 86.3 90.4 85.2 solid (2) (LC) (2) contained in 89.63 113.90 109.83 112.99 105.56 82.92 107.48 106.91 106.60 100.65 crude (g)

[0400] Table 16 provides the cumulative yields of pure product in the crude 3-methyl-2-nitrobenzoic acid (2) based on the 1,3-dimethyl-2-nitrobenzene (1) added to the process. Ignoring the initial 1,3-dimethyl-2-nitrobenzene (1) loading (experiment A), the data for examples 17A through 17J shows that the cumulative yield stays constant at about 69-74% across experiments B to J.

TABLE-US-00019 TABLE 16 Cumulative Yields for Examples 17A to 17J Yield 17A 17B 17C 17D 71E 17F 17G 17H 17I 17J Cumulative yield of (2) in 18.7 32.2 39.9 45.4 48.7 49.3 52.9 54.6 55.9 56.8 crude based on (1) added (%) Cumulative yield of (2) in 74.4 73.0 73.2 72.1 68.5 71.4 71.1 70.9 70.3 crude based on (1) added, excluding 1A (%)

[0401] The cumulative yield of 3-methyl-2-nitrobenzoic acid (2) in the crude solid were calculated in the following way:

[0402] Cumulative Yield (2) in crude solid from experiment A to experiment X =[(total moles 3-methyl-2-nitrobenzoic acid (2) isolated in experiment A through X)/(moles 1,3-dimethyl-2-nitrobenzene (1) loaded in experiment A through X)]100. Experiment X is either experiment B, C, D, E, F, G, H, I or J.

[0403] Cumulative Yield (2) in crude solid from experiment B to experiment X =[(total moles 3-methyl-2-nitrobenzoic acid (2) isolated in experiment B through X)/(moles 1,3-dimethyl-2-nitrobenzene (1) loaded in experiment B through X)]100. Experiment X is either experiment C, D, E, F, G, H, I or J.

EXAMPLE 18

Synthesis of 3-methyl-2-nitrobenzoic acid (2)Absence of Catalyst

[0404] Two experiments on the air oxidations of 1,3-dimethyl-2-nitrobenzene (1) to 3-methyl-2-nitrobenzoic acid (2), Examples 18-1 and 18-2, were completed with no cobalt catalyst added. The experiments were completed in the pressure reactor applying operation procedures similar to those described for Examples 1 - 9. The specific conditions for each experiment are provided in Table 17.

[0405] Prior to Example 18-1 the oxidation reactor was cleaned using methanol to remove trace Co catalyst from prior experiments. Based on the unexpected result for Example 18-1, Example 18-2 was completed. Prior to Example 18-2 the oxidation reactor was carefully cleaned using methanol (1600 g) at 50 C. and with acetic acid (2600 g) at 100 C. to remove trace Co catalyst from prior experiments

[0406] Process samples were collected at the termination of the run for Examples 18-1 and 18-2. These samples were analyzed by LC analysis and the reaction conversions and yields calculated. Table 18 provides the calculated 1,3-dimethyl-2-nitrobenzene (1) conversions and yields of 3-methyl-2-nitrobenzoic acid (2) for Examples 18-2 and 18-2 based on the samples taken at the termination of the oxidation experiments.

[0407] The data in Tables 17 and 18 demonstrates that the oxidation reaction can provide 3-methyl-2-nitrobenzoic acid (2) when no catalyst is present.

TABLE-US-00020 TABLE 17 Material Loads and Rates of Addition for Examples 18-1 and 18-2 18-1 18-2 Reactor Temperature ( C.) 100 100 1,3-dimethyl-2-nitrobenzene (1) (g) 400 400 Cobalt(II) acetate tetrahydrate (g) 0 0 Acetic acid (g) 200 200 Acetaldehyde Rate (mL/h) 40 40 Air Flow Rate (slpm) 2 2 Agitator Speed (rpm) 1600 1600 Reactor pressure (psig) 500 500 Run Time (h) 2.3 4

TABLE-US-00021 TABLE 18 Conversions and Yields at Specific Times for Examples 18-1 and 18-2 1-1 1-2 Time (h) 2.3 4 Calc'd Conv. of (1) (%) 13.8 23.0 Calc'd Select. to (2) (%) 35.0 37.9

[0408] The conversion of 1,3-dimethyl-2-nitrobenzene (1) and the yield of 3-methyl-2-nitrobenzoic acid (2) in the reaction mixture were calculated in the following way: Calc'd Conv. of (1) in reaction mixture=[{(moles 1,3-dimethyl-2-nitrobenzene (1) loaded)((moles 1,3-dimethyl-2-nitrobenzene (1) remaining in reaction mixture measured by LC)}/(moles 1, 3-dimethyl-2-nitrobenzene (1) loaded)]100

[0409] Calc'd Select. to (2) in reaction mixture =[(moles 3-methyl-2-nitrobenzoic acid (2) in reaction mixture measured by LC)/{(moles 1,3-dimethyl-2-nitrobenzene (1) loaded)((moles 1,3-dimethyl-2-nitrobenzene (1) remaining in reaction mixture measured by LC}]100.