HK1016578B - Process for the production of azomethines and alpha-haloacetanilides - Google Patents

Description

Process for producing azomethine compound and alpha-halogeno-acetanilide

The present invention relates to the preparation of azomethine compounds by reacting aniline with a formaldehyde supply (as hereinafter described) and to an improved process for the preparation of halogenated acetanilides from aniline by reacting aniline with a formaldehyde supply to form an azomethine compound and then reacting the azomethine compound with an acid halide and, if the N, N-disubstituted halogenated acetanilide is the final product, with a suitable reagent (e.g., an alcohol).

Conventional halogenated acetanilides are prepared in U.S. patent nos. 3,630,716; 3,637,847, respectively; 4,097,262 and 5,399,759.

In particular, the preparation of azomethine compounds and the final alpha-halogenated acetanilides by reacting aniline with a formaldehyde supply is described in the latter patents (the term "formaldehyde-alcohol mixture" in the patent is made by reacting paraformaldehyde with about 0.25 to 3 molar equivalents of an aliphatic alcohol having 1 to 4 carbon atoms in the presence of a catalytic amount of base). The process described in this patent is a stepwise reaction, and the several steps ultimately leading to the formation of the α -haloacetanilide can be carried out either in separate reactors, in a reaction unit, or even in a "one pot" operation, i.e. all steps are carried out in a single reactor.

The process described in us patent 5,399,759 provides several advantages over the prior art, such as a rapid reaction between the formaldehyde supply and aniline, making it possible to use paraformaldehyde as the starting material in the reaction, thereby overcoming the problems of sublimation and deposition of paraformaldehyde in the equipment, which have been encountered previously, but there is still room for improvement.

For example, the improvement may be carried out by removing water from the reaction. As described in that patent, water is removed from the reaction product by azeotropic distillation. It is preferred to start shortly after the start of the reaction itself and to carry out the continuous distillation for the majority of the reaction time. In order to complete the reaction, it is necessary to completely remove the water in the reaction, but according to the above-mentioned distillation method, it takes a long time for complete removal to occur.

In addition, it is necessary to minimize the reaction or residence time of the azomethine compound-forming step, since unnecessarily long retention times may lead to degradation of the product.

The invention comprises the following steps:

a process for preparing an aromatic azomethine compound by reacting aniline with a formaldehyde supply wherein the formaldehyde is prepared by reacting paraformaldehyde with from about 0.25 to about 3 molar equivalents of an aliphatic alcohol having from 1 to 4 carbon atoms in the presence of a catalytic amount of a base, characterized in that the process comprises: (a) continuously carrying out reaction; and (b) continuously evaporating water from the reaction mixture.

The entire sequence of the reaction, including the formation of azomethine compounds and the final alpha-haloacetanilide, is described in U.S. patent 5,399,759, which is incorporated herein by reference. The process described in this patent for the preparation of azomethine compounds and of the final alpha-halogenated acetanilides is carried out stepwise. In the azomethine step, the formaldehyde reactive form provided below is reacted with aniline to form azomethine.

Typically anilines have the formulaWherein R represents hydrogen or one or more substituents which are relatively unreactive with formaldehyde. In particular alkyl, alkoxy or halogen; the value of n is generally 0 to 5, preferably 0, 1, 2, or 3. Herbicidal anilides or halogenated anilides are usually prepared from anilines bearing one or more such substituents in the ortho position. Some typical starting anilines used to ultimately prepare the herbicide anilide or haloacetanilide include 2, 6-dimethylaniline, 2, 6-diethylaniline, 2-methyl-6-ethylaniline, 2-methyl-6-tert-butylaniline, 2-tert-butyl-6-haloaniline, 2, 4-dimethylaniline, 2-tert-butyl-5, 6-dimethylaniline, 2, 6-dimethyl-3, 4, 5-trichloroaniline, 2-methylaniline, 2-ethylaniline, 2-methoxyaniline and 2-ethoxyaniline.

The reaction products are mainly azomethine and water, and various by-products and impurities exist.

Reacting solid paraformaldehyde with about 0.25 to 3 molar equivalents of an aliphatic alcohol having 1 to 4 carbon atoms in the presence of a catalytic amount of a base to produce a product which serves as a formaldehyde supply source. This reaction step can be carried out either in a separate apparatus or in the main reactor for the preparation of the azomethine compound. Typical reaction temperatures are from 85 to 95 ℃. An inert solvent such as an aromatic solvent such as xylene may be present, but is not required.

The base used may be an organic or inorganic base, for example an alkali metal hydroxide, alkoxide, carbonate or oxide, or a tertiary amine, preferably a tertiary amine. Typical catalysts for this technology include: sodium hydroxide, potassium hydroxide, sodium methoxide, trialkylamines, such as trimethylamine, triethylamine and tri-N-butylamine, and heterocyclic amines including pyridine, N-alkylpiperidines and pyrrolidines (e.g., N-ethylpiperidine and N-methylpyrrolidine), tetraalkylguanidines and fused bicyclic amines such as 1, 8-diazabicyclo (5.4.0) undec-7-ene and 1, 5-diazabicyclo (4.3.0) non-5-ene. The amount of basic catalyst used is generally from about 0.01 to 1 molar equivalent of formaldehyde, preferably from 0.01 to 0.05.

The azomethine forming step may be carried out in the presence of a hydrocarbon solvent which forms an azeotrope with water at the reflux temperature of the solvent. Typical solvents include aromatic solvents such as benzene, toluene and xylene, and aliphatic and cycloaliphatic solvents such as n-hexane, n-heptane and cyclohexane. Depending on the solvent used, the reflux temperature of the reaction mixture is in the range of about 80 to 140 ℃. The reaction temperature is preferably from 80 to 100 ℃.

In addition, in the process of carrying out the present invention, the reaction can also be carried out without using a solvent.

In a multi-step reaction for the preparation of herbicidal halogenated acetanilides, when the first step is the preparation of azomethine, the final product (typically an α -halogenated acetanilide, or more commonly an α -chloro acetanilide) has the following general formula:wherein R and n areThe definition is the same as the previous definition; x is halogen, typically chlorine and bromine, most typically chlorine, and R is₁Are any of the several substituents already described as components of herbicidal compounds, most commonly various alkyl and alkoxyalkyl groups. Other substituents are described in U.S. patent 4,097,262.

Of course, water is a product of the step of forming the azomethine compound, and it is necessary to remove it in order to complete the reaction. Water was removed by distillation either during the reaction or after the reaction appeared to be complete, as before. However, in the stepwise preparation of azomethine compounds, the removal of water by the hitherto used processes has not proved entirely satisfactory. Too long a reaction or retention time may carry the risk of product degradation. In addition, it has proven very difficult to remove residual amounts of water from the reaction mixture.

According to the present invention, the azomethine preparation reaction is carried out continuously rather than stepwise, with the water of reaction being removed by continuous distillation, as described in greater detail below.

The following is a general description of some examples of the invention.

In a first example, an azomethine reaction mixture containing aniline and formaldehyde-alcohol complex (optionally in the presence of a solvent) is mixed, heated, and fed to one or a series of several downflow flooded evaporators. The reaction temperature of the system is generally 75 to 105 ℃ and the pressure is 0.2 to 0.4 bar (150-300 mmHg). The mixture fed is introduced from the top of the evaporator so as to establish countercurrent contact with the vapor. Azomethine compounds are collected from the bottom of the last evaporator of the series and the distillate is recycled to prepare fresh quantities of formaldehyde-alcohol complex. Wherein the evaporator may be a counter-current contact evaporator.

In a second example, the azomethine preparation step is carried out in a series of two or more successive downflow evaporators at a temperature generally between 75 ℃ and 115 ℃ and a pressure between 0.4 and 1.013 bar (300 and 760 mmHg). In this example, the reaction mixture was fed from the bottom of the evaporator so that a co-current flow of liquid and vapor was established in each evaporator. The liquid from the top of the last evaporator in the series is then fed to a falling film evaporator or downflow flooded evaporator to remove residual water and drive the reaction to completion.

In a third example, the azomethine preparation is carried out in a downflow flooded evaporator or in two or more successive upflow evaporators. Residual water is removed from the reaction mixture in one or more evaporators, each consisting of two parts-an upper part, which is the falling film part, and a lower part, which is the overflow part. In this example, the majority of the vapor is removed from the falling film portion of each evaporator. The overflow at the bottom of each evaporator provides additional residence time for the reaction to proceed to completion. Since most of the vapor is removed at the top, the amount of vapor released at the bottom overflow will be small enough to keep the evaporator in a hydrodynamically stable state.

In a fourth example, the azomethine preparation step is carried out in one or more continuously stirred tank reactors, and the reaction product is then passed through one or more falling-film evaporators, typically operating at a temperature of from 95 to 139 ℃ and a pressure of from 0.267 to 1.013 bar (200. sup. 760mmHg), and/or one or more downflow overflow evaporators, typically operating at a temperature of from 75 to 105 ℃ and a pressure of from 0.2 to 0.4 bar (150. sup. 300 mmHg).

In any of the above examples, the one or more evaporators may be packed columns. The use of such an evaporator may result in a slightly longer residence time of the reaction mixture and more complete vapor-liquid contact. When the packed column is a downflow evaporator, packing increases the hydrodynamic stability of the evaporator and improves heat and mass transfer efficiency. Although in most cases a longer retention time is undesirable due to product degradation, the retention time can be extended to a degree to achieve better heat and/or mass transfer efficiency.

The evaporator used to remove residual water from the azomethine preparation step preferably comprises a counter-contact of liquid and vapor.

The azomethine preparation is carried out in one or more falling-film evaporators, downflow flooded evaporators or combined evaporators having an upper falling-film portion and a lower flooded portion

Alternatively, any of the evaporators in the above examples may also include a means for spraying an inert gas (e.g., nitrogen) or an inert compressible vapor (e.g., xylene) onto the bottom of the evaporator. If xylene is used as the spray vapor, it can be obtained by recovery and recycle of the xylene solvent downstream of the process.

In a further embodiment of the invention, the azomethine compound can be converted to the alpha-haloacetanilide in two more steps after removal of the water, and this or both steps can be carried out continuously with the previous reaction.

In a second step, the azomethine compound is reacted with a haloacetylating agent, typically chloroacetyl chloride, in a suitable solvent. This reaction produces a 2-or alpha-halo (preferably chloro) N-halomethyl (preferably chloromethyl) acetanilide having the general formulaWherein X is halogen (typically chlorine and bromine), and R₁Is a halomethyl group (chloromethyl or bromomethyl). Halogenated acetanilides of this type are described as herbicides in U.S. Pat. Nos. 3,630,716 and 3,637,847.

This reaction can be carried out continuously by continuously feeding the azomethine compound and the haloacetylation agent into a single or series of continuously stirred tank reactors, operating at atmospheric pressure, at a temperature ranging from room temperature to about 80 ℃. Alternatively, the azomethine compound and the haloacetylating agent may be added continuously to a plug flow reactor or a pump reactor.

In the final step, the N-halomethyl product is reacted with a suitable aliphatic alcohol to produce the N-alkoxyalkyl- α -haloacetanilides of formula I above. This step may also be carried out continuously in one or a series of continuous tank reactors operating at atmospheric pressure and at temperatures ranging from room temperature to about 80 ℃. The product from the last reactor in the series is contacted with a base (e.g., ammonia, triethylamine or tri-n-butylamine) and then transferred to a holding tank or further continuously stirred tank reactor and allowed to remain for a longer period of time to drive the reaction toward completion.

It should be noted that in the practice of the present invention, it is not necessary to have the three steps of preparing the α -halogenated acetanilide occur in series. Which is only the best example. It is also satisfactory if, according to the prior art, only the first reaction step, i.e. the azomethine compound preparation, is carried out continuously, while the second and third reaction steps are carried out stepwise. In addition, the first and second reactions are carried out continuously, and the third reaction is carried out step by step, which is also convenient.

The advantages of having the first and any subsequent steps carried out continuously include the possibility of using smaller reactors and thus of saving costs, among other advantages already mentioned.

The following examples will further illustrate the invention:

example 1

This example illustrates a two-step continuous reaction process for the preparation of the aromatic azomethine compound intermediate 2-methyl-6-ethyl-N-ethoxymethyl-2-chloroanilide using a downflow flooded tube evaporator.

A304 stainless steel tubing string of 1.1cm (7/16 feet) internal diameter and 83.8cm (33 feet) in length was used with 5mm glass beads inside, which constituted the reactor/evaporator with an overhead condenser and vapor pressure lifter to control and maintain the liquid level in the tube at a constant level. The temperature in the top of the tube was maintained at 75-90 deg.C and the temperature in the bottom at 80-100 deg.C.

The formaldehyde-ethanol complex was prepared by mixing 20 moles (920g) of ethanol and 0.6 moles (61g) of triethylamine, adding 20 moles (659g) of paraformaldehyde beads (91%), heating and refluxing the resulting slurry at 89-90 deg.C until a clear solution was formed.

The material added to the azomethine compound reactor had the following composition

Molar weight of material

2-methyl-6-ethyl-aniline (1.0138 g)

Xylene 8.0848

Formaldehyde-ethanol complex 1.6128

(concentration 79.1g/mole CH)₂O)

The feed was continuously pumped into the reactor over 119 hours (batchwise) at a rate of from 0.78 to 3.25 g/min, so that the residence time in the reactor was from 12 to 47 minutes. The reaction in the evaporator is carried out at a pressure of 0.133 to 0.4 bar (100-300mmHg), and the reaction of the azomethine compound is brought to completion by distilling off water by reverse contact with the vapor.

The azomethine compound product was collected under various temperature and pressure conditions. The sample was converted to the 2-methyl-6-ethyl-N-ethoxymethyl-2-chloroanilide product by a derivatization step. Firstly, the N-chloro-methyl-alpha-chloro-N-acetanilide is reacted with chloroacetyl chloride in the environment to generate the N-chloro-methyl-alpha-chloro-N-acetanilide. Then reacting the chloroanilide with 12 molar equivalents of absolute ethanol for 15 minutes; ammonia gas is added to bring the pH to 8-9 to completely convert it to 2-methyl-6-ethyl-N-ethoxymethyl-2-chloro-N-acetanilide product. The crude mixture was purified by gas chromatography. The azomethine compound produces a higher quality product and is obtainedRelatively high conversions of 2-methyl-6-ethyl-N-ethoxymethyl-2-chloroanilide were achieved, with analytical results showing 95-97%, see Table 1.

Operation sequence number	Operating time [ hours ]]	Column temperature [ deg.C]	MEA∶CH2O [ ratio of]	R1[ minute ] of]	MEA[％]	Purity GC A% halogenated acetanilide
							1	4	93	(1∶1.6)	12	3	96
2	7	85	(1∶1.8)	13	5	96
							3	9	83	(1∶1.8)	13	5	98
4	14	86	(1∶1.8)	13	1	96
							5	24	87	(1∶1.6)	16	5	95
6	28	95	(1∶1.7)	14	2	97
							7	30	95	(1∶1.7)	15	5	96
8	33	95	(1∶1.7)	16	4	97
							9	46	96	(1∶1.7)	16	2	95
10	68	95	(1∶1.8)	15	4	97
							11	70	92	(1∶1.8)	13	4	96
12	89	75	(1∶1.8)	47	8	95
							13	97	95	(1∶1.8)	12	9	96
14	119	95	(1∶1.8)	12	11	96

(MEA is 2-methyl-6-ethylaniline)

Example 2

To an 1363.8 liter (300 gallon) reactor were charged 136.08kg (300lbs.) of 95% paraformaldehyde (9.5lb. moles), 198.22kg (437lbs.) of ethanol (9.5lb. moles), and 8.62kg (19lbs.) of (0.19lb. moles) triethylamine to prepare a formaldehyde-ethanol complex. The mixture was heated at 66 ℃ and 400.07kg (882lbs.) of 98% 2, 6-methylethylaniline (6.4lb. The mixture was heated at 88 ℃ under reflux for 2 hours and then the water formed was distilled off at atmospheric pressure. The distillation was stopped when the reaction temperature reached 95 ℃.

After the mixture was cooled, it was fed through an 227.3 liter (50 gallon) agitated tank and preheater into a falling film evaporator consisting of a 7.6cm (3 ') thick 487cm (16') long insulated stainless steel tube. The vapors (mainly water, ethanol and formaldehyde derivatives) condense at the top and are collected by a collector. The liquid at the bottom of the evaporator was collected and was the azomethine compound product.

The evaporator was operated for 6.5 hours at a pressure of 0.029-0.031 bar (22-23mmHg) and a bottom temperature of 125-128 ℃. The feed rate to the evaporator varied between 0.28 and 0.52 gpm.

For evaluation purposes, a sample taken from the azomethine compound product was converted to the 2-methyl-6-ethyl-N-ethoxymethyl-2-chloro-N-acetanilide product. I.e., by reacting azomethine with chloroacetyl chloride to form N-chloromethyl-2-chloro-N-acetanilide, which is then reacted with ethanol, see the process described in U.S. patent 5,399,759(U.S. patent 5,399,759). The purity of the ethoxymethyl acetanilide product is between 95 and 98 percent.

Example 3

This example was carried out under the same conditions as in example 2, except that the mixture fed to the reactor was distilled at atmospheric pressure and 110 ℃ to remove most of the water in the reaction.

In this case, the evaporator was operated for 28 hours, the feed rate to the evaporator varied between 0.15 and 0.25gpm, the pressure ranged from 0.027 to 0.037 bar (20-28mmHg), and the bottom temperature was between 107 ℃ and 124 ℃.

As in example 2, a sample of the azomethine compound product exiting the bottom of the falling film evaporator was converted to 2-methyl-6-ethyl-N-ethoxymethyl-2-chloro-N-acetanilide product having a purity of up to 98.6% and a concentration of non-chloromethylated halo-N-acetanilide impurity of less than 0.5%.

Example 4

This example describes the second reaction step in a Continuous Stirred Tank Reactor (CSTR) process. A50 ml glass reactor was equipped with an electromagnetic stirrer, overhead condenser, thermometer and heating bath. A24% solution of azomethine in xylene was continuously added to the reactor at a rate of 10.2 g/min, and chloroacetyl chloride was continuously added to the reactor at a rate of 2.4 g/min. The reactor was incubated at 114 ℃. The outflow rate of N-chloromethyl-2-chloro-N-acetanilide from the reactor was adjusted to maintain the residence time at 1.8 minutes. For evaluation purposes, a sample of the N-chloromethyl-2-chloro-N-acetanilide product remaining in the reactor was quenched in a large amount of ethanol to convert it to 2-methyl-6-ethyl-N-ethoxymethyl-2-chloro-N-acetanilide. The product was analyzed to have a purity of 96.8% by weight. The concentration of non-chloromethylated halo-acetanilide impurities is less than 0.7% by weight. The yield (corresponding to the methylethylaniline used in the preparation of the azomethine compound) was 92.7%.

Example 5

This example describes the third reaction step in a Continuous Stirred Tank Reactor (CSTR) process. A500 ml CSTR reactor was equipped with heaters and temperature controllers. To this reactor, 33% xylene solution of N-chloromethyl-2-chloro-N-acetanilide (prepared as described in example IV of U.S. Pat. No. 5,399,759) was continuously fed at a rate of 3.0 g/min, and the volume of the reaction mixture was adjusted to a constant retention time of 34 minutes. The effluent from the reactor was continuously fed to a neutralizer, a 150ml cstr glass reactor equipped with an electromagnetic stirrer and a pH control system. The tributylamine added into the neutralizer keeps the pH value in the neutralizer between 7.5 and 8.5 under the adjustment of a pH control system. The 2-methyl-6-ethyl-N-ethoxymethyl-2-chloro-N-acetanilide product from the neutralizer was collected in a receiver from which a sample was taken, washed and stripped in a rotary evaporator. The purity of the product was 97.2% by weight, while the concentration of non-chloromethylated halo-acetanilide impurities was 2.8% by weight.

Claims (9)

1. A process for preparing an aromatic azomethine compound by reacting aniline with a formaldehyde supply wherein the formaldehyde is prepared by reacting paraformaldehyde with from about 0.25 to about 3 molar equivalents of an aliphatic alcohol having from 1 to 4 carbon atoms in the presence of a catalytic amount of a base, characterized in that the process comprises: (a) continuously carrying out reaction; and (b) continuously evaporating water from the reaction mixture.

2. The process of claim 1, wherein the azomethine preparation is carried out by passing the reaction mixture through one or more evaporators.

3. The process of claim 2 wherein the evaporator is a countercurrent contact evaporator.

4. The process of claim 1 wherein step (a) is carried out in a continuously stirred tank reactor.

5. The process of claim 1, wherein the azomethine preparation is carried out in two or more successive upflow evaporators.

6. The process of claim 1, wherein the azomethine preparation is carried out in one or more falling film evaporators, downflow flooded evaporators or combined evaporators having an upper falling film portion and a lower flooded portion.

7. The process of claim 1, wherein step (a) and/or (b) is carried out in one or more evaporators, the bottom of which is sparged with an inert gas or a compressible gas.

8. The process of claim 1, wherein the preparation of the azomethine compound is carried out in the presence of an inert solvent.

9. The process of claim 1, wherein the azomethine compound is prepared in the absence of an inert solvent.