IL90702A - Method of preparing n-n-propyl-n-2-(2,4,6-trichloro-phenoxy)-ethyl amine - Google Patents

Description

90702/2 4.036 A METHOD OF PREPARING N-n-PROPYL-N- 2- (2.4.6-TRICHLOROPHENOXY)-ETHYL AMINE ( 'o ι D a i n "?D τϋ-6 , 4 , 2 ) -2-N-1? 1 a ι TS -n-N nr n"? HID 'ΐϋ BACKGROUND OF THE INVENTION The present invention concerns the improved process for preparing 2- ( 2 , 4 , 6-t r i ch 1 o r o phe nox ) -e hy 1 chloride and N-n-p o py l-N-2- ( 2 , 4 , -t r i h 1 o r o ph e noxy > e t hy 1 amine and their use in the manufacture of Prochlora;. 2- ( , , -Tr i ch 1 o r ophenoxy )-ethy 1 chloride and. -n-propyl -N-2- (2 , , 6-t r i ch 1 oro phenox ) -ethy 1 amine are used as intermediates in preparing the fungicide Prochloraz.

According to GB 1,469,772, the classical method of preparing Prochloraz begins with 2 , 4 , -t r i ch 1 o r opheno 1. This process suffers from several disadvantages. First of all, the t r i ch 1 or o phe no 1 must be in a highly pure form to avoid the formation of tarry by-products in the subsequent steps of preparing Prochloraz. Second, the processes used to purify , 4 , -t r i ch 1 o r o pheno 1 most often lead to the formation of po 1 ych 1 o r i nat ed p-dioxins - especially 2,3,7,8-tetrachloro-p-dioxin - the latter generally considered one of the most toxic compounds known. Furthermore, the use of 2, 4, 6-tr i chlorophenol to prepare Prochloraz requires the reaction of the former under basic conditions, which can also lead to the formation of tet rach lo r o-p-di o i ns .

Recent reports have tried to avoid the problems. Thus, EP 243,038 describes a process of preparing 2,4,6-tri-chlorophenol involving the slow controlled chlorination of phenol in the presence of a catalyst which is alleged to diminish the formation of the dioxin by-products. EP 299,892 describes the chlorination of a chlorophenol using a different type of catalyst.

Nevertheless, even if the formation of unwanted toxic by-products are avoided, the standard process for preparing Prochloraz according to GB 1,469,772 involves the need to handle 2, 4, 6-tri hlorophenol and ethylene di-bromide - themselves both highly toxic and carcinogenic materials.

OBJECTIVES OF THE INVENTION It is the objective of the present invention to provide a new and improved method for the preparation of 2- ( , 4 , 6-t r i chl o r ophenoxy ) ethyl chloride and N-n-propyl- N-2- ( 2 , 4 , 6-t r i chlorophenoxy >-ethyl amine. It is a further objective of the present invention to provide a method for the preparation of these compounds without having to handle the highly toxic and carcinogenic 2,4,6-trichlorophenol and ethylene dibromide. A further objective is the provision of a method for the preparation of these compounds in high yields substantially free of the toxic dioxins.

SUMMARY OF THE INVENTION It has unexpectedly been discovered that N-n-propyl-<2,4,6-trichlorophenoxy )-ethyl amine may be prepared comprising the steps ofs- 1. selectively chlorinating 2-phenoxy-ethano 1 by reacting it with chlorine in the presence of urea at a temperature of from 20°C to 55°C in a water/ carbon tetrachloride solvent mixture, to form 2- <2,4,6-trichlorophenoxy)-ethanol; 2. Reacting the 2- < 2 , 4 , 6-t r i ch 1 o ro phenoxy ) -ethano 1 with thionyl chloride in the presence of a catalytic amount of a tetra-alkyl ammonium halide at a temp. of from 30°C to 100°C, optionally in the presence of a solvent to form 2-<2,4,6-tri chlorophenoxy )- ethyl chloride; 3. Reacting the 2- ( 2 , 4 , 6-t r i hl o ro phenoxy ) -e thy1 chloride with n-propyl amine at a temperature of from 20°C to 150°C, optionally in the presence of water, to form N-n-pro py l-N-2- (2, 4, -t chlorophenoxy )-ethyl amine; and 4. Recovering the N-n-pr o pyl-N-2- ( 2 , 4 , 6-t r i chlorophen- oxy)-ethyl amine formed.

DETAILED DESCRIPTION OF THE INVENTION The reaction process is generally illustrated below, on a batch-wise basis! - In carrying out the process of Stage I of the present invention, chlorine is reacted with 2-phenoxyethanol at a temperature of from 20°C to 55°C in the presence of urea. The most suitable rate at which the chlorine gas is fed will vary with the reaction temperature. This stage can only be carried out by reacting at least three moles of chlorine per mole of 2-phenoxy-ethanol . In practice, an excess of 20 percent of chlorine is used.

A small amount of urea was found to markedly improve the yield of the reaction and the purity of the product of Stage I. The ratio of urea to 2-phenoxy-ethanol which was found to improve the reaction is 1:4 to 1:70, preferably 1:10 to 1:20 and most preferably 1M4, by weight.

Running Stage I without water afforded black polymeric material. If this stage is not run in the presence of carbon tetrachloride, the selectivity of the chlorina-tion is greatly effected. The reaction is, therefore, preferably run in the presence of a mixed water/carbon 90702/2 4 tetrachloride solvent, in a ratio of 1:1 to 1:50, preferably 1:10 by volume.

The temperature of reaction of Stage II may range from 30°C to 100°C. At the lower end of the temperature range the reaction is not economical. At the higher end of the temperature range the reaction is difficult to control. The preferred temperature range is from about 50°C to 80°C.

Stage II may be run either with or without the use of a solvent. If a solvent is used halogenated hydrocarbons such as chloroform, dichloroethane and carbon tetrachloride are preferred, with carbon tetrachloride being the most preferred. In addition, the use of a catalyst such as a tetra-alkyl ammonium halide, was found necessary for this stage. The alkyl group of the tetra-alkyl ammonium halide may be chosen from the group consisting of straight or branched alkyl groups having from 1 to 16 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, heptyl, decyl, and the like, cyclic alkyl groups such as cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and the like and benzyl.

Preferred alkyl groups are straight chain alkyl groups having from 1 to 18 carbon atoms and benzyl. Most preferred are methyl and benzyl, with the preferred halide as chloride. An especially preferred catalyst is benzyl trimethyl ammonium chloride. The ratio of t e t r aa 1 ky 1 ammonium halide to 2-<2,4,6 - trichloro-phenoxy) - alcohol in Stage II is 1 to 250, preferably 1 to 60 by weight.

The temperatures of reaction of Stage III may range from 20°C to 150°C. At the lower end of the temperature range the reaction is too slow to be economical. At the higher end of the temperature range lower yields are obtained due to polymerization and decomposition. The preferred temperature range is from about 75°C to 90°C.

Stage III may be either run neat or in the presence of water. It is preferred from a chemical point of view to run the reaction in water, for then a lower temperature (75°C instead of 90°C) and lower pressure (1.7 to 2.3 atmospheres instead of 2.2 to 3 atmospheres) can be used. However, for technical reasons, it is sometimes preferred to run this stage without water.

The final amine product can be isolated as a mineral acid salt, preferably as the hydrochloride acid addition salt, which forms nice white crystals which are easily handled. However, if necessary, the free amine may be isolated by treating the hydrochloride salt with a base such as, for example, aqueous sodium carbonate to neutralize to pM 7, separate the phases and distill the organic layer to yield an oil boiling at 112-114°C/0.2 mm Hg .

Thus the present invention affords a process for preparing 2- ( 2 , 4 , 6-t r i c h 1 o ro phenoxy ) -e h 1 chloride and N-n-pr opyl-N-2- ( , 4 , 6-t r i h 1 o ro henoxy ) ethyl amine in high yield, without having to handle the highly toxic and carcinogenic 2, 47 -t r i ch 1 o pheno 1 and ethylene dibromide. In addition, the latter amine product may be reacted with phosgene and subsequently with imidazole according to GB 1,469,772 to afford Prochloraz, having essentially no detectable amount of the highly toxic 2,3,7, 8-tet rach 1 oro-p-dioxin.

While the invention will now be described in connection with certain preferred embodiments in the following examples, it will be understood that it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most use-ful and readily understood description of procedures as well as of the principles and conceptual aspects of the i nventi on.

EXAMPLE 1 Preparation Of 2-(2, 4, -tri chlorophenoxy )-ethanol : Into a three-necked, round-bottomed 1-liter flask fitted with a stirrer, a dip-pipe to convey gas, a thermometer and a reflux condenser, 140 g 2-phenoxy ethanol, 250 ml carbon tetrachloride, 25 ml water and 10 g urea were introduced. Chlorine gas was then added while stirring and keeping the temperature at 20°C via cooling. When the temperature reached about 55°C the rate of chlorine addition was lowered so that the cooling kept the temp, at 55°C in spite of the exotherm. Chlorine gas was added until the solution became yellow. The rate of chlorine addition was further lowered until the yellow color disappeared. At this stage it became necessary to heat the reaction mixture to keep the temperature at 55°C. The end of the reaction was determined by GLC .

Addition of chlorine was stopped and the mixture washed with NaHS03 (107.) and then with water. The mixture was then washed with a bicarbonate solution until a H of 8 was reached and then with additional water. Cooling the organic phase to 5°C with gentle stirring caused the precipitation of white crystals to afford filtration of 135 g of 2- (2 , 4 , 6-t r i 1 o r o phenoxy ) -e t hano 1 at a concentration of 96%. The mother liquor was recycled as solvent for subsequent batches of ch 1 o r i nat i on , purging about 157.. The overall yield after several runs of chlorination reaches 807.

EXAMPLE 2 Preparation of 2- < 2 , 4 , 6-t i h 1 o r o phenoxy ) -e hy 1 chloride Into a three-ne ked, round-bottom flask fitted with a stirrer, thermometer, reflux condenser and dropping funnel was added 250 g of 967. 2- ( 2, 4 , 6-t i ch 1 o o phenoxy > ethanol, 250 ml carbon tetrachloride and 4 g of bensyl-trimethyl-ammonium chloride. The mixture was heated to 55°C and 146 g thionyl chloride was added dropwise over 1.5 hours. After the addition of the thionyl chloride the temperature of the reaction was slowly raised to 80°C for a total reaction time of 2.5 to 3 hours. The end of the reaction was determined by GLC . The mixture was cooled to 60°C and water slowly added to decompose the excess thionyl chloride. The phases were separated and the organic phase was washed wi'th a 107. sodium hydroxide solution until it reached a pH of 7. After an additional separation of the phases the organic phase was washed again with water. After a further separation of phases, the carbon tetrachloride was distilled off to yield an oil which slowly crystallized to form 257 g of 2-(2,4,6-tri ch 1 o ro phenoxy )-ethyl chloride in a purity of 967.-987. and yield of 987..

EXAMPLE 3 Following the method of Example 2, the reaction was run without carbon tetrachloride as solvent. The only differences are as follows: - The thionyl chloride was added dropwise to a melted 2- < 2 ,4 , 6-t ri hl o ro henoxy ) -ethanol at a temperature of 70°C. After addition of about 107. of the thionyl chloride, the temperature was lowered to 50°C and the reaction continued as before. At the end of the reaction, when the final separation of the organic layer was done, there was no need to distill off any solvent, affording a similar yield and purity.

EXAMPLE 4 Preparation of N-n- pr o py1 -N-2- ( 2 , 4 , 6-t r i ch 1 o o phenox ethyl amine: Into a 1-liter glass reactor, which could withstand pressure of 6 atmospheres, fitted with a stirrer, heating mantle and a pressure gauge, were added 270.8 g 2-<2,4,6-tri ch 1 o r o phenoxy ) ethyl chloride and 350 g n-propyl amine. The mixture was slowly heated with stirring over a period of 8 hours at a temperature of 90°C. The initial pressure under these conditions was 3 atmospheres, which dropped during the reaction to about 2.2 atmospheres. The end of the reaction was determined by GLC. At the end of the reaction the mixture was cooled to 55°C, whereupon the pressure dropped to atmospheric. The excess n— ropyl amine was distilled off and it could be recycled for use in a subsequent batch, until a bottom temperature of 85°C was reached. At the end of the distillation the mixture was cooled to 40°C, 300 ml of a 20% hydrogen chloride solution and 1 g of an emulgator GAF RM-510 were added. The temperature rose to 70°C, the mixture was stirred for one hour at this temperature and the product precipitates as white crystals of the amine hydrochloride salt. The slurry is cooled to 40°C, filtered, re-slurried in 250 ml xylene and filtered again. This affords 312 g of white hydrochloride salt of N-n-pr opyl-N-2- ( 2 , 4 , 6-t r i chl orophen-oxy)-ethyl amine in 93% yield and purity of 96%-98%.

EXAMPLE 5 Following the method of Example 4, the same reaction was run in the presence of 60 g water. The only differences were that the maximum temperature was only 75°C , with a total reaction time of only 5 hours; the initial pressure was 2.3 atmospheres and the final pressure 1.7 to 1.8 atmospheres. This afforded N-n-propyl-N-2-(2,4,6-t r ch 1 o ro phenoxy ) -ethyl amine of similar yield and purity.

Claims (1)

1. C L M S A process for pr op 2 chlorophertoxy amine of the characterized in ethanol of the formula is selectively chlorinated by reaction with chlorine in the presence of urea at a temperature of to in a tetrachloride solvent to form 4 ophenoxy ethanol of the formulas CI the 2 r i 1 o r phenoxy is reacted with thionyl chloride in the presence of a catalytic amount of ammonium halide at a temperature of to optionally in the presence of a to form chlorophenoxy chloride of the formulas the r i 1 o r o phenoxy chloride is reacted with amine at a temperature of from to optionally in the presence of to form 2 4 r i hl o and recovering the r o y 2 4 r i 1 phenox amine A process in accordance with Claim 1 wherein the ratio of urea to in Stage 1 ranges from to by A process in accordance with any of Claims 1 or 2 wherein the ratio of urea to 1 in Stage I is by A process in accordance with any of Claims 1 to 3 wherein the ratio of water to carbon tetrachloride in Stage I ranges from to by A process in accordance with any of Claims 1 to 4 wherein the ratio of water to carbon tetrachloride in Stage I is by A process in accordance with any of Claims 1 to wherein the solvent of Stage II is a chlorinated hydrocarbon A process in accordance with any of Claims 1 to 6 wherein the solvent of Stage II is chosen from the group consisting of di 1 r omethane di chloroethane and carbon A process in accordance with any of Claims 1 to 7 wherein the solvent of Stage is carbon chloride A process in accordance with any of Claims 1 to 8 wherein the ammonium halide in Stage II is ammonium A process in accordance with any of Claims 1 to 9 wherein the group of the ammo urn halide in Stage II is chosen from the group i ng of straight or branched alkyl groups having from 1 to 16 carbon atoms and A process in accordance with any of Claims 1 to 10 wherein the alkyl group of the ammonium halide in Stage II is chosen from the group consist ing of straight chain alkyl groups having from 1 to 6 carbon atoms and A process in accordance with any of Claims 1 to wherein the ammonium halide in Stage II is A process in accordance with any of Claims 1 to 12 wherein the ratio of tet halide to 4 r i ch phenoxy coho 1 in Stage II is 1 to preferably 1 to 60 by A process in accordance with any of Claims 1 to 13 wherein the temperature of Stage II ranges from to A process in accordance with any of Claims 1 to 14 wherein Stage III is run in the presence of A process in accordance with any of Claims 1 to 15 wherein the temperature of Stage III ranges from to A process for preparing o py 2 r chlorophenoxy amine characte ised in is selectively chlorinated by the reaction of chlorine in the presence of in a ratio of urea to of 1 to 14 by weight at a temperature of to in a tetrachloride solvent in a ratio of water to carbon of 1 to 10 by volume to form chlorophenoxy ethanol reacting the hlorophenoxy with thionyl chloride in the presence of r chloride in a ratio of by at a temperature of from to in the presence of carbon tetrachloride as solvent to form chlorophenoxy ch 1 o r i de reacting the chloride with in the presence of water at temperature of from to to fo m ethyl and recovering the y 2 4 r i 1 phenoxy amine A process for preparing 2 4 i phenoxy ethyl chloride characte in ethanol is selectively chlorinated by the reaction of chlor ne in the presence of urea in a ratio of urea to of 1 to 14 by weight at a temperature of to in a tetrachloride solvent in a ratio of water to carbon tetrachloride of 1 to 10 by volume to form 2 4 r i 1 phenoxy ethanol reacting the with thionyl chloride in the presence of trimethyl ammonium chloride in a ratio of by weight at a temperature of from to in the resence of ca bon tetra hloride as solvent to form 2 4 r 1 r y t hy 1 and recovering the 2 4 i r phe xy t hy 1 py when prepared by the process claimed in any of Claims 1 to i ch 1 o henoxy chloride when prepared by the process claimed in any of Claims 1 to 16 and insufficientOCRQuality