The method of obtaining cycloalkyl or halogenated-o - aminophenylamino (options)

 

(57) Abstract:

Obtaining on-aminophenylamino General formula (I), where R denotes3-C6-cycloalkyl or1-C6-halogenated,

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lead from aniline via the intermediate formation of the nitrile of the formula R-CN where R above, with trihalogen boron and the subsequent interaction of the complex with aniline in the presence of Lewis acid. In addition, the compound of formula (1), specifically about aminophenylacetate, can be obtained by dehydrohalogenation 1-(o-AMINOPHENYL)-4-halogen-1-butanone in the presence of aqueous base and the phase transfer catalyst, for example, dialkylaminoalkyl or tetraalkylammonium. 1-(o-AMINOPHENYL)-4-halogen-1-butanone can be obtained from aniline and nitrile as described above. This reduces the amount of by-products and increases the yield of the target product. 3 S. and 13 C.p. f-crystals, 2 tab.

Cycloalkyl and halogenated o-aminophenylthio are used as starting products in the production of herbicide sulfamoyl of urea derivatives. Regiospecific obtaining derivatives of o-aminophenylamino described in the Patent Us 4160784. Specified patentlean and unsubstituted o-aminophenylamino. However, in many cases, the formation of undesirable by-products may result in lower outputs and cumbersome methods of selection of product.

Connection o-aminophenylacetate, in particular, is used to obtain derivatives of 1-(o-cyclopropanecarbonyl)phenylsulfonylacetate that are highly effective, safe for the environment herbicides for cereals. In known methods for producing o-aminophenylacetylene, such as described in patents US 4160784 and 5009600, as the source material is cyclopropylmethyl. However, cyclopropylmethyl is not readily available commercially, whereas 4-chlorobutyronitrile is commercially available. However, there is no effective way to obtain o-aminopenicillanic of 4-halogenations precursor, 1-(o-AMINOPHENYL)-4-halogen-1-butanone.

Therefore, an object of the present invention is an improved method of obtaining cycloalkyl and halogenated o-aminophenylamino which offers substantial reduced formation of by-products and increased the yield of the target product.

Further object of this invention is effectivethan.

Further, the object of this invention is economical and convenient source of raw materials for obtaining herbicide sulfamoyl of urea derivatives.

The present invention relates to an improved method of producing o-aminophenylamino formula I

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where R is a C3-C6-ciological or C1-C6-halogenated, which includes the following stages:

(1) the interaction of nitrile of the formula II

R-CN

with trihalogen boron in the presence of a solvent with obtaining donor complex is 1:1,

(2) the interaction of the complex with aniline in the presence of a Lewis acid to obtain the reaction mixture,

(3) bubbling into the reaction mixture an inert gas, such as nitrogen, at elevated temperature for a period of 1 to 24 hours and

(4) the damping barbotirovany the reaction mixture with water to obtain a product of formula I.

Following the method shown in process scheme I, where R is a C3-C6-cycloalkyl, such as cyclopropylmethyl, or C1-C6-halogenated, such as 4-halogenosilanes, in particular 4-chlorobutyronitrile and X denotes chlorine or bromine.

Scheme of the process I

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Mainly, the donor is of the usual solvents. It was unexpectedly found that primary education donor complex 1: 1 nitrile and trihalogen boron and subsequent addition of aniline and acid Lewis avoids the formation of undesirable side products, which bind aniline original product and make it unable to formation of the reaction product. Introduction nitrogen ozonation to facilitate the removal of cleaners containing hydrochloride of the product increases then the product yield and purity by reducing or eliminating kislotosoderjasimi adverse reactions. Currently, it is found that in industrial scale external pressure is essential for efficient removal side of gaseous hydrogen chloride, and, thus, prevent side reactions and decomposition of the reactants.

Solvents suitable for use in the process according to the invention are organic solvents, such as halogenated hydrocarbons, for example methylene chloride, dichloroethane, dichlorophen and the like; aromatic hydrocarbons such as toluene, coral, benzene and the like; halogenated aromatic compounds such as chlorobenzene, dichlorobenzene and the like. Preferred RA is chlorate.

The preferred Lewis acid for use according to the method of the invention is aluminum chloride.

Nitrogen loading accelerates the removal of gaseous hydrogen chloride and helps to direct the reaction toward completion.

This acceleration and the use of an inert gas, such as nitrogen, are essential to improve product yield and quality improvement. Reaction time while bubbling nitrogen can vary from about 1 to 24 hours, preferably about 8 to 16 hours, and more preferably about 12 hours.

The reaction rate increases with increasing temperature, however, increased temperature also increases the decomposition of reagents and other undesirable side reactions. High temperature, suitable for the time period ozonation nitrogen is about 30 - 150oC, preferably about 80 to 110oC.

Although suitable are the stoichiometric ratio of the reactants, the preferred ratio of the nitrile of the formula II to one molar equivalent of aniline is about 1 to 2 moles and more preferably about 1.5 to 1.5 moles.

The present invention further concerns a method for obtaining o-aminopenicillanic the least one molar equivalent of aqueous base in the presence of a phase transfer catalyst and optionally in the presence of an organic solvent.

o-Aminopenicillanic can be conveniently obtained with a minimum formation of by-products by dehydrohalogenating 1-(o-AMINOPHENYL)-4-halogen-1-butanone using at least one molar equivalent, preferably of 1.1 to 3.0 molar equivalents of aqueous base in the presence of a catalyst transfer and optionally in the presence of an organic solvent.

Although it is known that dehydrohalogenating-halogenation using water base leads to the formation of the corresponding cyclic ketone, for example, as described in Organic Synthesis, Coll. Vol. 4, pp. 597-600 (1963), in the implementation of these methods on a 4-halogenating the compounds of formula I, where X denotes chlorine or bromine, the reaction proceeds slowly, and the main product is basically the 4-hydroxy analog of formula III.

It has been unexpectedly discovered that when the reaction mixture is a phase transfer catalyst (ILC), the reaction rate increases significantly, and the main product is the desired cyclopropylamine formula I". The reaction scheme is presented in scheme II.

Chart II

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The phase transfer catalysts suitable for the and ammonium, for example trialkylamine salt or tetraalkylammonium salt, preferably three or tetrabutylammonium halides. An effective amount of catalyst may vary within the scope of 0.001 - of 0.50 molar equivalents.

Water base suitable for receiving o-aminophenylacetylene according to the present method, include the hydroxides, carbonates or bicarbonates of sodium and potassium or mixtures thereof at a concentration of aqueous solution of about 15% to 50% by weight in an amount sufficient to provide at least one molar equivalent, preferably about 1.1 to 3.0 molar equivalents, and more preferably about 1.5 to 2.5 molar equivalents.

The organic solvent may be inert water-insoluble solvent or mixtures of solvents, such as halogenated hydrocarbons, alkyl or aromatic ethers, aromatic hydrocarbons, halogenated aromatic hydrocarbons, and the like, preferably halogenated hydrocarbons, such as methylenechloride, ethylene dichloride, propylaniline and the like.

In accordance with the method according to the invention 4-halogenation compound of formula I', not necessarily dissolve what Lenton water base, preferably about 1.1 to 3.0 molar equivalents, more preferably about 1.5 to 2.5 molar equivalents, and Quaternary ammonium phase transfer catalyst, preferably methyltrioctylammonium in an amount of about 0.001 to 0.50 in molar equivalents, preferably about 0,025 - and 0.50 molar equivalents.

For a more complete understanding of the invention further presents specific examples of its implementation. These examples are given for illustration only and should not be construed as limiting the scope or underlying principles of the invention.

Denote URGH and GC denote liquid chromatography high resolution gas chromatography, respectively.

Example 1

Receiving o-aminophenylacetylene

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Stir in dichloroethane mixture BCl3(RUR 145.2 g, 1,238 mol) is treated with cyclopropylmethanol (to 101.8 g of 1.45 mol) over a period of 45 minutes at -3 to -5oC, stirred for 1 hour at 5 to 10oC, treated with aniline (to 112.2 g, 1,205 mol) over 1 hour period at between 7 and 12oC, stirred for 1 hour, handles one portion of AlCl3(170,7 g 1,281 mol) and stirred at room temperature for 1 hour. In the reaction mixtures is Uchenie 17 - 18. Heated and barbotirovany the mixture is cooled to 15oC add approximately 2-fold volume of water (based on the initial volume of the reaction mixture) for a period of 30 minutes at from 9 to 38oC and stirred at 35 to 38oC for 1 hour. Share phase, and the aqueous phase is extracted with methylene chloride. The organic phases are combined and concentrated in vacuo to obtain specified in the header of the product as an orange oil, which crystallized upon standing, 149,8 g, 95.6% of purity, the output of 73.7%, identified by VRIJ analysis.

Example 2

Obtaining 1-(o-AMINOPHENYL)-4-chloro-1-butanone

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Stir in dichloroethane mixture BCl3(59,2 g, 0.50 mol) is treated with 4-chlorobutyronitrile (62.5 g, 0,604 mol) over a 1 hour period at -8 to 0oC, stirred for 1 hour at 0 to 5oC, treated with aniline (45.1 g, 0,485 mol) over 1 hour period at 2 to 9oC, stirred for 1 hour, treated with a single portion of AlCl3(68,8 g, 0,515 mol) at room temperature. In the reaction mixture is bubbled nitrogen and heated at boiling temperature under reflux for 17 hours. Heated and barbotirovany the mixture is cooled to 35oC and add approximately 2-crates phase, and the aqueous phase is washed with 1,2-dichloroethane. The organic phases are combined and concentrated in vacuo to obtain the solution specified in the header of the product containing 85,9 g of the desired o-aminophenylthio, the yield of 89.7%, identified by VRIJ analysis.

Example 3

Comparative obtain 1-(o-AMINOPHENYL) cyclopropylmethyl

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The method used in this example is essentially the same as described in the patent US 4160784.

A solution of aniline (2.7 g, 0,029 mol) of aniline in dichloromethane is treated with BCl3(3,40 g 0,029 mol) over a period of 20 minutes at -8 to 5oC, stirred at -2 to 5oC for 35 minutes, treated with cyclopropylmethanol (2.9 g, 0,043 mol) over a 15 minute period at 0 to 5oC handle one portion of AlCl3(4,2 g, 0,0315 mol) and stirred at room temperature for 1.5 hours. The reaction mixture is heated at the boiling point under reflux for 18 hours, add the excess volume of water and stirred for 16 hours. Share phase, and the aqueous phase is extracted with methylene chloride. The organic phases are combined and concentrated in vacuo to obtain specified in the header of the product, to 2.55 g, 90% purity, yield 49.1 per cent, identificireba the

Following the method described in patent US 4988695.

To a solution of trichloride boron (55 g) in 1,2-dichloroethane (200 ml) at 0oC is added dropwise a solution of aniline (39,1 g, 0.42 mol) in 1,2-dichloroethane (50 ml), keeping the temperature below 5oC. after sequentially added 4-chlorobutyronitrile (41,4 g, 0.42 mol) and aluminofluoride (53,34 g, 0.42 mol) and the reaction mixture allowed to warm to room temperature, then heated under reflux for 20 hours. Then allowed to cool, add 2n. hydrochloric acid (100 ml), the reaction mixture is heated under reflux for 0.5 hours. The obtained solid product is collected by filtration, treated with water and extracted with chloroform (5 x 200 ml). The chloroform extracts are combined, washed with diluted basis, then water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain oil. The oil is dissolved in ether and added ethanolic HCl, the resulting solid product is collected by filtration and dried, 28.5 g, yield 29%. Recrystallization from ethanol/diethyl ether gives cleaners containing hydrochloride salt of the product, so pl. 152 - 154oC.

Example 5

Receiving o-aminophenylacetylene by dehydrohalogenating the AMINOPHENYL)-4-chloro-1-butanone (32,6 g, 0,165 mol) in ethylene dichloride process 147,3 g of 20% aqueous NaOH (0,736 mol NaOH) and 2,31 g of 75% aqueous methyltrioctylammonium (0,0074 mol) and stirred at 50 - 53oC for about 4 hours. (Samples are taken at intervals and analyzed URGH). The reaction is cooled to room temperature and separated phases. The organic phase is washed with water and concentrated in vacuo to obtain specified in the header of the product, 29,84 g, 70.6 per cent purity, output 79,2 % tests URGH and GC.

The reaction shown in table 1 (see end of description)

To estimate the effects of the phase transfer catalyst to dehydrohalogenation 1-(o-AMINOPHENYL)-4-chloro-1-butanone

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The main method

A mixture of 1-(o-AMINOPHENYL)-4-chloro-1-butanone (36,6 g, 0.18 mol) in a mixture solvent of ethylene dichloride and methylenechloride and 146 g of 20% aqueous NaOH (0.73 mol) was stirred at 50 - 85oC for 9 hours. After a period of 9 hours add methyltrioctylammonium (1,74 g, 0,0074 mol), and the stirring is continued for an additional 0.5 hours. Selected aliquots of the reaction mixture at intervals of 0.5 - 1 hour and examined for the presence of the original product (A), 1-(o-AMINOPHENYL)-4-hydroxy-1-butanone (B) and o-aminophenylacetylene (C). The results are summarized and shown"ptx2">

As can be seen from table 2 above, in the absence of a phase transfer catalyst (sample 1 - 11) of the original 4-chlorobutane (A) and preferably slowly converted into unwanted 4-hydroxybutanoic by-product (B). However, 0.5 hour after the addition of the phase transfer catalyst (sample 12) source product is completely converted into preferred desired cyclopropylmethyl product (C). Therefore the reaction rate to obtain the desired product (C) in almost 250 times higher in the presence of phase transfer catalyst in comparison with the absence of the phase transfer catalyst.

1. The method of obtaining on-aminophenylamino formula I

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where R is a C3-C6-cycloalkyl or C1-C6-halogenated,

from aniline using nitrile, trihalogen Bohr and Lewis acid in a solvent, characterized in that perform the following process stages: (1) the interaction of nitrile of the formula II

R - CH,

where R is indicated above,

with trihalogen boron in the presence of a solvent with obtaining donor complex 1:1; (2) the interaction of the complex with aniline in the presence of a Lewis acid with obtaining a reaction mixture; (3) bubbling inert tirovannoj the reaction mixture with water to obtain a product of formula I.

2. The method according to p. 1, characterized in that the solvent used dichloropropan or dichloroethane, as trihalogen boron use trichloride boron, as the Lewis acid used luminiare, and as the inert gas is nitrogen, and the process is conducted at a temperature of about 30 to 110oC and duration of ozonation of about 8 to 16 hours

3. The method according to p. 2, characterized in that the solvent used dichloroethane and duration of ozonation is around 12 o'clock

4. The method according to p. 2, wherein the process is conducted at a molar ratio of the compounds of formula II to anilino about 1:1 to 2:1.

5. The method according to p. 4, wherein the process is conducted at a molar ratio of the compounds of formula II to anilino about 1.3:1 to 1.5:1.

6. The method according to p. 1, characterized in that as a nitrile of the formula II used cyclopropylmethyl.

7. The method according to p. 1, characterized in that as the nitrile of formula II using 4-halogenosilanes.

8. The method according to p. 7, characterized in that as a 4-halogenosilanes use 4-chlorobutyronitrile.

9. The method of obtaining on-aminophenylacetylene by the interaction of the compounds of General forms of the aqueous solution in the presence of phase transfer catalyst using, if necessary, an organic solvent.

10. The method according to p. 9. characterized in that the organic solvent used ethylene dichloride, methylenechloride, propylaniline or their mixture, as the phase transfer catalyst used dialkylaminoalkyl or tetraalkylammonium, as water base use NaOH or KOH.

11. The method according to p. 10, characterized in that is used as a compound of General formula I' where X is chlorine.

12. The method according to p. 10, wherein the process is conducted in the presence of aqueous base in an amount of about 1.5 to 2.5 molar equivalents.

13. The method according to p. 10, characterized in that as the phase transfer catalyst used methyltrioctylammonium chloride, as the aqueous base used NaOH.

14. The method of obtaining on-aminophenylacetylene of aniline in the presence of a solvent, characterized in that carry out the following stages: (1) the interaction of 4-halogenosilanes with trihalogen boron in the presence of a solvent with obtaining donor complex 1: 1; (2) the interaction of the complex with aniline in the presence of a Lewis acid to obtain the reaction mixture; the s barbotirovany the reaction mixture with water to obtain the compounds of formula I'

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where X denotes chlorine or bromine,

further interact the compounds of formula I' with at least one molar equivalent of aqueous base in the presence of a phase transfer catalyst and, if necessary, using an organic solvent.

15. The method according to p. 14, characterized in that the solvent used dichloroethane or dichloropropane as 4-halogenosilanes use 4-chlorobutyronitrile at a molar ratio of 4-halogenosilanes to anilino about 1: 1 to 2:1, as trihalogen boron use trichloride boron, and the Lewis acid used luminiare, as the inert gas using nitrogen, the process is conducted at elevated temperatures of about 20 - 110oC, when the duration of ozonation of about 8 to 16 hours

16. The method according to p. 15, wherein as the organic solvent, if necessary, use ethylene dichloride, methylenechloride, propylaniline or their mixture, as water base use NaOH or KOH as the phase transfer catalyst used methyltrioctylammonium.

Priority points:

30.11.93 - PP.1 - 8;

30.12.93 - PP.9 - 16.

 

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