MXPA98010187A - Conversion of n- (4-fluorophenyl) -2-hydroxy-n- (1-methylthyl) acetamide in n- (4-fluorophenyl) -2-hydroxy-n- (1-methylthyl) acetam - Google Patents

Abstract

A process for preparing N- (4-fluorophenyl) -2- hydroxy-N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide, consisting of the steps of: (a) reacting N-acetate (4-fluorophenyl) -2-hydroxyN- (1-methylethyl) acetamide with an alkali metal base in the presence of water and an aromatic-aromatic solvent to form a reaction product having an aqueous and an organic phase and (b) recover N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide of the organic phase

Description

CONVERSION OF N-T ACETATE (4-FLUOROFENIL) -2- HYDROXY-N- (l-METHYLTHYL) ACETAMIDE IN N- (4-FLUOROFENYL) 2-HYDROXY-N- (1-METHYLTHYL) ACETAMIDE TECHNICAL FIELD OF THE INVENTION The field of the present invention is the synthesis of hydroxyacetamides. More specifically, the invention relates to methods for producing N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide. BACKGROUND OF THE INVENTION Hydroxyacetamides are useful intermediates in the preparation of thiadiazoleacetamide herbicides. An example of such herbicides is N- (4-fluorophenyl-N- (1-methylethyl) -2- [[5- (trifluoromethyl-1,3,4-thiadiazol-2-yl] oxy]] acetamide. , for example, US Pat. No. 5,101,034.) This thiadiazoleacetamide can be prepared by reaction of N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide with 2-methyl-sulfonyl-5- trifluoromethyl-1,3,4-thiadiazole (see, for example, US Patent 5,101,034) Typically, the formation of N- (4-fluorophenyl) -2-hydroxy-N- (1 -methylethyl) acetamide is carried out by conversion of the corresponding chloride (i.e., [2-chloro-N- (4-fluorophenyl) -N- (1-methylethyl) acetamide]) into N- (4-) acetate. fluoro-phenyl) -2-hydroxy-N- (1-methylethyl) acetamide and then hydrolysis of the intermediate acetate to the final hydroxyacetamide using an alcohol US Patent 4,334,073 describes the production of N-methylamide hydroxyacetic acid and of hydroxyacetic acid-2-ethylpiperidine The methylamide compound is prepared by reaction of chloroacetic acid-N-methylanilide in toluene with sodium acetate and benzyltrimethylammonium chloride to form acetoxyacetic acid-N-methylanilide and subsequent hydrolysis of that intermediate acetate with methanol to form N-methylamide of hydroxyacetic acid. A byproduct of that reaction, however, is methyl acetate, which must be removed by distillation. In a similar manner, the piperidine compound is prepared by reaction of chloroacetic acid-N-ethylpiperidine in toluene with sodium acetate and benzyltrimethylammonium chloride to form acetoxyacetic acid-N-ethylpiperidine and subsequent hydrolysis of that intermediate acetate with methanol to form hydroxyacetic acid -N-ethylpiperidine. Methyl acetate is also formed as a by-product of that reaction and needs to be removed by distillation. A method is therefore needed in the art to produce hydroxyacetamides such as N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide, the method of which avoids the formation of methyl acetate and avoids This way the need for an additional stage of distillation. BRIEF COMPENDI OF THE INVENTION The present invention provides a process for preparing N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide. The process converts N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide. The process includes the step of reacting N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate with an alkali metal base in the presence of water and an aromatic aprotic solvent. The N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate used in the process is produced by the reaction of 2-chloro-N- (4-fluorophenyl) -N- (1-methylethyl) Acetamide with sodium acetate. The reaction of the acetate with base and water in the solvent produces a reaction product having an aqueous phase and an organic phase. The process can also include the step * of the recovery of N- (4-fluorophenyl) -2-hydroxy-N- (1-methyl-ethyl) acetamide from an organic phase. Preferred solvents include toluene, xylene, eumeno or mesitylene. Toluene is most preferred. The base is a water soluble base. Preferably, the base is an alkali metal base, such as an alkali metal hydroxide or an alkali metal carbonate. Preferred alkali metals are sodium, potassium and lithium. An especially preferred alkali metal hydroxide is sodium hydroxide. Especially preferred alkali metal carbonates are sodium carbonate and potassium carbonate. Preferably, the alkali metal base is in the form of an aqueous solution containing from about 15 weight percent to about 50 weight percent of the base. More preferably, the aqueous solution contains from about 20 weight percent to about 30 weight percent base. The molar ratio of base to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate is from about 1: 1 to about 4: 1. The reaction mixture is maintained at a temperature of about 15 ° C to about 50 ° C, for a period of time sufficient for the conversion of the acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1- methylethyl) -acetamide. The time will vary with the reaction temperature. When the reaction temperature is about 25 ° C, the reaction is maintained at that temperature for about 6 to about 18 hours. In a preferred embodiment, a process of the invention includes the steps of mixing N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate in toluene with an aqueous solution of sodium hydroxide, for forming a reaction product having an aqueous phase and an organic phase, keeping the reaction product at a temperature of about 25 ° C until the N- (4-fluorophenyl) -2-hydroxy acetate has been fully hydrolyzed. N- (1-methylethyl) acetamide. This elegant conversion can be controlled using techniques such as gas chromatography (C.G.) or high pressure liquid chromatography (CLAP). In another aspect, the present invention provides a process for converting N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- ( 1-methylethyl) acetamide. The process includes the step of reacting N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate with water in the presence of an aromatic aprotic solvent. The N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate used in the process is produced by the reaction of 2-chloro-N- (4-fluorophenyl) -N- (1-methylethyl) ) -acetamide with sodium acetate. The reaction of the acetate with water in the solvent produces a reaction product having an aqueous phase and an organic phase. The process may also include the step of recovering N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide from the organic phase. Preferred solvents include toluene, xylene, eumeno or mesitylene. The most preferred is toluene. The reaction mixture is maintained at a temperature of about 15 ° C to about 50 ° C, for a period of time sufficient for the conversion of the acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide The time will vary with the temperature of the reaction. When the temperature of the reaction is about 25 ° C, the reaction is maintained at that temperature for about 40 hours. In a preferred embodiment, the conversion process includes the steps of mixing N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate in toluene with water to form a reaction product having an aqueous phase and an organic phase and the maintenance of the reaction product at a temperature of about 25 ° C until the N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate disappears from the product of reaction. DETAILED DESCRIPTION OF THE INVENTION I. The Invention This invention relates to processes for synthesizing N- (4-fluorophenyl) -2-hydroxy-N- (1-methyl-ethyl) acetamide (FOE-hydroxy). The procedures provide (a) conversion of N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate (FOE-acetate) to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide (FOE-hydroxy) using inorganic bases and (b) conversion of FOE-acetate to FOE-hydroxy using only water and an aromatic aprotic solvent. II. Conversion of N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide using aqueous alkali In a appearanceou. , the present invention provides a process for preparing FOE-hydroxy, by which N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide (FOE-acetate) acetate is converted to FOE-hydroxy. The conversion involves the hydrolysis of the FOE-acetate with an aqueous alkali. The acetate used in the process can be prepared by any means. Preferably, however, the acetate is prepared by reaction of FOE-chloride with sodium acetate, with or without catalysts. As indicated hereinbefore, the reaction of sodium acetate and FOE-chloride with the subsequent hydrolysis of FOE-acetate to FOE-hydroxy is an existing method for preparing FOE-hydroxy (see, for example, US Pat. 4,334,073, the description of which is hereby incorporated by reference). According to that method, hydrolysis of the FOE-acetate is carried out with the use of an alcohol, such as methanol. The use of methanol, however, results in the formation of substantial amounts of the byproduct, methyl acetate. This by-product must be removed from the reaction product using a distillation step. The present process prevents the formation of the methyl by-product acetate and, therefore, eliminates the distillation step. A process of the present invention uses an alkali or aqueous base to hydrolyze the intermediate FOE-acetate. More specifically, the method includes the step of reacting the FOE-acetate with an alkali metal base in the presence of water and an appropriate organic solvent. A preferred solvent for use in the process is an aromatic organic aprotic solvent. Such solvents are well known in the art. Preferred examples of such solvents are toluene, xylene, eumeno and mesitylene. The most preferred is toluene. The molar ratio of solvent to FOE-acetate is from about 4: 1 to about 8: 1. The base used in the process is a water-soluble base. Preferably, the base is an alkali metal base, such as an alkali metal hydroxide or an alkali metal carbonate. Preferred alkali metals are sodium, potassium and lithium. An especially preferred alkali metal hydroxide is sodium hydroxide. Particularly preferred alkali metal carbonates are sodium carbonate and potassium carbonate. Preferably, the alkali metal base is in the form of an aqueous solution containing from about 15 weight percent to about 50 weight percent of the base. More preferably, the aqueous solution contains from about 20 weight percent to about 30 weight percent base. The molar ratio of base to FOE-acetate is from about 1: 1 to about 4: 1. The reaction is initiated by mixing the EOS-acetate in the solvent (eg, toluene) with base and water. The reaction mixture, therefore, contains both an aqueous phase and an organic phase. The total amount of base can be added at one time or, preferably, in aliquots over 1 to 2 hours. The molar ratio of water added to FOE-acetate is from about 25: 1 to about 50: 1. The reaction mixture is heated until substantially complete hydrolysis of the FOE-acetate. The total time necessary for the completion of the reaction varies, as is well known in the art, with the temperature of the reaction. Typically, the reaction mixture is maintained at a temperature of about 15 ° C to about 50 ° C. A particularly preferred reaction temperature is room temperature (approximately 25 ° C). When the reaction temperature is about 25 ° C, the reaction is maintained at that temperature for about 6 to about 18 hours (overnight). The method may further include the step of recovering FOE-hydroxy from the organic phase. The means to recover the FOE-hydroxy are the same as those indicated in Section II. In a preferred embodiment, a method of the invention includes the steps of blending FOE-acetate in toluene with an aqueous solution of sodium hydroxide to form a reaction product having an aqueous phase and an organic phase, keeping the reaction product at a temperature of approximately 25 ° C until the FOE-acetate has been completely hydrolysed, and recovery of the EOS-hydroxy.

III. Conversion of N- (4-fluorophenyl) -2- hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide through hydrolysis in solvent and water The present invention provides an additional means to convert the FOE-acetate into FOE-hydroxy, which means avoids the use of both methanol and aqueous alkali. According to this procedure, the FOE-acetate is hydrolyzed to FOE-hydroxy with water in the presence of solvent. The by-product is acetic acid, which is easily biodegradable, not giving rise to any saline load of sodium acetate in the waste stream. The preferred solvents are the same as those indicated above. Toluene is the most preferred solvent. The hydrolysis is carried out by dissolving or suspending in some other way FOE-acetate in the solvent. The preferred solvent ratios to FOE-acetate are as indicated above. The FOE-acetate in solvent is then mixed with water in the molar ratio of about 5 to about 30 moles of water per mole of FOE-acetate. Preferably, that molar ratio is from about 25: 1 to about 30: 1. The mixture of FOE-acetate, solvent and water is then maintained at a temperature suitable for hydrolysis for a sufficient period of time for hydrolysis of the FOE-acetate to FOE-hydroxy. The time required for substantially complete hydrolysis will vary, as is well known in the art, depending on the hydrolysis temperature employed. Typically, hydrolysis with water is carried out at a temperature of about 20 ° C to about 50 ° C. More preferably, the temperature is from about 20 ° C to about 30 ° C. This temperature range corresponds to the ambient temperature conditions of the room. When the hydrolysis is carried out at room temperature in the room, the time necessary for the substantially complete hydrolysis of the FOE-acetate is from about 35 to about 45 hours. The progress of the hydrolysis reaction can be controlled using C.G. analysis. or of CJLAP and finalized when disappearing the FOE-acetate. The FOE-hydroxy prepared according to this hydrolysis is recovered and isolated using means well known in the art, as indicated above. The examples given below illustrate preferred embodiments of the present invention and are not limiting of the specification or the claims in any way. EXAMPLES Example 1: Conversion of N- (-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide using aqueous alkali and toluene they put 253.24 grams (1.0 mole) of FOE-acetate in a flask. 600 grams of toluene was added with stirring to the flask at room temperature (25 ° C). 600 grams of water were then added to the stirred mixture, followed by addition of 160 grams of 50% NaOH (2 moles). The mixture was stirred at various temperatures (25 ° C to 80 ° C) for several times (4 to 10 hours). The analysis of C.G. and the CLAP analysis of the organic phase indicated the completion of the reaction. The phases were separated and the aqueous phase was washed with 100 grams of toluene. The toluene wash was combined with the organic phase. The solvent was removed by vacuum purification and the FOE-hydroxy was isolated by desquamation. The results are summarized in the following table.

Example 2: Conversion of N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide using water and toluene 253.24 grams (1.0 mole) of FOE-acetate was placed in a flask. Approximately 600 grams of toluene were added with stirring at room temperature (25 ° C). Approximately 600 grams of water was then added to the stirred mixture at 25 ° C. The mixture was stirred at various temperatures (25 ° C-80 ° C) for several times (12-48 hours). The analysis of C.G. and the CLAP analysis of the organic phase indicated the completion of the reaction (a ° C, approx. 50% completion at the end of 24 hours). The phases were separated and the aqueous phase was washed with 100 grams of toluene. The toluene wash was combined with the organic phase. The solvent was removed by vacuum purification and the FOE-hydroxy was isolated by desquamation. The results are shown in the following table.

Although the invention has been described in detail in the foregoing for purposes of illustration, it is to be understood that said detail has. only that end and that those skilled in the art can make variations therein without departing from the spirit and scope of the invention, except as may be limited by the claims.

Claims (21)

1. CLAIMS 1. A process for preparing N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide, consisting of the steps of: (a) reacting N- (4-fluorophenyl) -2 acetate -hydroxy-N- (1-methylethyl) -acetamide with an alkali metal base in the presence of water and an aromatic aprotic solvent to form a reaction product having an aqueous phase and an organic phase and (b) recovering the N- (4-fluorophenyl) -2- hydroxy-N- (1-methylethyl) acetamide of the organic phase.
2. 2. The process of Claim 1, wherein the solvent is toluene, xylene, eumeno or mesitylene.
3. 3. The method of Claim 2, wherein the solvent is toluene.
4. 4. The process of Claim 1, wherein the alkali metal base is an alkali metal hydroxide or an alkali metal carbonate.
5. 5. The method of Claim 4, wherein the alkali metal is sodium, potassium or lithium.
6. 6. The process of Claim 5, wherein the alkali metal hydroxide is sodium hydroxide.
7. 7. The process of Claim 5, wherein the alkali metal carbonate is potassium carbonate.
8. 8. The process of Claim 1, wherein the base molar ratio of alkali metal to acetate of N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide is from about 1: 1 to about 4: 1.
9. The method of Claim 1, wherein the alkali metal aqueous base is an aqueous solution of about 1 weight percent to about 50 weight percent alkali metal base.
10. The process of Claim 9, wherein the alkali metal base is sodium hydroxide.
11. 11. The process of Claim 1, wherein the N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate in toluene is mixed with an aqueous solution of sodium hydroxide to form a product of reaction and the reaction product is maintained at a temperature of about 20 ° C to about 45 ° C, until the N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate disappears from the reaction product.
12. The method of Claim 1, wherein the N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate is formed by the reaction of 2-chloro-N- (4-fluorophenyl) - N- (1-methylethyl) acetamide with sodium acetate.
13. 13. A process for converting N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide, consisting of the step of hydrolyzing N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate with water in the presence of an aromatic aprotic solvent.
14. 14. The process of Claim 13, wherein the solvent is toluene, eumeno, xylene or mesitylene.
15. 15. The process of Claim 14, wherein the solvent is toluene.
16. 16. The method of Claim 15, wherein the molar ratio of toluene to N- (4-fluorophe- nyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate is from about 3: 1 to about 10: 1.
17. 17. The method of Claim 16, wherein the molar ratio of toluene to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate is from about 4: 1 to about 5: 1
18. 18. The method of Claim 13, wherein the molar ratio of water to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate is from about 10: 1 to about 30: 1.
19. 19. The method of Claim 18, wherein the molar ratio of water to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate is from about 20: 1 to about 30: 1.
20. The process of Claim 13, wherein the hydrolysis is carried out at a temperature of from about 20 ° C to about 30 ° C, for about 35 to about 45 hours.
21. 21. A process for converting N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate to N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide, consisting of the steps of: (a) adding water to a mixture of N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide acetate in toluene to form a reaction mixture having a phase aqueous phase and an organic phase, (b) heating the reaction mixture of step (a) to a temperature of from about 20 ° C to about 30 ° C for about 35 hours to about 45 hours, (c) separating the organic phase of the aqueous phase and (d) recovering N- (4-fluorophenyl) -2-hydroxy-N- (1-methylethyl) acetamide from the organic phase.