WO1998005630A1

WO1998005630A1 - Process for the preparation of organic nitriles

Info

Publication number: WO1998005630A1
Application number: PCT/US1997/013940
Authority: WO
Inventors: Chempolil Thomas Mathew; Heng Su; Baihua Wu
Original assignee: AlliedSignal Inc
Current assignee: Honeywell International Inc
Priority date: 1996-08-08
Filing date: 1997-08-08
Publication date: 1998-02-12
Anticipated expiration: 1999-02-08
Also published as: AU3829297A

Abstract

The invention provides a process for the production of organic nitriles from the corresponding aldoxime. More particularly, the invention provides a process in which acid salts are used to convert an aldoxime to its corresponding nitrile, which process produces the nitrile in very high yield.

Description

PROCESS FOR THE PREPARATION OF ORGANIC NITRJLES

Field of the Invention The invention relates to the production of organic nitriles from the coσesrjonding aldoxime More particularly, the invention provides a process in which acid salts are used to convert an aldoxime to its corresponding nitπle, which process produces the nitrile in very high yield

Background of the Invention

Organic nitriles, such as benzonitriles, are used in a variety of processes For example, 4-bromo- and 2-bromobenzonιtπle are used as intermediates in the production of pharmaceutical compounds 2-Fluoro-4-hydroxybenzonitπle is used in the production of liquid crystal displays Additionally, 2-hydroxybenzorutnle is an intermediate in the synthesis of agricultural products such as fungicides

One widely used method for producing organic nitriles involves the dehydration of an aldoxime to its corresponding organic nitπle A number of dehydrating agents have been used in the process including tnchloroacetylchloride- triethylamine, montmorillonite KSF, phosgene, thionyi chloride, phosphorous chloride, orthoester, and dicyclohexylcarbodiirrude WO 94/19317 discloses the use of formic acid in the presence of sodium formate as a dehydrating agent for the synthesis of ortho-hydroxy substituted aromatic nitriles The use of copper (II) acetate monohydrate also has been disclosed 9 Synthesis, 741- 42 (1983) These methods are disadvantageous in that the agents may be expensive, hazardous, or inconvenient to use Further, the dehydration reactions are exothermic reactions that are difficult to control United States Patent No 4,456,562 discloses a dehydration reaction for producing an organic nitrile in which an acid dehydration catalyst is used. Acid dehydration catalysts are disadvantageous in that the acid may react violently and is corrosive. Additionally, the use of an acid dehydration catalyst results in formation of a significant amount of aldehyde byproduct. Finally, the use of an acid catalyst requires neutralization of the acid for reaction product purification.

Thus, a need exists in the art for a simple, convenient, and economical process for producing organic nitriles. The present invention provides a process for the production of organic nitriles that overcomes some of the disadvantages of the prior art reactions.

Description of the Invention and Preferred Embodiments This invention provides a process for the production of organic nitrile compounds from the corresponding aldoxime in high yield. By organic nitrile is meant nitriles of the formula R-CN wherein R is a substituted or unsubstituted alkyl of I to 15 carbon atoms, alkenyl of 1 to 15 carbon atoms, aryl, or aralkyl radical and wherein R may be substituted by one or more alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, nitro, halogen, or aryl radical.

The process of the invention comprises the steps of: (A) mixing an effective amount of an acid salt and an aldoxime to form a reaction mixture; and (B) heating the reaction mixture at a temperature and for a time sufficient to form a reaction product comprising an organic nitrile. It has been discovered that the process of the invention provides a simple, easily controlled method for producing organic nitriles in high yield and with decreased byproduct formation as compared to known processes. The aldoximes useful in the process of the invention are of the formula RCH=NOH wherein R is substituted or unsubstituted alkyl of 1 to 15 carbon atoms, alkenyl of 1 to 15 carbon atoms, aryl, or aralkyl and wherein R may be substituted by one or more alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, akylthio of I to 6 carbon atoms, nitro, halogen, or aryl radical. Preferably, R is substituted or unsubstituted aryl.

Illustrative useful aldoximes include, without limitation, undecylic aldehyde oxime, benzaldehyde oxime, 2-methoxybenzaldehyde oxime, 4- methoxybenzaldehyde oxime, 2,4-dimethoxybenzaldehyde oxime, 2,3- dimethoxybenzaldehyde oxime, 2,6-dimethoxybenzaldehyde oxime, 2- hydroxybenzaldehyde oxime, 4-hydroxybenzaldehyde oxime, 2,4,6- trimethylbenzaldehyde oxime, 2-chlorobenzaldehyde oxime, 3-chlorobenzaldehyde oxime, 4-chlorobenzaldehyde oxime, 2-bromobenzaldehyde oxime, 3- bromobenzaldehyde oxime, 4-bromobenzaldehyde oxime, 2-fluorobenzaldehyde oxime, 3-fluorobenzaldehyde oxime, 4-fluorobenzaldehyde oxime, 2-fluoro-4- methoxybenzaldehyde oxime, 2-chloro-6-fluorobenzaldehyde oxime and 4- phenylbenzaldehyde oxime. More preferably, the aldoxime is one of the above- listed bromo, chloro, or fluoro substituted benzaldoximes, methoxybenzaldoximes, hydroxybenzaldoximes, 4-phenylbenzaldoxime, or 2,4,6-trimethylbenzaldoxime Most preferably, the aldoxime is 2-bromobenzaldehyde oxime, 4- bromobenzaldehyde oxime, or 2-fluoro-4-methoxybenzaldehyde oxime.

Generally, the aldoximes useful in the invention are commercially available Alternatively, the aldoximes may be prepared by reacting the corresponding aldehyde with hydroxylamine by any known process, for example as set forth in United States Patent No. 4,323,706, which is incorporated in its entirety herein by reference. The aldoximes produced by these processes may be used in this invention without purification. In the case of aldoximes prepared in the presence of a solvent, the solution of the oxime in the solvent also may be directly used in the process of the invention.

The acid salts useful in this invention, generally, are salts of acids having a pKa of about 5 or less. In particular, acid salts of mineral acids are used. The preferred acid for use in the process of the invention is sulfuric acid.

The acid salt counterion may be ammonium or any alkali metal cation including without limitation, sodium or potassium. The preferred cation is sodium. The acid salts are commercially available. Alternatively, the acid salts may be formed |n_ situ by neutralization of the acid with a stoichiometric amount of a suitable base followed by the evaporation of water. The base suitable for acid neutralization will be readily determinable by one ordinarily skilled in the art depending on the acid selected.

In step (A) of the process of the invention, an effective amount of the acid salt and the aldoxime are mixed together, in any order, to form a reaction mixture. An effective amount of acid salt is an amount effective to catalyze the dehydration reaction. Generally, the amount of acid salt used is from about 5 to about 100 weight percent based on the weight of the aldoxime. Preferably, from about 20 to about 50, more preferably from about 25 to about 35, weight percent is used. The acid salt used may be in any form, but preferably is in the form of crystals.

The mixing of the acid salt and aldoxime occurs in the presence of any solvent that is chemically inert to the reactants. Preferably, the boiling point of the solvent is at least about 75° C. More preferably, the boiling point is from about 105° C to about 150° C at the operating pressure. Any suitable solvent may be used including, without limitation, toluene, xylene, chlorobenzene, or dichlorobenzene. In step (B) of the process, the reaction mixture is heated under conditions suitable to form the reaction product, which product contains the organic nitrile, unreacted starting material, solvent, and byproducts. Generally, the reaction mixture is heated to a temperature from about 80 to about 200° C, preferably from about 100 to about 150° C, and maintained at that temperature for between about 10 minutes to about 10 hours, preferably from about 30 minutes to about three hours. The time for which the reaction is maintained at the reaction temperature will depend on the structure of the aldoxime used. The pressure at which the process is performed is not critical. Atmospheric pressure may be conveniently used.

In an optional step (C), the organic nitrile formed in step (B) may be recovered from the reaction product by filtering of the reaction product to remove the acid salt followed by removal of the solvent. Alternatively, the acid salt may be removed by adding a sufficient amount of water to the reaction product to dissolve the salt followed by the separation of the aqueous solution of the salt. Further, the organic nitrile may be purified, in an optional step (D), to remove reaction byproducts and form purified organic nitrile by any convenient means including, without limitation, distillation or crystallization.

The invention will be clarified further by the following illustrative examples.

Examples Example 1 To a 100 mL round-bottomed flask equipped with a heating mantle, a magnetic stirrer, a thermometer, and a Dean-Stark trap with condenser, were added 1.0 g of 2-chloro-6-fluorobenzaldoxime, 0.5 g sodium bisulfate, and 1 1.7 g of xylenes. The reaction mixture was heated under stirring to 143° C. The reaction was held at the same temperature until gas chromatography indicated that the dehydration reaction was complete, approximately 3 hours. After cooling to room temperature, the resulting mixture was filtered. The solid, sodium bisulfate, was washed with 2 x 10 mL xylene. The wash xylene was combined with the filtrate. Removal of the xylene using rotary evaporation provided 0 84 g of 2- chloro-6-fluorobenzonitrile, 98.2 % purity and 94 % yield. The melting point was measured to be 60 - 62° C. Infra-red scan showed a distinctive absorption peak at 2220 cm^'1 for nitrile groups.

Example 2 To a 100 mL three-necked flask, fitted with a mechanical agitator, a thermometer, a heating mantle and a Dean-Stark trap with a condenser was charged 3.0 g of 98 % 2-methoxybenzaldoxime, 1 5 g potassium bisulfate, and 20 g xylenes. The reaction mixture was heated to 143° C at reflux for two hours and then cooled to room temperature. After removal of the potassium bisulfate by filtration, the filtrate was evaporated to afford 2.59 g of 98 4 % 2- methoxybenzonitrile, a yield of 96.4 % with a 99 6 % conversion. The product was identified by GC and ER spectrography.

Example 3 The procedure of Example 2 was used except that 3.0 g of 98 % mesitaldehyde oxime, 1.5 g sodium bisulfate, and 20 g xylenes were used. The reaction mixture was heated at reflux for one hour and cooled to room temperature. After removal of the sodium bisulfate, the filtrate was evaporated to provide 2.56 g of 95.5 % 2,4,6-trimethylbenzonitrile, mp 45 - 51° C, with 93 4 % yield and 100 % conversion. Example 4 To a 1000 mL three-necked, round-bottomed flask equipped with a mechanical agitator, thermometer, heating mantle, and a dropping funnel were added a 547 6 g solution of crude 2-fluoro-4-methoxybenzaldehyde (FMBA) in xylenes containing 79 7 g (0.517 mol) of FMBA as 100 %, 328 g of 30 % hydroxylamine sulfate (0 6 mol). The reaction mixture was heated to 50° C and a 50 % by weight sodium hydroxide solution (96. Ig, 1 2 mol) was added through the dropping funnel over a period of 30 minutes while maintaining the temperature at 50° C. After the reaction was held at 50° C for 60 minutes, GC scan indicated that the starting material, FMBA, had completely converted to oxime. The resulting reaction mixture was kept at 50° C without stirring for 15 minutes to achieve good phase separation. The lower phase (aqueous solution, 411.9 g) was discarded. The organic phase remaining in the pot weighed 550.5 g. The dropping funnel was replaced by a Dean-Stark trap with condenser. The organic solution was refluxed for 4 hours to completely remove the moisture and then cooled to 100° C. Sodium bisulfate crystals, 34.3 g, were added. When the reaction mixture was heated at 143° C for 1.5 hours, GC scan indicated that a 99 8% conversion had been reached. The reaction mixture was cooled to room temperature and filtration of the resulting mixture provided 373.2 g 2-fluoro-4-methoxybenzonitrile (FMBN) solution. The determination of FMBN by internal standard indicated that 75.2 g (0.497 mol) of FMBN was formed with an overall yield of 96 % based on 2-fluoro-4-methoxybenzaldehyde. Further purification was accomplished by removal of xylenes followed by simple distillation under vacuum. Three cuts were collected: front cut, 7.15 g, 94.9 % purity; main cut, 54.4 g, bp 113° C, 3 torr, mp 64 -65° C, 97 7 % purity; and late cut, 11.52 g, 85.3 % purity. An overall yield of 89 % was achieved after distillation based on the starting FMBA. Example 5 To a three-necked flask equipped with a mechanical agitator, thermometer, heating mantle and Dean-Stark trap with condenser, were added 2.1 g of 99 2 % 4-bromobenzaldoxime, 1.05 g sodium bisulfate, and 20 g xylenes. The reaction mixture was heated to 1 12° C at reflux for 9 5 hours and then cooled to room temperature. GC analysis of the reaction indicated a 99 3 % conversion forming 96.9 % of the corresponding nitrile, 0.75 % of aldehyde, and 1.7 % of high boilers such as amide.

Example 5a In a comparative example to Example 5, a mixture of 3.0 g of 99 2 % 4- bromobenzaldoxime, 0.21 g 98 % sulfuric acid, and 20 g xylenes were heated at reflux for 2 hours and cooled to room temperature. GC analysis of the resulting mixture indicated a 99.8 % conversion forming 88.2 % of the corresponding nitrile, along with 5 6 % of the aldehyde and 5 7 % of the high boilers such as amide

Examples 5 and 5a demonstrate the superiority of the process of the invention to the prior art process that uses an acid dehydration catalyst. The result of using an acid dehydration catalyst, as shown in Example 5a, is the formation of a large amount of byproducts including aidehdye. The process of the invention, as exemplified in Example 5, using the acid salt results in minimization of byproduct formation.

Examples 6 - 20 For Examples 6 through 18, the procedure of Example 1 was used except that the reactants, reaction times, and products were as listed on Table I For Examples 6 - 10, 13 - 16, and 18 -20, 3 0 g aldoxime were used^. 10 g aldoxime were used for Example 1 1 and 2.0 g were used for Examples 12 and 17 20 g solvent were used in all of the examples.

Table 1

Table 1 (Continued)

Table 1 (Continued)

Ex. Aldoxime Acid Salt Solvent Reaction Conversion Nitrile Aldehyde

(% by t Time (h) (GC area*/.) (GC area*/.) (GC area*/.) aldoxime)

19 trans-Cinnamaldoxime NaHSO₄ Xylenes 0.75 100 81.1 2.7 (50%) o

20 Mesitaldoxime NaHSO₄ 1,2- 0.5 100 92.7 1.1 ro

(26%) Dichloro- I benzene

- 10/3 -

As the examples illustrate, the process of the invention produces the desired organic nitrile in high yield. Additionally, the results on Table 1 demonstrate that the organic nitrile product is produced with only minimal formation of aldehyde byproduct.

Claims

11 -What is claimed is:

1. A process for producing an organic nitrile comprising the steps of:

(A) mixing an effective amount of an acid salt and an aldoxime to form a reaction mixture; and

(B) heating the reaction mixture at a temperature and for a time sufficient to form a reaction product comprising the organic nitrile.

2. The process of claim 1 wherein the aldoxime is of the formula RCH=NOH wherein R is a substituted or unsubstituted alkyl of I to 15 carbon atoms, alkenyl of 1 to 15 carbon atoms, aryl, or aralkyl radical.

3. The process of claim 1 wherein the aldoxime is selected from the group consisting of undecylic aldehyde oxime, benzaldehyde oxime, 2- methoxybenzaldehyde oxime, 4-methoxybenzaldehyde oxime, 2,4- dimethoxybenzaldehyde oxime, 2,3-dimethoxybenzaldehyde oxime, 2,6- dimethoxybenzaldehyde oxime, 2-hydroxybenzaldehyde oxime, 4- hydroxybenzaldehyde oxime, 2,4,6-trimethylbenzaldehyde oxime, 2- chlorobenzaldehyde oxime, 3-chlorobenzaldehyde oxime, 4-chlorobenzaldehyde oxime, 2-bromobenzaldehyde oxime, 3 -bromobenzaldehyde oxime, 4- bromobenzaldehyde oxime, 2-fluorobenzaldehyde oxime, 3-fluorobenzaldehyde oxime, 4-fluorobenzaldehyde oxime, 2-fluoro-4-methoxybenzaldehyde oxime, 2- chloro-6-fluorobenzaldehyde oxime and 4-phenylbenzaldehyde oxime.

4. The process of claim 1 wherein the aldoxime is 2-bromobenzaldehyde oxime.

5. The process of claim 1 wherein the aldoxime is 2-fluoro-4- methoxybenzaldehyde oxime. - 12 -

6. The process of claim 1 wherein the acid salt is a salt of sulfuric acid.

7. The process of claim 1 wherein the acid salt is sodium bisulfate.

8. A process for producing an organic nitrile comprising the steps of:

(A) mixing an acid salt and an aldoxime to form a reaction mixture, the acid salt present in an amount of from about 5 to about 100 weight percent based on the weight of the aldoxime and being a salt of an acid having a pKa of about 5 or less and the aldoxime being of the formula RCH^*=NOH wherein R is a substituted or unsubstituted alkyl of 1 to 15 carbon atoms, alkenyl of 1 to 15 carbon atoms, aryl, or aralkyl radical;

(B) heating the reaction mixture at from about 80° C to about 200° C for between about 10 minutes and about 10 hours.

9. A process for producing an organic nitrile comprising the steps of:

(A) mixing an acid salt and an aldoxime to form a reaction mixture, the acid salt present in an amount of from about 20 to about 50 weight percent based on the weight of the aldoxime and being a salt of an acid having a pKa of about 5 or less and the aldoxime being selected from the group consisting of undecylic aldehyde oxime, benzaldehyde oxime, 2-methoxybenzaldehyde oxime, 4- methoxybenzaldehyde oxime, 2,4-dimethoxybenzaldehyde oxime, 2,3- dimethoxybenzaldehyde oxime, 2.6-dimethoxybenzaldehyde oxime, 2- hydroxybenzaldehyde oxime, 4-hydroxybenzaldehyde oxime, 2,4,6- trimethylbenzaldehyde oxime, 2-chlorobenzaldehyde oxime, 3-chlorobenzaldehyde oxime, 4-chlorobenzaldehyde oxime, 2-bromobenzaldehyde oxime, 3- bromobenzaldehyde oxime, 4-bromobenzaldehyde oxime, 2-fluorobenzaldehyde oxime, 3-fluorobenzaldehyde oxime, 4-fluorobenzaldehyde oxime, 2-fluoro-4- - 13 -

methoxybenzaldehyde oxime, 2-chloro-6-fluorobenzaldehyde oxime and 4- phenylbenzaldehyde oxime;

(B) heating the reaction mixture at from about 100° C to about 150° C for between about 30 minutes and about 3 hours

10. The process of claim 9 wherein the acid salt is sodium bisulfate.