FLUORINATION OF ACRYLATE ESTERS AND DERIVATIVES

Abstract

The present invention generally relates to processes for converting acrylate esters or a derivative thereof to difluoropropionic acid or a derivative thereof. This process is generally performed using fluorine gas in a hydrofluorocarbon solvent.

Claims

1.-38. (canceled)

39. A continuous process for fluorinating a double bond to form a compound of formula 2 comprising: forming a reaction stream comprising a compound of formula 1 dissolved in 2H,3H-decafluoropentane, ##STR00018## wherein R.sub.1 is alkoxy; the reaction stream flowing through a continuous fluorination reactor at a flow rate of from about 0.2 mL/minute to about 2 mL/minute and fluorine gas flows through the continuous fluorination reactor at a gas flow rate of from about 0.2 mmol/minute to about 2 mmol/minute; whereby reaction of the compound of formula 1 with the fluorine gas forms a compound of formula 2 ##STR00019## wherein R.sub.2 is alkoxy, and further reacting the compound of formula 2 with an alcohol and a catalyst, wherein the reaction is a transesterification.

40. The continuous process of claim 39, wherein the compound of formula 1 is dissolved in 2H,3H-decafluoropentane at a concentration from about 2 wt. % to about 20 wt. %.

41. The continuous process of claim 40, wherein the fluorine gas has a concentration of about 1% to about 20% fluorine gas in helium.

42. The continuous process of claim 39, wherein the continuous fluorination reactor is at a temperature from about 25 C. to about 80 C.

43. The continuous process of claim 41, wherein the continuous fluorination reactor is at a temperature from about 25 C. to about 80 C.

44. The continuous process of claim 41, wherein the continuous fluorination reactor is at a temperature of about 15 C.

45. The continuous process of claim 39, wherein the compound of formula 2 is collected in a receiving flask.

46. The continuous process of claim 39, wherein the fluorine gas has a concentration of about 1% to about 20% fluorine gas in helium.

47. The continuous process of claim 39, wherein the residence time of the reactants in the continuous fluorination reactor is from about 0.5 seconds to about 1 minute.

48. The continuous process of claim 44, wherein the residence time of the reactants in the continuous fluorination reactor is from about 0.5 seconds to about 1 minute.

49. The continuous process of claim 47, wherein the residence time of the reactants in the continuous fluorination reactor is from about 1 second to about 10 seconds.

50. The continuous process of claim 39, wherein R.sub.1 is methoxy.

51. The continuous process of claim 50, wherein R.sub.2 is methoxy.

52. The continuous process of claim 39, wherein the alcohol is methanol or ethanol.

53. The continuous process of claim 39, wherein the catalyst is an acid or a base.

54. The continuous process of claim 53, wherein the acid comprises toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, formic acid, triflic acid, trifluoroacetic acid, boron tribromide, aluminum oxide, titanium tetraethoxide, or a combination thereof.

55. The continuous process of claim 54, wherein the base comprises dimethylaminopyridine, diethylhydroxyamine, triethylamine, N,N-dii sopropylethylamine (Hunig's base), pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof.

Description

EXAMPLES

[0039] The following non-limiting examples are provided to further illustrate the present invention.

[0040] General procedure for fluorination of methyl acrylate. The fluorine line set-up was described in Organic Synthesis, Coll. Vol. 8, p. 286-295 (1993) by Teruo Umemoto, Kyoichi Tomita and Kosuke Kawada. All the work was conducted in an efficient fume hood with a fluorine gas detector in the hood. A cylinder of premixed 20% fluorine in helium was obtained from Matheson Tri-gas, Inc. The reaction was monitored by GC/MS on a DB-5 column.

Example 1: General Procedure for the Synthesis of methyl 2,3-difluoropropanoate (B)

[0041] A 100-mL round-bottomed reaction flask was charged with methyl acrylate and solvent. The system was purged with helium. The reaction was chilled to 78 C. in a dry ice/acetone bath. A slow stream of 20% fluorine in helium was introduced to the bottom of the flask under vigorous stirring. The flow rate was adjusted to 47.2 mL/min (0.39 mmol/min) and maintained at this rate while keeping the reaction at 78 C. for 2 hours. The reaction was then purged with helium and warmed to room temperature. Solvent was removed. GC/MS was used to analyze the reaction. When assuming the same response factor for each compound, the product mixture contained 46.8 wt. % of desired product, methyl 2,3-difluoropropanoate (B), along with 4.5 wt. % of starting material (A), 13.8 wt. % of methyl 2,3,3-trifluoropropanoate (D), 11.7 wt. % of fluoromethyl 2,3,3-trifluoropropanoate (E), and 23.2 wt. % of fluoromethyl 2,3-difluoropropanoate (C).

##STR00009##

TABLE-US-00001 TABLE 1 Experimental conditions using different solvents, temperatures, and fluorine concentrations Start- ing Experi- mate- Amount Temp F.sub.2 F.sub.2 ment rial (mol) Solvent ( C.) Conc Equiv. 1 A 0.033 acetonitrile 50 15 20% 1.8 mL 2 A 0.022 acetonitrile 50 40 20% 2.3 mL 3 A 0.022 Dichloro- 60 78 20% 2.1 methane mL 4 A 0.022 Pentafluoro- 60 15 20% 2.1 butane mL 5 A 0.022 2H,3H- 60 78 20% 2.1 decafluoro- mL pentane 6 A 0.022 2H,3H- 60 40 20% 2.1 decafluoro- mL pentane 7 A 0.022 2H,3H- 60 78 10% 2.1 decafluoro- mL pentane

TABLE-US-00002 TABLE 2 Results of using different solvents, temperatures and fluorine concentrations Product distribution (area %) Experiment A B C D E 1 45.8 13.4 2 63.1 11.8 3 61.8 18.4 4 12.9 27.1 4.2 5 14.9 35.5 18.4 14.5 11.5 6 3.1 33.6 20 18.5 14.6 7 28.4 37.9 15 11.1 7.6

TABLE-US-00003 TABLE 3 Experimental conditions using different additives and solvent combinations All reactions were conducted at 78 C. using 20% fluorine in helium Starting Amount F.sub.2 Experiment material (mol) Solvent Equiv. 8 A 0.022 2H,3H- .sup.50 mL:0.1 mL 2.5 decafluoropentane:ethanol 9 A 0.022 2H,3H- 60 mL:1 mL 2.5 decafluoropentane:ethanol 10 A 0.022 2H,3H- .sup.50 mL:0.5 mL 2.5 decafluoropentane:CF.sub.3SO.sub.3H 11 A 0.022 2H,3H- 50 mL:5 mL 2.5 decafluoropentane:methanol 12 A 0.022 2H,3H- 30 mL:30 mL 2.5 decafluoropentane:dichloromethane 13 A 0.022 2H,3H- 50 mL:1 mL 2.5 decafluoropentane:2,2,2-trifluoroethanol

TABLE-US-00004 TABLE 4 Results from different additives and solvent combinations Product Distribution (area %) Experiment A B C D E 8 17.7 44.1 15.8 9.73 6.1 9 11.4 48.5 14 14.2 6.1 10 16.2 30.8 15.4 15.1 11.7 11 32.8 39.9 5.5 7.8 12 27.2 13.5 1.6 13 33 37.7 11.3 9.8 6

Example 2: Synthesis of 2,3-difluoropropionic acid (G)

[0042] To a solution of acrylic acid in 2H,3H-decafluoropentane was added sodium fluoride as scavenger for HF. The suspension was cooled to 78 C. under vigorous stirring. Fluorine was introduced to the mixture under the same conditions as example 1. After the reaction, the mixture was filtered and analyzed by GC/MS.

##STR00010##

Example 3: Synthesis of methyl 2,3-difluoropropanoate (B) via acryloyl chloride

[0043] To a solution of acryloyl chloride in 2H,3H-decafluoropentane was added sodium fluoride as HF scavenger. The suspension was cooled to 78 C. under vigorous stirring. Fluorine was introduced to the mixture under the same conditions described in example 1. After the reaction, the mixture was filtered. Sodium carbonate (Na.sub.2CO.sub.3) was added to the filtrate followed by methanol at 0-4 C. The reaction was stirred at room temperature for 2 hours. The mixture was filtered and analyzed by GC/MS.

##STR00011##

Example 4: Synthesis of 2,3-difluoropropanenitrile (L)

[0044] A solution of acrylonitrile in 2H,3H-decafluoropentane was cooled to 78 C. Fluorine was introduced to the mixture under the same conditions described in example 1. After removal of solvent, the mixture was analyzed by GC/MS.

##STR00012##

TABLE-US-00005 TABLE 5 Experimental conditions of examples 2-4 All reactions were conducted at 78 C. using 20% fluorine in helium Starting Amount F.sub.2 Experiment Material (mol) Solvent Equivalent 14 F 0.029 2H,3H-decafluoropentane 50 mL 1.6 NaF (2.44 g, 0.058 mol) 15 J 0.025 2H,3H-decafluoropentane 60 mL 2.8 NaF (2.1 g, 0.05 mol) 16 K 0.0304 2H,3H-decafluoropentane 60 mL 2.3

TABLE-US-00006 TABLE 6 Results of using different starting materials Product Distribution (area %) Experiment F G H I 14 40.5 40 10.8 5.8 A B D 15 15.2 43.5 12.5 K L M 16 38.2 24.3 10.7

Example 5: Transesterification

[0045] To a solution of 2 mL of fluorination reaction mixture was added methanol and a catalyst. The reaction was stirred at room temperature for 48 hours and analyzed by GC/MS.

##STR00013##

TABLE-US-00007 TABLE 7 Results for transesterification Product Distribution (area %) Experiment Catalyst Amount A E D C B 17 18.35 7.06 10.42 14.17 35.37 18 TsOH 5 mg 19.75 0.00 18.42 0.37 48.23 19 DMAP 10 mg 19.54 0.00 18.46 1.72 46.75 20 H.sub.2SO.sub.4 50 L 19.23 0.00 17.74 0.51 47.63 (98%)

[0046] To a solution of 2 mL of reaction mixture from direct fluorination was added ROH or methanol and a catalyst. The reaction was stirred at room temperature for 24 hours and analyzed by GC/MS.

##STR00014##

TABLE-US-00008 Product Distribution (area %) Experiment R ROH N O B 21 Et EtOH 41.4 39 MeOH 36.3 9 43.9 22 n-Bu n-BuOH 47.1 43.7 MeOH 38.3 7.6 28.2

Example 6: Synthesis of methyl 2,3-difluoropropanoate

[0047] ##STR00015##

[0048] Ethyl acrylate (2 mL) was mixed with 50 mL 2H,3H-Decafluoropentane and cooled in an isopropanol/dry ice bath (78 C.). The solution was treated with fluorine (20% in helium) at a fluorine flow rate of 0.1 standard cubic feet per hour (SCFH) for 120 minutes. The overfluorinated product ester was trans-esterified by adding methanol or ethanol and DMAP. The conversion was approximately 60%. The difluoro ethyl ester and difluoro methyl ester were observed by Gas Chromatograph-Mass Spec (GCMS).

[0049] Example 7: Synthesis of n-butyl 2,3-difluoropropanoate

##STR00016##

[0050] n-Butyl acrylate (2 mL) was mixed with 50 mL 2H,3H-decafluoropentane and cooled in an isopropanol/dry ice bath (78 C.). The solution was treated with fluorine (20% in helium) at a fluorine flow rate of 0.1 SCFH for 120 minutes. The overfluorinated product was trans esterified by adding methanol and DMAP. The conversion was approximately 40%. n-Butyl 2,3-difluoropropanoate was detected by GCMS.

Example 8: Synthesis of methyl 2,3-difluoropropanoate via t-butyl 2,3-difluoropropanoate

[0051] ##STR00017##

[0052] t-Butyl acrylate (2 mL) was mixed with 50 mL 2H,3H-decafluoropentane and cooled in an isoproanol/dry ice bath (78 C.). The solution was treated with fluorine (20% in helium) at a fluorine flow rate of 0.1 SCFH for 120 minutes. The overfluorinated product ester was trans esterified by adding methanol and DMAP. Gas Chromatography-Mass Spec (GCMS) analysis showed that the starting material was mostly consumed. The mixture was less clean than the methyl acrylate, but the desired product (methyl 2,3-difluoropropanoate) was detected.

[0053] Example 9: Continuous Fluorination Process

[0054] The continuous fluorination process was tested using a microreactor using a design similar to that in Chambers, R.C. et al., Microreactors for elemental fluorine, Chem. Commun., 1999, 883-884. The methyl acrylate solution was drawn into a 20 mL syringe, and the solution was slowly pumped into the reactor using a syringe pump at a defined rate of addition. The tube for the fluorine gas was connected to a manifold setup that was resistant to corrosion by the fluorine gas. The manifold also allows further dilution of the fluorine gas with helium. The fluorine was supplied as a 20% mixture in helium. The exit stream from the reactor was transfered to a round bottom flask chilled at 78 C. using an isopropanol/dry ice bath. There was an outlet from the round bottom flask that transfers the reaction atmosphere through a tube that contains Alumina.

[0055] Methyl acrylate (1 mL) was dissolved in 2H,3H-decafluoropentane (20 mL) and slowly pumped at 0.7 mL/minute through the reactor. The reactor was placed on a cold surface having a temperature of 15 C. Concurrently, fluorine gas was passed through the reactor at a rate of 0.78 mmol/minute. The two streams mix inside the reactor, react, and were collected in a receiving flask cooled at 78 C. GCMS analysis showed the desired product as the major peaks (7.6 and 7.9 min) as the methyl and fluoromethyl esters. The conversion of reactant was approximately 90%.

[0056] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

[0057] As various changes could be made in the above methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.