CA2957164A1 - Low temperature free radical initiated process for the preparation of 3-((3,3,3-trifluoropropyl)thio)propionic acid and esters thereof - Google Patents

Abstract

3-((3,3,3-Trifluoropropyl)thio)propionic acid and esters thereof are prepared by a low temperature free radical process involving the free radical coupling of 3-mercaptopropionic acid and esters thereof with 3,3,3-trifluoropropene. The ratio of linear to branched isomer is enhanced.

Description

2 LOW TEMPERATURE FREE RADICAL INITIATED PROCESS FOR THE
PREPARATION OF 3-((3,3,3-TRIFLUOROPROPYL)THIO)PROPIONIC ACID AND
ESTERS THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
This Application claims the benefit of U.S. Provisional Application Serial No.

62/034,452, filed August 7, 2014, the entire disclosure of which is hereby expressly incorporated by reference into this Application.
TECHNICAL FIELD
The present invention concerns a process for the preparation of 3-((3,3,3-trifluoro-propyl)thio)propionic acid and esters thereof. More particularly, the present invention concerns a process for the preparation of 3-((3,3,3-trifluoropropyl)thio)-propionic acid and esters thereof by the free radical coupling of 3-mercaptopropionic acid and esters thereof with 3,3,3-trifluoropropene.
BACKGROUND

3-((3,3,3-Trifluoropropyl)thio)propionic acid and methyl 3-((3,3,3-trifluoropropy1)-thio)propionate are useful to produce pesticidal thioether and pesticidal sulfoxides such as N-(3-chloro-1-(pyridin-3-y1)-1H-pyrazol-4-y1)-N-ethy1-3-((3,3,3-trifluoropropyl)thio)-propanamide.
Fv.......F

I /

N
Methyl 3-((3,3,3-trifluoropropyl)thio)propionate has typically been produced by the free radical addition of methyl 3-mercaptopropionate to 3,3,3-trifluoropropene in the presence of a free radical initiator such as a-azobisisobutyronitrile (AIBN) at high temperatures. The ratio of the desired linear isomer to the undesired branched isomer is approximately 10:1.

F
0 F 0 F F--..,..õ...
H3CFõ õ....,_ .......---, ,,,......õ,,,,...< + H3Cõ
,......_ _....._ ..õ..--..õ
Linear Branched It would be desirable to more selectively prepare methyl 3-((3,3,3-trifluoropropyl)thio)-propionate or 3-((3,3,3-trifluoropropyl)thio)propionic acid with less of the branched isomer.
SUMMARY
The present invention concerns a process for the preparation of 3-((3,3,3-trifluoro-propyl)thio)propionic acid or esters thereof by the low temperature free radical initiated coupling of 3-mercaptopropionic acid or esters thereof with 3,3,3-trifluoropropene. More particularly, the present invention concerns a process for the preparation of 3-((3,3,3-trifluoropropyl)thio)propionic acid or esters thereof (Formula I) F
R.0/\/\S/\/<F (I) wherein R represents H or (Ci-C4) alkyl which comprises coupling 3-mercaptopropionic acid or esters thereof (Formula II) wherein R is as previously defined with 3,3,3-trifluoropropene (Formula III) F
H2C<F
F (III) in the presence of 2,2'-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70) initiator at temperatures of about ¨50 C to about 40 C in an inert organic solvent.

\I:D

N
N
\¨CH3 /PCH3 0 \CH3 N
CH3 (V-70) DETAILED DESCRIPTION

As used herein, the term "alkyl" denotes branched or unbranched hydrocarbon chains.
The low temperature free radical initiated coupling of the present invention more selectively prepares 3-((3,3,3-trifluoropropyl)thio)propionic acid or esters thereof. The ratio of linear to branched isomer is enhanced from about 10:1 to about 40:1 or greater for the acid and is enhanced from about 10:1 to about 20:1 or greater for the esters.
While stoichiometric amounts of 3-mercaptopropionic acid or esters thereof and 3,3,3-trifluoropropene are required, because of its low boiling point, excess 3,3,3-trifluoropropene is usually employed to compensate for routine losses.
From about 1 to about 10 mole percent initiator, V-70, is typically used, with about 5 mole percent being preferred.
The low temperature free radical initiated coupling is conducted in an inert organic solvent. Typical inert organic solvents must remain liquid to ¨50 C, must remain relatively inert to the free radical conditions and must dissolve the reactants at reaction temperatures.
Preferred inert organic solvents are solvents such as toluene, ethyl acetate, and methanol.
The temperature at which the reaction is conducted is from about 0 C to about 40 C.
After the reaction is complete it is necessary to heat the mixture to about 50 C to decompose any remaining V-70.
In a typical reaction, the 3-mercaptopropionic acid or esters thereof and V-70 are added to an inert organic solvent. The solution is cooled to less than about ¨50 C
and the 3,3,3-trifluoropropene is transferred into the reaction mixture. After stirring at room temperature for 24 hours, the reaction mixture is heated to about 50 C for about 1 hour to decompose any remaining V-70 initiator followed by cooling and solvent removal.
The following examples are presented to illustrate the invention.
Examples Weight percent purities were determined using a GC internal standard assay with octanophenone as the internal standard. Linear/branched ratios are based on GC
area percent of the respective linear and branched products. GC Method Details: Agilent DB-5MS
(122-5532) column 30m x 0.25 mm x 0.25 um; heater: 250 C; control mode, flow: 2 mL/min;
oven program: 50 C for 2 min then 20 C/min to 280 C for 8 min.
1. Low temperature free radical initiated synthesis of 3-((3,3,3-trifluoropropyl)thio)-propanoic acid A 100 mL stainless steel Parr reactor was charged with 3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g), and 2,2'-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.20 g, 33.3 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20 C. After 24 hours, the reaction was heated to 50 C for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated by rotary evaporation to provide the title compound (6.80 g, 77.5 wt% linear isomer by GC internal standard assay, 5.27 g active, 76%, 200:1 linear:branched by GC, 40:1 linear:branched by fluorine NMR): 1H NMR
(400 MHz, CDC13) 6 2.83 (td, J= 7.1, 0.9 Hz, 2H), 2.76 - 2.64 (m, 4H), 2.47 -2.30 (m, 2H);
13C NMR (101 MHz, CDC13) 6 177.68, 125.91 (q, J= 277.1 Hz), 34.58 (q, J= 28.8 Hz), 34.39, 26.63, 24.09 (q, J = 3.3 Hz); 19F NMR (376 MHz, CDC13) 6 -66.49.
2. High temperature free radical initiator synthesis of 3-((3,3,3-trifluoropropyl)thio)-propanoic acid:
A 100 mL stainless steel Parr reactor was charged with azobisisobutyronitrile (AIBN, 0.231 g, 1.41 mmol), toluene (45 mL), 3-mercaptopropionic acid (3.40 g, 32.0 mmol), and octanophenone (526.2 mg) as an internal standard and was purged and pressure checked with nitrogen. The reactor was cooled with dry ice and the 3,3,3-trifluoropropene (3.10 g, 32.3 mmol) was condensed into the reactor. The ice bath was removed and the reactor heated to 60 C and stirred for 27 hours. The internal yield of the reaction was determined to be 80% by use of the octanophenone internal standard (12.2:1 linear:branched isomer by GC).
The pressure was released and the crude mixture removed from the reactor. The mixture was concentrated by rotary evaporation and sodium hydroxide (10 wt%, 50 mL) was added. The solution was washed with methyl tert-butyl ether (50 mL) then acidified to pH -1 with hydrochloric acid (6 N). The product was extracted with 100 mL methyl tert-butyl ether, dried over magnesium sulfate, filtered, and concentrated to give the crude titled compound as an oil (5.34 g, 11.9:1 linear:branched isomer by GC, 88 area% pure linear isomer by GC): 1H NMR (400 MHz, CDC13) 6 3.71 (s, 3H), 2.82, (td, .1= 7.3, 0.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.63 (td, .1= 7.2, 0.6 Hz, 2H), 2.47-2.31 (m, 2H); 13C NMR (101 MHz, CDC13) 6 172.04, 125.93 (q, J=
277.2 Hz), 51.86 , 34.68 (q, J= 28.6 Hz), 34.39 ,27.06 ,24.11 (q, J= 3.3 Hz); 19F NMR
(376 MHz, CDC13) 6 -66.53.
3. Low temperature free radical initiated synthesis of methyl 3- ((3,3

-4-A 100 mL stainless steel Parr reactor was charged with methyl 3-mercaptopropionate (4.15 g, 34.5 mmol), toluene (30.3 g), and 2,2'-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.531 g, 1.72 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.40 g, 35.4 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20 C. After 23 hours the reaction was heated to 50 C for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated to provide the title compound (7.01 g, 66%, 70.3 wt% linear isomer by GC internal standard assay, 4.93 g active, 66%, 24:1 linear:branched by GC, 18:1 linear:branched by fluorine NMR): 1H NMR
(400 MHz, CDC13) 6 3.71 (s, 3H), 2.82, (td, .1= 7.3, 0.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.63 (td, .1= 7.2, 0.6 Hz, 2H), 2.47-2.31 (m, 2H); 13C NMR (101 MHz, CDC13) 6 172.04, 125.93 (q, J=
277.2 Hz), 51.86 , 34.68 (q, J= 28.6 Hz), 34.39 ,27.06 ,24.11 (q, J= 3.3 Hz); 19F NMR
(376 MHz, CDC13) 6 -66.53.
4. High temperature free radical initiator synthesis of methyl 34(3,3,3-trifluoropropy1)-thio)propionate A 2 L autoclave reactor was charged with toluene (716.45 g), methyl 3-mercapto-propionate (187.78 g, 1562.6 mmol), and a-azobisisobutyronitrile (12.890 g, 78.500 mmol).
The reactor was sealed and pressurized with nitrogen (-100 psig) three times to purge the system of air. 3,3,3-Trifluoropropene (153.20 g, 1595.0 mmol) was added via transfer cylinder at 12 C (cold water bath). The reaction was heated to 80 C and stirred for 21 hours. The reaction was allowed to cool to room temperature and vacuum transferred out of the reactor.
The crude solution was concentrated by rotary evaporation (bath: 40 C, 12 mm Hg) to provide a clear yellow liquid (371.95 g, 9.8:1 linear: branched isomer by GC, 69 wt%
pure linear isomer determined by a GC internal standard assay, 257.39 g active, 76% in pot yield).

-5-

Claims (3)

WHAT IS CLAIMED IS:

1. A process for the preparation of 3-((3,3,3-trifluoropropyl)thio)propionic acid or esters thereof (Formula I) wherein R represents H or (C1-C4) alkyl which comprises coupling 3-mercaptopropionic acid or esters thereof (Formula II) wherein R is as previously defined with 3,3,3-trifluoropropene (Formula III) in the presence of 2,2'-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70) initiator at temperatures of about 0°C to about 40°C in an inert organic solvent.

2. The process of Claim 1 in which R represents H or CH3.

3. The process of Claims 1 or 2 in which the inert organic solvent is toluene.