CA1202977A - Chlorine exchange for fluorine in 2-fluoro-pyridine compounds - Google Patents
Chlorine exchange for fluorine in 2-fluoro-pyridine compoundsInfo
- Publication number
- CA1202977A CA1202977A CA000441965A CA441965A CA1202977A CA 1202977 A CA1202977 A CA 1202977A CA 000441965 A CA000441965 A CA 000441965A CA 441965 A CA441965 A CA 441965A CA 1202977 A CA1202977 A CA 1202977A
- Authority
- CA
- Canada
- Prior art keywords
- fluoro
- pyridine
- chloro
- trifluoromethyl
- pressure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Pyridine Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
2-Fluoro-pyridine compounds are contacted with a chlorinating agent at superatmospheric pressures to yield 2-chloro-pyridine compounds.
2-Fluoro-pyridine compounds are contacted with a chlorinating agent at superatmospheric pressures to yield 2-chloro-pyridine compounds.
Description
~2~2~
CHLORINE EXCHANGE FOR FLUORINE IN
CHLORINE EXCHANGE FOR FLUORINE IN
2-FLUORO-P~RIDINE COMPOUNDS
The present invention relates to a method of exchanging chlorine atoms for fluorine atoms in 2-fluoro--pyridine compounds.
2-Chloro-5-(trifluoromethyl)pyridine compounds are commercially valuable chemical in-termediates useful in the preparation of medicinal agents and agricultural chemicals. 2-Chloro-5-(trifluoromethyl)pyridine compounds are generally prepared by fluorinating a (trichloromethyl)-pyridine compound.
Problems associated with the preparation of 2-chloro-5-(trifluoromethyl)pyridine compounds include ~1) an over fluorinated end product, i.e., 2-fluoro-5--~trifluoromethyl)pyridines, and (2) the formation of a 2-1uoro isomer of the desired (trifluoromethyl)pyridine product generally described as a 2-fluoro-5-(chloro-difluoromethyl)pyridine compound. These 2~fluoro--pyridine by-products reduce the yield of the desired (trifluoromethyl)pyridines and nec~ssitate additional separatory procedures which are both bothersome 30,863-F
-2~
and expensive. The 2-fluoro isomer is a particularly annoying by-product because of the difficulty in separating it from the desired (trifluoromethyl~pyridine product.
In accordance with the present invention, a 2-fluoro pyridine compound is reacted with a chlorinating agent at superatmospheric pressures to replace the fluorine atom in the 2-position of the pyridine ring with a chlorine atom. The chlorina-ted products of this method are useful as intermediates in the synthesis of biologically active compounds, such as, medicinals and herbicides.
Of particular interest in the practice of this invention is a method of replacing the fluorine atom at the 2-ring position of 3-chloro-2-fluoro-5--(trifluoromethyl)pyridine with a chlorine atom yielding 2,3-dichloro-5-(trifluoromethyl)pyridine, an intermediate in the manufacture of agricultural chemicals.
Also of interest are methods of replacing the fluorine atoms at the 2-position of 2-fluoro-5-(trifluoro-methyl)pyridine; 3-chloro-2-fluoro-5-(chlorodifluoro-mPthyl~pyridine; and 2-fluoro-5-(chlorodifluoromethyl)-pyridine with a chlorine atom yielding 2-chloro-5--(trifluoromethyl)- or (chlorodifluoromethyl)-pyridine .
compounds.
In conducting the present reaction, a 2-fluoro-pyridine compound is contacted with a chlorinating agent at a superatmospheric pressure usually in the range of from 25 to 400 pounds per square inch guage (psig) advantageously a~ a temperature in the range of from 50C to 200C.
30,863-F -2
The present invention relates to a method of exchanging chlorine atoms for fluorine atoms in 2-fluoro--pyridine compounds.
2-Chloro-5-(trifluoromethyl)pyridine compounds are commercially valuable chemical in-termediates useful in the preparation of medicinal agents and agricultural chemicals. 2-Chloro-5-(trifluoromethyl)pyridine compounds are generally prepared by fluorinating a (trichloromethyl)-pyridine compound.
Problems associated with the preparation of 2-chloro-5-(trifluoromethyl)pyridine compounds include ~1) an over fluorinated end product, i.e., 2-fluoro-5--~trifluoromethyl)pyridines, and (2) the formation of a 2-1uoro isomer of the desired (trifluoromethyl)pyridine product generally described as a 2-fluoro-5-(chloro-difluoromethyl)pyridine compound. These 2~fluoro--pyridine by-products reduce the yield of the desired (trifluoromethyl)pyridines and nec~ssitate additional separatory procedures which are both bothersome 30,863-F
-2~
and expensive. The 2-fluoro isomer is a particularly annoying by-product because of the difficulty in separating it from the desired (trifluoromethyl~pyridine product.
In accordance with the present invention, a 2-fluoro pyridine compound is reacted with a chlorinating agent at superatmospheric pressures to replace the fluorine atom in the 2-position of the pyridine ring with a chlorine atom. The chlorina-ted products of this method are useful as intermediates in the synthesis of biologically active compounds, such as, medicinals and herbicides.
Of particular interest in the practice of this invention is a method of replacing the fluorine atom at the 2-ring position of 3-chloro-2-fluoro-5--(trifluoromethyl)pyridine with a chlorine atom yielding 2,3-dichloro-5-(trifluoromethyl)pyridine, an intermediate in the manufacture of agricultural chemicals.
Also of interest are methods of replacing the fluorine atoms at the 2-position of 2-fluoro-5-(trifluoro-methyl)pyridine; 3-chloro-2-fluoro-5-(chlorodifluoro-mPthyl~pyridine; and 2-fluoro-5-(chlorodifluoromethyl)-pyridine with a chlorine atom yielding 2-chloro-5--(trifluoromethyl)- or (chlorodifluoromethyl)-pyridine .
compounds.
In conducting the present reaction, a 2-fluoro-pyridine compound is contacted with a chlorinating agent at a superatmospheric pressure usually in the range of from 25 to 400 pounds per square inch guage (psig) advantageously a~ a temperature in the range of from 50C to 200C.
30,863-F -2
-3~
2-Fluoro-pyridine compounds include 3 chloro-2~fluoro-5-(trifluoromethyl)pyridine; 2-fluoro--5-(-trifluoromethyl)pyridine; and the above compounds wherein Ichlorodifluoromethyl or -dichlorofluoromethyl groups are substituted for the trifluoromethyl groups.
The 2-fluoro-pyridine compounds can be reacted separately or as a mixture con-taining more than one 2-fluoro-pyridine compound.
In a preferred embodiment, a mixture containing chlorinated~(trifluoromethyl)pyridines and one or more 2 fluoro-pyridine compounds is reacted according to the present invention whereby a chlorine atom is exchanged for the fluorine atom attached to the 2-position of the pyridine ring. The above mixtures are advantageously obtained from the reaction products in the preparation of (trifluoromethyl)pyridine compounds such as, for example, 2,3-dichLoro-5-~trifluoromethyl)pyridine and 2-chloro--S-(trifluoromethyl)pyridine, whereby the 2-fluoro--pyridine compounds are undesirable by-products.
The employment of a chlorinating agent is a critical component of the present invention and HCl is suitably employed. Suitable chlorinating agents are pre-ferably supplied in amounts to provide at least about one mole of chlorine atoms per mole of fluorine atoms to be displaced on the 2-fluoro-pyridine compounds. An excess of chlorinating agent is preferably employed and is not detrimental to the present process.
Generally, the present reaction is conducted neat or in the absence of a solvent.
30,863-F -3-
2-Fluoro-pyridine compounds include 3 chloro-2~fluoro-5-(trifluoromethyl)pyridine; 2-fluoro--5-(-trifluoromethyl)pyridine; and the above compounds wherein Ichlorodifluoromethyl or -dichlorofluoromethyl groups are substituted for the trifluoromethyl groups.
The 2-fluoro-pyridine compounds can be reacted separately or as a mixture con-taining more than one 2-fluoro-pyridine compound.
In a preferred embodiment, a mixture containing chlorinated~(trifluoromethyl)pyridines and one or more 2 fluoro-pyridine compounds is reacted according to the present invention whereby a chlorine atom is exchanged for the fluorine atom attached to the 2-position of the pyridine ring. The above mixtures are advantageously obtained from the reaction products in the preparation of (trifluoromethyl)pyridine compounds such as, for example, 2,3-dichLoro-5-~trifluoromethyl)pyridine and 2-chloro--S-(trifluoromethyl)pyridine, whereby the 2-fluoro--pyridine compounds are undesirable by-products.
The employment of a chlorinating agent is a critical component of the present invention and HCl is suitably employed. Suitable chlorinating agents are pre-ferably supplied in amounts to provide at least about one mole of chlorine atoms per mole of fluorine atoms to be displaced on the 2-fluoro-pyridine compounds. An excess of chlorinating agent is preferably employed and is not detrimental to the present process.
Generally, the present reaction is conducted neat or in the absence of a solvent.
30,863-F -3-
-4- ~ ~ ~ ~ ~ 0 In practicing -~he present invention, superatmospheric pressures are employed. The present reaction is conduc-ted at a pressure of at least 5 psig and usually at a pressure of from 25 to 400 psig, while 20~ psig represents a preferred pressure. The upper pressure limit, i.e., 400 psig, is not meant to be a limitation of the present invention but is only set forth as an economical consideration. Conducting the present reaction at a superatmospheric pressure provides conversion of the 2-fluoro-pyridines to their corresponding 2-chloro analogs at an accelerated rate when compared to conducting the reaction at atmospheric pressure. Furthermore, the excellent yield of the desired products (about 98 percent of theoretical~
avoids the use of a catalyst and provides a cleaner reaction eliminating the costs, material handling, recovery and/or disposal eforts associated with the use of catalys-ts.
The present reaction is a~vantageously con-ducted in the liquid phase at a temperature of between50C and 200C and preferably between 100C and 125C.
A particularly preferred -temperature to conduct the present reac-tion is 110C. The present reaction is typically conducted in the presence of agitation sufficient to disperse the HCl in the liquid phase.
In conducting the present reaction, neither the rate of addition of the chlorinating agent nor the order of addition of the reactants is critical. Pre-ferably, the suitable chlorinating agent is added in gaseous form to the 2-fluoro-pyridine compounds. A
typical reaction according to the present invention generally requires from 1/2 to 24 hours to be substan-tially complete.
30,863-F _4-_5~
In a preferred embodiment of the present invention, the reaction product in the preparation of 2-chloro-5-(trifluoromethyl)pyridine, which con-tains 2-fluoro-pyridines, such as, 2-fluoro-5-ttri-fluoromethyl)pyridine and 2-fluoro-5-(chlorodifluoro-methyl~pyridine, in addition to the desired 2-chloro-
avoids the use of a catalyst and provides a cleaner reaction eliminating the costs, material handling, recovery and/or disposal eforts associated with the use of catalys-ts.
The present reaction is a~vantageously con-ducted in the liquid phase at a temperature of between50C and 200C and preferably between 100C and 125C.
A particularly preferred -temperature to conduct the present reac-tion is 110C. The present reaction is typically conducted in the presence of agitation sufficient to disperse the HCl in the liquid phase.
In conducting the present reaction, neither the rate of addition of the chlorinating agent nor the order of addition of the reactants is critical. Pre-ferably, the suitable chlorinating agent is added in gaseous form to the 2-fluoro-pyridine compounds. A
typical reaction according to the present invention generally requires from 1/2 to 24 hours to be substan-tially complete.
30,863-F _4-_5~
In a preferred embodiment of the present invention, the reaction product in the preparation of 2-chloro-5-(trifluoromethyl)pyridine, which con-tains 2-fluoro-pyridines, such as, 2-fluoro-5-ttri-fluoromethyl)pyridine and 2-fluoro-5-(chlorodifluoro-methyl~pyridine, in addition to the desired 2-chloro-
-5-(trifluoromethyl)pyridine, is contacted with HCl at superatmospheric pressures and elevated tempera-tures as described herein to convert the 2-fluoro--pyridines to their corresponding 2-chloro analo~s.
The desired 2 chloro-5-(trifluoromethyl)pyridine is then readily separa~le from the reaction mixture by distillation since the 2-fluoro isomer, i.e. 2-fluoro--5-~chlorodifluoromethyl)pyridine, is converted to 2-chloro-5-(chlorodifluoromethyl)pyridine which has a boiling point different from the desired product.
In an especially preferred embodiment of the present invention, the reaction product in the prepara-tion of 2,3-dichloro-5-(trifluoromethyl~pyridine, which contains 2-fluoro-pyridines, such as, 3 chloro--2~fluoro-5-(trifluoromethyl)pyridine and 3-chloro -2-fluoro-5-(chlorodifluoromethyl)pyridine, in adddition to the desired 2,3~dichloro-5-(trifluoromethyl)pyridine, is contacted with HC1 at supera-tmospheric pressures and elevated temperatures as described herein to con-vert the 2-fluoro-pyridines to their corresponding 2-chloro analogs. The desired 2,3-dichloro-5-(tri-fluoromethyl)pyridine is then readily separable from the reaction mi~ture by distillation since the 2-fluoro isomer, i.e., 3-chloro-2-fluoro-5-(chlorodifluoromethyl)-pyridine, is converted to 2,3-dichloro-5-(chlorodi-fluoromethyl)pyridine which has a boiling point dif-ferent from the desired product.
30,863-F -5-~6--The following example illustrates the practice of the present invention.
Example 1 - Preparation of 2,3-Dichloro-5-(trifluoro-methyl~pyridine A 45 milliliter (ml) Teflon~-lined Parr bomb, which was equipped with a pressure gauge, rupture disk and needle valve, was charged with 2 grams (g) of 3-chloro-2-fluoro-5-trifluoromethylpyridine and then pressurized with anhydrous HCl to 200 psig. The bomb was placed in a heated rocker and kept at 110C for 20 hours. The maximum pressure was 220 psig. The bomb was removed from the heater and allowed to cool to room temperature, at which time it was placed in an ice bath. The bomb was vented to a caustic scrubber and 2.5 g of a light tan liquid consisting of HF and 84.3% 2,3-dichloro-5-trifluoromethylpyridine (by wt.).
This represents a 97.7% yield of 2,3-dichloro-5--trifluoromethylpyridine (by wt.) with 0.4% of 3~chloro~2-fluoro-5 trifluoromethylpyridine r~ai ni ng.
No additional products were observed by analysis with gas chromatography.
On repeating the above procedures using other substituted ring-fluorinated pyridine compounds, described herein as starting materials, substantially the same results are obtained, i.e., chloro displaces the ring-fluoro. Additionally, the present reaction may be conducted as a continuous process whereby similar results are obtained.
30,863-F -6
The desired 2 chloro-5-(trifluoromethyl)pyridine is then readily separa~le from the reaction mixture by distillation since the 2-fluoro isomer, i.e. 2-fluoro--5-~chlorodifluoromethyl)pyridine, is converted to 2-chloro-5-(chlorodifluoromethyl)pyridine which has a boiling point different from the desired product.
In an especially preferred embodiment of the present invention, the reaction product in the prepara-tion of 2,3-dichloro-5-(trifluoromethyl~pyridine, which contains 2-fluoro-pyridines, such as, 3 chloro--2~fluoro-5-(trifluoromethyl)pyridine and 3-chloro -2-fluoro-5-(chlorodifluoromethyl)pyridine, in adddition to the desired 2,3~dichloro-5-(trifluoromethyl)pyridine, is contacted with HC1 at supera-tmospheric pressures and elevated temperatures as described herein to con-vert the 2-fluoro-pyridines to their corresponding 2-chloro analogs. The desired 2,3-dichloro-5-(tri-fluoromethyl)pyridine is then readily separable from the reaction mi~ture by distillation since the 2-fluoro isomer, i.e., 3-chloro-2-fluoro-5-(chlorodifluoromethyl)-pyridine, is converted to 2,3-dichloro-5-(chlorodi-fluoromethyl)pyridine which has a boiling point dif-ferent from the desired product.
30,863-F -5-~6--The following example illustrates the practice of the present invention.
Example 1 - Preparation of 2,3-Dichloro-5-(trifluoro-methyl~pyridine A 45 milliliter (ml) Teflon~-lined Parr bomb, which was equipped with a pressure gauge, rupture disk and needle valve, was charged with 2 grams (g) of 3-chloro-2-fluoro-5-trifluoromethylpyridine and then pressurized with anhydrous HCl to 200 psig. The bomb was placed in a heated rocker and kept at 110C for 20 hours. The maximum pressure was 220 psig. The bomb was removed from the heater and allowed to cool to room temperature, at which time it was placed in an ice bath. The bomb was vented to a caustic scrubber and 2.5 g of a light tan liquid consisting of HF and 84.3% 2,3-dichloro-5-trifluoromethylpyridine (by wt.).
This represents a 97.7% yield of 2,3-dichloro-5--trifluoromethylpyridine (by wt.) with 0.4% of 3~chloro~2-fluoro-5 trifluoromethylpyridine r~ai ni ng.
No additional products were observed by analysis with gas chromatography.
On repeating the above procedures using other substituted ring-fluorinated pyridine compounds, described herein as starting materials, substantially the same results are obtained, i.e., chloro displaces the ring-fluoro. Additionally, the present reaction may be conducted as a continuous process whereby similar results are obtained.
30,863-F -6
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of exchanging a chlorine atom for a fluorine atom at the 2-position of a 2-fluoro--pyridine compound which comprises contacting a 2--fluoro-pyridine compound with HCl at a superatmospheric pressure under conditions sufficient to cause the exchange of the chlorine atom for the fluorine atom in the 2-position of the pyridine ring.
2. The method of Claim 1 wherein said 2-fluoro-pyridine compound is a compound or a mixture of compounds of the formula wherein R represents -H, -CF3, -CF2Cl, -CFCl2 or -CCl3; each X independently represents F, Cl or H
with the proviso that at least one X is always F; and Y represents Cl or H.
with the proviso that at least one X is always F; and Y represents Cl or H.
3. The method of Claim 2 conducted at a temperature of at least 50°C.
4. The method of Claim 3 wherein said 2-fluoro-pyridine compound is 3-chloro-2-fluoro-5--(trifluoromethyl)pyridine; 3-chloro-2-fluoro-5--(chlorodifluoromethyl)pyridine; 3-chloro-2-fluoro--5-(dichlorofluoromethyl)pyridine; or mixtures thereof.
5. The method of Claim 4 wherein said temperature is from 50°C to 200°C and said pressure is from 25 to 400 psig.
6. The method of Claim 5 wherein said pressure is about 200 psig.
7. The method of Claim 3 wherein said 2-fluoro-pyridine compound is 2-fluoro-5-(trifluoro-methyl)pyridine; 2-fluoro-5-(chlorodifluoromethyl)-pyridine; 2-fluoro-5-(dichlorofluoromethyl)pyridine;
or mixtures thereof.
or mixtures thereof.
8. The method of Claim 7 wherein said temperature is from 50°C to 200°C and said pressure is from 25 to 400 psig.
9. The method of Claim 8 wherein said pressure is about 200 psig.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000441965A CA1202977A (en) | 1983-11-25 | 1983-11-25 | Chlorine exchange for fluorine in 2-fluoro-pyridine compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000441965A CA1202977A (en) | 1983-11-25 | 1983-11-25 | Chlorine exchange for fluorine in 2-fluoro-pyridine compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1202977A true CA1202977A (en) | 1986-04-08 |
Family
ID=4126602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000441965A Expired CA1202977A (en) | 1983-11-25 | 1983-11-25 | Chlorine exchange for fluorine in 2-fluoro-pyridine compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1202977A (en) |
-
1983
- 1983-11-25 CA CA000441965A patent/CA1202977A/en not_active Expired
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |