Process for the production of alpha,beta-difluoro pyridines and beta,gamma-difluoropyridines

PREPARATION OF DIFLUOROPYRIDINE COMPOUNDS

The present invention relates to the preparation of alpha, beta and beta, gamma-difluoropyridine compounds employing potassium fluoride (KF) and/or cesium fluoride (CsF) as the fluorinating agent.

Alkali metal fluorides are well-known agents for the conversion of ring-chlorinated pyridines to the corresponding fluoropyridines. Thus, Finger, et al. (J. Org. Chem. 28, 1666 (1963)), found that KF in dimethyl sulfone at 200°C over a period of time converted 2-chloro10 pyridine to 2-fluoropyridine. Similarly, 2,3,5-trichloroand 2,3,5,6-tetrachloropyridine gave the 2-fluoro- and

2,6-difluoro-3,5-dichloropyridines.

It isequally well-known that the exchange of chlorine on pyridine for fluorine using the nucleophilic 15 action of fluoride ion very strongly favors replacement at the alpha or gamma positions of chloropyridines., with a beta-chlorine remaining essentially inert. Thus, in

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-2addition to the above cases, it has been noted by Chambers, et al. (Proc. Chem. Soc. 1964, 83) that pentachloropyridine, for example, strongly favors exchange at the alpha and gamma-positions when heated to ca. 200°C in a polar, aprotic diluent, and only under extreme conditions (anhydrous KF, 400-500°C, 24 hr) does the exchange of the beta (3- and 5-) chlorines occur. Moreover, whenever this exchange at the beta (3- and/or 5-) position has been observed, it has been limited to fully-substituted chloropyridines: the above-mentioned 2,3,5,6-tetrachloropyridine (having a hydrogen at the 4-position) gives only decomposition products under these conditions (Chambers, 10c cit.). In closely-related substitution reactions, a beta-chloropyridine has been found to be 10,000-100,000 times less reactive than the alpha-chloro- or gamma-chloropyridine, and theoretical explanations have been offered (Newkome and Paudler, ^,׳Contemporary Heterocyclic Chemistry, New York, John Wiley (1982), pp 262-3).

European Patent Application Number 63,872 teaches that it is known to react chloropyridines with KF, in the presence or absence of a polar aprotic diluent, in order to replace chlorine by fluorine. This reference discloses on page 5 that when 2,3-dichloro-5-(trichloromethyl)pyridine is allowed to react with KF the chlorine in the 3-position (beta-position) remains unchanged while all the other chlorine atoms are replaced by fluorine. The resulting product is 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (I).

Similarly, the use of CsF as a fluorinating agent is taught in, e.g., European Patent Applications 104,715 and 97,460. These applications teach what are believed to be the first examples of direct substitution

32,328A-F /2 (with fluoride ion) of fluorine for the chlorine on a

3-chloropyridine having hydrogen on the ring. EP 97,460 cites the reaction of CsF with 3-chloro-2-cyano-5-(trifluoromethyl)pyridine, II, to yield the beta-fluoropyridine,

III.

<img file="IL73807A_D0001.tif" />

In this example, the well-known influence of an adjacent cyano group on an aromatic ring, which powerfully activates a halogen (chlorine) towards substitution (by fluoride), is believed to be operating.

corresponding to local patent 68824

EP 104,715/discloses that fluoride ion from cesium fluoride in an aprotic diluent will react with 3-chloro-2-fluoro-

5-(trifluoromethyl)pyridine (I) to give 2,3-difluoro-5(trifluoromethyl)pyridine, IV:

<img file="IL73807A_D0002.tif" />

<img file="IL73807A_D0003.tif" />

<img file="IL73807A_D0004.tif" />

IV

This reference teaches in a preferred embodiment the use of about 50 percent molar excess of CsF in dimethyl

32,328A-F /2 sulfoxide (DMSO) diluent at 120-125° for about 48 hours, and the method gives yields of 48-58 percent IV.

The present invention represents a substantial improvement over the process taught in the above EP application 104,715, in that yields are much improved (up to 90 percent or more), reaction times are shorter, and the reaction may be effectively carried out with both CsF and the much less expensive KF. In addition, the new procedure has been shown to be applicable for the preparation of a number of other valuable alpha, beta, and beta, gamma-difluoropyridines from a wide variety of starting materials. It has also been found that the required alpha- or gamma-fluoro-beta-halopyridine starting material may be generated in situ from often more readilyavailable materials.

There is provided process for the production of alpha,teta-dlfLuoropyridines and of beta,gamma-difluoropyridines of the Formulae (VI) and (VIII)

<img file="IL73807A_D0005.tif" />

<img file="IL73807A_D0006.tif" />

wherein Hal = Cl, Br or I; X = F or Hal; A and B are individually H, CH״, CF״, F or Hal; R = H, CH_, CF_q/ F, w «ע w עי

Hal or CN; Y is A or F with the proviso that Y becomes F if Λ is Hal; Z is B or F with the proviso that Z becomes F if B is Hal; and S is R or F with the proviso that S becomes F when R is Hal and either A or B is F or Hal.

which comprises reacting a compound of the Formula V or a compound of the Formula VII, respectively, with an effective amount of KF or CsF under substantially anhydrous conditions in a suitable polar aprotic diluent at an elevated temperature, and removing the product compound essentially as it is formed, and optionally adding the starting compound (V) or (VII),respectively, as the product compound (VI) or (VIII) is removed.

<img file="IL73807A_D0007.tif" />

<img file="IL73807A_D0008.tif" />

wherein Hal = Cl, Br or I; X = F or Hal; A and B are individually H, CH3, CF^, F or Hal; R = H, CH^, CF^, F, Hal or CN; Y is A or F with the proviso that Y becomes F if A is Hal; Z is B or F with the proviso that Z becomes F if B is Hal; and S is R or F with the proviso that S becomes F when R is Hal and either A or B is F or Hal.

In accordance with the present invention, alpha, beta- (X) or beta, gamma-difluoropyridines (XII) are prepared by a process which comprises causing an alpha (IX) or gamma-fluoro-beta-halopyridine (XI), where halo represents chloro, bromo or iodo, to react with potassium fluoride or cesium fluoride under substantially anhydrous conditions in a suitable polar aprotic diluent at elevated temperatures, while removing the product difluoropyridine (X or XII) by distillation essentially as it is formed:

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<img file="IL73807A_D0009.tif" />

In the above formula (IX-XII), the other substituents (represented by R^) on the ring may be any group or groups which is or are stable under the reaction conditions, such as H, CH_3׳ CF^, F, Cl, Br, I, etc., with the special provision that when the substituent is Cl, Br or I in the alpha- or gamma-positions, it is also converted to fluoro. Preferred reactants have the formula

<img file="IL73807A_D0010.tif" />

where Y is CF_3׳ Br or Cl and X is Cl or Br.

Of particular interest in the practice of the present invention is a method of preparing 2,3-difluoro-

5-(trifluoromethyl)pyridine (IV) from 3-chloro-2-fluoro-

5-(trifluoromethyl)pyridine (I):

<img file="IL73807A_D0011.tif" />

<img file="IL73807A_D0012.tif" />

F

IV

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Compound IV is useful as a chemical intermediate in the preparation of 2-(4-((3-fluoro-5-(trifluoromethyl)pyridinyl)-2-oxy)phenoxy propionic acid and agriculturally acceptable derivatives thereof, i.e., salts, esters and amides, which are known herbicidal agents as described in EP 97,460.

In a variant of this invention, the alpha- or gamma-fluoro-beta-halopyridine starting material (IX or XI) may optionally be generated in situ by starting with an alpha, beta- (XIII) or beta, gamma-dihalopyridine (XIV) (where halo again represents chloro, bromo, or iodo), and taking advantage of the previously-mentioned, well-known tendency of alpha or gamma-halopyridines to exchange with fluoride ion. Under the reaction conditions, use of additional fluoride (KF or CsF) allows the generation of the required alpha- or gamma-fluoro-beta-halopyridine, which is then converted to the desired product alpha, beta- or beta, gamma-difluoropyridine:

<img file="IL73807A_D0013.tif" />

Hal = Cl, Br or I

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-8Of particular interest in this variant form are the conversions of 2,3,5-trichloropyridine (XV) and 2,3,5-tribromopyridine (XVIII) to 2,3־difluoro-5-chlornpyridine (XVII) and 2,3-difluoro-5-bromopyridine (XX), respectively. The latter two compounds are useful as chemical intermediates in the preparation of 2-(4-((5-chloro(or bromo)-3-fluoro)pyridinyl-2-oxy)phenoxy propionic acid and agriculturally acceptable derivatives thereof, i.e., for example, salts, esters and amides, which are known herbicidal agents as taught in EPO patent application 83,556:

<img file="IL73807A_D0014.tif" />

<img file="IL73807A_D0015.tif" />

and

<img file="IL73807A_D0016.tif" />

XVIII XIX XX

As mentioned above, if there is a halo (Cl, Br or I) present in the molecule at an alpha or gamma-position, it is likewise converted to fluoro in the final product, assuming that sufficient KF or CsF is present. Thus,

2,3,6-trichloropyridine XXI is transformed into 2,3,6-trifluoropyridine, XXIII.

<img file="IL73807A_D0017.tif" />

Cl Cl F F F F

XXI XXII XXIII

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-9Note also that two essentially equivalent ¹׳betapositions״ may exist in a pyridine molecule, and if the above requirements are met for both beta-positions then both are eventually converted to the difluoropyridine derivatives by providing sufficient fluoride salt under suitable reaction conditions. Thus, 2,3,5,6-tetrachloropyridine (XXIV) may be converted stepwise to the corresponding tetrafluoropyridine (XXV) in the presence of at least 4 moles of KF or CsF:

<img file="IL73807A_D0018.tif" />

<img file="IL73807A_D0019.tif" />

In the process of this invention, the starting material, IX or XI, is often advantageously added at essentially the rate of removal of the product difluoropyridine (X or XII), thus helping to minimize contact of both the starting material and the product with the reaction medium, in which they tend to decompose.

KF and CsF are the fluorinating agents employed in the present reaction and are commercially available compounds. Substantially anhydrous and finely-divided KF or CsF are preferred. Amorphous or spray-dried forms are particularly preferred. Substantially anhydrous KF and CsF can be prepared, for example, by drying in vacuo at 140-250°C for several hours.

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-10Polar aprotic diluents are employed as the reaction medium in the present process. Suitable polar aprotic diluents include dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethylacetamide, methyl isobutyl ketone, hexamethylphosphoric acid triamide, tetramethylurea, sulfolane (tetramethylenesulfone), and N-methylpyrrolidinone (NMP). Preferred diluents . include NMP, DMSO and sulfolane.

Optionally, the reaction may be conducted in the presence of (a) an acid scavenger, such as, an alkali metal carbonate, and/or in the case of employing KF as the fluorinating agent, (b) a phase-transfer catalyst.

The present reaction is conducted under substantially anhydrous conditions at elevated temperatures of from 50°C up to the boiling point of the solvent. Preferred temperature ranges are from 100°C to 200°C when CsF is used, and from 150°C up to the boiling point of the solvent when KF is used.

Pressures of from 10 mm Hg to 10 atm may also be employed, with preferred pressures of 50 mm Hg to 1 atm.

A fractional distillation system having 1 to 100 theoretical plates is conveniently employed to separate the product from the starting material. A preferred system has 5 to 20 theoretical plates.

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-11The optimum combination of temperature and pressure is actually a function of the particular system being studied and can be determined by routine experimentation. In general the pressure is chosen so as to provide convenient separation of the desired product from the starting material through the fractional distillation system while allowing a reaction temperature (distillation pot temperature) high enough to maintain a satisfactory reaction rate. Experimental determination of the reaction rate can be conveniently judged by observing the drop in the observed reflux temperature in the distillation column from that of the starting material to that of the product.

When 2,3-difluoro-5-(trifluoromethyl)pyridine (IV) is being prepared from 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (I) using KF and NMP, for example, a pressure of 1 atmosphere and reaction temperatures of 190-205°C are optimally employed. When CsF and DMSO are used to effect the same conversion, a pressure of 150 mm Hg and reactor temperatures of 120-140°C are conveniently used.

Substantially anhydrous reaction conditions are preferred; these may be achieved employing standard drying techniques. For example a typical glass laboratory reactor can be dried by distilling the polar aprotic solvent under a vacuum before addition of the reactants. Optionally, a small amount (5-10 percent by weight of the polar aprotic solvent) of a non-polar solvent such־ as an aromatic hydrocarbon (toluene, xylene, etc.) may be added to the polar aprotic solvent to aid in the removal of water by azeotropic distillation. Residual water in the reactor system is also often removed by azeotropic distillation with the product X or XII or the starting material IX or XI.

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-12The amount of polar aprotic solvent is not critical but it is advantageous to employ enough solvent to keep the starting material IX or XI in solution at reaction temperatures, generally 2 to 25 parts by weight solvent per part by weight pyridine starting material. The relative proportions of reactants to be employed are not critical because some of the product will be formed when employing any proportion of reactants. The reaction consumes the reactants, however, in the ratio of one mole of fluorinating agent per mole of exchangeable halogen atoms present in the starting material. For example, if 2,3-dichloro-5-(trifluoromethyl)pyridine is the starting material, then about 2 molar equivalents of KF or CsF per molar equivalent pyridine starting material can be employed, and if 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine is the starting material, then about equimolar amounts of KF or CsF and pyridine starting material can be employed. Usually from 0.75 to 1.5 moles of KF or CsF are employed per mole of exchangeable halogen in the pyridine starting material.

In carrying out the present reaction, neither the rate nor the order of addition of the reactants is critical. Usually, the solvent and fluorinating agent are added to an appropriate reaction vessel and the reaction is dried by distilling a small portion of the solvent. The starting material (IX or XI) or precursor compound (XIII or XIV) is then added to the reaction vessel which is thereafter followed by heating of the reaction mixture at a suitable pressure, usually 50 mm Hg to 1 atm, to provide convenient separation of the desired product as it is formed. In an especially preferred mode, the starting material is added to the fluorinating agent (KF or CsF) in the solvent under the optimized

32,328A-F

-13reaction conditions at about the same molar rate as the formation and removal of the product. If an acid scavenger, a non-polar solvent, or catalyst is employed in the reaction, then they are advantageously added to the solvent/fluorinating agent mixture prior to drying the reactor vessel.

The present reaction is typically conducted in the presence of agitation sufficient to maintain an essentially uniform dispersion of the reactants in the solvent.

Usually the reaction using KF without a catalyst is complete in 16 to 24 hours. Catalysts are optionally employed, when KF is used, to increase the reaction rate. When a catalyst is used with KF, 8 to 16 hours are usually required. When CsF is used, 2 to 8 hours are normally sufficient. Suitable catalysts include phase-transfer catalysts. The catalyst is added to the present reaction mixture in an amount of from 0.0001 to 0.1 mole per mole of pyridine starting material, advantageously from 0.001 to 0.075 molar equivalents and preferably from 0.01 to 0.05 molar equivalents.

Phase-transfer catalysts are well known compounds and include (a) quaternary ammonium or phosphonium salts containing 10 or more carbon atoms and (b) macrocyclic polyethers commonly known as crown ethers. Suitable crown ether catalysts include 18-crown-6; dicyclohexano-18crown-6; dibenzo-18-crown-6; 15-crown-5. A related species, tris(3,6-dioxaheptyl)amine is also efficaceous. Suitable quaternary ammonium and phosphonium salts include tetran-alkylammonium salts and tetra-n-alkylphosphonium salts. Particular catalysts include benzyltriethyl32,328A-F

-14ammonium chloride, methyl trioctylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydrogen sulfate, tetran-butylphosphonium chloride and cetyl trimethylammonium bromide. The anion of the phosphonium and ammonium salts of F or any anion which Q θ θ Θ readily converts to F , such as for example, Cl, Br, I, OH, OAc, etc. Preferred catalysts include 18-crown-6 and cetyltrimethylammonium bromide.

Acid scavengers are optionally employed in the present reaction to consume or inactivate traces of HC1 or HF which may be present or generated during the reaction. Suitable acid scavengers include alkali metal carbonates such as anhydrous K₂CO₃ and anhydrous NaCO₃. A preferred acid scavenger is anhydrous K₂CO₃. The acid scavengers are added to the present reaction mixture in an amount of from 0.001 to 0.1 mole per mole of pyridine starting material. Preferably, from 0.03 to 0.05 molar equivalents are employed.

The solvent used in the process of this invention may be distilled to recover it free from impurities and re-used. Alternatively, it has been found that, under certain conditions, the solvent may be re-used without distillation by simply filtering or decanting from the spent potassium or cesium salts and charging fresh KF or CsF. Solvents such as NMP have been re-used as many as 4 times in this manner before further purification was necessary, and additional recycles may be possible.

The following examples illustrate the practice of the present invention and should not be construed as limiting. No attempt has been made to balance any chemical equations described herein. All temperatures are in °C

32,328A-F

-15and boiling points are at atmospheric pressure unless otherwise stated.

Example 1

A one-liter 3-necked flask was equipped with an efficient stirrer, a thermometer, temperature controller, 250 watt infrared heat lamp, a reduced pressure control device and a 2.54 cm CD 7-tray glass Oldershaw (sieve plate) distillation column having a vapor fraction cutter, condenser and a water-jacketed receiver. This flask was charged with 500 milliliters (ml) of sulfolane (tetramethylene sulfone), 43.5 grams (g) (0.75 mole) of KF which had been dried in vacuo at 140°C for 48 hours and then pulverized, and 5 g of anhydrous potassium carbonate.

This mixture was heated with vigorous stirring under 100 millimeters (mm) pressure and 10-15 ml of sulfolane was distilled (head temperature raised to 209°C/100 mm) to dry the system. The vacuum was released and 100 g (0.5 mole) of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine was added to the reaction mixture. The reaction mixture was stirred at atmospheric pressure for 16 hours, the pot temperature was reduced, and a vacuum of 100 mm was applied to the system to begin distillation with continued stirring. A total of 32 g of colorless oil, having a boiling point (b.p.) of 54°-75°C/100 mm, was removed over 1 1/2 hours, with the pot temperature being 144°C. Gas-liquid phase chromatographic (glpc) analysis indicated the presence of 27 g of desired product and 4 g of starting material.

The reaction mixture was then heated again to 220°C/l atm with continued good stirring for 4 1/2 hours. The pot was cooled and the pressure again reduced to

32,328A-F

-16100 nun to resume distillation. A total of 23.6 g of colorless oil having b.p. 54°-67°C/100 mm, was removed while raising the pot temperature to 203°C; glpc analysis showed an additional 21.8 g of desired product and 1.5 g of starting material. Continued heating of the reaction mixture for 15 hours at 220°C/1 atm followed by a third distillation yielded only an additional 3.1 g of oil found by glpc analysis to be 69 percent desired product and 13 percent starting material. Total yield of 2,3-difluoro-5-(trifluoromethyl)pyridine was 60 percent at 94 percent conversion of starting material.

Redistillation of the combined fractions gave substantially pure 2,3-difluoro-5-(trifluoromethyl)pyridine, as a colorless oil having a b.p. of 104°-106°C. The proton and fluorine nuclear magnetic resonance (NMR) spectra were consistent with the assigned structure.

Example 2

To the same apparatus as described in Example 1, was charged 550 ml of sulfolane, 43.5 g (0.75 mole) of KF (dried in vacuo 48 hours at 140°-160°C and then pulverized) and 5 g of K₂CO₃. About 10 ml of sulfolane and water was distilled (b.p. 53°-210°C/100 mm) to dry the system and then the vacuum was released to add 100 g (0.5 mole) of

3-chloro-2-fluoro-5-(trifluoromethyl)pyridine. Heating was resumed at 201°-202°C with vigorous stirring, and the distillation head temperature was observed to drop from 139°C to about 117°C/1 atm over 2 hours, at which point slow distillation (20-40:1 reflux) was begun. Over the next 25 hours, 36 g of liquid, b.p. 109°-122°C/l atm, containing (by glpc) 30.9 g of desired product and 5.4 g of starting material, was obtained, while the pot temperature was slowly increased to 225°C. The pot was then

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-17cooled and the pressure reduced to 250 mm at this point, and an additional 20.6 g of material, containing 18.7 g of desired product and 0.3 g of starting material, was recovered, b.p. 53°-90°C/250 mm. The yield of 2,3-difluoro-5-(trifluoromethyl)pyridine was 60 percent at 94 percent conversion of starting material. Redistillation of this product at atmospheric pressure gave excellent recovery of both desired product and starting material.

Example 3

To the same apparatus as described in Example 1 was charged 515 ml of sulfolane, 43.5 g (0.75 mole) of KF which had been dried at 140°C in vacuo for 48 hours and then pulverized, 5 g of K״CO״ and 5 g of 18-crown-6 ether. The system was dried by distillation of about 25 ml of solvent (b.p. 160°-121°C/100 mm) and then 100 g (0.5 mole) of 2,3-difluoro-5-(trifluoromethyl)pyridine was added after releasing the vacuum on the system. The mixture was stirred vigorously at 195°-200°C/l atm for 1 hour during which time the observed head temperature dropped rapidly to about 114°C, and then distillation was begun. A total of 45.4 g of distillate was taken off over 5 hours at 111°-118°C/1 atm, and glpc analysis indicated the presence of 40.9 g of desired product.

The reaction mixture was then allowed to stir an additional 15 hours at 220°C/l atm. Distillation yielded an additional 24.4 g of material having a b.p. of 53°-180°C/100 mm and containing 22.9 g of desired product and 0.4 g of starting material as indicated by glpc analysis. The total yield of 2,3-difluoro-5-(trifluoromethyl)pyridine was 71 percent at 98 percent conversion of starting material.

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-18Example 4

To a 2 L flask, equipped as described in Example 1, was charged one liter (IL) of N-methyl pyrrolidinone (NMP) which was heated under 20 mm at 120°C to dry the system. About 20 ml of NMP and water were removed. The vacuum was released and 100 g (1.7 moles) of KF (dried in vacuo 24 hours at 140°-160°C and then pulverized), 20 g of K2^CO3 (anhydrous) and 400 g (2.0 moles) of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine were added. Heating was resumed with vigorous stirring under a nitrogen atmosphere fed into the top of the reaction flask. The temperature was increased to 190°-195°C and the distillation head temperature was observed to drop from 138°C to 104°C over 2 hours, at which point slow product takeoff (120/1 reflux to takeoff) was begun. Over the next 21 hours 211 g of distillate were recovered. The distillate contained 90 percent 2,3-difluoro-5-(trifluoromethyl)pyridine equivalent to 190.2 g (61 percent yield) based on KF as indicated by glpc.

Example 5

To 3L flask, equipped as described in Example 1, was charged 1.3L of N-methyl pyrrolidinone (NMP) which was heated under 20 mmHg at 120°C to dry the system. About 20 ml of NMP and water were removed. The vacuum was released and 116 g (2 moles) of KF (dried in vacuo 24 hours and then pulverized), 20 g of K₂CO₃ (anhydrous) and 500 g (2.5 moles) of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine were added. Heating was resumed with vigorous stirring under a nitrogen atmosphere fed into the top of the reaction flask. The temperature was increased to 190°-195°C and the distillation head temperature was observed to drop from 138°C to 104°C over 2 hours, at which point slow product takeoff (120/1 reflux to takeoff)

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-19was begun. Over the next 16 hours, 389 g of distillate t were recovered. The distillate contained 75.5 percent 2,3-difluoro-5-(trifluoromethyl)pyridine equivalent to 294g (80 percent yield) based on KF as indicated by glpc.

Example 6

A 5-liter flask equipped as in Example 1 was charged with 3,500 ml of NMP, 290 g (5.0 moles) of powdered KF which had been dried at 140°C in vacuo. A total of 80 ml of distillate (NMP and water) was removed (b.p. 140°142°C/170 mm) and then 376 g (2.06 moles) of 2,3,5-trichloropyridine was added. The mixture was stirred vigorously at 140°C for 17 hours, and then the temperature was increased to 190°C under a nitrogen atmosphere for the next 16 hours. The reaction mixture was cooled and subjected to vacuum distillation to remove 135 g of liquid, b.p. 86°-126°C/150 mm, which contained, by glpc analysis, 45 g, 33 percent of 5-chloro-2,3-difluoropyridine and 86 g, 64 percent of 3,5-dichloro-2-fluoropyridine.

The reaction mixture was again heated to 190°C with good stirring for 20 hours, cooled and subjected agin to vacuum distillation to yield 198g of liquid, b.p. 100°127°C/100 mm, which was found by glpc analysis to contain 15 percent of 5-chloro-2,3-fluoropyridine and 71 percent of 3,5-dichloro-2-fluoropyridine. The total net yield, therefore, of 5-chloro-2,3-difluoroPyridine was

74.1 g, 24 percent with a 227.5 g, 67 percent yield of the intermediate, 3,5-dichloro-2-fluoropyridine being available for recycle. There was 91 percent recovery of product and by-product.

A purified sample of 5-chloro-2,3-difluoropyridine was found to have a b.p. of 135°-136°C (1 atm.).

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3,5-dichloro-2-fluoropyridine was found to have a b.p. of 173°-174°C (1 atm.). Both compounds had proton and fluorine NMR spectra consistent with their assigned structures.

Example 7

To a 3L flask, equipped as described in Example 1, was charged 2L of N-methyl pyrrolidinone (NMP) which was heated under 20 mm at 120°C to dry the system. About 20 ml of NMP and water were removed. The vacuum was released and 116 g (2 moles) of KF (dried in vacuo 24 hours at 140°-160°C and then pulverized), 10 g of I^COg (anhydrous) and 400 g (2.0 moles) of 3-chloro-2-fluoro-5-trifluoromethylpyridine were added to the flask. Heating was resumed with vigorous stirring under a nitrogen atmosphere fed into the top of the reaction flask. The temperature was increased to 190°-195°C and the distillation head temperature was observed to drop from 138°C to 104°C over 2 hours, at which point a slow product takeoff (120/1 reflux to takeoff) was begun. Over the next 20 hours 283 g of distillate were recovered. The distillate contained 88 percent 2,3-difluoro-5-(trifluoromethyl)pyridine equivalent to 249 g (68 percent yield) based on KF.

Example 8

To a 3L flask, equipped as described in Example 1, was charged 2L of N-methyl pyrrolidinone (NMP) which was heated under 20 mm at 120°C to dry the system. About 200 ml of NMP and water were removed. The vacuum was released and 174 g (3 moles) of KF (dried in vacuo 24 hours at 140°-160°C and then pulverized), 20 g of K₂CC>₃ (anhydrous) and 800 g (4 moles) of 3-chloro-2-fluoro-5-trifluoromethylpyridine were added slowly to the flask over a 6 hour

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-21period. Heating was resumed with vigorous stirring under a nitrogen atmosphere fed into the top of the reaction flask. The temperature was increased to 190°-195°C and the distillation head temperature was observed to drop from 138°C to 104°C over 1/2 hour, at which point a slow product takeoff (40/1 reflux to takeoff) was begun. Over the next 22 hours 532 g of distillate were recovered.

The distillate contained 85 percent 2,3-difluoro-5-(trifluoromethyl)pyridine equivalent to 452 g (82 percent yield) based on KF.

Example 9

To a 3L flask, equipped as described in Example 1, was charged 2L of N-methyl pyrrolidinone (NMP) which was recovered from example 8 by removing the KC1 salt formed in the reaction by filtration and returning the solvent to the reaction flask. 174 Grams (3 moles) of KF (dried in vacuo 24 hours at 140°-160°C and then pulverized), 20 g of K״CO_q (anhydrous) and 800 g (4 moles) of 3-chloro-2Λλ w fluoro-5-(trifluoromethyl)pyridine were added slowly to the flask over an 8 hour period. Heating was resumed with vigorous stirring under a nitrogen atmosphere fed into the top of the reaction flask. The temperature was increased to 190°-195°C and the distillation head temperature was observed to drop from 138°C to 104°C over 1/2 hour, at which point a slow product takeoff (40/1 reflux to takeoff) was begun. Over the next 24 hours 596 g of distillate were recovered. The distillate contained 75 percent 2,3-difluoro-5-(trifluoromethyl)pyridine equivalent to 447 g (81 percent yield) based on KF.

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-22Example

Preparation of 2,3-Difluoro-3-(trifluoromethyl)pyridine A 2 liter 3-necked flask was equipped with an efficient stirrer, a 1 inch ID seven tray glass Oldershaw (sieve plate) distillation column having a vapor fraction cutter condenser and a water-jacketed receiver. The apparatus was also fitted with a thermometer, temperature controller, 250 W infrared heat lamp, and an efficient reduced pressure control device. To this apparatus was charged 1200 ml of dimethylsulfoxide (DMSO). The mixture was heated with stirring under a pressure of 150 mm Hg to reflux, and ca. 35 ml of the solvent was distilled at 136-139°C/15O mm to dry the system. The vacuum was released, and there was added 213 g (1.4 g-mol) of cesium fluoride, which had been dried in vacuo at 250° for 24 hours and then pulverized, followed by 6 g of potassium carbonate and 199.5 g (1.0 g-mol) of 2-fluoro-3-chloro-5(trifluoromethyl)pyridine. The pressure was again reduced to 150 mm Hg, and the mixture was heated with vigorous stirring to reflux. The distillation head temperature was observed to drop to 70°/150 mm after 30 minutes. Distillation was then begun and maintained at 5:1 reflux over the next 4 1/2 hours, during which time 163.7 g of liquid was removed, b.p. 67-74°/150 mm; during the final 15 minutes of the reaction, the head temperature increased rapidly to 136^QC. The pot temperature was steadily increased from an initial 122°C to 140°C over the five hours of reaction time. Gas-liquid phase chromatograph (glpc) analysis of the product showed the presence of 144.7 g (79 percent yield) of 2,3-difluoro-5-(trifluoromethyl) pyridine and 9 percent recovery of 3-chloro-2fluoro-5-(trifluoromethyl)pyridine. The net yield of the desired product was therefore 87 percent at 91 percent conversion.

32,328A-F

-23Example Preparation of 5-chloro-2,3-difluoropyridine from

2.3.5- tr1chloropyr1dme

To a 1 liter 3-necked flask equipped as described in Example 1 was charged 600 ml of DMSO, and 20 ml of solvent was distilled (b.p. 140-142°/150 mm) to dry the system. The vacuum was released and there was added 224 g (1.47 g-mol) of CsF which had been dried in vacuo at 250°C for 16 hours and then pulverized, followed by 3 g of potassium carbonate and 104 g (0.57 g-mol) of 2,3>5-trichloropyridine. The mixture was heated to reflux at 200 mm pressure for 2 hours, during which time the head temperature was observed to drop from 122° to 100°C. The pressure was then reduced from 177 mm, and slow distillation over the next 7 hours while the pot temperature was being raised from 133°C to 142°C gave a total of 60.2 g of material, b.p. 96-108°C/175 mm. Glpc analysis indicated the presence of 45.6 g of 5-chloro-2,3-difluoropyridine and 7.9 g of 3,5-dichloro-2-fluoropyridine. Redistillation yielded 43 g of the former as a colorless oil, b.p. 83-84°C/150 mm and 7.9 g of a semisolid fraction, b.p. 122-123°C.150 mm, which was determined by glpc analysis to be 93.5 percent pure 3,5-dichloro-2-fluoropyridine. The proton and fluorine NMR spectra were consistent with the assigned structures.

Example Preparation of 5-chloro-2,3-difluoropyridine from

3.5- dichloro-2-fluoropyridine

To a 1 liter 3-necked flask equipped as described in Example 1 was charged 600 ml of DMSO, and the material was heated to distill ca. 15 ml of solvent to dry the system (b.p. 140°C/200 mm). The vacuum was released and 186 g (1.22 g-mol) CsF (dried 16 hours at 200°C in vacuo),

32,328A-F g of potassium carbonate and 133 g (0.80 g-mol) of

3,5-dichloro-2-fluoropyridine was added. The mixture was heated to reflux at 200 mm; the head temperature dropped from an initial 126°C to 97°C/200 mm over 30 minutes, and distillation was then carried out over 5.25 hours at 97-106°C/200 mm, pot temperature 139-144°C, to yield 68.8 g of material. Distillation was interrupted at this point and the reaction was shut down overnight. Continuation the next day yielded an additional 21.7 g of material, b.p. 96-118°C/200 mm over 3 more hours while the pot temperature was raised from 142°C to 145°C. Analysis of the product showed the presence of a total of 74.8 g of

5-chloro-2,3-difluoropyridine and 10.1 g of the starting material, for a yield of 67 percent at 92 percent conversion. Redistillation gave a recovery of 74 g of 5-chloro-2,3difluoropyridine, b.p. 84-86°/ 150 mm (135-136°C/1 atm.) which was 99.1 percent pure by glpc analysis.

Example

Preparation of 2,3-difluoro-5-(trifluoromethyl)pyridine showing the effect of not drying the system on the yield

The apparatus and procedure was essentially the same as in Example 1 excepting that the CsF was not pre-dried and the system-drying step (distillation of DMSO prior to adding the other reactants) was omitted. The initial head temperature was 120°C/150 mm, and distillation of the product as it was formed was at 66-82°C/150 mm over 5 hours. The distillate weighed

140.2 g and was found to contain 130.7 g of 2,3-difluoro5-(trifluoromethyl)pyridine and 2.2 g of starting material (74 percent yield at 97 percent conversion.

32,328A-F

-25Example 14

To the apparatus described in Example 1 was charged 600 ml of DMSO, and ca. 30 ml of DMSO were distilled at 136°C/ 150 mm to dry the system. There was then added 160 g (1.05 mole) of dry CsF, 100 g (0.46 mole) of 2,3-dichloro-5-(trifluoromethyl)pyridine and 3 g of K₂ C0₃- The mixture was heated with stirring to reflux at 150 mm for 1 hour, during which time the head temperature dropped to ca. 90°C. Slow distillation was then begun, there being recovered 20.2 g of product consisting mostly of 2,3-difluoro-5-(trifluoromethyl)pyridine over 5 hours.

Distillation was interrupted at this point and the mixture was allowed to stir at 135°C overnight. Continuation of the distillation gave an additional 63.7 g of material b.p. 58-137°/150 mm. Analysis of the combined products by glpc showed the presence of 39.2 g of 2,3-difluoro-5(trifluoromethyl)pyridine and 25.3 g of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine.

Example 15

To the apparatus described in Example 1 was charged 500 ml of NMP and 32 g (0.55 mole) of dry KF. Ca. 30 ml of NMP was distilled at 106-139°C/125 mm to dry the system and then 108 g (0.5 mole) of 2,3dichloro-5-(trifluoromethyl)pyridine was added. The mixture was heated to 140°C for 4¾ hours. Glpc analysis of a sample showed that conversion to the intermediate, 3-chloro-2-fluoro-5(trifluoromethyl)pyridine, was only ca. 70 percent complete, so an additional 28 g (0.5 mole) of dry KF was added. Conversion to the intermediate was found to be complete after an additional 1 hour, so 28 g (0.5 mole) more of dry KF was added, and the mixture was heated to reflux at 1 atmosphere pressure. The head temperature dropped over

32,328A-F

-26ca. \ hour to ca 111°C, and takeoff of ca. 10 g of product was initiated over the next % hour before the reaction was shut down overnight.

Resumption of distillation yielded an additional 60 g of product, b.p. 110-180°C over 3¾ more hours before sampling disclosed the absence of further volatiles other than

NMP.

Analysis of the product by glpc showed the presence of

59.1 g of 2,3-difluoro-5-(trifluoromethyl)pyridine and

8.1 g of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (77 percent yield of IV at 84 percent conversion).

Example 16

To the apparatus described in Example 1 was charged 19 g (0.31 mole) of dried KF and 300 ml of sulfolane. A small amount of the solvent was distilled in vacuo to dry the system and then 50 g (0.16 mole) of 2,3,5-tribromopyridine was added. The mixture was heated with stirring to 210° for 3.5 hours and then vacuum (190 mm) was applied to bring the system to reflux. Ca. 4 g of liquid, b.p. 90-140°/190mm was removed, and then 9 g (0.15 mole) of additional dried KF was charged. Over the next 18 hours an additional 5 g of material was distilled, b.p. 110-160°/ 190 mm, with the pot temperatue rising to 225°C. Analysis of the combined products by glpc showed the presence of ca. 3.3g of 5-bromo-2,3-difluoropyridine and 1.4 g of 5bromo-2-fluoropyridine, plus a smaller amount of material tentatively identified as 2,3,5-trifluoropyridine. Analysis of the material remaining in the reaction flask showed the presence of 13.6 g of 3,5-dibromo-2-fluoropyridine.

32,328A-F

-27A purified sample of 5-bromo-2,3-difluoropyndme 1 ^: 19 had b.p. ca. 154° and the H and F NMR spectra were consistent with the assigned structure. A sample of 5-bromo-2-fluoropyridine had b.p. 175° and the NMR spectra were likewise consistent with the assigned structure.

Example 17

To a IL 3-necked flask equipped with a simple distillation head, thermometer, stirrer and heater was charged 72 g (0.47 mole) of dried CsF, 2.5 g of I^CO^ and 400 ml of sulfolane. Ca. 20 ml of the solvent was distilled in vacuo to dry the system, and 50 (0.16 mole) of 2,3,5-tribromopyridine was added. The mixture was heated to 180-190°C for 7 hr. Vacuum distillation yielded a mixture which, by glpc analysis, showed the presence of a 45 percent yield of 2,3-difluoro-5-bromopyridine, and small amounts of 2-fluoro-5-bromopyridine and 2,3,5-trifluoropyridine. Analysis of the residual material in the sulfolane showed the presence of 3,5-dibromo-2-fluoropyridine.

In similar operations employing the procedures described herein and the various starting materials, solvents, acid scavengers, catalysts and pressure and temperature conditions, other 2,3- and 3,4-difluoropyridines are prepared in a good yield.