Methods of preparing 2',6-BIS(difluoromethyl)-5-fluoro-2,4'-bipyridine

Abstract

Disclosed herein are methods of preparing 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine, a synthetic intermediate used in the manufacture of pilavapadin.

Description

[0001] METHODS OF PREPARING 2',6-BIS(DIFLUOROMETHYL)-5-FLUORO-2,4'-BIPYRIDINE

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to United States Provisional Application number 63 / 789,529, filed April 16, 2025, and to international patent application number PCT / CN2025 / 085406, filed March 27, 2025, the entireties of both of which are hereby incorporated by reference.

[0004] 1. BACKGROUND

[0005] Inhibitors of adaptor associated kinase 1 (AAK1) have shown promise for the treatment of pain and other disorders. See, e.g., Yuan, Y-H et al, “Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents” J Enz Inhibition Med Chem 2023, 38(1): 2279906. One such inhibitor, (S)-l-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2 -amine (pilavapadin, LX9211), is currently in human clinical trials for the treatment of diabetic peripheral neuropathy. Id. at 2.

[0006] 2. SUMMARY

[0007] This invention is directed to synthetic methods useful in the preparation of 2', 6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine, a synthetic intermediate used in the manufacture of AAK1 inhibitors such as pilavapadin.

[0008] In particular, this invention encompasses a method of preparing 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound A):

[0009]

[0010] which comprises, in a continuous flow reactor: flowing a reaction mixture through a reaction module having an inlet and an outlet; flowing the reaction mixture through a cooling module having an inlet and an outlet to provide a cooled reaction mixture; contacting the cooled reaction mixture with an aqueous base to provide a product mixture; and isolating Compound A from the product mixture;

[0011] wherein:the reaction mixture comprises a fluorinating agent, triethylamine, a solvent, and 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound B):

[0012]

[0013] the solvent is compatible with fluorination conditions; the reaction module is maintained at a first temperature and a first pressure sufficient for the formation of Compound A; the reaction mixture resides in the reaction module for a reaction residence time sufficient for the formation of Compound A; the cooling module is maintained at a second temperature and second pressure sufficient to inhibit decomposition of the fluorinating agent; and the reaction mixture resides in the cooling module for a time sufficient to provide a cooled reaction mixture having a temperature approximately equal to the second temperature.

[0014] In some embodiments of the invention, the aqueous base is aqueous K2CO3 or ISfeCOs. In others, the aqueous base is K3PO4 or Na^PCU. In some embodiments, the fluorinating agent is DAST.

[0015] In some embodiments, the solvent is chlorobenzene, DCM, ethyl acetate, isopropyl acetate, or toluene. A preferred solvent is DCM.

[0016] In some embodiments of the invention, the first temperature is from about 85 to about 95°C. In some embodiments, the first pressure is from about 0.3 to about 1 MPa (e.g., about 0.4, 0.5, 0.6, 0.8, 0.9 MPa). In some embodiments, the reaction residence time is at least 10 minutes (e.g., at least 20, 30, 40, 50 minutes).

[0017] In some embodiments, the second temperature is less than about 40°C (e.g., from about 0 to about 40°C, from about 0 to about 30°C, from about 0 to about 20°C). In some embodiments, the second pressure is the same as the first pressure.

[0018] In some embodiments of the invention, aqueous and organic components of the product mixture are separated prior to the isolation of Compound A.

[0019] In some embodiments, the outlet of the reaction module is directly coupled to the inlet of the cooling module. In some embodiments, the reaction module comprises tubing through which the reaction mixture flows, which tubing is immersed in a temperature bath. In some embodiments, the cooling module comprises tubing through which the reaction mixture flows, which tubing is immersed in a temperature bath.

[0020] 3. BRIEF DESCRIPTION OF THE FIGURES

[0021] Aspects of some embodiments of the invention may be understood from the attached figure. FIG. 1 provides a schematic representation of a continuous flow reactor used in a particular embodiment of the invention.4. DETAILED DESCRIPTION

[0022] This invention is directed, in part, to continuous flow methods of preparing a synthetic intermediate used in the preparation of certain AAK1 inhibitors.

[0023] 4.1.1. Definitions

[0024] Unless otherwise indicated, the term “about” means ± 10% of the indicated range.

[0025] Unless otherwise indicated, the term “approximately equal” used to describe a first value in relation to a second value means that the first value is equal to the second value ± 20%.

[0026] Unless otherwise indicated, “DAST” refers to diethylaminosulfur trifluoride (A,A-diethyl-l,l,l-trifl uoro- -sulfanam i ne) .

[0027] Unless otherwise indicated, “DCM” refers to dichloromethane or methylene chloride.

[0028] Unless otherwise indicated, “MPa” refers to megapascals.

[0029] 4.1.2. Fluorination Process

[0030] A particular AAK1 inhibitor that has shown particular promise in the treatment of neuropathic pain is pilavapadin:

[0031]

[0032] The compound may be prepared by a number of methods. See, e.g., U.S. patent no. 8,703,953; U.S. patent application no. 18 / 114,050, filed February 24, 2023. One approach includes the reaction shown below in Scheme 1:

[0033] Scheme 1

[0034]

[0035] wherein the intermediate 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound A) is prepared by fluorination of 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound B) as shown below:Scheme 2

[0036] fluorinating agent

[0037]

[0038] Compound B

[0039]

[0040] using any of a variety of fluorinating agents, such as SF4, PhSFs, R2NSF3 (e.g., DAST, morpholinosulfur trifluoride (Morph-DAST)), dialkylamidodifluorosulfinium tetrafluoroborate (e.g., XtalFluor-E®, XtalFluor-M®), Deoxo-Fluor® (BAST), Selectfluor™, and 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride.

[0041] While this approach is viable, performing the Scheme 2 reaction on a large, commercial scale can be difficult and dangerous with some fluorinating agents. DAST in particular is volatile, thermally unstable, and highly explosive, which is why agents such as Deoxo-Fluor® and XtalFluor® were developed. Lee et al. “Advances in Continuous Flow Fluorination Reactions” Chem. Asian J. 2023, 18:e202300723 at 6. This invention is based on the discovery of a continuous flow method of fluorinating Compound B that allows the use of fluorination agents such DAST while mitigating the dangers associated with their conventional use.

[0042] When using DAST in methods of this invention, the fluorination of Compound B occurs as shown below in Scheme 3 :

[0043] Scheme 3

[0044]

[0045] wherein the solvent is compatible with fluorination conditions. Examples of such solvents are known in the art, and include chlorobenzene, DCM, ethyl acetate, isopropyl acetate, and toluene.

[0046] Byproducts of the reaction (including unreacted DAST) are quenched by treating the reaction mixture with an aqueous base, such as an aqueous solution of a carbonate salt (e.g., K2CO3), which provides the reactions shown below in Scheme 4:Scheme 4

[0047] + K2CO3KF + CO2

[0048] + K2CO33KF + 2CO2

[0049]

[0050] In methods of this invention, the reaction of Compound B with a fluorinating agent is performed in a continuous flow reactor. Reagents are prepared and stored in vessels connected by flow lines — with valves, pumps and pressure regulators positioned as necessary to control flow rates and temperature — to a “reaction module” wherein the reagents are combined under conditions (e.g., temperature, pressure) sufficient for the reaction to occur. While many continuous flow reactors employ a reaction vessel with input and output flow line(s) into which multiple input loads of reagents are continuously fed (and out of which one or more output loads flow), the fluorination reactions of this invention preferably occur as the reaction mixture flows through tubing or channeling contained, for example, in a temperature bath that allows for a constant reaction temperature.

[0051] Continuous flow reactors are well known in the art and can vary widely depending on the application. See, e.g., U.S. patent nos. 11,834,388; 11,802,112; 11,732,003; 11,731,101; and 7,541,008. Examples include pipe / laminar flow systems, falling fdm reactors, “counter current” flow reactors, spinning disc devices, pipe-in-pipe systems, and parallel multichannel reactors. Here, a suitable flow reactor is made from materials (e.g., Hastelloy®, perfluoroalkoxy alkane (PFA)) that can withstand the corrosive effects of fluorination conditions. A continuous flow reactor may be a single integrated apparatus or may comprise two or more pieces of individual parts that combine to produce an overall continuous flow apparatus.

[0052] A continuous flow reactor comprises two or more flow lines that carry reactants — typically solvated — from storage vessels to the reaction module. The flow rates and relative amounts of the reagents may be controlled by pumps, valves, and pressure release mechanisms. Once the reagents have passed through the reaction module, they are conveyed through a “cooling module”, where they are cooled to a temperature well below the decomposition temperature of the fluorination reagent being used. Although the reaction and cooling modules may be of any shape or size, preferred embodiments of the invention use a coiled tube or pipe suspended in a temperature bath. Consequently, while the reaction and cooling modules are distinct from a functional point of view, they may actually be parts of a contiguous whole (e.g. , parts of one tube that passes through a heated bath to effect the fluorination reaction and then through a cooling bath to cool the mixture).After flowing through the cooling module, the resulting cooled reaction mixture is treated with reagents useful for the stabilization and isolation of the reaction products. In preferred embodiments of the invention, this occurs in a final reaction vessel coupled to the cooling module. Valves and pumps are used to control the rate of flow of other reactants (e.g., K2CO3 in water) into the final reaction vessel. In preferred embodiments, the product mixture formed in the final reaction vessel is moved through one or more lines (e.g., tubes) connecting the final reaction vessel to a mix-settler, which allows the separation of aqueous and organic solvents and isolation of the final product.

[0053] FIG. 1 provides a schematic representation of a continuous flow reactor used in a particular embodiment of the invention discussed in more detail below, wherein 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound A) was fluorinated using DAST. In this reactor, the reaction reagents are loaded into flow vessels under nitrogen. Flow vessel 1 (FLV1) is loaded with Compound A in solvent; flow vessel 2 (FLV2) is loaded with triethylamine (TEA) in solvent; and flow vessel 3 (FLV3) is loaded with solvated DAST. Flow vessel 4 (FLV4) is loaded with K2CO3 dissolved in water, which is used to quench the reaction byproducts.

[0054] In general, pumps are used to move reagents through flow lines of a continuous reactor at rates and times that can be further controlled with valves. The flow lines converge so that a reaction mixture of all of the reagents enters the flow reactor. Pump pressure and valve settings are used to control the flow rate of the reaction mixture through the flow reactor, which is maintained at a temperature sufficient for the fluorination of Compound A, after which point the reaction mixture enters a cooling module where it is cooled. The resulting cooled reaction mixture flows from the cooling module to a collection vessel at a rate that can be controlled using additional valves. The aqueous K2CO3, initially contained in FLV4, also flows into the collection vessel after having been cooled, where it reacts with the byproducts of the fluorination reaction to provide water-soluble salts. The resulting product mixture is then transferred to a mix-settler at a rate determined by pump rates and valve settings, where the aqueous and organic phases of the product mixture are separated and from which the final product are extracted.

[0055] 4.1.3. Representative Example

[0056] One hundred grams 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound B) were fluorinated using the reagents listed in Table 1.Table 1

[0057] Material MW Weight (g) Moles Equivalents Ratio (w / w) Compound B 230.19 100.0 0.43 1.0 1.00X

[0058] DCM 84.93 1600.0 16.0X Triethylamine 101.19 2.64 0.026 0.06 0.026X

[0059] DCM 84.93 400.0 4.0X

[0060] DAST 161.19 168.06 1.043 2.4 1.68X

[0061] DCM 84.93 660.0 6.6X

[0062] K2CO3 138.21 300.0 2.17 5.0 3.0X

[0063] Water 18.02 2700.0 27.0X

[0064] The reaction occurred in a continuous flow reactor that is schematically represented in FIG. 1. In this example, 40 meters of quarter-inch outer diameter (OD) Hastelloy® tubing with a wall thickness of 0.047 inches, coiled and suspended in a temperature bath maintained at about 85 - 95°C (e.g., 90°C), constituted the reaction module (flow reactor 1, FLR1). That tubing was connected to one meter of 0.125 inch OD (0.03 inch wall thickness) Hastelloy® tubing suspended in a temperature bath maintained at a temperature of from 0 to about 20°C (e.g., 15°C), which constituted the reaction cooling module.

[0065] Here, a vessel was charged with 800 g DCM, then 100 g Compound B, then an additional 800 g DCM, and the resulting mixture was stirred for more than one hour at 20-30 °C to obtain a clear solution. The solution was then transferred through a filter into flow vessel 1 (FLV1). In a second vessel, 2.64 g ethylamine was stirred with 400 g DCM for more than 10 minutes at 15-25 °C to obtain a clear solution, which was then transferred through a filter into flow vessel 2 (FLV2). A third vessel was charged with 176.9 g DAST and 663 g DCM, which mixture was stirred for more than one hour at 20-30°C to obtain a clear solution, which was then transferred through a filter into flow vessel 3 (FLV3). The flow vessels were maintained under inert atmosphere (e.g., N2). A fourth vessel was charged with 2000 g water, 300.0 g K2CO3, and then another 700 g water, and the resulting solution was stirred and transferred through a filter into flow vessel 4 (FLV4).

[0066] A piston pump P3 was used to move the reagents in FLV3 to the combined input of the reaction module FLR1. Piston pumps Pl and P2 were used to move the reagents from FLV1 and FLV2, respectively, to the combined input of the reaction module. Pump flow rates and valve settings were adjusted to provide reactor residence time of about 40 minutes (e.g., from about 35 to about 45 minutes), after which point the reaction mixture passed into the cooling module. The pressures in the reaction and cooling modules were controlled, in part, by a back-pressure regulator (BPR) positioned after the reaction cooling module. In this example, the pressure was maintained at about 100 psi.

[0067] The cooled reaction mixture flowed through the BPM, through a valve configured to allow sample testing (Sampling 1), and into flow reactor 2 (FLR2), which in this case was a glass, 100 mL vessel maintained at a temperature of from about 0 to about 20°C. Contemporaneously, contents of FLV4 were moved by peristaltic pump P4 through a pre-cooling module — in this case, the same type of apparatusused for the reaction cooling module — into FLR2, where they were stirred for a time (e.g., about 10 minutes) sufficient for the carbonate salt to react with fluorination reaction byproducts and any unreacted DAST. Output from the flow rector was moved by peristaltic pump P5 through a valve that allows sample collection (Sampling2) to a mix-settler at a rate set to provide an average FLR2 residence time of about 10 minutes.

[0068] From the mix-settler, aqueous and organic phases were continuously transferred to collection drums via valves that allowed for the testing of each phase (Samplings, Sampling4), and the drums were placed in cooled storage. The organic phase was then further processed to isolate pure Compound A.

[0069] All publications (e.g. , patents and patent applications) cited above are incorporated herein by reference in their entireties.

[0070] * * *

Claims

CLAIMSWhat is claimed is:

1. A method of preparing 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound A):NNwhich comprises, in a continuous flow reactor:flowing a reaction mixture through a reaction module having an inlet and an outlet;flowing the reaction mixture through a cooling module having an inlet and an outlet to provide a cooled reaction mixture;contacting the cooled reaction mixture with an aqueous base to provide a product mixture; and isolating Compound A from the product mixture;wherein:the reaction mixture comprises a fluorinating agent, triethylamine, a solvent, and 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound B):NNthe solvent is compatible with fluorination conditions;the reaction module is maintained at a first temperature and a first pressure sufficient for the formation of Compound A;the reaction mixture resides in the reaction module for a reaction residence time sufficient for the formation of Compound A;the cooling module is maintained at a second temperature and second pressure sufficient to inhibit decomposition of the fluorinating agent; andthe reaction mixture resides in the cooling module for a time sufficient to provide a cooled reaction mixture having a temperature approximately equal to the second temperature.

2. The method of claim 1, wherein the aqueous base is aqueous K2CO3, ISfeCOs, K3PO4, or NasPOs3. The method of claim 1 or 2, wherein the fluorinating agent is diethylaminosulfur trifluoride (jV,jV-diethyl-l,l,l-trifluoro-X4-sulfanamine) (DAST).

4. The method of any of the preceding claims, wherein the solvent is chlorobenzene, dichloromethane, ethyl acetate, isopropyl acetate, or toluene.

5. The method of claim 4, wherein the solvent is dichloromethane.

6. The method of any of the previous claims, wherein the first temperature is from about 85 to about 95°C.

7. The method of any of the previous claims, wherein the first pressure is from about 0.3 to about 1 MPa (e.g., about 0.4, 0.5, 0.6, 0.8, 0.9 MPa).

8. The method of any of the previous claims, wherein the reaction residence time is at least 10 minutes (e.g., at least 20, 30, 40, 50 minutes).

9. The method of any of the previous claims, wherein the second temperature is less than about 40°C (e.g., from about 0 to about 40°C, from about 0 to about 30°C, from about 0 to about 20°C).

10. The method of any of the previous claims, wherein the second pressure is the same as the first pressure.

11. The method of any of the previous claims, wherein aqueous and organic components of the product mixture are separated prior to the isolation of Compound A.

12. The method of any of the previous claims, wherein the outlet of the reaction module is directly coupled to the inlet of the cooling module.

13. The method of any of the previous claims, wherein the reaction module comprises tubing through which the reaction mixture flows, which tubing is immersed in a temperature bath.

14. The method of any of the previous claims, wherein the cooling module comprises tubing through which the reaction mixture flows, which tubing is immersed in a temperature bath.

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