HK1187494A

HK1187494A - Process for the preparation of 4-amino-5-fluoro-3-halo-6-(substituted)picolinates

Info

Publication number: HK1187494A
Application number: HK14100576.6A
Authority: HK
Inventors: Gregory T. Whiteker; Kim E. Arndt; James M. Renga; Yuanming Zhu; Christian T. LOWE; Thomas L. Siddall; David E. Podhorez; Gary Alan Roth; Scott P. WEST
Original assignee: 陶氏益农公司
Priority date: 2011-01-25
Filing date: 2012-01-24
Publication date: 2014-04-11

Description

Process for preparing 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters

Technical Field

The present invention relates to a process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters. More particularly, the present invention relates to a process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylates wherein the 5-fluoro substituent is introduced by halogen exchange early in the operating scheme.

Background

U.S. patent 6,297,197B1 specifically describes certain 6- (alkoxy or aryloxy) -4-amino-3-chloro-5-fluoropyridine-2-carboxylate compounds and their use as pesticides, among others. U.S. Pat. nos. 6,784,137B2 and 7,314,849B2 specifically describe certain 6- (aryl) -4-amino-3-chloro-5-fluoropyridine-2-carboxylate compounds and their use as pesticides, among others. U.S. patent 7,432,227B2 specifically describes certain 6- (alkyl) -4-amino-3-chloro-5-fluoropyridine-2-carboxylate compounds and their use as pesticides, among others. Each of these patents describes the preparation of 4-amino-3-chloro-5-fluoropyridine-2-carboxylate starting materials by fluorination of the corresponding 5-unsubstituted pyridine with 1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate). It would be advantageous to prepare 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters without having to resort to direct fluorination of the 5-position of the pyridine ring with an expensive fluorinating agent such as 1- (fluoromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate).

Disclosure of Invention

The present invention relates to a process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters from 4,5, 6-trichloropyridine-2-carboxylic acid esters. More particularly, the present invention relates to a process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters of formula I,

wherein

W represents Cl, Br or I;

r represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl or phenyl, said phenyl substituted with 1-4 substituents independently selected from: halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄An alkoxy group; and

R¹is represented by C₁-C₁₂Alkyl or unsubstituted or substituted C₇-C₁₁An arylalkyl group;

the method comprises the following steps:

a) fluorinating a 4,5, 6-trichloropyridine-2-carboxylate ester of formula a with a fluoride ion source to produce a 4,5, 6-trifluoropyridine-2-carboxylate ester of formula B:

wherein R is¹As defined above;

the formula B is as follows:

wherein R is¹As defined above;

b) amination of 4,5, 6-trifluoropyridine-2-carboxylate of formula B with ammonia to prepare 4-amino-5, 6-difluoropyridine-2-carboxylate of formula C,

wherein R is¹As defined above;

c) exchanging a fluoro substituent at the 6-position of a 4-amino-5, 6-difluoro-pyridine-2-carboxylate of formula C with an iodo substituent, a bromo substituent, or a chloro substituent by treatment with an iodide source, a bromide source, or a chloride source to produce a 4-amino-5-fluoro-6-halopyridine-2-carboxylate of formula D:

wherein X represents Cl, Br or I;

and R¹As defined above;

d) halogenating a 4-amino-5-fluoro-6-halopyridine-2-carboxylate of formula D with a halogen source to produce a 4-amino-3, 6-dihalo-5-fluoropyridine-2-carboxylate of formula E,

wherein W and X independently represent Cl, Br or I;

and R¹As defined above; and

e) coupling a 4-amino-3, 6-dihalo-5-fluoropyridine-2-carboxylate of formula E with an aryl, alkyl or alkenyl metal compound of formula F in the presence of a transition metal catalyst to produce a 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylate of formula I:

R-Met F，

wherein R is as defined above and Met represents Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper, OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl groups, or together form an ethylene or propylene group.

Steps a) to e) may be carried out in the order listed, as shown in scheme I.

Scheme I

Alternatively, the order of execution of the steps may be rearranged, for example, as shown in schemes II and III.

Scheme II

According to scheme II, the present invention relates to a process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters of formula I:

wherein

W represents Cl, Br or I;

r represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl, or phenyl substituted with 1-4 substituents independently selected from: halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄An alkoxy group; and

the method comprises the following steps:

wherein R is¹As defined above;

the formula B is as follows:

wherein R is¹As defined above;

b) aminating a 4,5, 6-trifluoropyridine-2-carboxylate of formula B with ammonia to produce a 4-amino-5, 6-difluoropyridine-2-carboxylate of formula C:

wherein R is¹As defined above;

c) exchanging the fluoro substituent at the 6-position of the 4-amino-5, 6-difluoropyridine-2-carboxylate of formula C with an iodo substituent, a bromo substituent or a chloro substituent by treatment with an iodide source, a bromide source or a chloride source to produce a 4-amino-5-fluoro-6-halopyridine-2-carboxylate of formula D,

wherein X represents Cl, Br or I; and

R¹as defined above;

d) coupling a 4-amino-5-fluoro-6-halopyridine-2-carboxylate of formula D with an aryl, alkyl, or alkenyl metal compound of formula F in the presence of a transition metal catalyst to produce a 4-amino-5-fluoro-6- (substituted) -pyridine-2-carboxylate of formula G:

R-Met F

wherein R is as defined above and Met represents Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper, OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl, or together form an ethylene or propylene group, said formula G being:

wherein R and R¹As defined above; and

e) halogenating a 4-amino-5-fluoro-6- (substituted) pyridine-2-carboxylate of formula G with a halogen source to produce a 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylate of formula I.

Scheme III

In scheme III, iodine, bromine or chlorine exchange step c) is not necessary. Accordingly, the present invention also relates to a process for the preparation of 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylic acid esters of formula I:

wherein

W represents Cl, Br or I;

the method comprises the following steps:

a) coupling a 4,5, 6-trichloropyridine-2-carboxylic acid ester of formula a with an aryl, alkyl, or alkenyl metal compound of formula F in the presence of a transition metal catalyst to produce a 4, 5-dichloro-6- (substituted) pyridine-2-carboxylic acid ester of formula H, said formula a being:

wherein R is¹As defined above;

the formula F is:

R-Met F

wherein R is as defined above and Met represents Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper, OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl, or together form an ethylene or propylene group, said formula H being:

wherein R and R¹As defined above;

b) fluorinating a 4, 5-dichloro-6- (substituted) pyridine-2-carboxylate ester of formula H with a fluoride ion source to produce a 4, 5-difluoro-6- (substituted) pyridine-2-carboxylate ester of formula J:

wherein R is¹As defined above;

c) aminating a 4, 5-difluoro-6- (substituted) pyridine-2-carboxylate ester of formula J with ammonia to produce a 4-amino-5-fluoro-6- (substituted) pyridine-2-carboxylate ester of formula K:

wherein R and R¹As defined above; and

d) halogenating a 4-amino-5-fluoro-6- (substituted) pyridine-2-carboxylate of formula K with a halogen source to produce a 4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylate of formula I.

In any of the steps in schemes I-III, different R may optionally be used¹Exchange of substituents for the ester substituent R¹. These esters (including unsubstituted or substituted C)₇-C₁₁Arylalkyl esters) can be prepared by direct esterification or transesterification using techniques well known in the art.

Another aspect of the present invention is a novel intermediate prepared during the process of the present invention, i.e. a compound selected from the group consisting of:

wherein R represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl or phenyl, said phenyl substituted with 1-4 substituents independently selected from: halogen, C₁-C₄Alkyl radicalHalogen substituted C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄Alkoxy, and R¹Is represented by C₁-C₁₂Alkyl or unsubstituted or substituted C₇-C₁₁An arylalkyl group;

b)

wherein X represents I, Br, Cl or F, Y¹Represents H, Cl, Br or I, with the proviso that when X is Cl, Y¹H, Br or I; and R¹Is represented by C₁-C₁₂Alkyl or unsubstituted or substituted C₇-C₁₁An arylalkyl group;

c)

wherein Y is²Represents H, Br or I, and R represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl or phenyl, said phenyl substituted with 1-4 substituents independently selected from: halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄Alkoxy, and R¹Is represented by C₁-C₁₂Alkyl or unsubstituted or substituted C₇-C₁₁An arylalkyl group; and

d)

wherein R represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl, or phenyl substituted with 1-4 substituents independently selected from: halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄Alkoxy, and R¹Is represented by C₁-C₁₂Alkyl or unsubstituted or substituted C₇-C₁₁An arylalkyl group.

The terms "alkyl", "alkenyl" and "alkynyl" as well as derivative terms such as "alkoxy", "acyl", "alkylthio" and "alkylsulfonyl" as used herein include within their scope straight chain, branched chain and cyclic moieties. Unless otherwise specifically stated, each group may be unsubstituted or substituted with one or more substituents selected from, but not limited to, halogen, hydroxy, alkoxy, alkylthio, C₁-C₆Acyl, formyl, cyano, aryloxy or aryl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy. The terms "alkenyl" and "alkynyl" are intended to include one or more unsaturated bonds.

The term "arylalkyl" as used herein refers to a phenyl-substituted alkyl group having a total of 7 to 11 carbon atoms, such as benzyl (-CH)₂C₆H₅) 2-methylnaphthyl (-CH)₂C₁₀H₇) And 1-or 2-phenylethyl (-CH)₂CH₂C₆H₅or-CH (CH)₃)C₆H₅). The phenyl group itself may be unsubstituted or substituted with one or more substituents independently selected from halogen, nitro, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogenated C₁-C₆Alkyl, halogenated C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, C (O) OC₁-C₆Alkyl, or-O (CH) when two adjacent substituents are combined₂)_nO-, wherein n =1 or 2, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy.

Unless otherwise specifically limited, the term "halogen" and derivative terms such as "halo" refer to fluorine, chlorine, bromine, and iodine.

Substituted with 1-4 substituents independently selected from halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄The 6-phenyl group as a substituent of the alkoxy group may have any orientation, but is preferably a 4-substituted phenyl group, a 2, 4-disubstituted phenyl group, a 2,3, 4-trisubstituted phenyl group, a 2,4, 5-trisubstituted phenyl group, and a 2,3,4, 6-tetrasubstituted phenyl isomer.

4-amino-5-fluoro-3-halo-6- (substituted) pyridine-2-carboxylate is prepared from 4,5, 6-trichloropyridine-2-carboxylate by a series of steps including fluorine exchange, amination, halogen exchange, halogenation, and transition metal assisted coupling. The various steps may be performed in a different order.

The starting materials of 4,5, 6-trichloropyridine-2-formic ether are known compounds; see, for example, example 3 in U.S. patent 6,784,137B 2. Higher esters (including unsubstituted or substituted C)₇-C₁₁Arylalkyl esters) can be prepared by direct esterification or transesterification using techniques well known in the art.

In the fluoride exchange reaction, a fluorinated pyridine-2-carboxylate is prepared by: the corresponding chlorinated pyridine-2-carboxylate ester is reacted with at least one equivalent of a fluoride ion source to exchange each of the cyclic chloride substituents.

Typical fluoride ion sources are alkali metal fluorides including sodium fluoride (NaF), potassium fluoride (KF) and cesium fluoride (CsF), preferably KF and CsF. Can also makeWith fluorine salts, e.g. tetrabutylammonium fluoride (n-Bu)₄NF). Preferably, the reaction is carried out in a polar aprotic solvent or reaction medium such as dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP), N-Dimethylformamide (DMF), Hexamethylphosphoramide (HMPA) or sulfolane. Additives such as crown ethers or phase transfer agents known to increase the rate of fluorine exchange may also be used. The temperature at which the reaction is carried out is not critical, but is generally from 70 ℃ to 180 ℃ and preferably from 80 ℃ to 120 ℃. The optimum temperature will vary depending on the solvent used in a particular reaction. Generally, the lower the temperature, the slower the reaction rate. The reaction of the present invention is typically carried out with vigorous stirring sufficient to maintain a substantially uniformly dispersed reaction mixture.

Neither the rate nor the order of addition of the reactants is critical in carrying out the fluorination reaction. Typically, the solvent and the alkali metal fluoride are combined prior to adding the chlorinated pyridine-2-carboxylate to the reaction mixture. Typical reactions generally take 2 to 100 hours and are usually carried out at ambient pressure.

Although the precise amounts of the reactants are not critical, it is preferred to use amounts of alkali metal fluoride such that: it will provide at least an equimolar amount of fluorine atoms, i.e. at least an equimolar amount of alkali metal fluoride, based on the number of chlorine atoms to be exchanged in the starting material. After completion of the reaction, the desired product is recovered by using standard separation and purification techniques.

In amination, 4-fluoropyridine-2-carboxylate is reacted with ammonia to replace the fluorine atom with an amino group.

Although only a stoichiometric amount of ammonia is required, it is often suitable to use a large excess of ammonia. The reaction is carried out in an inert solvent, preferably a polar aprotic solvent or reaction medium such as DMSO, NMP, DMF, HMPA or sulfolane. Alternatively, aqueous ammonium hydroxide may be used with or without an organic solvent. The temperature at which the reaction is carried out is not critical, but is generally from 0 ℃ to 45 ℃ and preferably from 10 ℃ to 30 ℃.

In carrying out the amination reaction, 4-fluoropyridine-2-carboxylate is dissolved in a solvent and ammonia is added to the reaction mixture with cooling. Excess ammonia is typically bubbled into the reaction mixture. Typical reactions generally take from 0.5 to 5 hours and are usually carried out at ambient pressure.

The amine-containing product or intermediate obtained by any of these methods can be recovered by conventional methods such as evaporation or extraction and can be purified by standard procedures such as recrystallization or chromatography. Purification of the amine-containing product or intermediate may also be carried out by: protonating with an acid to form a salt, and isolating the salt in higher purity by crystallization, precipitation or extraction. Various acids such as hydrochloric acid, hydrobromic acid, nitric acid, acetic acid or sulfuric acid may be used. Anhydrous hydrochloric acid is the preferred acid. The purified salt is then neutralized with a base to form a neutral amine-containing product or intermediate. Inorganic bases such as sodium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate may also be used. Organic bases such as triethylamine are preferred. Purification of the amine-containing product or intermediate can be carried out in this way immediately after the amination step or after subsequent reactions, such as halogenation, coupling, have been carried out.

In a halogen (iodine, bromine or chlorine) exchange reaction, 6-iodinated, 6-brominated or 6-chlorinated pyridine-2-carboxylic acid esters are prepared by: the corresponding 6-fluorinated pyridine-2-carboxylic acid ester is reacted with at least one equivalent of iodine, bromine or chlorine.

Typically, the halogen exchange reaction is carried out in the presence of a large excess of anhydrous Hydrogen Iodide (HI), hydrogen bromide (HBr), or hydrogen chloride (HCl). The reaction is typically carried out in the absence of water, thereby minimizing the formation of by-products. Halogen exchange generally requires 5 to 50 equivalents of HI, HBr or HCl, preferably 10 to 20 equivalents. The reaction is carried out in an inert solvent, preferably a polar solvent such as dioxane or acetic acid. The temperature at which the reaction is carried out is not critical, but is generally from 75 ℃ to 150 ℃ and preferably from 100 ℃ to 125 ℃. The reaction is typically carried out in a sealed pressure reactor, which can contain HI, HBr, or HCl gas. Typical reactions usually take 0.5 to 5 hours.

In the halogenation reaction, a chlorine atom, a bromine atom or an iodine atom is introduced into the 3-position of pyridine-2-carboxylic acid ester by reacting 3-unsubstituted pyridine-2-carboxylic acid ester with a halogen source in an inert solvent.

When the halogen atom at the 3-position is Cl, the chlorine source may be chlorine (Cl)₂) As such or a reagent such as sulfonyl chloride, N-chlorosuccinimide or 1, 3-dichloro-5, 5-dimethylhexanoyl urea. When chlorine or sulfuryl chloride is used, a large excess of chlorinating agent is used. When chlorine is used, the reaction is carried out in an inert solvent, preferably a solvent such as dichloromethane, dichloromethane-water or acetic acid. When using sulfonyl chloride, the reaction can be carried out in an inert solvent such as dichloromethane or in pure sulfonyl chloride. The temperature at which the reaction is carried out is not critical, but is generally from 0 ℃ to 45 ℃ and preferably from 10 ℃ to 30 ℃. Typical reactions usually take 0.5 to 5 hours. The chlorination reaction is typically carried out at ambient pressure.

When the chlorinating agent used is N-chlorosuccinimide or 1, 3-dichloro-5, 5-dimethylhexanolactam, the reaction is carried out using a stoichiometric amount of chlorinating agent. For chlorination using 1, 3-dichloro-5, 5-dimethylhexanolactam as the chlorinating agent, it was found that both of the chlorides in hexanolactam were reacted. The reaction is carried out in an inert polar solvent such as DMF or acetonitrile. The temperature at which the reaction is carried out is not critical, but is generally from 20 ℃ to 85 ℃ and preferably from 50 ℃ to 80 ℃. When acetonitrile is used as solvent, it is suitable to carry out the reaction at reflux temperature. Typical reactions usually take 0.5 to 5 hours. The chlorination reaction is typically carried out at ambient pressure.

When the halogen atom at the 3-position is Br, the bromine source can be bromine (Br)₂) Either by itself or as a reagent such as sulfonyl bromide, N-bromosuccinimide or 1, 3-dibromo-5, 5-dimethylhexanoyl urea. When using Br₂As brominating agent, a large excess can be used and the reaction is carried out in an inert solvent, preferably a solvent such as dichloromethane, dichloromethane-water or acetic acid. The temperature at which the reaction is carried out is not critical, but is generally from 0 ℃ to 45 ℃ and preferably from 10 ℃ to 30 ℃. Typical reactions usually take 0.5 to 5 hours. The bromination reaction is typically carried out at ambient pressure.

When the brominating agent used is N-bromosuccinimide or 1, 3-dibromo-5, 5-dimethylhexanolactam, the reaction is carried out using a stoichiometric amount of brominating agent. The reaction is carried out in an inert solvent such as DMF or acetonitrile. The temperature at which the reaction is carried out is not critical, but is generally from 20 ℃ to 85 ℃ and preferably from 50 ℃ to 80 ℃. When acetonitrile is used as solvent, it is suitable to carry out the reaction at reflux temperature. Typical reactions usually take 0.5 to 5 hours. The bromination reaction is typically carried out at ambient pressure.

When the halogen atom at the 3-position is I, the iodine source may be iodine (I)₂) Either by itself or as a reagent such as iodine monochloride or N-iodosuccinimide. Periodic acid and I can be added₂Can be used in combination. When using I₂As iodinating agents, large excesses of I may be used₂And the reaction is carried out in an inert solvent, preferably a solvent such as dichloromethane, dichloromethane-water, methanol or acetic acid. The temperature at which the reaction is carried out is not critical, but is generally from 0 ℃ to 45 ℃ and preferably from 10 ℃ to 30 ℃. Typical reactions usually take 0.5 to 5 hours. The iodination reaction is usually carried out at ambient pressure.

In the coupling reaction, in the presence of a transition metal catalyst, 6-iodopyridine-Reacting 2-formate, 6-bromopyridine-2-formate or 6-chloropyridine-2-formate with an aryl metal compound, an alkyl metal compound or an alkenyl metal compound, wherein the metal is Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper, OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl groups, or together form an ethylene or propylene group.

"catalyst" is a transition metal catalyst, specifically a palladium catalyst such as palladium diacetate or bis (triphenylphosphine) palladium (II) dichloride, or a nickel catalyst such as nickel (II) acetylacetonate or bis (triphenylphosphine) nickel (II) dichloride. Alternatively, the catalyst may be prepared in situ from a metal salt and a ligand such as palladium acetate and triphenylphosphine or nickel (II) dichloride and triphenylphosphine. These in situ catalysts can be prepared by the following methods: the metal salt and ligand are first reacted and then added to the reaction mixture, or the metal salt and ligand are added separately directly to the reaction mixture.

Typically, the coupling reaction is carried out in the absence of oxygen using an inert gas such as nitrogen or argon. Techniques for excluding oxygen from the coupling reaction mixture, such as sparging with an inert gas, are well known to those skilled in the art. An example of this technique is described in The management of Air-sensitive Compounds,2^nded., Shriver, D.F., Drezdzon, M.A., eds., Wiley-Interscience, 1986. A sub-stoichiometric amount of catalyst is used, typically from 0.0001 to 0.1 equivalents. Optionally, additional amounts of ligand may be added to increase catalyst stability and activity. In addition, additives such as Na are generally used₂CO₃、K₂CO₃KF, CsF and NaF were added to the coupling reaction. The coupling reaction generally requires 1 to 5 equivalents of such additives, preferably 1 to 2 equivalents. Optionally, water may be added to the coupling reaction to increase theseSolubility of the additive. The coupling reaction generally requires 1 to 3 equivalents of the metal aryl, metal alkyl or metal alkenyl compound, preferably 1 to 1.5 equivalents. The reaction is carried out in an inert solvent such as toluene, Tetrahydrofuran (THF), dioxane or acetonitrile. The temperature at which the reaction is carried out is not critical, but is generally from 25 ℃ to 150 ℃ and preferably from 50 ℃ to 125 ℃. Typical reactions usually take from 0.5 to 24 hours. A particular order of addition of the reactants is not generally required. It is often operationally simpler to combine all reactants except the catalyst and then deoxygenate the reaction solution. After deoxygenation, a catalyst can be added to initiate the coupling reaction.

When the Met moiety of the aryl metal compound, alkyl metal compound or alkenyl metal compound is Zn-halide, Zn-R or copper, protection of the reactive functional group may be necessary. For example, if an amino substituent (-NHR or-NH) is present₂) Then it may be necessary to protect these reactive groups. Various groups are known in the art for protecting amino groups from reaction with organometallic reagents. Examples of such protecting Groups are described in Protective Groups in Organic Synthesis,3^rded., respectively; greene, t.w.; wuts, p.g.m., eds.; Wiley-Interscience, 1999. The choice of which metal to use in R-Met is influenced by many factors, such as cost, stability, reactivity and the need to protect reactive functional groups.

The product obtained by any of these methods can be recovered by conventional methods such as evaporation or extraction, and can be purified by standard procedures such as recrystallization or chromatography.

The following examples are provided to illustrate the invention.

Detailed Description

Examples

Preparation of starting Material

Example A.4,5, 6-trichloropyridine-2-carboxylic acid propan-2-ester

In a 250mL round bottom flask equipped with Dean-Stark hydrazine and reflux condenser, methyl 4,5, 6-trichloropyridine-2-carboxylate (14.19 g, 59.0 mmol) was slurried in 2-propanol (150mL (mL)). Sulfuric acid (98% H) was added₂SO₄(ii) a 8.07g,82mmol) and the reaction mixture was heated to reflux. After refluxing for 20 hours (h), most of the 2-propanol (100mL) was distilled overhead. The contents of the can (pot) solidified upon cooling to room temperature. The resulting solid was combined with ethyl acetate (EtOAc; 500mL) and saturated (satd) sodium bicarbonate (aq) solution (NaHCO)₃(ii) a 500mL) were stirred together. The organic layer was separated, washed with brine, and then filtered through Celite (Celite). The organic extracts were concentrated to 150mL by rotary evaporation. Hexane (100mL) was added and the solution was stored at-20 ℃ overnight. The crystals were collected, washed with hexane and air dried (7.58g, mp 104.6-105.7 ℃). The second batch was obtained by concentrating the filtrate to yield a total of 10.36g (65%).¹H NMR(400MHz,DMSO-d₆) δ 8.23(s,1H, pyridine H),5.16 (heptad, J =6.3Hz,1H, CHMe)₂),1.34(d,J=6.3Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,CDCl₃)δ161.9(CO₂R),150.6,145.9,145.0,133.1,125.4(C3),70.7(CHMe₂),21.7(Me)。C₉H₈Cl₃NO₂Analysis calculated value: c, 40.26; h, 3.00; and N, 5.22. Measured value: c, 40.25; h, 3.02; and N, 5.22.

Example B.4,5, 6-trichloropyridine-2-carboxylic acid benzyl ester

A mixture of methyl 4,5, 6-trichloropyridine-2-carboxylate (25g,0.10 moles (mol)) and benzyl alcohol (100g,0.2mol) in a 250mL three-necked round bottom flask was heated at 100 ℃ under nitrogen. Titanium isopropoxide (0.6g,0.02mol) was added. After 4h at 100 ℃ the almost colorless solution was cooled and transferred to a 250mL round bottom single neck flask. Excess benzyl alcohol was removed under vacuum to give an almost white solid (31g, 94%): mp 125-126.5 ℃;¹H NMR(400MHz,CDCl₃) Δ 8.08(s,1H, pyridine H),7.42(m,2H, phenyl), 7.31(m,3H, phenyl), 5.40(s,2H, CH)₂Ph)；¹³C{¹H}NMR(101MHz,CDCl₃)δ162.0(CO₂R),150.4,145.0,144.9,134.7,133.1,128.3 (phenyl CH),125.4 (pyridine CH),67.88 (CH)₂Ph)。

Example C.4,5, 6-trichloropyridine-2-carboxylic acid benzyl ester

A22L round bottom flask was equipped with a thermocouple, mechanical stirrer, and Dean-Stark hydrazine, which was connected to a nitrogen bubbler. The vessel was purged with nitrogen and then 4,5, 6-trichloropyridine-2-carboxylate (2547g,10.07mol), pyridinium p-toluenesulfonate (PPTS; 130g,0.52mol), benzyl alcohol (2249g,20.8mol) and xylene (10278g) were added. Stirring was started and the contents of the tank were heated to 140-145 ℃. The xylene/water azeotrope was collected in Dean-Stark hydrazine over a 5 hour period. The total amount of distillate collected was 4750g (415g was water). After the water stops distilling overhead, a reactor sample is removed and analyzed by High Performance Liquid Chromatography (HPLC) to ensure that less than 1.5 area% of the starting carboxylic acid remains. The reaction mixture was cooled to room temperature and stirred overnight. Xylene (4000g) was removed by vacuum distillation. The solution was cooled to 85-100 ℃ and then vacuum transferred to a 30L jacketed crystallization vessel that had been equipped with a mechanical stirrer and thermocouple. The vacuum was released with nitrogen and a nitrogen bubbler was placed on the crystallization vessel. Isopropanol (IPA; 6200g) was added to the xylene solution over a period of 15 minutes (min). The resulting slurry was slowly cooled to room temperature and then further cooled to 5 ℃. The solid was collected by filtration and the filter cake was washed with cold (5-10 ℃) IPA (3731 g). The solid was air dried to constant weight to give white crystals (2765g, 96.5% purity by Gas Chromatography (GC) internal standard, 84.3%).

Fluorine exchange

Example 1a.4,5, 6-Trifluoropyridine-2-carboxylic acid propan-2-ester

A250 mL three-necked flask was equipped with a mechanical stirrer, Dean-Stark hydrazine with nitrogen inlet, and a thermocouple. The flask was purged with nitrogen and CsF (23.38g,154mmol) was added. Anhydrous DMSO (124mL) was added and the suspension was evacuated/back-filled with nitrogen (5 ×). The suspension was heated at 80 ℃ for 30 minutes. DMSO (20mL) was distilled under vacuum at 75 ℃ to remove any residual water. Propan-2-yl 4,5, 6-trichloropyridine-2-carboxylate (13.45g,50.1mmol) was added under a nitrogen purge. The reaction mixture was evacuated/back-filled (3 ×) and heated at 100 ℃ for 1 hour with vigorous stirring.

A second 250mL three-necked flask was equipped with a mechanical stirrer, Dean-Stark hydrazine with nitrogen inlet, and a thermocouple. The flask was purged with nitrogen and CsF (24.41g,0.160mmol) was added. Anhydrous DMSO (30mL) was added and the suspension was evacuated/back-filled with nitrogen (5 ×). The suspension was heated to 80 ℃ and held for 30 minutes. DMSO (22mL) was distilled under vacuum at 75 ℃ to remove residual water. The cooled reaction mixture in the first flask was filtered through a cannula into the second flask under nitrogen. The reaction mixture was evacuated/back-filled (5x), then heated to 100 ℃ and held for 1h, then held at 110 ℃ for another 90 minutes. An aliquot was analyzed by GC and showed 96% propan-2-4, 5, 6-trifluoropyridine-2-carboxylate, with only 1.4% propan-2-5-chloro-4, 6-difluoropyridine-2-carboxylate present. The crude product solution was used directly in the amination step without further purification. Alternatively, the product can be worked up by aqueous work-up, extraction with EtOAc and dryingIsolated to give a light brown oil:¹H NMR(400MHz,CDCl₃)δ7.94(dd,J_F-H=4.5,8.7Hz,1H, H3),5.30 (heptad, J)_H-H=6.3Hz,1H,CHMe₂),1.44(d,J_H-H=6.3Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,CDCl₃)δ161.2(s,CO₂iPr),157.3(ddd,J_F-C=266,8,6Hz,C4/C6),152.2(ddd,J_F-C=241,12,5Hz,C4/C6),141.1(dt,J_F-C=14,7Hz,C2),137.0(ddd,J_F-C=270,31,13Hz,C5),113.8(dd,J_F-C=17,4Hz,C3),70.4(s,CHMe₂),21.33(s,Me)；¹⁹F NMR(376MHz,CDCl₃)δ-74.29(dd,J_F-F=24,22Hz,F6),-112.67(ddd,J_F-F=22,19,J_F-H=8.3Hz,F4),-151.58(ddd,J_F-F=24,19,J_F-H=4.7Hz,F5)。

Example 1b.4, 5-difluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -pyridine-2-carboxylic acid propan-2-ester

A250 mL three-necked flask was equipped with a distillation head, nitrogen inlet, mechanical stirrer, and thermocouple. CsF (14.2g,93.0mmol) was added to the flask. Anhydrous DMSO (80mL) was added and the suspension was evacuated/back-filled with nitrogen (5 ×). The suspension was heated at 80 ℃ for 30 minutes. The DMSO (20mL) was distilled under vacuum to remove any residual water. Solid 4, 5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid propan-2-ester (10.44g,26.6mmol) was added and the solution was evacuated/back-filled with nitrogen (5 ×). The reaction mixture was heated to 105 ℃ under nitrogen. After 4h at 105 ℃, an aliquot was analyzed by GC, showing a 91:6 ratio of difluoro to monofluoro products. The reaction mixture was cooled to room temperature.

A second 250mL three-necked flask was equipped with a mechanical stirrer, a distillation head with nitrogen inlet, and a thermocouple. The flask was purged with nitrogen and CsF (7.5g,49.4mmol) was added. Anhydrous DMSO (20mL) was added and the suspension was evacuated/back-filled with nitrogen(5 x). The suspension was heated at 80 ℃ for 30 minutes. DMSO (15mL) was distilled under vacuum to remove residual water. The cooled reaction mixture in the first flask was filtered through a cannula into the second flask under nitrogen. The reaction mixture was evacuated/back-filled (5x) and then heated to 100 ℃ and held for 2 hours. An aliquot was analyzed by GC and showed a 93:2 ratio of the desired product, the monofluoro intermediate. The reaction mixture was poured into ice-water (550g) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with water (5 × 100mL) and brine, and with magnesium sulfate (MgSO)₄) Drying and concentration under reduced pressure gave a brown oil (8.57g) which crystallized upon standing. The solid was purified by silica gel chromatography (330g silica gel column; 0-50% EtOAc-hexane gradient) to afford a white solid (4.98g, 52%): mp 98.4-100.0 deg.C;¹h NMR (400MHz, acetone-d₆)δ8.16(dd,J_F-H=10.0,5.6Hz,1H, pyridine H),7.43(m,2H, phenyl), 5.24 (heptad, J)_H-H=6.3Hz,1H,CHMe₂),4.01(d,J_F-H=1.1Hz,3H,OMe),1.37(d,J_H-H=6.3Hz,6H,CHMe₂)；¹³C{¹H } NMR (101MHz, acetone-d₆)δ163.1(CO₂R),157.1(dd,J_F-C=264,12Hz,C4/C5),154.8(d,J_F-C=254Hz, C2' phenyl), 148.6(dd, J)_F-C=267,11Hz,C4/C5),147.4(t,J_F-C=6Hz),145.5(d,J_F-C=13Hz),144.6(d,J_F-C=13Hz),131.0,126.8,126.6(d,J_F-C=3.7Hz),123.2,115.8(d,J_F-C=16Hz),70.6(CHMe₂),62.1(d,J_F-C=4Hz,OMe),21.9(CHMe₂)；¹⁹F NMR(376MHz,CDCl₃)δ-124.82(dd,J_F-F=21Hz,J_F-H=9.9Hz,F4),-129.45(dd,J_F-F=27.8Hz,J_F-H=6.9Hz, phenyl F), -141.81(m, F5). C₁₆H₁₃ClF₃NO₃Analysis calculated value: c, 53.42; h, 3.64; and N, 3.89. Measured value: c, 53.77; h, 3.70; and N, 3.95. An aliquot was analyzed by GC and showed the product to be 95.5% pure with 1.7% monofluoro impurity.

Example 1c.4, 5-difluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid benzyl ester

A250 mL three-necked flask was equipped with a distillation head, nitrogen inlet, mechanical stirrer, and thermocouple. CsF (21.07g,139.0mmol) was added to the flask. Anhydrous DMSO (100mL) was added and the suspension was evacuated/back-filled with nitrogen (5 ×). The suspension was heated at 80 ℃ for 30 minutes. The DMSO (30mL) was distilled under vacuum to remove any residual water. Solid 4, 5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid benzyl ester (15.34g,34.8mmol) was added and the solution was evacuated/back-filled with nitrogen (5 ×). The reaction mixture was heated to 105 ℃ under nitrogen. After 6h at 105 ℃, an aliquot was analyzed by GC, showing no peak for monofluoro intermediate. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice-water (400g) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were extracted with saturated NaHCO₃The solution, water (5x100mL) and brine. The extract was dried (MgSO)₄) And concentrated under reduced pressure to give a brown solid (12.97 g). The solid was purified by flash chromatography (330g silica gel column; 0-20% EtOAc-gradient) to afford a white solid (9.95 g; 70%): mp 114-116 ℃;¹H NMR(400MHz,CDCl₃)δ8.01(dd,J_F-H=9.4,5.5Hz,1H, pyridine H), 7.53-7.20 (m,7H, phenyl), 5.44(s,2H, CH)₂Ph),3.99(d,J_F-H=1.2Hz,3H,OMe)；¹³C NMR(101MHz,CDCl₃)δ162.8(d,J_F-C=3Hz,CO₂Bn,156.2(dd,J_F-C=267,12Hz),153.9(d,J_F-C=255Hz),148.0(dd,J_F-C=269,11Hz),145.4(t,J_F-C=7Hz),144.7(d,J_F-C=13Hz),144.6(dd,J_F-C=13,2Hz),135.2(s),130.6(d,J_F-C=3Hz),125.6(d,J_F-C=4Hz),125.4(d,J_F-C=2Hz),122.0(d,J_F-C=14Hz),115.0(d,J_F-C=16Hz),67.9(s,CH₂Ph),61.6(d,J_F-C=5Hz,OMe)；¹⁹F{¹H}NMR(376MHz,CDCl₃)δ-123.90(d,J_F-F=19.7Hz,F4),-128.37(d,J_F-F=33.5Hz,F2’),-139.64(dd,J_F-F=33.5,19.7Hz,F5)。C₂₀H₁₃ClF₃NO₃Analysis calculated value: c, 58.91; h, 3.21; n, 3.43. Measured value: c, 59.03; h, 3.20; and N, 3.39.

Example 1d.4, 5-difluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid benzyl ester

A22L straight walled jacketed reactor was equipped with an overhead stirrer, condenser, nitrogen inlet and outlet, and plugged solids addition ports. The reactor was purged with nitrogen for 2 days. The addition port was opened and benzyl 4, 5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (2032g,4.12mol,89.3% purity) was added quickly to the reactor. CsF (2500g,16.46mol) was poured into the reactor quickly. Then, anhydrous (<100ppm water) DMSO (8869g) was added to the reactor. The mixture was heated to 110 ℃ and held for 2 hours. The mixture was cooled to 35 ℃ and then filtered. The filtered salt was washed with DMSO (2x1108 g). The combined filtrates were cooled to 15-20 ℃ and water (3023g) was added over 1h with stirring. The mixture was cooled to 10-12 ℃ and then filtered. The collected solid was washed with 3:1 DMSO/water (1814g) followed by water (2000 g). The resulting brown solid was dried to give the title compound (1626g,85.7wt% HPLC purity (internal standard of hexanophenone), 83%).

Amination

Example 2a.4-amino-5, 6-trifluoropyridine-2-carboxylic acid propan-2-ester

The reaction mixture of example 1a was filtered to remove the Cs salts and the salts were washed with DMSO (50 mL). The DMSO wash solution was added to a DMSO solution (150mL) that had been saturated with ammonia for 15 minutes. Keep the flask warmHeld in a cold bath which maintains the temperature at approximately 16 ℃. Ammonia was bubbled through the reaction mixture for 30 minutes, during which time a white precipitate formed. After 90 minutes, an aliquot was analyzed by GC, showing a single major peak of 4-amino product. The reaction mixture was purified by the sequential addition of saturated ammonium chloride (NH)₄Cl) aqueous solution (100mL) and water (400 mL). The aqueous solution was extracted successively to diethyl ether (Et)₂O3x150mL) and EtOAc (3x150 mL). The combined organic extracts were washed with water (5 × 150mL) followed by brine. The extract was dried (MgSO)₄) And evaporated to a brown solid, which was washed with 1:1 hexane-ether to give a light brown powder (5.57g, 51.4% total): mp 168-170 ℃;¹H NMR(400MHz,CDCl₃)δ7.42(d,J_F-H=5.5Hz,1H, pyridine H),5.22 (heptad, J =6.2Hz,1H, CHMe)₂),4.75(s,2H,NH₂),1.35(d,J=6.2Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,DMSO-d₆)δ162.8(CO₂R),151.2(dd,J_F-C=228,12Hz,C6),146.5(dd,J_F-C=9,6Hz,C2/C4),139.3(dd,J_F-C=16,5Hz,C2/C4),133.8(dd,J_F-C=252,31Hz,C5),112.3(C3),68.8(CHMe₂),21.5(Me)；¹⁹FNMR(376MHz,DMSO-d₆)δ-91.9(d,J_F-F=26.6Hz,F6),-163.9(dd,J_F-F=26.6,J_H-F=5.6Hz,F5)。C₉H₁₀F₂N₂O₂Analysis calculated value: c, 50.00; h, 4.66; and N, 12.96. Measured value: c, 49.96; h, 4.65; and N, 12.91.

Example 2b.4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -pyridine-2-carboxylic acid propan-2-ester

Propan-2-ester 4, 5-difluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid (4.89g,13.9mmol) was dissolved in DMSO (100 mL). Ammonia gas was bubbled through the solution over a period of 48h, for a total of 100 minutes. Mixing the reactionThe contents were poured into ice-water (500 mL). The product was extracted into EtOAc (3 × 250 mL). The combined organic extracts were washed with water (5 × 100mL) followed by brine, dried (MgSO)₄) And concentrated under reduced pressure to give a white solid (4.36g, 88%): mp 180.2-181.9 ℃;¹H NMR(400MHz,CDCl₃)δ7.54(d,J_F-H=6.5Hz,1H, pyridine H),7.27(m,2H, phenyl), 5.27 (heptad, J)_H-H=6.3Hz,1H,CHMe₂),4.69(s,2H,NH₂),3.96(d,J_F-H=0.9Hz,3H,OMe),1.38(d,J_H-H=6.3Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,DMSO-d₆)δ163.7(CO₂R),153.2(d,J_F-C=252Hz),146.8(d,J_F-C=254Hz),144.2(d,J_F-C=4Hz),143.9,143.7,139.0(d,J_F-C=14Hz),128.2(d,J_F-C=3Hz),126.0(d,J=3Hz),125.4(d,J_F-C=3Hz),123.9(dd,J_F-C=14,3Hz),112.5(d,J_F-C=5Hz),68.5(CHMe₂),61.5(d,J_F-C=4Hz,OMe),21.56(CHMe₂)；¹⁹F NMR(376MHz,CDCl₃)δ-128.43(dd,J_F-F=32.0,J_F-H=6.6Hz),-142.27(dd,dd,J_F-F=32.0,J_F-H=6.3Hz)。C₁₆H₁₅ClF₂N₂O₃Analysis calculated value: c, 53.87; h, 4.24; and N, 7.85. Measured value: c, 53.65; h, 4.28; and N, 7.75.

Example 2c.4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoro-pyridine-2-carboxylic acid benzyl ester

Benzyl 4, 5-difluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (4.99g,12.2mmol) was slurried in DMSO (100 mL). Ammonia gas was bubbled through the solution for 30 minutes. After stirring overnight, the reaction mixture was poured into ice-water (500 mL). The product was extracted into EtOAc (3 × 150 mL). The combined organic extracts were washed with water (5 × 100mL) and brine, dried (MgSO)₄) And concentrating under reduced pressure to obtain whiteSolid (4.99g, 101%);¹H NMR(400MHz,CDCl₃)δ7.52(d,J_F-H=6.5Hz,1H, pyridine H3), 7.45-7.38 (m,2H), 7.37-7.17 (m,5H),5.38(s,2H, CH)₂Ph),4.67 (broad singlet, 2H, NH)₂),3.94(d,J_F-H=1.1Hz,3H,OMe)；¹³C{¹H}NMR(101MHz,CDCl₃)δ164.4(CO₂R),153.9(d,J_F-C=254Hz),147.6(d,J_F-C=256Hz),144.4(d,J_F-C=14Hz),144.0(d,J_F-C=5Hz),142.2(d,J_F-C=12Hz),140.4(d,J_F-C=15Hz),135.6(s),129.5(d,J_F-C=3Hz),128.5(CH),128.3(CH),128.3(CH),125.6(d,J_F-C=3Hz,CH),125.2(d,J_F-C=4Hz,CH),123.3(dd,J_F-C=14,4Hz),113.1(d,J_F-C=4Hz,C3),67.3(s,CH₂Ph),61.5(d,J_F-C=4Hz,OMe)；¹⁹F{¹H}NMR(376MHz,CDCl₃)δ-128.54(dd,J=30.7,5.2Hz,F2’),-141.84(dd,J=30.8,6.5Hz,F5)。HRMS-ESI(m/z)：[M]⁺C₂₀H₁₅ClF₂N₂O₃Calculated value, 404.0739; found 404.0757.

Example 2d.4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoro-pyridine-2-carboxylic acid benzyl ester

A solution of benzyl 4, 5-difluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (65.0g,0.16mol,87% pure) in DMSO (400mL) was prepared in a 1L 4-necked flask equipped with a mechanical stirrer, a thermometer, an ammonia inlet, and a gas outlet. Ammonia (8.1g,0.48mol,3 equivalents) was added by: bubbling through a Teflon tube under the surface of the DMSO solution for 20 minutes. During the ammonia addition, the reaction mixture turned pink/light red and the internal temperature rose to 30 ℃. After stirring for 5h, additional ammonia (6.1g,0.36mol,2.25 eq) was added over 20 minutes. After an additional 2.5h stirring, HPLC analysis showed complete consumption of the starting material. Nitrogen was bubbled into the reaction mixture, and the reaction mixture was stirred overnight. The reaction mixture was filtered to remove the salts formed in the reaction and the solid was washed with DMSO (50 mL). Water (225mL) was added dropwise to the DMSO solution over 1 hour. The resulting precipitate was filtered and then washed first and second with DMSO/water (2:1,2x40mL) and water (2x50 mL). The solid was dried to give the title compound (55.35g,87%,87% purity by HPLC (internal standard for phenylhexanone)).

Halogen exchange

Example 3a.4-amino-6-chloro-5-fluoropyridine-2-carboxylic acid propan-2-ester

In a 100mL Hastalloy stirred Parr reactor, 4-amino-5, 6-difluoropyridine-2-carboxylic acid propan-2-ester (4.25g,19.7mmol) was dissolved in hydrochloric acid (HCl,4M in dioxane; 65 mL). The reactor was heated to 100 ℃ and held for 2 hours. After standing overnight at room temperature, a yellow crystalline solid formed. This solid was insoluble in EtOAc, but was not dissolved in saturated NaHCO₃The aqueous solution (500mL) and EtOAc (300mL) were shaken together and dissolved. The aqueous layer was extracted with EtOAc (2 × 250 mL). The combined organic extracts were washed with water (5 × 50mL) followed by brine. The extract was dried (MgSO)₄) And concentrated under vacuum to give an off-white solid. The crude product was purified by column chromatography (120g silica gel column; 0-100% hexane-EtOAc gradient) to afford a white solid (2.11g, 46%): mp 190.7-192.4 ℃;¹H NMR(400MHz,DMSO-d₆)δ7.543(d,J_F-H=5.7Hz,1H),6.91 (broad singlet, 2H, NH)₂) 5.09 (heptad, J =6Hz,1H, CHMe)₂),1.29(d,J=6Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,DMSO-d₆)δ162.8(CO₂R),144.8(d,J_F-C=12Hz,C2/C4),143.4(d,J_F-C=254Hz,C5),142.7(d,J_F-C=4.8Hz,C2/C4),136.5(d,J_F-C=17Hz,C6),112.8(d,J_F-C=5Hz,C3),68.9(CHMe₂),21.6(Me)；¹⁹F NMR(376MHz,DMSO-d₆)δ-141.0(d,J_F-H=6Hz)。C₉H₁₀ClFN₂O₂Analysis calculated value: c, 46.47; h, 4.33; and N, 12.04. Measured value: c, 46.50; h, 4.33; n, 11.96.

Halogenation

Example 4a.4-amino-3, 6-dichloro-5-fluoropyridine-2-carboxylic acid propan-2-ester

4-amino-6-chloro-5-fluoropyridine-2-carboxylic acid propan-2-ester (1.191g,5.12mmol) was almost completely dissolved in CH₂Cl₂(40 mL). Water (40mL) was added. Chlorine gas was bubbled through the solution for 5 minutes. After 30 minutes, an aliquot of the reaction mixture was analyzed by GC, showing the desired product and only 1.7% starting material. The aqueous layer was separated and washed with CH₂Cl₂(50mL) extraction. The combined organic extracts were then washed with NaHCO₃Saturated aqueous solution and brine. The extract was dried (MgSO)₄) And concentrated under reduced pressure to give an orange oil. Flash chromatography (120g silica gel column; 0-50% EtOAc-hexane gradient) afforded a bright yellow crystalline solid (394mg, 28%):¹H NMR(400MHz,CDCl₃) δ 5.29 (heptad, J =6.3Hz,1H, CHMe)₂) 5.19 (broad singlet, 2H, NH)₂),1.40(d,J=6.3Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,CDCl₃)δ163.2(CO₂R),143.3(d,J_F-C=5Hz,C2),142.8(d,J_F-C=270Hz,C5),141.0(d,J_F-C=26Hz,C4),135.3(d,J_F-C=17Hz,C6),114.9(s,C3),70.6(CHMe₂),21.6(s,Me)；¹⁹F NMR(376MHz,CDCl₃)δ-136.5。

Example 4b.4-amino-3, 6-dichloro-5-fluoropyridine-2-carboxylic acid propan-2-ester

Propan-2-ester 4-amino-6-chloro-5-fluoropyridine-2-carboxylic acid (634 mg, 2.73mmol) was slurried in acetonitrile (11 mL). 1, 3-dichloro-5, 5-dimethyl-hexanolactam (303mg,1.54mmol) was added as a solid and the reaction mixture was stirred at reflux for 2.5 h. Additional 1, 3-dichloro-5, 5-dimethylhexanolactam (50mg,0.25mmol) was added and the reaction mixture was stirred at reflux for an additional 1 hour. Water (20mL) was added. Acetonitrile was then removed by rotary evaporation to give an oily yellow solid which was extracted with EtOAc (2 × 20 mL). The combined organic extracts were extracted with 10% sodium bisulfite (NaHSO)₃) Solution, NaHCO₃Washed with saturated aqueous solution and brine, and dried (MgSO)₄) And concentrated under reduced pressure to give a light orange solid (671mg, 92%):¹H NMR(400MHz,CDCl₃) δ 5.29 (heptad, J =6.3Hz,1H, CHMe)₂) 5.19 (broad singlet, 2H, NH)₂),1.40(d,J=6.3Hz,6H,CHMe₂)；¹⁹F NMR(376MHz,CDCl₃)δ-136.5。

Example 4c.4-amino-3-bromo-6-chloro-5-fluoropyridine-2-carboxylic acid methyl ester

4-amino-6-chloro-5-fluoropyridine-2-carboxylic acid methyl ester (1.0g,4.9mmol) was mixed with 1, 3-dibromo-5, 5-dimethylhexanolactam urea (1.7g,5.9mmol) in 1, 2-dichloroethane (15mL) and heated under reflux (83 ℃ C.) for 4 hours. The cooled mixture was mixed with 10% NaHSO₃The solution was stirred with EtOAc (30 mL). The organic phase was separated, washed with water (2 × 20mL), brine (10mL), dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexanes) to give an orange solid (840mg, 61%): mp 138-139 ℃; EIMS m/z282,284;¹H NMR(400MHz,CDCl₃)δ5.09(s,2H,NH₂),3.97(s,3H,Me)；¹⁹F NMR(376MHz,CDCl₃)δ-135.55(s)。

example 4d.4-amino-6-chloro-5-fluoro-3-iodopyridine-2-carboxylic acid methyl ester

4-amino-6-chloro-5-fluoropyridine-2-carboxylic acid methyl ester (2.2g,10.8mmol) was dissolved in methanol (CH)₃OH; 20 mL). The solution was treated with periodic acid (880mg,3.9mmol) and iodine (2.2g,8.6mmol) and then heated to reflux and held for 20 hours. The mixture was cooled and the volatiles were removed under vacuum. The residue was dissolved in EtOAc (50mL) and then reacted with 10% NaHSO₃The solutions (20mL) were stirred together for 10 minutes. The organic phase was separated, washed with brine (10mL) and dried (Na)₂SO₄) And evaporated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexanes gradient) to give the title compound as a light orange solid (2.5g, 70%): mp 149-151 ℃; ESIMS M/z330([ M)]⁺)；¹HNMR(400MHz,CDCl₃)δ5.17(s,2H,NH₂),3.97(s,3H,OMe)；¹⁹F NMR(376MHz,CDCl₃)δ-135.79(s)。

Example 4e.4-amino-3-chloro-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid propyl ester -2-esters

Propan-2-yl 4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (3.065g,8.59mmol) was dissolved in sulfonyl chloride (150 mL). The solution was stirred at room temperature under nitrogen for 8 hours. During which a white precipitate formed. Hexane (100mL) was added and the mixture was stored at-20 ℃ overnight. The product was filtered, washed with hexanes, and then slurried in EtOAc (100 mL). The organic suspension is treated with NaHCO₃Saturated aqueous solutionNeutralization, which results in the dissolution of all solids. The organic layer was separated and washed with 10% NaHSO₃The aqueous solution and brine were washed and dried (MgSO)₄) And concentrated under reduced pressure to give a white solid (1.962g, 58%): mp 109-111 ℃;¹H NMR(400MHz,CDCl₃) δ 7.25(m,2H),5.32 (heptad, J =6.3Hz,1H, CHMe)₂) 5.07 (broad singlet, 2H),3.97(d, J)_F-H=1.0Hz,3H,OMe),1.40(d,J=6.3Hz,6H,CHMe₂)；¹⁹F NMR(376MHz,CDCl₃)δ-128.16(dd,J_F-F=33.3Hz,J_F-H=2.5Hz, phenyl F), -138.35(d, J)_F-F=33.4Hz, pyridine F5).

Example 4f.4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid benzyl ester Esters

In a scintillation vial, benzyl 4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylate (2.07g,5.12mmol) was slurried in acetonitrile (20 mL). 1, 3-dichloro-5, 5-dimethylhexanolactam (554mg,2.181mmol) was added as a solid and the reaction mixture was stirred at reflux for 1 hour. After cooling to room temperature, water (40mL) was added and the product precipitated. The solid was collected on a buchner funnel and washed with water. Drying at 55 ℃ under vacuum gave a white solid (2.187g, 97%):¹H NMR(400MHz,CDCl₃) Δ 7.50-7.41 (m,2H, aromatic), 7.41-7.20 (m,5H, aromatic), 5.42(s,2H, CH)₂Ph),4.92 (broad singlet, 2H, NH)₂),3.97(d,J=1.2Hz,3H,OMe)；¹⁹F{¹H}NMR(CDCl₃)δ-128.19(d,J=33.9Hz,F2’),-137.79(d,J=33.8Hz,F5)。

Example 4g.4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid benzyl ester Esters

A solution of 4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid benzyl ester (53.0g,0.131mol,95% purity) in acetonitrile (450mL) was prepared in a 1L 3-necked round bottom flask equipped with a mechanical stirrer and thermometer. 1, 3-dichloro-5, 5-dimethylhexanolactam (14.2g,0.072mol,0.55 eq) was added. The reaction mixture was heated at 80 ℃ for 3 hours. The reaction mixture was cooled to room temperature and then added dropwise to sodium bisulfite (NaHSO) over a period of 1 hour₃) Dilute solution (990mL,7.5g NaHSO)₃). The resulting precipitate was isolated by filtration and washed with acetonitrile-water (1:1v/v,2x50mL) followed by water (2x50 mL). The solid was dried to give a pale yellow powder (53.44g,94%,96.1% HPLC purity (phenyloctanone internal standard)).

Example 4h.4-amino-3-iodo-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid propyl ester -2-esters

Propan-2-yl 4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (600mg,1.682mmol) was dissolved in acetic acid (5.6 mL). Sodium acetate (1.5g,18.50mmol) and iodine monochloride (2.2g,13.45mmol) were added successively. An exotherm of about 10 ℃ was observed during the addition. The reaction mixture was heated at 80 ℃ for 20 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water and NaHCO₃Washed with saturated aqueous solution and dried (MgSO)₄) Then concentrated to dryness. The residue was applied to a silica gel column (80g) and then eluted (0-70% acetone-hexane gradient) to give an orange solid (343mg, 42%): mp 134-135 deg.C;¹h NMR (400MHz, acetone-d₆) δ 7.41(dd, J =8.5,1.6Hz,1H),7.33(dd, J =8.5,6.8Hz,1H),6.29(s,2H), 5.29-5.14 (heptad, 1H),3.98(d, J =1.1Hz,3H),1.37(d, J =6.3Hz, 6H); EIMS m/z 396.

Example 4i.4-amino-3-bromo-5-fluoro-6- (4-Chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid propyl ester -2-esters

Propan-2-yl 4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (500mg,1.402mmol) was dissolved in dichloromethane (3.2 mL). N-bromo-succinimide (299mg,1.682mmol) was added and the solution was stirred at ambient temperature for 20 hours. The reaction mixture was then concentrated to dryness. The residue was purified by chromatography (40g silica gel column; 0-70% EtOAc-hexanes) to give a brown solid (504mg, 83%):¹H NMR(400MHz,DMSO-d₆)δ7.47(dd,J=8.5,1.6Hz,1H),7.29(dd,J=8.5,7.1Hz,1H),7.01(s,2H),5.22–5.10(m,1H),3.93(d,J=0.9Hz,3H),1.32(d,J=6.3Hz,6H)；EIMS m/z350。

coupling of

Example 5a.4-amino-3-chloro-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid propyl ester -2-esters

To a 50mL Schlenk flask were added propan-2-4-amino-3, 6-dichloro-5-fluoropyridine-2-carboxylic acid ester (2.162g,8.09mmol), 2- (4-chloro-2-fluoro-3-methoxyphenyl) -1,3, 2-dioxaborolan (2.775g,11.35mmol), and CsF (2.601g,17.12 mmol). Acetonitrile (20mL) and water (7mL) were added. The solution was evacuated/back-filled with nitrogen (5 ×). Solid bis (triphenylphosphine) palladium (II) dichloride (Pd (PPh) was added₃)₂Cl₂(ii) a 281mg,4.9 mol%). The solution was evacuated/back-filled with nitrogen (5 ×), then heated at 70 ℃ under nitrogen for 3 hours. After 3 hours, the reaction mixture was cooled to room temperature. The aqueous layer was separated. Water (20mL) was added to the organic layer. The resulting dark brown precipitate was filtered and washed with water. The solid was dissolved in EtOAc (60mL) and passedFilter to remove a small amount of black solid. The EtOAc solution was treated with activated charcoal (175mg) and filtered to give a wine colored solution. Evaporation under reduced pressure gave a dark red solid. Purification (120g silica gel column; 0-50% EtOAc-hexane gradient) afforded a white solid (2.59g, 82%): mp 110.6-112.1 ℃;¹H NMR(400MHz,CDCl₃) δ 7.25(m,2H),5.32 (heptad, J =6.3Hz,1H, CHMe)₂) 5.07 (broad singlet, 2H),3.97(d, J)_F-H=1.0Hz,3H,OMe),1.40(d,J=6.3Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,CDCl₃)δ164.2(CO₂R),153.8(d,J_F-C=254Hz,C5/C2’),145.5(d,J_F-C=258Hz,C5/C2’),145.0(d,J_F-C=5Hz),144.4(d,J_F-C=14Hz),140.0(d,J_F-C=13Hz),137.5(d,J_F-C=14Hz),129.7(d,J_F-C=3Hz),125.4(d,J_F-C=2Hz,C5’/C6’),125.2(d,J_F-C=3Hz,C5’C6’),122.7(dd,J_F-C=14,4Hz,C1’),114.6(C3),70.2(CHMe₂),61.5(d,J_F-C=4Hz,OMe),21.6(CHMe₂)；¹⁹F NMR(376MHz,CDCl₃)δ-128.16(dd,J_F-F=33.3Hz,J_F-H=2.5Hz, phenyl F), -138.35(d, J)_F-F=33.4Hz, pyridine F5). C₁₆H₁₄Cl₂F₂N₂O₃Analysis calculated value: c, 49.12; h, 3.61; and N, 7.16. Measured value: c, 49.30; h, 3.69; and N, 7.08. The product was found to be 97.5% pure by HPLC.

Example 5b.4, 5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -pyridine-2-carboxylic acid propan-2-ester

To a 100mL Schlenk flask were added propan-2-4, 5, 6-trichloropyridine-2-carboxylate (10.46g,39.0mmol), 2- (4-chloro-2-fluoro-3-methoxyphenyl) -1,3, 2-dioxaborolan (13.27g,54.3mmol), and CsF (11.76g,77.0 mmol). Acetonitrile (75mL) and water (25mL) were added. Evacuating/purging the reaction mixture with N₂Backfill (5 x). Additive for foodReinforced solid Pd (PPh)₃)₂Cl₂(1.331g,1.896 mmol). Emptying/applying N to the solution₂Backfilled (5x) and then stirred at reflux for 2 hours. A white solid precipitated after cooling to room temperature. The solid was filtered, washed with water and air dried (10.56g, 69%): mp 123.8-127.7 ℃;¹H NMR(400MHz,CDCl₃) Δ 8.20(s,1H, pyridine), 7.28(dd, J)_H-H=8.5Hz,J_F-H=1.6Hz,1H),7.13(dd,J_H-H=8.5Hz,J_F-H=6.8Hz,1H),5.32 (heptad, J =6.3Hz,1H, CHMe)₂),3.99(d,J=1.2Hz,3H,OMe),1.41(d,J=6.3Hz,6H,CHMe₂)；¹³C{¹H}NMR(101MHz,CDCl₃)δ162.7(CO₂R),153.8,153.6(d,J_F-C=253Hz,C2’),146.7,144.5(d,J_F-C=13Hz),144.0,134.0,130.0(d,J_F-C=3.4Hz),125.9,125.3(d,J_F-C=3Hz),125.1(d,J_F-C=3Hz),70.4(CHMe₂),61.6(d,J_F-C=4Hz,OMe),21.7(CHMe₂). Analytical calculation C₁₆H₁₃Cl₃NO₃: c, 48.94; h, 3.34; and N, 3.57. Measured value: c, 48.91; h, 3.50; n, 3.51.

Example 5c.4, 5-dichloro-6-ethylpyridine-2-carboxylic acid methyl ester

To a 100mL three-necked flask equipped with a reflux condenser and a nitrogen inlet was added methyl 4,5, 6-trichloropyridine-2-carboxylate (2.40g,9.98 mmol). Anhydrous THF (50mL) and N, N-dimethylethanolamine (0.20g) were added sequentially. The reaction mixture was purged with nitrogen for 15 minutes. Solid Pd (PPh) is added₃)₂Cl₂(140mg,0.2 mmol). The reaction mixture was stirred under nitrogen for 20 minutes. Diethyl zinc (1M solution in hexane; 10mL,10mmol) was added in 2mL portions. When no starting material was observed by GC analysis, the reaction mixture was quenched with water and extracted into EtOAc. The combined organic extracts were washed with brine and dried (MgSO)₄) And concentrating under reduced pressure toWhite solid (2.34 g). Analysis by GC-MS showed that the solid contained 11% of the starting methyl 4,5, 6-trichloropyridine-2-carboxylate.¹H NMR(400MHz,CDCl₃) Δ 8.06(s,1H, pyridine H),4.01(s,3H, CO)₂Me),3.10(q,J=8Hz,2H,CH₂),1.33(t,J=8Hz,3H,CH₂CH₃)；¹³C{¹H}NMR(101MHz,CDCl₃)δ164.4,162.8,145.4,143.3,132.9,124.5(C3),53.1(CO₂Me),30.0(CH₂),12.3(CH₂CH₃)。

Example 5d.4, 5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid benzyl ester

To a 250mL three-necked flask equipped with a reflux condenser and nitrogen inlet were added benzyl 4,5, 6-trichloropyridine-2-carboxylate (17.77g,56.10mmol), 2- (4-chloro-2-fluoro-3-methoxyphenyl) -1,3, 2-dioxaborolan (19.20g,79.0mmol), and CsF (17.04g,112.0 mmol). Acetonitrile (100mL) and water (30mL) were added. The reaction mixture was evacuated/back-filled with nitrogen (5 ×). Solid Pd (PPh) is added₃)₂Cl₂(1.724g,2.456 mmol). The solution was evacuated/back-filled with nitrogen (5 ×) and then stirred at reflux for 90 minutes. A white solid precipitated after cooling to room temperature. The solid was filtered, washed with water and air dried (18.66g, 75%):¹H NMR(400MHz,CDCl₃) Δ 8.23(s,1H, pyridine H), 7.52-7.32 (m,5H, phenyl), 7.27(dd, J)_H-H=8.4Hz,J_F-H=1.7Hz,1H, aromatic), 7.10(dd, J)_H-H=8.4Hz,J_F-H=6.8Hz,1H, aromatic), 5.44(s,2H, CH)₂Ph),3.98(d,J J_F-H=1.3Hz,3H,OMe)；¹³C{¹H}NMR(101MHz,CDCl₃)δ163.0,153.7,153.5(d,J_F-C=253Hz,C2’),146.0,144.5(d,J_F-C=13Hz),144.1,135.0,134.2,129.9(d,J_F-C=3Hz),128.5,126.1,125.8(d,J_F-C=14Hz),125.3(d,J_F-C=3Hz),124.9(d,J_F-C=2Hz),67.9(CH₂),61.5(d,J_F-C=4Hz,OMe)。C₂₀H₁₃Cl₃FNO₃Analysis calculated value: c, 54.51; h, 2.97; and N, 3.18. Measured value: c, 54.60; h, 3.08; and N, 3.16.

Example 5e.4, 5-dichloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid benzyl ester

Tap water (3403g) was added to a 22-L straight wall reactor equipped with a mechanical stirrer. Then adding dipotassium hydrogen phosphate (K)₂HPO₄(ii) a 2596g,14.9mol) and the mixture was stirred while being flushed with a stream of nitrogen until all the solid had dissolved. After all solids were dissolved, acetonitrile (8173g) was added to the reactor. To a separate 30-L straight walled jacketed reactor equipped with a bottom discharge and an overhead mechanical stirrer were added 2- (4-chloro-2-fluoro-3-methoxyphenyl) -1,3, 2-dioxaborolan (1724g,7.01mol) and benzyl 4,5, 6-trichloropyridine-2-carboxylate (1630g,4.97 mol). The reactor was evacuated and filled with nitrogen (3 ×). Then will contain K₂HPO₄acetonitrile/H of₂The O mixture was transferred to a 30-L reactor and the line was rinsed with acetonitrile (1434 g). The slurry was purged with nitrogen for 30 minutes, then triphenylphosphine (114.8g,0.44mol) was added. The slurry was then purged with nitrogen for 15 minutes, then bis (benzonitrile) palladium (II) chloride (83.8g,0.22mol) was added. The bright yellow slurry was purged with nitrogen for 15 minutes and then the mixture was heated to 74-75 ℃. After stirring at 74 ℃ for 3.3 hours, the reaction was deemed complete by HPLC analysis. At this stage, the reactor cooling temperature was set to 5 ℃ and cold water (4448g, ca. 3 ℃) was immediately added to the reactor. The resulting precipitate was filtered to give a milky white filter cake. The filter cake is treated with cold acetonitrile/H₂O (3345g,1.4:1, 8-10 ℃ C.) gave an off-white wet cake. The filter cake was dried under a stream of nitrogen to a constant weight of 2044 g. HPLC analysis using an internal standard (tetraphenylethylene) showed the product to be 90.0% pure and to contain 1840g (84.0%) of product.

Purification of ammonium salts

Example 6a.4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoro-pyridine-2-carboxylic acid propan-2-ester

Propan-2-yl 4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (1.50g,71% pure, obtained by LC area) was added to tetrahydrofuran (THF; 10mL) and heated to 40 ℃ to give a clear yellow solution. The solution was cooled to room temperature and HCl (4M in dioxane; 1.3mL,5.2mmol) was added. After addition of HCl, a solid precipitated out of solution and the reaction mixture was cooled to 0 ℃. The solid was isolated by vacuum filtration and washed with cold THF (5 mL). The wet cake of salt was added to THF (10mL) and water (5 mL). Triethylamine (Et)₃N; 0.8mL,5.7mmol) was added to the mixture and the reaction mixture formed a clear two-phase solution. The reaction mixture was transferred to a separatory funnel and the organic layer was separated. Hexane (20mL) was added to the organic layer and a solid precipitated out of solution. The reaction mixture was cooled to 0 ℃ and stirred for 30 minutes. The solid was isolated by vacuum filtration, washed with hexane (10mL) and dried in a vacuum oven at 40 ℃ to give 4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid propan-2-ester as a white solid (0.90g,89% purity by LC area): mp 174-176 ℃;¹H NMR(400MHz,CDCl₃) δ 7.54(d, J =6.4Hz,1H), 7.34-7.22 (m,2H),5.27 (heptad, J =6.3Hz,1H),4.56 (broad singlet, 2H),3.97(d, J =1.0Hz,3H),1.39(d, J =6.3Hz, 6H);¹³C NMR(101MHz,CDCl₃)δ164.03,154.07(d,J=253.7Hz),147.70(d,J=256.1Hz),144.92(d,J=5.0Hz),144.48(d,J=13.9Hz),142.01(d,J=12.2Hz),140.58(d,J=14.4Hz),129.59(d,J=3.4Hz),125.85(d,J=3.7Hz),125.29(d,J=3.8Hz),123.57(dd,J=14.1,3.7Hz),112.85(d,J=3.7Hz),69.58(s),61.63(d,J=4.5Hz),21.86(s)；¹⁹F NMR(376MHz,CDCl₃)δ-128.44(d,J=32.7Hz),-142.30(d,J=31.3Hz)。

example 6b.4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) 5-fluoropyridine-2-carboxylic acid propyl ester -2-esters

Propan-2-ester 4-amino-3-chloro-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid (1.75g,95% purity, obtained by LC area) was added to dichloromethane (15mL) and the mixture was heated to 40 ℃ to give a clear yellow solution. The solution was cooled to room temperature and HCl (4M in dioxane; 1.25mL,5mmol) was added. After addition of HCl, a solid precipitated out of solution and the reaction mixture was cooled to 0 ℃. The solid was isolated by vacuum filtration and washed with cold dichloromethane (5 mL). The wet cake of salt was added to dichloromethane (10mL) and water (5 mL). Adding Et₃N (0.6mL,4.3mmol) was added to the mixture and the reaction mixture formed a clear biphasic solution. The reaction mixture was transferred to a separatory funnel and the organic layer was separated. Hexane (20mL) was added to the organic layer and the solid was precipitated out of solution. The reaction mixture was cooled to 0 ℃, the solid was isolated by vacuum filtration and washed with hexane (10 mL). The solid was dried in a vacuum oven at 40 ℃ to give 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid propan-2-ester as a white solid. (1.02g,99% purity, by LC area): mp 115-117 ℃;¹H NMR(400MHz,CDCl₃) δ 7.31-7.22 (m,2H),5.32 (heptad, J =6.3Hz,1H),4.93 (broad singlet, 2H),3.98(d, J =1.1Hz,3H),1.41(d, J =6.3Hz, 6H);¹³C NMR(101MHz,CDCl₃)δ164.28,153.93(d,J=254.4Hz),145.79(d,J=230.6Hz),145.23(d,J=4.9Hz),144.44(d,J=13.8Hz),139.97(d,J=13.5Hz),137.72(d,J=13.8Hz),129.90(d,J=3.4Hz),125.59(d,J=3.2Hz),125.41(d,J=3.7Hz),122.82(dd,J=14.0,4.4Hz),114.82,70.36,61.66(d,J=4.7Hz),21.76；¹⁹F NMR(376MHz,CDCl₃)δ-128.15(d,J=34.1Hz),-138.44(d,J=34.1Hz)。

example 6c.4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid methyl ester

4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylic acid benzyl ester (3.00g, 7.41mmol) was added to CH₃OH (35 mL). Sodium methoxide (25 wt.% in CH)₃OH 2.0mL, 8.9mmol) was added to the reaction mixture and stirred for 24 hours. Water (50mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove most of the CH₃And (5) OH. The mixture was extracted with EtOAc (2X40mL), and the combined organic layers were washed with water (40mL) and saturated sodium chloride (40mL) and concentrated under reduced pressure to give 4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid methyl ester as a pale yellow solid (1.86 g; 67% purity by LC area).

Methyl 4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) pyridine-2-carboxylate (1.50g,67% purity by LC area) was added to THF (10mL) and dichloromethane (5mL) and the mixture was heated to 40 ℃ to give a clear yellow solution. The solution was cooled to room temperature and HCl (4M in dioxane; 1.4mL,5.6mmol) was added. After addition of HCl, a solid precipitated out of solution and the reaction mixture was cooled to 0 ℃. The solid was isolated by vacuum filtration and washed with cold THF (5 mL). The wet cake of salt was added to THF (25mL) and water (10 mL). Adding Et₃N (0.8mL,5.7mmol) was added to the mixture and the reaction mixture formed a clear biphasic solution. The reaction mixture was transferred to a separatory funnel and the organic layer was separated and concentrated to a solution of-10 mL. Hexane (20mL) was added to the organic layer and a solid precipitated out of solution. The reaction mixture was cooled to 0 ℃, the solid was isolated by vacuum filtration and washed with hexane (10 mL). The solid was dried in a vacuum oven at 40 ℃ to give methyl 4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylate as a white solid (0.53g,89% purity by LC area)To obtain): mp 203-204 ℃;¹H NMR(400MHz,CDCl₃) δ 7.60(d, J =6.4Hz,1H), 7.28-7.25 (m,2H),4.58 (broad singlet, 2H),3.97(d, J =1.1Hz,3H),3.96(s, 3H);¹³C NMR(101MHz,CDCl₃)δ165.27,154.05(d,J=254.1Hz),147.83(d,J=256.3Hz),144.56(d,J=13.7Hz),144.31(d,J=5.1Hz),142.16(d,J=12.4Hz),140.63(d,J=14.5Hz),129.69(d,J=3.5Hz),125.63(d,J=3.1Hz),125.41(d,J=3.7Hz),123.43(dd,J=14.1,3.6Hz),113.05(d,J=3.7Hz),61.64(d,J=4.5Hz),52.98；¹⁹F NMR(376MHz,CDCl₃)δ-128.71(d,J=28.6Hz),-141.94(d,J=28.6Hz)。

example 6d.4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) 5-fluoropyridine-2-carboxylic acid methyl ester

4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid benzyl ester (3.00g, 6.83mmol) was added to CH₃OH (35 mL). Sodium methoxide (25 wt.% in CH)₃OH, 1.9mL,8.2mmol) was added to the reaction mixture and the reaction mixture was stirred for 24 hours. Water (50mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure to remove most of the CH₃And (5) OH. The mixture was extracted with EtOAc (2 × 40mL) and the combined organic layers were washed with water (40mL) and saturated sodium chloride (40 mL). The volatiles were concentrated under reduced pressure to give 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid methyl ester as a pale yellow solid (2.04g,88% purity by LC area).

Methyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylate (1.25g,88% pure by LC area) was added to dichloromethane (15mL) and THF (3mL), and the mixture was heated to 40 ℃ to give a clear yellow solution. The solution was cooled to room temperature and HCl (4M in dioxane; 0.95mL, 3.8mmol) was added. After addition of HCl, a solid precipitated out of solution and the reaction mixture was cooled to 0 ℃. Will be fixedThe bodies were isolated by vacuum filtration and washed with cold dichloromethane (5 mL). The wet cake of salt was added to dichloromethane (20mL) and water (10 mL). Adding Et₃N (0.6mL,4.3mmol) was added to the mixture and the reaction mixture formed a clear biphasic solution. The reaction mixture was transferred to a separatory funnel, the organic layer was separated and concentrated under reduced pressure to a-10 mL solution. Hexane (20mL) was added to the organic layer and a solid precipitated out of solution. The reaction mixture was cooled to 0 ℃, the solid was isolated by vacuum filtration and washed with hexane (10 mL). The solid was dried in a vacuum oven at 40 ℃ to give 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid methyl ester as a white solid (0.51g,96% purity, by LC area): mp 170-171 ℃;¹H NMR(400MHz,CDCl₃) δ 7.30-7.20 (m,2H),4.98 (broad singlet, 2H),3.98(m, 6H);¹³C NMR(101MHz,CDCl₃)δ164.67,153.95(d,J=254.7Hz),145.93(d,J=245.8Hz),144.57(s),143.65(d,J=4.6Hz),140.21(d,J=13.3Hz),137.71(d,J=13.9Hz),130.02(d,J=3.5Hz),125.49(d,J=7.1Hz),125.49,122.70(dd,J=14.1,4.3Hz),115.89(d,J=1.5Hz),61.67(d,J=4.5Hz),53.06；¹⁹F NMR(376MHz,CDCl₃)δ-128.34(d,J=31.3Hz),-137.60(d,J=32.7Hz)。

example 6e.4-amino-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoro-pyridine-2-carboxylic acid benzyl ester

A slurry of 4-amino-5-fluoro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -pyridine-2-carboxylic acid benzyl ester (98g,0.209mol,86.5% purity) in THF (300mL) was gently heated to 28 ℃ to give a clear amber solution. The solution was cooled to 20 ℃ and HCl (4M in 1, 4-dioxane; 55mL,0.219mol,1.05 eq) was added over 1 minute by syringe. As a solid formed, the solution quickly became cloudy and the mixture temperature reached 28 ℃. The mixture was cooled to below 10 ℃. The precipitate was filtered and rinsed with cold THF (2 × 40mL) to give a white colorSolid (120.4 g). This solid was stirred with THF (300mL) and water (100 mL). Et was added to the slurry via syringe over 1 minute₃N (30.5mL,0.219mol) and the solid dissolved to give a cloudy mixture. The organic layer was separated. Hexane (450mL) was added with stirring and the solution was cooled to below 10 ℃. The resulting precipitate was filtered and rinsed with hexanes (2x40mL) to give a white solid (76.1g,95.1wt% HPLC purity (internal standard for benzophenones)). By concentrating the filtrate, another 7.56g of 93.9% pure product was obtained. Of the isolated product¹H and¹⁹the F NMR spectrum was the same as observed in example 2c.

Example 6f.4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylic acid benzyl ester Esters

To a solution of benzyl 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoropyridine-2-carboxylate (5.00g, 87% purity by LC area, 88wt% by LC) in dichloromethane (25mL) was added HCl (4M in 1, 4-dioxane; 3.1mL,12.4mmol) by syringe. After stirring for 1 minute, the solution became cloudy due to solid formation. The mixture was cooled to below 10 ℃ in an ice bath, filtered and rinsed with cold dichloromethane (5mL) to give a white solid. This solid was stirred with dichloromethane (30mL) and water (15mL) and Et was added₃N (1.98mL,14.2 mmol). The solids dissolved to give a biphasic mixture. After stirring for 15 minutes, the mixture was transferred to a separatory funnel and the phases were separated over a 15 minute period. The organic layer was separated, hexane (60mL) was added, and the mixture was cooled to below 10 ℃. The solution quickly became cloudy and a solid precipitated from the mixture. The mixture was filtered under vacuum to give a white solid which was dried in a vacuum oven at 40 ℃ to give 4-amino-3-chloro-6- (4-chloro-2-fluoro-3-methoxyphenyl) -5-fluoro-pyridine-2-carboxylic acid benzyl ester as a white solid (3.11g,70%, 97% purity by LC area, 97% by LC assay by wt%). Of the isolated product¹H and¹⁹the FNMR spectra were the same as observed in example 4f.

Claims

1. A process for preparing 4-amino-5-fluoro-3-halo-6- (substituted) -pyridine-2-carboxylic acid esters of formula I:

wherein

W represents Cl, Br or I;

r represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl orPhenyl substituted with 1-4 substituents independently selected from the group consisting of: halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄An alkoxy group; and

the method comprises the following steps:

wherein R is¹As defined above;

the formula B is as follows:

wherein R is¹As defined above;

c) exchanging a fluoro substituent at the 6-position of a 4-amino-5, 6-difluoropyridine-2-carboxylate of formula C with an iodo substituent, a bromo substituent or a chloro substituent by treatment with an iodide source, a bromide source or a chloride source to produce a 4-amino-5-fluoro-6-halopyridine-2-carboxylate of formula D:

wherein X represents Cl, Br or I,

and R¹As defined above;

d) halogenating a 4-amino-5-fluoro-6-halopyridine-2-carboxylate of formula D with a halogen source to produce a 4-amino-3, 6-dihalo-5-fluoropyridine-2-carboxylate of formula E:

wherein W and X independently represent Cl, Br or I,

and R¹As defined above; and

R-Met F，

wherein R is as defined above and Met represents Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl groups either together form ethylene or propylene.

2. The process of claim 1, wherein the amine-containing product or intermediate is purified by: a) protonating with an acid to form a salt, b) isolating the higher purity salt by crystallization, precipitation or extraction, and c) neutralizing the purified salt with a base to form a purified neutral amine-containing product or intermediate.

3. A process for preparing 4-amino-5-fluoro-3-halo-6- (substituted) -pyridine-2-carboxylic acid esters of formula I:

wherein

W represents Cl, Br or I;

the method comprises the following steps:

wherein R is¹As defined above;

the formula B is as follows:

wherein R is¹As defined above;

wherein X represents Cl, Br or I; and

R¹as defined above;

R-Met F，

wherein R is as defined above and Met represents Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl groups together form an ethylene or propylene group, and the formula G is:

r, R therein¹As defined above; and

4. The process of claim 3, wherein the amine-containing product or intermediate is purified by: a) protonating with an acid to form a salt, b) isolating the higher purity salt by crystallization, precipitation or extraction, and c) neutralizing the purified salt with a base to form a purified neutral amine-containing product or intermediate.

5. A process for preparing 4-amino-5-fluoro-3-halo-6- (substituted) -pyridine-2-carboxylic acid esters of formula I:

wherein

W represents Cl, Br or I;

the method comprises the following steps:

wherein R is¹As defined above; the formula F is:

R-Met F，

wherein R is as defined aboveDefinitions and Met denotes Zn-halide, Zn-R, tri- (C)₁-C₄Alkyl) tin, copper OR B (OR)²)(OR³) Wherein R is²And R³Independently of one another are hydrogen, C₁-C₄Alkyl groups together form an ethylene or propylene group, the formula H being:

wherein R and R¹As defined above;

b) fluorinating a 4, 5-dichloro-6- (substituted) pyridine-2-carboxylate ester of formula H with a fluoride ion source to produce a 4, 5-difluoro-6- (substituted) pyridine-2-carboxylate ester of formula J,

wherein R is¹As defined above;

c) aminating a 4, 5-difluoro-6- (substituted) pyridine-2-carboxylate ester of formula J with ammonia to produce a 4-amino-5-fluoro-6- (substituted) pyridine-2-carboxylate ester of formula K,

wherein R and R¹As defined above; and

6. The process of claim 5, wherein the amine-containing product or intermediate is purified by: a) protonating with an acid to form a salt, b) isolating the higher purity salt by crystallization, precipitation or extraction, and c) neutralizing the purified salt with a base to form a purified neutral amine-containing product or intermediate.

7. A compound selected from:

a)

wherein R represents C₁-C₄Alkyl, cyclopropyl, C₂-C₄Alkenyl or phenyl, said phenyl substituted with 1-4 substituents independently selected from: halogen, C₁-C₄Alkyl, halo C₁-C₄Alkyl radical, C₁-C₄Alkoxy or halo C₁-C₄Alkoxy, and R¹Is represented by C₁-C₁₂Alkyl or unsubstituted or substituted C₇-C₁₁An arylalkyl group;

b)

c)

d)