Process for preparing pyridinone compounds

0001The present invention generally relates to a method for producing a pyridinone compound.

0002Met (also called hepatocyte growth factor receptor (HGFR)) is expressed primarily in epithelial cells, but has also been identified in endothelial cells, myoblasts, hematopoietic cells, and motor neurons. Overexpression of hepatocyte growth factor and activation of Met are associated with onset and progression in a number of different tumor types and in the promotion of metastatic disease.

0003U.S. Patent Application Publication 2008/0114033 A1 discloses pyridinone compounds useful in the treatment of Met-related cancers. The disclosed pyridinone compounds, including amide bonds and amine-substituted pyridyl groups, are formulated in formula (Ia) :.<chemistry num="1"><img id="000002" he="49" wi="70" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Ia) Has the structure of.

0004References also disclose a multi-step synthetic method for producing pyridinone compounds. The method involves reacting the aniline compound with the carboxylic acid compound to form an amide bond in the compound of formula (Ia). The disclosed method also includes a Hofmann rearrangement reaction in which the amide substituent is converted to an amine group to give an amine substituted pyridyl group in the structure of formula (Ia).

0005US Patent Application Publication 2008/0114033 There are drawbacks associated with adapting the multistage synthesis disclosed in A1 to larger scale synthesis (eg, production on a pilot plant or manufacturing scale). One difficulty is that the Hofmann rearrangement step has not been easily adapted to commercial scale synthesis. In addition, there is a continuous need to find ways to obtain higher yields in order to improve manufacturing economics and / or reduce waste. Preferably, the novel method uses cheaper starting materials.

0006A method suitable for producing a larger amount of the pyridinone compound of formula (I) than typically produced by a laboratory scale method is desirable. A method for obtaining a pyridinone compound of the formula (I) in a higher yield than the method disclosed above is also desirable.

0007The present invention relates to one or both of these, as well as other important aspects.

0008(Outline of the invention) Equation (I):<chemistry num="2"><img id="000003" he="33" wi="42" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (I) It is a method for producing the compound of Equation (a) (III):<chemistry num="3"><img id="000004" he="12" wi="17" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(III) Carboxylic acid compound or its activated carboxylic acid compound and formula (II):<chemistry num="4"><img id="000005" he="30" wi="38" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (II) [In the formula, PAm is a protected amine group] By reacting with the aniline compound of the formula (IV):<chemistry num="5"><img id="000006" he="33" wi="43" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IV) Get the compound of; The protected amine group bonded to the compound of the formula (IV) of the formula (IV) is converted into an amine group, and the formula (I): [During the ceremony, G is<chemistry num="6"><img id="000007" he="30" wi="62" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Is; Each R¹Are independently alkyl, haloalkyl, halogen, or CN; Each R²Are independently alkyl, haloalkyl, halogen, or CN; R³Is an alkyl, haloalkyl, halogen, or CN substituted phenyl; Each R⁴Are independently alkyl, haloalkyl, alkoxy, halogen, or CN; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; p is 0, 1 or 2; and q is 0, 1, 2, or 3] A method comprising the step of obtaining a compound of is described herein.

0009Compounds useful for the above methods and methods for producing these compounds are also disclosed.

0010(Detailed explanation) Definitions of various terms used to describe the present invention are listed below. These definitions apply to those terms when used throughout the specification, either individually or as part of a larger group (unless otherwise specified in a particular example).

0011The terms "alkyl" and "alk" are straight or branched chains containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. An alkane (hydrocarbon) group. Examples of "alkyl" and / or "alk" groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl. , Decyl, and dodecyl are included.

0012The term "lower alkyl" refers to an "alkyl" and / or "arc" group containing 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. When the subscript is used with reference to alkyl or other groups, the subscript refers to the number of carbon atoms that the group can contain. For example, the term "C₀-C₄"Alkyl" includes alkyl groups containing a single bond and 1 to 4 carbon atoms, the term "C".₁-C₄"Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms. Examples of lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl.

0013The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.

0014The term "haloalkyl" refers to an alkyl group substituted with a halo substituent at one or more positions. Examples of haloalkyl groups include, but are not limited to, haloalkyls having a single halo substituent, such as -CH.₂F, -CH₂Cl, and -CH₂Br, as well as haloalkyl with multiple halo substituents, eg-CHF₂, -CF₃, -CHCl₂, And -CCl₃Is included.

0015The term "cyano" refers to -CN.

0016The term "amine" is -NH₂To say.

0017The term "carboxylic acid" refers to -C (O) OH, which is<chemistry num="7"><img id="000008" he="12" wi="16" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Can be drawn as.

0018The term "alkoxy" refers to -O-alkyl. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, and t-butoxy.

0019The term "amide bond" refers to -NHC (O)-, which is<chemistry num="8"><img id="000009" he="15" wi="19" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Can be drawn as.

0020The pyridinone compound of formula (V) has the following formula:<chemistry num="9"><img id="000010" he="20" wi="31" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(V-Enol) It can exist in the enol form represented by.

0021As used herein, the terms "compound of formula (V)" and "compound of formula (V-enol)" are formulas for keto, enol, or mixtures of keto and enol. Refers to the compound of (V).

0022One aspect of the present invention relates to a method for producing a compound of formula (I), wherein the compound of formula (I) comprises an amide bond and an amine-substituted pyridyl group.<chemistry num="10"><img id="000011" he="37" wi="75" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (I)

0023The amide bond in the compound of formula (I) can be produced by reacting the carboxylic acid compound of formula (III) or its activated carboxylic acid compound with the aniline compound of formula (II), in which the formula The aniline compound of (II) includes a pyridyl group having a protected amine group (PAm). The amide bond is formed by reacting an amine group bonded to a phenyl ring (aniline group of a compound of formula (II)) with a carboxylic acid group of a compound of formula (III) or an activated carboxylic acid group thereof. .. The protected amine group minimizes competing side reactions between the amine functional group attached to the pyridyl group of the compound of formula (II) and the carboxylic acid compound of formula (III) or its activated carboxylic acid compound and / or Exclude.<chemistry num="11"><img id="000012" he="34" wi="130" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0024After the formation of the amide bond, the protected amine group (PAm) attached to the compound of formula (IV) is converted to an amine group to give the compound of formula (I):<chemistry num="12"><img id="000013" he="33" wi="114" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0025A protected amine group (PAm) contains a nitrogen atom directly attached to the pyridyl ring, and further includes one or two protecting groups (blocking groups) attached to the nitrogen atom. The protecting group minimizes or eliminates the reaction of nitrogen atoms attached to the pyridyl ring during the formation of the amide bond between the aniline compound and the carboxylic acid compound. The protected amine group is non-reactive or substantially non-reactive during the formation of the amide bond. After the formation of the amide bond, the protecting group is removed to give the amine-substituted pyridyl group of the compound of formula (I). A protected amine group is a group in which the nitrogen atom is not directly attached to the pyridal ring, such as -C (O) NH.₂Is clearly excluded.

0026Various protected amine groups can be used in the methods of the invention. Examples of suitable protected amine groups include, but are not limited to, imines, alkylamines, arylamines, carbamates, amides, imides, benzylamines, allylamines, silylamines, phosphonamides, Includes sulfonamides, and triazinanones. table 1 Protective amine group<tables num="1"><img id="000014" he="183" wi="145" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0027Preferred protected amine groups include imines, amides, carbamates, imides, sulfonamides, silylamines, benzylamines, allylamines, phosphonamides, and triadinanones. More preferred protected amine groups include imines, amides, carbamates, imides, and sulfonamides.

0028Stage I: Formation of amide bond Various synthetic routes can be used to form an amide bond by the reaction of the carboxylic acid compound of formula (III) with the aniline compound of formula (II). One pathway is the reaction of the carboxylic acid compound of formula (III) with the aniline compound of formula (II) in the presence of a suitable catalyst, such as an acid or base catalyst, as appropriate. Another pathway is the reaction of the activated carboxylic acid compound of formula (III) with the aniline compound of formula (II). The activated carboxylic acid compound of formula (III) is obtained by reacting the carboxylic acid compound of formula (III) with an activator to obtain the activated carboxylic acid compound of formula (III), and then the aniline of formula (II). It can be produced by reacting with a compound. As used herein, at the stage of reaction of the carboxylic acid compound of formula (III) with the aniline compound of formula (II), the carboxylic acid compound of formula (III) and / or its activated carboxylic acid compound Includes the reaction between and the aniline compound of formula (II).

0029In one embodiment, the method of the invention a) The activated carboxylic acid compound of formula (III) is reacted with the aniline compound of formula (II) to obtain the compound of formula (IV); b) Convert the protected amine group bonded to the compound of formula (IV) to an amine group to obtain the compound of formula (I). The compound of the formula (I) is produced by. For example, an activated carboxylic acid compound of formula (IIIc), such as an acid halide of formula (IIIc), may be reacted with an aniline compound of formula (II) to give the compound of formula (IV).<chemistry num="13"><img id="000015" he="34" wi="130" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>[In the formula, X is an activating group, eg chlorine] Methods for activating carboxylic acid groups to form amide bonds, such as activators, solvents, and reaction conditions, are described in Han, S.-Y. Et al., Tetrahedron 60 (2004) 2447-2467. ..

0030The activated carboxylic acid compound of formula (IIIc) is a carboxylic acid compound of formula (III) with various additives such as, but not limited to, acid halides such as acid chlorides such as oxalyl chloride (COCl). )₂, Sulfonyl chloride (SO₂Cl), Vilsmeier reagent (N-chloromethylene-N, N-dimethylammonium chloride), phosphoryl chloride (POCl)₃), PO (OEt)₂Cl, and pivaloyl chloride (t-BuCOCl); uronium salts such as O-benzotriazole-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and O- (7-). Azabenzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU); dicarbodiimides such as dicyclohexylcarbodiimide and N- (3-dimethylaminopropyl) -N' -Ethyldicarbodiimide (with or without 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt)); 2-hydroxypyridine-1-oxide; 4- (4,6-dimethoxy) [1,3,5] Triazine-2-yl) -4-methylmorpholinium chloride (DMTMM); Chloroformate ester (general formula ROCOCl), eg tert-butyl chloroformate, isobutyl chloroformate, and isopropyl chloroformate; It can be prepared by reacting with propylphosphonic acid anhydride; diethyl chloroformate; Mitsunobu reagents such as diethyl azodicarboxylate and triphenylphosphine; and trimethylsilyl-isothiocyanate (TMS-ITC). Preferred reagents include dicyclohexylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethyldicarbodiimide, Bilsmeier reagent, oxalyl chloride, thionyl chloride, propylphosphonic acid anhydride, diethyl chlorophosphate, pivaloyl chloride, chloroformate. Esters such as tert-butyl chloroformate, isobutyl chloroformate, isopropyl chloroformate, trimethylsilyl-isothiocyanate, and Konobu reagents (diethyl azodicarboxylate and triphenylphosphine) are included. More preferred reagents include Vilsmeier reagents, oxalyl chloride, and thionyl chloride.

0031The reaction of the carboxylic acid compound of formula (III) or the activated carboxylic acid compound of formula (IIIc) with the aniline compound of formula (II) involves various synthetic additives such as organic bases such as triethylamine and potassium tert-. It can be done in the presence of butoxide, sodium 2-ethylhexanoate, and N, N-diisopropylethylamine (DIPEA); and inorganic bases such as sodium carbonate and cesium carbonate. Other suitable additives include acylation catalysts such as 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole, 2-pyridone, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1, Includes 8-diazabicyclo [5.4.0] undeca-7-ene (DBU), and 2,6-lutidine. Preferred synthetic additives include organic bases such as triethylamine, potassium tert-butoxide, and sodium 2-ethylhexanoate; and acylation catalysts such as 2-pyridone, 4-dimethylaminopyridine, 1-hydroxybenzotriazol. Includes 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, and 2,6-lutidine. The most preferred synthetic additives include sodium 2-ethylhexanoate.

0032The reaction between the carboxylic acid compound of formula (III) or the activated carboxylic acid compound of formula (IIIc) and the aniline compound of formula (II) can be carried out in various solvents or mixtures thereof. Examples of suitable solvents include, but are not limited to, polar aproton solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; ether solvents such as tetrahydrofuran, 2-methyltetraxane, methyl t-butyl ether, and di. Ethoxymethane; hydrocarbons such as benzene, toluene, hexane, and heptane; halogenated solvents such as dichloromethane and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate, and other solvents such as acetonitrile. , Methylvinylketone, N, N-dimethylacetamide; and mixtures thereof. Preferred solvents include ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, and diethoxymethane; hydrocarbons such as toluene and heptane; and halogenated solvents such as dichloromethane and 1,2-dichloroethane. More preferred solvents include halogenated solvents such as dichloromethane and 1,2-dichloroethane.

0033Suitable reaction temperatures for the reaction between the carboxylic acid compound of formula (III) or its activated carboxylic acid compound and the aniline compound of formula (II) range from about -50 ° C to about 150 ° C. Temperatures in the range of -25 ° C to about 100 ° C, more preferably in the range of 0 ° C to 50 ° C are included.

0034In one embodiment, the activated carboxylic acid compound of formula (IIIa) is in a halogenated solvent such as dichloromethane and / or dimethylformamide at a temperature in the range of -20 ° C to -40 ° C, formula (III). It is produced by reacting the carboxylic acid compound of oxalyl chloride with oxalyl chloride.

0035Step II: Removal of protecting groups to produce amines After the formation of the compound of formula (IV), the protected amine group bonded to the pyridyl group of the compound is converted into an amine group to obtain the compound of formula (I). Various methods can be used to convert protected amine groups to amine groups without affecting the amide bond. An example of a suitable method is: a) Treat with organic, inorganic, or Lewis acid in the presence of water (suitable acids include formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, citric acid, hydrochloric acid, phosphoric acid sulfate, magnesium trif Includes rate, and lithium bromide), b) Treat with organic, inorganic, or Lewis acid without the addition of water (suitable acids include, for example, formic acid, acetic acid, magnesium triflate, and lithium bromide). c) Organic or inorganic bases such as carbonates (M)_mCO₃)_n), For example K₂CO₃, Na₂CO₃, And Cs₂CO₃Hydroxide (M_m(OH)_n), For example KOH, NaOH, and LiOH; alcoholate (M)_m(OR)_n), For example NaOCH₃, KO (t-butyl), and Na (O-ethyl); phosphate (M)_m(PO₄)_n), For example K₂HPO₄And K₃PO₄And amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,4-diazabicyclo [2.2.2] octane (DABCO), and 1,8-diazabicyclo [5.4.0] undeca-7- To process with En, d) Treating by heating in the presence of water, e) Treat with fluoride, f) Treatment with oxidizing agents such as cerium ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is included.

0036Suitable solvents for the conversion of protected amine groups include, for example, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; ether solvents such as tetrahydrofuran, 2-methyltetra, methyl t-butyl ether, and di. Ethoxymethane; hydrocarbons such as toluene, heptane, benzene, and hexanes; halogenated solvents such as dichloromethane and 1,2-dichloroethane; acetic acids such as ethyl acetate, isopropyl acetate, and butyl acetate; alcohols such as methanol, ethanol , And isopropanol; and other solvents such as acetonitrile, methylvinyl ketone, and N, N-dimethylacetamide; and mixtures thereof. Preferred solvents include tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, toluene, N-methylpyrrolidinone, dimethylformamide, N, N-dimethylacetamide, and ethanol.

0037Suitable reaction temperatures for converting protected amine groups to amine groups range from about -78 ° C to about 200 ° C, preferably in the range of -25 ° C to about 150 ° C, more preferably 0 °. Includes temperatures in the range C ~ 100 ° C.

0038Compounds of formula (I) and compounds of formula (IV) can be isolated and / or purified by a variety of methods known in the art. Suitable methods include chromatography, crystallization, filtration, and distillation.

0039In one embodiment, the method for producing the compound of formula (I) uses an aniline compound of formula (II) and / or a compound of formula (IV), wherein the PAm, which is a protected amine group, is-. NH-R^b, -NHC (O) OR^a, -NHC (= O) R^a, -NH (CH)₂R^c), -NHSi (R^d)₃, -NH (PO (OR)^d)₂), -NHSO₂R^e, -N (R)^b)₂, -N (C (O) OR^a)₂, -N (C (O) R^a)₂, -N (CH₂R^c)₂, -N (Si (R)^d)₃)₂, -N = C (R)^a)₂, Or<chemistry num="14"><img id="000016" he="24" wi="23" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Is; Each R^aAre independently H, alkyl, haloalkyl, benzyl, and / or aryl; Each R^bAre independently alkyl, haloalkyl, benzyl, methoxybenzyl, and / or aryl; Each R^cAre independently allyl or alkoxy; Each R^dIs independently alkyl; R^eIs alkyl, -Si (alkyl)₃Alkyl, phenyl, or nitrophenyl substituted with; Each R^fAre independently alkyl or benzyl. Preferably, the PAm is an imine, imide, carbamate, amide, or sulfonamide. More preferably, the PAm is an imine or an imide.

0040In one embodiment, the method for producing the compound of formula (I) is R.¹Is a halogen and is used to make compounds of formula (I) where m is 0, 1, or 2. Preferably m is 1. Preferably R¹Is F or Cl, more preferably F. More preferably, R¹Is F, and m is 1.

0041In one embodiment, the method for producing the compound of formula (I) is R.²Is a halogen and is used to make compounds of formula (I) where n is 0, 1, or 2. Preferably n is 1. Preferably R²Is F or Cl, more preferably F. More preferably, R²Is F, and n is 1.

0042In one embodiment, the method for producing the compound of formula (I) is R.³But C₁-C₄Alkyl, C₁-C₃Used to make compounds of formula (I) that are haloalkyl, halogen, or CN-substituted phenyls; preferably R³Is methyl, ethyl, trifluoromethyl, pentafluoroethyl, halogen, or CN; more preferably R³Is methyl, trifluoromethyl, F, Cl, or CN.

0043In one embodiment, the method for producing the compound of formula (I) is R.³Is used to make compounds of formula (I) that are halogen-substituted phenyls; more preferably R³Is a phenyl substituted with F or Cl; and even more preferably R³Is fluorophenyl, for example 4-fluorophenyl.

0044In one embodiment, the method for producing the compound of formula (I) is the pyridinone compound N- (4- (2-amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -4-ethoxy-. 1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide (having a structure represented by the formula (Ia))<chemistry num="15"><img id="000017" he="49" wi="70" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Ia) , Or the pyridinone compound N- (4- (2-amino-3-chloropyridine-4-yloxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine -3-Carboxamide (has a structure represented by formula (Ib))<chemistry num="16"><img id="000018" he="42" wi="72" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Ib) Used to manufacture.

0045U.S. Patent Application Publication 2008/0114033 A1 discloses a compound of formula (Ia), which is hereby incorporated by reference in its entirety. US Provisional Patent Application 61/022848 discloses compounds of formula (Ib) and prodrugs thereof, which are hereby incorporated by reference in their entirety. This application claims the priority of US provisional patent application 61/022848. These compounds are Met kinase inhibitors and cancers such as bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic / bile sac cancer, prostate cancer, thyroid It is useful in the treatment of cancer, osteosarcoma, rhabdomyomyoma, malignant fibrous histiocytoma (MFH), fibrosarcoma, glioblastoma / stellate cell tumor, melanoma, and mesenteric tumor.

0046In one embodiment, N- (4- (2-amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1, Compound of formula (Ia) which is 2-dihydropyridine-3-carboxamide<chemistry num="17"><img id="000019" he="49" wi="70" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Ia) Manufacturing method is provided.

0047In this aspect, the method Equation (a) (IIb):<chemistry num="18"><img id="000020" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIb) Aniline compound and formula (IIIa):<chemistry num="19"><img id="000021" he="30" wi="43" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIIa) Reacting with the carboxylic acid compound of the above or its activated carboxylic acid compound, the formula (IVa):<chemistry num="20"><img id="000022" he="48" wi="71" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IVa) [In the formula, PAm is a protected amine group] Get the compound of; (b) It is characterized by comprising the step of converting the protected amine group bonded to the compound of the formula (IVa) into an amine group to obtain the compound of the formula (Ia). In one embodiment, Equation (Ib):<chemistry num="21"><img id="000023" he="44" wi="70" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Ib) A method for producing the compound of is provided. In this aspect, the method a) Equation (IIb):<chemistry num="22"><img id="000024" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIb) Aniline compound of the formula (IIIb):<chemistry num="23"><img id="000025" he="25" wi="42" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIIb) Reacting with the carboxylic acid compound of or its activated carboxylic acid compound, formula (IVb):<chemistry num="24"><img id="000026" he="43" wi="71" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IVb) [In the formula, PAm is a protected amine group] Get the compound of; b) It is characterized by comprising the step of converting the protected amine group bonded to the compound of the formula (IVb) into an amine group to obtain the compound of the formula (Ib).

0048Compounds of formula (Ib) may be provided as prodrugs, as disclosed in US Provisional Patent Application 61/022848.

0049One aspect is the structure:<chemistry num="25"><img id="000027" he="15" wi="21" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(VIIIa) [In the formula, PAm is synonymous with the above] Provided is a compound of formula (VIIIa) having. An example of a compound of this embodiment is 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one, which is of formula (3A) :.<chemistry num="26"><img id="000028" he="23" wi="22" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3A) Has the structure of.

0050In another embodiment, a method comprising reacting 2,3-dichloropyridine with benzophenone imine to give 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one. Provided.<chemistry num="27"><img id="000029" he="23" wi="92" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0051Various solvents, synthetic additives, and reaction conditions can be used in the method of this embodiment. Examples of suitable solvents include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, and diethoxymethane; hydrocarbons. , Such as toluene, heptane, benzene, and hexanes; halogenated solvents such as dichloromethane and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate; other solvents such as acetonitrile and methyl vinyl ketone; Or a mixture thereof is included. The reaction can be carried out in the presence of various synthetic additives such as catalysts, bases and / or ligands. Examples of suitable catalysts include, but are not limited to, palladium catalysts such as palladium acetate and tetrakis (triphenylphosphine) palladium; copper catalysts such as copper halide (I) and copper trifluoromethanesulfonate (II); Nickel catalysts such as bis (1,5-cyclooctadiene) nickel (0) are included; it can be present in the range 0.0001 to 1.5 equivalents. Examples of suitable ligands include, but are not limited to, phosphine ligands such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthylene, P (alkyl).₂(Phenyl), P (alkyl) (phenyl)₂, And P (phenyl)₃And nitrogen heterocycles such as imidazole and hydroxypyridine, which can be present in the range of 0.0001 to 1.5 equivalents. Examples of suitable bases include, but are not limited to, inorganic bases such as sodium carbonate and cesium carbonate; and organic bases such as triethylamine and potassium butoxide; they can be present in the range of 1-10 equivalents. Preferably, the reaction of this embodiment is at least one solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, toluene, and / or heptane; more preferably, tetrahydrofuran, 2-methyltetrahydrofuran, and / or di. Performed in ethoxymethane. Preferably, the reaction of this embodiment is carried out in the presence of at least a base selected from sodium carbonate and / or cesium carbonate. Preferably, the reaction of this embodiment is carried out in the presence of at least one palladium catalyst, for example palladium acetate and / or tetrakis (triphenylphosphine) palladium. Preferably, the reaction of this embodiment is 2,2'-bis (diphenylphosphino) -1,1'-binaphthylene, P (alkyl).₂(Phenyl), P (alkyl) (phenyl)₂, And P (phenyl)₃It is performed in the presence of at least one phosphine ligand selected from. For example, the reaction of this embodiment is in at least one solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and / or diethoxymethane, cesium carbonate, palladium acetate, and 2,2'-bis (diphenylphosphino)-. 1,1'-Can be done in the presence of binaphthylene. In this embodiment, the reaction for producing 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one is in the range of about -78 ° C to about 200 ° C, preferably -25 ° C. It can be carried out at temperatures in the range of ~ about 150 ° C, more preferably in the range of 0 ° C to 100 ° C. The reaction product can be separated and purified by methods known in the art.

0052One aspect is the structure:<chemistry num="28"><img id="000030" he="23" wi="21" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Vb) [In the formula, PAm is synonymous with the above] Provided is a compound of formula (Vb) having. An example of a compound of this embodiment is 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one, which is of formula (3B) :.<chemistry num="29"><img id="000031" he="27" wi="23" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3B) Has the structure of.

0053One embodiment is in equation (VIIa) :.<chemistry num="30"><img id="000032" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (VIIa) [During the ceremony, Each R¹Are independently alkyl, haloalkyl, halogen, or CN; Each R²Are independently alkyl, haloalkyl, halogen, or CN; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; and PAm is a protected amine group] Compounds are provided. Preferably R¹Is halogen, m is 1, R²Is a halogen, and n is 1. Preferably, the PAm is an imine, imide, carbamate, amide, or sulfonamide. More preferably, the PAm is an imine or an imide.

0054In one embodiment, equation (VIIb):<chemistry num="31"><img id="000033" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (VIIb) [In the formula, PAm is synonymous with the above] Compounds are provided. Preferably, the PAm is an imine, imide, carbamate, amide, or sulfonamide. More preferably, the PAm is an imine or an imide.

0055One aspect is equation (II) :.<chemistry num="32"><img id="000034" he="30" wi="38" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (II) Aniline compounds or salts thereof; and / or formula (IIa):<chemistry num="33"><img id="000035" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIa) [In the above formula, Each R¹Are independently alkyl, haloalkyl, halogen, or CN; Each R²Are independently alkyl, haloalkyl, halogen, or CN; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; and PAm is a protected amine group] Aniline compound or a salt thereof. Preferably R¹Is halogen, m is 1, R²Is a halogen, and n is 1. Preferably, the PAm is an imine, imide, carbamate, amide, or sulfonamide. More preferably, the PAm is an imine or an imide.

0056In one embodiment, equation (IIc):<chemistry num="34"><img id="000036" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIc) [In the formula, PAm is synonymous with the above] The compound or salt thereof is provided. Preferably, the PAm is an imine, imide, carbamate, amide, or sulfonamide. More preferably, the PAm is an imine or an imide.

0057Production of aniline compound of formula (II) The following reaction schemes show various general synthetic routes for producing compounds of formula (VIIb) that are useful as precursors to compounds of formula (IIc).<chemistry num="35"><img id="000037" he="128" wi="110" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0058In one embodiment, there is provided a method for producing a compound of formula (V), which comprises the step of oxidizing the compound of formula (VIII).<chemistry num="36"><img id="000038" he="23" wi="96" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0059The compound of formula (VII) is converted to the compound of formula (V) by deprotonation followed by direct oxidation; or by deprotonation followed by volalation followed by oxidation. For example, the method of this embodiment is 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) by oxidizing 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one. -Can be used to make on.<chemistry num="37"><img id="000039" he="27" wi="96" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0060Various solvents, synthetic additives, and reaction conditions can be used in the method of this embodiment. Examples of suitable solvents include, but are not limited to, polar aproton solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; ether solvents such as tetrahydrofuran, 2-methyltetrachloride, and diethoxymethane; hydrocarbons. , For example toluene, heptane, benzene, and hexanes; and halogenated solvents such as dichloromethane and 1,2-dichloroethane, or mixtures thereof. The reaction involves various synthetic additives such as oxidants such as hydrogen peroxide, sodium percarbonate, potassium peroxymonosulfate (Oxone® compound), and sodium tetrafluoroborate; peroxides such as t-butyl. Hydrogen peroxide (t-butyl hydrogen peroxide) Peroxide) and m-chloroperoxybenzoic acid; trialkoxyboric acid; and / or can be carried out in the presence of lithium amides such as lithium diisopropylamide. Suitable amounts of peroxide, trialkoxyboric acid, and lithium amide include 1 to 4 equivalents, respectively. Preferred solvents include tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, toluene, and heptane, or mixtures thereof. Preferred oxidants include hydrogen peroxide, sodium percarbonate, and potassium peroxymonosulfate. For example, the method of this embodiment comprises 1-3 equivalents of lithium diisopropylamide, 1-4 equivalents of triiso in a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, toluene, and heptane, or mixtures thereof. By reacting 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one in the presence of propoxyboric acid and an oxidizing agent selected from sodium percarbonate and / or potassium peroxymonosulfate. It can be used to make 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one.

0061In another embodiment, a method for producing a compound of formula (VIIb) is provided, which comprises reacting the compound of formula (Vb) with 1,2-difluoro-4-nitrobenzene.<chemistry num="38"><img id="000040" he="30" wi="130" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0062Various solvents, synthetic additives, and reaction conditions can be used in the method of this embodiment. Examples of suitable solvents include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, and diethoxymethane; hydrocarbons. , Such as toluene, heptane, benzene, and hexanes; halogenated solvents such as dichloromethane and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate; other solvents such as acetonitrile and methyl vinyl ketone; Or a mixture thereof is included. The reaction can be carried out in the presence of various synthetic additives, such as bases. Examples of suitable bases include, but are not limited to, inorganic bases such as sodium carbonate, lithium carbonate, and cesium carbonate; and organic bases such as triethylamine and potassium butoxide. The method of this embodiment is carried out at a temperature in the range of about -78 ° C to about 200 ° C, preferably in the range of -25 ° C to about 150 ° C, more preferably in the range of 0 ° C to 100 ° C. sell. The reaction product can be separated and purified by methods known in the art. Preferably, the reaction of this embodiment is carried out in a solvent selected from dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidinone, or a mixture thereof. Preferably, the reaction of this embodiment is carried out in the presence of at least an inorganic base such as sodium carbonate, lithium carbonate, and / or cesium carbonate. For example, the method of this embodiment can be carried out in the presence of lithium carbonate and / or cesium carbonate in a solvent selected from dimethylformamide, N-methylpyrrolidinone, and mixtures thereof.

0063In another embodiment, a method for producing an aniline compound of formula (II) is provided, which comprises the step of converting a compound of formula (VII) into a compound of formula (II).<chemistry num="39"><img id="000041" he="30" wi="114" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0064For example, the method of this embodiment can be used to produce an aniline compound of formula (IIb) from a compound of formula (VIIb).<chemistry num="40"><img id="000042" he="30" wi="120" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>

0065Various solvents, synthetic additives, and reaction conditions can be used in the method of this embodiment. Examples of suitable solvents include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidinone; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, and diethoxymethane; alcohols. , Such as ethanol and isopropanol; hydrocarbons such as toluene, heptane, benzene, and hexanes; halogenated solvents such as dichloromethane and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate; other solvents. , For example acetonitrile and methyl vinyl ketone; or mixtures thereof. The reaction can be carried out in the presence of various synthetic additives such as, but not limited to, bases, reducing agents, transition metals, catalysts, and hydrogen sources. Examples of suitable reducing agents include, but are not limited to, sodium dithionite, sodium sulfide, ammonium sulfide, FeSO.₄, And sodium borohydride. Examples of suitable transition metals include, but are not limited to, Fe, Pd, Rh, and Ir. Suitable hydrogen sources include hydrogen gas and formic acid. Examples of suitable bases include, but are not limited to, inorganic bases such as sodium carbonate, lithium carbonate, and cesium carbonate; and organic bases such as triethylamine and potassium butoxide. The method of this embodiment is carried out at a temperature in the range of about -78 ° C to about 200 ° C, preferably in the range of -25 ° C to about 150 ° C, more preferably in the range of 0 ° C to 100 ° C. sell. The compound of formula (II), which is the reaction product, can be separated and purified by methods known in the art. Preferably, the reaction of this embodiment is carried out in a solvent selected from dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidinone, tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, ethanol, isopropanol, or a mixture thereof. Preferably, the reaction of this embodiment is sodium sulfide, ammonium sulfide, and FeSO.₄It is carried out in the presence of a reducing agent selected from. Preferably, the reaction of this embodiment is carried out in the presence of a transition metal selected from Pd or Ni. For example, the method of this embodiment can be carried out in the presence of ammonium sulfide, nickel, such as Raney Ni, a hydrogen source, and a base in a solvent selected from isopropanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, and mixtures thereof. ..

0066In one embodiment, 2,3-dichloro-1,4-dihydropyridine-4-ol is reacted with 1,2-difluoro-4-nitrobenzene to give the compound of formula (IX).<chemistry num="41"><img id="000043" he="31" wi="117" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Provided is a method for producing a compound of formula (VIIb), which comprises the step of converting a compound of formula (IX) into a compound of formula (II). Suitable solvents, synthetic additives, and reaction conditions are disclosed above.

0067In one embodiment a) Equation (V):<chemistry num="42"><img id="000044" he="23" wi="30" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (V) The pyridinone compound of, formula (VI):<chemistry num="43"><img id="000045" he="25" wi="21" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (VI) [In the above formula, X is a halogen and PAm is a protected amine group] By reacting with the 4-halo-nitrobenzene compound of Formula (VII):<chemistry num="44"><img id="000046" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (VII) Get the compound of; b) The compound of the above formula (VII) is combined with the formula (II):<chemistry num="45"><img id="000047" he="30" wi="38" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (II) A method for producing an aniline compound of formula (II) is provided, which comprises a step of converting the aniline compound of the above.

0068Preferably, in the method of this embodiment, X is preferably F or Cl. Solvents, synthetic additives, and reaction conditions are disclosed above.

0069In one embodiment a) Equation (Va):<chemistry num="46"><img id="000048" he="23" wi="31" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Va) [In the formula, PAm is a protected amine group] Is reacted with the 4-halo-nitrobenzene compound of formula (VI) to formulate (VIIa) :.<chemistry num="47"><img id="000049" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (VIIa) Get the compound of; b) The compound of the above formula (VIIa) is combined with the formula (IIa) :.<chemistry num="48"><img id="000050" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIa) Provided is a method for producing an aniline compound of formula (IIa), which comprises a step of converting to an aniline compound of.

0070Preferably, in the method of this embodiment, X is preferably F or Cl.

0071In one embodiment a) Equation (Vb):<chemistry num="49"><img id="000051" he="23" wi="21" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (Vb) [In the formula, PAm is a protected amine group] The pyridinone compound of formula (VI) is reacted with the 4-halo-nitrobenzene compound of formula (VI) to formulate (VIIb) :.<chemistry num="50"><img id="000052" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (VIIb) Get the compound of; b) The compound of the above formula (VIIb) is combined with the formula (IIb) :.<chemistry num="51"><img id="000053" he="30" wi="39" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (IIb) A method for producing an aniline compound of formula (IIb) is provided, which comprises a step of converting the aniline compound of the above.

0072Suitable solvents, synthetic additives, and reaction conditions for steps (a) and (b) are disclosed above and in Examples. (Example)<u style="single">Abbreviation</u>BuOAc Butyl Acetate DCM dichloromethane DMF dimethylformamide EtOH ethanol Et ethyl EtOAc Ethyl Acetate HPLC high performance liquid chromatography hrs time LDA Lithium diisopropylamine LOD dry weight loss Me methyl MeCN acetonitrile MeOH Methanol MeTHF 2-methyltetrahydrofurne min minutes MTBE Methyl tert-Butyl Ether NaOEt sodium ethoxylate Ph phenyl rac-BINAP 2,2'-bis (diphenylphosphino) -1,1'-binafutilene THF tetrahydrofuran

0073<u style="single">Example 1</u>N- (4- (2-Amino-3-chloropyridine-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3 -Manufacture of carboxamide<chemistry num="52"><img id="000054" he="49" wi="70" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Step 1. Preparation of 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one<chemistry num="53"><img id="000055" he="27" wi="23" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> MeTHF (35 L) and 2,3 dichloropyridine (5.0 kg) were placed in the reactor, and stirring was started. Next, palladium acetate (0.155 kg), rac-BINAP (0.64 kg) and cesium carbonate (23.0 kg) were added to the above reaction mixture while maintaining a temperature of 25-28 ° C, followed by benzophenone imine (6.2) kg) was added. The reaction mixture was heated to 80-85 ° C and stirred for 24 hours. After the reaction was complete, the reaction mixture was cooled to 25-30 ° C. The precipitate was filtered off and the solid was washed twice with THF (20L). The filtrate was returned to the device and concentrated to the smallest volume.

0074In another reactor, THF (35 L) and diisopropylamine (10 L) were added under a nitrogen atmosphere. The mixture was cooled to -20 to -25 ° C and n-butyllithium (13.3 kg) was added over 30 minutes to prepare a lithium diisopropylamide (LDA) solution. The mixture was then cooled to -75 to -80 ° C and the concentrated filtrate dissolved in THF (25 L) was slowly applied to the LDA solution while maintaining a temperature of -75 to -80 ° C. The reaction mixture was stirred for 2 hours. Then triisopropyl borate (10.0 L) was added and the temperature was slowly raised to 20 ° C. The reaction mixture was stirred at 20 ° C. for 2 hours. The reaction mixture was then cooled to 0 ° C., water (50 L) was added to the reaction mixture, followed by the Oxone® compound (potassium peroxymonosulfate) while maintaining a temperature of 20-25 ° C. 30 kg) was added. The reaction mixture was stirred for 1 hour until the reaction was complete. Water (270 L) was then added and the reaction mixture was stirred for 12 hours. The slurry was then filtered and the solids washed with water (40 L). The solid was returned to the reactor and re-slurried in ethyl acetate (25 L) for 30 minutes. After filtration, the solids were washed with petroleum ether (10 L). The resulting material was removed from the filter and dried at 35-40 ° C for 12 hours. 3-Chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one yield: Off-white solid (6.1 kg; 60% yield).

0075Step 2. Preparation of 3-chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridine-2-amine<chemistry num="54"><img id="000056" he="38" wi="41" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> In the reactor, 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one (24 g), DMF (100 mL), cesium carbonate (12.7 g; 0.5 eq) and difluoronitrobenzene (9.3 mL; 1.1 eq) ) Was added. The reaction mixture was heated to 95 ° C and stirred for 3 hours. After the reaction was complete, the reaction mixture was poured onto crushed ice, the solids were filtered off and washed with water. The unpurified solid was returned to the reactor and dissolved in THF (200 mL). Methanol was added and the mixture was distilled in a constant volume of 350 mL until THF was azeotropically distilled. Additional methanol (100 mL) was added and the suspension was cooled to room temperature. The solid was filtered and dried under reduced pressure to give 3-chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (23.3 g; 67% yield). It was.

0076Step 3. Preparation of 4- (4-amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridin-2-amine<chemistry num="55"><img id="000057" he="38" wi="41" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> In the reactor, 3-chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (10 g), Ra-nickel (1.4 g, A- from Johnson Massey) Type 5001) and Me-THF (100 mL) were added. Reactor 3 times nitrogen / hydrogen swing (nitrogen / hydrogen) It was inactivated by swing) and then pressurized to 25 psig with hydrogen. The reaction mixture was stirred at 25 ° C under 25 psig of hydrogen until the uptake of hydrogen was completed (1.6 L consumption), and it was judged that the reaction was completed by HPLC. BuOAc (50 mL) was added to the reaction mixture and MeTHF was distilled off under atmospheric pressure until &lt;1% Me-THF was detected by GC. Heptane (50 mL) was added over 20 minutes, maintaining a batch temperature of 90 ° C. The solution was then cooled to room temperature over 8 hours. The solids were filtered off and the cake was washed with heptane (50 mL). The solid was dried in a vacuum oven at 60 ° C for 12 hours to give a bright yellow crystalline solid, 4- (4-amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridine-2. -Amine (8.88 g; 95% yield) was obtained.

0077Step 4. Preparation of (4E) -2-cyano-5- (dimethylamino) -3-ethoxypenta-2,4-ethyl dieneate<chemistry num="56"><img id="000058" he="28" wi="26" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> Acetic acid (0.43 kg), ethyl cyanoacetate (16 kg) and triethyl orthoacetate (7.5 kg) were placed in a reactor equipped with a distillation head. The reaction mixture was heated to 110-115 ° C until EtOH was distilled from the reaction mixture. Additional triethyl orthoacetate (4.8 kg) and acetic acid (0.43 kg) were added and EtOH distillation was continued. This procedure was repeated until &lt;2% ethyl cyanoacetate was detected in the reaction mixture by GC. High vacuum was applied to the reaction mixture at 110-115 ° C to remove residual EtOH and triethyl orthoacetate. The reaction mass was cooled to 50 ° C. and N, N'-dimethylformamide diethyl acetal (25.3 kg), DMF and EtOH were added. The mixture was heated to 70 ° C. for 2 hours until the reaction was determined to be complete by HPLC. After cooling to room temperature, DMF (5.6 L) and EtOH (200 proof, 16 L) were added. The mixture was heated to 40 ° C until all solids were dissolved. Water was added while maintaining the temperature in the range of 35-40 ° C. The resulting slurry was cooled to 15-20 ° C. After 2 hours, the solids were filtered and the cake was washed with water (30 L) followed by petroleum ether (64 L). After drying under reduced pressure, ethyl (4E) -2-cyano-5- (dimethylamino) -3-ethoxypenta-2,4-dienoate (31.5 kg; yield 93%) was obtained as a brown solid.

0078Step 5. Preparation of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate<chemistry num="57"><img id="000059" he="20" wi="29" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> Ethyl (4E) -2-cyano-5- (dimethylamino) -3-ethoxypenta-2,4-dienoate (20 kg) and acetic acid (126 L) are placed in a reactor and evaluated by HPLC to complete the reaction. Heated to 100 ° C for 3 hours. Acetic acid was removed by cooling the reaction mass to 55 ° C and distilling under reduced pressure at 65-75 ° C. After distillation, the mixture was cooled to room temperature and water (3 L) was added. The pH of the mixture was adjusted to 8 by adding sodium carbonate solution (30%, 100 L). The solid was filtered off and washed with water (10 L). The aqueous layers were combined and extracted 3 times with DCM (100L). The DCM layers were combined, washed with brine, then dried over sodium sulphate and concentrated to dryness. Ethyl acetate was added to the concentrate. The mixture was heated to 40 ° C and then cooled to 25 ° C. The solids were filtered off, washed with petroleum ether and dried at room temperature for 12 hours to give ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (10.3 kg; yield 58.5%). Obtained.

0079Step 6. Preparation of ethyl 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate<chemistry num="58"><img id="000060" he="23" wi="45" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> DMF (9 L) and cesium carbonate (3.1 kg) were placed in the reactor under nitrogen and stirred at room temperature for 10 minutes. To this mixture was added a DMF solution of 8-hydroxyquinoline (0.275 kg) (1 L), copper iodide (0.27 kg) and 1-fluoro-4-iodobenzene (1.576 kg) under nitrogen. Ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (1 kg) was then added and the reaction mixture was heated to 100 ° C. under nitrogen for 20 hours. After the reaction was complete, the mixture was filtered through Celite. Water (100 L) was added to the filtrate and the mixture was extracted 3 times with DCM (25 L). The DCM layers were combined, washed twice with water (20 L), twice with HCl (1.5 N, 5 L), and once with saline (10 L), then dried over sodium sulfate and concentrated to dryness. Petroleum ether (5 L) was added to the concentrate and the resulting slurry was stirred for 30 minutes. The solid is filtered and dried under reduced pressure at room temperature to give unpurified ethyl 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate (1.1 kg). It was.

0080Step 7. Carboxylic acid compound: Preparation of 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid<chemistry num="59"><img id="000061" he="23" wi="44" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> At room temperature, HCl (2.75N, 7.7L) of unpurified ethyl 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate (1.1kg) EtOH It was added to the solution (3.85 L). The mixture was heated to 60-64 ° C for 10 hours. The mixture was then cooled to 50-54 ° C and the methanol was removed by vacuum distillation. The pH was adjusted to 8.0-8.5 by cooling the mixture to 20-25 ° C and adding sodium carbonate solution (30%, 8.5 L). The phases were separated and the aqueous layer was washed 3 times with DCM (4L). Charcoal (0.7 kg) was then placed in an aqueous layer and the layer was filtered through a Celite bed. HCl (1.5N) was added to the filtrate until the pH reached 2.0. The resulting slurry was stirred at room temperature for 20 minutes. The solids were filtered off, washed with water (15 L) and dried under reduced pressure at 50-55 ° C until the dry weight loss was less than 5% by weight. The crude product was suspended in ethyl acetate (5 L) and slurryed at 40 ° C for 15 minutes. After cooling to room temperature, the solids are filtered off, washed with ethyl acetate (1 L), dried under reduced pressure at 40-45 ° C for 10 hours, 4-ethoxy-1- (4-fluorophenyl) -2-. Oxo-1,2-dihydropyridine-3-carboxylic acid (0.76 kg; 58% yield for steps 6 and 7) was obtained.

0081Step 8. N- (4- (3-Chloro-2- (diphenylmethyleneamino) Pyridine-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo- Production of 1,2-dihydropyridine-3-carboxamide<chemistry num="60"><img id="000062" he="45" wi="72" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> 4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.20 equivalent; 79.62 g), DCM (500.00 mL), and oxalyl chloride (23.88 mL), Added to the Chemigrass reactor at 25 ° C. DMF (20.00 mL) was added over about 20 minutes and the solution was stirred at 20 ° C for 30 minutes. The resulting acid chloride solution was cooled to -5 ° C.

0082In another reactor, 4- (4-amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridin-2-amine (1.00 eq; 100 g), DCM (500 mL), and 2-ethyl Sodium hexanoate (95.45 g) was added and the resulting mixture (aniline solution) was cooled to -5 ° C.

0083A pre-cooled acid chloride solution was then added to the aniline solution, keeping the batch temperature below 5 ° C. The mixture was stirred at -5 ° C for 3 hours. After the reaction was indicated by HPLC to be complete, the reaction was quenched with methanol (29.06 mL). DCM (500 mL), sodium bicarbonate water (500 mL), and water (500 mL) were added to the solution and the solution was heated to 25 ° C with stirring. The layers were separated and the aqueous layer was discarded. The DCM layer was washed with sodium bicarbonate (500 mL) and water (500 mL). Diethoxymethane (1500 mL total) was added to the DCM layer while keeping the volume constant at 10 L / kg, and the DCM was distilled off until the batch temperature reached 85 ° C. After GC analysis of the reaction mixture showed a diethoxymethane / DCM ratio of 99: 1, distillation was stopped and the mixture was cooled to 25 ° C. The precipitate was filtered off and the cake was washed with diethoxymethane (1.00 L) and then with methyl t-butyl ether (500 mL). The solid is dried in a vacuum oven at 60 ° C for 12 hours to give a white solid, N- (4- (3-chloro-2- (diphenylmethyleneamino) pyridine-4-yloxy) -3-fluorophenyl). -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide (0.97 equivalent; 157.02 g; yield 96.90%) was obtained.

0084Step 9. N- (4- (2-Amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2- Production of dihydropyridine-3-carboxamide<chemistry num="61"><img id="000063" he="40" wi="72" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> In a 250 mL container, N- (4- (3-chloro-2- (diphenylmethyleneamino) pyridine-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo -1,2-Dihydropyridine-3-carboxamide (100.0 g, 147.7 mmol, 1.0 eq) and methanol (900 mL) were added. The white slurry was cooled to 10 ° C and concentrated HCl (16.3 g, 163.3 mmol, 1.105 eq) was added while maintaining the reaction temperature below 10 ° C. The reaction mixture was kept at 10 ° C for about 2.5 hours until HPLC showed a relative area% of starting material of 0.5. Water (500 mL) and MTBE (500 mL) were added and the reaction mixture was heated to 20 ° C. Next, 1N while maintaining a temperature of 15-20 ° C NaOH (184.08 g, 177.0 mL, 177 mmol, 1.20 eq) was added dropwise over 20 minutes. The resulting slurry was cooled to 10 ° C and aged for at least 10 minutes. The precipitate was filtered off and the cake was washed with water (2 x 350 mL) followed by a mixture of methanol: MTBE (10:90) (1 x 300 mL). The cake was then dried in a vacuum oven at 50-60 ° C until LOD analysis showed less than 1% by weight of volatiles. N- (4- (2-Amino-3-chloropyridine-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3 -Carboxamide: 79.5g (98.1 AP and 99.4% by weight) With potency, yield 95%). The resulting product (35.0 g) was subsequently recrystallized from THF (367.2 mL) / EtOH (200 proof, 244.8 mL) / n-heptane (350 mL) to N- (4- (2-amino-3). -Chloropyridine-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide (30.8 g,&gt; 99.9 AP and 99.7) With weight% resistance, a yield of 88%) was obtained.

0085<u style="single">Comparative Example 2</u>US 2008/0114033 N- (4- (2-amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) according to the method disclosed in A1. Production of -2-oxo-1,2-dihydropyridine-3-carboxamide<chemistry num="62"><img id="000064" he="49" wi="70" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Step 1. Production of 3,4-dichloropicolinic acid<chemistry num="63"><img id="000065" he="21" wi="23" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> 2,2,6,6-tetramethylpiperidin (8.84 mL, 52 mmol, aldrich) as previously described in Marzi, E. et al. (Eur. J. Org. Chem. 2001, 1371-1376). ) Into an ether solution (50 mL) at 0 ° C. n-BuLi (33 mL, 52 mmol, Aldrich, 1.6 M hexane). After stirring at 0 ° C for 30 minutes, the solution was cooled to -78 ° C and an ether solution (5 mL) of 3,4-dichloropyridine (7.0 g, 47 mmol, matrix) was added. After stirring at -78 ° C for 2 hours, carbon dioxide (dry ice) was cannulated into the reaction mixture, when the solution became non-uniform. After bubbling carbon dioxide into the reaction solution for 10 minutes at -78 ° C, CO₂The cooling bath was removed and the reaction mixture was warmed to room temperature while continuing to bubble the solution. The reaction was quenched with saturated aqueous ammonium chloride solution (~ 50 mL) and stirred at room temperature for 5 minutes in an air atmosphere. The reaction mixture was diluted with water (~ 150 mL) and extracted with ethyl acetate (2 x 75 mL) to remove any residual starting material. The aqueous layer was acidified to pH 1-2 with aqueous HCl (1N) and extracted with ethyl acetate (2 x 100 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3,4-dichloropicolinic acid (3.5 g, 39%) as a yellow solid.¹H NMR (DMSO-d₆) δ 8.53 (d, 1H, J = 5.2 Hz), 7.90 (d, 1H, J = 5.2 Hz); MS (ESI)⁺) m / z 192.08 (M + H)⁺.

0086Step 2. Production of 3,4-dichloropicoline amide<chemistry num="64"><img id="000066" he="26" wi="25" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> An excess thionyl chloride (10 mL, Aldrich Reagent Plus 99.5%) solution of 3,4-dichloropicolinic acid (3.5 g, 18 mmol) was stirred at 80 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride and then suspended in ether (50 mL). A acid chloride solution of ether was added to ammonium hydroxide (50 mL) at 0 ° C. The product was collected by vacuum filtration, washed with water and then triturated with ether to give 3,4-dichloropicolinamide (2.6 g, 76%) as a beige solid. mp 174-175 ° C; ¹1 H NMR (400MHz, DMSO-d₆) δ 8.50 (d, 1H, J = 5.2 Hz), 8.12 (br s, 1H), 7.83 (d, 1H, J = 5.2 Hz), 7.82 (br s, 1H); ¹³C NMR (100MHz, DMSO-d₆) δ 166.2, 154.2, 147.9, 142.3, 126.1, 126.0; MS (ESI⁺) m / z 191.10 (M + H)⁺.

0087Step 3. Preparation of 4- (4-amino-2-fluorophenoxy) -3-chloropicolinamide<chemistry num="65"><img id="000067" he="36" wi="44" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> Potassium tert-butoxide (8.8 g, 79 mmol) was added to a DMF solution (100 mL) of 4-amino-2-fluorophenol (9.3 g, 73 mmol, 3B Medical Systems, 3B3290). After stirring at room temperature for 30 minutes, 3,4-dichloropicoline amide (10 g, 52 mmol) was added. The reaction mixture was stirred at 50 ° C. for 2.5 hours. After cooling the reaction to room temperature, the mixture was diluted with ethyl acetate (400 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (400 mL). The aqueous layer was back extracted with ethyl acetate (300 mL). The organic phases were combined, washed with aqueous lithium chloride solution (10%), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting brown solid was suspended in ethyl acetate, filtered and washed with ether to give the product (7.4 g) as a tan solid. The filtrate was concentrated under reduced pressure and then purified by silica gel flash chromatography (2% methanol / ethyl acetate). The resulting brown solid is triturated with ether to give an additional 4.3 g of 4- (4-amino-2-fluorophenoxy) -3-chloropicoline amide (79% combined yield) as a pale yellow solid. It was. mp 217-2 18 ° C; ¹1 H NMR (400 MHz, CD₃OD) δ 8.29 (d, 1H, J = 5.6 Hz), 7.00 (t, 1H, J = 8.8 Hz), 6.79 (d, 1H, J = 5.6 Hz), 6.63-6.55 (m, 2H); MS ( ESI⁺) m / z 282.21 (M + H)⁺.

0088Step 4. Production of 4-iodo-2-methoxynicotinaldehyde<chemistry num="66"><img id="000068" he="21" wi="18" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> In anhydrous THF solution (6.5 L) of diisopropylamine (260 g, 2.57 mol), N₂At -30 to -40 ° C under the blanket, n-BuLi (156 g, 2.45 mol) was added by dropping with a cannula. The resulting solution was warmed to 0 ° C and stirred at this temperature for 35 minutes. The solution was then cooled to 78 ° C. and 2-fluoropyridine (250 g, 2.57 mol, Alpha) was added dropwise. The reaction mixture was stirred at 78 ° C. for 2 hours. This mixture is then N₂At -20 ° C below, iodine (654 g, 2.57 mol) was added to an anhydrous THF solution (1.96 L) by cannula. After the reaction was complete, the mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with sodium thiosulfate, followed by water and saline. Then dry the organic matter (Na₂SO₄) And concentration under reduced pressure to obtain 2-fluoro-3-iodopyridine (450 g, 78%) as a solid.

0089In anhydrous THF solution (5 L) of diisopropylamine (345 mL, 249 g, 2.46 mol), N₂At -8 to -10 ° C below the blanket, n-BuLi (880 mL, 158 g, 2.46 mol) was added dropwise by cannula. The mixture was stirred at -10 ° C for 30 minutes, cooled to -78 ° C and a dry THF solution (2 L) of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) was added dropwise. After addition, the reaction mixture was heated to -60 ° C and maintained at this temperature for 2 hours. The mixture was then cooled to 78 ° C. and treated dropwise with ethyl formate (183 g, 2.47 mol), followed by sodium methoxide (149 g, 2.75 mol) in MeOH solution (1.5 L) to ambient temperature. It was heated. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers are separated, the organic phase is washed with water, saline and dried (Na₂SO₄) And concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give 4-iodo-2-methoxynicotinaldehyde (380 g, 64%) as a solid.

0090Step 5. Preparation of 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde<chemistry num="67"><img id="000069" he="19" wi="19" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> 4-Iodo-2-methoxynicotinaldehyde (25 g, 95 mmol) and sodium iodide (31.0 g, 285 mmol, Aldrich) were stirred together in acetonitrile (500 mL). To this solution was added chlorotrimethylsilane (36.0 mL, 285 mmol, Aldrich 99%) dropwise over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The product was suspended in ethyl acetate, water, and saturated aqueous sodium hydrogen carbonate and then filtered to give a dark brown solid. This solid is triturated with acetonitrile to give 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (21.3 g, 90%) (mixture of tautomers) as a yellow solid. It was. MS (ESI)⁺) m / z 250.04 (M + H)⁺.

0091Step 6.1 Preparation of 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde<chemistry num="68"><img id="000070" he="21" wi="33" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> 4-Iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (16.0 g, 64.3 mmol), 4-fluorophenylboronic acid (26.8 g, 193 mmol, aldrich), copper acetate (II) (23.4 g,) 129 mmol (Aldrich), and myristic acid (58.7 g, 257 mmol, Aldrich) were stirred together in toluene (800 mL). To this solution, 2,6-lutidine (60 mL, 514 mmol, Aldrich) was added, and the reaction solution was vigorously stirred for 1 day. Additional 4-fluorophenylboronic acid (5 g) was added and the reaction was vigorously stirred for another 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting substance was reduced to 10%. Suspended in methanol / ethyl acetate. Celite® was added and the mixture was stirred for 5 minutes. The mixture was then filtered through a Celite® plug, concentrated under reduced pressure and the resulting material suspended in ethyl acetate and water. The mixture was filtered again through Celite® to remove any additional copper that had precipitated and washed well with ethyl acetate. The filtrate was washed with aqueous HCl (1N), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate to give a yellow solid, 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (9.25 g, 42%). ) Was obtained. The filtrate was concentrated under reduced pressure and the remaining solid was triturated again with ethyl acetate to give an additional 5.75 g (68% overall yield) of the desired product as a yellow solid.¹H NMR (DMSO-d₆) δ 9.57 (s, 1H), 7.68 (d, 1H, J = 7.2 Hz), 7.58-7.54 (m, 2H), 7.40 (t, 2H, J = 8.8 Hz), 7.02 (d, 1H, J = 7.2 Hz); MS (ESI)⁺) m / z 344.13 (M + H)⁺.

0092Step 7.1 Preparation of 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid<chemistry num="69"><img id="000071" he="21" wi="40" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (10.0 g, 29.2 mmol) and sodium dihydrofuran phosphate (sodium phosphate monobasic) (10.1 g, 73 mmol) , Aldrich) was vigorously stirred in 35 mL each of THF, tert-butanol, and water at 0 ° C. 2-Methyl-2-butene (45.2 mL, 2.0 M) THF solution, Aldrich) was added to the reaction mixture, followed by sodium chlorite (6.06 g, 67.1 mmol, Aldrich). The ice bath was removed and the reaction mixture was warmed to room temperature with very fast stirring. After a few minutes, the product of interest began to precipitate from the solution. Stirring was continued for 1 hour, then HCl water (1N, 20 mL) was added and stirring was continued for an additional 5 minutes. The product of interest was filtered off and then washed with water, ethyl acetate, and ether. The filtrate was taken and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was suspended in ethyl acetate, filtered and washed with ethyl acetate and ether to give the desired product. Combined with the pale yellow solids, 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (8.22 g, 78%) (purity 92%, 8%) The starting material remains). This material was dissolved in a minimum amount of NaOH water (1N). Ethyl acetate was added and the mixture was vigorously stirred for 5 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate. PH the aqueous layer with concentrated HCl with stirring Acidified to 1. Precipitated pale yellow solids are collected from the solution, washed with water, ethyl acetate, diethyl ether and then dried under reduced pressure to 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine. -3-Carboxylic acid (7.33 g, 70%) (purity 95.4% by HPLC) was obtained.¹H NMR (DMSO-d₆) δ 13.53 (s, 1H), 7.52-7.49 (m, 3H), 7.38 (t, 2H, J = 8.8 Hz), 6.81 (d, 1H, J = 7.2 Hz); MS (ESI)⁺) m / z 360.14 (M + H)⁺.

0093Step 8. Preparation of 3-chloro-4- (2-fluoro-4- (1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamide) phenoxy) picoline amide<chemistry num="70"><img id="000072" he="44" wi="77" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> In a mixed suspension solution of 1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (36.3 g, 101 mmol) in DCM (500 mL) and DMF (0.25 mL). Oxalyl chloride (38.5 g, 26.5 mL, 303 mmol) was added dropwise over 0.5 hours at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture became homogeneous, which was then concentrated under reduced pressure. The resulting residue was resuspended in DCM (200 mL) and the mixture was concentrated again under reduced pressure to remove any residual oxalyl chloride (twice). The unpurified acid chloride was then dried under high vacuum for 0.5 hours. While drying the carboxyl chloride, 4- (4-amino-2-fluorophenoxy) -3-chloropicoline amide (22.8 g, 81 mmol) was dissolved in THF (200 mL) and DMF (50 mL). The solution was cooled to 0 ° C. and pyridine (12.8 g, 162 mmol) was added. A DCM solution of the carboxyl chloride (250 mL) was then added dropwise to the reaction mixture over 40 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 0.5 hours and then quenched with water (50 mL). Volatile was evaporated under reduced pressure until the volume was reduced to about 100 mL. Dissolve the contents of the flask in EtOAc (1 L) and add the solution to HCl (1N, 2 x 200 mL), saturated acrylamide.₃It was washed continuously with water (2 x 200 mL), LiCl aqueous solution (10%, 3 x 200 mL) and saturated NaCl aqueous solution (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered through a pad of silica gel (washed with 500 mL EtOAc) and the filtrate concentrated under reduced pressure. The crude product was triturated with MeOH (100 mL), the solids were filtered, washed with MeOH (10 mL) and collected. The filtrate was concentrated under reduced pressure, and the pulverization step was repeated. Two batches of solids were combined, suspended in EtOH (100 mL) and concentrated under reduced pressure. The solid was suspended again in EtOH (50 mL) and concentrated under reduced pressure. The resulting solid is dried overnight under high vacuum to give an off-white solid, 3-chloro-4- (2-fluoro-4- (1- (4-fluorophenyl) -4-iodo-2-). Oxo-1,2-dihydropyridine-3-carboxamide) phenoxy) picoline amide (40.3 g, 80%) was obtained.¹1 H NMR (400 MHz, CD₃OD) δ 8.34 (d, 1H, J = 5.6 Hz), 7.92 (dd, 1H, J = 12.4, 2.4 Hz), 7.51-7.47 (m, 4H), 7.37-7.29 (m, 3H), 6.99 (d) , 1H, J = 7.2 Hz), 6.86 (d, 1H, J = 5.6 Hz); MS (ESI)⁺) m / z 623.08 (M + H)⁺.

0094Step 9. Preparation of 3-chloro-4- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide) -2-fluorophenoxy) picoline amide<chemistry num="71"><img id="000073" he="44" wi="76" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> EtOH (80 mL, Aldrich&gt; 99.5%, 200 proof) was slowly added to a THF suspension solution (26 mL) of NaH (1.87 g, 77.9 mmol) under nitrogen, and the resulting homogeneous solution was stirred for 10 minutes. Sodium ethoxide solution followed by 3-chloro-4- (2-fluoro-4- (1- (4-fluorophenyl) -4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamide) phenoxy) picolin It was added to a mixed solution of amide (37.3 g, 59.9 mmol) in THF (100 mL) and EtOH (46 mL), and the resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was suspended in water (500 mL) and the mixture was sonicated and stirred at room temperature for about 1 hour until the remaining solids became a filterable powder. The resulting powder is collected, triturated with ethyl ether (50 mL) and dried under high vacuum for 48 hours as a pale yellow solid, 3-chloro-4- (4- (4-ethoxy-1- (4-)). Fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide) -2-fluorophenoxy) picoline amide (30.8 g, 95%) was obtained.¹1 H NMR (400 MHz, CD₃OD) δ 8.34 (d, 1H, J = 5.6 Hz), 7.94 (dd, 1H, J = 12.4, 2.4 Hz), 7.80 (d, 1H, J = 8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J = 5.6 Hz), 6.61 (d, 1H, J = 7.2 Hz), 4.34 (q, 2H, J = 7.2 Hz), 1.45 (t, 3H) , J = 7.2 Hz); MS (ESI)⁺) m / z 541.11 (M + H)⁺.

0095Step 10. N- (4- (2-Amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2- Production of dihydropyridine-3-carboxamide 3-Chloro-4- (4- (4-ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide) -2-fluorophenoxy) picolinamide (13.9 g, 25.7) Iodobenzene diacetate (9.93 g, 30.8 mmol) was added to a mixed solution of EtOAc (200 mL), MeCN (200 mL), and water (100 mL) of mmol) at 0 ° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The resulting precipitate was filtered and washed with ethyl acetate. The filtrates were combined, washed with saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Combined with this residue and the first precipitate, flash chromatography (SiO)₂, 0 ~ 2% methanol / chloroform gradient elution) as an off-white solid, N- (4- (2-amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -4 -Ethoxy-1- (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-carboxamide (9.8 g, 74%) was obtained.¹H NMR (DMSO-d₆) δ 10.57 (s, 1H), 7.83-7.79 (m, 2H), 7.67 (d, 1H, J = 5.6 Hz), 7.41-7.38 (m, 3H), 7.36-7.22 (m, 3H), 6.44 ( d, 1H, J = 7.6 Hz), 6.36 (br s, 2H), 5.86 (d, 1H, J = 6.0 Hz), 4.18 (q, 2H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz); MS (ESI)⁺) m / z 513.09 (M + H)⁺.. Table 2 Comparison of Steps of Example 1 and Comparative Example 2<img id="000074" he="62" wi="141" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" />

0096<u style="single">Example 3</u>N- (4- (2-Amino-3-chloropyridin-4-yloxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxamide<chemistry num="72"><img id="000075" he="42" wi="72" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3) Manufacture 3A: 3-Chloro-N- (diphenylmethylene) Pyridine-2-amine<chemistry num="73"><img id="000076" he="22" wi="23" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3A) 2,3-Dichloropyridine (105.00g, 710 mmol), Pd (OAc)₂(3.98 g, 17.74 mmol), rac-BINAP (16.57 g, 26.61 mmol), cesium carbonate (346.76 g, 1065 mmol), THF (1.05 L), and benzophenone imine (124.67 mL, 745 mmol), mechanical stirrer and reflux cooling Added to a 2 L chemigrass reactor with a vessel attached. The mixture was heated to reflux with stirring for 18 hours. The material was filtered and washed with THF (100 mL). The resulting filtrate was concentrated under reduced pressure to 1/3 volume and used without further purification.¹1 H NMR (CDCl₃) δ 6.79 (dd, 1 H, J = 4.6, 7.6 Hz), 7.19-7.60 (m, 9 H), 7.79-7.95 (m, 2 H), 8.16 (dd, 1 H, J = 1.5, 5.1 Hz) ); MS (ESI)⁺) m / z 293.1 (M + H)⁺.

0097Manufacture 3B: 3-Chloro-2- (diphenylmethyleneamino) Pyridine-4 (1H) -one<chemistry num="74"><img id="000077" he="27" wi="23" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3B) Unpurified 3-chloro-N- (diphenylmethylene) pyridin-2-amine and triisopropyl borate (196.38 mL, 852 mmol) were added to a 4 L chemigrass reactor (nitrogen blanket with dropping funnel). The resulting solution was cooled to 0 ° C. In another reactor, diisopropylamine (169.78 mL, 1207 mmol) and THF (1.05 L) were added. The solution was cooled to 0 ° C. and n-butyllithium (683.22 mL, 923 mmol) was added slowly. After stirring at 0 ° C, this solution was slowly added to the first solution. The reaction mixture was stirred for 30 minutes without a cooling bath (HPLC showed consumption of starting material). Water (1.05 L) was added to the mixture, followed by sodium percarbonate (336.34 g, 1065 mmol) in a single dose. The mixture was stirred at 20 ° C for 1 hour. NaHSO₃Saturated solution (~ 1L) was added slowly. The aqueous layer was removed, DMF (840.00 mL) was added to the organic layer and THF was distilled off (solvent exchange from THF to DMF). DMF was used without further purification.¹1 H NMR (CDCl₃) δ 6.02 (d, 1 H, J = 7.1 Hz), 7.10 (d, 1 H, J = 7.1 Hz), 7.20-7.80 (m, 10 H); MS (ESI⁺) m / z 309.07 (M + H)⁺.

0098Manufacture 3C: 3-Chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) Pyridine-2-amine<chemistry num="75"><img id="000078" he="38" wi="41" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3C) Unpurified 3-chloro-2- (diphenylmethyleneamino) pyridine-4 (1H) -one (from the above, this time DMF solution) and cesium carbonate (300.52 g, 923 mmol) were added to the 2 L chemigrass reactor, followed by 3,4-Difluoronitrobenzene (118.15 mL, 1065 mmol) was added. The mixture was heated to about 90 ° C with stirring for 2 hours. The mixture was cooled to 25 ° C with stirring for 10 minutes. Water (1 L) was added to this solution. The mixture was extracted with EtOAc (1 L) and the aqueous phase was discarded. The organic matter was concentrated to give the oil. The oil was dissolved in EtOH (200 mL) (sometimes requires heating). After allowing the solution to stand at 25 ° C for 4 hours, the solids are collected by filtration and as a yellow solid, 3-chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridine. -2-Amine (104.00 g; yield 32.73%) was obtained.¹1 H NMR (CDCl₃) δ 6.52 (d, 1 H, J = 5.6 Hz), 6.80 (dd, 1 H, J = 8.1, 9.1 Hz), 7.21-7.60 (m, 8 H), 7.78-7.95 (m, 2 H), 8.00 (m, 1 H), 8.11 (dd, 1 H, J = 2.5, 9.6 Hz), 8.17 (d, 1 H, J = 5.6 Hz); MS (ESI)⁺) m / z 448.01 (M + H)⁺.

0099Manufacture 3D: 4- (4-amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridin-2-amine<chemistry num="76"><img id="000079" he="38" wi="41" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3D) The following substances were added to a 2 L chemigrass reactor: 3-chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (110.00 g, 221 mmol), isopropyl alcohol (110.00 g, 221 mmol). 990.00 mL), and ammonium sulfide (~ 40%) Aqueous solution, 297.00 mL, 2324 mmol). The mixture was stirred at 20 ° C for 3-4 hours. 3-Chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridine-2-amine was not detected by HPLC analysis. The reaction mixture was heated to 70 ° C. and stirred for 3-4 hours. Once the reaction was complete, water (14 mL / g · LR) was added. The reaction mixture was cooled to 20 ° C (reaction temperature) over 1 hour. The precipitated solid was cooled, filtered off, washed with water (12.5 mL / g · LR), followed by heptane: MTBE (4: 1; 5 mL / g · LR). After LOD (~ 25%), unpurified 4- (4-amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridin-2-amine (90AP) was obtained (95.3 g). .. Unpurified 4- (4-amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridin-2-amine by heating to about 85 ° C, n-BuOAc (7 mL / g) Dissolved in LR). At 85 ° C, heptane (7 mL / g · LR) was added dropwise until the solution became turbid. The solution was then cooled to 20 ° C with stirring. At 20 ° C, the slurry was aged for 8 hours. The solid is filtered, washed with heptane (5 mL / g · LR) and then dried in a vacuum oven at 60 ° C overnight to give a pale yellow solid, 4- (4-amino-2-fluorophenoxy)-. 3-Chloro-N- (diphenylmethylene) pyridine-2-amine (62.53 g; yield 67.69%) was obtained.¹1 H NMR (CDCl₃) δ 6.23 (dd, 1 H, J = 1.0, 5.6 Hz), 6.43 (m, 1 H), 6.49 (dd, 1 H, J = 2.5, 12.1 Hz), 6.92 (t, 1 H, J = 8.6) Hz), 7.25-7.60 (m, 8 H), 7.87 (m, 2 H), 7.95 (d, 1 H, J = 6.1 Hz); MS (ESI)⁺) m / z 418.6 (M + H)⁺.

0100Manufacture 3E: Ethyl 4- (4-fluorophenyl) -3-oxobutanoate<chemistry num="77"><img id="000080" he="15" wi="49" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3E) A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (meldrum's acid, 8.0 g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) and pyridine (11 mL) at 0 ° C in a nitrogen atmosphere. So, 2- (4-fluorophenyl) acetyl chloride (7.6 mL, 9.6 g, 56 mmol) was added slowly. The red solution was stirred at 0 ° C for 1.5 hours. The reaction mixture was treated with HCl (1N, 13 mL) and diluted with methylene chloride (200 mL). The layers are separated, the organic layer is washed with saturated aqueous sodium chloride solution, dried and concentrated under reduced pressure to 5- (2- (4-fluorophenyl) acetyl) -2,2-dimethyl-1,3-dioxane- Obtained 4,6-Zeon. The unpurified intermediate was suspended in anhydrous EtOH (150 mL) and the resulting mixture was refluxed for 4 hours. The solvent was then distilled off under reduced pressure and the residue was subjected to flash column chromatography (SiO).₂, 230-400 mesh, 8: 1 hexane-ethyl acetate gradient elution) to give the desired product (4.6 g, 37%).¹1 H NMR (CDCl₃) δ 7.23-7.15 (m, 2 H), 7.05-6.98 (m, 2 H), 4.18 (q, 2 H, J = 7.0 Hz), 3.81 (s, 2 H), 3.46 (s, 2 H) , 1.26 (t, 3 H, J = 7.0 Hz); MS (ESI)⁺) m / z 225 (M + H)⁺.

0101Production 3F: 5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid<chemistry num="78"><img id="000081" he="26" wi="43" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3F) Ethyl 4- (4-fluorophenyl) -3-oxobutanoate (4.6 g, 21 mmol) in anhydrous EtOH solution (45 mL), NaOEt solution (21% NaOEt EtOH solution, 7.7 mL) and triazine (1.67 g, 21 mmol) Was added. The resulting mixture was heated to 85 ° C for 1.5 hours, cooled to room temperature and treated with additional triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt EtOH solution, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated under reduced pressure. The residue was treated with HCl (1N) until the pH of the reaction was about 2. The precipitate is collected to give the desired ester intermediate, ethyl 5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. It was. MS (ESI)⁺) m / z 262 (M + H)⁺.

0102The above ester (1.0 g, 3.8 mmol) was dissolved in NaOH (2N, 20 mL) and heated to 65 ° C for 2 hours. The resulting transparent mixture was cooled to ambient temperature and the solids were filtered off. The filtrate was then acidified to pH = 1 with HCl (1N) and the resulting yellow precipitate was collected as the desired product (0.73 g, 82%).¹H NMR (DMSO-d₆) δ 13.52 (br s, 1 H), 8.86 (s, 1 H), 8.51 (s, 1 H), 7.99-7.96 (m, 2 H), 7.55-7.51 (m, 2 H); MS (ESI)⁺) m / z 234 (M + H)⁺.

0103Manufacture 3G: N- (4- (3-chloro-2- (diphenylmethyleneamino) pyridin-4-yloxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1,4- Dihydropyridine-3-carboxamide<chemistry num="79"><img id="000082" he="50" wi="75" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (3G) 4- (4-Amino-2-fluorophenoxy) -3-chloro-N- (diphenylmethylene) pyridin-2-amine (836 mg, 2.0 mmol) and 5- (4-fluorophenyl) -4-oxo-1, HATU (913 mg, 2.4 mmol) and DIPEA (1.05 mL, 6.0 mmol) were added to a DMF solution (10 mL) of 4-dihydropyridine-3-carboxylic acid (490 mg, 2.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then quenched by the addition of cold water (50 mL). The solids formed were collected by filtration and washed with water and ether. Dissolve the solid in DCM and perform flash column chromatography (SiO)₂, DCM ~ 10% MeOH DCM solution) to give the desired product (987 mg, 78%) as a bright yellow solid. MS (ESI)⁺) m / z 633 (M + H)⁺.

0104Example 3 N- (4- (3-Chloro-2- (diphenylmethyleneamino) pyridine-4-yloxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3 -HCl water (2M, 0.81 mL, 1.62 mmol) was added to a THF solution (10 mL) of carboxamide (410 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Cold 5% LVDS₃Water (5 mL) was then added to the residue. The solids formed were collected by filtration, washed with water, then with ether and dried under reduced pressure to give the desired product (275 mg, 90%).¹H NMR (DMSO-d₆) δ 13.31 (s, 1 H), 12.70 (br s, 1 H), 8.63 (d, 1 H, J = 1.30 Hz), 8.09 (d, 1 H, J = 1.50 Hz), 8.02 (dd, 1) H, J = 2.50, 13.10 Hz), 7.76 (d, 1 H, J = 5.50 Hz), 7.71 (m, 2 H), 7.44 (dd, 1 H, J = 1.50, 8.80 Hz), 7.31 (t, 1 H, J = 8.80 Hz), 7.27 (t, 2 H, J = 8.80 Hz), 6.43 (br s, 2 H), 5.96 (d, 1 H, J = 5.60 Hz); MS (ESI)⁺) m / z 469 (M + H)⁺.

0105N- (4- (2-Amino-3-chloropyridine-4-yloxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxamide, hydrochloric acid salt N- (4- (3-Chloro-2- (diphenylmethyleneamino) pyridine-4-yloxy) -3-fluorophenyl) -5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3 -N-(4- (2-Amino-3-chloropyridin-4-yloxy) -3-fluorophenyl)-by treating a THF solution of carboxamide (manufactured 3G) with excess HCl water at room temperature. An HCl salt of 5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxamide (Example 3) was obtained. The volatile matter was evaporated under reduced pressure to obtain the desired compound.

0106<u style="single">Example 4</u>Another Synthesis of 3-Chloro-N- (Diphenylmethylene) -4- (2-Fluoro-4-Nitrophenoxy) Pyridine-2-amine Manufacture 4A: 2,3-dichloropyridin-4-ol<chemistry num="80"><img id="000083" he="20" wi="18" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (4A) The first solution was prepared by dissolving 2.3-dichloropyridine (100 g, 0.68 mol) and triisopropyl borate (315 mL, 1.37 mol) in THF (150 mL). The resulting solution was cooled to -10 ° C. A second solution was prepared by dissolving diisopropylamine (150 mL, 1.07 mol) in THF (500 mL) in another reactor. The second solution was cooled to -10 ° C and n-butyllithium (420 mL, 1.05 mol) was added over 20 minutes under nitrogen. After stirring for 10 minutes, the second solution was slowly added to the first solution by vacuum transfer.

0107The reaction mixture was stirred at 22 ° C. for 3 hours until HPLC analysis showed completion of the reaction. Water (1.00 L) was added to the mixture, followed by sodium percarbonate (238 g) in two portions. The resulting mixture was stirred at 20 ° C for 1 hour. The pH of the mixture was adjusted to pH 2-3 by adding concentrated HCl (300 mL). Next, solid NaHSO₃(85g) was added. The aqueous layer was separated and extracted with toluene (150 mL). The organic layers were combined, washed with water (100 mL twice) and concentrated to about 500 mL by atmospheric distillation (distillation temperature up to 90 ° C). The resulting slurry was cooled to 20 ° C and filtered through a Büchner funnel. The cake was washed with heptane (100 mL twice) and then dried to give 2,3-dichloropyridin-4-ol (100.9 g, 91%) as a white solid.

0108Manufacture 4B: 2,3-dichloro-4- (2-fluoro-4-nitrophenoxy) pyridine<chemistry num="81"><img id="000084" he="30" wi="36" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (4B) In a 2 L chemigrass reactor, add 2,3-dichloropyridinol (90 g, 0.55 mol), 3,4-difluoronitrobenzene (100 g, 0.63 mol), lithium carbonate (59.4 g, 0.80 mol) and dimethyl sulfoxide (360 mL). added. The mixture was heated to 115 ° C for 21 hours until the reaction appeared to be complete by HPLC analysis. The mixture was cooled to 25 ° C., methanol (180 mL) was added, followed by water (960 mL). The mixture was neutralized by adding concentrated HCl (60 g) and the resulting slurry was stirred at 35 ° C. for 1 hour. After cooling to 28 ° C, the slurry was filtered through a Büchner funnel and the filtered cake was washed with water (4 times 250 mL). The unpurified cake was then suspended in methanol (20 mL) and water (250 mL) and the resulting mixture was stirred at 45 ° C for 20 minutes. After cooling to 25 ° C, the slurry was filtered. The resulting cake was washed with heptane (75 mL twice), dried under reduced pressure and as a yellow solid, 2,3-dichloro-4- (2-fluoro-4-nitrophenoxy) pyridine (164.68 g, 99%). Got

0109Manufacture 4C: 3-Chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) Pyridine-2-amine<chemistry num="82"><img id="000085" he="38" wi="41" file="JP5693239B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (4C) In a 2.5L chemigrass reactor, 2,3-dichloro-4- (2-fluoro-4-nitrophenoxy) pyridine (50g, 0.165mol), benzoimine (30g, 0.165mol), cesium carbonate (110g, 0.321mol), Palladium acetate (0.9 g, 4.0 mmol), racemic 2,2'-bis (diphenylphosphino) 1,1'-binaphthyl (3.25 g, 5.1 mmol), and xylene (300 mL) were added. The mixture was heated to 125 ° C for 11 hours. The mixture was cooled to 50 ° C. and silica gel (20 g) and xylene (300 mL) were added. The suspension was stirred at 50-55 ° C for 30 minutes and filtered through a Büchner funnel. The filtered cake was washed with xylene (100 mL twice). The filtrates were combined, washed with water (150 mL twice) and concentrated to approximately 150 mL by distillation on a rotary evaporator. After cooling to 25 ° C, heptane (300 mL) was added to the mixture. The resulting slurry was stirred at 25 ° C for 16 hours. Additional heptane (150 mL) was added to the slurry and the slurry was filtered through a Büchner funnel. Xylene cake 1:10 Washed with a mixture of heptane (100 mL) followed by n-heptane (twice 100 mL). After drying under reduced pressure, 3-chloro-N- (diphenylmethylene) -4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (47.41 g, 64%) was obtained.¹1 H NMR (CDCl₃) δ; MS (ESI⁺) m / z (M + H)⁺.