Process for manufacturing 6-perfluorophenyl benzoxazinones

Abstract

The present application relates to processes and intermediates used in the manufacture of polyfluorophenyl benzoxazinones.

Description

26327-20017.40PROCESS FOR MANUFACTURING 6-PERFLUOROPHENYL BENZOXAZINONESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 715,915, filed November 4, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] The present invention relates to processes and intermediates used in the manufacture of 6-pentafluorophenyl benzoxazinones.BACKGROUND

[0003] Herbicides that inhibit protoporphyrinogen oxidase (hereinafter referred to as Protox or PPO; EC:1.3.3.4), a key enzyme in the biosynthesis of protoporphyrin IX, have been used for selective weed control since the 1960s. PPO catalyzes the last common step in chlorophyll and heme biosynthesis, which is the oxidation of protoporphyrinogen IX to protoporphyrin IX [Matringe M. et al., Protoporphyrinogen oxidase as a molecular target for diphenyl ether herbicides, Biochemistry Journal (1989) 260: 231-235], Application of PPO- inhibiting herbicides results in the accumulation of protoporphyrinogen IX in the chloroplast and mitochondria, which is believed to leak into the cytosol where it is oxidized by a peroxidase. When exposed to light, protoporphyrin IX causes formation of singlet oxygen in the cytosol and the formation of other reactive oxygen species, which can cause lipid peroxidation and membrane disruption leading to rapid cell death [Lee H.J. et al., Cellular localization of protoporphyrinogen-oxidizing activities of etiolated barley leaves, Plant Physiology (1993) 102: 881],

[0004] PPO-inhibiting herbicides having a benzoxazinone core have been described in the literature. See Hao, et al., Protoporphyrinogen oxidase inhibitor: an ideal target for herbicide discovery, Chimia (2011), Vol. 65(12), pgs. 961-969. Methods of their manufacture have also been reported. See U.S. Pat. No. 9,359,312. A common element found in commercially-available PPO benzoxazinone herbicides is a heterocyclic ring at the benzoxazinone 6-position. To date, no registered benzoxazinone herbicide has a phenyl ring at this position. The present invention describes methods of preparing such compounds, where the phenyl ring is further substituted with 5 fluorine atoms.1MF-36131289826327-20017.40BRIEF SUMMARY

[0005] Provided herein are methods of preparing fluorinated phenyl PPO inhibitors that have high herbicidal activity, even at low application rates.

[0006] Accordingly, provided is a method of preparing a compound of formula I:or a salt thereof, wherein:R1is alkyl, alkenyl, alkynyl, cyclopropyl, CFE-cycloalkyl, or alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(O)Rla, Rlb, and up to 3 F or Cl atoms;Rlais ORlb, CH2OC(O)alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2alkyl, or NHORlb; and each Rlbis, independently, H, cycloalkyl, CH2phenyl, or alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlb.DETAILED DESCRIPTION

[0007] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by,” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, or method that includes or comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.2MF-36131289826327-20017.40

[0008] Further, unless expressly stated to the contrary, “or” refers to an inclusive ‘or’ and not to an exclusive ‘or.’ For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0009] Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0010] In the above recitations, the term “alkyl,” used either alone or in compound words includes straight-chain or branched alkyl, such as, methyl, ethyl, / / -propyl, z-propyl, or the different butyl, pentyl, or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1 -propenyl, 2-propenyl, and the different butenyl, pentenyl, and hexenyl isomers. “Alkenyl” also includes polyenes such as 1 ,2-propadienyl and 2,4- hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1- propynyl, 2-propynyl, and the different butynyl, pentynyl, and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.

[0011] “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0012] The total number of carbon atoms in a substituent group is indicated by the “Ci- Cj” or “Ci-j” prefix, where i and j are numbers from 1 to 10. For example, Ci-4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2 alkoxyalkyl designates CH3OCH2-; C3 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CH2OCH2-; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.

[0013] When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, the substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (R^m, where m is 0, 1, 2 or 3. Further, when the subscript indicates a range, e.g. (R)i-j, then the number of substituents may be selected from the integers between ‘i’ and ‘j’ inclusive. When a group3MF-36131289826327-20017.40 contains a substituent, which can be hydrogen (H), for example, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to the group being unsubstituted. When a variable group is shown to be optionally attached to a position, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be “not substituted” or “unsubstituted,” then hydrogen atoms are attached to take up any free valency.

[0014] The term “optionally substituted” in connection with the heterocyclic rings refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the biological activity possessed by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated. The term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term “(un)substituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.Preparation of Compounds of the Invention

[0015] A wide variety of synthetic methods are known in the art to enable preparation of aromatic and nonaromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve-volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.

[0016] One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus, a wide variety of salts of compounds of the invention are useful for control of undesired vegetation (i.e. are agriculturally suitable). The salts of compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic, or valeric acids. When a compound of the invention contains an acidic moiety such as a carboxylic acid or phenol, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine, or ammonia, or amides,4MF-36131289826327-20017.40 hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium, or barium.

[0017] In some embodiments, compounds of Formula I can be prepared as shown in Scheme 1.Scheme 1

[0018] As shown in step 1 of Scheme 1, compounds of Formula A may be prepared by reacting 2,4-difluoronitrobenzene with a halogenating agent, for example in the presence of sulfuric acid, to form a compound of Formula A, wherein Rxis I. As shown in step 2 of Scheme 1, compounds of Formula B may be prepared by hydroxylating a compound of Formula A, for example in the presence of KOH, THF, and water, to form a compound of5MF-36131289826327-20017.40Formula B, wherein Rxis I. As shown in step 3 of Scheme 1, compounds of Formula D may be prepared by reacting a compound of Formula B with a compound of Formula C, for example in the presence of a suitable copper catalyst, such as copper idodide, 1,10- phenanthroline, K3PO4, and DMF, to form a compound of Formula D, wherein Rxis I and Rzis H. As shown in step 4 of Scheme 1, compounds of Formula E may be prepared by reducing a compound of Formula D, for example in the presence of Na2S2O4, Na2COj, MeOH, THF, and water, to form a compound of Formula E. As shown in step 5 of Scheme 1, compounds of Formula G may be prepared by reacting a compound of Formula E with a compond of Formula F, for example in the presence of DIPEA and MeOH, to form a compound of Formula G. As shown in step 6 of Scheme 1, compounds of Formula H may be prepared by cyclizing a compound of Formula G, for example in the presence of K2CO3 and DMF, to form a compound of Formula H. As shown in step 7 of Scheme 1, compounds of Formula I may be prepared by reacting a compound of Formula H with a compound of Formula J, for example in the presence of K2CO3 and DMF, to form a compound of Formula I, wherein Ryis a suitable leaving group, and wherein R1is alkyl, alkenyl, alkynyl, cyclopropyl, CH2- cycloalkyl, or alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(O)Rla, Rlb, and up to 3 F or Cl atoms; Rlais ORlb, CH2OC(O)alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2alkyl, or NHORlb; and each Rlbis, independently, H, cycloalkyl, CH2phenyl, or alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlb.

[0019] It should be understood that certain compounds in Scheme 1 above, including for example the compounds of Formulas A, B, C, D, E, F, and H, as well as 2,4- difluoronitrobenzene, 1,10-phenanthroline, and other reagents used, may be obtained from any commercially available sources, or produced according to any methods or techniques known in the art.

[0020] In some embodiemnts of the compound of Formula I, R1is, where Rlbis H, alkyl, or cyclopropyl. In a further embodiment, Rlbis H. In another embodiment, R1is CH(CH3)C(O)OCi-4alkyl. In another embodiment, R1is CH(CH3)C(O)OH.6MF-36131289826327-20017.40

[0021] In one embodiment, the compound of Formula I is:salt thereof.

[0022] In one aspect, provided is a method of preparing a compound of Formula I as described herein, or a salt thereof, according to Scheme 1-A:Scheme 1-A

[0023] In some embodiments, the method comprises: reacting a compound of Formula B with a compound of Formula C in the presence of a copper catalyst to produce a compound of Formula D, wherein the compounds of Formula B, Formula C, and Formula D have the following structures: wherein Rxis iodide,or a salt thereof, wherein Rzis hydrogen, and7MF-36131289826327-20017.40subjecting the compound of Formula D to the following reactions: i) reducing the nitro group to an amino group, ii) alkylating the hydroxyl group, and iii) amidating the amino group, to produce a compound of Formula H:or a salt thereof; and alkylating the compound of Formula H, or a salt thereof, at the amide nitrogen with an alkylating agent of Formula J, having the structure of:R’-R' (J) wherein R1is as defined for Formula I and Ryis a suitable leaving group, to produce the compound of Formula I, or a salt thereof.

[0024] In certain variations of the foregoing, the copper catalyst is a copper (I) catalyst. In certain variations, the copper catalyst comprises copper (I). In certain variations, the copper catalyst comprises copper (I) halide. In one variation, the copper catalyst comprises copper bromide or copper iodide. In other variations, the copper catalyst comprises a bidentate ligand. In another variation, the bidentate ligand comprises 1,10-phenanthroline.

[0025] In certain variations of the foregoing, R1is an alkyl, alkenyl, alkynyl, or alkylidenyl group. In certain variations, R1is an alkyl group optionally substituted with an alkyl, alkenyl, alkynyl, or aryl group. In certain variations, R1is -CH2CCH.8MF-36131289826327-20017.40

[0026] In certain variations of the foregoing, the suitable leaving group of Ryis mesylate, tosylate, nonaflate, or triflate. In other variations, the suitable leaving group is a halide. In one variation, the suitable leaving group is chloride, bromide, or iodide

[0027] In certain variations, the alkylating agent is an alkyl chloride, an alkyl bromide, or an alkyl iodide. In some variations, the alkylating agent is a propargyl halide or a propargyl sulfonate. In some variations, the alkylating agent is an alkyl mesylate, an alkyl nonaflate, an alkyl triflate, or an alkyl tosylate. In some variations, the alkylating agent is propargyl chloride, propargyl bromide, propargyl iodide, propargyl mesylate, propargyl nonaflate, propargyl triflate, or propargyl tosylate.

[0028] In certain embodiments, the compound of Formula B is prepared by reacting a compound of Formula A, having the structure of:or a salt thereof, wherein Rxis as defined in Formula B, with a suitable base in the presence of water.

[0029] In some variations of the foregoing, the suitable base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, calcium carbonate, magnesium carbonate, rubidium carbonate, rubidium bicarbonate, caesium carbonate, caesium bicarbonate, strontium carbonate, or barium carbonate. In some variations, the suitable base comprises a metal hydroxide. In some variations, the suitable base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide or barium hydroxide. In some variations, the suitable base comprises a trialkylamine. In some variations, the suitable base comprises trimethylamine, triethylamine, tributylamine, tripropylamine, triisopropylamine, trihexylamine, or diisopropylethylamine. In certain variations, any combination of the bases described herein may also be used.

[0030] In other embodiments, the compound of Formula B is prepared by reacting a compound of Formula A, having the structure of:9MF-36131289826327-20017.40or a salt thereof, wherein Rxis as defined in Formula B, under basic conditions in the presence of water.

[0031] In some variations, reducing the nitro group to an amino group comprises: reducing a compound of Formula D:or a salt thereof, to produce a compound of Formula E:or a salt thereof.

[0032] The compound of Formula D may be reduced to the compound of Formula E under suitable conditions and the ues of suitable reagents. In some variations, the compound of Formula D is subjected to catalytic hydrogenation under a hydrogen atmosphere. In some variations, the compound of Formula D is reacted with a a metal in the presence of acid. In some variations, the compound of Formula D is reacted with a metal hydride. In some variations, the compound of Formula D is reacted with sodium dithionate.

[0033] In some variations, alkylating the hydroxyl group comprises: reacting a compound of Formula E:10MF-36131289826327-20017.40with a compound of Formula F:to produce a compound of Formula G:or a salt thereof.

[0034] The hydroxyl group of the compound of Formula E may be alkylated to yield the compound of Formula G under suitable conditions and the ues of suitable reagents. In some variations, the compound of Formula E is alkylated by reacting the compound of Formula E with an alkyl halide or alkyl sulfonate in the presence of a base. In some variations, the compound of Formula E is alkylated by reacting the compound of Formula E with an alkyl chloride, alkyl bromide, or alkyl iodide in the presence of a base. In some variations, the base is a metal carbonate or metal bicarbonate. In some variations, the base is a trialkylamine. In some variations, the base is diisopropylethylamine. In some variations, the compound of Formula E is reacted with ethyl 2-bromo-2,2-difluoroacetate. In some variations, the hydroxyl group is alkylated by reacting the compound of Formula E with ethyl 2-bromo-2,2- difluoroacetate in the presence of diisopropylethylamine.

[0035] In some variations, amidating the amino group comprises: reacting a compound of Formula G:11MF-36131289826327-20017.40or a salt thereof, with a suitable base, to produce a compound of Formula H:or a salt thereof.

[0036] In certain variations, amidating the amino group comprises: reacting a compound of Formula G:or a salt thereof, under basic conditions to produce a compound of Formula H:or a salt thereof.12MF-36131289826327-20017.40

[0037] The amino group of the compound of Formula G may be amidated to yield the compound of Formula H under suitable conditions and the ues of suitable reagents. For example, in certain variations, the suitable base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, calcium carbonate, magnesium carbonate, rubidium carbonate, rubidium bicarbonate, caesium carbonate, caesium bicarbonate, strontium carbonate, or barium carbonate. In some variations, the suitable base comprises a metal hydroxide. In some variations, the suitable base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide or barium hydroxide. In some variations, the suitable base comprises a trialkylamine. In some variations, the suitable base comprises trimethylamine, triethylamine, tributylamine, tripropylamine, triisopropylamine, trihexylamine, or diisopropylethylamine. In certain variations, any combination of the bases described herein may also be used.

[0038] In some variations, the method comprises: i) reacting a compound of Formula B with a compound of Formula C to yield a compound of Formula D, ii) reducing the nitro group of a compound of Formula D to yield a compound ofFormula E, iii) alkylating the hydroxyl group of a compound of Formula E to yield a compound of Formula G:iv) amidating the amino group of a compound of Formula G to yield a compound ofFormula H:13MF-36131289826327-20017.40v) alkylating the amide group of a compound of Formula H to yield a compound of Formula I.

[0039] In another aspect, provided is a method of preparing a compound of formula I as described herein, or a salt thereof, according to Scheme 1-B:Scheme 1-B

[0040] In some embodiments, the method comprises: contacting a compound of Formula G:with a suitable base to yield a compound of Formlua H:14MF-36131289826327-20017.40 or a salt thereof; and alkylating the amide group in the compound of Formula H to yield the compound ofFormula I.

[0041] In some variations, the suitable base comprises a metal carbonate. In some variations, the suitable base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, calcium carbonate, magnesium carbonate, rubidium carbonate, rubidium bicarbonate, caesium carbonate, caesium bicarbonate, strontium carbonate, or barium carbonate. In some variations, the suitable base comprises a metal hydroxide. In some variations, the suitable base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide or barium hydroxide. In some variations, the suitable base comprises a trialkylamine. In some variations, the suitable base comprises trimethylamine, triethylamine, tributylamine, tripropylamine, triisopropylamine, trihexylamine, or diisopropylethylamine. In certain variations, any combination of the bases described herein may also be used.

[0042] In some embodiments, the method comprises: contacting a compound of Formula G:under basic conditions to yield a compound of Formlua H:or a salt thereof; and15MF-36131289826327-20017.40 alkylating the amide group in the compound of Formula H to yield the compound ofFormula I.

[0043] In some embodiments, alkylating the amide group in the compound of Formula H comprises: contacting the compound of Formula H, or a salt thereof, with a compound of Formula J:R’-R' (J), or a salt thereof, wherein R1is as defined for Formula I and Ryis a suitable leaving group, to produce the compound of Formula I.

[0044] In certain variations of the foregoing, R1is an alkyl, alkenyl, alkynyl, or alkylidenyl group. In certain variations, R1is an alkyl group optionally substituted with an alkyl, alkenyl, alkynyl, or aryl group. In certain variations, R1is -CFfcCCH.

[0045] In certain variations of the foregoing, the suitable leaving group of Ryis mesylate, tosylate, nonaflate, or triflate. In other variations, the suitable leaving group is a halide. In one variation, the suitable leaving group is chloride, bromide, or iodide.

[0046] In certain variations, the compound of Formula J is an alkyl halide or an alkyl sulfonate. In some variations, the compound of Formula J is an alkyl chloride, an alkyl bromide, or an alkyl iodide. In some variations, the compound of Formula J is an alkyl mesylate, an alkyl nonaflate, an alkyl triflate, or an alkyl tosylate. In some variations, the compound of Formula J is a propargyl halide or a propargyl sulfonate. In some variations, the compound of Formula J is propargyl bromide, propargyl mesylate, propargyl nonaflate, propargyl triflate, or propargyl tosylate.

[0047] In another aspect, provided is a method of preparing a compound of formula I as described herein, or a salt thereof, according to Scheme 1-C:16MF-36131289826327-20017.40Scheme 1-C

[0048] In some embodiments, the method comprises: reacting a compound of Formula B or a salt thereof in the presence of a copper catalyst with a compound of Formula C to yield a compound of Formula D, wherein the compounds of Formula B, Formula C, and Formula D have the following structures:or salts thereof; reducing the nitro group of a compound of Formula D or a salt thereof, yielding a compound of Formula E:(E) 5 or a salt thereof; alkylating the compound of Formula E or a salt thereof with an alkylating agent ofFormula F:17MF-36131289826327-20017.40to produce a compound of Formula G:or a salt thereof; and amidating the amino group of the compound of Formula G or a salt thereof, to produce a compound of Formula H:or a salt thereof; and alkylating the compound of Formula H at the amide nitrogen with an alkylating agent of Formula J, having the structure of:R’-R' (J) wherein R1is as defined for Formula I and Ryis a suitable leaving group, to produce the compound of Formula I.

[0049] In certain variations of the foregoing, the copper catalyst is a copper (I) catalyst. In certain variations, the copper catalyst comprises copper (I). In certain variations, the copper catalyst comprises copper (I) halide. In one variation, the copper catalyst comprises copper bromide or copper iodie. In other variations, the copper catalyst comprises a bidentate ligand. In another variation, the bidentate ligand comprises 1,10-phenanthroline.18MF-36131289826327-20017.40

[0050] In certain variations of the foregoing, R1is an alkyl, alkenyl, alkynyl, or alkylidenyl group. In certain variations, R1is an alkyl group optionally substituted with an alkyl, alkenyl, alkynyl, or aryl group. In certain variations, R1is -CH2CCH.

[0051] In certain variations of the foregoing, the suitable leaving group of Ryis mesylate, tosylate, nonaflate, or triflate. In other variations, the suitable leaving group is a halide. In one variation, the suitable leaving group is chloride, bromide, or iodide.

[0052] In certain variations, the alkylating agent is an alkyl halide or an alkyl sulfonate. In some variations, the alkylating agent is an alkyl chloride, an alkyl bromide, or an alkyl iodide. In some variations, the alkylating agent is a propargyl halide or a propargyl sulfonate. In some variations, the alkylating agent is an alkyl mesylate, an alkyl nonaflate, an alkyl triflate, or an alkyl tosylate. In some variations, the alkylating agent is propargyl chloride, propargyl bromide, propargyl iodide, propargyl mesylate, propargyl nonaflate, propargyl triflate, or propargyl tosylate.

[0053] In another aspect provided is a method of preparing a compound of formula H as described herein, or a salt thereof, according to Scheme 1-D:Scheme 1-DAs noted herein, the compound of Formula H may be used to produce the compound ofFormula I.

[0054] In some embodiments, the method comprises: amidating the amino group of a compound of Formula G:19MF-36131289826327-20017.40or a salt thereof.

[0055] In another aspect, provided is a compound selected from:salts of any of the foregoing.

[0056] In one aspect, provided is a compound having the structure:salt thereof.

[0057] In another aspect, provided is a composition, comprising: a compound of Formula G:20MF-36131289826327-20017.40or a salt thereof, wherein Rylis a suitable leaving group; and and a compound of Formula H:or a salt thereof.

[0058] In some variations, the suitable leaving group of Rylis Ci-Ce alkoxy. In some variations, Rylis ethoxy and the compound of Formula G’ is a compound of Formula G.

[0059] In another aspect, provided is a composition comprising a compound of FormulaI, having the structure of:or a salt thereof, wherein:R1is alkyl, alkenyl, alkynyl, cyclopropyl, CH2-cycloalkyl, or alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(O)Rla, Rlb, and up to 3 F or Cl atoms;Rlais ORlb, CH2OC(O)alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2alkyl, or NHORlb; and21MF-36131289826327-20017.40 each Rlbis, independently, H, cycloalkyl, CFfcphenyl, or alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlb. wherein the composition has no detectable amounts of non-copper metal.

[0060] In some embodiments of the foregoing, the composition has no detectable amount of palladium.

[0061] In some variations of the foregoing aspect and embodiments,R1is Ci-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, cyclopropyl, CH2C3-6 cycloalkyl, or Ci- 2 alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(O)Rla, Rlb, and up to 3 F or Cl atoms;Rlais ORlb, CH2OC(O)CI-4alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2CI-4alkyl, or NHORlb; and each Rlbis, independently, H, C3-6 cycloalkyl, CFfc-phenyl, or CM alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or C1-4 alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlb.

[0062] In some embodiments of the compound of Formula I, R1iswhere Rlbis H, alkyl, or cyclopropyl. In a further embodiment, Rlbis H. In another embodiment, R1is CH(CH3)C(O)OCi-4alkyl. In another embodiment, R1is CH(CH3)C(O)OH.

[0063] In one embodiment, the compound of Formula I is:22MF-36131289826327-20017.40salt thereof.EXAMPLES

[0064] The presently disclosed subject matter will be better understood by reference to the following examples, which are provided as exemplary of the invention, and not by way of limitation.

[0065] Steps in the following examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a procedure described in other Examples or Steps.1H-NMR spectra are reported in ppm downfield from tetramethylsilane; “s” means singlet, “d” means doublet, “t” means triplet, “q” means quartet, “m” means multiplet, “dd” means doublet of doublets, “dt” means doublet of triplets, and “br s” means broad singlet. Mass spectra (MS) are reported as the molecular weight of the highest isotopic abundance parent ion (M+l) formed by addition of H+(molecular weight of 1) to the molecule, or (M-l) formed by the loss of H+(molecular weight of 1) from the molecule, observed by using liquid chrom“tog”aphy coupled to a mass spectrometer (LCMS) using either atmospheric pressure chemical ionization (AP+) where "amu" stands for unified atomic mass units or electrospray ionization (ES+).23MF-36131289826327-20017.40Example 1. Preparation of an Exemplary Compound of Formula IScheme 2

[0066] As shown in Step 1 of Scheme 2, a 50 L reactor vessel was charged with sulfuric acid (8 L) at RT (20 - 25 °C) followed by the addition of 2,4-difluoronitrobenzene (Compound 1, 2.0 kg, 1.0 equiv.) at RT and rinsing the addition port was with sulfuric acid (2 L) at RT. The reaction mixture was cooled to -3 to 0 °C and A-iodosuccinimide (NIS, 1.52 kg, 0.54 equiv.) was added under an atmosphere of nitrogen slowly in 5 lots, maintaining the internal reaction temperature below 5 °C. After addition was complete, the mixture was stirred for 30 minutes at 0 - 5 °C, then slowly warmed to RT over 30 minutes and stirred for 5 h at RT. Dichloromethane (16 L) was added and the reaction mixture stirred for 30 min at RT. The mixture was allowed to stand for 30 min until clear layer separation was observed. The organic layer was washed with 8% w / w aqueous sodium bicarbonate solution (10 L) at RT followed by washing with 8% aqueous sodium thiosulphate solution (10 L) at RT. The24MF-36131289826327-20017.40 volatiles were removed under reduced pressure at 35 - 40 °C to a volume of 6 L, THF (6 L) added, and the distillation continued to reduce the volume again to 6 L. HPLC analysis indicated that the resulting crude l,5-difluoro-2-iodo-4-nitrobenzene (Compound 2) was 90% pure. A small aliquot was removed, worked up, and characterized:1H-NMR (CDCh, 400 MHz) 5 8.45 (dd, J = 8.1, 6.3 Hz, 1H), 7.00 (dd, J = 10.4, 7.1 Hz, 1H);13C-NMR (CDCh, 101 MHz) 5 164.94 (dd, JC-F = 258.1, 11.1 Hz), 156.68 (dd, JC-F = 269.2, 12.0 Hz), 136.62 (dd, JC-F = 4.5, 2.4 Hz), 106.74 (d, JC-F = 29.0 Hz), 106.49 (d, JC-F = 29.0 Hz), 74.85 (dd, JC-F = 28.3, 4.6 Hz);19F-NMR (CDC13, 376 MHz) 5 -78.25 (d, J = 15.3 Hz), -111.23 (d, J = 15.3 Hz). The 90% pure crude material was carried forward in Step 2 as is.

[0067] As shown in Step 2 of Scheme 2, after cooling the l,5-difluoro-2-iodo-4- nitrobenzene mixture from Step 1 to RT, 20% aq. KOH (3 L) was added and the mixture heated to 46 - 50 °C and stirred at this temperature for 12 hours. After cooling to RT, agitation was stopped and the mixture allowed to stand until phase separation was affected. The bottom aqueous layer was discarded and the top organic layer washed with aqueous brine (2 x 3 L) and neutralized with acetic acid. The volatiles were removed under reduced pressure at 45 °C until a volume of 3 L was reached, followed by the addition of isopropyl alcohol (6 L). Distillation at reduced pressure was continued as 45 °C until a volume of 2 L was reached, at which time the desired product (Compound 3, 5-fluoro-4-iodo-2-nitrophenol) began to precipitate. Additional isopropyl alcohol (10 L) was added and the reaction mixture heated to 52 °C to obtain a clear solution. After the addition of 1.2 L of water a precipitate formed. The mixture was allowed to stand for 1 hour and water (4 L) was added over 1 hour while cooling the mixture slowly to RT. The resulting slurry was filtered and washed with cold isopropanol / water (1:1), collected, and dried under reduced pressure at 40 °C to afford 5- fluoro-4-iodo-2-nitrophenol (Compound 3, 2.20 kg, 62% yield over 2 steps): H NMR (CDCh, 400 MHz,) 5 10.60 (s, 1H), 8.46 (d, J = 6.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H);13C- NMR (CDCh, 101 MHz) 5 166.43 (d, JC-F = 258.0 Hz), 157.07 (d, JC-F = 14.0 Hz), 135.96 (d, JC-F = 5.3 Hz), 106.65, 106.37, 69.94 (d, JC-F = 29.0 Hz);19F-NMR (CDC13, 376 MHz) 5 -77.99.

[0068] As shown in Step 3 of Scheme 2, a 30 L reactor equipped with a condenser was charged with DMF (3.5 L) at 20 - 25 °C under a positive stream of N2 and 5-fluoro-4-iodo-2- nitrophenol (Compound 3, 1.0 kg, 3.53 mol, 1.00 equiv.) along with 1,10-phenanthroline (150 g, 0.25 equiv.) were added. The mixture was agitated and sparged with nitrogen and25MF-36131289826327-20017.40 potassium phosphate tribasic (3 kg, 4.0 equiv.) was added and the mixture heated to 40 - 45 °C. Copper iodide (135 g, 0.2 equiv.) was added to the mixture followed by the addition of pentafluorobenzene (0.89 kg, 1.5 equiv.). The mixture was heated to 80 - 85 °C and heating continued for 24 hours. The mixture was cooled to 25 °C and methyl / -butyl ether (MTBE, 5 L) was added with stirring, followed by allowing the mixture to stand for 2 hours. The resulting top organic layer was decanted and saved. Additional MTBE (4 L) and DMF (I L) were added to the reactor and the resulting slurry was stirred for 30 mins, the stirring stopped, and the top organic layer decanted and combined to the previously decanted organic layer. 2 M aq. HC1 was added slowly to the combined organic layers until a neutral pH was obtained (about 2 L 2N HC1). The mixture was washed with water, 10% aq. sodium thiosulphate, and 10% aq. sodium chloride, followed by distillation of the organics under reduced pressure to a volume of 3.5 L. Methanol was added in two 5 L lots and distillation continued after each lot addition to a volume of 5 L to remove residual MTBE to less than 1%. The resulting mixture was heated to 40 - 45 °C result! ng in a clear solution and 1 L of water added followed by cooling to 35 °C. The resulting slurry was stirred for 1 hour followed by the addition of additional water in two lots. The first lot (I L) was added over 1 hour, followed by the addition of the second lot (10 L) over 1.5 h. The resulting slurry was cooled to 20 - 25 °C at 0.5 C / min and allowed to stand for 1 hour after the addition was complete. The resulting solid was collected by filtration, washed with 1:1 v / v MeOH / water (1.5 L), water (3 x 1.5 L), and dried in a vacuum oven for 20 h at 45 °C to provide 2,2',3',4',5',6'-hexafluoro-5-nitro-[l,T- biphenyl]-4-ol (Compound 4, 1.06 kg, 93% yield): ’ H-NMR (DMSO-de, 400 MHz) 5 12.10 (brs, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz.;19F-NMR (376 MHz, DMSO) 5 - 103.44 (t, J = 12.0 Hz), -140.73 to -140.80 (m), -153.78 (t, J = 16.0 Hz), -162.23 to -162.37 (m).

[0069] As shown in Steps 4 and 5 of Scheme 2, to a 30 L jacketed reactor equipped with a condenser, 6 L water was added followed by the addition of Na2S2O4 (2.20 kg, 6.0 equiv.) and the resulting slurry was cooled to 10 °C. Na2CCL (1.48 kg, 5.9 L of a 20% aqueous solution, 6 equiv.) was added portion-wise over 1.5 hours maintaining the internal temperature at less than 25 °C. The reaction mixture was cooled to 10 °C and 2,2’,3',4',5’,6’- hexafluoro-5-nitro-[l,T-biphenyl]-4-ol (Compound 4, 750 g, 2.32 mol, 1 equiv.) dissolved in EtOH (6 L, 10 V) was added slowly to the mixture, keeping internal temperature below 25 °C. The mixture was warmed to 20 - 25 °C and stirred for 3 hours. The top organic layer was decanted, 6 L of water was added to the mixture followed by the addition of 5 L MTBE. The26MF-36131289826327-20017.40 resulting biphasic mixture was stirred for 30 minutes and the top MTBE layer collected and saved after stirring was stopped. The aqueous layer was washed with 2 L MTBE and organic layer combined with the previously saved organics. The combined organics were washed with 10% aq. brine (2 x 3 L) and MTBE was distilled off under reduced pressure to a volume of 2 L. MTBE (5 L) was added and the distillation under reduced pressure was repeated. The process of MTBE addition and removal by disti I lation was continued until the water content of the mixture was less than 0.2 weight percent. A small aliquot of the organic layer was removed and concentrated under reduced pressure to provide -amino-2,2',3',4',5',6'- hexafluoro-[l,T -biphenyl] -4-ol (Compound 5) as an off-white solid^H-NMR (400 MHz, DMSO-d6) 5 6.67 (d, J = 11.1 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H);19F-NMR (376 MHz, DMSO-d6) 5 -127.59 (t, J = 10.0 Hz), -141.38 (ddd, J = 24.7, 10.5, 7.9 Hz), -155.94 (t, J = 22.3 Hz), -162.93 (ddd, J = 24.7, 22.0, 7.6 Hz);13C-NMR (101 MHz, DMSO) 5 151.53 (d, J = 236.6 Hz), 147.10 (d, J = 10.5 Hz), 144.24 (d, J = 243.7 Hz), 141.98 - 135.48 (m), 134.27 (d, J = 2.0 Hz), 115.22 (d, J = 3.0 Hz), 112.80 to 110.02 (m), 102.54 (d, J = 25.1 Hz).

[0070] To the remaining MTBE layer containing Compound 5 was added triethylamine (970 mL, 3 equiv.) at 20 - 25 °C, followed by the addition of ethyl bromodifluoroacetate (298 mL, 1.3 equiv.). The mixture heated to 50 - 54 °C at this temperature for 16 hours. The mixture was then cooled to 10 - 15 °C and the organic layer quenched with 13% aq. citric acid (4 L), maintaining the internal temperature below 25 °C. The mixture was agitated for 30 minutes followed by removal of the aqueous layer. The organics were washed with water (3 L) and distilled to a volume of 3 L, followed by the addition of / / -heptane (3 L). Distillation at less than 75 °C was continued to a volume of 2.5 L, at which time a precipitate forms. Additional / / -heptane (3.5 L) was added and distillation continued at 70 - 75 °C to a volume of 2.5 L. / / -Heptane (500 mL) was added at 70 - 75 °C followed by the addition of isopropyl alcohol (75 mL). The mixture was stirred at 70 - 75 °C for 1 hour, cooled to 20 °C over 2 hours and stirred an additional 1 hour at 20 °C. The product was collected by filtration, washed with n-heptane (3 x 1 L), and dried under vacuum at 40 °C to produce ethyl 2-((5- amino-2,2',3',4',5',6'-hexafluoro-[l,T-biphenyl]-4-yl)oxy)-2,2-difluoroacetate (Compound 6, 675 g, 70 % yield):1H-NMR (400 MHz, DMSO-d6) 5 7.48 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 11.2 Hz, 1H);19F-NMR (376 MHz, DMSO-d6) 5 -60.00, -113.22, -141.10 (ddd, J = 24.6, 10.8, 7.7 Hz), -154.95 (t, J = 22.2 Hz), -159.32 to -164.22 (m).27MF-36131289826327-20017.40

[0071] As shown in Steps 6 and 7 of Scheme 2, a reaction vessel was charged with ethyl 2-((5-amino-2,2',3',4',5',6'-hexafluoro-[l,r-biphenyl]-4-yl)oxy)-2,2-difluoroacetate (Compound 6, 3.0 kg, 1.0 equiv.), followed by the addition of DMF (5 L) and K2CO3 (1.02 kg, 1.2 equiv.) at room temperature under an atmosphere of nitrogen. The suspension was then heated to 50 - 60 °C and the mixture stirred at this temperature for 12 h. A small aliquot was removed and worked up to provide 2,2,7-trifluoro-6-(perfluorophenyl)-2H- benzo[Z?][l,4]oxazin-3(4Z / )-one (Compound 7): ’ H-NMR (DMSO-de, 400 MHz) 5 12.21 (s, 1H), 7.69 (d, J = 9.9 Hz, 1H), 7.23 (d, J = 6.6 Hz, 1H);13C-NMR (101 MHz, DMSO-d6) 5 155.5 (d, JC-F = 246.2 Hz), 153.3 (t, JC-F = 37.3 Hz), 144.3 (dm, JC-F = 246.7 Hz), 141.3 (dm, JC-F = 257.4 Hz), 140.03 (d, JC-F = 12.7 Hz), 137.8 (dm, JC-F = 246.1 Hz), 122.6 (dm, JC-F = 2.9 Hz), 119.3 (s), 113.2 (t, JC-F = 262.5 Hz), 110.4 (d, JC-F = 17.9 Hz), 108.7 (td, JC-F = 18.6, 3.7 Hz), 106.5 (d, JC-F = 28.3 Hz) ppm;19F-NMR (376 MHz, DMSO) 5 -75.13, -116.76 (t, J = 10.0 Hz), -141.13 (dt, J = 24.5, 8.0 Hz), -153.51 (t, J = 22.3 Hz), -155.41 to - 172.00 (m) ppm; LCMS: m / z [M-l]’ calculated for C14H3F8NO2 368.00; found 367.7.

[0072] The remaining reaction mixture was cooled to 20 - 30 °C, propargyl mesylate (1.35 kg, 1.5 equiv.) added, and the mixture stirred at 35 °C for 4 hours. The mixture was cooled to 15 - 25 °C and 2 M aq. HC1 solution (I L) was added slowly, maintaining the internal temperature at less than 35 °C. To the resulting solution was added MTBE (2.5 L), followed by the addition of water (2.5 L). The mixture was distilled under reduced pressure to a volume of 2 L and / / -propanol (3 L) was added. The resulting slurry was reduced in volume under reduced pressure and the resulting solid collected by filtration.Recrystallization from n-propanol / water provided 2,2,7-trifluoro-6-(perfluorophenyl)-4- (prop-2-yn- l -yl)-2 / / -benzo|6|| 1 ,4]oxazin-3(4H)-one (Compound 8, 2.50 kg, 85 % yield):XH- NMR (DMSO-de, 400 MHz) 5 7.80 - 7.75 (two overlapping d, 2H), 4.88 (d, J = 4 Hz, 2H), 3.45 (t, J = 4 Hz, 1H);13C-NMR (101 MHz, DMSO-de) 5 -74.85, -115.53 (t, 11.3 Hz), (-) 140.44 to -140.51 (m), -153.05, -161.91 to -162.02.28MF-361312898

Claims

26327-20017.40CLAIMSWhat is claimed is:

1. A method for preparing a compound of Formula I:or a salt thereof, wherein:R1is Ci-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, cyclopropyl, CH2C3-6 cycloalkyl, or C1-2 alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(0)Rla, Rlb, and up to 3 F or Cl atoms;Rlais ORlb, CH2OC(O)CI-4alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2Ci-4alkyl, or NHORlb; and each Rlbis, independently, H, C3-6 cycloalkyl, CFL-phenyl, or C1-4 alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or CM alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlb, the method comprising: reacting a compound of Formula B with a compound of Formula C in the presence of a copper catalyst to produce a compound of Formula D, wherein the compounds of Formula B, Formula C, and Formula D have the following structures:29MF-36131289826327-20017.40 wherein Rxis iodide,5 or a salt thereof, wherein Rzis hydrogen, and(D) 5 or a salt thereof; subjecting the compound of Formula D to the following reactions: i) reducing the nitro group to an amino group, ii) alkylating the hydroxyl group, and iii) amidating the amino group, to produce a compound of Formula H:30MF-36131289826327-20017.40 or a salt thereof; and alkylating the compound of Formula H, or a salt thereof, at the amide nitrogen with an alkylating agent of Formula J:R’-R' (J) wherein R1is as defined for Formula I and Ryis a suitable leaving group, to produce the compound of Formula I, or a salt thereof.

2. The method of claim 1, wherein the compound of Formula B is prepared by reacting a compound of Formula A:or a salt thereof, wherein Rxis as defined in Formula B, with a suitable base or under basic conditions in the presence of water.

3. The method of claim 1 or 2, wherein reducing the nitro group to an amino group comprises: reducing a compound of Formula D:or a salt thereof, to produce a compound of Formula E:31MF-36131289826327-20017.40or a salt thereof.

4. The method of any one of claims 1-3, wherein alkylating the hydroxyl group comprises: reacting a compound of Formula E:with a compound of Formula F:to produce a compound of Formula G:or a salt thereof.

5. The method of any one of claims 1-4, wherein amidating the amino group comprises:32MF-36131289826327-20017.40 reacting a compound of Formula G:or a salt thereof, with a suitable base or under basic conditions, to produce a compound of Formula H:or a salt thereof.

6. The method of any one of claims 1-5, wherein the method comprises: i) reach ng the compound of Formula B with the compound of Formula C to yield a compound of Formula D:ii) reducing the nitro group of the compound of Formula D to yield a compound of Formula E:33MF-36131289826327-20017.40iii) alkylating the hydroxyl group of the compound of Formula E to yield a compound of Formula G:iv) amidating the amino group of the compound of Formula G to yield a compound ofFormula H:v) alkylating the amide group of the compound of Formula H to yield the compound of Formula I.

7. A method for preparing a compound of Formula I:34MF-36131289826327-20017.40 or a salt thereof, wherein:R1is Ci-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, cyclopropyl, CH2C3-6 cycloalkyl, or C1-2 alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(0)Rla, Rlb, and up to 3 F or Cl atoms;Rlais ORlb, CH2OC(O)CI-4alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2CI-4alkyl, or NHORlb; and each Rlbis, independently, H, C3-6 cycloalkyl, CFF-phenyl, or C1-4 alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or CM alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)2 and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlb, the method comprising: contacting a compound of Formula G:with a suitable base or under basic condi tions to yield a compound of FormulaH:35MF-36131289826327-20017.40 or a salt thereof; and alkylating the amide group in the compound of Formula H to yield the compound of Formula I.

8. The method of claim 7, wherein alkylating the amide group in the compound of Formula H comprises: contacting the compound of Formula H, or a salt thereof, with a compound of Formula J:R'-R' (J), or a salt thereof, wherein R1is as defined for Formula I and Ryis a suitable leaving group, to produce the compound of Formula I.

9. A method for preparing a compound of Formula I:or a salt thereof, wherein:R1is Ci-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, cyclopropyl, CH2C3-6 cycloalkyl, or C1-2 alkyl-phenyl, each optionally substituted with C(O)Rla, CH2C(0)Rla, Rlb, and up to 3 F or Cl atoms;Rlais ORlb, CH2OC(O)CI-4alkyl, C(O)ORlb, N(Rlb)(Rlc), ON(Rlb)(Rlc), NHN(Rlb)(Rlc), NHS(O)2N(Rlb)2, NHS(O)2Ci-4alkyl, or NHORlb; and each Rlbis, independently, H, C3-6 cycloalkyl, CFF-phenyl, or C1-4 alkyl optionally substituted with up to 3 F or Cl atoms; and Rlcis H or CM alkyl optionally substituted with C(O)ORlbor Rlband Rlctogether with an intervening nitrogen atom form a 4 to 6 membered heterocyclic ring, optionally containing an additional atom or group selected from N, O, S, S(O)236MF-36131289826327-20017.40 and optionally substituted with one or more groups selected from -C(O)ORlband -C(O)Rlbthe method comprising: reacting a compound of Formula B or a salt thereof in the presence of a copper catalyst with a compound of Formula C to yield a compound of Formula D, wherein the compounds of Formula B, Formula C, and Formula D have the following structures:or salts thereof; reducing the nitro group of a compound of Formula D or a salt thereof, yielding a compound of Formula E:37MF-36131289826327-20017.40 or a salt thereof; alkylating the compound of Formula E or a salt thereof with an alkylating agent ofFormula F:to produce a compound of Formula G:or a salt thereof; and amidating the amino group of the compound of Formula G or a salt thereof, to produce a compound of Formula H:or a salt thereof; and alkylating the compound of Formula H at the amide nitrogen with an alkylating agent of Formula J, having the structure of:R’-R' (J) wherein R1is as defined for Formula I and Ryis a suitable leaving group,38MF-36131289826327-20017.40 to produce the compound of Formula I.

10. A method for preparing a compound of Formula H, the method comprising: amidating the amino group of a compound of Formula G:or a salt thereof, to produce a compound of Formula H:or a salt thereof.

11. The method of any one of claims 1-6 and 9, wherein the copper catalyst comprises copper (I).

12. The method of claim 11, wherein the copper catalyst comprises copper (I) iodide.

13. The method of claim 11, wherein the copper catalyst comprises copper (I) bromide.

14. The method of any one of claims 1-6, 9, or 11-13, wherein the copper catalyst comprises a bidentate ligand.

15. The method of claim 14, wherein the bidentate ligand comprises 1,10-phenanthroline.

16. The method of any one of claims 1-9, and 11-15, wherein R1is -CH2CCH.39MF-36131289826327-20017.4017. The method of any one of claims 1-9, and 11-15, wherein the compound of Formula Ior a salt thereof.

18. A compound having the structure:or a salt thereof.

19. A composition comprising: a compound of Formula G’ :or a salt thereof, wherein Rylis Ci-Ce alkoxy; and and a compound of Formula H:40MF-36131289826327-20017.40or a salt thereof.41MF-361312898

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