Process for producing 6-perfluorophenylbenzooxazinon

Abstract

This application relates to a process and intermediates used in the production of polyfluorophenylbenzooxazinon.

Description

Detailed description of the invention

[0001] [Cross-reference of related applications] This application claims priority to U.S. Provisional Patent Application No. 63 / 502,350, filed on 15 May 2023, and U.S. Provisional Patent Application No. 63 / 502,346, filed on 15 May 2023, each of which is incorporated herein by reference in its entirety.

[0002] [Technical Field] This invention relates to steps and intermediates used in the production of 6-pentafluorophenylbenzooxazinon.

[0003] [Background technology] 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 final common step in the biosynthesis of chlorophyll and heme, namely 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]. It is thought that when PPO-inhibiting herbicides are sprayed, protoporphyrinogen IX accumulates in chloroplasts and mitochondria, leaks into the cytoplasm, and is oxidized by peroxidase. When exposed to light, protoporphyrin IX induces the formation of singlet oxygen and other reactive oxygen species in the cytosol, which can lead to lipid peroxidation and membrane disruption, potentially resulting in rapid cell death [Lee HJet al., Cellular localization of protoporphyrinogen-oxidizing activities of etiolated barley leaves, Plant Physiology (1993) 102:881].

[0004] PPO inhibitor herbicides having benzoxazinone as the 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 for their production have also been reported. See U.S. Patent No. 9,359,312. An element frequently seen in commercially available PPO benzoxazinone herbicides is the heterocycle at the 6-position of benzoxazinone. To date, there has been no registration of benzoxazinone herbicides having a phenyl ring at this position. The present invention describes a method for preparing such compounds, in which the phenyl ring is further substituted with five fluorine atoms.

[0005] Summary of the Invention This specification provides a method for preparing a fluorinated phenyl PPO inhibitor having high herbicidal activity even at a low application rate.

[0006] Therefore, a method for preparing a benzoxazinone having the formula (I):

Chemical formula

[0007] [Modes for carrying out the invention] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains,” “containing,” “characterized by,” or any other variation thereof, are intended to encompass non-exclusive inclusions and are subject to any express limitations. For example, a composition, mixture, process, or method that is included in or contains an element is not necessarily limited to that element alone and may include other elements not expressly enumerated or that are specific to such composition, mixture, process, or method.

[0008] Furthermore, unless explicitly stated otherwise, "or" refers to an inclusive "or" rather than an exclusive "or." For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0009] Furthermore, the indefinite articles "a" and "an" preceding an element or component of the present invention are not limiting in terms of the number of instances (i.e., frequency of occurrence) of that element or component. Thus, "a" or "an" should be interpreted as including one or at least one, and the singular form of the element or component also includes its plural form unless its number clearly indicates singular.

[0010] In the above description, the term "alkyl," used alone or in compound terms such as "alkylthio" or "haloalkyl," includes linear or branched alkyls, such as methyl, ethyl, n-propyl, i-propyl, or various butyl, pentyl, or hexyl isomers. "Alkenyl" includes linear or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and various butenyl, pentenyl, and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes linear or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl, and various butynyl, pentynyl, and hexynyl isomers. "Alkynyl" also includes moieties consisting of multiple triple bonds, such as 2,5-hexadienyl.

[0011] "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and various butoxy, pentoxy, and hexyloxy isomers.

[0012] The examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0013] When the terms "halogen" or "halo" are used alone, in compound words such as "haloalkyl," or in descriptions such as "halogen-substituted alkyl," they include fluorine, chlorine, bromine, or iodine.

[0014] The total number of carbon atoms in the substituent is "C i -C j " or "C i-j It is indicated by the prefix "j". Here, i and j are numbers from 1 to 10. For example, C 1-4 Alkylsulfonyls range from methylsulfonyl to butylsulfonyl, C2 alkoxyalkyls represent CH3OCH2-, C3 alkoxyalkyls represent, for example, CH3CH(OCH3)-, CH3OCH2CH2-, or CH3CH2OCH2-, and C4 alkoxyalkyls represent various isomers of alkyl groups substituted with alkoxy groups containing a total of four carbon atoms, examples of which include CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.

[0015] If a compound is substituted with substituents that have a subscript indicating that the number of substituents may be greater than one, the substituents (if greater than one) are defined as a group of substituents, e.g., (R 1 ) m Selected independently from, where m is 0, 1, 2, or 3. Furthermore, if a subscript indicates a range, for example, (R) ijIn this case, the number of substituents can be selected from an integer between 'i' and 'j'. If a group contains a substituent (which could be hydrogen (H)), and this substituent is hydrogen, then it is recognized as equivalent to an unsubstituted group. If a variable group is shown to be bonded at an arbitrary position, then hydrogen may be present at that position even if it is not stated in the definition of a variable group. If one or more positions of a group are said to be "unsubstituted", then a hydrogen atom is bonded there and can have any free valence.

[0016] In relation to heterocycles, the term “optionally substituted” refers to a group having at least one non-hydrogen substituent that does not cause the non-substituted or unsubstituted analogue to lose its biological activity. Where used herein, unless otherwise specified, the following definitions shall apply: The term “optionally substituted” is used interchangeably with the phrases “substituted or unsubstituted” or the term “(un)substituted.” Unless otherwise indicated, an optionally substituted group may have substituents at each of its substituted positions, and each substitution is independent of the others.

[0017] The term "active ester" refers to an activated carboxylic acid ester that can react with an amino group to form an amide. Examples of active esters include intermediate products resulting from the reaction of carboxylic acids with carbodiimides, uronium salts, and phosphonium salts. Methods for preparing active esters are described by Hollanders, et al., A New Wave of Amide Bond Formations for Peptide Synthesis, Synthesis (2019), Vol. 51(11), pages 2261-2277, and by Albericio & El-Faham, Choosing the Right Coupling Reagent for Peptides: A Twenty-Five-Year Journey, Organic Process Research & Development (2018), Vol. 22(7), pages 760-772, the entire contents of which are incorporated herein by reference.

[0018] Preparation of the compound of the present invention A wide variety of synthetic methods are known in the art that enable the preparation of aromatic and non-aromatic heterocycles and cyclic systems. For detailed reviews, please refer to Comprehensive Heterocyclic Chemistry, AR Katritzky and CWRees editors-in-chief, Pergamon Press, Oxford, 1984 (8 volumes) and Comprehensive Heterocyclic Chemistry II, AR Katritzky, CWRees and EFVScriven editors-in-chief, Pergamon Press, Oxford, 1996 (12 volumes).

[0019] Those skilled in the art will recognize that, under environmental and physiological conditions, salts of chemical substances are in equilibrium with their corresponding unsalted forms, and therefore salts share the biological utility of their unsalted forms. Accordingly, a wide variety of salts of the compounds of the present invention are useful (i.e., agrochemically suitable) for the management of undesirable vegetation. Salts of the compounds of the present invention include acid addition salts with inorganic or organic acids, such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, butyric acid, fumaric acid, lactic acid, maleic acid, malonic acid, oxalic acid, propionic acid, salicylic acid, tartaric acid, 4-toluenesulfonic acid, or valeric acid. If the compounds of the present invention contain an acidic moiety such as a carboxylic acid or phenol, the salts may also include those formed with organic or inorganic bases, such as pyridine, triethylamine, or ammonia, or amides, sodium, potassium, lithium, calcium, magnesium, or barium hydrides, hydroxides, or carbonates.

[0020] Scheme A1 In some embodiments, the compound of formula (I) can be prepared as shown in scheme A1. [ka] As shown in step 1 of scheme A1, the compound of formula (c) can be prepared by acylating the aniline of formula (a) with compound formula (b) in the presence of a non-nucleophilic base (wherein X is Br or I). 1 It can be F or Cl, or L 1C(O) may be an alkyl ester or an active ester. Suitable bases include trialkylamines such as ethyldiisopropylamine, or other non-nucleophilic bases, such as inorganic hydrides (e.g., sodium hydride), non-nucleophilic alkoxides (e.g., sodium or potassium tert-butoxide), or inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium phosphate, or potassium phosphate). The compound of formula (c) can be isolated as a phenol or as a phenolate salt (d), or it can be directly cyclized in the presence of a non-nucleophilic base similar to that used in step 1, as shown in step 2, to form the compound of formula (e). As shown in step 3, the compound of formula (e) can be reacted with 2 to 2.5 equivalents of alkyllithium reagent at a low temperature of -30°C to -78°C to form a dilithio intermediate, which can then be directly reacted with hexafluorobenzene at a low temperature of -30°C to -78°C, as shown in step 4, and then warmed to 25°C to form the compound of formula (f). As shown in step 5, the compound of formula (f) is given by formula RL 2 It can be N-alkylated with the compound, in which L 2 is a leaving group such as iodine, bromo, chloro, or sulfonate, or L 2 R is an intermediate produced as a result of the reaction with diazodicarboxylate in the Mitsunobu reaction. 1-6 Alkyl, C 3-4 Alkenil, C 3-4 Alkinyl, Cyclopropyl, CH2C 3-6 Cycloalkyl, phenyl, or C 1-2 It can be an alkylphenyl, each of which is arbitrarily selected, C(O)R 1a Or CH2C(O)R 1a Substitutions are made, each optionally, by up to 3 F atoms or Cl atoms, and each C 1-6 Alkyl is also optional, OR 1b It is substituted with, and in the formula, R 1a is OR 1b CH2OC(O)C 1-4 Alkyl, C(O)OR 1b , N(R 1b )(R1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1-4 Alkyl, or NHOR 1b And each R 1b H and C are independent of each other. 3-6 Cycloalkyl, CH2phenyl, or C substituted with up to three optionally substituted F or Cl atoms 1-4 It is alkyl, R 1c H, or optionally C(O)OR 1b C is replaced by 1-4 Alkyl or R 1b and R 1c However, together with the intervening nitrogen atom, it forms a 4-6 membered heterocycle and optionally contains an additional atom or group selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b It is replaced by one or more elements selected from the following.

[0021] Therefore, in one embodiment, a compound of formula (I) described herein, or a salt thereof: [ka] A method for preparing this is provided, which includes, Reacting a compound of formula (a) or a salt thereof with a base and a compound of formula (b) to produce a compound of formula (c) or a salt thereof. [ka] [In the formula, X is Br, L 1 is either F or Cl, or L 1 C(O) is an alkyl ester or an active ester, and it produces an amide or a salt thereof of formula (c)]. Treating the compound of formula (c) with a base to form an intermediate of formula (d), and then forming a compound of formula (e).

Chem.

Chem.

Chem.

[0022] It should be understood that the compounds of formula (a) can be obtained from any commercially available source or generated according to any method or technique known in the art. For example, in some variations, the compounds of formula (a) can be obtained according to the following scheme:

Chemical formula

[0023] In one embodiment, the compound of formula (a), or a salt thereof, is the compound

Chemical formula

[0024] In another embodiment, X is introduced without using a protecting group (i.e., R p (Since it is H, the deprotection step is not necessary).

[0025] In one embodiment, compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one. In another embodiment, compound (e) is 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazine-3(4H)-one.

[0026] In another embodiment, compound (e) is reacted with 2.0 to 2.5 equivalents of an alkyllithium reagent such as n-butyllithium or secondary butyllithium in an aprotic solvent such as pentane, hexane, heptane, methyl tert-butyl ether, THF, 2-methyl-THF, or a mixture thereof at -30°C to -78°C.

[0027] In one embodiment, R is [ka] And in the formula, R 1b is H, alkyl, or cyclopropyl. In further embodiments, R 1b H is H.

[0028] In another embodiment, R is CH(CH3)C(O)OC 1-4 It is alkyl.

[0029] In another embodiment, R is CH(CH3)C(O)OH.

[0030] In another embodiment, [ka] Compounds selected from those salts are also provided.

[0031] In one embodiment, [ka] A compound selected from the above is provided.

[0032] In another embodiment, [ka] Compounds selected from these salts are provided.

[0033] In further embodiments, [ka] A compound selected from the above is provided.

[0034] Scheme B1 In other embodiments, the compound of formula (I) can be prepared as shown in scheme B1. [ka] As shown in step 1 of scheme B1, the compound of formula (c) can be prepared by acylating the aniline of formula (a) with compound formula (b) in the presence of a non-nucleophilic base (wherein X is Br or I). 1 It can be F or Cl, or L 1 C(O) may be an alkyl ester or an active ester. Suitable bases include trialkylamines such as ethyldiisopropylamine, or other non-nucleophilic bases, such as inorganic hydrides (e.g., sodium hydride), non-nucleophilic alkoxides (e.g., sodium or potassium tert-butoxide), or inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium phosphate, or potassium phosphate). The compound of formula (c) can be isolated as a phenol or as a phenolate salt (d), or, as shown in step 2, can be directly cyclized in the presence of a non-nucleophilic base similar to that used in step 1 to form the compound of formula (e). As shown in step 3, the compound of formula (e) can be reacted with pentafluorobenzene in the presence of CuI and 1,10-phenanthroline to form the compound of formula (f). Other Cu(I) salts such as CuBr and CuCl can also be used. As shown in step 4, the compound of formula (f) can be cyclized into the compound of formula RL 2 It can be N-alkylated with the compound, in which L 2 is a leaving group such as iodine, bromo, chloro, or sulfonate, or L 2 R is an intermediate produced as a result of the reaction with diazodicarboxylate in the Mitsunobu reaction. 1-6 Alkyl, C 3-4 Alkenil, C 3-4 Alkinyl, Cyclopropyl, CH2C 3-6 Cycloalkyl, phenyl, or C 1-2 It can be an alkylphenyl, each of which is arbitrarily selected, C(O)R 1a Or CH2C(O)R 1a Substitutions are made, each optionally, by up to 3 F atoms or Cl atoms, and each C 1-6Alkyl is also optional, OR 1b It is substituted with, and in the formula, R 1a is OR 1b CH2OC(O)C 1-4 Alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1-4 Alkyl, or NHOR 1b And each R 1b H and C are independent of each other. 3-6 Cycloalkyl, CH2phenyl, or C substituted with up to three optionally substituted F or Cl atoms 1-4 It is alkyl, R 1c H, or optionally C(O)OR 1b C is replaced by 1-4 Alkyl or R 1b and R 1c However, together with the intervening nitrogen atom, it forms a 4-6 membered heterocycle and optionally contains an additional atom or group selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b It is replaced by one or more elements selected from the following.

[0035] Therefore, in one embodiment, a compound of formula (I) described herein, or a salt thereof: [ka] A method for preparing this is provided, which includes, Reacting a compound of formula (a) or a salt thereof with a base and a compound of formula (b) to produce a compound of formula (c) or a salt thereof. [ka] [In the formula, X is Br or I, and L 1is either F or Cl, or L 1 C(O) is an alkyl ester or an active ester, and it produces an amide or a salt thereof of formula (c)]. The compound of formula (c) is treated with a base to produce the intermediate of formula (d), and then the compound of formula (e) is produced. [ka] The compound of formula (e) is reacted with pentafluorobenzene in the presence of CuI and a copper ligand to produce the compound of formula (f). [ka] And the compound of formula (f) is alkylating agent L 2 -R[where L 2 [The reaction intermediate is either iodine, bromo, chloro, or sulfonate, or an alcohol, which is produced by reacting it with an azodicarboxylate in the Mitsunobu reaction] and alkylates it to produce the compound of formula (I). [ka] [In the formula, R is C 1-6 Alkyl, C 3-4 Alkenil, C 3-4 Alkinyl, Cyclopropyl, CH2C 3-6 Cycloalkyl, phenyl, or C 1-2 It is an alkylphenyl, and each is arbitrarily selected, C(O)R 1a CH2C(O)R 1a , R 1b , and substituted with up to 3 F atoms or Cl atoms, in the formula, R 1a is OR 1b CH2OC(O)C 1-4 Alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c), NHS(O)2N(R 1b )2, NHS(O)2C 1-4 Alkyl, or NHOR 1b And each R 1b H and C are independent of each other. 3-6 Cycloalkyl, CH2phenyl, or C substituted with up to three optionally substituted F or Cl atoms 1-4 It is alkyl, R 1c H, or optionally C(O)OR 1b C is replaced by 1-4 Alkyl or R 1b and R 1c However, together with the intervening nitrogen atom, it forms a 4-6 membered heterocycle and optionally contains an additional atom or group selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b This includes being replaced by one or more elements selected from the following.

[0036] In some embodiments, the compound of formula (e) is reacted with pentafluorobenzene in the presence of a Cu(I) salt and a copper ligand to produce the compound of formula (f). In some such embodiments, the Cu(I) salt is CuCl, CuBr, or CuI. In some such embodiments, the Cu(I) salt is CuCl. In some such embodiments, the Cu(I) salt is CuBr. In some such embodiments, the Cu(I) salt is CuI.

[0037] It should be understood that the compound of formula (a) can be obtained from any commercially available source, or produced according to any method or technique known in the art. For example, in some variations, the compound of formula (a) can be obtained according to the following scheme: [ka] [In the formula, R p[ is a suitable protecting group, where X is as defined for formula (a) above.] As shown in the scheme above, the initial compound undergoes substitution (step 1), deprotection (step 2), and then reduction (step 3) to obtain the compound of formula (a). However, those skilled in the art will understand that the compound of formula (a) can be produced by changing the order of substitution, deprotection, and reduction using suitable starting materials and reaction conditions.

[0038] In one embodiment, the compound of formula (a), or a salt thereof, is a compound [ka] Therefore, the compound of formula (a) is formed by reduction of the -NO2 group to form an -NH2 group in the compound of formula (a). In another embodiment, the compound of formula (a), or a salt thereof, is a compound [ka] [In the formula, R p is a suitable protecting group] which is formed from and the compound undergoes deprotection and reduction in either order. In yet another embodiment, the compound of formula (a), or a salt thereof, is a compound [ka] [In the formula, R p The compound is formed from a suitable protecting group, and under preferred conditions, it undergoes substitution, deprotection, and reduction in any preferred order.

[0039] In another embodiment, X is introduced without using a protecting group (i.e., R p (Since it is H, the deprotection step is not necessary).

[0040] In one embodiment, compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one. In another embodiment, compound (e) is 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazine-3(4H)-one.

[0041] In one embodiment, the reaction of pentafluorobenzene with the compound of formula (e) is carried out in DMF at 100°C to 140°C in the presence of K3PO4 and a bidentate ligand of Cu(I). In a further embodiment, the ligand is 1,10-phenanthroline. In yet another further embodiment, the bidentate ligand is selected from oxalic acid diamides such as 1,2-dimethylethylenediamine (DMEDA), trans-1,2-cyclohexanediamine (CyDA), trans-N,N'-dimethyl-1,2-cyclohexanediamine (DMCyDA), 2,2-bipyridine (BPY), or BTMPO, BPMPO, BPPO, BMPO, BHMPO, BBPO, BFMO, BTMO, DPEO, DBO, BNMO, PMPBO, PPBO, NFO, MNFO, MNBO, or MNPMO.

[0042] In one embodiment, R is [ka] And in the formula, R 1b is H, alkyl, or cyclopropyl. In further embodiments, R 1b H is H.

[0043] In another embodiment, R is CH(CH3)C(O)OC 1-4 It is alkyl.

[0044] In another embodiment, R is CH(CH3)C(O)OH.

[0045] In another embodiment, [ka] Compounds selected from those salts are also provided.

[0046] In one embodiment, [ka] A compound selected from the above is provided.

[0047] In another embodiment, [ka] Compounds selected from these salts are provided.

[0048] In further embodiments, [ka] A compound selected from the above is provided.

[0049] List of embodiments The following listed embodiments represent several aspects of the present invention. 1. Equation (I), [ka] Compounds of or salts thereof [in the formula, R is C 1-6 Alkyl, C 3-4 Alkenil, C 3-4 Alkinyl, Cyclopropyl, CH2C 3-6 Cycloalkyl, phenyl, or C 1-2 It is an alkylphenyl, and each is arbitrarily selected, C(O)R 1a CH2C(O)R 1a , R 1b , and substituted with up to 3 F atoms or Cl atoms, R 1a is OR 1b CH2OC(O)C 1-4Alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1-4 Alkyl, or NHOR 1b And, Each R 1b H and C are independent of each other. 3-6 Cycloalkyl, CH2phenyl, or C substituted with up to three optionally substituted F or Cl atoms 1-4 It is alkyl, R 1c H, or optionally C(O)OR 1b C is replaced by 1-4 Alkyl or R 1b and R 1c However, together with the intervening nitrogen atom, it forms a 4-6 membered heterocycle and optionally contains an additional atom or group selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b A process for manufacturing [which is replaced by one or more groups selected from], The compound of formula (a), or a salt thereof, is reacted with a non-nucleophilic base and the compound of formula (b) to produce the compound of formula (c), or a salt thereof. [ka] [In the formula, X is Br, L 1 is either F or Cl, or L 1 C(O) is an alkyl ester or an active ester, and it produces the amide of formula (c), or a salt thereof. The compound of formula (c), or a salt thereof, is treated with an additional non-nucleophilic base to produce the intermediate of formula (d), and then the compound of formula (e), or a salt thereof, [ka] The compound of formula (e), or a salt thereof, is reacted with 2 to 2.5 equivalents of an alkyllithium reagent to produce a dilithio intermediate, and then the dilithio intermediate is treated with hexafluorobenzene to produce the compound of formula (f), or a salt thereof. [ka] The compound of formula (f), or a salt thereof, is subjected to alkylating agent L. 2 -R[where L 2 [This is an intermediate resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with triphenylphosphine and azodicarboxylate in the Mitsunobu reaction] which is alkylated to produce the compound of formula (I) or a salt thereof, [ka] The process including the above.

[0050] 2. The step according to Embodiment 1, wherein compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one or a salt thereof.

[0051] 3. R ​​is, [ka] And in the formula, R 1b The step according to Embodiment 1, wherein the element is H, alkyl, or cyclopropyl.

[0052] 4.R 1b However, the process described in Embodiment 3 is H.

[0053] 5. R is CH(CH3)C(O)OC 1-4 The process according to Embodiment 1, wherein the alkyl group is used.

[0054] 6. The process according to Embodiment 1, wherein R is CH(CH3)C(O)OH.

[0055] 7. The step according to any one of Embodiments 1 to 6, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base.

[0056] 8. The step according to any one of Embodiments 1 to 6, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases.

[0057] 9. Structure:

Chemical formula

[0058] 10. The compound according to Embodiment 9, wherein the compound is an alkylammonium salt.

[0059] 11. The compound according to Embodiment 9, wherein the compound is

Chemical formula

[0060] 12. A step comprising: Combining a compound of formula (e), or a salt thereof, with 2 to 2.5 equivalents of an alkyllithium reagent under suitable conditions to form a dilithio intermediate, wherein the compound of formula (e), or a salt thereof, is

Chemical formula

Chemical formula

[0061] 13. The step according to Embodiment 12, wherein combining the compound of formula (e1) with the dilithio intermediate includes adding the compound of formula (e1) to the dilithio intermediate.

[0062] 14. The step according to Embodiment 12, wherein combining the compound of formula (e1) with the dilithio intermediate includes adding the dilithio intermediate to the compound of formula (e1).

[0063] 15. Combining a compound of formula (c) or a salt thereof with a non-nucleophilic base to produce a compound of formula (e) or a salt thereof, wherein the compound of formula (c) or a salt thereof is [ka] The step according to any one of embodiments 12 to 14, further comprising the combination of the formula, where X is Br.

[0064] 16. Combining the compound of formula (a) or a salt thereof with an additional non-nucleophilic base and the compound of formula (b) to produce the compound of formula (c) or a salt thereof, wherein the compounds of formula (a) and formula (b) are [ka] In the formula, X is Br, and L 1 is either F or Cl, or L 1 The step according to any one of embodiments 12 to 15, further comprising the combination of C(O) to form an alkyl ester or an activated ester group.

[0065] 17. The step according to Embodiment 16, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base when they are present at the same time.

[0066] 18. The step according to Embodiment 16, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases when they are present at the same time.

[0067] 19. Alkylate the compound of formula (f) or a salt thereof with an alkylating agent to obtain formula (I): [ka] The process involves producing a compound or a salt thereof, The alkylating agent is L 2 -R[wherein, L 2 These are reaction intermediates resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with azodicarboxylate in the Mitsunobu reaction. R is C 1-6 Alkyl, C 3-4 Alkenil, C 3-4 Alkinyl, Cyclopropyl, CH2C 3-6 Cycloalkyl, phenyl, or C 1-2 It is an alkylphenyl, and each is arbitrarily selected, C(O)R 1a CH2C(O)R 1a , R 1b , and substituted with up to 3 F atoms or Cl atoms, R 1a is OR 1b CH2OC(O)C 1-4 Alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1-4 Alkyl, or NHOR 1b and Each R 1b H and C are independent of each other. 3-6 Cycloalkyl, CH2phenyl, or C substituted with up to three optionally substituted F or Cl atoms 1-4is alkyl, R 1c is H, or optionally C(O)OR 1b substituted C 1-4 alkyl, or R 1b and R 1c together with the intervening nitrogen atom form a 4- to 6-membered heterocycle, optionally containing an additional atom or group selected from N, O, S, S(O)2, and optionally substituted with -C(O)OR 1b and -C(O)R 1b with one or more groups selected from], the step of alkylating, further comprising, according to any one of embodiments 12 to 18.

[0068] 20. Formula (I),

Chemical formula

[0069] 21. The step according to Embodiment 20, wherein the Cu(I) salt is CuCl, CuBr, or CuI.

[0070] 22. The step according to Embodiment 20 or Embodiment 21, wherein compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one or a salt thereof.

[0071] 23. The step according to Embodiment 20 or Embodiment 21, wherein compound (e) is 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazine-3(4H)-one or a salt thereof.

[0072] 24.R is, [ka] And in the formula, R 1b The step according to Embodiment 20 or Embodiment 21, wherein is H, alkyl, or cyclopropyl.

[0073] 25.R 1b However, the process described in Embodiment 24 is H.

[0074] 26. R is CH(CH3)C(O)OC 1-4 The step according to Embodiment 20 or Embodiment 21, wherein the alkyl group is used.

[0075] 27. The step according to Embodiment 20 or Embodiment 21, wherein R is CH(CH3)C(O)OH.

[0076] 28. The step according to any one of Embodiments 20 to 27, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base.

[0077] 29. The step according to any one of Embodiments 20 to 27, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases.

[0078] 30. Structure: [ka] A compound having, or a salt thereof.

[0079] 31. The compound according to Embodiment 30, wherein the compound is an alkylammonium salt.

[0080] 32. The compound is [ka] The compound described in Embodiment 30.

[0081] 33. Process, The compound of formula (e), or a salt thereof, is combined with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce the compound of formula (f), or a salt thereof. The compound of formula (e) above, or a salt thereof, [ka] In the formula, X is either Br or I, The compound of formula (f) above, or a salt thereof, [ka] The process includes the step of combining the above.

[0082] 34. The step according to Embodiment 33, wherein the Cu(I) salt is CuCl, CuBr, or CuI.

[0083] 35. Combining a compound of formula (c) or a salt thereof with a non-nucleophilic base to produce a compound of formula (e) or a salt thereof, wherein the compound of formula (c) or a salt thereof is [ka] The step according to Embodiment 33 or Embodiment 34, further comprising the aforementioned combination.

[0084] 36. Combining the compound of formula (a) or a salt thereof with an additional non-nucleophilic base and the compound of formula (b) to produce the compound of formula (c) or a salt thereof, wherein the compounds of formula (a) and formula (b) are [ka] And in the formula, L 1 is either F or Cl, or L 1 The step according to any one of embodiments 33 to 35, further comprising the combination of C(O) to form an alkyl ester or an activated ester group.

[0085] 37. The step according to Embodiment 36, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base when they are present at the same time.

[0086] 38. The step according to Embodiment 36, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases when they are present at the same time.

[0087] 39. Alkylate the compound of formula (f) or a salt thereof with an alkylating agent to obtain formula (I): [ka] The process involves producing a compound or a salt thereof, The alkylating agent is L 2 -R[wherein, L 2 These are reaction intermediates resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with triphenylphosphine and azodicarboxylate in the Mitsunobu reaction. R is C 1-6 Alkyl, C 3-4 Alkenil, C 3-4 Alkinyl, Cyclopropyl, CH2C 3-6 Cycloalkyl, phenyl, or C 1-2 It is an alkylphenyl, and each is arbitrarily selected, C(O)R 1a CH2C(O)R 1a , R 1b , and substituted with up to 3 F atoms or Cl atoms, R 1a is OR 1b CH2OC(O)C 1-4 Alkyl, C(O)OR 1b , N(R 1b )(R 1c ), ON(R 1b )(R 1c ), NHN(R 1b )(R 1c ), NHS(O)2N(R 1b )2, NHS(O)2C 1-4 Alkyl, or NHOR 1b and Each R 1b H and C are independent of each other. 3-6 Cycloalkyl, CH2phenyl, or C substituted with up to three optionally substituted F or Cl atoms 1-4 It is alkyl, R 1c H, or optionally C(O)OR 1b C is replaced by 1-4 Alkyl or R 1b and R 1cHowever, together with the intervening nitrogen atom, it forms a 4-6 membered heterocycle and optionally contains an additional atom or group selected from N, O, S, S(O)2, and optionally -C(O)OR 1b and -C(O)R 1b The step according to any one of embodiments 33 to 38, further comprising alkylating, which is substituted with one or more groups selected from.

[0088] [Examples] The subject matter of the present disclosure is provided as an example of the present invention and will not be limited thereto, and will be better understood by referring to the following embodiments.

[0089] The steps in the following examples describe the procedure of each step within the overall synthetic transformation, and the starting materials for each step are not necessarily prepared by the procedures described in other examples or steps. 1 ¹H NMR spectra are reported in ppm on the lower magnetic field side from tetramethylsilane, where 's' means single, 'd' means double, 't' means triple, 'q' means quadruple, 'm' means multiline, 'dd' means double double, 'dt' means double triple, and 'br s' means broad single. Mass spectra (MS) are obtained by atmospheric pressure chemical ionization (AP+) ('amu' represents unified atomic mass units) or electrospray ionization (ES). + H to molecules, observed by using liquid chromatography connected to a mass spectrometer (LCMS) using one of the following methods. + (M+1) is formed by the addition of (molecular weight 1), or H from the molecule. + (M-1), formed by the elimination of (molecular weight 1), is reported as the molecular weight of the parent ion with the highest isotopic abundance.

[0090] Example 1. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(propa-2-in-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] As shown in step 1 of scheme A2, concentrated sulfuric acid (600 mL) was added to a furnace-dried 5 L four-necked round-bottom flask connected to a nitrogen inlet, thermocouple, and overhead stirrer, and stirring was started. To the mixture, anhydrous triflulinic acid (16.5 g, 0.058 mol, 0.1 equivalent), followed by N-bromosuccinimide (NBS, 68.64 g, 0.385 mol, 0.6 equivalent), and the mixture was stirred at room temperature for 1 hour to obtain a deep red solution. To this stirring mixture, 5-fluoro-2-nitroanisole (100 g, 0.584 mol) was added at room temperature, and stirring was continued at room temperature for 1 hour. Additional NBS (45.76 g, 0.32 mol, 0.5 equivalent) was added, and stirring was continued at room temperature for a further 2 hours. The reaction mixture was cooled to 0-5°C, and ice water (1000 mL) was added gradually over 30 minutes (exothermic). The mixture was heated to room temperature and stirred for at least 2 hours to obtain a yellow suspension. The suspension was filtered, and the cake was washed with water (3 times), followed by washing with hexane (3 times). The wet cake was added to a 1 L three-necked round-bottom flask equipped with an overhead stirrer, followed by the addition of hexane (300 mL), and the resulting slurry was stirred at room temperature for at least 2 hours. The suspension was then filtered, the cake was washed with hexane (3 times), dried under reduced pressure for 1 hour, and then dried in a vacuum oven at 40°C for at least 12 hours to obtain 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (compound 1) as a pale yellow solid in 59% yield and 98.5% purity by HPLC. 1 H-NMR (DMSO-d6, 400 MHz) δ 8.35 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 10.8 Hz, 2 H), 3.95 (s, 3H) ppm; 13C-NMR (DMSO-d6, 101 MHz) δ 161.7 (d, JC-F = 252.0 Hz), 154.1 (d, JC-F = 10.9 Hz), 136.7 (d, JC-F = 3.2 Hz), 130.1 (d, JC-F = 3.10 Hz), 104.3 (d, JC-F = 28.29 Hz), 98.4 (d, JC-F = 23.6 Hz), 58.2 ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -97.01 ppm;EI-MS (M + ) Calculated value for C7H5BrFNO3: 348.94, measured value: 349.0.

[0091] In a similar manner, the reaction of 5-fluoro-2-nitroanisole with N-iodosuccinimide (NIS) produced 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (compound 2): 1 H-NMR (DMSO-d6, 400 MHz) δ 8.38 (d, J = 6.63 Hz, 1H), 7.43 (d, J = 10.1 Hz, 1H), 3.94 (s, 3H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 164.6 (d, JC-F = 249.3 Hz), 154.8 (d, JC-F = 11.0 Hz), 137.2 (d, JC-F = 2.47 Hz), 135.4 (d, JC-F = 5.5 Hz), 103.4 (d, JC-F = 30.5 Hz), 70.7 (d, JC-F = 29.63 Hz), 58.03 ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -84.35 ppm;EI-MS (M + ) Calculated value for C7H5FINO3: 296.93, measured value: 297.1.

[0092] As shown in step 2 of scheme A2, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (90.0 g, 89.6 wt%) and CH2Cl2 (5V) were added to a 3 L three-necked round-bottom flask equipped with an overhead stirrer and thermocouple, and the mixture was cooled to 0°C. A solution of 1 M BCl3-containing CH2Cl2 (2 equivalents) was slowly added using an addition funnel. The mixture was heated to room temperature and stirred for 18 hours. After this time, the mixture was cooled again to 0°C, an additional BCl3 (1 equivalent) was added, and stirring was continued at room temperature for a further 24 hours, at which point complete conversion of the starting materials was shown by HPLC analysis. The mixture was cooled to 0°C, treated with saturated NaHCO3 (5V), diluted with water, and extracted with CH2Cl2 (three times with 3-4V). The organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 4-bromo-5-fluoro-2-nitrophenol (compound 3, 85.3 g, 89 wt% by NMR, 98% yield) as a pale yellow solid: 1 H-NMR (DMSO-d6, 400 MHz) δ 11.78 (s, 1H), 8.26 (d, J = 7.4 Hz), 7.08 (d, J = 10.11 Hz) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 161.6 (d, JC-F = 252.9 Hz), 154.0 (d, JC-F = 12.32 Hz), 135.0 (d, JC-F = 2.57 Hz), 130.4 (d, JC-F = 3.42 Hz), 107.2 (d, JC-F = 26.00 Hz), 97.3 (d, JC-F = 23.64 Hz) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -97.92 ppm;EI-MS (M + ) Calculated value for C6H3BrFNO3: 234.93, measured value: 235.1.

[0093] In a similar manner, the reaction of 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (compound 2) with BCl3 yielded 5-fluoro-4-iodo-2-nitrophenol (compound 4): 1H-NMR (DMSO-d6, 400 MHz) δ 11.71 (br d, J = 8 Hz, 1H), 8.32 (d, J = 4 Hz, 1H), 6.98 (d, J = 12 Hz, 1H) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -85.37 ppm.

[0094] As shown in step 3 of scheme A2, 4-bromo-5-fluoro-2-nitrophenol (99 g, 0.407 mol) was added to a 2 L jacketed reactor equipped with a cooler, overhead stirrer, and thermocouple, followed by the addition of EtOH (7.5 V) and water (7.5 V). The mixture was stirred and cooled to 10-12°C (internal), and Na2S2O4 (212 g, 85% purity, 1.06 mmol) was gradually added to the resulting yellow suspension while maintaining the temperature below 30°C. The resulting suspension was gradually heated to 80°C and stirred at this temperature for 2 hours, at which point the suspension turned into a clear orange solution. The mixture was gradually cooled to room temperature, stirring was maintained overnight, and then EtOH was removed by distillation using a rotary evaporator at 40°C. The resulting yellow suspension was filtered, and the cake was washed with water, then hexane. The obtained solid was dried in a vacuum oven at 40°C for 12-14 hours to obtain 2-amino-4-bromo-5-fluorophenol (43.4 g, 87% by weight, 97% purity) as a yellow solid: 1 H-NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1H), 6.77 (d, J = 7.39 Hz), 6.61 (s, J = 10.06 Hz), 4.64 (br s, 1H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 150.1 (d, JC-F = 232.0 Hz), 144.7 (d, JC-F = 9.24 Hz), 135.5 (d, JC-F = 1.93 Hz), 116.2, 103.3 (d, JC-F = 25.18 Hz), 95.7 (d, JC-F = 21.42 Hz) ppm; 19F-NMR (DMSO-d6, 376.5 MHz) δ -123.75 ppm;EI-MS (M + ) Calculated value for C6H5BrFNO: 204.95, measured value: 205.0.

[0095] In a similar manner, 2-amino-5-fluoro-4-iodophenol (compound 6) was obtained by the reaction of 5-fluoro-4-iodophenol (compound 4) with Na2S2O4: EI-MS(M + ) Calculated value for C6H5FINO: 252.94, measured value: 253.1.

[0096] As shown in step 4 of scheme A2, diisopropylethylamine (DIEA, 6 equivalents) was added to a MeOH solution (10V) of 2-amino-4-bromo-5-fluorophenol (19.0 g) and bromodifluoroethyl acetate (3.0 equivalents) while stirring to obtain a reddish-orange solution. The mixture was stirred at room temperature for 2 hours, and volatile substances were removed by rotary evaporation at 30°C to obtain a yellow suspension. The solid was filtered, and the cake was washed with hexane until a clear filtrate was obtained (4 times at 3V). The obtained solid was dried under suction for 2 hours, then dried for 14 hours to obtain 4-bromo-2-(2-bromo-2,2-difluoroacetamide)-5-fluorophenolate, N-ethyl-N-isopropylpropane-2-aminium salt (compound 7, 44 g, yield 97%): EI-MS(M + ) Calculated value for C8H4BrF3NO2 (free base) is 360.86, measured value is 360.9.

[0097] In a similar manner, the reaction of 2-amino-5-fluoro-4-iodophenol with ethyl bromodifluoroethyl yielded 2-(2-bromo-2,2-difluoroacetamide)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropane-2-aminium salt: (compound 8).

[0098] As shown in step 5 of scheme A2, K2CO3 (2.5 equivalents) was added to a stirred DMF solution (10V) of 4-bromo-2-(2-bromo-2,2-difluoroacetamide)-5-fluorophenolate, N-ethyl-N-isopropylpropane-2-aminium salt (compound 7, 38.0 g), and the mixture was stirred at 50°C for 14 hours. The mixture was acidified with 2M HCl (aq) until the pH was 4-5, diluted with water, and extracted with siRNA (three times at 2V). The combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting dark brown wet solid was treated with water, stirred, and filtered. The resulting dark solid was made into a slurry in CH2Cl2 (3V), filtered, and the cake was washed with CH2Cl2, then washed with hexane (1V) to obtain the product as a pink solid (14.7 g, first sample). Following the same procedure, a second sample (4.6 g) was obtained from the CH2Cl2 mother liquor to obtain 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 9, 19.3 g, 74.8%): 1 H-NMR (DMSO-d6, 400 MHz) δ 12.08 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 6.7 Hz, 1H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 154.6 (d, JC-F = 242.1 Hz) 153.2 (d, JC-F = 37.62 Hz) 138.1 (dt, JC-F = 11.58 and 2.19 Hz), 123.2 (d, JC-F = 3.11 Hz), 120.2, 113.2 (d JC-F = 262.64 Hz), 107.1 (d, JC-F = 28.62 Hz), 104.0 (d, JC-F = 22.86 Hz) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -75.55, -111.73 ppm;EI-MS (M + ) Calculated value for C8H3BrF3NO2: 280.93, measured value: 281.0.

[0099] In a similar manner, 2-(2-bromo-2,2-difluoroacetamide)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropane-2-aminium salt (compound 8, 9.8 g, 23.67 mmol) and DMF (45 mL, 5V) were added to a 250 mL round-bottom flask, followed by the addition of K2CO3 (5.0 g, 48 mmol, 2 equivalents). The mixture was stirred at 50°C for 12 hours, cooled to room temperature, and the pH was adjusted to 7. The resulting aqueous phase was extracted with SiO2 (twice at 10V), the combined organic matter was washed with brine (10V), dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (100% hexane to 10% SiO2 / hexane) to obtain 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 10, 3.63g, 62% yield from compound 6) as an orange solid: 1 H-NMR (DMSO-d6, 400 MHz) 12.02 (br s, 1H), 7.46-7.44 (m, 2H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 157.7 (d, JC-F = 239.18 Hz), 153.2 (t, JC-F = 37.53 Hz), 138.9 (d, JC-F = 11.68 Hz), 125.6 (d, JC-F = 3.06 Hz), 123.5 (d, JC-F = 3.14 Hz), 113.2 (t, JC-F = 262.56 Hz), 106.0 (d, JC-F = 30.81 Hz), 77.3 (d, JC-F = 28.4 Hz) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -75.61, -98.86 ppm;EI-MS (M + ) Calculated value for C8H3F3INO2: 328.92, measured value: 329.1.

[0100] As shown in steps 6 and 7 of Scheme A2, 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 9, 0.5 g, 1.77 mmol) was placed in a 50 mL Schlenk flask, and anhydrous THF (3.5 mL), MTBE (3.5 mL), and heptane (3.5 mL) were added under a nitrogen atmosphere. The mixture was cooled to -78°C, and hexane containing 1.6 M n-BuLi (2.33 mL, 3.72 mmol, 2.1 equivalents) was added dropwise over 5 minutes. The mixture was stirred at -78°C for 20 minutes, and a THF solution of hexafluorobenzene (0.61 mL, 5.32 mmol, 3 equivalents) (5.0 mL) was added dropwise to the reaction mixture at -78°C for 5 minutes. The reaction temperature was raised to -40°C over 4 hours, the reaction was quenched with an aqueous NH4Cl solution, and the temperature was raised to 21°C. The reaction mixture was diluted, extracted with ELISA (3 times with 10 mL), dried over Na2SO4, filtered, volatile substances were removed under reduced pressure, and the crude product was purified by flash column chromatography (10% ELISA / hexane) to obtain 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 11, 0.36 g, yield 55%) as a white solid. 1 H-NMR (DMSO-d6, 400 MHz) δ 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) δ 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; 19 F-NMR (376 MHz, DMSO) δ -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~-172.00 (m) ppm;LCMS:m / z [M-1] - C 14 The calculated value of H3F8NO2 is 368.00, and the measured value is 367.7.

[0101] As shown in step 8 of scheme A2, 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 11, 200 mg, 0.54 mmol) was added to a DMF solution (2 mL) with K2CO3 (74 mg, 0.54 mmol) and 3-bromopropa-1-yne (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0-30% ethyl acetate in petroleum ether) to obtain 2,2,7-trifluoro-6-(perfluorophenyl)-4-(propa-2-in-1-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 12, 120 mg, yield 54%) as an off-white solid: GCMS (C 17 Calculated value for H5F8NO2) is 407.0, measured value is 407.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.81 - 7.67 (m, 2H), 4.88 (s, 2H), 3.45 (s, 1H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.85, -115.56, -140.50, -153.03, -162.01.

[0102] Compound 11 was reacted with a suitable alkyl halide or alkyl triflate by a procedure similar to that of step 8 of scheme A2 to produce the following compounds: 2,2,7-trifluoro-4-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 15 Calculated value for H5F8NO2) is 383.0, measured value is 383.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.87 - 7.62 (m, 2H), 3.43 (s, 3H); 19F-NMR (376 MHz, DMSO-d6) δ -74.05, -116.55, -140.32, -153.34, -162.15; 4-benzyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: Calculated value 459.1 and measured value 459.0 for GCMS (C21H9F8NO2); 1H-NMR (400 MHz, methanol-d4) δ 7.42 - 7.37 (m, 4H), 7.35 - 7.31 (m, 3H), 5.33 (s, 2H); 19F-NMR (376 MHz, methanol-d4) δ -78.80, -116.83, -142.52, -155.24 -164.83;

[0103] 4-allyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid. GCMS (C 17 Calculated value 409.0 and measured value 409.0 for H7F8NO2; 1H-NMR (400 MHz, DMSO-d6) δ 7.79 - 7.74 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 5.88 (m, 1H), 5.27 - 5.14 (m, 2H), 4.68 - 4.62 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.67, -116.18, -140.50, -153.27, -162.03;

[0104] 4-Ethyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 16 Calculated value for H7F8NO2) is 397.0, measured value is 397.0; 1H-NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.4 Hz, 1H), 7.78 - 7.72 (m, 1H), 4.05 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.60, -116.48, -140.36, -153.44, -162.15;

[0105] 2,2,7-trifluoro-6-(perfluorophenyl)-4-propyl-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 17 The calculated value for H9F8NO2 is 411.1, and the measured value is 411.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.82 - 7.72 (m, 2H), 3.98 (t, J = 7.2 Hz, 2H), 1.65 - 1.59 (m, 2H), 0.91 (t, J = 6.8 Hz, 3H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.70, -116.40, -140.10, -153.46, -162.12;

[0106] 4-(3-cyclopropylpropane-2-in-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 20 Calculated value for H9F8NO2) is 447.1, measured value is 447.1; 1 H-NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 6.4 Hz, 1H), 4.80 (s, 2H), 1.32 - 1.24 (m, 1H), 0.80 - 0.69 (m, 2H), 0.58 - 0.50 (m, 2H); 19F-NMR (376 MHz, DMSO-d6) δ -74.72, -115.70, -140.77, -153.12, -162.06;

[0107] 4-(buta-2-in-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 18 The calculated value for H7F8NO2 is 421.0, and the measured value is 421.1; 1 H-NMR (400 MHz, DMSO-d6) δ 7.78 - 7.73 (m, 2H), 4.83 - 4.78 (m, 2H), 1.78 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.68, -115.65, -140.58, -153.09, -161.96;

[0108] 2,2,7-trifluoro-4-(2-methylallyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 18 Calculated value for H9F8NO2) is 423.0, measured value is 423.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 4.92 - 4.88 (m, 1H), 4.72 - 4.66 (m, 1H), 4.56 (s, 2H), 1.75 (d, J = 1.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.05, -116.00, -140.57, -153.23, -162.01;

[0109] 2,2,7-trifluoro-6-(perfluorophenyl)-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 16 H4F 11Calculated value for NO2) 451.0, measured value 451.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 5.08 - 4.97 (m, 2H); 19 F-NMR (400 MHz, DMSO-d6) δ -67.95, -75.15, -115.30, -140.49, -152.81, -161.86;

[0110] 2,2,7-trifluoro-4-(2-fluorobenzyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: MS (ESI) (C 21 Calculated value for H8F9NO2) [M+1] + 478.2, measured value 477.9; 1 H-NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.33 - 7.21 (m, 2H), 7.18 - 7.16 (m, 1H), 5.32 (s, 2H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.91, -115.69, -117.44, -140.68, -153.15, -162.02;

[0111] 2,2,7-trifluoro-4-isopropyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a pale yellow solid: GCMS (C 17 Calculated value for H9F8NO2) is 411.0, measured value is 411.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.72 - 7.62 (m, 2H), 5.41 - 5.30 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H); 19F-NMR (400 MHz, DMSO-d6) δ -67.27, -112.83, -140.84, -153.73, -162.21.

[0112] Example 2. Preparation of 2,2,7-trifluoro-6-(perfluorophenyl)-4-(propa-2-in-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] As shown in step 1 of scheme B2, concentrated sulfuric acid (600 mL) was added to a furnace-dried 5 L four-necked round-bottom flask connected to a nitrogen inlet, thermocouple, and overhead stirrer, and stirring was started. To the mixture, anhydrous triflulinic acid (16.5 g, 0.058 mol, 0.1 equivalent), followed by N-bromosuccinimide (NBS, 68.64 g, 0.385 mol, 0.6 equivalent), and the mixture was stirred at room temperature for 1 hour to obtain a deep red solution. To this stirring mixture, 5-fluoro-2-nitroanisole (100 g, 0.584 mol) was added at room temperature, and stirring was continued at room temperature for 1 hour. Additional NBS (45.76 g, 0.32 mol, 0.5 equivalent) was added, and stirring was continued at room temperature for a further 2 hours. The reaction mixture was cooled to 0-5°C, and ice water (1000 mL) was added gradually over 30 minutes (exothermic). The mixture was heated to room temperature and stirred for at least 2 hours to obtain a yellow suspension. The suspension was filtered, and the cake was washed with water (3 times), followed by washing with hexane (3 times). The wet cake was added to a 1 L three-necked round-bottom flask equipped with an overhead stirrer, followed by the addition of hexane (300 mL), and the resulting slurry was stirred at room temperature for at least 2 hours. The suspension was then filtered, the cake was washed with hexane (3 times), dried under reduced pressure for 1 hour, and then dried in a vacuum oven at 40°C for at least 12 hours to obtain 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (compound 1) as a pale yellow solid in 59% yield and 98.5% purity by HPLC. 1H-NMR (DMSO-d6, 400 MHz) δ 8.35 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 10.8 Hz, 2 H), 3.95 (s, 3H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 161.7 (d, JC-F = 252.0 Hz), 154.1 (d, JC-F = 10.9 Hz), 136.7 (d, JC-F = 3.2 Hz), 130.1 (d, JC-F = 3.10 Hz), 104.3 (d, JC-F = 28.29 Hz), 98.4 (d, JC-F = 23.6 Hz), 58.2 ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -97.01 ppm;EI-MS (M + ) Calculated value for C7H5BrFNO3: 348.94, measured value: 349.0.

[0113] In a similar manner, the reaction of 5-fluoro-2-nitroanisole with N-iodosuccinimide (NIS) produced 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (compound 2): 1 H-NMR (DMSO-d6, 400 MHz) δ 8.38 (d, J = 6.63 Hz, 1H), 7.43 (d, J = 10.1 Hz, 1H), 3.94 (s, 3H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 164.6 (d, JC-F = 249.3 Hz), 154.8 (d, JC-F = 11.0 Hz), 137.2 (d, JC-F = 2.47 Hz), 135.4 (d, JC-F = 5.5 Hz), 103.4 (d, JC-F = 30.5 Hz), 70.7 (d, JC-F = 29.63 Hz), 58.03 ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -84.35 ppm;EI-MS (M + ) Calculated value for C7H5FINO3: 296.93, measured value: 297.1.

[0114] As shown in step 2 of scheme B2, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (90.0 g, 89.6 wt%) and CH2Cl2 (5V) were added to a 3 L three-necked round-bottom flask equipped with an overhead stirrer and thermocouple, and the mixture was cooled to 0°C. A solution of 1 M BCl3-containing CH2Cl2 (2 equivalents) was slowly added using an addition funnel. The mixture was heated to room temperature and stirred for 18 hours. After this time, the mixture was cooled again to 0°C, an additional BCl3 (1 equivalent) was added, and stirring was continued at room temperature for a further 24 hours, at which point complete conversion of the starting materials was shown by HPLC analysis. The mixture was cooled to 0°C, treated with saturated NaHCO3 (5V), diluted with water, and extracted with CH2Cl2 (three times at 3-4V). The organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 4-bromo-5-fluoro-2-nitrophenol (compound 3, 85.3 g, 89 wt% by NMR, 98% yield) as a pale yellow solid: 1 H-NMR (DMSO-d6, 400 MHz) δ 11.78 (s, 1H), 8.26 (d, J = 7.4 Hz), 7.08 (d, J = 10.11 Hz) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 161.6 (d, JC-F = 252.9 Hz), 154.0 (d, JC-F = 12.32 Hz), 135.0 (d, JC-F = 2.57 Hz), 130.4 (d, JC-F = 3.42 Hz), 107.2 (d, JC-F = 26.00 Hz), 97.3 (d, JC-F = 23.64 Hz) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -97.92 ppm;EI-MS (M + ) Calculated value for C6H3BrFNO3: 234.93, measured value: 235.1.

[0115] In a similar manner, the reaction of 1-fluoro-2-iodo-5-methoxy-4-nitrobenzene (compound 2) with BCl3 yielded 5-fluoro-4-iodo-2-nitrophenol (compound 4):1 H-NMR (DMSO-d6, 400 MHz) δ 11.71 (br d, J = 8 Hz, 1H), 8.32 (d, J = 4 Hz, 1H), 6.98 (d, J = 12 Hz, 1H) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -85.37 ppm.

[0116] As shown in step 3 of scheme B2, 4-bromo-5-fluoro-2-nitrophenol (99 g, 0.407 mol) was added to a 2 L jacketed reactor equipped with a cooler, overhead stirrer, and thermocouple, followed by the addition of EtOH (7.5 V) and water (7.5 V). The mixture was stirred and cooled to 10-12°C (internal), and Na2S2O4 (212 g, 85% purity, 1.06 mmol) was gradually added to the resulting yellow suspension while maintaining the temperature below 30°C. The resulting suspension was gradually heated to 80°C and stirred at this temperature for 2 hours, at which point the suspension turned into a clear orange solution. The mixture was gradually cooled to room temperature, stirred overnight, and then EtOH was removed by distillation using a rotary evaporator at 40°C. The resulting yellow suspension was filtered, and the cake was washed with water, then hexane. The obtained solid was dried in a vacuum oven at 40°C for 12-14 hours to obtain 2-amino-4-bromo-5-fluorophenol (43.4 g, 87% by weight, 97% purity) as a yellow solid: 1 H-NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1H), 6.77 (d, J = 7.39 Hz), 6.61 (s, J = 10.06 Hz), 4.64 (br s, 1H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 150.1 (d, JC-F = 232.0 Hz), 144.7 (d, JC-F = 9.24 Hz), 135.5 (d, JC-F = 1.93 Hz), 116.2, 103.3 (d, JC-F = 25.18 Hz), 95.7 (d, JC-F = 21.42 Hz) ppm; 19F-NMR (DMSO-d6, 376.5 MHz) δ -123.75 ppm;EI-MS (M + ) Calculated value for C6H5BrFNO: 204.95, measured value: 205.0.

[0117] In a similar manner, 2-amino-5-fluoro-4-iodophenol (compound 6) was obtained by the reaction of 5-fluoro-4-iodophenol (compound 4) with Na2S2O4: EI-MS(M + ) Calculated value for C6H5FINO: 252.94, measured value: 253.1.

[0118] As shown in step 4 of scheme B2, diisopropylethylamine (DIEA, 6 equivalents) was added to a MeOH solution (10V) of 2-amino-4-bromo-5-fluorophenol (19.0 g) and bromodifluoroethyl acetate (3.0 equivalents) while stirring to obtain a reddish-orange solution. The mixture was stirred at room temperature for 2 hours, and volatile substances were removed by rotary evaporation at 30°C to obtain a yellow suspension. The solid was filtered, and the cake was washed with hexane until a clear filtrate was obtained (4 times at 3V). The obtained solid was dried under suction for 2 hours, then dried for 14 hours to obtain 4-bromo-2-(2-bromo-2,2-difluoroacetamide)-5-fluorophenolate, N-ethyl-N-isopropylpropane-2-aminium salt (compound 7, 44 g, yield 97%): EI-MS(M + ) Calculated value for C8H4BrF3NO2 (free base) is 360.86, measured value is 360.9.

[0119] In a similar manner, the reaction of 2-amino-5-fluoro-4-iodophenol with ethyl bromodifluoroethyl yielded 2-(2-bromo-2,2-difluoroacetamide)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropane-2-aminium salt: (compound 8).

[0120] As shown in step 5 of scheme B2, K2CO3 (2.5 equivalents) was added to a stirred DMF solution (10V) of 4-bromo-2-(2-bromo-2,2-difluoroacetamide)-5-fluorophenolate, N-ethyl-N-isopropylpropane-2-aminium salt (compound 7, 38.0 g), and the mixture was stirred at 50°C for 14 hours. The mixture was acidified with 2M HCl (aq) until the pH was 4-5, diluted with water, and extracted with siRNA (three times at 2V). The combined organic matter was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting dark brown wet solid was treated with water, stirred, and filtered. The resulting dark solid was made into a slurry in CH2Cl2 (3V), filtered, and the cake was washed with CH2Cl2, then washed with hexane (1V) to obtain the product as a pink solid (14.7 g, first sample). Following the same procedure, a second sample (4.6 g) was obtained from the CH2Cl2 mother liquor to obtain 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 9, 19.3 g, 74.8%): 1 H-NMR (DMSO-d6, 400 MHz) δ 12.08 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 6.7 Hz, 1H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 154.6 (d, JC-F = 242.1 Hz) 153.2 (d, JC-F = 37.62 Hz) 138.1 (dt, JC-F = 11.58 and 2.19 Hz), 123.2 (d, JC-F = 3.11 Hz), 120.2, 113.2 (d JC-F = 262.64 Hz), 107.1 (d, JC-F = 28.62 Hz), 104.0 (d, JC-F = 22.86 Hz) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -75.55, -111.73 ppm;EI-MS (M + ) Calculated value for C8H3BrF3NO2: 280.93, measured value: 281.0.

[0121] In a similar manner, 2-(2-bromo-2,2-difluoroacetamide)-5-fluoro-4-iodophenolate, N-ethyl-N-isopropylpropane-2-aminium salt (compound 8, 9.8 g, 23.67 mmol) and DMF (45 mL, 5V) were added to a 250 mL round-bottom flask, followed by the addition of K2CO3 (5.0 g, 48 mmol, 2 equivalents). The mixture was stirred at 50°C for 12 hours, cooled to room temperature, and the pH was adjusted to 7. The resulting aqueous phase was extracted with SiO2 (twice at 10V), the combined organic matter was washed with brine (10V), dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (100% hexane to 10% SiO2 / hexane) to obtain 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 10, 3.63g, 62% yield from compound 6) as an orange solid: 1 H-NMR (DMSO-d6, 400 MHz) 12.02 (br s, 1H), 7.46-7.44 (m, 2H) ppm; 13 C-NMR (DMSO-d6, 101 MHz) δ 157.7 (d, JC-F = 239.18 Hz), 153.2 (t, JC-F = 37.53 Hz), 138.9 (d, JC-F = 11.68 Hz), 125.6 (d, JC-F = 3.06 Hz), 123.5 (d, JC-F = 3.14 Hz), 113.2 (t, JC-F = 262.56 Hz), 106.0 (d, JC-F = 30.81 Hz), 77.3 (d, JC-F = 28.4 Hz) ppm; 19 F-NMR (DMSO-d6, 376.5 MHz) δ -75.61, -98.86 ppm;EI-MS (M + ) Calculated value for C8H3F3INO2: 328.92, measured value: 329.1.

[0122] As shown in step 6 of scheme B2, 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 10, 1.47 g, 4.47 mmol) and 1,10-phenanthroline (202 mg, 1.12 mmol, 0.25 equivalents) were added to a 75 mL Schlenk tube. In a glove box under a nitrogen atmosphere, K3PO4 (3.8 g, 17.9 mmol, 4 equivalents), CuI (170 mg, 0.9 mmol, 0.2 equivalents) and DMF (15 mL, 10V) were added, followed by pentafluorobenzene (1.5 mL, 13.4 mmol, 3 equivalents). The tube was sealed in the glove box and pre-mixed at room temperature for 15 minutes, then stirred at 110°C for 20 hours. After this time, the reaction mixture was diluted with SiO2 (10V), washed with saturated brine (twice at 10V), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (15% SiO2 / hexane) to obtain 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 11, 1.33 g, yield 74%) as a white solid: 1 H-NMR (DMSO-d6, 400 MHz) δ 12.21 (s, 1H), 7.69 (d, J = 9.9 Hz, 1H), 7.23 (d, J = 6.6 Hz, 1H); 13 C-NMR (101 MHz, DMSO-d6) δ 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;19 F-NMR (376 MHz, DMSO) δ -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~-172.00 (m) ppm;LCMS:m / z [M-1] - C 14 The calculated value for H3F8NO2 was 368.00, and the measured value was 367.7.

[0123] 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one could also be produced in a similar manner from 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 9).

[0124] As shown in step 7 of scheme B2, 2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 11, 200 mg, 0.54 mmol) was added to a DMF solution (2 mL) with K2CO3 (74 mg, 0.54 mmol) and 3-bromopropa-1-yne (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash chromatography (0-30% ethyl acetate in petroleum ether) to obtain 2,2,7-trifluoro-6-(perfluorophenyl)-4-(propa-2-in-1-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one (compound 12, 120 mg, yield 54%) as an off-white solid: GCMS (C 17 Calculated value for H5F8NO2) is 407.0, measured value is 407.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.81 - 7.67 (m, 2H), 4.88 (s, 2H), 3.45 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ -74.85, -115.56, -140.50, -153.03, -162.01.

[0125] Compound 11 was reacted with a suitable alkyl halide or alkyl triflate by a procedure similar to that of step 7 of scheme B2 to produce the following compounds: 2,2,7-trifluoro-4-methyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 15 Calculated value for H5F8NO2) is 383.0, measured value is 383.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.87 - 7.62 (m, 2H), 3.43 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.05, -116.55, -140.32, -153.34, -162.15; 4-benzyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: Calculated value 459.1 and measured value 459.0 for GCMS (C21H9F8NO2); 1H-NMR (400 MHz, methanol-d4) δ 7.42 - 7.37 (m, 4H), 7.35 - 7.31 (m, 3H), 5.33 (s, 2H); 19F-NMR (376 MHz, methanol-d4) δ -78.80, -116.83, -142.52, -155.24 -164.83;

[0126] 4-allyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid. GCMS (C 17Calculated value 409.0 and measured value 409.0 for H7F8NO2; 1H-NMR (400 MHz, DMSO-d6) δ 7.79 - 7.74 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 5.88 (m, 1H), 5.27 - 5.14 (m, 2H), 4.68 - 4.62 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.67, -116.18, -140.50, -153.27, -162.03;

[0127] 4-Ethyl-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 16 Calculated value for H7F8NO2) is 397.0, measured value is 397.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.4 Hz, 1H), 7.78 - 7.72 (m, 1H), 4.05 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.60, -116.48, -140.36, -153.44, -162.15;

[0128] 2,2,7-trifluoro-6-(perfluorophenyl)-4-propyl-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 17 The calculated value for H9F8NO2 is 411.1, and the measured value is 411.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.82 - 7.72 (m, 2H), 3.98 (t, J = 7.2 Hz, 2H), 1.65 - 1.59 (m, 2H), 0.91 (t, J = 6.8 Hz, 3H); 19 F-NMR (400 MHz, DMSO-d6) δ -74.70, -116.40, -140.10, -153.46, -162.12;

[0129] 4-(3-cyclopropylpropane-2-in-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 20 Calculated value for H9F8NO2) is 447.1, measured value is 447.1; 1 H-NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 6.4 Hz, 1H), 4.80 (s, 2H), 1.32 - 1.24 (m, 1H), 0.80 - 0.69 (m, 2H), 0.58 - 0.50 (m, 2H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.72, -115.70, -140.77, -153.12, -162.06;

[0130] 4-(buta-2-in-1-yl)-2,2,7-trifluoro-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 18 The calculated value for H7F8NO2 is 421.0, and the measured value is 421.1; 1 H-NMR (400 MHz, DMSO-d6) δ 7.78 - 7.73 (m, 2H), 4.83 - 4.78 (m, 2H), 1.78 (s, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -74.68, -115.65, -140.58, -153.09, -161.96;

[0131] 2,2,7-trifluoro-4-(2-methylallyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 18 Calculated value for H9F8NO2) is 423.0, measured value is 423.0; 1H-NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 9.6 Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 4.92 - 4.88 (m, 1H), 4.72 - 4.66 (m, 1H), 4.56 (s, 2H), 1.75 (d, J = 1.2 Hz, 3H); 19 F-NMR (376 MHz, DMSO-d6) δ -75.05, -116.00, -140.57, -153.23, -162.01;

[0132] 2,2,7-trifluoro-6-(perfluorophenyl)-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: GCMS (C 16 H4F 11 Calculated value for NO2) 451.0, measured value 451.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 5.08 - 4.97 (m, 2H); 19 F-NMR (400 MHz, DMSO-d6) δ -67.95, -75.15, -115.30, -140.49, -152.81, -161.86;

[0133] 2,2,7-trifluoro-4-(2-fluorobenzyl)-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a white solid: MS (ESI) (C 21 Calculated value for H8F9NO2) [M+1] + 478.2, measured value 477.9; 1 H-NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.33 - 7.21 (m, 2H), 7.18 - 7.16 (m, 1H), 5.32 (s, 2H);19 F-NMR (400 MHz, DMSO-d6) δ -74.91, -115.69, -117.44, -140.68, -153.15, -162.02;

[0134] 2,2,7-trifluoro-4-isopropyl-6-(perfluorophenyl)-2H-benzo[b][1,4]oxazine-3(4H)-one as a pale yellow solid: GCMS (C 17 Calculated value for H9F8NO2) is 411.0, measured value is 411.0; 1 H-NMR (400 MHz, DMSO-d6) δ 7.72 - 7.62 (m, 2H), 5.41 - 5.30 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H); 19 F-NMR (400 MHz, DMSO-d6) δ -67.27, -112.83, -140.84, -153.73, -162.21.

Claims

1. Equation (I), 【Chemistry 1】 Compounds of or salts thereof [in the formula, R is C １－６ alkyl, C ３－４ alkenyl, C ３－４ alkynyl, cyclopropyl, CH ２ C ３－６ cycloalkyl, phenyl or C １－２ alkyl-phenyl, each optionally being C(O)R １ａ , CH ２ C(O)R １ａ , R １ｂ and substituted with up to three F atoms or Cl atoms, R １ａ OR １ｂ ,CH ２ OC(O)C １－４ Alkyl, C(O)OR １ｂ , N(R １ｂ ) (Caution １ｃ ), ON (R １ｂ ) (Caution １ｃ ), NHN(R １ｂ ) (Caution １ｃ ), NHS(O) ２ N(R) １ｂ ) ２ NHS (O) ２ C １－４ Alkyl, or NHOR １ｂ And, Each R １ｂ H and C are independent of each other. ３－６ Cycloalkyl, CH ２ C is substituted with phenyl or, optionally, up to three F or Cl atoms. １－４ It is alkyl, R １ｃ is H, or optionally C(O)OR １ｂ C is replaced by １－４ Alkyl or R １ｂ and R １ｃ However, together with the intervening nitrogen atom, it forms a 4-6 member heterocycle, and optionally, N, O, S, S(O) ２ It contains additional atoms or groups selected from, and optionally -C(O)OR １ｂ and -C(O)R １ｂ A process for manufacturing [which is replaced by one or more groups selected from], The compound of formula (a), or a salt thereof, is reacted with a non-nucleophilic base and the compound of formula (b) to produce the compound of formula (c), or a salt thereof. 【Chemistry 2】 [In the formula, X is Br, L １ is either F or Cl, or L １ C(O) is an alkyl ester or an activated ester, and it produces the amide of formula (c) or a salt thereof. The compound of formula (c), or a salt thereof, is treated with an additional non-nucleophilic base to produce the intermediate of formula (d), and then the compound of formula (e), or a salt thereof, 【Transformation 3】 The compound of formula (e), or a salt thereof, is reacted with 2 to 2.5 equivalents of an alkyllithium reagent to produce a dilithio intermediate, and then the dilithio intermediate is treated with hexafluorobenzene to produce the compound of formula (f), or a salt thereof. 【Chemistry 4】 The compound of formula (f), or a salt thereof, is subjected to alkylating agent L. ２ -R [wherein, L ２ [This is an intermediate resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with triphenylphosphine and azodicarboxylate in the Mitsunobu reaction] which is alkylated to produce the compound of formula (I) or a salt thereof, 【Transformation 5】 The process including the above.

2. The step according to claim 1, wherein compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one or a salt thereof.

3. R is, 【Transformation 6】 And in the formula, R １ｂ The step according to claim 1, wherein is H, alkyl, or cyclopropyl.

4. R １ｂ The process according to claim 3, wherein H.

5. R is CH(CH ３ )C(O)OC １－４ The step according to claim 1, wherein the alkyl group is used.

6. R is CH(CH ３ The process according to claim 1, wherein the result is C(O)OH.

7. The step according to any one of claims 1 to 6, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base.

8. The step according to any one of claims 1 to 6, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases.

9. structure: 【Transformation 7】 A compound having, or a salt thereof.

10. The compound according to claim 9, wherein the compound is an alkylammonium salt.

11. The aforementioned compound, 【Transformation 8】 The compound according to claim 9.

12. It is a process, The compound of formula (e), or a salt thereof, is combined with 2 to 2.5 equivalents of an alkyllithium reagent under suitable conditions to form a dilithio intermediate, wherein the compound of formula (e), or a salt thereof, 【Chemistry 9】 And in the formula, X is Br, and the above combination, The compound of formula (e1) is combined with the dilithio intermediate to produce the compound of formula (f) or a salt thereof, wherein the compounds of formula (e1) and (f) are 【Chemistry 10】 The process includes the combination described above.

13. The step according to claim 12, wherein combining the compound of formula (e1) with the dilithio intermediate includes adding the compound of formula (e1) to the dilithio intermediate.

14. The step according to claim 12, wherein combining the compound of formula (e1) with the dilithio intermediate includes adding the dilithio intermediate to the compound of formula (e1).

15. The compound of formula (c), or a salt thereof, is combined with a non-nucleophilic base to produce the compound of formula (e), wherein the compound of formula (c), or a salt thereof, 【Chemistry 11】 The step according to any one of claims 12 to 14, further comprising the combination of the formula, wherein X is Br.

16. The compound of formula (a) or a salt thereof is combined with an additional non-nucleophilic base and a compound of formula (b) to produce a compound of formula (c) or a salt thereof, wherein the compounds of formula (a) and formula (b) are 【Chemistry 12】 In the formula, X is Br, and L １ is either F or Cl, or L １ The step according to any one of claims 12 to 15, further comprising the combination of C(O) to form an alkyl ester or an activated ester group.

17. The step according to claim 16, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base when they are present at the same time.

18. The step according to claim 16, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases when they are present at the same time.

19. The compound of formula (f) or a salt thereof is alkylated with an alkylating agent to obtain formula (I): 【Chemistry 13】 The process involves producing a compound or a salt thereof, The alkylating agent is L ２ -R [in the formula, L ２ These are reaction intermediates resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with azodicarboxylate in the Mitsunobu reaction. R is C １－６ Alkyl, C ３－４ Alkenil, C ３－４ Alkinyl, cyclopropyl, CH ２ C ３－６ Cycloalkyl, phenyl, or C １－２ It is an alkylphenyl, and each is arbitrarily selected, C(O)R １ａ ,CH ２ C(O)R １ａ , R １ｂ , and substituted with up to three F atoms or Cl atoms, R １ａ OR １ｂ ,CH ２ OC(O)C １－４ Alkyl, C(O)OR １ｂ , N(R １ｂ ) (Caution １ｃ ), ON (R １ｂ ) (Caution １ｃ ), NHN(R １ｂ ) (Caution １ｃ ), NHS(O) ２ N(R) １ｂ ) ２ NHS (O) ２ C １－４ Alkyl, or NHOR １ｂ and Each R １ｂ is independently H, C ３－６ cycloalkyl, CH ２ phenyl, or C optionally substituted with up to 3 F or Cl atoms １－４ alkyl, and R １ｃ is H, or C optionally substituted with C(O)OR １ｂ alkyl, or R １－４ and R １ｂ together with the intervening nitrogen atom form a 4- to 6-membered heterocycle, optionally containing an additional atom or group selected from N, O, S, S(O) １ｃ and optionally substituted with one or more groups selected from -C(O)OR ２ and -C(O)R １ｂ The process according to any one of claims 12 to 18, further comprising said alkylating, wherein １ｂ １ｂ is substituted with one or more groups selected from

20. Equation (I), 【Chemistry 14】 Compounds of or salts thereof [in the formula, R is C １－６ alkyl, C ３－４ alkenyl, C ３－４ alkynyl, cyclopropyl, CH ２ C ３－６ cycloalkyl, phenyl or C １－２ alkyl-phenyl, each optionally being C(O)R １ａ , CH ２ C(O)R １ａ , R １ｂ , and substituted with up to three F atoms or Cl atoms, R １ａ OR １ｂ ,CH ２ OC(O)C １－４ Alkyl, C(O)OR １ｂ , N(R １ｂ ) (Caution １ｃ ), ON (R １ｂ ) (Caution １ｃ ), NHN(R １ｂ ) (Caution １ｃ ), NHS(O) ２ N(R) １ｂ ) ２ NHS (O) ２ C １－４ Alkyl, or NHOR １ｂ And, Each R １ｂ These are H and C, independently. ３－６ Cycloalkyl, CH ２ C is substituted with phenyl or, optionally, up to three F or Cl atoms. １－４ It is alkyl, R １ｃ is H, or optionally C(O)OR １ｂ C is replaced by １－４ Alkyl or R １ｂ and R １ｃ However, together with the intervening nitrogen atom, it forms a 4-6 member heterocycle, and optionally, N, O, S, S(O) ２ It contains additional atoms or groups selected from, and optionally -C(O)OR １ｂ and -C(O)R １ｂ A process for manufacturing [which is replaced by one or more groups selected from], The compound of formula (a), or a salt thereof, is reacted with a non-nucleophilic base and the compound of formula (b) to produce the compound of formula (c), or a salt thereof. 【Chemistry 15】 [In the formula, X is Br or I, and L １ is either F or Cl, or L １ C(O) is an alkyl ester or an activated ester, and it produces the amide of formula (c) or a salt thereof. The compound of formula (c), or a salt thereof, is treated with an additional non-nucleophilic base to produce the intermediate of formula (d), and then the compound of formula (e), or a salt thereof, 【Chemistry 16】 The compound of formula (e), or a salt thereof, is reacted with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce the compound of formula (f), or a salt thereof. 【Chemistry 17】 The compound of formula (f), or a salt thereof, is subjected to alkylating agent L. ２ -R [wherein, L ２ [This is an intermediate resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with triphenylphosphine and azodicarboxylate in the Mitsunobu reaction] which is alkylated to produce the compound of formula (I) or a salt thereof, [Chemistry 18] The process including the above.

21. The step according to claim 20, wherein the Cu(I) salt is CuCl, CuBr, or CuI.

22. The step according to claim 20 or claim 21, wherein the compound (e) is 6-bromo-2,2,7-trifluoro-2H-benzo[b][1,4]oxazine-3(4H)-one or a salt thereof.

23. The step according to claim 20 or claim 21, wherein the compound (e) is 2,2,7-trifluoro-6-iodo-2H-benzo[b][1,4]oxazine-3(4H)-one or a salt thereof.

24. R is, 【Chemistry 19】 And in the formula, R １ｂ The step according to claim 20 or claim 21, wherein is H, alkyl, or cyclopropyl.

25. R １ｂ The process according to claim 24, wherein H.

26. R is CH(CH ３ )C(O)OC １－４ The step according to claim 20 or claim 21, wherein the alkyl group is used.

27. R is CH(CH ３ The process according to claim 20 or claim 21, wherein the result is C(O)OH.

28. The step according to any one of claims 20 to 27, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base.

29. The step according to any one of claims 20 to 27, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases.

30. structure: 【Chemistry 20】 A compound having, or a salt thereof.

31. The compound according to claim 30, wherein the compound is an alkylammonium salt.

32. The aforementioned compound, 【Chemistry 21】 The compound according to claim 30.

33. It is a process, The compound of formula (e), or a salt thereof, is combined with pentafluorobenzene in the presence of a Cu(I) salt and 1,10-phenanthroline to produce the compound of formula (f), wherein the compound of formula (e), or a salt thereof, 【Chemistry 22】 In the formula, X is either Br or I, The compound of formula (f) or a salt thereof, 【Chemistry 23】 The process includes the step of combining the above.

34. The step according to claim 33, wherein the Cu(I) salt is CuCl, CuBr, or CuI.

35. The compound of formula (c), or a salt thereof, is combined with a non-nucleophilic base to produce the compound of formula (e), wherein the compound of formula (c), or a salt thereof, 【Chemistry 24】 The step according to claim 33 or claim 34, further comprising the step of combining the above.

36. The compound of formula (a) or a salt thereof is combined with an additional non-nucleophilic base and a compound of formula (b) to produce a compound of formula (c) or a salt thereof, wherein the compounds of formula (a) and formula (b) are 【Chemistry 25】 And in the formula, L １ is either F or Cl, or L １ The step according to any one of claims 33 to 35, further comprising the combination of C(O) to form an alkyl ester or an activated ester group.

37. The step according to claim 36, wherein the non-nucleophilic base and the additional non-nucleophilic base are the same base when they are present at the same time.

38. The step according to claim 36, wherein the non-nucleophilic base and the additional non-nucleophilic base are different bases when they are present at the same time.

39. The compound of formula (f) or a salt thereof is alkylated with an alkylating agent to obtain formula (I): 【Chemistry 26】 The process involves producing a compound or a salt thereof, The alkylating agent is L ２ -R [in the formula, L ２ These are reaction intermediates resulting from the reaction of iodine, bromo, chloro, sulfonate, or alcohol with triphenylphosphine and azodicarboxylate in the Mitsunobu reaction. R is C １－６ Alkyl, C ３－４ Alkenil, C ３－４ Alkinyl, cyclopropyl, CH ２ C ３－６ Cycloalkyl, phenyl, or C １－２ It is an alkylphenyl, and each is arbitrarily selected, C(O)R １ａ ,CH ２ C(O)R １ａ , R １ｂ , and substituted with up to three F atoms or Cl atoms, R １ａ OR １ｂ ,CH ２ OC(O)C １－４ Alkyl, C(O)OR １ｂ , N(R １ｂ ) (Caution １ｃ ), ON (R １ｂ ) (Caution １ｃ ), NHN(R １ｂ ) (Caution １ｃ ), NHS(O) ２ N(R) １ｂ ) ２ NHS (O) ２ C １－４ Alkyl, or NHOR １ｂ and Each R １ｂ These are H and C, independently. ３－６ Cycloalkyl, CH ２ C is substituted with phenyl or, optionally, up to three F or Cl atoms. １－４ It is alkyl, R １ｃ is H, or optionally C(O)OR １ｂ C is replaced by １－４ Alkyl or R １ｂ and R １ｃ However, together with the intervening nitrogen atom, it forms a 4-6 member heterocycle, and optionally, N, O, S, S(O) ２ It contains additional atoms or groups selected from, and optionally -C(O)OR １ｂ and -C(O)R １ｂ The step according to any one of claims 33 to 38, further comprising alkylating, wherein the group is substituted with one or more groups selected from the following.

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