Preparation method of substituted phenylacetonitrile and substituted phenylacetic acid

Abstract

Methods for preparing substituted phenylacetonitrile and substituted phenylacetic acid are provided. The methods disclosed herein provide for yields of phenylacetic acid or derivatives thereof, as determined from benzoic acid starting materials, of greater than 75%, and require fewer steps or dangerous reagents and solvents than known methods. These substituted phenylacetic acids can be found for use in the preparation of novel active ingredients, such as GLP-1 receptor agonists, in the field of diabetes.

Description

Technical Background

[0001] This invention relates to methods for preparing substituted phenylacetonitrile and substituted phenylacetic acid. These compounds are intermediates in the preparation of certain glucagon-like peptide-1 (GLP-1) receptor agonists.

[0002] background Substituted phenylacetonitrile and substituted phenylacetic acid are intermediates in the preparation of certain GLP-1 receptor agonists, including the benzimidazole compounds disclosed in WO2020 / 263695. The methods disclosed in WO2020 / 263695 for preparing the intermediates of substituted phenylacetonitrile and phenylacetic acid are cumbersome because they involve multiple time-consuming purification and separation steps. Previously disclosed methods also involve the use of toxic reagents such as dichloromethane (DCM).

[0003] There is a need for improved methods that are less resource-intensive, cheaper, more environmentally friendly, and / or facilitate more efficient production. More specifically, there is a need for methods that reduce material waste (such as solvents), reduce or avoid the use of toxic and hazardous reagents and solvents, improve atom economy to increase yields, and / or reduce energy and time requirements.

[0004] Brief Overview The telescoped method of this invention addresses one or more of these needs. The subsequent organic reactions proceed in combination without separating intermediates, preventing the waste of materials and solvent forms required for separation, resulting in increased yields and / or reduced time and energy loads. In this method, non-hazardous solvents (such as non-halogenated solvents) are used.

[0005] In a first aspect, this disclosure provides a method for preparing compounds of the following formula or salts thereof: R1 is selected from H, F and CH3, R2 is selected from H, F and CH3, and R3 is selected from H, F and CH3, and R1, R2 and R3 are not the same.

[0006] In one implementation, the method includes: i. Combining a non-halogenated solvent with benzoic acid of the following formula: ii. Add a reducing agent to form benzyl alcohol of the following formula: iii. Combining benzyl alcohol with a reagent in a second non-halogenated solvent to form a first intermediate of the following formula: Where X is selected from Cl, Br, I, sulfonate and tosylate; iv. Combining the first intermediate with cyanide to form benzyl nitrile of the following formula v. To combine benzyl nitrile with hydroxide; One or more of the following are not separated before the next step: benzyl alcohol from step (ii), the first intermediate from step (iii), and benzyl nitrile from step (iv).

[0007] In one particular implementation, X is Br.

[0008] In one embodiment, the method according to the first aspect may further include (step vi) combining the phenylacetic acid obtained from step v with a borane reagent and a catalyst to form a boronic ester of the following formula: Where R s For forming cyclic borate esters, the C1-C6 alkyl or C2-C6 alkylene groups. In one particular embodiment, R s It is a C6 alkylene group.

[0009] In one embodiment, the borane reagent is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopentane) (or bis(pinacolyl)diborane): .

[0010] In yet another embodiment, the method may further include (step vii) combining the borate ester with a compound of the following formula. To obtain the following compound R1, R2, and R3 are as defined above, and It is phenyl; 5- or 6-heteroaryl; or pyridone; wherein the phenyl, 5- or 6-heteroaryl, or pyridone is optionally surrounded by one or two R 1a replace; R 1a Each time it appears, it is independently selected from: CN; halogen; C1-C3 alkyl that may be optionally substituted with OH; C1-C3 haloalkyl; C1-C3 alkoxy; C3-C5 cycloalkyl; -SO2C1-C3 alkyl; -C(O)NH2; and Each X9 It is independently CH or N, and the ring contains no more than one X. 9 For N, each R e Independently selected from: H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl and C1-C3 alkyl optionally substituted with OH, R h H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl, OH, -NR c R d Or C1-C3 alkyl groups optionally substituted with OH; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from the following: C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c R d -NR c R d And C1-C3 alkyl groups optionally substituted with OH; -A- can be -CH2O-; -OCH2- or -CH2NH-; Y 3 Y 4 Y 5 and Y 6 Independently N; CH or CR 2a ; where Y 3 Y 4 Y 5 and Y 6 The two are not more than N and Y 3 Y 4 Y 5 and Y 6 No more than two of them are CR 2a ; R 2a Each time it appears, it is independently either halogenated or methyl; and R c and R d Each is independently H or C1-C3 alkyl.

[0011] In one implementation scheme The phenyl group is substituted with a halogen, preferably F and CN.

[0012] In one particular implementation scheme, for .

[0013] In one implementation, -A- is -CH2O-.

[0014] In one implementation, Y 3 For N and Y 4 Y 5 and Y 6 All are CH.

[0015] In one embodiment of the above compound, R1 is F, R2 is H and R3 is CH3.

[0016] In one embodiment, the non-halogenated solvent and the second non-halogenated solvent according to the first aspect of the method may be different or the same. In one embodiment, the non-halogenated solvent and the second non-halogenated solvent may be independently selected from acetone, acetonitrile, anisole, butyl acetate, tert-butyl methyl ether, cumene, cyclohexane, dimethylformamide (DMF), dimethyl sulfoxide, ethanol, ethyl acetate (EtOAc), ethyl ether, heptane, hexane, isopropanol, methanol (MeOH), methyl butyl ketone, methyl ethyl ketone, pentane, pyridine, tetrahydrofuran (THF), toluene, and xylene, or combinations thereof. In a particular embodiment, the non-halogenated solvent is independently selected from THF and toluene.

[0017] In yet another embodiment, the reducing agent according to the method of the first aspect may be selected from diborane, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride, and hydrogen, or combinations thereof. In one embodiment, the reducing agent is sodium borohydride. In a particular embodiment, sodium borohydride is used in conjunction with borontrifluoride etherate.

[0018] In a further embodiment, the reagent in step iii of the method of the first aspect may be selected from HBr, aqueous HBr solution, alcoholic HBr solution, PBr3, dibromodimethylhydantoin, N-bromosuccinimide, HI, aqueous HI solution, PCl3, and toluenesulfonyl chloride, or combinations thereof. In one embodiment, the reagent is an aqueous HBr solution.

[0019] In one embodiment, the cyanide according to the method of the first aspect may be selected from LiCN, NH4CN, N(CH3)4CN, N(Et)4CN, N(n-Pr)4CN, N(i-Pr)4CN, N(n-Bu)4CN, N(t-Bu)4CN, HCN, NaCN, KCN, Zn(CN)2, and (CH3)3SiCN, or combinations thereof. In one embodiment, the cyanide is selected from N(t-Bu)4CN, NaCN, Zn(CN)2, and (CH3)3SiCN. In a particular embodiment, the cyanide is NaCN.

[0020] In one embodiment, the hydroxide according to the method of the first aspect may be selected from LiOH, NaOH, KOH, Mg(OH)2, Ca(OH)2, or Sr(OH)2 or combinations thereof. In a particular embodiment, the hydroxide is KOH.

[0021] In one embodiment, the yield of phenylacetic acid (step v) calculated from benzoic acid (step i) according to the method of the first aspect is at least 70% by weight, at least 75% by weight, at least 78% by weight, at least 80% by weight, at least 82% by weight, or at least 85% by weight.

[0022] In another embodiment, the formula calculated from the compound obtained from phenylacetic acid (step v) according to the method of the first aspect is provided. The yield of the compound is at least 60 wt%, at least 65 wt%, at least 70 wt%, or at least 72 wt%.

[0023] In another embodiment, in the method according to the first aspect, benzyl alcohol (obtained from step ii) is not separated before the reagent is combined with the second non-halogenated solvent. In yet another embodiment, in the method according to the first aspect, benzyl alcohol (obtained from step ii) is not separated before the reagent is combined with the second non-halogenated solvent, and the first intermediate (obtained from step iii) is not separated before combination with cyanide. In a further embodiment, in the method according to the first aspect, benzyl alcohol (obtained from step ii) is not separated before the reagent is combined with the second non-halogenated solvent, and the first intermediate (obtained from step iii) is not separated before combination with cyanide, and benzyl nitrile (obtained from step iv) is not separated before combination with hydroxide. In yet another embodiment, the method for preparing the compound is chromatography-free. In yet another embodiment, the method for preparing the compound includes at least one, at least two, or at least three chromatography-free method steps (such as steps ii, iii, iv, or any combination thereof).

[0024] In a second aspect, this disclosure provides a method for preparing compounds of the following formula: Or the method of using its salt.

[0025] In one implementation scheme, the method according to the second aspect includes: i. Combining 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene with a cyanide in a non-halogenated solvent to form a benzyl nitrile of the following formula. ii. Combining benzyl nitrile with hydroxide to produce a compound, Benzyl nitrile is not separated before step (ii).

[0026] In one implementation scheme, the method according to the second aspect further includes iii. The compound obtained from step (ii) is combined with a borane reagent and a catalyst to form a boronic ester of the following formula. Where R s For forming cyclic borate esters, the C1-C6 alkyl or C2-C6 alkylene groups; iv. Combine the borate ester from step (iii) with pyridine of the following formula: To obtain compounds with the following formula: .

[0027] In one embodiment, the borane reagent is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopentane) (or bis(pinacolyl)diborane). In one embodiment, the borate ester according to the method of the second aspect is... .

[0028] In another embodiment, the method according to the second aspect further includes the following steps: a. The following compound: It undergoes an amide coupling reaction with a compound of the following formula: Where R is H or an acid protecting group; To produce compounds of the following formula: Or its salt.

[0029] b. Cyclize the compound obtained in step (a) to produce a compound of the following formula: And optionally react to form its pharmaceutically acceptable salt.

[0030] In one particular embodiment, R is H or a C1-C4 alkyl group.

[0031] In another embodiment, where R is an acid protecting group, the method further includes the step of hydrolyzing the ester compound to produce an acid compound of the following formula: Optionally, it reacts to form its pharmaceutically acceptable salt. In a preferred embodiment, the acid compound has the following formula: The salt is a tert-butylamine salt.

[0032] In one embodiment, in the method according to the second aspect, the borate ester is not separated before being combined with pyridine.

[0033] In another embodiment, the non-halogenated solvent may be selected from acetone, acetonitrile, anisole, butyl acetate, tert-butyl methyl ether, cumene, cyclohexane, DMF, dimethyl sulfoxide, ethanol, EtOAc, ethyl ether, heptane, hexane, isopropanol, MeOH, methyl butyl ketone, methyl ethyl ketone, pentane, pyridine, THF, toluene, and xylene, or combinations thereof. In a particular embodiment, the non-halogenated solvent is independently selected from THF and toluene.

[0034] In another embodiment, 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzyl alcohol is obtained by combining 4-bromo-2-fluoro-5-methylbenzyl alcohol with a brominating agent. In another embodiment, the 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzyl alcohol obtained from 4-bromo-2-fluoro-5-methylbenzyl alcohol is not separated prior to combination with cyanide. In one embodiment, the brominating agent according to the foregoing steps may be selected from HBr, aqueous HBr solution, alcoholic HBr solution, PBr3, dibromodimethylhydantoin, and N-bromosuccinimide or combinations thereof. In one embodiment, the brominating agent is an aqueous HBr solution.

[0035] In another embodiment, 4-bromo-2-fluoro-5-methylbenzyl alcohol according to the method of the second aspect is obtained by combining 4-bromo-2-fluoro-5-methylbenzoic acid or its salt or ester with a reducing agent in a non-halogenated solvent. In another embodiment, 4-bromo-2-fluoro-5-methylbenzyl alcohol obtained from 4-bromo-2-fluoro-5-methylbenzoic acid, its salt or ester is not isolated prior to combination with the brominating agent.

[0036] In one embodiment, the cyanide according to the method of the second aspect may be selected from LiCN, NH4CN, N(CH3)4CN, N(Et)4CN, N(n-Pr)4CN, N(i-Pr)4CN, N(n-Bu)4CN, N(t-Bu)4CN, HCN, NaCN, KCN, Zn(CN)2, and (CH3)3SiCN or combinations thereof. In one embodiment, the cyanide is selected from N(t-Bu)4CN, NaCN, Zn(CN)2, or (CH3)3SiCN. In a particular embodiment, the cyanide is NaCN.

[0037] In one embodiment, the reducing agent according to the second aspect of the method may be selected from diborane, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride, and hydrogen, or combinations thereof. In one embodiment, the reducing agent is sodium borohydride. In a particular embodiment, sodium borohydride is used in conjunction with boron trifluoride ether.

[0038] In one embodiment, the hydroxide according to the method of the second aspect may be selected from LiOH, NaOH, KOH, Mg(OH)2, Ca(OH)2, and Sr(OH)2 or combinations thereof. In a particular embodiment, the hydroxide is KOH.

[0039] Detailed description In this disclosure, it should be understood that separation or being separated means that the compound obtained from the synthesis step is separated and purified before being used in subsequent synthesis steps. In practice, separation of the compound is considered when the compound has a purity of at least 80% by weight, such as at least 85% by weight, at least 87% by weight, at least 90% by weight, at least 92% by weight, at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, or at least 99% by weight.

[0040] As is known in the art, separation or being separated includes organic chemical separation and purification methods, including but not limited to distillation, precipitation, crystallization, chromatography, or any combination thereof. If the reaction mixture is used in its crude form in the next step, the compound is not separated. Purification steps that remove byproducts or solvents (e.g., distilling the solvent to concentrate the reaction mixture or product mixture) do not constitute separation.

[0041] As is further known in the art, a method or method step is chromatographically inactive when purification is not performed using chromatography during the method or method step. This excludes the use of chromatography for analytical purposes, such as monitoring product formation and reaction completion.

[0042] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0043] The term "C1-C" n "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to n carbon atoms. Examples of C1-C3 alkyl groups include, but are not limited to, methyl, ethyl, and propyl.

[0044] The term "C2-C6 alkylene" refers to divalent C2-C6 alkyl groups.

[0045] The term “C1-C3 haloalkyl” refers to a C1-C3 alkyl group substituted with one or more halogens as defined herein. Examples of C1-C3 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0046] The term "C1-C3 alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing one to three carbon atoms connected to the remainder of a compound via an oxygen atom, i.e., -O (alkyl). Examples of C1-C3 alkoxy compounds include, but are not limited to, methoxy, ethoxy, and propoxy.

[0047] The term “C1-C3 haloalkoxy” refers to a C1-C3 alkoxy group that is substituted with one or more halogens as defined herein. Examples of C1-C3 haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and pentafluoroethoxy.

[0048] The term "C3-C5 cycloalkyl" refers to a monocyclic saturated carbon ring containing 3 to 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, or cyclopentyl.

[0049] The term "5- or 6-membered heteroaryl" refers to a 5- or 6-membered monocyclic aromatic ring containing one or more heteroatoms preferably selected from N, S, and O. Examples of 5-membered heteroaryl groups include, but are not limited to, pyrazoles, triazoles, and thiazoles. Examples of 6-membered heteroaryl groups include, but are not limited to, pyridines and pyridazines.

[0050] The term "C4-C5 heterocyclic group" refers to a 4- or 5-membered monocyclic saturated ring containing one or more heteroatoms, such as oxetane.

[0051] As used herein, the term "pharmaceuticalally acceptable salt" refers to a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methods for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," P. Stahl et al., 2nd revised edition, Wiley-VCH, 2011, and SM Berge et al., "Pharmaceutical Salts." Journal of Pharmaceutical Sciences , 1977, 66(1), 1-19.

[0052] Some abbreviations are defined as follows: "DCM" refers to dichloromethane; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "Et" refers to ethyl; "EtOAc" refers to ethyl acetate; "h" refers to multiple hours or one hour; "i-Pr" refers to isopropyl or -CH(CH3)2; "KOAc" refers to potassium acetate; "MeOH" refers to methanol or methyl alcohol; "min" refers to one minute or more minutes; "MTBE" refers to methyl tert-butyl ether; "n-Bu" refers to n-butyl or -CH2CH2CH2CH3; "n-Pr" refers to n-propyl or -CH2CH2CH3; "t-Bu" refers to tert-butyl or -C(CH3)3; and "THF" refers to tetrahydrofuran.

[0053] experiment Example 1 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid [Step 1] Dissolve 4-bromo-2-fluoro-5-methylbenzoic acid (200 g, 0.858 mol, 1 eq) in THF (600 mL). Add sodium borohydride (52 g, 1.375 mol, 1.6 eq) to the reactor, followed by THF (1.1 L). Stir the mixture at 27°C for at least 30 minutes, then cool to 5°C. Slowly add benzoic acid from THF to the reactor, maintaining the temperature <25°C. Maintain the mixture at 10°C, then add boron trifluoride ether (256 g, 1.80 mol, 2.1 eq), maintaining the temperature <30°C. Stir the mixture at 25°C until the reaction is complete (approximately 2 hours, with no more than 5.0% of the starting material remaining). Add toluene (1 L) and cool the mixture to 5°C. Toluene (300 mL) and MeOH (300 mL) were slowly added while maintaining the temperature <30 °C. Then, 1 M hydrochloric acid (2 L) was added, and the temperature was maintained <30 °C. Toluene (1 L) was then added, and the layers were separated. The organic layer was washed with an aqueous solution of NaHCO3 (50 g of NaHCO3 in 1 L of water) and then with water (1 L). The organic layer was concentrated to a final volume of 800 mL under reduced pressure, and the product (4-bromo-2-fluoro-5-methylphenyl)methanol was further concentrated in solution (containing 183 g, 97% yield). 1 H NMR (400 MHz, DMSO- d 6) δ7.44 (d,J = 9.4 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 5.30 (t, J = 5.7 Hz, 1H), 4.47(d, J = 5.7 Hz, 2H), 2.31 (s, 3H).

[0054] [Step 2] A toluene solution of (4-bromo-2-fluoro-5-methylphenyl)methanol from Step 1 (containing 183 g, 0.835 mol, 1.0 eq) was added to the reaction vessel. 48% HBr in water (640 mL) was added to the reactor, and the mixture was heated to 90 °C. After the reaction was complete (approximately 3 hours), the mixture was cooled to 27 °C. The layers were separated, and the organic layer was washed with water (915 mL), followed by two washes with an aqueous solution of NaHCO3 (46 g NaHCO3 in 915 mL, twice) to obtain the product 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene dissolved in the organic layer. 1 H NMR (400 MHz, DMSO- d 6) δ 7.58 (d, J = 9.5 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 4.64 (d, J = 1.0 Hz, 2H), 2.31 (s, 3H).

[0055] [Step 3] Water (457 mL) was added to the reaction vessel, followed by sodium cyanide (45 g, 0.918 mol, 1.1 eq). The mixture was stirred to dissolve at 27 °C, then cooled to 10 °C. DMSO (915 mL) was added, followed by the 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene solution in toluene prepared in Step 2, and the resulting mixture was heated to 35 °C. After the reaction was complete (approximately 24 hours), water (457 mL) and toluene (1.1 L) were added, and the temperature was lowered to 27 °C. The layers were separated, and the organic layer was washed three times with water (732 mL, then 549 mL, then 549 mL). The layers were then separated, and the organic layer was concentrated under reduced pressure to provide the product 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile (183 g, 0.802 mol, 96% yield for both steps). 1 H NMR (400 MHz, DMSO- d 6) δ 7.62 (d, J= 9.4 Hz, 1H), 7.44 (dd, J =8.1, 0.8 Hz, 1H), 4.01 (d, J = 1.0 Hz, 2H), 2.33 (s, 3H).

[0056] [Step 4] Add water (732 mL) to the reaction vessel, then add KOH (140 g, 3.0 eq). Add ethanol (640 mL) to the 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile prepared in Step 3, then add the resulting solution to a reactor containing an aqueous solution of KOH. Heat the mixture to 80°C. After the reaction is complete (approximately 4 hours), cool the mixture to 27°C, then add water (2.0 L) and MTBE (915 mL). Separate the layers and treat the aqueous layer with concentrated HCl until the pH of the mixture is <4.00. Extract the aqueous layer twice with MTBE (2.2 L, then 732 mL). Combine the two MTBE layers and wash with water (915 mL). Separate the layers and concentrate the organic layer under reduced pressure until it reaches a volume of approximately 732 mL. Add heptane (1.1 L) and redistill the mixture under reduced pressure until the volume is approximately 732 mL. Heptane (1.1 L) was added again, and the mixture was redistilled under reduced pressure until the volume was approximately 732 mL. The mixture was heated to 85 °C to dissolve the contents, then cooled to 20 °C, during which time the product crystallized. The product was separated by filtration, washed with heptane (183 mL), and dried under vacuum to produce 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid (170 g, 0.688 mol, 86% yield) as a nearly white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.52 (s, 1H), 7.49 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 3.57 (d, J = 1.4 Hz, 2H), 2.29 (s, 3H).

[0057] Example 2 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetic acid Preparation of 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile 2-Bromo-6-fluoropyridine (100 g, 0.568 mol, 1 eq) was added to the reaction vessel, followed by 3-fluoro-4-(hydroxymethyl)benzonitrile (90 g, 0.596 mol, 1.05 eq) and THF (600 mL). The mixture was cooled to 0°C, and then a solution of potassium tert-butoxide in THF (1.0 M, 568 mL, 0.568 mol, 1.0 eq) was added, maintaining the temperature below 10°C. The mixture was stirred at 5°C for approximately 1 hour. In a separate reactor, water (2 L) and a concentrated aqueous solution of HCl (10 mL) were added, and the mixture was cooled to 5°C. The reaction mixture from the first reaction vessel was slowly added, maintaining the temperature below 10°C. The mixture was stirred at 2.5°C for at least 1 hour, then filtered and washed with water (300 mL). The solids were loaded into the reaction vessel, followed by isopropanol (500 mL). The mixture was heated to 65°C for at least 30 minutes and then cooled to 10°C. The mixture was stirred for at least 1 hour, then filtered and washed with water (200 mL). The solid was dried under vacuum to give the product 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (165 g, 0.537 mol, 95% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 10.0 Hz, 1H), 7.75 (t, J =1.6 Hz, 1H), 7.74 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 7.7, 8.1 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 5.43 (d, J = 1.1 Hz, 2H).

[0058] An alternative method for preparing 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile: 3-fluoro-4-(hydroxymethyl)benzonitrile (36 kg, 240 mmol), 2-methyltetrahydrofuran (324 L), 2-bromo-6-fluoropyridine (43.2 kg, 245 mmol), and 1,2-dimethoxyethane (108 L) were charged into a reactor under argon atmosphere. The solution was heated to 29 °C, and powdered KOH (20.16 kg, 359.3 mmol) was added to the solution in two portions. The mixture was then heated to 45 °C until the content of 3-fluoro-4-(hydroxymethyl)benzonitrile was <3.0 area% as determined by HPLC (5 h). The reaction mixture was allowed to cool to 27°C, and then adjusted to pH 5.50–7.50 at 27°C using an aqueous acetic acid solution (prepared by diluting 6.84 L of acetic acid with 180 L of water). The reaction mixture was stirred and then allowed to settle. The bottom aqueous layer was separated from the top layer containing the organic product. The lower aqueous layer was back-extracted with 108 L of 2-methyltetrahydrofuran, and the organic layers were combined. The combined organic layers were washed with an aqueous NaCl solution (prepared from 18 kg of NaCl and 180 L of water). The resulting organic product solution was concentrated to a volume of 180 L under reduced pressure and below 55°C. Simultaneously, isopropanol (180 L) was added to the contents at 55°C, and then the concentration was further increased to 5 ± 1 volumes under reduced pressure and below 60°C. The addition of isopropanol (180 L) and concentration to 5 ± 1 volumes was repeated twice to give a white heterogeneous mixture. The temperature was raised to 65 °C and water (72 L) was slowly added while maintaining the temperature at 65 °C. The mixture was then stirred for 1 hour after the addition was complete. The reaction was cooled to 10 °C over a 6-hour period and then stirred at 5-10 °C for 2 hours. The solid was collected, washed with water, and then dried under reduced pressure at 55 °C to give 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (62.55 kg, 203.7 mmol, 85% yield) as a pale yellow solid with a purity of 99.4% (HPLC area %).

[0059] 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid (50 g, 0.202 mol, 1 eq) was added to the reaction vessel, followed by isopropanol (450 mL). The mixture was stirred at 30 °C, and then bis(pinacol)diboron (56.5 g, 0.222 mol, 1.1 eq) was added, followed by KOAc (61.5 g, 0.626 mol, 3.1 eq). The mixture was purged with an inert gas for at least 30 min, and then purged with 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II). The DCM complex (2.5 g, 0.003 mol, 0.015 eq) was added. The mixture was heated to 80 °C for approximately 10 hours. The mixture was cooled to 30°C, and then 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (62.1 g, 0.202 mol, 1.0 eq) was added. An aqueous solution of potassium carbonate (56 g K₂CO₃ in 200 mL of water) was added, and the reactor was purged with an inert gas. The mixture was heated to 80°C. After approximately 3 hours, the mixture was cooled to 60°C and then concentrated under reduced pressure until the remaining volume was approximately 300 mL. The mixture was cooled to 27°C, and then water (850 mL) was added. Concentrated HCl was added to water (30 mL), followed by MTBE (1 L), and then additional concentrated HCl was added to water (55 mL). Once the pH reached <4.00, the mixture was heated to 45°C. The layers were separated, and the organic layer was washed with water (250 mL). The organic layer was treated with activated charcoal (7.5 g), then filtered via Celite® Hyflo Super Cel® filter aid and washed with MTBE (200 mL). The filtrate was concentrated under reduced pressure until the remaining volume was approximately 250 mL. Heptane (500 mL) was added, and the mixture was stirred at 45°C for at least 1 hour, then cooled to 25°C. The resulting mixture was filtered, and the filter cake was washed with heptane (50 mL). The crude solids were added to the reaction vessel, followed by isopropanol (200 mL) and water (200 mL). The mixture was heated to 75°C and then cooled to 20°C. The mixture was filtered, and the filter cake was washed with water (50 mL). The solids were added to the reaction vessel, followed by water (300 mL). The mixture was heated to 40°C, stirred for at least 30 minutes, then filtered at 40°C, and the filter cake was washed with water (50 mL). The obtained solid was dried under vacuum to provide the product 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetic acid (58 g, 0.147 mol, 73% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.89 (d, J = 10.6 Hz, 1H), 7.85 (dd, J = 8.2, 7.4 Hz, 1H), 7.72 (s, 1H), 7.71 (m, 1H), 7.23 (d, J = 7.7Hz, 1H), 7.21 (dd, J = 7.4, 6.7 Hz, 1H), 7.17 (d, J = 10.6 Hz, 1H), 6.94 (d,J = 8.2 Hz, 1H), 5.51 (s, 2H), 3.63 (s, 2H), 2.23 (s, 3H).

[0060] Comparative Example 3 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid [Step 1] 4-Bromo-2-fluoro-5-methylbenzoic acid (2.0 g, 8.4 mmol, 1 eq) was added to the reactor. THF (20 mL) was added, followed by a solution of the borane dimethyl sulfide complex (2 M solution in THF, 5 mL, 10 mmol). The mixture was stirred at 25 °C. After the reaction was complete, MeOH (5 mL) was added. The mixture was concentrated, and then EtOAc (40 mL) and 1 M HCl in water (20 mL) were added. The layers were separated and the organic layer was washed with a saturated aqueous NaCl solution (40 mL). The organic matter was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography using EtOAc / hexane (10–35% EtOAc, for 15 min) to provide the product (4-bromo-2-fluoro-5-methylphenyl)methanol (97 wt%, 1.9 g, 8.4 mmol, quantitative yield) as a solid. 1 H NMR (400 MHz, DMSO- d 6) δ 7.44 (d, J = 9.4 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 5.30 (t, J = 5.7 Hz, 1H), 4.47 (d, J = 5.7 Hz, 2H), 2.31 (s, 3H).

[0061] [Step 2] (4-Bromo-2-fluoro-5-methylphenyl)methanol (97 wt%, 1.9 g, 8.4 mmol 1 eq) was added to the reaction vessel. DCM (20 mL) was added. The mixture was cooled to 0 °C, and then phosphorus tribromide (1.0 mL, 2.85 g, 10.5 mmol, 1.25 eq) was slowly added. The mixture was stirred at 0 °C for 15 minutes, and then a saturated aqueous solution of NaHCO3 (30 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (40 mL). The combined organic layers were washed with a saturated aqueous solution of NaCl (30 mL), dried over Na2SO4, filtered, and concentrated to give 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene as a solid, the entire amount of which was used in step 3. 1 H NMR (400 MHz, DMSO- d 6) δ 7.58 (d, J = 9.5 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 4.64 (d, J = 1.0 Hz, 2H), 2.31 (s, 3H).

[0062] [Step 3] Dissolve 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene (as prepared in Step 2) in DMSO (10 mL), then add sodium cyanide (0.6 g, 12.2 mmol, 1.45 eq). Stir the mixture at 25 °C for approximately 1 hour. Add EtOAc (50 mL), followed by water (50 mL). Separate the layers and wash the organic layer with a saturated NaCl aqueous solution (50 mL). Dry the organic layer with Na2SO4 and concentrate to dryness to provide the product 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile (1.3 g, 5.7 mmol, 68% yield of Steps 2 and 3) as a solid. 1 H NMR (400 MHz, DMSO- d 6) δ7.62 (d, J = 9.4 Hz, 1H), 7.44 (dd, J = 8.1, 0.8 Hz, 1H), 4.01 (d, J = 1.0 Hz, 2H), 2.33 (s, 3H).

[0063] [Step 4] 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile (1.2 g, 5.1 mmol, 1 eq) was added to the reaction vessel. Ethanol (5 mL) and water (3 mL) were added, followed by KOH (0.9 g). The mixture was heated to 90 °C and stirred overnight. The mixture was cooled to 5 °C, and then 1 M HCl was added until the pH was between 4 and 5. EtOAc (30 mL) and water (30 mL) were added. The layers were separated and the organic layer was washed with a saturated aqueous NaCl solution (30 mL). The layers were separated, and the organic layer was dried over Na2SO4 and then concentrated to provide the product 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid (1.0 g, 4.1 mmol, 80% yield) as a solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.52 (s, 1H), 7.49 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 3.57 (d, J = 1.4 Hz, 2H), 2.29 (s, 3H).

Claims

1. A method for preparing a compound of the following formula or a salt thereof: in R1 is selected from H, F, and CH3; R2 is selected from H, F, and CH3; R3 is selected from H, F, and CH3; and R1, R2, and R3 are not the same; It includes the following steps: i. Combining a non-halogenated solvent with benzoic acid of the following formula: ii. Add a reducing agent to form benzyl alcohol of the following formula: iii. The benzyl alcohol is combined with the reagent in a second non-halogenated solvent to form a first intermediate of the following formula: ,in X is selected from Cl, Br, I, sulfonate and toluenesulfonate; iv. Combining the first intermediate with cyanide to form benzyl nitrile of the following formula v. Combining the benzyl nitrile with hydroxide; One or more of the following are not separated before the next step: the benzyl alcohol of step (ii), the first intermediate of step (iii), and the benzyl nitrile of step (iv).

2. The method according to claim 1, further comprising the following steps: vi. Combine the compound obtained from step (v) with a borane reagent and a catalyst to form a boronic ester of the following formula: Where R s For forming cyclic borate esters, the C1-C6 alkyl or C2-C6 alkylene groups; vii. Combining the borate ester with a compound of the following formula To obtain the following compound Wherein R1, R2 and R3 are as defined in claim 1, and It is phenyl; 5- or 6-heteroaryl; or pyridone; wherein the phenyl, 5- or 6-heteroaryl, or pyridone is optionally surrounded by one or two R 1a replace; R 1a Each time it appears, it is independently selected from: CN; halogen; C1-C3 alkyl that may be optionally substituted with OH; C1-C3 haloalkyl; C1-C3 alkoxy; C3-C5 cycloalkyl; -SO2C1-C3 alkyl; -C(O)NH2; and Each X 9 It is independently CH or N, and the ring contains no more than one X. 9 For N, each R e Independently selected from: H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl and C1-C3 alkyl optionally substituted with OH, R h H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl, OH, -NR c R d Or C1-C3 alkyl groups optionally substituted with OH; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from the following: C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic, -CH2-C4-C5 heterocyclic, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c R d -NR c R d And C1-C3 alkyl groups optionally substituted with OH; -A- can be -CH2O-; -OCH2- or -CH2NH-; Y 3 Y 4 Y 5 and Y 6 Independently N; CH or CR 2a ; where Y 3 Y 4 Y 5 and Y 6 The two are not more than N and Y 3 Y 4 Y 5 and Y 6 No more than two of them are CR 2a ; R 2a Each time it appears, it is independently either halogenated or methyl; and R c and R d Each is independently H or C1-C3 alkyl.

3. The method according to claim 1 or claim 2, wherein the non-halogenated solvent and the second non-halogenated solvent may be independently selected from acetone, acetonitrile, anisole, butyl acetate, tert-butyl methyl ether, cumene, cyclohexane, dimethylformamide, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, heptane, hexane, isopropanol, methanol, methyl butyl ketone, methyl ethyl ketone, pentane, pyridine, tetrahydrofuran, toluene, and xylene or combinations thereof.

4. The method according to any one of claims 1 to 3, wherein the reducing agent is selected from diborane, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride, and hydrogen or combinations thereof.

5. The method according to any one of claims 1 to 4, wherein the reagent in step iii is selected from HBr, aqueous HBr solution, alcoholic HBr solution, PBr3, dibromodimethylhydantoin, N-bromosuccinimide, HI, aqueous HI solution, PCl3, and toluenesulfonyl chloride or combinations thereof.

6. The method according to any one of claims 1 to 5, wherein the cyanide is selected from LiCN, NH4CN, N(CH3)4CN, N(Et)4CN, N(n-Pr)4CN, N(i-Pr)4CN, N(n-Bu)4CN, N(t-Bu)4CN, HCN, NaCN, KCN, Zn(CN)2 and (CH3)3SiCN or combinations thereof.

7. The method according to any one of claims 1 to 6, wherein the hydroxide is selected from LiOH, NaOH, KOH, Mg(OH)2, Ca(OH)2 or Sr(OH)2 or a combination thereof.

8. The method according to claim 1, wherein the yield of the compound obtained from step (v) calculated from the benzoic acid in step (i) is at least 70% by weight, at least 75% by weight, at least 78% by weight, at least 80% by weight, at least 82% by weight, or at least 85% by weight.

9. The method of claim 2, wherein the yield of the compound obtained from step (v) is calculated to be at least 60% by weight, at least 65% by weight, at least 70% by weight, or at least 72% by weight.

10. The method according to any one of the preceding claims, wherein The benzyl alcohol from step (ii) is not separated before step (iii), and The first intermediate from step (iii) is not separated before step (iv), and The benzyl nitrile from step (iv) is not separated before step (v).

11. A method for preparing a compound of the following formula or a salt thereof: It includes the following steps: i. Combining 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene with a cyanide in a non-halogenated solvent to form a benzyl nitrile of the following formula. ii. Combining the benzyl nitrile with a hydroxide to produce the compound, wherein the benzyl nitrile is not separated prior to step (ii).

12. The method of claim 11, further comprising: iii. Combining the compound obtained from step (ii) with a borane reagent and a catalyst to form a boronic ester of the following formula. Where R s C1-C6 alkyl or C2-C6 alkylene groups for forming cyclic borate esters iv. Combine the borate ester from step (iii) with pyridine of the following formula: To obtain the following compound 。 13. The method of claim 12, wherein the borate ester is not separated prior to combination with pyridine.

14. The method according to any one of claims 11 to 13, wherein the non-halogenated solvent is selected from acetone, acetonitrile, anisole, butyl acetate, tert-butyl methyl ether, cumene, cyclohexane, dimethylformamide, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, isopropanol, methanol, heptane, hexane, methyl butyl ketone, methyl ethyl ketone, pentane, pyridine, tetrahydrofuran, toluene, and xylene, or combinations thereof.

15. The method according to any one of claims 11 to 13, wherein the 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene is obtained by combining benzyl alcohol of the following formula with a brominating agent. 。 16. The method of claim 15, wherein the 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene is not separated prior to combination with cyanide.

17. The method according to claim 15 or claim 16, wherein the brominating agent is selected from HBr, aqueous HBr solution, alcoholic HBr solution, PBr3, dibromodimethylhydantoin and N-bromosuccinimide or combinations thereof.

18. The method according to any one of claims 15 to 17, wherein the benzyl alcohol is obtained by combining benzoic acid of the following formula with a reducing agent in a non-halogenated solvent. 。 19. The method of claim 18, wherein the benzyl alcohol is not separated prior to combination with the brominating agent.

20. The method according to claim 18 or claim 19, wherein the reducing agent is selected from diborane, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride, and hydrogen or combinations thereof.

21. The method according to any one of claims 11 to 20, wherein the cyanide is selected from LiCN, NH4CN, N(CH3)4CN, N(Et)4CN, N(n-Pr)4CN, N(i-Pr)4CN, N(n-Bu)4CN, N(t-Bu)4CN, HCN, NaCN, KCN, Zn(CN)2 and (CH3)3SiCN or combinations thereof.

22. The method according to any one of claims 11 to 21, wherein the hydroxide is selected from LiOH, NaOH, KOH, Mg(OH)2, Ca(OH)2 and Sr(OH)2 or combinations thereof.

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