Method for large-scale preparation of tunlametinib and intermediate thereof

Abstract

The present invention relates to a method for large-scale production of a benzo[d]thiazole intermediate for preparing tunlametinib, and a method for large-scale preparation of tunlametinib by using the intermediate. The method avoids costly and operationally complex column chromatography procedures and significantly increases the yield of the benzo[d]thiazole intermediate, thereby increasing the yield of the final product tunlametinib. Therefore, the method greatly reduces the cost and increases the yield, and is applicable to large-scale production.

Description

Process for the large scale preparation of tolebrutinib and intermediates thereof TECHNICAL FIELD

[0001] The present invention relates to a process for the large scale production of a benz[d]thiazole intermediate for the preparation of tolebrutinib, and a process for the large scale preparation of tolebrutinib using said intermediate, which avoids the costly and complex column chromatography operation, while significantly improving the yield of the benz[d]thiazole intermediate, and thus the yield of the final product tolebrutinib. Therefore, this process greatly reduces the cost, improves the yield, and is suitable for large scale production. BACKGROUND

[0002] Over-activation of the Ras / Raf / Mek / Erk signaling mechanism plays an important role in the proliferation and differentiation of cancer cells; Ras / Raf / Mek / Erk signaling mechanism has been found to be continuously activated or over-activated in a variety of cancers, such as pancreatic cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, skin cancer, breast cancer, etc. Inhibiting the Ras / Raf / Mek / Erk signaling pathway helps the treatment of such over-proliferative diseases, in which Mek, a target downstream of Ras and Raf, plays a key role in the pathway, and the substrate of Mek phosphorylation is MAP kinase Erk. If Mek is inhibited, the Ras / Raf / Mek / Erk signaling pathway will be closed, and thus the proliferation of cancer cells will be inhibited. Therefore, Mek inhibitors can inhibit the growth of cancer cells, especially for cancers caused by over-activation of Ras or Raf. At the same time, Mek is also involved in diseases and symptoms of inflammation, including acute and chronic inflammation.

[0003] Chinese Patent Application No. 201210190520.4 discloses a number of benzothiazole compounds which exhibit protein kinase Mek inhibitory activity, including the compound of Example 1, 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide (hereinafter sometimes referred to as "tolebrutinib"). In the synthesis of tolebrutinib in this application, the benz[d]thiazole intermediate is obtained by condensation cyclization of aryl mercaptide with orthoformate, and the aryl mercaptide is formed by deprotection of a protected mercaptide compound to form a disulfide intermediate, and then reduction of the disulfide bond of the disulfide. However, in this method, the formed disulfide intermediate is unstable, with low yield, and needs to be purified by column chromatography and the like, which results in increased preparation cost and is not suitable for large scale production of tolebrutinib.

[0004] Therefore, it is necessary to develop a new route for the synthesis of tolebrutinib, which avoids the use of expensive column chromatography operation and reduces the reaction steps, and improves the yield suitable for large scale production. SUMMARY

[0005] The methods disclosed herein are particularly suitable for the preparation of the benz[d]thiazole intermediate for tofacitinib in a high quality, high yield reproducible, commercial scale manner, and further tofacitinib. In addition, the method of the present invention for the preparation of the benz[d]thiazole intermediate is a two-step continuous feed process, which is simple to operate, simple to purify, and has a high yield.

[0006] The present invention provides a method for the synthesis of a compound of formula (IV), said method comprising: deprotection of a compound of formula (VII) in the presence of an acid 1 or a base, optionally in a solvent, followed by condensation cyclization with orthoformate in the presence of an acid 2, optionally in a solvent, to form a compound of formula (IV), wherein R 1 , R 2 , R 4 and R 5 are each independently selected from hydrogen or halogen; R 3 is selected from halogen, Ci-C6alkoxy, Ci-C6alkylthio, halo-Ci-C6alkoxy, halo-Ci-C6alkylthio, haloCi-C6alkyl; R 11 is hydrogen; R 14 is hydrogen or Ci-C6alkyl; R 15 is branched alkyl or straight chain alkyl carboxylate.

[0007] In some embodiments, R 1 and R 2 are each independently represent hydrogen, fluorine or chlorine.

[0008] In some embodiments, R 4 is hydrogen.

[0009] In some embodiments, R 5 is hydrogen, fluorine or chlorine.

[0010] In some embodiments, R 3 is bromo, iodo, methylthio, trifluoromethylthio, methoxy, trifluoromethoxy or trifluoromethyl. In some embodiments, R 3 is iodo.

[0011] In some embodiments, R 15 is C3-C6 branched alkyl selected from isopropyl (2-propyl), isobutyl (2-methylpropyl), sec-butyl (2-butyl), tert-butyl (2-methyl-2-propyl), isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), sec-pentyl (2-pentyl), tert-pentyl (2-methyl-2-butyl), isohexyl (3-methylpentyl), sec-hexyl (2-hexyl), and tert-hexyl (2-methyl-2-pentyl). In some embodiments, R15 is tert-butyl.

[0012] In some embodiments, the deprotection of the compound of formula (VII) occurs in the presence of an acid 1 to form a compound of formula (V) wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 14 are as defined above.

[0013] In some embodiments, the acid 1 is an organic acid or an inorganic acid. In some embodiments, the acid 1 is an organic acid selected from trifluoroacetic acid, acetic acid, glacial acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, or acetic acid-trifluoroacetic acid mixture. In some embodiments, the acid 1 is an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid, hydroiodic acid, or fluorohydric acid. In some embodiments, the acid 1 is p-toluenesulfonic acid, trifluoromethanesulfonic acid, or benzenesulfonic acid. In some embodiments, the acid 1 is trifluoromethanesulfonic acid.

[0014] In some embodiments, the deprotection reaction of the compound of formula (VII) in the presence of an acid 1 further comprises a carbocation trap. In some embodiments, the carbocation trap is selected from phenol, anisole, tetrabutylammonium hydroxide, 18-crown-6, tetraphenylphosphonium, benzyl mercaptan, or a trialkylsilane, such as triethylsilane, triisopropylsilane.

[0015] In some embodiments, the deprotection reaction of the compound of formula (VII) in the presence of an acid 1 is carried out at about 0 to about 35 °C, in some embodiments, at about 15 to about 35 °C, such as at about 20 °C, about 25 °C, or about 30 °C. In some embodiments, the deprotection reaction is carried out at 25 °C.

[0016] In some embodiments, R 15 is -(CH2) n -C(O)-OC 1-6 alkyl, wherein n is an integer from 1 to 8. In some embodiments, R 15 is -(CH2)2-C(O)-OMe.

[0017] In some embodiments, the deprotection of the compound of formula (VII) occurs in the presence of a base to form a compound of formula (V) wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 14 are as defined above.

[0018] In some embodiments, the base is an organometallic compound. In some embodiments, the base is a metal hydroxide and an alkali metal alkoxide. In some embodiments, the base is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, or potassium tert-butoxide.

[0019] In some embodiments, the orthoformic ester is selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, or triphenyl orthoformate.

[0020] In some embodiments, the deprotection is carried out in the absence of a solvent. In some embodiments, the solvent is those defined herein. In some embodiments, the solvent is water, methanol, dichloromethane, chloroform, dimethylsulfoxide, or N,N-dimethylformamide.

[0021] In some embodiments, the acid 2 is selected from p-toluenesulfonic acid, p- toluenesulfonic acid pyridinium salt, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid, or phosphoric acid.

[0022] In some embodiments, the compound of formula (IV) is

[0023] In some embodiments, the compound of formula (VII) is

[0024] In some embodiments, the compound of formula (V) is

[0025] The present application also provides a process for preparing a compound of formula (VII), said process comprising reducing a compound of formula (VIII), wherein R 1 , R 2 , R 3 , R 4 , R 14 and R 15 are as defined above.

[0026] In some embodiments, the reducing agent is palladium on carbon (Pd / C), stannous chloride, triphenylphosphine, sodium borohydride, borane, or Raney nickel.

[0027] In some embodiments, the solvent is those defined herein. In some embodiments, the solvent is methanol, tetrahydrofuran, ethyl acetate, or a mixture thereof.

[0028] In some embodiments, the compound of formula (VIII) is In some embodiments, the compound of formula (VIII) is

[0029] The present application also provides a process for preparing a compound of formula (VIII), said process comprising: reacting a compound of formula (IX) wherein R 1 , R 2 , R 3 , R 4 , R 14 and R 15 are as defined above.

[0030] In some embodiments, the azide is an alkali metal azide. In some embodiments, the azide is sodium azide or potassium azide.

[0031] In some embodiments, the solvent is those defined herein. In some embodiments, the solvent is dimethylsulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0032] In some embodiments, the compound of formula (IX) is

[0033] The present application also provides a process for preparing a compound of formula (IX), said process comprising: reacting a compound of formula (X) 15 with a thiol R wherein R 1 , R 2 , R 3 , R 4 , R 14 and R 15 are as defined above, in the presence of a base and a phosphine ligand, in a solvent, in the presence of a catalyst.

[0034] In some embodiments, the base is an organic base such as, but not limited to, N,N-diisopropylethylamine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropylamine, di-n-butylamine, diisopropylamine, 1,2-dimethylpropylamine and the like; an inorganic base such as, but not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide and the like. In some embodiments, the base is N,N-diisopropylethylamine.

[0035] In some embodiments, the catalyst is a palladium catalyst such as, but not limited to, tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) acetate and the like. In some embodiments, the catalyst is preferably tris(dibenzylideneacetone)dipalladium(0).

[0036] In some embodiments, the phosphine ligand is, for example, but not limited to, 4,5- bisdiphenylphosphin-9,9-dimethylxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tri(4-chlorophenyl)phosphine, triisopropylphosphine, tri(2,6-dimethoxyphenyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, and the like. In some embodiments, the phosphine ligand is 4,5-bisdiphenylphosphin-9,9-dimethylxanthene (Xantphos).

[0037] In some embodiments, the solvent is those defined herein. In some embodiments, the solvent is 1,4-dioxane.

[0038] In some embodiments, the compound of formula (X) is

[0039] The present application also provides a compound of formula (IV), (V) and (VII) prepared by the process of the present application, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 14 and R 15 are as defined above.

[0040] The present application also provides a compound of formula (VII) wherein R 1 , R 2 , R 4 and R 5 are each independently selected from hydrogen or halogen; R 3 is selected from halogen, C1-C6alkoxy, C1-C6alkylthio, halo-C1-C6alkoxy, halo-C1-C6alkylthio, haloC1-C6alkyl; R 11 is hydrogen; R 14 is hydrogen or C1-C6alkyl; R 15 is branched alkyl.

[0041] In some embodiments, R 15 is C3-C6branched alkyl selected from isopropyl (2-propyl), isobutyl (2-methylpropyl), sec-butyl (2-butyl), tert-butyl (2-methyl-2-propyl), isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), sec-pentyl (2-pentyl), tert-pentyl (2-methyl-2-butyl), isohexyl (3-methylpentyl), sec-hexyl (2-hexyl), and tert-hexyl (2-methyl-2-pentyl). In some embodiments, R 15 is tert-butyl.

[0042] In some embodiments, R 1 and R 2 each independently represents hydrogen, fluorine or chlorine.

[0043] In some embodiments, R 4 is hydrogen.

[0044] In some embodiments, R 5 is hydrogen, fluorine or chlorine.

[0045] In some embodiments, R 3 is bromine, iodine, methylthio, trifluoromethylthio, methoxy, trifluoromethoxy or trifluoromethyl. In some embodiments, R 3 is iodine. DETAILED DESCRIPTION

[0046] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those of an ordinary skilled artisan in the art to which the application pertains. All patents and publications referred to in this application are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods, devices, and materials are described.

[0047] In the present application, any solvent suitable for the purpose of the present application can be used. The solvent is, for example, water, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and o-dichlorobenzene), aliphatic and aromatic alcohols (e.g., methanol, ethanol, propanol, isopropanol, t-butanol, ethylene glycol, etc.), ethers (e.g., diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane, etc.), esters (e.g., methyl acetate or ethyl acetate, etc.), nitriles (e.g., acetonitrile or propionitrile, etc.), ketones (e.g., acetone, butanone, etc.), amides (e.g., dimethylformamide, dimethylacetamide, and N-methylpyrrolidone, etc.), and dimethyl sulfoxide, tetramethylene sulfone, and hexamethylphosphoric triamide, and N,N-dimethylpropylene urea (DMPU), etc.

[0048] In the present application, a straight chain alkyl group refers to a linear alkyl group having only a single carbon-carbon chain without any branching or branching structure. The straight chain alkyl group is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc.

[0049] In the present application, branched alkyl means an alkyl group having one or more alkyl groups selected from methyl, ethyl or isopropyl attached to the main carbon chain. C3-C6 branched alkyl groups are, for example, isopropyl (2-propyl), isobutyl (2-methylpropyl), sec-butyl (2-butyl), t-butyl (2-methyl-2-propyl), isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), sec-pentyl (2-pentyl), t-pentyl (2-methyl-2-butyl), isohexyl (3-methylpentyl), sec-hexyl (2-hexyl), and t-hexyl (2-methyl-2-pentyl).

[0050] The term "about" as used herein, unless otherwise indicated, means that the quantity (e.g., temperature, pH, volume, etc.) can vary from the stated value by plus or minus 10%, preferably plus or minus 5%.

[0051] The following synthetic procedures and specific examples further describe the application, but they should not be construed to limit or restrict the scope of the application in any way. Examples

[0052] The following examples are illustrative. While efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) used in these examples, some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperatures are in degrees Celsius. Reagents were purchased from commercial vendors such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated.

[0053] Unless otherwise indicated, the following reactions were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with a drying tube; reaction flasks were equipped with rubber septa for the introduction of substrates and reagents by syringe; glassware was oven dried and / or heated dried.

[0054] Unless otherwise indicated, column chromatography purifications were carried out on a Biotage system (Manufacturer: Dyax Corporation) with a silica gel column or on a silica SepPak cartridge (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica gel cartridges.

[0055] Varian instrument operating at 400 MHz 1 H NMR spectra, Bruker NMR spectrometer, AVANCE AV-500 MHz, make: LCMS-2010EV. Example 1

[0056] The following examples illustrate the preparation of benz[d]thiazole intermediates falling within the scope of formula (IV)

[0057] First step: 5L four-port bottle is added with compound 1 (450g), tris(dibenzylideneacetone) dipalladium (34.3g), Xanphos (43.4g), 1,4-dioxane (2250mL), DIPEA (323g) and tert-butyl mercaptan (124g), nitrogen replacement three times, temperature is raised to 95℃, and reaction is kept for 4h. After sampling detection reaction is completed, temperature is lowered to 10℃, filtration is carried out, heating is turned off, ice bath cooling is carried out to 10℃, filtration is carried out, filter cake is rinsed once with ethyl acetate (300mL), combined filtrate is distilled under reduced pressure to 1L at 60℃, methanol (1000mL) is added, and the concentration under reduced pressure is continued to 1L, methanol (2000mL) is added, after stirring for 30min, a large amount of solid is precipitated, 500mL of solvent is distilled off at 60℃ under reduced pressure, the distillation is stopped, temperature is lowered to 20℃, filtration is carried out, filter cake is rinsed once with methanol (300mL), filter cake is obtained, the filtrate is concentrated under reduced pressure to 1L at 50℃, the distillation is stopped, temperature is lowered to 10℃, stirring is carried out for 1h, filtration is carried out, filter cake is rinsed once with methanol (100mL), combined filter cake is dried to obtain compound 2, yellow solid, 408.0g, yield: 88.39%. 1 H NMR (500MHz, DMSO-d6) δ 9.08 (s, 1H), 7.88-7.89 (m, 1H), 7.24-7.28 (m, 1H), 7.10-7.16 (m, 3H), 3.86 (s, 3H), 1.29 (s, 9H). [M+H] + 370.

[0058] Second step: 5L four-port bottle is added with compound 2 (326.6g), dimethylacetamide (DMAC, 1633g) is stirred and dissolved, sodium azide (NaN3, 69g) is added, temperature is raised to 80-90℃, stirring is carried out for 3h, sampling detection reaction is completed, temperature is lowered to room temperature, water (1633mL) is added for quenching, and stirring is continued for 13h, filtration is carried out, filter cake is rinsed once with water (400mL), filter cake is slurried with methanol (1600mL) for 1h, and filtration is carried out to obtain 481g of yellow solid wet product compound 3. 1 H NMR (500MHz, DMSO-d6) δ 9.08 (s, 1H), 7.88-7.89 (m, 1H), 7.24-7.28 (m, 1H), 7.10-7.16 (m, 3H), 3.86 (s, 3H), 1.29 (s, 9H). [M+H]

[0059] Third step: 5L four-port bottle is added compound 3 (450g), 7.5% Pd / C (30g), tetrahydrofuran (1500mL) and methanol (1500mL) are stirred uniformly, then hydrogen is replaced three times, and the reaction is started at 20-25℃. Hydrogen is replaced every 0.5h, a total of 8 times. TLC monitoring shows that there is no raw material left. Filter through diatomite, filter the palladium carbon, rinse the filter cake with ethyl acetate (100mL) once, concentrate the filtrate to dryness at 50℃ under reduced pressure, then dissolve in ethyl acetate (2500mL), filter through diatomite, concentrate the filtrate to 1.5L at 45℃ under reduced pressure, add normal heptane (2000mL), continue to concentrate to 1.5L under reduced pressure, add normal heptane (1500mL) and beat for 1h, then filter and dry the filter cake to obtain compound 4, a white solid, 244.7g, yield (second and third steps): 75.5%. 1 H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.80 (s, 1H), 7.22 - 7.26 (m, 1H), 7.11-7.14 (m, 1H), 6.98 - 7.04 (m, 2H), 6.22 (s, 2H), 3.82 (s, 3H), 1.30 (s, 9H). [M+H] + 367.

[0060] Steps 4 and 5: Add 9.6 kg (phenol) and 102.0 kg (trifluoromethanesulfonic acid) to the reactor, cool to 5°C, and then add 15.0 kg in batches. N453 (4-amino-5-(tert-butylthio)-3-fluoro-2-((2-fluorophenyl)amino)methyl benzoate) was stirred and kept at 25°C for 5 hours. The reaction was monitored to ensure complete N453 reaction. During the incubation period, 150.0 kg of deionized water was added to another reactor, and the temperature was lowered to 5°C. The reacted liquid was then added dropwise to this reactor, with the temperature controlled below 10°C. The mixture was stirred for 40 minutes below 10°C, centrifuged, and rinsed with 15.0 kg of deionized water. The centrifuged solid, 0.75 kg of p-toluenesulfonic acid (monohydrate) and 73.0 kg of trimethyl orthoformate were added. The mixture was kept at 25°C for 1.5 hours, and the reaction was monitored to ensure complete reaction. The temperature was lowered to 5°C, and 75.0 kg of deionized water was added dropwise, controlled to 20°C. The mixture was stirred for 40 minutes below 20°C, centrifuged, and rinsed with 15.0 kg of deionized water. The reactor wall was rinsed with N007B (deionized water), and the solid was centrifuged and stirred with 51.0 kg (n-heptane) at 25 °C for 2 h. After centrifugation, the reactor wall was rinsed with 10.0 kg (n-heptane), and the solid was dried to give compound 6. Yield: 12.1 kg, 92.28%; (steps 4 and 5): 93%. ¹H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 7.23 (dd, J1 = 11.0 Hz, J2 = 8.2 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.91 -6.94 (m, 1H), 6.82-6.90 (m, 1H), 3.88 (s, 3H). [M+H] + 321. Example 2:

[0061] Step 1: Compound 1 (5.0 g), tris(dibenzylacetone)dipalladium (0.38 g), Xanphos (0.49 g), 1,4-dioxane (50 mL), DIPEA (3.6 g), and methyl 3-mercaptopropionate (1.75 g) were purged with nitrogen three times, heated to 100 °C, and reacted for 6 h. After confirming the reaction was complete, the mixture was cooled to 10 °C, concentrated under reduced pressure to obtain the crude product, dissolved in ethyl acetate, filtered to remove insoluble matter, concentrated the organic phase, and separated by column chromatography to obtain compound 7. Yield: 5.5 g, 98.9%. 1H NMR (400 MHz, CDC13) δ 9.21 (s, 1H), 7.97 (dd, J = 7.6, 2.1 Hz, 1H), 7.18 - 7.00 (m, 4H), 3.95 (s, 3H), 3.71 (s, 3H), 3.12 (t, J = 7.3 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H).

[0062] Step 2: Compound 7 (5.0 g) was added to a round bottom flask, stirred to dissolve in dimethylacetamide (DMAC, 25 mL), sodium azide (NaN3, 1.1 g) was added, and the reaction was stirred at 80-90 °C for 3 h. The reaction was sampled and determined to be complete. The reaction was cooled to room temperature, quenched with water (50 mL), and stirred. The reaction was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 8, 5.2 g, yield: 98.3%, which was used directly in the next step.

[0063] Step 3: A 250 mL round bottom flask was charged with compound 8 (5.2 g), 7.5% Pd / C (0.5 g), tetrahydrofuran (25 mL), and methanol (25 mL), stirred to dissolve, and purged with hydrogen three times. The reaction was stirred at 20-25 °C, and hydrogen was purged every 0.5 h for a total of 8 times. The reaction was monitored by TLC. The reaction was filtered through diatomite, and the filtrate was rinsed with ethyl acetate (100 mL). The filtrate was concentrated to dryness at 50 °C under reduced pressure, dissolved in ethyl acetate (100 mL), filtered through diatomite, and concentrated to dryness at 45 °C under reduced pressure. The residue was slurried with n-heptane (20 mL) for 1 h, filtered, and dried to give compound 9, a white solid, 4.2 g, yield: 86%. 1 H NMR (400 MHz, CDC13) δ 9.21 (s, 1H), 7.97 (dd, J = 7.6, 2.1 Hz, 1H), 7.18 - 7.00 (m, 4H), 3.95 (s, 3H), 3.71 (s, 3H), 3.12 (t, J = 7.3 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H).

[0064] Step 4: A 250 mL three-necked flask was charged with compound 9 (4.2 g) and anhydrous tetrahydrofuran (20 mL), cooled to -78 °C with a dry ice / ethanol bath under a nitrogen atmosphere, and 1 M potassium tert-butoxide in tetrahydrofuran (53.0 mL) was added dropwise. After the addition was complete, the reaction was stirred for 30 min. The reaction was quenched with 10% hydrochloric acid solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a mixture of compound 5 and compound 10, 2.52 g, yield: 74.4%. 1H NMR (400 MHz, CDC13) δ 9.34 (s, 1H), 7.46 (s, 1H), 7.09 (d, J = 22.3 Hz, 5H), 4.89 (s, 2H), 3.75 (s, 4H).

[0065] Step 5: Compound 5 and compound 10 (2.5 g) obtained from the previous step were dissolved in tetrahydrofuran / methanol (25 mL, v / v = 10 / 1), and sodium borohydride (0.8 g) was added in batches under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, 10% hydrochloric acid was added to adjust the pH of the reaction solution to 1-2, and dichloromethane was added for extraction. The organic phase was separated, and the crude compound 5 was concentrated and directly used in the next step.

[0066] Step 6: Compound 5 obtained from the previous step was dissolved in methyl orthoformate (12 mL), and p-toluenesulfonic acid (0.16 g) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, water (24 mL) was added, and a solid was precipitated. The solid was filtered, washed with water and petroleum ether, and dried to obtain compound 6 as a light yellow solid, 2.3 g, yield: 88.4%. 1 H NMR (400 MHz, CDC13) δ 9.34 (s, 1H), 7.46 (s, 1H), 7.09 (d, J = 22.3 Hz, 5H), 4.89 (s, 2H), 3.75 (s, 4H). It should be understood that various modifications and changes can be made to the present application by those skilled in the art having the benefit of the teachings presented in this specification and such modifications and changes are intended to fall within the scope of the claims.

Claims

1. A method of synthesizing a compound of Formula (IV), the method comprising: deprotecting a compound of formula (VII) in the presence of an acid 1 or a base, optionally in a solvent, followed by condensation cyclization with an orthoformate in the presence of an acid 2, optionally in a solvent, to form a compound of formula (IV), wherein R 1 , R 2 , R 4 , and R 5 are each independently selected from hydrogen or halogen; R 3 selected from halogen, C1-C6alkoxy, C1-C6alkylthio, halo-C1-C6alkoxy, halo-C1-C6alkylthio, haloC1-C6alkyl; R 11 is hydrogen; R 14 is hydrogen or CrC6alkyl; R 15 is branched or straight chain alkyl carboxylate.

2. The process of claim 1, wherein R 1 and R 2 each independently represents hydrogen, fluorine or chlorine; R 4 is hydrogen; R 5 is hydrogen, fluoro or chloro; and R 3 is bromo, iodo, methylthio, trifluoromethylthio, methoxy, trifluoromethoxy or trifluoromethyl.

3. The method of claim 1 or 2, wherein R 15 is C3-C6 branched alkyl selected from the group consisting of isopropyl (2-propyl), isobutyl (2-methylpropyl), sec-butyl (2-butyl), t-butyl (2-methyl-2-propyl), isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), sec-pentyl (2-pentyl), t-pentyl (2-methyl-2-butyl), isohexyl (3-methylpentyl), sec-hexyl (2-hexyl), and t-hexyl (2-methyl-2-pentyl).

4. The process of claim 3, wherein the deprotection of the compound of formula (VII) to form the compound of formula (V) occurs in the presence of acid 1 wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 14 are as defined above.

5. The process of any one of claims 1-3, wherein the acid 1 is an organic acid or an inorganic acid; preferably the acid 1 is an organic acid selected from trifluoroacetic acid, acetic acid, glacial acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, or an acetic acid-trifluoroacetic acid mixture; preferably the acid 1 is an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid, hydroiodic acid, or fluorohydric acid.

6. The process of any one of claims 1-3, wherein the deprotection reaction of the compound of formula (VII) in the presence of acid 1 further comprises a cationic trapping agent.

7. The process of any one of claims 1-3, wherein the deprotection reaction of the compound of formula (VII) in the presence of acid 1 is carried out at about 0 to about 35 °C.

8. The method of claim 1 or 2, wherein R 15 is -(CH2) n -C(O)-OC 1-6 alkyl, wherein n is an integer from 1 to 8.

9. The process of claim 9, wherein the deprotection of the compound of formula (VII) to form the compound of formula (V) occurs in the presence of a base wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 14 are as defined above.

10. The process of claim 9 or 10, wherein the base is an organometallic compound; preferably a metal hydroxide and an alkali metal alkoxide; more preferably sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, or potassium tert-butoxide.

11. The process of any one of claims 1-10, wherein the orthoformate is selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, or triphenyl orthoformate.

12. The process of any one of claims 1-11, wherein the acid 2 is selected from p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid, or phosphoric acid.

13. The process of claim 1, wherein The compound of formula (IV) is The compound of formula (VII) is and The compound of formula (V) is 14. The method of claim 1, further comprising: (VIII) in the presence of a reducing agent, in a solvent, to form a compound of formula (VII), wherein R 1 , R 2 , R 3 , R 4 , R 14 and R 15 are as defined above.

15. The method of claim 1, further comprising: reacting a compound of formula (IX) with an azide compound in a solvent, wherein R 1 , R 2 , R 3 , R 4 , R 14 and R 15 are as defined above.

16. The method of claim 1, further comprising: with a thiol R-SH in the presence of a base and a phosphine ligand in a solvent in the presence of a catalyst 15 -SH to give a compound of formula (XII) wherein R 1 , R 2 , R 3 , R 4 , R 14 and R 15 are as defined above.

17. A compound of formula (IV), formula (V) and formula (VII) prepared by the process of any one of claims 1 to 16, (VII), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 14 and R 15 are as defined above.

18. Compound of formula (VII) in R 1 , R 2 , R 4 and R 5 are each independently selected from hydrogen or halogen; R 3 selected from halogen, C1-C6alkoxy, C1-C6alkylthio, halo-C1-C6alkoxy, halo-C1-C6alkylthio, haloC1-C6alkyl; R 11 is hydrogen; R 14 is hydrogen or Ci-C6alkyl; R 15 is branched alkyl.

19. The compound of claim 18, wherein R 15 is C3-C6 branched alkyl selected from the group consisting of isopropyl (2-propyl), isobutyl (2-methylpropyl), sec-butyl (2-butyl), t-butyl (2-methyl-2-propyl), isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), sec-pentyl (2-pentyl), t-pentyl (2-methyl-2-butyl), isohexyl (3-methylpentyl), sec-hexyl (2-hexyl), and t-hexyl (2-methyl-2-pentyl).

20. The compound of claim 18, wherein R 15 is t-butyl.

21. The compound of claim 18, wherein R 1 and R2 each independently represents hydrogen, fluoro or chloro.

22. The compound of claim 18, wherein R 4 is hydrogen.

23. The compound of claim 18, wherein R 5 is hydrogen, fluoro, or chloro.

24. The compound of claim 18, wherein R 3 is bromo, iodo, methylthio, trifluoromethylthio, methoxy, trifluoromethoxy, or trifluoromethyl; preferably, R 3 is iodo.

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