Method for producing intermediate useful for synthesis of SGLT inhibitor

Abstract

To provide a novel method for producing a compound of Chemical Formula 9, which is an intermediate useful for the synthesis of an SGLT inhibitor.MEANS FOR SOLVING THE PROBLEM: Developed is a synthesis method utilizing a more commercially available starting material, having a short reaction step and a high total yield. A compound of Chemical Formula 9, which is an important intermediate for a compound of Chemical Formula I as an SGLT inhibitor, can be obtained with high yield and high quality.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for preparing intermediates useful in the synthesis of SGLT inhibitors. [Background technology]

[0002] Sodium-dependent glucose cotransporters (SGLTs) transport glucose against its concentration gradient while simultaneously transporting Na + Two important SGLT isoforms have been cloned and are known as SGLT1 and SGLT2. SGLT1 is located in the intestine, kidney, and heart and regulates cardiac glucose transport through its expression. SGLT1 is a high-affinity, low-capacity transporter, responsible for only a portion of glucose reabsorption in the kidney. In contrast, SGLT2 is a low-affinity, high-capacity transporter located primarily in the apical domain of epithelial cells in the early proximal convoluted tubule. In healthy individuals, more than 99% of plasma glucose filtered through the renal glomerulus is reabsorbed, and less than 1% of the total filtered glucose is excreted in the urine. It is estimated that 90% of renal glucose reabsorption is facilitated by SGLT2, while the remaining 10% is mediated by SGLT1 in the late proximal straight tubule. Genetic mutations in SGLT2 do not have any particular adverse effects on carbohydrate metabolism, but they induce increased renal glucose secretion of approximately 140 g / day. Studies of human mutations suggest that SGLT2 is responsible for most of the renal glucose reabsorption and has therefore been the subject of therapeutic research.

[0003] US Patent Publication No. 2015 / 0152075 (Patent Document 1) discloses compounds having a diphenylmethane residue that have inhibitory activity against SGLT2 and a method for preparing the same. The document also discloses that the diphenylmethane derivative compounds have superior inhibitory effects against human SGLT2 activity and are effective in treating diabetes by significantly reducing urinary glucose excretion in animals compared with dapagliflozin, a well-known SGLT2 inhibitor. Furthermore, US Patent Publication No. 2014 / 0274918 discloses diphenylmethane derivatives that are effective as dual inhibitors of sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2).

[0004] Example 172 of US Patent Publication No. 2015 / 0152075 (Patent Document 1) discloses a method for producing a diphenylmethane compound c28 useful as an SGLT inhibitor by the method shown in Reaction Scheme 1 below.

[0005] [ka]

[0006] [ka]

[0007] [ka]

[0008] However, the conventional method for preparing compound C28 employs a linear synthesis method, which involves coupling with a glucose group and then forming a pentagonal ring with an aglycon group. This linear synthesis method not only results in a complex route and low final yield, but also requires a tedious restart from the beginning if an error occurs during the synthesis of the glucose group substituent or the cyclopropylbenzyl group attached to dihydrobenzofuran, or if a different one is desired. Furthermore, the process of synthesizing the cyclopropyl group of compound C28 is performed by cyclizing an olefin through the Simmons-Smith reaction at the end of the synthetic route, which poses a problem in that the yield varies significantly depending on the condition (purity, anhydrousness, etc.) of the reagents (diethylzinc, solvent) and the reaction concentration.

[0009] Korean Patent Publication No. 2017-0142904 (Patent Document 2) discloses a method for producing a diphenylmethane derivative with inhibitory activity against SGLT2. The document discloses that the diphenylmethane derivative is produced by a convergent synthesis method in which major groups are individually synthesized and then coupled, as shown in Reaction Schemes 2a and 2b below. This method simplifies the synthesis route compared to the linear synthesis methods disclosed in previous documents, increases yields, and reduces the risks inherent in linear synthesis routes.

[0010] [ka]

[0011] [ka]

[0012] However, the synthesis of c40, a key intermediate for producing the diphenylmethane compound c28 useful as an SGLT inhibitor, requires a very long 14-step process (Reaction Scheme 2a), and when proceeding with c1 as a starting material, it requires special equipment such as an ozone generator, which poses difficulties in terms of overall yield and economy. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US Published Patent Publication No. 2015 / 0152075 [Patent Document 2] Korean Patent Publication No. 2017-0142904 Summary of the Invention [Problem to be solved by the invention]

[0014] The present invention provides a novel method for preparing the compound of formula 9, which is a useful intermediate for the synthesis of SGLT inhibitors. [Means for solving the problem]

[0015] The present inventors have developed a synthetic method for synthesizing the compound of Chemical Formula 9, which is a key intermediate for the compound of Chemical Formula I below, using commercially available starting materials with fewer reaction steps and a higher overall yield, thereby completing the present invention.

[0016] The compound of formula I, which is the final target compound and the active ingredient used in the SGLT inhibitor, is as follows: [ka]

[0017] In the above formula, n is 1 or 2, X is a halogen (e.g., F, Cl, Br, or I); B is [ka] and In this case, Ra, Rb, Rc, and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

[0018] In an embodiment of the present invention, the ring B-1 may be selected from the group consisting of: [ka]

[0019] In the above formula, R7 is hydrogen or C1-7 alkyl; R8a and R8b are each independently C1-7 alkyl or are linked together to form a 5-10 membered heterocycloalkyl (containing one or more heteroatoms selected from the group consisting of N, S, and O).

[0020] In other embodiments, the ring B-2 may be selected from the group consisting of: [ka]

[0021] According to a preferred example of the compound of formula I, n is 1; X is halogen; and B may be phenyl substituted or unsubstituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C alkyl, C cycloalkyl, and C alkoxy.

[0022] In addition, the compound of Formula I may be a compound in which the bonding site between the diphenylmethane derivative and the heterocycloalkyl ring is in the α-form, β-form, or racemic form thereof.

[0023] For example, the compound of formula I may be a compound of formula Ia: [ka] In the above formula, B, n and X are as defined above.

[0024] The present invention provides a method for preparing the compound of Chemical Formula 9, which is an intermediate used in the preparation of the diphenylmethane derivative of Chemical Formula I. [ka]

[0025] In the above formula, X and Y are each independently a halogen; B is [ka] and In this case, Ra, Rb, Rc, and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

[0026] The present invention provides a method for preparing a compound of formula 9, comprising the steps of: obtaining a compound of formula 6 from a compound of formula 5; and reacting the compound of formula 6 with the compound of formula 7 to obtain the compound of formula 8. [ka]

[0027] In the above formula, R 2 , R 3 , X and Y are each independently a halogen; B is [ka] and In this case, Ra, Rb, Rc, and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

[0028] In Korean Patent Publication No. 2017-0142904 (Patent Document 2), the process for producing the compound of Chemical Formula 9 consists of a total of 14 steps (Reaction Scheme 2a). In addition, when proceeding with the process using c1 as a starting material, there is a problem that special equipment such as an ozone generator is required. In the absence of ozone reaction equipment, s The reaction can be carried out using O4 / NaIO4, but when using OsO4 / NaIO4, the more the reaction is scaled up, the more impurities are formed, making it impossible to apply to production.

[0029] In order to solve the problems of the prior art, one embodiment of the present invention can use commercially available 2,3-dihydrobenzofuran (a compound of Chemical Formula 1 below), 2,3-dihydrobenzofuran-7-carboxylic acid (a compound of Chemical Formula 2 below), or 2,3-dihydrobenzofuran-7-amine (a compound of Chemical Formula 3 below) (including salt forms) as a starting material to obtain a compound of Chemical Formula 9.

[0030] In one embodiment of the present invention, the compound of Chemical Formula 9 can be synthesized in a high yield of 39% compared to the 26% total yield of the existing method disclosed in Korean Patent Publication No. 2017-0142904 (Patent Document 2) through a total of 7 efficient steps via selective bromination and formylation processes using 2,3-dihydrobenzofuran (the compound of Chemical Formula 1 below) as a starting material. The number of synthesis steps can also be reduced to a total of 7, maximizing production efficiency. Furthermore, the high yield allows production using general equipment without the need for specialized equipment such as an ozone generator, significantly improving economic efficiency.

[0031] In one embodiment, the method for preparing the compound of Formula 9 according to the present invention may include the following steps 1 to 7. The starting material may be a compound of Formula 1, a compound of Formula 2, a compound of Formula 3, or a compound of Formula 4. Therefore, one or more of steps 1 to 4 may not be required, if necessary: obtaining a compound of formula 2 from a compound of formula 1 (step 1); obtaining a compound of formula 3 from a compound of formula 2 (step 2); obtaining a compound of formula 4 from a compound of formula 3 (step 3); obtaining a compound of formula 5 from a compound of formula 4 (step 4); obtaining a compound of formula 6 from a compound of formula 5 (step 5); Reacting the compound of formula 6 with the compound of formula 7 to obtain the compound of formula 8 (step 6); Step 7: Obtaining Chemical Formula 9 from Chemical Formula 8.

[0032] [ka]

[0033] [ka]

[0034] In the above formula, R 1 is NH2, R 2 , R 3 , X and Y are each independently a halogen; B is [ka] and In this case, Ra, Rb, Rc, and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

[0035] The step of obtaining a compound of Chemical Formula 2 from a compound of Chemical Formula 1 (Step 1) may include lithiating a compound of Chemical Formula 1 in a solvent, followed by carboxylation using carbon dioxide gas to obtain a compound of Chemical Formula 2.

[0036] The lithiation can be carried out using a known organolithium reagent, which is an organometallic compound containing a carbon-lithium bond. In one embodiment of the present invention, organolithium reagents that can be used for the lithiation include methyllithium, n-butyllithium, sec-butyllithium, isopropyllithium, tert-butyllithium, phenyllithium, etc. For example, the organolithium reagent can be n-butyllithium.

[0037] The lithiation can be carried out using 1 to 2 equivalents, for example, 1.5 to 2 equivalents, of an organolithium reagent relative to 1 equivalent of the compound of Formula 1. For example, 1.6 equivalents or more of n-butyllithium can be used as the organolithium reagent. The reactivity of the lithiation of the compound of Formula 1 can be increased by further using tetramethylethylenediamine (TMEDA) in addition to the organolithium reagent. The solvent used in the step (Step 1) of obtaining the compound of Formula 2 from the compound of Formula 1 can be, but is not limited to, one or more solvents selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropylene urea, dimethyl sulfoxide, ethyl acetate, hexamethylphosphoramide, tetrahydrofuran, pentane, hexane, heptane, ether, and diethyl ether.

[0038] After the lithiation of the compound of Chemical Formula 1, a carboxyl group is introduced using carbon dioxide. In this case, the yield can be maximized by using CO2 gas to prevent moisture intrusion. Carboxylation using carbon dioxide gas can be carried out at -60°C to 0°C, for example, -60°C to -15°C. Preferably, the reaction is carried out at -60°C to -15°C to suppress heat generation and maximize the yield.

[0039] The step of obtaining the compound of formula 3 from the compound of formula 2 (step 2) comprises: The carboxy group of the compound of the formula 2 is converted to an acyl azide group to obtain a compound of the formula 2a below: obtaining a compound of formula 2b from a compound of formula 2a, This may include obtaining a compound of formula 3 from a compound of formula 2b.

[0040] [ka]

[0041] In the above formula, A represents C1-4 alkyl or C1-4 alkoxy.

[0042] Step 2 may include Step 2-1 of converting the carboxy group of the compound of Chemical Formula 2 to an acyl azide group to obtain a compound of Chemical Formula 2a below, and Step 2-2 of obtaining a compound of Chemical Formula 2b from the compound of Chemical Formula 2a, and Step 2-2 of obtaining a compound of Chemical Formula 3 from the compound of Chemical Formula 2b.

[0043] The solvent used in the synthesis of the compound of formula 2b from the compound of formula 2a and the step of obtaining the compound of formula 3 from the compound of formula 2b (step 2-1) can be selected from the group consisting of ethanol, propanol, butanol, and methoxyethanol. All of the above solvents are applicable, but the use of n-propanol may be advantageous when considering the reaction temperature for producing the compound of formula 2b and the ease of subsequent solvent removal by concentration. The solvent can be used in an amount of 4 to 9 times (w / v) the starting material.

[0044] The steps of obtaining a compound of Formula 2b from a compound of Formula 2a and obtaining a compound of Formula 3 from a compound of Formula 2b may be carried out at, but are not limited to, 70°C to 115°C. A preferred reaction temperature can be set to the reflux temperature of the solvent selected depending on the solvent. In one embodiment of the present invention, the steps of obtaining a compound of Formula 2b from a compound of Formula 2a and obtaining a compound of Formula 3 from a compound of Formula 2b are carried out in n-propanol, and the reaction temperature may be 90°C to 100°C.

[0045] The process of synthesizing a compound of Formula 2b using n-propanol and then synthesizing a compound of Formula 3 from the compound of Formula 2b is exemplified by the following reaction scheme. [ka] TEA (Triethylamine): Triethylamine DPPA (Diphenylphosphoryl azide): Diphenylphosphoryl azide

[0046] The azide compound of formula 2a is produced from the compound of formula 2 via TEA and DPPA through Curtius rearrangement. When n-propanol is added in-situ to the azide compound of formula 2a and heated, the compound of formula 2b is produced via the isocyanate compound (formula 2a'). In this case, the azide and isocyanate intermediates are unstable and the reaction proceeds in-situ.

[0047] In step 2-2 of obtaining the compound of Formula 3 from the compound of Formula 2b, the compound of Formula 2b is hydrolyzed with NaOH to obtain the compound of Formula 3. In this case, preferably, the compound of Formula 3 can be obtained with high purity by forming an HBr salt at pH 1-2 using hydrobromic acid / acetic acid to effectively remove impurities produced together.

[0048] The step of obtaining a compound of Formula 4 from a compound of Formula 3 (Step 3) may include reacting a compound of Formula 3 in a solvent with an N-halo succinimide to obtain a compound of Formula 4.

[0049] Step 3 is a reaction to selectively introduce two halogens into the ortho and para positions, and the equivalent amount of N-halosuccinimide, which is the halogen source, the reaction temperature, and the reaction solvent are important. In the examples of the present invention, bromine was used as the halogen. In this case, after forming monobromine on the compound of Formula 3, it is important to maximize the production of the compound of Formula 4, which corresponds to dibromine, while minimizing the production of tribromine.

[0050] The reaction solvent is preferably a solvent that can dissolve the compound of Formula 3 well and allow the reaction to proceed in a homogeneous state. Such a reaction solvent may be, but is not limited to, one or more solvents selected from the group consisting of ethanol, N,N-dimethylformamide, N,N-dimethylacetamide (DMAc), and N-methylpyrrolidone (NMP). The solvent can be used in an amount of 10 to 40 times (w / v) the amount of the compound of Formula 3.

[0051] Although not limited thereto, in one embodiment of the present invention, the solvent is ethanol, and can be used in an amount of 30 to 40 times the amount of the compound of Chemical Formula 3.

[0052] N-halosuccinimide can be used in an amount of 2 to 2.3 equivalents relative to the compound of Formula 3, and preferably in an amount of 2.05 to 2.15 equivalents to minimize the formation of impurities.

[0053] The reaction temperature in the step (Step 3) of obtaining the compound of Formula 4 from the compound of Formula 3 may be -10°C to 30°C, and is preferably -10°C to 5°C to minimize the formation of impurities. The step (Step 4) of obtaining the compound of Formula 5 from the compound of Formula 4 may include halogenating the amine of the compound of Formula 4 through a Sandmeyer reaction. The Sandmeyer reaction may include, but is not limited to, reacting the compound of Formula 4 with NaNO2 to form a diazonium salt of the compound of Formula 4, and then reacting the diazonium salt with a transition metal salt to obtain the compound of Formula 5. The transition metal salt refers to a salt of a transition metal, including, but not limited to, copper, iron, and cobalt. For example, it may be a copper salt, including CuCl and CuBr.

[0054] Although not limited thereto, NaNO2 can be used in an amount of 1 to 2 equivalents relative to the compound of Formula 4.

[0055] The reaction of the diazonium salt of the compound of Chemical Formula 4 with the transition metal salt can be carried out at 30° C. to 80° C., for example, 40° C. to 70° C., or 50° C. to 60° C. In order to minimize non-halogenated impurities, the reaction is preferably carried out at 50° C. to 60° C.

[0056] To purify impurities, the mixture can be washed with a solvent, such as ethanol, 1-propanol, isopropyl alcohol, etc. Step 4 may preferably further include a step of purifying the mixture with isopropyl alcohol.

[0057] The step (Step 5) of obtaining the compound of Chemical Formula 6 from the compound of Chemical Formula 5 may include selectively converting the X substituent of the compound of Chemical Formula 5 to an aldehyde group using an organomagnesium reagent and dimethylformamide (DMF) as reaction reagents, where the organomagnesium reagent is a compound represented by RMgX (R = alkyl or aryl, X = halogen).

[0058] In one embodiment of the present invention, isopropylmagnesium chloride, an example of an organomagnesium reagent, converts X at the ortho position of the compound of Chemical Formula 5 to MgX to form a Grignard reagent, which is then converted to an aldehyde group by reacting with DMF.

[0059] Although not limited thereto, the organomagnesium reagent can be used in an amount of 1 to 2 equivalents, preferably 1 to 1.7 equivalents, relative to 1 equivalent of the compound of Chemical Formula 5. DMF can be used in an amount of 3 to 6 equivalents, preferably 4 to 5 equivalents, relative to 1 equivalent of the compound of Chemical Formula 5.

[0060] In Step 5, tetrahydrofuran (THF), diethyl ether, 2-methyl tetrahydrofuran, etc. can be used as a reaction solvent. Without being limited thereto, the reaction solvent can be used in an amount of 5 to 15 times (w / v), preferably 8 to 12 times (w / v), the amount of the compound of Formula 5.

[0061] The reaction in Step 5 may be carried out at a temperature of -10°C to 50°C, for example, 0°C to 50°C, 10°C to 50°C, 20°C to 50°C, or 30°C to 50°C. To minimize the formation of related substances and reaction intermediates, the reaction may be carried out preferably at a temperature of 30°C to 50°C. However, since the temperature rises due to heat generation when DMF is added, the reaction initiation temperature is preferably lower, at 25°C to 30°C.

[0062] The step (Step 6) of obtaining the compound of Formula 8 by reacting the compound of Formula 6 with the compound of Formula 7 may include lithiating the halogen position of the compound of Formula 7 and then coupling with the compound of Formula 6. The lithiation may be performed using an organolithium reagent as described above. The lithiation may be performed using 1 to 1.3 equivalents of the organolithium reagent per equivalent of the compound of Formula 7. For example, n-BuLi may be used. If the amount of the organolithium reagent is too large compared to the compound of Formula 7, it may react with the halogen present in the compound of Formula 6, so it is recommended to use an appropriate equivalent. To maintain the stability of the resulting lithium salt, it is preferable to add butylmagnesium chloride or tert-butylmagnesium chloride to the compound of Formula 7 in a solvent before the lithiation reaction. When using only an organolithium reagent, the two impurities remaining in the final compound of Formula 9 were found to be 1-9% depending on the amount of organolithium reagent used. However, when butylmagnesium chloride or tert-butylmagnesium chloride, which form a complex with the lithium salt to further stabilize it, were used, the impurities could be reduced to a 0-1% level depending on the amount of butylmagnesium chloride or tert-butylmagnesium chloride used. Butylmagnesium chloride or tert-butylmagnesium chloride can be used in an amount of 0.2-1 equivalent, for example, 0.5-1 equivalent, or 0.5-0.7 equivalent, per equivalent of the compound of Formula 7.

[0063] The step of reacting the compound of Formula 6 with the compound of Formula 7 to obtain the compound of Formula 8 may include obtaining a compound of Formula 7′ from the compound of Formula 7, and coupling the compound of Formula 7′ with the compound of Formula 6. [ka]

[0064] The step of obtaining the compound of Chemical Formula 9 from the compound of Chemical Formula 8 (Step 7) can be carried out by a known method, including, but not limited to, the method disclosed in Korean Patent Publication No. 2017-0142904 (Patent Document 2), in which the compound of Chemical Formula 9 is obtained by reducing the compound of Chemical Formula 8.

[0065] According to this method, the compound of Chemical Formula 9, which is an important intermediate for the compound of Chemical Formula I, an SGLT inhibitor, can be obtained commercially more easily by using the compound of Chemical Formula 1 as a starting material, and the compound of Chemical Formula 9 and the final target compound, the compound of Chemical Formula I, can be obtained in high yield and high quality through a total of seven short reaction steps. Furthermore, the method for producing the SGLT inhibitor is economical because it can be produced without special equipment such as an ozone generator.

[0066] In another embodiment of the present invention, the compound of formula 9 can be prepared by a method comprising the steps of obtaining a compound of formula 11 from a compound of formula 10; reacting a compound of formula 11 with a compound of formula 12 to obtain a compound of formula 13; and obtaining a compound of formula 9 from a compound of formula 13.

[0067] The present invention provides a method for preparing a compound of formula 9, comprising the steps of: obtaining a compound of formula 11 from a compound of formula 10; reacting a compound of formula 11 with a compound of formula 12 to obtain a compound of formula 13; and Obtaining a compound of formula 9 from a compound of formula 13.

[0068] [ka]

[0069] In the above formula, X, Y, and R 4 are each independently a halogen; B is [ka] and In this case, Ra, Rb, Rc, and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

[0070] The step of obtaining the compound of Formula 11 from the compound of Formula 10 is a process of halogenating the carboxy group of the compound of Formula 10. The compound of Formula 10 is dissolved in a solvent and reacted with a halogenating reagent in the presence or absence of a catalyst. Examples of the solvent include dichloromethane and dichloroethane. Examples of the halogenating reagent include, but are not limited to, oxalyl halide and thionyl halide. When oxalyl halide is used as the halogenating reagent, dimethylformamide can be used as the catalyst, and can be used in an amount of 0.1 wt% to 1 wt% based on the compound of Formula 10, but is not limited to this.

[0071] The step of reacting the compound of Formula 11 with the compound of Formula 12 to obtain the compound of Formula 13 can be carried out at a reaction temperature of -35°C to -10°C to minimize side reactions. Preferably, the reaction temperature is -20°C to -10°C. The compound of Formula 12 can be used in an amount of 1 to 3 equivalents, preferably 2 to 3 equivalents, and more preferably 2 to 2.6 equivalents, based on the compound of Formula 11, without limitation. A Lewis acid such as AlCl3, FeCl3, BiCl3, ZnCl2, or Fe2O3, preferably AlCl3, can be used for the reaction of the compound of Formula 11 with the compound of Formula 12. The amount of the Lewis acid used can be, without limitation, 0.9 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, based on the compound of Formula 11.

[0072] The compound of formula 13 can be reduced to prepare the compound of formula 9.

[0073] The compound of Formula 12 is advantageous over the use of the compound of Formula 7 because it is cheaper and easier to control the quality.

[0074] The compound of Chemical Formula 10 can be produced from 1) the compound of Chemical Formula 5, 2) the compound of Chemical Formula 6, or 3) the compound of Chemical Formula 14.

[0075] In one embodiment, the compound of Formula 10 may be obtained by carboxylating the compound of Formula 5. [ka] In the above formula, R 2 , X and Y are each independently a halogen.

[0076] In another embodiment, the compound of Formula 10 may be obtained by converting the aldehyde group of the compound of Formula 6 to a carboxy group. [ka] In the above formula, R 2 and Y are each independently halogen.

[0077] In still another embodiment, the compound of Formula 10 may be obtained by carboxylating the compound of Formula 14. [ka] In the above formula, X and Y are each independently a halogen; R 5 is C 1-4 It is alkyl.

[0078] The compound of Chemical Formula 6 can be synthesized from the compound of Chemical Formula 5 or the compound of Chemical Formula 14.

[0079] In one embodiment of the present invention, the compound of Formula 6 may be obtained by selectively converting the X substituent of the compound of Formula 5 to an aldehyde group, as described above. [ka] In the above formula, R 2 , X and Y are each independently a halogen.

[0080] In another embodiment, The compound of Formula 6 is obtaining a compound of formula 15 from a compound of formula 14, It may be obtained by obtaining a compound of Chemical Formula 6 from a compound of Chemical Formula 15. [ka] In the above formula, X and Y are each independently a halogen; R 5 is C 1-4 It is alkyl.

[0081] The method for producing a compound of Chemical Formula 9 from 1) a compound of Chemical Formula 5, 2) a compound of Chemical Formula 6, or 3) a compound of Chemical Formula 14 to a compound of Chemical Formula 10 uses a compound of Chemical Formula 12. The compound of Chemical Formula 12 is cheaper than the compound of Chemical Formula 7 used in the conventional reaction scheme. Furthermore, the use of the compound of Chemical Formula 12 can solve the problem of impurities generated during the production of Chemical Formula 7, thereby enabling the production of a compound of Chemical Formula 9 and a final target substance with high quality. [Effects of the Invention]

[0082] According to the present invention, the compound of Chemical Formula 9, which is an important intermediate for the SGLT inhibitor compound of Chemical Formula I, can be obtained in high yield and with high quality. The method for producing the SGLT inhibitor according to the present invention does not require special equipment such as an ozone generator, and is therefore economically efficient. DETAILED DESCRIPTION OF THE INVENTION

[0083] The present invention will be described in more detail below with reference to examples. However, the following examples are merely for the purpose of illustrating the present invention, and the scope of the present invention is not limited to these examples.

[0084] [Abbreviation] The meanings of the abbreviations used in the following examples are as follows: -Ac2O (Acetic anhydride): Acetic anhydride -BF3OEt2 (Boron trifluoride etherate): Boron trifluoride etherate -n-BuLi (n-Butyl lithium): n-butyl lithium -DIPEA (Diisopropylethylamine): N,N-diisopropylethylamine -DMAP (4-Dimethylaminopyridine): 4-Dimethylaminopyridine -DMF (N,N-Dimethylformamide): N,N-Dimethylformamide - DCM (Dichloromethane): Dichloromethane -DPPA (Diphenylphosphorylazide): Diphenylphosphorylazide -EA (Ethyl acetate): Ethyl acetate -EtOH (Ethanol): Ethanol -Hex (Hexane): Hexane -MeOH (Methanol): Methanol -NBS (N-Bromosuccinimide): N-Bromosuccinimide -OXalylchloride: Oxalyl chloride -THF: tetrahydrofuran -Toluene: Toluene -HCl (Hydrochloride): Hydrochloride -HBr(Hydrobromide): Hydrobromide -TMEDA (Tetramethylethylenediamine): Tetramethylethylenediamine

[0085] The following Examples 1 and 2 illustrate the synthesis process of the c40 compound, which is a preferred example of the compound of Chemical Formula 9, and Example 3 illustrates the synthesis process of the c28 compound, which is a preferred example of the compound of Chemical Formula I, from the c40 compound. Furthermore, Example 4 illustrates the synthesis process of c40 centered on c51.

[0086] The following reaction scheme 3 is a schematic diagram of the synthesis process of the c40 compound exemplified in Examples 1 and 2. [ka] [Example]

[0087] Example 1: Synthesis of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (Compound 40)

[0088] Step 1: 2,3-Dihydrobenzofuran-7-carboxylic acid (compound 46) [ka]

[0089] A reactor was charged with n-heptane (12 L), 2,3-dihydrobenzofuran (c45: 1.2 kg, 1.0 eq) and TMEDA (1.74 kg, 1.5 eq), and cooled to 5°C to 15°C. To the cooled mixture, n-BuLi (6.4 L, 1.6 eq) was added dropwise while maintaining the temperature at 5°C to 15°C. The reaction mixture was stirred for 30 minutes and then cooled to -40°C to -55°C. CO2 (gas) was added to the cooled reaction mixture. During this time, the temperature rose to -10°C and continued to be added until it no longer rose. After confirming the completion of the reaction via HPLC, water (136 L) was added to terminate the reaction. MTBE (12 L) was added, stirred for 30 minutes, and then allowed to stand. The separated aqueous layer was transferred to another reactor, and c-HCl was added dropwise to adjust the pH to 1-2, resulting in precipitation of crystals. The crystallized mixture was stirred at 5-15°C for 2 hours. The crystallized mixture was further cooled to 0-5°C, filtered, and washed with water (4.8 L). The residue was dried at 60-70°C for 48 hours to obtain the yellow title compound (1.29 kg, 79%). 1 H NMR(500MHz, CDCl3)δ9.52(s, 1H), 7.84(d, J=7.9Hz, 1H), 7.38(t, 1H), 6.95(m, 1H), 4.76(m, 2H), 3.29(t, J=8.5Hz, 2H);[M+H] + 165

[0090] Step 2: 2,3-Dihydrobenzofuran-7-amine hydrobromide (compound 48) [ka]

[0091] The solvent used for the synthesis of compound c47 and hydrolysis to the amine was n-propanol / 2-methoxyethanol / n-butanol / ethanol. [Table 1] [ka]

[0092] However, n-propanol was selected as the solvent in consideration of the reaction temperature for producing the compound of Formula 2b and the ease of subsequent removal of the solvent by concentration.

[0093] n-Propanol, a reactant of isocyanate and used as a solvent, was used in an amount of 4 to 8 times, preferably 6 times, the amount of compound c2 to minimize the formation of urea impurities. The reaction temperature could be 70°C to 115°C, but preferably 90°C to 97°C, which is the reflux temperature of n-propanol.

[0094] A preferred synthesis example based on the above results is as follows. Toluene (12.5 L), 2,3-dihydrobenzofuran-7-carboxylic acid (C46: 2.5 kg, 1.0 eq), and triethylamine (1.7 kg, 1.1 eq) were added to a reactor and cooled to 0-5°C. DPPA (4.9 kg, 1.2 eq) was added to the mixture and stirred for 30 minutes, then heated to 25-35°C and stirred. The reaction was continued until less than 2% of C46 remained. 1-Propanol (15 L) was added to another reactor and heated to 95-100°C. The reaction mixture was added to the heated 1-propanol solution and stirred at 90-95°C for 30 minutes. After confirming that the reaction intermediates were less than 1%, the reaction solvent was concentrated and removed. 6N NaOH (325 L) was added to the concentrated reaction mixture and stirred at 90-100°C for 3-5 hours. When the concentration of c47 remained at 1% or less, the organic solvent was removed by concentration under reduced pressure. After cooling to 20-30°C, the mixture was extracted four times with toluene (5 L). The extracted toluene layers were combined, completely concentrated, cooled to 10-20°C, and then dissolved in toluene (17 L). A hydrobromic acid / acetic acid solution was added to the solution to adjust the pH to 1-2, followed by crystallization. The solution was cooled to 10-20°C and stirred for 1 hour. The resulting crystals were filtered and washed with toluene (3.2 L). The resulting crystals were dried at 60-70°C for 18 hours to obtain the yellow title compound (2.5 kg, 77%). 1H NMR (500MHz, DMSO d6+D2O) δ7.48-6.56(m, 3H), 4.62(m, J=9.2Hz, 2H), 3.21(t, J=8.5Hz, 2H); [M+H] + 136

[0095] Step 3: 4,6-Dibromo-2,3-dihydrobenzofuran-7-amine (c49) [ka]

[0096] Step 3 was a reaction to selectively introduce two bromine atoms at the ortho- and para-positions. The key factors were the amount of NBS (bromine source), the reaction temperature, and the reaction solvent. After the formation of monobromine, it was important to maximize the production of the title compound, dibromine, while minimizing the production of tribromine. The reaction solvent was selected from among these, based on its ability to dissolve c48 well and allow the reaction to proceed homogeneously. Examples of solvents used were EtOH, DMF, DMAc, and NMP. EtOH was selected as the solvent because it minimizes tribromide production. Its use volume was 30 times that of the original amount, allowing for complete dissolution of c48.

[0097] [Table 2]

[0098] *In Table 2 above, the ethoxylated and monobromide impurities are removed in the next stage of purification.

[0099] A preferred synthesis example based on the above results is as follows. Ethanol (36 L) and 2,3-dihydrobenzofuran-7-amine hydrobromide (C48: 1.2 kg, 1.0 eq) were added to a reactor and heated to 20-30°C until completely dissolved. The mixture was cooled to -10°C, and NBS (2.1 kg, 2.1 eq) was added in portions. The reaction temperature was raised to 0-5°C and stirred for 30 minutes. When it was confirmed that the monobromine remained within 5% concentration, the reaction mixture was added to an aqueous solution prepared by dissolving K2CO3 (1.2 kg, 1.0 wt / wt) and Na2SO3 (1.2 kg, 1.0 wt / wt) in water (12 L) to terminate the reaction. The reactor was washed with ethanol (1 L) and then added to the aqueous solution. After stirring for 30 minutes, the ethanol was removed by vacuum concentration, the temperature was lowered to 15-25°C, and the crystals were filtered. After washing with water (6 L), the precipitate was dried in vacuo at 50°C to 60°C for 16 hours to obtain the title compound (1.5 kg, 92%). 1 H NMR(61MHz, CDCl3)δ7.07(s, 1H), 4.65(t, J=8.5Hz, 2H), 3.91(s, 2H), 3.17(t, J=8.5Hz, 2H),;[M+H] + 294

[0100] Step 4: 4,6-Dibromo-7-chloro-2,3-dihydrobenzofuran (c50) [ka]

[0101] HCl (15 L) was added to the reactor, and the temperature was lowered to 0-5°C. Then, 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (c49: 3.0 kg, 1 eq) was added and stirred for 10 minutes. Next, a solution of sodium nitrite (1.1 kg, 1.5 eq) in water (2 L) was added dropwise to the reactor, and the mixture was stirred at 0-5°C for 30 minutes. The red solution turned black as the crystals dissolved. c-HCl (12.6 L) was added to another reactor, followed by copper(I) chloride (2.2 kg, 2.2 eq). The mixture was heated to 50-60°C, and the reaction mixture was added. The mixture was stirred at 50-60°C for 30 minutes to complete the reaction. After confirming the completion of the reaction, the mixture was cooled to 0-10°C and quenched by adding water (20 L). After stirring for 30 minutes, the mixture was filtered and washed with water (5 kg). The filtered crystals were then dissolved in DCM (20 L). To remove the color, silica gel (2 kg) was placed in a filter, and the DCM solution was added. The filter was then filtered and washed with DCM (5 L). The filtrate was concentrated under reduced pressure to remove the DCM. IPA (6 L) was added and reconcentrated to completely remove the remaining DCM. IPA (12 L) was added to the concentrate and heated to 70-80 °C to completely dissolve it. The solution was further cooled to 0-10 °C, stirred for 2 hours, and filtered at the same temperature. The filtered product was washed with IPA (3 L) cooled to 5-10 °C and dried in vacuo at 50-60 °C for 16 hours to obtain the title compound as reddish-purple crystals (2.27 kg, 71%). 1 H NMR (500MHz, DMSO) δ7.32(s, 1H), 4.72(t, J=7.3Hz, 1H), 3.22(t, J=9.2Hz, 1H); [M+H] + 313

[0102] Step 5: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (c36) [ka]

[0103] Step 5 is a reaction to selectively convert the bromine at the ortho position to an aldehyde, in which the amounts of i-PrMgCl and DMF used, and the reaction temperature were important. The amount of i-PrMgCl used can be 1.0 to 1.7 equivalents, but preferably 1.5 to 1.6 equivalents. The amount of DMF used can be 3.5 to 5.5 equivalents, but 4.5 to 5.5 equivalents is preferred. The reaction temperature can be -10°C to 50°C, but 30°C to 50°C is preferred. However, because the temperature rises due to heat generation when DMF is added, we selected a reaction starting temperature of 25°C to 30°C.

[0104] [Table 3]

[0105] A preferred synthesis example based on the above results is as follows. THF (22.5 L) was added to the reactor, and 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (C50: 2.25 kg, 1.0 eq) was added and dissolved. The atmosphere was replaced with nitrogen three times, and the mixture was cooled to 0-5°C. Isopropyl magnesium chloride (5.1 kg, 5.6 L, 2 M in THF, 1.5 eq.) was added dropwise to the solution, followed by stirring for 30 minutes. The reaction mixture was then further heated to 25-30°C, and DMF (2.4 kg, 4.5 eq) was added and stirred at 25-30°C for 30 minutes. After confirming the completion of the reaction, the reaction mixture was cooled to 0-10°C. Acetic acid (2.1 L) was added to adjust the pH to 4-6, and water (22.5 L) was added to terminate the reaction. After the reaction was completed, the solution was concentrated under vacuum to completely remove THF, cooled to 0-10°C, and filtered. The filtrate was washed with water (6.7 L). The resulting crystals were added to a reactor together with n-heptane (17 L), heated to 90°C, and stirred for 30 minutes. The solution was further cooled to 0-10°C and stirred for 2 hours, after which the crystals were filtered and washed with n-heptane (4.5 L). The resulting crystals were dried under vacuum at 50-60°C for 16 hours to obtain the yellow title compound (1.6 kg, 85%). 1H NMR(500MHz, CDCl3)δ10.34(s, 1H), 7.60(s, 1H), 4.80(t, J=9.2Hz, 1H), 3.35(t, J=9.2Hz, 1H);[M+H] + 263

[0106] Step 6: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (c39) [ka]

[0107] A reactor was charged with THF (800 mL) and 1-bromo-4-cyclopropylbenzene (C37: 98.0 g, 497.2 mmol) was added and dissolved. The atmosphere was replaced with nitrogen three times and then cooled to -10°C. t-Butyl magnesium chloride (114.8 mL, 229.5 mmol, 2 M in THF, 0.6 eq.) was slowly added dropwise. The mixture was stirred at the same temperature for 10 minutes and then cooled to -60°C to -70°C. To the cooled reaction mixture, n-butyllithium (176 mL, 2.5 M in Hex, 439.8 mmol, 1.15 eq.) was added dropwise, followed by the dropwise addition of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound 36: 100 g, 382.4 mmol, 1.0 eq.) dissolved in THF (1600 mL) and stirring for 30 minutes. After confirming completion of the reaction, 1N aqueous HCl (1000 mL) was added to terminate the reaction. The completed reaction mixture was concentrated under reduced pressure to remove THF. DCM (1000 mL) was added to the concentrate and stirred for 10 minutes, followed by layer separation. The separated DCM layer was concentrated under reduced pressure and used immediately in the next step, 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (c40), without further purification. 1H NMR (400MHz, CDCl3) δ7.33(s, 1H), 7.25(d, J=7.6Hz, 2H), 7.02(d, 8.1Hz, 1H), 6.0 7(s, 1H), 4.69(m, 2H), 3.27(m, 2H), 1.85(m, 1H), 0.93(m, 2H), 0.66(m, 2H); [M+H] + 281

[0108] Step 7: 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (c40) [ka]

[0109] The concentrated 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (c39) was dissolved in DCM (1000 mL) and then acetonitrile (1000 mL) was added. The reaction mixture was cooled to -20 °C, and then BF OEt (70.8 mL, 573.6 mmol, 1.5 eq) and triethylsilane (122 mL, 764.8 mmol, 2.0 eq) were added. The mixture was stirred at -20 °C to -25 °C for 1 h, then the temperature was raised to 20-30 °C and stirred for 1 h. After confirming completion of the reaction, saturated NaHCO solution (1000 mL) was added to the reaction mixture to terminate the reaction. The reaction mixture was concentrated under reduced pressure to 1000 mL, and DCM (1000 mL) was added. The mixture was stirred for 10 min and then the layers were separated. The organic layer was added with Na2SO4 to remove water, then filtered and concentrated. DCM (50 mL) was added to the concentrated solution, which was then dissolved. Methanol (800 mL) was added and crystallized at 20-30°C for 2 hours. The crystallized solution was filtered, washed with methanol (100 mL), and vacuum dried at 40-50°C to obtain the ivory-colored title compound (90.0 g, 64.7% yield, 7-step synthesis). 1H NMR (400MHz, CDCl3) δ7.07(d, J=8.0Hz, 2H), 6.99(d, J=8.0Hz, 2H), 6.80(s, 1H), 4.70(t, J=8.8Hz, 2H) ), 3.97(s, 2H), 3.26(t, J=8.8Hz, 2H), 1.88-1.84(m, 1H), 0.95-0.90(m, 2H), 0.68-0.64(m, 2H); [M+H] + 365

[0110] Example 2: Synthesis of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (Compound 40)

[0111] Step 6: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (Compound 39) [ka]

[0112] Preparation of (4-cyclopropylphenyl)magnesium bromide (compound c38): A 250 mL three-neck flask containing magnesium (cut pieces, 1.1 g, 46.6 mmol) was flame-dried. Under a nitrogen atmosphere, the flask was equipped with a condenser and a dropping funnel. 4-Cyclopropylphenyl bromide (compound c37) (6.0 mL, 42.4 mmol) in anhydrous THF (32.4 mL) was transferred to the dropping funnel. Approximately 5 mL of 4-cyclopropylphenyl bromide solution was used to initiate the Grignard reaction. The remaining bromide solution was added at room temperature for 4 h. The resulting solution was used immediately in the next step. To a solution of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound c36) (4.6 g, 17.6 mmol) in anhydrous THF (170 mL) at 0 °C under a nitrogen atmosphere was added a freshly prepared solution of (4-cyclopropylphenyl)magnesium bromide (compound c38) (30.0 mL of 0.85 M in THF, 26.4 mmol). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give the crude title compound (7.6 g, 20.0 mmol, 114%). The crude residue was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ7.33(s, 1H), 7.25(d, J=7.6Hz, 2H), 7.02(d, 8.1Hz, 1H), 6.0 7(s, 1H), 4.69(m, 2H), 3.27(m, 2H), 1.85(m, 1H), 0.93(m, 2H), 0.66(m, 2H); [M+H] + 280.68

[0113] Step 7: 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (Compound 40) [ka]

[0114] Triethylsilane (4.6 mL, 40 mmol) and BFOEt (3.8 mL, 30 mmol) were added to a solution of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (compound 39) (7.6 g, 20 mmol) in DCM / acetonitrile (100 mL / 100 mL) at −20 °C under a nitrogen atmosphere. The mixture was gradually warmed to room temperature and further stirred at room temperature for 50 min. The reaction mixture was quenched by the slow addition of saturated NaHCO solution (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (4.4 g, 12.1 mmol, 85% yield for two steps). 1 H NMR (400MHz, CDCl3) δ7.07(d, J=8.0Hz, 2H), 6.99(d, J=8.0Hz, 2H), 6.80(s, 1H), 4.70(t, J=8.8Hz, 2H) ), 3.97(s, 2H), 3.26(t, J=8.8Hz, 2H), 1.88-1.84(m, 1H), 0.95-0.90(m, 2H), 0.68-0.64(m, 2H): [M+H] + 364.68

[0115] Example 3: Synthesis of (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (c28) [ka]

[0116] Step 8: (3R,4S,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (compound 42) [ka]

[0117] To a solution of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (10.0 g, 27.5 mmol) in THF (80 mL) at -78 °C under a nitrogen atmosphere, n-butyllithium (2.5 M in hexane, 23.1 mL, 57.8 mmol) was added dropwise and stirred at the same temperature for 10–30 min. After confirming completion of the C3 formation reaction by TLC, a solution of c-HCl (6.32 mL, 71.5 mmol) in MeOH (100 mL) was added to the reaction mixture to terminate the coupling reaction and simultaneously remove the TMS protecting group to form compound c4 as an intermediate. To synthesize c5, the reaction temperature was gradually raised to room temperature and stirred for 7 hours or more. After confirming completion of the reaction by TLC, the reaction was terminated by adding 3% aqueous NaHCO3 (220 mL) and stirring for 10 minutes. The reaction mixture was concentrated to 160 mL under reduced pressure. Ethyl acetate (60 mL) and 100 mL of 20% NaCl aqueous solution were added to the concentrated reaction mixture and stirred for 10 minutes. The mixture was then allowed to stand, and the organic layer was separated. The aqueous layer was then re-extracted with 6 portions of ethyl acetate. MgSO4 (40 g) was added to the combined ethyl acetate layers to remove water, followed by filtration and washing with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give the title compound c42, which was used immediately in the next step without further purification. [M+Na]+499 and [M-OMe]+445.

[0118] Step 9: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound c43) [ka]

[0119] (3R,4S,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound c42: 13.12 g, 27.5 mmol, 1.0 eq) was concentrated under a nitrogen atmosphere and dissolved in DCM (100 mL) and acetonitrile (100 mL). The solution was then cooled to -45 °C. EtSiH (13.2 mL, 82.5 mmol) and BFEtO (10.2 mL, 82.5 mmol) were added sequentially to the cooled solution. The reaction mixture was stirred for 5 h while gradually increasing the temperature from -45 °C to 0 °C. After completion of the reaction was confirmed by TLC, the reaction mixture was quenched by adding saturated aqueous NaHCO (200 mL) and concentrated to 220 mL. The concentrated residue was extracted with ethyl acetate (100 mL). The extracted aqueous layer was re-extracted with ethyl acetate (50 mL), and the combined ethyl acetate layers were filtered through MgSO (40 g). The filtrate was concentrated in vacuo to give the title compound as a light brown solid (12.29 g, 100%). The product was used immediately in the next step without further purification.

[0120] Step 10: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound 27) [ka]

[0121] Compound 43 (12.29 g, 27.5 mmol) was concentrated under a nitrogen atmosphere at room temperature and dissolved in DCM (150 mL). DMAP (4.04 g, 33.2 mmol) and acetic anhydride (720.8 mL, 220.8 mmol) were then added and stirred at room temperature for 2 hours. Completion of the reaction was confirmed by TLC, and 1N HCl (100 mL) was added and stirred for 10 minutes to terminate the reaction. The mixture was then allowed to stand and separated. The aqueous layer was re-extracted with DCM (50 mL), and the combined DCM layers were added with MgSO (20 g), filtered, and dried. MeOH (20 mL) was added to the filtrate and concentrated under vacuum. MeOH (100 mL) was added to the concentrate and stirred at room temperature for 1 hour to precipitate crystals, which were then filtered. The residue was washed with MeOH (20 mL) and then dried under vacuum at 50° C. to obtain the title compound as a white solid (14.01 g, 82.9%). 1 H NMR (500MHz, CDCl3): δ7.04-7.02(m, 2H), 6.98-6.95(m, 2H), 6.53(s, 2H), 5.29-5.24(m, 1H), 5.1 8-5.12(m, 2H), 4.71-4.65(m, 2H), 4.31-4.26(m, 1H), 4.25-4.22(m, 1H), 4.15-4.11(m, 1H), 4.15 -4.11(m, 1H), 4.05-3.91(m, 2H), 3.79-3.74(m, 1H), 3.40-3.35(m, 2H), 2.60(s, 3H), 2.05(s, 3H) , 1.99(s, 3H), 1.88-1.81(m, 1H), 1.66(s, 3H), 0.94-0.89(m, 2H), 0.66-0.61(m, 2H); [M+Na]+637.

[0122] Step 11: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 28) [ka]

[0123] Compound 27 (5.0 g, 8.13 mmol) was added to THF (25 mL) and methanol (25 mL). After heating to 30-35°C, the slurry was added with 4N NaOH solution (10.2 mL, 40.7 mmol) and stirred for 2 h. Completion of the reaction was confirmed by TLC. After cooling to 0°C, the reaction mixture was terminated by adding 1N HCl to adjust the pH to 6.8-7.0. The reaction mixture was concentrated under reduced pressure to 60 mL and then extracted with water (100 mL) and ethyl acetate (100 mL). The aqueous layer was further extracted with ethyl acetate (100 mL), dried over MgSO4 (20 g), filtered, and concentrated under reduced pressure. The concentrated residue was completely dissolved in ethyl acetate (55 mL) at 80°C, gradually cooled to room temperature, and then crystallized. The mixture was stirred for 1 h. To the crystallized solution, IPE (91 mL) was added dropwise over 30 minutes, cooled to 0°C, and then stirred for an additional 1 hour at 0°C to 5°C. After standing at 0°C to 5°C for 1 hour, the mixture was filtered, washed twice with a 1:1 solution of IPE:ethyl acetate, and dried in vacuo at 50°C to obtain the title compound as a white solid (3.4 g, 93.1%). 1 H NMR (500MHz, CDCl3): δ7.02(d, J=8.0Hz, 2H), 6.92(d, J=8.0Hz, 2H), 6.81(s, 1H), 4.59(t, J=8.8Hz, 2H), 4.11(d, J=9.2Hz, 1H), 3.96(19.0Hz, 15.2Hz, 2H), 3.87-3.84(m, 1H), 3.67-3.63(m, 1H), 3.47-3.37(m, 3H), 3.35-3.33(m , 3H), 1.85-1.79(m, 1H), 0.91-0.86(m, 2H), 0.61-0.57(m, 2H); [M+Na]+469

[0124] Example 4: Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) The following reaction scheme 5 is a schematic diagram of the synthesis process of the c40 compound exemplified in Example 4. [ka]

[0125] [Route 1] Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) [ka]

[0126] Step 1: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (compound c51) Under a nitrogen atmosphere, 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (c50, 2.0 g, 6.40 mmol) was added to a reactor and dissolved in THF (20 mL). The reactor was cooled to 0-5°C, and isopropylmagnesium chloride (1 M in THF, 9.6 mL, 9.60 mmol) was added dropwise. After stirring at the same temperature for 15 minutes, the temperature was raised to room temperature and stirred for an additional 15 minutes. A cannula was connected to the reaction solution, and CO2 (g) was added for 1 hour. After confirming the completion of the reaction by TLC, the solution was cooled to 0-5°C. 1N HCl (20 mL) was added to the reactor to terminate the reaction, and the mixture was extracted twice with ethyl acetate (20 mL). Na2SO4 was added to the combined ethyl acetate layer to remove moisture, followed by filtration and concentration in vacuo. The concentrate was then added with methyl t-butyl ether (4 mL) and stirred at room temperature, and hexane (12 mL) was added to age the crystals for 1 hour. The resulting crystals were filtered, washed with hexane (4 mL), and dried under vacuum at 50 °C for 12 hours to give the title compound c51 (1.42 g, 80%). 1 H NMR (500MHz, CDCl3): δ7.69 (s, 1H), 4.76 (t, J=9.0Hz, 2H), 3.35 (t, J=9.0Hz, 2H); LC-MS: [M+H]+277.

[0127] [Route 2] Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) [ka]

[0128] Step 1: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (c36) [ka]

[0129] THF (22.5 L) was added to the reactor, and 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (C50: 2.25 kg, 1.0 eq) was added and dissolved. The atmosphere was replaced with nitrogen three times, and the mixture was cooled to 0-5°C. Isopropyl magnesium chloride (5.1 kg, 5.6 L, 2 M in THF, 1.5 eq.) was added dropwise to the solution, followed by stirring for 30 minutes. The reaction mixture was then further heated to 25-30°C, and DMF (2.4 kg, 4.5 eq) was added and stirred at 25-30°C for 30 minutes. After confirming the completion of the reaction, the reaction mixture was cooled to 0-10°C. Acetic acid (2.1 L) was added to adjust the pH to 4-6, and water (22.5 L) was added to terminate the reaction. After the reaction was completed, the solution was concentrated under vacuum to completely remove THF, cooled to 0-10°C, and filtered. The filtrate was washed with water (6.7 L). The resulting crystals were added to a reactor together with n-heptane (17 L), heated to 90°C, and stirred for 30 minutes. The solution was further cooled to 0-10°C and stirred for 2 hours, after which the crystals were filtered and washed with n-heptane (4.5 L). The resulting crystals were dried under vacuum at 50-60°C for 16 hours to obtain the yellow title compound (1.6 kg, 85%). 1 H NMR(500MHz, CDCl3)δ10.34(s, 1H), 7.60(s, 1H), 4.80(t, J=9.2Hz, 1H), 3.35(t, J=9.2Hz, 1H);[M+H]+263

[0130] Step 2: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) [ka]

[0131] After DMF (300 mL) was added to the reactor, 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (c36, 60 g, 229.5 mmol) was added and completely dissolved at room temperature. Oxone (48.9 g, 321.3 mmol) was added in portions at 20-30°C and stirred for 6 hours. After confirming the completion of the reaction by TLC, methyl t-butyl ether (300 mL) was added to precipitate crystals. The resulting crystals were filtered and washed with methyl t-butyl ether (120 mL). Water (600 mL) was added to the filtrate, and the mixture was stirred for 10 minutes. The layers were separated and then extracted twice with methyl t-butyl ether (180 mL). The combined organic layer was washed twice with water (180 mL), and then concentrated under reduced pressure. Methyl t-butyl ether (120 mL) was added to the concentrate and stirred for 10 minutes, and then hexane (360 mL) was added and the crystals were aged for 1 hour. The resulting crystals were filtered, washed with hexane (60 mL), and dried in vacuo at 50 °C for 12 hours to give the title compound c51 (57.3 g, 90.0%). 1 H NMR (500MHz, CDCl3): δ7.69 (s, 1H), 4.76 (t, J=9.0Hz, 2H), 3.35 (t, J=9.0Hz, 2H); LC-MS: [M+H]+277.

[0132] [Route 3] Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) [ka]

[0133] Step 1: (4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (c54) [ka]

[0134] Sodium borohydride (5.07 g, 133.98 mmol) was added slowly to a mixture of methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (c34, 13.0 g, 44.7 mmol) in THF / EtOH (150 mL / 75 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched by the addition of saturated NH4Cl at 0 °C and extracted with EtOAc (aqueous pH ~ 7.0). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (11.7 g, 99%) as a white solid. The crude product was used in the next step without further purification. 1 H NMR (500MHz, CDCl3) δ7.15(s, 1H), 4.73(m, 4H), 3.29(t, J=8.8Hz, 2H), 1.91(t, J=6.4Hz, 1H); [M-H2O]+245.

[0135] Step 2: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (c36) [ka]

[0136] Pyridinium chlorochromate (14.4 g, 66.6 mmol) was added slowly to a solution of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (11.7 g, 44.4 mmol) in CHCl (450 mL) at room temperature. After stirring for 8 h, the precipitate was filtered using a silica gel pad and washed with CHCl. ​​The filtrate was concentrated in vacuo to give the title compound (10.4 g, 39.8 mmol, 90%) as a white solid. The crude product was used in the next step without further purification. 1 H NMR (500MHz, CDCl3) δ10.33(s, 1H), 7.59(s, 1H), 4.79(t, J=8.8Hz, 2H), 3.35(t, J=8.8Hz, 2H); [M+H]+261.

[0137] [Route 4] Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) [ka]

[0138] Step 1: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylic acid (c51) To a mixture of methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (c34, 20.0 g, 68.6 mmol) in ethanol (200 mL) at room temperature was added 4N NaOH (51.4 mL, 205.8 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was quenched by adding 1N HCl (acidic pH ~ 1.0) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to obtain the title compound c51 (18.3 g, 44.4 mmol, 96.3%) as a white solid. 1 H NMR (500MHz, CDCl3): δ7.69 (s, 1H), 4.76 (t, J=9.0Hz, 2H), 3.35 (t, J=9.0Hz, 2H); LC-MS: [M+H]+277.

[0139] Example 5: Synthesis of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (c40) [ka]

[0140] Step 1-1: Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbonyl chloride (c52) Under a nitrogen atmosphere, c51 (5.0 g, 18.1 mmol) was dissolved in DCM (30 mL) and DMF (0.5% wt) was added as a catalyst. The reaction mixture was cooled to 0-10°C, and then oxalyl chloride (1.87 mL, 21.8 mmol, 1.2 eq) was added dropwise. The reaction mixture was heated to 20-30°C and stirred for 1 hour. After confirming the completion of the reaction, the reaction mixture was concentrated in vacuo. Further DCM (10 mL) was added to the concentrate, which was then concentrated in vacuo to remove excess oxalyl chloride. The quantitatively obtained off-white target compound was used in the next reaction without further purification.

[0141] Step 1-2: Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbonyl chloride (c52) Under a nitrogen atmosphere, c51 (5.0 g, 18.1 mmol) was dissolved in DCM (30 mL), and thionyl chloride (2.63 mL, 36.2 mmol, 2.0 eq) was added dropwise at 20-30°C. After the addition was complete, the mixture was heated and refluxed with stirring for 2 hours. After confirming the completion of the reaction, the reaction mixture was concentrated in vacuo. Further DCM (10 mL) was added to the concentrate, which was then concentrated in vacuo to remove excess thionyl chloride. The quantitatively obtained off-white target compound was used in the next reaction without further purification.

[0142] Step 2: Synthesis of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanone (c53) c51 (1.00 g, 3.60 mmol) was dissolved in dichloromethane (30 mL) at room temperature under a nitrogen atmosphere, and DMF (0.01 mL, 0.13 mmol) was added. Then, oxalyl chloride (0.34 mL, 3.96 mmol) was added dropwise. After stirring at room temperature for 1 hour, the mixture was cooled to -15 °C. Next, cyclopropylbenzene (0.91 mL, 7.20 mmol) was added to the reaction mixture and stirred for 5 minutes. AlCl3 (0.58 g, 4.32 mmol) was added to the reaction mixture and stirred at the same temperature for 60 minutes. After confirming the completion of the reaction by TLC, the reaction solution was quenched by adding 1N aqueous HCl and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrated residue was purified by silica gel chromatography to obtain the title compound c40 (1.18 g, 86.7%) as a white solid. 1 H NMR (500MHz, CDCl3): δ7.70(d, J=8.0Hz, 2H), 7.11(d, J=8.0Hz, 2H), 6.99(s, 1H), 4.78(t, J=9.0Hz) , 2H), 3.36(t, J=7.2Hz, 2H), 1.97-1.94(m, 1H), 1.10-1.07(m, 2H), 0.82-0.81(m, 2H);LC-MS:[M+H] + 377.

[0143] Step 3: Synthesis of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (c40) (4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanone (C53) (0.97 g, 2.57 mmol) was dissolved in dichloromethane (10 mL) and acetonitrile (10 mL) in a reactor and then cooled to -15 °C. EtSiH (1.2 mL, 7.71 mmol) and BF-EtO (0.79 mL, 6.42 mmol) were added sequentially to the reaction mixture, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After confirming completion of the reaction by TLC, saturated aqueous NaHCO (40 mL) was added to the reaction mixture to quench the reaction and extract with ethyl acetate. The organic layer obtained from the extraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The concentrated residue was purified by silica gel chromatography to obtain the target compound C40 (0.84 g, 89.9%) as a white solid. 1 H NMR (500MHz, CDCl3): δ7.07(d, J=10.0Hz, 2H), 6.99(d, J=10.0Hz, 2H), 6.80(s, 1H), 4.70(t, J=11.0Hz, 2H), 3. 97(s, 2H), 3.26(t, J=11.0Hz, 2H), 1.88-1.84(m, 1H), 0.95-0.90(m, 2H), 0.68-0.64(m, 2H); LC-MS: [M+H]+363.

[0144] [Table 4]

[0145] Reaction Scheme 3 has the fewest reaction steps and is therefore more competitive than the existing C40 synthesis method of Korean Patent Publication No. 2017-0142904. Reaction Scheme 5 utilizes the C50 intermediate and uses cyclopropylbenzene, which is one-fourth cheaper than the expensive 1-bromo-4-cyclopropylbenzene and is easy to control the quality of, as a coupling compound. This has enabled the optimization of the Friedel-Crafts acylation reaction conditions to ensure competitiveness.

Claims

1. A method for preparing a compound of formula 9, comprising the steps of: obtaining a compound of formula 6 from a compound of formula 5; and reacting the compound of formula 6 with the compound of formula 7 to obtain the compound of formula 8; 【Chemistry 1】 In the above formula, R ２ , R ３ , X and Y are each independently a halogen; B is, 【Chemistry 2】 and In this case, Ra, Rb, Rc and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

2. 2. The method of claim 1, wherein the step of obtaining the compound of Formula 6 from the compound of Formula 5 comprises selectively converting the X substituent of the compound of Formula 5 to an aldehyde group using an organomagnesium reagent and dimethylformamide (DMF) as reaction reagents.

3. The method of claim 2, wherein the organomagnesium reagent is used in an amount of 1 to 2 equivalents relative to 1 equivalent of the compound of formula 5, and the dimethylformamide is used in an amount of 3 to 6 equivalents relative to 1 equivalent of the compound of formula 5.

4. The method of claim 2, wherein the reaction is carried out using tetrahydrofuran (THF), diethyl ether, 2-methyl tetrahydrofuran, or a mixture thereof as a reaction solvent, and the reaction solvent is used in an amount of 5 to 15 times (w / v) the amount of the compound of Formula 5.

5. The method according to claim 2, wherein the reaction is carried out at a temperature of from -10°C to 50°C.

6. 2. The method of claim 1, wherein the step of reacting the compound of Chemical Formula 6 with the compound of Chemical Formula 7 to obtain the compound of Chemical Formula 8 comprises lithiating a halogen position of the compound of Chemical Formula 7 and then coupling the compound of Chemical Formula 6 with the compound of Chemical Formula 6.

7. The method of claim 6, wherein the lithiation is carried out using an organolithium reagent in an amount of 1 to 1.3 equivalents per equivalent of the compound of Formula 7.

8. 7. The method of claim 6, comprising adding butyl magnesium chloride or tert-butyl magnesium chloride to the compound of Formula 7 in a solvent prior to the lithiation reaction.

9. The method according to claim 8, wherein the butyl magnesium chloride or tert-butyl magnesium chloride is used in an amount of 0.2 to 1 equivalent per equivalent of the compound of Formula 7.

10. The method of claim 1, wherein the step of reacting the compound of Chemical Formula 6 with the compound of Chemical Formula 7 to obtain the compound of Chemical Formula 8 comprises obtaining a compound of Chemical Formula 7' from the compound of Chemical Formula 7, and coupling the compound of Chemical Formula 7' with the compound of Chemical Formula 6. 【Transformation 3】

11. The method according to claim 1, wherein the compound of Formula 5 is obtained by halogenating the amine of the compound of Formula 4 by a Sandmeyer reaction. 【Chemistry 4】 In the above formula, X and Y are each independently a halogen.

12. The Sandmeyer reaction involves reacting a compound of formula 4 with NaNO ２ to form a diazonium salt of the compound of formula 4, which is reacted with a transition metal salt to obtain the compound of formula 5.

13. NaNO ２ is used in an amount of 1 to 2 equivalents relative to the compound of formula 4, and the reaction of the diazonium salt of the compound of formula 4 with the transition metal salt is carried out at 30°C to 80°C.

14. A method for preparing a compound of formula 9, comprising the steps of: obtaining a compound of formula 11 from a compound of formula 10; reacting a compound of formula 11 with a compound of formula 12 to obtain a compound of formula 13; and obtaining a compound of formula 9 from a compound of formula 13; 【Transformation 5】 In the above formula, X, Y, and R ４ are each independently a halogen; B is, 【Transformation 6】 and In this case, Ra, Rb, Rc and Rd each independently represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C1-7 alkyl, C1-7 alkylthio, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkyl, C2-7 alkenyl-C1-7 alkyloxy, C2-7 alkynyl-C1-7 alkyloxy, C3-10 cycloalkyl, C3-7 cycloalkylthio, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, C3-10 cycloalkyloxy-C1-7 alkoxy, phenyl-C1-7 alkyl, C1-7 alkylthio-phenyl, phenyl-C1-7 alkoxy , mono- or di-C1-7 alkylamino, mono- or di-C1-7 alkylamino-C1-7 alkyl, C1-7 alkanoyl, C1-7 alkanoylamino, C1-7 alkylcarbonyl, C1-7 alkoxycarbonyl, carbamoyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfinyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, 5-13-membered heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered heterocycloalkyl-C1-7 alkyl, or 5-10-membered heterocycloalkyl-C1-7 alkoxy; Ring C is C3-10 cycloalkyl, C5-10 cycloalkenyl, C6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; The alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, and C2-7 alkynyl; wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy; The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

15. The method according to claim 14, wherein the compound of Formula 10 is obtained by carboxylating the compound of Formula 5. 【Transformation 7】 In the above formula, R ２ , X and Y are each independently a halogen.

16. The method for preparing the compound of formula 9 according to claim 14, wherein the compound of formula 10 is obtained by converting the aldehyde group of the compound of formula 6 to a carboxy group. 【Transformation 8】 In the above formula, R ２ and Y are each independently a halogen.

17. The method for preparing the compound of Formula 9 according to claim 14, wherein the compound of Formula 10 is obtained by carboxylating the compound of Formula 14. 【Chemistry 9】 In the above formula, X and Y are each independently a halogen; R ５ is C １－４ It is alkyl.

18. The method according to claim 16, wherein the compound of Formula 6 is obtained by selectively converting the X substituent of the compound of Formula 5 into an aldehyde group. 【Chemistry 10】 In the above formula, R ２ , X and Y are each independently a halogen.

19. The compound of Formula 6 is obtaining a compound of formula 15 from a compound of formula 14, The method according to claim 16, wherein the compound of formula 6 is obtained from the compound of formula 15. 【Chemistry 11】 In the above formula, X and Y are each independently a halogen; R ５ is C １－４ It is alkyl.

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