Method for the preparation of intermediates useful in the synthesis of SGLT inhibitors

Abstract

The present invention relates to a method for producing an intermediate useful for the synthesis of an SGLT inhibitor. According to the present invention, the compound of formula 9, which is an important intermediate of the compound of formula I, an SGLT inhibitor, can be obtained in high yield and high quality. The method for producing an SGLT inhibitor according to the present invention can be produced without special equipment such as an ozone generator, and the economic efficiency is greatly improved.

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of 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 and is therefore responsible for only a portion of glucose reabsorption in the kidney. In contrast, SGLT2 is a low affinity, high capacity transporter that is primarily located in the apica domain of epithelial cells in the early proximal convoluted tubule. In healthy individuals, more than 99% of plasma glucose filtered in the kidney 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 and the remaining 10% is mediated by SGLT1 in the late proximal straight tubule. Genetic mutations in SGLT2 have no particular adverse effect on carbohydrate metabolism, but the mutation induces increased renal glucose secretion of approximately 140 g / day. Human mutation studies suggest that SGLT2 is responsible for most of the glucose reabsorption in the kidney and has therefore been the subject of therapeutic investigation.

[0003] US Patent Publication No. 2015 / 0152075 (Patent Document 1) discloses a compound having a diphenylmethane residue with inhibitory activity against SGLT2 and a method for producing the same. The document discloses that the diphenylmethane derivative compound has an excellent inhibitory effect against human SGLT2 activity, and is effective in treating diabetes by significantly reducing urinary glucose excretion in animals compared to dapagliflozin, a well-known SGLT2 inhibitor. In addition, US Patent Publication No. 2014 / 0274918 discloses a diphenylmethane derivative that is effective as a dual inhibitor against 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 producing compound c28 employs a linear synthesis method, such as forming a pentagonal ring with an aglycon group after coupling with a glucose group. In the case of such linear synthesis, not only is the route complicated and the final yield low, but if the synthesis of the substituent of the glucose group or the cyclopropylbenzyl group bound to dihydrobenzofuran is incorrect or if you want to change it to something else, you have to start the synthesis again from the beginning, which is troublesome. In addition, the process of synthesizing the cyclopropyl group of compound c28 is also performed by cyclizing an olefin through the Simmons-Smith reaction at the end of the synthetic route, so there is a problem that the yield varies greatly depending on the state (purity, anhydrous, etc.) of the reagents (diethylzinc, solvent) and the reaction concentration.

[0009] In addition, Korean Patent Publication No. 2017-0142904 (Patent Document 2) discloses a method for producing a diphenylmethane derivative having 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 the following reaction schemes 2a and 2b, and therefore the synthesis route is simpler than the linear synthesis method disclosed in the conventional document, the yield can be increased, and the risk factors inherent in the linear synthesis route can be reduced.

[0010] [ka]

[0011] [ka]

[0012] However, the synthesis of c40, which is an important intermediate for producing the diphenylmethane compound c28 useful as an SGLT inhibitor, requires an extremely long process (14 steps) (Reaction Scheme 2a), and when proceeding with the synthesis using c1 as a starting material, it requires special equipment such as an ozone generator, which poses difficulties in terms of the 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 process 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 synthesis method for the compound of Chemical Formula 9, which is an important intermediate of the compound of Chemical Formula I below, using a more commercially available starting material, 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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 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.

[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 embodiment of the compound of formula I, n is 1; X is halogen; and B is phenyl substituted or unsubstituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-7 alkyl, C3-10 cycloalkyl, and C1-7 alkoxy.

[0022] In addition, the compound of formula I may be a compound in which the binding 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 Formula 9, which is an intermediate used for preparing the diphenylmethane derivative of 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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 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.

[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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 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.

[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 reaction 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 O 4 / NaIO 4 The reaction can be carried out using OsO 4 / NaIO 4 When using this method, the more the scale is increased, the more impurities are formed, making it impossible to apply the method to production.

[0029] In order to solve the problems of the prior art, one embodiment of the present invention may use commercially available 2,3-dihydrobenzofuran (compound of Chemical Formula 1 below), 2,3-dihydrobenzofuran-7-carboxylic acid (compound of Chemical Formula 2 below), or 2,3-dihydrobenzofuran-7-amine (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 total yield of 26% in the existing method according to Korean Patent Publication No. 2017-0142904 (Patent Document 2) through selective bromination and formylation processes using 2,3-dihydrobenzofuran (the compound of Chemical Formula 1 below) as a starting material, and the number of synthesis steps can be reduced to a total of 7, maximizing production efficiency. In addition, since special equipment such as an ozone generator is not required, it can be produced in general equipment, and the economy can be greatly improved by producing it in a high yield.

[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, and 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); Obtaining chemical formula 9 from chemical formula 8 (Step 7).

[0032] [ka]

[0033] [ka]

[0034] In the above formula, R 1 NH 2 and 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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 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.

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

[0037] The lithiation may be carried out with 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 may be used as the organolithium reagent. Although not limited thereto, the reactivity of the lithiation of the compound of formula 1 may be increased by further using tetramethylethylenediamine (TMEDA) in the organolithium reagent. The solvent used in the step of obtaining the compound of formula 2 from the compound of formula 1 (step 1) may be one or more selected from the group consisting of, but not limited to, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethylpropyleneurea, dimethylsulfoxide, ethyl acetate, hexamethylphosphoramide, tetrahydrofuran, pentane, hexane, heptane, ether, and diethyl ether.

[0038] After the lithium conversion of the compound of formula 1, a carboxyl group is introduced using carbon dioxide. 2 The yield can be maximized by using a gas. Carboxylation using carbon dioxide gas can be carried out at -60°C to 0°C, for example, at -60°C to -15°C. Preferably, the yield can be maximized by suppressing heat generation by carrying out the reaction at -60°C to -15°C.

[0039] The step of obtaining a compound of formula 3 from a compound of formula 2 (step 2) comprises the steps of: 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, 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 a carboxy group of a 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 3 from the compound of Chemical Formula 2a.

[0043] The solvent used in the step of synthesizing the compound of formula 2b from the compound of formula 2a and obtaining the compound of formula 3 from the compound of formula 2b (step 2-1) may be selected from the group consisting of ethanol, propanol, butanol, and methoxyethanol. All of the above solvents are applicable, but it may be advantageous to use n-propanol when considering the reaction temperature for producing the compound of formula 2b and the ease of subsequent concentration and removal of the solvent. The solvent may 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 is not limited to, 70°C to 115°C. The preferred reaction temperature may be set to the reflux temperature of the solvent depending on the solvent selected. 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 illustrated in the following reaction scheme. [ka] TEA (Triethylamine): Triethylamine DPPA (Diphenylphosphoryl azide): Diphenylphosphoryl azide

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

[0047] In step 2-2 of obtaining a compound of formula 3 from a compound of formula 2b, the compound of formula 2b is hydrolyzed with NaOH to obtain a compound of formula 3. In this case, it is preferable to obtain a compound of formula 3 with high purity by forming 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 embodiment of the present invention, bromine is used as the halogen, and in this case, it is important to maximize the production of the compound of formula 4, which corresponds to dibromine, while minimizing the production of tribromine, after forming monobromine on the compound of formula 3.

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

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

[0052] N-halosuccinimide may be used in an amount of 2 to 2.3 equivalents based on the compound of Formula 3, and preferably in an amount of 2.05 to 2.15 equivalents in order to minimize the generation 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 in order to minimize the generation 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 be carried out by, but is not limited to, reacting the compound of Formula 4 with NaNO 2 to form a diazonium salt of the compound of formula 4, which can then be reacted 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, and can be, for example, a copper salt, including CuCl, CuBr.

[0054] Although not limited thereto, the NaNO 2can be used in an amount of 1 to 2 equivalents based on the compound of Chemical 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 may be washed with a solvent, such as ethanol, 1-propanol, isopropyl alcohol, etc. Step 4 may further include purifying the mixture with isopropyl alcohol.

[0057] The step of obtaining the compound of Formula 6 from the compound of Formula 5 (Step 5) may include 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, 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 Formula 5 to MgX to become a Grignard reagent, which is 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. Although not 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) of the compound of Chemical Formula 5.

[0061] The reaction of step 5 may be carried out at -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. In order to minimize the production of related substances and reaction intermediates, the reaction may be preferably carried out at 30°C to 50°C. However, since there is a temperature rise due to heat generation when DMF is added, it is preferable that the reaction start temperature is lower than this, that is, 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 an organolithium reagent per equivalent of the compound of Formula 7, but is not limited thereto. For example, n-BuLi may be used. If the organolithium reagent is too much compared to the compound of Formula 7, it may react with the halogen present in the compound of Formula 6, so it is better to use an appropriate equivalent. In addition, in order to keep the lithium salt produced more stable, 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 only an organolithium reagent is used, the two impurities remaining in the final compound of formula 9 are generated at 1-9% depending on the equivalent of the organolithium reagent used, whereas when butylmagnesium chloride or tert-butylmagnesium chloride, which can form a complex with a lithium salt to further stabilize the lithium salt, is used, it has been confirmed that the impurities can be reduced to a level of 0-1% depending on the equivalent 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, relative to 1 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. Without being limited thereto, the compound of Chemical Formula 9 can be obtained by reducing the compound of Chemical Formula 8 according to the disclosure of Korean Patent Publication No. 2017-0142904 (Patent Document 2).

[0065] According to the method, the compound of Chemical Formula 9, which is an important intermediate of the compound of Chemical Formula I, an SGLT inhibitor, can be commercially obtained more easily by using the compound of Chemical Formula 1 as a starting material, and the compound of Chemical Formula 9 and the compound of Chemical Formula I, which is the final target compound, can be obtained in high yield and high quality through a total of seven short reaction steps. In addition, 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 including 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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 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.

[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 agent in the presence or absence of a catalyst. The solvent may be dichloromethane, dichloroethane, or the like. The halogenating agent may be, but is not limited to, oxalyl halide, thionyl halide, or the like. When oxalyl halide is used as the halogenating agent, dimethylformamide may be used as the catalyst, but is not limited to, and may be used at 0.1 wt% to 1 wt% with respect to the compound of formula 10.

[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. Although not limited thereto, 1 to 3 equivalents, preferably 2 to 3 equivalents, more preferably 2 to 2.6 equivalents of the compound of formula 12 can be used relative to the compound of formula 11. For the reaction of the compound of formula 11 with the compound of formula 12, AlCl 3 , FeCl 3 , BiCl 3 , ZnCl 2 , Fe 2 O 3 Lewis acids such as, preferably, AlCl 3Although not limited thereto, the Lewis acid can be used in an amount of 0.9 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, based on the compound of Chemical Formula 11.

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

[0073] The compound of Chemical Formula 12 is less expensive than the compound of Chemical Formula 7 and is easier to control the quality of, and therefore has advantages over the use of the compound of Chemical Formula 7.

[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 carboxylation of 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 a halogen.

[0077] In still another embodiment, the compound of formula (10) may be obtained by carboxylation of 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 an 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 a process of 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 an alkyl.

[0081] The method of producing a compound of Chemical Formula 10 from 1) a compound of Chemical Formula 5, 2) a compound of Chemical Formula 6, or 3) a compound of Chemical Formula 14, and then producing a compound of Chemical Formula 9 from the compound of Chemical Formula 10, uses a compound of Chemical Formula 12. The compound of Chemical Formula 12 is less expensive than the compound of Chemical Formula 7 used in the conventional reaction scheme, and when the compound of Chemical Formula 12 is used, problems caused by impurities generated during the production of Chemical Formula 7 can be solved, and a compound of Chemical Formula 9 and a final target substance of high quality can be obtained. Effect of the Invention

[0082] According to the present invention, the compound of Chemical Formula 9, which is an important intermediate of the compound of Chemical Formula I, an SGLT inhibitor, can be obtained in high yield and 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 the cost efficiency is greatly improved. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 abbreviations used in the following examples have the following meanings: -Ac 2 O(Acetic anhydride): Acetic anhydride -B.F. 3 OEt 2 (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] In the following Examples 1 and 2, the synthesis process of the c40 compound, which is a preferred example of the compound of Chemical Formula 9, is illustrated, and in Example 3, the synthesis process of the c28 compound, which is a preferred example of the compound of Chemical Formula I, from the c40 compound is illustrated. In addition, 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] EXAMPLES

[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] The 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. n-BuLi (6.4 L, 1.6 eq) was added dropwise to the cooled mixture 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. CO was added to the cooled reaction mixture. 2 (gas) was added. At this time, the temperature rose to -10°C, and it was added until the temperature did not rise any further. After confirming the completion of the reaction through 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 to precipitate crystals. The crystallized mixture was adjusted to 5°C-15°C and stirred for 2 hours. The crystallized liquid was further cooled to 0°C-5°C, filtered, and washed with water (4.8 L). The filtrate was dried at 60°C-70°C for 48 hours to obtain the yellow title compound (1.29 kg, 79%). 1 H NMR (500 MHz, CDCl 3 )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] As the solvent used for the synthesis of compound c47 and hydrolysis to the amine, n-propanol / 2-methoxyethanol / n-butanol / ethanol was applicable. [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, which is a reactant of isocyanate and used as a solvent, is used in an amount of 4 to 8 times, preferably 6 times, the amount of compound c2 in order to minimize the generation of urea impurities. The reaction temperature can be 70°C to 115°C, but is 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 (12.5L), 2,3-dihydrobenzofuran-7-carboxylic acid (c46: 2.5kg, 1.0eq) and triethylamine (1.7kg, 1.1eq) were added to the reactor and cooled to 0℃-5℃. DPPA (4.9kg, 1.2eq) was added to the mixture and stirred for 30 minutes, then heated to 25℃-35℃ and stirred. The reaction was continued until C46 remained at 2% or less. 1-propanol (15L) was added to another reactor and heated to 95℃-100℃. The reaction solution was added to the heated 1-propanol solution and stirred at 90℃-95℃ for 30 minutes. After confirming that the reaction intermediate was 1% or less, the reaction solvent was concentrated and removed. 6N NaOH (325L) was added to the concentrated reaction solution and stirred at 90℃-100℃ for 3-5 hours. When c47 remained at 1% or less, the organic solvent was removed by vacuum concentration, cooled to 20°C to 30°C, and extracted four times with toluene (5L). The extracted toluene layers were combined, completely concentrated, cooled to 10°C to 20°C, and dissolved by adding toluene (17L). A hydrobromic acid / acetic acid solution was added to the solution to adjust the pH to 1-2, and crystallization was carried out, cooled to 10°C to 20°C, and stirred for 1 hour. The generated crystals were filtered and washed with toluene (3.2L). The obtained crystals were dried at 60°C to 70°C for 18 hours to obtain the yellow title compound (2.5kg, 77%). 1 H NMR (500MHz, DMSO d6 + D2 O)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 is a reaction to selectively introduce two bromines at the ortho and para positions, and the amount of NBS, the bromine source, the reaction temperature, and the reaction solvent were important. After the formation of monobromine, it was important to maximize the production of the title substance, dibromine, while minimizing the production of tribromine. Among these, the reaction solvent was selected from those that could dissolve c48 well and proceed with the reaction in a homogeneous state, and the solvents used were EtOH, DMF, DMAc, and NMP. This solvent was able to minimize the production of tribromide, and EtOH was selected in consideration of the highest yield, the minimum tribromide production, and the purification of impurities, and the amount used was 30 times that of c48 so that it could be completely dissolved.

[0097] [Table 2]

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

[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 the reactor and dissolved at 20°C to 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°C to 5°C and stirred for 30 minutes. When it was confirmed that the monobromine remained within 5%, K was added to water (12 L). 2 CO 3 (1.2kg, 1.0wt / wt) and Na 2 S 2 O 3 The reaction solution was poured into an aqueous solution containing 1.2 kg (1.0 wt / wt) and dissolved therein, and the reaction was terminated. The reactor was washed with ethanol (1 L) and then poured into the aqueous solution. After stirring for 30 minutes, the ethanol was removed through vacuum concentration, and the temperature was lowered to 15°C to 25°C, and the crystals were filtered. After washing with water (6 L), the crystals were dried in vacuum at 50°C to 60°C for 16 hours to obtain the title compound (1.5 kg, 92%). 1 H NMR (61 MHz, CDCl 3 )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 (15L) was added to the reactor, the temperature was lowered to 0℃-5℃, and then 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (c49: 3.0kg, 1eq) was added and stirred for 10 minutes. Next, a solution of sodium nitrite (1.1kg, 1.5eq) dissolved in water (2L) was added dropwise to the reactor and stirred at 0℃-5℃ for 30 minutes. The crystals dissolved, and the red solution turned black. c-HCl (12.6L) was added to another reactor, followed by copper(I) chloride (2.2kg, 2.2eq.), and the mixture was heated to 50℃-60℃, and the reaction solution was added thereto and stirred at 50℃-60℃ for 30 minutes to complete the reaction. After confirming that the reaction was complete, it was cooled to 0℃-10℃, and water (20L) was added thereto to terminate the reaction. After stirring for 30 minutes, the mixture was filtered and washed with water (5 kg), and the filtered crystals were dissolved in DCM (20 L). To remove the color, silica gel (2 kg) was placed on the filter, DCM solution was added, filtered, and washed with DCM (5 L). The filtrate was concentrated under reduced pressure to remove DCM, and IPA (6 L) was added and reconcentrated to completely remove the remaining DCM. IPA (12 L) was added to the concentrate, and the mixture was heated to 70-80°C to completely dissolve. The solution was further cooled to 0°C-10°C, stirred for 2 hours, and filtered at the same temperature. The filtered product was washed with IPA (3 L) cooled to 5°C-10°C, and vacuum dried at 50°C-60°C for 16 hours to obtain the title compound as red-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 bromine at the ortho position to an aldehyde, and 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 is preferably 1.5 to 1.6 equivalents, and the amount of DMF used can be 3.5 to 5.5 equivalents, but is preferably 4.5 to 5.5 equivalents. The reaction temperature can be -10°C to 50°C, and is preferably 30°C to 50°C, but since there is a temperature rise due to heat generation when DMF is added, a reaction starting temperature of 25°C to 30°C was selected.

[0104] [Table 3]

[0105] A preferred synthesis example based on the above results is as follows. THF (22.5L) was added to the reactor, and 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (c50: 2.25kg, 1.0eq) was added and dissolved. The air was replaced with nitrogen three times, and then cooled to 0℃-5℃. Isopropyl magnesium chloride (5.1kg, 5.6L, 2M in THF, 1.5eq.) was added dropwise to the solution, and then stirred for 30 minutes. The temperature of the reaction solution was further raised to 25℃-30℃, DMF (2.4kg, 4.5eq) was added, and the mixture was stirred at 25℃-30℃ for 30 minutes. After confirming the completion of the reaction, the reaction solution was cooled to 0℃-10℃. Acetic acid (2.1L) was added to adjust the pH to 4-6, and water (22.5L) was added to terminate the reaction. The solution after the reaction was concentrated under vacuum to completely remove THF, and then cooled to 0°C to 10°C and filtered. The filtrate was washed with water (6.7L). The obtained crystals were placed in a reactor together with n-heptane (17L), heated to 90°C, and stirred for 30 minutes. The solution was further cooled to 0°C to 10°C, stirred for 2 hours, filtered, and washed with n-heptane (4.5L). The obtained crystals were vacuum dried at 50°C to 60°C for 16 hours to obtain the yellow title compound (1.6kg, 85%). 1 H NMR (500 MHz, CDCl 3)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] THF (800 mL) was added to the reactor, and 1-bromo-4-cyclopropylbenzene (c37: 98.0 g, 497.2 mmol) was added and dissolved. The air was replaced with nitrogen three times, and then cooled to -10°C. t-Butyl magnesium chloride (114.8 mL, 229.5 mmol 2M in THF, 0.6 eq.) was gradually added dropwise. After stirring at the same temperature for 10 minutes, it was cooled to -60°C to -70°C. After adding n-butyllithium (176mL, 2.5M in Hex, 439.8mmol 1.15eq.) dropwise to the cooled reaction solution, 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound 36: 100g, 382.4mmol 1.0eq.) dissolved in THF (1600mL) was added dropwise and stirred for 30 minutes. After confirming the completion of the reaction, 1N-HCl (1000mL) aqueous solution was added to terminate the reaction. The completed reaction solution was concentrated under reduced pressure to remove THF. DCM (1000mL) was added to the concentrated solution and stirred for 10 minutes, followed by layer separation. The separated DCM layer was concentrated under reduced pressure and used immediately for the production of the next step compound, 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (c40), without further purification. 1 H NMR (400 MHz, CDCl 3)δ7.33(s, 1H), 7.25(d, J=7.6Hz, 2H), 7.02(d, 8.1Hz, 1H), 6.07(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 acetonitrile (1000 mL) was added. The reaction solution was cooled to -20°C, and then BF 3 OEt 2 (70.8mL, 573.6mmol, 1.5eq) and triethylsilane (122mL, 764.8mmol, 2.0eq) were added and stirred at -20℃ to -25℃ for 1 hour, then the temperature was raised to 20 to 30℃ and stirred for 1 hour. After confirming the completion of the reaction, saturated NaHCO 3 The reaction was terminated by adding the solution (1000 mL) to the reaction solution. The solution after the reaction was concentrated under reduced pressure until the volume was 1000 mL, and then DCM (1000 mL) was added and stirred for 10 minutes, followed by layer separation. The organic layer contained Na 2 SO 4 The water was removed by adding DCM (50 mL), and the concentrate was filtered and concentrated. DCM (50 mL) was added to the concentrate to dissolve it, and then 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%_6, 7-step synthesis). 1 H NMR (400 MHz, CDCl 3)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 3-neck flask containing magnesium (cut pieces, 1.1 g, 46.6 mmol) was flame dried. The flask was fitted with a condenser and a dropping funnel under a nitrogen atmosphere. 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 nitrogen atmosphere was added a freshly prepared solution of (4-cyclopropylphenyl)magnesium bromide (compound c38) (0.85 M in THF 30.0 mL, 26.4 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with MgSO4 The crude residue was carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl 3 )δ7.33(s, 1H), 7.25(d, J=7.6Hz, 2H), 7.02(d, 8.1Hz, 1H), 6.07(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] 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 nitrogen atmosphere was treated with triethylsilane (4.6 mL, 40 mmol) and BF 3 OEt 2 (3.8 mL, 30 mmol) was added. The mixture was allowed to warm to room temperature gradually and stirred at room temperature for an additional 50 min. The reaction mixture was diluted with saturated NaHCO 3 The reaction was quenched by slowly adding ethyl acetate (100 mL) and the organic layer was extracted with MgSO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the title compound (4.4 g, 12.1 mmol, 85% for two steps). 1 H NMR (400 MHz, CDCl 3)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] At -78 °C under nitrogen atmosphere, n-butyllithium (2.5 M in hexane, 23.1 mL, 57.8 mmol) was added dropwise to a solution of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (10.0 g, 27.5 mmol) in THF (80 mL), and then stirred at the same temperature for 10 to 30 min. After confirming the completion of the C3 production reaction by TLC, a solution prepared by adding c-HCl (6.32 mL, 71.5 mmol) to MeOH (100 mL) was added to the reaction mixture to terminate the coupling reaction, and at the same time, the TMS protecting group was removed to form c4 compound as an intermediate. For the synthesis of c5, the reaction temperature was gradually raised to room temperature and stirred for more than 7 h. After confirming the completion of the reaction by TLC, 3% NaHCO 3The reaction was terminated by adding an aqueous solution (220 mL) and stirring for 10 minutes. The solution after the reaction was terminated was concentrated to 160 mL through vacuum concentration. Ethyl acetate (60 mL) and 100 mL of 20% NaCl aqueous solution were added to the concentrated reaction solution, stirred for 10 minutes, and then allowed to stand to separate the organic layer. The aqueous layer was further extracted again by adding 6 times the amount of ethyl acetate. The combined ethyl acetate layers were diluted with MgSO 4 (40 g) was added to remove moisture, then filtered and washed 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), and then cooled to -45°C. The cooled solution was diluted with Et 3 SiH (13.2 mL, 82.5 mmol) and BF 3 Et 2 The reaction mixture was stirred for 5 hours while gradually increasing the temperature from -45°C to 0°C. After confirming the completion of the reaction by TLC, the reaction mixture was diluted with saturated NaHCO 3The reaction was terminated by adding an aqueous solution (200 mL) and the mixture was concentrated to 220 mL. Ethyl acetate (100 mL) was added to the concentrated residue for extraction. Ethyl acetate (50 mL) was added to the extracted aqueous layer for re-extraction, and the ethyl acetate layers were combined and washed with MgSO 4 (40 g). The filtrate was concentrated in vacuum to give the title compound as a light brown color (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 at room temperature in a nitrogen (gas) atmosphere, and DCM (150 mL) was added to dissolve it. 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. The completion of the reaction was confirmed by TLC, and 1N HCl (100 mL) was added and stirred for 10 minutes to terminate the reaction, and the mixture was allowed to stand and separated into layers. DCM (50 mL) was added to the aqueous layer to extract again, and the DCM layers were combined and washed with MgSO 4 (20g) was added, filtered, and dried. MeOH (20mL) was added to the filtrate, which was then concentrated under vacuum. MeOH (100mL) was added to the concentrate, which was stirred at room temperature for 1 hour to precipitate crystals, and then filtered. The filtrate was washed with MeOH (20mL) and dried under vacuum at 50℃ to obtain the title compound as a white product (14.01g, 82.9%). 1 H NMR (500 MHz, CDCl 3):δ7.04-7.02(m, 2H), 6.98-6.95(m, 2H), 6.53(s, 2H), 5.29-5.24(m, 1H), 5.18-5.12(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), 1.9 9(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 with THF (25 mL) and methanol (25 mL). After heating to 30°C to 35°C, 4N-NaOH solution (10.2 mL, 40.7 mmol) was added to the slurry solution and stirred for 2 hours. Completion of the reaction was confirmed by TLC, and the mixture was cooled to 0°C, and then 1N HCl was added to adjust the pH of the reaction solution to 6.8 to 7.0 to terminate the reaction. The reaction mixture was concentrated under reduced pressure to 60 mL, and then water (100 mL) and ethyl acetate (100 mL) were added for extraction. Ethyl acetate (100 mL) was added to the aqueous layer for re-extraction, and then MgSO 4(20g) was added, dried, filtered, and concentrated under reduced pressure in a vacuum. Ethyl acetate (55mL) was added to the concentrated residue and completely dissolved at 80℃, then slowly cooled to room temperature to precipitate crystals, and stirred for 1 hour. IPE (91mL) was added dropwise to the crystallized solution for 30 minutes, cooled to 0℃, and further stirred at 0℃~5℃ for 1 hour. After standing at 0℃~5℃ for 1 hour, it was filtered, washed with IPE:ethyl acetate=1:1 solution twice, and dried at 50℃ in a vacuum to obtain the title compound as a white solid (3.4g, 93.1%). 1 H NMR (500 MHz, CDCl 3 ): 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) In a nitrogen atmosphere, 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (C50, 2.0 g, 6.40 mmol) was added to the reactor, and THF (20 mL) was added to dissolve it. The reactor was cooled to 0°C to 5°C, and isopropyl magnesium 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 another 15 minutes. A cannula was connected to the reaction solution, and CO was added. 2 (g) was added for 1 hour. After the completion of the reaction was confirmed by TLC, the reaction was cooled to 0°C to 5°C. 1N-HCl (20 mL) was added to the reactor to terminate the reaction, and the reactor was extracted twice with ethyl acetate (20 mL). The collected ethyl acetate layer was added with Na 2 SO 4 After removing water by adding ethyl acetate, the mixture was filtered and concentrated under vacuum. Then, methyl t-butyl ether (4 mL) was added to the concentrate and stirred at room temperature, and hexane (12 mL) was further added to mature 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 obtain 1.42 g (80%) of the title compound c51. 1 H NMR (500 MHz, CDCl 3 ): 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 (22.5L) was added to the reactor, and 4,6-dibromo-7-chloro-2,3-dihydrobenzofuran (c50: 2.25kg, 1.0eq) was added and dissolved. The air was replaced with nitrogen three times, and then cooled to 0℃-5℃. Isopropyl magnesium chloride (5.1kg, 5.6L, 2M in THF, 1.5eq.) was added dropwise to the solution, and then stirred for 30 minutes. The temperature of the reaction solution was further increased to 25℃-30℃, DMF (2.4kg, 4.5eq) was added, and the solution was stirred at 25℃-30℃ for 30 minutes. After confirming the completion of the reaction, the reaction solution was cooled to 0℃-10℃. Acetic acid (2.1L) was added to adjust the pH to 4-6, and water (22.5L) was added to terminate the reaction. The solution after the reaction was concentrated under vacuum to completely remove THF, and then cooled to 0-10°C and filtered. The filtrate was washed with water (6.7L). The obtained crystals were charged into a reactor together with n-heptane (17L), heated to 90°C, and stirred for 30 minutes. The solution was further cooled to 0°C-10°C, stirred for 2 hours, filtered, and washed with n-heptane (4.5L). The obtained crystals were vacuum dried at 50°C-60°C for 16 hours to obtain the yellow title compound (1.6kg, 85%). 1 H NMR (500 MHz, CDCl 3 )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°C to 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 generated crystals were filtered and washed with methyl t-butyl ether (120 mL). Water (600 mL) was added to the filtrate and stirred for 10 minutes, followed by layer separation, and then additional extraction with methyl t-butyl ether (180 mL) twice. The collected organic layer was washed twice with water (180 mL), and the organic layer was 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 to mature the crystals for 1 hour. The crystals formed were filtered, washed with hexane (60 mL), and vacuum dried at 50° C. for 12 hours to obtain 57.3 g (90.0%) of the title compound c51. 1 H NMR (500 MHz, CDCl 3 ): 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 slowly added 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 diluted with saturated NH 4 The reaction was quenched by adding Cl and extracted with EtOAc (aqueous pH ~7.0). The organic layer was washed with MgSO 4 It was dried over ice, 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 (500 MHz, CDCl 3 )δ7.15(s, 1H), 4.73(m, 4H), 3.29(t, J=8.8Hz, 2H), 1.91(t, J=6.4Hz, 1H);[MH 2 O]+245.

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

[0136] CH at room temperature 2 Cl 2 To a solution of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (11.7 g, 44.4 mmol) in (450 mL) was slowly added pyridinium chlorochromate (14.4 g, 66.6 mmol). 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 (500 MHz, CDCl 3)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) 4N-NaOH (51.4mL, 205.8mmol) was added to a mixture of methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (c34, 20.0g, 68.6mmol) in ethanol (200mL) at room temperature. The mixture was stirred at room temperature for 2 hours, and the completion of the reaction was confirmed by TLC. Then, 1N-HCl was added to the reaction solution (acidic pH ~ 1.0) to terminate the reaction, and the reaction was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum to obtain the title compound c51 (18.3g, 44.4mmol, 96.3%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ): 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) C51 (5.0 g, 18.1 mmol) was dissolved in DCM (30 mL) under a nitrogen atmosphere, and DMF (0.5% wt) was added as a catalyst. The reaction solution was cooled to 0°C to 10°C, and then oxalyl chloride (1.87 mL, 21.8 mmol, 1.2 eq) was added dropwise. The reaction solution was heated to 20°C to 30°C and stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated in vacuum. DCM (10 mL) was further added to the concentrated solution, which was then concentrated in vacuum to remove excess oxalyl chloride. The quantitatively obtained gray-white target compound was used immediately in the next reaction without purification.

[0141] Step 1-2: Synthesis of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbonyl chloride (c52) C51 (5.0 g, 18.1 mmol) was dissolved in DCM (30 mL) under a nitrogen atmosphere, and thionyl chloride (2.63 mL, 36.2 mmol, 2.0 eq) was added dropwise at 20°C to 30°C. After the addition was completed, the mixture was heated and stirred under reflux for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated in vacuum. Further DCM (10 mL) was added to the concentrated solution, which was then concentrated in vacuum to remove excess thionyl chloride. The quantitatively obtained gray-white target compound was used immediately in the next reaction without 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 nitrogen atmosphere, DMF (0.01 mL, 0.13 mmol) was added, and 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, and AlCl was added to the reaction mixture. 3(0.58g, 4.32mmol) was added and stirred at the same temperature for 60 minutes. After confirming the completion of the reaction by TLC, 1N-HCl aqueous solution was added to the reaction solution to terminate the reaction, and the reaction was extracted with ethyl acetate. The organic layer obtained by extraction was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuum. The concentrated residue was purified by silica gel chromatography to obtain the title compound c40 (1.18g, 86.7%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ): 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), 3.3 6(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. Et 3 SiH (1.2 mL, 7.71 mmol) and BF 3 -Et 2 After adding 2H2O (0.79 mL, 6.42 mmol) in order, the reaction mixture was warmed to room temperature and stirred for 4 hours. After confirming the completion of the reaction by TLC, the reaction solution was diluted with saturated NaHCO 3 The reaction was terminated by adding aqueous solution (40 mL) and extracted with ethyl acetate. The organic layer obtained by extraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. 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 (500 MHz, CDCl 3):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 1 / 4 cheaper than expensive 1-bromo-4-cyclopropylbenzene and is easy to control the quality, as a coupling compound, thereby optimizing the Friedel-Crafts acylation reaction conditions and ensuring 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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 5-10 membered heterocycloalkyl; said 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; 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. 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 according to claim 2, wherein the organomagnesium reagent is used in an amount of 1-2 equivalents relative to 1 equivalent of the compound of formula 5, and the dimethylformamide is used in an amount of 3-6 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. The method according to 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 8.

7. The method according to 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 butylmagnesium chloride or tert-butylmagnesium 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 based on 1 equivalent of the compound of formula 7.

10. The method of claim 1, wherein the step of reacting the compound of formula 6 with the compound of formula 7 to obtain the compound of formula 8 comprises 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. 【Chemistry 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 through a Sandmeyer reaction. 【Chemistry 4】 In the above formula, X and Y are each independently a halogen.

12. The Sandmeyer reaction is carried out by 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. 【Chemistry 5】 In the above formula, X, Y, and R ４ are each independently a halogen; B is, 【Chemistry 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 a C3-10 cycloalkyl, a C5-10 cycloalkenyl, a C6-14 aryl, a 5-13 membered heteroaryl, or a 5-10 membered heterocycloalkyl; said 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; 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. 【Chemistry 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. 【Chemistry 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 an 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, which is obtained by obtaining a compound of formula 6 from a 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 an alkyl.

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