Method for producing diphenylmethane derivatives

Abstract

To provide a crystalline form of a diphenylmethane derivative effective as a sodium-dependent glucose cotransporter (SGLT) inhibitor.SOLUTION: The present disclosure provides a crystal of a compound of Formula (c28), wherein the crystalline form has an XRD (X-ray diffraction) spectrum that includes peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 23.5°±0.2° when irradiated using a Cu-Kα light source.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for preparing diphenylmethane derivatives, and more particularly to an improved method for preparing diphenylmethane derivatives useful as inhibitors of the sodium-dependent glucose cotransporter (SGLT). [Background technology]

[0002] Sodium-dependent glucose cotransporters (SGLTs) transport Na + It allows the transport of glucose against its concentration gradient while allowing the transport of glucose up to the intestine. Currently, two important SGLT isoforms, known as SGLT1 and SGLT2, have been cloned. SGLT1 is present in the intestine, kidney and heart and regulates cardiac glucose transport by their expression. Being a high affinity, low capacity transporter, SGLT1 is responsible for only a portion of the glucose reabsorption in the kidney. In contrast, SGLT2 is a low affinity, high capacity transporter that is present mainly in the apical region of the epithelial cells of the early proximal 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. However, the mutation increases renal glucose secretion by approximately 140 g / day. Human mutation studies suggest that SGLT2 is responsible for most renal glucose reabsorption and, therefore, is the subject of therapeutic research.

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

[0004] In Example 172 of U.S. Patent Publication No. 2015 / 0152075, a method for producing a diphenylmethane compound c28 in a manner similar to that in Reaction Scheme 1 below is disclosed.

[0005] [Reaction Scheme 1] [ka] [ka] [ka] [ka]

[0006] However, in the conventional manufacturing method of compound c28, a linear synthesis method such as forming a pentagonal ring on the aglycon group after coupling with the glucose group is used. In the case of such linear synthesis, the final yield is low due to the complicated route. In addition, if the synthesis of the glucose group or the cyclopropylbenzyl group bound to the dihydrobenzofuran fails in the middle, or if it is intended to change the substituent or the cyclopropylbenzyl group to another group, it is inconvenient that the synthesis must be performed again from the beginning. In addition, in the step of synthesizing the cyclopropyl group of compound c28, the yield changes greatly depending on the state (purity, anhydride, etc.) of the reagents (diethylzinc, solvent) and the reaction concentration, so the method is. It is carried out by cyclizing the olefin by the Simon-Smith reaction at the end of the synthetic route.

[0007] Therefore, the present inventors have found that diphenylmethane derivatives can be efficiently produced by a convergent synthesis method in which each main group is separately synthesized and then bonded, rather than by the conventional linear synthesis method, and have thus completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] It is therefore an object of the present invention to provide an improved process for the preparation of diphenylmethane derivatives useful as inhibitors of SGLTs. [Means for solving the problem]

[0009] According to one aspect of the present invention, there is provided a method for preparing a compound of formula 1a: (1) reacting a compound of the following formula 2 with a compound of the following formula 3, and subjecting the resulting product to a cyclization reaction to obtain a compound of the following formula 4; (2) dehydrating or amidating a compound of formula 4, reacting it with a compound of formula 5 below, and carrying out reduction to obtain a compound of formula 6 below; and (3) reacting a compound of formula 6 with a compound of formula 7 below, followed by deprotection and reduction; [ka] [In the formula, A is oxygen (O) or sulfur (S); n is 1 or 2; PG is a protecting group; X' is halogen or C 1-7 is alkyl; X, Y, and Hal are each independently a halogen; B is, (B-1) [ka] or (B-2) [ka] is; where Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C 1-7 Alkyl, C 1-7 Alkylthio, C 2-7 Alkenyl, C 2-7 Alkynyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl, C 2-7 Alkenyl-C 1-7 Alkyloxy, C 2-7 Alkynyl-C 1-7 Alkyloxy, C 3-10 Cycloalkyl, C 3-7 Cycloalkylthio, C 5-10 Cycloalkenyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkyloxy-C 1-7 Alkoxy, Phenyl-C 1-7 Alkyl, C 1-7 Alkylthio-phenyl, phenyl-C 1-7 Alkoxy, mono- or di-C 1-7 Alkylamino, mono- or di-C 1-7Alkylamino-C 1-7 Alkyl, C 1-7 Alkanoyl, C 1-7 Alkanoylamino, C 1-7 Alkyl carbonyl, C 1-7 Alkoxycarbonyl, carbamoyl, mono- or di-C 1-7 Alkylcarbamoyl, C 1-7 Alkyl sulfonylamino, phenyl sulfonylamino, C 1-7 Alkylsulfinyl, C 6-14 Arylsulfanyl, C 6-14 Arylsulfonyl, C 6-14 Aryl, 5-13 membered heteroaryl, 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl-C 1-7 Alkyl, or 5-10 membered heterocycloalkyl-C 1-7 is alkoxy; Ring C is C 3-10 Cycloalkyl, C 5-10 Cycloalkenyl, C 6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; Alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 Alkyl, and C 2-7 having one or more substituents selected from the group consisting of alkynyl; Cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-4 Alkyl, and C 1-4 having one or more substituents selected from the group consisting of alkoxy; and Heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O. A method is provided that includes:

[0010] According to another aspect of the present invention, there is provided a method for preparing a compound of formula 1b: (1) reacting a compound of the following formula 2 with a compound of the following formula 3, and subjecting the resulting product to a cyclization reaction to obtain a compound of the following formula 4; (2) dehydrating or amidating a compound of formula 4, reacting it with a compound of formula 5, and carrying out reduction to obtain a compound of formula 6 below; and (3) reacting a compound of formula 6 with a compound of formula 8 below, followed by reduction to obtain a compound of formula 9 below; (4) forming a furanose ring of the compound of formula 9 into a pyranose ring under acidic conditions, followed by introducing a protecting group to obtain a compound of formula 10 below; and (5) The compound of formula 10 is treated with thiourea and the resulting product is C 1-7 reacting with an alkyl halide followed by reduction; [ka] [ka] [ka] [In the formula, R is C 1-7 is alkylthio; B, n, PG, X', X, Y and Hal are as defined above in Formula 1. A method is provided that includes:

[0011] According to yet another aspect of the present invention, there is provided a crystalline form of the compound prepared by the above method, specifically, a crystalline form of the compound of formula c28 below:

[0012] [Formula c28] [ka] Effect of the Invention

[0013] The method for preparing the diphenylmethane derivatives of the present invention is carried out by a convergent synthesis method in which key groups are synthesized separately and then bonded together. Thus, compared with the linear synthesis methods disclosed in the prior art documents, a simple synthesis route and high yield are achieved, and reproducibility is improved by reducing risk factors inherent in linear synthesis routes (such as returning to the beginning of the route and repeating the synthesis at the point of failure in the middle of the synthesis).

[0014] In particular, according to the methods disclosed in the prior art, even after coupling of the glucose group with the aglycon group, the residues of the aglycon group must be synthesized. On the other hand, according to the present invention, all the residues of the aglycon group can be formed before binding with the glucose group. In addition, the aryl group bound to the terminal group of the aglycon can be easily synthesized, and various designs of the terminal group are possible.

[0015] Furthermore, the crystalline form of the compound produced by the above method has excellent physicochemical properties and can be effectively used in fields such as pharmaceutical production. [Brief description of the drawings]

[0016] [Figure 1-2] 1 shows the XRD and DSC spectra of crystalline form A obtained in Experimental Example 4, respectively. [Diagram 3-4] 1 shows the XRD and DSC spectra of crystalline form B obtained in Experimental Example 4, respectively. [Figure 5-6] 1 shows the XRD and DSC spectra of crystalline form C obtained in Experimental Example 4, respectively. [Figure 7-8] 1 shows the XRD and DSC spectra of crystalline form D obtained in Experimental Example 4, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Best Mode for Carrying Out the Invention The present invention relates to a compound of formula 1: [Formula 1] [ka] The present invention relates to a method for producing the compound of the formula (I).

[0018] During the ceremony, A is oxygen (O) or sulfur (S); R is hydroxymethyl or C 1-7 is alkylthio; n is 1 or 2; X' is a halogen (e.g., F, Cl, Br, or I) or C 1-7 is alkyl; B is, (B-1) [ka] or (B-2) [ka] is; where Ra, Rb, Rc, and Rd are each independently hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C 1-7 Alkyl, C 1-7 Alkylthio, C 2-7 Alkenyl, C 2-7 Alkynyl, C 1-7 Alkoxy, C 1-7 Alkoxy-C 1-7 Alkyl, C 2-7 Alkenyl-C 1-7 Alkyloxy, C 2-7 Alkynyl-C 1-7 Alkyloxy, C 3-10 Cycloalkyl, C 3-7 Cycloalkylthio, C 5-10 Cycloalkenyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkyloxy-C 1-7 Alkoxy, Phenyl-C 1-7 Alkyl, C 1-7 Alkylthio-phenyl, phenyl-C 1-7 Alkoxy, mono- or di-C 1-7Alkylamino, mono- or di-C 1-7 Alkylamino-C 1-7 Alkyl, C 1-7 Alkanoyl, C 1-7 Alkanoylamino, C 1-7 Alkyl carbonyl, C 1-7 Alkoxycarbonyl, carbamoyl, mono- or di-C 1-7 Alkylcarbamoyl, C 1-7 Alkyl sulfonylamino, phenyl sulfonylamino, C 1-7 Alkylsulfinyl, C 6-14 Arylsulfanyl, C 6-14 Arylsulfonyl, C 6-14 Aryl, 5-13 membered heteroaryl, 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl-C 1-7 Alkyl, or 5-10 membered heterocycloalkyl-C 1-7 is alkoxy; Ring C is C 3-10 Cycloalkyl, C 5-10 Cycloalkenyl, C 6-14 aryl, 5-13 membered heteroaryl, or 5-10 membered heterocycloalkyl; Alkyl, alkenyl, alkynyl, and alkoxy are each independently unsubstituted or selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 Alkyl, and C 2-7 having one or more substituents selected from the group consisting of alkynyl; Cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl are each independently unsubstituted or selected from halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-4 Alkyl, and C 1-4 having one or more substituents selected from the group consisting of alkoxy; and The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S, and O.

[0019] As a particular example, ring B-1 is [ka] may be selected from the group consisting of:

[0020] In the above formula, R 7 is hydrogen or C 1-7 R is alkyl; 8a and R 8b are each independently 1-7 alkyl or joined together to form a 5-10 membered heterocycloalkyl (containing at least one heteroatom selected from the group consisting of N, S, and O).

[0021] As another specific example, ring B-2 is [ka] may be selected from the group consisting of:

[0022] Preferably, the compound of formula 1 may be a compound represented by the following formula 1a or a compound represented by the following formula 1b: [ka] where A, B, R, X′, and n are as defined above in Formula 1.

[0023] According to a preferred embodiment of the compound of formula 1a, A may be oxygen; n may be 1; X′ may be halogen; and B may be unsubstituted phenyl or halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 Alkyl, C 3-10 Cycloalkyl, and C 1-7 It may be phenyl substituted with one or two substituents selected from the group consisting of alkoxy.

[0024] Furthermore, the compounds of formula 1a and 1b may be compounds in which glucose is in the α-form, β-form, or racemic form thereof.

[0025] Preferably, the compounds of formulae 1a and 1b may be compounds in which glucose is in the β form.

[0026] Method for preparing compounds of formula 1a (formula 1 where R=hydroxymethyl) According to one aspect of the present invention, there is provided a method for preparing a compound of formula 1a (formula 1 where R=hydroxymethyl), comprising the steps of: (1) reacting a compound of the following formula 2 with a compound of the following formula 3, and subjecting the resulting product to a cyclization reaction to obtain a compound of the following formula 4; (2) dehydrating or amidating a compound of formula 4, reacting it with a compound of formula 5 below, and carrying out reduction to obtain a compound of formula 6 below; and (3) reacting a compound of formula 6 with a compound of formula 7 below, followed by deprotection and reduction; A method is provided that includes: [ka]

[0027] [In the formula, A is oxygen (O) or sulfur (S); n is 1 or 2; PG is a protecting group; X' is halogen or C 1-7 is alkyl; X, Y, and Hal are each independently a halogen; B is as defined above in Formula 1.

[0028] The compound of formula 2 used as a starting material in the above-mentioned production method can be produced by a synthetic route described in the prior art (US Patent Publication No. 2015 / 0152075). For example, the compound of formula 2 can be produced by the following steps: (i) subjecting a carboxylic acid compound of the following formula 2a to an esterification reaction to obtain a methyl ester compound of the following formula 2b: (ii) subjecting the compound of formula 2b to a hydrogenation reaction to reduce the nitro group, thereby obtaining an amine compound of formula 2c below; (iii) reacting the compound of formula 2c with a halogenation reagent to obtain a halogenated compound of formula 2d: (iv) subjecting the compound of formula 2d to a Sandmeyer reaction; [ka] The composition can be produced by including

[0029] In the formula, Y is a halogen.

[0030] As used herein, the term "halogen" means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0031] Process (1) In step (1), a compound of formula 2 is reacted with a compound of formula 3, and the resultant is subjected to a cyclization reaction to give a compound of formula 4.

[0032] Thus, a pentagonal or hexagonal ring containing oxygen in the aglycone group can be preformed prior to attachment to the glucose group and also prior to forming the terminal residue of the aglycone group (ie, ring B).

[0033] As a specific example, step (1) comprises the steps of: (i) reacting a compound of formula 2 with a compound of formula 3 to obtain a compound of formula 3a: (ii) rearrangement of the allyl group of the compound of formula 3a, followed by oxidation or ozonation and then reduction to obtain a compound of formula 3d: (iii) subjecting the compound of formula 3d to a cyclization reaction to obtain a compound of formula 4; [ka] may include.

[0034] wherein n is 1 or 2; and X and Y are each independently a halogen.

[0035] In step (i), the compound of formula 2 may be subjected to a demethylation step before reacting with the compound of formula 3. For example, the compound of formula 2 may be subjected to demethylation to give a compound of formula 2e below, which may then be reacted with a compound of formula 3: [Formula 2e] [ka]

[0036] In the formula, X and Y are each independently a halogen.

[0037] The rearrangement reaction in step (ii) may be carried out, for example, in a Claisen rearrangement reaction.

[0038] The rearrangement reaction may be carried out by adding a Lewis acid, which may be at least one selected from the group consisting of diisobutylaluminum chloride, diethylaluminum chloride, aluminum chloride, and boron trichloride.

[0039] Furthermore, the rearrangement reaction may be carried out in a solvent-free reaction or in diethylamine under heating conditions at high temperatures (eg, 150° C. to 170° C.).

[0040] After the rearrangement reaction in step (ii), the compound of formula 3a is converted to a compound of formula 3b: [Formula 3b] [ka] It can be obtained as the compound

[0041] wherein n is 1 or 2; and X and Y are each independently a halogen.

[0042] The oxidation or ozonation reaction in step (ii) is carried out using osmium tetroxide (OsO 4 ), potassium osmate(VI) dihydrate, or ozone (O 3 This may be achieved by adding

[0043] After being subjected to an oxidation or ozonation reaction in step (ii), the compound represented by the following formula (3c): [Formula 3c] [ka] As a compound of formula (3b), a compound of formula (3b) can be obtained.

[0044] wherein n is 1 or 2; and X and Y are each independently a halogen.

[0045] The compound of formula 3c can then be reduced to give the compound of formula 3d.

[0046] In step (iii), the compound of formula 3d is subjected to a cyclization reaction to obtain a compound of formula 4. This method can improve the yield compared to the cyclization method disclosed in the prior art (US Patent Application Publication No. 2015 / 0152075).

[0047] The cyclization reaction may be a Vilsmeier reagent cyclization reaction, a leaving group cyclization reaction, a halide cyclization reaction, or a Mitsunobu reaction cyclization reaction.

[0048] According to one example, the cyclization reaction may be carried out by adding a Vilsmeier reagent to the compound of formula 3d. The reaction may be carried out at a temperature of 0° C. to room temperature. The Vilsmeier reagent is preferably produced and used quickly in the synthesis in terms of yield. For example, dimethylformamide (DMF) and SOCl 2 or POCl 3 Vilsmeier reagent prepared by reaction with

[0049] According to another example, the cyclization reaction may be carried out by introducing a tosyl or mesyl group as a leaving group. According to yet another example, the cyclization reaction may be carried out by introducing a tosyl or mesyl group as a leaving group. 2 and PBr 3 According to yet another example, the cyclization reaction may also be carried out by a Mitsunobu reaction using diisopropyl azodicarboxylate (DIAD), etc.

[0050] These reactions are those in which a primary alcohol group is replaced with a group capable of acting as a leaving group, such that the substituent acts as a nucleophile towards the phenol group, resulting in a cyclization reaction.

[0051] Process (2) In step (2), the compound of formula 4 is subjected to aldehyde formation or amidation, and then reacted with the compound of formula 5. The resulting product is reduced to give the compound of formula 6.

[0052] As an example, step (2) comprises subjecting a compound of formula 4 to aldehyde conversion to obtain a compound of formula 4a: [Formula 4a] [ka] with a compound of formula 5.

[0053] wherein n is 1 or 2; and X and Y are each independently a halogen.

[0054] Specifically, the compound of formula 4 is reduced to obtain a compound of formula 4c below, and then the compound of formula 4 is reacted with pyridinium chlorochromate (PCC), magnesium dioxide, sulfur trioxide-pyridine complex, etc., to carry out the aldehyde formation reaction. As a result, the compound of formula 4a: [Formula 4c] [ka] It is possible to obtain a compound of the formula:

[0055] wherein n is 1 or 2; and X and Y are each independently a halogen.

[0056] At this point, NaBH 4 and LiBH 4 A reducing agent such as ethanol, tetrahydrofuran (THF), or a mixture thereof may be used as a solvent during reduction. In a preferred example, a mixed solvent of ethanol and THF may be used during reduction, with the mixed volume ratio being 1:1 to 1:3. Furthermore, a Lewis acid may be further used during reduction. Examples of the Lewis acid that can be used include LiCl and CaCl 2 Examples include:

[0057] The compound of formula 4a is then reacted with a compound of formula 5 to give the compound of formula 6a: [Formula 6a] [ka] It is possible to obtain a compound of the formula:

[0058] wherein n is 1 or 2, X and Y are each independently a halogen, and B is as defined above in formula 1.

[0059] The compound of formula 6a can be reduced to give the compound of formula 6.

[0060] As another example, step (2) comprises amidating a compound of formula 4 to obtain a compound of formula 4b: [Formula 4b] [ka] with a compound of formula 5.

[0061] wherein n is 1 or 2; and X and Y are each independently a halogen.

[0062] Specifically, compounds of formula 4 can be hydrolyzed and then reacted with N,O-dimethylhydroxyamine hydrochloride (e.g., MeO(Me)NH HCl) to produce Weinreb amides such as formula 4b.

[0063] The compound of formula 4b is then reacted with a compound of formula 5 to give the compound of formula 6b: [Formula 6b] [ka] It is possible to obtain a compound of the formula:

[0064] wherein n is 1 or 2; X and Y are each independently a halogen, and B is as defined above in formula 1.

[0065] The compound of formula 6b can then be reduced to give the compound of formula 6.

[0066] The compound of formula 5 may be a Grignard reagent.

[0067] A typical method for preparing a Grignard reagent is to prepare a compound of formula 5a: [Formula 5a] [ka] can be reacted with magnesium metal (Mg) to produce a compound of formula 5.

[0068] wherein B is as defined above in formula 1 and Hal is a halogen.

[0069] As described above, according to the present invention, the B group of the final compound (compound of formula 1a) can be easily introduced in advance by the method of preparing the Grignard reagent before the coupling of the aglycon group with the glucose group, which not only allows various derivatizations but also improves the final yield.

[0070] On the other hand, according to the prior art (US Patent Publication No. 2015 / 0152075A1), a complicated synthesis process is required at the end of the synthesis route after coupling with the glucose group to complete the B group of the final compound, and therefore there is a problem that the reaction yield and reaction reproducibility change greatly due to the long process.

[0071] Process (3) In step (3), a compound of formula 6 is reacted with a compound of formula 7, followed by deprotection and reduction.

[0072] The reaction of compounds of formula 6 with compounds of formula 7 may be carried out in the presence of n-butyllithium, sec-butyllithium, t-butyllithium, isopropylmagnesium chloride (i-PrMgCl), and the like.

[0073] The compound of formula 6 is reacted with a compound of formula 7 to form a compound of formula 7a: [Formula 7a] [ka] It is possible to obtain a compound of the formula:

[0074] wherein A is oxygen or sulfur; n is 1 or 2; X is a halogen; PG is a protecting group; and B is as defined above in formula 1.

[0075] The protecting group may be, for example, a trimethylsilyl (TMS) group, a benzyl group, or an acetyl group.

[0076] The compound of formula 7a can then be deprotected to give the compound of formula 1a. For example, if the protecting group is a trimethylsilyl (TMS) group, then the protecting group can be deprotected to give the compound of formula 1a. 3 SO 3 H) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) can be added to compounds of formula 7a to give compounds of formula 1a.

[0077] Alternatively, after deprotection, further reduction can be carried out to give the compound of formula 1a. At this point, dichloromethane (CH 2 Cl 2 ) and acetonitrile (CH 2 Cl 2 ) may be used in combination as a solvent.

[0078] The compound of formula 1a obtained through the above steps may be a compound in which α- and β-glucose forms are mixed.

[0079] In this way, further separation can be performed to obtain only the desired α or β form, i.e., after the deprotection and reduction steps, only the compound in which glucose is in the β form can be further isolated.

[0080] For example, a protecting group is introduced into the resulting compound by deprotection and reduction, which can then be heated in alcohol, ethyl acetate, or dichloromethane, and the resulting precipitate isolated and then deprotected to obtain only the β form.

[0081] Specifically, the hydroxyl group of glucose in the compound obtained by deprotection and reduction is protected with an acetyl group or the like. 1-6 The mixture is heated and stirred in an alcohol solvent (such as ethanol or isopropanol) and the resulting precipitate is isolated to obtain a compound represented by the following formula 7b: [Formula 7b] [ka] It is possible to obtain a compound of the formula:

[0082] wherein A is oxygen or sulfur; n is 1 or 2; X is a halogen; PG is a protecting group; and B is as defined above in formula 1.

[0083] Compounds of formula 7b are then deprotected to finally give compounds of formula 7c: [Formula 7c] [ka] Only the β type can be obtained, which can be expressed as

[0084] where A, B, n, and X′ are as defined above in Formula 1.

[0085] In a preferred embodiment, step (3) is carried out by the following steps: (3a-1) reacting a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium or isopropylmagnesium chloride to obtain a compound of formula 7a: (3a-2) subjecting the compound of formula 7a to a deprotection and methylation reaction in the presence of methanol under acidic conditions to obtain a compound of formula 7d below; (3b) reducing the compound of formula 7b to obtain a compound of formula 7e: (3c) introducing a protecting group into the compound of formula 7e, heating the resultant in alcohol, ethyl acetate or dichloromethane, and isolating and deprotecting the resulting precipitate to obtain only the β-form; [ka] The method can be carried out by a method comprising:

[0086] where PG is a protecting group; and A, B, n, and X are as defined above in formula 1a.

[0087] After the reaction in step (3a-1), further steps such as evaporation, extraction, drying, and filtration are carried out to obtain the compound of formula 7a, which is preferably used in the next step (3a-2).

[0088] The acid used in step (3a-2) may be hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrogen chloride gas, and the like.

[0089] In another preferred embodiment, step (3) comprises the steps of: (3a') reacting a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium or isopropylmagnesium chloride, and subjecting the resultant, without separation and purification, to a deprotection and methylation reaction in the presence of methanol under acidic conditions to obtain a compound of formula 7d below; (3b') reducing the compound of formula 7d to obtain a compound of formula 7e: (3c') a step of introducing a protecting group into the compound of formula 7e, isolating only the β-form, and performing deprotection; [ka] The method can be carried out by a method comprising:

[0090] where A, B, n, and X are as defined above in formula 1a.

[0091] In step (3a'), first, a coupling reaction is carried out, and at this point, each of the compounds of formula 7 and the reaction reagent (i.e., n-butyl lithium, sec-butyl lithium, t-butyl lithium or isopropyl magnesium chloride) can be used in an amount of 1.5 to 2.5 equivalents, more preferably 1.7 to 2.3 equivalents, particularly 2.0 equivalents, per equivalent of the compound of formula 6. The reaction at this point can be carried out at -80°C to -10°C, more preferably -70°C to -60°C, for 1 to 12 hours, or 1 to 3 hours. Furthermore, as the reaction solvent, a single solvent such as tetrahydrofuran or ether, a mixed solvent such as tetrahydrofuran / toluene (1:1), etc. can be used.

[0092] Further, in step (3a'), deprotection and methylation reactions are carried out under acidic conditions. Examples of the acid used at this stage include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrogen chloride gas, and the like. The acid may be used in an amount of 2 to 5 equivalents, more preferably 3 equivalents, per equivalent of the compound of formula 6. The reaction at this stage may be carried out at 0°C to 40°C, more preferably 20°C to 30°C, for 6 to 24 hours or 6 to 12 hours. Methanol, and the like, may be used as a reaction solvent.

[0093] Next, in step (3b'), a reduction reaction is carried out, and at this point, a reducing agent and an acid may be used. Examples of the reducing agent include, for example, triethylsilane, triisopropylsilane, t-butyldimethylsilane, and sodium borohydride. Examples of the acid include boron trifluoride diethyl ether, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, trifluoroacetic acid, and trifluoromethanesulfonic acid. The amount of the reducing agent used is 2 to 5 equivalents, more preferably about 3 equivalents, and the amount of the acid used is 1.5 to 3 equivalents, more preferably about 2 equivalents. The reaction at this point can be carried out at -50°C to 0°C, more preferably -20°C to -10°C, for 2 to 12 hours or 2 to 5 hours. Furthermore, as the reaction solvent, a single solvent such as dichloromethane, 1,2-dichloroethane, or acetonitrile, a mixed solvent such as dichloromethane / acetonitrile (1:1) and 1,2-dichloromethane / acetonitrile (1:1), and the like can be used.

[0094] Next, a protecting group is introduced in step (3c'), and at this point, a reaction using an acetylating agent and a base may be carried out. Examples of the acetylating agent include acetyl chloride, acetyl bromide, and acetic anhydride, and examples of the base include sodium hydroxide, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, lutidine, and 4-dimethylaminopyridine. The acetylating agent may be used in an amount of 4 to 12 equivalents, more preferably about 8 equivalents, and the base may be used in an amount of 1 to 4 equivalents, more preferably about 1.5 equivalents. The reaction at this point may be carried out at 0°C to 50°C, more preferably -0°C to 30°C, for 1 to 12 hours or 1 to 3 hours. As a reaction solvent, acetone, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, etc. may be used.

[0095] Finally, in step (3c'), a deprotection reaction is carried out, at which point, reagents such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide can be used in 2 to 12 equivalents, more preferably about 5 equivalents. The reaction at this point can be carried out at a temperature of 0°C to 50°C, more preferably 20°C to 30°C, for 1 to 12 hours, or 1 to 3 hours. As a solvent, methanol / water (1:1 to 3:1), dichloromethane / methanol (1:1 to 1:2), dichloromethane / ethanol (1:1 to 1:2), tetrahydrofuran / methanol (1:1 to 1:2), tetrahydrofuran / ethanol (1:1 to 1:2), tetrahydrofuran / methanol / water (1:1:3 to 2:1:3), tetrahydrofuran / ethanol / water (1:1:3 to 2:1:3), etc. can be used.

[0096] In yet another preferred embodiment, step (3) comprises the steps of: (3a″) reacting a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium or isopropylmagnesium chloride, and subjecting the resultant, without separation and purification, to a deprotection and methylation reaction in the presence of methanol under acidic conditions to obtain a compound of formula 7d below; (3b″) introducing a protecting group into a compound of formula 7d to obtain a compound of formula 7f: (3c″) isolating only the β-form of the compound of formula 7f, reducing it, and then deprotecting it; [ka] The method can be carried out by a method comprising:

[0097] where PG is a protecting group; and A, B, n, and X are as defined above in formula 1a.

[0098] In step (3a''), coupling reaction, deprotection, and methylation are carried out. The preferred conditions at this stage, such as the equivalent ratio, reaction temperature, and solvent, are as exemplified in step (3a').

[0099] Next, in step (3b''), a protecting group is introduced, and at this point, a reaction using an acetylating agent and a base may be carried out. Preferred conditions such as the type of acetylating agent, the type of base, the equivalent ratio, the reaction temperature, and the solvent are as exemplified in step (3c') above.

[0100] Next, a reduction reaction is carried out in step (3c''). At this point, a reducing agent and an acid may be used, and preferred conditions such as the type of reducing agent, the type of acid, the equivalent ratio, the reaction temperature, and the solvent are as exemplified in step (3b') above.

[0101] Further, in step (3c''), a deprotection reaction is carried out. The preferred conditions at this stage, such as the types of reagents, the equivalent ratio, the reaction temperature, and the solvent, are as exemplified in step (3c') above.

[0102] As shown in the above preferred example, the process of obtaining the compound of formula 7d can be carried out in two steps, or can be carried out as an in-situ reaction in one step, which further improves the final yield.Furthermore, when carried out as an in-situ reaction in one step, it can obtain a crude concentrated residue containing the compound of formula 7b, or it can be crystallized to obtain the compound of formula 7d as a solid content, which can be used in the next step.In the latter case, it is easy to achieve the improvement of quality by removing reaction by-products and the control of water content.

[0103] Furthermore, the compound of formula 7d can be used in the next step after purification after synthesis, for example, (i) after synthesis, the compound of formula 7d can be azeotroped with an organic solvent such as toluene, and the residue obtained by repeating the concentration step to remove the remaining water can be used in the next step, or (ii) after synthesis, the compound of formula 7d can be crystallized and the remaining water can be removed by vacuum drying to obtain a solid fraction that can be used in the next step.

[0104] Alkylation Step Furthermore, according to the present invention, after step (3), an alkylation reaction can be further included, so that X' in formula 1 is C 1-7 It may be alkyl.

[0105] For example, the product after step (4) can be reacted with methylboronic acid to give a compound of formula 1a where X' is substituted with methyl.

[0106] Crystallization process The compound of formula 1a can be prepared in crystalline form, amorphous form, or a mixture thereof. However, the compound of formula 1a in crystalline form is preferred due to its stability, non-hygroscopicity, and physicochemical properties that facilitate formulation.

[0107] Therefore, the method of the present invention can further comprise the step of crystallizing the compound of formula 1a after step (3). The crystallization can be carried out using a variety of solvents, thus resulting in a variety of crystal forms.

[0108] As an example, the solvent used for crystallization can be selected from toluene; ethyl acetate; dichloromethane; acetone; acetonitrile; a mixture of 2-propanol, tetrahydrofuran, and dichloromethane; and a mixture of tetrahydrofuran and n-hexane, resulting in the production of crystalline form A.

[0109] As another example, the solvent used for crystallization can be selected from a mixture of methanol and distilled water; a mixture of methanol and n-hexane; and a mixture of methanol, dichloromethane and n-hexane, resulting in the production of crystalline form B.

[0110] As yet another example, the solvent used for crystallization can be selected from a mixture of ethanol, distilled water and n-hexane; and a mixture of tetrahydrofuran and toluene, resulting in the production of crystalline form C.

[0111] As yet another example, the solvent used for crystallization may be a mixture of ethanol and hexane, resulting in the production of crystalline form D.

[0112] As a preferred example, the solvent used for crystallization may be selected from the group consisting of toluene, ethyl acetate, dichloromethane, a mixture of tetrahydrofuran and dichloromethane, and a mixture of tetrahydrofuran and n-hexane.

[0113] Method for preparing compounds of formula 1b (formula 1 where R=alkylthio and A=oxygen) According to another aspect of the present invention, there is provided a method for preparing a compound of formula 1b (formula 1 where R=alkylthio and A=oxygen), comprising the steps of: (1) reacting a compound of the following formula 2 with a compound of the following formula 3, and subjecting the resulting product to a cyclization reaction to obtain a compound of the following formula 4; (2) dehydrating or amidating a compound of formula 4, reacting it with a compound of formula 5, and carrying out reduction to obtain a compound of formula 6 below; and (3) reacting a compound of formula 6 with a compound of formula 8 below, followed by reduction to obtain a compound of formula 9 below; (4) forming a furanose ring of the compound of formula 9 into a pyranose ring under acidic conditions, followed by introducing a protecting group to obtain a compound of formula 10 below; and (5) The compound of formula 10 is treated with thiourea and the resulting product is C 1-7 reacting with an alkyl halide followed by reduction; A method is provided that includes:

[0114] [ka] [ka] [ka]

[0115] During the ceremony, R is C 1-7is alkylthio; n is 1 or 2; PG is a protecting group; X' is halogen or C 1-7 is alkyl; X, Y, and Hal are each independently a halogen; and B is as defined above in Formula 1.

[0116] In the above process, steps (1) and (2) can be carried out in the same manner as steps (1) and (2) in the preparation of the compound of formula 1a (formula 1 where R=hydroxymethyl).

[0117] Steps (3) to (5) will be described in detail below.

[0118] Process (3) In step (3), a compound of formula 6 is reacted with a compound of formula 8 to give a compound of formula 9.

[0119] The compound of formula 8 can be prepared according to known methods, for example, the methods disclosed in WO 2009 / 014970. In particular, the compound of formula 8 can be prepared according to the methods disclosed in WO 2009 / 014970 starting from L-xylose.

[0120] According to one example, a compound of formula 6 can be reacted with a compound of formula 8 to give a compound of formula 9a: [Formula 9a] [ka]

[0121] where B, n, and X are as defined above in Formula 1.

[0122] The compound of formula 9a can then be reduced to give the compound of formula 9.

[0123] Process (4) In step (4), the furanose ring of the compound of formula 9 is converted to a pyranose ring under acidic conditions, and then a protecting group is introduced to obtain a compound of formula 10. This step completes the pyranose ring that constitutes the glucose group.

[0124] The protecting group may be, for example, an acetyl group.

[0125] Process (5) In step (5), the compound of formula 10 is treated with thiourea to give C 1-7 Reaction with an alkyl halide followed by reduction allows the introduction of an alkylthio group into the final compound (compound of formula 1b).

[0126] C 1-7 Alkyl halides include, for example, C 1-7 It may also be an alkyl iodide.

[0127] Furthermore, after step (5), a further alkylation reaction can be carried out, so that X′ becomes C 1-7 Compounds of formula 1b can be obtained which are alkyl.

[0128] Crystal form According to yet another aspect of the present invention, there is provided a crystalline form of the compound produced by the above process.

[0129] As one example, the present invention provides a crystalline form of the compound of formula 1a.

[0130] As a specific example, the present invention provides a crystalline form of the compound of formula 1a, wherein A is O, B is cyclopropylphenyl, n is 1, and X' is Cl, which is the β form.

[0131] That is, the present invention provides a crystalline form of the compound represented by the following formula c28: [Formula c28] [ka]

[0132] Compounds of formula c28 can be prepared by the above method for preparing compounds of formula 1a.

[0133] According to the present invention, the compound of formula c28 can be in various crystal forms, each of which is described in detail below.

[0134] Hereinafter, the term "about" may mean within 5%, preferably within 2%, of a given value or range. For example, "about 10%" may mean 9.5-10.5%, preferably 9.8-10.2%. As another example, "about 100°C" may mean 95°C-105°C, preferably 98°C-102°C.

[0135] First, the present invention provides a crystalline form A of the compound of formula c28. The crystalline form A is a Cu-K α When illuminated with the light source, it has an XRD spectrum that includes peaks at diffraction angles (2θ) of 6.2°±0.2°, 7.2°±0.2°, 8.8°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°. These peaks have relative intensities (I / I o ) may be a peak of about 5% or more, preferably about 10% or more.

[0136] The XRD spectrum of crystalline form A may further include peaks at diffraction angles (2θ) of 15.4°±0.2°, 18.6°±0.2°, 21.6°±0.2°, and 23.8°±0.2°.

[0137] Additionally, this crystalline form may have an endothermic peak with an onset at about 157°C and a minimum at about 159°C in DSC (10°C / min).

[0138] Furthermore, the present invention provides crystalline form B of the compound of formula c28. Crystalline form B is Cu-K αWhen illuminated with a light source, it has an XRD spectrum that includes peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 23.5°±0.2°. These peaks have relative intensities (I / I o ) may be a peak of about 5% or more, preferably about 10% or more.

[0139] The XRD spectrum of crystalline form B may further include peaks at diffraction angles (2θ) of 5.6°±0.2°, 9.4°±0.2°, and 11.0°±0.2°.

[0140] Further, this crystalline form may have an endothermic peak with an onset of about 79° C. and a minimum of about 88° C., and an endothermic peak with an onset of about 103° C. and a minimum of about 111° C. in DSC (10° C. / min).

[0141] Furthermore, the present invention provides crystalline form C of the compound of formula c28. Crystalline form C is Cu-K α When illuminated with the light source, it has an XRD spectrum that includes peaks at diffraction angles (2θ) of 5.6°±0.2°, 7.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.9°±0.2°, 21.2°±0.2°, and 21.9°±0.2°. These peaks have relative intensities (I / I o ) may be a peak of about 5% or more, preferably about 10% or more.

[0142] The XRD spectrum of crystalline form C may further include peaks at diffraction angles (2θ) of 19.9°±0.2° and 23.1°±0.2°.

[0143] Additionally, this crystalline form may have an endothermic peak with an onset at about 157°C and a minimum at about 159°C in DSC (10°C / min).

[0144] Furthermore, the present invention provides a crystalline form D of the compound of formula c28. The crystalline form D is a Cu-K αWhen illuminated with the light source, it has an XRD spectrum that includes peaks at diffraction angles (2θ) of 5.5°±0.2°, 7.2°±0.2°, 15.3°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.9°±0.2°, and 21.1°±0.2°. These peaks have relative intensities (I / I o ) may be a peak of about 5% or more.

[0145] The XRD spectrum of crystalline form D may further include peaks at diffraction angles (2θ) of 0.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°.

[0146] Additionally, this crystalline form may have an endothermic peak with an onset at about 157°C and a minimum at about 160°C in DSC (10°C / min).

[0147] Such a crystalline form of compound c28 has excellent physicochemical properties (eg, hygroscopicity and chemical stability) and can therefore be easily handled in various fields (eg, pharmaceutical production).

[0148] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail below with reference to examples. However, the following examples are for the purpose of illustrating the present invention, and the scope of the present invention is not limited to these examples.

[0149] The abbreviations used in the following examples have the following meanings: AcOH: acetic acid ACN: Acetonitrile Ac 2 O: Acetic anhydride BF 3 ·OEt 2 : Boron trifluoride etherate DIPEA: N,N-diisopropylethylamine DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide EtOAc: ethyl acetate EtOH: Ethanol Et 3 SiH: Triethylsilane HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate Hex: Hexane i-PrOH: Isopropyl alcohol MeI: Iodomethane MeOH: Methanol MsCl: Mesyl chloride NaOMe: Sodium methoxide NBS: N-bromosuccinimide PCC: Pyridinium chlorochromate Pd(PPh 3 ) 4 :Tetrakis(triphenylphosphine)palladium(0) TEA: Triethylamine TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxazinyl THF: tetrahydrofuran TMSOTf: Trimethylsilyl trifluoromethanesulfonate RT or rt: room temperature EXAMPLES

[0150] Comparative Example 1: 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

[0151] The title compound was prepared by the method disclosed in U.S. Patent Publication No. 2015 / 0152075. For the specific synthesis steps of Comparative Example 1, refer to Scheme 1 as described above in the Background section.

[0152] Step 1: Methyl 3-methoxy-2-nitrobenzoate (compound c2) 3-Methoxy-2-nitrobenzoic acid (25.0 g, 126 mmol) and K in DMF (126 mL) 2 CO 3(35.0 g, 253 mmol) was added MeI (15.8 mL, 253 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. Water (200 mL) was poured into the mixture, and then stirred at 5° C. for 30 min. The precipitated solid was collected by filtration and washed with water and hexane. The solid was dried in vacuum to give the title compound as a white solid as crude material (26.2 g, 98%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60(dd, J = 8.2, 1.2 Hz, 1H), 7.50(t, J = 8.2 Hz, 1H), 7.26(dd, J = 8.2, 1.2 Hz, 1H), 3.39(s, 3H), 3.99(s, 3H);[M+Na] + 235.

[0153] Step 2: Methyl 2-amino-3-methoxybenzoate (compound c3) A suspension of methyl 3-methoxy-2-nitrobenzoate (26.2 g, 124 mmol) and Pd / C (10 wt%, 6.0 g) in THF (400 mL) and MeOH (200 mL) was added to H 2 The mixture was stirred at room temperature under atmospheric conditions for 18 hours. EtOAc (300 mL) was added to the mixture, which was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the title compound as a colorless oil (22.4 g, 99%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47(dd, J = 8.2, 1.2 Hz, 1H), 6.85(dd, J = 8.2, 1.2 Hz, 1H), 6.58(t, J = 8.2 Hz, 1H), 6.00(brs, 2H), 3.87(s, 3H);[M+H] + 182.

[0154] Step 3: 2-amino-5-bromo-3-methoxybenzoate methyl (compound c4) To a solution of methyl 2-amino-3-methoxybenzoate (22.4 g, 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Water was added to the mixture and extracted with EtOAc (500 mL x 2). The combined organic layer was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel chromatography to give the title compound as a white solid (27.5 g, 86%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60(d, J = 2.2 Hz, 1H), 6.90(d, J = 2.2 Hz, 1H), 6.03(brs, 1H), 3.87(s, 3H);[M+H] + 260.

[0155] Step 4: 5-bromo-2-chloro-3-methoxybenzoate methyl (compound c5) H 2 To a solution of methyl 2-amino-5-bromo-3-methoxybenzoate (27.0 g, 103 mmol) in HO (70 mL) and concentrated HCl (70 mL) was added H 2 NaNO in O (50 mL) 2 (21.5 g, 311 mmol) was added dropwise at 0 °C. After stirring for 1 h, a solution of Cu(I)Cl in concentrated HCl (80 mL) was added dropwise to the reaction mixture at 0 °C. The mixture was stirred at room temperature for 18 h. To the mixture was added water (300 mL) and extracted with EtOAc (500 mL). The organic layer was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The crude title compound was dried under high vacuum and used in the next step without further purification as a white solid (29.0 g, 100%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.49(d, J = 2.4 Hz, 1H), 7.16(d, J = 2.4 Hz, 1H), 3.93(s, 36H), 3.92(s, 3H);[M+H] + 278

[0156] Step 5: 5-Bromo-2-chloro-3-methoxybenzoic acid (compound c6) THF (100 mL), 2 To a solution of methyl 5-bromo-2-chloro-3-methoxybenzoate (25.0 g, 89.4 mmol) in 2H2O (100 mL) and MeOH (100 mL) was added dropwise aqueous 5 N NaOH solution at 0 °C. The mixture was stirred at room temperature for 1 h. To acidify the mixture, concentrated HCl was added and the mixture was extracted with EtOAc (500 mL x 2). The combined organic layers were washed with MgSO 4 Dry at 40° C., filter and concentrate in vacuo to give the title compound as an orange solid (22.6 g, 96%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.55(s, 1H), 7.13(s, 1H), 3.89(s, 3H);[M+H] + 265.

[0157] Step 6: 5-bromo-2-chloro-3-methoxybenzoyl chloride (compound c7) CH 2 Cl 2 To a suspension of 5-bromo-2-chloro-3-methoxybenzoic acid (6.0 g, 22.6 mmol) in 100 mL of ethyl acetate was added oxalyl chloride (2.4 mL, 27.1 mmol) and a catalytic amount of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuum and dried in vacuum to give the crude title compound. 1 H NMR (400 MHz, CDCl 3 ) δ 7.49(d, J = 2.4 Hz, 1H), 7.16(d, J = 2.4 Hz, 1H), 3.93(s, 3H), 3.92(s, 3H).

[0158] Step 7: (5-bromo-2-chloro-3-hydroxyphenyl)(phenyl)methanone (compound c8) The crude 5-bromo-2-chloro-3-methoxybenzoyl chloride was dissolved in benzene (100 mL) and cooled to 0° C. The reaction mixture was added with AlCl 3(6.9 g, 52.0 mmol) was added portionwise at 0 °C. The mixture was stirred at 90 °C for 15 h. The mixture was cooled to room temperature and evaporated in vacuum. The residue was cooled to 0 °C and aqueous 1N HCl solution was added. The mixture was extracted with EtOAc (150 mL x 1). The organic layer was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel chromatography to give the title compound (7.33 g, quantitative yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.85-7.82(m, 2H), 7.70-7.64(m, 1H), 7.55-7.49(m, 2H), 7.37(d, J = 2.2 Hz, 1H), 7.13(d, J = 2.2 Hz, 1H), 5.94(s, 1H).

[0159] Step 8: 3-benzyl-5-bromo-2-chlorophenol (compound c9) To a mixture of (5-bromo-2-chloro-3-hydroxyphenyl)(phenyl)methanone (362 mg, 1.16 mmol) in trifluoroacetic acid (3 mL) was added triethylsilane (0.37 mL, 2.32 mmol) and catalytic triflic acid at 0° C. The mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with saturated NaHCO 3 The solution was quenched at 0 °C by addition of EtOAc and the organic layer was extracted with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (267 mg, 77%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.32(m, 2H), 7.30-7.27(m, 1H), 7.22-7.19(m, 2H), 7.13(d, J = 2.4 Hz, 1H), 6.92(d, J = 2.0 Hz, 1H), 4.07(s, 2H). [M+H] + 297.

[0160] Step 9: 1-(allyloxy)-3-benzyl-5-bromo-2-chlorobenzene (compound c10) 3-Benzyl-5-bromo-2-chlorophenol (1.72 g, 5.78 mmol) and K in acetone (35 mL) 2 CO 3 To a mixture of (1.6 g, 11.56 mmol) was added allyl bromide (0.73 mL, 8.67 mmol) at room temperature. The reaction mixture was stirred at 65° C. for 12 h. The resulting mixture was filtered to remove inorganic materials. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (1.96 g, 100%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.32-7.27(m, 2H), 7.25-7.22(m, 1H), 7.21-7.17(m, 2H), 6.92(d, J = 2.4 Hz, 1H), 6.92(d, J = 2.0 Hz, 1H), 6.10-6.00(m, 1H), 5.48(dq, J = 17.2 Hz, 1.6 Hz, 1H), 5.33(dq, J = 12.4, 1.6 Hz, 1H), 4.59(dt, J = 4.4 Hz, 1.6 Hz, 2H), 4.08(s, 2H). [M+H] + 337.

[0161] Step 10: (3R,4S,5S,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (compound c12) To a solution of 1-(allyloxy)-3-benzyl-5-bromo-2-chlorobenzene (1.96 g, 5.82 mmol) in tetrahydrofuran (5.5 mL) / toluene (11 mL) was added n-butyllithium (2.5M in hexane, 2.6 mL, 6.41 mmol) dropwise at −78° C. under nitrogen atmosphere. After stirring for 1 h, a solution of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (c11; 3.54 g, 7.58 mmol) in tetrahydrofuran (6.6 mL) was added dropwise to the mixture at −78° C. via cannula over 20 min. The reaction mixture was stirred at −78° C. for 3 h. CH3 SO 3 H (0.6 mL, 9.25 mmol) was added dropwise to the mixture at 0 °C. The mixture was allowed to warm to room temperature over 18 h and then saturated NaHCO 3 The mixture was quenched with 1,2-dichloromethane at 0° C. The mixture was evaporated under reduced pressure to remove volatiles. The aqueous residue was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with MgSO 4 Drying at 40° C., filtering and concentrating in vacuo gave the crude title product as a yellow solid. [M+Na] + 473.

[0162] Step 11: (3R,4R,5S,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound c13) CH 2 Cl 2 (30 mL) and CH 3 To a mixture of (3R,4S,5S,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (2.55 g, 5.65 mmol) in CN (30 mL) was added Et 3 SiH (1.82 mL, 11.3 mmol) and BF 3 Et 2 O (1.07 mL, 8.48 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was diluted with saturated NaHCO 3 The solution was quenched with ethyl acetate, extracted with EtOAc, and the organic layer was washed with MgSO 4 The mixture was dried at 4° C., filtered and concentrated in vacuo, and the crude product was used in the next step without further purification.

[0163] Step 12: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(allyloxy)-5-benzyl-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c14) CH 2 Cl 2 To a mixture of (3R,4R,5S,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (c13) in (12 mL), 2O (4.7 mL, 49.72 mmol), pyridine (4.0 mL, 49.45 mmol), and DMAP (35 mg, 0.28 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with EtOAc and washed with 1N HCl solution. The organic layer was washed with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (1.55 g, 47%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.31-7.27(m, 2H), 7.22-7.21(m, 1H), 7.19-7.16(m, 2H), 7.09(d, J = 1.6 Hz, 1H), 6.88(d, J = 1.6 Hz, 1H), 6.12-6.03(m, 1H), 5.47(dq, J = 17.6, 2.0 Hz, 1H), 5.35(t, J = 9.6 Hz, 1H), 5.30(dq, J = 10.4, 1.6 Hz, 1H), 5.12(t, J = 9.6 Hz, 1H), 5.06(t, J = 9.6 [M+Na] + 611.

[0164] Step 13: (2S,3R,4R,5S,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound c15) To a mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(allyloxy)-5-benzyl-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.55 g, 2.63 mmol) in MeOH (50 mL) was added NaOMe (25 wt % in MeOH, 2.34 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The resulting mixture was neutralized with glacial AcOH. The mixture was diluted with EtOAc and saturated NaHCO 3 The organic layer was washed with MgSO 4The mixture was dried over 1000 ml, filtered and concentrated in vacuo. The crude product was used in the next step without further purification. [M+Na] + 443.

[0165] Step 14: (2S,3S,4R,5R,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (compound c16) To a mixture of (2S,3R,4R,5S,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol in DMF (26 mL) was added NaH (60% mineral oil dispersion, 842 mg, 21.0 mmol) at 0° C. and stirred at room temperature for 1 h. To the reaction mixture was added benzyl bromide (2.5 mL, 21.0 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 12 h. The resulting mixture was quenched by adding water and extracted with EtOAc. The organic layer was washed with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (1.80 g, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.31(m, 13H), 7.26-7.19(m, 10H), 6.94(d, J = 1.6 Hz, 2H), 6.91(dd, J = 14.8, 2.0 Hz, 2H), 6.10-6.00(m, 1H), 5.46(dq, J = 17.2, 1.6 Hz, 1H), 5.31(dq, J = 10.8, 1.6 Hz, 1H), 4.94(ABq, J AB = 15.2 Hz, 2H), 4.90(d, J = 10.8 Hz, 1H), 4.70-4.64(m, 2H), 4.57(d, J = 12.4 Hz, 1H), 4.52-4.49(m, 2H), 4.46(d, J = 10.8 [M+Na] + 803.

[0166] Step 15: 3-benzyl-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenol (compound c17) To a mixture of ((2S,3S,4R,5R,6R)-2-(3-(allyloxy)-5-benzyl-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (1.80 g, 2.30 mmol) in THF (25 mL), NaBH 4 (700 mg, 18.4 mmol) and Pd(PPh 3 ) 4 (266 mg, 0.23 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with saturated NaHCO 3 The solution was added to quench the reaction and extracted with EtOAc. The organic layer was washed with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (1.62 g, 95%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.31(m, 13H), 7.27-7.21(m, 8H), 7.18-7.16(m, 2H), 7.08(d, J = 2.0 Hz, 1H), 6.98(dd, J = 7.6, 2.0 Hz, 2H), 6.89(d, J = 2.0 Hz, 1H), 4.93(ABq, J AB = 16.0 Hz, 2H), 4.89(d, J = 10.8 Hz, 1H), 4.67(d, J = 4.8 Hz, 1H), 4.64(d, J = 6.0 Hz, 1H), 4.57(d, J = 12.4 Hz, 1H), 4.46(d, J = 10.4 [M+Na] + 763.

[0167] Step 16: 3-benzyl-6-bromo-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenol (compound c18) To a mixture of 3-benzyl-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenol (1.62 g, 2.18 mmol) in 1,2-dichloro-2H-pyran-2-yl)phenol (1.62 g, 2.18 mmol) in 1,2-dichloro-2H-pyran-2-yl)phenol (1.62 g, 2.18 mmol) was added triethylamine (0.46 mL, 3.27 mmol) and bromine (0.11 mL, 2.18 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with saturated NaHCO 3 The solution was added to quench the reaction and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 4° C., filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (1.04 g, 58%). [M+Na] + 841.

[0168] Step 17: 3-(3-benzyl-6-bromo-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenoxy)propan-1-ol (compound c19) 3-Benzyl-6-bromo-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenol (1.04 g, 1.27 mmol) in acetone (13 mL) and K 2 CO 3 (0.35 g, 2.54 mmol) was added 2-bromoethanol (0.14 mL, 1.90 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 12 h. The resulting mixture was filtered to remove inorganic materials. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give compound c19 (1.10 g, 100%). [M+Na] + 899.

[0169] Step 18: (2S,3S,4R,5R,6R)-2-(5-benzyl-2-bromo-4-chloro-3-(2-chloroethoxy)phenyl)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (compound c20) CH 3To a mixture of 3-(3-benzyl-6-bromo-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenoxy)propan-1-ol (1.09 g, 1.25 mmol) and triphenylphosphine (1.64 g, 6.28 mmol) in CN (12 mL) was added carbon tetrachloride (12 mL, 134 mmol) at room temperature. The reaction mixture was stirred at 55° C. for 12 h. The resulting mixture was evaporated to remove the solvent. The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (0.61 g, 55%). [M+Na] + 903.

[0170] Step 19: 6-benzyl-7-chloro-4-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (compound c21) To a mixture of (2S,3S,4R,5R,6R)-2-(5-benzyl-2-bromo-4-chloro-3-(2-chloroethoxy)phenyl)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran (10.02 g, 11.4 mmol) in THF (114 mL) was added n-butyllithium (2.5 M in hexane, 6.8 mL, 17.0 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 3 h. The resulting mixture was quenched by the addition of 1N HCl solution (100 mL) and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 4° C., filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (6.0 g, 69%). [M+Na] + 789.

[0171] Step 20: (2S,3R,4R,5S,6R)-2-(6-benzyl-7-chloro-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound c22) A mixture of 6-benzyl-7-chloro-4-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (6.0 g, 7.82 mmol) and Pd / C (0.35 g, 2.54 mmol) in MeOH (220 mL) / THF (220 mL) was reacted with H 2 The mixture was stirred at room temperature for 5 hours under reduced pressure. The resulting mixture was filtered through Celite to remove inorganic materials. The filtrate was concentrated in vacuo to give the title compound (quantitative yield). The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CD 3 OD) δ 7.28-7.14(m, 5H), 6.89(s, 1H), 4.65(t, J = 8.6 Hz, 2H), 4.17(d, J = 8.8 Hz, 1H), ), 4.07(ABq, Δν AB = 18.0 Hz, J AB [M+Na] + 507.

[0172] Step 21: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(6-benzyl-7-chloro-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c23) CH 2 Cl 2 To a mixture of (2S,3R,4R,5S,6R)-2-(6-benzyl-7-chloro-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol in (78 mL) was added Ac 2 O (5.9 mL, 62.6 mmol), pyridine (5.0 mL, 62.6 mmol), and DMAP (48 mg, 0.39 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with EtOAc and washed with 1N HCl solution. The organic layer was diluted with MgSO 4The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (4.54 g, 100%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.32-7.28(m, 2H), 7.25-7.18(m, 3H), 6.59(s, 1H), 5.30(t, J = 9.2 Hz, 2H), 5.19(t, J = 9.6 Hz, 1H), 4.77-4.68(m, 2H), 4.35-4.32(m, 1H), 4.31-4.26(m, 1H), 4.21-4.14(m, 1H), 4.11(m, 1H), 4.02(d, J = 15.6 Hz, 1H), 3.83-3.79(m, 1H), 3.42(td, J = 8.8, 1.6 Hz, 2H), 2.10(s, 3H), 2.09(s, 3H), 2.03(s, 3H), 1.70(s, 3H); [M+Na] + 597.

[0173] Step 22: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(6-(4-acetylbenzyl)-7-chloro-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c24) CH 2 Cl 2 To a mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(6-benzyl-7-chloro-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3.75 g, 6.52 mmol) in (78 mL) was added acetyl chloride (3.71 mL, 52.16 mmol) and aluminum chloride (6.95 mg, 52.16 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched by adding ice-water and then diluted with CH 2 Cl 2 The organic layer was extracted with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (3.73 g, 93%). 1H NMR (400 MHz, CDCl 3 ) δ 7.92-7.89(m, 2H), 7.29-7.28(m, 2H), 6.63(s, 1H), 5.34-5.31(m, 1H) , 5.24-5.18(m, 2H), 4.78-4.68(m, 2H), 4.37-4.27(m, 2H), 4.19-4.16 (m, 1H), 4.16-4.08(m, 2H), 3.84-3.77(m, 1H), 3.45-3.40(m, 2H), 2.61(s, 3H), 2.10(s, 3H), 2.09(s, 3H), 2.03(s, 3H), 1.70(s, 3H); [M+Na] + 639.

[0174] Step 23: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-(1-hydroxyethyl)benzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c25) To a mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(6-(4-acetylbenzyl)-7-chloro-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.0 g, 1.62 mmol) in THF (7 mL) was added sodium borohydride (0.12 g, 3.24 mmol) slowly at -20°C, and then MeOH (0.24 mL) was added dropwise to the mixture. The mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate and extracted with EtOAc. The organic layer was diluted with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (0.52 g, 52%). 1 H NMR (400 MHz, CDCl 3) δ 7.29-7.27(m, 2H), 7.15-7.12(m, 2H), 6.54(d, J = 5.2 Hz, 1H), 5.29-5.26(m, 1H), 5.18-5.13(m, 2H), 4.89-4.84(m, 2H), 4.71-4.66(m, 2H), 4.32-4.29(m, 1H), 4.27-4.22(m, 1H), 4.15-4 .11(m, 1H), 4.04-3.96(m, 2H), 3.80-3.75(m, 1H), 3.40-3.35(m, 2H), 2.06(s, 3H), 2.05(s, 3H), 1.99(s, 3H), 1.68(s, 3H), 1.47(d, J = 6.4 Hz, 3H);[M+Na] + 641.

[0175] Step 24: (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-vinylbenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c26) A mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-(1-hydroxyethyl)benzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (520 mg, 0.84 mmol) and p-toluenesulfonic acid monohydrate (16 mg, 0.084 mmol) in toluene (10 mL) was stirred at 120 °C for 2 h. The resulting mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (407 mg, 81%). 1 H NMR (400 MHz, CDCl 3) δ 7.32-7.30(m, 2H), 7.12-7.10(m, 2H), 6.71-6.63(m, 1H), 6.55(s, 1H), 5.71-5.6 6(m, 1H), 5.29-5.25(m, 1H), 5.25-5.13(m, 3H), 4.71-4.66(m, 2H), 4.33-4.29(m , 1H), 4.28-4.22(m, 1H), 4.15-4.11(m, 1H), 4.08-3.96(m, 2H), 3.79-3.75(m, 1H) ), 3.41-3.35(m, 2H), 2.06(s, 3H), 2.05(s, 3H), 1.99(s, 3H), 1.68(s, 3H); [M+Na] + 623.

[0176] Step 25: (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 c27) CH 2 Cl 2 A solution of diethylzinc (1.1M in toluene, 1.74 mL, 1.91 mmol) in 1 mL of CH 2 Cl 2 Trifluoroacetic acid (0.15 mL, 1.91 mmol) in 1.5 mL of CH 2 Cl 2 Diiodomethane (0.16 mL, 1.91 mmol) in 1.5 mL of diiodomethane was added dropwise to the mixture at 0 °C. After 1 h, CH 2 Cl 2 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-vinylbenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (460 mg, 0.77 mmol) in (3 mL) was slowly added to the mixture at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with saturated NH 4 The mixture was quenched with Cl solution and extracted with EtOAc. The organic layer was washed with MgSO 4 The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system, EtOAc / Hex) to give the title compound (285 mg, 60%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.04-7.02(m, 2H), 6.98-6.95(m, 2H), 6.53(s, 1H), 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), 4.0 5-3.91(m, 2H), 3.79-3.74(m, 1H), 3.40-3.35(m, 2H), 2.06(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.

[0177] Step 26: (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 c28) (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 (298 mg, 0.48 mmol) in MeOH (20 mL) and K 2 CO 3 A mixture of (536 mg, 3.88 mmol) and 1,2-dichloro-1,3-dichloro-2,4-tetrahydrofuran (1H, 1H, 2H) was stirred at 37° C. for 12 h. The resulting mixture was filtered to remove inorganic materials. The filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (Gilson system, CH 3 CN / H 2 O) to give the title compound (101 mg, 47%).

[0178] According to the synthetic route of steps 1 to 26 above, the total yield of the final compound of Comparative Example 1 was calculated to be 1% or less. 1 H NMR (400 MHz, CD 3 OD) δ 7.02(d, J = 8.0 Hz, 2H), 6.92(d, J = 8.0 Hz, 2H), 6.81(s, 1H), 4.59(t, J = 8.8 Hz, 2H), 4.11(d, J = 9.2 Hz, 1H), 3.96(ABq, ΔνAB = 19.0 Hz, J AB = 15.2 Hz, 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.

[0179] Example 1: 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 [ka] [ka]

[0180] Step 1: 5-bromo-2-chloro-3-hydroxybenzoate methyl (compound c29 ) CH 2 Cl 2 To a solution of methyl 5-bromo-2-chloro-3-methoxybenzoate (compound c5; 30.0 g, 107.3 mmol) in 100 mL of BBr 3 (25.9 mL, 268.3 mmol) was added slowly at 0° C. under nitrogen atmosphere. The mixture was slowly warmed to room temperature and stirred at room temperature for 15 h. The reaction mixture was quenched by the addition of MeOH (100 mL) at 0° C. The mixture was evaporated under reduced pressure to CH 2 Cl 2 was removed and then MeOH (150 mL) was added to it. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound (29.4 g, 110.8 mmol, 103%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60(d, J = 2.4 Hz, 1H), 7.36(d, J = 2.4 Hz, 1H), 6.00(s, 1H), 3.94(s, 1H);[M+H] + 265.

[0181] Step 2: 3-(allyloxy)-5-bromo-2-chlorobenzoate methyl (compound c30) A solution of methyl 5-bromo-2-chloro-3-hydroxybenzoate (38.2 g, 143.9 mmol) in acetone (700 mL) was added with allyl bromide (14.9 mL, 172.7 mmol) and K 2 CO 3 (29.8 g, 215.9 mmol) was added at room temperature. The mixture was stirred at 60° C. for 12 h and then cooled to room temperature. After removing insoluble salts by filtration through Celite, the filtrate was evaporated under reduced pressure and the residue was dissolved in EtOAc (500 mL). The organic solution was washed with brine and MgSO 4 It was dried over rt, filtered and concentrated in vacuo (44.1 g, 144.3 mmol, 100%). The crude residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 7.49(d, J = 2.4 Hz, 1H), 7.16(d, J = 2.4 Hz, 1H), 6.09-6.00(m, 1H), 5.48(dd, J = 17.2 Hz, 1.2 Hz, 1H), 5.35(dd, J = 10.6 Hz, 1.4 Hz, 1H), 4.63-4.61(m, 2H), 3.93(s, 3H); [M+H] + 305.

[0182] Step 3: 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate methyl (compound c31) CH 2 Cl 2 To a solution of methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (10.0 g, 32.7 mmol) in 150 mL of ethyl acetate was added diisobutylaluminum chloride (25% in hexane, 64.0 mL) dropwise (0.5-1 h) under nitrogen atmosphere at 0 °C. The mixture was allowed to warm slowly to room temperature and stirred at room temperature for an additional 12 h. The reaction mixture was cooled to 0 °C and quenched with 1M HCl (50 mL), then extracted with EtOAc (150 mL x 2). The combined organic layers were washed with MgSO 4 It was dried over rt, filtered and concentrated in vacuo (9.9 g, 32.3 mmol, 99%). The crude residue was used in the next step without further purification to give the title compound. 1H NMR (400 MHz, CDCl 3 ) δ 7.23(s, 1H), 6.20(s, 1H), 5.96-5.86(m, 1H), 5.11-5.07(m, 2H), 3.92(s, 3H), 3.65(dt, J = 5.4 Hz, 1.4 Hz, 2H);[M+H] + 305.

[0183] Step 4: 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate methyl (compound c33) Method A) Synthesis by reduction of aldehydes THF / H 2 A mixture of methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (9.9 g, 32.3 mmol) in HO (100 mL / 100 mL) was added to NaIO 4 (20.8 g, 97.0 mmol) and OsO 4 (82 mg, 0.32 mmol) was added at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was warmed to room temperature and stirred at room temperature for 2 h. The mixture was filtered to remove insoluble material. The filtrate was diluted with Na 2 S 2 O 3 (100 mL) and the mixture was extracted with EtOAc (200 mL x 2). The organic layer was washed with MgSO 4 The crude residue was used in the next step without further purification to give methyl 5-bromo-2-chloro-3-hydroxy-4-(2-oxoethyl)benzoate (compound c32). [M+H] + 307.

[0184] A solution of methyl 5-bromo-2-chloro-3-hydroxy-4-(2-oxoethyl)benzoate (20.1 g, 65.3 mmol) in THF (200 mL) was added to NaBH 4 (2.72 g, 71.8 mmol) was added at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2 h. The mixture was diluted with saturated NH 4 The mixture was quenched with Cl (100 mL) and extracted with EtOAc (100 mL x 2) [one extraction was not sufficient]. The combined organic layers were washed with MgSO4 The residue was dried at 40° C., filtered and concentrated in vacuo (19.9 g). To a suspension of the residue in EtOAc (20 mL) was added hexanes (10-20 mL). The resulting precipitate was collected by filtration and washed with hexanes (50 mL). The precipitate was dried in vacuo to give the title compound (14.3 g, 72%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68(s, 1H), 7.35(s, 1H), 3.97-3.93(m, 2H), 3.92(s, 3H), 3.21(t, J = 6.2 Hz, 2H);[M+H] + 309.

[0185] Method B) Synthesis by ozonation and subsequent reduction CH 2 Cl 2 Ozone gas was bubbled into methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (10.2 g, 33.4 mmol, 80% purity) in 1H / MeOH (150 mL / 35 mL) at -78°C for 4 h (the color of the solution changed from yellow to pale green). After ozone addition was stopped, the reaction solution was purged with nitrogen until the green color disappeared (the color of the solution returned to yellow). Sodium borohydride (2.5 g, 66.8 mmol) was added in portions at -78°C. The resulting mixture was allowed to warm slowly to room temperature for 2 h, concentrated, suspended in EtOAc, and concentrated. To the residue was added 1N aqueous HCl (200 ml) and stirred for 30 min. The precipitate was collected by filtration (quantitative, 80% purity). The precipitate was suspended in EtOAc and stirred. To the resulting mixture, hexane was slowly added. The precipitate was collected by filtration to give the title compound (7.9 g, 76.4%, purity 92%). 1 H NMR(400 MHz, MeOD) δ 7.57(s, 1H), 3.93(s, 3H), 3.76(t, J = 7.24 Hz, 2H), 3.20(t, J = 7.28 Hz, 2H);[M+H] + 309.

[0186] Step 5: 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate methyl (compound c34) Preparation of Vilsmeier reagent: To a solution of N,N-dimethylformamide (7.9 ml, 102.2 mmol), add SOCl 2 (7.5 ml, 102.2 mmol) was added at room temperature. The reaction mixture was stirred at 40° C. for 2 hours. The resulting mixture was concentrated in vacuo to give a hydrous white solid.

[0187] To a mixture of Vilsmeier reagent (13.08 g, 102.2 mmol) in DMF (100 mL) was slowly added methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (21.08 g, 68.10 mmol) in DMF (130 mL) at 0°C. The mixture was stirred at 0°C to 15°C (gradual warming) for 1 h. The reaction mixture was quenched by the addition of triethylamine (38 ml, 272.4 mmol) in DMF (38 ml) at 0°C. After stirring for 10 min, the mixture was poured into water (1400 ml) at 0°C and stirred at room temperature for 2 h. The resulting precipitate was collected by filtration, washed with water, and concentrated to dryness in vacuo to give the title compound as a pale yellow solid (13.0 g, 44.6 mmol, 65%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.53(s, 1H), 4.75(t, J = 8.8 Hz, 2H), 3.91(s, 3H), 3.33(t, J = 8.8 Hz, 2H);[M+H] + 291.

[0188] Step 6: (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (compound c35) To a mixture of methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (13.0 g, 44.7 mmol) in THF / EtOH (150 mL / 75 mL) was added sodium borohydride (5.07 g, 133.98 mmol) slowly at room temperature. The mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with saturated NH 4 The mixture was quenched by addition of Cl at 0 °C and extracted with EtOAc (aqueous pH ~7.0). The organic layer was washed with MgSO 4Drying at 40° C., filtration and concentration in vacuo afforded the title compound as a white solid (11.7 g, 44.4 mmol, 99%) which was used crude in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 7.15(s, 1H), 4.73(m, 4H), 3.29(t, J = 8.8 Hz, 2H), 1.91(t, J = 6.4 Hz, 1H);[MH 2 O] + 245.

[0189] Step 7: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound c36) CH 2 Cl 2 To a solution of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (11.7 g, 44.4 mmol) in 1,2-dihydrobenzofuran-6-yl (450 ml) was added PCC (14.4 g, 66.6 mmol, pyridinium chlorochromate) slowly at room temperature. After stirring for 8 h, the precipitate was removed by filtration using a silica gel pad and then dissolved in CH 2 Cl 2 The filtrate was concentrated in vacuo to give the title compound as a white solid (10.4 g, 39.8 mmol, 90%). The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 10.33(s, 1H), 7.59(s, 1H), 4.79(t, J = 8.8 Hz, 2H), 3.35(t, J = 8.8 Hz, 2H);[M+H] + 261.

[0190] Step 8: (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (compound c39) Preparation of (4-cyclopropylphenyl)magnesium bromide (compound c38): A 250 mL three-neck flask containing magnesium (shavings, 1.1 g, 46.6 mmol) was flame dried. The flask was fitted with a condenser and an addition funnel under a nitrogen atmosphere. 4-Cyclopropylphenyl bromide (PepTech, USA) (6.0 ml, 42.4 mmol) in anhydrous THF (32.4 mL) was transferred to the addition funnel. The Grignard reaction was initiated with approximately 5 mL of 4-cyclopropylphenyl bromide solution. The remaining bromide solution was added at room temperature for 4 h. The resulting solution was used directly in the next step.

[0191] To a solution of 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (4.6 g, 17.6 mmol) in anhydrous THF (170 mL) was added a freshly prepared solution of (4-cyclopropylphenyl)magnesium bromide (compound c38) (30.0 mL of a 0.85 M THF solution, 26.4 mmol) at 0 °C under nitrogen atmosphere. 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 EtOAc (100 mL). The organic layer was diluted with MgSO 4 The crude residue was used in the next step without further purification to give the crude title compound. [MH 2 O] + 361.

[0192] Step 9: 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (compound c40) CH 2 Cl 2 / CH 3To a solution of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (7.6 g, 20.0 mmol) in CN (100 mL / 100 mL) was added triethylsilane (4.6 mL, 40 mmol) and boron trifluoride diethyl etherate (3.8 mL, 30 mmol) under nitrogen at -20 °C. The mixture was allowed to warm gradually to room temperature and stirred at room temperature for an additional 50 min. The reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched by slow addition of 200 mL of ethyl acetate and extracted with 100 mL of EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel chromatography to give the title product (4.4 g, 12.1 mmol, 85% over two steps). 1 H NMR (400 MHz, CDCl 3 ) δ 7.07(d, J = 8.0 Hz, 2H), 6.99(d, J = 8.0 Hz, 2H), 6.80(s, 1H), 4.70(t, J = 8.8 Hz, 2H), 3.97(s, 2H), 3.26(t, J = 8.8 Hz, 2H), 1.88-1.84(m, 1H), 0.95-0.90(m, 2H), 0.68-0.64(m, 2H).

[0193] Step 10: (3R,4S,5R,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol (compound c41) To a solution of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (5.16 g, 14.2 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (2.5 M in hexane, 7.38 mL, 18.4 mmol) dropwise under nitrogen atmosphere at -78 °C. After stirring at the same temperature for 40-60 min (yellowish solution), the mixture was added dropwise via cannula over 20 min to a pre-cooled (at -78 °C) solution of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (compound c11; 8.6 g, 18.4 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at the same temperature for 2-3 h (yellowish solution).

[0194] The reaction mixture was quenched with 1% acetic acid (20 mL) at -78 °C and then evaporated under reduced pressure to remove volatiles. The aqueous residue was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with MgSO 4 Drying at 40° C., filtration and concentration in vacuo afforded the crude title compound as a pale yellow oil (11.8 g, quantitative). The crude residue was used in the next step without further purification.

[0195] Step 11: (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) To a solution of (3R,4S,5R,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol; 11.8 g) in MeOH (150 mL) was added CH 3 SO 3 H (1.5 mL, 23.5 mmol) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature over 18 h and then saturated NaHCO 3 The mixture was quenched with 1,2-dichloromethane at 0° C. The mixture was evaporated under reduced pressure to remove volatiles. The aqueous residue was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with MgSO 4Drying at 40° C., filtering and concentrating in vacuo gave the crude title compound as a yellow solid (6.0 g, 88% over two steps). [M+Na] + 499 and [M-OMe] + 445.

[0196] Step 12: (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) CH 2 Cl 2 / CH 3 To a stirred solution of (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 (6.0 g, 12.6 mmol) in CN (v:v=1:1, 120 mL) was added Et 3 SiH (6.0 mL, 37.8 mmol), followed by BF 3 . OEt 2 (3.2 mL, 25.2 mmol) was added dropwise at -50 to -45 °C. The reaction mixture was warmed to -10 to 0 °C over 3 to 3.5 h, and then saturated NaHCO 3 (130 mL). The mixture was evaporated under reduced pressure to remove volatiles and the resulting residue was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with MgSO 4 Drying at 40° C., filtration and concentration in vacuo afforded the crude title compound as a yellow solid (5.8 g, 12.9 mmol, 102%). [M+Na] + 469.

[0197] Step 13: (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 c27) CH 2 Cl 2 To a solution of (3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (5.8 g, 12.9 mmol) in 120 mL of ethyl acetate was added DMAP (1.9 g, 15.5 mmol) and Ac 2O (9.7 mL, 103.76 mmol) was added at room temperature. After stirring at room temperature for 18 h, the reaction was quenched by adding water (120 mL). The resulting mixture was diluted with CH 2 Cl 2 (100 mL x 2). After washing with 1M HCl and brine, the combined organic layers were washed with MgSO 4 The residue was slurried in EtOH (45 mL) and heated to reflux at 80° C. for 1 h. The mixture was allowed to cool to room temperature with stirring for 18 h. The resulting precipitate was filtered, washed with EtOH and dried in vacuo to give the title compound as a white solid (4.7 g, 7.6 mmol, 59 %). 1 H NMR (400 MHz, CDCl 3 ) δ 7.04-7.02(m, 2H), 6.98-6.95(m, 2H), 6.53(s, 1H), 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), 4.05-3.91(m, 2H), 3.79-3.74(m, 1H), 3.40-3.35(m, 2H), 2.06(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.

[0198] Step 14: (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 c28) To a solution of (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 (1.5 g, 2.44 mmol) in THF / MeOH (5.4 mL / 10.8 mL; 0.15 M) was added 4M aqueous NaOH (2.8 mL). The reaction mixture was stirred at room temperature for 1.5 h. The solution was cooled to 0 °C and then neutralized with 1N HCl. The reaction solution was diluted with EtOAc and water. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with MgSO 4 Dry at 40° C., filter and concentrate in vacuo to give the crude title compound.

[0199] A suspension of the crude title compound in toluene (8 mL) was heated at 40° C. for 30 min (viscous solution→clear solution→white solid formed) and cooled to room temperature. The slurry was filtered through a filter funnel and the cake was washed with 2 times its volume of toluene. The wet cake was dried in vacuum to give 1.0 g (2.24 mmol, quantitative) of the title compound.

[0200] According to the synthetic route of steps 1 to 14 above, the total yield of the final compound of Example 1 was calculated to be about 12%. 1 H NMR (400 MHz, CD 3 OD) δ 7.02(d, J = 8.0 Hz, 2H), 6.92(d, J = 8.0 Hz, 2H), 6.81(s, 1H), 4.59(t, J = 8.8 Hz, 2H), 4.11(d, J = 9.2 Hz, 1H), 3.96(ABq, Δν AB = 19.0 Hz, J AB = 15.2 Hz, 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.

[0201] Example 2: 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 [ka]

[0202] Step 1: (3R,4S,5R,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol (compound c41) To a solution of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (compound c40, 5.00 g, 13.8 mmol) in tetrahydrofuran (140 mL), n-butyllithium (2.5M in hexane, 8.28 mL, 20.7 mmol) was added dropwise at −78° C. under nitrogen atmosphere. After stirring at the same temperature for 5 min, the mixture was added dropwise with a solution of TMS-protected lactone (compound c11; 7.70 g, 16.6 mmol) in tetrahydrofuran for 30 min. The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched by adding aqueous Cl (300 mL) at 0° C. and extracted with EtOAc. The organic layer was extracted with Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo afforded the crude title compound as a yellow oil (10.3 g, quantitative). The crude residue was used in the next step without further purification.

[0203] Step 2: (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) CH 2 Cl 2 (70 mL) and CH 3 To the crude (3R,4S,5R,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol (10.3 g) in CN (70 mL) was added triethylsilane (8.8 mL, 55.2 mmol) and TMSOTf (10 mL, 55.2 mmol) at -78 °C. After stirring at -78 °C for 1 h, the reaction mixture was quenched by the addition of water (200 mL) at 0 °C and purified by CH 2 Cl 2 (300 mL). The organic layer was extracted with Na 2 SO4 Drying at 40° C., filtration and concentration in vacuo afforded the crude title compound as a yellow oil (6.3 g, quantitative). The crude residue was used in the next step without further purification.

[0204] Step 3: (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 c27) CH 2 CL 2 A solution of (3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (6.3 g, 13.8 mmol) in 140 mL of ethyl acetate was treated with DMAP (0.84 g, 6.9 mmol) and Ac 2 O (13.0 mL, 13.8 mmol) was added at room temperature. After stirring at room temperature for 18 h, the reaction mixture was quenched by the addition of water (120 mL) and extracted with DCM (200 mL). The organic layer was extracted with NaHCO 3 Wash with aqueous solution (100 mL) and add Na 2 SO 4 The residue was slurried in isopropyl alcohol (20 mL) and heated at 80° C. for 10 min and cooled to room temperature. The resulting precipitate was then filtered and concentrated in vacuo to give the title compound as a beta white solid (4.52 g, 7.35 mmol, 53%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.04-7.02(m, 2H), 6.98-6.95(m, 2H), 6.53(s, 1H), 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), 4.05-3.91(m, 2H), 3.79-3.74(m, 1H), 3.40-3.35(m, 2H), 2.06(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.

[0205] Step 4: (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 c28) To a solution of (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 (4.52 g, 7.35 mmol) in MeOH (70 mL) was added NaOMe (25 wt%, 0.35 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo, diluted with water (200 mL) and extracted with EtOAc (300 mL). The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 4° C., filtered and concentrated in vacuo The residue was purified by recrystallization in toluene to give the β form of the title compound as a yellow solid (3.16 g, 96%). 1 H NMR (400 MHz, CD 3 OD) δ 7.02(d, J = 8.0 Hz, 2H), 6.92(d, J = 8.0 Hz, 2H), 6.81(s, 1H), 4.59(t, J = 8.8 Hz, 2H), 4.11(d, J = 9.2 Hz, 1H), 3.96(ABq, ΔνAB = 19.0 Hz, JAB = 15.2 Hz, 2H), 3.87-3.84(m, 1H), 3.67-3.63(m, 1H), 3.47-3.37(m, 3H), 3.35-3.3 3(m, 3H), 1.85-1.79(m, 1H), 0.91-0.86(m, 2H), 0.61-0.57(m, 2H);[M+Na]+ 469.

[0206] Example 3: Synthesis of (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol [ka]

[0207] Step 1: (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-thiopyran-2-ol (compound c52) The synthesis procedure of step 8 of Example 4 was repeated except that 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde was used as the starting material and (4-methoxyphenyl) magnesium bromide (compound c48) was used as the Grignard reagent to obtain (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl) (4-methoxyphenyl) methanol (compound c49). Then, the synthesis procedure of step 9 of Example 4 was repeated except that (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl) (4-methoxyphenyl) methanol (compound c49) was used as the starting material to obtain 4-bromo-7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran (compound c50).

[0208] To a solution of 4-bromo-7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran (compound c50, 859 mg, 2.43 mmol) in tetrahydrofuran (8 mL), n-butyllithium (2.5 M in hexane, 1.3 mL, 3.24 mmol) was added dropwise at −78° C. under nitrogen atmosphere, and the mixture was stirred at the same temperature for 1.5 h. Then, a solution of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one (compound c51, 898 mg, 1.62 mmol, this compound was synthesized with reference to H. Driguez and B. Henrissat, Tetrahedron Lett. 1981, 22, 5061-5062; Kakinuma, H., et al., J. Med. Chem. 2010, 53, 3247-3261) in tetrahydrofuran (4 mL) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution. After the addition was complete, the solution was allowed to warm gradually to room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give crude compound (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-thiopyran-2-ol (quantitative yield).

[0209] Step 2: 7-chloro-6-(4-methoxybenzyl)-4-((2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-yl)-2,3-dihydrobenzofuran (compound c53) To a stirred solution of lactol (c52) in dichloromethane (16 mL) at -20°C, triethylsilane (1.6 mL, 9.72 mmol) was added followed by boron trifluoride diethyl etherate (0.8 mL, 6.48 mmol) at a rate such that the temperature was maintained between -20 and 0°C. The solution was warmed to 0°C over 1.5 hours before being quenched with saturated sodium bicarbonate solution. After removing the organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (silica gel, 3-25% ethyl acetate in hexane) to give the crude compound 7-chloro-6-(4-methoxybenzyl)-4-((2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-yl)-2,3-dihydrobenzofuran as a white solid (603 mg, 46% for two steps). [M+Na] + 835.

[0210] Step 3: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol (compound c47) To a solution of 7-chloro-6-(4-methoxybenzyl)-4-((2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-yl)-2,3-dihydrobenzofuran (C53, 570 mg, 0.70 mmol) in dichloromethane (8 mL), was added BCl 3 (1.0M in dichloromethane, 2.8 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h. After quenching the reaction with methanol, the solvent was evaporated under reduced pressure. Purification by reverse phase preparative HPLC (Gilson, SunFire™ Prep, 5-50% acetonitrile / water gradient) afforded the title compound as a white solid (18 mg, 6%). 1 H NMR (400 MHz, CD 3OD) δ 7.07(d, J = 8.4 Hz, 2H), 6.79(d, J = 8.8 Hz, 2H), 6.76(s, 1H), 4.63(td, J = 8.0, 1.6 Hz, 2H), 3.95(s, 2H), 3.92(d, J = 3.6 Hz, 1H), 3.79-3.75(m, 3H), 3.74(s, 3H), 3.71(d, J = 6.4 Hz, 1H), 3.56(dd, J = 10.0, 8.8 Hz, 1H), 3.42-3.35(m, 2H), 3.24-3.20(m, 1H), 3.01-2.96(m, 1H), 0.90(t, J = 7.2 Hz, 3H);[M+Na] + 475.

[0211] Example 4: Preparation of (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol [ka]

[0212] Step 1: ((3aS,5S,6R,6aS)-5-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol L-(-)-Xylose (19.15 g, 127.5 mmol) and MgSO in acetone (190 mL). 4 A suspension of (30.72 g, 255.0 mmol) was added to concentrated H 2 SO 4 (1.9 mL) was added at room temperature. After 12 h, the reaction mixture (all L-(-)-xylose had been consumed) was filtered and the combined solids were washed twice with acetone (20 mL per wash). The yellow filtrate was stirred while adding NH 4 The mixture was neutralized to about pH 9 with OH solution. The suspended solids were removed by filtration. The filtrate was concentrated to give the bisacetonide intermediate as a yellow oil. The yellow oil was suspended in water (5 mL) and then the pH was adjusted from 9 to 2 with 1N HCl aqueous solution. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with 25% (w / w) K 3 PO 4 The mixture was neutralized by the addition of aqueous solution until the pH was about 7. The mixture was extracted with EtOAc. The organic layer was washed with MgSO 4It was dried at 40° C., filtered and concentrated in vacuo The crude product was purified by silica gel chromatography to give the title compound as a yellow oil (12.63 g, 52%). 1 H NMR (400 MHz, CD 3 OD) δ 5.88(d, J = 4.0 Hz, 1H), 4.47(d, J = 4.0 Hz, 1H), 4.18-4.14(m, 1H), 4.11(d, J = 2.8 Hz, 1H), 3.83-3.71(m, 2H), 1.45(s, 3H), 1.29(s, 3H).

[0213] Step 2: (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol (14.6 g, 76.7 mmol), NaHCO in acetone / water (120 mL / 40 mL). 3 To a solution of 19.3 g (230.3 mmol) and NaBr (1.6 g, 15.4 mmol) was added TEMPO (0.24 g, 1.5 mmol) at room temperature. The mixture was cooled to 0° C., and then trichloroisocyanuric acid (17.8 g, 76.7 mmol) was added in portions. The suspension was stirred at room temperature for 12 h. Methanol (2.0 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered and washed with acetone (2 times, 20 mL per wash). The organic solvent was removed in vacuum, the aqueous layer was extracted with EtOAc, and the organic layer was concentrated in vacuum. Acetone was added to it, and the mixture was filtered. The filtrate was concentrated to give the desired acid as a pale yellow solid (9.0 g, 58%). 1 H NMR (400 MHz, CD 3 OD) δ 5.98(d, J = 3.6 Hz, 1H), 4.71(d, J = 3.2 Hz, 1H), 4.51(d, J = 3.6 Hz, 1H), 4.36(d, J = 3.6 Hz, 1H), 1.45(s, 3H), 1.31(s, 3H).

[0214] Step 3: ((3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-2-yl)(morpholino)methanone (compound c56) To a suspension of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and HBTU (25.1 g, 66.3 mmol, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in tetrahydrofuran, 4-methylmorpholine (7.3 mL, 66.3 mmol) was added at room temperature. After 1 h, morpholine (5.8 mL, 66.3 mmol) was added to the mixture at room temperature. After 12 h, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the crude material was purified by silica gel chromatography to give the title compound as a yellow solid (5.8 g, 48%). 1 H NMR (400 MHz, CD 3 OD) δ 6.01(d, J = 3.6 Hz, 1H), 5.10(s, 1H), 4.59(d, J = 2.4 Hz, 1H), 4.57(d, J = 3.6 Hz, 1H), 4.47(d, J = 2.4 Hz, 1H), 3.85-3.62(m, 6H), 3.53-3.49(m, 2H), 1.49(s, 3H), 1.33(s, 3H). [M+H] + 274.

[0215] Step 4: (7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (compound c58) To a solution of 4-bromo-7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran (compound c57, 0.7 g, 1.90 mmol) in THF (17.5 mL) was added n-BuLi (2.5 M in hexane, 0.9 mL, 2.28 mmol) at −78° C. After 1 h, the mixture was treated with ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)(morpholino)methanone (compound c56, 0.17 g, 0.63 mmol) in THF (8.0 mL) dropwise at −78° C. After 4 h, the resulting mixture was diluted with saturated NH 4 The mixture was quenched with Cl solution and extracted with EtOAc. The organic layer was washed with MgSO 4The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH purification system) to give the title compound (0.13 g, 43%); [M + H] + 475.

[0216] Step 5: (3aS,5S,6R,6aS)-5-((S)-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)(hydroxyl)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (compound c59) A solution of (7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxol-5-yl)methanone (0.13 g, 0.27 mmol) in methanol (18 mL) was added with CeCl 3 .7H 2 O (0.12 g, 0.32 mmol) was added and the mixture was stirred at room temperature until all solids were dissolved. The mixture was then cooled to -78 °C and NaBH 4 (0.012 g, 0.32 mmol) was added portionwise. The mixture was stirred at -78 °C for 2 h, slowly warmed to 0 °C and saturated NH 4 The mixture was concentrated under reduced pressure and quenched with CH 3 The OH was removed, extracted with EtOAc, and washed with saturated NaCl solution. The organic layer was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The crude title compound was dried under high vacuum as a white solid (0.13 g) which was used in the next step without purification. [M + Na] + 499.

[0217] Step 6: (3S,4R,5S,6S)-6-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (compound c60) A solution of (3aS,5S,6R,6aS)-5-((S)-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)(hydroxyl)methyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (0.13 g, 0.27 mmol) in AcOH / water (4.0 / 2.5 mL) was stirred at 100 °C for 12 h. The resulting mixture was cooled to room temperature and concentrated in vacuo. The crude oil was treated with acetic anhydride (0.2 mL, 2.16 mmol) in pyridine (0.7 mL) at 0 °C. The mixture was stirred at room temperature for 8 h. The resulting mixture was quenched with water, extracted with EtOAc, and washed with brine. The organic layer was washed with MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound as a white solid (0.16 g, 96%). [M + Na] + 627.

[0218] Step 7: (2S,3S,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c61) To a solution of (3S,4R,5S,6S)-6-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (160 mg, 0.26 mmol) and thiourea (39 mg, 0.52 mmol) in 1,4-dioxane (3.1 mL), TMSOTf (70 μl, 0.39 mmol) was added and the reaction mixture was heated at 80 °C for 4 h. The mixture was cooled to room temperature and MeI (40 μl, 0.65 mmol) and DIPEA (452 ​​μl, 2.60 mmol) were added thereto and stirred for 3 h. The resulting mixture was diluted with EtOAc and washed with water. The organic layer was washed with MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated in vacuo. The crude title compound was dried under high vacuum as a white solid (150 mg, 48%) which was used in the next step without purification. [M + Na] + 615.

[0219] Step 8: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol (compound c54) CH 3A suspension of (2S,3S,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (150 mg, 0.25 mmol) in OH (0.7 mL) was added to NaOMe (catalytic, 25% CH 3 OH solution) was added at room temperature. After 20 h, the resulting mixture was concentrated in vacuo. The crude product was diluted with EtOAc and filtered through a membrane. The crude product was purified by preparative HPLC (Gilson system, CH 3 CN / H 2 O) to give the title compound (41 mg, 35%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.09(d, J = 8.4 Hz, 2H), 6.80(d, J = 8.8 Hz, 2H), 6.68(s, 1H), 4.69-4.64(m, 2H), 4.35(d, J = 10.0 Hz, 1H), 4.20(d, J = 9.2 Hz, 1H), 4.02-3.88(m, 4H), 3.67-3.65(m, 2H), 3.61-3.58(m, 1H), 3.56-3 .52(m, 1H), 3.42-3.40(m, 2H), 3.29-3.27(m, 2H), 2.17(s, 3H), 1.40(t, J = 7.0 Hz, 3H);[M+Na] + 489.

[0220] Example 5: Preparation of (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol The synthetic procedure of Example 4 was repeated, except that in step 4, 4-bromo-7-chloro-6-(4-ethylbenzyl)-2,3-dihydrobenzofuran was used instead of 4-bromo-7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran, to give the title compound. 1 H NMR (400 MHz, CDCl 3) δ 7.10-7.90(m, 4H), 6.71(s, 1H), 4.68-4.62(m, 2H), 4.33(d, J = 9.6 Hz, 1H), 4.18(d, J = 9.2 Hz, 1H), 4.07-4.00(m, 2H), 3.63-3.57(m, 3H), 3.52-3.49(m, 1H), 3.39-3.37(m, 2H), 3.27-3.25(m, 2H), 2.60(q, J = 7.4 Hz, 2H), 2.15(s, 3H), 1.20(t, J = 7.6 Hz, 3H); [M+Na] + 473.

[0221] Example 6: Preparation 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 [ka]

[0222] Step 1: (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) The title compound was synthesized by route 1a or 1b below.

[0223] (1a) 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (250 g, 0.687 mol), (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (642 g, 1.38 mol), and anhydrous tetrahydrofuran (2.00 L) were added dropwise to a reaction vessel under nitrogen at room temperature until the mixture was completely dissolved. After the reaction vessel was cooled to -78°C, n-butyllithium (550 mL, 2.0 M hexane solution, 1.38 mol) was added dropwise thereto over 1 h while maintaining the internal temperature at -60°C or less. After the addition of n-butyllithium was complete, the mixture was further stirred at -78°C for 40 min. A solution of concentrated hydrochloric acid / methanol (152 mL / 1,750 mL) was added dropwise to the reaction mixture over 20 minutes while maintaining the internal temperature below -30°C. After the addition was complete, the reaction vessel was allowed to warm to room temperature and stirred for 18 hours. After confirming the completion of the reaction, the reaction vessel was cooled to 0°C and saturated NaHCO 3An aqueous solution (2.5 L) was added and the pH was adjusted to 9-10 using a pH meter, then the reaction solvent was removed using a vacuum concentrator. The concentrate was diluted with EtOAc (2.5 L), distilled water (1.25 L), and brine (1.25 L) and layered. The organic layers were then pooled and the aqueous layer was extracted with EtOAc (2 x 1.25 L). The organic layers were combined and rinsed with distilled water (2.5 L) and brine (2.5 L). The organic layer was washed with MgSO 4 (50 g) and filtered. The filtrate was then concentrated under reduced pressure to remove the solvent. The residue was diluted with toluene (500 mL) and removed by distillation under reduced pressure twice to give the title compound as a yellow liquid (328 g). The crude residue was used in the next step without further purification.

[0224] (1b) 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (10.0 g, 27.5 mol), (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (25.7 g, 54.9 mol) and anhydrous tetrahydrofuran (80 mL) were added dropwise to a reaction vessel at room temperature under nitrogen until the mixture was completely dissolved. After the reaction vessel was cooled to -78°C, n-butyllithium (22.1 mL, 2.5M in hexane, 54.9 mmol) was added dropwise to it over 15 minutes while maintaining the internal temperature below -60°C. After the addition of n-butyllithium was complete, the mixture was further stirred at -78°C for 30 minutes. A solution of concentrated hydrochloric acid / methanol (7.01 mL / 70 mL) was added dropwise to the reaction mixture over 10 minutes while maintaining the internal temperature below -30°C. After the addition was complete, the reaction vessel was allowed to warm to room temperature and stirred for 18 hours. After confirming the completion of the reaction, the reaction vessel was cooled to 0°C and saturated NaHCO 3An aqueous solution (60 L) was added and the pH was adjusted to 9-10 using a pH meter, then the reaction solvent was removed using a vacuum concentrator. The concentrate was diluted with EtOAc (60 mL), distilled water (60 mL), and brine (60 mL) and layered. The organic layers were then pooled and the aqueous layer was extracted with EtOAc (2 x 30 mL). The organic layers were combined and rinsed with distilled water (60 mL) and brine (60 mL). The organic layer was washed with MgSO 4 (5 g), filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was diluted with toluene (50 mL), and then the toluene solution was slowly added dropwise to hexane (200 mL) at room temperature while stirring the hexane. The resulting suspension was stirred at the same temperature for 1 hour and then vacuum filtered. The resulting filtrate was washed with hexane (10 mL), and then dried in a vacuum oven (40° C.) until its moisture content was less than 1% by Karl Fischer analysis to give the title compound as a yellow solid (12.6 g, 96%). 1 H NMR (500 MHz, CDCl 3 ):δ 7.02(d, J = 8.0 Hz, 2H), 6.92(d, J = 8.0 Hz, 2H), 6.81(s, 1H), 4.64(m, 1H), 4.57(m, 1H), 4.05(d, J = 15.0 Hz, 1H), 3.96(d, J = 15.0 Hz, 1H), 3.93(dd, J = 11.8, 3.0 Hz, 1H), 3.87(m, 2H), 3.65(m, 2H), 3.51(m, 1H), 3.30(d, J = 9.5 Hz, 1H), 3.14(s, 3H), 1.83(m, 1H), 0.91(m, 2H), 0.63(m, 2H);LC-MS:[M-OMe] + 445.

[0225] Step 2: (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) In a reaction vessel, the crude residue (328 g, 0.687 mol) obtained by reaction pathway 1a in step 1 was dissolved in CH 2 Cl 2 / CH 3The CN (=v / v, 1:1, 5.00 L) solution was stirred under nitrogen at room temperature until complete dissolution. The reaction vessel was cooled to -50°C and then Et 3 SiH (329 mL, 2.08 mol) and BF 3 -OEt 2 (170 mL, 1.37 mol) was added dropwise over 10 min, maintaining the internal temperature below -45 °C. The reaction mixture was allowed to warm slowly to -10 °C for 1 h, and the resulting mixture was allowed to warm to 0 °C. After stirring at 0 °C for 3 h, the reaction mixture was added with saturated NaHCO 3 Aqueous solution (5.5 L) was added and the pH was adjusted to 7.0-7.5 using a pH meter. The organic solvent was removed from the mixture using a vacuum concentrator, and the concentrate was diluted with EtOAc (2.5 L). The organic layer was then isolated. The aqueous layer was diluted with EtOAc (2 x 125 L) and extracted. All the organic layers were combined and washed with anhydrous MgSO 4 (50 g), filtered, and then the filtrate was concentrated under reduced pressure to remove the solvent. The residue was dried in vacuum to give the title compound as a yellow liquid (307 g). The crude residue thus obtained was used in the next step without further purification. 1 H NMR (500 MHz, CD 3 OD):δ 7.04(d, J = 8.0 Hz, 2H), 6.93(d, J = 8.0 Hz, 2H), 6.83(s, 1H), 4.61(t, J = 9.0 Hz, 2H), 4.13(d, J = 9.0 Hz, 1H), 3.99(d, J = 15.0 Hz, 1H), 3.94(d, J = 15.0 Hz, 1H), 3.87(d, J = 12.0 Hz, 1H), 3.66(m, 1H), 3.44(m, 1H), 3.41(t, J = 9.0 Hz, 2H), 3.36(m, 2H), 3.31(m, 1H), 1.83(m, 1H), 0.91(m, 2H), 0.63(m, 2H);LC-MS:[M+Na] + 469.

[0226] Step 3: (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 c27) A reaction vessel was charged with the crude residue from step 2 (307 g, 0.687 mol) in CH 2 Cl 2(5.00 L) solution was stirred and diluted with DMAP (101 g, 0.825 mol) and Ac 2 HO (520 mL, 5.50 mol) was added dropwise continuously at room temperature. The resulting yellow reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of distilled water (500 mL). The mixture was layered. The organic layer was kept and the aqueous layer was extracted with dichloromethane (2 x 1.25 L). All organic layers were combined and rinsed with 1N aqueous HCl (2.5 L) and brine (2.5 L). The organic layers were washed with MgSO 4 (50 g), filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with MeOH (2.5 L) and stirred at room temperature for 30 min. The resulting solid was filtered under reduced pressure, and the filtrate was rinsed with MeOH (500 mL). The filtered solid was dried to give the title compound as a white solid (357 g, yield: 84%, purity: > 97.6%). 1 H NMR (500 MHz, CDCl 3 ):δ 7.04(d, J = 8.0 Hz, 2H), 6.95(d, J = 8.0 Hz, 2H), 6.53(s, 1H), 5.24(dd, J = 9.5, 9.5 Hz, 1H), 5.12(m, 2H), 4.67(m, 2H), 4.29(d, J = 10.0 Hz, 1H), 4.24(dd, J = 12.5, 4.5 Hz, 1H), 4.13(dd, J = 12.5, 1.5 Hz, 1H), 4.02(d, J = 15.0 Hz, 1H), 3.92(d, J = 15.0 Hz, 1H), 3.77(m, 1H), 3.38(m, 2H), 2.07(s, 3H), 2.06(s, 3H), 1.99(s, 3H), 1.84(m, 1H), 1.66(s, 3H), 0.92(m, 2H), 0.63(m, 2H);LC-MS:[M+Na] + 637.

[0227] Step 4: (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 c28) To a suspension of (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 (357 g, 0.580 mol) in THF / MeOH (= v / v, 1:2, 4.28 L), 4M aqueous NaOH solution (668 mL, 2.67 mol) was added dropwise at room temperature for 20 minutes while stirring the suspension. The resulting suspension was further stirred at room temperature for 2 hours. After cooling the reaction vessel to 0°C, 1N aqueous HCl solution (1.18 L) was slowly added dropwise to the reaction mixture, and the pH was adjusted to 6.5-7.0 using a pH meter. The reaction solvent was removed using a vacuum concentrator, and the concentrate was diluted with EtOAc (5.36 L) and distilled water (5.36 L). The mixture was layered. The organic layer was saved and the aqueous layer was extracted with EtOAc (2 x 1.79 L). All organic layers were combined and rinsed with distilled water (1.79 L). The organic layer was washed with MgSO 4 (710 g), filtered, and the filtrate was concentrated in vacuo to give the crude title compound.

[0228] The crude title compound was diluted with EtOAc (3.89 L) and then stirred at reflux for 30 min to completely dissolve the solid. The resultant was then cooled to room temperature. To the resulting suspension, isopropyl ether (1.29 L) was added dropwise for 10 min and stirred for 30 min (including the time for addition). The step of adding isopropyl ether was repeated twice. The reaction vessel was then cooled to 0° C. and stirred for 30 min. The resulting solid was filtered under reduced pressure, and the filtrate was rinsed with a mixture of EtOAc / isopropyl ether (= v / v, 1:1, 357 mL). The filtered solid was dried in a vacuum oven (40° C., 18 h) to obtain the title compound as a white solid (236 g, yield: 92%, purity: > 99.7%). Furthermore, according to the synthetic route of steps 1 to 4 above, the total yield of the final compound of Example 6 was calculated to be about 77%. 1 H NMR (500 MHz, CD 3OD):δ 7.04(d, J = 8.0 Hz, 2H), 6.93(d, J = 8.0 Hz, 2H), 6.83(s, 1H), 4.61(t, J = 9.0 Hz, 2H), 4.13(d, J = 9.0 Hz, 1H), 3.99(d, J = 15.0 Hz, 1H), 3.94(d, J = 15.0 Hz, 1H), 3.87(d, J = 12.0 Hz, 1H), 3.66(m, 1H), 3.44(m, 1H), 3.41(t, J = 9.0 Hz, 2H), 3.36(m, 2H), 3.31(m, 1H), 1.83(m, 1H), 0.91(m, 2H), 0.63(m, 2H);LC-MS:[M+Na] + 469.

[0229] Example 7: Preparation 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 [ka]

[0230] Step 1: (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) According to the synthetic route of 1b in step 1 of Example 6, the title compound was obtained as a pale yellow solid (26.2 g, 93%) using 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (21.6 g).

[0231] Step 2: (3R,4S,5R,6R)-6-(acetoxymethyl)-2-[7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl]-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c44) A reaction vessel was charged with DMAP (8.06 g, 66.0 mmol) and Ac 2 HO (51.8 mL, 550 mol) was dissolved in (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 (26.2 g, 55.0 mmol) in CH 2 Cl 2 (65.5 L) solution was added dropwise continuously with stirring at room temperature. The resulting yellow reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched by the addition of distilled water (50 mL). The mixture was layered. The organic layer was kept and the aqueous layer was separated by CH 2 Cl2 (2 x 30 mL). All organic layers were combined and rinsed with 1N aqueous HCl (50 mL) and brine (30 mL). The organic layer was washed with MgSO 4 (6 g), filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with MeOH (100 mL) and stirred at room temperature for 12 hours. The resulting solid was filtered under reduced pressure, and the filtrate was rinsed with MeOH (30 mL). The filtered solid was dried to give the title compound as a white solid (29.2 g, 71% total for two steps). 1 H NMR (500 MHz, CDCl 3 ):δ 7.01(d, J = 8.5 Hz, 2H), 6.95(d, J = 8.5 Hz, 2H), 6.65(s, 1H), 5.53(dd, J = 10.0, 9.5 Hz, 1H), 5.19(dd, J = 10.0, 9.5 Hz, 1H), 4.99(d, j = 10.0 Hz, 1H), 4.63(m, 2H), 4.34(dd, J = 12.0, 4.5 Hz, 1H), 4.14(dd, J = 12.0, 2.0 Hz, 1H), 4.05(d, J = 15.5 Hz, 1H), 4.01(m, 1H), 3.99(d, J = 15.5 Hz.

[0232] Step 3: (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 c27) In a reaction vessel, add f(3R,4S,5R,6R)-6-(acetoxymethyl)-2-[7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl]-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (5.00 g, 7.75 mmol) to CH 2 Cl 2 / CH 3 The CN (=v / v, 1:10, 550 mL) solution was stirred at room temperature to completely dissolve the solution. The reaction vessel was cooled to 0° C., and then Et 3SiH (9.89 mL, 62.0 mmol) and BF 3 -OEt 2 (4.96 mL, 40.3 mmol) was added dropwise continuously over 10 min while maintaining the internal temperature below 5° C. The reaction mixture was stirred below 5° C. for 1 h. The reaction mixture was then warmed to 10° C. and stirred for an additional 2 h. The reaction mixture was then diluted with saturated NaHCO 3 An aqueous solution was added and a pH meter was used to check whether the pH was 7.0-7.5. The organic solvent was then removed using a vacuum concentrator. The concentrate was diluted with EtOAc (50 mL) to isolate the organic layer. The aqueous layer was extracted with EtOAc (2 x 30 mL). All the organic layers were combined and diluted with MgSO 4 (5 g), filtered, and the filtrate was concentrated under reduced pressure. The residue was 2 Cl 2 (5 mL), hexane (10 mL) was added thereto, and the mixture was stirred at room temperature for 5 minutes. Isopropyl ether (20 mL) was added to the mixture, and the mixture was stirred for 30 minutes. To the resulting suspension, further isopropyl ether (20 mL) was added. The reaction vessel was cooled to 0° C. and stirred for 2 hours. The resulting solid was filtered under reduced pressure, and the filtrate was rinsed with isopropyl ether (10 mL). The filtered solid was dried in vacuum to give the title compound as a white solid (4.38 g, 92%).

[0233] Step 4: (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 c28) According to the synthesis method described in step 4 of Example 1 above, (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 (4.38 g, 7.12 mmol) was used to obtain the crude title compound. The residue was diluted with EtOAc (45.3 mL) and then stirred at reflux for 10 minutes to completely dissolve the solid. The resultant was cooled to room temperature. To the resulting suspension, isopropyl ether (15.1 mL) was added dropwise for 10 minutes and stirred for 30 minutes (including the dropwise addition time). The step of adding isopropyl ether was repeated twice. The reaction vessel was then cooled to 0° C. and stirred for 30 minutes. The resulting solid was filtered under reduced pressure and the filtrate was rinsed with isopropyl ether (10 mL). The filtered solid was dried in a vacuum oven (40°C, 18 hours) to give the title compound as a white solid (2.93 g, yield: 92%, purity: >99.5%). According to the synthetic route of steps 1-4 above, the total yield of the final compound of Example 2 was calculated to be about 60%.

[0234] Experimental Example 1: Evaluation of yield depending on rearrangement reaction conditions [ka]

[0235] (1) Reactions using amine solvents or reactions without solvents The starting material, methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30), was subjected to a rearrangement reaction at 160° C. to obtain methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (compound c31), and the yield was calculated.

[0236] At this point, the amounts of starting materials and reaction conditions were adjusted as shown in Table 1 below. The reaction was carried out using 5M diethylamine (DEA) as the reaction solvent or without any solvent.

[0237] As a result, the yield was a maximum of 67% and did not increase further. [Table 1]

[0238] (2) Reaction with the addition of Lewis acid The starting material, methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30), was dissolved in a solvent and subjected to a rearrangement reaction.The residue was then purified by silica gel chromatography to obtain methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (compound c31), and its yield was calculated.

[0239] At this point, the reaction solvent, reaction temperature, and Lewis acid were adjusted as shown in Table 2 below, and the reaction was carried out with or without Lewis acid.

[0240] As a result, the Lewis acid diisobutylaluminum chloride ((i-Bu) 2 AlCl) or diethylaluminum chloride (Et 2 When AlCl) was added, the yield increased to 80%. [Table 2]

[0241] Experimental Example 2: Evaluation of yield depending on cyclization reaction conditions (1) Cyclization using Vilsmeier reagent [ka]

[0242] Preparation of Vilsmeier reagent (product A): Add SOCl to a solution of N,N-dimethylformamide (5.6 mL, 74.24 mmol). 2 (5.3 mL, 72.24 mmol) was added at room temperature. The mixture was stirred at 40° C. for 2 h and then concentrated in vacuo to give the Vilsmeier reagent as a hygroscopic white solid.

[0243] Preparation of Vilsmeier Reagent (Product Reagent B): In a solution of N,N-dimethylformamide (2.9 mL, 37.07 mmol), add SOCl 2 (2.7 mL, 37.07 mmol) was added at room temperature. The mixture was stirred at 40° C. for 2 h and then concentrated in vacuo to give the Vilsmeier reagent as a hygroscopic white solid.

[0244] Then, 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl) methyl benzoate (compound c33) in DMF was slowly added to the mixture of Vilsmeier reagent in DMF. The mixture was stirred and subjected to cyclization reaction for 1 hour to obtain 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate methyl ester (compound c34), and the yield was calculated.

[0245] At this point, the starting materials, reaction temperature, etc. were adjusted as shown in Table 3 below, and the reaction was carried out.

[0246] As a result, the cyclized product was obtained in high yields overall, however, when the starting material was impure, the product was recovered in lower yields. [Table 3]

[0247] (2) Cyclization using leaving groups [ka]

[0248] Mesyl chloride (MsCl) was added to the starting material methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33) together with the solvent. The mixture was subjected to a cyclization reaction to obtain methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34), and the yield was calculated.

[0249] At this point, the amounts of reagents used, the methods of addition, and the reaction conditions were adjusted as shown in Table 4 below, and the reaction was carried out.

[0250] As a result, the desired compound could be obtained in high yields, but there were some inconveniences due to the need for MsCl and the equivalent control of the dropwise addition.

[0251] [Table 4]

[0252] (3) Cyclization using halide or Mitsunobu reaction The starting material, 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoic acid methyl ester (compound c33), was subjected to a cyclization reaction by halide or Mitsunobu reaction to obtain 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate methyl ester (compound c34), and the yield was calculated.

[0253] At this point, triphenylphosphine (PPh 3 ), imidazole, iodine (I 2 ), and toluene were used as a reagent for the Mitsunobu reaction. 3 The reagent used was a combination of 1,2-dichlorophenyl ether (PHENOL), diisopropyl azodicarboxylate (DIAD), and tetrahydrofuran (THF).

[0254] As a result, a maximum yield of about 60% was obtained, but there was a disadvantage in that the by-product triphenylphosphine oxide had to be removed after the reaction.

[0255] Experimental Example 3: Evaluation of yield depending on reduction reaction conditions [ka]

[0256] The starting material, 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate methyl (compound c34), was reacted with NaBH 4 (3 equivalents) was added, and Lewis acid was added or not added. The mixture was then subjected to reduction reaction in a solvent at room temperature to obtain (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (compound c35), and the yield was calculated. In addition, the amount of by-product 1 (compound c35-1) was also measured.

[0257] (1) The reaction was carried out by adjusting the reaction solvent and the amount of Lewis acid added as shown in Table 5 below. As a result, when THF / EtOH (1:1) was used as the reaction solvent, it was possible to obtain the product in the highest yield, and NaBH 4 Even when only 1,000g of ethanol was used, a good yield of 95% was obtained. [Table 5]

[0258] (2) Reaction solvent and NaBH without the addition of Lewis acid 4 The amount of NaBH was adjusted as shown in Table 6 below, and the reaction was carried out. As a result, NaBH was added in an amount of 3 equivalents under the conditions of THF / EtOH (1:1) or THF / EtOH (2:1) as the reaction solvent. 4 When 1,2-dichlorophenyl ether was added, a good yield of 95% was obtained without any by-products. [Table 6]

[0259] (3) Reaction solvent, NaBH 4 The reaction was carried out by adjusting the amount of the Lewis acid and the amount of the Lewis acid added as shown in Table 7 below. As a result, the reaction did not proceed when THF alone or THF / i-PrOH was used as the reaction solvent. On the other hand, when THF / ethanol was used as the reaction solvent, NaBH 4 By using only this, a good yield of over 95% was obtained. [Table 7]

[0260] Experimental Example 4: Preparation and analysis of crystalline forms Crystals were obtained from the compound produced according to the method of the present invention, in particular, crude (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 c28) obtained according to steps 1 to 14 of Example 1, through a crystallization process in various solvents, and analyzed.

[0261] XRD spectrum was measured by a Cu-K X-ray diffractometer according to the usual method. α Powder X-ray diffraction was measured by irradiating the sample with X-rays (wavelength λ = 1.54056 Å).

[0262] Differential scanning calorimetry (DSC) was performed using a differential scanning calorimeter at a rate of +1° C. / min.

[0263] (1) Preparation of crystals using toluene solvent Crystallization using toluene was the same as that described in the latter half of the procedure of step 14 of Example 1. Specifically, a solution of crude compound c28 in toluene (8 times the weight of c28) was dissolved by heating at 40° C. for 30 minutes, and then cooled to room temperature. After a suspension was formed at room temperature, it was stirred for another 30 minutes. The resulting precipitate was filtered, washed with toluene (2 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 91.8%).

[0264] The XRD spectrum of the produced crystals showed the crystal form (crystal form A) as shown in Figure 1, and the diffraction angles (2θ), interplanar spacings (d), and relative intensities (I / I 0×100) of the characteristic peaks are summarized in Table 8. [Table 8]

[0265] As shown in FIG. 2, the melting endothermic peak of the crystals was confirmed by the DSC spectrum.

[0266] (2) Preparation of crystals using ethyl acetate solvent Crystallization using ethyl acetate was the same as that described in the latter half of the procedure in step 14 of Example 6. Specifically, a solution of crude compound c28 in ethyl acetate (15 times the weight of c28) was dissolved by refluxing and then cooled to room temperature. After a suspension was formed at room temperature, the mixture was stirred for another 30 minutes. To the resulting mixture, isopropyl ether (15 times the weight of c28) was added dropwise over 30 minutes, and the mixture was stirred for another 30 minutes at room temperature. The resulting precipitate was filtered, washed with ethyl acetate (2 times the weight of c28) at 0°C, and then dried in a vacuum oven (50°C, 12 hours) to obtain a white solid (yield: 88.3%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as that of (1) in Experimental Example 4.

[0267] (3) Preparation of crystals using dichloromethane solvent A solution of crude compound c28 in dichloromethane (17 times the weight of c28) was dissolved by heating at 40° C., and then cooled to room temperature. The mixture was stirred at room temperature for 30 minutes. Compound c28 (10 mg, seed) obtained in step 4 of Example 6 was added to the reaction mixture, and then stirred for 12 hours. The resulting precipitate was filtered, washed with dichloromethane (2 times the weight of 28), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 50.1%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as that of (1) in Experimental Example 4.

[0268] (4) Preparation of crystals using acetone solvent The crude compound c28 was dissolved by refluxing a solution of acetone (35 times the weight of c28) and then cooled to room temperature. After a suspension was formed at room temperature, the mixture was stirred for another 3 hours. The resulting precipitate was filtered, washed with acetone (2 times the volume of the filtrate), and then dried in a vacuum oven (50°C, 12 hours) to obtain a white solid (yield: 38.2%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as in Experimental Example 4 (1).

[0269] (5) Preparation of crystals using acetonitrile solvent Crude compound c28 was dissolved by heating a solution of acetonitrile (10 times the weight of c28) at 60° C., then cooled to room temperature. After a suspension was formed at room temperature, it was stirred for another hour. The resulting precipitate was filtered, washed with acetonitrile (twice the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 39.4%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as in Experimental Example 4 (1).

[0270] (6) Preparation of crystals using 2-propanol solvent A solution of crude compound c28 in 2-propanol (10 times the weight of c28) was dissolved by heating at 60° C., and then cooled to room temperature. After a suspension was formed at room temperature, it was stirred for another 30 minutes. 2-propanol (5 times the weight of c28) was added dropwise to the reaction mixture, and then it was stirred for 30 minutes. The resulting precipitate was filtered, washed with 2-propanol (2 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 9.5%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as that of Experimental Example 4 (1).

[0271] (7) Preparation of crystals using tetrahydrofuran / dichloromethane solvent A solution of crude compound c28 in tetrahydrofuran (5 times the weight of c28) was dissolved by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The concentrated residue was diluted with dichloromethane (30 times the weight of 28) and stirred at room temperature. After a suspension was formed at room temperature, it was stirred for another 30 minutes. The resulting precipitate was filtered, washed with dichloromethane (2 times the weight of c28), and then dried in a vacuum oven (50°C, 12 hours) to obtain a white solid (yield: 65.3%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as that of (1) in Experimental Example 4.

[0272] (8) Preparation of crystals using tetrahydrofuran / n-hexane solvent A solution of crude compound c28 in tetrahydrofuran (5 times the weight of c28) was dissolved by stirring at room temperature for 30 minutes. n-Hexane (10 times the weight of c28) was added dropwise to the reaction mixture and stirred for 1 hour. n-Hexane (10 times the weight of c28) was further added dropwise to the resulting suspension and then stirred for 30 minutes. n-Hexane (5 times the weight of c28) was repeatedly added dropwise to the reaction suspension and then stirred for 30 minutes. The resulting precipitate was filtered, washed with n-hexane (5 times the volume of the filtrate), and then dried in a vacuum oven (50°C, 12 hours) to obtain a white solid (yield: 99.6%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form A) as in Experimental Example 4 (1).

[0273] (9) Methanol / distilled water solvent Crude compound c28 was dissolved in methanol (5 times the weight of c28) by stirring at room temperature for 30 minutes. Distilled water (10 times the weight of 28) was added dropwise to the reaction mixture, and then stirred for 30 minutes. Distilled water (10 times the weight of c28) was further added dropwise to the resulting suspension, and then stirred for 1 hour. The resulting precipitate was filtered, washed with distilled water (2 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 100%).

[0274] The XRD spectrum of the produced crystals showed the crystal form (crystal form B) as shown in Figure 3, and the diffraction angles (2θ), interplanar spacings (d), and relative intensities (I / I 0×100) of the characteristic peaks are summarized in Table 9. [Table 9]

[0275] As shown in FIG. 4, the melting endothermic peak of the crystals was confirmed by the DSC spectrum.

[0276] (10) Preparation of crystals using methanol / n-hexane solvent Crude compound c28 was dissolved in methanol (5 times the weight of c28) by stirring at room temperature for 30 minutes. n-Hexane (15 times the weight of 28) was added dropwise to the reaction mixture and stirred for 30 minutes. n-Hexane (10 times the weight of c28) was further added dropwise to the resulting suspension and stirred for 1 hour. The resulting precipitate was filtered, washed with n-hexane (5 times the volume of the filtrate), and then dried in a vacuum oven (50°C, 12 hours) to obtain a white solid (yield: 97.1%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form B) as that of (9) in Experimental Example 4.

[0277] (11) Preparation of crystals using methanol / dichloromethane / n-hexane solvent Crude compound c28 was dissolved in dichloromethane / methanol (20:1 times the weight of c28) by stirring at room temperature for 30 minutes. n-Hexane (10 times the weight of 28) was added dropwise to the reaction mixture and stirred for 30 minutes. n-Hexane (5 times the weight of c28) was repeatedly added dropwise to the reaction suspension and stirred for 30 minutes. The resulting precipitate was filtered, washed with n-hexane (5 times the volume of the filtrate), and then dried in a vacuum oven (50°C, 12 hours) to obtain a white solid (yield: 99.2%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form B) as (9) in Experimental Example 4.

[0278] (12) Preparation of crystals using tetrahydrofuran / toluene solvent The crude compound c28 was dissolved by stirring a solution of tetrahydrofuran (5 times the weight of c28) at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The concentrated residue was diluted with toluene (30 times the weight of 28) and stirred at room temperature for 1 hour. The resulting precipitate was filtered, washed with toluene (5 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 76.1%).

[0279] The XRD spectrum of the produced crystals showed the crystal form (crystal form C) as shown in Figure 5, and the diffraction angles (2θ), interplanar spacings (d), and relative intensities (I / I 0×100) of the characteristic peaks are summarized in Table 10. [Table 10]

[0280] As shown in FIG. 6, the melting endothermic peak of the crystals was confirmed by the DSC spectrum.

[0281] (13) Preparation of crystals using ethanol / distilled water / n-hexane solvent Crude compound c28 was dissolved in ethanol (5 times the weight of c28) by heating at 50° C., then cooled to room temperature. Distilled water (10 times the weight of 28) was added dropwise to the reaction mixture, and then stirred for 1 hour. Distilled water (10 times the weight of c28) was further added dropwise to the resulting suspension, and stirred for 30 minutes. n-hexane (1 time the weight of c28) was added dropwise to the reaction suspension, and stirred for 1 hour. The resulting precipitate was filtered, washed with distilled water (2 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 95.8%). XRD spectrum analysis of the produced crystals showed the same crystal form (crystal form C) as (12) in Experimental Example 4.

[0282] (14) Preparation of crystals using ethanol / n-hexane solvent Crude compound c28 was dissolved by heating a solution of ethanol (5 times the weight of c28) at 50° C., then cooled to room temperature. n-Hexane (5 times the weight of c28) was added dropwise to the reaction mixture and stirred for 30 minutes. n-Hexane (10-fold, 10 times the weight of c28) was further added dropwise to the resulting suspension and stirred for 30 minutes. n-Hexane (5 times the weight of c28) was repeatedly added dropwise to the reaction suspension and stirred for 30 minutes. The resulting precipitate was filtered, washed with n-Hexane (5 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white solid (yield: 96.5%).

[0283] The XRD spectrum of the produced crystals showed the crystal form (crystal form D) as shown in FIG. 7, and the diffraction angles (2θ), interplanar spacings (d), and relative intensities (I / I 0×100) of the characteristic peaks are summarized in Table 11.

[0284] [Table 11]

[0285] As shown in FIG. 8, the melting endothermic peak of the crystals was confirmed by the DSC spectrum.

[0286] Experimental Example 5: Confirmation of stability of crystal form Using the crystalline form produced in Experimental Example 4(2), stability confirmation tests for properties, identification tests, water content, specific rotation, related substances, and content were conducted for 3 months under accelerated test conditions (temperature: 40±2°C, relative humidity: 75±5%) and long-term test conditions (temperature: 25±2°C, relative humidity: 60±5%). The results of the stability confirmation tests are shown in Table 12.

[0287] [Table 12]

[0288] (1) Property testing confirmed that there was no change in the properties of the crystalline form under accelerated or long-term conditions.

[0289] (2) Identification tests were conducted using infrared spectrophotometry and liquid chromatography, which are general testing methods specified in the Korean Pharmacopoeia, and it was confirmed that the crystalline form showed the same spectrum as the standard product by both test methods. <Analysis conditions> - Column: Capcdell-pak C18 MG(USPL1), 250 x 4.6 mm, 5 μm - Temperature: 35℃ - Detector: Photodiode array (PDA) detector (measurement wavelength: 225 nm) - Flow rate: 1.0 mL / min - Mobile phase: Buffer / methanol (25:75) - Buffer solution: a buffer solution obtained by dissolving 1.36 g of potassium dihydrogen phosphate in 1,000 mL of distilled water and then adjusting the pH to 3.0 with phosphoric acid.

[0290] (3) In the case of XRD spectrum, it was confirmed that there was no change in the crystal form under accelerated and long-term conditions.

[0291] (4) When measured according to the moisture determination method among the general test methods specified in the Korean Pharmacopoeia, the moisture content test confirmed that the crystalline form showed almost no moisture content under accelerated and long-term conditions.

[0292] (5) The specific rotation confirmation test confirmed the structural stability of the crystal form under accelerated and long-term conditions.

[0293] (6) Among the general test methods prescribed in the Korean Pharmacopoeia, the stability confirmation test for related substances was performed by liquid chromatography. The analysis time of the sample solution was performed so that it was measured up to three times the retention time of the main peak. The peak areas of the standard solution (0.05 mg / mL) and the sample solution (1 mg / mL) other than all peaks appearing in the blank test solution were calculated by a formula. As a result, the stability of the crystal form of related substances under accelerated and long-term conditions was confirmed. - Analytical conditions: Liquid chromatography analytical conditions for the confirmation test in Experimental Example 5(2) - Calculation formula: Other individual related substances (%) = (peak area of ​​each related substance in the test sample x amount of standard product used x purity of standard product) / (peak area of ​​main peak of standard solution x amount of sample used x dilution ratio)

[0294] (7) For the confirmation test, a methanol solution of the standard product was used as the standard solution (0.2 mg / mL), and a methanol solution of the crystalline form was used as the sample solution (1 mg / mL). The sample solution and the standard solution were tested by the liquid chromatography method in the general test method specified in the Korean Pharmacopoeia, and the peak areas of the standard solution and the sample solution were used to perform calculations according to the following formula. As a result, there was almost no change in content under accelerated and long-term conditions, and the stability of the crystalline form was confirmed. - Analytical conditions: Liquid chromatography analytical conditions for the confirmation test in Experimental Example 5(2) - Calculation formula: Other individual related substances (%) = (peak area of ​​main peak of test sample x amount of standard product used x purity of standard product) / [peak area of ​​main peak of standard solution x amount of sample used x (100-water content of sample)]

Claims

[Claim 1] The crystal form is Cu-K α When irradiated with a light source, the compound has an X-ray diffraction (XRD) spectrum including peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 23.5°±0.2° of the following formula (c28): Crystal of the compound.

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