Method for producing diphenylmethane derivatives

Abstract

To provide an improved method for producing a diphenylmethane derivative which is effective as a sodium-dependent glucose cotransporter (SGLT) inhibitor.SOLUTION: The present invention relates to a method for producing a compound of the formula Ia implemented by a convergent synthesis method. The method comprises: reacting a compound of the formula 2 with a compound of the formula 3, and subjecting the resultant to a cyclization reaction to obtain a compound of the formula 4; subjecting the resultant to dehydration or amidation, reacting the resultant with a compound of the formula 5, and performing reduction to obtain a compound of the formula 6; and reacting the resultant with a compound of the formula 7 and performing deprotection and reduction.SELECTED DRAWING: Figure 1

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 sodium-dependent glucose cotransporters (SGLTs). [Background technology]

[0002] Sodium-dependent glucose cotransporters (SGLTs) transport Na along a concentration gradient. + It allows the transport of glucose against its concentration gradient while also allowing the transport of glucose against its concentration gradient. Currently, two important SGLT isoforms, known as SGLT1 and SGLT2, have been cloned. SGLT1 is present in the intestine, kidney, and heart, and its expression regulates cardiac glucose transport. Being a high-affinity, low-capacity transporter, SGLT1 is responsible for only a portion of renal glucose reabsorption. In contrast, SGLT2 is a low-affinity, high-capacity transporter that is primarily present in the apical region of epithelial cells in the early proximal tubule. In healthy individuals, more than 99% of plasma glucose filtered by the renal glomerulus is reabsorbed, with less than 1% of the total filtered glucose being excreted in the urine. It is estimated that 90% of renal glucose reabsorption is facilitated by SGLT2, while the remaining 10% is mediated by SGLT1 in the late proximal straight tubule. Genetic mutations in SGLT2 do not have any particular adverse effects on carbohydrate metabolism. However, mutations increase renal glucose secretion by approximately 140 g / day. Human mutation studies suggest that SGLT2 is responsible for most of the renal glucose reabsorption and is therefore a target of therapeutic research.

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

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

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

[0006] However, conventional methods for producing compound C28 involve a linear synthesis, such as coupling with a glucose group followed by the formation of a pentagonal ring on the aglycone group. This linear synthesis method results in low final yields due to the complex route. Furthermore, if the synthesis of the glucose group or cyclopropylbenzyl group attached to the dihydrobenzofuran fails midway through, or if the intended substitution of the glucose group or cyclopropylbenzyl group is to be replaced with another group, the synthesis must be restarted from the beginning. Furthermore, the yield during the synthesis of the cyclopropyl group of compound C28 varies significantly depending on the condition (purity, anhydride, etc.) of the reagents (diethylzinc, solvent) and the reaction concentration. The synthesis is carried out by cyclizing the olefin via a Simon-Smith reaction at the end of the synthetic pathway.

[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 synthesized separately and then bonded together, 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 performing reduction to obtain a compound of formula 6 below; and (3) reacting the 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 a 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; wherein Ra, Rb, Rc, and Rd each independently represent 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 the group consisting of 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 substituted with 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 performing reduction to obtain a compound of formula 6: (3) reacting a compound of formula 6 with a compound of formula 8 below and carrying out reduction to obtain a compound of formula 9 below; (4) converting the furanose ring of the compound of formula 9 into a pyranose ring under acidic conditions, and then introducing a protecting group to obtain a compound of formula 10: (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 It 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 produced by the above method, specifically a crystalline form of the compound of formula c28 below:

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

[0013] The method for producing 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 achieving a simpler synthetic route and higher yields than the linear synthetic methods disclosed in the prior art literature, and improving reproducibility by reducing risk factors inherent in linear synthetic routes (such as returning to the beginning of the route and repeating the synthesis at the point of failure midway through the synthesis).

[0014] In particular, according to the methods disclosed in the prior art, even after coupling of the glucose group and the aglycon group, the aglycon group residues must be synthesized. In contrast, according to the present invention, all the aglycon group residues can be formed before coupling with the glucose group. Furthermore, the aryl group attached to the terminal group of the aglycon can be easily synthesized, allowing for diverse designs of the terminal group.

[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 explanation of the drawings]

[0016] [Figure 1-2] 1 shows the XRD and DSC spectra of crystalline form A obtained in Experimental Example 4, respectively. [Figure 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 INVENTION

[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 It 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; wherein Ra, Rb, Rc, and Rd each independently represent 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 the group consisting of 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 substituted with 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, R7 is hydrogen or C 1-7 alkyl; R 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] In another particular 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] wherein A, B, R, X′, and n are as defined above in Formula 1.

[0023] According to a preferred example 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 formula 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 performing reduction to obtain a compound of formula 6 below; and (3) reacting the 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 a 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 production method can be produced by a synthetic route described in a prior art document (US Patent Publication No. 2015 / 0152075). For example, the compound of formula 2 can be produced by the following steps: (i) a step of 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: (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 resulting product 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 before attachment to the glucose group and also before forming the terminal residue of the aglycone group (i.e., ring B).

[0033] In a particular 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) rearranging the allyl group of the compound of formula 3a, and then oxidizing or ozonizing the resulting product, followed by 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 being reacted 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, and the compound of formula 2e may be reacted with the 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, by 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 (for example, 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] 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) may be carried out by adding osmium tetroxide (OsO4), potassium osmate(VI) dihydrate, or ozone (O3).

[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 the formula (3b), a compound of the 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 document (U.S. 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] In one example, the cyclization reaction may be carried out by adding a Vilsmeier reagent to the compound of formula 3d. This reaction may be carried out at a temperature of 0°C to room temperature. In terms of yield, it is preferable that the Vilsmeier reagent be rapidly produced and used during synthesis. For example, a Vilsmeier reagent produced by the reaction of dimethylformamide (DMF) with SOCl2 or POCl3 may be used.

[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 using I2 and a halide such as PBr3. According to yet another example, the cyclization reaction may also be carried out by the Mitsunobu reaction using diisopropyl azodicarboxylate (DIAD).

[0050] These reactions involve the substitution of a primary alcohol group with a group that can act as a leaving group, with the substituent acting as a nucleophile towards the phenol group to effect a cyclization reaction.

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

[0052] In one 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] The compound of formula (I) can be obtained.

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

[0056] At this point, a reducing agent such as NaBH4 or LiBH4 may be used to reduce the compound of formula 4. Furthermore, alcohol, tetrahydrofuran (THF), or a mixture thereof may be used as a solvent during the reduction. A preferred example is a mixed solvent of ethanol and THF, with a volume ratio of 1:1 to 1:3 during the reduction. Furthermore, a Lewis acid may be used during the reduction. Examples of Lewis acids that can be used include LiCl and CaCl2.

[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] The compound of formula (I) can be obtained.

[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] In 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 amidated with N,O-dimethylhydroxyamine hydrochloride (e.g., MeO(Me)NH HCl) to give Weinreb amides such as formula 4b.

[0063] The compound of formula 4b is then reacted with a compound of formula 5 to form a compound of formula 6b: [Formula 6b] [ka] The compound of formula (I) can be obtained.

[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] Compounds of formula 6b can then be reduced to give compounds of formula 6.

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

[0067] A common method for preparing Grignard reagents is to prepare compounds of formula 5a: [Formula 5a] [ka] can be reacted with magnesium (Mg) metal 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 preparing a Grignard reagent before coupling the aglycon group with the glucose group, which not only enables various derivatizations but also improves the final yield.

[0070] On the other hand, according to a prior art document (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 vary 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] A compound of formula 6 is reacted with a compound of formula 7 to form a compound of formula 7a: [Formula 7a] [ka] The compound of formula (I) can be obtained.

[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, methanesulfonic acid (CHSOH) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) can be added to the compound of formula 7a to give the compound of formula 1a.

[0077] Alternatively, deprotection can be followed by further reduction to give compounds of formula 1a. At this point, dichloromethane (CH2Cl2) and acetonitrile (CH2Cl2) can be used in combination as solvents.

[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 can be 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 hydroxy group of glucose in the compound obtained by deprotection and reduction is protected with an acetyl group or the like. 1-6 The resulting precipitate is isolated by heating and stirring in an alcohol solvent (such as ethanol or isopropanol), whereby a compound represented by the following formula 7b, in which glucose is in the β-form, is obtained: [Formula 7b] [ka] The compound of formula (I) can be obtained.

[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-form 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 example, 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) a step of 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 resulting compound in alcohol, ethyl acetate, or dichloromethane, and isolating and deprotecting the resulting precipitate to obtain only the β-form; [ka] This can be done by a method comprising:

[0086] wherein 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 preferably carried out to obtain the compound of formula 7a, which is then 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, or the like.

[0089] In another preferred embodiment, step (3) comprises the following steps: (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 resulting compound, without separation or purification, to deprotection and methylation 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') introducing a protecting group into the compound of formula 7e, isolating only the β-form, and then deprotecting the compound; [ka] The method can be carried out by a method comprising:

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

[0091] In step (3a'), first, a coupling reaction is carried out. At this point, the compound of formula 7 and the reaction reagent (i.e., n-butyllithium, sec-butyllithium, t-butyllithium, or isopropylmagnesium chloride) can be used in an amount of 1.5 to 2.5 equivalents, more preferably 1.7 to 2.3 equivalents, and particularly 2.0 equivalents, per equivalent of the compound of formula 6. The reaction 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, the reaction solvent can be a single solvent such as tetrahydrofuran or ether, or a mixed solvent such as tetrahydrofuran / toluene (1:1).

[0092] Furthermore, in step (3a'), deprotection and methylation reactions are carried out under acidic conditions. Acids used at this stage include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and hydrogen chloride gas. 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 or the like may be used as a reaction solvent.

[0093] Next, a reduction reaction is carried out in step (3b'). At this point, a reducing agent and an acid may be used. Examples of reducing agents include triethylsilane, triisopropylsilane, t-butyldimethylsilane, and sodium borohydride. Examples of acids include boron trifluoride diethyl etherate, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, trifluoroacetic acid, and trifluoromethanesulfonic acid. The amount of reducing agent used is 2 to 5 equivalents, more preferably about 3 equivalents, and the amount of 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, or a mixed solvent such as dichloromethane / acetonitrile (1:1) and 1,2-dichloromethane / acetonitrile (1:1), can be used.

[0094] Next, in step (3c'), a protecting group is introduced. At this point, a reaction using an acetylating agent and a base may be carried out. Examples of acetylating agents include acetyl chloride, acetyl bromide, and acetic anhydride. Examples of bases 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. Acetone, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, or the like may be used as a reaction solvent.

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

[0096] In yet another preferred embodiment, step (3) comprises the following steps: (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 resulting compound, without separation or 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 the 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] wherein 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, type of acid, equivalent ratio, reaction temperature, and solvent are as exemplified in step (3b') above.

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

[0102] As shown in the preferred example above, the process for obtaining the compound of formula 7d can be carried out in two steps, or can be carried out in one step as an in situ reaction, which further improves the final yield. Furthermore, when carried out in one step as an in situ reaction, a crude concentrated residue containing the compound of formula 7b can be obtained, or the compound of formula 7d can be obtained as a solid content by crystallization, which can be used in the next step. In the latter case, the quality can be improved by removing the reaction by-products, and the water content can be easily controlled.

[0103] Furthermore, the compound of formula 7d can be purified after synthesis and used in the next step. 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 repeatedly concentrating the mixture to remove residual water can be used in the next step, or (ii) after synthesis, the compound of formula 7d can be crystallized, and the residual water can be removed by vacuum drying to obtain a solid, which 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 can be C 1-7 It may also 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 obtaining a variety of crystalline forms.

[0108] For 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, which can result 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, which can result 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, which may result 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 performing reduction to obtain a compound of formula 6: (3) reacting a compound of formula 6 with a compound of formula 8 below and carrying out reduction to obtain a compound of formula 9 below; (4) converting the furanose ring of the compound of formula 9 into a pyranose ring under acidic conditions, and then introducing a protecting group to obtain a compound of formula 10: (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 1-7 It is alkylthio; n is 1 or 2; PG is a protecting group; X' is a 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 steps, steps (1) and (2) can be carried out in the same manner as steps (1) and (2) in the method for producing 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 method disclosed in WO 2009 / 014970. Specifically, the compound of formula 8 can be prepared according to the method 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] wherein B, n, and X are as defined above in Formula 1.

[0122] Compounds of formula 9a can then be reduced to give compounds 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 1-7Reaction 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-described production method.

[0129] In 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 of the following formula c28: [Formula c28] [ka]

[0132] The compound of formula c28 can be prepared by the preparation method of formula 1a above.

[0133] According to the present invention, the compound of formula c28 can be in various crystalline 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 to 10.5%, preferably 9.8 to 10.2%. As another example, "about 100°C" may mean 95 to 105°C, preferably 98 to 102°C.

[0135] First, the present invention provides crystalline form A of the compound of formula c28. Crystalline form A is Cu—K α When illuminated with a light source, it has an XRD spectrum containing 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] Furthermore, 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 α When illuminated with a light source, it has an XRD spectrum containing 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] Furthermore, this crystalline form may have an endothermic peak with an onset of about 79°C and a minimum of about 88°C in DSC (10°C / min), and an endothermic peak with an onset of about 103°C and a minimum of about 111°C.

[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 a light source, it has an XRD spectrum containing 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] Furthermore, 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 crystalline form D of the compound of formula c28. Crystalline form D is Cu—K α When illuminated with a light source, it has an XRD spectrum containing 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] Furthermore, 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] MODE FOR CARRYING OUT THE INVENTION 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 Ac2O: acetic anhydride BF3·OEt2: Boron trifluoride etherate DIPEA: N,N-diisopropylethylamine DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide EtOAc: ethyl acetate EtOH: ethanol Et3SiH: 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(PPh3)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 [Example]

[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 synthetic steps of Comparative Example 1, see Scheme 1, as discussed above in the Background section.

[0152] Step 1: Methyl 3-methoxy-2-nitrobenzoate (compound c2) To a mixture of 3-methoxy-2-nitrobenzoic acid (25.0 g, 126 mmol) and K2CO3 (35.0 g, 253 mmol) in DMF (126 mL) was added MeI (15.8 mL, 253 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Water (200 mL) was poured into the mixture, which was then stirred at 5 °C for 30 minutes. The precipitated solid was collected by filtration and washed with water and hexane. The solid was dried in vacuo to give the title compound as a white solid in crude form (26.2 g, 98%). 1 H NMR(400 MHz, CDCl3) 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 stirred under an H atmosphere at room temperature 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 (22.4 g, 99%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) 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: methyl 2-amino-5-bromo-3-methoxybenzoate (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, which was then extracted with EtOAc (500 mL x 2). The combined organic layers were dried over MgSO4, 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, CDCl3) 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: methyl 5-bromo-2-chloro-3-methoxybenzoate (compound c5) 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 a solution of NaNO (21.5 g, 311 mmol) in HO (50 mL) 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. Water (300 mL) was added to the mixture and extracted with EtOAc (500 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude title compound was dried under high vacuum and used in the next step as a white solid without further purification (29.0 g, 100%). 1 H NMR(400 MHz, CDCl3) 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) To a solution of methyl 5-bromo-2-chloro-3-methoxybenzoate (25.0 g, 89.4 mmol) in THF (100 mL), HO (100 mL), and MeOH (100 mL) was added dropwise 5 N aqueous 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 dried over MgSO, filtered, and concentrated in vacuo to give the title compound as an orange solid (22.6 g, 96%). 1 H NMR (400 MHz, CDCl3) 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) To a suspension of 5-bromo-2-chloro-3-methoxybenzoic acid (6.0 g, 22.6 mmol) in CHCl (100 mL) 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 vacuo and dried in vacuo to give the crude title compound. 1 H NMR (400 MHz, CDCl3) 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) Crude 5-bromo-2-chloro-3-methoxybenzoyl chloride was dissolved in benzene (100 mL) and cooled to 0 °C. To the reaction mixture, AlCl (6.9 g, 52.0 mmol) was added portionwise at 0 °C. The mixture was stirred at 90 °C for 15 hours. The mixture was cooled to room temperature and evaporated in vacuo. 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 dried over MgSO, 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, CDCl3) 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 quenched by the addition of saturated NaHCO3 solution at 0 °C and extracted with EtOAc. The organic layer was dried over MgSO4, 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 (267 mg, 77%). 1 H NMR (400 MHz, CDCl3) 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) To a mixture of 3-benzyl-5-bromo-2-chlorophenol (1.72 g, 5.78 mmol) and K2CO3 (1.6 g, 11.56 mmol) in acetone (35 mL) was added allyl bromide (0.73 mL, 8.67 mmol) at room temperature. The reaction mixture was stirred at 65 °C for 12 hours. 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%). 1H NMR (400 MHz, CDCl3) 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), n-butyllithium (2.5 M in hexane, 2.6 mL, 6.41 mmol) was added dropwise at −78° C. under a nitrogen atmosphere. After stirring for 1 hour, 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 via cannula to the mixture at −78° C. over 20 minutes. The reaction mixture was stirred at −78° C. for 3 hours. CH3SO3H (0.6 mL, 9.25 mmol) in MeOH (15 mL) was added dropwise to the mixture at 0 °C. The mixture was allowed to warm to room temperature over 18 h and then quenched with saturated NaHCO3 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 dried over MgSO4, filtered, and concentrated in vacuo to give 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) 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 CHCl (30 mL) and CHCN (30 mL) was added EtSiH (1.82 mL, 11.3 mmol) and BF·EtO (1.07 mL, 8.48 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was quenched with saturated NaHCO solution and extracted with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. 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) 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 CHCl (12 mL) was added AcO (4.7 mL, 49.72 mmol), pyridine (4.0 mL, 49.45 mmol), and DMAP (35 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with EtOAc and washed with 1N HCl solution. The organic layer was dried over MgSO, 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 (1.55 g, 47%). 1H NMR (400 MHz, DMSO-d6) 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 hours. The resulting mixture was neutralized with glacial AcOH. The mixture was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic layer was dried over MgSO4, 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. Benzyl bromide (2.5 mL, 21.0 mmol) was added dropwise to the reaction mixture at 0° C. The mixture was stirred at room temperature for 12 h. The resulting mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, 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 (1.80 g, 88%). 1 H NMR (400 MHz, CDCl3) 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) was added NaBH (700 mg, 18.4 mmol) and Pd(PPh) (266 mg, 0.23 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched by the addition of saturated NaHCO solution and extracted with EtOAc. The organic layer was dried over MgSO, 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 (1.62 g, 95%). 1 H NMR (400 MHz, CDCl3) 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 1,4-dichloro-2H-pyran-2-yl)phenol (1.62 g, 2.18 mmol) 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 1,4-dichloro-2H-pyran-2-yl)phenol (11 mL) 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 hours. The resulting mixture was quenched by the addition of saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over MgSO4, 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) To a mixture of 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) and K2CO3 (0.35 g, 2.54 mmol) in acetone (13 mL) was added 2-bromoethanol (0.14 mL, 1.90 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 12 hours. 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) To 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 CHCN (12 mL) was added carbon tetrachloride (12 mL, 134 mmol) at room temperature. The reaction mixture was stirred at 55° C. for 12 hours. 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 hexane solution, 6.8 mL, 17.0 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 3 hours. The resulting mixture was quenched by the addition of 1N HCl solution (100 mL) and extracted with EtOAc. The organic layer was dried over MgSO4, 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 stirred under H at room temperature for 5 h. 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, CD3OD) 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) 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 CHCl (78 mL) was added AcO (5.9 mL, 62.6 mmol), pyridine (5.0 mL, 62.6 mmol), and DMAP (48 mg, 0.39 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with EtOAc and washed with 1N HCl solution. The organic layer was dried over MgSO, 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 (4.54 g, 100%). 1 H NMR (400 MHz, CDCl3) 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) 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 CHCl (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 with ice-water and extracted with CHCl. ​​The organic layer was dried over MgSO, 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 (3.73 g, 93%). 1H NMR (400 MHz, CDCl3) 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 hours. The resulting mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, 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 (0.52 g, 52%). 1H NMR (400 MHz, CDCl3) 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, 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 (407 mg, 81%). 1H NMR (400 MHz, CDCl3) 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) To a solution of diethylzinc (1.1 M toluene solution, 1.74 mL, 1.91 mmol) in CHCl (3 mL) was added trifluoroacetic acid (0.15 mL, 1.91 mmol) in CHCl (1.5 mL) dropwise at 0 °C. After 1 h, diiodomethane (0.16 mL, 1.91 mmol) in CHCl (1.5 mL) was added dropwise to the mixture at 0 °C. After 1 h, (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 CHCl (3 mL) was slowly added to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was dried over MgSO4, 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 (285 mg, 60%). 1H NMR (400 MHz, CDCl3) 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) A mixture 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 (298 mg, 0.48 mmol) and K2CO3 (536 mg, 3.88 mmol) in MeOH (20 mL) was stirred at RT 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, CH3CN / HO) 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, CD3OD) 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.

[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: Methyl 5-bromo-2-chloro-3-hydroxybenzoate (compound c29) ) To a solution of methyl 5-bromo-2-chloro-3-methoxybenzoate (compound c5; 30.0 g, 107.3 mmol) in CHCl (300 mL) was added BBr (25.9 mL, 268.3 mmol) slowly under a nitrogen atmosphere at 0° C. The mixture was slowly warmed to room temperature and stirred at room temperature for 15 hours. The reaction mixture was quenched by adding MeOH (100 mL) at 0° C. The mixture was evaporated under reduced pressure to remove CHCl, 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, CDCl3) 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: methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30) To a solution of methyl 5-bromo-2-chloro-3-hydroxybenzoate (38.2 g, 143.9 mmol) in acetone (700 mL) were added allyl bromide (14.9 mL, 172.7 mmol) and K2CO3 (29.8 g, 215.9 mmol) at room temperature. The mixture was stirred at 60 °C for 12 h and then cooled to room temperature. After filtering off insoluble salts 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, dried over MgSO4, 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, CDCl3) 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) To a solution of methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (10.0 g, 32.7 mmol) in CHCl (150 mL) was added diisobutylaluminum chloride (25% in hexane, 64.0 mL) dropwise (0.5–1 h) under a nitrogen atmosphere at 0°C. The mixture was slowly warmed to room temperature and stirred at room temperature for an additional 12 h. The reaction mixture was cooled to 0°C, quenched with 1 M HCl (50 mL), and then extracted with EtOAc (150 mL x 2). The combined organic layers were dried over MgSO, 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, CDCl3) 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: methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33) Method A) Synthesis by reduction of aldehydes To a mixture of methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (9.9 g, 32.3 mmol) in THF / HO (100 mL / 100 mL) was added NaIO (20.8 g, 97.0 mmol) and OsO (82 mg, 0.32 mmol) 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 poured into a saturated solution of NaSO (100 mL), and the mixture was extracted with EtOAc (200 mL × 2). The organic layer was dried over MgSO, filtered, and concentrated in vacuo (9.0 g, 29.4 mmol, 91%). 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] To 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 NaBH (2.72 g, 71.8 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was quenched with saturated NH Cl (100 mL) and extracted with EtOAc (100 mL x 2) [one extraction was not sufficient]. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo (19.9 g). To a suspension of the residue in EtOAc (20 mL), hexane (10–20 mL) was added. The resulting precipitate was collected by filtration and washed with hexane (50 mL). The precipitate was dried in vacuo to give the title compound (14.3 g, 72%). 1 H NMR (400 MHz, CDCl3) 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 Ozone gas was bubbled through methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (10.2 g, 33.4 mmol, 80% purity) in CHCl / MeOH (150 mL / 35 mL) at −78°C for 4 hours (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 portionwise at −78°C. The resulting mixture was allowed to warm slowly to room temperature for 2 hours, concentrated, suspended in EtOAc, and concentrated. 1N aqueous HCl (200 ml) was added to the residue and stirred for 30 minutes. The precipitate was collected by filtration (quantitative, 80% purity). The precipitate was suspended in EtOAc and stirred. Hexane was slowly added to the resulting mixture. The precipitate was collected by filtration to give the title compound (7.9 g, 76.4%, purity 92%). 1H 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 ester (compound c34) Preparation of Vilsmeier reagent: To a solution of N,N-dimethylformamide (7.9 ml, 102.2 mmol) was added SOCl (7.5 ml, 102.2 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 2 h. 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, CDCl3) 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 quenched by the addition of saturated NH4Cl at 0 °C and extracted with EtOAc (aqueous pH ~7.0). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid (11.7 g, 44.4 mmol, 99%). The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) 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); [M-H2O] + 245.

[0189] Step 7: 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound c36) To a solution of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (11.7 g, 44.4 mmol) in CHCl (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 filtered off using a silica gel pad and washed with CHCl. ​​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, CDCl3) 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-necked flask containing magnesium (shavings, 1.1 g, 46.6 mmol) was flame-dried. Under a nitrogen atmosphere, the flask was fitted with a condenser and an addition funnel. 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 a 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 dried over MgSO, filtered, and concentrated in vacuo to give the crude title product (7.6 g, 20.0 mmol, 114%). The crude residue was used in the next step without further purification to give the crude title compound. [M-H2O] + 361.

[0192] Step 9: 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (compound c40) To a solution of (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (7.6 g, 20.0 mmol) in CHCl / CHCN (100 mL / 100 mL) was added triethylsilane (4.6 mL, 40 mmol) and boron trifluoride diethyl etherate (3.8 mL, 30 mmol) under a nitrogen atmosphere at -20 °C. The mixture was gradually warmed to room temperature and stirred at room temperature for an additional 50 min. The reaction mixture was quenched by the slow addition of saturated NaHCO solution (200 mL) and extracted with EtOAc (100 mL). The organic layer was dried over MgSO, 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, CDCl3) 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), n-butyllithium (2.5 M hexane solution, 7.38 mL, 18.4 mmol) was added dropwise under a nitrogen atmosphere at −78°C. After stirring at the same temperature for 40–60 min (yellowish solution), a precooled (−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) was added dropwise via cannula over 20 min. The reaction mixture was stirred at the same temperature for 2–3 h (yellowish solution).

[0194] The reaction mixture was quenched at -78°C with 1% acetic acid (20 mL) 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 dried over MgSO4, filtered, and concentrated in vacuo to give 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 CHSOH (1.5 mL, 23.5 mmol) dropwise at 0 °C. The mixture was allowed to warm to room temperature over 18 h and then quenched with saturated NaHCO 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 dried over MgSO, filtered, and concentrated in vacuo to give 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) 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 CHCl / CHCN (v:v=1:1, 120 mL) was added EtSiH (6.0 mL, 37.8 mmol), followed by BF .OEt2 (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 quenched with saturated NaHCO3 (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 dried over MgSO4, filtered, and concentrated in vacuo to give 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) 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 CHCl (120 mL) was added DMAP (1.9 g, 15.5 mmol) and AcO (9.7 mL, 103.76 mmol) at room temperature. After stirring at room temperature for 18 h, the reaction was quenched by the addition of water (120 mL). The resulting mixture was extracted with CHCl (100 mL × 2). After washing with 1 M HCl and brine, the combined organic layers were dried over MgSO, filtered, and evaporated under reduced pressure (7.0 g, crude material). The residue was slurried with EtOH (45 mL) and heated to reflux at 80 °C for 1 h. The mixture was allowed to cool to room temperature while stirring for 18 hours. 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%). 1H NMR (400 MHz, CDCl3) 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 hours. 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 dried over MgSO4, filtered, and concentrated 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 twice its volume of toluene. The wet cake was dried under 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%. 1H NMR (400 MHz, CD3OD) 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 (2.5 M hexane solution, 8.28 mL, 20.7 mmol) was added dropwise at −78° C. under a nitrogen atmosphere. After stirring at the same temperature for 5 minutes, a solution of TMS-protected lactone (compound c11; 7.70 g, 16.6 mmol) in tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (300 mL) at 0° C. and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 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) To 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 CHCl (70 mL) and CHCN (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 extracted with CHCl (300 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give 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) 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 (6.3 g, 13.8 mmol) in CHCl (140 mL) was added DMAP (0.84 g, 6.9 mmol) and AcO (13.0 mL, 13.8 mmol) at room temperature. After stirring at room temperature for 18 h, the reaction mixture was quenched with water (120 mL) and extracted with DCM (200 mL). The organic layer was washed with aqueous NaHCO (100 mL), dried over NaSO, filtered, and concentrated in vacuo. 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%). 1H NMR (400 MHz, CDCl3) 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 dried over NaSO, 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, CD3OD) 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 synthetic 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 give (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-methoxyphenyl)methanol (Compound C49). Then, the synthetic 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 give 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 hexane solution, 1.3 mL, 3.24 mmol) was added dropwise at −78° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1.5 hours. 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, 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 h and then 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 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 crude 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% over 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 BCl3 (1.0 M in dichloromethane, 2.8 mL) 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 (18 mg, 6%) as a white solid. 1H NMR (400 MHz, CD3OD) 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 To a suspension of L-(-)-xylose (19.15 g, 127.5 mmol) and MgSO (30.72 g, 255.0 mmol) in acetone (190 mL) was added concentrated HSO (1.9 mL) 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 neutralized to approximately pH 9 with NHOH solution while stirring. 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 aqueous HCl. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was neutralized to approximately pH 7 by the addition of 25% (w / w) aqueous KPO. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, 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%). 1H NMR (400 MHz, CD3OD) 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 To a solution of ((3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol (14.6 g, 76.7 mmol), NaHCO3 (19.3 g, 230.3 mmol), and NaBr (1.6 g, 15.4 mmol) in acetone / water (120 mL / 40 mL) 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 portionwise. The suspension was stirred at room temperature for 12 hours. Methanol (2.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and washed with acetone (twice, 20 mL per wash). mL). The organic solvent was removed in vacuo, the aqueous layer was extracted with EtOAc, and the organic layer was concentrated in vacuo. Acetone was added thereto, 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, CD3OD) 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 hour, morpholine (5.8 mL, 66.3 mmol) was added to the mixture at room temperature. After 12 hours, 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, CD3OD) 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 hexane solution, 0.9 mL, 2.28 mmol) at −78 °C. After 1 h, ((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) was added dropwise at −78 °C. After 4 h, the resulting mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The 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) To 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 CeCl3.7H2O (0.12 g, 0.32 mmol), and the mixture was stirred at room temperature until all solids dissolved. The mixture was then cooled to −78 °C, and NaBH4 (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 quenched with saturated NH4Cl solution. The mixture was concentrated under reduced pressure to remove CH3OH, extracted with EtOAc, and washed with saturated NaCl solution. The organic layer was dried over MgSO4, 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 dried over MgSO4, 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 hours. The mixture was cooled to room temperature, and to it were added MeI (40 μL, 0.65 mmol) and DIPEA (452 ​​μL, 2.60 mmol), and the mixture was stirred for 3 hours. The resulting mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude title compound was dried under high vacuum and used in the next step without purification as a white solid (150 mg, 48%). [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) To a 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 CHOH (0.7 mL) was added NaOMe (catalytic amount, 25% solution in CHOH) 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, CHCN / HO) to give the title compound (41 mg, 35%). 1 H NMR (400 MHz, CDCl3) 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. 1H NMR (400 MHz, CDCl3) 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 the following route 1a or 1b.

[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. The reaction vessel was cooled to −78°C, and n-butyllithium (550 mL, 2.0 M hexane solution, 1.38 mol) was added dropwise over 1 hour 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 40 minutes. A solution of concentrated hydrochloric acid / methanol (152 mL / 1,750 mL) was added dropwise to the reaction mixture over 20 minutes, 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, saturated aqueous NaHCO3 (2.5 L) was added, and the pH was adjusted to 9-10 using a pH meter. The reaction solvent was then 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 layers were dried over MgSO4 (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 (328 g) as a yellow liquid. 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 under nitrogen at room temperature, and the mixture was completely dissolved. The reaction vessel was cooled to −78°C, and n-butyllithium (22.1 mL, 2.5 M hexane solution, 54.9 mmol) was added dropwise 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, 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, saturated aqueous NaHCO3 (60 L) was added, and the pH was adjusted to 9-10 using a pH meter. The reaction solvent was then 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 dried over MgSO4 (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 water content was 1% or less by Karl Fischer analysis to obtain the title compound as a yellow solid (12.6 g, 96%). 1H NMR (500 MHz, CDCl3): 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) The crude residue (328 g, 0.687 mol) obtained via Reaction Route 1a in Step 1 was dissolved completely in CHCl / CHCN (1:1 v / v, 5.00 L) under nitrogen at room temperature with stirring in a reaction vessel. The reaction vessel was cooled to -50 °C, and then EtSiH (329 mL, 2.08 mol) and BF-OEt (170 mL, 1.37 mol) were added dropwise over 10 min, maintaining the internal temperature below -45 °C. The reaction mixture was slowly warmed to -10 °C for 1 h, and then the resulting mixture was warmed to 0 °C. After stirring at 0 °C for 3 h, saturated aqueous NaHCO (5.5 L) was added to the reaction mixture, 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 organic layers were combined, dried over anhydrous MgSO4 (50 g), filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was dried in vacuo 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. 1H NMR (500 MHz, CD3OD): 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) To a stirred reaction vessel was added a solution of the crude residue from Step 2 (307 g, 0.687 mol) in CHCl (5.00 L) at room temperature, while DMAP (101 g, 0.825 mol) and AcO (520 mL, 5.50 mol) were added dropwise successively. The resulting yellow reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of distilled water (500 mL). The mixture was layered. The organic layer was saved, 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 layer was dried over MgSO (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 minutes. 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%). 1H NMR (500 MHz, CDCl3): 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) was added 4 M aqueous NaOH (668 mL, 2.67 mol) dropwise over 20 min at room temperature while stirring. The resulting suspension was further stirred at room temperature for 2 h. After cooling the reaction vessel to 0 °C, 1 N aqueous HCl (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 dried over MgSO4 (710 g), filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound.

[0228] The crude title compound was diluted with EtOAc (3.89 L) and then refluxed for 30 minutes to completely dissolve the solid. The resulting mixture was then cooled to room temperature. Isopropyl ether (1.29 L) was added dropwise to the resulting suspension over 10 minutes and stirred for 30 minutes (including the dropwise addition time). The isopropyl ether addition process 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 a mixture of EtOAc / isopropyl ether (= v / v, 1:1, 357 mL). The filtered solid was dried in a vacuum oven (40°C, 18 hours) to obtain the title compound as a white solid (236 g, yield: 92%, purity: >99.7%). Furthermore, based on the synthetic route of steps 1 to 4 above, the overall yield of the final compound of Example 6 was calculated to be approximately 77%. 1 H NMR (500 MHz, CD3OD): 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) DMAP (8.06 g, 66.0 mmol) and AcO (51.8 mL, 550 mol) were added dropwise 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 (26.2 g, 55.0 mmol) in CHCl (65.5 L) at room temperature. The resulting yellow reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched by the addition of distilled water (50 mL). The mixture was layered. The organic layer was saved, and the aqueous layer was extracted with CHCl (2 × 30 mL). All organic layers were combined and rinsed with 1N aqueous HCl (50 mL) and brine (30 mL). The organic layer was dried over MgSO4 (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, CDCl3): 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, 1H), 3.49(m, 1H), 3.33(m, 1H), 3.17(s, 3H), 2.08(s, 3H), 2.05(s, 3H), 1.94(s, 3H), 1.83(m, 1H), 1.61(s, 3H), 0.90(m, 2H), 0.62(m, 2H).

[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, a solution of 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) in CHCl / CHCN (=v / v, 1:10, 550 mL) was dissolved completely with stirring at room temperature. After cooling the reaction vessel to 0 °C, EtSiH (9.89 mL, 62.0 mmol) and BF-OEt (4.96 mL, 40.3 mmol) were added dropwise continuously over 10 min while maintaining the internal temperature below 5 °C. The reaction mixture was stirred at below 5 °C for 1 h. The reaction mixture was then warmed to 10 °C and stirred for an additional 2 h. Saturated aqueous NaHCO3 was added to the reaction mixture, and a pH meter was used to confirm that 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) and the organic layer was isolated. The aqueous layer was extracted with EtOAc (2 x 30 mL). All organic layers were combined, dried over MgSO4 (5 g), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CHCl2 (5 mL), and hexane (10 mL) was added and 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, additional 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 under 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 refluxed and stirred for 10 minutes to completely dissolve the solid. The mixture was cooled to room temperature. Isopropyl ether (15.1 mL) was added dropwise to the resulting suspension over 10 minutes and stirred for 30 minutes (including the dropwise addition time). The isopropyl ether addition step 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 to 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 solvent-free reactions Methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30) as a starting material 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 the 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 yield increased to 80% when the Lewis acids diisobutylaluminum chloride ((i-Bu)2AlCl) or diethylaluminum chloride (Et2AlCl) were added. [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 reagent A): To a solution of N,N-dimethylformamide (5.6 mL, 74.24 mmol) was added SOCl (5.3 mL, 72.24 mmol) 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): To a solution of N,N-dimethylformamide (2.9 mL, 37.07 mmol) was added SOCl (2.7 mL, 37.07 mmol) 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, methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33) in DMF was slowly added to the mixture of Vilsmeier reagent in DMF. The mixture was stirred for 1 hour to undergo cyclization reaction, yielding methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (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 low yield. [Table 3]

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

[0248] To the starting material, methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (Compound c33), was added mesyl chloride (MsCl) as a 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 yield, but there were some disadvantages 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, methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33), was subjected to a cyclization reaction using a halide or Mitsunobu reaction to obtain methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34), and the yield was calculated.

[0253] At this point, a reagent combination of triphenylphosphine (PPh3), imidazole, iodine (I2), and toluene was used for cyclization with halides, and a reagent combination of triphenylphosphine (PPh3), diisopropyl azodicarboxylate (DIAD), and tetrahydrofuran (THF) was used for the Mitsunobu reaction.

[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, methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (Compound C34), was added with NaBH (3 equivalents) with or without Lewis acid. The mixture was then subjected to a 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. Furthermore, the amount of by-product 1 (Compound C35-1) was also measured.

[0257] (1) The reaction was carried out by adjusting the amounts of reaction solvent and Lewis acid added as shown in Table 5 below. As a result, when THF / EtOH (1:1) was used as the reaction solvent, the product could be obtained in the highest yield, and even when NaBH4 alone was used without a Lewis acid, a good yield of 95% was obtained. [Table 5]

[0258] (2) The reaction was carried out without the addition of a Lewis acid by adjusting the reaction solvent and the amount of NaBH4 added as shown in Table 6. As a result, when NaBH4 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, a good yield of 95% was obtained without any by-products. [Table 6]

[0259] (3) The reaction solvent, the amount of NaBH4 added, and the amount of Lewis acid added were adjusted as shown in Table 7 below, and the reaction was carried out. As a result, when THF alone or THF / i-PrOH was used as the reaction solvent, the reaction did not proceed. On the other hand, when THF / ethanol was used as the reaction solvent, a good yield of over 95% was obtained by using only NaBH4 without a Lewis acid. [Table 7]

[0260] Experimental Example 4: Preparation and analysis of crystalline forms Crystals were obtained from the compounds 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 crystallization steps in various solvents, and analyzed.

[0261] For XRD spectra, Cu-K was measured using an 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) Crystallization using toluene solvent Crystallization using toluene was the same as that described in the latter half of the procedure in 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, the mixture was stirred for another 30 minutes. The resulting precipitate was filtered, washed with toluene (twice 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 crystalline form (crystalline 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 DSC spectrum confirmed the melting endothermic peak of the crystals.

[0266] (2) Crystallization using ethyl acetate as a solvent The crystallization using ethyl acetate was similar to that described in the latter half of 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 an additional 30 minutes. Isopropyl ether (15 times the weight of c28) was added dropwise to the resulting mixture over 30 minutes, and the mixture was stirred for an additional 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 resulting crystals indicated the same crystalline form (crystalline form A) as in Experimental Example 4 (1).

[0267] (3) Crystallization 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 crystalline form (crystalline form A) as that of Experimental Example 4 (1).

[0268] (4) Crystallization using acetone solvent A solution of crude compound c28 in acetone (35 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 an additional 3 hours. The resulting precipitate was filtered, washed with acetone (twice 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 resulting crystals showed the same crystalline form (crystalline form A) as in Experimental Example 4 (1).

[0269] (5) Crystallization using acetonitrile solvent A solution of crude compound c28 in acetonitrile (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, the mixture was stirred for an additional 1 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 resulting crystals showed the same crystalline form (crystalline form A) as in Experimental Example 4 (1).

[0270] (6) Crystallization 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, the mixture was stirred for an additional 30 minutes. 2-propanol (5 times the weight of c28) was added dropwise to the reaction mixture, followed by stirring for 30 minutes. The resulting precipitate was filtered, washed with 2-propanol (twice 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 resulting crystals indicated the same crystalline form (crystalline form A) as in 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, the mixture was stirred for an additional 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 resulting crystals showed the same crystalline form (crystalline form A) as in Experimental Example 4 (1).

[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. To the reaction mixture, n-hexane (10 times the weight of c28) was added dropwise, followed by stirring for 1 hour. To the resulting suspension, n-hexane (10 times the weight of c28) was further added dropwise, followed by stirring for 30 minutes. To the reaction suspension, n-hexane (5 times the weight of c28) was repeatedly added dropwise, followed by stirring 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 resulting crystals indicated the same crystalline form (crystalline form A) as in Experimental Example 4 (1).

[0273] (9) Methanol / distilled water solvent A solution of crude compound c28 in methanol (5 times the weight of c28) was dissolved by stirring at room temperature for 30 minutes. Distilled water (10 times the weight of 28) was added dropwise to the reaction mixture, followed by stirring for 30 minutes. Distilled water (10 times the weight of c28) was further added dropwise to the resulting suspension, followed by stirring 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 crystalline form (crystalline 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 DSC spectrum confirmed the melting endothermic peak of the crystals.

[0276] (10) Crystallization using methanol / n-hexane solvent A solution of crude compound c28 in methanol (5 times the weight of c28) was dissolved by stirring at room temperature for 30 minutes. To the reaction mixture, n-hexane (15 times the weight of 28) was added dropwise, and the mixture was stirred for 30 minutes. To the resulting suspension, n-hexane (10 times the weight of c28) was further added dropwise, and the mixture was 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 resulting crystals indicated the same crystalline form (crystalline form B) as that of (9) in Experimental Example 4.

[0277] (11) Crystallization using methanol / dichloromethane / n-hexane solvent Crude compound c28 was dissolved in dichloromethane / methanol (20:1 relative to the weight of c28) by stirring at room temperature for 30 minutes. To the reaction mixture, n-hexane (10 times the weight of 28) was added dropwise and stirred for 30 minutes. To the reaction suspension, n-hexane (5 times the weight of c28) was added dropwise repeatedly 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 resulting crystals indicated the same crystalline form (crystalline form B) as (9) in Experimental Example 4.

[0278] (12) Preparation of crystals using tetrahydrofuran / toluene solvent The crude compound c28 was dissolved in tetrahydrofuran (5 times the weight of c28) 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 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 crystalline form (crystalline 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 DSC spectrum confirmed the melting endothermic peak of the crystals.

[0281] (13) Crystallization using ethanol / distilled water / n-hexane solvent A solution of crude compound c28 in ethanol (5 times the weight of c28) was dissolved by heating at 50°C and 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 resulting crystals showed the same crystalline form (crystal form C) as (12) in Experimental Example 4.

[0282] (14) Crystallization using ethanol / n-hexane solvent A solution of crude compound c28 in ethanol (5 times the weight of c28) was dissolved by heating at 50°C and 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 crystalline form (crystalline form D) as shown in Figure 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 DSC spectrum confirmed the melting endothermic peak of the crystals.

[0286] Experimental Example 5: Confirmation of stability of crystalline form Using the crystalline form prepared in Experimental Example 4(2), stability confirmation tests for properties, identification, 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) The property tests confirmed that there was no change in the properties of the crystalline form under accelerated and 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 in 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 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 testing methods specified in the Korean Pharmacopoeia, stability confirmation tests for related substances were conducted using liquid chromatography. The analysis time of the sample solution was set so that the measurement was performed 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), excluding all peaks appearing in the blank test solution, were calculated using a formula. As a result, the stability of the crystalline forms of related substances under accelerated and long-term conditions was confirmed. - Analysis conditions: Liquid chromatography analysis 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 × amount of standard product used × purity of standard product) / (peak area of ​​the main peak of the standard solution × amount of sample used × dilution rate)

[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 standard solution were tested using the liquid chromatography method in the general testing method specified in the Korean Pharmacopoeia, and the peak areas of the standard solution and sample solution were used to perform calculations using the following formula. As a result, there was almost no change in content under accelerated or long-term conditions, confirming the stability of the crystalline form. - Analysis conditions: Liquid chromatography analysis conditions for the confirmation test in Experimental Example 5 (2) - Calculation formula: Other individual related substances (%) = (peak area of ​​the main peak of the test sample × amount of standard product used × purity of the standard product) / [peak area of ​​the main peak of the standard solution × amount of sample used × (100 - water content of the sample)]

Claims

1. When irradiated with a Cu-Kα light source, the compound has an X-ray diffraction (XRD) spectrum including 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° of the following formula (c28): Crystals of the compound.

2. When irradiated with a Cu-Kα light source, the compound has an X-ray diffraction (XRD) spectrum including 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° of the following formula (c28): Crystals of the compound.

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