RU2814846C1 - Method of producing dephenylmethane derivative - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: embodiments of the method of obtaining crystalline of form A of the compound (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) having an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ), equal to 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° in case of irradiation using Cu-K_α radiation source. One of the embodiments of the method includes the following steps: (1) dissolving the crude compound c28 in methanol (5 times the mass of c28) while stirring at room temperature for 30 minutes; (2) adding distilled water (10 times the amount by weight of c28) dropwise to the reaction mixture and then stirring for 30 minutes; (3) additional addition of distilled water dropwise to the resulting suspension (10 times the amount by weight c28); (4) stirring for 1 hour; (5) filtering and washing the resulting precipitate with distilled water and (6) drying the resulting filtrate in a vacuum oven (50°C, 12 hours) to obtain a white crystal of form B.

EFFECT: obtaining the crystalline form of compound c28.

3 cl, 8 dwg, 12 tbl, 13 ex

Description

Field of technology

The present invention relates to a method for producing a diphenylmethane derivative and, in particular, to an improved method for producing a diphenylmethane derivative that is used as a sodium-dependent glucose cotransporter (SGLT) inhibitor.

State of the art

The sodium-dependent glucose cotransporter (SGLT) mediates Na ⁺ transport that follows a concentration gradient while at the same time mediating glucose transport that does not follow a concentration gradient. Currently, two important isoforms of SGLT have been cloned, known as SGLT1 and SGLT2. SGLT1 is located in the intestine, kidney and heart, and regulates glucose transport in the heart through its expression. Due to the fact that SGLT1 is a high-affinity, low-throughput transporter, it is responsible only for the reabsorption of glucose in the kidneys. On the other hand, SGLT2 is a low-affinity, high-throughput transporter that is mainly located in the apical domains of epithelial cells in the initial part of the proximal convoluted tubule. In healthy individuals, more than 99% of plasma glucose that is filtered by the glomeruli is reabsorbed, and less than 1% of the total filtered glucose is excreted in the urine. SGLT2 is thought to account for 90% of renal glucose reabsorption, with the remaining 10% mediated by SGLT1 in the terminal proximal straight tubule. The SGLT2 genetic mutation does not have any specific adverse effects on carbohydrate metabolism. However, increased glucose secretion in the kidneys, amounting to about 140 g/day, is caused depending on the mutation. According to mutation studies in humans, SGLT2 has been the subject of therapeutic research because SGLT2 is estimated to be responsible for the majority of glucose reabsorption in the kidney.

US Patent Laid-Open No. 2015/0152075 describes a compound having a diphenylmethane moiety that has SGLT2 inhibitory activity, as well as a method for its preparation. The document describes that the diphenylmethane derivative compound is effective in the treatment of diabetes, since the diphenylmethane derivative compound shows an excellent inhibitory effect on human SGLT2 activity and significantly reduces urinary sugar excretion in animals compared to the drug dapagliflozin, which is a well-known SGLT2 inhibitor. In addition, US Patent Laid-Open No. 2014/0274918 discloses a diphenylmethane derivative that is effective as a dual inhibitor of sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2).

In Example 172 of US Patent Publication Laid-Open No. 2015/0152075 or the like. describes a method for obtaining diphenylmethane compound C28, similar to that presented in the following reaction scheme 1.

[Reaction Scheme 1]

However, according to the conventional method for preparing compound c28, a linear synthesis method is used, such as the formation of a pentagonal ring in the aglycone group after binding to the glucose group. In the case of such a linear synthesis, due to the complex synthesis route, a low final product yield is obtained. Moreover, in the case where the synthesis of a glucose substituent or a cyclopropylbenzyl group which is linked to dihydrobenzofuran does not proceed properly in the middle of the synthesis, or if it is implied that the substituent or cyclopropylbenzyl group is replaced by another group, there is a disadvantage associated with the need to carry out its synthesis again from the very beginning. In addition, even for the process of synthesizing the cyclopropyl group of compound c28, the process is carried out by cyclization of the olefin through the Simons-Smith reaction at the end of the synthesis route, whereby the yield varies greatly depending on the state (purity, anhydrous or the like) of the reagent (diethylzinc, solvent ) and the like, and the concentration of the reaction.

Based on the above, the inventors of the present invention have discovered that a diphenylmethane derivative can be efficiently produced by a convergent synthesis method in which the corresponding main groups are synthesized separately and then combined with each other, as opposed to the conventional linear synthesis method, and thus the present invention is accomplished.

Detailed Description of the Invention

Technical problem

Accordingly, it is an object of the present invention to provide an improved process for preparing a diphenylmethane derivative which is useful as an SGLT inhibitor.

The solution of the problem

According to an aspect of the present invention, there is provided a method for preparing a compound of the following formula 1a, comprising the steps of:

(1) reacting a compound of the following formula 2 with a compound of the following formula 3 and cyclizing the resulting reaction product to obtain a compound of the following formula 4;

(2) aldehyde or amidate a compound of formula 4, followed by reacting the resulting compound with a compound of the following formula 5 and performing reduction to obtain a compound of the following formula 6; And

(3) reacting a compound of formula 6 with a compound of the following formula 7 and deprotecting and reducing,

in formulas,

A represents oxygen (O) or sulfur (S);

n is 1 or 2;

PG represents a protecting group;

X' represents halogen or C _1-7 alkyl;

X, Y and Hal are each independently halogen;

B represents (B-1) or (B-2) ,

where Ra, Rb, Rc and Rd are each independently hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C _1-7 alkyl, C _1-7 alkylthio, C _2-7 alkenyl, C _{2 -7} alkynyl, C _1-7 alkoxy, C _1-7 alkoxy-C _1-7 alkyl, C _2-7 alkenyl-C _1-7 alkyloxy, C _2-7 alkynyl-C _1-7 alkyloxy, C _3-10 cycloalkyl, C _3-7 cycloalkylthio, C _5-10 cycloalkenyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkyloxy-C _1-7 alkoxy, phenyl-C _1-7 alkyl, C _1-7 alkylthio-phenyl, phenyl- C _1-7 alkoxy, mono- or di-C _1-7 alkylamino, mono- or di-C _1-7 alkylamino-C _1-7 alkyl, C _1-7 alkanoyl, C _1-7 alkanoylamino, C _1-7 alkylcarbonyl, C _1-7 alkoxycarbonyl, carbamoyl, mono- or di-C _1-7 alkylcarbamoyl, C _1-7 alkylsulfonylamino, phenylsulfonylamino, 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 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 have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-7 alkyl and C _2-7 alkynyl;

cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-4 alkyl and C _1-4 alkoxy; And

each heteroaryl and heterocycloalkyl independently contains one or more heteroatoms selected from the group consisting of N, S and O.

In accordance with another aspect of the present invention, there is provided a method for preparing a compound of the following formula 1b, comprising the steps of:

(1) reacting a compound of the following formula 2 with a compound of the following formula 3 and cyclizing the resulting reaction product to obtain a compound of the following formula 4;

(2) the compound of formula 4 undergoes aldehydeation or amidation, followed by reacting the resulting compound with a compound of formula 5 and reducing it to obtain the compound of the following formula 6;

(3) reacting a compound of formula 6 with a compound of the following formula 8 and then performing reduction to obtain a compound of the following formula 9;

(4) converting the furanose ring of the compound of formula 9 into a pyranose ring under acidic conditions and then introducing a protecting group thereto to obtain the compound of the following formula 10; And

(5) treating the compound of formula 10 with thiourea, reacting the resulting product with a C _1-7 alkyl halide and subsequent reduction,

where in the formulas,

R represents C _1-7 alkylthio;

B, n, PG, X', X, Y and Hal are as defined above in Formula 1.

According to another aspect of the present invention, there is provided a crystalline form of the compound obtained by the above method, in particular a crystalline form of the compound of the following formula c28.

[Formula c28]

Advantageous effects of the invention

The method for producing the diphenylmethane derivative of the present invention is carried out by a convergent synthesis method in which the main groups are synthesized separately and then linked to each other. Thus, compared with the linear synthesis method described in the prior art document, a simple synthesis route and high product yield can be achieved, and the reproducibility is improved due to the fact that risk factors (such as returning to the beginning of the route and repeating the synthesis at mid-synthesis failures) that are inherent in the linear synthesis path can be reduced.

Specifically, according to the method described in the prior art document, aglycone group residues must be synthesized even after the glucose group has been bound to the aglycone group. On the other hand, according to the present invention, all residues of the aglycone group can be formed before they are associated with the glucose group. In addition, the aryl group attached to the end group of the aglycone can be easily synthesized, so that various designs of the end group are possible.

Moreover, the crystalline form of the compound obtained by the above method has excellent physicochemical properties and thus can be effectively used in fields such as the production of pharmaceuticals.

Brief description of drawings

1 and 2 show the X-ray diffraction (XRD) and differential scanning calorimetry (DSC) spectra of crystal Form A obtained in Experimental Example 4, respectively.

FIGS. 3 and 4 show the XRD and DSC spectra of crystal Form B obtained in Experimental Example 4, respectively.

FIGS. 5 and 6 show the XRD and DSC spectra of crystalline Form C obtained in Experimental Example 4, respectively.

FIGS. 7 and 8 show the XRD and DSC spectra of crystalline Form D obtained in Experimental Example 4, respectively.

The best way to carry out the invention

The present invention relates to a process for preparing a compound of formula 1:

[Formula 1]

in the formula,

A represents oxygen (O) or sulfur (S);

R represents hydroxymethyl or C _1-7 alkylthio;

n is 1 or 2;

X' represents halogen (eg F, Cl, Br or I) or C _1-7 alkyl;

B represents (B-1) or (B-2) ,

where Ra, Rb, Rc and Rd are each independently hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C _1-7 alkyl, C _1-7 alkylthio, C _2-7 alkenyl, C _{2 -7} alkynyl, C _1-7 alkoxy, C _1-7 alkoxy-C _1-7 alkyl, C _2-7 alkenyl-C _1-7 alkyloxy, C _2-7 alkynyl-C _1-7 alkyloxy, C _3-10 cycloalkyl, C _3-7 cycloalkylthio, C _5-10 cycloalkenyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkyloxy-C _1-7 alkoxy, phenyl-C _1-7 alkyl, C _1-7 alkylthio-phenyl, phenyl- C _1-7 alkoxy, mono- or di-C _1-7 alkylamino, mono- or di-C _1-7 alkylamino-C _1-7 alkyl, C _1-7 alkanoyl, C _1-7 alkanoylamino, C _1-7 alkylcarbonyl, C _1-7 alkoxycarbonyl, carbamoyl, mono- or di-C _1-7 alkylcarbamoyl, C _1-7 alkylsulfonylamino, phenylsulfonylamino, 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 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 have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-7 alkyl and C _2-7 alkynyl;

cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are each independently unsubstituted or have one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-4 alkyl and C _1-4 alkoxy; And

each heteroaryl and heterocycloalkyl independently contains one or more heteroatoms selected from the group consisting of N, S and O.

As a specific example, ring B-1 may be selected from the group consisting of:

In the formulas, R ₇ represents hydrogen or C _1-7 alkyl; R _8a and R _8b are each independently C _1-7 alkyl or linked together to form a 5-10 membered heterocycloalkyl (which contains at least one heteroatom selected from the group consisting of N, S and O) .

As another specific example, ring B-2 may be selected from the group consisting of:

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:

In the formulas, A, B, R, X' and n are as defined above in Formula 1.

According to a preferred example of a compound of formula 1a, A may be oxygen; n can be equal to 1; X' may represent a halogen; and B may be phenyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-7 alkyl, C _3-10 cycloalkyl and C _{1- 7} alkoxy.

In addition, the compounds of formulas 1a and 1b may be compounds in which glucose is in the α-form, β-form or racemic form.

Preferably, the compounds of formulas 1a and 1b may be compounds in which glucose is in the β-form.

Method for preparing the compound of formula 1a (formula 1 in which R=hydroxymethyl)

According to an aspect of the present invention, there is provided a method for preparing a compound of formula 1a (formula 1 in which R=hydroxymethyl) comprising the following steps:

(1) reacting a compound of the following formula 2 with a compound of the following formula 3 and cyclizing the resulting product to obtain a compound of the following formula 4;

(2) aldehyde or amidate a compound of formula 4, followed by reacting the resulting compound with a compound of formula 5 and performing reduction to obtain a compound of the following formula 6; And

(3) reacting a compound of formula 6 with a compound of the following formula 7 and effecting deprotection and reduction.

in formulas,

A represents oxygen (O) or sulfur (S);

n is 1 or 2;

PG represents a protecting group;

X' represents halogen or C _1-7 alkyl;

X, Y and Hal are each independently halogen; And

B is as defined above in Formula 1.

The compound of formula 2 used as a starting material in the above production method can be obtained by synthesis published in a prior art document (US Patent Laid-Open Publication No. 2015/0152075 A1). For example, a compound of formula 2 can be prepared by including the following steps:

(i) esterifying the following carboxylic acid compound of formula 2a to obtain the following methyl ester compound of formula 2b;

(ii) hydrogenating the compound of formula 2b to reduce the nitro group to obtain the following amine compound of formula 2c;

(iii) reacting a compound of formula 2c with a halogenating reagent to obtain the following halogenated compound of formula 2d; And

(iv) the compound of formula 2d undergoes a Sandmeyer reaction.

In the formulas, Y represents halogen.

As used herein, the term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Stage (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 produce a compound of formula 4.

Thus, before binding to the glucose group, and also before the formation of the terminal residue (ie, ring B) of the aglycone group, a pentagonal or hexagonal ring containing the oxygen in the aglycone group can be preformed.

As a specific example, step (1) may include the steps:

(i) reacting a compound of formula 2 with a compound of formula 3 to obtain a compound of the following formula 3a;

(ii) the allylic group of the compound of formula 3a undergoes a rearrangement reaction, and the resulting product undergoes an oxidation or ozonation reaction followed by reduction to obtain the compound of the following formula 3d; And

(iii) the compound of formula 3d undergoes a cyclization reaction to give the compound of formula 4:

In formulas, n is 1 or 2; and X and Y are each independently halogen.

In step (i), the compound of formula 2 may be subjected to a demethylation step before reacting with the compound of formula 3. For example, the compound of formula 2 may be demethylated to produce a compound of the following formula 2e, and the compound of formula 2e may be reacted with the compound of formula 3:

[Formula 2e]

In the formula, X and Y each independently represent a halogen.

The rearrangement reaction in step (ii) can be carried out, for example, in a Claisen rearrangement reaction.

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

In addition, the rearrangement reaction can be carried out in a reaction without solvent or under heating conditions at high temperature (for example, from 150°C to 170°C) in diethylamine.

After carrying out the rearrangement reaction in step (ii), the compound of formula 3a can be obtained as a compound of the following formula 3b:

[Formula 3b]

In the formula, n is 1 or 2; and X and Y are each independently halogen.

The oxidation or ozonation reaction in step (ii) can be carried out by adding osmium tetroxide (OsO ₄ ), potassium osmate (VI) dihydrate or ozone (O ₃ ).

After carrying out the oxidation or ozonation reaction in step (ii), the compound of formula 3b can be obtained as a compound of the following formula 3c:

[Formula 3c]

in the formula, n is 1 or 2; and X and Y are each independently halogen.

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

In step (iii), the compound of formula 3d can be subjected to a cyclization reaction to obtain the compound of formula 4. According to such a method, the yield can be improved compared to the cyclization method described in the prior art document (US Patent Laid-Open Publication No. 2015/0152075 A1).

The cyclization reaction may be a cyclization reaction using a Vilsmeyer reagent, a cyclization reaction using a leaving group, a cyclization reaction using a halide, or a cyclization reaction using a Mitsunobu reaction.

According to the example, the cyclization reaction can be carried out by adding Vilsmeyer's reagent to the compound of formula 3d. The reaction at this time can be carried out at a temperature from 0°C to normal temperature. From the point of view of yield, it is preferable that the above Vilsmeier reagent is obtained directly from the synthesis process and used, and, for example, a Vilsmeier reagent obtained by reacting dimethylformamide (DMF) with SOCl ₂ or POCl ₃ can be used.

According to another example, the cyclization reaction can be carried out by introducing a tosyl group or a mesyl group as a leaving group. According to another example, the cyclization reaction can be carried out using a halide such as I ₂ and PBr ₃ . According to another example, the cyclization reaction can also be carried out through the Mitsunobu reaction using diisopropyl azodicarboxylate (DIAD) or the like.

These reactions are reactions in which a primary alcohol group is replaced by a group capable of acting as a leaving group, and the substituted group acts as a nucleophile for a phenolic group, resulting in a cyclization reaction.

Stage (2)

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

For example, step (2) may involve aldehyde of a compound of formula 4 to obtain a compound of the following formula 4a, and then reacting the compounds of formula 4a with a compound of formula 5:

[Formula 4a]

In the formula, n is 1 or 2; and X and Y are each independently halogen.

In particular, the aldehyde reaction can be carried out by reducing the compound of formula 4 to obtain the compound of the following formula 4c, followed by reacting the compounds of formula 4 with pyridinium chlorochromate (PCC), magnesium dioxide, sulfur trioxide-pyridine complex or the like. As a result, a compound of formula 4a can be obtained:

[Formula 4c]

In the formula, n is 1 or 2; and X and Y are each independently halogen.

Here, a reducing agent such as NaBH ₄ and LiBH ₄ can be used during the reduction of the compound of formula 4. Additionally, an alcohol, tetrahydrofuran (THF) or a mixture thereof can be used as a solvent during the reduction. As a preferred example, a mixed solvent of ethanol and THF may be used during reduction, and its mixing volume ratio may be 1:1 to 1:3. In addition, Lewis acid can be further used during reduction, and examples of Lewis acid that can be used include LiCl and CaCl ₂ .

The compound of formula 4a can then be reacted with a compound of formula 5 to produce a compound of the following formula 6a:

[Formula 6a]

In the formula, n is 1 or 2, X and Y are each independently a halogen, and B is as defined above in Formula 1.

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

As another example, step (2) may involve amidating a compound of formula 4 to obtain a compound of the following formula 4b, and then reacting a compound of formula 4b with a compound of formula 5:

[Formula 4b]

In the formula, n is 1 or 2; and X and Y are each independently halogen.

In particular, the amidation reaction can be carried out by subjecting the compound of Formula 4 to hydrolysis, followed by reacting the resulting product with N,O-dimethylhydroxyamine hydrochloride (MeO(Me)NH⋅HCl) or the like. The result can be a Weinreb amide form such as formula 4b.

The compound of formula 4b can then be reacted with a compound of formula 5 to produce a compound of the following formula 6b:

[Formula 6b]

In the formula, n is 1 or 2; X and Y are each independently halogen, and B is as defined above in Formula 1.

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

The compound of formula 5 may be a Grignard reagent.

According to the general method for preparing the Grignard reagent, a compound of the following formula 5a can be reacted with the metal magnesium (Mg) to obtain a compound of formula 5.

[Formula 5a]

in the formula, B is as defined above in Formula 1, and Hal represents a halogen.

As described above, according to the present invention, the B group of the final compound (the compound of formula 1a) can be easily pre-introduced according to the Grignard reagent preparation process before coupling the aglycone group with the glucose group, which not only provides different derivatization, but also allows the final yield to be improved.

On the other hand, according to the prior art document (US Patent Laid-Open Publication No. 2015/0152075 A1), in order to complete the B group of the final compound, after combining with the glucose group, a complex synthesis process is required at the end of the synthesis path, and thus there is the problem is that the reaction yield and reproducibility of the reaction vary greatly due to the long process.

Stage (3)

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

The reaction of a compound of formula 6 with a compound of formula 7 can be carried out in the presence of n-butyllithium, sec-butyllithium, tert-butyllithium, isopropylmagnesium chloride (i-PrMgCl) or the like.

A compound of formula 6 can be reacted with a compound of formula 7 to produce a compound of the following formula 7a:

[Formula 7a]

In the formula, A represents oxygen or sulfur; n is 1 or 2; X is halogen; PG represents a protecting group; and B is as defined above in Formula 1.

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

The protecting group can then be removed from the compound of formula 7a to produce the compound of formula 1a. For example, in the case where the protecting group is a trimethylsilyl (TMS) group, deprotection is carried out by adding methanesulfonic acid (CH ₃ SO ₃ H) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) to the compound of formula 7a, whereby the compound of formula 1a can be obtained .

In addition, after removal of the protecting group, reduction can further be carried out to obtain the compound of formula 1a. At this time, dichloromethane (CH ₂ Cl ₂ ) and acetonitrile (CH ₃ CN) can be used in combination as a solvent.

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

Thus, further isolation can be performed to obtain only the desired α-form or β-form. That is, after or during the process of deprotection and reduction, it is possible to further isolate only the compound in which glucose is in the β-form.

For example, a protecting group is introduced into a compound obtained by deprotection and reduction. The resulting product is then heated in alcohol, ethyl acetate or dichloromethane, and the resulting precipitate is isolated and further deprotected, after which only the β-form can be obtained.

Specifically, the hydroxy group of glucose in the compound obtained by deprotection and reduction is protected by an acetyl group or the like. The resulting product is then heated and stirred in a C _1-6 alcohol solvent (ethanol, isopropanol or the like) and the resulting precipitate is isolated, whereby only the compound of the following formula 7b, in which glucose is in the β-form, can be obtained:

[Formula 7b]

In the formula, A represents oxygen or sulfur; n is 1 or 2; X represents halogen; PG represents a protecting group; and B is as defined above in Formula 1.

The compound of formula 7b can then be deprotected to ultimately yield only the β-form, which can be represented by the following formula 7c:

[Formula 7c]

In the formula, A, B, n and X' are as defined above in Formula 1.

According to a preferred example, step (3) can be carried out in a method comprising the steps of:

(3a-1) reacting a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride to obtain a compound of the following formula 7a;

(3a-2) removing the protecting group and methylating the compound of formula 7a under acidic conditions in the presence of methanol to obtain the compound of the following formula 7d;

(3b) reducing the compound of formula 7b to obtain the compound of the following formula 7e; And

(3c) introducing a protecting group into the compound of formula 7e, heating the resulting product in alcohol, ethyl acetate or dichloromethane and isolating and deprotecting the resulting precipitate to give only the β-form:

In the formulas, PG represents a protecting group; and A, B, n and X are as defined above in Formula 1a.

After reacting in step (3a-1), it is preferable that the compound of formula 7a is obtained by further evaporation, extraction, drying, filtration or the like, and then used in the next step (3a-2),

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

According to another preferred example, step (3) can be carried out in a method comprising the steps of:

(3a') reacting a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride, and the resulting product is subjected to deprotection and methylation reactions under acidic conditions in the presence of methanol without separate purification to give the compound following formula 7d;

(3b') reducing the compound of formula 7d to obtain the compound of the following formula 7e; And

(3c') introducing a protecting group into the compound of formula 7e to isolate only the β-form and performing deprotection:

In the formulas, A, B, n and X are as defined above in Formula 1a.

In step (3a'), a coupling reaction is first carried out and, at this stage, each of the compounds of formula 7 and the reaction reagent (i.e. n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride) can be used for the reaction in an amount of from 1.5 to 2.5 equivalents, more preferably 1.7 to 2.3 equivalents, and in particular about 2.0 equivalents, relative to 1 equivalent of the compound of formula 6. The reaction can be carried out at temperatures ranging from -80°C to -10°C, and more preferably -70°C to -60°C, for 1 to 12 hours or for 1 to 3 hours. In addition, a separate solvent of tetrahydrofuran or ether, a mixed solvent consisting of tetrahydrofuran and toluene (1:1) or the like can be used as the reaction solvent.

Moreover, in step (3a'), deprotection and methylation reactions are carried out under acidic conditions. Examples of the acid used in this step 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 from 2 to 5 equivalents and more preferably in an amount of 3 equivalents relative to 1 equivalent of the compound of formula 6. The reaction can be carried out at a temperature ranging from 0°C to 40°C and more preferably from 20°C to 30°C, from 6 to 24 hours or from 6 to 12 hours. As the reaction solvent, methanol or the like can be used.

The reduction reaction is then carried out in step (3b'), and a reducing agent and an acid can be used at this stage. Examples of the reducing agent may include triethylsilane, triisopropylsilane, tert-butyldimethylsilane and sodium borohydride. Examples of the acid may include boron trifluoride diethyl ether, trimethylsilyl trifluoromethanesulfonate, aluminum chloride, trifluoroacetic acid and trifluoromethanesulfonic acid. The reducing agent can be used in an amount from 2 to 5 equivalents, and more preferably about 3 equivalents, and the acid can be used in an amount from 1.5 to 3 equivalents, and more preferably about 2 equivalents. In this case, the reaction can be carried out at a temperature in the range from -50 to 0°C and more preferably in the range from -20 to -10°C for 2 to 12 hours or for 2 hours to 5 hours. In addition, 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 as the reaction solvent. 1).

The protecting group is then introduced in step (3c'), at which point the reaction can be carried out using an acetylating agent and a base. Examples of the acetylating agent include acetyl chloride, acetyl bromide and acetic anhydride, and examples of the base include sodium hydroxide, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, lutidine and 4-dimethylaminopyridine. The acetylating agent can be used in an amount from 4 to 12 equivalents, and more preferably about 8 equivalents, and the base can be used in an amount from 1 to 4 equivalents, and more preferably about 1.5 equivalents. In this case, the reaction can be carried out at a temperature in the range from 0 to 50°C and more preferably from 20 to 30°C for 1 to 12 hours or 1 to 3 hours. As the reaction solvent, acetone, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform or the like can be used.

Finally, the deprotection reaction is carried out in step (3c') and in this step reagents such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide can be used in an amount of 2 to 12 equivalents and more preferably about 5 equivalents. In this case, the reaction can be carried out at a temperature in the range from 0 to 50°C and more preferably from 20 to 30°C for 1 to 12 hours or 1 to 3 hours. The reaction solvent can be a mixture of methanol/water (1:1-3:1), dichloromethane/methanol (1:1-1:2), dichloromethane/ethanol (1:1-1:2), tetrahydrofuran/methanol (1:1-1:2), tetrahydrofuran/ethanol (1:1-1:2), tetrahydrofuran/methanol/water (1:1:3-2:1:3), tetrahydrofuran/ethanol/water (1: 1:3-2:1:3) or the like.

According to another preferred example, step (3) can be carried out in a method comprising the steps of:

(3a'') reacting a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride, and the resulting product is subjected to deprotection and methylation reactions under acidic conditions in the presence of methanol without separate purification to give compounds of the following formula 7d;

(3b'') introducing a protecting group into the compound of formula 7d to obtain a compound of the following formula 7f; And

(3c") isolating only the β-form of the compound of formula 7f and performing a reduction reaction followed by a deprotection reaction:

In the formulas, PG represents a protecting group; and A, B, n and X are as defined above in Formula 1a.

At stage (3a''), the coupling reaction, removal of protecting groups and methylation are carried out. Here, preferred conditions such as equivalent ratio, reaction temperature and solvent are as illustrated in step (3a').

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

Next, the reduction reaction is carried out at stage (3c''). In this step, a reducing agent and an acid may be used, and preferred conditions such as type of reducing agent, type of acid, equivalent ratio, reaction temperature and solvent are as illustrated in step (3b') above.

In addition, the deprotection reaction is carried out in step (3c''), and preferred conditions such as reagent type, equivalent ratio, reaction temperature and solvent are as illustrated in step (3c') above.

As shown in the above preferred illustrative examples, the process for preparing 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, whereby the final yield is further increased. In addition, if the preparation is 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 from it as a solid by crystallization and used in the next step. In the latter case, quality improvement and moisture control can be easily achieved by removing reaction by-products.

In addition, the compound of formula 7d can be used in the next step by purifying it after synthesis. For example, (i) after synthesis, the compound of formula 7d can form an azeotrope with an organic solvent such as toluene, and the residue obtained by repeating the concentration process to remove residual moisture can be used in the next step, or (ii) after synthesis, the compound of formula 7d can be subjected to crystallization, and the solid volume obtained by removing residual moisture by vacuum drying can be used in the next step.

Alkylation stage

Moreover, according to the present invention, an alkylation reaction can be further included after step (3), and as a result, X' in Formula 1 can represent C _1-7 alkyl.

For example, the product from step (4) can be reacted with methyl boronic acid to produce a compound of formula 1a in which X' is replaced with methyl.

Crystallization stage

The compound of formula 1a can be obtained in crystalline form, amorphous form or as a mixture thereof. However, the compound of formula 1a in crystalline form is preferred from the point of view of excellent stability and non-hygroscopicity and, accordingly, the presence of physicochemical properties that facilitate the preparation of the drug.

Therefore, the method of the present invention may further comprise crystallizing the compound of formula 1a after step (3). Crystallization can be carried out using various solvents, and thus various crystalline forms can be obtained.

As an example, the solvent used for crystallization may be selected from toluene; ethyl acetate; dichloromethane; acetone; acetonitrile; mixtures of 2-propanol, tetrahydrofuran and dichloromethane; and mixtures of tetrahydrofuran and n-hexane, and as a result crystalline form A can be obtained.

As another example, the solvent used for crystallization may be selected from a mixture of methanol and distilled water; mixtures of methanol and n-hexane; and mixtures of methanol, dichloromethane and n-hexane, and as a result crystalline form B can be obtained.

As another example, the solvent used for crystallization may be selected from a mixture of ethanol, distilled water and n-hexane; and mixtures of tetrahydrofuran and toluene, and as a result, crystalline form C can be obtained.

As another example, the solvent used for crystallization may be a mixture of ethanol and n-hexane, and as a result, crystalline Form D may be obtained.

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.

Method for preparing the compound of formula 1b (formula 1 in which R=alkylthio and A=oxygen)

In accordance with yet another aspect of the present invention, there is provided a method for preparing a compound of formula 1b (formula 1 in which R=C _1-7 alkylthio and A=oxygen), the method comprising the following steps:

(1) reacting a compound of the following formula 2 with a compound of the following formula 3 and cyclizing the resulting product to obtain a compound of the following formula 4;

(2) aldehyde or amidate a compound of formula 4, followed by reacting the resulting compound with a compound of formula 5 and performing reduction to obtain a compound of the following formula 6;

(3) reacting a compound of formula 6 with a compound of the following formula 8 and then performing reduction to obtain a compound of the following formula 9;

(4) converting the furanose ring of the compound of formula 9 into a pyranose ring under acidic conditions and then introducing a protecting group thereto to obtain the compound of the following formula 10; And

(5) treating the compound of formula 10 with thiourea, reacting the resulting product with a C _1-7 alkyl halide and subsequent reduction.

In formulas,

R represents C _1-7 alkylthio;

n is 1 or 2;

PG represents a protecting group;

X' represents halogen or C _1-7 alkyl;

X, Y and Hal are each independently halogen; And

B is as defined above in Formula 1.

In the above steps, steps (1) and (2) can be performed in the same manner as steps (1) and (2) of the method for producing the compound of formula 1a (formula 1 in which R=hydroxymethyl).

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

Stage (3)

In step (3), a compound of formula 6 is reacted with a compound of formula 8 to produce a compound of formula 9.

The compound of formula 8 can be prepared according to a known method, for example the method described in WO 2009/014970. In particular, the compound of formula 8 can be prepared according to the method described in WO 2009/014970 starting from L-xylose.

According to an example, a compound of formula 6 can be reacted with a compound of formula 8 to produce a compound of the following formula 9a.

[Formula 9a]

In the formula, B, n and X are as defined above in Formula 1.

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

Stage (4)

In step (4), the furanose ring of the compound of formula 9 is converted into a pyranose ring under acidic conditions, and then a protecting group is introduced into it to obtain the compound of formula 10. In this step, the pyranose ring constituting a glucose group can be formed.

The protecting group can be, for example, an acetyl group.

Stage (5)

In step (5), the compound of formula 10 is treated with thiourea, reacted with a C _1-7 alkyl halide, and then reduced. At this stage, an alkylthio group (compound of formula 1b) may be introduced into the final compound.

The _1-7 alkyl halide can be, for example, a C _1-7 alkyl iodide.

In addition, after step (5), an alkylation reaction can be further included, and, as a result, a compound of formula 1b can be obtained, in which X' represents C _1-7 alkyl.

Crystal form

In accordance with yet another aspect of the present invention, a crystalline form of the compound obtained in accordance with the above-described production method is provided.

By way of example, the present invention provides a crystalline form of the compound of formula 1a.

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

That is, the present invention relates to a crystalline form of the compound of the following formula c28.

[Formula c28]

The compound of formula c28 can be prepared by the method described above for preparing the compound of formula 1a.

In accordance with the present invention, it is possible that the compound of formula c28 exists in various crystalline forms, and the corresponding crystalline forms will be described in detail below.

Further, the term “about” can mean a deviation of 5%, and preferably 2%, from a predetermined value or range. For example, “about 10%” may mean from 9.5% to 10.5%, and preferably from 9.8% to 10.2%. As another example, "about 100°C" may mean from 95°C to 105°C, and preferably from 98°C to 102°C.

First, the present invention relates to crystalline Form A of the compound of formula C28. Crystalline Form A has an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 6.2° ± 0.2°, 7.2° ± 0.2°, 8.8° ± 0.2°, 17.6 ° ± 0.2°, 19.0° ± 0.2°, 22.5° ± 0.2° and 25.1° ± 0.2° in the case of irradiation using a Cu-K _α light source. These peaks may be peaks with a relative intensity (I/I _o ) of about 5% or higher, and preferably about 10% or higher.

The X-ray diffraction spectrum of crystalline Form A may additionally include peaks at diffraction angles (2θ) of 15.4°±0.2°, 18.6°±0.2°, 21.6°±0.2° and 23.8° ±0.2°.

In addition, the crystalline form may have an endothermic peak where the starting point is about 157°C and the low point is about 159°C at DSC (10°C/minute).

In addition, the present invention relates to crystalline Form B of the compound of formula c28. Crystal Form B has an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18 ,8°±0.2°, 20.6°±0.2°, 21.8°±0.2° and 23.5°±0.2° in the case of irradiation using a Cu-K _α radiation source. These peaks may be peaks with a relative intensity (I/I _o ) of about 5% or higher, and preferably about 10% or higher.

The X-ray diffraction 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°.

In addition, the crystalline form may have an endothermic peak in which the starting point is about 79°C and a low point is about 88°C, and an endothermic peak in which the starting point is about 103°C and the low point is about 111° C, at DSC (10°C/min).

In addition, the present invention relates to crystalline Form C of the compound of formula c28. Crystal form C has an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 5.6°±0.2°, 7.3°±0.2°, 15.7°±0.2°, 17.2 °±0.2°, 18.9°±0.2°, 21.2°±0.2° and 21.9°±0.2° in the case of irradiation using a Cu-K _α radiation source. These peaks may be peaks with a relative intensity (I/I _o ) of about 5% or higher, and preferably about 10% or higher.

The X-ray diffraction spectrum of crystalline Form C may further include peaks at diffraction angles (2θ) of 19.9°±0.2° and 23.1°±0.2°.

In addition, the crystalline form may have an endothermic peak in which the starting point is about 157°C and the low point is about 159°C, at DSC (10°C/minute).

Furthermore, the present invention relates to crystalline Form D of the compound of formula C28. Crystal form D has an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 5.5°±0.2°, 7.2°±0.2°, 15.3°±0.2°, 17.2 °±0.2°, 17.6°±0.2°, 18.9°±0.2° and 21.1°±0.2° in the case of irradiation using a Cu-K _α radiation source. These peaks may be peaks with a relative intensity (I/I _o ) of about 5% or higher.

The X-ray diffraction spectrum of crystalline Form D may further include peaks at diffraction angles (2θ) of 20.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°.

In addition, the crystalline form may have an endothermic peak, in which the starting point corresponds to about 157°C and the low point corresponds to about 160°C, at DSC (10°C/minute).

Such crystalline forms of the compound of formula c28 are excellent in terms of physicochemical properties (eg hygroscopicity and chemical stability) and can thus be easily processed in various applications (eg pharmaceutical production).

Method for carrying out the invention

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are intended to illustrate the present invention only, and the scope of the present invention is not limited to these examples.

The meanings of the abbreviations shown in the following examples are as follows.

- AcOH: Acetic acid

- ACN: Acetonitrile

- Ac ₂ O: Acetic anhydride

- BF ₃ .OEt ₂ : Boron trifluoride ether

- DIPEA: N,N-diisopropylethylamine

- DCM: Dichloromethane

- DMAP: 4-Dimethylaminopyridine

- DMF: N,N-Dimethylformamide

- EtOAc: Ethyl acetate

- EtOH: Ethanol

- Et ₃ SiH: Triethylsilane

- HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

- Hex: Hexane

- i-PrOH: Isopropyl alcohol

- MeI: Iodomethane

- MeOH: Methanol

- MsCl: Mesyl chloride

- NaOMe: Sodium methoxide

- NBS: N-bromosuccinimide

- PCC: Pyridinium Chlorochromate

- Pd(PPh ₃ ) ₄ : Tetrakis(triphenylphosphine)palladium (0)

- TEA: Triethylamine

- TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)oxadinyl

- THF: Tetrahydrofuran

- TMSOTf: Trimethylsilyl trifluoromethanesulfonate

- K.T. or c.t.: Room temperature

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

The title compound was prepared by the method described in US Patent Laid-Open Publication No. 2015/0152075. For specific steps in the synthesis of Comparative Example 1, reference is made to Scheme 1 as described in the Background section above.

Step 1: Methyl 3-methoxy-2-nitrobenzoate (compound c2 )

To a mixture of 3-methoxy-2-nitrobenzoic acid (25.0 g, 126 mmol) and K ₂ CO ₃ (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 and then stirred at 5°C for 30 minutes. The precipitated solid was collected by filtration, washed with water and hexane. The solid was dried under reduced pressure to obtain the crude title compound (26.2 g, 98%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (dd, J=8.2, 1.2 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.26 (dd, J=8.2, 1.2 Hz, 1H), 3.39 (s, 3H), 3.99 (s, 3H); [M+Na] ⁺ 235.

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 H ₂ at temperature 18 hours. EtOAc (300 ml) was added to the mixture and 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, CDCl ₃ ) δ 7.47 (dd, J=8.2, 1.2 Hz, 1H), 6.85 (dd, J=8.2, 1.2 Hz, 1H) , 6.58 (t, J=8.2 Hz, 1H), 6.00 (br.s, 2H), 3.87 (s, 3H); [M+H] ⁺ 182.

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) N-bromosuccinimide (21.9 g, 123 mmol) was added portionwise at 0°C. The mixture was stirred at 0°C for 0.5 h. Water was added to the mixture and extracted with EtOAc (500 ml x 2). The combined organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (27.5 g, 86%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J=2.2 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 6.03 (br.s , 1H), 3.87 (s, 3H); [M+H] ⁺ 260.

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 H ₂ O (70 ml) and conc. HCl (70 ml) was added dropwise to a solution of NaNO ₂ (21.5 g, 311 mmol) in H ₂ O (50 ml) at 0°C. After stirring for 1 hour, a solution of Cu(I)Cl in conc. was added dropwise to the reaction mixture. HCl (80 ml) at 0°C. The mixture was stirred at room temperature for 18 hours. Water (300 ml) was added to the mixture and extracted with EtOAc (500 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude title compound was dried under high vacuum and used in the next step without further purification (29.0 g, 100%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 3.93 (s, 36H ), 3.92 (s, 3H); [M+H] ⁺ 278

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), H ₂ O (100 ml) and MeOH (100 ml) was added an aqueous 5 N NaOH solution drop by drop at 0°C. The mixture was stirred at room temperature for 1 hour. Conc. was added to the mixture. HCl to acidify, and the mixture was extracted with EtOAc (500 ml x 2). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (22.6 g, 96%) as an orange solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (s, 1H), 7.13 (s, 1H), 3.89 (s, 3H); [M+H] ⁺ 265.

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 CH ₂ Cl ₂ (100 ml) was added oxalyl chloride (2.4 ml, 27.1 mmol) and a catalytic amount DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum to give the crude title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 3.93 (s, 3H ), 3.92 (s, 3H).

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. AlCl ₃ (6.9 g, 52.0 mmol) was added to the reaction mixture in portions at 0°C. The mixture was stirred at 90°C for 15 hours. The mixture was cooled to room temperature and evaporated in vacuum. The residue was cooled to 0°C and an aqueous solution of 1N HCl was added. The mixture was extracted with EtOAc (150 ml x 1). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (7.33 g, quantitative yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.82 (m, 2H), 7.70-7.64 (m, 1H), 7.55-7.49 (m, 2H), 7.37 (d, J=2.2 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 5.94 (s, 1H).

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 triflate acid at 0°C. The mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched with saturated NaHCO ₃ solution at 0°C and extracted with EtOAc. The organic layer was dried over MgSO ₄ , 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%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.32 (m, 2H), 7.30-7.27 (m, 1H), 7.22-7.19 (m, 2H), 7.13 (d, J=2.4 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 4.07 (s, 2H). [M+H] ⁺ 297.

Step 9: 1-(Allyloxy)-3-benzyl-5-bromo-2-chlorobenzene (compound c10 )

_{Allyl bromide} (0 .73 ml, 8.67 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 65°C. The resulting mixture was filtered to remove inorganic substances. 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, CDCl ₃ ) δ 7.32-7.27 (m, 2H), 7.25-7.22 (m, 1H), 7.21-7.17 (m, 2H), 6.92 (d, J=2.4 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.10-6.00 (m, 1H), 5.48 (dkv , J=17.2 Hz, 1.6 Hz, 1H), 5.33 (dkv, 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.

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 was added dropwise (2.5 M in hexane, 2.6 mL, 6.41 mmol) at -78°C under nitrogen. 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) by cannula for 20 min at -78°C. The reaction mixture was stirred for 3 hours at -78°C. CH ₃ SO ₃ H (0.6 ml, 9.25 mmol) in MeOH (15 ml) was added dropwise to the mixture at 0°C. The mixture was warmed to room temperature for 18 hours, and then quenched with a saturated NaHCO ₃ solution at 0°C. The mixture was evaporated under reduced pressure to remove volatile substances. The aqueous residue was extracted with EtOAc (100 ml x 2). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the crude title product as a yellow solid. [M+Na] ⁺ 473.

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 CH ₂ Cl ₂ (30 ml) and CH ₃ CN (30 ml) was added dropwise with Et ₃ SiH (1.82 ml, 11.3 mmol) and BF ₃ ⋅ Et ₂ O (1.07 ml, 8.48 mmol) at 0°C. The reaction mixture was stirred for 5 hours at room temperature. The resulting mixture was quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was used in the next step without further purification.

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 CH ₂ Cl ₂ (12 ml) was added Ac ₂ O (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 for 12 hours at room temperature. The resulting mixture was diluted with EtOAc and washed with 1N HCl solution. The organic layer was dried over MgSO ₄ , 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 (dkv, J=17.6, 2.0 Hz, 1H), 5.35 (t, J=9.6 Hz, 1H), 5.30 (dkv, J=10.4, 1.6 Hz, 1H), 5.12 (t, J=9.6 Hz, 1H), 5.06 (t, J=9.6 Hz, 1H), 4.66-4.62 (m, 3H), 4, 13-4.03 (m, 5H), 2.04 (s, 3H), 2.03 (s, 3H), 1.95 (s, 3H), 1.70 (s, 3H); [M+Na] ⁺ 611.

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 ice-cold AcOH. The mixture was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was used in the next step without further purification. [M+Na] ⁺ 443.

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) add NaH (60% dispersion in mineral oil, 842 mg, 21.0 mmol) at 0°C and stir for 1 hour at room temperature. Benzyl bromide (2.5 mL, 21.0 mmol) was added dropwise to the reaction mixture at 0°C. The mixture was stirred for 12 hours at room temperature. The resulting mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO ₄ , 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, CDCl ₃ ) δ 7.36-7.31 (m, 13H), 7.26-7.19 (m, 10H), 6.94 (d, J=1.6 Hz, 2H), 6.91 (dd, J=14.8, 2.0 Hz, 2H), 6.10-6.00 (m, 1H), 5.46 (dkv, J=17.2, 1, 6 Hz, 1H), 5.31 (dkv, J=10.8, 1.6 Hz, 1H), 4.94 (ABkv, 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 Hz, 1H), 4.23-4.16 (m, 2H), 4.08 (d, J=15.2 Hz, 1H), 3.89 ( d, J=10.8 Hz, 1H), 3.84-3.75 (m, 4H), 3.61-3.57 (m, 1H), 3.48-3.44 (m, 1H) ; [M+Na] ⁺ 803.

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 ₄ (700 mg, 18.4 mmol) and Pd(PPh ₃ ) ₄ (266 mg, 0.23 mmol) at room temperature. The reaction mixture was stirred for 12 hours at room temperature. The resulting mixture was quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera™ FLASH Purification System, EtOAc/Hex) to obtain the title compound (1.62 g, 95%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.31 (m, 13H), 7.27-7.21 (m, 8H), 7.18-7.16 (m, 2H), 7.08 (d, J=2.0 Hz, 1H), 6.98 (dd, J=7.6, 2.0 Hz, 2H), 6.89 (d, J=2.0 Hz, 1H ), 4.93 (ABkv, 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 Hz, 1H), 4 ,19-4.12 (m, 2H), 4.03 (d, J=15.2 Hz, 1H), 3.95 (d, J=10.4 Hz, 1H), 3.82-3, 75 (m, 4H), 3.61-3.57 (m, 1H), 3.49-3.45 (m, 1H); [M+Na] ⁺ 763.

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 AcOH (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 for 12 hours at room temperature. The resulting mixture was quenched with saturated NaHCO ₃ solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , 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.

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 K ₂ CO ₃ (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 for 12 hours at 50°C. The resulting mixture was filtered to remove inorganic substances. 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 c19 (1.10 g, 100%). [M+Na] ⁺ 899.

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 CH ₃ CN (12 ml) carbon tetrachloride (12 mL, 134 mmol) was added at room temperature. The reaction mixture was stirred for 12 hours at 55°C. The resulting mixture was evaporated to remove the solvents. 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.

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 dropwise with n-butyllithium (2.5 M in hexane, 6.8 ml, 17 .0 mmol) at -78°C. The reaction mixture was stirred for 3 hours at -78°C. The resulting mixture was quenched with 1N HCl (100 ml) and extracted with EtOAc. The organic layer was dried over MgSO ₄ , 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.

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 )

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) were stirred for 5 hours at room temperature in an _H2 atmosphere. The resulting mixture was filtered to remove inorganic substances through celite. The filtrate was concentrated in vacuo to give the title compound (quantitative value). The crude product was used in the next step without further purification.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.28-7.14 (m, 5H), 6.89 (s, 1H), 4.65 (t, J=8.6 Hz, 2H), 4.17 (d, J=8.8 Hz, 1H), 4.07 (ABkv, Δν _AB =18.0 Hz, J _AB =15.0 Hz, 2H), 3.90 (dd, J =11.8, 1.4 Hz, 1H), 3.72-3.67 (m, 1H), 3.53-3.42 (m, 3H), 3.40-3.37 (m, 2H ); [M+Na] ⁺ 507.

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 CH ₂ Cl ₂ (78 ml) was added Ac ₂ O (5.9 ml, 62.6 mmol), pyridine (5.0 ml, 62.6 mmol) and DMAP (48 mg, 0.39 mmol) at room temperature. The reaction mixture was stirred for 12 hours at room temperature. The resulting mixture was diluted with EtOAc and washed with 1 N HCl solution. The organic layer was dried over MgSO ₄ , 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%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.28 (m, 2H), 7.25-7.18 (m, 3H), 6.59 (s, 1H), 5.30 ( t, J=9.2 Hz, 2H), 5.19 (t, J=9.6 Hz, 1H), 4.77-4.68 (m, 2H), 4.35-4.32 (m , 1H), 4.31-4.26 (m, 1H), 4.21-4.14 (m, 1H), 4.11 (m, 1H), 4.02 (d, J=15.6 Hz, 1H), 3.83-3.79 (m, 1H), 3.42 (td, J=8.8, 1.6 Hz, 2H), 2.10 (s, 3H), 2, 09 (s, 3H), 2.03 (s, 3H), 1.70 (s, 3H); [M+Na] ⁺ 597.

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 CH ₂ Cl ₂ (78 ml) was added dropwise with acetyl chloride (3.71 ml, 52.16 mmol) and aluminum chloride (6.95 mg, 52 .16 mmol) at 0°C. The reaction mixture was stirred for 12 hours at room temperature. The resulting mixture was quenched with ice water and extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , 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, CDCl ₃ ) δ 7.92-7.89 (m, 2H), 7.29-7.28 (m, 2H), 6.63 (s, 1H), 5.34- 5.31 (m, 1H), 5.24-5.18 (m, 2H), 4.78-4.68 (m, 2H), 4.37-4.27 (m, 2H), 4. 19-4.16 (m, 1H), 4.16-4.08 (m, 2H), 3.84-3.77 (m, 1H), 3.45-3.40 (m, 2H), 2.61 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H), 1.70 (s, 3H); [M+Na] ⁺ 639.

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), sodium borohydride (0.12 g, 3.24 mmol) was slowly added at -20°C, and then to MeOH (0.24 ml) was added dropwise to the mixture. The mixture was stirred for 3 hours at room temperature. The resulting mixture was quenched with saturated NaHCO ₃ and extracted with EtOAc. The organic layer was dried over MgSO ₄ , 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%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29-7.27 (m, 2H), 7.15-7.12 (m, 2H), 6.54 (d, J=5.2 Hz, 1H), 5.29-5.26 (m, 1H), 5.18-5.13 (m, 2H), 4.89-4.84 (m, 2H), 4.71-4.66 ( m, 2H), 4.32-4.29 (m, 1H), 4.27-4.22 (m, 1H), 4.15-4.11 (m, 1H), 4.04-3, 96 (m, 2H), 3.80-3.75 (m, 1H), 3.40-3.35 (m, 2H), 2.06 (s, 3H), 2.05 (s, 3H) , 1.99 (s, 3H), 1.68 (s, 3H), 1.47 (d, J=6.4 Hz, 3H); [M+Na] ⁺ 641.

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 )

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) were stirred for 2 hours at 120°C . The resulting mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO ₄ , 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, CDCl ₃ ) δ 7.32-7.30 (m, 2H), 7.12-7.10 (m, 2H), 6.71-6.63 (m, 1H), 6.55 (s, 1H), 5.71-5.66 (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.

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 in toluene, 1.74 ml, 1.91 mmol) in CH ₂ Cl ₂ (3 ml) was added dropwise trifluoroacetic acid (0.15 ml, 1.91 mmol) in CH ₂ Cl ₂ (1.5 ml) at 0°C. After 1 hour, diomethane (0.16 ml, 1.91 mmol) in CH ₂ Cl ₂ (1.5 ml) was added dropwise to the mixture at 0°C. After 1 hour, (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-vinylbenzyl)-2,3-dihydrobenzofuran-4-yl) was slowly added to the mixture. tetrahydro-2H-pyran-3,4,5-triyl triacetate (460 mg, 0.77 mmol) in CH ₂ Cl ₂ (3 ml) at 0°C. The reaction mixture was stirred for 12 hours at room temperature. The resulting mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , 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, CDCl ₃ ) δ 7.04-7.02 (m, 2H), 6.98-6.95 (m, 2H), 6.53 (s, 1H), 5.29- 5.24 (m, 1H), 5.18-5.12 (m, 2H), 4.71-4.65 (m, 2H), 4.31-4.26 (m, 1H), 4. 25-4.22 (m, 1H), 4.15-4.11 (m, 1H), 4.05-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.40-3.35 (m, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.66 (s, 3H), 0.94-0.89 (m, 2H), 0.66-0.61 (m, 2H); [M+Na] ⁺ 637.

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 K ₂ CO ₃ (536 mg, 3.88 mmol) in MeOH (20 ml) were stirred for 12 hours. To remove inorganic substances, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (Gilson system, CH ₃ CN/H ₂ O) to give the title compound (101 mg, 47%).

The total yield of the final compound of Comparative Example 1 according to the synthesis route of the above steps 1 to 26 was determined to be 1% or less.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.11 (d, J=9.2 Hz, 1H), 3.96 (ABkv, 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.

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

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 CH ₂ Cl ₂ (300 ml) was added slowly BBr ₃ (25.9 ml, 268.3 mmol) at 0°C in a nitrogen atmosphere. The mixture was warmed to room temperature slowly and stirred at room temperature for 15 hours. The reaction mixture was quenched with MeOH (100 ml) at 0°C. The mixture was evaporated under reduced pressure to remove CH ₂ Cl ₂ and then MeOH (150 ml) was added thereto. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound (29.4 g, 110.8 mmol, 103%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.00 (s, 1H ), 3.94 (s, 1H); [M+H] ⁺ 265.

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) was added allyl bromide (14.9 ml, 172.7 mmol) and K ₂ CO ₃ ( 29.8 g, 215.9 mmol) at room temperature. The mixture was stirred at 60 °C for 12 hours, and then left to cool to room temperature. After filtering off the insoluble salt 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 MgSO ₄ , filtered and concentrated in vacuo (44.1 g, 144.3 mmol, 100%). The crude residue was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.09-6.00 (m, 1H), 5.48 (dd, J=17.2 Hz, 1.2 Hz, 1H), 5.35 (dd, J=10.6 Hz, 1.4 Hz, 1H), 4, 63-4.61 (m, 2H), 3.93 (s, 3H); [M+H] ⁺ 305.

Step 3: Methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (compound c31 )

To a solution of methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (10.0 g, 32.7 mmol) in CH ₂ Cl ₂ (150 ml) was added diisobutylaluminum chloride (25% in hexane, 64.0 ml) dropwise (0.5-1 h) at 0°C in a nitrogen atmosphere. The mixture was warmed to room temperature slowly and further stirred at room temperature for 12 hours. The reaction mixture was cooled to 0°C and quenched with 1 M HCl (50 ml), then extracted with EtOAc (150 ml x 2). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo (9.9 g, 32.3 mmol, 99%). The crude residue was used in the next step without further purification to give the title compound.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.23 (s, 1H), 6.20 (s, 1H), 5.96-5.86 (m, 1H), 5.11-5.07 ( m, 2H), 3.92 (s, 3H), 3.65 (dt, J=5.4 Hz, 1.4 Hz, 2H); [M+H] ⁺ 305.

Step 4: Methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33 )

Method A) Synthesis by aldehyde reduction

To a mixture of methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (9.9 g, 32.3 mmol) in THF/H ₂ O (100 ml/100 ml) was added NaIO ₄ (20.8 g , 97.0 mmol) and OsO ₄ (82 mg, 0.32 mmol) at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble substances. The filtrate was poured into saturated Na ₂ S ₂ O ₃ solution (100 ml) and the mixture was extracted with EtOAc (200 ml x 2). The organic layer was dried over MgSO ₄ , 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.

NaBH ₄ (2.72 g, 71 .8 mmol) at 0°C in a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NH ₄ Cl (100 ml) and extracted with EtOAc (100 ml x 2) [Extraction alone may not be sufficient]. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo (19.9 g). Hexane (10-20 ml) was added to a suspension of the residue in EtOAc (20 ml). The resulting precipitate was collected by filtration and washed with hexane (50 ml). The residue was dried under high vacuum to give the title compound (14.3 g, 72%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.68 (s, 1H), 7.35 (s, 1H), 3.97-3.93 (m, 2H), 3.92 (s, 3H) , 3.21 (t, J=6.2 Hz, 2H); [M+H] ⁺ 309.

Method B) Synthesis by ozonation followed by reduction

Ozone gas was bubbled through methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (10.2 g, 33.4 mmol, 80% purity) in CH ₂ Cl ₂ /MeOH (150 ml/35 ml) at -78°C for 4 hours (the color of the solution changed from yellow to pale green). After the addition of ozone was stopped, the reaction solution was purged with nitrogen until the green color changed (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 slowly warmed to room temperature over 2 hours, concentrated, suspended in EtOAc and concentrated. An aqueous solution of 1N 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 obtained by filtration to give the title compound (7.9 g, 76.4%, 92% purity).

¹ H NMR (400 MHz, MeOD) δ 7.57 (s, 1H), 3.93 (s, 3H), 3.76 (t, J=7.24 Hz, 2H), 3.20 (t, J=7.28 Hz, 2H); [M+H] ⁺ 309.

Step 5: Methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34 )

Preparation of Vilsmeyer's reagent; SOCl ₂ (7.5 mL, 102.2 mmol) was added to a solution of N,N-dimethylformamide (7.9 mL, 102.2 mmol) at room temperature. The reaction mixture was stirred for 2 hours at 40°C. The resulting mixture was concentrated in vacuo to obtain a hygroscopic white solid.

To a mixture of Vilsmeyer's reagent (13.08 g, 102.2 mmol) in DMF (100 ml), 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 for 1 hour at a temperature of 0°C - 15°C (heated evenly). The reaction mixture was quenched with triethylamine (38 ml, 272.4 mmol) in DMF (38 ml) at 0°C. After stirring for 10 minutes, the mixture was poured into water (1400 ml) at 0°C and stirred for 2 hours at room temperature. The resulting precipitate was collected by filtration, washed with water and dried, concentrated in vacuo to give the title compound (13.0 g, 44.6 mmol, 65%) as a pale yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.53 (s, 1H), 4.75 (t, J=8.8 Hz, 2H), 3.91 (s, 3H), 3.33 (t , J=8.8 Hz, 2H); [M+H] ⁺ 291.

Step 6: (4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (compound c35 )

Sodium borohydride (5.07 g, 133.98 mmol) at room temperature. The mixture was stirred for 12 hours at room temperature. The resulting mixture was quenched with saturated NH ₄ Cl solution at 0°C and extracted with EtOAc (aq, pH ~7.0). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (11.7 g, 44.4 mmol, 99%) as a white solid. The crude product was used in the next step without further purification.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.15 (s, 1H), 4.73 (m, 4H), 3.29 (t, J=8.8 Hz, 2H), 1.91 (t , J=6.4 Hz, 1H); [MH ₂ O] ⁺ 245.

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 CH ₂ Cl ₂ (450 ml) was slowly added PCC (14.4 g , 66.6 mmol, pyridinium chlorochromate) at room temperature. After stirring for 8 hours, the precipitate was filtered through a pad of silica gel and washed with CH ₂ Cl ₂ . The filtrate was concentrated in vacuo to give the title compound (10.4 g, 39.8 mmol, 90%) as a white solid. The crude product was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.33 (s, 1H), 7.59 (s, 1H), 4.79 (t, J=8.8 Hz, 2H), 3.35 (t , J=8.8 Hz, 2H); [M+H] ⁺ 261.

Step 8: (4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-cyclopropylphenyl)methanol (compound c39 )

Preparation of (4-cyclopropylphenyl)magnesium bromide (compound c38 ); A 250 mL three-neck flask containing magnesium (chips, 1.1 g, 46.6 mmol) was flame dried. The flask was equipped with a condenser and an additional dropping funnel in a nitrogen atmosphere. 4-Cyclopropylphenyl bromide (PepTech, USA) (6.0 ml, 42.4 mmol) in anhydrous THF (32.4 ml) was transferred into a dropping funnel. The Grignard reaction was initiated with approximately 5 ml of 4-cyclopropylphenyl bromide solution. The remaining bromide solution was added at room temperature over 4 hours. The resulting solution was directly used in the next step.

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 0.85 M in THF, 26.4 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (100 ml). The organic layer was dried over MgSO ₄ , 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. [MH ₂ O] ⁺ 361.

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 CH ₂ Cl ₂ /CH ₃ CN (100 ml / 100 ml) triethylsilane (4.6 ml, 40 mmol) and boron trifluoride diethyl etherate (3.8 ml, 30 mmol) were added at -20°C under nitrogen atmosphere. The mixture was gradually warmed to room temperature and further stirred at room temperature for 50 minutes. The reaction mixture was quenched by slow addition of saturated NaHCO ₃ solution (200 ml) and extracted with EtOAc (100 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (4.4 g, 12.1 mmol, 2 steps 85%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.07 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.80 (s, 1H ), 4.70 (t, J=8.8 Hz, 2H), 3.97 (s, 2H), 3.26 (t, J=8.8 Hz, 2H), 1.88-1.84 (m, 1H), 0.95-0.90 (m, 2H), 0.68-0.64 (m, 2H).

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 )

n-Butyllithium (2.5 M in hexane, 7.38 ml, 18.4 mmol) at -78°C under nitrogen. After stirring for 40-60 minutes at the same temperature (yellowish solution), a pre-cooled (at -78°C) solution of (3R,4S,5R,6R)-3,4,5-tris was added dropwise to the mixture ((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (compound c11 ; 8.6 g, 18.4 mmol) in tetrahydrofuran (20 ml) by cannula within 20 min. The reaction mixture was stirred for 2-3 hours at the same temperature (yellowish solution).

The reaction mixture was quenched with 1% acetic acid (20 ml) at -78°C, and then evaporated under reduced pressure to remove volatiles. The aqueous residue was extracted with EtOAc (150 ml x 2). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the crude title compound (11.8 g, quantitative) as a pale yellow oil. The crude residue was used in the next step without further purification

Step 11: (3R,4S,5S,6R)-2-(7-Chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H -pyran-3,4,5-triol (compound c42 )

To a solution of (3R,4S,5R,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-3,4,5-tris(trimethylsilyloxy)-6 -((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol (11.8 g) in MeOH (150 ml) was added CH ₃ SO ₃ H (1.5 ml, 23.5 mmol) at 0° C. drops. The mixture was warmed to room temperature for 18 hours, and then quenched with saturated NaHCO ₃ at 0°C. The mixture was evaporated under reduced pressure to remove volatile substances. The aqueous residue was extracted with EtOAc (100 ml x 2). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the crude title compound (6.0 g, 88% Step 2) as a yellow solid. [M+Na] ⁺ 499 and [M-OMe] ⁺ 445.

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 CH ₂ Cl ₂ /CH ₃ CN (v/v=1:1, 120 ml) was added dropwise with Et ₃ SiH (6 .0 ml, 37.8 mmol), then BF ₃ ^. OEt ₂ (3.2 ml, 25.2 mmol) at -50 to -45°C. The reaction mixture was heated to -10-0°C for 3-3.5 hours before quenching with saturated NaHCO ₃ (130 ml). The mixture was evaporated under reduced pressure to remove volatiles, and the resulting residue was extracted with EtOAc (150 ml x 2). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the crude title compound (5.8 g, 12.9 mmol, 102%) as a yellow solid. [M+Na] ⁺ 469.

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 CH ₂ Cl ₂ (120 ml) was added DMAP (1.9 g, 15.5 mmol) and Ac ₂ O (9.7 ml, 103 .76 mmol) at room temperature. After stirring for 18 hours at room temperature, the reaction was quenched with water (120 ml). The resulting mixture was extracted with CH ₂ Cl ₂ (100 ml x 2). After washing with 1 M HCl and brine, the combined organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure (7.0 g, crude). The suspended residue in EtOH (45 ml) was heated at 80°C until condensation occurred for 1 hour. The mixture was cooled to room temperature with stirring for 18 hours. The resulting precipitate was filtered, washed with EtOH and dried in vacuo to give the title compound (4.7 g, 7.6 mmol, 59%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.04-7.02 (m, 2H), 6.98-6.95 (m, 2H), 6.53 (s, 1H), 5.29- 5.24 (m, 1H), 5.18-5.12 (m, 2H), 4.71-4.65 (m, 2H), 4.31-4.26 (m, 1H), 4. 25-4.22 (m, 1H), 4.15-4.11 (m, 1H), 4.05-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.40-3.35 (m, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.66 (s, 3H), 0.94-0.89 (m, 2H), 0.66-0.61 (m, 2H); [M+Na] ⁺ 637.

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 4 M aqueous NaOH (2.8 ml). The reaction mixture was stirred at room temperature for 1.5 hours. The solution was cooled to 0°C before neutralization 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 MgSO ₄ , filtered and concentrated in vacuo to give the crude title compound.

A suspension of the crude title compound in toluene (8 ml) was heated at 40°C for 30 min (sticky solution -> clear solution -> white solid formation) and cooled to room temperature. The suspension was filtered in a filter funnel, and the filtered precipitate was washed with toluene in a volume equal to two volumes of the filtered precipitate. The filter cake was dried in vacuo to obtain 1.0 g (2.24 mmol; quantitative) of the title compound.

The overall yield of the final compound of Example 1 according to the synthesis steps 1-14 above was determined to be about 12%.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.11 (d, J=9.2 Hz, 1H), 3.96 (ABkv, 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.

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

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 )

n-Butyllithium ( 2.5 M in hexane, 8.28 ml, 20.7 mmol) at -78°C under nitrogen. 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 to the mixture over 30 minutes. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (300 ml) at 0°C and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude title compound (10.3 g, quantitative) as a yellow oil. The crude residue was used in the next step without further purification.

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 CH ₂ Cl ₂ (70 ml) and CH ₃ CN (70 ml) was added triethylsilane (8.8 ml, 55.2 mmol) and TMSOTf (10 ml, 55.2 mmol) at -78°C. After stirring at -78°C for 1 hour, the reaction mixture was quenched with water (200 ml) at 0°C and extraction was performed with CH ₂ Cl ₂ (300 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude title compound (6.3 g, quantitative) as a yellow oil. The crude residue was used in the next step without further purification.

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 CH ₂ CL ₂ (140 ml) was added DMAP (0.84 g, 6.9 mmol) and Ac ₂ O (13.0 ml, 13 .8 mmol) at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was quenched with water (120 ml) and extraction was carried out with DCM (200 ml). The organic layer was washed with aqueous NaHCO ₃ (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue suspended in isopropyl alcohol (20 ml) was heated at 80°C for 10 minutes and cooled to room temperature. The resulting precipitate was then filtered and concentrated in vacuo to give the title compound (4.52 g, 7.35 mmol, 53%) in the β form as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.04-7.02 (m, 2H), 6.98-6.95 (m, 2H), 6.53 (s, 1H), 5.29- 5.24 (m, 1H), 5.18-5.12 (m, 2H), 4.71-4.65 (m, 2H), 4.31-4.26 (m, 1H), 4. 25-4.22 (m, 1H), 4.15-4.11 (m, 1H), 4.05-3.91 (m, 2H), 3.79-3.74 (m, 1H), 3.40-3.35 (m, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.88-1.81 (m, 1H), 1.66 (s, 3H), 0.94-0.89 (m, 2H), 0.66-0.61 (m, 2H); [M+Na]+ 637.

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 hours, the reaction mixture was concentrated in vacuo, diluted with water (200 ml) and extracted with EtOAc (300 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by recrystallization in toluene to give the title compound (3.16 g, 96%) in β-form as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.11 (d, J=9.2 Hz, 1H), 3.96 (ABkv, 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 -3.33 (m, 3H), 1.85-1.79 (m, 1H), 0.91-0.86 (m, 2H), 0.61-0.57 (m, 2H); [M+Na]+ 469.

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

Step 1: (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(7-chloro-6-(4-methoxybenzyl)-2, 3-dihydrobenzofuran-4-yl)tetrahydro-2H-thiopyran-2-ol (compound c52 )

The synthesis procedure of step 8 in 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 was used as the Grignard reagent (compound c48), to give (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)(4-methoxyphenyl)methanol (compound c49 ). The synthesis procedure of step 9 in example 4 was then 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 ).

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) at -78°C under nitrogen was added n-butyllithium (2.5 M in hexane, 1.3 mL, 3.24 mmol) was added dropwise and the mixture was stirred for 1.5 hours at the same temperature. Then a solution of (3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one (compound c51 , 898 mg, 1.62 mmol, this compound was synthesized with reference to N. 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), and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was quenched by adding a saturated ammonium chloride solution. After addition was completed, the temperature of the solution was gradually raised 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 the 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).

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 the addition of boron trifluoride diethyl etherate (0.8 ml, 6.48 mmol) with this speed so that the reaction temperature is maintained between -20 and 0°C. Before quenching with saturated sodium bicarbonate solution, the solution was allowed to warm to 0°C for 1.5 hours. After removing the organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. After extracting the aqueous layer with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (silica gel, 3-25% ethyl acetate in hexane) to give the crude compound 7-chloro-6-(4-methoxybenzyl)-4-((2S,3R,4R,5S,6R)-3, 4,5-Tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-yl)-2,3-dihydrobenzofuran (603 mg, 46%, 2 stages) as a white solid. [M+Na] ⁺ 835.

Step 3: (2S,3R,4R,5S,6R)-2-(7-Chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H- thiopyran-3,4,5-triol (compound c47 )

To a solution of 7-chloro-6-(4-methoxybenzyl)-4-((2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro- 2H-thiopyran-2-yl)-2,3-dihydrobenzofuran ( c53 , 570 mg, 0.70 mmol) in dichloromethane (8 ml) was added BCl ₃ (1.0 M in dichloromethane, 2.8 ml) at 0° C. The reaction mixture was stirred at 0°C for 1 hour. After quenching the reaction with methanol, the solvent was evaporated under reduced pressure. Purification by preparative reverse phase HPLC (Gilson, SunFire™ Prep, gradient 5-50% acetonitrile in water) gave the title compound (18 mg, 6%) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) 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.

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

Step 1: ((3aS,5S,6R,6aS)-5-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol

Concentrated H ₂ SO ₄ ( _1.9 ml) at room temperature. After 12 hours, the reaction mixture (in which all L-(-)-xylose had been consumed) was filtered and the combined solid was washed twice with acetone (20 ml per wash). The yellow filtrate was neutralized to a pH of about 9 with NH ₄ OH solution with stirring. The suspended solid was removed by filtration. The filtrate was concentrated to give the bis-acetonide intermediate as a yellow oil. The yellow oil was suspended in water (5 ml) and then the pH was adjusted from 9 to 2 using a 1N solution of HCl in water. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was neutralized by adding 25% (w/w) K ₃ PO ₄ in water until the pH value was about 7. The mixture was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give the title compound (12.63 g, 52%) as a yellow oil.

¹ H NMR (400 MHz, CD ₃ OD) δ 5.88 (d, J=4.0 Hz, 1H), 4.47 (d, J=4.0 Hz, 1H), 4.18-4, 14 (m, 1H), 4.11 (d, J=2.8 Hz, 1H), 3.83-3.71 (m, 2H), 1.45 (s, 3H), 1.29 (s , 3H).

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), NaHCO ₃ (19.3 g, 230.3 mmol) and NaBr (1.6 g, 15.4 mmol) in a mixture of 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 in small portions. The suspension was stirred at room temperature for 12 hours. Methanol (2.0 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and washed with acetone (twice, 20 ml per wash). 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 and the mixture was filtered. The filtrate was concentrated to give the desired acid (9.0 g, 58%) as a light yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 5.98 (d, J=3.6 Hz, 1H), 4.71 (d, J=3.2 Hz, 1H), 4.51 (d, J=3.6 Hz, 1H), 4.36 (d, J=3.6 Hz, 1H), 1.45 (s, 3H), 1.31 (s, 3H).

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) was added , 66.3 mmol) 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 filtered precipitate was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography to give the title compound (5.8 g, 48%) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 6.01 (d, J=3.6 Hz, 1H), 5.10 (s, 1H), 4.59 (d, J=2.4 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.47 (d, J=2.4 Hz, 1H), 3.85-3.62 (m, 6H), 3, 53-3.49 (m, 2H), 1.49 (s, 3H), 1.33 (s, 3H). [M+H] ⁺ 274.

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 )

n - BuLi ( 2.5 M solution in hexane, 0.9 ml, 2.28 mmol) at -78°C. After 1 hour, ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)(morpholino)methanone was added dropwise to the mixture (compound c56 , 0.17 g, 0.63 mmol) in THF (8.0 ml) at -78°C. After 4 hours, the resulting mixture was quenched with saturated NH ₄ Cl solution and extraction was performed with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera ^TM FLASH Purification System) to give the title compound (0.13 g, 43%); [M+H] ⁺ 475.

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 CeCl ₃ ⋅ 7H ₂ O (0.12 g, 0.32 mmol), and the mixture was stirred at room temperature until all solids were dissolved. The mixture was then cooled to -78°C and NaBH ₄ (0.012 g, 0.32 mmol) was added in small portions. The mixture was stirred at -78°C for 2 hours, slowly heated to 0°C and quenched with a saturated solution of NH ₄ Cl. The mixture was concentrated under reduced pressure to remove CH ₃ OH, extracted with EtOAc and washed with saturated NaCl solution. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude title compound was dried under high vacuum and used in the next step as a white solid (0.13 g) without purification.

[M+Na] ⁺ 499.

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 )

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 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. 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 hours. The resulting mixture was quenched with water, extracted with EtOAc and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (0.16 g, 96%) as a white solid. [M+Na] ⁺ 627.

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, MeI (40 μL, 0.65 mmol) and DIPEA (452 μL, 2.60 mmol) were added and stirred for 3 hours. The resulting mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude title compound was dried under high vacuum and used in the next step as a white solid (150 mg, 48%) without purification. [M+Na] ⁺ 615.

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 CH ₃ OH (0.7 ml) was added NaOMe (catalytic amount, 25% solution in CH ₃ OH) at room temperature. After 20 hours, the resulting mixture was concentrated in vacuo. The crude product was diluted with EtOAc and filtered through a membrane. The crude product was purified by preparative HPLC (Gilson system, CH ₃ CN/H ₂ O) to give the title compound (41 mg, 35%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.09 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.68 (s, 1H ), 4.69-4.64 (m, 2H), 4.35 (d, J=10.0 Hz, 1H), 4.20 (d, J=9.2 Hz, 1H), 4.02 -3.88 (m, 4H), 3.67-3.65 (m, 2H), 3.61-3.58 (m, 1H), 3.56-3.52 (m, 1H), 3 .42-3.40 (m, 2H), 3.29-3.27 (m, 2H), 2.17 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); [M+Na] ⁺ 489.

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 title compound was prepared by repeating the synthesis procedure of Example 4, except that in Step 4, 4-bromo-7-chloro was used instead of 4-bromo-7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran -6-(4-ethylbenzyl)-2,3-dihydrobenzofuran.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.10-7.90(m, 4H), 6.71 (s, 1H), 4.68-4.62 (m, 2H), 4.33 ( d, J=9.6 Hz, 1H), 4.18 (d, J=9.2 Hz, 1H), 4.07-4.00 (m, 2H), 3.63-3.57 (m , 3H), 3.52-3.49 (m, 1H), 3.39-3.37 (m, 2H), 3.27-3.25 (m, 2H), 2.60 (sq, J =7.4 Hz, 2H), 2.15 (s, 3H), 1.20 (t, J=7.6 Hz, 3H); [M+Na] ⁺ 473.

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

Step 1: (3R,4S,5S,6R)-2-[7-Chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl])-6-(hydroxyemethyl)-2-methoxytetrahydro- 2 H -pyran-3,4,5-triol (compound c42 )

The title compound was synthesized by the following route 1a or 1b.

(1a) 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (250 g, 0.687 mol), (3R,4S,5R,6R)-3, was added dropwise to the reaction vessel. 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) at room temperature under a nitrogen atmosphere, and the mixture was completely dissolved. After cooling the reaction vessel to -78°C, n-butyllithium (550 mL, 2.0 M in hexane, 1.38 mol) was added dropwise over 1 hour, maintaining the internal temperature at -60°C or below. After the dropwise addition of n-butyllithium was completed, the mixture was further stirred at -78°C for 40 minutes. A solution of concentrated hydrochloric acid in methanol (152 ml/1.750 ml) was added dropwise to the reaction mixture over 20 minutes, maintaining the internal temperature at -30°C or lower. After the dropwise addition was completed, the reaction vessel was placed at room temperature and stirred for 18 hours. After confirming the completion of the reaction, the reaction vessel was cooled to 0°C, saturated aqueous NaHCO ₃ solution (2.5 L) was added, the pH value was adjusted to 9-10 using a pH meter, and then the reaction solvent was removed using a vacuum concentrator . The concentrate was diluted with EtOAc (2.5 L), distilled water (1.25 L) and brine (1.25 L) and layers were formed. The organic layers were then combined and the aqueous layer was extracted with EtOAc (2×1.25 L). The organic layers were combined and washed with distilled water (2.5 L) and brine (2.5 L). The organic layer was dried over MgSO ₄ (50 g) and filtered. The filtrate was then concentrated under reduced pressure to remove the solvent. The procedure of diluting the residue with toluene (500 ml) and removing by distillation under reduced pressure was repeated twice to obtain the title compound (328 g) as a yellow liquid. The crude residue was used in the next step without further purification.

(1b) 4-Bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (10.0 g, 27.5 mol), (3R,4S,5R,6R) was added dropwise to the reaction vessel )-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) at room temperature under nitrogen atmosphere, and the mixture was completely dissolved. After cooling the reaction vessel to -78°C, n-butyllithium (22.1 mL, 2.5 M in hexane, 54.9 mmol) was added dropwise over 15 minutes, maintaining the internal temperature at -60°C or below. After the dropwise addition of n-butyllithium was completed, the mixture was further stirred at -78°C for 30 minutes. A solution of concentrated hydrochloric acid in methanol (7.01 ml/70 ml) was added dropwise to the reaction mixture over 10 minutes, maintaining the internal temperature at -30°C or lower. After the dropwise addition was completed, the reaction vessel was placed at room temperature and stirred for 18 hours. After confirming the completion of the reaction, the reaction vessel was cooled to 0°C, a saturated aqueous solution of NaHCO ₃ (60 ml) was added, the pH was adjusted to 9-10 using a pH meter, and then the reaction solvent was removed using a vacuum concentrator. The concentrate was diluted with EtOAc (60 ml), distilled water (60 ml) and brine (60 ml), and layers were formed. The organic layers were then combined and the aqueous layer was extracted with EtOAc (2 x 30 mL). The organic layers were combined and washed with distilled water (60 ml) and brine (60 ml). The organic layer was dried over MgSO ₄ (5 g), filtered and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was diluted with toluene (50 ml), and then the toluene solution was slowly added dropwise to hexane (200 ml) at room temperature while the hexane was stirred. The resulting suspension was stirred at the same temperature for 1 hour and then filtered in vacuum. The resulting filtrate was washed with hexane (10 ml) and then dried in a vacuum oven (40°C) until its moisture content was 1% or lower by Karl-Fischer analysis to give the title compound ( 12.6 g, 96%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.64 (m, 1H), 4.57 (m, 1H), 4.05 (d, J=15.0 Hz, 1H), 3.96 (d, J=15.0 Hz, 1H), 3.93 (dd, J=11.8, 3.0 Hz, 1H), 3.87 (m, 2H), 3.65 (m, 2H), 3.51 (m, 1H), 3.30 (d, J=9.5 Hz, 1H), 3.14 (s, 3H), 1.83 (m, 1H), 0.91 (m, 2H), 0.63 (m, 2H ); LC-MS: [M-OMe] ⁺ 445.

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

In the reaction vessel, the crude residue (328 g, 0.687 mol) obtained according to reaction route 1a in step 1 was completely dissolved in CH ₂ Cl ₂ /CH ₃ CN (=v/v, 1:1, 5.00 L) with stirring at room temperature under a nitrogen atmosphere. The reaction vessel was cooled to -50°C, and then Et ₃ SiH (329 ml, 2.08 mol) and BF ₃ -OEt ₂ (170 ml, 1.37 mol) were added dropwise over 10 minutes, maintaining the internal temperature at -45°C or lower. The reaction mixture was slowly heated to -10°C over 1 hour and the resulting mixture was heated to 0°C. After stirring for 3 hours at 0°C, a saturated aqueous NaHCO ₃ solution (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). Then the organic layer was isolated. The aqueous layer was diluted with EtOAc (2 x 125 L) and extraction was performed. All organic layers were combined, dried over anhydrous MgSO ₄ (50 g), filtered and then the filtrate was concentrated under reduced pressure to remove the solvent. The residue was dried in vacuo to give the title compound (307 g) as a yellow liquid. The crude residue thus obtained was used in the next step without further purification.

¹ H NMR (500 MHz, CD ₃ OD): δ 7.04 (d, J=8.0 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 6.83 (s , 1H), 4.61 (t, J=9.0 Hz, 2H), 4.13 (d, J=9.0 Hz, 1H), 3.99 (d, J=15.0 Hz, 1H ), 3.94 (d, J=15.0 Hz, 1H), 3.87 (d, J=12.0 Hz, 1H), 3.66 (m, 1H), 3.44 (m, 1H ), 3.41 (t, J=9.0 Hz, 2H), 3.36 (m, 2H), 3.31 (m, 1H), 1.83 (m, 1H), 0.91 (m , 2H), 0.63 (m, 2H); LC-MS: [M+Na] ⁺ 469.

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 )

DMAP (101 g, 0.825 mol) and Ac ₂ O (520 ml, 5.50 mol) were sequentially added dropwise to the reaction vessel at room temperature while stirring CH ₂ Cl ₂ solution (5.00 L) of the crude residue (307 g, 0.687 mol) in step 2. The resulting yellow reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with distilled water (500 ml). The mixture was divided into layers. The organic layer was saved and the aqueous layer was extracted with dichloromethane (2 x 1.25 L). All organic layers were combined and washed with aqueous 1N HCl (2.5 L) and brine (2.5 L). The organic layer was dried over MgSO ₄ (50 g), filtered and then 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 washed with MeOH (500 ml). The filtered solid was dried to obtain the title compound (357 g, yield: 84%, purity: >97.6%) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.04 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 6.53 (s, 1H), 5.24 (dd, J=9.5, 9.5 Hz, 1H), 5.12 (m, 2H), 4.67 (m, 2H), 4.29 (d, J=10 .0 Hz, 1H), 4.24 (dd, J=12.5, 4.5 Hz, 1H), 4.13 (dd, J=12.5, 1.5 Hz, 1H), 4.02 (d, J=15.0 Hz, 1H), 3.92 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 3.38 (m, 2H), 2.07 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (m, 1H), 1.66 (s, 3H), 0.92 (m, 2H) , 0.63 (m, 2H); LC-MS: [M+Na] ⁺ 637.

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-2 H - pyran-3,4,5-triyl triacetate (357 g, 0.580 mol) in THF/MeOH (= v/v, 1:2, 4.28 L) was added dropwise with 4 M aqueous NaOH solution (668 ml, 2. 67 mol) at room temperature for 20 minutes while stirring the suspension. The resulting suspension was further stirred at room temperature for 2 hours. After cooling the reaction vessel to 0°C, an aqueous solution of 1N 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 separated. The organic layer was saved and the aqueous layer was extracted with EtOAc (2 x 1.79 L). All organic layers were combined and washed with distilled water (1.79 L). The organic layer was dried over MgSO ₄ (710 g), filtered and then the filtrate was concentrated under reduced pressure to obtain the crude title compound.

The crude title compound was diluted with EtOAc (3.89 L) and then stirred at reflux for 30 minutes until the solid dissolved completely. The resulting product 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 time of dropwise addition). The procedure for adding isopropyl ether was repeated twice. The reaction vessel was then cooled to 0°C and stirred for 30 minutes. The resulting solid was filtered under reduced pressure, and the filtrate was washed with a mixed liquid 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 (236 g, yield: 92%, purity: >99.7%) as a white solid. In addition, the overall yield of the final compound of Example 6, according to the synthesis route of steps 1-4 above, was determined to be about 77%.

¹ H NMR (500 MHz, CD ₃ OD): δ 7.04 (d, J=8.0 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 6.83 (s , 1H), 4.61 (t, J=9.0 Hz, 2H), 4.13 (d, J=9.0 Hz, 1H), 3.99 (d, J=15.0 Hz, 1H ), 3.94 (d, J=15.0 Hz, 1H), 3.87 (d, J=12.0 Hz, 1H), 3.66 (m, 1H), 3.44 (m, 1H ), 3.41 (t, J=9.0 Hz, 2H), 3.36 (m, 2H), 3.31 (m, 1H), 1.83 (m, 1H), 0.91 (m , 2H), 0.63 (m, 2H); LC-MS: [M+Na] ⁺ 469.

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

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 )

Reaction Route 1b in Step 1 of Example 6 used 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (21.6 g) to give the title compound (26.2 g, 93 %) in the form of a light yellow solid.

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 Ac ₂ O (51.8 ml, 550 mol) were sequentially added dropwise to the reaction vessel at room temperature while stirring the (3R,4S,5S,6R)-2- solution [7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl]-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (26.2 g , 55.0 mmol) in CH ₂ Cl ₂ (65.5 l). The resulting yellow reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with distilled water (50 ml). The mixture separated. The organic layer was saved and the aqueous layer was extracted with CH ₂ Cl ₂ (2×30 ml). All organic layers were combined and washed with 1N aqueous HCl (50 ml) and brine (30 ml). The organic layer was dried over MgSO ₄ (6 g), filtered, and then 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 washed with MeOH (30 ml). The filtered solid was dried to give the title compound (29.2 g, 71% total over two steps) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.01 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 5.53 (dd, J=10.0, 9.5 Hz, 1H), 5.19 (dd, J=10.0, 9.5 Hz, 1H), 4.99 (d, j =10.0 Hz, 1H), 4.63 (m, 2H), 4.34 (dd, J=12.0, 4.5 Hz, 1H), 4.14 (dd, J=12.0, 2.0 Hz, 1H), 4.05 (d, J=15.5 Hz, 1H), 4.01 (m, 1H), 3.99 (d, J=15.5 Hz, 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).

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 )

(3R,4S,5R,6R)-6-(acetoxymethyl)-2-[7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl]-2-methoxytetrahydro was completely dissolved in the reaction vessel -2H- pyran-3,4,5-triyl triacetate (5.00 g, 7.75 mmol) in CH ₂ Cl ₂ /CH ₃ CN (= v/v, 1:10, 550 ml), stirring at room temperature. After cooling the reaction vessel to 0°C, Et ₃ SiH (9.89 ml, 62.0 mmol) and BF ₃ -OEt ₂ (4.96 ml, 40.3 mmol) were sequentially added dropwise over 10 minutes, maintaining internal temperature at 5°C or lower. The reaction mixture was stirred at 5°C or lower for 1 hour. The reaction mixture was then heated to 10°C and further stirred for 2 hours. A saturated aqueous NaHCO ₃ solution was added to the reaction mixture, and the pH value was confirmed to be 7.0-7.5 using a pH meter. Then the organic solvent was 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 MgSO ₄ (5 g), filtered and then the filtrate was concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (5 ml), hexane (10 ml) was added and stirred at room temperature for 5 minutes. Isopropyl ether (20 ml) was added to the mixture and stirred for 30 minutes. Isopropyl ether (20 ml) was additionally added to the resulting suspension. 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 washed with isopropyl ether (10 ml). The filtered solid was dried in vacuo to give the title compound (4.38 g, 92%) as a white solid.

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 )

In accordance with the synthesis method described in step 4 of example 1, as above, (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-[7-chloro-6-(4-cyclopropylbenzyl) was used -2,3-dihydrobenzofuran-4-yl]tetrahydro-2H-pyran-3,4,5-triyl triacetate (4.38 g, 7.12 mmol) to give the crude title compound. The residue was diluted with EtOAc (45.3 ml) and then stirred at reflux for 10 minutes until the solid was completely dissolved. The resulting product 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 time of dropwise addition). The process of adding isopropyl ether was repeated twice. The reaction vessel was then cooled to 0°C and stirred for 30 minutes. The resulting solid was filtered under reduced pressure, and the filtrate was washed with isopropyl ether (10 ml). The filtered solid was dried in a vacuum oven (40°C, 18 hours) to obtain the title compound (2.93 g, yield: 92%, purity: >99.5%) as a white solid. The overall yield of the final compound of Example 2, according to the synthesis route of steps 1-4 above, was determined to be about 60%.

Experimental Example 1: Estimation of Yield as a Function of Rearrangement Reaction Conditions

(1) Reaction using amine-based solvent or without using solvent

Methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30 ) as starting material was rearranged at 160°C to give methyl 4-allyl-5-bromo-2-chloro-3 -hydroxybenzoate (compound c31) and its yield was calculated.

At this time, the amount of starting material and reaction conditions were adjusted as shown in Table 1 below. 5 M diethylamine (DEA) was used as the reaction solvent or the reaction was carried out without any solvent.

As a result, the yield was a maximum of 67% and did not increase further.

[Table 1] Test No. Purification of the starting material Amount of starting material (g) Reaction solvent Reaction temperature(°C) Reaction time
(h) Product quantity (g) Exit (%) 1 Unrefined 5 DEA (5M) 160 6 2.0 40 2 Unrefined 11.2 DEA (5M) 160 13 6.4 57 3 Unrefined 10.6 DEA (5M) 160 18 7.1 67 4 Unrefined 5.4 DEA (5M) 160 24 3.4 63 5 Unrefined 10 DEA (5M) 160 13 5.7 57 6 Unrefined 1 - 160 6 0.2 20 7 Unrefined 10 - 160 5 2.9 29 8 Unrefined 10 - 160 13 5.8 58 9 Unrefined 18.6 - 160 12.5 11.1 60 10 Unrefined 13.6 - 160 12 8.7 64 eleven Unrefined 10 - 160 18 6.1 61 12 Purified 10.5 - 160 12.5 4.8 46 13 Purified 9.9 - 160 18 3.3 33

(2) Lewis acid addition reaction

Methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30 ) as a starting material was dissolved in a solvent and subjected to a rearrangement reaction. The residue was then purified by silica gel column chromatography to give methyl 4-allyl-5-bromo-2-chloro-3-hydroxybenzoate (compound c31 ) and its yield was calculated.

Here, 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 the addition of Lewis acid.

As a result, when diisobutylaluminum chloride ((i-Bu) _2AlCl ) or diethylaluminum chloride ( _Et2AlCl ), which is a Lewis acid, was added, the yield increased to 80%.

[Table 2] Test No. Lewis acid Reaction solvent Reaction temperature Exit 1 BCl _{3 CH2Cl2 ​} -25°C - room temperature 17% 2 (i-Bu) _2AlCl Hexane/CH ₂ Cl ₂ 0°C - k.t. 71% 3 _TiCl4 Methylimidazole k.t. Unreacted 4 _{TiCl4 CH2Cl2 ​} k.t. Unreacted 5 - Water k.t. Unreacted 6 BF ₃ .OEt _{2 CH2Cl2 ​} 0°C - k.t. Unreacted 7 _{AlCl3 CH2Cl2 ​} 0°C - k.t. 35% 8 (i-Bu) _2AlCl Hexane/CH ₂ Cl ₂ 0°C - k.t. 80% 9 _Et2AlCl Hexane/CH ₂ Cl ₂ 0°C - k.t. 72%

Experimental example 2: Estimation of yield depending on cyclization reaction conditions

(1) Cyclization using Vilsmeyer's reagent

Preparation of Vilsmeyer's reagent (production reagent A); SOCl ₂ (5.3 mL, 72.24 mmol) was added to a solution of N,N-dimethylformamide (5.6 mL, 74.24 mmol) at room temperature. The mixture was stirred at 40°C for 2 hours and then concentrated in vacuo to obtain Vilsmeyer's reagent, which is a hygroscopic white solid.

Preparation of Vilsmeyer's reagent (production reagent B); SOCl ₂ (2.7 mL, 37.07 mmol) was added to a solution of N,N-dimethylformamide (2.9 mL, 37.07 mmol) at room temperature. The mixture was stirred at 40°C for 2 hours and then concentrated in vacuo to obtain Vilsmeyer's reagent, which is a hygroscopic white solid.

Next, methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33 ) in DMF was slowly added to the Vilsmeyer reagent mixture in DMF. The mixture was subjected to a cyclization reaction with stirring for 1 hour to obtain methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34 ) and its yield was calculated.

Here, the starting material, reaction temperature and the like were adjusted as shown in Table 3 below, and the reaction was carried out.

The result was a cyclized product in generally high yield. However, in the case where the starting material was crude, the product was recovered in low yield.

[Table 3] Test No. Properties of the starting substance Amount of starting material Vilsmeyer reagent Reaction temperature Product color Product quantity Exit 1 Brown solid 0.5 g Reagent manufactured by Sigma-Aldrich Co. LLC -20°C Light yellow 0.31 g 66% 2 Brown solid 1.0 g Production Reagent A -20°C Light yellow 0.66 g 70% 3 Brown solid 5.4 g Production Reagent A -20°C Light yellow 3.57 g 70% 4 White solid 1.0 g Production Reagent A 0°C - 15°C Light yellow 0.75 g 80% 5 Viscous brown solid 1.0 g Production Reagent A 0°C - 15°C Light yellow 0.12 g 13% 6 Brown solid 7.6 g Production Reagent B 0°C - 15°C Light brown 5.86 g 81%

(2) Cyclization using leaving group

To methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33 ) as a starting material, mesyl chloride (MsCl) was added along with a solvent. The mixture was subjected to a cyclization reaction to give methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34 ) and its yield was calculated.

At this time, the amount of reagent used, the addition method and the reaction conditions were adjusted as shown in Table 4 below, and the reaction was carried out.

As a result, the desired compound was sometimes obtained in high yield. However, there was a deficiency caused by the equivalent MsCl control and dropwise addition.

[Table 4] Test No. Reagent Solvent Add method Reaction temperature Reaction time Product (c34) output By-product (c34-1) output 1 MsCl 1.1 eq. Pyridine/DCM Addition -18°C During the night 62% 34% 2 MsCl 3.3 eq. Pyridine/DCM Add dropwise over 2 hours k.t. During the night 19% 35% 3 MsCl 3.3 eq. Pyridine/DCM Add dropwise over 2 hours k.t. 1 hour 46% 47% 4 MsCl 1.2 eq. Pyridine/DCM Add dropwise over 2 hours 0°C 1 hour 51% 46% 5 MsCl 1.2 eq. Pyridine/DCM Add dropwise over 2 hours 55°C 1 hour 86% 9% 6 MsCl 1.1 eq. Pyridine/DCM Adding a small amount 55°C 1 hour 71% 7 MsCl 1.1 eq. Pyridine/DCM Adding a small amount 55°C 1 hour 56% 8 MsCl 1.1 eq. Pyridine/DCM Add dropwise over 2 hours 60°C 1 hour 90%

(3) Cyclization using halide or Mitsunobu reaction

Methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33 ) as starting material, subjected to halide cyclization reaction or Mitsunobu reaction to give methyl 4-bromo-7-chloro -2,3-dihydrobenzofuran-6-carboxylate (compound c34 ) and its yield was calculated.

In this case, a reagent combining triphenylphosphine (PPh3), imidazole, iodine (I2) and toluene was used for the cyclization reaction using halide, and a reagent combining triphenylphosphine (PPh3), diisopropyl azodicarboxylate (DIAD) and tetrahydrofuran (THF) used for the Mitsunobu reaction.

The result was a yield of up to approximately 60%. However, a difficulty arose due to the need to remove triphenylphosphine oxide, which is a by-product formed after the reaction.

Experimental Example 3: Estimation of Yield as a Function of Reduction Reaction Conditions

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

(1) The reaction solvent and the added amount of Lewis acid were adjusted as shown in Table 5 below, and the reaction was carried out. As a result, it was possible to obtain the highest yield product when THF/EtOH (1:1) was used as the reaction solvent, and a good yield of 95% was obtained even when only NaBH ₄ was used without Lewis acid .

[Table 5] Test No. Reaction solvent NaBH ₄ (eq.) Lewis acid Reaction result (mass ratio) (substance: product: by-product 1) 1 Methanol 3.0 - 68:31: - 2 Ethanol 3.0 - -:77:21 3 THF/methanol (1:1) 3.0 - 52:43: - 4 THF/ethanol (1:1) 3.0 - -:95: - 5 THF/water (1:1) 3.0 - 50:48: - 6 Dioxane/water (1:1) 3.0 - 42:57: - 7 THF/methanol (1:1) 3.0 LiCl (1.5 eq.) 52:43: - 8 THF/ethanol (1:1) 3.0 LiCl (1.5 eq.) -:93:6

(2) Without adding Lewis acid, the reaction solvent and the added amount of NaBH4 were adjusted as shown in Table 6 below, and the reaction was carried out. As a result, in the case when NaBH ₄ was added in an amount of 3 eq. using THF/EtOH (1:1) or THF/EtOH (2:1) as the reaction solvent, a good yield of 95% was obtained without by-product.

[Table 6] Test No. Reagent NaBH ₄ (eq.) Reaction result (mass ratio) (specified substance: product: by-product 1: by-product 2) 1 Methanol 3.0 68:31: -: - 2 Ethanol 3.0 -:77:21: - 3 THF/methanol (1:1) 3.0 52:43: -: - 4 THF/ethanol (1:1) 3.0 -:95: -: - 5 THF/water (1:1) 3.0 50:48: -: - 6 Dioxane/water (1:1) 3.0 42:57: -: - 7 THF/ethanol (2:1) 3.0 -:95: -: - 8 THF/ethanol (5:1) 3.0 30:60: -:10 9 THF/ethanol (10:1) 3.0 -:70: -:30 10 THF/ethanol (1:1) 1.2 50:50: -: - eleven THF/ethanol (1:1) 1.5 25:75: -: - 12 THF/ethanol (2:1) 2.0 10:90: -: - 13 THF/ethanol (2:1) 1.2 21:53:25: - 14 THF/ethanol (2:1) 1.5 18:58:24: - 15 THF/ethanol (2:1) 2.0 17:63:19: - *By-product 2: Unidentified substance

(3) The reaction solvent, the added amount of NaBH ₄ and the added amount of Lewis acid were adjusted as shown in Table 7 below, and the reaction was carried out. As a result, the reaction did not proceed when only THF or a mixture of THF/i-PrOH was used as the reaction solvent. On the other hand, in the case where THF/ethanol was used as the reaction solvent, a good yield of 95% or higher was obtained even when using only NaBH ₄ without Lewis acid.

[Table 7] Test No. Reagent NaBH ₄ (eq.) Lewis acid Reaction result (mass ratio) (specified substance: product: by-product 1) 1 THF 2.0 - 100: -: - 2 Ethanol/water (4:1) 2.0 CaCl ₂ (1.0 eq.) -:60:40 3 THF/methanol (1:1) 3.0 CaCl ₂ (1.5 eq.) 70:30: - 4 THF/ethanol (1:1) 2.4 CaCl ₂ (1.2 eq.) -:100: - 5 THF/ethanol (1:1) 3.0 CaCl ₂ (1.5 eq.) -:100: - 6 THF/ethanol (2:1) 3.0 - -:100: - 7 THF/isopropanol (1:1) 3.0 CaCl ₂ (1.5 eq.) 100: -: -

Experimental Example 4: Preparation and Analysis of Crystalline Form

From the compound obtained in accordance with 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 ), which was prepared according to steps 1 to 14 in Example 1, was prepared into crystals through a crystallization process in various solvents and analyzed.

For the XRD spectrum, powder X-ray diffraction was determined using an X-ray diffractometer by irradiating with Cu-K _α rays (wavelength 40=1.54056 Å) according to the conventional method.

For differential scanning calorimetry (DSC), the measurement was carried out at a rate of +1°C/min using a differential scanning calorimeter.

(1) Preparation of crystal using toluene solvent

Crystallization using toluene is similar to that described in the later part of the procedure of step 14 in example 1. In particular, the crude compoundc28dissolved in toluene (8 times the amount by weightc28) when heated at 40°C for 30 minutes, and then cooled to room temperature. After the suspension was formed at room temperature, further stirring was performed for 30 minutes. The resulting precipitate was filtered, washed with toluene (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 91.8%).

The XRD spectrum of the resulting crystal showed a crystalline form (crystal form A) as shown in Figure 1, and the diffraction angles (2θ), interplanar distances (d) and relative intensities (I/I _o × 100) of the characteristic peaks are shown in Table 8.

[Table 8] 2θ (±0.2°) d(Å) I/I _o (%) 2θ (±0.2°) d(Å) I/I _o (%) 6.2 14.1 10.1 19.0 4.6 21.7 7.2 12.1 20.7 21.6 4.1 5.4 8.8 10.0 11.5 22.5 3.9 15.3 15.4 5.8 9.6 23.8 3.7 7.3 17.6 5.0 20.1 25.1 3.5 13.3 18.6 4.7 9.9

As shown in Figure 2, the DSC spectrum confirmed the endothermic melting peak of the crystal.

(2) Preparation of crystal using ethyl acetate solvent

The crystallization using ethyl acetate is similar to that described in the later part of step 4 in example 6. Specifically, the crude compound c28 was dissolved in ethyl acetate (15 times the amount by weight of c28 ) by stirring under reflux and then cooled to room temperature. After the suspension was formed at room temperature, further stirring was performed for 30 minutes. Isopropyl ether (15 times the weight of c28 ) was added dropwise to the resulting mixture over 30 minutes, and further stirring was performed at room temperature for 30 minutes. The resulting precipitate was filtered, washed with 0°C ethyl acetate (2 times the amount by weight of c28 ) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 88.3%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(3) Preparation of crystal using dichloromethane solvent

The crude compound c28 was dissolved in dichloromethane (170 times the weight of c28 ) with 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, followed by stirring for 12 hours. The resulting precipitate was filtered, washed with dichloromethane (twice by weight of c28 ) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 50.1%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(4) Preparation of crystal using acetone solvent

The crude compound c28 was dissolved in acetone (35 times the weight of c28 ) by refluxing and then cooled to room temperature. After the suspension was formed at room temperature, stirring was further performed for 3 hours. The resulting precipitate was filtered, washed with acetone (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 38.2%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(5) Preparation of crystal using acetonitrile solvent

The crude compound c28 was dissolved in acetonitrile (10 times the amount by weight of c28 ) while heating at 60°C, and then cooled to room temperature. After the suspension was formed at room temperature, stirring was further carried out for 1 hour. The resulting precipitate was filtered, washed with acetonitrile (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 39.4%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(6) Preparation of crystal using 2-propanol solvent

A solution of crude compound c28 in 2-propanol (10 times the amount by weight of c28 ) was dissolved by heating at 60°C and then cooled to room temperature. After the suspension was formed at room temperature, further stirring was performed for 30 minutes. 2-propanol (5 times the amount by weight of c28 ) was further added dropwise to the reaction mixture, and then stirring was performed for 30 minutes. The resulting precipitate was filtered, washed with 2-propanol (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 9.5%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(7) Preparation of crystal using tetrahydrofuran/dichloromethane solvent

The crude compound c28 was dissolved in tetrahydrofuran (5 times the amount by weight of c28 ) with 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 amount by weight of c28 ) and stirred at room temperature. After the suspension was formed, stirring was additionally performed for 30 minutes. The resulting precipitate was filtered, washed with dichloromethane (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 65.3%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(8) Preparation of crystal using tetrahydrofuran/n-hexane solvent

The crude compound c28 was dissolved in tetrahydrofuran (5 times the amount by weight of c28 ) with stirring at room temperature for 30 minutes. n-hexane (10 times the amount by weight of c28 ) was added dropwise to the reaction mixture and stirring was performed for 1 hour. n-hexane (10 times the amount by weight of c28 ) was further added dropwise to the resulting suspension and then stirred for 30 minutes. n-hexane (5 times the amount by 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 crystal (yield: 99.6%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form A) similar to that shown in step (1) of Experimental Example 4.

(9) Preparation of crystal using methanol/distilled water solvent

The crude compound c28 was dissolved in methanol (5 times the amount by weight of c28 ) with stirring at room temperature for 30 minutes. Distilled water (10 times the amount by weight of c28 ) was added dropwise to the reaction mixture, and then stirring was performed for 30 minutes. Distilled water (10 times the amount by weight of c28 ) was additionally added dropwise to the resulting suspension and then stirred for 1 hour. The resulting precipitate was filtered, washed with distilled water (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 100%).

The XRD spectrum of the resulting crystal showed a crystal form (crystal form B) similar to that shown in Figure 3, and the diffraction angles (2θ), interplanar distances (d) and relative intensities (I/I _o × 100) of the characteristic peaks are shown in Table 9.

[Table 9] 2θ (±0.2°) d(Å) I/I _o (%) 2θ (±0.2°) d(Å) I/I _o (%) 5.6 15.7 30.5 17.7 4.9 85.6 7.0 12.5 100 18.8 4.7 71.9 9.4 9.3 28.9 20.6 4.3 58.9 11.0 8.0 23.9 21.8 4.0 64.0 14.9 5.9 67.6 23.5 3.7 87.6

As shown in Figure 4, the DSC spectrum was able to confirm the endothermic melting peak of the crystal.

(10) Preparation of crystal using methanol/n-hexane solvent

The crude compound c28A was dissolved in methanol (5 times the amount by weight of c28 ) with stirring at room temperature for 30 minutes. n-hexane (15 times the amount by weight of c28 ) was added dropwise to the reaction mixture and stirred for 30 minutes. n-hexane (10 times the amount by weight of c28 ) was additionally added dropwise to the resulting suspension and stirring was carried out 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 crystal (yield: 97.1%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form B) similar to that shown in paragraph (9) of Experimental Example 4.

(11) Preparation of crystal using methanol/dichloromethane/n-hexane solvent

The crude compound c28 was dissolved in dichloromethane/methanol (20:1 by weight of c28 ) with stirring at room temperature for 30 minutes. n-hexane (10 times the amount by weight of c28 ) was added dropwise to the reaction mixture and stirred for 1 hour. n-hexane (10 times the amount by weight of c28 ) was additionally added dropwise to the resulting suspension and stirring was carried out for 30 minutes. n-hexane (5 times the amount by 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 crystal (yield: 99.2%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form B) similar to that shown in paragraph (9) of Experimental Example 4.

(12) Preparation of crystal using tetrahydrofuran/toluene solvent

The crude compound c28 was dissolved in tetrahydrofuran (5 times the amount by weight of c28 ) with 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 amount by weight of c28 ) and then stirred at room temperature for 1 hour. The resulting precipitate was filtered, washed with toluene (2 times the volume of the filtrate) and then dried in a vacuum oven (50°C, 12 hours) to obtain a white crystal (yield: 76.1%).

The X-ray diffraction spectrum of the resulting crystal showed a crystal form (crystal form C) similar to that shown in Fig. 5, and Table 10 shows the diffraction angles (2θ), interplanar distances (d) and relative intensities (I/I _o ×100) of the characteristic peaks .

[Table 10] 2θ (±0.2°) d(Å) I/I _o (%) 2θ (±0.2°) d(Å) I/I _o (%) 5.6 15.9 26.9 19.9 4.4 21.2 7.3 12.0 39.9 21.2 4.1 25.4 15.7 5.6 29.1 21.9 4.0 29.2 17.2 5.1 26.2 23.1 3.8 24.7 18.9 4.6 100.0

As shown in Fig. 6, the DSC spectrum was able to confirm the endothermic melting peak of the crystal.

(13) Preparation of crystal using ethanol/distilled water/n-hexane solvent

Unpurified compoundc28dissolved in ethanol (5 times the amount by weightc28) when heated at 50°C and then cooled to room temperature. Distilled water was added dropwise to the reaction mixture (10 times the amount by weightc28) and stirring was carried out for 1 hour. Distilled water was additionally added dropwise to the resulting suspension (10 times the amount by weightc28) and carried out stirring for 30 minutes. n-hexane was added dropwise to the reaction suspension (1-fold amount by weightc28) and carried out 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 crystal (yield: 95.8%). XRD spectral analysis of the resulting crystal showed a crystal form (crystal form C) similar to that shown in paragraph (12) of Experimental Example 4.

(14) Preparation of crystal using ethanol/n-hexane solvent

Unpurified compoundc28dissolved in ethanol (5 times the amount by weightc28) when heated at 50°C, and then cooled to room temperature. n-hexane was added dropwise to the reaction mixture (5 times the amount by weightc28) and carried out stirring for 30 minutes. n-hexane was additionally added dropwise to the resulting suspension (10 times the amount by weightc28) and carried out stirring for 30 minutes. n-hexane was repeatedly added dropwise to the reaction suspension (5 times the amount by weightc28) and carried out 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 crystal (yield: 96.5%).

The X-ray diffraction spectrum of the obtained crystals showed a similar crystal form (crystal form D) as shown in Fig. 7, and the diffraction angles (2θ), interplanar distances (d) and relative intensities (I/I _o ×100) of the characteristic peaks are given in the table eleven.

[Table 11] 2θ (±0.2°) d(Å) I/I _o (%) 2θ (±0.2°) d(Å) I/I _o (%) 5.5 15.8 6.1 18.9 4.6 31.3 7.2 12.2 17.5 20.0 4.4 5.2 15.3 5.7 12.7 21.1 4.2 6.6 17.2 5.1 9.8 22.5 3.9 3.3 17.6 5.0 9.8 25.1 3.5 2.9

As shown in Fig. 8, the DSC spectrum was able to confirm the endothermic melting peak of the crystal.

Experimental Example 5: Confirmation of Crystal Form Stability

Using the crystalline form obtained in step (2) of Experimental Example 4, stability confirmation studies related to properties, identification analysis, moisture content, specific rotation, related substances and content were carried out for 3 months under accelerated conditions (temperature: 40 ± 2°C, relative humidity: 75 ± 5%) and long-term (temperature: 25 ± 2°C, relative humidity: 60 ± 5%) studies. The results of stability confirmation studies are shown in Table 12.

[Table 12] Subject of study Parameter Initial period Expedited, within 1 month Expedited, within 3 months Long-term, within 3 months Properties White or off-white powder White powder White powder White powder White powder Identification Analysis L.C. Compliant Compliant Compliant Compliant Compliant IR Compliant Compliant Compliant Compliant Compliant XRD Compliant Compliant Compliant Compliant Compliant Humidity (%) 0.5 or lower 0.19 0.20 0.14 0.18 0.19 Specific rotation (°) +37 - +41 38.0 37.9 38.9 38.8 Related substances(%) Other individual related substances <0.1 0.05 0.05 0.05 0.05 Content (%) Total related substances <1.0 0.15 0.16 0.16 0.16 98.0~102.0 99.50 99.60 100.97 100.20

(1) The properties study confirmed the absence of any changes in the properties of the crystalline form under the conditions of accelerated and long-term studies.

(2) Identification analysis was carried out using infrared spectrophotometry and liquid chromatography, which are among the general research methods prescribed by the Korean Pharmacopoeia, and the analysis confirmed that the crystalline form exhibited a spectrum similar to that of the standard product in both examination methods.

<Analytical conditions>

- Column: Capcdell-pak C18 MG (USPL1), 250 × 4.6 mm, 5 µm

- Temperature: 35°C

- Detector: LED detector (PDA) (measurement wavelength: 225 nm)

- Flow rate: 1.0 ml/min

- Mobile phase: buffer/methanol (25:75)

- Buffer: a buffer prepared by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 ml of distilled water and then adjusting the pH to 3.0 with phosphoric acid.

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

(4) In the case of measurement in accordance with the moisture measurement method, which is among the general test methods prescribed by the Korean Pharmacopoeia, the moisture content test can confirm the results indicating that the crystalline form has only a slight property of containing moisture under conditions for accelerated and long-term studies.

(5) Specific rotation testing can confirm the structural stability of the crystal form under conditions for accelerated and long-term studies.

(6) A study confirming stability against related substances was carried out by liquid chromatography, which is among the general testing methods prescribed by the Korean Pharmacopoeia. The analysis time of the sample solution was such that the measurement was carried out up to three times the retention time of the main peak. The peak areas of the standard solution (0.05 mg/mL) and sample solution (1 mg/mL), excluding all peaks present in the blank analytical solution, were determined according to the calculation expression. As a result, the stability of the crystalline form for related substances under accelerated and long-term study conditions can be confirmed.

Analytical conditions: Liquid chromatography analytical conditions for the confirmatory study in step (2) of Experimental Example 5

- Calculation expression: other individual related substances (%) = (peak area of each related substance in the analytical 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 factor)

(7) To test the content, the methanol solution of the standard product (0.2 mg/mL) was used as the standard solution, and the methanol solution of the crystalline form was used as the sample solution (1 mg/mL). The sample solution and standard solution were analyzed by liquid chromatography, which is among the general research methods prescribed by the Korean Pharmacopoeia, and the peak areas of the standard solution and sample solution were used to perform the calculation using the expression below. As a result, the stability of the crystalline form can be confirmed, which practically does not change in content under conditions for conducting accelerated and long-term studies.

- Analytical conditions: Liquid chromatography analytical conditions for the confirmatory study in point (2) of Experimental Example 5

- Calculation expression: 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 - moisture content of the sample )]

Claims (24)

1. Method for obtaining crystalline form B of the compound (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), having an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°± 0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2° and 23.5°± 0.2° in the case of irradiation using a Cu-K _α radiation source, where the method includes the stages: (1) dissolving the crude compound c28 in methanol (5 times the mass of c28) while stirring at room temperature for 30 minutes; (2) adding distilled water (10 times the amount by weight of c28) dropwise to the reaction mixture and then stirring for 30 minutes; (3) additional addition of distilled water dropwise to the resulting suspension (10 times the amount by weight c28); (4) stirring for 1 hour; (5) filtering and washing the resulting precipitate with distilled water; And (6) drying the resulting filtrate in a vacuum oven (50°C, 12 hours) to obtain a white crystal of Form B. 2. Method for obtaining crystalline form B of the compound (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), having an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°± 0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2° and 23.5°± 0.2° in the case of irradiation using a Cu-K _α radiation source, where the method includes the stages: (1) dissolving the crude compound c28 in methanol (5 times the mass of c28) while stirring at room temperature for 30 minutes; (2) adding n-hexane (15 times the mass of c28) to the reaction mixture dropwise and stirring for 30 minutes; (3) additional addition of n-hexane dropwise to the resulting suspension (10 times the amount by weight c28); (4) stirring for 1 hour: (5) filtering and washing the resulting precipitate with n-hexane; And (6) drying the resulting filtrate in a vacuum oven (50°C, 12 hours) to obtain a white crystal of Form B. 3. Method for obtaining crystalline form B of compound (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), having an X-ray diffraction spectrum that includes peaks at diffraction angles (2θ) of 7.0°±0.2°, 14.9°± 0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2° and 23.5°± 0.2° in the case of irradiation using a Cu-K _α radiation source, where the method includes the stages: (1) dissolving the crude compound c28 in a mixture of dichloromethane/methanol (20:1 by weight of c28), stirring at room temperature for 30 minutes; (2) adding n-hexane dropwise to the reaction mixture (10 times the amount by weight of c28); (3) carrying out stirring for 1 hour; (4) additional addition of n-hexane dropwise to the resulting suspension (10 times the amount by weight c28); (5) stirring the resulting suspension for 30 minutes; (6) repeated dropwise addition of n-hexane to the reaction suspension (5 times the amount by weight c28); (7) stirring; (8) filtering and washing the resulting filtrate with n-hexane; And (9) drying in a vacuum oven (50°C, 12 hours) to obtain a white crystal of Form B.