RU2774998C2 - Method for production of diphenylmethane derivative - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for the production of a compound of the following formula 1, which is effective as an inhibitor of sodium-dependent glucose cotransporter (SGLT). The method includes following stages: (1) interaction of a compound of the following formula 2 with a compound of the following formula 3, and cyclization of the resulting product to obtain a compound of the following formula 4; (2) the compound of formula 4 is subjected to aldehydation or amidation, followed by interaction of the resulting product with a compound of the following formula 5 and the reduction to obtain a compound of the following formula 6; and (3) (a) interaction of the compound of the formula 6 with either a compound of the following formula 7, and removal of protective groups and reduction to obtain the compound of the formula 1, where R is hydroxymethyl, or (b) interaction of the compound of the formula 6 with a compound of the following formula 8, and reduction to obtain a compound of the following formula 9, transformation of a furanose ring of the compound of the formula 9 into a pyranose ring under acidic conditions, and then, the introduction of a protective group into it to obtain a compound of the following formula 10; treatment of the compound of the formula 10 with thiourea, interaction of the resulting product with C_1-7alkyl halide and subsequent reduction to obtain the compound of the formula 1, where R is C_1-7alkylthio. In this case, the cyclization reaction is a cyclization reaction using the Wilsmeyer reagent, a cyclization reaction using an outgoing group, a cyclization reaction using halide, or a cyclization reaction using the Mitsunobu reaction.

, where in formulas, A is oxygen (O) or sulfur (S); R is hydroxymethyl or C_1-7alkylthio; n is 1 or 2; PG is a protective group; X' is halogen; X, Y and Hal, each independently, is halogen; B is (B-1)

, where Rb is hydrogen, Ra is C_1-7alkoxy or C_3-10cycloalkyl.

EFFECT: provision of an improved method for the production of a diphenylmethane derivative.

11 cl, 8 dwg, 12 tbl, 13 ex

Description

Technical field

The present invention relates to a process for the production of a diphenylmethane derivative, and in particular to an improved process for the production of a diphenylmethane derivative which is used as a sodium dependent glucose cotransporter (SGLT) inhibitor.

State of the art

The sodium-dependent glucose co-transporter (SGLT) provides Na ⁺ transport that follows a concentration gradient, while at the same time providing glucose transport that does not follow a concentration gradient. Two important isoforms of SGLT have been cloned to date, known as SGLT1 and SGLT2. SGLT1 is located in the intestine, kidney and heart and regulates glucose transport in the heart through its expression. Because SGLT1 is a high-affinity, low-throughput transporter, it is only responsible for glucose reabsorption 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 proximal convoluted tubule proximal. In healthy individuals, more than 99% of the plasma glucose that is filtered by the renal glomeruli is reabsorbed, and less than 1% of the total filtered glucose is excreted in the urine. It is assumed that SGLT2 provides 90% of renal glucose reabsorption, and the remaining 10% is mediated by SGLT1 in the terminal proximal tubule. The SGLT2 genetic mutation does not have any specific adverse effects on carbohydrate metabolism. However, increased renal glucose secretion of up to about 140 g/day is caused depending on the mutation. According to mutation studies in humans, SGLT2 has been the subject of therapeutic studies because SGLT2 is estimated to be responsible for the majority of glucose reabsorption in the kidney.

US Patent Laid-Open Publication No. 2015/0152075 describes a compound having a diphenylmethane moiety that has SGLT2 inhibitory activity, as well as a method for preparing the same. The document describes that the diphenylmethane derivative compound is effective in the treatment of diabetes because the diphenylmethane derivative compound exhibits an excellent inhibitory effect on human SGLT2 activity and significantly reduces urinary sugar excretion in animals compared to the drug dapagliflozin, which is well known as an SGLT2 inhibitor. In addition, US Patent Laid-Open No. 2014/0274918 describes 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 U.S. Laid-Open Publication No. 2015/0152075 or the like. describes a method for obtaining diphenylmethane compound c28, similar to that shown 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 yield of the product is obtained. In addition, in the case where the synthesis of a substituent of a glucose group or a cyclopropylbenzyl group that is bonded to dihydrobenzofuran proceeds inappropriately in the middle of the synthesis, or if it is understood that a substituent or a cyclopropylbenzyl group is substituted with another group, there is a disadvantage of having to carry out its synthesis again from the beginning. In addition, even for the process of synthesizing the cyclopropyl group of the compound c28, this process is carried out by cyclizing the olefin by the Simons-Smith reaction at the end of the synthesis path, whereby the yield greatly changes depending on the state (purity, anhydrous, or the like) of the reagent (diethylzinc, solvent ) and the like, and reaction concentrations.

Based on the above, the present inventors have found that a diphenylmethane derivative can be efficiently produced by a convergent synthesis method in which the respective basic groups are synthesized separately and then combined with each other, unlike the conventional linear synthesis method, and thus the present invention is carried out.

Detailed description of the invention

Technical task

Accordingly, it is an object of the present invention to provide an improved method for producing a diphenylmethane derivative that is used as an SGLT inhibitor.

The solution of the problem

According to an aspect of the present invention, there is provided a process 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 amidation of a compound of formula 4, followed by reacting the resulting compound with a compound of the following formula 5 and performing a 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 is a protecting group;

X' is halo or C _1-7 alkyl;

X, Y and Hal are each independently halogen;

или (B-2)

,B is (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 alkoylamino, 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 halo, 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 halo, 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.

According to another aspect of the present invention, there is provided a process 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 is subjected to aldehyde or amidation, followed by the interaction of the obtained compound with the compound of formula 5 and the implementation of reduction to obtain the compounds of the following formula 6;

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

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

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

where in the formulas,

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

In particular, according to the method described in the document from the prior art, the residues of the aglycone group must be synthesized even after the binding of the glucose group 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 aglycone end group can be easily synthesized, whereby various end group designs are possible.

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

Brief description of the drawings

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

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

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

7 and 8 show the XRD and DSC spectra of the 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 the preparation of a compound of formula 1:

[Formula 1]

in the formula

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

R is hydroxymethyl or C _1-7 alkylthio;

n is 1 or 2;

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

или (B-2)

,B is (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 alkoylamino, 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 halo, 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 halo, 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 is hydrogen or C _1-7 alkyl; R _8a and R _8b are each independently C _1-7 alkyl or bonded to each other 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, the B-2 ring 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 may be equal to 1; X' may be halogen; and B may be phenyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of halo, 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 α-form, β-form or racemic form.

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

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

According to an aspect of the present invention, there is provided a process for preparing a compound of formula 1a (formula 1 wherein R=hydroxymethyl) 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 product to give a compound of the following formula 4;

(2) aldehyde or amidation of a compound of formula 4, followed by reacting the resulting compound with a compound of formula 5 and performing a 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 performing deprotection and reduction.

in formulas

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

n is 1 or 2;

PG is a protecting group;

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

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

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

(iii) reacting a compound of formula 2c with a halogenating reagent to give the next halogenated compound of formula 2d; and

(iv) the compound of formula 2d is subjected to a Sandmeyer reaction.

In the formulas, Y represents halogen.

The term "halogen" as used herein means 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 give a compound of formula 4.

Thus, prior to binding to the glucose group, and also prior to the formation of the terminal residue (ie ring B) of the aglycone group, a pentagonal or hexagonal ring can be pre-formed, which contains the oxygen in the aglycone group.

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

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

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

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

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

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

[Formula 2e]

In the formula, X and Y are each independently 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 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 a 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 a 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 a compound of formula 3d.

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

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

According to an example, the cyclization reaction can be carried out by adding a Vilsmeier reagent to a compound of formula 3d. The reaction at this time can be carried out at a temperature from 0°C to normal temperature. From the viewpoint of yield, it is preferable that the above Vilsmeier reagent is obtained directly from the synthesis 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 yet another example, the cyclization reaction can be carried out using a halide such as I ₂ and PBr ₃ . According to yet another example, the cyclization reaction can also be carried out by a Mitsunobu reaction using diisopropyl azodicarboxylate (DIAD) or the like.

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

Stage (2)

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

For example, step (2) may include aldehydeation of a compound of formula 4 to give a compound of the following formula 4a, and then reacting 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 a compound of formula 4 to give a compound of the following formula 4c, followed by reacting compounds of formula 4 with pyridinium chlorochromate (PCC), magnesium dioxide, a 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.

In this case, a reducing agent such as NaBH ₄ and LiBH ₄ can be used during the reduction of the compound of formula 4. In addition, alcohol, tetrahydrofuran (THF) or a mixture thereof can be used as a solvent during the reduction. As a preferred example, a mixed solvent consisting of ethanol and THF may be used during the reduction, and its mixing ratio by volume may be 1:1-1:3. In addition, a Lewis acid can be additionally used during reduction, and examples of a 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 give a compound of the following formula 6a:

[Formula 6a]

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

As another example, step (2) may include amidating a compound of formula 4 to give 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. As a result, a form of Weinreb amide such as formula 4b can be obtained.

The compound of formula 4b can then be reacted with a compound of formula 5 to give 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 a compound of formula 6.

The compound of formula 5 may be a Grignard reagent.

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

[Formula 5a]

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

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

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 coupling with the glucose group, a complex synthesis process is required at the end of the synthesis pathway, and thus there is the problem that the reaction yield and the reproducibility of the reaction change significantly due to the long process.

Stage (3)

In step (3), a 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, t-butyllithium, isopropylmagnesium chloride (i-PrMgCl) or the like.

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

[Formula 7a]

In formula A is oxygen or sulfur; n is 1 or 2; X is halogen; PG is 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 obtain a 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 a compound of formula 7a, whereby a compound of formula 1a can be obtained .

In addition, after removal of the protecting group, reduction can be further carried out to obtain a 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 by 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 deprotection and reduction process, isolation of only the compound in which glucose is in the β-form can be further carried out.

For example, a protecting group is introduced into a compound obtained by deprotection and reduction. Then the resulting product is 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.

In particular, the hydroxy group of glucose in the compound obtained by deprotection and reduction is protected by an acetyl group or the like. Then, the resulting product is 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 is halogen; PG is a protecting group; and B is as defined above in Formula 1.

The compound of formula 7b can then be deprotected, ultimately yielding 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) may be carried out in a manner 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, t-butyllithium or isopropylmagnesium chloride to give a compound of the following formula 7a;

(3a-2) deprotection and methylation of a compound of formula 7a under acidic conditions in the presence of methanol to give a compound of the following formula 7d;

(3b) restoring a compound of formula 7b to give a compound of the following formula 7e; and

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

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

After the reaction in step (3a-1), it is preferable that the compound of formula 7a be 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) may be carried out in a manner 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, t-butyllithium or isopropylmagnesium chloride, and subjecting the resulting product 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 a compound of formula 7e to isolate the β-form only 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 step, each of the compounds of formula 7 and a reaction reagent (i.e., n-butyllithium, sec-butyllithium, t-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 a compound of formula 6. The reaction may be carried out at a temperature 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. Further, as the reaction solvent, a single solvent of tetrahydrofuran or ether, a mixed solvent of tetrahydrofuran and toluene (1:1) or the like can be used.

In addition, in step (3a'), the 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 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 may be carried out at a temperature in the range from 0°C to 40°C, and more preferably from 20°C to 30°C, 6 to 24 hours or 6 to 12 hours. As the reaction solvent, methanol or the like can be used.

Then, in step (3b'), a reduction reaction is carried out, and a reducing agent and an acid can be used at this step. Examples of the reducing agent may include triethylsilane, triisopropylsilane, t-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 of 2 to 5 equivalents, and more preferably about 3 equivalents, and the acid can be used in an amount of 1.5 to 3 equivalents, and more preferably about 2 equivalents. While 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. one).

Then, in step (3c'), a protecting group is introduced, and at this step, a 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 of 4 to 12 equivalents, and more preferably about 8 equivalents, and the base can be used in an amount of 1 to 4 equivalents, and more preferably about 1.5 equivalents. While 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 reagents such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide can be used in this step in an amount of 2 to 12 equivalents, and more preferably about 5 equivalents. While 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 reaction solvent, methanol/water (1:1-3:1), dichloromethane/methanol (1:1-1:2), dichloromethane/ethanol (1:1-1:2), tetrahydrofuran/methanol can be used. (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) may be carried out in a manner comprising the steps of:

(3a'') reaction of a compound of formula 6 with a compound of formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium or isopropylmagnesium chloride, and the resulting product is subjected to deprotection and methylation reactions under acidic conditions in the presence of methanol without separate purification to obtain compounds of the following formula 7d;

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

(3c") isolation of only the β-form of the compound of formula 7f and carrying out the reduction reaction, and then carrying out the deprotection reaction:

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

In step (3a'') the coupling reaction, deprotection and methylation take place. Here, the 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, a reaction can be carried out using an acetylating agent and a base. Preferred conditions such as type of acetylating agent, type of base, equivalent ratio, reaction temperature and solvent are as illustrated in step (3c') above.

Next, the reduction reaction in step (3c'') is carried out. In this step, a reducing agent and an acid can be used, and the 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 the 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 obtaining the compound of formula 7d can be carried out in two stages or can be carried out in one stage in the form of an in-situ reaction, whereby the final yield is further increased. In addition, in the case of carrying out the preparation 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, a compound of formula 7d may form an azeotrope with an organic solvent such as toluene, and the residue obtained by repeating the concentration process to remove residual moisture may be used in the next step, or (ii) after synthesis, a compound of formula 7d may be subjected to crystallization and the volume of solid obtained by removing residual moisture by vacuum drying may be used in the next step.

Alkylation step

In addition, according to the present invention, it is possible to further include an alkylation reaction after step (3), and as a result, X' in formula 1 may be C _1-7 alkyl.

For example, the product after step (4) may be reacted with methylboronic acid to give a compound of formula 1a in which X' is substituted 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 physico-chemical 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, crystal 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, the 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, crystal 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.

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

In accordance with another aspect of the present invention, there is provided a process for the preparation of a compound of formula 1b (formula 1 wherein R=C _1-7 alkylthio and A=oxygen), the process 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 product to give a compound of the following formula 4;

(2) aldehyde or amidation of a compound of formula 4, followed by reacting the resulting compound with a compound of formula 5 and carrying out 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 a reduction to obtain a compound of the following formula 9;

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

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

In the formulas

R is C _1-7 alkylthio;

n is 1 or 2;

PG is a protecting group;

X' is halo 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 preparing a compound of formula 1a (formula 1 in which R=hydroxymethyl).

Steps (3) -(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 give a compound of formula 9.

The compound of formula 8 can be obtained in accordance with a known method, for example the method described in WO 2009/014970. In particular, the compound of formula 8 can be obtained in accordance with 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 give 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 a compound of formula 9.

Stage (4)

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

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

Stage (5)

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

C _1-7 alkyl halide may be, for example, 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 in which X' is C _1-7 alkyl can be obtained.

crystalline form

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

As an 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 obtained by the method described above for the preparation of the compound of formula 1a.

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

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

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

In addition, the crystalline form may have an endothermic peak in which the starting point corresponds to about 157°C, and the lower point corresponds to 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 case of irradiation using Cu-K _α radiation source. These peaks may be peaks with a relative intensity (I/I _o ) of about 5% or more, and preferably about 10% or more.

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 start point corresponds to about 79°C and the bottom point corresponds to about 88°C, and an endothermic peak in which the start point corresponds to about 103°C and the bottom point corresponds to about 111°C. C, at DSC (10°C/min).

In addition, the present invention relates to the 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 case of irradiation using Cu-K _α radiation source. These peaks may be peaks with a relative intensity (I/I _o ) of about 5% or more, and preferably about 10% or more.

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 bottom point is about 159°C, at DSC (10°C/minute).

In addition, the present invention relates to the 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 case of irradiation using 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 lower 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 thus can be easily processed in various applications (eg, in the manufacture of pharmaceuticals).

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 only intended to illustrate the present invention, and the scope of the present invention is not limited to these examples.

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

- AcOH: Acetic acid

- ACN: Acetonitrile

- Ac ₂ O: Acetic anhydride

- BF ₃ .OEt ₂ : Boron trifluoride etherate

- DIPEA: N,N-diisopropylethylamine

- DCM: Dichloromethane

- DMAP: 4-Dimethylaminopyridine

- DMF: N,N-Dimethylformamide

- EtOAc: Ethyl acetate

- EtOH: Ethanol

- Et ₃ SiH: Triethylsilane

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

- Hex: Hexane

- i-PrOH: Isopropyl alcohol

- MeI: Iodomethane

- MeOH: Methanol

- MsCl: Mesyl chloride

- NaOMe: sodium methoxide

- NBS: N-bromosuccinimide

- PCC: Pyridinium chlorochromate

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

- TEA: Triethylamine

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

- THF: Tetrahydrofuran

- TMSOTf: Trimethylsilyl trifluoromethanesulfonate

- K.T. or R.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 Pat. Laid-open Publication No. 2015/0152075. For the specific synthesis steps of Comparative Example 1, reference is made to Scheme 1 as described above in the Background section.

Stage 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 give the title compound crude (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.

Stage 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 atmosphere 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 (broad s, 2H), 3.87 (s, 3H); [M+H] ⁺ 182.

Stage 3: Methyl 2-amino-5-bromo-3-methoxybenzoate (compound c4 )

To a solution of methyl 2-amino-3-methoxybenzoate (22.4 g, 123 mmol) in DMF (250 ml) was added N-bromosuccinimide (21.9 g, 123 mmol) in portions 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×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 (broad s , 1H), 3.87 (s, 3H); [M+H] ⁺ 260.

Stage 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 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. 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.

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

Stage 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 aqueous 5N NaOH drop by drop at 0°C. The mixture was stirred at room temperature for 1 hour. To the mixture was added conc. HCl for acidification 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.

Stage 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 of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried in 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).

Stage 7: (5-Bromo-2-chloro-3-hydroxyphenyl)(phenyl)methanone (compound c8 )

The crude 5-bromo-2-chloro-3-methoxybenzoyl chloride was dissolved in benzene (100 ml) and cooled to 0°C. 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 vacuo. The residue was cooled to 0°C and was added an aqueous solution of 1N HCl. 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).

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

Stage 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%).

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

Stage 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%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.27 (m, 2H), 7.25-7.22 (m, 1H), 7.21-7.17 (m, 2H), 6.92 (d, J=2.4 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.10-6.00 (m, 1H), 5.48 (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) was added dropwise n-butyllithium (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 saturated NaHCO ₃ solution at 0°C. The mixture was evaporated under reduced pressure to remove volatiles. The aqueous residue was extracted with EtOAc (100 ml x 2). The combined organic layers were dried over MgSO 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) were added dropwise 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 sat. NaHCO ₃ 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) were 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. 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%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31-7.27 (m, 2H), 7.22-7.21 (m, 1H), 7.19-7.16 (m, 2H ), 7.09 (d, J=1.6 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 6.12-6.03 (m, 1H), 5.47 (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) was added NaH (60% dispersion in mineral oil, 842 mg, 21.0 mmol) at 0°C and stirred 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 (dQ, J=17.2, 1, 6 Hz, 1H), 5.31 (dkv, J=10.8, 1.6 Hz, 1H), 4.94 (ABq, J _AB =15.2 Hz, 2H), 4.90 (d, J =10.8 Hz, 1H), 4.70-4.64 (m, 2H), 4.57 (d, J=12.4 Hz, 1H), 4.52-4.49 (m, 2H) , 4.46 (d, J=10.8 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 give the title compound (1.62 g, 95%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.31 (m, 13H), 7.27-7.21 (m, 8H), 7.18-7.16 (m, 2H), 7.08 (d, J=2.0 Hz, 1H), 6.98 (dd, J=7.6, 2.0 Hz, 2H), 6.89 (d, J=2.0 Hz, 1H ), 4.93 (ABq, J _AB =16.0 Hz, 2H), 4.89 (d, J=10.8 Hz, 1H), 4.67 (d, J=4.8 Hz, 1H) , 4.64 (d, J=6.0 Hz, 1H), 4.57 (d, J=12.4 Hz, 1H), 4.46 (d, J=10.4 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) were 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 compound 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 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 )

A mixture of 6-benzyl-7-chloro-4-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2 -yl)-2,3-dihydrobenzofuran (6.0 g, 7.82 mmol) and Pd/C (0.35 g, 2.54 mmol) in MeOH (220 mL)/THF (220 mL) were stirred for 5 hours at room temperature under H ₂ atmosphere. The resulting mixture was filtered to remove inorganic substances through celite. The filtrate was concentrated in vacuo to give the title compound (quantitative). The crude product was used in the next step without further purification.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.28-7.14 (m, 5H), 6.89 (s, 1H), 4.65 (t, J=8.6 Hz, 2H), 4.17 (d, J=8.8 Hz, 1H), 4.07 (ABq, Δν _AB =18.0 Hz, J _AB =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) were 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, 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 (4.54 g, 100%).

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

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) were added dropwise 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%).

¹ H 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) was added slowly sodium borohydride (0.12 g, 3.24 mmol) at -20°C, and then to the mixture was added dropwise MeOH (0.24 ml). 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 )

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(7-chloro-6-(4-(1-hydroxyethyl)benzyl)-2,3-dihydrobenzofuran-4-yl)tetrahydro mixture -2H-pyran-3,4,5-triyl triacetate (520 mg, 0.84 mmol) and p-toluenesulfonic acid monohydrate (16 mg, 0.084 mmol) in toluene (10 mL) was stirred 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%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.30 (m, 2H), 7.12-7.10 (m, 2H), 6.71-6.63 (m, 1H), 6.55 (s, 1H), 5.71-5.66 (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, diodomethane (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%).

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

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. The resulting mixture was filtered to remove inorganic substances. 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 overall yield of the final compound of Comparative Example 1 according to the synthesis route of Steps 1 to 26 above 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 (ABq, Δν _AB =19.0 Hz, J _AB = 15.2 Hz, 2H), 3.87-3.84 (m, 1H), 3.67-3.63 (m, 1H), 3.47-3.37 (m, 3H), 3 .35-3.33 (m, 3H), 1.85-1.79 (m, 1H), 0.91-0.86 (m, 2H), 0.61-0.57 (m, 2H) ; [M + Na] ⁺ 469.

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

Stage 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) mmol) at 0°C under 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 )

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 allowed 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 extinguished with 1 M HCl (50 ml), then was extracted with EtOAc (150 ml × 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.

¹ H 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

_{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 insolubles. The filtrate was poured into a saturated solution of Na ₂ S ₂ O ₃ (100 ml) and the mixture was extracted with EtOAc (200 ml × 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 under nitrogen. 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 × 2) [One extraction may not be enough]. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo (19.9 g). To a suspension of the residue in EtOAc (20 ml) was added hexane (10-20 ml). The resulting precipitate was collected by filtration and washed with hexane (50 ml). The precipitate was dried under high vacuum to give the title compound (14.3 g, 72%).

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

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 h (solution color 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 to another (the color of the solution returned to yellow). Sodium borohydride (2.5 g, 66.8 mmol) was added in portions at -78°C. The resulting mixture was slowly warmed to room temperature over 2 h, 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% pure). The precipitate was suspended in EtOAc and stirred. Hexane was slowly added to the resulting mixture. A precipitate was obtained by filtration to give the title compound (7.9 g, 76.4%, 92% pure).

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 the Vilsmeyer reagent; To a solution of N,N-dimethylformamide (7.9 ml, 102.2 mmol) was added SOCl ₂ (7.5 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 give a hygroscopic white solid.

To a mixture of Vilsmeier's reagent (13.08 g, 102.2 mmol) in DMF (100 ml) was slowly added methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (21.08 g, 68.10 mmol) in DMF (130 ml) at 0°C. The mixture was stirred 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 min, 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.

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

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 a saturated solution of NH ₄ Cl at 0°C and was extracted with EtOAc (aqueous, 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.

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

Stage 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) , 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 )

Obtaining (4-cyclopropylphenyl)magnesium bromide (compound c38 ); A 250 ml three-necked 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 under a nitrogen atmosphere. 4-Cyclopropylphenyl bromide (PepTech, USA) (6.0 ml, 42.4 mmol) in anhydrous THF (32.4 ml) was transferred to an addition funnel. The Grignard reaction was initiated with approximately 5 ml of a solution of 4-cyclopropylphenyl bromide. 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 min. 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%).

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

Step 10: (3R,4S,5R,6R)-2-(7-Chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-3,4,5-tris(trimethylsilyloxy)- 6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-ol (compound c41 )

To a solution of 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (5.16 g, 14.2 mmol) in tetrahydrofuran (80 ml), M in hexane, 7.38 ml, 18.4 mmol) at -78° C. under nitrogen. After stirring for 40-60 min at the same temperature (yellowish solution), a pre-cooled (at -78°C) solution of (3R,4S,5R,6R)-3,4,5-tris ((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (compound c11 ; 8.6 g, 18.4 mmol) in tetrahydrofuran (20 mL) via 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 by drops. The mixture was heated 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 volatiles. 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% 2 steps) 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 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 × 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 appeared within 1 h. 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.

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

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 solution (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 formed) and cooled to room temperature. The suspension was filtered in a filter funnel, and the filter cake was washed with toluene in a volume equal to two volumes of the filter cake. The filter cake was dried in vacuo to give 1.0 g (2.24 mmol; quantitative) of the title compound.

It was determined that the total yield of the final compound of example 1 in accordance with the way of synthesis of the above stages 1-14 is about 12%.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.02 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 4.11 (d, J=9.2 Hz, 1H), 3.96 (ABq, Δν _AB =19.0 Hz, J _AB = 15.2 Hz, 2H), 3.87-3.84 (m, 1H), 3.67-3.63 (m, 1H), 3.47-3.37 (m, 3H), 3 .35-3.33 (m, 3H), 1.85-1.79 (m, 1H), 0.91-0.86 (m, 2H), 0.61-0.57 (m, 2H) ; [M + Na] ⁺ 469.

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- Butyl lithium ( 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 performed extraction 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 performed extraction 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 extracted 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 suspended residue 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 β-form as a white solid.

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

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) NaOMe (25 wt%, 0.35 ml) was added. 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 (ABq, ΔνAB=19.0 Hz, JAB= 15.2 Hz, 2H), 3.87-3.84 (m, 1H), 3.67-3.63 (m, 1H), 3.47-3.37 (m, 3H), 3.35 -3.33 (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 obtain (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 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 atmosphere was added n-butyllithium (2.5 M in hexane, 1.3 ml, 3.24 mmol) was dropped, 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 H. Driguez and B. Henrissat, Tetrahedron Lett 1981, 22, 5061-5062, Kakinuma, H., et al., J. Med Chem 2010, 53, 3247 -3261) in tetrahydrofuran (4 ml) and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was quenched by adding saturated ammonium chloride solution. After completion of the addition, 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).

Stage 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 -20° C. stirred solution of lactol ( c52 ) in dichloromethane (16 ml) was added triethylsilane (1.6 ml, 9.72 mmol) followed by boron trifluoride diethyl etherate (0.8 ml, 6.48 mmol) with 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 removal of 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 steps) 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) BCl ₃ (1.0 M in dichloromethane, 2.8 ml) was added 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 reverse phase preparative 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

To a suspension of L-(-)-xylose (19.15 g, 127.5 mmol) and MgSO ₄ (30.72 g, 255.0 mmol) in acetone (190 ml) was added concentrated H ₂ SO ₄ (1.9 ml) at room temperature. After 12 hours, the reaction mixture (in which all L-(-)-xylose was 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 with 1N 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 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 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=3.6Hz, 1H), 4.36(d, J=3.6Hz, 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) 4-methylmorpholine (7.3 ml , 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 filter cake 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 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) 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 had 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 warmed to 0°C and extinguished 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 )

(3aS,5S,6R,6aS)-5-((S)-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-4-yl)(hydroxyl)methyl]-2,2 solution -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 over 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 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) was added TMSOTf (70 μl, 0.39 mmol) 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) NaOMe (catalytic amount, 25% solution in CH ₃ OH) was added 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%).

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

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 of Example 4 except that 4-bromo-7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzofuran was used in step 4 instead of 4-bromo-7-chloro -6-(4-ethylbenzyl)-2,3-dihydrobenzofuran.

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

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 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 (642g, 1.38mol) and anhydrous tetrahydrofuran (2.00L) at room temperature under nitrogen atmosphere, and the mixture was completely dissolved. After the reaction vessel was cooled to -78°C, n-butyl lithium (550 ml, 2.0 M in hexane, 1.38 mol) was added dropwise over 1 hour while maintaining the internal temperature at -60°C or below. After completion of the dropwise addition of n-butyllithium, 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 while maintaining the internal temperature at -30° C. or lower. After completion of the dropwise addition, the reaction vessel was placed at room temperature and stirred for 18 hours. After confirming completion of the reaction, the reaction vessel was cooled to 0°C, saturated aqueous NaHCO ₃ (2.5 L) 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 (2.5 L), distilled water (1.25 L) and brine (1.25 L) and layers formed. Then the organic layers were 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 the reaction vessel was cooled to -78°C, n-butyl lithium (22.1 ml, 2.5 M in hexane, 54.9 mmol) was added dropwise over 15 minutes while maintaining the internal temperature at -60°C or below. After completion of the dropwise addition of n-butyllithium, 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 while maintaining the internal temperature at -30° C. or lower. After completion of the dropwise addition, the reaction vessel was placed at room temperature and stirred for 18 hours. After the completion of the reaction was confirmed, the reaction vessel was cooled to 0°C, a saturated NaHCO ₃ aqueous solution (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 formed. Then the organic layers were combined and the aqueous layer was extracted with EtOAc (2×30 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 stirring the hexane. The resulting suspension was stirred at the same temperature for 1 hour and then filtered under 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 less, as determined 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 path 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 added dropwise Et ₃ SiH (329 ml, 2.08 mol) and BF ₃ -OEt ₂ (170 ml, 1.37 mol) over 10 minutes, maintaining the internal temperature at -45°C or lower. The reaction mixture was slowly heated to -10°C for 1 hour and the resulting mixture was heated to 0°C. After stirring for 3 hours at 0°C, a saturated NaHCO ₃ aqueous 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 extracted. 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 successively added dropwise to the reaction vessel at room temperature while a solution of CH ₂ Cl ₂ (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 separated 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 give 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 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 the reaction vessel was cooled 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 loosened up. 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 give the crude title compound.

The crude title compound was diluted with EtOAc (3.89 L) and then stirred at reflux for 30 minutes until complete dissolution of the solid. Then the resulting product was 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 drop time). The procedure for adding isopropyl ether was repeated twice. Then the reaction vessel was 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 give the title compound (236 g, yield: 92%, purity: >99.7%) as a white solid. In addition, it was determined that the total yield of the final compound of example 6, in accordance with the way of synthesis of the above stages 1-4, is 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 )

According to reaction route 1b, 4-bromo-7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran (21.6 g) was used in Step 1 of Example 6 to give the title compound (26.2 g, 93 %) as 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 successively added dropwise to the reaction vessel at room temperature while stirring a solution of (3R,4S,5S,6R)-2- [7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl]-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (26.2 g , 55.0 mmol) in 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 loosened up. 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 -2 H -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) while stirring at room temperature. After the reaction vessel was cooled to 0°C, Et ₃ SiH (9.89 ml, 62.0 mmol) and BF ₃ -OEt ₂ (4.96 ml, 40.3 mmol) were added dropwise successively over 10 minutes, maintaining internal temperature at 5°C or lower. The reaction mixture was stirred at 5°C or below for 1 hour. Then the reaction mixture was heated to 10°C and further stirred for 2 hours. A saturated NaHCO ₃ aqueous solution was added to the reaction mixture, and the pH value was confirmed to be 7.0-7.5 using a pH meter. The organic solvent was then removed using a vacuum concentrator. The concentrate was diluted with EtOAc (50 ml) and the organic layer was isolated. The aqueous layer was extracted with EtOAc (2×30 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 further 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 )

According to 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 complete dissolution of the solid. 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 drop time). The process of adding isopropyl ether was repeated twice. Then the reaction vessel was 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 give the title compound (2.93 g, yield: 92%, purity: >99.5%) as a white solid. It was determined that the total yield of the final compound of example 2, in accordance with the way of synthesis of the above stages 1-4, is about 60%.

Experimental Example 1 Evaluation of Yield Depending on Rearrangement Reaction Conditions

(1) Reaction with or without amine solvent

Methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate (compound c30 ), as starting material, was subjected to a rearrangement reaction at 160°C, resulting in 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.

The result was a maximum yield of 67% and no further increase.

[Table 1]

Test No. Purification of the original substance Amount of original substance (g) Reactive solvent Reaction temperature(°C) Reaction time(h) Product quantity (g) Exit (%) one 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 eighteen 7.1 67 four unrefined 5.4 DEA (5M) 160 24 3.4 63 5 unrefined ten DEA (5M) 160 13 5.7 57 6 unrefined one - 160 6 0.2 twenty 7 unrefined ten - 160 5 2.9 29 eight unrefined ten - 160 13 5.8 58 9 unrefined 18.6 - 160 12.5 11.1 60 ten unrefined 13.6 - 160 12 8.7 64 eleven unrefined ten - 160 eighteen 6.1 61 12 Purified 10.5 - 160 12.5 4.8 46 13 Purified 9.9 - 160 eighteen 3.3 33

(2) Lewis acid addition reaction

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

Meanwhile, the reaction solvent, the reaction temperature, and the Lewis acid were adjusted as shown in Table 2 below, and the reaction was carried out with or without addition of the Lewis acid.

As a result, in the case where diisobutylaluminum chloride ((i-Bu) ₂ AlCl) or diethylaluminum chloride (Et ₂ AlCl), which is a Lewis acid, was added, the yield increased to 80%.

[Table 2]

Test No. Lewis acid Reactive solvent Reaction temperature Exit one BCl _{3 CH2Cl2 _} -25°C - R.T. 17% 2 (i-Bu) ₂ AlCl Hexane/CH ₂ Cl ₂ 0°C - R.T. 71% 3 TiCl ₄ Methylimidazole k.t. unreacted four TiCl _{4 CH2Cl2 _} k.t. unreacted 5 - Water k.t. unreacted 6 BF ₃ .OEt _{2 CH2Cl2 _} 0°C - R.T. unreacted 7 AlCl _{3 CH2Cl2 _} 0°C - R.T. 35% eight (i-Bu) ₂ AlCl Hexane/CH ₂ Cl ₂ 0°C - R.T. 80% 9 _Et2AlCl Hexane/CH ₂ Cl ₂ 0°C - R.T. 72%

Experimental Example 2 Evaluation of Yield Depending on Cyclization Reaction Conditions

(1) Cyclization using Vilsmeier's reagent

Obtaining the Vilsmeier 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 give the Vilsmeier reagent which is a hygroscopic white solid.

Obtaining the Vilsmeier 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 give the Vilsmeier 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 Vilsmeier reagent mixture in DMF. The mixture was subjected to a cyclization reaction with stirring for 1 hour to give methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34 ) and its yield was calculated.

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

This resulted in 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 original substance The amount of the original substance Vilsmeyer reagent Reaction temperature Product color Product Quantity Exit one brown solid Reagent manufactured by Sigma-Aldrich Co. LLC -20°C Light yellow 66% 2 brown solid Production Reagent A -20°C Light yellow 70% 3 brown solid Production Reagent A -20°C Light yellow 70% four White solid Production Reagent A 0°C - 15°C Light yellow 80% 5 Viscous brown solid Production Reagent A 0°C - 15°C Light yellow 13% 6 brown solid Production Reagent B 0°C - 15°C Light brown 81%

(2) Cyclization using a leaving group

To methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate (compound c33 ), as a starting material, was added mesyl chloride (MsCl) 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.

Here, the amount of the reagent used, the method of addition, 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 disadvantage caused by an equivalent MsCl control and dropwise addition.

[Table 4]

Test No. Reagent Solvent Adding method Reaction temperature Reaction time Product (c34) output By-product (c34-1) output one MsCl 1.1 equiv. Pyridine/DCM Addendum -18°C During the night 62% 34% 2 MsCl 3.3 equiv. Pyridine/DCM Drop by drop over 2 hours k.t. During the night 19% 35% 3 MsCl 3.3 equiv. Pyridine/DCM Drop by drop over 2 hours k.t. 1 hour 46% 47% four MsCl 1.2 equiv. Pyridine/DCM Drop by drop over 2 hours 0°C 1 hour 51% 46% 5 MsCl 1.2 equiv. Pyridine/DCM Drop by drop over 2 hours 55°C 1 hour 86% 9% 6 MsCl 1.1 equiv. Pyridine/DCM Adding a small amount 55°C 1 hour 71% 7 MsCl 1.1 equiv. Pyridine/DCM Adding a small amount 55°C 1 hour 56% eight MsCl 1.1 equiv. Pyridine/DCM Drop by drop 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 a starting material, was subjected to a cyclization reaction using a halide or a Mitsunobu reaction to give methyl 4-bromo-7-chloro -2,3-dihydrobenzofuran-6-carboxylate (compound c34 ) and its yield was calculated.

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

This resulted in a yield of up to about 60%. However, there was a difficulty due to the need to remove triphenylphosphine oxide, which is a by-product formed after the reaction.

Experimental Example 3 Evaluation of Yield Depending on Reduction Reaction Conditions

To methyl 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carboxylate (compound c34 ), as starting material, was added NaBH ₄ (3 eq.) and either or no Lewis acid was added. The mixture was then subjected to a reduction reaction in a solvent at room temperature to obtain (4-bromo-7-chloro-2,3-dihydrobenzofuran-6-yl)methanol (compound c35 ) and 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 became 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. Reactive solvent NaBH ₄ (equiv.) Lewis acid Reaction result (mass ratio) (substance: product: by-product 1) one methanol 3.0 - 68:31:- 2 ethanol 3.0 - -:77:21 3 THF/methanol (1:1) 3.0 - 52:43:- four 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 equiv.) 52:43:- eight THF/ethanol (1:1) 3.0 LiCl (1.5 equiv.) -:93:6

(2) Without adding a 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 the 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 any by-product.

[Table 6]

Test No. Reagent NaBH ₄ (equiv.) Reaction result (mass ratio) (determined substance: product: by-product 1: by-product 2) one methanol 3.0 68:31:-:- 2 ethanol 3.0 -:77:21:- 3 THF/methanol (1:1) 3.0 52:43:-:- four 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: -: - eight THF/ethanol (5:1) 3.0 30:60:-:10 9 THF/ethanol (10:1) 3.0 -:70: -:30 ten 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:- fourteen THF/ethanol (2:1) 1.5 18:58:24:- fifteen 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 THF/i-PrOH mixture 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 more was obtained even when only NaBH ₄ was used without a Lewis acid.

[Table 7]

Test No. Reagent NaBH ₄ (equiv.) Lewis acid Reaction result (mass ratio) (determined substance: product: by-product 1) one 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 equiv.) 70:30:- four THF/ethanol (1:1) 2.4 CaCl ₂ (1.2 eq.) -:100: - 5 THF/ethanol (1:1) 3.0 CaCl ₂ (1.5 equiv.) -:100: - 6 THF/ethanol (2:1) 3.0 - -:100: - 7 THF/isopropanol (1:1) 3.0 CaCl ₂ (1.5 equiv.) 100: -: -

Experimental Example 4: Obtaining and Analyzing the Crystal Form

From the compound obtained according to the method of the present invention, in particular the 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 obtained in accordance with steps 1-14 in example 1, was obtained crystals through a crystallization process in various solvents and analyzed.

For the XRD spectrum, X-ray powder diffraction was determined using an X-ray diffractometer by irradiating 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) Obtaining a crystal using the solvent of toluene

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, stirring was additionally 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 obtained crystal showed a crystal form (crystal form A) as shown in Fig. 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 FIG. 2, the DSC spectrum confirmed the endothermic melting peak of the crystal.

(2) Preparation of a crystal using an ethyl acetate solvent

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 mass of c28 ) by stirring at reflux and then cooled to room temperature. After the suspension was formed at room temperature, stirring was additionally performed for 30 minutes. Isopropyl ether (15 times by weight of c28 ) was added dropwise to the resulting mixture over 30 minutes, and stirring was further performed at room temperature for 30 minutes. The resulting precipitate was filtered, washed with 0° C. ethyl acetate (2x c28 by mass), and then dried in a vacuum oven (50° C., 12 hours) to give a white crystal (yield: 88.3%). XRD spectral analysis of the obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(3) Preparation of a crystal using dichloromethane solvent

The crude compound c28 was dissolved in dichloromethane (170 times the mass 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 relative to c28 mass), and then dried in a vacuum oven (50° C., 12 hours) to give a white crystal (yield: 50.1%). XRD spectral analysis of the obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(4) Obtaining a crystal using acetone solvent

The crude compound c28 was dissolved in acetone (35 times the mass of c28 ) by performing heating under reflux, and then cooled to room temperature. After the suspension was formed at room temperature, further stirring was 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 obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(5) Crystal preparation using acetonitrile solvent

The crude compound c28 was dissolved in acetonitrile (10 times the mass of c28 ) by heating at 60°C, and then cooled to room temperature. After the suspension was formed at room temperature, stirring was further performed 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 obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(6) Obtaining a crystal using 2-propanol solvent

A solution of the crude compound c28 A in 2-propanol (10 times the mass of c28 ) was dissolved by heating at 60°C and then cooled to room temperature. After the suspension was formed at room temperature, further mixing was performed for 30 minutes. To the reaction mixture was further added dropwise 2-propanol (5 times the mass of c28 ), 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 give a white crystal (yield: 9.5%). XRD spectral analysis of the obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(7) Crystal preparation using tetrahydrofuran/dichloromethane solvent

The crude compound c28 A was dissolved in tetrahydrofuran (5 times the amount by weight of c28 ) by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The concentrated residue was diluted with dichloromethane (30-fold by weight 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 obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(8) Crystal preparation using tetrahydrofuran/n-hexane solvent

The crude compound c28 was dissolved in tetrahydrofuran (5 times the amount by weight of c28 ) while stirring at room temperature for 30 minutes. n-hexane (10 times by mass c28 ) was added dropwise to the reaction mixture, and stirring was performed for 1 hour. To the resulting suspension, n-hexane (10 times by mass c28 ) was further added dropwise, and then stirring was performed for 30 minutes. n-hexane (5-fold by weight of c28 ) was added dropwise repeatedly 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 obtained crystal showed a crystal form (crystal form A) similar to that shown in item (1) of Experimental Example 4.

(9) Crystal preparation using methanol/distilled water solvent

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

The XRD spectrum of the obtained crystal showed a crystal form (crystal form B) similar to that shown in Fig. 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 FIG. 4, the DSC spectrum made it possible to confirm the endothermic peak of crystal melting.

(10) Crystal preparation using methanol/n-hexane solvent

The crude compound c28 A was dissolved in methanol (5 times the amount by weight of c28 ) while stirring at room temperature for 30 minutes. n-hexane (15 times by weight c28 ) was added dropwise to the reaction mixture and stirred for 30 minutes. To the resulting suspension was further added dropwise n-hexane (10-fold by weight of c28 ) and stirred for 1 hour. The resulting precipitate was filtered, washed with n-hexane (5 times the volume of the filtrate), and then dried in a vacuum oven (50° C., 12 hours) to obtain a white crystal (yield: 97.1%). XRD spectral analysis of the obtained crystal showed a crystal form (crystal form B) similar to that shown in item (9) of Experimental Example 4.

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

The crude compound c28 was dissolved in dichloromethane/methanol (20:1 by weight c28 ) while stirring at room temperature for 30 minutes. n-hexane (10 times by weight c28 ) was added dropwise to the reaction mixture and stirred for 1 hour. To the resulting suspension was further added dropwise n-hexane (10-fold by weight of c28 ) and stirred for 30 minutes. n-hexane (5-fold by weight of c28 ) was added dropwise repeatedly 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 obtained crystal showed a crystal form (crystal form B) similar to that shown in item (9) of Experimental Example 4.

(12) Crystal preparation using tetrahydrofuran/toluene solvent

The crude compound c28 was dissolved in tetrahydrofuran (5 times the amount by weight of c28 ) while 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-fold by weight 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 obtained crystal showed a crystal form (crystal form C) similar to that shown in FIG. .

[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 confirmed the endothermic melting peak of the crystal.

(13) Crystal preparation 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 (10 times by weight) was added dropwise to the reaction mixture.c28) and stirring was carried out for 1 hour. Distilled water (10 times the amount by weight) was added dropwise to the resulting suspension.c28) and carried out was stirred for 30 minutes. To the reaction suspension was added dropwise n-hexane (1-fold by weightc28) and carried out was 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: 95.8%). XRD spectral analysis of the obtained crystal showed a crystal form (crystal form C) similar to that shown in item (12) of Experimental Example 4.

(14) Crystal preparation 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 (5 times by weight) was added dropwise to the reaction mixture.c28) and carried out was stirred for 30 minutes. To the resulting suspension was added dropwise n-hexane (10 times the amount by weightc28) and carried out was stirred for 30 minutes. n-hexane (5-fold by weight) was repeatedly added dropwise to the reaction suspension.c28) and carried out was 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: 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 shown 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 confirmed the endothermic melting peak of the crystal.

Experimental Example 5: Confirmation of Crystal Form Stability

Using the crystalline form obtained in item (2) of Experimental Example 4, stability confirmation studies related to properties, identification analysis, moisture content, specific rotation, related substances, and content 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 Accelerated, within 1 month Accelerated, within 3 months Long term, within 3 months Properties White or whitish powder White powder White powder White powder White powder Identification analysis LC Corresponds Corresponds Corresponds Corresponds Corresponds IR Corresponds Corresponds Corresponds Corresponds Corresponds XRD Corresponds Corresponds Corresponds Corresponds Corresponds Humidity (%) 0.5 or below 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 study of properties confirmed the absence of any change in the properties of the crystalline form under the conditions of accelerated and long-term studies.

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

<Analytical Conditions>

- Column: Capcdell-pak C18 MG (USPL1), 250 x 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: 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 crystalline form under the conditions for conducting accelerated and long-term studies.

(4) When measured according to the moisture measurement method, which is among the general test methods prescribed by the Korean Pharmacopoeia, the moisture content test can confirm the results that the crystalline form only slightly has the property of containing moisture under conditions for accelerated and long-term research.

(5) The study confirming the specific rotation can confirm the structural stability of the crystalline form under the conditions for conducting accelerated and long-term studies.

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

Analytical Conditions: Liquid Chromatography Analytical Conditions for Confirmatory Study in Item (2) of Experimental Example 5

- Expression for calculation: 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) For the content test, a methanol solution of the standard product (0.2 mg/mL) was used as the standard solution, and a methanol solution of the crystalline form was used as the sample solution (1 mg/mL). The sample solution and the standard solution were analyzed by liquid chromatography, which is among the general examination methods prescribed by the Korean Pharmacopoeia, and the peak areas of the standard solution and the sample solution were used to perform the calculation using the following expression. 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 confirmatory study in point (2) of Experimental Example 5

- Expression for calculation: 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 (64)

1. A method for obtaining a compound of the following formula 1, comprising the steps: (1) reacting a compound of the following formula 2 with a compound of the following formula 3 and cyclizing the resulting product to give a compound of the following formula 4; (2) the compound of formula 4 is subjected to aldehydeation or amidation, followed by the interaction of the obtained product with the compound of the following formula 5 and carrying out reduction to obtain the compound of the following formula 6; and (3) (a) reacting a compound of formula 6 with either a compound of the following formula 7 and deprotection and reduction to give a compound of formula 1 wherein R is hydroxymethyl, or (b) reacting a compound of formula 6 with a compound of the following formula 8 and reducing to give a compound of the following formula 9, converting the furanose ring of the compound of formula 9 to a pyranose ring under acidic conditions, and then introducing a protecting group thereto to give a compound of the following formula 10; treating a compound of formula 10 with thiourea, reacting the resulting product with a C _1-7 alkyl halide and then carrying out a reduction to obtain a compound of formula 1, where R is a C _1-7 alkylthio; where the cyclization reaction is a cyclization reaction using a Vilsmeier reagent, a cyclization reaction using a leaving group, a cyclization reaction using a halide, or a cyclization reaction using a Mitsunobu reaction

, where in the formulas, A represents oxygen (O) or sulfur (S); R is hydroxymethyl or C _1-7 alkylthio; n is 1 or 2; PG is a protecting group; X' is halogen; X, Y and Hal are each independently halogen; B is (B-1)

, where Rb is hydrogen, Ra is C _1-7 alkoxy or C _3-10 cycloalkyl. 2. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (1) includes the steps of: (i) reacting a compound of formula 2 with a compound of formula 3 to give a compound of the following formula 3a; (ii) the allyl group of the compound of formula 3a is subjected to a rearrangement reaction, and the resulting product is subjected to an oxidation or ozonation reaction, followed by reduction to obtain a compound of the following formula 3d; and (iii) the compound of formula 3d undergoes a cyclization reaction to give a compound of formula 4

, where in the formulas, n, X and Y are as defined in paragraph 1. 3. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (2) comprises aldehydeing a compound of formula 4 to give a compound of the following formula 4a and then reacting a compound of formula 4a with a compound of formula 5 [Formula 4a]

, where in the formula, n, X and Y are as defined in paragraph 1. 4. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (2) comprises amidating a compound of formula 4 to give a compound of the following formula 4b and further reacting a compound of formula 4b with a compound of formula 5 [Formula 4b]

, where n, X and Y are as defined in claim 1. 5. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (3) further comprises isolating only the compound in which the glucose is in the β-form after or during the deprotection and reduction process. 6. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (3) is carried out in a manner 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, t-butyllithium or isopropylmagnesium chloride to give a compound of the following formula 7a; (3a-2) a compound of formula 7a undergoes deprotection and methylation reactions under acidic conditions in the presence of methanol to give a compound of the following formula 7d; (3b) restoring a compound of formula 7d to give a 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

, where in the formulas, PG is a protecting group; and A, B, n and X are as defined in claim 1. 7. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (3) is carried out in a manner 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, t-butyllithium or isopropylmagnesium chloride and subjecting the resulting product 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 a compound of formula 7e to isolate the β-form only and performing deprotection:

, where in the formulas, A, B, n and X are as defined in paragraph 1. 8. A method for obtaining a compound of formula 1 according to claim 1, characterized in that step (3) is carried out in a manner 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, t-butyllithium or isopropylmagnesium chloride and subjecting the resulting product to deprotection and methylation reactions under acidic conditions in the presence of methanol without separate purification to obtain compounds of the following formula 7d; (3b'') introducing a protecting group into a compound of formula 7d to give a compound of the following formula 7f; and (3c'') isolating only the β-form of the compound of formula 7f and carrying out the reduction reaction, and then carrying out the deprotection reaction:

where in the formulas, PG is a protecting group; and A, B, n and X are as defined in claim 1. 9. A method for preparing a compound of formula 1 according to claim 8 or 9, characterized in that each compound of formula 7 and n-butyllithium is used in an amount of 1.5 to 2.5 equivalents relative to 1 equivalent of the compound of formula 6. 10. A method for obtaining a compound of formula 1 according to claim 1, characterized in that the method further comprises the step of performing crystallization using a solvent selected from the group consisting of toluene, ethyl acetate, dichloromethane, a mixture of tetrahydrofuran and dichloromethane, and a mixture of tetrahydrofuran and n-hexane, after step (3). 11. A method for preparing a compound of formula 1 according to claim 1, where n is 1.

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