KR101770302B1 - Method for preparing diphenylmethane derivatives - Google Patents

Abstract

The present invention relates to an improved process for preparing a diphenyl methane derivative which is useful as an inhibitor of a sodium-dependent glucose transporter (SGLT). Since the process of the present invention is performed by convergent synthesis in which main groups are individually synthesized and then coupled, the synthesis route can be simplified, the yield can be increased, and risk elements which are embedded in the sequential synthesis route can be reduced, compared to a linear synthesis method disclosed in the prior art.

Description

[0001] METHOD FOR PREPARING DIPHENYLMETHANE DERIVATIVES [0002]

The present invention relates to a process for preparing diphenylmethane derivatives, and more particularly to an improved process for preparing diphenylmethane derivatives useful as inhibitors of sodium-dependent glucose transporters (SGLT).

Sodium-dependent glucose transporters (SGLT) allow the transport of glucose against concentration gradient and the simultaneous transport of Na ^{+ with} concentration gradient. Currently, two important SGLT isoforms have been cloned and are known as SGLT1 and SGLT2. SGLT1 is located in the bowel, kidney and heart, and regulates cardiac glucose transport through expression. Since SGLT1 is a high-affinity, low-capacity transporter, it plays only part of renal glucose reabsorption. In contrast, SGLT2 is a low affinity high capacity transporter that is predominantly located in the apica domain of the epithelial cells in the early proximal gyrus canaliculus. In healthy individuals, over 99% of the plasma glucose filtered from the renal glomeruli is reabsorbed and less than 1% of the total filtered glucose is excreted in the urine. It is estimated that 90% of renal glucose reabsorption is promoted by SGLT2 and the remaining 10% is mediated by SGLT1 in the late proximal tubule. The genetic mutation of SGLT2 does not adversely affect carbohydrate metabolism, but it causes an increase in renal glucose secretion of about 140 g / day, depending on the mutation. Human mutation studies have been the subject of treatment studies because SGLT2 is thought to be responsible for most renal glucose reabsorption.

US Patent Publication No. 2015/0152075 discloses a compound having a diphenylmethane moiety having an inhibitory activity against SGLT2 and a method for producing the same. This document discloses that the diphenylmethane derivative compound is superior in inhibiting effect on human SGLT2 activity and is significantly effective in treating diabetes by significantly reducing urinary sugar excretion in animals than is known as SGLT2 inhibitor. In addition, US Patent Publication No. 2014/0274918 discloses diphenylmethane derivatives that are effective as dual inhibitors for sodium-dependent glucose transporter 1 (SGLT1) and sodium-dependent glucose transporter 2 (SGLT2) have.

Example 158 of US Patent Publication No. 2015/0152075 and the like discloses a method for producing a diphenylmethane compound c18 in the same manner as in the following Reaction Scheme 1.

[Reaction Scheme 1]

However, according to the above-mentioned conventional method for producing the compound c18, when the aglycon group to be bonded to the glucose group is synthesized, the end of the aglycon (i.e., the cyclopropylphenyl group) is firstly prepared and then the benzodioxole 5 rings are formed by an alkylation reaction. In the case of such a sequential synthesis, not only the final route is complicated, but also the final yield is low. In addition, if the synthesis of the end portion of the aglycon is mistakenly changed or if it is desired to change to another, there is a need to proceed the synthesis again from the beginning. In addition, in the above-mentioned conventional synthesis method, since iron (Fe) is used in the process of producing the compound c5, it is troublesome to process by-products.

Accordingly, the inventors of the present invention have found that a diphenylmethane derivative can be produced efficiently by a convergent synthesis method in which not only the conventional sequential synthesis method as described above but also synthesis and coupling are separately performed for each main group, Step, the main intermediate can be synthesized at a stable high yield, and the present invention has been completed.

US Patent Publication No. 2015/0152075 US Patent Publication No. 2014/0274918

It is therefore an object of the present invention to provide an improved process for preparing diphenylmethane derivatives useful as inhibitors of SGLT.

According to one aspect of the present invention, there is provided a process for preparing a compound of formula (I), comprising: (1) esterifying and halogenating 3,4-dihydrobenzoic acid to obtain a compound of formula (2) reacting the compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4); (3) aldehyde or amidation of the compound of formula (4) followed by reduction with a compound of formula (5) to obtain a compound of formula (6); And (4) reacting the compound of formula (6) with a compound of formula (7), deprotecting and reducing the compound of formula

In this formula,

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

R is hydroxymethyl;

n is an integer of 1 to 3,

PG is a protecting group;

X 'is a halogen or C _1-7 alkyl;

X, Y and Hal are each independently halogen;

또는 (B-2)

이되, B is (B-1)

Or (B-2)

However,

Wherein 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 carbonyl -C _{1 - 7} alkyloxy, C _3-10 cycloalkyl, C _3-7 cycloalkyl, thiophenyl, C _5-10 cycloalkenyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkyloxy ₁ -C _-7 alkoxy, phenyl -C _1-7 alkyl, C _1-7 alkylthio-phenyl, phenyl -C _1-7 alkoxy, mono- or di -C _1-7 alkylamino, mono- or di -C _1-7 alkylamino, -C _1-7 alkyl, C _1-7 alkanoyl, C _1-7 alkanoylamino, C _1-7 alkylcarbonyl, C _1-7 alkoxycarbonyl, carbamoyl, mono- or di -C _{1 -7} alkyl-carbamoyl, C _1-7 alkylsulfonyl amino, phenylsulfonyl amino, C _1-7 alkylsulfinyl, C _6-14 aryl sulfanyl, 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;

It said alkyl, alkenyl, alkynyl and alkoxy are each independently unsubstituted or substituted with halogen, hydroxy, cyano, nitro, amino, mercapto, C _{1 -} to _7-alkynyl-7 alkyl, and C ₂ ≪ / RTI >

Said cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl, each independently, an unsubstituted or halogen, hydroxyl, cyano, nitro, amino, mercapto, C _{1 - 4} alkyl, and C _{1 - 4} alkoxy have one or more substituents selected from the group consisting of;

The heteroaryl and heterocycloalkyl each independently contain 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 the preparation of a compound of formula (I), comprising: (1) esterifying and halogenating a 3,4-dihydrobenzoic acid to obtain a compound of formula (2) reacting the compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4); (3) aldehyde or amidation of the compound of formula (4) followed by reduction with a compound of formula (5) to obtain a compound of formula (6); (4) reacting the compound of formula (6) with a compound of formula (8) and reducing to obtain a compound of formula (9); (5) forming a furanos ring of the compound of formula (9) in a pyranose ring under acidic conditions and introducing a protecting group to obtain a compound of formula (10); And (6) treating the compound of formula (10) with thiourea and reacting with a C _1-7 alkyl halide followed by reduction.

In this formula,

A is oxygen (O);

R is C _1-7 alkylthio;

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

Since the process for producing the diphenylmethane derivative of the present invention is carried out by a convergent synthesis method in which the main groups are separately synthesized and then coupled to each other, the synthetic route is more advantageous than the linear synthesis method disclosed in the prior art It is possible to shorten the yield and to reduce the risk factors inherent in the sequential synthesis path (such as returning to the first path and repeating synthesis in the middle of synthesis).

In particular, according to the method disclosed in the prior art, it is necessary to synthesize residues of the aglycone group even after coupling the glucose group with the aglycone group, whereas according to the present invention, the residues of the aglycone group before the coupling with the glucose group Can be completed. In addition, the aryl group bonded to the terminal group of the aglycon can be easily synthesized, so that various designs of terminal groups are possible.

Also, according to the present invention, it is possible to synthesize an intermediate compound with a stable and high yield while drastically reducing the reaction step for the synthesis of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate, So that the yield and synthesis efficiency of the final compound can be increased.

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

[Chemical Formula 1]

In this formula,

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

R is hydroxymethyl or Ci- ₇ alkylthio;

n is an integer from 1 to 3;

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

또는 (B-2)

이되, B is (B-1)

Or (B-2)

However,

Wherein 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 carbonyl -C _{1 - 7} alkyloxy, C _3-10 cycloalkyl, C _3-7 cycloalkyl, thiophenyl, C _5-10 cycloalkenyl, C _3-10 cycloalkyloxy, C _{3 - 10} cycloalkyloxy ₁ -C _{- 7} alkoxy, phenyl -C _{1 - 6} alkyl, C _{1 - 6} alkylthio-phenyl, phenyl -C _{1 - 6} alkoxy, mono- or di -C _{1 - 6} alkyl, amino, mono- or di -C _{1 - 7} alkylamino, -C _{1 - 7} alkyl, C _{1 - 7} alkanoyl, C _{1 - 7} alkanoylamino, C _{1 - 7} alkyl-carbonyl, C _{1 - 7} alkoxy-carbonyl, carbamoyl, mono- or di -C _{1 -7} alkyl-carbamoyl, C _1-7 alkylsulfonyl amino, phenylsulfonyl amino, C _1-7 alkylsulfinyl, C _6-14 aryl sulfanyl, 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;

It said alkyl, alkenyl, alkynyl and alkoxy are each independently unsubstituted or substituted with halogen, hydroxy, cyano, nitro, amino, mercapto, C _{1 -} to _7-alkynyl-7 alkyl, and C ₂ ≪ / RTI >

Said cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl, each independently, an unsubstituted or halogen, hydroxyl, cyano, nitro, amino, mercapto, C _{1 - 4} alkyl, and C _{1 - 4} alkoxy have one or more substituents selected from the group consisting of;

The heteroaryl and heterocycloalkyl each independently contain 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 this formula,

R ₇ is hydrogen or C _1-7 alkyl;

R _8a and R _8b are each independently C _1-7 alkyl or are linked to form 5-10 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, S and O, do.

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

According to an example of the compound of formula (1), A is oxygen; Wherein R is hydroxymethyl; Wherein n is 1; Wherein X 'is halogen; Wherein B is halogen, hydroxy, cyano, nitro, amino, mercapto, substituted with C _1-4 alkyl, C _3-6 cycloalkyl, and C _1-4 alkoxy at least one substituent selected from the group consisting of or unsubstituted Lt; / RTI >

In addition, the compound of Formula 1 may be a compound having an? -Formed glucose or? -Formed glucose.

Method for producing compound of formula (1) (R = hydroxymethyl)

The present invention provides, in accordance with one embodiment, a process for preparing a compound of formula 1 (R = hydroxymethyl) comprising the steps of:

(1) esterifying and halogenating 3,4-dihydrobenzoic acid to obtain a compound of formula (2);

(2) reacting the compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4);

(3) aldehyde or amidation of the compound of formula (4) followed by reduction with a compound of formula (5) to obtain a compound of formula (6); And

(4) reacting the compound of formula (6) with a compound of formula (7), deprotecting and reducing.

In this formula,

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

R is hydroxymethyl;

n is an integer from 1 to 3;

PG is a protecting group;

X 'is a halogen or C _1-7 alkyl;

X, Y and Hal are each independently halogen;

B is as defined in formula (1).

Step (1)

In step (1), 3,4-dihydrobenzoic acid is esterified and halogenated to give the compound of formula (2).

First, methyl 3,4-dihydroxybenzoate can be obtained via esterification from 3,4-dihydrobenzoic acid. The methyl 3,4-dihydroxybenzoate can then undergo a halogenation reaction.

The halogenation reaction may include a chlorination reaction and / or a bromination reaction. Preferably, the halogenation reaction comprises a chlorination reaction.

Chlorosuccinimide (NCS), sulfuryl chloride (SO ₂ Cl ₂ ), dichoromin-T (DCT), PCl ₃ , N, N-dichlorourethane, It is possible to use HgO / Cl ₂ , t-butoxychloride, H ₂ O / Ca (OCl) ₂ , Cl ₂ NPO (OCH ₂ CH ₃ ) ₂ , NaOCl or a combination thereof, You can use the image.

In the chlorination reaction, chloroform (CHCl ₃ ), acetic acid, acetonitrile, N, N-dimethylformamide (DMF), or a mixed solvent thereof may be used as a solvent. Preferably, in the chlorination reaction, a solvent containing chloroform may be used.

As a preferred example, the substituent X in the above formula (2) is chloro, and the halogenation reaction includes a chlorination reaction, wherein the chlorination reaction may use N-chlorosuccinimide as a chlorinating agent. Also, at this time, the chlorination reaction can be carried out using a solvent containing chloroform.

Preferably, the halogenation reaction may include a chlorination reaction after the bromination reaction. Also, the substituent X in the above formula (2) may be chloro and Y may be bromo.

Step (2)

In step (2), the compound of formula (2) is reacted with the compound of formula (3) to give the compound of formula (4).

Thus, prior to coupling with the glucose group, and before forming the terminal residue (i. E., Ring B) of the aglycon group, a pentagonal or hexagonal ring containing oxygen in the aglycone group, Can be formed in advance.

The compound of formula 3 may be, for example, dibromomethane, dibromoethane, dibromopropane, bromochloromethane, bromochloroethane, bromochloropropane, and the like.

The reaction in this step can be carried out in the presence of a metal salt. The metal salt may be, for example, potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ) and the like.

Step (3)

In step (3), the compound of formula (4) is reacted with the compound of formula (5) after aldehyde or amidation, followed by reduction to obtain the compound of formula (6).

As an example, step (3) may include aldehyde the compound of formula (4) to obtain a compound of formula (4a) and then reacting it with a compound of formula (5)

[Chemical Formula 4a]

Wherein n is an integer from 1 to 3; X and Y are each independently halogen.

Specifically, the aldehyde reaction may be carried out by reducing the compound of Formula 4 and then reacting with pyridinium chlorochromate (PCC), magnesium dioxide, or the like. As a result, the compound of Formula 4a can be obtained.

Then, the compound of formula (4a) may be reacted with the compound of formula (5) to obtain a compound of formula (6a): < EMI ID =

[Chemical Formula 6a]

Wherein n is an integer from 1 to 3; X and Y are each independently halogen; B is the same as defined in the above formula (1).

Thereafter, the compound of formula (6) can be reduced to give the compound of formula (6).

As another example, step (3) above may include amidating the compound of formula (4) to obtain a compound of formula (4b) and then reacting it with the compound of formula (5)

(4b)

Wherein n is an integer from 1 to 3; X and Y are each independently halogen.

Specifically, the amidation reaction may be performed by hydrolyzing the compound of Formula 4 and then reacting with N, O-dimethylhydroxyamine hydrochloride (MeO (Me) NH · HCl) or the like, Weinreb amide forms such as 4b can be obtained.

Subsequently, the compound of formula (4b) can be reacted with the compound of formula (5) to give a compound of formula (6b): < EMI ID =

[Formula 6b]

Wherein n is an integer from 1 to 3; X and Y are each independently halogen; B is the same as defined in the above formula (1).

Thereafter, the compound of formula (6b) may be reduced to give the compound of formula (6).

The compound of Chemical Formula 5 may be a Grignard reagent.

According to the general method of Grignard reagent, the compound of formula (5) can be prepared by reacting a compound of the following formula (5a) with a metal magnesium (Mg)

[Chemical Formula 5a]

Wherein B is as defined in Formula 1 above; Hal is a halogen.

As described above, according to the present invention, the group B of the final compound (compound of formula (1)) can be easily introduced in advance according to the Grignard reagent method before coupling of the aglycon group and the glucose group, The final yield can also be improved.

On the other hand, according to the prior art (US Patent Publication No. 2014/0274918), in order to complete the group B of the final compound, a complicated synthesis process is required at the end of the synthesis route after coupling with the glucose group, And the reaction concentration.

Step (4)

In step (4), the compound of formula (6) is reacted with the compound of formula (7), followed by deprotection and reduction.

The reaction between the compound of Formula 6 and the compound of Formula 7 may be carried out in the presence of n-butyllithium, sec-butyllithium, t-butyllithium, i-propylmagnesium chloride (i-PrMgCl).

As an example, the compound of formula (6) can be reacted with the compound of formula (7) to give a compound of formula (7a): <

[Formula 7a]

Wherein A is oxygen or sulfur; n is an integer from 1 to 3; X is halogen; PG is a protecting group; B is the same as defined in the above formula (1). The protecting group may be, for example, a trimethylsilyl group (TMS), a benzyl group, or an acetyl group.

Thereafter, the compound of formula (7a) can be deprotected and reduced to give the compound of formula (1).

For example, when the protecting group is trimethylsilyl (TMS), deprotection is performed by adding methanesulfonic acid (CH ₃ SO ₃ H) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) to the compound of Formula 7a , The compound of the above formula (1) can be obtained. It is also preferable to use dichloromethane (CH ₂ Cl ₂ ) and acetonitrile (CH ₃ CN) as a solvent at this time.

Purification step

The compound of formula (1) obtained through the above steps may be a compound in which the? -Form and the? -Form of glucose are mixed. Therefore, additional separation steps can be performed to obtain only the desired? - or? -Form.

For example, after step (4) of the present invention, a precipitate formed by introducing a protecting group into the compound of formula (1) and heating in alcohol, ethyl acetate, or dichloromethane is separated and deprotected to obtain β- Only the form can be obtained.

For example, by protecting the hydroxy group of glucose of the compound of Formula 1 with an acetyl group and then heating and stirring in an alcohol solvent (such as ethanol or isopropanol) to separate the resulting precipitate, Only the compound of 7b can be obtained:

[Formula 7b]

Wherein A is oxygen or sulfur; n is an integer from 1 to 3; X is halogen; PG is a protecting group; B is the same as defined in the above formula (1).

The compound of formula (7b) may then be deprotected to yield only the β-form of the compound of formula (1), which may be represented by formula (7c)

[Formula 7c]

Wherein A, B, R, n and X 'are as defined in the above formula (1).

Alkylation step

According to the present invention, it is possible to further include an alkylation reaction after the step (4), and as a result, X 'in the formula (1) may be C _1-7 alkyl.

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

Compounds of formula 1 (R = C _1-7 Alkylthio, A = oxygen)

The present invention provides, in accordance with another aspect, a process for preparing a compound of formula 1 (R = C _1-7 alkylthio, A = oxygen) comprising the steps of:

(1) esterifying and halogenating 3,4-dihydrobenzoic acid to obtain a compound of formula (2);

(2) reacting the compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4);

(3) aldehyde or amidation of the compound of formula (4) followed by reduction with a compound of formula (5) to obtain a compound of formula (6);

(4) reacting the compound of formula (6) with a compound of formula (8) and reducing to obtain a compound of formula (9);

(5) forming a furanos ring of the compound of formula (9) in a pyranose ring under acidic conditions and introducing a protecting group to obtain a compound of formula (10); And

(6) treating the compound of formula (10) with thiourea, reacting with a C _1-7 alkyl halide, and reducing.

In this formula,

A is oxygen (O);

R is C _1-7 alkylthio;

n is an integer from 1 to 3;

PG is a protecting group;

X 'is a halogen or C _1-7 alkyl;

X, Y and Hal are each independently halogen;

B is as defined in formula (1).

Among the above steps, steps (1) to (3) can be carried out in the same manner as in steps (1) to (3) of the method for producing the compound of formula (1) (R = hydroxymethyl).

Steps (4) to (6) will be described in detail below.

 Step (4)

In step (4), the compound of formula (6) is reacted with the compound of formula (8) to give the compound of formula (9).

The compound of formula (8) can be prepared according to a known method, for example, the method disclosed in PCT Publication No. WO 2009/014970. Specifically, the compound of Formula 8 may be prepared according to the method disclosed in WO 2009/014970 starting from L-xylose.

According to one example, the compound of formula 6 may be reacted with the compound of formula 8 to obtain a compound of formula 9a:

[Formula 9a]

Wherein B, n and X are the same as defined in the above formula (1).

Then, the compound of formula (9) can be reduced to give the compound of formula (9).

Step (5)

In step (5), the furanose ring of the compound of formula (9) is formed into a pyranose ring under acidic conditions and then a protecting group is introduced to obtain the compound of formula (10). Through this step, the pyranose ring constituting the glucose group can be completed.

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

Step (6)

In step (6), the compound of formula (10) is treated with thiourea, reacted with a C _1-7 alkyl halide and then reduced. Through this step, the alkyl thio group can be introduced into the final compound (compound of formula (1)).

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

Further, after the step (6), an alkylation reaction may be further included. As a result, a compound of the formula (1) wherein X 'is C _1-7 alkyl can be obtained.

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

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

- AcOH: acetic acid

- Ac ₂ O: Acetic anhydride

- DCM: dichloromethane

- DIPEA: N, N-diisopropylethylamine

- DMA: N, N-dimethylacetamide

- DMAP: 4-dimethylaminopyridine

- EtOAc: ethyl acetate

- EtOH: ethanol

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

- Hex: hexane

- MeI: Iodomethane

- MeOH: methanol

- NaOMe: sodium methoxide

- TEMPO: 2,2,6,6-tetramethylpiperidin-1-yl) oxadinyl

- THF: tetrahydrofuran

- TMSOTf: Trimethylsilyl trifluoromethanesulfonate

- RT or rt: room temperature

Comparative Example 1: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4-cyclopropylbenzyl) benzo [d] [1,3] dioxol- - (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

The title compound was prepared by the method described in US Patent Publication No. 2014/0274918. The specific synthesis step of Comparative Example 1 will be described below with reference to the reaction formula 1 described in the Background Art.

Step 1: 4-Formyl-2-methoxy-3-nitrophenylacetate (Compound c2 )

To the fuming HNO ₃ (230 mL) was added 4-formyl-2-methoxyphenylacetate (56 g, 288 mmol) portionwise while maintaining the temperature between -20 ° C and 0 ° C. After the addition was complete, the mixture was stirred at 0 < 0 > C for 30 minutes. The mixture was poured into water (1.3 L) with stirring. The mixture was stirred at room temperature for 1 hour and the crude product precipitated. The crude product was filtered, washed with H ₂ O (1 L) and dried under high vacuum to give the crude title compound.

Step 2: 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (Compound c3 )

A _{THF / MeOH / H 2 O (} 450 mL / 150 mL / 150 mL) of crude 4-formyl-2-methoxy -3- LiOH monohydrate in a mixture of nitro-phenyl acetate (25 g, 576 mmol) in . The mixture was stirred at room temperature for 15 hours. The mixture was acidified with 10% aqueous HCl (pH ~ 5). The mixture was extracted with EtOAc (500 mL x 2). 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 (38 g, 67%, step 2).

^{1 H NMR (400 MHz, DMSO} -d 6) δ 11.83 (s, 1H), 9.75 (s, 1H), 7.65 (d, J = 8.57 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H) , 3.85 (s, 3 H).

Step 3: 5-Bromo-4-hydroxy-3-methoxy-2-nitrobenzaldehyde (compound c4 )

To a mixture of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (28.0 g, 142 mmol) and I ₂ (1.5 g) in AcOH (160 mL) at 0 ° C was added Br ₂ (8.0 mL, 157 mmol ). The mixture was warmed to room temperature and stirred at room temperature for 15 hours. The mixture was poured into water (2.0 L) with stirring. The mixture was stirred at room temperature for 30 minutes. The mixture was extracted with EtOAc (1 L x 2). The organic layer was dried over MgSO _4, filtered and concentrated in vacuo to give the title compound (38 g, 98%).

¹ H NMR (400 MHz, DMSO-d ₆ )? 11.53 (s, IH), 10.12 (s, IH), 7.80 (s, IH), 3.81 (s, 3H).

Step 4: 2-Amino-5-bromo-4-hydroxy-3-methoxybenzaldehyde (Compound c5 )

5-bromo-4-hydroxy-3-methoxy-2-nitro _{EtOH / H 2 O (350 mL} / 100 mL) to a mixture of benzaldehyde (25.4 g, 92 mmol) FeSO 4 · 7H 2 O (4.7 g) and Fe powder (47 g). The mixture was stirred at 100 < 0 > C for 1 hour. The mixture was cooled to 50 < 0 > C and filtered through celite to remove inorganic material. The filtrate was concentrated in vacuo to give the title compound (19.0 g, 84%).

^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.57 (s, 1H), 9.63 (s, 1H), 7.56 (s, 1H), 6.94 (brs, 2H), 3.65 (s, 3H).

Step 5: 5-Bromo-2-chloro-4-hydroxy-3-methoxybenzaldehyde (compound c6 )

conc. H ₂ O (20 mL) was added to a mixture of 2-amino-5-bromo-4-hydroxy-3-methoxybenzaldehyde (13.0 g, 52.8 mmol) in HCl (40 mL) The mixture was cooled to 0 < 0 > C. From 0 ℃ NaNO ₂ was added slowly little by little to (5 g) to the mixture, and conc. CuCI (8.0 g) dissolved in HCl (80 mL) was added very slowly at 0 < 0 > C. The mixture was stirred at 100 < 0 > C for 1 hour and cooled to room temperature. The product was precipitated, filtered, washed with H ₂ O (500 mL) and dried under high vacuum to give the title compound (12.9 g, 92%).

¹ H NMR (400 MHz, DMSO-d ₆ )? 11.51 (s, IH), 10.11 (s, IH), 7.80 (s, IH), 3.12 (s, 3H).

Step 6: 5-Bromo-2-chloro-3,4-dimethoxybenzaldehyde (compound c7 )

To a mixture of 5-bromo-2-chloro-4-hydroxy-3-methoxybenzaldehyde (15.0 g, 56.5 mmol) in THF (300 mL) was added dimethylsulfate (7.0 mL, 73.5 mmol) and LiOH monohydrate (3.1 g, 73.5 mmol). The mixture was stirred at 65 < 0 > C for 3 hours. The mixture was cooled to room temperature and filtered through celite to remove insoluble material. The filtrate was extracted with EtOAc / 50% aqueous NaCl solution (200 mL / 500 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 compound (11.1 g, 70%).

¹ H NMR (400 MHz, CDCl ₃ )? 10.37 (s, IH), 7.96 (s, IH), 3.97 (s, 3H), 3.94 (s, 3H).

Step 7: 5-Bromo-2-chloro-3,4-dimethoxybenzoic acid (compound c8 )

A mixture of 5-bromo-2-chloro-3,4-dimethoxybenzaldehyde (11.1 g, 39.4 mmol), 2-methyl-2-butene (105 mL, 985 mmol) in t- It was added to the _{KH 2 PO 4 (38 g,} 276 mmol). NaClO ₂ (32 g, 355 mmol) dissolved in H ₂ O (160 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 15 hours. The mixture was evaporated in vacuo to remove the solvent. The residue was extracted with EtOAc / 5% aqueous HCl (500 mL / 300 mL). The organic layer was dried over MgSO _4, filtered and concentrated in vacuo to give the title compound (11.6 g, 99%).

¹ H NMR (400 MHz, DMSO- d ₆ )? 13.51 (s, IH), 7.80 (s, IH), 3.91 (s, 3H), 3.87 (s, 3H).

Step 8: 5-Bromo-2-chloro-3,4-dimethoxybenzoyl chloride (compound c9 )

To a suspension of 5-bromo-2-chloro-3,4-dimethoxybenzoic acid (3.0 g, 10.2 mmol) in CH ₂ Cl ₂ (50 mL) at room temperature was added oxalyl chloride (1.1 mL, 12.2 mmol) Of DMF was added. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and dried under high vacuum. The crude title compound was obtained and used in the next step without further purification.

Step 9: (5-Bromo-2-chloro-3,4-dimethoxyphenyl) (4-cyclopropylphenyl) methanone c11 )

The crude 5-bromo-2-chloro-3,4-dimethoxybenzoyl chloride was dissolved in CH ₂ Cl ₂ (50 mL) and cooled to 0 ° C. Cyclopropylbenzene (1.6 mL, 12.2 mmol) and AlCl ₃ (1.35 g, 10.2 mmol) were added in portions to the mixture at 0 ° C. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and 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 (3.45 g, 85%).

[M + H] < ⁺ >

Step 10: 1-Bromo-4-chloro-5- (4-cyclopropylbenzyl) -2,3-dimethoxybenzene c12 )

(5-Bromo-2-chloro-3,4-dimethoxyphenyl) (4-cyclopropylphenyl) methanone (3.45 g) in CH ₂ Cl ₂ (25 mL) / CH ₃ CN g, 8.72 mmol) in dichloromethane (5 mL) was added triethylsilane (3.5 mL, 21.8 mmol) and trifluoro borate etherate (2.8 mL, 21.8 mmol). 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. Purification of the crude product by silica gel column chromatography (Biotage Isolera ™ FLASH Purification System), EtOAc / Hex) gave the title compound (2.25 g, 68%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.13-7.09 (m, 3H), 7.05 (d, J = 8.2 Hz, 2H), 4.01 (s, 2H), 3.94 (s, 3H), 3,92 ( s, 3H), 1.95-1.85 (m, 1H), 1.01-0.94 (m, 2H), 0.75-0.67 (m, 2H).

Step 11: 6-Bromo-3-chloro-4- (4-cyclopropylbenzyl) benzene- c13 )

To a solution of l-bromo-4-chloro-5- (4-cyclopropylbenzyl) -2,3-dimethoxybenzene (2.21 g, 5.79 mmol) and sodium ethanethiolate (2.2, 26.1 mmol ) Was stirred at 90 < 0 > C for 12 hours. The resulting mixture was diluted with EtOAc and washed with saturated NH ₄ Cl 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 (TM) FLASH Purification System, EtOAc / Hex) to give the title compound (1.73 g, 85%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.09 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 6.90 (s, 1H), 5.74 (s, 1H), 5 (M, 2H), 1.91-0.94 (m, 2H), 0.73-0.67 (m, 2H).

Step 12: 7-Bromo-4-chloro-5- (4-cyclopropylbenzyl) benzo [d] [1,3] dioxole c14 )

To a solution of 6-bromo-3-chloro-4- (4-cyclopropylbenzyl) benzene-1,2-diol (1.75 g, 4.95 mmol) in DMF (25 mL) at room temperature was added dibromomethane a, 5.94 mmol) and _{Cs 2 CO 3 (5.7 g,} 17.3 mmol) was added. The mixture was stirred at 90 < 0 > C for 12 hours. The mixture was cooled to room temperature and filtered to remove inorganic salts. The filtrate was extracted with EtOAc / 50% aqueous NaCl solution (100 mL / 500 mL). The organic layer was washed with brine, dried over MgSO _4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (1.17 g, 65%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.05 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 6.77 (s, 1H), 6.10 (s, 2H), 3 , 93 (s, 2H), 1.91-1.83 (m, 1H), 0.99-0.90 (m, 2H), 0.69-0.63 (m, 2H).

Step 13: (3R, 4S, 5R, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- Tris ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran- c16 )

To a solution of 7-bromo-4-chloro-5- (4-cyclopropylbenzyl) benzo [d] [l, 3] dioxole in 15 mL of tetrahydrofuran / toluene (1.17 g, 3.20 mmol) in dichloromethane (5 mL) was added n-butyllithium (2.5 M in hexane, 1.6 mL, 3.84 mmol) dropwise. After stirring for 1 hour, a solution of (3R, 4S, 5R, 6R) -3,4,5-tris ((trimethylsilyl) oxy) -6- Methyl) tetrahydro-2H-pyran-2-one (compound c15 ; 1.8 g, 3.84 mmol) was added dropwise to the mixture via cannula. The reaction mixture was stirred at -78 < 0 > C for 2 hours to give the title compound. The mixture containing the title compound was used in the next step without purification.

Step 14: (3R, 4S, 5S, 6R) -2- (7-Chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- 2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound c17 )

Methanesulfonic acid (0.6 N in MeOH, 10.7 mL, 6.40 mmol) was added to a solution of crude (3R, 4S, 5R, 6R) -2- (7-chloro-6- (Trimethylsilyl) oxy) methyl) tetrahydro-2H-benzo [d] [1,3] dioxol- -Pyran-2-ol. ≪ / RTI > The reaction mixture was slowly warmed to room temperature and stirred for 12 hours. Saturated NaHCO ₃ solution was added to the resulting mixture to terminate the reaction and extracted with EtOAc. The organic layer was dried over MgSO _4, filtered and concentrated under vacuum to give the title compound (quantitative amount). The crude title compound was used in the next step without further purification.

Step 15: (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- (Hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Compound c18 )

-65 ℃ (3R, 4S, 5S , 6R) in _{CH 2 Cl 2 (20 mL)} / CH 3 CN (20 mL) at-2- (7-chloro-6- (4-cyclopropyl-benzyl) benzo [d ] [1,3] dioxol-4-yl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol (1.37 g, 2.86 mmol) Was added triethylsilane (0.92 mL, 5.72 mmol) and boron trifluoride diethyl etherate (0.72 mL, 5.72 mmol). The reaction mixture was slowly warmed to 0 < 0 > C. To the resulting mixture was added a saturated NaHCO ₃ (30 mL) solution at 0 ° C, the reaction was terminated and extracted with EtOAc. The organic layer was dried over MgSO _4, filtered, and concentrated in vacuo. Purification of the crude product by preparative _{HPLC (Gilson system, CH 3 CN} / H 2 O) to give the title compound (183 mg, 13%). In addition, the total yield of the final compound of Comparative Example 1 according to the synthetic routes of Steps 1 to 15 was calculated to be about 2% or less .

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.07 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 6.06 (dd, J = 7.0 Hz, 1.0 Hz, 2H), 4.85 (s, 4H), 4.28 (d, J = 9.6 Hz, 1H), 3.98 (ABq, Δv AB = 10.9 Hz, J AB = 15.2 Hz, 2H), 3.88 (d, 1H, J = 10.5 Hz, 1H), 3.72-3.63 (m, 1H), 3.60 (t, J = 9.2 Hz, 1H), 3.49-3.33 (m, 3H), 1.93-1.81 , 89 (m, 2H), 0.68-0. 60 (m, 2H); [M + Na] < ⁺ >

Example 1: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- - (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

Step 1: Methyl 3,4-dihydroxybenzoate (compound c22 )

To the mixture of 3,4-dihydrobenzoic acid (20 g, 129.7 mmol) in MeOH (260 mL) was added concentrated sulfuric acid (13.8 mL, 259.5 mmol). The reaction mixture was stirred at 80 < 0 > C for 5 hours. The resulting mixture was concentrated in vacuo. The crude product was washed with H ₂ O and dried under high vacuum to give the title compound (21.5 g, 98%).

^{1 H NMR (400 MHz, DMSO} -d 6) δ 9.80 (brs, 1H), 9.37 (brs, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 8.0, 2.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H); [M + H] < ⁺ >

Step 2: Preparation of methyl 3-bromo-4,5-dihydroxybenzoate (compound c23 )

Methyl 3,4- dihydroxybenzoate (45.0 g, 268 mmol) and sodium acetate (33 g, 402 mmol) were suspended in acetic acid (900 mL, 0.3 M). The mixture was stirred at room temperature until the solution became clear. Bromine (13.8 mL, 270 mmol) in a solution of acetic acid (135 mL, 2.0 M) was added dropwise to the mixture. The resulting mixture was stirred for 12 hours. Diethyl ether (900 mL) was added to the mixture and the precipitate was removed. The filtrate was concentrated and diluted in dichloromethane (300 mL). Hexane (1800 mL) was added to the mixture and stirred for 3 hours. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (43 g, 65%).

^{1 H NMR (400 MHz, DMSO} -d 6) δ 10.34 (brs, 1H), 10.15 (brs, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H) , 3.79 (s, 3 H).

Step 3: Methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate (compound c24 )

Methyl 3-bromo-4,5-dihydroxybenzoate (43.0 g, 174 mmol) and N-chlorosuccinimide (28 g, 210 mmol) were suspended in chloroform (600 mL, 0.3 M). The mixture was stirred at 60 < 0 > C for 17 hours and cooled to room temperature. The resulting mixture was concentrated and diluted with ethyl acetate (500 mL) and water (500 mL). The mixture was extracted with ethyl acetate (250 mL x 2). The organic layer was washed with water (250 mL) and brine (250 mL), dried over magnesium sulfate and concentrated. The residue was diluted in dichloromethane (100 mL) and added dropwise to hexane (1000 mL) with stirring. A precipitate was obtained by filtration and dried under reduced pressure to give the title compound (40 g, 83%).

¹ H NMR (400 MHz, DMSO-d ₆ )? 10.48 (brs, 1H), 10.08 (brs, 1H), 7.53 (s, 1H), 3.79

Step 4: Methyl 7-bromo-4-chlorobenzo [d] [1,3] dioxole-5-carboxylate c25 )

To a mixture of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate (80 g, 284.2 mmol) and K ₂ CO ₃ (79 g, 568.4 mmol) in DMA (960 mL) (40 mL, 568.4 mmol). The reaction mixture was stirred at 80 < 0 > C for 24 hours. The resulting mixture was poured into cold H ₂ O (7000 mL) and stirred at room temperature for 12 hours. The precipitate was washed with H ₂ O and dried under high vacuum to give the title compound (65.3 g, 78%).

¹ H NMR (400 MHz, CDCl ₃ )? 7.70 (s, 1 H), 6.20 (s, 2H), 3.91 (s, 3H); [M + H] < ⁺ >

Step 5: 7-Bromo-4-chlorobenzo [d] [1,3] dioxole-5-carboxylic acid (compound  c26 )

THF (700 mL) and H ₂ O (700 mL) methyl 7-bromo-4-chloro-benzo [d] [1,3] dioxol-5-carboxylate (121.4 g, 410.9 mmol) and LiOH monohydrate of (52 g, 1233 mmol) was stirred at room temperature for 12 hours. The resulting mixture was concentrated in vacuo. The crude product was diluted with H ₂ O (1000 mL). An aqueous 1 N HCI solution at 0 < 0 > C was added dropwise to the mixture. The precipitate was washed with H ₂ O (500 mL) and dried under high vacuum to give the title compound (117 g, quantitative yield).

^{1 H NMR (400 MHz, DMSO} -d 6) δ 13.38 (brs, 1H), 7.61 (s, 1H), 6.32 (s, 2H).

Step 6: 7-Bromo-4-chlorobenzo [d] [1,3] dioxole-5-carbonyl chloride  c27 )

To a solution of 7-bromo-4-chlorobenzo [d] [1,3] dioxole-5-carboxylic acid (30.0 g, 107 mmol) in toluene (430 mL) at room temperature was added SOCl ₂ (12.0 mL, 161 mmol) Was added. After refluxing for 22 h, the reaction mixture was cooled to room temperature and concentrated in vacuo to give the title compound as a yellow oil. The crude residue was used in the next step without further purification.

Step 7: 7-Bromo-4-chloro-N-methoxy-N-methylbenzo [d] [1,3] dioxole-5-carboxamide  c28 )

To a solution of 7-bromo-4-chlorobenzo [d] [1,3] dioxol-5-carbonyl chloride in CH ₂ Cl ₂ (430 mL) at room temperature was added N, O-dimethylhydroxylamine hydrochloride (15.7 g, 161 mmol) and pyridine (44.7 mL, 537 mmol). After stirring at room temperature for 21 hours, the reaction was terminated by adding 1 N HCl (100 mL) to the reaction mixture, washed with water (300 mL) and extracted with CH ₂ Cl ₂ (500 mL x 2). The combined organic layers were dried over MgSO _4, filtered, and concentrated in vacuo. The residue was purified by filtration through a pad of silica gel with hexane / EtOAc (1/1) solution to give the title compound (36.5 g, 99%) as a light yellow solid.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.06 (s, 1H), 6.20 (s, 2H), 3.56 (brs, 3H), 3.38 (brs, 3H).

Step 8: (7- bromo-4-chlorobenzo [d] [1,3] dioxol-5-yl) c31 )

A 500 mL three-necked flask containing magnesium (piece, 8.7 g, 360 mmol) was flame-dried. The flask was equipped with a condenser and an addition funnel under a nitrogen atmosphere. 4-Cyclopropyl phenyl bromide (PepTech, USA) (63.8 g, 323 mmol) in anhydrous THF (50 mL) was transferred to the addition funnel. To a suspension of magnesium in THF (280 mL) at room temperature was added 4-cyclopropylphenyl bromide. The reaction mixture was stirred at room temperature for 2 hours to prepare (4-cyclopropylphenyl) magnesium bromide (compound c30 ). The resulting solution was used immediately in the next step.

To a stirred solution of 7-bromo-4-chloro-N-methoxy-N-methylbenzo [d] [1,3] dioxole-5- carboxamide (36.5 g, , 113 mmol) was added a freshly prepared solution of (4-cyclopropylphenyl) magnesium bromide (1.03 M in THF, 323 mL, 323 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with aqueous NH ₄ Cl (300 mL) and extracted with EtOAc (300 mL). The organic layer was dried over MgSO _4, filtered, and concentrated in vacuo. The residue was purified by precipitation in hexane and CH ₂ Cl _{2 to} give the title compound (39.0 g, 96%) as a white solid.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 1.93-2.00 (m, 1H) , 1.09-1.12 (m, 2H), 0.81-0.83 (m, 2H).

Step 9: 7-Bromo-4-chloro-5- (4-cyclopropylbenzyl) benzo [d] [1,3] dioxole c14 )

(7-bromo-4-chlorobenzo [d] [1,3] dioxol-5-yl) (4-cyclohexylmethanone) in CH ₂ Cl ₂ / CH ₃ CN (345 mL / Triethylsilane (49.6 mL, 311 mmol) and boron trifluoride diethyl etherate (39.0 mL, 311 mmol) were added to a solution of the title compound (39.0 g, 104 mmol) After stirring at room temperature for 18 hours, water (500 mL) was added to the reaction mixture to terminate the reaction and extracted with CH ₂ Cl ₂ (300 mL). The organic layer was washed with saturated aqueous NaHCO ₃ solution (300 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by precipitation in hexane and CH ₂ Cl _{2 to} give the title compound (31.4 g, 83%) as a white solid.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.10 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 1.87-1.94 (m, 1H) , 0.92-1.00 (m, 2H), 0.68-0.72 (m, 2H).

Step 10: (3R, 4S, 5R, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- Tris ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran- c16 )

To a solution of 7-bromo-4-chloro-5- (4-cyclopropylbenzyl) benzo [d] [l, 3] dioxole (5 mL) in tetrahydrofuran (50 mL) and toluene 5.00 g, 13.7 mmol) in THF (20 mL) was added n-butyllithium (2.5 M in hexanes, 11.0 mL, 27.4 mmol) dropwise. After stirring at the same temperature for 5 minutes (orange solution), a solution of the TMS-protected lactone (compound c15 ; 7.70 g, 16.5 mmol) in toluene (50 mL) 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 by addition of aqueous saturated NH ₄ Cl (300 mL) at 0 ° C and extracted with EtOAc (300 mL). The organic layer was dried over Na ₂ SO _4, filtered and concentrated in vacuo to afford the title compound (12.0 g, quantitative) of the crude was obtained as a pale yellow oil. The crude residue was used in the next step without further purification.

Step 11: (3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- Gt; < RTI ID = 0.0 > methyl) tetrahydro-2H-pyran-  c32 )

At -78 ℃ of the crude in CH ₂ Cl ₂ (70 mL) and _{CH 3 CN (70 mL) (} 3R, 4S, 5R, 6R) -2- (7- chloro-6- (4-cyclopropyl-benzyl) (Trimethylsilyl) oxy) methyl) tetrahydro-2H-benzo [d] [1,3] dioxol- -Pyran-2-ol (12.0 g) was added triethylsilane (8.75 mL, 54.8 mmol) and TMSOTf (9.92 mL, 54.8 mmol). After stirring at -78 ° C for 1 hour, the reaction mixture was quenched with water (200 mL) at 0 ° C and extracted with CH ₂ Cl ₂ (300 mL). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was purified by precipitation in CH ₂ Cl ₂ and hexane to give the title compound (4.03 g, 66%, step 2) as a white solid.

Step 12: (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (7-chloro-6- (4- cyclopropylbenzyl) benzo [ -4-yl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c33 )

(3R, 4R, 5S, 6R ) in CH ₂ Cl ₂ (90 mL) at room temperature, 2- (7-chloro-6- (4-cyclopropyl-benzyl) benzo [d] [1,3] dioxole -4 Was added DMAP (550 mg, 4.50 mmol) and Ac2O (5.1 eq.) In tetrahydrofuran ( ₁ ml) mL, 54.0 mmol). After stirring at room temperature for 18 hours, water (120 mL) was added to the reaction mixture, and the reaction was terminated 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 slurried residue was heated at 80 < 0 > C for 10 minutes in isopropyl alcohol (20 mL), cooled to room temperature, and the resulting precipitate was filtered and concentrated in vacuo to give the title compound (3.79 g, 6.14 mmol , 68%) as a white solid.

^{1 H NMR (400 MHz, CDCl} 3) (β- type) δ 7.03 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.67 (s, 1H), 6.08 (d J = 9.2 Hz, 1H), 5.20 (t, J = 1.2 Hz, 1H) = 9.6 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.24 (dd, J = 12.4,4.8 Hz, 1H) _{, Δν AB = 11.8 Hz, J} AB = 15.4 Hz, 2H), 3.81-3.76 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.88-1.81 ( m, 1 H), 1.78 (s, 3H), 0.95-0.89 (m, 2H), 0.67-0.62 (m, 2H); [M + Na] < ⁺ >

^{1 H NMR (400 MHz, CDCl} 3) (α- type) δ 7.04 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 6.01 (s 2H), 5.50 (d, J = 3.6 Hz, 1H), 5.38 (s, 2H), 5.2-5.23 (m, 1H), 4.61 (dd, J = J = 9.6, 3.6 Hz, 1H), 4.19 (dd, J = 12.2, 5.8 Hz, 1H), 4.06 (d, J = 15.2 Hz, 1H) (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H), 1.87-1.80 (m, 2H); [M + Na] < ⁺ >

Step 13: (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- (Hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Compound c18 )

To a solution of (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (7-chloro-6- (4- cyclopropylbenzyl) ] Dioxol-4-yl) tetrahydro-2H-pyran-3,4,5-triyltriacetate (3.79 g, 6.14 mmol) in DMF (5 mL) was added NaOMe (25 wt%, 0.30 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo, diluted with water (200 mL) and extracted with EtOAc (300 mL). The organic layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was purified by recrystallization in DCM and hexanes to give the title compound as a p-form (2.69 g, 5.99 mmol, 98%) as a white solid. In addition, the total yield of the final compound of Example 1 according to the synthetic route of the above Step 1 to 13 was calculated as about 11% .

^{1 H NMR (400 MHz, CD} 3 OD) (β- type) δ 7.07 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 6.06 ( dd, J = 7.0 Hz, 1.0 Hz, 2H), 4.85 (s, 4H), 4.28 (d, J = 9.6 Hz, 1H), 3.98 (ABq, Δν AB = 10.9 Hz, J AB = 15.2 Hz, 2H) , 3.88 (d, J = 10.5 Hz, 1H), 3.72-3.63 (m, 1H), 3.60 (t, J = 9.2 Hz, 1H), 3.49-3.33 ), 0.97-0.89 (m, 2H), 0.68-0.60 (m, 2H); [M + Na] < ⁺ >

^{1 H NMR (400 MHz, CD} 3 OD) (α- type) δ 7.03 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.02 ( (d, J = 12.4 Hz, 2H), 5.26 (d, J = 3.2 Hz, 1H), 4.31 J = 8.4,3.2 Hz, 1H), 3.97-3.90 (m, 3H), 3.82 (dd, J = 11.4, 3.4 Hz, 1H), 3.65 (m, 1H), 0.92-0.87 (m, 2H), 0.63-0.59 (m, 2H); [M + Na] < ⁺ >

Example 2: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- - (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

Step 1: (3R, 4S, 5R, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- Tris ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-  c16 )

To a solution of 7-bromo-4-chloro-5- (4-cyclopropylbenzyl) benzo [d] [l, 3] dioxole in 15 mL of tetrahydrofuran / toluene (2.0 g, 5.47 mmol) in dichloromethane (5 mL) was added n-butyllithium (2.5 M in hexanes, 4.4 mL, 10.9 mmol) dropwise. After stirring for 40 minutes, a solution of (3R, 4S, 5R, 6R) -3,4,5-tris ((trimethylsilyl) oxy) -6 - Methyl) tetrahydro-2H-pyran-2-one (compound c15 ; 3.1 g, 6.56 mmol) was added dropwise to the mixture via cannula. The reaction mixture was stirred at -78 < 0 > C for 60 minutes. AcOH (1% aqueous solution, 30 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. Extract the resulting mixture with EtOAc, and the organic layer was dried over MgSO ₄ filtered and concentrated in vacuo to give the title compound. The crude product was used in the next step without further purification.

Step 2: (3R, 4S, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- 2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound c17 )

To a solution of (3R, 4S, 5R, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- To a solution of 3,4,5-tris ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro-2H- Catalytic amount). The reaction mixture was stirred at 40 < 0 > C for 20 min. The resulting mixture was concentrated in vacuo. The mixture was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The organic layer was dried over MgSO _4, filtered and concentrated under vacuum to give the title compound. The crude product was used in the next step without further purification.

Step 3: (3R, 4R, 5S, 6R) -2- (7-Chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- Gt; < RTI ID = 0.0 > methyl) tetrahydro-2H-pyran- c32 )

At _{-50 ℃ CH 2 Cl 2 (25} mL) / CH in _{3 CN (25 mL) (3R} , 4S, 5S, 6R) -2- (7- chloro-6- (4-cyclopropyl-benzyl) benzo [d ] [1,3] dioxol-4-yl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5- , 15.5 mmol) and boron trifluoride diethyl etherate (2.0 mL, 15.5 mmol). The reaction mixture was slowly warmed to -20 < 0 > C. The resulting mixture was cooled to -50 ℃ was complete the reaction was added to saturated NaHCO ₃ solution. The mixture was extracted twice with EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and concentrated in vacuo to give the title compound.

Step 4: (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (7-chloro-6- (4- cyclopropylbenzyl) benzo [ -4-yl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c33 )

(3R, 4R, 5S, 6R ) of from _{0 ℃ CH 2 Cl 2 (50} mL) -2- (7- chloro-6- (4-cyclopropyl-benzyl) benzo [d] [1,3] dioxol- 4-yl) -6- (hydroxymethyl) tetrahydro -2H- pyran -3,4,5 a mixture of triols _{Ac 2 O (4.5 mL, 48.1} mmol), pyridine (3.9 mL, 48.1 mmol) and DMAP (0.33 g, 2.7 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with EtOAc and washed with 1 N HCl solution. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (Biotage Isolera (TM) FLASH Purification System, EtOAc / Hex).

The resulting product (1.44 g) in EtOH (15 mL) was heated at 80 < 0 > C (clear solution). The mixture was cooled to room temperature and stirred for 12 hours. The precipitate was obtained by filtration, washed with cold EtOH and dried under vacuum to give the title compound as a white solid in the [beta] -form (1.12 g, 33%, step 4).

^{1 H NMR (400 MHz, CDCl} 3) (β- type) δ 7.03 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.67 (s, 1H), 6.08 (d J = 9.2 Hz, 1H), 5.20 (t, J = 1.2 Hz, 1H) = 9.6 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.24 (dd, J = 12.4,4.8 Hz, 1H) _{, Δv AB = 11.8 Hz, J} AB = 15.4 Hz, 2H), 3.81-3.76 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.88-1.81 ( m, 1 H), 1.78 (s, 3H), 0.95-0.89 (m, 2H), 0.67-0.62 (m, 2H); [M + Na] < ⁺ >

^{1 H NMR (400 MHz, CDCl} 3) (α- type) δ 7.04 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 6.01 (s 2H), 5.50 (d, J = 3.6 Hz, 1H), 5.38 (s, 2H), 5.2-5.23 (m, 1H), 4.61 (dd, J = J = 9.6, 3.6 Hz, 1H), 4.19 (dd, J = 12.2, 5.8 Hz, 1H), 4.06 (d, J = 15.2 Hz, 1H) (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H), 1.87-1.80 (m, 2H); [M + Na] < ⁺ >

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1,3] dioxol- (Hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Compound c18 )

To a solution of (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (7-chloro-6- (4- cyclopropylbenzyl) benzo [d] [1 (25% by weight in MeOH, 0.30 mL) was added to a mixture of 2-chloro-2-methyl- Respectively. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was acidified with AcOH (catalytic amount). The mixture was concentrated in vacuo, diluted with EtOAc and washed with 50% aqueous NaCl solution. The organic layer was dried over MgSO _4, filtered and concentrated in vacuo to give the title compound (2.69 g, 98%) of β- form as a white solid.

^{1 H NMR (400 MHz, CD} 3 OD) (β- type) δ 7.07 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.88 (s, 1H), 6.06 ( dd, J = 7.0 Hz, 1.0 Hz, 1H), 4.85 (s, 4H), 4.28 (d, J = 9.6 Hz, 1H), 3.98 (ABq, Δv AB = 10.9 Hz, J AB = 15.2 Hz, 2H) , 3.88 (d, J = 10.5 Hz, 1H), 3.72-3.63 (m, 1H), 3.60 (t, J = 9.2 Hz, 1H), 3.49-3.33 ), 0.97-0.89 (m, 2H), 0.68-0.60 (m, 2H); [M + Na] < ⁺ >

^{1 H NMR (400 MHz, CD} 3 OD) (α- type) δ 7.03 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.02 ( (d, J = 12.4 Hz, 2H), 5.26 (d, J = 3.2 Hz, 1H), 4.31 J = 8.4,3.2 Hz, 1H), 3.97-3.90 (m, 3H), 3.82 (dd, J = 11.4, 3.4 Hz, 1H), 3.65 (m, 1H), 0.92-0.87 (m, 2H), 0.63-0.59 (m, 2H); [M + Na] < ⁺ >

Examples 3 to 5

The compounds of Examples 3 to 5 below were synthesized using the appropriate Grignard reagent instead of (4-cyclopropylphenyl) magnesium bromide (compound c30 ) by repeating the synthetic procedure of Example 1 above.

Example 3: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- ethoxybenzyl) benzo [d] [1,3] dioxol- - (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.10 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.06 (dd, J = 6.9 Hz, 1.1 Hz, 2H), 4.86 (s, 4H), 4.28 (d, J = 9.6 Hz, 1H), 4.02 (ABq, Δν AB = 12.1 Hz, J AB = 7.0 Hz, 2H), 3.96 (d, 2H), 3.89 (dd, J = 11.9 Hz, 1.6 Hz, 1H), 3.71-3.64 (m, 1H), 3.66-3.57 (m, 3.41-3.35 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H); [M + Na] < ⁺ >

Example 4: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4-methylbenzyl) benzo [d] [1,3] dioxol- (Hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.08 (s, 4H), 6.88 (s, 1H), 6.05 (dd, J = 7.8 Hz, 0.96 Hz, 2H), 4.85 (s, 4H), 4.28 ( d, J = 9.6 Hz, 1H ), 3.99 (ABq, Δν AB = 10.9 Hz, J AB = 15.3 Hz, 2H), 3.80 (d, J = 11.9 Hz, 1H), 3.77-3.58 (m, 2H), 3.51-3.39 (m, 3H), 2.30 (s, 3H); [M + Na] < ⁺ >

Example 5: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- ethylbenzyl) benzo [d] [1,3] dioxol- (Hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.10 (s, 4H), 6.89 (s, 1H), 6.06 (dd, J = 7.0 Hz, 1.1 Hz, 2H), 4.86 (s, 4H), 4.28 ( d, J = 9.6 Hz, 1H ), 4.00 (ABq, Δν AB = 10.4 Hz, J AB = 15.2 Hz, 2H), 3.89 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 3.71-3.63 (m, 1H), 3.64-3.55 (m, 1H), 3.51-3.43 (m, 1H), 3.41-3.35 (m, 2H), 2.62 (q, J = 7.6 Hz, 2H) , 3H); [M + Na] < ⁺ >

Intermediate 1: Preparation of methyl 8-bromo-5-chloro-2,3-dihydrobenzo [b] [1,4] dioxin-6-carboxylate

To a mixture of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate (25 g, 88.81 mmol) and K ₂ CO ₃ (36.8 g, 266.44 mmol) in DMA (350 mL) -Dibromoethane (15.3 mL, 177.62 mmol). The mixture was stirred at 80 < 0 > C for 12 hours. The resulting mixture was poured into cold H ₂ O (2400 mL) and stirred at room temperature for 4 hours. The precipitate was washed with H ₂ O and dried under high vacuum to give the title compound (24.8 g, 91%).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.72 (s, 1H), 4.43-4.39 (m, 4H), 3.91 (s, 3H); [M + H] < ⁺ >

Examples 6 to 9

The synthesis procedure of steps 5-13 of Example 1 above was repeated except that in step 5 methyl 8-bromo-5-chloro-2,3-dihydrobenzo [b] [1,4] dioxin -6-carboxylate and using the appropriate Grignard reagent instead of (4-cyclopropylphenyl) magnesium bromide (compound c30 ) in step 8, the following compounds of examples 6-9 were synthesized.

Example 6: (2S, 3R, 4R, 5S, 6R) -2- (8-chloro-7- (4-methylbenzyl) -2,3-dihydrobenzo [ -Yl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD) 7.06-7.02 (m, 4H), 6.92 (s, 1H), 4.57-4.55 (m, 1H), 4.33-4.30 , 2H), 3.97 (ABq, Δν AB = 12.4 Hz, J AB = 15.2 Hz, 2H), 3.86-3.83 (m, 1H), 3.67-3.62 (m, 1H), 3.47-3.35 (m, 2H), 3.36 - 3.33 (m, 2 H), 2.27 (s, 3 H); [M + Na] < ^{+ &} gt ^; = 459.

Example 7: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (8-chloro-7- (4- (methylthio) benzyl) -2,3- dihydrobenzo [ Dioxin-5-yl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, MeOD} ) δ 7.16 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 4.57 (d, J = 9.6 Hz, 1H), 4.33-4.30 (m, 2H ), 4.28-4.22 (m, 2H), 3.98 (ABq, Δν AB = 12.4 Hz, J AB = 15.2 Hz, 2H), 3.85 (d, J = 11.2 Hz, 1H ), 3.68-3.63 (m, 1H), 3.48-3.54 (m, 2H), 3.38-3.36 (m, 2H), 2.43 (s, 3H); [M + Na] ⁺ 491.

Example 8: (2S, 3R, 4R, 5S, 6R) -2- (8-chloro-7- (4-propylbenzyl) -2,3-dihydrobenzo [ -Yl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, MeOD} ) δ 7.07 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 4.58-4.55 (m, 1H), 4.33-4.30 (m, 2H), 4.28-4.22 (m, 2H), 3.98 (ABq, Δν AB = 11.1 Hz, J AB = 15.2 Hz, 2H), 3.85 (d, J = 12.0 Hz, 1H), 3.68 2H), 3.63-3.55 (m, 2H), 0.91 (t, J = , ≪ / RTI > J = 7.4 Hz, 3H); [M + Na] < ⁺ > 487.

Example 9: (2S, 3R, 4R, 5S, 6R) -2- (8-chloro-7- (4-isopropylbenzyl) -2,3-dihydrobenzo [ 5-yl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, MeOD} ) δ 7.11-7.06 (m, 4H), 6.94 (s, 1H), 4.58-4.55 (m, 1H), 4.33-4.30 (m, 2H), 4.28-4.24 (m, 2H), 3.98 (ABq, Δν AB = 10.4 Hz, J AB = 15.2 Hz, 2H), 3.85 (d, J = 12.0 Hz, 1H), 3.66-3.63 (m, 1H), 3.50-3.43 (m, 2H ), 3.37-3.36 (m, 2H), 2.88-2.80 (m, 1H), 1.21 (d, J = 7.2 Hz, 6H); [M + Na] < ⁺ > 487.

Example 10: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- ethoxybenzyl) benzo [d] [1,3] dioxol- - (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-

To the suspension of L - (-) - xylose (19.15 g, 127.5 mmol) and MgSO ₄ (30.72 g, 255.0 mmol) in acetone (190 mL) at room temperature was added concentrated H ₂ SO ₄ (1.9 mL). After 12 hours, the reaction mixture (all L - (-) - xylose consumed) was filtered and the collected solid was washed with acetone (2 times, 20 mL per wash). The yellow filtrate was neutralized to pH about 9 with NH ₄ OH solution while stirring. The suspended solids were 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 the pH was adjusted from 9 to 2 with 1 N HCl solution in water. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was neutralized by the addition of 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-

To a solution of ((3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,2- d] [1 Was added TEMPO (0.24 g, 1.5 mmol) to a solution of _4- bromo- _3- methyl-3,6- dioxol-6-ol (14.6 g, 76.7 mmol), NaHCO3 (19.3 g, 230.3 mmol) and NaBr (1.6 g, 15.4 mmol) The mixture was cooled to 0 DEG 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) was added and the mixture was stirred at room temperature for 2 hours The mixture was filtered and washed with acetone (2 times, 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. Filtered. The filtrate was concentrated to give the title compound (9.0 g, 58%) as a light yellow solid.

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

Step 3: ((3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2- d] [1,3] dioxol- Methanone (Compound c42 )

To a solution of (3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2- d] [1,3] dioxole-5-carboxylic acid To a suspension of HBTU (25.1 g, 66.3 mmol, N, N, N ', N'-tetramethyl-O- (lH-benzotriazol- l-yl) uronium hexafluorophosphate) 4-Methylmorpholine (7.3 mL, 66.3 mmol) was added. 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 1H), 4.47 (d, J = 2.4 Hz, 1H), 3.85-3.62 (m, 6H), 3.53-3.49 (m, 2H), 1.49 (s, [M + H] < ⁺ >

Step 4: ((3aS, 5R, 6S, 6aS) -6-Hydroxy-2 < RTI ID = 0.0 & , 2-dimethyltetrahydrofuro [2,3-d] [1,3] dioxol-5-yl) methanone (Compound c43 )

To a solution of 7-bromo-4-chloro-5- (4-ethoxybenzyl) benzo [d] [1,3] dioxole (compound c42-1 , 1.75 g, 4.73 mmol) in THF (17.5 mL) Was added n-BuLi (2.5 M solution in hexanes, 2.3 mL, 5.69 mmol). After 1 hour, a solution of ((3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2- d] [1,3 ] Dioxol-5-yl) (morpholino) methanone (compound c42 , 0.43 g, 1.58 mmol) was added dropwise to the mixture. After 4 h, the reaction was quenched by adding saturated NH ₄ Cl solution to the resulting mixture 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 (TM) FLASH Purification System) to give the title compound (0.43 g, 19%); [M + H] < ⁺ >

Step 5: (3aS, 5S, 6R, 6aS) -5- ((S) - (7-chloro-6- (4- ethoxybenzyl) benzo [d] [1,3] dioxol- (Hydroxy) methyl) -2,2-dimethyltetrahydrofuro [2,3-d] [1,3] dioxol-6-ol c44 )

CH ₃ OH (18 mL) solution of (7-chloro-6- (4-methoxybenzyl) benzo [d] [1,3] dioxol-4-yl) ((3aS, 5R, 6S , 6aS) -6 -hydroxy-2,2-dimethyl-tetrahydro-furo [2,3-d] [1,3] dioxol-5-yl) -methanone to a solution of CeCl _{(0.43 g, 0.90 mmol) 3} · 7H 2 O (0.40 g, 1.08 mmol) was added and the mixture was stirred at room temperature until all solids dissolved. The mixture was cooled to -78 ℃, was added _{NaBH 4 (0.04 g, 1.08 mmol} ) little by little. The mixture was stirred at -78 ℃, and the temperature was gradually raised to 0 ℃ to stop the reaction was added to saturated NH ₄ Cl solution. The mixture was concentrated under reduced pressure to remove the CH ₃ OH and then extracted with EtOAc and washed with saturated NaCl 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 (TM) FLASH Purification System) to give the title compound (0.25 g, 58%); [M + Na] < ⁺ >

Step 6: (3S, 4R, 5S, 6S) -6- (7-Chloro-6- (4-ethoxybenzyl) benzo [d] [1,3] dioxol- Pyran-2,3,4,5-tetrayl tetraacetate (compound c45 )

(3aS, 5S, 6R, 6aS) -5 - ((S) -7-chloro-6- (4-ethoxybenzyl) benzo [d] [1,3] dioxane in AcOH / water (1.7 / 2-dimethyltetrahydrofuro [2.3-d] [1,3] dioxol-6-ol (0.25 g, 0.52 mmol) in toluene Lt; / RTI > for 12 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude oil was treated with acetic anhydride (0.39 mL, 4.16 mmol) and DMAP (0.03 g, 0.26 mmol) in dichloromethane (6.5 mL) at 0 ° C. The mixture was stirred at room temperature for 8 hours. Water was added to the resulting mixture to terminate the reaction, 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 (0.19 g, 60%) as a white solid; [M + Na] < ⁺ >

Step 7: (2S, 3S, 4R, 5S, 6R) -2- (7-chloro-6- (4- ethoxybenzyl) benzo [d] [1,3] dioxol- (Methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c46 )

To a solution of (3S, 4R, 5S, 6S) -6- (7-chloro-6- (4-ethoxybenzyl) benzo [d] [1,3] dioxol- TMSOTf (80 L, 0.47 mmol) was added to a solution of tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (190 mg, 0.31 mmol) and thiourea (50 mg, 0.62 mmol) And the reaction mixture was heated to 80 < 0 > C for 4 hours. The mixture was cooled to room temperature and MeI (50 L, 0.78 mmol) and DIPEA (540 L, 3.10 mmol) were added and the mixture was stirred for 3 hours. The resulting mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO _4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (41 mg, 22%) as a white solid

^{1 H NMR (400 MHz, CDCl} 3) δ 7.04 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.60 (s, 1H), 6.08 (s, 1H), 6.01 (s, 1H), 5.35-5.27 (m, 4H), 5.19 (t, J = 8.9 Hz, 2H), 4.49-4. 45 (m, 2H), 4.03-3.98 = 6.6 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.78 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H); [M + Na] < ⁺ >

Step 8: (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4- ethoxybenzyl) benzo [d] [1,3] dioxol- (Methylthio) tetrahydro-2H-pyran-3,4,5-triol (Compound c47 )

2- (7-chloro-6- (ethoxybenzyl 4-) (2S, 3S, 4R , 5S, 6R) in CH ₃ OH (0.7 mL) at room temperature benzo [d] [1,3] dioxol- (25% solution in CH ₃ OH) was added to a suspension of 4- (4-pyridyl) -6- (methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (41 mg, Was added. After 20 hours, the resulting mixture was concentrated in vacuo. The crude product was diluted with EtOAc and filtered through a membrane. The filtrate was concentrated in vacuo to give the title compound (31 mg, 97%) as a white solid

^{1 H NMR (400 MHz, CDCl} 3) δ 7.13 (d, J = 8.56 Hz, 2H), 6.85 (d, J = 8.68 Hz, 2H), 6.81 (s, 1H), 6.09 (d, J = 4.4 Hz 2H), 4.40 (d, J = 9.56 Hz, 1H), 4.33 (d, J = 9.72 Hz, 1H) J = 9.34 Hz, 1H), 3.48 (t, J = 8.84 Hz, 1H), 3.40 (d, J = 9.4 Hz, 1H) ); [M + Na] ⁺ 491.

Example 11: (2S, 3R, 4R, 5S, 6R) -2- (8-chloro-7- (4-ethoxybenzyl) -2,3-dihydrobenzo [ 5-yl) -6- (methylthio) tetrahydro-2H-pyran-3,4,5-triol

The above intermediate 1 (methyl 8-bromo-5-chloro-2,3-dihydrobenzo [b] [1,4] dioxin-6-carboxylate) was reacted with the appropriate Grignard reagent to give 8- -Chloro-6- (4-ethoxybenzyl) -2,3-dihydrobenzo [b] [1,4] dioxin. The synthesis procedure of Example 10 was repeated, except that 7-bromo-4-chloro-5- (4-ethoxybenzyl) benzo [d] [1,3] dioxole (compound c42-1) Using the previously synthesized 8-bromo-5-chloro-6- (4-ethoxybenzyl) -2,3-dihydrobenzo [b] [1,4] dioxine, the title compound was obtained.

^{1 H NMR (400 MHz, CDCl} 3) 7.08 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 6.79 (d, J = 2.4 Hz, 2H), 4.67 (d, J = 9.6 Hz, 2H), 3.55-3.51 (m, 1H), 2.78 (m, 2H), 4.83-4.34 1H), 2.49 (br.s, 1H), 2.14 (s, 3H), 2.10 (br.s, 1H), 1.39 (t, J = 7.0 Hz, 3H); [M + Na] < ⁺ >

Example 12: (2S, 3R, 4R, 5S, 6R) -2- (6- (4-ethoxybenzyl) -7-methylbenzo [d] [1,3] dioxol- - (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

To a solution of (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (7-chloro-6- (4-ethoxybenzyl) (1.16 g, 1.61 mmol), methylboronic acid (0.29 g, 4.83 mmol), potassium tertiary phosphate (1.71 g, , 8.05 mmol), palladium (II) acetate (0.04 g, 0.16 mmol), and 2-dicyclohexylphosphino-2 ', 6'- dimethoxybiphenyl (S- Phos, 0.07 g, 0.16 mmol) The mixture was stirred at 110 ^° C for 2 days. The resulting mixture was cooled to room temperature and the insoluble material was removed by filtration through celite. The filtrate was concentrated in vacuo to give (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (6- (4- ethoxybenzyl) -7- ] Dioxol -4-yl) tetrahydro-2H-pyran-3,4,5- triyl triacetate (formula c53, crude). To a solution of (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (6- (4- ethoxybenzyl) -7- ] Dioxol-4-yl) tetrahydro-2H-pyran-3,4,5-triyl triacetate in THF (20 mL) was added NaOMe (25 wt%, 0.40 mL). The reaction mixture was stirred at room temperature for 21 hours and concentrated in vacuo. Purification of the crude product by preparative _{HPLC (Gilson system, CH 3 CN} / H 2 O) to give the title compound (0.34 g, 48%).

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.04 (d, J = 8.56 Hz, 2H), 6.81 (d, J = 8.56 Hz, 2H), 6.77 (s, 1H), 5.95 (d, J = 8.2 2H), 4.29 (d, J = 9.64 Hz, 1H), 4.01 (q, J = 6.96 Hz, 2H), 3.91-3.88 (m, 3H), 3.70-3.68 (m, 1H), 3.41-3.39 (m, 2H), 2.05 (s, 3H), 1.38 (t, J = 6.98 Hz, 3H); [M + Na] < ⁺ >

Examples 13 and 14

The synthesis procedure of Example 12 was repeated except that (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (7-chloro-6- (4-ethoxybenzyl) benzo [ ] [1,3] dioxol-4-yl) tetrahydro-2H-pyran-3,4,5- triyl triacetate (compound c52 ) Compounds were synthesized.

Example 13: Preparation of (2R, 3S, 4R, 5R, 6S) -2- (hydroxymethyl) -6- -4-yl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.06 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 5.95 (dd, J = 8.7 2H), 4.84 (s, 4H), 4.29 (d, J = 9.7 Hz, 1H), 3.92-3.85 (m, 3H), 3.72-3.64 (M, 2H), 2.30 (s, 3H), 2.04 (s, 3H); [M + Na] < ⁺ >

Example 14: Preparation of (2R, 3S, 4R, 5R, 6S) -2- (hydroxymethyl) -6- (6- (4- methoxybenzyl) Sol-4-yl) tetrahydro-2H-pyran-3,4,5-triol

^{1 H NMR (400 MHz, CD} 3 OD) δ 7.05 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 5.95 (dd, J = 9.0 (M, 2H), 3.85 (s, 3H), 3.71-3.64 (m, 2H) ), 3.51-3.39 (m, 3H), 2.04 (s, 3H); [M + Na] < ⁺ >

Experimental Example 1: Evaluation of synthesis yield of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate

(1) Synthesis using sulfuryl chloride as the chlorinating agent

The procedure of Step 3 of Example 1 was repeated except that the synthesis was carried out using 1 eq, 1.5 eq, 3 eq and 5 eq of sulfuryl chloride (SO ₂ Cl ₂ ) instead of N-chlorosuccinimide as the chlorinating agent The product was analyzed by LC-Mass and summarized in Table 1 below.

SO ₂ Cl ₂ 1 eq 1.5 eq 3 eq 5 eq A: B: C
(Weight ratio) 40: 20: 35 10: 40: 50 20: 40: 40 30: 30: 40

(2) Synthesis using N-chlorosuccinimide as the chlorinating agent

The procedure of Step 3 of Example 1 was repeated except that N-chlorosuccinimide (NCS) was used as the chlorinating agent. The temperature and the solvent were changed as shown in Table 2 below, The product after the time was analyzed by LC-Mass and summarized in Table 2 below.

menstruum DMF CH ₃ CN AcOH CHCl ₃ Temperature Room temperature Room temperature 60 ° C 60 ° C c23: A: B
(Weight ratio) 1: 1: 1.5 1: 2: 1 1: 5: 3 1: 5: 0

As shown in Tables 1 and 2, the yield of the target compound c24 was highest when NCS was used as a chlorinating agent and chlorination was performed using chloroform as a solvent.

Claims (10)

(1) esterifying and halogenating 3,4-dihydrobenzoic acid to obtain a compound of formula (2);
(2) reacting the compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4);
(3) aldehyde or amidation of the compound of formula (4) followed by reduction with a compound of formula (5) to obtain a compound of formula (6); And
(4) reacting the compound of formula (6) with a compound of formula (7), deprotecting and reducing the compound of formula

In this formula,
A is oxygen (O) or sulfur (S);
R is hydroxymethyl;
n is an integer from 1 to 3;
PG is a protecting group;
X 'is a halogen or C _1-7 alkyl;
X, Y and Hal are each independently halogen;
B is one or more _members selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-7 alkylthio, C _1-7 alkyl, C _3-10 cycloalkyl and C _1-7 alkoxy Or phenyl unsubstituted or substituted with a substituent.
The method according to claim 1,
Wherein X is chloro,
Wherein the halogenation reaction of step (1) comprises a chlorination reaction,
Wherein the chlorination reaction is carried out using N-chlorosuccinimide as the chlorinating agent.
3. The method of claim 2,
The method of producing a compound of formula (I) wherein the chlorination is carried out using a solvent containing chloroform (CHCl _3).
The method according to claim 1,
Wherein X is chloro, Y is bromo,
Wherein the halogenation reaction of step (1) comprises a chlorination reaction after the bromination reaction.
The method according to claim 1,
Wherein the step (3) comprises aldehyde the compound of formula (4) to obtain a compound of formula (4a), and then reacting it with the compound of formula (5)
[Chemical Formula 4a]

Wherein n, X and Y are as defined in claim 1.
The method according to claim 1,
In step (3)
Wherein the step (3) comprises amidating the compound of the formula (4) to obtain a compound of the formula (4b) and then reacting it with the compound of the formula (5)
(4b)

Wherein n, X and Y are as defined in claim 1.
The method according to claim 1,
Wherein the method further comprises an alkylation reaction after step (4)
Wherein X < ₁ > is C1-7 alkyl.
The method according to claim 1,
Wherein the method further comprises, after step (4)
Further comprising the step of isolating and deprotecting the precipitate formed by heating in alcohol, ethyl acetate, or dichloromethane after introducing a protecting group into the compound of formula 1 to obtain only the? -Form Gt;
The method according to claim 1,
Wherein A is oxygen (O);
R is hydroxymethyl;
Wherein n is 1;
Wherein X 'is halogen;
Wherein B is halogen, hydroxy, cyano, nitro, amino, mercapto, substituted with C _1-4 alkyl, C _3-6 cycloalkyl, and C _1-4 alkoxy at least one substituent selected from the group consisting of or unsubstituted Wherein R < 1 >
(1) esterifying and halogenating 3,4-dihydrobenzoic acid to obtain a compound of formula (2);
(2) reacting the compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4);
(3) aldehyde or amidation of the compound of formula (4) followed by reduction with a compound of formula (5) to obtain a compound of formula (6);
(4) reacting the compound of formula (6) with a compound of formula (8) and reducing to obtain a compound of formula (9);
(5) forming a furanos ring of the compound of formula (9) in a pyranose ring under acidic conditions and introducing a protecting group to obtain a compound of formula (10); And
(6) A process for producing a compound represented by the following formula (1), which comprises treating the compound of the formula (10) with thiourea, reacting it with a C _1-7 alkyl halide,

In this formula,
A is oxygen (O);
R is C _1-7 alkylthio;
n is an integer from 1 to 3;
PG is a protecting group;
X 'is a halogen or C _1-7 alkyl;
X, Y and Hal are each independently halogen;
B is one or more _members selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C _1-7 alkylthio, C _1-7 alkyl, C _3-10 cycloalkyl and C _1-7 alkoxy Or phenyl unsubstituted or substituted with a substituent.