WO2017217792A1 - 다이페닐메탄 유도체의 제조방법 - Google Patents

다이페닐메탄 유도체의 제조방법 Download PDF

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WO2017217792A1
WO2017217792A1 PCT/KR2017/006271 KR2017006271W WO2017217792A1 WO 2017217792 A1 WO2017217792 A1 WO 2017217792A1 KR 2017006271 W KR2017006271 W KR 2017006271W WO 2017217792 A1 WO2017217792 A1 WO 2017217792A1
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Prior art keywords
compound
formula
reaction
alkyl
mmol
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PCT/KR2017/006271
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English (en)
French (fr)
Korean (ko)
Inventor
윤희균
박세환
윤지성
최순규
서희정
박은정
공영규
송광섭
김민주
박소옥
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Daewoong Pharmaceutical Co Ltd
GC Biopharma Corp
Original Assignee
Green Cross Corp Korea
Daewoong Pharmaceutical Co Ltd
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Priority to DK17813615.6T priority Critical patent/DK3473621T3/da
Priority to MA44545A priority patent/MA44545B2/fr
Priority to ES17813615T priority patent/ES2891825T3/es
Priority to PL20152959T priority patent/PL3663292T3/pl
Priority to EP17813615.6A priority patent/EP3473621B1/en
Priority to TNP/2018/000437A priority patent/TN2018000437A1/en
Priority to CA3026756A priority patent/CA3026756C/en
Priority to MX2021008988A priority patent/MX392177B/es
Priority to BR112018076243-1A priority patent/BR112018076243B1/pt
Priority to CN202110860586.9A priority patent/CN113651803B/zh
Priority to NZ749398A priority patent/NZ749398A/en
Priority to MA50774A priority patent/MA50774B1/fr
Priority to SG11201811154QA priority patent/SG11201811154QA/en
Priority to PL17813615T priority patent/PL3473621T3/pl
Priority to EP20152959.1A priority patent/EP3663292B1/en
Priority to RU2019101056A priority patent/RU2774998C2/ru
Priority to CN201780036968.1A priority patent/CN109311861B/zh
Application filed by Green Cross Corp Korea, Daewoong Pharmaceutical Co Ltd filed Critical Green Cross Corp Korea
Priority to AU2017285813A priority patent/AU2017285813B2/en
Priority to PE2023002240A priority patent/PE20240590A1/es
Priority to MX2018015647A priority patent/MX385640B/es
Priority to JP2018565754A priority patent/JP6763978B2/ja
Priority to US16/310,005 priority patent/US10640496B2/en
Priority to MYPI2018002498A priority patent/MY203941A/en
Publication of WO2017217792A1 publication Critical patent/WO2017217792A1/ko
Priority to SA521422474A priority patent/SA521422474B1/ar
Priority to SA518400666A priority patent/SA518400666B1/ar
Priority to PH12018550206A priority patent/PH12018550206A1/en
Anticipated expiration legal-status Critical
Priority to CONC2018/0014018A priority patent/CO2018014018A2/es
Priority to US16/557,180 priority patent/US10889574B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of diphenylmethane derivatives, and more particularly to an improved process for preparing diphenylmethane derivatives useful as inhibitors of sodium-dependent glucose cotransporters (SGLT).
  • SGLT sodium-dependent glucose cotransporters
  • SGLT Sodium-dependent glucose cotransporter
  • SGLT1 is located in the intestine, kidney and heart and regulates cardiac glucose transport through expression.
  • SGLT1 is a high affinity low dose transporter and therefore only accounts for a portion of renal glucose reuptake.
  • SGLT2 is a low affinity, high dose transporter primarily located in the apica domain of epithelial cells in the early proximal manure tubules.
  • US Patent Publication No. 2015/0152075 discloses a compound having a diphenylmethane moiety having inhibitory activity against SGLT2 and a process for preparing the same.
  • the document discloses that the diphenylmethane derivative compound has an excellent inhibitory effect on human SGLT2 activity and is effective in treating diabetes by significantly reducing urine glucose excretion in animals than dapagliflozin, which is well known as an SGLT2 inhibitor.
  • US Patent Publication No. 2014/0274918 also discloses diphenylmethane derivatives effective as dual inhibitors for sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2). have.
  • Example 172 and the like of US Patent Application Publication No. 2015/0152075 disclose a method for preparing diphenylmethane compound c28 in the same manner as in Scheme 1 below.
  • diphenylmethane derivatives can be effectively produced by a convergent synthesis method in which each main group is separately synthesized and then coupled instead of the conventional sequential synthesis method.
  • the invention has been completed.
  • A is oxygen (O) or sulfur (S);
  • n 1 or 2;
  • PG is a protecting group
  • X ' is halogen or C 1-7 alkyl
  • X, Y and Hal are each independently halogen
  • 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 alkoxy Neyl-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
  • 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 halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 alkyl, and C 2-7 alkynyl
  • substituents selected from the group consisting of;
  • cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are each independently unsubstituted or halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-4 alkyl, and C One or more substituents selected from the group consisting of 1-4 alkoxy;
  • heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S and O.
  • R is C 1-7 alkylthio
  • a crystalline form of the compound prepared by the above method specifically, a crystalline form of the compound of formula c28.
  • the method for preparing a diphenylmethane derivative of the present invention is performed by a convergent synthesis method in which the main groups are individually synthesized and then coupled, the synthesis route is lower than that of the linear synthesis method disclosed in the prior art. It improves reproducibility by reducing concise and higher yields and reducing the risks inherent in sequential synthesis pathways (such as the need to go back to the first route if a failure occurs in the middle of synthesis).
  • the residues of the aglycone group must be synthesized even after the glucose group is coupled with the aglycone group, but according to the present invention, all of the residues of the aglycone group are combined before the coupling with the glucose group. Can be formed.
  • aryl groups bonded to the end groups of the aglycone can also be easily synthesized, allowing various designs of end groups.
  • the crystalline form of the compound prepared by the method is excellent in physicochemical properties, it can be usefully used in the field of pharmaceutical production.
  • the present invention relates to a process for preparing a compound of formula (I):
  • A is oxygen (O) or sulfur (S);
  • R is hydroxymethyl or C 1-7 alkylthio
  • n 1 or 2;
  • X ' is halogen (eg F, Cl, Br or I) or C 1-7 alkyl;
  • 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 alkoxy Neyl-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
  • 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 halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 alkyl, and C 2-7 alkynyl
  • substituents selected from the group consisting of;
  • cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are each independently unsubstituted or halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-4 alkyl, and C One or more substituents selected from the group consisting of 1-4 alkoxy;
  • heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from the group consisting of N, S and O.
  • the ring B-1 may be selected from the group consisting of:
  • R 7 is hydrogen or C 1-7 alkyl
  • R 8a and R 8b are each, independently, C 1-7 alkyl or linked to each other to form a 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, S and O .
  • the ring B-2 may be selected from the group consisting of:
  • the compound of Formula 1 may be a compound of Formula 1a or a compound represented by Formula 1b:
  • A, B, R, X 'and n are the same as defined in Formula 1 above.
  • A is oxygen; N is 1; X 'is halogen; B is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 alkyl, C 3-10 cycloalkyl, and C 1-7 alkoxy Or unsubstituted phenyl.
  • the compounds of Formulas 1a and 1b may be compounds in which the glucose is in ⁇ -form, ⁇ -form, or racemic forms thereof.
  • the compound of Formula 1a and 1b may be a compound having a ⁇ - form of glucose.
  • A is oxygen (O) or sulfur (S);
  • n 1 or 2;
  • PG is a protecting group
  • X ' is halogen or C 1-7 alkyl
  • X, Y and Hal are each independently halogen
  • the compound of Formula 2 used as a starting material in the preparation method may be prepared by a synthetic route disclosed in the prior art (US Patent Publication No. 2015/0152075 A1).
  • the compound of Formula 2 may be prepared by the following steps:
  • halogen means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • step (1) the compound of Formula 2 is reacted with a compound of Formula 3 and cyclized to obtain a compound of Formula 4.
  • five- or six-membered rings containing oxygen in the aglycon group can be preformed prior to coupling with the glucose group and also before forming the terminal residues (ie ring B) of the aglycon group.
  • Step (1) is a specific example
  • n 1 or 2; X and Y are each independently halogen.
  • step (i) the compound of Formula 2 may undergo a demethylation step before reacting with the compound of Formula 3.
  • the compound of Formula 2 may be demethylated to obtain a compound of Formula 2e, and the compound of Formula 2e may be reacted with the compound of Formula 3:
  • X and Y are each independently halogen.
  • the displacement reaction in step (ii) can be carried out, for example, as a claisen rearrangement reaction.
  • the displacement reaction can be carried out by the addition of 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.
  • the repositioning reaction may be carried out in a solvent-free reaction, or may be carried out under heating conditions of a high temperature (eg 150 ⁇ 170 °C) in diethylamine.
  • a high temperature eg 150 ⁇ 170 °C
  • the compound of formula 3a may be obtained as a compound of formula 3b after the displacement reaction in step (ii):
  • n 1 or 2; X and Y are each independently halogen.
  • the oxidation or ozonation reaction in step (ii) may be performed by osmium tetroxide (OsO 4 ), potassium osmate (VI) dihydrate, or ozone (O 3 ). Can be performed by addition.
  • OsO 4 osmium tetroxide
  • VI potassium osmate
  • O 3 ozone
  • the compound of formula 3b may be obtained as a compound of formula 3c after the oxidation or ozonation reaction in step (ii):
  • n 1 or 2; X and Y are each independently halogen.
  • step (iii) the compound of Chemical Formula 3d may be obtained as a compound of Chemical Formula 4 through a cyclization reaction. According to this method, the yield can be improved compared to the cyclization method disclosed in the prior art (US Patent 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.
  • the cyclization reaction may be performed by adding a Vilsmeier reagent to the compound of Formula 3d. At this time, the reaction may be carried out at a temperature of 0 °C to room temperature.
  • the Vilsmeier reagent is preferably prepared immediately in the synthesis, in terms of yield.
  • the Vilsmeier reagent may be prepared by the reaction of dimethylformamide (DMF) with SOCl 2 or POCl 3 .
  • the cyclization reaction may be performed by introducing a tosyl group or a mesyl group as a leaving group.
  • the cyclization reaction may be performed using a halide such as I 2 , PBr 3 and the like.
  • the cyclization reaction may also be carried out through a Mitsunobu reaction using DIAD (Diisopropyl azodicarboxylate) or the like.
  • These reactions are reactions in which a primary alcohol group is substituted with a group capable of acting as a leaving group and a cyclization reaction occurs by acting as a nucleophile in a phenol group.
  • step (2) the compound of formula 4 is aldehydeized or amideized, reacted with the compound of formula 5 and reduced to obtain a compound of formula 6.
  • step (2) may include aldehydeizing the compound of Formula 4 to obtain a compound of Formula 4a, and then reacting it with the compound of Formula 5:
  • n 1 or 2; X and Y are each independently halogen.
  • the aldehyde reaction may be carried out by reducing the compound of Formula 4 to obtain a compound of Formula 4c, followed by reaction with PCC (pyridinium chlorochromate) or magnesium dioxide, sulfur trioxide pyridine complex, and the like.
  • PCC pyridinium chlorochromate
  • magnesium dioxide magnesium dioxide
  • sulfur trioxide pyridine complex and the like.
  • n 1 or 2; X and Y are each independently halogen.
  • a reducing agent such as NaBH 4, LiBH 4, and the like may be used when the compound of Formula 4 is reduced.
  • Alcohol, tetrahydrofuran (THF), or mixtures thereof may also be used as solvent in the reduction.
  • a mixed solvent of ethanol and THF may be used in the reduction, and the mixing volume ratio thereof may be 1: 1 to 1: 3.
  • a Lewis acid may be further used in the reduction, and examples of the Lewis acid usable include LiCl, CaCl 2 and the like.
  • n 1 or 2
  • X and Y are each independently halogen
  • B is as defined in the formula (1).
  • the compound of Chemical Formula 6 may be obtained by reducing the compound of Chemical Formula 6a.
  • step (2) 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:
  • n 1 or 2; X and Y are each independently halogen.
  • the amidation reaction may be carried out by hydrolyzing the compound of Formula 4 and then reacting with N, O-dimethylhydroxyamine hydrochloride (MeO (Me) NH.HCl) and the like, and as a result, Weinreb amide form such as 4b can be obtained.
  • MeO (Me) NH.HCl N, O-dimethylhydroxyamine hydrochloride
  • Weinreb amide form such as 4b can be obtained.
  • the compound of Formula 5 may be a Grignard reagent.
  • the compound of Formula 5 may be prepared by reacting the compound of Formula 5a with metal magnesium (Mg):
  • Group B of the final compound (Compound 1a) can be easily introduced in advance according to the Grignard reagent preparation method before coupling the aglycone group to the glucose group, thereby enabling various derivatization. Final yield can also be improved.
  • step (3) the compound of Formula 6 is reacted with the compound of Formula 7, followed by deprotection and reduction.
  • reaction of 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) and the like.
  • the compound of formula 6 may be reacted with the compound of formula 7 to obtain a compound of formula 7a:
  • A is oxygen or sulfur; n is 1 or 2; X is halogen; PG is a protecting group; B is as defined in the formula (1).
  • the protecting group may be, for example, trimethylsilyl group (TMS), benzyl group, or acetyl group.
  • the compound of Formula 7a may be deprotected to obtain the compound of Formula 1a.
  • the protecting group is trimethylsilyl (TMS), methanesulfonic acid (CH 3 SO 3 H) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) is added to the compound of Formula 7a to deprotect it.
  • TMS trimethylsilyl
  • CH 3 SO 3 H methanesulfonic acid
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • reduction may be further performed after the deprotection to obtain the compound of Formula 1a.
  • the compound of Formula 1a obtained through the above steps may be a compound in which the ⁇ - and ⁇ -forms of glucose are mixed.
  • a precipitate formed by heating in alcohol, ethyl acetate, or dichloromethane may be separated and then deprotected to obtain only the ⁇ -form.
  • A is oxygen or sulfur; n is 1 or 2; X is halogen; PG is a protecting group; B is as defined in the formula (1).
  • A, B, n and X ' are as defined in Formula 1 above.
  • step (3) (3)
  • (3c) may be carried out by introducing a protecting group into the compound of Formula 7e and then separating and deprotecting the precipitate produced by heating in alcohol, ethyl acetate, or dichloromethane to obtain only ⁇ -form:
  • PG is a protecting group
  • A, B, n and X are as defined in the general formula (1a).
  • step (3a-1) After the reaction of step (3a-1), it is preferable to further evaporate, extract, dry, filter, etc. to obtain the compound of Formula 7a, and then use it 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.
  • step (3) (3)
  • (3c ') may be carried out by introducing a protecting group into the compound of Formula 7e to separate and deprotect only the ⁇ -form:
  • A, B, n and X are as defined in Formula 1a.
  • a coupling reaction is first performed, wherein the compound of Formula 7 and the reaction reagent (ie, n-butyllithium, sec-butyllithium, t-butyllithium) are used in comparison to 1 equivalent of the compound of Formula 6 Or i-propylmagnesium chloride) can each be used in the reaction in the range of 1.5 to 2.5 equivalents, more preferably in the range of 1.7 to 2.3 equivalents, in particular about 2.0 equivalents.
  • the reaction may be performed at a temperature in the range of -80 ° C to -10 ° C, more preferably at -70 ° C to -60 ° C, for 1 to 12 hours, or 1 to 3 hours.
  • a single solvent of tetrahydrofuran or an ether, a tetrahydrofuran / toluene (1: 1) mixed solvent, or the like may be used as the reaction solvent.
  • step (3a ') deprotection and methylation reactions are carried out in acid conditions.
  • the acid used may include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrogen chloride gas, and the like.
  • a range of 2 to 5 equivalents, more preferably 3 equivalents of acid may be used.
  • the reaction may be performed at a temperature in the range of 0 to 40 ° C, more preferably in the range of 20 to 30 ° C, for 6 to 24 hours, or for 6 to 12 hours.
  • methanol or the like may be used as the reaction solvent.
  • a reduction reaction is performed in the step (3b '), wherein a reducing agent and an acid may be used.
  • the reducing agent may be triethylsilane, triisopropylsilane, t-butyldimethylsilane, sodium borohydride and the like
  • the acid may be boron trifluoride diethyl ether, trimethylsilyltrifluoromethanesulfonate, aluminum Chlorite, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like.
  • the reducing agent may be used in the range of 2 to 5 equivalents, more preferably about 3 equivalents, and the acid may be used in 1.5 to 3 equivalents, more preferably about 2 equivalents.
  • the reaction may be performed at a temperature in the range of ⁇ 50 ° C. to 0 ° C., more preferably at ⁇ 20 ° C. to ⁇ 10 ° C., for 2 to 12 hours, or 2 to 5 hours.
  • a single solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, or dichloromethane / acetonitrile (1: 1), 1,2-dichloroethane / acetonitrile (1: Mixed solvents such as 1) may be used.
  • a protecting group is introduced in the step (3c '), wherein a reaction using an acetylating agent and a base may be performed.
  • the acetylating agent include acetyl chloride, acetyl bromide and acetic anhydride
  • the base includes sodium hydroxide, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, lutidine, and 4-dimethylaminopyridine.
  • the acetylating agent may be used in the range of 4-12 equivalents, more preferably about 8 equivalents
  • the base may be used in the range of 1-4 equivalents, more preferably about 1.5 equivalents.
  • the reaction may be performed at a temperature in the range of 0 to 50 ° C., more preferably in the range of 20 to 30 ° C., for 1 to 12 hours, or 1 to 3 hours.
  • the reaction solvent acetone, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform and the like may be used.
  • step (3c ') the deprotection reaction is carried out in step (3c '), wherein 2 to 12 equivalents of reagents such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and more preferably about 5 It can be used in the equivalent range.
  • the reaction may be performed at a temperature in the range of 0 to 50 ° C., more preferably in the range of 20 to 30 ° C., for 1 to 12 hours, or 1 to 3 hours.
  • Reaction solvents include methanol / water (1: 1 to 3: 1), dichloromethane / methanol (1: 1 to 1: 2), dichloromethane / ethanol (1: 1 to 1: 2), tetrahydrofuran Methanol (1: 1 to 1: 2), tetrahydrofuran / ethanol (1: 1 to 1: 2), tetrahydrofuran / methanol / water (1: 1: 3 to 2: 1: 3), tetrahydro Furan / ethanol / water (1: 1: 3 ⁇ 2: 1: 3) and the like can be used.
  • step (3) (3)
  • (3c '') may be performed by separating, reducing and deprotecting only the ⁇ -form of the compound of Formula 7f:
  • PG is a protecting group
  • A, B, n and X are as defined in the general formula (1a).
  • step (3a '') the coupling reaction, deprotection and methylation are carried out, and the preferable equivalence ratio, the reaction temperature and the solvent conditions are the same as those exemplified in the above (3a ').
  • the protecting group is introduced in the step (3b ''), and the reaction using the acetylating agent and the base may be performed, and the conditions of the preferred type of acetylating agent, the type of base, the equivalent ratio, the reaction temperature and the solvent It is as having illustrated at (3c ').
  • step (3c '') a reduction reaction is carried out in the step (3c ''), wherein a reducing agent and an acid may be used, and the conditions of the preferred reducing agent, acid type, equivalence ratio, reaction temperature and solvent are described in (3b '). As illustrated.
  • the deprotection reaction is carried out in the step (3c ′′), and the conditions such as the type, equivalent ratio, reaction temperature and solvent of the preferred reagent at this time are as exemplified in (3c ').
  • the process of obtaining the compound of Formula 7d may be performed in two steps, or may be performed in one step in an in-situ reaction, thereby further improving final yield.
  • a crude residue containing the compound of Formula 7d may be obtained, or the compound of Formula 7d may be obtained as a solid by crystallization and used in the next step. In the latter case, it is easier to improve the quality and control the moisture content by removing the reaction by-products.
  • next step after the purification process after the synthesis of the compound of Formula 7d, for example (i) after the synthesis of the compound of Formula 7d to form an azeotropic mixture (azotropic mixture) with an organic solvent such as toluene The residue obtained by removing the residual moisture by repeating the concentration process is used in the next step, or (ii) after the synthesis of the compound of formula 7d is crystallized and the residual moisture is removed by vacuum drying to obtain a solid Can be used for steps.
  • azeotropic mixture azotropic mixture
  • organic solvent such as toluene
  • step (3) may further include an alkylation reaction, as a result X 'in Formula 1 may be C 1-7 alkyl.
  • the product after step (4) may be reacted with methylboronic acid to obtain a compound of Formula 1a wherein X 'is substituted with methyl.
  • the compound of Formula 1a may be prepared in a crystalline form, an amorphous form, or a mixture thereof, but the crystalline form is preferable in terms of stability and non-hygroscopicity and thus has physicochemical properties that are easy to formulate.
  • the method of the present invention may further comprise crystallizing the compound of Formula 1a after step (3).
  • the crystallization may be performed using a variety of solvents, thereby obtaining a variety of crystal forms.
  • the solvent used for the crystallization may be toluene; Ethyl acetate; Dichloromethane; Acetone; Acetonitrile; A mixture of 2-propanol, tetrahydrofuran and dichloromethane; And a mixture of tetrahydrofuran and n-hexane, with the result that Form A can be produced.
  • the solvent used for the crystallization may be a mixture of methanol and distilled water; A mixture of methanol and n-hexane; And a mixture of methanol, dichloromethane and n-hexane, which can result in Form B.
  • the solvent used for the crystallization may be a mixture of ethanol, distilled water and n-hexane; And a mixture of tetrahydrofuran and toluene, with the result that Form C can be produced.
  • the solvent used for the crystallization may be a mixture of ethanol and n-hexane, resulting in Form D.
  • the solvent used for the 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.
  • R is C 1-7 alkylthio
  • n 1 or 2;
  • PG is a protecting group
  • X ' is halogen or C 1-7 alkyl
  • X, Y and Hal are each independently halogen
  • step (3) the compound of Formula 6 is reacted with the compound of Formula 8 to obtain a compound of Formula 9.
  • the compound of formula 8 may be prepared according to known methods, for example the method disclosed in 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.
  • the compound of Formula 6 may be reacted with the compound of Formula 8 to obtain a compound of Formula 9a.
  • B, n and X are as defined in the formula (1).
  • step (4) the furanose ring of the compound of formula 9 is formed as a pyranose ring under acidic conditions, and then a protecting group is introduced to obtain a compound of formula 10.
  • This step can complete the pyranose ring forming the glucose group.
  • the protecting group may be, for example, an acetyl group.
  • step (5) the compound of Formula 10 is treated with thiourea, reacted with C 1-7 alkyl halide and then reduced. Through this step, an alkylthio group may be introduced into the final compound (Compound 1b).
  • the C 1-7 alkyl halide may be, for example, C 1-7 alkyl iodide.
  • step (5) an alkylation reaction may be further included after step (5), and as a result, a compound of Formula 1b, wherein X ′ is C 1-7 alkyl, may be obtained.
  • a crystalline form of a compound prepared according to the above preparation method is provided.
  • the present invention provides a crystalline form of the compound of Formula 1a.
  • the present invention provides a crystalline form of a compound of Formula 1a wherein A is O, B is cyclopropylphenyl, n is 1, X 'is Cl and ⁇ -form.
  • the present invention provides a crystalline form of the compound of formula c28.
  • the compound of Chemical Formula c28 may be prepared by the above-mentioned method of preparing Chemical Formula 1a.
  • the compound of Chemical Formula c28 may have various crystalline forms, and each crystalline form will be described in detail below.
  • the term "about” may mean within 5%, preferably within 2% of a predetermined value or range.
  • “about 10%” can mean 9.5% to 10.5%, preferably 9.8% to 10.2%.
  • “about 100 ° C.” can mean 95 ° C. to 105 ° C., preferably 98 ° C. to 102 ° C.
  • the present invention provides Form A of the compound of Formula c28.
  • the crystal form A is 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 when irradiated with Cu-K ⁇ light source.
  • the XRD spectrum of Form A may further comprise peaks at diffraction angles (2 ⁇ ) of 15.4 ° ⁇ 0.2 °, 18.6 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 ° and 23.8 ° ⁇ 0.2 °.
  • the crystalline form may have an endothermic peak having a minimum point of about 159 ° C. at about 157 ° C. in DSC (10 ° C./min).
  • the present invention also provides Form B of the compound of Formula c28.
  • the crystalline form B is 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 when irradiated with Cu-K ⁇ light source Has an XRD spectrum including peaks at a diffraction angle (2 ⁇ ) of ° ⁇ 0.2 °. These peaks may be peaks having a relative intensity (I / I o ) of at least about 5%, preferably at least about 10%.
  • the XRD spectrum of Form B may further comprise peaks at diffraction angles (2 ⁇ ) of 5.6 ° ⁇ 0.2 °, 9.4 ° ⁇ 0.2 ° and 11.0 ° ⁇ 0.2 °.
  • the crystalline form may have an endothermic peak having a minimum point of about 88 ° C. at about 79 ° C. in the DSC (10 ° C./min), and an endothermic peak having a minimum point of about 111 ° C. at about 103 ° C. as a starting point.
  • the present invention also provides Form C of the compound of Formula c28.
  • Form C is 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 when irradiated with Cu-K ⁇ light source.
  • Has an XRD spectrum including peaks at a diffraction angle (2 ⁇ ) of ° ⁇ 0.2 °. These peaks may be peaks having a relative intensity (I / I o ) of at least about 5%, preferably at least about 10%.
  • the XRD spectrum of Form C may further include peaks at diffraction angles 2 ⁇ of 19.9 ° ⁇ 0.2 ° and 23.1 ° ⁇ 0.2 °.
  • the crystalline form may have an endothermic peak having a minimum point of about 159 ° C. at about 157 ° C. in DSC (10 ° C./min).
  • the present invention also provides Form D of the compound of Formula c28.
  • the crystalline form D is 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 when irradiated with Cu-K ⁇ light source Has an XRD spectrum including peaks at a diffraction angle (2 ⁇ ) of ° ⁇ 0.2 °. These peaks may be peaks with a relative intensity (I / I o ) of about 5% or more.
  • the XRD spectrum of Form D may further comprise peaks at diffraction angles (2 ⁇ ) of 20.0 ° ⁇ 0.2 °, 22.5 ° ⁇ 0.2 ° and 25.1 ° ⁇ 0.2 °.
  • the crystalline form may have an endothermic peak having a lowest point of about 160 ° C. at about 157 ° C. in DSC (10 ° C./min).
  • Such a crystalline form of the compound of formula c28 is excellent in physicochemical properties (for example, hygroscopicity, chemical stability, etc.), and thus can be easily handled in various fields (for example, pharmaceutical preparation).
  • DIPEA N, N-diisopropylethylamine
  • NaOMe sodium methoxide
  • NBS N-bromosuccinimide
  • PCC pyridinium chlorochromate
  • Pd (PPh 3 ) 4 tetrakis (triphenylphosphine) palladium (0)
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • N-bromosuccinimide (21.9 g, 123 mmol) was added in portions to a solution of methyl 2-amino-3-methoxybenzoate (22.4 g, 123 mmol) in DMF (250 mL) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h. Water was added to the mixture and extracted with EtOAc (500 mL x 2). The combined organic layers were 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.
  • Oxalyl chloride (2.4 mL, 27.1 mmol) and catalytic amount of DMF were added to a suspension of 5-bromo-2-chloro-3-methoxybenzoic acid (6.0 g, 22.6 mmol) in CH 2 Cl 2 (100 mL) at room temperature. It was. The mixture was stirred at rt for 2 h. The mixture was evaporated in vacuo and dried under high vacuum to afford the crude title compound.
  • Step 7 (5-Bromo-2-chloro-3-hydroxyphenyl) (phenyl) methanone (compound c8 )
  • Step 8 3-benzyl-5-bromo-2-chlorophenol (compound c9 )
  • Step 9 1- (allyloxy) -3-benzyl-5-bromo-2-chlorobenzene (compound c10 )
  • 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 )
  • Step 11 (3R, 4R, 5S, 6R) -2- (3- (allyloxy) -5-benzyl-4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4 , 5-triol (compound c13 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • Step 22 (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (6- (4-acetylbenzyl) -7-chloro-2,3-dihydrobenzofuran-4- Tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound) c24 )
  • Step 23 (2R, 3R, 4R, 5S, 6S) -2- (Acetoxymethyl) -6- (7-chloro-6- (4- (1-hydroxyethyl) benzyl) -2,3-di Hydrobenzofuran-4-yl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c25 )
  • Step 24 (2R, 3R, 4R, 5S, 6S) -2- (Acetoxymethyl) -6- (7-chloro-6- (4-vinylbenzyl) -2,3-dihydrobenzofuran-4- Tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound) c26 )
  • 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 )
  • Step 26 (2S, 3R, 4R, 5S, 6R) -2- (7-Chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran-4-yl) -6- (hydr Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol (compound c28 )
  • the total yield of the final compound of Comparative Example 1 according to the synthetic route of steps 1 to 26 was calculated to be about 1% or less.
  • Step 2 methyl 3- (allyloxy) -5-bromo-2-chlorobenzoate (compound c30 )
  • Step 4 methyl 5-bromo-2-chloro-3-hydroxy-4- (2-hydroxyethyl) benzoate (compound c33 )
  • Step 7 4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound c36 )
  • Step 8 (4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl) (4-cyclopropylphenyl) methanol (compound c39 )
  • Step 9 4-bromo-7-chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran (compound c40 )
  • 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 )
  • 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 )
  • 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 )
  • 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 )
  • Step 14 (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran-4-yl) -6- (hydr Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol (compound c28 )
  • reaction solution was diluted with EtOAc and water.
  • 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 afford the title compound as a crude.
  • the total yield of the final compound of Example 1 according to the synthetic route of steps 1 to 14 was calculated to be about 12%.
  • 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 )
  • 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 )
  • 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 )
  • Step 4 (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran-4-yl) -6- (hydr Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol (compound c28 )
  • 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 )
  • step 8 of Example 1 The synthesis procedure of step 8 of Example 1 was repeated with 4-bromo-7-chloro-2,3-dihydrobenzofuran-6-carbaldehyde (compound c36 ) as a starting material, as Grignard reagent (4 (4-Bromo-7-chloro-2,3-dihydrobenzofuran-6-yl) (4-methoxyphenyl) methanol (compound c49 ) was prepared using -methoxyphenyl) magnesium bromide (compound 48 ). Prepared.
  • Step 2 7-chloro-6- (4-methoxybenzyl) -4-((2S, 3R, 4R, 5S, 6R) -3,4,5-tris (benzyloxy) -6-((benzyloxy Methyl) tetrahydro-2H-thiopyran-2-yl) -2,3-dihydrobenzofuran (compound c53 )
  • Step 1 ((3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,2-d] [1,3] dioxol-6-ol
  • the yellow oil was suspended in water (5 mL), then the pH was adjusted from 9 to 2 with 1 N HCl solution in water. The reaction mixture was stirred at rt for 12 h. The resulting mixture was neutralized by addition of 25% (w / w) K 3 PO 4 in water until the pH reached 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.
  • Step 2 (3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d] [1,3] dioxol-5-carboxylic acid
  • Step 3 ((3aS, 5R, 6S, 6aS) -6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d] [1,3] dioxol-5-yl) (morphopoly No) methanone (compound) c56 )
  • 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 )
  • Step 5 (3aS, 5S, 6R, 6aS) -5-((S)-(7-chloro-6- (4-ethoxybenzyl) -2,3-dihydrobenzofuran-4-yl) (hydr Roxy) methyl) -2,2-dimethyltetrahydrofuro [2,3-d] [1,3] dioxol-6-ol (compound c59 )
  • 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 )
  • Step 7 (2S, 3S, 4R, 5S, 6R) -2- (7-Chloro-6- (4-ethoxybenzyl) -2,3-dihydrobenzofuran-4-yl) -6- (methyl Thio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound c61 )
  • Step 8 (2S, 3R, 4R, 5S, 6R) -2- (7-chloro-6- (4-ethoxybenzyl) -2,3-dihydrobenzofuran-4-yl) -6- (methyl Thio) tetrahydro-2H-pyran-3,4,5-triol (compound c54 )
  • step 4 4-bromo-7-chloro instead of 4-bromo-7-chloro-6- (4-ethoxybenzyl) -2,3-dihydrobenzofuran
  • the title compound was obtained using -6- (4-ethylbenzyl) -2,3-dihydrobenzofuran.
  • Step 1 (3R, 4S, 5S, 6R) -2- [7-chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran-4-yl])-6- (hydroxy Methyl) -2-methoxytetrahydro-2 H Pyran-3,4,5-triol (compound c42 )
  • the title compound was synthesized via the route below 1a or 1b.
  • n -butyllithium (550 mL, 2.0 M in hexanes, 1.38 mol) was added dropwise for 1 hour while maintaining the internal temperature below -60 ° C.
  • n -butyllithium dropping was completed, the mixture was further stirred at -78 ° C for 40 minutes.
  • the concentrated hydrochloric acid / methanol (152 mL / 1750 mL) solution was added dropwise to the reaction mixture for 20 minutes while maintaining the internal temperature below -30 ° C.
  • the reaction vessel was transferred to room temperature and stirred for 18 hours.
  • the reaction vessel was cooled to 0 ° C., saturated aqueous NaHCO 3 (2.5 L) was added thereto, adjusted to pH 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), after layer separation the organic layers were combined and the aqueous layer was extracted with EtOAc (2 x 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), filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the residue was diluted with toluene (500 mL) and distilled off under reduced pressure twice to give the title compound (328 g) as a yellow liquid.
  • the crude residue was used for next step without further purification.
  • n-butyllithium (22.1 mL, 2.5 M in hexanes, 54.9 mmol) was added dropwise for 15 minutes while maintaining the internal temperature below -60 ° C.
  • n-butyllithium dropping was completed, the mixture was further stirred at -78 ° C for 30 minutes.
  • the concentrated hydrochloric acid / methanol (7.01 mL / 70 mL) solution was added dropwise to the reaction mixture for 10 minutes while maintaining the internal temperature below -30 ° C.
  • the reaction vessel was transferred to room temperature and stirred for 18 hours.
  • the reaction vessel was cooled to 0 ° C., saturated aqueous NaHCO 3 solution (60 mL) was added thereto, adjusted to pH 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), after layer separation, the organic layers were collected and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were 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.
  • 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 )
  • 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 )
  • Step 4 (2S, 3R, 4R, 5S, 6R) -2- [7-chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran-4-yl] -6- (hydro Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol (compound c28 )
  • the crude title compound was diluted with EtOAc (3.89 L) and then stirred at reflux for 30 minutes to completely dissolve the solid and then cooled to room temperature.
  • 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 )
  • 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 )
  • the mixture was separated by layer to keep the organic layer and the aqueous layer extracted with CH 2 Cl 2 (2 ⁇ 30 mL).
  • the combined organic layers were washed with 1N HCl aqueous solution (50 mL) and brine (30 mL).
  • the organic layer was dried over MgSO 4 (6 g), filtered and the filtrate was concentrated under reduced pressure.
  • the residue was diluted with MeOH (100 mL) and stirred at rt for 12 h.
  • 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, 2 steps total 71%) as a white solid.
  • 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 )
  • Step 4 (2S, 3R, 4R, 5S, 6R) -2- [7-chloro-6- (4-cyclopropylbenzyl) -2,3-dihydrobenzofuran-4-yl] -6- (hydro Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol (compound c28 )
  • reaction solvent and the temperature was adjusted to Lewis acid as shown in Table 2 below, and reacted by adding or not adding Lewis acid.
  • the yield increased to 80% when diisobutylaluminum chloride ((i-Bu) 2 AlCl) or diethylaluminum chloride (Et 2 AlCl), which is a Lewis acid, was added.
  • triphenylphosphine (PPh 3 ), imidazole, iodine (I 2 ) and toluene were used for the cyclization reaction using a halide
  • triphenylphosphine (PPh 3 ) Reagents in which diisopropylazodicarboxylate (DIAD) and tetrahydrofuran (THF) were combined were used.
  • DIAD diisopropylazodicarboxylate
  • THF tetrahydrofuran
  • DSC Differential scanning calorimetry
  • Crystallization with toluene is similar to that described later in the procedure of step 14 of Example 1 above. Specifically, the toluene (8 times by weight of c28 weight) solution of crude compound c28 was dissolved by heating at 40 ° C. for 30 minutes and then cooled to room temperature. It was further stirred for 30 minutes after the suspension was formed at room temperature. The resulting precipitate was filtered, washed with toluene (two times the volume of the filtrate) and dried in a vacuum oven (50 ° C., 12 hours) to give white crystals (yield: 91.8%).
  • the XRD spectra of the prepared crystals showed the crystalline form (crystalline form A) as shown in FIG. 1, and summarized the diffraction angle (2 ⁇ ), the interplanar spacing (d) and the relative intensity (I / I o x 100) of the characteristic peaks.
  • Table 8 is as follows.
  • the DSC spectrum could confirm the melting endothermic peak of the crystal.
  • Crystallization with ethyl acetate is similar to that described at the end of step 4 of Example 6 above. Specifically, the ethyl acetate (15 times c28 weight) solution of the crude compound c28 was dissolved by reflux stirring, and then cooled to room temperature. It was further stirred for 30 minutes after the suspension was formed at room temperature. Isopropyl ether (15 times by weight of c28 ) was added dropwise to the resulting mixture over 30 minutes, and further stirred at room temperature for 30 minutes. The resulting precipitate was filtered, washed with 0 ° C.
  • a tetrahydrofuran (5 times by weight of c28 ) solution of crude compound c28 was dissolved by stirring at room temperature for 30 minutes.
  • N-hexane (10 times the weight of c28 ) was added dropwise to the reaction mixture, followed by stirring for 1 hour.
  • N-hexane (10 times the weight of c28 ) was further added dropwise to the resulting suspension, followed by stirring for 30 minutes.
  • n-hexane (5 times the weight of c28 ) to the reaction suspension was stirred for 30 minutes.
  • a methanol ( 5x weight of c28 ) solution of crude compound c28 was dissolved by stirring at room temperature for 30 minutes. Distilled water (10 times the weight of c28 ) was added dropwise to the reaction mixture, followed by stirring for 30 minutes. Distilled water (10 times the weight of c28 ) was further added dropwise to the resulting suspension, followed by stirring for 1 hour. The resulting precipitate was filtered, washed with distilled water (two times the volume of the filtrate) and dried in a vacuum oven (50 ° C., 12 hours) to give white crystals (yield: 100%).
  • the XRD spectra of the prepared crystals showed the crystal form as shown in Fig. 3 (crystalline form B), and summarized the diffraction angle (2 ⁇ ), the interplanar spacing (d) and the relative intensity (I / I o x 100) of the characteristic peaks. If it is as shown in Table 9.
  • the DSC spectrum could confirm the melting endothermic peak of the crystal.
  • a dichloromethane / methanol (20: 1 times by weight of c28 ) solution of crude compound c28 was dissolved by stirring at room temperature for 30 minutes.
  • N-hexane (10 times by weight of c28 ) was added dropwise to the reaction mixture, followed by stirring for 1 hour.
  • To the resulting suspension was further added dropwise n-hexane (10 times c28 weight) and stirred for 30 minutes.
  • XRD spectra of the prepared crystals showed the crystal form as shown in Fig. 5 (Crystal Form C), and summarized the diffraction angle (2 ⁇ ), the interplanar distance (d) and the relative intensity (I / I o x 100) of the characteristic peaks.
  • Table 10 is as follows.
  • the DSC spectrum could confirm the melting endothermic peak of the crystal.
  • the XRD spectra of the prepared crystals showed the crystal form as shown in Fig. 7 (crystalline form D), and summarized the diffraction angle (2 ⁇ ), the interplanar spacing (d) and the relative intensity (I / I o x 100) of the characteristic peaks. It is shown in Table 11 below.
  • the DSC spectrum could confirm the melting endothermic peak of the crystal.
  • Detector photo-diode array (PDA) detector (side wavelength: 225 nm)
  • Buffer Dissolve 1.36 g of potassium dihydrogen phosphate in 1000 mL of distilled water and adjust to pH 3.0 with phosphoric acid.
  • the non-photoluminescence identification test confirmed the structural stability of the crystalline form under accelerated and long-term conditions.
  • the stability test in the flexible material was carried out by liquid chromatography in the general test method of the Korean Pharmacopoeia.
  • the analysis time of the sample solution was measured up to three times the main peak holding time, and the peak areas of the standard solution (0.05 mg / mL) and the sample solution (1 mg / mL) were calculated according to the calculation except for all peaks appearing in the blank test solution. .
  • the crystal form was confirmed to be stable in the flexible material under accelerated and long-term conditions.
  • the methanol solution of the standard product was used as the standard solution (0.2 mg / mL), and the methanol solution of the crystalline form was used as the test solution (1 mg / mL).
  • the sample solution and the standard solution were tested by the liquid chromatography method in the general test method of the Korean Pharmacopoeia, and the peak area of the standard solution and the solution was calculated by the following formula. As a result, it could be confirmed that there was little change in the content of the crystal form under acceleration and long term conditions.

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EP20152959.1A EP3663292B1 (en) 2016-06-17 2017-06-15 Diphenylmethane derivative in crystalline form
ES17813615T ES2891825T3 (es) 2016-06-17 2017-06-15 Método para producir un derivado de difenilmetano
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CN201780036968.1A CN109311861B (zh) 2016-06-17 2017-06-15 用于制备二苯基甲烷衍生物的方法
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MA50774A MA50774B1 (fr) 2016-06-17 2017-06-15 Procédé de production d'un dérivé de diphénylméthane
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JP2021534174A (ja) * 2018-08-13 2021-12-09 デーウン ファーマシューティカル カンパニー リミテッド Ｓｇｌｔ阻害剤の合成に有用な中間体の製造
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US11661406B2 (en) 2018-08-13 2023-05-30 Daewoong Pharmaceutical Co., Ltd. Method for producing intermediate useful for synthesis of SGLT inhibitor
CN115087649A (zh) * 2020-02-27 2022-09-20 株式会社大熊制药 用于合成sglt抑制剂的中间体和使用该中间体制备sglt抑制剂的方法
US12497390B2 (en) 2020-02-27 2025-12-16 Daewoong Pharmaceutical Co., Ltd. Intermediate useful for synthesis of SGLT inhibitor and method for preparing SGLT inhibitor using same
WO2024136385A1 (ko) 2022-12-21 2024-06-27 주식회사 대웅테라퓨틱스 이나보글리플로진을 포함하는 점안제 형태의 약학 조성물
KR20240099055A (ko) 2022-12-21 2024-06-28 주식회사 대웅테라퓨틱스 이나보글리플로진을 포함하는 점안제 형태의 약학 조성물
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BR112018076243A2 (pt) 2019-03-26
MA44545B1 (fr) 2020-05-29
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AU2017285813B2 (en) 2020-02-06
ECSP19000185A (es) 2019-01-31
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CN109311861A (zh) 2019-02-05
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MX392177B (es) 2025-03-19
RU2019101056A (ru) 2020-07-17
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CL2018003645A1 (es) 2019-03-22
RS62550B1 (sr) 2021-12-31
PL3663292T3 (pl) 2022-01-17
RU2019101056A3 (enExample) 2020-07-17
MA50774A1 (fr) 2021-03-31
SI3663292T1 (sl) 2022-01-31
MX385640B (es) 2025-03-18
MA50774B1 (fr) 2022-02-28
KR102233229B1 (ko) 2021-03-29
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