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【结 构 式】 
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【药物名称】Canagliflozin；JNJ-28431754;TA-7284 【化学名称】1-Deoxy-1-[3-[5-(4-fluorophenyl)thien-2-ylmethyl]-4-methylphenyl]-β-D-glucopyranoside；1,5-Anhydro-1(S)-[3-[5-(4-fluorophenyl)thien-2-ylmethyl]-4-methylphenyl]-D-glucitol 【CA登记号】842133-18-0；928672-86-0 【 分 子 式 】C24H25FO5S 【 分 子 量 】444.516 |
【开发单位】Mitsubishi Tanabe Pharma Corp. (JP); licensed to Johnson & Johnson Pharmaceutical Research & Development, LLC (US) 【药理作用】Sodium/Glucose Cotransporter 2 Inhibitor；Treatment of Type 2 Diabetes；Treatment of Obesity |
合成路线1
O-Protection of gluconolactone (I) with TMSCl in the presence of NMM in THF yields the tetrasilylgluconolactone (II) , which by coupling with either 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl) thiophene (III), with previous treatment with BuLi in THF/toluene at –78 °C , or with iodobenzyl derivative (IV), with previous treatment with Me3SiCH2Li in THF at –40 °C or i-PrMg-Cl·LiCl in THF at 0 °C , provides the D-glucopyranose derivative (V) . Finally, D-glucopyranose (V) is desilylated and reduced stereospecifically by means of Et3SiH and BF3·Et2O in dichloroethane .
Alternatively, glucosidation and cleavage of the silyl protecting groups in intermediate (V) with MeOH and MsOH affords the methyl D-glucopyranoside derivative (VI) , which then undergoes enantiospecific reduction in the presence of TIPS or Et3SiH and BF3·Et2O .
Acetylation of the hydroxyl groups of the methyl D-glucopyranoside (VI) with Ac2O in the presence of NMM and DMAP in toluene/EtOAc leads to tetraacetate derivative (VII), which is then reduced by means of Et3SiH and BF3·Et2O in acetonitrile to give stereospecifically the Dglucitol derivative (X). Finally, glucitol (X) is hydrolyzed with LiOH·H2O in MeOH/THF or with NaOMe in refluxing MeOH and subsequently treated with AcOH .
D-Glucitol derivative (X) can also be prepared by treatment of iodobenzyl derivative (IV), with s-BuMgCl·LiCl in THF at 2 °C and addition of the resulting Grignard reagent to a solution of the tetraacetyl gluconolactone (VIII) in THF at –35 °C to give the D-glucopyranose derivative (IX), which then undergoes enantiospecific reduction by means of Et3SiH and BF3·Et2O or BF3·THF in acetonitrile or in the presence of AlCl3 and (Me2SiH)2O in acetonitrile .
| 【1】 Abdel-Magid, A.F., Chisholm, M., Mehrman, S. et al. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. CN 101801371, EP 2200606, JP 2010539092, WO 2009035969. |
| 【2】 Ellsworth, B., Washburn, W.N., Sher, P.M., Wu, G., Meng, W. (Bristol-Myers Squibb Co.). C-Aryl glucoside SGLT2 inhibitors and method. EP 1506211, JP 2005531588, JP 2009275050, US 2002137903, US 6515117, WO 2003099836. |
| 【3】 Nomura, S., Ueta, K., Kawanishi, E. (Mitsubishi Tanabe Pharma Corp.). Novel compounds having inhibitory activity against sodium-dependant transporter. EP 1651658, JP 2007518683, JP 2008266328, WO 2005012326. |
| 【4】 Nomura, S., Sakamaki, S., Hongu, M. et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010, 53(17): 6355-60. |
| 【5】 Filliers, W.F.M., Broeckx, R.L.M., Nieste, P.H.J., Hatsuda, M., Yoshinaga, M., Yada, M. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. US 2010099883, WO 2010043682. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 65747 | D-Gluconolactone；GLUCONIC ACID DELTA-LACTONE；D-(+)-GLUCONO-1,5-LACTONE;DELTA-LACTONE;GLUCONIC ANHYDRIDE;GLUCONIC-D-LACTONE | 4253-68-3 | C6H10O6 | 详情 | 详情 |
| (II) | 65748 | 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone; D-2,3,4,6-Tetrakis-O-(trimethylsilyl)-gluconic acid delta-lactone; (3R,4S,5R,6R)-3,4,5-Tris[(trimethylsilyl)oxy]-6-[[(trimethylsilyl)oxy]methyl]tetrahydropyran-2-one | 32384-65-9 | C18H42O6Si4 | 详情 | 详情 |
| (III) | 68782 | 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene | 1030825-20-7 | C18H14BrFS | 详情 | 详情 |
| (IV) | 68783 | 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene | 898566-17-1 | C18H14FIS | 详情 | 详情 |
| (V) | 68789 | (3S,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-ol | C36H57FO6SSi4 | 详情 | 详情 | |
| (VI) | 68788 | (3S,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol | C25H27FO6S | 详情 | 详情 | |
| (VII) | 68786 | (3S,4S,5S,6R)-6-(acetoxymethyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate | C33H35FO10S | 详情 | 详情 | |
| (VIII) | 68787 | (2S,3S,4S,5R)-2-(acetoxymethyl)-6-oxotetrahydro-2H-pyran-3,4,5-triyl triacetate | C14H18O10 | 详情 | 详情 | |
| (IX) | 68785 | (3S,4S,5S,6R)-6-(acetoxymethyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-hydroxytetrahydro-2H-pyran-3,4,5-triyl triacetate | C32H33FO10S | 详情 | 详情 | |
| (X) | 68784 | (2R,3S,4S,5S,6R)-2-(acetoxymethyl)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate | C32H33FO9S | 详情 | 详情 |
合成路线2
In one method, metalation of 1-bromo-4-fluorobenzene (XI) with Mg in 2-MeTHF at 90 °C gives 4-fluorophenyl magnesium bromide (XII), which then couples with 2-bromothiophene (XIII) in the presence of NiCl2·dppe and AcOH in 2-MeTHF at 22 °C or in the presence of Pd(OAc)2 and DPPP in THF to yield 2-(4-fluorophenyl)thiophene (XIV). Finally, this compound undergoes Friedel–Crafts acylation with 5-iodo-2-methylbenzoic acid (XV) (initially chlorinated with SOCl2 in CH2Cl2) using AlCl3 in CH2Cl2, and subsequent reduction with (Me2SiH)2O in refluxing acetonitrile .
In another method, hydrolysis of methyl 5-bromo-2-methylbenzoate (XVI) with NaOH in MeOH at 50 °C gives rise to the benzoic acid (XVII) , which is then chlorinated with (COCl)2 in the presence of DMF in CH2Cl2 to yield 5-bromo-2-methylbenzoyl chloride (XVIII). Friedel–Crafts reaction of acyl chloride (XVIII) with 2-(4-fluorophenyl) thiophene (XIV) in the presence of AlCl3 in CH2Cl2 affords ketone (XIX), which is then reduced by means of Et3SiH and BF3·Et2O in CH2Cl2/acetonitrile to afford 2-(5-bromo-2-methylbenzoyl)-5-(4-fluorophenyl)thiophene (III) . Finally, compound (III) is iodinated with NaI and CuI in the presence of (MeNHCH2)2 in refluxing toluene/diglyme (IV) .
Alternatively, coupling of 4-fluorophenylboronic acid (XX) with either 2-bromothiophene (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in dimethoxyethane at 75-80 °C or with 2-iodothiophene (XXI) in the presence of PdCl2(PPh3)2 at 50 °C affords 2-(4-fluorophenyl) thiophene (XIV) .
| 【1】 Abdel-Magid, A.F., Chisholm, M., Mehrman, S. et al. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. CN 101801371, EP 2200606, JP 2010539092, WO 2009035969. |
| 【2】 Nomura, S., Ueta, K., Kawanishi, E. (Mitsubishi Tanabe Pharma Corp.). Novel compounds having inhibitory activity against sodium-dependant transporter. EP 1651658, JP 2007518683, JP 2008266328, WO 2005012326. |
| 【3】 Nomura, S., Sakamaki, S., Hongu, M. et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010, 53(17): 6355-60. |
| 【4】 Filliers, W.F.M., Broeckx, R.L.M., Nieste, P.H.J., Hatsuda, M., Yoshinaga, M., Yada, M. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. US 2010099883, WO 2010043682. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 68782 | 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene | 1030825-20-7 | C18H14BrFS | 详情 | 详情 |
| (IV) | 68783 | 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene | 898566-17-1 | C18H14FIS | 详情 | 详情 |
| (XI) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (XII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XIII) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
| (XIV) | 68790 | 2-(4-fluorophenyl)thiophene | 58861-49-7 | C10H7FS | 详情 | 详情 |
| (XV) | 68791 | 5-iodo-2-methylbenzoic acid;2-Methyl-5-iodobenzoicacid | 54811-38-0 | C8H7IO2 | 详情 | 详情 |
| (XVI) | 68792 | methyl 5-bromo-2-methylbenzoate;methyl 5-bromo-o-toluate | 79669-50-4 | C9H9BrO2 | 详情 | 详情 |
| (XVII) | 68793 | 5-bromo-2-methylbenzoic acid;2-Methyl-5-bromobenzoic acid | 79669-49-1 | C8H7BrO2 | 详情 | 详情 |
| (XVIII) | 68794 | 5-bromo-2-methylbenzoyl chloride | C8H6BrClO | 详情 | 详情 | |
| (XIX) | 68795 | (5-bromo-2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone | C18H12BrFOS | 详情 | 详情 | |
| (XX) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (XXI) | 43394 | 2-iodothiophene | 3437-95-4 | C4H3IS | 详情 | 详情 |