Citation: Yong-Hai Liu, Ting-Ming Fu, Chun-Yan Ou, Wen-Ling Fan, Guo-Ping Peng. Improved preparation of (1S,3’R,4’S,5’S,6’R)-5-chloro-6-[(4-ethylphenyl)methyl]-3’,4’,5’,6’-tetrahydro-6’-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2’-[2H]pyran]-3’,4’,5’-triol[J]. Chinese Chemical Letters, ;2013, 24(2): 131-133. shu

Improved preparation of (1S,3’R,4’S,5’S,6’R)-5-chloro-6-[(4-ethylphenyl)methyl]-3’,4’,5’,6’-tetrahydro-6’-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2’-[2H]pyran]-3’,4’,5’-triol

1.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

Corresponding author: Guo-Ping Peng,
Received Date: 9 November 2012
Available Online: 3 December 2012
Fund Project: This work was financially supported by the Open Project Program of National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, PAPD (ysxk-2010). (ysxk-2010)

A convenient approach for the preparation of (1S,3'R,4'S,5'S,6'R)-5-chloro-6-[(4-ethylphenyl)methyl]-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)-spiro[isobenzofuran-1(3H), 2'-[2H]pyran]-3',4',5'-triol is developed. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and the isomers of undesired ortho-products were avoided during the preparation.
- Type 2 diabetes,
- Sodium glucose co-transporter 2,
- Inhibitor,
- Preparation
1. [1]
  [1] D. Mathis, L. Vence, C. Benoist, beta-Cell death during progression to diabetes, Nature 414 (2001) 792-798.
2. [2]
  [2] T. Asano, T. Ogihara, H. Katagiri, Glucose transporter and Na⁺/glucose cotransporter as molecular targets of anti-diabetic drugs, Curr. Med. Chem. 11 (2004) 2717-2724.
3. [3]
  [3] J.R.L. Ehrenkranz, N.G. Lewis, C.R. Kahn, J. Roth, Phlorizin: a review, Diabetes Metab. Res. Rev. 21 (2005) 31-38.
4. [4]
  [4] L. Binhua, X. Baihua, Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, Bioorg. Med. Chem. Lett. 19 (2009) 6877-6881.
5. [5]
  [5] L. Binhua, X. Baihua, ortho-Substituted C-aryl glucosides as highly potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors, Bioorg. Med. Chem. Lett. 18 (2010) 4422-4432.
6. [6]
  [6] S. Tsutomu, H. Kiyofumi, et al., EU Patent, EP 2048153A1, 2009.
7. [7]
  [7] L. Sandrine, A. Mohamed, Selective double Suzuki cross-coupling reactions. Synthesis of unsymmetrical diaryl (or heteroaryl) methanes, Tetrahedron Lett. 44 (2003) 9255-9258.
8. [8]
  [8] C. Sultan, E.G. Paris, Palladium catalyzed cross-coupling between phenyl or naphthylboronic acids and benzylic bromides, Tetrahedron Lett. 40 (1999) 7599-7603.
9. [9]
  [9] M.N. Sabrina, L.M. Adriano, Synthesis of diarylmethane derivatives from Pdcatalyzed cross-coupling reactions of benzylic halides with arylboronic acids, Tetrahedron Lett. 45 (2004) 8225-8228.
10. [10]
  [10] Typical procedure for the synthesis of 6: To a solution of 4-ethylphenylboronic acid (0.225 g, 1.5 mmol) in toluene (5 mL) was added Pd(OAc)₂ (2.3 mg, 0.01 mmol) under an argon atmosphere, and PPh₃ (1.5 mg, 0.005 mmol) and K₃PO₄ (0.4 g, 2 mmol) were added sequentially. The mixture was stirred for 10 min at room temperature, and 5 (0.26 g, 1 mmol) was added. The reaction mixture was stirred for 4 h at 80℃ under an argon atmosphere, cooled to room temperature, and treated with water. The resultant mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow oil (0.3 g, 82%).
11. [11]
  [11] Typical procedure for the synthesis of 9: To a stirred 78℃ solution of 8 (0.41 g, 1 mmol) in 1:2 anhydrous THF/toluene (10 mL) was slowly added n-BuLi (1 mL, 1.1 mol/L in hexane) to maintain the temperature below 70℃. After stirring for 30 min, this solution was added to a stirred solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-pyran-2-one 10 (0.64 g, 1.2 mmol) in toluene (5 mL) to maintain the temperature below 65℃, then the solution was stirred for 5 h at 78℃, and the reaction was quenched by a solution of methanesulfonic acid (214 mg, 2.2 mmol) in THF (5 mL). The mixture was stirred for 24 h at room temperature and quenched with saturated NaHCO3. The mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give oil, which was purified by silicon column chromatography to get a colorless oil (0.62 g, 79%). R_f = 0.35 (petroleum ether/EtOAc, 8:1, v/v).
12. [12]
  [12] Typical procedure for the synthesis of 1: To a solution of 9 (2.6 g, 3.33 mmol) in 2:3 EtOAc/MeOH (30 mL), 0.25 g palladium on carbon and 1,2-dichlorobenzene (10 mL) was added sequentially. The air of the reactor was removed by argon, then the 0.1 MPa H2 was applied for 12 h at 25℃. The solvent was filtrated, the filter cake was washed by EtOAc, and the filtrate was concentrated in vacuo to give oil. The oil was purified by silicon column chromatography to get a glassy off white solid (1.35 g, 96%). R_f = 0.35 (MeOH/EtOAc, 1:5, v/v).
13. [13]
  [13] Selected data compounds: 6: ¹H NMR: (300 MHz, CDCl₃): δ 7.96 (s, 1H), 7.54 (s, 1H), 7.32 (d, 2H, J = 7.8 Hz), 7.11 (d, 2H, J = 7.8 Hz), 4.11 (s, 2H), 3.82 (s, 3H), 2.74 (q, 2H, J = 7.8 Hz), 1.26 (t, 3H, J = 7.8 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 168.9, 150.3, 142.4, 138.9, 134.6, 133.6, 132.8, 130.9, 129.5, 128.7, 121.7, 53.5, 36.3, 28.5, 14.7; MS: m/z 366 [M+]; 389 [M⁺+Na⁺]; Anal. Calcd. for C₁₇H₁₆BrClO₂: C 55.53, H 4.39; Found: C 55.49, H 4.41; 9 ¹H NMR (300 MHz, CDCl₃): δ 7.52 (d, 1H, J = 1.5 Hz), 7.38-7.42 (m, 6H), 7.29-7.32 (m, 9H), 7.17-7.21 (m, 4H), 7.11 (d, 4H, J = 1.2 Hz), 7.08 (d, 2H, J = 8.4 Hz), 4.88-4.96 (m, 3H), 4.72 (S, 2H), 4.56-4.67 (m, 3H), 4.46 (d, 1H, J = 10.8 Hz), 4.16-4.22 (m, 2H), 3.88 (d, 1H, J = 8.4 Hz), 3.82 (s, 1H), 3.66-3.77 (m, 4H), 3.36 (d, 1H, J = 9.6 Hz), 2.60 (q, 2H, J = 7.6 Hz), 1.24 (t, 3H, J = 7.6 Hz); ¹³C NMR (100 MHz, CH₂₃OD): δ 139.8, 138.6, 137.6, 130.5, 129.5, 129.1, 129.0, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.4, 101.2, 85.6, 84.9, 79.8, 78.9, 78.5, 77.5, 76.4, 75.6, 74.9, 73.6, 70.2, 62.7, 39.4, 28.8, 16.0; MS:m/z 780 [M+]; 803 [M⁺+Na⁺]; Anal. Calcd. for C₅₀H₄₉ClO₆: C 76.86, H 6.32; Found: C 76.47, H 6.43; 1: ¹H NMR (300 MHz, CH₂₃OD): δ 1.19 (t, 3H, J = 7.5 Hz), 2.57 (q, 2H, J = 7.5, 7.8 Hz), 3.41-3.47 (1H, m), 3.64 (dd, 1H, J = 6 Hz), 3.73-3.83 (m, 4H), 3.95 (s, 2H), 5.11 (dd, 2H, J = 7.8, 12.3 Hz), 7.06-7.12 (m, 4H), 7.16-7.23 (m, 3H); ¹³C NMR (100 MHz, CH₂₃OD): δ 143.3, 142.8, 140.8, 139.7, 138.2, 131.6, 130.8, 129.6, 128.8, 127.8, 125.6, 83.6, 77.2, 72.6, 71.4, 66.1, 62.7, 36.8, 28.6, 15.6; MS: m/z 420 [M+]; 443 [M⁺+Na⁺]; Anal. Calcd. for C₂₂H₂₅ClO₆: C 62.78, H 5.99; Found: C 62.71, H 6.02.
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沈阳化工大学材料科学与工程学院沈阳 110142