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Methods for preparing benzo ring derivative with benzylic quaternary carbon center and ethazocine hydrobromide

A compound, heterocyclic aryl technology, applied in the field of benzo ring derivatives, can solve problems such as low efficiency and long synthetic route

Inactive Publication Date: 2018-09-14
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The clinical drug etazocine hydrobromide has the effect of treating cancer pain and postoperative pain. In the existing report method, it needs 7 to 20 steps to complete the synthesis ([1] S.Shiotani, T.Kometani, K.Mitsuhashi , T.Nozawa, A.Kurobe, O.Futsukaichi, J.Med.Chem.1976,19,803; [2] T.Takemoto, M.Sodeoka, H.Sasai, M.Shibasaki, J.Am.Chem.Soc. 1993,115,8477; [3]A.N.Hulme,S.S.Henry,A.I.Meyers,J.Org.Chem.1995,60,1265;[4]S.Shiotani,H.Okada,T.Yamamoto,K.Nakamata,J .Adachi,H.Nakamoto,Heterocycles 1996,43,113;[5]A.Fadel,P.Arzel,Tetrahedron:Asymmetry 1997,8,371;[6]S.K.Taylor,M.Ivanovic,L.J.Simons,M.M.Davis,Tetrahedron:Asymmetry 2003 ,14,743; [7]Y.Nakao,S.Ebata,A.Yada,T.Hiyama,M.Ikawa,S.Ogoshi,J.Am.Chem.Soc.2008,130,12874;[8]Q.Chen , X.Huo, Z.Yang, X.She, Chem.Asian J.2012, 7, 2543), the synthetic route is long and the efficiency is low

Method used

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  • Methods for preparing benzo ring derivative with benzylic quaternary carbon center and ethazocine hydrobromide
  • Methods for preparing benzo ring derivative with benzylic quaternary carbon center and ethazocine hydrobromide
  • Methods for preparing benzo ring derivative with benzylic quaternary carbon center and ethazocine hydrobromide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the preparation of compound I-1

[0054]

[0055] Under the protection of argon gas, add catalyst allylpalladium chloride dimer (3.7mg, 0.01mmol), ligand XPhos (10.5mg, 0.022mmol), potassium carbonate to a dry reaction tube equipped with a magnetic stirrer (69.1 mg, 0.5 mmol) and dry acetonitrile (1.0 mL), the mixture was stirred at room temperature for 15 minutes. Dissolve aryl iodide [1-iodonaphthalene (61mg, 0.24mmol)], alkyl bromide [trans-6-bromo-3-methyl-2-hexen-1-ol (38.6mg, 0.2mmol )] and 5-norbornene-2-carboxylic acid (5.5mg, 0.04mmol) in dry acetonitrile (1.0mL) were added to the reaction tube, and then heated to 70°C for 24 hours under an argon atmosphere. After the reaction was cooled to room temperature, the mixture was filtered with celite, washed with ethyl acetate, the solvent was removed under reduced pressure, and purified by column chromatography to obtain compound I-1 (colorless oily liquid, yield 81%). 1 H NMR (400MHz, CDCl 3 ): ...

Embodiment 2

[0056] Embodiment 2: the preparation of compound 1-2

[0057]

[0058]The alkyl bromide used was trans 7-bromo-4-methyl-3-hepten-1-ol (41.4 mg, 0.2 mmol), and other conditions were the same as in Example 1 to obtain compound I-2 (colorless oily liquid, 68% yield). 1 H NMR (400MHz, CDCl 3 ): δ9.58(t, J=1.6Hz, 1H), 8.34(d, J=8.7Hz, 1H), 7.79(dd, J=8.0, 1.7Hz, 1H), 7.60(d, J=8.3Hz ,1H),7.46–7.36(m,2H),7.17(d,J=8.4Hz,1H),2.98–2.87(m,2H),2.78–2.71(m,1H),2.31–2.22(m,1H ),2.13–2.06(m,1H),1.95–1.81(m,4H),1.73–1.67(m,4H); 13 C NMR (100MHz, CDCl 3 ): δ202.7, 137.2, 136.6, 133.7, 132.4, 129.6, 128.8, 127.2, 125.5, 125.3, 124.3, 40.7, 40.3, 38.0, 34.0, 33.1, 28.6, 19.1; HRMS (ESI-TOF): theoretically calculated value: C 18 h 20 NaO[M+Na + ] 275.1406, measured value: 275.1406.

Embodiment 3

[0059] Embodiment 3: the preparation of compound 1-3

[0060]

[0061] The aryl iodide used was 2-methyliodobenzene (52.3 mg, 0.24 mmol), and other conditions were the same as in Example 1 to obtain compound I-3 (colorless oily liquid, yield 65%). 1 H NMR (400MHz, CDCl 3 ): δ9.50(t, J=3.0Hz, 1H), 7.04–7.01(m, 1H), 6.96–6.94(m, 2H), 3.15(dd, J=16.2, 3.2Hz, 1H), 2.85– 2.82(m,2H),2.53(dd,J=16.2,2.8Hz,1H),2.49(s,3H),2.04–1.94(m,1H),1.86–1.76(m,3H),1.50(s, 3H); 13 CNMR (100MHz, CDCl 3 ): δ203.4, 140.0, 138.0, 136.3, 131.2, 128.4, 126.3, 54.1, 41.7, 37.0, 32.3, 27.9, 23.8, 19.3; HRMS (ESI-TOF): Theoretical calculation value: C 14 h 18 NaO[M+Na + ] 225.1250, measured value: 225.1247.

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Abstract

The invention provides methods for preparing a benzo ring derivative with a benzylic quaternary carbon center and ethazocine hydrobromide. An aryl iodide and an alkylating agent as starting materialsare stirred for reaction in an organic solvent at 30 DEG C to 120 DEG C under the action of a palladium catalyst, a phosphine ligand, a norbornene derivative, and a base to obtain the benzo ring derivative with the benzylic quaternary carbon center. The raw materials used in the method are cheap and easy to obtain, reaction conditions are mild, substrate universality is good, yield is high, and the preparation process is simple. Meanwhile, the present invention also provides a method for synthesizing an ethazocine hydrobromide compound based on a 1,2,3,4-tetrahydronaphthalene compound having abenzylic all-carbon quaternary carbon center synthesized by the method, the drug ethazocine hydrobromide for treatment of cancer pain and post-operative pain can be synthesized only by four steps. The method has short synthetic steps, simple operation and high total yield.

Description

technical field [0001] The invention relates to a benzocyclic derivative with a benzylic quaternary carbon center and a preparation method of etazocine hydrobromide, a medicine for treating cancer pain and postoperative pain, belonging to the fields of organic synthesis and medicinal chemistry. Background technique [0002] The 1,2,3,4-tetrahydronaphthalene or 1,2-indane structural skeleton with a benzylic quaternary carbon center is an important class of structural units, which widely exist in biologically active natural products and pharmaceutical reagents ( [1] D.M.Roll, P.J.Scheuer, J.Am.Chem.Soc.1983, 105, 6177. [2] P.W.Brian, J.C.McGowan, Nature 1945, 156, 144; [3] J.MacMillan, A.E.Vanstone, S.K.Yeboah, Chem.Commun.1968,613; c) J.R.Hanson, Nat.Prod.Rep.1995,12,381.[4]C.A.L.Bercht,J.P.C.M.Van Dongen,W.Heerma,R.J.J.C.Lousberg,F.J.E.M.Küppers,Tetrahedron 1976,32,2939. [5] L. Garrido, E. ZubHa, M. J. Ortega, J. Salva, J. Org. Chem. 2003, 68, 293. [6] S. Shiotani, T. Komet...

Claims

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Application Information

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IPC IPC(8): C07B41/06C07C45/51C07C47/235C07C47/24C07C47/277C07C269/06C07F7/18C07C201/12C07C205/44C07C67/343C07D317/72C07D217/24C07D221/12C07D319/08C07C41/30C07C43/168C07C49/225C07C47/27C07D313/10C07D223/14
CPCC07B41/06C07C41/30C07C43/168C07C45/512C07C47/235C07C47/24C07C47/27C07C47/277C07C49/225C07C67/343C07C201/12C07C205/44C07C269/06C07D217/24C07D221/12C07D223/14C07D313/10C07D317/72C07D319/08C07F7/1892C07C2602/08C07C2602/10C07C2603/16C07C2603/26C07C2603/30C07C271/30C07C69/76Y02P20/55
Inventor 周强辉刘泽水钱光印
Owner WUHAN UNIV
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