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Synlett 2003(11): 1683-1687
DOI: 10.1055/s-2003-41426
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Dianhydrohexitole-based Benzamidines as Factor Xa Inhibitors Using Cross Couplings, Phenyl Ether and Amidine Formations as Key Steps

Marko Voglera, Ulrich Koert*a, Dieter Dorschb, Johannes Gleitzb, Peter Raddatzb
a Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
b Merck KgaA, Preclinical Research & Development, 64271 Darmstadt, Germany
Fax: +49(6421)2825677; e-Mail: koert@chemie.uni-marburg.de;
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Publication History

Received 23 June 2003
Publication Date:
22 September 2003 (online)

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Abstract

Starting with isosorbide or isomannide several dianhydrohexitole-based benzamidines were synthesized as potential factor Xa inhibitors. The key steps for the synthesis of the bisbenzamidines were nucleophilic aromatic substitutions and Mitsunobu reactions to build up phenylethers. Another type of monobenzamidines had ortho-substituted biphenyl groups. Their synthesis necessitated an optimization of cross coupling procedures due to the great sterical hindrance of the ortho-substituent. The benz­amidines showed biological activity against factor Xa and selectivity against other serine proteases.

Key words

isosorbide - dianhydrohexitoles - amidines - Negishi reaction - factor Xa inhibitors

    References

  • 1 Davie EW. Fujikawa K. Kisiel W. Biochemistry  1991,  30:  10363 
    CrossrefPubMedGoogle Scholar
  • 2a Rai R. Sprengeler PA. Elrod KC. Young WB. Curr. Med. Chem.  2001,  8:  101 
    CrossrefGoogle Scholar
  • 2b Samama MM. Thromb. Res.  2002,  106:  V267 
    CrossrefGoogle Scholar
  • 2c Kaiser B. Cell. Mol. Life Sci.  2002,  59:  189 
    CrossrefGoogle Scholar
  • 2d Leadley RJ. Curr. Top. Med. Chem.  2001,  1:  151 
    CrossrefGoogle Scholar
  • 3 Osterkamp F. Wehlan H. Koert U. Wiesner M. Raddatz P. Goodman SL. Tetrahedron  1999,  55:  10713 
    CrossrefGoogle Scholar
  • 4 Brimacombe JS. Foster AB. Stacey M. Whiffen DH. Tetrahedron  1958,  4:  351 
    CrossrefGoogle Scholar
  • 5 Hopton FJ. Thomas GHS. Can. J. Chem.  1969,  47:  2395 
    Google Scholar
  • 6 Boeré RT. Oakley RT. Reed RW. J. Orgmet. Chem.  1987,  331:  161 
    CrossrefGoogle Scholar
  • 7a

    General procedure for the preparation of bisamidines 3 and 4 from bisnitriles by the LiHMDS [6] method: A oven-dried Schlenck-flask equipped with a rubber septum is charged with HMDS (2.6 mmol) in THF (3 mL) under argon atmosphere and cooled by an ice bath. After addition of n-BuLi (3.0 mmol, 2.5 M in hexane) and stirring for 1 h a solution of the bisnitrile (0.52 mmol) in THF (3 mL) was added. The reaction mixture turned dark red or brown. It was stirred for 24 h at room temperature and then quenched with 6 M HCl in ethanol (2 mL). After 1 h the solvents were removed in vacuo. The residue was solved in few MeOH and purified by preparative HPLC (Rainin RP18, H2O/CH3CN mixtures with 0.1% TFA). The bisamidine was isolated as a TFA salt by lyophilization resulting in a colorless powder.

  • 7b

    Analytical data of 3 and 4: 2-O-(4′-Amidinophenyl)-5-O-(3′′-amidinophenyl)-1,4:3,6-dianhydro-d-sorbitol trifluoroacetic acid salt (3):
    [α]D 20 = +49, [α]578 20 = +51, [α]546 20 = +58, [α]436 20 = +100, [α]365 20 = +160 (c 0.099, H2O); 1H NMR (300 MHz, DMSO-d 6) δ = 3.87-4.05 (m, 4 H, 1-H2, 6-H2), 4.61 (d, J = 4.1 Hz, 1 H, 3-H), 5.02-5.13 (m, 3 H, 2-H, 4-H, 5-H), 7.19-7.44 (m, 5 H, 2′-H, 6′-H, 2′′-H, 4′′-H, 6′′-H), 7.55 (t, J = 7.9 Hz, 1 H, 5′′-H), 7.79 (pd, J = 9.0 Hz, 2 H, 3′-H, 5′-H), 8.88-9.29 [m, 8 H, 2 × C(NH2)2]. 13C NMR (75 MHz, DMSO-d 6) δ = 71.2, 72.7 (C-1, C-6), 77.4, 81.1, 81.5, 86.0 (C-2, C-3, C-4, C-5), 115.1 (C-2′′), 115.4 (C-2′, C-6′), 120.1 (C-4′), 120.8, 121.1 (C-4′′, C-6′′), 129.9 (C-3′′), 130.3 (C-3′, C-5′), 130.8 (C-5′′), 156.9 (C-1′′), 162.5 (C-1′), 164.9, 165.4 [2 × C(NH2)2]; HRMS (FAB): m/z calcd 383.1719, found 383.1717 (C20H23N4O4, M + H+). 2-O-(3′-Amidinophenyl)-5-O-(4′′-amidinophenyl)-1,4:3,6-dianhydro-d-sorbitol trifluoroacetic acid salt (4):
    [α]D 21 = +46, [α]578 21 = +49, [α]546 21 = +55, [α]436 21 = +94, [α]365 21 = +157 (c 0.267, H2O); 1H NMR (300 MHz, DMSO-d 6) δ = 3.86-4.10 (m, 4 H, 1-H2, 6-H2), 4.60 (d, J = 4.7 Hz, 1 H, 3-H), 5.00-5.15 (m, 3 H, 2-H, 4-H, 5-H), 7.18 (pd, J = 9.0 Hz, 2H, 2′′-H, 6′′-H), 7.34-7.45 (m, 3 H, 2′-H, 4′-H, 6′-H), 7.53 (t, J = 7.9 Hz, 1 H, 5′-H), 7.83 (pd, J = 8.9 Hz, 2 H, 3′′-H, 5′′-H), 9.00-9.35 [m, 8 H, 2 × C(NH2)2]; 13C NMR (75 MHz, DMSO-d 6) δ = 70.9, 72.8 (C-1, C-6), 77.3, 80.8, 81.6, 86.0 (C-2, C-3, C-4, C-5), 114.6 (C-2′), 115.7 (C-2′′, C-6′′), 120.5, 120.7 (C-4′, C-6′), 120.6 (C-4′′), 129.6 (C-3′), 130.6 (C-3′′, C-5′′), 158.0 (C-1′), 161.1 (C-1′′), 164.9, 165.5 [2 × C(NH2)2]; HRMS (FAB): m/z calcd. 383.1719, found 383.1715 (C20H23N4O4, M + H+).

  • 8 McDougal PG. Rico JG. Oh Y.-I. Condon BD. J. Org. Chem.  1986,  51:  3388 
    Google Scholar
  • 9a Quan ML. Liauw AY. Ellis CD. Pruitt JR. Carini DJ. Bostrom LL. Huang PP. Harrison K. Knabb RM. Thoolen MJ. Wong PC. Wexler RR. J. Med. Chem.  1999,  42:  2752 
    CrossrefGoogle Scholar
  • 9b Quan ML. Ellis CD. Liauw AY. Alexander RS. Knabb RM. Lam G. Wright MR. Wong PC. Wexler RR. J. Med. Chem.  1999,  42:  2760 
    CrossrefGoogle Scholar
  • 9c Fevig JM. Pinto DJ. Han Q. Quan ML. Pruitt JR. Jacobson IC. Galemmo RA. Wang SA. Orwat MJ. Bostrom LL. Wong PC. Lam PYS. Wexler RR. Bioorg. Med. Chem. Lett.  2001,  11:  641 
    CrossrefGoogle Scholar
  • 9d Jia ZJ. Wu Y. Huang W. Goldman E. Zhang P. Woolfrey J. Wong P. Huang B. Sinha U. Park G. Reed A. Scarborough RM. Zhu B.-Y. Bioorg. Med. Chem. Lett.  2002,  12:  1651 
    CrossrefGoogle Scholar
  • 9e Su T. Wu Y. Doughan B. Jia ZJ. Woolfrey J. Huang B. Park G. Sinha U. Scarborough RM. Zhu B.-Y. Bioorg. Med. Chem. Lett.  2001,  11:  2947 
    CrossrefGoogle Scholar
  • 9f Pruitt JR. Pinto DJ. Estrella MJ. Bostrom LL. Knabb RM. Wong PC. Wright MR. Wexler RR. Bioorg. Med. Chem. Lett.  2000,  10:  685 
    CrossrefGoogle Scholar
  • 10 Courtin A. Helv. Chim. Acta  1983,  66:  68 
    CrossrefGoogle Scholar
  • 11 Dains FB. Eberly F. Org. Synth., Coll. Vol. II   Wiley; New York: 1943.  p.355 
    Google Scholar
  • 12 Doyle MP. Siegfried B. Dellaria JF. J. Org. Chem.  1977,  42:  2426 
    CrossrefGoogle Scholar
  • 13 Baik W. Kim JM. Kim YS. Lee SW. European Symposium on Organic Chemistry 12   Poster presentation; Groningen Netherlands: 2001. 
    Google Scholar
  • Coupling of boronic acid 19 using several Suzuki methods:
  • 14a Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 ; standard conditions: PdCl2(PPh3)2, Bu4NBr (cat.), aq. Na2CO3, PhMe reflux, 44%
    Article in Thieme ConnectGoogle Scholar
  • 14b Wallow TI. Novak BM. J. Org. Chem.  1994,  59:  5034 ; Pd(OAc)2, aq. Na2CO3, THF reflux, 0%
    Article in Thieme ConnectGoogle Scholar
  • 14c Wolfe JP. Singer RA. Yang BH. Buchwald SL. J. Am. Chem. Soc.  1999,  121:  9550 ; Pd(OAc)2, 2-(di-tert-butylphosphino)-biphenyl, KF, THF reflux, 0%
    Article in Thieme ConnectGoogle Scholar
  • 14d Alo BI. Kandil A. Patil PA. Sharp MJ. Siddiqui MA. Snieckus V. J. Org. Chem.  1991,  56:  3763 ; Pd2(dba)3, PPh3, aq. Na2CO3, DME reflux, 35%
    Article in Thieme ConnectGoogle Scholar
  • 14e Watanabe T. Miyaura N. Suzuki A. Synlett  1992,  207 ; Pd2(dba)3, PPh3, Ba(OH)2, DME/H2O reflux, 39%
    Article in Thieme ConnectGoogle Scholar
  • 15a Savage SA. Smith AP. Fraser CL. J. Org. Chem.  1998,  63:  10048 
    CrossrefGoogle Scholar
  • 15b

    Negishi coupling of aryl iodide 18: An oven-dried Schlenk-flask equipped with a rubber septum was charged with 1.29 g (6.0 mmol) PhSO2NHt-Bu in 15 mL THF under an argon atmosphere and cooled in an ice bath. After addition of 8.2 mL n-BuLi (1.6 M in hexanes) the solution was stirred for 2 h. A thick, pale yellow precipitate formed. 1.82 g (13.4 mmol) ZnCl2 beads were added (the precipitate dissolves) and 1 h later a solution of 2.19 g (5.0 mmol) 18, 185 mg (0.2 mmol) Pd2(dba)3 and 262 mg (1.0 mmol) PPh3 in 10 mL THF was transferred into the reaction mixture. After addition of 424 mg (10.0 mmol) dried LiCl the reaction mixture was refluxed for 70 h. 100 mL sat. aq. NH4Cl and 100 mL MTBE were added and the aqueous layer was extracted three times with MTBE. The combined organic fractions were washed with brine and dried over MgSO4. Purification by flash chromatography (pentane/MTBE 2:1→1:1) yielded 2.18 g (4.2 mmol, 83%) pure 21.
    Crossref
  • 15c

    Analytical data of 2-O-benzyl-5-O-[4′-(2′′-tert-butylamino-sulfonylphenyl)-phenyl]-1,4:3,6-dianhydro-d-mannitol (21): colorless solid; Mp 62 °C; [α]D 20 = +128, [α]578 20 = +133, [α]546 20 = +152 (c 1.008, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 0.98 [s, 9 H, C(CH3)3], 3.58 (s, 1 H, NH), 3.78 (t, J = 8.7 Hz, 1H, 1-H), 3.94 (dd, J = 8.6 Hz, 7.0 Hz, 1H, 1-H), 4.06-4.12 (m, 2 H, 2-H, 6-H), 4.20 (dd, J = 9.4 Hz, 6.0 Hz, 1 H, 6-H), 4.60 (d, J = 11.9 Hz, 1 H, CHHPh), 4.62 (t, J = 4.7 Hz, 1 H, 3-H), 4.78 (d, J = 11.9 Hz, 1 H, CHHPh), 4.79-4.85 (m, 2 H, 4-H, 5-H), 7.04 (pd, J = 8.7 Hz, 2H, 2′-H, 6′-H), 7.29 (dd, J = 7.7 Hz, 1.0 Hz, 1 H, 6′′′-H), 7.29-7.40 (m, 5 H, Ph-H), 7.43-7.47 (m, 3 H, 3′-H, 5′-H, 4′′′-H), 7.53 (td, J = 7.6 Hz, 1.2 Hz, 1H, 5′′′-H), 8.15 (dd, J = 7.9 Hz, 1.0 Hz, 1H, 3′′′-H); 13C NMR (75 MHz, CDCl3) δ = 29.7 [C(CH3)3], 54.3 [C(CH3)3], 71.0, 71.6, 72.6 (C-1, C-6, CH 2Ph), 77.9, 78.9, 80.6, 80.8 (C-2, C-3, C-4, C-5), 114.9 (C-2′, C-6′), 127.6, 128.1 (C-3′′, C-6′′), 127.9, 128.4 (Ph-C), 131.1 (C-3′, C-5′), 131.7, 132.4 (C-4′′, C-5′′), 132.2 (C-4′), 137.6 (Ph-Cq), 139.4 (C-1′′), 142.2 (C-2′′), 158.1 (C-1′); IR(film): 3371, 2973, 2876, 1607, 1514, 1467, 1324, 1245, 1152, 1128, 1076, 988, 834, 765 cm-1; Anal. calcd. for C29H33NO6S (523.65) C 66.52, H 6.35, N 2.68, found C 66.41, H 6.01, N 2.48.
    Crossref
  • 16a Judkins BD. Allen DG. Cook TA. Evans B. Sardharwala TE. Synth. Commun.  1996,  26:  4351 
    CrossrefGoogle Scholar
  • 16b

    Preparation of benzamidine 5 via amide oxime: Benzonitrile 23 (1 mmol) was dissolved in 10 mL THF/EtOH (1:1). After addition of NH2OH·HCl (3 mmol), Na2CO3 (2 mmol) and 10 mL water the mixture was heated to 80 °C and stirred for 20 h (TLC monitoring). After cooling 20 mL water was added and the aqueous layer was extracted three times each with 20 mL CH2Cl2. The combined organic fractions were dried over MgSO4 and the solvents were removed in vacuo. The crude amide oxime was then dissolved in 30 mL MeOH/HOAc (1:1) and Ac2O (2 mmol) was added. After 30 min Pd/C was added and the reaction mixture was vigorously stirred under hydrogen atmosphere (HPLC monitoring, Rainin RP18, H2O/CH3CN mixtures + 0.1% TFA). Finally, the solution was filtrated over a pad of celite and the solvents were completely removed in vacuo. The crude bezamidine was then stirred under an argon atmosphere in dry TFA/anisole (10:1) for 24 h. Purification by flash chromatography (CH2Cl2/MeOH/TFA, 100:2:1 → 100:5:1), concentration of all product fractions and subsequent precipitation with MTBE/hexane gave 5 as TFA salt.
    Crossref
  • 16c

    Analytical data of 2-O-(4′-amidinophenyl)-5-O-[4′′-(2′′′-aminosulfonylphenyl)-phenyl]-1,4:3,6-dianhydro-d-sorbitol trifluoroacetic acid salt (5): colorless solid; [α]D 20 = +51, [α]578 20 = +54, [α]546 20 = +61, [α]436 20 = +108, [α]365 20 = +174 (c 0.407, CH2Cl2/MeOH, 1:1); 1H NMR (500 MHz, DMSO-d 6) δ = 3.56 (d, J = 10.4 Hz, 1 H, 1-H), 3.89 (dd, J = 9.4 Hz, 5.4 Hz, 1 H, 6-H), 4.07 (dd, J = 9.4 Hz, 5.7 Hz, 1 H, 6-H), 4.11 (dd, J = 10.4 Hz, 3.8 Hz, 1 H, 1-H), 4.62 (d, J = 5.1 Hz, 1 H, 3-H), 4.97 (q, J = 5.5 Hz, 1 H, 5-H), 5.04 (t, J = 5.0 Hz, 1 H, 4-H), 5.11 (d, J = 3.3 Hz, 1 H, 2-H), 7.02 (pd, J = 8.7 Hz, 2 H, 2′′-H, 6′′-H), 7.13 (s, 2 H, SO2NH2), 7.20 (pd, J = 8.9 Hz, 2 H, 2′-H, 6′-H), 7.29 (d, J = 7.5 Hz, 1 H, 6′′′-H), 7.32 (pd, J = 8.7 Hz, 2 H, 3′′-H, 5′′-H), 7.53 (t, J = 7.5 Hz, 1 H), 7.59 (t, J = 7.4 Hz, 1 H, 4′′′-H, 5′′′-H), 7.83 (pd, J = 8.8 Hz, 2 H, 3′-H, 5′-H), 8.01 (d, J = 7.8 Hz, 1 H, 3′′′-H), 9.01/9.15 [s/s, 4 H, C(NH2)2]; 13C NMR (75 MHz, DMSO-d 6) δ = 70.9, 71.7 (C-1, C-6), 77.1, 80.7, 81.8, 86.0 (C-2, C-3, C-4, C-5), 114.3 (C-2′′, C-6′′), 115.7 (C-2′, C-6′), 120.6 (C-4′), 127.4 (C-3′′′, C-6′′′), 130.5, 130.6 (C-3′, C-5′, C-3′′, C-5′′), 131.6, 132.7 (C-4′′, C-4′′′, C-5′′′), 139.8 (C-1′′′), 142.4 (C-2′′′), 157.3 (C-1′′), 161.2 (C-1′), 164.9 [C(NH2)2]; HRMS (ESI) m/z calcd. 496.1542, found 496.1544 (C25H26N3O6S, M + H+).
    Crossref
  • 18 Brougham P. Cooper MS. Cummerson DA. Heaney H. Thompson N. Synthesis  1987,  1015 
    Article in Thieme ConnectGoogle Scholar
  • 19 Krone W. Chem. Ber.  1891,  24:  834 
    Google Scholar
17

Pd/C is preferred, since the use of Raney-nickel in MeOH/AcOH leads to the formation of minor amounts of Ni(OAc)2, which is difficult to remove by chromatography.