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Example 3 Synthesis of 9-Hydroxymethyl-2-amino fluorene 13.0 g 9-Hydroxymethyl-2-(Boc-amino)fluorene was dissolved in 110 ml acetonitrile and stirred under reflux. 42 ml 2 N HCl (2.0 equiv, 84 mmol) was added drop-wise. The reaction mixture was stirred under reflux for 45 min. The reaction mixture was cooled to room temperature and the reaction was monitored by TLC [Rf=0.1 PE-MTBE (1:2)]. The solvent was partially eliminated by rotary evaporation and the residue was dissolved in 70 ml 2 N HCl. The solution was carefully washed with 2*50 ml MTBE. The aqueous phase was adjusted to pH 9 by Na2CO3 and extracted with 2*70 ml EtOAc. The organic phase was washed with 50 ml brine and dried over Na2SO4. The solvent was eliminated by rotary evaporation. The product was used without further purification. The structural identity was verified by NMR (8.76 g, 99% yield). 1H NMR (200 MHz/DMSO) delta=7.69-7.40 (3H; m; 3*Ar-H); 7.37-7.02 (2H; m; 2*Ar-H); 6.87 (1H; s; Ar-H); 6.68 (1H; d; J=8.34 Hz; Ar-H); 5.19 (2H; s; NH2); 5.03 (1H; t; J=4.93 Hz; OH); 3.93-3.58 (3H; m; H9, CH2) 13C NMR (50 MHz/DMSO) delta=148.36 (Ar-Cqu); 146.81 (Ar-Cqu); 143.97 (Ar-Cqu); 141.87 (Ar-Cqu); 129.03 (Ar-Cqu); 126.92 (Ar-CH); 124.85 (Ar-CH); 124.24 (ArCH); 120.40 (Ar-CH); 117.81 (Ar-CH); 113.00 (Ar-CH); 110.76 (Ar-CH); 64.27 (CH2); 49.90 (CH)
84%
With hydrogenchloride; In 1,4-dioxane; for 1h;
Intermediate h (1.4 g, 4.5 mmol) obtained in step 9(c) wasdissolved in 110 ml SN HC1 in dioxane. Afier 1 hour, the solvent was concentrated by evaporation and the product was precipitated with ether and lyophilized. Intermediate i was obtained in 84%, yield (0.79 g, 3.78 mmol). TLC (chloroform:methanol, 9:1, v:v), Rf=0.38; calculated ESMS=2 11.26 Da. found ESMS for [M+H]=211.10 Da.
Example 4 Synthesis of tert-Butyldimethylsiloxy-9-methyl-2-aminofluorene 5.91 g Imidazole (86.8 mmol, 2.1 equiv) was dissolved in 24 ml dry DMF and stirred 10 min in an iced bath under argon atmosphere. 7.47 g tertButyldimethylsilyl chloride (49.6 mmol, 1.2 equiv) dissolved in dry DMF was added. After 15 min stirring on ice 8.73 g <strong>[162021-14-9]9-Hydroxymethyl-2-amino fluorene</strong> (41.3 mmol) dissolved in 40 ml dry DMF was added drop wise under cooling and argon atmosphere. The reaction was continued 15 min on ice and then at room temperature. The reaction was monitored by TLC [title product Rf=0.6, PE-MTBE (1:2)]. After 2 hours the starting product [Rf=0.1 PE-MTBE (1:2)] had disappeared and the reaction mixture was diluted with 400 ml CH2Cl2 and 100 ml 5% NaHCO3 was added. The organic phase was washed with 5*200 ml H2O and dried over Na2SO4. CH2Cl2 was eliminated by rotary evaporation and DMF was eliminated by azeotropic distillation with toluene. The residual brown oil (13.4 g, 99% yield) was analyzed by NMR and was used without further purification. 1H NMR (200 MHz/DMSO) delta=7.67-7.40 (3H; m; 3*Ar-H); 7.34-7.00 (2H; m; 2*Ar-H); 6.81 (1H; s; 1*Ar-H); 6.59 (1*; dd; J=8.02 Hz & 1.83 Hz; 1*Ar-H); 5.19 (2H; s; NH2); 3.97-3.76 (2H; m; CH2); 3.75-3.57 (1H; m; CH); 0.88 (9H; s; 3*CH3); 0.03 (6H; s; 2*CH3) 13C NMR (50 MHz/DMSO) delta=148.40 (Ar-Cqu); 145.81 (Ar-Cqu); 143.67 (Ar-Cqu); 141.88 (Ar-Cqu); 129.08 (Ar-Cqu); 127.10 (Ar-CH); 124.97 (Ar-CH); 124.16 (Ar-CH); 120.47 (Ar-CH); 117.87 (Ar-CH); 113.22 (Ar-CH); 110.58 (Ar-CH); 66.04 (CH2-OH); 49.60 (C9); 25.88 (3*CH3; t-Bu); 18.04 (Cqu; t-Bu), -5.04 (2CH3; Si-CH3)
With sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; for 0.666667h;
9-Hydroxymethyl-2-amino-fluorene (Intermediate i; (0.4g, 1.9 mmol) and NaHCO3 (0.74 g, 8.85 mmol) were dissolved in water and 3-maleimidopropionic anhydride in DMF (12 ml, 2.95 mmol) was added. The reaction mixture was stirred for 40 mm and product formation monitored by analytical HPLC on a Chromolith colunm (Rt=4.46 mm, 10-100% B in 10 mm, 3 ml/min). The crude product, Intermediate k, was purified using preparative HPLC (RP-1 8 column, 10-100% acetonitril:water [75:25; v:v], 60 mm, 12 mi/mm). Yield: 57%, 1.08 mmol, 0.39 g. Calculated ESMS=3 62.38 Da. found ESMS=3 62.42 Da).
9-hydroxymethyl-2-(3-(acetylthio)propionylamino)fluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium hydrogencarbonate; In 1,4-dioxane; water; N,N-dimethyl-formamide; for 1h;
9(g). Synthesis of 9-hydroxymethyl-2-(3-acetylthiopropionyl-amino)-fluorene (Intermediate j) Intermediate i (0.422 g, 2 mmol) obtained in step 9(d) and NaHCO3 (0.74 g, 18 mmol) were dissolved in water/dioxane (1:1, 20 ml) and 3-S-acetylthiopropionic anhydride of step 9(f) in DMF (17 ml, 6 mmol) was added. The reaction solution was stirred for 1 hour. The organic solvents were removed by vacuum and the liquid solution was extracted with ether, washed with Na2SO4 (0.5N) and water and dried by vacuum. The obtained crude product, Intermediate j, was further purified by flash chromatography on silica gel column and elution with ethyl acetate:hexane (1:1, v:v). Yield: 60%, 0.4 g, 1.2 mmol. ESMS, (ca. 431) M+Na+: 464, dimer 2M: 682, dimer 2M: Na+: 705.67. 1H-NMR (CDCl3) delta: HPLC (Chromolith column) 5.3 min (10-100% solution B in 10 min, 3 ml/min).
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