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The preparation and cyclization of 4-carboxy-DL-tryptophan

Author:N/A    | Post time:2012-10-11

4-Cyanogramine (I) treated with AcNHCH(CN)CO2Et (II) in the presence of Me2SO4 yielded Et α-acetamino-α-cyano-β-(4-cyano-3-indole) propionate (III), alk. hydrolysis of which afforded 4-carboxy-DL-tryptophan (IV).  The cyclization of IV with Ac2O in the presence of KCN gave 1-acetyl-4-diacetamido-5-acetoxy-1,2-dihydrobenz[cd] indole (V).  II (10.2 g.) in 120 cc. abs. EtOH and then 10.0 g. I added to 1.38 g. Na in 50 cc. abs. EtOH, the mixt. treated dropwise with stirring and cooling during 1 hr. with 12.6 g. Me2SO4, the mixt. kept 48 hrs. at room temp., dild. with H2O, and distd. to remove the EtOH, and the solid product washed with H2O and recrystd. from EtOH yielded 13.4 g. III, m. 238-40°.  III (9.28 g.) added in 10 portions during 3 hrs. to 15.8 g. KOH in 36 cc. H2O, the mixt. refluxed 60 hrs., cooled, treated with 23.2 cc. concd. HCl, and filtered, the filtrate kept 24 hrs. at 0°, the deposit (5.42 g.) filtered off, the filtrate concd. in vacuo and extd. with 30 cc. EtOH, the ext. evapd., and the residue recrystd. from H2O yielded an addnl. 1.35 g. product which recrystd. from dil. HCl gave IV.HCl, m. 200-25°.  IV.HCl in H2O neutralized with NaOAc, treated with satd. aq. Cu(OAc)2, kept 24 hrs. at 0°, and filtered, the green filter residue washed with cold H2O, suspended in H2O, treated with H2S, and filtered, the filtrate concd. in vacuo, and the residue recrystd. from H2O gave IV, m. 280-300°.  IV.HCl (1.14 g.) in 20 cc. H2O treated with 6 cc. 2N aq. NaOH, the mixt. cooled with stirring, treated during 2 hrs. with 2.04 g. Ac2O in 10 equal portions (each portion being followed after 10 min. by 1.8 cc. 2N aq. NaOH), treated with 3.8 cc. concd. HCl, and kept 36 hrs. at 0°, and the deposit recrystd. from H2O gave 1.0 g. N-Ac deriv. (VI) monohydrate of V, m. 146-7°.  VI.H2O repeatedly evapd. in vacuo in abs. EtOH-C6H6 gave VI, m. 228-9°.  VI.H2O (3.08 g.) mixed with finely ground 0.65 g. KCN added in 10 equal portions in the dark to 125 cc. refluxing Ac2O, the mixt. refluxed 45 hrs., the Ac2O distd. off in vacuo, the residue extd. with refluxing C6H6, the ext. filtered and evapd. in vacuo, and the residue crystd. from abs. EtOH gave 2.05 g. V, m. 190-2°; it gave a yellow color with dil. aq. NaOH and H2SO4.  VI.H2O (0.616 g.) mixed with 0.13 g. KCN added during 2 hrs. in 8 portions to 25 cc. refluxing Ac2O in the dark, the dark soln. evapd. in vacuo, the residue dissolved in a small amt. MeOH at 40°, kept 12 hrs. at 0°, and filtered from 70 mg. deposit, the mother liquor concd. under N by 50% and kept 36 hrs. at 0° to give an addnl. 215 mg. solid, and the combined product dissolved in MeOH at 40° and kept 1 hr. at 0° gave the 4-AcNH analog (VII) of V, m. 253-5° (from EtOH); the mother liquor from the original sepn. gave some V, m. 190-2° (from abs. EtOH).  4-Amino-5-hydroxy-1,2-dihydrobenz[cd]indole (VIII) di-HBr salt (50 mg.) in 1 cc. H2O treated with a few drops Ac2O and then aq. NaOAc, the resulting cryst. deposit dissolved with EtOH, the soln. adjusted to pH 10 with dil. aq. NaOH and again treated with Ac2O, the soln. dild. after 15 min. with H2O, and the ppt. filtered off and recrystd. from abs. EtOH gave VII, m. 253-5°.  V (354 mg.) refluxed 1 hr. with 1.5 cc. glacial AcOH and 2.5 cc. 48% HBr and kept 20 hrs. at 0° gave 280 mg.  VIII.2HBr, m. above 360°.  V (106 mg.) in 20 cc. EtOH treated at 0° with 1 cc. 2N NaOH, the soln. kept 4 hrs. at 0°, acidified with AcOH, and distd. in vacuo, and the cryst. solid residue recrystd. from EtOH yielded 70 mg. 1-acetyl-4-acetamido-5-hydroxy-1,2-dihydrobenz[cd]indole, m. 249-51°.  VIII.2HBr (200 mg.) in 1 cc. H2O treated at 0° with 1 cc. satd. aq. NaOAc and the cryst. deposit filtered after 1 hr. at 0° and washed with a little H2O gave 100 mg. base, m. 135-40°; the free VIII dried 1 hr. in vacuo and added in small amts. during 1 hr. to 15 cc. Tetralin and 25 cc. xylene contg. 200 mg. 10% Pd-C at reflux temp. while passing in a rapid stream of H, the mixt. refluxed 5 hrs., filtered, and extd. with 0.1N HCl, the acid ext. treated with satd. aq. NaOAc and kept 1 hr. at 0°, and the deposit recrystd. from EtOAc and then MeOH gave 40 mg. 4-acetamido-5-oxo-1,5-dihydro-benz[cd]indole (IX), m. 254-6°.  In a similar run the reflux period was discontinued while H was still passed in, the mixt. treated with 0.5 cc. Ac2O, filtered, and distd. in vacuo, the residue treated with petr. ether, and the orange deposit crystd. from MeOH gave a few mg. unidentified material, m. 262-3°; the mother liquors contained mostly IX.

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