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The product of claim 1 wherein said indole compound is selected from the group consisting of...3-methyl-5,6-dihydroxyindole,2,3-dimethyl-5,6-dihydroxyindole,2-carboxy-5,6-dihydroxyindole,4-hydroxy-5-methylindole,2-carboxy-6-hydroxyindole,6-hydroxy-N-methylindole,2-ethoxycarbonyl-5,6-dihydroxyindole,4-hydroxy-7-methoxy-2,3-dimethylindole,...
The process of claim 1 wherein said indole colorant is selected from the group consisting of...6-acetoxy-1-methyl-2,3-dimethoxycarbonylindole,6-acetoxy-1,2-dimethylindole,6-hydroxy-1,2-dimethylindole,6-hydroxy-2-methylindole,6-hydroxy-2-carboxyindole,6-hydroxy-2,3-dimethylindole,6-hydroxy-3-carboxyindole,6-hydroxy-3-ethoxycarbonylindole,...
The compounds particularly preferred, according to the invention, are chosen more particularly from:...5-hydroxy-6-methoxyindole6-hydroxyindole6-hydroxy-7-methoxyindole5-methoxy-6-hydroxyindole2-carboxy-6-hydroxyindole2-ethoxycarbonyl-6-hydroxyindole7-hydroxyindole2,3-dimethyl-7-hydroxy-4-methoxyindole...
5
[ 771-99-3 ]
[ 40047-23-2 ]
(6-hydroxy-1<i>H</i>-indol-2-yl)-(4-phenyl-piperidin-1-yl)-methanone[ No CAS ]
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N-methyl-acetamide;
EXAMPLE 21 1-(4-Benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone (45 13579) A mixture of 5.0 g (28.2 mmol) of <strong>[40047-23-2]6-hydroxy-indole-2-carboxylic acid</strong> [J. Chem. Soc. 1605-1608. (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0 g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU (Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at room temperature for 6 h. The precipitated product is filtered off and recrystallized from ethanol to yield 6.75 g (71percent) of the title compound. Mp: 214-215° C. (ethanol).
6.75 g (71%)
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N-methyl-acetamide;
a 1-(4-Benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone A mixture of 5.0 g (28.2 mmol) of <strong>[40047-23-2]6-hydroxy-indole-2-carboxylic acid</strong> [J. Chem. Soc. 1605-1608. (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0 g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU (Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at room temperature for 6 h. The precipitated product is filtered off and recrystallized from ethanol to yield 6.75 g (71percent) of the title compound. Mp: 214-215° C. (ethanol).
The residue was taken up in methanol (20 mL), and thionyl chloride (1.06 mL, 14.6 mmol) was added. The solution was heated at reflux for 1 h, then concentrated, and the residue was purified by silica gel chromatography eluting with 3:2 ethyl acetate :hexanes to give 580 mg (62percent) of methyl 6-(hydroxy)-lH-indole-2- carboxylate as a white solid. 1H NMR (400 MHz, d6-DMSO): delta 11.44 (s, IH), 9.34 (s, IH), 7.40 (d, J = 9 Hz, IH), 7.00 (s, IH), 6.75 (s, IH), 6.58 (d, J = 9 Hz, IH), 3.80 (s, 3H).
The methyl 6-hydroxy-1H-indole-2-carboxylate can be prepared in the following way: 0.144 ml (2.70 mmol) of concentrated sulfuric acid is added, at ambient temperature, to a solution of 5.98 g (33.75 mmol) of <strong>[40047-23-2]6-hydroxy-1H-indole-2-carboxylic acid</strong> in 350 ml of methanol. The mixture is refluxed for 9 days and the reaction mixture is then concentrated to dryness under reduced pressure. The residue obtained is taken up in water and alkalinized to pH9 with a 38percent potassium hydroxide solution, and the product is then extracted 6 times with ethyl acetate. The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 5.81 g of methyl 6-hydroxy-1H-indole-2-carboxylate in the form of a brown solid. EI: m/z=191 (M+) base peak, m/z=159 (M-CH3OH)+, m/z=131 (m/z=159-CO)+.
Boron tribromide (1.0 M in dichloromethane, 14.6 mL, 14.6 mmol) was added dropwise to a solution of methyl 6-(methyloxy)-lH-indole-2-carboxylate (1.0 g, 4.87 mmol) in dichloromethane (10 mL) at 0 0C, and the resulting mixture was stirred at room temperature for 2 h. Boron tribromide (1.0 M in dichloromethane, 14.6 mL, 14.6 mmol) was added and the mixture stirred for 16 h. The mixture was poured into saturated sodium bicarbonate (aq, 150 mL), then the peta was adjusted to 6 with hydrochloric acid (37percent aq). The solution was extracted three times with ethyl acetate, then the combined extracts were washed with water and brine, then concentrated.
The 6-hydroxy-1H-indole-2-carboxylic acid can be prepared in the following way: 146 ml (146 mmol) of 1M boron tribromide in methylene chloride are added slowly, at 0° C., to a solution of 10 g (48.73 mmol) of methyl 6-methoxy-2-indole carboxylate in 500 ml of methylene chloride. The reaction medium is stirred at 0° C. for 1 h and at ambient temperature for 2 h. The reaction medium is cooled to 0° C. and 100 ml (100 mmol) of 1M boron tribromide in methylene chloride are added slowly, at 0° C. The reaction is stirred at 0° C. for 1 h and at ambient temperature for 16 h. The reaction medium is then cooled to approximately 0° C. and a 1N hydrochloric acid solution (247 ml) is added slowly with stirring. The mixture obtained is filtered over sintered glass. The organic phase (methylene chloride) of the filtrate is separated and the aqueous phase is then acidified with 5N hydrochloric acid and extracted with ethyl acetate. The organic phase (ethyl acetate) is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 6.39 g of 6-hydroxy-1H-indole-2-carboxylic acid in the form of a brown solid. ES: m/z=176 (M-H)-base peak
1-[4-(4-Fluorobenzyl)piperidine-1-yl]-1-(6-hydroxy-1H-indole-2-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
EXAMPLE 22 1-[4-(4-Fluorobenzyl)piperidine-1-yl]-1-(6-hydroxy-1H-indole-2-yl)methanone (45 13848) The title compound is prepared from 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903. (1992)] and <strong>[40047-23-2]6-hydroxy-1H-indole-2-carboxylic acid</strong> in acetonitrile at room temperature. The reaction mixture is concentrated and the residue is purified by column chromatography using Kiesel gel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent. Mp.: 180-182° C. (toluene).
6-hydroxy-N-methylindole-2-carboxylic acid[ No CAS ]
[ 40047-23-2 ]
Yield
Reaction Conditions
Operation in experiment
6-Hydroxy-1H-indole-2-carboxylic acid 6-Methoxy-1H-indole-2-carboxylic acid methyl ester when subjected to Step 2 gave 6-hydroxy-1H-indole-2-carboxylic acid which was used in the preparation of compounds 2-5, 2-13, 2-17, and 2-19.
6-Hydroxy-1H-indole-2-carboxylic acid 6-Methoxy-1H-indole-2-carboxylic acid methyl ester when subjected to Step 2 gave 6-hydroxy-1H-indole-2-carboxylic acid which was used in the preparation of compounds 2-5, 2-13, 2-17, and 2-19 in the manner described in Example 1.
A 2M solution of trimethylsilyldiazomethane in hexanes was added to a solution of 6- hydroxy-1 H-indole-2-carboxylic acid (0.500 g, 2.82 mmol) in MeOH until the solution remained yellow in color. The solution was stirred at RT until the starting material was consumed as evident by TLC. The reaction mixture was partitioned between water and EtOAc then the organic layer was separated, dried over MgSO4, filtered and concentrated. Purification was accomplished by column chromatography (EtOAc/hexanes) to afford the title compound (0.464 g, 86 percent yield). 1H NMR (400 MHz, Acetone-de): delta ppm 10.55 (br. s., 1 H), 8.32 (s, 1 H), 7.50 (d, 1 H), 7.09 (d, 1 H), 6.95 (d, 1 H), 6.74 (dd, 1 H), 3.85 (s, 3 H). MS m/z = 191.9 (M+1 ).
With potassium carbonate; In dimethyl sulfoxide; at 140 - 150℃; for 12h;
A solution of A (500 mg, 1.61 mmol) and 221-1 (286 mg, 1.61 mmol) and K2CO3 (446 g, 3.23 mmol) in DMSO (4 mL) is heated for 2 h at 140 °C and 10 h at 150 °C. The reaction is poured into H2O, extracted thrice with EtOAc, washed thrice with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated to give 221-2. The aqueous phase is acidified with concentrated HCl and extracted four times with EtOAc, washed with H20, dried over Na2SO4, filtered and concentrated to provide additional 221-2.
Preparation Example 60 To a solution of <strong>[40047-23-2]6-hydroxy-1H-indole-2-carboxylic acid</strong> (2.66 g) in N,N-dimethylformamide (25.0 mL) was added lithium carbonate (1.22 g), followed by stirring at room temperature for 10 minutes. Benzyl bromide (2.14 mL) was added thereto, followed by stirring at 100°C for 2 hours. The reaction mixture was lowered to 60°C, and 1 M hydrochloric acid (40.0 mL) was added thereto, followed by leaving to be cooled and extracting with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the crude purified product was washed with cold ethanol (5.00 mL) to obtain benzyl 6-hydroxy-1H-indole-2-carboxylate (1.95 g).
General procedure: All linear peptides were assembled using standard Fmoc peptide synthesisprotocol with the Rink amide resin on 433A Peptide Synthesizer (Applied Biosystems).For each coupling reaction, 10 equiv of Fmoc-amino acid, 0.45 Msolution of HOBt/HBTU (9 equiv) in DMF, 2 M solution of DIEA in NMP wereused. The coupling reaction was allowed to proceed for 9 min. Fmoc deprotectionwas performed by treating the resin-bound peptide with 20percent piperidinein DMF for 10 min. The peptide was cleaved from the resin by treating the resin with a cleavage cocktail containing 94percent TFA, 2percent water, 2percent triisopropylsilane,2percent phenol for 3 hr. All protecting groups were also removedduring this cleavage reaction. TFA was removed under reduced pressureand the peptides were precipitated in diethyl ether, centrifuged, and washedwith diethyl ether before drying in high vacuum. The crude peptides werepurified by preparative reverse phase high-performance liquid chromatography(HPLC). The final compound was characterized by NMR and MALDIMS.All compounds were > 95percent purity. The synthetic approaches for123B9-L2-PTX and the scrambled XDP-L2-PTX are similar to what we haverecently reported