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With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; at 0 - 20℃;
To a cold (0 C.) mixture of ethyl-5-hydroxyindole-2-carboxylate (purchased at Biosynth, H-6350, 20.5 g, 1.0 eq.), (R)-1-benzyl-3-pyrrolidinol (23 g, 1.3 eq.) and tri-n-butylphosphine (58 mL, 2.0 eq.) was slowly added 1,1'-(azodicarbonyl)dipiperidine (50.4 g, 2.0 eq.) in several portions. The reaction mixture was stirred at room temperature overnight and then filtered off. The filtrate was concentrated in vacuo and diethylether was added. The precipitate was filtered off and the filtrate was concentrated in vacuo and purified on silica eluding with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 18 mg (49%) of the desired product as light yellow foam. MS (m/e): 365.5 (MH+, 100%).
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 20℃; for 17h;
Example 135; J 5-( (S)-l- Isopropyl-pyrrolidin-3-yloxy)-lH -indol-2-yll-morphotin-4-yl-methanone; a) Step 1: 5-((S)-l-Benzyl-pyrrolidin-3-yloxy)-lH-indole-2-carboxylic acid ethyl ester; A mixture of 20.5 g (0.1 mol) ethyl-5-hydroxyindole-2-carboxylate, 23 g ( 0.13 mol) (R)-l-benzyl-pyrrolidine, 58 ml (0.2 mol) tri-n-butyl-phosphine and 50 g (0.2 mol) 1,1'- azodicarbonyl dipiperidine in 600 ml THF was stirred for 17 h at room temperature. The suspension was filtered and the filtrate was evaporated to dryness. The residue was taken up in 100 ml heptane/DCM 1/1 and the precipitate was filtered off and washed with 100 ml heptane/DCM 1/1. The filtrate was evaporated to dryness and the residue was taken up in 100 ml DCM and purified by flash column chromatography on silica eluting with a gradient of ethyl acetate/ heptane 1/3 to 2/1. The product containing fractions were pooled and evaporated to dryness and again purified on silica eluting with a gradient from DCM/ 2N NH3 in MeOH 99/1 to 19/1. 6.2g of pure product were obtained from pooling and evaporation of pure fractions. This was recrystallised from diethyl ether and heptane and washed with diethyl ether/ heptane to yield 3.5 g of pure product MS (m/e): 365.1 (MH+, 100%). 26 g of impure product were obtained from pooling and evaporation of the respective fractions. This was recrystallised from diethyl ether and heptane and washed with diethyl ether/ heptane to yield 9.0 g of pure product. All filtrates were pooled and evaporated to dryness to yield 14 g of slightly impure product which was used without further purification in the consecutive steps.
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