Crystalline forms of intermediates of (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl] pyrrolidin-3-yl] -2,2-diphenyl-acetamide
Publication Date: 2014-Jan-15
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Crystalline forms of intermediates of (S)-2-[1-[2-(2,3-dihydrobenzofuran-5- yl)ethyl] pyrrolidin-3-yl] -2,2-diphenyl-acetamide
Disclosed hereinafter are crystalline forms of intermediates in the synthesis of (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl] pyrrolidin-3-yl] -2,2- diphenyl-acetamide
Preparation of (3-(s)(carbamoyl-1,1-diphenylmethyl)pyrrolidine tartarate)
To (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hvdrobromide (1.0 kg) Toluene (3.0L) and DM water(0.21L) were added and heated to 45-50ºC. To it a solution of sodium hydroxide (0.13 kg in 0.30L) was added at 45-50ºC. Mass was stirred and layers separated. Organic layer was washed twice with DM water
0.44L each and finally concentrated up to toluene content <35.0%. Organic layer was added to a mixture sulfuric acid (3.11 kg) and DM water (0.28L) at 50-100ºC. Reaction mass was further heated and maintained at 105-110ºC with reaction monitoring. Reaction was quenched by cooling to 20-30ºC followed by adding it to a mixture of toluene (5.0L) and Sodium hydroxide solution (3.0 kg in 14.5L water) at 55-60ºC. Reaction mass was stirred and layers separated. Aqueous layer was extracted with toluene (1.65L). Combined organic layer was washed with water (2.5L) at 60-65ºC. To the organic layer, n-Butanol (2.10L) and water
(0.21L) were added at 60-65ºC. To the mass, L (+) tartaric acid (0.44 kg) was added and stirred at 60-65ºC for 1 hour. Mass was cooled to 15-25ºC and stirred for 2 hours. Isolated solid was filtered, washed with n-Butanol 1.60L and dried at 60-65ºC under vacuum to yield the titled compound in 85-90% yield. The product was analyzed by XRPD.
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Figure 1: XRPD of (3-(s)(carbamoyl-1,1-diphenylmethyl)pyrrolidine tartarate)
Main PXRD peaks:
5.4, 13.3, 15.7, 17.4, 18.3, 19.2, 19.7, 22.4, 23.3 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta.
Preparation of 5-(2-Chloroethyl)-2,3-dihydrobenzofuran:
Step 1: Preparation of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran
A solution of borontrifluoride etherate (143ml) was added over a period of 60-90min. to the suspension of sodium borohydride (23.5gm) in tetrahydrofuran (T.H.F, 200ml) at -10 to 0ºC. The mixture was stirred for 30 min and added dropwise solution of 2,3-dihydrobenzofuran-5-acetic acid (DBFAcOH)(100 gm ) in T.H.F.(200ml) at -10 to 0ºC. The mixture was stirred for 30 min. at -10 to 0ºC. The progress of reaction was monitored by HPLC, after completion...